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The Physiologic Basis and Clinical Implications of Paired Pulse Stimulation of the Heart*
DISEASES of the CHEST Volume 49
Number 6
June, 1966
The Physiologic Basis and Clinical Implications of Paired Pulse Stimulation of the Heart* PAUL
F.
CRANEFIELD, M.D., PH.D.** AND BRIAN
F.
HOFFMAN, M.D.
New York, New York
T
H E TECHNIQUE OF
the stimulus needed to evoke excitation is essentially independent of the interval in diastole at which it is delivered. In the terminal part of the T wave, when excitation still arises at the cathode, a stronger stimulus must be used to evoke excitation. This shows that the terminal part of the T wave corresponds to part of the relative refractory period of heart muscle. Still earlier in the cardiac cycle an even stronger stimulus is needed and the excitation will be seen to arise at the anode. All of the above phenomena can be observed with comparatively brief stimuli whose duration is of the order of a few milliseconds. An important feature of the electrical excitability of the heart concerns the socalled "vulnerable period." During an interval which roughly corresponds to the middle third of the T wave, a single stimulus delivered to the ventricle will, if it is sufficiently long and sufficiently strong, give rise to ventricular fibrillation. The existence of the vulnerable period has assumed new importance in connection with "cardioversion." Its importance for cardioversion and for other methods of stimulating the heart electrically is that if a stimulus falls outside the vulnerable period it will not give rise to fibrillation. If a stimulus falls in the period between the QRS complex and the vulnerable period it will not excite the heart in any way. If it falls between the end of the vulnerable period and the next QRS complex, it will produce a single extrasystole, or, if it is subthreshold, no effect. If a stim-
PAIRED PULSE
stimulation of the heart consists of causing each regular contraction of the heart to be followed by an extrasystole.1 This may be done either by initiating both beats with artificial electrical stimulation (paired pulse stimulation) or by permitting each regular QRS complex to trigger an artificial stimulus which gives rise to an extrasystole (coupled pacing). The method has been used, on a trial basis, for the control of tachycardias and for increasing the force of contraction of the heart in both acute and chronic heart failure. I" The following review of the rationale of the method may be useful in making its potentialities and limitations clear.
Excitation of the Heart by Electrical Stimuli If two small metal electrodes (of say 1 mm. diameter) are placed directly on the heart and connected to a source of brief electrical pulses, it is possible to excite the heart artificially."" One of the electrodes will be a cathode, the other an anode. Under most conditions, excitation will occur at the cathode during all of diastole and during the terminal part of the T wave. Throughout diastole, excitation not only arises at the cathode, but the strength of *The preparation of this manuscript and original research was supported by a grant-in-aid from the American Heart Association, a grant from the New York Heart Assocation, and a grant from the National Heart Institute (HE-08508.) **From the Department of Phannacology, College of Physicians and Surgeons of Columbia University.
Copyright, 1966, by the American College of Chest Physicians
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ulus does fall in the vulnerable period, it need not necessarily cause fibrillation. It will do so only if it is fairly long and fairly strong. It is found in experiments on dogs that a stimulus must be about 10 milliseconds long and perhaps 20 times diastolic threshold in strength to evoke fibrillation. A weaker or shorter stimulus may evoke multiple extrasystoles, a single extrasystole, or have no effect at all. It will be seen, therefore, that although the vulnerable period should be treated with a good deal of respect, it is by no means true that a stimulus which falls during the vulnerable period will necessarily provoke a catastrophe.
The Force 0/ Contraction 0/ an Extrasystole It is well known that an extrasystole is commonly associated with a diminished force of contraction of the heart. I' Relatively late extrasystoles may provoke a contraction which is sufficient to open the valves and eject blood from the ventricles, but the rise in arterial pressure caused by such extrasystoles is usually less than normal. Somewhat earlier extrasystoles may provoke a contraction which increases intraventricular pressure too little even to open the valves and result in ejection of blood. Very early extrasystoles produce so little contraction that no rise in intraventricular pressure is seen when records are taken with an intraventricular catheter and the customary measuring devices. Such very early extrasystoles do produce some slight contraction, but it can be detected only with sensitive devices and only when it is looked for carefully. Although the impression is sometimes given that the weakness of the premature contraction is ass0ciated with the fact that a shortened diastole has not allowed enough time for the heart to fill, this impression is largely misleading. The diminished force of a premature contraction depends upon changes in the myocardium itself and can readily be shown on isolated strips of heart muscle, or in hearts in which no filling or emptying is permitted."
