- Email: [email protected]
Parasympathetic and sympathetic mechanisms in sudden death
EMERGENCYFORUM
Parasympathetic and Sympathetic Mechanisms in Sudden Death George R. Schwartz, MD Venice, California
Schwartz GR: Parasympathetic and sympathetic mechanisms in sudden death. JACEP 6:455-457, October, 1977. sudden death. INTRODUCTION There a r e more t h a n h a l f a m i l l i o n s u d d e n d e a t h s annually. ~ W h i l e the major u n d e r l y i n g cause is h e a r t disease and the most common final e v e n t is v e n t r i c u l a r fibrillation, 2 t h e e v e n t s l e a d i n g to t h e fatal outcome are unclear. The role of the s y m p a t h e t i c n e r v o u s s y s t e m h a s been s t u d i e d w i d e l y l e a d i n g to a c o m m o n e x p l a n a t i o n that a surge of c a t e c h o l a m i n e s causes r a p i d lowering of the t h r e s h o l d for v e n t r i c u l a r fibrillation. On the o t h e r hand, r e l a t i v e l y little a t t e n t i o n has been given to the parasympathetic nervous system c o n t r i b u t i o n s to s u d d e n death.
DISCUSSION When C a n n o n wrote The Wisdom o f the Body, 3 he was primarily concerned w i t h the s y m p a t h e t i c nervous systern, most p a r t i c u l a r l y the e m e r g e n c y function of the adrenal medulla.3,4 W h i l e acute body r e s p o n s e s i n v o l v i n g catecholamine release m a y be protective, t h e y m a y also predispose to s u d d e n death. S y m p a t h e t i c nervous s y s t e m discharge after m y o c a r d i a l infarction is felt to be l a r g e l y responsible for t h e increased predisposition to v e n t r i c u l a r fibrillation d u r i n g the e a r l y period after coronary a r t e r y °cclusion. 5 Lown2, 6 t e r m s such v e n t r i c u l a r fibrillation a n "electrical accident" since m a n y p a t i e n t s who are defibrillated m a y live m a n y years. The p r e d i s p o s i n g effects of neural s t i m u l i m e d i a t e d t h r o u g h the h y p o t h a l a m u s and Other b r a i n c e n t e r s m a y also be i m p o r t a n t . The n e t r e s u l t of s u c h n e u r a l i n f l u e n c e s is a m a r k e d l y r e d u c e d Presented at the annual University Association for Emergency Medicine meeting in Kansas City, Missouri, May, 1977. Address for reprints: George R. Schwartz,MD, PO Box 1048, Venice, California 90291.
~ )
6:10 (Oct) 1977
t h r e s h o l d for v e n t r i c u l a r fibrillation. 2 Propranolol's count e r a c t i o n of such effects suggests a d r e n e r g i c mediation. The a d r e n e r g i c responses of the body have been s t u d i e d and subdivided. A h l q u i s t 7 described the a l p h a a n d b e t a responses and the b e t a - a d r e n e r g i c responses have been further divided into Beta-1 a n d Beta-2. The B-1 (eg, cardiacinotropic a n d lipolitic actions) and B-2 (broncho- a n d v a s o d i l a t i o n ) h a v e s e r v e d to f u r t h e r d i f f e r e n t i a t e n o r e p i n e p h r i n e from e p i n e p h r i n e actions. A p r o p o s e d t h i r d a d r e n e r g i c response, one m e d i a t e d by d o p a m i n e , h a s been identified, p a r t i c u l a r l y affecting r e n a l a n d cereb r a l vasculature.S, 9 W h e n c o n t r a s t e d w i t h the a d r e n e r g i c responses, the p a r a s y m p a t h e t i c effects (used i n t e r c h a n g e a b l y w i t h the t e r m cholinergic effects a l t h o u g h t h e y are not e x a c t l y the same) are much less d r a m a t i c , b u t m a y be as i m p o r t a n t . The sympathetic-parasympathetic balance has been noted for m a n y y e a r s and s y m p a t h e t i c activity often is accompanied by a competitive p a r a s y m p a t h e t i c response. A n e x a m p l e of such i n t e r a c t i o n is when the e n h a n c e d s y m p a t h e t i c a c t i v i t y a f t e r m y o c a r d i a l ischemia, w h i c h lowers the t h r e s h o l d for v e n t r i c u l a r fibrillation, is count e r a c t e d by e n h a n c e d v a g a l activity.5,1° The s i t u a t i o n is r e n d e r e d still more Complex, however, when w h a t a p p e a r s to be e n h a n c e d v a g a l tone or a slower h e a r t rate is associated w i t h a n increased risk of cardiac d e a t h in m i d d l e - a g e d men. 11 F u r t h e r , enhanced cholinergic factors seem to be involved in sudden d e a t h in y o u n g athletes. 