Producing Proteus Spp. Clinical Isolates in Zenica-Doboj Canton, Bosnia and Herzegovina Selma Uzunović, Amir Ibrahimagić, Dunja Hodžić, Branka Bedenić

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Official Publication of the Medical Association of Zenica-Doboj Canton, Bosnia and Herzegovina Volume 12, Number 2, August 2016 Free full-text online at: www.ljkzedo.com.ba, and www.doaj.org (DOAJ, Directory of Open Access Journals)

Original 68 Effects of magnesium sulfate on airway smooth muscle contraction in rats article Hatice Betul Altinisik, Pakize Kirdemir, Ugur Altinisik, Osman Gokalp

75 Relation of red cell distribution width with dipper and non-dipper hypertension Eyup Buyukkaya, Ali Erayman, Esra Karakas, Alper Bugra Nacar, Mustafa Kurt, Sule Buyukkaya, Adnan Burak Akcay, Nihat Sen

82 Comparison of the accuracy and correctness of mortality estimates for Intensive Care Unit patients in internal clinics of the Czech Republic using APACHE II, APACHE IV, SAPS 3 and MPMoIII models Pavel Sedloň, Libor Kameník, Jan Škvařil, Martin Malý, Miloš Táborský, Miroslav Zavoral

90 Relationship between ultrasonographically determined kidney volume and progression of chronic kidney disease Sandra Vegar Zubović, Spomenka Kristić, Irmina Sefić Pašić

95 Occipital sulci patterns in patients with schizophrenia and migraine headache using magnetic resonance imaging (MRI) Gorana Sulejmanpašić, Enra Suljić, Selma Šabanagić-Hajrić

103 Molecular epidemiology and antimicrobial susceptibility of AmpC- and/or extended-spectrum (ESBL) ß-lactamase- producing Proteus spp. clinical isolates in Zenica-Doboj Canton, Bosnia and Herzegovina Selma Uzunović, Amir Ibrahimagić, Dunja Hodžić, Branka Bedenić

113 Frequency of thyroid cancer in patients operated at Cantonal Hospital Zenica, Bosnia and Herzegovina, in the period 2007- 2014 Nermin Hrnčić, Amna Goga, Selma Hrnčić, Marijana Filipovska-Mušanović, Haris Hatibović, Ðenad Hodžić

118 IGFBP-1 marker of cervical ripening and predictor of preterm birth Larisa Mešić Ðogić, Dragana Mićić, Feđa Omeragić, Refka Kovač, Seid Fazlagić

125 Secular trend of anthropometric parameters of newborns in municipalities of Tuzla Canton (1976 – 2007) Amela Begić, Jasminka H. Halilović, Lejla Mešalić, Sabina H.Halilović 136 Impact of timing on surgical outcome in patients with cauda equina syndrome caused by lumbar disc herniation Hakija Bečulić, Rasim Skomorac, Aldin Jusić, Fahrudin Alić, Melica Imamović, Alma Mekić-Abazović, Alma Efendić, Harun Brkić, Amir Denjalić

142 Radiological evaluation of lumbosacral spine for post discectomy segmental instability Rasim Skomorac, Jasmin Delić, Hakija Bečulić, Aldin Jusić

148 Application of high viscosity bone cement in vertebroplasty for treatment of painful vertebral body fracture Saša Rapan, Karin Krnić, Vjeran Rapan, Vjekoslav Kolarević 154 Incidence of mental retardation as compared with other psychiatric disorders and necessary support to persons placed at the Public Institution for Placement of Persons with Mental Disabilities „Drin“ Fojnica, Bosnia and Herzegovina Edin Bjelošević, Amar Karahmet, Halima Hadžikapetanović, Sonja Bjelošević

161 Impact of self-rated health among elderly on visits tofamily physicians Amira Kurspahić-Mujčić, Melisa Čalkić, Suad Sivić

Medicinski Glasnik is indexed by MEDLINE, EMBASE (Exerpta Medica), EBSCO, Scopus, and Di- rectory of Research Journals Indexing (DRJI) ORIGINAL ARTICLE

Effects of magnesium sulfate on airway smooth muscle contraction in rats

Hatice Betul Altinisik1, Pakize Kirdemir1, Ugur Altinisik1, Osman Gokalp2

1Department of Anesthesiology and Reanimation, 2Department of Pharmacology; Suleyman Demirel University, School of Medicine, Isparta, Turkey

ABSTRACT

Aim To investigate the effect of magnesium sulfate (MgSO4) at different doses on isolated tracheal smooth muscle contraction in rats induced by different mechanisms.

Methods Twelve rats’ tracheas were placed into organ bath. Consecutively, acetylcholine (10−6,10−5,10−4 M), histamine (10−8,10−5,10−3 M) and KCl (30,60 mM) solutions was administe- −4 −1 red for contractions. MgSO4 from 10 to 10 M concentrations were subsequently administered after each constrictive agent and relaxation degrees were recorded.

Results In the acetylcholine and KCl groups, dose dependent strong contractions were observed, but not in the histamine group and that group was excluded. Significant relaxation occurred with

gradually increasing doses of MgSO4. In the high dose KCl group, Corresponding author: a slight increase in contractions after the administration of 10−4 and −3 Ugur Altinisik 10 M MgSO4 was recorded. Canakkale Onsekiz Mart University, Conclusion We suggest that MgSO4 is effective in relaxing airway Medicine Faculty, Canakkale, Turkey smooth muscle contractions caused by different factors; however, Sahil Yolu Street, No:5, it must be considered that low doses of MgSO4 may only lead to a Kepez/Canakkale, 17100 slight increase in contractions. Phone: +90 552 233 75 25; Key words: acetylcholine, histamine, potassium chloride Fax: +90 286 263 59 56; E-mail: [email protected]

Original submission: 23 May 2016; Revised submission: 22 June 2016; Accepted: 29 June 2016. doi: 10.17392/862-16

Med Glas (Zenica) 2016; 13(2):68-74

68 Altinisik et al. Magnesium airway

INTRODUCTION effects through different mechanisms in isolated rat trachea in the in vitro environment. Magnesium (Mg) is the fourth most commonly found cation in the human body and the second MATERIALS AND METHODS most important intracellular one (1). Magnesium plays an active role in many enzyme systems. The study was performed after an approval had It acts as a natural antagonist of calcium in the been obtained from the Ethics Committee of Su- cell (2). Low magnesium concentrations induce leyman Demirel University, Isparta, Turkey, for contractions; however, hypocalcemia stimulates Animal Studies. relaxation (3). Low magnesium concentrations Twelve adolescent, female, 250-350 g Wistar albi- cause rapid and passive calcium release from no rats were used. After mild ether anesthesia, the the sarcoplasmic reticulum. Magnesium com- animals were sacrificed, and chests were speedily petitively blocks calcium entry into presynap- explored soon after which tracheas were removed. tic endings (4). High magnesium levels reduce Adjacent lipid and connective tissues were clea- acetylcholine (ACh) release from the presynap- ned with maximum care to prevent any damage. tic interval. In addition, magnesium reduces the Three millimeter ring cross-sections were prepa- ACh effects on postsynaptic muscle receptors. red from the trachea and thereafter, were bound to It has been shown to be effective on the axonal little triangular shaped wires and to a transducer stimuli threshold (5). Hypomagnesaemia has via tight strings. A micro positioner coupled with been shown to cause neuromuscular hyperexcit- a transducer was placed in a four channel isolated ability, whereas hypermagnesemia is reported to organ bath, which contained 25 mL Krebs solu- cause neuromuscular weakness and loss of deep tion in each channel. Thus, the experiment could tendon reflexes (6). Magnesium has effects on be carried within four tracheal rings concurrently. adrenal medulla and adrenergic postganglionic One gram of tension was applied to the hanging rings that were resting at 37°C continuous 95% O sympathetic fibers, excess serum magnesium 2 and 5% CO conditioned Krebs’ solution for 1.5 h concentrations produce progressive inhibition of 2 catecholamine release (7,8). to allow adaptation to the medium, while the solutions were replaced every 15 min. The first study of magnesium effects on bronchial All tracheas were first pretreated with−6 10 M smooth muscle was published by Trendelenburg ACh. Ten-minute contractions were awaited to in 1912 (9) showing that magnesium could cause reach a plateau. Formed contractions were first re- bovine bronchial smooth muscle relaxation. leased by means of 10−4 M MgSO administration However, since then, despite known effects, it 4 and afterwards were gradually increased to 10−3, 3 has not entered routine clinical use. In fact, mag- × 10−3, 5 × 10−3, 10−2, 3 × 10−2, and finally 10−1 M at nesium sulfate (MgSO ) is known to be used by 4 10 min intervals. After the process the tissues were asthmatic cases by intravenous (IV), inhaler and left to rest for 30 min along with Krebs solution oral routes (10). In recent years, the clinical im- refreshing every 15 min. All procedures were then portance of magnesium has increased because of followed for 10−5 and 10−4 M ACh. updated information about magnesium’s action −8 as a direct calcium agonist receptor; as a result, Histamine was administered after the rest. A 10 magnesium plays a role reducing ACh release M dose was first used before the 10-min wait for −5 and depolarization in nerve muscle junctions af- stabilization and then higher doses were used (10 −3 fects prostaglandin-dependent smooth muscle re- and 10 M) following a rest period for each dose. laxation and is necessary for β-agonist receptor A dose of 30 mM KCl was administered first af- complex interactions. It has been reported to be ter the rest. However, a 20-min interval for sta- beneficial in severe acute bronchospasm attacks, bilization was set apart from other groups. 10−4, particularly those that do not respond to other 10−3, 3 × 10−3, 5 × 10−3, 10−2, 3 × 10−2, and 10−1 M treatments (11-13). MgSO4 administrations followed within 10-min The aim of this study was to investigate the intervals. The procedure was repeated with 60 bronchodilator effects of different doses of mM KCl treatment after 30-min rest (Figure 1). MgSO4 in bronchospasm induced by ACh, hi- In all groups the first values measured before stamine, and potassium chloride (KCl), showing drug application were recorded as control valu-

69 Medicinski Glasnik, Volume 13, Number 2, August 2016

Figure 1. Procedure of the experiment applied to time course. (1) 10−6 M ACh was first administered to the tracheae, following a 10

minute interval. 10 minute relaxation periods were observed after 10-minute wait with increasing doses of MgSO4, afterwards, cleansing twice with a 15-minute rest was given. Next, the same procedure was repeated with 10−5 and 10−4 M ACh; 10−8, 10−5, and 10−3 M histamine

(2); and 30 and 60 mMKCl (3). The rest was adjusted to 20 minute for KCl group with exception ACh, acetylcholin; MgSO4, magnesium sulfate; KCl, potassium chloride RESULTS es, and the measured values after the contracting 10−6M ACh administration achieved a weak con- agent was administered were recorded as contraction, whereas increasing concentrations pro- traction values. Results after MgSO admini- 4 vided better responses. A dose of 10−4 M MgSO , stration were calculated, and the relaxation was 4 administered after 10−6 M ACh did not produce evaluated by a percentage value (contraction dilatation, however increasing concentrations value: 0%; control value: 100%). succeeded. Doses of 10−3 M and 10−2M, provided For statistical analyses, the significance of evident dilatation (p<0.05). Concentrations be- differences was evaluated by using Wilcoxon ginning from 3 × 10−2 M had much more dilated test; p value<0.05 was considered significantly muscles than those in the controls. The highest different. dilatation value was 140% (Table 1, Figure 2A).

Table 1. Relaxation values after MgSO4 applications MgSO4 concentration 10-6 M ACh 10-5 M ACh 10-4 M ACh 30 mM KCl 60 mM KCl 10-4 M 0±0 -0,87±7,00 -2,32±6,63 5,05±13,95 -7,70±8,94† 10-3 M 27,65±23,67* 1,5±8,98 -0,35±9,03 39,75±21,17* -8,01±12,88† 3x10-3 M 36,87±21,46* 10,05±10,27* 2,41±8,38 87,84±22,35* 1,82±15,33 5x10-3 M 48,07±25,03* 16,18±10,25* 6,32±9,82 103,63±21,22* 13,23±17,88* 10-2 M 74,50±21,49* 27,54±8,98* 11,6±11,32* 108,14±19,36* 52,97±18,51* 3x10-2 M 116,61±28,94* 57,35±19,30* 30,37±17,86* 109,97±19,27* 107,43±17,89* 10-1 M 140,04±16,59* 93,57±19,16* 71,69±15,20* 109,97±19,27* 107,43±17,89* The values are described as percentage (contraction value: 0%; control value: 100%; mean±SD); *p < 0.05, when consisting relaxing response compared to basal muscle tonus; †p < 0.05, when consisting contracting response compared to basal muscle tonus; Ach, acetylcholine; KCl, potassium chloride;

A) B) C)

Figure 2. Logarithmical relaxation curve caused by increasing doses of magnesium sulfate (MgSO4) over tracheal rings, which are contracted with A) 10−6 M, B) 10−5 M, and C) 10−4 M acetylcholine (ACh) *p<0.05

70 Altinisik et al. Magnesium airway

Muscles contracted with 10−5 M ACh were gi- manner. The 30 mM KCl group gave no respon- −4 −4 ven 10 M MgSO4, and a minor contraction se of significant dilatation after 10 M MgSO4 was observed but the results were not significant (p>0.05), nevertheless 10−3 M and more concen- −3 (p>0.05). 10 M MgSO4 did not achieve a dilatati- trated doses provided a faster dilatation (p<0.05). on (p>0.05), whereas evident dilatations were seen Doses beginning at 5 × 10−3 M provided stronger at higher doses (p<0.05). Concentrations >3 × 10−2 dilatations than those of starting values. The di-

M provided fast dilatation. The most powerful dilatation occurred when the dose of MgSO4 was latation was 93.6% (Table 1, Figure 2B). incrementally increased from 10−3 M up to 10−2 M 10−4 M ACh provided clearly a stronger contracti- was statistically significant (p<0.05). The stron- on initially. Though low doses (10−4 and 10−3 M) gest dilatation was 110% (Table 1, Figure 3A). −4 −3 of MgSO4 provided a mild contraction, the results 10 and 10 M MgSO4 administration to the were not significant (p>0.05). MgSO4 gave signifi- 60 mM KCl group provided mild contractions cant results when the doses were elevated from 10−3 (p<0.05). With increasing doses, dilatation res- M to 10−2 M (p<0.05) with the knowledge that none ponses were mounted. A dose of >3× 10−2 M di- of the doses gave a complete dilatation. The stron- lated the muscles more than the starting concen- gest dilatation was 71.7% (Table 1, Figure 2C). trations did. The differences in dilatation of 10−2 No significant contraction response occurred af- M were significant (p<0.05). The most intense ter 10−8, 10−5, and 10−3 M histamine administrati- dilatation was 107.4% (Table 1, Figure 3B). ons. It was concluded that histamine had no con- DISCUSSION tractile effects on the trachea, and thus, MgSO4 was not administered to this group (Table 1). Airway smooth muscle contraction is the main component of acute asthma and other bronchos- A starting contraction response was produced pasms. Release of histamine, ACh and other from administration of KCl in a dose-dependent mediators via inhaled allergenic or some other stimulants may cause bronchoconstriction. The- re are two major mechanisms in the pathophysi- A) ology of smooth muscle contraction. The first mechanism includes Ca++ influx into the cell via ligand-gated ion channels or Ca++ release from intracellular stores (14,15). ACh, histamine, hormones, and many drugs act via this pathway. The second mechanism is the influx of Ca++ via voltage-gated ion channels because of electrical depolarization of the membrane (16). KCl causes smooth muscle contractions by means of this mechanism (17). In this study, we performed these two different mechanisms for the airway smo- B) oth muscle contraction rat model. In the present study, the application of 30-60 mM KCl and 10−6 to 10−4 M ACh was observed to provide strong and dose-dependent contractions. Within these applications, the strongest contractions were obtained by 10−4 M ACh. Kumasaka et al. (18) studied the contraction responses of the trachea to 10−9 to 10−4 M carbachol and 10-140 mM KCl administration in an organ bath prepa-

Figure 3. Logarithmical curve of relaxation caused by increas- red with three different doses of MgSO4 (1.2, 2.2, ing doses of magnesium sulfate (MgSO4) over tracheal rings, and 9.2 mM). Maximum contraction values were which are contracted with potassium chloride (KCl) of A) 30 found to be similar in both carbachol and KCl mM (*p<0.05) and B) 60 mM (*p<0.05 when consisting relaxing response compared; **p<0.05 when consisting contracting conditions for each concentration of MgSO4. Fifty response compared) percent of maximum contraction values (EC50)

71 Medicinski Glasnik, Volume 13, Number 2, August 2016

differed in KCl group according to the dose of rent nerves and other mediators act on. In addition,

MgSO4, whereas it was found similar for each car- it is known that airways of various species react in bachol doses. Gourgoulianis et al. (19) reported a different degrees to histamine (27). Guinea pig is strong contraction produced by 85 mM KCl and the most sensitive animal to the bronchoconstrictor 10−4 M ACh. The results of these two latter studi- effect of histamine. This condition may arise becau- es were similar with the results of the present stu- se of the number of histamine receptors placed in dy. However, distinct results have been reported the airway of animal (28). according to the location of the airway segment The results of the present study show that the strong after the application of different substances in the airway smooth muscle contraction achieved via

literature (20). In a comprehensive study, bradyki- ACh and KCl could be managed by MgSO4 in a nin, histamine, neurokinin-A, serotonin, substan- dose-dependent manner. Moreover, high doses of

ce-P, tromboxane-A2 (TxA2) mimetic, carbachol MgSO4 administrations were observed to produce a and carbachol plus potassium were compared considerable dilatation as compared to control, par- with regard to their bronchoconstrictive effects on ticularly the KCl group. However, even high doses

the trachea, bronchi and bronchiole of Wistar and of MgSO4 did not exert complete dilatation in the Fisher 344 rats (21). The most potent effect was high dose ACh group. Similar results were also de- exerted by carbachol on all airway segments; sero- monstrated in previous studies. Kumasaka et al. (18)

tonin, bradykinin, and TxA2 mimetics were found reported that while MgSO4 could revert the tracheal more effective on bronchioli, and carbachol plus contraction, which occurred as a result of KCl and potassium was more effective on trachea. On the KCl + ACh administration, it was observed to be basis of the given data, we considered that the use insufficient for reversing the tracheal contraction in- of the rat trachea would be an appropriate experi- duced by only ACh itself. Gourgoulianis et al. (19) mental model for evaluating the efficacy of ACh have revealed a complete dilatation of constructed

and KCl on tracheal contraction. tracheas induced by KCl after MgSO4 administrati-

Although histamine is known to have a conside- on, and reported residual contractions with MgSO4 rable bronchoconstrictor effect in both humans after giving ACh. This condition was interpreted in

and animals (19), no significant contractions were a way that MgSO4 could block the voltage-gated determined in different doses of histamine in our ion channels stimulated by KCl, whereas it cannot study. In the mechanism of bronchoconstriction, affect the receptor-dependent channels and the in- histamine directly induces the smooth muscle cells tracellular Ca stores stimulated by ACh. and afferent endings leading to an increase in rele- The debates about the use of magnesium for clini- ase of other bronchoconstrictor endogen mediators. cal treatment of bronchospasm continue. It is no- Nowadays, histamine has been frequently used in teworthy that magnesium is successful in the tre- provocation studies of asthmatic patients (22-24). atment of severe acute asthma attacks. Skobeloff et This effect of histamine was also shown in animal al. (29) showed that for patients with acute severe studies. Hirota et al. (25) reported bronchoconstric- asthma attacks IV applying magnesium treatment tion due to the use of 10 µM histamine in both in positively affected peak expiratory flow (PEF) vivo and in vitro dog model. In contrast, there are values and duration of hospital stay. On the other also other studies reporting histamine as a weak hand, some serious clinical researchers have repor- bronchoconstrictor agent in vitro. Voorde et al. ted that MgSO4 infusion is not effective (30-31). In (21) described that the concentration of histamine some randomized controlled studies of children the used the same way we used it caused no effect in use of magnesium was recommended, while other rat tracheae and main bronchi, and reported a faint studies reported negative results (32-34). These bronchoconstriction in bronchiole in their model. A different interpretations in the literature may be re- similar study demonstrated a feeble contraction in lated to the infusion duration and dose of MgSO4. an isolated pig trachea model with the use of hista- In our study, all high doses of MgSO4 administered mine compared to ACh, and this effect could have for bronchoconstriction caused by different mecha- been augmented by tetraethylammonium and K+ nisms were shown to cause dilatation (even more administration (26). Substantially, deprivation of than initial values). However, we observed that the bronchoconstrictor effect of histamine in isolated use of low dose MgSO4 resulted in insufficient di- rat trachea may be because of many factors. Isola- latation. There appear to be similar conclusions in tion of trachea blocks the pathway, which the affe- clinical studies in the literature. While all studies

72 Altinisik et al. Magnesium airway

using 2 g MgSO4 with infusion durations longer that the production of endogenous NO results in a than 20 min were ineffective (34,35), in studies long-term deleterious effect, and may be involved with high concentrations and rapid administrati- in the orchestration of eosinophilic inflammation on like 10-20 g MgSO4 over 1 hour (36) and 2 g that characterizes asthma. The iNOS may be expre- MgSO4 in less than 2 min (37) effective treatment ssed in macrophages and in epithelial cells. Respi- was reported. The results of our study lead to the ratory tract infections may induce iNOS expression consideration that the use of clinically higher doses and NO production is increased in epithelial cells of MgSO4 may be beneficial. Additionally, care in case of infection (41). These mechanisms can be should be taken in terms of toxic dose. in vivo although we used isolated tracheas in our We obtained an unexpected finding from the pre- study. Therefore, we think that these factors are not sent study that low doses of MgSO4 administrati- effective in our experiment. on provided a mild increase in tracheal contraction The limitations of our study include studying iso- in the high-dose KCl group. A similar contraction lated rat trachea to avoid effects on afferent nerves −4 was also observed with 10 M MgSO4 administra- and via other mediators. Another limiting factor is tion in the high-dose ACh group. This effect may that while we studied the trachea it is known that be because of K+ channel inhibition or a direct both muscle constrictor and dilatator medications electrical stimulant causing contraction, although have different effects on different localizations in the design of this study did not include such the- the airway. It will be beneficial to complete future se applications. This condition was not reported studies with these targets in mind. in literature. Nevertheless, some clinical studies In conclusion, we obtained evident dilatations showed that low dose and slow infusion of MgSO4 with increasing doses of MgSO4 in the contracted is ineffective in treating bronchospasm (38,39). If tracheal smooth muscle produced by both ACh the finding we have experienced in rat trachea in and KCl in various doses. Besides that, histamine vitro is the same in humans, low doses of MgSO4 appears to be an inappropriate agent to produce used in the treatment of bronchospasm may pro- smooth muscle contraction in trachea isolated duce a more severe reaction. Further studies are from rats. We suggest that low doses of MgSO4 required to resolve this issue. could cause a slight increase in airway smooth Nitric oxide (NO) related smooth muscle dilatation muscle contraction. However, further studies are is another issue. Nitric oxide is a bronchodilator, needed to confirm our proposals. plays a significant role in the physiological regula- ACKNOWLEDGMENTS tion of airway function, but the effect is not com- The authors are grateful to the Scientific Rese- pletely clear (40). Nitric oxide synthase (NOS) is arch Project Department of Suleyman Demirel an enzyme for the production of NO, which exists University for providing necessary facilities to in severa1 isoforms. Constitutive NOS (cNOS) carry out this work. isoforms are inducible by intracellular calcium ions. Also, magnesium acts as a natural calcium FUNDING antagonist. The other form of NOS, iNOS, is acti- This research was supported from Scientific Re- vated by proinflammatory cytokines. Nitric oxide search Project Department of Suleyman Demirel is produced by a variety of cells in the airways. The University (Project Number: 1519-TU-07). cNOS is involved in the regulation of bronchial blood flow and in neutrally mediated bronchodi- TRANSPARENCY DECLARATIONS lation. However, NO may also have deleterious Competing interest; none to declare. effects as it may increase bronchial blood flow and plasma exudation in the airways. It is also possible 4. Swaminathan R. Magnesium metabolism and its dis- REFERENCES orders. Clin Biochem Rev 2003; 24:47-66. 1. Gupta K, Vohra V, Sood J. The role of magnesium as 5. Sun YX, Gong CH, Liu S, Yuan XP, Yin LJ, Yan L, Shi an adjuvant during general anaesthesia. Anaesthesia TT, Dai JH. Effect of inhaled MgSO4 on FEV1 and 2006; 61:1058-63. PEF in children with asthma induced by acetylcholi- 2. Fawcett WJ, Haxby EJ, Male DA. Magnesium physio- ne: a randomized controlled clinical trail of 330 cases. logy and pharmacology. Br J Anaesth 1999; 83:302–20. J Trop Pediatr 2014; 60:141-7. 3. Iannello S, Belfiore F. Hypomagnesemia. A review 6. Gröber U, Schmidt J, Kisters K. Magnesium in pre- of pathophysiological, clinical and therapeutical as- vention and therapy. Nutrients 2015; 7:8199-226. pects. Panminerva Med 2001; 43:177-209. 7. Wallace C. Magnesium. Emerg Med (Fremantle) 2003; 15:92–6.

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8. Dubé L, Granry JC. The therapeutic use of magnesi- 25. Hirota K, Sato T, Hashimoto Y, Yoshioka H, Ohtomo um in anesthesiology, intensive care and emergency N, Ishihara H, Matsuki A. Relaxant effect of magne- medicine: a review. Can J Anaesth 2003; 50:732-46. sium and zinc on histamine-induced bronchoconstric- 9. Trendelenburg F. Physiologische and Pharmakologis- tion in dogs. Crit Care Med 1999; 27:1159-63. che untersuchungen an der Isolierten Bronchialmu- 26. Mitchell HW. Electromechanical effects of tetra- skulatur. Arch Exp Pharmacol Ther 1912; 69:79-107. ethylammonium and K+ on histamine-induced con- 10. Davalos Bichara M, Goldman RD. Magnesium for traction in pig isolated tracheal smooth muscle. Lung treatment of asthma in children. Can Fam Physician 1987; 165:129-42. 2009; 55:887-9. 27. Seehase S, Schlepütz M, Switalla S, Mätz-Rensing K, 11. Kew KM, Kirtchuk L, Michell CI. Intravenous ma- Kaup FJ, Zöller M, Schlumbohm C, Fuchs E, Lauen- gnesium sulfate for treating adults with acute asthma stein HD, Winkler C, Kuehl AR, Uhlig S, Braun A, in the emergency department. Cochrane Database Sewald K, Martin C. Bronchoconstriction in nonhu- Syst Rev 2014; 28:5. man primates: a species comparison. J Appl Physiol 12. Egelund TA, Wassil SK, Edwards EM, Linden S, 2011; 111:791-8. Irazuzta JE. High-dose magnesium sulfate infusion 28. Ressmeyer AR, Larsson AK, Vollmer E, Dahlèn SE, protocol for status asthmaticus: a safety and pharma- Uhlig S, Martin C. Characterisation of guinea pig cokinetics cohort study. Intensive Care Med 2013; precision-cut lung slices: comparison with human ti- 39:117-22. ssues. Eur Respir J 2006; 28:603-11. 13. Albertson TE, Sutter ME, Chan AL. The acute ma- 29. Skobeloff EM, Spivey WH, McNamara RM, Green- nagement of asthma. Clin Rev Allergy Immunol spon L. Intravenous magnesium sulfate for the tre- 2015; 48:114-25. atment of acute asthma in the emergency department. 14. Jiang Y, Dai A, Zhou Y, Peng G, Hu G, Li B, Sham JAMA 1989; 262:1210-3. JS, Ran P. Nicotine elevated intracellular Ca² in rat 30. Tiffany BR, Berk WA, Todd IK, White SR. Magnesi- airway smooth muscle cells via activating and up- um bolus or infusion fails to improve expiratory flow regulating α7-nicotinic acetylcholine receptor.⁺ Cell in acute asthma exacerbations. Chest 1993; 104:831- Physiol Biochem 2014; 33:389-401. 4. 15. Montaño LM, Carbajal V, Vargas MH, García- 31. Hill JM, Britton J. Effect of intravenous magnesium Hernández LM, Díaz-Hernández V, Checa M, Ba- sulfate on airway calibre and airway reactivity to hi- rajas-López C. Histamine, carbachol, and serotonin stamine in asthmatic subjects. Br J Clin Pharmacol induce hyperresponsiveness to ATP in guinea pig 1996; 42:629-31. tracheas: involvement of COX-2 pathway. Pflugers 32. Gurkan F, Haspolat K, Bosnak M, Dikici B, Derman Arch 2013; 465:1171-9. O, Ece A. Intravenous magnesium sulphate in the 16. De Proost I, Brouns I, Pintelon I, Timmermans JP, management of moderate to severe acute asthmatic Adriaensen D. Pulmonary expression of voltage-gated children nonresponding to conventional therapy. Eur calcium channels: special reference to sensory airway J Emerg Med 1999; 6:201-5. receptors. Histochem Cell Biol 2007; 128:301-16 33. Ciarollo L, Brousseau D, Reinert S. Higher dose in- 17. Sutovska M, Franova S, Sutovsky J. The influence of travenous magnesium therapy for children with mo- animal species on the relationship between ATP-sen- derate to severe acute asthma. Arch Pediatr Adolesc sitive potassium ion channels and defense reflexes of Med 2000; 154:971-3. the airways. Bratisl Lek Listy 2009; 110:269-75. 34. Scarfone RJ, Loiselle JM, Joffe MD, Mull CC, Stiller S, 18. Kumasaka D, Lindeman KS, Clancy J, Lande B, Thompson K, Gracely EJ. A randomised trial of magne- Croxton TL, Hirshman CA. MgSO4 relaxes porcine sium in the emergency department treatment of children airway smooth muscle by reducing Ca2+ entry. Am J with asthma. Ann Emerg Med 2000; 36:572-8. Physiol 1996; 270:469-74. 35. Kuitert LM, Kletchko SL. Intravenous magnesium 19. Gourgoulianis KI, Chatziparasidis G, Chatziefthi- sulfate in acute, life-threatening asthma. Ann Emerg miou A, Molyvdas PA. Magnesium as a relaxing fac- Med 1991; 20:1243-5. tor of airway smooth muscles. J Aerosol Med 2001; 36. Sydow M, Crozier TA, Zielmann S, Radke J, Burc- 14:301-7. hardi H. High-dose intravenous magnesium sulfate in 20. Fujiwara T, Itoh T, Kuriyama H. Regional differences the management of life-threatening status asthmati- in the mechanical properties of rabbit airway smooth cus. Intensive Care Med 1993; 19:467-71. muscle. Br. J. Pharmacol 1988; 94:389–96. 37. Schiermeyer RP, Finkelstein JA. Rapid infusion of 21. Van de Voorde J, Joos G. Regionally different influ- magnesium sulfate obviates need for intubation in ence of contractile agonists on isolated rat airway se- status asthmaticus. Am J Emerg Med 1994; 12:164-6 gments. Respir Physiol 1998; 112:185-94. 38. Bradshaw TA, Matusiewicz SP, Crompton GK, Innes 22. Baxter MA, Coates D, Wilson AM. Airways resi- JA, Greening AP. Intravenous magnesium sulphate stance in bronchial challenge testing. J Asthma 2014; provides no additive benefit to standard management 19:1-6. in acute asthma. Respir Med 2008; 102:143-9. 23. Short PM, Williamson PA, Lipworth BJ. Effects of 39. Villeneuve EJ, Zed PJ. Nebulized magnesium sulfate hydrocortisone on acute β-adrenoceptor blocker and in the management of acute exacerbations of asthma. histamine induced bronchoconstriction. Br J Clin Ann Pharmacother 2006; 40:1118-24. Pharmacol 2012; 73:717-26. 40. Keskin O, Tor MM, Altın R, Atalay F, Örnek T. The 24. De Peuter S, Lemaigre V, Van Diest I, Verleden G, Importance of Exhaled Nitric Oxide Concentration in Demedts M, Van den Bergh O. Differentiation betwe- Asthmatic Patients and Factors that Impact its Mea- en the sensory and affective aspects of histamine- surement. J Chest Dis Crit Care Med 2014; 1:11-6. induced bronchoconstriction in asthma. Respir Med 41. Barnes PJ, Liew FY. Nitric oxide and asthmatic in- 2007; 101:925-32. flammation. Immunol Today 1995; 16:128-30.

74 ORIGINAL ARTICLE

Relation of red cell distribution width with dipper and non-dipper hypertension

Eyup Buyukkaya1, Ali Erayman1, Esra Karakas2, Alper Bugra Nacar1, Mustafa Kurt1, Sule Buyukkaya3, Adnan Burak Akcay1, Nihat Sen1

1Department of Cardiology, 2Department of Endocrinology and Metabolism; Mustafa Kemal University, Tayfur Ata Sokmen Medical School, 3Department of Cardiology, Antakya State Hospital; Hatay, Turkey

ABSTRACT

Aim Red cell distribution width (RDW), an index of erythrocyte size, is associated with high risk for cardiovascular disease. Non- dipping hypertension (HT) is lack of nocturnal fall in blood pressure (BP). The association between RDW and non-dipping BP in normotensive and hypertensive patients was investigated.

Methods A total of 170 patients were categorized into 4 groups: Normotensive-Dipper (NT-D), Normotensive-Non-dipper (NT- ND), Hypertensive-Dipper (HT-D) and Hypertensive-Non-dipper (HT-ND). RDW and hs-CRP levels were measured.

Results Hypertensive patients had higher RDW and hs-CRP levels (14.5 ± 0.87 vs.12.7 ± 0.66, p<0.001 for RDW; 0.99 ± 0.52 Corresponding author: vs.0.63 ± 0.43, p<0.001 for hs-CRP). Besides, the RDW levels Eyup Buyukkaya were higher in non-dippers (13.0 ± 0.63 vs.12.4 ± 0.55, p<0.001 Department of Cardiology, for NT-ND and NT-D; 14.9 ± 0.78 vs.14.2 ± 0.82, p<0.001 for Mustafa Kemal University, HT-ND and HT-D) Tayfur Ata Sokmen Medical School Conclusion RDW is elevated in non-dipping BP both in normo- Serinyol, Antakya 31005, Turkey tensive and hypertensive subjects, which may be related with Phone: +90 530 016 39 13; increased inflammatory state. Fax: +90 326 245 5305; Key words: blood pressure, circadian rhythm, erythrocyte size, Email: [email protected] inflammation

Original submission: 25 April 2016; Revised submission: 21 June 2016; Accepted: 26 June 2016. doi: 10.17392/859-16

Med Glas (Zenica) 2016; 13(2):75-81

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INTRODUCTION (NT-ND), “Hypertensive-Dipper” (HT-D) and “Hypertensive-Non-dipper” (HT-ND) group. A Red cell distribution width (RDW), an index monitor recorded heart rate, systolic BP, and dia- for size variability of circulating erythrocytes, stolic BP readings every 15 minutes during the is a routine component of complete blood co- daytime (7 AM to 11 PM) and every 30 minutes unt (CBC) analysis and traditionally used in the overnight (11 PM to 7 AM) for the 24-hour pe- differential diagnosis of anemia (1). An elevated riod. A greater than 10% fall both in the noctur- RDW value is seen in hematological disorders nal systolic and diastolic BP than those of the such as hemolysis, impaired red cell producti- day time values was defined as dipping pattern on due to iron, vitamin B12 or folate deficiency in concordance with the definition reported by as well as some certain clinical settings, na- Verdecchia (17). Detection of less than 10% de- mely hypertension, prehypertension, pregnancy, crease in either systolic BP or diastolic BP was thrombotic thrombocytopenic purpura (TTP), regarded as non-dipper HT. and inflammatory bowel diseases (IBDs) (2-5). Moreover, RDW was found to be associated with Patients with known coronary artery disease, se- adverse outcomes in patients with heart failure, condary HT, renal failure, hepatic failure, chro- coronary artery disease and acute myocardial in- nic obstructive lung disease and/or manifest heart farction (6-9). disease, such as cardiac failure (left ventricular ejection fraction<50%), atrial fibrillation and Hypertension (HT) is well established and modi- moderate to severe cardiac valve disease, diabe- fiable risk factor for cardiovascular disease (10). tes mellitus, anemia, any prior blood transfusion, Blood pressure (BP) levels show a circadian pregnancy, hyperthyroidism, TTP, IBDs were pattern in which both the systolic and diastolic excluded from the study. All the participants BP decrease more than 10% in the night. Non- included in the study were informed about the dipping HT is defined as lack of nocturnal fall study and their oral and written consents on vo- in the circadian BP pattern which was shown to luntary participation were obtained. be associated with higher risk of cardiovascular, renal and cerebrovascular diseases (11-13). The- After questioning clinical history of risk factors re are few reports about the association between such as age, sex, hypercholesterolemia, smok- RDW and the dipping and non-dipping patterns ing and family history, prior medication for each of BP in normotensive and hypertensive patients, participant, height and weight were measured. however none of these studies involved newly By dividing weight in kilograms by height in me- 2 diagnosed hypertensive patients (14-15). The- ters squared (kg/m ), the body mass index (BMI) refore, in this study we aimed to investigate the was calculated. All, hemoglobin (Hb), RDW, and association between RDW, a routinely reported white blood cell (WBC) counts were measured parameter of CBC analysis, with the dipping and as part of the automated complete blood count non-dipping patterns of BP in normotensive su- analyzed by Beckman-Coulter Gen-S system de- bjects and in patients with newly diagnosed HT. vice (Beckman-Coulter Inc., USA). Anemia was defined as a baseline Hb < 13 g/dL in males and PATIENTS AND METHODS Hb < 12 g/dL in females in accordance with the criteria of the World Health Organization (18). A total of 170 patients were recruited in this prospective randomized controlled study. In one hun- Serum glucose, urea, creatinine, plasma total dred and ten newly diagnosed hypertensive pati- cholesterol, triglycerides (TG), high-density lipo- ents according to the Joint National Committee protein-cholesterol (HDL), low-density lipopro- (JNC) 7 criteria (16) were evaluated by ambu- tein cholesterol (LDL) levels and high-sensitivity latory blood pressure monitoring (ABPM) (Sun- C-reactive protein (hs-CRP) were measured in tech Medical Inc., Morrisville, NC, USA) for the venous blood samples obtained in the morning dipping and non-dipping pattern. Sixty age- and after eight-hour fasting. Blood urea nitrogen, sex- matched outpatient subjects without HT serum creatinine, thyroid stimulating hormone were taken as a control group. The patients were (TSH), serum levels of high-density lipoprotein, categorized into 4 groups as “Normotensive- low-density lipoprotein and triglycerides were Dipper” (NT-D), “Normotensive-Non-dipper” recorded. hs-CRP was measured in serum by EIA

76 Buyukkaya et al. RDW and non-dipper hypertension

(Immage hs-CRP EIA kit, Beckman Coulter Inc., Table 1. Baseline clinical and laboratory characteristics of USA). Transthoracic echocardiography was per- patient groups formed and biplane Simpson’s ejection fraction Normo- Normoten- Hyper- Hyperten- tensive sive- tensive- sive-Non- Variables p (%) was calculated before coronary angiography. - Dipper Non-dipper Dipper dipper The study was approved by the Dicle University (n=31) (n=29) (n=59) (n=51) Medical Faculty Ethics Committee. Age (years) 41.4±3.2 41.8±2.6 42.6±2.9 42.9±2.9 0.08 Sex, males 21(67%) 18 (62%) 37 (62.7%) 33(64.7%) 0.81 (%) Statistical analyses BMI (kg/ 25.6±2.5 25.6±4.3 27.3±5.0 26.0 ±5.1 0.1 m2) Continuous variables were expressed as mean Smoking 14 (45.2%) 14 (48.3%) 27 (45.8%) 22 (43.1%) 0.68 ± standard deviation, whereas categorical varia- (%) bles were presented as percentages. The diffe- Ejection Fraction 60.2±4.1 61±2.7 59.3±3.1 61±2.8 0.46 rences in numeric variables were evaluated by (%) Mann-Whitney U test or Kruskal-Wallis varian- Medications (%) ce analysis as appropriate. Chi–square (χ2) test Aspirin 5 (16) 5 (17) 10 (16.9) 9 (17.6) 0.62 was employed for the comparison of categorical Statin 10 (25.8) 8 (27.5) 16 (27.1) 13 (25.5) 0.22 Glucose variables. In order to determine the independent 86.4±12.5 87.3±18.1 84.7±15.1 86.9±17.4 0.68 (mg/dL) predictors of “non-dipping pattern” in patients HDL-C 33.0±9.2 34.4±9.9 34.5±8.7 35.4±9.6 0.72 with HT, uni- and multivariate analysis were per- (mg/dL) LDL-C formed. The parameters that were found to have 106.7±30.5 116.6±32.7 122.5±33.9 123.1±30.6 0.17 a significance (p<0.10) in the univariate analysis (mg/dL) TG (mg/dL) 162.5±94.5 177.4±122.7 178.8±85 158.1±92.1 0.17 were evaluated by stepwise logistic regression Creatinine 0.90±0.3 0.93±0.2 0.9±0.19 0.93±0.2 0.73 analysis. Ninety-five percent confidence interval TSH 1.6±0.1 1.36±1.08 1.34±0.82 1.52±1.4 0.45 and odds ratios (OR) were presented together. An hsCRP 0.47±0.29 0.78±0.5 0.86±0.42 1.12±0.06 <0.001 Hemoglobin explanatory evaluation of additional cut points 13.1±1.4 13.1±0.99 13.5±1.1 13.4±1.4 0.33 was performed using the receiver operating cha- (g/dL) RDW (%) 12.3±0.5 12.9±0.6 14.2±0.82 14.9±0.78 <0.001 racteristics (ROC) curve analysis. A p < 0.05 was BMI, body mass index; HDL-C, high density lipoprotein cholesterol; considered as statistically significant. hsCRP, high sensitivity C reactive protein; LDL-C, low density lipoprotein cholesterol; RDW, red cell distribution width; TSH, thyroid RESULTS stimulating hormone. In total 170 patients (42.4 ± 3.0 years, 64.1% comprised of males) were included in the study. (157.0±11.8 vs. 149.8±10.9, p=0.001; 95.0±5.4 Baseline clinical and laboratory characteristics vs. 90.0±5.9, p<0.001) and nighttime systolic of the patients relative to dipping and non-dip- and diastolic BP (152.5±12.0 vs. 134.8±10.9, ping status were shown in Table 1. Age, sex, p<0.001; 91.0±5.4 vs. 78.3±7.1, p<0.001) (Table BMI and medication were not different between 2). Daytime and nighttime heart rate values were the groups. In the normotensive group, dippers similar in all groups. and non-dippers had similar daytime systo- The patients with HT had higher RDW and serum lic and diastolic BP (114.5±6.2 vs. 111.9±9.1, hs-CRP levels than the normotensive patients p=0.24; 73.2±5.5 vs. 71.6±9.0, p=0.46), and 24- (14.5 ± 0.87 vs.12.7 ± 0.66, p<0.001 for RDW; hour mean systolic and diastolic BP (108.9±6.4 0.99 ± 0.52 vs.0.63 ± 0.43, p<0.001 for hs-CRP). vs. 110.8±8.4, p=0.40; 68.16±5.9 vs.70.7±8.4, Moreover, the RDW levels were higher in non- p=0.26); however non-dippers had significantly dippers than the dippers in the groups (13.0 ± higher nighttime systolic and diastolic BP 0.63 vs.12.4 ± 0.55, p<0.001 for NT-ND and NT- (108.7±7.6 vs. 97.8±7.8, p<0.001; 68.7±7.6 vs. D; 14.9 ± 0.78 vs.14.2 ± 0.82, p<0.001 for HT- 57.8±7.8, p<0.001). In the hypertensive patients, ND and HT-D) (Figure 1). Similarly, serum hs- however, while daytime systolic and diastolic BP CRP levels were higher in non-dippers than the (157.3±11.1 vs. 159.2±11.9, p=0.47; 95.8±6.2 vs. dippers in the groups as well (0.78 ± 0.5 vs.0.48 96.9±6.0, p=0.39) was similar in the dippers and ± 0.3, p=0.017 for NT-ND and NT-D; 1.13 ± 0.6 non-dippers, the hypertensive non-dippers had vs.0.86 ± 0.42, p=0.016 for HT-ND and HT-D) higher 24-hour mean systolic and diastolic BP (Figure 1). When subgroups were analyzed it was

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Table 2. Ambulatory blood pressure monitoring results of dippers and non-dippers among individuals with normal and high 24-h blood pressure Normotensive subjects Hypertensive subjects Variables Dipper Non-dipper p Dipper Non-dipper p 24-h systolic 108.9±6.4 110.8±8.4 p:0.40 149.8±10.9 157.0±11.8 p:0.001 24-h diastolic 68.16±5.9 70.7±8.4 p:0.26 89.9±5.9 95.0±5.4 p<0.001 Day-time systolic 114.5±6.2 111.9±9.1 p:0.24 157.3±11.2 159.2±11.9 p:0.47 Day-time diastolic 73.2.6±5.5 71.6±9.0 p:0.46 95.8±6.2 96.9±6.0 p:0.39 Night-time systolic 97.8±7.7 108.7±7.5 p<0.001 134.8±10.9 152.5±12.0 p<0.001 Night-time diastolic 57.8±7.8 68.7±7.6 p<0.001 78.3±7.1 91.0±5.4 p<0.001 24-hour heart rate 68.4±5.8 70.2±6.5 p:0.45 67.3±6.5 69.6±5.8 p:0.66

Figure 2. RDW and hs-CRP levels according to the blood pressure groups The ROC curve analysis further revealed that RDW was a strong indicator of the “non-dipping status” in patients with HT with an AUC of 0.74 (95% CI: 0.64 to 0.83) (Figure 3). The optimal threshold of RDW level that maximized the combined specificity and sensitivity to predict the “non-dipping status” was 14.5%. Sensitivity, specificity, positive predictive value and negative predictive value to identify “non-dipper hypertensive” patients was 75%, 60%, 78, and 54%, respectively.

