key: cord-0757750-q44wxcy8
authors: Mallet, Vincent
title: Intravenous ketamine and progressive cholangiopathy in Covid-19 patients
date: 2021-02-19
journal: J Hepatol
DOI: 10.1016/j.jhep.2021.02.007
sha: 3ed7efda1b17a95a33141e01152fcafba67e1e08
doc_id: 757750
cord_uid: q44wxcy8

nan

Ketamine, a nonbarbiturate general anaesthetic drug, has been proposed, off-label, as a second-line agent for maintenance sedation of patients with acute respiratory distress syndrome (ARDS) requiring mechanical ventilation, including those with coronavirus infectious diseases 2019 . (1) Cholangiopathy is reported after chronic exposition to ketamine, including in drug users and in burned patients. (2, 3) We observed five Covid-19 patients from five distinct tertiary centers (one in Germany, and four in France) with cholangiopathy after exposure to intravenous ketamine, between March 20, 2020 and April 6, 2020, during the first pandemic wave in Europe. Liver injury was dose-dependent, progressive, and total ketamine exposure correlated with outcome, including liver death. The ECRP and MRI characteristics suggested diffuse intrahepatic biliary obstructions.

Ketamine undergoes extensive metabolism in the liver, initially via nitrogen demethylation to norketamine, a water-insoluble by-product. Forensic studies have shown that norketamine is present in human bile after ketamine poisoning.(4) We speculate that our patients were overexposed to ketamine, leading to biliary precipitations of norketamine, biliary strictures, cholangitis, secondary biliary cirrhosis, and end-stage liver disease; but there is no experimental proof yet.

The mechanism of ketamine toxicity could be, however, more complex. Ketamine could act as a second hit in a previously injured biliary tract, either by Sars-CoV-2, (there is little, inconsistent, evidence that Sars-CoV-2 can infect biliary cells); (5) by other medications; by the systemic inflammatory response syndrome; and/or by hypoxia, although none of our patients had profound shock or profound hypoxemia. Critical illness cholangiopathy is the main differential diagnosis. While our observations suggest that ketamine toxicity was dose-dependent, an idiosyncratic reaction is also possible, as for most drug-induced liver injuries. Whether ketamine contributed, or not, to acute kidney injury in our series is a very important question, but is beyond the scope of this study.

In conclusion, intravenous ketamine at the recommended doses for maintenance 

Analgesia and sedation in patients with ARDS

Agence nationale de sécurité du médicament et des produits de santé (ANSM)

Ketamine: risk of serious liver damage during prolonged use and / or at high doses -Information Point

Magnetic resonance cholangiogram patterns and clinical profiles of ketamine-related cholangiopathy in drug users

A fatal ketamine poisoning

SARS CoV 2 was found in the bile juice from a patient