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Pneumonitis with pleural and pericardial effusion and neuropathy during amiodarone therapy
International Journal of Cardiology, 8 (1985) 81-88 Elsevier
81
IJC 00252
Pneumonitis with pleural and pericardial effusion and neuropathy during amiodarone therapy Bernard Clarke I, David E. Ward and Michael Honey Department (Received
of Cardioiop,
Brompton Hospital, London, U.K.
26 March 1984; revision accepted
12 December
1984)
Clarke B, Ward DE, Honey M. Pneumonitis with pleural and pericardial effusion and neuropathy during amiodarone therapy. Int J Cardiol 1985;8:81-88. A patient with sinuatrial disease and implanted pacemaker was treated with amiodarone (maximum dose 1000 mg, maintenance dose 800 mg daily) for 10 months, for control of supraventricular tachyarrhythmias. He developed pneumonitis, pleural and pericardial effusions, and a predominantly proximal motor neuropathy. Immediate but gradual improvement followed withdrawal of amiodarone and treatment with prednisolone. Review of this and preiiously reported cases indicates the need for early diagnosis of amiodarone pneumonitis, immediate withdrawal of amiodarone, and prompt but continued steroid therapy to ensure full recovery.
(Key words: side-effects; drug treatment; pharmacology)
Amiodarone is a potent anti-arrhythmic agent, effective against a variety of ventricular and supraventricular tachyarrhythmias. There have however been many reports of side-effects, including corneal microcrystalline deposits of the drug, photosensitive skin eruptions and abnormal pigmentation, disturbances of thyroid function, pneumonitis [l-5,7,8-29], neuropathy, and arthropathy occurring during long-term treatment. We report here a patient with sinuatrial disease who developed four manifestations of amiodarone toxicity, including proximal motor neuropathy, pneumonitis with pleural effusions, pericardial effusion - a previously unrecorded side-effect, and a photosensitive skin eruption. These all resolved with steroid therapy after withdrawal of the drug. Reprint requests to: Dr. M. Honey, Department U.K. ’ Present address: Hammersmith Hospital, London,
0167-5273/85/$03.30
of Cardiology,
Brompton
Hospital,
U.K.
0 1985 Elsevier Science Publishers
B.V. (Biomedical
Division)
London
SW3,
82
Case Report A 29-year-old man gave an B-month history of frequent attacks of rapid palpitation. Electrocardiograms had shown paroxysmal atria1 flutter and fibrillation. Previous treatment had been ineffective. Twenty-four-hour electrocardiographic recordings showed sinus rhythm with heart rate ranging from 22 to 56/min, frequent conducted and blocked atria1 premature beats, paroxysms of atrial fibrillation and of atria1 flutter, and a period of asystole of 6 set duration following termination of a paroxysm of atria1 flutter. He was treated with amiodarone, initially in a dose of 600 mg daily, reducing to 400 mg daily. On this treatment he continued to have frequent paroxysms of atria1 flutter or fibrillation, and further 24-hr ECGs showed many sinus pauses. A permanent endocardial pacing system (WI) (Medtronic Spectrax-SX, Model 5985) was implanted after 2 months of treatment. Following pacemaker implantation amiodarone dosage was progressively increased to 1 g daily with concurrent administration of first quinidine 500 mg twice a day (Kinidin durules) and then atenolol 50 mg daily, with eventual successful control of tachyarrhythmias; for 7 months, he continued to take 800 mg amiodarone daily with no recurrence of rapid palpitation. After 9 months of treatment he complained of increasing muscular weakness and unsteadiness, pleuritic chest pain and breathlessness, nausea, vomiting, and weight loss, and excessive facial sunburn, and was readmitted to hospital. On examination, he was febrile (38-39”(Z), and the skin was pigmented. He was in a paced rhythm at ‘IO/mm and there was no clinical abnormality in the cardiovascular system. Blood pressure was 150/70 without pulsus paradoxus. There were bilateral pleural effusions. There was pronounced proximal muscle weakness more severe in