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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
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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.
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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.
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Hemodynamic Effects of Adding Simvastatin to Carvedilol for Primary Prophylaxis of Variceal Bleeding: A Randomized Controlled Trial
Vijayaraghavan R, Jindal A, Arora V, Choudhary A, Kumar G, Sarin SK
The American journal of gastroenterology. 2020
Abstract
INTRODUCTION Beta-blockers are the mainstay agents for portal pressure reduction and to modestly reduce hepatic venous pressure gradient (HVPG). We studied whether addition of simvastatin to carvedilol in cirrhotic patients for primary prophylaxis improves the hemodynamic response. METHODS Cirrhotic patients with esophageal varices and with baseline HVPG > 12 mm Hg were prospectively randomized for primary prophylaxis to receive either carvedilol (group A, n = 110) or carvedilol plus simvastatin (group B, n = 110). Primary objective was to compare hemodynamic response (HVPG reduction of ≥20% or <12 mm Hg) at 3 months, and secondary objectives were to compare first bleed episodes, death, and adverse events. RESULTS The groups were comparable at baseline. The proportion of patients achieving HVPG response at 3 months was comparable between groups (group A-36/62 [58.1%], group B-36/59 [61%], P = 0.85). The degree of mean HVPG reduction (17.3% and 17.8%, respectively, P = 0.98) and hemodynamic response (odds ratio [OR]: 0.88; 95% confidence interval [CI]: 0.43-1.83, P = 0.74) was also not different between the groups. Patients who achieved target heart rate with no hypotensive episodes in either group showed better hemodynamic response (77.8% vs 59.2%, P = 0.04). Failure to achieve target heart rate (OR: 0.48; 95% CI: 0.22-1.06) and Child C cirrhosis (OR: 4.49; 95% CI: 1.20-16.8) predicted nonresponse. Three (3.7%) patients on simvastatin developed transient transaminitis and elevated creatine phosphokinase and improved with drug withdrawal. Two patients in each group bled (P = 0.99). Three patients and 1 patient, respectively, in group A and B died (P = 0.32), with sepsis being the cause of death. DISCUSSION Addition of simvastatin to carvedilol for 3 months for primary prophylaxis of variceal bleeding does not improve hemodynamic response over carvedilol monotherapy. Simvastatin usage should be closely monitored for adverse effects in Child C cirrhotic patients.
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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.
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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.