International Journal of Cardiology, 37 (1992) l-5 0 1992 Elsevier Science Publishers B.V. All rights reserved
CARD10
1 0167-5273/92/$05.00
01528
Review
Mechanism of cyanotic spells in tetralogy of Fdlot - the missing link? Shyam Sunder Kothari Cardiothoracic Centre, All India Institute of Medical Sciences, New Delhi, India (Received
Kothari SS. Mechanism 1992;37:1-5.
18 November
1991: revision
of cyanotic spells in tetralogy
accepted
17 May 1992)
of Fallot - the missing link? Int J Cardiol
The mechanism of cyanotic spells in patients with tetralogy of Fallot is not clear. Increases in infundibular contractility or hyperpnoea have been considered as the key factors, but this explanation appears inadequate. In this review, arguments are presented against these commonly held views. Preliminary evidence is synthesised in favour of another more plausible hypothesis that cyanotic spells may result from mechanoreceptor stimulation from the right ventricle. Increased contractility (due to catecholamines) and decreased right ventricular size (due to various factors) can trigger a reflex resulting in hyperventilation, some peripheral vasodilation without bradycardia, and this may initiate a spell. This mechanism explains most of the precipitating events and many other issues about cyanotic spells more satisfactorily. Key words: Tetralogy of Fallot; Cyanosis; Syncope; Mechanoreceptor
Introduction The episodes of paroxysmal dyspnoea with marked cyanosis (cyanotic spells) in infants and young children with tetralogy of Fallot are common and serious [l-4]. The episodes may last from a few minutes to several hours and the marked arterial hypoxaemia during the spells may result in brain damage or death, although usually these spells are self limiting. The cyanotic spells frequently occur without warning, although cry-
Correspondence tot Dr. S.S. Kothari, Cardiothoracic tre, All India Institute of Medical Sciences, Ansari New Delhi-l 10029, India.
CenNagar,
ing, bowel movement or feeding can precipitate them [l]. The spells increase in frequency during summer months, and with infections [2]. Cardiac catheterization [5], and supraventricular tachycardia [6] are also known to precipitate these spells. In fact, the circumstances precipitating the spells have been so different and varied that it has been difficult to envisage a common environmental factor [2]. It is clear that these episodes result from drastic reduction of pulmonary blood flow, with an accompanying increase in the right-to-left shunt and a drop in systemic arterial oxygen saturation. However, the precise mechanism of the spells has not been understood. Increase in infundibular contractility [7], peripheral vasodilation [8], or
2
hyperventilation the key factors.
[93 have been incriminated
Increase in infundibular
as
contractility
Most workers now believe that increase in contractility of right ventricular infundibular musculature results in a decrease in pulmonary blood flow, and other features of the cyanotic spells [2-4,7,10]. The clinical findings of reduction in intensity of murmur across the right ventricular outflow during the spell appear to favour this view. In fact, marked reduction in forward blood flow to the lungs has been angiographically demonstrated during a spell [lO,ll]. Johnson suggested that [12] increase in the contractility may result from increase in endogenous norepinephrine (which is possible during most of the precipitating events listed). The salutary effects of beta-blockers in the patients with spells also support this view [ll]. The occurrence of spells, albeit rare in patients with pulmonary atresia and ventricular septal defect, casts doubt on the importance of infundibular contractility as the sole mechanism [7]. Furthermore, as discussed below, peripheral vasodilation in patients with tetralogy of Fallot may also reduce the intensity of the murmur and blood flow to the lungs. Increase in catecholamines has not been demonstrated preceding the spells. Although an increase in infundibular obstruction may appear a simple explanation of the spells, it remains to be clarified why every-day activities like crying, feeding etc. only occasionally result in spells. By itself, an increase in contractility due to endogenous catecholamines does not seem to explain completely the dramatic clinical presentation of these patients. Peripheral
vasodilation
