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Three Part Question

In [adults with bradyasystolic cardiac arrest] does [the use of aminophylline as second line agent] increase [restoration of spontaneous circulation (ROSC) and improve long terms survival]?

Clinical Scenario

A 59 year old man has a witnessed out of hospital cardiac arrest and immediate bystander cardiopulmonary resuscitation (CPR). When the paramedic ambulance crew arrive after 8 minutes the first recorded rhythm is asystole. Resuscitation continues according to current ALS guidelines. The patient is intubated, ventilated with high flow oxygen and receives 1mg of adrenaline and 3mg of atropine iv. He remains in asystole after a further cycle (2 minutes) of CPR. You have heard that other agents may be useful at this stage and wonder if there is any evidence that iv aminophylline is effective.

Search Strategy

Medline 1950 to May Week 5 2007, Embase 1980 to 2007 Week 22, Cinahl 1982 to June Week 1 2007:
[exp xanthines/ methylxanthines.mp OR exp aminophylline/ aminophylline.mp OR exp theophylline/ theophylline.mp] AND [exp bradycardia/ bradycardia.mp OR exp heart arrest/ asystole.mp OR bradyasystole.mp OR cardiac adj arrest]
The Cochrane Library Issue 2 2007: (aminophylline):ti,ab,kw AND (cardiac arrest):ti,ab,kw 4 articles (duplicated in table)

Search Outcome

1154 papers were found from Medline, Embase and Cinahl databases, of which 4 were relevant and of a sufficient standard of evidence to critically appraise. Cochrane identified the same 4 articles and no additional articles.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Abu-Laban et al, 2006, Canada	971 patients older than 16 years with asystole or pulseless electrical activity at fewer than 60 beats per minute, and who were unresponsive to initial treatment with epinephrine and atropine. 486 aminophylline vs 485 control	Double-blind randomised control trial	ROSC	24•5% vs 23•7%	Average delay of 13min from paramedic arrival to drug administration. Adequacy of CPR not controlled for..
			Survival to hospital admission	NSD
			Survival to hospital discharge	NSD
Mader et al, 2003, USA	112, non-pregnant, normothermic adults (>21years) suffering nontraumatic out-of-hospital cardiac arrest with asystolic arrest for 2 minutes after administration of both atropine and epinephrine (doses not specified 66 aminophylline vs 45 control	Prospective, randomized, double-blinded, placebo-controlled trial	ROSC	22.7% (13% - 35%) vs 15.6% (6% - 29%)	Small trial
			Reversal of asystole	40.9% (29% - 54%) vs 26.7% (15% - 42%)
Mader et al, 1999, USA	82, non-pregnant, normothermic adults suffering nontraumatic out-of-hospital cardiac arrest with asystole. 37 aminophylline vs 45 control	Randomized, double-blinded, placebo-controlled trial	ROSC (defined as a palpable pulse of any duration)	27% (14-44%) 20%; (10-35%)	Small trial
Mader et al, 1997, USA	22 adults with nontraumatic asystolic out-of-hospital cardiac arrest. (14 aminophylline vs 8 control)	Prospective, randomized, double-blinded, placebo-controlled trial	Return of electrical activity defined as the occurrence of regular QRS complexes at a rate of (at or greater than)40 beats/min for at least 60 seconds, within 5 minutes of the study drug and before the administration of further drugs.	0 vs 7	Very small study. Results did not show any statistical improvement in ROSC. Disparity in presenting rhythm - control group contained significantly more patients with an initial rhythm of VF or PEA (p=0.008)
			ROSC	5 vs 1 (P=0.35)

Comment(s)

Aminophylline acts as adenosine antagonists on A1/A2 receptors. Adenosine is an endogenous purine nucleoside that depresses the sinoatrial node, blocks atrioventricular conduction, inhibits the pacemaker activity of the His-Purkinje system and attenuates the effects of catecholamines. Adenosine is produced and released by myocardial cells during ischaemia and hypoxia. Aminophylline blocking the actions of adenosine may therefore be useful in the treatment of bradyasystolic cardiac arrest. Out of the four relevant randomised control trails available none show a significant difference between the treatment and control groups with respect to ROSC. Since these trials were completed we now know that the quality of CPR is an important determinant of outcome from CPR. Unfortunately in these studies and all previous drug studies in cardiac arrest patients there is no measure to ensure the patients received good quality CPR

Clinical Bottom Line

Aminophylline does not improve survival from bradyasystolic cardiac arrest

References

1. Abu-Laban RB, McIntyre CM, Christenson JM, et al. Aminophylline in bradyasystolic cardiac arrest: a randomised placebo-controlled trial. Lancet 2006;367: 1577-84.
2. Mader TJ, Sminthline HA, Durkin L, et al. A randomized controlled trial of intravenous aminophylline for atropine-resistant out-of-hospital asystolic cardiac arrest. Acad Emerg Med 2003;10(3):192-7.
3. Mader TJ, Smithline HA, Gibson P. Aminophylline in undifferentiated out-of-hospital asystolic cardiac arrest. Resuscitation 1999;41(1):39-45.
4. Mader TJ, Gibson P. Adenosine receptor antagonism in refractory asystolic cardiac arrest: results of a human pilot study. Resuscitation 1997;35(1):3-7.