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Protocol for a randomised controlled trial of VAsopressin versus Noradrenaline as Initial therapy in Septic sHock (VANISH).

ABSTRACT: Vasopressin is an alternative vasopressor in the management of septic shock. It spares catecholamine use but whether it improves outcome remains uncertain. Current evidence suggests that it may be most effective if used early and possibly in conjunction with corticosteroids. This trial will compare vasopressin to noradrenaline as initial vasopressor in the management of adult septic shock and investigate whether there is an interaction of vasopressin with corticosteroids.This is a multicentre, factorial (2×2), randomised, double-blind, placebo-controlled trial. 412 patients will be recruited from multiple UK intensive care units and randomised to receive vasopressin (0-0.06?U/min) or noradrenaline (0-12?µg/min) as a continuous intravenous infusion as initial vasopressor therapy. If maximum infusion rates of this first study drug are reached, the patient will be treated with either hydrocortisone (initially 50?mg intravenous bolus six-hourly) or placebo, before additional open-label catecholamine vasopressors are prescribed. The primary outcome of the trial will be the difference in renal failure-free days between treatment groups. Secondary outcomes include need for renal replacement therapy, survival rates, other organ failures and resource utilisation.The trial protocol and information sheets have received a favourable opinion from the Oxford A Research Ethics Committee (12/SC/0014). There is an independent Data Monitoring and Ethics Committee and independent membership of the Trial Steering Committee including patient and public involvement. The trial results will be published in peer-reviewed journals and presented at national and international scientific meetings.ISRCTN 20769191 and EudraCT 2011-005363-24.

SUBMITTER: Gordon AC

PROVIDER: S-EPMC4091463 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Protocol for a randomised controlled trial of VAsopressin versus Noradrenaline as Initial therapy in Septic sHock (VANISH).

Gordon Anthony C AC Mason Alexina J AJ Perkins Gavin D GD Ashby Deborah D Brett Stephen J SJ

BMJ open 20140703 7

<h4>Introduction</h4>Vasopressin is an alternative vasopressor in the management of septic shock. It spares catecholamine use but whether it improves outcome remains uncertain. Current evidence suggests that it may be most effective if used early and possibly in conjunction with corticosteroids. This trial will compare vasopressin to noradrenaline as initial vasopressor in the management of adult septic shock and investigate whether there is an interaction of vasopressin with corticosteroids.<h4 ...[more]

PMID: 24993769

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Project description:IntroductionRecent clinical data suggest that early administration of vasopressin analogues may be advantageous compared to a last resort therapy. However, it is still unknown whether vasopressin and terlipressin are equally effective for hemodynamic support in septic shock. The aim of the present prospective, randomized, controlled pilot trial study was, therefore, to compare the impact of continuous infusions of either vasopressin or terlipressin, when given as first-line therapy in septic shock patients, on open-label norepinephrine requirements.MethodsWe enrolled septic shock patients (n = 45) with a mean arterial pressure below 65 mmHg despite adequate volume resuscitation. Patients were randomized to receive continuous infusions of either terlipressin (1.3 microg.kg-1.h-1), vasopressin (.03 U.min-1) or norepinephrine (15 microg.min-1; n = 15 per group). In all groups, open-label norepinephrine was added to achieve a mean arterial pressure between 65 and 75 mmHg, if necessary. Data from right heart and thermo-dye dilution catheterization, gastric tonometry, as well as laboratory variables of organ function were obtained at baseline, 12, 24, 36 and 48 hours after randomization. Differences within and between groups were analyzed using a two-way ANOVA for repeated measurements with group and time as factors. Time-independent variables were compared with one-way ANOVA.ResultsThere were no differences among groups in terms of systemic and regional hemodynamics. Compared with infusion of .03 U of vasopressin or 15 microg.min-1 of norepinephrine, 1.3 microg.kg-1.h-1 of terlipressin allowed a marked reduction in catecholamine requirements (0.8 +/- 1.3 and 1.2 +/- 1.4 vs. 0.2 +/- 0.4 microg.kg-1.min-1 at 48 hours; each P < 0.05) and was associated with less rebound hypotension (P < 0.05). At the end of the 48-hour intervention period, bilirubin concentrations were higher in the vasopressin and norepinephrine groups as compared with the terlipressin group (2.3 +/- 2.8 and 2.8 +/- 2.5 vs. 0.9 +/- 0.3 mg.dL-1; each P < 0.05). A time-dependent decrease in platelet count was only observed in the terlipressin group (P < 0.001 48 hours vs. BL).ConclusionsThe present study provides evidence that continuous infusion of low-dose terlipressin--when given as first-line vasopressor agent in septic shock--is effective in reversing sepsis-induced arterial hypotension and in reducing norepinephrine requirements.

