Adenosine and the Treatment of Supraventricular Tachycardia ANDREWC. RANKIN, M.D., Ross BROOKS,M.D., JEREMYN. RUSKIN, M.D., BRIANA. MCGOVERN,M.D., Boston, Massachusetts

Adenosine has recently become widely available for the treatment of paroxysmal supraventricular tachycardia. In order to evaluate its role in the management of arrhythmias, we have reviewed the literature on the cellular mechanisms, metabolism, potential for adverse effects, and clinical experience of the efficacy and safety of intravenous adenosine. Adenosine produces transient atrioventricular nodal block when injected as an intravenous bolus. This is of therapeutic value in the conversion to sinus rhythm of the majority of paroxysmal supraventricular tachycardias, which involve the atrioventricular node in a re-entrant circuit. The mean success rate was 93% from over 699 reported episodes. Compared with other ant&rhythmic agents, adenosine is remarkable for its rapid metabolism and brevity of action, with a half-life of a few seconds. It commonly produces subjective symptoms, particularly chest discomfort, dyspnea, and flushing, which are of short duration only. No serious adverse effect has been reported. Arrhythmias may recur within minutes in a minority of patients. Comparative studies have shown that adenosine is as effective as verapamil in the treatment of supraventricular tachycardia, and has less potential for adverse effects. Patients with supraventricular tachycardia should initially be treated using vagotonic physical maneuvers. Immediate electrical cardioversion is indicated if the arrhythmia is associated with hemodynamic collapse. Adenosine is the preferred drug in those patients in whom verapamil has failed or may cause adverse effects, such as those with heart failure or wide-complex tachycardia. The safety profile of adenosine suggests that it should be the drug of fiit choice for the treatment of supraventricular tachycardia, but From the Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts. Dr. Rankin held a British-American Research Fellowship of the American Heart Association and the British Heart Foundation. Requestsfor reprintsshould be addressed to Brian A. McGovern, M.D., Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts 02114. Dr. Rankin’s current address: University Department of Medical Cardiology, Royal Infirmary. Glasgow, G31 2ER, Scotland. Manuscript submitted April 4. 1991, and accepted in revised form October 15, 1991.

only limited comparative data to support view are available at present.

this

A

denosine (Adenocard, Fujisawa, Deerfield, IL) is an endogenous, rapidly metabolized, purine nucleoside that has recently been approved by the Food and Drug Administration for the treatment of paroxysmal supraventricular tachycardia. Therapeutic efficacy is attributable to the ability of a rapidly administered bolus of intravenous adenosine to slow conduction through the atrioventricular node and produce transient heart block [1,2]. This results in the termination of the majority of paroxysmal supraventricular tachycardias [3-71 whose substrate is a re-entrant circuit that includes the atrioventricular node [8] (Figures 1 and 2). This effect of intravenous adenosine is of rapid onset and of very short duration due to cellular uptake and enzymatic breakdown [9]. The half-life of adenosine in blood is very short [lO,ll] and its effects disappear in less than a minute. This brevity of effect is sufficient for its antiarrhythmic action, while it confers safety because any adverse effects are likely to be of similar short duration. These properties would appear to make adenosine an ideal drug for the termination of paroxysmal supraventricular tachycardia. In this review, we evaluate the role of adenosine in the management of patients who present with supraventricular tachycardia.

CLINICALEXPERIENCEWITH ADENOSINE The atrioventricular nodal blocking properties of intravenous adenosine were first described in humans in 1930 [l]. By 1984, when a previous review article suggested that adenosine might be the drug of choice for treating supraventricular tachycardia [12], there had only been a single report of its clinical efficacy [3]. Since then, however, many studies of adenosine use, in a wide variety of clinical settings, have been published (Table I). Its efficacy in the conversion to sinus rhythm of paroxysmal supraventricular tachycardia has been confirmed [4-7,13-161, with reported conversion rates of 80% to loo%, and a mean success rate of 93% from over 600 reported episodes. This applies to patients in whom the arrhythmia has been induced at electrophysiologic study [3,5,7,13-151 or to those with June

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ADENOSINE AND SUPRAVENTRICULAR TACHYCARDIA / RANKIN ET AL A)

