-
1.
Low-dose continuous terlipressin infusion is effective and safer than intravenous bolus injections in reducing portal pressure and control of acute variceal bleeding
Arora V, Choudhary SP, Maiwall R, Vijayaraghavan R, Jindal A, Kumar G, Sarin SK
Hepatology international. 2022
-
-
-
Full text
-
Editor's Choice
Abstract
BACKGROUND AND AIMS Continuous infusion of terlipressin is better tolerated, and equally effective at lower doses than intravenous boluses in type 1 hepatorenal syndrome. This approach in cirrhosis patients with acute esophageal variceal bleed was investigated by comparing the efficacy and adverse events of continuous versus bolus administration of terlipressin. METHODS One hundred ten consecutive cirrhosis patients with acute esophageal variceal bleed (AEVB) were randomized to receive either terlipressin as bolus (BOL, n = 55), 2 mg every 4 h, or, continuous infusion (CONI, n = 55), 4 mg/24 h for 5 days. Hepatic venous pressure gradient (HVPG) was measured at baseline, 12 and 24 h and response to terlipressin was defined as > 10% decline from baseline. RESULTS Baseline demographics, model for end-stage liver disease (MELD) and HVPG were comparable between groups. The primary objective of HVPG response at 24 h was achieved in significantly more patients in CONI than BOL group {47/55(85.4%) vs. 32/55(58.2%), p = 0.002}. Early HVPG response at 12 h was also higher in CONI group (71.5 vs. 49.1%, p < 0.01). Median dose of terlipressin was significantly lower {4.25 ± 1.26 mg vs. 7.42 ± 1.42 mg/24 h, p < 0.001)} and adverse events were fewer {20/55(36.3%) vs. 31/55(56.4%), p = 0.03} in the CONI than BOL group. Significantly higher incidence of very early rebleed was noted in BOL group {8/55 (14.5%) vs. 1/55, (1.8%), p = 0.03}. Baseline HVPG (OR 1.90, 95% CI = 1.25-2.89, p = 0.002) and MELD (OR 1.18, 95% CI = 0.99-1.41, p = 0.05) were predictors of rebleed. CONCLUSION "HVPG-tailored" continuous terlipressin infusion is more effective than bolus administration in reducing HVPG at a lower dose with fewer adverse events in cirrhotic patients. CLINICAL TRIAL IDENTIFIER NCT02695862.
PICO Summary
Population
Patients with cirrhosis and acute esophageal variceal bleed (n= 110).
Intervention
Intravenous bolus injections of terlipressin (BOL group), (n= 55).
Comparison
Low-dose of continuous terlipressin infusion (CONI group), (n= 55).
Outcome
The primary objective of hepatic venous pressure gradient (HVPG) response at 24 hours was achieved in significantly more patients in CONI than BOL group (47/55 (85.4%) vs. 32/55 (58.2%)). Early HVPG response at 12 hours was also higher in CONI group (71.5 vs. 49.1%). Median dose of terlipressin was significantly lower (4.25 ± 1.26 mg vs. 7.42 ± 1.42 mg/24 h) and adverse events were fewer (20/55 (36.3%) vs. 31/55 (56.4%)) in the CONI than BOL group. Significantly higher incidence of very early rebleed was noted in BOL group (8/55 (14.5%) vs. 1/55, (1.8%)). Baseline HVPG (OR 1.90, 95% CI 1.25 to 2.89) and model for end-stage liver disease (OR 1.18, 95% CI 0.99 to 1.41) were predictors of rebleed.
-
2.