the upper than in the lower limbs, but tendon reflexes were normal and plantar responses flexor; there was no sensory loss. Chest X-ray showed diffuse patchy shadowing throughout both lung fields, bilateral pleural effusions, and cardiac enlargement (CTR 0.56) (Fig. 1). Electrocardiogram showed paced and conducted beats with appropriate inhibition, and ST depression in conducted beats. On a formal treadmill exercise test (Bruce protocol) he was stopped during stage 2 by breathlessness and weakness of the legs. An echocardiogram (M-mode and cross-sectional) showed normal left ventricular cavity dimensions and wall movement, normal valves, and a posterior pericardial effusion (Fig. 1). Pulmonary function tests (Table 1) showed reduced lung volumes consistent with a restrictive ventilatory defect. Full blood count, blood urea and plasma electrolytes, liver function tests, and thyroid function tests (T4 116 nmol/l, FTI 115) were normal. ESR was 65 mm in 1 hr. Haemagglutination test for rheumatoid factor and ANF were negative. C-reactive protein was increased (280 mg/l). Serum angiotensin converting enzyme was normal (46 nmol/ml per mm). Plasma amiodarone and desethylamiodarone were 4.4 and 7.5 mg/l respectively. Fibreoptic bronchoscopy showed no abnormality; transbronchial lung biopsy showed filling of alveoli with foamy macrophages but no granulomata. Pleural biopsy showed inflammatory changes only. A left thoracotomy showed that the pleural space was obliterated by fibrinous and oedematous vascular adhesions; the
Fig. 1. Above: chest radiograph. Below: M-mode echocardiogram showing (EFF). AV = aortic valve; EFF = pericardial effusion; LV = left ventricular
posterior pericardial effusion cavity; MV = mitral valve.
84 TABLE 1 Lung function test results.
FEY (mQ FVC (ml) TLC (ml) DLCO (Sl units) KC0 (SI units)
Pre-treatment
1 month
3 months
4 months
2150 3020 3660 5.13 1.55
2480 2 820 4350 6.36 1.71
2470 3550 4690 7.83 1.89
2480 3450 4890 8.46 1.99
was turgid containing yellow nodules and the pericardium contained a small quantity of clear fluid. Open lung biopsy showed changes which are described in detail by Costa-Jussa et al. [32], the appearances being those of an organizing lipid pneumonia with filling of alveoli by foamy macrophages. Pericardial biopsy showed slight thickening by granulation tissue and organising fibrin on the surface. Cultures of sputum, pleural fluid, biopsy material from lung, pleura, pericardium, and urine were all negative for M tuberculosis, and no pathogenic fungi were isolated. Nerve conduction studies (National Hospital for Nervous Diseases) showed features of a predominantly motor neuropathy, with minimal sensory nerve abnormalities. There were electromyographic changes of chronic partial denervation in both proximal and distal muscle groups. Sural nerve biopsy showed changes previously reported in cases of amiodarone neuropathy. Muscle biopsy (vastus medialis) showed changes indicating denervation. The clinical features and results of the investigations suggested a diagnosis of amiodarone toxicity with pneumonitis and motor neuropathy. No other aetiological agent was identified. Amiodarone was therefore discontinued. Treatment with prednisolone (60 mg daily) was started 12 days later, reducing to 40 mg daily after 2 weeks; subsequently the dose was progressively reduced and steroid therapy was finally discontinued after eight months’ treatment. There was rapid improvement in breathlessness with return to normal exercise tolerance within 3 months. Muscle power also improved rapidly during the first 2 weeks of treatment, though full clinical recovery took 6 months. Nerve conduction studies after 3 months of treatment showed improvement in motor conduction velocity. Serial chest X-rays showed progressive clearing of pulmonary shadowing and pleural effusions with complete resolution except for obliteration of the left costophrenic angle within 3.5 months. Concurrently heart size returned to normal and pericardial effusion was no longer demonstrable by echocardiography. Lung function tests also showed improvement (Table 1).