\

Atria

Atria

AP

f

/

I

Ventricles

Ventricles

Figure

1. Simplified schematic diagrams of the two most common re-entry circuits that underlie paroxysmal supraventricular tachycardia, and the sites of action of adenosine. The atrioventricular node (shaded area) and the conducting system (His bundle and bundle branches) are illustrated. A. Atrioventricular nodal re-entrant tachycardia. The circuit involves dual pathways within the atrioventricular node. The common form of tachycardia is shown, with antegrade conduction via the slower pathway. Adenosine terminates the tachycardia by blocking conduction in the slower pathway most commonly, but may act on either nodal pathway. B. Atrioventricular re-entrant tachycardia. Retrograde conduction is via an accessory pathway (AP). Adenosine terminates the tachycardia by blocking the antegrade conduction through the atrioventricular node.

spontaneous tachycardias treated in the emergency room [4-7,13,14,16]. A small number of infants and children have also been successfully treated, including those with drug-resistant arrhythmias or heart failure [17-211. Adenosine has been shown to be at least as effective as verapamil, the calcium antago-

nist widely considered to be the drug of choice in this clinical contest [22], both in retrospective [13,16] and prospective controlled studies [14,15]. As expected from its mainly nodal blocking action, adenosine is not effective in terminating the majority of arrhythmias without atrioventricular nodal involvement, whether of atria1 [5-71 or ventricular [7,23,24] origin. Its action, however, may provide diagnostic information in patients with such arrhythmias [5,7,24]. For example, adenosine-induced atrioventricular nodal block may reveal an underlying atrial arrhythmia by slowing the ventricular rate (Figure 3). No serious adverse effect following the use of adenosine has been reported to date. Thus, the comparative efficacy and relative safety of intravenous adenosine have been established, but limitations to its value have also been revealed [7]. In order to optimize the clinical use of adenosine, an understanding of its mechanism of action, metabolism, and potential for adverse effects is desirable.

CELLULARMECHANISMSAND METABOLISMOF ADENOSINE The antiarrhythmic actions of adenosine are mediated by extracellular adenosine receptors, which, in addition to the negative dromotropic action on atrioventricular nodal conduction, also regulate a number of other cardiac actions, including negative chronotropic, coronary vasodilator, and antiadrenergic effects [9,25,26]. Receptors sensitive to adenyl compounds are found in many other body tissues, and a classification has been suggested based on

IS

Figure

2. Termination of paroxysmal supraventricular tachycardia by intravenous adenosine. Atrioventricular re-entrant tachycardia, in a patient with a concealed accessory pathway, was induced during electrophysiologic studies. A bolus of 6 mg of adenosine was injected 20 seconds prior to termination. The last QRS complex of the tachycardia is followed by a P wave (in the ST segment), and the last intracardiac electrograms are atrial, indicating block in the antegrade atrioventricular nodal conduction. There is progressive delay in atrioventricular nodal conduction, with increasing AH intervals, prior to termination of the tachycardia. Surface lead II tracing and intracardiac recordings from high right atrium (HRA), atrioventricular junction with His bundle recording (His), and right ventricular apex (RVA) are shown. In the His bundle recording, the atrial (A), His bundle (H), and ventricular (V) deflections are indicated. The AH intervals (milliseconds) are shown.

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TABLEI Published Data on the Use of Intravenous Adenosine for the Treatment of ParoxysmalTachycardia PSVT Refer- Total ence Patients Patients Episodes El1

17

515

32132

Dose

Mean

82 wzikg

Range 112-262.5

Spontaneous IV or Induced? Site

pg/kg

Atrial

VT

O/l

-

Adverse Effects 29%

Comments

I

P

SA(L$V=n$l function

s

P--

Sorl

P

0115

-

35%

s

P

o/4

-

100%

Potentiation by dipyridamole

I

C

-

4118

NA

Adenosine-sensitive ventricular tachycardia

5.3 mg [41

6

[51

46

616

8110

140 pgikg

5-20 mg

6.4 mg 86 w/kg

2-23 mg 37.5-287.5

lO/lO

8.8 mg 135 &kg

5.6-12

122@kg

75-225

7.8mg

37.5-300

kg/kg

Sor I

PorC

l/5

O/2

78%

Comparison with verapamil (retrospective)

