PROFILE OF LIVER CHOLESTATIC BIOMARKERS FOLLOWING PROLONGED KETAMINE ADMINISTRATION IN PATIENTS WITH COVID-19

doi:10.21203/rs.3.rs-1664793/v1

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Research Article

PROFILE OF LIVER CHOLESTATIC BIOMARKERS FOLLOWING PROLONGED KETAMINE ADMINISTRATION IN PATIENTS WITH COVID-19

https://doi.org/10.21203/rs.3.rs-1664793/v1

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Background. To investigate the possible influence of prolonged ketamine (K) or esketamine (ESK) infusion on the profile of liver cholestatic biomarkers in patients with COVID-19 infection.

Methods. A retrospective analysis was performed on 135 patients with COVID-19 related ARDS who received prolonged K or ESK infusion. They were compared to 15 COVID-19 ICU patients who did not receive K/ESK while being mechanically ventilated and 108 COVID-19 patients who did not receive mechanical ventilation nor K/ESK. The profile of the liver function tests was analysed in the groups.

Results. Peak values of ALP, GGT and bilirubin were higher in the K/ESK group, but not for AST and ALT. Peak values of ALP were significantly higher among patients who underwent mechanical ventilation and who received K/ESK, compared with mechanically ventilated patients who did not receive K/ESK. There was correlation between these peak values and the cumulative dose and duration of K/ESK therapy.

Conclusions. Based on the observations of biliary anomalies in chronic ketamine abusers, prolonged exposure to ketamine sedation during mechanical ventilation may also be involved, in addition to viral infection causing secondary sclerosing cholangitis. The safety of prolonged ketamine sedation on the biliary tract requires further investigations.

COVID-19

ARDS

mechanical ventilation

ketamine/esketamine

prolonged infusion

cholestasis

cholangitis

Optimal analgesia and sedation in patients with COVID-19 requiring prolonged mechanical ventilation in the Intensive Care Unit (ICU) remain challenging ^[1]. The quantity of sedation used in this population appears much higher than that usually prescribed in patients with adult respiratory syndrome (ARDS) from another origin ^[2]. The management of sedation must take into account patient characteristics as well and individual properties and side effect profiles of different agents. A frequent strategy is to opt for a multimodal sedation regimen involving medications from different pharmacological classes. Ketamine (K) is a N-methyl-D-aspartate (NMDA) receptor antagonist that can be used at sub-anesthetic doses for its analgesic and sedative dose-sparing effects in mechanically ventilated patients ^[3]. Esketamine (ESK) is the S(+) enantiomer of K. The use of K is usually limited by its psychomimetic effects, but short-term K infusion is usually not associated with liver or biliary injury, contrasting with the potential toxicity observed in long-term K abusers. Side effects of ESK therapy should be rather similar as those of K. On the other hand, COVID-19 itself has been associated with abnormal liver tests. The objective of this work was to compare the profile of liver cholestatic biomarkers in patients with COVID-19 receiving prolonged K or ESK infusion in the multimodal sedation regimen to the profile of COVID-19 patients, mechanically ventilated or not, who did never receive K/ESK.

A retrospective analysis was performed on 258 patients with COVID-19 who were admitted to the ICU during the consecutive epidemic waves between March 1, 2020 and March 1, 2022. The study was approved by the Institutional Review Board (IRB) and a written informed consent was waived for a retrospective analysis based on the chart data. On the whole, 307 patients were admitted in the ICU over this period. However, 49 patients were excluded from the analysis for the following reasons: diagnosis of COVID-19 pneumonia not confirmed by RT-PCR (n = 2), incomplete chart data (n = 5), pre-existing liver disease (n = 19), acute liver failure related to shock (cardiogenic, septic, haemorrhagic) during ICU stay (n = 23). Among the 258 remaining patients, 135 patients with COVID-19 related ARDS received during the period of mechanical ventilation a multimodal sedation regimen including propofol, sufentanil, midazolam, and K/ESK. Clonidine was given as adjunctive therapy to some patients. Cisatracurium was used as neuromuscular blocking agent at least during the first week of mechanical ventilation. K was infused at a rate ranging from 0.25 to 0.5 mg/kg/hour. When availability of K was reduced, ESK was used at the rate of 0.125 to 0.25 mg/kg/hour. A comparison was done with 15 COVID-19 patients who never received K/ESK during mechanical ventilation and 108 COVID-19 patients who never received K/ESK as high-flow nasal oxygen therapy was sufficient to control hypoxemia. For the comparison, the patients who received K, ESK, or both, were considered as a single group, at the exception of the calculation of the cumulative dose for the patients who received both drugs.