lung
Discussion This patient developed lung disease and proximal motor neuropathy while on treatment with amiodarone. Because both of these manifestations of amiodarone toxicity had previously been described, because no other cause was found for their
85
occurrence in this case, and because they regressed after stopping the drug and steroid administration, there can be no doubt that they should be attributed to the drug. Pericardial effusion has not previously been recorded as a side-effect of treatment with amiodarone. There was no echocardiographic evidence of left ventricular dysfunction and there was no response to diuretics given before prednisolone was started; thus, the radiological changes could not be attributed to left ventricular failure. Previous descriptions of biopsy or post-mortem histology in cases of amiodarone pneumonitis [1,11,20,21,29] refer to interstitial fibrosis, organising pneumonitis, and bronchiolitis obliterans, or to the occurrence of alveolar exudation comprising hyperplastic pneumocytes and chronic inflammatory cells. The histological appearances in our case however were similar to those reported in experimental animals after administration of iprindole [30] or chlorphentermine [31]. In an experimental study of amiodarone toxicity in rats, using very large doses (450 mg/day), Costa-Jussa et al. [32] have observed giant foamy alveolar macrophages, containing lamellated bodies, characteristic of phospholipid accumulation in drug-induced lipidoses. It is apparent that amiodarone pneumonitis is a clearly defined entity with the early appearance of foamy microphages in the alveoli and later organisation and interstitial fibrosis. In 48 out of a total of 60 reported cases (including our own) of amiodarone pneumonitis, the dose of amiodarone was stated. In 20 the daily maintenance dose was 400 mg or less and in 28 600 mg or more; in only 3 was the daily dose only 200 mg. Information about the duration of amiodarone treatment is available in 40 cases; this was 1 year or more in 12, between 6 and 11 months in 11, and < 6 months in 17. Of 13 patients in whom both dose and duration of treatment are known, and in whom the daily dose was 400 mg or less, 8 had received the drug for one year or more. These observations give support to the suggestion that severe side-effects of amiodarone are much less likely to occur when the daily dose is no more than 400 mg [15,33]; at this dose level, however, duration of treatment may also be important. The sex of the patient was stated in only 31 cases; 24 were men and only 7 women. This male preponderance may have arisen because relatively large doses of the drug were used predominantly in patients with severe coronary disease and resistant ventricular tachyarrhythmias. The occurrence of amiodarone pneumonitis does not seem to be related to the nature of the underlying heart disease nor to be dependent on the presence of associated pulmonary congestion resulting from heart failure. Even in patients with a history of previous heart failure, pulmonary artery wedge pressure has been found to be normal. Thirty-seven of the reported cases (including our patient) received steroid therapy. Amiodarone was stopped in 34; 24 of these made a complete recovery, but in 5 recovery was only partial. In 2 of the 5 who died, death was from respiratory failure, but the other 3 died from other causes (late cardiac arrest in one, opportunistic lung infections in 2). Three patients were treated with steroids but continued amiodarone; of these one died and 2 improved. In another patient, amiodarone was restarted; recurrence of pneumonitis was controlled by an increase in steroid dose [23]. Five patients died while still taking amiodarone without receiving steroid therapy. Five
