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Shang Y, Wang C, Lu H, Chai L, Xu W, Bernardi M, Qi X. Incidence and type of adverse events in patients with cirrhosis receiving terlipressin: A systematic review and meta-analysis. Hepatol Commun 2024; 8:e0526. [PMID: 39298544 PMCID: PMC11412712 DOI: 10.1097/hc9.0000000000000526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 07/25/2024] [Indexed: 09/22/2024] Open
Abstract
BACKGROUND Terlipressin has been widely used for various cirrhosis-related complications, but its safety profile remains controversial. Herein, this issue was systematically evaluated. METHODS All studies reporting adverse events (AEs) of terlipressin in cirrhosis were screened. Incidences were pooled using a random-effects model. Subgroup analyses were performed according to the patient's characteristics and treatment regimens. Interaction among subgroups was evaluated. RESULTS Seventy-eight studies with 7257 patients with cirrhosis were included. The pooled incidences of any AEs, treatment-related AEs, any serious AEs (SAEs), treatment-related SAEs, treatment withdrawal due to AEs, and treatment withdrawal due to treatment-related AEs were 31%, 22%, 5%, 5%, 4%, and 4% in patients with cirrhosis receiving terlipressin, respectively. Patients with hepatorenal syndrome had higher incidences of any SAEs (29% vs. 0% vs. 0%, pinteraction = 0.01) and treatment-related SAEs (8% vs. 1% vs. 7%, pinteraction = 0.02) than those with variceal bleeding or ascites. Patients who received terlipressin with human albumin had higher incidences of any SAEs (18% vs. 1%, pinteraction = 0.04) and treatment-related SAEs (7% vs. 0%, pinteraction = 0.09) than those without albumin. Patients with total bilirubin level >4.3 mg/dL had higher incidences of any AEs (69% vs. 24%, pinteraction = 0.02), any SAEs (64% vs. 0%, pinteraction < 0.01), and treatment-related SAEs (8% vs. 1%, pinteraction = 0.04) than those ≤4.3 mg/dL. CONCLUSIONS AEs are common in patients with cirrhosis receiving terlipressin and influenced by clinical scenarios, combination with albumin, and bilirubin levels.
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Affiliation(s)
- Yiyang Shang
- Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, China
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
| | - Cai’e Wang
- Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, China
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
| | - Huiyuan Lu
- Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, China
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
| | - Lu Chai
- Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, China
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
| | - Wentao Xu
- Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, China
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
| | - Mauro Bernardi
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Xingshun Qi
- Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, China
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
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Wan YM, Huang SQ, Wu HM, Li YH, Yin HJ, Xu Y. Terlipressin versus placebo or noradrenalin in the treatment of hepatorenal syndrome: a systematic review and meta-analysis. Front Pharmacol 2024; 15:1418826. [PMID: 39295934 PMCID: PMC11408352 DOI: 10.3389/fphar.2024.1418826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 08/27/2024] [Indexed: 09/21/2024] Open
Abstract
Background Hepatorenal syndrome (HRS) bears a very poor prognosis with unmet need for safe and effective therapies. This systematic review and meta-analysis aimed to re-assess safety and efficacy of terlipressin versus placebo or noradrenaline for HRS, based on previous randomized controlled trials (RCTs). Methods PubMed, EMBASE, MEDLINE (OvidSP) and Cochrane registers were searched for trials reporting HRS treatment by terlipressin or noradrenaline. Search terms included: "hepatorenal syndrome", "terlipressin", "noradrenaline", and corresponding synonyms. Comparisons between terlipressin, noradreanaline, placebo and albumin were included. Meta-analysis was conducted for treatment response (both HRS reversal and complete response), mortality and adverse events. Results 15 RCTs were included, enrolling 1236 HRS patients (type 1: 1166, type 2: 70). Treatment with terlipressin+albumin resulted in significantly higher treatment response than placebo+albumin or albumin alone (risk ratio [RR]:2.75, 95% confidence interval [CI]:1.96 to 3.84; I2 = 28%, p = 0.23; n = 6). Noradrenaline was equally effective in treatment response compared to terlipressin (RR:1.19, 95% CI:0.96 to 1.46; I2 = 16%, p = 0.31; n = 7), but trials were limited by its non-blind design and small size. Sensitivity analysis showed no survival benefit with terlipressin compared to either placebo (RR:1.03, 95% CI:0.83 to 1.28; I2 = 0%, p = 0.72; n = 3) or noradreanline (RR:0.83, 95% CI:0.69 to 1.00; I2 = 4%, p = 0.39; n = 7) at 30 days of follow-up. Terlipressin carried higher risk of treatment-related adverse events compared to either placebo (RR:2.92, 95% CI:1.48 to 5.77; I2 = 0%, p = 0.75; n = 3) or noradrenaline (RR:2.45, 95% CI:1.37 to 4.37; I2 = 0%, p = 0.92; n = 5). Conclusion Terlipressin is superior to placebo, and comparable to noradreanline in treatment response, but survival benefit is lacking. Noradrenaline, with low certainty, may be a better alternative for HRS.
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Affiliation(s)
- Yue-Meng Wan
- Gastroenterology Department II, The 2nd Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| | - Song-Quan Huang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Hua-Mei Wu
- Gastroenterology Department II, The 2nd Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| | - Yu-Hua Li
- Gastroenterology Department II, The 2nd Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| | - Hong-Jing Yin
- Gastroenterology Department II, The 2nd Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| | - Ying Xu
- Gastroenterology Department II, The 2nd Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
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Arabi YM, Belley-Cote E, Carsetti A, De Backer D, Donadello K, Juffermans NP, Hammond N, Laake JH, Liu D, Maitland K, Messina A, Møller MH, Poole D, Mac Sweeney R, Vincent JL, Zampieri FG, AlShamsi F. European Society of Intensive Care Medicine clinical practice guideline on fluid therapy in adult critically ill patients. Part 1: the choice of resuscitation fluids. Intensive Care Med 2024; 50:813-831. [PMID: 38771364 DOI: 10.1007/s00134-024-07369-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Accepted: 02/20/2024] [Indexed: 05/22/2024]
Abstract
PURPOSE This is the first of three parts of the clinical practice guideline from the European Society of Intensive Care Medicine (ESICM) on resuscitation fluids in adult critically ill patients. This part addresses fluid choice and the other two will separately address fluid amount and fluid removal. METHODS This guideline was formulated by an international panel of clinical experts and methodologists. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was applied to evaluate the certainty of evidence and to move from evidence to decision. RESULTS For volume expansion, the guideline provides conditional recommendations for using crystalloids rather than albumin in critically ill patients in general (moderate certainty of evidence), in patients with sepsis (moderate certainty of evidence), in patients with acute respiratory failure (very low certainty of evidence) and in patients in the perioperative period and patients at risk for bleeding (very low certainty of evidence). There is a conditional recommendation for using isotonic saline rather than albumin in patients with traumatic brain injury (very low certainty of evidence). There is a conditional recommendation for using albumin rather than crystalloids in patients with cirrhosis (very low certainty of evidence). The guideline provides conditional recommendations for using balanced crystalloids rather than isotonic saline in critically ill patients in general (low certainty of evidence), in patients with sepsis (low certainty of evidence) and in patients with kidney injury (very low certainty of evidence). There is a conditional recommendation for using isotonic saline rather than balanced crystalloids in patients with traumatic brain injury (very low certainty of evidence). There is a conditional recommendation for using isotonic crystalloids rather than small-volume hypertonic crystalloids in critically ill patients in general (very low certainty of evidence). CONCLUSIONS This guideline provides eleven recommendations to inform clinicians on resuscitation fluid choice in critically ill patients.
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Affiliation(s)
- Yaseen M Arabi
- Intensive Care Department, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, King Abdullah International Medical Research Center, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
| | - Emilie Belley-Cote
- Divisions of Cardiology and Critical Care, McMaster University, Riyadh, Saudi Arabia
| | - Andrea Carsetti
- Department of Biomedical Sciences and Public Health, Università Politecnica delle Marche, Ancona, Italy
| | - Daniel De Backer
- Department of Intensive Care, CHIREC Hospitals, Université Libre de Bruxelles, Brussels, Belgium
| | - Katia Donadello
- Department of Surgery, Dentistry, Gynaecology and Paediatrics, University of Verona, Verona, Italy
- Anaesthesia and Intensive Care B Unit, AOUI-University Hospital Integrated Trust of Verona, Verona, Italy
| | - Nicole P Juffermans
- Department of Intensive Care, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Naomi Hammond
- Critical Care Program, The George Institute for Global Health and UNSW, Sydney, Australia
- Malcolm Fisher Department of Intensive Care, Royal North Shore Hospital, Sydney, Australia
| | - Jon Henrik Laake
- Department of Anaesthesiology and Intensive Care Medicine, Division of Emergencies and Critical Care, Oslo University Hospital, Oslo, Norway
| | - Dawei Liu
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Beijing, China
| | - Kathryn Maitland
- Institute of Global Health and Innovation, Division of Medicine, Imperial College, London, UK
| | - Antonio Messina
- IRCCS Humanitas Research Hospital, Department of Anesthesia and Intensive Care Medicine, Rozzano, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Morten Hylander Møller
- Department of Intensive Care, Copenhagen University Hospital-Rigshospitalet, København, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Daniele Poole
- Operative Unit of Anesthesia and Intensive Care, S. Martino Hospital, Belluno, Italy
| | - Rob Mac Sweeney
- Regional Intensive Care Unit, Royal Victoria Hospital, Belfast, Northern Ireland
| | - Jean-Louis Vincent
- Department of Intensive Care, Erasme Hospital, Université libre de Bruxelles, Brussels, Belgium
| | - Fernando G Zampieri
- Department of Critical Care Medicine, University of Alberta, Edmonton, Canada
| | - Fayez AlShamsi
- Department of Internal Medicine, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
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Erstad BL. Hepatorenal Syndrome With Acute Kidney Injury: Diagnosis and Medical Management. Ann Pharmacother 2024; 58:156-164. [PMID: 37271967 DOI: 10.1177/10600280231177698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2023] Open
Abstract
OBJECTIVES To review the current definitions and diagnostic criteria for acute kidney injury (AKI) and type 1 hepatorenal syndrome (HRS) now termed HRS-AKI and discuss the challenges in deciding the most appropriate medication regimens to treat patients with HRS-AKI. DATA SOURCES PubMed (inception to April 2023) with bibliographies of retrieved articles searched for additional articles; organizational websites for clinical practice guidelines (CPGs). STUDY SELECTION AND DATA EXTRACTION Randomized controlled trials (RCTs) evaluating albumin and vasoconstrictors for HRS-AKI. DATA SYNTHESIS A major change in the most recent revision of definitions and diagnostic criteria for HRS-AKI is the elimination of the set cutoff serum creatinine values for AKI. This change should be considered when comparing studies of HRS-AKI over time. Albumin has been administered to both vasoconstrictor treatment and placebo groups in all recent RCTs; however, there has never been a large RCT evaluating a no-albumin group. Most prospective trials comparing a midodrine/octreotide combination or norepinephrine to placebo or terlipressin have enrolled less than 100 patients limiting any conclusions regarding clinically important outcomes. Terlipressin with albumin has shown mixed results for complete HRS-AKI reversal with no reductions in crude mortality but adverse effect concerns involving ischemic and pulmonary events. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE Type 1 hepatorenal syndrome with acute kidney injury is a potentially life-threatening syndrome with diagnostic and treatment challenges. Albumin plus a vasoconstrictor has become the routine HRS-AKI treatment even though there has not been a large RCT evaluating a no-albumin group. Terlipressin is the vasoconstrictor of choice for HRS-AKI in current CPGs, but it has adverse effect concerns and, until recently, was not available in the United States. CONCLUSIONS In conjunction with changes in the definitions and diagnostic criteria for HRS-AKI, debate continues regarding the optimal therapy for HRS-AKI, particularly considering recent trials demonstrating ischemic and pulmonary adverse events with terlipressin used in combination with albumin.
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Affiliation(s)
- Brian L Erstad
- Department of Pharmacy Practice and Science, R. Ken Coit College of Pharmacy, University of Arizona, Tucson, AZ, USA
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Gonzalez SA, Chirikov VV, Wang WJ, Huang X, Jamil K, Simonetto DA. Terlipressin vs Midodrine Plus Octreotide for Hepatorenal Syndrome-Acute Kidney Injury: A Propensity Score-Matched Comparison. Clin Transl Gastroenterol 2023; 14:e00627. [PMID: 37622521 PMCID: PMC10749708 DOI: 10.14309/ctg.0000000000000627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 07/24/2023] [Indexed: 08/26/2023] Open
Abstract
INTRODUCTION Evidence on the comparison of treatments for hepatorenal syndrome-acute kidney injury (HRS-AKI) in a US population is limited. An indirect comparison of terlipressin plus albumin vs midodrine and octreotide plus albumin (MO) may provide further insight into treatment efficacy. METHODS Cohorts of patients treated for HRS-AKI characterized by inclusion of patients with serum creatinine (SCr) <5 mg/dL and baseline acute-on-chronic liver failure grades 0-2 and exclusion of patients listed for transplant if model for end-stage liver disease scores ≥35 were pooled from (i) the CONFIRM and REVERSE randomized controlled trials (N = 159 meeting eligibility criteria from N = 216 overall, treated with terlipressin) and (ii) a retrospective review of medical records from 10 US tertiary hospitals (2016-2019; N = 55 treated with MO meeting eligibility criteria from N = 200 overall). The primary end point comparing the 2 cohorts was HRS reversal defined as achieving SCr ≤1.5 mg/dL at least once during the treatment. Covariate balancing propensity scoring was used to adjust for differences in baseline characteristics. RESULTS HRS-AKI reversal was achieved in 52.35% of terlipressin-treated patients compared with 20% of MO-treated patients (adjusted mean difference 32.35%, 95% confidence interval [CI] 17.40-47.30, P < 0.0001). Terlipressin-treated patients had increased overall survival (adjusted hazard ratio 0.57, 95% CI 0.35-0.93, P = 0.02) but similar transplant-free survival (adjusted hazard ratio 0.79, 95% CI 0.53-1.17, P = 0.24). Achievement of HRS-AKI reversal was associated with increased OS and TFS regardless of treatment ( P < 0.001). DISCUSSION Consistent with prior reports, terlipressin plus albumin is more effective in improving kidney function and achieving HRS-AKI reversal than MO plus albumin based on indirect comparison in a US population.
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Affiliation(s)
- Stevan A. Gonzalez
- Division of Hepatology, Annette C. and Harold C. Simmons Transplant Institute, Baylor Scott & White All Saints Medical Center, Fort Worth, Texas, USA
- Department of Medicine, Burnett School of Medicine at TCU, Fort Worth, Texas, USA
| | | | | | - Xingyue Huang
- Mallinckrodt Pharmaceuticals, Hampton, New Jersey, USA
| | - Khurram Jamil
- Mallinckrodt Pharmaceuticals, Hampton, New Jersey, USA
| | - Douglas A. Simonetto
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
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Kiani C, Zori AG. Recent advances in pathophysiology, diagnosis and management of hepatorenal syndrome: A review. World J Hepatol 2023; 15:741-754. [PMID: 37397940 PMCID: PMC10308288 DOI: 10.4254/wjh.v15.i6.741] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 04/18/2023] [Accepted: 05/06/2023] [Indexed: 06/25/2023] Open
Abstract
Hepatorenal syndrome with acute kidney injury (HRS-AKI) is a form of rapidly progressive kidney dysfunction in patients with decompensated cirrhosis and/or acute severe liver injury such as acute liver failure. Current data suggest that HRS-AKI occurs secondary to circulatory dysfunction characterized by marked splanchnic vasodilation, leading to reduction of effective arterial blood volume and glomerular filtration rate. Thus, volume expansion and splanchnic vasoconstriction constitute the mainstay of medical therapy. However, a significant proportion of patients do not respond to medical management. These patients often require renal replacement therapy and may be eligible for liver or combined liver-kidney transplantation. Although there have been advances in the management of patients with HRS-AKI including novel biomarkers and medications, better-calibrated studies, more widely available biomarkers, and improved prognostic models are sorely needed to further improve diagnosis and treatment of HRS-AKI.
