CAREGIVER Randomized Trial of Two Mindfulness Methods to Improve the Burden and Distress of Caring for Persons with Cirrhosis.

BACKGROUND: Patient caregivers experience burden and distress that negatively impacts health-related quality of life (HRQOL). Mindfulness may alleviate caregiver burden but randomized trials of mindfulness activities on caregiver burden and distress are lacking. METHODS: Caregivers for patients with advanced liver disease were recruited from the Universities of Michigan and Pennsylvania (12/2019-12/2021) and followed for 8 weeks. Participants were randomized 1:1:1 to: written emotional disclosure for 4 weeks, resilience training for 4 weeks, or control (no active intervention). All completed assessments at baseline, week 4 and 8. The primary outcome was change in the Zarit Caregiver Burden Index-12 (ZBI) at week 8. Secondary outcomes included changes at week 4 and 8 in the ZBI, distress thermometer (DT), HRQOL visual analog scale (VAS), and caregiver captivity index (CCI). RESULTS: Eighty seven caregivers were enrolled, 59(72%) completed the study. In unadjusted analyses at week 4, the burden measured by ZBI was not significantly different between arms, increasing by 0.6 ± 5.7 and 2.5 ± 5.2 points, for the written emotional disclosure and resilience training study arms, respectively, and by 2.9 ± 6.1 points in the control arm. At week 8, the non-significant ZBI change was - 1.0 ± 8.9, 2.8 ± 6.1, and 1.5 ± 7.4 for written emotional disclosure, resilience training, at week 8, respectively. The DT and VAS worsened in all arms, however, it worsened the least in the written emotional disclosure arm. In analyses adjusted for differences in baseline characteristics, the ZBI declined by - 4.21 ± 2.03(p = 0.04) in the emotional disclosure arm at week 4. This decrease was attenuated week 8, - 1.13 ± 2.6(p = 0.67). There were no significant differences in secondary outcomes save for resilience training reducing the CCI at week 4 by 1.36 ± 0.67(p = 0.04). CONCLUSION: Written emotional disclosure may reduce caregiver burden in the short term among caregivers for patients with cirrhosis. REGISTRATION: NCT04205396.

Lactulose therapy for patients with cirrhosis, portal hypertension, and poor patient-reported outcomes: The Mi-Kristal trial.

BACKGROUND AND AIMS: Poor patient-reported outcomes (PROs) are common in cirrhosis, including poor sleep and health-related quality of life (HRQOL). HE is a major driver of poor PROs. Many clinicians initiate lactulose therapy to address poor PROs. PRO-triggered therapy, however, has not been studied till date. METHODS: We conducted a 28-day randomized trial of crystalline lactulose therapy (20 g BID) compared with no HE-directed therapy in 52 patients with cirrhosis, portal hypertension, no prior HE, and high Work Productivity and Activity Impairment scores (0-10) attributed to cirrhosis. The primary outcome was change in global HRQOL measured with Short Form-8 Health Survey. Secondary outcomes included change in Animal Naming Test score, Work Productivity and Activity Impairment, and sleep quality (scored "very bad" to "very good"). APPROACH AND RESULTS: Overall, 52 patients underwent randomization; 3 subjects withdrew from the crystalline lactulose arm (1 before medication initiation, 1 due to an unrelated condition, and 1 due to high baseline bowel movements). The average age was 60 years, the average Model for Endstage Liver Disease-Sodium score was 10.5, and 56% of the patients had ascites. Baseline bowel movements were 2.3/day, with 35% of the patients having Bristol Stool Scale >4. At 28 days, there was no improvement in HRQOL: patients receiving crystalline lactulose had an 8.1-point (95% CI: 3.7-12.4) increase compared with 6.6 (95% CI: 2.3-10.8) in the control group ( p = 0.6). Lactulose was associated with a significantly ( p = 0.002) increased Animal Naming Test score (3.7, 95% CI: 2.1-5.4) versus the control group (0.2, 95% CI: -1.7, 1.4). Lactulose users reported more good sleep (92% vs. 52%, p = 0.001) and lower activity impairment (3.0 vs. 4.8, p = 0.02). CONCLUSIONS: Lactulose improves sleep and activity impairment in patients with poor PROs. We did not observe any improvement in global HRQOL after 28 days using the Short Form-8 Health Survey instrument.