patients discontinued amiodarone but received no steroid therapy; 2 died but 3 recovered. In our case, radiological improvement was apparent within days of starting steroid treatment, though complete resolution took 3 months. Likewise clinical recovery of both pneumonitis and motor neuropathy started soon after initiation of steroid treatment, though full recovery of muscle power took 6 months. The early improvement cannot be attributed to withdrawal of amiodarone alone, as there was no improvement during the 11 days before steroid therapy was started. Elimination of amiodarone and of its metabolite desethyl amiodarone is extremely slow, with plasma elimination half-life averaging 53 days in 8 patients studied by Holt et al. [34], although Haffajee et al. [6] reported a shorter elimination half-life in 3 patients. Thus, prompt reversal of side-effects cannot be expected after withdrawal of drug alone. Furthermore, steroid therapy must necessarily be continued for many weeks or months while the drug remains in the blood and tissues. In our patient the plasma level of amiodarone at the time drug administration was discontinued was 4.4 mg/l; although the plasma level was not measured again, it is possible that this was still within the therapeutic range (above 1 mg/l) 3 months later. It is likely that slow recovery is due not only to slow clearance of the drug but also to slow resolution of pathological changes in the lung; even slower recovery from the motor neuropathy is probably related to the time-course of regeneration of myelin and of denervated and atrophic muscle. It has been shown in one patient that clearance of the drug can be expedited by plasma exchange to remove circulating immune complexes, with resulting improvement in clinical response [27], but these observations have not yet been confirmed. The suggestion that amiodarone can be restarted under steroid cover seems unwise, however intractable the tachyarrhythmia. Amiodarone pneumonitis may be lethal if unrecognised and untreated. It is vital therefore to recognise it at an early stage; extra vigilance is necessary when the maintenance dose exceeds 400 mg daily. Increasing dyspnoea and radiological abnormalities should not be attributed to pulmonary oedema unless there is other evidence of heart failure or prompt response to diuretic therapy. Measurement of pulmonary artery and wedge pressure may be necessary if doubt remains. Effective treatment must include prompt withdrawal of amiodarone and institution of steroid therapy, which may need to be continued in relatively high doses during the period of weeks or months before the drug is cleared from plasma and tissues. Acknowledgments We thank Dr. John Morgan-Hughes, Dr. Jean Jacobs, and Dr. N.M.F. Murray for the neurological assessment and investigations, and Professor Bryan Corrin for his report on the pulmonary histopathology. References 1 Heger JJ, Prystowsky EN, Jackman WM, et al. Amiodarone: clinical efficacy and electrophysiology during long-term therapy for recurrent ventricular tachycardia or ventricular fibrillation. N Engl J Med 1981;305:539-545.
87 2 Waxman HL, Groh WC, Marchlinski FE, et al. Amiodarone for control of sustained ventricular tachyarrhythmia: clinical and electrophysiologic effects in 51 patients. Am J Cardiol 1982;50:1066-1074. 3 Fogoros RN, Anderson KP, Winkle RA, Swerdlow CD, Mason JW. Amiodarone: clinical efficacy and toxicity in 96 patients with recurrent drug-refractory arrhythmias. Circulation 1983;68:88-94. 4 Graboys TB, Podrid PJ, Lown B. Efficacy of amiodarone for refractory supraventricular arrhythmias. Am Heart J 1983;106:870-875. 5 Heger JJ, Prystowsky EN, Zipes DP. Clinical efficacy of amiodarone in treatment of recurrent ventricular tachycardia and ventricular fibrillation. Am Heart J 1983;106:887-893. 6 Haffajee CI, Love JC, Canada AT, Lesko LJ, Asdourian G, Alpert JS. Clinical pharmacokinetics and efficacy of amiodarone for refractory tachyarrhythmias. Circulation 1983;67:1347-1355. 7 Harris L, McKenna WJ, Rowland E, Holt DW, Storey GCA, Krikler DM. Side effects of long-term amiodarone therapy. Circulation 1983;67:45-51. 8 Rotmensch HH, Liron M, Tupilski M, Laniado S. Possible association of pneumonitis with amiodarone therapy. Am Heart J 1980;100:412-413. 9 Riley SA, Williams SE. Cooke NJ. Alveolitis after treatment with amiodarone. Br Med J 1982;284:161-162. 10 Wright AJ, Brackenridge RG. Pulmonary infiltration and bone marrow depression complicating treatment with amiodarone. Br Med J 1982;284:1303. 