12 The p a r a s y m p a t h e t i c - s y m p a t h e t i c interaction can most r e a d i l y been seen as a n o t h e r body m e c h a n i s m to preserve homeostasis. F o r e x a m p l e , s h o r t l y after a "simple" faint via a v a s o v a g a l m e c h a n i s m t h e r e is a s y m p a t h e t i c urge c o u n t e r a c t i n g t h e b r a d y c a r d i a and v a s o d i l a t a t i o n . ~ . ~ n v e r s e l y , a n e x c e s s or s u r g e of c a t e c h o l a m i n e s is shortly m e t by e n h a n c e d v a g a l and o t h e r p a r a s y m p a t h e tic m e c h a n i s m s . W h e n e i t h e r of the systems is h i g h l y active, or in the period prior to t h e c o m p e n s a t o r y response
455/41
(which m a y be seconds or minutes) t h e r e seems to be a h e i g h t e n e d chance of sudden death.
CASE STUDIES Of the 300 cases of sudden d e a t h reviewed, 20 were ass o c i a t e d w i t h a slow h e a r t r a t e a n d if f i b r i l l a t i o n occ u r r e d it did so only as the very l a s t e v e n t a f t e r the e x t r e m e b r a d y c a r d i a or i d i o v e n t r i c u l a r r h y t h m had produced an a g o n a l state. C a s e N u m b e r O n e . A 55-year-old w o m a n w i t h no history of h e a r t disease but with a h i s t o r y of e p i l e p s y (taking D i l a n t i n 100 m g t.i.d.) h a d a spell of severe v o m i t i n g a n d collapsed. She was b r o u g h t to t h e e m e r g e n c y dep a r t m e n t unconscious and with a g o n a l r e s p i r a t i o n s . H e r i n i t i a l h e a r t r a t e w a s 54 b e a t s / m i n u t e a n d she was in a sinus r h y t h m . The e l e c t r o c a r d i o g r a m (EKG) t r a c i n g demo n s t r a t e d a p r o g r e s s i o n to an i d i o v e n t r i c u l a r r h y t h m and e v e n t u a l asystole. F u l l r e s u s c i t a t i v e m e a s u r e s were unsuccessful a l t h o u g h i n t r a c a r d i a c e p i n e p h r i n e did produce a f i b r i l l a t o r y - t y p e E K G p a t t e r n . N u m e r o u s countershocks could not r e - e s t a b l i s h a r e g u l a r r h y t h m . The only m e d i c a t i o n b e i n g t a k e n , D i l a n t i n , m i g h t have had some c a r d i a c effects. C a s e N u m b e r T w o . A 56-year-old m a n was b r o u g h t to the h o s p i t a l because he had collapsed a t home and h a d been s h o r t of b r e a t h . He had no h i s t o r y of h e a r t disease and w a s t a k i n g no m e d i c a t i o n s . On a d m i s s i o n to t h e e m e r g e n c y d e p a r t m e n t his h e a r t r a t e w a s 60 b e a t s / minute, r e s p i r a t i o n s were 32/minute, a n d blood p r e s s u r e (BP) w a s 146/88 m m Hg. He w a s m a r k e d l y s h o r t of b r e a t h and was cyanotic. He h a d p u l m o n a r y t a l e s and wheezing. D u r i n g i n t r a v e n o u s (IV) insertion, he suffered asystole, d e m o n s t r a t e d in the EKG. R e s u s c i t a t i v e m e a s ures were unsuccessful. C a s e N u m b e r T h r e e . A 70-year-old m a n t a k i n g digitalis for congestive h e a r t failure developed severe subs t e r n a l chest p a i n a n d w a s b r o u g h t to t h e e m e r g e n c y dep a r t m e n t . He was restless, cyanotic a n d w i t h a u d i b l e rales. His pulse was 82 b e a t s / m i n u t e i n i t i a l l y and BP was 150/90 m m Hg. W i t h i n m i n u t e s he developed A-V dissociation a n d a p r o g r e s s i v e l y slower h e a r t r a t e and arr e s t e d on asystole. R e s u s c i t a t i o n was a t t e m p t e d for an hour and, despite periods of r e t u r n , he could not s u s t a i n a cardiac r h y t h m n o r his BP. T r e a t m e n t included t h a t for p u l m o n a r y e d e m a , m o r p h i n e and diuretics, b u t this too was ineffective.