Standard-Volume Plasma Exchange Improves Outcomes in Patients With Acute Liver Failure: A Randomized Controlled Trial
Maiwall R, Bajpai M, Singh A, Agarwal T, Kumar G, Bharadwaj A, Nautiyal N, Tevethia H, Jagdish RK, Vijayaraghavan R, et al
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2022;20(4):e831-e854
-
-
-
-
Editor's Choice
Abstract
BACKGROUND High volume plasma-exchange (HVPE) improves survival in patients with acute liver failure (ALF), but apprehension regarding volume overload and worsening of cerebral edema remain. METHODS In an open-label randomized controlled trial, 40 consecutive patients of ALF were randomized 1:1 to either standard medical treatment (SMT) or SMT with standard-volume plasma-exchange (SVPE). SVPE was performed using centrifugal apheresis [target volume of 1.5 to 2.0 plasma volumes per session] until desired response was achieved. Cerebral edema was assessed by brain imaging. Results were analyzed in an intention-to-treat analysis. Primary outcome was 21-day transplant-free survival. The levels of cytokines, damage-associated molecular patterns (DAMPs) and endotoxins were analyzed at baseline and day 5. RESULTS ALF patients [aged 31.5 ± 12.2 years, 60% male, 78% viral, 83% hyperacute, 70% with SIRS were included. At day 5, SVPE [mean sessions 2.15 ± 1.42, median plasma volume replaced 5.049 L] compared to SMT alone, resulted in higher lactate clearance (p = .02), amelioration of SIRS (84% vs. 26%; P = .02), reduction in ammonia levels [(221.5 ± 96.9) vs.(439 ± 385.6) μg/dl, P = .02) and SOFA scores [9.9(±3.3) vs. 14.6(±4.8); P = .001]. There were no treatment related deaths. SVPE was associated with a higher 21-day transplant free-survival [75% vs. 45%; P = .04, HR 0.30, 95%CI 0.01-0.88]. A significant decrease in levels of pro-inflammatory cytokines and an increase in anti-inflammatory cytokines along with a decrease in endotoxin and DAMPs was seen with SVPE. CONCLUSION In ALF patients with cerebral edema, SVPE is safe and effective and improves survival possibly by a reduction in cytokine storm and ammonia. CLINICALTRIAL gov (identifier: NCT02718079).
PICO Summary
Population
Patients with acute liver failure (n= 40).
Intervention
Standard medical treatment with standard volume plasma exchange (SVPE), (n= 20).
Comparison
Standard medical treatment (n= 20).
Outcome
Compared to standard medical treatment alone, at day five SVPE resulted in higher lactate clearance, amelioration of systemic inflammatory response syndrome (84% vs. 26%), reduction in ammonia levels [(221.5 ± 96.9) vs. (439 ± 385.6) μg/dl] and sequential organ failure assessment scores [9.9(±3.3) vs. 14.6(±4.8)]. There were no treatment related deaths. SVPE was associated with a higher 21-day transplant free-survival (75% vs. 45%). A significant decrease in levels of pro-inflammatory cytokines and an increase in anti-inflammatory cytokines along with a decrease in endotoxin and damage-associated molecular patterns was seen with SVPE.
-
3.
A randomized-controlled trial comparing 20% albumin to plasmalyte in patients with cirrhosis and sepsis-induced hypotension [ALPS trial]
Maiwall R, Kumar A, Pasupuleti SSR, Hidam AK, Tevethia H, Kumar G, Sahney A, Mitra LG, Sarin SK
Journal of hepatology. 2022
Abstract
BACKGROUND AND AIM The choice of resuscitation fluid in cirrhosis patients with sepsis-induced hypotension (SIH) is unclear. 5% albumin has been superior to normal saline in the FRISC study. We compared the efficacy and safety of 20% albumin, which has greater oncotic properties with plasmalyte in reversing SIH. METHODS Critically-ill cirrhosis(CIC) patients underwent open-label randomization to receive either 20% albumin [0.5-1.0gm/kg over 3 hours; n=50] or plasmalyte (30ml/kg over 3 hours, n=50). The primary end-point of the study was the attainment of mean arterial pressure (MAP) above 65 mmHg at three hours. RESULTS Baseline characteristics were comparable in albumin and plasmalyte groups; arterial lactate(mmol/L) [6.16±3.18 vs. 6.38±4.77; p=0.78), MAP (mmHg) [51.4±6.52 vs. 49.9±4.45; p=0.17] and SOFA score [10.8±2.96 vs. 11.1±4.2; p=0.68] respectively. Most patients were alcoholics (39%) and had pneumonia (40%). In the intention-to-treat (ITT) analysis, albumin was superior to plasmalyte in achieving the primary end-point (62% vs. 22%; p<0.001). A rapid decline in arterial lactate (P=0.03), a lesser proportion of dialysis [48% vs. 62%; p=0.16], and a higher time to initiation of dialysis (in hours) [68.13±47.79 vs. 99.7± 63.4; p=0.06] was seen with albumin. However, the 28-day mortality was not different (58% vs. 62%, p=0.57). Patients in the albumin group required discontinuation of therapy in 11 (22%) patients due to adverse effects compared to none in plasmalyte group. CONCLUSION In patients with cirrhosis and SIH, 20% albumin transiently improves the hemodynamics with early lactate clearance than plasmalyte but needs monitoring as it is more often attended with pulmonary complications. Both fluids provide comparable 28 days survival. NCT02721238 LAY SUMMARY The current randomized controlled trial performed in critically ill patients with cirrhosis and sepsis-induced hypotension highlights that 20% albumin restores hemodynamics but causes more pulmonary complications than plasmalyte. The impact on renal functions was also modest. These effects did not result in improvement in deaths at 28-days. Plasmalyte is safer and well-tolerated and can be considered for volume resuscitation in patients with cirrhosis and sepsis-induced hypotension.
