Aminophylline in the treatment of atropine-resistant bradyasystole

Resuscitation 47 (2000) 105 – 112 www.elsevier.com/locate/resuscitation

Review article

Aminophylline in the treatment of atropine-resistant bradyasystole Timothy J. Mader a,b,*, Barry Bertolet c, Joseph P. Ornato d, Jeffrey M. Gutterman a,b a

Department of Emergency Medicine, Baystate Medical Center, 759 Chestnut Street, Springfield, MA 01199, USA b Tufts Uni6ersity School of Medicine, Boston, MA, USA c Cardiology Associates of North Mississippi, North Mississippi Medical Center, Tupelo, MS, USA d Department of Emergency Medicine, Virginia Commonwealth Uni6ersity’s Medical College of Virginia, Richmond, VA, USA Received 16 February 2000; received in revised form 12 May 2000; accepted 24 May 2000

Keywords: Aminophylline; Atropine; Bradyasystole

1. Introduction Aminophylline is a non-specific adenosine receptor antagonist that may have a clinical use in the treatment of patients with certain types of bradyasystole. The pathogenesis of ischemia-related bradyasystole, with respect to the role of endogenous adenosine, provides a compelling rationale for potential beneficial effects of aminophylline in certain types of bradyasystolic conditions but the evidence is primarily anecdotal and to date, clinical trials have been inconclusive. We present a comprehensive literature review of aminophylline use in human subjects with bradyasystole and provide recommendations for clinical use and future study.

ventricular fibrillation on paramedic arrival have a significantly better prognosis (30–33% survival) [3–5] than those whose initial rhythm is asystole (B 3% survival) [6–13]. The low rate of successful resuscitation from bradyasystolic cardiac arrest has led to speculation that asystole, in this setting, is little more than an objective confirmation of death rather than a rhythm requiring treatment [5]. However, it is now widely accepted that endogenous adenosine plays a major role in the development and perpetuation of bradyasystole in some patients. Adenosine receptor antagonism may provide a new and innovative treatment strategy for a subset of patients with this condition.

3. Bradyasystole 2. Background In the United States each year, nearly 500 000 deaths are attributed to coronary artery disease and sudden cardiac death [1–4]. Survival from a sudden cardiac death event is uncommon ( B10%) [2]. In the prehospital setting, patients found in * Corresponding author. Tel.: +1-413-7843343; fax: + 1-4135968926. E-mail address: [email protected] (T.J. Mader).

Bradyasystole is one of the most common and least understood conditions encountered during resuscitation. Bradyasystole refers to a cardiac rhythm that has a ventricular rate below 60 beats per minute and/or greater than or equal to 5-s periods of absent heart rhythm [6]. Bradyasystolic cardiac arrest is a clinical situation during which bradyasystole is the dominant rhythm and perfusion of vital organs is inadequate. The varied clinical situations in which symptomatic

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bradyasystole develops determines the likely etiology, appropriate treatment and ultimate prognosis. Bradyasystole may be either primary or secondary [6]. Primary bradyasystole occurs when the cardiac electrical system intrinsically fails to generate and/or propagate adequate ventricular depolarizations to sustain sufficient cardiac output to maintain vital organ perfusion and function [6]. The most common disorder that affects the primary pacemaker mechanism is sick sinus syndrome, a diffuse, age-related, degenerative disease of the heart’s electrical generation and conduction system. Idiopathic sclerodegeneration of the AV node and the bundle branches (Lenegre’s disease) or invasion of the conduction system by fibrosis or calcification spreading from adjacent cardiac structures (Lev’s disease) may also lead to bradyasystolic heart block with or without cardiac arrest. Secondary bradyasystole develops when factors external to the cardiac electrical system of the heart cause it to fail. Metabolic imbalance, including cellular hypoxia, may impede normal electrical impulse generation and propagation. Severe ischemia of the sinoatrial (SA) node can disable cellular metabolism, preventing pacemaker cells

from actively transporting the ions necessary to control the transmembrane action potential. Ischemia and/or infarction of the AV node can disrupt normal conduction and result in AV block. Pacemaker cells and conducting tissue can be affected by a variety of endogenous chemical, hormonal, pharmacologic, and neurogenic influences. Receptor-mediated inhibition of pacemaker function is one important etiology and includes acetylcholine and adenosine receptors (Fig. 1). Hypoxia and hypercarbia due to respiratory arrest frequently cause bradyasystole, due to direct depression of cardiac pacemaker cells and increased parasympathetic discharge. Other examples of common clinical conditions that often cause secondary bradyasystole which require specific therapy include suffocation, hypothermia, central nervous system disorders, and cardiotoxic drug overdose. Asystole in the setting of sudden cardiac death typically results when another non-perfusing rhythm, such as ventricular fibrillation or ventricular tachycardia, exhausts the energy substrate of the heart with gradual degeneration to irreversible asystole. In this scenario, asystole is a terminal situation from which the patient is unlikely to be resuscitated. The literature would suggest, however, that some patients presenting with asystole under these circumstances have a reversible condition amenable to appropriate intervention [7–9]. 4. Current treatment recommendations

