Hypoxia and ischemia lead to the interstitial accumulation of endogenous adenosine [3], a metabolite with pronounced depressant effects on atrioventricular nodal conduction as well as on automaticity of cardiac pacemakers (sinus node, atrioventricular junction, His bundle, and Purkinje fibers) [3-5]. Aminophylline, a competitive antagonist of adenosine [6], has been used to treat atrioventricular conduction disturbances related to inferior myocardial infarction, with conflicting results [7, 8]. These and other studies on the effects of aminophylline on bradyarrhythmias [3] have been of relatively stable patients. We evaluated the effects of aminophylline during bradyasystolic arrest refractory to conventional therapy.

Methods

Top Methods Results Discussion Author & Article Info References

The Tel Aviv Medical Center is a 650-bed university hospital. If cardiac arrest occurs, a resuscitation team including a cardiologist can be summoned. Basic and advance life support are started immediately by medical personnel in the ward, including defibrillation and administration of a "first round" of drugs. Thus, if the resuscitation team is summoned, it is usually for patients who failed to respond to these initial resuscitation procedures.

Beginning in 1992, the cardiologist in the resuscitation team administered aminophylline to all patients who fulfilled all of the following criteria: 1) apnea without central pulse; 2) asystole or severe bradyarrhythmia [heart rate < 30 beats/min] documented as a primary arrhythmia or after defibrillation; 3) failure to respond to closed-chest cardiac massage and mechanical ventilation with 100% oxygen; 4) failure to respond to atropine ( 2 mg) and epinephrine [ 2 mg] given intravenously and followed by saline flushing; 5) consent from the physician in charge of the patient at the ward. Patients with cardiac arrest secondary to trauma or terminal cardiogenic shock were not included. Aminophylline (Teva Pharmaceuticals, Jerusalem, Israel), 250 mg, was administered as a rapid bolus through the same vein where the previous drugs had been given. The study was approved by the Ethical Committee of the hospital.

Results

Top Methods Results Discussion Author & Article Info References

Fifteen consecutive patients (11 men and 4 women, aged 71 ± 11 years) with cardiac arrest not responding to atropine and epinephrine were treated with aminophylline. Cardiac arrest occurred after myocardial infarction or deterioration of heart failure or sepsis in five, eight, and one patient, respectively. One patient had in-hospital sudden death after surgery. Cardiac arrest was not witnessed in nine patients. Asystole was the first rhythm recorded during cardiac arrest in 11 patients, whereas asystole or a pulseless bradyarrhythmia occurred after defibrillation in the last 4 patients. Before aminophylline administration, all patients received 2 to 7 mg (3.8 ± 2.2 mg) epinephrine and atropine (2 mg), and one patient also received isoproterenol.

Immediate Response to Aminophylline

In 11 of the 15 patients with cardiac arrest refractory to epinephrine and atropine, a stable heart rhythm (rate 75 beats/min with measurable blood pressure) appeared within 30 seconds of the aminophylline injection (Figure 1). In all but 4 of these 11 patients, a supraventricular rhythm occurred after aminophylline injection. In the last four a regular wide QRS tachycardia, probably of ventricular origin (110 to 160 beats/min), was initially recorded; the tachycardia eventually converted to sinus rhythm without additional intervention. Sinus rhythm without palpable pulses was obtained in one additional patient. Thus, cardiac electrical activity was restored in 12 of 15 patients after aminophylline injection. The other three patients, who showed no restoration of spontaneous electrical activity, had cardiac arrest that was not witnessed: These patients failed to respond to atropine, high-dose epinephrine, and aminophylline; they also failed to respond to isoproterenol and cardiac pacing.