11 Sobol S, Rakita L. Pneumonitis and pulmonary fibrosis associated with amiodarone treatment: a possible complication of a new antiarrhythmic drug. Circulation 1982;65:819-824. 12 Morera J, Vidal R, Morel1 F, Ruiz J, Bemado Ll, Laporte JR. Pulmonary fibrosis and amiodarone. Br Med J 1982;285:895. 13 Schlaeffer F. Gold B, Hirsch M, Keynan A. Case of interstitial pneumonitis during amiodarone therapy. Israel J Med Sci 1982;18:809-811. 14 Marchlinski FE, Gansler TS, Waxman HL, Josephson ME. Amiodarone pulmonary toxicity. Ann Intern Med 1982;50:1066-1074. 15 Rotmensch HH, Belhassen B, Ferguson RK. Amiodarone - benefits and risks in perspective. Am Heart J 1982;104:1117-1119. 16 Morera J, Vidal R, Morel1 F, Ruiz J, Bernado Ll, Laporte JR. Amiodarone and pulmonary fibrosis. Eur J Clin Pharmacol 1983;23:591-593. 17 Suarez LD, Poderoso JJ, Elsner B, Bunster AM, Esteva H, Bellotti M. Subacute pneumopathy during amiodarone therapy. Chest 1983;83:566-568. 18 Rakita L, Sobol SM, Mostow N, Vrobel T. Amiodarone pulmonary toxicity. Am Heart J 1983;106:906-914. 19 Manresa F, Cequier A, Escarabill J, Perez Ayuso MJ, Sabater X, Gausi C. Amiodarone and lung function. Lancet 1983;2:1367. 20 Quyyumi AA, Ormerod LP, Clarke SW, Evans TR, Ward RL. Pulmonary fibrosis - a serious side-effect of amiodarone therapy. Eur Heart J 1983;4:521-524. 21 McGovern B, Garan H, Kelly E, Ruskin JN. Adverse reactions during treatment with amiodarone hydrochloride. Br Med J 1983;287:175-180. 22 Dake MD, Golden JA. Amiodarone and pulmonary effects. Ann Intern Med 1983;98:1028. 23 Zaher C, Hamer A, Peter M, Mandel W. Low-dose steroid therapy for prophylaxis of amiodarone induced pulmonary infiltrates. N Engl J Med 1983;308:779. 24 Jirik FR, Henning R, Huckell VF, Ostrow DVN. Diffuse alveolar damage associated with amiodarone therapy. Can Med Assoc J 1983;128:1192-1195. 25 Chebat J, Caubarrere I. Pneumopathie grave et amiodarone. Therapie 1983;38:111-112. 26 Gefter WB, Epstein DM, Pietra GG, Miller WT. Lung disease caused by amiodarone. a new antiarrhythmic agent. Radiology 1983;147:339-344. 27 Russell DC, Paton L, Douglas AS. Amiodarone associated alveolitis and polyarthropathy: treatment by plasma exchange. Br Heart J 1983;50:491-494. 28 Van Zandwijk N, Darmanata JI, Diiren DR, Alberts C, Durrer D, Wagenvoort CA. Amiodarone pneumonitis. Eur J Respir Dis 1983;64:313-317. 29 Darmanata JI, Van Zandwijk N, Diiren DR, et al. Amiodarone pneumonitis: three further cases with a review of published reports. Thorax 1984;39:57-64.
88 30 Vijeyaratnam GS, Corrin B. Pulmonary histiocytosis simulating desquamative interstitial pneumonia in rats receiving oral iprindole. J Path 1972;108:105-113. 31 Heath D, Smith P, Haselton PS. Effects of chlorphentermine on the rat lung. Thorax 1973;28:551-558. 32 Costa-Jussk F, Corrin B, Jacobs JM. Amiodarone lung toxicity: a human and experimental study. J Path01 1984;143:73-79. 33 Sideris DA, Makris D, Boukis M, et al. Long-term low-dose amiodarone treatment. Eur Heart J 1984;5:(suppl B):131. 34 Holt DW, Tucker GT, Jackson PR, Storey GCA. Amiodarone pharmacokinetics. Am Heart J 1983;106:840-846.
81
IJC 00252
Pneumonitis with pleural and pericardial effusion and neuropathy during amiodarone therapy Bernard Clarke I, David E. Ward and Michael Honey Department (Received
of Cardioiop,
Brompton Hospital, London, U.K.
26 March 1984; revision accepted
12 December
1984)
Clarke B, Ward DE, Honey M. Pneumonitis with pleural and pericardial effusion and neuropathy during amiodarone therapy. Int J Cardiol 1985;8:81-88. A patient with sinuatrial disease and implanted pacemaker was treated with amiodarone (maximum dose 1000 mg, maintenance dose 800 mg daily) for 10 months, for control of supraventricular tachyarrhythmias. He developed pneumonitis, pleural and pericardial effusions, and a predominantly proximal motor neuropathy. Immediate but gradual improvement followed withdrawal of amiodarone and treatment with prednisolone. Review of this and preiiously reported cases indicates the need for early diagnosis of amiodarone pneumonitis, immediate withdrawal of amiodarone, and prompt but continued steroid therapy to ensure full recovery.