Association between widespread pain and associated symptoms in patients with cirrhosis.

BACKGROUND: Chronic pain is common in cirrhosis; however, the mechanistic classifications are not well characterized. Nociplastic pain, for instance, is associated with comorbid nonpain symptoms and responds to different treatments than nociceptive pain. METHODS: We conducted a survey study in February 2022 of adult patients with cirrhosis at the University of Michigan (N = 238) to evaluate pain widespreadedness, associated nociplastic symptoms, and pain intensity. FINDINGS: Pain and pain widespreadedness were associated with mood and cognitive disturbance, fatigue, sleep difficulty, and physical and social functioning. Patient-reported Outcomes, such as body maps, can be useful to phenotype patients for pain mechanisms.

The emotional burden of caregiving for patients with cirrhosis.

Caregivers for patients with cirrhosis face immense physical and psychological strain that negatively impact quality of life and ability to care for oneself. The aim is to explore the caregiver experience for patients with cirrhosis, identify prominent stressors, and understand the multidimensional contributors to caregiver burden, to help tailor effective interventions. The caregivers of 25 patients with decompensated cirrhosis underwent semistructured in-person interviews and completed written exercises targeting emotional disclosure or resilience training that were analyzed for dominant emotions and themes. Burden was quantified using the Zarit Burden Interview-12 (ZBI, range 0-48), Distress Thermometer (0-10), and Caregiver Captivity Index (0-4). Quality of life was assessed with a visual analog scale (0-100). Median ZBI was moderate (14 [10-19]), as was distress (5 [2-7]), and captivity (2 [1-4]). Quality of life was fair (80 [70-85]). Dominant emotions included anxiety, guilt, fear, frustration, captivity, and resentment. Prominent themes included lack of time for self-care, hierarchy of caregiver role, support from versus frustration with medical professionals, social support, spirituality and religion, and disease-related restrictions. Hepatic encephalopathy, and need to follow strict nutrition and diet recommendations, are frequent sources of disease-related caregiver burden. The health care system confers some degree of burden, especially when doubts arise regarding physician competence. Conclusion: Caregiver burden is significant. The impact of interventions to alleviate caregiver burden should be explored, so that their appreciated efforts do not have such detrimental effects on their quality of life.

Pickle Juice Intervention for Cirrhotic Cramps Reduction: The PICCLES Randomized Controlled Trial.

INTRODUCTION: Muscle cramps are common among persons with cirrhosis and associated with poor health-related quality of life. Treatment options are limited. We sought to determine whether pickle juice can improve muscle cramp severity. METHODS: We enrolled 82 patients with cirrhosis and a history of >4 muscle cramps in the previous month from December 2020 to December 2021. Patients were randomized 1:1 to sips of pickle juice vs tap water at cramp onset. Our primary outcome assessed at 28 days was the change in cramp severity measured by the visual analog scale for cramps (VAS-cramps, scaled 0-10). Cramps were assessed 10 times over 28 days using interactive text messages. Secondary outcomes included the proportion of days with VAS-cramps <5, change in sleep quality, and global health-related quality of life measured using the EQ-5D. RESULTS: Overall, 74 patients completed the trial, aged 56.6 ± 11.5 years, 54% male, 41% with ascites, 38% with encephalopathy, and model for end-stage liver disease-sodium score 11.2 ± 4.9. Many patients were receiving other cramp therapies at baseline. The baseline VAS for cramps was 4.2 ± 3.4, the EQ-5D was 0.80 ± 0.10, and 43% rated sleep as poor. At trial completion, the respective values for the pickle juice and control arms were -2.25 ± 3.61 points on the VAS for cramps, compared with control tap water (-0.36 ± 2.87), P = 0.03; a proportion of cramp-days with VAS-cramps <5 were 46% vs 35% (P = 0.2); and the change in sleep quality was not different (P = 0.1). The end-of-trial EQ-5D was 0.78 ± 0.10 vs 0.80 ± 0.10 (P = 0.3). No differences in weight change were observed for those with and without ascites. DISCUSSION: In a randomized trial, sips of pickle brine consumed at cramp onset improve cramp severity without adverse events.

