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.
【저자키워드】 cholestasis, Chemical and drug-induced liver injury, Cholangiopathy, Cholangitis, Hypnotics and sedatives., 【초록키워드】 ARDS, risk, ICU, Critically ill, Patient, Liver injury, incidence, liver, COVID-19 patients, acute respiratory distress, Chemical, Analysis, Bilirubin, propofol, COVID-19 patient, regimen, Critically ill patient, Ketamine, Sedation, High-dose, confidence interval, total bilirubin, syndrome, Post hoc analysis, doses, mechanically ventilated, cumulative, mixed-effects model, COVID-19-associated ARDS, multivariable, shown, receiving, adjusted, competing, rising, infused, mechanically ventilated patient, positively correlated, prospective observational cohort, 【제목키워드】 Liver injury, acute respiratory distress, syndrome,