Peripheral vasodilation in patients with tetralogy of Fallot would increase shunting of the right ventricular blood to the aorta through ventricular septal defect, and decrease pulmonary blood flow. Previously suggested by Hamilton [8] as an important reason for the cyanotic spells, subsequent workers did not consider it important as there
was no fall in systolic blood pressure during the spells. The diastolic pressure was not low, nor did the pulse pressure widen [4,5,7]. Thus, marked vasodilation does not accompany the spells. However, peripheral vasodilation with amyl nitrite in the patients with tetralogy of Fallot has been shown to result in a marked reduction in the murmur and increase in cyanosis with relatively less hypotension [13]. The question of peripheral vasodilation in cyanotic spells does not seem to have been adequately investigated. Hyperventilation Hyperpnoea increases oxygen demand and cardiac output [14]. In patients with tetralogy of Fallot, hyperpnoea results in an increase in arterial desaturation due to an increase in right-to-left shunt in the face of increased cardiac output but a relatively fixed pulmonary blood flow [9]. Guntheroth et al. suggest that hyperpnoea may be the important factor initiating and maintaining the cyanotic spells [93. To account for the frequent occurrence of spells in the morning hours of the day after a good night’s sleep [3], they propose that the respiratory drive mechanism may be more sensitive to changes in blood gases when the patients wake up in a reasonable metabolic status after sleep. During such times a sudden decrease in arterial p0, and pH and an increase in arterial pC0, induced by a relatively sudden increase in activity, or a Valsalva-like manoeuvre (such as crying or bowel movement) may trigger marked hyperpnoea. The hyperpnoea will increase cardiac output and decrease pulmonary blood flow resulting in further right-to-left shunt and greater arterial hypoxaemia. A vicious cycle may thus be established resulting in the spell. They also state that in most of these patients on most days, there is either an adjustment in sensitivity of respiratory drive mechanism or an adjustment in bicarbonate, which prevents the occurrence of spells [93. This elusive sequence of events has never been proved or disproved. Furthermore, it does not explain the fact that spells indeed occur at any time of the day [4]. Moreover, it may be relevant to note that the sensitivity of the respiratory centre to hypoxia is known to be blunted in
patients with cyanotic heart disease [15], and is not restored even years after corrective surgery
1161. In the absence of any better alternative the scheme suggested by Guntheroth et al. has provided a good working hypothesis up to now. However, I believe that the following hypothesis may explain the mechanism of spells and the events precipitating these spells more satisfactorily. Hypothesis The cyanotic spells in patients with tetralogy of Fallot may result from the stimulation of right ventricular mechanoreceptors. Increased contractility (due to endogenous catecholamines), and a decrease in right ventricular cavity size (such as can occur with Valsalva-like manoeuvre) may trigger a reflex response resulting in hyperventilation, some peripheral vasodilation, without bradycardia. The hyperpnoea may perpetuate a vicious cycle, as discussed previously. It is well known now that a combination of decreased left ventricular volume and raised sympathetic tone may stimulate left ventricular mechanoreceptors that may trigger marked peripheral vasodilation and bradycardia (vasovagal syncope) [17]. The ventricular receptors are a heterogeneous population of receptor subgroups with varying thresholds of activation, and varying reflex effects [18]. Response to some vagal afferents may not alter heart rate 1181,but may cause hyperventilation and peripheral vasodilation. The response to left ventricular and right ventricular receptor stimulation may also differ [ 191. Experimental mechanoreceptor stimulation from the right ventricle in sympathectomised dogs has been reported to cause hyperventilation and hypotension without bradycardia [20]. Moreover, in some of the head-up tilt table studies done to provoke left ventricular mechanoreceptors and vasovagal response, a few patients develop marked hyperventilation without bradycardia or hypotension 117,211. Although the authors did not comment on this, it may be speculated that receptors from the right ventricle elicited such a response. Such studies in patients with tetralogy of Fallot would be interesting. Indeed, in 1953 while studying the effects of pos-
