Sleep disturbance in patients with cirrhosis and transjugular intrahepatic portosystemic shunt | BMC Gastroenterology | Full Text

Oct 28, 2024

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Sleep disturbance (SD) is a common occurrence in individuals with cirrhosis and significantly impacts their quality of life. Datas regarding post transjugular intrahepatic portosystemic shunt (TIPS) SD are scarce. This study aimed to explore the incidence and outcomes of post-TIPS SD.

From August 2018 to November 2019, 73 patients who underwent TIPS were prospectively recruited for the study. Sleep quality was evaluated via the Pittsburgh Sleep Quality Index (PSQI), and the presence of hepatic encephalopathy was evaluated according to the West Haven criteria before and after the TIPS procedure.

Nineteen patients (26%) experienced new-onset SD after TIPS, with a median latency of 67 (40–98) days from the procedure. The median time from TIPS creation to occurrence was 67 (40–98) days. Minimal hepatic encephalopathy (MHE) post-TIPS emerged as an independent predictor of SD, with an odds ratio of 3 (95% CI: 1.04–8.78, P = 0.046). Notably, five of the six (83%) patients with SD experienced improvement after being administered eszopiclone. Ten of the thirteen (77%) patients with SD improved spontaneously without treatment. Furthermore, the prevalence of MHE was significantly greater among patients with SD than among those without SD (58% vs. 31%, P = 0.04).

SD is prevalent in patients who undergo TIPS. MHE is an independent risk factor for the development of SD post-TIPS. Eszopiclone may be a safe and effective treatment option for patients with SD after TIPS. The study was registered with ClinicalTrials.gov under the identifier NCT03685994, with a registration date of September 23, 2018.

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Sleep disturbance (SD) is not rare in patients with cirrhosis and is associated with impaired quality of life. A total of 26–70% of cirrhotic patients rated themselves as poor sleepers [1,2,3,4]. The symptoms of SD include difficulty initiating sleep and multiple night awakenings [5,6,7,8]. The pathophysiology of SD in patients with cirrhosis is not fully understood. Hyperammonaemia, abnormalities in the circadian rhythm of melatonin, and disturbances in the 24-h rhythm of skin temperature are associated with SD [1, 9, 10].

Transjugular intrahepatic portosystemic shunt (TIPS) is an artificial shunt for decompressing the portal venous system. It has been established as an effective treatment for variceal bleeding or refractory ascites [11, 12]. The incidence of post-TIPS SD was found to be as high as that in cirrhotic patients [13]. Generally, post-TIPS SD may be overlooked in clinical practice. The present study aimed to investigate the incidence and outcomes of post-TIPS SD in a large-volume TIPS centre.

Patients with cirrhosis who underwent TIPS at West China Hospital between August 2018 and November 2019 were screened. The inclusion criteria were age between 18 to 75 years, cirrhosis, treatment with TIPS, agreement to participate in the study, and compliance with requirements. The exclusion criteria were SD before TIPS, illiteracy, previous psychiatric and neurological disorders, a Hamilton anxiety scale point of more than 14 and/or a Hamilton depression scale point of more than 18 before TIPS, or active alcohol consumption. All authors had access to the study data, critically reviewed the manuscript, and approved the final draft. The study was approved by the West China Hospital Institutional Review Board.

The standard TIPS procedure was performed as described previously [11]. Generally, a right internal jugular vein is used to advance the TIPS set (RUPS-100, Cook, Bloomington, USA) into the right hepatic vein. Once the portal vein is catheterized, the intrahepatic parenchymal tract is dilated with an 8 × 60 mm balloon (Cordis, Roden, The Netherlands), followed by the insertion of an 8-mm ePTFE-covered stent (Fluency Plus, Bard&BD, Murray Hill, USA). The ePTFE-covered stent is implanted with its proximal end at the hepatocaval junction and its distal end at the proximal portion of the main portal vein. The stent is subsequently dilated with the same balloon. Before April 2019, we adopted a covered/bare stent combination to emulate the dedicated TIPS stent structure. Haemodynamic assessments of pressure reduction were performed before and after TIPS insertion. Lactulose therapy was given to all patients for 1 year after TIPS. Starting at a dose of 10 ml every 8 h and titrated accordingly, the stool frequency ranged from 1 to 2 per day.

The Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep quality over the preceding month before and after TIPS. Sleep quality was assessed at 1, 3, 6, 12 months after TIPS and semiannual intervals thereafter. If the patient had symptoms of SD, such as difficulty initiating sleep and multiple night awakenings, they would contact doctors for sleep quality assessing. The overall score ranges from 0 to 21 points. A higher score signifies worse sleep quality; a score > 5 indicates SD [14]. We derived total sleep time (TST), sleep latency (SL), number of awakenings, and quality from the habitual bedtimes and sleep times reported on the PSQI.