Kg/kg

S

NA

-

-

NA

Pediatrics

I

C

-

-

NA

Atypical “long RP” tachycardia

P

l/l0

1117

39%

Broad complex tachycardias

Sorl

PorC

O/7

-

24%

Pediatrics

S or I

PorC

1120

1114

63%

Narrow and broad complex tachycardias

30131

pg/kg

mg

[61

7

[171

18

-

-

DO1

44

26126

43143

[141

4

414

137.5 pgikg

loo-250

[451

10

9/10

4 mg

1.4-7.3

mg

(181

41

13114

120&kg

50-250

pgikg

[151

25

13113

114 kg/kg

37.5-225

[71

64

29129

8.8 mg

2.5-25

[121

20

20/20

125 &kg

50-200

kg/kg

I

NA

-

-

“Majority”

Comparison with verapamil (EP lab)

1161

50

NAi36

NA

50-250

pglkg

Sor I

NA

l/l1

-

“Common”

Pediatrics

359

2061224

6.2 mg

3-12

S or I

NA

0136

-

36%

Comparison with verapamil (placebo-controlled)

63 &kg

37.5-112.5

C

-

-

NA

Potentiation by dipyridamole

O/9

-

81%

Comparison with ATP

72%

Comparison with verapamil (retrospective)

[ill

313

33%

52154

88/102

&kg

kg/kg mg

mg

[301

6

616

&kg

[321

29

20/20

25127

7.3 mg

2.5-20

mg

Sorl

PorC

[131

25

25125

49152

10mg

2.5-30

mg

S

P--

#VT= paroxysmal supraventricular tachycardia; IV = intravenous; VT = ventricular tachycardia; I = induced; S = spontaneous; P = peripheral; C = central; SA = sinoatrial; AV = atrioventricular; ATP = adenosinetriphosphate; EP lab = electrophysioiogy laboratory; NA = not available.

their relative sensitivities to adenosine and adenine nucleotides [27]. PI purinoceptors respond to adenosine rather than to the nucleotide, adenosine triphosphate (ATP), while PZ receptors are sensitive to ATP and not to adenosine. Methylxanthines, such as theophylline, competitively antagonize the action of adenosine at P1 receptors. Extracellular adenosine receptors have been further subclassified as A1 or AZ depending on adenosine analog affinity and modulation of adenylate cyclase activity [28]. Responses to adenosine, adenyl analogs, and antagonism by theophylline indicate that the cardiac actions of adenosine are due to activation of PI receptors of the A1 type [2,9,29-311. Interaction of adenosine with the A1 receptor causes an increase in potassium (K+) conductance

in atria1 and sinus tissue [32,33], which results in hyperpolarization of the cell membrane and slowing or block of spontaneous activity [34,35]. This is due to opening of potassium channels, identical to those opened by acetylcholine [36], which has many similar cardiac actions. Both the adenosine A1 receptor and the muscarinic receptor are coupled to the potassium channels by guanine nucleotide binding regulatory proteins, or G proteins [36,37]. While it has yet to be directly demonstrated, it is likely that the same effects on potassium channels underlie the negative dromotropic actions of adenosine. The adenosine receptors are also coupled to an inhibition of adenylate cyclase activity, and adenosine therefore may inhibit effects of catecholamine stimulation. An effect on the inward calcium current has June

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Figure 3. Atrial flutter revealed by adenosineinduced block. A. Prior to adenosine administration, a regular, narrow-complex tachycardia. B. Administration of 10 mg of adenosine causes transient increase in atrioventricular conduction delay to reveal underlying atrial flutter. C. Further decrease in ventricular rate with higher dose (20 mg) more clearly shows the atrial flutter. Lead II, paper speed 25 mm/s.

also been observed, secondary to this antiadrenergic action of adenosine, with a decrease in calcium current in the presence of catecholamine stimulation [38]. Adenosine is rapidly metabolized, mainly by enzymatic deamination, either extracellularly, or intracellularly following uptake into the cell [9]. Endothelial cells, for example, have an effective adenosine transport mechanism and can rapidly remove adenosine from the circulation [39]. Blockers of this transport mechanism, such as dipyridamole [lo], greatly enhance the actions of circulating adenosine [40], supporting a major role for uptake in the removal of adenosine in Go. The half-life of adenosine (in the physiologic concentration range, 0.1 to 1 PM) in human plasma has been estimated to be as short as 0.6 to 1.5 seconds [ll]. The rapid uptake and metabolism ensure that a bolus of injected adenosine is rapidly removed from the circulation, and the effects of adenosine are therefore correspondingly brief.