Diseases of the Chest
Postextrasystolic Potentiation The contraction which follows an extrasystole is usually more than normally forceful.!"!· It is this fact which has led to investigations of the use of paired pulse stimulation in the treatment of heart failure! Just as the diminished force of contraction of the premature beat has been explained by altered filling, so has the increased force of contraction of the postextrasystolic contraction been explained by increased filling. That explanation is also misleading. It is true that if a compensatory pause occurs, as it often does, there will be a longer period for filling, there will be more filling and greater stretch of the myocardial wall, and there will be a more forceful contraction in accord with Starling's law of the heart. But all of the phenomena of postextrasystolic potentiation can be seen in strips of heart muscle and in hearts in which filling is kept constant or in which filling and emptying are entirely prevented.":" Moreover, postextrasystolic potentiation is seen on a maintained basis when every regular contraction is followed by an extrasystole. In this situation the filling interval not only does not alter from beat to beat, but can be exactly the same as the filling interval of a heart with the same basic rate but no extrasystoles. It is important, therefore, to avoid thinking of postextrasystolic potentiation as dependent in any important way on filling. Many of the effects of postextrasystolic potentiation can be described most simply by considering the effect of a single extrasystole on the contractions which follow it. To exclude all questions related to filling, let us assume that a very early extrasystole is evoked, one which produces no detectable mechanical response, and one which is interpolated so that it produces no compensatory pause and no prolongations of the filling interval. II The next beat will be more forceful; it will give rise to a greater intraventricular pressure and to a greater rise in arterial pressure, it will show an increased rapidity of contraction (i.e., the period of isometric contraction will be shorter), and the stroke volume will probably be
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June 1966
PAIRED PULSE STIMULATION OF THE HEART
increased. All of these changes will persist, in diminishing degree, for several beats. If the various changes mentioned are detected with sensitive devices, it may be found that they persist for as many as eight or ten beats, each successive beat being, of course, less potentiated than its predecessor. There is an inverse relationship between the timing of the extrasystole and the amount of potentiation it produces in the postextrasystolic contraction. The earlier the extrasystole arises, the less will its own force of contraction be, but the greater will be the potentiation of the following beat. A possible exception to this is the exceedingly early extrasystole, probably produced by anodal excitation, which may evoke less potentiation than a slightly later extrasystole. The fact that the effect of a single extrasystole in producing postextrasystolic potentiation persists for several beats suggests that if the next regular beat is also followed by an extrasystole the second extrasystole might add its potentiating effect to the p0tentiation still present from the first extrasystole. This is in fact true. When each regular contraction is followed by an extrasystole, the amount of postextrasystolic contraction gradually increases until it reaches a stable level which is considerably greater than that produced by a single extrasystole. When a period of maintained postextrasystolic potentiations is tenninated, the potentiation wanes over a number of beats and is occasionally followed by an apparent depression of contractile force. It has been suggested that this depression may be disadvantageous in the clinical use of the method, but it seems probable that the problem, if real, can be overcome by weaning the patient from the potentiation in any of several ways.":" The effects of maintained paired pulse stimulation and maintained postextrasystolic potentiation manifest themselves very differently according to the state of the cardiovascular system. If the heart is normal and if all the cardiovascular reflexes are intact, very little change in arterial
pressure or cardiac output is seen, although changes such as increased rate of contraction may still be detected. It is in the presence of acute cardiac failure that potentiation exerts its most dramatic effects, especially if the outflow resistance is high. The heart in acute failure, contracting against a heavy resistive load, may be brought into virtually normal function by paired pulse stimulation. If however, the peripheral resistance is low, if there is venous pooling and if cardiovascular reflexes are depressed, the beneficial effects of the potentiation are not translated into beneficial effects on cardiac output and blood pressure. In this respect the positive inotropic effect of paired pulse stimulation in many respects resembles the positive inotropic effects of digitalis. The Treatment of Tachycardias It will be seen from the above summary of excitability and contractility that in paired pulse stimulation or coupled pacing there is alternation between mechanically ineffective beats and potentiated beats. If the rhythm is a regular one exactly half of the beats will be mechanically ineffective, which is to say that the rate of mechanically effective contractions will be half that of the rate as determined electrically. We may look at this in a slightly different way by saying that each mechanically effective beat will be immediately followed by an extrasystole which gives rise to little or no mechanical activity. This second full cycle of electrical activity provides a second refractory period during which the ventricle is protected from any supraventricular stimuli; it also suppresses incipient foci of ventricular extrasystolic activity simply because a second wave of depolarization has propagated throughout the ventricle. If the basic rhythm is irregular and coupled pacing is used, the rate of effective mechanical activity will not be precisely halved. Nor, in general, will the rhythm become regular. Each spontaneous systole will trigger an extrasystole and thereby be followed by a second period of refractoriness during
CRANEFIELD AND HOFFMAN
which another spontaneous extrasystole cannot arise. The reduction in the rate of mechanically effective contractions will be roughly 50 per cent and there will be some regularization of the rhythm, but the basic determinants of the rhythm will remain the spontaneous and irregular activity of the heart. Considerable experience has accumulated on the use of paired pacing or coupled pacing in the treatment of tachycardias and on one point there can be no doubt. In situations where ventricular tachycardias entirely resistant to drug treatment and to countershock have become a threat to life, paired or coupled pacing has been successful in slowing the mechanical rate and restoring competence to the heart. In such situations, in which the initiation of paired or coupled pacing is not of instant urgency, it seems reasonable to deliver the necessary stimuli via a transvenous catheter electrode, which can be left in place for a long time. Paired Pacing and Heart Failure The potentiation of the force of contraction seen in paired or coupled pacing can be very substantial and can fully reverse acute low-output failure in animals." For that reason, it has been suggested that paired pacing be used in the treatment of certain forms of acute low-output failure in man. Its use has been suggested and, in fact, attempted, in myocardial infarction accompanied by shock, in irreversible shock of other cause, in acute failure after cardiac bypass, in the acute failure associated with pulmonary embolism, and in the acute heart failure associated with difficult or prolonged resuscitations. The present status of the technique as a means of treating these forms of acute heart failure has been been examined elsewhere.••11 The present discussion will concentrate upon a single condition, that of prolonged and delayed resuscitation. Of the conditions listed above, the two most commonly seen are myocardial infarction with shock and unsuccessful resuscitation. The latter condi-
Diseasesof the Chest
tion is emphasized because it represents an area where therapeutic activism is generally regarded as acceptable, because it represents a condition where the patient is legally and medically dead, and because all studies on animals suggest that paired pulse stimulation should be able to increase markedly the rate of survival in resuscitations. Paired Pacing and Resuscitation An unsuccessful resuscitation is not infrequently charcterized by the following cardiovascular findings: electrical activity has been restored either by means of a pacemaker or by the reappearance of spontaneous rhythm; mechanical activity is present, but the force of contraction is weak; cardiac output is either zero or very low; the peripheral circulation is profoundly depressed; and the patient is either "dead" or is moribund and demonstrates all of the findings of profound cardiogenic shock. It is in these circumstances that paired pulse stimulation may be shown to produce dramatically beneficial effects in animal experiments. After prolonged and difficult defibrillation, the clinical picture seen in a dog may exactly resemble that described above. The application of paired stimuli to the ventricle of such dogs, with the resultant potentiation of the force of contraction, results in a dramatic increase in contractility and in cardiac output and, not unusually, the animal returns to a normal cardiovascular status which is maintained after cessation of paired pulse stimulation. All that is required to effect this result is the application of electrodes to the heart and the delivery of paired stimuli through them. The same maneuver may be accomplished in the human with great ease, applying electrodes directly to the heart if the chest is open, or by percutaneous insertion if the chest is not open. In certain cases known to us, the use of this method has produced the same dramatic results in man which are regularly obtained in dogs. Yet, on the whole, the use of the method has been