Fig. 1. Relationship of adenosine (A1-R), muscurinic (M2-R) and b-adrenergic (bA-R) receptor-effector coupling systems. The cardiac actions of adenosine and acetylcholine are mediated by the same intracellular mechanism stimulated by the activation of different cell surface receptors. (ADO, adenosine; ACh, acetylcholine; ISO, isoproterenol; Gi and Gs, guanine nucleotide binding regulatory proteins; AC, adenylyl cyclase; +, activation; −, inhibition; IkACh, ADO, ACh- and ADO-regulated inward rectifying potassium current; ICa, inward calcium current; IF, time- and voltage-dependent inward current activated by hyperpolarization (pacemaker current); ITI, transient inward current; cAMP, cyclic adenosine monophosphate) [62].

General treatment measures for symptomatic bradyasystole include support of ventilation and closed-chest compressions [5]. Pharmacotherapy of bradyasystole begins with administration of atropine to antagonize the effects of acetylcholine plus b-adrenergic stimulation with epinephrine to maintain arterial perfusion pressure (i.e. coronary and cerebral perfusion) [10]. A one-milligram dose of atropine is administered intravenously and is repeated every 3–5 min if bradyasystole persists to a total dose of 0.04 mg/kg. Three milligrams is generally considered a fully vagolytic dose in most patients [11]. The American Heart Association also recommends 0.5–1.0 mg epinephrine every 3–5 min for treating cardiac arrest patients with bradyasystole [5]. Most studies have not shown any improve-

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should not be delayed when it is indicated [20,23]. Despite these established therapies, the successful return of a hemodynamically stable rhythm following bradyasystolic cardiac arrest is rare. 5. Adenosine in bradyasystole

Fig. 2. Adenosine is formed by dephosphorylation of adenosine monophysphate. This conversion is catalyzed by the enzyme 5%-nucleotidase and takes place both inside and outside the cell. Only extracellular adenosine, however, can bind to cell surface receptors and form a receptor-effector complex. Degradation of S-adenosylhomocysteine (catalyzed by the enzyme S-adenosylhomocysteine hydrolase) also results in accumulation of adenosine but under hypoxic conditions the ATP pathway is the main source. Termination of the action of adenosine occurs by cellular uptake and metabolism of the nucleotide to inosine and hypoxanthine (not shown) [62]. Table 1 Cardiac effects of adenosine A1 mediated Slows heart rate Blocks A-V conduction Suppresses automaticity Attenuates b-adrenergic mediated Increases in contractility Mediates painful sensation A2 mediated Coronary artery vasodilation

ment in survival to hospital discharge using higher doses of epinephrine in treating adults or children with bradyasystolic cardiac arrest [12–19]. Cardiac pacing (transvenous, transthoracic, or transcutaneous) is considered useful and effective in the treatment of bradyasystole but it rarely influences survival in the unwitnessed cardiac arrest patient who has been found initially with asystole or bradycardia without a pulse [20–23]. Pacing is extremely useful, however, for bradycardic patients with a pulse and in selected patients in whom a pacemaker can be placed immediately after the development of the conduction disturbance. Placement of a pacemaker

During the past decade, evidence has been mounting implicating endogenous adenosine in the pathogenesis of several types of ischemia-related bradyasystoles and some bradyasystolic arrest situations [6]. Adenosine is an endogenous nucleotide that acts as an extracellular messenger to regulate myocardial oxygen supply and demand [24,25]. During normal aerobic metabolism, adenosine is formed by intracellular degradation of S-adenosylhomocysteine (SAH), catalyzed by the enzyme S-adenosylhomocysteine hydrolase (SAH pathway) (Fig. 2). Cellular hypoxia is a potent stimulus for increased formation and liberation of endogenous adenosine. During myocardial ischemia, high concentrations of adenosine are created by dephosphorylation of adenosine monophosphate (AMP), catalyzed by the enzyme 5%-nucleotidase (ATP pathway). Endogenous adenosine, acting through at least two specific cell surface receptors (A1 and A2a), favorably shifts the ratio of myocardial oxygen delivery and consumption [25–32] (Table 1). Activation of the A1-receptor subtype results in slowing of the heart rate (negative chronotropic effect), slowing and blocking of atrioventricular (AV) nodal conduction (negative dromotropic effect), and antagonism of cardiac stimulatory effects (e.g. inotropic and arrhythmogenic) of adrenergic agonists (anti-adrenergic effect) [26]. In addition to its depressant effects on the SA and AV nodes, adenosine may suppress ventricular pacemaker function. The SA nodal, AV nodal, and ventricular pacemakers, respectively, appear to have decreasing sensitivities to adenosine [24]. This observation explains why a very slow ventricular escape rhythm often accompanies adenosine-induced third degree AV block. Additionally, it appears that activation of the A1 receptor mediates a painful sensation [33]. This adenosine-induced discomfort halts physical activity, which may further diminish myocardial ischemia. These electrophysiological effects of adenosine reduce myocardial oxygen consumption.