ture on saturation in patients with tetralogy of Fallot, Lurie reported precipitating hyperventilation and syncope (spell) in a patient during a tilt to 70” [22]. It is recognised that the right ventricle is only sparsely innervated [181, and more recent experimental studies indicate no important role of right ventricle mechanoreceptors in Gardiac or respiratory control normally [231. However, the situation in tetralogy of Fallot wherein the anatomy is altered, may be different from normals. The hypertrophied ventricular walls, rotated conal septum, or other factors may be important. How the increase in catecholamines and decrease in the cavity size in this distinct pathoanatomy of tetralogy of Fallot predispose the receptors to trigger responses remains to be established. It may be relevant that amongst the patients with tetralogy of Fallot, a slightly different anatomy is seen from that in patients who present with frequent cyanotic spells [24]. The relationship of precipitating events seems clearer with the proposed mechanisms. (a> Crying, defaecation, suprauentricular tachycardia and feeding: It is easy to envisage increased contractility due to catecholamines and decreased cavity size of the right ventricle during crying, bowel movement (due to Valsalva-like manoeuvre) or supraventricular tachycardia (due to shortened diastole) [25] that can induce a cyanotic spell. Similarly feeding also induces increase in cardiac output and heart rate and decrease in cavity size [26]. (b) Hot weather, infections: Peripheral vasodilation during summer, or with infection [27] facilitates better emptying of right ventricle into aorta. This could reduce the cavity size and may increase the susceptibility to cyanotic spells. Cc) Cardiac catheterization : Direct mechanical stimulation of the receptors by a cardiac catheter 151may induce a cyanotic spell. Dehydration due to overnight fasting (which may decrease the right ventricular size), or peripheral vasodilation induced by premeditation may also be contributory. Cd) Time of the day: The more frequent occurrence of spells during the morning hours may relate to catecholamine secretion on awakening or to circadian variations in the endogenous catecholamines secretions [2X].
4
(e) Cyanotic spells in pulmonary atresia: The reflexes originating from the hypertrophied ventricles in the patients with pulmonary atresia and ventricular septal defect can trigger hyperventilation, vasodilation and the sequence of the spells. Blood flow to the lungs through collaterals or patent ductus arteriosus would be reduced with peripheral dilation, and hyperventilation would increase the metabolic demands. Similar considerations may apply to other cyanotic heart diseases where spell occurs. (f) The effects of beta-blockers and morphine: Beta-blockers are useful in the treatment and prevention of cyanotic spells because they decrease myocardial contractility. Akin to the use of beta-blockers in vasovagal syncope [29], the decrease in contractility may also be important in preventing mechanoreceptor stimulation and hence the spells. Morphine is very effective in the treatment of cyanotic spells [l], but its mechanism of action is not clear. It may be relevant that endogenous opioids inhibit the sympathetic system, and more recently have been implicated in pathogenesis of vasodepressor syncope [30]. (g) Age of the patients: The cyanotic spells generally start from 2 months of age and mysteriously disappear after about 2 yr. Although entirely speculative, it may be related to growth of ventricular cavity and infundibulum such that it results in decreased susceptibility of receptors to stimulation. Although the hypothesis explains many facts as listed above, it remains to be investigated if the right ventricle in patients with tetralogy of Fallot has a higher receptor density, and that such reflexes do indeed occur. The cardiac mechanoreflexes are involved in the genesis of many clinical conditions including vasovagal syncope, syncope in patients with aortic stenosis, hypotension during exercise, bradycardia with vasodilators etc. [31]. Cyanotic spells in tetralogy of Fallot may be added to this list in the future.
Acknowledgement I thank Dr. Dinesh Verma, FRCS (Ophth.) for critical review of the manuscript.
