Vasopressin Versus Norepinephrine in Patients with Vasoplegic Shock after Cardiac Surgery: The VANCS Randomized Controlled Trial
Hajjar LA, Vincent JL, Barbosa Gomes Galas FR, et al. Anesthesiology. 2017; 126(1): 85–93.
Reviewers: Melissa A. Burger, MD1; Yong G. Peng, MD PhD FASE1
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL
Vasoplegic shock is a type of systemic inflammatory response characterized by hypotension refractory to fluids or vasopressors, low systemic vascular resistance, and high cardiac index. During cardiac bypass, vasodilator mechanisms are inappropriately activated. Decreased intracellular ATP, acidosis, and elevated lactate lead to opening of KATP channels, which hyperpolarizes the cells and inactivates voltage-gated calcium channels, rendering them unable to open in response to vasoconstrictors and contract vascular smooth muscle. Concomitantly, inflammatory cytokines lead to increased nitric oxide production and further vasodilation. To counteract inappropriate vasodilation, there is initially a massive release of vasopressin. As neurohypophyseal stores are depleted, a relative vasopressin deficiency develops. Smaller studies have suggested that vasopressin may be used in vasoplegia to reduce the total catecholamine requirement and associated side effects without causing other adverse events. This study is the first to directly compare vasopressin to norepinephrine for vasoplegia following cardiac bypass.
A prospective, randomized, double-blind, controlled, single-center trial was performed to compare vasopressin and norepinephrine in patients undergoing elective coronary artery bypass graft or valve repair/replacement who developed vasoplegic shock. Vasoplegic shock was defined as refractory hypotension (MAP<65 mmHg) resistant to fluid challenge (at least 1,000 ml crystalloid) with a cardiac index >2.2 L/min2/m2. Vasopressin (0.01–0.06 U/min) or norepinephrine (10–60 ug/min) was titrated to achieve MAP>65. Researchers modified the Society of Thoracic Surgeons risk score to create a composite score as a primary endpoint that included 30-day mortality, stroke, mechanical ventilation >48 hrs, deep sternal wound infection, reoperation, or acute kidney injury (AKI), defined as creatinine >2mg/dL, doubling of baseline creatinine, or need for renal replacement therapy (RRT).
Three hundred patients met criteria to receive the study medication, with 149 randomized to vasopressin and 151 randomized to norepinephrine. The primary composite outcome of death or postoperative complications within 30 days after surgery was 49% in the norepinephrine group and 32% in the vasopressin group (P=.0014; number needed to treat = 6). This difference was driven primarily by a reduction in AKI, from 35.8% with norepinephrine vs 10.3% with vasopressin. Post-hoc analysis using Acute Kidney Injury Network (AKIN) criteria demonstrated AKIN stage 2 and 3 AKI in 11.9% and 32.5% of the norepinephrine group vs 6.2% and 8.3% in the vasopressin group. Need for RRT was reduced from 13.9% to 2.7%. No difference was found in 30-day mortality, occurrence of stroke, mechanical ventilation requirement, deep sternal wound infection, or reoperation.
Secondary outcomes analysis found reduced occurrence of atrial fibrillation in the vasopressin group (63.8%) vs the norepinephrine group (82.1%). There was no difference in 30-day incidence of infection, septic shock, digital ischemia, mesenteric ischemia, acute myocardial infarctions, or hemodynamic effects. Median intensive care unit stay was reduced by 1 day, and median hospital stay was reduced by 3 days in the vasopressin group. The benefit of vasopressin was maintained regardless of beta-blocker use, but vasopressin did not reduce the primary endpoint in patients with recent use of angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists or blockers (ACEI/ARB).
Use of vasopressin in vasoplegic syndrome following cardiac surgery is associated with reduced risk of AKI and atrial fibrillation and may therefore be superior to norepinephrine. No increase in adverse events was observed in the vasopressin group.
Vasopressin has been associated with reduced risk of AKI and need for RRT in other trials. Vasopressin constricts glomerular efferent arterioles, increasing glomerular filtration, while norepinephrine constricts the afferent arterioles, decreasing glomerular filtration. This may translate to a clinically relevant difference. The VANISH trial, comparing vasopressin to norepinephrine in septic shock, found a reduced need for RRT in patients receiving vasopressin vs those receiving norepinephrine (25% vs 35%), although there was no difference in the broader composite endpoint of AKIN Stage 3 AKI. In the VASST trial, comparing vasopressin to norepinephrine in septic shock, vasopressin group patients in the RIFLE “Risk” category for AKI trended toward a lower rate of progression to “Failure” or “Loss” categories, and the vasopressin group required less RRT.
Norepinephrine acting on beta-1 receptors may increase incidence of atrial fibrillation. Patients treated with vasopressin required a shorter average duration of dobutamine, a beta-1 agonist, than patients with norepinephrine (40 vs 54 hours), which may have affected incidence of atrial fibrillation.
As a prospective, randomized, double-blinded trial that achieved adequate sample size to calculate the primary endpoint outcomes, the study design is strong. It was not powered to detect a difference in 30-day mortality. The VASST trial did not find a difference in 28-day mortality. Of some concern is the change in primary endpoint during patient data collection from the Brussels criteria to a modified STS score, apparently due to limited available outcome data on vasoplegia postcardiac surgery. This is a single-center trial, which reflects the healthcare outcomes and patient population of the Heart Institute at the University of Sao Paulo, Brazil. Further multicenter trials powered to detect mortality are warranted.