Propofol is a short-acting intravenous (i.v.) anaesthetic which is used frequently for short-term anaesthesia . There is a rapid recovery after long-term infusion of propofol which makes it a suitable drug for use as a sedative agent during intensive care . Although propofol has been on the market for almost 15 years, new and unexpected properties are still being discovered. Recent reports [2-4] have indicated a possible relation between the use of propofol and pancreatitis.
In this study, the effects of propofol administered as a bolus or infusion on histopathological changes in the rat pancreas were evaluated.
After obtaining approval from the Hospital Ethics Committee, 75 female Wistar rats weighing 200-350 g were studied. They were fed standard rat chow and given free access to water. The rats' tail veins were cannulated with a 24-gauge catheter. Groups I (n=30) and II (n=30) received 10 mg kg−1 i.v. bolus of propofol dissolved in soya bean extract (diprivan®, Zeneca Limited, Macclesfield, Cheshire, UK), and group II was administered propofol at an infusion rate of 10 mg kg−1 hr−1 for 30 min via a syringe pump (JMS model SP-100 s, JMS Co. Ltd., Hiroshima, Japan) immediately after the initial bolus doses. Propofol was administered as described by Rocchiccioli et al.. Propofol was diluted with 5% dextrose (0.2 mg mL−1). Group III (n=15) was the control group; these rats received only 2 mL of 5% dextrose.
The animals all breathed spontaneously throughout the study period. External heating was applied to all animals during the experiment. A median laparotomy was performed, under ether anaesthesia, 24 h after propofol administration. Blood samples were obtained, pancreatic tissue biopsies were taken and the animals were sacrificed by exsanguination. Plasma cholesterol, triglyceride, amylase and lipase levels were measured. Pancreatic specimens were immediately fixed in 4% buffered neutral formalin. Paraffin-embedded tissues were sectioned at 4-5 μm thickness. Sections were stained with haematoxyline and eosin, and were examined under light microscopy by a pathologist blind to the experiment.
The Mann-Whitney U-test was used for statistical analysis of plasma cholesterol, triglyceride, amylase and lipase levels. Histopathological changes were compared using the Fisher exact test. A value of P<0.05 was considered significant. Results are expressed as mean±standard error for plasma cholesterol, triglyceride, amylase and lipase levels.
Plasma cholesterol levels were 61.0±1.5 mg dL−1 in group I, 86.4±5.3 mg dL−1 in group II, and 53.1±3.3 mg dL−1 in group III and triglyceride levels were 67.3±6.1, 106.6±11.3, and 63.1±4.1 mg dL−1, respectively. These values were higher in group II than in the other groups and the difference was significant (P<0.05). Plasma amylase levels were 1158.0±39.0 U dL−1 in group I, 1225.4±61.8 U dL−1 in group II, and 992.3±72.6 U dL−1 in group III and lipase levels were 114.1±9.7, 130.3±24.8, and 106.5±13.6 U dL−1, respectively. There were no significant differences in plasma amylase and lipase levels between the groups (P>0.05).
Examination of the specimens under light microscopy revealed normal pancreatic tissue in group I, while acute pancreatitis was identified in three rats in group II and in one rat in the control group. The respective group incidences of acute pancreatitis were not significant (P>0.05).
Light microscopic examination showed a diffuse infiltration of neutrophils, lymphocytes and plasma cells in the pancreatic tissue of two rats in group II, and of one rat in the control group. Interstitial oedema and a focal fibroblastic reaction were also observed (Fig. 1a). In one rat in group II, necrotizing vasculitis was seen in the peripancreatic fat, in addition to morphological findings of acute pancreatitis (Fig. 1b).
Wingfield  reported four patients who developed acute pancreatitis after abdominal surgery. Death in two of these resulted from respiratory distress syndrome, which developed after the onset of pancreatitis. In both of these patients, anaesthesia was induced with propofol. In commenting on this report , Zeneca Ltd evaluated all reported cases associated with the administration of Diprivan® and determined the number of instances of pancreatitis to be eight. They also found that the medical histories of these patients included biliary stones, alcohol abuse, or hypertriglyceridaemia and concluded that a relation between post-operative pancreatitis and bolus induction doses of propofol was unlikely.
However, other case reports [2,4] describe two patients who developed acute pancreatitis following propofol administration. Metkus et al. have recently reported a previously healthy patient who developed necrotizing pancreatitis after continuous propofol infusion. They suggested that propofol-induced hypertriglyceridaemia was the most likely cause of necrotizing pancreatitis in this patient. Leisure et al. described the case of another previously healthy patient who underwent non-abdominal surgery, and proposed a possible link between the use of propofol and pancreatitis.
In light of these reports [2-4], we investigated the histopathological effects of propofol on the rat pancreas. To our knowledge this is the first study in which the relation between propofol and pancreatitis is examined. No histopathological changes consistent with ischaemia or hypoxia were observed in any of the rats. While no pancreatic tissue changes were detected in the bolus propofol group, three rats (10%) in the infusion group had histopathological changes consistent with acute pancreatitis. However, this finding could not be attributed solely to propofol infusion, as one of the rats (6.6%) in the control group suffered pancreatitis and the differences between these two incidences was not significant (P>0.05).
In recent years, several human and animal studies have shown that hyperlipaemia may be an aetiological factor in pancreatitis , but the mechanism or mechanisms involved remain unexplained. Several authors have recorded that acute pancreatitis and hyperlipaemia coincide in 12 to 38% of patients .
Propofol has many advantages, in intensive care, over other more commonly used sedatives, although prolonged infusion at high rates can raise serum lipid concentrations . Our results demonstrated a similar increase (P<0.05) in plasma cholesterol and triglyceride levels in group II, but it remains unclear whether hyperlipaemia secondary to i.v. propofol administration is a precondition for the development of acute pancreatitis.
In conclusion, histopathological investigations have revealed three cases of acute pancreatitis in 30 rats following a propofol infusion group (P>0.05). The mechanism of any relation between pancreatitis and propofol remains undefined. However, pancreatitis is a life-threatening disorder which may lead to multiorgan failure and sepsis, anaesthesiologists should therefore be aware of this undesired but possible effect.
Further controlled studies are required to confirm the relation which is postulated between propofol administration and pancreatitis, and the importance of dose and duration.
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Hyperlipaemia intensifies the course of acute oedematous and acute necrotising pancreatitis
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