(Key words: side-effects; drug treatment; pharmacology)
Amiodarone is a potent anti-arrhythmic agent, effective against a variety of ventricular and supraventricular tachyarrhythmias. There have however been many reports of side-effects, including corneal microcrystalline deposits of the drug, photosensitive skin eruptions and abnormal pigmentation, disturbances of thyroid function, pneumonitis [l-5,7,8-29], neuropathy, and arthropathy occurring during long-term treatment. We report here a patient with sinuatrial disease who developed four manifestations of amiodarone toxicity, including proximal motor neuropathy, pneumonitis with pleural effusions, pericardial effusion - a previously unrecorded side-effect, and a photosensitive skin eruption. These all resolved with steroid therapy after withdrawal of the drug. Reprint requests to: Dr. M. Honey, Department U.K. ’ Present address: Hammersmith Hospital, London,
0167-5273/85/$03.30
of Cardiology,
Brompton
Hospital,
U.K.
0 1985 Elsevier Science Publishers
B.V. (Biomedical
Division)
London
SW3,
82
Case Report A 29-year-old man gave an B-month history of frequent attacks of rapid palpitation. Electrocardiograms had shown paroxysmal atria1 flutter and fibrillation. Previous treatment had been ineffective. Twenty-four-hour electrocardiographic recordings showed sinus rhythm with heart rate ranging from 22 to 56/min, frequent conducted and blocked atria1 premature beats, paroxysms of atrial fibrillation and of atria1 flutter, and a period of asystole of 6 set duration following termination of a paroxysm of atria1 flutter. He was treated with amiodarone, initially in a dose of 600 mg daily, reducing to 400 mg daily. On this treatment he continued to have frequent paroxysms of atria1 flutter or fibrillation, and further 24-hr ECGs showed many sinus pauses. A permanent endocardial pacing system (WI) (Medtronic Spectrax-SX, Model 5985) was implanted after 2 months of treatment. Following pacemaker implantation amiodarone dosage was progressively increased to 1 g daily with concurrent administration of first quinidine 500 mg twice a day (Kinidin durules) and then atenolol 50 mg daily, with eventual successful control of tachyarrhythmias; for 7 months, he continued to take 800 mg amiodarone daily with no recurrence of rapid palpitation. After 9 months of treatment he complained of increasing muscular weakness and unsteadiness, pleuritic chest pain and breathlessness, nausea, vomiting, and weight loss, and excessive facial sunburn, and was readmitted to hospital. On examination, he was febrile (38-39”(Z), and the skin was pigmented. He was in a paced rhythm at ‘IO/mm and there was no clinical abnormality in the cardiovascular system. Blood pressure was 150/70 without pulsus paradoxus. There were bilateral pleural effusions. There was pronounced proximal muscle weakness more severe in the upper than in the lower limbs, but tendon reflexes were normal and plantar responses flexor; there was no sensory loss. Chest X-ray showed diffuse patchy shadowing throughout both lung fields, bilateral pleural effusions, and cardiac enlargement (CTR 0.56) (Fig. 1). Electrocardiogram showed paced and conducted beats with appropriate inhibition, and ST depression in conducted beats. On a formal treadmill exercise test (Bruce protocol) he was stopped during stage 2 by breathlessness and weakness of the legs. An echocardiogram (M-mode and cross-sectional) showed normal left ventricular cavity dimensions and wall movement, normal valves, and a posterior pericardial effusion (Fig. 1). Pulmonary function tests (Table 1) showed reduced lung volumes consistent with a restrictive ventilatory defect. Full blood count, blood urea and plasma electrolytes, liver function tests, and thyroid function tests (T4 116 nmol/l, FTI 115) were normal. ESR was 65 mm in 1 hr. Haemagglutination test for rheumatoid factor and ANF were negative. C-reactive protein was increased (280 mg/l). Serum angiotensin converting enzyme was normal (46 nmol/ml per mm). Plasma amiodarone and desethylamiodarone were 4.4 and 7.5 mg/l respectively. Fibreoptic bronchoscopy showed no abnormality; transbronchial lung biopsy showed filling of alveoli with foamy macrophages but no granulomata. Pleural biopsy showed inflammatory changes only. A left thoracotomy showed that the pleural space was obliterated by fibrinous and oedematous vascular adhesions; the
Fig. 1. Above: chest radiograph. Below: M-mode echocardiogram showing (EFF). AV = aortic valve; EFF = pericardial effusion; LV = left ventricular
posterior pericardial effusion cavity; MV = mitral valve.
