Bidirectional Tachycardia Induced by Herbal Aconite Poisoning YAU-TING TAI, CHU-PAK LAU, PAUL PUI-HAY BUT,* PING-CHING FONG, and JOHN PO-SHAN LI From the Division of Cardiology, Department of Medicine, University of Hong Kong, and the *Department of Biology and Chinese Medicinal Material Research Centre, Chinese University of Hong Kong, Hong Kong
TAI, Y .-T., ET AL.: Bidirectional Tachycardia Induced by Herbal Aconite Poisoning. This report details the clinical, electrocardiographic, and electropharmacological characteristics of an unusual case of bidirectional tachycardia induced by aconites present in a Chinese herbal decoction consumed by a previously healthy subject. The tachycardia showed marked susceptibility to vagotonic maneuvers, cholinesterase inhibition, and adenosine triphosphate. The incessant nature of the tachycardia, rapid recurrence after transient suppression, and failure to respond to direct current cardioversion suggested an automatic tachycardia mechanism consistent with known data on the cellular electrophysiological mechanism of aconitine-mediated arrhythmogenesis. A fascicular or ventricular myocardial origin of the tachycardia with alternating activation patterns, or dual foci with alternate discharge, appeared most plausible. The rootstocks of aconitum plants have been commonly employed in traditional Chinese herbal recipes for “cardiotonic” actions and for relieving “rheumatism.” Multiple pitfalls could occur during the processing of these herbs that might have predisposed to aconite poisoning. The need for strict control and surveillance of herbal substances with low margins of safety is highlighted. (PACE, Vol. 15, May 1992) bidirectional tachycardia, aconite poisoning, triggered automaticity, Chinese medicine, Aconitum carmichaeli, Aconitum kusnezoffii
Introduction Bidirectional tachycardia is a rare but highly intriguing arrhythmia, during which there is beatto-beat alternation in the direction of the QRS complexes on the electrocardiogram (ECG).’-’’ The majority of previously reported cases occurred in patients with advanced cardiac disease and digitalis toxicity. In this report, we detail the occurrence of bidirectional tachycardia in a previously healthy subject after ingestion of a Chinese
This study was partly supported by Cardiac Research Fund 360-041-0615 of the University of Hong Kong and by the Chinese Medicinal Material Research Centre, Chinese University of Hong Kong. Address for reprints: Dr. Yau-Ting Tai, University Department of Medicine, Professorial Block, Queen Mary Hospital, Pokfulam Road, Hong Kong. Fax: (852) 8551143. Received November 27, 1991; revision January 6, 1992; accepted January 28, 1992.
PACE, Vol. 15
herbal decoction that contained aconites. Careful observations were made on the responses of the tachycardia to various autonomic and pharmacological interventions. These provided additional information for better understanding of the bidirectional tachycardia in the light of known cellular electrophysiological mechanisms of aconitine-mediated arrhythmogenesis.
Case Report A 45-year-old previously healthy Chinese woman was admitted with sudden onset of severe palpitation, nausea, vomiting, and numbness of the extremities. Two hours earlier she had ingested a bowl of herbal decoction, prepared from boiling a combination of herbs that included the “cured” (processed) rootstocks of Aconitum carmichaeli and Aconitum kusnezoffii, prescribed for treating rheumatism. There had never been a
May 1992
831
TAI, ET AL.
A
B
WSN
I
V1
I1
v2
AVR
v4
AVL
VS
AVF
v6
Figure 1. (A] Twelve-lead ECG of tachycardia, with sustained bidirectional alternation and cycle length alternans. (B) Run of tachycardia with a predominant single QRS morphology (right bundle branch block-like) and a regular cycle length. Note the transient pauses in leads I and AVL with reinitiation of tachycardia following a junctional beat and a wide complex ectopic beat corresponding to the second morphology during bidirectional alternation. 832
May 1992
PACE, Vol. 15
ACONITE-INDUCED BIDIRECTIONAL TACHYCARDIA
history of palpitation or syncope, and she had not been taking any other medication. On examination the patient had a blood pressure of 90/50 mmHg and a pulse of 176/niin with pulsus alternans. The 12-lead ECG on admission revealed a wide QRS complex tachycardia (Fig. IA), with discrete beatto-beat alternation in the morphology and the axis of the QRS complexes between a left bundle branch block- and a right bundle branch blocklike configuration. There was also consistent slight alternation in the cycle length of the tachycardia (360/380 msec). This bidirectional alternation persisted most of the time, but there were periods when the tachycardia occurred with only one of the QRS configurations (right bundle branch-like morphology) and a regular cycle length (Fig. 1B). Intermittently after long runs the tachycardia spontaneously terminated, then restarted following one or two junctional beats. Of interest was that sinus P waves were never observed during these brief pauses, suggesting the occurrence of significant sinus node suppression. The patient remained alert during the tachycardia, and the hemodynamic status was rapidly stabilized with intravenous fluids upon admission. Response of Tachycardia to Autonomic and Pharmacological Interventions As the patient was acutely admitted in the middle of the night, it was not feasible to obtain intracardiac or intraesophageal recordings during the tachycardia in our local setting. With the sustained tachycardia and the relatively stable hemodynamic state, we were able to evaluate the response of the tachycardia to a number of autonomic and pharmacological interventions at bedside. Vagotonic maneuvers like vomiting and carotid sinus massage consistently resulted in transient suppression of the bidirectional tachycardia (Fig. 2). Intravenous adenosine triphosphate (20 mg bolus: Fig. 3) and edrophonium hydrochloride (10 mg) also resulted in short-lived suppression of the tachycardia. Intravenous lignocaine (1mg/kg bolus) had no effect on the tachycardia, nor did attempted synchronized direct current cardioversion (200 joules [ J]). Flecainide acetate was administered by slow intravenous infusion during the tachycardia, at a rate of 10 mg/min and under close hemodynamic monitoring. The tachycardia terminated after 40 mg (0.7 mg/kg) of flecai-
PACE, Vol. 15
vomit
csm h
1
....
.
a ,
.
