Propofol Infusion Syndrome?
Dr. Kofke calls our attention to a review of the FDA surveillance data on the association of propofol infusions for non procedural, long term sedation and death in both children and adults. Wysowski and Pollock (1) reviewed the reported adverse event data for children and adults >16 years old) in which propofol was thought to the suspect drug from the time of marketing through April, 2005. Particular emphasis was placed on identification of patients with propofol infusion syndrome which was defined as metabolic acidosis and/or rhabdomyolysis with progressive myocardial failure. With respect to the adult data there were 68 reports of patients who died after administration of propofol for non procedural sedation. The mean duration of propofol use was reported as 7.3 days (the median duration was 4.4 days and the range was < 1 h to 42 days). The peak propofol dose was about 120 mcg/kg/min with a median of 90 and a range of 10 – 416. Twenty-one of the 68 patients had disorders consistent with propofol infusion syndrome and 6 more had disorders probably or possibly related to this syndrome.
The authors compared their findings from the FDA surveillance data with some of the published case reports. They found five reports involving adults published from the United States and two from other countries. The patients typically received propofol for an extended period at a high dose. Studies of propofol exposure typically identify hypotension ad the most frequent and serious acute adverse event. However the studies typically used lower infusion rates of propofol.
Of greater concern to me are two reports of intraoperative metabolic acidosis that the authors associated with an anesthetic infusion of propofol (2,3). In one case (2) a 31 year old, 217 lb woman developed a metabolic acidosis during radiofrequency ablation for pulmonary vein isolation. The propofol infusion ranged from 50 to 125 mcg/kg/min. The patient was breathing spontaneously by face mask. The authors noted that the patient developed a metabolic acidosis during the course of the procedure and 7 hours into the surgery the pH was 7.30 and the BE was – 8. During the course of the procedure to that point she had received normal saline 2 – 3l. Serum chloride, glucose or lactate concentrations were not measured, no other instability was noted. The fact that the patient got a mild metabolic acidosis during a propofol infusion and that the acidosis resolved when the propofol was stopped is a very weak association in the absence of laboratory studies to eliminate the more likely causes of the metabolic abnormality.
In the second report (3) a 64 y/o, 156 lb male underwent a radical prostatectomy using infusions of propofol, remifentanil and mevacurium. 2.5 g of propofol and 6 mg of remifentanil was used during the 4.5 h case. The authors note that 3 hours into the case the patient became tachycardic. As the case proceeded the authors noted a progressive metabolic acidosis which they attributed to propofol. At one point (hour 4) they found the following ABG values: pH 7.28, PO2 177, PCO2 43.5, lactate 6.99 mM, HCO3 20.8 mM. base excess -5.1 mM, glucose 136 mg/dl. They provided no information about fluid replacement or blood loss, nor did they test for the more common causes of intraoperative metabolic acidosis such as hyperchloremia.
The editorial that discussed these two reports (4) addressed briefly some of the criticisms I raised, but did not address the key logical flaw of both reports. Just because event “A” occurs at the same time as event “B” does not mean that A and B are related. At UPENN I have given a very large number of intraoperative propofol infusions for long duration surgery yet this phenomena of intraoperative propofol induced intraoperative metabolic acidosis has never been noticed. However I do see a significant number of patients both with and without propofol infusions who develop intra operative base deficits in the range of -4 to -8. Most of these appear to be associated with intraoperative use of 2 to 6 liters of 0.9% sodium chloride for volume replacement with resulting serum chloride levels of 105 – 115 mEq/l. Perhaps if the authors of the two case reports had been able to measure serum chloride the cause of intraoperative acidosis might have seemed less ominous? Of interest is a recent letter to the editor by Rozert and Lam (5) which also addresses some of the concerns I have raised in reference to a more recent retrospective study in which the term “propofol infusion syndrome” was used, to my way of thinking, inappropriately.
The AstraZenica package insert for propofol 1% dated August 2005 notes that “very rare reports of metabolic acidosis, rhabdomyolysis, hyperkalemia and/or cardiac failure, in some cases with a fatal outcome, have been received concerning seriously ill patients receiving propofol for ICU sedation. However the package insert does not mandate dose or infusion duration limitations.
I have not mentioned issues related to propofol infusions in children as my practice is limited to adults. However, the propofol infusion syndrome appears to be more frequent in the younger age group.
References:
- Wysowski DK, Pollock ML: Reports of death with use of propofol (Diprivan) for nonprocedural (Long –term) sedation and literature review. Anesthesiology 2006:105:1047-51
- Burow BK et al: Metabolic acidosis associated with propofol in the absence of other causative factors. Anesthesiology 2004;101:239-41
- Salengros J-C et al: lactic acidosis during propofol-remifentanil anesthesia in an adult. Anesthesiology 2004;101:241 – 243
- Funston JS, Prough DS: Two reports of propofol anesthesia associated with metabolic acidosis in adults (editorial). Anesthesiology 2004;101:6-8
- Rozert I, Lam AK: Propofol infusion syndrome or probably overinterpretation syndrome? Anesthesiology 2008;108:330
WA Kofke is Professor of Anesthesiology and Critical Care at the University of Pennsylvania
David S. Smith, M.D., Ph.D.
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