Figure 1. Correlation plot for RDW and hs-CRP

found that the serum hs-CRP levels were higher in the HT-ND group, and similar in HT-D and NT-ND groups (for HT-ND vs. HT-D groups 1.13 ± 0.6 vs.0.86 ± 0.42, p=0.016; for HT-ND vs. NT- ND groups 1.13 ± 0.6 vs. 0.78 ± 0.5, p=0.010; for HT-D vs. NT-ND groups 0.86 ± 0.42 vs. 0.78 ± 0.5, p=0.36). The serum hs-CRP levels were significantly lower than all groups in the NT-D group. Univariate correlation analysis revealed a positive correlation between RDW levels and hs- Figure 3. ROC curve showing the sensitivity and specificity of CRP levels (Rho=0.40, p<0.001) (Figure 2). RDW with regard to “non-dipping status” in patients with hypertension. (RDW≥14.5)

78 Buyukkaya et al. RDW and non-dipper hypertension

For determining predictors of the “non-dipping production due to iron, vitamin B12 or folate defi- pattern” in patients with hypertension, uni- and ciency, hypertension, prehypertension, pregnancy, multivariate analyses were performed. For pre- thrombotic thrombocytopenic purpura (TTP), dicting the “non-dipping pattern” in patients with stroke, colon cancer and inflammatory bowel di- hypertension, the RDW score was dichotomized seases (IBDs), the RDW values were found to be into high (RDW≥14.5) and low (<14.5) grou- elevated (2-5, 21-22). Additionally, in patients ps. In the multivariate analysis, the parameters with heart failure, coronary artery disease and acu- showing significance in the univariate analysis te myocardial infarction (6-9, 23) RDW was fo- (mean systolic BP, mean diastolic BP, hs-CRP) und to be associated with adverse outcomes (24). were evaluated by multivariate analysis in order Hypertension is a well known risk factor for left to determine independent predictors of “non-dip- ventricular dysfunction and atherosclerotic cardi- ping pattern”. Thus, mean diastolic BP and hs- ovascular disease with inflammatory background CRP were found as independent predictors of the (25-27). Blood pressure level shows a circadian “non-dipping pattern” (Table 3). pattern in which both the systolic and diastolic BP decrease more than 10% in the night. Non- Table 3. Significant predictors of “non-dipping pattern” in patients with hypertension in invariable and stepwise multivari- dipping HT is defined as a lack of nocturnal fall able logistic regression analyses for the red cell distribution in the BP (11,28). Daily nocturnal BP fall is a width (RDW) cutoff of 14.5% pattern which is seen not only in hypertensive Univariate Stepwise multivariate Variable patients but also in normotensive people (28). OR (95 % CI) p OR (95 % CI) p There are many studies showing that the non- “Non-dipping pattern” in HT patients dipping of blood pressure means higher risk for Age 1.01 (0.88-1.15) 0.88 cardiovascular diseases for both hypertensive Sex 1.00 (0.45-2.20) 0.99 BMI 0.98 (0.91-1.06) 0.69 and normotensive subjects (28-30). Smoking 0.89 (0.42-1.9) 0.78 Results of the present study have shown that Mean systolic BP 1.04 (1.04-1.08) 0.03 0.96 (0.92-1.00) 0.067 hypertensive patients had higher RDW level Mean diastolic BP 1.06 (0.99-1.13) 0.05 0.85 (0.78-0.93) <0.001 when compared to normotensive subjects, which Glucose 0.99 (0.97-1.01) 0.41 is in accordance with the previous studies (31). LDL-C 1.0 (0.98-1.01) 0.38 HDL-C 1.02 (0.89-1.06) 0.37 It is well established that HT has inflammatory Triglyceride 0.99 (0.99-1.00) 0.54 background (25) and the association of RDW hs-CRP 2.5 (1.09-5.8) 0.03 0.39 (0.16-0.96) 0.04 with inflammatory markers is well known, which TSH 1.06 (0.75-1.5) 0.72 both may be related with the increased inflamma- BP, blood pressure; CI, confidence interval; HDL-C, high density tory status in patients with HT (24). In addition, lipoprotein cholesterol; hs-CRP, high sensitivity C-reactive protein; LDL-C, low density lipoprotein cholesterol; OR, odds ratio; TSH, this study has found that RDW and hs-CRP levels thyroid stimulating hormone were correlated, which in turn reflected the increase of inflammatory status. However, according DISCUSSION to subgroup analysis, hs-CRP levels of HT-D and In this study the relationship between RDW and NT-ND groups were not different. Based on this dipping and non-dipping patterns of BP both in finding, it could be concluded that HT-D patients normotensive and hypertensive subjects was in- have similar inflammatory status as NT-ND pa- vestigated. This study revealed that non-dipping tients, and accordingly, non-dipping BP may be pattern in the circadian BP course was associated concurrently present with an undiagnosed in- with elevated RDW levels in both normotensive flammatory condition, which may be the reason and hypertensive subjects, which may be related for the non-dipping pattern as well. The exact with increased inflammatory state. pathophysiological mechanism for non-dipping BP is not clearly established for the time being, The RDW is an index for the size variability of the however it is known that non-dippers have higher circulating erythrocytes routinely reported with cardiovascular risk (28-30). On the other hand, complete blood count analysis and commonly higher RDW levels are found to be a consequence used in the differential diagnosis of anemia (19- of oxidative stress causing cytoskeletal structural 20). Recent studies revealed that in many clinical changes and endothelial dysfunction (32-33). settings including hemolysis, impaired red cell

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Non-dippers had higher RDW levels than the prehypertensive subjects (7) but there is no data dippers for both normotensive and hypertensive about the circadian BP patterns in prehypertensi- subjects in this study. Thus, the link between high ve subjects. So it may be regarded as a limitation RDW and hs-CRP levels may be oxidative stress that we did not include subjects with prehyper- causing endothelial dysfunction, which in turn tension. Because there is a lack of data for long- impairs the autonomic nervous system and cir- term follow-up, this study did not provide any cadian BP pattern. According to the multivariate prognostic data in terms of future cardiovascular analysis, independent predictors of non-dipper events and effects of antihypertensive medicati- HT were found to be mean diastolic pressure and on, which is another limitation of the study. hs-CRP, which may imply that an inflammatory In conclusion, RDW, a routinely reported he- condition is the reason for the change of the cir- matological parameter, is elevated in non-dip- cadian BP pattern; however the exact mechanism ping BP both in normotensive and hypertensive seems to be obscure for the time being. patients, which may be related to increased in- A major limitation of the current study is the lack flammatory state. of other anemia parameters such as iron, vitamin B12, folate and other inflammatory markers such FUNDING as IL-6, TNF-alpha. Besides, it would be better No specific funding was received for this study. to include more patients in order to increase the statistical power. Another point is that we did not TRANSPARENCY DECLARATION include patients with prehypertension. In one stu- Conflict of interest: None to declare. dy, the RDW levels were found to be elevated in

REFERENCES 1. Greer JP, Foerster J, Lukens JN, Rodgers GM, Para- 8. Dabbah S, Hammerman H, Markiewicz W, Aronson skevas F, Glader B. Wintrobe’s Clinical Hematology. D. Relation between red cell distribution width and Wolters Kluwer: Lippincott Williams&Wilkins, clinical outcomes after acute myocardial infarction. 2003. Am J Cardiol 2010; 105:312-7. 2. Clarke K, Sagunarthy R, Kansal S. RDW as an addi- 9. Felker GM, Allen LA, Pocock SJ, Shaw LK, tional marker in inflammatory bowel disease/un- McMurray JJ, Pfeffer MA, Swedberg K, Wang D, differentiated colitis. Dig Dis Sci 2008; 53:2521-3. Yusuf S, Michelson EL, Granger CB. Red cell dis- 3. Shehata HA, Ali MM, Evans-Jones JC, Upton GJ, tribution width as a novel prognostic marker in he- Manyonda IT. Red cell distribution width (RDW) art failure: data from the CHARM Program and the changes in pregnancy. Int J Gynaecol Obstet 1998; Duke Databank. J Am Coll Cardiol 2007; 50:40-7. 62:43-6. 10. Messerli FH, Williams B, Ritz E. Essential hyperten- 4. Nagajothi N, Braverman A. Elevated red cell distri- sion. Lancet 2007; 370:591-603. bution width in the diagnosis of thrombotic throm- 11. Kurpesa M, Trzos E, Drozdz J, Bednarkiewicz Z, bocytopenic purpura in patients presenting with Krzeminska-Pakula M. Myocardial ischemia and anemia and thrombocytopenia. South Med J 2007; autonomic activity in dippers and non-dippers with 100:257-9. coronary artery disease: assessment of normoten- 5. Fukuta H, Ohte N, Mukai S, Saeki T, Asada K, Wa- sive and hypertensive patients. Int J Cardiol 2002; kami K, Kimura G. Elevated plasma levels of B-ty- 83:133-42. pe natriuretic peptide but not C-reactive protein are 12. Lurbe E, Redon J, Kesani A, Pascual JM, Tacons J, associated with higher red cell distribution width Alvarez V, Batlle D. Increase in nocturnal blood pre- in patients with coronary artery disease. Int Heart J ssure and progression to microalbuminuria in type 1 2009; 50: 301-12. diabetes. N Engl J Med 2002; 347:797-805. 6. Isik T, Uyarel H, Tanboga IH, Kurt M, Ekinci M, 13. Kario K, Pickering TG, Matsuo T, Hoshide S, Kaya A, Ayhan E, Ergelen M, Bayram E, Gibson Schwartz JE, Shimada K. Stroke prognosis and ab- CM. Relation of red cell distribution width with the normal nocturnal blood pressure falls in older hyper- presence, severity, and complexity of coronary ar- tensives. Hypertension 2001; 38:852-7. tery disease. Coron Artery Dis 2012; 23:51-6. 14. Ozcan F, Turak O, Durak A, Isleyen A, Ucar F, Ginis 7. Uyarel H, Ergelen M, Cicek G, Kaya MG, Ayhan E, Z, Basar FN, Aydogdu S. Red cell distribution width Turkkan C, Yildirim E, Kirbas V, Onturk ET, Erer and inflammation in patients with non-dipper hyper- HB, Yesilcimen K, Gibson CM. Red cell distribution tension. Blood Press 2013; 22:80-5. width as a novel prognostic marker in patients un- 15. Gunebakmaz O, Kaya MG, Duran M, Akpek M, El- dergoing primary angioplasty for acute myocardial cik D, Eryol NK. Red blood cell distribution width infarction. Coron Artery Dis 201; 22:138-44. in ‘non-dippers’ versus ‘dippers’. Cardiology 2012; 123:154-9.

80 Buyukkaya et al. RDW and non-dipper hypertension

16. Chobanian AV, Bakris GL, Black HR, Cushman 25. Sesso HD, Buring JE, Rifai N, Blake GJ, Gaziano WC, Green LA, Izzo JL, Jr., Jones DW, Materson JM, Ridker PM. C-reactive protein and the risk of BJ, Oparil S, Wright JT, Jr., Roccella EJ. The Se- developing hypertension. JAMA 2003; 290:2945- venth Report of the Joint National Committee on 51. Prevention, Detection, Evaluation, and Treatment of 26. Birkenhager AM, van den Meiracker AH. Causes High Blood Pressure: the JNC 7 report. JAMA 2003; and consequences of a non-dipping blood pressure 289:2560-72. profile. Neth J Med 2007; 65:127-31. 17. Verdecchia P, Schillaci G, Guerrieri M, Gatteschi 27. Karakas MF, Buyukkaya E, Kurt M, Karakas E, C, Benemio G, Boldrini F, Porcellati C. Circadian Buyukkaya S, Akcay AB, Sen N. Assessment of left blood pressure changes and left ventricular hyper- ventricular dyssynchrony in dipper and non-dipper trophy in essential hypertension. Circulation 1990; hypertension. Blood Press 2013; 22:144-50. 81:528-36. 28. Ohkubo T, Hozawa A, Yamaguchi J, Kikuya M, 18. Nutritional anaemias. Report of a WHO scientific Ohmori K, Michimata M, Matsubara M, Hashimo- group. World Health Organ Tech Rep Ser 1968; to J, Hoshi H, Araki T, Tsuji I, Satoh H, Hisamichi 405:5. S, Imai Y. Prognostic significance of the nocturnal 19. Hogg K, Swedberg K, McMurray J. Heart failure decline in blood pressure in individuals with and with preserved left ventricular systolic function; epi- without high 24-h blood pressure: the Ohasama stu- demiology, clinical characteristics, and prognosis. J dy. J Hypertens 2002; 20:2183-9. Am Coll Cardiol. 2004; 43:317-27. 29. Hoshide S, Kario K, Hoshide Y, Umeda Y, Hashi- 20. Simel DL, DeLong ER, Feussner JR, Weinberg JB, moto T, Kunii O, Ojima T, Shimada K. Associati- Crawford J. Erythrocyte anisocytosis. Visual in- ons between nondipping of nocturnal blood pressure spection of blood films vs automated analysis of red decrease and cardiovascular target organ damage in blood cell distribution width. Arch Intern Med 1988; strictly selected community-dwelling normotensi- 148:822-4. ves. Am J Hypertens 2003; 16:434-8. 21. Ani C, Ovbiagele B. Elevated red blood cell dis- 30. Verdecchia P, Schillaci G, Boldrini F, Guerrieri M, tribution width predicts mortality in persons with Porcellati C. Sex, cardiac hypertrophy and diurnal known stroke. J Neurol Sci 2009; 277:103-8. blood pressure variations in essential hypertension. 22. Spell DW, Jones DV, Jr., Harper WF, David Be- J Hypertens 1992; 10:683-92. ssman J. The value of a complete blood count in 31. Tanindi A, Topal FE, Topal F, Celik B. Red cell dis- predicting cancer of the colon. Cancer Detect Prev tribution width in patients with prehypertension and 2004; 2837-42. hypertension. Blood Press 2012; 21:177-81. 23. Tonelli M, Sacks F, Arnold M, Moye L, Davis B, 32. Minetti M, Malorni W. Redox control of red blood Pfeffer M. Relation between red blood cell distribu- cell biology: the red blood cell as a target and source tion width and cardiovascular event rate in people of prooxidant species. Antioxid Redox Signal 2006; with coronary disease. Circulation 2008; 117:163-8. 8:1165-9. 24. Lippi G, Targher G, Montagnana M, Salvagno GL, 33. Berliner S, Rogowski O, Aharonov S, Mardi T, Zoppini G, Guidi GC. Relation between red blood Tolshinsky T, Rozenblat M, Justo D, Deutsch V, Se- cell distribution width and inflammatory biomarkers rov J, Shapira I, Zeltzer D. Erythrocyte adhesivene- in a large cohort of unselected outpatients. Arch Pat- ss/aggregation: a novel biomarker for the detection hol Lab Med 2009; 133:628-32. of low-grade internal inflammation in individuals with atherothrombotic risk factors and proven vas- cular disease. Am Heart J 2005; 149:260-7.

81 ORIGINAL ARTICLE

Comparison of the accuracy and correctness of mortality estimates for Intensive Care Unit patients in internal clinics of the Czech Republic using APACHE II, APACHE IV, SAPS 3 and MPMoIII models

Pavel Sedloň1,2, Libor Kameník1,2, Jan Škvařil1, Martin Malý1,2, Miloš Táborský3, Miroslav Zavoral1,2

1Department of Internal Medicine, Central Military Hospital, 21st Faculty of Medicine, Charles University in Prague; Prague, 3Department of Internal Medicine I - Cardiology, University Hospital Olomouc; Czech Republic

ABSTRACT

Aim To verify and compare the accuracies of mortality predictions in the Intensive Care Unit (ICU) of the Internal Clinic of Central Military Hospital in Prague, Czech Republic, using model APACHE II and the newer systems of the APACHE IV, SAPS 3

and MPMoIII. Methods The data were collected retrospectively between 2011 and 2012, 1000 patients were evaluated. The assessment of the overall accuracy of the mortality predictions was performed using the standardized mortality ratio (SMR), and the calibration was assessed using the Lemeshow-Hosmer “goodness-of-fit” C sta- Corresponding author: tistic. Discrimination was evaluated using ROC curves based on Pavel Sedloň calculations of the areas under the curve (AUCs). Department of Internal Medicine (Cardiol- Results The APACHE II, SAPS 3, and MPMoIII systems signifi- ogy), 1st Faculty of Medicine, Charles cantly overestimated the expected mortality, whereas the APAC- University, Military University Hospital HE IV model led to correct estimations of the overall mortality. U Vojenské nemocnice 1200, The discrimination capabilities of the models assessed according Prague 6 Czech Republic to the constructions of the ROC curves were evaluated as good, Phone: +420 973 203 043; only the APACHE II was evaluated as satisfactory. The calibrations of all models were evaluated as unsatisfactory. Fax: +420 973 203 038; E-mail: [email protected] Conclusion The best mortality estimation for the investigated population sample was provided by the APACHE IV system. The discrimination capabilities of all models for the studied population were satisfactory, but the calibration of all of the systems was un- Original submission: satisfactory. The conclusions of our study are limited by the rela- 26 April 2015; tively small size of the investigated sample and the fact that this Revised submission: study was conducted at only a single site. 20 June 2015; Key words: intensive care units, Czech Republic, mortality, pro- Accepted: gnosis, humans, models, calibration, health status indicators, ROC 22 June 2016. curve, retrospective studies doi: 10.17392/860-16

Med Glas (Zenica) 2016; 13(2):82-89

82 Sedloň et al. Comparison of four mortality models

INTRODUCTION PATIENTS AND METHODS Prognostic scoring systems have been developed Patients and study design by companies for intensive medicine in an effort to objectively describe and quantify the severity The Central Military Hospital in Prague, Czech of the conditions of selected groups of critically Republic, is a university hospital of the third ill patients (1). Furthermore, an independent type which covers urban referral area including evaluation of the severity of a condition allows approximately 150.000 inhabitants. The intensi- for the relatively objective assessments of the ve care unit (ICU) of the internal clinic has 9 beds workloads required by intensive care units and that are fully equipped to provide comprehensi- resuscitation care units (2). To a certain extent, ve intensive care including artificial ventilation such independent evaluations also allow for the support and continual renal replacement therapy. comparison of the quality and effectiveness of It admits approximately 800 patients with preva- the care between these facilities (2,3) iling internal diagnoses per year to this ICU. The There is a large number of prognostic models hospital also houses a surgical intensive care unit (3). Some generally focus on covering the enti- and a resuscitation care unit (KARIM). It was re population of critically ill patients, and some retrospectively collected data from patients who narrowly focus on predicting the prognosis and were consecutively admitted to the internal ICU severity of narrowly defined conditions. The between 01 January 2011 and 31 August 2012. most used general prognostic scoring models The data were obtained by revision of medical re- include systems such as the Acute Physiology cords and electronic documents stored in an inter- and Chronic Health Evaluation (APACHE), nal hospitalization system database (AMIS). All Simplified Acute Physiology Score (SAPS) and tests and data were recorded in accordance with the Mortality Probability Model (MPM) (4–7). standard processes in relation to the underlying The oldest general complex systems are the disease. An approval from the Central Military APACHE system, which was published in 1981 Hospital Ethics Committee was obtained before (8), and the SAPS system from 1983 (9). The initiation of the study. APACHE system was revised in 1985 and sub In total, data from 1009 patients were duly proce- sequently published as the APACHE II system ssed, and the data from 1000 patients were used (4). With regard to the rapid development of for our study (i.e., 99.1%); nine patient records health care opportunities and improvements in were excluded due to incompleteness or the una- treatment procedures, the prognoses of a num- vailability of significant values. To suppress the ber of critical conditions have improved over a variability in the data collection, all values were relatively short time; therefore, the original pro- recorded by a single trained and experienced me- gnostic systems have become relatively absolu- dical professional and subsequently revised by te and require revision. Before using these mo- the authors of the study. dels, all of these models should be validated for the specific population to which they should be Methods and statistical analysis applied (10,11). The analyses focused on the following data: The most recent revisions of the mentioned pro- the demographic characteristics, APACHE II gnostic models were published between 2005 and scores, APACHE IV scores, SAPS3 scores, 2007; e.g., the APACHE IV model in 2006(8), the and the variables of MPM0 III system. Valu- European SAPS 3 model in 2005 (6,7) and the es obtained at the time of admission or within the first 24 hours of hospitalization were used. MPM0III model in 2007 (12). To date no published test has been performed in the Czech Republic. In accordance with the original methodology Our work was committed to verifying the applica- of data collection, the values with the greatest bility of systems, such as the APACHE II and IV, deviations from the normal (physiological) values were used. Individual cases were reviewed MPMoIII and SAPS3, in a set number of ICU patients of an internal clinic in a tertiary care hospital in in cases of missing values. If a missing value Prague, Czech Republic. was assessed as insignificant, it was taken to be normal. Patients with missing values that were

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considered significant were not included in the area under the curve (AUC). AUC values > 0.75 assessment. Equally to all evaluated models, were evaluated as satisfactory, AUC values > 0.8 the mortality of the patients was assessed upon were evaluated as good, and AUC values > 0.9 discharge from the hospital. The patients who were evaluated as very good. The classification were transferred to another facility for hospita- matrices were processed with the classification lization or intensive care were further monito- criteria of 10%, 30% and 50%, and based on the- red, and their mortalities were assessed at disc- se criteria, the sensitivities and specificities of the harge to home care or when they were moved to individual tests were determined. facilities that provided long-term nursing and RESULTS rehabilitative care. The APACHE II scores and mortality estimates Demographic characteristics of the patients were calculated according to the original equa- tion (4) as were the predictions of mortality ba- The mean age of the patients was 69.9 years, sed on the APACHE IV, MPMoIII and SAPS3 and the representations of both sexes were re- (6–8,12). The standardized mortality ratio (SMR) latively proportional (56% males versus 44% was calculated as the ratio of the observed hospi- females). The total mortality at discharge was talization mortality and the predicted mortality. 10.9% (109 patients). The representation of sur- The 95% confidence intervals (CI95%) were gical patients was very low, 11 (1.1%) patients. obtained using the observed mortality as a Poi- Total of 638 patients (63.8%) were admitted due sson variable and then using the 95% CI divided to emergency situations. Significantly higher by the predicted mortality. We further verified the mortality was observed in the group of patients general accuracy of the models by determining who were moved to the ICU from wards, 47 the Brier score (13). (23%) patients. The group of the deceased also exhibited longer histories of previous hospitali- Because the Brier scores depend on the preva- zation. The deceased patients were older (78.5 lence of the reference character in the populati- years vs. 68.8 years; p <0.001), and at a lower on (mortality in our case), it is not suitable for level of significance a difference in mortality comparing the accuracies of models in different between the sexes (the mortality of the females populations. Therefore, we completed the calcu- was 19%, and the mortality of the males was lation by determining the “scaled” Brier score 11%; p <0.05) was also found. Factors associa- (BS ), which is independent of the starting set. scaled ted with higher mortality included cardiopulmo- (14) Verification of the system’s applicability to nary resuscitation before or at the time of ad- studied cohort of patients was conducted by re- mission ant the need for mechanical ventilation viewing its calibration and discrimination. Cali- (p<0.001). In a greater proportion of patients, bration, which expresses the ability of the test to hospitalization was discontinued with discharge determine the probability of death in accordance to home care, 702 (70%). Some patients were with the observed mortality, was calculated using moved to facilities for long-term follow-up care the Hosmer-Lemeshow test (15). Rejection of the (n = 189, 19%). A total of 109 (10.9%) patients null hypothesis, i.e., the assumption of the absen- died during hospitalization (Table 1). ce of a difference between the predicted and actual mortality in each group, was performed at a Table 2 shows the actual mortality and the mor- significance level of p<0.05. talities predicted based on the examinations of the scoring systems. Mortality was predicted The abilities of the individual systems to distin- correctly only with the APACHE IV system. In guish survivors and non-survivors according to all other systems, the SMRs were significantly the estimated mortality (discrimination) were below 1, which indicated an overestimation of assessed using receiver operating characteristic the set estimated mortality. The Brier scores (ROC) curves and 2x2 classification matrices. were satisfactory for all models. Values modifi- The ROC curves were constructed as discrimi- ed using the “scaled” Brier score (13,14) reve- nation measurements with distributions per 10% aled relatively better prediction accuracies for according to the predicted mortality. The obtai- the APACHE IV and SAPS 3 models, a border- ned curves were compared using the calculated

84 Sedloň et al. Comparison of four mortality models

Table 1. Baseline characteristics of the patients Table 2. In-hospital mortalities predicted by the systems Actual Predicted Brier BS Mean ± SD System SMR 95%CI mortality mortality score scaled Non-survi- Parameter Total Survivors p vors APACHE II 0.109 0.166 0.66 0.63-0.69 0.0909 6.30% Total 1000 891 109 APACHE IV 0.109 0.098 1.11 1.00-1.22 0.0806 17% Mean age (years) 69.9 ± 16.3 68.8 ± 16.7 78.5 ± 9,5 <0.001* SAPS3 0.109 0.162 0.67 0.63-0.71 0.0764 21.30% Sex (%) MPM0III 0.109 0.134 0.81 0.75-0.87 0.0873 10% Male 560 (56) 505 (56.7) 55 (50.5) <0,05† SMR, standardized mortality ratio abbreviation in full; BS, Brier score; Female 440 (44) 386 (43.3) 54 (49.5) <0,05† Type of admission (%) Transfer from ward 199 (19.9) 152 (17) 47 (43.1) <0.001 From other hospitals 163 (16.3) 157 (17.6) 6 (5.5) <0.01 Estimated mortality based on primary diagnosis Duration of previous 1.68 ± 5.34 1.42 ± 5.05 3.8 ± 6.95 <0,001* at admission hospitalization Need for mechanical 52 (5.2) 30 (3.3) 22 (20.2) <0.001 The division of the total set into categories accor- ventilation (%) ding to primary diagnosis at admission (Table 3) Surgical procedure 11 (1.1) 10 (1.1) 1 NS before admission (%) resulted in the total accuracies of the mortality Cardiopulmonary 39 (3.9) 28 (3.1) 11 (10) <0.01 predictions slightly decreasing in most of the resuscitation (%) systems. All systems achieve the best prediction Hospital discharge location (%) of total mortality for respiratory diseases. The Home 702 (70.2) 702 (78.7) 0 Other 189 (18.9) 189 (21.2) 0 mortality was most overestimated for cardiovas- Death 109 (10.9) 0 109 cular diseases, particularly in patients with acute Mortality probabi- myocardial infarction (MI) (Table 4). 16.6 ± 12.8 15.1 ± 11.7 28.4 ± 15.5 <0.001* lity, APACHE II (%) Mortality proba- Calibration bility, APACHE 9.85 ± 15.1 11.5 ± 7.6 27.9 ± 25.4 <0.001* IV (%) For all systems, the χ2 values were not very sat- Mortality probabi- 16.2 ± 16.4 12.9 ± 13.4 39.3 ± 22.4 <0.001* isfactory, and p values <0.05 were observed in lity, SAPS3 (%) Mortality probabi- all cases. Relatively, the best calibration was ob- 13.5 ± 17.1 14.1 ± 11.2 31.7 ± 26.3 <0.001* lity, MPM0 III (%) served for the APACHE IV system (χ2 =24.2) with *survivors vs non-survivors; †male vs female mortality a p value of 0.002, for APACHE II system wasχ2 value slightly higher (χ2=25.7) with p value of line prediction accuracy for the MPMoIII model, 0.001. The SAPS3 and the MPMoIII systems ex- and a relatively unsatisfactory prediction accu- hibited the worst calibrations in our group, with racy for the APACHE II model. high χ2 values (31.1 and 43.2) and p values <0.001.

Table 3. Standardized mortality ratio (SMR) according to reason for admission Standardized mortality ratio Subcategory No of patients Died APACHE II APACHE IV SAPS 3 MPMoIII 0.49 0.78 0.47 0.47 Cardiovascular 610 41 (0.46-0.53) (0.69-0.89) (0.44-0.51) (0.43-0.52) 1.03 1.21 0.89 1.42 Respiratory 112 22 (0.91-1.19) (1.00-1.52) (0.76-1.07) (1.13-1.87) 0.51 0.91 0.47 0.88 Gastrointestinal and metabolic 193 12 (0.49-0.59) (0.73-1.2) (0.42-0.55) (0.74-1.09) 1.84 2.23 1.27 1.75 Other 85 33 (1.60-2.17) (1.76-3.03) (1.1-1.52) (1.43-2.24)

Table 4. Standardized mortality ratio (SMR) according to presence of myocardial infarction Standardized mortality ratio Subcategory No of patients Died APACHE II APACHE IV SAPS 3 MPMoIII 0.29 0.59 0.33 0.37 Myocardial infarction (MI)(16) 200 7 (0.27-0.33) (0.49-0.75) (0.30-0.38) (0.31-0.45) 0.72 1.17 0.72 0.88 Non-MI patients 800 102 (0.62-0.83) (1.12-1.24) (0.70-1.24) (0.77-1.03)

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Discrimination limits lead to potential limitations regarding the use of scoring systems in different populations The worst correctness of the classification was and in different eras (2) observed with the APACHE II system. At the . selected discriminating levels of 30 and 50% all All of the systems under investigation were de- of the other systems reached values of overall veloped in sample populations with compositions classification accuracy of approximately 88 and that differed from the set of our workplace. Alt- 89%, respectively (Table 5). hough the diagnoses and conditions occurring in our group were part of the spectrum of diagnoses Table 5. Results of the analysis of the classification matrices of the cohorts of patients used to develop the te- Died Survived sted models, their proportions and profiles of the Sensitivity Specificity severities of the conditions were different. System PD PS PD PS OCCR (95% CI) (95% CI) In our work, we observed an overestimation of Cutoff 10% APACHE II 101 8 576 315 92 (86-96) 35 (32-39) 42% the estimated mortality that applied to all mo- APACHE IV 72 37 166 725 66 (56-74) 81 (79-84) 80% dels with the exception of the most recent and MPMoIII 86 23 293 598 79 (70-85) 67 (64-70) 68% most comprehensive model, i.e., the APACHE SAPS3 102 7 386 505 94 (87-97) 57 (53-60) 61% IV. This overestimation of predicted mortality Cutoff 30% was particularly strong in the subgroup of pa- APACHE II 48 61 109 782 44 (35-54) 88 (85-90) 83% tients with acute myocardial infarction (16). APACHE IV 36 73 43 846 33 (24-42) 95 (94-96) 88% This finding correlates well with the decrea- MPMoIII 40 69 55 836 37 (28-46) 94 (92-95) 88% SAPS3 65 44 81 810 60 (50-68) 90 (88-92) 88% se in mortality in these patients that has been Cutoff 50% documented in recent years in connection with APACHE II 9 100 13 878 8 (4-15) 99 (98-99) 89% the development of acute reperfusion therapy APACHE IV 23 86 20 871 21 (15-30) 98 (97-99) 89% (17). In the Czech Republic, the predominant MPMoIII 26 83 29 862 24 (17-33) 97 (95-98) 89% mode of treatment for patients with acute coro- SAPS3 37 72 32 859 34 (26-43) 96 (95-97) 90% nary syndrome is acute PCI, which is expected PD, death predicted; PS, survival predicted; OCCR, overall correct classification rate to lead to significant reductions in mortality in patients who are admitted to the hospital with acute myocardial infarction (18). However, this ROC curves were constructed for all the me- conclusion may not be universally valid as de- asured systems. Good discrimination capabili- monstrated by the study by Nassara Jr. et al. ties were demonstrated by the SAPS 3 (AUC from 2013 that was conducted at the University 0.867) and APACHE IV (AUC 0.841) systems, Hospital in Sao Paulo; in this study, the overall and a slightly worse but still good discrimi- predictions of mortality and the discrimination nation capability was also observed for the capabilities of the APACHE IV and SAPS 3 te- MPMoIII system (AUC 0.807). As expected, sts for this group of patients were good (19). If the oldest system, i.e., the APACHE II, exhibi- we exclude the group of patients with myocardi- ted the worst value, although it was still satis- al infarction in our sample from the evaluation, factory (AUC 0.766). the overall accuracy of the mortality classification according to the SMR significantly impro- DISCUSSION ves for all newer systems. Only the APACHE The construction of prognostic scoring systems II system also significantly overestimated the is always determined by the population sample overall mortality in this group of patients (SMR used for the calibration and subsequent valida- 0.72, CI 0.62 to 0.83). tion of the model. Similarly, the construction We found a number of studies that compared of models is always limited by the time of their the prediction accuracies of the APACHE IV,

creation, and the results are always related to SAPS II and MPMoIII systems (20–23). There the current level of medicine at that time. Fi- are also many published papers that have de- nally, the outputs of models are limited by the scribed the functionality of the selected general resources invested in medical care within the gi- scoring systems in various intensive care units ven population under examination. All of these in different countries (21,24–26). Kuzniewitz

86 Sedloň et al. Comparison of four mortality models

et al. (22) compared the functionalities of the ons of patients with low overall risks (28). Other

APACHE IV, SAPS II and MPMoIII models in causes may also include regional differences in a study involving 11,300 patients who were ad- the approach to decisions about terminating mitted to 35 intensive care units in California. care, differences in the diagnoses of certain di- When applied to the US population, the best seases and regional differences in the manner of discrimination capability was observed for the providing medical care (15,29). APACHE IV (AUC 0.892) model followed by The results of our work should be evaluated the SAPS 2 (AUC 0.873) and MPMoIII (AUC with caution due to the present limitations and 0.809) models, and these results agree well with restrictions. This work is limited in scope to a our own. Similarly, Keegan et al. (23) compared single workplace that predominantly provides the APACHE III, APACHE IV, SAPS 3 and care to patients with diagnoses of internal me- MPMoIII models in 2596 patients from three dical natures. The number of patients included intensive care units (Rochester, Mayo Medical in the evaluation was not small; however, this Centre). Regarding the discrimination capabili- number was significantly smaller compared to ties as expressed by ROC curves, these authors the large multicentre studies or sets based on found the best results for the APACHE IV (AUC which the assessed models were constructed. 0.861), satisfactory results for the SAPS (AUC Therefore, our findings may not be fully tran- 0.801) and the worst results for the MPMoIII sferable and valid for other intensive care units. (AUC 0.721). Again, these findings confirm the In conclusion, our findings revealed that the in- values in the cases of the SAPS 3and APACHE vestigated systems overestimated the expected IV models observed in our work and the quite total mortality with the exception of the APAC- significant difference for the MPMoIII. The cal- HE IV, which is the most comprehensive system ibrations of the models examined in this study but is rarely used in our conditions. However, were generally poor with χ2 values of 21.8 for when the patients with diagnosed myocardial the MPMoIII (p<0.05) and 31 (p<0.05) for the infarctions were removed from the evaluation, APACHE IV, which correspond to the similarly the total mortality predictions of the MPM III disappointing calibration values for all of the o and SAPS III systems significantly improved. models in our work. Lee et al. (26) compared The APACHE II overestimated the mortalities the APACHE IV with the APACHE II and SAPS for all groups of patients. In the patients with 3 models for patients who were admitted to a diagnoses of acute myocardial infarction, the surgical intensive care unit of a university hos- prediction of mortality was dramatically ove- pital (South Korea). These authors described restimated by all of the investigated models, good discrimination capabilities of these sys- and these systems should not be used in this tems when applied to different populations but patient group without further modifications. Re- distinctly unsatisfactory calibrations for all of garding our group, the discrimination capabili- the models, and these results are analogous to ties as evaluated with ROC curves were good those from our work for all of the newer models and satisfactory for There are many possible reasons for which the the APACHE II model. The calibrations of all calibrations of assessed systems did not reach of the systems for our patient population were satisfactory values for the sample under exa- assessed as unsatisfactory. Nevertheless, the mination. The most frequently mentioned rea- conclusions of our work need to be interpreted sons include differences in the evaluated sets or with caution due to the limitations and restricti- differences in the sizes of cohorts used to deve- ons, particularly the relatively small scale of the lop and validate the models (27). In our work, a studied population with prevailing internal dise- major role was also played by the significantly ases and the fact that the study was conducted at higher proportion of patients with cardiovascu- only a single site. lar issues, especially the patients with myocardial infarctions, and the practical absence of sur- ACKNOWLEDGMENT gical patients. Poor model calibrations can also We thank Petra Hajslova who provided the data be associated with a relatively higher proporti- collection.

87 Medicinski Glasnik, Volume 13, Number 2, August 2016

FUNDING TRANSPARENCY DECLARATION This work is supported by the Intent of Deve- Conflict of interest: None to declare. lopment of the Central Military Hospital, Mini- stry of Defense, MO 1012.

REFERENCES 15. Lemeshow S, Hosmer DW Jr. A review of goodness 1. Keegan MT, Gajic O, Afessa B. Severity of illness of fit statistics for use in the development of logistic scoring systems in the intensive care unit. Crit Care regression models. Am J Epidemiol 1982; 115:92– Med 2011; 39:163–9. 106. 2. Glance LG, Osler TM, Dick A. Rating the quality 16. Thygesen K, Alpert JS, White HD, Joint ESC/ of intensive care units: is it a function of the inten- ACCF/AHA/WHF Task Force for the Redefiniti- sive care unit scoring system? Crit Care Med 2002; on of Myocardial Infarction. Universal definition 30:1976–82. of myocardial infarction. J Am Coll Cardiol 2007; 3. Strand K, Flaatten H. Severity scoring in the ICU: a 50:2173–95. review. Acta Anaesthesiol Scand 2008; 52:467–78. 17. Widimský P1, Budesínský T, Vorác D, Groch L, 4. Knaus WA, Draper EA, Wagner DP, Zimmerman Zelízko M, Aschermann M, Branny M, St’ásek J, JE. APACHE II: a severity of disease classification Formánek P; ‘PRAGUE’ Study Group Investigators. system. Crit Care Med 1985; 13:818–29. Long distance transport for primary angioplasty vs 5. Higgins TL, Kramer AA, Nathanson BH, Copes W, immediate thrombolysis in acute myocardial infarcti- Stark M, Teres D. Prospective validation of the inten- on. Final results of the randomized national multicen- sive care unit admission Mortality Probability Model tre trial--PRAGUE-2. Eur Heart J 2003; 24:94–104. (MPM0-III). Crit Care Med 2009; 37:1619–23. 18. Widimsky P, Zelizko M, Jansky P, Tousek F, Holm 6. Metnitz PGH, Moreno RP, Almeida E, Jordan B, Bau- F, Aschermann M, CZECH investigators. The inci- er P, Campos RA, Iapichino G, Edbrooke D, Capuzzo dence, treatment strategies and outcomes of acute M, Le Gall JR; SAPS 3 Investigators. SAPS 3--From coronary syndromes in the “reperfusion network” of evaluation of the patient to evaluation of the intensive different hospital types in the Czech Republic: results care unit. Part 1: Objectives, methods and cohort des- of the Czech evaluation of acute coronary syndromes cription. Intensive Care Med 2005; 31:1336–44. in hospitalized patients (CZECH) registry. Int J Car- 7. Moreno RP, Metnitz PGH, Almeida E, Jordan B, Bau- diol 2007; 119:212–9. er P, Campos RA, Iapichino G, Edbrooke D, Capuzzo 19. Nassar Junior AP1, Mocelin AO, Andrade FM, Brauer M, Le Gall JR; SAPS 3 Investigators. SAPS 3--From L, Giannini FP, Nunes AL, Dias CA. SAPS 3, APAC- evaluation of the patient to evaluation of the intensive HE IV or GRACE: which score to choose for acute care unit. Part 2: Development of a prognostic mo- coronary syndrome patients in intensive care units? del for hospital mortality at ICU admission. Intensive São Paulo Med J Rev Paul Med 2013; 131:173–8. Care Med 2005; 31:1345–55. 20. Costa e Silva VT, de Castro I, Liaño F, Muriel A, 8. Zimmerman JE, Kramer AA, McNair DS, Malila Rodríguez-Palomares JR, Yu L. Performance of the FM. Acute Physiology and Chronic Health Evaluati- third-generation models of severity scoring systems on (APACHE) IV: hospital mortality assessment for (APACHE IV, SAPS 3 and MPM-III) in acute kidney today’s critically ill patients. Crit Care Med 2006; injury critically ill patients. Nephrol Dial Transplant 34:1297–310. 2011; 26:3894–901. 9. Le Gall JR, Loirat P, Alperovitch A, Glaser P, Granthil 21. Arabi Y, Haddad S, Goraj R, Al-Shimemeri A, Al- C, Mathieu D, Mercier P, Thomas R, Villers D. A sim- Malik S. Assessment of performance of four mortality plified acute physiology score for ICU patients. Crit prediction systems in a Saudi Arabian intensive care Care Med 1984; 12:975–7. unit. Crit Care 2002; 6:166–74. 10. Lemeshow S, Le Gall JR. Modeling the severity of 22. Kuzniewicz MW, Vasilevskis EE, Lane R, Dean ML, illness of ICU patients. A systems update. JAMA Trivedi NG, Rennie DJ, Clay T, Kotler PL, Dudley 1994; 272:1049–55. RA. Variation in ICU risk-adjusted mortality: impact 11. Teres D, Lemeshow S. Why severity models should of methods of assessment and potential confounders. be used with caution. Crit Care Clin 1994; 10:93–110; Chest 2008; 133:1319–27. discussion 111–5. 23. Keegan MT, Gajic O, Afessa B. Comparison of 12. Higgins TL, Teres D, Copes WS, Nathanson BH, APACHE III, APACHE IV, SAPS 3, and MPM0III Stark M, Kramer AA. Assessing contemporary inten- and influence of resuscitation status on model perfor- sive care unit outcome: an updated Mortality Proba- mance. Chest 2012; 142:851–8. bility Admission Model (MPM0-III). Crit Care Med 24. Katsaragakis S, Papadimitropoulos K, Antonakis P, 2007; 35:827–35. Strergiopoulos S, Konstadoulakis MM, Androulakis 13. Brier GW. Verification of forecasts expressed in terms G. Comparison of Acute Physiology and Chronic He- of probability. Mon Wea Rev 1950:1–3. alth Evaluation II (APACHE II) and Simplified Acute 14. Wu Y-C, Lee W-C. Alternative Performance Measures Physiology Score II (SAPS II) scoring systems in a for Prediction Models. PLoS One 2014; 9:e91249 single Greek intensive care unit. Crit Care Med 2000; 28:426–32.

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25. Cook DA. Performance of APACHE III models in an 28. Beck DH, Smith GB, Taylor BL. The impact of low- Australian ICU. Chest 2000; 118:1732–8. risk intensive care unit admissions on mortality pro- 26. Lee H, Shon Y-J, Kim H, Paik H, Park H-P. Validation babilities by SAPS II, APACHE II and APACHE III. of the APACHE IV model and its comparison with the Anaesthesia 2002; 57:21–6. APACHE II, SAPS 3, and Korean SAPS 3 models for 29. Brinkman S1, Bakhshi-Raiez F, Abu-Hanna A, de the prediction of hospital mortality in a Korean sur- Jonge E, Bosman RJ, Peelen L, de Keizer NF. Exter- gical intensive care unit. Korean J Anesthesiol 2014; nal validation of Acute Physiology and Chronic He- 67:115–22. alth Evaluation IV in Dutch intensive care units and 27. Murphy-Filkins R, Teres D, Lemeshow S, Hosmer comparison with Acute Physiology and Chronic He- DW. Effect of changing patient mix on the performan- alth Evaluation II and Simplified Acute Physiology ce of an intensive care unit severity-of-illness model: Score II. J Crit Care 2011; 26:105.e11–8. how to distinguish a general from a specialty intensive care unit. Crit Care Med 1996; 24:1968–73.

89 ORIGINAL ARTICLE

Relationship between ultrasonographically determined kidney volume and progression of chronic kidney disease

Sandra Vegar Zubović, Spomenka Kristić, Irmina Sefić Pašić

Radiology Clinic, University Clinical Center Sarajevo, Sarajevo, Bosnia and Herzegovina

ABSTRACT

Aim To investigate a correlation between calculated creatinine clearance as a measure of kidney’s functional abilities and ultrasonographically determined kidney volume, which represents actual size of the kidney, in fact residual renal mass in chronic kidney disease, in order to determine possibilities of ultrasound as a diagnostic method in diagnosing and follow up of chronic renal disease.

Methods Prospective study included 150 patients with registered demographic and anthropometric data, and also with relevant laboratory tests of renal function. Longitudinal diameter, thickness and width of the kidney and renal volume calculated according to the Dinkel’s formula were measured by ultrasound. A correlation between the measured volume of the kidneys and calculated creatinine clearance was done by the Spearman method, with statistical significance of p<0.05. Corresponding author: Results Statistically significant correlation between the estimated Spomenka Kristić creatinine clearance values and the average of the calculated va- Radiology Clinic, University Clinical lues of kidney volume was found (p<0.01). Average value of the Center Sarajevo kidneys’ volume showed a linear decrease with the progression of Bolnička 25, 71000 Sarajevo, chronic kidney disease: the kidney volume in the control healthy Bosnia and Herzegovina group was 171.7 ± 32.6 mL (95.22- 229.59 mL), and in the subjects classified in stage IV it was 74.7 ± 24.6 mL (43.22-165.65 Phone +387 33 298 156; mL). fax: +387 33 297 811; E-mail: [email protected] Conclusion Calculated volume of kidney well correlated with creatinine clearance as a measure of functional ability of the kidneys and with the stage of chronic renal disease. It can be used in clinical practice for monitoring of chronic kidney disease in conjuncti- on with other clinical and laboratory parameters. Original submission: Key words: ultrasound, kidneys, CKD 24 February 2016; Revised submission: 31 March 2016; Accepted: 18 May 2016. doi: 10.17392/852-16

Med Glas (Zenica) 2016; 13(2):90-94

90 Vegar Zubović et al. Kidney volume and CKD

INTRODUCTION gnostics in routine clinical practice and a large number of patients with chronic kidney disease, Chronic kidney disease is a major public health we decided to examine the usefulness of ultraso- problem due to the increasing incidence and pre- nographically determined kidney volume in the valence, resulting number of undesirable outco- evaluation of chronic kidney disease. mes of this disease worldwide (1,2). This disease is characterized by the destruction of renal mass The aim of this study was to assess the possibility of with irreversible sclerosis and loss of nephrons, using ultrasonographically determined kidney vo- which results in the progressive decline in renal lume as an indicator for diagnosing and monitoring function which reflecting glomerular filtration stages of progression of chronic kidney disease. rate (3,4). The most accurate parameter for deter- The results of this study should be of benefit pri- mining the functional status of the kidneys is to marily to clinicians - nephrologists for diagno- calculate nephrons’ number, which represents the sing and monitoring the progression of chronic total number of nephrons in the kidneys (5-8). Stu- kidney disease. The numerical expression of resi- dies have shown that there is a significant correla- dual renal mass and of kidneys volume reduction tion between renal masses and nephrons’ number, during the progression of kidney disease should in fact renal mass is directly proportional to this stimulate patients to adopt healthier lifestyles and number (8). In other words, the above studies have follow up the guidelines for patients suffering shown that there is a direct correlation between from chronic kidney disease. the size of the kidneys and number of nephrons (9), and that there is a direct correlation between PATIENTS AND METHODS the size of the kidney and its functions (10). Mea- Patients and study design surement of renal mass and nephrons’ number can only be done ex vivo (8). On the other hand, the One-year prospective study (January 2011– Ja- renal volume is proportional to renal masses and nuary 2012) included 150 patients admitted to the as such can be used as an in vivo surrogate for nep- Nephrology Clinic of University Clinical Center hron number as in the healthy population and in Sarajevo (UCCS), Sarajevo, Bosnia and Herze- the population of patients diagnosed with chronic govina, or visited in the Nephrology Outpatient kidney disease (11). Ninan et al. have shown that Department of this Clinic. Patients were divided the size of the kidney measured by ultrasound, in into 5 groups, with 30 patients in each group. comparison with other radiological methods, best Patients diagnosed with chronic kidney disease corresponded to the size of the kidney measured by a referring nephrologist were classified in the during the surgical procedure (12), which is con- groups 1-4 according to the chronic kidney dise- sidered to be the gold standard for measuring the ase stage based on the value of estimated creati- size of the kidney (13). nine clearance according to the criteria of Kidney Numerous authors have proven that in normal po- Disease Outcomes Quality Initiative (K/DOQI) pulation the actual size of the kidney best corre- (1). The group 5 consisted of healthy individu- lated with volume of the kidney measured by als (control group) with demonstrated absence of ultrasound, kidney volume is the most accurate chronic kidney disease according to the results of measure of the actual size of the kidney (13,14). complete laboratory analysis performed as rou- Studies on the relationship between the kidney tine control of renal function at the Nephrology volume measured by ultrasound, as a parameter Outpatient Department. Patients in the terminal of remained functional renal mass in patients stage of chronic kidney disease (dialysis popula- suffering from chronic kidney disease and the tion), kidney transplant, unstable renal function, size of creatinine clearance, as the parameter of patients diagnosed with diabetic nephropathy and renal function, could contribute significantly to polycystic kidney disease (diseases that lead to the understanding of the relationship that exists nephromegaly with simultaneous reduction in the between changes in morphological characteri- functional ability of the kidneys), patients with stics and functional status of the kidneys within hydronephrosis, anomalies of the number of kid- chronic renal disease (14). neys, kidney tumors, decompensated concomi- Given the great availability of ultrasound dia- tant disease (liver, heart, etc.), extremely obese

91 Medicinski Glasnik, Volume 13, Number 2, August 2016

patients (body mass index, BMI ≥ 40 kg / m²) for variables that do not have a normal distribu- were excluded from the study. tion. For categorical variables χ2 test was used. To estimate the correlation between the measured Methods volume of the kidneys and the calculated creati- Serum creatinine concentration was determined nine clearance Spearman’s nonparametric biva- by using a modification of the kinetic Jaffe reac- riate correlation was used. Accepted statistical tion (15) on laser Nephelometer BN II machine significance was p<0.05. (Siemens AG, Erlangen, Germany). RESULTS Assessment of creatinine clearance was calculated with Cockroft-Goult formula (16). Of the total 150 patients, 71 (47%) were males and 79 (53%) females. The average age of the After detailed laboratory and clinical manage- patients was 55.43 years. ment of patients and their classification in the different stages of chronic kidney disease (CKD) Analysis of the average value of the kidneys volu- according to the criteria of Kidney Disease me showed a linear decrease of the kidneys volu- Outcomes Quality Initiative (K/DOQI) (1), ultra- me with the progression of CKD: the subjects in sound examination was performed. the control group had a maximum value of 171.7 ± 32.6 mL (95.22- 229.59 mL), and the patients All patients were examined with ultrasound classified in stage IV had at least 74.7 ± 24.6 mL machine GE Voluson 730 PRO (GE medical (43.22-165.65 mL) (p=0.0001) (Table 1). Systems, Zipf, Austria) at the Radiology Clinic, University Clinical Center Sarajevo, with convex An analysis of correlation coefficients showed that probe of 3.5 MHz in the grey scale and real – there was a statistically significant correlation (p time. The examinations were done in patients’ <0.01) between the calculated values of creatinine supine and lateral position. Ultrasound measure- clearance and the measured volume of the kidney: ments were registered on the scans depicting the patients classified into a higher stage of chronic maximum orthogonal, longitudinal and transver- kidney disease had lower estimated creatinine cle- se cross-section of the kidney. All the examinati- arance and a smaller volume of the kidney. In the ons were made by the same radiologist. Volume control group the average creatinine clearance was of the kidney was calculated using the formula 127.767 (mL/min) and the average kidney volume by Dinkel et al.: 0,523xLxWx (D1 + D2) /2 (17). was 171.72 mL. In the stage 1 group the average creatinine clearance was 118.076 (mL/min) and Because the kidneys are paired organs, which to- the average kidney volume was 138.86 mL, in the gether contribute to the clearance of creatinine, stage 2 group 70.958 (mL/min) and 113.63 mL, after calculating the volume (V) of each kidney in the stage 3 group 49.010 (mL/min) and 91.69 of each patient according to the Dinkel’s formula, mL, and in the stage 4 group 23.075 (mL/min) and their median value was calculated by the formu- 74.68 mL, respectively (Table 1). la: V = (V1 + V2) /2. Table 1. Average size of the kidney volume, creatinine and Statistical analysis creatinine clearance in different stages of chronic kidney disease (CKD)

The test results were analyzed using descriptive Kidney volume Creatinine Creatinine statistics, which comprises determining the mean Group (No) of (minimum/maxi- (minimum/ clearance X patients mum) maximum) (mL/min) value ( ), standard deviation (SD) and stan- (mL) p<0.01 (µmol) p<0.01 p<0.01 dard error (SEM). Comparisons of mean values 171.7163 73.47 127.767 Control (30) between the groups were performed using Stu- (95.22/229.59) (49/95) (91.4/195.3) 138.8557 72.30 118.076 dent t-test for variables with normal distribution, Stage I (30) (105.61/167.55) (40/140) (90.5/177.9) or the Mann-Whitney test (U) for variables that 113.6253 103.87 70.958 Stage II (30) do not have a normal distribution. Statistical si- (73.13/154.03) (54/162) (60.6/88.2) 91.6907 142.33 49.010 gnificance of differences in mean values between Stage III (30) (64.15/128.72) (81/269) (32.9/58.5) the samples was determined using the Student 74.6783 321.70 23.075 Stage IV (30) t-test (t) and ANOVA (F) methods for variables (43.22/165.65) (162/610) (14.3/29.7) 118.1133 142.73 77.777 with normal distribution, and Mann-Whitney test Total (150) (43.22/229.59) (40/610) (14.3/195.3)

92 Vegar Zubović et al. Kidney volume and CKD

DISCUSSION According to K/DOQI criteria, CKD stage 1 is characterized by preserved renal function, i.e. The average value of kidney volume in subjects measuring only creatinine clearance does not classified in the control (healthy) group was 171.7 allow the diagnosis and for this purpose we use ± 32.6 mL, and this value can be considered as a other indicators of kidney damage, such as patho- reference value for the volume of kidneys in he- logic findings of urine and imaging examination. althy population (18). Statistical analysis of ave- Ultrasonographically established kidney volume rage values of the kidney volume showed a linear reduction can therefore be used as one of the cri- decrease in volume of the kidney with chronic teria for the diagnosis of CKD stage 1 (1). kidney disease progresses, so the patients who were in the stage 1 of CKD had the highest, while Since the ultrasound is one of the most commonly the patients classified into the CKD stage 4 had used screening methods, the pathologic kidney a smallest kidney volume. The obtained data are volume values should indicate the need for the consistent with data from the literature reporting evaluation of renal function in terms of creati- kidney volume as a predictor of renal mass and nine clearance measurements in asymptomatic the number of nephrons which are not destroyed patients, given the fact that kidney disease is si- during the course of chronic kidney disease (9- lent for long time and does not give symptoms. 11,13). It is therefore considered that the volume Our findings confirmed that a measured volume of kidney reflects remaining functional ability of kidney by ultrasound correlates well with the of the kidneys measured by estimated creatinine stage and progression of chronic kidney disease, clearance values (14). suggesting this method can be reliably used in In Bosnia and Herzegovina the exact number of clinical practice for the diagnosis, evaluation and patients with all stages of chronic kidney disease monitoring of chronic renal disease. All patients is unknown. The only precise data are related to with diagnosed CKD regardless of the stage sho- the number of patients with end stage renal dise- uld have renal ultrasound including the measure- ase (ESRD). According to the Renal Registry of ment of kidney volume performed as a part of Bosnia and Herzegovina, the number of ESRD normal follow-up every 6 months. prevalent patients in Bosnia and Herzegovina was FUNDING increased 66.2% in the 2002-2012 period (1.531 and 2.544 prevalent ESRD patients) (19). The in- No specific funding was received for this study. cidence of ESRD patients in Bosnia and Herzego- TRANSPARENCY DECLARATION vina is in line with the European average, and the increment of number of prevalent ESRD patients Conflict of interest: None to declare. in Bosnia and Herzegovina is to be expected.

