Title: Effect of Early Vasopressin Vs Norepinephrine on Kidney Failure in Patients with Septic Shock: The VANISH Randomized Clinical Trial.
Gordon AC, Mason AJ, Thirunavukkarasu N, Perkins GD, Cecconi M, Cepkova M, Pogson DG, Hollmann DA HD, Anjum A, Frazier GJ, Santhakumaran S, Ashby D, Brett SJ for the VANISH Investigators. JAMA. 2016;316(5):509-518.
Back ground & Clinical Question:
Norepinephrine is the recommended first-line vasopressor in septic shock. A relative vasopressin deficiency in septic shock was described and there has been growing interest in the use of vasopressin as an adjunctive agent. Secondary analysis from VAAST study have suggested that early vasopressin might prevent deterioration in organ function, particularly kidney function. The Vasopressin Vs Norepinephrine as Initial Therapy in Septic Shock (VANISH) trial was designed to evaluate whether early vasopressin use would improve kidney outcomes compared with norepinephrine.
Factorial (2×2), multicenter, double blind, randomized clinical trial.
Setting (Population, Time frame & Enrolment):
Patients (≥16 years) who had sepsis (2 of 4 systemic inflammatory response (SIRS) criteria due to known or suspected infection) and required vasopressors after adequate intravenous fluid resuscitation.
February 2013 and May 2015.
18 general adult intensive care units (ICU) in the United Kingdom.
Patients were randomized to 1 of 4 treatment groups on 1:1:1:1 basis i.e. (vasopressin + hydrocortisone, vasopressin + placebo, norepinephrine + hydrocortisone, or norepinephrine + placebo) computer-generated random numbers, stratified by center.
Study drug 1- Noradrenaline and Vassopressin
Vasopressin (titrated up to 0.06U/min)
Norepinephrine (titrated up to 12 μg/min)
Mean arterial pressure (MAP) of 65 mm Hg.
Study drug 2 – Hydrocortisone or placebo
If maximum infusion rate of study drug 1 was reached. It was allowed to be weaned off more quickly if the shock had already resolved.
Hydrocortisone phosphate or placebo (intravenous I.V bolus every 6 hours for 5 days, every 12 hours for 3 days, and then once daily for 3 days).
Open-label catecholamine was added if hypotension persisted and weaned off prior to weaning of study drug 1.
The number of days alive and free of kidney failure, defined by the Acute Kidney Injury Network (AKIN) group stage 3 definition. As this outcome measure was not normally distributed and had a peak distribution at 28 days due to survivors who never developed renal failure, so they reported the data using two surrogate measures (decided prospectively)-
(1) Survivors who never developed kidney failure (nonsignificant among groups).
(2) the median number of days alive and free of kidney failure for the
other patients who did not survive, who experienced kidney failure, or both at any time (nonsignificant among groups).
Fewer patients in the vasopressin group required renal replacement therapy as compared to norepinephrine group in the initial 3 to 6 days particularly in the case of non-survivors. There was no significant difference in mortality rates between the groups in terms of mortality (28-day mortality, ICU mortality or hospital mortality).
Among adult patients presenting with septic shock, early use of vasopressin compared to norepinephrine did not improve the number of kidney failure–free days.
1.Double blind study
2.Adequate power of the study
3.Baseline characteristics are well matched in the groups
1.Short time outcomes (28 day and hospital mortality) without taking any long term outcome measures into consideration.
2.The exact timing of initiation of renal replacement therapy and the levels of hemodynamic monitoring were not controlled, only specifying that sites should follow the international guidelines.
3. Health economic analysis was not planned in a systematic manner.
Relevance to current practice:
Use of vasopressin for prevention of renal failure in septic shock cannot be justified. Though use of vasopressin in septic shock as a catecholamine sparing agent continues to be the current recommended practice.
Literature before this study and basis of the current trial:
Vasopressin & renal failure
A relative vasopressin deficiency has been proven in septic shock. It was postulated to be due to the following reasons (1)
Impaired vasomotor reflex in sepsis causing vasodilatory shock. When exogenous vasopressin was supplemented in these patients, a marked pressor response was demonstrated in this study. This was contributed to impaired autonomic function encountered in sepsis.
