Parenclitic network mapping identifies response to targeted albumin therapy in patients hospitalized with decompensated cirrhosis
Clinical and translational gastroenterology. 2023
BACKGROUND The efficacy of targeted albumin therapy in the management of decompensatory events in cirrhosis is unclear with different reports showing conflicting results. It is possible that only certain subgroups of patients may benefit from targeted albumin administration. However, extensive conventional subgroup analyses have not yet identified these subgroups. Albumin is an important regulator of physiological networks and may interact with homeostatic mechanism differently in patients according to the integrity of their physiological network. In the present study we aimed to assess the value of network mapping in predicting response to targeted albumin therapy in patients with cirrhosis. METHOD This is a sub-study of the ATTIRE trial; a multicentre, randomized trial conducted to assess the effect of targeted albumin therapy in cirrhosis. Baseline serum bilirubin, albumin, sodium, creatinine, CRP, and white cell count (WCC), international normalised ratio, heart rate, and blood pressure of 777 patients followed up for 6 months were used for network mapping using parenclitic analysis. Parenclitic network analysis involves measuring the deviation of each individual patient from the existing network of physiological interactions in a reference population. RESULT Overall network connectivity as well as deviations along WCC-CRP axis predicted 6-month survival independent of age and model for end-stage liver disease (MELD) in the standard care arm. Patients with lower deviation along the WCC-CRP axis showed lower survival in response to targeted albumin administration over 6-month follow-up period. Likewise, patients with higher overall physiological connectivity survived significantly less than the standard care group following targeted albumin infusion. CONCLUSION The parenclitic network mapping can predict survival of patients with cirrhosis and identify patient subgroups that don't benefit from targeted albumin therapy.
The Efficacy and Safety of Intra-articular Low Molecular Weight Fraction of Human Serum Albumin for the Management of Moderate to Moderately Severe Knee Osteoarthritis: A Systematic Review and Meta-Analysis
Osteoarthritis is a chronic degenerative joint disease that affects weight-bearing joints. Low molecular weight fraction of 5% (LMWF-5A) human serum albumin is an intra-articular injection that emerged for the treatment of knee osteoarthritis. The aim of this review is to assess the efficacy and safety of LMWF-5A versus placebo through a systematic review and meta-analysis. The Cochrane Central Register of Controlled Trials (CENTRAL), Medical Literature Analysis and Retrieval System Online (MEDLINE), EBSCO, and ClinicalTrials.gov registry databases were utilized to search for studies. Only randomized controlled trials (RCTs) that evaluated the efficacy of LMWF-5A versus placebo were included. Efficacy endpoints were represented by Western Ontario and McMaster Universities Arthritis Index (WOMAC) A and C scores for pain and function, respectively. Serious adverse events (SAEs), non-serious adverse events (NSAEs), and mortality rates were used to evaluate the safety of the drug. The revised Cochrane risk of bias tool was used for the risk of bias assessment. Seven RCTs (n=2939) that met the inclusion criteria were included. The meta-analysis did not find significant improvement in pain (WOMAC A) (standardized mean difference (SMD)= -0.01, 95% confidence interval (CI) -0.10 - 0.09, P=0.87, I²=30%). Additionally, no significant change in function was noted (WOMAC C) (SMD=0.01, 95% CI -0.08 - 0.10, P=0.87, I²=22%). The pooled analysis did not find a significant difference between LMWF-5A and placebo regarding the incidence of joint swelling (P=0.84), joint stiffness (P=0.53), arthralgia (P=0.53), extremity pain (P=0.45), NSAEs (P=0.21), SAEs (P=0.92), or mortality (P=1.00). However, the subgroup analysis showed a significant reduction of 42% in NSAEs upon administration of 10 mL of LMWF-5A (risk ratio (RR)=0.58, 95% CI 0.35-0.97, P=0.04). In summary, our meta-analysis did not find significant differences between LMWF-5A and placebo regarding the incidence of NSAEs, SAEs, or mortality. On the other hand, LMWF-5A did not demonstrate superiority over saline in terms of efficacy. Therefore, it is not an effective drug for managing knee osteoarthritis.