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Affiliation(s)
- Calvin Kiani
- Department of Internal Medicine, Section of Gastroenterology and Hepatology, University of Florida, Gainesville, FL 32610, United States
| | - Andreas G Zori
- Department of Internal Medicine, Section of Gastroenterology and Hepatology, University of Florida, Gainesville, FL 32610, United States
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Cooper KM, Colletta A, Moulton K, Ralto KM, Devuni D. Kidney disease in patients with chronic liver disease: Does sex matter? World J Clin Cases 2023; 11:3980-3992. [PMID: 37388789 PMCID: PMC10303604 DOI: 10.12998/wjcc.v11.i17.3980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 04/30/2023] [Accepted: 05/16/2023] [Indexed: 06/12/2023] Open
Abstract
Kidney disease in patients with liver disease is serious and increases mortality. Up to 50% of patients hospitalized experience an episode of acute kidney injury. In general, men with liver disease are thought to be at increased risk of kidney disease. However, this association should be considered with caution because most studies use creatinine-based inclusion criteria, which is negatively biased against women. In this review, we synthesize data on sex differences in kidney disease in patients with chronic liver disease in the clinical setting and discuss potential physiologic underpinnings.
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Affiliation(s)
- Katherine M Cooper
- Department of Medicine, UMass Chan Medical School, Worcester, MA 01665, United States
| | - Alessandro Colletta
- Department of Medicine, UMass Chan Medical School, Worcester, MA 01665, United States
| | - Kristen Moulton
- Department of Medicine, Division of Gastroenterology, UMass Chan Medical School, Worcester, MA 01665, United States
| | - Kenneth M Ralto
- Department of Medicine, Division of Renal Medicine, UMass Chan Medical School, Worcester, MA 01665, United States
| | - Deepika Devuni
- Department of Medicine, Division of Gastroenterology, UMass Chan Medical School, Worcester, MA 01665, United States
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Singh V, Jayachandran A, De A, Singh A, Chandel S, Sharma N. Combination of terlipressin and noradrenaline versus terlipressin in hepatorenal syndrome with early non-response to terlipressin infusion: A randomized trial. Indian J Gastroenterol 2023; 42:388-395. [PMID: 37145232 DOI: 10.1007/s12664-023-01356-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 02/03/2023] [Indexed: 05/06/2023]
Abstract
BACKGROUND Terlipressin and noradrenaline are effective in the management of hepatorenal syndrome (HRS). There are no reports on the combination of these vasoconstrictors in type-1 HRS. AIM To evaluate terlipressin with or without noradrenaline in type-1 HRS not responding to terlipressin at 48 hours. METHODS Sixty patients were randomized to receive either terlipressin (group A; n = 30) or a combination of terlipressin and noradrenaline infusion (group B; n = 30). In group A, terlipressin infusion was started at 2 mg/day and increased by 1 mg/day (maximum 12 mg/day). In group B, terlipressin was given at a constant dose of 2 mg/day. Noradrenaline infusion was started at 0.5 mg/h at baseline and increased to 3 mg/h in a stepwise manner. The primary outcome was treatment response at 15 days. Secondary outcomes were 30-day survival, cost-benefit analysis and adverse events. RESULTS There was no significant difference in the response rate between the groups (50% vs. 76.7%, p = 0.06) and 30-day survival was similar (36.7% vs. 53.3%, p = 0.13). Treatment was more expensive in group A (USD 750 vs. 350, p < 0.001). Adverse events were more frequent in group A (36.7% vs. 13.3%, p < 0.05). CONCLUSIONS The combination of noradrenaline and terlipressin infusion results in a non-significantly higher rate of HRS resolution with significantly fewer adverse effects in HRS patients who do not respond to terlipressin within 48 hours. TRIAL REGISTRATION CLINICALTRIALS gov (NCT03822091).
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Affiliation(s)
- Virendra Singh
- Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, 160 012, India.
| | - Akshaya Jayachandran
- Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Arka De
- Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Akash Singh
- Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Shivani Chandel
- Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Navneet Sharma
- Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, 160 012, India
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Jimenez JV, Garcia-Tsao G, Saffo S. Emerging concepts in the care of patients with cirrhosis and septic shock. World J Hepatol 2023; 15:497-514. [PMID: 37206653 PMCID: PMC10190696 DOI: 10.4254/wjh.v15.i4.497] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 01/19/2023] [Accepted: 03/23/2023] [Indexed: 04/20/2023] Open
Abstract
Septic shock impacts approximately 6% of hospitalized patients with cirrhosis and is associated with high rates of morbidity and mortality. Although a number of landmark clinical trials have paved the way for incremental improvements in the diagnosis and management of septic shock in the general population, patients with cirrhosis have largely been excluded from these studies and critical knowledge gaps continue to impact the care of these individuals. In this review, we discuss nuances in the care of patients with cirrhosis and septic shock using a pathophysiology-based approach. We illustrate that septic shock may be challenging to diagnose in this population in the context of factors such as chronic hypotension, impaired lactate metabolism, and concomitant hepatic encephalopathy. Furthermore, we demonstrate that the application of routine interventions such as intravenous fluids, vasopressors, antibiotics, and steroids should be carefully considered among those with decompensated cirrhosis in light of hemodynamic, metabolic, hormonal, and immunologic disturbances. We propose that future research should include and characterize patients with cirrhosis in a systematic manner, and clinical practice guidelines may need to be refined accordingly.
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Affiliation(s)
- Jose Victor Jimenez
- Section of Digestive Diseases, Yale School of Medicine, New Haven, CT 06520, United States
| | - Guadalupe Garcia-Tsao
- Section of Digestive Diseases, Yale School of Medicine, New Haven, CT 06520, United States
| | - Saad Saffo
- Section of Digestive Diseases, Yale School of Medicine, New Haven, CT 06520, United States.
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Singal AK, Palmer G, Melick L, Abdallah M, Kwo P. Vasoconstrictor Therapy for Acute Kidney Injury Hepatorenal Syndrome: A Meta-Analysis of Randomized Studies. GASTRO HEP ADVANCES 2023; 2:455-464. [PMID: 39132033 PMCID: PMC11308464 DOI: 10.1016/j.gastha.2023.01.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 01/11/2023] [Indexed: 08/13/2024]
Abstract
Background and Aims Type 1 hepatorenal syndrome (HRS) is a rapid deterioration in kidney function in patients with cirrhosis. Data on efficacy of vasoconstrictors for type 1 HRS have shown mixed results. Methods Literature searched for randomized controlled trials comparing pharmacological therapy for HRS vs placebo or another drug for HRS. Primary outcome was HRS reversal (serum creatinine <1.5mg/dL on 2 readings), and secondary outcomes were liver transplant (LT) free survival and serious adverse events (SAE). Results Sixteen studies on 1244 patients (mean age 50.3 yrs., 67.5% males, serum creatinine of 3.07 mg/dL, serum sodium 127.2 mEq/liter, and Model for End-stage Liver Disease (MELD) score of 30.9, and Child-Pugh score 11) with type 1 HRS treated with vasoconstrictors vs placebo or another drug were analyzed. All the patients received intravenous albumin infusion. (A) terlipressin vs placebo: Odds of HRS reversal were 3.3 folds with terlipressin without difference on LT-free patient survival. Terlipressin was associated with higher odds of SAE. (B) Nor-epinephrine (NE) vs terlipressin: No difference on HRS reversal, LT-free survival, and SAE. (C) Terlipressin or NE vs midodrine and octreotide: 91% lower odds of HRS reversal with midodrine and octreotide. There were no differences on SAE (10 of 64 vs 10 of 58, P = .812). Non-responders vs responders had higher mean MELD score (29 vs 27.8), P = .014 and serum creatinine (3.5 vs 3.1), P = .027. Conclusion Terlipressin and NE are similar and superior to midodrine octreotide combination for HRS reversal. No therapy improves LT-free patient survival. Response to treatment is better with lower baseline serum creatinine and MELD score. The risk of adverse effects is similar with terlipressin and NE. Studies are needed as basis to identify candidates with best response to treatment with excellent safety profile.
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Affiliation(s)
- Ashwani K. Singal
- Department of Medicine, University of South Dakota Sanford School of Medicine, Sioux Falls, South Dakota
- Transplant Hepatology, Avera Transplant Institute, Sioux Falls, South Dakota
| | - Geralyn Palmer
- Department of Medicine, University of South Dakota Sanford School of Medicine, Sioux Falls, South Dakota
| | - Lauren Melick
- Department of Medicine, University of South Dakota Sanford School of Medicine, Sioux Falls, South Dakota
| | - Mohamed Abdallah
- Division of Gastroenterology, University of Minnesota, Minneapolis, Minnesota
| | - Paul Kwo
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, California
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Costa-Pinto R, Jones DA, Udy AA, Warrillow SJ, Bellomo R. Midodrine use in critically ill patients: a narrative review. CRIT CARE RESUSC 2022; 24:298-308. [PMID: 38047013 PMCID: PMC10692611 DOI: 10.51893/2022.4.r] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Midodrine is a peripherally acting, oral α-agonist that is increasingly used in intensive care units despite conflicting evidence for its effectiveness. It has pharmacological effects on blood vessels as well as pupillary, cardiac, renal, gastrointestinal, genitourinary, lymphatic and skin tissue. It has approval for use as a treatment for orthostatic hypotension, but a surge in interest over the past decade has prompted its use for a growing number of off-label indications. In critically ill patients, midodrine has been used as either an adjunctive oral therapy to wean vasoplegic patients off low dose intravenous vasopressor infusions, or as an oral vasopressor agent to prevent or minimise the need for intravenous infusion. Clinical trials have mostly focused on midodrine as an intravenous vasopressor weaning agent. Early retrospective studies supported its use for this indication, but more recent randomised controlled trials have largely refuted this practice. Key questions remain on its role in managing critically ill patients before intensive care admission, during intensive care stay, and following discharge. This narrative review presents a comprehensive overview of midodrine use for the critical care physician and highlights why lingering questions around ideal patient selection, dosing, timing of initiation, and efficacy of midodrine for critically ill patients remain unanswered.
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Affiliation(s)
- Rahul Costa-Pinto
- Department of Intensive Care, Austin Hospital, Melbourne, VIC, Australia
- Department of Critical Care, Department of Medicine, University of Melbourne, Melbourne, VIC, Australia
| | - Daryl A. Jones
- Department of Intensive Care, Austin Hospital, Melbourne, VIC, Australia
- Department of Critical Care, Department of Medicine, University of Melbourne, Melbourne, VIC, Australia
| | - Andrew A. Udy
- Department of Intensive Care, Alfred Hospital, Melbourne, VIC, Australia
- Australian and New Zealand Intensive Care Research Centre, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia
| | - Stephen J. Warrillow
- Department of Intensive Care, Austin Hospital, Melbourne, VIC, Australia
- Department of Critical Care, Department of Medicine, University of Melbourne, Melbourne, VIC, Australia
| | - Rinaldo Bellomo
- Department of Intensive Care, Austin Hospital, Melbourne, VIC, Australia
- Department of Critical Care, Department of Medicine, University of Melbourne, Melbourne, VIC, Australia
- Australian and New Zealand Intensive Care Research Centre, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia
- Data Analytics Research and Evaluation Centre, University of Melbourne and Austin Hospital, Melbourne, VIC, Australia
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Allegretti AS, Subramanian RM, Francoz C, Olson JC, Cárdenas A. Respiratory events with terlipressin and albumin in hepatorenal syndrome: A review and clinical guidance. Liver Int 2022; 42:2124-2130. [PMID: 35838488 PMCID: PMC9762017 DOI: 10.1111/liv.15367] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 07/06/2022] [Accepted: 07/12/2022] [Indexed: 12/13/2022]
Abstract
Hepatorenal syndrome-acute kidney injury (HRS-AKI) is a serious complication of severe liver disease with a clinically poor prognosis. Supportive care using vasoconstrictors and intravenous albumin are the current mainstays of therapy. Terlipressin is an efficacious vasoconstrictor that has been used for 2 decades as the first-line treatment for HRS-AKI in Europe and has demonstrated greater efficacy in improving renal function compared to placebo and other vasoconstrictors. One of the challenges associated with terlipressin use is monitoring and mitigating serious adverse events, specifically adverse respiratory events, which were noted in a subset of patients in the recently published CONFIRM trial, the largest randomized trial examining terlipressin use for HRS-AKI. In this article, we review terlipressin's pharmacology, hypothesize how its mechanism contributes to the risk of respiratory compromise and propose strategies that will decrease the frequency of these events by rationally selecting patients at lower risk for these events.
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Affiliation(s)
- Andrew S. Allegretti
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Ram M. Subramanian
- Divisions of Gastroenterology and Hepatology and Pulmonary and Critical Care Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Claire Francoz
- Hepatology and Liver intensive Care Unit, Hospital Beaujon, Clichy, France
| | - Jody C. Olson
- Divisions of Gastroenterology, Hepatology, Pulmonary and Critical Care Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Andrés Cárdenas
- GI and Liver Unit, Institut de Malalties Digestives, Hospital Clinic, Barcelona, Spain. Institut d'Investigacions Biomèdiques August Pi-Sunyer (IDIBAPS), Barcelona and Ciber de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
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13
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Hu SC, Xia H, Ye QQ, Xia C, Xu YL, Xiang XJ, Ma HZ, Gao XF, Chen HB. Reversal of hepatorenal syndrome and kidney recovery: When renal has more to offer. Semin Dial 2022; 35:366-371. [PMID: 35460110 DOI: 10.1111/sdi.13083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 03/20/2022] [Accepted: 04/01/2022] [Indexed: 11/30/2022]
Abstract
Hepatorenal syndrome (HRS) is one of the most severe complications in advanced cirrhosis. Type-1 HRS is relatively uncommon, yet carries considerably higher mortality rate. Effective treatment for HRS, especially therapy towards survival benefits, is still limited. However, the role for dialysis in HRS has been questioned over the years. The initiation of dialysis remains controversial for those who aren't transplant candidates. Meanwhile, there's a growing attention towards the successful use of peritoneal dialysis (PD) in cirrhotic patients. Herein, we report a case of HRS-1 in a 76-year-old male patient with decompensated cirrhosis. Through a series of adjustments of hemodialysis regimens and pharmacological prescriptions, patient stabilized and the opportunity for transjugular intrahepatic portosystemic shunt (TIPS) insertion was gained. PD was initiated after TIPS placement. With a gradual decrease of dialysis dose, patient successfully weaned off PD and achieved both reversal of HRS and kidney recovery. Markedly improved nutritional status and quality of life were reported. The potential role of dialysis and TIPS in HRS may be worth revisiting. Further studies regarding the optimal timing of dialysis initiation, choices of dialysis modality, and efficacy of dialysis therapy in combination with TIPS in HRS patients are warranted.