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PAIRED PULSE STIMULATION OF THE HEART
halting, indecisive and largely ineffective in the clinic. In view of the essentially hopeless nature of the situation and the possibly great benefits offered by this method, one may well ask why it has not been applied more regularly and effectively. One readily understandable reason appears to be the reluctance to use this new method except as a last resort. It is most often used only after all the other components of the "conventional" technique of resuscitation have been used without success for a very long period of time. If "conventional" means have been of no avail for 30 minutes or more, it is not likely that paired pulse stimulation will save the day (although it has done so even under those circumstances). In view of the fact that resuscitation is itself a last resort, and in view of the comparatively low success rate of the "conventional" techniques, there seems to be no particular merit in regarding the present sequence' of procedures as one which deserves to be promoted into a fixed and invariable method. Paired pulse stimulation offers not only a positive inotropic effect to a myocardium which badly needs it, but it also provides a pacemaker in a situation where standstill is an ever present threat. It further offers an antiarrhythmic effect where arrhythmias are a threat. It is our belief that the rapid introduction of electrodes into the myocardium and the initiation of paired pulse stimulation should be effected within the first few moments of any resuscitation procedure, even if things seem to be going well. (We naturally exclude those cases where apparent full recovery appears within two or three minutes) . The introduction of electrodes and of paired stimulation early in the procedure should rarely, if ever, diminish the chances of a favorable result and would probably very often increase the chances for such a result. But a large exception must be made to this statement, an exception which probably explains the frequent lack of success in those cases where the method has been tried, early or late. The insertion of elec-
trades into the myocardium must not be associated with any prolonged interruption of cardiac massage and ventilation, whether that massage is closed or direct. Suitable electrodes can be inserted through the chest wall and into the ventricular myocardium in 10 to 30 seconds. If the insertion is unsuccessful, a further period of massage must intervene before another attempt is made (there is no need ever to interrupt ventilation). If the insertion is successful, massage must continue actively while attempts to capture the rhythm of the heart and initiate paired stimulation are underway. Under no circumstances should paired pulse stimulation be regarded as a substitute for cardiac massage. It must progress simultaneously with cardiac massage and ventilation until cardiac function is restored. The question therefore seems to tum on the type of electrode and on the means of inserting it. The percutaneous plunge electrode proposed by Thevenet, et ale l' can undoubtedly be implanted rapidly by those familiar with its use. We believe that the electrode introduced by Ross and Hoffman" can be inserted even more rapidly. In the Ross-Hoffman electrode, a wire, insulated except for a few millimeters at the tip, is brought through a hypodermic needle and the tip is bent over the end of the needle to form a hook. The entire device is then sterilized. The wire is selected so that when the needle enters the myocardium and is retracted, the hook is stiff enough to permit the electrode to secure itself in the myocardium. On the other hand the wire is somewhat flexible so that a finn pull on it will straighten out the hook and pull the wire out of the myocardium without marked damage. The rapid insertion of a transthoracic electrode into the myocardium may be practiced both on animals and on cadavers. The technique is neither difficult nor dangerous. Granted the rapid insertion of the electrode, the successful induction of paired pulse stimulation, and the continuation of effective massage and ventilation, the status
Diseasesof
CRANEFIELD AND HOFFMAN
the Chest
of the peripheral circulation becomes a matter of crucial importance. Adequate peripheral resistance and adequate venous return are as essential to the success of paired pulse stimulation as they are to any other form of resuscitation. If paired pulse stimulation is rapidly and markedly effective, however, the need for vasoconstrictive agents may diminish rather more rapidly than in the usual situation.
extrasystolic potentiation. The method offers considerable benefits in the treatment of refractory tachycardias. Its usefulness in treating acute low-output cardiac failure is less well established clinically. It is urged that the method receive serious and extensive trial in acute low-output failure associated with resuscitation procedures.
Hazards 01 Paired and Coupled Pacing
siste en hacer que cada contracci6n normal sea seguida de un extrasistole precoz. Este proceso proteje al corazon del efecto perjudicial de las taquicardias determinando que el mimero de contracciones rnecanicamente efectivas se reduzcan a la mitad del ritmo electrico. Asimismo aurnenta la energia de las contracciones por el efecto de potenciacion post extrasist6lica. EI metodo es de beneficio considerable en el tratamiento de las taquicardias refractarias. Su utilidad en las insuficiencias agudas por bajo rendimiento cardiaco no esta clinicamente bien probada. Su empleo extensivo y bien controlado en la insuficiencia aguda con bajo rendimiento cardiaco debe ser urgentemente considerado.
The two hazards which have given rise to the greatest concern are the possible increase in the oxygen demands of the myocardium which results from the increased force of contraction and the danger of ventricular fibrillation. The risk of ventricular fibrillation is probably significantly increased if paired pacing is used in the presence of a recent myocardial infarction. Apart from that situation, the risk of ventricular fibrillation may be virtually abolished by using a stimulus which is short and not too strong (2 or 3 milliseconds and 2 to 3 times diastolic threshold), and by not permitting the stimulus to fall in the vulnerable period. In the presence of tachycardia which has become life-threatening because of a reduction in cardiac output, the slowing of the heart by paired or coupled pacing will almost undoubtedly reduce the oxygen demands of the heart and enhance the coronary flow. The risks of either fibrillation or increased oxygen demand accompanying paired pulse stimulation in resuscitation procedures may assuredly be assumed with complete propriety, especially when there is reason to believe that the heart was substantially normal prior to the events which necessitated resuscitation. SUMMARY
The technique of paired or coupled pacing of the heart depends upon causing each regular beat to be followed by an early extrasystole. This protects the heart from tachycardias by causing the rate of mechanically effective contractions to fall to half the electrical rate. It also strengthens the force of contraction by producing post-
RESUMEN
La tecnica del ritrno pareado del coraz6n con-
RESUME
La technique de la stimulation couplee du coeur se fait en amenant chaque battement regulier a etre suivi par une extrasystole precoce. Ceci protege le coeur contre la tachycardie en amenant Ie taux des contractions mecaniquement efficaces a tomber a la moitie du taux electrique. Cette technique renforce egalement la force de contraction en produisant un renforcement postextrasystolique. La methode ofIre des avantages considerables dans Ie traitement des tachycardies refractaires. Son utilite dans le traitement de la defaillance cardiaque aigue a faible debit est moins bien etablie sur des bases cliniques. II est souhaitable que cette methode beneficie d' essais serieux et etendus dans les defaillances aigues a faible debit, en association avec les techniques de reanimation. ZUSAMMENFASSUNG
Die Technik der gepaarten oder gekoppelten Schrittmacher des Herzens hangt davon ab, daP sie zu einer regelmassigen Schlagfolge in dem Sinne fiihren miissen, dap jeder regulare Schlag von einer friihzeitigen Extrasystole begleitet ist. Dieses schiitzt das Herz vor Tachycardie, weil es dazu fiihrt, daJ3 die Anzahl der mechanisch wirksamen Kontraktionen sich auf die Halfte der elektrischen Rate verringert. Es verstarkt aber auch die Kontraktionskraft durch Bildung von postextrasystolischer Potenzierung. Die Methode bietet betrachtliche Vorziige bei der Behandlung refraktarer Tachycardien. Ihr Nutzen bei der
Volume 49. No.6 June 1966
PAIRED PULSE STIMULATION OF THE HEART
Behandlung akuter Herzinsuffizienzen mit Diedrigem Minutenvolumen ist jedoch klinisch weniger sichergestellt. Es wird darauf Wert gelegt, da{3 die Methode sorfaltige und ausgedehnte weitere Erprobungen erfahrt bei Fallen von akuter Insuffizienz mit niedrigem Minutenvolumen in Verbindung mit Ma{3nahmen zur Wiederbelebung.
