Articles Prevalence and clinical impact of alcohol withdrawal syndrome in alcohol-associated hepatitis and the potential role of prophylaxis: a multinational, retrospective cohort study David Marti-Aguado,a,b,m Amir Gougol,a,c,m Concepcion Gomez-Medina,b Arsia Jamali,a Abdelrhman Abo-Zed,a Dalia Morales-Arraez,d Alejandro Jimenez-Sosa,e Keith Burns,a Aditi Bawa,a Anjara Hernández,d Claudia Pujol,f Edilmar Alvarado-Tapias,a,f ,g Justyna Szafranska,h Wai Kan Chiu,a Ares Villagrasa,i Meritxell Ventura-Cots,g,i Haritha Gandicheruvu,a Paloma Lluch,b Hui-Wei Chen,j Vikrant Rachakonda,k Andres Duarte-Rojo,a and Ramon Batallera,l,∗ a Center for Liver Diseases, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, PA, USA b Digestive Disease Department, Clinic University Hospital, Biomedical Research Institute (INCLIVA), Valencia, Spain c University of California, San Francisco (UCSF), San Francisco, CA, USA d Department of Gastroenterology, Hospital Universitario de Canarias, Tenerife, Spain e Statistical Consultant Research Unit, Hospital Universitario de Canarias, Tenerife, Spain f Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Institut de Recerca Sant Pau, Universidad Autónoma de Barcelona, Barcelona, Spain g Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain h Department of Pathology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain i Liver Unit, Hospital Universitari Vall d’Hebron, Vall d’Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain j Allegheny General Hospital, Pittsburgh, PA, USA k University of California, Davis, CA, USA l Liver Unit, Hospital Clinic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Summary eClinicalMedicine 2023;61: 102046 Background The prevalence and impact of alcohol withdrawal syndrome (AWS) in patients with alcohol-associated hepatitis (AH) are unknown. In this study, we aimed to investigate the prevalence, predictors, management, and Published Online xxx https://doi.org/10. clinical impact of AWS in patients hospitalized with AH. 1016/j.eclinm.2023. 102046 Methods A multinational, retrospective cohort study enrolling patients hospitalized with AH at 5 medical centres in Spain and in the USA was performed between January 1st, 2016 to January 31st, 2021. Data were retrospectively retrieved from electronic health records. Diagnosis of AWS was based on clinical criteria and use of sedatives to control AWS symptoms. The primary outcome was mortality. Multivariable models controlling for demographic variables and disease severity were performed to determine predictors of AWS (adjusted odds ratio [OR]) and the impact of AWS condition and management on clinical outcomes (adjusted hazard ratio [HR]). Findings In total, 432 patients were included. The median MELD score at admission was 21.9 (18.3–27.3). The overall prevalence of AWS was 32%. Lower platelet levels (OR = 1.61, 95% CI 1.05–2.48) and previous history of AWS (OR = 2.09, 95% CI 1.31–3.33) were associated with a higher rate of incident AWS, whereas the use of prophylaxis decreased the risk (OR = 0.58, 95% CI 0.36–0.93). The use of intravenous benzodiazepines (HR = 2.18, 95% CI 1.02–4.64) and phenobarbital (HR = 2.99, 95% CI 1.07–8.37) for AWS treatment were independently associated with a higher mortality. The development of AWS increased the rate of infections (OR = 2.24, 95% CI 1.44–3.49), the need for mechanical ventilation (OR = 2.49, 95% CI 1.38–4.49), and ICU admission (OR = 1.96, 95% CI 1.19–3.23). Finally, AWS was associated with higher 28-day (HR = 2.31, 95% CI 1.40–3.82), 90-day (HR = 1.78, 95% CI 1.18–2.69), and 180-day mortality (HR = 1.54, 95% CI 1.06–2.24). Interpretation AWS commonly occurs in patients hospitalized with AH and complicates the hospitalization course. Routine prophylaxis is associated with a lower prevalence of AWS. Prospective studies should determine diagnostic criteria and prophylaxis regimens for AWS management in patients with AH. *Corresponding author. Liver Unit, Hospital Clinic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. E-mail address: bataller@clinic.cat (R. Bataller). m These authors have contributed equally to this work and share first authorship. www.thelancet.com Vol 61 July, 2023 1 Articles Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Copyright © 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Keywords: Alcohol withdrawal syndrome; Alcohol-associated hepatitis; Benzodiazepines; Alcohol use disorder Research in context Evidence before this study prevalence of AWS along with overall better outcomes. Alcohol withdrawal syndrome (AWS) is common in Patients with AH who developed AWS received a higher dose hospitalized patients with alcohol use disorder and is of benzodiazepines (BZD) compared to previously reported in associated with increased morbidity and mortality. Recent patients without AH. This is counterintuitive as sedatives excessive alcohol intake is key diagnostic criterion for alcohol- mainly have hepatic metabolism and can cause hepatic associated hepatitis (AH). Thus, hospitalized patients with AH encephalopathy, suggesting that current assessment scales are at high risk of developing AWS. We searched PubMed for based on symptom-triggered approach need further studies published by 1st January 2021 for articles in English validation in patients with AH. The use of intravenous BZD using the search term “alcohol withdrawal hepatitis” and and phenobarbital were associated with a higher mortality “alcohol-associated hepatitis”. There