Midodrine versus Albumin to Prevent Paracentesis Induced Circulatory Dysfunction in Acute on Chronic Liver Failure Patients in the Outpatient Clinic-a Randomized Controlled Trial
Journal of clinical and experimental hepatology. 2023;13(4):576-585
BACKGROUND Paracentesis-induced circulatory disturbance (PICD) occurs in 12-20% of patients receiving human albumin for large-volume paracentesis, and can occur at lower than five liter paracentesis in acute-on-chronic liver failure (ACLF). Albumin infusions are associated with higher costs and more prolonged daycare admissions. The aim of the study was to determine if oral midodrine-hydrochloride can prevent PICD in these patients by increasing the mean arterial pressure (MAP). METHODS This open-labeled randomized controlled trial included ACLF patients undergoing paracentesis between 3 and 5 L, who were randomized to receive either 20% human albumin or midodrine hydrochloride 7.5 mg thrice daily for three days, 2 h before paracentesis. MAP was recorded daily. The primary outcome was the plasma renin activity (PRA) on day six, and a 50% increase from baseline was considered PICD. RESULTS 183 consecutive patients of ACLF were screened, and 50 patients were randomized to either arms. Alcohol was the most common underlying cause of cirrhosis. On day 6, PRA was non-significantly (P = 0.056) higher in the midodrine group. The absolute change of PRA between the two groups was not significant (P = 0.093). Four (16%) patients in the albumin group and five (20%) in the midodrine group developed PICD. MAP increase was not different between the albumin and midodrine arms (P = 0.851). Midodrine was found to be more cost-effective. CONCLUSIONS Three days of oral midodrine is as effective as a human-albumin infusion in preventing PICD in ACLF patients undergoing paracentesis lesser than that done in large volume paracentesis.
Terlipressin in combination with albumin as a therapy for hepatorenal syndrome in patients aged 65 years or older
Annals of hepatology. 2023;28(5):101126
INTRODUCTION AND OBJECTIVES Clinical data for older patients with advanced liver disease are limited. This post hoc analysis evaluated the efficacy and safety of terlipressin in patients aged ≥65 years with hepatorenal syndrome using data from 3 Phase III, randomized, placebo-controlled studies (OT-0401, REVERSE, CONFIRM). PATIENTS AND METHODS The pooled population of patients aged ≥65 years (terlipressin, n = 54; placebo, n = 36) was evaluated for hepatorenal syndrome reversal-defined as a serum creatinine level ≤1.5 mg/dL (≤132.6 μmol/L) while receiving terlipressin or placebo, without renal replacement therapy, liver transplantation, or death-and the incidence of renal replacement therapy (RRT). Safety analyses included an assessment of adverse events. RESULTS Hepatorenal syndrome reversal was almost 2-times higher in terlipressin-treated patients compared with patients who received placebo (31.5% vs 16.7%; P = 0.143). Among surviving patients, the need for RRT was significantly reduced in the terlipressin group, with an almost 3-times lower incidence of RRT versus the placebo group (Day 90: 25.0% vs 70.6%; P = 0.005). Among 23 liver-transplant-listed patients, significantly fewer patients in the terlipressin versus placebo group needed RRT by Days 30 and 60 (P = 0.027 each). Fewer patients in the terlipressin group needed RRT post-transplant (P = 0.011). More terlipressin-treated patients who were listed for and received a liver transplant were alive and RRT-free by Day 90. No new safety signals were revealed in the older subpopulation compared with previously published data. CONCLUSIONS Terlipressin therapy may lead to clinical improvements in highly vulnerable patients aged ≥65 years with hepatorenal syndrome. CLINICAL TRIAL NUMBERS OT-0401, NCT00089570; REVERSE, NCT01143246; CONFIRM, NCT02770716.
