Galician Medical Journal. 2015; 22(1)

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M.H.Honchar, D.M.Vynnyk EXPERIMENTAL TREATMENT OF ACUTE INTERSTITIAL PANCREATITIS USING LOCAL HYPOTHERMIA Department of Surgery of Stomatological Faculty (Head of the Department – O.V. Pyptiuk) Ivano-Frankivsk National Medical University, Ivano-Frankivsk, Ukraine Abstract. Acute interstitial pancreatitis (AIP) is one of the simplest forms of acute pancreatitis treated conservatively in most cases. However, AIP transforms into destructive forms of acute pancreatitis when treating inadequately (15% of cases). The mortality rate for patients with acute interstitial pancreatitis is 1.6-3.1% while the mortality rate for patients with its destructive forms reaches 80%. Materials and Methods. Local hypothermia (LGP) of pancreas by using 0.9% NaCl solution with an initial temperature of 4 °C was performed experimentally on 60 white rats after modeling of AIP. The enzymatic activity in the pancreas and the level of inflammatory mediators before and after the application of LGP were investigated. Results. The use of LGP in experimental rats with AIP reduced the level of alpha-amylase by 3.2 times and decreased levels of interleukin 6 by 2.3 times. Conclusions. It was revealed that the activity of the inflammatory process reduced gradually after application of local hypothermia for 8-10 hours. It can be explained by the inhibition of the cascade of enzymatic reactions and decrease in the synthesis of active enzymes, and significantly slower metabolic processes of the pancreas. Keywords: pancreas, local hypothermia, acute interstitial pancreatitis. Problem statement and analysis of recent research In the structure of surgical diseases the proportion of patients with AIP constitutes 10-15% of the pathology of the abdominal cavity [5]. Its growth rate is far ahead of all other surgical pathological processes in the abdominal cavity [6, 7]. Treatment of pancreatitis at the interstitial phase is critical for long-term results because according to B.I. Alperovych and A.A. Shalimov, timely treatment can prevent transformation of AIP into its destructive forms. Mortality from AIP is 1.6-3.1%, while mortality due to its destructive forms constitutes 80% [1,3,4,8]. Among the therapeutic arsenal existing in pancreatology, some researchers recommend the use of local hypothermia. An investigation of cryodestruction of the pancreas in acute experimental pancreatitis shows that low temperature blocks pathological processes, relieves enzymatic toxemia, and in most cases lead to the patient’s recovery [9, 10, 11]. According to B.I. Alperovych and A.A. Shalimov using hypothermia in acute pancreatitis allows us to cure the patient during the first three days of onset. A number of clinicians indicate that hypothermia can change the mechanism of inflammation and protect experimental animals from the harmful effects of AIP (which was simulated by injection of cerulein) [5, 7, 9, 11, 12]. The main morphological criteria are macroscopically interstitial edema, microscopically leukocyte (mainly neutrophil) imbibition with small areas of necrosis of acinar cells and parapancreatic fat. Modern methods of hypothermia are based on the temperature reduction from +35 to + 10°C, which does not affect the structure and function of islets of Langerhans, but inhibits the exocrine apparatus. Local hypothermia in experimental pancreatitis reduces the need for oxygen, which is also due to inhibition of metabolic processes at low temperature. Effect of local hypothermia on the course of acute pancreatitis is associated with a reduction in metabolism, anti-hypoxic effect, analgesic effect and time factor (the ability to save time for adequate pathogenetic therapy). The objective of the research was to develop an efficient method of using local hypothermia in treatment of acute experimental pancreatitis. Material and Methods Experiments were performed on 60 albino Wistar rats, their average weight constituted 0.2-0.3 kg. “Cerulein model” was selected for experimental modelling of AP by means of intraperitoneal injection of 0.5 - 1.0 ml of cerulein (50 mg / kg). All experimental rats were divided into 3 groups: group I included rats with AIP received hypothermia by means of proposed method and conservative therapy (according to standard protocols); group II included rats with AIP underwent laparotomy and conservative therapy; group III included rats with untreated AIP. The likelihood of development of AIP was evaluated histologically (Figure 1), by increased level of AA and the presence of pro-inflammatory mediators (IL1, IL6). Hypothermia in group I was performed as follows: 3-5 hours after the cerulein injection laparotomy was performed under general anesthesia, drainage pipe with holes was installed through the side apertures. The drainage was connected to the infusomat that cooled pancreas with the help of 0.9% NaCl at an average temperature of 4°C for 10-12 hours. Laparatomy wound was stitched up. Group II (the comparative group, n = 20) underwent a classic conservative treatment of AIP (H2 blockers, proton pump inhibitors, enzyme inhibitors, analgesics). All drugs were administered in terms of body weight of experimental rats. In addition to conservative treatment group II underwent laparatomy. Group III (n = 20) was not treated. Histological examination was performed under ether anaesthesia and blood sample was obtained from the abdominal aorta (AA IL1, IL6, C-



Galician Medical Journal. 2015; 22(1)