Project description:INTRODUCTION:Observational evidence suggests physiological benefits and lower mortality with lower chloride solutions; however, 0.9% saline remains the most widely used fluid worldwide. Given uncertainty regarding the association of lower chloride on mortality, it is unlikely that practice will change without direct randomised clinical trial (RCT) evidence. This pilot RCT will investigate the feasibility of a large-scale trial directly comparing low chloride with high chloride fluids in patients with septic shock. METHODS AND ANALYSIS:This is a randomised, concealed, blinded parallel-group multicentre pilot trial. We will include adult critically ill patients with septic shock, defined as ongoing hypotension despite 1 L of fluid, or a serum lactate >4?mmol/L, who are within 6?hours of hospital presentation or rapid response team activation. We will exclude patients if they have an aetiology of shock other than sepsis, if they have acute burn injury, elevated intracranial pressure, intent to withdraw life support or previous enrolment in this or a competing trial. Following informed consent, patients will be randomised to a low chloride fluid strategy or a high chloride fluid strategy for the duration of their ICU stay or until 30 days postrandomisation. Clinicians, patients, families and research staff will be blinded. The primary outcome for this trial will be feasibility, assessed by consent rate, recruitment success and protocol adherence. Patient-important clinical outcomes include mortality, receipt of renal replacement therapy, intensive care unit and hospital lengths of stay and surrogate outcomes of incidence of acidosis, hyperkalaemia and acute kidney injury. ETHICS AND DISSEMINATION:This pilot trial will test the feasibility of conducting the main trial, which will examine the effect of high versus low chloride fluids in patients with septic shock on patient-important outcomes. TRIAL REGISTRATION NUMBER:NCT02748382, registered 8 April 2016. PROTOCOL DATE:1 July 2016.

Project description:IntroductionPositive hemodynamic response to vasopressin after 6 hours of infusion was independently associated with lower mortality in a previous retrospective study of patients with septic shock. However, factors previously associated with higher plasma vasopressin concentration were not associated with response, and the relationship between plasma vasopressin concentration and hemodynamic response has not been evaluated.ObjectivesThis cross-sectional study compared plasma vasopressin concentrations in hemodynamic responders and nonresponders to vasopressin in patients with septic shock to evaluate plasma vasopressin concentration as a therapeutic target for hemodynamic response to vasopressin.MethodsAdult patients with septic shock were included if they were treated with fixed-dose vasopressin as an adjunct to catecholamines for at least 3 hours. Patients were assigned to groups based on vasopressin response.ResultsTen hemodynamic responders to vasopressin and eight nonresponders were included. Blood samples for plasma vasopressin concentration were collected 3-6 hours after vasopressin initiation. Baseline characteristics were similar between groups. No difference was detected in plasma vasopressin concentrations between hemodynamic responders and nonresponders (median 88.6 pg/ml [interquartile range (IQR) 84.4-107.5 pg/ml] vs 89.9 pg/ml [IQR 67.5-157.4 pg/ml], p=0.79, respectively). We also did not detect a difference between groups after correcting for vasopressin dose; median vasopressin plasma concentration per 0.01 units/minute of vasopressin infusion for responders was 25.9 pg/ml (IQR 21.8-31.8 pg/ml) versus 29.5 pg/ml (IQR 23.0-57.5 pg/ml, p=0.48) for nonresponders. No difference in clinical outcomes was detected between groups. The findings were robust to multiple sensitivity analyses.ConclusionsThis study does not support the use of plasma vasopressin concentrations as a therapeutic target to predict hemodynamic response to exogenous vasopressin in septic shock.

Project description:This review of vasopressin in septic shock differs from previous reviews by providing more information on the physiology and pathophysiology of vasopressin and vasopressin receptors, particularly because of recent interest in more specific AVPR1a agonists and new information from the Vasopressin and Septic Shock Trial (VASST), a randomized trial of vasopressin versus norepinephrine in septic shock. Relevant literature regarding vasopressin and other AVPR1a agonists was reviewed and synthesized. Vasopressin, a key stress hormone in response to hypotension, stimulates a family of receptors: AVPR1a, AVPR1b, AVPR2, oxytocin receptors and purinergic receptors. Rationales for use of vasopressin in septic shock are as follows: first, a deficiency of vasopressin in septic shock; second, low-dose vasopressin infusion improves blood pressure, decreases requirements for norepinephrine and improves renal function; and third, a recent randomized, controlled, concealed trial of vasopressin versus norepinephrine (VASST) suggests low-dose vasopressin may decrease mortality of less severe septic shock. Previous clinical studies of vasopressin in septic shock were small or not controlled. There was no difference in 28-day mortality between vasopressin-treated versus norepinephrine-treated patients (35% versus 39%, respectively) in VASST. There was potential benefit in the prospectively defined stratum of patients with less severe septic shock (5 to 14 ?g/minute norepinephrine at randomization): vasopressin may have lowered mortality compared with norepinephrine (26% versus 36%, respectively, P = 0.04 within stratum). The result was robust: vasopressin also decreased mortality (compared with norepinephrine) if less severe septic shock was defined by the lowest quartile of arterial lactate or by use of one (versus more than one) vasopressor at baseline. Other investigators found greater hemodynamic effects of higher dose of vasopressin (0.06 units/minute) but also unique adverse effects (elevated liver enzymes and serum bilirubin). Use of higher dose vasopressin requires further evaluation of efficacy and safety. There are very few studies of interactions of therapies in critical care--or septic shock--and effects on mortality. Therefore, the interaction of vasopressin infusion, corticosteroid treatment and mortality of septic shock was evaluated in VASST. Low-dose vasopressin infusion plus corticosteroids significantly decreased 28-day mortality compared with corticosteroids plus norepinephrine (44% versus 35%, respectively, P = 0.03; P = 0.008 interaction statistic). Prospective randomized controlled trials would be necessary to confirm this interesting interaction. In conclusion, low-dose vasopressin may be effective in patients who have less severe septic shock already receiving norepinephrine (such as patients with modest norepinephrine infusion (5 to 15 ?g/minute) or low serum lactate levels). The interaction of vasopressin infusion and corticosteroid treatment in septic shock requires further study.

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Protocol for a randomised controlled trial of VAsopressin versus Noradrenaline as Initial therapy in Septic sHock (VANISH).

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Protocol for a randomised controlled trial of VAsopressin versus Noradrenaline as Initial therapy in Septic sHock (VANISH).

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