REFERENCES 1. National Kidney Foundation. K/DOQI clinical prac- 6. Luyckx VA, Brenner BM. The clinical importance of tice guidelines for chronic kidney disease: evalua- nephron mass. J Am Soc Nephrol 2010; 21:898-910. tion, classification, and stratification. Am J Kidney 7. Abitbol CL, Ingelfinger JR. Nephron mass and car- Dis 2002; 39 (Suppl 1):S1-266. diovascular and renal disease risks. Semin Nephrol 2. Zoccali C, Kramer A, Jager KJ. Epidemiology of 2009; 29:445-54. CKD in Europe: an uncertain scenario. Nephrol Dial 8. Keijzer-Veen MG, Devos AS, Meradji M, Dekker Transplant 2010; 25:1731-3. FW, Nauta J, Van der Heijden BJ. Reduced renal 3. McNamara BJ, Diouf B, Douglas-Denton RN, lenght and volume 20 years after very preterm birth. Hughson MD, Hoy WE, Bertram JF. A comparison Pediatr Nephrol 2010; 25:499-507. of nephron number, glomerular volume and kidney 9. Paleologo G, Abdelkawy H, Barsotti M, Basha A, weight in Senegalese Africans and African Ameri- Bernabini G, Bianchi A, Caprio F, Emad A, Grassi cans. Nephrol Dial Transplant 2010; 25:1514-20. G, Nerucci B, Tregnaghi C, Rizzo G, Donadio C. 4. Hoy WE, Bertram JF, Denton-Douglas R, Zimanyi Kidney Dimensions at Sonography are Correlated M, Samuel T, Hughson MD. Nephron number, glo- With Glomerular Filtration Rate in Renal Transplant merular volume, renal disease and hypertension. Recipients and in Kidney Donors. Transplant Proc Curr Opin Nephrol Hypertens 2008; 17:258-65. 2007; 39:1779-81. 5. Douglas-Denton RN, McNamara BJ, Hoy WE, 10. Kariyanna SS, Light RP, Agarwal R. A longitudi- Hughson MD, Bertram JF. Does nephron number nal study of kidney structure and function in adults. matter in the development of kidney disease? Ethn Nephrol Dial Transplan 2010; 25:1120-6. Dis 2006; 16 (Suppl 2):S2-40-5.

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11. Imasawa T, Nakazato T, Ikehira H, Fujikawa H, Na- clearance and other parameters in chronic kidney kajima R, Ito T, Ando Y, Yoshimura M, Nakayama disease (CKD). Nephorl Dial Transplant 2009; M, Yahata K, Sasaki O, Yaomura T, Katafuchi R, 24:1690-4. Yamamura T, Kawaguchi T, Nishimura M, Kitamura 15. Bacon BL, Pardue HL. Kinetic study of the Jaffé re- H, Kenmochi T, Shimatsu A. Predicting the outcome action for quantifying creatinine in serum: 2. Evalua- of chronic kidney disease by the estimated nephron tion of buffered reagent and comparison of different number: The rationale and design of PRONEP, a data-processing options. Clin Chem 1989; 35:360-3. prospective, multicenter, observational cohort study. 16. Cockcroft D, Gault M. Prediction of creatinine clea- BMC Nephrol 2012; 13:11. rance from serum creatinine. Nephron 1976; 16:31- 12. Ninan VT, Koshi KT, Niyamthullah MM, Jacob CK, 41. Gopalakrishnan G, Pandey AP, Shastry JC. Compa- 17. Dinkel E, Ertel M, Dittrich M, Peters H, Berres M, rative study of methods of estimating renal size in Schulte-Wissermann H. Kidney size in childhood. normal adults. Nephrol Dial Transplant 1990; 5:851- Sonographical growth charts for kidney length and 4. volume. Pediatr Radiol 1985; 15:38-43. 13. Emamian SA, Nielsen MB, Pedersen JF. Kidney di- 18. Raza M, Hameed A, Khan MI. Ultrasonographic mensions at sonography: correlation with age, sex assessment of renal size and its correlation with and habitus in 665 adult volunteers. AJR Am J Ro- body mass index in adults without known renal di- entgenol 1993; 160:83-6. sease. J Ayub Med Coll Abbottabad 2011; 23:64-8. 14. Sanusi AA, Arogundade FA, Famurewa OC, Akin- 19. Renal Registry for Bosnia and Herzegovina. Saraje- tomide AO, Soyinka FO, Ojo OE, Akinsola A. Rela- vo: Association of Nephrology, Dialysis and Kidney fionship of ultrasonographically determined kidney transplantation of Bosnia and Herzegovina; 2012. volume with measured GFR, calculated creatinine www.undt.ba (15 January 2015)

Odnos ultrazvučno određenog volumena bubrega i progresije hronične bubrežne bolesti Sandra Vegar Zubović, Spomenka Kristić, Irmina Sefić Pašić Klinika za radiologiju, Univerzitetski klinički centar Sarajevo, Sarajevo, Bosna i Hercegovina

SAŽETAK

Cilj Ispitati korelaciju između izračunatog kreatinin klirensa kao mjere funkcionalne sposobnosti bubrega i ultrazvučno određenog volumena bubrega koji predstavlja stvarnu veličinu bubrega, tj. ostatnu renalnu masu u sklopu hronične bubrežne bolesti, kako bi se utvrdile mogućnosti ultrazvuka kao dija- gnostičke metode za dijagnosticiranje i praćenje hronične bubrežne bolesti.

Metode Prospektivna studija obuhvatila je 150 pacijenata kojima su registrirani demografski i antro- pometrijski podaci, te rezultati laboratorijskih ispitivanja bubrežne funkcije. Ultrazvučno su izmjereni longitudinalni dijametar, debljina i širina bubrega, te izračunat volumen bubrega koristeći Dinkelovu formulu. Korelacija između izmjerenog volumena bubrega i izračunatog kreatinin klirensa ispitana je korištenjem Spearmanove metode uz statističku značajnost p<0.05.

Rezultati Uočena je statistički značajna korelacija između izračunatog kreatinin klirensa i prosječnih izračunatih vrijednosti volumena bubrega (p<0.01). Prosječne vrijednosti volumena bubrega pokazivale su linearno smanjenje s progresijom hronične bubrežne bolesti: volumen bubrega u kontrolnoj skupini zdravih ispitanika je iznosio 171,7 ± 32,6 mL (95,22 – 229,59 mL), dok je u skupini ispitanika klasifi- ciranih u stadij IV iznosio 74,7 ± 24,6 mL (43,22 – 165,65 mL).

Zaključak Izmjereni volumen bubrega dobro korelira s kreatinin klirensom kao mjerom funkcionalne sposobnosti bubrega, tj. sa stadijem hronične bubrežne bolesti. Zajedno s drugim kliničkim i laborato- rijskim parametrima može se koristiti u kliničkoj praksi za praćenje hronične bubrežne bolesti.

Ključne riječi: ultrazvuk, bubrezi, CKD

94 ORIGINAL ARTICLE

Occipital sulci patterns in patients with schizophrenia and migraine headache using magnetic resonance imaging (MRI)

Gorana Sulejmanpašić1, Enra Suljić2, Selma Šabanagić-Hajrić2

1Department of Psychiatry, 2Department of Neurology; University Clinical Center Sarajevo, Sarajevo, Bosnia and Herzegovina

ABSTRACT

Aim To examine the presence of morphologic variations of occipital sulci patternsin patients with schizophrenia and migraine he- adacheregarding gender and laterality using magnetic resonance imaging (MRI).

MethodsThis study included 80 patients and brain scans were performed to analyze interhemispheric symmetry and the sulcal patterns of the occipital region of both hemispheres. Average total volumes of both hemispheres of the healthy population were used for comparison.

Results There was statistically significant difference between subjects considering gender (p=0.012)with no difference regarding Corresponding author: age(p=0.1821). Parameters of parieto-occipital fissure (p=0.0314), Gorana Sulejmanpašić body of the calcarine sulcus (p=0.0213), inferior sagittal sulcus (p=0.0443), and lateral occipital sulcus (p=0.0411) showed stati- Department of Psychiatry, Clinical Center stically significant difference only of left hemisphere in male pati- University of Sarajevo ents with schizophrenia with shallowerdepth of the sulcus. Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina Conclusion Representation of neuroanatomical structures suggests the existence of structural neuroanatomic disorders with focal Phone: +387 33 29 75 38; brain changes. Comparative analysis of occipital lobe and their Fax:+387 33 29 85 23; morphologic structures (cortical dysmorphology) in patients with E mail: [email protected] schizophreniausing MRI, according to genderindicates a significant cortical reduction in the left hemisphere only in the group of male patients compared to female patients and the control group.

Keywords: morphologic variations, neuropathology, neuroradio- Original submission: logy 18 March 2016; Revised submission: 02 May 2016; Accepted: 23 May 2016. doi: 10.17392/855-16

Med Glas (Zenica) 2016; 13(2):95-102

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INTRODUCTION The aim of the study was to determine the morp- hologicdifferences in the brain structuresof occi- Schizophrenia is a complex mental disorder whe- pital region regarding gender and lateralitybetwe- re environmental factors interacting with the ge- en patients with schizophrenia and patients with netic susceptibility and early neurodevelopmen- migraine headacheusing MRI. tal aberrations, precede the onset of psychotic symptoms. It remains one of the most intriguing PATIENTS AND METHODS psychiatric research topics with a worldwide prevalence of 1% leading to lifelong disability in Patients and study design more than 50% of the sufferers (1). This brain dis- This prospective, comparative study included order strikes persons as they are entering the prime 80 patients of both sexes, 21–67 years old, cla- of their life and, in many cases, runs a recurrent ssified into two groups: S groupincluded 40 pa- and ultimately chronic course. This most deva- tients with schizophrenia (21 malesand 19 fema- stating of mental illnesses affects the essence of les)andM (control) group with 40 patientswith what makes people human: their personality and migraine headache (10 malesand 30 females). intellect and it is considered the prototypic mental The study was conducted atthe Department of illness (2). Premorbid abnormalities in brain deve- Psychiatry and Neurology, University Clinical lopment might lead to anatomical and physiolo- Center Sarajevo, during the period of four years gical alterations in widely distributed cortical and (2011-2015). Magnetic resonance imaging (MRI) subcortical networks. The so-called „neurodeve- scans of both the left and the right hemispheres of lopmental hypothesis“ suggeststhat schizophrenia occipital lobe of 80 human brains were exami- is related to adverse conditions leading to abnor- ned at the Department of Radiology,University mal brain development during the pre or postnatal Clinical Center Sarajevo. Coronal sections and period, whereas symptoms of the disease appear descriptive analysis of the occipital lobe were in early adulthood (3). It has been hypothesized performed according to gender. The sulci (regi- that the disorder originates from brain neurodeve- ons) of interestof the occipital lobe through the lopmental neuropathology with symptoms and ne- magnetic resonance imaging volume of a single uropsychological deficits arising from alterations patient(control and patient with schizophrenia) in described brain regions or functional neuronal wereidentified (ROI): parieto-occipital fissure circuits(4). The neuropathological process may (POF), temporo-occipital incisure (TO), body of be related to a pre-existing neurodevelopmental the calcarine sulcus (BCS), anterior sulcus calca- loss of synaptic contacts to ongoing deficits on the rinus (ACS), retrocalcarine sulcus (RCS),inferior synaptic and molecular level, resulting in an exce- sagittal sulcus (ISGS), superior sagittal sulcus ssive loss of neuronal connectivity(5). (SSGS), transverse occipital sulcus (TOS), late- Magnetic resonance imaging (MRI) has been ral occipital sulcus (LOS), inferior occipital sul- helpful in revealing subtle structural brain abnor- cus (IOS), posterior collateral sulcus (PCS) 3.8, malities in schizophrenia and it seems likely that lingual sulcus (LiS) 1.7, lunate sulcus (LuS). the occipital lobe is involved in some aspects of The Ethics Committee of the University Clinical the pathophysiology of disease (6). Center Sarajevo had givenan ethical consent to Meta-analyses of structural MRI studies reveal perform the study. All subjectssigned a written brain volume deficit and it is possible that at least informed consent before the enrollment. in some patients, an additional neurodegenera- Patients (S group) included in the study were 18 tive process, beginning at the time of symptom to 67 yearsoldwho were on the hospital treatment onset, may play a role in the pathophysiology of and under antipsychoticdrugs at the Department the disease (7).Studies using MRI have shown of Psychiatry, and had been diagnosed with the significance of the occipital lobe as the bra- schizophreniaaccording to ICD-10 criteria(11). in region of higher interest for understanding Patients were included into the research on the the schizophrenic psychosis (8-10). The search basis of consecutive admissions taking into acco- for the regions of cerebral mass responsible for unt that all of them were with a long psychiatric generating schizophrenic symptoms lead to new history (at least 5 years of hospital treatment) insights on its functional organization.

96 Sulejmanpašićet al. Occipital sulci patterns in schizophrenia

andobtained signed information consent within hods, group analysis of size and interhemispheric clinical research. symmetry, were used in order to test significant The criteria for the exclusion referred to: the differences of sulcus depth between groups. appearance of psychotic phenomenology within Volumes of the sulcal patterns of the occipital neurological disease, organic psychosyndrome, region (cc) of both left and right hemispheres somatic disease, neurological disorder (head tra- for each patientwere investigated to providea uma, brain insult, epilepsy), information on drug quantitative description of the variability of the or alcohol abuse,metal content in the body or the location of a given brain structure (a sulcus). absence of signed informed consent for voluntary Anatomical variability of the sulci of the occi- participation. pital region in standard stereotaxic space in the For the group of patients with schizophrenia, form of probability maps was examined. The the average age was 41.50 (SD±10.44; range image data were resampled onto a standard grid 22–67) years. with cubical voxels 1 mm wide. The gray-matter voxels extending for 1 mm on either side of the The control group (M group)represented patients banks of the sulcus were included in the set of 18 to 55 years old, based on admissionsat the De- voxels constituting the sulcus. We identified partment of Neurology, diagnosed with migraine occipital sulci and marked their corresponding headache criteria(12), whowere tested with the gray matter voxel on magnetic resonance images test scales of assessment with the signed informed around POF, TO, BCS, ACS, RCS,ISGS, SSGS, consent for voluntary participation. This group TOS, LOS, IOS, PCS, LiS, and LuS. included subjects who had never suffered psychotic or severe neurological disorders (head injuries, Average total volumes(cubic centimeters, cc) of epilepsy) or diseases, and in whose anamnesis both left and right hemispheres of the healthy there had beenno information on drug or alcohol population for comparison were as follows: abuse,with nometal content in the body and who si- POF24.0, TO 1.1, BCS 11.2, ACS 7.5, RCS 2.7, gnedinformed consent for voluntary participation. ISGS 1.9,SSGS 1.8, TOS 7.2, LOS 5.8, IOS 1.9, PCS 3.8, LiS 1.7, and LuS 2.5 (13,14). The average age was 38.50 (SD±6.59; range 30– 53) years. Statistical analysis The groups were equal according to age The research task was to define the differences (p=0.691). betweenpatients with schizophrenia andpatients Methods with migraine headacheaccording to demographic data (gender,age) and morphology of the Neuroradiology method-Magnetic resonance brain regions using MRI of both groups.For the imaging (MRI) purposes of correlation and associative analysis multivariate analysis of variance, Pearson’s cor- The MRI scans were performed on a Siemens relation coefficientand Point-biserial correlation 3T superconducting magnet system to get very wereapplied using χ2 test, T-test of independent strong and homogeneous field-T2TSE3D-RST- samples, T-test of paired samples, Kolmogorov- TRA(Avanto, Siemens, Erlangen, Germany). The Smirnov testand Levene`s test for equality of relaxation time T2 (TR=750/TE114) with sequ- variances. ences of turbo spin echo (TSE) in transverse pla- Statistically significant differences were conside- nes and layer thickness of 0.6 mm, T1 sequence red p<0.05. (voxel resolution: 1mm×1mm×1.25mm, TI:20ms, TD:500ms, TR:9.7ms, TE:4.0ms, FLIP:10, Ma- RESULTS trix:256×256, Rect. FOV: 7/8, Partitions:128, Time=13 min and 12 seconds)were applied. For Demographic data the purpose of group analysis sulcus depth(mm), t-statistical map was generated for each hemisphe- The study was conducted on a group of 80 sure with the application of t>2.66 (p<0.01, with bjects divided into two groups: patients with the rate of freedom of 61). Two statistical met- schizophrenia (40) and control group (40) with migraine headache.

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Among 40 patients with schizophrenia 21 Comparative analysis ofoccipital lobe and their (52.5%) were males and 19 (47.5%) females;in morphologic structures using MRI according to the control group 10 (25.0% ) patients were ma- gender (controls and patients) les and 30 (75.0%) females(p=0.012) (Table 1). The morphological variation of the sulci of the occipital region of the human brain was exami- Table1. Age distribution of patients ned in both left and right hemispheres in 80 pa- No (%) of patients tients (controls and patients with schizophrenia) Age (years) Schizophrenia group Control group on magnetic resonance images. Male Female Male Female Significant differences between the groups were 20-30 5 (23.8) 1 (5.3) 4 (0.4) 6 (0.2) 30-40 8 (38.1) 5 (26.3) 1 (0.1) 12 (0.4) registered onthe left hemisphere of occipital lobe 40-50 5 (23.8) 8 (42.1) 3 (0.3) 9 (0.3) with some specific regions only in male patients 50-60 2 (9.5) 4 (21.1) 2 (0.2) 3 (0.1) with schizophrenia (Figure 1, 2). 60-70 1 (4.8) 1 (5.3) / / Total 21 19 10 30

Average age of patients with schizophreniawas 41.50±10.43 years, and of controls 38.50±9.48 years. The youngest subject in schizophrenia group was 22, and the oldest one 67; in the control group the youngest was 20, and the oldest 55 (Ta- ble 2) (p=0.1821).

Table 2. Morphologic structures ofoccipital lobe according to gender Figure 1. Coronal sections of the occipital lobe through the Volume (cubic centimeters) magnetic resonance imaging volume (controls) (Hodžić M., Institutzaradiologiju UKCS, 2013) M MS (mean Group of patients / variables p (mean) square) POF, parieto-occipital fissure, TO,temporo-occipital incisure, BCS, body of the calcarine sulcus, ISGS, inferior sagittal sulcus, TOS, Schizophrenia transverse occipital sulcus,LOS, lateral occipital sulcus, IOS, infe- Parieto-occipital fissure(POF) 22.490 84.872 0.0314 rior occipital sulcus, LiS, lingual sulcus, LuS, lunate sulcus left (male) Parieto-occipital fissure (POF) 22.404 82.595 0.0377 right (male) Control Parieto-occipital fissure (POF) 24.550 85.421 left(male) Parieto-occipital fissure(POF) 23.560 85.513 right (male) Schizophrenia Body of the calcarine sulcus 9.713 33.411 0.0213 (BCS) left (male) Control Body of the calcarine sulcus 11.005 36.138 (BCS) left(male) Schizophrenia Inferior sagittal sulcus (ISGS) 1.730 1.378 0.0443 left (male) Control Inferior sagittal sulcus (ISGS) 1.993 2.779 left (male) Schizophrenia Figure 2. Coronal sections of the occipital lobe through the Lateral occipital sulcus (LOS) 5.545 11.705 0.0411 magnetic resonance imaging volume (patients)(Mašić R./In- left (male) stitutzaradiologiju UKCS, 2013) Control POF, parieto-occipital fissure, BCS, body of the calcarine sulcus, Lateral occipital sulcus(LOS) 6.310 19.090 ISGS, inferior sagittal sulcus, LOS, lateral occipital sulcus, PCS, left (male) posterior collateral sulcus

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The appearance of the different patterns of the indicate that although the developing the disease sulci of parieto-occipital fissure regarding gender is roughly the same among genders, men tend to showed statistically more significant difference develop schizophrenia earlier, with a worse pro- on the left side (M=22.490;SD=9.073;p=0.0314) gnosis and a premorbid history(17). This is the compared to the right side (M=22.403; so-called period of high risk for schizophrenia and SD=9.215;p=0.0377) only in male patients with occurs between the ages of 20 and 39(15). Men, schizophrenia (Table 2). therefore, tend to be younger than women at the Patterns of body of the calcarine sulcus showed onset of the disease(16).Age distribution is very statistically significant differences in these para- important when it comes to evaluating the possibi- meters regarding gender only in male patients with lity or risk of the development of the disorder. This schizophrenia (M=9.713; SD=4.530;p=0.0213), concerns lifetime risk and in order to evaluate it, it without differences on the right side in the same is necessary to consider the age distribution of the group (m=10.218; SD=5.977). (Table 2). population that we are examining(17). The lifetime risk for schizophrenia is between In parameters of inferior sagittal sulcus regarding 0.3 and 3.7% depending on the methodology gender statistically significant difference was no- used (17).In our study, with regard to the age of ticed only in male patients with schizophrenia patients, the minimum age in both groups was (m=1.730; SD=1.656;p=0.0443), without differen- around 20, while the maximum age in the gro- ces on the right (m=1.490; SD=0.909) (Table 2). up of patients with schizophrenia was 67, and Statistically significant difference in para- in the control group 55. Members of the group meters of lateral occipital sulcus regarding diagnosed with schizophrenia were on average gender was noted only in male patients with 3.5 years older than those in the control group. schizophrenia(m=5.545; SD=4.467;p=0.0411), The illness was manifested differently among with no differences on the right side of these pa- the genders, with men having undergone previo- tients (M=4.640;SD=4.326) (Table 2). us psychiatric treatment and hospitalization, and In all investigated parameters of occipital sulci also in relation to various socio-cultural factors patterns in the control group there were no stati- which have an influenceon early diagnosis of the stically significant differences (Table 2). disease among males (20).One hypothesis as to why schizophrenia develops later in women is DISCUSSION the protective effect of estrogen, as it has been Schizophrenia is linked to damaged structure of the determined that there is a negative correlation occipital cortex. Understanding any alteration of betweenthe negative symptoms of schizophrenia the brain among people suffering from schizophre- and plasma concentrations of estrogen(20). The nia, as well as the occipital lobe functions, can effects may be structural or functional. Structu- contribute to a better understanding of changes in ral effects are due to developmental changes the brain associated with early stages of the dise- in regard to earlier development of the brain in ase or its progression (15). Gender differences are women, from the prenatal period to adolescen- evident in the morphology of brain structure in a ce. Neuronal connections, lateralization of brain healthy population, and studies point to identical functions and axonal myelination are established differences in regions of the brain among men earlier in female brains than in those of males. and women suffering from schizophrenia using This slower level of development could make the MRI (16). Castle and Murray investigated these male brain more vulnerable to earlier damages, regions and concluded that evidence ofsuchdiffe- resulting in structural brain abnormalities asso- rences exists (17). Studies conducted using MRI ciated with the early onset of the illness and its revealed a reduction of the coronal brain region, a negative symptoms(21). The hypothesis that small left hippocampal formation and enlargement estrogen has an antipsychotic effect, modifying of the lateral ventricle in men, but not in women the functional operation of neurotransmitters and (18). Research conducted using MRI suggests that plays a protective role against the development many of the structural changes occur in sexually of psychotic symptoms explains the gender- dimorphic areas of the brain (19).Studies of gen- differences in schizophrenia. Five MRI studies der differences in the context of schizophrenia, reported volume reduction in the occipital lobe

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in schizophrenia while Davatzikos et al. reported and right hemisphere, did not exhibit statistically reduced gray matter in occipital association are- significant differences among the two groups. asin patients with schizophrenia (22).Our resear- Our findings are consistent with studies that ch conducted using MRI revealed changes in the examined the morphology of the cortical surfa- occipital lobe, especially of the left hemisphere ce, and those which recorded a reduction of the (shallower depth of sulcus). gyrus index in both cerebral hemispheres of 3% In terms of gender, among a group of male pa- -4.5%, but it was more pronounced in the area of tients with schizophrenia, significant differences the left side (30-33), which is consistent with the were registered in the parieto-occipital fissure, findings of five studies conducted in relation to calcarine sulcus, lower sagittal sulcus and the the volume of the occipital lobes in schizophre- lateral occipital sulcus, which is consistent with nia (34-38).In our study a descriptive compara- a study conducted by Andreasen and associates tive analysis of morphological variations in the (23,24).The results of our study are consistent occipital sulcus region of both hemispheres using with a study that compared the morphology of MRI revealed the presence of significant diffe- the cerebral cortex and its pattern of gyri and rences particularly in the area of the left hemi- sulci depth of the occipital lobe in patients with sphere in the group of male patients. schizophrenia, and in the area of the left hemi- The consistency of the findings reveals distinct sphere; a difference in the depth of the sulcus multiple brain regions, which show changes in (shallower) was evident and was correlated with the gray matter of patients with chronic forms of the degree of impairment of working memory schizophrenia (39-41). and occipital lobe executive function (25).A stu- What has become known as the “typical” pattern dy examining cortical dysmorphology in pati- of anatomical asymmetry, the dominance of the ents with schizophrenia revealed diffuse cortical left parieto-occipital region– was described in the reduction in the left hemisphere in the group of early years of the 20th century with speculations male patients, which correlates with our results that it is connected to the functional improvement (25, 26, 27). Among the group of male patients of the cerebral hemispheres. The possibility of higher right occipital lobes in relation to the left, the development of mental diseases can be asso- and lower left frontal lobes in relation the right ciated with a “disorder” of the normal models of were recorded and also a change in the asymme- brain asymmetry. Representation of neuroanato- try of the occipital lobe, but not the frontal lobe, mical structures in vivo suggests the existence while Luchins and his team reproduced their ear- of structural neuroanatomic disorders, ranging lier findings of changes in the normal asymmetry from evidence of focal brain changes, primarily of the occipital and frontal lobes in patients with of gray matter and its identification, and focus on schizophrenia (28,29).Descriptive statistical pa- damage of the brain. Schizophrenia is a heteroge- rameter values of the region of interest, as part of neous disorder with varying manifestations and the occipital lobe, indicate significant differences pathophysiology. It does not have a single sine in the group of male patients compared to female qua non symptom, but rather a variety of symp- patients and the control group. Changes are pre- toms which can occur in individual patients. sent only on the left side of the calcarine sulcus, lower sagittal sulcus and the lateral occipital sul- FUNDING cus, while the areas of the temporo-occipital inci- No specific funding was received for this study. sure, the posterior and anterior ends of the calcarine sulcus, transverse occipital sulcus, the lower TRANSPARENCY DECLARATION occipital sulcus, the occipital region of the left Conflict of interest: None to declare.

REFERENCES 1. Watt DC, Katz K, Sheperd M. The natural history 2. Häfner H, Heiden W. Course and outcome of of schizophrenia: a 5-year prospective follow-up of schizophrenia. In: Hirsch&Weinberger (Eds.). arepresentative sample of schizophrenics by means Schizophrenia.Oxford:Blackwell Publishing 2003; of a standardized clinical and social assessment. 101-39. Psychol Med 1983; 13:663-70.

100 Sulejmanpašićet al. Occipital sulci patterns in schizophrenia

3. Palmer BW, Dawes SE, Heaton RK. What do 21. Hambrecht M, Maurer K, Hafner H. Evidence for a we know about neuropsychological aspects of gender bias in epidemiological studies of schizophre- schizophrenia? Neuropsychol Rev 2009; 19:365-84. nia. Schizophr Res 1992; 8:223-31. 4. Kitiş O, Eker MC, Zengin B, Akyılmaz DA, Yal- 22. Palmer BW, Dawes SE, Heaton RK. What do vaç D, Ozdemir HI, IşmanHaznedaroğlu D, Bilgi we know about neuropsychological aspects of MM, Gönül AS. The disrupted connection betwe- schizophrenia? Neuropsychol Rev 2009; 19:365-84. en cerebral hemispheres in schizophrenia patients: 23. Crespo-Facorro B, Barbadillo L, Pelayo-Terán JM, a diffusion tensor imagining study. Turk Psykia- Rodriguez-Sánchez JM. Neuropsychological func- tryDerg2011; 22:213-21. tioning and brain structure inschizophrenia. Int 5. Fitzsimmons J, Kubicki M, Shenton M.E. Review of RevPsychiatry 2007; 19:325-36. functional and anatomical brain connectivity findin- 24. Zhang Y, Lin L, Lin CP, Zhou Y, Chou KH, Lo Cy, gs in schizophrenia. CurrOpin 2013; 26:72-87. Su TP, Jiang T.Abnormal topological organization of 6. Shenton ME, Dickey CC, Frumin M, McCarley structural brain networks in schizophrenia. Schizoph RW. A review of MRI findings in schizophrenia. Res 2012; 141:109-18. SchizophrRes2001; 49:1-52. 25. Bora E, Fornito A, Radua J, Walterfang M,Seal 7. Steen RG, Mull C, McClure R, Hamer RM, Lieber- M, Wood SJ, Yücel M, Velakoulis D, Pantelis man JA.Brain volume in first-episode schizophrenia: C.Neuroanatomical abnormalities in schizophrenia: systematic review and meta-analysis of magnetic a multimodal voxelwise meta-analysis and meta-re- resonance imaging studies. Br J Psychiatry 2006; gression analysis. SchizophrRes 2011; 127:46-57. 188:510-8. 26. Collin G, Cahn W, Hulshoff Pol, Kahn RS. Distur- 8. Collin G, de Reus MA, Cahn W, Hulshoff Pol bed grey matter coupling in schizophrenia. EurNeu- HE, Kahn RS, van den Heuvel MP. Disturbed grey ropsychopharmacol 2013; 23:46-54. matter coupling in schizophrenia.EurNeuropsychop- 27. Zalesky A, Fornito A, Bullmore ET. Network-based harmacol2013; 23:46-54. ststistic: identifying differences in brain networorks. 9. Arnone D, Cavanagh J, Gerber D, Lawrie SM, Neuroimage 2010; 53:1197-207. Ebmeier KP, McIntosh AM. Magnetic resonance ima- 28. Davatzkikos C, Shen D, Gur RC, Wu X, Liu D, Fan ging studies in bipolar disorder and schizophrenia: Y, Hughett P, Turetsky BI, Gur RE. Whole-brain meta-analysis. Br J Psychiatry 2009; 195:194–01. morphometric study of schizophrenia revealing a 10. Baiano M, David A, Versace A, Churchill R, Ba- spatially complex set of focal abnormalities. Arch lestrieri M &Brambilla P. Anterior cingulate vo- Gen Psychiatry 2005;62:1218–27. lumes in schizophrenia: a systematic review and a 29. Andreasen NC, Ehrhardt JC, Swayze VW meta-analysis of MRI studies. Schizophr Res 2007; 2nd,Alliger RJ, Yuh WT, Cohen G, Ziebel. Magne- 93:1–12. tic resonance imaging of the brain in schizophrenia. 11. World Health Organization. The ICD-10 Classifica- The pathophysiologic significance of structural ab- tion of Mental and Behavioural Disorders. Diagno- normalities. ArchGenPsychiatry1990;47:35–44. stic Criteria for Research. World Health Organizati- 30. TononiG, Edelman GM. Schizophrenia and the on, Geneva, 1993. mechanisms of conscious integration.Brain Re- 12. Headache Classification Subcommittee of the Inter- sRev2000; 31:391–00. national Headache Society. The International Cla- 31. Biswal BB, Mennes M, Zuo XN, Gohel S, Kelly ssification of Headache Disorders. 2nd Ed. Oxford: C, Smith SM, Beckmann CF, Adelstein JS, Buckner Blackwell Publishing2004. RL, Colcombe S, Dogonowski AM, Ernst M, Fair 13. Watkins KE, Paus T, Lerch JP, Zijdenbos A, Collins D,Hampson M, Hoptman MJ, Hyde JS, Kivinie- DL, Neelin P, Taylor J, mi VJ, Kötter R, Li SJ, Lin CP, Lowe MJ, Mackay 14. Worsley KJ, Evans AC.Structural asymmetries in C, Madden DJ, Madsen KH, Margulies DS, Mayberg the human brain: a voxel-based statistical analysis of HS, McMahon K, Monk CS, Mostofsky SH, Nagel 142 MRI scans.CerebCortex 2001; 11:868-77. BJ, Pekar JJ, Peltier SJ, Petersen SE, Riedl V, Rom- 15. Malikovic A, Vucetic B, Milisavljevic M, Tosevski bouts SA, Rypma B, Schlaggar BL, Schmidt J, Sazdanovic P, Milojevic B, Malobabic S.Occipital S, Seidler RD, Siegle GJ,Sorg C, Teng GJ, Veijola sulci of the human brain: variability and morphome- J, Villringer A, Walter M, Wang L, Weng XC, Whit- try.AnatSciInt2012; 87:61-70. field-Gabrieli S, Williamson P, Windischberger 16. Rubinov M, Bullmore E. Schizophrenia and abnor- C, Zang YF, Zhang HY, Castellanos FX,Milham MP. mal brain network hubs. Dialogues ClinNeurosci Toward discovery science of human brain function. 2013; 15: 339-49. Proc NatlAcadSciUSA 2010; 107:4734–9. 17. Hambrecht M, Maurer K, Hafner H. Evidence for a 32. Andreasen NC, Flashman L, Flaum M, Arndt S, gender bias in epidemiological studies of schizophre- Swayze V 2nd, O’Leary DS. Regional brain abnor- nia. Schizophr Res 1992; 8:223-31. malities in schizophrenia measured with magnetic 18. Abbs B, Liang L, Makris N, Tsuang M. Covariance resonance imaging. JAMA 1994; 272:1763-9. modeling of MRI brain volumes in memory circuitry 33. Falkai P, Schneider T, Greve B, Klieser E, Bogerts in schizophrenia: sex differences are critical. Neuro- B. Reduced frontal and occipital lobe asymmetry on image 2011; 56:1865-74. the CT-scans of schizophrenic patients. Its specifi- 19. AndreasenNC,Erhardt JC, Swayze VW, Alliger RJ, city and clinical significance. J Neural Transm Gen Yuh WTC, Cohen G, ZiebellS. MRI of the brain in Sect 1995; 99:63-77. Schizophrenia.Arch GenPsychatry1990; 47:35-44. 34. Phillips OR, Nuechterlein KH, Asarnow RF, Clark 20. Castle DJ, Abel K, Takei N,Murray RM. Gender KA, Cabeen R, Yang Y, Woods RP, Toga AW, Narr differences in Schizophrenia: Hormonal effect or KL. Mapping corticocortical structural integrity in sub-types. Schizophr Bull1995; 1:1-12. schizophrenia and effects of genetic liability. Biol Psychiatry 2011; 70:680-9.

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35. Alexander-Bloch A, Giedd JN,Bullmore E. Imaging 39. Thorn CA, Atallah H, Howe M, Graybiel AM. Diffe- structural co-variance between human brain regions. rential dynamics of activity changes in dorsolateral Nat RevNeurosci 2013; 14:322-36. and dorsomedial striatal loops during learning. Neu- 36. Andreasen NC, Dennert JW, Olsen SA, Damasio, ron 2010; 66:781-95. AR. Hemispheric asymmetries and schizophrenia. 40. Skudlarski P, Jagannathan K, Anderson K, Ste- Am J Psychiatry 1982; 139:427-30. vens MC, Calhoun VD, Skudlarska BA, Pearlson 37. Keshavan MS, Tandon R, Boutros NN, Nasrallah G.Brain connectivity is not only lower but different HA. Schizophrenia,”just the facts”: what we know in schizophrenia: a combined anatomical and functi- in 2008 Part 3: neurobiology.Schizophr Res 2008; onal approach. Biol Psychiatry 2010; 68:61-9. 106:89-107. 41. Stephan KE, Baldeweg T, Friston KJ. Synaptic 38. Eyler LT, Jeste DV, Brown GG. Brain response ab- plasticity and disconnection in schizophrenia. Bi- normalities during verbal learning among patients olPsychiatry 2006; 59:929-39. with schizophrenia.Psychiatry Res 2008; 162:11-25. 42. Wang Q, Su TP, Zhou Y, Chou KH, Chen IY, Jiang T, Lin CP.Anatomical insights into disrupted small- worldnetworks in schizophrenia. Neuroimage 2011; 59:1085-93.

Okcipitalna regijapacijenata oboljelih od shizofrenije i migrenozne glavobolje primjenom magnetno rezonantnog prikaza (MRI) Gorana Sulejmanpašić1, Enra Suljić2, Selma Šabanagić-Hajrić2 1Psihijatrijska klinika, 2Klinika za neurologiju; Univerzitetski klinički centarSarajevo, Bosna i Hercegovina

SAŽETAK

Cilj Istražiti prisustvo morfoloških razlika sulkusa okcipitalnog režnja pacijenata oboljelih od shizofrenije i migrenozne glavobolje u odnosu na spol i lateralnost primjenom magnetno razonantnog snimanja (MRI).

Metode Studija je uključila 80 pacijenata kod kojih je urađeno magnetno snimanje u svrhu analize in- terhemisferne simetrije i uzoraka sulkusa okcipitalne regije obje hemisfere svakog ispitanika. Prosječne ukupne vrijednosti volumena obje hemisfere zdrave populacije primijenjene su u komparativne svrhe.

Rezultati Statistički značajne razlike između ispitanika evidentirane su u odnosu na spol (p=0,012), bez razlika kada se posmatra dobna struktura (p=0,1821). Kada se posmatraju vrijednosti parametaraparieto- okipitalne fisure (p=0,0314), tijela sulkus kalkarinusa(p=0,0213), donjeg sagitalnog sulkusa(p=0,0443), lateralnog okcipitalnog sulkusa(p=0,0411), postojale su statistički značajne razlike samo u području lijeve hemisfere muških ispitanika oboljelih od shizofrenije s plićim sulkusima.

Zaključak Prikaz neuroanatomskih moždanih struktura ukazuje na prisustvo strukturalnih neuroanatomskih promjena s fokalnim moždanim promjenama. Komparativna analiza okcipitalnog režnja i njegovih morfoloških struktura (kortikalna dismorfologija) kod pacijenata oboljelih od shizofrenije u odnosu na spol primjenom MRI-a, ukazuje na značajnu kortikalnu redukciju lijeve hemisfere samo u grupi muških ispitanika komparirano sispitanicama i kontrolnom grupom.

Ključne riječi:morfološke varijacije, neuropatologija, neuroradiologija

102 ORIGINAL ARTICLE

Molecular epidemiology and antimicrobial susceptibility of AmpC- and/or extended-spectrum (ESBL) ß-lactamase- producing Proteus spp. clinical isolates in Zenica-Doboj Canton, Bosnia and Herzegovina Selma Uzunović1, Amir Ibrahimagić1, Dunja Hodžić2, Branka Bedenić3,4

1Department for Laboratory Diagnostics, Institute for Public Health and Food Safety, 2Public Health Institute of Sarajevo Canton, Sara- jevo; Bosnia and Herzegovina, 3School of Medicine, University of Zagreb, 4Clinical Department of Clinical and Molecular Microbiology, University Hospital Center Zagreb; Zagreb, Croatia

ABSTRACT

Aim To investigate prevalence, antimicrobial susceptibility, molecular characteristics, and genetic relationship of AmpC- and/ or extended spectrum beta lactamase (ESBL)- producing Proteus spp. clinical isolates in Zenica-Doboj Canton, Bosnia and Herze- govina.

Methods Antibiotic susceptibility was determined by disc diffusion and broth microdilution methods according to CLSI guidelines. Double-disk synergy test was performed in order to screen for ESBLs, and combined disk test with phenylboronic acid to detect

AmpC β -lactamases. PCR was used to detect blaESBL/blacarb genes. Genetic relatedness of the strains was determined by pulsed-field- gel-electrophoresis (PFGE).

Corresponding author: Results Eleven ESBL-producing isolates were included in the Amir Ibrahimagić study (six inpatients and five outpatients). Susceptibility rate to Department of Laboratory Diagnostics, amoxicillin-clavulanic acid, imipenem and meropenem was 100%. Resistance rate to cefuroxime was 100%, gentamicine 90.9%, pi- Institute for Public Health and Food Safety peracillin/tazobactam 81.8%, cefotaxim, ceftriaxone and ceftazi- Zenica dime 72.7%, cefoxitine and ciprofloxacine 63.6% and to cefepime Fra Ivana Jukića 2, 72000 Zenica, 45.5%. In five (out of 11) isolates multi-drug resistance (MDR) to Bosnia and Herzegovina cephalosporins, cefamicines, amynocligosides and fluoroquinolo- Phone: +387 32 443 580; nes was detected. Besides TEM-1 which was detected in all iso- Fax: +387 32 443 530; lates, CTX-M+OXA-1 β-lactamases were detected in seven (out of 11; 63.6%) isolates (five bla and two bla genes), E-mail: [email protected] CTX-M-1 CTX-M-15 and CMY-2 β-lactamase in two isolates. PFGE showed no genetic relatedness.

Conclusion Because of high prevalence of MDR strains in epide- Original submission: miologically unrelated patients with AmpC- and/or ESBL produ- 14 March 2016; cing Proteus spp. infection, further surveillance is needed. Mole- Accepted: cular characterization and strain typing, or at least phenotypic test 04 April 2016. for AmpC/ESBL production is important for appropriate therapy doi: 10.17392/853-16 and the detection of sources and modes of spread, which is the main step in order to design targeted infection control strategies.

Key words: ESBL, CMY-2, antimicrobial resistance

Med Glas (Zenica) 2016; 13(2):103-112

103 Medicinski Glasnik, Volume 13, Number 2, August 2016

INTRODUCTION β-lactamases have been detected among isolates from Iran (1), France (2), Saudi Arabia (14), Italy Proteus spp. cause various human infections and (15), and Japan (16). it was firstly documented as extended-spectrum beta-lactamase (ESBL)-producer in 1987 (1). Pro- Investigations of molecular characteristics and teus spp. were susceptible to beta (β)-lactam anti- epidemiology of β-lactamase producing Proteus biotics (2), but progressive increase of resistance spp. in Bosnia and Herzegovina (B&H) are scar- to beta-lactam antibiotics mediated by the produc- ce. TEM, CTX-M and AmpC genes have been tion of acquired beta-lactamases has occurred (3). recently reported in Gram-negative bacteria, Extended-spectrum β -lactamases showing acti- including Proteus spp., causing urinary tract in- vity to extended-spectrum cephalosporins have fections in Zenica-Doboj Canton (17). also started to spread, including most frequently The aim of the study was to investigate molecular TEM-type derivatives, but also other enzymes (4). epidemiology and genetic relatedness of AmpC Numerous outbreaks of infections with organisms β-lactamase- and ESBL-producing Proteus spp. producing ESBLs have been observed in many inpatient and outpatient isolates, as well as their countries (5-7). Resistance to beta-lactam drugs antimicrobial susceptibility. is caused by chromosomal and plasmid encoded enzymes (5). Horizontal acquisition of AmpC MATERIALS AND METHODS β -lactamases represents an important driver of Setting, bacterial isolates and study design increasing resistance in Europe, and it is associated with the clonal expansion of resistant strains (8). During the period December 2009 - May 2010, The organism has achieved ability to cause infecti- the total of 9092 and 16037 samples from the ons leading to prolonged hospital stay, an increase inpatients and outpatients, respectively, were of morbidity and mortality, and consequently an collected at the Microbiology Laboratory of the increase of health care associated costs (9). Cantonal Hospital Zenica. Among inpatients, ESBL-producing Gram-negative isolates are re- Gram-negative bacteria were isolated from 1254 sistant to extended-spectrum cephalosporins and (72.7%) samples, of which ESBL and/or AmpC monobactams, except cefamycins, carbapenems, β-lactamase producing bacteria were detected in and β-lactam/ β-lactamase inhibitors; AmpC be- 126 (out of 1254, 10%) samples; Proteus spp. ta-lactamases producing isolates are resistant to were isolated from 201 (out of 1254, 16.0%) penicillins, cephalosporins, cephamycins, mono- samples, of which 27 (out of 201; 13.4%) were bactams and β-lactam/β-lactamase inhibitor, but ESBL and/or AmpC β-lactamase producing iso- usually sensitive to carbapenems (10). Proteus lates. Among outpatients, Gram-negative bac- spp. are intrinsically resistant to nitrofuranto- teria were isolated from 2857 (80.9%) samples, in and tetracycline. Although Proteus spp. are of which 184 (6.4%) were ESBL- and/or AmpC intrinsically susceptible to aminoglycosides, β-lactamase producing bacteria; Proteus spp. fluoroquinolones, and trimethoprim-sulfamet- were isolated from 365 (out of 2857; 12.8%) hoxazole, co-resistance to these drugs has been samples, of which 26 (out of 365; 7.1%) were frequently reported among ESBL-producing β-lactamase producing isolates. Proteus spp. isolates, and the treatment is often Among 53 ESBL- and /or AmpC β-lactamase- limited to carbapenems (11). Reportedly, suscep- producing Proteus spp. (27 in- and 26 outpati- tibility of Proteus spp. to β-lactam/β-lactamase ents), 11 (six inpatient and five outpatient) were inhibitors, ciprofloxacin, and third generation available for further analysis. cephalosporins varies widely, 74- 94%, 60- 90%, Institutional review board approval from the Et- and 90- 99%, respectively, depending on pati- hics Committee of the Cantonal Hospital Zenica ents’ age, gender, hospital department, duration was obtained prior to the initiation of the study. of hospitalization and infection type (12). The ESBLs commonly reported among Pro- Antimicrobial susceptibility testing teus spp. are TEM and CTX-M, while other ESBLs (SHV, TEM β-lactamase inhibitors) Susceptibility testing to 12 antimicrobials was are less frequent (13). TEM, CTX-M and other performed by a twofold microdilution technique

104 Uzunović et al. AmpC and ESBL producing Proteus spp.

according to CLSI (Clinical and Laboratory screened for production of AmpC β -lactamases by Standards Institute) standard procedure (18): combined disk test using 3-amino phenylboronic amoxycillin+clavulanic acid (AMC), cefazolin acid (PBA) (Sigma-Aldrich, Steinheim, Germany). (CZ), cefuroxime (CXM), ceftazidime (CAZ), The stock solution was prepared as previously re- cefotaxime (CTX), ceftriaxone (CRO), cefoxi- commended (19) by dissolving PBA (benzenebo- tin (FOX), cefepime (FEP), imipenem (IMP), ronic acid; Sigma-Aldrich, Steinheim, Germany) in meropenem (MEM), gentamicin (GM), and ci- dimethyl sulfoxide at a concentration of 20 mg/mL. profloxacin (CIP). The following MIC resistan- 20 μL (containing 400 μg of boronic acid) of the so- ce breakpoints were used: ≥32 for amoxicillin/ lution was dispensed onto antibiotic disks. The dis- clavulanic, cefazolin, cefuroxime, ceftazidime, ks were then dried and used within 60 min. The te- cefoxitime and cefepime; ≥64 for cefotaxime and sts were performed by inoculating Mueller-Hinton ceftriaxone; ≥16 for imipenem and meropenem; agar by the standard diffusion method and placing ≥8 for gentamicine; and ≥4 for ciprofloxacin. E. disks containing four different β-lactams (CAZ, 10 coli ATCC 25922 (ESBL negative) and K. pne- µg; CRO, 30 µg; CTX, 5 µg; FEP, 30 µg) with or umoniae 700603 (ESBL positive) were used as without boronic acid onto the agar. The agar plates quality control strains. were incubated at 37°C overnight. The diameter of the growth-inhibitory zone around a β-lactam disk Detection of ESBLs, AmpC beta-lactamases and with boronic acid was compared with that around carbapenemases the corresponding β-lactam disk without boronic ESBL production was determined by double- acid. The test was considered positive for the detec- disk-synergy test (DDST). Overnight broth cul- tion of AmpC production when the diameter of the ture of test strain was diluted in saline, adjusted growth-inhibitory zone around a β-lactam disk with to McFarland standard suspension 0.5 and inocu- boronic acid was ≥5 mm larger than that around a lated onto Mueller-Hinton agar (MH); disk con- disk containing the β-lactam substrate alone (20). taining amoxicillin/clavulanate (20/10 µg) was Production of carbapenemases of group A or gro- placed in the middle of the plate and surroun- up B was confirmed by combined disk-test using ded (20 mm distance center to center) by disks meropenem disks with PBA and EDTA (ethyle- containing cefotaxime (5 µg), ceftriaxone (30 nediaminetetraacetic acid) (Sigma-Aldrich, µg), ceftazidime (10 µg), and cefepime (30 µg) Steinheim, Germany), respectively (21). Three (Becton-Dickinson, USA). Plates were incubated meropenem (MEM) disks were placed on Mu- overnight at 37 °C. Any distortion or increase of eller-Hinton agar plate inoculated with test strain. the inhibition zones around cephalosporin disks 10 µL of EDTA (300 mg) and PBA (300 mg) was toward amoxicillin/clavulanate disk was indica- added on the first and third disks, respectively. tive of ESBL production (18). The difference in zone size of ≥5 mm between Production of ESBLs was confirmed by CLSI disks with and without EDTA was suggesting combined disk test. Disks containing 30 μg of ce- production of carbapenemase group B, and the fotaxime and ceftazidime, and disks containing a difference in zone size of ≥5 mm between disks combination of the two drugs plus 10 μL (10μg ) with and without PBA was suggesting production of clavulanic acid (Becton Dickinson, USA) were of carbapenemase group A (21). placed independently, 20 mm apart, on a lawn cul- PCR detection of bla , bla , bla , and bla ture of 0.5 McFarland opacity of the test isolate CTX-M SHV TEM KPC genes on the Mueller-Hinton agar plate and incubated for 18-24 hours at 35°C. Isolates were considered PCR was used to detect alleles encoding ESBL ESBL positive if the inhibition zone measured aro- enzymes. und one of the combination disks after overnight The presence of blaTEM, blaSHV, blaCTX-M genes was incubation was at least 5 mm larger than that of the investigated by polymerase chain reaction (PCR) corresponding cephalosporin disk (18). using primers and conditions as described pre- Proteus spp. isolates resistant to extended-spectrum viously (22). Designation of bla genes based on cephalosporins and β-lactam/ β-lactamase inhibitor identified mutations was done according to Bush combination (amoxicillin/clavulanic acid) were K and Jacoby GA (23).