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Affiliation(s)
- Shou-Ci Hu
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
| | - Hong Xia
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
| | - Qing-Qing Ye
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
| | - Cong Xia
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
| | - Yu-Lin Xu
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
| | - Xiao-Jun Xiang
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
| | - Hong-Zhen Ma
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
| | - Xiang-Fu Gao
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
| | - Hong-Bo Chen
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
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Li F, Wang T, Zhan L, Jia Z, Luo T, Chen S, Zhao Q, Guo Z, He X, Wang D. Clinical Outcomes of Liver Transplantation in Patients With Hepatorenal Syndrome: A Single Center Study in China. Front Surg 2022; 8:781648. [PMID: 35155548 PMCID: PMC8831834 DOI: 10.3389/fsurg.2021.781648] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 12/22/2021] [Indexed: 12/15/2022] Open
Abstract
Background: Liver transplantation (LT) is an optimal treatment for hepatorenal syndrome (HRS) patients but renal function recovery is not universal after operation. The aim of this study is to explore the association between stages of hepatorenal syndrome—acute kidney injury (HRS-AKI) and incidence of post-operation chronic kidney disease (CKD). Methods Data of HRS-AKI patients who received LT were collected from the First Affiliated Hospital of Sun Yat-sen University from 2016 to 2020. A survival and incidence curve and multivariable model were established to analyze the impacts of HRS-AKI stages and variables on 90-day survival and CKD within 12 months. Results A total of 62 HRS-AKI patients were enrolled in this study. Overall, 35 (57%), 17 (27%), and 10 (16%) patients were diagnosed as stages 1, 2, and 3, respectively. The patients at stage 3 had the poorest outcomes with the lowest rate of 90-day survival and the highest incidence of CKD in 12 months. Stage 3 (SHR = 7.186, 95% CI, 1.661–32.043) and postoperative renal replacement therapy (RRT) (SHR = 3.228, 95% CI, 1.115–9.345) were found as useful indicators for poor prognosis. Conclusions In our study, the classification of HRS-AKI stages can be used to predict the prognosis of HRS patients after LT. The peak serum creatinine level is a risky predictor in high HRS-AKI stage patients.
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Bai Z, Zou M, Zhang X, Cheng G. Human Serum Albumin Infusion in Liver Cirrhosis. PHARMACOTHERAPY FOR LIVER CIRRHOSIS AND ITS COMPLICATIONS 2022:113-125. [DOI: 10.1007/978-981-19-2615-0_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Liu S, Meng Q, Xu Y, Zhou J. Hepatorenal syndrome in acute-on-chronic liver failure with acute kidney injury: more questions requiring discussion. Gastroenterol Rep (Oxf) 2021; 9:505-520. [PMID: 34925848 PMCID: PMC8677535 DOI: 10.1093/gastro/goab040] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 07/04/2021] [Accepted: 07/29/2021] [Indexed: 12/13/2022] Open
Abstract
In cirrhosis with ascites, hepatorenal syndrome (HRS) is a specific prerenal dysfunction unresponsive to fluid volume expansion. Acute-on-chronic liver failure (ACLF) comprises a group of clinical syndromes with multiple organ failure and early high mortality. There are differences in the characterization of ACLF between the Eastern and Western medical communities. Patients with ACLF and acute kidney injury (AKI) have more structural injuries, contributing to confusion in diagnosing HRS-AKI. In this review, we discuss progress in the pathogenesis, diagnosis, and management of HRS-AKI, especially in patients with ACLF. Controversy regarding HRS-AKI in ACLF and acute liver failure, hepatic carcinoma, shock, sepsis, and chronic kidney disease is also discussed. Research on the treatment of HRS-AKI with ACLF needs to be more actively pursued to improve disease prognosis.
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Affiliation(s)
- Songtao Liu
- Department of Critical Care Medicine, Beijing Tiantan Hospital, Capital Medical University, Beijing, P. R. China
- Department of Severe Liver Disease, Beijing You’an Hospital, Capital Medical University, Beijing, P. R. China
| | - Qinghua Meng
- Department of Severe Liver Disease, Beijing You’an Hospital, Capital Medical University, Beijing, P. R. China
| | - Yuan Xu
- Department of Critical Care Medicine, Beijing Tsinghua Chang Gung Hospital, Beijing, P. R. China
| | - Jianxin Zhou
- Department of Critical Care Medicine, Beijing Tiantan Hospital, Capital Medical University, Beijing, P. R. China
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Sangroongruangsri S, Kittrongsiri K, Charatcharoenwitthaya P, Sobhonslidsuk A, Chaikledkaew U. Cost-Utility Analysis of Vasoconstrictors Plus Albumin in the Treatment of Thai Patients with Type 1 Hepatorenal Syndrome. CLINICOECONOMICS AND OUTCOMES RESEARCH 2021; 13:703-715. [PMID: 34349534 PMCID: PMC8328389 DOI: 10.2147/ceor.s317390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 07/16/2021] [Indexed: 12/01/2022] Open
Abstract
Purpose Type 1 hepatorenal syndrome (type 1 HRS) or hepatorenal syndrome-acute renal injury (HRS-AKI) leads to high short-term mortality rates in patients with cirrhosis. Vasoconstrictor therapy effectively improves survival of these patients and has been a bridge to liver transplantation. The aim of this study was to assess the cost-utility of terlipressin plus albumin (T+A) and noradrenaline plus albumin (N+A) compared to best supportive care (BSC) for treating type 1 HRS patients in Thailand. Methods A cost-utility analysis using a six-state Markov model was performed from societal and payer perspectives over a lifetime horizon. The clinical outcomes, costs, and utility parameters were obtained from literature, network meta-analyses, and expert opinion. One-way and probabilistic sensitivity analyses were conducted to account for uncertainty. Results The T+A yielded the highest cost (848,325 Thai Baht (THB)) and health outcomes (2.82 life-years (LY) and 2.27 quality-adjusted life-years (QALY)). Compared to BSC, incremental cost-effectiveness ratios (ICERs) of the T+A and N+A were 377,566 and 412,979 THB per QALY gained, respectively. If N+A is administered outside the intensive care unit, the ICER was 308,964 THB per QALY. The treatment cost after liver transplantation from year 3 onwards was the most influential factor for ICERs, followed by the cost of terlipressin, duration of noradrenaline treatment, and cost of albumin. At the Thai societal willingness-to-pay threshold of 160,000 THB per QALY gained, the probabilities of being cost-effective for T+A, N+A, and BSC were 11%, 20%, and 69%, respectively. Conclusion The T+A and N+A treatments would not be cost-effective compared to BSC in the Thai setting.
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Affiliation(s)
- Sermsiri Sangroongruangsri
- Social and Administrative Pharmacy Division, Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand
| | - Kankamon Kittrongsiri
- Social, Economic and Administrative Pharmacy (SEAP) Graduate Program, Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand
| | - Phunchai Charatcharoenwitthaya
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Abhasnee Sobhonslidsuk
- Division of Gastroenterology and Hepatology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Usa Chaikledkaew
- Social and Administrative Pharmacy Division, Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand.,Mahidol University Health Technology Assessment (MUHTA) Graduate Program, Mahidol University, Bangkok, Thailand
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18
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Yu YT, Liu J, Hu B, Wang RL, Yang XH, Shang XL, Wang G, Wang CS, Li BL, Gong Y, Zhang S, Li X, Wang L, Shao M, Meng M, Zhu F, Shang Y, Xu QH, Wu ZX, Chen DC. Expert consensus on the use of human serum albumin in critically ill patients. Chin Med J (Engl) 2021; 134:1639-1654. [PMID: 34397592 PMCID: PMC8318641 DOI: 10.1097/cm9.0000000000001661] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Indexed: 02/05/2023] Open
Affiliation(s)
- Yue-Tian Yu
- Department of Critical Care Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200001, China
| | - Jiao Liu
- Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Bo Hu
- Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China
| | - Rui-Lan Wang
- Department of Critical Care Medicine, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 201620, China
| | - Xiang-Hong Yang
- Department of Critical Care Medicine, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang 310014, China
| | - Xiu-Ling Shang
- Department of Critical Care Medicine, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian 350001, China
| | - Gang Wang
- Department of Critical Care Medicine, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710004, China
| | - Chang-Song Wang
- Department of Critical Care Medicine, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150081, China
| | - Bai-Ling Li
- Department of Cardiovascular Surgery, Changhai Hospital, Naval Military Medical University (The Second Military Medical University), Shanghai 200433, China
| | - Ye Gong
- Department of Critical Care Medicine, Department of Neurosurgery, HuaShan Hospital, Fudan University, Shanghai 200040, China
| | - Sheng Zhang
- Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Xin Li
- Department of Cardiovascular Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Lu Wang
- Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
| | - Min Shao
- Department of Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Mei Meng
- Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Feng Zhu
- Department of Burn and Trauma Intensive Care Unit, The First Affiliated Hospital, Naval Medical University, Shanghai 200433, China
| | - You Shang
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
| | - Qiang-Hong Xu
- Department of Critical Care Medicine, Zhejiang Hospital, Hangzhou, Zhejiang 310013, China
| | - Zhi-Xiong Wu
- Department of Critical Care Medicine, Huadong Hospital, Fudan University, Shanghai 200040, China
| | - De-Chang Chen
- Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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Komolafe O, Buzzetti E, Linden A, Best LM, Madden AM, Roberts D, Chase TJ, Fritche D, Freeman SC, Cooper NJ, Sutton AJ, Milne EJ, Wright K, Pavlov CS, Davidson BR, Tsochatzis E, Gurusamy KS. Nutritional supplementation for nonalcohol-related fatty liver disease: a network meta-analysis. Cochrane Database Syst Rev 2021; 7:CD013157. [PMID: 34280304 PMCID: PMC8406904 DOI: 10.1002/14651858.cd013157.pub2] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND The prevalence of non-alcohol-related fatty liver disease (NAFLD) varies between 19% and 33% in different populations. NAFLD decreases life expectancy and increases risks of liver cirrhosis, hepatocellular carcinoma, and the requirement for liver transplantation. Uncertainty surrounds relative benefits and harms of various nutritional supplements in NAFLD. Currently no nutritional supplement is recommended for people with NAFLD. OBJECTIVES • To assess the benefits and harms of different nutritional supplements for treatment of NAFLD through a network meta-analysis • To generate rankings of different nutritional supplements according to their safety and efficacy SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Science Citation Index Expanded, Conference Proceedings Citation Index-Science, the World Health Organization International Clinical Trials Registry Platform, and trials registers until February 2021 to identify randomised clinical trials in people with NAFLD. SELECTION CRITERIA We included only randomised clinical trials (irrespective of language, blinding, or status) for people with NAFLD, irrespective of method of diagnosis, age and diabetic status of participants, or presence of non-alcoholic steatohepatitis (NASH). We excluded randomised clinical trials in which participants had previously undergone liver transplantation. DATA COLLECTION AND ANALYSIS We performed a network meta-analysis with OpenBUGS using Bayesian methods whenever possible and calculated differences in treatments using hazard ratios (HRs), odds ratios (ORs), and rate ratios with 95% credible intervals (CrIs) based on an available-case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance. MAIN RESULTS We included in the review a total of 202 randomised clinical trials (14,200 participants). Nineteen trials were at low risk of bias. A total of 32 different interventions were compared in these trials. A total of 115 trials (7732 participants) were included in one or more comparisons. The remaining trials did not report any of the outcomes of interest for this review. Follow-up ranged from 1 month to 28 months. The follow-up period in trials that reported clinical outcomes was 2 months to 28 months. During this follow-up period, clinical events related to NAFLD such as mortality, liver cirrhosis, liver decompensation, liver transplantation, hepatocellular carcinoma, and liver-related mortality were sparse. We did not calculate effect estimates for mortality because of sparse data (zero events for at least one of the groups in the trial). None of the trials reported that they measured overall health-related quality of life using a validated scale. The evidence is very uncertain about effects of interventions on serious adverse events (number of people or number of events). We are very uncertain about effects on adverse events of most of the supplements that we investigated, as the evidence is of very low certainty. However, people taking PUFA (polyunsaturated fatty acid) may be more likely to experience an adverse event than those not receiving an active intervention (network meta-analysis results: OR 4.44, 95% CrI 2.40 to 8.48; low-certainty evidence; 4 trials, 203 participants; direct evidence: OR 4.43, 95% CrI 2.43 to 8.42). People who take other supplements (a category that includes nutritional supplements other than vitamins, fatty acids, phospholipids, and antioxidants) had higher numbers of adverse events than those not receiving an active intervention (network meta-analysis: rate ratio 1.73, 95% CrI 1.26 to 2.41; 6 trials, 291 participants; direct evidence: rate ratio 1.72, 95% CrI 1.25 to 2.40; low-certainty evidence). Data were sparse (zero events in all groups in the trial) for liver transplantation, liver decompensation, and hepatocellular carcinoma. So, we did not perform formal analysis for these outcomes. The evidence is very uncertain about effects of other antioxidants (antioxidants other than vitamins) compared to no active intervention on liver cirrhosis (HR 1.68, 95% CrI 0.23 to 15.10; 1 trial, 99 participants; very low-certainty evidence). The evidence is very uncertain about effects of interventions in any of the remaining comparisons, or data were sparse (with zero events in at least one of the groups), precluding formal calculations of effect estimates. Data were probably because of the very short follow-up period (2 months to 28 months). It takes follow-up of 8 to 28 years to detect differences in mortality between people with NAFLD and the general population. Therefore, it is unlikely that differences in clinical outcomes are noted in trials providing less than 5 to 10 years of follow-up. AUTHORS' CONCLUSIONS The evidence indicates considerable uncertainty about effects of nutritional supplementation compared to no additional intervention on all clinical outcomes for people with non-alcohol-related fatty liver disease. Accordingly, high-quality randomised comparative clinical trials with adequate follow-up are needed. We propose registry-based randomised clinical trials or cohort multiple randomised clinical trials (study design in which multiple interventions are trialed within large longitudinal cohorts of patients to gain efficiencies and align trials more closely to standard clinical practice) comparing interventions such as vitamin E, prebiotics/probiotics/synbiotics, PUFAs, and no nutritional supplementation. The reason for the choice of interventions is the impact of these interventions on indirect outcomes, which may translate to clinical benefit. Outcomes in such trials should be mortality, health-related quality of life, decompensated liver cirrhosis, liver transplantation, and resource utilisation measures including costs of intervention and decreased healthcare utilisation after minimum follow-up of 8 years (to find meaningful differences in clinically important outcomes).
