Key words : Alcohol, Liver cirrhosis, Liver transplantation, Postoperative delirium

Introduction

Delirium, characterized by an acute change in mental status, is a common issue in critically ill patients. This condition is often associated with increased costs, mortality, length of hospital stay, and long-term cognitive impairment.1-4 Delirium after liver transplant has an incidence of 1.6% to 47.4%,5-12 and it has a negative effect on clinical outcomes.5-7,9,11-13 An increased incidence of delirium in the intensive care unit (ICU) is related to the complexity of the surgical procedure, severity of illness, neural structural changes after hepatic encephalopathy, metabolic disturbances, and drug neurotoxicity.14-16 There are several risk factors for delirium after liver transplant, including preoperative encephalopathy,7,9,11 preoperative renal replacement therapy,5,8,11 high Acute Physiology and Chronic Health Evaluation II (APACHE II) scores,9,11,12 extended mechanical ventilation duration posttransplant,5,9 and blood transfusions.5,7,10-12

Alcohol-associated liver disease is also a crucial risk factor for delirium.6,9,12 However, the incidence of delirium remains controversial among various populations (2.6% to 42.3%) of transplant recipients with alcoholic cirrhosis.5-12 Alcoholic liver disease is a common indication for liver transplant, with an average of 28.68% among patients from an American database17 and of 19% among a European database.18 The risk of alcoholic relapse is considered before public organ allocation. In Asia, patients with alcoholic cirrhosis with life-threatening conditions may receive an emergent living donor liver transplant (LDLT) after a rigorous assessment. However, the duration of alcohol abstinence remains controversial. No single study has focused on delirium in transplant patients with alcoholic cirrhosis. Thus, this study aimed to clarify the association between posttransplant delirium in liver transplant recipients with alcoholic cirrhosisand the clinical outcomes of these patients after LDLT.

Materials and Methods

This retrospective study included data collected from a single medical center in Taiwan between January 1, 2014, and December 31, 2019. During this period, 338 patients underwent LDLT. From this cohort, 84 patients with alcoholic liver disease were included in our study. In emergency situations (with rapidly worsening liver function and potentially fatal outcomes), LDLT may be considered as a life-saving treatment after patients undergo a preliminary psychosocial assessment, a cautious preoperative evaluation, and comprehensive conversations that include the patient and their families. Patients who showed insight into their alcohol use, made a commitment to lifelong abstinence, had an absence of comorbid psychiatric disorders, and had sufficient psychosocial support were potential candidates for a liver transplant. Patients required being considered as low risk for relapse after an assessment by psychiatrists and social workers. Appropriately selected patients and matched living donors, who were up to the recipients’ third-degree relatives, underwent LDLT. All information was collected from electronic medical records. The study was approved by the Institutional Review Board of Changhua Christian Hospital (document no. 191244).

Delirium assessment
Delirium was diagnosed as disturbances in cognition, attention, and awareness over a short duration in an acute or fluctuating course. However, it was not diagnosed in conditions of severely reduced levels of arousal, such as coma.19 Several bedside screening tools have been developed by various health care providers for regular monitoring and timely intervention of delirium. The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU),20 which has a sensitivity of 80% and a specificity of 95.9%,21,22 has been recommended for routine clinical practice.23 It is also utilized in patients who are receiving mechanical ventilation or patients with cirrhosis.24

A prerequisite for a delirium evaluation is an assessment of a patient’s arousal level as defined by the Richmond Agitation-Sedation Scale (RASS).25,26 This scale has also been validated for clinicaluse.27 Patients in a coma who were not able to respond to verbal stimulation were categorized as “unable to assess,” with a score of -4 (deep sedation) to -5 (unarousable). Otherwise, if patients could be aroused and they could be categorized with a RASS score of between +4 (combative status) and -3 (moderate sedation status), the delirium evaluation then proceeded to a CAM-ICU assessment.