181
Figure 2. Transient suppression of bidirectional tachycardia by vagotonic maneuvers. Upon vomiting (A), sustained tachycardia is transiently suppressed, and bidirectional couplets are preceded by narrow complex junctional beats. Carotid sinus massage (B) results in short-lived total suppression of tachycardia.
nide was given (Fig. 4). The patient remained in junctional rhythm for 4 hours before returning to sinus rhythm. There was no subsequent arrhythmia recurrence. Cardiological Evaluation The initial ECG in sinus rhythm revealed reduced voltage of the P waves. There was evidence of prolonged and abnormal repolarization, with a QT interval of 465 msec (QTc 526 msec), JT interval of 387 msec (JTc438 msec), and diffuse flattening of the T waves. These abnormalities were normalized 10 hours later. The creatinine kinase peaked early at 1050 IU/L (normal range 34-138), then returned to normal over the next 24 hours. The serum biochemistry including potassium, calcium and magnesium levels, the autoimmune antibodies, and paired sera for viral antibody titers
May 1992
833
TAI. ET AL.
comprising a maximum of two extrastimuli following two paced drives (cycle lengths 600, 400 msec), and incremental ventricular pacing down to a cycle length of 220 msec, at twice diastolic threshold with a pulse width of 2 msec, delivered at two right ventricular sites at base line and during intravenous infusion of isoprenaline ( 3 kg/ min). The patient has remained asymptomatic during a follow-up period of 6 months, with satisfactory blood pressure control by a calcium antagonist.
ATP 20mg
,
.)
.
,
4
WSN
Figure 3. Intravenous adenosine triphosphate (20-mg bolus) results in abrupt termination of the bidirectional tachycardia [arrowhead). This is followed by irregular junctional beats with narrow QRS complexes, and occasional ectopic beats of the same morphology as the bidirectional tachycardia. Note reinitiation of tachycardia following a sinus beat [open arrow). The ECG tracings are continuous.
were all normal. Echocardiography and cardiac catheterization revealed mild left ventricular hypertrophy secondary to previously undiagnosed essential hypertension, with satisfactory left ventricular contraction and a normal coronary anatomy. An electrophysiological study performed 5 days after admission revealed a normal His-to-ventricular conduction interval (50 msec). Upon atrial extrastimulus testing and incremental pacing, atrioventricular conduction was limited by block within the atrioventricular node (supra-Hisian), and there was no evidence of infra-Hisian conduction delay and block. There was no inducible ventricular arrhythmia with a stimulation protocol
834
Toxicologic Evaluation A multipanel toxicological screening on commonly encountered Western medications (including digoxin, salicylates, and tricyclic antidepressants) was performed on serum, urine, and gastric lavage fluid obtained upon admission, and was negative. Analysis of the traditional herbal prescription taken by the patient (Table I) and the herb samples revealed that apart from the aconites derived from the rootstocks of A. carmichaeli and A. kusnezoffii, the other herbs had not been known to be associated with cardiac arrhythmias. The extract of one herb had been observed to lead to suppression of myocardial contractility when injected into experimental animals, and another to hypotension. These might have aggravated the hemodynamic state of our patient during the tachycardia. A total of 4 g each of the cured rootstocks of A. cormichaeli and A. kusnezoffii were prescribed. The compositions of mesaconitine, aconitine, and hypaconitine-the three aconite alkaloids with the highest degree of cardiotoxicity-in an authentic herbal prescription, purchased from the same drugstore within 2 days of the diagnosis of poisoning, and the contents of these alkaloids in an authentic decoction, prepared in exactly the same manner as had been performed by the patient (boiling in water for 2.5 hours), were evaluated by high performance liquid chromatography. The results are shown in Table 11. It was estimated that a total of at least 0.6 mg of the three aconite alkaloids had been ingested by the patient.
Discussion Bidirectional Tachycardia Bidirectional tachycardia is an intriguing arrhythmic rarity characterized by beat-to-beat alter-
May 1992
PACE, Vol. 1 5
ACONITE-INDUCED BIDIRECTIONAL TACHYCARDIA
.
.
I
.
win
Figure 4. Termination of bidirectional tachycardia by intravenous flecainide acetate (40 rng, 0.7 mg/kgJ. Junctional rhythm occurs with occasional capture by slow and irregular sinus P waves (arrowsJ.
Table I. Composition of the Herbal Prescription
Herb
Prescribed Amount (9)
41
1. Radix Aconiti Carmichaeli Preparata 2. Radix Aconiti Kusnezoffii Preparata 3. Radix Achyranthes Bidentatae
4 10
4. Radix Angelicae Pubescentis
10
5. 6. 7. 8. 9. 10.
Radix Saposhnikoviae Ramulus Cinnamomi Rhizoma Atractylodis Radix Angelicae Sinensis Semen Coicis Herba Psychotriae
PACE, Vol. 15
10
Comment Contains aconite alkaloids Suppression of myocardial contractility in isolated toad & canine hearts Hypotensive effect
No known toxicity
30 10
May 1992
835
TAI, ET AL.
Table II.
Contents of Aconite Alkaloids in the Crude Herbal Prescription and the Decoction
Mesacon it i ne Acon it i ne Hypaconitine
Cured rootstocks of A. carmichaeli
Cured rootstocks of A. kusnezoffii
Authentic Decoction
0.006°/0
0.0013%
0.0037% 0.022%
present*
189 PS 250 P9 189 P9
0.0017%
Present in substantial quantities but cannot be absolutely quantified because of other overlapping components
nation in the axis and morphology of the QRS complexes of the tachycardia. Since the first report by Schwensen in 1922, approximately 70 cases of bidirectional tachycardia have been documented in the literature.'-l2 The most common ECG presentation comprised a predominant right bundle branch block-like configuration in Vl with alternating left and right shift of the frontal QRS axis, resembling an alternating bifascicular block pattern. Alternating left and right bundle branch block-like morphologies have also been observed. As such, bidirectional tachycardia represents an extreme form of electrical alternans. An alternating pattern of ventricular activation has been considered to be the underlying electrophysiological mechanism. Most cases of bidirectional tachycardia were reported in the preelectrophysiology era, thus localization of the tachycardia origin and evaluation of the tachycardia mechanism remained imprecise and often largely conjectural. Postulated mechanisms include: a supraventricular (including junctional) origin with an alternating bifascicular pattern of intraventricular conduction aberration,6 dual supraventricular and ventricular origins,2and dual ventricular foci with alternating firing and capture of the ventricular m y o c a r d i ~ m .Reports ~.~ on intracardiac electrophysiological evaluation of bidirectional tachycardia have remained rare, owing to the uncommon incidence and the sporadic nature of the arrhythmia, and because electrophysiological evaluation is usually not clinically indicated in these cases. From the few reports available, it is evident that multiple sites of tachycardia origin and mechanisms could have been operative. A supraventricular origin in the setting of severe trifascicu-
