The prospective, randomized, controlled, multicenter study was conducted to assess the effects of vasopressin and epinephrine on survival among adults who had an out-of-hospital cardiac arrest and who presented with ventricular fibrillation, pulseless electrical activity, or asystole requiring CPR.

In total, 1186 patients were randomized to receive two ampules of 1-mg epinephrine or two ampules of 40-IU vasopressin. If spontaneous circulation was not restored within three minutes after the first injection of the study drug, the same drug at the same dose was injected again. If spontaneous circulation still failed, the patient was given an additional injection of epinephrine at the discretion of the emergency physician administering CPR.

The primary end point of the study was survival to hospital admission, and the secondary end point was survival to hospital discharge.

The rates of survival to hospital admission were similar between the two treatment groups for both patients with ventricular fibrillation and those with pulseless electrical activity. However, patients with asystole were more likely to survive to hospital admission and to hospital discharge if they were treated with vasopressin than if they received epinephrine as initial therapy.

The entire study was a bit of a surprise.

"The entire study was a bit of a surprise," said Wenzel. "We saw advantages in the ventricular-fibrillation models in the laboratory, so we expected an advantage with vasopressin in these patients, which we didn't find. On the other hand, in the asystole cardiac patients we found an advantage with vasopressin, which we hadn't been expecting."

Wenzel added, however, that the findings are in agreement with previous laboratory studies that showed vasopressin appears to work best when ischemia is substantial. Such observations also appear to be supported by the results of the subgroup analysis, those patients requiring more than two injections who were treated with epinephrine in accordance with the study's protocol.

In the analysis of the 732 patients in whom spontaneous circulation was not restored with the administration of the initial study drug, additional treatment with epinephrine resulted in a significant improvement in the survival rate in the vasopressin patients but not the patients who received epinephrine.

Wenzel said investigators are unclear why the administration of epinephrine after vasopressin improved the rate of survival to hospital admission and hospital discharge in these patients. In the discussion section of the paper, the investigators speculate that the interactions among vasopressin, epinephrine, and the underlying degree of ischemia during CPR may be more complex than previously thought.

"The impression that we have is that the two vasopressors just seem to help each other," said Wenzel. "If the ischemia is substantial and immediately life-threatening, vasopressin probably helps. We also found this in our intensive care unit during cases of septic shock. When we injected both drugs, things seem to work out better."

Wenzel and colleagues report that cerebral performance was similar in the vasopressin and epinephrine patients who survived to discharge.

In an enthusiastic editorial accompanying the published study, Dr Kevin M McIntyre (Brigham and Women's Hospital, Boston, MA) called the demonstrated success of vasopressin alone and vasopressin followed by epinephrine in refractory asystolic cardiac arrest an important breakthrough in the science of resuscitation.2

"These advances should be translated into a new standard of care without delay," writes McIntyre. "Medical policy makers should do whatever is necessary to facilitate the orderly implementation of new guidelines based on this new information."

These advances should be translated into a new standard of care without delay.

Because of the size and power of the present study, the dismal rate of resuscitation among these patients, and the apparent absence of any added risk of injury to patients treated with the new sequence of therapy, McIntyre encourages practitioners to incorporate the use of vasopressin into their resuscitation protocols immediately.

"The best approach to optimizing survival as soon as possible would be to have the appropriate committees of the American Heart Association and the American College of Cardiology convene in order to issue an interim guideline incorporating these important new therapeutic advances," concludes McIntyre.

Wenzel, who is cochair of the Advanced Cardiac Life Support committee of the European Resuscitation Council, said the council would likely publish a position paper based on this research to disseminate the information to a wider audience. He also added that the continued delivery and marketing of vasopressin is essential to the drug being used by emergency physicians treating cardiac-arrest patients.

"Vasopressin is an orphan drug," said Wenzel. "Currently in the US, there are no delivery problems, but in Europe we have plenty of them, which we think is ridiculous. Fortunately, we have found a small French company that is willing and able to market the drug. Otherwise, this would have been an academic phenomenon caught in a black hole."