Ketamine restriction correlates with reduced cholestatic liver injury and improved outcomes in critically ill patients with burn injury

Abstract

Background & aims: Ketamine-associated cholestatic liver injury is reported in patients with severe burn injury, but its association with patient outcome is unclear. We investigated the relationship between ketamine exposure, cholestatic liver injury, and outcome of critically ill patients with burn injury.

Methods: In a retrospective study, patients with severe burn injury were analysed across two periods: unrestricted ketamine prescription (ketamine-liberal) and capped ketamine dosage (ketamine-restricted). The primary endpoint was cholestatic liver injury, and the secondary endpoint was 3-month mortality. Binary logistic regression models and the revised electronic causality assessment method were used to measure the strength of associations and causality assessment, respectively.

Results: Of 279 patients (median age 51 [IQR 31-67] years; 63.1% men; burned surface area 28.5%, IQR 20-45%), 155 (56%) were in the ketamine-liberal group, and 124 (44%) were in the ketamine-restricted group, with comparable clinical characteristics, except for ketamine exposure (median doses 265.0 [IQR 0-8,021] mg and 20 [IQR 0-105] mg, respectively; p <0.001). A dose- and time-dependent relationship was observed between ketamine exposure and cholestatic liver injury. Ketamine restriction was associated with a reduced risk of cholestatic liver injury (adjusted odds ratio 0.16, 95% CI 0.04-0.50; p = 0.003) and with a higher probability of 3-month survival (p = 0.035). The revised electronic causality assessment method indicated that ketamine was probably and possibly the cause of cholestatic liver injury for 14 and 10 patients, respectively. Cholangitis was not observed in the ketamine-restricted group. In propensity-matched patients, the risk of 3-month mortality was higher (adjusted odds ratio 9.92, 95% CI 2.76-39.05; p = 0.001) in patients with cholestatic liver injury and ketamine exposure ≥10,000 mg. Other sedative drugs were not associated with liver and patient outcome.

Conclusions: In this cohort, ketamine restriction was associated with less cholestatic liver injury and reduced 3-month mortality.

Impact and implications: In a cohort of 279 critically ill patients with burn injury, ketamine was associated with a risk of liver bile duct toxicity. The risk was found to be dependent on both the dosage and duration of ketamine use. A restriction policy of ketamine prescription was associated with a risk reduction of liver injury and 3-month mortality. These findings have implications for the analgesia and sedation of critically ill patients with ketamine, with higher doses raising safety concerns.

Keywords: Burn injury; Cholestatic liver injury; Drug toxicity; Drug-induced liver injury; Ketamine; Mortality.

Graphical abstract

Fig. 1

Probabilty of cholestatic liver injury according to the number of days of ketamine infusion and dose exposure. Probabilities were computed using binary logistic regression according to the restrictive cubic spline method, using four knots.

Fig. 2

Study flow chart. Cholestatic liver injury corresponded to the association of cholestasis (serum ALP level ≥1.5 × ULN, with serum GGT level ≥3 × ULN) and hyperbilirubinaemia (total serum bilirubin ≥1 × ULN). ALP, alkaline phosphatase; GGT, gamma glutamyl transferase; ULN, upper limit of normal.

Fig. 3

Liver tests evolution by ketamine period. Global p values were computed using a mix model. The two-groups comparison at each time point were performed using the Mann–Whitney U test, (n.s., p >0.05; *p <0.05; **p <0.01; ***p <0.001; ****p <0.0001). We defined two time periods, according to ketamine prescription modalities: a ketamine-liberal period, from December 2014 to end of March 2017, when ketamine prescription was ‘liberally’ used for maintenance sedation (≥ 1 mg/kg/h), and a ketamine-restricted period, from April 2017 to June 2019, when ketamine was only used as a second line co-analgesic drug with a capped dose (<0.015 mg/kg/h). ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; PT, prothrombin time; TBIL, total bilirubin; ULN, upper limit of normal.

Fig. 4

Probability of 3-month survival by ketamine restriction period. We defined two time periods, according to ketamine prescription modalities: a ketamine-liberal period, from December 2014 to end of March 2017, when ketamine prescription was ‘liberally’ used for maintenance sedation (≥1 mg/kg/h), and a ketamine-restricted period, from April 2017 to June 2019, when ketamine was only used as a second line co-analgesic drug with a capped dose (<0.015 mg/kg/h).