Inclusion and exclusion criteria
Among the 338 patients who received LDLTs between January 1, 2014, and December 31, 2019, in our medical center, 84 patients with alcoholic liver disease were enrolled in this study. All patients were diagnosed with alcohol use disorder19 by hepatologists, psychologists, and social workers. Patients with other etiologies of liver disease such as viral hepatitis, autoimmune hepatitis, nonalcoholic fatty liver disease, primary biliary cholangitis, or primary sclerosing cholangitis were excluded. Postoperative delirium development was initially defined as a RASS score between +4 (combative status) and -3 (moderate sedation status), with patients then assessed with the CAM-ICU test. According to this assessment, bedside nurses would evaluate the patient 3 times per day. If the assessment was positive, physicians would reassess the patient for confirmation of the score. After factors contributing to delirium were surveyed by laboratory and imaging examinations, none of the patients with alcohol withdrawal syndrome, hepatic encephalopathy, cardiovascular diseases, neurotoxic conditions related to drugs (such as tacrolimus), intracranial hemorrhage, or infarction were categorized into the delirium group.

Because of difficulties in differentiating among delirium, alcohol withdrawal syndrome, and hepatic encephalopathy, we discreetly evaluated the latest drinking period28 to decide whether the symptoms constituted alcohol withdrawal syndrome and ordered a biochemistry test for hyperammonemia. Subsequently, all patients were divided into a delirium (n = 46, 54.8%) and a nondelirium group (n = 38, 45.2%).

Data collection
All patients were preoperatively assessed for their profile information (age and sex), clinical presentations of hepatic encephalopathy, and severity of chronic liver disease (Model for End-Stage Liver Disease [MELD] score). Each patient also received a psychiatric evaluation (duration of alcohol use disorder and alcohol abstinence duration). A patient who achieved preoperative abstinence was defined as one who had attained at least 1 month of sobriety with a low risk of relapse after an initial psychosocial assessment. Perioperative procedures, including operation time and amount of blood loss, were recorded. After the transplant procedure, all patients received critical care with routine assessment of their APACHE II scores. Calcineurin inhibitor-based immunosuppression was initiated with tacrolimus (target level of 5-10 ng/mL), mycophenolate, and methylprednisolone. The serum tacrolimus level on postoperative day 7 was measured. Postoperative infections, including respiratory tract infections, intra-abdominal infections, urinary tract infections, bloodstream infections, wound infections, and catheter-related infections, were assessed through culture examinations. Postoperative sepsis was further defined as life-threatening organ dysfunction accompanied by an increase of 2 points in the Sequential Organ Failure Assessment score. Outcomes posttransplant were assessed by analyzing the mechanical ventilator duration, hospital mortality, and length of ICU and hospital stays. The alcohol abstinence duration was further divided into ?3, 3 to 6, and >6 months to evaluate the effects of duration of abstinence on postoperative delirium.

Statistical analyses
Patient data are expressed as means ± SD, and categorical variables are expressed as numbers and percentages. A Mann-Whitney U test was used to compare the differences in continuous variables, and a chi-square or Fisher exact test was used to compare the differences in categorical variables. Significant variables in the univariate analyses were then included in a forward, stepwise multiple logistic regression model to identify the most important risk factors for developing delirium in the ICU after LDLT surgery.

A chi-square test was performed to compare the 2 groups. Statistical significance was defined as P < .05. We performed statistical analyses on a personal computer using the statistical package SPSS for Windows (version 20).

Results

We included a total of 84 patients, 46 (54.8%) of whom developed delirium after transplant, in this study. Age, sex, duration of alcohol use disorder, abstinence duration, operative duration, APACHE II score, and tacrolimus levels on postoperative day 7 were not significantly associated with delirium.

Before transplant, we observed a higher pro-portion of preoperative hepatic encephalopathy (58.7% vs 31.6%; P = .013), higher MELD scores (27.05 ± 10.56 vs 18.85 ± 7.96; P < .001), and lower percentage of preoperative alcohol abstinence (43.5% vs 68.4%; P = .022) in the posttransplant delirium group versus the nondelirium group. Furthermore, during the transplant procedure, blood loss (4235.87 ± 2632.00 mL vs 2676.32 ± 2341.97 mL; P = .001) was significantly greater in the delirium group. Patients in the posttransplant delirium group had longer durations of mechanical ventilation (7.57 ± 7.82 vs 2.50 ± 5.96 days; P = .001) and prolonged ICU stays (14.85 ± 15.01 vs 8.84 ± 7.84 days; P = .021) and hospital stays (37.89 ± 18.85 vs 27.15 ± 10.43 days; P = .002) compared with the nondelirium group. However, neither postoperative sepsis (17.4% vs 7.9%; P = .330) nor hospital mortality (13% vs 5.3%; P = .284) were significantly different between the groups (Table 1).