84 TABLE 1 Lung function test results.
FEY (mQ FVC (ml) TLC (ml) DLCO (Sl units) KC0 (SI units)
Pre-treatment
1 month
3 months
4 months
2150 3020 3660 5.13 1.55
2480 2 820 4350 6.36 1.71
2470 3550 4690 7.83 1.89
2480 3450 4890 8.46 1.99
was turgid containing yellow nodules and the pericardium contained a small quantity of clear fluid. Open lung biopsy showed changes which are described in detail by Costa-Jussa et al. [32], the appearances being those of an organizing lipid pneumonia with filling of alveoli by foamy macrophages. Pericardial biopsy showed slight thickening by granulation tissue and organising fibrin on the surface. Cultures of sputum, pleural fluid, biopsy material from lung, pleura, pericardium, and urine were all negative for M tuberculosis, and no pathogenic fungi were isolated. Nerve conduction studies (National Hospital for Nervous Diseases) showed features of a predominantly motor neuropathy, with minimal sensory nerve abnormalities. There were electromyographic changes of chronic partial denervation in both proximal and distal muscle groups. Sural nerve biopsy showed changes previously reported in cases of amiodarone neuropathy. Muscle biopsy (vastus medialis) showed changes indicating denervation. The clinical features and results of the investigations suggested a diagnosis of amiodarone toxicity with pneumonitis and motor neuropathy. No other aetiological agent was identified. Amiodarone was therefore discontinued. Treatment with prednisolone (60 mg daily) was started 12 days later, reducing to 40 mg daily after 2 weeks; subsequently the dose was progressively reduced and steroid therapy was finally discontinued after eight months’ treatment. There was rapid improvement in breathlessness with return to normal exercise tolerance within 3 months. Muscle power also improved rapidly during the first 2 weeks of treatment, though full clinical recovery took 6 months. Nerve conduction studies after 3 months of treatment showed improvement in motor conduction velocity. Serial chest X-rays showed progressive clearing of pulmonary shadowing and pleural effusions with complete resolution except for obliteration of the left costophrenic angle within 3.5 months. Concurrently heart size returned to normal and pericardial effusion was no longer demonstrable by echocardiography. Lung function tests also showed improvement (Table 1).
lung
Discussion This patient developed lung disease and proximal motor neuropathy while on treatment with amiodarone. Because both of these manifestations of amiodarone toxicity had previously been described, because no other cause was found for their
85
occurrence in this case, and because they regressed after stopping the drug and steroid administration, there can be no doubt that they should be attributed to the drug. Pericardial effusion has not previously been recorded as a side-effect of treatment with amiodarone. There was no echocardiographic evidence of left ventricular dysfunction and there was no response to diuretics given before prednisolone was started; thus, the radiological changes could not be attributed to left ventricular failure. Previous descriptions of biopsy or post-mortem histology in cases of amiodarone pneumonitis [1,11,20,21,29] refer to interstitial fibrosis, organising pneumonitis, and bronchiolitis obliterans, or to the occurrence of alveolar exudation comprising hyperplastic pneumocytes and chronic inflammatory cells. The histological appearances in our case however were similar to those reported in experimental animals after administration of iprindole [30] or chlorphentermine [31]. In an experimental study of amiodarone toxicity in rats, using very large doses (450 mg/day), Costa-Jussa et al. [32] have observed giant foamy alveolar macrophages, containing lamellated bodies, characteristic of phospholipid accumulation in drug-induced lipidoses. It is apparent that amiodarone pneumonitis is a clearly defined entity with the early appearance of foamy microphages in the alveoli and later organisation and interstitial fibrosis. In 48 out of a total of 60 reported cases (including our own) of amiodarone pneumonitis, the dose of amiodarone was stated. In 20 the daily maintenance dose was 400 mg or less and in 28 600 mg or more; in only 3 was the daily dose only 200 mg. Information about the duration of amiodarone treatment is available in 40 cases; this was 1 year or more in 12, between 6 and 11 months in 11, and < 6 months in 17. Of 13 patients in whom both dose and duration of treatment are known, and in whom the daily dose was 400 mg or less, 8 had received the drug for one year or more. These observations give support