are no original articles rate compared to oral BZD. evaluating the prevalence, clinical characteristics, and Implications of all the available evidence management of AWS in patients with liver disease. This fact Our novel findings underscore the high rate and clinical influences that most liver societies do not recommend impact of AWS in patients with AH and can serve as proof of homogeneous protocols to manage AWS. This is the first concept for frequent monitoring of AWS-related symptoms. study evaluating the burden, outcomes, and treatment Our data also should warn clinicians on overutilization of strategies of AWS in patients hospitalised with AH. sedatives in patients with AH as it is associated with worse Added value of this study outcomes. As current AWS assessment scores are not This is the first study evaluating AWS in patients with AH. Our validated in patients with AH, we recommend favouring findings highlight the high burden of AWS in patients with clinical judgment for dosing sedatives on the basis of scaling AH. We also demonstrated that the development of AWS is assessment. Our findings highlight the urgent need to negatively associated with increased morbidity and mortality, conduct clinical trials to 1) assess the efficacy of AWS regardless of AH severity. Centres that provided universal prophylaxis and 2) compare different AWS treatment AWS prophylaxis to all patients with AH had a lower modalities in patients with AH. Introduction Prolonged, heavy alcohol drinking is the most com- Excessive alcohol use is associated with a high risk of mon aetiology of advanced liver disease globally.7 In morbidity and mortality, accounting for more than 3 parallel with the epidemic of AUD, the incidence and million deaths per year worldwide.1,2 Over the last mortality of alcohol-associated liver disease (ALD) are on decade, the prevalence of alcohol use disorder (AUD) the rise representing about half of all liver-related has increased at an alarming rate with a greater rise in mortality.2 While the majority of patients with ALD women, youth, and racial minorities.3 About 50% of exhibit chronic hepatic changes such as steatosis or patients with excessive alcohol intake develop some cirrhosis, a subgroup of patients present with alcohol- degree of alcohol withdrawal syndrome (AWS) after associated hepatitis (AH), a form of acute-on-chronic abrupt cessation or reduction in alcohol intake.4 The liver failure (ACLF) manifesting as rapid onset of presentation of AWS ranges from mild symptoms such jaundice and systemic inflammation in the setting as irritability, tachycardia, and tremulousness to severe of prolonged heavy alcohol use.8 Importantly, about 75% forms with seizure and delirium tremens (characterized of patients with AH has undiagnosed cirrhosis at the by alteration in mental status and severe autonomic time of initial presentation.9 Prolonged and heavy hyperactivity).5 When patients with AUD are admitted alcohol consumption coupled with the need for hospi- into the hospital, regardless of the reason for admission, talization puts the patients AH at a high risk for the they are at risk for developing AWS. Based on a recent development of AWS. systematic review, among patients hospitalized for any The incidence and clinical impact of AWS in patients medical condition with a history of excessive alcohol with liver disease are unknown.10 It is plausible that use, 2–7% develop severe AWS.6 early identification and appropriate management of 2 www.thelancet.com Vol 61 July, 2023 Articles AWS is associated with favourable outcomes. Moreover, the a priori approval of the institutional review boards the safety of current therapies has not been validated in from all participating hospitals (2021/139, CHUC_ patients with profound liver failure such as AH.11,12 2021_33, PR (AG)404/2021, and STUDY 19090128). Although practice guidelines for the management of Informed consent from patients was deemed unnec- AH include some comments on management of AWS, essary by the ethics committees for this retrospective there is little evidence to support the use of AWS pro- study. The study was conducted and reported in phylaxis. Subsequently, significant variation among compliance with the STROBE guidelines for cohort different centres.13,14 While some European centres have studies. adopted prophylactic pharmacotherapy in patients at high risk for the development of AWS, universal pro- Data collection phylaxis is highly uncommon in US centres. Further- Data were retrospectively retrieved from electronic more, most tertiary care centres adopt control of AWS health records. Patients with a diagnosis of AH admitted symptoms guided by assessment scales; however, other to the participating centres were consecutively enrolled. centres use clinical judgment for dosing of sedatives to Demographic data, clinical features, laboratory tests, control AWS symptoms.15 management strategies, and outcomes were recorded In this multi-national study, we aimed to describe the for every patient. Longitudinal laboratory variables were prevalence, clinical characteristics, management strate- collected and used to calculate model for end-stage liver gies, and outcomes of AWS in patients hospitalized with disease (MELD), albumin-bilirubin-INR-creatinine AH. We also explore the potential beneficial effects of (ABIC), and ACLF scores at different time points of prophylactic therapy in patients admitted with AH by admission. The development of