ADMINISTRATION OF ADENOSINE The method of administration of adenosine is unusual, compared with that of other intravenous antiarrhythmic drugs, because its rapid metabolism allows repeated incremental doses to be administered. An initial low dose may be administered, and further increasingly larger doses can then be given, after a minute or two, once the effects of the preceding dose have passed. Adenosine is available in 6-mg vials containing 3 mg/mL, with a recommended initial dose of 6 mg, followed by a second 12-mg dose if the first dose is ineffective. This dosage schedule will restore sinus rhythm in over 90% of patients with paroxysmal supraventricular tachycardia l-141. Some patients would respond to lower doses [5,7], and higher doses can be safely used in resistant 658

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cases [7], with further stepwise dosage increments. Titration of the dose is advisable to minimize side effects because there may be a lo-fold variation between patients in the minimum effective dose [5,7]. The rate and route of the intravenous injection may be factors that contribute to this variability [5-71. The removal of adenosine is of such rapidity that the effective dose acting at the heart may be considerably reduced if it has been injected into a small peripheral vein, and conversely, lower doses are required with central administration [5,7,13]. Many authors have recommended weight-related dosages, e.g., pg/kg, but in the context of the dose variability and the dependence on the site of injection, it is doubtful whether this is important, other than in small children. The magnitude of the bolus arriving at the heart is likely to be more important than any subsequent redistribution to the body mass. Even after taking weight and route of injection into account, there appears to be considerable variability in effective dosage [41], and other factors, such as autonomic influences on the atrioventricular node and drug interactions, may be important. Adenosine should be administered by rapid bolus injection, within 1 second, into a large peripheral vein, followed by a saline flush. Its effects occur within 20 to 30 seconds. The cardiac rhythm should be monitored electrocardiographically for at least 30 seconds after the administration of each dose of adenosine, because important diagnostic information can often be obtained from close examination of the tracings at the time of the adenosine effect, whether or not the arrhythmia is terminated. Symptoms, in particular flushing, dyspnea, and chest discomfort, are common after adenosine administration. It is advisable to warn the patient that these may occur, but to reassure them that they will be transient and will pass after less than 1 minute. Finally, it is important to be aware of specific drug interactions with adenosine. Dipyridamole, an adenosine uptake blocker, potentiates the action of adenosine by a factor of four [6,40]. Therefore, adenosine should be used with caution in patients taking dipyridamole, as profound bradycardia and asystolic pauses may occur [6,16]. Methylxanthines are known competitive antagonists of the adenosine receptors and theophylline may block the actions of adenosine [2].

ADVERSEEFFECTSOF ADENOSINE Adenosine has many actions at noncardiac sites that potentially could cause adverse effects. The reported incidence of adverse symptoms varies considerably, ranging from about 30% [3,5,14,18] to over 70% [6,13,16,42]. This may depend on how