Specific treatment for COVID-19 included hydroxychloroquine during the first period of ICU admission, and dexamethasone for the last periods. Other medications, including antibiotics, were administered according to patient’s condition. All patients received enteral nutrition. Liver tests included serum aspartate transferase (AST), alanine transferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), total bilirubin (TBIL). The laboratory reference upper limit of normal value (ULN) was: AST > 36; ALT > 35, ALP > 105, GGT > 40, TBIL > 1.2.

The distribution of liver function tests was reported as within the normal range and two times higher than the upper limit of normal (ULN) in three time points during ICU stay.

Statistical analysis

Statistical analyses were performed using SPSS 21 (IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY) and figures were created using Graphpad Prism 9 (GraphPad Software, LaJolla, CA). Values were expressed as median (first-third quartiles) for continuous values and counts (per percent of group) for qualitative variables. The data were subjected to Kolmogorov-Smirnov normality test and Bartlett’s test for homogeneity of variance. We compared clinical, demographic variables and relevant biochemical analysis between the three group of patients (IMV+/Ketamine + vs IMV+/Ketamine- vs IMV-/Ketamine-), using the chi-squared test (or Fisher’s exact test when appropriate) for categorical variables and Kruskall-Wallis test (with a Dunn’s post-test to correct for multiple comparisons) for quantitative data. Relevant biochemical values between K/ESK groups were compared using unpaired T test. All tests were two-sided, with significance level set at 0.05.

Baseline characteristics and outcomes of the whole population (n=258) are shown in Table 1. Among the type of ketamine administered, 60.7% of the patients received exclusively K, 26.7% exclusively ESK and 12.6% both K and ESK. Cumulative dose was expressed only for the patients who received exclusively K or ESK, as no exact equivalence could be determined in case of combined therapy.

Baseline values of ALP, GGT, bilirubin, AST and ALT are shown in Table II. At baseline, 40 (15%) patients had abnormal ALP, 160 (61.5%) had abnormal GGT, 10 (3.8%) had abnormal bilirubin, 163 (62.7%) abnormal AST, and 117 (45%) abnormal ALT.

The comparison between K/ESK versus no K/ESK group showed that the peak value for ALP, GGT and bilirubin was significantly higher in the K/ESK group (p value respectively <0.0001, <0.0001, =0.0005). (Table 2, Figure 1) No significant difference existed for peak AST (p=0.069) and ALT (p=0.059) values, despite a trend towards higher value in the K/ESK group. When looking at subgroups, patients with K/ESK and mechanical ventilation had a higher peak ALP value than the patients with IMV but without K/ESK (p=0.018) and the patients who did not require neither mechanical ventilation nor K/ESK (p<0.0001 ). For the other peak values (GGT, bilirubin, AST, ALT), the difference was only significant between the mechanically ventilated patients with K/ESK and the patients without mechanical ventilation and K/ESK. There was no significant difference regarding peak values of ALP, GGT, bilirubin, AST and ALT between patients who received K, ESK or both (Supplemental material). Besides, there was a moderate correlation between the cumulative dose of K/ESK over the ICU stay and the peak value for ALP (Pearson’s correlation coefficient R=0.33, p<0.0001)’s, GGT (R=0.41, p<0.0001) and bilirubin (R=0.37, p<0.0001) (Figure 2). The same observation applied to the correlation between the duration of K/ESK therapy and peak values for ALP (R=0.3, p=0.0004) and GGT (R=0.36, p<0.0001) (Figure 2). The median “time to peak value” of ALP (for the values at least two times higher than ULN, n=85) was 14 days (IQR 7-23).

