European Heart Journal (1992) 13 (Supplement H), 144-148

Aviation and antiarrhythmic medication A. P. M. GORGELS, H. J. J. WELLENS AND M. A. VOS

Cardiovascular Research Institute Maastricht, University Hospital Maastricht, The Netherlands KEY WORDS: Aircrew licensing, aviation, medication, arrhythmias, anti-arrhythmic drugs.

Introduction

Classification of cardiac arrhythmias Cardiac arrhythmias include both (1) depressed normal impulse formation and conduction (bradycardia) and (2) increased ectopic impulse formation, such asextrasystoles and tachycardias. The former, when sufficiently symptomatic, usually lead to pacemaker implantation and therefore do not fall within the scope of the topic under discussion here.

ECTOPIC IMPULSE FORMATION

Ectopic impulse formation can be classified according to site of origin, mechanism, clinical presentation, aetiology, duration, symptomatology, and prognostic features (Table 1). All aspects have to be taken into consideration to define the impact of an arrhythmia in a specific patient. Most important is classification of the arrhythmia according to the site of origin (Table 1 -1) because this is related to many other characteristics of the tachycardia, such as mechanism, symptoms, prognosis and mode of treatment. Another classification which has become increasingly important in recent years is the division according to the underlying mechanism (Table 1-2)1101. This approach also Correspondenct: Anlon P. M. Gorgds, MD, Department of Cardiology, Cardiovascular Research Institute Maastricht, University Hospital Maastricht, P.O Box 5800,6202 AZ Maastricht, The Netherlands. 019J-668X92/0H0I44 + 05 $08.00,0

Approach to the patient presenting with an arrhythmia DOCUMENTATION OF THE ARRHYTHMIA

The different aspects discussed in Table 1 have to be assessed in every patient in whom an arrhythmia is present. For this purpose, different diagnostic tools are available, ranging from a good clinical history and physical examination to electrocardiography, signal averaging of the surface ECG, 24 hour registration of the heart © 1992 The European Society of Cardiology

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The use of antiarrhythmic drug therapy in aviation depends on the characteristics of the arrhythmia on the one hand and of the antiarrhythmic drug on the other. Factors of relevance include the site of origin, aetiology, rate, duration and frequency of occurrence, and the resulting symptoms in the particular individual. Variables related to the antiarrhythmic drug include (1) its efficacy, both as far as termination of the arrhythmia and prevention of a recurrence are concerned, (2) ability to obtain a haemodynamically acceptable ventricular rate and (3) possible cardiac and extracardiac side effects. Recently it has become increasingly clear that antiarrhythmic drugs frequently have a pro-arrhythmic potential'1"91 both by impairing impulse formation and conduction (bradycardias) and by enhancing ectopic impulse formation (tachycardias). Therefore, appropriate evaluation is obligatory when an antiarrhythmic drug is being considered in the context of aviation.

has therapeutic consequences. For instance, atrial or ventricular tachycardia due to reentry will respond to class III antiarrhythmic agents in contrast to arrhythmias due to triggered activity (based on delayed after depolarizations), whereas arrhythmias due to early after depolarizations may be provoked1"1. The electrocardiographic presentation (Table 1-3) is also important when considering an arrhythmia: single premature beats, especially occurring without demonstrable structural heart disease, will have little influence on prognosis, whereas premature beats, non-sustained and sustained tachycardias occurring in the setting of a recent myocardial infarction indicate a worse prognosis. Furthermore, the configuration of an arrhythmia (monomorphic vs polymorphic) can be related to symptoms and prognosis. Knowledge about the aetiology (Table 1-4) allows a more rational approach to arrhythmia treatment, sometimes leading to avoidance of specific antiarrhythmic drug treatment, for example in the case of ischaemia, pump failure and electrolyte disturbances. The presence of symptoms (Table 1 -5) and their severity is crucial in decision making in arrhythmia patients. Some arrhythmias such as atrial or ventricular premature beats or chronic atrial fibrillation can be completely asymptomatic especially in the older age group, whereas paroxysmal forms of many arrhythmias may lead to symptoms as palpitations, dizziness, syncope and to sudden death, or to symptoms of angina and heart failure. Finally, prognosis plays a role in the approach to the patient with an arrhythmia (Table 1-6) and in the consideration of certification to fly. Benign arrhythmias such as atrial and ventricular premature beats and also sustained forms of tachycardias occurring without demonstrable heart disease, in general, carry a good prognosis, whereas the prognosis is impaired in ventricular tachycardia following myocardial infarction, especially when occurring in the setting of depressed ventricular function or when the arrhythmia is poorly tolerated'12'.

