Use of Recombinant Human Activated Protein C in Treatment of Severe

Home , Drotrecogin alfa, Enoxaparin sodium

Received: 2004.07.20 Accepted: 2005.01.21 Use of recombinant human activated protein C in Published: 2005.06.01 treatment of severe sepsis in a pregnant patient with CS fully symptomatic ovarian hyperstimulation syndrome Authors’ Contribution: A Study Design B Data Collection Małgorzata Mikaszewska-SokolewiczABCDEFG, Ewa Mayzner-ZawadzkaACDE C Statistical Analysis D Data Interpretation 1st Department and Chair of Anesthesiology and Intensive Care, Medical University of Warsaw, Warsaw, Poland E Manuscript Preparation F Literature Search Source of support: Departmental sources G Funds Collection

Summary

Background: Severe sepsis during pregnancy is a life-threatening condition for the mother, due to multiorgan failure and uncontrolled infl ammatory response. It is associated with high risk of death for the fetus. Case Report: The paper presents the course and treatment of severe iatrogenic sepsis in a patient in very early pregnancy. The sepsis was a result of complications after overstimulation of the ovaries in the course of treatment of infertility. The risk of the patient’s death, assessed in the Intensive Care Unit according to APACHE II and SAPS II scores was 73%, whereas indirect assessment of the embryo in the 3rd week of pregnancy, based on determination of serum gestational hormone levels was ambiguous, but rather unfavorable. The patient’s condition improved considerably after intensive treatment, including, among others, the use of activated protein C (APC). After the com- pletion of treatment, in the 5th week of pregnancy, the gestational hormone levels increased to the values appropriate for such fetal age. The development of pregnancy was also confi rmed by ultrasonography. Conclusions: The paper presents a case of severe sepsis in the course of ovarian hyperstimulation syndrome, not described in the literature so far, as well as the fi rst successful administration of activated protein C in 21-day pregnancy.

key words: severe sepsis • ovarian hyperstimulation syndrome • recombinant human activated protein C (rhAPC)

Full-text PDF: http://www.MedSciMonit.com/pub/vol_11/no_6/6069.pdf Word count: 2365 Tables: 3 Figures: 4 References: 18

Author’s address: Dr Małgorzata Mikaszewska-Sokolewicz, Department and Chair of Anesthesiology and Intensive Care, Medical University of Warsaw, ul. W. Lindleya 4, 02-005 Warsaw, Poland, e-mail: [email protected]