Among the patients who developed abnormal cholestatic biomarkers during ICU stay, 38 were investigated by abdomen ultrasonography. Examination was normal in 16 patients, abnormal in 22 patients, predominantly in the K/ESK group. The most frequent anomaly was gallbladder sludge (n=14), followed by liver steatosis (n=5), gallbladder hydrops (n=5), and acute cholecystitis (n=2). In the K/ESK group, two patients needed percutaneous drainage of the gallbladder and one patient required additional surgical drainage for biliary peritonitis.

Among the patients who were excluded from the analysis for pre-existing liver disease, a 30-year-old woman had a Child-Pugh B liver cirrhosis as an unusual complication of Turner syndrome (non alcoholic steatohepatitis). When mechanically ventilated for COVID-19 related ARDS, she received a cumulative dose of 2040 mg of K and 2370 mg of ESK over a period of 28 days. We noted a marked increase in plasma ALP levels (Figure 3, left). Due to the progression of liver failure, a liver transplantation was required 28 days after the cessation of ESK. Ultrastructural examination of the explanted liver was consistent with a cholestatic injury (Figure 3, right). The responsibility of K/ESK remained speculative as the patient also experienced infectious complications, but without shock.

Otherwise, in this case series of COVID-19 patients with K/ESK, no patient required a liver transplantation and a progressive decrease of ALP levels was noted in most of the patients who survived.

Previous publications have identified that increased liver tests (mainly AST and ALT) may be found in 14–78% of individuals affected by COVID-19 ^[4–7]. The pattern of liver injury seems predominantly hepatocellular rather than cholestatic, as indicated by the milder elevation of total bilirubin and alkaline phosphatase in most of the publications ^[8]. In addition, abnormal liver function tests were more frequently observed in the patients who required ICU admission. Cholestatic liver function tests were incompletely reported in 510 patients ^[9]. Mean levels of ALP were 71 IU/L across three studies, and mean levels of GGT were 40.6 IU/L across four studies ^{[6, 10, 11]}. The role of drug-induced liver injury remains difficult to investigate as numerous medications are usually co-administered to a single patient during the disease course in the ICU. For exemple, hydroxychloroquine, lopinavir/ritonavir, remdesivir and tocelizumab were associated with the risk to develop abnormal liver transaminases during hospitalization, while no association was found with total bilirubin or alkaline phosphatase ^[12]. At least, two types of cholangiopathies have been associated with SARS-CoV-2 ^[13]. The first form has probably an autoimmune origin resembling primary biliary cholangitis (PBC), while the second has the characteristics of a secondary sclerosing cholangitis (SSC) ^[14–21]. This last condition was mainly observed in the most severe ICU patients with ARDS, renal and cardiocirculatory support. The progressive increase of ALP and GGT is usually contrasting with the modest increase in AST and ALT. Liver transplantation was required in some patients ^[22]. The diagnosis can be made by magnetic resonance cholangiopancreatography (MRCP) showing dilatations and strictures of intrahepatic bile ducts, with alterations of the common bile duct.

Among the potential causes of SCC, the role of ketamine sedation has to be investigated ^[23]. During the first pandemic wave in Europe (March-April, 2020), five COVID-19 patients presented a dose-dependent, progressive cholangiopathy after a mean duration of 16 (6–26) days of intravenous ketamine administration, with a mean cumulative dose of 9.5 (3.8–95.9) grams. Histological features of cholangitis were documented by liver biopsy in 4/5 patients ^[14]. In a large cohort of 293 burned patients who required mechanical ventilation, a higher incidence of cholestasis or proven SSC was observed in the subgroup that received a ketamine-based sedation ^[24]. In a comparison of 34 intubated patients with COVID-19 and 34 intubated patients with influenza, four developed SSC in the first group and none in the second group; ketamine was used for sedation in the COVID-19 group, and not in the second group ^[25].