836
lar conduction d i s e a ~ e ,an ~ infra-Hisian fascicular origin,a and a ventricular origin of the t a c h y ~ a r d i a ~have - ~ ~ all been confirmed in individual cases. Automaticity has generally been incriminated as the electrophysiological mechanism of these tachycardias. In one report," a reentry circuit involving the two fascicles of the left bundle branch was suggested, with alternating reversal of direction of activation in consecutive tachycardia cycles. The vast majority of reported cases of bidirectional tachycardia occurred in patients with advanced structural heart disease in the setting of digitalis overdose. The patient in this report presented with bidirectional tachycardia soon after ingestion of a herbal decoction that contained abundant quantities of aconite compounds. The absence of symptoms of tachyarrhythmias prior to this attack and the close temporal relationship between the two events suggested a causal role of the herbal aconites. Apart from mild left ventricular hypertrophy, there was no evidence of structural cardiac disease, and no tachyarrhythmia could be induced with an exhaustive programmed stimulation protocol. An extensive search of the relevant pharmacological literature (Western and Chinese) also did not reveal any other substance in the prescription that could have been causally related to arrhythmogenesis in our patient. Aconitine (C33H47N01,)and the related alkaloids are well-known c a r d i o t o ~ i n s . l ~ In- experi~~ mental animals aconitine is fatally arrhythmogenic at very low doses (induction of ventricular fibrillation), and is an established model for evaluation of the efficacy of new antiarrhythmic drugs. Cellular electrophysiological experiments have
May 1992
PACE, Vol. 15
ACONITE-INDUCED BIDIRECTIONAL TACHYCARDIA
shown that in canine Purkinje fibers, aconitine induces early afterdepolarizations and bursts of rhythmic activity upon attainment of depolarization t h r e ~ h o l d . ’Aconitine ~ has also been observed to lead to sustained automaticity in paced (but not in quiescent) canine ventricular myocardial fibers.l” Triggered automaticity is, thus, the most likely electrophysiological mechanism of aconitine-induced arrhythmias. In the light of data on cellular electrophysiological mechanisms of aconitine-mediated arrhythmogenesis, our clinical and electropharmacological observations on the bidirectional tachycardia in this patient might provide additional information for better understanding of the tachycardia. The tachycardia was highly susceptible to vagotonic maneuvers, cholinesterase inhibition, and adenosine triphosphate. A tachycardia origin in the atrioventricular junction could easily have been invoked from these features. However, this entails an additional postulation of alternating functional left and right bundle branch block that occurred exclusively during tachycardia but not during junctional beats, which were recorded upon transient tachycardia suppression. Justification of such a postulation is difficult, as there was no evidence of infra-Hisian conduction delay, and some of the narrow complex junctional beats actually had coupling intervals that were similar to the cycle length of the tachycardia. A fascicular or ventricular myocardial origin of the tachycardia with alternating activation patterns, or dual foci with alternating discharges, would have provided a more feasible explanation for the remarkable bidirectional alternation and cycle length alternans during tachycardia. It is known that in Purkinje fibers, abnormal (“enhanced”) automaticity at relatively high membrane potentials could be depressed (though not totally abolished) by adenosine, especially under high adrenergic states.17 However, early afterdepolarization-induced triggered rhythms have not been observed to be adenosine-suppressible. Clinically, rare but specific variants of “idiopathic” ventricular tachycardia are known to be catecholamine-mediated and suppressible by vagal stimulation and by adenosine,18 and cyclic AMP-mediated delayed afterdepolarizations and triggered automaticity have been suggested as the tachycardia mechanism in these cases.18 With a fascicular or ventricular origin of
PACE, Vol. 1 5
the tachycardia in our patient, it is postulated that aconite toxicity might have led to alterations in cellular electrophysiological properties of the Purkinje fibers or ventricular myocytes, resulting in sensitivity to cholinergic stimulation and to adenosine triphosphate. In the absence of detailed intracardiac electrophysiological assessment, these discussions on tachycardia origin and the mechanism of bidirectional alternation necessarily have to remain speculative. It would be informative to design basic experiments to correlate with these interesting clinical observations. The rapid recurrence of the bidirectional tachycardia after transient suppression, the incessant nature of the rhythm, and the lack of response to cardioversion were consistent with features of triggered automatic tachycardias. Further information like the pattern of resetting of tachycardia by programmed electrical tim mu la ti on'^ and monophasic action potential recordings would be helpful for more definitive evaluation of the tachycardia mechanism in vivo. The dramatic suppression of the tachycardia by flecainide was consistent with the action of a Class Ic agent on triggered automaticity, but was nonspecific regarding elucidation of arrhythmia mechanism. The ECG changes suggesting abnormal and prolonged repolarization early after return to sinus rhythm were also in accord with the known effects of aconitine on membrane r e p ~ l a r i z a t i o n .The ~ ~ .elevation ~~ of the creatinine kinase level could have been due to aconite-mediated toxic myocardial injury and the effect of direct current shock. Aconite Poisoning Previous reports on aconite-induced arrhythmias have been scarce in the English literat ~ r e , ~ O -as’ ~aconite compounds have virtually no place in modern Western medicine. The rootstocks of aconitum plants are, however, commonly employed in Chinese herbal medicine for “cardiotonic” actions (related to coryneine and higenamine within the cured herbs) and for treating “rheumatism” (local anesthetidanalgesic effects of aconite alkaloid^).'^-^^ The whole family of aconite alkaloids possess cardiotoxic and arrhythmogenic properties, particularly aconitine, hypaconitine, and mesaconitine, and the potentially serious side-effects of aconite-containing
May 1992
837
TAI, ET AL.