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BACKGROUND Examination of the abdomen revealed tenderness, weak muscle guarding and no bowel sounds. Ultrasonography, Sepsis in pregnancy may have various etiology. Pregnancy transabdominal and with a vaginal probe, did not reveal causes numerous changes in the woman’s organism which the presence of any abscesses in the ovaries and abdominal may affect the quality of infl ammatory response in the course cavity. On the other hand, the examinations confi rmed the of sepsis and increase the probability of septic shock. Severe presence of a blastula in the uterus and fl uid in the perito- sepsis is associated with multiorgan failure syndrome, which neal cavity. Complete hemodynamic monitoring (invasive develops as a result of excessive or imbalanced response of measurements of cardiac output, systemic and pulmonary the organism to an infection. pressures), monitoring of ventilation parameters (airway presure, lung compliance and capnometry), diuresis and Ovarian hyperstimulation syndrome is a result of excessive metabolism was started. Empirical antibiotic therapy was ex- reaction of iatrogenic etiology, caused by pharmacological tended by instituting carbapenem meropenem. The patient induction of ovulation during the treatment of infertility. was sedated by i.v. diprivan infusion and received treatment Severe sepsis coincident with ovarian hyperstimulation syn- supporting the impaired function of organs. Initially, she drome leads to disturbances of blood supply to, and func- required ventilation with FiO2=1.0 and cardiovascular function of many organs, together with coagulation abnormali- tion assistance with epinephrine, norepinephrine and dob- ties, and reduced blood supply to the uterus can cause fetal utamine infusion. Diuresis was promoted by administration death, additionally worsening the patient’s condition and of fractionated furosemide doses. The treatment with plas- prognosis. Each of these disorders separately is life-threat- ma preparations and albumins was also continued. ening for the patient. The paper presents the fi rst successful administration of activated protein C in a patient with After the initial compensating treatment and stabilization severe sepsis in 21-day pregnancy. of the patient’s general condition, the case was consulted with the following specialists (Table 1). CASE REPORT The patient was diagnosed with severe sepsis, developed in A female patient aged 31 was admitted to the ICU at the the course of ovarian hyperstimulation syndrome (Table 2). onset of septic shock. During the period immediately pre- Staphylococcal etiology was suspected. ceding the admission to the ICU she had been hospitalized in the gynecological ward, where she had been treated for The dynamics of sepsis progression, low effi cacy of stand- ovarian hyperstimulation syndrome due to treatment of in- ard therapy and high risk of the patient’s death was con- fertility and preparation of the patient for in vitro fertiliza- sidered to necessitate a quick decision concerning the ad- tion with subsequent embryo transfer. ditional use of recombinant human activated protein C (rhAPC) in the therapy. On the 10th post-transfer day, the patient returned to the hos- pital because of malaise, faintness and ascites. Fully symp- Before the institution of the drug, the indications for, and tomatic ovarian hyperstimulation syndrome was diagnosed benefi ts of the therapy, as well as the risks associated with and symptomatic treatment with anticoagulation prophylac- the use of activated protein C, were analyzed thorough- tics enoxaparin sodium was instituted. The patient received ly (Table 3). FFP and albumin infusions and decompressing puncture of the peritoneal cavity was performed twice, resulting in evac- The patient required the dose of 138.2 mg rhAPC adminis- uation of the total of 3000 ml exudate from the peritoneal tered as i.v. infusion over 96 h. According to the manufactur- cavity. On the 21st post-transfer day, the patient’s tempera- er’s instructions, the drug was infused at 24 mcg/kg/h rate. ture increased to 38°C, with progressive faintness, dyspnea and vision disturbances. Physical examination revealed dis- On the second day of activated protein C infusion, the pa- turbances of consciousness in the form of confusion and hal- tient’ general condition improved signifi cantly. The fever lucinations, progressive vision disturbances, hypotension 60/ subsided, the leukocytosis and CRP level in the serum de- 40 mmHg, tachycardia 170/min, dyspnea and anuria. After creased (Figure 1). Blood cultures confi rmed Staphylococcus fl uid resuscitation, dopamine infusion and administration of aureus infection. The strain was sensitive to chinolones. furosemide, scanty diuresis was obtained. Material for micro- biological investigation was collected ( blood, sputum and Hemodynamic parametrs were assessed by measurements urine), with subsequent institution of antibiotic therapy (cip- and calculations obtained from pulmonary artery catheter, rofl oxacin). Because of dyspnea aggravation (PaO2 decrease and noninvasivly from esophageal Doppler electrode fi rst to 40 mmHg, pleural exudate in clinical examination and and later from Echocardiography ( Figure 2). on chest X-ray), circulatory failure and renal dysfunction, the patient was transferred to the intensive care unit where Stabilization of the cardiovascular system allowing to dis- she was intubated. On intubation, the presence of purulent continue epinephrine and norepinephrine infusion was ob- discharge in the airways was observed. The bronchial secre- tained. Persistent systolic murmur over the mitral valve was tion was taken for cultures. The patient required ventilation still detectable on auscultation. with 100% oxygen, the use of catecholamines and diuresis forced with high furosemide doses. Chest auscultation re- Sedation was discontinued and oxygen supply in the gas mix- vealed disseminated rales over the pulmonary fi elds as well ture reduced, the ventilation mode was changed to sponta- as systolic murmur over the heart. Transthoracic echocar- neous respiration with PS and PEEP, and on the subsequent diography did not reveal impaired myocardial contractility, day assisted ventilation was stopped. The values of PaO2/FiO2 valve defects or exudate in the pericardial sac. ratio were improved during the tratment (Figure 3). CS28 Med Sci Monit, 2005; 11(6): CS27-32 Mikaszewska-Sokolewicz M et al – Use of APC in pregnant patient with severe sepsis

Table 1. Specialist consultations.

