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

Abstract

IntroductionVasopressin 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.Methods and analysisThis 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.Ethics and disseminationThe 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.Trial registration number:ISRCTN 20769191 and EudraCT 2011-005363-24.

What’s new in vasopressin?

“…Taken together all these results suggest that vasopressin may have the most benefit in septic shock when used early in less severely shocked patients, titrating up to higher doses if needed and potentially in combination with corticosteroids to prevent further deterioration, rather than as a rescue therapy in refractory shock. However, as much of this data comes from multiple subgroup analyses we await new evidence from ongoing trials such as the Vasopressin versus Noradrenaline as Initial Therapy in Septic Shock (VANISH) trial (ISRCTN20769191) [11] to confirm or refute these recommendations.…”

Evidence about inotropes: when is enough, enough?

“…It is interesting that in the vasopressin and septic shock trial (VASST) there was a significant reduction of heart rate in the vasopressintreated patients in the less severe shock group [12], the same group who also had a reduction in mortality in the overall trial. We await the results of ongoing trials to see if this effect can be repeated when vasopressin is administered early and in higher doses to maximise norepinephrine avoidance [13].…”

“…A target mean arterial pressure of 65 mmHg is recommended as a reasonable starting point [3], only increasing in those individuals who may have a history of hypertension or atherosclerosis, but also perhaps accepting lower targets in the young previously fit patient. If then vasopressors or inotropes are needed we should use the lowest doses of catecholamines possible and maybe consider alternatives, such as vasopressin or levosimendan, accepting that we still await further evidence from ongoing trials [13,15]. …”

Shock Management For Cardio-Surgical ICU Patients — The Golden Hours

“…63 A survival benefit could not be shown for patients with mild septic shock and for those who received glucocorticoids. 23,62,64 Patients with cardiogenic shock might even be harmed by the increase in afterload and the coronary vasoconstriction. 65 In accordance with others, a maximum dose of 0,04 U/min is recommended.…”

“…57,58 Vasopressin is used in patients with noradrenalin doses >0.5 mcg/kg/min. In septic shock, vasopressor deficiency can occur 59 and its supplementation is safe [60][61][62] with a catecholamine sparing effect. 63 A survival benefit could not be shown for patients with mild septic shock and for those who received glucocorticoids.…”