References 1 Taussig HB. Tetralogy of Fallot: Especially the care of the cyanotic infant and child. Pediatrics 1948;1:307-314. 2 Keith JD. Rowe RD, Vlad P. Heart disease in Infancy and Childhood. New York: Macmillan 1958;401. 3 Nadas AS. Pediatric cardiology. 2nd ed. Philadelphia: W.B. Saunders, 1963;353. 4 Gasul BM, Arsilla RA, Lev M. Heart disease in children. Diagnosis and treatment. London, Philadelphia: Pitman Medical Publishing Co., 1968;577. 5 Braudo JL, Zion MM. Cyanotic spells and loss of consciousness induced by cardiac catheterization in patients with Fallot’s tetralogy. Am Heart J 1960;59:10-18. 6 Young D, Elbl F. Supraventricular tachycardia as cause of cyanotic syncopal attacks in tetralogy of Fallot. N Engl J Med 1971;284:1359-1360. 7 Wood P. Attacks of deeper cyanosis and loss of consciousness (syncope) in Fallot’s tetralogy. Br Heart J 1958; 20:282-286. 8 Hamilton WF, Winslow JA, Hamilton WF, Jr. Notes on a case of congenital heart disease with cyanotic episodes. J Clin Invest 1950;29:20. 9 Guntheroth WG, Morgan BC. Mullins GL. Physiologic studies of paroxysmal hyperpnea in cyanotic congenital heart disease. Circulation 1965;31:70-6. 10 Anderson RH, McCartney FJ, Shinebourne EA. Tynan M. Pediatric cardiology. Edinburgh, London, New York: Churchill Livingstone 1987;777. 11 Honey M, Chamberlain DA, Howard J. The effect of beta sympathetic blockade on arterial oxygen saturation in Fallot’s tetralogy. Circulation 1964;30:501-510. 12 Johnson AM. Norepinephrine and cyanotic attacks in Fallot’s tetralogy. Br Heart J 1961;23:197-202. 13 Vogelpoel L, Schirire V, Nellen M, Swanepoel A. The use of amyl nitrite in the differentiation of Fallot’s tetralogy and pulmonary stenosis with intact ventricular septum. Am Heart J 1959;57:803-19. 14 Van Lingen B, Whidborne J. Oximetry in congenital heart disease with special reference to the effects of voluntary hyperventilation. Circulation 1952;6:740-748. 15 Edelman NH, Cherniack NS, Lahiri S, Brando L, Fishman AP. The ventilatory response to hypoxia in cyanotic congenital heart disease. Clin Res 1968;16:369. 16 Sorenson SC, Severinghaus JW. Respiratory insensitivity to acute hypoxia persisting after correction of tetralogy of Fallot. J Appl Physiol 1968;25:221-223. 17 Epstein SE, Stampfer M, Beiser GD. Role of capacitance and resistance vessels in vasovagal syncope. Circulation 1968;37:524-533. 18 Thoren P. Role of cardiac vagal C fibres in cardiovascular control. Rev Physiol Biochem Pharmacol 1979;86:1-94. 19 Ross J Jr, Frahm CJ, Braunwald E. Influence of intracardiac baroreceptors on venons return, systemic vascular volume and peripheral resistance. J Clin Invest 1961: 40:563-72. 20 Kostreva DR. Hopp FA, Zupkerku EJ. Kampine JP. Ap-
21
22 23
24
25
nea. tachypnea and hypotension elicited by cardiac vagal afferens. J Appl Physiol 1979;47:312-318. Strasberg B, Recharia E. Sagie A et al. The head up tilt table test in patients with syncope of unknown origin. Am Heart J 1989;118:923-927. Lurie PR. Postural effects in tetralogy of Fallot. Am J Med 1953;15:297-306. Crisp AJ. Hainsworth R. Tutt SM. The absence of cardiovascular and respiratory responses to changes in right ventricular pressure in anaesthetised dogs. J Physiol (London) 1988;407:1-13. Shinebourne EA, Anderson RH, Bowyer JJ. Variation in clinical presentation of tetralogy of Fallot in infancy. Angiographic and pathogenetic implications. Br Heart J 1975;37:946-955. Sonnenblick EH, Braunwald E, William JF Jr, Glick G. Effects of exercise on myocardial force velocity relation in intact unanesthetised man. Relative roles of changes in heart rate, sympathetic activity and ventricular dimensions J Clin Invest 1965:44;2051-2062.
