Traumatic Injury of the Superior Mesenteric Vessels

Benha M. J. Vol. 29 No 1 Jan. 2012 TRAUMATIC INJURY OF THE SUPERIOR MESENTERIC VESSELS

Khaled Mowafy MD, Hosam Roshdy MD, Khaled El Alfy MD and Mohamed Gad MD Departments of AGeneral & Vascular Surgery, Faculty of Medicine, Mansoura University, EGYPT .

Abstract Background : Superior mesenteric vessels injury is an uncommon and the majority of injuries occurred due to penetrating trauma. These injuries are devastating entity with mortality rates reported as high as 64%. Exsanguinating hemorrhage accounts for the majority of early deaths. The purpose of this study is to review our experience with superior mesenteric vessels injury, to analyze Fullen's anatomical zones for their predictive value and outcome for primary repair versus ligation. Patients and Methods : This case series study was conducted in Emergency hospital at Mansoura University between January 2007 to January 2011, seven patients presented during this period by injury of superior mesenteric vessels. Operative findings analyzed included the presence of active hemorrhage, associated abdominal injuries; surgical procedure performed in addition general morbidity and mortality. Results : The mechanism of injuries were blunt abdominal Trauma three patients (43%) (Motor accident and falling from height), penetrating injury four patients (57%) (Three stab wound & one gunshot wound). The mean age was 27.5 ± 14 years (range 18 - 72 years) and 6 patients (85.7%) were male and one patient (14.3%) was a female, There were associated intra-abdominal organ injuries in all patients with different combination (spleen in two patients, liver in three patients, colon in one patient, small bowel in two case, pancrease in two patients, kidney in one patient and stomach in one patient) . Three patients (43%) had combined SMA & SMV repair, one patient(14.3%) had repair of isolated SMA, one patient (14.3%) had ligation of both vessels , one patient (14.3%) had ligation of SMV and one patient (14.3%) had ligation of jejunal branches of SMA (Fullen's grade IV). Mortality rate was 43% (three

9 Khaled Mowafy, et al... patients, one patient died intraoperatively, another one died 12 hours postoperative and one patient died 8 days postoperative). Two patient (28.6%) needed for second look operation 2 days post operative one patient who had repair of SMA ; arterial thrombectomy was done to SMA and the other patient who had ligation of SMV and there was negative exploration just oedema in the intestine which treated conservatively by anticoagulant. Conclusion: Superior mesenteric vessels injuries are highly lethal injury, the time of surgical intervention, injury grade of SMA and associated injuries are predictive for mortality; Ligation appear to be safe and should be selected for haemodynamically unstable patients. Key words: Superior mesenteric vessels injuries, penetrating trauma, blunt abdominal trauma, vascular repair.

Introduction trauma in the urbanized world. Superior mesenteric vessels in- Thus growing number of patients jury is an uncommon and the ma- with blunt abdominal injury is jority of injuries occurred due to thought to be due to high-speed penetrating trauma(1). Penetrating motor accidents and the use of trauma account for 67% of inju- seat belts (4). The diagnosis of ries and blunt trauma account for mesenteric injury represents a 33% of that injuries. (2) challenge to clini¬cians when faced with victims of blunt abdom- Mesenteric injury after blunt inal trauma and a correct and abdominal trauma is rare and speed diagnosis is particu¬larly may be difficult to diagnose. How- important because early surgical ever, the conse¬quences of missed intervention significantly decreas- injury are significant in the form es morbidity and mortality of of higher morbidity and mortality these patients (5). (3). The mechanism of the mesen- The incidence of blunt bowel teric injury in blunt abdominal and mesenteric injury has in- trauma is direct crushing of the creased in recent years due to the small bowel against the vertebral high incidence of blunt abdominal column (6). Tearing and shearing

10 Benha M. J. Vol. 29 No 1 Jan. 2012 forces, especially seat belts in car ic vessels injury has been correlat- accidents, applied to the abdo- ed with the presence of shock men, particularly at points of mes- upon admission, the number of enteric attachment, can also be associated injuries, the anatomic the mechanism. According to the location of injury, the method of surgical literature, proximal jeju- surgical repair and the presence of num and distal ileum are more "black bowel" upon entering the prone to injury from blunt trauma abdominal cavity(9,10). because of the short mesentery in these areas (2). Diagnostic peritoneal lavage is used in the trauma setting for Injury to the superior mesen- detecting intraperitoneal hemor- teric artery (SMA) is an uncom- rhage or ` intestinal content leak- mon and devastating entity with age, but it lacks sensitivity for de- mortality rates reported as high as tecting retroperitoneal injuries (6). 64%. Exsanguinating hemorrhage Alternatively, Focused Abdominal accounts for the majority of early Sonography for Trauma (FAST) fa- deaths. Late deaths usually occur cilitates the detection of intraperit- secondary to sepsis, multiple sys- oneal free fluid in abdominal trau- tems organ failure (MSOF), and ma. Computed Tomography (CT) the sequelae of ischemic bowel in scan was performed in stable pa- those who survive their initial sur- tients with suspicious of injury or gical procedure (7). positive FAST (11).

Injuries to the superior mesen- Fullen and altemeier made the teric vein (SMV) are uncom- first attempt to classify SMA inju- mon¬but devastating, incurring ries in a series of eight patients. very high morbidity and mortality. Their grading system was based The rarity of this injury prevents on location of injury and degree of sur¬geons from developing signifi- ischemia present (12) (Table 1). cant experience with their management (8). The purpose of this study is to review our experience with Outcome of superior mesenter- superior mesenteric vessels inju-

11 Khaled Mowafy, et al... ry, to analyze Fullen's anatomical the FAST was considered positive zones for their predictive value and the patient was a candidate and outcome for primary repair for operative intervention. versus ligation Computed Tomography (CT) Patients and Methods was done in three patients (stable This case series study has con- patients with suspicious of intra- ducted in Emergency hospital at abdominal injury or a positive Mansoura University from Janu- FAST). ary 2007 to January 2011. Calculation of the Glasgow Seven patients presented dur- Coma Score (GCS). ing this period by injury of superi- or mesenteric vessels all patients Operative findings analyzed presented at the emergency room included the presence of active and after initial evaluation and re- hemorrhage, associated abdomi- suscitation underwent operative nal injuries; surgical procedure intervention. performed in addition general morbidity and mortality. Resuscitation included rapid infusion of warm fluids and blood. Operative procedure included Data Collected included, Demo- lateral arteriorrhophy (Three pa- graphics, mechanism of injury, tient, two with saphenous patch haemodynamically instability (sys- and one direct repair), primary tolic blood pressure < 90 mm/Hg end-to-end anatomists (one pa- and pulse > 100). tient) and venorrhaphy (three patients, all with saphenous patch). In haemodynamically, unstable Three patients required combined Traumatic patients, Diagnostic vessel repair; one patient required peritoneal large (DPL) or Focused ligation of superior mesenteric Abdominal Sonography for Trau- vein, one patient required ligation ma (FAST) were performed in the of jejunal branches of SMA (Ful- Trauma room. The presence of len's grade IV) and one patient re- free intraperitoneal fluid during quired ligation of both vein and

12 Benha M. J. Vol. 29 No 1 Jan. 2012 artery with bowel resection. ed with hypovolemic shock in which resuscitation was done Second look operations were and FAST diagnosed intraperito- performed in two patients. neal fluid and aspirate blood; all of these patients underwent Superior mesenteric artery rapid exploratory laboratory, three (SMA) injuries had been classi- patients presented fully consci- fied according to Fullen's classifi- ness without any signs of hypovo- cation. laimic shock in which CT was done then exploratory laporotomy Exposure of the superior mes- was done. enteric vessels through a Mattox maneuver (Medial visceral rota- - The mean age was 27.5 ± 14 tion) or exposure through the less- years (range 18- 72 years) and six er sac. patients (85.7 %) were male and one patient (14.3 %) was a female Results (Table 2). From January 2007 to May 2011, seven patients had superior There were associated intra- mesenteric vessels injuries 4 pa- abdominal organ injuries in all patients had both SMA & SMV inju- tients with different combination, ries, 2 patients had isolated SMA spleen in two patients, liver in injury and one patient had isolat- three patients, colon in one paed SMV injury. tient, small bowel in two case, pancrease in two patients, kidney The mechanism of injuries were in one patient and stomach in one blunt abdominal Trauma three pa- patient (Table 3). tients (43%) (Motor accident and falling from height), penetrating Surgical management included injury four patients (57%) (Three primary suture repair to SMA (ar- stab wound & one gunshot teriorrhaphy) in three patients, wound). primary end-to-end anastomosis in one patient and venorrhaphy of - Four patients (57%) present- SMV in three patients.

13 Khaled Mowafy, et al...

Three patients had combined intra abdominal infection. SMA & SMV repair, one patient had ligation of both vessels, Two patient had second look one patient had ligation of operation 2 days post operative SMV and one patient had liga- one patient who had repair of tion of jejunal branches of SMA SMA, arterial thrombectomy was (grade IV) (Table 4,5). done to thromsed SMA and the other patient who had ligation of Mortality rate was 43% (three SMV and there was negative ex- patients out of seven patients) ploration just oedema in the intes- one patient died intraoperative- tine which treated conservatively ly due to active bleeding after by anticoagulant.(Continued ve- ligation of both SMA & SMV. nous drainage after ligation of Another one died 12 hours post- SMV from the bowel is typically operative in ICU who had repair achieved via the inferior mesenter- of both SMA & SMV due to irre- ic vein, retro peritoneal perfora- versible shock and one patient tors and Porto systemic collateral died 8 days postoperative due to circulation (8).

14 Benha M. J. Vol. 29 No 1 Jan. 2012

15 Khaled Mowafy, et al...

Discussion of the trauma can also be influ- Superior mesenteric vessels in- enced by the type of motor vehicle juries is an uncommon but poten- and/or the type of security sys- tially lethal injury, their rarity pre- tems or restraints of the vehicle. vent, surgeons from developing a The principles of the pathophysio- significant experience with their logy of these injuries were de- management (13). scribed by Vance(16) in 1923. Three mechanisms were catego- The majority of superior mesen- rized: (a) crushing force applied to teric vessels injuries reported in the bowel against the spine; (b) the literature occur from penetrat- shearing force of the bowel and ing trauma however, it is occa- mesentery along the lines of at- sionally associated with blunt tachment; and (c) bursting force trauma of the abdomen (14). occurring secondary to increased intra¬luminal pressure. The abdomen is a frequent site of injuries during a motor-vehicle The diagnosis of these poten- crash (MVC) which represents the tially lethal injuries is based espe- primary cause of blunt trauma in cially on clinical examination, developed countries. Isolated vas- FAST, or diagnostic peritoneal cular injuries are rare but seem to lavage(17). When the general con- be increasing as reported in sever- dition is not critical, Computed al studies and are the stated Tomography scan (Computed To- cause in 5% to 15% of all blunt mography Angiography) can also trauma(15). The pathophysiology help to obtain the diagnosis with a

16 Benha M. J. Vol. 29 No 1 Jan. 2012 high sensitivity and specificity of sio's (1) Multi-Institutional Study 88.3% and 94%, respectively, and of 250 SMA injuries, 84 (34%) pa- an accuracy of 99.9%(18). A delay tients had associated SMV inju- in the diagnosis of these major in- ries. Blunt mech¬anism of injury tra-abdominal vascular injuries accounted for 48% of these inju- can result in higher mortality and ries. morbidity related to shock. Emer- gency laparotomy is often the best In ours, study blunt abdominal approach for patients in shock or trauma occurred in three patients with unstable circulation. (43%) while penetrating trauma occurred in four patients (57%). Ulvestad(19) in 1954 reported the first case of an SMV injury in In our study associated intra a patient that sustained an asso- abdominal organs injury was ciated SMA injury; the SMV was present in all patients with differ- ligated and the SMA was primarily ent percentage, splenic injury repaired resulting in patient survi- present in two patients (28.6%) in val. Fullen, in his classical study, which splenectomy was done in describing the anatomic zones and one patient and splenprrhophy in ischemia grades of superior mes- the other patient. hepatic tear oc- enteric artery injuries, described curred in three patients (43%) in only one patient with an associat- with treated by hepatic sutures. ed SMV injury. Small bowel injuries in two pa- Courcy (20) in 1984 reported a tients (28.6%) which treated by series of 13 patients with com- resection and anastomosis, colon- bined SMA and SMV injuries, of ic injury in the transverse colon in which 12 patients incurred blunt one patients (14.3%) which treat- SMV injuries. Asensio(8) in 2001 ed by transverse colostomy. pan- reported 35 patients with SMA in- creatic injury in two patients juries with 17 (49%) associated (28.6%) in which treated by distal SMV injuries, of these patients, 8 pancreatectomy in one patient (23%) sustained their injuries sec- and the other patient treated by ondary to blunt trauma. In Asen- simple repair of the tear.

17 Khaled Mowafy, et al...

Huge renal tears occur in one 1984 in which reported 57% mor- patent (14.3%) treated by nephrec- tality rate after superior mesenter- tomy. ic vessels injuries. While in Aren- sio et al(22) 2000 study, the While stomach tear occurred in mortality rate after SMA injury one patient (14.3%) and treated by was 47.6% and SMV injury was suture of the gastric tear in two 52.7%. but Sirinek and Levine re- layers. ported 19% mortality rate (23).

Asaylai et al (21) 2009 report There is limitation in this study associated intra-abdominal organ the number of patients is small. injures after blunt bowel and mesenteric injures were spleen 18.9% Conclusion liver 15.7% pancrease 1.8% kid- Superior mesenteric vessels in- ney 1%.;- These incidence is low- juries are highly lethal injury, the er than our study due to type 2 time of surgical intervention, inju- error (small number of patients in ry grade of SMA and associated our study). However, in Asensio et injuries are predictive for mortal- al (13) 2007 study reported the in- ity; Ligation appear to be safe and cidence of associated intraabdomi- should be selected for haemody- nal organ injuries with superior namically unstable patients. mesenteric venous injuries nearly equal to our study. References 1. Asensio J. A., Britt L. D., Mortality rate in our study was Borzotta A., et al., (2001) : Mul- 43% (3 patients) one patient intra- ti-institutional experience with the operative due to active bleeding, management of superior mesen- one patient 12 hours post opera- teric artery injuries. 1 Am Coll tive after ligation of both SMA & Surg.; 193:354-356. SMV due to irreversible shock and another patient died 8 days post 2. Aydin U., Unalp O. and Ya- operative due to intraabdominal zici P., et al., (2007) : Success of sepsis. This mortality rate is less microvascular surgery; repair than which reported by Peter et al mesenteric injury and prevent

18 Benha M. J. Vol. 29 No 1 Jan. 2012 short bowel syndrome : a case re- 7. Feliciano D. V., Burch J. port; BMC Emergency Medicine, M. and Graham J. M. (1996) : 7:11. Abdominal vascular injury. In: Mattox KL, et al (eds). Trauma. 3. McAnena O. J., Moore E. Appleton and Lange; PP 621-622. E. and Marx J. A. (1990) : Initial evaluation of the patient with 8. Asensio J. A., Forno W., blunt abdominal trauma. Surg Rold'in G., et al., (2002) : Viscer- Clin North Am; 70:495-515. al vascular injuries. Surg Clin North Ain.; 82:1-20. 4. Sokolove P. E., Kupper- mann N. and Holmes J. F. 9. Lucas A. E., Richardson J. (2005) : Association between the D., Flint L. M., et al. (1981) : "seat belt sign" and intra- Traumatic injury of the proximal abdominal injury in children with superior mesenteric artery. Ann blunt torso trauma. Acad Emerg Surg.; 193:30-34. Med; 12:808-13. 10. Accola K. D., Feliciano D. 5. Brownstein M. R., Bunting V., Mattox K. L., et al.. (1986) : T., Meyer A. A., et al., (2000) : Management of injuries to the su- Diagnosis and management of perior mesenteric artery. J Trau- blunt small bowel injury: a sur- ma.; 26:313-319. vey of the membership of the American Association for the Sur- 11. Xeropotamos N. S., Nousi- gery of Trauma. 1 Trauma; 48 : as V. E., loannou H. V., et al., 402-7. (2001) : Mesenteric injury after blunt abdominal trauma. Eur J 6. Watts D. D. and Fakhry S. Surg;167:106-q. M. (2003) : Group EM-IHVIR. In- cidence of hollow viscus injury in 12. Fullen W. D., Hunt J. and blunt trauma: an analysis from Altemeier W. A. (1972) : The clin- 275.557 trauma admissions from ical spectrum of penetrating injury the East multi-institutional trial ; to the superior mesenteric arterial J. Trauma;54: 289-94. circulation.J Trauma.;12:656-664.

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13. Asenio J. A., Petrone P., puted tomography. J Trauma; 48 : Nunez L. G., et al., (2007) : Su- 991-8. perior Mesenteric Venous Inju- ries : To Ligate or to Repair Re- 19. Ulvestad L. E. (1954) : Re- mains the Question; J Trauma.; pair of laceration of superior mes- 62 : 668-675. enteric artery acquired by non- penetrating injury to the abdo- 14. Graham J. M., Mattox K. men. Ann Surg.; 140:752-754. L., Beall A. C., et al., (1978) : In- juries to the visceral arteries. Sur- 20. Courcy P. A., Brotman S., gery.; 84:835-839. Oster-Granite M. L., et al., (1984) : Superior mesenteric ar- 15. Frick E. J., Pasquale M. tery and vein injuries from blunt and Cipolee M. (1999) : Small abdominal trauma. J. Trauma.; bowel and mesentery injuries in 24:843-845. blunt trauma. J Trauma; 46 : 920-6. 21. Alsayali M., Atkin C., Winnett J., Rahim Reza, Nigge- 16. Vance B. M. (1923) : Trau- meyer L. and Kossmann T. matic lesions of the intestine (2009) : Management of blunt caused by non penetrating blunt bowel and mesenteric injuries : force. Arch Surg;7:197-212. Experience at the Alfred Hospital; Eur J Trauma Surg. No. 5. 17. Wisner D. H. (1996) : In- jury to the stomach and small 22. Asenio J A., Chahwan S., bowel. In : Feliciano DV, Moore Hanpeter D.,et al., (2000) : Oper- EE, Mattox KL, editors. Trauma. ative management and outcome of 3rd ed. Stanford (Conn): Appleton 302 abdominal vascular injuries: and Lange;. pp. 557-8. Am J surg. Dec;180(6):528-33.

18. Malhorta A. K., Fabian T. 23. Sirinek K. R. and Levine C., Katsis S. B., et al., (2000) : B. A. (1985) : Traumatic injury to Blunt bowel and mesenteric inju- the proximal su¬perior mesenteric ries : the role of screening com- vessels. Surgery.;98:831-835.

20 Benha M. J. REPRINTVol. 29 No 1 Jan. 2012 BENHA MEDICAL JOURNAL

TRAUMATIC INJURY OF THE SUPERIOR MESENTERIC VESSELS

Khaled Mowafy MD, Hosam Roshdy MD, Khaled El Alfy MD and Mohamed Gad MD

Published by Benha Faculty of Medicine Volume 29 Number 1 Jan. 2012

21 Benha M. J. Vol. 29 No 1 Jan. 2012 COMBINED EFFECT OF ANGIOTENSIN RECEPTOR BLOCKER, AND ANTIOXIDANTS ON RECOVERABILITY OF RENAL FUNCTIONS AFTER RELIEF OF PARTIAL URETERAL OBSTRUCTION OF SOLITARY KIDNEY

Abdel-Aziz M. Hussein MD, Azza Abdel-Aziz MD*, Amira Awadalla MD** and Nashwa Barakat MD** Departments of Physiology, Pathology*, Faculty of Medicine, Urology and Nephrology Center**, Mansoura, University, Egypt

Abstract Objectives: To evaluate the effect of a combination of angiotensin receptor blocker losartan, and antioxidant Ferulic acid on the recovery of renal function and renal damage after relief of partial ureteral obstruction (PUO) of a solitary kidney. Methods: thirty-two male mongrel dogs were classified into three groups: sham (8), control (12) and study (12). Right nephrectomy was done and dogs in the study and control groups were subjected to 4 weeks of PUO. Serum creatinine, creatinine clearance (CrCl), and renographic clearance (RC) were measured at baseline, 4 weeks of obstruction and 8 weeks after relief of obstruction. Markers of lipid peroxidation (malondialdehyde MDA), superoxide dismutase (SOD), and reduced glutathione (GSH), and immunostaining of markers of apoptosis (caspase 3 and Bcl2), cell proliferation (ki67) and interstitial fibrosis in the kidney were evaluated at the end of experiment. Re- sults: a combination of losartan and FA enhanced the recovery of serum creatinine, CrCl and RC by an extra 30%, 30%, and 47% of the basal values at 8 weeks, after relief of 4 weeks obstruction, respectively. Also, this combination caused significant decrease in MDA, and significant increase in GSH and SOD. Moreover, this combination significantly reduced the interstitial fibrosis, and caspase 3 expression, and significantly increased the expression of Bcl2 and ki67 in kidney tissues at 8th week after relief of obstruction. Conclusion: combination of losartan and FA enhances the recoverability of renal function and minimizes

21 Abdel-Aziz M. Hussein, et al... the renal damage through reduction of oxidative stress, tubular apoptosis and the interstitial fibrosis in the solitary kidney after relief of PUO.

Introduction play an important role in pa- Obstructive uropathy is the thophysiology of obstructive eventual outcome of many urologi- uropathy(9). They may have an im- cal disorders such as urinary portant role in the tubulointersti- stone and ureteric stricture. Ure- tial inflammation associated with teric obstruction (UO) is a com- obstructive nephropathy (10), due mon clinical finding in a solitary to the tubular injury caused by kidney(1). The pathophysiology of mechanical disturbance, which renal damage in UO is complex leads to a proinflammatory state and it was reported that the renal and tubulointerstitial fibrosis(11). damage continues even after relief After release of the obstruction, of UO2,(3). Within the first week ROS12 causes overexpression of of induction of UO, a network of fibrogenic cytokines and chemoat- inflammatory, vasoactive and ap- tractants(11). It was reported that optotic processes results in the reduction of endogenous antioxi- appearance of signs of tubular dants (such as catalase) during atrophy and features of tubuloin- obstructive uropathy aggravates terstitial fibrosis(4). Ureteral ob- renal apoptosis, while the admin- struction triggers tubular cell istration of exogenous antioxi- death by apoptosis and necro- dants attenuates tubular apoptosis(5), interstitial inflammatory in- sis(13,14). Also, chronic UO filtration(6), and progressive fibro- increases the renal expression of sis with loss of renal parenchyma, tumor necrosis factor [alpha] myofibroblast activation and ex- (TNF-alpha), FAS ligand, and cas- tracellular matrix deposition(7,8). pase activity(15). In a recently All these changes contribute to re- study from our lab, we found that nal parenchymal damage leading ferulic acid (FA), powerful antioxi- to sustained decrease in renal dant, enhanced the recovery of re- function. nal functions when given after relief of obstruction(16). This was Reactive oxygen species (ROS) done increasing the activity of Bcl

22 Benha M. J. Vol. 29 No 1 Jan. 2012

2 (proapoptotic protein) and de- tan (AT1 receptor blocker) en- creasing the activity of caspase hanced the recovery of renal func- 316. tions in a canine model of chronic partial ureteral obstruction (25). Angiotensin II, a potent vaso- constrictor, mediates its biological On the basis of the observa- action through its interaction with tions that reactive oxygen species one of two receptors: angiotensin and AngII are imperative in initiat- (17) II type 1 (AT1) and AT2 . AT1 re- ing and promoting renal damage, ceptors are more abundant and apoptosis, and fibrosis even after appear to be more biologically sig- relief of obstruction, we hypothe- nificant than AT2 receptors in sized that a combined therapy mammalian kidneys(18,19). In pro- with exogenous antioxidant and longed UUO, a significant rise is AngII blockade may have additive noted in both AT1 receptor expres- or synergistic effects on recovery sion and renal angiotensin II con- of renal functions after release of (20) tent . Angiotensin II and AT1 obstruction by simultaneously receptors have been linked to blocking the pathogenic actions of many of the pathophysiologic pro- ROS and Ang II. In this study, we cesses involved in renal obstruc- aimed to study the impact of a tion, including alterations in renal combination of losartan and ferul- hemodynamics, fibrosis, and ic acid on the recovery of renal apoptosis(21,22). Angiotensin II functions after relief of UO in a up-regulates the expression of solitary kidney, and its effect on several profibrotic cytokines and apoptosis, fibrosis, and oxidative transcription factors, including stress markers after UO relief. TGF-β1, TNF-α, and NF-κB (23,24). Moreover, the blockade of AT1 re- Materials and Methods ceptor inhibition has been corre- Experimental animals and de- lated with a reduction in collagen sign : expression, macrophage recruit- Thirty two male mongrel dogs ment, and renal tubulointerstitial aged 2-3 years, weighing 18-25 kg fibrosis(24). Also, in a recent study were involved in this study. The by our lab, we reported that losar- dogs were randomly divided into 3

23 Abdel-Aziz M. Hussein, et al... groups: i) Sham group: 8 dogs; performed as described by Sho- right nephrectomy + left sham keir, (26). The study and control surgery + no medications, ii) Con- groups were subjected to 4 weeks trol group: 12 dogs; right nephrec- of left PUO. Then, were reopened tomy + left partial ureteral ob- and subjected to Lich-Grigoir ure- struction (PUO) + no medications, terovesical re-implantation. All and iii) Study (FA and Losartan) dogs of the control and study group: 12 dogs; right nephrectomy groups were sacrificed by the end + PUO + FA. The dogs were of the 8th week after relief of ob- housed in individual boxes under struction. habitual conditions in a temperature controlled room (24oC). They Sham operated animals received a balanced diet plus free The abdomen was entered access to water. Experiments were with a midline incision and performed according to the Guide right nephrectomy was done. The for the Care and Use of Laboratory bladder was opened, a 6 F ure- Animals. All protocols were ap- teric catheter was inserted into proved by our local committee of the left ureteric orifice for 2 hours Animal Care and Use Committee. for collection of urine samples and Our institution approved the a blood sample was taken from study and animal care standards the left renal vein. The catheter were adhered to Institute for La- was then removed and the bladder boratory Animal Research, Nation- and wound were closed without al Research Council, Washington, induction of left PUO. Dogs of the DC: National Academy Press, no. sham group were subjected to 85-23, revised 1996. sham surgery at basal condition, 4 and 8 weeks and sacrificed Experimental model thereafter. Dogs were anaesthetized by thiopental sodium (10mg/kg) with Ferulic acid and losartan endotracheal intubation and me- treatment chanical ventilation. Right neph- Dogs of the study group were rectomy was carried out. The given FA (purchased from Sigma, model of unilateral left PUO was USA) in the drinking water (or

24 Benha M. J. Vol. 29 No 1 Jan. 2012 milk or bone soup) at a dose 70 Doppler ultrasonography and mg/Kg per day with the onset of resistive index relief of 4 -week obstruction and Doppler ultrasonography (DUS) continued until sacrifice. Also, Lo- with measurement of renal resis- sartan was given at a dose of 2 tive index (RI) of the correspond- mg/kg once daily in drinking wa- ing kidney were carried out at ba- ter (after overnight fasting of dogs) sal condition before induction of throughout the duration of the obstruction, just before relief of study. obstruction (at 4th week of obstruction) and at 4 and 8 weeks Renal functions : after relief of obstruction. Blood and urine samples were collected from the corre- Renograms : sponding kidney during surgery Radioisotope renography with just before induction of obstruc- calculation of the split function of tion, during relief of obstruction the corresponding kidney was per- (at 4 weeks of obstruction) and at formed. Renogram was carried out sacrifice of the dogs at the end of at basal condition before induc- the 8th week after relief of ob- tion of obstruction, just before re- struction. Two urine samples were lief of obstruction (at 4th week of collected, each for 2 hours from obstruction) and at 4 and 8 weeks the corresponding ureter and after relief of obstruction as previ- blood samples obtained from the ously described28. corresponding renal vein. Blood samples and the mean of two Morphometric evaluation of readings of urine samples were renal interstitial fibrosis used for calculation of the creati- Kidney tissues for the histologi- nine clearance (CrCl) from the fol- cal study were ﬁxed in 10% for- lowing equation(27): malin (pH 7.4) and embedded in Urine creatinine (mg/dl) paraffin. Sections (3 µm thick) X urine volume (ml/24hr) were prepared, and stained with CrCl (ml/min) = Hx & E and Masson’s trichrome Serum creatinine (mg/dl) to evaluate the ﬁbrosis of corti- X 1440 (minutes) cal interstitium. The sections were

25 Abdel-Aziz M. Hussein, et al... observed on a Olymbus BX51 light Subsequently, an indirect immu- microscopy. Pictures were ob- noperoxidase technique was ap- tained by a PC-driven digital cam- plied, using monoclonal antibod- era (Olymbus E-620). The comput- ies for: Anti-caspase 3 (Abcam er software (Cell* Olymbus Soft Cat.# ab79123) cytoplasmic stain- Imaging Solution GmbH) allowed ing with human tonsils as positive the performance of morphometric control. Anti-Bcl2 (Abcam Cat.# analysis. Interstitial volume index ab59348) cytoplasmic staining was determined as described be- with human colon carcinoma tis- fore(29) by superposing a grid con- sue as positive control. Anti-K67 taining 100 (10x10) sampling (Abcam Cat.# ab86373) nuclear points on pictures of 10 non- staining with human lymph node overlapping fields (x 200) of Mas- as positive control. Indirect immu- son’s trichrome stained sectons. noperoxidase was performed using The number of points overlaying ImmunoPure Ultra-Sensitive ABC interstitial space were counted Peroxidase (Thermo Scientific Cat. and expressed as percentage of all # 32052) with (DAB) as chromo- points. Large arteries and glome- gen. ruli are excluded from the quantification. Apoptotic index and antiapoptotic activity were assessed with a Immunohistochemistry for as- standard point counting method sessment of apoptotic index, an- for the percentage of labelled tu- tiapoptotic activity and prolifera- bular cells in each of the exam- tive index ined ten non-overlapping random- For immunohistochemistry, 3 ly selected X 400 fields of each µm thick sections were prepared slide. Labelling indices were ex- on coated slides and deparaffin- pressed as the average scores of ised. All sections were incubated the(10) ﬁelds(30). The proliferation for 30min with 0.3% hydrogen index was defined as the percent- peroxide in methanol and micro- age of the counted immunoreac- wave heated in 10mM citrate tive nuclei per at least 1000 tubu- buffer, pH 6.0, for 10-20 min. lar cells(31).

26 Benha M. J. Vol. 29 No 1 Jan. 2012 Estimation of oxidative and Results antioxidative parameters. Changes in the serum creati- Kidney tissue was perfused nine : with a PBS (phosphate buffered The mean values of serum saline) solution, pH 7.4 containing creatinine were comparable 0.16 mg / ml heparin to remove among dogs of the sham, control any red blood cells and clots. and combination groups at the Then, kidney was weighed, basal conditions. The sham oper- minced, homogenized in 5 - 10 ml ated group showed stable serum cold buffer (i.e. 50 mM potassium creatinine level during the whole phosphate, pH 7.5. 1 mM EDTA). duration of the study (Fig. 1). By Homogenates were centrifuged at the end of the 4th week of obstruc- 10000 x g for 15 minutes at 4°C tion, the mean values of serum and the supernatant was kept at - creatinine of both the combination 80oC till used for analysis of lipid and control groups were signifi- peroxides malondialdehyde, MDA), cantly higher than the sham superoxide dismutase (SOD), and group (P < 0.01) (Fig. 1). There reduced glutathione (GSH). MDA, was no significant difference in SOD, and GSH were measured by the mean value of serum creati- using colorimetric kit (Bio- nine of the combination group (4.1 Diagnostics, Dokki, Giza, Egypt) ± 0.8 mg/ dl) and the control according to manufacturer’s in- group (3.5 ± 0.62 mg/ dl) at the structions. end of the 4th week of obstruction (Fig. 1). The mean serum creati- Statistical analysis : nine of the combination group (1.2 The data of dogs of the three ± 0.3 mg/ dl) was significantly groups were compared at differ- lower than that of the control ent time points of assessment. group (2.1 ± 0.19 mg/ dl) by the Statistical analyses were carried end of the 8th week after relief of out with the 2-tail student's t obstruction, (P<0.01) (Fig. 1). At 4 and ANOVA tests. A p value weeks of obstruction; there was no <0.05 was considered as signifi- significant difference in the per- cant. centage decrease of serum creati-

27 Abdel-Aziz M. Hussein, et al... nine in both combination and the 4th week of obstruction (P = control groups. The ability of the 0.39) (Fig. 2). The mean creatinine kidney to regain its function at 8 clearance of the combination weeks after relief of obstruction group (34.8 ± 3.5ml/ min) was sig- was significantly better in the nificantly higher than that of the combination group compared with control group (31.5 ± 4.5 ml/ min) the control one. Combination of by the end of the 8th week after losartan and Ferulic acid en- relief of obstruction, (P< 0.01) (Fig. hanced regain of the serum 2). At 4 weeks of obstruction; creatinine at 8-weeks after relief there was no significant difference of obstruction by extra 30% in in the percentage decrease of crea- comparison to the control group tinine clearance in both combina- (Table 1). tion and control groups. The ability of the kidney to regain its Changes in the Creatinine function at 8 weeks after relief of clearance obstruction was significantly bet- The mean values of creatinine ter in the combination group com- clearance of the left kidney were pared with the control one. Com- comparable among dogs of the bination of losartan and Ferulic three groups at the basal condi- acid enhanced regain of creatinine tions. The sham operated group clearance at 8-weeks after relief of showed stable creatinine clear- obstruction by extra 30% of the ance level of the left kidney during basal value in comparison to the the whole duration of the study control group (Table 1). (Fig. 2). By the end of the 4th week of obstruction, the mean val- Changes in the renographic ues of creatinine clearance of both clearance : the combination and control The mean values of split reno- groups were significantly lower graphic clearance of the left kid- than the sham group. There was ney were comparable among dogs no significant difference in the of the three groups at the basal mean value of creatinine clearance conditions. The sham operated of the combination group (22.8 ± group showed stable split reno- 2.6 ml/ min) and control group graphic clearance level of the left (25.6 ± 2.8 ml/ min) at the end of kidney during the whole duration

28 Benha M. J. Vol. 29 No 1 Jan. 2012 of the study (Fig. 3). By the end of bination of losartan and Ferulic the 4th week of obstruction, the acid enhanced regain of split reno- mean values of renographic clear- graphic clearance at 8-weeks after ance of both the combination and relief of obstruction by extra 47 % control groups were significantly of the basal value in comparison lower than the sham group. There to the control group (Table 1). was no significant difference in the mean value of renographic Renal resistive index (RI) clearance of the combination There was no significant differ- group (21.93 ± 3.6 ml/min) and ence in the mean RI of the left kid- the control group (23.8 ± 2.4ml/ ney of the sham (0.45 ± 0.04); min) at the end of the 4th week of control (0.47 ± 0.03) and combina- obstruction (P = 0.67) (Fig. 3). Sig- tion group (0.49 ± 0.06) groups at nificant higher values of the split basal condition. The mean RI of renographic clearance in combina- the sham operated group re- tion group compared with the con- mained stable during the whole trol one was observed at 4 and 8 study duration (Fig.4). After 4 weeks after relief of obstruction weeks of obstruction, there was a (Fig. 3). The mean split renograph- significant rise in mean renal RI ic clearance in combination group from a basal value of 0.47 ± 0.03 (36.4 ± 1.7 ml/min) is significantly to 0.71 ± 0.02 in the control group higher than the control group and from a basal value of (28.2 ± 4.2 ml/min) at 8 weeks af- 0.48±0.04 to 0.7±0.05 in the com- ter relief of obstruction (P<0.01). bination group; (P values < 0.001 At 4 weeks of obstruction; there & < 0.001, respectively). By the was no significant difference in end of the 4th week of obstruc- the percentage decrease of reno- tion, there was no significant dif- graphic clearance in both combi- ference in the mean RI of the com- nation and control groups. The bination group (0.7 ± 0.05) and ability of the kidney to regain its the control one (0.71 ± 0.02). function at 8 weeks after relief of Marked drop of the RI to near ba- obstruction was significantly bet- sal values was observed at 4 ter in the combination group com- weeks after relief of obstruction in pared with the control one. Com- both the control (0.48±0.02) and

29 Abdel-Aziz M. Hussein, et al... the combination (0.47 ± 0.05) Assessment of apoptotic indi- groups. Follow-up of RI at 8 weeks ces, antiapoptotic activity and after relief of obstruction showed proliferation indices: almost stable values similar to There was significantly lower those of 4 weeks after relief of ob- tubular apoptosis, higher expres- struction in both the control and sion of Bcl2, and higher expres- combination groups (Fig. 4). sion of Ki 67 in the kidneys harvested from animals treated with Morphometric evaluation of FA and losartan compared with renal interstitial fibrosis the control one (table 2). A combi- Compared with the sham- nation of FA and losartan reduced operated animals, the harvested apoptosis by 58.86%, increased kidneys of the control group ex- expression of Bcl2 by 191.64%, hibited a marked interstitial fibro- and increased expression of Ki 67 sis mostly in perivascular and in- by 98.01% compared with control tertubular areas, indicated by a group (table 2). Figures 6-a & b, positive blue color in Masson’s tri- 7-a & b, and 8-a & b are examples chrome-stained sections. In con- of the tubular apoptosis indices, trast, harvested kidneys from ani- Bcl2, and Ki67 expression in the mals treated with FA and losartan control and combination groups, had significantly less sclerotic respectively. damage. The mean percentage of Assay of oxidants and antiox- fibrosis in the animals treated idants : with FA and losartan was signifi- There was significantly lower cantly lower than the control MDA, higher GSH, and higher group (p< 0.05) (table 2). A combi- SOD levels in the combination nation of FA and losartan reduced group compared with the control interstitial fibrosis by 49.23% in one (p<0.05). A combination of lo- comparison with control. Figure 5- sartan and FA reduced MDA by a represents one of the sham 57.27%, increased levels of GSH group, figure 5-b represents the by 85.06%, and increased levels of control group, while figure 5-c SOD by 70.65% compared with represents one of the animals the control group respectively (ta- treated with FA and losartan. ble 3).

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Discussion clearance by extra 22%, 26%, and Many factors may play an ac- 33.7% respectively. Also, Soliman tive role in the progression of re- et al(25) found that losartan en- nal damage in obstructive uropa- hanced regain of creatinine clear- thy after relief of obstruction. In ance, and renographic clearance this regard, it is not surprising to by extra 26%, and 26%, respec- find out that targeting hyperactive tively. These findings indicate that RAS alone as in current clinical this combination do not provide therapy may only have limited effi- more protection than each drug cacy in preventing the progressive alone in enhancing the recovery of loss of renal function in UO. In, renal functions after relief of UO the present study we examined in solitary kidney. the hypothesis that a combined therapy by simultaneously target- Both oxidative stress and hy- ing multiple pathogenic pathways peractive renin angiotensin sys- may be more effective in prevent- tem are involved in pathogenesis ing the progression of chronic re- of renal damage caused by UO. nal fibrosis and damage in UO in Also, many studies reported that solitary kidney. In the present they are involved in progression of study, we found that a combina- renal damage after relief of ob- tion of losartan and ferulic acid struction(2,16). The renal damage enhanced regain of the serum involves tubular cell apoptosis creatinine, creatinine clearance, and necrosis(5), interstitial inflam- and renographic clearance at 8- matory infiltration(6), and progres- weeks after relief of obstruction by sive fibrosis with deposition of ex- extra 30%, 30%, and 47% respec- tracellular matrix(7,8). So, the tively in comparison to the control next step of our study was to in- group. These findings indicate this vestigate the impact of the combi- combination enhanced the recov- nation on renal fibrosis induced ery of renal function after relief of by UO. In the present study, we UO. In a recent study from our lab found that a combination of losar- we found that FA alone enhanced tan and ferulic acid improved re- regain of serum creatinine, creati- nal fibrosis by 49.23%. This is nine clearance, and renographic more than FA alone because FA

36 Benha M. J. Vol. 29 No 1 Jan. 2012 alone improved renal fibrosis by apoptosis by 58.86%, increased 34.81%(16). These findings sug- expression of Bcl2 by 191.64%, gest that addition of AT1 receptor and increased expression of Ki 67 blocker to FA might stop or slow by 98.01% compared with control the process of fibrosis. In agree- group. This effect is better than ment with our results, Young et FA alone as reported by our previ- al.,(12) examined a combination of ous study(16). AT1 receptor blocker, losartan, and hepatocyte growth factor As mentioned in the back- (HGF) in protection against renal ground, oxidative stress plays damage caused by UO. They an important role in pathogene- found that AT1 blocker synergisti- sis of tubulo-interstitial inflamma- cally inhibits renal smooth muscle tion during obstructive nephropa- actin (SMA) expression (marker of thy(32), and after relief of renal fibrosis) and myofibroblast obstruction(12). Manucha et al.(33) activation and attenuates renal in- and Sugiyama et al.,(34) demon- terstitial fibrosis in obstructive strated an increase in the concen- nephropathy in mice. tration of reactive oxygen species (ROS) in obstructed kidney, to- In a previous study by our gether with decreased activities of group, we reported that tubular the major protective antioxidant cell apoptosis (as indicated by sig- enzymes superoxide dismutase nificant elevation of caspase3 and (SOD), catalase (CAT) and glutath- significant lowering of antiapoptot- ione peroxidase (GSH-Px). The ic protein Bcl-2) was still evident downregulation of antioxidant en- after 8 weeks after UO release. zymes CAT, GSH-Px, and SOD Moreover, tubular cell prolifera- from tubular cells from the ob- tion (as indicated by significant el- structed kidney increases the vul- evation of ki67) was significantly nerability of the kidney to oxida- increased in obstructed kidney tive damage(35). The results of our when compared to sham group16. study are in consistence with the In the present study we found findings of the previous studies. In that a combination of losartan the present study, a combination and FA significantly reduced of losartan and FA reduced MDA

37 Abdel-Aziz M. Hussein, et al... by 57.27%, increased levels of mechanisms of this combination GSH by 85.06%, and increased in inhibition of renal fibrosis. levels of SOD by 70.65% compared with the control group re- Acknowledgment spectively. When we compare This work was funded through these findings with the results of the science and technology devel- our previous study(16), we can say opment fund (STDF), Egypt-grant that addition of losartan to FA no.996. don’t offer more protective effect on oxidative stress in UO than FA References alone. These findings suggest 1. Gulmi F. A., et al. (2002) : that this combination might Pathophysiology of Urinary Tract slow the progress of fibrosis by Obstruction. In Campbell´s Urolo- a mechanism other than inhibi- gy, edn 2 411-462 (Eds Walsh PC tion of oxidative stress. This may et al.) Philadelphia: Saunders. include inhibition of the release of transforming growth factor β 2. Ito K., Chen J., Chaar M., (TGF-β). Both losartan and FA et al. (2004) : Renal damage pro- might act synergistically to inhibit gresses despite improvement of re- the expression of TGF-β. However, nal function after relief of unilater- in our study this was not meas- al ureteral obstruction in adult ured, so this point is one of the rats. Am J Physiol 287(6):F1283- limitations of our study and it will 93. considered on a next studies. 3. Chan W., Krieg R. J., J. R., Ward K., et al. (2001) : Pro- In conclusion, a combination of gression after release of obstruc- FA and losartan did not enhance tive nephropathy. Ped Nephrol the recovery of renal functions in 16:238-244. UO of a solitary kidney model of dogs. However, this combination 4. Chevalier R. L., Smith C. slows the progress of fibrosis and D., Wolstenholme J., Krajewski apoptosis of renal tubular cells. S. and Reed J. C. (2000) : Further studies are recommended Chronic ureteral obstruction in to understand the underlying the rat suppresses renal tubular

38 Benha M. J. Vol. 29 No 1 Jan. 2012 Bcl-2 and stimulates apoptosis. of protective effects of red wine. Exp Nephrol 8(2):115-22. Free Radic Biol Med 33:409-422.

5. Cachat F., Lange-Spera- 10. Klahr S. (2001) : Urinary ndio B., Chang A. Y., et al. tract obstruction. Semin Nephrol (2003) : Ureteral obstruction in 21: 133-145. neonatal mice elicits segment- specific tubular cell responses 11. Ricardo S. D. and Dia- leading to nephron loss. Kidney mond J. R. (1998) : The role of Int 63: 564-575. macrophages and reactive oxygen species in experimental hydro- 6. Schreiner G. F., Harris K. nephrosis. Semin Nephrol 18:612- P., Purkerson M. L. and Klahr S. 621. (1988) : Immunological aspects of acute ureteral obstruction: im- 12. Young M., Young I., mune cell infiltrate in the kidney. Johnston S. and Rowlands B. Kidney Int 34(4):487-93. (1996) : Lipid peroxidation assessment of free radical produc- 7. Sharma A. K., Mauer S. tion following release of obstruc- M., Kim Y. and Michael A. F. tive uropathy. J Urol 156:1828- (1993) : Interstitial fibrosis in ob- 1832. structive nephropathy. Kidney Int 44: 774-788. 13. Sunami R., Sugiyama H., Wang D. H., et al., (2004) : 8. Vaughan E. D. Jr., Mari- Acatalasemia sensitizes renal tu- on D., Poppas D. P. and Felsen bular epithelial cells to apoptosis D. (2004) : Pathophysiology of and exacerbates renal fibrosis af- unilateral ureteral obstruction: ter unilateral ureteral obstruction. studies from Charlottesville to Am J Physiol 286:F1030-F1038. New York J Urol 172 : 2563-2569. 14. Pat B., Yang T., Kong C., 9. Rodrigo R. and Rivera G. et al., (2005) : Activation of ERK (2002) : Renal damage mediated in renal fibrosis after unilateral by oxidative stress: a hypothesis ureteral obstruction: modulation

39 Abdel-Aziz M. Hussein, et al... by antioxidants. Kidney Int. 67: subtypes in rat and human kid- 931-943. ney. Am. J. Physiol., 262 (1992), p. F236. 15. Misseri R., Meldrum D. R., Dinarello C. A., et al., 20. Yoo K. H., Thornhill B. (2004) : TNF-alpha mediates ob- A., Wolstenholme J. T., et al., struction-induced renal tubular (1998) : Tissue-specific regulation cell apoptosis and proapoptotic of growth factors and clusterin by signaling. Am J Physiol 288:F406- angiotensin II. Am. J. Hypertens., F411. 11, p. 715.

16. Shokeir A. A., Hussein 21. Klahr S. and Morrissey A. M., Soliman S. A., et al., J. J. (1997) : Comparative study (2011) : Recoverability of Renal of ACE inhibitors and angiotensin Functions after Relief of Partial II receptor antagonists in intersti- Ureteral Obstruction of Solitary tial scarring. Kidney Int. Suppl., Kidney : Impact of Ferulic Acid. 63, p. S111. british J of urology international article in press. 22. Klahr S., Harris K. and Purkerson M. L. (1988) : Effects 17. Bernstein K. E. and of obstruction on renal functions. Berk B. C. (1993) : The biology of Pediatr. Nephrol., 2, p. 34. angiotensin II receptors. Am. J. Kidney Dis., 22, p. 745. 23. Guo G., Morrissey J., McCracken R., et al., (2001) : 18. Meister B., Lippoldt A., Contributions of angiotensin II Bunnemann B., et al., (1993) : and tumor necrosis factor-alpha Cellular expression of angiotensin to the development of renal fibro- type-1 receptor mRNA in the kid- sis. Am. J. Physiol. Renal Physiol., ney. Kidney Int., 44, p. 331. 280, p. F777.

19. Sechi L. A., Grady E. F., 24. Morrissey J. J. and Griffin C. A., et al., (1992) : Dis- Klahr S. (1999) : Effect of AT2 re- tribution of angiotensin II receptor ceptor blockade on the pathogene-

40 Benha M. J. Vol. 29 No 1 Jan. 2012 sis of renal fibrosis. Am J Physiol 29. Vielhauer V., Berning E., 276: F39-F45. Eis V., et al., (2004) : CCR1 blockade reduces interstitial 25. Soliman S. A., Shokeir inflammation and fibrosis in mice A. A., Mosbah A., et al., (2010) : with glomerulosclerosis and neph- Recoverability of Renal Function rotic syndrome. Kidney Int, 66 : After Relief of Chronic Partial 2264-2278 . Unilateral Ureteral Obstruction: Study of the Effect of Angiotensin 30. Duan W. R., Garner D. Receptor Blocker (Losartan). Urol S., Williams S. D., et al., 75: 848-852. (2003) : Comparison of immunohistochemistry for activated cas- 26. Shokeir A. A. (1995) : pase-3 and cleaved cytokeratin 18 Partial ureteral obstruction: a new with the TUNEL method for quan- variable and reversible canine ex- tification of apoptosis in histologi- perimental model. Urol 45:953- cal sections of PC-3 subcutaneous 957. xenografts. J Pathol 199 : 221- 228. 27. Edelstein C. L. and Cro- nin R. E. (2000) : The patient 31. Lindboe C. F. and Torp with acute renal failure. In Schri- S. H. (2002) : Comparison of Ki- er RW, ed. Manual of nephrolo- 67 equivalent antibodies J Clin gy.Lippincott Williams &Wilkins Pathol. 55(6): 467-471. London, 132. 32. Yagisawa M., Yuo A., Yo- 28. Shokeir A. A., Nljman R. nemaru M., et al., (1996) : Su- J. M. and El-Azab M. (1996) : peroxide release and NADPH oxi- Provoost AP. Partial ureteral ob- dase component in mature human struction: a study of Doppler ul- phagocytes : correlation between trasonography and diuretic renog- functional capacity and amount of raphy in different grades and functional proteins. Biochem Bio- duration of obstruction. Br J Urol phys Res Commun 228 : 510- 78: 829-835. 516.

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33. Manucha W., Carrizo L., Telmisartan inhibits both oxida- Ruete C., et al.. (2005) : Angio- tive stress and renal fibrosis after tensin II type I antagonist on oxi- unilateral ureteral obstruction in dative stress and heat shock pro- acatalasemic mice. Nephrol. Dial. tein 70 (HSP 70) expression in Transplant. 20: 2670-2680. obstructive nephropathy. Cell. Mol. Biol. (Noisy-le-grand) 51 : 35. Cvetkovic T., Vlahovic 547-555. P., Pavlovic D., et al. (1998): Low catalase activity in rats with uret- 34. Sugiyama H., Kobayashi eral ligation: relation to lipid per- M., Wang D. H., et al. (2005) : oxidation. Exp Nephrol 6:74-77.

42 Benha M. J. REPRINTVol. 29 No 1 Jan. 2012 BENHA MEDICAL JOURNAL

COMBINED EFFECT OF ANGIOTENSIN RECEPTOR BLOCKER, AND ANTIOXIDANTS ON RECOVERABILITY OF RENAL FUNCTIONS AFTER RELIEF OF PARTIAL URETERAL OBSTRUCTION OF SOLITARY KIDNEY

Abdel-Aziz M. Hussein MD, Azza Abdel-Aziz MD, Amira Awadalla MD and Nashwa Barakat MD

Published by Benha Faculty of Medicine Volume 29 Number 1 Jan. 2012

43 Benha M. J. Vol. 29 No 1 Jan. 2012 PSYCHIATRIC ADVERSE EFFECTS DURING COMBINATION THERAPY OF PEGYLATED INTERFERON PLUS RIBAVIRIN FOR CHRONIC HEPATITIS C PATIENTS : A PROSPECTIVE LONGITUDINAL STUDY

El-Sayed El-Nagar MD, Mohamed E. Khater MD, Gamal Shiha MD*, Salwa S. Tobar MD, and Ibtihal M. A. Ibrahim MD Departments of Psychiatry & Internal Medicine, Hepatology*, Faculty of Medicine, Mansoura university, Egypt

Abstract Background : Quality of life is an area of increasing interest in hepatology. Health related quality of life (HQL) issues have been examined in patients with chronic HCV infection, recurrent infection, and those undergoing treatment. Objective: the present study is designed to explore the relation between psychiatric comorbidity and its effect on quality of life (QOL) of those patients. Methods : 485 patients who fulfilled the inclusion and exclusion criteria were assessed using psychological [social class scale, mini international neuropsychiatric interview (MINI), and hepatitis quality of life questionnaire (HQOLQ)]. Results: Quality of life subscales median scores were lower in those showing psychiatric disorders than those who don’t at baseline assessment and throughout treatment. The mostly affected domains were Mental Health scale, Vitality scale and social functioning. As for the subscales concerned with HCV, the low scores were for Positive well being and Hepatitis specific health distress. Mental component summary scores were lower than physical component summary. Con- clusions: the combination therapy of pegylated interferon plus ribavirin affects quality of life in HCV patients. Presence of psychiatric comorbidity makes the condition worse. Keywords: Hepatitis C; Genotype 4; Psychiatry; Quality of Life, Egypt.

43 El-Sayed El-Nagar, et al...

Introduction who were treated with IFN-α and Hepatitis C virus (HCV) is a ri- found that the health status of bonucleic acid (RNA) virus belong- these patients was similar to that ing to the Flaviviridae family. It is of the general U.S. population a major cause of liver disease and did not change during IFN-α worldwide, to the degree that the therapy. In contrast, Bonkovsky World Health Organization (WHO) et al.6, in a much larger study, declared that HCV is a global showed that successful therapy health problem and about 3% of with IFN-α improves quality of life the population worldwide is infect- and that the degree of improve- ed with HCV1. In Egypt the situa- ment is related to sustained viro- tion is quite worse as it has a high logical or biochemical response to prevalence of HCV specially HCV- treatment. However, the patients 4 (which is responsible for nearly were not blinded to their state of 90% of infections). According to infection. Further study is needed the Egyptian Demographic and to establish whether eradication of Health Survey (EDHS) the preva- hepatitis C improves quality of lence of HCV in Egyptians is; 15 % life. in the age group 15 - 59 years old and 39.4 % in the age group 55- Interferon therapy may exacer- 59 years old, while the prevalence bate health-related quality of life in males is 17.4 % and 12.2 % in (HRQL) deficits associated with females2,3. hepatitis C virus (HCV) early in the course of therapy. Treatment Several studies have shown with polyethylene glycol-modified that patients with chronic hepati- interferon (peginterferon) alfa-2a tis C have a reduced quality of provides improved sustained re- life4. Reduction in quality of life is sponse over interferon alfa-2a, but not associated with how the infec- its effect on health-related quality tion is acquired or with the severi- of life (HRQOL) is unknown. The ty of the liver disease5,6. The im- purpose of this study was to eval- pact of IFN-α treatment is less uate the effect of chronic hepatitis clear. Hunt et al7 prospectively C infection on patients’ percep- followed patients with hepatitis C tions of HRQOL and to evaluate

44 Benha M. J. Vol. 29 No 1 Jan. 2012 how treatment with interferon af- Exclusion Criteria: Patients fects HRQOL. were excluded if they were women with ongoing pregnancy or Patients and Methods breast feeding; on therapy with Patients: 485 patients with any systemic anti-neoplastic or chronic HCV were recruited from immunomodulatory treatment (in- the outpatient clinic of the As- cluding supraphysiologic doses sociation of Hepatic Patients Care of steroids and radiation); ≤ 6 in Mansoura. The patients who months prior to the first dose of came to the clinic on Saturdays interferon; on any investigational and Mondays (days of visit to drug ≤ 6 weeks prior to the first the clinic) from June 2009 till dose of interferon; presence of co- May 2011 to start their investiga- infection with active hepatitis A; tions to begin the combination hepatitis B and / or human im- therapy of pegylated interferon munodeficiency virus (HIV); histo- plus ribavirin were chosen. The ry or other evidence of a medical study protocol was approved by condition associated with chronic the Research Ethics Committee of liver disease other than HCV (e.g. Mansoura Faculty of Medicine, hemochromatosis; autoimmune Mansoura University. All individ- hepatitis; metabolic liver disease; uals provided written informed toxin exposures); signs or symp- consent prior to their participa- toms of hepatocellular carcinoma; tion. history or other evidence of bleeding from esophageal varices or Inclusion Criteria: Patients other conditions consistent with were eligible to participate if they decompensated liver disease; ina- were; males or female ≥18 years bility or unwillingness to provide of age, with serologic evidence of informed consent. chronic HCV infection by anti- HCV antibody test, and liver biop- Methods: For each patient the sy findings consistent with the di- following was done: agnosis of chronic HCV infection 1. Clinical examination. with or without compensated cir- 2. Semi-structured psychiatric rhosis. interview:

45 El-Sayed El-Nagar, et al...

- The patients were interviewed ric disorders are called (free) Vs concerning demographic charac- those who show psychiatric disor- teristics (name, age, sex, occupa- ders (cases). In the current study tion, marital status and educa- males were found to be more tion). Social class will be assessed (68.7%) than females (31.3%) and by using the social class scale 8. there was a highly statistically significant difference between both 3. Psychometric assessment: groups as females were more in • Mini international neuropsy- the cases (55.7%). Regarding age, chiatric interview (MINI) to there was no statistically signifi- detect presence of any psy- cant difference between groups chiatric disorders. (where in both groups those above • Hepatitis quality of life ques- 40 years old constitute about tionnaire (HQOLQ) for assess- 50%) so as to marital status. As ment of quality of life. for education there was a statistically significant difference in edu- Statistical Analysis: cation between both groups. There The statistical analysis of data was a high rate of illiterates in our was done by using excel program sample (32.4%) as well as secon- and SPSS (SPSS, Inc, Chicago, IL, dary school education (36.5%). program statistical package for so- The percentage of persons in the cial science version 16). To test cases group is more in the lower the normality of data distribution educational levels. As for social K-S (Kolmogorov-Smirnov) test class there was a predominance of was done. The description of the class IV in both groups while the data was done in the form of mean other classes particularly I was (+/-) SD for quantitative data. higher among cases. The sample While frequency and proportion contained more rural patients in were used for qualitative data. both groups. Housewives, manual workers, farmers, skilled workers Results constituted about 81% of both Table (1): shows the sociodem- groups. ographic data of the studied group (those who did not show psychiat- Table 2 showed highly statisti-

46 Benha M. J. Vol. 29 No 1 Jan. 2012 cally significant difference be- baseline assessment and after 3, 6 tween those who showed psychiat- and 9 months of treatment and no ric disorders (cases) and those statistically significant difference who did not (free) regarding Physi- after 12 months of treatment. cal functioning (PF) at baseline as- General health (GH) perception sessment and after 3 months of tended to be lower in both group treatment and a statistically sig- but more in the cases group. nificant difference after 6 and 9 months of treatment where no sig- Table 3 showed that there was nificant difference was detected at a highly statistically significant the end of treatment (P=0.137). difference between those who Physical functioning tended to be showed psychiatric disorders (cas- lower in cases group than in free es) and those who did not (free) re- group from the beginning till the garding Vitality Scale (VT) at base- end. line assessment and after 3, 6 and As for Role physical function- 9 months of treatment and no sta- ing, there was a highly statistically tistically significant difference at significant difference between the end of treatment. Vitality tend- those who showed psychiatric dis- ed to be lower in cases group than orders (cases) and those who did in free group from the beginning not (free) at baseline assessment till the end. and after 3, 6 and 9 months of treatment and a statistically sig- For the Social functioning, nificant difference after 12 months there was a highly statistically sig- of treatment. Role Physical func- nificant difference between those tioning tended to be more limited who showed psychiatric disorders in cases group than in free group (cases) and those who did not from the beginning till the end. (free) at baseline assessment and after 3 and 9 months of treatment For general health scale, there and a statistically significant dif- was a highly statistically signifi- ference after 12 months of treat- cant difference between those who ment. No statistically significant showed psychiatric disorders (cas- difference was found at 6 months. es) and those who did not (free) at Social functioning tended to be

47 El-Sayed El-Nagar, et al... better in the free group than in ence at 6 (P= 0.695) and 9 (P= the cases group from the begin- 0.504) months of follow up. ning till the end. For the Mental Component For Role Emotional, there was Summary (MCS), there was highly highly statistically significant dif- statistically significant difference ference between those who between those who showed psy- showed psychiatric disorders (cas- chiatric disorders (cases) and es) and those who did not (free) at those who did not (free) at base- baseline assessment and through- line and throughout treatment out treatment till the end of treatment. Role Emotional (RE) tended Table 5 showed a highly statis- to be better in the free group than tically significant difference be- in the cases group. tween those who showed psychiatric disorders (cases) and those For mental health scale (MH), who did not (free) regarding here was highly statistically signif- Health Distress (HD) at baseline icant difference between those and throughout treatment. Health who showed psychiatric disorders distress was less in the free group (cases) and those who did not than in the cases group. (free) at baseline assessment and throughout treatment till the end For Positive Well-being (PWB), of treatment. Better Mental health there was there was highly statis- (MH) was found in the free group tically significant difference be- than in the cases group. tween those who showed psychiatric disorders (cases) and those Table 4 showed a highly statis- who did not (free) at baseline and tically significant difference beat 3 months. There was a statisti- tween between those who showed cally significant difference at 9 psychiatric disorders (cases) and months. No statistical significant those who did not (free) regarding difference was found between both Physical Component Summary groups at 6 and 12 months of (PCS) at baseline, 3 and 12 treatment. The mean of scores in months of treatment. There was both groups tended to be low but no statistically significant differ- much lower in the cases group.

48 Benha M. J. Vol. 29 No 1 Jan. 2012 For Hepatitis Specific Limita- For Hepatitis Specific Health tion (HLIM), there was there was Distress (HHD), there was there highly statistically significant dif- was highly statistically significant ference between those who difference between those who showed psychiatric disorders (cas- showed psychiatric disorders (cases) and those who did not (free) at es) and those who did not (free) at baseline, 3, 9 and 12 months. 6, 9, and 12 months of treatment. There was a statistically signifi- There was a statistically significant difference at 6 months. Limi- cant difference at 3 months. Dis- tations related to hepatitis were tress related to hepatitis was ob- observed to be more in the cases served to be more in the cases group. group.

49 El-Sayed El-Nagar, et al...

50 Benha M. J. Vol. 29 No 1 Jan. 2012

51 El-Sayed El-Nagar, et al...

Discussion servations are consistent with oth- Hepatitis C virus (HCV), a er studies demonstrating a strong member of the Flaviviridae family link between emotional status and of RNA viruses. At least 6 major health-related quality of life15,16. HCV genotypes are identified2. The mostly affected domains were Egypt has the highest prevalence Mental Health scale, Vitality scale of HCV worldwide (15%)3 and the and social functioning. As for the highest prevalence of HCV-4, subscales concerned with HCV, which is responsible for almost the low scores were for Positive 90% of infections9. It is common well being and Hepatitis specific in persons with significant medi- health distress. Mental component cal illnesses to have comorbid psy- summary scores were lower than chological symptoms and for their physical component summary. A quality of life to be affected10,11. systematic review of 15 studies comparing HRQoL in HCV- The current standard and only infected patients vs healthy con- effective treatment for chronic trols showed that HCV infection hepatitis C (CHC) is pegylated most profoundly impaired vitality, (PEG) interferon alfa in combina- general health, physical function tion with ribavirin12,13. Under op- and social function. Of these, vi- timal treatment conditions it is tality was considered the most impossible to achieve a sustained portant scale to patients 17. virological response (SVR) in 60% to 80% of cases. Achieving such a Several studies have shown good SVR depends importantly on that patients with chronic hepati- management of the drugs’ side ef- tis C have a reduced quality of fects14. life4. Reduction in quality of life is not associated with how the infec- In the current study, all Quali- tion is acquired or with the severity of life subscales median scores ty of the liver disease 5,6. The im- were lower in those showing psy- pact of IFN-α treatment is less chiatric disorders than those who clear. Hunt et al.7 prospectively don’t at baseline assessment and followed patients with hepatitis C throughout treatment. These ob- who were treated with IFN-α and

52 Benha M. J. Vol. 29 No 1 Jan. 2012 found that the health status of that health related quality of life these patients was similar to that Mean scores declined during treat- of the general U.S. population and ment. Scales most affected were did not change during IFN-α ther- role-physical, vitality, social func- apy. In contrast, 6 in a much larg- tioning and role-emotional, which er study, showed that successful showed decrements at the 12 therapy with IFN-α improves week on-treatment assessment. quality of life and that the degree An analysis of subgroups showed of improvement is related to sus- that for two scales (physical func- tained virological or biochemical tioning and role-physical), combi- response to treatment. However, nation therapy patients showed a the patients were not blinded to transient but slightly deeper de- their state of infection. cline during treatment, in both the 24 and 48 week arms. At follow- Fontana et al 18 found that up week 24 all scores had re- Baseline physical health and men- turned to pretreatment levels. tal health summary scores of the entire group were significantly References lower than those of healthy com- 1. World Health Organiza- parison subjects in the population (WHO). Hepatitis C. (2002) : tion. During the first 24 weeks of World Health Organization. treatment, the mean physical and mental health summary scores of 2. Nguyen M. H. and Keeffe the 15 patients with psychiatric E. B. (2005) : Prevalence and problems were lower than those of treatment of hepatitis C virus gen- the 11 patients without neuropsy- otypes 4, 5, and 6. Clin. Gastroen- chiatric problems (p<0.0001). terol. Hepatol.; 3(Suppl 2):S97- However, more striking differences S101. were noted in the role emotional and mental health subscale scores 3. El-Zanaty F. and Way A. over time in the two patient (2009) : Egypt Demographic and groups (p<0.0001). Health Survey, 2008. Cairo, Egypt: Ministry of Health and Pop- McHutchison et al. 19 reported ulation.

53 El-Sayed El-Nagar, et al...

4. Davis G., Balart L., Schiff 8. Fahmy S. I., A. F. El- E., Lindsay K., Bodenheimer H., Sherbiny, (1983) : Determining Perrillo R., Carey W., Jacobson simple parameters for social clas- I., Payne J., Dienstag J., Van- sifications for health research. Thiel D., Tamburro C., Martino Bulletin of the High Institute of F., Sangvhi B. and Albrecht J. Public Health, vol XIII. (1994) : Assessing health-related quality of life in chronic hepatitis 9. Abdel-Aziz F., Habib M., C using the sickness impact pro- Mohamed M. K., Abdel-Hamid file. Clin Ther; 16:334-343. M., Gamil F., Madkour S., et al., (2000) : Hepatitis C virus (HCV) 5. Foster G. R., Goldin R. D. infection in a community in the and Thomas H. C. (1998) : Nile Delta: population description Chronic hepatitis C virus infec- and HCV prevalence. HEPATOLO- tion causes a significant reduction GY; 32 : 111-115. in quality of life in the absence of cirrhosis. Hepatology; 27 : 209- 10. Dieperink E., Ho S. B., 212. Thuras P., et al. (2003) : A prospective study of neuropsychiatric 6. Bonkovsky H. L. and symptoms associated with inter- Woolley J. M. (1999) : (Consen- feron-a-2b and ribavirin therapy sus Interferon Study Group) : Re- for patients with chronic hepatitis duction of health-related quality of C. Psychosomatics.;44 (2):104-12. life in chronic hepatitis C and improvement with interferon thera- 11. Cordoba J., Flavia M., py. Hepatology; 29:264-270. Jacas C., et al. (2003) : Quality of life and cognitive function in 7. Hunt C. M., Dominitz J. hepatitis C at different stages of A., Bute B. P., Waters B., Blasi liver disease. J Hepatol; 39 (2): U. and Williams D. M. (1997) : 231-8. Effect of interferon-α treatment of chronic hepatitis C on health- 12. Fried M. W., Shiffman related quality of life. Dig Dis Sci; M. L., Rajender K. Reddy et al. 42:2482-2486. (2002) : “Peginterferon alfa-2a

54 Benha M. J. Vol. 29 No 1 Jan. 2012 plus ribavirin for chronic hepatitis McCaffrey D., Burnam A., Long- C virus infection,” The New Eng- shore D., Eggan F., Bozzette S. land Journal of Medicine, vol. A. and Shapiro M. F. (2000) : Im- 347, no. 13, pp. 975-982. pact of psychiatric conditions on health-related quality of life in 13. Manns M. P., McHutchi- persons with HIV infection. Am J son J. G., Gordon S. C., et al., Psychiatry; 157:248-254. (2001) : “Peginterferon alfa-2b plus ribavirin compared with in- 17. Spiegel B. M., Younossi terferonalfa-2b plus ribavirin for Z. M., Hays R. D., Revicki D., initial treatment of chronic hepati- Robbins S. and Kanwal F. tis C: a randomised trial,” The (2005) : Impact of hepatitis C on Lancet, vol. 358, no. 9286, pp. health related quality of life: a sys- 958-965. tematic review and quantitative assessment. Hepatology; 41: 790- 14. Fried M. W. (2002) : Side 800. effects of therapy of hepatitis C and their management. Hepatolo- 18. Fontana R. J., Schwartz gy; 36 : S237-S244. S. M., Gebremariam A., et al. (2002) : Emotional distress during 15. Jacobson A. M., deGroot interferon-?-2B and ribavirin M. and Samson J. A. (1997) : treatment of chronic hepatitis C. The effects of psychiatric disorders Psychosomatics.;43 (5):378-85. and symptoms in quality of life in patients with type I and type II di- 19. McHutchison J., Ware abetes mellitus. Qual Life Res; J., Bayliss M., et al. (2001) : The 6:11-20. effects of interferon alpha-2b in combination with ribavirin on 16. Sherbourne C. D., Hays health related quality of life and R. D., Fleishman J. A., Vitiello work productivity. J Hepatol; 34: B., Magruder K. M., Bing E. G., 140-7.

55 REPRINTEl-Sayed El-Nagar, et al... BENHA MEDICAL JOURNAL

PSYCHIATRIC ADVERSE EFFECTS DURING COMBINATION THERAPY OF PEGYLATED INTERFERON PLUS RIBAVIRIN FOR CHRONIC HEPATITIS C PATIENTS : A PROSPECTIVE LONGITUDINAL STUDY

El-Sayed El-Nagar MD, Mohamed E. Khater MD, Gamal Shiha MD, Salwa S. Tobar MD, and Ibtihal M. A. Ibrahim MD

Published by Benha Faculty of Medicine Volume 29 Number 1 Jan. 2012

56 Benha M. J. Vol. 29 No 1 Jan. 2012 POPLITEAL SCIATIC NERVE BLOCK FOR ANKLE AND FOOT SURGERY, A COMPARITIVE STUDY BETWEEN THE MODIFIED INTERTENDINOUS AND THE LATERAL APPROACHES

Ibrahim M. Abd Elmoeti MD, Mohamed Y. Serry MD, Ahmed Mostafa MD and Ahmed Hamdy M.Sc Departments of Departments of Anesthesia, ICU & Pain Management , Egypt

Abstract Aim: The aim of this study is to compare a single injection modified intertendinous with the lateral approach to popliteal sciatic nerve(SN) block by using the peripheral nerve stimulator for patients undergoing ankle and foot surgery for intraoperative anesthesia and postoperative analgesia. Patients& methods: This is a randomized interventional prospective study, where patients were randomly allocated into two equal groups, 60 patients in each group; group A( the modified intertendinous approach) and group B(the lateral approach).Each group was subdivided into three equal subgroups (I,II,III) according to the medications they received: subgroup I received plain bupivacaine + 1ml saline 0.9%, subgroup II received plain bupivacaine + 1ml of clonidine (100 µg) and subgroup III received plain bupivacaine + 1ml of hyaluronidase (1500 IU). The initial stimulation of tibial nerve and common peroneal nerve, the time required to perform the block, the number of attempts till successful nerve localization and their complicatios and sensory block assessement (onset, peak, duration and postoperative analgesia "VAS") and the motor block assessement (onset, peak and duration) were recorded. Results: The technique in group A is easier with a higher success rate than that in group B but the quality of block for both groups is the same. In subgroups AII and BII the duration of

57 Ibrahim M. Abd Elmoeti, et al... sensory block, postoperative analgesia and motor block is more than in other subgroups (p <0.05). In subgroups AIII and BIII the onset of sensory and motor block is faster than in other subgroups (p <0.05). Conclusion: Although the lateral approach has the advantage that it can be done while the patient lying supine; the modified intertendinous approach proved to be easier. The addition of 100 µg clonidine to bupivacaine 0.5% prolonges the duration of sensory block, postoperative analgesia and motor block duration during popliteal sciatic nerve blockade. The addition of hyaluronidase (1500 IU) to bupivacaine 0.5% speeds the onset of sensory and motor block but it has no effect on the peak, duration of anaesthesia and post operative analgesia. Introduction The modified intertendinous The sciatic nerve supplies approach to the SN in the popli- motor innervation to the entire teal fossa requires placement of lower leg via the posterior tibial the patient in the prone position nerve, superficial and deep pero- which may be contraindicated in neal nerves, and the sural nerve. pregnant women or impossible in The sural nerve is sensory only. trauma patients. McLeod et al These major branches of the 1995(4) described another tech- sciatic nerve also supply sensory nique of blocking the SN in the innervation to the lower leg, ex- popliteal fossa using a lateral ap- cept for the medial inner strip, proach with the patient lying su- which is supplied by the saphe- pine. A subcutaneous block of the nous nerve (a branch of the femo- saphenous nerve as described by ral nerve)(1),(2). Blockade of the SN Scott was later added for addition- at this level provides an appropri- al pain control(5). Popliteal block- ate anesthesia / analgesia with a ade with bupivacaine, can reduce duration that exceeds, in many postoperative pain for 14-20h af- cases, 18 hours. Additionally, ter major foot and ankle surgery this blockade has the advantage, with minimal side effects. Moreo- over more proximal blockades, of ver the choice of additives to local preserving the flexion of the anaesthetic influence the onset knee and allowing early ambula- and, particularily,the duration of tion with crutches(3). the blockade(6). Clonidine is an al-

58 Benha M. J. Vol. 29 No 1 Jan. 2012 pha-2 adrenergic agonist which ripheral neuropathy, pregnancy produces analgesia through cen- and infection at the site of punc- tral and peripheral mechanisms it ture. is associated with specific side effects specially bradycardia and All patients were visited before hypotension. It enhances both surgery and were given a full ex- sensory and motor blockade from planation; informed consent was epidural or peripheral nerve injec- obtained and patients were in- tion of local anaesthetics, it blocks structed to the use of the visual conduction of C and A gamma fi- analogue scale (VAS) of pain.All bres, increases and intensifies patients were subjected to careful conduction block of LA(7). A major history taking, clinical examina- component of connective tissue is tion and laboratory investigations. hyaluronic acid, which is reversi- After 8 hours of fasting premedi- bly depolymerized by hyaluroni- cation was given in the form of 0.1 dase, initially called “skin spread- mg/kg diazepam orally 1 hour being factor”. fore starting the block. On the patient's arrival to the operating Patients and Methods room a 20G intravenous cannula This study was conducted on was inserted in the forearm before 120 patients of both sexes, ASA I- starting the block, perioperative III presented for elective surgery of fluid requirements were calculated the foot or ankle in The Benha and administered throughout the University Hospital. Their ages procedure, full non invasive moni- was ≥ 18 years and their weight toring commenced [Baseline level ranged from 60 to 85 Kg.Approval of consciousness, Pulse oximter, of ethical committee. Vital signs (Respiratory rate, Blood pressure and Heart rate) Exclusion criteria included and ECG and oxygen 2- 4 liters/ patients refusing local anesthet- min was administered through a ic technique, patients with coag- nasal pronge. Patients were ran- ulopathy, patients with known domly allocated into two equal sensitivity to the investigated groups A and B according to the drugs,dementia,patients with pe- technique of block.

59 Ibrahim M. Abd Elmoeti, et al...

Popliteal sciatic block was per- muscle overlap(8). formed using the peripheral nerve stimulation method. PLEX-GON The skin was cleaned with an nerve stimulator was used togeth- antiseptic solution (Povidon io- er with 50mm & 100mm LOCO- dine) and then anesthetized with PLEX® insulated needles for modi- 4-5 ml lidocaine 2%. The stimulat- fied intertendinous approach and ing needle (a 22G-50mm insulat- lateral approach respectively. it ed) was connected to the negative was set at a frequency of 2 Hz, lead of the nerve stimulator, pulse width 100 µs, and current whereas the positive lead was con- intensity 1.5 mA to locate the nected to the lateral calf via an nerve branches then reduction of ECG electrode. the stimulating current to ≤0.5mA was done to confirm close proxim- The needle was inserted per- ity to the nerves. pendiculary to a depth of 2-5cm until motor response was elicited Group A: with the nerve stimulator. If the In this group, the modified in- nerve was not localized on the first tertendinous popliteal block using needle insertion, the needle was a peripheral nerve stimulator was slowly withdrawn to the skin and performed on 60 patients present- reinserted through the same skin ing for surgery of the foot or ankle. puncture at an angle 5o then 10o With the patient lying prone with lateral to the initial insertion the leg on the side to be blocked is plane(first attempt). Failure to supported to permit unrestricted stimulate the sciatic nerve, result- movement of the foot. The modi- ed in removal of the needle and fied intertendinous approach site repetition of the same maneuvers was determined by palpating the through a new puncture site 5mm groove between the biceps femoris lateral to the initial insertion site and semitendinosus muscle until (second attempt). The needle posi- the point of overlap. The point of tion will be considered acceptable needle insertion was identified in if an evoked motor response of the intermuscular groove perpen- plantar flexion, inversion, eversion dicular to the skin just distal to or a dorsiflexion of the ipsilateral

60 Benha M. J. Vol. 29 No 1 Jan. 2012 foot is elicited at ≤0.5 mA. then stimulator was performed on 60 the local anesthetic was injected, patients presenting for surgery of the proximity of the insulated nee- the foot or ankle. While the pa- dle to the nerve was confirmed tient is placed in the supine posi- when an injection of 1 or 2 ml of tion, with the leg extended at the local anesthetic results in an im- knee joint, a 10-pound sandbag or mediate cessation of the elicited a bump will be placed beneath the motor response. calf and the leg internally rotated by an assistant. The point of nee- Patients of this group were fur- dle insertion was identified as a ther subdivided into three sub- point in the groove between vastus groups according to the used lateralis and biceps femoris,which drugs number of each=20: lies 7cm cephalad to the lateral femoral epicondyle. Subgroup AI : Patients of this subgroup re- After preparation as for group A ceived 0.4 ml /kg (24-34ml) of using a 22G-100mm insulated 0.5% bupivacain plus 1ml saline. short-bevel needle, it is inserted through the identified site at a Subgroup AII: horizontal plane and the needle Patients of this subgroup re- was advanced until the shaft of ceived 0.4 ml /kg (24-34ml) of the femur bone was intentionally 0.5% bupivacain plus 1ml Cloni- contacted. After the femur was dine (100 µg). contacted, the needle was then withdrawn to the skin and redi- Subgroup AIII: rected posteriorly at a 30o angle to Patients of this subgroup re- the horizontal plane. The biceps ceived 0.4 ml/kg (24-34ml) of femoris muscle fibers will be stim- 0.5% bupivacain plus 1ml hyalu- ulated and contract until the nee- ronidase (1500 IU). dle passes completely through. Advancing the needle further will Group B: then stimulate the CP branch of In this group, the lateral ap- the SN and cause eversion and proach using a peripheral nerve dorsiflexion of the foot. Continue

61 Ibrahim M. Abd Elmoeti, et al... to advance the needle until the ceived 0.4 ml/kg (24-34ml) of more medial TN stimulates the 0.5% bupivacain plus 1ml Cloni- flexor muscles to the toes If, after dine (100 µg). stimulating the CP branch, the flexor muscles are not reacting, Subgroup B III: the needle needs to be withdrawn Patients of this subgroup re- to the skin and reinserted through ceived 0.4 ml/kg (24-34ml) of the same skin puncture, first 5- 0.5% bupivacain plus 1ml hyalu- 10o anterior and then 5-10o pos- ronidase (1500 I.U). terior relative to the initial insertion plane (30o). if this redirection In both groups, the saphenous (first attempt) did not result in nerve was then blocked by subcu- nerve localization, the same tech- taneous infilteration at the antero- nique is repeated through new medial side of the upper part of skin punctures. The needle posi- the leg with 3-5ml of 2% lidocain tion will be considered acceptable solution. if an evoked motor response of plantar flexion, inversion, eversion Difficulty in obtaining a proper or a dorsiflexion of the ipsilateral motor response to a stimulus foot is elicited at ≤0.5 mA, then <0.5mA 2Hz and the initial re- the local anesthetic was injected. sponse to electrical stimulation of the tibial and common peroneal Patients of this group were fur- nerves was recorded along with ther subdivided into three sub- the time needed to perform the groups according to the used block. drugs. Sensory block was assessed by Subgroup B I: the pin-prick test using 27G nee- Patients of this subgroup re- dle in the skin areas along the dis- ceived 0.4 ml /kg (24-34ml)of tribution of the superficial and 0.5% bupivacain plus 1ml saline. deep peroneal nerves, and medial plantar, lateral plantar, and calca- Subgroup B II: neal branches of the tibial nerve. Patients of this subgroup re- the patient was given a degree

62 Benha M. J. Vol. 29 No 1 Jan. 2012 from a 3-point scale rating (2= no the tibial nerve( medial plantar, block, 1= hypoesthesia, 0= anes- lateral plantar, and calcaneal thesia). branches), sole of the foot, within 30min and absence of pain on Motor assessments included surgical instrumentation. Anes- plantar flexion and dorsiflexion of thetic failure was managed with the foot at the ankle, and toes general anesthesia as appropriate. movement. Onset of motor block- Intraoperative sedation was pro- ade ,time to peak motor blockade vided by an intermittent bolus of and the duration of motor block- 1mg midazolam and 50µg fenta- ade were recorded. the patient nyl. was given a degree from a 3-point scale rating (2= no block, 1= pare- A failed block was the one sis, 0= paralysis). where there was no elicited motor response or where the sensory Time from injection to onset of blockade involved only a single or sensory blockade (loss of sensa- none of the following nerves: the tion of sharpness) and time from superficial and deep peroneal injection to peak sensory effect nerves, and medial plantar, lateral (loss of touch sensation) were re- plantar, and calcaneal branches of corded. Duration of anesthesia the tibial nerve. was taken from establishment of peak sensory effect until first re- After completion of the block turn of pinprick sensation in any procedure, all patients were moni- skin dermatome supplied by the tored for signs of local anesthetic TN and CPN. toxicity for 30 minutes after block placement(dizziness, visual and A successful complete block auditory disturbances, tinnitus, was defined as pinprick sensory tremors, muscular twitching, con- anesthesia and motor paralysis af- vulsions and metalic taste). fecting both divisions of the sciatic nerve i.e. the peroneal nerve (the The complications of the used superficial and deep peroneal drugs as hypotention and brady- nerves) (dorsum of the foot) and cardia for clonidine and hypersen-

63 Ibrahim M. Abd Elmoeti, et al... sitivity or anaphylaxis for hyalu- tively. motor response to electri- rinidase was also recorded. Pa- cal stimulation ≤ 0.5 mA 2Hz was tients were also observed for other elicited after first attempt (Easy) in complications as bruising, bleed- 58.3% & 16.7% of cases in the ing at the injection site, arterial groups A & B respectively puncture (hematoma) and periph- (P<0.001). Motor response to elec- eral nerve injury (parasthesia). trical stimulation ≤ 0.5 mA 2Hz was elicited after second attempt Postoperative analgesia was as- (Intermediate) in 18.3% & 30.0%of sessed using the visual analog cases in the groups A & B respec- scale (VAS). Duration of postoper- tively (P<0.001). Motor response to ative analgesia was recorded as electrical stimulation ≤ 0.5 mA the time elapsed from the first re- 2Hz was elicited after third at- turn of pinprick sensation in any tempt (Difficult) in 18.3% & 43.3% skin dermatome supplied by the of cases in the groups A & B re- blocked nerves up to the patient's spectively (P<0.001). Motor re- first request for analgesia for pain sponse to electrical stimulation ≤ in the vicinity of the operation. 0.5 mA 2Hz elicited hardly in Rescue analgesia in the form of 5.0% & 10.0% of cases in the paracetamol 500mg tablets up to groups A & B respectively. In 8 tablets/24 hr orally or mepri- group (A) 3 cases required general dine 0.5mg/kg IM will be available anesthesia while in group (B) 6 on patient request or if VAS ≥4. cases required general anesthesia i.e. failed block, fig (1). Results There was no statistically sig- In this study, motor response nificant difference (P>0.05) be- to electrical stimulation to tibial tween the 6 subgroups as regard nerve (inversion and planter flex- age, weight, sex and type of sur- tion of the foot) occurred in gery table (1) and table (2). 76.7% and 28.3% for the groups A & B respectively (P<0.001). Mo- During the performance of the tor response to electrical stimula- blocks success rate was 95% and tion to common peroneal nerve 90% in the groups A & B respec- (eversion and dorsiflexion of the

64 Benha M. J. Vol. 29 No 1 Jan. 2012 foot) occurred in 23.3% and 71.7% Duration of motor block was 4.97 for the groups A & B respectively ±0.469 hr , fig (5)-(6). (P<0.001), fig (1). In subgroup AII, the onset Mean time to perform the block time of sensory nerve blockade (start of skin disinfection – end of was 14.87 ± 0.549 min. Peak injection) was 8.3 ± 1.4 and 10.9 ± sensory effect was 26.66±0.8 1.3 min for group A and B respec- min. the, Duration of anesthe- tively (P<0.001) fig. (2) sia was 6.289±0.6 hr, Postop- erative analgesia was 8.47±0.889 In subgroup AI, the onset hr, fig (3)-(4). The onset time of time of sensory nerve blockade motor nerve blockade was 11.05 ± was 14.84±0.800 min. Peak sen- 0.643 min. Peak motor effect sory effect was 26.84±0.8 min. was 23.79 ± 0.805 min. Duration Duration of anesthesia was of motor block was 6.82 ± 0.582 4.711±0.7 hr. Postoperative anal- hr, fig (5)-(6) . gesia was 6.92±0.629 hr., fig (3)-(4). The onset time of motor In subgroup BII, the onset time nerve blockade was 11.89 ± 0.922 of sensory nerve blockade was min. Peak motor effect was 23.45± 14.94 ± 0.682 min. Peak sensory 1.189 min. Duration of motor effect was 25.56 ± 0.837 min. Du- block was 4.18 ± 0.803 hr., fig ration of anesthesia was 6.839± (5)-(6). 0.7823 hr. Postoperative analgesia was 8.1 ± 0.912 hr. fig (3)-(4). The In subgroup BI, the onset time onset time of motor nerve block- of sensory nerve blockade was ade was 12.18 ± 0.752 min. Peak 15.39 ± 0.979 min. Peak sensory motor effect was 24.36 ± 0.837 effect was 26.44 ± 1.626 min. Du- min. Duration of motor block was ration of anesthesia was 4.694± 6.12 ± 0.712hr fig (5)-(6). These 0.6216 hr. Postoperative analgesia results show that there is en- was 6.83±0.728 hr., fig (3)-(4). The hancement of sensory and motor onset time of motor nerve block- blockade by clonidine added to ade was 12.33±0.891 min. Peak bupivacain during popliteal motor effect was 23.00±0.922 min. sciatic nerve blockade as regards

65 Ibrahim M. Abd Elmoeti, et al... duration of sensory block, postop- blockade speeds the onset of sen- erative analgesia and duration of sory and motor blockade but it motor blockade and there was no had no effect on the peak, dura- complications from its use. tion of anaesthesia and post operative analgesia and there was no In subgroup AIII, the onset complications from its use. time of sensory nerve blockade was 12.13±0.704 min. Peak sen- There was no statistically sig- sory effect was 26.76±1.032min. nificant difference (P > 0.05) be- the, Duration of anesthesia tween six subgroups AI, AII, AIII, was 4.537 ± 0.6946 hr, Postop- BI, BII and BIII as regards the erative analgesia was 6.93± postoperative analgesic character- 0.513hr., fig (3-(4). The onset time istics (VAS and analgesic supple- of motor nerve blockade was ments) (4h), (6h) and (8h) postop- 9.53±0.230min. Peak motor effect eratively. There was statistically was 23.58±0.902min. Duration of significant difference (P < 0.05) be- motor block was 4.74±0.632 hr, tween the 6 subgroups (10h) and fig 5)-(6). (12h) postoperatively. The mean VAS (10h) was 4.40±1.56, In subgroup BIII, the onset 3.8±0.89, 4.41±1.46, 4.43±0.84, time of sensory nerve blockade 3.9±.04 and 4.48±0.78 for sub- was 12.67 ± 0.618min. Peak sen- groups AI, AII, AIII, BI, BII and sory effect was 26.33 ± 1.455 BIII respectively. The mean VAS min. Duration of anesthesia was (12h) was 5.4±1.56, 4.57±0.89, 4.411±0.5830 hr. Postoperative 5.41±1.46, 5.43±1.84, 4.47±0.04 analgesia was 6.81±0.730 hr, fig and 5.48±0.78 for subgroups AI, (3)-(4). The onset time of motor AII, AIII, BI, BII and BIII respec- nerve blockade was 10.61 ± tively fig (7). 0.631min. Peak motor effect was 24.61 ± 0.979min. Duration of Complications during perfor- motor block was 4.69 ± 0.572 hr, mance of procedures are summar- fig (5)-(6). These results show that ized in (Table 8). hematoma was adding hyaluronidase to bupiva- observed in 8.3% and 6.7% of cain during popliteal sciatic nerve group A and B respectively. There

66 Benha M. J. Vol. 29 No 1 Jan. 2012 was no statistically significant dif- nitus and anxiety (occurred 5 min ference between the 2 groups (P > after the injection of local anes- 0.05). Accidental puncture of pop- thetic , lasted for only 5 min and liteal vesseles was observed in resolved spontaneously without 3.3% and 1.7% of group A and B any intervention it may be a sign respectively. There was no statisti- of CNS toxicity of bupivacain ) was cally significant difference be- observed in 5% and 3.3% of group tween the 2 groups (P > 0.05). Tin- A and B respectively.

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69 Ibrahim M. Abd Elmoeti, et al...

70 Benha M. J. Vol. 29 No 1 Jan. 2012 Discussion tertendinous approach that is only In this current study, the block relies upon manual identification performance time is significantly of the intermuscular plane separ- longer (P<0.001) in the lateral ap- ating the biceps femoris and semi- proach than in the modified inter- tendinosus / semimembranosus tendinous approach and this was muscles or may be due to the lack probably because of the fact that of experience with the lateral ap- the 100 mm, needle used tended proach. to bend on insertion between the tendons of biceps femoris and vas- Borgeat et al, 2006(10) in their tus lateralis muscles in the lateral clinical study of the continuous approach which does not happen popliteal nerve block in a 1001- in the modified intertendinos ap- case survey, and all patients re- proach. ceived the modified posterior approach, they stated that, for 97% In the study performed by Zet- of the patients, one puncture at- loui P et al, 1988(9), a shorter per- tempt was sufficient to obtain in- formance time for lateral ap- version or plantar flexion. A sec- proach was also obtained ond puncture site (more lateral) (4.10+1.26 min). This could be at- was necessary in 3%. Borgeat et tributed to the fact that they per- al, 2004(11) in their Clinical eval- formed the block using a shorter uation of the modified posterior needle (50 mm insulated) which anatomical approach for per- has less tendency to bend during forming the popliteal block in progression leading to a more con- Five-hundred patients undergo- sistent needle path or may be due ing surgery of ankle or foot were to racial difference. prospectively included also showed in their results that The In the present study, the lateral first attempt was successful in approach required more attempts 97.5% of the patients, as we no- to perform the block than the ticed this very high percentages modified intertendinous approach, may be due to the more experi- this may be due to the more sim- ence they had in performing this ple technique of the modified in- technique.

71 Ibrahim M. Abd Elmoeti, et al...

Regarding the initial response showed in their results complete to electrical stimulation, the re- sensory and motor block in 94% sults of the present study showed of the patients had the block and significant difference between the they stated that this technique two approaches . has a high success rate thus the location of the needle insertion These results agrees with the point is assessed without any results of Palaniappan et al, measurement, thus avoiding inac- 2006 (12) in their study as in pos- curacies caused by repeated skin- terior (classic) approach group, distance measurements so this the tibial nerve got stimulated in goes definitely with our study in 69% resulting in plantar flexion the modified intertendinous ap- and inversion. In the lateral approach. proach group, the peroneal nerve got stimulated in 72% of the pa- Michael et al,2010(13) hypothe- tients resulting in dorsiflexion and sized that blocking the tibial and eversion. This difference was sta- common peroneal nerves individu- tistically significant. ally in the popliteal fossa using the lateral approach using ultra- Regarding success rate (90%) sound distal to sciatic bifurcation of group B showed complete sen- would decrease time to complete sory and motor block and only block. A mixture of 28 mL 1.5% (10%) had paraesthesia and pare- mepivacaine with 100 µg clonidine sis, while in group A (95%) was used. Ultrasound was used to showed complete sensory and mo- guide needle adjustments to tor block and only (5%) had para- achieve circumferential spread. esthesia and paresis this may be Patients had significantly faster due to the more difficult lateral time to complete block than that technique. in our study (19.2 vs 25.56 min), this may explained by the accu- Borgeat et al, 2004(11) in their rate visualization and identifica- Clinical evaluation of the modified tion of both divisions of the sciatic posterior anatomical approach for nerve using U/S guided technique performing the popliteal block also or may be due to the use of mepiv-

72 Benha M. J. Vol. 29 No 1 Jan. 2012 acaine which has a faster onset tion rather than by blind stimula- than bupivacaine. tion.