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Affiliation(s)
| | - Elena Buzzetti
- Sheila Sherlock Liver Centre, Royal Free Hospital and the UCL Institute of Liver and Digestive Health, London, UK
| | - Audrey Linden
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Lawrence Mj Best
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Angela M Madden
- School of Life and Medical Sciences, University of Hertfordshire, Hatfield, UK
| | - Danielle Roberts
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Thomas Jg Chase
- Department of General Surgery, Homerton University Hospital NHS Foundation Trust, London, UK
| | | | - Suzanne C Freeman
- Department of Health Sciences, University of Leicester, Leicester, UK
| | - Nicola J Cooper
- Department of Health Sciences, University of Leicester, Leicester, UK
| | - Alex J Sutton
- Department of Health Sciences, University of Leicester, Leicester, UK
| | | | - Kathy Wright
- Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Capital Region of Denmark, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Chavdar S Pavlov
- Department of Therapy, I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Brian R Davidson
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Emmanuel Tsochatzis
- Sheila Sherlock Liver Centre, Royal Free Hospital and the UCL Institute of Liver and Digestive Health, London, UK
| | - Kurinchi Selvan Gurusamy
- Division of Surgery and Interventional Science, University College London, London, UK
- Department of Therapy, I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
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Simbrunner B, Trauner M, Reiberger T, Mandorfer M. Recent advances in the understanding and management of hepatorenal syndrome. Fac Rev 2021; 10:48. [PMID: 34131658 PMCID: PMC8170686 DOI: 10.12703/r/10-48] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Renal dysfunction occurs frequently in hospitalized patients with advanced chronic liver disease (ACLD)/cirrhosis and has profound prognostic implications. In ACLD patients with ascites, hepatorenal syndrome (HRS) may result from circulatory dysfunction that leads to reduced kidney perfusion and glomerular filtration rate (in the absence of structural kidney damage). The traditional subclassification of HRS has recently been replaced by acute kidney injury (AKI) type of HRS (HRS-AKI) and non-AKI type of HRS (HRS-NAKI), replacing the terms “HRS type 1” and “HRS type 2”, respectively. Importantly, the concept of absolute serum creatinine (sCr) cutoffs for diagnosing HRS was partly abandoned and short term sCr dynamics now may suffice for AKI diagnosis, which facilitates early treatment initiation that may prevent the progression to HRS-AKI or increase the chances of AKI/HRS-AKI reversal. Recent randomized controlled trials have established (a) the efficacy of (long-term) albumin in the prevention of complications of ascites (including HRS-AKI), (b) the benefits of transjugular intrahepatic portosystemic shunt placement in patients with recurrent ascites, and (c) the superiority of terlipressin over noradrenaline for the treatment of HRS-AKI in the context of acute-on-chronic liver failure. This review article aims to summarize recent advances in the understanding and management of HRS.
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Affiliation(s)
- Benedikt Simbrunner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Mattias Mandorfer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
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Buzzetti E, Linden A, Best LM, Madden AM, Roberts D, Chase TJG, Freeman SC, Cooper NJ, Sutton AJ, Fritche D, Milne EJ, Wright K, Pavlov CS, Davidson BR, Tsochatzis E, Gurusamy KS. Lifestyle modifications for nonalcohol-related fatty liver disease: a network meta-analysis. Cochrane Database Syst Rev 2021; 6:CD013156. [PMID: 34114650 PMCID: PMC8193812 DOI: 10.1002/14651858.cd013156.pub2] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND The prevalence of nonalcohol-related fatty liver disease (NAFLD) varies between 19% and 33% in different populations. NAFLD decreases life expectancy and increases the risks of liver cirrhosis, hepatocellular carcinoma, and requirement for liver transplantation. There is uncertainty surrounding the relative benefits and harms of various lifestyle interventions for people with NAFLD. OBJECTIVES To assess the comparative benefits and harms of different lifestyle interventions in the treatment of NAFLD through a network meta-analysis, and to generate rankings of the different lifestyle interventions according to their safety and efficacy. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, Conference Proceedings Citation Index - Science, World Health Organization International Clinical Trials Registry Platform, and trials registers until February 2021 to identify randomised clinical trials in people with NAFLD. SELECTION CRITERIA We included only randomised clinical trials (irrespective of language, blinding, or status) in people with NAFLD, whatever the method of diagnosis, age, and diabetic status of participants, or presence of non-alcoholic steatohepatitis (NASH). We excluded randomised clinical trials in which participants had previously undergone liver transplantation. DATA COLLECTION AND ANALYSIS We planned to perform a network meta-analysis with OpenBUGS using Bayesian methods and to calculate the differences in treatments using hazard ratios (HRs), odds ratios (ORs), and rate ratios (RaRs) with 95% credible intervals (CrIs) based on an available-participant analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance. However, the data were too sparse for the clinical outcomes. We therefore performed only direct comparisons (head-to-head comparisons) with OpenBUGS using Bayesian methods. MAIN RESULTS We included a total of 59 randomised clinical trials (3631 participants) in the review. All but two trials were at high risk of bias. A total of 33 different interventions, ranging from advice to supervised exercise and special diets, or a combination of these and no additional intervention were compared in these trials. The reference treatment was no active intervention. Twenty-eight trials (1942 participants) were included in one or more comparisons. The follow-up ranged from 1 month to 24 months. The remaining trials did not report any of the outcomes of interest for this review. The follow-up period in the trials that reported clinical outcomes was 2 months to 24 months. During this short follow-up period, clinical events related to NAFLD such as mortality, liver cirrhosis, liver decompensation, liver transplantation, hepatocellular carcinoma, and liver-related mortality were sparse. This is probably because of the very short follow-up periods. It takes a follow-up of 8 years to 28 years to detect differences in mortality between people with NAFLD and the general population. It is therefore unlikely that differences by clinical outcomes will be noted in trials with less than 5 years to 10 years of follow-up. In one trial, one participant developed an adverse event. There were no adverse events in any of the remaining participants in this trial, or in any of the remaining trials, which seemed to be directly related to the intervention. AUTHORS' CONCLUSIONS The evidence indicates considerable uncertainty about the effects of the lifestyle interventions compared with no additional intervention (to general public health advice) on any of the clinical outcomes after a short follow-up period of 2 months to 24 months in people with nonalcohol-related fatty liver disease. Accordingly, high-quality randomised clinical trials with adequate follow-up are needed. We propose registry-based randomised clinical trials or cohort multiple randomised clinical trials (a study design in which multiple interventions are trialed within large longitudinal cohorts of participants to gain efficiencies and align trials more closely to standard clinical practice), comparing aerobic exercise and dietary advice versus standard of care (exercise and dietary advice received as part of national health promotion). The reason for the choice of aerobic exercise and dietary advice is the impact of these interventions on indirect outcomes which may translate to clinical benefit. The outcomes in such trials should be mortality, health-related quality of life, decompensated liver cirrhosis, liver transplantation, and resource use measures including costs of intervention and decreased healthcare use after a minimum follow-up of eight years, to find meaningful differences in the clinically important outcomes.
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Affiliation(s)
- Elena Buzzetti
- Sheila Sherlock Liver Centre, Royal Free Hospital and the UCL Institute of Liver and Digestive Health, London, UK
| | - Audrey Linden
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Lawrence Mj Best
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Angela M Madden
- School of Life and Medical Sciences, University of Hertfordshire, Hatfield, UK
| | - Danielle Roberts
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Thomas J G Chase
- Department of General Surgery, Homerton University Hospital NHS Foundation Trust, London, UK
| | - Suzanne C Freeman
- Department of Health Sciences, University of Leicester, Leicester, UK
| | - Nicola J Cooper
- Department of Health Sciences, University of Leicester, Leicester, UK
| | - Alex J Sutton
- Department of Health Sciences, University of Leicester, Leicester, UK
| | | | | | - Kathy Wright
- Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Capital Region of Denmark, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Chavdar S Pavlov
- Department of Therapy, I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Brian R Davidson
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Emmanuel Tsochatzis
- Sheila Sherlock Liver Centre, Royal Free Hospital and the UCL Institute of Liver and Digestive Health, London, UK
| | - Kurinchi Selvan Gurusamy
- Division of Surgery and Interventional Science, University College London, London, UK
- Department of Therapy, I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
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22
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Sheng XY, Lin FY, Wu J, Cao HC. Development and validation of a prognostic model for patients with hepatorenal syndrome: A retrospective cohort study. World J Gastroenterol 2021; 27:2615-2629. [PMID: 34092979 PMCID: PMC8160623 DOI: 10.3748/wjg.v27.i20.2615] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 02/23/2021] [Accepted: 04/08/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatorenal syndrome (HRS) is a severe complication of cirrhosis with high mortality, which necessitates accurate clinical decision. However, studies on prognostic factors and scoring systems to predict overall survival of HRS are not enough. Meanwhile, a multicenter cohort study with a long span of time could be more convincing. AIM To develop a novel and effective prognostic model for patients with HRS and clarify new prognostic factors. METHODS We retrospectively enrolled 1667 patients from four hospitals, and 371 eligible patients were finally analyzed to develop and validate a novel prognostic model for patients with HRS. Characteristics were compared between survivors and non-survivors, and potential prognostic factors were selected according to the impact on 28-d mortality. Accuracy in predicting 28-d mortality was compared between the novel and other scoring systems, including Model for End-Stage Liver Disease (MELD), Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA), and Chinese Group on the Study of Severe Hepatitis B-Acute-on-Chronic Liver Failure (COSSH-ACLF). RESULTS Five prognostic factors, comprised of gender, international normalized ratio, mean corpuscular hemoglobin concentration, neutrophil percentage, and stage, were integrated into a new score, GIMNS; stage is a binary variable defined by the number of failed organs. GIMNS was positively correlated with MELD, CLIF-SOFA, and COSSH-ACLF. Additionally, it had better accuracy [area under the receiver operating characteristic curve (AUROC): 0.830] than MELD (AUROC: 0.759), CLIF-SOFA (AUROC: 0.767), and COSSH-ACLF (AUROC: 0.759) in the derivation cohort (P < 0.05). It performed better than MELD and CLIF-SOFA in the validation cohort (P < 0.050) and had a higher AUROC than COSSH-ACLF (P = 0.122). CONCLUSION We have developed a new scoring system, GIMNS, to predict 28-d mortality of HRS patients. Mean corpuscular hemoglobin concentration and stage were first proposed and found to be related to the mortality of HRS. Additionally, the GIMNS score showed better accuracy than MELD and CLIF-SOFA, and the AUROC was higher than that of COSSH-ACLF.
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Affiliation(s)
- Xin-Yu Sheng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
- National Clinical Research Center for Infectious Diseases, Hangzhou 310003, Zhejiang Province, China
| | - Fei-Yan Lin
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
- National Clinical Research Center for Infectious Diseases, Hangzhou 310003, Zhejiang Province, China
| | - Jian Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
- National Clinical Research Center for Infectious Diseases, Hangzhou 310003, Zhejiang Province, China
| | - Hong-Cui Cao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
- National Clinical Research Center for Infectious Diseases, Hangzhou 310003, Zhejiang Province, China
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23
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Wong YJ, Kumar R, Chua YJJ, Ang TL. Long-term albumin infusion in decompensated cirrhosis: A review of current literature. World J Hepatol 2021; 13:421-432. [PMID: 33959225 PMCID: PMC8080546 DOI: 10.4254/wjh.v13.i4.421] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 03/22/2021] [Accepted: 04/13/2021] [Indexed: 02/06/2023] Open
Abstract
Decompensated cirrhosis is characterized by chronic inflammation and severe portal hypertension leading to systemic circulatory dysfunction. Albumin infusion has been widely used in decompensated cirrhosis in patients with spontaneous bacterial peritonitis, large-volume paracentesis and hepatorenal syndrome. Emerging data suggest long-term albumin infusion has both oncotic and non-oncotic properties which may improve the clinical outcomes in decompensated cirrhosis patients. We review the current literature on both the established and potential role of albumin, and specifically address the controversies of long-term albumin infusion in decompensated cirrhosis patients.
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Affiliation(s)
- Yu Jun Wong
- Department ofGastroenterology and Hepatology, Changi General Hospital, Singapore 529889, Singapore
| | - Rahul Kumar
- Department ofGastroenterology and Hepatology, Changi General Hospital, Singapore 529889, Singapore
| | - Yu Jing Jonathan Chua
- Department of Internal Medicine, Yong Loo Lin School of Medicine, Singapore 117597, Singapore
| | - Tiing Leong Ang
- Department ofGastroenterology and Hepatology, Changi General Hospital, Singapore 529889, Singapore.
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24
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Roberts D, Best LM, Freeman SC, Sutton AJ, Cooper NJ, Arunan S, Begum T, Williams NR, Walshaw D, Milne EJ, Tapp M, Csenar M, Pavlov CS, Davidson BR, Tsochatzis E, Gurusamy KS. Treatment for bleeding oesophageal varices in people with decompensated liver cirrhosis: a network meta-analysis. Cochrane Database Syst Rev 2021; 4:CD013155. [PMID: 33837526 PMCID: PMC8094233 DOI: 10.1002/14651858.cd013155.pub2] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND Approximately 40% to 95% of people with liver cirrhosis have oesophageal varices. About 15% to 20% of oesophageal varices bleed within about one to three years after diagnosis. Several different treatments are available, including, among others, endoscopic sclerotherapy, variceal band ligation, somatostatin analogues, vasopressin analogues, and balloon tamponade. However, there is uncertainty surrounding the individual and relative benefits and harms of these treatments. OBJECTIVES To compare the benefits and harms of different initial treatments for variceal bleeding from oesophageal varices in adults with decompensated liver cirrhosis, through a network meta-analysis; and to generate rankings of the different treatments for acute bleeding oesophageal varices, according to their benefits and harms. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers until 17 December 2019, to identify randomised clinical trials (RCTs) in people with cirrhosis and acute bleeding from oesophageal varices. SELECTION CRITERIA We included only RCTs (irrespective of language, blinding, or status) in adults with cirrhosis and acutely bleeding oesophageal varices. We excluded RCTs in which participants had bleeding only from gastric varices, those who failed previous treatment (refractory bleeding), those in whom initial haemostasis was achieved before inclusion into the trial, and those who had previously undergone liver transplantation. DATA COLLECTION AND ANALYSIS We performed a network meta-analysis with OpenBUGS software, using Bayesian methods, and calculated the differences in treatments using odds ratios (OR) and rate ratios with 95% credible intervals (CrI) based on an available-case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance. We performed also the direct comparisons from RCTs using the same codes and the same technical details. MAIN RESULTS We included a total of 52 RCTs (4580 participants) in the review. Forty-eight trials (4042 participants) were included in one or more comparisons in the review. The trials that provided the information included people with cirrhosis due to varied aetiologies and those with and without a previous history of bleeding. We included outcomes assessed up to six weeks. All trials were at high risk of bias. A total of 19 interventions were compared in the trials (sclerotherapy, somatostatin analogues, vasopressin analogues, sclerotherapy plus somatostatin analogues, variceal band ligation, balloon tamponade, somatostatin analogues plus variceal band ligation, nitrates plus vasopressin analogues, no active intervention, sclerotherapy plus variceal band ligation, balloon tamponade plus sclerotherapy, balloon tamponade plus somatostatin analogues, balloon tamponade plus vasopressin analogues, variceal band ligation plus vasopressin analogues, balloon tamponade plus nitrates plus vasopressin analogues, balloon tamponade plus variceal band ligation, portocaval shunt, sclerotherapy plus transjugular intrahepatic portosystemic shunt (TIPS), and sclerotherapy plus vasopressin analogues). We have reported the effect estimates for the primary and secondary outcomes when there was evidence of differences between the interventions against the reference treatment of sclerotherapy, but reported the other results of the primary and secondary outcomes versus the reference treatment of sclerotherapy without the effect estimates when there was no evidence of differences in order to provide a concise summary of the results. Overall, 15.8% of the trial participants who received the reference treatment of sclerotherapy (chosen because this was the commonest treatment compared in the trials) died during the follow-up periods, which ranged from three days to six weeks. Based on moderate-certainty evidence, somatostatin analogues alone had higher mortality than sclerotherapy (OR 1.57, 95% CrI 1.04 to 2.41; network estimate; direct comparison: 4 trials; 353 participants) and vasopressin analogues alone had higher mortality than sclerotherapy (OR 1.70, 95% CrI 1.13 to 2.62; network estimate; direct comparison: 2 trials; 438 participants). None of the trials reported health-related quality of life. Based on low-certainty evidence, a higher proportion of people receiving balloon tamponade plus sclerotherapy had more serious adverse events than those receiving only sclerotherapy (OR 4.23, 95% CrI 1.22 to 17.80; direct estimate; 1 RCT; 60 participants). Based on moderate-certainty evidence, people receiving vasopressin analogues alone and those receiving variceal band ligation had fewer adverse events than those receiving only sclerotherapy (rate ratio 0.59, 95% CrI 0.35 to 0.96; network estimate; direct comparison: 1 RCT; 219 participants; and rate ratio 0.40, 95% CrI 0.21 to 0.74; network estimate; direct comparison: 1 RCT; 77 participants; respectively). Based on low-certainty evidence, the proportion of people who developed symptomatic rebleed was smaller in people who received sclerotherapy plus somatostatin analogues than those receiving only sclerotherapy (OR 0.21, 95% CrI 0.03 to 0.94; direct estimate; 1 RCT; 105 participants). The evidence suggests considerable uncertainty about the effect of the interventions in the remaining comparisons where sclerotherapy was the control intervention. AUTHORS' CONCLUSIONS Based on moderate-certainty evidence, somatostatin analogues alone and vasopressin analogues alone (with supportive therapy) probably result in increased mortality, compared to endoscopic sclerotherapy. Based on moderate-certainty evidence, vasopressin analogues alone and band ligation alone probably result in fewer adverse events compared to endoscopic sclerotherapy. Based on low-certainty evidence, balloon tamponade plus sclerotherapy may result in large increases in serious adverse events compared to sclerotherapy. Based on low-certainty evidence, sclerotherapy plus somatostatin analogues may result in large decreases in symptomatic rebleed compared to sclerotherapy. In the remaining comparisons, the evidence indicates considerable uncertainty about the effects of the interventions, compared to sclerotherapy.