On multivariate analysis, preoperative alcohol abstinence (odds ratio of 4.953; 95% CI, 1.519-16.152; P = .008) placed patients at high risk for developing posttransplant delirium (Table 2).

To evaluate the effect of the duration of alcohol abstinence before liver transplant on postoperative delirium, we further analyzed various cutoff durations for alcohol abstinence: <3, 3 to 6, and >6 months. In the delirium group, a higher percentage of patients with statistically significant abstinence times of <3 months (60.9% vs 34.2%, P = .048) was observed (Table 3).

Discussion

In our study, a high percentage of patients with alcoholic cirrhosis (up to 54.8%) developed postoperative delirium after LDLT. Multivariate analysis revealed that preoperative alcohol abstinence was an independent risk factor. After the cutoffs of abstinence times were divided into 3 and 6 months, a shortened abstinence duration was significantly associated with postoperative delirium. Moreover, postoperative delirium had a negative impact on the duration of mechanical ventilation, ICU stay, and hospital stay, but not on hospital mortality.

In previous studies, the incidence of delirium after liver transplant was shown to range from 1.6% to 47.4%.5-12 An increasing number of patients with alcoholic cirrhosis of the liver are receiving liver transplants.17 A history of alcohol abuse is a predictive factor for delirium after liver transplant.6,9,12 An alcoholic etiology has been positively correlated with the incidence of posttransplant delirium, although the rate has been reported to vary between 2.6% and 42.3%.5-12 Two studies with a relatively small sample size had a high incidence rate of posttransplant delirium. Wang and colleagues reported a high incidence (47.4%), with alcoholic etiologies of posttransplant delirium accounting for 42.3% of the cases.9 In another prospective study, Beckmann and colleagues also reported a high incidence (45.2%) but reported a low proportion of patients with alcoholic etiologies (9.5%) according to comprehensive assessments in the ICU and the hospital unit.5 To clarify the association between posttransplant delirium and its alcoholic etiologies, we focused on patients with alcoholic cirrhosis (incidence rate of 54.8%). In our study, more than half of the patients with alcoholic cirrhosis developed delirium after liver transplant.

The requirement of a 6-month alcohol abstinence before liver transplant has been generally adopted since 1997. This was recommended by the American Society of Transplant Physicians and the American Association for Study of Liver Diseases.29 The so-called “6- month rule” promoted improvements in liver function and evaluated patients’ risks of potential relapse of alcohol consumption before public organ allocation. However, several trials on early transplant in patients with severe acute alcoholic hepatitis (who were not responsive to corticosteroid therapy and had a high 6-month mortality rate of >75%30) showed favorable outcomes. Patients in these trials had a 6-month survival rate between 77% and 100%.31-34 Consensus statements for liver transplant in select patients with acute alcoholic hepatitis and a short interval of abstinence duration between 1 and 3 months35-37 had a significant impact on clinical practice in Europe38 and the United States.39 In Taiwan, an abstinence duration of >6 months remains a requirement before being listed for deceased donor liver transplant. However, LDLTs may be considered as a life-saving treatment for patients with rapid worsening of liver function and those unable to achieve 6-month sobriety. Potential transplant candidates with a low risk of alcohol relapse are selected because sustained alcohol use posttransplant has shown a negative impact on long-term survival rates.40

The role of abstinence time and its association with posttransplant alcohol relapse remain controversial in LDLT.41,42 This might be explained by a strong social and psychological support from close family members who could help protect the individual against alcohol relapse.43,44 This protective factor is especially true when the donor is living with the recipient in the same household.

In our study, 45.2% of patients did not achieve necessary alcohol abstinence before transplant. The absence of preoperative abstinence was identified as a significant independent risk factor for post-transplant delirium with an odds ratio of 4.953. We might assume that preoperative abstinence may reduce the risk of posttransplant delirium and its negative impact on the duration of mechanical ventilation, ICU stay, and hospital stay. With proper treatment, our data supported that there was no significant difference in hospital mortality in the delirium group. However, further research is required to investigate the association between preoperative abstinence duration and long-term outcomes.