new organ failure dur- comparing centres with different management strategies. ing hospitalization was captured. Acute kidney injury (AKI) was defined according to the International Ascites Club. Respiratory failure was defined as SpO2/FiO2 Methods ≤214. Cardiovascular failure was defined as mean arte- Study design and population rial pressure less than 65 mmHg or need for vasopres- We performed a multinational, observational study sors. Altered mental status was defined based on the identifying patients hospitalized with AH consecutively presence of hepatic encephalopathy grade II or higher.15 admitted between January 1st, 2016 and January 31st, Then, we calculated acute-on-chronic liver failure 2021. Patients from 5 tertiary medical centres were (ACLF) score and categorized patients into 4 classes: no included in this study: 4 centres from Spain (Clinic ACLF, ACLF grade I, ACLF grade II, and ACLF grade University Hospital of Valencia, University Hospital of III.16 Empirical use of antibiotic in patients with severe Canarias, Vall d’Hebron University Hospital of Barce- AH was not standard of care in any of participating lona, and Santa Creu i Sant Pau Hospital of Barcelona) centres. Use of antibiotics was based on clinician’s and one centre from the US (University of Pittsburgh judgement. Medical Center). All patients were aged 18 years or older Data related to AWS were captured by clinicians with at the time of hospitalization for AH. The diagnosis of experience taking care of patients hospitalized with AH. AH was based on criteria by the National Institute on The diagnosis of AWS was made based on the clinical Alcohol Abuse and Alcoholism (NIAAA).13,14 Patients judgment of the primary clinician following the patient with histologic confirmation of AH (definite AH) and and the need for sedative therapy to control AWS patients with clinical characteristics of AH without any symptoms. Medications used for control of AWS were confounding findings (probable AH) were included. categorized into benzodiazepines and phenobarbital. Briefly, the clinical diagnostic criteria of AH include: 1) The route of therapy [oral versus intravenous (IV)] was history of alcohol use of >60 g/day in men and >40 g/ recorded as well. Patients who received both oral and IV day in women, 2) an aspartate aminotransferase (AST) therapy were categorized in the IV group. In Spanish elevated >1.5 times the upper limit of normal but <400 centres, phenobarbital is not utilized for AWS treat- U/l with AST/ALT ratio >1.5, 3) Serum γ-glutamyl ment. The amount of benzodiazepine was detailed in transpeptidase (GGT) levels >80 mg/dL, 4) altered diazepam-equivalent format (https://www.benzo.org. coagulation tests [prolonged prothrombin time and/or uk/bzequiv.htm). The duration of AWS therapy was international ratio (INR) values], and 5) serum bilirubin determined by the time a patient required medication to levels >3 mg/dL. Severe AH was defined as MELD score control AWS-related symptoms. AWS severity was >20. Exclusion criteria include 1) presence of other categorized into severe and non-severe based on the identifiable causes of liver disease such as viral or presence of hallucination, delirium tremens, and/or autoimmune hepatitis, 2) alternative diagnosis on liver seizures. The severity of AWS symptoms was quantified biopsy, 3) hepatocellular carcinoma and/or other ma- by clinical institute withdrawal assessment-alcohol lignancies, and 4) other extrahepatic severe illness with revised (CIWA-Ar) scoring system. We also obtained low life expectancy. The study conformed to the ethical clinical complications associated with AWS, such as guidelines of the 1975 Declaration of Helsinki and had intubation and ICU admission. Participating centers www.thelancet.com Vol 61 July, 2023 3 Articles shared similar ICU admission protocols and none of functions that are proportional over the time t, and (II) them considered having alcohol use disorder or AH as a Martingale and Schoenfeld residuals plots tested that contraindication for ICU admission. Of note, the clinical the relationship between the log hazard and each co- protocols for the management of AWS differed between variate was linear. The results of multivariable Cox US and Spanish centres. In Spain, AWS prophylaxis is analysis are presented as estimated hazard ratios (HR) universally administered in all patients with a history of with corresponding 95% confidence interval (95% CI) recent excessive alcohol use, including all patients and p-values. Collinearity was assessed among the var- admitted with AH. As a standard of care protocol, AWS iables included in the multivariable analysis by using prophylaxis is given at the time of admission to all pa- variance inflation factors (VIF). VIFs value of less than 5 tients with AH. Prophylaxis is largely based on clome- show absence of any significant collinearity. In addition, thiazole.17 Clomethiazole is a thiamine derivative with a a multivariable binary logistic regression model GABA agonist effect commonly used for the treatment adjusted for age and MELD score was performed to of AWS symptoms. It has been shown clomethiazole evaluate factors associated with AWS (predictors and efficacy to control AWS symptoms is not inferior to clinical outcomes). We tested assumptions for logistic chlordiazepoxide.18 Use of clomethiazole as a prophy- regression models that included independence of er- laxis agent in patients at risk for AWS is common in rors, linearity