Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock: The VANISH Randomized Clinical Trial.

Gordon, AC, et al. JAMA 2016 [paper]

Why I chose this article

The kidney is painfully fragile, often one of the first organs to fail in septic shock. According to the last several iterations of the Surviving Sepsis Campaign Guidelines, it is recommended that norepinephrine (NE) be used as first line therapy in septic shock refractory to volume resuscitation (strong recommendation, moderate quality of evidence). This seems to be related to the beat down it has put on dopamine in head-to-head trials.  However, in some studies there has been evidence that vasopressin may have a mortality and/or renoprotective effect when added to the vasopressor mix.

Background

The Vasopressin and Septic Shock Trial (VASST) studied open-label NE plus NE (5-15ucg/min) or vasopressin (up to 0.03 u/min) in septic shock. There was no overall mortality difference but a subgroup analysis demonstrated an absolute reduction in mortality among patients with less severe sepsis, defined as requiring initially less than 15ucg/min of NE. There was also a suggestion that vasopressin prevented organ deterioration, particularly kidney function.

Research Goal

The background discussion led to the much anticipated VANISH trial, which sought “to test whether early vasopressin use, titrated up to 0.06 U/min, would improve kidney outcomes compared with norepinephrine.”

Design

Factorial (2×2), multicenter, double-blind, RCT

Inclusion

  • Adults (16 years and up)
  • Sepsis as defined by SIRS 2/4 and known/suspected infection
  • Requiring vasopressors despite adequate fluid resuscitation,
  • vasopressors started within 6-hr recruitment window

Exclusion

  • Previous continuous infusion of vasopressors during this ICU admission
  • Known ongoing requirement for systemic steroid treatment
  • ESRD
  • Mesenteric ischemia
  • Raynaud’s
  • Systemic sclerosis or other vasospastic disease
  • Patient or medical team preference to have limitations to medical care
  • Known pregnancy
  • Enrollment in another trial
  • Hypersensitivity to the study drugs

Protocol

Patients were randomized to 1 of 4 groups: vasopressin and hydrocortisone, vasopressin and placebo, norepinephrine and hydrocortisone, norepinephrine and placebo. Vasopressin was titrated up to 0.06 U/min while NE was titrated to 12ucg/min as the initial vasopressor. MAP goal 65-75. Once the maximum initial vasopressor was being infused, patients got 50mg of hydrocortisone or placebo depending on their randomization. After both study drugs were utilized additional catecholamine vasopressors were used at the physician’s discretion for persistent hypotension. Recruited patients could have started open label catecholamine vasopressors during initial resuscitation due to availability of study drugs and timing to enrollment.

Outcomes

  • Primary: kidney-failure free days as defined by the AKIN-3 definition 28 days after randomization.
  • Secondary: Rates and duration of renal replacement therapy, length of kidney failure in survivors and non-survivors, 28-day mortality rates, organ-failure free days in the first 28 days assessed using the SOFA score.

Results

With regards to the primary outcome, there was no statistically significant difference in the distribution of kidney failure-free days, as defined by AKIN-3, between vasopressin and norepinephrine groups. However, the upper limit of the 95% confidence intervals of the difference between the groups favored the vasopressin group by 5 days. The number of survivors who never developed kidney failure was similar between the 2 groups.

Mortality was not significantly different. Serum creatinine was lower and urine output higher over the first 7 days for the vasopressin group, reaching statistical significance days 3-6 and days 5/7, respectively. The rate of renal replacement therapy was 25.4% in the vasopressin group vs 35.3% in the norepinephrine group, which was statistically significant. Steroids weren’t a lot of help, again (prior to this study hypothesized that they might play a synergistic role with vasopressin in renoprotection).

Discussion

The authors of this study conclude that their primary outcome did not reach statistical significance, which is true, but that some of their data pointed towards a trend in clinically important benefit for vasopressin, also true, and something a large trial might tease out. Interestingly, their primary outcome, AKIN stage 3 renal failure, is really a composite outcome composed of some things that seem clinically less significant and one that seems more clinically significant – as pointed out by the prolific Josh Farkas. Renal failure as defined by AKIN stage 3 is determined by meeting one of the following criteria:

  • Cr > 3x baseline
  • Cr > 4
  • UOP <0.3 ml/kg/hr for 24 hrs
  • Anuria for 12 hours
  • Dialysis

While vasopressin groups had lower creatinine levels, better urine output, and less need for dialysis they had no difference in AKIN stage 3 renal failure (a binary, composite outcome). Perhaps the use of this as the primary outcome is what made the results not significant. Arguably, renal failure requiring HD is the least arbitrary of all of these measures, and that was the only outcome, albeit a secondary outcome, that met statistical and clinical significance with regard to favorability of vasopressin.

So what does this all mean for my practice? I think that there is modest evidence that points to the renoprotective and mortality benefits of using vasopressin as a vasopressor in septic shock, while very little evidence that low dose vasopressin causes significant adverse effects. I don’t think that this study is evidence that vasopressin should replace norepinephrine as first line therapy for septic shock. But, I will be using vasopressin early, as an adjunct to norepinephrine, in the first line treatment of septic shock given the potential to improve renal outcomes.

 

Gabriel Hoffman is a PGY4 EM/IM Resident