-
4.
Comparison of 5% human albumin and normal saline for fluid resuscitation in sepsis induced hypotension among patients with cirrhosis (FRISC study): a randomized controlled trial
Philips CA, Maiwall R, Sharma MK, Jindal A, Choudhury AK, Kumar G, Bhardwaj A, Mitra LG, Agarwal PM, Sarin SK
Hepatology international. 2021
Abstract
AIMS: Sepsis and septic shock are common causes of hospitalization and mortality in patients with cirrhosis. There is no data on the choice of fluid and resuscitation protocols in sepsis-induced hypotension in cirrhosis. METHODS In this open-label trial conducted at a single center, we enrolled 308 cirrhotics with sepsis-induced hypotension and randomized them to receive either 5% albumin or normal saline. The primary endpoint was a reversal of hypotension [mean arterial pressure, MAP, ≥ 65 mmHg] at 3 h. Secondary endpoints included serial effects on heart rate, arterial lactate and urine output. RESULTS 154 patients each received 5% albumin (males, 79.8%, mean MAP 52.9 ± 7.0 mm Hg) or 0.9% saline (85.1%, 53.4 ± 6.3 mm Hg) with comparable baseline parameters and liver disease severity. Reversal of hypotension was higher in patients receiving 5% albumin than saline at the end of one hour [25.3% and 11.7%, p = 0.03, Odds ratio (95% CI)-1.9 (1.08-3.42)] and at the end of three hours [11.7% and 3.2%, p = 0.008, 3.9 (1.42-10.9)]. Sustained reduction in heart rate and hyperlactatemia (p < 0.001) was better in the albumin group. At one week, the proportion of patients surviving was higher in the albumin group than those receiving saline (43.5% vs 38.3%, p = 0.03). Female gender and SOFA ≥ 11 were predictors of non-response to fluid. CONCLUSIONS 5% human albumin is safe and beneficial in reversing sepsis-induced hypotension compared to normal saline in patients with cirrhosis improving clinically assessable parameters of systemic hemodynamics, tissue perfusion and in-hospital short-term survival of cirrhosis patients with sepsis.
-
5.
Paracentesis-induced circulatory dysfunction with modest-volume paracentesis is partly ameliorated by albumin infusion in ACLF
Arora V, Vijayaraghavan R, Maiwall R, Sahney A, Thomas SS, Ali R, Jain P, Kumar G, Sarin SK
Hepatology (Baltimore, Md.). 2019
Abstract
Paracentesis-induced circulatory dysfunction (PICD) is a serious complication of large-volume (>5 L) paracentesis in cirrhosis and is reduced with albumin infusion. There is a lack of data on PICD in acute-on-chronic liver failure (ACLF). Because ACLF patients have greater hemodynamic derangements than patients with decompensated cirrhosis, we investigated whether PICD could develop with modest-volume paracentesis (MVP) and the role of albumin infusion. A total of 80 ACLF patients undergoing <5 L paracentesis were randomized to receive albumin (8-10 g/L of ascitic fluid; n = 40) or no albumin (n = 40) and were serially followed to detect PICD. Baseline characteristics were comparable between groups, including volume of ascitic tap (4.16 +/- 0.23 vs. 4.14 +/- 0.27 L; P = 0.72) and plasma renin activity (PRA) (20.5 +/- 7.03 vs. 23.2 +/- 8.24 ng/mL/hour; P = 0.12). PICD was more frequent in the no-albumin group than the albumin group (70% vs. 30%; P = 0.001), with higher incidence of hepatic encephalopathy (50% vs. 27.5%; P = 0.04), hyponatremia (67.5% vs. 22.5%; P < 0.001), acute kidney injury (62.5% vs. 30%; P = 0.001), and in-house mortality (62.5% vs. 27.5%; P = 0.003). PRA of 25.15 ng/mL at day 3 had sensitivity and specificity of 71% and 68% for development of PICD at day 6. Albumin infusion decreased the incidence of PICD at day six (odds ratio, 0.068; 95% confidence interval, 0.011-0.43; P = 0.005). Conclusion: PICD is common and develops even with MVP in ACLF patients. Albumin infusion decreases the incidence of PICD and mortality in ACLF patients.