Alcohol-related brain injury has been discussed in recent studies. Proposed mechanisms include nutritional deficiencies, hepatic dysfunction, ethanol-specific effects, systemic neuroinflammation, and synergistic effects.45,46 Abstinence may improve brain structure and biochemical status.47 This could explain why a longer duration of abstinence decreased the risk of posttransplant delirium in our study. However, the distinct pathophysiology of alcohol-related brain damage and postoperative delirium requires further investigation.

Similar to the short-term outcomes shown in other studies, our study showed that posttransplant delirium was associated with prolonged mechanical ventilation5,7,9,11,12 with an average of 5.07 days, prolonged ICU stays6,7,11,12 with an average of 6.01 days, and prolonged hospital stays6-8,11,12 with an average of 10.64 days. These issues may be compounded further by frequent episodes of sepsis,11 urinary tract infection, and pneumonia.6 However, in our study, neither postoperative sepsis (17.4% vs 7.9%; P = .330) nor hospital mortality (13% vs 5.3%; P = .284) was significantly different between the groups. We assumed that the appropriate management of postoperative delirium could achieve similar outcomes for hospital mortality. Compared with other studies that reported a higher hospital mortality of 6 months11 or 1 year,7 the study by Lee and colleagues showed no significant difference in hospital and 1-year mortality.12 Whether delirium is a reversible condition and whether it affects long-term outcomes remain to be resolved.2,3,48 Further research is required regarding this issue.

Considering its negative effect on outcomes, postoperative delirium should be prevented and treated using multicomponent nonpharmacological risk factor methods, comprehensive assessments, and timely pharmacological interventions.48-50 In the ICU, a standard assessment by ICU-CAM was used to detect delirium in its early stages. Benzodiazepine use is a risk factor for delirium in ICU patients.23 Thus, we preferred propofol, haloperidol, or quetiapine as our medications of choice. We also adopted early mobilization and encouraged family support by transferring patients to ordinary hospital units when they were stable. This is compatible with previous study.12 This strategy may explain why the incidence of postoperative sepsis was not significantly different in patients with delirium versus those without delirium.

Our study had certain limitations. First, the study was retrospective in design, and the data were collected from medical records. Second, post-transplant delirium was assessed by individual and bedside nurses. However, the RASS and CAM-ICU have been consistently applied in clinical practice. Third, the sample size was relatively small (ie, from a single medical center). Fourth, our findings were limited to patients with alcoholic liver disease. We note that patients with viral or autoimmune hepatitis require further analysis. As the concept of early transplant for severe alcoholic hepatitis was advocated and LDLT gained popularity in Asia, we were the first to focus on alcohol hepatitis and LDLT for posttransplant delirium. Moreover, data on long-term outcomes remain lacking. Further studies are needed to discuss the relapse rate and its impact on LDLT.

Conclusions

We concluded that a high incidence of posttransplant delirium in alcoholic cirrhotic recipients was associated with preoperative abstinence. Abstinence >6 months prior to LDLT is suggested to reduce the risk of posttransplant delirium.

References:

1. Ely EW, Gautam S, Margolin R, et al. The impact of delirium in the intensive care unit on hospital length of stay. Intensive Care Med. 2001;27(12):1892-1900. doi:10.1007/s00134-001-1132-2
   CrossRef - PubMed
   
2. Ely EW, Shintani A, Truman B, et al. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA. 2004;291(14):1753-1762. doi:10.1001/jama.291.14.1753
   CrossRef - PubMed
   
3. Girard TD, Jackson JC, Pandharipande PP, et al. Delirium as a predictor of long-term cognitive impairment in survivors of critical illness. Crit Care Med. 2010;38(7):1513-1520. doi:10.1097/CCM.0b013e3181e47be1
   CrossRef - PubMed
   
4. Milbrandt EB, Deppen S, Harrison PL, et al. Costs associated with delirium in mechanically ventilated patients. Crit Care Med. 2004;32(4):955-962. doi:10.1097/01.ccm.0000119429.16055.92
   CrossRef - PubMed
   