Animal Naming Test Is Associated With Poor Patient-Reported Outcomes and Frailty in People With and Without Cirrhosis: A Prospective Cohort Study.

INTRODUCTION: Cognitive dysfunction is a major driver of care complexity, poor patient-reported outcomes, and frailty for people with cirrhosis. The performance and clinical associations of the animal naming test (ANT) in the general population are unknown. We evaluated ANT performance in a representative sample of older Americans with and without chronic liver disease (CLD). METHODS: We analyzed 6,661 subjects enrolled in the 2010-2016 Health and Retirement Survey, a representative cohort of >30,000 US adults. Average age of participants was 75 years. We evaluated 3 subject subgroups: (i) without CLD, (ii) noncirrhosis CLD, and (iii) cirrhosis. We determined the association between the ANT (overall) and S-ANT1 <10 (adjusted for age and education) and health status, basic and instrumental activities of daily living, healthcare utilization (care hours received and hospitalizations), and frailty measures (hand grip and walk speed). RESULTS: Overall, 8.2% of the sample had noncirrhotic CLD and 1.3% had cirrhosis. CLD or cirrhosis was not independently associated with ANT. Poor ANT performance was associated with poor health status and frailty overall. An S-ANT <10 was associated with fair-poor self-reported health (odds ratio [OR] 1.37; 95% confidence interval [CI]: 1.20-1.56), care hours received (incidence rate ratio [IRR] 2.39; 95% CI: 1.79-3.19), and hospitalizations (IRR 1.14; 95% CI: 1.03-1.26). S-ANT <10 was also associated with activities of daily living disability (OR 1.31; 95% CI: 1.13-1.51), instrumental activities of daily living disability (OR 1.85; 95% CI: 1.59-2.14), weaker hand grip (IRR 0.94; 95% CI: 0.92-0.96), and time to walk 2.5 m (IRR 1.23; 95% CI: 1.17-1.29). DISCUSSION: ANT performance is not specific to CLD/cirrhosis but is associated with patient-reported outcomes and frailty in a nationally representative sample of elderly subjects with and without CLD.

Falls are common, morbid, and predictable in patients with cirrhosis.

BACKGROUND & AIMS: Falls are a devastating complication of cirrhosis. The risk of falls in patients without hepatic encephalopathy (HE) is unclear. Further, bedside tools for predicting falls are lacking. Thus, we aimed to internally validate a predictive model for falls and evaluate the association between incident falls and mortality. METHODS: We prospectively enrolled 299 patients with currently compensated Child A-B (70% Child-Pugh A) cirrhosis and portal hypertension without prior HE from 7/2016-8/2018. We followed patients for a median of 1,003 days (IQR 640-1,102) for incident falls accounting for the competing risk of death or transplantation. Candidate baseline fall predictors included patient-reported outcomes (e.g. Short-Form-8), physical function (e.g. chair-stands), blood tests (e.g. model for end-stage liver disease-sodium [MELD-Na] and its components), and cognitive function (using inhibitory control testing). RESULTS: During follow-up: 141 (47%) patients experienced falls, with 38 (13%) sustaining injuries, 49 (16%) died and 13 (4%) received transplants. Median time to a fall was 279 (98-595) days. The overall probability of falls was 28.8% and 50.2% at years 1 and 3; the probability of injurious falls was 9.1% and 16.5%, respectively. We derived a predictive model for falls. The FallSSS score (prior falls, chair-stands, sodium, and SF-8) had an AUROC for injurious falls at 6- and 12-months of 0.79 and 0.81, while MELD-Na's AUROC was 0.57 for both. Adjusting for baseline Child-Pugh class, MELD-Na, albumin level, disability status, and comorbidities, both incident falls (subdistribution hazard ratio [sHR] 2.76; 95% CI 1.46-5.24) and HE (sHR 4.25; 95% CI 2.15-8.41) were strongly and independently associated with mortality. CONCLUSION: Our prospective study of patients with cirrhosis without a baseline history of HE demonstrates that falls are common, morbid, and predictable. These data highlight both the value of expanding screening to patients with cirrhosis and the potential for benefit in studies of interventions to address fall-risk in this vulnerable population. LAY SUMMARY: Falls are a devastating complication of cirrhosis. Bedside tools for predicting falls are lacking. We found that falls were very common and often associated with serious injuries. Falls were also associated with an increased risk of death. Falls could be predicted with an algorithm called FallSSS - based on prior history of falls, blood sodium level, number of chair-stands performed in 30 seconds, and quality of life.

