Can We Improve Our Vasopressor Management in Patients with Septic Shock?
Can We Improve Our Vasopressor Management in Patients with Septic Shock?
Abstract & Commentary
By Andrew M. Luks, MD, Pulmonary and Critical Care Medicine, University of Washington, Seattle, is Associate Editor for Critical Care Alert.
Synopsis: This multi-center, randomized, double-blind clinical trial demonstrated that the addition of vasopressin to patients receiving norepinephrine for management of septic shock had no effect on mortality when compared to increasing the norepinephrine dose.
Source: Russell JA, et al. N Engl J Med. 2008;358(9): 877-887.
Despite the large role that vasopressors play in the management of septic shock, an unfortunately common problem associated with high mortality, few data exist to support using one vasopressor regimen over another. Existing data focus on narrow endpoints such as changes in blood pressure or renal function and do not include information on broader endpoints such as mortality. Russell and colleagues addressed this problem by conducting a multi-center, randomized, double-blind trial to determine whether adding vasopressin in patients already receiving low doses of norepinephrine improved mortality as compared to increasing the norepinephrine dose.
The authors included patients over the age of 16 who had septic shock, had not responded to fluid administration, and required vasopressors including low-dose norepinephrine (> 5 µg/min). Patients were excluded if they had active myocardial ischemia or heart failure. Patients were stratified a prior as having "less severe" shock (requiring treatment with 5 to 14 µg/min of norepinephrine) or "more severe" shock (requiring treatment with >15 µg/min of norepinephrine). Patients were randomized to receive either vasopressin 0.03 U/min or norepinephrine at a dose of 5-15 µg/min. At the same time that patients received these study drugs, nurses titrated open-label vasopressors to maintain mean arterial pressures (MAP) of 65-75 mm Hg, with up-titration of these open-label agents performed only if the target MAP was not achieved at the maximal dose of the study drugs. When the target MAP was achieved, open-label vasopressors were titrated off before tapering of the study drugs commenced. Study drug infusions were stopped if patients developed acute ST elevations, life-threatening arrhythmias, acute mesenteric or digital ischemia, or hyponatremia (sodium < 130 mmol/L). The primary endpoint of the trial was 28-day mortality. The authors also examined 90-day mortality, the incidence of adverse events, and whether outcomes varied based on the severity of illness.
A total of 779 patients were included in the study. The 396 patients in the vasopressin group and the 382 patients in the norepinephrine group were well-matched except for a slight difference in age between the two groups. Of note, at the time of enrollment, the mean arterial pressures in the vasopressin and norepinephrine groups were 73 + 10 and 72 + 9 mm Hg, respectively. There was no significant difference between the vasopressin and norepinephrine groups in 28-day mortality (35.4% vs. 39.3%, p = 0.26), 90-day mortality (43.9% vs 49.6%, p=0.11) or the rates of serious adverse events (10.3% vs. 10.5%, p=1.0). When outcomes were examined according to the severity of illness, mortality at 28-days in patients with less severe septic shock was lower in the vasopressin group (26.5% vs. 35.7%, p=0.05) but there were no significant differences between treatments for patients with more severe disease (44% vs. 42.5%, p = 0.76).
Commentary
On the surface, this study is exactly the type of trial we need more of in critical care medicine. It focuses on a common problem and on commonly used therapeutic agents for which we currently lack sufficient data regarding their optimal use. Unfortunately, however, this particular trial does nothing to clear up questions regarding optimal vasopressor management in septic shock. A critical aspect of the study was the fact that the average MAP at the time the study drugs were initiated was 72-73 mm Hg, a value well above the level (65 mm Hg) most practitioners would consider adequate in septic shock. As a result, the data reveals little about how to manage septic shock in patients who are refractory to catecholamines, and instead only helps us decide whether vasopressin can have a catecholamine-sparing effect in patients who have an adequate blood pressure on such agents. The fact that 28-day and 90-day mortality did not differ between the treatment groups suggests that vasopressin may, in fact, have a catecholamine-sparing effect but, given that the incidence of adverse events was equal between the two groups, it is not clear that such an effect is of any real clinical significance. In the absence of such a benefit, it is hard to justify the additional time demands on pharmacy and nursing staffs and the financial cost to the patient associated with adding the second vasopressor if they already have an adequate MAP.
In the end this study does not do much to advance our knowledge about how to manage patients with septic shock. We are still left with the major questions regarding vasopressor management that we had before this trial: what is the best first-line vasopressor for patients with septic shock refractory to fluid administration, and, what is the optimal second-line vasopressor for those patients who fail to respond to first-line agents. The trial by Russell and colleagues shows that it is possible to study these questions in a multi-center framework, but more work is necessary before we have hard evidence to guide clinical practice.
Despite the large role that vasopressors play in the management of septic shock, an unfortunately common problem associated with high mortality, few data exist to support using one vasopressor regimen over another.Subscribe Now for Access
You have reached your article limit for the month. We hope you found our articles both enjoyable and insightful. For information on new subscriptions, product trials, alternative billing arrangements or group and site discounts please call 800-688-2421. We look forward to having you as a long-term member of the Relias Media community.