in the logit for continuous variables, several European countries such as Germany or Spain.19 absence of multicollinearity, and lack of strongly influ- In the US, prophylaxis is rarely used and patients do not ential outliers. The results of multivariable logistic receive any pharmacologic therapy until AWS symp- regression are presented as estimated odds ratio (OR) toms start. To conduct a comparison, cases were defined with corresponding 95% CI and p-values. All tests were as patients diagnosed with AH by an attending physi- two-sided and a p-value less than 0.05 was considered cian and requiring sedative therapy to control symptoms statistically significant. All analyses were performed of AWS.8 As controls, we included all patients with AH with the IBM SPSS Statistics for Windows, Version who did not develop AWS during the index episode. The 25.0, Armonk, NY. The software Statistica 14.0.1.25 primary outcome of the study was 28-day, 90-day, and (tibco Software Inc.) was used to check the Cox pro- 180-day mortality. portional hazard model assumptions. Statistical analysis Role of the funding source Qualitative and quantitative variables were reported as There was no funding source for the study. All authors absolute frequencies/percentages and median with had full access to the data in this study and accept re- interquartile range (IQR), respectively. Comparisons sponsibility for the decision to submit the manuscript between groups were conducted using Mann–Whitney for publication. U test for continuous variables and chi-square or Fisher test for categorical variables, as appropriated. For time-to-event analysis, the day of admission for AH was Results defined as the baseline point (time 0). Censoring time Patient characteristic was defined as the last available patient encounter, time The clinical characteristics, relevant laboratory markers, of death, or study closure at 180-days, whichever complications, and outcomes of patients with AH are occurred first. Time-to-event analysis was performed depicted in Table 1. In total, 432 patients with probable using Kaplan–Meier method. Survival curves were (n = 393) or definite diagnosis (n = 39) of AH were compared using the log-rank test to identify parameters included. Patients were admitted consecutively to modifying 28-day, 90-day, and 180-day mortality. participating centres between January 2016 and January Multivariable Cox proportional hazard regression ana- 2021. Of them, 55% (n = 239) were recruited in the US lyses was performed to determine the independent and 45% (n = 193) in Spain (Supplementary Table S1). contribution of AWS on mortality, adjusted for age, The median MELD score was 21.9 (18.3–27.3). Preva- MELD score, ALCF class, in-hospital infection, hepatic lence of severe AH and treatment with corticosteroids encephalopathy (HE), and corticosteroid use (all was 64% (n = 277) and 44% (n = 192), respectively. The considered confounding factors of AH mortality). A median MELD score and Maddrey’s discriminant second model of multivariable Cox regression was per- function (mDF) were significantly higher in patients formed to determine in patients who developed AWS treated with corticosteroids: MELD of 20 (16–26) vs. 23 the independent contribution of AWS management on (20–28), p < 0.0010; and mDF of 45 (23–80) vs. 65 mortality, adjusted for age, MELD, HE and severity of (44–83), p < 0.0010. Overall, 24.5% (n = 106) of patients AWS (all considered confounding factors influencing met criteria for ACLF (6% grade I, 10.6% grade II and AWS management and mortality). The use of Cox pro- 7.9% grade III), with a mean CLIF-C ACLF score of portional hazards models needs two assumptions that 51 ± 9. Antibiotic therapy was used in 58% (n = 249) of were checked as follows: (I) Sc. Schoenfeld plot tested the patients, being their main indication of use an active that survival curves for different strata have hazard infection (n = 159), prophylaxis in the setting of GI 4 www.thelancet.com Vol 61 July, 2023 Articles explored the clinical and laboratory parameters associ- Characteristic Total (n = 432) ated with the development of AWS (Supplementary Anthropometric and history Table S2). There was no significant difference in the Age, years, median (IQR) 48 (40–56) degree of liver dysfunction based on MELD score be- Sex, female, n (%) 157 (36.3%) tween patients with and without AWS. Among patients Sex, male, n (%) 275 (63.7%) who underwent liver biopsy, histologic severity of AH Race, white, n (%) 391 (90.5%) determined by alcoholic hepatitis histologic score BMI, kg/m2, median (IQR) 27.9 (24.2–32.5) (AHHS) was not associated with the development of History of AH, n (%) 134 (31.1%) History of AWS, n (%) 116 (26.8%) AWS (Supplementary Table S3). In the univariate History of hepatic encephalopathy, n (%) 91 (21.1%) analysis, patients who developed AWS were younger (46 Corticosteroid use, n (%) 192 (44.4%) vs. 49 years, p = 0.0060) and more commonly had a Data on Admission previous history of AWS (37.1% vs. 22.2%, p = 0.0010). Creatinine (mg/dL), median (IQR) 0.77 (0.6–1.2) Among laboratory parameters at admission, platelet Na (mmol/L), median (IQR) 133 (128–137) levels were inversely associated with the rate of AWS Bilirubin (mg/dL), median (IQR) 9.9 (6.3–19.1) (124.1/dL vs. 139.7/dL, p = 0.045). To identify inde- INR, median (IQR) 1.7 (1.4–2.1) pendent predictors of AWS, a multivariable logistic Albumin (g/dL), median (IQR) 2.6 (2.2–3) regression analysis