Implications of Illustrative Cases T h a t not all p a t i e n t s who die s u d d e n l y have v e n t r i c u l a r f i b r i l l a t i o n is well known. In fact, Cobb 1 points out t h a t while v e n t r i c u l a r fibrillation is t h e a p p a r e n t t e r m i n a l e v e n t in the m a j o r i t y t h e r e is a m i n o r i t y who die while e x p e r i e n c i n g a v a r i e t y of b r a d y a r r h y t h m i a s , as in the p r e c e d i n g cases. My hypothesis is t h a t such p a t i e n t s are m a n i f e s t i n g excess c h o l i n e r g i c / p a r a s y m p a t h e t i c act i v i t y l e a d i n g to the b r a d y a r r h y t h m i a s and the accomp a n y i n g p u l m o n a r y difficulties.
Implications for Therapy Propranolol or o t h e r beta-blocking m e a s u r e s have been
42/456
reported to improve the prognosis after myocardial in. farction 13 and decrease the incidence of sudden deatb~ Basically, t h e t r e a t m e n t philosophy in such cases is to r e s t r a i n the c h e m i c a l t r i g g e r l e a d i n g to v e n t r i c u l a r fib. rillation. However, those i n d i v i d u a l s who die suddenly without evidence of s y m p a t h e t i c h y p e r a c t i v i t y or fibrilla. tion m i g h t not benefit from such t h e r a p y . In fact, with excess v a g a l tone a l r e a d y p r e s e n t , such sympathetic blockade m i g h t compromise t h e i r compensation. In a like m a n n e r , the s y m p a t h e t i c d e p r e s s a n t antihypertensives, including the r a u w o l f i a alkaloids, g u a n e t h i d i n e methyl. dopa, c l o n i d i n e h y d r o c h l o r i d e a n d a l p h a - a d r e n e r g i c blocking agents, m i g h t protect t h e m a j o r i t y who are predisposed to respond to excess a d r e n e r g i c activity by ven. t r i c u l a r fibrillation, b u t reduce t h e a b i l i t y to compensate of those who, for w h a t e v e r reasons, respond with excess p a r a s y m p a t h e t i c / c h o l i n e r g i c actions. The l a t t e r p a t i e n t s m i g h t be difficult to detect and any u n t o w a r d effects of a n t i s y m p a t h e t i c t h e r a p y would be obscured due to the o v e r a l l benefits to the majority. If such p a t i e n t s could be detected, t h e o r e t i c a l l y t h e y might respond b e t t e r to vasolytic or a n t i c h o l i n e r g i c therapy. V i e w i n g s u d d e n d e a t h f r o m t h e p e r s p e c t i v e of p a r a s y m p a t h e t i c - s y m p a t h e t i c i n t e r a c t i o n s , a further t h e o r e t i c a l possible t r e a t m e n t is suggested, ie, the comb i n a t i o n of cholinergic a g e n t s w i t h the antisympathetic a g e n t s to f u r t h e r reduce the chance of v e n t r i c u l a r fibril. lation. This a p p r o a c h is not only to counteract the sym. p a t h e t i c t r i g g e r s ( t h r o u g h a l p h a a n d b e t a adrenergic blockade), b u t to e n h a n c e the p a r a s y m p a t h e t i c system which a p p e a r s to be the n a t u r a l body system antagonistic to the s y m p a t h e t i c . A f u r t h e r p o s s i b i l i t y is t h e use of p a r a s y m p a t h e t i c s t i m u l a t i n g a g e n t s in conditions such as sudden infant d e a t h syndrome, w h e r e poor a u t o n o m i c control is sagg e s t e d a l o n g w i t h p o s s i b l y d e l a y e d m a t u r a t i o n of cholinergic system. 