Br Heart J: first published as 10.1136/hrt.53.6.654 on 1 June 1985. Downloaded from Br Heart J 1985; 53: 654-8

Ventricular induced by withdrawal

SUSUMU NAKAGAWA, YOSHITAKA YAMAMOTO, YASUSHI KOIWAYA From the First Department ofInternal Medicine, Miyazaki Medical College, Kiyotake, Miyazaki, Japan

SUMMARY Ventricular tachycardia developed after the abrupt withdrawal of clonidine in a patient with atrial septal defect of the ostium secundum type, renal insufficiency, and hypertension. Ven- tricular tachycardia was completely suppressed by intravenous phentolamine, which contrasted with the limited effectiveness of intravenous lignocaine and procainamide. Sublingual glyceryl trinitrate or inhaled amyl nitrate reduced the blood pressure to a level similar to that after phentolamine but had no effect on the ventricular tachycardia. Ventricular tachycardia was probably produced by humoral or neural stimulation, or both, of upregulated myocardial alpha adrenoceptors.

It is known that the abrupt withdrawal of clonidine eight months later. Two days before admission she hydrochloride (clonidine) is often associated with a had stopped taking clonidine (Fig. 1). syndrome characterised by excessive efferent sym- On admission, her height was 148 cm, weight pathetic activity producing raised serum 46 kg, body temperature 36 3°C, and blood pressure catecholamine concentrations and clinical manifesta- 130/80 mm Hg. No cyanosis was noticed. The jugular tions similar to those in . 1-4 veins were slightly distended and minimal pretibial Although frequent atrial and ventricular extrasystoles pitting oedema was present. The pulse was irregular rate was have been reported,' serious ventricular arrhythmias at a rate of 120 beats/min, the respiratory http://heart.bmj.com/ are rare in the clonidine withdrawal syndrome. To our 18/min, and a grade 3/6 early systolic murmur was knowledge, only one case of ventricular fibrillation heard most clearly in the third intercostal space at the has been reported 12 hours after the withdrawal of left sternal border. The two components of the second clonidine during aortocoronary bypass surgery.2 heart sound were widely separated, which was We report a patient with atrial septal defect of the confirmed by a phonocardiogram. The resting elec- ostium secundum type, chronic renal failure, and trocardiogram showed normal sinus rhythm with hypertension, who experienced paroxysmal ventricu- paroxysmal ventricular tachycardia (Fig. 2a) and inverted T waves in the precordial leads. lar tachycardia two days after stopping oral clonidine. on October 6, 2021 by guest. Protected copyright. A chest radiograph showed increased pulmonary Case report markings, a pronounced convexity of the cardiac shadow to the right of the sternum, a normal sized A 60 year old woman with atrial septal defect had an aortic knuckle, and a prominent pulmonary knuckle. eight year history of hypertension and intermittent M mode and cross sectional echocardiograms showed pretibial oedema. Her blood pressure was 165/ an enlarged right ventricle, paradoxical motion of the 105 mm Hg, and she was treated with 0-45 mg interventricular septum, a narrow left ventricular clonidine daily. One month later her blood urea outflow tract, and a high D point of the mitral valve. nitrogen concentration was 18-9 mmol/l (53.0 mg/ Serum sodium concentration was 148 mmol/l, 100 ml) and serum creatinine concentration potassium 4 9 mmol/l, chloride 111 mmol/l, bicarbo- 203 mmol/l (2-3 g/100 ml). She was admitted to our nate 16-2 mmol/l, calcium 77 mg/l, phosphorus clinic for further evaluation of progressive oedema 62 mg/l, lactate dehydrogenase activity 564 IU/l, serum aspartate aminotransferase activity 46 IU/l, serum alanine aminotransferase activity 48 IU/l, and creatine phosphokinase activity 131 IU/1. Packed Requests for reprints to Dr Susumu Nakagawa, First Department of Internal Medicine, Miyazaki Medical College, 5200 Kihara, cell volume was 36-8%, haemoglobin 118 g/dl, red Kiyotake, Miyazaki 889-16, Japan. blood cell count 4-13 x 10'2/1, and white blood cell 654 Br Heart J: first published as 10.1136/hrt.53.6.654 on 1 June 1985. Downloaded from Ventricular tachycardia induced by clonidine withdrawal 655 _,'hentolamine MCloniine 0225mg/day I P M ; ; 200 C:lonidine 0 45mg i --

