Vasopressin Offers No Survival Benefit for Septic Shock

By Crystal Phend
VANCOUVER, British Columbia, Feb. 27 -- Low-dose vasopressin does not reduce septic shock mortality when used as an adjunct to conventional catecholamine vasopressors, according to a randomized controlled trial.Mortality was similar whether patients received vasopressin or norepinephrine with open-label vasopressor therapy (P=0.26 at 28 days and P=0.11 at 90 days), reported James A. Russell, M.D., of St. Paul's Hospital here, and colleagues in the Feb. 28 issue of the New England Journal of Medicine.However, the lack of benefit may have been related to timing, commented Joseph E. Parrillo, M.D., of the University of Medicine and Dentistry of New Jersey and Cooper University Hospital, both in Camden, N.J., in an accompanying editorial.
Time from meeting the diagnostic criteria to infusion of the study drug averaged about 12 hours, whereas earlier studies have suggested treatment in the first six hours is most critical for survival.
"Treatment initiated at an average of 12 hours after the onset of septic shock may be too late for any vasopressor agent to show a significant effect on mortality," Dr. Parrillo wrote.
The timing of vasopressor therapy may be more important than the specific agent used, he said.
Although vasopressin is given widely in clinical practice, its use has been based on only two small, randomized trials that were underpowered to determine mortality, organ dysfunction, or safety outcomes, the researchers said.
So, they undertook an international trial of 778 critically ill patients with septic shock who were receiving at least 5 μg of norepinephrine per minute at baseline.
All patients received open-label vasopressors and were randomized to double-blind treatment with either low-dose vasopressin (0.01 to 0.03 U per minute) or norepinephrine (5 to 15 μg per minute).
These infusions were titrated and tapered per-protocol to maintain a target blood pressure.
At 28 days, there were no differences between the vasopressin and norepinephrine groups in the primary outcome of death from any cause (35.4% versus 39.3%, P=0.26).
Likewise, 90-day all cause mortality was similar for vasopressin and norepinephrine (43.9% and 49.6%, P=0.11), as were rates of organ dysfunction (P=NS for all organ systems).
Multivariate analysis did not change the lack of benefit for 28-day mortality (OR 0.88, 95% CI 0.62 to 1.26) or 90-day mortality (OR 0.81, 95% CI 0.57 to 1.16).
Adverse event rates were similar in the vasopressin and norepinephrine groups overall (10.3% versus 10.5%, P=1.00). Individual adverse event rates were similar as well.
Notably, though, cardiac arrest tended to be more common in the norepinephrine group than in the vasopressin group (2.1% versus 0.8%, P=0.14). Previous studies had suggested vasopressin could increase the incidence of cardiac arrest.
The lack of adverse cardiovascular events might have been because of the low vasopressin dose used an exclusion of patients with acute coronary syndrome or severe heart failure, the researchers said.
"If vasopressin becomes routine therapy and is given at higher doses or to patients with septic shock who have coexisting heart disease," they wrote, "the adverse reactions to vasopressin could be increased."
Another surprise, the researchers said, was that patients who had less severe septic shock tended to benefit from vasopressin more than patients who had more severe shock.
Survival trends and some post-hoc interaction analyses favored vasopressin in patients with less severe shock whereas there were no differences among more severely ill patients.
In the prospectively defined group of less severe septic shock, the mortality rate was lower in the vasopressin group than in the norepinepherine group at 28 days (26.5% versus 35.7%, P=0.05).
In the more severe septic shock group there was no significant difference in 28-day mortality (44.0% and 42.5%, respectively, P=0.76).
The researchers noted that the study may have been limited by treating without using vasopressin levels to guide the dose or duration of the infusion. In addition, many high-risk patients were excluded, a selection bias that might produce different results in a more "real-world" population.
Also, they said, since the mean arterial pressure at baseline was 72 to 73 mm Hg, the study was essentially of low-dose vasopressin as a "catecholamine-sparing drug" rather than for catecholamine-unresponsive refractory shock.
Dr. Parrillo concluded that there is no compelling reason for use of vasopressin, although it is apparently safe. He emphasized early treatment as a better way to improve survival.
"In both clinical practice and clinical trials," he concluded, "once hypotension occurs in septic shock, we need to initiate immediate antimicrobial therapy, cardiovascular support, and other effective therapies recommended by current guidelines."
The study was supported by a grant from the Canadian Institutes of Health Research.
Dr. Russell and two colleagues reported serving as officers and holding stock in Sirius Genomics, which has submitted a patent, owned by the University of British Columbia and licensed to Sirius Genomics, that is related to the genetics of vasopressin. The University of British Columbia has also submitted a patent related to the use of vasopressin in septic shock, on which Dr. Russell and two co-authors reported being inventors. Dr. Russell and a co-author reported receiving consulting fees from Ferring, which manufactures vasopressin. Dr. Russell reported receiving grant support from Sirius Genomics, Novartis, and Eli Lilly while another author reported support from Sirius Genomics.
Dr. Parrillo reported no conflicts of interest.
Primary source: New England Journal of MedicineSource reference:Parrillo JE "Septic shock -- vasopressin, norepinephrine, and urgency" N Engl J Med 2008; 358: 954-56. Additional source: New England Journal of MedicineSource reference: Russell JA, et al "Vasopressin versus norepinephrine infusion in patients with septic shock" N Engl J Med 2008; 358: 877-87.