Vancouver, BC - A study investigating the use of aminophylline in bradyasystolic cardiac arrest patients unresponsive to initial intervention has shown that the adenosine antagonist does not result in a return of spontaneous circulation [1]. Although the drug appeared to increase nonsinus tachyarrhythmias, investigators say that the routine addition of aminophylline to current treatment for bradyasystolic cardiac arrest is not recommended.

"The results are disappointing, but I am confident that we undertook a very rigorous study and that the answer to the question we asked is negative. Aminophylline does not have an overall effect as big, or bigger, than the one we were looking for," lead investigator Dr Riyad Abu-Laban (University of British Columbia, Vancouver, BC) told heartwire. "Whether there is no role for this drug is another question. There is certainly a suggestion that the drug is making a difference—it's clear that people have more tachyarrhythmias, that they change from bradyasystole to ventricular fibrillation and ventricular tachycardia at a quite a significantly higher rate than people who didn't get the drug—but it didn't translate to any benefit."

The results of the study are published in the May 13, 2006 issue of the Lancet.

Speaking with heartwire, Abu-Laban said that endogenous adenosine, which accumulates during hypoxia and ischemia, is thought to cause or perpetuate bradyasystole. Adenosine depresses the sinoatrial node, blocks atrioventricular conduction, inhibits pacemaker activity of the His-Purkinje system, and inhibits the effects of catecholamines. Smaller studies, as well as anecdotal reports, had suggested that aminophylline, an adenosine antagonist, could block the effects of adenosine and be used to improve the outcomes of bradyasystolic cardiac arrest patients, he said.

"Bradyasystole, pulseless bradycardia and asystole, accounts for a significant proportion of cardiac arrest, being the first rhythm in about half of all cardiac arrest patients," said Abu-Laban. "The outcome, at this point, is really quite dismal. And yet, within that group of bradyasystolic patients, there are those who do survive. It's a subgroup of cardiac arrest that has not been studied as extensively as ventricular fibrillation and ventricular tachycardia, but there is a lot of potential for interventions that, if they could make a difference in this group, would save a lot of lives downstream, even if the impact of the drug was modest."

Eight advanced life-support paramedic stations in the greater Vancouver and Chilliwack region of British Columbia participated in this randomized, placebo-controlled trial assessing the effects of aminophylline during cardiopulmonary resuscitation (CPR) of patients with out-of-hospital cardiac arrest. Paramedics treated the patients with protocols outlined by the American Heart Association guidelines. All patients underwent intubation, received ventilation, and were given 3 mg of atropine and 1 mg of epinephrine.

If normal resuscitation efforts failed, eligible patients received treatment with a drug kit randomized to contain either two 10-mL ampoules of placebo or 250 mg of aminophylline. The first ampoule was given as an intravenous bolus, and if the patient remained pulseless and in bradyasystole after 90 seconds of CPR, the second ampoule was administered. Resuscitation efforts were continued for 10 minutes after the last dose of aminophylline.

Overall, 94% of patients in the aminophylline group received both doses of the study drug, resulting in a total aminophylline dose of 500 mg. In terms of the primary end point, the return of spontaneous circulation, defined as the development of a palpable pulse of any duration, there was no difference between the use of aminophylline or placebo. Aminophylline did not improve survival to hospital admission, nor did the drug increase the proportion of patients who arrived at the hospital with a pulse.

Treatment with aminophylline did result in a significant 8.4% absolute increase in nonsinus tachyarrhythmias after aminophylline administration. According to investigators, the finding suggests that the drug does have a cardiovascular effect in the setting of cardiac arrest, but whether or not this will translate into a clinically meaningful benefit in certain subgroups is unknown.

Abu-Laban noted that the time from the arrival of paramedics until drug administration was approximately 13 minutes, due largely to the administration of standard medical treatment. It is not known whether earlier administration of aminophylline might have produced different results, although he said that this is approximately the same amount of time before drug administration in the earlier positive trials and is not likely to have affected the results.

Although the results of the study are definitive, Abu-Laban said that the effective use of medications in the CPR setting depends on proper resuscitation techniques. In particular, he notes that recent studies have shown that many health professionals do not perform CPR optimally. In many cases, compression rates are too low and ventilation rates too high, resulting in less perfusion, and it is possible that aminophylline administered with optimized CPR might result in different results, he noted.

"The problem is that it calls into question all of these negative drug trials in the past few years, including ours," said Abu-Laban. "It is possible that this drug, with optimized CPR, might be more beneficial, and we just couldn't detect it. It remains possible that this could be true for a lot of things we have looked at over the years."