14 U ~ o r t u n a t e l y , t h e r e do not appear to be a n y r e l i a b l e t e s t s of such a u t o n o m i c functions in an infant. CONCLUSION Since C a n n o n ' s 4 work more t h a n 50 y e a r s ago, attention has been focused on the s y m p a t h e t i c nervous system a n d a d r e n e r g i c responses while the b a l a n c i n g parasympathetic nervous system/cholinergic responses have been less studied. There are indications t h a t both portions of the i n v o l u n t a r y nervous s y s t e m a r e associated, by dint of t h e i r h y p e r a c t i v i t y , w i t h s u d d e n d e a t h . J u s t w h y the g r e a t m a j o r i t y of people r e s p o n d in diverse conditions w i t h a p r e d o m i n a n c e of a d r e n e r g i c effects while only a s m a l l n u m b e r d e m o n s t r a t e p r e d o m i n a n c e of cholinergic responses to s i m i l a r s t i m u l i is not a p p a r e n t . However, recognition of the b a l a n c i n g n a t u r e of the systems opens up new a v e n u e s of t r e a t m e n t .
REFERENCES 1. Cobb L: Sudden death, Emergency Medicine Schwartz ders Co, 1977. 2. Lown B, Verrier R: Neural tion. N. Engl J Med 294:1165,
in Principles and Practice of G, (ed). Philadelphia, W B Saul" activity and ventricular fibrilla" 1976.
6:10 (Oct) 1977J ~ P
3. Cannon WB: The Wisdom of the Body, New York, W W Norton, 1932. 4. Cannon WB: The emergeney function of the adrenal medulla in pain and the major emotions. A m J Physiol 33:356, 1914. 5. t3rown AM: Excitation of afferent cardiac sympathetic nerve fiberS during myocardial isehemia, d Physiol 190:35, 1967. 6. bown B, et al: Psychological stress and the threshold for repetitive v e n t r i c u l a r response. Science 182:834,1973. 7. Ahlquist RP: A study of the adrenotropie receptors. A m J Physiol 153:586, 1948. 8. befkowitz R J: Beta-adrenergic receptors: recognition a n d regulation. N Engl J Med 295:323, 1976. 9. I v e r s o n LL: D o p a m i n e r e c e p t o r s in t h e b r a i n . Science 188;1085, 1975.
~P
6:10 (Oct) 1977
10. Kent KM, Smith ER, Redwood OR, et al: Electrical stability of acutely ischemic myoeardium; influences of h e a r t rate and vagal stimulation. Circulation 47:291, 1973. 11. Hinkle LE: Slow h e a r t rate a n d increased risk of cardiac death in middle-aged men. Arch Int Med 129:132, 1972. 12. J a m e s TN, Froggatt P, M a r s h a l l TK, et al: Sudden death in young athletes. Ann Intern Med 67:1013-1021, 1967. 13. Green KG, C h a m b e r l a i n DA, Fulton RM, et al: Improvement in prognosis of MI by long t e r m beta-adrenoreceptor blockade. Br Med J, 1975, pp 735-740. 14. Salk L, Grellong BA, Dietrich J, et al: Sudden infant death: normal cardiac h a b i t u a t i o n and poor autonomic control. N Engl J Med 291:219-222, 1974.