2 3
4 5
6
7
REFERENCES LOPEZ, J. F., EDELIST, A. AND KATZ, L. N.: "Slowing of the Heart Rate by Artificial Electrical Stimulation with Pulses of Long Duration in the Dog," Circulation, 28: 759, 1963. DEAN, D., CHAllDACIt.. W. AND GAGE, A.: "Slowing of the Heart Rate by Paired Electrical Stimuli," cu« Res... 12: 180, 1964. CRANEFIELD, P. F., SCHERLAG.. B. J., YEH.. B. K. and HOFFMAN.. B. F.: "Treatment of Acute Heart Failure by Maintained Postextrasystolic Potentiations," Bull. N. Y. Acad. M ed., 40: 903, 1964. CHARDACK.. W. M., GAGE.. A. A. AND DEAN.. D. C.: "Slowing of the Heart by Paired Pulse Pacemaking," Am. }. Cardiol... 14:374, 1964. BRAUNWALD, N. S., GAY.. W. A., Monow.. A. G. AND BRAUNWALD, E.: "Sustained, Paired, Electrical Stimuli, Slowing of the Ventricular Rate and Augmentation of the Contractile Force," Am. t. Cardiol., 14: 385, 1964. CRANEFIELD, P. F. (ed).: "Conference on Paired Pulse Stimulation and Postextrasystolic Potentiation in the Heart," Bull. N. Y. Acad. Med., 41 :417, 1965. This symposium contains contributions from many authors, extensive bibliographies and a complete review of the status of this technique as of early 1965. BROOKS, C. McC., HOFFMAN, B. F., SUCKLING, E. E. AND ORIAS, 0.: E%citability of the Heart, Grune and Stratton, New York, 1955.
8 HOFFMAN, B. F. AND CRANEFIELD, P. F.: Electrophysiology of the Heart, McGraw-Hill, New York, 1960. 9 HOFFMAN, B. F. AND CRANEFIELD, P. F.: "The Physiological Basis of Cardiac Arrhythmias," Am. t. Med., 37:670, 1964. 10 CIlANEFIELD, P. F.: "The Force of Contraction of Extrasystoles and the Potentiation of the Force of the Postextrasystolic Contraction: a Historical Review," Bull. N. Y. .A cad. Med., 41: 419, 1965. 11 SIEBENS, A. A., HOFFMAN, B. F., CIlANEFIELD, P. F. AND BROOKS, C. McC.: "Regulation of Contractile Force During Ventricular Arrhythmias," Am. t. Physiol., 197: 791, 1959. 12 LENDRUM, B., FEINBERG, H., BoYD, E. AND KATZ, L. N.: "Rhythm Effects on Contractility of the Beating Isovolumic Left Ventricle," Am. t. Physiol., 199: 1115, 1960. 13 HOFFMAN, B. F., BARTELSTONE, H. J., SCHERLAG, B. F. AND CRANEFIELD, P. F.: "Effects of Postextrasystolic Potentiation on Normal and Failing Hearts," Bull. N. Y. Acad, Med., 41: 498, 1965. 14 CIlANEFIELD, P. F.: "Graded Control of Cardiac Output by Paired Pulse Stimulation," Fed. Proc., 24:651, 1965. 15 CRANEFIELD, P. F.: "Paired Pulse Stimulation and Postextrasystolic Pot en t i at ion in the Heart," Prog, Cardiouas. Dis., in press, 1966. 16 THEVENET.. R., HODGES, P. C. AND LILLEHEI, C. W.: "The Use of a Myocardial Electrode Inserted Percutaneously for Control of Complete Atrioventricular Block by an Artificial Pacemaker," Dis. Chest, 34: 1, 1958. 17 Ross, S. R. AND HOFFMAN, B. F.: "A Bipolar Pacemaker for Immediate Treatment of Cardiac arrest," }. Appl. Phvsiol., 15: 974, 1960.
For reprints, please write Dr. Cranefield, Department of Pharmacology, Columbia University, 630 West 168th Street, New York, New York.
THE LUNGS IN CIRRHOSIS Infection of the pulmonary artery with a micropaque gelatin suspensIon was made In 13 post-mortem lungs from patients with various types of llver cirrhosis. one patient with subacute massive necrosis of the liver and six with normal lungs. A marked arterial dilation was seen In the ftne peripheral branches of the pulmonary artery within the respiratory part of the lung In all 13 cases of cirrhosis and on the pleura where "spider nevi" were apparent In six. This dilatation was at the precaplllary level and
affected chiefly arterial branches below 500 microns in diameter. In one case. obvious peripheral pulmonary arteriovenous shunts were demonstrated. The pathogenesis of this vasodilatation Is not clear; It Is unlikely to be due to portal hypertension. and a humoral mecbanlam Is poll1ble. BERTHELOT.
P.,
WALKER,
J. G.•
SHERLOCK, S.