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Adenosine is also a potent coronary artery vasodilator. This action is mediated primarily by the adenosine receptor A2a subtype [32,34]. Vasodilation improves coronary flow and increases myocardial oxygen supply. In summary, the cardiac actions of adenosine serve to protect the heart from ischemic injury. High concentrations of endogenous adenosine may also increase defibrillation threshold and lessen the effectiveness of exogenous catecholamines [25,26,35,36]. While the action of adenosine on cardiac physiology are ordinarily a cardioprotective response to myocardial ischemia in the setting of myocardial infarction, hypotension, or bradyasystolic arrest, adenosine may have a detrimental effect by inducing a state of refractory bradyasystole. 6. Aminophylline The adenosine A1-receptor mediated cardiac effects are concentration-dependent and can be antagonized competitively by xanthine derivatives [26]. Theophylline and caffeine are two structurally related alkaloids, which are commonly available methylxanthines. The solubility of methylxanthines is low but is enhanced by formation of complexes such as aminophylline, which is a combination of 85% anhydrous theophylline and ethylenediamine (Fig. 3). The suggested pharmacological effects of aminophylline include: (1) inhibition of phosphodiesterase; (2) direct and indirect effects on intracellular calcium concentration; (3) uncoupling of intracellular calcium; and (4) antagonism of adenosine receptors. Adenosine receptor antagonism is believed to be the dominant mechanism of action of methylxanthines when they are administered in therapeutic doses.

Fig. 3. Chemical structure of theophylline.

While aminophylline pharmacologically is a non-selective adenosine receptor antagonist, its actions in vivo are more consistent with a selective adenosine A1-receptor antagonist. The dose of aminophylline required to antagonize adenosine is relatively low. Complete A1-receptor antagonism is accomplished by 5 mg/kg [37]. 7. The literature in human subjects The speculation that endogenous adenosine is one of the mediators of bradyasystole and the wide availability of aminophylline have lead many investigators to experiment with aminophylline as a therapy for bradyasystole. There are currently 16 citations in the medical literature describing the use of aminophylline in human subjects for bradycardia and asystole [7– 9,38–50] (Table 2). In 1986, Wesley [39] presented the first report in the literature discussing the potential role of aminophylline as a competitive adenosine antagonist in the reversal of late, atropine-resistant, AV block complicating acute inferior wall myocardial infarction. The patient described was given 400 mg of aminophylline over 30 min with prompt restoration of AV conduction. Since that first report, four similar articles have been published involving a total of 18 patients [38,42,43,50]. AV conduction was restored in all but four patients in an average of 90 s using dosages ranging from 125 to 300 mg of aminophylline given over 10–20 min. In 1990, Tomcsanyi et al. [41] reported prompt resolution of ischemia–related, atropine-resistant, sinus node arrest after a 240-mg infusion of aminophylline. The following year, Strasberg [40] reported on 15 consecutively enrolled acute inferior wall myocardial infarction patients with late, AV block, given 7 mg/kg of aminophylline over 20 min. They found that AV conduction improved in only three of the 15 subjects. Unlike previous investigators, the authors used aminophylline as first line treatment and did not select for atropineresistance prior to inclusion. Overall, adenosine antagonism seems to be most effective for high grade AV block that develops within 24 h of onset of myocardial infarction. Beyond 24 h, tissue edema and conduction system disease may be more causative than the actions of adenosine. Other papers have since described the use of aminophylline to abort AV block in cardiac trans-

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Table 2 Summary of studies using aminophylline for bradyasystole in humansa Reference

Study type

Setting

Wesley [27] Shah [38] Tomcsanyi [41]

Case report Case report Case report

In-hospital In-hospital In-hospital

1 2 1

Strasberg [40]

Consecutive series Case report

In-hospital

15

In-hospital

1

In-hospital In-hospital

6 15

Haught [45]

Series Consecutive series Case report

In-hospital

1

Bertolet [47]

Case report

In-hospital

2

Goodfellow [46]

Case report

In-hospital

3

Bertolet [48] Bertolet [49]

Series In-hospital Case control In-hospital

8 29

Mader [8]

RCT

Prehospital

14

Altun [50] Perouansky [9]

Series Case report

In-hospital Prehospital

8 1

Mader [7]

RCT

Prehospital

82

Gupta [42] Onodera [43] Viskin [44]

