This study provides the first quantitative estimate of the incidence of mild metabolic acidosis during prolonged propofol infusion in non-critically ill patients, where there is no apparent cause of the acidosis except propofol: 24%, significantly greater than the 8% incidence of metabolic acidosis in the nonpropofol comparator group. This surprisingly high incidence is not an indication of the number of patients at risk for serious injury from the fulminant form of propofol infusion syndrome, because the study criterion (BE ≤ -2) was designed to detect early, mild, reversible cases. Indeed, none of the patients in this study showed evidence of permanent injury from their mild metabolic acidosis. However, our data do support the hypothesis that clinically significant propofol infusion syndrome is an extreme manifestation of a more common, initially reversible syndrome, rather than an extremely rare, idiosyncratic drug reaction.
The criteria we used for alternate causes of metabolic acidosis were designed to exclude stringently any possible nonpropofol cause. The few cases in the lower left quadrant of figure 1 (low propofol dose, severe metabolic acidosis) are most likely to be those not caused by propofol, although we cannot exclude an effect of propofol to worsen an already significant metabolic acidosis. It is possible that some of the milder alternate cause cases developed a metabolic acidosis secondary to propofol as well (e.g., well-controlled diabetes, mild stable lung disease causing an oxygen saturation measured by pulse oximetry of 94%), so that the incidence of 24% would be an underestimate of the effect of propofol to cause metabolic acidosis.
There are several limitations inherent in the retrospective nature of this study. However, the study design is unlikely to artifactually increase the observed incidence. Because most ABGs in the propofol RFA patients were drawn as a check on respiratory depression, rather than consistently during the propofol infusion, some cases of metabolic acidosis could have been completely missed. The retrospective study design thus creates a bias toward underestimate, rather than overestimate, of the incidence of mild propofol infusion syndrome.
A secondary objective of this investigation was to determine the dose-response curve of metabolic acidosis related to propofol. However, the data did not display a statistically significant relation between propofol dose and metabolic acidosis (fig. 1). Although this does not add further support to a causal relation, the limitation inherent in a retrospective chart review, with nonuniform, sporadic sampling of ABGs, is the most likely explanation. Most patients had only one or two ABGs sampled, at times that were not necessarily optimized to detect the maximal negative BE. It is also possible that the dose-response relation was obscured because, although the dose was high for sedation (approximately 50 μg · kg-1 · min-1), it was relatively low compared with most reported cases of propofol infusion syndrome, with infusions often 100 μg · kg-1 · min-1 or higher.
Another limitation of this study is that our population of patients undergoing RFA during the study period included almost no patients not receiving propofol, so that there was not a control group identical except for propofol administration. We added CEA patients as a nonpropofol comparator group after the original data analysis of the RFA propofol patients. This provided a comparator group that should compensate for any institution-specific bias in ABG collection method or analysis. Use of CEA patients before surgical incision also provided comparators with low levels of surgical stress similar to the nonsurgical RFA procedure, and an adequate number for statistical comparisons. This did result in a difference in ABG collection time between the groups, with propofol ABGs drawn throughout the anesthetic, and nonpropofol CEA ABGs drawn at the beginning of the anesthetic. However, available data do not suggest a time-dependent change in BE during anesthesia in the absence of factors known to cause metabolic acidosis.20 Our analysis is clearly limited by the lack of a true control group, and must be assessed with caution. However, we could not find any area at our institution that would yield a true control group for a retrospective study such as this, and it is unlikely that we could propose and conduct a prospective study without the estimate of propofol-associated metabolic acidosis provided by this retrospective study.
This study was also limited by not having available other data that would be helpful in determining the etiology of the metabolic acidosis, particularly serum lactate and chloride. Our analysis of potential nonpropofol causes of metabolic acidosis, and of the relation of intravenous saline administration to acidosis, partially compensates for the lack of data on lactate and chloride. A subsequent prospective study should certainly collect this data as well as ABGs. While some reports of propofol infusion syndrome have described elevated serum lactate, until the etiology of the syndrome is better understood, elevated lactate should be considered suggestive rather than a requirement for the diagnosis of the syndrome.
In summary, this study provides evidence that even in a non-critically ill population, prolonged high-dose propofol infusion is associated with otherwise unexplained metabolic acidosis in a significant number of patients, rather than being extremely rare. The study is limited by its retrospective nature and lack of a true control group. A prospective study designed specifically to assess metabolic acidosis during prolonged propofol infusion is needed, but has been difficult to plan in terms of sample size without the data provided here. All of the patients we studied showed no lasting adverse effect from their metabolic acidosis, suggesting that it was reversible. Although this is reassuring, it also suggests that the potential for propofol infusion syndrome exists in a significant part of the population and that caution with frequent surveillance for metabolic acidosis is appropriate with propofol infusions in patients where metabolic acidosis could worsen other disease processes.
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