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Affiliation(s)
- Danielle Roberts
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Lawrence Mj Best
- Division of Surgery and Interventional Science, University College London, London, UK
- Department of Therapy, I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Suzanne C Freeman
- Department of Health Sciences, University of Leicester, Leicester, UK
| | - Alex J Sutton
- Department of Health Sciences, University of Leicester, Leicester, UK
| | - Nicola J Cooper
- Department of Health Sciences, University of Leicester, Leicester, UK
| | - Sivapatham Arunan
- General and Colorectal Surgery, Ealing Hospital and Imperial College, London, Northwood, UK
| | | | - Norman R Williams
- Surgical & Interventional Trials Unit (SITU), UCL Division of Surgery & Interventional Science, London, UK
| | - Dana Walshaw
- Acute Medicine, Barts and The London NHS Trust, London, UK
| | | | | | - Mario Csenar
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Chavdar S Pavlov
- Department of Therapy, I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Brian R Davidson
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Emmanuel Tsochatzis
- Sheila Sherlock Liver Centre, Royal Free Hospital and the UCL Institute of Liver and Digestive Health, London, UK
| | - Kurinchi Selvan Gurusamy
- Division of Surgery and Interventional Science, University College London, London, UK
- Department of Therapy, I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
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25
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Roccarina D, Best LM, Freeman SC, Roberts D, Cooper NJ, Sutton AJ, Benmassaoud A, Plaz Torres MC, Iogna Prat L, Csenar M, Arunan S, Begum T, Milne EJ, Tapp M, Pavlov CS, Davidson BR, Tsochatzis E, Williams NR, Gurusamy KS. Primary prevention of variceal bleeding in people with oesophageal varices due to liver cirrhosis: a network meta-analysis. Cochrane Database Syst Rev 2021; 4:CD013121. [PMID: 33822357 PMCID: PMC8092414 DOI: 10.1002/14651858.cd013121.pub2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND Approximately 40% to 95% of people with cirrhosis have oesophageal varices. About 15% to 20% of oesophageal varices bleed in about one to three years. There are several different treatments to prevent bleeding, including: beta-blockers, endoscopic sclerotherapy, and variceal band ligation. However, there is uncertainty surrounding their individual and relative benefits and harms. OBJECTIVES To compare the benefits and harms of different treatments for prevention of first variceal bleeding from oesophageal varices in adults with liver cirrhosis through a network meta-analysis and to generate rankings of the different treatments for prevention of first variceal bleeding from oesophageal varices according to their safety and efficacy. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers to December 2019 to identify randomised clinical trials in people with cirrhosis and oesophageal varices with no history of bleeding. SELECTION CRITERIA We included only randomised clinical trials (irrespective of language, blinding, or status) in adults with cirrhosis and oesophageal varices with no history of bleeding. We excluded randomised clinical trials in which participants had previous bleeding from oesophageal varices and those who had previously undergone liver transplantation or previously received prophylactic treatment for oesophageal varices. DATA COLLECTION AND ANALYSIS We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the differences in treatments using hazard ratios (HR), odds ratios (OR), and rate ratios with 95% credible intervals (CrI) based on an available-case analysis, according to National Institute for Health and Care Excellence Decision Support Unit guidance. We performed the direct comparisons from randomised clinical trials using the same codes and the same technical details. MAIN RESULTS We included 66 randomised clinical trials (6653 participants) in the review. Sixty trials (6212 participants) provided data for one or more comparisons in the review. The trials that provided the information included people with cirrhosis due to varied aetiologies and those at high risk of bleeding from oesophageal varices. The follow-up in the trials that reported outcomes ranged from 6 months to 60 months. All but one of the trials were at high risk of bias. The interventions compared included beta-blockers, no active intervention, variceal band ligation, sclerotherapy, beta-blockers plus variceal band ligation, beta-blockers plus nitrates, nitrates, beta-blockers plus sclerotherapy, and portocaval shunt. Overall, 21.2% of participants who received non-selective beta-blockers ('beta-blockers') - the reference treatment (chosen because this was the most common treatment compared in the trials) - died during 8-month to 60-month follow-up. Based on low-certainty evidence, beta-blockers, variceal band ligation, sclerotherapy, and beta-blockers plus nitrates all had lower mortality versus no active intervention (beta-blockers: HR 0.49, 95% CrI 0.36 to 0.67; direct comparison HR: 0.59, 95% CrI 0.42 to 0.83; 10 trials, 1200 participants; variceal band ligation: HR 0.51, 95% CrI 0.35 to 0.74; direct comparison HR 0.49, 95% CrI 0.12 to 2.14; 3 trials, 355 participants; sclerotherapy: HR 0.66, 95% CrI 0.51 to 0.85; direct comparison HR 0.61, 95% CrI 0.41 to 0.90; 18 trials, 1666 participants; beta-blockers plus nitrates: HR 0.41, 95% CrI 0.20 to 0.85; no direct comparison). No trials reported health-related quality of life. Based on low-certainty evidence, variceal band ligation had a higher number of serious adverse events (number of events) than beta-blockers (rate ratio 10.49, 95% CrI 2.83 to 60.64; 1 trial, 168 participants). Based on low-certainty evidence, beta-blockers plus nitrates had a higher number of 'any adverse events (number of participants)' than beta-blockers alone (OR 3.41, 95% CrI 1.11 to 11.28; 1 trial, 57 participants). Based on low-certainty evidence, adverse events (number of events) were higher in sclerotherapy than in beta-blockers (rate ratio 2.49, 95% CrI 1.53 to 4.22; direct comparison rate ratio 2.47, 95% CrI 1.27 to 5.06; 2 trials, 90 participants), and in beta-blockers plus variceal band ligation than in beta-blockers (direct comparison rate ratio 1.72, 95% CrI 1.08 to 2.76; 1 trial, 140 participants). Based on low-certainty evidence, any variceal bleed was lower in beta-blockers plus variceal band ligation than in beta-blockers (direct comparison HR 0.21, 95% CrI 0.04 to 0.71; 1 trial, 173 participants). Based on low-certainty evidence, any variceal bleed was higher in nitrates than beta-blockers (direct comparison HR 6.40, 95% CrI 1.58 to 47.42; 1 trial, 52 participants). The evidence indicates considerable uncertainty about the effect of the interventions in the remaining comparisons. AUTHORS' CONCLUSIONS Based on low-certainty evidence, beta-blockers, variceal band ligation, sclerotherapy, and beta-blockers plus nitrates may decrease mortality compared to no intervention in people with high-risk oesophageal varices in people with cirrhosis and no previous history of bleeding. Based on low-certainty evidence, variceal band ligation may result in a higher number of serious adverse events than beta-blockers. The evidence indicates considerable uncertainty about the effect of beta-blockers versus variceal band ligation on variceal bleeding. The evidence also indicates considerable uncertainty about the effect of the interventions in most of the remaining comparisons.
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Affiliation(s)
- Davide Roccarina
- Sheila Sherlock Liver Centre, Royal Free Hospital and the UCL Institute of Liver and Digestive Health, London, UK
| | - Lawrence Mj Best
- Division of Surgery and Interventional Science, University College London, London, UK
- Department of Therapy, I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Suzanne C Freeman
- Department of Health Sciences, University of Leicester, Leicester, UK
| | - Danielle Roberts
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Nicola J Cooper
- Department of Health Sciences, University of Leicester, Leicester, UK
| | - Alex J Sutton
- Department of Health Sciences, University of Leicester, Leicester, UK
| | - Amine Benmassaoud
- Sheila Sherlock Liver Centre, Royal Free Hospital and the UCL Institute of Liver and Digestive Health, London, UK
| | | | - Laura Iogna Prat
- Sheila Sherlock Liver Centre, Royal Free Hospital and the UCL Institute of Liver and Digestive Health, London, UK
| | - Mario Csenar
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Sivapatham Arunan
- General and Colorectal Surgery, Ealing Hospital and Imperial College, London, Northwood, UK
| | | | | | | | - Chavdar S Pavlov
- Department of Therapy, I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Brian R Davidson
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Emmanuel Tsochatzis
- Sheila Sherlock Liver Centre, Royal Free Hospital and the UCL Institute of Liver and Digestive Health, London, UK
| | - Norman R Williams
- Surgical & Interventional Trials Unit (SITU), UCL Division of Surgery & Interventional Science, London, UK
| | - Kurinchi Selvan Gurusamy
- Division of Surgery and Interventional Science, University College London, London, UK
- Department of Therapy, I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
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26
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Plaz Torres MC, Best LM, Freeman SC, Roberts D, Cooper NJ, Sutton AJ, Roccarina D, Benmassaoud A, Iogna Prat L, Williams NR, Csenar M, Fritche D, Begum T, Arunan S, Tapp M, Milne EJ, Pavlov CS, Davidson BR, Tsochatzis E, Gurusamy KS. Secondary prevention of variceal bleeding in adults with previous oesophageal variceal bleeding due to decompensated liver cirrhosis: a network meta-analysis. Cochrane Database Syst Rev 2021; 3:CD013122. [PMID: 33784794 PMCID: PMC8094621 DOI: 10.1002/14651858.cd013122.pub2] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND Approximately 40% to 95% of people with cirrhosis have oesophageal varices. About 15% to 20% of oesophageal varices bleed in about one to three years of diagnosis. Several different treatments are available, which include endoscopic sclerotherapy, variceal band ligation, beta-blockers, transjugular intrahepatic portosystemic shunt (TIPS), and surgical portocaval shunts, among others. However, there is uncertainty surrounding their individual and relative benefits and harms. OBJECTIVES To compare the benefits and harms of different initial treatments for secondary prevention of variceal bleeding in adults with previous oesophageal variceal bleeding due to decompensated liver cirrhosis through a network meta-analysis and to generate rankings of the different treatments for secondary prevention according to their safety and efficacy. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers until December 2019 to identify randomised clinical trials in people with cirrhosis and a previous history of bleeding from oesophageal varices. SELECTION CRITERIA We included only randomised clinical trials (irrespective of language, blinding, or status) in adults with cirrhosis and previous history of bleeding from oesophageal varices. We excluded randomised clinical trials in which participants had no previous history of bleeding from oesophageal varices, previous history of bleeding only from gastric varices, those who failed previous treatment (refractory bleeding), those who had acute bleeding at the time of treatment, and those who had previously undergone liver transplantation. DATA COLLECTION AND ANALYSIS We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the differences in treatments using hazard ratios (HR), odds ratios (OR) and rate ratios with 95% credible intervals (CrI) based on an available-case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance. MAIN RESULTS We included a total of 48 randomised clinical trials (3526 participants) in the review. Forty-six trials (3442 participants) were included in one or more comparisons. The trials that provided the information included people with cirrhosis due to varied aetiologies. The follow-up ranged from two months to 61 months. All the trials were at high risk of bias. A total of 12 interventions were compared in these trials (sclerotherapy, beta-blockers, variceal band ligation, beta-blockers plus sclerotherapy, no active intervention, TIPS (transjugular intrahepatic portosystemic shunt), beta-blockers plus nitrates, portocaval shunt, sclerotherapy plus variceal band ligation, beta-blockers plus nitrates plus variceal band ligation, beta-blockers plus variceal band ligation, sclerotherapy plus nitrates). Overall, 22.5% of the trial participants who received the reference treatment (chosen because this was the commonest treatment compared in the trials) of sclerotherapy died during the follow-up period ranging from two months to 61 months. There was considerable uncertainty in the effects of interventions on mortality. Accordingly, none of the interventions showed superiority over another. None of the trials reported health-related quality of life. Based on low-certainty evidence, variceal band ligation may result in fewer serious adverse events (number of people) than sclerotherapy (OR 0.19; 95% CrI 0.06 to 0.54; 1 trial; 100 participants). Based on low or very low-certainty evidence, the adverse events (number of participants) and adverse events (number of events) may be different across many comparisons; however, these differences are due to very small trials at high risk of bias showing large differences in some comparisons leading to many differences despite absence of direct evidence. Based on low-certainty evidence, TIPS may result in large decrease in symptomatic rebleed than variceal band ligation (HR 0.12; 95% CrI 0.03 to 0.41; 1 trial; 58 participants). Based on moderate-certainty evidence, any variceal rebleed was probably lower in sclerotherapy than in no active intervention (HR 0.62; 95% CrI 0.35 to 0.99, direct comparison HR 0.66; 95% CrI 0.11 to 3.13; 3 trials; 296 participants), beta-blockers plus sclerotherapy than sclerotherapy alone (HR 0.60; 95% CrI 0.37 to 0.95; direct comparison HR 0.50; 95% CrI 0.07 to 2.96; 4 trials; 231 participants); TIPS than sclerotherapy (HR 0.18; 95% CrI 0.08 to 0.38; direct comparison HR 0.22; 95% CrI 0.01 to 7.51; 2 trials; 109 participants), and in portocaval shunt than sclerotherapy (HR 0.21; 95% CrI 0.05 to 0.77; no direct comparison) groups. Based on low-certainty evidence, beta-blockers alone and TIPS might result in more, other compensation, events than sclerotherapy (rate ratio 2.37; 95% CrI 1.35 to 4.67; 1 trial; 65 participants and rate ratio 2.30; 95% CrI 1.20 to 4.65; 2 trials; 109 participants; low-certainty evidence). The evidence indicates considerable uncertainty about the effect of the interventions including those related to beta-blockers plus variceal band ligation in the remaining comparisons. AUTHORS' CONCLUSIONS The evidence indicates considerable uncertainty about the effect of the interventions on mortality. Variceal band ligation might result in fewer serious adverse events than sclerotherapy. TIPS might result in a large decrease in symptomatic rebleed than variceal band ligation. Sclerotherapy probably results in fewer 'any' variceal rebleeding than no active intervention. Beta-blockers plus sclerotherapy and TIPS probably result in fewer 'any' variceal rebleeding than sclerotherapy. Beta-blockers alone and TIPS might result in more other compensation events than sclerotherapy. The evidence indicates considerable uncertainty about the effect of the interventions in the remaining comparisons. Accordingly, high-quality randomised comparative clinical trials are needed.