Geffen et al,2009(14) done Ran- The addition of clonidine (100 domized controlled clinical study µg) in our study to bupivacain of ultrasound guided versus nerve (subgroup AII and BII) resulted stimulation guided distal sciatic in increased duration of anaesthe- nerve block at the popliteal fossa sia and post operative analgesia on 40 adult patients undergoing but it had no effect on the onset foot or ankle surgery receiving and peak of anaesthesia and there only a popliteal fossa sciatic nerve was no complications from its use. block. The block success rate was Jacques et al 2008(15) in their 100% in the US-guided group and study support our results, they 75% in the NS-guided group. Of stated that Clonidine significantly the NS-guided group, the nerve prolongs the analgesic duration could not be located in 2 patients after popliteal fossa nerve block- and the block was not performed. ade with bupivacaine. Patients re- Success rate in the patients who ceived a popliteal fossa block did receive a block was 83%. The (nerve stimulator technique, via median local anesthetic volume the posterior approach) using 30 used was 17 vs 37 mL in the US- mL 0.375% bupivacaine, with epi- guided and NS-guided groups re- nephrine. Patients were random- spectively. Block performance ized to receive no clonidine, 100 time, onset and duration were µg clonidine IM, or 100 µg cloni- similar between the two groups. dine with bupivacaine for the pop- Significantly fewer needle inser- liteal block. Patients also received tion attempts were required in the a combined spinal epidural anes- US-guided group. This very high thetic, a saphenous nerve block, success rate is also higher than and postoperative IV patient con- that of our study as U/S guided trolled analgesia.Duration of anal- nerve block provides a real visuali- gesia was statistically longer in zation of the nerve to be blocked the block clonidine group (18 ± 6 and local anesthetic spread can be h for clonidine with bupivacaine observed in real time during injec- vs 14 ± 7 h for IM clonidine and

73 Ibrahim M. Abd Elmoeti, et al...

15 ± 7 h for control, P = 0.016 for tal group), No significant differenc- control vs clonidine with bupiva- es were noted between groups for caine). Pain scores, analgesic use, pain intensity scores, duration of and side effects attributable to sensory analgesia, postoperative pain management were similar analgesic requirements or overall among groups. patient satisfaction. Both groups reported minimal amounts of Also Colin, et al 2007(16) sup- postoperative pain and high anal- port our study they stated that gesic satisfaction scores. This may Clonidine improves duration of be due the fact that the sciatic analgesia and anesthesia when nerve is thicker and deeper in its used as an adjunct to intermedi- origin than it is in the popliteal ate-acting local anesthetics for fossa, or may be due to the use of some peripheral nerve blocks. lower doses of clonidine than we Side-effects appear to be limited at used. doses up to 150 µg. Based on qualitative analysis, clonidine ap- The addition of hyaluronidase peared to prolong analgesia when (1500 IU) in our study to bupiva- added to intermediate-acting local cain 0.5% (subgroup AIII and anesthetics for axillary and peri- BIII) resulted in speeds the onset bulbar blocks. of anaesthesia only but it had no effect on the peak, duration of an- On the other hand Dareen, et aesthesia and post operative anal- al 2004(17) do not recommend the gesia. There are many controver- addition of clonidine to a femo- sies about the use of ral-sciatic nerve block when given hyaluronidase in peripheral nerve to facilitate postoperative analge- blocks and regional anaesthesia. sia in patients undergoing ACL Keeler et al 1992(18) studied the reconstruction. Patients are as- effect of adding hyaluronidase to signed randomly to receive a fe- bupivacaine during axillary bra- moral-sciatic nerve block using 30 chial plexus block (BPB) in a dou- ml 0.5% bupivacaine (control ble-blind design. Patients received group) or 30 ml 0.5%bupivacaine BPB using bupivacaine 2 mg kg-1 and 1 µg /kg clonidine (expremen- with adrenaline 1 in 200000,

74 Benha M. J. Vol. 29 No 1 Jan. 2012 either with or without hyaluroni- tween the 2 groups, Accidental dase (3000 IU), in a volume of 0.5 puncture of popliteal vesseles was ml per 2.54 cm of the patient's observed in 3.3% and 1.7% of height. The use of hyaluronidase group A and B respectively. There did not increase the speed of onset was no statistically significant dif- of anaesthesia or reduce the inci- ference between the 2 groups. Tin- dence of inadequate nerve block. nitus and anxiety (occurred 5 min Hyaluronidase produced a signifi- after the injection of local anes- cant reduction in the duration of thetic, lasted for only 5 min and anaesthesia. resolved spontaneously without any intervention it may be a sign Tempestini 2008(19) performed of CNS toxicity of bupivacain) was third molar surgeries in 20 observed in 5% and 3.3% of group healthy patients. Inferior alveolar A and B respectively. nerve block was induced using 2.8 mL 2% mepivacaine with epineph- Borgeat et al, 2006(10) in their rine. Hyaluronidase (75 IU) or a Clinical study, all patients re- placebo was injected 40 minutes ceived the modified posterior ap- after the beginning of pulpar anes- proach, they found that acute thesia (randomized and double- complications were observed in blind trial). In both tissues, the (1.7%), (0.5%) reported transient duration of anesthetic effect paresthesias during nerve localiza- with hyaluronidase was longer tion, which resolved immediately (P<0.01) than with the placebo. after needle repositioning, (0.8%) Hyaluronidase increases the dura- noted painful sensations during tion of mepivacaine in inferior al- application of local anesthetic, veolar nerve blocks. which resolved after slight withdrawal of the catheter. In (0.4%), As regard Complications during blood was aspirated through the performance of procedures, he- needle. In these patients, the nee- matoma was observed in 8.3% dle was withdrawn, the puncture and 6.7% of group A and B re- point compressed until bleeding spectively. There was no statisti- stopped, and the block was suc- cally significant difference be- cessfully performed. No central

75 Ibrahim M. Abd Elmoeti, et al... nervous system or cardiac toxicity References occurred. 1- Vloka J., Hadzic A., April E. and Thys D. M. (2001) : The Compere et al 2005(20) report- division of the sciatic nerve in the ed a case of thigh abscess as a popliteal fossa: Anatomical impli- complication of continuous popli- cations for popliteal nerve block- teal sciatic nerve block . Five days ade. Anesth Analg; 92:215. after surgery, the catheter was removed. Fifteen days after, the pa- 2- Drake A., Wayne Vogl, tient complained of pain in the Adam W. M. Mitchell, and Ab- thigh with fever. Ultrasonography dulrahaman Dia; (2007) : Elsevi- revealed a thigh mass and the aber, Gray anatomy for students- scess was treated by surgery. www.studentconsult.com,lower limb innervation, Pages 477-480. Conclusion In conclusion, the sciatic nerve 3- Casalia A. G., Carradori block in the popliteal fossa by a G., Moreno M., et al., (2006) : single injection using either the Techniques in Regional Anesthe- modified intertendinous approach sia and Pain Management, Elsevi- or the lateral approach by aid of er, October; Vol 10, No 4. the peripheral nerve stimulator and that have been proven to be 4- Mcloed D. H., Wong D. H. useful, simple, safe and reliable. W., Vaghadia H, et al., (1995) : But the use of U/S guided nerve Lateral popliteal Sciatic nerve block seemed to be more useful as block compared with ankle block it provides a higher success rate. for analgesia following foot surgery, Can. J. Anaesthesia; 42 : Using additive (clonidine and 765-9. hyaluronidase) with local anesthetic prolonges the duration of 5- Michaud J. M., Claridge J. sensory and motor block (cloni- R. and Kile A. T. (2005) : Anato- dine ) and speeds the onset of sen- my, Techniques in foot and ankle sory and motor block (hyaluroni- surgery lippincott. Williams & Wil- dase) . kins, Philadelphia, 4 (1); 18-21.

76 Benha M. J. Vol. 29 No 1 Jan. 2012 6- Buckenmaier C. C. and 11- Borgeat A., Blumenthal Bleckner L. L. (2005) : Anaes- S., Karovic D., et al., (2004) : thetic agents for advanced region- Clinical evaluation of the modified al anaesthesia. A North American posterior anatomical approach for perspective. Drugs; 65:745-59. performing the popliteal block, Reg. Anaesth.Pain Med, May-Jun; 7- Erlacher W., Schuschnig 29 (3): 290-6. C., Kapral S., et al., (2000) : The effects of clonidine on ropiva- 12- Palaniappan T., Vani S., caine 0.75% in axillary perivascu- Ravikumar S., et al., (2006) : lar plexus block. Acta Anaesthes- Comparison of Lateral Versus Pos- iol Scandinavica;44:53-7. terior Approach of Popliteal Nerve Block for Diabetic Foot Surgeries, 8- Nader A., Kendall C. M., Indian J. Anaesth.; 50 (4) : 262 - McCarthey J. R., et al., (2009) : 265. Randomized comparison of a modified intertendinous and clas- 13- Michael J. B., Christo- sic post. approach to popliteal pher D. A., Firoz V., et al., sciatic nerve block. Anaesth. (2010) : Ultrasound-Guided Sciat- Analg.; 108 : 359-63. ic Nerve Block in the Popliteal Fossa Using a Lateral Approach: 9- Zetloui P. J., et al., Onset Time Comparing Separate (1988) : lateral approach to sciat- Tibial and Common Peroneal ic nerve block in the popliteal fos- Nerve Injections Versus Injecting sa. Anesthesia Analgesia, 87:79- Proximal to the Bifurcation, 82. (Anesth Analg; 110:635-7).

10- Borgeat A., Blumenthal 14- Geffen G. J., van den S., Lambery M., et al., (2006) : Broek E., Braak G. J. J., et al. The Feasibility and Complications (2009) : A prospective randomized of the Continuous Popliteal Nerve controlled trial of ultrasound guid- Block in a 1001-Case Survey; An- ed versus nerve stimulation guid- esthesia Analgesia July vol. 103 ed distal sciatic nerve block at the no. 1 229-233. popliteal fossa. Anaesthesia and

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Intensive Care Jan; 37(1): 32-37. tive, randomized, double blind study, AANA journal / August / 15- Jacques T., YaDeau, Vin- vol.72, No. 4. cent R. LaSala and Leonardo Pa- roli et al., (2008) : Clonidine and 18- Keeler J. F., Canaes F., Analgesic Duration After Popliteal Simpson K., et al., (1992) : Effect Fossa Nerve Blockade : Random- of addition of hyaluronidase to ized, Double-Blind, Placebo Con- bupivacaine during axillary bra- trolled Study; (Anesth Analg; 106 : chial plexus block. British 1916-20. Journal of Anesthesia; Vol. 68, No. 168-71. 16- Colin J. L. and Edel Dug- gan (2007) : Should We Add Clon- 19- Tempestini H., Simonetti idine to Local Anesthetic for Pe- M. P., Rocha R. G., et al., ripheral Nerve Blockade? A (2008) : Hyaluronidase increases Qualitative Systematic Review of the duration of mepivacaine in in- the Literature Reg Anesth Pain ferior alveolar nerve blocks.J oral Med; 32:330-338. maxillofac Surgery, Feb; 66 (2) : 286-90. 17- Dareen J., LT Heather M., and LCDR John P., et al., 20- Compere V., Cornet C., (2004) : Addition of clonidine to Dureuil B., et al., (2005) : Case a femoral - sciatic nerve block Report thigh abscess as a compli- when given to facilitate postopera- cation of continuous popliteal tive analgesia in patients undergo- sciatic nerve block, Br J Anaesth; ing ACL reconstruction. prospec- 95: 255-6.

78 Benha M. J. REPRINTVol. 29 No 1 Jan. 2012 BENHA MEDICAL JOURNAL

POPLITEAL SCIATIC NERVE BLOCK FOR ANKLE AND FOOT SURGERY, A COMPARITIVE STUDY BETWEEN THE MODIFIED INTERTENDINOUS AND THE LATERAL APPROACHES

Ibrahim M. Abd Elmoeti MD, Mohamed Y. Serry MD, Ahmed Mostafa MD and Ahmed Hamdy M.Sc

Published by Benha Faculty of Medicine Volume 29 Number 1 Jan. 2012

79 Benha M. J. Vol. 29 No 1 Jan. 2012 MANSOURA EXPERIENCE IN PARTIAL ULNAR NERVE TRANSFER TO RESTORE ELBOW FLEXION IN UPPER TRUNK TRAUMATIC BRACHIAL PLEXUS INJURY

Yahia E. Bassiony MD, Mostafa A. El-Saied MD, Tarek A. El-Gammal MD*, Mohamed A. El-Said MD, Yaser Y. Abd El-Rahman MD and Khaled A. Nour M.Sc Departments of Orthopedic, Faculty of Medicine, Mansoura University & Assuit University*, EGYPT .

Abstract Purpose: Restoration of elbow flexion following upper trunk brachial plexus injury is a critical priority. Partial ulnar nerve transfer to musculocutaneous branch of biceps muscle is an innovating reconstructive procedure. We evaluate our results of this procedure in upper limb surgery unit in orthopedic department in Mansoura University Hospital. Method: Retrospective review was performed on 10 consecutive patients who had direct nerve transfer of a motor fascicle of ulnar nerve to the musculocutaneous branch of biceps muscle. Outcome assessment included recovery of elbow flexion. Results: Clinical evidence of reinnervation was noted at (3.9± 0.99) months ranging from 2 to 5 months after surgery. Mean follow up period was 2.2 years ranging from 2 to 3 years. 9 patients had biceps power graded at least as M4. Conclusion: Transfer of ulnar nerve fascicles to restore elbow flexion is a reliable technique.

Introduction nor of neurons and their axons, Nerve transfers (neurotization) which will reinnervate the distal involve the repair of a distal den- targets. The concept is to sacrifice ervated nerve element using a the function of a (lesser valued) proximal foreign nerve as the do- donor muscle to revive function in

79 Yahia E. Bassiony, et al... the recipient nerve and muscle structures. that will undergo reinnervation (1). 4. Major limb trauma with segmental loss of nerve tis- The first report of neurotization sue. in an attempt to restore injured 5. As an alternative to nerve plexus function was published by grafting when time from inju- Tuttle(2) in 1913. A review of the ry to reconstruction is pro- historical precedents as well as longed. the anatomical basis and rationale 6. Partial nerve injuries with a for nerve transfers in brachial defined functional loss; plexus surgery was most clearly 7. Spinal cord root avulsion presented 20 years ago by Nara- injuries. kas(3). Since then, nerve transfers 8. Nerve injuries in which the have become increasingly popular level of injury is uncertain, and used for the repair of BPIs, such as with idiopathic neuri- Specially in cases in which the tides or radiation trauma and proximal motor source of the den- nerve injuries with multiple ervated element is absent due to levels of injury. avulsion from the spinal cord(4). Rationale And Principles Of Susan Mackinnon(5) reported Neurotization the following indications for nerve The suitability of one nerve as a transfer in brachial plexus inju- donor in nerve transfer proce- ries: dures is determined predominant- 1. Brachial plexus injuries in ly by its anatomic proximity to the which only very proximal or brachial plexus elements, the ex- no nerve is available for graft- tent of brachial plexus damage, ing. the patient’s functional impair- 2. High proximal injuries that ment after donor nerve sacrifice, require a long distance for re- and the number of nerve fibers. generation. Although the functional relation- 3. Avoidance of scarred areas ship between the donor and recip- in critical locations with po- ient nerves is advantageous, cen- tential for injury to critical tral plasticity may be efficient in

80 Benha M. J. Vol. 29 No 1 Jan. 2012 producing useful functional recov- • Immobilization of the repair ery even if there is a great func- site is carried out until nerve fi- tional difference, such as in inter- bers have crossed from one stump costal nerves transfer. The into the other (2-3 weeks). technically ideal nerve transfer al- • Whenever possible, motor lows direct nerve anastomosis be- fascicles are connected to motor tween the donor and recipient fascicles. nerves. The relative efficiency of • Conjectural concerns are neurotization in humans is ex- the reciprocal proportion of num- plained by the fact that the neuro- bers and types of nerve fibers ver- tizer is severed with minimal trau- sus mass and numbers of muscle ma with a very sharp instrument, fibers in donors compared with far from the neuron. It is connect- those of recipients. These factors ed within minutes to the recipient probably influence power, speed, nerve; thus, the time during which and endurance in reinnervated its stump is in a pathologic state muscles. The musculocutaneous is minimal. This may favor the nerve contains approximately production of healthy vigorous 3000 motor fibers, of which 60% sprouts(6). are efferent and 40% afferent. Ideally it should be reinnervated Nerve regeneration following by the same number of nerve fi- nerve transfer relies on well- bers. known phenomena that govern • An anastomosis should be nerve repair. Certain principles performed as close to the recipi- must be respected in order to ent muscle as feasible. Greater achieve success(5-7): distances for axonal regeneration • An adequate neurosynthesis decrease the likelihood that an between the donor and recipient axon will remain on its intended nerves should be ensured so that course. Neurotization of cords the healthy proximal stump sup- and trunks has met with poor re- plies a maximal number of axon sults because there are too many sprouts to the distal stump. The opportunities for the regenerating latter is undergoing wallerian de- axon to travel along the wrong generation. pathway.

81 Yahia E. Bassiony, et al...

• Anastomosis should be per- 1. The reinnervation of the bi- formed as soon after the injury as ceps gives better results than possible. Atrophic changes are evi- palliative treatment. dent in denervated muscles soon 2. The closest normal nerve to after the injury, and by 2 years the biceps is the ulnar nerve. the muscle cells become fragment- This close proximity allows a ed and disintegrated. Controversy direct repair that results in exists as to how long after the ini- rapid reinnervation of the bi- tial injury surgery can be per- ceps. formed. Some authors reported a 3. The nerve of the biceps is 25% failure rate in neurotization very small and needs only a cases done 4 to 6 months after the thin fascicle for reinnerva- injury and 60% failure rate in tion. The selection of a suita- those performed 7 to 9 months. ble fascicle for transfer is facilitated by electrical stimu- In cases of upper-trunk palsy lation of the nerve during involving loss of shoulder function surgery. and the flexion of the elbow, the C5 and C6 roots are often found Patients and Methods avulsed from the spinal card and We present our experience in this precludes nerve grafting. In Mansoura University Hospital, in such cases, conventional surgery orthopedic department with 10 involved palliative procedures(8) consecutive cases of traumatic such as a Stiendler flexoplasty brachial plexus injury treated by combined with arthrodesis of the this set of nerve transfer, involving shoulder or nerve transfers to su- partial transfer of ulnar nerve to prascapular and musculocutane- biceps motor branch. ous nerves(1). This is a retrospective study of The transfer of some fascicles 10 consecutive cases of traumatic from the intact ulnar nerve to brachial plexus injury with lost the nerve to the biceps is a tech- active elbow flexion with good nique supported by several hy- hand function who presented to potheses(9): us within 10 months of injury

82 Benha M. J. Vol. 29 No 1 Jan. 2012 during period of 2006 and 2010. bachioradialis was graded as - The average age of patients M0 according to Medical Re- was (21.3) years. It varies search Council Scoring. from 5 to 49 years. - In 8 cases, supra and infra - They were all males. clavicular exploration was - In 9 cases the mode of injury performed. While direct neu- was road traffic accident rotization was performed in 2 while one patient was a vic- cases due to relatively pro- tim of traction injury by a longed denervation time. cart. - All the patients were right Technique handed. Left side was affected We use the original technique, in 9 cases, while right side 1st described by Oberlin(9). was affected in only one case. - The average denervation All the patients received anaes- time was (4.4) months, it var- thesia without muscle relaxation ies from 1 to 10 months. and maintained on opiod or isoflu- - The average follow up period rane. was (2.2) years, it varies from 2 to 3 years. The origin of the branch of the - A careful meticulous de- musculocutaneous nerve to the tailed history was taken from biceps muscle is marked on the all patients or their relatives, skin over the anterior aspect of including handeness, side of the arm, four centimeters distal to injury, mechanism of injury the humeral insertion of the pec- and denervation time. toralis major tendon. The skin is - Motor power examination of incised longitudinally over 8–10 muscles of upper limb was cm, straddling this point. The fas- assessed and recorded in bra- cia covering the biceps is incised, chial plexus sheet (fig. 1(10)). and the muscle is retracted later- - Sensory examination in all ally. The musculocutaneous nerve dermatomes was done and is approached between the biceps perception of pain and touch. and the coracobrachialis muscles. - In all patients biceps and The nerve to the biceps is identi-

83 Yahia E. Bassiony, et al... fied. Twelve centimeters is the sponse in the extrinsic flexors and mean distance from the acromion those corresponding to the intrin- to the origin of the nerve to the bi- sic muscles of the hand. In these ceps . The ulnar nerve is ap- cases, the fascicles innervating proached at the same level. Its the flexor carpi ulnaris are select- identification is formally assessed ed for transfer. This fascicle is of- by means of electrical stimulation. ten located anteriorly and medially Further dissection is performed within the ulnar nerve. The cho- under microscopic magnification. sen fascicle is separated from the rest of the ulnar nerve over 2 cm The branch(s) destined to the and divided distally (Fig. 2). The biceps are identified. Usually, the fascicle is turned laterally and su- vascular pedicle. to the biceps has tured to the nerve to the biceps, a more transverse orientation and with 10.0 nylon without any ten- does not interfere with the dissec- sion at the repair site. The nerve tion of the nerve. repair is performed in front of the brachial vascular bundle. The branch(s) to the biceps muscle is (are) split proximally Outcome assessment from the musculocutaneous nerve Strength of muscle was graded for approximately 2 cm and tran- using MRC scoring and range of sected. The distal part is then ro- movements was recorded with tated medially toward the previ- Goniometry. The range of elbow ously dissected ulnar nerve. flexion was measured as the angle formed between the long axis of The epineurium of the ulnar the arm and the forearm. Elbow nerve is incised. One (or two) fas- function were graded using the cicle(s) with an adequate size is scale proposed by Waikakul et al (are) selected. They are subjected (11)with minimal modification as to low intensity electrical stimula- shown in table (1). tion. It is possible to distinguish To detect any consequence of precisely between sensory and sectioning of ulnar nerve fascicles, motor fascicles. Usually, one is preoperative and postoperative able to locate fascicles with a re- grasping and key pinch strength

84 Benha M. J. Vol. 29 No 1 Jan. 2012 were compared and ulnar side power graded as at least M4 of hand sensibility was assessed. while only in one patient it was M2. Physiotherapy protocol - The average time required Stretching exercises are start- for clinical reinnervation of ed at three weeks and electrical biceps (flicker of movement) stimulation is started after 6 was (3.9±.99) months. weeks(12). - The details of patients and final grading of their elbow Results flexion are shown in table - 9 of ten patients have biceps (2).

85 Yahia E. Bassiony, et al...

Fig 1 : Brachial plexus chart (10)

Fig 2 : Motor fascicles of the ulnar nerve(arrow) are separated from the rest of the nerve over 2-3 cm distance and turned laterally towards the biceps motor branch (head arrow)

Fig 3: Clinical photo of case number 3 showing excellent results of elbow flexion. The patient could easily do more than 30 repetitions of elbow flexion with 2 kg weight.

86 Benha M. J. Vol. 29 No 1 Jan. 2012

Fig 4: clinical photo of case Fig 5: clinical photo of case number 5 showing results of el- number 6 showing results of elbow flexion . bow flexion.

Discussion jective or subjective sequlae of the In 1994 Oberlin and coworkers hand which is in accordance with introduced a new technique for the published studies. restoration of elbow flexion (13). They transferred about 10% of the Several aspects accounted for fascicles of ulnar nerve to the mo- the success of the proposed sur- tor branch of the biceps. Presence gery(20): of interfascicular connection pre- 1. The use of motor nerve vents any deficit in the ulnar transfers to recipient motor nerve distribution following this nerves, which avoided exterocep- procedure(13). Bertelli and Ghizo- tive sensory and motor mismatch- ni(14), Loy et al. (15), Leechaveng- ing. vongs et al. (16), Sungpet et al. 2. Nerve transfer performed (17), Kakinoki et al. (18) and Ven- close to the target muscle. This al- katramani et al. (19) have used lows faster recovery and distal in- this method in 10, 18, 15, 36, 8 spection of the recipient nerves, and 15 cases respectively with excluding double lesions and consistent good results. In our se- probably favoring the contact of ries, good and excellent results healthy donor and recipient were seen in 90% without any ob- nerves.

87 Yahia E. Bassiony, et al...

3. The use of synergistic nerve cess rate depends on the level transfer. Digital and wrist flexion of the intercostal nerve transac- is synergic to elbow flexion. More- tion, the number of nerves over, hand function (i.e., digital anatomosed, and use of nerve flexion) has a large cortical repre- graft. El-Gammal & Fathi (23) re- sentation. These aspects favor pa- ported good results in 89.5% tient postoperative re-education probably because three nerves and voluntary control of the trans- were used and they were di- fer. Conversely, when “clumsy” rectly coapted to the musculoc- nerves such as the intercostals utaneous nerve. Phrenic to mus- and phrenic nerves are used, vol- culocutaneous has a reported untary control may be acquired success rate of about 75% but only after several years(21); moreo- involuntary movements with res- ver, despite the acquisition of ac- piration and cough persist for tive control, respiration will per- about two years. Samardzic et al. manently influence muscular (24) reported 65% recovery rate target contraction(22). with spinal accessory to musculocutaneous nerve transfer and 4. Non use of nerve grafts. Waikakul et al. (11) reported good The use of nerve grafts in nerve recovery in 83% of their cases. transfer negatively affects the out- But since this, transfer necessi- come(13). tates use of nerve graft the reinnervation takes long time. In 5. Nerve coaptation performed Waikakul's (11) series the electro- without any tension, allowing limb myographic evidence of reinnerva- motion without rupture. Intraop- tion was first seen at an average of erative checking of the nerve coap- 11.5 months. tation after the patient’s limb motion should be performed The greatest advantage of ober- routinely. lin procedure is early recovery as nerve coaptation is done close to Success rate of intercostals to the target muscle without any in- musculocutaneous reported in lit- terposing graft. In our cases, the erature is 33–87% (23). The suc- site of coaptation was about 2 cm

88 Benha M. J. Vol. 29 No 1 Jan. 2012 from the biceps muscle(20). tion and results. Clin Orthop; 237: 43-56. Merrel et al.(25) in systematic review and meta-analysis of the [2] Tuttle H. K. (1913) : Expo- results of neurotization and nerve sure of the brachial plexus with graft in cases of traumatic brachi- nerve transplantation. JAMA; al plexus palsies, concluded that 61:15-17. results of restoration of elbow function improved with nerve [3] Narakas A. O. (1984) : transfer rather than autogenous Thoughts on neurotization or graft. They recommended direct nerve transfers in irreparable nerve transfer without exploration nerve lesions. Clin Plast Surg ; in patients with upper trunk bra- 11:153-159 . chial plexus injury without clinical or electromyographic evidence of [4] Songcharoen P. (1995) : recovery within 3-6 months after Brachial plexus injury in Thai- injury. land: a report of 520 cases. Micro- surgery ;16:35-39. Conclusion Use of ulnar nerve fascicles to [5] Weber R. V. and Mackin- restore elbow flexion is reliable non S. E. (2004) : Nerve transfer technique provided that the dener- in upper extremity. Am J Hand vation time does not exceed 10 Surg.; 4(3):200-213. months and the ulnar nerve function is not downgraded. [6] Samardzic M., Grujicic D., Rasulic L. and Bacetic D. T. Competing interests (2002) : Transfer of the Medial The authors declare that they Pectoral Nerve: Myth or Reality?. have no competing interests. Neurosurgery; 50(6): 1277-82.

References [7] Midha R. (2004) : Nerve [1] Narakas A. O. and Hentz transfers for severe brachial plex- V. R. (1988) : Neurotization in us injuries: a review. Neurosur- brachial plexus injuries. Indica- gery; 16( 5):1-10.

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[8] Alnot J. Y. and Oberlin C. [12] Venkatramani H., Bhard- (1991) : Muscular transfers in waj P., Faruquee S. R. and Sa- paralysis of elbow flexion and ex- bapathy S. R. (2008) : Function- tension. In: Tubiana R, ed. The al outcome of nerve transfer for hand, Vol. 4, R. Tubiana, ed. Phil- restoration of shoulder and el- adelphia : W. B. Saunders; 162- bow function in upper brachial 75. plexus injury. Journal of Brachial Plexus and Peripheral Nerve Inju- [9] Oberlin C., Ameur N. E., ry; 3:15. Teboul F., Beaulieu J. Y. and Vacher C. (2002) : Restoration of [13] Oberlin C., Beal D., Lee- elbow flexion in brachial plexus chavengvongs S., Salon A., injury by transfer of ulnar nerve Dauge M. C. and Sarry J. J. fascicles to the nerve to the biceps (1994) : Nerve transfer to bi- muscle. Techniques in Hand and ceps muscle using part of ulnar Upper Extremity Surgery; 6(2):86- nerve for C5-C6 avulsion of the 90. brachial plexus: anatomical study and report of four cases. J Hand [10] Alnot J. Y. (1995) : Surg [Am]; 19(2):232-237. Traumatic brachial plexus lesions in the adult: indications and re- [14] Bertelli J. A. and Ghizoni sults. In: Grossman JAI, ed. Bra- M. F. (2004) : Reconstruction of chial Plexus Surgery. Hand Clinics C5-C6 brachial plexus avulsion (Nov). WB Saunders: Philadelphia; injury by multiple nerve transfers: 623-32. XI to suprascapular, ulnar fascicle to biceps branch, and triceps long [11] Waikakul S., Wongtra- or lateral head branch to axillary gul S. and Vandurongwan V. nerve. J Hand Surg [Am]; 29A (2001) : Restoration of elbow flex- (1):131-139. ion in brachial plexus avulsion injury comparing spinal accessory [15] Loy S., Bhatia A., Asfa- nerve transfer with intercostals zadourian H. and Oberlin C. nerve transfer. J Hand Surg [Am]; (1997) : Ulnar nerve fascicle 24A(3):571-576. transfer onto to the biceps muscle

90 Benha M. J. Vol. 29 No 1 Jan. 2012 nerve in C5-C6 or C5 - C6 - C7 [19] Venkatramani H., Bhard- avulsions of the brachial plex- waj P., Faruquee S. R. and Sa- us. Eighteen cases. Ann Chir bapathy S. R. (2008) : Functional Main Memb Super; 16 (4) : 275 outcome of nerve transfer for res- - 84. toration of shoulder and elbow function in upper brachial plexus [16] Leechavengvongs S., Wi- injury. J Brachial Plex Peripher toonchart K., Uerpairojkit C., Nerve Inj.; 3:15. Thuvasethakul P. and Malung- paishrope K. (2006) : Combined [20] Bertelli J. A., Floriano´ nerve transfers for C5 and C6 polis., Ghizoni M. F. and Tu- brachial plexus avulsion injury. bara˜O. (2004) : Reconstruction J Hand Surg Am.; 31 : 183 - of C5 and C6 Brachial Plexus 9. Avulsion Injury by Multiple Nerve Transfers: Spinal Accessory to Su- [17] Sungpet A., Suphachat- prascapular, Ulnar Fascicles to Bi- wong C., Kawinwonggowit V. ceps Branch, and Triceps Long or and Patradul A. (2000) : Trans- Lateral Head Branch to Axillary fer of a single fascicle from the ul- Nerve. J Hand Surg Am.; nar nerve to the biceps muscle af- 29A:131-139. ter avulsions of upper roots of the brachial plexus. J Hand Surg [21] Narakas A. O. (1995) : Br.;25:325-8. Brachial plexus lesions. Microsur- gery in orthopaedic practice. [18] Kakinoki R., Ikeguchi R., Leung PC, Gu YD, Ikuta Y, Nara- Dunkan S. F., Nakayama K., kas A, Landi A, Weiland AJ. ed Matsumoto T., Ohta S. and Singapore: World Scientific; 188- Nakamura T. (2010) : Compari- 254. son between partial ulnar and intercostal nerve transfers for recon- [22] Malessy M. J. A., Van structing elbow flexion in patients Dijk G. and Thomeer RWTM. with upper brachial plexus inju- (1993) : Respiration related activi- ries. J Brachial Plex Peripher ty in the biceps brachii muscle Nerve Inj.; 5:4. after intercosta musculocutane-

91 Yahia E. Bassiony, et al... ous nerve transfer. Clin Neurol (2000) : Results of nerve transfer Neurosurg.; 95:95-102. to the musculocutaneous and axillary nerves. Neurosurgery.; [23] El-Gammal T. A. and Fa- 46:93-103. thi N. A. (2002) : Outcome of surgical treatment of brachial [25] Garg R., Merrell G. A., plexus injuries using nerve graft- Hillstrom H. J. and Wolfe S. W. ing and nerve transfers. J Re- (2011) : Comparison of nerve constr Microsurg.; 18(1):7-15. transfers and nerve grafting for traumatic upper plexus palsy: a [24] Samardzic M., Rasulic L., systematic review and analysis. J Grujicic D. and Milicic B. Bone Joint Surg Am.; 93:819-29.

92 Benha M. J. REPRINTVol. 29 No 1 Jan. 2012 BENHA MEDICAL JOURNAL

MANSOURA EXPERIENCE IN PARTIAL ULNAR NERVE TRANSFER TO RESTORE ELBOW FLEXION IN UPPER TRUNK TRAUMATIC BRACHIAL PLEXUS INJURY

Yahia E. Bassiony MD, Mostafa A. El-Saied MD, Tarek A. El-Gammal MD, Mohamed A. El-Said MD, Yaser Y. Abd El-Rahman MD and Khaled A. Nour M.Sc

Published by Benha Faculty of Medicine Volume 29 Number 1 Jan. 2012

93 Benha M. J. Vol. 29 No 1 Jan. 2012 PREDICTIVE VALUE OF TISSUE DOPPLER ECHOCARDIOGRAPHY IN DIFFERENTIATING PRIMARY DILATED CARDIOMYOPATHY FROM ISCHEMIC CARDIOMYOPATHY

Mohammed B. Shehab El-Din MD, Eman E. El-Safty MD, Maged Z. Amer MD and El-Saeed M. El-Saeed M.Sc. Department of Cardiology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.

Abstract Background: Differentiating ischemic from non-ischemic etiology of left ventricular dysfunction has important clinical and therapeutic implications. The gold standard method for such differentiation is the coronary angiography. Many non-invasive techniques were studied for this purpose; however, the results were always controversial. Aim of the work: To identify the accuracy of pulsed wave tissue Dop- pler imaging (PW-TDI), especially tricuspid annular velocities, as a non- invasive diagnostic tool in differentiation between primary and ischemic dilated cardiomyopathy. Patients and Methods: According to the results of coronary angiography, we studied 40 patients with ischemic cardiomyopathy (ICM group) and 40 patients with primary dilated cardiomyopathy (DCM group) and 20 healthy volunteers as a control group. All patients were subjected to thorough history taking, clinical examination, 12-lead surface electrocardiogram and most importantly echo-Doppler study. Results: In ischemic group there were statistically significant lower peak mitral annular systolic (Sa) and early diastolic (Ea) velocities in all studied portions of mitral annulus as well as their averaged values compared with DCM patients, with no significant difference between both groups regarding peak late diastolic (Aa) velocity. Also, there were significantly higher peak tricuspid annular systolic and late diastolic velocities with lower early diastolic velocity in ischemic group. The ratios of

93 Mohammed B. Shehab El-Din, et al... early to late diastolic annular velocities of both mitral and tricuspid valves were significantly lower in ischemic patients. Another two important parameters for diagnosing ischemic etiology in the present study were a) lateral tricuspid annular Sa velocity with a cut point of ≥ 8.5 cm/sec. which has 88% sensitivity and 93% specificity and b) the tricuspid to average mitral Sa ratio with a cut point of ≥ 1.2 which has 100% sensitivity and 95% specificity. Conclusion: RV dysfunction is more pronounced in patients with DCM than in patients with ICM. PW-TDI (especially of the tricuspid annulus) can be used as an easy, widely available and reproducible non- invasive technique for diagnosing ischemic etiology of heart failure. Key Words: Primary dilated cardiomyopathy; Ischemic cardiomyopathy; Tissue Doppler echocardiography.

Introduction methods for such differentiation Chronic heart failure (CHF) has are the presence of chest pain, emerged as the most prevalent ECG ischemic changes or resting cause of mortality, morbidity and segmental wall motion abnor- hospitalization in industrialized malities (SWMA) in patients with countries over the past years.1 ischemic cardiomyopathy.3 How- ever; this is not a fixed role. Chest Differentiation between the two pain, ECG ischemic changes main causes of CHF (ischemic and and SWMA may be present in primary cardiomyopathy) is a very up to two thirds of patients important issue. Patients with is- with non-ischemic cardiomyopa- chemic cardiomyopathy tend to thy, whereas patients with is- have a poorer prognosis because chemic cardiomyopathy might of the residual ischemia, and their have uniform hypokinesis.4 Sev- prognosis usually changes dra- eral non-invasive techniques matically when revascularization (i.e. echocardiography, dobuta- done, either surgically or interven- mine echocardiography, thallium- tionally.2 scintigraphy, positron emission tomography, magnetic resonance) The traditional non-invasive have been proposed to establish

94 Benha M. J. Vol. 29 No 1 Jan. 2012 the etiology of left ventricular dys- healthy subjects without any his- function, but the results are con- tory of cardiac symptoms or risk troversial and the optimal strategy factors and normal bed-side inves- remains unsettled.5 Tissue Dop- tigations (ECG and echo-Doppler). pler imaging (TDI) is an easy, They were 14 males and 6 females widely used, non-invasive, objec- with a mean age of 32.25 ± 7 tive promising tool for differentiat- years. Their parameters were taking ischemic from non-ischemic en as reference values. etiologies of cardiomyopathy.6 It does not only quantify left ventric- Regarding patients, there were ular function, but moreover, it is a 80 patients with evidence of heart promising objective tool in the de- failure (EF < 40%, LVEDD > 57 tection of RV dysfunction which is mm and ESD > 40 mm) which claimed to be a powerful predictor were furtherly divided according to of mortality in patients with CHF.7 the results of coronary angiogra- Accordingly, the present study phy into group II (ischemic cardi- aimed to identify the accuracy of omyopathy; ICM group) which tissue Doppler study (especially consists of 40 patients with signif- tricuspid annular velocities) as a icant epicardial coronary lesions non-invasive diagnostic tool in dif- (at least 70% narrowing in one or ferentiating primary from ischemic more of the major epicardial coro- cardiomyopathy. naries or 50% narrowing in the left main trunk)5 and group III (id- Patients and Methods iopathic dilated cardiomyopathy; The study is a case control ana- DCM group) which consists of 40 lytic randomized study that was patients with normal coronary an- conducted during the period from giogram.8 January 2010 to September 2011 in Cardiology Department, Faculty Exclusion criteria included pa- of Medicine; Mansoura University; tients with recent onset heart fail- Egypt. ure within 2 weeks, MI within 3 month, unstable angina within 1 This study included 3 groups; month, valvular heart disease, group I which consists of 20 congenital heart disease, atrial fib-

95 Mohammed B. Shehab El-Din, et al... rillation and left bundle branch method in 2-dimensional echocar- block (LBBB). diography.

All patients were subjected to Assessment of resting segmen- thorough history taking, clinical tal wall motion abnormalities examination, routine laboratory (SWMA) was recorded according to tests, chest X-ray, ECG, echo- the American society of Echocardi- Doppler study, pulsed-wave tissue ography criteria which divided LV Doppler imaging (PW-TDI) and into 16 segments. coronary angiography. To obtain tricuspid annular 1) Transthoracic conventional plane systolic excursion (TAPSE), echo-Doppler study: the apical four-chamber view was We used General Electric Sys- used, and an M-mode cursor was tem Vivid-3 machine having tissue placed through the lateral tricus- Doppler imaging capability with pid annulus in real time. Off-line, (2.5-5) MHZ probe at Mansoura the brightness was adjusted to Specialized Medical Hospital. The maximize the contrast between echocardiogram was performed the M-mode signal arising from with the patient breathing quietly the tricuspid annulus and the and lying in the left lateral posi- background. TAPSE was meas- tion. Simultaneously recorded ured as the total displacement of ECG renders the cardiac cycle the tricuspid annulus (in millime- phase reference. All standard ters) from end-diastole to end- views were obtained according to systole, with values representing the recommendation of American the average TAPSE of three to five society of Echocardiography.9 The beats.10 following measures were obtained guided by parasternal long axis Mitral and tricuspid regurgita- view; end-diastolic and end- tions were assessed quantitatively systolic diameters of the LV, RV by color Doppler according to sur- end-diastolic dimension. Left ven- face area of regurgitant jet as fol- tricular ejection fraction was ob- lows; mild regurge (grade I) if jet tained by using Simpson’s biplane area < 4 cm2, moderate regurge

96 Benha M. J. Vol. 29 No 1 Jan. 2012 (grade II) if jet are = 4-8 cm2, mod- apical 4 chamber view to obtain erately severe regurge (grade III) if septal and lateral angles, b) apical jet area > 8 cm2 and severe reg- 2-chamber view to obtain anterior urge (grade IV) if jet area > 8 cm2 and inferior angles. On studying and associated with retrograde tricuspid annulus, the sample vol- flow through pulmonary veins in ume was placed on its angle at the case of MR and through inferior lateral free wall of RV in the apical vena cava (IVC) in case of TR. 11 4-chamber view.

Pulmonary artery flow was re- To avoid beat-to-beat variations corded from parasternal short axis TDI measures were averaged over view by placing the sample volume three consecutive cardiac cycles. between the leaflet tips in the cen- For each annular site, we meas- ter of the flow stream and the ured peak TDI velocities in cm/s mean pulmonary artery pressure as the following; systolic velocity was calculated according to the (Sa), early diastolic filling velocity following equation; (Ea) and late diastolic filling veloc- PAMP= 80-1/2 acceleration time12 ity (Aa).13

2) Pulsed wave-tissue Doppler 3) Coronary angiography: imaging (PW-TDI): Coronary angiography was We obtained best quality of PW- done utilizing the retrograde per- TDI by minimizing the gain, by- cutaneous transfemoral technique passing the filter, and decreasing (Judkin's technique). The study the velocity scale to a range be- was carried out with Siemens im- tween - 20 and + 20 cm /s with a aging system and was stored us- sample gate of 2-4 mm and a ing a DICOM digital system. Multi- sweep of 100-150 mm/s, the sample angulated views of each ple volume was placed at the an- coronary artery were obtained. gles of the mitral valve annulus Coronary stenosis was evaluated with a special care to obtain an ul- qualitatively by an experienced ob- trasound beam parallel to the di- server, unaware of our study. A rection of the mitral annular mo- coronary stenosis was considered tion in the following views; a) significant when the vessel diame-

97 Mohammed B. Shehab El-Din, et al... ter was narrowed by ≥ 50% of left Figure 1 represents the differ- main trunk or by ≥ 70% of major ence between both groups regard- epicardial coronary vessels.5 ing the therapeutic history. Show- ing more use of anti-ischemic 4) Statistical analysis: drugs (nitrates, beta blockers, as- The SPSS statistical program pirin, colopidogrel and statins) in version 15 (SPSS Inc., Chicago, IL) ischemic group while anti-failure was used for statistical study. drugs (diuretics and digoxin) were Continuous variables were given more prescribed in the idiopathic as mean ± SD, and categorical group. variables were given as percentages. A value of P < 0.05 was consid- Table 2 represents the differ- ered statistically significant. A re- ence in echo-Doppler parameters ceiver operating characteristic between both groups. Showing curve (ROC) was constructed to that there were statistically signifi- establish the sensitivity and speci- cant higher chamber dimensions ficity of cut-off values for TDI pain idiopathic DCM group whereas rameters. there was no significant difference in EF and FS. Ischemic group Results showed significantly higher pul- Table 1 represents the dif- monary artery mean pressure ference between both groups (PAMP) and tricuspid annular regarding clinical and demo- plane systolic excursion (TAPSE) graphic criteria that showed sta- compared with idiopathic group. tistically significant younger age, Tricuspid regurge (TR) was signifi- higher heart rate, lower blood cantly more severe among patients pressure and more evident mani- with idiopathic DCM whereas festations of HF (dyspnea, con- there was no significant difference gested neck veins, lower limbs between both groups regarding oedema and cardiomegaly) in idio- mitral regurge (MR). pathic DCM compared with ischemic group. There was no sig- Table 3 represents PW-TDI nificant difference regarding sex parameters in both groups show- distribution. ing significantly lower peak mitral

98 Benha M. J. Vol. 29 No 1 Jan. 2012 annular systolic (Sa) and early tients. The ratios of early to late diastolic (Ea) velocities from diastolic annular velocities of both septal, anterior, inferior and lat- mitral and tricuspid valves were eral portions of the mitral an- significantly lower in ischemic pa- nulus in ischemic patients com- tients. pared with idiopathic DCM patients as well as their aver- Based on the ROC analysis aged values. There was no sta- (Fig. 3), lateral tricuspid annular tistically significant difference be- Sa velocity with cut point of ≥ 8.5 tween both groups regarding can be used as a distinguishing peak mitral annular late diastol- parameter for ischemic cardiomyo- ic (Aa) velocity from all recorded pathy with 88 % sensitivity and 93 portions of the mitral annulus as % specificity (Fig. 3a). The tricus- well as their averaged value. Re- pid to average mitral Sa ratio can garding tricuspid annular veloci- be used as another differentiating ties there were statistically signifi- parameter with a cut point of ≥ cant higher peak systolic and late 1.2 which has 100% sensitivity diastolic velocities whereas lower and 95% specificity for diagnosing early diastolic velocity in ischemic ischemic etiology of dilated cardi- patients compared with DCM pa- omyopathy (Fig. 3b).

99 Mohammed B. Shehab El-Din, et al...

100 Benha M. J. Vol. 29 No 1 Jan. 2012

Figure 1: represents the difference between both groups regarding the therapeutic history. Showing more use of anti-ischemic drugs (nitrates, beta blockers, aspirin, colopidogrel and statins) in ischemic group while anti-failure drugs (diuretics and digoxin) were more prescribed in the idiopathic group.

(A) (B) Figure 2: PW-TDI of lateral tricuspid annulus in a patient with ischemic cardiomyopathy (Fig.2a) and another with idiopathic dilated cardiomyopathy (Fig.2b) with reduced tricuspid systolic velocity in the patient with idiopathic dilated cardiomyopathy.

(A) (B)

Figure 3: Receiver-operating characteristic curves (ROC) for prediction of ischemic etiology in patients with dilated cardiomyopathy. a) Tricuspid Sa velocity, b) Tricuspid to average mitral Sa ratio.

101 Mohammed B. Shehab El-Din, et al...

Discussion are logic because therapy was pre- The present study aimed to scribed to ischemic patients based identify the accuracy of tissue on their angiographic evidence of Doppler study (especially tricuspid CAD, while DCM patients had annular velocities) as a non inva- more clinical and radiological sive diagnostic tool in differentia- manifestations of heart failure tion between primary and ischem- (dyspnea, tachycardia, hypoten- ic cardiomyopathy. In our study it sion, congested neck veins, lower was found that patients with ICM limb oedema and cardiomegally). were significantly older than those These results are in agreement with DCM. This is in agreement with those of previous series.15 with previous reports14 which explained this finding by the fact Regarding the history of angi- that acute coronary syndromes nal attacks and ischemic changes are more prevalent in older pain ECG, the present study re- tients unlike myocarditis which is vealed no statistically significant more prevalent in younger age difference in-between the two pa- population. Risk factors for is- tient groups. These results are chemic heart disease (IHD) were supported by Plewka et al5 who found to be more common in is- found that many patients with idi- chemic group but without statisti- opathic dilated cardiomyopathy cally significant difference (P value report episodes of angina and > 0.05). have electrocardiographic signs suggesting previous myocardial Anti-ischemic drugs (nitrates, infarction when there is extensive beta blockers, aspirin, colopido- left ventricular fibrosis even with- grel and statins) were more used out discreet myocardial scar. On in ICM patients whereas, anti- the other hand, these results failure therapy (diuretics and di- are discordant to that of Pirwitz et goxin) were more prescribed in al.16 who stated that the presence DCM group. There was no statisti- of any diagnostic Q wave had a cally significant difference be- positive predictive value of 92%, tween both patient groups regard- sensitivity of 57%, and specificity ing the use of ACEI. These results of 80% for identifying severe CAD.

102 Benha M. J. Vol. 29 No 1 Jan. 2012 Ventricular dimensions were Regarding atrioventricular (A- higher in DCM patients compared V) incompetence, there was with ICM group. These results are more severe tricuspid regurge in accordance to a previous report (TR) in DCM group in compari- that explained these findings by son to ICM, while there was no the more diffuse nature of myocar- significant difference between ditis in idiopathic DCM group con- both groups in the degree of mi- tradictory to the localized scar in tral regurgitation (MR). These find- the territory of occluded vessel in ings can be explained by larger di- case of ICM group17. mensions of RV in DCM patients leading to more dilatation of tri- There was no statistically sig- cuspid ring with more resultant nificant difference in prevalence of functional TR, whereas the resul- SWMA in the two groups. This re- tant rise in the degree of function- sult was in agreement with Diaz et al MR because of larger dimen- al.4 who reported that large areas sions of LV in DCM group is of scarring may also develop after nullified by occurrence of ischemic myocarditis and mild to moderate MR in ICM patients and this re- regional dyssynergy is common in sult coincides with the report of primary DCM. Whereas, global left weiland et al20 who demonstrated ventricular dysfunction occurs in that a large percentage of patients patients with diffuse coronary ar- with severe LV systolic dysfunc- tery disease. Another supporting tion have clinically relevant MR opinion was that of Vigna et al18 whatever the cause of left ventric- who do not agree that SWMA ular failure. alone is a reliable method for differentiation. On contrary, Medina et We found that DCM group has al19 reported that the presence of a significantly lower pulmonary SWMA by 2D echocardiography artery mean pressure (PAMP) com- had 83% sensitivity, 57% specific- pared to ischemic patients, which ity, and a 77% predictive accuracy can be explained by larger dimen- in detecting CAD in patients with sions of RV with more resultant DCM and thus in distinguishing TR and right sided heart failure ischemic from idiopathic DCM. (RSHF) that act as a decongestant

103 Mohammed B. Shehab El-Din, et al... factor for pulmonary bed. This re- Also, it was found that early di- sult was in accordance to Parchar- astolic annular velocity is lower in idou et al.21 ischemic group. This can be explained by the observation of As regards PW-TDI of the mitral Shan et al.,26 who stated that; in annulus, our study revealed that patients with ischemic left ventric- all segments which had been ular dysfunction systolic and early studied with tissue-Doppler diastolic velocities are strongly de- showed significantly smaller S- pendent on both the percent of in- wave in ICM than in DCM pa- terstitial fibrosis and the myocar- tients. Similar results were found dial beta-adrenergic receptor by other auothers.22,23 This re- density, which is abnormal in sult can be explained by the fact heart failure, whereas Schwarz et that ischemia is more affecting al.,27 observed an increase in fi- subendocardial layer which con- ber diameter in patients with idio- sists mainly of longitudinal fibers pathic cardiomyopathy. An in- leading to weaker long axis motion crease in fibrosis and reduction in of the heart with resultant smaller myofibrilar mass was not observed S-wave in ischemic patients.24 except when the ejection fraction The greater sensitivity of changes is markedly declined. in long-axis function over wall motion score index (WMSI) might Unlike the left ventricle, which have several explanations. The mi- shortens relatively in a symmetri- tral ring gives rise to a strong cal manner through the trans- echo, even when image quality is verse and longitudinal planes, suboptimal, so that systolic ampli- muscle fiber orientation of the tude and signals are simple to right ventricle dictates that con- quantify even in patients with traction occurs predominantly LBBB, thereby providing objective along the longitudinal plane.28 As and reproducible measure- a result, systolic displacement of ments.25 In contrast, WMSI analy- the tricuspid annulus toward the sis remains semi-quantitative and RV apex (longitudinal plane), re- dependent on operator experi- ferred to as tricuspid annular ence.3 plane systolic excursion (TAPSE),

104 Benha M. J. Vol. 29 No 1 Jan. 2012 closely correlates with RV ejection In DCM group, we found a fraction.29 Importantly, TAPSE statistically significant positive does not require geometric as- correlation between RV dysfunc- sumptions or RV endocardial defi- tion (represented by low tricus- nition, and thus has been found pid annular motion and veloci- to be highly reproducible and ty) and LV dysfunction practical30. Our study revealed (represented by low EF). On the that tricuspid annular systolic other side such correlation was motion (TAPSE) and velocity (S- absent in ischemic patients con- wave by PW-TDI) were signifi- firming the observation of previ- cantly higher in ICM patients in- ous reports that primary cardi- dicating that RV systolic func- omyopathy is a biventricular tion is preserved in ischemic disease.33 In addition, this result group unlike the idiopathic one. coincides with WHO definition This finding coincides with pre- of idiopathic dilated cardiomyopa- vious reports that reached the thy.8 In agreement with this defi- same result despite the different nition; another confirming result methods of measurement of RV of our study is the presence of a ejection fraction (multigated radio- significant positive correlation be- nuclide angiography31, thermodi- tween LV and RV dimensions with lution technique32 or cardiac lower LV/RV ratio in idiopathic catheterization33). group and absence of such correlation with higher LV/RV ratio in Diastolic dysfunction of both the ischemic one. ventricles (as evidenced by reversed Ea/Aa ratio at both mitral It is known that RV function is and tricuspid annuli) was signifi- strongly afterload dependent so cantly more prevalent in ischemic that an increase in pulmonary patients. This result could be ex- pressure translates into a de- plained by the fact that diastolic crease in RV systolic function.34 dysfunction precedes systolic one A negative correlation between in ischemic cascade. A similar re- pulmonary artery pressure and sult was found in a previous se- RV ejection fraction has been ob- ries.21 served in different series.35 In our

105 Mohammed B. Shehab El-Din, et al... series, a non significant negative present study with a cut point of correlation between pulmonary ar- 8.5 cm/s (or more) which has tery pressures and RV ejection 88 % sensitivity and 93 % specific- fraction was found in DCM pa- ity. Another important measure is tients, whereas the same two vari- the ratio of tricuspid annular sys- ables showed a significant nega- tolic velocity divided by averaged tive correlation in ischemic group. mitral annular systolic velocity Thus, among determinants of RV with a cut point of 1.2 (> or = 1.2) dysfunction, the relative role of which has 100% sensitivity and pulmonary hypertension is less 95% specificity for diagnosing is- relevant in DCM compared with chemic etiology of dilated cardiom- CAD for the same entity of LV dys- yopathy. function. On the basis of all these observations, we can conclude Study limitations: that RV systolic dysfunction in A limitation of velocity meas- CAD represents a marker for ad- urements by TDI is that these vanced disease, in which a signifi- data may be affected by cardiac cant role is played by an elevation rotation or whole heart motion. of pulmonary pressures. On the Our study evaluated RV longitudi- other hand, RV dysfunction may nal systolic function in apical 4- be found in earlier stages of idio- chamber view only, evaluation of pathic DCM as a consequence of other views might be beneficial the diffuse nature of the disease. inspite of its technical difficul- In this instance, RV dysfunction ties. seems to be related more to the entity of concomitant LV dysfunc- Conclusion tion than to pulmonary hyperten- Tissue Doppler echocardiogra- sion. phy is a quantitative, reproducible and non-invasive diagnostic tool Finally, we can say that ab- that could be complementary to sence of RV dysfunction (as evi- clinical and standard echocardio- denced by preserved tricuspid an- graphic findings in differentiating nular velocity) is the major ischemic from primary dilated car- characteristic sign for ICM in the diomyopathy.

106 Benha M. J. Vol. 29 No 1 Jan. 2012 References 6- Drozdz J., Ciesielczyk M., 1- Cleland J. G., Khand A. Kasprzak J., et al. (2000): Quan- and Clark A. (2001) : The heart titative evaluation of myocardial failure epidemic: Exactly how big contractility by tissue Doppler is it? Eur Heart J 22: 623 - 626. echocardiography. Kardiol Pol; / 53:/210-/4. 2- Agricola E., Oppizzi M., Pisani M. and Margonato A. 7- Gondi S. and Dokainish H. (2004) : Stress echocardiography (2007): Right ventricular tissue in heart failure. Cardiovasc Ultra- Doppler and strain imaging: sound; 2: 11-13. Ready for clinical use? Echocardi- ography; 24: 522- 532. 3- Gurevich M. A. and Gor- dienko B. V. (2003): Dilated and 8- Richardson P., McKenna ischemic cardiomyopathy: diffe- W., Bristow M., et al. (1996): rential diagnosis. Klin Med; 81: Report of the 1995 World 68-71. Health Organization/International Society and Federation of Cardiol- 4- Diaz R. A., Nihoyannopou- ogy Task Force on the Definition los P., Athanassopoulos G. and and Classification of the Cardi- Oakley C. M. (1991): Usefulness omyopathies. Circulation; 93 : of echocardiography to differen- 841-2. tiate dilated cardiomyopathy from coronary-induced congestive heart 9- Schiller N. B., Shah P. M., failure. Am J Cardiol; 68: 1224- Crawford M., DeMaria A., Dever- 1247. eux R., Feigenbaum H., Gutge- sell H., Reichek N., Sahn D., 5- Plewka M., Krzeminska- Schnittger I., Silverman N. H. Pakula M,Drozdz J., Ciesielczyk and Tajik A. J. (1989): Recom- M., Wierzbowska K. and Kaspr- mendations for quantitation of the zak J. D. (2005): Tissue Doppler left ventricle by two-dimensional echocardiographic identification of echocardiography. J Am Soc Ech- ischemic etiology in patients with ocardiogr; 2:358-367. dilated cardiomyopathy. Scandi- navian Cardiovascualr Journal; 10- Samad B. A., Alam M. 39: 334-341. and Jensen-Urstad K. (2002):

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Prognostic impact of right ventric- (1999): Prognostic value of noc- ular involvement as assessed by turnal, cheyne-stokes respiration tricuspid annular motion in pain chronic heart failure. Circula- tients with acute myocardial in- tion, 99: 1435. farction.Am J Cardiol;90:778-781. 16- Pirwitz M. J., Lange R. A., 11- Rivera J. M., Vadervoort Landau C., MeShack B. M., Hil- P. M., Morris E., et al. (1994): lis L. D. and Willard J. E. Visual, assessment of valvular re- (1996): Utility of the 12-lead elec- gurgitation: Comparison with trocardiogram in identifying un- quantitative Doppler measure- derlying coronary artery disease in ments. J Am Soc. Pchocardiogr 7: patients with depressed left ven- 480-487. tricular systolic function. Am J Cardiol. 77(15):1289-92. Erratum 12- Stevenson J. G. (1989): in: Am J Cardiol 1997;79(7): 1004 Comparison of several, non- invasive methods for estimation of 17- Ruan Q. and Nagueh S. pulmonary artery press. J Am. F. (2006): Usefulness of isovolum- Soc. Ecocardiogr 2:157-171. ic and systolic ejection signals by tissue Doppler for the assessment 13- Zamorano J. and Wall- of left ventricular systolic function bridge Dge J. (1997): Assessment in ischemic or idiopathic dilated of cardiac physiology by Tissue cardiomyopathy. Am J Cardiol; Doppler echocardiography. Eur. 97(6): 872-875. Heart J; 18: 330- 339. 18- Vigna C., Russo A. and 14- Windler E., Schöffauer M. De Rito V. (1996): Regional wall and Zyriax B. C. (2007): The sig- motion analysis by dobutamine nificance of low HDL-cholesterol stress echocardiography to distin- levels in an aging society at in- guish between ischemic and non- creased risk for cardiovascular ischemic dilated cardiomyopathy. diseases. Diab Vasc Dis Res; 4(2): Am Heart J; 131: 537-543. 136-142. 19- Medina R., Panidis I. P., 15- Lanfranchi, P. A., Braghi- Morganroth J., Kotler M. N. and roli, A., Bosimini, E., et al. Mint/. G. S. (1985): The value of

108 Benha M. J. Vol. 29 No 1 Jan. 2012 echocardiographic regional, wall butamine stress echocardiography motion abnormalities in detecting in distinguishing ischemic from coronary artery disease in patients non-ischemic dilated cardiomyo- with or without a dilated left ven- pathy. Med Pregl; 58: 541-547. tricle, Am, Heart J. Apr; 109 (4): 799-803. 24- Sutherland G., Di Salvo G., Claus P., et al. (2004): Strain 20- Weiland D. S., Konstam and strain rate imaging: a new M. A., Salem D. N., Martin T. T., clinical approach to quantifying Cohen S. R., Zile M. R. and regional myocardial function. J Das D. (1986): Contribution Am Soc Echocardiogr; 17:788-02. of reduced mitral regurgitant volume to vasodilator effect in severe 25- Christopher J. H., Lucia- left ventricular failure secondary no R. and Rosenhamer G. to coronary artery disease or idio- (1990): Functional importance of pathic dilated cardiomyopathy. long axis dynamics of the human Am J Cardiol. Nov 1;558:1046-50. left ventricle. Br Heart J; 63: 215.

21- Parcharidou D. G., Gian- 26- Shan K., Bick R., Poin- nakoulas G., Efthimiadis G. K., dexter B., et al. (2000): Relation Karvounis H., Papadopoulou K. of tissue Doppler derived myocar- N., Dalamanga E., Styliadis I. dial velocities to myocardial struc- and Parcharidis G. E. (2008): ture and beta-adrenergicreceptor Right ventricular function in is- density in humans. J Am Coll chemic or idiopathic dilated cardi- Cardiol; / 3:/891-/6. omyopathy. Circ J.; 72(2):238-44. 27- Schwarz F., Mall G., Zebe 22- Duncan A., O'Sullivan C. H., et al. (1983): Quantitative and Carr-White G. (2001): Long morphologic findings of the myo- axis electro-mechanics during do- cardium in idiopathic dilated car- butamine stress in patients with diomyopathy. Am J Cardiol; /51:/ coronary artery disease and left 501-/6. ventricular dysfunction. Heart; 86: 397-404. 28- Rushmer R. F., Crystal D. K. and Wagner C. (1953): The 23- Miloradovic V., Iric-Cupic functional anatomy of ventricular V. and Popovic A. D. (2005): Do- contraction. Circ Res; 1:162-170.

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29- Wahl A., Praz F., 32- Juilliere Y., Buffet P., Schwerzmann M., Bonel H., Marie P. Y., Berdcr V., Danchin Koestner S. C., Hullin R., N. and Cherrier F. (1994) : Schmid J. P., Stuber T., Delac- Comparison of right ventricular rétaz E., Hess O. M., Meier B. systolic function in idiopathic and Seiler C. (2011): Assessment dilated cardiomyopathy and of right ventricular systolic func- healed anterior wall myocardial, tion: Comparison between cardiac infarction associated with atheros- magnetic resonance derived ejec- clerotic coronary artery disease. tion fraction and pulsed-wave tis- Am J Cardiol, Mar 15; 73 (8): 588- sue Doppler imaging of the tricus- 90. pid annulus. Int J Cardiol.; 151 (1):58-62. 33- La Vecchia L., Zanolla L., Varrotto L., Bonanno C., et al. 30- Karatasakis G. T., Kara- (2001): Reduced right ventricular gounis L. A., Kalyvas P. A., Man- ejection fraction as a marker for ginas A., Athanassopoulos G. idiopathic dilated cardiomyopathy D., Aggelakas S. A. and Cokki- compared with ischemic left ven- nos D. V. (1998): Prognostic sig- tricular dysfunction. Am Heart J. nificance of echocardiographically 142:181-189. estimated right ventricular shortening in advanced heart failure. 34- Oakley C. (1988): Impor- Am J Cardiol; 82:329-334. tance of right ventricular function in congestive heart failure. Am J 31- Iskandrian A. S., Helfeld Cardiol; 62:14-9A. H., Lemlek J., Lee J., Iskandrian B. and Heo J (1992): Differentia- 35- Grose R., Strain J. and tion between primary dilated car- Yipintosoi T. (1983): Right ven- diomyopathy and ischemic cardi- tricular function in valvular heart omyopathy based on right disease: relation to pulmonary ar- ventricular performance. Am tery pressure. J Am Coll Cardiol; Heart J. Mar: 123 (3): 768-73. 2:225.

110 Benha M. J. REPRINTVol. 29 No 1 Jan. 2012 BENHA MEDICAL JOURNAL

PREDICTIVE VALUE OF TISSUE DOPPLER ECHOCARDIOGRAPHY IN DIFFERENTIATING PRIMARY DILATED CARDIOMYOPATHY FROM ISCHEMIC CARDIOMYOPATHY

Mohammed B. Shehab El-Din MD, Eman E. El-Safty MD, Maged Z. Amer MD and El-Saeed M. El-Saeed M.Sc.

Published by Benha Faculty of Medicine Volume 29 Number 1 Jan. 2012

111 Benha M. J. Vol. 29 No 1 Jan. 2012 POSTOPERATIVE COGNITIVE DYSFUNCTION IN DIABETIC VERSUS NON DIABETIC PATIENTS: EFFECTS OF PERIOPERATIVE BLOOD GLUCOSE CONTROL REGIMENS

Ahmed M. F. Hassan M.Sc.*, Gihan A. Tarabih MD, Mohammed A.E. Al-Hadedy MD, Mahmoud M. Othman MD and Golinar E. Hammouda MD Departments of Anesthesia and Surgical ICU*, Faculty of Medicine, Mansoura University, Egypt.

Abstract Introduction: Increasingly, postoperative cognitive dysfunction (POCD) is recognized as a complication after non cardiac surgery in the elderly. Diabetes is considered an independent risk factor for POCD. Aim of the work (Objective): This prospective, randomized study was designed to investigate the early and late post operative cognitive dysfunction (POCD) in patients with type 2 diabetes after major abdominal surgery with general anesthesia as a primary outcome. The possible effect of targeting intra operative blood glucose either more than 100 mg/dl or more than 150 mg/dl on POCD was the second outcome. Patients & Methods: 105 patients were enrolled for the study. 35 patients were allocated for non diabetic group. 70 patients were allocated for diabetic group. Diabetic patients were randomly assigned to continuous insulin infusion either (target glucose 100-150 mg/dl) or (target glucose 150-200 mg/dl). Patients undergoing different abdominal surgical procedures expected to be > 2 hours. Mini mental state examination (MMSE) test was administered 3 times: the day before surgery, postoperatively at 5- 7 day, and again 3 months later. The test was considered positive if change is more than 2S.D from basal. Results: The rate of early POCD development was 31.4% in the non diabetic group and 50% in diabetic patients. On the other hand, the rate of late POCD development was 13.6% in the non diabetic group,

111 Ahmed M. F. Hassan, et al...

36.9% in diabetic patients. Both MMSE1week scores and MMSE3month scores were insignificant when evaluated in the two diabetic groups. Conclusion: From the study we can conclude that, advancing age, duration of diabetes, postoperative pain and low education level were associated with early POCD while, advancing age and early POCD were risk factors for late POCD. No beneficial effect of the both intraoperative blood glucose control regimens among diabetic patients concerning performance in the (MMSE) test, while, duration of diabetes was the main determent of POCD occurrence. Key Words: postoperative cognitive dysfunction (POCD); diabetes mellitus; perioperative blood glucose control.

Introduction this field agreed that a variety of The early study of Bedford medications can precipitate acute (1955) on a retrospective obser- cognitive decline. Pre-existing pa- vational report for old patients tient factors as well as intra oper- who underwent surgery and an- ative and post operative changes esthesia, minor degrees of de- can be also involved e.g. age of pa- mentia were common in this tients, prior cognitive impairment, group of patients and 7% experi- type of surgery, duration of anes- enced extreme dementia. This was thesia, and peri-operative hypoxe- the first published data about this mia and hypotension(3). Postoper- issue (1). ative pain and methods to manage associated with cognitive decline, The majority of researches on so proper management of postop- POCD had focused on cardiac sur- erative pain has particular inter- gery, but similar cognitive changes est to minimize its incidence(4). were reported with off pump cardiac surgery(2). The study of POCD Among patient related and pre- associated with non cardiac sur- existing factors, diabetes has been gery is still in its infancy and the claimed for possible decline in field is relatively new. The etiology cognition. Abnormalities in cogni- of POCD and delirium is still not tive functions mediated by frontal understood, but most of studies in lobe (executive functions), includ-

112 Benha M. J. Vol. 29 No 1 Jan. 2012 ing a number of complex behav- betic group of patients following iors such as problem solving, non cardiac surgery. planning, organization, reasoning, and attention, are noted in pa- The association between acute tients with diabetes(5). Diabetes is hyperglycemia and impaired cog- associated with rapid fluctuation nitive function(7), raised a second of blood sugar and as the brain is question, can control of blood glu- dependent on continuous flow of cose through continuous insulin glucose as it is the principle infusion in perioperative period source of energy, changes of blood provide a protection against the glucose concentration can rapidly expected decline in cerebral func- affect cerebral function. Evidence tions and minimizing the POCD in is accumulating that diabetic pa- this group of patients or not? tients are at high risk of developing cognitive impairment. This is Patients and Methods probably a consequence of inter- After institutional approval, in- action between metabolic derange- formed consents were obtained by ment associated with diabetes and all participants in this prospective functional changes of CNS as trial. apart of normal aging process(6). • The first group (non diabetic group): ASA I & II surgical pa- Sommerfield AJ and col- tients. leagues(7), reported that acute hy- • The second group: type 2 di- perglycemia impair cognitive per- abetic patients. formance in people with type II diabetes mellitus, so diabetic pa- Patients included in this group tients if exposed to stress of anes- were divided randomly using com- thesia and surgery might have dif- puter generated, random lists ac- ferent patterns of postoperative cording to blood glucose control cognitive impairment. No previous regimen during the operation time trial investigates this issue before. into two subgroups. In this study a prospective clinical 1- Group BG>100 : the target trial was carried out to compare blood glucose concentration was the POCD in diabetic and non dia- 100-150 mg/dl. If blood glucose

113 Ahmed M. F. Hassan, et al... levels exceeded 150 mg/dl, a con- disease with residual deficit, un- tinuous insulin infusion was ini- controlled hypertension, alcohol- tiated. Adjustments to the insulin ism, psychiatric illness, cardiac infusion were determined by both disease defined as ejection frac- the current blood glucose concen- tion less than 50%, renal disease trations and insulin infusion (defined as creatinine > 2 mg/dL), rates (8). liver cirrhosis and liver dysfunction (defined by a serum total bi- 2-Group BG>150: the target lirubin concentration >2.0 mg/ blood glucose concentration was dL), less than six years of educa- 150-200 mg/dl. If blood glucose tion, or certain types of surgery levels exceeded 180 mg/dl, a con- e.g. cardiac, carotid artery, thyroid tinuous insulin infusion was ini- or cranial surgery. Additional ex- tiated. Adjustments to the insulin clusion criteria included a score of infusion rate (9). 23 or less on the mini-mental state examination (MMSE) before During the intraoperative peri- surgery. od, the infusion of dextrose was maintained at the rate 5 g/h for Preoperative management: the both groups. All patients were clinically examined and routine laboratory in- Inclusion criteria: vestigations for inclusion criteria Adult patients of both sexes were done before surgery. ranging in age from 50 to 70 yr were exposed to different abdomi- Diabetic patients were preoper- nal surgical procedures expected ativelly controlled and the level of to be > 2 hours and the duration fasting blood sugar before the op- of diabetes was not less than 4 eration was below 150 mg/dl. Oral years for the diabetic groups were hypoglycemics and normal subcu- included in the study. taneous insulin were stopped 1-2 days before operation. Exclusion criteria: Patients were excluded if they Anesthetic management: had a history of cerebrovascular Standard monitoring included

114 Benha M. J. Vol. 29 No 1 Jan. 2012 three-lead ECG, pulse oximetry, mean arterial blood pressure), noninvasive arterial pressure were measured immediately before measurements, and the measure- the induction of anesthesia and ment of end-tidal carbon dioxide, were recorded every 15 min. and anesthetic gas concentrations. Pos-operative data 1- Hemodynamics (heart rate Analgesia was carried out ei- and mean arterial blood pressure), ther with preemptive single epidu- and blood glucose level were re- ral injection of bupivacaine and corded every 30 min for two hours fentanyl or intraoperative incre- in PACU. ments of intra venous fentanyl 20 2- Axillary body temperature. ug every 30-40 min. 3- Pain was estimated by using a 100-mm visual analog scale All patients received intra- (VAS) (with 0 mm representing no venous midazolam 0.03 mg kg-1, pain and 100 mm representing fentanyl 1ug kg-1, thiopentone so- the worst imaginable pain). dium 5-6 mg kg-1, and rocronium 0.6 mg kg-1 then 0.1 mg kg-1 Cognitive test: when needed. Maintenance of an- Mini mental state examination esthesia was carried out with Iso- (MMSE) test (10), was adminis- flurane with air and O2 mixture tered 3 times: the day before sur- Fio2 0.35. Residual neuromuscu- gery, postoperatively at 5- 7 day, lar block was antagonized with and again 3 months later. 0.04mg kg-1 neostigmine and 0.02mg kg-1 atropine at the end of Statistical Analysis: operation. Power analysis was performed by G power program version Intra-operative data: 3.0.4.The sample size was based Blood glucose concentration on estimated enrollment over 30 was measured immediately after months period for diabetic pa- the induction of anesthesia and tients exposed to 2 different blood was repeated every 30 min. Hemo- glucose levels during major ab- dynamic data (heart rate and dominal surgery and postoperative

115 Ahmed M. F. Hassan, et al... cognitive dysfunction was studied dysfunction in diabetic patients. as a primary outcome variant. A Estimate of adjusted odds ratios post. hoc power analysis showed (ORS), 95% confidence interval that the study had 78% power to (CIS) and results of likelihood get effect size convention 0.3 at an tests for significance were com- α-error of 0.05. pared.

The description of the data was The statistical analysis of data done in form of mean ± SD, Fre- done by using SPSS program (sta- quency (proportion) and median tistical package for social science (IQR). Kolmogorov Smirnov (K-S) Inc, Chicago, IL version 16). Sta- test was used to test the normal tistical significance was consid- distribution of data. One way ered at p < 0.05. ANOVA test was applied to compare demographic, preoperative Results and immediate postoperative in- This study was conducted on vestigations in the three studied 105 adult patients of either sex, groups. Kruskals- Wallis test was with an age ranging from 50 to 70 used for analysis of mini mental years, were exposed to different state examination (MMSE) scores abdominal surgical procedures ex- followed by Mann- Whitney U-test pected to be > 2 hours and the for intergroup significant differ- duration of diabetes was not less ence. Wilcoxon Rank Sum Test than four years for the diabetic was used for intragroup differ- patients. Patients of the three ence. Chi- square test was applied groups showed no significant dif- for categorical data. ferences concerning age, sex, BMI, levels of education, history of hy- Factors found to be statistically pertension or smoking. Also pa- significant from univariate analy- tients of the two diabetic groups sis were fitted in a multivariable were comparable concerning dura- logistic regression model in a for- tion of diabetes and their associat- ward stepwise selection manner ed therapy (table 1). for analysis of independent risk factors of postoperative cognitive Tables 2 and 3 show periopera-

116 Benha M. J. Vol. 29 No 1 Jan. 2012 tive investigations that include late MMSE3 month scores after 3 blood hemoglobin, hematocrit, months postoperatively were lower serum sodium and serum potas- than basal MMSE scores but not sium, serum creatinine, serum al- reach statistically significant in bumin and liver enzymes. There the three studied groups. Both was no significant difference be- MMSE1 week scores and MMSE3 tween the studied three groups month scores were insignificant whether in the preoperative or in when evaluated in the two diabetic the immediate post operative peri- groups (table 5). od. The rate of early POCD develop- As regard to the table 4, seven ment was 31.4% in the non dia- patients of BG>100 group showed betic group and 50% in diabetic (1-2) episodes of blood glucose patients. On the other hand, the less than 65 mg/dl. However, only rate of late POCD development two patients in that group showed was 13.6% in the non diabetic one and two events of blood glu- group, 36.9% in diabetic patients cose more than 200mg/dl. On the distributed as 30% in the BG>100 other hand, in BG>150 group no group and 43.4% in the BG>150 patients showed blood glucose group (table 6). less than 65mg/dl and 9 patients showed episodes of blood glucose Table (7) shows univariate more than 200mg/dl. The hypo- analysis of possible associated tension was comparable in the risk factors. Neither hypoglyce- studied groups. mic, hyperglycemic nor hypotension episodes has significant risk Basal mini mental state exami- factors for early (POCD). Howev- nation (MMSE) score was signifi- er, age >60 years, duration of di- cantly lower in the two diabetic abetes >10 years, education level groups when compared with the ≤ 12 years, anesthesia time >3 non diabetic group. The early hours, post operative pain (VAS MMSE1 week scores were signifi- ≥ 30) are significant risk factors cantly lower than basal in the for early (POCD). These risky fac- three studied groups. However, tors were fitted in the multivaria-

117 Ahmed M. F. Hassan, et al... ble logistic regression model (table POCD, neither hypoglycemic, hy- 8). Patients with age > 60 years perglycemic nor hypotension epi- had 2.6 time higher risk for early sodes has significant risk factors POCD development if compared for POCD. However, age > 60 with patients aged <60 years (CI years, duration of diabetes > 10 95% 1.047-6.004). Also patients years, education level ≤ 12 years with longer duration of diabetes and early POCD are significant had 2.3 times higher risk for early risk factors for late (POCD) (table POCD development in comparison 7). These significant risk factors with duration of diabetes < 10 were entered in a multivariable lo- years (CI 95% 1.237-5.9). Addi- gistic regression model (table 9). tionally, patients who developed Patients aged > 60 years continue postoperative pain had higher risk to have higher risk for POCD if for early POCD development (CI compared with patients aged < 60 95% 1.193-7.187). However, low years (CI 95% 1.071-32.381). Also education level reveals a strong patients who developed early association for early POCD devel- POCD had approximating 49 opment (CI 95% 1.193-7.187). times higher rate for late POCD development (CI 95% 4.558- In univariate analysis of late 53.043).

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Discussion 45.70% in the BG>100 group and The current results indicate 54.30% in the BG>150 group. On that advancing age, duration of di- the other hand, the rate of late abetes, postoperative pain and low POCD development was 13.6% in education level were associated the non diabetic group, 36.9% in with early POCD while, advancing diabetic patients distributed as age and early POCD were risk fac- 30% in the BG>100 group and tors for late POCD. Also this study 43.4% in the BG>150 group. showed that, the rate of early POCD development was 31.4% in In this study, basal MMSE the non diabetic group and 50% in score was significantly lower in diabetic patients distributed as the two diabetic groups when

122 Benha M. J. Vol. 29 No 1 Jan. 2012 compared with the non diabetic ternational Study of Postoperative group. This finding is in accor- Cognitive Dysfunction (ISPOCD1) dance with previous study which which evaluated cognitive decline studied 60 diabetic patients, in 1,218 elderly patients, aged 60 amongst whom, 30 had a well- yr or older, who had undergone controlled diabetes status and the major noncardiac surgery, and other 30 had not. These patients found that cognitive dysfunction were compared to 60 non-diabetic was present in 26% of older pa- controls whose age, sex and edu- tients 1 week after surgery and in cational class matched with the 10% 3 months after surgery (12). individuals of the first group and Dijkstra et al., (13) investigated concluded that, subjects with di- the severity and character of post- abetes had lower MMSE score operative cognitive dysfunction af- than those without diabetes (11). ter major non cardiac surgery in While there were no significant patients older than 65yr at one differences between postoperative week after surgery 27% of patients MMSE scores (MMSE1week and develop POCD and 8% of patients MMSE 3 month) in the two dia- develop POCD three months after betic groups indicating that there surgery which nearly similar to was no beneficial effect of the two our results. In another study, 336 glucose control regimens concern- elderly patients (median age 69 ing MMSE score. This may ex- years, range 60-86) was studied plained by the main determent of after major surgery under general cognitive performance among dia- anesthesia. Cognitive dysfunction betic patients is the long dura- was found in 80 out of 322 pa- tion of the disease as shown in tients tested one week after sur- (table 7). gery by the rate of 24.8%. At the 2nd postoperative test 3 months The present study demonstrat- after the operation, cognitive dys- ed that, the rate of cognitive dysfunction was found in 33 out of function was 31.4% at 1 week and 326 tested patients by the rate of 13.6% at 3 months after surgery 10.3% which nearly similar to our in non diabetic patients. The re- result (14). While the prevalence of sults are nearly similar to the In- cognitive dysfunction was 50% at

123 Ahmed M. F. Hassan, et al...

1 week and 36.9% at 3 months af- operative cognitive decline, and ter surgery in diabetic patients. were documented that one of the This finding is nearly similar to main pre-operative predisposing previous results documented that factors was primarily found to be that rate of early POCD is 50% advanced age. Elderly patients and rate of late POCD 23.3% in di- may have preexisting conditions abetic patients (15). or limited cognitive reserve to cope with the physiologic challenges of Our results show, advanced anesthesia and surgery (18). The age has been identified as a risk aged human brain differs from the factor for both early and late younger adult brain in several re- POCD development. This result spects, including size, distribution runs parallel to Monk et al., (16) and type of neurotransmitters, who studied one thousand sixty- metabolic function, and capacity four patients aged 18 yr or older for plasticity, suggesting that it completed neuropsychological might be more susceptible to an- tests before surgery, at hospital esthetic mediated changes (19). discharge, and 3 months after surgery. Patients were categorized In our study, the duration of di- as young (18-39 yr), middle-aged abetes was a stronger determinant (40-59 yr), or elderly (60 yr or old- for early POCD development. This er) and concluded that the elderly result in agreement with Roberts patients had a higher incidence of RO et al., (20) who were compared POCD than the middle-aged pa- 329 subjects having mild cognitive tients. Also, similar results were impairment with 1640 subjects reported by Bitsch et al.,(17) who free of mild cognitive impairment studied one hundred hip fracture and dementia. And founded that, patients. Patients were tested cognitive impairment was asso- upon admission and on the sec- ciated with DM duration of 10 ond, fourth and seventh post- years or longer. Long duration of operative days with the mini men- DM may be associated with great- tal state examination (MMSE) er cerebral macrovascular disease, score. Thirty-two per cent of pa- clinical cerebral infarctions, and tients developed a significant post- subclinical infarctions that may

124 Benha M. J. Vol. 29 No 1 Jan. 2012 impair cognitive functions (21). controlled analgesia in the elderly after major abdominal surgery In this study, patients with low and concluded that, the epidural education level had greater risk route using local anesthetics and for early POCD development when an opioid provides better pain re- compared to that high education lief and improves mental status. level. Our study confirms the find- Another study, demonstrated that ings of ISPOCD1, which found the incidence of POCD at 1week that advancing age and lower edu- was significantly lower in elderly cational levels are risk factors for patients undergoing minor sur- the development of cognitive de- gery than major surgery and one cline after noncardiac surgery (12). of several factors may be im- One proposed theory for this rela- portant to explain differences in tionship involves the concept of rates of POCD between major and cerebral cognitive reserve; howev- minor surgery is postoperative er, it is not clear how a greater pain (23). number of years of education translates to a cognitive reserve. In this study, hypotensive epi- Education presumably increases sodes during surgery have no in- the synaptic density in the neocor- fluence on POCD development as tex by recruiting neurons, increas- MAP < 60 mmHge did not show ing neuronal communication, and any significant risk for early POCD minimizing the signs of cognitive development. This result in accor- and functional impairment. Thus dance with Williams-Russo et al., the educational level serves as a (24). who evaluated the impact of marker of cognitive reserve (18). intraoperative hypotension on POCD by studying a group of hy- In our study, postoperative pertensive patients undergoing pain carries risk for early POCD major orthopaedic surgery. MAP development. Our results are in was maintained at either 45-55 or agreement with those reported 55-70mmHg, which was substan- with Mann c et al., (22). who con- tially lower than the patients’ nor- ducted a study of comparison of mal level, but no significant differ- intravenous or epidural patient ence in the occurrence of POCD

125 Ahmed M. F. Hassan, et al... was found. The first international study, duration of anesthesia was study of postoperative cognitive a significant risk for POCD at 7 dysfunction (ISPOCD1) revealed days. In that study the incidence that perioperative hypotension of POCD at 1 week was 18% when (mean arterial pressure < 60% of the duration was less than 2 h basal for >30 minutes) was not and 27% when the duration was significant risk factor for the de- longer (12). This difference may be velopment of POCD (12). attributable to the higher median age 68 (61-79) and longer dura- Additionally, Hypoglycemia BG tion of anesthesia which more ≥60 mg/dl carries no risk for than 241min in 33% of patients POCD in our study. The usually than in our study. Also Smith et short duration of hypoglycemia al., (26) studied the mental func- and the capability of the brain to tion after general anaesthesia for use alternative substrates during transurethral procedures founded hypoglycemia might explain this that duration of anesthesia (mean finding. This finding concluded by 30.9 min) was not a contributing a study was investigated the effect risk factor for mental dysfunction of infusing lactate (a potential after transurethral procedures in non-glucose fuel for brain metabo- elderly patients and the risk of lism) on protective, symptomatic POCD probably increases when neurohumoral responses and on surgery lasts longer than 1 h. brain function during hypoglyce- This may be explained by the dif- mic episodes. Lactate was asso- ference of the surgical procedures ciated with a significant lowering of that study which may be play a of the glucose level at which brain role of cognition performance. Also function deteriorated, suggesting this result is in contrast to previ- that brain function was protected ous study that investigated cogni- during the hypoglycemia (25). tive dysfunction 1-2 years after non-cardiac surgery in 336 the Our data illustrate the duration elderly patients after major sur- of anesthesia more 3 hours was gery under general anesthesia not found a significant risk for that documented that 18% of pa- POCD. In contrast to the ISPOCD1 tients whom duration of anesthe-

126 Benha M. J. Vol. 29 No 1 Jan. 2012 sia less than 120 min were not de- clude that, advancing age, dura- veloped POCD at one week postop- tion of diabetes, postoperative erative in contrast to 33% patients pain and low education level were whom duration of anesthesia associated with early POCD while, more than 240 min were devel- advancing age and early POCD oped POCD at one week postoper- were risk factors for late POCD. ative (14). This is may be attribut- No beneficial effect of the both ined to the higher median age of traoperative blood glucose control patients of that study 69 years, regimens among diabetic patients range 60-86 y than in the current concerning performance in the study and the duration of anes- (MMSE) test, while, duration of di- thesia at which POCD is more abetes was the main determent of prominent was more than 4 hours POCD occurrence.

We found a significant correla- References tion between early POCD (7 days (1) Bedford P. D. (1955) : Ad- postoperative) and late cognitive verse cerebral effects of anesthesia dysfunction (3 months later) and on old people. Lancet; 2:259-63. this result supported by a previous study documented that the (2) Jensen B. O., Hughes P., patients with early POCD were at Rasmussen L. S., et al. (2006) : significantly greater risk for long- Cognitive outcomes in elderly term cognitive dysfunction (14). high-risk patients after off-pump Surprising there is only one pa- versus conventional coronary ar- tient had late POCD without de- tery bypass grafting: A random- veloping early POCD and this find- ized trial. Circulation; 113:2790-5. ing may be attributed to, some patients may be able to compen- (3) Fong H. K., Sands L. P., sate for a period of time and then leung J. M. (2006) : The Role of relapse into the group fulfilling Postoperative Analgesia in Deliri- the criteria for cognitive dysfunc- um and Cognitive Decline in Eld- tion (14). erly Patients: A Systematic Re- view. Anesth Analg; 102 : 1255- From the study we can con- 66.

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(4) Johnson T., Monk T., Ras- (9) Subramaniam B., Panzica mussen L., et al. (2002) : Postop- P. J, Novack V., et al. (2009): erative cognitive dysfunction in Continuous Perioperative Insulin middle-aged patients. Anesthesio- Infusion Decreases Major Cardio- logy; 96:1351. vascular Events in Patients Un- dergoing Vascular Surgery A Pros- (5) Stewart R. and Liolitsa D. pective, Randomized Trial. (1999) : Type 2 diabetes mellitus, Anesthesiology; 110:970-7. cognitive impairment and dementia. Diabet Med.; 16:93-112. (10) Folstein M. F., Folstein S. E. and McHugh P. R. (1975): (6) Munshi M., Grande L., "Mini-mental state". A practical Hayes M., et al. (2006) : Cogni- method for grading the cognitive tive Dysfunction Is Associated state of patients for the clinician. With Poor Diabetes Control in Old- J Psychiatr Res; 12:189-98. er Adults. Diabetes Care; 29:1794-99. (11) Ebady S. A., Arami M. A. and Shafigh M. H. (2008) : In- (7) Sommerfield A. J., Deary vestigation on the relationship be- I. J. and Frier B. M. (2004) : tween diabetes mellitus type 2 and Acute Hyperglycemia Alters Mood cognitive impairment. Diabetes State and Impairs Cognitive Per- Res Clin Pract.; 82:305-9. formance in People With Type 2 Diabetes. Diabetes Care; 27:2335- (12) Moller J. T, Cluitmans P, 40. Rasmussen L. S., et al. (1999): Long-term postoperative cognitive (8) Ouattara A., Lecomte P., dysfunction in the elderly IS- Le Manach Y., et al., (2005) : POCD1 study. Lancet; 351:857- Poor Intraoperative Blood Glucose 61. Control Is Associated with a Worsened Hospital Outcome after (13) Dijkstra J. B., Houx P. J. Cardiac Surgery in Diabetic Pa- and Jolles J. (1999) : Cognition tients. Anesthesiology; 103 : 687- after major surgery in the elderly: 94. test performance and complaints.

128 Benha M. J. Vol. 29 No 1 Jan. 2012 Br J Anaesth. ; 82:867-74. dysfunction in the elderly. Anes- thesiol Clin. ; 27:485-96. (14) Abildstrom H., Rasmus- sen L. S., Rentowl P., et al. (19) Mrak R. E., Griffin S. T. (2000) : Cognitive dysfunction 1-2 and Graham D. I. (1997) : Aging- years after non-cardiac surgery in associated changes in human the elderly. Acta Anaesthesiol brain. J Neuropathol Exp Neurol.; Scand. ; 44:1246-51. 56: 1269-75.

(15) Kadoi Y., Kawauchi C., (20) Roberts R. O., Geda Y. Ide M., et al. (2011): Preoperative E., Knopman D. S., et al. depression is a risk factor for (2008) : Association of duration postoperative short-term and and severity of diabetes mellitus long-term cognitive dysfunction in with mild cognitive impairment. patients with diabetes mellitus. J Arch Neurol.; 65:1066-73. Anesth. ; 25:10-7. (21) van Harten B., Ooster- (16) Monk T. G., Weldon B. man J. M., Potter van Loon B. C., Garvan C. W., et al. (2008): J., et al. (2007) : Brain lesions on Predictors of cognitive dysfunction MRI in elderly patients with type 2 after major noncardiac surgery. diabetes mellitus. Eur Neurol. ; Anesthesiology ; 108:18-30. 57:70-74.

(17) Bitsch M. S, Foss N. B., (22) Mann C., Pouzeratte Y., Kristensen B. B. and Kehlet H. Boccara G., et al. (2000): Com- (2006) : Acute cognitive dysfunc- parison of intravenous or epidural tion after hip fracture: frequency patient-controlled analgesia in the and risk factors in an optimized, elderly after major abdominal sur- multimodal, rehabilitation pro- gery. Anesthesiology. ; 92433-41. gram. Acta Anaesthesiol Scand. ; 50:428-36. (23)Canet J., Raeder J., Ras- mussen L. S., et al. (2003) : Cog- (18) Ramaiah R. and Lam A. nitive dysfunction after minor M. (2009): Postoperative cognitive surgery in the elderly. Acta Anaes-

129 Ahmed M. F. Hassan, et al... thesiol Scand; 47: 1204-1210. Lomas J., et al. (1994) : Protec- tion by lactate of cerebral function (24) Williams-Russo P., Shar- during hypoglycemia. Lancet; rock N. E., Mattis S., et al. 343:16-20. (1999) : Randomized trial of hypotensive epidural anesthesia in old- (26) Smith C., Carter M., Seb- er adults. Anesthesiology; 91: el P. and Yate P. (1991) : Mental 926-35. function after general anaesthesia for transurethral procedures. Br J (25) Maran A., Cranston I., Anaesth; 67: 262-8.