Identifying Patients With Hepatic Encephalopathy Using Administrative Data in the ICD-10 Era.

Hepatic encephalopathy (HE) is a common complication of cirrhosis resulting in relapsing-remitting mental status changes ranging from deficits in executive function to coma. Incident HE is associated with an abrupt increase in mortality1 and frequent hospitalization.2 To further the understanding of the burden and impact of HE at the population level, valid algorithms are required to identify patients in administrative data. An International Classification of Diseases (ICD)-9 code is specific for HE (572.2), offering a 0.92 positive predictive value (PPV) and 0.36 negative predictive value (NPV).3 When applied in an algorithm to patients with ICD-9 codes for cirrhosis (eg, 571.5), Kanwal et al4 found a PPV and NPV of 0.86 and 0.87. Unfortunately, the switch to ICD-10 in 2015 rendered algorithms validated using ICD-9 invalid. Kaplan et al5 previously showed that lactulose and rifaximin use correlated with grade of HE for Child classification. Herein, we validate a diagnostic coding algorithm for HE using ICD-10 and medication records.

Incidence and Bedside Predictors of the First Episode of Overt Hepatic Encephalopathy in Patients With Cirrhosis.

INTRODUCTION: Hepatic encephalopathy (HE) is associated with marked increases in morbidity and mortality for patients with cirrhosis. We aimed to determine the risk of and predictors for HE in contemporary patients. METHODS: We prospectively enrolled 294 subjects with Child A-B (70% Child A) cirrhosis and portal hypertension without previous HE from July 2016 to August 2018. The primary outcome was the development of overt HE (grade >2). We assessed the predictive power of model for end-stage liver disease-sodium (MELD-Na) score, the Inhibitory Control Test, the Sickness Impact Profile score, and the Bilirubin-Albumin-Beta-Blocker-Statin score. We also derived a novel predictive model incorporating MELD-Na score, impact of cirrhosis on daily activity (Likert 1-9), frailty (chair-stands per 30 seconds), and health-related quality of life (Short-Form 8, 0-100). RESULTS: The cohort's median age was 60 years, 56% were men, and the median MELD-Na score was 9. During a follow-up of 548 ± 281 days, 62 (21%) had incident overt HE with 1-year probability of 14% ± 2%, 10% ± 2%, and 25% ± 5% for Child A and B. The best model for predicting the risk of overt HE included MELD-Na, Short-Form 8, impact on activity rating, and chair-stands within 30 seconds. This model-MELDNa-Actvity-Chairstands-Quality of Life Hepatic Encephalopathy Score-offered an area under the receiver operating curve (AUROC) for HE development at 12 months of 0.82 compared with 0.55, 0.61, 0.70, and 0.72 for the Inhibitory Control Test, Sickness Impact Profile, Bilirubin-Albumin-Beta-Blocker-Statin, and MELD-Na, respectively. The AUROC for HE-related hospitalization was 0.92. DISCUSSION: This study provides the incidence of HE in a well-characterized cohort of contemporary patients. Bedside measures such as activity, quality of life, and physical function accurately stratified the patient's risk for overt HE.