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Affiliation(s)
| | - Lawrence Mj Best
- Division of Surgery and Interventional Science, University College London, London, UK
- Department of Therapy, I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Suzanne C Freeman
- Department of Health Sciences, University of Leicester, Leicester, UK
| | - Danielle Roberts
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Nicola J Cooper
- Department of Health Sciences, University of Leicester, Leicester, UK
| | - Alex J Sutton
- Department of Health Sciences, University of Leicester, Leicester, UK
| | - Davide Roccarina
- Sheila Sherlock Liver Centre, Royal Free Hospital and the UCL Institute of Liver and Digestive Health, London, UK
| | - Amine Benmassaoud
- Sheila Sherlock Liver Centre, Royal Free Hospital and the UCL Institute of Liver and Digestive Health, London, UK
| | - Laura Iogna Prat
- Sheila Sherlock Liver Centre, Royal Free Hospital and the UCL Institute of Liver and Digestive Health, London, UK
| | - Norman R Williams
- Surgical & Interventional Trials Unit (SITU), UCL Division of Surgery & Interventional Science, London, UK
| | - Mario Csenar
- Division of Surgery and Interventional Science, University College London, London, UK
| | | | | | - Sivapatham Arunan
- General and Colorectal Surgery, Ealing Hospital and Imperial College, London, Northwood, UK
| | | | | | - Chavdar S Pavlov
- Department of Therapy, I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Brian R Davidson
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Emmanuel Tsochatzis
- Sheila Sherlock Liver Centre, Royal Free Hospital and the UCL Institute of Liver and Digestive Health, London, UK
| | - Kurinchi Selvan Gurusamy
- Division of Surgery and Interventional Science, University College London, London, UK
- Department of Therapy, I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
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Matyas C, Haskó G, Liaudet L, Trojnar E, Pacher P. Interplay of cardiovascular mediators, oxidative stress and inflammation in liver disease and its complications. Nat Rev Cardiol 2021; 18:117-135. [PMID: 32999450 DOI: 10.1038/s41569-020-0433-5] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/11/2020] [Indexed: 12/11/2022]
Abstract
The liver is a crucial metabolic organ that has a key role in maintaining immune and endocrine homeostasis. Accumulating evidence suggests that chronic liver disease might promote the development of various cardiac disorders (such as arrhythmias and cardiomyopathy) and circulatory complications (including systemic, splanchnic and pulmonary complications), which can eventually culminate in clinical conditions ranging from portal and pulmonary hypertension to pulmonary, cardiac and renal failure, ascites and encephalopathy. Liver diseases can affect cardiovascular function during the early stages of disease progression. The development of cardiovascular diseases in patients with chronic liver failure is associated with increased morbidity and mortality, and cardiovascular complications can in turn affect liver function and liver disease progression. Furthermore, numerous infectious, inflammatory, metabolic and genetic diseases, as well as alcohol abuse can also influence both hepatic and cardiovascular outcomes. In this Review, we highlight how chronic liver diseases and associated cardiovascular effects can influence different organ pathologies. Furthermore, we explore the potential roles of inflammation, oxidative stress, vasoactive mediator imbalance, dysregulated endocannabinoid and autonomic nervous systems and endothelial dysfunction in mediating the complex interplay between the liver and the systemic vasculature that results in the development of the extrahepatic complications of chronic liver disease. The roles of ageing, sex, the gut microbiome and organ transplantation in this complex interplay are also discussed.
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Affiliation(s)
- Csaba Matyas
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD, USA
| | - György Haskó
- Department of Anesthesiology, Columbia University, New York, NY, USA
| | - Lucas Liaudet
- Department of Intensive Care Medicine and Burn Center, University Hospital Medical Center, Faculty of Biology and Medicine, Lausanne, Switzerland
| | - Eszter Trojnar
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD, USA
| | - Pal Pacher
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD, USA.
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ASSESSMENT OF THE FREQUENCY AND RATIONALITY OF PRESCRIBED MEDICINES IN PATIENTS WITH LIVER CIRRHOSIS. EUREKA: HEALTH SCIENCES 2021. [DOI: 10.21303/2504-5679.2021.001599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The aim. Assessment of the dynamics of prescribing drugs to patients with liver cirrhosis (LC, K 74), in terms of real clinical practice by methods of clinical and economic analysis.
Materials and methods. 355 medical cards of inpatients with cirrhosis of the liver, which were divided into 4 groups depending on the period of stay of patients in the hospital. Methods: compatible retrospective ABC-frequency analysis, which ranked drugs consumed by patients in real clinical practice, according to the frequency of appointment using ABC-segmentation according to the Pareto principle (A – 80 % of drugs appointments: B – 15 %: C – 5 %); VEN-analysis, which divides the consumed drugs on a formal basis depending on the presence / absence of a particular drug in the regulations: vital (Vital or V), necessary (Essential or E) and secondary (Non-essential or N).
Results. Cirrhosis of the liver in recent years has been on the 10th - 11th place among the causes of death in the world. The analysis of prescribed drugs to patients with LC in real clinical practice in Ivano-Frankivsk region of Ukraine revealed that over the years doctors prescribed fewer drugs on average per patient (11.4 drugs → 8.8 drugs), which can be considered a positive fact. Among the prescribed drugs, drugs of group A – “Drugs that affect the digestive system and metabolism” prevailed, the share of which increased and was the highest in 2019 – 2020 (2007–2009 – 44.6 %; 2012–2013 – 46.6 %; 2015–2016 – 48.1 %; 2019–2020 – 48.55 %); the share of dietary supplements also increased from 1.65 % to 6.52 %.
Conclusions. Combined ABC-frequency and VEN-analyzes showed that the leaders in the years of hospital stay were the following drugs: Sodium chloride, Ademetionine, Pantoprazole, Spironolactone, Thioctic acid, Ornithine, Asparaginate K-Mg, Torasemide, Furosemide. However, the vital class V included only 9–11 % of drugs from the whole set of prescribed drugs, which requires systemic correction in accordance with European recommendations.
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Chou YT, Liu TT, Yang UC, Huang CC, Liu CW, Huang SF, Li TH, Liu HM, Lin MW, Yang YY, Lee TY, Huang YH, Hou MC, Lin HC. Intestinal SIRT1 Deficiency-Related Intestinal Inflammation and Dysbiosis Aggravate TNFα-Mediated Renal Dysfunction in Cirrhotic Ascitic Mice. Int J Mol Sci 2021; 22:ijms22031233. [PMID: 33513830 PMCID: PMC7865325 DOI: 10.3390/ijms22031233] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 01/21/2021] [Accepted: 01/22/2021] [Indexed: 12/14/2022] Open
Abstract
In advanced cirrhosis, the TNFα-mediated intestinal inflammation and bacteria dysbiosis are involved in the development of inflammation and vasoconstriction-related renal dysfunction. In colitis and acute kidney injury models, activation of SIRT1 attenuates the TNFα-mediated intestinal and renal abnormalities. This study explores the impacts of intestinal SIRT1 deficiency and TNFα-mediated intestinal abnormalities on the development of cirrhosis-related renal dysfunction. Systemic and renal hemodynamics, intestinal dysbiosis [cirrhosis dysbiosis ratio (CDR) as marker of dysbiosis], and direct renal vasoconstrictive response (renal vascular resistance (RVR) and glomerular filtration rate (GFR)) to cumulative doses of TNFα were measured in bile duct ligated (BDL)-cirrhotic ascitic mice. In SIRT1IEC-KO-BDL-ascitic mice, the worsening of intestinal dysbiosis exacerbates intestinal inflammation/barrier dysfunction, the upregulation of the expressions of intestinal/renal TNFα-related pathogenic signals, higher TNFα-induced increase in RVR, and decrease in GFR in perfused kidney. In intestinal SIRT1 knockout groups, the positive correlations were identified between intestinal SIRT1 activity and CDR. Particularly, the negative correlations were identified between CDR and RVR, with the positive correlation between CDR and GFR. In mice with advanced cirrhosis, the expression of intestinal SIRT1 is involved in the linkage between intestinal dysbiosis and vasoconstriction/hypoperfusion-related renal dysfunction through the crosstalk between intestinal/renal TNFα-related pathogenic inflammatory signals.
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Affiliation(s)
- Yu-Te Chou
- Department of Medicine, Taipei Veterans General Hospital, Taipei 11267, Taiwan; (Y.-T.C.); (C.-W.L.); (Y.-H.H.); (M.-C.H.)
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11267, Taiwan; (T.-T.L.); (U.-C.Y.); (C.-C.H.); (S.-F.H.); (T.-H.L.); (M.-W.L.)
| | - Tze-Tze Liu
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11267, Taiwan; (T.-T.L.); (U.-C.Y.); (C.-C.H.); (S.-F.H.); (T.-H.L.); (M.-W.L.)
- Genomic Research Center, National Yang Ming Chiao Tung University, Taipei 11267, Taiwan
| | - Ueng-Cheng Yang
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11267, Taiwan; (T.-T.L.); (U.-C.Y.); (C.-C.H.); (S.-F.H.); (T.-H.L.); (M.-W.L.)
- Institute of Biomedical Informatics, Taipei 11267, Taiwan
| | - Chia-Chang Huang
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11267, Taiwan; (T.-T.L.); (U.-C.Y.); (C.-C.H.); (S.-F.H.); (T.-H.L.); (M.-W.L.)
- Division of Clinical Skills Training Center, Department of Medical Education, Taipei Veterans General Hospital, Taipei 112, Taiwan
- Institute of Clinical Medicine, National Yang-Ming University, Taipei 11267, Taiwan
| | - Chih-Wei Liu
- Department of Medicine, Taipei Veterans General Hospital, Taipei 11267, Taiwan; (Y.-T.C.); (C.-W.L.); (Y.-H.H.); (M.-C.H.)
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11267, Taiwan; (T.-T.L.); (U.-C.Y.); (C.-C.H.); (S.-F.H.); (T.-H.L.); (M.-W.L.)
- Institute of Clinical Medicine, National Yang-Ming University, Taipei 11267, Taiwan
| | - Shiang-Fen Huang
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11267, Taiwan; (T.-T.L.); (U.-C.Y.); (C.-C.H.); (S.-F.H.); (T.-H.L.); (M.-W.L.)
- Division of Infection, Taipei Veterans General Hospital, Taipei 11267, Taiwan
| | - Tzu-Hao Li
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11267, Taiwan; (T.-T.L.); (U.-C.Y.); (C.-C.H.); (S.-F.H.); (T.-H.L.); (M.-W.L.)
- Institute of Clinical Medicine, National Yang-Ming University, Taipei 11267, Taiwan
- Division of Allergy, Immunology, and Rheumatology, Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 11267, Taiwan
| | - Hsuan-Miao Liu
- Graduate Institute of Traditional Chinese Medicine, Chang Guang Memorial Hospital, Linkou 33371, Taiwan; (H.-M.L.); (T.-Y.L.)
| | - Ming-Wei Lin
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11267, Taiwan; (T.-T.L.); (U.-C.Y.); (C.-C.H.); (S.-F.H.); (T.-H.L.); (M.-W.L.)
- Institute of Public Health, National Yang-Ming University, Taipei 11267, Taiwan
| | - Ying-Ying Yang
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11267, Taiwan; (T.-T.L.); (U.-C.Y.); (C.-C.H.); (S.-F.H.); (T.-H.L.); (M.-W.L.)
- Division of Clinical Skills Training Center, Department of Medical Education, Taipei Veterans General Hospital, Taipei 112, Taiwan
- Institute of Clinical Medicine, National Yang-Ming University, Taipei 11267, Taiwan
- Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei 11267, Taiwan
- Correspondence: (Y.-Y.Y.); (H.-C.L.); Tel.: +886-2-2875-7725 (Y.-Y.Y.); +886-2-2875-2249 (H.-C.L.); Fax: +886-2-2875-7726 (Y.-Y.Y.); +886-2-2875-7809 (H.-C.L.)
| | - Tzung-Yan Lee
- Graduate Institute of Traditional Chinese Medicine, Chang Guang Memorial Hospital, Linkou 33371, Taiwan; (H.-M.L.); (T.-Y.L.)
| | - Yi-Hsiang Huang
- Department of Medicine, Taipei Veterans General Hospital, Taipei 11267, Taiwan; (Y.-T.C.); (C.-W.L.); (Y.-H.H.); (M.-C.H.)
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11267, Taiwan; (T.-T.L.); (U.-C.Y.); (C.-C.H.); (S.-F.H.); (T.-H.L.); (M.-W.L.)
- Institute of Public Health, National Yang-Ming University, Taipei 11267, Taiwan
- Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei 11267, Taiwan
| | - Ming-Chih Hou
- Department of Medicine, Taipei Veterans General Hospital, Taipei 11267, Taiwan; (Y.-T.C.); (C.-W.L.); (Y.-H.H.); (M.-C.H.)
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11267, Taiwan; (T.-T.L.); (U.-C.Y.); (C.-C.H.); (S.-F.H.); (T.-H.L.); (M.-W.L.)
| | - Han-Chieh Lin
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11267, Taiwan; (T.-T.L.); (U.-C.Y.); (C.-C.H.); (S.-F.H.); (T.-H.L.); (M.-W.L.)
- Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei 11267, Taiwan
- Correspondence: (Y.-Y.Y.); (H.-C.L.); Tel.: +886-2-2875-7725 (Y.-Y.Y.); +886-2-2875-2249 (H.-C.L.); Fax: +886-2-2875-7726 (Y.-Y.Y.); +886-2-2875-7809 (H.-C.L.)
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Zaccherini G, Tufoni M, Bernardi M. Albumin Administration is Efficacious in the Management of Patients with Cirrhosis: A Systematic Review of the Literature. Hepat Med 2020; 12:153-172. [PMID: 33149707 PMCID: PMC7602890 DOI: 10.2147/hmer.s264231] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Accepted: 09/18/2020] [Indexed: 12/15/2022] Open
Abstract
The use of albumin in patients with cirrhosis has been extensively discussed over recent years. Current treatment approaches depend on targeting related complications, aiming to treat and/or prevent circulatory dysfunction, bacterial infections and multi-organ failure. Albumin has been shown to prolong survival and reduce complications in patients with cirrhosis. This review aims to ascertain whether the use of albumin is justified in patients with cirrhosis. A systematic review of randomized controlled trials (RCTs) and meta-analyses evaluating albumin use in patients with cirrhosis published between 1985 and February 2020 was conducted; the quality and risk of bias of the included studies were assessed. In total, 45 RCTs and 10 meta-analyses were included. Based on the included evidence, albumin is superior at preventing and controlling the incidence of cirrhosis complications vs other plasma expanders. Recent studies reported that long-term albumin administration to patients with decompensated cirrhosis improves survival with a 38% reduction in the mortality hazard ratio compared with standard medical treatment alone. Albumin infusions are justified for routine use in patients with cirrhosis, and the use of albumin either alone or in combination with other treatments leads to clinical benefits. Long-term administration of albumin should be considered in some patients.