130 Benha M. J. REPRINTVol. 29 No 1 Jan. 2012 BENHA MEDICAL JOURNAL

POSTOPERATIVE COGNITIVE DYSFUNCTION IN DIABETIC VERSUS NON DIABETIC PATIENTS: EFFECTS OF PERIOPERATIVE BLOOD GLUCOSE CONTROL REGIMENS

Ahmed M. F. Hassan M.Sc., Gihan A. Tarabih MD, Mohammed A.E. Al-Hadedy MD, Mahmoud M. Othman MD and Golinar E. Hammouda MD

Published by Benha Faculty of Medicine Volume 29 Number 1 Jan. 2012

131 Benha M. J. Vol. 29 No 1 Jan. 2012 BCL10 PROTEIN EXPRESSION IN MALT LYMPHOMA

Afaf T. Ibrahiem M.Sc, Amira K. El-Hawary MD, Dina A. El-Tantawy MD, Ibrahiem El-Shawaf and Ahmed A. El-Hanafy MD Department of Pathology, Faculty of Medicine, Mansoura University, Egypt

Abstract Mmucosa - associated lymphoid tissue (MALT) lymphoma is a low- grade B-cell lymphoma. Chromosomal translocations t (1; 14) (p22; q32) resulting in BCL10 rearrangements have been identified in MALT lymphomas. The aim of this study is to evaluate diagnostic role of BCL-10 protein expression in MALT Lymphoma. Twenty six cases of extranodal MALT lymphoma of different organs (17 gastric, 4 salivary gland, 3 small intestine, one in thyroid and one in nasopharyngeal area) were collected from pathology laboratory of Gastroenterology Surgery Center and pathology department, Mansoura University during the period 2007 to 2011. All cases were reviewed and diagnosed as extranodal marginal zone lymphomas according to the recent criteria of the WHO. Addition- al 17 cases of lymphoid hyperplasia were included in the study. Immu- nohistochemical staining was performed. The following antibodies were used: CD20, CD3, Ig M and BCL10. MALT lymphoma cases showed lymphoepithelial lesion in 100% of cases, reactive follicles in 61.5%, colonized follicles in 34.6% and subepithelial sheeting of plasma cells in 19.2% of cases. In comparison, eleven of reactive cases showed lymphoepithelial lesion and seven of them were located in the nasopharengx. The remaining three nasopharengeal reactive lesions showed transmigrating lymphocyte. None of the reactive lesions showed colonized follicles or subepithelial sheeting of plasma cells. Centrocyte like cells predominated in 76.9% of MALT lymphoma cases, monocytoid cells in 35.2%, plasmacytoid cells in 11.5% of cases. Comparatively, the

131 Afaf T. Ibrahiem, et al... reactive cases showed predominant lymphoplasma cellular infiltrate. All cases of MALT lymphoma were CD20 positive, CD3 negative. About 96% of MALT cases were IgM positive and about 85% of cases were BCL10 positive. The reactive cases were positive for CD20 and CD3 and negative for IgM except for only scattered positive plasma cells. A weak expression of the BCL10 protein was restricted to the cytoplasm of germinal centre cells and marginal zone cells. On the other hand, nuclear staining was not seen in the reactive cases. In conclusion, most MALT lymphoma express either strong nuclear or strong nuclear and cytoplasmic BCL10 protein. In contrast, benign lymphoproliferative disorders express no nuclear BCL10 staining. So, BCL10 may carry some diagnostic implications in assessment of MALT lymphoma.

Introduction immune processes, such as Hash- MALT lymphoma is a low-grade imoto thyroiditis. MALT lymphoma B-cell lymphoma, firstly, described commonly involves the sites of ac- by Isaacson and Wright (1). quired MALT and rarely in sites of MALT lymphoma represents the native MALT (3). third most frequent subtype of Non Hodgekin lymphoma (NHL) B Several genetic aberrations cell type (after diffuse large B-cell have been identified in MALT lym- lymphoma and follicular lympho- phomas, some of which appear to ma). It comprises about 7% of all be specific for, or at least closely newly diagnosed NHL (2). related to, this subtype of marginal zone (MZ) lymphoma. Chro- Two types of MALT can be iden- mosomal translocations t(1;14) tified in disparate organs: native (p22;q32), t(14;18) (q32; q21), t type consists of lymphoid tissue (11;18) (q21;q21) and t(3;14) physiologically present in Peyer (p13;q32) occur with variable fre- patches and tonsil, whereas ac- quencies in MALT lymphomas, required MALT develops in sites of sulting in BCL10, MALT1, API2- inflammation in response to either MALT1 and forkhead box protein infectious conditions, such as He- P1 (FOXP1) rearrangements, re- licobacter pylori gastritis, or auto- spectively(4). In contrast, both

132 Benha M. J. Vol. 29 No 1 Jan. 2012 mantle cell and follicular lympho- ditional 17 cases of reactive lym- mas generally don’t show Bcl10 phoproliferative disorders were in- expression suggesting that dere- cluded in the study. gulation of Bcl10 expression is unlikely to be involved in the de- Immunohistochemical stain- velopment of these tumors (5, 6). ing: Immunohistochemical staining MALT lymphoma may be diffi- was performed using the avidin- cult to diagnose as there are com- biotin-peroxidase complex detec- mon histological features with tion technique with DAB as chro- mucosa-associated lymphoid tis- mogen. The following antibodies sue, namely, prominent reactive- were used: CD20 (Monoclonal appearing lymphoid follicles, plas- mouse, antihuman, code M0755, ma cells, and transmigrating epi- ready to use, DAKO Cytomation), thelial lymphocytes(7). It is this CD3 (Monoclonal mouse, antihu- category that benefits the most by man,code M7254, 1:50, DAKO De- using immunophenotyping. The nemark), IgM (polyclonal rabbit, aim of this study is to evaluate di- antihuman, code A0425, 1:250 agnostic role of BCL-10 protein ex- DAKO Cytomation), BCL10 (Mono- pression in MALT Lymphoma. clonal mouse, antihuman, code M7260, 1:300, DAKO Cytoma- Patients and Methods tion). In brief, 4 mm paraffin sec- This study was performed on tions were dewaxed in xylene and 26 cases of extranodal MALT lym- rehydrated in decreasing concen- phoma of different organs. The trations of ethanol. Slides were cases were collected from patholo- placed in citrate buffer ph 6.0 and gy laboratory of Gastroenterology heated using a microwave oven for Surgery Center and pathology de- 5 min to perform epitope retrieval. partment, Mansoura University Incubation with the antibodies during the period 2007 to 2011. was carried out for 45 minutes. All cases were reviewed and diag- All incubation steps were followed nosed as extranodal marginal by a wash in three changes of zone lymphomas according to the phosphate-buffered saline (pH recent criteria of the WHO (8). Ad- 7.6).

133 Afaf T. Ibrahiem, et al...

Interpretation of immunohis- cases (58.8%) were located in the tochemical staining: nasopharyngeal region, 3 (17.7%) The results were interpreted in in the salivary gland, 2 (11.9%) in light of the appropriate staining of the stomach, one case (5.8%) in all positive and negative controls, the small intestine and one case compared with H & E slides. A (5.8%). of cases in the thyroid brown precipitate at sites of spe- gland (table1). Both two groups of cific cellular antigen localization cases didn’t differ in the present- indicates a positive reaction. The ing clinical symptoms. tissue reaction to specific stain considered negative when less Microscopic features: than 10% of the tissue appeared As showen in table (1), MALT stained. BCL10 appears as cyto- lymphoma cases showed lymphoe- plasmic and or nuclear brownish pithelial lesion in 100% of cases in staining. It considered positive if which atypical lymphocytes infil- the lymphoid infiltrate shows dif- trate the epithelium with degener- fuse cytoplasmic and/or nuclear ative changes. Reactive follicles staining(6). were seen in 61.5% of cases, colonized follicles in 34.6%, subepi- Results thelial sheeting of plasma cells in Among the 26 cases of MALT 19.2% of cases. In comparison, lymphoma, 14 were females and eleven of reactive cases (64.7%) 12 were males. The age ranged showed lymphoepithelial lesion from 24 to 70 years with mean age and seven of them were located in 46 years. Seventeen cases (65.3%) the nasopharengx. The remaining were located in the stomach, 4 three nasopharengeal reactive le- (15.4%) in salivary gland, 3 sions showed transmigrating (11.6%) in small intestine, one lymphocyte. None of the reactive case (3.8%) in thyroid gland and lesions showed colonized follicles one (3.8%) in nasopharyngeal re- or subepithelial sheeting of plas- gion. The reactive lymphoprolifera- ma cells. tive lesions were 17 cases with age ranging from 25 to 68 years The neoplastic cells presented a with mean age 45.5 years. Ten serial small cell lineage of centro-

134 Benha M. J. Vol. 29 No 1 Jan. 2012 cyte-like cell, monocyte-like B cell, CD3 negative. Twenty four cases plasmacytoid cell, with scattered (96.2%) were IgM positive (figure centroblast like cells. In all MALT 2). Twenty -two cases (84.6%) cases, the above cells were in a were BCL10 positive. BCL10 was mixed distribution, but usually expressed in two patterns (nuclear one type of cells was predomi- and cytoplasmic in 19 cases (fig- nant. Centrocyte like cells pre- ure 3, 4), exclusively nuclear in 2 dominated in 76.9% of cases, cases, and strong cytoplasmic in monocytoid cells predominated in one case. The reactive cases 35.2%, plasmacytoid cells pre- showed positive CD20 and CD3, dominated in 11.5% of cases. negative IgM with only scattered Comparatively, the reactive cases positive plasma cells. A weak ex- showed predominant lymphoplas- pression of the BCL10 protein, re- ma cellular infiltrate. stricted to the cytoplasm of germinal centre cells and marginal zone Immunohistochemical results: cells. In none of the reactive le- All cases of MALT lymphoma sions analyzed, nuclear staining were CD20 positive (figure 1) and was observed (Table 1).

Fig. (1): Diffuse positive membra- Fig. (2): Diffuse staining for IgM in nous staining for CD20. Lymphoepi- gastric MALT lymphoma (DAB x 100). thelial cells formed by neoplastic B lymphocyte in gastric MALT lymphoma was seen (DAB x 200).

135 Afaf T. Ibrahiem, et al...

Fig. (3): Diffuse nuclear and cyto- Fig. (4): Diffuse nuclear and cytoplasmic positive staining for BCL10in plasmic staining for BCL10 in salivary gastric MALT lymphoma (DABX 200). gland MALT lymphoma (DABX 400).

136 Benha M. J. Vol. 29 No 1 Jan. 2012 Discussion et al.,(12). In this study, about In this study, the stomach was half of the cases of nasopharyn- the commonest site for MALT lym- geal reactive lymphoproliferative phoma while salivary gland was lesion showed lymphoepithelial le- the prevalent extragastric site. sion. Boyaka et al.,(13) reported These results are in agreement that lymphocytes may infiltrate with the results of the study per- overlying epithelium but this does formed by Mokhtar and Khaled(9). not indicate lymphoma at this Different results recorded by Woh- site. rer et al.(3) as 39% of their MALT lymphoma cases were gastric and In the studied cases, centrocyte 61% was extragastric. This is like cells predominated in about could be explained by high preva- 80% of MALT cases and monocy- lence of H Pylori organism in toid B cells in about one third of Egypt(9). In this study, only one cases. These results are in agree- case of MALT lymphoma was lo- ment with results obtained by cated in the nasopharyngeal area. Cheng et al.,(12) and Malikhova et Also, Menaarguez et al.,(10) report- al.,(14). Lymphoplasmacytic diffe- ed only one case and Sagaert et rentiation was detected in 11.5% al.,(6) reported four cases. cases of our MALT lymphoma cases. Wohrer et al.,(3) and Malikhova In this study, lymphoepithelial et al.,(14) demonstrated somewhat lesions were demonstrated in all higher percentage of plasmacytic MALT lymphoma cases and colo- differentiation in their series. This nized follicle in about one third of could be explained by higher per- cases. These results are in agree- centage of extragastric MALT lym- ment with Issacson et al., (11) who phoma cases in their series as reported that both lymphoepithe- plasmacytic differentiation is more lial lesion and follicular coloniza- common with extragastric MALT tion are characteristic features for lymphoma(15). The MALT lympho- diagnosis of MALT lymphoma, ma exhibiting plasmacytic diffe- but they could only be seen in rentiation explained by the capac- some of the cases. Also, these re- ity of post germinal center sults are in agreement with Cheng marginal zone cells (MZC) for diffe-

137 Afaf T. Ibrahiem, et al... rentiation into plasma cells during The IgM negative cases could be the course of Bcell development. probably explained by possible ex- When plasmacytic differentiation pression of other types of immu- is extensive, it can be confused noglobulin like IgA or IgG (11,20). with plasmacytoma (16). In the present study, BCL10 In this study, CD20 and CD3 exhibited two pattern of expres- highlighted the proportion of B sion strong nuclear, strong nucle- and T lymphocytes in the infiltrate ar and cytoplasmic in MALT lym- and all MALT lymphoma cases phoma cases. Weak cytoplasmic showed extensive diffuse positive staining were recorded in reactive staining for CD20 with negative cases. These results are of much or scattered positive CD3 T cells. higher incidence as compared to These results cope with almost of the data published by Sagaert et the previous studies(9,17). The al.,(6) who documented that 66% scattered positive CD3 cells in of MALT lymphomas were posi- MALT lymphoma cases could be tive. They described five patterns explained by the fact that B of BCL10 expression: an exclu- cells need to be in contact with sive nuclear BCL10 expression, a the intratumoral T cells to receive combined nuclear and cytoplas- costimulatory signals (CD40- mic BCL10 positivity, a perinu- CD40L) favor continuous prolife- clear BCL10 expression, a strong ration(18,19). diffuse cytoplasmic BCL10 expression, and a weak diffuse cytoplas- In the present study, 96.2% mic BCL10 expression. They re- of MALT cases expressed IgM. ported that the latter staining The remaining MALT lymphoma pattern did not differ in any way and reactive cases were complete- from the BCL10 expression in ger- ly negative apart from scattered minal centre cells and marginal positive plasma cells. These re- zone cells in control tissues and sults are in agreement with Bacon was therefore not considered to be et al,(16) who mentioned that abnormal. Thus, presence of aber- MALT lymphoma express IgM rant bcl-10 expression found by mostly, IgA or IgG to lesser extent. immunohistochemistry is helpful

138 Benha M. J. Vol. 29 No 1 Jan. 2012 in the diagnosis of MALT lympho- contrast, reactive lymphoprolifera- mas and this finding might be an tive disorders express weak cyto- indication of an underlying genetic plasmic with no nuclear BCL10 anomaly either involving the staining. So, BCL10 may carry BCL10 or MALT1 gene. Ye et al.,(5) some diagnostic implications in reported that t (1; 14)-positive assessment of MALT lymphoma. MALT lymphoma cells have a strong BCL10 expression both in References the cytoplasm and in the nucleus 1- Isaacson P. and Wright while normal marginal zone B D. H. (1983) : Malignant lympho- cells present BCL10 cytoplasmic ma of mucosa-associated lym- expression. Liu et al., (21) reported phoid tissue: a distinctive type of that more than half of MALT lym- B-cell lymphoma. Cancer. 52 : phomas without the t(1;14) also 1410-6. show moderate cytoplasmic and nuclear expression and the t 2- Troch M. and Raderer M. (11;18) API2/MLT chimeric tran- (2009) : Gastric MALT lymphoma. script might determine the abnor- Memo magazine of European med- mal subcellular localisation of ical oncology, 2 (3): 130-133. BCL10. All t (11;18)-positive MALT lymphomas showed nuclear 3- Wohrer S., Troch M., BCL10 expression, whereas only Streubel B., et al. (2007): PPa- 23% without t (11;18) have detect- thology and clinical course of able BCL10 in nuclei. Moreover, MALT lymphoma with plasmacytic many studies stated that BCL10 differentiation. Annals of oncol, has prognostic value in gastric (18):2020-2024. MALT lymphoma as it is closely associated with advanced-stage 4- Thome M. (2004): CARMA1, diseases (5,7). BCL-10 and MALT1 in lymphocyte development and activation. Na- In conclusion, most MALT lym- ture Reviews Immunology,4:348- phoma expresses either strong nu- 359. clear or strong nuclear and cytoplasmic BCL10 protein. In 5- Ye H., Dogan A., Karran L.,

139 Afaf T. Ibrahiem, et al... et al. (2000): BCL10 expression nicopathological study of 79 cas- in normal and neoplastic lym- es. Histopathology. 24 (1):13- 22. phoid tissue: nuclear localization in MALT lymphoma. Am J Pathol, 11- Isaacson P., Hermelink 157: 1147-1154. H., Piris M., et al. (2001): Extra- nodal marginal zone lymphoma of 6- Sagaert X., Laurent M., muocsa-associated lymphoid tis- Baens M., et al. (2006): MALT1 sue (MALT lymphoma). In:Jaffe and BCL10 aberrations in MALT ES, Harris NL, Stein H, Vardiman lymphomas and their effect on the JW, eds. World Health Organisa- expression of BCL10 in the tu- tion Classification of Tu- mour cells. Modern Pathology 19, mours.Pathology and genetics of 225-232. tumours of haematopoieticand lymphoid tissues. Lyon: IARC 7- Cavalli F., Isaacson P., Press:157-60. Gascoyne R., et al. (2001): MALT Lymphomas. American Society of 12- Cheng H., Wang J., Hematology, 1:241- 258. Zhang C., Yan P., et al. (2003): Clinicopathologic study of muco- 8- Jaffe E., Harris N., Stein sa-associated lymphoid tissue H., et al. (2004): World Health lymphoma in gastroscopic biopsy. Organisation Classification of Tu- World J Gastroenterology, 9(6): mours: Pathology and Genetics: 1270-1272. Tumours of Haemopoietic and Lymphoid Tissues. IAR Press: 13- Boyaka N., Wright F., Lyon, France. Marinaro M., et al. (2000) : Hu- man nasopharyngeal-associated 9- Mokhtar N. and Khaled H. lymphoreticular tissues. Function- (2002): Lymphoma. 1st ed. Cai- al analysis of subepithelial and in- ro,Egypt. traepithelial B and T cells from ad- enoids and tonsils. Am J Pathol, 10- Menaarguez J., Mollejo 157: 2023-2035. M. Carrioan R., et al. (2007): Waldeyer ring lymphomas. A cli- 14- Malikhova O. A., Poddub-

140 Benha M. J. Vol. 29 No 1 Jan. 2012 nyi B. K., Poddubunaia I. V., et 18- Guindi M. (2000): Role of al. (2010): Clinical and morpho- activated host T cells in the pro- logical aspects of MALT-gastric motion of MALT lymphoma lymphoma. Eksp Klin Gastroente- growth. Semin Cancer Biol, 10: rol,(6):24-9. 341-344.

15- Klein N., Elis A., Radnay 19- Sagaert X., De Wolf- J., et al. (2009): Transformation Peeters C. and Noels H. (2007) : of MALT Lymphoma to Pure Plas- The pathogenesis of MALT lym- ma Cell Histology: Possible Associ- phomas: where do we stand? Leu- ation with Anti-CD20 Antibody kemia 21, 389-396. Treatment. IMAJ,11: 703-704. 20- Psyrri A., Papageorgiou S. 16- Bacon C., Du M. and Do- and Economopoulos T. (2008): gan A. (2007) : Mucosa- Primary extranodal lymphomas of associated lymphoid tissue (MALT) stomach: clinical presentation, di- lymphoma: a practical guide for agnostic pitfalls and management. pathologists J Clin Pathol, 60: Annals of Oncology,19:1992-1999. 361- 372. 21- Liu H., Ye H., Dogan A., 17- Katic V., Dimov D., Katic et al. (2001) : T (11; 18) (q21;q21) K., et al. (2004): The histopa- is associated with advanced mu- thology and immunohistology of cosa-associated lymphoid tissue gastric MALT lymphoma Arch On- lymphoma that expresses nucle- col, 12:5-6. ar BCL10. Blood, 98:1182-1187.

141 Afaf T. Ibrahiem, et al...

Fig. (1): Diffuse positive membranous staining for CD20. Lymphoepithelial cells formed by neoplastic B lymphocyte in gastric MALT lymphoma was seen (DAB x 200).

Fig. (2): Diffuse staining for IgM in gastric MALT lymphoma (DAB x 100).

142 Benha M. J. Vol. 29 No 1 Jan. 2012

Fig. (3): Diffuse nuclear and cytoplasmic positive staining for BCL10in gastric MALT lymphoma (DABX 200).

Fig. (4): Diffuse nuclear and cytoplasmic staining for BCL10 in salivary gland MALT lymphoma (DABX 400).

143 REPRINTAfaf T. Ibrahiem, et al... BENHA MEDICAL JOURNAL

BCL10 PROTEIN EXPRESSION IN MALT LYMPHOMA

Afaf T. Ibrahiem M.Sc, Amira K. El-Hawary MD, Dina A. El-Tantawy MD, Ibrahiem El-Shawaf and Ahmed A. El-Hanafy MD

Published by Benha Faculty of Medicine Volume 29 Number 1 Jan. 2012

144 Benha M. J. Vol. 29 No 1 Jan. 2012 ROLE OF GAMMA KNIFE IN MANAGEMENT OF SKULL BASE TUMORS

Wael K. Zakaria MD, Mohamed S. Ibrahim MD, Nabil M. Ali MD, Raef F. Hafez MD* and Ahmed A. Zaher MD Department of Neurosurgery, Military Medical Academy*, Mansoura University, Mansoura, Egypt.

Abstract Background: Skull base tumors arise from the cranial base or reach it, either from an intracranial or extra cranial origin. A diverse group, these tumors present unique management challenges because of their relative rarity, typically deep location, close proximity to critical neurovascular structures, and extension beyond classically taught anatomic and specialty boundaries. To decrease the morbidity associated with surgical resection of small sized tumors, gamma knife radiosurgery (GKS) was performed as an alternative in 50 patients with different types of skull base tumors to evaluate its safety and efficacy. Methods: A review of 50 residual or unresectable skull base tumors treated with GKS between 2007 and 2011. Results: The tumor volume decreased in 32 patients and stable in size in 14 patients with reduced central contrast enhancement indicating marked tumor necrosis and local tumor control, the rest 4 patients showed enlargement of the tumor size. all 18 pituitary adenoma patients (100% of pituitary adenoma) were had hormonal response (HR) after six months of gamma knife treatment and 16 patients with pituitary adenoma (88.88% of pituitary adenoma patients) were had hormonal normalization (HN) within 16 to 24 months after gamma knife treatment Conclusion: The long term outcome following GKRS for many of skull base tumors treatment favourably compares with the results obtained by microsurgery, conventional radiotherapy.The apparently bet-

143 Wael K. Zakaria, et al... ter results of GKRS in the treatment for skull base tumors should provide the impetus for even more aggressive application of this approach as a primary management of skull base tumors.

Introduction come. Pathologies such as parana- Skull base tumors may origi- sal sinus carcinomas may, howev- nate from the neurovascular er, require induction chemothera- structures of the base of the brain py, surgical excision, and and the basal meninges (e.g., me- radiation therapy (RT) to achieve ningioma, pituitary adenoma, local control and possibly cure. In schwannoma, paraganglioma), the general, the outcome of surgery cranial base itself (e.g., chordoma, for basal tumors depends on the chondrosarcoma), or the subcrani- type, size, and location of the neo- al structures of the head and neck plasm, patient’s age and general (e.g., paranasal sinus carcino- medical status, and extent of pre- mas). A unified classification sys- operative neurologic disability (1). tem does not exist for the plethora of pathologies, some quite rare, Stereotactic radiosurgery dif- that may affect this area of the fers from open surgery insofar as brain (Table 1). stereotactic radiosurgery has no immediate cytoreductive role. In- Tumor location is also the stead, the goal of radiosurgery is prime determinant of the surgical to change the biology of tumor approach that is selected. Where- cells so as to inhibit their prolife- as location is the most important rative potential. A successful out- consideration for surgical plan- come of radiosurgical treatment is ning, the tumor’s biologic behavior therefore arrest of tumor growth, dictates the need for, and order of, not disappearance of the tumor. the various available therapies Radiosurgery is therefore inappro- needed to optimize patient out- priate for patients who are symp- come. Some tumors, such as me- tomatic from mass effect of tu- ningiomas and schwannomas, mors. Regardless of mass effect, may require complete surgical ex- however, another limiting aspect cision only to optimize patient out- of radiosurgery is tumor size: Be-

144 Benha M. J. Vol. 29 No 1 Jan. 2012 cause external beam techniques bilitation. For these reasons, radi- can achieve only a limited degree osurgery is a compelling treatment of conformity, radiosurgical treat- alternative for many patients. For ment of larger tumors may expose patients who are medically fragile normal tissue to an unacceptably or who cannot accept the potential high level of radiation. Large tu- complications of surgery (eg, risks mors may require surgical debulk- inherent in blood transfusion), ra- ing (ie, to reduce tumor volume) so diosurgery may be the only feasi- that single-fraction radiosurgical ble treatment alternative (2). treatment can be used (2). In 1949, Leksell described a Radiosurgery has been used ex- system, which concentrated radia- tensively for treating benign tu- tion therapy on intracranial tar- mors of the central nervous sys- gets within the brain (3). tem. The most extensively developed data for radiosurgical He conceived image guided, treatments have pertained to multiple, cross-firing, tightly colli- treatment of acoustic neuroma mated and small radiation portals (vestibular schwannoma) and me- ‘‘focusing’’ a high single radiother- ningioma of the skull base. The apy dose on an intracranial target. clear margins and discrete imag- His first clinical work was ing characteristics of these tumors aimed at destroying intracerebral make them ideal candidates for pathways in functional disorders radiosurgical treatment (2). and he coined the name stereotactic ‘‘radiosurgery’’ - a nickname Radiosurgical treatment elimi- which has endured. The early nates risks of blood loss, infection, work was hampered by inade- anesthesia complications, and quate equipment, as only a 200 other perioperative risks. In addi- KV X-ray apparatus was availa- tion, radiosurgery is administered ble (3). on an outpatient basis, thereby eliminating the need for hospitali- The concept was next furthered zation, specialized care in the in- in 1968, again in Sweden .Gamma tensive care unit (ICU), and reha- Knife; Electa Instruments AB, Lin-

145 Wael K. Zakaria, et al... ko¨ ping, Sweden is 201 fixed co- brought to clinical attention in in- balt-60 sources, each a thin rod of ternational medical center (IMC) 1 mm diameter, the long axis of in Cairo, during a period starting which is oriented along a radius of from January 2007 up to June a hemisphere – the helmet, into 2011. This study contained 9 dif- which the patient’s head, within a ferent types of pathological stereotactic frame, fits. The centre groups: chordoma, craniopharyn- point (or isocentre) of this hemi- gioma, gloms jugular tumor, na- sphere is the point at which them sopharyngeal carcinoma, acoustic stereotactic co-ordinates of the neuroma, skull base meningioma mapped intracranial target are po- and three pathological types of sitioned (4). fuctional secretory pituitary adenoma which are prolactinoma, GH Materials and Methods secreting adenoma and ACTH se- Objective: creting adenoma. 4 patients har- This thesis aims to present boring chordoma (8% of all pa- the response of skull base tumous tients), 2 patients harboring treated with Gamma knife and craniopharyngioma (4% of all pa- evaluation the efficacy of gamma tients), 4 patients harboring glo- knife by clinical picture improve- mus jugular tumor (8% of all pa- ment and follow up with MRI im- tients), 7 patients harboring skull aging's to asses the role of gam- base meningioma(14% of all pa- ma knife as a useful modality for tients), 14 patients harboring treatment of primary, residual, re- acoustic neroma (28% of all pa- current skull base tumours or tu- tients), 8 patients harboring GH mours in medically fragile patient secreting adenoma (16% of all pa- can not stand the risk of open tients), 6 patients harboring pro- surgery. lactin secreting adenoma (12% of all patients), 4patients harboring Methods: ACTH secreting adenoma (4% of Fifty patients with skull base all patients), so there were 18 pa- tumors with tumor size less than tients of pituitary adenoma (36% 3.5 cm in diameter are included of all patients), and one patient in this study. These cases were harboring nasophayngeal carcino-

146 Benha M. J. Vol. 29 No 1 Jan. 2012 ma (2% of all patients) (figure 1). patients ranged between 13years All patients had serial MRI brain and 69 years with mean and imaging at 6,12,24,36,48 months stander deviation is 42.6 ± 13.9. after gamma knife and follow up Twenty six patients were males period ranged from 8 to 54 (52% of all patients) and twenty months (mean 31.9). four were females (48% of all patients). Radiosurgery technique: The Elekta Leksell gamma knife All of the tumors that under- was used for the treatment. Target went GKS , the tumor diameter localization was achieved using ranged between .5-3.5 cm. The tu- MRI performed with T1 axial and mor peripheral dose ranged be- coronal-weighted sequence at 2 tween 10-30 Gy(mean 16.76) (ta- mm slice thickness with and with- ble 2) usually at 35% to 50% out contrast, T1- fat saturation se- (mean 41.6%) isodose curve (Ta- quence and also T2 axial sequence ble 3). was used to eliminate tumor ede- ma. Treatment planning was per- The follow up period ranged formed with Elekta Leksell Gam- from 8 to 54 months (mean 31.9). ma Plan. Treatment peripheral All patients had serial MRI brain dose ranged between 10-30 Gy imaging at 6,12,24,36,48 months (mean 16.76) usually at 35% to after gamma knife. 50% (mean 41.6%) isodose curve. The maximum dose to the adja- The tumor volume decreased cent brain stem area ranged be- in 32 patients and stable in size tween 10-12 Gy. in 14 patients with reduced central contrast enhancement in- Results dicating marked tumor necrosis Seventeen patients were treat- and local tumor control, the rest ed surgically for there skull base 4 patients showed enlargement tumors prior to gamma knife of the tumor size (table 4, Fig- treatment, the rest of patients un- ure 2). derwent gamma knife surgery as primary treatment. The age of the In pituitary adenoma cases we

147 Wael K. Zakaria, et al... compared hormonal profiles pre We found that, all 18 pituitary and post gamma knife treatment adenoma patients (100% of pitui- to identify the hormonal control tary adenoma ) were had hormo- (HC) which either : nal response (HR) after six months • Hormonal response (HR): de- of gamma knife treatment and 16 cline the hormone to more than patients with pituitary adenoma 50% of previous level before gam- (88.88% of pituitary adenoma pa- ma knife treatment. tients) were had hormonal normal- • Hormonal normalization ization (HN) within 16 to 24 (HN): reach the normal hormonal months after gamma knife treat- level after gamma knife treatment. ment (table 5).

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152 Benha M. J. Vol. 29 No 1 Jan. 2012 Discussion ing loss in one, vocal cord paraly- As regard skull base meningio- sis and hearing loss in one, and ma , within the past few years, temporary imbalance and/or verti- GKRS has begun to play an in- go in one). In 26 patients in whom creasingly important role as a hearing could be tested before non-invasive alternative therapeu- GKS, hearing preservation was tic modality for patients with skull achieved in 86% and 81% at 1 base meningiomas. Excellent re- and 4 years post treatment, results were related in the early to spectively (17). interim gamma knife series (table 6) (5,6,7,8,9,10,11,12,13). In our study , GKS was used as the primary management in 3 As regard Glomus jagulare tu- patients and for recurrent glomus mors which is radioresistant, radi- jugulare tumors for one patient. ation has been found to be helpful All our patients showed shrinkage in controlling tumor growth by in- in their tumor size with local tu- ducing fibrosis around the supply- mor control and this closely simi- ing vessels (14,15,16). lar to Pollock (17) study.

In a study by Pollock (2004) As regard acoustic neuroma, GKS was used as the primary the results reported here are a tu- management in 19 patients and mor control rate of 100%, shrink- for recurrent glomus jugulare tu- age in 71.43% combined with a mors for 23 patients. Of these, 12 85.71% hearing preservation rate, tumors (31%) decreased in size, and a risk of persisting trigeminal 26 (67%) remained unchanged, neuropathies of 0%. It is possible and one (2%) grew. The patient that careful patient selection was whose tumor grew underwent re- the cause of these results. peated GKS. Progression-free survival after GKS was 100% at 3 and These results are broadly close 7 years, and 75% at 10 years. Six to those reported by other radio- patients (15%) experienced new surgery groups (table 7), although deficits (hearing loss alone in there are differences both in three, facial numbness and hear- complication rates and tumour

153 Wael K. Zakaria, et al... control rates (18,19,20,21,22). showed a mean tumor control rate of 96%. Considering only the As regard the treatment of pi- series with mean or median fol- tuitary adenomas, radiotherapy is low-up of 4 years or more, the classically indicated in cases of in- control ranged from 83 to 100%. complete resection or recurrent Importantly, in all cases, control tumors, functioning tumors un- was defined as the persistence or controlled by medical therapy and reduction of tumor volume, as in patients inoperable or who refuse our study. surgery. The objectives of radiotherapy are the control of tumor The reduction in tumor volume, growth and/or the normalization as observed in 12 cases in our se- of hormonal secretion, the mainte- ries (66.67%), with 100% tumor nance of pituitary function and control which is closely similar for preservation of neurological func- that which reported by others. tion, especially visual acuity. In our study, we found hor- In a recent review, Prasad re- mone normalization in 100% of ported a control rate of tumor patients with Cushing’s disease, growth 67-100% with convention- 100% of acromegalic patients and al radiotherapy (23). 75% of patients with prolactinoma. Brada et al., reported tumor progression-free survival at 10 When we compare our results and 20 years of 94% and 89%, re- with recent retrospective series of spectively (24). patients treated with the RS and criteria for radiological control and The various retrospective series hormonal defined and similar, we with RS published to date have observe similar results. shown the same results as conventional radiotherapy. Petrovich et al.(26) reported a median time to normalization of Sheehan et al.(25) in an exten- hormonal 22, 18 and 24 months sive review of 1283 patients for patients with tumors that pro-

154 Benha M. J. Vol. 29 No 1 Jan. 2012 duce ACTH, GH and PRL, respec- PFS of 62 and 52%, respectively, tively. In our series, we observed a in their 100-patient cohort. median time to hormonal normalization of 24, 18 and 24 months The reasonable explanation respectively. for the above discrepancies could be attributed to small number of Choi et al.(27) reported a mean patients in our series. As regard time to hormonal normalization of nasopharyngeal carcinoma, stere- 21 months (2.8-59.1 months) and otactic radiotherapy has occasion- actuarial incidence of hormonal ally been employed for NPC recur- normalization at 1 and 3 years of rence; the majority of cases have 16.1% and 37.6%. used linear accelerator-based methods. In such a series of three More recently, Niranjan et al. patients, one remained disease- (28) reported that the overall sur- free 1 year after radiosurgery, one vival rate following GKS was had neurological deterioration 6 97.5% at 5 years, and the 3- and months after treatment, and one 5-year local tumor control rate (for had recurrence 6 months after ra- solid portion of tumor control) diosurgery (30). were both 91.6% based on their long-term follow-up (mean 62.2 Gamma Knife radiosurgery has months) of 46 patients. The goals previously been used in a small set by them were pathological con- number of patients with NPC both firmation, surgical decompression at recurrence and as a primary of optic chiasm, neural and endo- treatment. Treatment was found crine preservation, and long-term to be effective for a short period of tumor control. time but reported follow-up peri- ods are brief (31). In our current study, the local tumor control rate were 100%. The 2-year follow-up of O’DON- Our results are closely similar to NELL et al.(32) first patient treated Niranjan et al. (28), but we are dif- withGamma Knife has been event ferent to Hasegawa et al. (29) free. No clinical evidence of recur- demonstrated a 5- and 10-year rence has manifest and, reassur-

155 Wael K. Zakaria, et al... ingly, a recent PET scan has not we found that their were declined shown any FDG uptake in the na- in the tumor control rate with long sopharynx, or indeed elsewhere, follow up time (21.4% at 5 years) to suggest recurrent disease. In which correlated with radio resist- the second case presented, treat- ant nature of skull base chordo- ment also appears successful, al- ma. beit with shorter follow-up. On the other hands all skull In our study, we are similar to base chordoma patient com- O’DONNELL et al.(32) results as plained from symptoms due to tu- our single patient with NPC were mor mass effect which were not event free in 4 year follow up. prospected to respond to gamma knife radiosurgery as the aim of In our current study. We treat- this type of treatment was the lo- ed skull base chordoma with fail- cal tumor control, So we advise to ure of tumor control in all four pa- surgical intervention rather than tients, two tumors were stable in gamma knife radiosurgey for this their size just for 18 months and type of skull base tumors. then there were progressed in their size, the other two patients Conclusion showed progression in their tu- The long term outcome follow- mors in their first year of treating GKRS for many of skull base ment without sign of central tu- tumors treatment favourably com- mor necrosis which is different to pares with the results obtained by Liu et al (33) who showed tumor microsurgery, conventional radio- control rate 64.2 % and 21.4% af- therapy.The apparently better re- ter 3 and 5 years, respectively on sults of GKRS in the treatment for their 32 patients of skull base skull base tumors should provide chordoma treated with gamma the impetus for even more aggres- knife radiosurgery. sive application of this approach as a primary management of This difference in results may skull base tumors. related to our few cases in our current study, but in Liu AL et al. With regard to the possibility of

156 Benha M. J. Vol. 29 No 1 Jan. 2012 an additional radiosurgical ap- 2- Joseph C. T. (2006) : proach to residual tumours and Chen, Michael R Girvigian. Stereo- the excellent results, following tactic Radiosurgery : Indications combined microsurgical- radiosur- and Results. The Permanente gical treatment, the objective of Journal / Spring 2006/ Volume 10 No. 1. surgical treatment of skull base tumors should be preservation of 3- Leksell L. (1949) : A stereo- function and of as much normal taxic apparatus for intracerebral tissue as possible, rather than surgery. Acta Chir Scand;99:231. radical resection. Patients har- bouring recurrences of skull base 4- Leksell L. (1968) : Cerebral tumors should receive GKRS rath- radiosurgery I. Gamma thalamoto- er than undergo repeated open re- my in two cases of intrac table section. pain. Acta Chir Scand; 134: 585- 95. In patients with advanced age, significant concomitant 5- Aichholzer M., Bertalanffy medical problems, high risk tu- A., Dietrich W., et al. (2000) : mour location or patients who Gamma knife radiosurgery of are not willing to undergo an open skull base meningiomas. Acta microsurgical procedure, we Neurochir (Wien);142:647-52. would recommend performing GKRS as a safe and effective alter- 6- Pendl G., Schrottner O., Eustacchio S., et al. (1997) : native primary treatment modal- Stereotactic radiosurgery of skull ity, with close and frequent clini- base meningiomas. Minim Inva- cal and neuroradiological follow sive Neurosurg;40:87-90. up.

7- Pendl G., Schrottner O., References Eustacchio S., et al. (1998) : 1- Lang D. A., Neil-Dwyer G. Cavernous sinus meningiomas and Garfield J. (1999) : Outcome what is the strategy: upfront or after complex neurosurgery: the adjuvant gamma knife surgery? caregiver’s burden is forgotten. J Stereotact Funct Neurosurg;70 Neurosurg 91:359-363. (suppl 1):33-40.

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8- Subach B. R., Lunsford L. Kawamoto S., et al. (1996) : Pri- D., Kondziolka D., et al. (1998) : mary cavernous sinus malignant Management of petroclival menin- lymphoma treated by gamma giomas by stereotactic radiosur- knife radiosurgery: case report gery. Neurosurgery;42:437-43. and review of the literature. Surg Neurol;46:272-8. 9- Duma C. M., Lunsford L. D., Kondziolka D., et al. (1993) : 14- Guss Z. D, Batra S., Li Stereotactic radiosurgery of cav- G., et al. (2009) : Radiosurgery ernous sinus meningiomas as an for glomus jugulare: history and addition or alternative to micro- recent progress. Neurosurg Focus, surgery. Neurosurgery; 32 : 699- 27(6):E5. 704. 15- Sharma M. S., Gupta A., 10- Iwai Y., Yamanaka K., Ya- Kale S. S., et al. (2008) : Gamma sui T., et al. (1999) : Gamma knife radiosurgery for glomus jug- knife surgery for skull base me- ulare tumors: therapeutic advan- ningiomas. The effectiveness of tages of minimalism in the skull low-dose treatment. Surg Neu- base. Neurol India, 56(1):57-61. rol;52:40--4. 16- Patel S. J., Sekhar L. N., 11- Liscak R., Simonova G., Cass S. P., et al. (1994) : Com- Vymazal J., et al. (1999) : Gam- bined approaches for resection of ma knife radiosurgery of menin- extensive glomus jugulare tumors. giomas in the cavernous sinus re- A review of 12 cases. J Neurosurg, gion. Acta Neurochir(Wien) ; 80:1026-1038. 141:473--80. 17- Pollock B. E. (2004) : 12- Muthukumar N., Kondzi- Stereotactic radiosurgery in pa- olka D., Lunsford L. D., et al. tients with glomus jugulare tu- (1999) : Stereotactic radiosurgery mors. Neurosurg Focus, 17 for anterior foramen magnum me- (2):E10. ningiomas. Surg Neurol;51:268- 73. 18- Prasad D., Steiner M. and Steiner L. (2000) : Gamma sur- 13- Nakatomi H., Sasaki T., gery for vestibular schwannoma. J

158 Benha M. J. Vol. 29 No 1 Jan. 2012 Neurosurg;92:745-59. 24- Brada M., Rajan B., Traish D., et al. (1993) : The 19- Unger F., Walch C., Ha- long-term efficacy of conservative selberger K., et al. (1999) : Radi- surgery and radiotherapy in the osurgery of vestibular schwanno- control of pituitary adenomas. mas: a minimally invasive Clin Endocrinol (Oxf), 38:571-578. alternative to microsurgery. Acta Neurochir (Wien);141:1281-5. 25- Sheehan J., Kondziolka D., Flickinger J., et al. (2005) : 20- Ito K., Shin M., Matsuza- Gamma knife surgery for glomus ki M., et al. (2000) : Risk factors jugulare tumors: an intermediate for neurological complications af- report on efficacy and safety. J ter acoustic neuroma radiosur- Neurosurg, 102(Suppl):241-246. gery: refinement from further experience. Int J Radiat Oncol Biol 26- Petrovich Z., Yu C., Gian- Phys;48:75-80. notta S. L., et al. (2003) : Gam- ma Knife radiosurgery for pitui- 21- Foote K. D., Friedman W. tary adenoma: early results. A., Buatti J. M., et al. (2001) : Neurosurgery, 53:51-59. Analysis of risk factors associated with radiosurgery for vestibular 27- Choi J. Y., Chang J. H., schwannoma. J Neurosurg; 95: Chang J. W., et al. (2003) : Ra- 440-9. diological and hormonal responses of functioning pituitary adenomas 22- Rowe J. G., Radatz M. W. after gamma knife radiosurgery. R., Walton L., et al. (2003) : Yonsei Med J, 44:602-607. Gamma knife stereotactic radiosurgery for unilateral acoustic 28- Niranjan A., Kano H., Ma- neuromas, J Neurol Neurosurg thieu D., et al. (2010) : Radio- Psychiatry;74:1536–1542. surgery for craniopharyngioma. Int J Radiat Oncol Biol Phys; 23- Prasad D. (2006) : Clini- 78:64-71. cal results of conformal radiotherapy and radiosurgery for pituitary 29- Hasegawa T., Kobayashi adenoma. Neurosurg Clin N Am, T. and Kida Y. (2010) : Toler- 17:129-141. ance of the optic apparatus in sin-

159 Wael K. Zakaria, et al... gle-fraction irradiation using ster- in the treatment of nasopharyn- eotactic radiosurgery: evaluation geal carcinoma. Stereotact Funct in 100 patients with craniopha- Neurosurg; 66(Supp1):201-7. ryngioma. Neurosurgery; 66:688- 694 (discussion 694-685). 32- O’Donnell H. E., Plow- man P. N., Khaira M. K., et al. 30- Buatti J. M., Friedman (2008) : PET scanning and Gam- W. A., Bova F. J., et al. (1995) : ma KnifeH radiosurgery in the Linac radiosurgery for locally re- early diagnosis and salvage ‘‘cure’’ current nasopharyngeal carcino- of locally recurrent nasopharyn- ma: rationale and technique. Head geal carcinoma, The British Jour- Neck;17: 14-9. nal of Radiology, January.

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160 Benha M. J. REPRINTVol. 29 No 1 Jan. 2012 BENHA MEDICAL JOURNAL

ROLE OF GAMMA KNIFE IN MANAGEMENT OF SKULL BASE TUMORS

Wael K. Zakaria MD, Mohamed S. Ibrahim MD, Nabil M. Ali MD, Raef F. Hafez MD and Ahmed A. Zaher MD

Published by Benha Faculty of Medicine Volume 29 Number 1 Jan. 2012

161 Benha M. J. Vol. 29 No 1 Jan. 2012 IMMEDIATE MATERNAL AND NEONATAL MORBIDITY ASSOCIATED WITH VACUUM EXTRACTOR DELIVERY, AT UNIVERSITY TEACHING HOSPITAL EXPERIENCE

Nabeel Bondagji MD Frcs(C) and Hisham Ramadani Frcs(C) Department of Obstetrics, Gynaecology, King Abdul-Aziz University Hospital and Princess Aljawhra Centre of Excellence for Hereditary Disorders, Egypt.

Abstract Objectives: to compare the immediate maternal and neonatal morbidity associated with ventouse delivery at full cervical dilation in a teaching hospital in the western region of Saudi Arabia with those reported in the literature. Material and Methods: A retrospective case study of 436 women, who had term, singleton, cephalic pregnancies requiring operative delivery at full cervical dilatation for 6 year period. . Maternal morbidities’ including the presence of genital tract tears and lacerations, extended episiotomy post partum hemorrhage, the need for blood transfusion and emergency cesarean section were studied. Neonatal outcome evaluations were Apgar scores, neonatal intensive care unit admissions, ceph- alohematomas, instrument marks and bruising, intracranial hemorrhage and bone fractures. Results: During the study period 436 women had vacuum assisted vaginal delivery at King Abdul-Aziz university hospital. The success rate for vaginal delivery was 91.1%, the majority of patients were primgravi- das 64.7%.The most frequent indication was fetal distress. Seventy five percent of cases had episiotomy, 12.4% had perineal tears, 5.5% were third and fourth degree tears .The neonatal outcome showed that 19 % of all newborns hat at least one complication, the commonest complication was cephalohematoma that occurred in 14.4% of the neoborns, 8.9% of the neonates were admitted to Special care baby unit or neonatal intensive care unit.

161 Nabeel Bondagji and Hisham Ramadani

Conclusions: The rate of Soft tissue injuries associate with vacuum extraction is comparable with the literature. There is higher failure rate for the procedure. The commonest reported maternal complication is perineal tears and the most frequent neonatal complication is cephalohematoma. Key words: Ventouse, Instrumental delivery, cephalohematoma, maternal and neonatal rabidity.

Introduction assisted deliveries (15). In the middle of the nineteenth century a Swedish obstetrician, By 1992, in the United States Malmström T (1957), introduced a the number of vacuum assisted stainless steel metal cup for vacu- deliveries surpassed the number um assisted delivery to the clinical of forceps deliveries, and by 2000, practice. Suction tubing attached approximately two-thirds of opera- to the dome of the cup and a trac- tive vaginal deliveries were by vac- tion chain passed through the uum (8). Generally the vacuum de- tubing subsequently added to vises are safer than obstetric form the currently available vacu- forceps for the mother, easier to um extractor systems Miksovsky, apply, place less force on the fetal P, et al (2001), Vacca, A (2004). head, require less anesthesia and results in less maternal soft tissue In the developed countries 4.5 injury compared to forceps. The percent of the vaginal deliveries maternal and fetal outcome de- are achieved by instrumental depends on many confounding vari- liveries including vacuum extrac- ables including parity, experience tor (ventouse) and obstetric for- of the operator, the type, size and ceps, however the number of position of the cup. It also in- vaginal deliveries conducted by cludes the head position and sta- vacuum extractor has been in- tion during the application as well creasing in the last few decades as the appropriate patient’s selec- and is now four times the rate of tion. Complications of the vacuum obstetric forceps with 0.8% with may affect the mother and the ne- forceps assisted and 3.7% vacuum onate. This retrospective chart re-

162 Benha M. J. Vol. 29 No 1 Jan. 2012 view study was designed to test dramnios, premature rupture of the immediate maternal and neo- membranes, intrauterine fetal de- natal outcomes in teaching ter- mise, infertility, previous cesarean tiary care center. section were examined.

Patients and Methods Data regarding the onset of la- This is a retrospective chart re- bor, the use of oxytocin and the view study of all cases of ventouse indication for instrumental deliv- delivery at King Abdul-Aziz univer- ery were also collected. The course sity hospital in Jeddah Kingdome of delivery including fetal head po- of Saudi Arabia which is the larg- sition and the presence of caput est teaching hospital in the west- or moulding. ern part of Saudi Arabia during the period between January 2000 Maternal morbidity including till the end of December 2005 .All extended episiotomy vaginal lacer- women who delivered a singleton ations, perineal 1st 2nd, 3rd and fetus in vertex presentation at full 4th degree tears, paraurethral cervical dilation were included. tears and lacerations, urethral he- Women who delivered by elective matoma, cervical tears, postpar- cesarean section, or had multiple tum hemorrhage , blood transfu- pregnancies were excluded. Medi- sion, disseminated intravascular cal records of those women were coagulopathy and failure of the retrieved and data of the outcome procedure ending by cesarean de- were collected in SPSS spread livery were reported. sheet. Neonatal outcomes evaluated Maternal demographic data in- were Apgar scores, birth weight, cluded age, nationality, parity; shoulder dystocia neonatal inten- gestational age and booking stat- sive care unit admissions, special us are reported. care baby unit SCBU admission, birth asphyxia, respiratory dis- Risk factors associated with tress syndrome (RDS), cephalohe- pregnancy including medical com- matomas, instrument marks and plications of pregnancy, oligohy- bruising, intracranial hemorrhage,

163 Nabeel Bondagji and Hisham Ramadani brachial plexus injury, skull frac- Forceps deliveries were exclud- tures, long bones fractures, neo- ed from any further analysis and natal seizures. the four hundred and thirty six ventouse deliveries were statisti- All maternal and neonatal data cally analyzed. were collected and statistical analysis was done using SPSS version The maternal age among the 16. vacuum delivery group, range between 16 and 49 years with a Results mean of 26 years +2SD. During the study period between January 2000 till December The majority of the women 2005, 24643 women gave birth in (62%) were Saudi, the non Saudi King Abdul-Aziz University hos- represented (38%). Out of the 436 pital, Jeddah, Kingdome of Sau- women who had ventouse delivery di Arabia. Four thousands and (358, 82%) were booked and (34, sixty six (4066) women delivered 18%) unbooked, the gestational by elective cesarean section, age range from 37 to 42 weeks 344 had breech delivery and with a mean gestational age at de- 403 women had multiple pregnan- livery of 38 weeks. cies these women were excluded from any further analysis as they Two hundred and eighty two do not fulfill the inclusion crite- (282, 64.7%) women were primi- ria’s. gravidas and one hundred fifty four (35.3%) were multiparous The total number of instrumen- women. tal deliveries was 455with a rate of 1.9%, 436 were ventouse and only Exploring the risk factors for 19 women had low forceps deliver- the women who delivered by ven- ies indicating that for each 22 ve- touse revealed that 37 women nouse delivery there is one forceps (8.5%) had a previous cesarean delivery, the rate of cesarean sec- and planned to have vaginal tion during the study period was birth after cesarean section 16.5%. (VBAC), ten women 2.3% had

164 Benha M. J. Vol. 29 No 1 Jan. 2012 gestational diabetes mellitus, 9 tal deliveries were as follow 261 women 2.1% had a history of in- (59.8%) fetal distress,82 (18.8%) fertility, 9 women 2.1% were poor maternal effort,78 (17.9%) known to have cardiac disease prolonged second stage and 15 and (8, 1.8%) women presented women (3.4%) to shorten the sec- with premature rupture of the ond stage of labor because of med- membranes. ical condition.

Regarding the onset of labor The success rate in fetal dis- 370 (84.9%) cases had spontane- tress 246 cases (94%), in pro- ous onset, out of those 333 (90%) longed second stage 60(77%), poor had successful ventouse vaginal maternal effort 71(86.6) and delivery, 37 (1%) failed of which 9 shortening second stage 15(100%) had forceps delivery and 28 deliv- Tab 1. ered by cesarean section. The overall success rate for Sixty six women (15.3%) were women who had ventouse delivery induced for obstetrical indica- was (90.1%). Sixteen women tions. 44 women (10.1%) had (3.7%) had forceps after failed ven- prostein induction, 2 (0.5%) wom- tous with successful vaginal deliv- en induced with propess and 20 ery and 38, 8.7% women had (4.6%) women induced by artificial emergency cesarean section. rupture of membranes and oxytocin. Fetal head position was reported in 157 patients only, 99 were One hundred thirty nine wom- occipito- anterior, 32 were occipi- en (31.9%) needed augmentation to- posterior 26 occipito- trans- during labor. Of those women 122 verse.Vaginal assisted vacuum de- (87.8%) had successful vaginal livery was more successful if the vacuum delivery and 17 (12.2%) head position was occipito anteri- failed ventouse and ended by ce- or 87%, followed by occipito- sarean section. transverse 34% and the least successful was occipito-transverse The indications for instrumen- 23%.

165 Nabeel Bondagji and Hisham Ramadani

Maternal outcome showed 328 hemorrhage. 40 women (9.2%) (75.2%) women had episiotomy. had intact perineum Tab 3. Seventy eight women had soft tissue injury during the assisted de- Nine women had shoulder dys- livery with a prevalence of (17.9%). tocia with favorable outcome ex- Fifty four women (12.4%) had per- cept for one case who had clavicu- ineal tears as follow, 19 had first lar fracture. degree tear, 12 second degree, 22 third degree and one patient had The neonatal outcome showed fourth degree tear.14 women sixty three cases (14.4%) of cepha- (3.2%) had lateral vaginal tear, 2 lohematoma, fifteen cases (3.4%) cases paraurethral tear, one case of scalp lacerations, five cases of extended episiotomy and one (1.1%) of birth asphyxia, two cases case of urethral hematoma.5 of Erbs palsy, 2 developed RDS, women (1.4%) had cervical tear one clavicular fracture, one case needed repair under anesthesia. of meningitis, one subdural he- One patient with previous cesare- matoma, one neonate developed an had rupture uterus which was neonatal seizures., one cut repaired under general anesthe- wound on the scalp and One neo- sia. nate had multiple bruises on the body. 24 (5.5%) babies were ad- Twenty eight women (6.4%) had mitted to the special care baby post partum hemorrhage, three unit SCBU and 15 (3.4%) were ad- patients needed blood transfusion mitted to the NICU. Two babies and one developed DIC. One wom- were still born due to causes that an was admitted to the intensive are not related to the instrumental care unit after severe postpartum delivery.

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167 Nabeel Bondagji and Hisham Ramadani

Discussion an obstetrical unit in the united Assisted vaginal birth is com- Kingdome over ten years period, monly used to expedite birth for showed increasing preference for the benefit of either mother or the ventouse over forceps ratio baby or both. It is sometimes as- from 0.2:1 in favor of forceps to sociated with significant complica- 1.9:1 in favor of ventouse over the tions for the mother and her baby. decade (p = 0.002). In the current The choice of instrument may be study the use of vacuum extractor influenced by clinical circum- for assisted vaginal delivery sur- stances, operator experience and passes forceps significantly, over choice and availability of specific the study period only 19 women instruments. delivered using forceps with ventouse to forceps ratio of 22:1, The increasing risks of failed these findings are alarming and delivery with the chosen instru- indicating that residents in train- ment from forceps to metal cup ing are not gaining enough skills and the risks for the maternal and to perform forceps assisted vaginal neonatal trauma need to be con- deliveries this issue should be ad- sidered when choosing an instru- dressed and appropriate steps ment(19). A recent review by(13) in should be taken to ensure that

168 Benha M. J. Vol. 29 No 1 Jan. 2012 residents are getting enough train- and perineal tears.(18) The neona- ing In assisted vaginal deliveries tal outcome was based on Apgar particularly forceps deliveries. score only and concluded that In- strumental delivery should be en- In the same study by Loudon couraged. The limitation of their an increasing failures of operative study was the small number of vaginal delivery, especially using patients and the limited neonatal the ventouse and reduced at- outcomes they reported. tempts at instrumentation was observed (13). In the current study only vacuum assisted deliveries were stud- In concurrence with the Lou- ied with a total of 436 women and don report, our study showed that the neonatal outcome was exam- the rate of instrumental delivery ined in detail. was noticeably lower than what was reported in the developed Regarding the early neonatal countries being only 1.9 % com- outcome assessment, Benedetto et pared to 4.5 in the united al (2007) studied women with an- state (14), this is probably because tenatally normal singleton preg- of reduced attempts of assisted nancies at term, who underwent vaginal delivery. instrumental vaginal delivery (no. 201), spontaneous delivery (no. In a study from developing 402), planned caesarean section country by Nkwabong et al(2011) without labor (no. 402) and cae- to assess the prevalence, indica- sarean section in labor (no. 402) tions, neonatal wellbeing and ma- and they concluded that, in ternal complications of instrumen- healthy women with antenatally tal deliveries, of 3623 vaginal normal singleton pregnancies at deliveries, 84 (2.3%) instrumental term, instrumental deliveries are deliveries were conducted these associated with the highest rate of figures are similar to our figures of short-term maternal and neonatal 1.9% instrumental deliveries. They complications the findings are reported a low rate of maternal similar to what we have observed complications including vaginal in our study.

169 Nabeel Bondagji and Hisham Ramadani

• Vacuum assisted delivery and 4th degree tears can be ex- should be indicated for specific plained by the liberal use of epi- obstetrical indications including siotomy in vacuum assisted vagi- prolonged second stage of labor, nal deliveries. The relationship non reassuring fetal cadiotocogra- between episiotomy and preaneal phy and maternal cardiac or neu- tears is beyond the scope of this rological disease (10) . study.

In the current study the In recent years, the success main indication for vacuum as- rate for operative vaginal deliver- sisted delivery was fetal distress ies has been quite high (99 per- (59.8%), followed by poor maternal cent) (6). This likely reflects appro- effort(18.8%), prolonged second priate choice of candidates for this stage(17.9%) and shortening of intervention. In the current study the second stage (23,15) which the success rate was 91.1% which showed no major difference than is lower than what was reported what was reported in the litera- from the developed countries, this ture(10). is probably related to patient selection and the differences in the Routine episiotomy is not social cultures. necessary for an assisted vaginal birth and may increase the Some experts have recommend- risk of significant perineal trau- ed abandoning the procedure after ma (12). In a series of 1000 con- three pulls. A cohort study found secutive omnicup-ventouse assist- that 82 percent of completed oper- ed deliveries, the incidence of ative deliveries occurred with one third and fourth degree tears to three pulls, and that pulling with versus without an episiotomy more than three times was asso- was 15.8 and 5.8 percent, respec- ciated with neonatal trauma in 45 tively (3). In the current study the percent of such deliveries (17). In incidence of episiotomy was 75.2% the current study the number of and the incidence of the third and pulls were max of three with a fourth degree perineal tears was success rate of 90.1% and a neo- 5.5%, the high incidence of 3rd natal injury of 19%.

170 Benha M. J. Vol. 29 No 1 Jan. 2012 In a meta-analysis from the Co- ly are not associated with long- chrane data base by Johanson R, term complications. Menon V (2000) included, ten trials the use of the vacuum ex- In a randomized controlled trial tractor for assisted vaginal deliv- by Dell et al (1985) at least one ery when compared to forceps de- maternal adverse outcome was re- livery was associated with ported with a prevalence of 22 % significantly less maternal trauma in metallic cup vacuum extractor. (odds ratio 0.41, 95% confidence interval 0.33 to 0.50) and with The prevalence of maternal soft less general and regional anesthe- tissue injuries in the current sia. There were more deliveries study was 17.7% which concurs with vacuum extraction (odds ra- with the reported figures in Dells tio 1.69, 95% confidence interval trail. 1.31 to 2.19). Fewer caesarean sections were carried out in the In a retrospective study by An- vacuum extractor group. However gioli et al (2000) of 50,210 vagi- the vacuum extractor was asso- nal deliveries they reported a rate ciated with an increase in neona- of third and fourth degree lacera- tal cephalhaematomata and reti- tions for spontaneous, vacuum ex- nal hemorrhages. Serious traction, and forceps delivery were neonatal injury was uncommon approximately 2, 10, and 20 per- with either instrument. The au- cent, respectively. The rate of thors concluded that Using of vac- third and fourth degree in our uum extractor rather than forceps study was 5.3% which lower than for assisted delivery appears to re- what was reported in Angioli duce maternal complications. study which is reporting a high rate of tears in all the three Neonates delivered by vacuum groups that were studied. extraction had more neonatal cephalohematoma (OR 2.38) and The incidence of postpartum retinal hemorrhages (OR 1.99) hemorrhage report in our study is than those delivered by for- 6.2% with no difference than the ceps (10). These problems general- incidence among normal sponta-

171 Nabeel Bondagji and Hisham Ramadani neous vaginal deliveries reported bruises were reported in 83 ne- in the literature. onates with a rate of 19% the higher figure may be due to the in- The incidence of serious neona- clusion of minor complications tal complications with vacuum ex- unlike other studies which in- traction is approximately 5 per- clude only major serious compli- cent (20). Torsion and traction of cations. the vacuum cup can cause fetal scalp abrasions and lacerations, Cephalohematoma, in particu- separation of the scalp from un- lar, is more common after vacu- derlying structures leading to um-assisted extraction than for- cephalohematoma, subgaleal he- ceps delivery (approximately 15 matoma occurs in 26 to 45 per versus 2 percent) (8, 10). 1000 vacuum deliveries (ACOG Practice Bulletin 2000), intracra- In general, the incidence of ret- nial hemorrhage, hyperbilirubine- inal hemorrhage is higher for vac- mia, and retinal hemorrhage are uum-assisted than for spontane- also recognized complications of ous vaginal or cesarean deliveries vacuum assisted deliveries (22). 75, 33, and 7 percent, respectively (9). These hemorrhages typically Towner D et al (1999) reported resolve without sequelae within in a large study, the incidence of four weeks of birth, no cases of subdural or cerebral hemorrhage retinal hemorrhage observed in or in infants delivered by vacuum study this is one of the limitation alone was approximately 10 per of the current study as minor self 10,000 births. limited conditions are rarely reported. In the current study the reported neonatal complications related Cephalohematoma was the to ventous delivery including commonest neonatal complica- cephalohematoma, scalp injury tions occurred in 63 newborns, Erbs palsy clavicular fracture, (14.5%), followed by scalp lacera- subdural hematoma, neonatal sei- tions and clavicular fracture sub- zures cut wound and multiple sequently.

172 Benha M. J. Vol. 29 No 1 Jan. 2012 Other reported complications was reported in the literature. The which may or may not be related commonest maternal complication to the delivery itself including was perineal tears and the com- SCBU admission 5.5%, NICU ad- monest neonatal was cephalohe- mission 3.4% and birth asphyxia matoma. 1.2%. The cause of these complications may be due to the risk fac- References tors with those cases that had led 1. ACOG Practice Bulletin to the assisted deliveries. Shoul- (2000): Operative vaginal delivery. der dystocia was reported to oc- American College of Obstetricians curs in higher frequency with vac- and Gynecologists. uum assisted delivery (5). In the current study 9 cases of shoulder 2. Angioli R., Gómez-Marín dystocia with an incidence of O., Cantuaria G. and O'sullivan, 2.1%The early neonatal complica- M. J. (2000): Severe perineal lac- tions was reported in prospective erations during vaginal delivery: study that follows 79 term infants the University of Miami experi- after vacuum assisted delivery ence. Am J Obstet Gynecol, Vol found all delivery related com- 182 pp10-24. plaints were identified within the first 10 hours of life (21). In the 3. Basket T. F., Fanning C. current study most of the neona- A. and Young (2008): DC. A pros- tal complications were recognized pective observational study of in the first 24 hours of the neona- 1000 vacuum assisted deliveries tal life. with the Omni Cup device. J Ob- stet Gynaecol Can Vol 30 pp573- Conclusion 85. Vacuum extractor deliveries exceed forceps delivery with a rate of 4. Benedetto C., Marozio L., 22:1.The failure rate for the proce- Prandi G., Roccia A., Blefari S. dure was higher than what was and Fabris C. (2007): Short-term reported in the literature. Compli- maternal and neonatal outcomes cations rate of ventouse delivery in by mode of delivery. A case- our study are comparable to what controlled study.Eur J Obstet

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6. Clark S. L., Belfort M. A., 11. Johanson R. B. (2001) : Hankins G. D., et al. (2007): Instrumental vaginal delivery. Variation in the rates of operative Guidelines and Audit Committee delivery in the United States. Am of the Royal College of Obstetri- J Obstet Gynecol Vol 196 pp526- cians and Gynaecologists. 34. 12. Kudish B., Blackwell S., 7. Dell D. L., Sightler S. E. Mcneeley S. G., et al. (2006): and Plauché W. C. (1985): SSoft Operative vaginal delivery and cup vacuum extraction: a compar- midline episiotomy: a bad combi- ison of outlet delivery. Obstet nation for the perineum. Am J Ob- Gynecol Vol 66 pp624-32. stet Gynecol Vol 195 pp749-57.

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175 REPRINTNabeel Bondagji and Hisham Ramadani BENHA MEDICAL JOURNAL

IMMEDIATE MATERNAL AND NEONATAL MORBIDITY ASSOCIATED WITH VACUUM EXTRACTOR DELIVERY, AT UNIVERSITY TEACHING HOSPITAL EXPERIENCE

Nabeel Bondagji MD Frcs(C) and Hisham Ramadani Frcs(C)

Published by Benha Faculty of Medicine Volume 29 Number 1 Jan. 2012

176 Benha M. J. Vol. 29 No 1 Jan. 2012 EVALUATION OF N-ACETYL CYSTEINE (NAC) AS A POSSIBLE PROTECTIVE FACTOR IN THE PREVENTION OF RETINOPATHY OF PREMATURITY (ROP) : HISTOLOGICAL AND IMMUNOHISTOCHEMICAL STUDY

Azza R. El-Hadidy Ph.D, Essam A. El-Mohandess Ph.D, Samar A.Asker Ph.D and Fatma M. Ghonaim MS.c Department of Histology& Cell Biology, Faculty of Medicine, Mansoura University, Egypt

Abstract Background: Retinopathy of prematurity (ROP) is a vasoprolifrative disorder of the eye that primarily affects premature infants. It occurs when the normal pattern of progressive blood vessel growth within the retina is interrupted by premature birth. Aim of the work: This work was carried out to study that hyperoxia potentiates retinal neovascularization and to study the possible protective role of N-acetyl cysteine (NAC) in preventing abnormal angiogenesis. Moreover, to evaluate the role of insulin-like growth factor-1 (IGF-1) in the treatment of ROP. Materials & Methods: 60 litters of rats were obtained and classified into 3 groups. Group I raised from birth in room air and served as control. Group II exposed to 60% oxygen continuously for 14 days then removed with their mothers to room air. Group III placed in the same condition as group II and received intraperitoneal (IP) injection of a single dose of NAC (150 mg/Kg) at the postnatal days 2,6,10. After 35 days, the two eyes from all groups were enucleated and stained with haematoxylin and eosin and immunohistochemical stain for localization of IGF-1. Frozen sections were stained for adenosine triphosphatase (ATPase) enzyme. Results: Signs of neovascularization be- gan to appear in group II while in group III, the neovascularization was less marked. Conclusion: High concentration of oxygen could induce retinopathy in newborn rats and NAC can be used in the treatment of ROP.

177 Azza R. El-Hadidy, et al...

Introduction culty of Medicine. Immediately The blood vessels of the retina after birth a total of 60 litters of begin to develop 3 months after rats were obtained. The duration conception and complete their de- of the experiment was 35 days. velopment at the time of normal The rats were classified into 3 birth. When a baby is born prema- groups: turely, normal blood vessel devel- Group I : It included 20 rats. opment may cease and abnormal They were raised from birth in growth may begin (1). Retinopathy room air, served as control and of prematurity (ROP) was reported sacrificed after 35 days of birth. to be a serious vasoproliferative disorder occurring in infants that Group II : It included 20 rats. are born prematurely and receive They were placed with their moth- high levels of oxygen postnatally ers in an incubat (modified iso- to compensate for their unstable lette) especially designed for this pulmonary status (2). IGF-1 is an experiment and exposed to 60% important contributer to the phys- oxygen continuously for 14 days iological development of the reti- then abruptly removed with their nal vasculature (3). The absence of mothers to room air and sacrificed IGF-1 prevents normal retinal vas- at P35 (21 days after stoppage of cular growth despite the presence O2). of VEGF (4). IGF-I can act as a direct angiogenic factor on retinal Group III : It included 20 rats. endothelial cells or indirectly They were placed in the same con- through increased VEGF gene ex- dition as group II. They received IP pression (5). Following hypoxic ex- (intra peritoneal) injection of a sin- posure, sever ROP has been asso- gle dose of NAC (150 mg/Kg) at ciated with increase in serum IGF- the postnatal days 2,6,10 then 1 level (3). abruptly removed with their mothers to room air and sacrificed at Materials & Methods P35 (21 days after stoppage of Timed pregnant albino rats O2). (250-275 gm) were obtained from the animal house of Mansoura Fa- The two eyes from all groups

178 Benha M. J. Vol. 29 No 1 Jan. 2012 were enucleated and fixed in 10% photoreceptor cells (rod and cone neutral buffered formalin for 24 cells). It is formed of an outer hours. Dehydration was carried lightly stained segment formed of out in ascending grades of etha- parallel processes and an inner nol. Xylol was used as a clearing deeply stained segment. The agent. Impregnation and embed- third one is the outer nuclear ding was done in paraplast. Serial layer (ONL) which was formed of sections were cut at 4-5 micromet- densely stained packed nuclei ter (µm) in thickness and stained containing the cell bodies of rod by: and cone cells. The outer plexi- • Haematoxylin and Eosin form layer (OPL) had a reticular stain (6). appearance. The inner nuclear • Immunohistochemical stain layer (INL) seemed to be thinner for localization of IGF-1 by and its cells appeared larger and paler in comparison to those of Labeled Avidin-Biotin method the outer nuclear layer. The cells (LAB) (8) using polyclonal rabbit were variable in shape, size and anti-IGF-1. density. The inner plexiform layer (IPL) was located between the in- Frozen sections were pre- ner nuclear layer and the gan- pared for histochemical staining glion cell layer of the retina. It had for adenosine triphosphatase (AT- a reticular appearance. This layer Pase) enzymatic activity (7). was thicker than the outer plexiform layer. The ganglion cell layer Results (GCL) was formed of slightly ir- Group I (Control group): regular interrupted row of round- 1-Hx& E: ed variable sized cells. These cells Examination of paraffin sec- were larger and widely separated tions of the retina of the control from each other than those of the rats stained with Hx&E stain re- other nuclear layers. The nerve fi- vealed that it consisted from out- ber layer was composed of axons side to inside of nine layers. The of ganglion cells. The inner limit- first layer is the retinal pigment ing membrane (ILM) was the last epithelium. The 2nd layer is the layer which separated the retina

179 Azza R. El-Hadidy, et al... from the vitreous cavity. of the control retina with IGF-1 revealed weak IGF-I expression in There was normal pattern of the neurons of the ganglion cell vascularity, consisted of blood layer, the inner and outer plexi- vessels confined to the inner reti- form layers and the photoreceptor na which comprised the inner lim- layer of the retina (Fig. 3). iting membrane (ILM), ganglion cell layer (GCL), inner plexiform Group II:- layer (IPL) and inner nuclear layer 1- H x & E:- (INL). No blood vessels were seen Signs of neovascularization be- to extend beyond the internal lim- gan to appear. Patent vascular iting membrane (Fig. 1). loops were developed towards the vitreous (Fig. 4A). Superficial 2- ATPase: newly growing blood vessels were Examination of frozen sections also developed (Fig. 4B). The su- of the control retina stained with perficial newly growing blood ves- ATPase stain revealed that there sels were seen to be connected was a moderate to strong ATPase with the deep intra-retinal ones activity in the endothelium of the (Fig. 4C). There was canalization intra-retinal blood vessels. A of most of the blood vessels strong ATPase activity was seen in (Fig. 4D). the inner segment of photoreceptor cells while a moderate activity 2- ATPase: was seen in the outer and inner A strong positive ATPase ac- plexiform layers. The outer seg- tivity was observed in the endo- ment of photoreceptor cells, out- thelial lining of the patent vas- er nuclear layer, inner nuclear cular loops which extended layer and ganglion cell layer dis- toward the vitreous (Fig. 5A&B). played background levels of activi- Moreover, a strong positive AT- ty (Fig. 2). Pase activity was observed in the endothelium of both the superfi- 3- Immunohistochemical stain- cial and deep blood vessels ing: which were connected to each Immunohistochemical staining other (Fig. 5C).

180 Benha M. J. Vol. 29 No 1 Jan. 2012 3- Immunohistochemical stain- 2- ATPase: ing: There was a moderate to strong IGF-I expression was increased ATPase activity in the endothelium in neurons of the ganglion cell of the intra-retinal blood vessels layer, the inner and outer plexi- (Fig. 8). These findings were simi- forms, the photoreceptor layers of lar to that of the control rats. the retina and in the cytoplasm of the endothelial cells of the su- 3- Immunohistochemical stain- perficial and deep blood vessels ing: (Fig. 6). IGF-I expression in neurons of the ganglion cell layer, the Group III :- inner and outer plexiforms and 1- H x & E:- the photoreceptor layers of the The pattern of vascularization retina was similar to that of the was similar to that of the control age-matched room air-raised rats rats (Fig. 7). (Fig. 9).

Fig. (1): A photomicrograph of a paraffin Fig. (2): A photomicrograph of a frozen sec- section in the retina of control tion in the retina of control rats rats showing the retinal pigment showing a moderate to strong AT- epithelium (1), outer (2a) and in- Pase activity in the endothelium ner segments (2b) of photorecep- of the intra-retinal small blood tor cells, the cells of outer nucle- vessels (arrows). A strong ATPase ar layer (3), outer plexiform layer activity is seen in the inner seg- of reticular appearance (4), the ments (IS) of photoreceptor cells cells of inner nuclear layer (5), and a moderate activity is seen in thick inner plexiform layer of re- the outer plexiform layer (OPL) ticular appearance (6), ganglion and inner plexiform layer (IPL). cell layer (7), nerve fiber layer (8) The outer segment (OS) of photo- and the internal limiting mem- receptor cells, the outer nuclear brane (arrow). No blood vessels layer (ONL), inner nuclear layer (crossed arrows) are seen to ex- (INL) and ganglion cell layer tend beyond the inner limiting (GCL) display background levels membrane. (Hx & E x 400). of activity. (ATPase x 400). 181 Azza R. El-Hadidy, et al...

Fig. (3): A photomicrograph of a paraffin section in the retina of control rats showing weak IGF-I expression in neurons of the ganglion cell layer (1), the inner plexiform layer (2), the outer plexiform layer (3) and the photoreceptor layer of the retina (4) (IHC reaction of IGF-1 x 250) .

Fig. (4): A photomicrograph of a paraffin section in the retina of group II rats showing (A) a patent vascular loop (arrow) (B) superficial newly growing blood vessels (arrow) (C) the superficial newly growing blood vessels are connected with the deep intra-retinal ones (arrow) and (D) canalization of intra-retinal blood vessels (arrow). (Hx & E x 400) .

182 Benha M. J. Vol. 29 No 1 Jan. 2012

Fig. (5): A photomicrograph of a frozen section in the retina of group II rats showing a strong positive ATPase activity in (A and B) the patent vascular loop (arrow) which extends towards the vitreous and (C) the superficial newly growing blood vessels which connected with the deep intra-retinal ones (arrow) (ATPase x 250).

Fig. (6): A photomicrograph of a paraffin section in the retina of group II rat. It shows a strong positive IGF-I expression in neurons of the ganglion cell layer (1), the inner plexiform layer (2), the outer plexiform layer (3), the photoreceptor layer of the retina (4) and in the cytoplasm of the endothelial lining of the superficial (arrows) and deep (crossed arrows) blood vessels. (IHC reaction of IGF-1 x 400) .

183 Azza R. El-Hadidy, et al...

Fig. (7): A photomicrograph of a paraffin Fig. (8): A photomicrograph of a frozen sec- section in the retina of group III tion in the retina of group III rats. rats. The pattern of vasculariza- It shows the same pattern of vas- tion is similar to that of the con- cularity and ATPase enzymatic trol retina. (Hx & E x 400) activity as seen in the control retina. (ATPase x 250)

Fig. (9): A photomicrograph of a paraffin section in the retina of group III rats. It shows a weak IGF-I expression in neurons of the ganglion cell layer, the inner plexiform layer , the outer plexiform layer and the photoreceptor layer of the retina . (IHC reaction of IGF-1 x 400)

184 Benha M. J. Vol. 29 No 1 Jan. 2012 Discussion which is the result of an inade- Retinopathy of prematurity quate blood supply (2). (ROP) was reported to be a serious vasoproliferative disorder A disease model is required to occurring principally but not ex- study ROP. The eyes of animals clusively in infants that are such as mice, rats and cats, born prematurely and receive though born full term, are incom- high levels of oxygen postnatal- pletely vascularized at birth and ly to compensate for their un- are similar to the retinal vascular stable pulmonary status (2). Its development of premature infants. incidence has been rising in re- Exposure of these neonatal ani- cent years, probably because of mals to hyperoxia leads to cessa- the increased survival of very low- tion of normal retinal blood ves- birth weight premature infants in sels development, which mimics modern neonatal intensive care phase I of ROP. When animals re- units (9). Exposure of premature turn to room air, the non-perfused infants to hyperoxia or relative portions of the retina become hy- hyperoxia of the non uterine envi- poxic, similar to phase II of ROP. ronments is associated with this The ischemic portions of the reti- form of retinopathy. It usually na produce angiogenic factors that regresses but can lead to irre- result in neovascularization. This versible vision loss if there is ROP model has been useful to de- progression from retinal neovas- lineate the growth factor changes cularization to cicatrization and in both phases of the disease (11). retinal detachment(10). It is char- Therefore, the aim of this work acterized by two stages; primary was to develop oxygen induced re- stage of retinal vasoconstriction tinopathy in the newborn rat to in which vessels are obliterated in study the hypothesis that hyper- response to high levels of oxygen oxia potentiates pre-retinal neo- which prevents normal vascular vascularization and to establish a growth towards the retinal periph- more reliable animal model of ROP ery and a secondary stage of reti- for studying the possible protec- nal neovascularisation on the re- tive role of N-acetyl cysteine in turn to a normoxic environment preventing abnormal angiogenesis

185 Azza R. El-Hadidy, et al... and to evaluate the role of IGF-1 rat(20) and mice models(11), main the treatment of ROP. ture luminized vessels containing red blood cells was demonstrated. In the current study, the retina of the control rats (group I) was In the current work, the pos- found to consist of nine layers sible use of N- acetyl cysteine these findings were in agreement (NAC) in prevention and treat- with (16). On exposure to hyper- ment of retinopathy of prema- oxia (group II), patent vascular turity was studied. The use of loops and superficial newly grow- NAC was based on its antioxi- ing blood vessels continuous with dant(21), anti-angiogenic(22) and the deeper retinal vessels were de- anti-inflammatory effects(23). The veloped. This might occur as a re- oxidative compounds play a role sult of exposure of the retina to a in ROP. The retina is susceptible relative hypoxia on return to room to oxidative damage due to its air. The relatively low O2 tension high metabolic rate and rapid rate might stimulate the delivery of of oxygen consumption. In addi- some angiogenic factors in isolat- tion, the premature infant has a ed retina. These factors initiate reduced ability to scavenge reac- the second phase of oxygen in- tive oxidative species (OH, H2O2 duced retinopathy and resulted in and O2) increasing its vulnera- vascular proliferation. Complete bility to oxidative stress (24). NAC canalization of most of vessels was significantly reduced lipid peroxi- seen. dation and retinal neovascularization(21). A significant decrease in Growth of new vessels occurred retinal neovascularization and im- when an individual with signifi- munoreactivity was observed in cant obliterated retinal vessels be- the treated groups (group III). Our gan to breathe room air(17&18). results were postulated by(25),(26) The continuity of the superficial and confirmed recently by (21). blood vessels with the deeper retinal vessels confirmed their origin From the results of our study, to be from the retinal rather than it could be concluded that, expo- vitreal or hyaloid vessels(19). In sure to high concentration of oxy-

186 Benha M. J. Vol. 29 No 1 Jan. 2012 gen could induce retinopathy in ty. Proc. Natl. Acad. Sc. USA newborn rats as in human. NAC 98:5804- 5808. can be used in the treatment of ROP. Moreover, IGF-1 is overex- 4- Punglia R. S., Lu M., Hsu pressed during ROP and its role in J., Kuroki M., Tolentino M. J., facilitating the treatment is well Keough K., Levy A. P., Levy N. manifested. S., Goldberg M. A., D'Amato R. J. and Adamis A. P. (1997) : Reg- References ulation of vascular endothelial 1- Ushio-Fukai M. and Alex- growth factor expression by insu- ander R. W. (2004) : Reactive ox- lin-like growth factor I. Diabetes ygen species as mediators of an- 46:1619–1626. giogenesis signaling: role of NAD (P)H oxidase. Mol. Cell Biochem., 5- Smith L. E., Shen W., Per- 264:85-97. ruzzi C., Soker S., Kinose F., Xu X., Robinson G., Driver S., Bi- 2- Dorfman A. L., Joly S., schoff J., Zhang B., Schaeffer J. Hardy P., Chemtob S. and M. and Senger D. R. (1999) : Lachapelle P. (2009) : The effect Regulation of vascular endothelial of oxygen and light on the struc- growth factor-dependent retinal ture and function of the neonatal neovascularization by insulin-like rat retina. Doc. Ophthalmol. 118 : growth factor-1 receptor. Nat. 37-54. Med. 5(12):1390-1395.

3- Hellstrom A., Perruzzi C., 6- Bancroft J. D. and Gamble Ju M., Engstrom E., Hard A. L., M. (2008) : The Hematoxylin and Liu J. L., Albertsson-Wikland Eosin. In Theory and Practice of K., Carlsson B., Niklasson A., Histological Techniques. 6h edi- Sjodell L., Le-Roith D., Senger tion. Churchil Livingstone, Elsevi- D. R. and Smith L. E. (2001) : er. pp121-127. Low IGF-1 suppresses VEGF- survival signaling in retinal endo- 7- Bancroft J. D. and Gamble thelial cells: direct correlation with M. (2008) : Enzyme Histochemis- clinical retinopathy of prematuri- try and its Diagnostic applica-

187 Azza R. El-Hadidy, et al... tions. In Theory and Practice of Invest. Ophthalmol. Vis. Sci. Histological Techniques. 6h edi- 35:101-111. tion. Churchil Livingstone, Elsevi- er .pp405-432. 12- Fawcett D. W. and Jensh R. P. (1997) : The Retina. In 8- Bancroft J. D. and Gamble Bloom & Fawcett's Concise Histol- M. (2008) : Immunohistochemical ogy, 2nd edition. Chapman & Hall, techniques. In Theory and Prac- New York, Toronto, Washington. tice of Histological Techniques. 6h P;305-312. edition. Churchil Livingstone, El- sevier. pp433-472. 13- Ross M. H., Kaye G. H. and Pawlina W. (2003) : Eye. In 9- Good W. V., Hardy R. J., Histology A Text and Atlas. Lippin- Dobson V., Palmer E. A., cott Williams & Wilkins. New Phelps D. L., Quintos M. and York, London. P;799-807 Tung B. (2005) : The incidence and course of retinopathy of 14- Steven A. and Lowe J. S. prematurity: findings from the (2005) : Special senses, Eye. In early treatment for retinopathy of Human Histology. Elsevier Mosby, prematurity study. Pediatrics New York. P;405-409. 116: 15-23. 15- Moravski C. J., Kelly D. 10- Gilbert C. (2008) : Reti- J., Cooper M. E., Gilbert R. E., nopathy of prematurity: a global Bertram J. F., Shahinfar S., perspective of the epidemics, pop- Skinner S. L. and Wilkinson- ulation of babies at risk and impli- Berka J. L. (2000) : Retinal neo- cations for control. Early Hum. vascularization is prevented by Dev. 84: 77-82. blockade of the renin-angiotensin system. Hypertension 36:1099- 11- Smith L. E., Wesolowski 1104. E., McLellan A., Kostyk S. K., D’Amato R., Sullivan R. and 16- Sivakumar V., Zhang Y., D’Amore P. A. (1994): Oxygen- Ling E. A., Foulds W. S. and induced retinopathy in the mouse. Kaur C. (2008) : Insulin-Like

188 Benha M. J. Vol. 29 No 1 Jan. 2012 Growth Factors, Angiopoietin-2, A., Matragoon S., Al-Shabrawey and Pigment Epithelium–Derived M. and El-Remessy A. B. Growth Factor in the Hypoxic Ret- (2010) : Early Intervention of Ty- ina. Journal of Neuroscience Re- rosine Nitration Prevents Vaso- search 86:702-711. obliteration and Neovasculariza- tion in Ischemic Retinopathy. J 17- Lermann V. L., Fortes Fil- Pharmacol Exp Ther. 332(1):125- ho J. B. and Procianoy R. S. 34. (2006) : The prevalence of retinopathy of prematurity in very low 22- Agarwal A., Muñoz-Nájar birth weight newborn infants. J. U., Klueh U., Shih S. C. and Pediatr. (Rio J) 82: 27-32. Claffey K. P. (2004) : N-acetyl- cysteine promotes angiostatin pro- 18- Gilbert C. (2008) : Reti- duction and vascular collapse in nopathy of prematurity: a global an orthotopic model of breast can- perspective of the epidemics, pop- cer. Am. J. Pathol. 164(5):1683- ulation of babies at risk and impli- 96. cations for control. Early Hum. Dev. 84: 77-82. 23- Sadowska A. M., Manuel- Y-Keenoy B. and De Backer W. 19- Finer N. and Leone T. A. (2007) : Antioxidant and anti- (2009) : Oxygen saturation moni- inflammatory efficacy of NAC in toring for the preterm infant: the the treatment of COPD: discordant evidence basis for current prac- in vitro and in vivo dose-effects: a tice. Pediatr. Res.65: 375–380. review. Pulm. Pharmacol. Ther. 20:9-22. 20- Penn J. S., Tolman B. L. and Lowery L. A. (1993) : Vari- 24- Saito Y., Geisen P., Uppal able Oxygen Exposure Causes A. and Hartnett M. E. (2007) : Preretinal Neovascularization in Inhibition of NAD(P)H oxidase re- the newborn rat. Invest. Ophthal- duces apoptosis and avascular mol. Vis. Sci. retina in an animal model of retinopathy of prematurity. Mol. Vis. 21- Abdelsaid M. A., Pillai B. 12;13:840-53.

189 Azza R. El-Hadidy, et al... 25- Ozkan H., Duman N., 26- El-Remessy A. B., Al- Kumral A., Kasap B., Ozer E. A., Shabrawy M., Platt D. H., Beh- Lebe B., Yaman A., Berk T., Yil- zadian M. A., Bartoli M., Ghaly maz O. and Ozer E. (2006) : inhi- N., Tsai N. T., Motamed K. and bition of vascular endothelial Caldwell R. B. (2007) : Peroxyni- growth factor -induced retinal ne- trite mediates VEGF's angiogenic ovascularization by retinoic acid signal and function via nitration in experimental retinopathy of independent mechanism in endo- prematurity. Physiol. Res. 55 : thelial cells. FASEB J., 21:2528- 267-275. 2539.

190 Benha M. J. REPRINTVol. 29 No 1 Jan. 2012 BENHA MEDICAL JOURNAL

EVALUATION OF N-ACETYL CYSTEINE (NAC) AS A POSSIBLE PROTECTIVE FACTOR IN THE PREVENTION OF RETINOPATHY OF PREMATURITY (ROP): HISTOLOGICAL AND IMMUNOHISTOCHEMICAL STUDY

Azza R. El-Hadidy Ph.D, Essam A. El-Mohandess Ph.D, Samar A.Asker Ph.D and Fatma M. Ghonaim Ms.C

Published by Benha Faculty of Medicine Volume 29 Number 1 Jan. 2012

191 Benha M. J. Vol. 29 No 1 Jan. 2012 MICRODEBRIDER OUTCOME VERSUS PARTIAL TURBINECTOMY : IN CHRONIC HYPERTROPHIED TURBINATE

Mohamed A. M. Eltoukhy MD Department of ENT, Benha Teaching Hospital, Egypt

Abstract Background: Chronic hypertrophied inferior turbinate is a common cause of nasal airway obstruction. A variety of surgical procedures are performed in this aspect, but none of them is completely effective. Cau- terization, partial or total turbinate resection, cryosurgery, radiofrequency and laser therapy are different techniques that could be utilized. However, these procedures carry the disadvantages of bleeding, crusting, synechiae formation, imprecise volume reduction and atrophic changes. The ideal turbinate surgery would effectively reduce the volume of sub-mucosal stromal tissue, while preserving the overlying respiratory epithelium. The primary goal of therapy is to maximize the nasal airway for as extended period as possible while minimizing complications. Endoscopic microdebrider-assisted turbinoplasty is effective in decreasing nasal resistance with preservation of the respiratory mucosa. Objective: To compare the subjective and objective outcome results of sub-mucosal reduction by microdebrider versus partial trim- ming of chronic hypertrophied turbinate. Study design: A prospective blind-randomized clinical trial. Methods: Forty-two adult patients of both sexes with bilateral chronic hypertrophied turbinate, who had not responded to systemic or local treatment were enrolled in this study. They were divided equally and randomly into two groups. Group A, underwent inferior turbinate reduction by microdebrider while group B, were exposed to conventional partial turbinectomy. Subjective and objective assessments of nasal patency were done, pre-and up to 9 months postoperatively. Setting: Benha Teaching Hospital. Results: There were objective and subjective improvements in nasal patency for up to 6 months post-operative in both groups, however; 9 months follow up showed better subjective improvement in group A 67.6% compared

191 Mohamed A. M. Eltoukhy with 64.5% in group B (p=0.028). Conclusions: Both microdebrider- assisted turbinate reduction and conventional partial inferior turbinectomy were effective as regard objective and subjective improvement of nasal patency within a limited period postoperatively, however microdebrider technique had a better and longer term subjective outcome.

