Treating shock--old drugs, new ideas.

Circulatory shock is a medical emergency that is characterized by hypotension and decreased tis­ sue perfusion; if left untreated, it can lead to ir­ reversible cellular injury and death. Hypotension associated with shock can be the result of any of a number of factors, depending on the type of shock; these include biventricular dysfunction, in­ travascular hypovolemia, and the vascular effects of inflammatory responses. Irrespective of the un­ derlying cause of shock, the treatment includes initial resuscitation with vasopressors, volume ex­ pansion (performed cautiously in patients with heart failure), and additional therapy for multi­ organ system dysfunction, concomitantly with correction of the underlying cause. A critical ques­ tion is which vasopressor should be used initial­ ly. The answer is complicated by the difficulty in conducting prospective, randomized trials in­ volving acutely ill patients. Clinicians make an initial choice of vasopres­ sor on the basis of published guidelines, individ­ ual experience, and institutional bias. Dopamine, the precursor for norepinephrine in the sympa­ thetic nervous system, is recommended as a first­ line agent.1,2 However, patients in shock may have a diminished response to indirect­acting agents such as dopamine.3 In the case of patients with heart failure, a large component of the response to dopamine is neuronal release of norepineph­ rine.3 When endogenous norepinephrine is deplet­ ed in shock states, indirect­acting agonists such as dopamine are less able to produce this response.3 In this setting, direct­acting agents such as epi­ nephrine or norepinephrine may have improved efficacy. Epinephrine is used for resuscitation and to treat anaphylaxis, but its β2­adrenergic effects can cause hyperglycemia, acidosis, and other ad­ verse effects. Norepinephrine is an endogenous α1­adrenergic vasoconstrictor and a β1­adrenergic agonist that is stored in the sympathetic nerve terminal. In recent years, vasopressin has been increasingly used to treat the hypotension asso­ ciated with shock.4 Vasopressin may be partic­ ularly effective in reversing mediator­induced vasodilatory shock in patients with sepsis or anaphylaxis.4,5 In this issue of the Journal, De Backer et al. re­ port the results of a multicenter trial in which they randomly assigned 1679 patients to receive either dopamine or norepinephrine as first­line vaso­ pressor therapy to treat circulatory shock.6 The type of shock that occurred most frequently was septic shock (1044 patients, 62.2%), followed by cardiogenic shock (280 patients, 16.7%) and hypo­ volemic shock (263 patients, 15.7%). The primary outcome was the rate of death at 28 days after randomization; secondary end points included ad­ verse events and the number of days without need for organ support. The use of corticosteroids was similar in the two groups (40.1% of patients in the dopamine group and 39.7% of those in the nor­ epinephrine group), as was the use of activated human protein C in patients with septic shock (18.8% in the dopamine group and 19.1% in the norepinephrine group). There was no significant difference in the rate of death at 28 days between patients who were treated with dopamine (52.5; 95% confidence interval [CI], 49.2 to 55.9) and those who were treated with norepinephrine (48.5; 95% CI, 45.1 to 51.9). However, arrhythmias were more frequent in the dopamine group than in the norepinephrine group (24.1% vs. 12.4%, P<0.001), and among the patients with cardiogenic shock, the rate of death at 28 days was higher among those treated with dopamine than among those treated with norepinephrine (P = 0.03 by Kaplan–