457/43
Parasympathetic and Sympathetic Mechanisms in Sudden Death George R. Schwartz, MD Venice, California
Schwartz GR: Parasympathetic and sympathetic mechanisms in sudden death. JACEP 6:455-457, October, 1977. sudden death. INTRODUCTION There a r e more t h a n h a l f a m i l l i o n s u d d e n d e a t h s annually. ~ W h i l e the major u n d e r l y i n g cause is h e a r t disease and the most common final e v e n t is v e n t r i c u l a r fibrillation, 2 t h e e v e n t s l e a d i n g to t h e fatal outcome are unclear. The role of the s y m p a t h e t i c n e r v o u s s y s t e m h a s been s t u d i e d w i d e l y l e a d i n g to a c o m m o n e x p l a n a t i o n that a surge of c a t e c h o l a m i n e s causes r a p i d lowering of the t h r e s h o l d for v e n t r i c u l a r fibrillation. On the o t h e r hand, r e l a t i v e l y little a t t e n t i o n has been given to the parasympathetic nervous system c o n t r i b u t i o n s to s u d d e n death.
DISCUSSION When C a n n o n wrote The Wisdom o f the Body, 3 he was primarily concerned w i t h the s y m p a t h e t i c nervous systern, most p a r t i c u l a r l y the e m e r g e n c y function of the adrenal medulla.3,4 W h i l e acute body r e s p o n s e s i n v o l v i n g catecholamine release m a y be protective, t h e y m a y also predispose to s u d d e n death. S y m p a t h e t i c nervous s y s t e m discharge after m y o c a r d i a l infarction is felt to be l a r g e l y responsible for t h e increased predisposition to v e n t r i c u l a r fibrillation d u r i n g the e a r l y period after coronary a r t e r y °cclusion. 5 Lown2, 6 t e r m s such v e n t r i c u l a r fibrillation a n "electrical accident" since m a n y p a t i e n t s who are defibrillated m a y live m a n y years. The p r e d i s p o s i n g effects of neural s t i m u l i m e d i a t e d t h r o u g h the h y p o t h a l a m u s and Other b r a i n c e n t e r s m a y also be i m p o r t a n t . The n e t r e s u l t of s u c h n e u r a l i n f l u e n c e s is a m a r k e d l y r e d u c e d Presented at the annual University Association for Emergency Medicine meeting in Kansas City, Missouri, May, 1977. Address for reprints: George R. Schwartz,MD, PO Box 1048, Venice, California 90291.
~ )
6:10 (Oct) 1977
t h r e s h o l d for v e n t r i c u l a r fibrillation. 2 Propranolol's count e r a c t i o n of such effects suggests a d r e n e r g i c mediation. The a d r e n e r g i c responses of the body have been s t u d i e d and subdivided. A h l q u i s t 7 described the a l p h a a n d b e t a responses and the b e t a - a d r e n e r g i c responses have been further divided into Beta-1 a n d Beta-2. The B-1 (eg, cardiacinotropic a n d lipolitic actions) and B-2 (broncho- a n d v a s o d i l a t i o n ) h a v e s e r v e d to f u r t h e r d i f f e r e n t i a t e n o r e p i n e p h r i n e from e p i n e p h r i n e actions. A p r o p o s e d t h i r d a d r e n e r g i c response, one m e d i a t e d by d o p a m i n e , h a s been identified, p a r t i c u l a r l y affecting r e n a l a n d cereb r a l vasculature.S, 9 W h e n c o n t r a s t e d w i t h the a d r e n e r g i c responses, the p a r a s y m p a t h e t i c effects (used i n t e r c h a n g e a b l y w i t h the t e r m cholinergic effects a l t h o u g h t h e y are not e x a c t l y the same) are much less d r a m a t i c , b u t m a y be as i m p o r t a n t . The sympathetic-parasympathetic balance has been noted for m a n y y e a r s and s y m p a t h e t i c activity often is accompanied by a competitive p a r a s y m p a t h e t i c response. A n e x a m p l e of such i n t e r a c t i o n is when the e n h a n c e d s y m p a t h e t i c a c t i v i t y a f t e r m y o c a r d i a l ischemia, w h i c h lowers the t h r e s h o l d for v e n t r i c u l a r fibrillation, is count e r a c t e d by e n h a n c e d v a g a l activity.5,1° The s i t u a t i o n is r e n d e r e d still more Complex, however, when w h a t a p p e a r s to be e n h a n c e d v a g a l tone or a slower h e a r t rate is associated w i t h a n increased risk of cardiac d e a t h in m i d d l e - a g e d men. 11 F u r t h e r , enhanced cholinergic factors seem to be involved in sudden d e a t h in y o u n g athletes. 