View larger version (22K): [in this window] [in a new window]   Figure 1. Electrocardiographic recordings from a patient brought to the emergency room after unsuccessful out-of-hospital attempts at resuscitation. Recordings were done at 25 mm/sec paper speed during momentary discontinuation of closed-chest cardiac massage. First strip (recorded at 20:27 hours in a mobile coronary care unit) shows external cardiac pacing through chest wall leads with 2:1 pacing-block, after atropine (2 mg) plus epinephrine (1 mg) had no effect on asystole. Strips 2 and 3 (recorded at 20:29 and 20:31 hours during transportation to the hospital) show that external pacing with maximal output energy is less effective despite continuous ventilation with 100% oxygen and repeated epinephrine injections (1 and 5 mg). Strip 4 (recorded at the time of arrival to the emergency room, which was 20:32 hours) shows that external pacing was not effective; therefore, it was discontinued. Strip 5 (recorded at 20:34 hours) shows that, after aminophylline administration, sinus rhythm (75 beats/min) is restored. Total elapsed time between the first and fifth ECG strips was 7 minutes.

Short-Term Outcome

All the 11 patients who had a good immediate response to aminophylline were alive 60 minutes after resuscitation; however, 10 of these patients eventually died 4 hours to 15 days after resuscitation. Death was caused by cardiogenic shock after resuscitation (eight patients) or anoxic brain damage (two patients) without further attempts at resuscitation. Only one of these patients had a malignant ventricular tachyarrhythmia after aminophylline administration. This patient originally had ventricular fibrillation with eventual drug-refractory asystole. A spontaneous heart rhythm appeared after aminophylline injection, but ventricular fibrillation recurred 15 minutes later. Again, asystole occurred after defibrillation, and only sporadic QRS complexes appeared after repeated epinephrine and atropine administration. Isoproterenol failed to accelerate this ventricular rhythm. In contrast, aminophylline promptly restored spontaneous, stable heart rhythm once again. Finally, one patient was discharged alive and without brain damage.

Discussion

Top Methods Results Discussion Author & Article Info References

Our patients with bradyasystolic arrest responded immediately after aminophylline administration; their cardiac electrical activity was restored. A stable heart rhythm, with sufficient blood pressure to allow discontinuation of closed-chest cardiac massage, was achieved in 11 of 15 consecutive patients with bradyasystolic cardiac arrest who had been refractory to treatment with epinephrine plus atropine. This represents a new approach to the treatment of asystole, which until now has been limited to manipulations of the adrenergic system, using either higher epinephrine doses or specific -adrenergic stimulators [9].

Extreme bradycardia and transient asystole are dose-dependent effects of intravenously administered adenosine [3]. Thus, release of endogenous adenosine to the myocardial interstitium occurring during hypoxemia or anoxia [3] could cause or perpetuate such bradyarrhythmias. The salutary effects of aminophylline might have been mediated by its competitive antagonism with accumulated endogenous adenosine. In addition, aminophylline may have acted synergistically with previously administered epinephrine by inhibiting phosphodiesterase activity or by further releasing endogenous catecholamines [10]. Finally, adenosine attenuates the positive chronotropic effects of ß-adrenergic stimulation on ventricular pacemakers at the level of the His-Purkinje system, and this antiadrenergic effect of adenosine may be abolished with aminophylline [5].

Our doses of epinephrine are in agreement with current recommendations [2]. Restoration of sinus rhythm could have been coincidental and unrelated to aminophylline administration. However, appearance of a stable heart rhythm within seconds of aminophylline administration, regardless of the time previously spent with resuscitation maneuvers, is a result that makes this possibility unlikely. Endogenous adenosine may prevent reperfusion injury to the heart and brain [11]; thus, the eventual death of our patients could have been due to adenosine antagonism induced with aminophylline. A more plausible explanation for this poor outcome relates to several characteristics of our patients, which are known predictors of an adverse prognosis, namely, severe underlying disease, asystole, and cardiac arrest that is not witnessed [1]. Patients eventually responding to cardiac support maneuvers or to atropine or epinephrine were not included in our study; therefore, only patients at high risk for immediate death were actually treated with aminophylline. Thus, rather than discouraging the use of aminophylline, the dramatic response to aminophylline after prolonged unsuccessful efforts with other drugs indicates that aminophylline might be used earlier in resuscitation maneuvers.