5. Beckmann S, Schubert M, Burkhalter H, Dutkowski P, De Geest S. Postoperative delirium after liver transplantation is associated with increased length of stay and lower survival in a prospective cohort. Prog Transplant. 2017;27(1):23-30. doi:10.1177/1526924816679838
   CrossRef - PubMed
   
6. Bhattacharya B, Maung A, Barre K, et al. Postoperative delirium is associated with increased intensive care unit and hospital length of stays after liver transplantation. J Surg Res. 2017;207:223-228. doi:10.1016/j.jss.2016.08.084
   CrossRef - PubMed
   
7. Oliver N, Bohorquez H, Anders S, et al. Post-liver transplant delirium increases mortality and length of stay. Ochsner J. 2017;17(1):25-30.
   CrossRef - PubMed
8. Wu SY, Chen TW, Feng AC, Fan HL, Hsieh CB, Chung KP. Comprehensive risk assessment for early neurologic complications after liver transplantation. World J Gastroenterol. 2016;22(24):5548-5557. doi:10.3748/wjg.v22.i24.5548
   CrossRef - PubMed
   
9. Wang SH, Wang JY, Lin PY, et al. Predisposing risk factors for delirium in living donor liver transplantation patients in intensive care units. PLoS One. 2014;9(5):e96676. doi:10.1371/journal.pone.0096676
   CrossRef - PubMed
   
10. Pinero F, Mendizabal M, Quiros R, et al. Neurological events after liver transplantation: a single-center experience. Transpl Int. 2014;27(12):1244-1252. doi:10.1111/tri.12404
    CrossRef - PubMed
    
11. Lescot T, Karvellas CJ, Chaudhury P, et al. Postoperative delirium in the intensive care unit predicts worse outcomes in liver transplant recipients. Can J Gastroenterol. 2013;27(4):207-212. doi:10.1155/2013/289185
    CrossRef - PubMed
    
12. Lee H, Oh SY, Yu JH, Kim J, Yoon S, Ryu HG. Risk factors of postoperative delirium in the intensive care unit after liver transplantation. World J Surg. 2018;42(9):2992-2999. doi:10.1007/s00268-018-4563-4
    CrossRef - PubMed
    
13. Lee H, Ju JW, Oh SY, Kim J, Jung CW, Ryu HG. Impact of timing and duration of postoperative delirium: a retrospective observational study. Surgery. 2018;S0039-6060(18)30035-7. doi:10.1016/j.surg.2018.02.001
    CrossRef - PubMed
    
14. Balderramo D, Prieto J, Cardenas A, Navasa M. Hepatic encephalopathy and post-transplant hyponatremia predict early calcineurin inhibitor-induced neurotoxicity after liver transplantation. Transpl Int. 2011;24(8):812-819. doi:10.1111/j.1432-2277.2011.01280.x
    CrossRef - PubMed
    
15. DiMartini A, Fontes P, Dew MA, Lotrich FE, de Vera M. Age, model for end-stage liver disease score, and organ functioning predict posttransplant tacrolimus neurotoxicity. Liver Transpl. 2008;14(6):815-822. doi:10.1002/lt.21427
    CrossRef - PubMed
    
16. Garcia-Martinez R, Rovira A, Alonso J, et al. Hepatic encephalopathy is associated with posttransplant cognitive function and brain volume. Liver Transpl. 2011;17(1):38-46. doi:10.1002/lt.22197
    CrossRef - PubMed
    
17. Lee BP, Vittinghoff E, Dodge JL, Cullaro G, Terrault NA. National trends and long-term outcomes of liver transplant for alcohol-associated liver disease in the United States. JAMA Intern Med. 2019;179(3):340-348. doi:10.1001/jamainternmed.2018.6536
    CrossRef - PubMed
    
18. Adam R, Karam V, Cailliez V, et al. 2018 Annual report of the European Liver Transplant Registry (ELTR) - 50-year evolution of liver transplantation. Transpl Int. 2018;31(12):1293-1317. doi:10.1111/tri.13358
    CrossRef - PubMed
    
19. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-5). 5th ed. American Psychiatric Association; 2013.
    CrossRef - PubMed
    
20. Ely EW, Margolin R, Francis J, et al. Evaluation of delirium in critically ill patients: validation of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Crit Care Med. 2001;29(7):1370-1379. doi:10.1097/00003246-200107000-00012
    CrossRef - PubMed
    