complications. The clinical experience preparations have been well c a u t i ~ n e d . ~ ~ -rhythmic ~~ is too scanty for drawing any conclusion on the Preparation of the herbal decoction from the raw optimal antiarrhythmic therapy against tachycarrootstocks involves multiple steps (often perdias secondary to aconite-poisoning. Flecainide formed by lay persons] that result in hydrolysis of acetate was remarkably effective in terminating the aconites into less toxic derivatives like aconthe tachycardia in our patient, but a higher bolus ines. Nonadherance to recommended methods of dose of lignocaine might also have been helpful. preparation and excess in dosing could have preThese patients often present with critical hemodydisposed to aconite poisoning, which has been innamic states, thus intensive monitoring and suptermittently reported in Chinese medical literaportive therapy are mandatory to facilitate art ~ r e . The ’ ~ amount of aconites consumed in these rhythmia control and optimize patient recovery. cases were variable, but severe poisoning has been observed following ingestion of as little as 0.2 mg of aconitine, or consumption of decoctions preConclusion pared from prescriptions using 6 g of the cured We have detailed the clinical, electrocardiorootstocks of aconitum plants. The fatal dose of graphic, and electropharmacological characterisaconitine in humans is classically said to be 2 tics of a case of aconite-induced bidirectional mg.I3 In our patient, at least 0.6 mg of aconite alkatachycardia, and have highlighted the potentially loids had been ingested, from a total of 8 g of cured life-threatening sequel of this form of accidental herbs. A wide range of tachyarrhythmias have herb-induced poisoning. While previously rarely been observed, including atrial, junctional, and reported, aconite-induced poisoning and arrhythventricular ectopics (frequently multifocal) and mogenesis may be more frequently encountered in tachycardia, and ventricular fibrillati~n.’~ BradyWestern societies, with the trend of cross-mixing arrhythmias have been observed due to intense of populations worldwide. Health policymaking vagal stimulation by the aconites, resulting in authorities and the medical community as well as atrioventricular dissociation, junctional bradycarthe general public should be made aware of these dia and sinus arrest, the latter being also evident traditional herbal substances, which have low during brief pauses of tachycardia in our patient. margins of safety, and strict surveillance and conCases of aconite-poisoning have been reported in trol should be exercised over the prescription, proother parts of the world where consumption of cessing, and quantitation of such materials. herb-derived materials is a prevalent ethnic custom, e.g., India.28-30 Acknowledgment: The authors thank Kris Law and Venus There is no specific antidote to this highly seYuen for their expert secretarial assistance, and Hui Cao and rious form of intoxication. Anticholinergic mediFan-Wah Lau for their technical assistance in analyzing the contents of aconitine alkaloids. cations have been advocated for treating bradyarReferences 1. Schwensen C. Ventricular tachycardia as the result of the administration of digitalis. Heart 1922;
9:199-205. Zimdahl WT, Kramer LI. On the mechanism of paroxysmal tachycardia with rhythmic alternation in the direction of the ventricular complexes. Am Heart J 1947; 33:218-227. 3. Castellanos A, Jr. The genesis of bidirectional tachycardia. Am Heart J 1961; 61:733-739. 4. Scherf D, Bornemann C. Tachycardias with alternation of the ventricular complexes. Am Heart J 1967; 74~667-674. 5. Castellanos A, Sung RJ, Myerburg RJ. Bidirectional tachycardia. In 0s Narula (ed.): Cardiac Arrhythmias: Electrophysiology and Management. Baltimore, MD, William & Wilkins, 1979, pp. 419-435. 2.
838
6.
7.
8. 9. 10. 11.
May 1992
Rosenbaum MI, Elizari MV, Lazzari 70. The mechanism of bidirectional tachycardia. Am Heart J 1969; 7814-12. Cohen SI, Voukydis P. Supraventricular origin of bidirectional tachycardia. Circulation 1974; 50: 634-638. Gavrilescu S, Luca C. His bundle electrogram during bidirectional tachycardia. Br Heart J 1975; 3 7 9 198-1201. Cohen SI, Deisseroth A, Hecht HS. Infra-His bundle origin of bidirectional tachycardia. Circulation 1973; 47~1260-1266. Kastor JA, Goldreyer BN. Ventricular origin of bidirectional tachycardia: Case report of a patient not toxic from digitalis. Circulation 1973; 48:897-903. Morris SN, Zipes DP. His bundle electrocardiogra-
PACE, Vol. 15
ACONITE-INDUCED BIDIRECTIONAL TACHYCARDIA
12.
13.
14.
15.
16. 17.
18.
19.
20.
phy during bidirectional tachycardia. Circulation 1973; 48~32-36. Levy S, Hilaire J, Clementy J, et al. Bidirectional tachycardia: Mechanism derived from intracardiac recordings and programmed electrical stimulation. PACE 1982; 5:633-638. Wade A. Supplementary drugs and ancillary substances: Aconite and aconitine. In W. Martindale (ed.): The Extra Pharmacopoeia. 27th ed. London, Pharmaceutical Press, 1977, p. 1716. Pepper K, Trautwein W. The effect of aconitine on the membrane current in cardiac muscle. Pflugers Archiv 1967; 296:328-336. Leichter D, Danilo P, Jr, Boyden P, et al. A canine model of torsades de pointes. PACE 1988; 11: 2235-2245. Matsuda K, Hoshi T, Kameyama S. Effects of aconitine on the cardiac membrane potential of the dog. Japan J Physiol 1959; 9:419-429. Rosen MR, Danilo P, Jr, Weiss RM. Actions of adenosine on normal and abnormal impulse initiation in canine ventricle. Am J Physiol 1983; 244: H7155H721. Lerman BB, Belardinelli L, West GA, et al. Adenosine-sensitive ventricular tachycardia: Evidence suggesting cyclic AMP-mediated triggered activity. Circulation 1986; 74270-280. Almendral JM, Stamato NJ, Rosenthal ME, et al. Resetting response patterns during sustained ventricular tachycardia: Relationship to the excitable gap. Circulation 1986; 74:722-730. Hartung EF. A case of aconitine poisoning causing cardiac collapse. J Amer Med Assoc 1930; 95:1265.
PACE, Vol. 15
21.
22. 23. 24.
25.
26.
27.
28.
29.
30.
May 1992
French G. Aconite-induced cardiac arrhythmia. Br Heart J 1958; 20:140-142. Fiddes FS. Poisoning by aconitine: Report of two cases. Br Heart J 1958; 779-780. Kelly SP. Aconite poisoning. (letter) Med J Australia 1990; 153:499. Pharmacopoeia Committee (ed.). Pharmacopoeia of the People’s Republic of China (1990 ed.), Vol. 1. Beijing, People’s Health Publishing House and Chemical Technology Press, 1990, pp. 26-28 and 211-213. Wu TK. Fuzi and Chuan Wu. In HM Chang, PPH But (eds.). Pharmacology and Applications of Chinese Materia Medica, Vol. 1. Singapore, World Scientific Press, 1986; pp. 668-673. Liu CW. Cao Wu. In HM Chang, PPH But (eds.). Pharmacology and Applications of Chinese Materia Medica, Vol. 2. Singapore, World Scientific Press, 1987, pp. 864-866. Wu YB. Aconite poisoning: A review of experience in China over the past 30 years. Jiangsu Zhong Yi (Jiangsu J Chinese Med) 1988; 12:39-42 [in Chinese). Merchant HC, Choksi ND, Ramamoorthy K, et al. Aconite poisoning and cardiac arrhythmias: Report of 3 cases. Indian J Med Scien 1963; 17~857-865. Kapoor SC, Sen AK. Cardiovascular aspects of aconite poisoning in human beings. Indian Heart J 1969; 25~329-338. Sharma SN, Talwar KK, Bhatia ML. Aconite-induced reversible ventricular dysrhythmia. (letter) J Assoc Physicians India 1990; 38:381.
