Secondary sclerosing cholangitis: an emerging complication in critically ill COVID-19 patients

Meersseman, Philippe; Blondeel, Joris; Vlieger, Greet De; Merwe, Schalk van der; Monbaliu, Diethard; Wauters, Joost; Wilmer, Alexander; Gilbo, Nicholas; Jochmans, Ina; Pirenne, Jacques; Sainz-Barriga, Mauricio; Debaveye, Yves; Gunst, Jan; Meyfroidt, Geert; Laleman, Wim; Nevens, Frederik; Malenstein, Hannah van; Verbeek, Jef; Verslype, Chris; Roskams, Tania; Vandecaveye, Vincent; Balthazar, Tim; Vandenbriele, Christophe; Hermans, Greet; Rogiers, Peter; Verhaegen, Marleen

doi:10.1007/s00134-021-06445-8

Cited by 36 publications

(56 citation statements)

References 6 publications

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“…Evidence on the systemic effects of long-term infusion of ketamine is limited; however, its prolonged infusion in doses above 1 mg/kg/h has been associated with hepatotoxicity [ 3 ], leading the French National Agency for the Safety of Medicine to issue an alert cautioning against its use in high doses [ 4 ]. Recently, an increasing incidence of cholangiopathies, including secondary sclerosing cholangitis (SSC), has been noted in mechanically ventilated COVID-19 patients receiving long-term infusion of ketamine [ 5 – 8 ].…”

Section: Introductionmentioning

confidence: 99%

Long-term ketamine infusion-induced cholestatic liver injury in COVID-19-associated acute respiratory distress syndrome

et al. 2022

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Background A higher-than-usual resistance to standard sedation regimens in COVID-19 patients suffering from acute respiratory distress syndrome (ARDS) has led to the frequent use of the second-line anaesthetic agent ketamine. Simultaneously, an increased incidence of cholangiopathies in mechanically ventilated patients receiving prolonged infusion of high-dose ketamine has been noted. Therefore, the objective of this study was to investigate a potential dose–response relationship between ketamine and bilirubin levels. Methods Post hoc analysis of a prospective observational cohort of patients suffering from COVID-19-associated ARDS between March 2020 and August 2021. A time-varying, multivariable adjusted, cumulative weighted exposure mixed-effects model was employed to analyse the exposure–effect relationship between ketamine infusion and total bilirubin levels. Results Two-hundred forty-three critically ill patients were included into the analysis. Ketamine was infused to 170 (70%) patients at a rate of 1.4 [0.9–2.0] mg/kg/h for 9 [4–18] days. The mixed-effects model revealed a positively correlated infusion duration–effect as well as dose–effect relationship between ketamine infusion and rising bilirubin levels (p < 0.0001). In comparison, long-term infusion of propofol and sufentanil, even at high doses, was not associated with increasing bilirubin levels (p = 0.421, p = 0.258). Patients having received ketamine infusion had a multivariable adjusted competing risk hazard of developing a cholestatic liver injury during their ICU stay of 3.2 [95% confidence interval, 1.3–7.8] (p = 0.01). Conclusions A causally plausible, dose–effect relationship between long-term infusion of ketamine and rising total bilirubin levels, as well as an augmented, ketamine-associated, hazard of cholestatic liver injury in critically ill COVID-19 patients could be shown. High-dose ketamine should be refrained from whenever possible for the long-term analgosedation of mechanically ventilated COVID-19 patients.

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Section: Introductionmentioning

confidence: 99%

Long-term ketamine infusion-induced cholestatic liver injury in COVID-19-associated acute respiratory distress syndrome

et al. 2022

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“…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 ].…”

mentioning

confidence: 99%

“…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.…”

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confidence: 99%

Ketamine-induced cholangiopathy in ARDS patients

et al. 2021

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“…Therefore, the biliary vasculature is thought to be more susceptible to hypoperfusion and consecutive ischemia [ 57 ]. SSC-CIP has previously been observed after ECMO therapy, including in cases of COVID-19, and a direct viral tropism with detection of SARS-CoV-2 RNA and associated nucleocapsid protein in cholangiocytes and bile ducts has been proposed [ 58 , 59 ]. Finally, endotheliitis resulting in hypercoagulability in the peribiliary vascular plexus may also aggravate ischemia of the biliary tract.…”

Section: Discussionmentioning

confidence: 99%

“…This is particularly relevant since it has been reported that about one-third of patients critically ill with COVID-19 suffer from liver dysfunction associated with high mortality [ 60 ]. Moreover, this is the first report of SSC-CIP treated with hemadsorption, especially relevant since SSC-CIP affects a considerable number of COVID-19 patients requiring ECMO therapy [ 58 ]. By combining hemadsorption with hemodialysis treatment, successful bilirubin and ammonia elimination were observed.…”

Section: Discussionmentioning

confidence: 99%

Kinetics of Bilirubin and Ammonia Elimination during Hemadsorption Therapy in Secondary Sclerosing Cholangitis Following ECMO Therapy and Severe COVID-19

et al. 2021

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In critically ill patients, liver dysfunction often results in coagulopathy and encephalopathy and is associated with high mortality. Extracorporeal clearance of hepatotoxic metabolites, including bilirubin and ammonia, aims to attenuate further hepatocyte damage and liver injury, resulting in decreased mortality. The efficacy of hemadsorption combined with conventional hemodialysis to eliminate bilirubin and ammonia to support the liver’s excretory function in acute liver injury has been described previously. However, the optimal use of liver support systems in chronic liver dysfunction due to secondary sclerosing cholangitis in critically ill patients (SSC-CIP) has not been defined yet. We herein describe the kinetics of successful bilirubin and ammonia elimination by hemadsorption in a patient with SSC-CIP after extracorporeal membrane oxygenation (ECMO) therapy for severe acute respiratory distress syndrome (ARDS) in a patient with coronavirus disease 2019 (COVID-19). During the course of the disease, the patient developed laboratory signs of liver injury during ECMO therapy before clinically detectable jaundice or elevated bilirubin levels. A diagnosis of SSC-CIP was confirmed by endoscopic retrograde cholangiopancreatography (ERCP) based on intraductal filling defects in the intrahepatic bile ducts due to biliary casts. The patient showed stable elevations of bilirubin and ammonia levels thereafter, but presented with progressive nausea, vomiting, weakness, and exhaustion. Based on these laboratory findings, hemadsorption was combined with hemodialysis treatment and successfully eliminated bilirubin and ammonia. Moreover, direct comparison revealed that ammonia is more efficiently eliminated by hemadsorption than bilirubin levels. Clinical symptoms of nausea, vomiting, weakness, and exhaustion improved. In summary, bilirubin and ammonia were successfully eliminated by hemadsorption combined with hemodialysis treatment in SSC-CIP following ECMO therapy and severe COVID-19. This observation is particularly relevant since it has been reported that a considerable subset of critically ill patients with COVID-19 suffer from liver dysfunction associated with high mortality.

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Secondary sclerosing cholangitis: an emerging complication in critically ill COVID-19 patients

Cited by 36 publications

References 6 publications

Long-term ketamine infusion-induced cholestatic liver injury in COVID-19-associated acute respiratory distress syndrome

Long-term ketamine infusion-induced cholestatic liver injury in COVID-19-associated acute respiratory distress syndrome

Ketamine-induced cholangiopathy in ARDS patients

Kinetics of Bilirubin and Ammonia Elimination during Hemadsorption Therapy in Secondary Sclerosing Cholangitis Following ECMO Therapy and Severe COVID-19

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