-
6.
Thromboelastography-Guided Blood Component Use in Patients With Cirrhosis With Nonvariceal Bleeding: A Randomized Controlled Trial
Kumar M, Ahmad J, Maiwall R, Choudhury A, Bajpai M, Mitra LG, Saluja V, Mohan Agarwal P, Bihari C, Shasthry SM, et al
Hepatology (Baltimore, Md.). 2019
Abstract
Thromboelastography (TEG) provides a more comprehensive global coagulation assessment than routine tests (international normalized ratio [INR] and platelet [PLT] count), and its use may avoid unnecessary blood component transfusion in patients with advanced cirrhosis and significant coagulopathy who have nonvariceal upper gastrointestinal (GI) bleeding. A total of 96 patients with significant coagulopathy (defined in this study as INR >1.8 and/or PLT count <50 x 10(9) /L) and nonvariceal upper GI bleed (diagnosed after doing upper gastrointestinal endoscopy [UGIE], which showed ongoing bleed from a nonvariceal source) were randomly allocated to TEG-guided transfusion strategy (TEG group; n = 49) or standard-of-care (SOC) group (n = 47). In the TEG group, only 26.5% patients were transfused with all three blood components (fresh frozen plasma [FFP], PLTs, and cryoprecipitate) versus 87.2% in the SOC group (P < 0.001). Whereas 7 (14.3%) patients in the TEG group received no blood component transfusion, there were no such patients in the SOC group (P = 0.012). Also, there was a significantly lower use of blood components (FFP, PLTs, and cryoprecipitate) in the TEG group compared to the SOC group. Failure to control bleed, failure to prevent rebleeds, and mortality between the two groups were similar. CONCLUSION In patients with advanced cirrhosis with coagulopathy and nonvariceal upper GI bleeding, TEG-guided transfusion strategy leads to a significantly lower use of blood components compared to SOC (transfusion guided by INR and PLT count), without an increase in failure to control bleed, failure to prevent rebleed, and mortality.
-
7.
Terlipressin is superior to noradrenaline in the management of acute kidney injury in acute on chronic liver failure
Arora V, Maiwall R, Vijayaraghavan R, Jindal A, Saggere Muralikrishna S, Kumar G, Jain P, Sarin SK
Hepatology (Baltimore, Md.). 2018
Abstract
BACKGROUND Hepatorenal syndrome (HRS) carries a high short-term mortality in patients with cirrhosis and ACLF. Terlipressin and noradrenaline are routinely used in cirrhosis with HRS and have been found to be equally effective. There is no data comparing the efficacy of terlipressin with noradrenaline in ACLF patients with HRS. METHODS In an open-label RCT, consecutive patients with ACLF diagnosed with HRS-AKI, were randomised to albumin with infusion of terlipressin (2-12 mg/d) (n=60) or noradrenaline (0.5-3 mg/hr) (n=60). The response to treatment, course of AKI and outcome were studied. RESULTS Baseline characteristics including AKI stage and sepsis-related HRS-AKI were comparable between the groups. Compared to noradrenaline, terlipressin achieved greater day4 (26.1% vs.11.7%,p=0.03) and day 7 (41.7% vs. 20%,p=0.01) response. Reversal of HRS was also better with terlipressin (40% vs.16.7%,p=0.004) with a significant reduction in the requirement of renal replacement therapy(56.6% vs. 80%,p=0.006)and improved 28-day survival (48.3% vs. 20%,p=0.001). Adverse events limiting use of drugs were higher with terlipressin than noradrenaline[23.3% versus 8.3%,p=0.02], but were reversible. On multivariate analysis, high MELD (OR 1.10, CI=1.009-1.20,p=0.03) and noradrenaline compared to terlipressin (OR 3.05,CI=1.27-7.33,p=0.01)predicted non-response to therapy. Use ofnoradrenaline compared to terlipressin was also predictive of higher mortality (HR 2.08, CI=1.323.30,p=0.002). CONCLUSIONS Acute kidney injury in ACLF carries a high mortality. Infusion of terlipressin gives earlier and higher response than noradrenaline with improved survival in ACLF patients with HRS-AKI. This article is protected by copyright. All rights reserved.
-
8.
A randomized trial comparing terlipressin and noradrenaline in patients with cirrhosis and septic shock
Choudhury A, Kumar Kedarisetty C, Vashishtha C, Saini D, Kumar S, Maiwall R, Kumar Sharma M, Bhadoria AS, Kumar G, Joshi YK, et al
Liver International : Official Journal of the International Association for the Study of the Liver. 2016;37((4):):552-561.