105 Medicinski Glasnik, Volume 13, Number 2, August 2016

Primers IS26F (5’-GCG-GTA-AAT-CGT-GGA- and Throat each, two from Pediatric and Physical GTG-AT-3) and IS26R (5’-ATT-CGG-CAA- Medicine and Rehabilitation Departments each GTT-TTT-GCT-GT-3’) were used to amplify and one from Oncology, Infection and Urology 400 bp fragment spanning the link between IS26 Departments each.

insertion sequence and blaCTX-M gene in CTX-M Amoxicillin/clavulanic acid, cefazolin and me- producing isolate (24, 25). tronidazole were mostly used for the treatment Genes encoding carbapenemases of class A of infections associated with Proteus spp., in (KPC), class B (MBLs belonging to VIM, IMP eight, seven and six cases, respectively; twelve and NDM family) and OXA-48 was detected by inpatients received corticosteroid therapy. Nine PCR as described previously (21). patients had positive history of hospitalization in previous twelve months, and 21 inpatients had Pulsed-field gel electrophoresis (PFGE) of bacte- contact with persons with positive history of re- rial DNA cent hospitalization. Fifteen (out of 26; 57.7%) outpatients were 19- Isolation of genomic DNA, digestion with the 59 years of age. Other data for outpatients were XbaI restriction enzyme (Invitrogen) and PFGE missing. of the resulting fragments was performed as des- Overall resistance rates to cephalexin, cefuroxi- cribed by Kaufman et al (26). The electrophore- me, ceftazidime, ceftriaxone, cefotaxime, and sis was carried out with a CHEF-DRII appara- cefepime by disk-diffusion method of 80.4%, tus (Bio-Rad Laboratories, Hercules, CA). The 71.7%, 67.9%, 67.9%, 56.4% and 45.3, respec- PFGE patterns were compared following the cri- tively, were noticed in 53 AmpC- and/or ESBL teria of Tenover et al. (27) and analyzed by the producing strains. Resistance rates for cefixime, GelComparII software (Applied Maths, St Mar- trimethoprim/sulfamethoxazole, gentamicine, tens, Belgium). ciprofloxacine, nitrofurantoin, amoxicillin/clavu- RESULTS lanic and amikacin were 80.0%, 75.5%, 68.7%, 60.8%, 52.6%, 41.5% and 26.4%, respectively All Proteus spp. isolates (data have not shown). Infections caused by Proteus spp. were represen- AmpC- and/or ESBL producing Proteus spp. ted in our sample with 16% and 12.8% prevalen- Eleven (six inpatients and five outpatients) ce among Gram-negative bacteria in the inpati- AmpC- and/or ESBL producing Proteus spp. (se- ents and outpatients, respectively. ven Proteus mirabilis and four Proteus vulgaris) A total of 53 ESBL and/or AmpC beta-lactamase isolates were available for further analysis: four producing Proteus spp. (27 in- and 26 outpati- from urine, two wound swabs and one swab of ents) were isolated: 22 (41.5%) were from urine each stoma, cannula, ear, skin and soft tissue in- samples (15 from outpatients), 18 (34.0%) from fection (SSTI) and genital tract (vaginal swab). wound infections (nine from outpatients), three Antibiotic susceptibility (5.7%) from stoma, two in each catheter, skin, and upper respiratory tract (URT, outpatient), and Susceptibility rate for 11 AmpC- and/or ESBL- one in each cannula, ear, genital tract (outpati- producing Proteus spp. (seven Proteus mirabi- ent vaginal swab) and umbilicus. Samples were lis and four Proteus vulgaris) isolates was 100% collected from six different municipalities of Ze- for amoxicillin-clavulanic acid, imipenem and nica-Doboj Canton, predominantly from Zenica meropenem. city (56.6%). Resistance rate to cefuroxime was100%, to gen- Fourteen (out of 27; 51.8%) inpatients were older tamicine 90.9%, cefotaxim, ceftriaxone and cef- than 60 years of age. The duration of hospitaliza- tazidime 72.7% each, cefoxitine and ciprofloxa- tion of patients was 3-53 days (median=15). Six cine 63.6% each, and for cefepime 45.5%. patients were from the Surgery Department, four In five (out of 11) isolates multi-drug resi- from Internal Medicine and four from Neuro- stance (MDR) to cephalosporins, cefamicines, logy Department, three from Intensive Care Unit amynocligosides and fluoroquinolones was de- (ICU) and from the Department for Ear, Nose tected.

106 Uzunović et al. AmpC and ESBL producing Proteus spp.

Seven cefoxitin-resistant isolates (five in- and A and B consisted of two outpatient isolates. Clo- two -outpatients) additionally showed resistan- ne C comprised three, and clone D consisted of ce to amoxicillin (100%), gentamicine (100%), two inpatient isolates (Figure 1, Table 1). the first, second, third cephalosporin generation (85.7%), ciprofloxacin (71.4%), and cefepime DISCUSSION (42.9%), but they remained sensitive (100%) to The prevalence of ESBLs in Proteus spp. has an amoxicillin/clavulanic acid. increasing trend in worldwide, including the Uni- All outpatient isolates were 100% resistant to ted States, Asia and Europe (28). The results of aminoglycosides. this study have shown 9.4% ESBL and/or AmpC producers among 566 Proteus spp. isolated from Detection and characterisation of ß-lactamases clinical specimens, which indicates a low pre- Eleven Proteus spp. isolates were positive on valence. This result is similar with reports from β-lactamases by phenotypic test. All isolates pro- Tehran (12%), Japan (7-13%) and Nigeria (8%) duced nature TEM-1 β-lactamase. No isolates (1,16,29,30). Higher prevalence of ESBL-pro- possessed SHV β-lactamase. ducing Proteus spp. was noticed in India (60%) All six inpatient isolates, besides TEM-1 (31), Croatia (21%) (32) and Uganda (14%) (33). β-lactamase, produced CTX-M β-lactamase (four Risk factors for infection caused by ESBL and/ isolates harboured blaCTX-M-1 and two blaCTX-M-15 or AmpC- beta lactamase producing isolates are genes) and OXA-1 β-lactamase; one isolate addi- long hospitalization, female sex, older age and tionally co-produced CMY-2 AmpC β-lactamase previous treatment with antibiotics (1). Elderly (Table 1). patients and previous treatment with antibiotics One outpatient isolate, besides TEM-1 in this study were factors associated with the β-lactamase, was positive for CTX-M-and OXA- presence of ESBL-producing isolates, and it is 1 β-lactamase, and one isolate harbored, except similar to a report from Taiwan (12). Wang et

TEM-1, AmpC β-lactamase too (blaCMY-2 gene) al. reported that both prior antibiotic use and/or (Table 1). broad-spectrum antibiotic exposure could result in acquisition of drug-resistance genes (12). Ba- PFGE typing sed on our results, 82% ESBL-producers were Eleven isolates were tested for genetic relatedne- obtained from males, and it is similar to reports ss by PFGE typing. Four clones (A-D) and two from France (2) and Italy (34). singletons were identified among 11Proteus spp. ESBL and/or AmpC- beta lactamase producing using a similarity threshold of 80%. Both clones Proteus spp. isolates in this research have shown

Figure 1. Dendogram shows genetic relatedness of 11 Proteus spp. isolates by PFGE typing using the 80% similarity. Clones A and B consisted of two outpatient isolates. Clone C consisted of three inpatient, and clone D of two inpatient isolates SSTI, skin and soft tissue infection; ENT, Ear, nose and Throat;

107 Medicinski Glasnik, Volume 13, Number 2, August 2016 S S B C A C B C A D D clone PFGE TEM-1 TEM-1 TEM-1 OXA-1 OXA-1 OXA-1 OXA-1 OXA-1 OXA-1 β-lactamase TEM-1, CMY-2 OXA-1, CMY-2 TEM-1, CTX-M-1, TEM-1, CTX-M-1, TEM-1, CTX-M-1, TEM-1, CTX-M-1, TEM-1, CTX-M-1, TEM-1, CTX-M-15, TEM-1, CTX-M-15, 64 32 32 0.5 128 256 128 CIP 0.25 (S/S) (S/S) (S/S) (S/S) >128 (R/R) (R/R) (R/R) (R/R) (R/R) (R/R) (R/R) <0.12 <0.25 (≥4/≥4) 8 8 64 64 64 64 32 64 32 0,5 GM (R/I) (R/I) (S/S) >256 (R/R) (R/R) (R/R) (R/R) (R/R) (R/R) (R/R) (R/R) (≥8/≥16) 2 8 0.25 (S/I) (S/S) (S/S) (S/S) (S/S) (S/S) (S/S) (S/S) (S/S) (S/S) (S/R) <0.06 <0.06 <0.06 <0.06 <0.06 <0.06 <0.06 <0.06 MEM (≥16/≥4) 2 2 2 2 2 IMI 0.12 0,25 (S/I) (S/I) (S/I) (S/I) (S/I) (S/S) (S/S) (S/S) (S/S) (S/S) (S/S) <0.06 <0.06 <0.06 <0.06 (≥16/≥4) , cefepime; IMI, imipenem; MEM, meropenem; GEN, gentamicin; CIP, cipro - , cefepime; IMI, imipenem; MEM, meropenem; GEN, gentamicin; CIP, 16 16 32 64 16 16 16 16 128 256 FEP (I/R) (I/R) (I/R) (I/R) (I/R) (I/R) (S/S) (R/R) (R/R) (R/R) (R/R) <0.12 (≥32/≥16) 1 4 4 16 256 128 256 (I/I) >256 (S/S) (S/S) >256 (S/S) >256 >256 FOX (R/R) (R/R) (R/R) (R/R) (R/R) (R/R) (R/R) (≥32/≥32) 8 64 64 32 64 64 128 256 (I/R) (S/S) >256 >256 (S/R) CRO (R/R) (R/R) (R/R) (R/R) (R/R) (R/R) (R/R) (R/R) <0,12 (≥64/≥4) 8 64 64 32 128 128 128 256 128 (I/R) (S/S) >256 CTX (S/R) (R/R) (R/R) (R/R) (R/R) (R/R) (R/R) (R/R) (R/R) <0.12 (≥64/≥4) 4 64 32 32 64 32 64 64 256 (S/S) (S/S) (S/S) CAZ (R/R) (R/R) (R/R) (R/R) (R/R) (R/R) (R/R) (R/R) <0.12 <0.12 (≥32/≥16) >256 >256 >256 >256 >256 >256 >256 >256 >256 >256 >256 (R/R) (R/R) (R/R) (R/R) (R/R) (R/R) (R/R) (R/R) (R/R) (R/R) (R/R) CXM (≥32/≥32) 8 CZ >32 >32 >32 >32 >32 >32 >32 >32 >32 >32 (S/S) (R/R) (R/R) (R/R) (R/R) (R/R) (R/R) (R/R) (R/R) (R/R) (R/R) (≥32/≥32) Minimal inhibitory concentration (MIC, mg/L) of antibiotics* according to CLSI 2009/2014 (2009/2014 breakpoint) 8 8 8 4 4 1 16 16 16 16 16 (S/S) (S/S) (S/S) (S/S) (S/S) (S/S) (S/S) (S/S) (S/S) (S/S) (S/S) AMC (≥32/≥32) ENT Hospital Physiatry Oncology Outpatient Outpatient Outpatient Outpatient Outpatient Neurology Neurology Neurology present stay present department at 58 66 54 53 28 40 28 02 49 58 01 Age (years) Ear SSTI swab Urine Urine Urine Urine origin Stoma Isolate Wound Wound Vaginal Vaginal Cannula F F M M M M M M M M M der der Gen - P. mirabilis P. Agent P. mirabilis P. P. mirabilis P. P. mirabilis P. P. mirabilis P. P. vulgaris P. P. vulgaris P. P. mirabilis P. P. vulgaris P. P. vulgaris P. mirabilis P. 6858 floxacin; F, female, M, male; ENT, Ear, Nose and Throat Department Nose and Ear, F, female, M, male; ENT, floxacin; Proteus spp. strains Proteus 1. Antibiotic susceptibility of 11 AmpC- and/or ESBL-producing Table *AMC, amoxicillin+clavulanic acid; CZ, cefazolin; CXM, cefuroxime; CAZ, ceftazidime; CTX, cefotaxime; CRO, ceftriaxone; FOX, cefoxitin; FEP Protocol Protocol No 7627 26351 22367 13011 9314 52158 23421 10913 8608 6627

108 Uzunović et al. AmpC and ESBL producing Proteus spp.

highest susceptibility rate to cefepime (64%), shown MIC of 8µg/mL). It has usually described which is far higher than in the Tijjani et al. report large difference in carbapenem susceptibility (38%) (30), but susceptibility to cefoxitin and using imipenem different CLSI breakpoints (12). ciprofloxacin (36% and 40%, respectively) was According to CDC document Facility Guidance similar in both studies. Besides, ten (out of 11) for Control of Carbapenem-resistant Enterobac- ESBL-producing isolates were resistant to genta- teriaceae (37) for bacteria that have intrinsic imi- micin, which is similar to the reports from Tehran penem non-susceptibility, including Morganella (1) and France (2). morganii, Proteus spp., and Providencia spp., A patient with the infection caused by ESBL and/ reporting of resistance to carbapenems other than or AmpC- beta lactamase producing Proteus spp. imipenem is recommended, which is confirmed showed a high-prevalence of MDR to various in our study. classes of antibiotics, which is similar to a report Many ESBL genes are situated on large plasmids from Ireland (8). Therefore, infections caused by which carry multiple resistance genes, and this such multidrug-resistant strains are more likely can explain an appearance of resistance to multi- to result in therapeutic failure (1,17). ple antibiotics (36). TEM-1 (natural) β-lactamase Clinical and Laboratory Standards Institute was noticed in all Proteus spp. isolates in this (CLSI) revised the criteria for interpretation of study, and it is similar to Tehran and Nigeria stu- breakpoints for some beta-lactam antibiotics in dies with 100% TEM-1 prevalence (1,38). On Enterobacteriaceae to achieve easier identifica- the other hand, TEM-52 was found in all Proteus tion of ESBLs and AmpC production (18, 35). ESBL-producing isolates in the report from Cro- Our results showed that the revised 2014 CLSI atia (32). In this study, CTX-M-1 and CTXM-15 breakpoints (35) have significant (increasing) were detected in 64% cases, similarly to the re- impact to resistance in Proteus spp. comparing port from Tehran (1), but contradictory with the to 2009 CLSI (18) for both cefotaxime and report from Japan, where CTX-M-2 gene was ceftriaxone, 90.9% /72.7%, for cefepime 90.9 noticed in 67% cases (16). /45.5, and even meropenem, 9.1/ 0, respectively. The CMY-2 AmpC beta-lactamase was found in Similar results were obtained in the report from two Proteus spp. isolates in this study (one in- Taiwan (12). Resistance for gentamicine was and one outpatient, both from urine), and both lower considering CLSI 2014 revised version, isolates were resistant to all cephalosporins te- 72.7%/90.9%, respectively, because breakpoint sted, aminoglycosides and fluroquinolones, but in 2009 was ≥8, but in revised CLSI 2014 it was susceptible to carbapenems and amoxicillin/ ≥16. Unfortunately, only 11 AmpC/ESBL- pro- clavulanic acid, which is in concordance with ducing Proteus spp. isolates were available for the report from Taiwan (12). AmpC β-lactamase the analysis, and accordingly, there was no po- producing isolates are usually resistant to seve- ssibility to compare the differences in resistance ral groups of antimicrobials, such as penicillins, between Proteus spp. isolates with and without oxyimino-, 7-α-methoxycephalosporins and mo- ESBL/AmpC production in light of recent 2014 nobactams (39). This could result in treatment CLSI breakpoint revision toward CLSI 2009 bre- failure as a consequence of inadequate empirical akpoint. Additionally, analysis of very low num- therapy in patients with unrecognized AmpC- ber of AmpC/ESBL producing strains obtained in carrying Proteus infections (31). It has been re- this study could resulte in resistance rates bias, cently shown that ceftazidime-avibactam (non but it has not affected obvious overall increase of β-lactam/β-lactamase inhibitor) demonstrated resistance rates considering 2014 CLSI revision potent activity against (molecularly confirmed) breakpoints comparing to the 2009 one. ESBL-, plasmid-mediated AmpC-, and ESBL/

All AmpC/ESBL-producing Proteus spp. isola- AmpC producing isolates of P. mirabilis (MIC90 tes from this study were susceptible to imipenem of 0.06 μg/mL), as well as for other Gram-nega- and meropenem according to CLSI 2009 docu- tive bacteria (40,41). ment; similarly to the reports from Tanzania (36). Different PFGE profiles among inpatient and But, resistance to meropenem showed up when outpatient AmpC- and/or ESBL-positive Proteus considering CLSI 2014 (in one strain, which has spp. strains indicate that in our settings the spre-

109 Medicinski Glasnik, Volume 13, Number 2, August 2016

ading of these bacteria was not due to a single study, further local surveillance is needed. Mo- clone, but rather to the horizontal transfer of pla- lecular characterization and strain typing, or at smids containing different genes between diffe- least phenotypic test for AmpC/ESBL production rent species of Enterobacteriaceae. In the hospital of Proteus spp, as well as other Gram-negative environment, under selection pressure, plasmids bacteria, is important for appropriate therapy and could be transferred between the patients and the detection of the sources and modes of spread, hospital personnel by hands (24). which is the main step in order to design targeted The main limitation of this study is the small num- infection control strategies. ber of AmpC- and/or ESBL-producing Proteus FUNDING spp. isolates collected/available for the analysis because of short time span (six months) and the- This study was supported by a grant from the ir low prevalence in infections. Still, reduced Federation Ministry of Education and Science, susceptibility of Proteus isolates is a matter of an Bosnia and Herzegovina. increasing clinical concern worldwide. Because of high prevalence of MDR strains in epidemi- TRANSPARENCY DECLARATION ologically unrelated patients with AmpC- and/ Competing interests: None to declare. or ESBL producing Proteus spp. infection in this

REFERENCES 1. Malekjamshidi MR, Shahcheraghi F, Feizabadi MM. 8. Mac Aogáin M, Rogers TR, Crowley B. Identification Detection and PFGE analysis of ESBL-producing of emergent bla CMY-2 -carrying Proteus mirabilis li- isolates of Proteus species isolated from patients at neages by whole-genome sequencing. New Microbes Tehran hospitals. Med Sci Monit 2010; 16:327-32. New Infect 2015; 9:58-62. 2. Biendo M, Thomas D, Laurans G, Hamdad-Daoudi 9. Wollheim C, Guerra IM, Conte VD, Hoffman SP, F, Canarelli B, Rousseau F, Castelain S, Eb F. Mole- Schreiner FJ, Delamare AP, Barth AL, Echeverriga- cular diversity of Proteus mirabilis isolates producing ray S, Costa SO. Nosocomial and community infec- extended-spectrum beta-lactamases in a French uni- tions due to class A extended-spectrum β-lactamase versity hospital. Clin Microbiol Infect 2005; 11:395- (ESBLA)-producing Escherichia coli and Klebsie- 401. lla spp. in southern Brazil. Braz J Infect Dis 2011; 3. Chanal C, Bonnet R, De Champs C, Sirot D, Labia R, 15:138-43. Sirot J. Prevalence of beta-lactamases among 1,072 10. Grover N, Sahni AK, Bhattacharya S. Therapeutic clinical strains of Proteus mirabilis: a 2-year survey challenges of ESBLS and AmpC beta-lactamase pro- in a French hospital. Antimicrob Agents Chemother ducers in a tertiary care center. Med J Armed Forces 2000; 44:1930-5. India 2013; 69:4-10. 4. Perilli M, Dell’Amico E, Segatore B, de Massis MR, 11. Endimiani A, Luzzaro F, Brigante G, Perilli M, Lom- Bianchi C, Luzzaro F, Rossolini GM, Toniolo A, Ni- bardi G, Amicosante G, Rossolini GM, Toniolo A. coletti G, Amicosante G. Molecular characterization Proteus mirabilis bloodstream infections: risk fac- of extended-spectrum beta-lactamases produced by tors and treatment outcome related to the expression nosocomial isolates of Enterobacteriaceae from an of extended-spectrum beta-lactamases. Antimicrob Italian nationwide survey. J Clin Microbiol 2002; 40: Agents Chemother 2005; 49:2598-605. 611-4. 12. Wang JT, Chen PC, Chang SC, Shiau YR, Wang HY, 5. Logan LK, Braykov NP, Weinstein RA, Laxmina- Lai JF, Huang IW, Tan MC, Lauderdale TL1; TSAR rayan R; CDC Epicenters Prevention Program. Exten- Hospitals. Antimicrobial susceptibilities of Prote- ded-Spectrum β-Lactamase-Producing and Third-Ge- us mirabilis: a longitudinal nationwide study from neration Cephalosporin-Resistant Enterobacteriaceae the Taiwan surveillance of antimicrobial resistance in Children: Trends in the United States, 1999-2011. J (TSAR) program. BMC Infect Dis 2014; 14:486. Pediatric Infect Dis Soc 2014; 3:320-8. 13. Aragón LM, Mirelis B, Miró E, Mata C, Gómez L, 6. El-Hady SA, Adel LA. Occurrence and detection of Rivera A, Coll P, Navarro F. Increase in beta-lactam- AmpC β-lactamases among Enterobacteriaceae isola- resistant Proteus mirabilis strains due to CTX-M- and tes from patients at Ain Shams University Hospital. CMY-type as well as new VEB- and inhibitor-resi- Egypt J Med Hum Genet 2015; 16:239-44. stant TEM-type beta-lactamases. J Antimicrob Che- 7. Adwan G, Jaber AA. Frequency and molecular cha- mother 2008; 61:1029-32. racterization of β-lactamases producing Escherichia 14. Hassan MI, Alkharsah KR, Alzahrani AJ, Obeid OE, coli isolated from North of Palestine. BMRJ 2016; Khamis AH, Diab A. Detection of extended spectrum 11:1-13. beta-lactamases-producing isolates and effect of AmpC overlapping. J Infect Dev Ctries 2013; 7:618- 29.

110 Uzunović et al. AmpC and ESBL producing Proteus spp.

15. Pagani L, Migliavacca R, Pallecchi L, Matti C, Gia- 28. Nagano N, Shibata N, Saitou Y, Nagano Y, Arakawa cobone E, Amicosante G, Romero E, Rossolini GM. Y. Nosocomial outbreak of infections by Proteus mira- Emerging extended-spectrum beta-lactamases in Pro- bilis that produces extended-spectrum CTX-M-2 type teus mirabilis. J Clin Microbiol 2002; 40:1549-52. beta-lactamase. J Clin Microbiol 2003; 41:5530-6. 16. Chong Y, Shimoda S, Yakushiji H, Ito Y, Miyamoto 29. Nakamura T, Komatsu M, Yamasaki K, Fukuda S, T, Kamimura T, Shimono N, Akashi K. Community Miyamoto Y, Higuchi T, Ono T, Nishio H, Sueyoshi spread of extended-spectrum β-lactamase-producing N, Kida K, Satoh K, Toda H, Toyokawa M, Nishi I, Escherichia coli, Klebsiella pneumoniae and Proteus Sakamoto M, Akagi M, Nakai I, Kofuku T, Orita T, mirabilis: a long-term study in Japan. J Med Microbi- Wada Y, Zikimoto T, Koike C, Kinoshita S, Hirai I, ol 2013; 62:1038-43. Takahashi H, Matsuura N, Yamamoto Y. Epidemio- 17. Ibrahimagić A, Bedenić B, Kamberović F, Uzunović logy of Escherichia coli, Klebsiella species, and Pro- S. High prevalence of CTX-M-15 and first report of teus mirabilis strains producing extended-spectrum CTX-M-3, CTX-M-22, CTX-M-28 and plasmid-me- β-lactamases from clinical samples in the Kinki Re- diated AmpC beta-lactamase producing Enterobacte- gion of Japan. Am J Clin Pathol 2012; 137:620-6. riaceae causing urinary tract infections in Bosnia and 30. Tijjani J, Arzai AH, Sadiq NM. Antimicrobial suscep- Herzegovina in hospital and community settings. J tibility pattern of extended spectrum betalactamase Infect Chemother 2015; 21:363-9. producers in Gram-negative urogenital isolates in 18. Clinical and Laboratory Standards Institute. Perfor- Kano, Nigeria. Bayero Journal of Pure and Applied mance Standards for Antimicrobial Susceptibility Te- Sciences 2012; 5:20-5. sting. Nineteenth informational Supplement. M100- 31. Datta P, Gupta V, Arora S, Garg S, Chander J. Epide- S19. Clinical and Laboratory Standards Institute miology of extended-spectrum β-lactamase, AmpC, (CLSI). Wayne, PA: CLSI 2009. and carbapenemase production in Proteus mirabilis. 19. Coudron PE. Inhibitor-based methods for detection of Jpn J Infect Dis 2014; 67:44-6. plasmid-mediated AmpC beta-lactamases in Klebsie- 32. Tonkic M, Mohar B, Sisko-Kraljević K, Mesko-Me- lla spp., Escherichia coli, and Proteus mirabilis. J Clin glic K, Goić-Barisić I, Novak A, Kovacić A, Punda- Microbiol 2005; 43: 4163-7. Polić V. High prevalence and molecular characteri- 20. Tenover F, Emery SL, Spiegel A, Bradford P, Eels S, zation of extended-spectrum β-lactamase-producing Endimiani A, Bonomo RA, McGowan JE Jr. Identi- Proteus mirabilis strains in southern Croatia. J Med fication of plasmid-mediated AmpC beta-lactamases Microbiol 2010; 59:1185-90. in Escherichia coli, Klebsiella spp., and Proteus spp. 33. Kateregga JN, Kantume R, Atuhaire C, Lubowa MN, can potentially improve reporting of cephalosporins Ndukui JG. Phenotypic expression and prevalence susceptibility testing results. J Clin Microbiol 2009; of ESBL-producing Enterobacteriaceae in samples 47:294-9. collected from patients in various wards of Mulago 21. Song W, Hong SG, Yong D, Jeong SH, Kim HS, Kim Hospital, Uganda. BMC Pharmacol Toxicol 2015; HS, Kim JS, Bae IK. Combined use of the modified 16:14. Hodge test and carbapenemase inhibition test for de- 34. Endimiani A, Luzzaro F, Brigante G, Perilli M, Lom- tection of carbapenemase-producing Enterobacteria- bardi G, Amicosante G, Rossolini GM, Toniolo A. ceae and metallo-β-lactamase-producing Pseudomo- Proteus mirabilis bloodstream infections: risk fac- nas spp. Ann Lab Med 2015; 35: 212-9. tors and treatment outcome related to the expression 22. Dallenne C, Da Costa A, Decre D, Favier C, Arlet G. of extended-spectrum beta-lactamases. Antimicrob Development of a set of multiplex PCR assays for the Agents Chemother 2005; 49:2598-605. detection of genes encoding important beta-lactama- 35. Clinical and Laboratory Standards Institute. Perfor- ses in Enterobacteriaceae. J Antimicrob Chemother mance Standards for Antimicrobial Susceptibility 2010; 65:490-5. Testing. Twenty-fourth Informational Supplement. 23. Lahey Clinic. ß-Lactamase classification and amino M100-S24. Clinical and Laboratory Standards Insti- acid sequences for TEM, SHV and OXA extended- tute (CLSI), Wayne, PA: CLSI 2014. spectrum and inhibitor resistant enzymes. http:// 36. Mshana SE, Kamugisha E, Mirambo M, Chakraborty www.lahey.org/studies/ (February 03 2016) T, Lyamuya EF. Prevalence of multiresistant gram- 24. Gulamber C, Altindis M, Kalayci R, Bozdogan B and negative organisms in a tertiary hospital in Mwanza, Aktepe OC. Molecular characterization of nosocomi- Tanzania. BMC Res Notes 2009; 2:49. al CTX-M type β-lactamase producing Enterobac- 37. Centers for Diseases Control and Prevention. The teriaceae from University Hospital in Turkey. Afr J CDC guidance for control of Carbapenem-resistant Microbiol Res 2012; 6: 5552-7. Enterobacteriaceae (CRE). November 2015 Update - 25. Pasanen T, Jalava J, Horsma J, Salo E, Pakarinen M, CRE Toolkit. (March 09 2016) http://www.cdc.gov/ Tarkka E, Vaara M, Tissari P. An outbreak of CTX- hai/pdfs/cre/CRE-guidance-508.pdf. M-15-producing Escherichia coli, Enterobacter cloa- 38. Alabi S, Mendonca N, Adeleke O, Da Silva G. An- cae, and Klebsiella in a children’s hospital in Finland. timicrobial resistance and prevalence of extended- Scand J Infect Dis 2014; 46:225-30. spectrum beta-lactamase Proteus spp. strains from 26. Kaufman ME. Pulsed-field gel electrophoresis. In: southwestern Nigeria hospitals. 23rd European Con- Woodfor N, Johnsons A, eds. Molecular biology. Pro- gress of Clinical Microbiology and Infectious Dise- tocols and clinical applications. 1st Ed. New York: ases (ECCMID), 27-30 April 2013, Berlin/Germany. Humana Press, Inc. Totowa, 1998:33-51. Clin Microbiol Infect 2013. Supplement (e). Poster 27. Tenover FC, Arbeit RD, Goerling RV, Mickelsen PA, No P1308. Murray BE, Persing DH, Swaminathan B. Interpre- 39. Seral C, Gude MJ, Castillo FJ. Emergence of plasmid ting chromosomal DNA restriction patterns produced mediated AmpC β-lactamasas: origin, importance, by pulsed-field gel electrophoresis; criteria for bacte- detection and therapeutical options. Rev Esp Quimio- rial strain typing. J Clin Microbiol 1995; 33:2233-9. ter 2012; 25:89-99.

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40. Zhanel GG, Lawson CD, Adam H, Schweizer F, Ze- 41. Karlowsky JA, Biedenbach DJ, Kazmierczak KM, lenitsky S, Lagacé-Wiens PR, Denisuik A, Rubinste- Stone GG, Sahm DF. The activity of ceftazidime- in E, Gin AS, Hoban DJ, Lynch JP 3rd, Karlowsky avibactam against extended-spectrum and AmpC JA. Ceftazidime-avibactam: a novel cephalosporin/ β-lactamase-producing Enterobacteriaceae collected β-lactamase inhibitor combination. Drugs 2013; in the INFORM Global Surveillance Study in 2012- 73:159-77. 2014. Antimicrob Agents Chemother 2016 [Epub ahead of print].

Molekularna epidemiologija i antimikrobna osjetljivost kliničkih izolata Proteus spp. koji produciraju AmpC- i/ili beta-laktamaza proširenog spektra djelovanja u Zeničko-Dobojskom kantonu, Bosna i Hercegovina Selma Uzunović1, Amir Ibrahimagić1, Dunja Hodžić2, Branka Bedenić3,4 1Služba za Laboratorijsku dijagnostiku, Institut za zdravlje i sigurnost hrane Zenica, 2Zavod za javno zdravstvo kantona Sarajevo; Bosna i Hercegovina; 3Medicinski fakultet, Sveučilište u Zagrebu, 4Klinički zavod za kliničku i molekularnu mikrobiologiju, Klinički bolnički centar Zagreb, Zagreb, Hrvatska

SAŽETAK

Cilj Istražiti prevalenciju, molekularne karakteristike i klonsku pripadnost kliničkih izolata Proteus spp. koji produciraju AmpC- i(li) beta (β)-laktamaze proširenog spektra (ESBL), te njihovu antimikrobnu osjetljivost u Zeničko-dobojskom kantonu u Bosni i Hercegovini.

Metode Za određivanje antimikrobne osjetljivosti korištena je disk-difuzijska i mikrodilucijska me- toda prema CLSI-standardima, a za detekciju ESBL-a dvostruki disk-sinergistički test i kombinirani disk-test s fenil-boroničnom kiselinom za detekciju AmpC β-laktamaza. Za potvrdu lučenja ESBL-a i AmpC-a korišten je PCR. Klonska pripadnost izolata ispitivana je uz pomoć elektroforeze u pulsiraju- ćem polju (PFGE).

Rezultati U analizu je uključeno 11 (6 bolničkih i 5 vanbolničkih) AmpC- i(li) ESBL-producirajućih Proteus spp. izolata. Svi izolati su pokazali 100% osjetljivost na amoksicilin/klavulansku kiselinu, imipenem i meropenem. Rezistencija na cefuroksim zabilježena je u 100%, na gentamicin 90,9%, pipera- cilin/tazobaktam 81,8%, cefotaksim, ceftriakson i ceftazidim 72,7%, cefoksitin i ciprofloksacin 63,6% i na cefepim u 45,5% slučajeva. TEM-1 β-laktamaza detektirana je kod svih izolata, a kod 7 (od 11; 63,6%) izolata dodatno iCTX-M (pet CTX-M-1 i dvije CTX-M-15) i OXA-1 β-laktamaze. Dva izolata su producirala CMY-2 β-laktamazu, dok SHV beta-laktamaze nisu zabilježene. Nije zabilježena klonska pripadnost.

Zaključak Molekularna karakterizacija i tipizacija, te fenotipski testovi za detekciju AmpC i ESBL- producirajućih Proteus spp. izolata, kao i drugih gram-negativnih bakterija, važni su koraci u dizajni- ranju i primjeni terapije, u detekciji izvora i širenju izolata, kao i za pripremu strategije u sprečavanju širenja ovih infekcija.

Ključne riječi: ESBL, CMY-2, antimikrobna otpornost

112 ORIGINAL ARTICLE

Frequency of thyroid cancer in patients operated at Cantonal Hospital Zenica, Bosnia and Herzegovina, in the period 2007- 2014

Nermin Hrnčić¹, Amna Goga¹, Selma Hrnčić², Marijana Filipovska-Mušanović3, Haris Hatibović¹, Ðenad Hodžić¹

1Ear, Nose and Throat Department, Cantonal Hospital Zenica, 2Cantonal Institute for Occupational Health and Sports Medicine Zenica- Doboj Canton; Zenica, 3Public Health Centre Kakanj; Bosnia and Herzegovina

ABSTRACT

Aim To determine frequency and type of thyroid cancer (TC) as well as gender and age distribution of patients operated at the De- partment of Ear, Nose and Throat (ENT), Cantonal Hospital Zeni- ca, Bosnia and Herzegovina.

Methods A retrospective analysis of data obtained from an operating protocol and disease history of patients operated in the eight- year period (2007- 2014) was made according to the frequency and type of thyroid cancer, as well as age and gender of the patients. χ2 test was used for statistical with p˂0.05.

Results A total of 818 surgeries of the thyroid gland were conducted, in 714 (87.29%) female and 104 (12.71%) male patients. Malignancies were diagnosed in 74 (9.05%) patients, of whom Corresponding author: 64 (86.49%) were females and 10 (13.51%) were males, resulting in the gender prevalence of 8.96% and 9.62%, respectively. Nermin Hrnčić The most often presented type was papillary carcinoma, in 48 Department of Ear, Nose and Throat, (out of 74, 64.86%) patients, followed by follicular carcinoma in Cantonal Hospital Zenica 10 (13.51%), medullary carcinoma in four (5.41%), Hurthle cell Crkvice 67, 72000 Zenica, carcinoma in four (5.41%) patients, while anaplastic carcinoma Bosnia and Herzegovina was found in one (1.35%) patient. The number of diagnosed ma- Phone: +387 32 405 133; lignancy varied from 0% (in 2007) to 13.91% (in 2014) (p=0.05). Fax: +387 32 226 576; Conclusion The prevalence of thyroid cancer is low, but has an E-mail: [email protected] increasing trend. A large number of unnecessary surgeries on thyroid gland was performed. Preoperative diagnostic procedures for diseases of the thyroid gland in Cantonal Hospital Zenica should be improved in order to avoid unessential surgeries.

Original submission: Key words: thyroidectomy, malignant disease, thyroid nodule 07 January 2016; Revised submission: 29 January 2016; Accepted: 12 May 2016. doi: 10.17392/846-16

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INTRODUCTION reproductive and hormonal status (higher risk associated with high parity and late menarche) (13). Thyroid carcinomas (TC) are rare tumors with the rate of 1% of all malignoma (1). It is the Epidemiology of TC in the developed world is most common endocrine carcinoma and includes sufficiently described (2,6,14). In Bosnia and about 5% of all thyroid nodules (2). In general Herzegovina and other Balkan countries there are population it is considered that 20-50% of peo- only a few reports (15,16). The aim of this retros- ple have nodules in the thyroid gland (3). About pective study was to review hospital records in 8% of the adult population have palpable nodu- order to assess data on TC prevalence as well as les (4). Majority of the nodules are benign and characteristics (age, gender, type of TC) of pati- only 10% harbor malignancy (5). In an autopsy ents operated at the Department of Ear, Nose and series from Malmoe, Sweden, comprising 821 Throat (ENT), Cantonal Hospital Zenica, Bosnia thyroid glands, the reported nodule prevalence and Herzegovina. was 49.5% (3). Some statistics indicate that one PATIENTS AND METHODS quarter of the population (13-35%) has papillary thyroid carcinoma (PTC), detected in 3-9 cases Patients and study design per 100000 yearly mostly by accident (3). Thyro- id cancer is 2-4 times more frequent in females A retrospective analysis of data obtained from than in males (2). Also, the incidence of TC has operating protocols and disease history of pati- been on the continuous rise in the last 20 years ents with the diagnosis of multinodular goiter or (1). There is a report describing overall preva- suspicions of malignancy of thyroid gland ope- lence of TC in 53 856 patients from the United rated at the Ear, Nose and Throat (ENT) Depar- States with approximately 79% of cases with pa- tment of Cantonal Hospital Zenica in the eight- pillary carcinoma (PTC), 13% of follicular carci- year period (January 01, 2007- December 31, noma (FTC), and approximately 3% of Hurthle 2014) was conducted. cell carcinoma. Medullary thyroid cancer (MTC) Methods accounts for about 4% of thyroid carcinomas (6). Anaplastic carcinomas, lymphoma and metasta- Indications for surgery including multinodular tic disease make a small portion of thyroid mali- goiter, big goiter with compression syndrome gnancies (6). There are many reports showing an or suspicions of TC were assessed at the Depar- increasing incidence of TC (7-9). tment of Nuclear Medicine and patients were re- There are different methods of diagnostic evalua- ferred to ENT department for surgery. Majority tion but it always begins with history and clinical of patients were diagnosed with multinodular examination (10). The diagnostics continues with goiter. Depending on an extent of the disease in laboratory tests (thyroid hormone, thyroid anti- the entire gland, or only a portion of the gland, bodies, thyroglobulin, and calcitonin) and then is more or less extensive surgery was planned, e.g., expanded to ultrasonography (US), thyroid scin- biopsy, lobectomy, isthmectomy, enucleation of tigraphy, fine needle aspiration biopsy (FNAB) cysts, subtotal thyroidectomy, and total thyroi- (10). The evaluation and management of cold dectomy with or without neck dissection. Total thyroid nodules remains the area of controversy thyroidectomy with or without neck dissection in (11). In most centers, FNAB has supplanted ima- all patients with histologically verified TC was ging studies as the routine initial procedure for performed. Histopathological examination was differentiating benign from malignant nodules done at the Pathology Department of the Canto- (12). Cytological diagnosis is reliable and inex- nal Hospital Zenica. Immunohistochemistry was pensive, and it results in better selection of pati- performed at the Institute of Pathology at Clini- ents for surgery (12). cal University Center in Sarajevo or Tuzla. Risk factors for TC include low alimentary iodi- All patients with histological confirmation of TC ne intake, genetics, certain familial syndromes were selected. Age, gender, number and type of (e.g. familial polyposis coli, Gardner syndrome), operation were recorded. Histologically, tumors obesity (women), ionizing radiation (especially in are classified according to the WHO classifica- childhood, children tend to get papillary cancer), tion into 4 main types: papillary (PTC), follicu-

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lar (FTC), medullar (MTC) and anaplastic) (17). in gender prevalence of 8.96% and 9.62%, res- Adenocarcinoma and squamous cell carcinoma pectively, without statistically significant diffe- (SCC) in the thyroid gland were considered as rence (p=0.83). metastases from other organs (17). The median age in all patients with TC was 51 year with a range spanning from 14 to 75 years. Statistical analysis In female patients the median age was 52 years, Age, gender and type of TC as well as annual and in male patients it was 50 years. The majority prevalence were analyzed using χ2 test with sta- of patients with malignant disease aged over 41 tistically significance limit of p ˂0.05. years, 58 (78.38%) (Table 2).

RESULTS Table 2. Age and gender distribution of patients with thyroid carcinoma In the eight-year period 818 surgeries on the No (%) of patients thyroid gland were performed. There were 714 Age (years) Males Females Total (87.29%) females and 104 (12.71%) males. Three 1-20 1 (10.00) 2 (3.13) 3 (4.05) oldest patients at the time of surgery were 79 ye- 21-30 0 4 (6.25) 4 (5.41) 31-40 2 (20.00) 7 (10.94) 9 (12.61) ars old (without malignancy); the youngest patient 41-50 1 (10.00) 13 (20.31) 14 (18.92) was a 12-year old girl operated due to suspicion 51-60 3 (30.00) 19 (29.69) 22 (29.73) of MTC, but after lobectomy no malignancy was 61-80 3 (30.00) 19 (29.69) 22 (29.73) found on histopathological examination. Total 10 (13.51) 64 (86.49) 74 (100) Among 818 surgeries there were 385 total thyro- The largest proportion of patients had PTC tumor idectomies, 379 lobectomies, 28 subtotal thyro- type, 48 (64.86%) (five males and 43 females), of idectomies, 15 cyst enucleations, and 11 other which eight were micro carcinoma; 10 patients types of surgeries (biopsy, isthmectomy). (13.51%) had FTC (one male and nine females); The number of operations had an increasing four (5.41%) patients had MTC (all females); four trend during the 2007-2014 period (the lowest (5.41%) patients had Hurthle cell carcinoma (all number was recorded in 2008 with 62 patients, females); one male patient (1.35%) had anaplastic and highest in 2012 with 156 patients). The num- type of TC. Of the remaining seven patients three ber of diagnosed malignancy varied from 0% (in had adenocarcinoma (one male and two females) 2007) to 13.91% (in 2014) with cutoff statisti- and four had squamous cell carcinoma (SCC) (two cally significant difference (p=0.05). Every year males and two females) (Table 3). The distribution a large number of operations was done on pati- of TC type according to gender has shown statisti- ents without the malignant disease (86.09% and cally significant difference (p=0.03). 100% in 2014 and 2007, respectively) (Table 1). Table 3. Distribution of thyroid cancer (TC) according to Table 1. Number of surgeries and prevalence of thyroid histopathology of tumor and patient gender carcinoma (TC) in the period 2007-2014 No (%) of the patients No (%) of patients Histopathological type of tumors Females Males Total Year No. of surgeries With TC Without TC Papillary TC 43 (67.19) 5 (50.00) 48 (64.86) 2007 77 (9.41) 0 77 (100) Follicular TC 9 (14.06) 1 (10.00) 10 (13.51) 2008 62 (7.58) 6 (9.68) 56 (90.32) Medullar TC 4 (6.25) 0 4 (5.41) 2009 69 (8.44) 6 (8.70) 63 (91.30) Hurthle cell TC 4 (6.25) 0 4 (5.41) 2010 91 (11.12) 12 (13.19) 79 (86.81) Squamous cell carcinoma 2 (3.13) 2 (20.00) 4 (5.41) 2011 98 (11.98) 8 (8.16) 90 (91.84) Adenocarcinoma 2 (3.13) 1 (10.00) 3 (4.05) 2012 156 (19.07) 11 (7.05) 145 (92.95) Anaplastic TC 0 1 (10.00) 1 (1.35) 2013 150 (18.34) 15 (10.00) 135 (90.00) Total 64 (86.49) 10 (13.51) 74 (100) 2014 115 (14.06) 16 (13.91) 99 (86.09) Total 818 (100) 74 (9.05) 744 (90.95) DISCUSSION Among 818 surgeries there were 74 (9.05%) ve- The results of this study related to frequency of rified malignancies by histopathology, of which each histopathology type of thyroid cancer do 64 (86.49%) were found in females, and 10 not differ from the published literature; follicular (13.51%) in males (female:male 6.4:1) resulting and anaplastic TC were noticed less frequently,

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while Hurthle cell carcinoma was slightly more could avoid surgical treatments if the diagnostic common in our study (6,10,18). Data from this procedures were satisfactory. Additionally, mo- study on gender and age distribution are similar ney could be saved because the cost of FNAB to those of the relevant literature: TC was more diagnostic procedures is much lower than the frequent in females than in males (2), and the di- cost of unnecessary surgical treatment (11). Due agnosis of all carcinomas increased significantly to better diagnostic evaluation, a large number of from the age of 40 (18). patients with suspected TC are referred to surgery, There are two sets of data on the incidence of TC and this is the reason for a very extensive type of in the literature. In institutions where FNAB is surgery. In our daily practice each TC and even routinely performed preoperatively, the inciden- microcarcinoma undergo total thyroidectomy. An ce of TC is much higher, because this procedure analysis of autopsy material from Malmoe (Swe- has high sensitivity and specificity (19,20,21). den) showed high prevalence of undiagnosed TC The second group of data report incidentally dis- suggesting a large number of microcarcinomas covered TC in the patients undergoing surgery and slow growing well-differentiated TC, which without suspicion of malignancy, usually with do not require surgery, or operations may not be the diagnosis of multinodular goiter. The data too extensive (2,18, 25-27). from our study do not differ from the published In conclusion, a lot of unnecessary surgeries on literature (22-25). thyroid gland were performed. One of ten pati- In our institution the FNAB is not performed ents operated in our institution has TC. The de- routinely because of the lack of cytopathologists. velopment of a strategy for better preoperative In most cases the diagnostic process ends with diagnostic procedures is necessary to avoid une- ultrasonography (US) or scintigraphy. Relying ssential surgeries. This would reduce costs, and on such a diagnostic evaluation, majority of our more importantly, ensure better health care for patients were sent to surgery with the diagnosis our patients and getting closer to standards of the of multinodular goiter without suspected mali- developed countries. gnancy. A small number of patients was referred FUNDING to surgery with suspected malignancy after US No specific founding was received for this study. or scintigraphy, and even then in many cases the diagnosis was not confirmed by histopathological TRANSPARENCY DECLARATION analysis. Consequently, a large number of patients Competing interests: none to declare. REFERENCES 1. Salkić A, Brkić F, Cickusić A, Cickusić E, Altumbabić Mayo Clinic, 1946 through 1970: initial manifestati- H. Thyroid cancer in Tuzla region of Bosnia and Her- ons, pathologic findings, therapy, and outcome.Mayo zegovina: a 10-year study (1999-2008). Coll Antropol Clin Proc 1991; 66:11-22. 2012; 36:53-7. 9. Nel CJ, van Heerden JA, Goellner JR, Gharib H, 2. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, McConahey WM, Taylor WF, Grant CS. Anaplastic Thun MJ. Cancer statistics, 2008. Cancer J Clin 2008; carcinoma of the thyroid: a clinicopathologic study of 58:71–96. 82 cases. Mayo Clin Proc 1985; 60:51–58. 3. Members of the Guideline Development Group. Dia- 10. Amra Jakubović Čičkušić. Ultrazvučna dijagnostika u gnosis and management of metastatic malignant di- bolestima štitne žlijezde, Tuzla: Princom, 2015. sease of unknown primary origin. NICE 2010; 2:4-6. 11. Giuffrida D, Gharib H. Controversies in the manage- 4. Yeung MJ, Serpell JW. Management of the solitary ment of cold, hot, and occult thyroid nodules. Am J thyroid nodule. Oncologist 2008; 13:105–12. Med 1995; 99:642-50. 5. Layfield L. Fine-needle aspiration in the diagnosis of 12. Mazzaferri EL. Management of a solitary thyroid no- head and neck lesions: a review and discussion of dule. N Engl J Med 1993; 328:553–9. problems in differential diagnosis. Diagn Cytopathol 13. Hrnčić N, Ramaš A, Altumbabić H, Hodžić Ð, Hatibo- 2007; 35:798–805. vić H, Šehanović E, Salkić N. Papillary thyroid carci- 6. Hundahl SA, Fleming ID, Fremgen AM, Menck HR. noma in a female patient with squamous cell carcino- A National Cancer Data Base report on 53,856 cases ma of the larynx. Med Glas (Zenica) 2014; 11:241-3. of thyroid carcinoma treated in the U.S., 1985-1995. 14. Meurisse M, Claeys N, Paesmans M, Nguyen Dang Cancer 1998; 83:2638-48. M, Degauque C, Delmelle M, Larsimont D, T’Hooft- 7. Jossart G, Clark OH. Well-differentiated thyroid cancer. Andry M, Verhest A, Hamoir E, Andry G, Squifflet JP. Curr Probl Surg 1994; 21:933–1012. Belgian registry of thyroid cancer. Preliminary epide- 8. Brennan MD, Bergstralh EJ, van Heerden JA, McCo- miological characteristics revealed by a retrospective nahey WM. Follicular thyroid cancer treated at the study (1988-1995). Belgian Thyroid Cancer Study Group. Ann Endocrinol (Paris) 1997; 58:163-71.

