Michele De Rui

Sleep-wake abnormalities in patients with cirrhosis.

A considerable proportion of patients with cirrhosis exhibit insomnia, delayed sleep habits, and excessive daytime sleepiness. These have been variously attributed to hepatic encephalopathy and impaired hepatic melatonin metabolism, but the understanding of their pathophysiology remains limited and their treatment problematic. Sleep is regulated by the interaction of a homeostatic and a circadian process. The homeostatic process determines sleep propensity in relation to sleep‐wake history, thus the need to sleep increases with the duration of the waking period. The circadian process, which is marked by the 24‐hour rhythm of the hormone melatonin, is responsible for the alternation of high/low sleep propensity in relation to dark/light cues. Circadian sleep regulation has been studied in some depth in patients with cirrhosis, who show delays in the 24‐hour melatonin rhythm, most likely in relation to reduced sensitivity to light cues. However, while melatonin abnormalities are associated with delayed sleep habits, they do not seem to offer a comprehensive explanation to the insomnia exhibited by these patients. Fewer data are available on homeostatic sleep control: it has been recently hypothesized that patients with cirrhosis and hepatic encephalopathy might be unable, due to excessive daytime sleepiness, to accumulate the need/ability to produce restorative sleep. This review will describe in some detail the features of sleep‐wake disturbances in patients with cirrhosis, their mutual relationships, and those, if any, with hepatic failure/hepatic encephalopathy. A separate section will cover the available information on their pathophysiology. Finally, etiological treatment will be briefly discussed. (Hepatology 2014;59:705–712)

Covert hepatic encephalopathy: Agreement and predictive validity of different indices

AIM To investigate the agreement and prognostic value of different measures of covert hepatic encephalopathy (CHE). METHODS One-hundred-and-thirty-two cirrhotic outpatients underwent electroencephalography (EEG), paper-and-pencil psychometry (PHES) and critical flicker frequency, scored on the original/modified (CFFo/CFFm) thresholds. Eighty-four patients underwent Doppler-ultrasound to diagnose/exclude portal-systemic shunt. Seventy-nine were followed-up for 11 ± 7 mo in relation to the occurrence of hepatic encephalopathy (HE)-related hospitalisations. RESULTS On the day of study, 36% had grade I HE, 42% abnormal EEG, 33% abnormal PHES and 31/21% abnormal CFFo/CFFm. Significant associations were observed between combinations of test abnormalities; however, agreement was poor (Cohens κ < 0.4). The prevalence of EEG, PHES and CFFo/CFFm abnormalities was significantly higher in patients with grade I overt HE. The prevalence of EEG and CFFm abnormalities was higher in patients with shunt. The prevalence of EEG abnormalities was significantly higher in patients with a history of HE. During follow-up, 10 patients died, 10 were transplanted and 29 had HE-related hospitalisations. Grade I HE (P = 0.004), abnormal EEG (P = 0.008) and abnormal PHES (P = 0.04) at baseline all predicted the subsequent occurrence of HE; CFF did not. CONCLUSION CHE diagnosis probably requires a combination of clinical, neurophysiological and neuropsychological indices.

Prognostic benefit of the addition of a quantitative index of hepatic encephalopathy to the MELD score: the MELD-EEG.

A slowed electroencephalogram (EEG) is indicative of the presence of hepatic encephalopathy (HE). Since HE is not reflected in the MELD score and is an important prognostic parameter, we assess the prognostic benefit of the addition of an EEG‐based HE index to the MELD.

The animal naming test: An easy tool for the assessment of hepatic encephalopathy

