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
Acknowledgements
The Keta-Cov research group: Vincent Mallet, Université de Paris, AP-HP, Hôpital Cochin, DMU Cancérologie et spécialités médico-chirurgicales, Service d’Hépatologie, Paris, France; Kilian Bock, Dept. of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str.1, 30,625 Hannover, Germany & German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig; Paul Doumbe Mandengue, Université de Paris, AP-HP, Hôpital Cochin, DMU Cancérologie et spécialités médico-chirurgicales, Service d’Hépatologie, Paris, France; Nicolas Dufour, Centre Hospitalier René Dubos, Service de Réanimation Médico-chirurgicale, 95,300 Pontoise, France; Jean-Damien Ricard, Université de Paris, AP-HP, Hôpital Louis Mourier, DMU ESPRIT, Service de Réanimation Médico-Chirurgicale, Colombes, France; Pierre Isnard, Université de Paris, AP-HP, Hôpital Necker Enfants Malades, DMU IMAGINA, Service d’Anatomo-Pathologie, Paris, France; Jean-Paul Duong Van Huyen, Université de Paris, AP-HP, Hôpital Necker Enfants Malades, DMU IMAGINA, Service d’Anatomo-Pathologie, Paris, France; Jean-Michel Correas, Université de Paris, AP-HP, Hôpital Necker Enfants Malades, DMU IMAGINA, Service de Radiologie, Paris, France; Torsten Voigtländer, Dept. of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str.1, 30,625 Hannover, Germany & German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig; Vincent Frochot, Sorbonne Université, AP-HP, Hôpital Tenon, DMU BIOGEM, Service de Physiologie, F-75020 Paris, France; INSERM, UMR S 1155, Hôpital Tenon, F-75020 Paris, France; Emmanuel Letavernier, Sorbonne Université, AP-HP, Hôpital Tenon, DMU BIOGEM, Service de Physiologie, F-75020 Paris, France; INSERM, UMR S 1155, Hôpital Tenon, F-75020 Paris, France; Lucile Moga, Université de Paris, AP-HP, Hôpital Beaujon, Service d'Hépatologie, DMU DIGEST, Centre de Référence des Maladies Vasculaires du Foie, FILFOIE, ERN RARE-LIVER, Centre de recherche sur l'inflammation, Inserm, UMR 1149. Paris, France; Amandine Landrieux,8 Pierre-Emmanuel Rautou, Université de Paris, AP-HP, Hôpital Beaujon, Service d'Hépatologie, DMU DIGEST, Centre de Référence des Maladies Vasculaires du Foie, FILFOIE, ERN RARE-LIVER, Centre de recherche sur l'inflammation, Inserm, UMR 1149. Paris, France; Laurent Chouchana, Université de Paris, AP-HP, Hôpital Cochin, DMU PRIME, Service de pharmacovigilance, Paris, France; Coralie Gernez, 3.Université de Paris, AP-HP, Hôpital Louis Mourier, DMU ESPRIT, Service de Réanimation Médico-Chirurgicale, Colombes, France; Carole Burger, Université de Paris, AP-HP, Hôpital Necker Enfants Malades, DMU CARTE, Service de Néphrologie et de Transplantation rénale, Paris, France; Anne Scemla, Université de Paris, AP-HP, Hôpital Necker Enfants Malades, DMU CARTE, Service de Néphrologie et de Transplantation rénale, Paris, France; Lionel Lamhaut, Université de Paris, AP-HP, Hôpital Necker Enfants Malades, Département d’Anesthésie Réanimation, Paris, France; Rémi Flicoteau, Université de Paris, AP-HP, Hôpital Saint Louis, DMU PRISME, Service de Biostatistique et information médicale, Paris, France; Jean-Paul Duong Van Huyen, Centre Hospitalier René Dubos, Service de Réanimation Médico-chirurgicale, 95,300 Pontoise, France; Jean-Michel Correas, Université de Paris, AP-HP, Hôpital Necker Enfants Malades, Département d’Anesthésie Réanimation, Paris, France; Heiner Wedemeyer, Stanislas Pol, Université de Paris, AP-HP, Hôpital Cochin, DMU Cancérologie et spécialités médico-chirurgicales, Service d’Hépatologie, Paris, France.
Abbreviations
- COVID-19
coronavirus disease 2019
- SCC
secondary sclerosing cholangitis
- SAPSII
simplified acute physiology score II
Author contributions
FD: conception of the study, acquisition, analysis and interpretation of the data, draft of the manuscript; CT, FD, ED, ML, VM: conception of the study, acquisition, analysis and interpretation of the data, edition of the manuscript. The authors declare they have seen and approved the final version of the manuscript. All members of the Keta-Cov group facilitated the study or took care of the reported patients.
Funding
The study did not receive any external funding.
Declarations
Conflicts of interest
None.
Footnotes
The members of the Keta-Cov Research group are listed in the Acknowledgement section.
Publisher's Note
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Contributor Information
François Dépret, Email: francois.depret@aphp.fr.
on behalf of the Keta-Cov Research Group:
Vincent Mallet, Kilian Bock, Paul Doumbe Mandengue, Nicolas Dufour, Jean-Damien Ricard, Pierre Isnard, Jean-Paul Duong Van Huyen, Jean-Michel Correas, Torsten Voigtländer, Vincent Frochot, Emmanuel Letavernier, Lucile Moga, Amandine Landrieux, Laurent Chouchana, Coralie Gernez, Carole Burger, Anne Scemla, Lionel Lamhaut, Rémi Flicoteau, Jean-Paul Duong Van Huyen, Jean-Michel Correas, Heiner Wedemeyer, and Stanislas Pol
References
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