Introduction minimal short and long term com- Hypertrophied turbinate and plications. Microdebrider achieves nasal septum deviations are the volume reduction with mucosal main causes of chronic nasal ob- preservation, provides real time struction.1 Surgical interference suction and precise tissue resec- can be performed for hypertro- tion.11 Partial inferior turbinecto- phied inferior turbinate in patient my reduces not only nasal conges- refractory to medical treatment. tion, but also sneezing and rhino Moore et al2 confirmed that pa- rhea in patients with allergic rhin- tients suffering from chronic nasal itis.12 Our aim was to compare obstruction and hypertrophied the objective and subjective out- turbinate often benefit from tur- comes of inferior turbinate reduc- binate reduction when other tion using microdebrider versus regimens fail. Partial inferior tur- conventional method. binectomy,3 total inferior turbinectomy,4 cryosurgery,5 sub- Patients and Methods mucosal diathermy,6 laser sur- Forty two consecutive adult pa- gery,7 radiofrequency volume re- tients of both sexes with bilateral duction,8 coblation,9 and micro- nasal obstruction due to substan- debrider-assisted turbinoplasty10 tial mucosal hypertrophy of the in- are all performed indicating the ferior turbinate not responsive to lacking of consensus on a stan- systemic or local medical therapy dard technique with debatable ef- for at least 3 months were en- ficacy. The optimum turbinate rolled in the study. They were surgery would effectively reduce submitted to full medical, ENT the volume of sub-mucosal stro- exam, nasal, nasopharyngeal en- mal tissue and preserve the over- doscopic evaluations and comput- lying respiratory mucosa with er tomography of the paranasal

192 Benha M. J. Vol. 29 No 1 Jan. 2012 sinuses. The exclusion criteria gery by 1, 3, 6 and 9 months. It included: those who had under- was graded on 0-3 scales: 0= gone any kind of nasal; turbi- worse result, 1= no change, 2= nate surgery, significant septum partial improvement, 3= signifi- deviation, nasal valve collapse, cant improvement. Also, a 10 cm nasal polypoidal diseases, recur- visual analog scale (VAS) as sub- rent sinusitis and those who jective measure was used to grade were under antidepressant or nasal obstruction preoperatively hypertension medications. Pa- and after removal of the nasal tients were divided randomly and pack at the times of assessment; a equally into two groups. Group A, score of 0 represents no obstruc- age ranged (18-48 years) and tion and a score of 10 indicates a mean (23.6 yr) composed of 15 complete nasal obstruction. The men and 6 women who under- outcome was considered success- went inferior turbinate reduction ful when the difference between by microdebrider. Group B, age preoperative and postoperative as- ranged (19-53 years) and mean sessment without nasal deconges- (27.3 yr) included 18 males and 3 tion by (VAS) is 50% or more,13 females who were exposed to con- The participant filled out VAS conventional partial turbinectomy. cerning nasal obstruction. In both Method of randomization was car- groups, local infiltration with com- ried out by putting the odd num- bined 2% Lidocain HCL and ber of the patients into the 1st 1:100.1000 epinephrine into the group and the even number into inferior turbinate was done. In the 2nd one. Informed consent group A, Microdebrider (KARL was obtained from each case and STORZ, unidrive ECO- GmbH - all surgical procedures were per- Germany) set at a speed of 3500- formed under general anesthesia 2500 rpm, oscillating mode, was by the same surgeon. The subjec- used in performing inferior turbi- tive assessment of the nasal pa- nate reduction (turbinoplasty). An tency, nasal discharge, postnasal incision of 3-4mm is made medial drip, headache and smell changes to the muco-cutaneous junction was achieved by patient question- of the head of the turbinate with naire preoperatively and after sur- a scalpel, then a sub-mucosal

193 Mohamed A. M. Eltoukhy pocket is dissected by tunneling scope 30˚, 4mm diameter. Postop- with a sucker-dissector in an an- erative saline nasal douching was terior to posterior and superior to advised. Gertner’s method 15 for inferior sweeping motion. Once a objective assessment of nasal pa- pocket has been developed, the tency was done pre- and 1, 3, 6, 9 shaver blade is introduced and its months postoperatively.It is based cutting edge is rotated laterally to on measuring the area of vapor face the bony turbinete and the condensed on a metal plate that sub-mucosal layer is shaved and was placed under the nostrils. The sucked. We used a straight suc- patient was instructed to breathe tion shaver blade 3 mm Ø, length through the nose only with a 12cm (STORZ, Germany), with the closed mouth. By measuring the tip moving in a circular motion to area of condensed vapor, we could remove most of the stromal tissue measure the breathing function of inside the turbinate with preserva- the nose. In this study, we used a tion of the mucosal flap. Thinning flat mirror instead of the metal of the inferior bonny part of the plate.The volume of blood loss in- turbinate was carried out when tra-operatively, was collected in necessary without resection using the suction container and it was aggressive shaver. There were 5 considered significant volume cases of hypertrophied posterior when it is ≥ 100 ml. Post-operative turbinate tails (mulberry-tip) in complications were recorded in group A, where a secondary entry both groups up to 9 months follow point was made at the mid-portion up. Chi-square and t-student test of the inferior turbinate to gain were used for statistical analysis. better access to the posterior end. Partial inferior turbinectomy was Results performed in the 2nd group using We had missed 3 cases in the angled scissors with monopole di- 1st group and 4 cases in the 2nd athermy for hem stasis when nec- group after 6 months follow up. essary.14 It allows de-bulking of Also a further one patient in the the hypertrophied bony and soft 1st group did not follow up 9 vascular tissue after medialization months. of the turbinate. Both techniques were assisted using Hopkins tele- Post-operative outcome as

194 Benha M. J. Vol. 29 No 1 Jan. 2012 shown in table (1) revealed that tomy 19% compared with 4.7% in there was a statistical significant microdebrider group (p<0.05). We objective improvement in group A had mucosal tear in 7 cases repre- up to 69.1% after 6 months fol- senting 33.3% of group A, but low up that declined to 66.9% without mucosal loss. The mean after 9 months; compared with duration of the nasal packing with 81.7% objective improvement after shaver microdebrider was 24.2±6 6 months which decreased to hours, while it was 48.8±8 hours 74.5% at 9 months follow up in in partial turbinectomy and this group B. The objective improve- was due to the sacrificing of nasal ment showed significant results mucosa in the later technique. after the first month post- Most of the patients underwent operatively and it reached its peak microdebrider technique suffered at the 6th month in both groups. from nasal obstruction within the Subjective satisfaction of nasal pa- 1st week as a result of the reac- tency was felt after the 1st week in tionary tumescence of the turbi- the 1st group and after the 1st nate mucosa. The incidence of month in the 2nd group and post-operative infection in partial reached up to 65.9% and 67.6% at turbinectomy was double that oc- 6 and 9 months post-operative curred with microdebrider. Post- with microdebrider technique, nasal drip was lesser in microdeb- while it was 72.1% and 64.5% in rider procedure 28.5% compared comparable time with partial tur- with partial turbinectomy 57.1% binectomy. Long term follow up 9 that lasted up to 4 and 8 weeks months showed that subjective respectively. There was high rate improvement in group A was bet- of nasal crusting with secretions ter than in group B (p< 0.05). 76.2% in partial turbinectomy group compared with 14.2% in mi- The mean volume of blood loss crodebrider-assisted turbinoplas- was 36.1±7.4 ml with microdeb- ty. The incidence of synechiae for- rider technique and 57.8±9.5 ml mation was 9.5% in group A and in partial turbinectomy (mean ± 28.5% in group B; with no muco- SD). There was statistically signifi- sal atrophic changes in both cant blood loss in partial turbinec- groups.

195 Mohamed A. M. Eltoukhy

196 Benha M. J. Vol. 29 No 1 Jan. 2012 Discussion mucous resection of the inferior Partial inferior turbinectomy is turbinate with lateral displace- widely used for treatment of hy- ment of the turbinate bone achie- pertrophied inferior turbinate. It ves a long-lasting improvement of has the advantages of de-bulking the nasal passage with normali- both the mucosal and bony hy- zation of the mucociliary transport pertrophy of the inferior turbi- time and without post-operative nate. Microdebrider-assisted tur- bleeding. 21Yu-Lin et al22 had no binoplasty is mucosa-preserving active bleeding during or post- technique. It provides real time operative with microdebrider in suction with precise tissue resec- managing hypertrophied turbinate tion.16 Elwany and Harrison17 in 80 patients, while we had an showed 75% success rate of im- incidence of 4.7% significant intra proving the nasal patency with - operative bleeding in group A partial turbinectomy after one and this might be attributed to year. Youseph and Gabriel18 had non usage of hypotensive anesthe- 81% improvement of nasal paten- sia in our cases. Dawes 23 record- cy for one year follow up with pared 9% intra-operative bleeding tial turbinectomy in comparison with partial turbinectomy, com- with cryosurgery, while we had pared with 19% of significant satisfactory outcome of 74.5% in bleeding in our partial turbinecto- partial turbinectomy group up to my group. The relatively large 9 months follow up. Endoscopic blood volume loss in this group microdebrider-assisted inferior tu- was due to the inadvertent trauma rbinoplsty decreases nasal resis- to one of the branches of spheno- tance and improves quality of life palatine artery. Friedman et al24 in patients with perennial allergic in a group of 100 cases of chron- rhinitis.11 Microdebrider-assisted ic hypertrophied turbinate using turbinate reduction is superior to microdebrider had 1.6% intra- laser-assisted one.19 Liu et al20 operative bleeding, 55% mucosal had a sustained nasal patency tears and 5% postoperative syn- post reduction of the turbinate hy- echiae, while our results showed pertrophy up to 3 years using the incidence of 4.7%, 33.3% and microdebrider shaver. The sub- 9.5% respectively in group A. The

197 Mohamed A. M. Eltoukhy incidence of mucosal tears in the anatomy of the nasal valve area early patients of the 1st group with microdebrider-assisted proce- with 3500 rpm speed was high, dure. The internal nasal valve pro- which was minimized after reduc- duces the most turbulent air-flow tion the speed to 2500 rpm. and its existence, gives the sensation of nasal patency.26 It is The objective improvements in formed by the lower edge of the partial turbinectomy (group B) upper lateral cartilages, the adja- were better than in microdebrider- cent nasal septum and the anteri- assisted turbinoplasty (group A) at or end of the inferior turbinate.27 6 and 9 months follow up and this In partial turbinectomy, the turbi- may be due to the feasibility of nate head is not preserved and the soft tissue and bone removal in subsequent post-operative soft tis- group B. Postoperative improve- sue contraction may lead to nasal ment of symptoms like nasal dis- valve compromise with unsatisfac- charge, headache and smell tory subjective nasal patency. changes were not as significant as Rhinomanometry and acoustic the improvement of nasal patency, rhinometry are major techniques and this may be due to the con- used for measuring the nasal air- comitant pathological mucosal way.28 However, acoustic rhinom- changes. The persistence of post- etry causes distortation of the na- nasal drip in both groups, for up sal valve area during testing and to 4 and 8 weeks respectively may rhinomanomety has up to 50% be due to the des-improvement of day-today variation in results.29 the epithelial changes of chronic Ciprandi et al30 concluded that hypertrophied turbinate postoper- the use of visual analog scale for atively.25 The subjective improve- assessing the nasal obstruction ment of nasal patency was 67.6% appears clinically relevant in that in the first group, compared with it allows, with good reliability to 64.5% in the second group 9 quantify this symptom in the ab- months follow up and this may be sence of rhinomanometry. The due to the preservation of both: assessment of nasal patency in turbinate function; acclimatiza- this study was depended upon tion, humidification, cleaning and VAS and Gertner’s methods.

198 Benha M. J. Vol. 29 No 1 Jan. 2012 Scheithauer31 emphasized that due to bulky removal of soft tis- radical resection of the turbinate sues and bone within a limited pe- may lead to severe functional dis- riod; however, it carries more intra turbances developing a secondary and post-operative complications. atrophic rhinitis and the anterior Microdebrider - assisted turbino- turbinoplasty seems to fulfill the plasty has its advantages in pre- precautions of limited tissue re- serving functional nasal mucosa, duction and mucosa preservation. the internal nasal valve area and Our results showed that the out- bone together with substantial come improvement of nasal resis- volume reduction. We concluded tance might be consisted with pa- that both microdebrider-assisted tient’s subjective interpretations of turbinoplasty and conventional long term results and satisfaction partial turbinectomy are effective and not to positive objective out- in improving nasal objective and come. The perception of nasal ob- subjective nasal patency within struction at the level of the brain reasonable period, however, tur- needs to be elucidated. Hol & binoplasty has a longer subjective Huizing32 hypothesized that post- outcome term. Microdebrider tech- operative wider nasal cavity does nique keeps the morphological not always mean that the nose and physiological characteristics functions better and the rhino- of the turbinate and can be re- sinus physiological mechanisms peated with less intra and post- required about 2 years for restora- operative morbidity. tion after inferior turbinate surgery. Thus, a longer follow up pe- References riod might be needed in our study 1. Wentges R. R. (1979): Aller- for proper assessment of the ulti- gy and vasomotor rhinitis. Quoted mate outcome. from Clinical Otolaryngology; edit- ed by Maran A and Stell P; Black- Conclusion well scientific publication, p: 234. Partial inferior turbinectomy may give a better objective im- 2. Moore G. F., Freeman T. provement of nasal patency in J., Ogren F. P. and Yonkers A. chronic hypertrophied turbinate J. (1985) : Extended follow up of

199 Mohamed A. M. Eltoukhy inferior turbinate resection for re- 8. Kizilkaya Z., Ceylon K., lief of chronic nasal obstruction. Emir H., Yvangolu A., Unlu I., Laryngoscope; 95:1095-99. Samim E. and Akagun Mc. (2008) : Comparison of radiofre- 3. Sounders W. H. (1982) : quency tissue volume reduction Surgery of the inferior turbinate. and sub-mucosal resection with Annals Otol Rhinol; 91: 445-7. microdebrider in inferior turbinate hypertrophy. Otolaryngol HNS; 4. Salam M.A. and Wengref C. 138:176-81. (1993): Concho-antropexy or total inferior turbinectomy for the hy- 9. Jae Y. L. and Jong D. L. pertrophy of the inferior turbinate: (2006) : Comparative study on A prospective randomized study. J the Long Term Effectiveness be- Laryngol Otol;107:1125-28. tween Coblation-and Microdebrid- er-Assisted Partial Turbinoplasty. 5. Bumsted R. M. (1984) : Laryngoscope;116,issue 5:729-34. Cryosurgery for chronic vasomotor rhinitis : technique and pa- 10. Chia-Min L., Chung-Ding tients selection for improved re- T., Fei-Pong L., Kia-Nan L. and sults. Laryngoscope; 94 : 539-44. Hung-Meng H. (2009) : Micro- debrider-assisted versus radiofre- 6. Mc Comb A. W., Cook J. quency-assisted inferior turbino- and Jones A. S. (1992) : A com- plasty. Laryngoscope; 119:414-18. parison of laser cautery and sub- mucosal diathermy for vasomotor 11. Tsung W. H. and Cheng rhinitis. J Clinical Otolaryngol; 17: P. W. (2006) : Changes in nasal 297-99. resistance and quality of life after endoscopic microdebrider assisted 7. Maladina R., Risavi R. inferior turbinoplasty in patients and Subaric M. (1991) : CO2 la- with perennial allergic rhinitis. ser inferior turbinectomy in the Arch Otolaryngol HNS; Sep vol treatment of non-allergic vasorhi- 182: 673-76. nopathy. J laryngol Otol Rhinol; 29: 167-71. 12. Mori S., Fugida S., Yama-

200 Benha M. J. Vol. 29 No 1 Jan. 2012 da T., Kimura Y., Takahashi N. comparison of four techniques. J and Saito H. (2002) : Long term Laryngol Otol; 104: 206-9. effect of sub-mucous turbinectomy in patients with perennial al- 18. Youseph R. and Gabriel lergic rhinitis. Laryngoscope; 112: R. (1996) : A comparison study of 865-69. partial inferior turbinectomy and cryosurgery for hypertrophic infe- 13.Ciprandi G., Tosca M. A., rior turbinate. J Laryngol Otol; Signori A. and Cirillo I. (2011) : 110: 732-35. Visual analog scale assessment of nasal obstruction might define 19. Dong-Hee L. Eun H. K. patients candidates to spirometry. (2010) : Microdebrider-assisted Rhinology Aug; 49(3):292-6. versus laser-assisted turbinate reduction: comparison of improve- 14. Courtiss E. H., Goldwyn ment in nasal airway according to R. M. and Obriem J. J. (1978): type of turbinate hypertrophy. J Resection of obstructive inferior Ear, Nose & Throat;89(11):541-45. nasal turbinate. Plastic Reconst Surg; 62: 294-55. 20. Liu C. M., Tan C. D., Lee F. P., et al. (2009) : Microdebrid- 15. Gertner R., Podoshin L. er-assisted versus Radiofrequen- and Frodis M. (1984) : A sim- cy-assisted inferior turbinoplasty. ple method of measuring the Laryngoscope; 119(2):414-8. nasal airway in clinical work. J Laryngol Otol; 98: 351-55. 21. Passali D., Lauriello M., Anselmi M. and Bellusi L. 16. Setcliff R. C. and Par- (1999): Treatment of hypertrophy sons D. S. (1994) : The hummer: of the inferior turbinate: long-term new instrumentation for function- results in 382 patients randomly al endoscopic sinus surgery. Am J assigned to therapy. Annals of Rhinol; 8: 275-78. Olology, Rhinology, and Laryngol- ogy; 108: 569-75. 17. Elwany S. and Harrison R. (1990) : Inferior turbinectomy: 22. Yu-Lin C., Ching T. T.

201 Mohamed A. M. Eltoukhy and Hung-Meng H. (2008) : Long changes in anatomy and physiolo- Term Efficacy of microdebrider- gy in normal subjects. Rhinology; assisted inferior turbinoplasty 38: 7-12. with lateralization for hypertrophic inferior turbinate in patients 28. Clement P. A. and with Perennial Allergic Rhinitis. Gordts F. (2005) : Consensus re- Laryngoscope; 118: 1270-74. port on acoustic rhinometry and rhinomanometry. Rhinology; 43 : 23. Dawes P. J. D. (1987) : 169-79. The early complications of inferior turbinectomy. J Laryngol Otol; 29. Erdal S. (2009) : A New 101: 1136-39.6. Surgical Method of Dynamic Nasal Valve Collapse. Arch Otolaryngol 24. Friedman M., Tanyeri Head Neck Surg 135; (No.10) Oct H., Landsperg R. and Caldarelli 1010-1014. D. (1999) : A safe alternative technique for inferior turbinate reduc- 30. Ciprandi G., Mora F., tion. Laryngoscope; 109:1834-7. Cassano M., Gallina A. M. and Mora R. (2009) : Visual Analog 25. George G., Ilias K., Dimi- Scale (VAS) and nasal obstruction trios G. B., Dimitris K., Anasta- in persistent Allergic Rhinitis. sios K. M. and Alkaterini K. Otolaryngol HNS October; 141(4): (2009) : Mucosal changes in 527-29. chronic hypertrophic rhinitis after surgical turbinate reduction. Eu- 31. Scheithauer Marc oliver ropean Archives Oto Rhino Laryn- (2010) : Review article; Surgery of gol; vol 266, No 9:1409-16. the turbinate and empty nose syndrome. GMS Curr Top Otorhinola- 26. Bridger G. P. and Proct- ryngol HNS; Sep 9: Doc 3. er D. P. (1970) : Maximum inspi- ration flow and nasal resistance. 32. Hol M. K. and Huizing K. Annals of Otology; 79: 481-8. H. (2000) : Treatment of inferior turbinate pathology; a review and 27. Shida A. M. and Kenyon critical evaluation of the different G. S. (2000) : The nasal valves technique. Rhinology; 38:157-166.

202 Benha M. J. REPRINTVol. 29 No 1 Jan. 2012 BENHA MEDICAL JOURNAL

MICRODEBRIDER OUTCOME VERSUS PARTIAL TURBINECTOMY : IN CHRONIC HYPERTROPHIED TURBINATE

Mohamed A. M. Eltoukhy MD

Published by Benha Faculty of Medicine Volume 29 Number 1 Jan. 2012

203 Benha M. J. Vol. 29 No 1 Jan. 2012 PEGYLATED INTERFERON / RIBAVIRIN-INDUCED THYROID DYSFUNCTION IN PATIENTS WITH CHRONIC HEPATITIS C

Raghda E. Farag MD, Khaled Farid MD, Asmaa Hegazy MD*, Azza Abdel-Baky MD**, Basem S. Eldeek MD***, Lamiaa Arafa MD**** and Adel Abdel Salam MD* Departments of Tropical Medicine Unit,Internal Medicine*,Clinical Pathology** Community Medicine***,Biochemistry****,Mansoura Faculty of Medicine,Egypt & 4King Abdulaziz University, Kingodom Saudia Arabia

Abstract Background: The therapeutic use of interferon- alfa in treatment of chronic HCV patients is complicated by many autoimmune disorders including production of autoimmune antibodies and exacerbation of preexisting autoimmune diseases. As untreated HCV patients are at risk for developing dysthyroidism, the role of interferon alfa as a surrogate risk factor for developing thyroid dysfunction and a possible relation to treatment response need to be cleared. Aim of work: To determine the prevalence of thyroid dysfunction among patients with chronic hepatitis C under pegylated interferon / ribavirin therapy and to detect risk factors predicting thyroid dysfunction and its relation to treatment response. Patients and Methods: One hundred chronic HCV patients who received peg IFN-ribavirin therapy were included in this study during the period between January 2008 and June 2011 in the Tropical Mediicine Unit, Mansoura University Hospitals. The patients were selected according to the International Program Guideline Selection Criteria. Serum TSH, antithyroglobulin and antithyriod peroxidase antibodies were assayed by ELISA before and 6 months after therapy. Results: The median values and frequency of positive antithyroid antibodies (antithyroglobulin and antipyroxidase) were significantly higher in patients after therapy (p<0.001). In addition, the median TSH value and frequency of thyroid hypofunction were significantly higher after

203 Raghda E. Farag, et al... therapy (p<0.001). Thyroid hypofunction correlated significantly with age (p=0.03), female gender (p<0.001) and antithyroid antibodies (p<0.001) both before and after therapy. Comparison of the frequency of clinical and laboratory variables between responders and non responders revealed only a significantly higher frequency of mild fibrosis grades and lower viral load in the responders (p=0.002 & p=0.045) without significant difference regarding other variables including hypothyroidism (p=0.1). Mild fibrosis and lower viral load levels were also the most significant predictor of response in regression analysis (p=0.012 & p=0.048) without significant difference regarding other variables including hypothyroidism (p=0.34), antiperoxidase or antithyroglobuline antibodies (p=0.53, p=0.5). Conclusion: Interferon alfa therapy can induce thyroid autoimmunity and exacerbate pre-existing thyroid autoimmunity. Presence of antithyriod antibodies before and during interferon therapy correlate with development of thyroid dysfunction mainly hypothyroidism but it can not predict response to therapy. Assessment of thyroid functions and antithyriod antibodies prior and during interferon alfa therapy may help predicting thyroid dysfunction and early management. Keywords: HCV =Hepatitis C virus, SVR= sustained virological response, pegIFN -RBV= pegylated interferon-ribavirin, antithyriod antibodies, thyroid dysfunction. Introduction toid arthritis and autoimmune Chronic infection with hepatitis hepatitis. HCV infected patients C virus (HCV) represents a major also reported thyroid disorders cause of end-stage liver disease like thyroid autoimmunity, hypo- and liver cancer worldwide [1]. The thyroidism and papillary thyroid therapeutic use of IFN alfa/ carcinoma[2,3]. Untreated HCV ribavirin is complicated by many patients are at risk for developing autoimmune disorders including dysthyriodism. Diagnosis of thy- production of autoimmune anti- roid dysfunction may be delayed bodies and exacerbation of pre- as the manifestation of hypothy- existing autoimmune diseases roidism and interferon side effects such as systemic lupus, rheuma- are to some extent similar. So,

204 Benha M. J. Vol. 29 No 1 Jan. 2012 the role of interferon alfa as a surface antigen (HBsAg, Axysm. Ab- rogate risk factor for developing bott) and human immunodeficien- thyroid dysfunction need to be cy virus infection, Major uncon- cleared. The aim of this study is to trolled depressive illness, solid determine the prevalence of thy- organ transplant (renal, heart, or roid dysfunction among patients lung), autoimmune hepatitis or with chronic hepatitis c under other autoimmune condition pegylated interferon / ribavirin known to be exacerbated by pegy- therapy, and to detect risk factors lated-interferon and ribavirin, predicting thyroid dysfunction and pregnant or unwilling to comply its relation to treatment response. with adequate contraception, severe chronic medical disease, and Patients and Methods history of previous treatment with A comparative cross sectional IFN-Ribavirin therapy. Informed study was conducted on chronic consents were obtained from sub- HCV patients who received peg jects included in the study. The IFN-ribavirin therapy during the study was approved by ethical period between January 2008 and committee of Mansoura Faculty of June 2011 in the Tropical Medi- Medicine, Egypt. cine Unit, Mansoura University Hospitals. The patients were se- Liver Histopathology: lected according to following inclu- All patients had liver biopsy sion criteria: Age 18 -60 years, showing chronic hepatitis per- HCV RNA positive in serum, com- formed within 12 month prior to pensated liver disease and ac- starting therapy. Liver histology ceptable hematological and bio- was graded and staged according chemical indices (hemoglobin ≥ 13 to METAVIR fibrosis scaling sys- g/dL for men and 12 g/dL for tem that classifies fibrosis into five women; platelet count (not less stages (F0-F4) and activity into than) ≥ 90,000 mm, neutrophil four grades (A0-A3) [4]. count >1500 /mm3 and serum creatinine < 1.5 mg/dL. Exclu- Blood samples were obtained sion criteria : Overt thyroid dis- from all subjects before and 6 ease, positive for hepatitis B sur- months after initiation of therapy,

205 Raghda E. Farag, et al... serum was isolated and preserved HCV RNA at week 24 from the at -40 ¬C. HCV RNA quantifica- start of treatment or a decline of tion (Stratagene Mx3000P Real- HCV RNA of >2 log10 IU/mL at12 Time PCR System with a detection week of treatment) were enrolled, limit of 15 IU/ml.) was done be- patients with relapse were exclud- fore, and at 12, 24, 48, 72 weeks ed. Serum thyroglobulin and anti- of therapy. thyriod peroxidase antibodies were assayed by ELISA method Drug therapy and response to supplied by calbiotech inc 10461 treatment: Austin Dr, springvally, CA 91978 Patients were given pegylated from serum collected at baseline interferon alpha 2a in a fixed dose evaluation and after 6 month of of 180 micrograms weekly by sub- therapy. Serum TSH was assayed cutaneous injection. All of them at baseline evaluation and after received ribavirin in an adjusted 6,12,18 month of therapy. Thyriod dose according to body weight; pa- dysfunction was defined as TSH tients < 75 kg were given 1000/ level of either more than 4.0 (hy- day mg and those > 75 kg were pothyroidism or less than 0.3 (hy- given 1200 mg/day devided on perthyroidism) mU/L irrespective two or three doses. of freeT3/T4 levels.

Drug safety was assessed by Statistical analysis: clinical evaluation and laboratory Statistical analysis was done tests at week 1, 2, 4 and monthly by SPSS version 18. Quantitative thereafter during treatment. data were non parametric and Mann-Whitney test was used to At the end of the study, 52 of compare between these variables. patients achieved SVR (defined as Qualitative data were compared normalization of liver enzymes by Chi-square test. The associa- and negative HCV RNA PCR at the tion of variables was tested by end of therapy and for 6 months Spearman correlation while after therapy), and 48 of patients multiple regression analysis was who were non-responder (NR) (as used to test the predictive val- they failed to attain a negative ue of studied variables to

206 Benha M. J. Vol. 29 No 1 Jan. 2012 treatment outcome. Significance is (p=0.03), female gender (p<0.001) considered when p value was and presence of antithyroid anti- <0.05. bodies either before or after therapy (p<0.001) (table 4), but on lo- Results gistic regression analysis, only Clinical and demographic data young age (p=0.041), female gen- of the studied patients are pre- der (p=0.002) and presence of an- sented in table (1). During pegylat- tiperoxidase antidodies before ed interferon –ribavirin therapy, therapy (p<0.001) can predict de- hypothyroidism was developed in velopment of hypothyriodism dur- 9 (9%) of our cases while only one ing interferon therapy with an case developed hyperthyroidism overall predictivity (ie) accuracy of (1%) and subjected to subtotal this model 90.3% (table 5). thyroidectomy. Interestingly this female patients complete the Comparison of the frequency of coarse of therapy and develop hy- clinical and laboratory variables pothyroidism latter. The median between responders and non re- values and frequency of positive sponders revealed only a signifi- antithyroid antibodies were significantly higher frequency of mild fi- cantly higher in patients after brosis grades (p=0.002) and lower therapy (P<0.001). In addition, the viral load levels (p=0.045) in the median TSH value with a wide responders without significant dif- range from 1.34 to 112 mIU/ml ference regarding other variables and frequency of thyroid hypo- (table 6). In regression analysis function were significantly higher low fibrosis stage, low viral load after therapy (p<0.0001, P=0.002 were the most significant predictor respectively) (table 2,3). of response to therapy (p=0.012 and 0.048 respectively), with an On univariate analysis of fac- overall predictivity (ie) accuracy of tors correlated with development this model 77.5% while develop- of hypothyroidism during therapy, ment of thyroid dysfunction was thyroid hypofunction was correlat- not one of the predictors of SVR ed significantly with younger age (P=0.34) (table 7).

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Discussion bodies. The prevalence of dysthyr- Thyroid dysfunction is the most oidism during interferon -ribavirin common endocrinopathy associat- therapy ranged from 2.8% in the ed with hepatitis C and interferon- study of Betterle et al. to 16.2% based treatment. Thyroid dysfunc- in the study of Peoc'h et al.[8,9] tions includes hypothyroidism and with hypothyroidism representing to less extent hyperthyroidism most of cases in accordance with or without production of anti- with our results. In this study, thyroid antibodies[5]. In this development of hypothyroidism study, antithyroid antibody (anti- correlated significantly with age, thyroperoxidase and/or antithyro- female gender and presence of an- globulin) before therapy were tithyroid antibodies either before found in 7% of chronic HCV pa- or after therapy. In a study by Koh tients. This is very near to over all et al. they found that most of hy- prevalence worldwide (10%) with a pothyroidism patients developed wide range of 2.9% in a study con- antiperoxidase antibodies during ducted by Baudin et al. in France therapy[10]. As serum levels of an- to10.2% and 24% in another con- tithyriod antibodies usually in- ducted by Carella et al. and Anto- creased with interferon therapy, nelli et al. in Italy[6,7,2]. The wide presence of baseline antithyriod range in the prevalence is most antibodies may be a reliable probably due to the geographic marker of risk to develop dys- difference, genetic background thyroidism as in this study. and difference in gender of studied Many studies reported that up to population. 62.5% of patients with basal positive antithyroid antibodies During pegylated interferon - (especially antithyroperoxidase) ribavirin therapy, hypothyroidism will develop hypothyroidism com- was developed in 9% of our cases pared to patients negative for while only one case developed hy- antithyroid antibody[11,12]. How- perthyroidism (1%). Eight pa- ever, in some studies, hypothy- tients (8%) developed antithyro- roidism may developed during in- globulin antibody and 16% terferon therapy without presence developed anti-peroxidase anti- of antithyroid antibodies but due

212 Benha M. J. Vol. 29 No 1 Jan. 2012 to direct toxic effect of interfer- found that the addition of ribavi- on leads to destructive thyroidi- rin to pegylated interferon-alpha tis or non-autoimmune hypothyri- does not modify the thyroid auto- oditis [12,13,14.15]. antibody pattern but leads to four- fold increase the risk of developing Interferon alpha induced hypo- hypothyroidism [18]. thyroidism is generally benign with some cases resolved sponta- The use of interferon and ribav- neously after cessation of therapy irin in treatment of chronic HCV and most cases in many studies infection is usually associated reveal only partial reversal of thy- with autoimmune disorders. Inter- roid dysfunction [7]. Patients with feron and ribavirin synergize to positive antithyroid antibodies potently stimulate the immune present a better prognosis with system in order to eradicate the up to 80% spontaneous resolu- virus. Interferon -alpha seems to tion compared to 25% of patients act through major histocompati- negative for antithyroid antibod- bility complex class1 antigens to ies[12,16,17]. In this study only produce antithyroid antibodies three (about 33%) of patients who and thyroid dysfunction [19]. developed hypothyroidism get spontaneous recovery with de- The relation between develop- creasing the dose of replacement ment of thyroid dysfunction and hormonal therapy and complete response to therapy still unclear. stoppage of therapy within one In a study conducted by Tran et and half year. al., there was positive and significant association between thyroid The dual effect of pegylated in- disease and viral clearance. This terferon and ribavirin is a matter was not supported by the meta- of controversy. In study using peg- analysis,[5] On the other hand, ylated interferon and ribavirin, no many studies as well as this study aggravation of thyroid dysfunction detected no relation between thy- has been reported [7]. This in con- roid dysfunction and sustained trast with previous study that virological response [20,21].

213 Raghda E. Farag, et al...

Conclusion [4] Bedossa P. and Poynard T. Dysthyroidism is one of major (1995) : An algorithm for grading side effects during interferon ther- of activity in chronic hepatitis C, apy. Presence of antithyriod anti- The METAVIR Cooperative Study bodies before and during interfe- Group Hepatology, 22(6):696-9. rone therapy correlate with thyroid dysfunction mainly hypo- [5] Tran H. A., Malcolm- thyroidism. Assessment of TSH Reeves G. E. and Gibson R. and anti-thyroid antibodies prior (2009) : Development of thyroid and during treatment is recom- diseases in the treatment of mended, and patients should be chronic hepatitis C with alpha- informed about the risk of irrever- interferon may be a good prognos- sibility of thyroid dysfunction. ticator in achieving a sustained virological response: a meta- References analysis. J Gastroenterol Hepatol. [1] Shepard C. W., Finelli L. Jul;24(7):1163-8. and Alter M. J. (2005) : Global epidemiology of hepatitis C virus [6] Baudin E., Marcellin P., infection. Lancet Infect Dis;5: 558- Pouteau M., Colas-Linhart N., 567. Le Floch J. P., Lemmonier C., et al., (1993) : Reversibility of thy- [2] Antonelli A., Ferri C., roid dysfunction induced by re- Pampana A., Fallahi P., Nesti C., combinant alpha interferon in Pasquini M., et al., (2004) : Thy- chronic hepatitis C. Cli Endocrin- roid disorders in chronic hepatitis ol;39:657-661. C. Am J Med; 117:10-13. [7] Tran H. A., Attia J. R., [3] Antonelli A., Ferri C., Fal- Jones T. L. and Batey R. G. lahi P., Pampana A., Ferrari S. (2007) : Pegylated interferon al- M., Barani L., et al., (2006) : pha2 beta in combination with ri- Thyroid cancer in HCV-related bavirin does not aggrevate thyroid chronic hepatitis patients: a case- dysfunction in comparison to reg- control study. Thyroid; 17:447- ular interferon -alpha 2 beta in a 451. hepatitis C population: meta-

214 Benha M. J. Vol. 29 No 1 Jan. 2012 analysis. J Gastroenterol Hepatol: combinant interferon -alpha inter- 22: 472-476. feron.Am J Med; 101 : 482-487.

[8] Betterle C., Fabris P., Zan- [12] Huang J. F., Chuang W. chetta R., Pedini B., Tositti G., L., Dai C. Y., Chen S. C., Lin Z. Bosi E., et al, (2000) : Autoim- Y., Lee L. P., et al., (2006) : The munity against pancreatic islets role of thyroid autoantibodies in and other tissues before and after the development of thyroid dys- interferon-alpfa therapy in pa- function in Taiwanese chronic tients with hepatitis C virus hepatitis with interferon-alpha chronic infection. Diabetes Care; combination therapy. J Viral He- 23:1177-1181. pat;13: 396-401.

[9] Peoc'h K., Dubel L., Cha- [13] Mandac J. C., Chaudhry zouillères O., Ocwieja T., Duron S., Sherman K. E. and Tomer Y. F., Poupon R., et al. (2001) : (2006) : The clinical and physio- Polyspecificity of antimicrosomal logical spectrum of interferon- thyroid antibodies in hepatitis C alpha induced thyroiditis : toward virus-related infection. Am J Gas- a new classification. Hepatolo- troenterol; 96:2978-2983. gy;43: 661-672.

[10] Koh L. K., Greenspan F. [14] Kabbaj N., Guedira M. S. and Yeo P. P. (1997) : Interfer- M., El-Atmani H., El Alaoui M., on -alpha induced thyroid dys- Mohammadi M., Benabed K., et function: three clinical presenta- al., (2006) : Thyroid disorders tions and a review of literature. during interferon alpha therapy in Thyroid;7:891-896. 625 patients with chronic hepatitis C : a prospective cohort study. [11] Roti E., Minelli R., Giu- Ann Endocrinol; 67:343-347. berti T., Marchelli S., Schianchi C., Gardini E., et al., (1996) : [15] Carella C., Mazziotti G., MMultiple changes in thyroid func- Amato G., Braverman L. E. and tion in patients with chronic ac- Roti E. (2004) : Clinical review tive HCV hepatitis treated with re- 169 : Interferon -alpha related

215 Raghda E. Farag, et al... thyroid disease: Pathophysiologi- antibody pattern but increase the cal, epidemiological, and clinical risk of developing hypothyroid- aspects.J Clin Endocrinol Metab, ism. Eur J Endocrinol;146:743- 89:3656-3661. 749.

[16] Watanabe U., Hashimoto [19] Ward D. L. and Bing-You E., Hisamitsu T., Obata H. and R. G. (2001) : Autoimmune thy- Hayashi N. (1994) : The risk fac- roid dysfunction induced by inter- tors for development of thyroid feron-alpha treatment for chronic disease during interferon-alpha hepatitis C: screening and moni- therapy for chronic hepatitis C. toring recommendations. Endocr. Am J Gasteroenterol;89: 399-403. Pract.;7: 52-58.

[17] Lisker-Melman M., Di Bi- [20] Dalgard O., Bjøro K., Hel- sceglie A. M., Usala S. J., Wein- lum K., Myrvang B., Bjøro T., traub B., Murray L. M. and Haug E., et al. (2002) : Thyroid Hoofnagle J. H. (1992) : Develop- dysfunction during treatment of ment of thyroid disease during chronic hepatitis C with interfer- therapy of chronic viral hepatitis on-alpha : no association with ei- with interferon alpha. Gastroente- ther interferon dosage or efficacy. rology; 102: 2155-2160. J Intern Med; 251:400-406.

[18] Carella C., Mazziotti G., [21] Vezali E., Elefsiniotis I., Morisco F., Rotondi M., Cioffi Mihas C., Konstantinou E. and M., Tuccillo C., et al., (2002) : Saroglou G. (2009) : Thyroid dys- The addition of ribavirin to alpha function in patients with chronic therapy in patients with hepatitis hepatitis C: Virus -or therapy re- C virus related chronic hepatitis lated? J Gastro Hepatol; 24:1024- does not modify the thyroid auto- 1029.

216 Benha M. J. REPRINTVol. 29 No 1 Jan. 2012 BENHA MEDICAL JOURNAL

PEGYLATED INTERFERON / RIBAVIRIN-INDUCED THYROID DYSFUNCTION IN PATIENTS WITH CHRONIC HEPATITIS C

Raghda E. Farag MD, Khaled Farid MD, Asmaa Hegazy MD, Azza Abdel-Baky MD, Basem S. Eldeek MD, Lamiaa Arafa MD and Adel Abdel Salam MD

Published by Benha Faculty of Medicine Volume 29 Number 1 Jan. 2012

217 Benha M. J. Vol. 29 No 1 Jan. 2012 THE EFFECT OF STIMULATION OF PROTEIN KINASE Cα ON EPIDERMAL WOUND HEALING IN MICE

Dalia M. Abd El-Monem M.Sc, Omar M. Gabr MD, Kamal G. Botros MD, Rauf F. Bedir MD and Olfat N. Hasan MD Department of Anatomy and Embryology, Faculty of Medicine, Mansoura University, Egypt.

Abstract Background: Effective wound healing leads to restoration of tissue integrity and occurs through a highly organized multistage process involving various cell types. Protein kinase c alpha (PKCα) is thought to have a leading role in keratinocyte differentiation, epidermal tumor promotion and cutaneous inflammation. Aim of the work: The present work is undertaken to explore the involvement of PKCα in the process of epidermal wound healing through the assessment of PKCα stimulation on progress of healing process. Material and Methods: two paravertebral full thickness skin incisions were performed on the back of experimental mice. Tumor- promoting phorbol ester 4ß-12-O-Tetradecanoylphorbol-13-Acetate (TPA) which is stimulant for PKCα is topically applied on the skin wounds. Specimens were collected after 1st, 5th and 7th day. Histologi- cal sections were stained with hematoxylin and eosin and anti (PKCα) immunohistochemistry. Results: the regeneration of injured epidermis was faster in TPA treated group than in unmanipulated wound group as indicted by the increase in the leading edge ratio in TPA treated group as compared with unmanipulated wound group. TPA also promotes formation of intercellular junctions at wound edge and in the newly formed epidermis. TPA treatment also induce epidermal hyperplasia at wound edge and in the neoepidermis as compared with unmanipulated wound group. Conclusion: Stimulation of protein kinase c alpha promotes epidermal

217 Dalia M. Abd El-Monem, et al... hyperplasia which may progress to tumour formation in intact epidermis but precise control of the dose of the stimulant may be helpful to promote healing in wound conditions.

Introduction desmosomes in epithelial cell Healing of skin wounds is a sheets (4). complex programmed sequence of cellular and molecular processes The PKC isoforms have been that include inflammation, cell mi- grouped into three subfamilies of gration, angiogenesis, provisional enzymes: the conventional PKCs matrix synthesis, collagen deposi- (α, β1, β2 and γ), the novel PKCs tion, and re-epithelialization(1). (δ, ε, φ and η), and the atypical Epithelia of animal tissues are PKCs (ξ, λ, and τ). Only 5 mem- confluent cell sheets and remain bers of PKC family (α, δ, ε, η, ξ) are so unless wounded or diseased. expressed in Keratinocytes (5). Desmosomes in vivo are calcium independent (hyperadhesive de- TPA induces prolonged PKC as- smosomes). On wounding, when sociation with the plasma mem- greater tissue liability is required brane and sustained activation in to facilitate cell migration and which PKCα is translocated to the wound repair, desmosomes spon- entire membrane in living cells (6). taneously adopt a lower-affinity Topical application of TPA induced adhesive state. In doing so they epidermal hyperplasia consisting appear to become Ca2+ depen- of four to six nucleated cell layers dent, their intercellular space on day 2 in the wild-type mice(7). narrows and they lose the highly Activation of PKC triggerd desmo- organized structure of their adhe- some formation in low-calcium sive material (2 and 3). Desmoso- conditions, or in cells lacking de- mal adhesion may be rapidly mod- smosomes owing to mutation of ulated from calcium independent adherens junction proteins(8). to calcium dependant in response to wounding and this Materials and Methods modulation is signaled by protein • Animals used:used:- kinase C alpha (PKCα) which is Twenty eight male BALB/c localized to calcium dependant mice aged 8-10 weeks were used

218 Benha M. J. Vol. 29 No 1 Jan. 2012 in this experiment. The experi- mis, dermis and panniculus car- mental protocol and animal care nosus muscle). were in compliance with the re- The animals were subdivided quirements of regulations of the into two groups. It was decided to Committee on animals experimen- examine epidermal wounds at tation of Mansoura Univeristy. one, five and seven days after wounding, using four animals for • Drug used:- each time points. Tumor-promoting phorbol ester 4ß - 12 - O - Tetradecanoylphor- Group A (unmanipulatrd bol - 13 - Acetate (TPA). It is ap- wounds -ve control): plied in a dose of 10µg/200µL in Twelve mice used for studying Dimethyl sulfoxide (DMSO) per epidermal wound healing, distri- wound(7). bution and involvement of PKCα during this healing. Wounds are • Experimental design:- left unmanipulated. A- Collection of unwounded skin specimens: Group B (TPA treated group): Four mice were used. The ani- Twelve mice were used. TPA mals' back were shaved complete- was topically applied every 48 ly. Two unwounded skin speci- hours using micropipette to both mens of 1 cm X 1 cm were excised (right and left) wounds starting from the shaved area after animal immediately after wounding. sacrificaion. • Microscopic examination:- B- Wounding of mice skin:skin:- Paraffin sections were cut at 5 Twenty four mice were used. microns for Hematoxylin and Eo- The wounding done on marks of 3 sin stains and 4 microns for im- cm posterior to the animal's base munohistochemical stain for proof the skull, 1cm long, 2cm apart tein kinase c alpha. and 1cm lateral to the animal's • Morphometric study:- dorsal midline. 2 Full thickness 1. Migration assay (non and wounds were performed on these early healed sections):- marks (cutting through the epider- To quantify the migration of

219 Dalia M. Abd El-Monem, et al... keratinocytes in wound healing, Results the length of the leading edge ratio 1. Haematoxylin & Eosin in each wound was measured ac- stained sections:-sections: cording to the following formula:- •Unwounded skin specimens: Leading edge ratio= (a+b) /c (9) Examination of skin sections revealed normal parts of the skin which is divided into epidermis, dermis, stratum adiposum, panniculus carnosus and stratum fi- brosum. The epidermal thickness was (0.011 ± 0.002 mm) (Fig.1)

• First day after wounding: On the superficial part of the dermis, necrosis was observed. In 2. Epidermal thickness:- addition, a demarcation line con- The thickness of the epider- sisted of polymorph nuclear leuko- mis at the border of the wound cytes was observed under the ne- was evaluated. Ten measure- crotic tissue on the surface of the ments were performed per sec- incisions. tion (5 measurements on each side of the wound, from the Morphometric measurement of margin to 1 mm at the intact the epidermis at margins of unma- side)(10). nipulated wound and TPA treated groups showed increase in thick- Statistical study : The micro- ness (0.022 ± 0.008 and 0.027 ± scopic morphometric analysis of 0.015 mm respectively) as com- each specimen was recorded by pared with unwounded skin sec- digital camera at 4 x magnifica- tions (0.011 ± 0.002 mm). It was tion. The data obtained were sub- observed that epidermal thickness jected to statistical analysis using of TPA treated group was higher independent samples t- test. The than unmanipulated wound (Ta- significance level considered was P ble 1). The epidermis close to the ≤ 0.05 (11). wound margin was formed of 2-3

220 Benha M. J. Vol. 29 No 1 Jan. 2012 layers in unmanipulated wound nipulated wound group. The lead- group increasing to 3-5 layers in ing edge ratio increased in this TPA treated group (Figs. 2 and 3). group to (74.72 ± 15.75%) (Table 2) while in TPA treated group, skin Short Spur of proliferating ke- sections showed complete re- ratinocytes start to migrate (lead- epithelialisation in all mice of the ing edge) to cover raw surface be- group. The newly formed epider- neath blood clot. The leading edge mis was formed of 4 - 6 layers at ratio in unmanipulated wound the central part of neoepidermis. and TPA treated groups was (14.69 ± 7.71 and 29.46 ± 6.01% •Seventh day after wounding: respectively) (Table 2). Leading There was reduction in thick- edge ratio of TPA treated group ness of epidermis at the wound was significantly higher than un- edge of unmanipulated wound manipulated wound (p < 0.05). and TPA treated groups (0.043 ± 0.016 and 0.048 ± 0.020 mm re- •Fifth day after wounding: spectively) (Table 1). The epider- There is increase in thickness mis close to the wound margin of epidermis at the wound mar- was formed of 4 - 6 layers in un- gins of unmanipulated wound and manipulated wound increased to TPA treated groups (0.055 ± 0.016 6-8 in TPA treated group layers. and 0.062 ± 0.021 mm respective- There was also complete bridging ly) (Table 1). The epidermal thick- of the incisions with newly synthe- ness of TPA treated group was sized epithelial cells in all skin higher than unmanipulated sections (Figs. 6 and 7). The new wound. The epidermis at the epidermis is formed of 6-8 layers wound margin was formed of 10- in unmanipulated wound in- 12 layers in unmanipulated creased to 8-10 layers in TPA wound group increasing to 12-14 treated group. layers in TPA treated group. (Figs. 4 and 5). 3-Immunohistochemistry of protein kinase c alpha:alpha:- There is no evidence of com- •Unwounded skin specimens: plete re-epithelialisation in unma- Skin sections revealed positive

221 Dalia M. Abd El-Monem, et al...

PKCα immunoreactivity in the expressed in the cells at wound form of cytoplasmic brown gran- edge with narrow spaces between ules in epidermal cells mainly in them (Fig. 12). The leading edge basal layers (Fig. 8) however, showed positive membranous some cells showed positive mem- PKCα immunoreactivity with com- branous intercellular immuno- plete formation of intercellular reactivity (Fig. 9). junctions and cells become more closely packed together. •First day after wounding: Skin sections of unmanipulated TPA treated group showed wound group showed positive more localization of PKCα immu- weak membranous immunoreac- noreactivity to the membrane of tivity at the wound edge in few basal cells at the wound edge and numbers of basal cells in the form the cells are more closely packed of faint streaks with stepladder together. There was positive mem- appearance inbetween cells. The branous and cytoplasmic PKCα leading edge showed no immuno- immunoreactivity in the cells of reactivity and cells are widely sep- the basal and some suprabasal arated from each other (Fig. 10). layers in the part of neoepidermis close to the peripheral skin while TPA treated group showed at the reaction was weak in the basal the wound edge strong positive cells in the central part of neoepi- membranous PKCα immunoreac- dermis (Fig. 13). tivity as compared with unmanipulated wound group. Some cells in •Seventh day after wounding: the peripheral skin close to the Skin sections of unmanipulated wound edge exhibit very faint wound group showed positive cy- streaks with wide stepladder ap- toplasmic and membranous PKCα pearance (Fig. 11). immunoreactivity with complete formation of intercellular junction. •Fifth day after wounding: The neoepidermis showed strong Skin sections of unmanipulated positive cytoplasmic and membra- wound group showed positive nous immunoreactivity with com- membranous immunoreactivity plete formation of intercellular

222 Benha M. J. Vol. 29 No 1 Jan. 2012 junctions at both sides of neoepi- in the form of strong positive dermis close to the peripheral skin membranous immunoreactivity in (Fig.14). the basal and suprabasal layers of neoepidermis and complete for- TPA treated group showed re- mation of intercellular junction at sults similar to the 5th day with the wound edge and in the neoepi- more organization of cell junctions dermis (Fig.15).

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226 Benha M. J. Vol. 29 No 1 Jan. 2012 Discussion In the present study, skin sec- Cutaneous wound healing is a tions in unmanipulated wound complex process requiring the group revealed time course migra- collaborative interactions be- tion of keratinocytes to cover the tween distinct cell types that re- wound gap till complete re- side in different compartments epithelialisation on 7th day. This of the skin. The basic steps in- finding is in agreement with the clude clotting, inflammation, re- previous results of(14) who found epithelialisation, remodeling of the that re-epithelialisation started on extracellular matrix, and contrac- 6th day in about 20% of wound tion of the wound (1). group. They also reported that the stage of 4 to 7 days post wounding In the present study, histo- is marked by scab formation and logical assessment of skin sec- migration of the epidermal edges. tions in unmanipulated wound group showed time course in- In the present study, skin sec- crease of epidermal thickness tions in TPA treated group showed on wound margin. Similar find- increase of epidermal thickness on ing was reported by(12) in wound margin more than unma- which by one day after surgery nipulated wound. This was in the epidermis was thickened at agreement with(7) who noticed its cut edges because of the mi- that single topical application of totic activity of basal cells. In TPA at 10 µg induced the forma- the present work, on the other tion of a hyperplastic epidermis hand, skin sections in unmanipu- consisting of four to six nucleated lated wound group showed de- cell layers of 42 ± 4.3 µm (mean ± crease in epidermal thickness on SD) thickness on day 2 in the the wound edges on the 7th day. wild-type mice. In the present This can be explained by the fact study, skin sections in TPA treat- that the skin try to regain its ho- ed group revealed time course in- meostasis by differentiation of ke- crease in leading edge ratio more ratinocytes and excess cells un- than unmanipulated wound and dergo apoptosis to regain thin re-epithelialisation started earlier epidermis (13). on 5th day .

227 Dalia M. Abd El-Monem, et al...

The timing of re-epithelia- converging on tight junctions - de- lisation and sequence of hyperpla- smosomes at the cell surface and sia of neoepidermis was more or at cell membranes. less in agreement with (15) who reported that that by 3 days after Examination of wound edge of TPA treatment, there is almost skin sections of unmanipulated complete regeneration of the epi- wound group showed positive dermis, and over the next several membranous immunoreactivity at days there is a marked hyperplas- the wound edge of basal cells in tic response in the epidermis. the form of faint streaks with stepladder appearance inbetween cells PKCα had role in cell activities in the 1st day. Whereas, the cells involved in wound healing as cell showed positive membranous im- proliferation, migration, differenti- munoreactivity with narrow spac- ation, secretion of chemical medi- es between them close to the pe- ators and modulation of cell ad- ripheral skin in the 5th day hesion(4). Immunohistochemistry progressing to positive cytoplas- stained sections of unwounded mic and membranous PKCα im- skin sections for PKCα showed munoreactivity with complete for- positive cytoplasmic and membra- mation of intercellular junction on nous immunoreactivity mainly in the 7th day. This was in agree- basal layers. This was in agreement with(4) who reported that the ment with(16) who reported that distribution of PKCα was found to immunohistochemical and light change after wounding. They stat- microscopy of PKC within mouse ed PKCα was found to be localized skin revealed that basal epidermal to the cell periphery. The cause of cells displayed diffuse cytoplasmic translocation to the cell mem- staining by anti-PKCα antibody. brane could be explained by colo- They also investigated PKCα in in- calization of PKCα with the des- tact mouse skin by immunogold mosomal plaque (2). electron microscopy techniques and reported that Gold beads were Immunohistochemical study of localized primarily over the cyto- wound edge of skin sections of skeleton, including tonofilaments TPA treated group during the 1st

228 Benha M. J. Vol. 29 No 1 Jan. 2012 day showed strong positive PKCα and its central part. In the 7th immunoreactivity localized more day, The neoepidermis showed to the cell membrane as compared strong positive cytoplasmic and with unmanipulated wound membranous immunoreactivity of group. This was in agreement the basal and suprabasal with with(17) who reported that upon complete formation of intercellular activation, PKC enzymes are junctions mainly at both sides of translocated to the plasma mem- neoepidermis close to the periph- brane by RACK (receptor for ac- eral skin. tivated C kinase) proteins to conduct various other signal This could be explained by that transduction pathways. On the the basal cells are the first migrat- 5th day and 7th day, re-epithelia- ing cells so it begins to reform cell lisation process was completed junctions while suprabasal cells with strong immunoreactivity to migrate later so the spaces still the membrane of basal cells at the wide between them. This was in wound edge and the cells are more agreement with(4) who reported closely packed together with com- that PKCα was found to be en- plete formation of intercellular riched at the leading edges of la- junction. mellipodia both at the edge of the sheet and submarginally. Krawc- Examination of progress of zyk and Wilgram (1973)(18) also wound closure and its relation to reported that the dissolution of protein kinase c alpha immuno- desmosomes is a key step in reactivity in skin sections of un- wound healing. They found that manipulated wound revealed that restoration of desmosomes during the leading edge in the 1st day reepithelialization occurs in sever- showed no immunoreactivity. In al steps. the 5th day, leading edge showed positive membranous immuno- Skin sections of TPA treated reactivity with complete formation groups revealed that the leading of intercellular junctions in the edge in the 1st day showed no im- basal layers in the part of leading munoreactivity progressing to pos- edge close to the peripheral skin itive membranous and cytoplas-

229 Dalia M. Abd El-Monem, et al... mic PKCα immunoreactivity in the 3- Garrod, D. (2010) : Desmo- cells of the basal and some su- somes in vivo. Dermatol. Res. prabasal layers in the part of neo- Pract., Article ID 212439, 17 pag- epidermis close to the peripheral es. skin on the 5th day ending to include all parts of neoepidermis 4- Wallis, S.; Lioyd, S.; Wies, even the central part on the 7th I.; Ireland, G.: Fleming, T. P. day. This was in agreement and Garrod, D. (2000) : The al- with (8) who stated that activation pha isoform of protein kinase c is of PKC alpha triggerd desmosome involved in signaling the response formation in low-calcium condi- of desmosomes to wounding in tions as in case of wound edge in cultured epithelial cells. Molecular the present study, or in cells lack- Biology of the Cell, 11(3): 1077- ing desmosomes as in case of 1092. leading edge or neoepidermis in the present work owing to mu- 5- Denning, M. F. (2004) : Ep- tation of adherens junction pro- idermal keratinocytes: regulation teins. of multiple cell phenotypes by multiple protein kinase C iso- References forms. The International Journal 1- Singer, A. J. and Clark, R. of Biochemistry & Cell Biology; 36: A. (1999) : Mechanisms of Dis- 1141-1146. ease Cutaneous Wound Healing. N. Engl. J. Med.; 341(10) : 738- 6- Guan, L. (2007) : Function 746. and regulation of protein kinase c α in the intestinal epithelium. Ph. 2- Garrod, D. R.; Berika, M. D. Thesis, the Faculty of the Grad- Y.; Bardsley, W. F.; Holmes, D. uate School of the State University and Tabernero, L. (2005) : Hy- of New York at Buffalo. peradhesion in desmosomes: its regulation in wound healing and 7- Hara, T.; Saito,Y.; Hirai, possible relationship to cadherin T.; Nakamura, K.; Nakao, K.; crystal structure. J. Cell Sci., 118: Katsuki, M. and Chida, K. 5743-5754. (2005) : Deficiency of Protein

230 Benha M. J. Vol. 29 No 1 Jan. 2012 Kinase C in Mice Results in Im- mathematical model for healing pairment of Epidermal Hyperpla- and remodelling index. Vet. Arhiv. sia and Enhancement of Tumor 80: 637-652. Formation in Two-Stage Skin carcinogenesis. Cancer Research, 65: 11- Munor, H. B; Jacobsen, 7356-7362. S. B. and Bratmar, E. L. (2002) : Statistical methods for health care 8- Hengel, J. V.; Gohon, L.; research, 4th edn., pp: 1-412. Uni- Bruyneel, E.; Vermeulen, S.; veristy of Pennsilvania, Boston Cornelissen, M. and Mareel, M. College Lippinicot, USA. et al. (1997) : Protein kinase C activation upregulates intercellu- 12- Gál, P.; Toporcer, T.; Vi- lar adhesion of a-catenin-negative dinskα, B. ; Mokry, M. ; Novot- human colon cancer cell variants ny, M.; Kilík, R.; Smetana Jr, K.; via induction of desmosomes. J. Gál, T. and Sabo, J. (2006): Ear- Cell Biol., 137: 1103-1116. ly changes in the tensile strength and morphology of primary su- 9- Shirakata, Y.; Kimura, R;, tured skin wounds in rats. Folia Nanba, D.; Iwamoto, R.; Toku- Biologica (Praha)., 52: 109-115. maru, S.; Morimoto, C.; Yokota, K.; Nakamura, M.; Sayama, K.; 13- Woodley, D. T. (1996): Re- Mekada, E.; Higashiyama, S. epithelization, in: The Molecular and Hashimoto, K. (2005) : Hep- and Cellular Biology of Wound Re- arin-binding EGF-like growth fac- pair, Clark, R. A. F (Ed.), Plenum tor accelerates keratinocyte migra- Publishing Corporation, New York. tion and skin wound healing .J. Cell. Sci., 1; 118: 2363-2370. 14- Braiman-Wiksman, L.; Solomonik, I.; Spira, R. and Ten- 10- Lemo, N.; Marignac, G.; nenbaum, T. (2007) : Novel in- Reyes-Gomez, E.; Lilin, T.; Cro- sights into wound healing se- saz, O. and Dohan Ehrenfest D. quence of events. Toxicol. Pathol., M. (2010) : Cutaneous reepithe- 35(6): 767-779. lialization and wound contraction after skin biopsies in rabbits: a 15- Cataisson, C.; Joseloff,

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E.; Murillas, R.; Wang, A.; At- perplasia to the different skin well, C.; Torgerson, S.; Gerdes, tumor - promotion susceptibilities M.; Subleski, J.; Gao, J. L.; of protein kinase Cα, - δ and - Murphy, P. M.; Wiltrout, R. H.; ε transgenic mice. Int. J. Cancer, Vinson, C. and Yuspa, S. H. 93: 635-643. (2003) : Activation of cutaneous protein kinase c alpha induces 17- Goel, G.; Makkar, H. P.; keratinocyte apoptosis and in- Francis, G. and Becker, K. traepidermal inflammation by (2007) : Phorbol esters: structure, independent signaling pathways. biological activity, and toxicity in J. Immunol., 1; 171 (5) : 2703 - animals. Int. J. Toxicol., 26(4): 2713. 279-88.

16- Jansen, A. P.; Dreck- 18- Krawczyk, W. S. and Wil- schmidt, N. E.; Verwiebe, E. G.; gram, G. F. (1973) : Hemidesmo- Wheeler, D. L.; Oberley, T. D. some and desmosome morphogen- and Verma, A. K. (2001) : Rela- esis during epidermal wound tion of the induction of epidermal healing. J. Ultrastruct. Res., 45(1): ornithine decarboxylase and hy- 93-101.

232 Benha M. J. REPRINTVol. 29 No 1 Jan. 2012 BENHA MEDICAL JOURNAL

THE EFFECT OF STIMULATION OF PROTEIN KINASE Cα ON EPIDERMAL WOUND HEALING IN MICE

Dalia M. Abd El-Monem M.Sc, Omar M. Gabr MD, Kamal G. Botros MD, Rauf F. Bedir MD and Olfat N. Hasan MD

Published by Benha Faculty of Medicine Volume 29 Number 1 Jan. 2012

233 Benha M. J. Vol. 29 No 1 Jan. 2012 BIOCHEMICAL ALTERATIONS IN ADIPONECTIN AND THE ACTIVITY OF MYELOPEROXYDASE IN ACUTE MYOCARDIAL INFARCTION INDIVIDUALS

Hussein Abd El-Maksoud Ph.D, Raafat R. Gindi Ph.D* and Yaser M. Abdel-Nabi M.Sc. Department of Biochemistry Fac. of Vet. Med. Benha University and *Fellow in Benha University Hospital, EGYPT .

Abstract The aim of the present study is to find a relationship between plasma Adiponectin level, Myeloperoxidase (MPO) activity, lipid profile and serum nitrite / nitrate and severity of Acute myocardial infarction (AMI ) disease. In order to achieve this aim 30- AMI patients ranged from 35 to over 70 years old and 10- clinically healthy subjects used as control. The result of the present study showed a significant association between the occurrence of AMI and low Adiponectin level, high MPO activity, low Nitrite level, low Nitrate level, high total cholesterol level, high Triacyleglycerols (TG) level, high Low density lipoprotein-cholesterol (LDL-ch) level, low High density lipoprotein-cholesterol (HDL-ch ) level, and high LDL/HDL-ch ratio. These parametrers may all be regarded as predictors or risk factors for AMI. The findings of the present study suggest that hyperlipidemia and vascular inflammation, and oxidative stress are primary interacting mediators in the pathogenesis of AMI.

Introduction proportion of patients with sus- Acute myocardial infarction pected myocardial infraction, bio- (AMI) is a serious medical emer- chemical markers are needed for gency syndrome resulting in most clinical decision making at the cases from complete thrombotic time of admission, because elec- occlusion of infarct related coro- trocardiographic (ECG) recordings nary artery and in a substantial may be inconclusive (1).

233 Hussein Abd El-Maksoud, et al...

The role of adipose tissue as The aim of the present study an endocrinal organ capable of was to show the biochemical re- secreting a number of adipose lationship between Adiponectin, tissue-specific or enriched hor- Myeloperoxidase activity, Nitric mones, known as adipokines, oxide metabolites (nitrite / nitrate) which is an adipose tissue- and Lipid profile in acute Myocar- specific protein accounts for dial infarction patients. 0.01% of the total plasma proteins concentration. Increasing Materials and Methods attention has been paid to the This study conducted on 30 - vascular effects of adiponectin, patients who came in Emergen- where adiponectin was hypothe- cy Center in Hospital Faculty of sized to play a role in AMI (2). Medicine Alexandria University) were complaining of acute chest Myeloperoxidase (MPO) is a pain and (10- healthy individu- member of heme peroxidase als) as a control healthy group. superfamily, abundant in neu- After application of the Inclusion trophils, monocytes, and macro- Criteria and the Exclusion crite- phages. This enzyme plays a criti- ria for Diagnosis of AMI patients cal role as host defenses and according to (5): They classified inflammatory tissue injury. It also into four groups according to played a pathophysiologic role in ages: Group I: Control healthy in- AMI (3). dividuals consists of 10-persons with ages ranged from 35-70 Nitric oxide (NO) is a signal- years. ing molecule involved in the regulation of many biological process- And diseased groups : - es including activities in the Group II: Consisted from 10 - cardiovascular, nervous, and im- AMI patients with age from 30 to mune systems. It also had a role 50 years. in both acute and chronic inflam- Group III: Consisted from 10 - mation. Moreover, NO was pro- AMI patients with age from 51 to posed to play a role in AMI athero- 70 years. genesis (4). Group IV: Consisted from 10 -

234 Benha M. J. Vol. 29 No 1 Jan. 2012 AMI patients with age more than The remained 5ml blood 70 years. poured in tubes without anti- coagulants allowed to clot then, The diagnosis of AMI was final- and centrifuged for isolation of ly established at coronary care serum which used freshly for ni- unit (CCU) by a cardiologist guid- tric oxide metabolites (Nitrate/ ed by the world health organiza- Nitrite)(9), Total cholesterol(10), tion (WHO) criteria. Triacylglycerols (TG )(11). HDL-ch and LDL-ch concentrations(12), Sampling and VLDL-ch (13). Ten ml blood were withdrawn from cardiac catheter during coro- Results nary angiography for every patient The presented data revealed and control fasting healthy sub- that AMI is accompanied by sig- jects after overnight fasting and nificant decrease (P<0.05) in the collected. The blood samples di- mean values of plasma adiponec- vided into 2 portions the first one tin level, serum nitrite, serum ni- poured on 5% Ethylenediamine- trate and serum HDL-cholesterol tetraacetic acid (EDTA). Plasma and a significant increase (P<0.05) samples were collected after cen- in the activity of myeloperoxi- trifugation and used freshly for dase, serum total cholesterol, tria- determination of Adiponectin con- cylglycerol, LDL-cholesterol and centration (6), The resulting gra- VLDL-cholesterol on comparison nulocyte/ erythrocyte pellets were with the mean values recorded in further processed for separation of the control healthy individual Neutrophils to assess myeloperox- group. idase activity(7&8).

235 Hussein Abd El-Maksoud, et al...

236 Benha M. J. Vol. 29 No 1 Jan. 2012 Discussion associated with low adiponec- Millions of patients present in tin concentration as stated that hospitals annually with chest by(17). pain, but only 10-15% has myocardial infarction which is the ma- Moreover, the recorded de- jor killer in the western industrial- creased values of adiponectin in ized countries.. sensitive AMI may be related to accumula- biochemical assays are essential tion of adiponectin in atheroscle- for identification of novel markers rotic vascular walls through its associated with the extent or se- binding to collagens that are verity of AMI allowing better in- abundant in the vascular intimae. sight into the pathobiology of coro- Such accumulation may suppress nary atherosclerosis and may adiponectin elimination half-life facilitate the development of pre- from plasma. (18). ventive and therapeutic measures for that disease (14). The present study showed a significant negative correlation be- The present study showed that tween adiponectin level and age in plasma adiponectin level was sig- AMI patients. This result could be nificantly lower in AMI patient due to a possible disturbed adipo- groups (group II, III and IV com- kines synthesis or secretion in old pared to the control group which age individuals, an explanation were in agreement with (15&16) that might support the concept of who reported that the link be- old age being a risk factor (19). tween hypoadiponectinemia and AMI events which might be medi- The present study showed a ated by angiographically for quan- significant positive correlation be- tified the disease severity. tween adiponectin and nitric oxide metabolites (nitrite/nitrate) levels The recorded low adiponectin which could be explained by the concentration in AMI patients was assumption that adiponectin in- could be attributed due to adipo- creases NO production by promot- nectin gene mutations in AMI pa- ing the activity of eNOS or by ame- tients where, such mutations were liorating the suppression of eNOS

237 Hussein Abd El-Maksoud, et al... activity by ox-LDL (20). process, to accumulate within the sub-endothelial space, and to con- The MPO activities serve as a sume NO thus interfering with its strong and independent predictor atheroprotective effect (23). of endothelial dysfunction in human subjects, giving a mechanis- The present study showed that tic link between oxidation, inflam- serum levels of both nitric oxide mation and cardiovascular disease metabolites (nitrite and nitrate) (21). were significantly lower in AMI patient groups compared to the con- The present study showed a trol group. significant increase in MPO activity in AMI patient groups (group I, The degree of decrease in ni- II and III) compared to the control trite level was correlated with the subjects this might be related to increasing number of cardiovascu- it's secreted from activated leuko- lar risk factors. and there was cytes under inflammatory condi- high level of NO metabolites in tions which promotes numerous both acute and chronic inflamma- pathological events (22). tory conditions including atherosclerosis (24). In this respect MPO has been shown to active metalloproteinas- Reduced NO bioavailability is es and to promote destabilization the hallmark of endothelial dys- and rupture of atherosclerotic function occurring early in cardiac plaque surface, thus MPO could diseases. It has potentially anti be related to the future risk of AMI atherosclerotic as it inhibits events (21). platelet aggregation and adherence to endothelial cells, monocyte The present study showed a adherence to endothelial cells, ex- significant negative correlation be- pression of monocyte chemo- tween MPO activity and nitric ox- attractant proteins, vascular ide metabolites (nitrite/nitrate) smooth muscle proliferation, and levels due to it,s uptake by endo- in vivo intimae proliferative re- thelial cells through transcytotic sponse to cardiac injury (25).

238 Benha M. J. Vol. 29 No 1 Jan. 2012 The detected decreased values The present study showed a of NO could be related to the hy- significant positive correlation percholesterolemia was found to between levels of NO metabo- be accompanied by increased su- lites and adiponectin and a per-oxide production which ac- significant negative correlation counts for significant proportion between levels of NO metabolites of NO deficit (26). and MPO activity.

Moreover, it was reported that The low level of NO metabolites dyslipidemia decreases basal ac- in the current study could be col- tivity and protein expression of lectively due to Hypoadiponectine- cGMP-dependent protein kinase, mia, which results in decreased and increases activity of cGMP- production of NO and the in- phosphodiesterase. The latter ef- creased MPO activity which re- fect results in interference with sults in increased NO scavenging, NO signaling pathway as stated and MPO-derived oxidants (e.g. by (27). HOCL, chlorinated arginine) on NOS as proved by (25). Also the significantly decreased NO metabolites in AMI The recorded low level HDL-ch patients may be due to the in AMI patients could be due to hypertension followed AMI as HDL has a protective effect stated by(28) Who reported that against the inflammation followed hypertensive patients showed oxi- AMI which has been attributed to dation of BH4 which results in its role in reverse cholesterol loss of NOS demyelization and transport. This is beside the possi- generation of significant amounts ble anti - inflammatory and anti- of super oxide besides reduction oxidant actions of HDL It can pre- of endothelial NO production. vent LDL oxidation by hydrolyzing Meanwhile L-arginine, a NO pre- lipid peroxides, hydroperoxides cursor, acutely improves endo- and hydrogen peroxide and Parax- theliul-dependent dilatation of onase can also maintain the ca- brachial artery in hypertensive pa- pacity of HDL to induce reverse tients. cholesterol transport. (29)

239 Hussein Abd El-Maksoud, et al...

In addition, HDL-associated en- significant correlation between lip- zyme, lecithin cholesterol acyl id profile and Adiponectin and transferase (LCAT), can prevent MPO. In addition, a significant the accumulation of oxidized lip- correlation was found between lipids in LDL and increases lipopro- id profile and NO metabolites as tein oxidation and endothelial dys- mentioned before (33). function (30). In conclusion, AMI occurs ac- The recorded high serum level companied by low levels of adipo- of cholesterol might be due to in- nectin, nitrite, nitrate, and HDL- duction of thrombosis through ch, and high levels of MPO activi- stimulating platelet adhesion and ty, total cholesterol, TG, LDL-ch aggregation, enhancing the proco- ratio. These may all be regarded agulant activity of endothelium, as risk factors and could be used reducing the fibrinolytic activity as diagnostic tools for AMI. of endothelium, contributes to the formation of atherosclerotic The findings of the present plaques in arteries (31). study show the importance of NO as a predictor of AMI severity, a Moreover the hypertriacylegly- common mediator for the action of ceridemia causes an independent adiponectin and MPO, besides its risk factor for AMI, since high cir- possible interaction with dyslipi- culating levels of TG-rich lipopro- demia, hypertension. These find- teins can inhibit the efflux of cho- ings point to the importance of NO lesterol from macrophages to apo- in diagnosis and treatment of AMI. A1, they also directly influence endothelial function through modu- References lating NO and endothelin-1. and 1- Bakker A. J., Koelemoy M. may thereby inhibit the arterial re- J. and Gorgels J. P. (2003): Fail- verse cholesterol transport and ure of new biochemical markers to promote the formation of atheros- exclude acute myocardial infarc- clerotic lesion (32). tion.242:1220-2.

The present study showed a 2- Kershaw E. E. (2004): Adi-

240 Benha M. J. Vol. 29 No 1 Jan. 2012 pose tissue as an endocrine organ. pass surgery in morbidly obese J Clin Endocrinol Metab; 89(6): subjects. J Clin Endocrinol Metab; 2548-56. 88: 1594-602.

3- Abu-Soud H. M. and Hazen 7- Hjorth R., Jonsson A. K. S. L. (2000): "Nitric oxide modu- and Ketblad P. (1981) : Arapid lates the catalytic acitvity of mye- method for purification of hu- loperoxidase" J Boil Chem; 275 man graulocytes using percoll.A (8): 5425-30. copaison with dextran sedimenta- tion. J Immunol Methods; 43: 95- 4- Channon K. M., Qian H. 106. S. and George S. E. (2010): Nitric oxide synthase in athero- 8- Gross G. J. and Aucham- sclerosis and vascular injury. Ar- pach J. A. (1992): Blockage of terioscl Thromb Vasc Boil; 20: ATP - sensitive potassium chan- 1873. nels prevents myocardial precon- ditioning in dogs. Circ Res; 70: 5- Alpert J. S., Thygesen K., 223-33. Antman E. and Bassand J. P. (2010) : " Myocardial information 9- Bories P. N. and Bories C. redefined-a consensus document (1995) : Nitrate determination in of the joint European Society of biological fluids by enzymatic cardiology/ American College of one step assay with nitrate re- Cardiology committee for the re- ductase. J Clin Chem; 41 : 904- definition of myocardial informa- 7. tion". J Am Coll Cardial; 36(3): 959-69. 10- Allian C. C., Poon L. S., Chan C. G. S., Richmond W. 6- Faraj M., Havel O. J., and Fu P. C. (1974): Enzymatic Blank D. and Sniderman A. determination of total serum cho- D. (2003) : Plasma acylation- lesterol. J. Clin Chim 1974; 20 : stiulating protein, adiponectin, 470-5. leptin and ghrelin before and after weight loss induced by gastric by- 11- Carr T. P., Andresen C. J.

241 Hussein Abd El-Maksoud, et al... and Rudel L. L.(1993) : Enzymat- R. J. and Lip G. Y. H. (2005): ic determination of triglyceride, Adiponectin in coronary heart dis- free cholesterol, and total choles- ease: ethnic differences and rela- terol in tissue lipid extracts. Clin tion to coronary artery severity. Chem 1993; 26(1): 39-42. Heart; 91: 1605-6.

12- Baldo G. (1985): Choles- 17- Ohashi K., Ouchi N., Ki- terol determination in HDL, HDL2 hara S., Funahashi T., Nakamu- and HDL3 fractions after polyan- ra T. and Sumitsuji S. (2004): ion precipitation: a comparison Adiponectin I164T mutation is as- between chemical extractive and sociated with metabolic syndrome totally enzymatic procedure. Clin and coronary artery disease. J Am Chem Acta 1985; 146(1): 8 1-6. Coll Cardiol; 43(7): 1194-200.

13- Bauer J. D. (1982) : 18- Civitarese A. E., Ukropco- Clinical laboratory methods 9th, va B., Carling S., Hulver M., De Ed, the C.V.company waistline In- Fronzo R. A. and Mandarino L. dustrial Missorri:63116 chapter (2006): Role of adiponectin in hu- 33:555. man skeletal muscle bioenerget- ics. Cell Metabolism; 4(1): 75-87. 14- Ross R. (2009): Athero- sclerosis- an inflammatory dis- 19- Shoji T., Koyama H., Fu- ease. N Eng J Med; 340 (2):115- kumoto S., Maeno T., Yokoyama 26. H. and Shinohara K. (2005) : Platelet activation is associated 15- Tsukinoki R., Morimoto with hypoadiponectinemia and ca- K. and Nakayama K. (2005): rotid atherosclerosis. Atheroscler- Association between lifestyle fac- osis; 188(1): 190-5. tors aqnd plasma adiponectin level in Japanese men. Lipid in 20- Motoshima H., Wu X., Health and Disease; 4: 27. Mahadev K. and Goldstein B. J. (2004): Adiponectin suppresses 16- Lim H. S., Tayebjee M. H., proliferation and superoxide gen- Tan K. T., Patel J. V., Macfadyen eration and enhances NOS activity

242 Benha M. J. Vol. 29 No 1 Jan. 2012 in endothelial cells treated with Vasc Surg 2004; 40(1) 187-93. oxidized LDL. Bioch Biophys Res Comm.; 315(2): 267-71. 26- Pearson T. A., Mensah G. A. and Alexander R. W. (2003): 21- Baldus S., Heeschen C., Markers of inflammation and car- Meinertz T., Zeiher A. M., Eise- diovascular disease: application to rich J. P. and Munzel T. clinical and public health practice. (2003): Myeloperoxidase serum Circulation; 107:449-511. levels predict risk in patients with acute coronary syndromes. Circu- 27- August M., Wingerter O., lation; 108: 1440. Oelze M., Wenzel P., Kleschyov A. l. and Diaber A. (2006): 22- Yokoyama M. (2004): Ox- Mechanisms underlying dysfunc- idant stress and atherosclerosis. tion of carotid arteries in geneti- Curr Opin Pharmacol; 4(2): 110-5. cally hyperlipidemic rabbits . Ni- tric Oxide 2006. Article in press , 23- Baldus S., Eiserich J. P. Corrected Proof. and Mani A. (2001): Endothelial transcytosis of myeloperoxidase 28- Taniyama Y. (2003): Reac- confers specificity to vascular tive Oxygen species in the Vascu- ECM proteins as targets of tyro- lature. Molecular and Cellular sine nitration. J Clin Invest; 108: Mechanisms. Hypertension 2003 ; 1759-70. 42 : 1075.

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244 Benha M. J. REPRINTVol. 29 No 1 Jan. 2012 BENHA MEDICAL JOURNAL

BIOCHEMICAL ALTERATIONS IN ADIPONECTIN AND THE ACTIVITY OF MYELOPEROXYDASE IN ACUTE MYOCARDIAL INFARCTION INDIVIDUALS

Hussein Abd El-Maksoud Ph.D, Raafat R. Gindi Ph.D and Yaser M. Abdel-Nabi M.Sc.

Published by Benha Faculty of Medicine Volume 29 Number 1 Jan. 2012

245 Benha M. J. Vol. 29 No 1 Jan. 2012 PEDIATRIC ILIOINGUINAL/ILIOHYPOGASTRIC BLOCK (HIGH OR LOW APPROCHES) “ANALGESIC & SURGICAL OUTCOME-SATISFACTION “

Mohamed A. Ghanem MD Department of Anaesthesia and Surgical Intensive Care, Faculty of Medicine, Mansoura University, Egypt.

Abstract Background: Ilioinguinal/iliohypogastric (IHNB) levobupivacaine produces effective analgesia after herniorrhaphy. This present study comparing two different block techeques aiming to detect the block effectiveness, the postoperative analgesic outcome, the surgon satisfa- tion and surgical time prolongation in some cases of inguinal hernia repair have been observed in patients underwent IHNB block with accidental injection of the LA in the surgical field and to which extent this problem affect the surgical time, performance and results. Patients & Methods : 60 male pediatric patients admitted to pediatric surgery department IbnSina Hospital - ministry of health in Ku- wait for Inguinal hernia repair, aged from 3- 8 years, body weight 25 Kg or less, subdivided into two groups each group 30 patient underwent a separate analgesic technique: just after completion of anesthesia induction & LMA insertion in Group I (high block group- pediatric high approach ) 1cm above and 1 cm medial to the anterior superior iliac spine (ASIS) nerve block using 0.5 ml/kg of 0.5% levobupivacaine HCL plus 0.5ml epinephrine 1/200000. Group II (low block group-pediatric low approach) =1 cm below and 1 cm medial to the anterior superior iliac spine (ASIS) nerve block using 0.5 ml/kg of 0.5% levobupivacaine plus 0.5ml epinephrine 1/200000 . In both groups and just after the end of surgery& before LMA removal Intramuscular (IM) pethedine 1mg/Kg. For both groups an increase in heart rate under General anesthesia indicates block less effectiveness or even failure. Results : (OPS) pain score: Group II showed significant increase in comparison to group I at 60, 90,120minutes. Heart rate (HR) values in the 1st 20 min after surgical incision showed significant increase

245 Mohamed A. Ghanem in Group II in comparison to Group I at the 0 ,5,10 minutes. Duration of surgery showed Significant increase in pure operative time in Group II In comparison to Group I. Postoperative duration to discharge showed Significant increase in postoperative duration to home discharge in Group II In comparison to Group I. As regard the surgeon satisfaction about the field clarity showed that Group II revealed 20% surgeon non satisfaction compared to 0% in Group I . Conclusion: Ilioinguinal /iliohypogastric block at level above the ASIS just after anesthesia induction in pediatrics plus the IM pethedine injection just before recovery highblock group (group I ) produces efficient intraoperative &postoperative analgesia less operative time, early home discharge postoperatively with high surgeon satisfaction. • Key words Ilioinguinal, Iliohypogastric, pediatric, Approaches, Block. Introduction effective pain control after hernior- Preemptive analgesia is crucial rhaphy(1). for pediatric patients subjected to surgery as that age of pa- Ilioinguinal nerve originates tients mostly can’t explain from the lowest thoracic&1st their sufferings & pains except lumbar nerve roots then goes by crying and aggressive move- anteriorly near by the anterior ment. Pain following hernia re- superior iliac spine(ASIS) then pair is moderate to severe and branches to supply the tissues mostly opioids as a single anal- of the inguinal region and gesic is not enough to control upper scrotum(2). IHNB blocks such pain. (1) Simple opioid an- is effective for Analgesia and / algesic injection has the draw- or anesthesia for any somatic backs of respiratory depression procedure at the lower abdomi- & postoperative nausea, vomit- nal wall / inguinal region such ing, sedation and dizziness. Ili- as inguinal herniorrhaphy (3). oinguinal / iliohypogastric block, IHNB for herniorrhaphy helps in when perfectly done, utilizing le- rapid oral intake after surgery, vobupivacaine [less cardiotoxic less need for Postoperative analge- amide LA & pure S (-)- enantio- sia & shorter time to home readi- mere of racemic bupivacaine] (15), ness compared to spinal anes- alone produce to some extent thesia.(4)

246 Benha M. J. Vol. 29 No 1 Jan. 2012 Anatomical Consideration : the surgical field during dissection Union between lowest thoracic & which requires clear undisturbed 1st lumbar nerve roots gives rise surgical field planes(surgeon opin- to ilioinguinal nerve which comes ion goal directed issue). out of the lateral edge of the psoas muscle; then pierces the anterior Full detailed medical history abdominal wall near the iliac crest from the parents was taken .The &below the hypogastric nerve. selection of the patient as ASA then pierces the transversus ab- physical status I or II, undergoing dominis and internal oblique mus- minor day case surgical proce- cles supplying them& send neural dures in supine position in specif- branches connection to the iliohy- ic (Inguinal hernia repair), admit- pogastric nerve. The nerve then ted to pediatric surgery supplies sensory branches to in- department, patients aged from nervate the symphysis pubis, the 3- 8 years & body weight 25 Kg or superior and medial walls of the less, subdivided into two groups femoral triangle, the penil root & each group underwent a separate( anterior part of the scrotum in the block-analgesic) technique : male or the mons pubis and labia Group I (high block group): majora in the female.(4) IHNB block performed simultaneously by locating a point (pediat- Patients & methods ric high approach ) (7) 1cm above After approval by the ethics and 1 cm medial to the anterior committee of the regional Medical superior iliac spine (ASIS) nerve board and with parents written in- block using 0.5 ml/kg of 0.5% le- formed consent, 60 male pediatric vobupivacaine HCL (Chirocaine patients (dmitted to pediatric sur- 5mg/ml -0.5% -10 ml plastic vials gery department in IbnSina pedi- each ) plus 0.5ml epinephrine 1/ atric surgery Hospital - Ministry of 200000(5) can be injected to pro- health in Kuwait) were included in duce surface analgesia just after this present study &why male completion of the general anesthe- only ? this is for the seek of the sia induction IV line fixation & surgical importance of the pres- LMA insertion, then after the end ence of the spermatic cord near by of surgery & just before LMA re-

247 Mohamed A. Ghanem moval Intramuscular (IM) pethe- above 8 years, infection at the dine 1mg/Kg in the lateral aspect site of the block, temperature ≥ of the quadriceps femoris muscle. (38oC), respiratory tract infection, bronchial asthma ,and mono- Group II (low block group): amine oxidase inhibitors treated IHNB block performed simultane- patients as these drugs with ously by locating a point (pediat- pethdine such patients may suffer ric low approach) (9) =1 cm below agitation, delirium, headache, and 1 cm medial to the anterior convulsions. superior iliac spine (ASIS) nerve block using 0.5 ml/kg of 0.5% le- Basic monitoring tools Non in- vobupivacaine HCL (Chirocaine vasive blood pressure (NIBP), arte- 5mg/ml -0.5% -10 ml plastic vials rial O2 saturation oxymetry probe each ) plus 0.5ml epinephrine 1/ (SaO2), capniography, and ECG. 200000 (5)can be injected to pro- There was no sedative or analgesic duce surface analgesia just after premedication. LMA Size No 1 for completion of the general anesthe- child from <5 Kg bodyweight ,No sia induction, IV line fixation 1.5 for child from 5-10Kg body- &LMA insertion, then after the weight, size No 2 for child 10- end of surgery& just before LMA 20Kg ,and size no 2.5 for chil- removal, (IM) pethedine 1mg/Kg dren from 20-25 Kg bodyweight . in the lateral aspect of the quadriceps femoris muscle. The postop- For all cases preoperative fast- erative analgesic outcome of high ing fixed time 6 hours, se- and low techniques of IHNB block voflurane 8 % inhalational induc- is the same(9) For both groups tion with N2O/O2 ratio 2/1 an increase in heart rate during via mask T-piece bag re- the 1st 20 minutes after surgical breathing open system targeting incision under effective General deep inhalational anesthesia with anesthesia indicates less effective a preserved respiratory drive, or even unsuccessful block. during that time Intravenous access was secured and IV Exclusion criteria : Obesity fluid infusion connected and or bodyweight over 25 Kg ,age started (Dextrose 5% in Quarter

248 Benha M. J. Vol. 29 No 1 Jan. 2012 Normal saline). Muscle relaxants according each group as follow: were avoided. After loss of eyelid Group I : (high block tech- reflex, LMA insertion (after back nique): 1cm above and 1cm medi- lubrication positioning performed al ASIS(8). according to the published LMA instruction manual, semi-inflated Group II : (low block tech- cuff with the back toward the nique)1cm below and 1cm medial hard palate and the anterior ASIS(9) wall penetration to 1.5 cm cuff facing the tongue upper sur- should prevent this complication face then introduction deep till of gut perforation, using 22 gaged highest resistance then inflating needle that was inserted perpen- & securing the LMA). Airway pa- dicular then redirected laterally tency & lung aeration was con- and medially in 45 degrees fan firmed by regular full capniogram wise manner also up and down in- waves and bilaterally chest breath filtration (fan technique), needle sounds auscultation. The LMA introduction through the ‘tented’ was then taped to the chin and skin at the located point then after upper jaw. Spontaneous respirato- detecting the first ‘fascial click fol- ry drive dependant ventilation was lowing penetrating the (external instituted using a semi closed cir- oblique Aponeurosis and the inter- cle-absorber anesthesia system. nal oblique muscle fascia), The The patient’s head was supported needle was advanced slowly with in central position using a circular gentle pressure on the plunger of head rest. the syringe a sudden loss of resistance is felt, negative aspiration, IHNB blocks technique: The 0.5 ml/kg of 0.5% levobupivacaine skin site of block injection was HCL [less cardiotoxic amide LA & sterilized using Alcohol 70%. The pure S (-)- enantiomere of racemic block was performed by experi- bupivacaine](15) (Chirocaine 5mg/ enced anesthetist performed at ml) plus 0.5ml epinephrine 1/ least 400 IHNB blocks, the tech- 200000 was injected during nee- nique of IHNB nerves block in pe- dle withdrawal, in addition SC in- diatrics was performed simultane- filtration of 1/3 of the total LA ously by locating a point differs volume along a line from the pubic

249 Mohamed A. Ghanem tubercle till the ASIS improve the suring patent ventilated airway till block quality by blocking the up- complete recovery (opening eyes coming coetaneous branches of ,moving limbs with a continuous pudendal nerve (10). effective ventilation & maintained respiratory drive). Then children The anesthesia was contin- after 6 hours were discharged ued only via inhalational home, pain free without any med- agents in the form of sevoflu- ical indication for ward admission. rane 3-4 % and N2O/O2 ratio Oral acetaminophen suspension 2/1 fixed for all cases with (25 mg/kg) for further analgesia maintenance of the normal to be given by their parents at respiratory drive of the pa- home. tients and any case lost the drive and needed mechanical The following parameters & ventilation to be pressure con- scores to be recorded in the fol- trolled mode with inspiratory lowing order : pressure 12cmH2o in a rate of Postoperative modified objective 20-25 breath /minute and to be pain score “Diagrams” (OPS) (12) manipulated guided by an End just after LMA removal=0 minutes, tidal Co2 of 30-35mmhg all over then at minute 30, 60, 90, 120, the operative time putting in 150, 180 (see below) were moni- mind an effective inhalational an- tored in the recovery room 30 min esthetic level to avoid light anes- &then in the day case unite. OPS thesia drawbacks like laryngios- score was used to detect the effec- pasm, bronchospasm, desatura- tiveness of postoperative analgesia tion, coughing and bucking. using variables of objective behav- ioral (agitation, crying, posture, After at least 5 minutes of movement, and pain localization. N2O closure LMA removal out of Each criterion scores from 0 to 2 patients was done under deep to give a total score from(0-10) are anesthesia (to avoid N2O in- assessed. Additive postoperative duced diffusion hypoxia, then 5 analgesia to be given to children Litres O2 100% mask utilizing when their OPS reached 4 or chin lift jaw thrust maneuver en- more to be given rectal paraceta-

250 Benha M. J. Vol. 29 No 1 Jan. 2012 mol (25mg/kg) as supporting an- Results algesic for all the study cases. AS regard; Demographic data shown in Table (1) values are in Duration of postoperative anal- (Median &Range) showing no gesia was defined as the time from significant difference in between LMA removal till the first adminis- the two groups. tration of rescue analgesia.(10). As regard; OPS PAIN SCORE Pure operative time (from skin shown in Table (2) AT 0, 30, 60, incision till skin closure) recorded. 90, 120, 150, 180 min postoperative values are in (mean ± Stan- Postoperative duration to dis- dard deviation) Group II shows charge surgeon satisfaction (satis- significant increase in OPS pain fied = 1 & unsatisfied = 2). scoring in comparison to group I at 60, 90, 120 minutes statistical Statistical Analysis : results indicating less analgesia in Data entry and analyses were group II in comparison to group I. performed using SPSS statistical package version 10 (SPSS, Inc., OPS score 4 is the upper limit Chicago, IL, USA). The Chi-Square in this present study beyond test (χ2) was used to test the asso- which additional analgesia should ciation between raw and column be given at postoperative minute variables of nominal data. Student 150 and 180 and this indicates t-test (unpaired) was conducted to the endpoint of the analgesia of compare the mean of continuous both techniques. variables for the two groups at each point of time. The t-test was AS regard; Heart rate (HR) used in data proved to be nor- shown in Table (3) taken as a pre- mally distributed (Kolmogrove- dictor of block success in the 1st Smirnov test), while Man-Whitney- 20 min after surgical incision U test was used for data away (Values are in Median & Range) from normal distribution .The P table shows significant increase in value of <0.05 indicates signifi- HR in Group II in comparison to cant results. Group I at 0, 5,10 minutes statis-

251 Mohamed A. Ghanem tical result after skin incision a son to Group I. Also table (4) strong predictor of insufficient showed Significant increase in block analgesia in the low block postoperative duration to home technique (group II) in comparison discharge in Group II In compari- to high block technique (group1). son to Group I .

As regard; Duration of surgery As regard; The surgeon satis- & postoperative duration to dis- faction about the field clarity in charge shown in Table (4) values such a simple easy surgery Table are in (mean + / - SD) showed (5) Showed 20% surgeon no sat- Significant increase in pure opera- isfaction in group II compared to tive time in Group II In compari- 0% in Group I .

(Diagram 1) Modified OPS Score (12)

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253 Mohamed A. Ghanem

Discussion postoperative complication (he- The Ilioinguinal/iliohypogastric matoma, infection and swelling) block supposed to provides post- and longer time to home dis- operative analgesia after inguinal charge. incisions(11), for example orchi- dopexy or herniotomy but don’t AS regard duration of surgery cover peritoneal sac traction so & postoperative duration to home block alone is not enough for com- discharge values are in (mean+/- plete postoperative analgesia SD) shows Significant increase in (that’s why the addition of IM). pure operative time & postoperative duration to home discharge Drawbacks my happen with in Group11 (low block technique) this block for example transient In comparison to Group I (high femoral nerve block in a ratio of block technique) this prolongation 8.8% of the cases, even with cor- in intraoperative time and postop- rect technique, rapid local anes- erative time to home discharge thetic absorption Leeds to high was claimed to be attributed to plasma levels which occurs espe- the accidental injection of Local cially in young children), Perfora- anesthetic solution in the surgical tion of abdominal wall also colonic planes of dissection and near by injury may happen. Ilioinguinal/ the spermatic cord & vessels in iliohypogastric nerves are only 1- the low block technique (group II) 2 mm away from the peritoneal ,this could happen during the me- cavity, so intraperitoneal injec- dial direction during fan injection tions can occur(13), but injection of the block &this reflects the sta- inside the hernial sac and near by tistically significant increase in the cord with distortion of the an- Surgeon non satisfaction in low atomical planes of surgical dissec- block technique (Group II) com- tion may add difficulty to the pared to the high block technique surgical procedure (surgeon satis- (Group I) due to the added surgi- faction) and utilizing more surgical difficulty due to distortion of cal time leading to longer anesthe- the surgical planes of dissection sia exposure, also we can imagine and the postoperative burden of many problems of the surgical complication that could be expect-

254 Benha M. J. Vol. 29 No 1 Jan. 2012 ed (the own words of the surgeon point of the analgesia of both tech- complaint). niques utilizing levobupivacaine prolonged intense intraoperative & In line with this result Marion postoperative analgesia could be et al(14) reported that successful attributed to the use of epineph- ilioinguinal/iliohypogastric block rine 1/200000 as documented by is only 62% of the cases due to Doyletal (6) which produce local LA Accurate placement utilizing vasoconstriction with slow release technique depending on standard of the LA prolonging duration of anatomical landmark is around LA action that could be intensified this figer (62%) of the injected LA in this present study by the addi- and The remaining 38% of the LA tive analgesia from the IM injected were injected in the tissue nearby of pethedine just before LMA reso blind technique usually carry moval in both groups & also pro- high incidence of partially imper- longed the postoperative analgesia fect injection which also may dis- up to 2 hours and may be more. tort the surgical plans adding more difficulty to the surgical pro- In accordance to our result cedure. Clarifying this issue on Mark et al(15) documented that the other hand ultrasound-guided levobupivacaine injection in ili- techniques have achieved 100% oinguinal/iliohypogastric block in success, even with less doses in pediatrics for day case surgery children.(14) (herniorrhaphy), produced longer time till the 1st needed dose of ad- As regard OPS PAIN SCORE ditive analgesic administration, (Table 2) shows postoperative sig- also decreased the need for addi- nificant increase in OPS pain scor- tive analgesics needed and also ing in group II in comparison to less CHEOPS pain scores 15, 25, group I at 60,90,120 minute read- 30, and 60 minutes after surgery. ing, OPS score ≥ 4 is the higher limit beyond which additional In line with this, Joel et al(16) analgesia should be given as at stated that levobupivacaine in pe- postoperative minute 150 and diatrics has the advantages of be- 180 and this indicates the ending potentially less toxic, long-

255 Mohamed A. Ghanem acting, alternative to bupivacaine. Conclusion Ilioinguinal / iliohypogastric As regard the analgesic effec- block at level above the ASIS just tiveness of the blockade in both after anesthesia induction in pedi- groups intraoperative HR (Table 3) atrics plus the IM pethedine injec- was recorded as an effective pre- tion just before recovery highblock dictor of block success during group (group I) produces efficient the 1st 20 min after surgical inci- intraoperative & postoperative sion (IM pethedine was given after analgesia less operative time, ear- that time just before recovery) for ly home discharge postopera- that issue to clarify the real pure tively with high surgeon satisfac- blockade analgesic success. tion.