12 The p a r a s y m p a t h e t i c - s y m p a t h e t i c interaction can most r e a d i l y been seen as a n o t h e r body m e c h a n i s m to preserve homeostasis. F o r e x a m p l e , s h o r t l y after a "simple" faint via a v a s o v a g a l m e c h a n i s m t h e r e is a s y m p a t h e t i c urge c o u n t e r a c t i n g t h e b r a d y c a r d i a and v a s o d i l a t a t i o n . ~ . ~ n v e r s e l y , a n e x c e s s or s u r g e of c a t e c h o l a m i n e s is shortly m e t by e n h a n c e d v a g a l and o t h e r p a r a s y m p a t h e tic m e c h a n i s m s . W h e n e i t h e r of the systems is h i g h l y active, or in the period prior to t h e c o m p e n s a t o r y response
455/41
(which m a y be seconds or minutes) t h e r e seems to be a h e i g h t e n e d chance of sudden death.
CASE STUDIES Of the 300 cases of sudden d e a t h reviewed, 20 were ass o c i a t e d w i t h a slow h e a r t r a t e a n d if f i b r i l l a t i o n occ u r r e d it did so only as the very l a s t e v e n t a f t e r the e x t r e m e b r a d y c a r d i a or i d i o v e n t r i c u l a r r h y t h m had produced an a g o n a l state. C a s e N u m b e r O n e . A 55-year-old w o m a n w i t h no history of h e a r t disease but with a h i s t o r y of e p i l e p s y (taking D i l a n t i n 100 m g t.i.d.) h a d a spell of severe v o m i t i n g a n d collapsed. She was b r o u g h t to t h e e m e r g e n c y dep a r t m e n t unconscious and with a g o n a l r e s p i r a t i o n s . H e r i n i t i a l h e a r t r a t e w a s 54 b e a t s / m i n u t e a n d she was in a sinus r h y t h m . The e l e c t r o c a r d i o g r a m (EKG) t r a c i n g demo n s t r a t e d a p r o g r e s s i o n to an i d i o v e n t r i c u l a r r h y t h m and e v e n t u a l asystole. F u l l r e s u s c i t a t i v e m e a s u r e s were unsuccessful a l t h o u g h i n t r a c a r d i a c e p i n e p h r i n e did produce a f i b r i l l a t o r y - t y p e E K G p a t t e r n . N u m e r o u s countershocks could not r e - e s t a b l i s h a r e g u l a r r h y t h m . The only m e d i c a t i o n b e i n g t a k e n , D i l a n t i n , m i g h t have had some c a r d i a c effects. C a s e N u m b e r T w o . A 56-year-old m a n was b r o u g h t to the h o s p i t a l because he had collapsed a t home and h a d been s h o r t of b r e a t h . He had no h i s t o r y of h e a r t disease and w a s t a k i n g no m e d i c a t i o n s . On a d m i s s i o n to t h e e m e r g e n c y d e p a r t m e n t his h e a r t r a t e w a s 60 b e a t s / minute, r e s p i r a t i o n s were 32/minute, a n d blood p r e s s u r e (BP) w a s 146/88 m m Hg. He w a s m a r k e d l y s h o r t of b r e a t h and was cyanotic. He h a d p u l m o n a r y t a l e s and wheezing. D u r i n g i n t r a v e n o u s (IV) insertion, he suffered asystole, d e m o n s t r a t e d in the EKG. R e s u s c i t a t i v e m e a s ures were unsuccessful. C a s e N u m b e r T h r e e . A 70-year-old m a n t a k i n g digitalis for congestive h e a r t failure developed severe subs t e r n a l chest p a i n a n d w a s b r o u g h t to t h e e m e r g e n c y dep a r t m e n t . He was restless, cyanotic a n d w i t h a u d i b l e rales. His pulse was 82 b e a t s / m i n u t e i n i t i a l l y and BP was 150/90 m m Hg. W i t h i n m i n u t e s he developed A-V dissociation a n d a p r o g r e s s i v e l y slower h e a r t r a t e and arr e s t e d on asystole. R e s u s c i t a t i o n was a t t e m p t e d for an hour and, despite periods of r e t u r n , he could not s u s t a i n a cardiac r h y t h m n o r his BP. T r e a t m e n t included t h a t for p u l m o n a r y e d e m a , m o r p h i n e and diuretics, b u t this too was ineffective.
