Critical Care (May 2022)

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

  • Pedro David Wendel-Garcia,
  • Rolf Erlebach,
  • Daniel Andrea Hofmaenner,
  • Giovanni Camen,
  • Reto Andreas Schuepbach,
  • Christoph Jüngst,
  • Beat Müllhaupt,
  • Jan Bartussek,
  • Philipp Karl Buehler,
  • Rea Andermatt,
  • Sascha David

DOI
https://doi.org/10.1186/s13054-022-04019-8
Journal volume & issue
Vol. 26, no. 1
pp. 1 – 12

Abstract

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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.

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