Intraoperative HR during the References 1st 20 minutes after surgical inci- 1- Benyamin R., Trescot A. sion showed significant increase M., Datta S., et al., (2008) : ” Op- in the HR statistical values in ioid complications and side ef- group II (low block technique fects.” Pain Physician; 11(2 )more than in group I (high block Suppl) :S105-20. technique) at the minutes 0,5,10 indicating better analgesic out- 2- Yaster M. and Maxwell L. come in( group I) this could be at- G. (1989) :”Pediatric regional an- tributed to the anatomical consid- esthesia”. Anesthesiology; 70:324- eration as documented long time 38. back by two efficient studies by Yaster et al (2) & Dalens B(8) who 3- Toivonen J., Permi J. and recommended that both ilioingui- Rosenberg P. H. (2001) : ” Effect nal & iliohypogastric nerves can of preincisional ilioinguinal and be attacked simultaneously & iliohypogastric nerve block on more successfully by one injection postoperative analgesic require- point 1cm medial then 1cm above ment in day-surgery patients un- not below the ASIS (the high dergoing herniorrhaphy under spi- block technique) applicated in nal anesthesia “. Acta Anesthesiol group I in this present study. Scand;45: 603-607.

256 Benha M. J. Vol. 29 No 1 Jan. 2012 4- Krahenbuhl L., Striffeler Boon, A. T. Bosenberg (2005) : H., Baer H. U. and Buchler M. “Anatomical considerations of the W. (1997) : ” Retroperitoneal en- pediatric ilioinguinal/ doscopic neurectomy for nerve en- iliohypogastric nerve block” Pedi- trapment after hernia repair”. Br J atric Anesthesia ; 371-377. Surg.; 84 (2):216-9. 10- H. Willschke, P. Ma- 5- Wang and Haibo (2006) : rhofer, A. Bösenberg, et al., ”Is ilioinguinal-iliohypogastric (2005) : “ Ultrasonography for ili- nerve block an underused anes- oinguinal / iliohypogastric nerve thetic technique for inguinal her- blocks in children “ Br. J. niorrhaphy?” Southern Medical Anesth.; 95 (2): 226-230. Journal; Volume 99 - Issue 1 - p 15 . 11- Sami Abu-Halaweh, Is- lam Massad, Hamdi abo Ali et 6- Doyle E., Morton N. S. and al (2008) : ”Preemptive Ilioingui- McNicol L. R. (1997) : ” Plasma nal-Iliohypogastric Nerve Block” J bupivacaine levels after fascia ilia- Med J. Vol. 42(2) 87-93. ca compartment block with and without adrenaline”. Pediatric An- 12- Wilson G. A. M. and aesth;7:121-4. Doyle E. (1996) : ”Validation of three pediatric pain scores for use 7- Dr. R. P. Gehdoo (2004) : by parents” Anesthesia.; 51: 1005- ”Postoperative pain management 1007. in pediatric patients“ Indian Jour- nal of anesthesia;48-(5) 406-414. 13- Weintraud M., Marhofer P., Bosenberg A., et al., (2008) : 8- Dalens B. (1995) : ”Nerve ”Ilioinguinal / ilio=hypogastric blocks of the trunk. In: Dalens B, blocks in children: where do we ed. Regional anesthesia in infants, administer the local anesthetic children and adolescents”. Balti- without direct visualization? “ more: Williams & Wilkins 461-87. Anesth Analg; 106:89-93

9- A. N. Van Schoor, J. M. 14- Marion Weintraud, MD,

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Peter Marhofer, MD, Adrian Regional anesthesia and pain Bösenberg (2008) : ”Ilioinguinal/ Management” Drugs; 70 (6):761- Iliohypogastric Blocks in Children: 791. Where Do We Administer the Lo- cal Anesthetic Without Direct Vis- 16- Joel B., Gunter, MD, ualization?” Anesth Analg; vol. Theresa Gregg, Anna M. Varu- 106 no. 1 89-93. ghese, et al., (1999) : ” Levobu- pivacaine for Ilioinguinal / 15- Mark Sandford and Gil- Iliohypogastric Nerve Block in lian M. Keating (2010) : “Levob- Children” Anesth Analg; vol. 89 upivacaine, A Review of its Use in no. 3 -647.

258 Benha M. J. REPRINTVol. 29 No 1 Jan. 2012 BENHA MEDICAL JOURNAL

PEDIATRIC ILIOINGUINAL / ILIOHYPOGASTRIC BLOCK (HIGH OR LOW APPROCHES) “ANALGESIC & SURGICAL OUTCOME-SATISFACTION “

Mohamed A. Ghanem MD

Published by Benha Faculty of Medicine Volume 29 Number 1 Jan. 2012

259 Benha M. J. Vol. 29 No 1 Jan. 2012 LOCKED COMPRESSION PLATE FOR COMPLEX HUMERAL FRACTURES

Mahmoud Zayed MD Assistant Professor of Orthopaedics, Al- Azhar University, Cairo, Egypt.

Abstract Twenty two patients with humeral fractures had been treated by locking compression plate (LCP). There were 18 males and 4 females. Most of the fractures were closed injuries (86.4%). There were three open fractures (13.6%). one type I and two formed type II according to the Gustilo system. Four (18.2%) fractures were associated with multiple trauma. The average age was 43.3 years. The indications for LCP were cominnuted, segmental or intraarticular fractures, in addition to pathological and non-united fractures. The surgical technique had respected the biological principles. Autogenous bone graft had been used for all pathological and nonunited fractures. All fractures achieved complete union with excellent functional result. The aim of this study was to assess the outcome of LCP for treatment of complex humeral fractures. Conclusion: The use of locked plate is an effective tool for fixation of complex humeral fractures with indirect reduction. It is proved to have a high success rate of union. Good results using LCP require understanding the fixation principles of locked plate system.

Introduction Surgical treatment of humeral Fracture of the humeral shaft fractures should be considered for accounts for 1% to 3% of all frac- unaccepted closed reduction, seg- tures and approximately 20% of mental fractures, polytraumatized all fractures involving the bone(1). patients, pathological fractures, Most of humeral fractures are bilateral humeral fractures, pro- usually treated non-operatively. gressive or new onset of radial

259 Mahmoud Zayed nerve palsy after beginning of three (13.6%) were open fractures. non-operative treatment, open Two out of three open fractures fractures, ipsilateral upper ex- were grade II and the remaining tremity fracture, delayed union one was grade I according to Gus- and non union(6). tilo system(4). Four (18.2%) fractures were associated with multi- Various implants have been ple trauma. 15 patients had fresh used for fixation of humeral frac- fractures, 2 had pathological fractures such as conventional plate tures and 5 had nonunion after and intramedullary nails. Each of failure of previous treatment ei- the method has its own advantag- ther conservative in 4 patients es and complications. Recently, and implant failure with radial locked compression plate is a new nerve palsy in one. All fractures type for extramedullary system for were comminuted, segmental and treatment of difficult fractures. intaarticular. Most of fractures LCP was introduced to permits the were caused by high energy trau- use of standard screws and lock- ma. Seventeen were caused by ing head screws. The development road traffic accident (RTA) and five of locked plating in the 1990s by fall on the ground. Biological marked a turning point in fixation fixation was the treatment of technology by providing fracture choice for all fresh fractures, also stability by using fixed angle periosteum stripping was mini- screws with a plate (8,10). mized and the plate was placed over the periosteum. Only the Materials and Methods fracture side was exposed for Twenty two patients with com- freshen the edges, removal of soft plex humeral fractures were treat- tissues interposition and shin- ed by LCP from 2005 to 2009 at gling. Autogenous bone graft was Alzhraa University Hospital and used for nonunited and patho- El-Helal Hospital. Age of patients logical fractures. The side of frac- ranged from 20 to 65 with an av- tures was right in 16 patients erage of 43.3 years. There were 18 and left in 6 patients. The back- males and 4 females. Nineteen ground data for the series is fractures (86.4%) were closed and shown in (Table 1).

260 Benha M. J. Vol. 29 No 1 Jan. 2012 Results patients had no pain, in addition The average follow up was to normal shoulder and elbow 12.7 months (range 6-24). All functions. One patient had shoul- wounds healed without complica- der abduction less than 100 de- tions. There were no infection, grees as the patient did not follow neuro-vascular complications and in out patient clinic, after removal nonunion. All fresh fractures of sutures for 4 months postoper- united with an average of 9.1 atively. Pain relief and normal weeks (range 8-11), while the shoulder function had regained at average union time for patholog- latest follow up by intensive ical and nonunited fractures course of physiotherapy. Com- was 13.6 weeks (range 12-16). plete recovery of redial nerve palsy The overall average union time was obtained in patient with im- for all types of fractures was 10.6 plant failure 3 months postopera- weeks (range 8-16). Twenty one tively.

261 Mahmoud Zayed

ABB

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Disscusion A refined understanding of The original principles of bone biology and the roles tissue fracture fixation included direct vascularity and gap strain play in fracture exposure, precise reduc- fracture healing, contributed to tion, and rigid internal fixation the development of the concept of through compression in an ef- bridging plate osteosynthesis and fort to achieve an anatomic the use of locked plate technolo- fracture union(2,3). This conven- gy(2,5). tional fracture management technique often required a sig- Early fixed-angle plate sys- nificant surgical exposure, alter- tems evolved out of the goal to re- ing the biologic environment at duce plate contact with the perios- and around the fracture site teum, while providing fracture through soft tissue stripping and stability (9). devascularization (3,5). The LCP system with its vari- These techniques require com- ous types of screws (compression pression of the plate to the and locked) offers a very wide bone and rely on friction at range of possible applications. the bone-plate interface. With increasing axial loading cycles, Numerous studies have report- the screws can begin to toggle, ed the successful use of LCPs in a which decreases the friction force variety of clinical situations such and leads to plate loosening. If as metaphyseal fractures, intraar- this occurs prematurely, fracture ticular fractures, fractures in oste- instability will occur, leading to oporotic bones as well as difficult implant failure, delayed fracture non-unions (10,11). union, nonunion, and infection. Thus, the more difficult it is to The present study led to docu- achieve and maintain tight screw mentation of the results of the ap- fixation (as for example, in meta- plications of the LCP system to a physeal and osteoporotic bone), hetero-geneous patient population the more difficult it is to maintain and across a mixed spectrum of stability (8). indications. All fresh fractures

264 Benha M. J. Vol. 29 No 1 Jan. 2012 united in this series without the et al(12) did a comparative ret- need for any supplemental proce- rospective study between two dure. The overall average union groups of patients with delayed time was 10.6 weeks (range 8-16). or non-union of the humeral di- The average union time for fresh aphysis. They reported a hard- fractures (15 patients) was 9.1 ware failure in group A treated weeks and 13.6 weeks for patho- by 4.5-mm low-contact dynamic logical and nonunited fractures. compression plate due to osteoporosis which required re- In this study, all patients got osteosynthesis. Whereas, 100% 100% radiological union, this is union rate achieved in group B seems to be better than results treated by LCP. Although; the pa- published by Sommer et al (10). tients of group B were older, had They recorded 86% fracture heal- longer-lasting non-unions, more ing without complications but previous operations and more se- their study had included different vere initial injuries. sites of long bone fractures. They reported that the complications Ring et al(7) found that Locking and lower rate of healing which compression plates provide stable occurred predominantly in early fixation of poor quality bone in pa- phase. These were due to intra- tients with delayed union or nonoperative technical errors due to union of the humerus. Successful ignorance of the ideal fixation union and restoration of function principle. Walia et al(11) achieved are achieved in most patients. 100% fracture healing in their study of 50 cases of long bone In this study, as mentioned be- fractures treated with LCP. fore all patients got 100% radiological union, had no pain and ob- I agree with previous studies tained normal and elbow that LCP gave excellent results for functions at final follow up. This treatment of nonunited fractures. may attributed to early movement In this series 5 patients out of and rehablitation as LCP provide twenty two formed nonunited frac- good fixation even in osteoporotic tures had complete union. Wenzle bones. The locking implant provid-

265 Mahmoud Zayed ed good anchorage. With locked (2003) : Guidelines for the clinical fixation, a good purchase is application of the LCP. Injury.; 34 achieved between the threaded (suppl 2):63-77. plate and threaded screw head. The screws virtually act as pegs 4. Gustilo R. N., Mendoza R. resisting axial rotation, translation M. and Williams D. N. (1984) : and bending in porotic bone. Problems in the management of type III (severe) open fractures: a Conclusion: The use of locked new classification of type III open plate is an effective tool for fixa- fractures. J Trauma; 24(8): 742- tion of complex humeral fractures 746. with indirect reduction. It is proved to have a high success rate 5. Kubiak E. N., Fulkerson of union. Good results using LCP E., Strauss E. and Egol K. require understanding the fixation A. (2006) : The Evolution of principles of locked plate system. Locked Plates: JBJS Am; 88 : 189- 200. References 1. Ekholm R., Adami J., Ti- 6. Paul R., Gregory and Roy, dermark J., Hansson K., W. (1997) : Sanders: Compres- Törnkvist H. and Ponzer S. sion plating versus intramedullary (2006) : Fractures of the shaft of fixation of the humeral shaft frac- the humerus. An epidemiological tures. J Am Academy of Orthope- study of 401 fractures. J Bone dic Surgeons, Vol. 5, No. 4, July/ Joint Surg [Br]; 88-B:1469-1473. August: 215-223.

2. Frigg R. (2001) : Locking 7. Ring D., Kloen P., Kadziel- compression plate (LCP). An osteo- ski J., Helfet D. and Jupiter J. synthesis plate based on the Dy- B. (2004) : Locking compression namic Compression Plate and the plates for osteoporotic nonunions Point Contact Fixator (PC-Fix). In- of the diaphyseal humerus. Clin jury.; 32(suppl 2):63-66. Orthop Relat Res.; 425:50-4.

3. Gautier E. and Sommer C. 8. Smith W. R., Ziran B. H.,

266 Benha M. J. Vol. 29 No 1 Jan. 2012 Anglen J. O. and Stahel P. F. Plate; Injury Int. J. Care 34; S-B (2007) : Locking plates: tips and 43-54. tricks. J Bone Joint Surg Am, 89:2298-2307. 11. Walia J. P. S., Gupta A., Sahni G., Gupta G. and Walia S. 9. Soileau, Ramona M. S.; K. (2009) : role of locking com- Cartner, Jacob M. S. and Zheng, pression plate in long bone frac- Yanming Ph.D. (2007) : Locked tures in adults - a study of 50 cas- Versus Conventional Plate-Screw es. Pb J of Orthop; Vol-XI, NO. 1: Fixation in Osteoporotic Bone: 41- 43. Techniques in Orthopaedics; Vol. 22 - Issue 4 - pp 247-252. 12. Wenzl M. E., Porte T., Fuchs S., Faschingbauer M. and 10 Sommer C., Gautier E., Jurgens C. (2004) : Delayed and Müller M., Helfet D. L. and Wag- nonunion of the humeral diaphy- ner M. (2003) : First clinical resis-compression plate or internal sults of the Locking Compression plate fixator? Injury.;35:55-60.

267 REPRINTMahmoud Zayed BENHA MEDICAL JOURNAL

LOCKED COMPRESSION PLATE FOR COMPLEX HUMERAL FRACTURES

Mahmoud Zayed MD

Published by Benha Faculty of Medicine Volume 29 Number 1 Jan. 2012

268 Benha M. J. Vol. 29 No 1 Jan. 2012 PHENYTOIN : IS IT GENOTOXIC IN ISOLATED CULTURED HUMAN LYMPHOCYTES WITHOUT METABOLIC ACTIVATION?

Mahmoud A. Naga MD, Mohamad-Hesham Y. Daba MD, Nadia K. El-Gamal MD*, Mohamed A. Abd El-Azeaz MD and Sabry M. Zeid MD Department of Clinical Pharmacology, Mansoura University, Mansoura, Egypt, and *Department of Genetics, Mansoura University Children’s Hospital, Mansoura, Egypt

Abstract There is a debate around the phenytoin (PHT)-induced genotoxic effect observed in many conflicting reports. To test the genetic effect of PHT in comparison to the well known genotoxin Doxorubicin (DOX), an in vitro model of isolated cultured human lymphocytes was designed. After the end of culture period, the effects of PHT and DOX on the lymphocytes were investigated by levels of chromosomal aberrations (CAs); mitotic index (MI); reduced glutathione (GSH); malondialdehyde (MDA); and 8-hydroxydeoxyguanosine (8-OH-dG). DOX caused significant increase in the levels of structural CAs, MDA and 8-OH-dG together with significant decrease in the levels of MI and GSH when compared to non treated group. However, PHT caused only dose dependant increase in the MI and no significant changes were observed in the other parameters. The genotoxic effect of DOX may be due to oxidative stress as shown by increased MDA and 8-OH-dG together with decreased GSH. PHT was claimed to cause genotoxic effect by metabolic intermediates. However, by reviewing the distribution and activity of the enzymes responsible for PHT metabolism, we found that PHT is rarely metabolized in isolated cultured human lymphocytes. Hence, the present study is the first to record that PHT without metabolic activation in isolated human lymphocytes from non epileptic donors cause dose dependant direct toxic effect rather than genotoxic effect.

Introduction terations in DNA structure leading Genotoxins are compounds to inaccurate replication of that causing chemical or physical al- region of the genome (1). Approxi-

269 Mahmoud A. Naga, et al... mately 30% of all marketed drugs, non-smoking, non-alcoholic and exhibit genotoxic effect when test- they did not take any medications ed by the standard genetic toxicol- recently. The donors were ob- ogy tests(2). Doxorubicin (DOX) is tained from the blood-banking used in the treatment of several center of Mansoura university types of human malignancies. hospital, Mansoura faculty of However, it has a wide variety of medicine, Egypt. All blood sam- toxic effects, including cardiotoxic- ples were taken on heparin to pre- ity, cytotoxicity and the induction vent clotting. of chromosomal aberrations(3). DOX was selected in this study as 2. Chemicals: all chemicals it is an effective clastogenic that and reagents used in this study do not require enzymatic activa- except DOX were of the highest tion(4). Phenytoin (PHT), the well analytical grade from Sigma- known antiepileptic drug has Aldrich (St. Louis, MO, USA). been suspected for teratogenic Phenytoin was purchased as sodi- and mutagenic effects during um salt ≥ 99%, 25 g soluble in wa- pregnancy(5). However, there is a ter. Doxorubicin was purchased big debate around its genotoxic ef- as a 10 mg vial ready for infusion fect observed in many conflicting (Adriamycin® - Pharmacia), with a reports(6.7.8.9). The aim of this concentration of 2 mg/ml. study is to investigate the debate around the genotoxic effect of 3. Isolation and culture of hu- phenytoin in comparison to DOX man lymphocytes: lymphocytes in an in-vitro model using isolated were isolated from whole blood cultured human lymphocytes. samples and cultured as described by Durante et al. (10) with Materials and Methods minor modification. All blood sam- 1. Human blood samples: 10 ples were collected in an isolation ml fresh venous blood samples tube for blood cells. The sample were taken from 30 adult donors was centrifuged at 1600 g (2900 after consent. All donors were of rpm) for 20 min, and the layer of either sexes between the ages of mononuclear cells and platelets 20-45 years, apparently healthy, was collected by a pipette and

270 Benha M. J. Vol. 29 No 1 Jan. 2012 transferred to 10 ml centrifuge at the start of culture period to in- tube. PRMI 1640 medium was duce mitosis within 24 hr accord- added up to 10 ml. and the sam- ing to standard protocol of Poddar ple was centrifuged at 390 g (1500 et al.(14). The genoprotective drugs rpm) for 10 min. After the removal were added as a prophylactic ther- of the supernatant, the cell pellet apy 2 hr prior to addition of the was re-suspended in 10 ml RPMI genotoxic drug. 1640 medium at a density of 1.0 X 106 cells/ml. Isolated lympho- 5. Evaluation of the drug ef- cytes from each blood sample fects: to investigate the chromoso- were cultured in 10 ml RPMI mal effect induced by DOX and 1640 culture medium for a total PHT, cells were harvested at the period of 72 hrs at 370 c in the end of the culture period (72 hrs) dark in a 5 % CO2 humidified at- for screening CAs following the mosphere (11). standard protocol(15) in order to avoid heterogenecity of cycle stage 4. Plan of the study and of the treated cells and to score grouping of isolated lympho- only the first division mitotic cells. cytes: Isolated lymphocytes from Colcemid 0.1 ml. was added to each blood samples were divided stop mitosis and prevent spindle randomly into 5 groups, each of 6 formation and was left 1.5 samples: the 1st group was none hours. The isolated lymphocytes treated; the 2nd treated with DOX after recovery of from the incuba- 0.15 ug/ml (12); the 3rd treated tor were investigated for chro- with PHT 60 ug/ml(13); the 4th mosomal aberrations (CAs), mi- treated with PHT 90 ug/ml(13) totic index (MI), 8-hydroxy-2'- and the 5th treated with PHT 120 deoxyguanosine (8-OH-dG), re- ug/ml that was tried for the first duced glutathione (GSH) and mal- time by this study. The potential ondialdehyde (MDA). genotoxic drugs were added twice, at 24 hr and 48 hr from the start Assay of chromosomal aber- of culture period and after stimu- rations (Karyotype) in isolated lation of mitotic division with phy- lymphocytes using Gimsa stain: tohaemagglutinin that was added It was done according to the pro-

271 Mahmoud A. Naga, et al... tocol of Poddar et al.(14). Cells isolated lymphocytes was ex- were stained using 10% Giemsa tracted according to the method for 12 minutes immersed in dis- described by Anderson(19), and tilled water for washing and air- then reduced GSH was measured dried. Analysis of cytogenetic data according to the method described was performed using light micros- by Beulter et al.(20) employing col- copy. Slides were scored blind and orimetric method using spectro- individual aberrations were re- photometer determination method corded. Fifty metaphases were ex- (JENWAY 6405, spectrophotome- amined for each sample in the dif- ter). ferent groups (300 metaphase for each group), searching for any Measurement of malondialde- chromosomal anomalies either hyde level (MDA): Lipid peroxida- structurally or numerically. tion products (MDA) were released from isolated lymphocytes by soni- Determination of mitotic in- cation according to the method dex (MI) as a measure of cyto- described by Stacey and Klaas- toxicity: The mitotic index (MI) sen(21). Then MDA was measured was used as indicators of ade- by thiobarbituric acid (TBA) test quate cell proliferation. Its inhibi- according to the method described tion could be considered as cellu- by Draper and Hadley(22), employ- lar death, or delay in the cell ing colorimetric method using proliferation kinetics(16). The mi- spectrophotometer determination totic index evaluates the cytotoxic- method (JENWAY 6405, spectro- ity of chemical agents(17). MI, is photometer). easily assessed when CAs are performed. The number of lympho- Measurement of 8-hydroxy-2- cytes in metaphase was counted deoxy Guanosine (8-OH-dG): The in 2000 lymphocytes per sample 8-OH-dG was assayed using Cay- to determine the mitotic index(18). man 8-hydroxy-2-deoxy Guano- sine enzyme-linked immunosor- Measurement of intracellular bent assay (elisa = EIA) Kit reduced glutathione (GSH): In- (Cayman Chemical’s ACE™, USA). tracellular reduced GSH in the Cayman’s 8-OH-dG EIA is a com-

272 Benha M. J. Vol. 29 No 1 Jan. 2012 petitive assay that can be used for control normal group (Table 1, the quantification of 8-OH-dG in Fig 1). DOX caused also cytotoxic- urine, cell culture, plasma, and ity and decrease in lymphocyte other sample matrices. This assay proliferation indicated by signifi- is based on the competition be- cant decrease in the MI when tween 8-OH-dG and a 8-OH-dG- compared to control normal group acetylcholinesterase (AChE) conju- (table 1). In addition, there was gate (8-OH-dG Tracer) for a limit- significant increase in the MDA ed amount of 8-OH-dG Monoclo- level, 8-OH-dG level and signifi- nal Antibody (23.24). cant decrease in the GSH level when compared to control group Statistical Analysis : All statis- (Table 1). tical calculations of the data were performed with SPSS® version 2. In vitro effects of Phenytoin 15.0. Multiple comparisons of the (PHT) 60, 90 µg/ml : There was data for each biochemical parame- dose dependant increase in the ter were performed using one-way structural CAs (Table 1, Fig 1). analysis of variance (ANOVA) fol- However, these dose dependant lowed by post-Hoc test for com- changes in the CAs were not sig- paring the different groups with nificant when compared to each each other. P-value of ≤ 0.05 was other and to the non-treated considered significant. control group (Table 1). There was also dose dependant cyto- Results toxicity and decrease in lympho- The assessment of the types of cyte proliferation indicated by chromosomal aberrations (CAs) in significant decrease in the MI the isolated cultured human lym- when compared to each other phocytes in all groups of this and to the control normal group study caused only structural CAs (table 1). In addition, there was and no numerical CAs were found. no significant change in the 1. In vitro effects of Doxorubi- MDA, GSH, or 8-OH-dG levels cin (DOX): DOX 0.15 µg/ml when compared to each other and caused significant increase in the to the non-treated normal group structural CAs when compared to (Table 1).

273 Mahmoud A. Naga, et al...

3. In vitro effects of Phen- 4. Comparisons between in ytoin 120 µg/ml : PHT 120 µg/ml vitro effects of DOX 0.15 µg/ml induced cytotoxic effect resulting and PHT 60, 90 and 120 µg/ml: in death and shrinkage of most The toxic effects of DOX treated of cells with marked reduction group on CAs, MDA, GSH (Ta- in the number of analyzable ble 1), and 8-OH-dG were more clear metaphases in which evident and more significant when chromosomes are not clear to be compared to PHT 60, 90 µg/ml counted or differentiated from treated groups (Table 1, Fig. 1). each other (Fig. 1). There was However, the toxic effects of DOX significant decrease in the MI treated group on MI was non- when compared to control nor- significant when compared to PHT mal group (table 1). The levels of 60 µg/ml and less significant CAs, MDA, GSH, and 8-OH-dG when compared to the effects of could not be assessed in the cell PHT 90 µg/ml and PHT 120 µg/ml culture. treated groups (table 1).

274 Benha M. J. Vol. 29 No 1 Jan. 2012

Fig. 1: A microphotograph with Gimsa stain X 1000 of (A) normal metaphase and karyotyping, (B) Doxorubicin treated group showing multiple different structural chromosomal aberrations, (C) Phenytoin treated group 60 µg/ml shoeing little CAs, (D) Pheny- toin treated group 90 ug / ml showing little CAs, (E) Phenytoin 120 µg/ml treated group showing shrinked dead cells with ar- rested mitosis and few number of metaphases in which chromosomes are not clear to be counted or differentiated.

275 Mahmoud A. Naga, et al...

Discussion with oxygen, forming superoxide 1. In vitro effects of Doxorubi- anions, hydrogen peroxide, and cin (DOX) on the isolated cul- hydroxyl radicals. The second im- tured human lymphocytes. plicates the formation of highly re- DOX caused genotoxic effect active semiquinone intermediates with increased oxidative stress as through redox modifications (27). shown by increased levels of CAs, MDA, and 8-OH-dG, together with DOX is prone to redox modifi- decreased MI and GSH levels. The cations due to the relative reac- clastogenic effect of DOX reported tivity of its functional group by this study was also described quinone(29). Redox cycling is char- by Dhawan et al.(25), and Ramos acterized by enzymatic reduction et al.(26), they described the geno- of the quinone molecule to a high- toxic effect of DOX with increased ly reactive semiquinone upon the micronuclei in cultured human addition of one electron, or to hy- lymphocytes. Gülkaç et al.(27) de- droquinone by the addition of two- scribed the DOX-induced chromo- electrons(30). The subsequent somal aberrations in bone marrow non-enzymatic oxidation of the cells of rats. Fragiorge et al.(4) de- semiquinone or hydroquinone rad- scribed the direct genotoxicity of ical by molecular oxygen promotes DOX in somatic cells of Dro- the formation of ROS such as su- sophila melanogaster. In addi- peroxide anion, hydroxyl radicals, tion, many researchers found and hydrogen peroxide(31). The that acceleration of intracellular various forms of ROS formed dur- formation of reactive oxygen spe- ing DOX redox cycling may oxidize cies (ROS) may be one of the proteins, lipids and nucleic acids major causes of doxorubicin- and potentially cause DNA strand induced DNA damage and cell breaks and lipid peroxidation, death(28.4.29). Two different leading to cell death(29). In addi- routes of free radical formation by tion, different mechanisms of gen- DOX have been described. The otoxic effects of DOX have been first implicates a non-enzymatic proposed, including DNA interca- reaction of DOX with iron to form lation, inhibition of topoisomerase a stable complex, which reacts II, and induction of apoptosis(26).

276 Benha M. J. Vol. 29 No 1 Jan. 2012 There is a large body of evidence pounds from the cell proteins. to show that the dominant cellular target of doxorubicin is DNA, To the best of our knowledge, DOX intercalates DNA between this study was the first to record base pairs (27) resulting in DNA that PHT without metabolic acti- adducts and protein-associated vation is not genotoxic in isolated single and double strand DNA human lymphocytes collected breaks (32). from non epileptic donors. Howev- er, many studies reported that 2. In vitro effects of phenytoin PHT is not genotoxic in cultured (PHT) on the isolated cultured human lymphocytes isolated from human lymphocytes. epileptic patients pretreated with Apart from significantly deterio- PHT. Witczak et al.(34) assessed rated cell proliferation (MI), PHT the potential genotoxic effect of 60, 90 µg/ml did not show any PHT therapy in pregnancy on DNA statistically significant genotoxic of umbilical cord blood lympho- effect as shown by non significant cytes using Micronucleus (MN) as- changes in the CAs, MDA, GSH, or say. They did not show any signif- 8-OH-dG when compared to con- icant differences between the MN trol normal group. Additionally, rates of PHT-treated patients and when a larger dose of PHT (120 controls, indicating a lack of geno- µg/ml) was administered to isolat- toxicity of the PHT. Schaumann et ed lymphocytes, marked deteriora- al.(35), tested the potential geno- tion in MI and cytotoxic effects toxic effect of PHT using sister were observed, which shown by chromatid exchange (SCE) assay death of most of cells with in isolated cultured lymphocytes marked reduction in analyzable from adult epileptic patients treat- metaphases. The levels of MDA, ed with PHT. He did not show any GSH, and 8-OH-dG could not be significant differences between the assessed for this high dose SCE rates of PHT-treated patients (120 µg/ml), which may be due to and controls, indicating a lack of rapid cell death caused by the mutagenicity of the PHT. In addi- acidic pH of PHT (33) and inability tion, the negative tests for PHT to extract these measured com- genotoxicity were observed in

277 Mahmoud A. Naga, et al... germ cells of male Drosophila me- PHT. The first include the bioacti- lunogaster (36), many strains of vation of about 80% of PHT to re- Salmonella typhimurium (37), and active epoxides (arene oxide) cultured Chinese hamster ovary which is hydroxylated to form cells (38). the main metabolite para hydroxyphenyl phenyl hydantion (p- On the other hand, the positive HPPH)(44). This process is cata- tests for PHT genotoxicity were ob- lyzed primarily by the cytochrome served in Chinese hamster ovary P450 (CYP 450) system mainly the cell (39), rodents (40), and some CYP2C9 and to much lesser by isolated human cells (13.41). This CYP2C18 and CYP2C19(41). The strong debate around the ability of second pathway includes the bio- phenytoin to induce genotoxic ef- activation of PHT to reactive free fects observed in many conflicting radical intermediates through the reports (6.7.8.9). Most of the posi- hydroperoxidase component of tive genotoxic studies of PHT Prostaglandin endoperoxide syn- claimed that this toxic effect re- thetase pathway responsible for sulted from the action of some conversion of arachidonic acid PHT metabolic intermediates, to prostaglandins(45). The last mainly the para hydroxyphenyl metabolic pathway included the phenyl hydantion (p-HPPH)(5). bioactivation of PHT to reactive These metabolic intermediates in- free radical intermediates through duce production of ROS leading to the myeloperoxidase enzyme com- exhaustion of the cellular antioxi- monly present in leukocytes(46). dant systems(42) with subsequent However, by reviewing the distri- oxidation of DNA, proteins, and bution and activity of the enzymes lipids(43). This toxic effect will lead responsible for PHT metabolism, to oxidative DNA base modifica- we found that PHT is rarely me- tion with DNA strand breaks, lipid tabolized in isolated cultured hu- peroxidation and decreased GSH- man lymphocytes. This is because mediated cytoprotection (41). the CYP 450s are abundant in the liver(47) and quite low in leuko- There are three main metabolic cytes(48); thus, they are not con- pathways for the metabolism of sidered to be the main pathway

278 Benha M. J. Vol. 29 No 1 Jan. 2012 for drug metabolism in isolated bolic intermediates. This idea was lymphocytes. In addition, the supported by studies that report- CP450s present in lymphocytes ed PHT genotoxic effect after meta- are mainly CYP1A1, CYP1B1, CYP bolic activation in the presence of 2E1 and CYP3A4, while those in- an exogenous metabolic activation cluded in PHT metabolism are system (S9) in bacteria(52) and CYP2C9 and to much lesser by Chinese hamster ovary cells (53). CYP2C18 and CYP2C19(41). The prostaglandin endoperoxide syn- The dose dependant effect on thetase was found in relatively lymphocyte proliferation and cell high concentrations in lympho- death caused by PHT (60, 90, 120 cytes(49). However, this enzyme µg/ml) shown by MI was in accor- can not metabolize PHT without dance with the study of Bittigau et metabolic activation through addi- al.(54), they revealed that pheny- tion of high amounts of arachi- toin, cause apoptotic neurodegen- donic acid(50). The last enzyme eration and neuronal death in the myeloperoxidase was found to be developing rat brain. Moreover, distributed unequally between Kawamura et al.(55) reported the leucocytes where it is excess in induction of apoptosis by large nutrophils and very little in lym- dose PHT in human tumor cells, phocytes (51). when used to increase the cytotoxicity of the anticancer vinblastin. The absence of PHT metabolism Additionally, Ponnala et al.(13), in isolated cultured human lym- recorded partial cell death in iso- phocytes may support and explain lated human lymphpocytes but at the negative genotoxic effects of smaller doses (60 µg/ml). This PHT in this study and in the previ- large concentration is very danger- ously mentioned studies that used ous for the human where the fatal cultured cells to investigate the cases typically involve phenytoin genetic effect of PHT. These re- concentrations of more than 400- sults suggest that PHT it self is 500 µM/L (120-125 µg/ml)(33). not genotoxic and its toxicity could be achieved only after meta- Acknowledgement: The au- bolic activation to reactive meta- thors thank Faculty of Medicine,

279 Mahmoud A. Naga, et al...

Mansoura University, Egypt, for matic cells of Drosophila melano- their help in funding this re- gaster. Genet. Mol. Biol.; 30, 449- search. 455.

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286 Benha M. J. REPRINTVol. 29 No 1 Jan. 2012 BENHA MEDICAL JOURNAL

PHENYTOIN : IS IT GENOTOXIC IN ISOLATED CULTURED HUMAN LYMPHOCYTES WITHOUT METABOLIC ACTIVATION?

Mahmoud A. Naga MD, Mohamad-Hesham Y. Daba MD, Nadia K. El-Gamal MD, Mohamed A. Abd El-Azeaz MD and Sabry M. Zeid MD

Published by Benha Faculty of Medicine Volume 29 Number 1 Jan. 2012

287 Benha M. J. Vol. 29 No 1 Jan. 2012 THE ROLE OF TISSUE DOPPLER IMAGING DURING DOBUTAMINE STRESS ECHOCARDIOGRAPHY IN DIFFERENTIATING ISCHEMIC FROM NON-ISCHEMIC CASES OF DILATED CARDIOMYOPATHY

Hesham Rashid MD, Mohamed Hassan MD, Saad Ammar MD, Adel Gamal MD*, and Hitham Ahmed M.B.B.CH Departments of cardiology, Benha, and Ain Shams* Universities, Egypt

Abstract Background: Dobutamine stress echocardiography (DSE) has several potential advantages over currently used non-invasive techniques. It is inexpensive and provides an alternative in the patients who cannot perform leg or arm exercise. The equipment used is highly portable and thus studies can be performed in coronary care units. Objectives: To study the role of tissue Doppler imaging during dobutamine stress echocardiography for differentiating ischemic from non- ischemic cardiomyopathy. Patients and methods: forty six patients were included in this study, and diagnosed as dilated cardiomyopathy by resting conventional echocardiography. The patients were divided into two groups: group l (18 patients) with normal coronary angiography, and group ll(28 patients) with coronary artery disease. All patients were subjected to full history taking, clinical examination, resting surface electrocardiograms, echocardiography, low and peak dose DSE associated with tissue Dop- pler with detection of mitral annulus systolic and diastolic velocities in six sectors of LV myocardium ( anterior, inferior, anterior septum, posterior septum, posterior and lateral walls). Results: In group I, there was no change in the mean value of systolic velocities of all six sectors at baseline was (6.5±1.6 cm/s) and at low dose was (6.9±2.3 cm/s) p value > 0.05, while in group II there was significant improvement in the mean value of systolic velocities of six

287 Hesham Rashid, et al.... sectors at low dose (11.3±3.1 cm/s) compared to that in the baseline resting stat (7.0±1.6 cm/s) followed by gradual decrease in the systolic velocity to peak dose (9.1±2.6 cm/s) (Biphasic response) p value < 0.01. The E'/A' ratio of diastolic function estimated by TDI at base line and during DSE, there was insignificant changes in both groups. The sensitivity of tissue Doppler with DSE for detection of coronary artery disease in patients with dilated cardiomyopathy was 85.7%, and specificity was 77.8%. ConclusionConclusion: Tissue Doppler with DSE is non invasive simple method with high sensitivity and specificity for detection of coronary artery disease in patients with dilated cardiomyopathy. Introduction Aim of the work Dobutamine stress echocardi- To study the role of tissue Dop- ography (DSE) has several poten- pler imaging during dobutamine tial advantages over currently stress echocardiography for diffe- used non-invasive techniques. It rentiation of ischemic from non- is inexpensive and provides an al- ischemic cases of dilated cardiom- ternative in the patients who can- yopathy. not perform leg or arm exercise. The equipment used is highly Patients and methods portable and thus studies can be This study was carried out in performed in coronary care units. the cardiology department of both (1). Benha faculty of medicine and Ain Shams faculty of medicine during High quality images from DSE the period from August 2008 to may be obtained more easly than June 2010. those with exercise stress echocardiography because the Inclusion criteria: absence of patient motion and Patients who had documented respiratory interference, and the echocardiographic diagnosis of di- level of stress achieved can be lated cardiomyopathy: dilated LV controlled and the heart rate with generalized hypokinesis, pos- achieved can be suppressed by teriorly displaced mitral valve, es- B-Blockers (2). timated LV end diastolic diameter

288 Benha M. J. Vol. 29 No 1 Jan. 2012 > 60mm and percentage ejection 4- Uncontrolled hypertension fraction < 45%) (3). or diabetes mellitus. 5- History of chronic obstruc- All patients underwent left sid- tive airway disease. ed cardiac catheterization via fe- 6- Poor echocardiographic win- moral artery puncture using Sel- dow. denger's technique with left and 7- Echocardiographic evidence right coronary angiography in of left ventricular hypertrophy. multiple projections and angula- 8- Decompensated heart fail- tions. According to the results of ure. the diagnostic coronary angiogra- 9-Patients who didn’t complete phy, patients were divided into the test due to early development two groups: of complications.

Group I : patients with dilated Methods: All patients were cardiomyopathy and normal coro- subjected to: nary arteries (18 patients). 1) Careful history taking. 2) Thorough clinical examina- Group II: patients with dilated tion. cardiomyopathy and significant 3) Resting electro-cardiogram: narrowing of one or more coronary 12 leads surface resting electro- arteries. Significant narrowing cardiogram. was defined as > 70% reduction in the absolute lumen diameter of a 4) Echocardiographic study: major epicardial artery or major Trans-thoracic echocardio- branch vessel. (4) This group in- graphic examination using Vivid 5 cluded 28 patients. machine and probe 3S frequency 1.5 – 3.6 MHz GE Probe was done Exclusion criteria: for all subjects enrolled in the 1- Evidence of previous myo- study. cardial infarction. 2- Significant arrhythmias. M-mode, two dimensional as 3- Valvular or pericardial dis- well as color and pulsed Doppler ease. flow examination were done in su-

289 Hesham Rashid, et al.... pine and left lateral position. Ac- tamine started by rate 5 ug / kg / cording to the American Society of min. for 5 minutes increased grad- Echocardiography guide lines the ually 5 ug /kg /min. every 3 min- following measurements were ob- utes up to maximum dose 40 ug / tained: kg /min. 1) Left atrial diameter. 2) End diastolic and end systol- In patients not achieving 85% ic LV cavity dimensions and vol- of their maximum heart rate with- umes. Left ventricular Ejection out symptoms or signs of myocar- fraction (EF) was then calculated dial ischemia, atropine was ad- according to the equation: EF %=( ministered intravenously; starting LV diastolic volume–LV systolic dose was 0.25 mg up to maximum volume)/LV diastolic volume.(5) of 2.0mg within 8 minutes while continuing infusion of dobuta- Using apical 4-chamber view, mine. (6). Throughout dobutamine pulsed wave Doppler sample was infusion, continuous ECG moni- put at the tips of mitral valve leaf- toring was done and at each stage lets to record the mitral flow veloc- heart rate and blood pressure ities, E and A waves. The ratio of were measured ,left ventricular E/A was then calculated. wall motion was evaluated with two dimensional echocardiography Dobutamine stress Echocar- and mitral annular motion veloci- diography: ty patterns were recorded with Adequate arrangement of the pulsed TDI at rest and at a maxi- testing equipment, with availabili- mum dose of 40 ug / kg /m (7). ty of appropriate emergency equip- End points of the test: ment, dobutamine stress echocar- - Significant chest pain. diography was performed to all - Extensive new wall motion ab- patients in the fasting state; ni- normalities. trates were stopped 24 hours be- - Achievement of 85% of maxi- fore the test while beta blockers mum predicted target heart rate. and calcium channel blockers - Additional ST segment de- were stopped 48 hours before the pression or elevation about test. Intravenous infusion of dobu- 2.0mm in at least two contiguous

290 Benha M. J. Vol. 29 No 1 Jan. 2012 leads compared to the rest. Systolic mitral annular motion - Hypotension: systolic blood velocities at 6 mitral annular sites pressure < 90mm Hg or reduction reflect the synergy at the sites cor- more than 40mmHg of pretest lev- responding to the ischemic re- el or increased systolic pressure gions in patients with myocardial >200. ischemia, sample volumes were - Significant arrhythmia. set on the endocardial side at the mitral annulus in regions corre- Dobutamine stress echocardi- sponding to: ography (DSE) was considered positive for induced myocardial is- - Anterior mitral, posterior mi- chemia after detection of biphasic tral, inferior, anterior, lateral, and response that means at low dose posterior walls. The peak velocity of stress the contractile function of the systolic mitral annular mo- improved and at higher doses the tion (S) were determined, also the myocardial demand increased peak diastolic velocities (E', A’) leading to ischemia and systolic were determined from six consec- function deterioration again.(8) utive beats and the mean was calculated for each parameter and Pulsed wave tissue Doppler expressed in centimeters per sec- imaging study: ond. Recording and measure- The echocardiography machine ments were repeated at baseline, was switched to TDI mode thereby low dose (5ug /kg/min) and maxi- resulting in lowering of the veloci- mum dobutamine infusion rate. ty range to encode myocardial velocities. Statistical analysis Data were collected from all pa- The acoustic power and filter tients (group I and II), and ex- frequencies of the ultrasound scan pressed as the mean value, stan- system were set to the lowest val- dard deviation and percentages. ues possible. Sample volumes were set at the mitral annulus. Kruskal – Wallis test was used Mitral annular motion velocities to compare different parameters were recorded on a strip chart. between groups. When inter-group

291 Hesham Rashid, et al.... differences were found, Mann- only 3 patients (16.7%)had posi- Whitney test was performed to de- tive family history in group I ver- termine which group was signifi- sus11(39.3%) in group II. cantly different. Conventional echocardiogra- Categorical variables were ana- phy response during dobuta- lyzed with the Chi square test. mine stress: Paired student’s t-test was used to In group I EF was (35 ± 3.5) compare different parameters of with low dose DSE and nearly the DSE in studied groups. same with high dose DSE, and in group II EF was (45.2 ± 4.1) with A value of P < 0.05 was consid- low dose DSE, while it was (41.4 ± ered statistically significant. (9) 4.6) in high dose DSE. Statistical- ly significant difference was found Results between both groups (p value < Demographic data: Forty six 0.01). This means that in non- patients were included in this ischemic cardiomyopathy, dobuta- study their mean age was (42.5 mine stress induces no recordable ±7.1 years) in group I versus (59.4 change in global systolic function ± 6.9 years) in group II, 11 of them from the low dose to peak dose were males and 7 females in (mono-phase response). On the group I versus 17 males and 11 other hand, in ischemic cardiom- females in group II. yopathy there was an initial improvement at low dose followed by Seven patients (38.9%) were di- impairment of systolic function abetic in group I versus 18 (Biphasic response). Fig. (1). (64.3%) in group II, 5 patients were hypertensive (27.8%) in - LV diastolic function (E/A group I versus 15 (53.5%) in ratio): group II, 8 patients (44.4%) were In group I E/A ratio was (1.12 smokers in group I versus15 ±0.31) during resting state, (53.5%) in group II, 7 patients (1.1±0.27) at low dose DSE and (38.9) had dyslipidemia in group I became (1.05±0.26) at maximum versus 17(60.7) in group II, and dose DSE, and in group II E/A ra-

292 Benha M. J. Vol. 29 No 1 Jan. 2012 tio was (0.97±0.26) during resting - In posterior aspect S at state, (0.91±0.27) at low dose DSE baseline was (5.5 ±1.9) cm/s, S at and became (o.85 ± 0.46) at maxi- low dose (5.9 ±2.5) cm/s while S mum dose DSE, with statistically at peak dose became(6.2 ±3.1) significant difference between both cm/s. groups (P value < 0.01). These result means that in non-ischemic - In anterior septal aspect S at cardiomyopathy, there is insignifi- baseline was (5.9 ±1.7) cm/s, S at cant change in E/A ratio during low dose dobutamine was (6.1 dobutamine stress, while in is- ±2.4) cm/s while S at peak dose chemic group there is significant became (6.4 ±2.8) cm/s. decrease in this ratio, most probably due to stress induced myo- - In posterior septal aspect S cardial ischemia. Fig. (2). at baseline was (7.0 ±1.9) cm/s, S at low dose dobutamine was (8.2 Tissue Doppler parameters ±2.1) cm/s while S at peak dose during dobutamine stress echo- became (9.1 ±3.5) cm/s. cardiography: * Systolic velocities during - In lateral aspect S at base- DSE in group I: there is insignifi- line was (7.7 ±1.4) cm/s, S at low cant monophasic response in all dose dobutamine was (8.3 ±1.9) six sectors. (P value >0.05) (Tab.2, cm/s while S at peak dose became Fig. 3). (8.6 ±2.1) cm/s. - In anterior aspect S at baseline was (6.6 ±1.9) cm/s, at low * Diastolic velocities E’/A’ ra- dose dobutamine (6.8 ±2.1) cm/s tio during DSE in group I: The while S at peak dose became (7.1 mean value of diastolic velocity ±3.1) cm/s. (E'/A') in group I at baseline was (1.0 ±0.3) cm/s, at low dose dobu- - In inferior aspect S at base- tamine (1.0 ±0.2) cm/s, and be- line was (6.4 ±1.7) cm/s, S at low came (0.9±0.3) cm/s at high dose. dose (6.6 ±2.8) cm/s while S at (P value > 0.05). peak dose became (7.2 ±2.3) cm/ s. * Systolic velocities of myo-

293 Hesham Rashid, et al.... cardial aspects during DSE in dobutamine was (8.9 ±2.9) cm/s. group II: there is biphasic response with significant changes in - In lateral aspect S at base- all six sectors. (P value < 0.01) line was (8.7 ± 1.3) cm/s, at low (Tab.3, Fig.4) . dose dobutamine was (15.2 ±3.9) cm/s while S at peak dose of do- - In anterior aspect S at base- butamine was (10.4 ±2.3) cm/s. line was (7.4 ± 1.3) cm/s, S at low dose dobutamine was (14.6 ±4.7) * Diastolic velocities E?/A? cm/s, and became (9.1 ± 3.1) cm/ ratio in Group II: there is insig- s at high dose. nificant changes during DSE; the mean value at baseline was - In inferior aspect S at base- (0.93±0.3) cm/s, at low dose (97.0 line was (7.4 ±1.9) cm/s, S at low ±0.2) cm/s while S at peak dose dose dobutamine was (12.3±3.6) became (0.96±0.2) cm/s.(P value > cm/s, and became at peak dose 0.05). (10.7 ±2.8) cm/s. Complications during dobuta- - In posterior aspect S at mine stress echocardiography: baseline was (5.3 ± 1.1) cm/s, S at - Patients excluded from the low dose dobutamine was (10.4 test due to development of com- ±2.7) cm/s while became at peak plication included: dose (7.8 ±2.5) cm/s. 1- Two patients developed significant hypotension. - In anterior septal aspect S 2- Three patients developed at baseline was (5.6 ± 1.6) cm/s, rapid atrial fibrillation. at low dose dobutamine was (9.6 3- One patient developed runs ±3.1) cm/s while S at peak dose of of ventricular tachycardia. dobutamine was (7.2 ±2.7) cm/s. Specificity and sensitivity of - In posterior septal aspect S Dobutamine Stress Echocardiog- at baseline was (7.6 ± 1.2) cm/s, raphy: at low dose dobutamine was (11.9 - The test was positive for ±3.8) cm/s while S at peak dose of stress induced myocardial ische-

294 Benha M. J. Vol. 29 No 1 Jan. 2012 mia in 28 patients, 23 of them tolic velocity: was true positive while in 5 pa- - The test was positive for tients was false positive, also the stress induced myocardial ische- test was negative in 18 patients, mia in 28 patients, 24 of them 13 of them was true negative was true positive and only 4 pa- while 5 patients was false negative tients were falsely negative, also the test was negative in 18 pa- - The specificity of the test was tients, 14 of them were true and 72.2% and the sensitivity was only 4 were false. 82.1%. - The specificity of the test was Specificity and sensitivity of 77.8% and the sensitivity was TDI with DSE according to sys- 85.7%.

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Figure (1): variation of ejection fraction during Figure (2): variation of diastolic function during DSE in both studied groups. DSE in both studied groups.

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Discussion In the present work, group II Tissue Doppler imaging, ob- patients were significantly older tained from the apical windows than group I patients (mean age in during dobutamine stress, offers a years = 59.4 ± 6.9 versus 45 ± 7.1 quantitative and highly sensitive years, p<0.05) (table 1) mean for measuring systolic and diastolic alterations due to myo- In contrary, Vogel et al. (2003) cardial ischemia (10). reported that there is no significant difference in age in ischemic The present study aimed to cardiomyopathic patients and idi- compare the changes in myocar- opathic cardioyomyopathic pa- dial velocities as reflected by tients (56±6.3ys versus 53±4ys). measuring annular mitral veloci- (11) ties at rest and during dobutamine stress in ischemic and non- In present study, there is a sig- ischemic cardiomyopathy and nificant increase in the prevalence thus define criteria for differentiat- of diabetes in group II (18) (64.3%) ing between them. versus (7) patients (38.9%) in group I (P < 0.05). (Table 1) For this purpose, in the present study, forty-six patients with These results are in agreement dilated cardiomyopathy had been with those reported by Peter, et al. evaluated by TDI at rest and (2001) They found a higher preva- during dobutamine stress lence of diabetes in patients with echocardiography. All patients ischemic cardiomyopathy (22%) underwent coronary angiography than those who had non-ischemic within one week before the stress cardiomyopahty (5%). (12) test. According to the results of coronary angiography, the In the present study there is a patients were classified into two higher prevalence of dyslipidamia groups; group I who had normal in group II than in group I (60.7% coronary arteries and group II who versus 38.9%, p< 0.05). (Table 1) had significant coronary artery disease. This is in accord with Vogel et

298 Benha M. J. Vol. 29 No 1 Jan. 2012 al. (2003) who found a higher butamine stress. (14) prevalence of hypercholesterole- mia in patients with ischemic car- As regard diastolic parameters diomyopathy than in patients with during dobutamine stress in the non-ischemic cardiomyopathy present work, there is insignifi- (62% Vs 18%), p <0.05. (11) cant decrease in the E/A ratio in group I while there is significant In the present study, atropine decrease in that ratio in group II was used to reach the target (Fig. 2) stress level in 10 cases (55.5%) of group I and in 12 (42.8%) cases of This is in agreement with Ali- group II. son et al. (2003), who found that marked deterioration of diastolic This finding is in agreement function in ischemic than in idio- with that of Rambaldi et al. (1998) pathic cardiomyopathic patients who found that 47% of group I during dobutamine stress echo- needed addition of atropine com- cardiography. This deterioration of pared to 45% of the group II. (13) diastolic function may be due to increase of myocardial rigidity In the current study, the global during stress as a result of ische- systolic function as calculated by mia in group II. (5) EF in both groups , there was nearly no changes in group ? But this result not in agree- while in group II there is initial in- ment with, Hanekom et al. (2005), crease then decrease in EF from who reported that there is insignif- low dose to peak dose (Biphasic icant changes of diastolic function response) (fig.1 ). during dobutamine stress echo- cardiograthy in ischemic and idio- Pauliks et al. (2005) detect that pathic cardiomyopathy. (15) there is an increase in global LV systolic function in low dose dobu- In the present study the peak tamine stress echocardiography in systolic velocities in tissue Dop- ischemic cardiomypathy that de- pler during DSE study in group I, crease again with high doses do- at the six sectors show insignifi-

299 Hesham Rashid, et al.... cant and monophasic response. in ischemic patients when com- (Fig.3, Table 2). pared with myopathic patients. (17) While there is significant increase in systolic velocity at low On the other hand Tsutsi et al. dose compared to that in the base- (1998) demonstrated that pulse- line resting state and followed by wave Doppler tissue imaging at gradual decrease in the systolic rest could not differentiate be- velocity towards the peak dose in tween ischemic cardiomyopathy all six sectors (Biphasic response). and non-ischemic cardiomyopathy (Fig.4, Table 3). segments depending on the peak systolic velocity. This difference This is in accordance with Pe- may be related to different demo- teiro et al. (2001) who used pulsed graphic data and involvement of tissue Doppler imaging during do- multi-vessel disease in CAD butamine - atropine stress testing group. (18) to detect significant coronary lesions and they found that at rest Also the results of current peak systolic velocity in territories study are in accordance with Ali- supplied by diseased artery was son et al., (2003) who used dobu- insignificantly less than that of tamine tissue Doppler with meas- non-ischemic cardiomyopathy but urement of mitral trans-annular with low stress, the peak systolic systolic velocities, the study velocity was significantly higher in showed a reduction in systolic ve- ischemic cardiomyopathy. (16) locities in non-ischemic myopathic patients compared to CAD group. This is in agreement with the (5) results of Elzaky et al., (2005), who found that systolic velocities The diastolic parameters of tis- as assessed by pulsed tissue Dop- sue Doppler detected by E'/A' in pler imaging were significantly re- the present work were evaluated duced in ischemic region when during dobutamine stress, we compared with the corresponding found in group I, the E'/A' ratio at walls in healthy patients and high rest was 1.0±0.3, at low dose it

300 Benha M. J. Vol. 29 No 1 Jan. 2012 was 1.0±0.2 and at peak dose it duced in ischemic region when was 0.9±0.3 (Table 2). This means compared with the corresponding that there is insignificant decrease walls in idiopathic cardiomyopath- in E'/A' ratio in this group with ic patients. (5) non-ischemic cardiomyopathy. Contradictory results were ob- Similarly, in group II, the E'/A' tained by Elzaky et al., (2005) who ratio during the test were insignifi- found that diastolic velocities as cant changes as in group I (Table assessed by pulsed tissue Doppler 3). imaging were significantly reduced in ischemic region when compared So, there were no changes in with the corresponding walls in diastolic parameters as estimated healthy patients and high in is- by TDI during dobutamine stress chemic patients when compared in both groups. with other myopathic patients. (17)

This may be explained by non- Hegazy et al., (2007) concluded linear changes in diastolic myo- that mitral trans-annular systolic cardial velocities in response to is- and diastolic velocities were an in- chemia; the ratio may increase dicator for predicting significant with restrictive response or de- coronary stenosis, their study re- creased with abnormal relaxation vealed that the impaired TDI de- response. The different responses rived variables; S, E', A' and E'/A' of diastolic function may be relat- ratio, were an indicator for CAD. ed to the amount of myocardial fi- (19) brosis and level of end-diastolic pressure which is depends on pa- In the present study the sensi- tient age and duration of disease. tivity and specificity of TDI during DSE in prediction of coronary ar- Similar conclusions were ob- tery disease in myopathic patients tained by Alison et al. (2003), who were significantly higher than that found that diastolic velocities as of the conventional dobutamine assessed by pulsed tissue Doppler stress echocardiography: it was in imaging were insignificantly re- tissue Doppler 85.7% versus

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82.1% in conventional echocardi- 2- Pellikka P. A., Roger V. ography, specificity was 77.8% in L., O. H. J. K., Miller F. A., Sew- TDI versus 72.2%.(Table 4). ard J. B., Tajik J. (1995): Stress echocardiography. Dobutamine This is in accordance to Alison stress echocardiography: tech- et al. (2003) who found that, tis- niques, implementation, clinical sue Doppler imaging with dobuta- applications, and correlations. mine stress echocardiography Mayo Clin. Proc. 70:16. identified 41 of 48 of myopathic patients with CAD and 22 of 25 3- Morales A., Painter T., Li without CAD with a sensitivity R., Siegfried J. D., et al. (2008): 85% and specificity 88%. (5) Working Group on Myocardial &Pericardial Diseases. European The difference in values be- Society of Cardiology Newsletter tween the present study and other Issue 28 – September. studies may be attributed to the differences in age, gender, and 4- Duncan M., Darrel P., other risk factors like hyperten- Francis M., Derek G. et al, sion, diabetes mellitus, and dys- (2003): Differentiation of ischemic lipedamia, also maybe due to dif- from Non-ischemic Cardiomyopa- ferent degrees of diameter thy during Dobutamine Stress. stenosis, and various combina- Am. J Cardiol. June 10. tions of ischemic, hibernating, and infarcted myocardium. 5- Alison M., Duncan, M. R. C. P. , Darrel P. Francis, et al. References (2003): Differentiation of Ischemic 1- Sochowski R. A., Yvor- From Nonischemic Cardiomyopa- chuk K. J., Yang Y. Y., Rates M. thy During Dobutamine Stress by F., Chan K. L. (1995): Dobuta- Left Ventricular Long-Axis Func- mine and dipyridamole stress ech- tion . Circulation. 108:1214. ocardiography in patients with a low incidence of severe coronary 6- Cohen J. L., Greene T. O., artery disease. J Am Soc Echocar- Ottenweller J., Binenbaum S. diography 8:482. Z., Wilchfort S. D., Kim C. S.,

302 Benha M. J. Vol. 29 No 1 Jan. 2012 (2001): Dodutamine stress echo- Greenberg N.L., et al. (2004): cardiography for detecting coro- Noninvasive quantification of re- nary artery disease. Am J Cardiol gional myocardial function using 67:1311. Doppler-derived velocity, displacement, strain rate, and strain in 7- Sicari R., Picano E., healthy volunteers: Effects of ag- Landi P., Pingitore A., et al. ing. Journal of the American Soci- (2003): Prognostic value of dobu- ety of Echocardiography;17:132- tamine-atropine stress echocardi- 138. ography early after acute myocardial infarction. Echo. Dobutamine 11- Vogel M., Cheung M. M., International Cooperative (EDIC) Li J., et al. (2003): Noninvasive Study. J Am Coll Cardiol; assessment of left ventricular 29:254–260. force-frequency relationships using tissue Doppler-derived isovo- 8- Elhendy A., Cornel J. H., lumic acceleration: Validation in Roelandt J. R., et al. (2003): do- an animal model. Circula- butamine stress echocardiography tion;107:1647–1652. for the identification of multi- vessel coronary artery disease af- 12- Peter C. M., Terri B., ter uncomplicated myocardial in- Colin C. (2001): Explanation of farction: the impact of extent and heterogenicity in different sectors severity of left ventricular dysfunc- as regard diastolic velocities. AMJ; tion. Heart 76:7. Cardol; 87; 252-531.

9- Raymond, and Bayarri, 13- Rambaldi R., Polder- (2003): P Values are not Error mans D., Fioretti P.M., Cate Probabilities. A working paper F.J., Vletter W.B., Bax J.J., Roe- that explains the difference be- landT J.R. (1998): Usefulness of tween Fisher's evidential p-value pulse wave Doppler tissue and the Neyman–Pearson Type I sampling and dobutamine stress error rate ∝. echocardiography for the diagnosis of right coronary artery 10- Sun J. P., Popovic Z. B., narrowing. Am. J. Cardiol.: 81;

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1411-1415. atropine stress testing to detect coronary artery disease. Echocar- 14- Pauliks L.B., Vogel M., diography; 18:275-284. Madler C.F., et al. (2005): Regional response of myocardial 17- Elzaky M. M., Abu-El- acceleration during isovolumic Enin W. M., Al-Cekelly M.M., contraction during dobuatmine Taha O.M. (2005): Assessment of stress echocardiography: A color regional diastolic dysfunction in tissue Doppler study and coronary artery disease detected comparison with angiographic by tissue Doppler dobutamine findings. Echocardiography; stress Echocardiography,116. 22:797–808. 18- Tsutsi H., Uemastu M., 15- Hanekom L., Jenkins C., Loufoua J., et al. (1998): Com- Jeffries L., et al. (2005): Incre- parative usefulness of myocardial mental value of strain rate analy- velocity gradient in detecting is- sis as an adjunct to wall motion chemic myocardium by dobuta- scoring for assessment of myocar- mine challenge. J Am coll Cardiol; dial viability by dobutamine echo- 31:89-93. cardiography. A follow-up study after revascularization. Circula- 19- Hegazy M. A., Mousa A. tion; 112:3892. J., Alsayegh A., Bader A. (2007): Predictive accuracy of tissue Dop- 16- Peteiro J., Monserrat L., pler imaging for assessment of Fabregas R., et al. (2001): Com- non infarction myocardial region parison of two dimensional echo- in patients with acute myocardial cardiography and pulsed Doppler infarction. Medical principles and tissue imaging during dobutamine practice 16; 40-46.

304 Benha M. J. REPRINTVol. 29 No 1 Jan. 2012 BENHA MEDICAL JOURNAL

THE ROLE OF TISSUE DOPPLER IMAGING DURING DOBUTAMINE STRESS ECHOCARDIOGRAPHY IN DIFFERENTIATING ISCHEMIC FROM NON-ISCHEMIC CASES OF DILATED CARDIOMYOPATHY

Hesham Rashid MD, Mohamed Hassan MD, Saad Ammar MD, Adel Gamal MD*, and Hitham Ahmed M.B.B.CH

Published by Benha Faculty of Medicine Volume 29 Number 2 May 2012

305 Benha M. J. Vol. 29 No 1 Jan. 2012 PREDICTORS OF SUCCESS OF MICROSURGICAL EPIDIDYMOVASOSTOMY FOR OBSTRUCTIVE AZOOSPERMIA

Magdy A. El-Tabey MD and Samy Tosson MD Department of Urology, Benha Faculty of Medicine, Benha

Abstract Objective: To evaluate the outcome of seminal ductal Patency rate with different predictors after reconstructive surgery. Patients and Methods: This study comprised 40 patients (mean age 31.5 years, range 21-41 years), 30 patients operated upon with various reconstructive surgery (mainly epididymovasostomy ) for obstructive azoospermia and 10 patients were inoperable. All the patients followed for 1 year by semen analysis every 4 months. The patient's findings will be correlated with different factors that affect the surgical outcome. Results: Of 30 azoospermic patients due to operable causes, sperms appeared in seminal fluid in 15 patients (50%) postoperatively. Irrespec- tive to the type of surgery', factors affecting patency rate are studied and correlated with the patency rate. Conclusion: Although all techniques performed by microsurgery the success rate was low. The most important predictive factor is the demonstration of sperms in the epididymal fluid. Key words: infertility, epididymovasostomy, microsurgery. In- vitro fertilization, intracytoplasmic sperm injection. Abbreviations: -ART: assisted reproductive techniques. -ASA: antisperm antibodies -OA: obstructive azoospermia -IVF: invitro fertilization -ICSI: intracytoplasmic sperm injection

305 Magdy A. El-Tabey and Samy Tosson

Introduction Furthermore, the new tech- Treatment of patients with nique of vasoepididymostomy us- seminal tract obstruction consists ing a triangulation with epididy- of microsurgical repair of obstruc- mal invagination gives a success tion or sperm retrival and in-vitro rate 100%[11]. Recent reports fertilization (IVF) with or without have demonestrated that the out- intracytoplasmic sperm injection come of microsurgical reconstruc- [1], [2], [3]. tion in men with obstructive azoospermia is dependent on the Despite recent advances in as- etiology of obstruction. It is the sisted reproductive techniques best when the cause of obstruc- (ARTS), microsurgical reanastemo- tion is inflammation and the sis of the seminal tract remains worse when the cause is idiopath- the treatment of choice when ic obstructive azoospermia. possible as it results in high patency rate and equal or better Patients and Methods pregnancy rates with natural This study was conducted on intercourse than those achieved 40 patients proved by history, with assisted reproductive physical examination including techniques [4], [5]. testicular size and vasal palpation, and investigations including hor- Vasoepididymostomy is among monal assay (FSH, LH and testos- the most difficult microsurgical terone), seminal fructose test, technique performed by urologists seminal alpha glucosidase test. [6], [7]. The success rate of epididy- Seminal and serum antisperm an- movasostomy has improved mark- tibodies, transrectal ultrasonogra- edly with the development of spe- phy, and bilateral testicular biop- cific tubule end to end [8] and end sies. to side [9] microsurgical anastomosis, these microsurgical ap- By exploration and vasography proaches allow accurate approxi- at the time of reconstruction with mation of the vasal mucosa to repeated semen analysis the diag- that of a single epididymal lobule nosis of obstructive azoospermia [10] . was confirmed.

306 Benha M. J. Vol. 29 No 1 Jan. 2012 The mean age is 31.5 years struction of obstructive azoosper- ±11.5 (ranged from 21-42 years). mia are illustrated in table. The majority have primary infertility (95%) and secondary infertility The Causes of inoperability in in 5% with previous pregnancies 10 patients (25% ) were irrespective to its outcome. 1- Congenital Causes: 8 cases (80%). The duration of infertility rang- a- Congenital bilateral absence es from 2 to 15 years with a mean of the vas deference 6 cases (60)%. of 6.5 years ±3.5 years. Past histo- b- Mullerian duct cyst, 1 case ry of related surgical proce- detected during scrotal explora- dures was obtained in 5 patients tion and vasography. The cyst was (12.5%) which were removal of epi- present posterior to the bladder didymal mass in 1 patient, hydro- 4x4 cm in the midline compress- celectomy in 3 patients and drain- ing the distal part of the vas and age of scrotal abscess in one ejaculatory duct. patient. Pelvic operations were c- Ectopic insertion of the vas done to 8 patients (20%), ingui- deference in the left ejaculatory nal herniorrhaphy in 3 patients, duct which is atretic in one case. Pelvic uretero lithotomy in 3 patients, partial cystectomy in one 2- Acquired causes: 2 cases patient and pelvic fixation of rectal (20%) prolapse in one patient. Past his- a- Sever epididymal scarring tory of related medical disease was from previous surgery for removal obtained in 27 patients. Ten Pa- of epididymal mass (1 case). tients had history of epididymoor- b- Fixation of rectal prolapse chitis (37%), 15 patients had his- with open pelvic fixation leading to tory of bilharisiasis, 1 patient had pelvic adhesion and vasal ob- history of pulmonary tuberculosis struction in one case. and one patient had history of chronic obstructive pulmonary Results disease with repeated respirato- Post-operative seminal analyses ry tract infection (2.5%). The sur- were done every four months for gical techniques used for recon- one year. Anatomical success is

307 Magdy A. El-Tabey and Samy Tosson defined as presence of sperms in mu/ml, 14 patients out of 26 the seminal fluid regardless its (53.8%) versus 1 patient out of 4 count which indicate patency. (25%) with statistical significant difference. Patency rate in our operable 30 patients was detected in 15 pa- 2-Patency rate according to tients (50%), sperms appeared the presence of antisperm anti- postoperatively after a latency pe- bodies: we detected antisperm an- riod ranging from 4 months to l tibodies in 9 patients (30%) and year with a mean of 7 months negative in 21 patients (70%). Pa- ±S.D and sperm count ranging tency rate was 55.6% in the +ve from 100,000 to 4 millions/ml group and 47.6% in the -ve group with a mean of 3 millions/ml. with no statistical significance. Many factors were analyzed and correlated with the patency rate 3-Patency rate according to including : the type of operations: According 1. Seminal alpha-glucosidase to the four types of operations car- activity. ried out for reconstruction of the 2. Presence of antisperm anti- seminal patency, we found that bodies. side to side epididymovasostomy 3. Type of surgery done. had the highest patency rate, 12 4. Laterality of surgery. out of 23 patients (52.2%).Four 5. Causes of obstruction. patients had crossed transeptal 6. Level of anastomosis. epidiymovasostomy due to unre- 7. Presence of sperms proximal constructable vasal obstruction to obstruction (positive touch on one side and defective spermat- preparation test). ogenesis on the contralateral side. Post-operative patency rate 1-Patency rate according to was detected in one case (25%). seminal alpha-glucosidase activity: we found that when seminal End to end epididymovasosto- alpha-glucosidase activity below my was carried out in one case 20 mu/ml the patency rate was and patency was detected after 4 higher than if it was above 20 months with sperm count

308 Benha M. J. Vol. 29 No 1 Jan. 2012 4,000,000/ml. However statistical the level of anastomosis: The significance could not be docu- anastomosis of the vas to the epi- mented because it is only one didymis depends on the detection case. Non anastomotic operations of positive touch preparation test were carried out in two patients. at the epididymal site. If no The first for releasing external epi- sperms could be detected, higher didymal compression by fibrous level in the epididymis should be band & the second was sper- chosen. Therefore anastomosis matocele excision. Patency rate was carried out to the caput epi- occurred in one patient 50%. didymis in 12 cases and patency was detected in 3 cases 25%. In 4-Patency rate according to another 12 patients anastomosis the laterality of surgery: Bilateral was carried out to the corpus epi- reconstructive epididymovasosto- didymis, seven cases were bilater- my, had higher patency rate al. Touch preparation test was 69.2% than unilaterally managed positive in all and patency was de- cases 35.3% which showed statis- tected in 8 cases (66.7%). When tical significant difference. anastomosis was carried out to the cauda epididymis (3 cases), 5-Patency rate according to two cases were bilateral and pa- the cause of obstruction: the tency was detected in 2 cases. The causes of seminal tract obstruc- results show statistical signifi- tion was either idiopathic in 12 cant difference with higher paten- patients, post-inflammatory in 16 cy rate in cauda rather than cor- patients or post surgical in 2 pa- pus and the later rather than the tients. The best results of patency caput. rate was detected in the post inflammatory group with patency 7-Patency rate according to rate 62.5% in comparison with idi- the presence of intraepididymal opathic obstruction and post- sperms: (Positive touch prepara- surgical obstruction, 33.3% and tion test). Touch preparation test 50% respectively . was positive in 17 patients (60.7%) and 11 patients were neg- 6-Patency rate according to ative (39.3%). From the positive

309 Magdy A. El-Tabey and Samy Tosson group 10 patients had bilateral difference higher than negative epidiymovasosyomy. Patency rate touch preparation group where was detected in 13 patients patency was detected in one out of (76.5%) with statistical significant 11 patients (9.1%).

310 Benha M. J. Vol. 29 No 1 Jan. 2012 Discussion sperms in the vasal lumen with no Treatment of infertile patients vasal or ejaculatory duct obstruc- with seminal tract obstruction tion. In conjunction to reconstruc- may be either surgical reconstructive surgery for obstructive azoos- tion or sperm retrival and in vitro permia Hibi et al, confirmed the fertilization (IVF) with intracyto- necessity of sperm retrival during plasmic sperm injection ICSI [1]. It surgery and cryo-preservation for gives success rate 25-65% report- ART if surgery failed [11]. Schlegel ed in different centers [12]. calculated the cost per live birth to be approximately 87.000$ for Furthermore, testicular sperm surgical sperm aspiration and in- inspite of being with very poor mo- tracytoplasmic injection, while ep- tility, can achieve good motility & ididymovasostomy is 31,099$ [16]. good capacity of fertilizing ova by This is added to the female com- IVF with ICSI after 1-2 hour of plications of ARTs due to culture in a petridish at 37ºc after pharmacological super ovulation, washing and centrifugation [13], oocyte retrival and embryo trans- However, Hibi et al,[14] and Pas- fer [17]. On the other hand the qualotto et al,[15] stated that; de- success rate of epididymovasosto- spite the recent advances in as- my and vasovasostomy in pa- sisted reproductive techniques tients with primary epididymal or (ART), surgical reanastomosis of vasal obstruction unrelated to the seminal tract in ductal ob- vasectomy is unclear [18], Zhuo et struction remains the treatment of al, reported that surgery of the in- choice, when possible, as it re- guinal hernia in infancy & child- sults in high patency rate and hood is the commonest cause of equal or better pregnancy rates vasal injury and could not be cor- with natural intercourse than rected in adulthood[19], and, those achieved with assisted re- Smirkoli et al, concluded that the productive techniques. Vasoepi- pregnancy rates obtained after didymostomy is indicated when surgery were not statistically dif- testis biopsy reveals complete ferent from those obtained by spermatogenesis and scrotal ex- TESE-ICSI, but when considering ploration reveals the absence of multiple pregnancies, miscarriag-

311 Magdy A. El-Tabey and Samy Tosson es and side effects, the results ob- where patency rate in bilateral tained with surgery are better versus unilateral epididymovasos- than those obtained after TESE- tomv were 74% &52% respective- ICSI [20], and, Lee et al, stated ly[23], and also our results were that; recent analyses clearly indi- comparable to that of Schroeder- cate that specific treatments for Priittzen et al, who stated that pa- male factor infertility such as mi- tency and pregnancy rates are crosurgical reconstruction for ob- usually higher with bilateral re- structive azoospermia and varicoc- construction and recommended electomy for impaired testis aspiration and cryopreservation of function in properly selected pa- the epididymial spermatozoa tients, remain the safest and most before performing microsurgery to cost-effective ways of managing in- be used for ICSI in cases of surgi- fertile men [21]. Our present study cal failure[24], and our results aims to evaluate factors that may were also compatible to that of affect anatomical outcome (paten- Peng et al, who achieved patency cy of the seminal tract). rate 80.7% for bilateral cases and 27.6% for the unilateral cases [25]. We found that the patency rate after reconstructive surgery was Relative to the cause of ob- 50% (15/30) and Goldstein stated struction we found that the paten- that with the classic end to side or cy rate in patients with idiopathic end to end method of epididymov- obstruction was 33.3% while in asostomy, the patency rate is post-inflammatory it was 62.51% about 70% and 43% of men will and 50% patency rate was ob- impregnate their wives after a tained when the cause of obstruc- minimum follow up of 2 years tion was iatrogenic. This could be [22]. In our study the correlation explained in our study by the between patency rate and laterali- character of each cause. In idio- ty revealed that it was higher if pathic obstruction the site is usu- the cases underwent bilateral really in the upper half of the epidid- constructive surgery than unilat- ymis 80% which showed lower eral 69.2% versus 35.3% .This patency rate and positive touch was confirmed by Jarow et al, preparation test in only 30%. On

312 Benha M. J. Vol. 29 No 1 Jan. 2012 contrast, the site of obstruction in obstruction (66%). Nigam and post-inflammatory obstruction is Handry, reported similar results, present in the lower half of the ep- when the obstruction is caudal ididymis and the convoluted part block, epididymovasostomy gives of the vas which has higher posi- 52% patency rate & 38% pregnan- tive touch preperation test and cy while when it is capital (caput) higher patency rate 81.3%. This patency rate drops to 12% & preg- finding were confirmed by Hend- nancy to 3%. They explained their ery et al, who found that each pa- results by the finding of high inci- thology affect a different site [26], dence of ejaculatory duct and and in a study of Smirkoli and his seminal vesicles abnormalities in colleaques, they performed micro- men with idiopathic epididymal surgical side to side epididymova- obstruction 33% which may affect sostomy in 34 azoospermic men the surgical outcome [28]. with obstructive azoospermia mostly due to inflammation and In this study, antisperm anti- duct system patency was recov- bodies( ASA) were detected in 9 ered in 21 (63.6%) men that is patients (30%) and not detected in nearly comparable with our re- 70%, patency rate was 55.6% in sults [20]. the positive group and 47.6% in the negative group with no statis- Post inflammatory obstruction tical significance, Lee et al, stated typically occur in the body & tail that ASA is thought to be a of the epididymis near its junction consequence of the inflammatory with the vas deference (caudal process rather than cross block) and epididymovasosiomy reactivity to microorganisms[21]. has given better results of patency However, Bolduc et al, found that; 52% than caput block 12%, simi- according to multivariate analysis, lar results were reported by Jarvi there was a significant association et al, [27], the patency rate in men between the absence of ASA in the with obstructive azoospermia sec- seminal fluid and the success of ondary to infection was 100% fol- achieving pregnancy, and the lowed by post-surgical obstruction presence of high titres of ASA in (80%) and the least in idiopathic the semen decreased the probabil-

313 Magdy A. El-Tabey and Samy Tosson ity of achieving pregnancy after activity was lower than 20 mu/ surgery [29] . ml the patency rate was 50% , but when it exceeded 20 mu/ml the Regarding to the level of anas- patency reduced to the half (25%). tomosis and patency rate we Cooper, et al, explained this find- found that the lower the level of ings on the basis that the higher the anastomosis, the higher will the level of epididymal obstruc- be the rate of patency; Caput, cor- tion the higher the level of alpha- pus & cauda were 25%, 42.8% glucosidase activity and conse- and 66.7% respectively. This is quenlty the lower the rate of post- confirmed by Jarow et al, who epididymovasostomy patency [30]. found that the patency rate is The last and the most important higher when epididymovasostomy predictor for success of recon- done to the cauda 85% & less structive surgery of obstructive when done to the corpus 72% and azoospermia is the touch prepara- least when done to the caput epi- tion test. Shevnkin et al, found didymis (54%) [23], and in agree- that when no sperms could be de- ment to results of Jarvi et al, who tected in the proximal end of the concluded that moving from the seminal duct, the result was poor corpus to the caput epididymis in- [31]. When touch preparation test volves a significant adverse effect is positive i.e sperm detection upon patency and pregnancy out- proximal to the site of obstruction, come during surgical recommen- the patency rate will rise to dation [27], also,our results were 76.5%, while when the test is neg- inagreement with that of Peng and ative the patency rate will drop to his colleaques who found 100% 9.1% that is in agreement with the patency rate with caudal anastom- results of Peng et al,who achieved osis, with the least if it was done a patency rate of 87.2% with the with the capout 38.5% [25]. epididymal fullness [25]. Thus the presence of sperms in the epi- The correlation between semi- didymis at the site of anastomosis nal alpha-glucosidase enzyme ac- is the most significant predictor tivity and patency rate was stud- factor in our study. Also it may be ied. We found that when the the only factor that all previous

314 Benha M. J. Vol. 29 No 1 Jan. 2012 studies document its importance. mains the cornerstone in the Fox in his study reported that management of obstructive azoos- when touch preparation test is -ve permia, since it has lowered cost, during reconstructive surgery of less side effects and comparable azoospermic men, the patency results to in vitro fertilization rate is nil & all patients still az- (IVF) with intra cytoplasmic oospemic [32]. Kim et al, also re- sperm injection (ICSI). ported that intraoperative epididymal fluid quality correlates We prefer to offer ARTs to the positively with patency but not cases which are inoperable or with with pregnancy [18]. Jarow et al, history of repeated reconstruc- found a patency rate of 57% when tive surgical techniques. There the test is positive and 0% when it are several factors that improved was negative. He suggested that the anatomical success (patency). when the test is negative the ob- The most important predictor fac- struction may be in the rete testis tor is positivity of touch prepara- or the diagnosis of obstructive tion test. The negativity of this test azoospermia is incorrect, and the markedly lowers the rate of suc- patients have defect in spermato- cess. genesis rather than obstruction. Furthermore he reported that this The site of obstruction and con- spermatogenic defect may be sec- sequenty the level of anastomosis ondary to prolonged obstruction gives better results when it is in which promoting apoptosis [23]. the lower half of the epididymis Nieder-Berger and Ross found rather than the upper half. Also similar results and concluded that post-inflammatory obstruction demonstration of sperms in the shows better patency rate after epididymal fluid is the only pa- surgery than idiopathic or iatro- rameter that predict success [33]. genic obstruction. Bilateral surgery gives better results than if Conclusion surgery carried out on one side. Surgical treatment of obstructive azoospermia (epididymovasos- Seminal alpha-glucosidase ac- tomy and vasovasostomy). re- tivity could be used as a diagnos-

315 Magdy A. El-Tabey and Samy Tosson tic test for bilateral obstructive cific microanastomosis to the epi- azoospermia in proximal epididy- didymal tubule. Fert. Steril. 30: mal obstruction in which an over- 565. lap exists between obstructive and non obstructive azoospermia, 3- Sharma R. K., Pardon O. lower level of seminal alpha- F., Thomas A. J., Jr. and Agar- glucosidase enzymes activity wal A. (1997): Factors associated shows higher patency rate as it re- with the quality; before freezing flects lower site of obstruction. and after Thawing of sperm obtained by microsurgical epididy- Antisperm antibody has no cor- mal aspiration. Fert. Steril., 68: relation with the patency rate. Se- 262. men banking is recommended whenever possible during surgery 4- Belker A. M., Thomas A. for unfavourable surgical out- J., -Jr., Fuchs E. F, et al., come. Again if no sperms could be (1991): Results of 1,469 micro detected during surgery, testicular surgical vasectomy reversals . biopsy is recommended for revi- The Vasovasostomy Study Group. sion of the diagnosis and biopsy J. Urol., 145:505. banking for future assisted reproductive techniques . 5- Schlegel P. N. and Gold- stein M. (1983): Microsurgical References vasoepididymostomy: refinements 1- Nagy Z., Liu J., Cecile J., and results. J. Urol., 150: 1165. Silber et al., (1995): Using ejacu- lated, fresh and frozen- thawed 6- Jarow J. P., Sigman M., epididymal and testicular sper- Buch J. P. and Oates R. D. matozoa gives rise to comparable (1995): Delayed Appearance of results after intracytoplasmic sperm after end to side vasoe- sperm injection. Fertil. Ster- pididymostomy. J. Urol, il.63:808. 123:1156.

2- Silber S. J. (1978): Micro- 7- Thomas A. J. (1987): Va- scopic vasocpididymostomy, spe- soepididymostomy. J. Urol. clin.

316 Benha M. J. Vol. 29 No 1 Jan. 2012 North Am. 14: 527. development 16 (5): 561- 572.

8- Silber S. J., Van Steirte- 13 - Schoysman R., van Roo- ghem A.C., Liu J., et al., (1995): sendal E. Y., Bollcn N., et al., High fertilization and pregnancy (2001): Modern sperm retrieval rare after Intracytoplasmic sperm techniques and their usefulness in injection with spermatozoa ob- oocyte Fertilization .BJU inter tained from testicle biopsy. Hum. 88.2. Reprod. 10: 148. 14- Hibi. \H.,\ Yamada Y., 9- Fogdestam I. and Fail Honda N., Kukastu H. et al., M. (1983): Microsurgical end-to- (2000): Microsurgical epididymov- end and end-to-side epididymova- asostomy with sperm cryopres- sostomy to correct obstructive ervation for future assisted azoospermia. Scand. J. Plast Re- reproduction. International constr. Surg.. 17:137. Journal of Urology Vol.7, Issue 12, P. 435. 10- Chan P. T., Brandell R. A., Goldstein M. (2005): Prospec- 15- Pasqualotto F. F., Agar- tive analysis of outcomes after mi- wal A., Srivastava et al., (1999): crosurgical intussusception vasoe- Fertility outcome after repeat va- pididymostomy. BJU Inter 96(4): soepididymostomy. J. Urol., 162: 598-601. 1626.

11- Hibi H., Ohon, T., Amano 16- Schlegel P. N. (1996): T., et al., (2003): Clinical expe- Cost effectiveness of therapy for rience of vaso-epididy mostomy male Infertility-the case for man- using a triangulation technique. aged care. Society for male Re- Reproductive Medicine and Biolo- production, Onlando, Florida 4. gy Vol. 2, Issue, 3, 101-103. 17- Schenker J. G. and Ezra 12- Schlegel P. (2004): Causes Y. (1994): Complications of as- of azoospermia and their manage- sisted reproductive techniques. ment. Reproduction, Fertility and Fertil. Steril. 61:411.

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18- Kim E. D. Winkel E., Ore- ders Elsevier. juela F. et al., (1998): Pathologi- cal Epididymal Obstruction Unre- 23- Jarow J.P., Oates R.D., lated to vasectomy: Results with Buch J. P., et al., (1997): Effect microsurgical Reconstruction. J of level of anastomosis and quality UroL, I60:2078. of intraepididyimal sperm on the outcome of end to side epididy- 19- Zhu X. Y., Zeny Q., Deny movasostomv. Urology.49: 510. S.X. and Zhong K. B. (2001): A surgical techniques for long seg- 24- Schroeder-Printzen I., ment loss of the vas deference. Zumbe G., Bispink L. el al., BJU inter 88.9. (2000): Microsurgical epididymal sperm aspiration: aspirate analy- 20- Smirkoli T., Viron-Klun I., sis and straws available after cryo- Sirkorec J. et al., (2010): Epi- preservation in patients with non didvmovasostomv as the first-line reconstructive obstruction azoos- treatment of obstructive azoosper- permia. Hum. Reprod., 50: 2531- mia in young couples with normal 2535. spermatogenesis.Reproductive Bi- omedical online vol 20, issue 25- Peng J., yuan Y., Zhang 5,594-601. Z. et al., (2012): Factors affecting the results of microsurgical vasoe- 21- Lee R., Goldstein M., Ul- pididymostomy.Urology;79(1):119- lery B. W., et al., (2009): Value of 122. serum antisperm antibodies in diagnosing obstructive azoospermia 26- Hendray W. F., Levi- . J Urol;181(1):264-269. sohn D., Parkinson C. M., et al., (1990): Testicular obstruction: 22- Goldstein M. (2012): Mi- Clinco-pathological studies. Am cro surgical management of male R.. Coll. Surge. Engl. 72:396. infertility.In:Campbell-Walsh Urol- ogy.Kavoussi LR,Novick AC,Partin 27- Jarvi K., Zini A., Buck- AW,Peters CA editors,tenth edi- span M. B. et al., (1998): vasoe- tion,chapteR 22,paGe 666, Saun- pididymostomy outcomes for

318 Benha M. J. Vol. 29 No 1 Jan. 2012 Men with concomitant abnormali- human epididymal functions by ties in the prostate and seminal the use of inhibitors on the assay Vesicles. J. Urol., 160: 1410. of glucosidase in seminal plasma. Intern. J. of Androl. 13;297. 28- Nigam A. K. & Hendery W. F. (1999): Repeated epididy- 31- Shevnkin Y. R. Chen M. movasostomy: Are they worth E. and Goldstein M. (2000): In- while ? BJU international 83.7. travasal azoospermia- a surgical dilemma. 85.9. 29- Bolduc S., Fischer M. A., Deceuninck G. and Thabt M. 32- Fox M. (1997): Failed va- (2007): Factors predicting overall sectomy reversal is a turther success: A review of 747 micro- attempt, worthwhile using micro- surgecal vasovasostomies.Can surgery. Eur. Urol 31;436. Urol Assoc J. 1(4):388-394. 33- Niederberger C. and Ross 30- Cooper T. G., Yeting C. L. S. (1993): Microsurgical Epi- H., Nashan D., et al., (1990): Im- didymovasotomy: Predictors of provement in the assessment of success. J. Urol. 149: 1364.

319 REPRINTMagdy A. El-Tabey and Samy Tosson BENHA MEDICAL JOURNAL

PREDICTORS OF SUCCESS OF MICROSURGICAL EPIDIDYMOVASOSTOMY FOR OBSTRUCTIVE AZOOSPERMIA

Magdy A. El-Tabey, MD and Samy Tosson, MD

Published by Benha Faculty of Medicine Volume 29 Number 1 Jan. 2012

320 Benha M. J. Vol. 29 No 1 Jan. 2012 DIAGNOSTIC VALUES OF CRP, IL-6 AND ICAM-1 AS MARKERS OF BACTERIAL INFECTION IN THE NEONATES

Mohamed Al-Eraki MD and Lotfy Abdel-Fattah MD* Departments of Clinical pathology and Pediatrics*, Al-Azhar University, Damietta.

Abstract Background: Neonatal sepsis is the most common cause of neonatal morbidity and mortality, particularly in developing countries. The aim of the present study was to assess the value of these markers for the early diagnosis of bacterial Infection in the neonates. Methods: CRP, IL-6 and ICAM-1 were measured in blood samples collected from 60 neonates admitted to neonatal ICU in Demiatta hospital, Al-Azhar Universi- ty from March 2011 to August 2011. The diagnostic efficacies of these markers were evaluated calculating the sensitivity, specificity, and likelihood ratio of positive and negative results. Results: hematological markers (WBCs and platelets), CRP, and immunological markers (IL-6 and ICAM-1) were significantly different in patient versus control, infected versus non infected and bacterial culture positive versus bacterial negative neonates. Conclusion: increased CRP, IL6 and sICAM-1 levels can be detected as early as neonatal sepsis developed. Keywords: Intercellular adhesion molecule-1, interleukin 6 and C- reactive protein, Sepsis.