AND IlmD,
L.: ••Arterial Changes in the Lungs in Cirrhosis of the Liver-Luna Spider Nevi," N,w Bngl. t. M.J., 274:291. 1966.
Number 6
June, 1966
The Physiologic Basis and Clinical Implications of Paired Pulse Stimulation of the Heart* PAUL
F.
CRANEFIELD, M.D., PH.D.** AND BRIAN
F.
HOFFMAN, M.D.
New York, New York
T
H E TECHNIQUE OF
the stimulus needed to evoke excitation is essentially independent of the interval in diastole at which it is delivered. In the terminal part of the T wave, when excitation still arises at the cathode, a stronger stimulus must be used to evoke excitation. This shows that the terminal part of the T wave corresponds to part of the relative refractory period of heart muscle. Still earlier in the cardiac cycle an even stronger stimulus is needed and the excitation will be seen to arise at the anode. All of the above phenomena can be observed with comparatively brief stimuli whose duration is of the order of a few milliseconds. An important feature of the electrical excitability of the heart concerns the socalled "vulnerable period." During an interval which roughly corresponds to the middle third of the T wave, a single stimulus delivered to the ventricle will, if it is sufficiently long and sufficiently strong, give rise to ventricular fibrillation. The existence of the vulnerable period has assumed new importance in connection with "cardioversion." Its importance for cardioversion and for other methods of stimulating the heart electrically is that if a stimulus falls outside the vulnerable period it will not give rise to fibrillation. If a stimulus falls in the period between the QRS complex and the vulnerable period it will not excite the heart in any way. If it falls between the end of the vulnerable period and the next QRS complex, it will produce a single extrasystole, or, if it is subthreshold, no effect. If a stim-
PAIRED PULSE
stimulation of the heart consists of causing each regular contraction of the heart to be followed by an extrasystole.1 This may be done either by initiating both beats with artificial electrical stimulation (paired pulse stimulation) or by permitting each regular QRS complex to trigger an artificial stimulus which gives rise to an extrasystole (coupled pacing). The method has been used, on a trial basis, for the control of tachycardias and for increasing the force of contraction of the heart in both acute and chronic heart failure. I" The following review of the rationale of the method may be useful in making its potentialities and limitations clear.
Excitation of the Heart by Electrical Stimuli If two small metal electrodes (of say 1 mm. diameter) are placed directly on the heart and connected to a source of brief electrical pulses, it is possible to excite the heart artificially."" One of the electrodes will be a cathode, the other an anode. Under most conditions, excitation will occur at the cathode during all of diastole and during the terminal part of the T wave. Throughout diastole, excitation not only arises at the cathode, but the strength of *The preparation of this manuscript and original research was supported by a grant-in-aid from the American Heart Association, a grant from the New York Heart Assocation, and a grant from the National Heart Institute (HE-08508.) **From the Department of Phannacology, College of Physicians and Surgeons of Columbia University.
Copyright, 1966, by the American College of Chest Physicians
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ulus does fall in the vulnerable period, it need not necessarily cause fibrillation. It will do so only if it is fairly long and fairly strong. It is found in experiments on dogs that a stimulus must be about 10 milliseconds long and perhaps 20 times diastolic threshold in strength to evoke fibrillation. A weaker or shorter stimulus may evoke multiple extrasystoles, a single extrasystole, or have no effect at all. It will be seen, therefore, that although the vulnerable period should be treated with a good deal of respect, it is by no means true that a stimulus which falls during the vulnerable period will necessarily provoke a catastrophe.
The Force 0/ Contraction 0/ an Extrasystole It is well known that an extrasystole is commonly associated with a diminished force of contraction of the heart. I' Relatively late extrasystoles may provoke a contraction which is sufficient to open the valves and eject blood from the ventricles, but the rise in arterial pressure caused by such extrasystoles is usually less than normal. Somewhat earlier extrasystoles may provoke a contraction which increases intraventricular pressure too little even to open the valves and result in ejection of blood. Very early extrasystoles produce so little contraction that no rise in intraventricular pressure is seen when records are taken with an intraventricular catheter and the customary measuring devices. Such very early extrasystoles do produce some slight contraction, but it can be detected only with sensitive devices and only when it is looked for carefully. Although the impression is sometimes given that the weakness of the premature contraction is ass0ciated with the fact that a shortened diastole has not allowed enough time for the heart to fill, this impression is largely misleading. The diminished force of a premature contraction depends upon changes in the myocardium itself and can readily be shown on isolated strips of heart muscle, or in hearts in which no filling or emptying is permitted."