Long-term exposure in chronic ketamine abusers has been associated with cholestasis, biliary dilatation, biliary sepsis and decompensated cirrhosis. In a survey of 257 consecutive chronic abusers of ketamine with urinary tract dysfunction, the prevalence of biliary tract anomalies on MRCP was 61.9% ^[26]. A reversal of liver cholestatic biomarkers may be observed after ketamine withdrawal ^[27]. The exact mechanisms of ketamine toxicity on the biliary tract are not fully elucidated: NMDA receptor stimulation within smooth muscle cells of the bile duct leading to inflammation, fibrosis and structuring, direct toxicity to the surface epithelium or increased resistance to flow across the sphincter of Oddi.

The limitations of this retrospective analysis have to be acknowledged. First of all, the severity of the non-ventilated COVID-19 patients who never received ketamine was lower as expressed by the SOFA and APACHE II scores on admission. These patients had also a lower rate of complications (need for CRRT, vasoactive drugs) and a lower mortality rate. The severity of the COVID-19 ARDS patients who were mechanically ventilated without ketamine use was however similar as that of the ketamine group, but the number of observations was limited. Numerous drugs can induce a cholestatic reaction, but the most commonly used medications (other sedatives, antithrombotic agents,..) were equally balanced among the mechanically ventilated patients, with or without ketamine. Other causes may have contributed to biliary tract injury, including systemic inflammatory response syndrome, prolonged hypoxia or refractory shock, as SSC has also been described in critically ill patients needing mechanical ventilation for another aetiology than COVID-19 ^[28]. We excluded from our analysis the patients who presented an acute liver injury in relationship with shock from any aetiology (cardiogenic, septic,…). The number of patients who had extensive serological investigations (virus, auto-immunity, …) was also limited. However, the role of ketamine is still supported by the relationship with the time to peak for ALP (without significant changes in AST and ALT), and with the cumulative dose and total duration of ketamine therapy.

Ethics approval

The study was approved by the Institutional Review Board (IRB) (Cliniques Universitaires Saint-Luc (CUSL)). The research has been performed in accordance with the Declaration of Helsinki.

Consent to participate

A written informed consent from the participants was waived by the Institutional Review Board (Cliniques Universitaires Saint-Luc (CUSL) as the research was based on a retrospective analysis of an anonymized database with the patients chart data.

Consent for publication

Not applicable

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

No source of funding.

Authors’ contribution

JH, CD, AR, AL collected the chart data and drafted the first version of the manuscript; LG performed the statistical analysis; PB reviewed the pathological data; PFL, PH reviewed the clinical and statistical data, approved the final version of the manuscript.

Acknowledgements

Not applicable.

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Table 1

Baseline characteristics and outcomes, in severely ill COVID patients under invasive mechanical ventilation (IMV), under ketamine infusion, compared with COVID patients under IMV who did not receive ketamine, and patients with severe COVID who did not require IMV and received no sedation.

Variables	COVID+/IMV/Ketamine + (n=135)	COVID+/IMV+/ Ketamine – (15)	COVID+/IMV-/ Ketamine – (108)
Age, median (IQR), years	64 (55-72)	68 (58-74)	61 (53-71)
Male, n (%)	94 (69.6)	13 (86.7)	80 (74.1)
Alcohol abuse, n (%)	4 (3)	0	5 (4.6)
APACHE II, median (IQR)	15 (12-18)	18 (16-20)^*	13 (10-16)^*&
SOFA, median (IQR)	6 (4-8)	6 (5-8)	4 (3-5)^*
Invasive mechanical ventilation, n (%)	135 (100)	15 (100)	0^*&
Vasoactive drugs, n (%)	102 (75.6)	14 (93.3)	2 (1.9)^*&
CRRT, n (%)	34 (25.2)	2 (13.3)^*	3 (2.8)^*&
Adjunctive treatments, n (%) - Steroids - Hydroxychloroquine - Azithromycine	87 (64.4) 26 (19.3) 3 (2.2)	15 (100)^* 7 (46.7) 0	78 (72.2) 19 (17.6) 2 (1.9)
Duration of sedation, median (IQR), days	22 (11-35)	9 (3-18)^*	0^*&
Type of Ketamine used, n (%) - Ketamine - Esketamine - both	82 (60.7) 36 (26.7) 17 (12.6)
ICU mortality, n (%)	81 (60)	10 (66)	19 (17.6)^*&