Introduction set sepsis (after first week till 28 Neonatal sepsis remains a seri- days of life) has its environmental ous and potentially life- origin either in home or in hospi- threatening disease with a mortal- tal (2). ity rate ranging from 1.5-40% (1). Early onset (within first week of The blood culture is a gold life) neonatal sepsis is generally standard test for confirming diag- acquired from pathogens of mater- nosis of neonatal sepsis, however, nal genital tract, whereas late on- its results are not available for 48

321 Mohamed Al-Eraki and Lotfy Abdel-Fattah hours after starting the culture, Molecule 1) also known as CD54 and if blood cultures are drawn af- is a protein that in humans is en- ter administration of antibiotics, coded by the ICAM-1gene (7). growth of microorganisms can be ICAM-1 participates in the adhe- suppressed (3). Thus, it is ex- sion of leukocytes to the endothe- tremely important to make an lium and may be crucial in regu- early and accurate identification lating leukocyte activation at a of neonatal sepsis and its very early inflammatory response pathogenic factors for prompt (8). Expression of adhesion mole- antimicrobial therapy and better cules is regulated by cytokine acti- outcomes. vation, and it has been shown that several membrane-bound ad- C-reactive protein (CRP) is hesion molecules can be detected widely used as a marker of acute in the circulation in a soluble inflammation and one of the more form. Soluble ICAM-1 (sICAM-1) is studied sepsis biomarkers. CRP normally present in the serum of is thought to assist in comple- healthy adults, and recent studies ment binding to foreign and dam- examined the role of sICAM-1 in aged cells (4). As a classical acute neonatal infections, but with con- phase reactant, however, CRP ele- troversial results (9). vation alone has insufficient specificity for diagnosis of neonatal in- Patients and Methods fection (5). This study included sixty neonates with clinical signs and The interleukins have been log- symptoms suggestive of neonatal ical targets of sepsis biomarker in- infection with temperature insta- vestigations related to their role in bility, tachycardia or bradycardia, inflammation and sepsis. Interleu- poor perfusion, shock, apnea, cya- kin-6 (IL-6) is a pro-inflammatory nosis, intercostal retractions, ta- cytokine that is produced in re- chypnea, hypotonia, lethargy, sei- sponse to infection and other con- zures, abdominal distension, ditions of inflammation (6). gastrointestinal bleeding or pe- techiae. They were attending the ICAM-1 (Intercellular Adhesion neonatal ICU in Demiatta Hospi-

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tal, Al-Azhar University and twen- sistent with septicemia. ty neonates apparently normal as 6- Umbilical and throat swabs a control group. were taken from suspected cases of oompholitis and Preterm neonate, infant of dia- pneumonia. betic mother, neonates with jaun- 7- CRP was determined using dice or intracranial hemorrhage, Reactivos GPL CRP- babies, who had received antibio- TURBILATEX kit. tics prior to admission or had ma- 8- IL-6 estimated by ELISA jor surgical intervention, suspect- technique using commercial ed chromosomal disorder or major assay kit (Human IL-6, ELI- congenital anomalies were exclud- SA kit, Germany). ed from the study. 9- ICAM-1 estimated by ELI- SA technique (Human ICAM- All neonates underwent the 1, ELISA kit,Germany). following: 1- Detailed history with stress Peripheral blood samples prior on maternal risk factors for to the administration of antibiotics infection. were taken, 1.5-3 ml added to vial 2- Complete blood count with of blood culture while remaining differential leucocytic count. part used for CBC, while serum 3- Urine examination to ex- used for ICAM-1, IL-6 and CRP clude urinary tract infection was then separated and stored at (UTI) and culture was done -30°C until later analysis. Venous for specimens with WBCs blood samples were also taken at >10/mm3 in a 10 mL the time of routine vein puncture centrifuged sample. from a number of infants 4- Blood culture was done by undergoing intensive care with no ensuring standard antiseptic acute signs of deterioration, as measures. controls. 5- Lumber puncture done in 11 neonates in the presence Statistical Analysis of a positive blood culture or Data were expressed as mean ± if the clinical picture is con- SD. Comparisons between two

323 Mohamed Al-Eraki and Lotfy Abdel-Fattah groups were analyzed by Mann- and abnormal laboratory signs Whitney test. To determine a diag- consistent with infection or chest nostic cutoff value for CRP, IL6 radiographs suggestive of pneu- and ICAM-1 in newborns, a ROC monia with (abnormal hematologic curve was constructed for each values and/or elevated CRP) sampling point. The optimal cutoff (n=16). value for study measurements were selected on the graph with • The non-infection group sensitivity, specificity, PPV, NPV (group 2) comprised 19 neonates. and AUC. All data were analyzed These group characterized by using IBM SPSS ver. 18.0 (Med- there initially clinical symptoms calc® version 10.0.2.0) (IBM, New suggestive of sepsis but there was York, USA). A P value <0.05 was no hematological, microbiological considered to be statistically sig- or radiological evidence of infec- nificant. tion, their clinical deterioration was transient and no clinical im- Results provement after administration of 1. Characteristics of study antibiotics. population According to their clinical and/ • 21/60 (35.0%) were suspect- or laboratory findings, 60 neo- ed of infection in first week of life nates were assigned into two (early onset infection) and 39/60 groups, infection group (41 neo- (65.0%) of infection after first nates) and non-infection group (19 week and less than 28 days (late neonates). onset infection).

• The infection group (group 1) • 11/25 (44.0%) of positive bac- (n=41) consisted of neonates who terial culture were in early onset further sub-grouped into positive of sepsis while all negative bacteri- bacterial blood, urine or umbilical al culture 16 (100.0%) were in late culture plus clinical signs of infec- onset. tion (n=25) or negative bacterial culture but the presence of three • Twenty healthy neonates or more clinical signs of infection whose blood had been taken for

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other routine examinations were culture, there were statistically selected as a control group (group significant differences between 3). group with positive and group with negative bacterial culture as 2. CRP, IL-6, ICAM-1 and he- regard to CRP, IL-6, ICAM-1, and matologic profiles platelets with p value < 0.001, ne- WBCs, CRP, IL-6, and ICAM-1 onates with positive bacterial were significantly elevated in pa- culture have elevated levels as tient group (as compared with regard to CRP, IL6 and ICAM-1 control neonates with p value < with lower levels of platelets (table 0.0001. While platelets were sig- 4). nificantly decreased in patient group with p value = 0.0001 (ta- 3. Sensitivity, specificity, pos- ble, 1). itive predictive value (PPV) and negative predictive value (NPV) Also WBCs, CRP, IL-6, and of CRP, IL-6 and ICAM-1 (table, ICAM-1 were significantly elevated 5): in infected neonates as compared For diagnosis of infection, CRP, with non-infected neonates with p IL-6 and ICAM-1 had a sensitivity value < 0.01, while platelets were of 70.73%, 60.98% and 73.17%, a significantly decreased in infected specificity of 73.68%, 73.68% and neonates with p value < 0.0001 68.42%, a PPV of 85.3%, 83.3% (table, 2). and 83.3% and an NPV of 53.8%, 46.7% and 54.2%, respectively, When neonates sub-grouped with a cutoff value of 25 mg/L according to onset of infection into for CRP, 46 for IL6 and 398 for early and late onset, there were no ICAM-1. statistically significant differences between them as regard to CRP, For onset of infection, CRP, IL- IL-6, ICAM-1, WBCs and platelets 6 and ICAM-1 had a sensitivity of with p value > 0.05 (table, 3). 38.10%, 66.67% and 52.38%, a specificity of 76.92 %, 43.59% and When neonates sub-grouped 64.10%, a PPV of 47.1 %, 38.9% according to results of bacterial and 44.0% and an NPV of 69.8 %,

325 Mohamed Al-Eraki and Lotfy Abdel-Fattah

70.8% and 71.4%, respectively, For onset of sepsis, CRP had an with a cutoff value of 20 mg/L AUC of 0.558, IL-6 had an AUC for CRP, 52 for IL6 and 456 for of 0.479, whereas ICAM-1 had ICAM -1. AUC, of 0.503 with (P>0.05) (Fig- ure, 2). For culture-positive sepsis, CRP, IL-6 and ICAM-1 had a sen- For culture-positive sepsis, sitivity of 72%, 64% and 88%, a CRP had an AUC of 0.891, IL-6 specificity of 93.75%, 100% and had an AUC of 0.882, whereas 100%, a PPV of 94.7%, 100% and ICAM had an AUC of 0.966 in the 100% and an NPV of 68.2%, ROC analysis (P<0.001) (Figure, 64.0% and 84.2%, respectively, 3). with a cutoff value of 29 mg/L for CRP, 55 for IL-6 and 456 for Isolated Microorganisms: ICAM-1. Microorganisms identified by different sample cultured on 4. ROC-curve of CRP, IL-6 different media and identification and ICAM-1 of organism was done by different The ROC curves of CRP, IL-6 biochemical reactions in the cul- and ICAM-1 for the sepsis are tak- ture positive infection subgroup en using the control group as ref- (n= 25) included: Coagulase- erence (table 5). negative staphylococci were detected in 7 cases, E. coli in 5 cas- For the detection of sepsis, CRP es, Group B Streptococcus in 4 had an area under curve (AUC, cases, Staphylococcus aureus in 3 0.768) in the ROC analysis, IL-6 cases, Enterococci in 3 cases, had an AUC of 0.711, whereas Haemophilus influenzae in 2 cas- ICAM-1 had AUC, of 0.757 with es, Streptococcus Viridans in 1 (P<0.01) (Figure, 1). case (table; 6).

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Discussion platelets, a specificity of 94.74% Over recent years there has for WBCs, 94.74% for platelets, a been great interest in the potential PPV of 97.4% for WBCs, 97.0% for diagnostic value of a range of hae- platelets and an NPV of 81.8% for matological, and immunological WBCs, 66.7% for platelets, with a surrogate markers of infection(5). cutoff value of 29x1000/mm3 for WBCs, and 198x1000/mm3 for As regard to hematologic mark- platelets. WBCs had an AUC of ers, WBCs and platelet counts 0.945, whereas platelets had an were significantly differed among AUC of 0.889 (P<0.001) (table, 5). the studied groups. However, it These results were in agree with a has already been recognized that Da Silva et al.,(10) study that hematologic indices alone cannot showing variable sensitivity and be confidently used as decision specificity ranging from 17 to 90% criteria for the identification of for WBC and platelets. sepsis or for guiding antibiotic treatment(10). When WBC and Upon CRP recognition and platelet matched with diagnosis of binding to a phospholipid ex- infection, they had a sensitivity of pressed on the membranes of 90.24% for WBCs, 78.05% for many bacteria and damaged host

331 Mohamed Al-Eraki and Lotfy Abdel-Fattah cell walls, the acute phase inflam- 62%, and 81%; Pulliam et al., (16) matory response is initiated(11). found 70 mg/L, 18%, 79%, and Accordingly increased levels of 90%; Lacour et al.,(17) found 40 CRP are observed early in re- mg/L, 23%, 89, and 75; Galetto- sponse to severe bacterial infec- Lacour et al., (18) found 40 mg/L, tion (12). Plasma CRP levels were 29%, 79%, and 79%; Berger et found to be statistically signifi- al.,(19) found 20 mg/L, 25%, 83%, cantly higher in patients with sep- and 67%; Andreola et al., (20) tic syndrome symptoms, and CRP found >40 mg/L, 67%, 71%, and serum concentration correlated 81% for cut-off, correlating preva- with severity of a patient’s clinical lence, sensitivity and specificity state(13). In fatal cases high plas- respectively. ma CRP concentration was recorded during hospitalization, whereas In agreement with our results, in cases of recovery, rapid decline numerous studies have demon- of CRP was noted(14). In our strated CRP levels to be elevated study, CRP was found to be in- in sepsis(21,22). but the data sup- creased in patient (35.14±23.50 porting its use as a diagnostic bio- mg/L) than control (3.55±1.49 marker are less convincing(23,24). mg/L) groups. Therefore, plasma The marker performs better than CRP concentration in patients standard clinical parameters, with bacterial sepsis may be help- such as white blood cell count and ful in evaluation of severity of clin- temperature, in predicting infec- ical state and monitoring of the tion(25). Alone and combined with disease course as well as therapy five variables in a clinical predic- efficacy. tion score, CRP had reasonable diagnostic accuracy. It has been In our study CRP has 25.3 mg/ suggested that CRP may be used L, 68.3%, 70.73%, and 73.68% for to follow response to antibiotic cut-off, correlating prevalence, therapy(25,26) but CRP performs sensitivity and specificity respec- poorly in discriminating septic tively. These results were matched from nonseptic shock(24), so that with many studies: Isaacman and the CRP diagnostic accuracy var- Burke(15) found 44 mg/L, 11%, ies widely within an unacceptable

332 Benha M. J. Vol. 29 No 1 Jan. 2012 range of sensitivity(27,28,29,30,31). Concentrations of ICAM-1 are This may be related to the arbi- very high in neonates with sepsis trary choice of optimal cutoff regardless of their gestational age. points(32,33,34) as well as the in- Even though only 25 out of 41 sensitive analytic methods with (60.9%) neonates with infection various limits of quantification had positive blood culture, it is used in the past to detect the CRP well known that a negative blood pattern in the earliest course of culture does not exclude sepsis. neonatal infection. On the contrary, while the CRP levels, which are the most reliable Measurement of cytokine levels marker in use, were nearly normal has also been investigated as a at the day of sampling, the ICAM means to increase the diagnostic and IL6 values were elevated in all yield for neonatal sepsis. Our re- infected neonates of the study, sults show distinctly different pat- possibly indicative of a higher sen- terns of expression of IL6 among sitivity to infection of this marker. different groups, IL6 show The high number of negative blood (54.06±21.16 versus 22.2±3.04 cultures in cases of clinically diag- with p value < 0.01) for patients nosed sepsis in combination with and controls respectively, 59.03± delayed elevation of CRP levels in 22.97 versus 43.31±10.82 with neonates with infection further p value < 0.01 for infected and emphasizes the necessity for a non infected neonates respec- more reliable index for early diag- tively, 70.64±21.44 versus nosis. ICAM-1 and IL-6 measure- 40.9±9.84 with p value < 0.01 ment is not simpler than CRP de- for bacterial positive and nega- tection, but does, however, require tive groups respectively, but a minimum amount of serum, similar in early (55.47±21.99) and equipment available to most hos- late (53.3± 20.96) onset sepsis pital laboratories, gives results with p value >0.05. Like our re- within the day, and could prob- sults many studies have con- ably be incorporated in routine in- firmed the utility of interleukin-6 fection laboratory tests. as an early marker of neonatal sepsis (35,36,37,4,38). The cutoff values for interleu-

333 Mohamed Al-Eraki and Lotfy Abdel-Fattah kin-6 to diagnose sepsis in other shortened hospital stay and in- studies have ranged from 18 to 31 creased availability of high risk in- pg/mL(35,36,4,39). In our infected tensive care beds(6). IL-6 has a neonates, IL-6 cutoff value was 46 physiologic rise in the neonate pg /mL. peaking on day one of life. As regard to sensitivity, IL-6 has a sen- Sensitivity of IL6 for diagnosing sitivity of 60.98% lower than CRP sepsis was 60.9%, specificity was (70.73%) and as regard to specific- 73.6%. When compared to CRP, ity, IL6 has equal specificity to IL-6 was found to be less sensitive CRP (73.68%) and higher than in early diagnosis of sepsis as a specificity of ICAM (68.42%) (ta- single biomarker. In another study ble, 5) indicating a wide range in looking at children with sepsis clinical applicability. and septic shock, IL-6 was compared to procalcitonin (PCT) and ICAM was detected in all neo- IL-6 levels were markedly higher nates enrolled in this study. This at zero and twelve hours in the confirms the suggestion of Aust- septic shock group and septic gulen et al.(40) that constitutive group. Magudumana et al.(4) also shedding of at least this adhesion looked at sepsis in neonates and molecule is an established compo- found that a combination of IL-6 nent of the immune system. and CRP gave the best prediction of infection and that IL-6 alone at The present study show dis- the first sign of early infection can tinctly different patterns of expres- decrease the amount of unneces- sion of ICAM-1 among different sary antibiotics in the neonatal in- groups, ICAM-1 show (485.18± tensive care unit. 182.80 versus 199.50±37.40 with p value < 0.01) for patients and When comparing use of IL-6 controls respectively, 534.90± and CRP as biomarkers in sepsis 191.10 versus 377.89±102.92 includes cost, sensitivity and with p value < 0.01 for infected specificity, the cost of the assay and non infected neonates respec- seems to offset the benefit neo- tively, 642.12±167.82 versus nates would receive in terms of 367.37±56.87 with p value < 0.01

334 Benha M. J. Vol. 29 No 1 Jan. 2012 for bacterial positive and negative TEC system found 97% positive groups respectively, but similar in within 48 hours from starting of early (480.04±176.47) and late the blood culture, and microor- (487.94±188.34) onset sepsis with ganisms grown beyond 48 hours p value >0.05. from starting of the blood cultures should mostly be caused by con- This combination of infection tamination(43), and in most cir- with increased levels of ICAM-1 cumstances, if blood culture re- was in accordance with Kuster sults are not reported as positive and Degitz,(41) who showed that by 48 hours, then empiric admin- sICAM-1 levels increased in a istration of antibiotics may be dis- group of neonates with infection continued (35,44). and with Giannaki et al.,(42) who showed that in infection-free full- The most common organism term neonates there is an in- detected in the current study was creased release of both ICAM-1 coagulase-negative Staphylococ- and soluble vascular cell adhesion cus followed by E. coli, then molecule-1, although no infected Group B Streptococcus, Staphylo- neonates were included in this lat- coccus aureus, Enterococci, Hae- ter study. On the contrary, Aust- mophilus influenzae, and lastly gulen et al.(40) did not find any Streptococcus viridans. These re- differences in ICAM-1, vascular sults were similar to many cell adhesion molecule-1 as well studies (35,45,46,47,48,49). as E-selectin concentrations between the infected and non infect- In conclusion, increased CRP, ed neonates. The discrepancy IL6 and sICAM-1 levels can be de- among these studies may be due tected as early as neonatal sepsis to differences in the classification developed as a response of the im- of the newborn infected infants mune system to inflammatory and the postnatal age of neonates stimuli. at sampling. References Based on the previous evidenc- 1- Fanaroff A. A., Stoll B. J., es showing that pediatric BAC- Wright L. L., Carlo W. A., Eh-

335 Mohamed Al-Eraki and Lotfy Abdel-Fattah renkranz R. A. and Stark A. R. of soluble intercellular adhesion (2007): Trends in neonatal mor- molecule 1, highly sensitive C- bidity and mortality for very low reactive protein, soluble E-selectin birthweight infants. Am J Obstet and serum amyloid A in the diag- Gynecol;196:147.e1–8. nosis of neonatal infection. BMC Pediatrics, 10:22. 2- Zaidi A. K. M., Thaver D., Ali S. A. and Khan T. A. (2009): 6- Enguix A., Rey C., Concha Pathogens associated with sepsis A., Medina A., Coto D. and Die- in newborns and young infants in guez M. A. (2001): Comparison of developing countries. Pediatr In- procalcitonin with C-reactive pro- fect Dis J;28:S10–S18. tein and serum amyloid for the early diagnosis of bacterial sepsis 3- Icardi M., Erickson Y., Kil- in critically ill neonates and chil- born S., Stewart B., Grief B. and dren. Intensive Care Med; 27(1): Scharnweber G. (2009): CD64 in- 211-5. dex provides simple and predictive testing for detection and monitor- 7- Katz F. E., Parkar M., ing of sepsis and bacterial infec- Stanley K., Murray L. J., Clark tion in hospital patients. J Clin E. A. and Greaves M. F. (1985): Microbiol;47:3914-9. "Chromosome mapping of cell membrane antigens expressed on 4- Magudumana M. O., Ballot activated B cells". Eur. J. Immu- D. E. and Cooper P. A. (2000): nol.; 15 (1): 103–6. Serial interleukin 6 measurements in the early diagnosis of neonatal 8- Springer T. A. (1990): Ad- sepsis. J Trop Pediatr.; 46: hesion receptors of the immune 267–271. system. Nature; 346: 425–434.

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336 Benha M. J. Vol. 29 No 1 Jan. 2012 nates with infection. Mediators of 15- Isaacman D. J., Burke B. Inflammation,: 11; 95-98. L. (2002): Utility of the serum C- reactive protein for detection of oc- 10- Da Silva O., Ohlsson A. cult bacterial infection in children. and Kenyon C. (1995): Accuracy Arch Pediatr Adolesc Med; 156(9): of leukocyte indices and C- 905-9. reactive protein for diagnosis of neonatal sepsis: a critical review. 16- Pulliam P. N., Attia M. Pediatr Infect Dis J;14:362-6. W., Cronan K. M. (2001): C- reactive protein in febrile children 11- Gewurz H., Mold C., Sie- 1 to 36 months of age with clini- gel J. and Fiedel B. (1982): C- cally undetectable serious bacte- reactive protein and the acute rial infection. Pediatrics; 108(6): phase response. Advances in In- 1275-9. ternal Medicine, 27; 345-372. 17- Lacour A. G., Gervaix A., 12- Kanda T. (2001): C- Zamora S. A., et al. (2001): Pro- reactive protein (CRP) in the cardi- calcitonin, IL-6, IL-8, IL-1 receptor ovascular system. Rinsho Byori; antagonist and C-reactive protein 49, 395-401. as identificators of serious bacterial infections in children with fever 13- Kepa L. and Oczko- without localising signs. Eur J Pe- Grzesik B. (2001): Usefulness of diatr; 160(2): 95-100. plasma C-reactive protein (CRP) estimation in patients with bacte- 18- Galetto-Lacour A., Zamo- rial sepsis. Przegl. Epidemiol.; 55; ra S. A., Gervaix A. (2003): Bed- 63-67. side procalcitonin and C-reactive protein tests in children with fever 14- Parent C. and Eichacker without localizing signs of infec- P. Q. (1999): Neutrophil and en- tion seen in a referral center. Pedi- dothelial cell interactions in sep- atrics; 112(5): 1054-60. sis. The role of adhesion molecules. Infectious disease clinics of 19- Berger R. M., Berger M. North America; 13, 427-47, x. Y., van Steensel-Moll H. A.,

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Dzoljic-Danilovic G., Derksen- early acute respiratory distress Lubsen G. A. (1996): predictive syndrome by procalcitonin. Crit model to estimate the risk of seri- Care Med;27: 2172-6. ous bacterial infections in febrile infants. Eur J Pediatr; 155(6): 24- Clec’h C., Ferriere F. and 468-73. Karoubi P. (2004): Diagnostic and prognostic value of procalcito- 20- Andreola B., Bressan S., nin in patients withsepsis and Callegaro S., Liverani A., Plebani septic shock. Crit Care Med;32: M., Da Dalt L. (2007): Procalcito- 1166-9. nin and C-reactive protein as diagnostic markers of severe bacterial 25- Povoa P., Coelho L., Al- infections in febrile infants and meida E., Fernandes A., Mealha children in the emergency depart- R., Moreira P. and Sabino H. ment. Pediatr Infect Dis J; 26(8): (2006): Early identification of in- 672-7. tensive care unit-acquired infections with daily monitoring of C- 21- Povoa P., Coelho L., Al- reactive protein: a prospective ob- meida E., et al. (2004): C- servational study. Crit Care 2006, reactive protein as a marker of in- 10:R63. fection in critically ill patients. Clin Microbiol Infect;11:101-8. 26- Povoa P., Coelho L., Al- meida E., Fernandes A., Mealha 22- Castelli G. P., Pognani C. R., Moreira P. and Sabino H. and Meisner M. (2004): Procalcit- (2005): C-reactive protein as a onin and C-reactive protein during marker of infection in critically ill systemic inflammatory response patients. Clin Microbiol Infect, syndrome, sepsis and organ dys- 11:101-108. function. Crit Care;8: R234-42. 27- Benitz W., Han M. and 23- Brunkhorst F. M., Ebe- Madan A. (1998): Serial serum C- rhard O. K. and Brunkhorst R. reactive protein levels in the diag- (1999): Discrimination of infec- nosis of neonatal infection. Pediat- tious and noninfectious causes of rics; 102(4):e41.

338 Benha M. J. Vol. 29 No 1 Jan. 2012 28- Pourcyrous M., Bada H. 32- Resch B., Gusenleitner S., Korones S. B., Baselski V., W. and Müller W. D. (2003): Pro- Wong S. P. (1993): Significance of calcitonin and interleukin-6 in the serial C-reactive protein re- diagnosis of early-onset sepsis of sponses in neonatal infection the neonate. Acta Paediatr; 92: and other disorders. Pediatrics; 243-245. 92: 431-435. 33- Kordek A., Giedrys- 29- Laborada G., Rego M., Kalemba S., Pawlus B., Podraza Jain A., Guliano M., Stavola J. W. and Czajka R. (2003): Umbili- and Ballabh P. (2003): Diagnos- cal cord blood serum procalcitonin tic value of cytokines and C- concentration in the diagnosis of reactive protein in the first 24 h of early neonatal infection. J Perinat- neonatal sepsis. Am J Perinatol; ol; 23: 148-153. 20:491-501. 34- Berger C., Uehlinger J., 30- Joram N., Boscher C., De- Ghelfi D., Blau N. and Fanco- nizot S., Loubersac V., Winer N. ni S. (1995): Comparison of C- and Roze J. C. (2006): Umbilical reactive protein and white blood cord blood procalcitonin and C re- cell count with differential in active protein concentrations as neonates at risk for septicaemia. markers for early diagnosis of very Eur J Pediatr; 154: 138-144. early onset neonatal infection. Arch Dis Child Fetal Neonatal Ed; 35- Gonzalez B. E., Mercado 91:F65-F66. C. K., Johnson L., Brodsky N. L. and Bhandari V. (2003): Early 31- Kordek A., Halasa M. and markers of late-onset sepsis in Podraza W. (2008): Early detec- premature neonates: clinical, he- tion of an early onset infection in matological and cytokine proﬁle. J the neonate based on measure- Perinat Med.;31:60-68. ments of procalcitonin and C- reactive protein concentrations in 36- Kuster H., Weiss M. and cord blood. Clin Chem Lab Med; Willeitner A. E. (1998): Interleu- 46: 1143-1148. kin-1 receptor antagonist and in-

339 Mohamed Al-Eraki and Lotfy Abdel-Fattah terleukin-6 for early diagnosis of sociated with increase serum lev- neonatal sepsis 2 days before clin- els of ICAM-1 and E-selectin. Acta ical manifestation. Lancet.; 352: Paediatr; 86: 274-280. 1271-1277. 41- Kuster H. and Degitz K. 37- Bhandari V. (2000): Cyto- (1993): Circulating ICAM-1 in ne- kines in neonatal sepsis: diagnos- onatal sepsis. Lancet; 341: 506. tic and therapeutic considerations. In: Singhi S, ed. Current 42- Giannaki G., Xyni K., Ri- Concepts in Pediatric Intensive zos D. and Phokas I. (1999): Care. Chandigarh, India: Relume Comparative study of serum sol- Printec; 92-107. uble VCAM-1 and ICAM-1 levels in the early neonatal period. 38- Romagnoli C., Frezza S. Acta Paediatr 88: 1413-1414. and Cingolani A. (2001): Plasma levels of interleukin-6 and inter- 43- Rowley A. H. and Wald E. leukin-10 in preterm neonates R. (1986): Incubation period nec- evaluated for sepsis. Eur J Pedi- essary to detect bacteremia in ne- atr.;160:345-350. onates. Pediatr Infect Dis;5:590-1.

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340 Benha M. J. Vol. 29 No 1 Jan. 2012 Lerer T., Holman M. and Rowe Dis J.;17 :593- 598. J. (1997): Nosocomial sepsis in neonates with single lumen vascu- 48- Beck-Sague C. M., Azimi lar catheters. Indian J Pedi- P. and Fonseca S. N. (1994): atr.;64:529-535. Bloodstream infections in neonatal intensive care unit patients: re- 47- Fanaroff A. A., Korones S. sults of a multicenter study. Pedi- B. and Wright L. L. (1998): Inci- atr Infect Dis J.;13 :1110-1116. dence, presenting features, risk factors and significance of late 49- Bhandari V., Chao Wang, onset septicemia in very low Christine Rinder and Henry birth weight infants : National Rinder (2008): Hematologic Pro- Institute of Child Health and file of Sepsis in Neonates: Neu- Human Development Neonatal trophil CD64 as a Diagnostic Research Network. Pediatr Infect marker. Pediatrics; 121;129.

341 REPRINTMohamed Al-Eraki and Lotfy Abdel-Fattah BENHA MEDICAL JOURNAL

DIAGNOSTIC VALUES OF CRP, IL-6 AND ICAM-1 AS MARKERS OF BACTERIAL INFECTION IN THE NEONATES

Mohamed Al-Eraki MD and Lotfy Abdel-Fattah MD

Published by Benha Faculty of Medicine Volume 29 Number 1 Jan. 2012

342 Benha M. J. Vol. 29 No 1 Jan. 2012 TRIPLE ATTACK IN MANAGEMENT OF DDH IN CHILDREN AFTER WALKING AGE UP TO FIVE YEARS

Salah Youssef MD and Mohamed El Manawy MD Department of Orthopaedic, Faculty of Medicine, Al Azhar University Hospital, Damietta.

Abstract Developmental dysplasia of the hip (DDH) is the result of a disrup- tion in the normal relationship between the acetabulum and femoral head. Without a normal, stable relationship, neither the acetabulum nor femur will develop normally. The etiology of DDH is multifactorial involving both genetic, hormonal and intrauterine factors. Cases of developmental dislocation of the hip occur after walking age because of late or missed diagnosis and failed conservative or operative treatment. Up to now there is no consensus on the treatment of DDH after walking age. The purpose of this study was to evaluate the results of operative treatment in DDH after walking age in our patient population and to describe the treatment strategies and operative techniques used.

Introduction acetabulum. Because many of Developmental dysplasia of the these findings may not be present hip (DDH) is the preferred term to at birth, the term developmental describe the condition in which more accurately reflects the bio- the femoral head has an abnormal logic features than does the term relationship to the acetabulum. congenital(1). DDH includes frank dislocation, (subluxation), instability where in The term developmental dys- the femoral head comes in and plasia of the hip is necessarily out of the socket, and an array of general and encompasses many radiographic abnormalities that facts of the condition. This term reflect inadequate formation of the realistically indicates a dynamic

1 Salah Youssef and Mohamed El Manawy disorder, potentially capable of servative treatment is difficult be- getting better or worse and occur- cause of contracture of the extra- ring prenatal or postnatal (2). articular soft tissues, joint capsule, acetabular dysplasia and in- The incidence of DDH is still creased femoral anteversion. More about 1/1000 of all live births; force is required to reduce the dis- this incidence is higher with located femoral head into the ace- breach than cephalic presentation tabulum. Consequently, incom- (10/1), more common in females plete reduction, a high rate of than males 2/1, more common in complications, and unsatisfactory European than African popula- results can be expected (7,8). tion, and more on left than right side (3). The aim of this work is to assess the outcome of open re- Early diagnosis and treatment duction and triple attack in of developmental dysplasia of the management of DDH in children hip is important for normal devel- after walking age up to five opment (4). years.

Despite the widespread use of Patients and Methods screening programs and the devel- In this study, 36 hips in 30 pa- opment of methods for treating tients of DDH have bean treated newborns with congenital disloca- surgically (September 2004 to tion of the hip, children are still February 2007) in Al-Azhar Da- seen later in childhood with dys- mietta University Hospital. plastic hips (5). All cases of neuromuscular dis- Non-operative treatment is order were excluded from this re- usually used in the management search. of developmental dysplasia of the hip in children younger than 1 The age at time of surgery year old (4,6). ranged from 18-60 months with a mean average of 28.83 ± 8.89 By 18 months of age, the con- months 25 patients were girls with

2 Benha M. J. Vol. 29 No 1 Jan. 2012 an incidence 83.3% and 5 patients shaft angle had been measured in were boys with an incidence of every case. 16.7% with Male to Female ratio is 1: 5. CT with 3D formatting scans has been performed in some pa- 6 cases out of 30 cases (20.0%) tients postoperatively for follow up were bilaterally affected while 24 as the plain x- ray cannot define cases were unilateral (80%), 2 on the head was dislocated or re- right side (8.3%) and 22 on left duced. side (91.6%). The patients have been divided Obstetric history, 18 patients into two groups according preop- were normal delivery with cephalic erative acetabular index and the presentation with an incidence stability of the reduced hip in ex- 60% and 12 patients were deliv- tension intraoperatively. The first ered by caesarian section with an group with hip was stable in ex- incidence of 40%. tension. In this group Salter, pelvic osteotomy is not indicated. No similar conditions were re- Varus derotation femoral osteoto- ported in the other members of my was indicated whenever there the family. was hip instability due to excessive femoral anteversion and val- A detailed pre-operative sheet gus deformity. In cases where was always completed for every pulling the femoral head down- patient, general examination, local ward was difficult even after prop- examination and radiological ex- er soft tissue release (including amination. In all patients we did a adductor tenotomy) femoral short- routine plain x-ray pelvis (Neutral ening was performed in associa- A-P view & Frog lateral view) tion with other procedures .The showing both hip joints in neutral second group was unstable re- rotation. duced hip in extension. In such group Salter pelvic osteotomy was Central edge angle (CE), ace- indicated. The indication of varus tabular index (AI), as well as neck derotation femoral osteotomy was

3 Salah Youssef and Mohamed El Manawy the same as in the first group. Ac- The collected data was orga- cordingly, open reduction alone nized, tabulated and statistically was performed in 4 hips. Open re- analyzed using SPSS software sta- duction, pelvic osteotomy with tistical computer package version varus derotation femoral osteoto- 10. For quantitative data, the my and shortening was performed mean and standard deviation were in 32 hips. Adductor tenotomy calculated. The difference between was performed in 32 hips. Ap- two means was statistically ana- proach, the anterolateral Smith lyzed using the students (t) test. Peterson approach has been used For qualitative data the number in all cases. The advantage of this and percent distribution was cal- approach is that it include wide culated. Chi (X2) square was used exposure of the capsule especially as a test of significance. Signifi- the superolateral and inferomedial cance was adopted at P < 0.05 for parts. All obstructing elements are interpretation of results of tests of dealt with under direct vision, significance. capsulorrhaphy can be done easily and Salter pelvic osteotomy was Results performed through the same ap- We used a scoring system that proach. In cases that needed fe- depends on both clinical and radi- moral osteotomy a separate lateral ological criteria (Mc.kay1974 and approach was used. thomas 1989) (9,10).

We evaluate the results in this Relation between outcome study postoperatively according and age, excellent and good re- to McKay’s modification method sults were observed in the young- (clinical evaluation)(9) which emer age groups. In the age group phases the presence of pain, limp- from 18 - 36 months, there were 5 ing, Trendelenberg sign, combined cases out of 7 (71.4%) excellent range of motion and radiological while 18 cases out of 20 cases evaluation(10). (90.0%) were good in the same age group. We collect preoperative data of the patients in (Tab.1). Trendelenberg sign (T sign),

4 Benha M. J. Vol. 29 No 1 Jan. 2012 was positive in all cases in preop- Relation between outcome and erative period. technique, excellent results were observed in 6 hips out of 32 hips Postoperative T sign: On the (18.8%) in comparison to 1 out of left side (28 hips), 7 hips were 4 cases (25%) in open reduction positive (25%) and 21 hips were while good results were observed negative (75%) while on right side in 19 cases (59.4%) in triple at- (8 hips), 2 hips were positive (25%) tack in comparison to 1 case and 6 hips were negative (75%). (25%) in open reduction. Totally, 9 hips were negative (25%) and 27 hips were positive (75%). Relation between outcome and postoperative AI, it was noted Comparison between pre and that excellent outcome was asso- postoperative AI, there was statis- ciated with improvement of the tically significant decrease in post- acetabular index postoperatively. operative AI in comparison to its preoperative levels on right, left Regarding postoperative AVN, it and total values. (Tab.3 Fig.2). was positive in 5 hips out of 36 (13.9%) and negative in 31 hips Comparison between pre and (86.1%). postoperative neck shaft angle (NSA), there was statistically Final results, seven hips were highly significant decrease in excellent 19.4%, 20 were good postoperative neck shaft angle in (55.6%), four were fair (11.1%) comparison to its preoperative lev- and five were poor (13.9%). This els on right, left and total val- means that our excellent and good ues. results were 75%.

5 Salah Youssef and Mohamed El Manawy

6 Benha M. J. Vol. 29 No 1 Jan. 2012

7 Salah Youssef and Mohamed El Manawy

Fig. (1) : Pre-op radiological meas- Fig. (4) : Female patient, 1.5 y. urements. pre-op x ray bilateral DDH.

Fig. 2 : Comparison between pre Fig. (5) : post op- follow up x ray. and postoperative AI.

Fig. 3 : Comparison between pre Fig. (6) : post op x ray for both and postoperative neck hips. shaft angle (NSA).

8 Benha M. J. Vol. 29 No 1 Jan. 2012

Fig. (7) : 6 months post op follow up x ray.

Fig. 8 : Relation between outcome and technique

Fig. 9 : Postoperative AVN in studied cases.

9 Salah Youssef and Mohamed El Manawy

Discussion side involvement was more com- The patients in this work were mon (66.7%). This is may be due missed cases of DDH that is, cas- to the fact that the common intra- es diagnosed after the age of 1.5 uterine position has the left hip years up to 5 years when they are adducted against maternal sa- walking or after. Thus, they lost crum. the chance for conservative treatment. Harris et al., (1992) and Huang et al (1997) reported that left side The reported incidence of male affection was more common to female ratio in our study is 1: with an incidence of 75% while 5. Brougham et al., 1990 reported the right side was less com- that girls were more commonly af- monly affected with an inci- fected with an incidence of 75% dence of 15% and bilateral af- (that is a three fold higher than fection was of an incidence of boys)(11). Chen et al., 1994 and 10%(17,13). Huang et al., 1997 reported similar cases (12,13). The increased number of bilateral cases in the present series Carter et al., 1964 had a theory (20%) may be attributed to the low that there is a probable sex deter- number included in this study in mined quality in female ligaments comparison to other studies. On which may explain higher DDH the other hand, Bohm et al., frequency in girls (14). (1992) reported 18.7% bilateral cases and unilateral cases were Also, Vadivelu et al., 2004 re- 81.26% (16). ported that 74% females, and Bohm et al., 1992 reported 83.7% The average acetabular index female incidence in a study on (AI): was ranged preoperatively 73 patients of DDH that is from 30 to 42 in all studied cases. equal to that found in the present The mean postoperative AI study(15,16). was18.55 and S.D was 8.07 with statistically significant decrease In the present study the left in postoperative acetabular index

10 Benha M. J. Vol. 29 No 1 Jan. 2012

in comparison to its preoperative primary operative treatment in 33 levels. hips with no previous treatment or traction, they concluded that chil- In the present study, regarding dren who are 2 years or older type of operative intervention, with DDH safely treated by triple attack was done in 32 hips triple attack. The incidence of AVN out of 36 hips (88.88%) while open was 10% after follow up of 2 - 6 reduction was done in 4 cases years (21). (12.12%). Regarding outcome in studied Rayan et al., 1998 also prefer cases, it was excellent in 7 hips one stage procedure consisting of out of 36 hips (19.4%); good in 20 open reduction, femoral shorten- hips (55.6%); fair in 4 hips ing and Salter pelvic osteotomy for (11.1%) and poor in 5 hips (13.9%) previously untreated case who are with statistically non significant 3 -10 years old can result in re- difference between males and fe- modeling of the acetabulum and a males. functional hip (18). Excellent results were observed Also this study like to the in 6 hips out of 32 hips (18.8%) in study of Forlin et al., 2006. He comparison to 1 out of 4 cases prefers Triple attack after walking (25%) in open reduction while age (19). good results were observed in 19 cases (59.4%) in triple attack in In a series of 250 children who comparison to 1 case (25%) in underwent open reduction and open reduction. Salter osteotomies, Salter and Du- bois (1974) reported that 65 per- So, Triple attack is better for cent had excellent results, 28 treatment of DDH patients after percent had good outcomes, and the walking age due to less inci- only 7 percent had fair or poor re- dence of AVN (in our study sults (20). three cases developed AVN), no prolonged period of casting, ear- Galpin et al., 1989 reviewed the ly joint mobility postoperatively

11 Salah Youssef and Mohamed El Manawy and no joint stiffness, concluded that the test of stability is useful and reliable mean of as- Gulman et al., 1994 described sessing the need for a pelvic or fe- their results after open reduction moral osteotomy at the same time and Salter pelvic osteotomy per- as open reduction for DDH. This formed in 52 hips. Clinical and ra- is what we had followed in our diological results were evaluated work and we do agree with them according to the patient age at in that the intraoperative test of time of treatment. They concluded stability is a useful technique in that Salter provide good femoral the decision making with im- head coverage even with develop- proved final results (23). ing AVN (63.3%)(22). Forlin et al., 2006 reviewed 32 Rayan et al., 1998 reviewed the children who had 44 hips treated results of operative treatment of with open reduction and Salter os- DDH in 25 hips with no previous teotomy. Twenty-six hips had lines of treatment (preliminary preliminary skeletal traction and traction in 6 hips). They suggested 18 hips had a concomitant femo- that one stage procedure consist- ral shortening. There were 23 ing of open reduction, femoral good, 12 fair, and 9 poor results. shortening and Salter pelvic oste- Ten hips had avascular necrosis otomy (if necessary) for previously (31%) and four had redislocation untreated DDH in children who (12.5%)(21). are 3 to 10 years old can result in remodeling of the acetabulum and In another study from the same a functional hip(18). institution, the authors reviewed 24 hips of 20 patients treated af- Zadeh et al., 2000 reported the ter the age of 4 years (range, 4 to clinical and radiological outcome 12 years). The mean length of fol- in 95 hips with DDH treated by low up was 5 years. Seventy per- open reduction through an anteri- cent of the hips had an excellent or approach in which a test of sta- or good result. bility was used to asses the need for a concomitant osteotomy. They Avascular necrosis was seen in

12 Benha M. J. Vol. 29 No 1 Jan. 2012 six hips (30%). Results were relat- received prolonged closed treated to age at the time of operation; ment. They believe that the surgi- worse outcomes were found in pa- cal release of soft tissues, removal tients older than seven years at of the internal and external ob- the time of the operation. Femoral structing factors and casting in a shortening is usually necessary in slightly abducted, flexed and neu- children of this age group espe- trally rotated position are effective cially age of more than 3 years, in reducing pressure on the femo- when at the time of the reduction, ral head and hence avascular ne- there is tension or difficulty in crosis(6). Also, femoral shortening lowering the femoral head(11). has been recommended to avoid the complication of avascular ne- The combined use of open re- crosis, it allows the tight struc- duction and Salter’s innominate tures that cross the level of the os- osteotomy for developmental dys- teotomy to function as if they plasia of the hip under the same were lengthened and does so more anaesthesia is controversial. While effectively than a soft tissue re- some authors reported acceptable lease(13). results, it has been suggested that this combination may increase the In our study regarding post- rate of complications, in particular operative AVN, it was positive in of avascular necrosis of the femo- 5 hips out of 36 hips (13.9%) ral head. The redirection of the ac- and negative in 31 hips (86.1%) etabulum to provide increased an- with statistically non significant terior cover may lead to secondary difference between males and fe- posterior dislocation or subluxa- males. tion (4). The low AVN percentage in our Other authors reported that si- study may be due to age range in multaneous open reduction and our study 18-60 months, and may Salter’s innominate osteotomy be due to short term follow up 15 without preliminary traction re- -36 months. The cause of AVN in sulted in a lower rate of avascu- this study may be due to femoral lar necrosis than in those who shortening was not more enough

13 Salah Youssef and Mohamed El Manawy or excessive dissection during beyond 18 months concentric re- open reduction. duction could not be achieved by the closed methods. Open reduc- Lin et al., 2000 operate 89 chil- tion only was done in 4 hips. dren ageing 12 - 18 months by open reduction with result of AVN Open reduction, femoral osteot- 25 % after follow up ranged from omy and shortening and Salter in- 61 - 98 months and he investigat- nominate osteotomy was done in ed the correlating factors of intra- 32 hips.The anterolateral ap- operative instability as a guide to proach is a satisfactory one. The the additional Salter Osteotomy important soft tissue obstacles of and to evaluate the radiological re- reduction should be visualized sults. They concluded that the and managed properly. They in- Salter Osteotomy does not heart clude the iliopsoas tendon, invert- the hip with regard to acetabular ed labrum, ligamentum teres, and remodeling for children between transverse acetabular ligament. 12 and 18 months but make the hip more stable (24). Femoral shortening should be performed whenever reduction is Follow up period was ranged difficult or impossible during the from 10 to 39 month with a mean operation. After concentric reduc- of 23.86±6.45 months and there tion is achieved the femoral head was statistically non significant is fixed in a varus position. At the increase in follow up period in same time Salter Osteotomy had males in comparison to females, been done and a hip spica cast is this may be due to in this study applied for 8-12 weeks according there were four males only. to tale radiological healing.

Summary 36 hips were the material of Our scheme of management of this study; 32 hips of them were 36 hips of DDH in 30 patients be- treated by open reduction, Salter tween the age of 18 months and 5 osteotomy with varus derotation years was open reduction in all osteotomy and femoral shortening. cases due to the late presentation 6 patients were excellent (18.8%),

14 Benha M. J. Vol. 29 No 1 Jan. 2012

19 patients were good (59.4%), 3 References patients were fair (9.4%) and 4 pa- 1- Atar D., Lehman W. B., Te- tients were poor (12.5%). On the nenbaum Y., et al. (1993) : Pav- other hand 4 patients had been lik harness versus Frejka splint in treated by open reduction and the treatment of the hips: bicenter final results: One hip was excel- study. JPO; 13:311. lent (25%), one hip was good (25%), one hip was fair (25%) and 2- Barrett W. P., Staheli L. T. one hip was poor (25%). and Chew D. E. (1986) : The effectiveness of the Salter’s innomi- So, Triple attack is advanta- nate osteotomy in the treatment of geous in the treatment of DDH in congenital dislocation of the hip. this age group (beyond age of 18 JBJS; 68A: 79. months) due to the low incidence of AVN, no more casting, early 3- Weinstein S. L. and Buck- joint mobility postoperatively, no walter J. (1994) : Turek,s Ortho- joint stiffness and low incidence of pedics principle and their applica- recurrence and the good final re- tion. Developmental dysplasia of sults and minimal complications. the hip. (5th ed) 522. We are waiting for long term results. 4- Bennett J. T. and MacE- wen G. D. (1989) : Congenital Conclusion dislocation of the hip: recent ad- Although our study presents vances and current problems. Clin the results after a mid-term fol- Orthop; 247:15. low up the radiological results favor our clinical experience that 5- Morine C., Rabay G. and a single stage combined proce- Morel G. (1998) : Retrospective dure consisting of open reduc- review at skeletal maturity of the tion, pelvic osteotomy as well factors affecting the efficacy of as a corrective osteotomy within Salter’s Innominate osteotomy in the proximal femur with subse- congenital dislocated, subluxed quent shortening should be rec- and dysplastic hips. JPO; 18: ommended. 246.

15 Salah Youssef and Mohamed El Manawy

6- DeRosa G. and Feller N. 11- Brougham D. I., Brough- (1987) : Treatment of congenital ton N. S. and Cole W. G. (1990) : dislocation of the hip: manage- Avascular necrosis following ment before walking age. Clin Or- closed reduction of congenital dis- thop: 225:77. location of the hip. JPO; 72:557- 62. 7- Berkeley M. E. Dickson J. H. Cain T. E., et al. (1984) : 12- Chen I. H., Kuo K. N. and Surgical therapy for congenital Lubicky J. P. (1994) : Prognosti- dislocation of the hip in patients cating factors in acetabular devel- who are twelve to thirty-six opment following reduction of de- months old. JBJS; [AM]: 66:412- velopmental dysplasia of the hip. 20. JPO; 14:3-8.

8- Fisher R., O’Brien T. S. 13- Huang S. C. and Wang and D avis K. M. (1991) : Mag- J. H. (1997) : A comparative netic resonance imaging in con- study of nonoperative versus op- genital dysplasia of hip JPO; erative treatment of developmen- 11:617-622. tal dysplasia of the hip in patients of walking age. JPO; 9- Mckay D. W. (1974) : A 17:181. comparison of the innominate and pericapsular osteotomy in the 14-Carter C. D. and Wilkin- treatment of congenital disloca- son J. A. M. (1964) : Genetic and tion of the hip .Clin Orthop; 98 : environmental factors in the etiol- 124-2. ogy of congenital dislocation of the hip. Clin Orthop; 33:119. 10- Thomas I. H., Dunin A. J., Cole W. G. and Menelaus M. 15- Vadivelu R. and Clegg J. B. (1989) : Avascular necrosis af- (2004) : Incidence of acetabular ter open reduction for congenital dysplasia in breech babies who dislocation of the hip : Analysis of had early ultrasonographic abnor- causative factors and natural his- mality of hips. JBJS (Suppl III-B): tory .JPO;9:525-31. 315.

16 Benha M. J. Vol. 29 No 1 Jan. 2012 16- Bohm P. and Brzuska A. nate osteotomy in the treatment of (1992) : Salter innominate osteot- congenital dislocation and sublux- omy for the treatment of devel- ation of the hip. Clin Orthop; opmental dysplasia of the hip in 98:72. children. Results of seventy- three consecutive osteotomies af- 21- Galpin R. D., Roach J. ter twenty-six yeas of follow up, W., Wenger D. R., Herring J. A. JBJS; 84-A; 2:178-86. and Brich J. G. (1989) : One stage treatment of congenital dis- 17- Harris I. E., Dickens R. location of the hip in older chil- and Menelaus M. B. (1992) : dren, including femoral shorten- Use of the Pavlik harness for hip ing. JBJS; 71A: 734. displacements. Clin Orthop; 281 : 29. 22- Gulman B., Tuncay I. C. and Dabak N. (1994) : Salter's 18- Rayan M. G., Johnson L. innominate osteotomy in the treat- O. and Quanbeck D. S. (1998) : ment of congenital hip disloca- One stage treatment of congenital tion : A long term review. JPO; 14: dislocation of the hip in children 3 662-6. to 10 years old. JBJS; 80A:336- 344. 23- Zadeh H. G. (2000) : Test of stability as an aid to decide the 19- Forlin E., Cunha L. and need for pelvic osteotomy in asso- Figueiredo D. (2006) : Treatment ciation with open reduction in of developmental dysplasia of the DDH. JBJS; 82B:17-27. Hip After Walking age with open reduction, femoral shortening, 24-Lin C. H., Lin Y. T. and and acetabular osteotomy, Clin Lai K. A. (2000) : Intraoperative Orthop N Am; 37, 149-160. instability for developmental dysplasia of the hip in children 12 to 20- Salter R. and Dubois I. 18 months of age as a guide for (1974) : The first fifteen years' Salter osteotomy. JPO; 20:575- personal experience with innomi- 578.

17 REPRINTSalah Youssef and Mohamed El Manawy BENHA MEDICAL JOURNAL

TRIPLE ATTACK IN MANAGEMENT OF DDH IN CHILDREN AFTER WALKING AGE UP TO FIVE YEARS

Salah Youssef MD and Mohamed El Manawy MD

Published by Benha Faculty of Medicine Volume 29 Number 1 Jan. 2012

18 Benha M. J. Vol. 29 No 1 Jan. 2012 TIMING OF SURGERY IN ELDERLY PATIENTS WITH HIP FRACTURES

Salah Youssef MD, M. M. El-Menaway MD and Samir El Shora MD Departments of Damietta Faculty of Medicine Al-Azhar University

Abstract Hip fractures are associated with a high rate of complication, mortality and profound temporary and sometimes permanent impairment of quality of life. The effect of preoperative timing on complication, mortality and other patient-important outcomes across various age groups remains controversial and warrants a large randomized controlled trial to offer clear insights into the effects associated with early versus delayed surgery among hip fracture patients. We prospectively studied sixty elderly patients who had a fracture of the hip, to determine the effect of an operative delay on postoperative complication. We concluded that patients with hip fracture optimally should have the operation within two days after admission to the hospital.

Introduction hand, precipitous surgery and fail- Surgical repair is the key ele- ing to stabilize medical problems ment in the management of hip could increase the risk of periop- fracture. Before surgery, most pa- erative complications. tients are confined to bed. In theory, delay in surgery and mobiliza- It is not only the mortality rate tion could affect functional and following surgery that is impor- other outcomes by increasing bed tant. The quality of life of elderly rest-associated complications, in- patients who survive surgery and cluding thrombo embolism, uri- are expected to return, more or nary tract infections , atelectasis, less, to normal daily activity is and pressure ulcers. On the other also a critical issue. The impor-

361 Salah Youssef, et al.... tance of the economic aspects of patients who had been managed this controversy also cannot be with internal fixation or hip re- overemphasized (1). placement for hip fracture between January 2009 to December In the elderly patient with sig- 2010. nificant co morbidities, it is important to reverse easily correctible We investigated the relation medical conditions before surgery, ship of time-to-surgery with fre- but surgery should be performed quency of post-operative compli- as soon as reasonably possible. cations in elderly patients (age≥ Surgery should be performed 60) with isolated proximal femo- when optimal medical support is ral fracture (femoral neck fracture available, preferably during nor- or pertrochanteric femoral frac- mal surgical hours, because sur- ture). gery performed in less optimal conditions is associated with in- Polytrauma patients, patients creased risk of malreduction and with pathological fractures, a pre- other technical errors(2). vious fracture or operation on the ipsilateral hip and initial conser- Delaying surgery will prolong vative management were exclud- the pain and discomfort involved ed. Also we excluded patients with the injury and may also in- younger than 60 or patients who crease the length of hospital stay had other fractures rather than and may possibly reduce the hip fracture. chance of successful rehabilitation and the patient returning home. Also documented were the This study aimed to develop a con- times of the fracture event, of hos- sensus from the literature for the pital admission, and of the start of optimum timing of surgery for an the surgical intervention. Start of acute hip fracture. surgery within 48 hours after the fracture event was considered ear- Patients and Method ly surgery (short time-to-surgery), Study duration : start of surgery from 48 to one We reviewed the records of 60 week after the fracture event was

362 Benha M. J. Vol. 29 No 1 Jan. 2012

classified as intermediate and Mechanism of Injury: more than one week considered Diagnosis: Hip fracture (Intra- delayed surgery. capsular fracture / Extra-capsular fracture) Counting from the time of the Date and time of admission: fracture event, were compared for Procedure planned: patient characteristics, operative Dynamic hip screw procedures, and post-operative (DHS). Hemiarthroplasty. complications. Others. Reasons for delayed surgery: Data collection : Date and time of operation: Time Interval between Admis- Type of anaesthesia either spi- sion and Operation of Hip fracture nal anaesthesia or general anaes- in older patients Data Form thesia. Name: Age: blood loss, operative time, and Medical No.: Sex: complications. Chronic Medical Illness: Postoperative care: Diabetes mellitus (DM) Hyper- Ward ICU tension (HPT) Ischemic heart dis- Complications: ease (IHD) Duration of hospital stay: Others: Outcome of the patient:

Results Number of patients: 60

363 Salah Youssef, et al....

364 Benha M. J. Vol. 29 No 1 Jan. 2012

Discussion The majority of the patients Hip fractures are a common (63.4% patients) were female and and serious injury in older people 70% were trochanteric fractures. and considered the 2nd leading This might be attributed to the cause of hospitalization for elderly fact that osteoporosis is common people. On account of the advanc- in this age group Approximately 1 ing life expectancy, it is estimated in 1000 people each year in indus- that the numbers of these frac- trialized counties suffers a proxi- tures will be doubled by the year mal fracture of the femur (6). The 2040 (3). mortality rate after six months is reported to range between 12 % Hip fractures are uncommon in and 41%. Davis et al reported a young patients with normal bone. mortality rate of 24% and Sikorski The average age of the patients and Senior (7) and Lucke, Philipe with femoral neck fractures is 3 and Krause(8) 13% and 18% re- years younger than those with spectively after three months. trochanteric fractures, both oc- Proximal femoral fractures lead to curring most commonly in the significantly reduced life expectan- eighth decade (4). Studies suggest cy and, for about 50% of patients, that femoral neck fractures to an often dramatic deterioration should be considered fractures in health and social conditions. through pathologic bone secon- For many, such fractures lead to dary to either osteomalacia or os- loss of independence. Patients teoporosis(5). Intertrchanteric frac- who already required some assis- tures account for 50% of all tance prior to breaking their hip fractures of the proximal femur. may become entirely dependent The ratio of women to men ranges on nursing care after the fracture. from 2:1 to 8:1, likely because of postmenopausal metabolic chang- Management of hip fractures is es in bone. based on individual patient factors, such as pre-injured ambula- In our study hip fractures oc- tory status, age, co morbidities, curred in elderly population (aver- and on fracture factors, including age 66 years). fracture type and the degree of

365 Salah Youssef, et al.... displacement. Treatment options dressed in several studies and re- include nonsurgical management, mains controversial. Surgery for a percutaneous fixation, closed or hip fracture should be within 24 open reduction and internal fixa- hours of injury because earlier tion (ORIF), and arthroplasty surgery is associated with better (hemiarthroplasty or total hip ar- function outcome and lower rates throplasty ). Despite the variety of of perioperative complications and treatment options available, the mortality. Proponents of early question remains when and what treatment argue that this ap- is the best treatment of hip frac- proach minimize the length of tures in elderly patients (1). time a patient is confined to bed rest, thereby reducing the risk for The goals of treatment of hip associated complications, such as fractures are to achieve anatomic pressure sores, deep vein throm- reduction and to provide stability bosis chest and urinary tract in- to the fracture fragments in order fections. Those favouring delaying to maintain the reduction and al- surgery beyond the guideline rec- low complete fracture healing. In ommendations believe that this general, these goals are best approach is required to medically achieved in the operating room optimize patients and therefore with fracture reduction performed decrease the risk for perioperative under fluoroscopic guidance and complications(9). fracture stabilization with rigid internal fixation or prosthetic re- The timing of surgery is contro- placement. versial and relates both to different approaches to this issue in the Improvement in surgical tech- medical community, and to the niques and more aggressive treat- lack of adequate resources to opment have resulted in improved erate on every fit patient in the outcomes in the treatment of hip shortest possible time. Orosz and fractures. co-workers(10) presented data on the causes of delay in surgical re- The question of the optimum pair of hip fractures in four timing of surgery has been ad- hospitals in the New York City

366 Benha M. J. Vol. 29 No 1 Jan. 2012

metropolitan area. The main was delayed up to 96 hours. cause in their series was a delay in medical clearance in 52% of Sikorski and Senior(7) and those operated on later than 24 Dolk(16) believed hat early surgery hours after hospital arrival. How- would bring better surgery. and ever, in 29% the delay was caused was consistently associated with by the unavailability of an operat- decreased length of stay and less ing room or a surgeon. The argu- pain and probably with reduced ments presented by each side of major complications. They report- the controversy in this issue are ed that clinical reasons (waiting clear and persuasive. This being for test results or for medical sta- the case, how can we solve the bilization) were infrequent reasons problem and draw conclusions for delayed surgery in patients op- that will assist anesthetic doctors erated on less than 48 hours. In- and orthopedic surgeons in their stead, system problems (timely routine clinical work. consultation or availability of the surgeon or operating room) ac- The recommendation that fit counted for the majority of cases patients should undergo surgery of delay. Thus, it is feasible to im- as quickly as possible. A long se- prove surgical timing which could ries of studies has demonstrated in turn translate to improved effi- many advantages of an early sur- ciency and reductions in severe gical approach, i.e., within the pain. first 24 hours of hospital admission. These advantages include Fractures of the femoral neck improved 1 year survival[11], re- treated late present unique prob- duced hospital stay [12,13,14], and lems in management. improved activities of daily living. On the other hand, patients with According to Massie(17) when significant co morbidity and an ev- surgery is performed within 12 ident need for preoperative assess- hours of injury, there is a 25% in- ment and preparation, Moran et cidence of aseptic necrosis. The al. [15] reported that mortality incidence rises to 30% with a de- was not increased when surgery lay of 13 to 24 hours, to 40% be-

367 Salah Youssef, et al.... tween 24 hours and 48 hours, ical stabilization after the injury. and to 100% after 1 week. This This is may be particularly rele- direct relationship between the vant after an extra capsular frac- time from injury to internal fixa- ture, in which a more extensive tion and complication of aseptic blood loss from the fracture site necrosis and nonunion has also occurs. Other potential advantag- been reported by Brown and Abra- es of delaying surgery are that it mi(18) and Soto-Hall and col- allows more time for assessment leagues(19). This factor is impor- of the patients and for correction tant for patients who will be of dehydration and fluid replace- operated for osteosynthesis. ment. Many hip fracture patients are found to be hypovolaemic at Significantly higher mortality the time of surgery. This may even rates were reported by Todd et be reflected in an increase in moral(20) in patients operated on after tality. 48 hours. They found extensive medical investigation to be of no Hoeing et al(6) described a benefit. shorter hospital stay in patients who underwent early surgery but Parker and Pryor (21) recom- no difference in complication. mended surgical treatment within 48 hours of admission. The inci- Possible adverse effects of de- dence of age-related post-operative laying surgery are there may complications was significantly be an increase in the incidence higher in those patients who un- of the complications of recum- derwent surgery on or after the bency. Namely pressure sourc- third day compared with those es, thromboembolic complica- who underwent surgery on the tions, urinary infection and first or second days. pneumonia.

The theoretical advantage of al- The occurrence of pressure lowing a delay from admission to sore is a result of the damage of surgery for a hip fracture is that it prolonged skin constantly under will allow some time for physiolog- shear pressure due to prolonged

368 Benha M. J. Vol. 29 No 1 Jan. 2012 immobilization. Therefore, the ear- Length of stay is another im- lier the patient is mobilized, the portant reason why many trials lesser the chance of getting pres- were conducted to investigate the sure sore. Several authors have impact of timing of surgery is that investigated whether the incidence it has significant financial im- of pressure sores would be in- plication on the health care sys- creased with a delay of hip frac- tem(24,25). One of the important ture surgery. Published reports indicators of the resources needed generally supported the above the- is the number of days in hospital ory [22, 23-14]. or length of stay. Most of the evidence nowadays tends to agree Lefaivre et al(22) showed that that shortening the pre-operative when the surgery was delayed for waiting time would shorten the more than 24 h, it was significant- hospital stay in post-operative as ly related to increase in pressure well as the total period. Length of sore . Grimes et al(23) showed that stay in our hospital in the present the risk of decubitus ulcer in- study were 30% more than one creased as the surgery was de- week and 26.7% more than two layed for more than 96 h. Al-Ani et weeks. al.(14) further proved that the incidence of pressure sore was not Anaesthesia : only related to delay in surgery, The goal of the anaesthetic but the odds ratio increased pro- technique selected is to eliminate gressively as the delay increased pain, allow for appropriate intra- from 24 to 36 to 48 h . operative positioning and achieve muscle relaxation to effect the re- We could not identify any study duction. showing that the development of pressure ulcer is not related to Selection of anesthesia for sur- prolonged pre-operative waiting gical candidates is complex and time.In our study there was inci- multifactorial and must account dence of bed sores in the group of for factors such as age, co morbid patients who has been operated conditions, and patient prefer- after two days. ence.

369 Salah Youssef, et al....

In our study spinal anaesthesia of endotracheal general anesthe- were performed in most of our pa- sia. tients (58.3%). Spinal anesthesia patients generally did better than Summary general anesthesia patients on and Conclusion several different measures. Use Of the total 60 patients with of spinal anesthesia decreased in- hip fractures, 18 patients (30%) traoperative and postoperative were operated within 48 hours. blood loss, and transfusion requirement. It has less post surgi- 32 patients (53.3 %) were oper- cal confusion. It has lower inci- ated within one week. Still majori- dence of deep venous thrombosis. ty of patients 42(70%) patients These findings have significant im- were operated after 48 hours. In plications for maximization of our study the main cause for de- cost-effectiveness of the surgery lay the surgery were no available as well as for quality of patient ICU bed, cardiac problems, un- care and safety. But spinal anaes- controlled DM and other geriatric thesia may fail and converted to diseases. general anaesthesia. Although our sample size is General anaesthesia was found small, still our results are compar- to be significant contributor to the able with international standards. risk of DVT, compared with re- Our data suggest that early stabil- gional anaesthesia. On the other ization may be associated with a hand it has shorter time which is lower complication rate. an advantage for elderly patients with significant co morbidity. This The results of this review indi- finding is consistent with other cate that delaying surgery may in- similar studies(26). We conclude crease morbidity, particularly the that spinal anesthesia is superior incidence of pressure sores and to general anesthesia for hip sur- will increase hospital stay. Delay- gery, especially in older patients ing surgery will inevitably prolong or patients with significant co the distress involved from this in- morbidities that may preclude use jury. Therefore patients admitted

370 Benha M. J. Vol. 29 No 1 Jan. 2012 to hospital with a hip fracture, in References which there are no specific condi- 1- Ryan G., Miyamoto, Kevin tions that van be improved prior M., Kaplan, Brett R., Levine, to surgery, should have their oper- Kenneth A. Egol and Joseph D. ation as soon as possible after ad- (2008) : American J of Orthopaed- mission to hospital. Short delay ic Surgeons Volume 16, Number prior to surgery may be justified to 10, October. address medical problems. 2. Dorotka H., Schoechtner Need of ICU bed and hospital and W. Buchinger (2003) : J of stay remained a major concern. Bone and Joint Surgery (Br) Vol. 85, No. 8. P 1107-1113. Novem- We recommend that elderly pa- ber. tients with osteoporotic hip fractures should be operated on as 3- Zuckerman J. (2008) : soon as the body meets the basic American Academy of Orthopaedic anaesthetic requirements (within Surgeons Volume 26, Number 10, 48 hrs), during standard daytime, October (P.596-607). working hours including week- ends if their medical condition al- 4- Alfram P. A. (1964) : An Ep- lows. Surgical fixation should not idemiologic Study of Cervical and be delayed more than 48 hours trochanteric Fractures in Urban from admission unless there are Population. Acta Orthop.Scand clear reversible medical condi- (Suppl.), 65:1-109. tions. 5- Stot S., Gray D. H. and This retrospective study con- Stevenson W. (1980) : The Inci- firms the trend towards more mor- dence of Femoral Neck Fractures bidity and a longer length of hos- in New Zealand. N.Z. Med. J., pital stay if surgery for hip 91:6-9. fracture patients was delayed beyond two calendar day from ad- 6- Hoening H., Rubenstein L. mission. V., Sloane R., Horner R. and

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Kahn K. (1997) : What is the role in elderly. Arch Gerontol Geri- of timing in the surgical and the atr;39:179-85. rehabilitative care of community- dwelling older persons with acute 13- Fox H. J., Pooler J., Pro- hip fracture? Arch Intern Med; thero D. and Bannister G. C. 157:513-20. (1994) : Factors affecting the outcome after proximal femoral frac- 7- Sikorski J. M. and Senior tures. Injury 25 (5):297-300 J. (1993) : The domiciliary rehabilitation and support program. 14- Al-Ani A. N., Samuelsson Med J Aust 159:23-5. B., Tidermark J., Norling A., Ekström W., Cederholm T. and 8- Lucke C., Philip J. and Hedström M. (2008) : Early oper- Krause D. (1995) : Surgical re- ation on patients with a hip frac- sults of pertrochanteric fractures, ture improved the ability to return Unfallchirug, 98: 272-7. to independent living. A prospective study of 850 patients. J Bone 10- Orosz G. M., Hannan E. Joint Surg Am 90(7):1436-1442. L., Magaziner J., et al., (2002) : Hip fracture in the older patient: 15- Moran C. G., Wenn R. T., reasons for delay in hospitaliza- Sikand M. and Taylor A. M. tion and timing of surgical re- (2005) : Early mortality after hip pair. J Am Geriatr Soc; 50 : 1336- fracture: is delay before surgery 40. important? J Bone Joint Surg; 87: 483-9. 9- Kenneth J., Koval and Jo- seph D. (2006) : Zuckerman: 16-Dolk T. (1989) : Influence Hand Book of Fracture of p 332. of treatment factors on the outcome after hip fractures. UPsala J. 12- Doruk H., Mas M. R., Yil- med. sci., 94: 209-221. diz C., Sonmez A. and Kyrdemir V. (2004) : The effect of the timing 17- Massie W. K. (1973) : of hip fracture surgery on the ac- Treatment of Femoral Neck Frac- tivity of daily living and mortality tures Emphasizing Long Term

372 Benha M. J. Vol. 29 No 1 Jan. 2012 Follow-up observation on Aseptic gery in hip fractures. J Bone Joint Necrosis. Clin. Orthop., 92:16-62. Surg Br 91 (7): 922-927.

18- Brown J. T. and Abrami, 23- Grimes J. P., Gregory P. G. (1964) : Transcervical Femoral M., Noveck H., Butler M. S. and Fracture. J. Bone Joint Surg., Carson J. L. (2002) : The effects 46B: 648-663. of time-to-surgery on mortality and morbidity in patients follow- 19-Soto-Hall R. and Johan- ing hip fracture. Am J Med 112 son R. (1964) : Variations in the (9):702-709. intra-articular Pressure of the hip Joint in injury and disease. J. 24- Shabat S., Heller E., Bone Joint Surg., 46A:509-516. Mann G., Gepstein R., Fredman B. and Nyska M. (2003) : Eco- 20- Todd C. J., Freeman C. nomic consequences of operative J., Camilleri-Ferrant C., et al. delay for hip fractures in a non- (1995) : Differences in mortality profit institution. Orthopedics 26 after fracture of the hip:the east (12):1197-1199, discussion 1199. Anglian audit. BMJ; 310:904-8. 25- Hamilton B. H., Hamilton 21- Parker M. J. and Pryor G. V. H. and Mayo N. E. (1996) : A. (1992) : The timing of surgery What are the costs of queuing for for proximal femoral fractures. J hip fracture surgery in Canada? J Bone Joint Surg {Br};74-B:203-5. Health Econ 15 (2):161-185.

22- Lefaivre K. A., Macadam 26- Gabriel M. and Gurman S. A., Davidson D. J., Gandhi M. D. : (2006) : Surgery for Hip R., Chan H. and Broekhuyse H. Fracture: How Urgent? IMAJ. Vol. M. (2009) : Length of stay, mor- 8 • IMAJ September 2006; 8:663- tality, morbidity and delay to sur- 664.

373 REPRINTSalah Youssef, et al.... BENHA MEDICAL JOURNAL

TIMING OF SURGERY IN ELDERLY PATIENTS WITH HIP FRACTURES

Salah Youssef MD, M. M. El-Menaway MD and Samir El Shora MD

Published by Benha Faculty of Medicine Volume 29 Number 1 Jan. 2012

374 Benha M. J. Vol. 29 No 1 Jan. 2012 EFFECT OF MALARIA ON PREGNANCY OUTCOME IN HAJJAH GOVERNATE IN YEMEN

Ibrahim A. Abdel Motagaly MD*, Osama K. Raslan MD*, Ahmed T. Abdel-Fattah MD* and Said M. Al-Barshomy MD Departments of Obstetrics and Gynaecology, Faculty of Medicine, Al-Azhar University* & Internal Medicine and Nephrology, Faculty of Medicine, Zagazig University, Egypt

Abstract Background: Maternal or fetal malaria infection during pregnancy adversely affects development and survival of fetus through low birth weight, maternal anemia, and possibly abortion and stillbirth. These malaria induced medical problems constitute major clinical, public health and research challenges. Malaria during pregnancy is a major health problem in Yemen, where pregnant women are more susceptible to malaria than their non pregnant counterparts, the important aspect is that it is preventable cause of low birth weight deliveries worldwide. Objective: aim was to study the complications and outcome of malaria during pregnancy. In Hajjah governate in Yemen. Methods: This case control study was conducted at Saudi hospital in Hajjah governate in Yemen in period from Jan 2011 to end of the same year. Patients included in this study were 100 pregnant women, 50 were diagnosed with malaria as study group, and 50 were normal pregnancy as control group. Admitted at Saudi hospital in Hajjah . different kinds of variables were recorded on data sheet. These included demographic variables, miscellaneous variables and severity related variables. We compared between both group in age parity, week of pregnancy, mode of delivery, Apgar score, baby weight, parasite species, laboratory values, lines of treatment, length of hospital stay, pregnancy and malaria related complications, maternal and fetal morbidity and mortality).Results: in study group, Only 15 (30%) were primigravida, and 35 (70%) were multigravida while 13(26%) were primigravida, and 37 (74%) were multigravida in control group. In study group, most of patiets, 28 (56%) presented in second trimester, while 8 (16%) presented in 1st trimester of pregnancy, and 14 (28%) patients presented in 3rd

375 Ibrahim A. Abdel Motagaly, et al... trimesters. regarding pregnancy outcome, 5(10%) had spontaneous abortion, 10(20%) patients had pre-term labor,16(32%) developed puerperal pyrexia, 5(10%) babies of infected mothers died in neonatal period and Mean weight of babies in study group was 2.5 ± 0.6kg and 3.1± 0.4 kg in control group babies (P<0.05).10(20%) babies were delivered with preterm labor, all were< 2.5 kg in weight, 2 patients had IUFD. and congenital malformations were reported in two babies. Con- clusion: Maternal malaria adversely affects the pregnancy outcome. It increases the risk of spontaneous abortion, stillbirths, premature delivery and low birth weight. P. falciparum sp, and p.vivax sp, is identified as common cause of malaria during pregnancy in Yemen. Malaria is more common in multigravida and in second trimester of pregnancy. It is significantly associated with decreased maternal hemoglobin and low birth weight of newborn. Introduction malaria are more frequent and Malaria is a parasitic disease more severe during pregnancy and affecting red blood cells that is mortality rate is higher among transmitted by female mosquitoes them as compared to non- of the anopheles genus. Of the pregnant.(2) Various studies have four parasitic protozoa causing shown that pregnant women in malaria, plasmodium falciparum, endemic areas are highly suscepti- p.vivax, p.malariae, p.ovale, ble to malaria and both the fre- p.falciparum is the most common quency and the severity of the dis- and the most dangerous, causing ease is higher in pregnant than between 700,000 and 2, 7 million non-pregnant women.(3.4) This deaths annually, most of which higher susceptibility has been hy- are in children and pregnant pothesized to be due to transient mothers.(1) Malaria and pregnan- depression of cell mediated immu- cy usually affect the course of nity which improves with delivery each other adversely. The physio- of neonate and decreases with logical changes of pregnancy and number of subsequent pregnan- pathological changes due to ma- cies(5). Pregnant ladies with Plas- laria have a deleterious effect on modium falciparum are prone to the course of each other. In en- get high levels of parasitaemia, hy- demic areas, clinical episodes of poglycemia, acute pulmonary ede-

376 Benha M. J. Vol. 29 No 1 Jan. 2012 ma, fetal distress, premature la- mans and other primates.(10) ma- bor, spontaneous abortions and laria during pregnancy is a major still births. Also,(6) Malaria in health problem in Yemen, where pregnancy is significantly asso- pregnant women are more suscep- ciated with higher mortality and tible to malaria than their non morbidity including, cerebral ma- pregnant counterparts.(11) anemia laria, maternal anemia, intraute- is regarded as a major risk factor rine growth retardation,, and still- for an unfavorable outcome of birth.(7.8) In addition; drugs used pregnancy. It has been reported for treatment of malaria can also as a predictor of preterm labor, contribute significantly to compli- LBW, maternal and perinatal cations associated with this dis- mortalities.(12-16) approximately ease. maternal mortality associat- 60%of Yemen population live in ed with p.falciparum malaria is area endemic with malaria, and highest in area of low and unsta- p.falciparum account for more ble transmission or in epidemic, than 90%of malaria cases.17while where in area of higher transmis- there is much literature concerned sion, the main complication of p. with the epidemiology of malaria falciparum malaria during preg- and anemia during pregnancy in nancy are maternal anemia and other setting.(18-19) few published low birth weight. This effect is data are available on the topics of most severe in primigravida, but Yemen.(20) in area of low transmission, women of higher gravidity are also af- Patients and Methods fected.(9) It is well established that This case control study was anemia the most common conse- conducted at Saudi hospital in quence of P. falciparum malaria hajjah governate in Yemen in peri- infection and it is generally ac- od from Jan 2011 to end of the cepted that in malaria-endemic ar- same year. Saudi hospital in Haj- eas, P. falciparum is a major Con- jah, serve much population in tributor to anemia in pregnancy. It Yemen, especially in Hajjah and has been suggested that the ABO the surrounding subgovernates.. system has evolved under apposi- Malaria transmission in this area tive selection pressure in both hu- is perennial but usually at peak

377 Ibrahim A. Abdel Motagaly, et al... towards the end of the rainy sea- on the participants’ age, parity, son. This area is characterized by duration of pregnancy, occupa- unstable malaria transmission, tion, etc., was recorded. and p.falciparum, p.vivax are the main species in this area, with a Personal, present, obstetric and peak of infection following the past histories were obtained rainy season. In this population, .Information also was obtained malaria affects all age group and from the delivery room for labor most parasitimic episode is symp- outcome including; baby’s weight, tomatic. The most two group at sex, Apgar score, and mode of de- risk of malaria complication are livery. About 5 ml of the maternal children and pregnant women. peripheral blood was obtained from each participant by vene- Patients included in this study puncture technique into sterile were 100 pregnant women, 50 EDTA container for laboratory were diagnosed with malaria as analysis. Malaria was confirmed study group, and 50 were normal by microscopic examination of pregnancy as control group. Pa- Giemsa-stained thin films of blood tients were admitted at Saudi hos- smears after screening by malaria pital in Hajjah governate in Yemen kites. in period from Jan 2011 to end of the same year. Controls were ran- Three different kinds of vari- domly selected from pregnant pa- ables were recorded on data sheet. tients without malaria who were These included 1-demographic admitted for routine ANC and de- variables, 2- severity related vari- livery at Saudi hospital in Hajjah ables (parasite species, laboratory governate in Yemen in the period values, length of hospital stay, of the study. Before being admit- pregnancy and malaria related ted to the clinical study, the pa- complications, maternal and fetal tients consent to participate, after morbidity and mortality). the nature, scope, and possible consequences of the clinical study 3-miscellaneous variables (pari- have been explained in a form un- ty, week of pregnancy, mode of derstandable to them. Information delivery, Apgar score, baby

378 Benha M. J. Vol. 29 No 1 Jan. 2012 weight), The WHO definition of ate. P-value < 0.05 was considered anemia in pregnancy (anemia was as statistically significant and all defined as hemoglobin< 11 g / p-values are two sided. dL), low birth weight as weight < 2500 g, the birth weight was de- Results termined in kilogram (kg) using an A total of 50 pregnant pa- electronic weighing machine im- tients were identified with ma- mediately after childbirth. Preterm laria as study group and 50 labor was delivery before complet- pregnant women without malar- ing 37 weeks of pregnancy, and ia were taken as control group. abortion (miscarriage) as complete Mean age of study group was 28.6 expulsion of product of conception ± 4.4 (range 16-46) years and in before completing 28 weeks of ges- control patient was 26.56± 4.3 tation. Selection of treatment regi- (range 15- 43) years. In study men was based on individual phy- group, (86%) 43 patients were illit- sician's assessment and choice. erate, (78%) 39 lived in rural area Pregnant patients admitted with those whose occupation was farm- malaria were taken as cases and ing were significantly more infect- pregnant patients without malaria ed with malaria parasite than in- were taken as control. Data was dividuals of other occupations. recorded on standardized data Women, who had no formal edu- sheet and analyzed; the descrip- cation, recorded the highest prev- tive analysis was done for demo- alence of malaria infection. High- graphic and clinical features. Re- est malaria infection was recorded sults are expressed as mean ± among Women with blood group standard deviation for continuous ‘O’ followed by those of blood variables and number (percentage) group ‘A’ . for categorical variables. Univari- ate analysis was performed by us- In study group 15 (30%) ing the Independent Sample t-test were primigravida, and 35 (70%) corresponding to difference of were multigravida, while 13 (26%) means and Pearson Chi-square or were primigravida, and 37 (74%) Fisher's exact test corresponding were multigravida in control to proportion whenever appropri- group.

379 Ibrahim A. Abdel Motagaly, et al...

In study group, most of patiets, for 7 days. Two patients with cere- 28 (56%) presented in second tri- bral malaria died during treat- mester, while 8 (16%) presented in ment. 1st trimester of pregnancy. And 14 (28%) patients presented in 3rd All patients with falciparum trimesters. malaria were treated with Qui- nine. 18 patients with vivax ma- P. Falciparum was present laria were given quinine and two in 30 (60%). Patients, While P. patients of whom received arte- Vivax accounted for 20 (40%) mether. Drug regimen selection patients. History of fever in45 was based on individual physi- (90%) patients, while nausea cian’s choice. and vomiting in 23(46%) and myalgia in 12 (24%) patients. and 26 (54%) out of 50 patients of abdominal pain in 38(76%) pa- the study group had babies born tients. in Saudi hospital in hajjah. Total number of babies in study group 40(80%) patients had anemia. were lower because some preg- Mean hemoglobin was 9.6 ± 1.5g / nant patients who were admitted dL (range 5.2 - 12.2 g / dL) in in our hospital for malaria, deliv- study group and 12.4 ± 0.7g / dL ered their babies elsewhere and (range 11.4 - 14.8 g / dL) in con- hence remained unaccounted in trol group (P-value <0.001). 7 our records. Mean weight of ba- (14%) patients had hemoglobin in bies in study group was 2.5 ± the range of 5-8 g/dL. 40 (80%) 0.6kg and 3.1± 0.4 kg in control patients had platelets < 150,000 / babies (P<0.05). mm3, among them 6 (12%) patients had platelets < 50,000 / Regarding pregnancy outcome, mm3. The mean length of hospital 5 (10%) had spontaneous abor- stay was 3.2 ± 0.8 days (range 1-6 tion, 10 (20%) patients had pre- days). term labor, 16 (32%) developed puerperal pyrexia, 5(10%) babies All patients were treated with of infected mothers died in neona- Quinine, 10-15mg/kg body weight tal period and. 10 (20%) babies

380 Benha M. J. Vol. 29 No 1 Jan. 2012 were delivered with preterm labor, two babies. Two (4%) pregnant pa- all were< 2.5 kg in weight, 2(4%) tient died in third trimester secon- patients had IUFD. congenital dary to severe cerebral malaria malformations were reported in and ARDS.

381 Ibrahim A. Abdel Motagaly, et al...

382 Benha M. J. Vol. 29 No 1 Jan. 2012 Discussion ing pregnancy are more in primi- Maternal or fetal malaria infec- gravida than multigravida.(23) Lo- tion during pregnancy adversely cal placental productions of chem- affects development and survival okinesis increased in malaria of fetus through low birth which is an important trigger for weight, maternal anemia, and monocyte accumulation in placen- possibly abortion and stillbirth. ta,(24) these pigment containing These malaria induced medical placental monocytes are associat- problems constitute major clinical, ed with anemia and low birth public health and research chal- weight due to malaria and may be lenges.(21) The important aspect is causative in their development.(25) that it is preventable cause of low Maternal malaria not only affects birth weight deliveries worldwide. immediate infant health but can In women from non-endemic areas also result in high susceptibility of or travelers to area, infection is child to parasite during the first associated with high risk of mater- year of life.(26) nal and perinatal mortality. This infection can aggravate other in- Complications of malaria are fections, dual infection has addi- mostly seen in P. falciparum sp. tional detrimental effects on ma- The incidence of severity of infec- ternal and infant survival in an tion and pregnancy related com- area where HIV and malaria co- plications varies according to level exist.(22) of acquired immunity against infections and the parity.(27) al- Malaria poses a serious health though, Many studies have shown problem to pregnant women. We that primigravida are high risk have described important epidemi- group, as in areas of endemic ologic features and clinical char- transmission, the prevalence was acteristics of 50 patients who had high, ranging from 64% in prim- malaria during pregnancy and igravida to 30% in gravid.(5) In our compared some of the important study, the susceptibility to malar- complications with control 50 ia infection was high in multi- pregnant patients without malar- gravida compared to primigravida. ia. Complications of malaria dur- Patients but associated complica-

383 Ibrahim A. Abdel Motagaly, et al... tions were statistically higher in globinopathies. primigravida. This is in agreement to various studies published from In highly endemic areas the Indian subcontinent where com- peak level of falciparum parasite- plication rate was higher in primi- mia occurs between 9 to 16 weeks gravida compared to multigravida of gestation and then decreases patients.4, 28, 29 but in contrast progressively until delivery.(4) In to Maqsood et al., 2007, In which our study 56% of patients pre- the susceptibility to malaria infec- sented in second trimester of preg- tion was high in multigravida nancy, this is in agreement with compared to primigravida patients previously reported higher inci- but associated complications were dence in second trimester of preg- not statistically significant in both nancy.(4) but in contrast to Maq- groups.(30) sood et al., 2007. In which 55.8% of patients presented in third tri- In our study anemia affect 80% mester of pregnancy. 302 out of of infected patients which is in 50 patients died during hospitali- agreement with Anisah et al., zation due to underlying severe 2010 in a study done in Elhodai- cerebral malaria and ARDS. They dah governate which concluded presented in 28, 30th week of that anemia affect 76%of infected IUFD, delivered vaginally after in- women regardless their age or par- duction of labor. Both of them ity. and malaria was not a risky were with high parasitic load of factor for anemia, but it was a risk falciparum, hemoglobin was< 6 factor for LBW36. whever in other gm / dl and platelet count

384 Benha M. J. Vol. 29 No 1 Jan. 2012 reported figures from other coun- Plasmodium falciparum, and its tries.(4,29,31) highest prevalence was recorded in second trimester (59%). Re- In Kocher et al. associated sig- infection or treatment failure were nificant anemia (Hb. 5g%) was the found to be common, both in the prime cause of mortality in his co- infants and pregnant women.33In hort of patients. the prime cause study conducted in Koraput dis- of mortality in our study was trict of Orissa, a tribal area en- ARDS secondary to severe cere- demic for malaria in India, there bral malaria. In our patients ma- was significant different parasite laria was significantly associated incidence between primigravida with hemoglobin decline of at least and multigravida which clearly 2.6 gm compared to control group correlates with our study as well.4 (P<0.001), but it was not associat- It is clear that this infection con- ed with a higher mortality rate. tributes to major perinatal mortal- The reason could be that in our ity by affecting both mother and group, the severity of anemia was fetus independently. Placental ma- much lower compared to the co- laria is a significant cause of preg- hort in Kocher’s study with higher nancy related complications in the mortality.(4) form of low birth weight babies, preterm deliveries, still birth and Malarial infection also contrib- abortion.4 In our study, 10 preg- utes to preterm labor. Maternal fe- nant patients had preterm live ver close to term is also associated birth and all of those babies were with deaths of infant aged be- less than 2500 gm in weight. tween1 and 3 months, whereas no Overall there was 400 gm de- risk factors could be identified crease in birth weight of babies for deaths that occurred later born to pregnant women with main infancy.(32) The clinico- laria compared to pregnant pa- epidemiological pattern of malaria tient without malaria (P = 0.016). infection in a cohort of prenatal The biologic mechanism by which women and infants was analyzed placental malaria infection leads during malaria epidemic. They to low birth weight is not fully es- found that 88% infections were of tablished. P. falciparum infected

385 Ibrahim A. Abdel Motagaly, et al... placenta shows thickening of increases the risk of spontaneous basement membrane of placental abortion, stillbirths, premature trophoblast cells, potentially re- delivery and low birth weight. sulting in reduced nutrient transfer to the foetus.(34) Placental mi- 2- Malaria is more common croinfarcts have been reported; in multigravida and in second tri- transplacental passage of parasi- mester of pregnancy. It is signifi- tized RBC to fetus does occur, and cantly associated with decreased this may affect fetal nutrient use maternal hemoglobin and low or stimulate preterm labour. (34) birth weight of newborn. Limited data are available regarding spontaneous abortion as a 3- P. falciparum sp, and p.vivax complication of clinical malaria or sp, are identified as common associated anti-malarial drugs in cause of malaria during pregnan- therapeutic doses. In our study, 5 cy in Yemen. patients aborted. 4 patients were admitted with history of vaginal References bleeding prior to treatment with 1. National center for infec- quinine. The patients with abor- tious diseases, division of para- tion had some common features sitic diseases anopheles mosqui- like, falciparum malaria with, he- toes, april 23, 2004 http://www. moglobin < 10g/dL and platelet cdc. gov/ malaria/biology/ count of< 50,000 / mm3. Various mosquito authors from other parts of the 2. Ramsay S. (2003) : Prevent- world have reported that malar- ing malaria in Pregnancy. Lancet; ia is not an important cause of 3: 4. spontaneous abortion in highly endemic areas.4, 28, 35 Although, 3. Brain B. J. (1983) : An our all 5 patients had severe ma- Analysis of Malaria In Pregnancy laria. In Africa. Bull World Health Or- gan;61:1005-16. Conclusion 1- Maternal malaria adversely 4. Kocher D. K., Thanvi I., Jo- affects the pregnancy outcome. It shi A., Subhakaran, Aseri S.

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26. Shoklo Malaria Research 31. WHO. (1990) : Severe com- Unit (2001) : Mae Sod, Thailand. plicated malaria. Trans R. Soc Christine. Effects of malaria dur- Trop Med; 84:1-65. ing pregnancy on infant mortality in an area of low malaria trans- 32. Parise M. E., Lewis L. S., mission. American Journal of Epi- Ayisi J. G., Nahlen B. L., Stuts- demiology; 154: 459-65, 2001. ker L., Muga R., et al. (2003) : A rapid assessment approach for 27. Menendez C. (1995) : Ma- public health decision-making re-

389 Ibrahim A. Abdel Motagaly, et al... lated to the prevention of malaria (1989) : Plasmodium falciparum during pregnancy. Bulletin of the associated placental pathology: A World Health Organization; 81: light and electronmicroscopic and 316-23. immunohistologic study. Am J Trop Med Hyg; 41:161-8. 33. Newman R. D., Hailemari- am A., Jimma D., Degifie A., Ke- 35. McGregor I. A. (1983) : bode D., Rietveld A. E., et al. Epidemiology, malaria and preg- (2003) : Burden of malaria during nancy. Am J Trop Med Hyg; pregnancy in areas of stable and 33:517-25. unstable transmission in Ethiopia during an one pidemic year. Jour- 36. Anish H. Albiti, Ishag nal Infect Dis; 188:1259-61. Adam, Abdulla S Ghouth. (2010) : Placental Malaria And 34. Yamada M., Steketee R. Anemia And LBW In Yemen; Roy- W., Abramowsky C., Kida M., al Society Of Tropical Medicine Wirima J. and Heymann D. And Hygiene104;191-4

390 Benha M. J. REPRINTVol. 29 No 1 Jan. 2012 BENHA MEDICAL JOURNAL

EFFECT OF MALARIA ON PREGNANCY OUTCOME IN HAJJAH GOVERNATE IN YEMEN

Ibrahim A. Abdel Motagaly MD, Osama K. Raslan MD, Ahmed T. Abdel-Fattah MD and Said M. Al-Barshomy MD

Published by Benha Faculty of Medicine Volume 29 Number 1 Jan. 2012

391 Benha M. J. Vol. 29 No 1 Jan. 2012 COMPARISON BETWEEN TRANSPULMONARY VENOUS FLOW AND TISSUE DOPPLER OF DIASTOLIC FUNCTION IN HYPERTENSIVE PATIENTS

Hesham Rashid MD Department of Cardiology, Benha University, Egypt

Abstract Background: Systemic arterial hypertension has clearly been shown to be a major factor in the enhanced incidence of cardiac morbidity and mortality. Relaxation abnormalities are one of the earliest manifestations of cardiac dysfunction and frequently precede systolic dysfunction in hypertension. Severe diastolic dysfunction may cause pulmonary congestion even without any deterioration of systolic function. Thus assessment of left ventricular diastolic filling in individual patients is important from both the diagnostic and therapeutic points of view. Aim of the work: to evaluate left ventricular diastolic function by pulmonary venous flow with pulse tissue Doppler in hypertensive patients. Patients and Methods: Thirty hypertensive patients of both sexes were included in this study, and admitted at cardiology department of Benha University Hospital during the period from September 2010 to March 2011.The study also included ten apparently healthy volunteers as a control group with matched age and sex. All patients were evaluated by history taken, clinical examination. Conventional echocardiography was performed to all patients to assess LV functions, dimensions and hypertrophy. Pulmonary venous flow was done by Doppler to measure S, D wave and S/D ratio, also Doppler tissue imaging was performed on mitral annulus at apical four chamber view to measure E", A", and E"/A" ratio.

391 Hesham Rashid

Results: The maximal early diastolic flow velocity of conventional Echo. of the control group ranged from 45-116 cm/sec with a mean value 75.2+18.9 cm/sec, while that of patients group ranged from 48-76 cm/sec with a mean value 62.1+13.9 cm/sec. there was a significant decrease in mitral E wave in patients than that the control group (P<0.01). The mean of Em/Am Ratio of the patients group was 0.532+0.10 while that of controls groups was 1.426+0.4 There was significant decrease of E/A Ratio of patient group than in control group (P<0.01). The mean systolic forward flow maximal velocity of patients group was 60.1+9.75 while that of controls was 59.73+6.66, with insignificant difference (P>0.05), also the mean diastolic forward flow maximal velocity of pulmonary venous flow in patients group was 64.8+10.98 while that of controls was 39.09+11.55, with significant increase in D wave in cases than that controls (P<0.01). The S/D ratio show a significant decrease in patients group than the control in cases it was0.93+0.11 while in control it was 1.43+0.05, the difference was significant (P<0.05). The sensitivity of tissue Doppler for detection of diastolic function was 93.3% versus 70% in pulmonary venous flow, specificity was 90% in tissue Doppler while it was 60% in pulmonary venous flow.

Introduction pertension (1). Systemic arterial hypertension has clearly been shown to be a Severe diastolic dysfunction major factor in the enhanced may cause pulmonary congestion incidence of cardiac morbidity even without any deterioration of and mortality. Relaxation abnor- systolic function. Thus assess- malities are one of the earliest ment of left ventricular diastolic manifestations of cardiac dys- filling in individual patients is im- function and frequently pre- portant from both the diagnostic cede systolic dysfunction in hy- and therapeutic points of view (2).