Abstract
BACKGROUND AND AIMS The choice of vasopressor for treating cirrhosis with septic shock is unclear. While noradrenaline in general is the preferred vasopressor, terlipressin improves microcirculation in addition to vasopressor action in non-cirrhotics. We compared the efficacy and safety of noradrenaline and terlipressin in cirrhotics with septic shock. PATIENTS AND METHODS Cirrhotics with septic shock underwent open label randomization to receive either terlipressin (n=42)or noradrenaline (n=42) infusion at a titrated dose. The primary outcome wasmean arterial pressure (MAP)>65mmHg at 48hours. RESULTS aseline characteristics were comparable between the terlipressin and noradrenaline groups.SBPand pneumoniawere major sources of sepsis. A higher proportion of patients on terlipressin wereable to achieve MAP >65mm of Hg (92.9% vs. 69.1% p=0.005) at 48hours. Subsequent discontinuation of vasopressor after hemodynamic stability was better with terlipressin(33.3%vs.11.9%, P<0.05). Terlipressin compared to noradrenaline prevented variceal bleed (0%vs.9.5%, P=0.01) and improved survival at 48 hours(95.2%vs.71.4%, P=0.003). Percentage lactate clearance (LC) is an independent predictor of survival [p=0.0001, HR= 3.9(95CI 1.85-8.22)] after achieving the target MAP.Therapy related adverse effect were comparable in both the arms(40.5%vs.21.4%, P=0.06), mostly minor (GradeII-88%)andreversible. CONCLUSIONS Terlipressin is as effective as noradrenaline as a vasopressor in cirrhotics with septic shock and can serve as a useful drug. Terlipressin additionally provides early survival benefit, reduces risk of variceal bleed. Lactate clearance is abetter predictor of outcome even after achieving target MAP- suggesting the role of microcirculation in septic shock. This article is protected by copyright. All rights reserved.
-
9.
Combination of granulocyte colony-stimulating factor and erythropoietin improves outcomes of patients with decompensated cirrhosis
Kedarisetty CK, Anand L, Bhardwaj A, Bhadoria AS, Kumar G, Vyas AK, David P, Trehanpati N, Rastogi A, Bihari C, et al
Gastroenterology. 2015;148((7)):1362-1370.e7.
Abstract
BACKGROUND & AIMS Patients with decompensated cirrhosis have significantly reduced survival without liver transplantation. Granulocyte colony-stimulating factor (G-CSF) has been shown to increase survival in patients with acute-on-chronic liver failure, and erythropoietin promoted hepatic regeneration in animal studies. We performed a double-blind, randomized, placebo-controlled trial to determine whether co-administration of these growth factors improved outcomes for patients with advanced cirrhosis. METHODS In a prospective study, consecutive patients with decompensated cirrhosis seen at the Institute of Liver and Biliary Sciences, New Delhi (from May 2011 through June 2012) were randomly assigned to groups given subcutaneous G-CSF (5 mug/kg/d) for 5 days and then every third day (12 total doses), along with subcutaneous darbopoietin alpha(40 mcg/wk) for 4 weeks (GDP group, n = 29), or only placebos (control group, n = 26). All patients also received standard medical therapy and were followed for 12 months. Histology was performed on liver biopsies. The primary end point was survival at 12 months. RESULTS Baseline characteristics of patients were comparable; alcohol intake was the most common etiology of cirrhosis. A higher proportion of patients in the GDP group than controls survived until 12 months (68.6% vs 26.9%; P = .003). At 12 months, Child-Turcotte Pugh scores were reduced by 48.6% in the GDP group and 39.1% in the control group, from baseline (P = .001); Model for End Stage Liver Disease scores were reduced by 40.4% and 33%, respectively (P = .03). The need for large-volume paracentesis was significantly reduced in GDP group, compared with controls (P < .05). A lower proportion of patients in the GDP group developed septic shock (6.9%) during follow-up compared with controls (38.5%; P = .005). No major adverse events were observed in either group. CONCLUSIONS In a single-center randomized trial, a significantly larger proportion of patients with decompensated cirrhosis given a combination of G-CSF and darbopoietin alpha survived for 12 months more than patients given only placebo. The combination therapy also reduced liver severity scores and sepsis to a greater extent than placebo. Clinicaltrials.gov ID: NCT01384565.Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.