Ketamine restriction correlates with reduced cholestatic liver injury and improved outcomes in critically ill patients with burn injury
Christian De Tymowski,
François Dépret,
Emmanuel Dudoignon,
Nabila Moreno,
Anne-Marie Zagdanski,
Kyann Hodjat,
Benjamin Deniau,
Alexandre Mebazaa,
Matthieu Legrand,
Vincent Mallet
Affiliations
Christian De Tymowski
Université Paris Cité, Paris, France; Department of Anaesthesiology and Surgical Intensive Care Unit, Groupe Hospitalier Bichat Claude Bernard, DMU PARABOL, Assistance Publique–Hôpitaux de Paris, Paris, France; Department of Anaesthesiology, Hôpital Louis Mourier, DMU PARABOL, Assistance Publique–Hôpitaux de Paris, Paris, France; AP-HP.Nord, Groupe Hospitalier Saint Louis Lariboisière, DMU PARABOL, Département d’anesthésie réanimation et centre de traitement des brûlés, Paris, France; Université Paris Cité, Centre de Recherche sur l’Inflammation, INSERM UMR 1149, CNRS ERL8252, Paris, France
François Dépret
Université Paris Cité, Paris, France; AP-HP.Nord, Groupe Hospitalier Saint Louis Lariboisière, DMU PARABOL, Département d’anesthésie réanimation et centre de traitement des brûlés, Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM UMR-S 942 Mascot, Lariboisière Hospital, Paris, France; INI-CRCT Network, Nancy, France; FHU PROMICE, Paris, France
Emmanuel Dudoignon
Université Paris Cité, Paris, France; AP-HP.Nord, Groupe Hospitalier Saint Louis Lariboisière, DMU PARABOL, Département d’anesthésie réanimation et centre de traitement des brûlés, Paris, France; FHU PROMICE, Paris, France
Nabila Moreno
AP-HP.Nord, Groupe Hospitalier Saint Louis Lariboisière, Laboratoire de Biochimie, Paris, France
Anne-Marie Zagdanski
AP-HP.Nord, Groupe Hospitalier Saint Louis Lariboisière, Département de radiologie, Paris, France
Kyann Hodjat
AP-HP.Nord, Groupe Hospitalier Saint Louis Lariboisière, DMU PARABOL, Département d’anesthésie réanimation et centre de traitement des brûlés, Paris, France
Benjamin Deniau
Université Paris Cité, Paris, France; AP-HP.Nord, Groupe Hospitalier Saint Louis Lariboisière, DMU PARABOL, Département d’anesthésie réanimation et centre de traitement des brûlés, Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM UMR-S 942 Mascot, Lariboisière Hospital, Paris, France; FHU PROMICE, Paris, France
Alexandre Mebazaa
Université Paris Cité, Paris, France; AP-HP.Nord, Groupe Hospitalier Saint Louis Lariboisière, DMU PARABOL, Département d’anesthésie réanimation et centre de traitement des brûlés, Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM UMR-S 942 Mascot, Lariboisière Hospital, Paris, France; FHU PROMICE, Paris, France
Matthieu Legrand
INI-CRCT Network, Nancy, France; Department of Anesthesia and Peri-operative Care, Division of Critical Care Medicine, University of California, San Francisco, CA, USA
Vincent Mallet
Université Paris Cité, Paris, France; AP-HP.Nord, Groupe Hospitalier Saint Louis Lariboisière, DMU PARABOL, Département d’anesthésie réanimation et centre de traitement des brûlés, Paris, France; Assistance Publique–Hôpitaux de Paris (AP-HP), Groupe Hospitalier Cochin Port Royal, DMU Cancérologie et spécialités médico-chirurgicales, Service de Maladie du Foie, Paris, France; Corresponding author. Address: Assistance Publique–Hôpitaux de Paris, Hôpital Cochin, Hepatology Service, 27 rue du Faubourg Saint Jacques, 75014 Paris, France. Tel.: +33-1-58-41-30-01; Fax: +33-1-58-41-30-14.
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.