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count 6-9 x 109/1. Blood urea nitrogen concentration Intravenous lignocaine 100 mg and procainamide was 32 mmol/l (90-2 mg/100 ml), creatinine 200 mg failed to suppress the ventricular tachycardia 486 ,umol/l (5*5 mg/100 ml) and calculated creatinine completely. Nevertheless, an intravenous of clearance 9-24 ml/min. Urine analysis showed 10 mg phentolamine completely suppressed ventricu- 400 mg/l of protein. lar tachycardia within two minutes with a decrease in Blood pressure rose gradually to 220/120 mm Hg blood pressure and pronounced symptomatic by midday of the second hospital day (Fig. 1). improvement (Figs. 2b and c). Repeated doses of Nausea, vomiting, and cold sweats developed con- phentolamine achieved similar results, while serum comitantly, and the intervals between episodes of catecholamine concentrations were unchanged by paroxysmal ventricular tachycardia were shorter (Fig. phentolamine after 30 minutes (Fig. 2c). To examine 2b). Serum adrenaline and noradrenaline concentra- the effects of the fall in blood pressure and afterload tions appreciably increased (3-2 nmol/l (0-59 ng/ml) reduction of arrhythmias, we gave glyceryl trinitrate and 15-6 nmolIl (2-64 ng/ml) respectively) (Fig. 2c), or amyl nitrate. Sublingual glyceryl trinitrate 0*3 mg and a diagnosis of clonidine withdrawal syndrome was decreased arterial pressure from 196/106 mm Hg to made. 170/102 mm Hg, and the inhalation of amyl nitrate Br Heart J: first published as 10.1136/hrt.53.6.654 on 1 June 1985. Downloaded from 656 Nakagawa, Yamamoto, Koiwaya

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Fig. 2 (a) Electrocardiogram (lead V2) (V denotes P ware), (b) continuous electrocardiogram (lead CMS) before and after http://heart.bmj.com/ mtrave phentolanine, and (c) chronological changes m bloodpressue, senmn adrenaline, and noradrenaline concentratioms, and fregeny ofwide QRS conkplexes ( denotes nmber ofepisodes ofvetiuar tachycardia (>3 consecute wide QRS co plexes)) before and after travenou phenomine. Repeiime mns ofventcr tackycardia were recorded and were suppressed conpletely two minutes after intravenous phentolmine. Coneion: SI to tradiional units-adrenaline: 1 ngllOO md 0 054 rnolll; noradrenaline 1 ngilOO ml 0-059 n'nolll. from 184/116 mm Hg to 160/106 mm Hg. Neither headaches with neck rigidity. She collapsed suddenly agent, however, affected the occurrence or frequency and cardiopulmonary resuscitation was unsuccessful. of episodes of ventricular tachycardia. Necropsy showed a massive subarachnoid haemor- on October 6, 2021 by guest. Protected copyright. Renal function progressively deteriorated after rhage secondary to rupture of an aneurysm of the left admission, with the blood urea nitrogen concentration anterior communicating artery, a large ostium secun- rising to 46-4 mmol/l (130 mg/100 ml) and potassium dum defect, and chronic glomerulonephritis. No evi- concentration to 6-2 mmol/l. We began treatment dence of pheochromocytoma or significant coronary with 0-225 mg clonidine and 8 mg prazosin daily on atherosclerosis was found. the third and fourth hospital day respectively, which lowered the blood pressure to 120/90 mm Hg within Discussion 12 hours and symptoms subsided within 48 hours. The number of episodes of ventricular tachycardia In our patient, in whom paroxysmal ventricular decreased gradually, and the arrhythmia did not recur tachycardia occurred after abruptly stopping after the ninth hospital day (Fig. 1). The concentra- clonidine, the arrhythmia was probably a manifesta- tions of blood urea nitrogen, creatinine, and serum tion of clonidine withdrawal since it occurred in con- potassium fell to the values before admission on the junction with other clinical evidence of this syndrome ninth hospital day. including raised serum catecholamine concentra- The clinical course was uneventful with treatment tions. Furthermore, intravenous phentolamine or oral until two months later, when she developed severe clonidine (the usual therapeutic drugs for the Br Heart J: first published as 10.1136/hrt.53.6.654 on 1 June 1985. Downloaded from Ventricular tachycardia induced by clonidine withdrawal 657 clonidine withdrawal syndrome) was more effective noradrenaline-receptor interaction at the synapse with in controlling ventricular tachycardia than other regu- an increase of alpha receptor concentration postsynap- larly used antiarrhythmic agents. tically.910 The abrupt withdrawal of clonidine results The mechanism of ventricular tachycardia associ- in increased efferent sympathetic outflow with ated with clonidine withdrawal is unknown. enhanced release of catecholamines from the adrenal Nevertheless, there are several possible theories. gland and sympathetic nerve endings.4 Increased Firstly, high blood pressure is known to aggravate activation of synaptic alpha receptors, which had catecholamine induced arrhythmias. The effective- increased in number or affinity or both, by the ness of phentolamine in suppressing ventricular enhanced stimulus results in a withdrawal tachycardia in this patient might have been due to the syndrome. An increase in the alpha receptors of the accompanying fall in blood pressure. This possibility ventricular myocardium after long term treatment is, however, unlikely since sublingual glyceryl trini- with clonidine has been reported.'0 In the present trate or inhaled amyl nitrate, sufficient to reduce case increased sympathetic outflow to the heart and blood pressure to the level similar to that after phen- raised serum catecholamine concentrations would tolamine, had no effect on ventricular tachycardia. have stimulated the increased cardiac alpha receptors Secondly, ventricular tachycardia might have been and thus induced ventricular tachycardia. The antiar- caused by direct stimulation of the myocardial rhythmic action of phentolamine would have been adrenoceptors by circulating catecholamines or car- mediated by the inhibition of cardiac alpha recep- diac sympathetic nerves. The notable effect of phen- tors. tolamine on ventricular tachycardia in contrast to the The antiarrhythmic effect of phentolamine could limited effectiveness of the usual antiarrhythmic have been exerted in the central nervous system, but drugs strongly suggests that alpha adrenergic mechan- such a mechanism was probably not predominant isms were involved in the genesis of ventricular since phentolamine penetrates the blood-brain barrier tachycardia. A was notgiven because of poorly, while a bolus injection of 10 mg phentolamine possible worsening of the withdrawal syndrome.'-4 was sufficient to suppress ventricular tachycardia Recently, the presence of myocardial alpha recep- within two minutes. It is not likely that the minor tors has been reported experimentally,6 and their role like antiarrhythmic action of phen- in the genesis of some specific cardiac arrhythmias has tolamine"I played an important role in our case, since been clarified. Picrotoxin, a central nervous system other regularly used antiarrhythmic agents with stimulant, produces demonstrable ventricular quinidine like action were not as effective as phen-