839
TAI, Y .-T., ET AL.: Bidirectional Tachycardia Induced by Herbal Aconite Poisoning. This report details the clinical, electrocardiographic, and electropharmacological characteristics of an unusual case of bidirectional tachycardia induced by aconites present in a Chinese herbal decoction consumed by a previously healthy subject. The tachycardia showed marked susceptibility to vagotonic maneuvers, cholinesterase inhibition, and adenosine triphosphate. The incessant nature of the tachycardia, rapid recurrence after transient suppression, and failure to respond to direct current cardioversion suggested an automatic tachycardia mechanism consistent with known data on the cellular electrophysiological mechanism of aconitine-mediated arrhythmogenesis. A fascicular or ventricular myocardial origin of the tachycardia with alternating activation patterns, or dual foci with alternate discharge, appeared most plausible. The rootstocks of aconitum plants have been commonly employed in traditional Chinese herbal recipes for “cardiotonic” actions and for relieving “rheumatism.” Multiple pitfalls could occur during the processing of these herbs that might have predisposed to aconite poisoning. The need for strict control and surveillance of herbal substances with low margins of safety is highlighted. (PACE, Vol. 15, May 1992) bidirectional tachycardia, aconite poisoning, triggered automaticity, Chinese medicine, Aconitum carmichaeli, Aconitum kusnezoffii
Introduction Bidirectional tachycardia is a rare but highly intriguing arrhythmia, during which there is beatto-beat alternation in the direction of the QRS complexes on the electrocardiogram (ECG).’-’’ The majority of previously reported cases occurred in patients with advanced cardiac disease and digitalis toxicity. In this report, we detail the occurrence of bidirectional tachycardia in a previously healthy subject after ingestion of a Chinese
This study was partly supported by Cardiac Research Fund 360-041-0615 of the University of Hong Kong and by the Chinese Medicinal Material Research Centre, Chinese University of Hong Kong. Address for reprints: Dr. Yau-Ting Tai, University Department of Medicine, Professorial Block, Queen Mary Hospital, Pokfulam Road, Hong Kong. Fax: (852) 8551143. Received November 27, 1991; revision January 6, 1992; accepted January 28, 1992.
PACE, Vol. 15
herbal decoction that contained aconites. Careful observations were made on the responses of the tachycardia to various autonomic and pharmacological interventions. These provided additional information for better understanding of the bidirectional tachycardia in the light of known cellular electrophysiological mechanisms of aconitine-mediated arrhythmogenesis.
Case Report A 45-year-old previously healthy Chinese woman was admitted with sudden onset of severe palpitation, nausea, vomiting, and numbness of the extremities. Two hours earlier she had ingested a bowl of herbal decoction, prepared from boiling a combination of herbs that included the “cured” (processed) rootstocks of Aconitum carmichaeli and Aconitum kusnezoffii, prescribed for treating rheumatism. There had never been a
May 1992
831
TAI, ET AL.
A
B
WSN
I
V1
I1
v2
AVR
v4
AVL
VS
AVF
v6
Figure 1. (A] Twelve-lead ECG of tachycardia, with sustained bidirectional alternation and cycle length alternans. (B) Run of tachycardia with a predominant single QRS morphology (right bundle branch block-like) and a regular cycle length. Note the transient pauses in leads I and AVL with reinitiation of tachycardia following a junctional beat and a wide complex ectopic beat corresponding to the second morphology during bidirectional alternation. 832
May 1992
PACE, Vol. 15
ACONITE-INDUCED BIDIRECTIONAL TACHYCARDIA
history of palpitation or syncope, and she had not been taking any other medication. On examination the patient had a blood pressure of 90/50 mmHg and a pulse of 176/niin with pulsus alternans. The 12-lead ECG on admission revealed a wide QRS complex tachycardia (Fig. IA), with discrete beatto-beat alternation in the morphology and the axis of the QRS complexes between a left bundle branch block- and a right bundle branch blocklike configuration. There was also consistent slight alternation in the cycle length of the tachycardia (360/380 msec). This bidirectional alternation persisted most of the time, but there were periods when the tachycardia occurred with only one of the QRS configurations (right bundle branch-like morphology) and a regular cycle length (Fig. 1B). Intermittently after long runs the tachycardia spontaneously terminated, then restarted following one or two junctional beats. Of interest was that sinus P waves were never observed during these brief pauses, suggesting the occurrence of significant sinus node suppression. The patient remained alert during the tachycardia, and the hemodynamic status was rapidly stabilized with intravenous fluids upon admission. Response of Tachycardia to Autonomic and Pharmacological Interventions As the patient was acutely admitted in the middle of the night, it was not feasible to obtain intracardiac or intraesophageal recordings during the tachycardia in our local setting. With the sustained tachycardia and the relatively stable hemodynamic state, we were able to evaluate the response of the tachycardia to a number of autonomic and pharmacological interventions at bedside. Vagotonic maneuvers like vomiting and carotid sinus massage consistently resulted in transient suppression of the bidirectional tachycardia (Fig. 2). Intravenous adenosine triphosphate (20 mg bolus: Fig. 3) and edrophonium hydrochloride (10 mg) also resulted in short-lived suppression of the tachycardia. Intravenous lignocaine (1mg/kg bolus) had no effect on the tachycardia, nor did attempted synchronized direct current cardioversion (200 joules [ J]). Flecainide acetate was administered by slow intravenous infusion during the tachycardia, at a rate of 10 mg/min and under close hemodynamic monitoring. The tachycardia terminated after 40 mg (0.7 mg/kg) of flecai-
PACE, Vol. 15
vomit
csm h
1
....
.
a ,
.
181
Figure 2. Transient suppression of bidirectional tachycardia by vagotonic maneuvers. Upon vomiting (A), sustained tachycardia is transiently suppressed, and bidirectional couplets are preceded by narrow complex junctional beats. Carotid sinus massage (B) results in short-lived total suppression of tachycardia.
nide was given (Fig. 4). The patient remained in junctional rhythm for 4 hours before returning to sinus rhythm. There was no subsequent arrhythmia recurrence. Cardiological Evaluation The initial ECG in sinus rhythm revealed reduced voltage of the P waves. There was evidence of prolonged and abnormal repolarization, with a QT interval of 465 msec (QTc 526 msec), JT interval of 387 msec (JTc438 msec), and diffuse flattening of the T waves. These abnormalities were normalized 10 hours later. The creatinine kinase peaked early at 1050 IU/L (normal range 34-138), then returned to normal over the next 24 hours. The serum biochemistry including potassium, calcium and magnesium levels, the autoimmune antibodies, and paired sera for viral antibody titers
May 1992
833
TAI. ET AL.
comprising a maximum of two extrastimuli following two paced drives (cycle lengths 600, 400 msec), and incremental ventricular pacing down to a cycle length of 220 msec, at twice diastolic threshold with a pulse width of 2 msec, delivered at two right ventricular sites at base line and during intravenous infusion of isoprenaline ( 3 kg/ min). The patient has remained asymptomatic during a follow-up period of 6 months, with satisfactory blood pressure control by a calcium antagonist.