to the suggestion that severe side-effects of amiodarone are much less likely to occur when the daily dose is no more than 400 mg [15,33]; at this dose level, however, duration of treatment may also be important. The sex of the patient was stated in only 31 cases; 24 were men and only 7 women. This male preponderance may have arisen because relatively large doses of the drug were used predominantly in patients with severe coronary disease and resistant ventricular tachyarrhythmias. The occurrence of amiodarone pneumonitis does not seem to be related to the nature of the underlying heart disease nor to be dependent on the presence of associated pulmonary congestion resulting from heart failure. Even in patients with a history of previous heart failure, pulmonary artery wedge pressure has been found to be normal. Thirty-seven of the reported cases (including our patient) received steroid therapy. Amiodarone was stopped in 34; 24 of these made a complete recovery, but in 5 recovery was only partial. In 2 of the 5 who died, death was from respiratory failure, but the other 3 died from other causes (late cardiac arrest in one, opportunistic lung infections in 2). Three patients were treated with steroids but continued amiodarone; of these one died and 2 improved. In another patient, amiodarone was restarted; recurrence of pneumonitis was controlled by an increase in steroid dose [23]. Five patients died while still taking amiodarone without receiving steroid therapy. Five
patients discontinued amiodarone but received no steroid therapy; 2 died but 3 recovered. In our case, radiological improvement was apparent within days of starting steroid treatment, though complete resolution took 3 months. Likewise clinical recovery of both pneumonitis and motor neuropathy started soon after initiation of steroid treatment, though full recovery of muscle power took 6 months. The early improvement cannot be attributed to withdrawal of amiodarone alone, as there was no improvement during the 11 days before steroid therapy was started. Elimination of amiodarone and of its metabolite desethyl amiodarone is extremely slow, with plasma elimination half-life averaging 53 days in 8 patients studied by Holt et al. [34], although Haffajee et al. [6] reported a shorter elimination half-life in 3 patients. Thus, prompt reversal of side-effects cannot be expected after withdrawal of drug alone. Furthermore, steroid therapy must necessarily be continued for many weeks or months while the drug remains in the blood and tissues. In our patient the plasma level of amiodarone at the time drug administration was discontinued was 4.4 mg/l; although the plasma level was not measured again, it is possible that this was still within the therapeutic range (above 1 mg/l) 3 months later. It is likely that slow recovery is due not only to slow clearance of the drug but also to slow resolution of pathological changes in the lung; even slower recovery from the motor neuropathy is probably related to the time-course of regeneration of myelin and of denervated and atrophic muscle. It has been shown in one patient that clearance of the drug can be expedited by plasma exchange to remove circulating immune complexes, with resulting improvement in clinical response [27], but these observations have not yet been confirmed. The suggestion that amiodarone can be restarted under steroid cover seems unwise, however intractable the tachyarrhythmia. Amiodarone pneumonitis may be lethal if unrecognised and untreated. It is vital therefore to recognise it at an early stage; extra vigilance is necessary when the maintenance dose exceeds 400 mg daily. Increasing dyspnoea and radiological abnormalities should not be attributed to pulmonary oedema unless there is other evidence of heart failure or prompt response to diuretic therapy. Measurement of pulmonary artery and wedge pressure may be necessary if doubt remains. Effective treatment must include prompt withdrawal of amiodarone and institution of steroid therapy, which may need to be continued in relatively high doses during the period of weeks or months before the drug is cleared from plasma and tissues. Acknowledgments We thank Dr. John Morgan-Hughes, Dr. Jean Jacobs, and Dr. N.M.F. Murray for the neurological assessment and investigations, and Professor Bryan Corrin for his report on the pulmonary histopathology. References 1 Heger JJ, Prystowsky EN, Jackman WM, et al. Amiodarone: clinical efficacy and electrophysiology during long-term therapy for recurrent ventricular tachycardia or ventricular fibrillation. N Engl J Med 1981;305:539-545.
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