tachyarrhythmias in animals,7 and these tachyar- tolamine. http://heart.bmj.com/ rhythmias can be suppressed by phentolamine but not Our case was complicated by chronic by . These arrhythmias are thought to be glomerulonephritis with renal insufficiency, long caused by stimulation of myocardial alpha receptors standing hypertension, and atrial septal defect, which by cardiac sympathetic nerves or by circulating might have predisposed to ventricular tachycardia. catecholamines released from the adrenal gland or Renal insufficiency would have resulted in a high both. Cor and Crafford and Sheridan et al found blood concentration of clonidine and led to the with- alpha blockade to be effective in suppressing ventricu- drawal syndrome since clonidine is excreted mainly by the kidney.3 lar tachyarrhythmias induced by coronary artery on October 6, 2021 by guest. Protected copyright. reperfusion in cats.68 They found an increased number and affinity of myocardial alpha receptors in this experimental model.6 It is likely that sympathetic hyperactivity associated References with clonidine withdrawal involves predominantly 1 Goldberg AD, Wilkinson PR, Raftery EB. The over- alpha adrenergic mechanisms since alpha blockers shoot phenomenon on withdrawal of clonidine therapy. usually relieve the clinical symptoms of clonidine Postgrad Med J 1976; 52 (suppl 7): 128-34. withdrawal, while beta blockers occasionally make 2 O'Connor DE, Accelerated acute clonidine withdrawal them worse. 1-4 Why alpha adrenergic hyperactivity syndrome during coronary bypass surgery. A case report. predominates in this syndrome is not known, but it is Br J Anaesth 1981; 53: 431-3. of 3 Houston MC. Clonidine hydrochloride: review of phar- likely that upregulation alpha adrenergic receptors macologic and clinical aspects. Prog Cardiovasc Dis 1981; occurs after the abrupt withdrawal of clonidine.4 23: 337-50. Clonidine reduces the release of noradrenaline into 4 Whitsett TL. Abrupt cessation of treatment with cen- the synapse, acting as a presynaptic alpha receptor trally acting antihypertensive agents; a review. Chest agonist, and, furthermore, behaves as an alpha 1983; 83 (suppl): 400-2. postsynaptically. Thus sus- 5 Dresel P, Sutter MC. Factors modifying cyclopropane- tained treatment with clonidine results in a loss of epinephrine cardiac arrhythmias. Circ Res 1961; 9: Br Heart J: first published as 10.1136/hrt.53.6.654 on 1 June 1985. Downloaded from 658 Nakagawa, Yamamoto, Koiwaya 1284-90. 65: 161-71. 6 Corr PB, Crafford WA Jr. Enhanced alpha-adrenergic 9 Isaac L. Clonidine in the central nervous system: site and responsiveness in ischemic myocardium: role of alpha- mechanism of hypotensive action. J Cardiovasc Phar- adrenergic blockade. Am Heart J 1981; 102: 605-12. macol 1980; 2 (suppl 1): s5-19. 7 DiMicco JA, Prestel T, Pearle DL, Gillis RA. Mechan- 10 Yamada S, Yamamura HI, Roeske WR. An increase in ism of cardiovascular changes produced in cats by activa- cardiac alpha1-adrenoreceptors following chronic tion of the central nervous system with picrotoxin. Circ clonidine treatment. Naunyn Schmiedebergs Arch Phar- Res 1977; 41: 446 51. macol 1982; 320: 115-8. 8 Sheridan DJ, Penkoske PA, Sobel BE, Corr PB. Alpha- 11 Gould L, Reddy CVR, Weinstein T, Gomprecht RF. adrenergic contributions to dysrhythmia during myocar- Antiarrhythmic prophylaxis with phentolamine in acute dial ischemia and reperfusion in cats. J Clin Invest 1980; myocardial infarction.J Clin Pharmacol 1975; 15: 191-7. http://heart.bmj.com/ on October 6, 2021 by guest. Protected copyright.