Diseases of the Chest
Postextrasystolic Potentiation The contraction which follows an extrasystole is usually more than normally forceful.!"!· It is this fact which has led to investigations of the use of paired pulse stimulation in the treatment of heart failure! Just as the diminished force of contraction of the premature beat has been explained by altered filling, so has the increased force of contraction of the postextrasystolic contraction been explained by increased filling. That explanation is also misleading. It is true that if a compensatory pause occurs, as it often does, there will be a longer period for filling, there will be more filling and greater stretch of the myocardial wall, and there will be a more forceful contraction in accord with Starling's law of the heart. But all of the phenomena of postextrasystolic potentiation can be seen in strips of heart muscle and in hearts in which filling is kept constant or in which filling and emptying are entirely prevented.":" Moreover, postextrasystolic potentiation is seen on a maintained basis when every regular contraction is followed by an extrasystole. In this situation the filling interval not only does not alter from beat to beat, but can be exactly the same as the filling interval of a heart with the same basic rate but no extrasystoles. It is important, therefore, to avoid thinking of postextrasystolic potentiation as dependent in any important way on filling. Many of the effects of postextrasystolic potentiation can be described most simply by considering the effect of a single extrasystole on the contractions which follow it. To exclude all questions related to filling, let us assume that a very early extrasystole is evoked, one which produces no detectable mechanical response, and one which is interpolated so that it produces no compensatory pause and no prolongations of the filling interval. II The next beat will be more forceful; it will give rise to a greater intraventricular pressure and to a greater rise in arterial pressure, it will show an increased rapidity of contraction (i.e., the period of isometric contraction will be shorter), and the stroke volume will probably be
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June 1966
PAIRED PULSE STIMULATION OF THE HEART
increased. All of these changes will persist, in diminishing degree, for several beats. If the various changes mentioned are detected with sensitive devices, it may be found that they persist for as many as eight or ten beats, each successive beat being, of course, less potentiated than its predecessor. There is an inverse relationship between the timing of the extrasystole and the amount of potentiation it produces in the postextrasystolic contraction. The earlier the extrasystole arises, the less will its own force of contraction be, but the greater will be the potentiation of the following beat. A possible exception to this is the exceedingly early extrasystole, probably produced by anodal excitation, which may evoke less potentiation than a slightly later extrasystole. The fact that the effect of a single extrasystole in producing postextrasystolic potentiation persists for several beats suggests that if the next regular beat is also followed by an extrasystole the second extrasystole might add its potentiating effect to the p0tentiation still present from the first extrasystole. This is in fact true. When each regular contraction is followed by an extrasystole, the amount of postextrasystolic contraction gradually increases until it reaches a stable level which is considerably greater than that produced by a single extrasystole. When a period of maintained postextrasystolic potentiations is tenninated, the potentiation wanes over a number of beats and is occasionally followed by an apparent depression of contractile force. It has been suggested that this depression may be disadvantageous in the clinical use of the method, but it seems probable that the problem, if real, can be overcome by weaning the patient from the potentiation in any of several ways.":" The effects of maintained paired pulse stimulation and maintained postextrasystolic potentiation manifest themselves very differently according to the state of the cardiovascular system. If the heart is normal and if all the cardiovascular reflexes are intact, very little change in arterial
pressure or cardiac output is seen, although changes such as increased rate of contraction may still be detected. It is in the presence of acute cardiac failure that potentiation exerts its most dramatic effects, especially if the outflow resistance is high. The heart in acute failure, contracting against a heavy resistive load, may be brought into virtually normal function by paired pulse stimulation. If however, the peripheral resistance is low, if there is venous pooling and if cardiovascular reflexes are depressed, the beneficial effects of the potentiation are not translated into beneficial effects on cardiac output and blood pressure. In this respect the positive inotropic effect of paired pulse stimulation in many respects resembles the positive inotropic effects of digitalis. The Treatment of Tachycardias It will be seen from the above summary of excitability and contractility that in paired pulse stimulation or coupled pacing there is alternation between mechanically ineffective beats and potentiated beats. If the rhythm is a regular one exactly half of the beats will be mechanically ineffective, which is to say that the rate of mechanically effective contractions will be half that of the rate as determined electrically. We may look at this in a slightly different way by saying that each mechanically effective beat will be immediately followed by an extrasystole which gives rise to little or no mechanical activity. This second full cycle of electrical activity provides a second refractory period during which the ventricle is protected from any supraventricular stimuli; it also suppresses incipient foci of ventricular extrasystolic activity simply because a second wave of depolarization has propagated throughout the ventricle. If the basic rhythm is irregular and coupled pacing is used, the rate of effective mechanical activity will not be precisely halved. Nor, in general, will the rhythm become regular. Each spontaneous systole will trigger an extrasystole and thereby be followed by a second period of refractoriness during
CRANEFIELD AND HOFFMAN
which another spontaneous extrasystole cannot arise. The reduction in the rate of mechanically effective contractions will be roughly 50 per cent and there will be some regularization of the rhythm, but the basic determinants of the rhythm will remain the spontaneous and irregular activity of the heart. Considerable experience has accumulated on the use of paired pacing or coupled pacing in the treatment of tachycardias and on one point there can be no doubt. In situations where ventricular tachycardias entirely resistant to drug treatment and to countershock have become a threat to life, paired or coupled pacing has been successful in slowing the mechanical rate and restoring competence to the heart. In such situations, in which the initiation of paired or coupled pacing is not of instant urgency, it seems reasonable to deliver the necessary stimuli via a transvenous catheter electrode, which can be left in place for a long time. Paired Pacing and Heart Failure The potentiation of the force of contraction seen in paired or coupled pacing can be very substantial and can fully reverse acute low-output failure in animals." For that reason, it has been suggested that paired pacing be used in the treatment of certain forms of acute low-output failure in man. Its use has been suggested and, in fact, attempted, in myocardial infarction accompanied by shock, in irreversible shock of other cause, in acute failure after cardiac bypass, in the acute failure associated with pulmonary embolism, and in the acute heart failure associated with difficult or prolonged resuscitations. The present status of the technique as a means of treating these forms of acute heart failure has been been examined elsewhere.••11 The present discussion will concentrate upon a single condition, that of prolonged and delayed resuscitation. Of the conditions listed above, the two most commonly seen are myocardial infarction with shock and unsuccessful resuscitation. The latter condi-
Diseasesof the Chest
tion is emphasized because it represents an area where therapeutic activism is generally regarded as acceptable, because it represents a condition where the patient is legally and medically dead, and because all studies on animals suggest that paired pulse stimulation should be able to increase markedly the rate of survival in resuscitations. Paired Pacing and Resuscitation An unsuccessful resuscitation is not infrequently charcterized by the following cardiovascular findings: electrical activity has been restored either by means of a pacemaker or by the reappearance of spontaneous rhythm; mechanical activity is present, but the force of contraction is weak; cardiac output is either zero or very low; the peripheral circulation is profoundly depressed; and the patient is either "dead" or is moribund and demonstrates all of the findings of profound cardiogenic shock. It is in these circumstances that paired pulse stimulation may be shown to produce dramatically beneficial effects in animal experiments. After prolonged and difficult defibrillation, the clinical picture seen in a dog may exactly resemble that described above. The application of paired stimuli to the ventricle of such dogs, with the resultant potentiation of the force of contraction, results in a dramatic increase in contractility and in cardiac output and, not unusually, the animal returns to a normal cardiovascular status which is maintained after cessation of paired pulse stimulation. All that is required to effect this result is the application of electrodes to the heart and the delivery of paired stimuli through them. The same maneuver may be accomplished in the human with great ease, applying electrodes directly to the heart if the chest is open, or by percutaneous insertion if the chest is not open. In certain cases known to us, the use of this method has produced the same dramatic results in man which are regularly obtained in dogs. Yet, on the whole, the use of the method has been
