Hyperchylomicronemia

Recurrence of Pancreatitis After Rechallenge

We report a case of pancreatitis, which occurred while the patient was on a propofol drip and then recurred after resolution following an inadvertent rechallenge with propofol. The initial episode was associated with hypertriglyceridemia, whereas the latter was not. The association between propofol and pancreatitis is definite and may occur independently of significant hypertriglyceridemia.

(CHEST 1999; 115:1198-1199)

Key words: drug-induced pancreatitis; hypertriglyceridemia; propofol

CASE REPORT

A 51-year-old woman with a past medical history of seizure disorder, schizophrenia, and bronchial asthma was admitted to the hospital because of worsening dyspnea from a community-acquired pneumonia. The patient was transferred to the medical ICU, intubated, and mechanically ventilated for acute respiratory failure. A propofol (Diprivan; Zeneca; London, UK) infusion was started, and the dose was titrated to achieve adequate sedation. The patient was on a propofol infusion continuously for 7 days (maximum dose of 200 [micro]g/kg/min), receiving a total dose of 26.5 g over the same period.

On the fourth day of the propofol infusion, serum triglycerides were noted to be elevated at 938 mg/dL. By day 7, the serum triglyceride level peaked at 1,498 mg/dL, accompanied by elevated serum amylase and increasing serum lipase levels (Fig 1). This was associated with a mild elevation in liver transaminases and alkaline phosphatase levels (hepatocellular pattern; Fig 2). The patient also developed epigastric tenderness and abdominal distension; therefore, propofol infusion was stopped (day 7).

[Figures 1-2 ILLUSTRATION OMITTED]

That same day, the tracheostomy tube was dislodged due to patient agitation. This culminated in a brief episode of cardiac arrest requiring cardiopulmonary resuscitation. After resuscitation, the patient developed ischemic acute tubular necrosis requiring a brief course of dialytic therapy.

The lipase levels peaked 4 days after the discontinuation of the propofol infusion (622 mg/dL). The workup for pancreatitis included an ultrasound, which demonstrated that the patient had a normal liver, small gallstones in a normal gallbladder with no evidence of common bile duct enlargement, and a mildly hyperechoic pancreas. Serum triglycerides gradually subsided over the next 7 days, and pancreatitis responded to supportive therapy. The patient's past medical history was unremarkable for previous cholelithiasis, cholecystitis, pancreatitis, hypertriglyceridemia, and significant alcohol ingestion.

The patient underwent tracheostomy revision on hospital day 17. Postoperatively, the patient developed abdominal pain and elevated lipase levels (peaking at 564 mg/dL), and there was a mild elevation in triglyceride levels (380 mg/dL). On review of the anesthetic record, it was noted that the patient had received a dose of 200 mg of propofol for the procedure. The patient improved clinically, and the biochemical markers of pancreatitis resolved over the next several days. The patient was then transferred to a chronic care facility for weaning from the ventilator. A lipoprotein electrophoresis done prior to the patient's transfer revealed no hyperchylomicronemia.

DISCUSSION

To date there are 25 reported cases of pancreatitis associated with propofol in the federal drug administration registry. The only details available are those about three medical and eight surgical patients described in the literature.[1] Whereas six of these patients had confounding illnesses, the remaining five, all of whom were surgical patients (two with a fatal outcome), previously had been healthy individuals who developed pancreatitis after induction of anesthesia with propofol. The association between propofol and pancreatitis is regarded as probable, but causality remains to be proven.

There are more than 85 drugs reported to cause acute pancreatitis.[2] These drugs could be further classified as those with a definite association (azathioprine, mercaptopurine, estrogen, etc), those with a probable association (L-asparaginase and steroids, among others), and those with a proposed association but with inadequate evidence (amphetamines, opiates, rifampin, etc).[3] In the absence of other risk factors, the occurrence of pancreatitis during treatment with a drug, its resolution on drug withdrawal, and its recurrence on rechallenge with the same drug is sufficient evidence to place a drug under the definite association category.[3] Propofol meets these criteria in our patient in that the temporal profile of events, borderline elevations of alkaline phosphatase, and negative biliary ultrasonsography rule out gallstone pancreatitis despite the cholelithiasis.

