Ketamine-induced cholangiopathy in ARDS patients.

We read with interest the letter by Meersseman and colleagues [1]. The group reports four other cases of secondary sclerosing cholangitis (SCC) in critically ill coronavirus disease 2019 (COVID-19) patients, which suggests that critically ill COVID-19 patients could be at risk for SCC [2]. Risk factors of SCC in critically ill patients include biliary ischemia, high positive end-expiratory pressure, drug-induced bile duct injury and systemic inflammation [1]. There is mounting evidence that ketamine could contribute to SCC in critically ill, including COVID-19, patients. Ketamine has been widely used as a second-line sedative agent in intensive care units (ICUs) during the COVID-19 pandemic [2, 3]. In 2021, Bütikofer and colleagues compared 34 critically ill COVID-19 patients with 34 critically ill influenza patients [4]. Four patients in the COVID-19 group developed SCC compared to none in the influenza group despite a higher severity of influenza patients (i.e., higher sepsis related organ failure assessment (SOFA) score, higher simplified acute physiology (SAP) score II). All patients received ketamine in the COVID-19 group and none in the influenza group.

We have also observed an association between ketamine and SCC in a cohort of 293 patients with invasive mechanical ventilation after severe burn injury. From June 2012 (opening of our center) to April 2017 ketamine was largely prescribed (liberal period: 1–3 mg/kg/h). In 2017, the French National Agency for the Safety of Medicine issued an alert on potential liver toxicities of ketamine. [5] Ketamine prescriptions were restricted (restrictive period: 0.01–0.05 mg/kg/h) thereafter. The liberal and the restrictive periods comprised 219 (75%) and 74 (25%) patients, respectively. Patient severity (i.e., age, total body surface area burned, abbreviated burned severity index, SAPS II score, initial prescription of norepinephrine) was identical (all p values > 0.2). Cholestasis at discharge was more frequent during the liberal compared to the restrictive period (33% vs 20% respectively, p = 0.04). This difference was particularly striking for the more severe cholestasis (i.e., Alkaline phosphate ≥ 4 N) (Fig. 1). Finally, 9 (7.4%) SCC were diagnosed during the liberal period vs only 1 (1.4%) during the restricted period (p = 0.092). We speculate that critically ill COVID-19 patients with SCC were overexposed to ketamine, leading to biliary precipitations of norketamine, biliary obstructions and cholangitis. 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); by other medications; the systemic inflammatory response syndrome; and/or by ischemia. Providing the total cumulative dose of ketamine used during the ICU stay in the cases reported would be important to explore this potential contributing factor. Furthermore, a registry of critically ill patients with SCC including the dose of ketamine received seems necessary to better explore this potential severe side effect. Meanwhile, we do believe that ketamine-induced cholangiopathy should be suspected in COVID-19 patients with prolonged utilization or high doses of ketamine and increasing bilirubin.

Fig. 1

Proportion of patients with ALP < 4 N and ≥ 4 N between liberal and restrictive ketamine prescription period. KR ketamine restriction, ALP alkaline phosphatase, P p value