A viation and antiarrhythmic medication 145

Table 1 Classification of tachycardias 1. Site of origin 1. Supra ventricular .1 .2 .3 .4 .5 .6 .7 1.2 Ventricular 1.2.1 1.2.2 2. Mechanism 2.1 Reentry such as

2.2 2.3

Triggered activity 2.2.1 2.2.2

Sinus tachycardia Atrial tachycardia Atrial flutter Atrial fibrillation Chaotic atrial rhythm Atrioventricular nodal tachycardia Circus movement tachycardia using an accessory pathway between atrium and ventricle (atrioventricular reentrant tachycardia) Tachycardia Flutter and fibrillation Atrial flutter AV nodal tachycardia AV reentrant tachycardia Ventricular tachycardia during chronic stage of myocardial infarction Due to early after depolarizations, such as torsade de pointes Due to delayed after depolarizations, such as in digitalis toxity Abnormal automaticity i.e. spontaneous impulse formation arising from a reduced diastolic membrane potential, for instance during the subacute stage of myocardial infarction

3. Clinical presentation 3.1 Number of ectopic beats 3.1.1 Extrasystoles 3.1.2 Non-sustained tachycardia, i.e. less than 30 seconds 3.1.3 Sustained tachycardia, i.e. more than 30 seconds or leading to electrical cardioversion 3.2.1 Monomorphic 3.2.2 Polymorphic 3.3.1 Paroxysmal 3.3.2 Chronic 4. Aetiology 4.1 Idiopathic 4.2 Any underlying cause such as ischaemia, pump failure, scarring, degenerative disorders, repolarization abnormalities 5. Symptomatology 5.1 Asymptomatic 5.2 Symptomatic such as dizziness, collapse, sudden death, angina and pump failure 6. Prognosis 6.1 Benign such as premature beats without structural disease 6.2 Malignant such as polymorphic VT, ventricular fibrillation

rhythm, long-term telemetry and electrophysiological investigation. If the surface electrocardiogram does not disclose the true site of origin of the arrhythmia, intracardiac recordings are useful for an accurate localization. When the tachycardia does not occur spontaneously during the periods of observation, programmed electrical stimulation may be helpful, especially in the case of sustained monomorphic tachycardias. The mechanism is well established in many forms of arrhythmias, such as atrial fibrillation, atrial flutter, AV reentrant tachycardia, AV nodal tachycardia, but needs to be assessed in atrial tachycardia and different forms of ventricular tachycardia. For this purpose, signal averaging of the surface ECG to uncover a reentry mechanism may be useful, as well as the response of the arrhythmia to programmed stimulation and mechanism-specific drugs'131. The aetiology has to be studied in most arrhythmias, even in those known to be idiopathic, such as in AV reentrant tachycardia, where, apart from the accessory

pathway, no structural heart disease is likely to be present. To study the underlying cause, it may be necessary to perform non-invasive investigations, such as exercise testing, isotope studies, echocardiography and Doppler examination. Invasive studies such as haemodynamic evaluation, contrast ventriculography and coronary arteriography may also be required. Arrhythmias in relation to aviation responsibility

Antiarrhythmic drug therapy in aircrew should only be considered for the management of symptoms or potential symptoms. Any airmen with a rhythm disturbance which bears an adverse prognosis should be denied flying status, whether or not he/she is receiving treatment, as complete efficacy cannot be counted upon. However, supraventricular and ventricular arrhythmias may occur in normal hearts and therefore the question arises: do cirumstances exist, where, depending upon the type of arrhythmia and symptoms, the use of antiarrhythmic drug therapy can be compatible with Class I certification? In answering this