ADENOSINE

carefully symptoms are enquired after, and on the size of the incremental doses. It is likely that the majority of patients would experience symptoms if a sufficient dosage was given, because of the known pharmacologic effects of adenosine that underlie the most common symptoms, namely chest discomfort, dyspnea or respiratory stimulation, and flushing [5,7,13]. Intravenous adenosine causes chest discomfort, similar to typical cardiac chest pain, in normal volunteers [43] or patients with ischemic heart disease 6441. There is evidence to indicate that the chest pain of myocardial ischemia or infarction may be mediated by the release of endogenous adenosine that stimulates adenosine-sensitive pain receptors [44]. Respiratory stimulation occurs [45] because adenosine activates chemoreceptors in the carotid body [46,47]. Inhalation of adenosine may produce bronchoconstriction in asthmatics [48] but intravenous infusion does not [49]. There is a single report, in the French literature, of bronchospasm after bolus injection of adenosine [50]. It is prudent to advise caution, or alternative therapies, in patients with asthma. Adenosine is a potent vasodilator [51], and peripheral flushing is to be expected. Systemic hypotension has not been reported following bolus injection in conscious patients because of a reflex sympathetic discharge that tends to counteract the vasodilatory action of adenosine. This is in contrast to the effects of adenosine infusion, which has been used to induce hypotension during anesthesia [52]. Despite the potential for adverse effects, most patients tolerate the administration of intravenous adenosine, and allow incremental doses to be given. However, when specifically questioned, over a third of patients considered their symptoms to be of more than “moderate” severity [7,42]. It is for these reasons that it is advisable to warn patients that they may experience transient symptoms. The brevity of action of adenosine is its main advantage in the majority of patients, but is a disadvantage in a minority, whose arrhythmias recur shortly after restoration of sinus rhythm [7,16,19]. This is not simply due to the lack of persisting antiarrhythmic action in all cases, but the early recurrence of arrhythmia may be provoked by atria1 or ventricular premature complexes [7], or by the tachycardia that commonly follows adenosine-induced bradycardia [53]. The reported incidence of recurrence varies, depending on the patient populations being studied, and may be as high as 35% in patients with troublesome arrhythmias [7], but is lower in other reports [14,19]. Arrhythmias are commonly seen at the time of peak adenosine effect [5,7,15,19]. Ventricular and atria1 premature complexes are most common, but

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nonsustained ventricular tachycardia [7] or atria1 fibrillation [4,5] has been reported. Premature beats following adenyl compounds may occasionally be their method of termination of tachycardia [54], but may also cause reinitiation [7]. No serious outcome of the proarrhythmic effects of adenosine has yet been reported. However, it is possible that adenosine administration could convert stable reentrant tachycardia into atria1 fibrillation, which may be life-threatening in patients with Wolff-Parkinson-white syndrome. In these patients, rapid conduction from atria to ventricles over an accessory pathway may result in very rapid ventricular rates. This has not yet been reported, despite adenosine’s use in many such patients. Episodes of transient bradycardia, complete heart block, ventricular standstill, and asystole have also been reported following adenosine administration [7,18,19], but these are usually of short duration and resolve spontaneously after several seconds without intervention. There are two situations where such bradyarrhythmias may particularly occur. The first is in patients taking dipyridamole [6,16]. The second is in patients with sinus node dysfunction who may be more susceptible to the negative chronotropic actions of adenyl compounds [5,55]. This latter group of patients may commonly present with tachyarrhythmias (“the bradycardiatachycardia syndrome”) and, as adenosine is more widely used, they may represent a group in which adverse effects may occur.

ADENOSINEAND SPECIFICARRHYTHMIAS The majority of paroxysmal supraventricular tachycardias are responsive to adenosine because they have a re-entrant mechanism that includes the atrioventricular node in the circuit [8] (Figure 1). First, and most common, there is atrioventricular nodal re-entrant tachycardia, in which the substrate is dual pathways within the node [56]. During typical tachycardia, the slower pathway maintains antegrade conduction, and retrograde activation is via a faster pathway (Figure 1A). Second, there is atrioventricular re-entrant tachycardia, in which the re-entry circuit involves an extranodal accessory pathway, connecting atrium to ventricle. During sinus rhythm, such an accessory pathway may conduct antegradely resulting in ventricular pre-excitation, which is apparent on the surface electrocardiogram as a short PR interval with a delta wave at the upstroke of the QRS complex, as in Wolff-Parkinson-white syndrome [8]. Some pathways, however, conduct only in the retrograde direction, in which case the accessory pathway is “concealed,” because its presence is not apparent during sinus rhythm. The accessory pathway provides one limb June

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Figure 4. Increase in pre-excitation produced by adenosine (12 mg) in sinus rhythm. Initial beats show short PR interval and delta wave. During adenosine-induced atrioventricular nodal block, the QRS complexes become wide and fully preexcited. Chest leads VI to VS, paper speed 25 mm/s.

