Key Point

Compared with norepinephrine, low-dose vasopressin used in conjunction with catecholamine vasopressors in septic shock does not significantly reduce mortality.

Although it is common practice to use vasopressin as an adjunct to catecholamines in the treatment of severe septic shock, there is little in the medical literature to determine a safety or mortality profile. To shed some light on this issue, researchers led by James A. Russell, MD, from St. Paul’s Hospital in Vancouver, British Columbia, conducted a multicenter, randomized, head-to-head comparison of low-dose vasopressin and norepinephrine (both administered in conjunction with catecholamine vasopressors). Contrary to their hypothesis, the study authors found that, overall, vasopressin did not reduce mortality rates, compared with norepinephrine; however, there was a trend toward reduced mortality among patients with less severe septic shock.

“Our findings showed that in patients who had less severe septic shock, mortality was 26.5% for the vasopressin-treated group, compared to 35.7% for the norepinephrine-treated group,” Dr. Russell told Pulmonary Reviews. “This research provides more data for physicians and care teams to show that selective infusion of vasopressin in patients who have less severe septic shock has the potential to save the lives of thousands of septic patients.”

As reported in the February 28 New England Journal of Medicine, VASST (Vasopressin and Septic Shock Trial) was conducted in 27 centers in Canada, Australia, and the United States. Eligible patients were older than 16 and had septic shock that was resistant to fluids and low-dose norepinephrine. A total of 802 patients were randomized to infusion with either low-dose vasopressin (ie, 0.1 to 0.03 U per minute) or 5 to 15 μg of norepinephrine per minute; 778 patients were included in the final primary analysis of all-cause 28-day mortality.

There was no significant between-group difference in 28-day mortality (35.4% and 39.3% in the vasopressin and norepinephrine groups, respectively). With regard to secondary outcomes, there was no significant difference in 90-day mortality, rates of organ dysfunction, or rates of adverse events. In the norepinephrine group, there was a trend toward a higher rate of cardiac arrest than in the vasopressin group (2.1% vs 0.8%), while there was a trend toward a higher rate of digital ischemia among patients in the vasopressin group than in the norepinephrine group (2.0% vs 0.5%).

The researchers also assessed patients according to the a priori strata of having more severe septic shock (ie, requiring at least 15 μg of norepinephrine per minute or the equivalent at the time of randomization) and having less severe septic shock (requiring 5 to 14 μg of norepinephrine per minute). They found that there were trends in favor of the vasopressin group with respect to both 28- and 90-day mortality for patients with less severe septic shock. There were no significant differences in mortality between the two treatment groups among patients with more severe septic shock. Test results for heterogeneity between the two strata were not significant.

One limitation of the study was that the mean time from meeting the criteria for study entry to infusion of the study drug was 12 hours, the investigators pointed out. By contrast, research by Rivers et al identified early goal-directed therapy as six hours, “which may be one reason that we did not find a benefit of vasopressin as compared with norepinephrine,” Dr. Russell and colleagues pointed out.

“In light of our findings, some experts are recommending that a new trial of vasopressin in patients who have less severe septic shock is necessary to confidently determine whether vasopressin decreases their mortality,” Dr. Russell remarked.

“We suggest that early intervention is very important in treatment of septic shock, whether one uses norepinephrine alone or the combination of vasopressin and norepinephrine.”

The findings of vasopressin’s benefits among patients with less severe septic shock warrant further research, said editorialist Joseph E. Parrillo, MD, from the Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, and Cooper University Hospital, both in Camden, New Jersey. However, it seems that the timing rather than the specific agent may be the most important factor in improved outcomes.

“Once hypotension occurs in septic shock, we need to initiate immediate antimicrobial therapy, cardiovascular support, and other effective therapies recommended by current guidelines,” Dr. Parrillo concluded.

—Adriene Marshall

Suggested Reading
Parrillo JE. Septic shock: vasopressin, norepinephrine, and urgency. N Engl J Med. 2008;358(9):954-956.
Russell JA, Walley KR, Singer J, et al; VASST Investigators. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008;358(9):877-887.

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