Tolerance of standard dose albumin infused over 6 hrs for treatment of spontaneous bacterial peritonitis-A randomized controlled trial
Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology. 2023
BACKGROUND AND AIMS Twenty per cent albumin (1.5 g/kg at diagnosis and 1 g/kg on day three, infused over six-hour duration) is recommended particularly in high-risk spontaneous bacterial peritonitis (SBP). Whether reduced dose albumin infusion is as effective as the standard dose albumin infusion is not clear. The aim of this study was to compare standard dose albumin infusion with reduced dose albumin infusion in acute kidney injury (AKI) development or progression in patients with cirrhosis and high-risk SBP. METHODS Sixty-three patients were randomized to the standard dose albumin arm (n = 31) and reduced dose albumin arm (n = 32, 0.75 g/kg at diagnosis and 0.5 g/kg 48 h later). The albumin was infused over six-hour duration in both groups. When the patient developed respiratory distress, the albumin infusion was stopped and that dose (i.e. of day one or day three) was not restarted and no attempt was made to finish the whole dose of that day. However, the next dose was started at the pre-calculated infusion rate if there was no evidence of respiratory distress at the start of next infusion. RESULTS All 31 patients in standard dose and two (6.25%) in the reduced dose group developed symptomatic circulatory overload (p < 0.001), with infusions being stopped prematurely. The actual albumin dose received on day one was similar in both groups and only slightly higher in the standard dose group on day three. Resolution of SBP, progression of AKI to higher stage, in-hospital mortality and 28 days' mortality were similar in both groups. CONCLUSIONS For treatment of SBP, standard dose albumin infusion (1.5 g/kg at diagnosis and 1 g/kg 48 hours later) infused over six hours is not tolerated by Indian patients. The effectiveness of standard dose albumin infused over more prolonged periods, as compared to reduced dose albumin, should be evaluated in further studies. TRIAL REGISTRATION Clinical Trials.gov Identifier: NCT04273373 .
Human Albumin Infusion for the Management of Liver Cirrhosis and Its Complications: An Overview of Major Findings from Meta-analyses
Advances in therapy. 2023
INTRODUCTION The role of human albumin (HA) infusion in cirrhotic patients has been increasingly recognized. This paper aims to summarize the evidence from meta-analyses regarding HA infusion for the management of cirrhosis and its complications. METHODS A systematic search in the PubMed, EMBASE, and Cochrane library databases, and in reference lists was conducted. All relevant meta-analyses were identified and their findings were reviewed. The Assessment of Multiple Systematic Reviews 2 (AMSTAR-2) checklist was used to evaluate the methodological quality and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) system to assess the quality of evidence for significant outcomes. RESULTS Among 300 papers initially identified, 18 meta-analyses have been included. Short- and long-term HA infusion at high doses decreased the mortality of patients with decompensated cirrhosis. In cirrhotic patients with ascites, long-term HA infusion reduced the recurrence of ascites, but not mortality. In cirrhotic patients undergoing large-volume paracentesis (LVP), HA infusion reduced the incidence of post-paracentesis circulatory dysfunction and hyponatremia, but not mortality or renal impairment. In cirrhotic patients with overt hepatic encephalopathy (HE), HA infusion improved the severity of overt HE, but not overall mortality. In cirrhotic patients with spontaneous bacterial peritonitis (SBP), but not those with non-SBP infections, HA infusion reduced the mortality and renal impairment. In cirrhotic patients with type-1 hepatorenal syndrome (HRS), an increment of 100 g in cumulative HA dose increased 1.15-fold survival, but not HRS reversal. In these meta-analyses, the quality of methodology was low or critically low, and that of the evidence was from very low to moderate. CONCLUSIONS Based on the limited evidence from these meta-analyses, HA infusion appears to be beneficial in cirrhotic patients with ascites, overt HE, and SBP and in those undergoing LVP, but not in those with non-SBP infections.