26 Ehrlich W, Tosheff J. Caldini P, Abbey H, Brady JV. Adaptation of cardiac output, coronary flow and other circulatory functions in dogs to exercise and to eating. Johns Hopkins Med J 1972;130:216-234. 27 Thauer R. Circulatory adjustments to climatic requirements. In: Hamilton WF. Dow P, eds. Handbook of physiology. Section 2. Circulation volume III. Washington, DC: American Physiological Society 1965;1941-1947. 28 Turton MB, Deagn T. Circadian variations in plasma catecholamines. cortisol and immunoreactive insulin concentrations in supine subjects. Clin Chim Acta 1974;55:389. 29 Goldenberg IF, Almquist A. Dunbar DN. Milstein S. Pritzker MR, Benditt DC. Prevention of neurally mediated syncope by selective Bl adrenoreceptor blockade (abstract). Circulation 1987;76 (suppl IV):l33. 30 Perna GP, Ficola U, Salvatori MP et al. Increase of plasma beta endorphins in vasodepressor syncope. Am J Cardiol 1990;65:929-930. 31 Abboud FM. Ventricular syncope. Is the heart a sensory organ? N Engl J Med 1989:320:390-392.
CARD10
1 0167-5273/92/$05.00
01528
Review
Mechanism of cyanotic spells in tetralogy of Fdlot - the missing link? Shyam Sunder Kothari Cardiothoracic Centre, All India Institute of Medical Sciences, New Delhi, India (Received
Kothari SS. Mechanism 1992;37:1-5.
18 November
1991: revision
of cyanotic spells in tetralogy
accepted
17 May 1992)
of Fallot - the missing link? Int J Cardiol
The mechanism of cyanotic spells in patients with tetralogy of Fallot is not clear. Increases in infundibular contractility or hyperpnoea have been considered as the key factors, but this explanation appears inadequate. In this review, arguments are presented against these commonly held views. Preliminary evidence is synthesised in favour of another more plausible hypothesis that cyanotic spells may result from mechanoreceptor stimulation from the right ventricle. Increased contractility (due to catecholamines) and decreased right ventricular size (due to various factors) can trigger a reflex resulting in hyperventilation, some peripheral vasodilation without bradycardia, and this may initiate a spell. This mechanism explains most of the precipitating events and many other issues about cyanotic spells more satisfactorily. Key words: Tetralogy of Fallot; Cyanosis; Syncope; Mechanoreceptor
Introduction The episodes of paroxysmal dyspnoea with marked cyanosis (cyanotic spells) in infants and young children with tetralogy of Fallot are common and serious [l-4]. The episodes may last from a few minutes to several hours and the marked arterial hypoxaemia during the spells may result in brain damage or death, although usually these spells are self limiting. The cyanotic spells frequently occur without warning, although cry-
Correspondence tot Dr. S.S. Kothari, Cardiothoracic tre, All India Institute of Medical Sciences, Ansari New Delhi-l 10029, India.
CenNagar,
ing, bowel movement or feeding can precipitate them [l]. The spells increase in frequency during summer months, and with infections [2]. Cardiac catheterization [5], and supraventricular tachycardia [6] are also known to precipitate these spells. In fact, the circumstances precipitating the spells have been so different and varied that it has been difficult to envisage a common environmental factor [2]. It is clear that these episodes result from drastic reduction of pulmonary blood flow, with an accompanying increase in the right-to-left shunt and a drop in systemic arterial oxygen saturation. However, the precise mechanism of the spells has not been understood. Increase in infundibular contractility [7], peripheral vasodilation [8], or
2
hyperventilation the key factors.