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PAIRED PULSE STIMULATION OF THE HEART
halting, indecisive and largely ineffective in the clinic. In view of the essentially hopeless nature of the situation and the possibly great benefits offered by this method, one may well ask why it has not been applied more regularly and effectively. One readily understandable reason appears to be the reluctance to use this new method except as a last resort. It is most often used only after all the other components of the "conventional" technique of resuscitation have been used without success for a very long period of time. If "conventional" means have been of no avail for 30 minutes or more, it is not likely that paired pulse stimulation will save the day (although it has done so even under those circumstances). In view of the fact that resuscitation is itself a last resort, and in view of the comparatively low success rate of the "conventional" techniques, there seems to be no particular merit in regarding the present sequence' of procedures as one which deserves to be promoted into a fixed and invariable method. Paired pulse stimulation offers not only a positive inotropic effect to a myocardium which badly needs it, but it also provides a pacemaker in a situation where standstill is an ever present threat. It further offers an antiarrhythmic effect where arrhythmias are a threat. It is our belief that the rapid introduction of electrodes into the myocardium and the initiation of paired pulse stimulation should be effected within the first few moments of any resuscitation procedure, even if things seem to be going well. (We naturally exclude those cases where apparent full recovery appears within two or three minutes) . The introduction of electrodes and of paired stimulation early in the procedure should rarely, if ever, diminish the chances of a favorable result and would probably very often increase the chances for such a result. But a large exception must be made to this statement, an exception which probably explains the frequent lack of success in those cases where the method has been tried, early or late. The insertion of elec-
trades into the myocardium must not be associated with any prolonged interruption of cardiac massage and ventilation, whether that massage is closed or direct. Suitable electrodes can be inserted through the chest wall and into the ventricular myocardium in 10 to 30 seconds. If the insertion is unsuccessful, a further period of massage must intervene before another attempt is made (there is no need ever to interrupt ventilation). If the insertion is successful, massage must continue actively while attempts to capture the rhythm of the heart and initiate paired stimulation are underway. Under no circumstances should paired pulse stimulation be regarded as a substitute for cardiac massage. It must progress simultaneously with cardiac massage and ventilation until cardiac function is restored. The question therefore seems to tum on the type of electrode and on the means of inserting it. The percutaneous plunge electrode proposed by Thevenet, et ale l' can undoubtedly be implanted rapidly by those familiar with its use. We believe that the electrode introduced by Ross and Hoffman" can be inserted even more rapidly. In the Ross-Hoffman electrode, a wire, insulated except for a few millimeters at the tip, is brought through a hypodermic needle and the tip is bent over the end of the needle to form a hook. The entire device is then sterilized. The wire is selected so that when the needle enters the myocardium and is retracted, the hook is stiff enough to permit the electrode to secure itself in the myocardium. On the other hand the wire is somewhat flexible so that a finn pull on it will straighten out the hook and pull the wire out of the myocardium without marked damage. The rapid insertion of a transthoracic electrode into the myocardium may be practiced both on animals and on cadavers. The technique is neither difficult nor dangerous. Granted the rapid insertion of the electrode, the successful induction of paired pulse stimulation, and the continuation of effective massage and ventilation, the status
Diseasesof
CRANEFIELD AND HOFFMAN
the Chest
of the peripheral circulation becomes a matter of crucial importance. Adequate peripheral resistance and adequate venous return are as essential to the success of paired pulse stimulation as they are to any other form of resuscitation. If paired pulse stimulation is rapidly and markedly effective, however, the need for vasoconstrictive agents may diminish rather more rapidly than in the usual situation.
extrasystolic potentiation. The method offers considerable benefits in the treatment of refractory tachycardias. Its usefulness in treating acute low-output cardiac failure is less well established clinically. It is urged that the method receive serious and extensive trial in acute low-output failure associated with resuscitation procedures.
Hazards 01 Paired and Coupled Pacing
siste en hacer que cada contracci6n normal sea seguida de un extrasistole precoz. Este proceso proteje al corazon del efecto perjudicial de las taquicardias determinando que el mimero de contracciones rnecanicamente efectivas se reduzcan a la mitad del ritmo electrico. Asimismo aurnenta la energia de las contracciones por el efecto de potenciacion post extrasist6lica. EI metodo es de beneficio considerable en el tratamiento de las taquicardias refractarias. Su utilidad en las insuficiencias agudas por bajo rendimiento cardiaco no esta clinicamente bien probada. Su empleo extensivo y bien controlado en la insuficiencia aguda con bajo rendimiento cardiaco debe ser urgentemente considerado.
The two hazards which have given rise to the greatest concern are the possible increase in the oxygen demands of the myocardium which results from the increased force of contraction and the danger of ventricular fibrillation. The risk of ventricular fibrillation is probably significantly increased if paired pacing is used in the presence of a recent myocardial infarction. Apart from that situation, the risk of ventricular fibrillation may be virtually abolished by using a stimulus which is short and not too strong (2 or 3 milliseconds and 2 to 3 times diastolic threshold), and by not permitting the stimulus to fall in the vulnerable period. In the presence of tachycardia which has become life-threatening because of a reduction in cardiac output, the slowing of the heart by paired or coupled pacing will almost undoubtedly reduce the oxygen demands of the heart and enhance the coronary flow. The risks of either fibrillation or increased oxygen demand accompanying paired pulse stimulation in resuscitation procedures may assuredly be assumed with complete propriety, especially when there is reason to believe that the heart was substantially normal prior to the events which necessitated resuscitation. SUMMARY
The technique of paired or coupled pacing of the heart depends upon causing each regular beat to be followed by an early extrasystole. This protects the heart from tachycardias by causing the rate of mechanically effective contractions to fall to half the electrical rate. It also strengthens the force of contraction by producing post-
RESUMEN
La tecnica del ritrno pareado del coraz6n con-
RESUME
La technique de la stimulation couplee du coeur se fait en amenant chaque battement regulier a etre suivi par une extrasystole precoce. Ceci protege le coeur contre la tachycardie en amenant Ie taux des contractions mecaniquement efficaces a tomber a la moitie du taux electrique. Cette technique renforce egalement la force de contraction en produisant un renforcement postextrasystolique. La methode ofIre des avantages considerables dans Ie traitement des tachycardies refractaires. Son utilite dans le traitement de la defaillance cardiaque aigue a faible debit est moins bien etablie sur des bases cliniques. II est souhaitable que cette methode beneficie d' essais serieux et etendus dans les defaillances aigues a faible debit, en association avec les techniques de reanimation. ZUSAMMENFASSUNG
Die Technik der gepaarten oder gekoppelten Schrittmacher des Herzens hangt davon ab, daP sie zu einer regelmassigen Schlagfolge in dem Sinne fiihren miissen, dap jeder regulare Schlag von einer friihzeitigen Extrasystole begleitet ist. Dieses schiitzt das Herz vor Tachycardie, weil es dazu fiihrt, daJ3 die Anzahl der mechanisch wirksamen Kontraktionen sich auf die Halfte der elektrischen Rate verringert. Es verstarkt aber auch die Kontraktionskraft durch Bildung von postextrasystolischer Potenzierung. Die Methode bietet betrachtliche Vorziige bei der Behandlung refraktarer Tachycardien. Ihr Nutzen bei der
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PAIRED PULSE STIMULATION OF THE HEART
Behandlung akuter Herzinsuffizienzen mit Diedrigem Minutenvolumen ist jedoch klinisch weniger sichergestellt. Es wird darauf Wert gelegt, da{3 die Methode sorfaltige und ausgedehnte weitere Erprobungen erfahrt bei Fallen von akuter Insuffizienz mit niedrigem Minutenvolumen in Verbindung mit Ma{3nahmen zur Wiederbelebung.