The mechanism of drug-induced pancreatitis includes hypersensitivity (to azathioprine or mercaptopurine, among others) or direct toxic injury (from pentamidine or valproate, among others).[2] Estrogen, vitamin A, and fat emulsions in total parenteral nutrition cause pancreatitis indirectly by inducing hypertriglyceridemia.[4] Propofol has been speculated to cause pancreatitis by this mechanism.

Propofol is administered as a fat emulsion, and it has a fat content very similar to 10% fat emulsion in total parenteral nutrition solution (100 mg/mL soybean oil, 22.5 mg/mL glycerol, and 12 mg/mL egg lecithin). It has been shown to increase triglyceride levels when given as a prolonged infusion, usually after 72 h.[5] Serum triglyceride levels of [is greater than] 1,000 mg/dL are associated with pancreatitis, although there are case reports of pancreatitis at much lower levels of triglycerides. Hypertriglyceridemia leads to an increase in pancreatic lipase in pancreatic capillaries, which leads to lipolysis, ischemia, capillary damage, and microthrombi. The further release of lipase continues the inflammatory cycle.[6] Patients with moderate obesity, diabetes mellitus, alcohol ingestion, Fredrickson's type 4 and 5 lipoproteinemia, and a family history of diabetes or lipoproteinemia are reported to be more susceptible to hypertriglyceride-mediated pancreatitis.[4]

Not all propofol-associated pancreatitis can be explained by hypertriglycerides, especially the cases occurring after a single bolus is used for the induction of anesthesia. The initial bout of pancreatitis in our patient was associated with significant hypertriglyceridemia, but the pancreatitis on rechallenge with propofol was not. It has been shown by Cameron et al [4,6] that patients recovering from pancreatitis have a persistent defect in lipid metabolism for up to 6 months, and recurrence of pancreatitis can occur if patients are given a small fat load during recovery. This mechanism does not explain the recurrence of pancreatitis in our patient because there was only a small increase in serum triglyceride levels (380 mg/dL) on rechallenge with propofol. We postulate that there may be more than one mechanism for propofol-induced pancreatitis. This implies that monitoring triglyceride levels with propofol use is not a guarantee against the occurrence of pancreatitis in these patients. This is congruent with the observation that pancreatitis may occur without associated hypertriglyceridemia after a single bolus dose of propofol is used in healthy surgical patients.

Based on this experience and prior literature, we suggest that propofol should be included in the list of drugs with definite causal association with pancreatitis. We also propose that it could cause pancreatitis by a mechanism other than hypertriglyceridemia.

REFERENCES

[1] Leisure GS, O'Flaherty J, Green L, et al. Propofol and postoperative pancreatitis. Anesthesiology 1996; 84:224-227

[2] Steinberg W, Tenner S. Acute pancreatitis [review]. N Engl J Med 1994; 330:1198-1210

[3] Mallory A, Kern F Jr. Drug-induced pancreatitis: a critical review. Gastroenterology 1980; 78:813-820

[4] Toskes PF. Hyperlipidemic pancreatitis. Gastroenterol Clin North Am 1990; 19:4:783-791

[5] Carrasco G, Molina R, Costa J, et al. Propofol vs midazolam in short-, medium-, and long-term sedation of critically ill patients. Chest 1993; 103:557-564

[6] Cameron JL, Capuzzi DM, Zuidema GD, et al. Acute pancreatitis with hyperlipemia: evidence for a persistent defect in lipid metabolism. Am J Med 1974; 56:482-487

(*) From the Division of Cardiology (Dr. Kumar), Department of Anesthesiology (Dr. Schwartz), and the Division of Pulmonary and Critical Care Medicine (Dr. Lim), Michael Reese Hospital and Medical Center, Chicago, IL.

Manuscript received July 17, 1998; revision accepted September 29, 1998.

Correspondence to: Kaiser Lira, MD, Michael Reese Hospital and Medical Center, Bauragarten Room 114, 2929 S Ellis St, Chicago, IL 60616

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