The presence of hepatic encephalopathy was evaluated via the West Haven criteria [15]. Under standardized conditions, psychometric performance was assessed via Number Connection Tests A and B, the Digital Symbol Test, and the Line Tracing and Serial Dotting tests [16,17,18,19]. Individual psychometric test results were scored in relation to age- and education-adjusted Chinese reference values [20]. Psychometric performance was classified as impaired if the sum of the standard deviations for the individual tests, known as the Psychometric Hepatic Encephalopathy Score (PHES), was ≤ -4 [20].The West Haven classification categorizes hepatic encephalopathy (HE) into 5 grades: grade 0/minimal HE, grade I/subclinical HE, and the clinical grades II-IV. Overt hepatic encephalopathy (OHE) and minimal hepatic encephalopathy(MHE) are categories used by the ISHEN classification correlating to grades II-IV and 0 of the West Haven classification system.

The Hamilton Anxiety and Depression Scale was used to evaluate the incidence of anxiety and depression after TIPS. Scores ≥ 14 points and ≥ 18 points were considered anxiety and depression, respectively [21, 22].

Interventions for patients with SD after TIPS were administered according to the discretion of the physician. The primary outcome was the incidence of SD after TIPS. Patients were followed up for at least one year.

The data were processed via SPSS version 20.0 (IBM Corp., Armonk, NY, USA). All continuous variables with a normal distribution were recorded as the mean ± standard deviation, those with a skewed distribution were recorded as the median and quartile spacing, and the data of classified variables were recorded as percentages. For comparisons of continuous variables, the t test for normally distributed continuous variables was used, and the Mann‒Whitney U test was used for continuous variables that were not normally distributed. For comparisons of categorical variables, the chi-square test and Fisher’s exact test were used. First, univariate logistic regression analysis was used to analyse the factors related to SD, and then multivariate logistic regression analysis was used to analyse the factors with P < 0.1. P < 0.05 was considered significant.

A total of 119 patients with liver cirrhosis who underwent TIPS were included for screening. Forty-six patients were excluded due to SD before TIPS creation. The basic patient characteristics are presented in Table 1. The median age was 51 years, and 76.7% were male. Hepatitis B infection and alcohol use were identified as aetiologies of cirrhosis in 54.8% and 12.3% of our patients, respectively. The most common indication for TIPS creation was variceal bleeding (n = 66, 90.4%), and most patients had Child‒Pugh B disease (n = 39, 53.4%). The median MELD score before TIPS placement was 10. All the patients in the present study underwent 8-mm stent placement. No patient was lost to follow-up, with a median follow-up time of 18 months (range 12–24 months).

New-onset SD following TIPS occurred in 19 patients (26%). The median time from TIPS creation to the occurrence of SD was 67 days (range 40–98 days). SD patients presented with difficulty initiating sleep (n = 10, 52.6%), multiple night awakenings (n = 3, 15.8%) and worse sleep quality (n = 15, 78.9%). The sleep characteristics of the SD patients are presented in Table 2.

Seventy-three patients were analysed by univariate analysis with SD as the dependent variable, including sex, age, haemoglobin, AST, ALT, and other variables, to explore the relationships between the variables and SD. Univariate logistic regression revealed that minimal hepatic encephalopathy (MHE) after TIPS (OR = 3; 95% CI 1,8.78; P = 0.046) was an independent significant risk factor for SD (Table 3).

Six patients were treated with eszopiclone at an average dose of 1.3 mg for 12 weeks. Five of six (83%) patients improved after treatment. One patient had no significant improvement in SD and had to withdraw from the study due to daytime sleepiness. Following treatment, there was a significant improvement in the PSQI score (from a median [range] of 8 [6,7,8,9] to 4 [4,5,6,7], P < 0.05), an increase in the TST score (from a median [range] of 375 [345–420] min to 435 [390–488] min, P = 0.218), an increase in the SL score (from a median [range] of 120 [30–135] min to 30 [30–60] min, P < 0.05), and a decrease in the number of awakenings (from a median [range] of 1 [0–3] to 0 [0–1], P = 0.111). One (16.7%) patient had excessive daytime sleepiness (EDS) and improved after drug withdrawal. None of the patients developed overt hepatic encephalopathy (OHE) during treatment. Among the 13 patients who did not receive drug therapy, SD improved spontaneously in 9 patients, mildly improved in 1 patient, and did not improve in 3 patients. Compared with baseline, there was an improvement in the PSQI score (from a median [range] of 7 [6,7,8] to 5 [4,5,6], P < 0.01), an increase in the TST score (from a median [range] of 420 [420–495] min to 480 [435–570] min, P = 0.192), an increase in the SL score (from a median [range] of 60 [60–120] min to 30 [30–60] min, P < 0.05), and a decrease in the number of awakenings (from a median [range] of 2 [0–3] to 1 [0–3], P = 0.526).

Twenty (27%) patients developed OHE, and 28 (38%) patients experienced MHE during follow-up. Among the patients with SD, 11 patients were diagnosed with MHE, and 5 patients were complicated with OHE, which including 4 patients with grades II and 1 patient with grade IV. The incidence of MHE in patients with SD was greater than that in patients without SD (58% vs. 31%, P = 0.04) (Fig. 1A), but there was no significant difference in the incidence of OHE (Fig. 1B). One (1%) patient developed depression, which improved after treatment. None of the patients developed anxiety disorders.