No. of subjects

Circumstances

Day

Rhythm

Atropine

Inferior MI Inferior MI Unstable angina Inferior MI

\24 h \24 h \24h

A-V block A-V block SA arrest

\24 h

A-V block

None

Inferior MI w/STK Inferior MI Cardiac arrest Transplant rejection Inferior MI w/STK Inferior MI w/STK Inferior MI Transplant rejection Cardiac arrest Inferior MI Inferior MI in arrest Cardiac arrest

\24 h

A-V block

Yes

2 mg 2 mg 1.5 mg

Dose (mg)

400 300 240 7/kg 125

NS NA

A-V block 1 mg Bradyasystole \2 mg

250 250

NA

A-V block

NA

300

Acute

SA arrest

None

Acute

A-V block

1.2–1.8 mg

150

Acute POD 4

A-V block Bradycardia

6/8, 1 mg None

150–250 300

NA

Bradyasystole

2 mg

250

\24 h NA

A-V block Bradyasystole

1 mg 3 mg

240 (×2) 250

NA

Bradyasystole B1 mg

50 & 140

250

a Abbreviations: MI, myocardial infarction; NA, not applicable; NS, not specified; POD, post-op day; RCT, randomized controlled trial; STK, following streptokinase.

plant rejection [45], to reverse early sinus arrest and high degree AV block complicating acute inferior wall myocardial infarction [46–48], and to treat cardiac transplant patients with bradyarrhythmias [49]. The first reported use of aminophylline for bradyasystolic cardiac arrest appeared in 1993 [44]. In a small case series, aminophylline restored cardiac rhythm in cardiac arrest refractory to conventional therapy. Fifteen patients, in atropine-resistant bradyasystolic cardiac arrest, were given 250 mg of aminophylline prior to termination of resuscitation efforts. Twelve subjects had ‘immediate resumption of cardiac electrical activity’. Sustained return of spontaneous circulation was achieved in 11 patients and one patient survived to hospital discharge neurologically intact. The results were intriguing but the study was not randomized, blinded nor controlled.

There have been two published randomized controlled trials of aminophylline in asystolic cardiac arrest [7,8]. Both were conducted in the prehospital setting. The first of these was designed to determine if aminophylline would have any beneficial impact on cardiac electrical activity if given to patients in asystolic cardiac arrest after failure of conventional treatment. Despite the small sample size, the study confirmed that aminophylline could restore cardiac electrical activity in some patients refractory to standard therapy. The authors concluded that adenosine receptor antagonism may have a role in the treatment of cardiac asystole using it earlier in the resuscitation, and that further study, was warranted. The second randomized controlled trial attempted to determine whether aminophylline could increase the rate of return of spontaneous circulation if given early for asystole. This study

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enrolled 88 subjects over 18 months and found no difference between the control and treatment groups. The study had a power of 75 to detect an absolute increase of 20% in return of spontaneous circulation between the control and treatment groups at an a level of 0.05. The investigators concluded that failure to select for atropine-resistance accounted for their inability to detect a difference and suggest that future studies might address this limitation [40]. In 1998, Perouansky [9] described the use of aminophylline as treatment for a patient in refractory out-of-hospital bradyasystolic cardiac arrest that resulted in neurologically intact survival despite an exceptionally long paramedic response time interval, prolonged resuscitation and administration of aminophylline very late in the effort.

8. Availability and significance Aminophylline is a generically available nonspecific adenosine receptor antagonist that could be added to the resuscitation algorithm of bradyasystole with little added expense or inconvenience. It is given by slow peripheral intravenous injection or infusion. Aminophylline is currently available in 10 ml 250 mg prefilled single use syringes. Specific adenosine antagonists are currently being developed but they are not yet approved for clinical use. Survival for bradyasystolic cardiac arrest patients is currently poor (generally 5 7%) [1,4,51– 55]. There are approximately 700 episodes of sudden cardiac death per day in the United States [56]. Between 25 –56% of sudden cardiac death victims are found in bradyasystolic arrest on paramedic arrival [52,57–61]. Given the poor survival rate for prehospital cardiac arrest, a new intervention that improves survival by as little as 10% would result in approximately 100–500 additional patients per year being resuscitation who otherwise would face certain death.

9. Conclusions Adenosine receptor antagonism may reverse certain bradyarrhythmias and restore the effectiveness of exogenous catecholamines during resuscitation. The clinical impact on outcome has

not yet been established. Without evidence to the contrary, patients initially refractory to epinephrine and atropine should be considered candidates for adenosine-antagonism therapy. A large scale randomized controlled trial of aminophylline in bradyasystole is warranted to confirm whether this agent should be used routinely to treat bradyasystolic cardiac arrest patients. Appropriate patient selection, optimal dosing schedule, alternative modes of delivery, and finally, safety and efficacy, are all issues yet to be resolved.

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