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reactive protein (CRP)) 13-15 hours after onset. Temperature measurement was performed using an electric thermometer. Its conductor was installed on the surface of the pancreas and removed through aperture. Normal body temperature of rats was 38-40°C, pancreas was cooled to 36-30°C. Results and discussion The results showed that the activity of AA was inhibited mainly during the application of LHP and traditional treatment of AIP in the first and second groups, respectively. AA activity in both groups, where treatment of AIP was performed, decreased almost 4 times compared to group III (in some individuals AA levels constituted 512 U). In group I AA level decreased by 65.44±2.11 U., in group II it constituted 76.55±3.58 U (p<0.01), normal level was 60 U[4]. Indicators of specific inflammatory mediators IL1 in group I, where LHP was performed, declined and amounted to 3.94±0.48 pg/ml, in group II (classical treatment of AIP and laparotomy) indicators exceeded the reference values. They constituted 6.68±1.29 pg/ml, reference value was up to 5.0 pg/ml (p <0.05). IL1 constituted 4.61±3.12 pg/ml in the group of untreated rats with AIP. Indicators IL6, IL1 were decreased in group I where LHP was performed. IL6 level was 9.41±0.64 pg/ml., in group II (AIP classical treatment and laparotomy) the IL6 level was 12.60±1.34 pg/ml (normal level was up to 9.7 pg/ml) (p<0.05). CRP is the most often estimated marker to differentiate severity of AP. The results of the investigation of CRP in blood plasma showed that statistically significant differences between groups I and II were practically absent. They constituted 7.20±0.67 pg/ml and 7.97 ± 0.65 pg/ml (reference value was 5.0 pg/ml) (p <0.003). It pointed to an acute process that was still preserved in the body. In group III indicators of CRP were higher than the reference value and accounted to 10.68 pg/ml, which proved the effectiveness of the proposed treatment of AIP (Table 1). Conclusions 1. The use of LGP in experimental rats with AIP reduced enzyme activity by 3.2 times during the first 12 hours of onset and caused a reduction in inflammatory mediators IL6 and CRP that indicated a positive effect of hypothermia. 2. IL1 did not show specific sensitivity to AIP within the first 12 hours that indicated its inefficient use in diagnosis in the early stages of the disease. 3. IL6 showed specificity in AIP. It indicated its effectiveness in complex diagnostics of AIP. It can be used as a mediator of acute-phase proteins. IL6 reflects the activity of anti-inflammatory cytokines. 4. CRP is a reliable marker of acute progress and is an indicator of activation of the inflammatory response. References 1. Shalymov A.A., Lifshitz Yu.Z., Kryzhevskyi V.V. A modified approach to the management of patients with necrotizing pancreatitis. Klin. Khirurhiia. 1994; 11: 3-6. 2. Saveliev V.S., Buyanov V.M. Acute pancreatitis. Moskwa. Meditsina. 1983; 530. 3. Smirnov D.A. Acute pancreatitis. Khirurhiia. 1994; 1: 30-32. 4. Shalymov S.O., Radzyhovskyy A.P., Nychytailo M.Yu. Acute pancreatitis and its complications. Kyiv. Naukova dumka. 1990; 270 . 5 Shalymov A.A., Shalymov S.O., Nychytailo M.Yu. Pancreatic surgery. Sympheropol. Tavryda. 1997; 560. 6. Kozlov V.A., Starodubov V.I., Nikiforov A.I. Abdominization of the pancreas and local hypothermia in surgical treatment of pancreatitis. Materialy 30-go Vsesoyuznogo syezda khirurgov. Moskwa. Khirurgiya.1981; 218-219. 7. Lutsevich E.V., Chepelenko G.V. The pancreas as one of the targets of “autofermentative explosion” in pancreatitis. Khirurgiya. 2001; 9: 57–60. 8. Shalymov A.A., Shalymov S.O., Zemskov S.V. Hypothermia in pancreatic surgery. Klinicheskaya khirurgiya. 1982: 11; 1–7. 8. Bhagat L., Singh V.P., Song A.M. et al. Thermal stress-induced HSP70 mediates protection against intrapancreatic trypsinogen activation and acute pancreatitis in rats. Gastroenterology. 2002;122:156-65. 9. Formela L.J., Galloway S.W. et al. Inflammatory mediators in acute pancreatitits. Br J Surg. 1995; 82: 613. 10. Frossard J.L., Baghat L., Lee H.S. et al. Both thermal and non-thermal stress protect against caerulein induced pancreatitis and prevent trypsinogen activation in the pancreas. 2002; 50:78-83. 11. Grisé K., Kim F. et al. Hyperthermia induces heat-shock protein expression, reduces pancreatic injury, and improves survival in necrotizing pancreatitis. Pancreas. 2000; 21: 120. 12. Matsuoka K., Ueno T., Morita K., Kawano H. et al. Effects of hypothermia on cerulein-induced pancreatitis. Pancreas.Pancreas. 2003; 26: 7-12.



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