Can albumin reduce the mortality of patients with cirrhosis and ascites? A meta-analysis of randomized controlled trials
European journal of gastroenterology & hepatology. 2022
BACKGROUND Albumin therapy in patients with decompensated liver cirrhosis has always been a controversial issue. This study aimed to investigate the efficacy and safety of albumin in reducing mortality and controlling complications in patients with liver cirrhosis and provide a reference for relevant decision-making. METHODS Databases such as PubMed, EMBASE, and Web of Science were searched to collect eligible articles published before January 2022, which were analyzed by Revman 5.3. RESULTS A total of 10 randomized controlled trials (2040 patients) were included. Based on the meta-analysis results, no significant difference in mortality was shown between the albumin administration group and the control group (HR = 1.01; 95% CI, 0.97-1.05; P = 0.62). Subgroup analysis showed that albumin administration had no significant short-term or long-term survival benefits in patients with decompensated liver cirrhosis and increased the risk of pulmonary edema adverse reactions (RR = 3.14; 95% CI, 1.48-6.65; P = 0.003). Subgroup analysis based on albumin administration time showed that short-term (HR = 0.93; 95% CI, 0.76-1.13; P = 0.47) or long-term (HR = 0.97; 95% CI: 0.87-1.08; P = 0.58) administration of albumin could not significantly reduce the mortality of patients with decompensated liver cirrhosis. In contrast, albumin administration could significantly reduce the recurrence rate of ascites (RR = 0.56; 95% CI, 0.46-0.68; P = 0.000). CONCLUSION Short-term(<1 month) or long-term (>1 month) administration of albumin can not significantly reduce the mortality of patients with decompensated liver cirrhosis, and a large amount of albumin infusion will increase the risk of pulmonary edema.
Efficacy of Intravenous Albumin for Spontaneous Bacterial Peritonitis Infection Among Patients With Cirrhosis: A Meta-Analysis of Randomized Control Trials
Albumin is an important component in the standard therapeutic approach to spontaneous bacterial peritonitis (SBP). This meta-analysis aimed to determine the impact of intravenous human albumin in patients with cirrhosis and SBP. This study was conducted according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Two reviewers independently searched relevant studies using electronic databases including PubMed, Embase and Cochrane Library from the date of database inception to October 2022. The outcomes assessed in the current meta-analysis include 30-day mortality, renal impairment, changes in serum creatinine levels (mg/dl) and resolution of bacterial infection. It was found that the risk of all-cause mortality and renal impairment was significantly lower in patients receiving albumin compared to the control group. However, no significant difference was reported between the two groups in relation to changes in mean creatinine levels and resolution of infection.
Extracorporeal Albumin Dialysis in Liver Failure with MARS and SPAD: A Randomized Crossover Trial
Blood Purification. 2022;51(3):243-250
INTRODUCTION Liver failure is associated with hepatic and extrahepatic organ failure leading to a high short-term mortality rate. Extracorporeal albumin dialysis (ECAD) aims to reduce albumin-bound toxins accumulated during liver failure. ECAD detoxifies blood using albumin dialysis through an artificial semipermeable membrane with recirculation (molecular adsorbent recirculating system, MARS) or without (single-pass albumin dialysis, SPAD). METHODS We performed a randomized crossover open trial in a surgical intensive care unit. The primary outcome of the study was total bilirubin reduction during MARS and during SPAD therapies. The secondary outcomes were conjugated bilirubin and bile acid level reduction during MARS and SPAD sessions and tolerance of dialysis system devices. Inclusion criteria were adult patients presenting liver failure with factor V activity <50% associated with bilirubin ≥250 μmol/L and a complication (either hepatic encephalopathy, severe pruritus, or hepatorenal syndrome). For MARS and SPAD, the dialysis flow rate was equal to 1,000 mL/h. RESULTS Twenty crossovers have been performed. Baseline biochemical characteristics (bilirubin, ammonia, bile acids, creatinine, and urea) were not statistically different between MARS and SPAD. Both ECAD have led to a significant reduction in total bilirubin (-83 ± 67 μmol/L after MARS; -122 ± 118 μmol/L after SPAD session), conjugated bilirubin (-82 ± 61 μmol/L after MARS; -105 ± 96 μmol/L after SPAD session), and bile acid levels (-64 ± 75 μmol/L after MARS; -56 ± 56 μmol/L after SPAD session), all nondifferent comparing MARS to SPAD. CONCLUSION A simple-to-perform SPAD therapy with equal to MARS dialysate flow parameters provides the same efficacy in bilirubin and bile acid removal. However, clinically relevant endpoints have to be evaluated in randomized trials to compare MARS and SPAD therapies and to define the place of SPAD in the liver failure care program.