ATP 20mg
,
.)
.
,
4
WSN
Figure 3. Intravenous adenosine triphosphate (20-mg bolus) results in abrupt termination of the bidirectional tachycardia [arrowhead). This is followed by irregular junctional beats with narrow QRS complexes, and occasional ectopic beats of the same morphology as the bidirectional tachycardia. Note reinitiation of tachycardia following a sinus beat [open arrow). The ECG tracings are continuous.
were all normal. Echocardiography and cardiac catheterization revealed mild left ventricular hypertrophy secondary to previously undiagnosed essential hypertension, with satisfactory left ventricular contraction and a normal coronary anatomy. An electrophysiological study performed 5 days after admission revealed a normal His-to-ventricular conduction interval (50 msec). Upon atrial extrastimulus testing and incremental pacing, atrioventricular conduction was limited by block within the atrioventricular node (supra-Hisian), and there was no evidence of infra-Hisian conduction delay and block. There was no inducible ventricular arrhythmia with a stimulation protocol
834
Toxicologic Evaluation A multipanel toxicological screening on commonly encountered Western medications (including digoxin, salicylates, and tricyclic antidepressants) was performed on serum, urine, and gastric lavage fluid obtained upon admission, and was negative. Analysis of the traditional herbal prescription taken by the patient (Table I) and the herb samples revealed that apart from the aconites derived from the rootstocks of A. carmichaeli and A. kusnezoffii, the other herbs had not been known to be associated with cardiac arrhythmias. The extract of one herb had been observed to lead to suppression of myocardial contractility when injected into experimental animals, and another to hypotension. These might have aggravated the hemodynamic state of our patient during the tachycardia. A total of 4 g each of the cured rootstocks of A. cormichaeli and A. kusnezoffii were prescribed. The compositions of mesaconitine, aconitine, and hypaconitine-the three aconite alkaloids with the highest degree of cardiotoxicity-in an authentic herbal prescription, purchased from the same drugstore within 2 days of the diagnosis of poisoning, and the contents of these alkaloids in an authentic decoction, prepared in exactly the same manner as had been performed by the patient (boiling in water for 2.5 hours), were evaluated by high performance liquid chromatography. The results are shown in Table 11. It was estimated that a total of at least 0.6 mg of the three aconite alkaloids had been ingested by the patient.
Discussion Bidirectional Tachycardia Bidirectional tachycardia is an intriguing arrhythmic rarity characterized by beat-to-beat alter-
May 1992
PACE, Vol. 1 5
ACONITE-INDUCED BIDIRECTIONAL TACHYCARDIA
.
.
I
.
win
Figure 4. Termination of bidirectional tachycardia by intravenous flecainide acetate (40 rng, 0.7 mg/kgJ. Junctional rhythm occurs with occasional capture by slow and irregular sinus P waves (arrowsJ.
Table I. Composition of the Herbal Prescription
Herb
Prescribed Amount (9)
41
1. Radix Aconiti Carmichaeli Preparata 2. Radix Aconiti Kusnezoffii Preparata 3. Radix Achyranthes Bidentatae
4 10
4. Radix Angelicae Pubescentis
10
5. 6. 7. 8. 9. 10.
Radix Saposhnikoviae Ramulus Cinnamomi Rhizoma Atractylodis Radix Angelicae Sinensis Semen Coicis Herba Psychotriae
PACE, Vol. 15
10
Comment Contains aconite alkaloids Suppression of myocardial contractility in isolated toad & canine hearts Hypotensive effect
No known toxicity
30 10
May 1992
835
TAI, ET AL.
Table II.
Contents of Aconite Alkaloids in the Crude Herbal Prescription and the Decoction
Mesacon it i ne Acon it i ne Hypaconitine
Cured rootstocks of A. carmichaeli
Cured rootstocks of A. kusnezoffii
Authentic Decoction
0.006°/0
0.0013%
0.0037% 0.022%
present*
189 PS 250 P9 189 P9
0.0017%
Present in substantial quantities but cannot be absolutely quantified because of other overlapping components
nation in the axis and morphology of the QRS complexes of the tachycardia. Since the first report by Schwensen in 1922, approximately 70 cases of bidirectional tachycardia have been documented in the literature.'-l2 The most common ECG presentation comprised a predominant right bundle branch block-like configuration in Vl with alternating left and right shift of the frontal QRS axis, resembling an alternating bifascicular block pattern. Alternating left and right bundle branch block-like morphologies have also been observed. As such, bidirectional tachycardia represents an extreme form of electrical alternans. An alternating pattern of ventricular activation has been considered to be the underlying electrophysiological mechanism. Most cases of bidirectional tachycardia were reported in the preelectrophysiology era, thus localization of the tachycardia origin and evaluation of the tachycardia mechanism remained imprecise and often largely conjectural. Postulated mechanisms include: a supraventricular (including junctional) origin with an alternating bifascicular pattern of intraventricular conduction aberration,6 dual supraventricular and ventricular origins,2and dual ventricular foci with alternating firing and capture of the ventricular m y o c a r d i ~ m .Reports ~.~ on intracardiac electrophysiological evaluation of bidirectional tachycardia have remained rare, owing to the uncommon incidence and the sporadic nature of the arrhythmia, and because electrophysiological evaluation is usually not clinically indicated in these cases. From the few reports available, it is evident that multiple sites of tachycardia origin and mechanisms could have been operative. A supraventricular origin in the setting of severe trifascicu-
836
