Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock

Abstract

IMPORTANCE Norepinephrine is currently recommended as the first-line vasopressor in septic shock; however, early vasopressin use has been proposed as an alternative. OBJECTIVE To compare the effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock. DESIGN, SETTING, AND PARTICIPANTS A factorial (2×2), double-blind, randomized clinical trial conducted in 18 general adult intensive care units in the United Kingdom between February 2013 and May 2015, enrolling adult patients who had septic shock requiring vasopressors despite fluid resuscitation within a maximum of 6 hours after the onset of shock. INTERVENTIONS Patients were randomly allocated to vasopressin (titrated up to 0.06 U/min) and hydrocortisone (n = 101), vasopressin and placebo (n = 104), norepinephrine and hydrocortisone (n = 101), or norepinephrine and placebo (n = 103). MAIN OUTCOMES AND MEASURES The primary outcome was kidney failure-free days during the 28-day period after randomization, measured as (1) the proportion of patients who never developed kidney failure and (2) median number of days alive and free of kidney failure for patients who did not survive, who experienced kidney failure, or both. Rates of renal replacement therapy, mortality, and serious adverse events were secondary outcomes. RESULTS A total of 409 patients (median age, 66 years; men, 58.2%) were included in the study, with a median time to study drug administration of 3.5 hours after diagnosis of shock. The number of survivors who never developed kidney failure was 94 of 165 patients (57.0%) in the vasopressin group and 93 of 157 patients (59.2%) in the norepinephrine group (difference, −2.3% [95% CI, −13.0% to 8.5%]). The median number of kidney failure-free days for patients who did not survive, who experienced kidney failure, or both was 9 days (interquartile range [IQR], 1 to-24) in the vasopressin group and 13 days (IQR, 1 to-25) in the norepinephrine group (difference, −4 days [95% CI, −11 to 5]). There was less use of renal replacement therapy in the vasopressin group than in the norepinephrine group (25.4% for vasopressin vs 35.3% for norepinephrine; difference, −9.9% [95% CI, −19.3% to −0.6%]). There was no significant difference in mortality rates between groups. In total, 22 of 205 patients (10.7%) had a serious adverse event in the vasopressin group vs 17 of 204 patients (8.3%) in the norepinephrine group (difference, 2.5% [95% CI, −3.3% to 8.2%]). CONCLUSIONS AND RELEVANCE Among adults with septic shock, the early use of vasopressin compared with norepinephrine did not improve the number of kidney failure-free days. Although these findings do not support the use of vasopressin to replace norepinephrine as initial treatment in this situation, the confidence interval included a potential clinically important benefit for vasopressin, and larger trials may be warranted to assess this further.

The SEP-1 quality mandate may be harmful: How to drown a patient with 30 mL per kg fluid!

“…In order to justify the use of large volumes of fluid in patients with severe septic shock, it has been claimed that in the early goal directed therapy (EGDT) patients "received large amounts of crystalloid" prior to enrollment. It is however noteworthy that in the recent VANISH trial (conducted between 2013 and 2015) on average 1134 mL fluid was administered in the 4 hours prior to enrollment (and escalation of the dose of vasopressor) [18].…”

Vasopressin versus noradrenaline as initial therapy in septic shock. Is vasopressin-related renal protection doomed to “vanish” in the haze?

“…Therapy in Septic Shock (VANISH) trial comparing the effect of these two potent vasopressors on kidney failure in adult patients with septic shock (1). Rationale for this study was the landmark Vasopressin and Septic Shock Trial (VASST) which found an association between low-dose (0.01 to 0.03 U per minute) vasopressin and decreased mortality in less severe septic shock but no difference between vasopressin and noradrenaline on global mortality or organ dysfunction rates (2).…”

“…Unfortunately, the VANISH study did not find a difference in the number of kidney failurefree days in surviving patients receiving vasopressin or noradrenaline. The observation that, in the vasopressin group, fewer renal replacement therapy was required and that those who did not survive and/or experienced renal failure had less kidney failure-free days procured only some meagre scientific solace (1).…”

“…However, no data on baseline or serial preload measurement were provided. It is noteworthy that baseline central venous pressure measurement was not performed in 43% of patients enrolled in the VANISH study (1). Subsequent preload monitoring was omitted, type of resuscitation fluid was not specified, and information on the use of diuretics or potential concomitant nephrotoxic medication was lacking.…”

The intensive care medicine research agenda on septic shock

“…The potentially favourable effects of reduced vasopressor dosing [78], adjunctive vasopressin [79,80] or angiotensin-II [81], and/or beta-blocker(s) [82] support the notion that excess catecholamines be limited or avoided in septic shock. There is an imperative to conduct trials with low risk of bias to assess the effectiveness and safety of strategies aiming at reducing the effects of catecholamines in septic shock.…”