21. Gusmao-Flores D, Salluh JI, Chalhub RA, Quarantini LC. The confusion assessment method for the intensive care unit (CAM-ICU) and intensive care delirium screening checklist (ICDSC) for the diagnosis of delirium: a systematic review and meta-analysis of clinical studies. Crit Care. 2012;16(4):R115. doi:10.1186/cc11407
    CrossRef - PubMed
    
22. Neto AS, Nassar AP, Jr., Cardoso SO, et al. Delirium screening in critically ill patients: a systematic review and meta-analysis. Crit Care Med. 2012;40(6):1946-1951. doi:10.1097/CCM.0b013e31824e16c9
    CrossRef - PubMed
    
23. Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013;41(1):263-306. doi:10.1097/CCM.0b013e3182783b72
    CrossRef - PubMed
    
24. Orman ES, Perkins A, Ghabril M, Khan BA, Chalasani N, Boustani MA. The confusion assessment method for the intensive care unit in patients with cirrhosis. Metab Brain Dis. 2015;30(4):1063-1071. doi:10.1007/s11011-015-9679-8
    CrossRef - PubMed
    
25. Sessler CN, Gosnell MS, Grap MJ, et al. The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med. 2002;166(10):1338-1344. doi:10.1164/rccm.2107138
    CrossRef - PubMed
    
26. Ely EW, Truman B, Shintani A, et al. Monitoring sedation status over time in ICU patients: reliability and validity of the Richmond Agitation-Sedation Scale (RASS). JAMA. 2003;289(22):2983-2991. doi:10.1001/jama.289.22.2983
    CrossRef - PubMed
    
27. Khan BA, Guzman O, Campbell NL, et al. Comparison and agreement between the Richmond Agitation-Sedation Scale and the Riker Sedation-Agitation Scale in evaluating patients' eligibility for delirium assessment in the ICU. Chest. 2012;142(1):48-54. doi:10.1378/chest.11-2100
    CrossRef - PubMed
    
28. Mirijello A, D'Angelo C, Ferrulli A, et al. Identification and management of alcohol withdrawal syndrome. Drugs. 2015;75(4):353-365. doi:10.1007/s40265-015-0358-1
    CrossRef - PubMed
    
29. Lucey MR, Brown KA, Everson GT, et al. Minimal criteria for placement of adults on the liver transplant waiting list: a report of a national conference organized by the American Society of Transplant Physicians and the American Association for the Study of Liver Diseases. Liver Transpl Surg. 1997;3(6):628-637. doi:10.1002/lt.500030613
    CrossRef - PubMed
    
30. Louvet A, Naveau S, Abdelnour M, et al. The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids. Hepatology. 2007;45(6):1348-1354. doi:10.1002/hep.21607
    CrossRef - PubMed
    
31. Mathurin P, O'Grady J, Carithers RL, et al. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data. Gut. 2011;60(2):255-260. doi:10.1136/gut.2010.224097
    CrossRef - PubMed
    
32. Im GY, Kim-Schluger L, Shenoy A, et al. Early liver transplantation for severe alcoholic hepatitis in the United States--a single-center experience. Am J Transplant. 2016;16(3):841-849. doi:10.1111/ajt.13586
    CrossRef - PubMed
    
33. Lee BP, Chen PH, Haugen C, et al. Three-year results of a pilot program in early liver transplantation for severe alcoholic hepatitis. Ann Surg. 2017;265(1):20-29. doi:10.1097/SLA.0000000000001831
    CrossRef - PubMed
    
34. Weeks SR, Sun Z, McCaul ME, et al. Liver transplantation for severe alcoholic hepatitis, updated lessons from the world’s largest series. J Am Coll Surg. 2018;226(4):549-557. doi:10.1016/j.jamcollsurg.2017.12.044
    CrossRef - PubMed
    
35. Hajifathalian K, Humberson A, Hanouneh MA, et al. Ohio solid organ transplantation consortium criteria for liver transplantation in patients with alcoholic liver disease. World J Hepatol. 2016;8(27):1149-1154. doi:10.4254/wjh.v8.i27.1149
    CrossRef - PubMed
36. Consensus conference: Indications for Liver Transplantation, January 19 and 20, 2005, Lyon-Palais Des Congres: text of recommendations (long version). Liver Transpl. 2006;12(6):998-1011. doi:10.1002/lt.20765
    CrossRef - PubMed
    
