Adenosine-Induced Tachyarrhythmia and Cardiac Arrest

Adenosine, an endogenous purine nucleoside, induces transient atrioventricular blockade (AVB) by suppressing sinus and atrioventricular node conduction. A lower intravenous dose (3–12 mg) is commonly used as an antiarrhythmic agent. Adenosine is also a known potent vasodilator of coronary and cerebral resistance vessels [1,101]. Adenosine acts on the A2 cell membrane receptor to increase the potent vasodilator cAMP; its action on this receptor is inhibited by both caffeine and theophylline. Adenosine is competitively antagonized by methylxanthines and potentiated by blockers of nucleoside transport such as dipyridamole. Adenosine-induced bradycardia is unlikely to be reversed by atropine. Adenosine has been effectively administered in the presence of quinidine, b-blockers, calcium-channel blocker agents and angiotensin converting enzyme inhibitors, without any change in the adverse reaction profile. Digoxin and verapamil use may be rarely associated with ventricular fibrillation when combined with adenosine. Carbamazepine has been reported to increase the degree of heart block produced by other agents [101].

In healthy coronary arteries, the vasodilator response to the rise in cAMP during the standard protocol adenosine infusion results in a four- to five-fold increase in coronary blood flow. Therefore, adenosine has been used effectively in pharmacological myocardial stress tests [2]. Is it too safe? In coronary artery disease, the predisposing factors to the development of regional ischemia (or even myocardial infarction) from adenosine infusion included transmural steal or diversion of blood from the subendocardium to the subepicardium in territory supplied by a stenosed vessel, reduction of distal perfusion pressure arising from increased flow across a stenosis and a generalized fall in perfusion pressure secondary to adenosine-induced vasodilatation with a reduction in flow through high-resistance collateral vessels supplying vulnerable territory [2].

Therapeutically, adenosine is commonly used to treat supraventricular tachycardia (SVT). After a bolus injection, the heart rate is dose-dependently reduced until a complete AVB is reached. However, this effect on the atrioventricular node is transient and of short duration owing to the rapid inactivation of adenosine in human plasma by uptake into erythrocytes and endothelial cells. Is it too safe? Higher doses of adenosine cause high-degree AVB, resulting in ventricular asystole and profound hypotension.Therefore, doses greater than 12 mg are not recommended for adult or pediatric patients [101]. AVB is not uncommon when adenosine infusions are given during cardiac stress testing. In one study of 600 patients, adenosine infusion (140 µg/kg/min for 6 min) produced first-, second- and third-degree AVB in 13, 10 and 2% of patients, respectively [5,101]. The frequency of AVB depended upon the age group. The conduction block was of short duration and did not require discontinuation of adenosine administration. However, nuclear stress testing in patients with evidence of underlying conduction system disease may result in sustained second-degree AVB requiring the insertion of permanent pacemaker [3,4].

Adenosine side effects

Side effects of adenosine included; facial flushing (18%), headache (2%), sweating, palpitations, chest pain, hypotension (<1%), shortness of breath (12%), chest pressure (7%), hyperventilation and head pressure (<1%), lightheadedness (2%), dizziness, tingling in the arms, numbness (1%), apprehension, blurred vision, burning sensation, heaviness in the arms, neck and back pain (<1%), nausea (3%), metallic taste, tightness in the throat and pressure in the groin (<1%).

Postmarketing experience reported many adverse effects of adenosine such as prolonged asystole, ventricular tachycardia, ventricular fibrillation, transient increase in blood pressure, bradycardia, atrial fibrillation (AF), torsade de pointes, bronchospasm and seizure activity, including tonic clonic (grand mal) seizures and loss of consciousness [101].