Screening for hepatic encephalopathy (HE) that does not cause obvious disorientation or asterixis (minimal HE [MHE]/grade 1 HE) is important. We examined if the animal naming test (ANT1) (maximum number of animals listed in 1 minute) is useful in this context. In total, 208 healthy controls, 40 controls with inflammatory bowel disease, and 327 consecutive patients with cirrhosis underwent the ANT1. Patients were tested for MHE by the psychometric HE score, and 146 were assessed by electroencephalography; 202 patients were followed up regarding the occurrence of overt HE and death. In the healthy controls, ANT1 was influenced by limited education (<8 years) and advanced age (>80 years, P < 0.001). Using an age and education adjusting procedure, the simplified ANT1 (S‐ANT1) was obtained. An S‐ANT1 of <10 animals was abnormal. Of the patients, 169 were considered unimpaired, 32 as having HE ≥grade 2, and 126 as having MHE/grade 1 HE. This group had lower S‐ANT1 than unimpaired patients (12 ± 0.4 versus 16 ± 0.7, P < 0.001) and higher S‐ANT1 than those with HE ≥grade 2 (4 ± 0.9). In grade 1 HE the S‐ANT1 was lower than in MHE. Following receiver operating characteristic analysis (Youdens index), 15 animals produced the best discrimination between unimpaired and MHE/grade 1 HE patients. Thus, a three‐level score (0 for S‐ANT1 ≥15, 1 for 10 ≤ S‐ANT1 < 15, 2 for S‐ANT1 <10) was obtained. This score was correlated both to the psychometric HE score (P < 0.0001) and to electroencephalography (P = 0.007). By sample random split validation, both S‐ANT1 and its three‐level score showed prognostic value regarding the 1‐year risk of overt HE and death. No inflammatory bowel disease control had S‐ANT <15. Conclusion: The S‐ANT1 is an easily obtainable measure useful for the assessment of HE. (Hepatology 2017;66:198–208).

The Influence of Environmental Factors on Sleep Quality in Hospitalized Medical Patients

Introduction: Sleep–wake disturbances are common in hospitalized patients but few studies have assessed them systematically. The aim of the present study was to assess sleep quality in a group of medical inpatients, in relation to environmental factors, and the switch to daylight-saving time. Methods: Between March and April 2013, 118 consecutive inpatients were screened and 99 (76 ± 11 years; hospitalization: 8 ± 7 days) enrolled. They slept in double or quadruple rooms, facing South/South-East, and were qualified as sleeping near/far from the window. They underwent daily sleep assessment by standard questionnaires/diaries. Illuminance was measured by a luxmeter at each patient’s eye-level, four times per day. Noise was measured at the same times by a phonometer. Information was recorded on room lighting, position of the rolling shutters and number/type of extra people in the room. Results: Compliance with sleep-wake assessment was poor, with a range of completion of 2–59%, depending on the questionnaires. Reported sleep quality was sufficient and sleep timing dictated by hospital routine; 33% of the patients reported one/more sleepless nights. Illuminance was generally low, and rolling shutters half-way down for most of the 24 h. Patients who slept near the window were exposed to more light in the morning (i.e., 222 ± 72 vs. 174 ± 85 lux, p < 0.05 before the switch; 198 ± 72 vs. 141 ± 137 lux, p < 0.01 after the switch) and tended to sleep better (7.3 ± 1.8 vs. 5.8 ± 2.4 on a 1–10 scale, before the switch, p < 0.05; 7.7 ± 2.3 vs. 6.6 ± 1.8, n.s. after the switch). Noise levels were higher than recommended for care units but substantially comparable across times/room types. No significant differences were observed in sleep parameters before/after the switch. Conclusion: Medical wards appear to be noisy environments, in which limited attention is paid to light/dark hygiene. An association was observed between sleep quality and bed position/light exposure, which is worthy of further study.

Quantifying Memory in Complex Physiological Time-Series

In a time-series, memory is a statistical feature that lasts for a period of time and distinguishes the time-series from a random, or memory-less, process. In the present study, the concept of “memory length” was used to define the time period, or scale over which rare events within a physiological time-series do not appear randomly. The method is based on inverse statistical analysis and provides empiric evidence that rare fluctuations in cardio-respiratory time-series are ‘forgotten’ quickly in healthy subjects while the memory for such events is significantly prolonged in pathological conditions such as asthma (respiratory time-series) and liver cirrhosis (heart-beat time-series). The memory length was significantly higher in patients with uncontrolled asthma compared to healthy volunteers. Likewise, it was significantly higher in patients with decompensated cirrhosis compared to those with compensated cirrhosis and healthy volunteers. We also observed that the cardio-respiratory system has simple low order dynamics and short memory around its average, and high order dynamics around rare fluctuations.

A low-cost, user-friendly electroencephalographic recording system for the assessment of hepatic encephalopathy.