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7
REFERENCES LOPEZ, J. F., EDELIST, A. AND KATZ, L. N.: "Slowing of the Heart Rate by Artificial Electrical Stimulation with Pulses of Long Duration in the Dog," Circulation, 28: 759, 1963. DEAN, D., CHAllDACIt.. W. AND GAGE, A.: "Slowing of the Heart Rate by Paired Electrical Stimuli," cu« Res... 12: 180, 1964. CRANEFIELD, P. F., SCHERLAG.. B. J., YEH.. B. K. and HOFFMAN.. B. F.: "Treatment of Acute Heart Failure by Maintained Postextrasystolic Potentiations," Bull. N. Y. Acad. M ed., 40: 903, 1964. CHARDACK.. W. M., GAGE.. A. A. AND DEAN.. D. C.: "Slowing of the Heart by Paired Pulse Pacemaking," Am. }. Cardiol... 14:374, 1964. BRAUNWALD, N. S., GAY.. W. A., Monow.. A. G. AND BRAUNWALD, E.: "Sustained, Paired, Electrical Stimuli, Slowing of the Ventricular Rate and Augmentation of the Contractile Force," Am. t. Cardiol., 14: 385, 1964. CRANEFIELD, P. F. (ed).: "Conference on Paired Pulse Stimulation and Postextrasystolic Potentiation in the Heart," Bull. N. Y. Acad. Med., 41 :417, 1965. This symposium contains contributions from many authors, extensive bibliographies and a complete review of the status of this technique as of early 1965. BROOKS, C. McC., HOFFMAN, B. F., SUCKLING, E. E. AND ORIAS, 0.: E%citability of the Heart, Grune and Stratton, New York, 1955.
8 HOFFMAN, B. F. AND CRANEFIELD, P. F.: Electrophysiology of the Heart, McGraw-Hill, New York, 1960. 9 HOFFMAN, B. F. AND CRANEFIELD, P. F.: "The Physiological Basis of Cardiac Arrhythmias," Am. t. Med., 37:670, 1964. 10 CIlANEFIELD, P. F.: "The Force of Contraction of Extrasystoles and the Potentiation of the Force of the Postextrasystolic Contraction: a Historical Review," Bull. N. Y. .A cad. Med., 41: 419, 1965. 11 SIEBENS, A. A., HOFFMAN, B. F., CIlANEFIELD, P. F. AND BROOKS, C. McC.: "Regulation of Contractile Force During Ventricular Arrhythmias," Am. t. Physiol., 197: 791, 1959. 12 LENDRUM, B., FEINBERG, H., BoYD, E. AND KATZ, L. N.: "Rhythm Effects on Contractility of the Beating Isovolumic Left Ventricle," Am. t. Physiol., 199: 1115, 1960. 13 HOFFMAN, B. F., BARTELSTONE, H. J., SCHERLAG, B. F. AND CRANEFIELD, P. F.: "Effects of Postextrasystolic Potentiation on Normal and Failing Hearts," Bull. N. Y. Acad, Med., 41: 498, 1965. 14 CIlANEFIELD, P. F.: "Graded Control of Cardiac Output by Paired Pulse Stimulation," Fed. Proc., 24:651, 1965. 15 CRANEFIELD, P. F.: "Paired Pulse Stimulation and Postextrasystolic Pot en t i at ion in the Heart," Prog, Cardiouas. Dis., in press, 1966. 16 THEVENET.. R., HODGES, P. C. AND LILLEHEI, C. W.: "The Use of a Myocardial Electrode Inserted Percutaneously for Control of Complete Atrioventricular Block by an Artificial Pacemaker," Dis. Chest, 34: 1, 1958. 17 Ross, S. R. AND HOFFMAN, B. F.: "A Bipolar Pacemaker for Immediate Treatment of Cardiac arrest," }. Appl. Phvsiol., 15: 974, 1960.
For reprints, please write Dr. Cranefield, Department of Pharmacology, Columbia University, 630 West 168th Street, New York, New York.
THE LUNGS IN CIRRHOSIS Infection of the pulmonary artery with a micropaque gelatin suspensIon was made In 13 post-mortem lungs from patients with various types of llver cirrhosis. one patient with subacute massive necrosis of the liver and six with normal lungs. A marked arterial dilation was seen In the ftne peripheral branches of the pulmonary artery within the respiratory part of the lung In all 13 cases of cirrhosis and on the pleura where "spider nevi" were apparent In six. This dilatation was at the precaplllary level and
affected chiefly arterial branches below 500 microns in diameter. In one case. obvious peripheral pulmonary arteriovenous shunts were demonstrated. The pathogenesis of this vasodilatation Is not clear; It Is unlikely to be due to portal hypertension. and a humoral mecbanlam Is poll1ble. BERTHELOT.
P.,
WALKER,
J. G.•
SHERLOCK, S.
AND IlmD,
L.: ••Arterial Changes in the Lungs in Cirrhosis of the Liver-Luna Spider Nevi," N,w Bngl. t. M.J., 274:291. 1966.