392 Benha M. J. Vol. 29 No 1 Jan. 2012 Patients and Methods - Left ventricular and diastolic Thirty hypertensive patients of diameter ----left ventricular both sexes were included in this end systolic diameter. study, and admitted at cardiology department of Benha University D) Left ventricular mass: Hospital during the period from *It was calculated by Hofmann September 2010 to March 2011. et al., 1995; method in which: The study also included ten ap- mass (in grams) = 1.04 X [(posteri- parently healthy volunteers as a or wall thickness + septal thick- control group with matched age ness = left ventricular end- and sex. diastolic diameter) 3 - (left ventricular end diastolic diameter) 3]- Echocardiography : 13.6.(3). 1- M mode and two dimension- N.B normal value=180-200 al evaluations of cardiac chambers gram in a standard manner from parasternal views assessing (Masyama 2- Doppler echocardiographic et al., 2001). recordings using a Doppler echocardiographic and a transducer ar- A) Chamber size: ray of 3 MH.z, Recordings were - Left atruim (normal 19-40 made at a paper speed 100 unit/ mm). sec: - Left ventricle End diastolic di- A) Continuous wave Doppler to ameter (nor. 38-57 mm), End assess and exclude intra- systolic diameter (nor. 33-40 cavitary pressure gradients. mm). B) Pulsed wave Doppler echoc- B) Wall thickness: ardiographic recordings using - Inter ventricular septum (nor. color flow mapping. 7-11 mm). - Left ventricular posterior wall 1-Mitral flow velocity pattern. (nor. 7-11 mm). It was obtained in the apical C) Fractional shortening calcu- four-chamber view with the sam- lated as follows: ple volume carefully placed be-

393 Hesham Rashid tween the tips of the mitral valve mal range 27-47 cm/sec). leaflets and recordings maximal - S/D ratio (normal range 1.1 – flow. The following parameters 1.8). were recorded and measured. - E wave maximal velocity (nor- Tissue Doppler; mal range 48 - 76 cm/sec). - Each left ventricular wall was - A wave maximal velocity (nor- divided into myocardial seg- mal range 45 - 73 cm/sec). ments basal and mid wall. - E/A ratio (normal range 1- Apical segments were omitted 1.4). because it is near the field of echo transducer. The Doppler 2- Pulmonary venous flow ve- velocity range of -20 to + 20 locity pattern: was selected and velocity was It was obtained in the apical measured on line at speed of four-chamber view. Left atrial fill- 55 mm/s. ing from the pulmonary vein is - Pulse wave TDI of mitral an- characterized by red signal along nuals was obtained from the inter atrial septum in the upper apical four chambers view for part of the left atrium in the color the measurement of : Doppler mode. 1- E' = early diastolic velocity (11.1-18.3 cm/sec. The orifice of the right pulmo- 2- A' = late diastolic velocity nary vein is imaged at the bottom (8.2-13.2 cm/sec). of the flame like red signals and 3- E' at, A' at = time to peak the pulsed Doppler sample volume velocity was set just at the orifice of the 4- E' DT, A' DT = deceleration right pulmonary vein and the time waves were recorded. 5- E' dur, A' dur = duration of velocity profile. The following parameters were measured: Evaluation of regional diastolic - S wave maximal velocity (nor- function by TDI in the basal and mal range 53-71 cm/sec). mid segment in different myocar- - D wave maximal velocity (nor- dial wall from two (anterior and

394 Benha M. J. Vol. 29 No 1 Jan. 2012 inferior wall) and four chambers was a significant increase is view (septal and lateral wall) with LVESD in patients that that of measurement of:- control group (P<0.05). 1- Peak velocity and rapid filling phase (Em wave) The mean left ventricular end 2- Peak velocity during atrial diastolic diameter was 65+9.8 contraction (Am wave) while that of controls was 3- Em/Am ratio 44.1±9.0 mm, there was a significant increase in LVEDD in pa- Results tients than that the control group A- Demographic data of all (P<0.05). studied cases This study included 30 hyper- The mean ejection fraction of tensive patients, 21 males (70%), patients group was 50. ±02.9 and 9 females (30%). Their mean while that of controls was age was (55±9.5) years, also ten 64.1±7.2, there was a significant volunteers apparently normal as a decrease in EF in patients than control group 6 male (60%), And 4 that the control group (P<0.01). females (40%), their mean age was 55±7.1. Table I. Mitral flow velocity parameters: B- Conventional Echocardiog- 1- Early diastolic flow maxi- raphy: mal velocity (E) The means inter-ventricular The maximal early diastolic septum thickness of the patients flow velocity of the control group was 15.7±1.7 mm, while group ranged from 45-116 cm/ that of controls was 9. ±6.7, there sec with a mean value 72.2±18.9 was a significant group than that cm/sec, while that of patients the control group (P<0.01). group ranged from 48-76 cm/sec with a mean value 62.1±13.9 cm/ The mean left ventricular end sec. there was a significant de- systolic diameter of patients group crease in mitral E wave in patients was 33.4±11.2 mm while that of than that the control group controls was 28.3±6.2mm. There (P<0.01).

395 Hesham Rashid

2- Atrial systolic flow maxi- in cases than that in control mal velocity (A): group (P<0.05). The maximal atrial systolic flow velocity of the control The mean (Am'dur) of patients group ranged from 45-73 cm/ group was 0.13±0.05, while it was sec, mean value was 59.2±13.8 0.07±0.02 in control group, with cm/sec, while that of patient significant increase in Am'dur in group ranged from 40-92 cm/sec, cases than in control group with a mean value 75.1±18.9 cm/ (P<0.01). sec. There was a significant increase in mitral A wave in patients The mean of Em/Am Ratio of than that the control group the patients group was 0.53±0.10 (P<0.05). while that of controls groups was 1.42±0.4 There was no significant C- Analysis of tissues Doppler decrease of E/A Ratio of patient Doppler imagine of mitral an- group than in control group nulus: (Table 2) (P<0.01). The mean E'm of patients group was 11.16± 3.08 while that D- Pulmonary venous flow ve- of controls was 14.48±2.47, there locity Table(3 ) : was a significant decrease in E'm 1- Systolic forward flow maxi- in cases than that in control mal velocity (S): group (P<0.05). The mean systolic forward flow maximal velocity if patients The mean A'm of patient group group was 60.1±9.75 while that was 14.96±3.91 while of controls of controls was 59.73±6.66. The was 10.15±1.7, there was a signifi- difference between patients and cant increase in A'm in cases than controls show no significant differ- that in control group (P<0.01). ence (P>0.05).

The mean (Em'dur) of patients 2- Diastolic forward flow max- group was 0.08±0.05, while of imal velocity (D) : controls was 0.12±0.04, there was The mean diastolic forward flow a significant decrease in Em'dur maximal velocity of patients group

396 Benha M. J. Vol. 29 No 1 Jan. 2012 was 64.8±10.98 while that of con- The S/D ratio show a signifi- trols was 39.09±11.55. There was cant decrease in patients group a very high significant increase in than the control in cases it D wave in cases than that controls was0.93±0.11, while in control it (P<0.01). was 1.43±0.05, the difference was significant (P<0.05).

397 Hesham Rashid

Discussion systolic dysfunction in hyperten- Systemic arterial hypertension sion (1). has clearly been shown to be a major factor in the enhanced Severe diastolic dysfunction incidence of cardiac morbidity and may cause pulmonary congestion mortality. Relaxation abnormali- even without any deterioration of ties are one of the earliest systolic function. Thus assess- manifestations of cardiac dys- ment of left ventricular diastolic function and frequently precede filling in individual patients is im-

398 Benha M. J. Vol. 29 No 1 Jan. 2012 portant from both the diagnos- mean diastolic blood pressure was tic and therapeutic points of 105 mmHg in patients group and view (2). 80 mmHg in control group with a p value<0.05. The present work tries to characterize the pulmonary venous Conventional echo: flow velocity pattern in hyperten- Left ventricular echocardio- sive patients with and without left graphic parameters included the ventricular diastolic dysfunction mean of IVS was 15.7 mm in pa- and evaluate its usefulness in re- tient group versus 9.6 mm in con- lation to the tissue Doppler ima- trol group with a p value<0.05, gining of the mitral annuls and and LVPW thickness was 12.2 mm the mitral flow velocity pattern for in patients while in control group the assessment of left ventricular was 8.9 mm with (p value <0.05), diastolic function. also LV mass was 168 grams in patients versus 108 in control In order to achieve this aim the group (p value <0.01). The mitral present work was conducted on flow velocity pattern was observed 30 hypertensive patients and com- with "E" wave had a mean of 62.1 pared with 10 healthy volunteer of cm/sec in patient group and 75.2 matched age and sex. cm/sec in control group with a p value <0.01,"A" wave mean value Demographic data: was 75.1 cm/sec while in patient This study included 30 hyper- group 59.2 with a p value <0.01 tensive patients 21 males (70%) and E/A Ratio had a mean of 0.82 and 9 females (30%) their mean in patient group while 1.23 in con- age was (55±9.5) years also ten trol group with a P value < 0.05). volunteer apparently normal as a control group 6 male (60%) and 4 This result is in agreement females (40%) their mean age was with, Tisioufis et al (2005) who (55±7.1. Also patient group had a found that essential HTN is ac- mean systolic blood pressure 150 companied by LV diastolic dys- mmHg while 120 mmHg in control function. He studied 106 patients group with a p value <0.05. The (aged 51 years, 80 males) with es-

399 Hesham Rashid sential HTN, and 50 normoten- 0.01, the mean of A wave was sives matched age, sex. LV dia- 74.1 cm/sec while in patient stolic function was estimated group was 60 cm/sec with a P val- by echocardiography. Hyperten- ue < 0.01 and the mean of E/A ra- sive compared with normotensive tio was 0.80 in patient group exhibited greater LV mass index while was 1.1 in control group. than normotensive (155 versus Sensitivity and specificity of mi- 105 grams the P value <0.001), tral inflow was 70%, 53% re- the mean of E wave was 65 cm/ spectively.(6) sec in patient group (Hyperten- sive) and 75.1 cm/sec in control Brush C et al (2000) studied 2 group with a P value < 0.01, the groups of subjects with ejection mean of "A" wave was 7.2 cm in fraction > 45% 10 normal volun- control group while in patient teer (50±10 y, HYP group). The mi- group it was 61.1 cm/sec with a tral inflow profile (E, A, E/A) was P value < 0.01 and the mean of E/ measured by pulsed Doppler. The A ratio was 0.85 in patient group mean of E wave was 60 cm/sec in while 1.31 in control group the p HYP group and it was 77 cm/sec. value < 0.05.(5) in control group with a P value < 0.01, A wave had a mean of 74 Arroja I et al (2001), who stud- cm/sec while it was 58.6 cm/sec ied left ventricular diastolic func- in HYP group with a P value <0.01 tion in 2 population of normoten- and E/A Ratio had a mean of .084 sive and hypertensive, they in patient group while it was 1.4 studied a group of 50 patients in control group with a P value with the diagnosis of HTN (group <0.05, with sensitivity and speci- H), which was compared with pop- ficity was 72% and 56% respec- ulation of 50 normal subjects tively.(7) (group N) in each case pulsed Doppler mitral inflow was ana- Ito T et al (2000) found that lyzed they found that the mean of specificity and sensitivity of E/A E wave was 63 cm/sec in patient Ratio was 80%, 61% respectively group and was 72.5 cm/sec in in (41 HTN patient), E/A ratio < 1 control group with a P value < with a P value (0.01), so all these

400 Benha M. J. Vol. 29 No 1 Jan. 2012 studies agree with the present cm/sec with a p value > 0.05 study.(8) while "D" wave in patient group, mean was 64.8 cm/sec while in Kakavas A, et al 1999, studied control group it was 39.09 cm/sec 100 hypertensive patients of aver- with a P value < 0.01 so the S/D age 53±9 years, 50 normotensive ratio mean in patient group was subjects of average 53±9 years, 0.93 and in control group was and their performed conventional 1.43 the P value < 0.05. Sensitivi- echo of mitral inflow. Their study ty and specificity of pulmonary ve- showed that the mean of peal venous flow was 70%, 60% respec- locity of E wave decrease from 56 tively. cm/sec in normotensives to 44 cm/sec in hypertensive patients This study agreement with Ar- with a P< 0.05. The peak velocity roja I et al (2001), who studied left of A wave did not change.(9) ventricular diastolic function in 2 population of normotensive and The present study does not hypertensive individuals, They agree with kakavas, A, et al (1999) had studied group of 50 patients who found that, the mean of A with the diastolic of HTN (group wave peak velocity didn't change H), which was compared with a in their study of 100 hypertensive population of 50 normal subjects patient of (average 53±9 years) (group N) in each case pulsed they performing conventional echo Doppler flow of the right upper of mitral inflow and their study pulmonary venous and diastolic shows no difference. This may be inflow of the left ventricular cavity due to type of patient and severity was done. Peak velocities of sys- of hypertension. tolic, diastolic waves of pulmonary venous flow was found as "S" wave Pulmonary venous flow mean value was 61.1 cm/sec in The pulmonary venous flow ve- (group H) while in (group N) it was locity pattern in patients is as "S" 58.7 with a P value > 0.05, D wave wave in patient group, the mean had a mean of 41.1 cm/sec in value was 60.1 cm/sec while in (group N) it was 65.3 cm/sec in the control group it was 59.73 (group H) with a P value < 0.01.

401 Hesham Rashid

The S/D ratio in patient group spectively. This is may be due to (group H) had a mean of 0.91 and severity of hypertension and type in control group (group N) it was of patients.(5) 1.4 with a value < 0.05. Sensitivity and specificity of pulmonary flow Hofmann et al., 2001; have was 72%, 58% respectively.(6) studied the relation between the pulmonary venous flow and atrial Tsioufis et al 2005 found that hypertension and left ventricular the essential HTN is accompanied function in 84 patients (aged 55 by LV diastolic dysfunction. He years, 70 males) with essential studied 106 patients (aged 51 HTN, and 40 normotensive, as years. 80 males) with essential hy- control group with matched age pertension, and 50 normotensives and sex. They found that the with matched age and sex. Left mean of S wave in patient group ventricular diastolic function was was 62.1 cm/sec and 61.8 cm/sec estimated by pulmonary venous in control group with a p value > flow. Hypertensive compared with 0.05, D wave had a mean of 0.90 normotensives. The mean of "S" and in control group it was 1.44 wave in patient group was 60.5 with a p value <0.05 sensitivity cm/sec and it was 59.3 cm/sec in and specificity of pulmonary ve- control group with a P value nous flow was 71.5%, 59% respec- <0.05, the mean of D wave was tively.(4) 42.1 cm/sec in control group and it was 66 cm /sec in patient group Masuyama et al., 2003; com- with a P value <0.05. The mean of pared Transthoracic with Trans- S/D ratio in patient group was esophageal Doppler echocardio- 0.94 and control group was 1.39 graphic measurement of pulmo- with a P value < 0.05, and sensi- nary venous flow velocity pattern. tivity and specificity 45%, 35% re- They concluded that transthoracic spectively. This study doesn't measurement of pulmonary ve- agree with our study in the point nous velocity pattern are feasible of sensitivity and specificity be- and accurate in hypertensive pa- cause sensitivity and specificity in tient and may be used to assess our study was 70% and 60% re- left ventricular systolic function

402 Benha M. J. Vol. 29 No 1 Jan. 2012 through they study 150 hyperten- and sex. LV diastolic function was sive patient and 50 normotensive estimated by pulsed tissue ima- with matched age and sex. They gining (TDI) echocardiography, av- found "S" wave is not significant eraging diastolic mitral annular with a P value <0.05 S/D ratio is velocity measurements (E' wave, A' significant with a P value < 0.05; wave, E/A ratio) was calculated. pulmonary venous flow had speci- The mean of E wave was 12.1 cm/ ficity and sensitivity 72, 60.3 resec in patients group and it was spectively in a meaner similar to 15.5 cm/sec in control group with our results.(3) a p value < 0.05 while A wave id patients group had a mean of 16 Tissue Doppler cm/sec and it was 10.4 cm/sec in Tissue Doppler of the mitral an- control group, with a P value nulus revealed that true mean of <0.05. The E/A ratio of patients (E'm wave) in patient group was group had a mean of 0.553 and in 11.16 cm/sec and in control control group was 1.43, with sen- group was 14.48 cm/sec with a P sitivity and specificity if tissue value of <0.05, the mean of Em/ Doppler was 95.2%, 92.4% respec- Am ratio in patient group was tively. (5) 0.532 and in control group was 1.42 with a P value of <0.05, with Azvedo J et al., 2005, who com- sensitivity and specificity of Tissue pared 180 hypertensive patients Doppler imaging was 93.35%, (aged 54 years, 150 males) and 90% respectively. 100 normotensive individuals with matched age and sec to estimate This study agreement with Tsi- LV diastolic function by tissue oufis, et al., 2005; they studied LV Doppler imagining of mitral annu- systolic function in 2 groups of lus. They found the mean of E population normotensives and hy- wave in patients group was 11.41 pertensive subject. They studied cm/sec and in control group was 160 patients (aged 53 years, 150 14.1 cm/sec with a P value of < males) with essentials HTN, and 0.05 while A wave in patients 100 normotensive subjects as a group had a mean of 14.81 cm/ control group with matched age sec and in control group was

403 Hesham Rashid

10.21 cm/sec with a P value < , control group with a p value < the mean of E/A ratio in patient 0.05, the mean of E/A ratio in pa- group was 51.1 and in control tient was 53.3 and in control was group was 1.33 with a p value < 1.32 with a p value < 0.05, with 0.05 sensitivity and specificity and sensitivity and specificity of tissue tissue Doppler imagining was Doppler imagining 93.4, 92.1 re- 92.1, 91.3 respectively.(10) spectively.(11)

Schmermud A et al, 2006 they Lraidogolitia et al., 2006, stud- found the diastolic mitral annulus ied 20 patients with essentials hy- velocity assessed by tissue Dop- pertension of average age 54±10 pler echocardiography (TDE) was years. They performed DTI of mi- suggested to provide additional in- tral annulus versus conventional formation about LV diastolic func- eco pulsed Doppler and pulmo- tion affected by atrial hyperten- nary venous flow. Their study sion, they studied 50 hypertensive showed that TDI show an abnor- group (patient group) (aged 50 mal relaxation on essential hyper- years, 35 males) and 30 normotensive patients than with pulmo- tensive (control group) with nary venous flow and mitral flow matched age and sex. The mitral indices. They suggested that DTI systolic, early, and late diastolic in E/A ratio in the mitral annulus velocities of mitral annulus (E, A, is more sensitive by 90% than pul- E/A ratio) were assessed by monary venous flow and trans- pulsed Tissue Doppler Imagining mitral Doppler and specificity = (TDE). All studied individuals had 80%. (12) invasive measurement of left ventricular end diastolic pressure The present study agree with during left heart catheter. The these results because the sensitiv- mean of E wave in patient group ity of trans-mitral flow by pulsed was 12.3 cm/sec and in control Doppler was 66%, specificity of group was 14.7 cm/sec with a P 50% and in pulmonary venous value of < 0.05 while the mean of flow the sensitivity was 70% and (A') in patient group was 15 cm/ specificity of 93% detecting LV resec and it was 10.1 cm/sec in laxation abnormalities in hyper-

404 Benha M. J. Vol. 29 No 1 Jan. 2012 tensive patients group compared 983 - 994. to normal . 4- Hofmann T., keek A., sim- In the present study there was ic O., et al., (2001) : Simultane- a significant increase in both sen- ous measurement of pulmonary sitivity and specificity on mitral venous flow by intravascular cath- annulus tissue Doppler than both eter velocimetry and transpulmonary venous flow and mitral esophageal Doppler echocardiog- in-flow patterns, the pulmonary raphy: Relation to left atrial pres- venous flow is more sensitive and sure and left atrial and let ventric- specific than the mitral flow. ular function. J Am coll. Cardiol. 26(1): 239-49. References 1- Kaplan M. N. (2002) : 5- Tsioufis C., Chatzis D., Systemic hypertension: mecha- Dimitriadis K., et al., (2005) : nisms and diagnosis in: Braun- Left ventricular diastolic dysfunc- wald E. Ed. Heart disease, A Text- tion is accompanied by increase book of cardiovascular Medicine. aortic stiffness in the early stages 4th ed.philadelphia, Toronto, Lon- of essential hypertension: a TDI don, Montreal, Sydeny, Tokyo: WB approach. J Hypertension. 23: Saunder Company. 1:819. 1745-50.

2- Kannel W. B. (2005) : Hy- 6- Arroja I., Jacques A., Oli- pertensive cardiovascular disease: veira A., et al., (2001) : A pulsed The Framinghian Study. J Hyper- Doppler study of left atrial and tens; 23:297-304. ventricular inflow in 2 populations of normotensive and hypertensive 3- Masuyama T., Lee J. M., subjects. Rev Port Cardiol.12: (10) Yawmamato K., et al, (2003) : 827-39. Analysis of pulmonary venous flow velocity patterns in hypertensive 7- Brush C., Marin D., hearts: Its complementary value Kuntz S., et al. (2000) : Analysis in the interpretation of mitral flow of mitral annulus excursion with velocity pattern. Am heart J 124: tissue Doppler (TDE). Noninvasive

405 Hesham Rashid assessment of left ventricular, dia- normotensive and hypertensive stolic dysfunction. 88(5):353-62. subjects. Rev Port Cardiol. 22 (5):330-45. 8- Ito T., Suwa M., Hirota Y., et al., (2000). Influence of left 11- Schmermud A., Bartel atrial function on Doppler trans- T., Schaar J., et al., (2006): Tis- mitral and pulmonary venous flow sue Doppler as a noninvasive as- patterns in hypertensive hyper- sessment of left ventricular, dia- trophic cardiomyopathy. Am Heart stolic dysfunction in hypertensive J.131 (1): 122-30. patients. Z Kardiol. 95(5) : 454- 67. 9- Kakavas A., vlasseros I., Tousoulis D., et al., (1999) : Left 12- Laraidogolitia S., Nergi- ventricular diastolic dysfunction soglu G., Atmaca Y., et al., in hypertensive patients. J of Hy- (2006): Assessment of left ventric- pertension. 15(3):45-9. ular diastolic function with Dop- pler tissue imagining: in correla- 10- Azevedo J., Valle J. C., tion to echo and pulmonary Marques J. C., et al., (2006) : venous flow in hypertensive pa- Tissue Doppler study of left ven- tients. Int. J Cardiovasc. Imagin- tricular inflow in 2 populations for ing. 22(3):200-10.

406 Benha M. J. REPRINTVol. 29 No 1 Jan. 2012 BENHA MEDICAL JOURNAL

COMPARISON BETWEEN TRANSPULMONARY VENOUS FLOW AND TISSUE DOPPLER OF DIASTOLIC FUNCTION IN HYPERTENSIVE PATIENTS

Hesham Rashid MD

Published by Benha Faculty of Medicine Volume 29 Number 1 Jan. 2012

407 Benha M. J. Vol. 29 No 1 Jan. 2012 SERUM TRACE ELEMENTS CONCENTRATIONS (CA – CU – ZN – CU/CA AND CU/ZN RATIO) IN RELATION TO DISEASE ACTIVITY SCORES IN PATIENTS WITH RHEUMATOID ARTHRITIS

Reham M. Shaat MD, Afaf M. Attia MD and M. EL-Defrawy Ph.D. Rheumatology & Rehabilitation; Clinical Toxicology; Faculty of Medicine and Analytical Chemistry, Faculty of Science, Mansoura University

Abstract 48 patients with rheumatoid arthritis (RA) were selected from rheumatology and rehabilitation out patient clinic, Mansoura University hospital including 40 & 8 age ranged from 35-63 years, 12 healthy volunteers with matched age and sex served as control group. Assess- ment of over all disease activity in (RA) patients was performed using disease activity score and Eular Response criteria (DAS-28) including both clinical and laboratory markers. Determination of serum Cu, Zn and Ca levels were done using Per- kin-Elmer 2380 atomic absorption spectrophotometer. A significant decrease in both serum Ca and Zn levels and significant increase in serum Cu level (p=<0.04) was found among patients with (RA) compared with control group. A -ve correlation was found between disease activity scores (DAS) and both serum Ca and Zn Levels (p=<0.04) meanwhile a + ve correlation was observed between serum Cu level and disease activity (P=<0.04). Both serum Cu/Ca and Cu/Zn Ratio are sensitive indicies of disease activity however serum Cu/Ca ratio is probably more sensitive.

407 Reham M. Shaat, et al....

Introduction university hospital included 40 and Aim of the work and 8 age ranged from 35-63 Rheumatoid arthritis is a major years (RA) patients receiving estro- public health problem. Among the gen containing oral contraceptives many contributing agents that (Known to increase serum copper have been proposed to take part in values)(7) or wearing copper bracc- the pathogenesis of this condition, lets were excluded 12 healthy vol- nutritional status have also been unteers with matched age and sex investigated (1)(2)(3), The participa- served as control group. tion of micronutrients especially copper, zinc and calcium in the Assessment of over all disease normal development and mainte- activity in (RA) patients was pre- nance of skeleton is at least in formed using disease activity part related to their catalytic func- score and EULAR response crite- tions in organic bone matrix syn- ria (DAS-28) including both clini- thesis or in the functioning of cells cal and laboratory markers Deter- of bone or cartilage (4), Also Cu mination of serum Cu, Zn and Ca and Zn are components of the two levels were done in both patients major superoxide dismutase en- and volunteers using Perkin El- zymes which have been shown to mer 2380 Atomic absorption spec- fight against the reactive interme- trophotometer According to the diates that are linked to joint method described by stockwell damage in arthritis(5,6). The Aim and corns(9). of the present study was to investigate serum levels of micronutri- Using (DAS-28) scores patients ents Ca, Cu, Zn, Cu/Ca and Cu/ with (RA) were classified into, pa- Zn ratio in relation to disease tients with mild and moderate dis- activity sores in patients with ease activity 28 patients (24 (RA). and 4 ) and 20 patients with highly active disease (16 and 4 Material and Methods ). 48 patients with (RA) selected Results from rheumatology and Rehabili- 1) Significant increase in tation out patient clinic Mansoua serum Cu level was found

408 Benha M. J. Vol. 29 No 1 Jan. 2012 among patient with (RA) compared 4) A+ ve correlation was found with control group (P=<0.040 between serum Cu concentration Table I. and disease activity scores. Meanwhile a -ve correlation was 2) Significant decreases in found between both serum Ca and both serum Ca and Zn levels were Zn concentrations and diseases found among patient with (RA) activity scores (Table II, III, IV). compared with control group. (P=<0.04) Table I. 5) A highly significant increase in Both serum Cu/Ca ratio 3) Highly Significant increases (P=<0.001) and Cu/Zin Ratio in both serum Cu/Ca ratio (P=<0.002) were observed among (P=<0.001) and Cu/Zn Ratio (RA) patients with High disease (P=<0.002) were observed among activity scores compared with patients with (RA) compared with those with Mild and moderate Dis- control group. (Table I). ease activity (Table V).

409 Reham M. Shaat, et al....

410 Benha M. J. Vol. 29 No 1 Jan. 2012

Discussion take in our population which may Nutritional status is often im- exacerbate Ca deficiency at the paired in patients with (RA)(10). proximal tubules were Na+ and Ca Disability and pain can interfere absorption are Linked (12). Vita- with consumption of food. Tem- mine D is one important compo- promandibular pain can impair nent of Ca metabolism it is possi- mastication. Anti-iflammatory ble that the intermediate and anti-rheumatic medication metabolism of vitamine D may be commonly lead to nausea, dyspep- abnormal in (RA) (14). sia and altered Taste In the present study significant lower Significant increase in serum level of serum Ca was found Cu level was found among our pa- among patients with (RA) com- tients with (RA) compared with pared with control group Also a - control group. Also a +ve correla- ve correlation was observed be- tion was observed between disease tween disease activity scores activity scores and serum Cu level (DAS) and serum Ca level. Similar similar findings were previously findings were previously reported reported by some authors (1)(15) by some authors (11) (12) and re- and recently by Ala.(3) Copper is cently by afridi et al (13) low ser- an essential trace element that um Ca in our patients with (RA) may facilitate the activity of ceru- may result not only from malnu- loplasmin (acute phase reactive trition but also from high salt in- and serum cu carrier protein)

411 Reham M. Shaat, et al.... which is known to increase in rein serum Cu/Zn Ratio with con- sponse to inflammatory reactions comitant highly significant in- with concomitant elevation in ser- crease (P=<0.001) in serum Cu/ um Cu level, copper also is known Ca Ratio in our patient with high to activate copper-zinc super- disease activity scores (DAS) com- oxide dismutase which have anti- pared with those with low and oxidant and anti-inflammatory moderate disease activity scores properties that may prevent the indicating that both serum Cu/Ca onset of chronic joint disease (16). Ratio and serum Cu/Zn Ratio are sensitive indicies of disease ac- Significant decrease in serum tivity, however serum Cu/Ca Ratio Zinc concentration was observed is probably more sensitive. among our patients with (RA) compared with control group. Also References a -ve correlation was found be- 1- Yazar M. Sarban S., Koc- tween disease activity scores and yigit A., Isikan U. E. (2005): Syn- serum Zn levels, similar findings ovial fluid and plasma selenium, were previously reported by some copper zinc and iron concentra- authors (17) (18). Zinc supplemen- tions in patients with rheumatoid tation was reported to decrease arthritis and osteoarthritis: Biol peri-articular osteoporosis in (RA) trace Elem Res 106, 123-32. patients(15). Defects in skeletal development have been reported due 2- Heigeland M., Svendsen E., to zinc deficiency and also due to Farre O., Haugen M. (2000): Die- acrodermatitis enteropathica an tary intake and serum concentra- inherited disorder of zinc absorption of antioxidants in juvenile ar- tion (19). Zinc plays important role thritis: Clin. Exp. Rheumatol 18, in nucleic acid synthesis, Zinc has 637-41. also been shown to be required by enzymes which have specific func- 3- Ala S., Shokrzadeh M., Pur tions in bone metabolism. (20) shoja A. M. Saeedi Saravi. S. S. (2009): Zinc and copper plasma In the present study significant concentrations in rheumatoid ar- increase (P=<0.002) was observed thritis patients: Pak J Biol. Sci

412 Benha M. J. Vol. 29 No 1 Jan. 2012 12:1041-4. 15:79-84.

4- Grynpas M. (1990): Flou- 10- Melliwell M., Coombes E. ride effect on bone crystals J.; J., Moody B. l. (1984): Nutrition- Bone Miner Res. (5) 5169-75. al status in patients with rheumatoid arthritis; Ann Rheum Dis- 5- Soylak M., Kirnap M. ease, 43:386-90. (2001): Serum copper and Zinc concentration in patients with 11- D. L. Scott, M. farr, C. F. rheumatoid arthritis: Environ Bull Hawkins, R. Wilkinson and A. 10:409-10. M. Bold (1981): Serum Calcium levels in Rheumatoid arthritis: 6- Kuo S. (1999): In vivo archi- Ann Rheum Dis Dec, 40 (6) 580- tecture of the manganese superox- 83. ide dismutase promoter: J Biol Chem (277) (6) 3345-54. 12- Jonathan stone, Alane Doube, Denise Dudson and Ja- 7- Johnston N., Kheim C. T., neue Wallace (1997): inadequate Kauntz W. B. (1959): influence of calcium, Folic acid , Vitamine E, sex hormones on serum copper; Zinc and selenium intake in Rheu- proc soc exp Biol Med. 102 98-9. matoid arthritis patients: Semin Arthritis Rheum 27; 180-185, cop- 8- T. fransen J., Van Riel P. yright by W.B. Saunders compa- L. (2009): The Disease activity ny. score and EULAR response criteria; Rheum Dis clinical North Am 13- Afridi H. I., Kaei T. G., Nov., 35(4) 747-57 vii-viii Review. Kari N., Shah A. Q., Khan S., Kolachi Ne, Wadhwa S. K., Shah 9- Stockwell P. B. and Cornes F. (2012): Evaluation of calcium. W. T. (1993): The role of Atomic Magnesium, Potassium and sodi- Absorption flourescence spectrom- um in biological samples (Scalp etry in the automatic environmen- hair, serum, blood, urine): Clin tal monitoring of trace element lab 58 (1-2) 7-18. analysis; J automatic chemistry

413 Reham M. Shaat, et al....

14- Maddison P. J., Bacon P. (1998) vol. 17(5); Page 378-82. A. (1974): Vitamine D deficiency, spontaneous fracture and Osteo- 18- Taysi, Seyithan, Gulcin, penia in rheumatoid arthritis Br Ilhami, Sari, Rafic Ali, Kuskay Med. J. 4: 433-5. (2003): Trace elements and disease activity scores in patients 15- Honkamen V., Lamberg, with rheumatoid arthritis; Pain Vesterinen M., Lehto J., Wester- Clinic vol. (15) Number (4) pp. marck T. W. Mestak (1991): 435-39. Plasma Zinc and Copper concentration in rheumatoid arthritis: 19- Tudor R., Zalewski P., Am. J. Clin. Nutr. 54:1082-6. Ratnaike R. (2001): Zinc in health and chronic disease; Scand 16- Robert Disilvestro (1992): J. Rheumatol (2001) 30 208-12. Effect of Copper Supplementation in rheumatoid arthritis patients: 20- Hassan Imran Afridi, Tas- J. Am. Coll. Nutr. 11 (2) 177-80. neem Gul Kazi Dermot Braba- son, Sumsun Naher (2011): as- 17- Zoli A., Altamonte L., Ca- sociation between essential and riccho R., Mirone L., Ruffini M. toxic elements in scalp hair sam- P., Magaro M. (1998): Serum ples of smokers rheumatoid ar- Zinc and copper in active rheuma- thritis subjects: Science of the to- toid arthritis: Clinical rheumatol tal environments 412-413 93-100.

414 Benha M. J. REPRINTVol. 29 No 1 Jan. 2012 BENHA MEDICAL JOURNAL

SERUM TRACE ELEMENTS CONCENTRATIONS (CA – CU – ZN – CU/CA AND CU/ZN RATIO) IN RELATION TO DISEASE ACTIVITY SCORES IN PATIENTS WITH RHEUMATOID ARTHRITIS

Reham M. Shaat MD, Afaf M. Attia MD and M. EL-Defrawy Ph.D.

Published by Benha Faculty of Medicine Volume 29 Number 1 Jan. 2012

415 Benha M. J. Vol. 29 No 1 Jan. 2012 SURGICAL TREATMENT OF POSTERIOR WALL FRACTURES OF THE ACETABELUM

Mohamed El-Menawy MD Department of Orthopaedic Surgery, Faculty of Medecine Al-azhar University, Egypt

Abstract Back ground : Posterior wall fractures of the acetabulum are common. Hip with a posterior wall fracture fragment exceeding 40% are predicted to be unstable and theoretically must be treated with open reduction and internal fixation. The purpose of this study was to evaluate the clinical outcome in such patients. Patients and Methods : Eighteen patients with posterior wall fracture of the acetabulum were treated operatively and fixed using inter- fragmental screws and reconstruction plates. Results : Patients were followed up for a period from 10 - 30 months average 18 month, the clinical score was 13 patient excellent, 2 had good, 2 had fair and 1 had a poor result. Complications : Superficial infection occurred in 2 cases and needed debridement, antibiotics and dressing. Only one with deep infection with no response to repeated debridement and ended with destruction of the hip joint. Conclusion : Good results can be obtained in patients with posterior wall fracture of acetabulum after proper assessment preoperatively, proper incision and taking care of local nerves specially the sciatic nerve, also proper fixation and repair of soft tissue with meticulous adherence to postoperative rehabilitation program.

Introduction Non operative treatment of Posterior wall fractures of the these fractures is indicated only acetabulum are common and when joint congruity and hip comprise approximately up to stability are maintained after in- 30% of all acetabular fractures(1). jury(2). This situation occurs

415 Mohamed El-Menawy when the remaining intact part operatively(5,6). All other posterior of the acetabulum is large wall fractures including those that enough to maintain the femoral were not associated with a known head in normal relationship hip dislocation were considered with the acetabular roof. Histori- potentially unstable. In these cas- cally the size of the posterior es, dynamic fluoroscopic stress wall fragment as measured on a examination of the hip was per- two dimensional C.T scan has formed with the patient under been a commonly used predictor general anesthesia to identify frac- of the status of hip joint stability ture instability requiring surgical and the need for operative inter- treatment(7). vention.Hips with a posterior wall Fracture fragment exceeding 40% Classified by Letorurnel (1) as are predicated to be unstable and one of the elementary fracture theoretically must be treated with types, its simple appearance on open reduction and internal fixa- plain radiographs belies its poten- tion(3,4). tial complexity. Rather than being one simple fracture fragment, the Fractures involving < 20% of majority of posterior wall fractures the posterior wall are predicted to are comminuted. be stable and theoretically can be treated non operatively. Investigators reporting on relatively small numbers of opera- Historically the indication for tively treated fractures of poste- surgery was hip instability which rior acetabular wall have found was identified in several ways. that the outcome is unsatisfac- Patients presenting with a hip tory in approximately 30% of dislocation were treated with case (8,9,10). emergent reduction of the dislocation. Patients exhibiting gross The cause of this relatively poor instability on physical examina- prognosis for posterior wall fraction after closed reduction, de- tures as compared with the prog- fined as joint instability occurring nosis for other types of fractures at ≤ 40° of hip flexion are treated remains obscure(11).

416 Benha M. J. Vol. 29 No 1 Jan. 2012 The purpose of this study was dislocation. Patients who had a to evaluate the results of open re- fracture with gross instability duction and internal fixation of on physical examination after posterior wall fractures of the ace- closed reduction ………….. were tabulum. treated operatively. After a successful closed reduction as docu- Exclusion criteria: patients mented by plain radiography, the with a delay in surgery of more hip was further Evaluated by C.T than 3 weeks, those in whom the scan and if this modality showed fracture was the result of a gun- the fracture to involve >40% of the shot, those referred after previous posterior wall the fracture was surgical treatment and those oper- considered unstable. All other ated on for removal of incarcerat- posterior wall fractures including ed fragments of bone or soft tissue those that were not associated but not requiring internal fixation, with a known hip dislocation were other exclusion criteria were skel- considered potentially unstable. etal immaturity, other injuries involving the affected hip joint or The focus of the current study proximal part of ipsilateral femur. was on the outcome of acute treatment of unstable hip fractures Material and Methods caused by blunt trauma. This study was done from July 2007 to June 2010 at Al- During this time period, eight- AZHAR University hospital New een patients with posterior wall Damietta. Patients were either acetabular fracture were evaluat- directly admitted through the ed. All patients met the inclusion emergency department of our hos- criteria for the present study. Of pital or referred from another hos- the eighteen patients In the study pital especially for treatment of five were female and thirteen the acetabular fracture after sta- were male table 1, and they bilization of their general medi- ranged in age from seventeen to cal condition. Patients presented fifty-nine years (means thirty-one with hip dislocation were treated years) at the time of injury. Table with emergent reduction of the 2 five of eighteen patients had

417 Mohamed El-Menawy documented evidence of dislo- was isolated to the acetabulum. cation of the femoral head at The other fourteen patients sus- the time of the initial injury ta- tained additional injuries, includ- ble 3. six patients had a fracture ing eight patients with injuries to of the left acetabulum and the spine, seven with injuries to twelve had a fracture of the right other extremities, three with head table 4 . injuries, four with injuries to the face, and two with abdominal Sixteen patients were injured in trauma. Of the eighteen patients, road accident and two were in- fourteen had a fracture in the injured due to falling from height ta- termediate stability, size rang of ble 5 .In four patients, the injury 20% to 50% .

418 Benha M. J. Vol. 29 No 1 Jan. 2012

Surgical technique:- I prefer the kocher- Langen - while under general or spinal beck posterior approvh for routine anesthesia the patient is pos- posterior wall fracture of the ace- tioned prone on a radiolucent op- tabulum. erating table with a bean bag used To minimize the risk of iatro- for support with the patient prone genic sciatic nerve injury flexion on the operating table, The sterile of the ipsilateral knee is main- field consists of the buttock and tained throughout the operative the posterior and lateral aspects of procedure to place the nerve in a the thigh. relaxed position.

419 Mohamed El-Menawy

In our cases the skin incision is muscle cross the interval of dis- centered over the greater tro- section slightly more than halfway chanter, the proximal part of the between the level of the greater incision is directed toward the trochanter and the posterior su- posterior superior iliac spine, end- perior iliac spine. Therefore, split- ing approximately 6 cm short of ting of the muscle fibers should the osseous landmark. Distally, stop as soon as the first nerve the incision extends approximate- branch to the upper part of the ly 15 cm along the midlateral as- muscle is encountered. Partial re- pect of the thigh. The skin incision lease of the Glutus maximus in- is carried through the subcutane- sertion into the femur, which al- ous tissue and superficial fascia lows adequate posteromedial onto the fascia lata (The iliotibial retraction of the large mass of the tract) and the thin, deep fascia Glutus maximus muscle without overlying the Glutus maximus undue stretch of inferior gluteal muscle. The fascia lata is then di- nerve. The sciatic nerve is located vided in line with the skin inci- over the posterior surface of the sion, beginning at the distal as- Quadratus femoris muscle. pect of the wound, continuing proximally toward the greater tro- The piriformis and obuturator chanter and ending at the first internous tendons (with the su- sighting of the Glutus maximus perior and inferior gmelli muscles muscle fibers as they insert into on either side) are incised approxi- the iliotibial tract. The next step is mately 1.5 cm from their insertion the splitting of the Glutus maxi- points into the greater trochanter. mus muscle. Despite possessing a It is important to preserve this dual blood supply and thus hav- distance from the insertion site in ing the potential for an intervascu- order to avoid injury to the blood lar plane of dissection, the Glutus supply of the femoral head. After maximus muscle has innervations reflection of these short external from the inferior gluteal nerve rotators and elevation of the Glu- consequently, there is no interve- tus medius and minimus muscle nous plane, and the nerve branch- origins from the external surface es of the upper one - third of the of the ilium ,exposure of the pos-

420 Benha M. J. Vol. 29 No 1 Jan. 2012 terior acetabulum is essentially addition, each major posterior complete. A blunt Hohman retrac- wall fragment should be held by at tor can be placed into the lesser least one lag screw. These screws sciatic notch in front of tendon of can be inserted before or after the obturator internus to protect buttress- plate application. The the sciatic nerve and facilitate ex- hip is again inspected in all planes posure the posterior column. with C-arm to assess fracture reduction and hardware placement. After completion of the surgical The wound is then closed in layers approach, the next step is to de- over the suction drains. Before the fine all of the fracture fragments. patient is discharged from the Usually we find some free osteo- hospital, three standard radio- chondral fragments, in addition to graphs of the pelvis (anteroposteri- multiple wall pieces still maintain- or, internal oblique, external ing soft tissue attachments. The oblique )and two dimensional C.T fragments are cleared of debris. scan are made to assess fracture The hip must then be sublaxated reduction. Non weight bearing to allow inspection of the joint for with axillary crutches or a walker removal of free fragments and to is maintained for six weeks. then allow for joinr irrigation and de- toe - touch weight - bearing (10 - bridement. The posterior wall frag- 15 kg) for another six weeks. ments with their intact capsular attachments are then sequentially There is no range of motion reduced and held with a pointed restriction. Progression to full ball spike. weight - bearing should be individ- ualized on the basis of the appear- After this reduction is complet- ance of the follow up radiographs. ed, the hip is inspected in all Physical therapy is continued un- planes with C-arm fluoroscopy. til muscle strength and range of The entire construct is the further motion are regaines. supported with 3.5 mm reconstruction buttress plating. The Results plate should be placed as close to At the final follow up ex- the acetabular rim as possible. In amination, the functional outcome

421 Mohamed El-Menawy was evaluated using the clinical good, fair and poor) by elevating grading system adopted by Le- the clinical outcome grade of very tournal and Judet (1) and modified good to excellent. Then, the clini- by Matta (9). In this clinical gard- cal outcome score were divided ing system, pain, gait and the into two categories, good to excel- range of motion of the hip can lent and fair to poor. each be assigned a maximum score of six points. The three indi- The quality of fracture reduc- vidual scores are summed to drive tion as measured on the three the final clinical score, according standard plain radiographs of the to which the clinical results was pelvis was graded as anatomic in classified as excellent (18 points), seventeen hips and as imperfect in very good (17 points), good (15 - one hip. Table (6). 16 points), fair (13 - 14 points), poor (<13 points). Some residual defect (defined as a gap of >1 mm) was known to The radiographs were graded have been left in seven patients according to the criteria described when osteochondral fragments by Matta (9). were discarded during surgery. The clinical outcome was graded With this method a normal ap- as excellent in thirteen patients, pearing hip joint is given excellent. good in two patients and poor in A hip joint narrowing (≤1mm) with one patient .In the three patients mild changes and minimal sclero- with poor and fair results, one sis is given good. with a deep infection, one with preexisting O. A. of the hip the Intermediate changes with progressed until THR was re- moderate sclerosis and joint nar- quired, and one who had a de- rowing (<50%) is given fair. Ad- layed reduction of a hip disloca- vanced changes are given poor. tion and had the development of osteonecrosis requiring THR. The clinical outcome scores were collapsed from five to four The final radiographic results correspondig categories (excellent, were graded as excellent in four-

422 Benha M. J. Vol. 29 No 1 Jan. 2012 teen hips, good in one, fair in one - No patient had evidence of and poor in two. heterotopic ossification. - No iatrogenic nerve injuries. Heterotopic ossification was - D.V.T occurred in one patient. graded as class zero (absent ) in This patient after medical thirteen patients. treatment required the use of Class I in three and class II in pressure stocking. two patients. Factors that were found to con- Complications :- tribute to fair and poor results - One deep wound infection. were : - Two superficial infection. - Older age at the time of injury. The result after the deep infec- - Delayed in the time to re- tion was poor despite multiple ag- duction of the hip disloca- gressive debridements. tion of more than twelve - No patient had evidence of hours. penetration of the acetabular - Intra-articular comminution. articular surface. - Osteonecrosis.

423 Mohamed El-Menawy

Case 1: Male patient Twenty-four years old

Fig. 1: Pre op. x-ray. Fig. 2 : Pre op. CT showing posterior wall fracture with posterior wall fragment about 50%.

Fig. 3: Post op. x-ray.

424 Benha M. J. Vol. 29 No 1 Jan. 2012 Case 2 : Male patient Thirty-seven years old

Fig. 4 : pre op. x-ray. Fig. 5 : pre op. CT. showing posteri- or wall fracture of the acet- abulm with posterior sub- laxation of femoral head.

Fig. 6 : post op. x-ray.

Discussion The main indication for open The complex nature of posterior reduction and internal fixation of wall fractures of the acetabular a posterior fracture of the acetab- relative to their simple radiograph- ulum is hip instability, which can ic and the disparity between the be identified in several ways. Pa- accuracy of surgical fracture re- tients presenting with a hip dislo- duction (as determined, on plain cation should treated with emer- post operative radiographs) and gent reduction. Patients exhibiting clinical outcome were well de- gross instability on physical exam- scribed(12). ination after closed reduction,

425 Mohamed El-Menawy defined as joint instability occur- termine factors, other than the ap- ring at ≤ 40° of the hip flexion(6) pearance on immediate postopera- are treated operatively. Letournel tive plain radiographs, that may and Judet(1) Found that despite contribute to unsatisfactory clini- obtaining a perfect reduction in cal results. Our study showed 94% of posterior wall fractures of some prognostic factors including acetabulum, only 82% had good to delay of greater than twelve hours excellent clinical results. before the reduction of hip dislocation, age of more than fifty- five They attributed this disparity and the quality of fracture reduc- to the occurrence of osteonecrosis tion. Sever intra-articular commi- and to the fact that reconstruction nution was an additional prognos- of the severely comminuted frac- tic risk factors. tures was difficult to perform. Olson S A, et al (15) stated that In Matta’s series which includ- marked alteration in the mechan- ed twenty- two posterior wall frac- ics of load transmission across the tures, although the reduction of hip joint occurs after a fracture of all fractures over anatomic only the posterior wall of the acetabu- (68%) had a good to excellent clin- lum. ical results, Matta(9) suggested that three may be imperfections in Anatomic reconstruction of the the articular surface. acetabular articular surface remains the surgical goal. The satis- Other investigators (13,14) re- factory clinical results reported in ported up to 85% good to excel- our study support the opinion lent clinical score, which paral- that it is the actual healing of the leled the accuracy of the fracture fracture in an anatomic position reduction. that ultimatel. Restore hip joint mechanics(16). Our study was done to evaluate the results of the operatively treat- Conclusion ed posterior wall fractures of the - The main indication for open acetabulum in an attempt to de- reduction and internal fixation of

426 Benha M. J. Vol. 29 No 1 Jan. 2012 a posterior wall fracture of the ac- ed tomographic assessment of etabulum is hip instability. fractures of the posterior wall of the acetabulum after operative - Dynamic fluoroscopic stress treatment. J Bone Joint surg Am.; examination of the hip should be 85:512-22. performed with the patient under general anesthesia to identify in- 3- Baumgaertner M. R. stability requiring surgical treat- (1999): Fractures of the posterior ment. wall of the acetabulum. J AM Acad Orthop surg.; 7:54-65. - Accurate anatomic reduction of the fracture and rigid fixation is 4- Moed B. R. (2006) : Ace- mandatory to obtain better re- tabular fractures : Kocher- sults. Langenbeck approach. In : Wiss - Nerve injury is a serious DA, editor. Master techniques in complication of this procedure orthopedic surgery : fractures. and should be avoided as possi- 2nd ed.Philadelphia: Lippincott ble. Williams and Wilkins; p 685-709.

- Hardware must be placed in 5- Calkins M. S., Zych G., close proximity to the joint surface Latta L., Borja F. J. and Mnaym- in order to obtain stable fixation. neh W. (1988) : Computed tomography evaluation of stability in References posterior wall fracture dislocation 1- Letournel E. and Judet R. of the hip. Clin Orthop.; 227:152- (1993) : Fractures of the acetabu- 63. lum. Elson RA, editor and translator. New York: Springer; p 6- Vailas J. C., Hurwitz S. 29-43, 364-73, 417-21, 545-51, and Wiesel S. W. (1989) : Poste- 565-81, 583-90. rior acetabular fracture disloca- tions: fragment size, joint capsule, 2- Moed B. R., Willson Carr and stability. J Trauma.; 29149-6. S. E., Gruson K. I., Watson J. T. and Carig J. G. (2003) : Comput- 7- Tometta P. (1999) : 3rd.

427 Mohamed El-Menawy

Non-operative management of ace- Lee S. H., Maloney W. J., Papro- tabular fractures. The use of dy- sky W. G., Steinberg M. E. and namic stress views. J Bone Joint Wasielewski R. C. (1999) : Hip Surg Br.;81:67-70. and pelvis reconstruction. In: Beaty JH, editor. Orthopedic 8- Aho A. J., Isberg U. K. and Knowledge update 6. Rosemont, karevuo V. K. (1986) : cetabular IL: American Academy of Ortho- posterior wall fracture. 38 cases paedic Surgons; P455-92. followed for 5 years. Acta Orthop scand.; 57:101-5. 13- Larson C. B. (1973) : Fracture dislocation of The hip 9- Matta J. M. (1996) : Frac- Cin orthp Relat Res.;92:147-54. tures of the acetabulum: accuracy of reduction and clinical results in 14- Pantazopoulos T., Nicolo- patient managed operatively with- poulos C. S., Babis G. and Theo- in three weeks after the injury. J doropoulos T. (1993) : Surgical Bone Joint Surg AM.;78:1632-45. treatment of acetabular posterior wall fractures. Injury.; 24 : 319- 10- Saterback A. M., Marsh 23. J. L., Nepoa J. V., Brandser E. and Turbett T. (2002) : Clinical 15- Olson S. A., Bay B. K., failure after posterior wall acetab- Chapman M. W. and Sharkey N. ular fractures:the influence of ini- A. Biomechanical consequences of tial fracture patterns. J Orthop fracture and repair of posterior Trauma.;14:230-7. wall of the acetabulum. J Bone Joint Surg AM. 11- Olson S. A. and Finke- meier C. G. (1999) : Posterior 16- Moed B. R. and McMi- wall fractures. Op Tech Orthop.; chael J. C. (2007) : Outcomes of 9:148-60. posterior wall fractures of the acetabulum. J Bone Joint surg Am.; 12- Berry D. J., Garvin K. L., 89 : 1170-6.

428 Benha M. J. REPRINTVol. 29 No 1 Jan. 2012 BENHA MEDICAL JOURNAL

SURGICAL TREATMENT OF POSTERIOR WALL FRACTURES OF THE ACETABELUM

Mohamed El-Menawy MD

Published by Benha Faculty of Medicine Volume 29 Number 1 Jan. 2012

429 Benha M. J. Vol. 29 No 1 Jan. 2012 DEXMEDETOMIDINE, FENTANYLE AND KETAMINE PROVIDE DEEP SEDATION FOR DEBRIDEMENT AND DRESSING OF HAND SPACE INFECTION

Doaa G. Diab MD, Enas Abd El-Motlb MD and Hosam Ghazy MD* Departments of Anesthesiology, Surgery*, Faculty of Medicine, Mansoura Univresity, Egypt

Abstract Background: Dexmedetomidin is a specific α2-receptor agonist, used to reduce anxiety and tension, and to promote relaxation and sedation with hemodynamic stability beside the postoperative analgesia. This controlled randomized study compared the effect of dexmedetomidine alone, and when combined with fentanyl or ketamine as sedative analgesic regimen for pain management during debridement and dressing of hand space infection. Method: All patients received infusion of dexmedetomidine (0.5ug/ kg) ten minutes before dressing. Then DS group (n=20) received isotonic saline intravenous. DF (n=20) group received fentanyl 1ug/kg intravenous. DK (n=20) group received ketamine 1mg/kg intravenous. Patients were monitored for mean blood pressure, peripheral arterial oxygen saturation, heart rate, end-tidal Co2 and end-tidal concentration of sevoflurane. Pain score (VAS), sedation score (from 0 to 5) and recovery time were recorded. Results: Significant decrease in heart rate and blood pressure was noted 10 minutes after DEX infusion in the three groups. This significance was lost 10 minutes after ketamine injection in DK group. Pa- tients of DK group scored a significant lower pain score and higher sedation score (1 and 2 h postoperative), beside a significant longer time for eye opening in comparison with other groups. DEX-Ketamine regimen recorded a higher degree of acceptance by both patient and the surgeon in comparison with other groups.

429 Doaa G. Diab, et al....

Conclusion: DEX- Ketamine regimen provided higher sedation and lower hemodynamic discrepancy during debridement and dressing of hand space in comparison with DEX- Fentanyl regimen. Key Words: Hand infection, dexmedetomidine, sedation.

Introduction tion, bacteriology and X-ray- Hand injuries lead to high examination; then surgical inter- incidence of hand infections. vention including incision, irriga- The clinical signs of inflammation, drainage, excision of necrosis tion as pain, swelling, heat, and foreign bodies, early move- limitation of function and redness ment combined with ergotherapy are the most common presenta- and physiotherapy. Use of antibio- tion in all patients. More severe tics is indicated in sepsis, lym- are infections of tendon sheath, phangitis, osteomyelitis. If pus is joint, web space and deep palmer present in such cases there is no space (1). place for conservative treatment but operative treatment is Impera- Less common causes of hand tive (3). pain include atypical mycobacteri- al infection, occult fractures, bone Patients suffering from hand fragments, carpal ligament inju- infection commonly experience ries and tendinitis. Also, the dia- high levels of pain and anxiety, betic hand infection is less report- particularly during dressing and ed. Therefore, it is easily ignored debridement(4). Pain experienced and underestimated resulting in may be divided into a "back- increased morbidity. Diabetic ground" pain and a "break- hand is rapid in progression, ex- through" pain that associated with tensive with severe tissue destruc- the painful procedures. While the tion (2). background pain may be treated with opioids either intravenous or Treatment protocol of hand oral, breakthrough pain may be infections depends on the clini- treated with a variety of interven- cal picture, laboratory investigations (5).

430 Benha M. J. Vol. 29 No 1 Jan. 2012 Sedation for surgical proce- pain management during debride- dures can be achieved with a ment and dressing of hand space variety of intravenous medica- infection. tions, such as benzodiazepines, barbiturates, and propofol. That is Patients and Methods because, these agents produce The study was conducted at dose-related sedation as well as Mansoura University Principal amnesia and anxiolysis(6). Hospital.

Regarding analgesia, alterna- 60 ASA physical statuses I and tive methods may be beneficial to II adult patients suffering from avoid the known side effects and hand space infection who admit- complications of opioids, Local an- ted for debridement and dressing; aesthetic infusion either into the will be included in the study. After wound or as a local nerve block Individual informed written con- also used(7). sent, Patients will be randomly divided into three groups via sealed Dexmedetomidin is a specific envelope assignment. α2-receptor agonist, used to reduce anxiety and tension, and to General anaesthesia will be promote relaxation and sedation conducted by thiopental sodium with hemodynamic stability (8). 5mg/kg and vecuronium 0.1mg/ Dexmedetomidine was used to in- kg, then the patient will be intu- duce postoperative analgesia and bated and anesthesia will be reduce the use of postoperative maintained by sevoflurane 2% morphine (9). MAC (variable to maintain the hemodynamic within 20% of the ba- Objective: sal values) and vecuronium to This is a controlled randomized maintain muscle relaxation. study will be conducted to compare the effect of dexmedetomi- All patients will receive infu- dine alone, and when combined sion of dexmedetomidine (0.5ug/ with fentanyl or ketamine as kg) ten minutes before dressing. sedative analgesic regimen for Then DS group (n=20) will receive

431 Doaa G. Diab, et al.... isotonic saline intravenous. DF cases then baking of the wound (n=20) group will receive fentanyl was done. 1ug/kg intravenous. DK (n=20) group will receive ketamine At the end of the surgery and 1mg/kg intravenous. Patients will discontinuation of the inhalational be monitored for mean blood pres- anaesthesia, neuromusculare sure, peripheral arterial oxygen blockade will be reversed by atro- saturation, heart rate, end-tidal pine 0.02mg/kg and neostigmine Co2 and end-tidal concentration 0.04mg/kg, tracheal extubation of sevoflurane and recovery time and transfer to the PACU. Post- will be recorded. operative observation and monitoring for nausea and vomiting. Patients will be instructed on Patients' and surgeons' satisfac- the use of visual analogue scale tion also will be recorded. (VAS) self rating method. All patients used a 10 cm VAS device to The statistical analysis of data assess the level of pain (0= no done by using excel program for pain; 10= worst possible pain). Se- figures and SPSS (SPSS, Inc, dation will be assessed on a five Chicago, IL). program Statistical point scale( 0= no sedation- pa- Package for Social Science ver- tient wide awake and alert; 4= sion 16. deep sleep- difficult to arouse). Pain and sedation were assessed The description of the data by an assistant at 1, 2, 4, 6, 12 done in form of mean (+/-) SD for hours postoperatively. quantitative data .And Frequency & proportion for Qualitative data. All cases will be operated for drainage through generous The analysis of the data was incision of the skin associated done to test statistical significant with breaking of the subcutane- difference between groups. ous fibrous septa for free drainage and excision of necrotic For quantitative date student tissues. Wash with hydrogen per- t-test was used to compare be- oxide 5% was indicated in some tween two groups.

432 Benha M. J. Vol. 29 No 1 Jan. 2012 Chi square test was used for sion (Table 3). This significance qualitative data. was lost 10 minutes after ketamine injection in DK group, but N.B: P is significant if < or = continued in DS group for 10 0.05 at confidence interval 95%. minutes after saline injection and for 20 minutes after fentanyl in- Results jection in DF group. The characteristics of the 60 patients who completed the study Patients in DK group showed a are summarized in table (1). Dem- significant lower pain score (using ographic characteristics (age, the visual analogue scale) and a weight, sex) were similar among significant higher sedation score the groups. at 1 and 2 hours postoperative in comparison with the other groups The heart rate was decreased (DS, DF). Similarly, DF group has significantly in the three groups a significant lower pain score (at 10 minutes after DEX infusion, 1h, 2h) and significant higher se- this significant drop continues for dation score at 1 hour postopera- another 10 minutes after saline tive in comparison with DS group injection in DS group and for 20 (Table 4 & 5). A significant longer minutes after fentanyl injection in time for eye opening was noted DF group. Heart rates in DF group with DK group. was significantly decreased in comparison with DS group 10 The surgeon's opinion was in minutes after fentanyl injection; agreement with opinion of pa- whereas the DK group showed sig- tients. Nearly all patients of DK nificantly increased heart rates in group (19 patients) were very sat- comparison with the other groups isfied and accepted to repeat the (DS, DF) for 20 minutes after keta- same technique if a similar sur- mine injection (Table 2). gery is needed in the future. One patient in DF group who exposed A significant drop in mean to nausea and vomiting, refuse blood pressure was noted in all the technique due to the bad ex- groups 10 minutes after DEX infu- perience.

433 Doaa G. Diab, et al....

434 Benha M. J. Vol. 29 No 1 Jan. 2012

435 Doaa G. Diab, et al....

Discussion effects (13). In the same context, Dexmedetomidine (DEX) is a Arain et al 2004reported an ad- highly selective and specific α2- vantage for DEX over midazolam adrenergic agonist which is char- as the former decreases the anes- acterized by rapid tissue distribu- thetic and opioid requirements tion and short half life enabling it without increasing the respiratory to induce controlled postoperative depressant effect of opioids(14). sedation and analgesia(10,11). This randomized double blinded Moreover; DEX blunts the sympa- design study evaluates the added thetic mediated hyperdynamic benefits and side effects resulting response to surgical stress and from the use of DEX in combina- tracheal intubation(12). In com- tion with either ketamine or fenta- parison with midazolam; Koroglu nyl in comparison with the use of et al 2005 concluded that, DEX DEX alone in patients undergoing produces more sedation but simi- debridement and dressing of hand lar respiratory and hemodynamic space infection which is a painful

436 Benha M. J. Vol. 29 No 1 Jan. 2012 procedure and may require an op- of DEX. Patients in DK group erating room environment. lost the significant hemodynamic changes ten minutes after keta- DEX in a bolus dose of 1 µg/kg mine injection in comparison with over ten minutes results in a bi- basal value, while they gain signif- phasic hemodynamic response in icant elevation of heart rate and the form of reflex bradycardia and mean blood pressure in compari- a transient increase in blood pres- son with DF group. Push and pull sure(15). This increase in blood between ketamine and DEX can pressure starts one minute after be an explanation. DEX may pre- bolus injection and is explained by vent tachycardia and hyperten- the direct effects of α2- adrenocep- sion associated with ketamine. tor stimulation of vascular smooth While ketamine may prevent brad- muscle. Then, this direct effect on ycardia and hypotension which vasculature is overcome by inhibi- has been reported with DEX. tion of sympathetic outflow(16). However, Mauricio et al 2004 re- Because of the much higher se- ported that the preoperative ad- lectivity of DEX for α2 adrenocep- ministration of 1 αg/kg in 10 min- tor than other known agonist like utes resulted in <20% reductions clonidine, it can produce dose de- of HR and MAP in adults(17). pendant analgesia at spinal and supra-spinal sites without respira- All patients in the three groups tory depression(18 &19). showed significant drop of heart rate and mean blood pressure ten Ketamine is an agent that can minutes after DEX infusion. be used in burn patients for Twenty minutes after bolus fenta- achieving intra-operative and nyl, the significant decreased post-operative analgesia(20). Hum- heart rate and mean blood pres- phries et al 1997 reported better sure continued, while this signifi- analgesia and sedation with oral cance was lost twenty minutes af- ketamine compared with other ter saline injection in DS group, narcotics and sedatives during this potentiation of opioid is in wound care procedures in chil- line with the opioid sparing effect dren with burn(21). Similarly, Ow-

437 Doaa G. Diab, et al.... ens et al 2006 concluded that ket- tripsy(24). Both groups showed amine is effective and safe for bed- equally effective sedation with no side procedures in burn patients significant changes in hemody- with the advantage of preservation namic and respiratory parame- of airway patency and respira- ters, but the time for eye opening, tory function(22). This action of verbal response and cooperation ketamine can be explained by were significantly decreased in the N-methyl-D- aspartate (NMDA) DEX- ketamine group. receptor antagonism, opioid receptor antagonism, and voltage- In agreement with the results sensitive sodium channel interac- of Koruk et al 2010, our study tions(5& 23). reported a significant high level of sedation in DK compared with In this study, the DK group has other groups. Also, patients re- a significant lower pain score at 1 ceived DEX- fentanyl regimen and 2 hours postoperative in com- showed a significant higher level parison with other groups. At the of sedation in comparison with same time, DF group showed a DS group at 1 hour. The time for significant lower pain score in eye opening in DK group was comparison with DS group at 1 significantly longer than other and 2 hours, this potentiation of two groups which may be due analgesic effect of fentanyl is in to longer sedative effect of keta- line with the well known DEX opi- mine compared with fentanyl oid sparing effect(10&11). which has shorter duration of action(25). There are some reports in the literature about the use of DEX in The DEX-ketamine regimen combination with ketamine for has the consent of nearly all pa- procedural sedation. In this con- tients of this group as well the text, Koruk et al 2010 compared surgeon. The reported nausea and sedation using either regimen of vomiting in some cases of DEX- DEX and ketamine or regimen of fentanyl group may be the cause ketamine and midazolam during of less acceptance in comparison extracorporeal shock wave litho- with the former.

438 Benha M. J. Vol. 29 No 1 Jan. 2012 In conclusion, in patients un- aesthesiol Clin Pharmacol. Apr- dergoing debridement and dress- Jun; 27(2):220-4. ing of hand space infection, although both regimens , viz., DEX- 5- Gregoretti C., Decaroli D., ketamine and DEX- fentanyl, pro- Piacevoli Q., et al. (2008) : Anal- vide effective sedoanalgesia with- go - sedation of patients with out causing significant side ef- burns outside the operating room. fects, the former offered higher Drugs.; 68(17): 2427-43. sedation and lower hemodynamic discrepancy. 6- Ibrahim A. E., Ghoneim M. M., Kharasch E. D., et al. Referances (2001) : Speed of recovery and 1- Troeger H. (1995) : Infec- side effect profile of sevoflurane tion of the hand. Ther Umsch. sedation compared with midazo- Jan; 52 (1):75-81. lam. Anesthesiology; 94: 87-94.

2- Jalil A., Barlaan P. I., Fung 7- Dexmedetomidine (2008) : B. K., et al. (2011) : Hand infec- sedation, analgesia and beyond. tion in diabetic patients. Hand Expert Opin drug Metab Toxicol.; Surg.; 16(3): 307-12. 4: 619-27.

3- Imakado S., Kojima Y., 8- Ohtani N., Kida K., Shoji Hiyoshi T., et al. (2009) : Dis- K., et al. (2008) : Recovery pro- seminated mycobacterium mari- files from dexmedetomidine as a num infection in a patient with di- general anesthetic adjuvant in pa- abetic nephropathy. Diabetes Res tients undergoing lower abdominal Clin Pract; 83:e35-e36. surgery. Anesth Analg. Dec; 107 (6): 1871-4. 4- Gunduz M., Sakalli S., Gunes Y., et al. (2011) : Compa- 9- Horvath G., Joo G., Dobos resion of effects of ketamine, I., et al. (2001) : The synergistic ketamine - dexmedetomidine and antinociceptive interactions of en- ketamine - midazolam on dressing domorphin-1 with dexmedetomi- changes of burn patients. J An- dine and/or S (+)- ketamine in

439 Doaa G. Diab, et al.... rats. Anesth Analg.; 93: 1018-24. British Journal Of Anaesthesia; 94 (6) : 821- 824. 10- Jyrson G., Klamt, Walter V., Vicente, Luis V. Garcia, 14- Arain S. R., Ruehlow R. et al. (2010) : Effects of Dexmede- M., Uhrich T. D., et al. (2004) : tomidine- Fentanyl Infusion on The efficacy of dexmedetomidine Blood Pressure and Heart Rate versus morphine for postoperative during Cardiac Surgery in Chil- analgesia after major inpatient dren. Anesthesiol Res Pract; surgery. Anesth? Analg; 98(1): 869049. 153-158.

11- Gerlach A. T. and Dasta 15- Dyck J. B., Maze M., J. F. (2007) : Dexmedetomidine: Haack C., et al. (1993) : The an updated review. Annals of pharmacokinetics and hemody- pharmacotherapy; 41 (2) : 245- namic effects of intravenous and 254. intramuscular dexmedetomidine hydrochloride in adult human 12- McCutcheon C. A., Orme volunteers. Anesthesiology; 78 : R. M., Scott D. A., et al. (2006) : 813-20. A comparison of dexmedetomidine versus conventional therapy 16- Shahbaz R. and Thomas for sedation and hemodynamic J. (2002) : The efficacy, side ef- control during carotid endarterec- fects and recovery characteristics tomy performed under regional of dexmedetomidine versus pro- anesthesia. Anesth. & Analg.;102 pofol when used for intraoperative (3): 668-675. sedation. Anesth Analg; 95(2); 46- 466. 13- Koroglu A., Demirbilek S., Teksan H., et al. (2005) : 17- Mauricio E., Hernan R., Sedative, haemodynamic and Verena B., et al. (2004) : Single- respiratory effects of dexmede- dose dexmedetomidine reduces tomidine in children undergoing agitation after sevoflurane anes- magnetic response imaging ex- thesia in children. Anesth Analg; amination : preliminary results. 98:60- 63.

440 Benha M. J. Vol. 29 No 1 Jan. 2012 18- Peden C. J. and Prys- 22- Owens V. F., Palmieri T. Roberts C. (1992) : Dexmedetom- L., Comroe C. M., et al., (2006) : idine- a powerful new adjunct to Ketamine: a safe and effective anesthesia? Br J Anaesth.; 68: agent for painful procedures in 123- 5. the pediatric burn patient. J Burn Care Res.; 27:211-6. 19- Aantaa R., Kanto J., Scheinin M., et al. (1990) : Dex- 23- Smith D. J., Bouchal R. medetomidine, an alpha 2- adren- L., Monroe P. J., et al. (1987) : oceptor agonist, reduces anesthet- Properties of the interaction be- ic requirements for patients tween ketamine and opiate bind- undergoing minor gynecological ing sites in vivo and in vitro. Neu- surgery. Anesthesiology.; 73 : 230- ropharmacology.; 26 : 1253- 60. 235. 24- Koruk S., Mizrak A., Gul 20- Murat G., Sefika S., Yase- R., et al. (2010) : Dexmedetomi- min G., et al. (2011) : Compari- dine- Ketamine and midazolam- son of effects of ketamine, keta- ketamine combinations for seda- mine- dexmedetomidine and tion in pediatric patients under- ketamine- midazolam on dressing going extracorporeal shock wave changes of burn patients. J Anes- lithotripsy. A randomized pros- thesiol Clin Pharmacol. Apr- Jun; pective study. J Anesth.; 24 : 858- 27(2): 220-224. 63.

21- Humphries Y., Melson M. 25- Sukhminder B., Sukh- and Gore D. (1997) : Superiority minder K. and Jasbir K. (2010) : of oral ketamine as an analgesic Comparison of two drug combina- and sedative for wound care pro- tions in total intravenous anesthe- cedures in the pediatric patient sia: propofol- ketamine and pro- with burns. J Burn Care Rehabil.; pofol- fentanyl. Saudi J Anaesth.; 18: 34- 6. 4(2): 72-79.

441 REPRINTDoaa G. Diab, et al.... BENHA MEDICAL JOURNAL

DEXMEDETOMIDINE, FENTANYLE AND KETAMINE PROVIDE DEEP SEDATION FOR DEBRIDEMENT AND DRESSING OF HAND SPACE INFECTION

Doaa G. Diab MD, Enas Abd El-Motlb MD and Hosam Ghazy MD

Published by Benha Faculty of Medicine Volume 29 Number 1 Jan. 2012

442 Benha M. J. Vol. 29 No 1 Jan. 2012 BALLOON DISSECTION FOR EXTRAPLEURAL APPROACH IN (TRACHEO-ESOPHAGEAL FISTULA) TEF REPAIR

Basem Saied MD, Adham Elsaied MD and Hesham Sheir MD Departments of P Pediatric Surgery, Mansoura University Children’s Hospital, Mansoura Faculty of Medicine, Mansoura, Egypt

Abstract Purpose: Esophageal atresia is a relatively common congenital malformation. The extrapleural approach is preferred to transpleural in thoracotomy because the anastomosis is outside the pleural cavity. This study describes an easy way for performing extrapleural dissection. Methods: A novel technique for extrapleural dissection was performed for 16 patients with TEF/EA. It depends on using Foley’s catheter in dissection. The balloon of the catheter is inflated gradually after introducing the catheter’s tip between the pleura and the thoracic wall. By gradual increase of the size of the used catheter (10 F- 14 F) the pleura is dissected easily away from the chest wall. Results: By comparing this technique with usual methods of pleural dissection, the operative time for this part of operation is reduced significantly, the incidence of pleural tear is diminished, moreover it is more easy than the traditional long tedious and careful dissection. Conclusion: Balloon dissection makes extrapleural approach easier with less complications. Keywords: Tracheo-esophageal fistula, Esophageal atresia and Ex- trapleural thoracotomy .

Introduction constituting a TEF (1). It is a rela- Esophageal atresia (EA) is a tively common congenital malfor- congenital anomaly in which there mation occurring in 1:3000-4500 is a blind ending upper esophagus live births (2-4). The etiology of the and the distal esophagus com- anomaly is likely to be multifacto- monly connects to the trachea rial. The familial/syndromic cases

443 Basem Saied, et al.... represent less than 1% of the total and pleural tears during such dis- whereas the overwhelming majori- section are not an unusual event. ty of cases are sporadic/ Consequently, a novel method is nonsyndromic (5). described in this study using the balloon of Foley's catheter to push Surgery for TEF/EA is urgent the pleura away from the chest to prevent aspiration and respira- wall in easy manner and short tory complications. Surgery is time. usually performed on the first or second day of life after echocardiography and evaluation of co- Patients and Methods morbidities. The procedure in- This study included 16 patients volves fistula ligation and esopha- diagnosed as esophageal atresia geal anastomosis (6). The standard with distal tracheoesopageal fistu- approach is a right posterolateral, la (TEF/EA); managed at Pediatric muscle-sparing thoracotomy in Surgery unit and Neonatology unit the 4th intercostals space (2,7). in Mansoura University Children The extrapleural approach is pre- Hospital, Mansoura, Egypt. ferred by most pediatric surgeons because possible substantial The cases were included in the anastomotic leak will not be com- study randomly as regard age, plicated by empyema but causes sex, body weight and severity of an esophagocutaneous fistula, associated anomalies. They were which closes in 1-2 weeks. Howev- subjected to the usual screening er, those who use transpleural for associated anomalies and were route argue that the operative diagnosed by history of drooling time is shorter and the risk of and chocking with attempted feed- empyema after leak is minimal ing, failure to pass Ryle tube No. 8 with the current antibiotics cover- F, and plain X-ray chest showing age (8). the kinked Ryle tube at the upper esophagus. Preoperative prepara- Tedious dissection of the pleura tion included routine investiga- is almost always needed for extra- tions, stabilization of respiratory pleural approach of the esophagus condition, prophylactic antibiotics,

444 Benha M. J. Vol. 29 No 1 Jan. 2012 and preparation of 200 cc packed tal muscles till the azygus vein be- RBCs. came visible. Intraoperative pleural tears were reported; those that The standard posterolateral were 2 cm or less were considered thoracotomy through the 4th in- as minor tears and others decided tercostal space was used for the to be considered as major tears. surgical approach. The intercostal The patients were followed postop- muscles were divided and minimal eratively by regular chest exami- dissection was performed cau- nation and plain X-ray chest after tiously by a wet piece of gauze to 5 days looking for postoperative slightly separate the ribs and to pleural complications. create a space to introduce a catheter (Fig. 1). The tip of a Foley's Results catheter No. 10 F was introduced Sixteen patients (11 males and between the pleura and the rib- 5 females) with TEF/EA were in- cage. The balloon of the Foley's cluded in the study. Three cases catheter was inflated by 10 cm sa- were operated at age of 2 days line (Fig. 2, 3). Then, the balloon while one case was operated at was deflated and the catheter was age of 8 days. The rest of cases fall removed and the procedure was in between with the mean age at repeated using Foley's No 12 F time of operation was 4 days. and 14 F inflated with 20 and 30 Other associated anomalies were cm saline respectively until the reported in 7 cases (43.7%) with pleura was separated from the rib cardiac anomalies being the com- cage and the azygus vein became monest as they were reported in 4 visible (Fig. 4). The operation is cases (25%). completed as usual and a Nelaton catheter No 18 F was inserted in The operative time for pleural the chest outside the pleura as a dissection, using the balloon of drain at the end of the operation. Foley's catheters was calculated and the results were divided in 3 The time used for pleural dis- groups. Pleural dissection was ac- section was calculated beginning complished within 2-4 minutes in after finishing division of intercos- 7 cases (43.75%); on the other

445 Basem Saied, et al.... hand, more than 6 minutes were minor tears occurred in the pleura needed for such purpose in 2 cas- and they were left to heal alone. es (12.5%). The other 7 cases Major pleural tears did not occur (43.75%) needed 4-6 minutes for in any cases. The postoperative dissection (Table 1). The shortest follow up revealed no pleural com- time needed for balloon dissection plications in the form of pleural ef- of the pleura was 2 minutes and fusion, empyema or pneumotho- 47 seconds (167 seconds) whereas rax in any case (Table 2). the longest time was 6 minutes Anastomotic leak occurred in 3 and 18 seconds (378 seconds) cases (18.7%). They all develop with the mean dissection time was esophagocutaneous fistula that 266.4 seconds. were managed conservatively and closed in 7-10 days. These 3 cases A single minor pleural tear (2 didn't develop signs of sepsis and cm or less) occurred during dis- didn't need aggressive antibiotic section in one case and was ap- regimens. Otherwise, the postop- proximated by one Vicryl 5/0 su- erative clinical course of all cases ture. In another case, 3 separate was uneventful.

446 Benha M. J. Vol. 29 No 1 Jan. 2012

Fig. 1 : Minimal dissection of Fig. 3 : Pleura is separated the pleura. from the ribs.

Fig. 2 : Filling of the balloon of Fig. 4 : Intact pleura com- Foley's catheter be- pletely separated from tween the pleura and chest wall the ribcage.

447 Basem Saied, et al....

Discussion time of operation was 4 days. This Esophageal atresia (EA) is the is mostly because of delayed refer- most common congenital anomaly ral of some cases from other cen- of the esophagus. The survival of tres. these patients improved markedly over the last two decades as a re- Extrapleural approach is pre- sult of advances in neonatal inten- ferred nowadays by most pediatric sive care, neonatal anesthesia, surgeons; however it needs long ventilatory and nutritional sup- time and tedious dissection (8). In port, antibiotics, early surgical in- this study, such dissection was fa- tervention, surgical materials and cilitated by using the balloon of techniques(9). Associated con- Foley's catheter. The time needed genital anomalies occur in 40- for this task ranged from 2.5 to 6 60% of infants with oesophageal minutes with the mean time being atresia (10,11,12). Similarly, other about 4.5 minutes. So, this way of major birth defects were reported dissection obviously overcomes in 43.7% of the cases included in the drawback of lengthy tradition- this study. Cardiac anomalies de- al extrapleural dissection and tected in 25% of cases and were omits personal variation as well. found to be the commonest asso- Moreover, major pleural tears dur- ciation. This agrees with Chittmi- ing dissection didn't occur in any trappap et al., 1989 (13) who re- case and only minor tears were reported 29% co-incidence of ported in 2 cases only and didn't cardiac malformations. affect the postoperative outcome.

The ideal time for primary re- Anastmotic leaks occur in 14- pair is when the condition of the 21% of patients with EA (8,15-17). child is stable and the baby is fit Our 18.7% incidence of anastmot- for general anesthesia (14). Hosie ic leak falls within the same and Short, 2010 (1) suggested that range. McKinnon and Kosloske, the patient is stabilized and so the 1990(16) reported that the route surgery can be planned usually of repair (transpleural or retro- within the first 48 hours. In the pleural) didn't affect the inci- present study the mean age at dence of anastomotic complica-

448 Benha M. J. Vol. 29 No 1 Jan. 2012 tions. Moreover, Bishop et al, ner without incidence of signifi- 1985 (15); who used the trans- cant pleural tears. Moreover, it pleural approach and reported improves the outcome of possible 20% incidence of anastmotic leak, postoperative anastomotic leak found that the leak related mortal- without adding to the patient's ity falled from 88% during the pe- morbidity or the hospital cost. riod between 1951-1963 to 0% from 1974 to 1983. This is obvi- Referrences ously related to the development 1. Hosie G. P. and Short M. of more effective antibiotics. How- (2010) : Oesophageal atresia. Sur- ever, with transpleural approach gery; 28 (1): 38-42. anastmotic leaks may be complicated by empyema or tension 2. Spitz L. (2007) : Oesopha- pneumothrax (8) which add to the geal atresia. Orphanet J Rare Dis; morbidity of the patient and to the 2:24. hospital cost using more aggressive antibiotic regimens. On the 3. Goyal A., Jones M. O., other hand, with extrapleural ap- Couriel J. M. and Losty P. D. proach and a patent mediastinal (2006) : Esophageal atresia and drain, up to 95% of anastmotic tracheo-esophageal fistula. Ar- leaks close spontaneously(18). In chives of Disease in Childhood. the present study, all anastmotic Fetal and Neonatal Edition; 91: leaks closed smoothly without ad- 381-384. ditional morbidity and with the usual antiobiotics used in the 4. De Paepe A., Dolk H., Le- postoperative care of such condi- chat M. F., EUROCAT Working tion. Group. (1993) : The epidemiology of tracheo-oesophageal fistula and Conclusion oesophageal atresia in Europe. Balloon dissection is a valuable Arch Dis Child; 68:743-748. addition to management of esophageal atresia. It accomplishes 5. Spitz L. (2006) : Esopha- pleural separation from the rib- geal atresia: Lessons I have cage in short time and easy man- learned in a 40-year experience. J

449 Basem Saied, et al....

Pediatr Surg; 41: 1635-1640. atresia. Teratology; 52:220-232.

6. Knottenbelt G., Skinner 11. Garne E., Rasmussen L. A. and Seefelder C. (2010) : Tra- and Husby S. (2002) : Gastroin- cheo-oesophageal fistula and oe- testinal malformations in Funen sophageal atresia. Best Practice& County, Denmark-epidemiology, Research Clinic Anaeseth; 24 : associated malformations, surgery 387-401. and mortality. Eur J Pediatr Surg; 12:101-106. 7. Holland A. J. and Fitzge- rald D. A. (2010) : esophageal 12. Sparey C., Jawaheer G., atresia and tracheo-oesophageal Barrett A. M. and Robson S. C. fistula current management strat- (2000) : Esophageal atresia in the egies and complications. Pediatr Northern Region Congenital Resp Rev; 11 (2): 100-106. Anomaly Survey, 1985-1997: prenatal diagnosis and outcome. Am 8. Harmon C. M. and Coran J Obstet Gynecol; 182:427-431. A. G. (2006) : Congenital anomalies of the oesophagus. In: Gros- 13. Chittmitrappap S., Spitz feld JL, O'Neill JA, Fonkalsrud L., Kiely E. M. and Brereton R. EW, Coran AG, eds. Pediatric Sur- J. (1989) : Oesophageal atresia gery. Philadelphia: Mosby Elsevi- and associated anomalies. Arch er,; Chapt. 67: 1051-1081. Dis Child; 64:364-368.

9. Pinheiro P. F., Silva A. C. 14. Gupta D. K. and Sharma and Pereira R. M. (2012) : Cur- S. (2008) : Esophageal atresia: rent knowledge on esophageal the total care in a high-risk popu- atresia. World J Gasrtroenterol; lation. Seminars in Pediatr Surg; 18 (28) : 3662-3672. 17 (4): 236-243.

10. Torfs C. P., Curry C. J. 15. Bishop P. J., Klein M. and Bateson T. F. 1995) : Popu- D., Philippart A. I., Hixson D. S. lation-based study of tracheoe- and Hertzler J. H. (1985) : sophageal fistula and esophageal Transpleural repair of esophageal

450 Benha M. J. Vol. 29 No 1 Jan. 2012 atresia without a primary gastros- J. (1992) : Anastmotic leakage fol- tomy: 240 patients treated be- lowing surgery for oesophageal tween 1951 and 1983. J Pediatr atresia. J Pediatr Surg; 27 (1): 29- Surg; 20(6): 823-828. 32.

16. McKinnon L. J. and Kos- 18. Manning P. B., Morgan loske A. M. (1990) : Prediction R. A., Coran A. G., Wesley J. R., and prevention of anastomotic Polley T. Z., Behrendt D. M., complications of esophageal atre- Kirsh M. M. and Sloan H. E. sia and tracheoesophageal fistu- (1986) : Fifty years' experience la. J Pediatr Surg; 25 (7) : 778- with oesophageal atresia and tra- 781. cheo-oesophageal fistula. Begin- ning with Cameron Haight's first 17. Chittmitrappap S., Spitz operation in 1935. Ann Surg; 204: L., Kiely E. M. and Brereton R. 446-453.

451 REPRINTBasem Saied, et al.... BENHA MEDICAL JOURNAL

BALLOON DISSECTION FOR EXTRAPLEURAL APPROACH IN (TRACHEO-ESOPHAGEAL FISTULA) TEF REPAIR

Basem Saied MD, Adham Elsaied MD and Hesham Sheir MD

Published by Benha Faculty of Medicine Volume 29 Number 1 Jan. 2012

452 Benha M. J. Vol. 29 No 1 Jan. 2012 COLORECTAL CARCINOMA BELOW 30 YEARS : A RETROSPECTIVE STUDY ON EGYPTIAN PATIENTS : 2000-2010

Alaa Magdy MD, Waleed Thabet MD, Waleed Omar MD, Adham Elsaeed MD and Mohammed Farid MD Department of General Surgery, Colorectal Surgery Unit, Mansoura University, Egypt

Abstract Background: Colorectal cancer (CRC) is exceedingly rare in children and adolescents. Reports from small series indicate that poor prognostic factors are more common in children than in adults, resulting in worse outcome for the pediatric population. CRC is generally thought of as a disease of older persons; however a significant proportion of patients 30 years present with this disease. Many investigators have published single-institution series on CRC in the young, yet the data vary markedly. We performed a structured review of the current literature aiming to (1) Give an idea about increased incidence of CRC amongst young Egyptian adults. (2) Characterize CRC in the young population. Patients And Methods: A retrospective study of 120 cases of CRC below the age of 30 years admitted to colorectal surgical unit in Man- soura University Hospital, Mansoura, Egypt during 2000-2010 was carried out. Results: From January 2000 through December 2010, 120 children/adolescents (ages 4-30 years) were reported with a diagnosis of colorectal cancer. Rectal bleeding, change in bowel habit and abdominal pain were the commonest symptoms. The most common sites of involvement were the rectum (35%) and the transverse colon (28%). Adenocar- cinoma was the most common histiotype however; children/adolescents had more unfavorable histiotype (i.e. mucinous adenocarcinoma [80%] and signet ring cell carcinoma [20%]). Poorly differentiated and undiffer- entiated tumors (grades III and IV, respectively) and distant stage were common in 70% of patients. 18 patients had a positive family history,

453 Alaa Magdy, et al.... while 12 others were diagnosed as index cases of familial adenomatous polyposis. Curative resection was attempted for 69 patients. 31 underwent palliative resections, 2 had an ileostomy and 18 patients have died. Conclusion : Patients younger than 30 years with colorectal cancer have a high-risk features and worse outcome than older patients. A high index of suspicion for CRC among young Egyptian adults is necessary. Age does not affect survival and early diagnosis, radical resection and adjuvant therapy still form the cornerstone in management of colorectal carcinoma in this age group. Keywords: Young, colorectal carcinoma, risk factors, familial adenomatous polyposis.

Introduction more aggressive, presents at a lat- Many studies have reported on er stage and has poorer pathologic colorectal cancers in those under findings. In recent years, an in- the age of 40 years[1-4]. CRC has crease in incidence of CRC among been thought to be less common young adults has been noted amongst Africans compared with worldwide [6-17]. Some have quot- Caucasians. However, recent ed a poorer prognosis while others studies from Japan and Korea have shown no significant differ- have shown high incidence rates ence in survival when thus com- (which has equaled or surpassed pared [1,3,4]. Fewer studies have those in whites in the USA) with been reported recently about an increasing trend [5]. Most have those under 30 years [18,19] in a documented similar clinical pres- single centre. entations and a greater incidence of mucinous and signet ring carci- Patients and Methods nomas as compared to older pa- The study group comprised of tients [1,3]. Disease characteristics 120 patients (62 M: 58 F) were opin young adults are distinct from erated on from January 2000 - those in older patients in stage, December 2010 of CRC who at- grade, location of tumour and sur- tended the colorectal surgical unit vival. The disease in the young is in the department of surgery of

454 Benha M. J. Vol. 29 No 1 Jan. 2012 Mansoura University Hospital. A an follow-up was 20 months (2- retrospective review of patients 132 months); however eleven pa- aged 30 years, operated for color- tients were lost to follow-up. ectal cancer at our department, was carried out. This involved Results searching for such patients in our We identified 120 patients be- department’s operative database low the age of 30 years with color- and reviewing the case notes of ectal cancer who were diagnosed the patients. Standard workup inbetween January 2000 and De- cluded history and physical exam- cember 2010. The majority of pa- ination, rigid proctoscopy, com- tients were between the ages of plete colonoscopy with biopsy, 15-25 years at diagnosis. Only 36 transrectal ultrasound for rectal patients (30% of the cases) were carcinoma, CT scan of abdomen, aged <20 years (median age, 17.5 pelvis and chest (where indicated), years) and were selected for the chest X-ray, routine blood investi- analysis of children / adoles- gations and estimation of the ser- cents (among them, only 12 cases um carcinoembryonic antigen. (10%) were aged <12 years). We The patients received standard compared the distribution of the therapy. Histopathological exami- main clinical characteristics of nation of the resected specimen pediatric patients with those of was routinely carried out. The ex- adults. Unlike adults, who had tent of tumor spread was assessed nearly an equal distribution be- by AJCC classification based on tween males and females, a histological examination of the re- higher percentage of males (17%) sected specimen. were found in children / adolescents. The most common sites of Follow up : involvement in children / adoles- Survival status was evaluated cents were the rectum / anal ca- by review of the medical database nal and transverse colon, where- and telephone follow-up of all pa- as the rectum/anal canal and tients who had no regular outpa- ascending colon were the most tient department visits for more common sites of disease in adults than 3 months at least. The medi- (Table 1).

455 Alaa Magdy, et al....

18 patients had a family histo- tion of tumour (poor: 24%, mod- ry of familial adenomatous polypo- erate: 70%, well-differentiated : sis (FAP), with carcinoma diag- 6%) adenomatous adenocarcino- nosed in one of the polyps after ma (75%), mucinous adenocarcin- examination of the proctocolecto- oma (20%) and signet ring cell my specimen. 12 other patients carcinoma [5%]. Left-sided CRC were diagnosed as index cases for (defined as lesions distal to the FAP when colonoscopy showed a splenic flexure) was found in myriad of polyps within their co- 65% (rectal: 35%, left colon: 22%) lon. Their family members have of CRC patients. Of the patients since been invited for screening. with colon cancer, right - sided One patient, with a strong family lesion (defined as lesions be- history of colonic and ovarian can- tween caecum and splenic flex- cer, was diagnosed as an index ure) constituted 43% of the case of Hereditary Non-Polyposis group (Table 3). Colorectal Cancer (HNPCC) and the other 120 patients were spo- Curative resection was attempt- radic cases (Table 2). ed for 69 patients. 31 had undergone palliative resections, 2 had The two most common clinical required a defunctioning ileostomy presentations of the patients in for palliation of extensive pelvic the study group were rectal bleed- disease and liver metastases. An ing (32.7%) and unexplained abdominoperineal resection was weight loss and anaemia (26.2%). performed in only 2 cases. Among Other major presentations includ- those with curative resections, 8 ed large gut obstruction (13.1%), had recurrences at a median of 12 altered bowel habits (12.4%) and months (8-22 months) postopera- abdominal lump (11.4%). Our pa- tively. All were Duke’s C stage at tients presented at a mean of 4 first operation and most had un- months (0-60 months) from the dergone adjuvant chemotherapy. onset of symptoms. Tumour char- At median follow-up of 20 months, acteristics of patients under 30 18 patients had died of colorectal years in the study group showed cancer. All patients with Duke’s A predominance of poor differentia- and B tumours on follow-up were

456 Benha M. J. Vol. 29 No 1 Jan. 2012 alive with no evidence of disease. dence of disease on follow-up. The Six out of 14 patients with Duke’s remaining 11 patients were lost to C cancers were alive with no evi- follow-up (Table 4,5).