Comprehensive Health-State Utilities in Contemporary Patients With Cirrhosis.

Cost-effectiveness analysis depends on generalizable health-state utilities. Unfortunately, the available utilities for cirrhosis are dated, may not reflect contemporary patients, and do not capture the impact of cirrhosis symptoms. We aimed to determine health-state utilities for cirrhosis, using both the standard gamble (SG) and visual analog scale (VAS). We prospectively enrolled 305 patients. Disease severity (Child-Pugh [Child] class, Model for End-Stage Liver Disease with sodium [MELD-Na] scores), symptom burden (sleep quality, cramps, falls, pruritus), and disability (activities of daily living) were assessed. Multivariable models were constructed to determine independent clinical associations with utility values. The mean age was 57 ± 13 years, 54% were men, 30% had nonalcoholic steatohepatitis, 26% had alcohol-related cirrhosis, 49% were Child class A, and the median MELD-Na score was 12 (interquartile range [IQR], 8-18). VAS displayed a normal distribution with a wider range than SG. The Child-specific SG-derived utilities had a median value of 0.85 (IQR, 0.68-0.98) for Child A, 0.78 (IQR, 0.58-0.93) for Child B, and 0.78 (IQR, 0.58-0.93) for Child C. VAS-derived utilities had a median value of 0.70 (IQR, 0.60-0.85) for Child A, 0.61 (IQR, 0.50-0.75) for Child B, and 0.55 (IQR, 0.40-0.70) for Child C. VAS and SG were weakly correlated (Spearman's rank correlation coefficient, 0.12; 95% confidence interval, 0.006-0.23). In multivariable models, disability, muscle cramps, and MELD-Na were significantly associated with SG utilities. More clinical covariates were significantly associated with the VAS utilities, including poor sleep, MELD-Na, disability, falls, cramps, and ascites. Conclusion: We provide health-state utilities for contemporary patients with cirrhosis as well as estimates of the independent impact of specific symptoms on each patient's reported utility.

Medically tailored meals for the management of symptomatic ascites: the SALTYFOOD pilot randomized clinical trial.

BACKGROUND: Ascites is a costly, morbid complication of cirrhosis. Although a low-sodium diet is central to the clinical management of ascites, its efficacy is limited by poor adherence. We aimed to determine the feasibility and impact of low-sodium medically tailored meals (MTM) intervention. METHODS: We enrolled 40 persons with cirrhosis and ascites at the time of a paracentesis in a 12-week, 1:1 randomized trial of standard of care (SOC) (low-sodium diet educational handout) or MTM with <2,000 mg of sodium, >2,100 kcal, and >80 g of protein including a nocturnal protein supplement. We determined the proportion of eligible candidates recruited and adherence to MTM. The primary outcome was the number of paracenteses performed during weeks 0-12. We also collected ascites-specific quality-of-life (ASI-7) scores. RESULTS: The median age of the enrolled subjects was 54 (IQR, 47-63) years, 46% were female, with median MELD-Na 18 (IQR, 11-23) and albumin 2.7 (IQR, 2.5-3.3) g/dL. At baseline, subjects reported a median of two (IQR, 1-3) paracenteses in the prior 4 weeks. Adherence to the meal schedule was excellent save for when hospitalizations occurred. After 12 weeks, patients in the MTM arm required fewer paracenteses per week than those in the SOC group [median (IQR): 0.34 (0.14-0.54) vs 0.45 (0.25-0.64)]. During the trial, four (20%) SOC patients died, whereas two (10%) died and one (5%) was transplanted in the MTM arm. Ascites-specific quality of life improved to a greater degree in the MTM arm compared to the SOC arm, by 25% (IQR, -11% to 61%) vs 13% (IQR, -28% to 54%). CONCLUSION: A trial of MTM for persons with ascites is feasible and potentially effective. Both arms experienced benefits, highlighting the role for improved education and closer monitoring in this challenging condition.