lar conduction d i s e a ~ e ,an ~ infra-Hisian fascicular origin,a and a ventricular origin of the t a c h y ~ a r d i a ~have - ~ ~ all been confirmed in individual cases. Automaticity has generally been incriminated as the electrophysiological mechanism of these tachycardias. In one report," a reentry circuit involving the two fascicles of the left bundle branch was suggested, with alternating reversal of direction of activation in consecutive tachycardia cycles. The vast majority of reported cases of bidirectional tachycardia occurred in patients with advanced structural heart disease in the setting of digitalis overdose. The patient in this report presented with bidirectional tachycardia soon after ingestion of a herbal decoction that contained abundant quantities of aconite compounds. The absence of symptoms of tachyarrhythmias prior to this attack and the close temporal relationship between the two events suggested a causal role of the herbal aconites. Apart from mild left ventricular hypertrophy, there was no evidence of structural cardiac disease, and no tachyarrhythmia could be induced with an exhaustive programmed stimulation protocol. An extensive search of the relevant pharmacological literature (Western and Chinese) also did not reveal any other substance in the prescription that could have been causally related to arrhythmogenesis in our patient. Aconitine (C33H47N01,)and the related alkaloids are well-known c a r d i o t o ~ i n s . l ~ In- experi~~ mental animals aconitine is fatally arrhythmogenic at very low doses (induction of ventricular fibrillation), and is an established model for evaluation of the efficacy of new antiarrhythmic drugs. Cellular electrophysiological experiments have
May 1992
PACE, Vol. 15
ACONITE-INDUCED BIDIRECTIONAL TACHYCARDIA
shown that in canine Purkinje fibers, aconitine induces early afterdepolarizations and bursts of rhythmic activity upon attainment of depolarization t h r e ~ h o l d . ’Aconitine ~ has also been observed to lead to sustained automaticity in paced (but not in quiescent) canine ventricular myocardial fibers.l” Triggered automaticity is, thus, the most likely electrophysiological mechanism of aconitine-induced arrhythmias. In the light of data on cellular electrophysiological mechanisms of aconitine-mediated arrhythmogenesis, our clinical and electropharmacological observations on the bidirectional tachycardia in this patient might provide additional information for better understanding of the tachycardia. The tachycardia was highly susceptible to vagotonic maneuvers, cholinesterase inhibition, and adenosine triphosphate. A tachycardia origin in the atrioventricular junction could easily have been invoked from these features. However, this entails an additional postulation of alternating functional left and right bundle branch block that occurred exclusively during tachycardia but not during junctional beats, which were recorded upon transient tachycardia suppression. Justification of such a postulation is difficult, as there was no evidence of infra-Hisian conduction delay, and some of the narrow complex junctional beats actually had coupling intervals that were similar to the cycle length of the tachycardia. A fascicular or ventricular myocardial origin of the tachycardia with alternating activation patterns, or dual foci with alternating discharges, would have provided a more feasible explanation for the remarkable bidirectional alternation and cycle length alternans during tachycardia. It is known that in Purkinje fibers, abnormal (“enhanced”) automaticity at relatively high membrane potentials could be depressed (though not totally abolished) by adenosine, especially under high adrenergic states.17 However, early afterdepolarization-induced triggered rhythms have not been observed to be adenosine-suppressible. Clinically, rare but specific variants of “idiopathic” ventricular tachycardia are known to be catecholamine-mediated and suppressible by vagal stimulation and by adenosine,18 and cyclic AMP-mediated delayed afterdepolarizations and triggered automaticity have been suggested as the tachycardia mechanism in these cases.18 With a fascicular or ventricular origin of
PACE, Vol. 1 5
the tachycardia in our patient, it is postulated that aconite toxicity might have led to alterations in cellular electrophysiological properties of the Purkinje fibers or ventricular myocytes, resulting in sensitivity to cholinergic stimulation and to adenosine triphosphate. In the absence of detailed intracardiac electrophysiological assessment, these discussions on tachycardia origin and the mechanism of bidirectional alternation necessarily have to remain speculative. It would be informative to design basic experiments to correlate with these interesting clinical observations. The rapid recurrence of the bidirectional tachycardia after transient suppression, the incessant nature of the rhythm, and the lack of response to cardioversion were consistent with features of triggered automatic tachycardias. Further information like the pattern of resetting of tachycardia by programmed electrical tim mu la ti on'^ and monophasic action potential recordings would be helpful for more definitive evaluation of the tachycardia mechanism in vivo. The dramatic suppression of the tachycardia by flecainide was consistent with the action of a Class Ic agent on triggered automaticity, but was nonspecific regarding elucidation of arrhythmia mechanism. The ECG changes suggesting abnormal and prolonged repolarization early after return to sinus rhythm were also in accord with the known effects of aconitine on membrane r e p ~ l a r i z a t i o n .The ~ ~ .elevation ~~ of the creatinine kinase level could have been due to aconite-mediated toxic myocardial injury and the effect of direct current shock. Aconite Poisoning Previous reports on aconite-induced arrhythmias have been scarce in the English literat ~ r e , ~ O -as’ ~aconite compounds have virtually no place in modern Western medicine. The rootstocks of aconitum plants are, however, commonly employed in Chinese herbal medicine for “cardiotonic” actions (related to coryneine and higenamine within the cured herbs) and for treating “rheumatism” (local anesthetidanalgesic effects of aconite alkaloid^).'^-^^ The whole family of aconite alkaloids possess cardiotoxic and arrhythmogenic properties, particularly aconitine, hypaconitine, and mesaconitine, and the potentially serious side-effects of aconite-containing
May 1992
837
TAI, ET AL.