The value of neurological examination doubtful because of diprivan sedation. No signs of paresis of the Neurologist extremities, tendon refl exes normal, meningeal signs absent, cerebrospinal fl uid sterile, normal fl uid pattern in general examination. No abnormalities of the anterior portions of the eyeballs. The optic discs well-delineated, pale, course and Ophthalmologist diameter of blood vessels normal, the retina unaff ected. The patient’s acute blindness unlikely to be of central origin, e.g. as a result of sclerosis multiplex. CS Enhanced left lung contour on X-ray (purulent discharge found in the airways on intubation allows to interprete Radiologist the image abnormality as an infl ammatory lesion). Transabdominal USG shows no signs of progressive ascites. Fluid of low density. No abscesses on the ovaries and abdominal organs. A blastula present in the uterine cavity. Hyperkinetic circulation. Systolic murmur over the mitral valve. No echocardiographic evidence of infl ammatory Internal medicine specialist lesions on the valve leafl ets. No fl uid in the pericardial sac. The abdominal wall soft, with slight muscle guarding, peristalsis present with no signs of impotency, peritoneal Surgeon signs absent. No indications for surgical intervention. The vaginal portion hard, conical in shape, the cervical canal closed. The uterine body of normal size, slightly enlarged in ultrasound scan (performed using a vaginal probe). A blastula of 5–7 mm size present. Beta Gynecologist HCG (1888) level low as compared with gestational age. Qualitative assessment of pregnancy and prognosis concerning the embryo’s development and survival rather unfavorable. The patient’s condition indicates the necessity of further clinical observation. Mikrobiologist Growth of G+ cocci in tested blood.

Table 2. Severe sepsis identiﬁ cation chart.

Infection Increased number of G+ cocci in blood Inﬂ ammatory response Leukocytosis 18 k/μl, CRP 113.3 mg/dl, purulent discharge in the airways, interstitial changes in the left lung on X-ray Signs od multiorgan failure

• respiratory system PaO2/FiO2 =40–130, assisted ventilation FiO2 =1.0–0.7 Tachycardia 160/min, hypotension 60/40 requiring supply of 3 catecholamines, metabolic acidosis, peripheral • cardiovascular system perfusion impairment – tendency to development of bedsores • urinary tract Oliguria, creatinine =2.4 mg/dl • hematological system Thrombocytopenia 60 k/μl, elevated D-dimers, INR>1.2 • nervous system Confusion, hallucinations, acute blindness

Table 3. Qualiﬁ cation for treatment with recombinant human Gradual increase of serum platelet count with simultaneous activated protein. C decrease of D-dimer level was observed (Figure 4).

Age 31 APACHE 31 During the fi rst 24 h of rhAPC therapy, effi cient diuresis Gender F SAPS 48 was restored. Normalization of renal parameters and el- Patient’s data Height 170 cm MODS 15 evated hepatic enzyme levels was obtained on the second Weight 60 kg Mortality risk 73% and third infusion day. After discontinuation of sedative infusion, sedation and com- Severe sepsis yes plete awakening of the patient, she underwent neurological Indications High risk of the patient’s death yes and ophthalmological examinations. Neurological evaluation Low effi cacy of standard therapy yes revealed no consciousness disturbances or symptoms of central nervous system pathology – paresthesia, muscular dystonia, ab- Active hemorrhage no normal tendon refl exes or paralysis. During the fi rst 24 h after Thrombocytopenia (<30 k/μl) no awakening mild visual acuity disturbances were observed, which Contraindications History of head trauma no disappeared completely after the next two days. Blood micro- Surgery <12 h no biology did not demonstrate the presence of Staphylococcus Interventions with potential hemorrhage risk no aureus in any control sample, so antibiotic medication was discontinued on the 13th day of hospitalization. CS29 Case Study Med Sci Monit, 2005; 11(6): CS27-32