37. Testino G, Burra P, Bonino F, et al. Acute alcoholic hepatitis, end stage alcoholic liver disease and liver transplantation: an Italian position statement. World J Gastroenterol. 2014;20(40):14642-14651. doi:10.3748/wjg.v20.i40.14642
    CrossRef - PubMed
    
38. Antonini TM, Guillaud O, Dumortier J, et al. Impact of a first study of early transplantation in acute alcoholic hepatitis: results of a nationwide survey in french liver transplantation programs. Liver Transpl. 2018;24(6):841-844. doi:10.1002/lt.25039
    CrossRef - PubMed
    
39. Zhu J, Chen PY, Frankel M, Selby RR, Fong TL. Contemporary policies regarding alcohol and marijuana use among liver transplant programs in the United States. Transplantation. 2018;102(3):433-439. doi:10.1097/TP.0000000000001969
    CrossRef - PubMed
    
40. Kodali S, Kaif M, Tariq R, Singal AK. Alcohol relapse after liver transplantation for alcoholic cirrhosis-impact on liver graft and patient survival: a meta-analysis. Alcohol Alcohol. 2018;53(2):166-172. doi:10.1093/alcalc/agx098
    CrossRef - PubMed
    
41. Braun HJ, Ascher NL. Living donor liver transplantation for alcoholic liver disease. Alcohol Alcohol. 2018;53(2):178-183. doi:10.1093/alcalc/agx099
    CrossRef - PubMed
    
42. Chung HG, Sinn DH, Kang W, Choi GS, Kim JM, Joh JW. Incidence of and risk factors for alcohol relapse after liver transplantation for alcoholic liver disease: comparison between deceased donor and living donor liver transplantation. J Gastrointest Surg. 2021;25(3):672-680. doi:10.1007/s11605-020-04540-7
    CrossRef - PubMed
    
43. Satapathy SK, Eason JD, Nair S, et al. Recidivism in liver transplant recipients with alcoholic liver disease: analysis of demographic, psychosocial, and histology features. Exp Clin Transplant. 2015;13(5):430-440.
    CrossRef - PubMed
    
44. Saigal S, Choudhary NS, Yadav SK, et al. Lower relapse rates with good post-transplant outcome in alcoholic liver disease: experience from a living donor liver transplant center. Indian J Gastroenterol. 2016;35(2):123-128. doi:10.1007/s12664-016-0646-z
    CrossRef - PubMed
    
45. Hammoud N, Jimenez-Shahed J. Chronic neurologic effects of alcohol. Clin Liver Dis. 2019;23(1):141-155. doi:10.1016/j.cld.2018.09.010
    CrossRef - PubMed
    
46. Zahr NM, Kaufman KL, Harper CG. Clinical and pathological features of alcohol-related brain damage. Nat Rev Neurol. 2011;7(5):284-294. doi:10.1038/nrneurol.2011.42
    CrossRef - PubMed
    
47. Meyerhoff D. Brain spectroscopic imaging, morphometry, and cognition in social drinkers and recovering alcoholics. Alcohol Clin Exp Res. 2005;29:153-154.
    CrossRef - PubMed
    
48. Inouye SK, Westendorp RG, Saczynski JS. Delirium in elderly people. Lancet. 2014;383(9920):911-922. doi:10.1016/S0140-6736(13)60688-1
    CrossRef - PubMed
    
49. Young J, Murthy L, Westby M, Akunne A, O'Mahony R, Guideline Development Group. Diagnosis, prevention, and management of delirium: summary of NICE guidance. BMJ. 2010;341:c3704. doi:10.1136/bmj.c3704
    CrossRef - PubMed
    
50. Milbrandt EB, Kersten A, Kong L, et al. Haloperidol use is associated with lower hospital mortality in mechanically ventilated patients. Crit Care Med. 2005;33(1):226-229; discussion 263-225. doi:10.1097/01.ccm.0000150743.16005.9a
    CrossRef - PubMed