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Affiliation(s)
- Giacomo Zaccherini
- Department of Medical and Surgical Sciences, Alma Mater Studiorum - University of Bologna, Bologna 40138, Italy
| | - Manuel Tufoni
- Department of Medical and Surgical Sciences, Alma Mater Studiorum - University of Bologna, Bologna 40138, Italy
| | - Mauro Bernardi
- Department of Medical and Surgical Sciences, Alma Mater Studiorum - University of Bologna, Bologna 40138, Italy
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Benmassaoud A, Freeman SC, Roccarina D, Plaz Torres MC, Sutton AJ, Cooper NJ, Iogna Prat L, Cowlin M, Milne EJ, Hawkins N, Davidson BR, Pavlov CS, Thorburn D, Tsochatzis E, Gurusamy KS, Cochrane Hepato‐Biliary Group. Treatment for ascites in adults with decompensated liver cirrhosis: a network meta-analysis. Cochrane Database Syst Rev 2020; 1:CD013123. [PMID: 31978257 PMCID: PMC6984622 DOI: 10.1002/14651858.cd013123.pub2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Approximately 20% of people with cirrhosis develop ascites. Several different treatments are available; including, among others, paracentesis plus fluid replacement, transjugular intrahepatic portosystemic shunts, aldosterone antagonists, and loop diuretics. However, there is uncertainty surrounding their relative efficacy. OBJECTIVES To compare the benefits and harms of different treatments for ascites in people with decompensated liver cirrhosis through a network meta-analysis and to generate rankings of the different treatments for ascites according to their safety and efficacy. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers until May 2019 to identify randomised clinical trials in people with cirrhosis and ascites. SELECTION CRITERIA We included only randomised clinical trials (irrespective of language, blinding, or status) in adults with cirrhosis and ascites. We excluded randomised clinical trials in which participants had previously undergone liver transplantation. DATA COLLECTION AND ANALYSIS We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the odds ratio, rate ratio, and hazard ratio (HR) with 95% credible intervals (CrI) based on an available-case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance. MAIN RESULTS We included a total of 49 randomised clinical trials (3521 participants) in the review. Forty-two trials (2870 participants) were included in one or more outcomes in the review. The trials that provided the information included people with cirrhosis due to varied aetiologies, without other features of decompensation, having mainly grade 3 (severe), recurrent, or refractory ascites. The follow-up in the trials ranged from 0.1 to 84 months. All the trials were at high risk of bias, and the overall certainty of evidence was low or very low. Approximately 36.8% of participants who received paracentesis plus fluid replacement (reference group, the current standard treatment) died within 11 months. There was no evidence of differences in mortality, adverse events, or liver transplantation in people receiving different interventions compared to paracentesis plus fluid replacement (very low-certainty evidence). Resolution of ascites at maximal follow-up was higher with transjugular intrahepatic portosystemic shunt (HR 9.44; 95% CrI 1.93 to 62.68) and adding aldosterone antagonists to paracentesis plus fluid replacement (HR 30.63; 95% CrI 5.06 to 692.98) compared to paracentesis plus fluid replacement (very low-certainty evidence). Aldosterone antagonists plus loop diuretics had a higher rate of other decompensation events such as hepatic encephalopathy, hepatorenal syndrome, and variceal bleeding compared to paracentesis plus fluid replacement (rate ratio 2.04; 95% CrI 1.37 to 3.10) (very low-certainty evidence). None of the trials using paracentesis plus fluid replacement reported health-related quality of life or symptomatic recovery from ascites. FUNDING the source of funding for four trials were industries which would benefit from the results of the study; 24 trials received no additional funding or were funded by neutral organisations; and the source of funding for the remaining 21 trials was unclear. AUTHORS' CONCLUSIONS Based on very low-certainty evidence, there is considerable uncertainty about whether interventions for ascites in people with decompensated liver cirrhosis decrease mortality, adverse events, or liver transplantation compared to paracentesis plus fluid replacement in people with decompensated liver cirrhosis and ascites. Based on very low-certainty evidence, transjugular intrahepatic portosystemic shunt and adding aldosterone antagonists to paracentesis plus fluid replacement may increase the resolution of ascites compared to paracentesis plus fluid replacement. Based on very low-certainty evidence, aldosterone antagonists plus loop diuretics may increase the decompensation rate compared to paracentesis plus fluid replacement.
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Affiliation(s)
- Amine Benmassaoud
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentreLondonUK
| | - Suzanne C Freeman
- University of LeicesterDepartment of Health SciencesUniversity RoadLeicesterUKLE1 7RH
| | - Davide Roccarina
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentreLondonUK
| | | | - Alex J Sutton
- University of LeicesterDepartment of Health SciencesUniversity RoadLeicesterUKLE1 7RH
| | - Nicola J Cooper
- University of LeicesterDepartment of Health SciencesUniversity RoadLeicesterUKLE1 7RH
| | - Laura Iogna Prat
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentreLondonUK
| | | | | | - Neil Hawkins
- University of GlasgowHEHTAUniversity Ave Glasgow G12 8QQGlasgowUK
| | - Brian R Davidson
- University College LondonDivision of Surgery and Interventional ScienceLondonUKNW3 2QG
| | - Chavdar S Pavlov
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalCochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
- 'Sechenov' First Moscow State Medical UniversityCenter for Evidence‐Based MedicinePogodinskja st. 1\1MoscowRussian Federation119881
| | - Douglas Thorburn
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentreLondonUK
| | - Emmanuel Tsochatzis
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentreLondonUK
| | - Kurinchi Selvan Gurusamy
- University College LondonDivision of Surgery and Interventional ScienceLondonUKNW3 2QG
- 'Sechenov' First Moscow State Medical UniversityCenter for Evidence‐Based MedicinePogodinskja st. 1\1MoscowRussian Federation119881
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Komolafe O, Roberts D, Freeman SC, Wilson P, Sutton AJ, Cooper NJ, Pavlov CS, Milne EJ, Hawkins N, Cowlin M, Thorburn D, Davidson BR, Tsochatzis E, Gurusamy KS, Cochrane Hepato‐Biliary Group. Antibiotic prophylaxis to prevent spontaneous bacterial peritonitis in people with liver cirrhosis: a network meta-analysis. Cochrane Database Syst Rev 2020; 1:CD013125. [PMID: 31978256 PMCID: PMC6984637 DOI: 10.1002/14651858.cd013125.pub2] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Approximately 2.5% of all hospitalisations in people with liver cirrhosis are for spontaneous bacterial peritonitis. Spontaneous bacterial peritonitis is associated with significant short-term mortality; therefore, it is important to prevent spontaneous bacterial peritonitis in people at high risk of developing it. Antibiotic prophylaxis forms the mainstay preventive method, but this has to be balanced against the development of drug-resistant spontaneous bacterial peritonitis, which is difficult to treat, and other adverse events. Several different prophylactic antibiotic treatments are available; however, there is uncertainty surrounding their relative efficacy and optimal combination. OBJECTIVES To compare the benefits and harms of different prophylactic antibiotic treatments for prevention of spontaneous bacterial peritonitis in people with liver cirrhosis using a network meta-analysis and to generate rankings of the different prophylactic antibiotic treatments according to their safety and efficacy. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers to November 2018 to identify randomised clinical trials in people with cirrhosis at risk of developing spontaneous bacterial peritonitis. SELECTION CRITERIA We included only randomised clinical trials (irrespective of language, blinding, or status) in adults with cirrhosis undergoing prophylactic treatment to prevent spontaneous bacterial peritonitis. We excluded randomised clinical trials in which participants had previously undergone liver transplantation, or were receiving antibiotics for treatment of spontaneous bacterial peritonitis or other purposes. DATA COLLECTION AND ANALYSIS We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the odds ratio, rate ratio, and hazard ratio (HR) with 95% credible intervals (CrI) based on an available-case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance. MAIN RESULTS We included 29 randomised clinical trials (3896 participants; nine antibiotic regimens (ciprofloxacin, neomycin, norfloxacin, norfloxacin plus neomycin, norfloxacin plus rifaximin, rifaximin, rufloxacin, sparfloxacin, sulfamethoxazole plus trimethoprim), and 'no active intervention' in the review. Twenty-three trials (2587 participants) were included in one or more outcomes in the review. The trials that provided the information included people with cirrhosis due to varied aetiologies, with or without other features of decompensation, having ascites with low protein or previous history of spontaneous bacterial peritonitis. The follow-up in the trials ranged from 1 to 12 months. Many of the trials were at high risk of bias, and the overall certainty of evidence was low or very low. Overall, approximately 10% of trial participants developed spontaneous bacterial peritonitis and 15% of trial participants died. There was no evidence of differences between any of the antibiotics and no intervention in terms of mortality (very low certainty) or number of serious adverse events (very low certainty). However, because of the wide CrIs, clinically important differences in these outcomes cannot be ruled out. None of the trials reported health-related quality of life or the proportion of people with serious adverse events. There was no evidence of differences between any of the antibiotics and no intervention in terms of proportion of people with 'any adverse events' (very low certainty), liver transplantation (very low certainty), or the proportion of people who developed spontaneous bacterial peritonitis (very low certainty). The number of 'any' adverse events per participant was fewer with norfloxacin (rate ratio 0.74, 95% CrI 0.59 to 0.94; 4 trials, 546 participants; low certainty) and sulfamethoxazole plus trimethoprim (rate ratio 0.19, 95% CrI 0.02 to 0.81; 1 trial, 60 participants; low certainty) versus no active intervention. There was no evidence of differences between the other antibiotics and no intervention in the number of 'any' adverse events per participant (very low certainty). There were fewer other decompensation events with rifaximin versus no active intervention (rate ratio 0.61, 65% CrI 0.46 to 0.80; 3 trials, 575 participants; low certainty) and norfloxacin plus neomycin (rate ratio 0.06, 95% CrI 0.00 to 0.33; 1 trial, 22 participants; low certainty). There was no evidence of differences between the other antibiotics and no intervention in the number of decompensations events per participant (very low certainty). None of the trials reported health-related quality of life or development of symptomatic spontaneous bacterial peritonitis. One would expect some correlation between the above outcomes, with interventions demonstrating effectiveness across several outcomes. This was not the case. The possible reasons for this include sparse data and selective reporting bias, which makes the results unreliable. Therefore, one cannot draw any conclusions from these inconsistent differences based on sparse data. There was no evidence of any differences in the subgroup analyses (performed when possible) based on whether the prophylaxis was primary or secondary. FUNDING the source of funding for five trials were organisations who would benefit from the results of the study; six trials received no additional funding or were funded by neutral organisations; and the source of funding for the remaining 18 trials was unclear. AUTHORS' CONCLUSIONS Based on very low-certainty evidence, there is considerable uncertainty about whether antibiotic prophylaxis is beneficial, and if beneficial, which antibiotic prophylaxis is most beneficial in people with cirrhosis and ascites with low protein or history of spontaneous bacterial peritonitis. Future randomised clinical trials should be adequately powered, employ blinding, avoid postrandomisation dropouts (or perform intention-to-treat analysis), and use clinically important outcomes such as mortality, health-related quality of life, and decompensation events.
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Affiliation(s)
| | - Danielle Roberts
- University College LondonDivision of Surgery and Interventional ScienceLondonUKNW3 2PF
| | - Suzanne C Freeman
- University of LeicesterDepartment of Health SciencesUniversity RoadLeicesterUKLE1 7RH
| | - Peter Wilson
- University College London Hospitals NHS Foundation TrustClinical Microbiology and Virology5th Floor Central250 Euston RoadLondonUKNW1 2PG
| | - Alex J Sutton
- University of LeicesterDepartment of Health SciencesUniversity RoadLeicesterUKLE1 7RH
| | - Nicola J Cooper
- University of LeicesterDepartment of Health SciencesUniversity RoadLeicesterUKLE1 7RH
| | - Chavdar S Pavlov
- 'Sechenov' First Moscow State Medical UniversityCenter for Evidence‐Based MedicinePogodinskja st. 1\1MoscowRussian Federation119881
| | | | - Neil Hawkins
- University of GlasgowHEHTAUniversity Ave Glasgow G12 8QQGlasgowUK
| | | | - Douglas Thorburn
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentrePond StreetLondonUKNW3 2QG
| | - Brian R Davidson
- University College LondonDivision of Surgery and Interventional ScienceLondonUKNW3 2PF
| | - Emmanuel Tsochatzis
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentrePond StreetLondonUKNW3 2QG
| | - Kurinchi Selvan Gurusamy
- University College LondonDivision of Surgery and Interventional ScienceLondonUKNW3 2PF
- 'Sechenov' First Moscow State Medical UniversityCenter for Evidence‐Based MedicinePogodinskja st. 1\1MoscowRussian Federation119881
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Best LMJ, Leung J, Freeman SC, Sutton AJ, Cooper NJ, Milne EJ, Cowlin M, Payne A, Walshaw D, Thorburn D, Pavlov CS, Davidson BR, Tsochatzis E, Williams NR, Gurusamy KS, Cochrane Hepato‐Biliary Group. Induction immunosuppression in adults undergoing liver transplantation: a network meta-analysis. Cochrane Database Syst Rev 2020; 1:CD013203. [PMID: 31978255 PMCID: PMC6984652 DOI: 10.1002/14651858.cd013203.pub2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Liver transplantation is considered the definitive treatment for people with liver failure. As part of post-liver transplantation management, immunosuppression (suppressing the host immunity) is given to prevent graft rejections. Immunosuppressive drugs can be classified into those that are used for a short period during the beginning phase of immunosuppression (induction immunosuppression) and those that are used over the entire lifetime of the individual (maintenance immunosuppression), because it is widely believed that graft rejections are more common during the first few months after liver transplantation. Some drugs such as glucocorticosteroids may be used for both induction and maintenance immunosuppression because of their multiple modalities of action. There is considerable uncertainty as to whether induction immunosuppression is necessary and if so, the relative efficacy of different immunosuppressive agents. OBJECTIVES To assess the comparative benefits and harms of different induction immunosuppressive regimens in adults undergoing liver transplantation through a network meta-analysis and to generate rankings of the different induction immunosuppressive regimens according to their safety and efficacy. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers until July 2019 to identify randomised clinical trials in adults undergoing liver transplantation. SELECTION CRITERIA We included only randomised clinical trials (irrespective of language, blinding, or status) in adults undergoing liver transplantation. We excluded randomised clinical trials in which participants had multivisceral transplantation and those who already had graft rejections. DATA COLLECTION AND ANALYSIS We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the odds ratio (OR), rate ratio, and hazard ratio (HR) with 95% credible intervals (CrIs) based on an available case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance. MAIN RESULTS We included a total of 25 trials (3271 participants; 8 treatments) in the review. Twenty-three trials (3017 participants) were included in one or more outcomes in the review. The trials that provided the information included people undergoing primary liver transplantation for various indications and excluded those with HIV and those with renal impairment. The follow-up in the trials ranged from three to 76 months, with a median follow-up of 12 months among trials. All except one trial were at high risk of bias, and the overall certainty of evidence was very low. Overall, approximately 7.4% of people who received the standard regimen of glucocorticosteroid induction died and 12.2% developed graft failure. All-cause mortality and graft failure was lower with basiliximab compared with glucocorticosteroid induction: all-cause mortality (HR 0.53, 95% CrI 0.31 to 0.93; network estimate, based on 2 direct comparison trials (131 participants; low-certainty evidence)); and graft failure (HR 0.44, 95% CrI 0.28 to 0.70; direct estimate, based on 1 trial (47 participants; low-certainty evidence)). There was no evidence of differences in all-cause mortality and graft failure between other induction immunosuppressants and glucocorticosteroids in either the direct comparison or the network meta-analysis (very low-certainty evidence). There was also no evidence of differences in serious adverse events (proportion), serious adverse events (number), renal failure, any adverse events (proportion), any adverse events (number), liver retransplantation, graft rejections (any), or graft rejections (requiring treatment) between other induction immunosuppressants and glucocorticosteroids in either the direct comparison or the network meta-analysis (very low-certainty evidence). However, because of the wide CrIs, clinically important differences in these outcomes cannot be ruled out. None of the studies reported health-related quality of life. FUNDING the source of funding for 14 trials was drug companies who would benefit from the results of the study; two trials were funded by neutral organisations who have no vested interests in the results of the study; and the source of funding for the remaining nine trials was unclear. AUTHORS' CONCLUSIONS Based on low-certainty evidence, basiliximab induction may decrease mortality and graft failure compared to glucocorticosteroids induction in people undergoing liver transplantation. However, there is considerable uncertainty about this finding because this information is based on small trials at high risk of bias. The evidence is uncertain about the effects of different induction immunosuppressants on other clinical outcomes, including graft rejections. Future randomised clinical trials should be adequately powered, employ blinding, avoid post-randomisation dropouts (or perform intention-to-treat analysis), and use clinically important outcomes such as mortality, graft failure, and health-related quality of life.