A double-blind randomized placebo-controlled trial of albumin in patients with hepatic encephalopathy: HEAL study
Journal of hepatology. 2022
BACKGROUND AND AIMS Even after recovery from overt hepatic encephalopathy (HE), minimal HE (MHE), which impairs quality of life (QOL), can persist. Treatment options are limited. AIM: Determine the impact of albumin versus saline on MHE and QOL in patients with prior HE already on standard of care using double-blind, placebo-controlled randomized clinical trial. METHODS Outpatients with cirrhosis and prior HE, MHE and hypoalbuminemia already on HE-treatment were included. Patients on regular IV albumin infusions were excluded. Subjects were randomized 1:1 to receive either weekly infusions of 25% IV albumin 1.5g/kg or saline over 5 weeks (end-of-drug,EOD) and then 1-week post-infusion (end-of-study,EOS). MHE was defined using either Psychometric hepatic encephalopathy score (PHES), Stroop or Critical clicker frequency. MHE and QOL using Sickness Impact profile (SIP total, physical, psychosocial domain, higher=worse) and serum (inflammation, endothelial dysfunction, and ischemia-modified albumin IMA) were compared between baseline, EOD and EOS. RESULTS 48(24/group) subjects were randomized and were balanced at baseline, including HE-medication use. Adverse events were similar, with MELD and ammonia remaining stable between/within groups. Albumin levels increased and IMA decreased only in the albumin group at EOD and EOS vs baseline. PHES and Stroop MHE reversal and improvement was greater in albumin group at EOD and persisted at EOS. SIP total and psychosocial, but not physical domain improved in the albumin but not placebo group versus baseline at EOD and EOS along with significant reduction in IL-1β, and endothelial dysfunction markers. CONCLUSION In a double-blind, placebo controlled RCT of outpatients with cirrhosis, prior HE and current MHE, albumin infusions were associated with improved cognitive function and psychosocial quality of life likely through amelioration of endothelial dysfunction. LAY SUMMARY Patients who have liver cirrhosis often develop confusion that can result in difficulty thinking and processing information, which can negatively impact their quality of life. We performed a clinical trial of weekly injections of albumin (a protein normally made by the liver, and which is low in cirrhosis) and placebo in patients with cirrhosis and persistent brain problems and found that those who received albumin did better on their brain function and quality of life compared to those who received placebo. Albumin injections were also associated with reduction in inflammation and other blood factors that could potentially be a mechanism of this benefit.
Patients with hepatic encephalopathy enrolled in the HEAL study (n= 48).
Albumin (n= 24).
Saline (n= 24).
Adverse events were similar, with MELD and ammonia remaining stable between/within groups. Albumin levels increased and ischemia-modified albumin decreased only in the albumin group at end-of-drug and end-of-study vs. baseline. Psychometric hepatic encephalopathy score and Stroop minimal hepatic encephalopathy reversal and improvement was greater in albumin group at end-of-drug and persisted at end-of-study. Sickness impact profile total and psychosocial, but not physical domain improved in the albumin but not placebo group vs. baseline at end-of-drug and end-of-study along with significant reduction in IL-1β, and endothelial dysfunction markers.