was performed. After controlling for Platelets (×109/L), median (IQR) 114 (65–178) age and MELD score, previous history of AWS (OR 2.09, MELD score, median (IQR) 21.9 (18.3–27.3) 95% CI 1.31–3.33) and lower platelet levels (OR 1.61, MELD score >20, n (%) 277 (64%) 95% CI 1.05–2.48) were independently associated with a ABIC score, median (IQR) 7.5 (6.6–8.8) higher rate of AWS (Supplementary Table S2). Impor- Complications tantly, we found that the use of prophylaxis at the time AWS, n (%) 140 (32.4%) of admission decreased the risk of AWS by 42% (OR Gastrointestinal bleeding, n (%) 72 (16.6%) 0.58, 95% CI 0.36–0.93, p = 0.024). Ascites, n (%) 267 (61.8%) Infections, n (%) 173 (40.1%) Management AKI, n (%) 140 (32.4%) We next studied the impact of different modalities of Encephalopathy, n (%) 165 (38.2%) AWS treatment. Table 2 details the management stra- Shock, n (%) 34 (7.8%) tegies to control AWS symptoms. We compared the Need for intubation, n (%) 58 (13.4%) management strategies between US and Spanish co- Clinical outcomes horts. While most patients admitted with AH in Spain ICU admission, n (%) 118 (27.3%) received prophylaxis with clomethiazole at the time of Length of stay (days), median (IQR) 11.0 (6.0–22.0) ICU stay (days), median (IQR) 5.0 (2.0–10.0) admission, no patient received prophylactic therapy in Mortality on day 28, n (%) 75 (17.3%) the US. Remarkably, patients from the US had higher Mortality on day 90, n (%) 118 (27.3%) severity of AWS symptoms scaled by CIWA-Ar score Mortality on day 180, n (%) 145 (33.6%) (10 vs. 4, p = 0.0020). In the US, the dosage and route of sedatives to control AWS symptoms were dictated by Abbreviations: ABIC, Age-bilirubin-INR-creatinine score; AH, Alcohol-associated hepatitis; AKI, Acute kidney injury; AWS, Alcohol withdrawal syndrome; BMI, CIWA-Ar scale assessment, whereas in Spanish cen- Body mass index; ICU, Intensive care unit; INR, International ratio; IQR, tres clinical judgment by clinicians was main driver of Interquartile range; MELD, Model for end stage liver disease. sedative use. BZDs were more frequently administered Table 1: Clinical characteristics of patients with alcohol-associated via IV route in the US, compared to Spanish centres hepatitis. (48.3% vs. 31.7%, p = 0.032). Phenobarbital was used in a small proportion of patients (8.6%) as adjunctive therapy to BZD. Next, we performed a multivariable bleeding (n = 25), endotracheal intubation (n = 9), and Cox regression to assess the effect of different man- presence of ACLF with signs of systemic inflammation agement strategies on patient outcomes. After response (n = 12). The overall mortality rate at 28 days, controlling for age, HE, and severity of AH and AWS, 90 days, and 180 days were 17.3%, 27.3%, and 33.6%, we found that the use of BZD via IV route (HR 2.18, respectively. Only 20 patients (4.7%) underwent early 95% CI 1.02–4.64) and phenobarbital (HR 2.99, 95% liver transplantation. CI 1.07–8.37) were associated with a higher rate of 90-day mortality compared to the oral-only route Prevalence, severity, and risk factors (Supplementary Table S4). Fig. 1 illustrates Kaplan The clinical features of AWS during hospitalization are Meir curves depicting the impact of different treatment described in Table 2. During hospitalization, 32.4% modalities on the mortality of patients with AH who (n = 140) of patients developed AWS. In most cases developed AWS. (95%), symptoms of AWS started within the initial three Although AWS and HE are two distinct conditions, days of hospitalization and lasted for 5 days. Next, we they can have common symptoms and co-exist. In an www.thelancet.com Vol 61 July, 2023 5 Articles levels were higher in patients with HE [96 (75–126) ug/ Total (N = 140) USA (N = 89) Spain (N = 51) p-value dL vs. 79 (53–111) ug/dL; p = 0.11]. Timing AWS onset (days), median (IQR) 1 (0–2.5) 1 (0–3) 1 (0–2) Clinical outcomes Severity We finally investigated the clinical impact of AWS. WAS score on admission 4 (0–16) 5 (0–18) 2 (0–6) 0.0020 Table 3 summarizes the association between AWS and Maximum WAS score, median (IQR) 8 (0–21) 10 (0–24) 4 (0–11) 0.33 clinical outcomes. After controlling for MELD score and Hallucinations, n (%) 23 (16.4%) 15 (16.9%) 8 (15.7%) 0.86 age, the development of AWS was associated with Delirium tremens, n (%) 10 (7.1%) 5 (5.6%) 5 (9.8%) 0.36 Seizure, n (%) 5 (3.5%) 3 (3.4%) 2 (3.9%) 0.87 increased risk of in-hospital infection (OR 2.24, 95% CI AWS duration (days), median (IQR) 4 (2–6) 3 (2–6) 5 (3–9) 0.011 1.44–3.49), altered mental status (OR 2.41, 95% CI Management 1.52–3.83), ICU admission (OR 1.96, 95% CI Use of prophylaxis, n (%) 51 (36.4%) 0 (0%) 51 (100%) <0.0010 1.19–3.23), as well as the need for mechanical ventila- BZD use, n (%) 128 (91.4%) 87 (97.8%) 41 (80.4%) <0.0010 tion (OR 2.49, 95% CI 1.38–4.49). As illustrated in BZD use route, n (%) 0.036 Fig. 2, we used Kaplan–Meier curves to compare the PO only 51 (39.8%) 28 (32.2%) 23 (56.1%) short-term and long-term mortality between patients IV only 55 (43.0%) 42 (48.3%) 13 (31.7%) with and without AWS during AH hospitalization. A PO and IV 22 (17.2%) 17 (19.5%) 5 (12.2%) multivariable Cox regression analysis to determine the BZD dose (mg), median (IQR) 45 (20–148) 45 (22–180) 35 (15–105) 0.12 independent effect of AWS on mortality was adjusted Phenobarbital use, n (%) 12 (8.6%) 12 (13.5%) 0 (0%) 0.0060 for age, MELD, ACLF class, infection, HE, and cortico- Abbreviations: AWS, Alcohol withdrawal