116 Hrnčić et al. Frequency of thyroid cancer

15. Scheiden R, Keipes M, Bock C, Dippel W, Kieffer N, Lind P. Value of ultrasound-guided fine-needle aspi- Capesius C. Thyroid cancer in Luxembourg: a natio- ration biopsy of thyroid nodules in an endemic goitre- nal population-based data report (1983–1999) BMC area. Eur J Nucl Med 2000; 27:62-9. Cancer 2006; 6:102. 22. Gandolfi PP, Frisina A, Raffa M, Renda F, Rocchetti 16. Zivaljevic V, Paunovic I, Diklic A, Krgovic K, Kalezic O, Ruggeri C, Tombolini A. The incidence of thyro- N, Kazic M, Tatic S, Savic D, Stojanovic D, Peruno- id carcinoma in multinodular goiter: retrospective vic R. Acta Chir Belg 2008; 108:328-32. analysis. Acta Biomed 2004; 75:114-7. 17. Trimboli P, Ulisse S, Graziano FM, Marzullo A, Ru- 23. Pezzolla A, Lattarulo S, Milella M, Barile G, Pasca- ggieri M, Calvanese A, Piccirilli F, Cavaliere R, Fu- zio B, Ciampolillo A, Fabiano G, Palasciano N. In- marola A, D’Armiento M. Trend in thyroid carcinoma cidental carcinoma in thyroid pathology: our experi- size, age at diagnosis, and histology in a retrospective ence and review of the literature. Ann ItalChir 2010; study of 500 cases diagnosed over 20 years. Thyroid 81:165-9. 2006; 16:1151-5. 24. Slijepcevic N, Zivaljevic V, Marinkovic J, Sipetic S, 18. Šimunović D, Cvjetko I, Gladić V, Elez M, Glasnović Diklic A, Paunovic I. Retrospective evaluation of the M, Leniček T, Vučić M, Lechpammer M, Čupić H, incidental finding of 403 papillary thyroid microcar- Strnad M, Kusić Z, Krušlin B, Belicza M. Possible cinomas in 2466 patients undergoing thyroid surgery effects of the 1990-1995 war in Croatia on thyroid for presumed benign thyroid disease. BMC Cancer cancer epidemiology. Acta Clin Croat 2000; 39:155- 2015; 15:330. 60. 25. Pelizzo MR, Rubello D, Berbardi C, Gemo G, Ber- 19. Leonard N, Melcher DH. To operate or not to opera- tazza L, Schievano E, Fedeli U. Thyroid surgical te? The value of fine needle aspiration cytology in the practices shaping thyroid cancer incidence in North- assessment of thyroid swellings. J Clin Pathol 1997; Eastern Italy. Biomed Pharmacother 2014; 68:39-43. 50:941-3. 26. Carlini M, Giovannini C, Mercadante E, CAstaldi F, 20. Miseikyte-Kaubriene E, Ulys A, Trakymas M. The Dell´Avanzato R, Zazza S. Incidental thyroid micro- frequency of malignant disease in cytological group carcinoma in benign thyroid disease. Incidence in a of suspected cancer (ultrasound-guided fine-needle total of 100 consecutive thyroidectomies. Chir Ital aspiration biopsy of non palpable thyroid nodules). 2006; 58:441-7. Medicina (Kaunas) 2008; 44:189-94. 27. Sission JC. Medical treatment of benign and mali- 21. Mikosch P, Gallowitsch HJ, Kresnik E, Jester J, Würtz gnant thyroid tumors. Endocrinol Metab Clin N Am FG, Kerschbaumer K, Unterweger O, Dinges HP, 1989; 18:359-87.

Učestalost karcinoma štitne žlijezde kod pacijenata operisanih u Kantonalnoj bolnici Zenica u periodu od 2007. do 2014. godine Nermin Hrnčić¹, Amna Goga¹; Selma Hrnčić², Marijana Filipovska-Mušanović3, Haris Hatibović¹, Ðenad Hodžić¹ 1Kantonalna bolnica Zenica, ORL odjel, ²JU Zavod za medicinu rada i sportsku medicinu Zeničko-dobojskog kantona, Zenica 3JU Dom zdravlja Kakanj SAŽETAK

Cilj Utvrditi učestalost i vrstu, te spolnu i dobnu distribuciju karcinoma štitne žlijezde u pacijenata operisanih na Odjelu za bolesti uha, grla i nosa Kantonalne bolnice Zenica. Metode Napravljena je retrospektivna analiza podataka dobijenih iz operativnih protokola i historijâ bolesti pacijenata u periodu od 2007. do 2014. godine. Analizirana je učestalost i tip karcinoma, te spol- na i starosna dob pacijenata. Za statističku obradu korišten je χ2 test uz p≤0.05. Rezultati Ukupno je izvedeno 818 operativnih zahvata na štitnoj žlijezdi. Operisano je 714 (87.29%) žena i 104 (12.71%) muškarca. Dijagnosticirano je 74 (9.05%) maligniteta, 64 (86.49%) kod žena i 10 (13.51%) kod muškaraca. Zabilježena je učestalost karcinoma kod 9.62% (10/104) muškaraca i kod 8.96% (64/714) žena. Najčešće je bio zastupljen papilarni karcinom, u 48 od 74 (64.86%) pacijenta, folikularni karcinom kod 10 (13.51%) pacijenata, a po 4 (5.41%) pacijenta imala su medularni i Hurthle cell karcinom, dok je 1 (1.35%) pacijent imao anaplastični karcinom. Broj dijagnosticiranih karcinoma varirao je od 0% (2007. god.) do 13.91% (2014. god.) (p=0.05). Zaključak Učestalost karcinoma štitne žlijezde je niska, ali ima tendenciju porasta. Napravljen je veliki broj nepotrebnih hirurških zahvata na štitnoj žlijezdi. Preoperativne dijagnostičke procedure za bolesti štitne žlijezde u Kantonalnoj bolnici Zenica trebaju biti poboljšane ako se želi smanjiti broj nepotrebno urađenih operativnih zahvata. Ključne riječi: tireoidektomija, maligna bolest, čvor u štitnoj žlijezdi

117 ORIGINAL ARTICLE

IGFBP-1 marker of cervical ripening and predictor of preterm birth

Larisa Mešić Ðogić1, Dragana Mićić2 , Feđa Omeragić3,4, Refka Kovač5, Seid Fazlagić6

1Department of Gynecology and Obstetrics, General Hospital Tešanj, 2Hospital of Obstetrics and Gynecology, Clinical Hospital Centre ‘’Dragiša Mišović’’ Belgrade, Serbia, 3School of Medicine Tuzla, University Tuzla, 4Obstetrics and Gynecology Practice “Omeragić” Tuzla, 5Department of Pediatics, 6Department of Surgery; General Hospital Tešanj; Bosnia and Herzegovina

ABSTRACT

Aim To establish a correlation between positive values of IGFBP-1 (>10 mg/L, Actim Partus Test, APT) and premature cervical ripening in imminent preterm labor.

Methods A prospective study was conducted in primary health care centers in Tuzla, Gynecology and Obstetrics Clinic of the University Clinical Centre in Tuzla and General Hospital Tešanj. The study included 50 women (singleton pregnancy, 28-37 week) with imminent preterm labor diagnosed by cervical biometry and modified Bishop score) (examinees) and 30 healthy pregnant women (control group). The presence of IGFBP-1 was tested in cer- Corresponding author: vical secretion several times in weeks 28-37 until a positive test Larisa Mešić Ðogić was shown. Department of Gynecology and Results IGFBP-1 was positive in 43 (86%) examinees and in six Obstetrics, General Hospital Tešanj (20%) patients from the control group (p=0.001). In 31 (62%) Braće Pobrić bb, 74264 Tešanj, examinees APT was positive in weeks 28-30, and in nine (18%) Bosnia and Herzegovina in weeks 31- 33, while three (6%) examinees had positive test in 34-37 week; in the control group, three (10%) were tested positive Phone: +387 32 650 159; in weeks 31-33 and three (10%) in weeks 34-37. At first testing Fax: +387 32 650 655; (28-30 weeks) APT was statistically significantly more frequently Email: [email protected] positive in the examined group (p<0.05). Later, tests did not find statistically significant difference in the frequency of positivity between the control and examined group (p=0.08).

Conclusion Elevated values of IGFBP -1 in cervical secretion Original submission: were highly correlated with preterm labor. Screening for IGFBP 12 April 2016; could help in preventing preterm labor and its complications. Revised submission: Key words: insulin-like growth factor binding proteins, premature 15 May 2016; birth, cervix mucus Accepted: 07 July 2016. doi: 10.17392/856-16

Med Glas (Zenica) 2016; 13(2):118-124

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INTRODUCTION 184 countries, the rate of preterm birth ranges from 5% to 18% of babies (4). Prematurity is the Preterm labor is one of the main problems of mo- leading cause of death in children under the age dern perinatology, neonatology and medicine in of 5 (1-4, 6-8). general due to potential consequences for future life of a child. Preterm birth complications are the The best way for prevention of prematurity is leading cause of death among children under 5 ye- early screening of pregnant women with high ars of age, responsible for nearly 1 million deaths risk of preterm labor. Methods of selection of in 2013 (1-4). According to recommendations of pregnant women at risk include clinical and bi- the World Health Organization preterm is defined ochemical markers for preterm labor. Clinical as the birth of babies born alive before 37 weeks markers include changes of cervix, which could of pregnancy are completed (1). There are four be detected by regular vaginal examinations and sub-categories of preterm birth based on gestati- ultrasonography. Monitoring of occurrence of onal age: late preterm (born between 34 and 36 uterus contractions, vaginal bleeding and regi- weeks of pregnancy), moderately preterm (born stering of epidemiological risk factors are also between 32 and 34 weeks of pregnancy), very pre- performed (4-7). Biochemical methods include term (born at less than 32 weeks of pregnancy), monitoring of serum collagenase activity, cervi- and extremely preterm (born at or before 25 weeks covaginal elastosis and determination of cervico- of pregnancy) (1-3). Inequalities in survival rates vaginal fetal fibronectin and insulin-like growth around the world are expected. In low-income factor binding protein (IGFBP-1) (9-11). settings, half of the babies born at or below 32 In the last decades numerous studies identified weeks (2 months early) die due to a lack of fea- IGFBP-1 as a marker of cervical changes that sible, cost-effective care, such as warmth, breas- are related to preterm labor (9-11). Unfortuna- tfeeding support, and basic care for infections and tely, there were just few reports from Bosnia breathing difficulties. In high-income countries, and Herzegovina about the correlation between almost all of these babies survive (4). preterm labor and IGFBP-1 or other biochemical After 28 weeks of pregnancy it is possible to markers. This multi-centric study is designed to speed up maturation of fetal lungs using corti- show that even if two regions are not within the costeroid therapy whish increases chances for same health administration, if detected on time, survival (5). even in small healthcare center, prematurity treatment can be successfully performed in a nearest Often, the specific cause of premature birth is not well equipped center. clear. Many factors may increase the risk of premature birth including: having a previous prema- The aim of this study was to establish a correlation ture birth, pregnancy with twins, triplets or other between positive values of IGFBP-1 (>10 mg/L, multiples, an interval of less than six months Actim Partus test) and imminent preterm labor. between pregnancies, conceiving through in vitro PATIENTS AND METHODS fertilization, problems with the uterus, cervix or placenta, smoking cigarettes or using illicit dru- Study design and examinees gs, poor nutrition, not gaining enough weight during pregnancy, some infections (particularly of The prospective study was conducted in obste- the amniotic fluid and lower genital tract), some trics practice of primary health care centers in chronic conditions (such as high blood pressure Tuzla, Gynecologic and Obstetrics Clinic of the and diabetes), being underweight or overweight University Clinical Centre in Tuzla and General before pregnancy, stressful life events, such as Hospital Tešanj during the nine-month period the death of a loved one or domestic violence, between September 2013 and end of May 2014. multiple miscarriages or abortions, physical The estimated population of the cities Tuzla and injury or trauma (3,4). Tešanj is 400.000 inhabitants. More than one Every year, an estimated 15 million babies are center was selected to provide sufficient number born preterm (before 37 completed weeks of ge- of relevant data. The selection of the medical in- station), and this number is rising (1,4). Across stitution of Tuzla Canton and neighboring Tešanj region was based on regional similarity of the

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population within the area of 70 kilometers and age between the 28th and 37th week, who had no a possibility for quick transport “in utero” from changes identified by ultrasound biometry and mo- Tešanj to Tuzla for neonatal care. dified Bishop score that would indicate imminent Three (out of four) sub-categories of preterm birth preterm labor caused by cervical changes (Table 1).

(based on gestational age) (1-3) were tested: late Table 1. Assessment of the condition of cervix based of preterm (born between 34 and 36 weeks of pre- cervical length, dilatation, consistensy, position of cervical gnancy), moderately preterm (born between 32 axis and position of fetal head Index and 34 weeks of pregnancy), very preterm (born Parameters at less than 32 weeks of pregnancy). Extremely 0 1 2 3 Dilatation of cervical 5 and closed 1 – 2 3 - 4 preterm (born at or before 25 weeks of pregnancy) channel (cm) more was excluded due to poor prognosis and lack of Cervical length (cm) 3 2 1 0 prophylactic treatment for fetal lung maturation. Position of fetal head (cm) -3 -2 -1 1 +2 The pregnancies after the 28th week from the gro- Cervical consistency hard middle tempered soft maximal back slightly slightly ups of examinees (all other subgroups of preterm Position of cervical axis centered or front back front labor) with diagnosed preterm labor were on corticosteroid treatment. In order to avoid any differen- Approvals of the Ethics Committees of all in- ces between the tested groups caused by possible stitutions participating in the multicentric study influence of corticosteroid therapy to final results were obtained (Healt Center Tuzla, GeneralHos- on preterm labor, extremely preterm labor group pitah Tešanj, University Clinical Ceter Tuzla). was excluded from study. Methods A total number of 80 patients was included in study: an examined group of 50 pregnant women The diagnosis of imminent preterm labor caused with imminent preterm labor and a control group by cervical changes was determined by modifi- of 30 healthy pregnant women. ed Bishop score and ultrasound biometry according to cervix condition. Measured parameters Both groups included patients who had had no included: length of cervix, dilatation of cervical deliveries before, who had no diagnosed deve- channel, cervical consistency, position of fetal lopmental anomaly of uterus or any other di- head, and a position of cervical axis (Table 1). seases that would be treated as a risk factor for preterm labor. The criteria for inclusion in the The condition of uterus was further assessed by study (both groups) were: nulparity, absence of transvaginal and transabdominal ultrasound cer- anomalies of genital tract, absence of other pro- vical length measurement and elements were blems and surgery of the uterus, cervix, absence monitored and scored according to cervical len- of complications with placenta, absence of mul- gth measurement. Parameters measured included tiple miscarriages or abortions, absence of physi- length of cervix, dilatation of cervical channel, cal injury or trauma, no smoking cigarettes or and shape of internal ostium (“T” represented using illicit drugs, no chronic conditions (particu- closed cervical ostium and channel, “Y” initial larly high blood pressure and diabetes), not being dilatation, and “U” advanced dilatation). Each underweight or overweight before pregnancy, no parameter, dependently of measures, was mar- stressful life events (such as the death of a loved ked from 1 (for slight changes) to 3 (for extreme one or domestic violence), as well as absence of changes). A sum of marks represented cervical hard working conditions. All patients with uteri- score (CS) (Table 2). ne contraction were excluded. Table 2. Assessment of the condition of cervix by transvaginal The examined group included 50 healthy pre- and transabdominal ultrasound based on the measurement of cervical length, dilatation and internal ostium shape gnant women with singleton pregnancy of the Index gestation age between the 28th th Parameters and 37 week who 0 1 2 were diagnosed with imminent preterm labor ba- Cervical length (mm) 30 and more 20 less than 20 sed on two main criteria: modified Bishop score Dilatation of cervical channel 0 3 -5 more than 5 and ultrasound biometry. (mm) Shape of internal ostium T Y U The control group comprised 30 healthy pregnant T, closed cervical ostium and channel; Y, initial dilatation; U, advan- women with singleton pregnancy of the gestational ced dilatation

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Bishop score represents a sum of marks (index) Bishop score (BS) 2 was found in 23 (46%), BS from 1 to 3 for each of the parameters. Minimal 3 in 20 (40%), BS 4 in one (4%) of examinee. changes in Bishop score had to be shown by Bishop Most frequently diagnosed cervical changes were score 2 and higher, or at least 2 minimally changed shortening, in 21 (42%), dilatation in 16 (32%) parameters, or one significantly changed parameter. and softening in 10 (20%) patients. All patients were tested for the presence of Transvaginal cervical measurement showed IGFBP-1 in cervical secretion starting in gesta- changed values of cervical measurement score tional age of the 28th week (very preterm). The (CS). The highest number of the examinees (39) group of examinees had the test repeated in the had changes of cervical score (CS) CS2 and CS3, period 31st - 33rd week (moderately preterm), 34th which means that at least one parameter was -37th week (late preterm) until the positive result highly expressed (mark 2 or 3) or two parameters occurred, and if the third test remained negative, were moderately expressed (marks 1 and 2), or the test was definitely recorded as negative. In three parameters were slightly expressed (mark order to determine the presence of IGFBP-1 in 1). Most frequently diagnosed changes were fo- cervical secretion the Actim Partus test (APT) und on the shape of internal orifice of the uterus, (Medix Biochemica, Finland) was used (one- in 21 (42%), length in 16 (32%) and dilatation of step dipstick test for detecting the presence of cervical canal in 12 (24%) examinees. phosphorylated IGFBP-1 in cervical secretions Actim Partus test was positive in 43 (86%) exa- to observe the risk of preterm or imminent de- minees and six (20%) patients from the con- livery when fetal membranes are intact). Values trol group. The analysis of frequency of positi- higher than 10 mg/L are considered to be positive Actim Partus tests (APT) with regard to the ve and indicate the maturity of cervix, i.e. immi- examined group found a statistically significant nent preterm labor. difference, and the highest percentage of examinees from the examined group had it positive 43 Statistical analysis (86%) (p=0.001). 2 The χ test, standard deviation, Fisher test, Stu- In 31 (62%) examinees APT was positive in ge- dent T test was used, as well as a relative risk was station weeks 28-30, in nine (18%) examinees it calculated. APT value, Bishop Score and Cervi- was positive at the second testing between weeks cal Score were measured every two weeks and 31 and 33, while in three (6%) examinees the test compared between the group of examinees and was positive upon the third testing performed the control group in gestational age from 28 to 36 between gestation weeks 24 and 36. In patients weeks. The significance level was p≤0.05. from the control group three (10%) patients had the positive test in the period between 31stand RESULTS 33rdweek, while three (10%) patients had it posi- The average age of patients in the examined gro- tive in gestation weeks 34-37 (Figure 1). up was 25.4 years; the youngest patient was 16 years old, eldest one was 30. In the control group the average age of pregnant women was 27; the youngest patient was 17, and the eldest was 33. The total of 62% examinees lived in town, 10% in a smaller town, 28% lived in rural areas. In the control group 66.6% of patients lived in town, 10% in a smaller town, and 23% lived in villages. Both groups included an equal number of employed and unemployed with statistically insignificant difference in professional qualifica- Figure 1. Occurrence of positive Actim Partus test in observed tions. Everyday activities at home, either house- gestational periods keeping or performing duties at work, exposed Already at first testing (28-30 weeks of gestati- patients from both groups to equal physical effort on) APT was statistically significantly more of- or position (data are not shown). ten positive in the examined group in comparison

121 Medicinski Glasnik, Volume 13, Number 2, August 2016

with the control group (p<0.05). During later me- DISCUSSION asurements, nine (18%) and three (10%) patients Being the most frequent complication of the se- in examined and control group, respectively had cond semester of pregnancy, preterm labor is a positive test during 31-33 week; three patients significant health problem in perinatology and in each had positive test in examined (6%) and medicine in general (1-3). Cervical changes are control group (10%), respectively in 34-34 week. presented as shortening, softening and dilatation There was no statistically significant difference of the canal, which are thereafter followed by in the frequency of positive tests between the central position of cervix and descent of the pre- control and examined group in periods 31-33 and senting part of the fetus. This does not necessa- 34-37 weeks (p=0.08). rily have to happen in the sequence stated above Presence of infection in cervical chanel was but it is most likely to occur in that sequence (7, detected in 35 (70%) examinees and in four 8, 11-16). (13%) patients from the control (p=0.001). Most According to the first results of our survey, the frquent microbiological patogens found were: highest number of examinees (46%) had the Bis- Ureaplasma urealyticum in seven (20%), Myco- hop score 2, which means that at least one signi- plasma hominis in seven (20%), E. coli in five ficant change was noted for one of the parameters (14%), Trichomonas vaginalis in four (11%), or two smaller changes, while a lower number of Chlamydia trichomatis in three (9%) and other examinees (40%) had the Bishop score 3, which patogens in nine (26%) cases. Presence of urea- indicates at least one larger change or a signifi- plasma and mycoplasma infections (40%) was cant change of one parameter and/or several joi- statistically significant as compared to all other ned changes, i.e. several changed parameters. In patogens (p=0.001). 42% of examinees shortening of cervix was a lea- Preterm labor occurred in 30 (60%) patients of the ding parameter for the Bishop score, be it Bishop examined group, while 20 (40%) patients had term score 2, 3 or 4. It is followed by dilatation (32%) labor. In the control group all the patients had term and softening (20%), while descent of the pre- labor. The highest number of the examinees with senting part of the fetus (4%) and central cervical preterm labor was in the group of 34-36 weeks, position (2%) were noted less frequently. Similar i.e. in the group of late preterm prematurity, 19 results were obtained by other researchers (14- (63%) examinees of all preterm deliveries among 16). Values of cervical length measurement were the examinees. Moderate prematurity occurred in correlated with the Bishop scoring, tough the nine (10%) examinees of all preterm labors in the most frequent parameter registered by transvagi- examined group, while two (6%) examinees had nal cervical length measurement is the change of very premature labor (Table 3). internal orifice of the uterus (42%), while shortening (32%) and dilatation of cervical canal (24%) Table 3. Term of labor in the examined group are seen less frequently. These data correlate with Preterm labor Term labor data from the literature (13-16). Gestation week 28-31 32-33 34-36 37-40 Total No (%) of examinees 2 (4) 9 (18) 19 (38) 20 (40) 50 (100) In 2011 the Society of Gynecologists and Obste- tricians of Canada accepted recommendations of the Diagnostic Imaging Committee provided in In 29 (58%) examinees with preterm labor APT the guidelines for transvaginal cervical length was positive, but it was also positive in 14 (28%) measurement in imminent preterm labor, and examinees with term labor (predicative value of made recommendations for therapeutic procedu- 96% for preterm labors and 70% for term labors) re based on results of monitoring (17). (Table 4). The APT was positive in 86% of examinees and 14% of patients from the control group. The evi- Table 4. Actim Partus test (APT) and pregnancy outcome dent statistically significant difference between No (%) of examinees the results obtained for the examined and con- Labor APT positive APT negative Total trol group correlates with data from the literature Preterm 29 (58) 1 (2) 30 (60) (15-16, 18-21). On a sample of 80 asymptomatic Term 14 (28) 6 (12) 20 (40)

122 Mešić Đogić et al. IGFBP-1 and imminent labor

pregnant women Balić et al. found the positive therapeutic algorithm for monitoring the first and predicative test value of 44.4% and negative pre- second trimester of pregnancy and ensure that dicative test value of 98%, while the specificity measures are taken to prevent preterm labor and of the Bishop score was 83.7%, and they conclu- administer corticosteroid prophylaxis for lung ded that in asymptomatic pregnant women the maturity thus decreasing perinatal morbidity and value of positive APT indicated the presence of mortality rate (7-8, 20-23). imminent preterm labor (19). In conclusion, IGFBP-1 is a valuable marker for Preterm delivery occurred in 60% examinees in preterm labor. It could be a useful part of dia- present study, while in 40% of examinees the de- gnostic and therapeutic algorithm for monitoring livery was recorded as term labor. It is a statisti- during pregnancy and could be used to select cally significant difference when compared with patients who are in need of prophylactic admi- the control group where there was no record of nistration of corticosteroid therapy for fetal lung any preterm labor. In 58% of examinees with pre- maturation. Such an algorithm could be particu- term labor APT was positive. Reliability of the larly important for small hospitals and obstetrics test for the prediction of preterm labor correlates departments to prepare patients for transport with the data from the literature (18-23). Howe- “in utero” to centers with units for premature ver, the number of preterm deliveries would have newborns care. been probably higher if the risk had not been noted on time and if other measures of preventing ACKNOWLEDGEMENT preterm labor had not been taken. The author would like to thank Mersiha Mahmić- Timely identification of the problem and effici- Kaknjo for critical revision of the manuscript. ency of the therapy are likely to be the reason for the fact that 63% of examinees in this study gave FUNDING birth between the 34th and 36th week of gestati- No specific funding was received for this study. on, i.e. in the gestation age of mild prematurity according to the gravity clinical presentation of TRANSPARENCY DECLARATION prematurity. The screening for detection of eleva- Competing interests: None to declare. ted values of IGFBP-1 could set a diagnostic and

REFERENCES 1. Araújo BF, Zatti H, Madi JM, Coelho MB, Olmi FB, 6. The World Health Organization 2001 WHO ante- Canabarro CT. Analysis of neonatal morbidity and natal care randomized trial. Manual for the imple- mortality in late-preterm newborn infants. J Pediatr mentation of the new model. World Health Orga- 2012; 88:259-66. nisation, Geneva, 2002. http://apps.who.int/iris/ 2. Schleußner E The prevention, diagnosis and tre- bitstream/10665/42513/1/WHO_RHR_01.30.pdf atment of premature labor. Dtsch Arztebl Int 2013; (15 May 2016) 110:227-35. 7. Zeitlin J, Szamotulska K, Drewniak N, Mohangoo 3. Morais M, Mehta C, Murphy K, Shah PS, Giglia AD, Chalmers J, Sakkeus L, Irgens L, Gatt M, Gi- L, Smith PA, Bassil K, McDonald SD, Morais M, ssler M, Blondel B; Euro-Peristat Preterm Study Mehta C, Murphy. How often are late preterm births. Group. Preterm birth time trends in Europe: a study The result of non-evidence based practices: analysis of 19 countries. BJOG 2013; 120:1356-65. from a retrospective cohort study at two tertiary re- 8. Kinney MV, Lawn JE, Howson CP, Belizan J. 15 ferral centres in a nationalised healthcare system. Million preterm births annually: what has changed BJOG 2013; 120:1508-14. this year? Reprod Health 2012; 9:28. 4. Blencowe H, Cousens S, Oestergaard M, Chou D, 9. Abo El-Ezz AE, Askar AE. Predictive value of phos- Moller AB, Narwal R, Adler A, Garcia CV, Rohde S, phorylated insulin-like growth factor binding prote- Say L, Lawn JE. National, regional and worldwide in-1 (PIGFBP-1) (bedside test) in preterm labor. J estimates of preterm birth. The Lancet 2012; Egypt Soc Parasitol 2014; 44:525-30. 379:2162-72. 10. Kolev N, Ivanov S, Kovachev E, Slavchev S. The 5. Roberts D, Dalziel SR. Antenatal corticosteroids for insulin-like growth factor IGFBP-1--specific marker accelerating fetal lung maturation for women at risk for preterm delivery in pregnant women with clinical of preterm birth. Cochrane Database Syst Rev 2006; symptoms. Akush Ginekol (Sofiia) 2014; 53:6-8. (3):CD004454.

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11. Mayers KM, Feltovich H, Mazza E, Vink J, Bajka 18. Rutanen E, Pekonen F. Measurement of insulin-like M, Wapner RJ, Hall TJ, House M. The mechanical growth factor binding protein-1 in cervical / vaginal role of the cervix in pregnancy. J Biomech 2015; secretions: Comparison with the ROM-check mem- 48:1511-23. brane immunoassay in the diagnosis of ruptured 12. Villar J, Altman DG, Purwar M, Noble JA, Knight fetal membranes. Clin Chim Acta 1993; 214:73-81. HE, Ruyan P, Cheikh Ismail L, Barros FC, Lambert 19. Balić D, Latifagić A, Hudić I. Insulin-like growth A, Papageorghiou AT, Carvalho M, Jaffer YA, Ber- factor-binding protein-1 (IGFBP-1) in cervical se- tino E, Gravett MG, Bhutta ZA, Kennedy SH; In- cretions as a predictor of preterm delivery. J Matern ternational Fetal and Newborn Growth Consortium Fetal Neonatal Med 2008; 21:297-300. for the 21st Century. The objectives, design and im- 20. Cooley SM; Donnelly JC; Collins C; Geary MP; Ro- plementation of the INTERGROWTH-21st Project. deck CH; Hindmarsh PC. The relationship between BJOG 2013; 120 (Suppl 2):9-26. maternal insulin-like growth factors 1 and 2 (IGF-1, 13. Basu R, Malig B, Ostro B. High ambient temperatu- IGF-2) and IGFBP-3 to gestational age and preterm re and the risk of preterm delivery. Am J Epidemiol delivery. J Perinat Med 2010; 38:255-9. 2010; 172:1108-17. 21. Shin JE, Shin JC, Kim SJ, Lee Y, Park IY, Lee S. 14. Schleußner E. The prevention, diagnosis and tre- Early midtrimester serum insulin-like factors and atment of premature labor. Dtsch Arztebl Int 2013; cervical length to predict preterm delivery. Taiwan J 110:227-35. Obstet Gynecol 2016; 55:45-9. 15. Berghella V, Baxter JK, Hendrix NW. Cervical asse- 22. Conde-Agudelo A, Romero R. Cervical phosp- ssment by ultrasound for preventing preterm deli- horylated insulin-like growth factor binding pro- very. Cochrane Database Syst Rev 2013; 1. tein-1 test for the prediction of preterm birth: a 16. Lim K, Butt K, Crane J. Ultrasonographic Cervical systematic review and metaanalysis. Am J Obstet Length Assessment in Predicting Preterm Birth in Gynecol 2016; 214:57-73. Singleton Pregnancies J Obstet Gynaecol Can 2011; 23. Kolev N, Ivanov S, Kozovski I, Kovachev E, Kor- 33:486–99. novski Y, Bechev B, Ivanova V, Nikolova N. Com- 17. Joint SOGC/CAR Policy Statement on Non-medi- bined application of fetal fibronectin and insulin-like cal Use of Fetal Ultrasound. J Obstet Gynaecol Can growth factor in preterm delivery diagnosis--our re- 2014; 36:184-5. sults. Akush Ginekol (Sofiia) 2015; 54:8-12. IGFBP-1 marker cervikalnog sazrijevanja i prediktor prijevremenog porođaja Larisa Mešić Ðogić1, Dragana Mićić2, Feđa Omeragić3,4, Refka Kovač5, Seid Fazlagić6 1Odjel za ginekologiju i akušerstvo, Opća bolnica Tešanj, Bosna i Hercegovina; 2Bolnica za ginekologiju i akušerstvo, Klinički bolnički centar „Dragiša Mišović“, Beograd, Srbija; 3Medicinski fakultet, Univerzitet u Tuzli, 4Ordinacija za ginekologiju i akušerstvo „Omeragić“, Tuzla, 5Odjel za pedijatriju, Opća bolnica Tešanj, 6Odjel za hirurgiju, Opća bolnica Tešanj; Bosna i Hercegovina SAŽETAK

Cilj Istražiti korelaciju između pozitivnih vrijednosti IGFBP-1 (>10 mg/l, Actim Partus Test, APT) i preranog sazrijevanja grlića kod prijetećeg prijevremenog poroda. Metode Prospektivna studija, provedena u Domu zdravlja u Tuzli, Ginekološko-akušerskoj klinici Uni- verzitetskog kliničkog centra Tuzla i Općoj bolnici Tešanj, obuhvatila je 50 trudnica (ispitanice) (jedno čedo, 28-37 gestacijskih sedmica), kojima je dijagnosticiran prijeteći prijevremeni porod ultrazvučnom cerviometrijom i modificiranim Bishop-skorom, i 30 trudnica (kontrolna skupina) (jedno čedo, 28-37 gestacijskih sedmica) bez znakova prijetećeg prijevremenog poroda. Testirano je prisustvo IGFBP-1 u cervikalnom sekretu između 28. i 37. sedmice, sve dok test nije bio pozitivan. Rezultati IGFBP-1>10 mg/L bio je pozitivan kod 43 (86%) ispitanice i 6 (20%) pacijentica iz kontrolne skupine (p=0.001). Kod 31 (62%) ispitanice APT je bio pozitivan u periodu 28-30. sedmice, kod 9 (18%) ispitanica drugo testiranje bilo je pozitivno u periodu 31-33. sedmice i kod 3 (6%) ispitanice treće testiranje je bilo pozitivno u periodu 34-37. sedmice. U kontrolnoj skupini kod 3 (10%) pacijentice test je bio pozitivan između 31-33. sedmice i kod 3 (10%) između 34-37. sedmice. Pri prvom testiranju (28- 30. sedmica) APT je statistički signifikantno češće bio pozitivan kod ispitanica u odnosu na kontrolnu skupinu (p<0.05). Testiranjem u kasnijoj gestacijskoj dobi nije se statistički razlikovala učestalost pozitivnih nalaza između kontrolne i ispitivane skupine (p=0.08). Zaključak Povećane razine IGFBP -1 u cervikalnom sekretu jako su povezane s prijevremenim poro- dom. Probir pomoću IGFBP mogao bi pomoći u preveniranju prijevremenog poroda i njegovih kom- plikacija. Ključne riječi: insulinu slični proteini koji vezuju faktor rasta, prijevremeni porod, cervikalna sluz

124 ORIGINAL ARTICLE

Secular trend of anthropometric parameters of newborns in municipalities of Tuzla Canton (1976 – 2007)

Amela Begić1, Jasminka H. Halilović1, Lejla Mešalić2, Sabina H.Halilović1

1Biology Department, School of Natural Sciences and Mathematics, 2School of Medicine; University of Tuzla, Tuzla, Bosnia and Herzegovina

ABSTRACT

Aim To determine the acceleration of birth weight and birth length of newborns in the municipalities of Tuzla Canton in the last four decades. Tuzla Canton (TC) as an administrative territorial unit of the FBiH includes 13 municipalities.

Methods In this retrospective study data from the Protocol Book of Gynecology and Obstetrics Clinic, University Clinical Center, from 1976 to 2007 were used. The sample of live-born infants by municipalities was divided into four sub-samples: a subsample of infants born in 1976, 1987, 1997 and 2007. During the monitored years there were 19,312 live births in Tuzla Canton (TC), but the study included 17,907 newborns of both sexes. Statistical data pro- Corresponding author: cessing was performed using standard methods, descriptive and Amela Begić inference statistics. Biology Department,School of Results Ascertained results of the secular trend for birth weight Natural Sciences and Mathematics, showed that this parameter had positive values in seven municipa- Tuzla University lities, but in six municipalities it was negative. The highest values Tihomila Markovića 1, 75000 Tuzla, of increasing birth length of newborns, which were statistically Bosnia and Herzegovina significant, were found in the municipalities of Srebrenik and this Phone: +387 35 320 876; increase was 0.06 cm per year. Conclusion Different values of the Fax: +387 35 320 860; secular trend in the monitored TC are result of different socio-economic and ecological conditions in these municipalities, as well as E-mail: [email protected] of violent mass population migration that occurred as a result of the war in BiH in the period from 1992 to 1995.

Keywords: acceleration, birth length, birth weight Original submission: 22 February 2016; Revised submission: 20 May 2016; Accepted: 06 July 2016. doi: 10.17392/851-16

Med Glas (Zenica) 2016; 13(2):125-135

125 Medicinski Glasnik, Volume 13, Number 2, August 2016

INTRODUCTION weight was ≈3 g/year. In the USA, Ananth and Wen (5) reported an increase in birth weight in The word acceleration originates from the Latin white infants for ≈ 0.7 g year and the black ones word acceleratio meaning acceleration. This term for ≈ 2.1g/year. was introduced in literature by the German scientist Koh E.V. in the thirties of the twentieth century. The In Croatia, the secular changes of newborns be- term “secular trend” (“centuries-long tendency”) fore, during and after the Homeland War (1983 to has also been widely used in literature. The phe- 2003) were investigated by Bralić et al (7): secu- nomenon of secular trend represents the long-term lar trend of birth weight of infants was positive in systematic changes in a wide range of anthropo- the 3500-3999 g, 4000-4999 g and ≥ 4500 g ca- logical variables in subsequent generations of the tegories of newborns, and negative secular trend population living in the same territory (1). was recorded in the 1000-1499 g, 2500-2999 g, and 3000-3499 g categories of newborns. The phenomenon can be viewed in the size of newborns, during childhood and early youth, The secular change of anthropological parame- but also at the level of the entire population. Se- ters of infants, followed by a longer period of cular trend marks not only acceleration of the time in the area of BiH has not been studied. Sur- development of forthcoming generations, but veys were conducted only for the municipality of also acceleration of fetal growth, extension of Gračanica in the ten-year period (18). Due to the the reproductive period, shortening the length lack of data on this phenomenon, as well as the of premenarchal periods in girls, increase in the need for constant monitoring of anthropometric proportion of adult body, changes of mental de- parameters at birth, we decided to investigate this velopment, increase in certain organs, increase phenomenon. of the length of life etc. (1-4). It is known that The aim of this study was to determine the somatic status of a newborn depends on a whole acceleration of birth weight and birth length of range of factors as confirmed by many studies. newborns in the last four decades, and to compa- They studied birth weight, birth length and head re secular trend in municipalities of Tuzla Canton circumference of infants in relation to different in four time points (1976, 1987, 1997 and 2007). enodogenous and exogenous factors such as the impact of villages and towns, socio-economic EXAMINEES AND METHODS status, climatic and geographical factors, the Characteristics of test areas impact of polluted environment, birth height and weight of both parents, physical activity Tuzla Canton (TC) is an administrative-territorial of pregnant women, pregnancy and birth order, unit of the Federation of Bosnia and Herzegovina maternal smoking, taking drugs and narcotics, (FBiH) that was created after the war in Bosnia age of both parents, nutrition during pregnancy and Herzegovina by the Dayton Agreement in (2-4). Secular changes in birth weight and birth 1995. It was formed out of the parts of the former length of newborns were monitored in many co- area of north-eastern Bosnia, and Tuzla district. untries (5-13). According to the latest available Its territory covers complete or parts of thirteen literature largest secular changes were recorded municipalities: Banovici, Doboj-Istok, Gradačac, by Schack-Nielsen and colleagues in Denmark Gračanica, Kladanj, Kalesija, Čelic, Lukavac, showing positive secular trends in birth weight, Srebrenik, Teočak, Sapna, Živinice and Tuzla. birth length and ponderal index of the newborns Tuzla Canton occupies an area of 2.908 km2, or in all the tested categories: birth weight in the 11.1% of the territory of the Federation of Bosnia examined period 1973-2003 increased by 160 and Herzegovina, or 5.7% of the territory of Bo- g (≈5 g/year), and birth length had a negligible snia and Herzegovina. According to estimations increase of 2.4 mm and ponderal index increased from 1996, there were 611.500 inhabitants, out 3 to 0.8kg/m (12). of which 35% of displaced persons and refugees. Acceleration of body size of newborns in Sweden In the population of the Federation of Bosnia was recorded by Odlind et al. (14), in Norway and Herzegovina, Tuzla Canton participates with by Skjærven et al. (13), in Canada by Wen et al. 26.2%. In the former Tuzla region, according (15). In these countries the secular trend of birth to the 1991 Census, there were 949.621 inha-

126 Begić et al. Secular trend of anthropometric parameters

bitants, of which 525,427 Bosniaks (55.33%), Table 1. Distribution of newborns per municipalities of Tuzla 268,581 Serbs (28.28%), 83,320 Croats (8.78%) Canton and 72,293 (or 7.61%) residents who identified No of newborns Year themselves as others. Today Bosniaks make up Municipalities 1976 1987 1997 2007 Total about 90% of the population in the area of this Tuzla 1743 1819 1400 1094 6056 Canton, after all demographic migrations caused Živinice 376 885 804 697 2762 by the aggression on B&H. Kalesija 351 598 511 372 1832 Climatically, the Tuzla area has a moderate con- Lukavac 566 874 572 362 2374 tinental climate. The average annual temperature Srebrenik 209 549 517 384 1659 Kladanj 64 176 200 145 585 is relatively high at 10.2 to 11.4°C, with clearly Gračanica 29 127 215 138 509 distinguished seasons of a year. There used to be Banovići 117 254 284 259 914 some fluctuations in temperature in the spring and Gradačac - - 243 291 534 fall. The coldest month is January with an average Sapna - - 31 117 148 temperature between -0.2 and 2°C, and the war- D.Istok - - 49 24 73 mest is July with an average temperature between Teočak - - 67 61 128 Other municipalities 36 128 17 152 333 20- 22ºC. Maximum rainfall is in spring in May- Total 17907 June, and the minimum rainfall is in February or in March. The number of precipitation days is 90- 115 in average during the year. Annual average of the municipality of Lopare was included. This is sunshine hours is 1772-1972. In this area summers because in those years in GOC UCC Tuzla there are warm and winters cold, causing very large were many births in this municipality that belong annual fluctuations as a result of the influence of to Republika Srpska at the current regional divi- moderate continental climate (11). sions of Bosnia and Herzegovina.

Study design and sample Methods In this retrospective study the data from the Book Measurements of birth weight are carried out on of Protocols from the Gynecology and Obstetrics a special scale with stand, vessel, or by Weiner Clinic, University Clinical Centre in Tuzla (GOC and Louie (16). The measured values are rounded UCC Tuzla) were used: birth weight, birth len- to the nearest 10-gram value. The birth length of gth of newborns, parents’ place of residence. The newborns was measured in supine position. The sample is composed of four sub-samples of infants measurement was performed in Pirket’s bed or of both sexes, newborns from 1976, 1987, 1997 on horizontal board with two verticals (one fixed and 2007. In the observed calendar years at Ob- and one movable base) and fixed metal centi- stetrics and Gynecology Clinic there were 19.312 meter by the side. Units and categories used newborns, of which 10037 boys and 9275 girls, to express the results of measurements and the 233 stillbirths (129 boys and 104 girls). All still- corresponding observations were standardized births as well as newborns for which data related and acceptable (17). to parents’ residential place were missing in the protocol books have been excluded resulting in the Statistical analysis total of 17,907 newborns included in this research. The descriptive statistics for all taken parame- The sample in relation to the municipality affi- ters was calculated as follows: mean (XSR), the liation of the Tuzla Canton was divided to muni- standard mean error (+/- s), ranges of variation of cipalities in all the experimental years (Table 1). each parameter are determined (X min -; Xmax), Secular trend was observed in thirteen municipa- standard deviation (SD) and the median value lities: Banovici, Doboj-Istok, Gradačac, Gračani- for each parameter. The statistical significance of ca, Kladanj, Kalesija, Čelic, Lukavac, Srebrenik, differences between the mean values (t-test) of Teočak, Sapna, Živinice and Tuzla. birth weight and birth length were determined in Also in 1976 due to lack of data for the location the municipalities of TC. of housing (residence) a special category of un- Temporal differences (acceleration trend) of read municipalities was set. In 1976 and 1987, changes in the average birth length and birth

127 Medicinski Glasnik, Volume 13, Number 2, August 2016

weight of newborns for the thirty-year period Table 2. Statistically significant differences in compared birth was done comparing the obtained results with weight by calendar years in the total sample of newborns from the municipalities of Tuzla Canton appropriate data available in the literature. Compared Birth weight (g) p Municipalities years p(<0,05) RESULTS X 1 X 2 1976-1987 3,369.41 3,365.70 0.84 1976-1997 3,369.41 3,361.90 0.70 Secular trend of birth weight in the total sample 1976-2007 3,369.41 3,384.51 0.47 Tuzla of newborns in the municipalities of Tuzla Canton 1987-1997 3,365.70 3,361.90 0.84 from 1976 to 2007 1987-2007 3,365.70 3,384.51 0.34 1997-2007 3,361.90 3,384.51 0.29 Secular trend of birth weight in different muni- 1976-1987 3,405.61 3,336.25 0.03 1976-1997 3,405.61 3,341.37 0.06 cipalities of Tuzla Canton was positive for seven 1976-2007 3,405.61 3,377.52 0.42 Živinice municipalities and negative in six. The highest 1987-1997 3,336.25 3,341.37 0.84 values of the secular trend were in Kalesija (2.06 1987-2007 3,336.25 3,377.52 0.13 1997-2007 3,341.37 3,377.52 0.20 g/year), and the lowest one, with a negative va- 1976-1987 3,340.41 3,327.54 0.72 lue, in the municipality of Kladanj (-4.57 g/year). 1976-1997 3,340.41 3,378.94 0.27 1976-2007 3,340.41 3,402.42 0.12 High values of secular trends were discovered in Kalesija the municipality of Gradačac (16.04 g/year), but it 1987-1997 3,327.54 3,378.94 0.10 1987-2007 3,327.54 3,402.42 0.04 was monitored only in the last ten years as well as 1997-2007 3,378.94 3,402.42 0.51 in the municipality of Doboj Istok (-25.33 g/year), 1976-1987 3,391.80 3,362.85 0.31 where it appeared in very low values (Figure 1). 1976-1997 3,391.80 3,352.99 0.21 1976-2007 3,391.80 3,400.08 0.80 Lukavac 1987-1997 3,362.85 3,352.99 0.74 1987-2007 3,362.85 3,400.08 0.26 1997-2007 3,352.99 3,400.08 0.17 1976-1987 3,413.06 3,341.77 0.12 1976-1997 3,413.06 3,349.44 0.15 1976-2007 3,413.06 3,458.96 0.30 Srebrenik 1987-1997 3,341.77 3,349.44 0.82 1987-2007 3,341.77 3,458.96 0.00 1997-2007 3,349.44 3,458.96 0.00 1976-1987 3,508.44 3,322.27 0.03 1976-1997 3,508.44 3,372.85 0.08 1976-2007 3,508.44 3,371.45 0.08 Figure 1. Secular changes in birth weight of infants born alive Kladanj in the total sample in the municipalities of Tuzla Canton 1987-1997 3,322.27 3,372.85 0.38 1987-2007 3,322.27 3,371.45 0.44 1997-2007 3,372.85 3,371.45 0.98 Tuzla Municipality. The average value of birth 1976-1987 3,395.17 3,152.83 0.11 weight of the newborns in Tuzla Municipality 1976-1997 3,395.17 3,250.33 0.23 1976-2007 3,395.17 3,298.12 0.49 ranged from 3369.41g in 1976, then the monito- Gračanica 1987-1997 3,152.83 3,250.33 0.18 red parameter decreased to 3361.9 g in 1997 and 1987-2007 3,152.83 3,298.12 0.10 it increased again and then, the highest average 1997-2007 3,250.33 3,298.12 0.49 value was recorded in 2007 (3384.51 g). Secular 1976-1987 3,372.65 3,266.73 0.14 trend in this municipality in the monitored period 1976-1997 3,372.65 3,352.78 0.76 1976-2007 3,372.65 3,424.98 0.42 Banovići from 1976 to 2007 was 15.1g (or 5.03 g per deca- 1987-1997 3,266.73 3,352.78 0.10 des or 0.5 g/year) (Table 2). 1987-2007 3,266.73 3,424.98 0.00 1997-2007 3,352.78 3,424.98 0.13 Živinice Municipality. The average value of Gradačac 1997-2007 3,287.20 3,447.63 0.002 birth weight in infants in the municipality of Ži- Sapna 1997-2007 3,521.94 3,434.19 0.39 vinice reached maximum of 3,405.61g in 1976, Doboj East 1997-2007 3,208.78 2,955.42 0.14 Teočak 1997-2007 3,330.60 3,384.92 0.60 decreased rapidly to 3,341.37 g in 1987 and 1976-1987 3,329.17 3,111.64 0.11 increased again in 2007 to 3,377.52 g. The secu- 1976-1997 3,329.17 3,492.94 0.30 lar trend was negative (-28.09 g) in the last thirty Other 1976-2007 3,329.17 3,147.17 0.18 municipalities 1987-1997 3,111.64 3,492.94 0.04 years, e.g. decreased to 9.36 g dec, i.e. 0.936 g/ 1987-2007 3,111.64 3,147.17 0.70 year. Statistically significant differences were 1997-2007 3,492.94 3,147.17 0.07 found only in the comparison between 1976 and 1987 (p=0.03) (Table 2).