120 350 leukocytes thousand/l PaO2/FiO2 CRP mg/dl 100 300

80 250

60 200

40 150

20 100

0 50 123 4 5 6 7 Days of ICU treatment 0 12345 Figure 1. Changes of C-reactive protein (CRP) level and leukocytosis Days of ICU treatment as a result of treatment of severe sepsis with activated

protein C ( APC). Figure 3. Values of PaO2/FiO2 ratio during the treatment of severe sepsis with APC. (PaO2 – partial oxygen pressure in arterial blood, FiO2 – percentage concentration of oxygen in respiratory gas mixture). 160 140 120 500 100 450 80 400 350 60 300 40 250 20 200 0 150 12 3 4 5 6 7 100 Days of ICU treatment SV ml HR/min 50 C.0 x100 0 123 4 5 6 7 Days of ICU treatment platelets thousand/l Figure 2. Hemodynamic parameters during the ﬁ rst days of D-dimer mcg/dl treatment of severe sepsis: heart rate (HR), stroke volume (SV) and cardiac output (C.O.). Figure 4. Increase of serum platelet count and decrease of D-dimer level as a result of treatment of severe sepsis with APC.

The development of pregnancy was monitored every day with ultrasound and hormone level investigations. Consecutive ing as a result of excessive or imbalanced systemic response check-ups revealed the presence of transudate in the peri- to generalized infection [2]. toneal cavity and of the blastula, growing gradually, in the uterus. On the 13th day of ICU treatment (35th day after em- Ovarian hyperstimulation syndrome is observed in the course bryo transfer) ultrasound scan performed with a vaginal of response to hormonal therapy, as a result of pharmaco- probe detected the presence of fetal heart beat. logical hormonal induction during the fi rst 5 days after embryo transfer [3]. Both sepsis and ovarian hyperstimulation Starting from the 7th day, the patient was undergoing inten- syndrome impair perfusion of vital organs, leading to mul- sive rehabilitation. On the 15th day she was transferred to the tiorgan dysfunction, coagulation disturbances and death obstetric ward. In the evening of the day preceding discharge of the fetus, aggravating the patient’s condition and wors- from the ICU, the patient’s temperature rose to 38°C; the ening the prognosis [4–9]. Each of the above syndromes fever subsided after the administration of paracetamol. alone is a dynamic process associated with a considerable risk for the patient’s morbidity and mortality. The concur- DISCUSSION rence of the mentioned risks necessitates well-coordinated, quick and effective action. Sepsis of varied etiology may develop during pregnancy. According to the WHO report, sepsis accounts for 15% In the reported case, it was necessary to determine in de- deaths of pregnant patients on a global scale [1]. Severe tail the pathophysiology and pathomechanism of the ob- sepsis involves multiorgan dysfunction syndrome, develop- served pathologic symptoms. The infection developed in CS30 Med Sci Monit, 2005; 11(6): CS27-32 Mikaszewska-Sokolewicz M et al – Use of APC in pregnant patient with severe sepsis the organism previously treated with gonadotrophic hor- The patient was in developing septic shock, with severe mone. Vascular changes in ovarian hyperstimulation syn- multiorgan dysfunction (Table 2). Parallel to the decisions drome cause increased vascular permeability and transu- concerning antibiotic therapy, symptomatic treatment and dation of protein-rich fl uid into the body cavities, reduce support of impaired organ function, indications and con- the capacity of the vascular bed and lead to impaired per- traindications for treatment with recombinant human ac- fusion of vital organs due to hypovolemia and intravascu- tivated protein C were considered. lar clotting. The progressive symptoms of respiratory failure and renal dysfunction observed in the patient were regard- Activated protein C signifi cantly improves the effectiveness ed as the sequels of hormonal hyperstimulation which de- of treatment in severe sepsis. It has been demonstrated in a CS layed the diagnosis of developing sepsis. multicenter clinical trial PROWESS, as well as in many published case reports [14,15]. The infection could have been caused both by Gram-posi- tive and Gram-negative bacteria. A Staphylococcus aureus The prognosis depends on the number of organs affect- strain was grown in culture of blood samples collected from ed by dysfunction and on the extent of insuffi ciency. Thus, the patient. the time of intervention is very important because it has an indirect impact on the quality of systemic response to The infection could have originated from four potential treatment, and, consequently, on treatment effi cacy. The sources: ultimate result of treatment of severe sepsis depends on 1. Ovarian abscess developed after past