Objectives: History of alcohol abuse is a predictive factor for posttransplant delirium. We aimed to investigate whether preoperative abstinence was associated with posttransplant delirium in liver transplant recipients with alcohol-related cirrhosis.
Materials and Methods: From January 2014 to December 2019, 84 patients with alcohol-related cirrhosis who received living donor liver transplant were retrospectively reviewed and divided into a delirium group (n = 46, 54.8%) and a nondelirium group (n = 38, 45.2%) using the Richmond Agitation-Sedation Scale and the Confusion Assessment Method for the Intensive Care Unit.
Results: In the delirium group versus the nondelirium group, patients were more likely to have preoperative hepatic encephalopathy (58.7% vs 31.6%; P = .013), more likely to have higher Model for End-Stage Liver Disease scores (27.05 ± 10.56 vs 18.85 ± 7.96; P < .001), less likely to have preoperative alcohol abstinence (43.5% vs 68.4%; P = .022), had longer duration of mechanical ventilation (7.57 ± 7.82 vs 2.50 ± 5.96 days; P = .001), and had longer stays in the intensive care unit (14.85 ± 15.01 vs 8.84 ± 7.84 days; P = .021) and in the hospital (37.89 ± 18.85 vs 27.15 ± 10.43 days;
P = .002). Multivariate analysis revealed that preoperative alcohol abstinence (odds ratio 4.953; 95% CI, 1.519-16.152; P = .008) was a significant predictor and that more patients had abstinence durations <3 months (60.9% vs 34.2%; P = .048) in the delirium group.
Conclusions: A high incidence of posttransplant delirium in liver transplant recipients with alcohol-related cirrhosis was associated with preoperative abstinence. Abstinence >6 months before living donor liver transplant is suggested to reduce the risk of posttransplant delirium.
Key words : Alcohol, Liver cirrhosis, Liver transplantation, Postoperative delirium
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 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%).
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.
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).
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).
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.
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.
Volume : 20
Issue : 8
Pages : 750 - 756
DOI : 10.6002/ect.2022.0199
From the 1Department of General Surgery and the 2Department of Nursing, Changhua Christian Hospital, Changhua, Taiwan; and the 3Department of Surgery, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.Chia-En Hsieh, Kuo-Hua Lin, and Yao-Li Chen authors contributed equally to this article.
Corresponding author: Kuo-Hua Lin or Yao-Li Chen, Department of General Surgery, Changhua Christian Hospital. No. 135, St. Nanxiao, Changhua City, Changhua County 500209, Taiwan
Phone: +886 47238595
E-mail: firstname.lastname@example.org or email@example.com
Table 1. Demographic and Clinical Features of the Delirium and Nondelirium Groups
Table 2. Logistic Regression Analysis of Factors Contributing to Posttransplant Delirium
Table 3. Comparison of Various Cutoff Durations of Alcohol Abstinence Between the Delirium and Nondelirium Group