Propofol infusion syndrome: a structured review of experimental studies and 153 published case reports

Mitochondrial toxicity of many anaesthetics used in the 1980s [28] and the structural similarity of propofol to co-enzyme Q led to early formulation of the hypothesis that PRIS is caused by uncoupling or inhibition of the respiratory chain. A series of animal experiments addressed this. Branca et al. [29, 30] exposed isolated rat liver mitochondria to 0–100 μmol/l propofol (plasma concentration in patients sedated with propofol is in the range 5–30 μmol/l). They found a linear dose-dependent reduction of respiratory chain capacity (measured as maximal uncoupled respiration) and transmembranous potential (ΔΨ), but no impairment of ATP synthesis up to 75 μmol/l propofol. It should be stressed that in these experiments succinate was used as a mitochondrial substrate, feeding electrons to Complex II and bypassing Complex I, which is often damaged during mitochondria isolation. Rigoulet et al. [31] later demonstrated that Complex I in isolated rat liver mitochondria is more sensitive to inhibition by propofol than complex II and also demonstrated the ability of propofol (25–400 μmol/l) to cause a leak of protons through the inner mitochondrial membrane, probably via dysfunctional ATP synthase. Mitochondria isolated from rat hearts in similarly designed experiments seemed to be more resistant to propofol toxicity, as reduction of ΔΨ and inhibition of ATP synthesis were only observed at >300 μmol/l propofol [32]. In an ex-vivo study [33] on isolated perfused guinea pig hearts, supratherapeutic propofol concentrations (50–200 μmol/l) caused a delay in myoglobin desaturation and cytochrome c reduction after exposure to ischaemia, consistent with inhibition of the respiratory chain, but not with uncoupling. Of note, these effects were dependent on the dose of propofol, but not on the duration of infusion (0–120 minutes). Decreased activity of cytochrome c oxidase (complex IV) was independently found in skeletal muscle biopsies of two patients with PRIS [34, 35]. The defect was not present in skin fibroblasts suggesting an acquired rather than undetected inborn defect [35]. More recently, significantly reduced activities but normal concentrations of all respiratory complexes were found in a patient who died of PRIS [36], and complex IV was affected most.

New light has now been shed on the conflicting results by a landmark study of Vanlander et al. [36] who in a series of experiments combining a rat model of PRIS and in-vitro exposure of tissue homogenates to propofol demonstrated that propofol in therapeutic concentrations interacts with co-enzyme Q and blocks electron transfer from complexes I and II to complex III, whilst much higher concentrations of propofol are needed to block the activities of individual complexes. Out of these, the activity of complex IV was the most sensitive to inhibition by propofol and only this complex could be inhibited by the concentrations, which were achieved in tissues of animals treated with propofol.

Another proposed mechanism of PRIS is inhibition of fatty acid oxidation, formulated by Wolf et al. [37, 38] and Withington et al. [39] who observed increased plasma concentrations of acyl derivatives of carnitine in children with PRIS, which normalised after cessation of propofol infusion, suggesting a propofol-induced defect of fatty acid oxidation [40]. Also, in one case, PRIS seemed to be triggered by a ketogenic diet [41]. Critical illness itself causes a switch from carbohydrate utilisation to oxidation of lipids. High levels of stress hormones and insulin resistance activate endogenous lipolysis and plasma free fatty acid levels increase [42]. The lipid vehiculum of propofol may further increase the burden imposed on free fatty acid oxidation. Duration of exposure to propofol seems to be a crucial factor in the development of the defect of fatty acid oxidation: in a patient on a propofol infusion (4.1–6.6 mg/kg per hour) [38] plasma C4-carnitine species rose steadily over the period of 5 days. The mechanism by which propofol influences fatty acid oxidation is unknown. One animal study [43] demonstrated an inhibition of the transport of fatty acid into mitochondria at the level of carnitine-acyl transferase I. This enzyme is activated by adenosine monophosphate-activated kinase (AMPK). If propofol interferes with signalling function of co-enzyme Q [36], it may attenuate the activation of fatty acid oxidation by AMPK [44], but the activity of this enzyme has been increased in the myocardium of propofol-sedated rabbits [45]. Finally, propofol triggered apoptosis in human endothelial cell lines and increased vascular permeability in mice [46], but the doses required to elicit these effect were orders of magnitude higher than those seen in clinical situations.

In summary, current experimental data suggest that propofol, structurally similar to co-enzyme Q, interferes with electron flux from upstream complexes (I and II) to complex III. In addition it interferes with fatty acid oxidation, which builds up in plasma over time. Very high doses of propofol seem to directly inhibit the activity of complex IV and uncouple the respiratory chain by modifying the structure of F₁F₀ATPase.