Electroencephalography (EEG) is useful to objectively diagnose/grade hepatic encephalopathy (HE) across its spectrum of severity. However, it requires expensive equipment, and hepatogastroenterologists are generally unfamiliar with its acquisition/interpretation. Recent technological advances have led to the development of low‐cost, user‐friendly EEG systems, allowing EEG acquisition also in settings with limited neurophysiological experience. The aim of this study was to assess the relationship between EEG parameters obtained from a standard‐EEG system and from a commercial, low‐cost wireless headset (light‐EEG) in patients with cirrhosis and varying degrees of HE. Seventy‐two patients (58 males, 61 ± 9 years) underwent clinical evaluation, the Psychometric Hepatic Encephalopathy Score (PHES), and EEG recording with both systems. Automated EEG parameters were calculated on two derivations. Strong correlations were observed between automated parameters obtained from the two EEG systems. Bland and Altman analysis indicated that the two systems provided comparable automated parameters, and agreement between classifications (normal versus abnormal EEG) based on standard‐EEG and light‐EEG was good (0.6 < κ < 0.8). Automated parameters such as the mean dominant frequency obtained from the light‐EEG correlated significantly with the Model for End‐Stage Liver Disease score (r = −0.39, P < 0.05), fasting venous ammonia levels (r = −0.41, P < 0.01), and PHES (r = −0.49, P < 0.001). Finally, significant differences in light‐EEG parameters were observed in patients with varying degrees of HE. Conclusion: Reliable EEG parameters for HE diagnosing/grading can be obtained from a cheap, commercial, wireless headset; this may lead to more widespread use of this patient‐independent tool both in routine liver practice and in the research setting. (Hepatology 2016;63:1651‐1659)

Abnormalities in the 24-hour rhythm of skin temperature in cirrhosis: Sleep-wake and general clinical implications

Sleep preparation/onset are associated with peripheral vasodilatation and a decrease in body temperature. The hyperdynamic syndrome exhibited by patients with cirrhosis may impinge on sleep preparation, thus contributing to their difficulties falling asleep. The aim of this study was the assessment of skin temperature, in relation to sleep‐wake patterns, in patients with cirrhosis.

An educational tool for the prophylaxis of hepatic encephalopathy

Background Providing structured information for the understanding of hepatic encephalopathy (HE) might be relevant to the prevention and management of the syndrome. The aim of our study was to design a brief, structured educational intervention and evaluate its usefulness in preventing HE-related hospitalisation over time. Methods Thirty-nine cirrhotic outpatients with a history of HE were enrolled and randomly assigned to an intervention (group A; n=20) or control group (group B; n=19). All of them underwent evaluation of HE (clinical and quantitative neuropsychiatric assessment) and completed the Questionnaire on the Awareness of Encephalopathy. A 15 min educational session was then provided to patients in group A, including basic information on the pathophysiology, hygienic and medical management of HE. Results No demographic/clinical differences were observed at baseline between the two groups. Similarly, there were no significant differences in HE-related information available at baseline between the two groups; knowledge of HE was limited in both. The intervention was highly effective in increasing patients’ understanding of treatment of the condition (from 5% to 80%). The educational intervention also reduced the risk of developing an episode of HE over a period of 12 months. Conclusion The educational intervention confirmed the poor knowledge of patients with previous HE about their condition, served as a tool to increase patients’ awareness, and minimised HE-related readmission rates over a period of 1 year.

Which heart rate variability index is an independent predictor of mortality in cirrhosis

BACKGROUND Liver cirrhosis is associated with reduced heart rate variability (HRV), which indicates impaired integrity of cardiovascular control in this patient population. There are several different indices for HRV quantification. The present study was designed to: 1) determine which of the HRV indices is best at predicting mortality in patients with cirrhosis; 2) verify if such ability to predict mortality is independent of the severity of hepatic failure. METHODS Ten minutes electrocardiogram was recorded in 74 patients with cirrhosis. Heart rate fluctuations were quantified using statistical, geometrical and non-linear analysis. The patients were followed-up for 18months and information was collected on the occurrence of death/liver transplantation. RESULTS During the follow-up period, 24 patients (32%) died or were transplanted for hepatic decompensation. Coxs regression analysis showed that SDNN (total HRV), cSDNN (corrected SDNN), SD1 (short-term HRV), SD2 (long-terms HRV) and spectral indices could predict survival in these patients. However, only SD2 and cSDNN were shown to be independent of MELD in predicting survival. The prognostic value of HRV indices was independent of age, gender, use of beta blockers, and the aetiology of liver disease. CONCLUSION Two HRV indices were identified that could predict mortality in patients with cirrhosis, independently of MELD. These indices are potentially useful tools for survival prediction.