457 Alaa Magdy, et al....

Discussion sidered the second commonest A recent study revealed that cancer among Egypt males with colorectal cancer incidence rates an age-standardized rate of 37.5 for both males and females in- and the females 29.4. Our study creased in 27 of 51 countries of 120 patients below the age of worldwide between 1983 and 30 years represents approximately 2002, and the most likely cause 5% of the total number of patients was postulated to be an increas- with colorectal cancer operated at ingly “Western-style” diet con- our hospital from 2000 to 2010. sumed in those countries. The rise was seen primarily in developing Odone et al reported on 24 pa- countries including Eastern Euro- tients less than 20 years of age pean countries, most parts of (13 black) who had an eight- Asia, Africa and some countries in month median survival from diag- South America. nosis. Twenty-one of the 24 had poorly differentiated mucin adeno- Colorectal cancer may be con- carcinoma. The most common

458 Benha M. J. Vol. 29 No 1 Jan. 2012 presenting symptom was abdomi- attributed to piles and had under- nal pain-observed in all 24 pa- gone haemorrhoidectomy. One patients-followed in frequency by tient had an on-table rigid sigmoi- weight loss, nausea, vomiting, doscopy which showed a rectal constipation, diarrhea, anemia, tumour 7 cm from the anal verge. and anorexia. The most common Another patient had persistent symptom in the study patients bleeding even 9 months after his was rectal bleeding followed close- haemorrhoidectomy and a colo- ly by abdominal pain [24]. noscopy later revealed a rectal tumour 8 cm from the anal verge. Pitluk and Poticha stated that We therefore recommend that all abdominal pain, usually localized patients undergoing haemorrhoi- to the areas of the underlying tu- dectomy should have an on-table mor, was found almost twice as sigmoidoscopy, if no prior colonos- often as the other three important copy has been performed. Many of symptoms-rectal bleeding, change our patients had multiple symp- in bowel habits, and weight loss toms (3 or more) at presentation. with anorexia. They reported an An early colonoscopy may be of- average interval of four to six fered at the time of initial consul- months between the onset of tation for such patients. Neverthe- symptoms and histopathologic di- less, all patients with persistent agnosis. However, 45 percent of symptoms have been offered ei- the patients had delays in diagno- ther a colonoscopy, or a barium sis greater than six months, and enema. 32 percent, greater than one year. There was a 23 percent incidence Petrek et al reported that 50 of mucinous adenocarcinoma. The patients under 40 years of age prognosis was dependent upon (8.2 percent black) from a socioec- the stage of the disease, and that onomically disadvantaged popula- survival of patients with rectal dis- tion had an increased five year ease was dismal [25]. survival (36 percent) compared with their older counterparts (24 Three patients in our study had percent over 40 years), and young presented with per rectal bleeding women had significantly better

459 Alaa Magdy, et al.... survival than young men. They ciated with a poorer prognosis [20] noted that advanced stages, distribution of primary sites, precancer- Some studies have quoted 5- ous conditions, and the higher in- year survival of between 18 cidence of extracellular mucin and 26% in those under 40 production in cancers from young- years[5,19]. Others have reported er patients had no adverse effect 54-56%[1,18]. In a study of those on survival. This was not true of 30 years or younger, a 79% mor- the patients reported here [26]. tality was reported at median follow-up of 21.5 months[22]. This is Family history of colorectal in contrast to a mortality of 15% cancer was far more prevalent in in our median follow-up of 20 younger patients[23]. This ac- months. counted for 26% (31 ⁄120) of our patients, in comparison with 22% In this series rectal and recto- quoted in other studies [1]. Prompt sigmoid tumours made up 52% of surveillance in relatives of pro- all cancers in our series, while bands, especially early onset cas- right-sided tumours accounted for es, may lead to earlier detection only 43% of cases. Also, two fac- and better prognosis [27]. tors correlated with the observed low survival rate: (1) histologic Seventy-one percent of patients type of mucinous adenocarcinoma presented at a late stage. Recent (24%) and (2) delay in diagnosis studies have quoted figures of associated with an advanced stage between 59 and 78%[2,3]. Howev- of disease at operation. A high in- er, the median survival of young dex of suspicion for colorectal can- patients was no different from cer should be maintained in older patients when compared young patients with either rectal by stage[3,5]. Mucinous adeno- bleeding or abdominal pain. Only carcinomas accounted for 20% of in this way can the poor survival all malignancies. This histological rate be improved. subtype has been described more commonly in young pa- Conclusion tients[4,13,18] and may be asso- Rectal bleeding and pain are

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462 Benha M. J. Vol. 29 No 1 Jan. 2012 16. Fazeli M. S., Adel M. G., 21. Shahrudin M. D. and Lebaschi AH. (2007) : Colorectal Noori S. M. (1997) : Cancer of the carcinoma: a retrospective, de- colon and rectum in the first three scriptive study of age, gender, sub decades of life. Hepatogastroente- site, stage and differentiation in rol;44: 441-4. Iran from 1995 to 2001 as observed in Tehran University. Dis 22. Rodriguez-Bigas M. A., Colon Rectum; 50:990-5. Mahoney M. C., Weber T. K. and Petrelli N. J. (1996) : Colorectal 17. de Silva MV, Fernando cancer in patients aged 30 years MS, Fernando D. (2000) : Com- or younger. Surg Oncol; 5 : 189- parison of some clinical and histo- 94. logical features of colorectal carcinoma occurring in patients below 23. Parry B. R., Tan B. K., and above 40 years. Ceylon Med Parry S. and Goh H. S. (1995) : J; 45: 166-8. Colorectal cancer in the young adult. Singapore Med J; 36 : 306- 18. Cozart D. T., Lang N. P., 8. Hauer-Jensen M., et al. (1993) : Colorectal cancer in patients un- 23. Hall N. R., Bishop D. T., der 30 years if age. Am J Stephenson B. M. and Finan P. Surg;166: 764-7. J. (1996) : Hereditary susceptibility to colorectal cancer. Relatives 19. Chen L. K., Hwang S. J., of early onset cases are particular- Li A. F., Lin J. K. and Wu T. C. ly at risk. Dis Colon Rectum; (2001) : Colorectal cancer in pa- 39:739-43. tients 20 years old or less in Tai- wan. South Med J; 94 : 1202-5. 24. Odone V., Chang L., Cac- es J., et al. (1982) : The natural 20. Walton W. W., Hagihara history of colorectal carcinoma in P. F. and Griffen W. O. (1976) : adolescents. Cancer; 49 : 1716- Colorectal adenocarcinoma in pa- 1720. tients less than 40 years old. Dis Colon Rectum; 19: 529-34. 25. Pitluk H. and Poticha S.

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M. (1983) : Carcinoma of the co- A., Liu J. H., Etzioni D. A., Li- lon and rectum in patients less vingston E. H. and Ko C. Y. than 40 years of age. Surg Gyne- (2004) : Do young colon cancer col Obstet; 157(A):335-337. patients have worse outcomes? World J Surg; 28:558-62. 26. Petrek A. J., Sandberg W. A. and Bean P. K. (1985) : The 29. Hill D. A., Furman W. L., role of gender and other factors in Billups C. A., Riedley S. E., Cain the prognosis of young patients A. M., Rao B. N., Pratt C. B. and with colorectal cancer. Cancer; Spunt S. L. (2007) : Colorectal 56:952-955. carcinoma in childhood and ado- lescence: a clinicopathologic re- 27. Hall N. R., Bishop D. T., view. J Clin Oncol; 25 : 5808-14. Stephenson B. M. and Finan P. J. (1996) : Hereditary susceptibil- 30. Tohme C., Labaki M., Hajj ity to colorectal cancer. Relatives G., Abboud B., Noun R. and Sar- of early onset cases are particular- kis R. (2008) : Colorectal cancer ly at risk. Dis Colon Rectum; 39: in young patients: presentation, 739-43. clinicopathological characteristics and outcome. J Med Liban; 56 : 28. Connell J. B., Maggard M. 208-14.

464 Benha M. J. REPRINTVol. 29 No 1 Jan. 2012 BENHA MEDICAL JOURNAL

COLORECTAL CARCINOMA BELOW 30 YEARS : A RETROSPECTIVE STUDY ON EGYPTIAN PATIENTS : 2000-2010

Alaa Magdy MD, Waleed Thabet MD, Waleed Omar MD, Adham Elsaeed MD and Mohammed Farid MD

Published by Benha Faculty of Medicine Volume 29 Number 1 Jan. 2012

465 Benha M. J. Vol. 29 No 1 Jan. 2012 THE RELATION BETWEEN HEMOGLOBIN LEVEL AND NUTRITIONAL STATUS OF PRESCHOOL CHILDREN IN TRIPOLI CITY

Najat M. Burshan MD*, Mustafa Elheggiagi MD, Omar Abusnena MD* and Areej Elheggiagi MD Departments* of Community & Family Medicine & Parasitology, Faculty of Medicine, Tripoli University Tripoli (Libya)

Abstract A cross sectional study involved nine day care centers in Tripoli, Lib- ya. The study involved 932 preschool children attending those centers. Evaluation of nutritional status of those children was conducted. The examination included history, clinical, anthropometric and testing blood for hemoglobin, haematocrit value, and total RBCs count. The results showed that 3.4% of the anemic children were underweight. On the other hand 3.2% of the non anemic children were underweight. The difference was not statistically significant. 4.3% of anemic children had acute malnutrition as compared to 3.6% among non anemic children. The difference is statistically insignificant. Moreover 0.9% of anemic were stunted compared to 3.8% of non anemic children and there was no statistically significant difference between the groups. Conclusions: Nutritional anemia is not necessarily associated with total energy malnutrition. Iron deficiency anemia is caused by relative dietary deficiency in iron rather than total caloric deficiency.

Introduction concentration in peripheral blood Anemia is one of the major is lower than normal for age, sex signs of disease and not a final di- and pregnancy state of the sub- agnosis. It is never normal and its jects.' causes should always be investigated. It is also defined as a condi- Anemia is possibly the most tion in which the hemoglobin (Hb) common manifestation of diseases

465 Najat M. Burshan, et al.... in the tropics. Prevalence and in iron. With increasing age of morbidity are greatest in pre- children, their dietary intake is school aged children and pregnant improving which in turn leads to women. Anemia has multiple etiol- decrease in the prevalence of ane- ogies: it may be caused by nutri- mia.5'6'7 tional deficiencies or congenital abnormalities, or it may be asso- The objective of this work is to ciated with a number of condi- examine the relation between he- tions, such as chronic kidney dis- moglobin levels and nutritional ease, cancer, parasitic diseases or status of preschool children at- human immunodeficiency virus tending day care centers in Tripoli (HIV)2. Anemia plays an important city Libya Arab Jamahiriya. role in producing morbidity, especially in preschool age children Materials and Methods who constitute an important sec- Study design : tion of the population. In this vul- A cross sectional study involved nerable age group the increased nine day care centers in Tripoli, nutritional requirements due to Libya. The study involved 932 pre- accelerated growth rate coupled school children attending those with inadequate dietary intake will centers. Evaluation of nutritional lead to the development of ane- status of those children was con- mia. This is particularly true ducted. The examination included where anemia is possibly the most history, clinical, anthropometric common manifestation of diseases and testing blood for hemoglobin, in the tropics3. heamatocrit value, and total RBCs count. Calculationand interpreta- Anemia is more prevalent dur- tion of anthropometric measure- ing the first two years of life. Chil- ments: dren need a relatively high iron intake because they are growing The nutritional indices were very rapidly. Added to this, the calculated using Epi Info soft ware low iron intake of milk to meet in- (version 9.0). Individual data on fants requirement and also com- height for age, weight for height plementary foods are usually low and weight for age were compared

466 Benha M. J. Vol. 29 No 1 Jan. 2012 with the standard of the National 2 SD of the reference median. Center for Health Statistics (NCHS)8 which is a standard ref- In this study the child was con- erence population recommended sidered anemic when the values of for international use9'10. The data hemoglobin were below 11 gm/ were expressed in terms of stan- 100ml according to the recom- dard deviation scores (Z scores) mendation of the WHO (1968).(12). which equal to:- Results Individual value - median value Table (1) shows the association of reference population divided between underweight and anemia by the standard deviation of among the studied sample. The re- reference population. The Z-score sults show that 3.4% of the ane- cut-off point recommended by mic children were underweight. the WHO (1986)11 to classify low On the other hand 3.2% of the anthropocentric level is - 2SD non anemic children were under- units below the reference median weight. The difference was not sta- for the three following indices: tistically significant.

1- Chronic malnutrition or Table 2, shows the relation be- stunting: tween acute malnutrition and ane- This refers to the children mia. 4.3% of anemic children had whose height for age is less than - acute malnutrition as compared to 2 standard deviation (SD) of the 3.6% among non anemic children. reference median. 2- Acute malnu- The difference is statistically insig- trition or wasting: nificant. This refers to the children whose weight for height is less Table 3 shows the relation be- than -2 SD of the reference medi- tween anemia and chronic malan. nutrition. 0.9% of anemic were stunted compared to 3.8% of non 3- Under weight : anemic children and there was no This refers to the children statistically significant difference whose weight for age is less than - between the groups.

467 Najat M. Burshan, et al....

468 Benha M. J. Vol. 29 No 1 Jan. 2012 Discussion ed to developing countries. More than 2 billion people, mostly women and young chil- In this work it was noticed that dren, are thought to be iron defi- there was no association between cient17. anemia and energy malnutrition whether acute or chronic energy Iron is found in all plant foods malnutrition. Iron deficiency ane- but is more plentiful and bioavail- mia is due to consumption of diet able in meat. Deficiency results deficient in iron rather than its de- from insufficient absorption of ficiency in total calories. The iron iron or excess loss. Absorption is deficiency anemia is the common- tightly regulated in the intestines, est anemia in infants and children depending on the iron status of as reported by Abbasy13 in Egypt the individual, the type of iron, and Singla'14' in India. and other nutritional factors. Once iron is absorbed, it is well Anemic children showed sim- conserved. Iron is depleted pri- ilar prevalence of acute and marily through blood loss, includ- chronic malnutrition as non ane- ing from parasitic infections such mic children. This suggests that as schistosomiasis and hook- anemic children were fed an iron worm. deficient diet but with enough total calories. Nutrition is defined Mainly found in hemoglobin, not only by quantity of food but iron is essential for the binding particularly by quality of food. En- and transport of oxygenT, as well ergy, measured by calorie con- as for the regulation of cell growth sumption, and protein are referred and differentiation16. Iron defi- to as macronutrients while vita- ciency is the primary cause of mins and minerals also critical for anemia, although vitamin A defi- normal healthy development con- ciency, folate deficiency, malaria, stitute micronutrients. So dietary and HIV also result in anemia. iron deficiency is greater than to- Iron deficiency anemia is most tal dietary caloric deficiency. This prevalent in South Asia and Sub- is consistent with the findings of Saharan Africa, but it is not limit- the survey conducted to evaluate

469 Najat M. Burshan, et al.... the nutritional status of preschool 2. Foote M., Colowick A. and children at Gaza and West Bank Goodkin D. (2002) : Pharmaco- 200218. The prevalence of anemia logic and cytokine treatment of much exceed the prevalence of commonly encountered anemia. acute and chronic malnutrition. Cytokines Cell. Molec. Ther., 7 (2): The higher prevalence of anemic 49-59. children than acute and chronic malnutrition also suggests that 3. Aly II. E. (1977) : Nutri- prevalence of anemia is a more tional problems in Egypt. Practical sensitive measure that can be approaches to combat malnutri- used to evaluate the nutritional tion with special reference to status of children in the commu- mothers and children. Interna- nity as a whole. tional Conference, Cairo, May, 25". Also presence of iron deficiency anemia in a child is an early indi- 4. Abdel Fattah S. M., El Sed- cator for the presence of dietary fy H. H., El Sayed H. L., Abdel deficiency. Attention to child feed- Aziz H., Mosry T. A., Salama M. ing should then be given to evalu- M. I. and Hamdi Kh. N. (1994) : ate the quantity and quality of Seropositivity against pediculosis food given to the child for correc- in children with cervical lymphad- tion of the anemia and to correct enopathy. 5. J. Egypt. Soc. Para- other dietary deficiency to prevent sitol., 24 (1): 59-67. development of other nutritional diseases in the child like total ca- 5. Nutrition lnstitute / loric and protein malnutrition dis- UNICEF(1995) : Nutritional Sur- eases. vey for 332assessment of vitamin A status in Egypt. Final Report, References Cairo, Egypt. 1. llermiston, M. and Mentzcr W. (2002) : A practical approach 6. Ministry of Health Child to the evaluation of the anemic survival project in cooperation child. Pediatr. Clin. North. Am., with USAID (1996) : Anemia in 49 (5): 877-891. pregnancy and Lactation, study

470 Benha M. J. Vol. 29 No 1 Jan. 2012 conducted in Beheira Governo- Org ; 929-941. rate. EI-Helal Trading and offset printing. 12. W. H. O. (1968) : Nutri- tional anaemia: Report of a WHO 7. High Institute of Public scientific group. Tcchn. Rep. Se- Health, Maternal and Child ries, No. 405. Geneva. Health Sector, MOHP, UNICEF. (1998) : Assessment of vitamin A 13. Abassay A. A. (1981) : Pe- deficiency and anemia among pre- diatrics, Third edition Dar AI- school children in Alexandria Gov- Maaref, Cairo. ernment. Final Report, Carlo, Egypt. 14. Singla P. N., Gupta II. P., Chanchal A. and Agarwal K. 8. National Center for Health N. (1982) : Deficiency anemia's in Statistics (1977) : NCFIS growth preschool children, estimation of curves for children birth-18 years. prevalence based on response to Publication No. (PHS) 78-1650. haematinic supplementation. J. Rockville, Maryland: US Depart- Trop. Fed.; 28:77. ment of Health, Education and Welfare. 15. Agudelo G. M., Cardona O. E., Posada M., Montoya M. 9. Measuring changes in nu- N., Marin C. M., Correa M. C. tritional status. Geneva WHO, and Eopez C. (1999) : (Prevalence (1983) . of iron-deficiency anemia in schoolchildren and adolescents, 10. Hall A. (1993) : Intestinal Medellin, Columbia. Rev Panam parasitic worms and the growth of Salud Publica. 2003 Jan; 13(6): children. Trans R Soc Trap Med 367-86. Hyg; 87: 241-242. 16. Gillen F. D., Reiner D. S. 11. WHO Working Group. and Wang C. S. (1983) : Human (1986) : Use and interpretation of milk kills parasitic intestinal anthrapometric indicators of nu- protozoa. Science; 221 : 1290- tritional status. Bull World Hlth 1291.

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17 Beard, J. L. (2001) : Anemia.Washington, DC : ILSI "Iron Biology in Immune Press. Function, Muscle Metabolism, 19. Ziad Abdeen, Gregg Gree- and Neuronal Functioning." Jour- nough, Mohammad Shahin, nal of Nutrition 131 (2Suppl. 2): Matthew Tayback. (2002) : Nu- S568-79. tritional assessment at Gaza and West Bank strips. September. 18. Stoltzfus, R. J. and M. L. Center for International Emer- Dreyfuss. (1998) : Guidelines for gency, Disaster & Refugee the Use of Iron Supplements to Studies Johns Hopkins Bloomberg Prevent and Treat Iron Deficiency School of Public Health.

472 Benha M. J. REPRINTVol. 29 No 1 Jan. 2012 BENHA MEDICAL JOURNAL

THE RELATION BETWEEN HEMOGLOBIN LEVEL AND NUTRITIONAL STATUS OF PRESCHOOL CHILDREN IN TRIPOLI CITY

Najat M. Burshan MD, Mustafa Elheggiagi MD, Omar Abusnena MD and Areej Elheggiagi MD

Published by Benha Faculty of Medicine Volume 29 Number 1 Jan. 2012

473 Benha M. J. Vol. 29 No 1 Jan. 2012 EPIDEMIOLOGICAL FEATURES OF INTESTINAL AND ECTO-PARASITES IN PRESCHOOL CHILDREN IN TRIPOLI CITY

Najat M. Burshan MD*, Mustafa Elheggiagi MD, Omar Abusnena MD* and Areej Elheggiagi MD Department* of Community and Family Medicine & Parasitology, Faculty of medicine, Tripoli University Tripoli (Libya)

Abstract Objectives: To estimate the prevalence of intestinal parasites & ec- toparasites as pediculosis & scabies among a group of preschool children in nine day care centers in Tripoli city - Libyan Arab Jamahiriya .

Introduction Methodology: Intestinal parasites account for The study is a cross sectional large proportion of the morbidity study. It was carried out on the and mortality among infants and preschool children attending the young children; those who are un- nine day care centers in Tripoli der 5 years of age are the most af- city by multistage sampling meth- fected group world wide(1-3). Cur- od. The studied'Sample consisted rent estimates suggested that at of 1255 children (676 males and least one-quarter of the worlds' 579 females). Total stool samples population is chronically infected collected from 1056 children (577 with intestinal parasites with high males and 479 females). Micro- prevalence rates. Most of these in- scopic examination of the stool fected people live in developing samples was examined by using countries in tropical and sub- Merthiiolate formaldehyde (MF) di- tropical areas (4) where people ei- rect smear. MF preserved samples ther accept the parasites as a fact were concentrated using merthio- of life or are completely unaware late iodine formaldehyde concen- of themeis). tration technique. The total scotch

473 Najat M. Burshan, et al.... tape samples applied were 1204 program. After revision and verifi- (653 males and 551 females). cation of the data they were sub- Head louse infestation was diag- jected to the statically program nosed by direct inspection of the SPSS version 9.0 software for pro- child's hair and scalp, particularly cessing, tabulation and for statis- the nape of the neck and behind tical analysis, all test were tow the ears by using a hand lens and sided and the cut: off P-value for a flash-light battery. All children statistical significant was 0.05. are examined clinically, anthropometric measurement. The odds ratio (OR) together with its 95% confidence limits was The questioner sheets were de- used to estimate the risks of infec- signed to cover a variety of items tions in relation to different fac- concerning personal socioeconom- tors. ic data of the examined children which can be related to parasitic Results infections. Out of 1056 children who submitted stool samples, 394 Pilot study : (37.3%) Were infected with in- Pilot study was done in select- testinal parasites, including pro- ing setting for following reasons: tozoa and helminthes other than 1- To test the validity of the E.vermicularis, G.lamblia was the questioner. commonest protozoa detected 2- To estimate the number of (19.5%), E.histolytica (9.3%), equipments and materials E.coli (7.8%). The helminthes needed for the field work. parasites which were detected, H.nana (0.6%), A-lumbricoides Statistical analysis : (0.2%), and T.trichiura (0.2%). Once the questioner sheets By using the scotch tab tech- were filled out, the collected data nique the prevalence infection of were critically reviewed coded and E.vermicularis was (30.3%), Pedi- computerized using Epi-Info 2000 culosis (6.5%) and scabies 0%.

474 Benha M. J. Vol. 29 No 1 Jan. 2012

475 Najat M. Burshan, et al....

Fig. 1 : Prevalence of parasitic infections among the studied sample by age group.

Fig. 1 : Shows age distribution of the sample, it can be noted that in all day care centers 53.4% were of the age group 5+ years in age group 4-<5 and 3-<4 years (32%, 14.6% respectively).

476 Benha M. J. Vol. 29 No 1 Jan. 2012 Fig. 1 : Prevalence of parasitic infections among the studied sample by sex.

Fig. 2 : Shows that there is no statistical significant difference of intestinal parasitic infection between males & females. For pediculosis infestation the total number of infested children was 82, 10.4 of them were femals & 3.3% were males the risk of developing pediculosis infestation was statistically significant.

Discussion from a rural area of Kafr El- In the present study, the most Sheikh 31.6%(8), and in Cairo common protozoan parasites was 21%(6). G.lamblia which was detected in 19.5% of the children. This is a The present study showed that considerable low rate as compared (30.3%) of the examined children to the G.lamblia infection 33% re- were infected with E.vermicularis ported in Cairo(6), 26% reported in as indicated by the adhesive Alexandria(7) and in rural area of scotch tape and peri-anal swabs Kafr El-Sheikh 23%(8). Markedly techniques. High prevalence rats lower percentages were reported of pin-worm infections were rein India 6.4%(9) and in Gaza Strip ported (68.8%) and (51.40%)(13) 2.2%(10) and in Saudi Arabian among visually handicapped and children 9%(11). In the Sudanese control children in Alexandria re- towns the prevalence of Giardia spectively, and 43.8%(14) among was 56.8%(12). rural primary school children in Giza. Gilman et al. (1991)(15) re- As regards E.histolytica infec- ported that in Peruvian town 42% tion, the prevalence rate was of the primary school children and 9.3%. This rate of infection was approximately one fourth of both much lower than that recorded preschool arid secondary school

477 Najat M. Burshan, et al.... students were infected with pin- - Appropriate number of clean worms. toilets and washing facilities should be provided in DCC. On the other hand, the arthro- - Health education of mothers pod-ectoparasite or Pediculus hu- by stressing the importance manus (head lice) in this study,- of hygiene using attractive among 1255 children were exam- posters in very simple lan- ined the prevalence was 6.5%. In guage. Egypt, in school children in Qual- yob city (in the Nile Delta) the rate References of head lice infestation was 1. WHO Working Group 16.04%(16). (1986) : Use and interpretation of anthropometric indicators of nu- Recommendations: tritional status. Bull World Hlth Urgent remedial steps are need- Org; 929-941. ed on a community basis to improve their control of parasitic in- 2. Frangillo E. A., Jr 8 Han- fections. son KMP. (1995) : Determinants - Medical and sanitary supervi- of variability among nations in sion are needed in every DCC child growth. Ann Human Biol; to control the parasitic Infec- 22: 395-441. tions and improve the health status of preschoole children 3. Gorstein K., Sullivan R., who are the fastest through Yip M., et al. (1994) : Issues in the following points. the assessment of nutritional stat- - Health education programs us using; anthropometry. Bull. should focus on the impor- WHO; 72 (2): 273-283. tance of personal hygienic practices. 4. Karnar Z. A. and Rahim F. - Improvement of sanitary con- A. (1995) : Prevalence and risk ditions of DCC by proper re- factors of parasitic infections fuse and sewage disposal and among under five Sudanese chil- provision of safe water sup- dren: a community based study. E ply. Afr Med J; 72: 103-109.

478 Benha M. J. Vol. 29 No 1 Jan. 2012 5. Mangali A., Sasabbore P., dren. Trans R Sec Trop Med Hyg; Syafunddin S., et al., (1993) : 84:382-384. Intestinal parasitic infections in compalagin district, South Savlw- 10- Sallon S., El-Shawwa R., sesi, Indonesia SE Asian Trop Med Khalil M., Ginsburg G., El-Tayib Putl Heth; 29:313-320. J., El-Eila J., Green V. and Hart C. A. (1994) : Diarrhqeal disease 6- Ahmed L., El-Shinawy R. in children in Giza. Ann Trop Med and Hussein M. N. (1984) : Prev- parasitol. 99:175-182. alence of Giardia Lamblia in Egyp- tian children suffering from diar- 11- Prevalence of intestinal rhoea. J Egypt Soc Parasitol; 14: parasites in Saudi Children 283-288. (1995) : a community based study, Journal of Tropical pediat- 7- Youssef M., Amin S. M., rics, 4(1) 47-9. Feb. Khalifa A. M. and Abd El-Menem H. S. (1987) : Cryptosporidiosis 12- Salem G., Van de Velden among diarrhoeic children in Alex- L., Laloe F., Maire B. and Pon- andria. J Med Res Instil; (987) ton A., Traissac prost. A. (1994): (Suppl 2): 297-310. Intestinal parasitic diseases and environment in Sahelosudanese 8- El-Hakim M. A. and El- towns: Revue of Epidemiologie et Sahn A. (1996) : Association of Sante.Publiqui 42 (4): 322-333. parasites and diarrhoea among children less than 5 years of age 13- El-Fadly M. A. (1995) : in arural area, in Egypt. J Egypt Study of parasitic infection among Public Health Assoc.; 70 : 439- visually handcapped students in 463. Alexandria. MPH Thesis. HPH, Alexandria University. 9-.Shetty N., Narasimha M., Raghuveer T. S., Elliott E. and 14- Bahader S. M., Ali G. S., Farthing M. J. G. (1990) : Intes- Shaalan A. H., Khalid H. M. and tinal amoebiasis and giardiasis in Khalid N. M. (1995) : Effects of Southern Indian infants and chil- Enterobius vermicularis infection

479 Najat M. Burshan, et al.... on Intelligence Quotient (J.Q) and ruvian shanty town. Trans R Soc anthropometric measerments of Trop Med Hyg; 85: 761-764 Egyptian rural children. J Egypt Soc Parasit; 25:183-193. 16- Morsy T. A., Farrag A. M. K., Sabry A. A., Salama M. M. I. 15- Gilman R. H., Marquis G. and Arafa M. A. S. (1991) : Ecto S. and Miranda E. (1991) : Prev- and endoparasites in 2 primary alence and symptoms of Enterobi- schools in Qualyob J. Egypt. Soc. us vermicularis infectious in a Pe- Parasitol., 21(2): 391-401.

480 Benha M. J. REPRINTVol. 29 No 1 Jan. 2012 BENHA MEDICAL JOURNAL

EPIDEMIOLOGICAL FEATURES OF INTESTINAL AND ECTO-PARASITES IN PRESCHOOL CHILDREN IN TRIPOLI CITY

Najat M. Burshan MD, Mustafa Elheggiagi MD, Omar Abusnena MD and Areej Elheggiagi MD

Published by Benha Faculty of Medicine Volume 29 Number 1 Jan. 2012

481 Benha M. J. Vol. 29 No 1 Jan. 2012 TIVA VERSUS SEVOFLURANE EFFECT ON CEREBRAL BLOOD FLOW A TRANSCRANIAL DOPPLER STUDY

Mohammed A. Sultan MD, Ahmed E. Mahmoud MD*, Olfat M. Ismail MD and Tarek M. Shams MD Departments of *Lecturer of Anesthesia and ICU Mansoura University, Egypt

Abstract Transcranial Doppler ultrsongraphy is non invasive technique that measures cerebral blood flow velocity. Preliminary data on the effect of propofol on cerebral blood flow indicate that propofol causes decrease cerebral blood flow while there is some controversy concerning the effect of ketamine on cerebral circulation, conflicting results on the effect of sevoflurane on cerebral blood flow velocity. Purpose: this prospective, randomized controlled study was designed to evaluate the effect of propofol, ketamine, propofol-ketamine versus on middle cerebral artery blood flow velocity by using Transcranial Doppler ultrsongraphy. Methods: one hundred twenty patients scheduled for orthopedic lower limb surgeries were randomly classified into four groups thirty patients each. Group I (p): propofol was given as induction dose 2mg/kg and 6mg/ kg/h as continuous infusion. Group II (k): ketamine was given 2mg as induction dose then 2mg/ kg/h as infusion till the end of surgery. Group III (pk): propofol 1mg, ketamine 1mg/kg then continuous infusion of propofol 3mg/kg/h and ketamine 2mg/kg/h. Group IV (S): anesthesia was induced with sevoflurane 8% then maintained with sevoflurane 2%. In all groups TCD ultrasonography measurements of the middle cerebral artery mean flow velocity before induction, immediately after induction and every 30 minutes till the end of surgery.

481 Mohammed A. Sultan, et al....

Results: the middle cerebral artery main flow velocity (Vmca) was increased significantly (p<0.05) in group k and group s while decreased significantly (p<0.01) in group p. pulsatility index was significantly higher in group p than other three groups. Conclusion: propofol decrease both cerebral blood flow velocity and systemic blood pressure while ketamine and sevoflurane increased both. Key words: TCD- TIVA- Propofol-Ketamine-Sevoflurane- CBF.

Introduction ketamine on cerebral circulation, Propofol is used increasingly ketamine has been reported to in- for the induction and mainte- crease cerebral blood flow and in- nance of anesthesia. Its use is tracranial pressure.5 However, characterized by rapid clearance other have reported that ketamine and distribution, resulting in rap- does not increase CBF velocity or id emergence from anesthesia.1 ICP.6 Studies using Xenon 133(Xe) inhalation scintillography have demon- Inhaled induction of general strated that propofol causes a sig- anesthesia has not been popular nificant decrease in cerebral blood with patients or clinicians be- flow and increases cerebral vascu- cause of fear of excitement and lar resistance. 2 respiratory symptoms related to the pungency and speed of availa- Ketamine has gained atten- ble volatile anesthetics. However, tion as an analgesic for total sevoflurane has potential advan- intravenous anesthesia.3 The tages (a relatively low blood gas combination of propofol and solubility and a relative absence of ketamine is recommended for pungency) that make the inhaled total intravenous anesthesia be- induction technique a feasible op- cause the opposing effects of tion.7 Sevoflurane has been used the individual anesthetics result to provide an inhaled induction by in intraoperative hemodynamic using a vital capacity breath, stability.4 There is some contro- which is fast and has few side ef- versy concerning the effects of fects.8, 9

482 Benha M. J. Vol. 29 No 1 Jan. 2012 Inhalational anesthetics have reported including that sevoflu- been shown to produce a dose de- rane does not affect cerebral pendent increase in cerebral blood blood flow velocity15 and global flow. The magnitude of this in- cerebral blood flow16, increased crease is dependent on the bal- global or regional cerebral ance between the agents intrinsic blood flow13,17,18, along with a vasodilatory action and the vaso- decreased or unchanged cerebral conistriction secondary to flow metabolic rate for oxygen17,19 metabolism coupling.10 and decreased cerebral blood flow20,21,22 or cerebral blood Sevoflurane has an intrinsic flow velocity.23,24 The vasodilator dose-dependent cerebral vasodila- effect is dose dependent, and is tory effect less than that reported more pronounced with incremen- for halothane and isoflurane.11 tal clinical doses. 11,25,26

Sevoflurane has became one of In the majority of the previous the most widely used inhalational studies, different minimal alveolar agent in general anaesthesia due concentrations of sevoflurane were to its excellent physical, pharma- used. However, only a few studies codynamic and pharma-cokinetic measured the effect of sevoflurane properties.12 However, in neuro- on cerebral circulation at a level of surgical anaesthesia there has surgical anaesthesia as assessed been concern due to the known by a depth of anaesthesia moni- vasodilator effect of all inhalation- tor.23, 27 As the main goal of the al agents. As cere-bral vasodilata- routine anaesthesia practice is tion may result in increased cere- maintaining the level of appro- bral blood flow and blood volume, priate depth of anaesthesia and the use of an inhala-tional agent analge-sia during surgical proce- may contribute to a secondary in- dures, it seemed logical to assess crease of the intracranial pressure the effect of anaesthesia on cere- in patients with space-occupying bral blood flow under such cir- lesions.11,13,14 cumstances. Different methods have been used to assess the cere- Conflicting results have been brovascular effects among them

483 Mohammed A. Sultan, et al.... transcranial Doppler sonography non invasive ultrasonic technique (TCD), positron emission comput- that measures local blood flow ve- ed tomography and magnetic reso- locity and direction in the proxi- nance angiography.15 mal portions of large intracranial arteries.29 Transcranial Doppler sonography is an emerging technique The chief advantages of TCD that uses a hand held direction- are as follow: It can be performed al, microprocessor-controlled, low- at the bedside and repeated as frequency (2MHz), pulsed Doppler needed or applied for continuous transducer to measure the velocity monitoring, it is frequently less ex- and pulsatility of the blood flow pensive than other techniques, within the arteries of the circle of and dye contrast agents are not Willis and vertebrobasilar system used. Its chief limitation is that it the procedure is noninvasive, non can demonstrate cerebral blood ionizing protable, safe for serial or flow velocities only in certain seg- prolonged studies and performed ments of large intracranial ves- with relatively inexpensive equip- sels, although large-vessel intra- ment. cranial arterial disease commonly occurs at these locations. In The diagnostic accuracy de- general, TCD is most useful when pends on the knowledge, skill and the clinical question pertains to experience of the examiner, who those vessel segments. However, must be familiar with anatomy in some settings, TCD can detect and physiology of the intracranial indirect effects such as abnormal vasculature. In most cases, the waveform characteristics sugges- clearst understanding of transcra- tive of proximal hemodynamic or nial Doppler data requires an in- distal obstructive lesions. 30 tegration with the results of other neuroradiologic studies and The aim of this study was to clinical and laboratory determina- evaluate the effects of propofol tions. 28 alone, ketamine alone, propofol- ketamine versus sevoflurane on Transcranial Doppler (TCD) is a human middle cerebral artery

484 Benha M. J. Vol. 29 No 1 Jan. 2012 blood flow velocity by using trans- sitting position a local infiltration cranial Doppler ultrasonography of 2 ml 2% lidocaine subcutane- during orthopedic surgeries. ously was done, then 20 gauge catheter was inserted in the space Patients and Methods between L4,5 using 18 gauge Tou- This randomized prospective hy needle depending on loss of re- controlled study was carried out sistance to air technique then 15 on 120 patients ASA physical stat- ml of 0.75% concentration ropiva- us I and II of either sex aged be- caine was injected. tween 20 and 40 years scheduled for orthopedic lower limb surger- Group I: (P: propofol induction ies at Emergency hospital, Man- and maintenance) soura University from Jan 2007 - Anesthesia was induced with a May 2009. sleep dose of propofol till loss of eyelid reflex (1.5 - 2 mg/kg) and The protocol was approved by tracheal intubation was facilitated the scientific committee of the de- with the use of vecronium bro- partment and an informed con- mide 0.04 mg/kg. sent was secured from every pa- Anesthesia was maintained tients. with continuous infusion of propofol 12 mg/kg/h for the first 15 All patients were subjected to minutes, and then 9 mg/kg/h for thorough medical history, clinical the next 25 minutes and 6 mg/ examination and routine laborato- kg/h till the end of the surgery.31 ry investigation. Patients were randomly classified into four Group II: (K: Ketamine induc- groups 30 patients each. Eighteen tion and maintenance) gauge IV cannula was inserted Anesthesia was induced with a and 500 ml of lactated ringer’s so- sleep dose of ketamine (1.5 - 2 lution was infused. mg/kg) and tracheal intubation was facilitated with the use of ve- Epidural block was done to cronium bromide 0.04 mg/kg. all groups as follow: While, the patient was in the Anesthesia was maintained

485 Mohammed A. Sultan, et al.... with continuous infusion of keta- In all groups: mine 2 mg/kg/h till the end of the Muscle relaxation was main- surgery. tained by vecronium bromide 0.01 mg/kg, the lungs was venti- Group III: (PK: Propofol keta- lated with 100% O2 with tidal vol- mine group). ume 5 - 7 ml/kg and a rate of 14 Anesthesia was induced with a B/min to maintain end tidal CO2 sleep dose of propofol (1 mg/kg) between 30 - 35 mmHg. and ketamine (1 mg/kg) and tracheal intubation was facilitated At the end of surgery, residual with the use of vecronium bro- neuromuscular block was re- mide 0.04 mg/kg. versed with 40 µ/kg neostigmine Anesthesia was maintained and 20 µm/kg atropine. with continuous infusion of Fluid maintenance and replace- ketamine 2mg / kg / h through- ment of blood loss: out anaesthesia combined with a continuous infusion of propof- In all groups: ol 6 mg/kg/h for the first 15 Fluid was maintained at a rate minutes and then 4 mg/kg/h of 3 ml/kg/h lactated ringer’s for the next 25 minutes and 3 throughout the time of the opera- mg/kg/h to the end of the sur- tion. gery. Blood loss of less than 0.75 liter was replaced by ringer’s solu- Group IV: (S: Sevoflurane tion 3 ml/1 ml blood, more than group) 0.75 liter was replaced by whole Anesthesia was induced with blood. sevoflurane 8% in oxygen (100%) at 9 litre/m until loss of eye lash Transcranial Doppler ultraso- reflex, tracheal intubation was fa- nography: cilitated with use of vecronium A 2-MHz pulsed Doppler ul- bromide 0.04 mg/kg. trasound device (Multidop MDX4 Anesthesia was maintained TCD8; DWL Elektronische Sys- with sevoflurane 2% in 100% oxy- tem GmbH, Sipplingen, Germany) gen at 5 liters/min. (Fig. 1) was used for transcranial

486 Benha M. J. Vol. 29 No 1 Jan. 2012 measurements of CBFV in the Cerebral blood flow velocity and right middle cerebral artery (MCA). MABP changes were calculated as Insonation of the MCA was initiat- percent changes of baseline val- ed at a depth of 45mm. Confirma- ues. 33 tion of MCA identity was achieved by increasing insonation depth to Statistical Analysis visualization of the bi-directional - The statistical analysis of flow pattern typical of the birfur- data done using excel pro- cation of the internal carotid ar- gram and SPSS program (sta- tery into the MCA and anterior ce- tistical Package for Social Sci- rebral artery. After individual ence, version 10). adjustment of Doppler variables - The description of the data such as gain, sample volume and was done in form of mean ± power of ultrasound, the probe SD for quantitative data, and was handheld to obtain an opti- frequency and proportion for mal flow velocity trace and then qualitative data. fixed in position for the measure- - N.B The distribution of data ment period 32 (Fig. 2). normality done by Kolmo- grave Smirnove test, all re- Timing: vealed to be parametric. Basal before epidural block and - The analysis of the data was induction. done to test statistical signifi- Induction: immediately after in- cant difference between jection of induction drugs. groups. Intubation: one minute after in- - For quantitative data (mean tubation. ± SD), One Way ANOVA test Every 30 minutes until the end was used to compare between of the surgery. more than 2 groups. Student Continuous monitoring of ECG t-test was used to compare 2 (lead II), pulse oximetry, mean ar- groups. Post hoc test was terial blood pressure and end tidal used (least significant differ- CO2, Data were recorded at the ence). Paired sample t-test same times of measurement of was used to compare the 4 transcranial Doppler, parameters. groups at different times.

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- Chi-square test was used for significantly (P < 0.05) decreased qualitative data. Vmca after induction of anesthe- - P was significant if ≤ 0.05 at sia from 60.9 ± 11.5 to 51.5 ± 12.8 confidence interval 95%. indicating a significant reduction by 16%. Then the Vmca was sig- Results nificantly elevated from 51.5 ± This study included 120 ortho- 12.8 to 55.6 ± 12.8 by 8% immedi- pedic patients who were admitted ately after intubation. This de- at Emergency Hospital, Mansoura crease continued throughout the University. whole study period till it reached its maximum at recovery time, The epidural block was suc- when it reached to 32 ± 5.3 indi- cessful in all patients and trans- cating a significant reduction by cranial doppler measurements (33%) (Table 1, 4). were completed in all patients. Ventilatory variables remained un- During ketamine anesthesia changed throughout the study pe- Vmca was increased immediately riod for each patient. End tidal after induction from 61.3 ± 15 to PCO2 was kept within the planned 71 ± 17.1 by 17% and significantly range (between 30 and 35 mmHg) increased from 71 ± 17.1 to 79 ± throughout the study period. The 15.4 by 32% 1 min after intuba- middle cerebral artery mean flow tion and continued throughout velocity (Vmca) was increased sig- the study period (Table 1, 4). nificantly (P < 0.05) in group K, and group S, while it decreased During propofol / ketamine significantly (P < 0.01) in group P anesthesia Vmca was reduced im- compared with their basal values. mediately post induction from The middle cerebral artery mean 75.1 ± 11.1 to 68.1 ± 11 by 9% flow velocity (Vmca) showed signif- then was increased one minute af- icant differences between group K, ter intubation from 68.1 ± 11 to group PK and group S compared 84.1 ± 10.8 by 13% then Vmca re- with group P, being lower in group turned to decrease significantly P with the least value at recovery till the end of the operation time (240min) (table 1).1 Propofol (Table 1, 4).

488 Benha M. J. Vol. 29 No 1 Jan. 2012 Sevoflurane anesthesia caused study period apart from one read- a significant increase of Vmca ing immediately after intubation from 58.3 ± 14.2 to 64.7 ± 14.8 when it significantly (P < 0.05) de- by 12% immediately after induc- creased compared with basal val- tion. Then it was increased ue (Table 2). from 64.7 ± 14.8 to 73.3 ± 17.7 by 27% immediately after intuba- PI was significantly higher in tion. This elevation of Vmca was propofol group than in the other continued significantly throughout three groups throughout the the study period till recovery study period apart from few read- time (Table 1, 4). ings where the values were reversed but significantly (at 180 There was a significant (P < min, 210 min and 240 min) in 0.001) elevation of Vmca post in- group K, at 210 min in group PK tubation values compared with and at 240 min in group S. post induction values in the four groups (Table 1, 4). There was a significant (P < 0.05) reduction in PI between A statistically significant in- post induction and post intuba- crease in PI was observed in group tion values in group P and PK. P: after induction of anesthesia, at There was a strong significant (P < 120 min and 180 min compared 0.002) negative correlation be- with basal values. In group K, PI tween Vmca and PI in all groups did not show any significant (Table 2). change allover the study period apart from one reading at 60 min MABP during propofol anesthe- when it significantly (P < 0.05) de- sia decreased significantly (P < creased compared with basal val- 0.05) from 84.9 ± 9.5 to 74.8 ± 9.5 ue. In group PK, there was a sig- by 12% after induction of anesthe- nificant increase in PI at post sia, but the MABP was rose after induction, 60 min, 120 min and intubation from 74.8 ± 9.5 to 91.3 150 min compared with basal val- ± 16.9 by 7% then the MABP de- ue. In group S, PI did not show creased significantly again till the any significant change allover the end of the operation. The mean

489 Mohammed A. Sultan, et al.... arterial blood pressure (MABP) the MABP significantly (P < 0.05) was significantly increased in decreased immediately after in- group K from 85.2 ± 11.9 to duction from 87.8 ± 9.9 to 77.1 ± 94.5 ± 14.3 by 11% after induc- 10.5 by 12% then it rose after in- tion of anesthesia reaching its tubation from 77.1 ± 10.5 to 93.8 maximum increase 1 minute af- ± 14.4 by 7%, then at 30 min ter intubation 94.5 ± 14.3 to MABP decreased from 93.8 ± 14 to 102.4 ± 13.9 by 21% then the 84.2 ± 12.6, and this decrease increase continued till the end continued till recovery time. of study period. In group PK, There was a significant difference MABP decreased post induction in MABP between post induction from 85.6 ± 10.7 to 77 ± 9.2 by and post intubation values with (P 10% then the it rose post intuba- < 0.05) in all groups. MABP was tion from 77 ± 9.2 to 95.6 ± 10.3 significantly (P < 0.05) higher in by 12% then at 30 min it de- group K than in group P, PK and creased and the decrease contin- S throughout the study period ued till recovery time. In group S (Table 3, 5).

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494 Benha M. J. Vol. 29 No 1 Jan. 2012 Discussion with different anesthetic tech- One of the challenges of neuro- niques are of interest to neuroan- anesthesia is to maintain control aesthetists. Cerebral blood flow of cerebral haemodynamics and velocity (CBFV), as measured in hence intracranial pressure whilst the middle cerebral artery, is not a facilitating a rapid emergence and direct measurement of CBF 37 recovery postoperatively.34 Changes in CBFV have been shown to correlate reliably with Cerebral autoregulation main- changes in CBF in presence of tains cerebral blood flow (CBF) constant vessel diameter, which is constant during changes in cere- preserved in conduction vessels of bral perfusion pressure (CPP) be- which the middle cerebral artery tween 50 and 170 mmHg. Inhaled is an example. 38 anesthetics impair both the ability to autoregulate (static autoregula- Transcranial Doppler sonogra- tion) and the rate of autoregula- phy (TCD) is an exciting technolo- tion (dynamic autoregulation) in a gy. TCD equipment is portable, dose dependent manner.5 Meas- inexpensive surprisingly useful in urement of cerebral blood flow vol- multiple situations, and well suit- ume is required for identification ed to address specific problems. and quantification of focal or gen- Most importantly it provides real eralized perfusion disturbances in time information regarding the the course of traumatic, infectious physiology of the itnracranial cir- or neurodegenerative disorders 35 culation. TCD provides informa- Total cerebral blood flow volume is tion about the blood flow velocity defined as the blood flow through and direction of flow in major in- the right and left ICA and BA,36 tracranial arteries. The smallest calculated the intravascular flow TCD units are no longer than a volume as the product of time av- bread box and are easily portable eraged mean flow velocities and compared to other technologies the cross-sectional area of the ves- used to study cerebrovascular sel. anatomy and/or physiology, including MRI, CT, PET, SPECT and Changes in CBF associated invasive angiography. TCD is very

495 Mohammed A. Sultan, et al.... inexpensive. TCD is used in a lab, marily designed to study changes the operating room or at the pain cerebral blood flow during anes- tients bedsides. 39 thesia with propofol, ketamine, propofol ketamine versus sevoflu- Cerebral blood flow is one of rane with the use of a transcranial the most important factors in- Doppler ultrasonography. volved in the maintenance of brain metabolism CBF is known to be The middle cerebral artery is a regulated by several different conductance rather than a resis- mechanisms (e.g. coupling, auto- tance vessel. Changes in cerebral regulation). 40 vascular resistance are caused by changes in arteriolar diameter, Transcranial Doppler sonogra- rather than by changes in the di- phy is now widely used as surro- ameter of the arteries of the circle gate measure of cerebral blood of Willis. 43 flow. 41 In our study, the decrease in Interpatient variability in CBFV Vmca with propofol and pro- measurement can be due to varia- pofol-ketamine immediately after tions in Doppler probe positioning, induction of anesthesia is attrib- resulting in different angles of in- uted to intrinsic vasoconstrictive sonation (i.e. the angle at which properties on the cerebral vascula- the Doppler beam impacts on the ture.14,38 In addition, propofol artery). reduces CBF as a result of flow metabolism coupling 44 (table 4). Interpatient variability may result if the probe position changes Several physiological factors during the course of the study. are known to alter CBFV including Thus in order to minimize these PaCO2, surgical stimulation, body errors the Doppler probe should temperature, intrathoracic pres- be fixed to the subject’s head us- sure and hypoxia. The end tidal ing an established wheel fram.42 CO2, ventilatory variables and FiO2 were kept constant through- The present research was pri- out the study period and body

496 Benha M. J. Vol. 29 No 1 Jan. 2012 temperature and SPO2 remained cranial pathology.40 Propofol re- unchanged. The epidural block duces cerebral blood flow veloc- was effective in all cases, elimi- ity, CBF and cerebral metabolic nating cerebrovascular effects of demand without affecting car- surgical stimulation.45,46 Be- bon dioxide reactivity and cere- cause nitrous oxide increases ce- bral pressure autoregulation.50 rebral blood flow velocity and A number of studies have reported CMRO247, we did not use it. Vec- a significant reduction in CBFV uronium bromide does not alter occurring during propofol anes- cerebral blood flow, hence do not thesia.38,51 affect cerebral autoregulation.48 Anyhow, we did use it in all study Our findings are consistent groups. with52. They reported that propofol infusion results in 17% de- We chose to use a propofol increase in Vmca that outweighed fusion regimen previously shown the reduction (6%) in MABP. They to produce steady plasma concen- used propofol 2.5 mg/kg as induc- trations for up 90 minutes.49 Ce- tion followed by infusion of 15,13, rebral perfusion pressure autoreg- 11 mg/kg/h in 12 children aged ulation and vasoreactivity to one to 6 years requiring general arterial carbon dioxide tension are anesthesia for urologic surgical re- maintained during propofol anes- ceived caudal epidural block. thesia.10 They stated that cerebral vasoconstrictive properties may be primar- Propofol has been reported to ily responsible for this decrease in decrease both cerebral metabo- Vmca, also they demonstrated lism and blood flow and increase that propofol has the properties of cerebral vascular resistance in an ideal neuroanesthetic agent. healthy adults even when MAP was kept constant with the use of 24used propofol as induction phenylephrene infusion.2 The in- and maintenance agent in 30 travenous anesthetic propofol has patients requiring general anes- several properties that may be thesia for routine spinal surgery. beneficial to patients with intra- They evaluated the effectiveness of

497 Mohammed A. Sultan, et al.... propofol 1.5 mg/kg induction and lates the rise in ICP secondary to maintenance versus sevoflurane endotracheal intubation.56 Pro- 7% MAC induction and mainte- pofol acutely reduces intraocular nance and found that propofol re- pressure secondary to endotra- duced CBFV and systemic blood cheal intubation.57 flow velocity and the reduction in CBFV was more pronounced than In the present study the maxi- the reduction in systemic blood mum decrease in Vmca with pro- flow velocity, which might be due pofol anesthesia occurred at re- to lower cerebral metabolic de- covery time (Table 4). This may be mand. attributed to the fact propofol impairs its own clearance by de- 53clearly demonstrated that creasing hepatic blood flow.58 propofol is the agent of choice during procedures that require Our results showed that keta- intraoperative neurophysiologic mine produced a significant monitoring of the spinal cord. change in Vmca in ketamine anesthetized patients with mechanical- In our study Vmca was de- ly ventilated lung. Ketamine increased after intubation with pro- creased Vmca compared with pofol anesthesia compared with awake state and throughout the the basal value (table 4). Laryn- study period. goscopy and tracheal intubation may cause significant cerebral 5reported that ketamine in- and systemic hemodynamic reduced increase in CBF velocity sponses, including tachycardia, was not blocked by maintaining hypertension and increased intra- arterial pressure with esmolol cranial pressure. 54 and suggested that ketamine increases CBF velocity via a direct Controlling these responses on effect rather than a secondary ef- induction of anesthesia may be an fect caused by a change in arterial important factor in improving out- pressure. Another explanation for come in neurosurgical patients.55 the ketamine-induced increase in The administration of propofol ab- CBF is that ketamine-induced

498 Benha M. J. Vol. 29 No 1 Jan. 2012 central nervous excitation stimu- cephalogram activity and de- lates cerebral metabolism.59 re- creased CBF in patients during ported that the ketamine-induced propofol sedation or isoflurane / increase in CBF velocity was nitrous oxide anesthesia 6,62, on closely correlated to the increase the other hand,63 used propofol in neuronal activation in healthy 2.5 mg/kg and ketamine 2 mg/kg volunteers. IV induction and anesthesia was maintained with continuous infu- 60concluded that S-ketamine sion of propofol 6 mg/kg hr and increases cerebral blood flow ketamine, 2 mg/kg/hr in38 pa- while cerebral metabolic rate for tients scheduled for non neurolog- oxygen (CMR O2) and glucose ic elective surgery. They found metabolic rate (GMR) does not ketamine did not produce any change during ketamine anesthe- significant change in the middle sia. cerebral artery mean flow velocity in propofol anesthetized patients It was noticed that the addition with mechanically ventilated of ketamine to propofol attenuat- lungs, without neurologic compli- ed the decrease in Vmca and cations, and attributed the inhibi- MABP caused by propofol alone tion of the increase in CBF during and the attenuation was signifi- propofol-ketamine anesthesia to cant throughout the study period the possibility that propofol blocks (Table 4). Our result was support- ketamine induced increase in neu- ed by 61 they stated that the excit- ronal activity. atory properties of ketamine are blunted by propofol, and the seda- Comparison between inhala- tive effects of the combination of tional and intravenous anaesthet- ketamine and propofol were addi- ic agents are difficult, owing to dif- tive at hypotic and anesthesia end ferences in pharmacokinetics, the points. difficulty in measuring intravenous drug concentrations in real This result is contradictory to time and the lack of equivalence some studies which showed that for intravenous anaesthetics of ketamine decreased electroen- minimum alveolar concentrations

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(MAC) of inhalational anaesthet- found that sevoflurane significant ics.64 decreased CBF.

All volatile agents have been Under normal circumstances, demonstrated to cause, cerebral cerebral blood flow is coupled to vasodilatation which may be asso- the cerebral metabolic rate, with ciated with inferior surgical condi- changes in metabolic rate tions compared with propofol. In a matched closely by changes in recent study, the degree of cere- CBF. This flow metabolism bral swelling after opening the coupling has been shown to be al- dura in adults cerebral tumors tered but not abolished by volatile was found to be less in those pa- anesthetics such as halothane, tients receiving propofol compared isoflurane and desflurane. 65 with isoflurane or sevoflurane anesthesia. 14 The net effect of an inhaled anesthetic on CBF depends on the In the current study sevoflu- cerebral metabolic rate before the rane significantly elevated the drug is administered. When the middle cerebral artery mean flow cerebral metabolic rate is already velocity inspite of the reduction of depressed, the anesthetic increas- the mean arterial pressure at 8 es CBF by vasodilatation, but MAC induction and maintenance should it be administered to pa- with 2 MAC sevoflurane. This in- tients who are in a “light plane of crease in Vmca continued anesthesia” or awake, its cerebral throughout the study period apart metabolic depresent effect leads to from the recovery time, at which decrease in CBF. Hence, although the MAC of sevoflurane was re- the major effect on CBF is vaso- duced to 0.5%. Our results are constrictive secondary to flow me- comparable to the results of tabolism coupling at lower con- Mönkhoff et al. (2001), who used centrations, the direct sevoflurane 1.5% as induction fol- vasodilatory effect predominates lowed by 0.5% as maintenance with increases in CBF and loss of in 23 children aged (0.4 - 9.7 yr) cerebral autoregulation at high admitted for elective surgery, and concentrations. 10

500 Benha M. J. Vol. 29 No 1 Jan. 2012 Sevoflurane have less direct gated the influence of sevoflurane vasodilatory effect than either iso- on CBFV when used as the single flurane or desflurane and sevoflu- anesthesia agent, compared with rane (up to 1.5 MA) does not alter awake patient. In addition, they red blood cell velocity.44 The cere- reported a reduction in CBF in the bral vasculature remains capable absence of nitrous oxide. Moreo- of responding to changes in perfu- ver, 44 reported reduced brain ox- sion pressure during 1.5 MAC se- ygen consumption without an ef- voflurane anesthesia when it is fect on CBFV during inhalation of abolished during similar MAC high concentration of sevoflurane concentrations of isoflurane and during propofol anesthesia. Also, desflurane presumably because of 24 found that sevoflurane reduced cerebral vasodilatation. 5 CBFV compared with awake state when anesthesia was induced In another study the workers with 7% sevoflurane and main- recorded that 1.5 MAC of either tained with 1.5% versus propofol. sevoflurane or isoflurane in- At present the most widely accept- creased cerebral blood (17%, 25% ed explanation for the different ef- respectively) and decreased cere- fects of sevoflurane on cerebral bral metabolic rate of oxygen blood flow is that at low concen- (26%, 38% respectively). 19 trations sevoflurane processes an indirect vasoactive action secon- Using PET (positron emission dary to flow-metabolism coupling tomography) 26 demonstrated that so that with the reduction in cere- cerebral blood flow during sevoflu- bral metabolism during anaesthe- rane anaesthesia is dose depen- sia CBF is also reduced. With dent. The drug induces a decrease higher concentrations the direct in cerebral blood flow in all re- vasodilatory effects of sevoflurane gions of the brain of < 1 minimum are more important leading to in- alveolar concentration (MAC), crease in cerebral blood flow. 67 whereas CBF gradually increases in the frontal cortex at 1-1.5 MAC. The most important methodological limitation of TCD sonogra- On the other hand, 66 investi- phy is the fact that it is unable to

501 Mohammed A. Sultan, et al.... measure cerebral blood flow di- either nitrous oxide or air and rectly. Only changes in cerebral found that nitrous oxide increases blood flow velocity as measured in cerebral blood flow velocity in the vessel is proportional to the healthy children anaesthetized change in CBF in the correspond- with 1 MAC sevoflurane. ing vascular territory. The prereq- uisite of the measurements is to Our finding support the con- accept that the blood flow changes cept of 11 who stated that sevoflu- during TCD measurement may rane increased Vmca by 17% at only reflect changes in CBF when 1.5 MAC and sevoflurane has an the diameter of the large vessels intrinsic dose-dependent cerebral remains constant. 67 vasodilatory effect. However, his effect is less than that reported for For animal experiments inhala- halothane, isoflurane and desflu- tional agent exerts its dilative ef- rane at equipotent anesthetic fect on both large and small cere- concentrations. They stated that bral vessels via ATP-sensitive these findings suggest that sevof- potassium-channel activation. 25 lurane has a cerebral hemody- Nitrous oxide increases cerebral namic profile favoring its use in metabolism and CBF in humans neuroanesthesia. This conclusion and animals. 68 was based on their comparison of inhalational anesthetics (halo- 69 reported that administration thane, isoflurane and disflurane) of 50% nitrous oxide with 1 MAC but not with intravenous agents and 1.5 MAC sevoflurane increas- like propofol. es Vmca (2.66%, 3.99% respectively). The mechanism by which Our study showed that PI sig- nitrous oxide increase CBFV are nificantly increased in group P secondary to its excitatory effects compared with groups K, PK on cerebral metabolism. 70 and S. A statistically significant increase in PI was observed after 47 used 1 MAC sevoflurane in induction of anesthesia in propof- 30% oxygen with intermittent ol group and there is a significant positive pressure ventilation with negative correlation between Vmca

502 Benha M. J. Vol. 29 No 1 Jan. 2012 and PI in all groups (Table 5). Our middle cerebral artery did not finding agreed with the results change and concluded that PI of 63 who reported that when the does not change significantly and diameter of MCA is nearly con- CBFV correlates with CBF. They stant, the reduction in Vmca as- used 5 mg/kg thiopental for in- sociated with the an increase in duction of anesthesia which was PI during propofol or propofol- maintained with either sevoflu- ketamine anesthesia is explaina- rane 1.7% or 1.1% isoflurane with ble as a decrease in CBF. 71 dem- 67% nitrous oxide in oxygen with onstrated that mean PI increased epidural block using 1% mepeva- with advancing age, especially in caine in 30 patients. 73 subjects more than 40 years of age. In our study the age of The significant elevation in groups between 20 to 40 years of MABP in ketamine group com- age, which ablates the effect of ad- pared with other groups and with vancing age on PI. basal values throughout the whole period of the study (with its maxi- Moreover, other investigators mum elevation immediately after reported that increased PI usually intubation) (table 6) attributed to occurs because of increased cere- its stimulation to the cardiovascu- bral peripheral resistance secon- lar system which is usually asso- dary to increased intracranial ciated with increase in blood pres- pressure or hypocapnia while de- sure, heart rate and cardiac creased PI is typically displayed by output. Ketamine stimulates the vessels supplying an arteriove- circulatory system by attenuation nous malformation due to de- of baroreceptor function through creased peripheral resistance or the effect on NMDA receptors in downstream to high grade steno- the nucleus tractus solitaries. 74 sis. 72 Ketamine also causes the sym- pathoneuronal release of norepi- In another study the workers nephrine. 75 Our finding support recorded that no changes in PI at the concept of 60 who stated that 20 - 50 mmHg PCO2. This indi- ketamine infusion with serum cates that the resistance of the concentration 30 ng/ml caused

503 Mohammed A. Sultan, et al.... elevation of MABP by 15.3% using crease in MABP and Vmca with positron emission tomography. norepinephrin and phenylephrine There is weak positive correlation was observed during isoflurane between the MABP and Vmca in anesthesia but not during propof- our study. There are some expla- ol anesthesia. nations for the reported ketamine- induced increase in CBF. Keta- 24 found a significant reduc- mine is reported to increase CBF tion in MABP during propofol an- in part because of an increase in esthesia and the cerebral autoreg- MABP and a direct effect on the ulation is preserved, therefore, the brain. 76 reduction in MABP values during propofol anesthesia can’t explain The significant reduction in the observed reduction in CBFV MABP during propofol anesthesia values. in this study is due to direct myocardial depressant effects and vas- The MABP values during pro- odilatation. 77 pofol-ketamine anesthesia administration were slightly and insig- The maximum reduction in nificantly lower than those during MABP that occuerd at recovery the awake state. However, it is time is attributed to the cumula- unlikely that this slight decrease tive effect of poropofol. This rein MABP influenced the Vmca duction in MABP outweighs the, during the anesthesia. Propofol decrease in Vmca. Propofol’s cere- does not affect autoregulation of bral vasoconstrictive properties CBF in rats 40 or humans .10 If may be primarily responsible for autoregulation functions normal- this decrease in CBFV.52 ly, CBF does not change when cerebral perfusion pressure increas- 76 was administrated norepi- es or decreases within certain nephrine and phenylephrine infu- range. In the present study, sion in 40 patients scheduled for MABP did not decrease to < 60 lumbar laminectomy anesthetized mmHg. Thus, the differences in with isoflurane or propofol infu- MABP would not account for the sion, they found a significant in- low Vmca during anesthesia. Our

504 Benha M. J. Vol. 29 No 1 Jan. 2012 finding supports the results of 63 In the present study, the signif- who proved that ketamine does icant increase in HR in all groups not influence Vmca during propof- immediately after intubation is at- ol anesthesia. tributed to that tracheal intubation may cause systemic hemody- The reduction in MABP in se- namic responses, including voflurane group throughout the tachycardia, and hypertension. 54 study period is attributed to the decrease in systemic vascular re- HR was decreased but insig- sistance. 78 nificantly with propofol anesthesia throughout the study period Despite this decrease in MABP, (Table 3). This decrease is at- a significant increase in Vmca ob- tributed to the effect of propof- served in this group which sug- ol either on the baroreflex. 80 Pro- gests a direct cerebral vasodilatory pofol resets or inhibits the effect which partially counteracts baroreflex, thus reducing the the decrease in CBF associated tachycardia response to hypoten- with the reduction in CMR (cere- sion. 81 It attenuates the HR rebral metabolic rate). This hypoth- sponse to atropine in a dose- esis is supported by the investiga- dependent manner.82 tion by 44 The highly significant decrease 79 found that the use of 1 at most of study period is attribut- MAC sevoflurane anesthesia ed to the known depressant affect caused a decrease in global CBF of propofol on cardiovascular sys- as a consequence of reduction in tem. 77 CMR. They used 1 MAC of sevoflurane as a maintenance anesthe- The insignificant reduction in sia after induction with etomidate HR that occurred at 30min, 0.3 mg/kg and nor-epinephrine 120min, 210min and 240min may was administered IV infusion 2 - 5 be methodological in nature. The µg/min to keep the MABP con- significant increase in HR during stant compared with baseline val- ketamine anesthesia: immediately ues. after induction, postintubation

505 Mohammed A. Sultan, et al.... and at 30min is due to the cardio- The significant increase in HR vascular stimulant effect of keta- in sevoflurane group at post intu- mine. The mechanism by which bation time is due to sympathoa- ketamine stimulates the circulato- drenal effect of laryngescopy and ry system seems to be ketamine intubation.86 attenuates baroreceptor function through an effect on NMDA recep- Because of the use of 100% tors in the nucleus tractus solitar- O2 in this study that there ies. 74 The insignificant decrease was no significant alteration in in HR starting at 60min and the oxygen saturation in all throughout the study period till study patients. Also, the end ti- recovery time is attributed to that dal carbon dioxide was adjusted a second dose of ketamine produc- to be within the required physio- es hemodynamic effects less than logical range. The influence of or even opposite those of the first CO2 partial pressure and oxygen dose 83 saturation (and oxygen tension) on vessel diameter and Vmca is 84 suggested that is also possi- well known. Therefore both vari- ble to lessen the tachycardia and ables were maintained constant hypertension caused by ketamine throuughout the application of an- by using a continuous infusion esthesia technique with or without benzod- iazepine. Conclusion We found a decreased both In the current study the addi- cerebral blood flow velocity tion of ketamine to propofol anes- and systemic blood pressure thesia increased HR immediately at propofol anesthesia and an after induction and intubation, increase in systemic blood due to sympatho-adrenal reflex of pressure, cerebral blood flow intubation. The insignificant de- velocity at ketamine and se- crease in HR after that and voflurane anesthesia. These throughout study period, may be findings may have important attributed to the effect of propofol implications in the neurosurgi- on baroreceptors. 85 cal setting.

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515 REPRINTMohammed A. Sultan, et al.... BENHA MEDICAL JOURNAL

TIVA VERSUS SEVOFLURANE EFFECT ON CEREBRAL BLOOD FLOW A TRANSCRANIAL DOPPLER STUDY

Mohammed A. Sultan MD, Ahmed E. Mahmoud MD, Olfat M. Ismail MD and Tarek M. Shams MD

Published by Benha Faculty of Medicine Volume 29 Number 1 Jan. 2012

516 Benha M. J. Vol. 29 No 1 Jan. 2012 URINARY TRACT INFECTION IN INFANTS AND CHILDREN WITH DIARRHEA

Abdelhamid A. Abdelhamid MD, Ghada S. Abdelmotaleb MD, Yaser M Ismail MD* and Ehab M. Taher MBBCH. Departments of Pediatrics and Clinical Pathology*, Faculty of Medicine, Benha University, Egypt.

Abstract The urinary tract is the most common site for serious bacterial infections in infants and young children. The epidemiology of UTI is con- founded by the variability and non-specificity of signs and symptoms. Diarrhea may be the presenting symptom in younger children with UTI. Objective: to estimate the incidence of UTI in infants and children with diarrhea and to identify the clinical correlates which may help to identify UTI cases. Methods: we studied 160 patients presented with diarrhea aged 4 weeks to 5 years, admitted to Benha children hospital, in the period from April to November 2011. Blood sample was taken for CBC, CRP, urea and creatinine. Urine samples were taken from all patients and examined by dipstick; in dipstick positive cases (either for leucocytes or nitrite), another sample for culture was taken. Results: one hundred sixty patients were included in the study. The incidence rate was 6.8%, 63.6% of them were females. The majority of the patients (45.5%) were between 2 to 5 years of age. E.coli was the most common isolated organism (90.9%). Fever, recurrent diarrhea and artificial feeding were significantly associated with UTI. Conclusion: The results of our study shows that female, fever and history of recurrent diarrhea are significantly associated with UTI cases which presented by diarrhea.

Introduction dence of UTIs in childhood is not Urinary tract infections (UTIs) precisely known because it is not in children are common and a ma- a reportable disease and in many jor source of morbidity. The inci- cases, especially in infants, UTI

517 Abdelhamid A. Abdelhamid, et al.... are probably under diagnosed(1). may help to identify UTI cases. Although UTI is infrequently associated with mortality, delay in the Patients and Methods treatment of UTI can lead to vesi- One hundred and sixty patients co-ureteral reflux and renal scar- enrolled within the study aged 1 ring(2). Recognition that UTI can month to 5years from pediatric de- cause renal parenchymal and partment, Benha Children's Hos- functional loss has prompted rec- pital, in the period from April to ommendations for rapid diagnosis November 2011. and evaluation of UTI with genitourinary imaging techniques and Inclusion criteria : Diarrhea tests. In infants, UTI is a common less than 2 weeks is the present- cause of fever and may be the ing complaint and without use of most common cause of renal pa- antibiotics during the previous 48 renchymal damage and loss(3). hours. 1- Complete detailed history Diarrheal disease is a funda- was obtained from all cases with mental threat to the health of chil- special emphasis on: dren in the developing world. Sec- - Frequency, consistency and ond only to respiratory infection, volume of stool, the duration diarrheal disease is a leading of diarrhea, and presence of cause of death among the world’s mucus or blood in it. children, responsible for approxi- - Child activity, frequency of mately two million deaths annual- urination, information about ly, under the age of 5(4). Diarrhea oral intake or thirst. Associat- may be the presenting symptom in ed symptoms, such as fever younger children with UTI(5). preceding the onset of diarrhea, vomiting, abdominal Objective : pain (unexplained excessive The present study was under- crying in young infants). taken to estimate the incidence of - Any urinary symptoms like UTI in infants and children pre- e.g.: interrupted stream seen senting with diarrhea and to iden- by the mother, straining & tify the clinical correlates which crying with micturation.

518 Benha M. J. Vol. 29 No 1 Jan. 2012 2- Complete physical examina- stream in toilet trained and tion was performed, with particu- by catheterization in infants. lar attention to signs of dehydra- Then the sample was sent tion. immediately to the laboratory for culture. If the culture 3- Investigations : shows > 100,000 colony- All samples were taken after forming units/mL of a single parent consent and before start pathogen, the child was con- any medications. sidered to have a UTI.

A- Blood sample for: D- A stool sample was evaluat- - Complete blood count, C- ed to determine number of reactive protein pus cells, if >10/hpf, it was - Blood urea and serum invasive diarrhea and if <10 creatinine. it was non invasive diarrhea.

B- Urine sample was taken E- All patients who had UTI from all patients. In infants, were subjected to ultra- the application of collection sound examination of the bag after disinfection of the kidney, ureter and bladder, skin of the genitalia. In toilet to exclude congenital anom- trained children, the urine alies. sample was midstream. The sample was tested immedi- Statistical methodology: ately using urine dipstick. If The collected data were tabu- the tested urine was positive lated and analyzed using the suit- for nitrite or leukocyte este- able statistical methods": rase, the patient was consid- 1- Test of proportion (Z test) ered suspicious of UTI, and which used to compare be- then urine culture was done. tween 2 percentages. 2- Student t test which used to C- The urine culture was compare between 2 means withdrawn after disinfection and standard deviations of of the genitalia; it was mid- 2 groups.

519 Abdelhamid A. Abdelhamid, et al....

3- Paired "t" test which used to was statistically significant associ- compare between 2 means of ation. Fever among UTI cases was the same group before and 100% as compared to 23.5% after treatment. amongst those without UTI.

Results In our study, urinary symp- The overall incidence of UTI in toms like (interrupted stream seen children presenting primarily with by the mother, straining &crying diarrhea was 6.8%. As regard the with micturation) was present in sex distribution of UTI cases, we 45.5% of UTI cases, which was found that 63.6% of our cases statistically insignificant associa- were females. tion. As regard history of recurrent diarrhea, it was present in The distribution of our cases 81.8% of UTI cases, which was according to age was : (9.1%) in statistically significant association 1:5 months, (36.4%) in 6:11 fig. (1). months, (9.1%) in 12:23 months and (45.5%) in 2:5 years. As regard the distribution of UTI cases according to degree The incidence of UTI amongst of dehydration 54.5% no dehy- those with malnutrition (weight dration, 45.5% dehydrated less than 3rd percentile of the which was statistically insignifi- standard for age and sex) was cant. 6.1% as compared to 7.5% among those with no malnutrition. In our study, as regard type of feeding, among UTI cases 81.8% As regard the incidence of vom- was artificially fed, which was sta- iting among UTI cases was 63.6% tistically significant association with no significant difference. In with UTI cases. We found that our study, the duration of diar- E.coli was the most common iso- rhea (≥7 days) among UTI cases lated organism (90.9%) of cases, was 81.8% as compared to 18.2% followed by klebseilla (9.1%) of amongst those without UTI, which cases.

520 Benha M. J. Vol. 29 No 1 Jan. 2012

521 Abdelhamid A. Abdelhamid, et al....

Discussion The overall incidence of UTI in The urinary tract is a common children presenting primarily with site of infection in the pediatric diarrhea was 6.8% in agreement population.Unlike the generally with Thakar et al., 2000(7) 8 cases benign course of urinary tract in- (8%) out of 100 children with diar- fection (UTI) in the adult popula- rhea have UTI. Also 8 cases (6.7%) tion, UTI in the pediatric popula- out of 120 children with diarrhea tion is well recognized as a cause have UTI(8). of acute morbidity and chronic medical conditions, such as hy- As regard the sex distribution pertension and renal insufficien- of UTI cases, we found that 63.6% cy in adulthood. The true inci- of our cases were female which dence of pediatric UTI is difficult is consistent with Shah et al., to determine because there are 2008(9) study where (65.3%) were varying presentations that range females. Also agree with(8) 87.5% from an absence of specific uri- were females, Thakar et al., 2000. nary complaints to fulminate uro- sepsis(6). As regard the age distribution of our cases, the majority of UTI Diarrhea is a common manifes- cases were in the following age tation of UTI in this period. There groups : (45.5%) were between 2:5 have been a limited number of years and (36.4%) between 6:12 studies on the correlation between months. While in other reports UTI and acute diarrhea and it is (11.4%) in 12:24 months, (39.2%) still not clear when to investigate in 3 : 6 years(2). for UTI in young children presenting with diarrhea(7). In other study (12.5%) in 0:6 months, (75%) 6:12 months and Our study was undertaken to (12.5%) 12:24 months(7). estimate the incidence of UTI in infants and children presenting Shah et al., 2008(9) found that with diarrhea and to identify the (20.2%) were 24 to 47 months old, clinical correlates which may help and (32.7%) were greater than 4 to identify UTI cases. years of age.

522 Benha M. J. Vol. 29 No 1 Jan. 2012 The incidence of UTI among and(3) found that 67% of cases those with malnutrition (weight with UTI were feverish. less than 3rd percentile of the standard for age and sex) was In our study, urinary symp- 6.1% as compared to 7.5% toms (interrupted stream seen by amongst those with no malnutri- the mother, straining & crying tion, in contrast to other investiga- with micturation) were present in tors. UTI was found in 15.2% of 45.5% of UTI cases, with statisti- malnourished patients and (1.8%) cally insignificant association, in controls(10). Also UTI was found in agreement with(12) who found that 17.2 % of severe malnutrition cas- urinary symptoms was present in es & 4.2% among cases without 8.6% (insignificant). malnutrition(7). As regard history of recurrent As regard the incidence of vom- diarrhea, it was present in 81.8% iting among UTI cases was 63.6% of UTI cases, which was statisti- with no significant difference. cally significant, in agreement with(7). Thakar et al., 2000 who In our study, the duration of di- found that 75% of UTI cases had arrhea was (≥7 days) among UTI history of recurrent diarrhea. cases in 81.8% compared to 18.2% amongst those without UTI, As regard the distribution of which was statistically significant. UTI cases according to degree of dehydration 54.5% had no In this study, fever among UTI dehydration and 45.5% dehydrat- cases was 100% compared to ed which was statistically insig- 23.5% amongst those without UTI, nificant association, in contrast in agreement with Bay and An- to(7) : among UTI cases 75% were acleto (2010)(2) who found that dehydrated. fever was the most common presenting symptom, accounting for In our study, as regard type 63.6% of patients. Also Brein et of feeding among UTI cases al., 2011(11) said that fever was 81.8% of the cases was artificially present in 69% of UTI cases, fed, with statistically significant

523 Abdelhamid A. Abdelhamid, et al.... difference with breast fed ,in arrhea, it would be wise to screen agreement with study that found febrile infants specially females that ongoing exclusive breast feed- with recurrent diarrhea for UTI. ing has been shown to be associated with a significantly lower References risk of UTI.(13) 1- Bauer R. & Kogan B. (2008) : New developments in the Ladomenou 2010 found that diagnosis and management of pe- prolonged exclusive breastfeeding diatric UTIs. Urol Clin N Am; 35: was associated with fewer infec- 47-58. tious episodes. In contrast to (15) The study that found no signifi- 2- Bay A. and Anacleto F. cant difference between the rates (2010) : Clinical and laboratory of positive urine cultures in exclu- profile of urinary tract infection sively breast fed and formula-fed among children at the outpatient infants. clinic of a tertiary hospital. PIDSP Journal; 11 (1): 10 -16. We found that E.coli was the most common isolated organism 3- Shortliffe L. (2011) : Infec- from the cases, and secondly kleb- tion and Inflammation of the seilla (9.1%) of cases in agreement Pediatric Genitourinary Tract. In with (9) who found E. coli to be the Campbell-Walsh Urology, 10th cause of UTI in 82.7% of his pa- edition, Wein A, Kavoussi L & tients, followed by Enterococcus Novick A et al., editors. Philadel- spp, Staphylococcus spp, and phia, Saunders, Elsevier. Pp3085- then Proteus mirabilis/ Klebsiella 3122 / Streptococcus. Also agree with the study carried on 120 children 4- Sengupta A. & Mannan M. with diarrhea, who found that (2005) : Diarrheal diseases in E.coli in 87.5% of cases and children. Quarterly Medical Rview; 12.5% was pseudomonas(8). Vol. 56 : F-35.

Conclusion 5- Shortliffe L. (2002) : Uri- In children presenting with di- nary tract infections in infants

524 Benha M. J. Vol. 29 No 1 Jan. 2012 and children. In: Campbell’s urol- 11- Brein K., Stanton N. & ogy, 8th edition, Walsh PC et al, Edwards A. (2011) : Prevalence of editors. Philadelphia, WB Saun- urinary tract infection (UTI) in se- ders. Pp1846-84. quential acutely unwell children presenting in primary care: Ex- 6- Chang L. & Shortliffe L. ploratory study. Scandinavian (2006): Pediatric Urinary Tract In- Journal of Primary Health Care; fections. Pediatr Clin N Am; 53 : 29 : 19-22. 379-400. 12- Shaw K., Gorelick M., 7- Thakar R., Rath B., Pra- McGowan K., et al., (2011) : kash S., et al., (2000) : Urinary Prevalence of Urinary Tract Infec- tract infection in infants and tion in Febrile Young Children in young children with diarrhea. the Emergency Department. Paed- Indian pediatrics; 37 (8) : 886-9. iatrics; 102 (2): 1-5.

8- Fallahzadeh M. and Ghane 13- MÃ¥rild S. (2004) : Protec- F. (2006) : Urinary tract infec- tive effect of breastfeeding against tion in infants and children urinary tract infection. Acta Paedi- with diarrhea. Eastern Mediterra- atr; 93(2): 164-8. nean Health Journal; 12 (5):690- 694. 14- Ladomenou F. (2010) : Protective effect of exclusive 9- Shah L., Mandlik N., Ku- breastfeeding against infections mar P., et al., (2008) : Adherence during infancy: a prospective to AAP Practice Guidelines for Uri- study. Arch Dis Child; 95(12): nary Tract Infections at Our 1004-8. Teaching Institution. Clinical Pedi- atrics; 47(9):861-864. 15- Katikaneni R. (2009) : Breast feeding does not protect 10- Bagga A., Tripathi P., Ja- against urinary tract infection in tana V., et al., (2003) : Bacteru- the first 3 months of life, but vita- ria and urinary tract infections in min D supplementation increases malnourished children. Pediatr the risk by 76%.Clin Pediatr (Phi- Nephrol; 18:366-370. la); 48(7): 750-5. 525 REPRINTAbdelhamid A. Abdelhamid, et al.... BENHA MEDICAL JOURNAL

URINARY TRACT INFECTION IN INFANTS AND CHILDREN WITH DIARRHEA

Abdelhamid A. Abdelhamid MD, Ghada S. Abdelmotaleb MD, Yaser M Ismail MD and Ehab M. Taher MBBCH.

Published by Benha Faculty of Medicine Volume 29 Number 1 Jan. 2012

526 BENHA VOLUME 29 NO. 1 MEDICAL Jan. 2012 JOURNAL CONTENTS

1 TRAUMATIC INJURY OF THE SUPERIOR MESENTERIC VESSELS Khaled Mowafy MD, Hosam Roshdy MD, Khaled El Alfy MD and Mohamed Gad MD 9

2 COMBINED EFFECT OF ANGIOTENSIN RECEPTOR BLOCKER, AND ANTIOXIDANTS ON RECOVERABILITY OF RENAL FUNC- TIONS AFTER RELIEF OF PARTIAL URETERAL OBSTRUCTION OF SOLITARY KIDNEY Abdel-Aziz M. Hussein MD, Azza Abdel-Aziz MD, Amira Awadalla MD and Nashwa Barakat MD 21

3 PSYCHIATRIC ADVERSE EFFECTS DURING COMBINATION THERAPY OF PEGYLATED INTERFERON PLUS RIBAVIRIN FOR CHRONIC HEPATITIS C PATIENTS : A PROSPECTIVE LONGITUDI- NAL STUDY El-Sayed El-Nagar MD, Mohamed E. Khater MD, Gamal Shiha MD, Salwa S. Tobar MD, and Ibtihal M. A. Ibrahim MD 43

4 POPLITEAL SCIATIC NERVE BLOCK FOR ANKLE AND FOOT SUR- GERY, A COMPARITIVE STUDY BETWEEN THE MODIFIED IN- TERTENDINOUS AND THE LATERAL APPROACHES Ibrahim M. Abd Elmoeti MD, Mohamed Y. Serry MD, Ahmed Mos- tafa MD and Ahmed Hamdy M.Sc 57

5 MANSOURA EXPERIENCE IN PARTIAL ULNAR NERVE TRANSFER TO RESTORE ELBOW FLEXION IN UPPER TRUNK TRAUMATIC BRACHIAL PLEXUS INJURY Yahia E. Bassiony MD, Mostafa A. El-Saied MD, Tarek A. El- Gammal MD, Mohamed A. El-Said MD, Yaser Y. Abd El-Rahman MD and Khaled A. Nour M.Sc 79

6 PREDICTIVE VALUE OF TISSUE DOPPLER ECHOCARDIOGRAPHY IN DIFFERENTIATING PRIMARY DILATED CARDIOMYOPATHY FROM ISCHEMIC CARDIOMYOPATHY Mohammed B. Shehab El-Din MD, Eman E. El-Safty MD, Maged Z. Amer MD and El-Saeed M. El-Saeed M.Sc. 93

7 POSTOPERATIVE COGNITIVE DYSFUNCTION IN DIABETIC VER- SUS NON DIABETIC PATIENTS: EFFECTS OF PERIOPERATIVE BLOOD GLUCOSE CONTROL REGIMENS Ahmed M. F. Hassan M.Sc., Gihan A. Tarabih MD, Mohammed A.E. Al-Hadedy MD, Mahmoud M. Othman MD and Golinar E. Hammouda MD 111

8 BCL10 PROTEIN EXPRESSION IN MALT LYMPHOMA Afaf T. Ibrahiem M.Sc, Amira K. El-Hawary MD, Dina A. El- Tantawy MD, Ibrahiem El-Shawaf and Ahmed A. El-Hanafy MD 131 9 ROLE OF GAMMA KNIFE IN MANAGEMENT OF SKULL BASE TU- MORS Wael K. Zakaria MD, Mohamed S. Ibrahim MD, Nabil M. Ali MD, Raef F. Hafez MD and Ahmed A. Zaher MD 143

10 IMMEDIATE MATERNAL AND NEONATAL MORBIDITY ASSOCIAT- ED WITH VACUUM EXTRACTOR DELIVERY, AT UNIVERSITY TEACHING HOSPITAL EXPERIENCE Nabeel Bondagji MD Frcs(C) and Hisham Ramadani Frcs(C) 161

11 EVALUATION OF N-ACETYL CYSTEINE (NAC) AS A POSSIBLE PROTECTIVE FACTOR IN THE PREVENTION OF RETINOPATHY OF PREMATURITY (ROP) : HISTOLOGICAL AND IMMUNOHISTO- CHEMICAL STUDY Azza R. El-Hadidy Ph.D, Essam A. El-Mohandess Ph.D, Samar A.Asker Ph.D and Fatma M. Ghonaim MS.c 177

12 MICRODEBRIDER OUTCOME VERSUS PARTIAL TURBINECTOMY : IN CHRONIC HYPERTROPHIED TURBINATE Mohamed A. M. Eltoukhy MD 191

13 PEGYLATED INTERFERON / RIBAVIRIN-INDUCED THYROID DYS- FUNCTION IN PATIENTS WITH CHRONIC HEPATITIS C Raghda E. Farag MD, Khaled Farid MD, Asmaa Hegazy MD, Azza Abdel-Baky MD, Basem S. Eldeek MD, Lamiaa Arafa MD and Adel Abdel Salam MD 203

14 THE EFFECT OF STIMULATION OF PROTEIN KINASE Ca ON EPI- DERMAL WOUND HEALING IN MICE Dalia M. Abd El-Monem M.Sc, Omar M. Gabr MD, Kamal G. Botros MD, Rauf F. Bedir MD and Olfat N. Hasan MD 217

15 BIOCHEMICAL ALTERATIONS IN ADIPONECTIN AND THE ACTIV- ITY OF MYELOPEROXYDASE IN ACUTE MYOCARDIAL INFARC- TION INDIVIDUALS Hussein Abd El-Maksoud Ph.D, Raafat R. Gindi Ph.D and Yaser M. Abdel-Nabi M.Sc. 233

16 PEDIATRIC ILIOINGUINAL/ILIOHYPOGASTRIC BLOCK (HIGH OR LOW APPROCHES) “ANALGESIC & SURGICAL OUTCOME- SATISFACTION “ Mohamed A. Ghanem MD 245

17 LOCKED COMPRESSION PLATE FOR COMPLEX HUMERAL FRAC- TURES Mahmoud Zayed MD 259

18 PHENYTOIN : IS IT GENOTOXIC IN ISOLATED CULTURED HU- MAN LYMPHOCYTES WITHOUT METABOLIC ACTIVATION? Mahmoud A. Naga MD, Mohamad-Hesham Y. Daba MD, Nadia K. El-Gamal MD, Mohamed A. Abd El-Azeaz MD and Sabry M. Zeid MD 269

19 THE ROLE OF TISSUE DOPPLER IMAGING DURING DOBUTA- MINE STRESS ECHOCARDIOGRAPHY IN DIFFERENTIATING IS- CHEMIC FROM NON-ISCHEMIC CASES OF DILATED CARDIOM- YOPATHY Hesham Rashid MD, Mohamed Hassan MD, Saad Ammar MD, Adel Gamal MD and Hitham Ahmed M.B.B.CH 287 20 PREDICTORS OF SUCCESS OF MICROSURGICAL EPIDIDYMOVA- SOSTOMY FOR OBSTRUCTIVE AZOOSPERMIA Magdy A. El-Tabey MD and Samy Tosson MD 305

21 DIAGNOSTIC VALUES OF CRP, IL-6 AND ICAM-1 AS MARKERS OF BACTERIAL INFECTION IN THE NEONATES Mohamed Al-Eraki MD and Lotfy Abdel-Fattah MD 321

22 TRIPLE ATTACK IN MANAGEMENT OF DDH IN CHILDREN AFTER WALKING AGE UP TO FIVE YEARS Salah Youssef MD and Mohamed El Manawy MD 343

23 TIMING OF SURGERY IN ELDERLY PATIENTS WITH HIP FRAC- TURES Salah Youssef MD, M. M. El-Menaway MD and Samir El Shora MD 361 24 EFFECT OF MALARIA ON PREGNANCY OUTCOME IN HAJJAH GOVERNATE IN YEMEN Ibrahim A. Abdel Motagaly MD, Osama K. Raslan MD, Ahmed T. Abdel-Fattah MD and Said M. Al-Barshomy MD 375

25 COMPARISON BETWEEN TRANSPULMONARY VENOUS FLOW AND TISSUE DOPPLER OF DIASTOLIC FUNCTION IN HYPERTEN- SIVE PATIENTS Hesham Rashid MD 383

26 SERUM TRACE ELEMENTS CONCENTRATIONS (CA - CU - ZN - CU/CA AND CU/ZN RATIO) IN RELATION TO DISEASE ACTIVITY SCORES IN PATIENTS WITH RHEUMATOID ARTHRITIS Reham M. Shaat MD, Afaf M. Attia MD and M. EL-Defrawy Ph.D. 407

27 SURGICAL TREATMENT OF POSTERIOR WALL FRACTURES OF THE ACETABELUM Mohamed El-Menawy MD 415

28 DEXMEDETOMIDINE, FENTANYLE AND KETAMINE PROVIDE DEEP SEDATION FOR DEBRIDEMENT AND DRESSING OF HAND SPACE INFECTION Doaa G. Diab MD, Enas Abd El-Motlb MD and Hosam Ghazy MD 429

29 BALLOON DISSECTION FOR EXTRAPLEURAL APPROACH IN (TRACHEO-ESOPHAGEAL FISTULA) TEF REPAIR Basem Saied MD, Adham Elsaied MD and Hesham Sheir MD 443

30 COLORECTAL CARCINOMA BELOW 30 YEARS : A RETROSPEC- TIVE STUDY ON EGYPTIAN PATIENTS : 2000-2010 Alaa Magdy MD, Waleed Thabet MD, Waleed Omar MD, Adham El- saeed MD and Mohammed Farid MD 453

31 THE RELATION BETWEEN HEMOGLOBIN LEVEL AND NUTRI- TIONAL STATUS OF PRESCHOOL CHILDREN IN TRIPOLI CITY Najat M. Burshan MD, Mustafa Elheggiagi MD, Omar Abusnena MD and Areej Elheggiagi MD 465

32 EPIDEMIOLOGICAL FEATURES OF INTESTINAL AND ECTO- PARASITES IN PRESCHOOL CHILDREN IN TRIPOLI CITY Najat M. Burshan MD, Mustafa Elheggiagi MD, Omar Abusne- na MD and Areej Elheggiagi MD 473 33 TIVA VERSUS SEVOFLURANE EFFECT ON CEREBRAL BLOOD FLOW A TRANSCRANIAL DOPPLER STUDY Mohammed A. Sultan MD, Ahmed E. Mahmoud MD, Olfat M. Is- mail MD and Tarek M. Shams MD 481

34 URINARY TRACT INFECTION IN INFANTS AND CHILDREN WITH DIARRHEA Abdelhamid A. Abdelhamid MD, Ghada S. Abdelmotaleb MD, Yaser M Ismail MD and Ehab M. Taher MBBCH. 517 BENHA MEDICAL JOURNAL

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Authors should describc the plan of References to personal communica- their investigation indicating the num- tions and 'unpublished work' may be ber of expcrimental units (e. g. sub- quoted in the text but should not be jects; blood samples). For repeated ob- included in the references. servations, their numbers and timing Examples of the style to be used are should be specified. Control subjects given below: should be described as completely as Trudiner B.J., Lewis p.j. & petit, B. the experimental subjects . (2000); fetal breathing in intrauterine Measures of location (e.g. mean, me- growth retardation. Br J Obstet Gy- dian) should be accompanied by an naecol, 86:432. appropriate measure of variability, Hytten, F.F & Leitch I. (2000): The e.g. standard deviation (SD) or stan- physiology of Human pragnancy 2nd dard error of the mean (SEM). Meth- edn, Blackwell Scientific publications, ods of statistical analysis should be Oxford, p.26. indicated, but details are not required It must be noted that :- unless relevant to the discussion. In Publication will not be done and the multivariate analysis, an indication of letter of acceptance will not be given the goodness of fit of the model except after the approval for publica- should be given (e.g.multiple correlation by referees and payment of the tion coefficient). When a result is publication fees. claimed to be statistically significant Off Prints for contributors the test used and the level of probabil- Fifty off prints of each paper are ity should be specified (e.g. paired t- supplied free, but additional copies test p<0.01) When only one type of may be rdered on the printed card statistical test is used in the paper, it sent with the proofs.