syndrome; BZD, Benzodiazepine; IQR, Interquartile range; IV, steroid use. There was no significant collinearity among Intravenous; mg, milligrams; PO, Per oral; WAS, Withdrawal assessment scale. variables (Supplementary Table S5). We found that the development of AWS independently increased the risk Table 2: Clinical features and management of alcohol withdrawal syndrome. of short-term and long-term mortality. For 28-day mor- tality, the adjusted-HR was 2.31, 95% CI 1.40–3.82 (p = 0.0010); for 90-day mortality, the adjusted-HR was attempt to differentiate both conditions, ammonia levels 1.78, 95% CI 1.18–2.69 (p = 0.0060); and for 180-day were tested in a subgroup of patient (n = 163). Ammonia mortality, the adjusted-HR was 1.54, 95% CI 1.06–2.24 levels correlated with HE grades (r = 0.55, p = 0.011) but (p = 0.023). Supplementary Table S6 shows the com- not with CIWA-Ar scale assessment (r = 0.20, p = 0.070). plete multivariable analysis for the determination of Among patients with severe AH and AWS, ammonia factors associated with short and long-term mortality. Fig. 1: Kaplan Meier curves comparing the survival between different treatment strategies to control Alcohol Withdrawal Syndrome in Alcohol- associated Hepatitis patients. The blue line corresponds to oral benzodiazepines, the green line to intravenous benzodiazepine, and the purple line to phenobarbital. Raw p-values are presented. Abbreviations: IV, Intravenous; AWS, Alcohol withdrawal syndrome. 6 www.thelancet.com Vol 61 July, 2023 Articles Univariate Analysis Multivariable Analysis Clinical outcomes AWS No AWS p-value ORb 95% CI p-value AKI, n (%) 45 (32.1%) 95 (32.9%) 0.88 1.29 0.75–2.25 0.36 Cardiovascular failure, n (%) 16 (14.0%) 18 (7.6%) 0.054 2.18 0.96–4.95 0.062 HE during hospitalization, n (%) 67 (48.2%) 98 (33.9%) 0.0040 2.41 1.52–3.83 <0.0010 Infections, n (%) 73 (53.3%) 100 (34.6%) <0.0010 2.24 1.44–3.49 <0.0010 Need for intubation, n (%) 30 (21.4%) 28 (9.6%) 0.0010 2.49 1.38–4.49 0.0030 ACLF, n (%) 32 (22.9%) 74 (25.3%) 0.57 1.29 0.68–2.45 0.44 CLIF-C ACLFa (mean ± SD) 50 ± 10 51 ± 8 0.76 1.01 0.95–1.08 0.68 ICU admission, n (%) 50 (36.2) 68 (23.6) 0.0060 1.96 1.19–3.23 0.0090 ICU stay ≥7 days, n (%) 16 (32.0) 26 (38.8) 0.45 0.66 0.29–1.53 0.33 Hospitalization stay ≥7 days, n (%) 107 (76.4) 205 (71.2) 0.25 1.75 1.05–2.91 0.031 Mortality AWS No AWS p-value HRc 95% CI p-value Mortality on day 28, n (%) 35 (27.1) 40 (14.6) 0.0030 2.31 1.40–3.82 0.0010 Mortality on day 90; n (%) 47 (38.5) 71 (26.8) 0.019 1.78 1.18–2.69 0.0060 Mortality on day 180, n (%) 54 (45.4) 91 (36.5) 0.047 1.54 1.06–2.24 0.023 Abbreviations: ACLF, Acute-on-chronic liver failure; AKI, Acute kidney injury; AWS, Alcohol withdrawal syndrome; CI, Confidence interval; HE, Hepatic encephalopathy; HR, Hazard ratio; ICU, Intensive care unit; OR, Odds ratio. aCLIF-C score was only calculated in patients who developed ACLF. bFor clinical outcome variables, the effect of AWS was adjusted by age and MELD score. cFor mortalities, the effect of AWS was adjusted by age, MELD, ACLF class, hepatic encephalopathy, infection, and corticosteroid use. Table 3: Impact of alcohol withdrawal syndrome on outcomes of patients with alcohol-associated hepatitis. These results indicate that the development of AWS developing AWS received high doses of BZD and negatively impact the clinical course of AH. frequently through the IV route. Third, we showed that IV BZD and phenobarbital use were associated with Discussion worse clinical outcomes. Fourth, AWS complicated hos- Despite the high prevalence of AWS in AH, this is the pitalization course by increasing the risk of in-hospital first study investigating the clinical characteristics, infections, need for mechanical ventilation, and ICU management, and outcomes of AWS in patients hospi- admission. Fifth, we identified higher short-term and talized with AH. Our results revealed 6 key findings. long-term mortality in patients with AH who developed First, the development of AWS is common in patients AWS. Finally, we observed a significant disparity in the hospitalized with AH, affecting up to one-third of pa- management strategies between centres in the US and tients. Second, we found that patients with AH Spain. Strikingly, AWS prophylaxis at admission in Fig. 2: Kaplan–Meier curve comparing survival between patients with (green line) and without (blue line) Alcohol Withdrawal Syndrome during hospitalization for Alcohol-associated Hepatitis. Raw p-values are presented. Abbreviations: AWS, Alcohol withdrawal syndrome. www.thelancet.com Vol 61 July, 2023 7 Articles patients with AH was associated with a lower risk of AWS and HE have some common and distinctive symptoms development and related complications. and can co-exist, making the differential diagnosis quite In our study, up to one-third of patients with AH challenging. Currently, there is no specific diagnostic developed clinically significant AWS. In a USA cohort of test to reliably differentiate these two conditions and patients at the Veterans Health Administration, patients clinician judgement (i.e., timing of symptoms onset, with cirrhosis had higher prevalence of AWS.12 A small and presenting symptoms) is used for this purpose, study in patients with WDS undergoing a liver biopsy, raising concern over misdiagnosis. Although ammonia found histopathologic findings consistent with AH in level do not guide clinical management in HE, we 45% of patients.20 The high prevalence of AWS in