By Samuel Nadler, MD, PhD
Critical Care, Pulmonary Medicine, The Polyclinic Madison Center, Seattle; Clinical Instructor, University of Washington, Seattle
Dr. Nadler reports no financial relationships relevant to this field of study.
SYNOPSIS: The use of vasopressin as a vasopressor for septic shock produced similar outcomes as the use of norepinephrine.
SOURCE: Gordon AC, Mason AJ, Thirunavukkarasu N, et al. Effect of early vasopressin vs. norepinephrine on kidney failure in patients with septic shock: The VANISH Randomized Clinical Trial. JAMA 2016;316:509-518.
There has been continuous interest in the use of vasopressin for patients who suffer septic shock. Norepinephrine (NE) continues to be the recommended first-line vasopressor, but since the VASST trial in 2008, the use of vasopressin as an adjunct vasopressor has become widespread.1 That trial demonstrated that the addition of low-dose vasopressin (0.03 U/min) improved the mortality of patients in a subgroup of patients with less severe septic shock (defined as need for NE < 15 mcg/min). Other studies have implied that vasopressin may produce a synergistic effect with corticosteroids to prevent renal dysfunction. The Vasopressin as Initial Therapy in Septic Shock (VANISH) trial sought to determine if early vasopressin use as compared with standard NE infusions would improve patient outcomes.
The VANISH trial was a factorial (2 x 2), multicenter, double-blind, randomized, controlled trial that included 421 adult patients with sepsis as defined by systemic inflammatory response criteria with suspected or known infection. All patients underwent adequate fluid resuscitation yet required vasopressors. Patients were randomized to vasopressin (up to 0.06 U/min) or NE (up to 12 mcg/min) as a first vasopressor. If this intervention did not restore mean arterial pressure > 65 mmHg, patients also were randomized to receive hydrocortisone (50 mg intravenously every six hours for five days, then tapered) or placebo as an additional treatment. If patients remained hypotensive despite administration of both study drugs, additional open-label vasopressors were added. Exclusion criteria included previous vasopressor use during hospitalization, need for steroid treatments, endstage renal failure, known mesenteric ischemia, or vasospastic diseases such as systemic sclerosis. The primary outcome was kidney failure-free days up to 28 days. Secondary outcomes included renal replacement therapy, mortality and organ failure-free days, and Sequential Organ Failure Assessment scores.
Overall, the treatment groups were well balanced at baseline and received similar amounts of fluid. Study drugs were started within three hours of diagnosis, and the mean arterial pressures were similar in all groups. Two patients in the NE group received open-label vasopressin and were included in the intent-to-treat analysis. There were no significant differences in kidney failure-free days, mortality, new organ failure, or the need for renal replacement therapy in comparisons of vasopressin vs. NE or with the use of hydrocortisone. There also were no differences in duration of mechanical ventilation, ICU length of stay, hospital length of stay, time to shock reversal between groups, and no significant increase in adverse events.
COMMENTARY
The VANISH trial did not detect a statistically significant difference in primary or secondary endpoints. In the study’s power calculations, the sample size was chosen to detect a 20-25% relative risk reduction of kidney failure assuming an incidence of acute kidney failure of 30-50%. There was an incidence of renal failure of 40.6-49.5% in the four study groups. The absolute difference in kidney failure in the vasopressin vs. NE groups was -5.1% (95% confidence interval, -15.2% to 5%), which represents a relative risk reduction of 11.3%. Thus, this study was not powered to detect this degree of renal protection. Interestingly, the greatest benefit in terms of use of renal replacement, incidence, and duration of kidney failure (although not statistically significant, either) was in non-survivors.
Compared with NE, this study also showed that vasopressin statistically and non-significantly trended toward higher 28-day mortality (30.9% vs. 27.5%), ICU mortality (28.4% vs. 25.0%), and hospital mortality (33.3% vs. 29.4%). The time to shock reversal tended to be longer with vasopressin by six hours, the use of inotropes was greater by 6.7%, and there were greater rates of digital ischemia and acute coronary syndrome. Thus, while it may be expected that a larger trial may detect a small change in renal protection with vasopressin, it is equally likely that it will show increased mortality, length of stay, and complication rates that seem to be more important endpoints. If the benefit is greatest among non-survivors, as previously suggested, this is not truly an overall benefit.
The VANISH trial may be interpreted in the context of the prior VASST study. VASST added vasopressin to NE infusions and was a larger trial (n = 802). A notable difference in baseline demographics in this study was that the vasopressin arm was statistically younger (59.3 vs. 61.8 years; P = 0.03). Despite this difference, no statistically significant improvement was observed in the primary endpoints of 28-day mortality or secondary endpoints of 90-day mortality, days free of organ dysfunction, mechanical ventilation, use of renal replacement therapy, corticosteroid use, length of stay, or serious adverse events. Given that both VASST and VANISH did not demonstrate efficacy in their primary or secondary endpoints, reconsider the widespread use of vasopressin.
REFERENCE
- Russell JA, Walley KR, Singer J, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008;358:877-887.
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