of a circuit to maintain atrioventricular re-entrant tachycardia, most commonly with antegrade conduction to the ventricles via the atrioventricular node and His-Purkinje system, and retrograde activation of the atria via the accessory pathway (“orthodromic” tachycardia) (Figure 1B). In both the common types of tachycardias (atrioventricular nodal and atrioventricular re-entrant tachycardia), the retrograde conduction is the faster component of the circuit. Retrograde atria1 activation, therefore, occurs closely after ventricular activation, and hence an inverted P wave may be identified closely after the QRS complex, or simultaneous with it in many nodal tachycardias [57,58]. Electrocardiographic recordings show that, in the majority of instances, adenosine terminates the tachycardia by atrioventricular nodal block, with the last cardiac activation of the tachycardia being a P wave [7]. This is confirmed by intracardiac recordings that show progressive delay of conduction from atrium to His bundle (AH interval prolongation) in the cycles preceding the last atria1 electrogram, which is not followed by either His or ventricular deflections (Figure 2). In patients with dual atrioventricular nodal pathways, adenosine may also block the retrograde limb of the circuit, in which case no P wave or atria1 activation is associated with the last QRS of the tachycardia [5,7]. Block in the retrograde limb of the circuit is not specific for atrioventricular nodal tachycardia, however, as some accessory pathways may also block with adenyl compounds [5,7,59-611. An atypical form of atrioventricular nodal tachycardia occurs less commonly, with the slow nodal pathway conducting in the retrograde direction, and the P wave occurs late, preceding the next QRS complex. The re-entrant circuit in Wolff-Parkinson-White syndrome can also conduct in the reverse direction,

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with antegrade conduction via the accessory pathway (“antidromic” tachycardia), but this is uncommon. Both these atypical tachycardias, however, involve the atrioventricular node and may be terminated by adenosine. Despite the reported block of accessory pathways by adenosine [5,7,61], the vast majority of terminations by adenosine of atrioventricular re-entrant tachycardia are due to block of atrioventricular nodal conduction [5,7,13,15]. In some of these patients, adenosine may provide additional diagnostic information, because of persisting effect during the sinus beats following tachycardia termination. Preexcitation in sinus rhythm is not always obvious on the electrocardiogram, for instance with left-sided accessory pathways, when delay in atria1 conduction permits earlier conduction down the normal conducting system [62]. Adenosine-induced block of atrioventricular nodal conduction causes relative enhancement of conduction down the accessory pathway with resultant ventricular pre-excitation [3,7,15]. Thus, the first few sinus beats following termination of the tachycardia may show evidence of pre-excitation on the electrocardiogram due to persisting atrioventricular nodal blockade. Adenosine has been shown to be more effective than verapamil in this respect [15]. Pre-excitation may also be made apparent by the administration of adenosine in sinus rhythm [63] (Figure 4). Adenosine is ineffective in the termination of the majority of atria1 or ventricular arrhythmias [5,7], because the atrioventricular node is not an intrinsic component of the arrhythmia mechanism. However, in patients with atrial arrhythmias with rapid ventricular response rates, adenosine-induced block of atrioventricular conduction may slow the ventricular rate and reveal the underlying atria1 arrhythmia [5-71 (Figure 3). This has been reported to be of particular value in patients with wide-complex tachycardia, due to aberrant conduction such as bundle branch block, where atria1 activity, for example flutter waves, may be obscured by the QRS complex [7,24]. When the fact that most episodes of ventricular tachycardia are unresponsive to adenosine is also considered, the responses to intravenous adenosine have been shown to have a high positive predictive value in distinguishing supraventricular from ventricular arrhythmias in small numbers of patients with wide-complex tachycardias [7,24]. Rarely, adenosine may also allow the positive identification of ventricular tachycardia when retrograde conduction is present, with atria1 activation following every ventricular beat, by producing the characteristic features of ventriculoatrial dissociation [7]. The use of adenosine in the diagnosis of