IMV: Invasive Mechanical Ventilation; IQR: interquartile range; SOFA: Sequential Organ Failure Assessment; APACHE II: Acute Physiology and Chronic Health Evaluation II; LOS: Length of Stay.

^*indicates p<0.05 in comparison with COVID+/IMV+/Ketamine+; ^& indicates p<0.05 in comparison with COVID+/IMV+/Ketamine-

Table 2

Liver biomarkers in severely ill COVID patients under invasive mechanical ventilation and under ketamine/esketamine infusion, compared with COVID patients under IMV who did not receive ketamine/esketamine, and patients with severe COVID who did not require IMV and received no sedation.

Variables	COVID+/IMV+/ Ketamine + (n=135)	COVID+/IMV+/ Ketamine – (n=15)	COVID+/IMV–/ Ketamine – (n=108)
Baseline ALP, median (IQR), IU/L	69 (54-90)	66 (47-82)	60 (50-91)
Baseline GGT, median (IQR), IU/L	54 (30-100)	56 (22-82)	54 (34-113)
Baseline bilirubin, median (IQR), mg/dl	0.5 (0.4-0.7)	0.7 (0.5-0.8)	0.5 (0.4-0.7)
Baseline AST, median (IQR), IU/L	48 (34-70)	37 (25-73)	39 (28-61)
Baseline ALT, median (IQR), IU/L	34 (19-50)	39 (17-63)	31 (21-52)
Peak ALP, median (IQR), IU/L	218 (153-313)	150 (96-179)^*	91 (54-145)^*
Peak ALP > 2x reference value, n (%)	71 (52.6)	2 (13)^*	7 (6.5)^*
Peak GGT, median (IQR), IU/L	305 (151-495)	185 (80-324)	88 (52-175)^*
Peak GGT > 2x reference value, n (%)	119 (88.2)	11 (73.3)	57 (52.7)^*
Peak bilirubin, median (IQR), mg/dl	1.3 (0.8-2.2)	1.2 (0.6-1.3)	0.7 (0.5-0.9)^*
Peak bilirubin > 2x reference value, n (%)	29 (21.5)	0^*	5 (4.6)^*
Peak AST, median (IQR), IU/L	113 (68-168)	171 (65-258)	62 (39-104)^*
Peak AST > 2x reference value, n (%)	99 (73.3)	10 (66.7)	47 (43.5)^*&
Peak ALT, median (IQR), IU/L	88 (56-166)	118 (55-274)	72 (42-112)^*
Peak ALT > 2x reference value, n (%)	86 (63.7)	11 (73.3)	55 (50.9)^*&
Abnormal liver US, n (%)	19 (14.1)	1 (6.7)^*	2 (1.9)^*

IMV: Invasive Mechanical Ventilation; IQR: interquartile range; ALP: Alkaline phosphatase; GGT: Gamma-Glutamyltransferase; AST: Aspartate aminotransferase; ALT:Alanine aminotransferase; US: Ultrasound.

^*indicates p<0.05 in comparison with COVID+/IMV+/Ketamine+; ^& indicates p<0.05 in comparison with COVID+/IMV+/Ketamine-

No competing interests reported.

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PROFILE OF LIVER CHOLESTATIC BIOMARKERS FOLLOWING PROLONGED KETAMINE ADMINISTRATION IN PATIENTS WITH COVID-19

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Abstract

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Introduction

Material And Methods

Statistical analysis

Results

Discussion

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References

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Competing Interests

Supplementary Files

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