[93 have been incriminated
Increase in infundibular
as
contractility
Most workers now believe that increase in contractility of right ventricular infundibular musculature results in a decrease in pulmonary blood flow, and other features of the cyanotic spells [2-4,7,10]. The clinical findings of reduction in intensity of murmur across the right ventricular outflow during the spell appear to favour this view. In fact, marked reduction in forward blood flow to the lungs has been angiographically demonstrated during a spell [lO,ll]. Johnson suggested that [12] increase in the contractility may result from increase in endogenous norepinephrine (which is possible during most of the precipitating events listed). The salutary effects of beta-blockers in the patients with spells also support this view [ll]. The occurrence of spells, albeit rare in patients with pulmonary atresia and ventricular septal defect, casts doubt on the importance of infundibular contractility as the sole mechanism [7]. Furthermore, as discussed below, peripheral vasodilation in patients with tetralogy of Fallot may also reduce the intensity of the murmur and blood flow to the lungs. Increase in catecholamines has not been demonstrated preceding the spells. Although an increase in infundibular obstruction may appear a simple explanation of the spells, it remains to be clarified why every-day activities like crying, feeding etc. only occasionally result in spells. By itself, an increase in contractility due to endogenous catecholamines does not seem to explain completely the dramatic clinical presentation of these patients. Peripheral
vasodilation
Peripheral vasodilation in patients with tetralogy of Fallot would increase shunting of the right ventricular blood to the aorta through ventricular septal defect, and decrease pulmonary blood flow. Previously suggested by Hamilton [8] as an important reason for the cyanotic spells, subsequent workers did not consider it important as there
was no fall in systolic blood pressure during the spells. The diastolic pressure was not low, nor did the pulse pressure widen [4,5,7]. Thus, marked vasodilation does not accompany the spells. However, peripheral vasodilation with amyl nitrite in the patients with tetralogy of Fallot has been shown to result in a marked reduction in the murmur and increase in cyanosis with relatively less hypotension [13]. The question of peripheral vasodilation in cyanotic spells does not seem to have been adequately investigated. Hyperventilation Hyperpnoea increases oxygen demand and cardiac output [14]. In patients with tetralogy of Fallot, hyperpnoea results in an increase in arterial desaturation due to an increase in right-to-left shunt in the face of increased cardiac output but a relatively fixed pulmonary blood flow [9]. Guntheroth et al. suggest that hyperpnoea may be the important factor initiating and maintaining the cyanotic spells [93. To account for the frequent occurrence of spells in the morning hours of the day after a good night’s sleep [3], they propose that the respiratory drive mechanism may be more sensitive to changes in blood gases when the patients wake up in a reasonable metabolic status after sleep. During such times a sudden decrease in arterial p0, and pH and an increase in arterial pC0, induced by a relatively sudden increase in activity, or a Valsalva-like manoeuvre (such as crying or bowel movement) may trigger marked hyperpnoea. The hyperpnoea will increase cardiac output and decrease pulmonary blood flow resulting in further right-to-left shunt and greater arterial hypoxaemia. A vicious cycle may thus be established resulting in the spell. They also state that in most of these patients on most days, there is either an adjustment in sensitivity of respiratory drive mechanism or an adjustment in bicarbonate, which prevents the occurrence of spells [93. This elusive sequence of events has never been proved or disproved. Furthermore, it does not explain the fact that spells indeed occur at any time of the day [4]. Moreover, it may be relevant to note that the sensitivity of the respiratory centre to hypoxia is known to be blunted in
patients with cyanotic heart disease [15], and is not restored even years after corrective surgery
1161. In the absence of any better alternative the scheme suggested by Guntheroth et al. has provided a good working hypothesis up to now. However, I believe that the following hypothesis may explain the mechanism of spells and the events precipitating these spells more satisfactorily. Hypothesis The cyanotic spells in patients with tetralogy of Fallot may result from the stimulation of right ventricular mechanoreceptors. Increased contractility (due to endogenous catecholamines), and a decrease in right ventricular cavity size (such as can occur with Valsalva-like manoeuvre) may trigger a reflex response resulting in hyperventilation, some peripheral vasodilation, without bradycardia. The hyperpnoea may perpetuate a vicious cycle, as discussed previously. It is well known now that a combination of decreased left ventricular volume and raised sympathetic tone may stimulate left ventricular mechanoreceptors that may trigger marked peripheral vasodilation and bradycardia (vasovagal syncope) [17]. The ventricular receptors