146 A. P.M. C'orgels et al.

Table 2 Arrhythmias possibly acceptable in aircrew

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potential and have been found effective in supra ventricular and ventricular arrhythmias, such as atrial fibrillation 1. Supraventricular premature beats and atrial flutter, AV nodal tachycardia and ventricular Infrequent (< 2% of normal) tachycardia. Although initially promising, they have been 2. Ventricular premature beats found to be pro-arrhythmic in 5 to 30% of patients'151. Infrequent (< 2% of normal) 3. Chronic atrial fibrillation with acceptable ventricular rate Also, their effect on the central nervous system makes (< 100 min~') (usually controlled with medication) these drugs unacceptable for use in patients with flying 4. AV nodal tachycardia when completely controlled by per- responsibilities. missible antiarrhythmic drugs Class II drugs include beta-adrenoceptor blocking 5. A V reentrant tachycardia via an accessory pathway following agents. They are indicated in slowing the ventricular rate in demonstrably complete ablation atrial fibrillation and flutter. They can also terminate AV nodal and reentrant tachycardia or prevent recurrences, question it is important to determine whether the symp- and are useful in the congenital long QT syndrome and toms of the arrhythmia interfere with mental and physical digitalis-induced arrhythmias. Although they possess ability to fly an airplane. negative inotropic effects, influence sino-atrial and AV Symptoms during an arrhythmicepisode may range from nodal conduction and also have a variety of extracardiac none to syncope. The last situation is clearly unacceptable. side effects, the hydrophilic examples may be used in There are symptoms, however, such as palpitations, aviation because they usually have less in the way of 161 which, theoretically, do not hamper cardiac function, but central side effects than their lipophilic counterparts' . may give rise to anxiety and uncertainty, interfering with Class III drugs, such as amiodarone, have a wide indiobjective decision making. Such an effect will vary cation, but a particular drug does not base its efficacy on between individuals and even in the same individual pure class III effect only, and a similar performance between attacks. Objective assessment and decision should not be expected from the newer (pure) class III making may thus be difficult or impossible. drugs. Although amiodarone is a very effective drug, even Following the exclusion of organic heart disease, and in low dosages, its use is limited by many long-term side taking into account the above, a small category of per- effects. These include photosensitivity, corneal deposition sons will remain in whom an arrhythmia is occasionally and neurological complications such as tremor, sleep present, and who are not seriously affected mentally or disturbances, headache and less frequently, peripheral physically during the arrhythmia (Table 2). neuropathy. The efficacy, cardiac and extracardiac side effects, Other drugs with class III properties, such as sotalol, pro-arrhythmic effects of and patient compliance with, are also effective in many supraventricular and ventricuthe presently available antiarrhythmic drugs are now lar arrhythmias. Their use is restricted by a negative considered in relation to aircrew licensing. inotropic action, slowing of sinus node impulse formation and conduction (due to beta-blockade) and the risk of induction of torsade de pointes (due to prolongation of Antiarrhythmic therapy and aviation repolarization)'"1. Antiarrhythmic drugs are conventionally divided Class IV drugs such as verapamil and diltiazem are according to the Vaughan William classification'14'. indicated for slowing the ventricular rate in atrial arrhythClass I drugs predominantly prolong conduction by mias, for termination and prevention of recurrences in AV block of the fast sodium channel (Table 3). They are further nodal and reentrant tachycardia, and in digitalis-induced arrhythmias. Their side effects include negative inotropy divided into three subgroups A, B and C"51. Class la drugs slow conduction and prolong refrac- and impaired impulse formation and conduction. Extratoriness. Examples are quinidine, procainamide and cardiac side effects are gastro-intestinal i.e. constipation. disopyramide. Indications are frequent premature supra- Because this drug is usually well tolerated, verapamil may ventricular and ventricular premature beats, paroxysmal be considered as acceptable in aircrew. atrial fibrillation and flutter, ventricular tachycardia Digitalis is frequently used as a drug to reduce the venand prevention of AV reentrant tachycardia. Both cardiac tricular rate in atrial arrhythmias, such as atrial fibriland extracardiac side effects are frequent. Also pro- lation, flutter and chaotic atrial rhythm. It may increase arrhythmia may occur because torsade de pointes can be arrhythmias based on triggered activity1171 and may impair induced in susceptible patients, especially in the setting of sinus node impulse formation and AV nodal conduction. hypokalaemia or hypomagnesaemia. These drugs should This drug, at appropriate dose, is quite well tolerated. not be prescribed in aircrew. Therefore when toxicity is avoided it is acceptable for use Class Ib drugs slow conduction and shorten refrac- in aviation. toriness. Tocainide, mexilitene, diphenylhydantoin and also moricizine are effective in some forms of ventricular arrhythmia including the long QT syndrome and digitalis- Management of antiarrhythmic drug prescription induced arrhythmia. Their neurological side effects When a pilot presents with one of the above mentioned preclude their use in the context of aviation. arrhythmias (Table 2), in either paroxysmal or sustained Class Ic drugs, such as flecainide and encainide, pre- form, he should be grounded in order to assess the severity dominantly slow conduction with little effect on the action of the arrhythmia in terms of symptoms, duration and

