Aminophylline in bradyasystolic cardiac arrest

Date First Published:
June 19, 2007
Last Updated:
June 19, 2007
Report by:
Elizabeth Hayward 1, Laurie Showler 2, Jasmeet Soar 1, F2 Trainee, SHO Palliative Care, Consultant Anaesthetics & ICU respectively (Southmead Hospital, North Bristol NHS Trust 1, Dr Kershaw's Hospice, Royal Oldham Hospital 2)
Search checked by:
Laurie Showler, Southmead Hospital, North Bristol NHS Trust 1, Dr Kershaw's Hospice, Royal Oldham Hospital 2
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:
Search Details:
[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)
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):
Study Title Patient Group Study type (level of evidence) Outcomes Key results Study Weaknesses
Aminophylline in bradyasystolic cardiac arrest: a randomised placebo-controlled trial. Abu-Laban RB, McIntyre CM, Christenson JM, 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
A randomized controlled trial of intravenous aminophylline for atropine-resistant out-of-hospital asystolic cardiac arrest. Mader TJ, Sminthline HA, Durkin L, 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%)
Aminophylline in undifferentiated out-of-hospital asystolic cardiac arrest. Mader TJ, Smithline HA, Gibson P. 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
Adenosine receptor antagonism in refractory asystolic cardiac arrest: results of a human pilot study. Mader TJ, Gibson P. 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)
Author Commentary:
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
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.
  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.
  3. Mader TJ, Smithline HA, Gibson P.. Aminophylline in undifferentiated out-of-hospital asystolic cardiac arrest.
  4. Mader TJ, Gibson P.. Adenosine receptor antagonism in refractory asystolic cardiac arrest: results of a human pilot study.