are a heterogeneous population of receptor subgroups with varying thresholds of activation, and varying reflex effects [18]. Response to some vagal afferents may not alter heart rate 1181,but may cause hyperventilation and peripheral vasodilation. The response to left ventricular and right ventricular receptor stimulation may also differ [ 191. Experimental mechanoreceptor stimulation from the right ventricle in sympathectomised dogs has been reported to cause hyperventilation and hypotension without bradycardia [20]. Moreover, in some of the head-up tilt table studies done to provoke left ventricular mechanoreceptors and vasovagal response, a few patients develop marked hyperventilation without bradycardia or hypotension 117,211. Although the authors did not comment on this, it may be speculated that receptors from the right ventricle elicited such a response. Such studies in patients with tetralogy of Fallot would be interesting. Indeed, in 1953 while studying the effects of pos-
ture on saturation in patients with tetralogy of Fallot, Lurie reported precipitating hyperventilation and syncope (spell) in a patient during a tilt to 70” [22]. It is recognised that the right ventricle is only sparsely innervated [181, and more recent experimental studies indicate no important role of right ventricle mechanoreceptors in Gardiac or respiratory control normally [231. However, the situation in tetralogy of Fallot wherein the anatomy is altered, may be different from normals. The hypertrophied ventricular walls, rotated conal septum, or other factors may be important. How the increase in catecholamines and decrease in the cavity size in this distinct pathoanatomy of tetralogy of Fallot predispose the receptors to trigger responses remains to be established. It may be relevant that amongst the patients with tetralogy of Fallot, a slightly different anatomy is seen from that in patients who present with frequent cyanotic spells [24]. The relationship of precipitating events seems clearer with the proposed mechanisms. (a> Crying, defaecation, suprauentricular tachycardia and feeding: It is easy to envisage increased contractility due to catecholamines and decreased cavity size of the right ventricle during crying, bowel movement (due to Valsalva-like manoeuvre) or supraventricular tachycardia (due to shortened diastole) [25] that can induce a cyanotic spell. Similarly feeding also induces increase in cardiac output and heart rate and decrease in cavity size [26]. (b) Hot weather, infections: Peripheral vasodilation during summer, or with infection [27] facilitates better emptying of right ventricle into aorta. This could reduce the cavity size and may increase the susceptibility to cyanotic spells. Cc) Cardiac catheterization : Direct mechanical stimulation of the receptors by a cardiac catheter 151may induce a cyanotic spell. Dehydration due to overnight fasting (which may decrease the right ventricular size), or peripheral vasodilation induced by premeditation may also be contributory. Cd) Time of the day: The more frequent occurrence of spells during the morning hours may relate to catecholamine secretion on awakening or to circadian variations in the endogenous catecholamines secretions [2X].
4
(e) Cyanotic spells in pulmonary atresia: The reflexes originating from the hypertrophied ventricles in the patients with pulmonary atresia and ventricular septal defect can trigger hyperventilation, vasodilation and the sequence of the spells. Blood flow to the lungs through collaterals or patent ductus arteriosus would be reduced with peripheral dilation, and hyperventilation would increase the metabolic demands. Similar considerations may apply to other cyanotic heart diseases where spell occurs. (f) The effects of beta-blockers and morphine: Beta-blockers are useful in the treatment and prevention of cyanotic spells because they decrease myocardial contractility. Akin to the use of beta-blockers in vasovagal syncope [29], the decrease in contractility may also be important in preventing mechanoreceptor stimulation and hence the spells. Morphine is very effective in the treatment of cyanotic spells [l], but its mechanism of action is not clear. It may be relevant that endogenous opioids inhibit the sympathetic system, and more recently have been implicated in pathogenesis of vasodepressor syncope [30]. (g) Age of the patients: The cyanotic spells generally start from 2 months of age and mysteriously disappear after about 2 yr. Although entirely speculative, it may be related to growth of ventricular cavity and infundibulum such that it results in decreased susceptibility of receptors to stimulation. Although the hypothesis explains many facts as listed above, it remains to be investigated if the right ventricle in patients with tetralogy of Fallot has a higher receptor density, and that such reflexes do indeed occur. The cardiac mechanoreflexes are involved in the genesis of many clinical conditions including vasovagal syncope, syncope in patients with aortic stenosis, hypotension during exercise, bradycardia with vasodilators etc. [31]. Cyanotic spells in tetralogy of Fallot may be added to this list in the future.
Acknowledgement I thank Dr. Dinesh Verma, FRCS (Ophth.) for critical review of the manuscript.