Antiarrhythmic action

Extra-cardiac side effects

Conduction Sinoatrial la 1b Ic II III IV Digitalis | I 0 + — DAD EAD GI NS

AVnodal

Hispurkinje

Myoocardium

1 01 1 0 1 0 0 increase decrease no change effect no effect triggered activity based on delayed afterdepolanzations triggered activity based on early afterdepolarizations gastro-intcstinal side effects central and peripheral nervous system

Refractoriness Myocardium

T 1 ot 0

1 0

I

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Table 3 Aiiliarrhylhmic and cardiac and extra-cardiac action ofantiarrhythmic drugs

DAD

EAD

Cardiac contractility

NS

+ + + ± +

+

Use in aviation

+

+

+

+

No No No Yes No Yes Yes

§ a.

3

I 5'

148 A. P.M. Gorgels etal.

frequency of occurrence. Furthermore, concomitant organic heart disease should be sought. Subsequently, if a drug is prescribed, an observation period of at least 3 months is required to study efficacy and the presence or absence of cardiac and/or extracardiac side effects. Efficacy should be tested by repeated 12 lead ECGs, and 24 h recordings. A flight simulator check may be performed to observe any possible decrement in performance. Thereafter, restricted certification may be possible. A return to full and unrestricted aircrew certification is not recommended. Future developments

From the above it can be concluded that the present pharmacological armamentarium lacks efficacy and specificity and its use is accompanied by cardiac and extracardiac side effects and arrhythmogenecity. There is thus a need for the development of more specific and safer antiarrhythmic drugs. Such development requires better knowledge of mechanisms of arrhythmias at a cellular level and also of the influence of the autonomic nervous system. Appropriate non-invasive techniques need to be developed to assess pro-arrhythmia in particular patients. Promising results have been obtained by using exercise testing to predict increased risk of torsade de pointes by class I drugs'181 and monomorphic ventricular tachycardia in patients on class Ic drugs'191. Non-pharmacological approaches are being used in the treatment of cardiac arrhythmias. Especially promising is the use of radiofrequency catheter ablation in patients with accessory pathways and AV nodal tachycardia'20'. Long-term follow up will have to reveal absence of arrhythmogenicity of the induced scar tissue or any tendency to recurrence of the index rhythm disturbance. Conclusion

In conclusion, antiarrhythmic drug therapy in aviation is possible in the absence of organic heart disease, and when the arrhythmia is physically and mentally well tolerated. The prescribed drug should be sufficiently effective, without pro-arrhythmic and cardiac or extracardiac side effects and the patient complaint with the drug regimen. Currently only hydrophilic beta-blocking agents, calcium antagonists such as verapamil and digitalis glycosides remain acceptable drugs for personnel with flight deck duties. References [1] Velebit V, Podrid P, Lown B, Cohen BH, Graboys TB. Aggravation and provocation of ventricular arrhythmias by antiarrhythmic drugs. Circulation 1982; 65: 886-94.