128 Begić et al. Secular trend of anthropometric parameters

Kalesija Municipality. The average value of parison of the results on average values of birth birth weight of infants in Kalesija was 3,340.41g weight by the analyzed years by t-test showed in 1976. The analyzed parameter slightly fell to statistical significance only between 1976 and 3,327.54 g in 1987, when it had the lowest values 1987 (p= 0.03) (Table 2). too. After 1987 the average value of birth weight Gračanica Municipality. Average birth weight gradually grew, so in 2007 it was 3,3402.42 g. of infants in the Municipality of Gračanica had a The highest values of the secular trend were re- maximum value of 3,395.17 g in 1976. This para- corded in Kalesija in relation to all other muni- meter decreased rapidly to 3152.83 g in 1987 and cipalities of TC (total of 62.01g in the last thirty gradually increased again in 2007, when it amo- years, or 20.67 g/dec, ie. 2.06 g/year). It was fo- unted to 3,298.12g. Secular trend in Gračanica in und that only infants delivered in 2007 were si- the reporting period was negative and its value gnificantly “heavier” in relation to the newborns was -97.05 g in the last thirty years. Its decade in 1987, while there is no statistically significant value is -32.35 g or -3.34 g/year. Comparison of difference among others tested (Table 2). the results obtained from average values of birth Lukavac Municipality.The average value of birth weight analyzing annual data by t-test did not weight of infants in the municipality of Lukavac in show statistical significance among the examined 1976 had a value of 3,391.8 g. The monitored pa- years (Table 2). rameter fell in 1987 to 3,362.85 g and 1997 it was Banovići Municipality. The average value of 3352.99 g. The average birth weight value gra- birth weight of infants in the Municipality of dually increased until 2007, when it amounted to Banovići in 1976 was 3,372.65 g then it fell to 3,400.08 g. Minimal values of the secular trend in 3266.73 g in 1987 and increased again, so the relation to the municipalities with a positive trend highest value of 3,424.98 g was recorded in 2007. were recorded in Lukavac Municipality. It was Secular trend in this municipality in the reporting 8.28 g in the last thirty years. Decade value is 2.76 period from 1976 to 2007 was 52.33 g. Its de- g, i.e. 0.276 g/year. Comparing the results obtai- cade value is 17.44 g, or 1.74g/year. Comparing ned on average values of birth weight by analyzed the results obtained on average values of birth years by t-test there was no statistical significance weight through the tested years by t-test showed between the examined years (Table 2). statistical significance only for the period betwe- Srebrenik Municipality. The average value of en 1987 and 2007 (p= 0.02) (Table 2). birth weight of infants in the municipality of Sre- Municipalities of Gradačac, Sapna, Doboj brenik in 1976 was 3413.06 g. The monitored pa- Istok and Teočak. The average value of birth rameter fell in 1987 to 3,341.77 g, and from 1997 weight of infants in the municipalities of Grada- it began gradually to increase, so it was 3,458.96 čac, Sapna, Doboj Istok and Teočak was monito- g in 2007. The reported values of the secular red only in 1997 and 2007 because deliveries in trend in Srebrenik were 45.09 g in the last thirty those four municipalities happened only in those years.The decade value is 15.03 g, or 1.503 g/ years. In the municipalities of Sapna and Doboj year. Comparing the results obtained on average Istok negative values of the secular trend were values of birth weight overviewed by years by t- found. In the municipality of Sapna its decade test showed statistical significance between 1987 value is -87.75 g, or -8.78 g/year. Decade value and 2007 (p=0.03) and between 1997 and 2007 of the secular trend in the municipality of Do- (p= 0.00) (Table 2). boj Istok is -253.33 g, or -25.33 g/year. Gradačac Kladanj Municipality. The average value of and Teočak municipalities had a positive secular birth weight of infants from Kladanj reached a trend. In the municipality of Gradačac its decade maximum of 3508.44g in 1976. The monitored value is 160.43g, or 16.04 g/year, in the Muni- parameter decreased rapidly to 3,322.27 g in cipality of Teočak 54.32 g or 5.43 g/year. Com- 1987 and grew again in 2007 up to 3,371.45 g. paring the results obtained on average values of Secular trend of the Municipality of Kladanj in birth weight through the analyzed years by t-test the reporting period was negative and its value showed statistical significance in the compared was -136.99 g throughout the last thirty years. Its results of this parameter only in Gradačac (p= decade value is -45.66 -4.57g or g/year. A com- 0.002) (Table 2).

129 Medicinski Glasnik, Volume 13, Number 2, August 2016

Other municipalities of Bosnia and Herzegovi- Table 3. Statistical significance of differences in compared na. The average value of birth weight of infants birth length by calendar year in the total sample of newborns from the municipalities of Tuzla Canton whose parents are from other municipalities in Birth lenght (cm) BiH in 1976 amounted to 3,329.17 g, then the Municipalities Compared years p(<0,05) monitored parameter fell to 3,111.64g in 1987, X 1 X 2 and increased again, so the highest value was 1976-1987 51.46 53.61 - 1976-1997 51.46 52.88 - recorded in 1997, 3,492.94 g. Since 1997 the 1976-2007 51.46 52.82 - Tuzla monitored parameter had declined again and its 1987-1997 53.61 52.88 0.00 lowest value was in 2007, when it amounted to 1987-2007 53.61 52.82 0.00 1997-2007 52.88 52.82 0.62 3,147.17g. Secular trend in birth weight of in- 1976-1987 51.77 53.48 0.00 fants whose parents are not from the area of TC, 1976-1997 51.77 52.90 0.00 1976-2007 51.77 52.69 0.00 in the reporting period from 1976 to 2007 was Živinice 1987-1997 53.48 52.90 0.00 negative and amounted to -182.00 g. Its decade 1987-2007 53.48 52.69 0.00 value is -60.67 g, or 6.07 g/year. Comparing the 1997-2007 52.90 52.69 0.23 results obtained on average values of birth weight 1976-1987 51.30 53.27 0.00 1976-1997 51.30 53.15 0.00 in the tested years by t-test showed statistical si- 1976-2007 51.30 52.79 0.00 Kalesija gnificance of this parameter only between 1987 1987-1997 53.27 53.15 0.49 and 1997 (p= 0.04) (Table 2). 1987-2007 53.27 52.79 0.02 1997-2007 53.15 52.79 0.07 Secular trend of birth length in the total sample 1976-1987 51.60 53.60 - 1976-1997 51.60 52.99 0.00 of newborns in the municipalities of Tuzla Canton 1976-2007 51.60 53.08 0.00 Lukavac from 1976 to 2007 1987-1997 53.60 52.99 0.00 1987-2007 53.60 53.08 0.01 Secular trend of birth length in the total sample of 1997-2007 52.99 53.08 0.65 infants in TC in all the monitored municipalities 1976-1987 51.47 53.42 0.00 1976-1997 51.47 52.97 0.00 in the time points of 1976 and 2007 showed a po- 1976-2007 51.47 53.14 0.00 Srebrenik sitive trend. The negative trend in those time po- 1987-1997 53.42 52.97 0.03 ints was confirmed in a sample of infants whose 1987-2007 53.42 53.14 0.18 1997-2007 52.97 53.14 0.40 parents were originally from other municipalities 1976-1987 52.05 53.34 0.01 in BiH. In the municipalities where the secular 1976-1997 52.05 53.05 0.02 1976-2007 52.05 53.11 0.01 trend was monitored throughout ten years (from Kladanj 1987-1997 53.34 53.05 0.37 1997 to 2007) such as the municipalities of Gra- 1987-2007 53.34 53.11 0.50 dačac and Sapna, it was positive and in Doboj 1997-2007 53.05 53.11 0.85 Istok and Teočak it was negative (Figure 2). 1976-1987 51.03 52.49 0.12 1976-1997 51.03 52.74 0.01 1976-2007 51.03 52.52 0.06 Gračanica 1987-1997 52.49 52.74 0.57 1987-2007 52.49 52.52 0.96 1997-2007 52.74 52.52 0.58 1976-1987 51.32 53.28 0.00 1976-1997 51.32 52.92 0.00 1976-2007 51.32 53.13 0.00 Banovići 1987-1997 53.28 52.92 0.30 1987-2007 53.28 53.13 0.60 1997-2007 52.92 53.13 0.40 Gradačac 1997-2007 52.44 53.05 0.04 Sapna 1997-2007 53.10 53.23 0.81 Doboj east 1997-2007 52.80 50.63 0.04 Teočak 1997-2007 53.01 52.59 0.48 Figure 2. Secular changes in birth length of live-born infants in 1976-1987 51.86 52.28 0.60 the total sample in the municipalities of Tuzla Canton 1976-1997 51.86 53.76 0.02 Other 1976-2007 51.86 51.46 0.61 municipalities 1987-1997 52.28 53.76 0.19 Tuzla Municipality. The average value of birth 1987-2007 52.28 51.46 0.13 length of live-born infants in Tuzla Municipality 1997-2007 53.76 51.46 0.04 was 51.46 cm in 1976, then this parameter grew up to 53.61 cm in 1987, when its highest values

130 Begić et al. Secular trend of anthropometric parameters

were recorded. After 1987 the monitored para- Srebrenik Municipality. The average value of meter slowly decreased in 2007, so its value was birth length in live-born infants in the municipa- 52.82 cm. Secular trend in this municipality in the lity of Srebrenik in 1976 had the lowest value of period from 1976 to 2007 was 1.36 cm. Its decade 51.47 cm. The highest values of this parameter value was 0.5cm and 0.05 cm/year. Comparison were also found in other municipalities of TC in of the results on average values of birth length 1987 in the amount of 53.42 cm. Secular trend per year showed statistical significance in mutual in this municipality in the monitored period of comparison of the monitored years, except in the thirty years, 1976-2007 had the value of 1.67 cm comparison of 1997 and 2007 (Table 3). (or 0.56 cm/dec; or 0.06 cm/year). Comparison Živinice Municipality. In the municipality of of the results obtained on average values of birth Živinice the average value of birth length of li- length per year showed statistical significance ve-born infants was 51.77 cm in 1976, then this between 1976 and the years 1987, 1997, 2007, parameter grew up to 53.48 cm in 1987, when and between 1987 - 1997 , respectively (Table 3). we noted its maximal values. After 1987 this pa- Kladanj Municipality. The average value of rameter slowly declined, so its value was 52.69 birth length of live-born infants in the munici- cm in 2007. Secular trend in the monitored points pality of Kladanj had a minimum value in 1976 from 1976 to 2007 was 0.92 cm (or 0.31 cm/dec; 52.05 cm. The highest values of this parameter or 0.03 cm/year). Comparison of the results obta- were also found in other municipalities of TC in ined on average values of birth length per year 1987 and they amounted to 53.34 cm. After 1987 showed statistical significance, as well as in Tu- year, the monitored parameter slowly decreases, zla, in the mutual comparison of all years, except so in 2007 it is 53.11 cm. Secular trend in the for the comparison of 1997 with 2007 (Table 3). Municipality of Kladanj in the monitored points, Kalesija Municipality In Kalesija the average va- 1976 – 2007 year (thirty-year period), had a value of birth length of live-born infants was 51.30 lue of 1.06 cm, or 0.35 cm/dec (or 0.04 cm/year). cm in 1976, then this parameter increased and in Comparison the results obtained on average va- 1987 it amounted to 53.27 cm. After that period lues of birth length per year showed statistical the parameter slowly decreased, and in 2007 its significance between 1976 with the three years value was 52.79 cm. Secular trend in the moni- 1987, 1997and 2007, respectively (Table 3). tored points from 1976 to 2007 was 1.49 cm (or Gračanica Municipality. Average birth length of 0.5 cm/dec; or 0.05 cm/year). Comparision of the live-born infants in the municipality of Gračanica results on average values of birth length through was the lowest in 1976, 51.03 cm. The highest the years has shown no statistical significance for value of this parameter was found in 1997 in the the periods 1987-1997 and 1997-2007. In all other amount of 52.74 cm, but in 2007 it was 52.52 comparisons p<0.05 was found (Table 3). cm. Secular trend in this municipality in the pe- Lukavac Municipality. The average birth length riod from 1976-2007 had the same value as in of live-born infants in the municipality of Luka- Kalesija, and in the thirty-year period it amounts vac in 1976 was the lowest value of 51.60 cm. 1.49 cm (or 0.5 cm/dec; or 0.05 cm/year). Com- The highest values of this parameter in the amo- parison of the results obtained on average values unt of 53.60 cm were found in other municipali- of birth length per year showed statistical signi- ties of TC too in 1987. After 1987, the monitored ficance only between 1976 and 1997. In all the parameter slowly decreased, and in 2007 it was other comparisons p>0.05 was found (Table 3). 53.08 cm. Secular trend in this municipality in Banovići Municipality Average birth length the monitored period from 1976 to 2007 had the of live-born infants in the municipality of Ba- same values as in Kalesija Minicipality. It amou- novići had the lowest value in 1976, 51.32 cm. nted to 1.48cm (or 0.5 cm/dec, or 0.05 cm/year) The highest values of this parameter were found in the course of the thirty-year period. Compa- in other municipalities of TC too, in 1987 in the rison of the results obtained on average values amount of 53.28 cm. After 1987 the monitored pa- of birth length per year did not show statistical rameter slowly decreased and in 2007 it was 53.13 significance only in the comparison with 1997– cm. Secular trend in the municipality of Banovi- 2007 (Table 3). ći in the monitored time points, 1976 to 2007, in

131 Medicinski Glasnik, Volume 13, Number 2, August 2016

thirty-year period valued 1.81 cm and 0.6 cm/dec; cipalities (-60.67 g/dec), Kladanj (-45.66 g/dec), (or 0.06 cm/year). Comparing the results obtained Gračanica (-32.35 g/dec), and Živinice (-9.36 g/ on average values of birth length per year showed dec). Analyzing secular changes in birth length statistical significance between 1976 and 1987, over the ten-year period (1997-2007) positive 1997 and 2007, respectively (Table 3). values were recorded in ten municipalities and Municipalities Gradačac, Sapna, Doboj Istok negative values in three. Increase of birth length i Teočak. In the municipalities of Teočak and and positive secular changes were recorded in the Doboj Istok negative values of the secular trend municipalities of Gradačac (0.61 cm/dec), Ba- were found, but ten-year value in Teočak was novići (0.60 cm/dec), Srebrenik (0.56 cm/dec), -0.42 cm, or -0.04 cm/year. Ten-year value of the Kalesija (0.50 cm/dec), Lukavac (0.50 cm/dec ), secular trend in the municipality of Doboj Istok Gračanica (0.50 cm/dec), Tuzla (0.45 cm/dec), was -2.17 cm (or -0.22 cm/year). Municipaliti- Kladanj (0.35 cm/dec), Živinice (0.31 cm / dec), es of Gradačac and Sapna had positive secular Sapna (0.13 cm/dec). Reduction in birth length trend. Ten-year value in Gradačac was 0.61 cm, and negative secular changes were recorded in or 0.06 cm/year, but in Sapna it was 0.13 cm/dec the municipalities of Doboj East (-2.17 cm/dec), (or 0.01 cm/year). Comparing the average valu- and other municipalities of Bosnia and Herzego- es of birth length according to years, statistically vina (-0.13 cm/dec) and Teočak (-0.42 cm/dec). significant differences in the results obtained for DISCUSSION this parameter in the municipality of Gradačac and Doboj Istok were found (Table 3). This research contains considerations related to Other municipalities of Bosnia and Herzegovi- secular trend in Tuzla Canton municipalities, na. The average value of birth length of newborns Bosnia and Herzegovina. Acertained trend had whose parents were from other municipalities in different values during the period of thirty years. BiH was 51.86 cm in 1976. After 1976 this para- Statistically significant increase or decrease in meter increased and had the highest average va- birth weight in the monitored time points 1976- lue of 53.76 cm in 1997. In 2007 year, the value 2007 was not recorded. Statistically insignificant of the monitored parameter declined rapidly to its increase of birth weight was noted in the muni- smallest value ( X = 51.46 cm). Secular trend of cipalities of Tuzla, Kalesija, Lukavac, Srebrenik birth length of newborns whose parents were not and Banovići, while in Živinice, Kladanj and from territory of TC in the reporting period, from Gračanica statistically insignificant decrease in 1976 to 2007, had a negative value of -0.4cm (or birth weight was recorded. In four municipalities -0.13cm/dec; or -0.01cm/year). Comparison of (Gradačac, Sapna, Doboj Istok and Teočak) secu- the results obtained on average values of birth lar changes were monitored only in the last deca- length per year showed statistical significance de. In this period, a statistically significant incre- between the results obtained in 1976 and 1997 ase in birth weight was found only in mothers (p=0.02), 1997 and 2007, and 1997 and 2007 coming from Gradačac municipality. (p=0.02) (Table 3). Comparing the recognized secular trend of birth weight and birth length for the municipality of Ten-year secular changes Gračnica with the trend recorded previously Seven municipalities of TC had positive valu- (2009) by Hadžihalilović et al. (18) thirty-year es and six municipalities had negative values period secular trend of birth weight has had nega- in the ten-year period (1997-2007), resulting in tive values (-32.35g/year). However, an analysis positive secular changes and increase in infant of the last decade only (1997-2007) showed that birth weight in Gradačac (160.43 g/dec), Teočak the trend was positive and amounted to 47.79 (54.32 g/dec), Kalesija (20.67 g/dec), Banovi- g, which is much lower compared to 84.96 g/ ći (17.44 g/dec), Srebrenik (15.03 g/dec), Tuzla dec reported by Hadžihalilović et al. (18). The (5.3 g/dec), and Lukavac (2.76 g/dec). Negative reason for such a large difference between these secular changes and the reduction in birth weight two resports is probably the fact that in presented were recorded in the municipalities of Doboj East study data on births were used from the Book of (-253.3 g/dec), Sapna (-87.75 g/dec), other muni- Protocol of Gynecology and Obstetrics Clinic,

132 Begić et al. Secular trend of anthropometric parameters

University Clinical Centre (GOC, UCC) Tuzla, in the past 13 years, showing that the mean birth and Hadžihalilović et al. used data from the Book weight rose from 3.440g to 3.507 g during 1973- of Protocol of Department of Newborn Babies, 1986 periods (20). In England, Spencer et al. (21) Gynecology and Obstetrics Department, General recorded an increase in average birth weight of Hospital “Dr. M. Beganović “in Gračanica. Be- 34 g in the city of Sheffield between 1985 and cause of the long distance of Gračanica from Tu- 1994. In the period from 1980 to 1992, the ave- zla, usually only a small number of mothers, only rage birth weight of live births from singleton with high-risk and twin pregnancies, were sent to pregnancies in Scotland increased from 3326 g to give birth in GOC, UCC Tuzla. 3382 g (6). As in Gračanica, such high values of A statistically significant increase in birth length acceleration can be associated with the short time of newborns in the monitored time points 1976- period in which the survey was conducted (18). 2007 was identified in most municipalities of TC High values of the secular trend for a longer pe- (Gradačac, Banovići, Srebrenik, Kalesija, Luka- riod were found in Denmark (12), Sweden (14) vac, Tuzla, Kladanj and Živinice). In the same and Canada (15). period, statistically significant increases or de- Thus, the largest recorded acceleration over an creases in the monitored parameter in newborns extended period was measured in Denmark, whe- from Gračanica, Sapna, Teočak, as well as from re in the period from 1973 to 2003 the mean birth other municipalities of Bosnia and Herzegovina weight increased by about 160 g, corresponding were not monitored. Statistically significant re- to the equivalent of 5 g/year. The mean birth duction in birth length monitored in the time po- length had a small increase of 0.24cm/year. The ints 1997-2007 was found only in the newborns monitored increase in birth weight and birth len- from the Municipality of Doboj Istok. This large gth was greater for boys than for girls (12). Also, decline in birth weight (of -253.33g) and birth according to the research conducted by Odlind length (of -2.17g) was probably due to the relati- et al. (14) for the entire population of Sweden in vely small number of deliveries from this muni- the period from 1973 to 2000, the average birth cipality performed in GOC, UCC Tuzla. Namely, weight was increased by 75 g (2.7 g/year). out of the total number of newborns from Doboj Secular trend found in Canada (15) for the period Istok Municipality only about 30% were born in from 1981- 1983, 1995 - 1997 amounted to 35 g this hospital during the monitored years (19). (2.2 g/year). Secular trend is recorded in other countries aro- Unlike Lithuania, which is a country in transi- und the world as well. High values of acceleration like Bosnia and Herzegovina, the increase tion were recorded for immigrants in the USA in birth weight and birth length of newborns in (10), the UK (9), Sweden (14,20), Scotland (6), B&H was higher: in Lithuania birth length incre- England (21). ased, and birth weight remained on the same The highest values of acceleration in birth weight level through the thirty-year period (from 1974 of newborns were found in immigrants from to 2004) (22). Comparing our results with data South-East Asia to the United States (10). The aut- from the US (8,10), Great Britain (9), Denmark hors believe that the monitored increase in birth (12), England (9,21), Sweden (14,20), Scotland weight is a result of improved economic and he- (6) and Canada (15), the secular trend in Tuzla alth status of immigrants considering that most Canton is much lower. of them originated from underdeveloped parts of Tuzla Canton has higher values of the secular the country they came from (10). In Great Britain trend in relation to the trend in birth weight as- secular trend of birth weight was monitored from certained in Region Campinas (Brazil) (23) and 1975 to 1988, in the local population and in immi- Adais Ababa (Ethiopia) (11) where negative va- grants from South Asia to the city of Leicester. The lues of the secular trend were found. acertained acceleration in a thirteen-year period had higher values in the domicile population (9). Acceleration in birth weight and birth length by gender were surveyed in Russia (24), Brazil The large increase in the mean birth weight of (25), Illinois (8) (USA) and Gračanica town (18). about 5g/year was noted in the region of Gothe- Comparing the secular trend with these countri- nburg in Sweden, and also refers to the period

133 Medicinski Glasnik, Volume 13, Number 2, August 2016

es (cities), the monitored parameters had lower head circumference monitored by the weeks of values in TC compared to Saratov and Moscow gestation in infants in China in the period betwe- (Russia) (24), Illinois (8) (USA) and Gračani- en 1982-1986, and from 2000 to 2001 (27). Secu- ca (Bosnia and Herzegovina) (18). Accelerati- lar trend of birth weight, before, during, and after on in birth weight and birth length of male and the Homeland War (1983-2003) in Croatia mo- female newborns was higher in TC in relation nitored by Bralić et al. (7) showed a statistically to Khvalynsk (Russia) (24) and Ribeirao Preto significant increase in the number of live-born (Brazil) (25), where these parameters had nega- infants in the weight groups of 500-999 g, 3500- tive values. 3999 g, 4000-4499 g, and in the group greater Tretyak et al. (24) identifying secular trend in than 4500 g, while in the groups of 1000-1499 Russia found that in the last 100 years, periods g, 2500-2999 g, and 3000-3499 g negative trend of increase and decrease of anthropometric pa- was noticed. rameters at birth were recorded as a result of the In conclusion, general tendencies of change of socio-economic changes. The biggest decrease in anthropometric parameters at birth were dia- these parameters was recorded during the Second gnosed in the municipalities of TC. The identi- World War and the maximal values were noted in fied changes are yet another indication that the the mid eighties, which was the period of maxi- long-term and systematic monitoring of these pa- mal birth rate, as well (24). rameters is necessary in order to inform its own An increase in the average value of birth weight population. This study contributes to the field of was noted among parents and children in Illinois population anthropology and pediatric population (USA) in the periods 1956-1976 and 1989-1991. of TC it is a confirmation of the necessary need The ascertained increase has a greater value for to create its own (national) percentile growth cu- the whites (74g) than for the blacks (33 g), and in rves for newborns among the TC population and girls in relation to boys (8). In Ribeirao Preto and entire BiH. Campinas cities (Brazil) in the 1978-1994 peri- FUNDING od negative secular trend of birth weight in both sexes was recorded. The ascertained trend had a No specific funding was received for this study. greater decrease in girls than in boys (23,25,26). Statistically significant differences were found TRANSPARENCY DECLARATION in secular trend of birth weight, birth length and Competing interests: None to declare.

REFERENCES 1. Nikolić-Dovat V. Somatski razvoj i razvoj djeteta. 8. Chike-Obi U, Richard JD, Coutinho R, Wu SY. Birth Novi Sad: Institut za zdravstvenu zaštitu majke i dje- weight has increased over a generation. Am J Epide- teta, 1978, 19–25. miol 1996; 144:563-9. 2. Darmanović B, Ivanović B, Vujadinović V. Somat- 9. Chowdhury S, Ammari F, Burden CA, Gregory R. ski status novorođenčadi Titograda. Glasnik ADJ Secular trend in birth weight in native White and 1971/72; 8-9:65-76. immigrant South Asian populations in Leicester, 3. Ivanović MB. Dinamika fizičkog razvoja učenika UK: possible implications for incidence of type 2 Titograda. Institut za biološka istraživanja Beograd. diabetes in the future. Practical Diabetes Int 2000; Titograd: Biološki zavod, 1970, 8–23. 17:104-8. 4. Ivanović MB. Ontogenetski razvoj i antropološke 10. De-Kun L, Hanyu N, Schwartz MS, Daling RJ. Se- karakteristike omladine Crne Gore. Titograd. CANU cular change in birthweight among Southeast Asian 1985; 13–52. immigrants to the United States. Am J Public Health 5. Ananth CV, Wen SW. Trends in fetal growth in the 1990; 80:685-8. United States and Canada among singleton gesta- 11. Enquoselassie F, Minyilshewa A. Changes in birth- tions, 1985 through 1998. Semin Perinatol 2002; weight of hospital-delivered neonates in Addis Aba- 26:260-7. ba. Ethiop J Health Dev 2000; 14:169-76. 6. Bonellie SR, Raab GM. Why are babies getting he- 12. Schack-Nielsen L, Mølgaard C, Sørensen IAT, Gre- avier? Comparison of Scottish births from 1980 to isen G, Michaelsen KF. Secular change in size at 1992. BMJ 1997; 315:1205. birth from 1973 to 2003: national data from Den- 7. Bralić I, Rodin U, Vrdoljak J, Plavec D, Čapkun V. mark. Obesity 2006; 14:1257-1263. Secular birth weight changes in liveborn infants be- 13. Skjaerven R, Gjessing HK, Bakketeig LS. Birth fore, during, and after 1991-1995 homeland War in weight by gestational age in Norway. Acta Obstet Croatia. Croat Med J 2006; 47:452-8. Gynecol Scand 2000; 79:440-9.

134 Begić et al. Secular trend of anthropometric parameters

14. Odlind V, Haglund B, Pakkanen M, Otterblad OP. 21. Spencer NJ, Logan S, Gill L. Trends and social Deliveries, mothers and newborn infants in Sweden, patterning of birthweight in Sheffield, 1985–94. 1973-2000. Trends in obstetrics as reported to the Arch Dis Child Fetal Neonatal Ed 1999; 81:138–40. Swedish Medical Birth Register. Acta Obstet Gyne- 22. Tutkuviene J, Jakimaviciene EM, Drazdiene N, col Scand 2003; 82:516–28. Blaziene I, Drasutiene G. Changes in body size of 15. Wen SW, Kramer M, Platt R, Demissie K, Joseph newborns in Lithuania, 1974–2004. Coll Antropol KS, Liu S, Sauve R. Secular trends of fetal growth 2007; 31:69–77. in Canada, 1981 to 1997. Paediatr Perinat Epidemiol 23. Gladys GB, Mariotoni AA, Barros F. Birth weight 2003; 7:347–54. and maternal characteristics at the Maternity of 16. Weiner JS, Lourie JA. Human Biology; a guide to Campinas along 25 years. J Pediatr (Rio J) 2000; field methods, International biological programme. 76:55-64. Oxford and Edinburg: Blackwell scientific publica- 24. Tretyak A, Godina E, Zadorozhnaya L. Secular tren- tions, 1969. ds of sizes at birth in Russian infants born between 17. Hadžiselimović R, Lelo S. Bioantropološki prakti- 1987 and 2002. J Physiol Anthropol Appl Human kum. Univerzitet u Sarajevu. Prirodno-matematički Sci 2005; 24:403–6. fakultet, 2000. 25. Silva A A, Barbieri MA, Gomes UA, Bettiol H. Tren- 18. Hadžihalilović J, H.Halilović S, Brahimaj F, Begić ds in low birth weight: a comparison of two birth A, Tupkušić R, Mešalić L. Secular changes of ant- cohorts separated by a 15-year interval in Ribeirão hropometric parameters in newborns from Gračani- Preto, Brazil. Bulletin of the World Health Organi- ca area in the period from 1998 to 2008. Med Arh zation 1998; 76:73-84. 2009; 63:267-70. 26. Begić, A, Halilović J. The Acceleration of birth 19. Statistički godišnjak/Ljetopis Federacije Bosne i weight and birth length of hypotrophic and hyper- Hercegovine. Sarajevo: Federalni zavod za statisti- trophic newborns from Tuzla Canton from 1976 to ku, 2008. 2007. Coll Antropol 2015; 39: 353-62. 20. Elmén H, Hôglund D, Karlberg P, Niklasson A, 27. Fok TF, So HK, Wong E, Ng PC, Chang A, Lau J, N1lsson W. Birth weight for gestational age as a he- Chow CB, Lee WH, and the Hong Kong Neonatal alth indicator. Birth weight and mortality measures Measurements Working Group. Updated gestational at the local area level. European Journal Of Public age specific birth weight, crown-heel length, and Health 1996; 6:137-41. head circumference of Chinese newborns. Arch Dis Child Fetal Neonatal 2003; 88:F229-36.

Sekularni trend antropoloških parametara novorođenčadi u općinama Tuzlanskog kantona (1976–2007) Amela Begić¹, Jasminka H. Halilović¹, Lejla Mešalić2, Sabina H. Halilović¹ ¹Prirodno-matematički fakultet, Odsjek za biologiju, 2Medicinski fakultet; Univerzitet u Tuzli, Tuzla, Bosna i Hercegovina SAŽETAK

Cilj Utvrditi akceleraciju porođajne mase i dužine tijela novorođenčadi po općinama Tuzlanskog kantona u posljednje četiri decenije. Tuzlanski kanton (TK), kao administrativno-teritorijalna jedinica u FBiH, uključuje 13 općina.

Metode Ovo istraživanje predstavlja retrospektivnu studiju u kojoj su korišteni podaci iz knjige protokola Ginekološko-akušerske klinike Univerzitetskog kliničkog centra Tuzla, u periodu od 1976. do 2007. godine. Uzorak živorođene novorođenčadi po općinama podijeljen je u četiri poduzorka: poduzo- rak novorođenčadi rođene 1976, 1987, 1997. i 2007. godine. Tokom promatranih godina u Tuzlanskom kantonu (TK) bilo je 19.312 živorođenih, ali je u istraživanje uključeno 17.907 novorođenčadi oba spo- la. Statistička obrada podataka izvršena je standardnim postupcima deskriptivne i inferentne statistike.

Rezultati Konstatovane vrijednosti sekularnog trenda za porođajnu masu pokazuju da je taj parametar u sedam općina imao pozitivne vrijednosti, dok je u šest općina bio negativan. Najveće vrijednosti pove- ćanja porođajne dužine tijela novorođenčeta, koje su bile statistički značajne, konstatovane su u općini Srebrenik i to je povećanje iznosilo 0,06 cm godišnje.

Zaključak Različite vrijednosti sekularnog trenda u promatranim općinama TK-a rezultat su različitih socioekonomskih i ekoloških uvjeta u tim općinama, kao i nasilnih migracija stanovništva koje su se dešavale kao posljedica rata u BiH u razdoblju od 1992. do 1995. godine.

Ključne riječi: akceleracija, porođajna dužina, porođajna masa.

135 ORIGINAL ARTICLE

Impact of timing on surgical outcome in patients with cauda equina syndrome caused by lumbar disc herniation

Hakija Bečulić1, Rasim Skomorac1, Aldin Jusić1, Fahrudin Alić1, Melica Imamović2, Alma Mekić- Abazović3, Alma Efendić4, Harun Brkić5, Amir Denjalić6

1Department of Neurosurgery, 2Department of Emergency Medicine, 3Department of Oncology and Radiotherapy, 4Department of Radiology; Cantonal Hospital Zenica; 5Neurosurgery Clinic, University Clinical Centre, Tuzla,6Department of Surgery, General Hospital Tešanj; Bosnia and Herzegovina

ABSTRACT

Aim To analyze the relationship between timing of surgery and outcome in patients with cauda equina syndrome caused by lumbar disc herniation.

Methods A retrospective, non-randomized clinical study included 25 consecutive patients with cauda equina syndrome (CES) caused by lumbar disc herniation. All patients were operated within 24 hours after hospitalization at the Department of Neurosurgery, Cantonal Hospital Zenica, Bosnia and Herzegovina, between Janu- ary 2000 and December 2010. All patients were evaluated before surgery on the basis of complete history, neurological examination and neuroimaging evaluations using CT (computed tomography) Corresponding author: and MRI (magnetic resonance imaging). Hakija Bečulić Department of Neurosurgery, Results Statistically significant difference between preoperative and postoperative bladder (p=0.05) and bowel (p=0.05) function Cantonal Hospital Zenica was found. A significant number of patients had bladder and bowel Crkvice 67, 72 000 Zenica, recovery after surgery, nine (36%) and 11 (44%), respectively. Si- Bosna i Hercegovina gnificant recovery of muscle strength was noted with complete re- Phone: +387 32 405 133; covery (5/5) in 12 (48%) and partial recovery in 13 (52%) patients. Fax: +387 32 405 534; Complete sensory recovery was noted in 16 (64%), incomplete E-mail: [email protected] in four (16%), and in five (20%) patients there were no changes. Most commonly, patients with complete sensory recovery were operated within 48 hours of symptom onset. In most patients early surgery was associated with better outcome.

Conclusion This research showed that early decompression corre- Original submission: lated with better outcome. Patients with cauda equina syndrome 15 May 2016; must be cleared for surgery in optimal conditions and, if it possible Revised submission: within optimal timing for recovery (within 48 hours). 27 May 2016; Key words: sphincter dysfunction, early decompression, recovery Accepted: 30 May 2016. doi: 10.17392/861-16

Med Glas (Zenica) 2016; 13(2):136-141

136 Bečulić et al. Cauda equina syndrome

INTRODUCTION Neurological and clinical examination Cauda equina syndrome (CES) is a rare, but de- All patients included in this study had low back vastating neurological condition. The incidence pain and radicular pain before the appearance of CES secondary to lumbar disc herniation is of neurological dysfunction, complete urinary 2–6% (1). In 1929 Dandy first described CES retention, reduction of muscle strength and caused by lumbar disc herniation (2). Etiologies symmetric or asymmetric sensory disturbances of CES include lumbar disc herniation, trauma, specific to CES. Of those 25 patients, 22 (88%) hematomas, spinal anesthesia, metastatic invasi- had a complete and 3 (12%) patients had partial on or other tumors, inflammatory neuropathy, etc. bowel dysfunction. Preoperative and postopera- (3, 4). CES is a clinical diagnosis based on pati- tive muscle strength (six months after operation) ent history and neurological examination. The ra- was evaluated using the Medical Research Co- diological studies, especially magnetic resonance uncil (MRC) scale (0 – no contraction, 1 - flicker imaging (MRI), are used to confirm the diagno- or trace of contraction, 2 - active movement with sis, nature and location of a lesion (5). The signs gravity eliminated, 3 - active movement against and symptoms of CES include low back pain, gravity, 4 - active movement against gravity and unilateral or bilateral sciatica, motor weakness of resistance, 5 - normal power) (8). the lower extremities, sensory disturbances, and All patients had complete urinary retention. Po- loss of bowel or bladder function (6). CES is an stoperative urinary function outcome (six months indication for emergent surgical decompression after the operation) was defined as normal (with (2). Reportedly, early decompression, within 48 complete recovery of bladder function), partial re- hours, is associated with a better outcome (7). tention (with incomplete recovery of bladder func- The aim of this study was to analyze the relati- tion requiring catheterization), and poor (complete onship between timing of surgical intervention retention) (for permanent urinary retention and and outcome in patients with CES caused by requiring catheterization). Of 25 patients, 22 (88%) lumbar disc herniation. had complete and three (12%) patients had partial bowel dysfunction (retention or incontinence). PATIENTS AND METHODS Postoperative bowel function recovery was de- Patients and study design fined as complete, partial and incomplete. All patients had symmetric or asymmetric sensory A retrospective, non-randomized clinical study disturbances specific to CES. Preoperative and included 25 consecutive patients with complete postoperative evaluation of sensation was based cauda equina syndrome (CES) caused by lumbar on 3-point ordinal scale (0 – absent, 1 – impaired, disc herniation. All patients were operated at the 2 – normal) (9). Department of Neurosurgery, Cantonal Hospital We did not evaluate sexual function because the Zenica, Bosnia and Herzegovina, between Janu- study is retrospective and in most cases the data ary 2000 and December 2010. In this period 979 were missing in the patients’ history record. patients with herniated lumbar disc were operated. CES was detected in 25 patients. Patients with Of 25 patients with CES 10 (40%) had CES cau- CES caused by the tumor, vertebral fracture, spi- sed by herniated lumbar disc with consecutive spinal anesthesia, lumbar canal stenosis without si- nal canal stenosis, and in 15 (60%) patients CSE gnificant lumbar disc herniation and patients with was caused by the lumbar disc extrusion. The first spondylolisthesis were excluded from the study. group of patients was surgically treated by microdiscectomy, and the second group by sequestrec- All patients were operated within 24 hours after tomy or sequestrectomy and microdiscectomy. No hospitalization, 22 (88%) of whom were males complications were noticed in any group. and three (12%) were females; patient age was ranging from 29 to 68 years (median 49). Follow up All patients were evaluated before surgery on the All patients underwent postoperative physical basis of complete history, neurological exami- treatment and had a follow up. According to the nation and neuroimaging evaluations including protocol of the Department of Neurosurgery of the computed tomography (CT) and MRI.

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Cantonal Hospital Zenica all patients had the latest Table 1. Preoperative,and six months after surgery bladder and bowel function control examination six months after surgery. No (%) of patients Statistical analysis Preoperative Six months after surgery Function Bladder Bowel Bladder Bowel The methods of descriptive and comparative sta- Retention 25 (100) 23 (92) 7 (28) 7 (28) tistics were used (χ2 and p-test) and the results Partial retention 0 (0) 2 (8) 9 (36) 7 (28) are presented in tables and expressed by relative Normal 0 (0) 0 (0) 9 (36) 11 (44) Total 25 (100) 25 (100) 25 (100) 25 (100) values and mean value. Statistically significant difference was set to p<0.05. Before the surgery all patients had complete urinary retention, reduction of motor power and RESULTS symmetric or asymmetric sensory disturbances specific to CES. Of 25 patients, 22 (88%) had Patients’ characteristics complete, and three (12%) patients had partial Of the total number of 979 patients with hernia- bowel dysfunction. Six months after the surgery ted lumbar disc 25 (2.55%) patients with cauda postoperative recovery of the bladder and bowel equina syndrome were surgically treated at the function was noticed in nine (36%) and 11 (44%) Department of Neurosurgery of the Cantonal patients, respectively (Table 1). Hospital Zenica during the period 2000-2010. The comparison of the preoperative and postoperative bladder function in relation to timing Of those 25 patients, 22 (88%) were males and of surgery showed complete recovery of urinary three (12%) were females with the age ranging function in eight (89%) out of nine patients who from 29 to 68 years (median 49). were operated within 48 hours of onset of neuro- Clinical characteristics logical dysfunction (nine of 25 patients) (Table 2). Only one (11%) patient had partial urinary Low back pain, bilateral or unilateral sciatica retention. Of six (out of 25, 24%) patients who were initial manifestations in all patients before were operated in the period within 2-5 days of the cauda equina syndrome formation. onset of neurological dysfunction, complete re- Duration of radicular and low back pain before covery of urinary function was detected in one the cauda equine symptoms was less than 30 days (16.7%), partial recovery in four (66.7%), and in most patients, 18 (72%); four (12%) patients complete retention in one (16.7%) patient after had symptoms for more than six months, and in 6-month follow up. In 10 (out of 25, 40%) pati- one (4%) and two (8%) patients the duration of ents who were surgically treated after 5 days of these symptoms before CES was six months to onset of neurological dysfunction six (60%) pa- one year and more than one year, respectively. tients had complete urinary retention (Table 2). Duration time from the occurrence of cauda equi- Bowel function recovery was similar to bladder na symptoms, completion of diagnostic evaluation function recovery in patients surgically treated and surgical procedure was less than two days in within 48 hours of neurological dysfunction on- nine (36%), two to five days in six (24%), five to set. In patients who were operated after 48 hours 10 days in five (20%), 10 to 30 days in three (12%), the bowel function recovery was worse than and more than 30 days in only two (8%) patients. bladder one (Table 2). Table 2. Preoperative and postoperative sphincter function in relation to time duration between symptoms onset and surgery Time duration No (%) of patients between symptoms Preoperative Six months after surgery onset and surgery Bladder Bowel Bladder Bowel R PR N R PR N R PR N R PR N Less than 2 days 9 (36) 0 0 8 (32) 1 (4) 0 0 1 (4) 8 (32) 0 1 (4) 8 (32) 2 to 5 days 6 (24) 0 0 5 (20) 1 (4) 0 1 (4) 4 (16) 1 (4) 1 (4) 3 (12) 2 (8) 5 to 10 days 5 (20 0 0 5 (20) 0 0 2 (8) 3 (12) 0 1 (4) 3 (12) 1 (4) 10 to 30 days 3 (12) 0 0 3 (12) 0 0 2 (8) 1 (4) 0 3 (12) 0 0 More than 30 days 2 (8) 0 0 2 (8) 0 0 2 (8) 0 0 2 (8) 0 0 Total 25 (100) 0 0 23 (92%) 2 (8%) 0 7 (28%) 9 (36%) 9 (36%) 7 (28%) 7 (28%) 11(44%) R, retention; PR, partial retention; N, normal

138 Bečulić et al. Cauda equina syndrome

Statistically significant difference between preo- urosurgical technique (sequestrectomy, microdis- perative and postoperative bladder (p=0.05) and cectomy or both). Modality of surgery treatment bowel function (p=0.05) was found, e. g., a signi- included sequestrectomy and microdiscectomy ficant number of patients had bladder and bowel in 13 (52%) patients. Only in two (8%) patients recovery after surgery (Table 2). sequestrectomy was enough, and in 10 (40%) pa- Muscle strength function was evaluated using tients it was fulfilled with microdiscectomy. MRC scale. Complete recovery (5/5) was noted In 15 (80%) patients CT or MRI showed massive in 12 (48%) patients, and partial recovery was lumbar disc extrusion; in 10 (40%) patients si- noted in 13 (52%) patients (4/5, 3/5 and 0/5 in gnificant lumbar disc herniation with consecutive four (16%), 8 (32%) and one patient, respectively spinal canal stenosis was found. (4%) (Figure 1). In most cases surgery was performed on the level L4/L5 (Figure 2). There were no complications noticed. Percentage Percentage

Level of surgery

Figure 2. Level of microneurosurgery (sequestrectomy, microdiscectomy or both) in patients with cauda equine syndrome

Medical Research Council (MRC) scale DISCUSSION Preoperative muscule strenth

Postoperative muscule strenth Cauda equina syndrome (CES) is a rare, but de- vastating clinical condition that has been descri- Figure 1. Preoperative and postoperative muscle strength according to Medical Research Council (MRC) scale bed as a complex of symptoms and signs such as low back pain, unilateral or bilateral sciatica, Complete sensory recovery was noted in 16 motor weakness of lower extremities, sensory (64%) patients, incomplete in 4 (16%) and no disturbance in the saddle area, urinary retention changes were found in 5 (20%) of all patients. or overflow incontinence, constipation or fecal Most patients with complete sensory recovery incontinence (2,5). CES can be caused by many were operated within 48 hours of onset of symp- conditions such as lumbar disc herniation, lumbar toms. Complete sensory recovery occurred in spinal canal stenosis, trauma, hematoma, tumors, 11 (44%) patients, who were operated within 48 infection etc. (10,11). Lumbar disc herniation is hours of onset of symptoms, and 5 (20%) pati- the most common cause of CES. CES occurs in ents, who were operated after 48 hours of onset approximately 2-6% of cases of herniated lumbar of symptoms and had partial sensory recovery. disc and it is one of the few spinal surgical emer- Persistent sensory deficit was noticed in 9 (36%) gencies (1,5,12,13). In our study the prevalence patients (data are not shown). of CES among 979 patients surgically treated at In most patients early surgery was associated our department in the ten year period was 2.55 %. with a better outcome (Table 1, 2). Those data correspond to the literature (14). In the literature, CES caused by lumbar disc her- Surgery and complications niation is most common in middle-aged male All patients were urgently evaluated (neurologi- patients (15-17), which corresponds with our re- cal examination, laboratory, CT or/and MRI) and sults. In this study patients mostly had previous they underwent surgery within 24 hours of hospi- low back pain and sciatica, which is in concor- talization. The patients were treated by microne- dance with the literature (2-5, 18, 19).

139 Medicinski Glasnik, Volume 13, Number 2, August 2016

There is controversy about timing of surgical de- suboptimal conditions. Such patients were sche- compression in CES and its influence on outco- duled for surgery for next day when more quali- me. Some studies suggested that early decompre- fied staff and optimal conditions were available. ssion within 48 hours is associated with better Following surgery, the extent of recovery is va- outcome (3, 11, 12, 16, 20). A significant impro- riable. Some patients have pain, problems with vement in sensory and motor deficits as well as the bladder or bowel. Recovery of these func- urinary and rectal function occurred in patients tions depends on the duration and severity of who underwent decompression within 48 hours symptoms prior to surgery (1-5, 16). versus after 48 hours (14, 15, 21-23). Some stu- CES most commonly occurs in intervertebral disc dies suggested that there was no statistically si- herniation at the L4/L5 level (5, 12, 16). The re- gnificant difference in outcome between patients sults of our research correspond with the literature. who were operated within 48 hours and patients who were operated after 48 hours (5, 24, 25). In conclusion, although the controversies exist about the timing of surgery in patients with CES, Most researchers and clinicians now believe that our research showed that early decompression a good outcome can be achieved in patients who correlated with better outcome. Delayed surgery undergo surgery within 48 hours of onset of neu- could lead to potentially persistent neurological rological dysfunction, while significantly poorer dysfunction, but emergent surgery in suboptimal outcomes are associated with surgical interventi- conditions (late night or midnight) could expo- on after 48 hours (3, 12, 16, 20, 25-28). se patients to additional risk. For this reason, the The results of our study show that early decom- patients with cauda equina syndrome may be cle- pression was associated with better outcome. ared for surgery in optimal conditions and, if po- In practice, CES is a condition that requires ssible within optimal timing for recovery (within immediate surgery. It should not be forgotten 48 hours). that delayed treatment could lead to significant morbidity and potential persistent neurological FUNDING dysfunction (1,3,16). On the other hand, emer- No specific funding was received for this study. gent decompression could expose the patient to additional risk (16). For that reason we did not TRANSPARENCY DECLARATIONS perform CES surgery late at night or midnight in Competing interest; none to declare.

REFERENCES 8. Paternostro-Sluga T, Grim-Stieger M, Posch M, Schuhfried O, Vacariu G, Mittermaier C, Bittner C, 1. Gleave JRW, Macfarlane R. Prognosis of recovery Fialka-Moser V. Reliability and validity of the Me- of bladder function following lumbar central disc dical Research Council (MRC) scale and a modified prolapse. Br J Neurosurg 1990; 4:205-10. scale for testing muscle strength in patients with ra- 2. Adam D, Hornea I. Cauda equina syndrome secon- dial palsy. J Rehabil Med 2008; 40:665-71. dary to lumbar disc herniation. Report of three cases. 9. Maynard FM, Bracken MB, Creasey GJ, Ditunno JF, Romanian Neurosurgery 2013; 3:258-63. Donovan WH, Ducker TB, Garber SL, Marino RJ, 3. DeLong B, Polissar N, Neradilek B. Timing of sur- Stover SL, Tator CH, Waters RL. International stan- gery in cauda equina syndrome with urinary reten- dards for neurological and functional classification tion: meta – analysis of observational studies. JNS of spinal cord injury. Spinal cord 1997; 35:266-74. 2008; 8:305-20. 10. Jun W, Yi-Jun K, Xiang-Sheng Z, Jing W. Cauda 4. Başol B, Deniz FE, Gökçe E, Şahin F. A young pa- equina syndrome caused by a migrated bullet in du- tient with acute cauda equina syndrome due to trau- ral sac. Turk Neurosurg 2010; 20:566-9. matic disc herniation. JAEMCR 2015; 6:81-3. 11. Song H, Song Q, Sun C, Yu L, Wang Z, Li Y. Early 5. Gitelman A, Hishmeh S, Morelli BN, Joseph surgery predicts a better prognosis of urinary functi- SA,Casden A, Kuflik P, Neuwirth M, Stephen M. on in cauda equina syndrome with retention: a syste- Cauda equine syndrome: a comprehensive review. matic review and meta-analysis. Int J Clin Exp Med Am J Orthop 2008; 37:556-62. 2016; 9:544-51. 6. Nascone JW, Lauerman WC, Wiesel SW. Cauda 12. Kostuik JP, Harrington I, Alexander D, Rand W, equina syndrome: is it a surgical emergency? The Evans D. Cauda equine syndrome and lumbar disc University of Pennsylvania Orthopedic Journal herniation. J Bone Joint Surg Am 1986; 68:386-91. 1999; 12:73-6. 13. Henriques T, Olerud C, Petren-Mallmin M, Ahl T. 7. Bin M, Hong W, Lian-Shun J, Wen Y, Guo-Dong S, Cauda equina syndrome as a postoperative compli- Jian-Gang S. Cauda equina syndrome: a review of cation in five patients operated for lumbar disc her- clinical progress. Chin Med J 2009; 122:1214-22. niation. Spine 2001; 26:293-7.

