Which Vasopressor Is Best in Patients with Shock?

Abstract & Commentary

By Andrew M. Luks, MD, Pulmonary and Critical Care Medicine, University of Washington, Seattle. Dr. Luks reports no financial relationship to this field of study. This article originally appeared in the June 2010 issue of Critical Care Alert. It was edited by David J. Pierson, MD, and peer reviewed by William Thompson, MD. Dr. Pierson is Professor, Pulmonary and Critical Care Medicine, Harborview Medical Center, University of Washington, Seattle, and Dr. Thompson is Staff Pulmonologist, VA Medical Center; Associate Professor of Medicine, University of Washington; they both report no financial relationships relevant to this field of study

Synopsis: This randomized, multicenter trial showed no differences in 28-day mortality in patients with shock who received either norepinephrine or dopamine, but did reveal a higher incidence of arrhythmia in the dopamine-treated group.

Source: De Backer D, et al; SOAP II Investigators. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med. 2010;362:779-789.

Consensus guidelines recommend the use of either dopamine or norepinephrine as first-line therapy for patients with shock, but recent observational evidence suggests norepinephrine may be associated with better outcomes. De Backer et al sought to confirm these results in a prospective manner by evaluating whether one of these agents was associated with a lower mortality rate in patients with shock.

They conducted a double-blind, randomized trial at eight centers in three countries in which they enrolled patients at least 18 years of age who required a vasopressor for management of shock, defined as mean arterial pressure (MAP) < 70 mm Hg or SBP < 100 mm Hg despite receiving fluids, or having a central venous pressure (CVP) > 12 with signs of tissue hypoperfusion. Patients with all forms of shock, including septic, cardiogenic, and hypovolemic, were included. Patients were excluded if they had already received a vasopressor for > 4 hours during the current shock episode or had a serious arrhythmia (e.g., rapid atrial fibrillation).

Enrolled patients were randomized to receive either dopamine or norepinephrine. Dopamine was titrated in increments of 2 mg/kg/min up to a maximum of 20 mg/kg/min, for a target blood pressure determined by the treating physician, while norepinephrine was titrated in increments of 0.02 mg/kg/min up to a maximum dose of 0.19 mg/kg/min. Patients who remained hypotensive on the maximum dose of either agent were then started on open-label norepinephrine, while any patients on vasopressors at baseline were changed over to the study drug. Patients could still receive either hydrocortisone or recombinant activated protein C as part of sepsis management. The primary study endpoint was the rate of death at 28 days, while secondary endpoints included rates of death in the ICU, hospital, and at 6 and 12 months, ICU length of stay, number of days without organ support (e.g., mechanical ventilation, renal replacement therapy), time to reach MAP > 65 mm Hg, and use of dobutamine and other inotropic agents. The incidence of adverse events including arrhythmias, myocardial necrosis, skin necrosis, distal ischemia, or secondary infections, was also recorded.

A total of 1679 patients were enrolled in the study, including 858 in the dopamine group and 821 in the norepinephrine group. The groups were well matched in terms of major baseline characteristics including the use of hydrocortisone or activated protein C, but there were small differences in baseline physiologic variables such as the heart rate, PaCO2, and PaO2/FiO2 (P/F ratio). The majority (62%) of patients had septic shock, while 16.7% had cardiogenic shock and 15.7% had hypovolemic shock. With regard to the primary endpoint, there were no differences in the rate of death at 28 days between the dopamine and norepinephrine groups (52.5% vs. 48.5%; p = 0.10) and the trial was subsequently stopped due to a lack of evidence of benefit for one agent over the other. Of note, however, was the fact that the mortality rate in patients with cardiogenic shock was higher in those treated with dopamine than those treated with norepinephrine. ICU and hospital mortality and death rates at 6 and 12 months also showed no difference between the two groups. The incidence of adverse events was similar between the two groups except more patients in the dopamine group had arrhythmias, the most common of which was atrial fibrillation.

Commentary

Vasopressors are such commonly used medications in the ICU that it would be nice to have some data as to which agent is more effective for resolving hypotension and improving outcomes in critically ill patients. It is not clear, however, that this trial provides an adequate answer to that question, as there were some methodological issues that warrant concern. For example, patients received a fairly limited amount of intravenous fluids before the transition to vasopressors, and restrictions were placed on the doses of the vasopressors in an attempt to achieve "equipotent" doses despite the lack of data supporting such a practice.1

The biggest problem with the trial by De Backer and colleagues, however, is that they included patients with all forms of shock and did not restrict their study, for example, to patients with septic shock. It was particularly surprising that they included patients with hypovolemic shock, as the primary treatments for that problem are usually to stop any bleeding and restore intravascular volume with aggressive fluid administration. Given differences in the underlying pathophysiology and hemodynamic issues between the different forms of shock, the management of fluids and other medications in the different patient groups would be expected to vary significantly and perhaps make it difficult to tease out differences that one could attribute to one of the particular vasopressors. When one considers variations in physician practices not just between institutions but also between countries, it is not hard to see how many other factors may have been affecting outcomes beyond the choice of vasopressor.

Despite this issue, there are several interesting items that emerge from this study. The first pertains to the safety of using norepinephrine in the ICU. Many of us likely remember the days of reluctance to use that medication out of concern we might have been doing harm to our patients. The phrase "Levophed ... Leave 'em dead" was a not uncommon refrain early in my training before the institution made a broader move toward using that vasopressor and physicians became more comfortable with its application. This study and another recent study comparing vasopressin and norepinephrine2 provide reasonable evidence that such concerns are unwarranted and the medication is not associated with more severe adverse events when compared to dopamine.

The second item of note is the observed differences in mortality in the subgroup of patients with cardiogenic shock. From a theoretical point of view, one would expect a vasopressor with significant alpha-1 adrenergic activity to be problematic in patients with cardiomyopathy as the increase in afterload would impair left ventricular outflow. Dopamine has typically been favored in such situations because of its more prominent inotropic effects. The data from this study suggest, however, that the theoretical rationale may not hold in practice and perhaps give clinicians a little more leeway in their use of vasopressors in these patients, although further research is warranted to confirm this subgroup analysis finding before we make a wholesale change in practice. The fact that norepinephrine was associated with less arrhythmia than dopamine would be another advantage in this patient group.

References

1. Levy JH. Treating shock — old drugs, new ideas. N Engl J Med. 2010;362:841-843.

2. Russell JA, et al; VASST Investigators. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008;358:877-887.