Terlipressin use and respiratory failure in patients with hepatorenal syndrome type 1 and severe acute-on-chronic liver failure.

BACKGROUND: Previous studies suggested increased mortality in patients with hepatorenal syndrome type 1 (HRS1) and advanced acute-on-chronic liver failure (ACLF). AIM: To assess mortality and respiratory failure (RF) in patients with HRS1 and ACLF treated with terlipressin. METHODS: In the CONFIRM study, we randomised 299 patients with HRS1 2:1 to terlipressin or placebo, both with albumin. At enrolment, all patients were assessed for organ failure (OF) using a validated ACLF grading system. Post hoc analyses assessed the effects of terlipressin vs. placebo on the incidence of RF and 90-day mortality. RESULTS: The incidence of RF with terlipressin (n = 200) was 9.4% in patients with grades 1-2 ACLF, and 30% with grade 3 ACLF (p = 0.0002); no such difference was observed in placebo-treated patients (n = 99) (6.2% grades 1-2 vs. 0% grade 3 ACLF, p > 0.05). RF incidence between terlipressin and placebo in patients with grade 3 ACLF was significant (p = 0.01). Baseline predictors of RF with terlipressin were INR (p = 0.011), mean arterial pressure (p = 0.037), and SpO2 (p = 0.014). Prior albumin as a continuous variable was not a predictor of RF. 90-day survival between terlipressin and placebo arms was similar for grades 1-2 ACLF (55.5% and 56.6%, respectively), but lower for grade 3 ACLF (27.55% vs. 50.0%) (p = 0.122), mainly related to RF. CONCLUSION: Terlipressin should be used with caution in patients with HRS1 and grade 3 ACLF. Patients with hypoxaemia are at increased risk of RF and mortality.

Alcohol and the Law.

In the intersection of alcohol ingestion with the law, medical ethics, and public safety, physicians are often unsure about how to proceed. Physicians' primary focus should be on patient education with an ethical and legal duty to warn the patient of the adverse effects of alcohol. Warning third parties of potential harm related to alcohol-related impairment may involve a breach of patient confidentiality; therefore it should only be undertaken after careful analysis suggests that the risk for significant harm exceeds the burden that results to the patient from warning others. The law remains vague in this area.

In vitro binding and receptor-mediated activity of terlipressin at vasopressin receptors V1 and V2.

Terlipressin, a synthetic, systemic vasoconstrictor with selective activity at vasopressin-1 (V1) receptors, is a pro-drug for the endogenous/natural porcine hormone [Lys8]-vasopressin (LVP). We investigated binding and receptor-mediated cellular activities of terlipressin, LVP, and endogenous human hormone [Arg8]-vasopressin (AVP) at V1 and vasopressin-2 (V2) receptors. Cell membrane homogenates of Chinese hamster ovary cells expressing human V1 and V2 receptors were used in competitive binding assays to measure receptor-binding activity. These cells were used in functional assays to measure receptor-mediated cellular activity of terlipressin, LVP, and AVP. Binding was measured by [3H]AVP counts, and the activity was measured by fluorometric detection of intracellular calcium mobilization (V1) and cyclic adenosine monophosphate (V2). Binding potency at V1 and V2 was AVP>LVP>>terlipressin. LVP and terlipressin had approximately sixfold higher affinity for V1 than for V2. Cellular activity potency was also AVP>LVP>>terlipressin. Terlipressin was a partial agonist at V1 and a full agonist at V2; LVP was a full agonist at both V1 and V2. The in vivo response to terlipressin is likely due to the partial V1 agonist activity of terlipressin and full V1 agonist activity of its metabolite, LVP. These results provide supportive evidence for previous findings and further establish terlipressin pharmacology for vasopressin receptors.

Terlipressin Improves Renal Function and Reverses Hepatorenal Syndrome in Patients With Systemic Inflammatory Response Syndrome.