140 Bečulić et al. Cauda equina syndrome

14. Gardner A, Gardner E, Morley T. Cauda equina syn- on surgical outcome. Eur Spine J 2007; 16:2143-51. drome: a review of the current clinical and medico- 22. Chau AMT, Liang Xu L, Pelzer NR, Gragnaniello legal position. Eur Spine J 2011; 20:690-7. C. Timing of surgical intervention in cauda equina 15. Ahn Um, Ahn NU, Buchowski JM, Garret ES, Sie- syndrome: a systematic critical review. World Neu- ber AN, Kostuik JP. Cauda equina syndrome secon- rosurg 2014; 81:640-50. dary to lumbar disc herniation: a meta-analysis of 23. Raj D, Coleman N. Cauda equina syndrome secon- surgical outcomes. Spine 2000; 25:1515-22. dary to lumbar disc herniation. Acta Orthop Belg 16. Shapiro S. Medical realities of cauda equina syndro- 2008; 74:522-7. me secondary to lumbar disc herniation. Spine 2000; 24. Hussain SA, Gullan RW, Chitnavis BP. Cauda equi- 25:348-51. na syndrome: outcome and implications for manage- 17. Lavy C, James A, Wilson-MacDonald J, Fairbank J. ment. Br J Neurosurg 2003; 17:164-7. Cauda equina syndrome. BMJ 2009; 338:881-4. 25. MCarthy MJ, Aylott CE, Grevitt MP, Hegarty J. 18. Buchner M, Schiltenwolf M. Cauda equina syndro- Cauda equina syndrome: factors affecting long-term me caused by intervertebral disc prolapse: mild-term functional and sphincteric outcome. Spine 2007; results of 22 patients and literature review. Orthope- 32:207-16. dics 2002; 25:727-31. 26. Sonntag VK. Why not decompress early? The cauda 19. Celik EC, Kabatas S, Karatas M. Atypical presenta- equina syndrome. World Neurosurg 2014; 82:70-1. tion of cauda equina syndrome secondary to lumbar 27. Lee KY, Lim YH, Kim SH. Prognostic factors of cli- disc herniation. Journal of back and musculoskeletal nical outcome of postoperative cauda equina syndro- rehabilitation 2012; 25:1-3. me. J Korean Soc Spine Surg 2014; 21:30-35. 20. Nisaharan S, Alexander M, Simon C, John M. 28. Dhatt S, Tahasildar N, Tripathy SK, Bahadur R, Does early surgical decompression in cauda equina Dhillon M. Outcome of spinal decompression in syndrome improve bladder outcome. Spine 2015; cauda equina syndrome presenting late in develo- 40:580-3. ping countries: case series of 50 cases. Eur Spine J 21. Qureshi A, Sell P. Cauda equina syndrome treated 2011; 20:2235-9. by surgical decompression. The influence of timing

Utjecaj vremena do operacije na ishod kodpacijenata sa sindromom kaudeekvine uzrokovane lumbalnom diskushernijom Hakija Bečulić1, Rasim Skomorac1,Aldin Jusić1,Fahrudin Alić1, MelicaImamović2, Alma Mekić-Abazović3, Alma Efendić4, Harun Brkić5, Amir Denjalić6

1Služba zaneurohirurgiju, 2Služba zaurgentni i redovniprijembolesnika, 3Služba zaonkologiju i radioterapiju, 4Služba zaradiologiju;Kantonalna bolnicaZenica; 5Klinikazaneurohirurgiju,Univerzitetski kliničkicentar Tuzla,6Odjeljenje hirurgije, OpćabolnicaTešanj; Bosna i Hercegovina SAŽETAK

Cilj Ispitati povezanost između vremena proteklog do operacije i ishodak od pacijenata sa sindromom kaudeekvine. Metode Retrospektivna, nerandomizirana klinička studija uključila je 25 pacijenata sa sindromom kaudeekvine (CES)uzrokovane lumbalnom diskushernijom. Svi pacijenti uključeni u studiju operirani su unutar 24 sata od hospitalizacije u Službi za neurohirurgiju Kantonalne bolnice Zenica, u periodu od januara 2000. do decembra 2010. godine. Svi pacijenti su preoperativno dijagnostički obrađeni, što je uključivalo historiju bolesti, neurološki pregled, neuroradiološku obradu korištenjem CT-a (kompjute- rizirana tomografija) i MRI-a (magnetna rezonanca). Rezultati Ustanovljena je statistički značajna razlika između preoperativnog i postoperativnog nalaza funkcije pražnjenja mokraćnog mjehura (p=0,05) i pražnjenja crijeva (p=0,05).Značajan broj pacijenata imao je potpun oporavak funkcije pražnjenja mokraćnog mjehura i crijeva nakon operacije, 9 (36%), odnosno 11 (44%). U većini slučajeva je registriran značajan oporavak grube mišićne snage, potpun oporavak kod 12 (48%), a djelomičan kod 13 (52%) pacijenata.Kompletan oporavak senzibiliteta za- bilježen je kod 16 (64%) pacijenata, parcijalan kod 4 (16%), dok kod 5 (20%) pacijenata nije bilo promjena u odnosu na period prije operacije. Većina pacijenata s kompletnim oporavkom grube mišićne snage i senzibiliteta operirana je unutar 48 sati od pojave neurološkog deficita.Kod većine pacijenata rani operativni zahvat je rezultirao boljim ishodom. Zaključak Istraživanje je pokazalo da rana dekompresija rezultira boljim ishodom kod pacijenata sa sindromom kaude ekvine. Pacijenti sa sindromom kaude ekvine trebaju biti planirani za operativni zahvat u optimalnim uvjetima i, ukoliko je moguće, u optimalnom periodu (unutar 48 sati). Ključne riječi: sfinkterijalna disfunkcija, rana dekompresija, oporavak

141 ORIGINAL ARTICLE

Radiological evaluation of lumbosacral spine for post discectomy segmental instability

Rasim Skomorac1, Jasmin Delić2, Hakija Bečulić1, Aldin Jusić1

1Department of Neurosurgery, Canton Hospital Zenica, 2Department of Anatomy, School of Medicine Tuzla; Bosnia and Herzegovina

ABSTRACT

Aim To establish presence of segmental instability in patients operated with standard discectomy comparing measurement of translation and rotation on postoperative functional radiographs of lumbosacral spine with reference values,and to explore difference between patients operated on one or two levels.

Methods The study included 71 patients, who were operated due to herniated lumbar disc. They were divided into two groups operated on one level (group A) or two adjacent levels (group B). All patients had been imaged in a standing position with functional lateral radiography. Radiographic images were digitized and then computerized measurement of translation and rotation was made. Measurement data were compared between the groups and with reference values obtained in healthy adults.

Results Standard lumbar discectomy leads to an increase in Corresponding author: translation, however, it reached statistical significance only for L4/ Rasim Skomorac L5 level and a decrease of rotation, which showed statistical signi- Department of Neurosurgery, ficance for all samples, relative to the reference values. There was Cantonal Hospital Zenica no statistically significant difference in the values of translation Crkvice 67, 72000 Zenica, and rotation between the groups for corresponding levels, except for the value of the rotation for L4/L5 level as adjacent, unope- Bosnia and Herzegovina rated level. Comparison of translation and rotation between the Phone: +38732424650; operated and adjacent levels did not show a statistically significant Fax: +38732405534; difference. When it comes to comparing the measured and predic- E-mail: [email protected] ted translation, there was a statistically significant difference only at the L5/S1 as an unoperated level.

Conclusion Standard discectomy does not lead to radiologically significant segmental instability, and two-level surgery has not Original submission: caused more pronounced signs of instability comparing to one- 04 May 2015; level surgery. Revised submission: Key words: instability, spine, discectomy, flexion-extension radi- 01 July 2015; ographs Accepted: 13 May 2016. doi: 10.17392/817-16

Med Glas (Zenica) 2016; 13(2):142-147

142 Skomorac et al. Postoperative lumbar spine instability

INTRODUCTION stoperative stabilization after two-level surgery or wait for signs of clinical instability. Clinical instability is defined as an abnormal response to applied loads on the spine and is often There has been a constant debate on the nece- characterized by excessive mobility of the spinal ssity of spinal fusion after discectomy because of segment. In many cases the instability is identified the difficulties in intervertebral instability asse- only by functional radiography, but this technique ssments as a result of anatomical position of disc has limited reproducibility(1). Many surgeons use herniation and loss of the intervertebral disc(5). flexion-extension lateral views to disclose abnor- In modern spinal surgery solutions for this pro- mal vertebral motion before deciding on surgical blem can be either stabilization and fixation or fusion (2). However, this method is challenging lumbar arthroplasty. and debatable for the following three reasons: (a) In available literature we did not find a study its diagnostic value cannot be determined because comparing either radiological or clinical data of the lack of a non-traumatic and routinely appli- between patients with discectomy done on one cable reference standard to define intervertebral in- or two levels. stability; (b)its reproducibility is difficult, a slight variation in patient positioning or in the direction PATIENTS AND METHODS of the x-ray beam may result in a 10–15% variation in the range of vertebral displacement; (c)the Patients appropriate way to obtain flexion-extension radio- This prospective study involved 71 patients of graphs and the method to measure displacements both sexes aged 18-65 years, operated at the De- is still not standardized (3). There is no single mo- partment of Neurosurgeryof Cantonal Hospital dality that discriminates with sufficient certainty Zenica, Bosnia and Herzegovina, in the period “normal” and “abnormal” movement, questioning 2001-2007. All patients had lumbar disc hernia- the value of imaging methods for the diagnosis tion diagnosed by CT (computed tomography) of instability (1). A significant barrier for certain imaging or MRI (magnetic resonance imaging). diagnosis is non-specific nature of back pain and The patients were divided into two groups:group uncertain relationship between instability and pain A (35 patients) operated on one level, and group (1). Clinical instability of the spine is defined as B (36 patients) operated on two adjacent levels. a loss of spine’s ability to maintain its patterns of displacement under physiologic loads so there is Methods no initial or additional neurologic deficit, no major All patients 3-9 years postoperatively underwent deformity and no incapacitating pain (4). functional lateral radiography in flexion and Standard discectomy is a surgical procedure that extension in a standing position. Radiographs involves lesion of several anatomical structures were digitized and computerized measurement important for the stability of the spine and can of translation and rotation was done, using abso- lead to compromising segmental stability, especi- lute numbers by a modified method described ally if it is made at two adjacent levels. There is no previously by Brinckman et al. (6) and Frobin et agreement between surgeons whether to do two- al. (7). As a basis for measuring the four points level discectomy or not, because of the fear of on the body of vertebra were used, which can consecutive instability. In our material we had a be always identified on radiographs. Raw data considerable number of patients operated on two cannot be compared directly because the moti- levels, but we did not notice a clinical difference vation, pain or muscle spasms, the extent of ro- in the outcome. Since there is an agreement that tation and translation will vary from normal.The discectomy can lead to radiological instability we predicted value of translation was based on the decided to investigate and compare radiological following formula: Translation (predicted) = Ro- data of post discectomy spine with reference data tation (measured) x TPR (translation per degree from healthy adults and to compare data between of rotation).A comparison of the measured values patients operated on one or two levels. This study of individual translation with set points enables can help neurosurgeons and other spine surgeons quantification of mobility to normal, hyper-or to decide whether they should do immediate po- hypo mobility (7).

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The degree of translation and rotation on posto- Table 1. Cumulative measurement results for translation, perative functional radiographic images of lum- rotation and predicted translation on postoperative functional images for 71 patients operated on one/two adjacent levels bosacral spine was determined in patients opera- Rotation Translation (abso- Predicted No of ted with standard discectomy and compared with Level (degrees) lute numbers) translation patients reference values established by measurements in (SD) (SD) (SD) healthy adults:rotation (in degrees) L2/L3 13.9; L2/L3 1 10.51 L3/L4 14.2; L4/L5 16.4; L5/S1 13.2; translation 2.87 -0.03 -0.011 L3/L4 9 L2/L3 -0.0444; L3/L4 -0.0498; L4/L5 -0.0511; (5.54) (0.06) (0.021) 4.23 -0.02 -0.014 L4/L5 49 L5/S1 0.0017; TPR (translation per degree of ro- (6.05) (0.065) (0.021) 4.17 -0,007 -0.001 tation) L2/L3 -0.00325; L3/L4 -0.00371; L4/L5 L5/S1 45 (6.24) (0.057) (0.006) – 0.00313; L5/S1 -0.00012(6),It was compared- -0.31 0.021 0.00004 S1/S2 2 between patients operated on one level and the (3.15) (0,081) (0.0004) 4.46 -0.038 -0.01398 patients operated on two levels. L2/L3 adjacent 8 (4.94) (0.0598) (0.01658) 4.60 -0.038 -0.02011 L3/L4 adjacent 41 Statistical analysis (3.90) (0.0649) (0.0259) 5.15 -0.031 -0.0225 L4/L5 adjacent 22 To test the statistical significance of the difference (6.18) (0.042) (0.0249) 0.97 0.0254 -0.0003 between the measured parameters in comparison L5/S1 adjacent 24 (6.83) (0.0466) (0.0011) with the reference values, as well as between the SD, standard deviation group A and B, ANOVA test, t-test for dependent and independent samples and post hoc experiment Table 2. Measurement results for translation and rotation on (LSD) were used.The threshold for statistical si- postoperative functional images for 35 patients operated on gnificance was taken at p<0.05.T-test was applied one level Rotation Translation Predicted for independent samples and compared the obtai- No of Level (degrees) (absolute num- translation patients ned values of rotation and translation after surgery (SD) bers) (SD) (SD) in the total sample (both groups together), both 3.066 -0.0187 -0.012 L4/L5 16 operated and adjacent unoperated levels, with re- (6.196) (0.06799) (0.0238) 2.43 -0.0073 -0.0007 L5/S1 19 ference values and also for both groups separately. (5.54) (0.0543) (0.0012) 4.66 -0.0203 -0.0161 ANOVA test was used for comparing values of L3/L4 adjacent 16 translation and rotation between the groups A and (4.099) (0.05796) (0.0153) 3.99 -0.0295 -0.0192 L4/L5 adjacent 19 B for corresponding levels. (5.696) (0.0384) (0.0249) -0.285 0.0188 -0.0002 L5/S1 adjacent 16 RESULTS (7.81) (0.0496) (0.00137) SD, standard deviation In the patients operated on one level (group A), 16 patients were operated on L4/L5 and 19 pati- Table 3. Measurement results for translation, rotation and ents on the L5/S1 level. predicted translation on postoperative functional images for In the patients operated on two levels (group B), 36 patients operated on two adjacent levels Rotation Translation Predicted one patient was operated on L2/L3/L4 levels, No of Level (degrees) (absolute num- translation patients eight on L3/L4/L5 levels, 25 on L4/L5/S1, and (SD) bers) (SD) (SD) two patients operated on L5/S1/S2 levels. 2.87 -0.03 -0.011 L3/L4 9 (5.54) (0.06) (0.021) After measurements postoperative values of 4.79 -0.02 -0.014 L4/L5 33 translation and rotation for the whole sample (5.99) (0.063) (0.0204) 5.44 -0.007 -0.0019 L5/S1 27 were established (Table 1), and separately for (6.52) (0.061) (0.008) group A and group B (Tables 2 and 3). -0.32 0.021 0.00004 S1/S2 2 (3.15) (0.081) (0.00038) Statistically significant difference (p<0.05) for 4.46 -0.038 -0.01398 L2/L3 adjacent 8 all levels (L2/L3; L3/L4; L4/L5 and L5/S1)was (4.94) (0.0598) (0.0166) 4.56 -0.049 -0.0226 found for rotation(decreased).Translation for all L3/L4 adjacent 25 (3.85) (0.0678) (0.03088) levels operated and adjacent (L2/L3; L3/L4; L4/ 12.51 -0.04 -0.0435 L4/L5 adjacent 3 L5 and L5/S1)was increased, except for L5/S1as (3.84) (0.07158) (0.0120) 3.01 0.036 -0.00036 L5/S1 adjacent 8 an operated level,where it was decreased. Increa- (4.57) (0.04202) (0.00055) se in translation reached a statistically significant SD, standard deviation

144 Skomorac et al. Postoperative lumbar spine instability

difference (p<0.05) only for the L4/L5 level, ope- Post hoc experiment showed that the difference rated and unoperated. originated between the levels L4/L5 and L5/S1 In the group A, statistically significant decrease (p=0.007). (p<0.01) was found for all levels for the rotation, The comparison of the total value of translation operated and adjacent, while for the translation and rotation on the whole sample between the statistically significant increase (p<0.05) was fo- operated and adjacent, unoperated levels, showed und for adjacent level L3/L4 and for L4/L5 level no statistically significant difference, as well as as the adjacent and operated. In group B, the ro- the comparison between operated and adjacent tation was significantly different (p <0.01) for all levels within the groups. operated and adjacent levels, and it was decreased. A statistically significant increase (p<0.05) for A statistically significant increase in translation measured and predicted translation was found (p<0.05) was found for treated L4/L5 level and for in the whole sample at the level L5/S1, when it L5/S1, as an adjacent level (Figure 1). was not a treated level. When values were compared within the groups, a statistically significant increase (p<0.05) was also found for unoperated, adjacent L5/S1 level, in group B.

DISCUSSION This study investigated radiological data (segmental translation and rotation) of post discectomy spine and compared them with reference data from healthy adults, as well as between patients operated on one or two levels. Direct comparison of the results of our study with other studies is not possible because of methodological differences and non-existence of similar studies in the literature comparing patients with discectomy done on one Figure 1. Relationship between translation on operated level or two levels. In our earlier work we tried to iden- L4/L5 and reference values by groups tify signs of segmental instability on postoperative standard lateral radiographic images of the lumbo- A statistically significant difference between the sacral spine after discectomy on one or two levels groups (p<0.05) was found only for the rotation measuring height of disc space (HD), the angle at the L4/L5 level in the case of neighboring, between adjacent vertebrae (A) and translation unoperated level, and it was significantly higher (T). Comparison of preoperative with postope- in group B (p=0.022). Comparing the aggregate rative values showed that in patients operated on value of translation and rotation between the gro- one level there was a statistically significant diffe- ups, the statistically significant difference in the rence in HD, while in the other two parameters, rotation was found, and it was higher in group there were no statistically significant differences. B(p<0.05), but not for translation. In patients operated on two levels, we revealed a Comparison of translation and rotation between significant difference in preoperative and posto- different levels, for the total sample, showed a perative values for HD and A, while for T there statistically significant difference in translation was no statistically significant difference(8).White (p<0.05), but not for rotation. Post hoc experi- and Panjabi defined the criteria for the diagnosis ment (LSD) differentiated statistically signifi- of instability from flexion/extension images as a cant difference between the levels for transla- translation greater than 4.5 mm or more than 15% tion for L5/S1 compared to levels L3/L4 and of width of the vertebral body, or rotation greater L4/L5. than 15% at L1/L2, L2/L3 and L3/L4, greater than An analysis within the groups showed a stati- 20% at L4/L5 and greater than 25% at L5/S1 (4). stically significant difference between the le- Sagittal translation has a greater effect than se- vels for translation within group B (p=0.024). gmental angulation on lumbar symptoms and the

145 Medicinski Glasnik, Volume 13, Number 2, August 2016

presence of two radiological factors may be in- spinal mobile segment (16). Other authors repor- dicators of the presence of symptoms (9).There ted that at the place of surgical violation there can be different types of instability: rear opening, was less translational and rotational instability anterior translation in flexion, rear sliding in in subtotal than the total discectomy, but instabi- extension, or combinations of those(10).Segmen- lity at the level above is present regardless of the tal stability was radiographically investigated in volume of the removed nucleus (17). This is not 50 patients after standard discectomy using the confirmed in our study. Sato’s method of instability classification and it Standard discectomy inevitably leads to some was found that in 30 cases the images showed radiological changes postoperatively, which can instability,but there were only 9 symptomatic pa- be detected and measured differently. The re- tients (11). sults of present study suggest that there are no Different studies using different methods gained enough elements to conclude that standard dis- often contradictory results. A study comparing se- cectomy on one or two levels, conducted with gmental motion in the early postoperative phase maximum preservation of bony and ligamentous after lumbar discectomy and outcome after five elements, leads to statistically significant incre- years suggests that the increased initial displa- ase in translation, which is agreed to be a more cement of the vertebra in the early postoperative important element for proclaiming instability. phase was associated with poor clinical outcome Statistically significant decrease in rotation can (12). Others showed that the intervertebral angle be more connected with pronounced stiffness in flexion and a range of motion were the most than instability. There are no enough arguments important prognostic parameters for lumbar dis- against two level discectomy when it is needed, traction instability and medial facetectomy with as long as we adhere to surgical principles of removal of the rear ligament complex decreases minimal invasiveness and saving of bony and li- stiffness by 15% (13). Resection of bone or liga- gamentous structures. There is also no place for mentous posterior elements has a minor effect on immediate postoperative stabilization in case of the bio-mechanical characteristics of the adjacent two level discectomy. levels (14). The study using radiographic analysis before and three months after surgery showed a FUNDING significant increase in the range of motion in pa- No specific funding was received for this study. tients with fenestration and limited discectomy (15). Hou et al. showed that partial discectomy TRANSPARENCY DECLARATION significantly affected the stability of the lumbar Competing interests: None to declare.

REFERENCES 1. Ferguson S. Biomechanics of the Spine. In: Boos N, 6. Brinckmann P, Frobin W, Biggemann M, Hilweg D, Aebi M. Spinal Disorders Fundamentals of Diagno- Seidel S, Burton K, Tillotson M, Sandover J, Atha J sis and Treatment. 1sted.Berlin Heidelberg:Springer- and Quinnell R. Quantification of overload injuries Verlag, 2008: 42-60. to thoracolumbar vertebrae and disc in persons expo- 2. Leone A, Cassar-Pullicino VN, Guglielmi sed to heavy physical exertions or vibrations at the G,Bonomo L. Degenerative lumbar interverte- work-place. Part I. The shape of vertebrae and inter- bral instability:what is it and how does imaging vertebral discs-Study of young, healthy population contribute?Skeletal Radiol 2009; 38:529–33. and a middle aged control group. ClinBiomech 1994 3. Nizard R, Wybier M, Laredo JD. Radiologic asse- (Suppl 1):S1-S83, ssment of lumbar intervertebral instability and de- 7. Frobin W, Brinckmann P, Leivseth G, Biggemann generative spondylolisthesis. RadiolClin North Am M, Reikerås O. Precision measurement of segmental 2001; 39:55-71. motion from flexion - extension radiographs of the 4. White AA, Panjabi MM (Eds.) Clinical Biomecha- lumbar spine. ClinBiomech 1996; 11:457-65. nics of the Spine. 2nd ed. Philadelphia: Lippincott, 8. Skomorac R, Delić J, Jusić A, Bečulić H, Bajtarević 1990, 23-45. A, Hadžić E. Morphometric changes of the lumbar 5. Young DK, Seung JR, Dong JK. Radiological and intervertebral space following discectomy on one or clinical outcome after simple discectomy of central two levels. Med Glas(Zenica) 2011; 8:249-54. massive lumbar disc herniation J Korean Soc Spine Surg 2010; 17:169-76.

146 Skomorac et al. Postoperative lumbar spine instability

9. Iguchi T, Kanemura A, Kasahara K, Sato K, Kurihara of radiographic parameters indicating anterior co- A, Yoshiya S. Lumbar instability and clinical symp- lumn support in lumbar spinal fusion. Spine 2003; toms: which is the more critical factor for symptoms: 28:2368-72. sagittal translation or segment angulation?J Spinal 14. Zander T, Rohlmann A, Klockne C, Bergmann G. In- Disord Tech 2004; 17:284-90. fluence of graded facetectomy and laminectomy on 10. Sato H, Kikuchi S. The natural history of radio- spinal biomechanics. Eur Spine J 2003; 12:427-34. graphic instability of the lumbar spine. Spine 1993; 15. Tibrewal SB, Pearcy MJ, Portek I, Spivey J. A pros- 18:2075-79. pective study of lumbar spinal movements before 11. Padua R, Padua S, Romanini E, Padua, De Santis and after discectomy using biplanar radiography: E. Ten- to 15-year outcome of surgery for lumbar correlation of clinical and radiographic findings. disc herniation: radiographic instability and clinical Spine 1985; 10:455-60 findings. Eur Spine J 1999; 8:70-4. 16. Hou TS, Tu KY, Xu YK, Zhang WM, Wang HC, 12. Halldin K, Zoëga B, Kärrholm J, Lind BI, Nyberg Wang DL. Effect of partial discectomy on the stabi- P. Is increased segmental motion early after lumbar lity of the lumbar spine. A study of kinematics. Chin discectomy related to poor clinical outcome 5 years Med J (Engl) 1990; 103:396-9. later? IntOrthop 2005; 29:260-4. 17. Goel VK, Goyal S, Clark C. Kinematics of the who- 13. Kanayama M, Hashimoto T, Shigenobu K, Oha F, le lumbar spine: effect of discectomy. Spine 1985; Ishida T, Yamane S. Intraoperative biomechanical 10:543-54. assessment of lumbar spinal instability: validation

Radiološka evaluacija segmentne nestabilnosti lumbosakralne kičme nakon diskektomije Rasim Skomorac1, Jasmin Delić2, Hakija Bečulić1, Aldin Jusić1 1Služba za neurohirurgiju, Kantonalna bolnica Zenica, 2Katedra za anatomiju, Medicinski fakultet Tuzla; Bosna i Hercegovina

SAŽETAK

Cilj Ustanoviti prisustvo segmentne nestabilnosti kod pacijenata operisanih standardnom diskektomi- jom, upoređujući mjerenja translacije i rotacije na postoperativnim funkcionalnim rtg-snimcima lumbosakralne kičme s referentnim vrijednostima i ispitati postojanje razlike između pacijenata operisanih na jednom ili dva nivoa.

Metode U studiju je uključen 71 pacijent, operisan zbog hernije lumbalnog diska. Pacijenti su bili podijeljeni u dvije grupe: operisani na jednom nivou (grupa A) ili na dva nivoa (grupa B). Svim pacijentima su napravljeni funkcionalni lateralni rtg-snimci lumbosakralne kičme ustojećem položaju. Radiografski snimci su digitalizirani, a potom su načinjena kompjuterska mjerenja translacije i rotacije. Dobijena mjerenja su komparirana između grupa, kao i s referentnim vrijednostima dobijenim kod zdravih odra- slih osoba.

Rezultati Standardna lumbarna diskektomija dovela je do povećanja translacije koje je statistički zna- čajno samo za nivo L4/L5 i smanjenja rotacije koje je statistički značajno za cijeli uzorak, upoređujući s referentnim vrijednostima. Nije ustanovljena statistički značajna razlika u vrijednostima translacije i rotacije između grupa, za odgovarajuće nivoe, osim za vrijednosti rotacije na L4/L5 nivou, kao su- sjednom, neoperisanom nivou. Poređenje translacije i rotacije između operisanih i susjednih neoperisa- nih nivoa nije pokazalo statistički značajnu razliku. Kod usporedbe vrijednosti izmjerene i predviđene translacije, ustanovljena je statistički značajna razlika samo za nivo L5/S1(neoperisani nivo).

Zaključak Standardna diskektomija ne dovodi do radiološki značajne segmentne nestabilnosti, a ope- racija na dva susjedna nivoa ne uzrokuje izraženije znake segmentne nestabilnosti, u poređenju s dis- kektomijom na jednom nivou.

Ključne riječi: nestabilnost, kičma, diskektomija, funkcionalna radiografija

147 ORIGINAL ARTICLE

Application of high viscosity bone cement in vertebroplasty for treatment of painful vertebral body fracture

Saša Rapan, Karin Krnić, Vjeran Rapan, Vjekoslav Kolarević

Department of Orthopedic Surgery, University Hospital Centre Osijek, Osijek, Croatia

ABSTRACT

Aim To evaluate the effectiveness and complication of vertebroplasty with high viscosity cement (HVC).

Methods The patients with intensive pain caused by a fractured vertebrae were treated by application of HVC into the vertebral body, through unilateral transpedicular approach. The application was performed in 422 patients (221 were treated for osteoporosis and 201 for malignancy) on 846 vertebrae.

Results Preoperative Visual Analogue Scale (VAS) score was 8.35 and 2.21 (p<0.00001) 24 hours after surgery and 3 months later, respectively. There was no serious intra- and post-surgery compli- Corresponding author: cation. By diascopy during the surgery in 121 (14.3%) vertebrae Saša Rapan cement leakage from the fractured vertebral body was evidenced, Department of Orthopedic Surgery, which did not cause any aggravation of patients’ clinical status. Clinical Hospital Centre Osijek Huttlerova 4, 31000, Osijek, Croatia Conclusion Vertebroplasty with HVC is a method that successfully combines all advantages of this method but it also minimi- Phone: +385 31 511 802; zes the risk of extra-ossal cement leakage which makes it signifi- Fax: +385 31512 229 cantly safer for the surgeon and for the patient as well. E-mail: [email protected] Key words: bone cement, vertebral augmentation, Visual Analo- gue Scale

Original submission: 17 November 2015; Revised submission: 27 April 2016; Accepted: 07 May 2016. doi: 10.17392/842-16

Med Glas (Zenica) 2016; 13(2):148-153

148 Rapan et al. Vertebroplasty with high viscosity cement

INTRODUCTION jek. Ethics Committee of Clinical Hospital Osi- jek approved of this research. Compressive vertebral fracture is a frequent complication caused by osteoporosis and expan- The research covered patients with pain in the sion of malignant tumors into the skeleton (1). back caused by osteoporotic vertebral fractures, Frequency of these fractures increases with the who did not react positively to the conservative population age, and they include compression, method of treatment, or caused by a malignant collapse and wedging of the body causing kyp- process (hemangioma, multiple myeloma meta- hosis (1). Such fractures lead to the significant stasis) with or without previously performed hor- rate of morbidity and mortality, nourishment dis- monal, radio or chemotherapy. orders, lungs function troubles, lack of self-reli- For the purpose of the method efficiency eva- ance, increased pain and psychic disorder caused luation, all patients filled in the visual analogue by pain and drugs (1). scale (VAS) questionnaire with a scale from 1 to Traditional method of treating vertebrae fractures 10 before surgery, 24 hours and 3 months after include the use of narcotics, analgesics, non-ste- surgery (18). roidal anti-inflammatory drugs (NSAID), resting, and the use of orthosis, and in case of malignan- Methods cies – hormonal, radiotherapy and chemotherapy All surgeries were performed by the same sur- (2). In most patients, pain is reduced within 2 – 3 geon under local or general anesthesia (in cases months, while pain persists in a smaller number of non-tolerance of the local one). Surgery was of cases, so that they make a group where surgery carried out in a prone position, the fractured ver- is indicated as well (2). tebra was located by means of diascopy, the ope- Vertebroplasty is a stabilization surgery that ration area was washed and covered, and the skin achieves its effect by applying the cement thro- and subcutaneous tissue to the periosteum was ugh a needle into the broken vertebral body by anesthetized with 2% lidocaine when applying means of diascopy in situ, without correction local anesthesia. In five patients surgery was per- of kyphosis, and with the aim to relieve pain formed on the cervical spine due to the metasta- (3-13). tic process and fracture, and the procedure was A number of papers and studies describe verte- carried out openly, with standard left-anterior broplasty as a safe and efficient method in the approach to the cervical spine. treatment of pathological fractured vertebrae High viscosity cement (HVC) confidence was (1-11). This method is accompanied by some used for vertebral body augmentation in all pro- complications, both local and general ones (14). cedures. (19). Frequency rate of complications is much higher After the application of anesthetic, a needle in the treatment of malignancy than in osteopo- was placed in anterior posterior (AP) or late- rosis (15). ro lateral (LL) projection next to the joint of The most frequent complication includes the ce- the pedicle and the back vertebral body and ment leakage extra-ossal from the vertebra body then, the biopsy needle was introduced along to the surrounding tissue caused by too high qu- the cannula and a bone piece was taken for hi- antity of cement applied, inadequate selection of stopathological analysis. After performed bone patients, poor surgery technique or inadequate biopsy, we proceeded by preparing cement cement viscosity (14-17). (mixing) of appropriate viscosity, which was applied in the vertebral body. Diascopy was PATIENTS AND METHODS performed during the whole process of the cement application in order to detect its leakage Patients and study design and stop applying the cement on time to pre- In the period from October 2008 to July 2015, 422 vent more serious complications. patients were treated in 846 surgeries applying The cement application was completed when it the method of vertebroplasty in the Orthopedic was situated in the appropriate position in the last Department of the Clinical Hospital Centre Osi- quarter of the body in LL direction (Figure 1) or if

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mL) in lumbar segment and HVC 2.5 mL (2 – 4) applied in thoracic segment. Local anesthesia was applied in 356 and general anesthesia in 64 surgeries. The surgery using HVC was performed on 401 thoracic and 445 lumbar vertebrae (Figure 3).

Figure 1. Post-surgery x-ray image after high viscosity cement (HVC) application. Fractured vertebral body filled with high viscosity cement (Rapan, S., 2009) extra-ossal extravasation of cement occurred (Fi- gure 2). The needles were removed immediately after cement application was completed, which significantly shortens the procedure. The patient re- Figure 3. Pain intensity before and after vertebroplasty VAS, Visual Analogue Scale mained in bed for minimum one hour, and 24 hours after surgery the patient was discharged from hos- The surgery time was 17.5 (15-25) minutes, and pital, after having filled-in the VAS questionnaire. average stay in hospital was about 2 (1-4) days. The average time of pain suffering prior to surgery was 18 (2-124) days. According to VAS score pain reduction was significant ranging from 8.35 ± 0.82 before surgery to 2.21±0.77 (- 72.63%) 24 hours later and 2.13±0.72 three months after surgery, respectively. For patients in whom HVC was applied, a significant difference between preoperative VAS score and the value measured 24 hours after surgery (p<0.00001) and 3 months after surgery (p=0.00001) was demonstrated. A compliance between two VAS measurements after surgery Figure 2. Extra-ossal cement leakage: high viscosity cement was noticed indicating that the rapid achie- leaking in frontal part of vertebral body (Rapan, S., 2009) ved pain reduction remained stable during the Statistical analysis 3-month follow-up (Figure 3). Wilcoxon signed-rank test was used for the There were no serious intra- and post-surgery com- analysis of preoperative VAS score, 24 hours af- plications. By diascopy during the surgery in 121 ter surgery and 3 months after surgery. For sta- vertebrae (14.3%) cement leakage from the fractu- tistically significant difference p≤0.05 was used. red vertebral body was evidenced, which did not cause any aggravation of patients’ clinical status. RESULTS DISCUSSION The total of 422 patients (271 women, 151 men, aged from 29 to 82 years) underwent vi- In pathologically changed bone a vertebral fractu- sual analogue scale evaluation directly before re may result in constant pain despite analgesic surgery, immediately within 24 hours and 3 and anti-rheumatic treatment, resting or immobi- months after surgery. lization (1). As osteoporotic fractures are connected with older age, and metastatic with poor ge- The total of 422 surgeries (201 patients were tre- neral condition, beside the pain, the condition is ated for malignancy and in 221 for osteoporosis) worsened due to reduced mobility, urinary dis- were carried out on 846 vertebrae. The HVC volu- orders, depression or neurological disorder (2). me applied amounted to 3 mL on average (1.5 – 5 Similarly, because of bad quality of bones, con-

150 Rapan et al. Vertebroplasty with high viscosity cement

ventional surgery methods of stabilization, osteo- with the amount of cement applied or its leaka- synthesis and lumbar fusion have no success (2). ge. In spite of high percentage of cement leakage Vertebroplasty is a surgical method for achieving (0.5-65.6%) (14, 27-31), only about 7.5% of the stabilization of fracture in a pathologically chan- cases are symptomatic (20) and they respond to ged vertebral body, when due to osteoporosis, conservative treatment with anti-rheumatics and tumor or malignancy, the conventional methods the use of corticosteroids. Neurological distur- of treatment fail (3-13). By this method, stabi- bance which requires decompression of spinal lization is achieved about 10 minutes after the canal and cement removal accounts for only 1% application of cement into the vertebral body, and of complications (32-36). Cotton et al. (37) and analgesic effect is either the result of preventing Barragan-Campus et al. (38) stated that cement is micro-movements or only slightly less destructi- frequently leaking into the spinal canal (52%), the on of nerve ends by thermal reaction during the neuroforamen (27.6%), and into the intervertebral polymerization of cement (20). discus (about 27.6%). In our case, cement leakage occurred in 14.3% vertebrae treated when HVC The success of vertebroplasty with high viscosity was used, which corresponds to the results of An- cement method of treatment in pain reduction by selmetti et al. (27), wherein cement leakage into 75-90% is described by many authors (3-13), and the veins plexus occurred in 8.2 % and into the our result of pain reduction by 72.63% is in the discus it occurred in 6.1% cases. Georgy et al. (28) line with this statement. There is no direct rela- described high percentage of leakage when HVC tion between the quantity of cement applied and was used: extra-ossal leakage occurred in 50% of the level of reduction in pain (21,22). This met- cases, into epidural vein plexus in 25% of cases, hod also causes numerous complications, general and intradiscal leakage in about 20%, and paraver- and local ones. Frequency of complications is tebral leakage occurred in less than 5%. much higher in treatment of malignancy (up to 10 %) than in osteoporosis (1 to 3%) (8). Confirmation of cement leakage in our study was based on diascopy during surgery and X-ray The force enabling the cement flow through tra- taken after surgery. We did not take routine CT becular bone is of crucial importance for uniform scans or MRIs, because all the patients with no distribution of cement among trabeculae (18). occurrence of cement leakage had no subjective Extra-ossal leakage is the most frequent compli- disturbances, but it can be assumed that the per- cation of vertebroplasty, and it occurs on the trabe- centage of cement leakage into surrounding ti- cular bone with the lowest resistance (18). The risk ssue would be higher if these diagnostic methods of bone cement leakage into the spinal canal corre- were also used by routine. lates with bone destruction, so that the surgery is contra-indicated in more serious destructions of Hydraulic pump, higher cement viscosity, the vertebral body (23). Confidence system is based exact position of the punctuation needle and on the law of physics that enables direct impact diascopy throughout the procedure, particularly on the change in speed and pressure at the needle during the cement application are essential and end by changing the intra-system tube diameter significantly reduce the possibility of such serio- and friction. In such a way, high pressure at start us complications (19). of the system, which is required to push HVC into In conclusion, vertebroplasty with HVC retains all the needle, becomes low at end of the system and the advantages of vertebroplasty with low visco- inside the vertebral body, which provides additio- sity cement, but it also minimizes the risk of extra- nal preservation of trabecular bone structure (19). ossal cement leakage, which makes it significantly There is a direct dependence between cement safer for the surgeon and for the patient as well. leakage into the spinal canal and the quantity of cement applied during the surgery on the fractu- FUNDING red vertebral body (24, 25). Cement leakage into Funding: no specific funding was received for the inter-vertebral discus increases the risk of new this study fracture of adjacent vertebral body (27). Ali Ali et al. (13) did not notice dependence either TRANSPARENCY DECLARATION between the fracture of adjacent vertebral body Competing interests: None to declare

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REFERENCES 16. Athreya S, Mathias N, Rogers P, Edwards R. Retrie- val of cement embolus from inferior vena cava after 1. Kimi L, Kondo D.O. Osteoporotic compression verte- percutaneous vertebroplasty. Cardiovasc Intervent bral fracture and vertebral augmentation. Semin Inter- Radiol 2009; 32:817-9. vent Radiol 2008; 25:413-24. 17. Anselmetti GC, Manca A, Kanika K, Murphy K, 2. Longo UG, Loppini M, Denaro L, Maffulli N, Dena- Eminefendic H, Masala S, Regge D. Temperature ro V. Conservative management of patients with an measurement during polymerization of bone cement osteoporotic vertebral fracture: a review of literature. in percutaneous vertebroplasty: an in vivo study in J Bone Joint Surg 2012; 94:152-7. humans. Cardiovasc Intervent Radiol 2009; 32:491-8. 3. Anselmetti GC, Corgnier A, Debernadi F, Regge D. 18. McCormack HM, Horne DJ, Sheather S. Clinical Treatment of painful compression vertebral fractures applications of visual analogue scales: a critical re- with vertebroplasty: results and complications. Radi- view. Psychol Med 1988; 18:1007–19. ol Med 2005; 110:262-72. 19. Folman Y, Shabat S. A comparision of two new tehno- 4. Cheung G, Chow E, Holden L, Vidmar M, Danjoux logies for percutaneous vertebral augmentation: con- C, Yee AJ, Connoly R, Finklstein J. Percutaneous ver- fidence vertebroplasty vs sky kyphoplasty. Isr Med tebroplasty in patients with intractable pain from oste- Assoc J 2011; 13:394-7. oporotic or metastatic fractures: A prospective study 20. Barragan- Campos HM, Vallee Jn, Lo D, Cormier E, using quality-of-life assessment. Can Assoc Radiol J Jean B, Rose M, Astagnean P, Chiras J. Percutaneous 2006; 57:13-21. vertebroplasty for spinal matastases: complications. 5. Voormolen MH, Lohle PN, Frnsen H, Juttmann JR, Radiology 2006; 238:354-62. de Waal Malefijt J, Lampmann LE. Percutaneous ver- 21. Kaufmann TJ, Trout AT, Kallmes DF. The effects of tebroplasty in the treatment of osteoporotic vertebral cement volume on clinical outcomes of percutaneo- compression fractures: first short term results. Ned us vertebroplasty. AJNR Am J Neuroradiol 2006; Tijdschr Geneeskd 2003; 147:1549-53. 27:1933-7. 6. Fessl R, Roemer FW, Bohndorf K. Pescutaneous ver- 22. Baroud G, Crookshank M, Bohner M. High-viscosity tebroplasty for osteoporotic vertebral compression cement significantly enhances uniformity of cement fracture: experiences and prospective clinical otcome filling in vertebroplasty: an experimental model and in 26 consecutive patients with 50 vertebral fractures. study on cement leakage. Spine 2006; 31:2562-8. Rofo 2005; 177:884-92. 23. Ryu KS, Park CK, Kim MC, Kang JK. Dose- depen- 7. Hochmuth K, Proschek D, Schwarz W, Mack M, dent epidural leakage of PMMA after percutaneous Kurth AA, Vogl TJ. Percutaneous vertebroplasty in vertebroplasty in patients with osteoporotic vertebral the therapy of osteoporotic vertebral compression compression fractures. J Neurosurg 2002; 96:56-61. fractures: a critical review. Eur Radiol 2006; 16:998- 24. Ryu KS, Park CK, Kim MC, Kang JK. Dose-depen- 1004. dent epidural leakage of polymethylmethacrylate af- 8. Afzal S, Dhar S, Vasavada NB, Akbar S. Percuta- ter percutaneous vertebroplasty in patients with oste- neous vertebroplasty for osteoporotic fractures. Pain oporotic vertebral compression fractures. J Neurosurg Physician 2007; 10:559-63. 2002; 96:56-61. 9. Gill JB, Kuper M, Chin PC, Zhang Y, Schutt R Jr. 25. Boger A, Wheeler KD, Schenk B, Heini PF. Clinical Comparing pain reduction following kyphoplasty and investigations of polymethylmethacrylate cement vis- vertebroplasty for osteoporotic vertebral compression cosity during vertebroplasty and related in vitro mea- fractures. Pain Physician 2007; 10:583-90. surements. Eur Spine J 2009; 18:1272-8. 10. Rapan S, Jovanovic S, Gulan G. Vertebroplasty for 26. Figuerendo N, Barra F, Moraes L, Rotta R, Casula- Vertebral compression fracture. Coll Antropoll 2009; ri LA. Percutaneous vertebroplasty: a comparison 33:911-4. between the procedure using the traditional and the 11. Ewans Aj, Jensen ME, Kip KE, De Nardo AJ, Lawler new side-opening cannula for osteoporotic vertebral Gj, Negin GA, Remley KB, Boutin SM, Dunnagan fracture. Arq Neuropsiquiatr 2009; 67:377-81. SA. Vertebral compression fractures: pain reduction 27. Lin EP, Ekholm S, Hiwatashi A, Westesson PL. Ver- and improvement in functional mobility after percuta- tebroplasty: cement leakage into the disc increase the neous PMMA vertebroplasty retrospective report of risk of new fracture of adjacent vertebral body. AJNR 245 cases. Radiology 2003; 226:366-72. Am J Neuroradiol 2004; 25:175-80. 12. Pongsoipetch B. Pain reduction in patients with pa- 28. Anselmetti GC, Zoarski G, Manca A, Masala S, Emi- inful vertebral compression fractures undergoing nefendic H, Russo F, Regge D. Percutaneous verte- percutaneous vertebroplasty. J Med Assoc Thai 2007; broplasty and bone cement leakage: clinical expe- 90:479-84. rience with a new high-viscosity bone cement and 13. Ali Ali F, Barrow T, Luke K. Vertebroplasty: What is delivery system for vertebral augmentation in benign important and what is not. AJNR Am J Neuroradiol and malignant compression fractures. Cardiovasc In- 209; 30:1835-9. tervent Radiol 2008; 31:937-47. 14. Kim YJ, Lee JW, Park KW, Yeom JS, Jeong HS, Park 29. Wang HL, Jiang ZG, Wang ZG, Zhu J, Zhao HT. JM, Kang HS. Pulmonary cement embolism after Analysis of the complication and prevention on tre- percutaneous vertebroplasty in osteoporotic vertebral atment of osteoporotic vertebral compressive fractu- compression fractures: incidence, characteristics, and res by percutaneous vertebroplasty (PVP). Zhongguo risk factors. Radiology 2009; 25:250-9. Gu Shang 2009; 22:783-4. 15. Lee MJ, Dumonski M, Cahill P, Stanley T, Park D, 30. Koh YH, Han D, Cha JH, Seong CK, Kim J, Choi Singh K. Percutaneous treatment of vertebral com- YH. Vertebroplasty: magnetic resonance findings pression fractures: a meta-analysis of complications. related to cement leakage risk. Acta Radiol 2007; Spine 2009; 34:1228-32. 48:315-20.

152 Rapan et al. Vertebroplasty with high viscosity cement

31. Shapiro S, Abel T, Purvines S. Surgical removal of 35. Chen JK, Lee HM, Shih JT, Hung ST. Combi- epidural and intradural PMMA extravasation com- ned extraforaminal anf intradiscal cement leakage plicating percutaneous vertebroplasty for an osteo- following percutaneous vertebroplasty. Spine 2007; porotic lumbar compression fracture. Case report. J 32: E358-62. Neurosurg 2003; 98:90-2. 36. Le BJ, Lee SR, Yoo TY. Paraplegia as a complication 32. Wuu CC, Lin MH, Yang SH, Chen PQ, Shih TT. Sur- of percutaneous vertebroplasty with PMMA: a case gical removal of extravasated epidural and neurofora- report. Spine 2002; 27:419-22. minal polymethylmetacrylate after percutaneous ver- 37. Cotten A, Dewatre F, Cortet B, Cotton A, Dewatre tebroplasty in the thoracic spine. Eur Spine J 2007; F,Quartet B. Percutaneous vertebroplasty for oste- 3:326-31. olytic metastases and myeloma: effects of the per- 33. Chen YJ, Tn TS, Chen WH, Chen CC, Lee TS. Intra- centage of lesion filling and the leakage of methyl dural cement leakage: a devastatingly rare complica- methacrylate at clinical follow-up. Radiology 1996; tion of vertebroplasty. Spine 2006; 31:E379-82. 200:525–30. 34. Tsai TT, Chen WJ, Lai PL, Chen LH, Niu CC, Fu 38. Barragan- Campos HM, Vallee Jn, Lo D, Cormier E, TS, Wong CB. Polymethylmethacrylate cement dis- Jean B, Rose M, Astagnean P, Chiras J. Percutaneous lodgment foolowing percutaneous vertebroplasty: a vertebroplasty for spinal matastases: complications. case report. Spine 2003; 28: E457-60. Radiology 2006; 238:354-62.

Aplikacija visokoviskoznog koštanog cementa u vertebroplastici u liječenju bolnog prijeloma trupa kralješka Saša Rapan, Karin Krnić, Vjeran Rapan, Vjekoslav Kolarević Medicinski fakultet Osijek, Osijek, Hrvatska SAŽETAK

Cilj Ocijeniti uspješnost i komplikacije vertebroplastike s visokoviskoznim cementom (HVC).

Metode Pacijenti s jakom boli zbog prijeloma trupa kralješka liječeni su aplikacijom visokoviskoznog cementa (HVC) u trup kralješka unilateralnim transpedikularnim pristupom. Cement je apliciran kod 422 pacijenta, u 846 kralježaka.

Rezultati Prijeoperacijski VAS (Visual Analogue Scale) iznosio je 8,35 i 2,21 (p<0,00001) 24 sata, odnosno 3 mjeseca nakon operacije. Nije bilo ozbiljnijih intraoperacijskih i poslijeoperacijskih kom- plikacija. Dijaskopijom je, za vrijeme operacijskog zahvata, u 121 kralješku (14,3%) uočeno istjecanje cementa koje nije utjecalo na promjenu kliničkog statusa pacijenta.

Zaključak Vertebroplastika s HVC-om je procedura koja u sebi uspješno ujedinjuje sve prednosti ove metode do sada, ali i minimalizira mogućnost istjecanja cementa ekstraosalno, što ju čini znatno sigur- nijom kako za operatera, tako i za pacijenta.