Implications of Illustrative Cases T h a t not all p a t i e n t s who die s u d d e n l y have v e n t r i c u l a r f i b r i l l a t i o n is well known. In fact, Cobb 1 points out t h a t while v e n t r i c u l a r fibrillation is t h e a p p a r e n t t e r m i n a l e v e n t in the m a j o r i t y t h e r e is a m i n o r i t y who die while e x p e r i e n c i n g a v a r i e t y of b r a d y a r r h y t h m i a s , as in the p r e c e d i n g cases. My hypothesis is t h a t such p a t i e n t s are m a n i f e s t i n g excess c h o l i n e r g i c / p a r a s y m p a t h e t i c act i v i t y l e a d i n g to the b r a d y a r r h y t h m i a s and the accomp a n y i n g p u l m o n a r y difficulties.
Implications for Therapy Propranolol or o t h e r beta-blocking m e a s u r e s have been
42/456
reported to improve the prognosis after myocardial in. farction 13 and decrease the incidence of sudden deatb~ Basically, t h e t r e a t m e n t philosophy in such cases is to r e s t r a i n the c h e m i c a l t r i g g e r l e a d i n g to v e n t r i c u l a r fib. rillation. However, those i n d i v i d u a l s who die suddenly without evidence of s y m p a t h e t i c h y p e r a c t i v i t y or fibrilla. tion m i g h t not benefit from such t h e r a p y . In fact, with excess v a g a l tone a l r e a d y p r e s e n t , such sympathetic blockade m i g h t compromise t h e i r compensation. In a like m a n n e r , the s y m p a t h e t i c d e p r e s s a n t antihypertensives, including the r a u w o l f i a alkaloids, g u a n e t h i d i n e methyl. dopa, c l o n i d i n e h y d r o c h l o r i d e a n d a l p h a - a d r e n e r g i c blocking agents, m i g h t protect t h e m a j o r i t y who are predisposed to respond to excess a d r e n e r g i c activity by ven. t r i c u l a r fibrillation, b u t reduce t h e a b i l i t y to compensate of those who, for w h a t e v e r reasons, respond with excess p a r a s y m p a t h e t i c / c h o l i n e r g i c actions. The l a t t e r p a t i e n t s m i g h t be difficult to detect and any u n t o w a r d effects of a n t i s y m p a t h e t i c t h e r a p y would be obscured due to the o v e r a l l benefits to the majority. If such p a t i e n t s could be detected, t h e o r e t i c a l l y t h e y might respond b e t t e r to vasolytic or a n t i c h o l i n e r g i c therapy. V i e w i n g s u d d e n d e a t h f r o m t h e p e r s p e c t i v e of p a r a s y m p a t h e t i c - s y m p a t h e t i c i n t e r a c t i o n s , a further t h e o r e t i c a l possible t r e a t m e n t is suggested, ie, the comb i n a t i o n of cholinergic a g e n t s w i t h the antisympathetic a g e n t s to f u r t h e r reduce the chance of v e n t r i c u l a r fibril. lation. This a p p r o a c h is not only to counteract the sym. p a t h e t i c t r i g g e r s ( t h r o u g h a l p h a a n d b e t a adrenergic blockade), b u t to e n h a n c e the p a r a s y m p a t h e t i c system which a p p e a r s to be the n a t u r a l body system antagonistic to the s y m p a t h e t i c . A f u r t h e r p o s s i b i l i t y is t h e use of p a r a s y m p a t h e t i c s t i m u l a t i n g a g e n t s in conditions such as sudden infant d e a t h syndrome, w h e r e poor a u t o n o m i c control is sagg e s t e d a l o n g w i t h p o s s i b l y d e l a y e d m a t u r a t i o n of cholinergic system. 