Vasopressin: A Second Class Pressor?

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This week we'll be recapping the discussion of our most recent journal club where Dr. Christian Renne, Dr. Anita Goel, and Dr. Maika Dang led us in a discussion centering on the use of vasopressin both in sepsis and in vasoplegic shock states.  Take a listen to the podcast below and read the brief summaries of their articles to boost your understanding of Vasopressin.  Should you reach for it first or is it a second class pressor?

Russel J, Walley K, Singer J, et al. Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock. N Engl J Med 2008;358(9):877–87.

The Vasopressin And Septic Shock Trial (VASST) was published in 2008 and was a multicenter, randomized, double-blind trial that included 779 patients with septic shock resistant to 500 ml fluid challenge currently being treated with low-dose norepinephrine (minimum 5 hg/min). Patients were randomized to one or two arms: low dose vasopressin (0.01 to 0.03 units/min) vs norepinephrine (5-15 hg/min) in addition to open label vasopressors. 396 patients received vasopressin and 382 patients receive norepinephrine.

The primary endpoint was 28-day mortality. Secondary endpoints included 90-day mortality, days free of organ dysfunction, free of vasopressor use, free of mechanical ventilation, free of SIRS, free of steroid use, renal replacement requirement, and length of stay. There was no difference in primary or secondary endpoints between the two groups, including serious adverse events. The authors also prospectively defined a stratum of less severe (5-14 hg norepinephrine at randomization) vs more severe septic shock (15 or more hg norepinephrine). The less severe septic shock strata treated with vasopressin had a lower mortality compared to norepinephrine. However, a test for heterogeneity between the two strata was not significant. The study also found a vasopressin deficiency in both arms at baseline and those in the vasopressin group had increase in vasopressin levels following treatment.

Ultimately, this was a large study with interesting methods. Our discussion from journal club noted multiple criticisms particularly in the applicability to our patient population. This study excluded patients with heart failure NYHA class III and four as well as ischemic heart disease. As vasopressin is known to have adverse cardiovascular effects, it would be important to analyze its use in this patient population. Furthermore, the study makes no mention of fluid administration or time to antibiotics. Both of which are very important in the treatment of sepsis as we know today. It should be noted too, that this study was underpowered given the lower-than-expected mortality rate, which may also suggest a selection bias. Additional criticisms include a delay to randomization from meeting inclusion criteria and an average MAP at baseline > 65 mmHg where the utility of additional vasopressor is questionable. 

The take away from this study is that vasopressin used as an adjunct did not have a mortality difference when compared to norepinephrine. It has reaffirmed what we know from other literature in that low dose vasopressin increases blood pressure, decreases catecholamine requirements, and is safe. However, this study did not address vasopressin as a monotherapy or safety and efficacy in higher doses. 

Hajjar L, Vincent JL, Galas FRBG, et al. Vasopressin versus Norepinephrine in Patients with Vasoplegic Shock after Cardiac Surgery. Anesthesiology 2016;126(1):85–93.

VANCS, aka “vasopressin versus Norepinephrine in patients with vasoplegic shock after cardiac surgery” was a study in 2017 addressing the question “is administration of vasopressin to patients with vasoplegic shock after cardiac surgery associated with fewer post op complications compared to norepinephrine administration?”

The study was a single center randomized control double blinded study with data collected from 2012-2014 in Brazil at the Heart Institute. Patient’s with vasoplegic shock (defined by MAP less than 65 resistant to 1 L fluid bolus with cardiac index greater than 2.2) after cardiac surgery were randomized to receive vasopressin (0.01 to 0.06 U/min) or norepinephrine (10 to 60 ug/min) to maintain arterial pressure. The primary endpoint was mortality or severe complications (including stroke, requirement for mechanical ventilation for longer than 48 hours, deep sternal wound infection, re-operation, or acute renal failure) within 30 days. 300 total patient received the study drug after application of inclusion / exclusion criteria and randomization.

The primary outcome occurred in 49% of patients in the norepinephrine group and 32% of patients in the vasopressin group, which was statistically significant at a p value of 0.0014. However, upon further analyzing this data, the only statistically significant primary outcome individually was incidence of acute renal failure (less in vasopressin compared to norepinephrine) at a p value of less than 0.0001. Mortality difference was not significant at a p value of 0.98 and 0.73 after adjustment. Results also revealed in terms of adverse events a lower occurrence of atrial fibrillation in the vasopressin group compared to the norepinephrine group at a p value of 0.0004 with no different between groups in terms of other adverse events studied (digital ischemia, mesenteric ischemia, hyponatremia, and myocardial infarction).

Overall, this study was well designed and makes a great argument for the use of vasopressin in patient’s with vasoplegia (+/- septic shock if you feel comfortable saying the physiologic states are similar which I think an argument can be made for) especially in patients at risk for renal failure or atrial fibrillation.

Gordon AC, Mason AJ, Thirunavukkarasu N, et al. Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock. JAMA 2016;316(5):509–10.

VANISH is a randomized control trial published in 2016 designed to compare vasopressin and norepinephrine as first-line vasopressors in septic shock by assessing for benefit in reducing sepsis-related renal dysfunction. It also studied the effect of steroids on these outcomes.

This was a factorial 2 x 2 trial across 18 UK ICUs, randomizing approximately 400 septic shock patients to either norepinephrine (titrated to 12 ug/min) or vasopressin (titrated to 0.06 units/min). Patients who required more than the designated maximum dose of either pressor were then randomized to steroid versus placebo and assessed for differences in renal dysfunction (the primary endpoint). Renal dysfunction was measured by their composite endpoint of days free of AKIN-3 renal failure which, briefly, is defined as any of the following: creatinine 3 times baseline, creatinine greater than 4, urine output < 0.3 cc/kg/hour for 24 hours, anuria x 12 hours, or dialysis initiated at any point. Secondary endpoints were overall creatinine, urine output, and dialysis during the 28 day period.

There was no statistically significant difference between vasopressin and norepinephrine with respect to the primary endpoint of AKIN-3 renal failure free days. However, vasopressin did show benefit across all three secondary endpoints. Reassuringly, there was no statistically significant difference in mortality between the two medications as first line pressors. Finally, steroids had no benefit over placebo.

Ultimately, this study does not provide a compelling reason to start vasopressin first in allcomers with septic shock. It did, however, exhibit some signal of benefit toward vasopressin in its secondary metrics of renal function (Cr, UOP, and dialysis), and certainly did not show any robust renal or mortality advantage for norepinephrine as first-line over vasopressin. This leaves vasopressin as a viable frontline option in septic shock — perhaps beneficial in those with renal dysfunction, but certainly advantageous for cases where norepinephrine’s beta adrenergic effects might be undesirable (e.g., atrial fibrillation with rapid ventricular response, other tachydysrhythmias with demand ischemia). VANISH is not a game-changer, but it does add a layer of nuance to our resuscitation of septic shock — and might prompt some to consider a vasopressin-first strategy in the right patients.

References

  1. Russel J, Walley K, Singer J, et al. Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock. N Engl J Med 2008;358(9):877–87.
  2. Hajjar L, Vincent JL, Galas FRBG, et al. Vasopressin versus Norepinephrine in Patients with Vasoplegic Shock after Cardiac Surgery. Anesthesiology 2016;126(1):85–93.
  3. Gordon AC, Mason AJ, Thirunavukkarasu N, et al. Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock. JAMA 2016;316(5):509–10.

Authorship by:

  • VASST Summary - Dr. Maika Dang
  • VANCS Summary - Dr. Anita Goel
  • VANISH Summary - Dr. Christian Renne