Ključne riječi: koštani cement, vertebralno ojačanje, Visual Analogue Scale

153 ORIGINAL ARTICLE

Incidence of mental retardation as compared with other psychiatric disorders and necessary support to persons placed at the Public Institution for Placement of Persons with Mental Disabilities „Drin“ Fojnica, Bosnia and Herzegovina

Edin Bjelošević¹, Amar Karahmet², Halima Hadžikapetanović¹, Sonja Bjelošević1

1Mental Health Center, Health Center Zenica, ²Public Institution for Placement of Persons with Mental Disabilities „Drin“, Fojnica; Bosnia and Herzegovina

ABSTRACT

Aim To compare the frequency of mental retardation with other psychiatric disorders at the Institute for Mentally Disabled Persons „Drin“ Fojnica, Bosnia and Herzegovina, to asses psychosocial condition and necessary support to persons with mental retardation.

Methods In this retrospective, descriptive and epidemiologic study neuropsychiatric findings and reports of the Institute’s social services of 527 residents (beneficiaries) were analyzed in the period 2013-2014 (age, gender, mobility, years of life spent in the Institute, visits of family members and close relatives, visits to families, mental retardation – degree, required support). Corresponding author: Results The research included 213 (40.42%) women and 314 Edin Bjelošević (59.58%) men. The average age was 39.64 years. The avera- Mental Health Center, Health Center ge number of years spent in the Institute was 10.42.Fifty-four Zenica (25.47%) examinees with mental retardation had occasional visits Fra Ivana Jukića 2, 72000 Zenica, to their families, while 69 (32.54%) had regular visits. Thirty-four Bosnia and Herzegovina (16.04%) examinees had mild mental retardation, 70 (33.02%) Phone: +387 32 444 411; had moderate retardation, 52 (24.52%) were with severe, and 56 (26.42%) with profound retardation. It was found that 66 (31.13%) Fax: +387 32 242 113; beneficiaries with the diagnosis of mental retardation completely E-mail: [email protected] depended on other persons.

Conclusion The degree of mental retardation has a direct impact on the process of resocialization. A very small number of people diagnosed with mental retardation had been successfully involved Original submission: in the process of resocialization. It is necessary work intensively 16 Fabruary 2016; on thecreation of conditions for the realization of the Independent Revised submission: Living Support program, thus making a step forward to deinstitu- 23 March 2016; tionalization. Accepted: Keywords: support, rehabilitation, psychosis 02 May 2016. doi: 10.17392/849-16

Med Glas (Zenica) 2016; 13(2):154-160

154 Bjeloševićet et al. Support to persons with mental retardation

INTRODUCTION equal access to health care without any discrimination based on their disability. Without The World Health Organization describes men- adequate health care, medical problems of per- tal health as a state of wellbeing in which every sons with intellectual disability often remain person realizes its own potential and can face the unrecognized (10). Even when they are identi- normal stress of life, work productively and is ca- fied, such problems are often insufficiently or pable of contributing to his/her community. He- inadequately addressed (11,12). Such differen- alth is both physical and mental wellbeing rather ces among persons with intellectual disability than mere absence of a disease (1). in general population significantly increase the Mental retardation includes below-average in- risk for treatment of the disease and may lead to tellectual functioning with significant limitation early death (13). Stigma may be a key factor for of adaptive functioning, which occurs before failure to ask for assistance and has a negative the age of 18 (2). According to the International impact on seeking assistance. Facing and pre- Statistical Classification of Diseases and Rela- vention of stigma and discrimination should be ted Health Problems 10th Revision (ICD-X) (3), integral parts of a support process to all persons mental retardation is defined as a condition of with mental disorders, particularly children and delayed or incomplete development of the mind young people (14). Persons with intellectual di- characterized by impairment of skills contri- sability often have poor access to medical servi- buting to overall development of intelligence, ces and their treatment involves very high costs i.e. reasoning, speech, motor control and social for the health care system and the entire society contacts demonstrated during the development. (15-17). Despite those facts persons with in- Mental retardation is dividedto four sub-catego- tellectual disability are mostlyneglected in the ries (3): mild mental retardation (IQ 50 - 70), field of mental health, where specialized servi- moderate mental retardation (IQ 35 - 49), severe ces are limited. Such specialized services can be mental retardation (IQ 20 – 34), and profound provided mainly in countries with high income, mental retardation (IQ is below 20 (3). In the primarily western countries (18,19). next revision, ICD-11, it is expected that the The war in Bosnia and Herzegovinacaused se- term mental retardation will be replaced either rious suffering of the population and led to de- by the term intellectual disability or intellectual vastation of psychosocial institutions, therefore, developmental disorder, which are already used a small number of psychosocial institutions has by the American Psychiatric Association Dia- remained operational, the Public Institute for Pla- gnostic and Statistical Manual of Mental Disor- cement of Persons with Mental Disability “Drin” ders (Fifth ed.)(DSM-5) (2,4). Fojnica being among them. It also accommoda- Intellectual disability affects around 1-3% of the tes patients with psychiatric disorders and provi- general population (5,6). Global developmen- des them with psychological, social and medical tal delay (GDD) occurs in psychomotor deve- support in addition to persons with mental retar- lopment of 3% of children under the age of 5 dation, who were its original beneficiaries. and is defined as developmental disorder with a The aim of this retrospective study was to investi- delay in two or more developmental areas: gross gate frequency of mental retardation in compari- or fine motor skills, speech, cognition (cogniti- son with other psychiatric disorders at the Public ve processes), social functioning and everyday Institute for Placement of Persons with Mental activities (7). Around 75-90% of persons with Disabilities „Drin“ Fojnica, Bosnia and Herze- intellectual difficulties have mild intellectual govina (B&H), in the period 2013-2014 to asses disability. Approximately one quarter of cases psychosocial condition and necessary support for is caused by a genetic disorder (8). Due to high persons diagnosed with mental retardation de- incidence of physical and mental comorbidity pending on a degree of mental retardation. with intellectual disability, suchpersons require more attention than mere health care services The research will provide guidelines for the pro- and have a higher need for resources in health tection and promotion of mental health of per- care than persons from the general population sons placed in psychosocial institutions. (9). Persons with intellectual disability need

155 Medicinski Glasnik, Volume 13, Number 2, August 2016

EXAMINEES AND METHODS RESULTS This research included 527 examinees, of which Design of the study and sample 213 (40.42%) were females and 314 (59.58%) In this retrospective, descriptive and epidemiolo- were males (p< 0.01). Of the 527 beneficiaries, gical research using available data from medical 212(40.23%) were persons with the diagnosis of records of 527 beneficiaries of the Public Institute mental retardation, of whom 129 (60.85%) were for Persons with Mental Disorders (experimen- males and 83 (39.15%) females; 315(59.77%) had tal group) „Drin” Fojnica, B&H,of whom 212 the diagnosis of other psychiatric diseases, 185 were with the diagnosis of mental retardation and (58.73%) of them were males and 130 (41.17%) 315 with the diagnosis of other mental diseases females. Of all registered beneficiaries with men- (control group) (psychosis,schizophrenia-SCH, tal retardation, 34 (16.04%) had the diagnosis of persistent delusional disorder, bipolar affecti- mild mental retardation, 70 (33.02%) beneficiaries ve disorder, surdomutism, dementia, epileptic with the diagnosis of moderate mental retardation, psychosis, alcoholic paranoia, cerebral paralysis, 56 (26.41%) beneficiaries with the diagnosis of se- organic delusion, autism, Down syndrome), ne- vere mental retardation, 52 (24.53%) beneficiaries uropsychiatric findings and reports of the Soci- with the diagnosis of profound mental retardation al Services of the Institute were analyzed in the (Table 1). Out of the total number of beneficiari- period 2013-2014. The analysis included: age, es, in addition to mental retardation, the highest gender,mobility, years of life spent in the Institu- number had the SCH diagnosis, 212 (67.30%), te, visits of family members and close relatives, followed by psychosis in 47 (14.92%) beneficia- visits to families, education, marital status, degree ries (data have not shown). of mental retardation (mild mental retardation: IQ Table 1. Gender distribution of beneficiaries according to 50-70, moderate mental retardation: IQ 35-49), psychiatric disorders severe mental retardation: IQ 20–34), and profo- No (%) of beneficiaries with Other psychiatric und mental retardation: IQ below 20), psychiatric Mental retardation Total p disorders* diseases,psychosocial support including rehabili- Fema- Fe- Males Total Males Total tation, which supports the development of cogni- Gender les males 129 83 212 185 130 315 527 tive, functional, communication or social skills p<0.01 (62.6) (37.4) (100) (58.7) (41.3) (100) (100) of beneficiaries (taken by a psychologist, social Degree of mental retardation worker, work therapist and professional staff in 19 15 34 Mild order to preserve remaining skills or develop (14.73) (18.07) (16.04) 47 23 70 group cohesion), required support (occasional Moderate (36.43) (27.71) (33.02) support in some situations, permanent support 34 22 56 Severe of lower intensity, permanent support of higher (36.36) (26.51) (26.41) 29 23 52 intensity, complete dependence on others), and Profound (22.48) (27.71) (24.53) type of therapy (pharmacotherapy, occupational, *Psychosis, SCH, persistent delusional disorder, bipolar affective work, music and physical therapy). disorder, surdomutism, dementia, epileptic psychosis, alcoholic para- The research was approved by the Faculty of the noia, cerebral paralysis, organic delusion, autism, Down syndrome School of Health Care, University in Zenica. The highest number of examinees with mental retardation was aged d 31-40 years, 64 (30.19%), Statistical analysis and 19-30 years, 45 (21.22), while those with the Standard methods of descriptive statistics, t-test diagnosis of other psychiatric diseases were aged and χ²-test were used for testing statistical signi- 51-60 years, 97 (30.80%) and 41-50 years, 86 ficance of the relationship of mental retardation (23.30%) (Table 2). with other mental diseases, according togen- The highest number of examinees with the dia- der, age, education level, marital status, type of gnosis of mental retardation had no education, support, type of therapy, visiting home and visits 179 (85.24%), while the highest number of exa- by relatives, duration of stay and influence of a minees with the diagnosis of other psychiatric retardation degree on rehabilitation. The p<0.05 diseases had secondary school education,164 was considered as statistically significant. (52.06) (Table 2).

156 Bjeloševićet et al. Support to persons with mental retardation

Table 2. Demographic characteristicsof beneficiaries therapy and occupational and music therapy),

No (%) of beneficiaries with while in the group of examinees with other di- Mental retar- Other psychia- seases, occupationaltherapy is mostly applied in Age (years) Total dation tricdisorders* addition to pharmacotherapy (Table 3). 0-18 9 (13.68) 4 (1.27) 33 (6.26) 19-30 45 (21.22) 19 (6.03) 64 (12.14) Visits of relatives did not have any statistical si- 31-40 64 (30.19) 41 (13.02) 105 (19.92) gnificance in terms of determining the intensity of 41-50 39 (18.40) 86 (23.30) 125 (23.72) the need for psychosocial support at the Institute 51-60 20 (9.43) 97 (30.80) 117 (20.88) (p>0.05). There was a statistically significant diffe- 61 and more 15 (7.07) 68 (21.58) 83 (15.74) rence in the intensity of necessary psychosocial Education support to the examinees in relation to visits to the No any 179 (85.24) 70 (22.22) 249 (47.20) Primary school 30 (14.15) 68 (21.59) 98 (18.60) family (p< 0.01). Periodic visits to their primary fa- Secondary school 3 (1.41) 164 (52.06) 167 (31.68) mily have proved to be a significant positive factor High school 0 10 (3.17) 10 (1.90) in the process of resocialization (Table 3). University education 0 3 (0.95) 3 (0.6) Marital status Table 3.Types of psychosocial support

Married 0 20 (6.34) 20 (3.83) No (%) of beneficiaries with Not married 207 (97.64) 163 (51.75) 370 (70.20) Duration of stay Other Mental Divorced 2 (0.94) 83 (26.35) 85 (16.13) in the Institute psychia- Total p retardation Widow(er) 3 (1.42) 49 (15.56) 52 (9.84) (years) tricdisorders* 0-5 37 (17.45) 92 (29.21) 129 (24.48) The highest number of examinees from both gro- 6-10 71 (33.49) 145 (46.03) 216 (40.99) ups were not married 370 (70.22%) (Table 2). 11-15 22 (10.38) 44 (13.97) 66 (12.52) The highestnumber of beneficiaries, 216 16-20 33 (15.57) 14 (4.44) 47 (8.92) 21-25 19 (8.96) 7 (2.22) 26 (4.93) (40.99%), had stayed in the Institute for 6-10 26-30 16 (7.55) 6 (1.90) 22 (4.17) years, of whom 71 (33.49%) with the diagnosis >30 14 (6.60) 7 (2.22) 21 (3.98) of mental retardation and 145 (46.03%) with the Intensity of support Occasional support diagnosis of other psychiatricdiseases (Table 3). 30 (14.15) 86 (27.30) 116 (22.01) < 0.01 in some situations The highest number of the examinees, regardless Permanent support 69 (32.55) 141 (44.76) 210 (39.85) < 0.05 of their basic disease, needed continuous assi- of lower intensity Permanent support stance of lower intensity, 69 (32.55% ) exami- 47 (22.17) 63 (20.00) 110 (20.87) of higher intensity nees with mental retardation and 141 (44.76%) Completely depen- 66 (33.13) 25 (7.94) 91 (17.27) examinees with other psychiatric diseases (p dent on others < 0.05). Persons with mild and moderate men- Type of therapy tal retardation primarily demonstrated the need Pharmacotherapy 212 (100.00) 315 (100.00) 527 (100.00) <0.001 for occasional assistance in some situations, 30 Occupational 33 (45.56) 37 (11.74) 70 (13.28) Work 14 (6.60) 47 (14.92) 61(11.57) (14.15%), or with permanent support of lower Physical 24 (11.32) 9 (2.86) 33 (6.26) intensity, 69 (32.55%), while persons with se- Music 27 (12.73) 2 (0,63) 29 (5.50) vere and profound mental retardation primarily Visits of relatives needed continuous support of higher intensity, 47 YES 69 (32.54) 66 (20.95) 135 (25.61) >0.05 (22.17%), or they were completely dependent on NO 143 (67.46) 249 (79.05) 392 (74.39) others, 66 (31.13%) (p<0.01) (Table 3). Visiting home YES 20 (9.43) 37 (11.74) 57 (10.81) < 0.01 There was a statistically significant difference NO 192 (90.57) 278 (88.26) 470 (89.19) in the type of therapy applied to the group of examinees with mental retardation as compared DISSCUSSION with the group of examinees suffering from other diseases (p<0.01). Although all examinees from The research included 527 beneficiaries placed both groups received certain pharmacotherapy, in the Public Institute for Mentally Disabled yet in the group of examinees with mental retar- Persons „Drin“ Fojnica, B&H, of whom 40.23 dation there was a significantly higher percentage %were with mental retardation and 59.77 %with of those who get other therapeutic techniques in other mental diseases. A large percent of bene- addition to pharmacotherapy (primarily physical ficiaries (77.11) with other mental diseases has

157 Medicinski Glasnik, Volume 13, Number 2, August 2016

beenfoundin another institution in B&H(the did not go to their families. The examinees who Institute for Placement of Persons with Mental occasionally visited their families had a stati- Disabilities “Bakovici”, Fojnica; Nada Sušić-Si- stically significantly less need for psychosocial jerčić, personal communication, 2015). Such a support during their stay at the Institute regardle- ratio of beneficiaries could be expected because ss of their basic disease. Occasional visits to pri- the number of psychosocial institutions for place- mary family have proved to be a significant po- ment of persons with psychiatric disorders other sitive factor in the process of resocialization(20). than mental retardation has decreased in B&H, so Based on the assessment of psychosocial con- they are placed in institutions intended for place- dition and required support in this report it has ment of persons with mental retardation. Studies been proven that persons with mild and mode- conducted worldwide have shown that mentally rate mental retardation demonstrate primarily retarded persons are accommodated more often the need for occasional support in some situa- in apartments for independent living with the tions (14.15%) or continuous support of lower control of relevant services (20,21). intensity (32.55%), while persons with severe The highest number of beneficiaries with mental and profound mental retardation primarily show retardation was below30 years of age(34.90%) the need for permanent support of higher inten- and 31-40 years (30.19%). Such an age structu- sity (22.17%) or they are completely dependent re corresponds to the studies indicating that life on others (31.13%). The examinees with lower expectancy of mentally retarded persons is shor- degree of mental retardation also need a lower ter than in healthy persons (13).Life expectancy intensity of psychosocial support – the level of of persons with mental retardation is shorter necessary support is proportional to the level of than in general population (22) (average age was mental retardation of the examinees – that link 39.64 years). (correlation) is significant (3). Male/female structure of beneficiaries from this Deinstitutionalization of services for persons study(54.82 vs 44.88%) was similar tothe gen- with mental retardation has come into the focus der breakdown of the Institute for Placement of of disability policy in many countries. The new Persons with Mental Disabilities “Bakovici”, policy includes integration, equality and de- Fojnica, B&H (Nada Sušić-Sijerčić, personal institutionalization (20). In most cases studies communication, 2015), similarly as in other stu- support this strategy (21).Within the mental he- dies conducted worldwide (22). alth reform in B&H, the Federation of B&H has According to the results of this study, average ye- started a project of mental health in the commu- ars of beneficiaries spent at the Institute was 10.42 nity (23).After the implementation of the pro- years.Long-term placement raises concerns from gram of enabling persons with mental retardation the professional-psychiatric, ethical and legal as- inB&H to live in the community, with the aim of pect. Stigmatization prevents natural resociali- their true inclusion in the local community, ten zation of persons with mental retardation, which beneficiaries from this study moved into houses affects the course of the therapeutic process (14). rented by the Institute in its vicinity. Allof them have continued their life in the community with The results of this research have shown that 82.54% the assistance of employees of the “Drin” Insti- of persons with mental retardationwerecapable tute. Out of those ten beneficiaries, six have the moving withinthe Institute’s area, 6.13% persons diagnosis of moderate mental retardation, while were with difficult movement, 11.32% persons four beneficiaries are diagnosed with mild men- were unable to move. Persons with deep mental tal retardation suggestingthat a very low number retardation have serious limitations in communi- of persons with mental retardation have been cation and mobility and they need permanent assi- successfully included in the process of resocia- stance and care (3). Profound mental retardation is lization. Persons accommodated in apartmentsli- connected with decreased life expectancy, particu- ving with the support of a community improve larly those who are unable to move (22). their skills, social interaction and general quality According to records on visits to families, 9.43% of life (20). Following new trends at the territory examinees with mental retardation occasionally of the municipality of Zenica, ahumanitarian or- went to their families, while 90.57 examinees

158 Bjeloševićet et al. Support to persons with mental retardation

ganization providedaccommodation (housing) support, thus making a step forward to deinstitu- for persons with mental retardation where they tionalization in order to adopt modern European receive coordinated care. trends and solutions in this field of social life. It is In conclusion, the resocialization process is essential to ensure humanization of housing and affected by many factors, ranging from the de- living for persons placed at the Institute. Activiti- institutionalization process to stigmatization of es supporting persons with intellectual disabiliti- persons with mental retardation by the society. es should be expanded. It is necessary to work intensively on the imple- FUNDING mentation of projects related to the construction of new accommodation capacities and accessory No specific funding was received for this study. facilities, which should become functional in terms of creating conditions for the implemen- TRANSPARENCY DECLARATION tation of the project of independent living with Conflict of interest: None to declare.

REFERENCES 1. Anonymous. The World Health Report 2001. Men- 11. Ouellette-Kuntz H, Garcin N, Lewis MES, Minnes tal Health: New understanding, New Hope. World P, Martin C, Holden JJA. Addressing health dispa- Health Organization, 2001.http://www.Who.int/ rities through promoting equity for individuals with whr/2001/en/ (02 October 2015) intellectual disability. Can J Public Health 2005; 2. Anonymous. American Psychiatric Association Di- 96:8-22. agnostic and Statistical Manual of Mental Disor- 12. Beange H, McElduff A, Baker W. Medical disorders ders (5th ed.). Arlington, VA: American Psychiatric of adults with mental retardation: a population study. Publishing, 2013. Am J Ment Retard 1995; 99:595-604. 3. Svjetskazdravstvenaorganizacija. MKB-10 –Me- 13. Fisher K. Health disparities and mental retardation. J đunarodnaklasifikacijabolestisrodnihzdravstve- NursScholarsh 2004; 36:48–53. nihproblema. Desetarevizija. Svezak 1. Prijevod: 14. Clement S, Schauman O, Graham T, Maggio- Hrvatskizavodzajavnozdravstvo. Zagreb: Medicin- ni F, Evans-Lacko S, Bezborodovs N, Morgan skanaklada,1994. C, Rüsch N, Brown JS, Thornicroft G. What is the 4. Carulla LS, Reed M G, Vaez-azizi M L, Cooper S impact of mental health-related stigma on help-see- A,Leal R M, Bertelli M, Adnams C, Cooray S, Sho- king? A systematic review of quantitative and quali- umitro D, Dirani L A, Girimaj S C, Katz G, Kwok tative studies. Psychol Med 2015; 45:11-27. H, Luckasson R, Simeonsson R, Walsh K, Mu- 15. Beange H. Caring for a vulnerable population: nirK, Saxena S. Intellectual developmental disor- Who will take responsibility for those getting a raw ders: towards a new name, definition and framework deal from the health care system? MedJ Aust1996; for “mental retardation / intellectual disability” in 164:159-60. ICD-11. World Psychiatry 2011; 10:175-80. 16. Eastgate G, Lennox NG. Primary health care for 5. Bradley EA, Thompson A, Bryson SE. Mental retar- adults with intellectual disability. dation in teenagers: prevalence data from the Niaga- 17. AustFam Physician 2003; 32:330-33. ra region, Ontario. Can J Psychiatry 2002; 47:652-9. 18. Ben-Shlomo Y, Kuh D. A life course approach to 6. Leonard H, Wen X. The epidemiology of men- chronic disease epidemiology: conceptual models, tal retardation: challenges and opportunities in the empirical challenges and interdisciplinary perspec- new millennium. Ment Retard Dev Disabil Res tives.Int J Epidemiol 2002; 32:285-93. Rev 2002; 8:117-34. 19. Braveman P. Health disparities and health equity: 7. Shevell M, Ashwal S, Donley D. Practice parameter: Concepts and measurement. Annu Rev Public He- evaluation of the child with global developmental alth 2006; 27:176-94. delay. Neurology 2003; 60: 367-80. 20. Braveman P, Gruskin S. Defining equity in health. J 8. Daily DK, Ardinger HH, Holmes GE. Identificati- Epidemiol Community Health2003; 57:254-58. on and evaluation of mental retardation. Am Fam 21. Mansell J. Deinstitutionalization and community Physician 2000; 61:1059-67. living: Progress, problems and priorities. J Intellect 9. Polder JJ, Meerding WJ, Bonneux L, van der Maas Dev Disabil 2006; 31:65-76. PJ. Healthcare costs of intellectual disability in the 22. Molony H, Taplin J. Deinstitutionalization of peo- Netherlands: a cost-of-illness perspective. J Intellect ple with developmental disability.Australia and New Disabil Res 2002; 46:168-78. Zealand Journal of Developmental Disabilities2009; 10. US Department of Health and Human Services. Clo- 109-22. sing the Gap: ANationalBlueprint to improve the 23. Eyman RK, Grossman HJ, Chaney RH, Call TL.The Health of Persons with Mental Retardation. Washi- Life Expectancy of Profoundly Handicapped Peo- ngton, DC: US Department of Health and Human ple with Mental Retardation. N Engl J Med 1990; Services, 2002. http://www.surgeongeneral.gov/to- 323:584-89 pics/mentalretardation/(10 February 2016). 24. Čerkez G, Latinović M, Kapetanović T, Puratić V. Mental health in South-Eastern Europe. Med Arhiv 2007; 61:49.

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Učestalost mentalne retardacije u odnosu na druge psihijatrijske poremećaje i potrebna podrška kod osoba smještenih u Zavodu za zbrinjavanje mentalno invalidnih lica „Drin“ Fojnica u Bosni i Hercegovini Edin Bjelošević¹, Amar Karahmet², Halima Hadžikapetanović¹, Sonja Bjelošević1

1Centar zamentalnozdravlje, JU Dom zdravljaZenica; ²JU Zavodzazbrinjavanje mentalnoinvalidnihlica „Drin“, Fojnica; Bosna i Herce- govina

SAŽETAK

Cilj Uporediti učestalost mentalne retardacije s drugim psihijatrijskim poremećajima u Zavodu za zbrinjavanje mentalno invalidnih lica „Drin“ u Fojnici te utvrditi procjenu psihosocijalnog stanja i podrške potrebne osobama s dijagnozom mentalne retardacije.

Metode U ovom retrospektivnom, deskriptivnom i epidemiološkom istraživanju analizirani su ne- uropsihijatrijski nalazi i podaci dobiveni iz izvještaja Socijalne službe Zavoda (starosna dob, spol, pokretljivost, godine provedene u Zavodu, posjete članova porodice i bliskih srodnika, posjete porodici, stepen mentalne retardacije i potrebna podrška) za 527 osoba (korisnika) smještenih u periodu od 2013. do 2014. godine.

Rezultati Istraživanje je obuhvatilo 213 (40,42%) žena i 314 (59,58%) muškaraca. Prosječna dob ispitanika bila je 39,64 godina. Prosječan broj godina provedenih u Zavodu je 10,42. Pedeset i četiri (25,47%) ispitanika s mentalnom retardacijom imala su povremene posjete obitelji, a 69 (32,54%) je imalo redovne posjete. Trideset i četiri (16,04%) ispitanika imalo je blagu mentalnu retardaciju, 70 (33,02%) umjerenu, 52 (24,52%) tešku, a 56 (26,42%) duboku. Utvrđeno je da 66 (31,13%) korisnika s dijagnozom mentalne retardacije u potpunosti ovise o drugim osobama.

Zaključak Stepen mentalne retardacije ima direktan utjecaj na proces resocijalizacije. Veoma se mali broj osoba s dijagnozom mentalne retardacije uspješno uključuje u pomenuti proces. Potrebno je inten- zivno raditi na realizaciji projekata vezanih za izgradnju novih smještajnih i pratećih objekata, koji bi trebali da profunkcioniraju u smislu stvaranja pretpostavki za realizaciju projekta „Samostalno stanova- nje uz podršku“, te tako načiniti korak ka deinstitucionalizaciji.

Ključne riječi: podrška, rehabilitacija, psihoza

160 ORIGINAL ARTICLE

Impact of self-rated health among elderly on visits to family physicians

Amira Kurspahić-Mujčić1, Melisa Čalkić2, Suad Sivić3

1Department of Social Medicine, School of Medicine, University of Sarajevo, Sarajevo,2Primary Health Care Center, GornjiVakuf- Uskoplje,3Public Health Institute of Zenica-Doboj Canton, Zenica; Bosnia and Herzegovina

ABSTRACT

Aim To evaluate an impact of eight dimensions of self-rated health measured by the SF-36 questionnaire on visits to family physicians among people older than 65.

Methods This cross-sectional study was carried out in family medicine outpatient departments of the Public Institution Primary Health Care Center of Canton Sarajevo, Bosnia and Herzegovina. The study included 200 respondents divided into two age groups:18-65 (n=100) and older than 65 (n=100). The SF-36 questionnaire for self-assessment of health status and a questionnaire for the evaluation of socio-demographic characteristics of respondents and health care utilization were used.

Results In the group of respondents aged 18-65 the dimension that was related to physical functioning was assessed as best (79.1±25.6), while the dimension concerning the vitality was Corresponding author: assessed as the worst (56.1±19.9). In the group of respondents older than 65 the dimension related to social functioning was asse- Amira Kurspahić-Mujčić ssed as best (65.4±24.9), and the dimensions related to general School of Medicine, University of health was assessed as worst (47.7±20.4). Family physicians were Sarajevo visited by significantly more respondents older than 65 than tho- Čekaluša 90, 71000 Sarajevo, Bosnia and se from the age group 18-65 (94% vs.74%) (p= 0.000). Scores Herzegovina on the scales of general health (p=0.021) and social functioning Phone: +387 33 202 051; (p=0.024) in respondents older than 65 had a significant impact on visits to family physicians. Fax: +387 33 202 051; Email: [email protected] Conclusion Poor self-rated general health and better social functioning are important predictors of visiting family physicians by elderly persons.

Key words: age, primary health care, quality of life Original submission: 15 April 2016; Accepted: 01 June 2016. doi: 10.17392/857-16

Med Glas (Zenica) 2016; 13(2):161-166

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INTRODUCTION of Canton Sarajevo, Bosnia and Herzegovina Older age groups are vulnerable due to departure (B&H) in period March-August 2015. from the labor market with greater dependence The study was approved by the Ethics Committee on pensions, breakdown of extended families, of the School of Medicine, University of Sara- isolation due to the death of their contemporaries, jevo. For this investigation a written consent of especially of their spouses, and declining physi- the General Director of the Primary Health Care cal and mental capabilities (1). Changes in social Center of Sarajevo Canton was obtained. An in- and economic circumstances and health at older formed consent for participation in the study was age predict changes in quality of life (2-4). taken from all respondents. The interest in the quality of life of elderly has The respondents were patients who used health become relevant with the demographic shift that care services at the Primary Health Care Center has resulted in greying of the population (5). The during the study period. The study included 200 increasing life expectancy due to improvement in respondents based on the principle of systematic social and living conditions, health promotion and random sampling. The respondents were divided education, better access to health care services and into two groups according to their age: respon- people’s activity contribute to this process (6). dents older than 65 (n=100) and those aged 18- The increasing life expectancy raises the question 65 (n=100). The inclusion criteria encompassed of whether longer life spans result in more years of persons older than 18, who had a medical record life in good health, or whether it is associated with in the Primary Health Care Center of Sarajevo increased morbidity and more years spent in pro- Canton. According to exclusion criteria persons longed disability and dependency (7,8). The results under 18 years of age, persons who did not have of the conducted studies based on the application medical records at the Primary Health Care Cen- of modern techniques of subjective assessment of ter of the Sarajevo Canton and terminally ill per- health through structured questionnaires (SF-36 sons were not involved in the study. questionnaire) showed that people now live longer, healthier and more actively enjoy life (9-11). Methods It was also found that certain dimensions of self- The respondents were supposed to fill out a que- rated health can have a positive effect on the use of stionnaire that included questions about their so- health care services, which ultimately leads to im- cio-demographic characteristics and utilization of proved health (12). For elderly people regular use of health care and the SF-36 questionnaire. Socio- primary health care is of special significance (13). demographic characteristics were included: the They need visits to family physicians to prevent di- highest level of accomplished formal education, seases, control the therapeutic effect of used drugs self-assessed material status, age, gender,“live and improve general health (14). Pappa and Niakas alone”. As an indicator of health care utilization have found in the study conducted in Greece that visits to family physicians and visits to specia- self-perceived health status was the most important list on referral by family physicians in the last determinant for visiting family physicians (15). twelve months were observed. The respondents The aim of this study was to evaluate the impact were asked to provide “yes” or “no” answers to of eight dimensions of self-rated health measured the question whether he/she had visited a family by the SF-36 questionnaire on visits to family physician/family physician associated with spe- physicians among people older than 65 in family cialistin the last twelve months. medicine outpatient departments of the Public In- The SF-36 questionnaire was used to measure the stitution Primary Health Care Center of Canton self-rated health through eight dimensions of he- Sarajevo, Bosnia and Herzegovina. alth (16,17). The SF-36 Health Survey is a self-re- EXAMINEES AND METHODS port questionnaire in which a generic outcome measure is designed to examine a person’s perceived Study design health status. The SF-36 Health Survey includes This cross-sectional study was carried out in one multi-item scale measuring each of the eight family medicine outpatient departments of the health concepts: physical functioning (10 items), Public Institution Primary Health Care Center physical role limitations (four items), bodily pain

162 Kurspahić-Mujčić et al.Self-rated health and visits to doctor

(two items), general health perceptions (five items), Table 1.Socio-demographic characteristics of respondents energy/vitality (four items), social functioning (two No (%) of respondents Group 18-65 Group 65+ items), emotional role limitations (three items) and Characteristic p years (n=100) years (n=100) mental health (five items). The SF-36 Health Sur- Gender 0.777 vey items and scales were constructed using the Li- Males 45 (45.0) 47 (47.0) kert method of summated ratings. Answers to each Females 55 (55.0) 53 (53.0) question were scored (some items need to be reco- Education level 0.001 ded). These scores were summed to produce raw Incomplete elementary school 3 (3.0) 8 (8.0) scale scores for each health concept which were Completed elementary school 45 (45.0) 34 (34.0) then transformed to a 0 – 100 scale (18). High school diploma 18 (18.0) 39 (39.0) Completed high school/college 34 (34.0) 19 (19.0) Statistical methods Self-perceived financial status 0.005 Worse than average 12 (12.0) 31 (31.0) Testing of the difference between two groups of Average 59 (59.0) 46 (46.0) respondents, aged 18 to 65 and older than 65,was Better than average 29 (29.0) 23 (23.0) performed by χ2 and Student’s t tests for indepen- Lives alone 0.012 dent samples. The impact of health dimensions of Yes 16 (16.0) 31(31.0) No 84 (84.0) 69 (69.0) SF-36 questionnaire on the resulting visits to family physicians and visits to a specialist upon referral ral health (p=0.000), social functioning (p=0.021) by family physicians was determined by calculat- and mental health (p=0.001).In the group older ing the Odds Ratio (OR). Level of significance was than 65 the average score on all scales was lower set at p<0.05, and the confidence level was 95%. than the average score of the younger respondents from the 18-65 years group.Out of the eight di- RESULTS mensions of self-rated health in the 18-65 years The average age of the respondents in the total group of respondents the dimension that is related sample was 57.18±19.25 years; 41.40±13.79 ye- to physical functioning was assessed as the best ars (minimum 19, maximum 64) in the group of (79.1±25.6), and the dimension concerning the respondents aged 18 to 65 years, and 72.96±7.16 vitality as the worst (56.1±19.9). In the group of years (minimum 66, maximum 90) in the group respondents older than 65 the dimension that is re- older than 65. lated to social functioning was assessed as the best In both study age groups females were slightly (65.4±24.9), and the dimensions related to general more represented than males, 55%:45% in the health as the worst (47.7±20.4) (Table 2). group aged 18-65 years, and 53%:47% in the group older than 65, respectively. Table 2. Comparison of self-rated health through eight dimensions of health measured by the SF-36 questionnaire In the group aged 18-65 years 34% had comple- according to age ted college/university, while in the group older Dimension of health Age group (years) Mean value (SD) p than 65 19% of the respondents had a college/ 18-65 79.1 (25.6) university degree.In the group of the respondents Physical functioning ˃65 60.4 (24.6) p=0.000 older than 65 years there were more respondents Role limitations due 18-65 69.8 (39.6) who evaluated their financial status as worse than to physical problems ˃65 51.0 (45.6) 0.002 the average in the comparison to the group of 18-65 70.8 (25.8) Bodily pain respondents aged 18-65 years, 31.0% vs.12.0%. ˃65 60.9 (28.2) 0.010 18-65 63.5 (18.8) There were almost twice as many respondents General health who lived alone in the group of respondents older ˃65 47.7 (20.4) 0.000 18-65 56.1 (19.9) than 65 years, than in the 18-65 years group, 31% Vitality ˃65 51.6 (17.4) 0.086 and 16%, respectively (Table 1). 18-65 73.0 (21.2) Social functioning Self-rated health as measured by the SF-36 que- ˃65 65.4 (24.9) 0.021 stionnaire among the examined groups was signi- Role limitations due to 18-65 68.0 (41.0) emotional problems ficantly different according the six dimensions of ˃65 60.0 (45.7) 0.194 18-65 69.1 (18.5) health: physical functioning (p=0.000), physical Mental health ˃65 61.2 (15.9) 0.001 problems (p=0.002), bodily pain (p=0.010), gene- SD, standard deviation

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Table 3. Impact of eight dimensions of health measured by the SF-36 questionnaire on visits to family physicians and family physicians associated with specialist in the last twelve months for respondents over 65 years of age Family physicians Family physicians+ specialist Dimension of health Mean value p OR (95% CI) Mean value p OR (95% CI) Physical functioning 60.4 0.621 1.005(0.986-1.024) 60.4 0.688 0.997(0.982-1.012) Role limitations due to physical problems 51.0 0.150 0.988(0.971-1.005) 51.0 0.027 0.988(0.978-0.999) Bodily Pain 60.9 0.068 0.977(0.953-1.002) 60.9 0.011 0.977(0.959-0.995) General health 47.7 0.021 0.960(0.927-0.994) 47.7 0.002 0.989(0.934-0.985) Vitality 51.6 0.410 0.982 (0.912-1.074) 51.6 0.050 1.033(1.000-1.07) Social functioning 65.4 0.024 1.041(1.005-1.079) 65.4 0.406 1.010(0.986-1.035) Role limitations due to emotional problems 60.0 0.102 1.010(0.998-1.023) 60.0 0.194 1.006(0.997-1.015) Mental health 61.2 0.739 0.993(0.950-1.037) 61.2 0.777 1.005(0.973-1.038) OR, Odds Ratio; CI, confidence interval

In the last twelve months family physicians were re for self-rated general health is expected to be visited by significantly more respondents older worse. Emotional functioning changes little with than 65 years than respondents from the age gro- age (20). Findings might reflect that older adults up 18-65 (94 vs. 74) (p=0.000). In the last twelve are better able to control exposure or reaction to months family physicians associated with speci- difficult emotions and are able put one’s own life alists visited significantly more respondents ol- in a context, so that one reaches a state of self- der than 65 than the respondents from the 18-65 acceptance (21). group (68 vs. 33) (p=0.000) (data are not shown). Chronic pain was more common among older than In case of respondents older than 65 years, the in younger people in this study, which is in line scores on scales measured by the SF-36 questi- with the results of other researchers who suggest onnaireof general health (p=0.021) and social that nearly one third of older people suffer from functioning (p=0.024) had a significant impact chronic pain (22). The consequences of this pain on visits to family physicians. The dimension include impaired activities of daily living and im- of health, which describes bodily pain was bor- paired ambulation and depression (23). Pain may derline significant for visiting family physicians also be related to complications associated with (p=0.068). On visits to family physicians asso- deconditioning, gait abnormalities, accidents, ciated with visits to specialists scores on a scale polypharmacy, and cognitive decline (24). of physical problems, bodily pain, general health Ageing brings several physical as well as mental and vitality had a significant impact (Table 3). problems (25). As people are getting older they find it increasingly difficult to concentrate, they DISCUSSION are not happy with themselves as once when they This study explored self-rated health of older were younger, and because of numerous pro- people through eight dimensions of health (SF- blems their negative mood tends to increase (26). 36).The obtained results indicate that with the The result is visible in the field of mental health. increasing age, the respondents evaluated health Older people are less satisfied with the domain significantly worse in six dimensions of health of social functioning (1). For them, the absolute (physical functioning, physical problems, bodily value of satisfaction with social relations is redu- pain, general health, social functioning and men- ced for several reasons, e. g. a circle of friends at tal health), while the two dimensions of health that age is reduced and some close persons are vitality and emotional problems did not worsen probably no longer alive (27). Old people tend significantly with age. to have less of a chance to participate, especially In this study, respondents older than 65 evalua- after retirement (28), but the results of the stu- ted the dimension of health that relates to general dy conducted by Gilmour in Canada among 16 healt has worst. Aging is accompanied by physi- 369 respondents at age of 65 and older indicate ological disorders in terms of lower mobility and the existence of desire of older people for greater disability on one hand, and by suffering from va- participation in social activities (29). rious chronic diseases on the other hand (19) the- It is known that self-rated health affects the use

164 Kurspahić-Mujčić et al.Self-rated health and visits to doctor

of health care and that certain dimensions of se- that non-visiting rate among empty-nest elderly is lf-rated health differently affect visits to doctors significantly higher than that among non-empty- at primary and secondary levels of health care nest ones (39).Therefore, the future studies sho- (30,31). In the present study scores on scales of uld be dealing in detail with social functioning of general health and social functioning had signi- older people and ways to improve it. ficant influence on visits to the family physici- In conclusion, the results of this study show that ans. It was found that the perception of poor ge- poorer self-rated health is a predictor for the use neral health significantly affected the increased of general practice. The extent to which the per- number of visits to family physicians. This is in son with poorer self-rated of health will use pri- accordance with the study conducted by Chou at mary health care services depends primarily on al among the elderly in Hong Kong (32). Hansen the degree of its social functioning. A person with et al. showed self-related health as a function of better social functioning can more easily achieve disability associated with higher use of primary a visit to a family physicians and also in case of care services but not inpatient admissions (33). need, solve his/her health problem. It is therefore The results of this study show that people who important to work on the implementation of in- are poorly socially functioning visited family terventions that will be aimed at improving social physicians less, which is in line with the conduc- functioning of older people. The implementation ted studies which state that poorer social functio- of these interventions is needed for enabling ol- ning is recognized as a barrier to health care uti- der people to maintain active and independent lization and solving health problems. Increasing life as long as possible. social support and mobility facilitates access to FUNDING family physicians (34-37). People who live alone are in a particularly diffi- No funding was received for this study. cult situation. Despite having poorer self-reported TRANSPARENCY DECLARATION health, those living alone attend outpatient and general practice less often (38). Zhou et al found Competing interests: None to declare.

REFERENCES 11. Martin LG, Schoeni RF, Freedman VA, Andreski P. 1. Charles S, Carstensen LL. Social and emotional Feeling better? Trends in general health status. J Ge- aging. Annu Rev Psychol 2010;61:383–409. rontol B PsycholSciSocSci 2007;62:11–21. 2. Webb E, Blane D, McMunn A, Netuveli G. Proximal 12. Shi L, Starfield B, Politzer R, Regan J. Primary Care, predictors of change in quality of life at older ages. J Self-rated Health, and Reductions in Social Dispa- Epidemiol Community Health 2011;65:542-7. rities in Health. Health Serv Res 2002; 37:529–50. 3. Zaninotto P, Falaschetti E, Sacker A. Age trajectories 13. McGee HM, O’Hanlon A, Barker M, Hickey A, of quality of life among older adults: results from the Montgomery A, Conroy R, O’Neill D. Vulnerable English Longitudinal Study of Ageing. Qual Life older people in the community: relationship between Res 2009;18:1301-9. the Vulnerable Elders Survey and health service use. 4. Waidmann T, Bound J, Schoenbaum M. The illusion J Am GeriatrSoc 2008;56:8-15. of failure: trends in the self-reported health of the US 14. Laroche M. Health status and health services utili- elderly. Milbank Q 1995;73:253–87. zation of Canada´s immigrants and non-immigrant 5. Kalfoss M, Halvorsrud L. Important Issues to Qu- populations. Canadian Public Policy 2000;26:51-75. ality of Life Among Norwegian Older Adults: An 15. Pappa E, Niakas D. Assessment of health care needs Exploratory Study. Open Nurs J 2009;3:45–55. and utilization in a mixed public-private system: the 6. Kaczmarczyk M, Trafiałek E. Activating elderly pe- case of the Athens area. BMC Health Serv Res 2006; ople - a chance of good and satisfying aging. Geron- 6:146. tol Pol 2007; 15:116–8. 16. Ware JE, Snow K, Kosinski M, Gandek B. SF-36 7. Christensen K, Doblhammer G, Rau R, Vaupel JW. Health Survey: Manual and Interpretation Guide. Ageing populations: the challenges ahead. Lancet Lincoln (RI): Quality Metric Incorporated, 2000. 2009;374:1196–208. 17. McDowell I. Measuring Health. A guide to Rating 8. Carstensen LL, Turan B, Scheibe S, Ram N, Ersner- Scales and Questionnaires. 3rd Edition ed. New Hershfield H, Samanez-Larkin GR, Brooks KP, Ne- York: Oxford University Press, 2006. sselroade JR. Emotional experience improves with 18. Ware JE, Jr., Hays RD. Methods for measuring pa- age: Evidence based on over 10 years of experience tient satisfaction with specific medical encounters. sampling. Psychol Aging 2011;26:21–33. Med Care 1988; 26:393-402. 9. Schnittker J, Bacak V. The increasing predictive vali- 19. Robine JM. Trends in population health. Aging Cli- dity of self-rated health. PLoS ONE 2014;9:e84933. nExp Res 2006;18:349–51. 10. Freedman VA, Martin LG, Schoeni RF, Cornman JC. 20. Jokela M, Batty GD, Kivimäki M. Ageing and the Declines in late-life disability: The role of early-and prevalence and treatment of mental health problems. mid-life factors. SocSci Med 2008;66:1588–602. Psychol Med 2013;43:2037-45.

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21. Sarvimäki A, Stenbock-Hult B. Quality of life in old of middle aged and older Australians. SocSci Med age described as a sense of well-being, meaning and 2004;59:2121-9. value. J AdvNurs 2000;32:1025-33. 32. Chou KL, Chi I. Factors associated with use of pu- 22. Molton IR, Terrill AL. Overview of persistent pain blicly funded services by Hong Kong Chinese older in older adults. Am Psychol 2014;69:197-207. adults. SocSci Med 2004;58:1025–35. 23. AGS Panel on Persistent Pain in Older Persons. The 33. Hansen MS, Fink P, Frydenberg M, Oxhøj ML. Use management of persistent pain in older persons. J of health services, mental illness, and self-rated di- Am GeriatrSoc 2002;50:205-24. sability and health in medical inpatients. Psychosom 24. Hairi NN, Cumming RG, Blyth FM, Naganathan V. Med 2002;64:668–75. Chronic pain, impact of pain and pain severity with 34. Thorpe JM, Thorpe CT, Kennelty KA, Pandhi N. physical disability in older people--is there a gender Patterns of perceived barriers to medical care in ol- difference?Maturitas 2013;74:68-73. der adults: a latent class analysis. BMC Health Ser- 25. Parkar SR. Elderly mental health: needs. Mens Sana vices Research 2011;11:181. Monogr 2015;13:91–9. 35. Taylor DH, Hoenig H. Access to health care ser- 26. Singh A., Misra N. Loneliness, depression and so- vices for the disabled elderly. Health Serv Res ciability in old age. IndustPsychiat J 2009;18:51–5. 2006;41:743-58. 27. Cornwell EY, Waite LJ. Social disconnectedness, 36. Iezzoni LI, McCarthy EP, Davis RB, Siebens H. Mo- perceived isolation, and health among older adults. bility impairments and use of screening and preven- J Health SocBehav 2009;50:31–48. tive services. Am J Public Health 2000; 90:955-61. 28. Barnett I, van Sluijs EM., Ogilvie D. Physical ac- 37. Fiscella K, Epstein RM. So much to do, so little time: tivity and transitioning to retirement: a systematic care for the socially disadvantaged and the 15-minu- review. Am J PrevMed 2012;43:329–36. te visit. Arch Intern Med 2008;168:1843-52. 29. Gilmour H. Social participation and the health 38. Kharicha K, Iliffe S, Harari D, Swift C, Gillmann G, and well-being of Canadian seniors. Health Rep Stuck AE. Health risk appraisal in older people 1: 2012;23:23-32. are older people living alone an “at-risk” group? Br 30. Morris St, Sutton M, Gravelle H. Inequity and inequ- J Gen Pract 2007;57:271-6. ality in the use of health care in England: an empiri- 39. Zhou C, Ji C, Chu J, Medina A, Li C, Jiang S, Zheng W, cal investigation. SocSci Med 2005;60:1251-66. Liu J, Rozelle S. Non-use of health care service among 31. Parslow R, Jorm A, Christensen H, Jacomb P, Rod- empty-nest elderly in Shandong, China: a cross-sectio- gers B. Gender differences in factors affecting use nal study. BMC Health Serv Res 2015;15:294. of health services: an analysis of a community study

Utjecaj samoprocjenjenog osjećaja zdravlja starijih osoba na posjete ljekaru porodične medicine Amira Kurspahić-Mujčić1, Melisa Čalkić2, Suad Sivić3 1Katedra za socijalnu medicinu, Medicinski fakultet, Univerzitet u Sarajevu, Sarajevo; 2Dom zdravlja, Gornji Vakuf-Uskoplje; 3Kantonalni zavod za javno zdravstvo Zenica, Zenica; Bosna i Hercegovina SAŽETAK

Cilj Evaluirati utjecaj osam dimenzija samoprocjene zdravlja, mjerenih upitnikom SF-36, na posjete ljekaru porodične medicine kod osoba starijih od 65 godina. Metode Rad predstavlja studiju presjeka provedenu u ambulantama porodične medicine Javne ustanove Dom zdravlja kantona Sarajevo (Bosna i Hercegovina). U istraživanje je bilo uključeno 200 ispitanika koji su bili podijeljeni u dvije dobne grupe:od 18 do 65 godina (n=100) i stariji od 65 godina (n=100). Korišten je upitnik SF-36 za samoprocjenu zdravstvenog stanja i upitnik za evaluaciju sociodemograf- skih obilježja ispitanika i korištenja zdravstvene zaštite. Rezultati U grupi ispitanika u dobi od 18 do 65 godina najbolje je bila ocijenjena dimenzija koja se odnosila na fizičko funkcioniranje (79.1±25.6), a najlošije dimenzija koja se odnosila na vitalnost (56.1±19.9). U grupi ispitanika starijih od 65 godina najbolje je bila ocijenjena dimenzija koja se odnosila na socijalno funkcioniranje (65.4±24.9), a najlošije dimenzija koja se odnosila na opće zdravlje (47.7±20.4). Ljekara porodične medicine posjetilo je znatno više ispitanika starijih od 65 godina nego ispitanika mlađe dobne grupe (94% vs. 74%) (p=0.000). Skorovi na skalama općeg zdravlja (p=0,021) i socijalnog funkcioniranja (p=0.024) kod ispitanika starijih od 65 godina imali su signifikantan utjecaj na posjete ljekaru porodične medicine. Zaključak Loša percepcija općeg zdravlja i bolje socijalno funkcioniranje su značajni prediktori posjete ljekaru porodične medicine kod starijih osoba. Ključne riječi:star, primarna zdravstvena zaštita, kvalitet života

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