References 1 Taussig HB. Tetralogy of Fallot: Especially the care of the cyanotic infant and child. Pediatrics 1948;1:307-314. 2 Keith JD. Rowe RD, Vlad P. Heart disease in Infancy and Childhood. New York: Macmillan 1958;401. 3 Nadas AS. Pediatric cardiology. 2nd ed. Philadelphia: W.B. Saunders, 1963;353. 4 Gasul BM, Arsilla RA, Lev M. Heart disease in children. Diagnosis and treatment. London, Philadelphia: Pitman Medical Publishing Co., 1968;577. 5 Braudo JL, Zion MM. Cyanotic spells and loss of consciousness induced by cardiac catheterization in patients with Fallot’s tetralogy. Am Heart J 1960;59:10-18. 6 Young D, Elbl F. Supraventricular tachycardia as cause of cyanotic syncopal attacks in tetralogy of Fallot. N Engl J Med 1971;284:1359-1360. 7 Wood P. Attacks of deeper cyanosis and loss of consciousness (syncope) in Fallot’s tetralogy. Br Heart J 1958; 20:282-286. 8 Hamilton WF, Winslow JA, Hamilton WF, Jr. Notes on a case of congenital heart disease with cyanotic episodes. J Clin Invest 1950;29:20. 9 Guntheroth WG, Morgan BC. Mullins GL. Physiologic studies of paroxysmal hyperpnea in cyanotic congenital heart disease. Circulation 1965;31:70-6. 10 Anderson RH, McCartney FJ, Shinebourne EA. Tynan M. Pediatric cardiology. Edinburgh, London, New York: Churchill Livingstone 1987;777. 11 Honey M, Chamberlain DA, Howard J. The effect of beta sympathetic blockade on arterial oxygen saturation in Fallot’s tetralogy. Circulation 1964;30:501-510. 12 Johnson AM. Norepinephrine and cyanotic attacks in Fallot’s tetralogy. Br Heart J 1961;23:197-202. 13 Vogelpoel L, Schirire V, Nellen M, Swanepoel A. The use of amyl nitrite in the differentiation of Fallot’s tetralogy and pulmonary stenosis with intact ventricular septum. Am Heart J 1959;57:803-19. 14 Van Lingen B, Whidborne J. Oximetry in congenital heart disease with special reference to the effects of voluntary hyperventilation. Circulation 1952;6:740-748. 15 Edelman NH, Cherniack NS, Lahiri S, Brando L, Fishman AP. The ventilatory response to hypoxia in cyanotic congenital heart disease. Clin Res 1968;16:369. 16 Sorenson SC, Severinghaus JW. Respiratory insensitivity to acute hypoxia persisting after correction of tetralogy of Fallot. J Appl Physiol 1968;25:221-223. 17 Epstein SE, Stampfer M, Beiser GD. Role of capacitance and resistance vessels in vasovagal syncope. Circulation 1968;37:524-533. 18 Thoren P. Role of cardiac vagal C fibres in cardiovascular control. Rev Physiol Biochem Pharmacol 1979;86:1-94. 19 Ross J Jr, Frahm CJ, Braunwald E. Influence of intracardiac baroreceptors on venons return, systemic vascular volume and peripheral resistance. J Clin Invest 1961: 40:563-72. 20 Kostreva DR. Hopp FA, Zupkerku EJ. Kampine JP. Ap-
21
22 23
24
25
nea. tachypnea and hypotension elicited by cardiac vagal afferens. J Appl Physiol 1979;47:312-318. Strasberg B, Recharia E. Sagie A et al. The head up tilt table test in patients with syncope of unknown origin. Am Heart J 1989;118:923-927. Lurie PR. Postural effects in tetralogy of Fallot. Am J Med 1953;15:297-306. Crisp AJ. Hainsworth R. Tutt SM. The absence of cardiovascular and respiratory responses to changes in right ventricular pressure in anaesthetised dogs. J Physiol (London) 1988;407:1-13. Shinebourne EA, Anderson RH, Bowyer JJ. Variation in clinical presentation of tetralogy of Fallot in infancy. Angiographic and pathogenetic implications. Br Heart J 1975;37:946-955. Sonnenblick EH, Braunwald E, William JF Jr, Glick G. Effects of exercise on myocardial force velocity relation in intact unanesthetised man. Relative roles of changes in heart rate, sympathetic activity and ventricular dimensions J Clin Invest 1965:44;2051-2062.
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