infection or as a re- multidirectional intensive management, careful monitor- sult of puncture of the ovarian follicle performed to col- ing and adequate actions adjusted to changing clinical sit- lect the material for in vitro fertilization. It cannot be ex- uation [16,17]. cluded that the presence of a purulent ovarian cyst passed unnoticed when the patient was being prepared for in One of the most serious complications of rhAPC therapy vitro fertilization, or that infection of the adnexes devel- reported in the PROWESS study was increased frequency oped as a result of egg cell collection; of hemorrhagic incidents in the treated group (3.2%) as compared to control. If the patient is to be subjected to a 2. Iatrogenic infection as a result of peritoneal puncture. Such procedure posing the risk of hemorrhage, or to surgical in- diagnosis was supported by the presence of peritoneal signs: tervention, during the therapy, the administration of acti- increased tonus, tenderness on palpation, muscle guard- vated drotrecogin alfa should be interrupted two hours being, lack of bowel sounds. The onset of fever was observed fore the planned procedure and resumed 2 h after a less 7 days after the last puncture. The fever was accompanied invasive procedure or 12 h after surgery [18]. by diarrhea and tenderness of the abdominal wall. Repeated surgical and gynecological consultations, as well The decision to institute rhAPC therapy in the reported as ultrasound scans of the abdominal and pelvic cavity ex- case had been preceded by numerous specialist consulta- cluded the presence of abscesses and peritonitis, thus ne- tions aimed at the determination of indications for surgical gating the necessity of surgical intervention; or gynecological interventions, in order to avoid the necessity of interrupting the therapy once it was instituted. The 3. Blood-borne infection due to repeated transfusions of effectiveness of drotrecogin alfa (activated) in the treatment blood preparations. Such diagnosis might be supported of severe sepsis was confi rmed by the observations of the by dynamic development of severe sepsis symptoms ob- patient’s clinical condition and laboratory results. As early served in the patient: rapid aggravation of respiratory fail- as on the second day of APC infusion, the patient’s general ure, tachycardia, hypotension, anuria. In blood-borne in- condition improved signifi cantly. The signs of generalized fections, the symptoms of multiorgan dysfunction progress infl ammatory reaction subsided and the function of vital or- very rapidly. Bacteria present on the skin are the most com- gans improved. On the subsequent days, neurological signs mon source of infection, whereas insuffi ciently disinfected and vision disturbances normalized, and the development puncture/injection site is the porta of entry. Blood-borne of the embryo in the uterine cavity was confi rmed. infections can also be caused by transfusion of infected blood products. The patient had received repeated plas- Both severe sepsis and ovarian hyperstimulation syndrome ma transfusions and albumin infusions because of hy- affect the function of vascular endothelium, blood coagula- poalbuminemia in the course of ovarian hyperstimulation and signs of generalized infl ammatory response. Both tion syndrome. The estimates concerning the incidence syndromes are characterized by increased concentrations of infections caused by transfusions of blood products of the same cytokines [4–9]. Therefore, potential effective- vary in different reports and range from 0.3% to 10%, ness of activated protein C in the treatment of ovarian hy- whereas the mortality rate due to post-transfusion sepsis perstimulation syndrome might be implicated, which can has been estimated by FDA at 17% [10,11]. become the subject of further research.

4. Endocarditis. Endocarditis is reported in 17-34% of sepsis The course of disease in the reported case confi rms the ne- patients [12,13]. Physical examination on admission to cessity of thorough and active observation of the condition the Intensive Care Unit revealed the presence of a systolic of such patients. murmur. However, transthoracic echocardiography performed twice did not confi rm the signs of bacterial endo- The staphylococcal strains cultured from the patient’s carditis. Anamnesis fi ndings concerning past endocarditis blood were sensitive to ciprofl oxacin and this antibiotic were unclear. Echocardiographic evaluation of the heart appeared to be effective because the subsequent blood was diffi cult because of marked tachycardia. cultures showed no bacterial growth. Additionally, the fact CS31 Case Study Med Sci Monit, 2005; 11(6): CS27-32