The incidence of HE with SD and Non-SD in the patients undergoing TIPS. (A) The incidence of MHE in patients with SD and Non-SD; (B) The incidence of OHE in patients with SD and Non-SD

The incidence of post-TIPS SD is not uncommon. MHE was found to be an independent risk factor associated with SD. Symptoms improved in some patients who used eszopiclone, suggesting that post-TIPS SD may be transient or relieved spontaneously.

At present, SD after TIPS has rarely been reported. Wiltfangt J et al. reported that the incidence of SD at one month and three months after TIPS was 60% and 68%, respectively, among 43 patients. Arterial ammonia was significantly correlated with the occurrence of SD [13]. In our study, the incidence of SD after TIPS was 26%. This could be partially explained by the fact that 46 patients with baseline SD were excluded.

In this study, patients with SD were treated with eszopiclone. The initial dose was 1 mg for 12 weeks, and the maximum dose could be increased to 3 mg according to the therapeutic effect. Five of the six patients with early-stage (CTP class A or B) cirrhosis improved after treatment. One patient developed EDS during treatment, which improved after drug withdrawal. None of the patients developed OHE during treatment. A recent study by DeSilva AP et al. included 71 patients with early-stage (CTP class A or B) cirrhosis without HE who were randomized to placebo or 3 mg of melatonin for 2 weeks. Patients given melatonin had significantly lower PSQI and ESS scores than both pretreatment and post-placebo scores and the incidence of adverse events was similar, and no patient developed HE [23]. Sharma MK et al. reported that zolpidem was effective in the treatment of SD patients with cirrhosis. Fifty-two patients with SD and early-stage (CTP classes A and B) cirrhosis were randomized to placebo or 5 mg of zolpidem for 4 weeks. After treatment, patients with SD experienced significant increases in TST and sleep efficiency and improvements in the polysomnographic parameters of sleep initiation and maintenance without any significant changes in sleep architecture [24].

Bianchi et al. extracted sleep behaviour data from depression and mental health questionnaires completed by 156 patients with cirrhosis and reported that 69% of these patients complained of SD. Notably, SD was significantly correlated with psychological distress [2]. Mostacci et al. conducted interviews in conjunction with a validated questionnaire among 178 patients with cirrhosis, and 26% of the patients complained of night-time SD [3]. There are differences in the prevalence rates of SD reported in previously published studies and the current study. The most likely reasons are the difference in assessment tools used and the variations in the patients studied.

This study had several limitations. First, the number of patients who received treatment was small. Most patients who developed SD improved spontaneously. Second, the follow-up time was short, which may have affected the incidence of post-TIPS SD. Third, this study was nonrandomized at a single institution, and the sample size was small. Forth, blood ammonia in patients pre- and post-TIPS was not tested and the correlation with SD was unclear.

In conclusion, the present study revealed that SD is not uncommon in patients who undergo TIPS. MHE is an independent significant risk factor associated with post-TIPS SD. Eszopiclone may be effective and safe for patients with SD after TIPS.

The incidence of SD is not uncommon in patients who undergo TIPS. MHE is an independent risk factor associated with post-TIPS SD. Eszopiclone may be effective and safe for patients with SD after TIPS.

All the data and material are from the patient’s assay and examination of West China Hospital database, Sichuan University, which are real and credible.The data that support the findings of this study are not openly available due to reasons of Personal Information Protection and are available from the corresponding author upon reasonable request.

Sleep disturbance

Transjugular intrahepatic portosystemic shunt

Pittsburgh Sleep Quality Index

Total sleep time

Sleep latency

Psychometric hepatic encephalopathy score

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We thank Denghua Yao and other members in our interventional diagnosis and treatment center for the effort.

Written informed consent was obtained from the patient for publication of the clinical data.

Dr Xuefeng Luo received funds (2019HXFH055) from the 1·3·5 project for disciplines of excellence–Clinical Research Incubation Project, West China Hospital, Sichuan University. The funding body had no role in the design of the study, the collection, analysis and interpretation of the data, or the writing of the manuscript.

Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, Sichuan, China

Ming Zhao, Yuling Yan, Xiaoze Wang, Bangxi Liu & Xuefeng Luo

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All authors read and approved the final manuscript. LXF and WXZ mainly performed operation. ZM paid more effort in original draft writing. YYL and LBX paid effort in data collection.

Correspondence to Xuefeng Luo.

The study was conducted in accordance with the Declaration of Helsinki, and it was granted approval by the Ethics Committee of West China Hospital (Chengdu, China).

Consent for publication was obtained from the patients.

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Zhao, M., Yan, Y., Wang, X. et al. Sleep disturbance in patients with cirrhosis and transjugular intrahepatic portosystemic shunt. BMC Gastroenterol 24, 381 (2024). https://doi.org/10.1186/s12876-024-03470-x

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Received: 05 July 2024

Accepted: 18 October 2024

Published: 28 October 2024

DOI: https://doi.org/10.1186/s12876-024-03470-x

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