pa- showed that ammonia was slightly higher in severe AH tients with AH in our study is due to the fact that most patients with AWS and co-existing HE.37 Furthermore, of them have a history of recent excessive alcohol intake ammonia levels correlated with HE grades but not prior to hospitalization. In agreement with previous CIWA-Ar scale. Importantly, development of HE and reports, we showed that younger age and prior history of AWS are not mutually exclusive and they can co-exist in AWS increase the risk of AWS in patients with AH.21 about of half of patients with AH.38 It is conceivable that Unlike earlier reports in patients without AH, we did patients with a poor outcome after IV BZD adminis- not find any difference in the prevalence of AWS in AH tration could have, at least, some degree of concomitant between female and male sex.12 The high prevalence of HE. Prospective studies should identify novel specific AWS in patients with AH highlights the importance of diagnostic tools to differentiate between HE and AWS. close monitoring in all patients admitted with AH and Additional causes that mimic AWS such as Wernicke’s strongly suggests that early prophylaxis should be encephalopathy should also be further investigated. instituted in order to prevent the development and Our findings indicate that the development of AWS complications of AWS. is associated with a more than two-fold risk of short- While there are no randomized controlled trials in term mortality in patients admitted with AH. The the management of AWS in patients with AH, we negative impact of AWS was independent of the severity assessed various management strategies to provide of liver dysfunction, highlighting the appropriate man- insight into the safety of current treatment modalities agement of AWS as major part of AH care to improve and pave the way for future studies. We found that pa- overall outcomes. While overall mortality of AWS in tients with AH predominantly received a high dose of patients admitted with alcohol intoxication is relatively BZD and, in half of the cases, through an IV route. low, the clinical outcomes in patients admitted with any When comparing our results with previous studies in other indication are less favourable.39–41 While there is the management of AWS in patients without AH, a no study on patients with AH, previous reports showed higher dosage of BZD was utilized in our cohort of that patients with advanced liver disease are at higher patients with AH.22,23 We also found the use of BZD via risk of developing severe AWS and its related compli- IV route was independently associated with higher cations.42 Altered mental status resulting in a higher morbidity and mortality. BZD dosing and route of need for intubation and risk of aspiration pneumonia is administration are driven by a symptoms-triggered a potential mechanism explaining poor outcomes in approach using withdrawal assessment scales.23–26 patients with AH who develop AWS. AWS can trigger Higher BZD requirement in patients with AH devel- alteration in mental status directly or secondary to the oping AWS may be related to overestimation of AWS use of sedatives required to control psychomotor agita- severity by current scaling scores. The lack of validity of tion related to AWS. common AWS scoring systems in face of other acute An important finding of our study is the potential illness were previously shown during postoperative care, beneficial role of AWS prophylaxis.43,44 Given the high leading to inappropriately higher dose of sedative-hyp- burden and impact of AWS, an attempt to achieve an notics.27 We hypothesize that systemic inflammation effective preventive strategy was pursued by few related to AH may have led to the overestimation of studies.45,46 However, there are no head-to-head trial AWS severity, which subsequently led to higher BZD comparing the outcomes of prophylaxis with no pro- dose and higher frequency of IV routes.28–31 Validating phylaxis in patients at risk for developing AWS.47 Based current withdrawal severity scores in patients with AH on expert opinion, AWS prophylaxis is suggested in represents an urgent need to avoid over-utilization of patients at risk for the development of severe AWS and BZD in patients with AWS. Our results also warn cli- not actively experiencing AWS.48 Given the low level of nicians to use the minimum dose of BZD possible to evidence, significant variation exists among centres. A control the symptoms and avoid IV route and barbitu- small clinical trial compared clonidine vs. diazepam as rates, if possible, in patients with AH. prophylaxis agents in patients at risk of AWS undergo- Poor outcomes in patients with AH who received ing surgery; clonidine resulted in a lower rate of high dose of BZD or phenobarbital can be related to post-operative AWS.49 Clomethiazole, a fast-acting triggering or aggravating HE, which in turn, increase barbiturate-like drug, has been widely used for the the risk of aspiration and in-hospital infection.5,32–36 AWS treatment and prophylaxis of AWS in Europe.17,50 8 www.thelancet.com Vol 61 July, 2023 Articles Clomethiazole was found similarly effective to BZD for mortality and other clinical outcomes, fully weighed treatment and prophylaxis of AWS.43,51 To the best of our with respect to critical confounders. Finally, the diag- knowledge, no study has evaluated the effect of pro- nosis of AWS and its related complications relied on phylaxis against AWS in patients with