Long-term ketamine infusion-induced cholestatic liver injury in COVID-19-associated acute respiratory distress syndrome

Abstract

Background: A higher-than-usual resistance to standard sedation regimens in COVID-19 patients suffering from acute respiratory distress syndrome (ARDS) has led to the frequent use of the second-line anaesthetic agent ketamine. Simultaneously, an increased incidence of cholangiopathies in mechanically ventilated patients receiving prolonged infusion of high-dose ketamine has been noted. Therefore, the objective of this study was to investigate a potential dose-response relationship between ketamine and bilirubin levels.

Methods: Post hoc analysis of a prospective observational cohort of patients suffering from COVID-19-associated ARDS between March 2020 and August 2021. A time-varying, multivariable adjusted, cumulative weighted exposure mixed-effects model was employed to analyse the exposure-effect relationship between ketamine infusion and total bilirubin levels.

Results: Two-hundred forty-three critically ill patients were included into the analysis. Ketamine was infused to 170 (70%) patients at a rate of 1.4 [0.9-2.0] mg/kg/h for 9 [4-18] days. The mixed-effects model revealed a positively correlated infusion duration-effect as well as dose-effect relationship between ketamine infusion and rising bilirubin levels (p < 0.0001). In comparison, long-term infusion of propofol and sufentanil, even at high doses, was not associated with increasing bilirubin levels (p = 0.421, p = 0.258). Patients having received ketamine infusion had a multivariable adjusted competing risk hazard of developing a cholestatic liver injury during their ICU stay of 3.2 [95% confidence interval, 1.3-7.8] (p = 0.01).

Conclusions: A causally plausible, dose-effect relationship between long-term infusion of ketamine and rising total bilirubin levels, as well as an augmented, ketamine-associated, hazard of cholestatic liver injury in critically ill COVID-19 patients could be shown. High-dose ketamine should be refrained from whenever possible for the long-term analgosedation of mechanically ventilated COVID-19 patients.

Keywords: Chemical and drug-induced liver injury; Cholangiopathy; Cholangitis; Cholestasis; Hypnotics and sedatives.

Fig. 1

Study flow chart

Fig. 2

Association between quantiles of cumulatively infused ketamine and maximal bilirubin levels during mechanical ventilation. a Box plots presenting the distribution of maximal bilirubin levels during mechanical ventilation at different quantiles of cumulatively infused ketamine. b Unadjusted B-spline regression between maximal bilirubin levels and quantiles of cumulative ketamine. c Multivariable adjusted B-spline regression between maximal bilirubin levels and quantiles of cumulative ketamine. Worst values during the mechanical ventilation period were employed for all covariates in the model. Red lines represent regression estimates and the blue-shaded area 95% confidence intervals

Fig. 3

Duration–effect and dose–effect relationship between ketamine (propofol) and total bilirubin levels. Time-varying, weighted cumulative exposure mixed-effects model assessing the multivariable adjusted duration of infusion–effect (a) and dose–effect (b) relationship of ketamine (propofol (c, d)) on rising bilirubin levels. Model estimates are depicted as solid lines and 95% confidence intervals as shaded areas

Fig. 4

Incidence of cholestatic liver injury stratified by ketamine infusion. Kaplan–Meier curves for the 30-day incidence of a cholestatic liver injury and b severe cholestatic liver injury stratified by ketamine infusion. Shaded areas represent the crude 95% confidence intervals. The computed hazard ratio assesses the risk of ketamine-infused patients against those not having received it accounting for the competing risk of death. The 95% confidence interval is given in parentheses. Crude and multivariable adjusted hazard ratios are depicted. The underlying table presents the patients at risk per time point