ADENOSINE

wide-complex tachycardia is a promising application of this novel drug, but further evaluation is needed. It must be recognized that the diagnostic value of adenosine may be limited [5,7,24]. First, in light of the recognized variability in dosage, it may not be possible to be certain that sufficient adenosine has been administered. This is particularly true with wide-complex tachycardias that require larger doses [24], or if administration is via a peripheral vein. In addition, the actions of adenosine are not confined to the atrioventricular node, but may block accessory pathways, and infrequently may terminate atrial arrhythmias, such as atria1 flutter [7,24]. Finally, the effects of adenosine are not even specific for supraventricular arrhythmias, because a minority of ventricular arrhythmias may also respond [7,23,24]. A particular subgroup of patients with adenosine-sensitive ventricular tachycardia have been identified, who have structurally normal hearts and exercise- or isoproterenol-induced tachycardia, possibly due to triggered rather than re-entrant arrhythmias [23]. The action of adenosine on these arrhythmias is mediated by its inhibition of catecholamine-induced effects on ventricular myocardium. These may be related to changes in intracellular cyclic adenosine monophosphate (AMP), but adenosine may also inhibit actions of catecholamines on ventricular myocardium independent of changes in cyclic AMP [64].

COMPARISONOF ADENOSINEWITH OTHER DRUGS Many drugs with differing ant&rhythmic actions have been used with success in the treatment of supraventricular tachycardia [22], because the arrhythmias may be terminated by agents that slow or block conduction in either of the limbs of the reentrant circuit [8] (Figure 1). Drugs with effects on atrioventricular conduction have included edrophonium and phenylephrine, which act indirectly through the autonomic nervous system. These have been largely replaced by agents that exert more direct actions on the atrioventricular node, including calcium antagonists, e.g., verapamil[65-681 and diltiazem [69], P-adrenergic receptor blocking agents [70], and now adenosine [71]. Alternatively, drugs that act on the fast retrograde limb of the tachycardia circuit, whether an accessory pathway or a fast nodal pathway, may also be effective. Class Ia antiarrhythmic drugs such as procainamide, quinidine, or disopyramide [72], and the newer class Ic agents, such as flecainide [73], encainide, and propafenone [74], may terminate tachycardias in this way. Finally, the class III drugs amiodarone and sotalol (which

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is also a ,&blocker) may have effects on both antegrade and retrograde limbs of the tachycardia circuit [75,76]. Of all these drug options, intravenous verapamil has been the most widely used, having proven to be safe and effective therapy in the majority of patients [64-683, and it is the only agent, to date, with which adenosine has been directly compared [13-161. The only double-blind, placebo-controlled comparative study has shown that adenosine (up to 12 mg, by incremental dosage) and verapamil (up to 12.5 mg, by cumulative dosage) were equally effective in the conversion to sinus rhythm of paroxysmal supraventricular tachycardia in patients with spontaneous or induced arrhythmias, with success rates of 93% and 91%, respectively [14]. Another study has compared the two agents in patients with reciprocating tachycardias induced at electrophysiologic study. Adenosine (up to 200 pg/kg) was more effective than verapamil (145 pg/kg) in patients with accessory pathways and atrioventricular reentry tachycardia, both in terminating the arrhythmia and in revealing latent pre-excitation [15]. In addition, symptomatic pre-excited atria1 arrhythmias, with rapid ventricular responses due to conduction via accessory pathways, occurred in two patients after verapamil, but not after adenosine. Retrospective reviews of emergency room experience with adenosine and verapamil have reported similar efficacy but a small incidence of hypotension after verapamil, but not adenosine, administration [13,16]. More serious adverse effects with verapamil, including cardiac arrest, may occur particularly when it is administered inappropriately to patients with ventricular tachycardia [77-791 or pre-excited atrial fibrillation, with rapid ventricular activation via an accessory pathway [80,81]. It is likely that adenosine will also be administered to such patients, because the misdiagnosis of widecomplex tachycardias is a persisting problem [77,82]. Experience with adenosine in such patients is still very limited. No adverse effects have been reported in the small number of patients with ventricular tachycardia [7,13,23,24] or pre-excited atrial fibrillation [24] who have received adenosine, but the majority of these patients were studied in the controlled environment of the electrophysiology laboratory. Acceleration of the ventricular response during pre-excited atria1 fibrillation has been shown following administration of adenyl compounds but did not result in ventricular fibrillation in the reported cases [2,83]. Initial experience also suggests that adenosine may be used safely in patients with heart failure [19] or taking P-blockers [16], in whom the use of verapamil is inadvisable