AH. After con- subjective judgment of attending physician. To reduce trolling for age and AH severity, we found that centres this limitation, we confirmed their diagnosis with the adopting prophylaxis strategy had a significantly lower dose of as-needed sedative use and vital signs to rate of infection, need for mechanical ventilation, and decrease the subjective assessments in diagnosis of mortality. Results of this study strongly suggest benefi- AWS. cial effects of the prophylactic regimen in all patients In conclusion, this multi-center study demonstrates admitted with AH. Further randomized controlled trials that AWS is common in patients admitted with AH. is urgently warranted to confirm this observation. AWS complicates the clinical course of patients with Our study encompassed several strengths. First, to AH by increasing the risk of hepatic encephalopathy, the best of our knowledge, this is the first study inves- infection, and the need for mechanical ventilation. tigating the clinical characteristics, management, and AWS independently increased the short-term and long- outcomes of AWS in patients with AH. Given the high term mortality of AH. The higher dose of sedative prevalence of both AH and AWS, the clinical message of agents via IV route to control AWS symptoms is asso- this study is highly relevant to patient care. Second, ciated with worse outcomes. Comparing the prophy- despite the multi-centre design, the study leadership laxis strategies between centres, our findings suggest was central to ensuring universal methods for patient that adoption of universal prophylaxis with clomethia- selection, variable definitions, and data collection. Third, zole may be beneficial to prevent AWS and its related all clinical data were collected by clinician-investigators complications. with extensive experience in the management of pa- Contributors tients with AH and AWS. This should enhance the ac- DMA: Writing-Original Draft, Methodology, accessed and verified the curacy of data by limiting the risk of inappropriate underlying data, responsible for the decision to submit the manuscript. coding and documentation. Forth, detailed clinical data AG: Writing-Original Draft, Methodology, accessed and verified the on specific time-points were available and our study underlying data, responsible for the decision to submit the manuscript. contained very minimal missing data (n = 13 due to CGM: Resources, Project administration, accessed and verified the underlying data. non-reported critical laboratory values). And fifth, long- AJ: Formal analysis. term follow up was available in all patients, which AAZ: Resources. allowed us to assess long-term outcomes. There are, DM-A: Formal analysis. however, several limitations. First, Spanish and US co- AJS: Writing - Review & Editing. KB: Resources. horts differs in several clinical aspects, severity, and AB: Resources. management strategies of AWS. Differences represent AH: Resources. the heterogenous manner in which this complication is CP: Resources. being managed, influenced by the lack of scientific ev- EAT: Resources. idence and recommendations. Although fully adjusted JS: Resources. WKC: Resources. multivariable analysis were performed, considering HWC: Resources. together both cohorts can raise concern on the applica- AV: Resources. bility of the results as it may be influenced by local MVC: Writing - Review & Editing. healthcare systems and standard of care protocols. HG: Resources. PL: Resources. Nevertheless, this study allowed to compare two cohorts VR: Writing - Review & Editing. with different clinical management representing a ADR: Writing - Review & Editing. unique opportunity to assess the potential usefulness of RB: Conceptualization, Supervision, Writing - Review & Editing, AWS prophylaxis and the risk of different therapies. Our responsible for the decision to submit the manuscript. preliminary results can raise awareness of clinically All authors concur with the decision to submit the manuscript. relevant issues that should now be confirmed in clinical Data sharing statement trials. Second, retrospective design of study incurs se- De-identified individual participant data collected during the study will lection bias on prevalence and outcomes of AWS and be made available to request following publication, access to this data confounding variables. We included patients admitted will be granted to researchers who provide a methodologically sound proposal. Proposals should be directed to the corresponding author. consecutively in all participating centres to minimize this limitation. All participating centres were tertiary Declaration of interests care hospitals with high level of complexity, so a referral The authors declare no conflict of interest regarding this manuscript. bias was likely to occur. Thus, our results may not reflect the burden of AWS in community centres. We Acknowledgements DMA is recipient of a Joan Rodés award Instituto de Salud Carlos III, attempted to control potential confounding by con- Spanish Ministry of Science and Innovation (JR22/00002). This study ducting analysis adjusted by multiple variables and received no specific grant from any funding agency in the public, presenting the independent measure of AWS impact on commercial, or not-for-profit sectors. www.thelancet.com Vol 61 July, 2023 9 Articles Appendix A. Supplementary data 23 Daeppen JB, Gache P, Landry U, et al. 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