14 U ~ o r t u n a t e l y , t h e r e do not appear to be a n y r e l i a b l e t e s t s of such a u t o n o m i c functions in an infant. CONCLUSION Since C a n n o n ' s 4 work more t h a n 50 y e a r s ago, attention has been focused on the s y m p a t h e t i c nervous system a n d a d r e n e r g i c responses while the b a l a n c i n g parasympathetic nervous system/cholinergic responses have been less studied. There are indications t h a t both portions of the i n v o l u n t a r y nervous s y s t e m a r e associated, by dint of t h e i r h y p e r a c t i v i t y , w i t h s u d d e n d e a t h . J u s t w h y the g r e a t m a j o r i t y of people r e s p o n d in diverse conditions w i t h a p r e d o m i n a n c e of a d r e n e r g i c effects while only a s m a l l n u m b e r d e m o n s t r a t e p r e d o m i n a n c e of cholinergic responses to s i m i l a r s t i m u l i is not a p p a r e n t . However, recognition of the b a l a n c i n g n a t u r e of the systems opens up new a v e n u e s of t r e a t m e n t .
REFERENCES 1. Cobb L: Sudden death, Emergency Medicine Schwartz ders Co, 1977. 2. Lown B, Verrier R: Neural tion. N. Engl J Med 294:1165,
in Principles and Practice of G, (ed). Philadelphia, W B Saul" activity and ventricular fibrilla" 1976.
6:10 (Oct) 1977J ~ P
3. Cannon WB: The Wisdom of the Body, New York, W W Norton, 1932. 4. Cannon WB: The emergeney function of the adrenal medulla in pain and the major emotions. A m J Physiol 33:356, 1914. 5. t3rown AM: Excitation of afferent cardiac sympathetic nerve fiberS during myocardial isehemia, d Physiol 190:35, 1967. 6. bown B, et al: Psychological stress and the threshold for repetitive v e n t r i c u l a r response. Science 182:834,1973. 7. Ahlquist RP: A study of the adrenotropie receptors. A m J Physiol 153:586, 1948. 8. befkowitz R J: Beta-adrenergic receptors: recognition a n d regulation. N Engl J Med 295:323, 1976. 9. I v e r s o n LL: D o p a m i n e r e c e p t o r s in t h e b r a i n . Science 188;1085, 1975.
~P
6:10 (Oct) 1977
10. Kent KM, Smith ER, Redwood OR, et al: Electrical stability of acutely ischemic myoeardium; influences of h e a r t rate and vagal stimulation. Circulation 47:291, 1973. 11. Hinkle LE: Slow h e a r t rate a n d increased risk of cardiac death in middle-aged men. Arch Int Med 129:132, 1972. 12. J a m e s TN, Froggatt P, M a r s h a l l TK, et al: Sudden death in young athletes. Ann Intern Med 67:1013-1021, 1967. 13. Green KG, C h a m b e r l a i n DA, Fulton RM, et al: Improvement in prognosis of MI by long t e r m beta-adrenoreceptor blockade. Br Med J, 1975, pp 735-740. 14. Salk L, Grellong BA, Dietrich J, et al: Sudden infant death: normal cardiac h a b i t u a t i o n and poor autonomic control. N Engl J Med 291:219-222, 1974.
457/43