BACKGROUND & AIMS: Patients with systemic inflammatory response syndrome (SIRS) along with decompensated cirrhosis and renal dysfunction have a poor prognosis and a lower response to treatment. We evaluated the effect of SIRS on the response of hepatorenal syndrome type 1 (HRS-1) to terlipressin. METHODS: We performed a retrospective study of data from a trial of the effects of terlipressin (1 mg every 6 hours or placebo with concomitant albumin) in 198 patients with HRS-1, performed at 50 investigational sites in the United States and 2 in Canada from October 2010 through February 2013. We identified patients with 2 or more criteria for SIRS, without untreated infections (28 received terlipressin and 30 received placebo), and patients with less than 2 criteria for SIRS (control subjects). Primary endpoints included HRS reversal (a decrease in serum level of creatinine to ≤1.5 mg/dL), confirmed HRS reversal (defined as 2 serum creatinine levels ≤1.5 mg/dL, ≥ 48 hours apart), and survival for 90 days after treatment. RESULTS: Baseline characteristics were similar between groups, apart from slightly higher white blood cell counts and heart rates, and slightly lower serum levels of bicarbonate in patients with SIRS versus without SIRS. HRS was reversed in 42.9% of patients who received terlipressin with SIRS (12/28) versus 6.7% of patients who received placebo (2/30) (P = .0018); confirmed HRS reversal occurred in 32.1% of patients who received terlipressin with SIRS (9/28) versus 3.3% who received placebo (1/30) (P = .0048). A larger proportion of patients with SIRS who received terlipressin survived for 90 days without a transplant (13/28; 46.4%) than patients with SIRS who received placebo (7/30; 23.3%) (P = .076). CONCLUSIONS: In an analysis of data from a placebo-controlled study, we found that terlipressin improved renal function and reversed HRS in a higher proportion of patients with HRS-1 and SIRS than patients who received albumin plus placebo. ClincialTrials.gov, number NCT 01143246.

Terlipressin Plus Albumin Is More Effective Than Albumin Alone in Improving Renal Function in Patients With Cirrhosis and Hepatorenal Syndrome Type 1.

BACKGROUND & AIMS: Hepatorenal syndrome type 1 (HRS-1) in patients with cirrhosis and ascites is a functional, potentially reversible, form of acute kidney injury characterized by rapid (<2 wk) and progressive deterioration of renal function. Terlipressin is a synthetic vasopressin analogue that acts, via vascular vasopressin V1 receptors, as a systemic vasoconstrictor. We performed a phase 3 study to evaluate the efficacy and safety of intravenous terlipressin plus albumin vs placebo plus albumin in patients with HRS-1. METHODS: Adult patients with cirrhosis, ascites, and HRS-1 (based on the 2007 International Club of Ascites criteria of rapidly deteriorating renal function) were assigned randomly to groups given intravenous terlipressin (1 mg, n = 97) or placebo (n = 99) every 6 hours with concomitant albumin. Treatment continued through day 14 unless the following occurred: confirmed HRS reversal (CHRSR, defined as 2 serum creatinine [SCr] values ≤1.5 mg/dL, at least 40 hours apart, on treatment without renal replacement therapy or liver transplantation) or SCr at or above baseline on day 4. The primary end point was the percentage of patients with confirmed CHRSR. Secondary end points included the incidence of HRS reversal (defined as at least 1 SCr value ≤1.5 mg/dL while on treatment), transplant-free survival, and overall survival. The study was performed at 50 investigational sites in the United States and 2 in Canada, from October 2010 through February 2013. RESULTS: Baseline demographic/clinical characteristics were similar between groups. CHRSR was observed in 19 of 97 patients (19.6%) receiving terlipressin vs 13 of 99 patients (13.1%) receiving placebo (P = .22). HRS reversal was achieved in 23 of 97 (23.7%) patients receiving terlipressin vs 15 of 99 (15.2%) receiving placebo (P = .13). SCr decreased by 1.1 mg/dL in patients receiving terlipressin and by only 0.6 mg/dL in patients receiving placebo (P < .001). Decreases in SCr and survival were correlated (r(2) = .882; P < .001). Transplant-free and overall survival were similar between groups. A significantly greater proportion of patients with CHRSR who received terlipressin survived until day 90 than patients who did not have CHRSR after receiving terlipressin (P < .001); this difference was not observed in patients who did vs did not have CHRSR after receiving placebo (P = .28). There were similar numbers of adverse events in each group, but patients in the terlipressin group had more ischemic events. CONCLUSIONS: Terlipressin plus albumin was associated with greater improvement in renal function vs albumin alone in patients with cirrhosis and HRS-1. Patients had similar rates of HRS reversal with terlipressin as they did with albumin. ClinicalTrials.gov no: NCT01143246.