Adenosine-induced asystole

Adenosine-induced transient asystole has been used to facilitate cerebral aneurysm clipping, endovascular repair of thoracic aortic aneurysms and coronary artery bypass grafting. In such indications, adenosine-induced cardiac arrest is a preferable method in patients with prior heart surgery, old age or in some emergency settings [5]. However, dose–response characteristics of adenosine-induced ventricular asystole have not been well studied. Plaschke et al. studied hemodynamic and cerebral function after cardiac arrest induced by high doses of adenosine in patients undergoing thoracic aorta endovascular repair [5]. Cardiac arrest was induced by different doses of adenosine (0.4–1.8 mg/kg of bodyweight). After adenosine-induced cardiac arrest, changes in hemodynamic variables and electroencephalogram power spectra reversed completely (within 1 and 5 min, respectively) without persistent brain dysfunction after stent graft implantation [5]. Adenosine dose-dependently induced a rapid cardiac arrest during stent implantation in thoracic aorta endovascular surgery. This was paralleled by transient (<1 min) and significant (up to 70%) reductions in arterial pressure. Fast systemic regulatory mechanisms and rapid adenosine inactivation could be responsible for this short cardiac arrest. The half-life of adenosine in human plasma was determined to be less than 10 s at therapeutic doses. Therefore, cardiac arrest can only be reached when high adenosine doses are administered by bolus injection. A characteristic linear and curveilinear relationship was determined between changes in adenosine dose and the duration of cardiac arrest. With adenosine doses below 1.0 mg/kg, there was a linear relationship between the two parameters. By contrast, with higher adenosine doses (>1.0 mg/kg), a plateau was reached [5].

Furthermore, during endovascular embolization of cerebral arteriovenous malformations, Hashimoto et al. performed a series of adenosine test injections to establish a dose–response relationship in each patient [1]. The adenosine dose was 0.98 mg/kg and the dose range was 0.24–1.76 mg/kg (6–90 mg). The durations of asystole, mean arterial pressure less than 30 mmHg and mean arterial pressure less than 50 mmHg were 8 ± 3 s, 18 ± 12 s and 5 ± 29 s, respectively [1]. Based on the linear relationship, it was calculated that an adenosine dose of 0.017 mg/kg of bodyweight is necessary to obtain cardiac arrest for 1 s. For example, in a patient weighing 80 kg, the mean dose of adenosine required to reach cardiac arrest for at least 20 s in duration would be 30 mg.

Moreover, in cases of a sudden aneurysm rupture, adenosine-induced circulatory arrest was found to be a safe option to facilitate clipping of an aneurysm; this was demonstrated by Luostarinen et al.[6]. In this study, 12 patients were administered a single dose of adenosine and four multiple boluses for induction of cardiac arrest; the median total dose was 12 mg and 27 mg, respectively. The clipping of the aneurysm and the recovery of circulation were uneventful in all cases [6].

Suppressing atrial tachyarrhythmia may precipitate another tachyarrhythmia

Adenosine is effective in terminating AV nodal re-entry tachycardia, but this has also been reported as having been induced by adenosine; adenosine has also been shown to provoke an AV re-entry tachycardia [7,8]. AF has been reported after adenosine administration and even the induction of AF by adenosine is now well-recognized and in some cases it has been associated with ventricular pre-excitation and hemodynamic collapse [7]. In one study of 200 patients with SVT undergoing electrophysiologic testing, the incidence of AF after the administration of 12 mg of adenosine was 12% [7,9]. In another study, the occurrence of AF was related to the mechanism of the SVT (15% with atrioventricular re-entrant tachycardia, 11% with atrial tachycardia and 17% with a junctional reciprocating tachycardia) [10]. Adenosine-induced shortening of the atrial action potential and the atrial refractory period, and the induction of frequent ectopic complexes, are participating factors for the occurrence of AF [11].

Ventricular dysrhythmia after adenosine

Nonsustained monomorphic ventricular tachycardia is frequently seen after the administration of adenosine, and it has also occurred during pharmacological stress testing with adenosine [7,12]. Moreover, after therapeutic and diagnostic adenosine administration, ventricular standstill and asystole have been reported in addition to prolonged sinus arrest and bradycardia with subsequent syncope and seizure [7,13]. Increases of the ventricular rate in atrial flutter have followed the administration of adenosine, with conduction increasing from 2:1 to 1:1 after a brief period of high-grade AVB [7,14,15]. Adenosine has also been found to substantially increase the ventricular rate in an existing AV re-entry tachycardia [7].

One of the few prospective studies that evaluated the arrhythmogenic hazard of adenosine treatment in an emergency room concluded that, first, adenosine-induced proarrhythmia proved to be frequent in a consecutive emergency room series, and included potentially dangerous arrhythmias. Second, all adenosine-induced arrhythmias subsided spontaneously and did not require treatment [13].

In conclusion, despite the fact that adenosine is safe and effective in the emergency department and noninvasive cardiology imaging laboratory, serious life-threatening side effects can occur. Awareness of these undesirable drawbacks is mandatory and need strict protocol; however, cardiovascular and neurosurgeons are interested in adenosine administration for successful endovascular reconstruction and embolization, despite its undesirable drawbacks.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.