Our finding that mechanical cardiac failure and metabolic (in most cases lactic [12, 34, 47‐50]) acidosis occur early (often within the first few hours [7, 23, 34, 51‐53]) and in a dose-dependent manner, is consistent with a direct inhibition of aerobic phosphorylation observed in experimental studies. The heart is highly reliant on aerobic ATP synthesis [54] and acidosis may represent a combination of hypoperfusion and cytopathic hypoxia in tissues. Fever is reported more frequently with higher propofol infusion rates and this may reflect mitochondrial uncoupling and energy dissipation as heat. Fever is also an independent predictor of mortality in our model, possibly identifying subgroups of patients who are more susceptible to mitochondrial uncoupling. On the other hand, arrhythmia and ECG changes occurred more frequently in PRIS cases caused by prolonged propofol infusions and were the only signs which were not seen in animal models of PRIS triggered by short-term (<38 hours) high-dose propofol [36, 43, 45, 55]. A possible explanation is that arrhythmia and ECG changes are caused by elevated free fatty acids, which steadily increase over days during propofol administration [37] and are known to be proarrhythmogenic [56] (even more so in combination with metabolic acidosis). Similarly, rhabdomyolysis (a common feature of inborn defects of fatty acid oxidation [57, 58]) is associated with the duration of propofol administration and may also be related to the propofol-induced defect of fatty acid oxidation. The frequency of hypertriglyceridaemia seems to also increase with cumulative dose of propofol. If the dose of lipid emulsions exceeds the capacity of hydrolysis in plasma, triacylglyceroles accumulate in the blood and are taken up by the reticulo-endothelial system, causing hepatosplenomegaly, jaundice, and clotting disturbances (“fat overload syndrome” [59]). Recommended lipid dose for parenteral nutrition is 29–54 mg/kg per hour [60]. To match this dose, propofol as a 1 % solution in 10 % intralipid has to run at 2.9–5.4 mg/kg per hour. Most of the patients with PRIS exceeded this rate. Nonetheless, it seems that excessive doses of lipid emulsions are generally well tolerated; rapid infusions of lipid emulsions even in a range of 170–5000 mg/kg per hour have been accidentally administered without side effects [61]. In animal models of PRIS [45, 55], elevated triglycerides was the only sign observed in control animals receiving intralipid alone. In our study, even in the subgroup of patients with infusions at a rapid rate administered over an extended period of time, only a minority (40 %) developed hypertriglyceridaemia and this symptom had no relation to the outcome of PRIS. Possible explanation is that hypertriglyceridaemia represents an epiphenomenon rather than a genuine part of PRIS. Other features of lipid overload syndrome were absent in our series of patients with PRIS, with the exception of one patient with hyperbilirubinaemia [9]. AKI is reported in 39 % of patients with PRIS. It was associated with rhabdomyolysis in our series (R = 0.28, p = 0.0004) and myoglobin casts were found in kidneys of rabbits treated with propofol [55], but still there is no link to propofol dose or duration of infusion. It is likely that propofol may have been only a minor factor among many others causing AKI in sick ICU patients.

From the clinical perspective it is important to note that exceeding recommended doses of propofol is not only the main risk factor for the development of PRIS [16, 20], but also that the probability that PRIS will be deadly also increases—at least among the published cases of PRIS. On the other hand, our analysis shows that PRIS can develop with doses well within the recommended safety limits and even after a relatively short duration of administration. In these situations some typical features are often missing, which can make the diagnosis challenging. For example, with doses <4 mg/kg per hour the frequencies of hypertriglyceridaemia, fever, hepatomegaly and heart failure are <5 % in published cases of PRIS, while after short infusions of higher doses, ECG changes and arrhythmia may not be present and PRIS can be manifested as unexplained cardiac failure and metabolic acidosis. Propofol should automatically be suspected if any of the signs of PRIS appear without alternative explanation in an ICU patient on propofol infusion. There is no specific treatment for PRIS and the only way to prevent further deterioration and death is to recognize PRIS early and stop the infusion. Supplementation of co-enzyme Q may become a promising therapeutic strategy (a propofol “antidote”) in the near future [36].

The main limitation of our study is the risk of publication bias, i.e. that the published cases are not representative of the population of patients with PRIS. For example, in our mortality analysis, alternative explanations to a seemingly obvious causative relation between PRIS mortality and propofol cumulative dose is that non-fatal cases of PRIS may be more likely to be written up and published if caused by only a small dose of propofol. Analogously, after safety limits of dosage were introduced, authors may become less likely to report cases of PRIS caused by propofol doses which had exceeded these limits. Apart from the fact that not all cases of PRIS are recognised and published, there is no guarantee that all published cases analysed by us were reporting a condition causally related to propofol administration. PRIS is difficult to identify and to characterise in the critically ill patient because of the overlap of the syndrome with common ICU clinical conditions and our analysis is reliant on interpretation of clinical signs by the authors of original case reports. It is possible that the occurrence of a sign after the start of propofol infusion was just coincidental manifestation of another condition rather than a genuine manifestation of PRIS. Similarly, death reported to be due to PRIS might have occurred anyway, without a causal relation to propofol infusion. In light of this, our mortality analysis must be interpreted with caution. Unfortunately, obtaining prospectively collected data in this relatively rarely occurring syndrome would be extremely difficult. Adverse drug reaction databases may be an alternative source of information, potentially affected less by publication bias, but the main problem will be the large proportion of patients with missing data. The European Medicines Agency only provides cumulative data with basic demographic data and outcome [21], but further details of individual cases are not accessible. Fong et al. [62] looked up PRIS symptoms in the FDA MedWatch [63] database and aimed to determine predictors of death. Unfortunately, the outcome was reported for less than one-third of patients and among them the propofol infusion rate and duration were reported in only 18 % of cases, forcing the authors to remove these key variables from their mortality analysis. After doing so they found cardiac symptoms, rhabdomyolysis, hypotension, metabolic acidosis, renal failure, and age to affect survival in populations with at least one sign of PRIS. Even though most of these signs were associated with mortality in univariate analysis in our series, they were not significant in the multivariate model.