complications. The clinical experience preparations have been well c a u t i ~ n e d . ~ ~ -rhythmic ~~ is too scanty for drawing any conclusion on the Preparation of the herbal decoction from the raw optimal antiarrhythmic therapy against tachycarrootstocks involves multiple steps (often perdias secondary to aconite-poisoning. Flecainide formed by lay persons] that result in hydrolysis of acetate was remarkably effective in terminating the aconites into less toxic derivatives like aconthe tachycardia in our patient, but a higher bolus ines. Nonadherance to recommended methods of dose of lignocaine might also have been helpful. preparation and excess in dosing could have preThese patients often present with critical hemodydisposed to aconite poisoning, which has been innamic states, thus intensive monitoring and suptermittently reported in Chinese medical literaportive therapy are mandatory to facilitate art ~ r e . The ’ ~ amount of aconites consumed in these rhythmia control and optimize patient recovery. cases were variable, but severe poisoning has been observed following ingestion of as little as 0.2 mg of aconitine, or consumption of decoctions preConclusion pared from prescriptions using 6 g of the cured We have detailed the clinical, electrocardiorootstocks of aconitum plants. The fatal dose of graphic, and electropharmacological characterisaconitine in humans is classically said to be 2 tics of a case of aconite-induced bidirectional mg.I3 In our patient, at least 0.6 mg of aconite alkatachycardia, and have highlighted the potentially loids had been ingested, from a total of 8 g of cured life-threatening sequel of this form of accidental herbs. A wide range of tachyarrhythmias have herb-induced poisoning. While previously rarely been observed, including atrial, junctional, and reported, aconite-induced poisoning and arrhythventricular ectopics (frequently multifocal) and mogenesis may be more frequently encountered in tachycardia, and ventricular fibrillati~n.’~ BradyWestern societies, with the trend of cross-mixing arrhythmias have been observed due to intense of populations worldwide. Health policymaking vagal stimulation by the aconites, resulting in authorities and the medical community as well as atrioventricular dissociation, junctional bradycarthe general public should be made aware of these dia and sinus arrest, the latter being also evident traditional herbal substances, which have low during brief pauses of tachycardia in our patient. margins of safety, and strict surveillance and conCases of aconite-poisoning have been reported in trol should be exercised over the prescription, proother parts of the world where consumption of cessing, and quantitation of such materials. herb-derived materials is a prevalent ethnic custom, e.g., India.28-30 Acknowledgment: The authors thank Kris Law and Venus There is no specific antidote to this highly seYuen for their expert secretarial assistance, and Hui Cao and rious form of intoxication. Anticholinergic mediFan-Wah Lau for their technical assistance in analyzing the contents of aconitine alkaloids. cations have been advocated for treating bradyarReferences 1. Schwensen C. Ventricular tachycardia as the result of the administration of digitalis. Heart 1922;
9:199-205. Zimdahl WT, Kramer LI. On the mechanism of paroxysmal tachycardia with rhythmic alternation in the direction of the ventricular complexes. Am Heart J 1947; 33:218-227. 3. Castellanos A, Jr. The genesis of bidirectional tachycardia. Am Heart J 1961; 61:733-739. 4. Scherf D, Bornemann C. Tachycardias with alternation of the ventricular complexes. Am Heart J 1967; 74~667-674. 5. Castellanos A, Sung RJ, Myerburg RJ. Bidirectional tachycardia. In 0s Narula (ed.): Cardiac Arrhythmias: Electrophysiology and Management. Baltimore, MD, William & Wilkins, 1979, pp. 419-435. 2.
838
6.
7.
8. 9. 10. 11.
May 1992
Rosenbaum MI, Elizari MV, Lazzari 70. The mechanism of bidirectional tachycardia. Am Heart J 1969; 7814-12. Cohen SI, Voukydis P. Supraventricular origin of bidirectional tachycardia. Circulation 1974; 50: 634-638. Gavrilescu S, Luca C. His bundle electrogram during bidirectional tachycardia. Br Heart J 1975; 3 7 9 198-1201. Cohen SI, Deisseroth A, Hecht HS. Infra-His bundle origin of bidirectional tachycardia. Circulation 1973; 47~1260-1266. Kastor JA, Goldreyer BN. Ventricular origin of bidirectional tachycardia: Case report of a patient not toxic from digitalis. Circulation 1973; 48:897-903. Morris SN, Zipes DP. His bundle electrocardiogra-
PACE, Vol. 15
ACONITE-INDUCED BIDIRECTIONAL TACHYCARDIA
12.
13.
14.
15.
16. 17.
18.
19.
20.
phy during bidirectional tachycardia. Circulation 1973; 48~32-36. Levy S, Hilaire J, Clementy J, et al. Bidirectional tachycardia: Mechanism derived from intracardiac recordings and programmed electrical stimulation. PACE 1982; 5:633-638. Wade A. Supplementary drugs and ancillary substances: Aconite and aconitine. In W. Martindale (ed.): The Extra Pharmacopoeia. 27th ed. London, Pharmaceutical Press, 1977, p. 1716. Pepper K, Trautwein W. The effect of aconitine on the membrane current in cardiac muscle. Pflugers Archiv 1967; 296:328-336. Leichter D, Danilo P, Jr, Boyden P, et al. A canine model of torsades de pointes. PACE 1988; 11: 2235-2245. Matsuda K, Hoshi T, Kameyama S. Effects of aconitine on the cardiac membrane potential of the dog. Japan J Physiol 1959; 9:419-429. Rosen MR, Danilo P, Jr, Weiss RM. Actions of adenosine on normal and abnormal impulse initiation in canine ventricle. Am J Physiol 1983; 244: H7155H721. Lerman BB, Belardinelli L, West GA, et al. Adenosine-sensitive ventricular tachycardia: Evidence suggesting cyclic AMP-mediated triggered activity. Circulation 1986; 74270-280. Almendral JM, Stamato NJ, Rosenthal ME, et al. Resetting response patterns during sustained ventricular tachycardia: Relationship to the excitable gap. Circulation 1986; 74:722-730. Hartung EF. A case of aconitine poisoning causing cardiac collapse. J Amer Med Assoc 1930; 95:1265.
PACE, Vol. 15
21.
22. 23. 24.
25.
26.
27.
28.
29.
30.
May 1992
French G. Aconite-induced cardiac arrhythmia. Br Heart J 1958; 20:140-142. Fiddes FS. Poisoning by aconitine: Report of two cases. Br Heart J 1958; 779-780. Kelly SP. Aconite poisoning. (letter) Med J Australia 1990; 153:499. Pharmacopoeia Committee (ed.). Pharmacopoeia of the People’s Republic of China (1990 ed.), Vol. 1. Beijing, People’s Health Publishing House and Chemical Technology Press, 1990, pp. 26-28 and 211-213. Wu TK. Fuzi and Chuan Wu. In HM Chang, PPH But (eds.). Pharmacology and Applications of Chinese Materia Medica, Vol. 1. Singapore, World Scientific Press, 1986; pp. 668-673. Liu CW. Cao Wu. In HM Chang, PPH But (eds.). Pharmacology and Applications of Chinese Materia Medica, Vol. 2. Singapore, World Scientific Press, 1987, pp. 864-866. Wu YB. Aconite poisoning: A review of experience in China over the past 30 years. Jiangsu Zhong Yi (Jiangsu J Chinese Med) 1988; 12:39-42 [in Chinese). Merchant HC, Choksi ND, Ramamoorthy K, et al. Aconite poisoning and cardiac arrhythmias: Report of 3 cases. Indian J Med Scien 1963; 17~857-865. Kapoor SC, Sen AK. Cardiovascular aspects of aconite poisoning in human beings. Indian Heart J 1969; 25~329-338. Sharma SN, Talwar KK, Bhatia ML. Aconite-induced reversible ventricular dysrhythmia. (letter) J Assoc Physicians India 1990; 38:381.
839