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[84]. Whether adverse effects will occur with wider use of adenosine remains to be seen, but the evidence suggests that at least it is likely to have a better safety record than verapamil. Finally, it is of interest to note that adenosine is not the first adenyl compound to be used for the treatment of supraventricular tachycardia. ATP was shown to block atrioventricular nodal conduction in 1949 [85], and its therapeutic potential was recognized in the 1950s [86,87]. It became the drug of choice for termination of supraventricular tachycardia in many European countries [88]. Its effects are very similar to those of adenosine, with high reported success rates, similar side effects [42,89,90], and equal efficacy with verapamil 154,911. It has also been used as a diagnostic aid in patients with wide-complex tachycardia [83] and accessory pathways [92]. It has been suggested that adverse effects might be more frequent with ATP compared with adenosine [4], because PZ receptors are located at many noncardiac sites in the body, including visceral and vascular smooth muscle [27]. A double-blind comparison of the two adenyl compounds, however, failed to demonstrate any difference in incidence or severity of symptoms [42]. It is likely that, due to its rapid metabolism in the bloodstream, the cardiac actions of ATP may be largely mediated by adenosine [2,9]. The main difference between adenosine and ATP is their chemical stability, as ATP undergoes progressive, temperaturedependent, spontaneous breakdown in storage [42], and commercial preparations of ATP, available in Europe, have been shown to contain a mixture of adenyl nucleotides and adenosine [88]. The extensive European clinical experience with adenyl compounds in patients with arrhythmias provides further support for the safety profile of adenosine.

ROLEOF ADENOSINEIN TREATMENT Despite the diversity of drug options, the initial therapy for paroxysmal supraventricular tachycardia remains nonpharmacologic. A proportion of patients will respond to simple physical maneuvers that act by increasing vagal tone and thus slowing atrioventricular nodal conduction. The Valsalva maneuver has been shown to be more effective than carotid sinus massage or the diving reflex, with a success rate of 54% [93]. Electrical cardioversion is necessary in patients with severe hemodynamic decompensation. Previously available drug therapies have been relatively contraindicated in such patients, and although it is possible that adenosine could be used successfully, the experience with adenosine use in such compromised patients is very limited. Drug treatment of paroxysmal supraventricular tachycardia, therefore, is indicated in those 662

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patients in a stable clinical condition and with arrhythmias that are unresponsive to vagotonic physical maneuvers. Intravenous verapamil has been widely used as the drug of first choice because of its ease of administration, efficacy, and safety in the majority of patients [65-681. Adenosine is at least as effective as [14,15], and probably safer than [13,15,16], verapamil. It is relatively expensive, however, since the recommended initial dose of adenosine (6 mg) costs about $15, compared with 25 cents for 5 mg of verapamil. Adenosine should be used in preference to verapamil in patients with heart failure’, or in those who have received /3-adrenergic receptor blockers, particularly if given intravenously, and in patients with wide-complex tachycardias in whom the diagnosis is uncertain. In the absence of comparative trials with other antiarrhythmic agents, the relative role of adenosine and verapamil cannot be further defined at present.

CONCLUSIONS Adenosine is safe and effective therapy for the conversion of paroxysmal supraventricular tachycardia to sinus rhythm. It is the preferred drug in those patients in whom verapamil may cause adverse effects, in particular those with heart failure, or who have been given intravenous /3-adrenergic receptor blockers or who have wide-complex tachycardia. Its main limitations are the subjective symptoms that occur in many patients, and the occasional early recurrence of arrhythmia. Because of these factors, it has been suggested that adenosine should be reserved for patients in whom verapamil has been ineffective [22]. It can be argued, however, that frequent minor side effects with adenosine may be preferable to infrequent, but serious, adverse effects with verapamil. It remains to be seen whether the safety potential of adenosine is realized with wider usage. At present, adenosine is an effective alternative to verapamil in the treatment of supraventricular tachycardia, but can only be confidently recommended as superior to it in specific circumstances.

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