Therapy VASST - Vasopressin versus Norepinephrine Infusion in patients with Septic shock
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Summary
Posted By:	Amit Kansal
E-Mail:	akan95@gmail.com
Posted Date:	27/07/08
Title:	VASST - Vasopressin versus Norepinephrine Infusion in patients with Septic shock
Authors:	Russell et al
Reference:	NEJM 2008 Feb; 358(9):877
Link:	Click here for a direct link to the paper. A password may be required for access to fulltext.
Abstract:	Background - Vasopressin is commonly used as an adjunct to catecholamines to support blood pressure in refractory septic shock, but its effect on mortality is unknown. We hypothesized that low-dose vasopressin as compared with norepinephrine would decrease mortality among patients with septic shock who were being treated with conventional (catecholamine) vasopressors. Methods - In this multicenter, randomized, double-blind trial, we assigned patients who had septic shock and were receiving a minimum of 5 µg of norepinephrine per minute to receive either low-dose vasopressin (0.01 to 0.03 U per minute) or norepinephrine (5 to 15 µg per minute) in addition to open-label vasopressors. All vasopressor infusions were titrated and tapered according to protocols to maintain a target blood pressure. The primary end point was the mortality rate 28 days after the start of infusions. Results - A total of 778 patients underwent randomization, were infused with the study drug (396 patients received vasopressin, and 382 norepinephrine), and were included in the analysis. There was no significant difference between the vasopressin and norepinephrine groups in the 28-day mortality rate (35.4% and 39.3%, respectively; P=0.26) or in 90-day mortality (43.9% and 49.6%, respectively; P=0.11). There were no significant differences in the overall rates of serious adverse events (10.3% and 10.5%, respectively; P=1.00). In the prospectively defined stratum of less severe septic shock, the mortality rate was lower in the vasopressin group than in the norepinephrine group at 28 days (26.5% vs. 35.7%, P=0.05); in the stratum of more severe septic shock, there was no significant difference in 28-day mortality (44.0% and 42.5%, respectively; P=0.76). A test for heterogeneity between these two study strata was not significant (P=0.10). Conclusions - Low-dose vasopressin did not reduce mortality rates as compared with norepinephrine among patients with septic shock who were treated with catecholamine vasopressors.
Are the Results Valid?
1. Was the assignment of patients to treatments randomized? ( Was allocation concealment maintained?)
	Yes. Eligible patients were randomly assigned by central telephone randomization system. A computer-generated random list of variable permutted blocks of 2, 4 & 6 was used and was stratified by centre & severity of shock in the hour before randomization.
2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?
2a. Was followup complete?
	YES. Only one patient was lost to follow-up & one in each group withdrew consent.
2b. Were patients analyzed in the groups to which they were randomized?
	YES. ITT analysis was done. (Primary analysis was not ITT - although results were similar in both analysis).
3. Were patients, health workers, and study personnel blind to treatment?
	Yes.
4. Were the groups similar at the start of the trial?
	YES - almost similar. Some significant differences in Age, No. of organ dysfunction & hemotological/ coagulation - although severity score was similar. Results remained unchanged after multivariate logistic regression analysis.
5. Aside from the experimental intervention, were the groups treated equally?
	similar co-interventions - shown in supplement.
What are the Results?
1. How large was the treatment effect?
	ITT analysis - no significant difference in primary outcome of 28 day mortality in two groups. (Primary analysis was not ITT - similar results though). No significant difference in secondary outcomes of 90 day mortality or incidence of serious adverse events. Subgroup analysis - Invalid because of -VE test of interaction between treatment assignment & severity of shock subgroup. {There was a trend towards lower mortality with vasopressin in LESS SEVERE SEPTIC SHOCK (p value 0.05 for 28 day mortality) - this remains hypothesis generating because of above-mentioned reason}.
2. How precise was the estimate of the treatment effect?
	ITT analysis - ARR 3.3% (CI -3.4% to 10%) for primary outcome of 28 day mortality. Although: 1. inadequate power - because observed mortality was 40% as against expected mortality of 60%, on which power calculation was based. 2. mean time to start of study drug was 12 hrs after meeting inclusion criteria - may be a crucial time window was lost as suggested earlier by importance of EGDT (Rivers et al).
Will the Results Help Me In Caring For My Patients?
1. Can the results be applied to my patient care?
	1. Study patients were usual Septic shock patients requiring >5mcg/min of noradrenaline equivalent (>8ml/hr of 2mg/50ml Noradr). 2. ACS/ CCF patients were excluded - previous studies have repoted increased incidence of cardiac arrest with vasopressin infusion, esp large doses >0.04 units/min. 3. There are concerns regarding use of vasopressin in septic shock secondary to Ischemic gut. {In our practice we introduce vasopressin 0.04 units/min once noradr dose requirements are >25mcg/min (>20 ml/hr of 4mg/50ml noradr).
2. Were all clinically important outcomes considered?
	YES - all serious adverse events were recorded & compared (STEMI, arrhythmias, digital/gut ischemia & hyponatremia).
3. Are the likely treatment benefits worth the potential harms and costs?
	No difference in mortality between two groups. But: 1. lack of power. 2. late start of study drug infusion. So, there is inconclusive evidence to change practice. There is potential 10% benefit in favor of vasopressin (CI -3% to 10%) against a risk of 3% harm. Vasopressin may be avoided in patients with ACS/ CCF to prevent cardiac complications.
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