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Affiliation(s)
- Lawrence MJ Best
- University College LondonDivision of Surgery and Interventional ScienceRowland Hill StreetLondonUKNW32PF
| | - Jeffrey Leung
- University College LondonMedical SchoolGower StreetLondonUKWC1H6BT
| | - Suzanne C Freeman
- University of LeicesterDepartment of Health SciencesUniversity RoadLeicesterUKLE1 7RH
| | - Alex J Sutton
- University of LeicesterDepartment of Health SciencesUniversity RoadLeicesterUKLE1 7RH
| | - Nicola J Cooper
- University of LeicesterDepartment of Health SciencesUniversity RoadLeicesterUKLE1 7RH
| | | | | | - Anna Payne
- Royal Free London NHS Foundation TrustHPB and Liver Transplant SurgeryPond StreetLondonGreater LondonUKNW3 2QG
| | - Dana Walshaw
- Barts and The London NHS TrustAcute MedicineLondonUK
| | - Douglas Thorburn
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentrePond StreetLondonUKNW3 2QG
| | - Chavdar S Pavlov
- 'Sechenov' First Moscow State Medical UniversityCenter for Evidence‐Based MedicinePogodinskja st. 1\1MoscowRussian Federation119881
| | - Brian R Davidson
- University College LondonDivision of Surgery and Interventional ScienceRowland Hill StreetLondonUKNW32PF
| | - Emmanuel Tsochatzis
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentrePond StreetLondonUKNW3 2QG
| | - Norman R Williams
- UCL Division of Surgery & Interventional ScienceSurgical & Interventional Trials Unit (SITU)3rd Floor, Charles Bell House 43 – 45Foley StreetLondonUKW1W 7TY
| | - Kurinchi Selvan Gurusamy
- University College LondonDivision of Surgery and Interventional ScienceRowland Hill StreetLondonUKNW32PF
- 'Sechenov' First Moscow State Medical UniversityCenter for Evidence‐Based MedicinePogodinskja st. 1\1MoscowRussian Federation119881
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Iogna Prat L, Wilson P, Freeman SC, Sutton AJ, Cooper NJ, Roccarina D, Benmassaoud A, Plaz Torres MC, Hawkins N, Cowlin M, Milne EJ, Thorburn D, Pavlov CS, Davidson BR, Tsochatzis E, Gurusamy KS, Cochrane Hepato‐Biliary Group. Antibiotic treatment for spontaneous bacterial peritonitis in people with decompensated liver cirrhosis: a network meta-analysis. Cochrane Database Syst Rev 2019; 9:CD013120. [PMID: 31524949 PMCID: PMC6746213 DOI: 10.1002/14651858.cd013120.pub2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Approximately 2.5% of all hospitalisations in people with cirrhosis are for spontaneous bacterial peritonitis (SBP). Antibiotics, in addition to supportive treatment (fluid and electrolyte balance, treatment of shock), form the mainstay treatments of SBP. Various antibiotics are available for the treatment of SBP, but there is uncertainty regarding the best antibiotic for SBP. OBJECTIVES To compare the benefits and harms of different antibiotic treatments for spontaneous bacterial peritonitis (SBP) in people with decompensated liver cirrhosis. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers until November 2018 to identify randomised clinical trials on people with cirrhosis and SBP. SELECTION CRITERIA We included only randomised clinical trials (irrespective of language, blinding, or publication status) in adults with cirrhosis and SBP. We excluded randomised clinical trials in which participants had previously undergone liver transplantation. DATA COLLECTION AND ANALYSIS Two review authors independently identified eligible trials and collected data. The outcomes for this review included mortality, serious adverse events, any adverse events, resolution of SBP, liver transplantation, and other decompensation events. We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the odds ratio, rate ratio, and hazard ratio with 95% credible intervals (CrIs) based on an available-case analysis, according to the National Institute of Health and Care Excellence (NICE) Decision Support Unit guidance. MAIN RESULTS We included a total of 12 trials (1278 participants; 13 antibiotics) in the review. Ten trials (893 participants) were included in one or more outcomes in the review. The trials that provided the information included patients having cirrhosis with or without other features of decompensation of varied aetiologies. The follow-up in the trials ranged from one week to three months. All the trials were at high risk of bias. Only one trial was included under each comparison for most of the outcomes. Because of these reasons, there is very low certainty in all the results. The majority of the randomised clinical trials used third-generation cephalosporins, such as intravenous ceftriaxone, cefotaxime, or ciprofloxacin as one of the interventions.Overall, approximately 75% of trial participants recovered from SBP and 25% of people died within three months. There was no evidence of difference in any of the outcomes for which network meta-analysis was possible: mortality (9 trials; 653 participants), proportion of people with any adverse events (5 trials; 297 participants), resolution of SBP (as per standard definition, 9 trials; 873 participants), or other features of decompensation (6 trials; 535 participants). The effect estimates in the direct comparisons (when available) were very similar to those of network meta-analysis. For the comparisons where network meta-analysis was not possible, there was no evidence of difference in any of the outcomes (proportion of participants with serious adverse events, number of adverse events, and proportion of participants requiring liver transplantation). Due to the wide CrIs and the very low-certainty evidence for all the outcomes, significant benefits or harms of antibiotics are possible.None of the trials reported health-related quality of life, number of serious adverse events, or symptomatic recovery from SBP. FUNDING the source of funding for two trials were industrial organisations who would benefit from the results of the trial; the source of funding for the remaining 10 trials was unclear. AUTHORS' CONCLUSIONS Short-term mortality after SBP is about 25%. There is significant uncertainty about which antibiotic therapy is better in people with SBP.We need adequately powered randomised clinical trials, with adequate blinding, avoiding post-randomisation dropouts (or performing intention-to-treat analysis), and using clinically important outcomes, such as mortality, health-related quality of life, and adverse events.
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Affiliation(s)
- Laura Iogna Prat
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentreLondonUK
| | - Peter Wilson
- University College London Hospitals NHS Foundation TrustClinical Microbiology and Virology5th Floor Central250 Euston RoadLondonUKNW1 2PG
| | - Suzanne C Freeman
- University of LeicesterDepartment of Health SciencesUniversity RoadLeicesterUKLE1 7RH
| | - Alex J Sutton
- University of LeicesterDepartment of Health SciencesUniversity RoadLeicesterUKLE1 7RH
| | - Nicola J Cooper
- University of LeicesterDepartment of Health SciencesUniversity RoadLeicesterUKLE1 7RH
| | - Davide Roccarina
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentreLondonUK
| | - Amine Benmassaoud
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentreLondonUK
| | | | - Neil Hawkins
- University of GlasgowHEHTAUniversity Ave Glasgow G12 8QQGlasgowUK
| | | | | | - Douglas Thorburn
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentreLondonUK
| | - Chavdar S Pavlov
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalCochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
- 'Sechenov' First Moscow State Medical UniversityCenter for Evidence‐Based MedicinePogodinskja st. 1\1MoscowRussian Federation119881
| | - Brian R Davidson
- University College LondonDivision of Surgery and Interventional ScienceLondonUKNW3 2QG
| | - Emmanuel Tsochatzis
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentreLondonUK
| | - Kurinchi Selvan Gurusamy
- 'Sechenov' First Moscow State Medical UniversityCenter for Evidence‐Based MedicinePogodinskja st. 1\1MoscowRussian Federation119881
- University College LondonDivision of Surgery and Interventional ScienceLondonUKNW3 2QG
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Best LMJ, Freeman SC, Sutton AJ, Cooper NJ, Tng E, Csenar M, Hawkins N, Pavlov CS, Davidson BR, Thorburn D, Cowlin M, Milne EJ, Tsochatzis E, Gurusamy KS, Cochrane Hepato‐Biliary Group. Treatment for hepatorenal syndrome in people with decompensated liver cirrhosis: a network meta-analysis. Cochrane Database Syst Rev 2019; 9:CD013103. [PMID: 31513287 PMCID: PMC6740336 DOI: 10.1002/14651858.cd013103.pub2] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Hepatorenal syndrome is defined as renal failure in people with cirrhosis in the absence of other causes. In addition to supportive treatment such as albumin to restore fluid balance, the other potential treatments include systemic vasoconstrictor drugs (such as vasopressin analogues or noradrenaline), renal vasodilator drugs (such as dopamine), transjugular intrahepatic portosystemic shunt (TIPS), and liver support with molecular adsorbent recirculating system (MARS). There is uncertainty over the best treatment regimen for hepatorenal syndrome. OBJECTIVES To compare the benefits and harms of different treatments for hepatorenal syndrome in people with decompensated liver cirrhosis. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trial registers until December 2018 to identify randomised clinical trials on hepatorenal syndrome in people with cirrhosis. SELECTION CRITERIA We included only randomised clinical trials (irrespective of language, blinding, or publication status) in adults with cirrhosis and hepatorenal syndrome. We excluded randomised clinical trials in which participants had previously undergone liver transplantation. DATA COLLECTION AND ANALYSIS Two authors independently identified eligible trials and collected data. The outcomes for this review included mortality, serious adverse events, any adverse events, resolution of hepatorenal syndrome, liver transplantation, and other decompensation events. We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the odds ratio (OR), rate ratio, hazard ratio (HR), and mean difference (MD) with 95% credible intervals (CrI) based on an available-case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance. MAIN RESULTS We included a total of 25 trials (1263 participants; 12 interventions) in the review. Twenty-three trials (1185 participants) were included in one or more outcomes. All the trials were at high risk of bias, and all the evidence was of low or very low certainty. The trials included participants with liver cirrhosis of varied aetiologies as well as a mixture of type I hepatorenal syndrome only, type II hepatorenal syndrome only, or people with both type I and type II hepatorenal syndrome. Participant age ranged from 42 to 60 years, and the proportion of females ranged from 5.8% to 61.5% in the trials that reported this information. The follow-up in the trials ranged from one week to six months. Overall, 59% of participants died during this period and about 35% of participants recovered from hepatorenal syndrome. The most common interventions compared were albumin plus terlipressin, albumin plus noradrenaline, and albumin alone.There was no evidence of a difference in mortality (22 trials; 1153 participants) at maximal follow-up between the different interventions. None of the trials reported health-related quality of life. There was no evidence of differences in the proportion of people with serious adverse events (three trials; 428 participants), number of participants with serious adverse events per participant (two trials; 166 participants), proportion of participants with any adverse events (four trials; 402 participants), the proportion of people who underwent liver transplantation at maximal follow-up (four trials; 342 participants), or other features of decompensation at maximal follow-up (one trial; 466 participants). Five trials (293 participants) reported number of any adverse events, and five trials (219 participants) reported treatment costs. Albumin plus noradrenaline had fewer numbers of adverse events per participant (rate ratio 0.51, 95% CrI 0.28 to 0.87). Eighteen trials (1047 participants) reported recovery from hepatorenal syndrome (as per definition of hepatorenal syndrome). In terms of recovery from hepatorenal syndrome, in the direct comparisons, albumin plus midodrine plus octreotide and albumin plus octreotide had lower recovery from hepatorenal syndrome than albumin plus terlipressin (HR 0.04; 95% CrI 0.00 to 0.25 and HR 0.26, 95% CrI 0.07 to 0.80 respectively). There was no evidence of differences between the groups in any of the other direct comparisons. In the network meta-analysis, albumin and albumin plus midodrine plus octreotide had lower recovery from hepatorenal syndrome compared with albumin plus terlipressin. FUNDING two trials were funded by pharmaceutical companies; five trials were funded by parties who had no vested interest in the results of the trial; and 18 trials did not report the source of funding. AUTHORS' CONCLUSIONS Based on very low-certainty evidence, there is no evidence of benefit or harm of any of the interventions for hepatorenal syndrome with regards to the following outcomes: all-cause mortality, serious adverse events (proportion), number of serious adverse events per participant, any adverse events (proportion), liver transplantation, or other decompensation events. Low-certainty evidence suggests that albumin plus noradrenaline had fewer 'any adverse events per participant' than albumin plus terlipressin. Low- or very low-certainty evidence also found that albumin plus midodrine plus octreotide and albumin alone had lower recovery from hepatorenal syndrome compared with albumin plus terlipressin.Future randomised clinical trials should be adequately powered; employ blinding, avoid post-randomisation dropouts or planned cross-overs (or perform an intention-to-treat analysis); and report clinically important outcomes such as mortality, health-related quality of life, adverse events, and recovery from hepatorenal syndrome. Albumin plus noradrenaline and albumin plus terlipressin appear to be the interventions that should be compared in future trials.
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Affiliation(s)
- Lawrence MJ Best
- University College LondonDivision of Surgery and Interventional ScienceRowland Hill StreetLondonUKNW32PF
| | - Suzanne C Freeman
- University of LeicesterDepartment of Health SciencesUniversity RoadLeicesterUKLE1 7RH
| | - Alex J Sutton
- University of LeicesterDepartment of Health SciencesUniversity RoadLeicesterUKLE1 7RH
| | - Nicola J Cooper
- University of LeicesterDepartment of Health SciencesUniversity RoadLeicesterUKLE1 7RH
| | - Eng‐Loon Tng
- Ng Teng Fong General Hospital National University Health SystemDepartment of Medicine1 Jurong East Street 21SingaporeSingapore609606
| | - Mario Csenar
- University College LondonDivision of Surgery and Interventional ScienceRowland Hill StreetLondonUKNW32PF
| | - Neil Hawkins
- University of GlasgowHEHTAUniversity Ave Glasgow G12 8QQGlasgowUK
| | - Chavdar S Pavlov
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalCochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
- 'Sechenov' First Moscow State Medical UniversityCenter for Evidence‐Based MedicinePogodinskja st. 1\1MoscowRussian Federation119881
| | - Brian R Davidson
- University College LondonDivision of Surgery and Interventional ScienceRowland Hill StreetLondonUKNW32PF
| | - Douglas Thorburn
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentrePond StreetLondonUKNW3 2QG
| | | | | | - Emmanuel Tsochatzis
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentrePond StreetLondonUKNW3 2QG
| | - Kurinchi Selvan Gurusamy
- University College LondonDivision of Surgery and Interventional ScienceRowland Hill StreetLondonUKNW32PF
- 'Sechenov' First Moscow State Medical UniversityCenter for Evidence‐Based MedicinePogodinskja st. 1\1MoscowRussian Federation119881
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