[2] Ruskin JN, McGovern MB, Garan H, DiMarco JP, Kelly E. Antiarrhythmic drugs: A possible cause of out of hospital cardiac arrest. N Engl J Med 1983; 309. 1302-6. [3] Rosen MR, Wit AL. Arrhythmogenic actions of antiarrhythmic drugs. Am J Cardiol 1987; 59: 10E-18E. [4] Bigger JT, Sahar DJ. Clinical types of proarrhythmic response to antiarrhythmic drugs. Am J Cardiol 1987; 59: 2E-9E. [5] Brugada P, Wellens HJJ. Arrhythmogenesis of antiarrhythmic response to antiarrhythmic drugs. Am J Cardiol 1988; 61: 1108-11. [6] The Cardiac Arrhythmic Suppression Trial (CAST) Investigators. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med 1989; 321: 406-12. [7] Echt DS, Leibsan PR, Mitchell LB el al. Mortality and morbidity of patients receiving encainide, flecainide or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991; 324: 781-8. [8] Woosley RL, Roden DM. Pharmacologic causes of arrhythmogenic actions of antiarrhythmic drugs. Am J Cardiol 1987; 59: 19E-25E. [9] Wellens HJJ, Smeets JL, Vos M, Gorgels APM. Antiarrhythmic drug therapy. The need for continuous vigilance. Br Heart J 1992; 67: 25-33. [10] Hoffman BF, Rosen MR. Cellular mechanisms for cardiac arrhythmias. Circ Res 1981; 49: 1-15. [11] Kuck KA, Kunze KP, Roewer N, Bleifeld W. Sotalol induced torsade de pointes. Am Heart J 1984; 107: 179-83. [12] Brugada P, Talajic M, Smeets J, Mulleneers R, Wellens HJJ. Risk stratification of patients with ventricular tachycardia or ventricular fibrillation after myocardial infarction. The value of the clinical history. Eur Heart J 1989; 10:717-52. [13] Gorgels APM, Vos MA, Smeets JLRM, Kriek E, Brugada P, Wellens HJJ. Delayed Afterdepolarizations and Atrial and Ventricular arrhythmias. In: Hoffman BF, Rosen MR, Janse MJ, Wit AL, eds. Cardiac Electrophysiology. A Textbook. Mount Kisco, New York: Futura Publishing Company, Inc., 1990:341-55. [14] Vaughan Williams EM. Classification of antiarrhythmic drugs. Pages 449-472. In: Sandoe E, Flensted-Jensen E, Olesen KH, eds. Symposium of Cardiac Arrhythmias. AB Astra, 1970. [15] Zipes DP. Management of cardiac arrhythmias: pharmacological, electrical and surgical techniques. In: Braunwald E. ed. fourth edition. Philadelphia: W. B. Saunders Co, 1991: 157-61. [ 16] Clayton AB, Harvey PG, Betts TA. The psychomotor effects of atenolol and other antihypertensive agents. Postgrad Med J 1977; 53 (Suppl 3): 157-61. [17] Gorgels APM, Wit de B, Beekman HDM, Dassen WRM, Wellens HJJ. Triggered activity induced by pacing during digitalis intoxication. Observations during programmed electrical stimulation in the conscious dog with chronic complete atrioventricular block. Pace 1987; 15: 1309-21. [18] Kadish AH, Weisman HF, Veltri EP, Epstein AE, Slepian MJ, Levine JH. Paradoxical effects of exercise on the QT interval in patients with polymorphic ventricular tachycardia receiving type la antiarrhythmic agents. Circulation 1990; 81: 14-9. [19] Ranger S, Talajic M, Lemery R, Roy D, Nattel S. Amplification of flecainide-induced ventricular conduction slowing by exercise: a potentially significant clinical consequence of use-dependent sodium channel blockade. Circulation 1989; 79: 1000-6. [20] Jackman WM, Wang X, Friday KJ el at. Catheter ablation of accessory atrioventricular pathways (Wolff-Parkinson-White syndrome) by radiofrequency current. N Engl J Med 1991; 324: 1605-11.

Aviation and antiarrhythmic medication.

European Heart Journal (1992) 13 (Supplement H), 144-148 Aviation and antiarrhythmic medication A. P. M. GORGELS, H. J. J. WELLENS AND M. A. VOS Car...
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