4. McElhinney B, McLure N: Ovarian hyperstimulation syndrome. of transient vision disturbances observed during intensive Baillieres Clinical Obstetrics and Gynecology, 2000; 14: 103–122 therapy may suggest staphylococcal etiology – purulent ob- 5. Loret De Mola JR, Flores JP, Baumgardner GP et al: Elevated struction of retinal blood vessels causing blindness has been interleukin-6 levels in the ovarian hyperstimulation syndrome; immu- described in staphylococcal sepsis [12]. However, it was im- nohistochemical localization of interleukin -6 signal, Obst et Gynecol, possible either to confi rm or to exclude such diagnosis in 1996; 87:4, 581–86 6. Pellicer A, Albert C, Mercader A et al The pathogenesis of ovar- the reported case. ian hyperstimulation syndrome: In vivo studies investigating the role of interleukin-beta,interleukin-6, and vascular endothelial growth factor. The patient will require further follow-up for neurologi- Fertility and Sterility, 1999; 71: 482–89 cal symptoms and blindness. Her mother and brother suf- 7. Kinasevitz GT, Yan SB, Basson B et al: Universal changes in bi- fer from sclerosis multiplex. The neurological symptoms omarkers of coagulation and infl ammation occur in patients with severe sepsis, regardless of causative microrganisam. CCM, 2004 observed in the patient were initially differentiated with 8. Levi M, Van der Pol: The central role of endothelium in the this diagnosis. crosstalk between coagulation and infl amation in sepsis. Advances in Sepsis, 2004; 3: 91–97 CONCLUSIONS 9. Aird WC: The role of endothelium in severe sepsis and multi- ple organ dysfunction syndrome. Blood, 2003; 101, 3765–77 1. The case report presents complex pathomechanism of 10. Goldman M, Blajchman MA: Blood Products-Associated Bacterial Sepsis. multiorgan failure resulting from coincident symptoms Transf Med Rev, 1991; 5: 73–83 11. Lee JH: Workshop on Bacteria Contamination of Platelet CBER, FDA of hormonal hyperstimulation and severe sepsis. September 24,1999. http: //www.fda.gov/cber/workshop-min.htm (June 1, 2000) 2. The resolution of symptoms of severe sepsis was achieved 12. Issa NC, Rodney L Thompson MD: Staphylococcal toxic shock syn- by timely, aggressive, goal directed, symptomatic and sub- drome. Postgraduate Medicine, 2001, 110(4): stitusion therapy comprising blood products and drot- 13. Andersen DJ, Murdoch DR, Sexton DJ et al: Risk factors of infective recogin alfa (activated). endocarditis in patients with enterococcal bacteriemia: a case control study Infection, 2004; 32: 72–77 14. Bernard GR, Vincent JL, Laterre PF et al: Effi cacy and safety of recom- 3. The fact of saving the pregnancy and further develop- binant Human Activated Protein C for severe sepsis. N Eng J Med, 2001; ment of the embryo deserves to be emphasized. 344: 699–709 15. Mikaszewska-Sokolewicz M, Nierebinska M, Mayzner Zawadzka E: The REFERENCES: use of drotrecogin alfa (activated) in severe sepsis – description of two cases Med Sci Monit, 2003; 9(8): CS80–87 16. Laterre PF, Witteboe X: Clinical review: Drotrecogin alfa (activated) as 1. WHO. Making Pregnancy Safer. Februar 2001 adjunctive therapy for severe sepsis – practical aspects at the bedside 2. Webb S: The role of mediators in sepsis resolution Advances In and patient identifi cation. Crit Care, 2003; 7(6): 445–50 sepsis. 2002; 2: 8–14 17. Dellinger RP, Carlet JM, Masur H et al: Surviving sepsis campaign guide- 3. Ong A, Eisen V, Rennie D et al: The pathogenesis of ovari- lines for management of severe sepsis and septic shock. Intensive Care an hyperstimulation syndrome: a possible role of ovarian renin. Cli. Med, 2004; 30: 536–55 Endocrinol. (OXf), 1991; 34: 43–49 18. Laterre PF, Heiselman D: Management of patients with severe sepsis, treated by drotrecogin alfa (activated). Am J Surg, 2002; 184: S39–46

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