Depletion of neuro-hypophyseal store of vasopressin, which has been experimentally proven by injection of endotoxin in to animal models. The injection was followed by abrupt rise in vasopressin level in plasma followed by rapid decline over next few hours.(2)
When evaluating the better clinical profile of vasopressin compared to noradrenaline, two small studies published (3,4) and the posthoc analysis of VASST trial suggested a better renal outcome in terms of less number of renal failure and/or less requirement of renal replacement therapy in patients who received vasopressin. VAAST study analysis also concluded a mortality benefit for patients who are classified in “Risk” category of RIFLE classification on enrolment to the study.(5) But, none of the large clinical trial or meta-analysis (6) revealed any mortality benefit with vasopressin compared to noradrenaline.
Vasopressin & corticosteroid interaction in sepsis
Corticosteroids are reported to increase vasopressin mRNA.(7) Vasopressin also increases corticotroph responsiveness to corticotrophin releasing factor thereby increasing adre- nocorticotropic hormone. This response is even seen with high corticosteroid level.(8)
Multiple clinical trials reported a possible interaction between vasopressin and corticosteroid in reversing shock in sepsis. An initial animal study demonstrated that there was progressive decline in vasopressor response to vasopressin in induced endotoxemia which was significantly reversed with steroid (Methylprednisolone) administration.(9) Two retrospective case control studies demonstrated mortality benefit when steroid was added along with vasopressin compared to vasopressin alone in septic shock patients.(10,11) The posthoc analysis of VASST study also demonstrated a statistically significant interaction between vasopressin and corticosteroid and was reflected in the form of decreased mortality and organ dysfunction compared to norepinephrine and corticosteroid.(12)
Reference & further reading:
Landry DW, Levin HR, Gallant EM, et al. Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation. 1997;95 (5):1122-1125.
Wilson MF, Brackett DJ, Hinshaw LB, Tompkins P, Archer LT, Benjamin BA. Vasopressin release during sepsis and septic shock in baboons and dogs. Surg Gynecol Obstet.. 1981;153:869-872.
Patel BM, Chittock DR, Russell JA, Walley KR. Beneficial effects of short-term vasopressin infusion during severe septic shock. Anesthesiology. 2002;96(3):576-582.
Lauzier F, Lévy B, Lamarre P, Lesur O. Vasopressin or norepinephrine in early hyperdynamic septic shock: a randomized clinical trial. Intensive Care Med. 2006;32(11):1782-1789.
Gordon AC,Russell JA,Walley KR,etal. The effects of vasopressin on acute kidney injury in septic shock. Intensive Care Med. 2010;36(1):83-91.
Polito A Parisini E, Ricci Z, Picardo S, Annane D. Vasopressin for treatment of vasodilatory shock: an ESICM systematic review and meta-analysis. Intensive Care Med. 2012;38(1):9-19.
Pietranera L, Saravia F, Roig P, et al: Mineralo- corticoid treatment upregulates the hypotha- lamic vasopressinergic system of spontane- ously hypertensive rats. Neuroendocrinology 2004; 80:100 –110.
Aguilera G, Rabadan-Diehl C: Vasopressiner- gic regulation of the hypothalamic-pituitary- adrenal axis: Implications for stress adapta- tion. Regul Pept 2000; 96:23–29.
Ertmer C,Bone HG,Morelli A,etal. Methylprednisolone reverses vasopressin hyporesponsiveness in ovine endotoxemia. Shock. 2007;27(3):281-288.
Bauer SR,Lam SW,Cha SS,Oyen LJ. Effectof corticosteroids on arginine vasopressin-containing vasopressor therapy for septic shock: a case control study. J Crit Care. 2008;23(4):500-506.
orgersen C,Luckner G,Schröder DCH,etal. Concomitant arginine-vasopressin and hydrocortisone therapy in severe septic shock: association with mortality. Intensive Care Med. 2011; 37(9):1432-1437.
Russell JA,Walley KR,Gordon AC,etal;for the Vasopressin and Septic Shock Trial Investigators. Interaction of vasopressin infusion, corticosteroid treatment, and mortality of septic shock. Crit Care Med. 2009;37(3):811-818.
MD, FNB, FCCP,EDIC