Pulmonary Fibrosis Associated with Tocainide: Report of a Case with Literature Review 1 •2
LAURIE FEINBERG, WILLIAM D. TRAVIS, VICTOR FERRANS, NORIKO SATO, and HORACE F. BERNTON
Introduction 'L>cainide is a new, oral Class I an tiarrhythmic used for treating ventricu lar arrhythmias (1-3). It was approved for marketing in the United States in November 1984, but it has been used in thiscountry in clinical trials since the mid-1970s. Tocainide is a primary amine analogue of lidocaine and has similar electrophysiologic properties, but it differs in its oral bioavailability and plasma half-life of about 15 h (1-3). The use of tocainide has been associated with a variety of side effects, most commonly, dizziness, tremor, paresthesia, and vomiting (4-7), but also with a low incidence of agranulocytosis (8-10) and pulmonary toxicity (5, 11-14). Wereport the clinical and pathologic featur es of a case of severe pulmonary fibrosis tha t developed after 14months of tocain ide therapy.
SUMMARY A report is presented of an 85-yr-old woman who developed severe pulmonary fibrosis while receiving tocainide for treatment of ventricular arrhythmias. Severe bilateral interst itial fibrosis was documented in this patient by open lung biopsy and at autopsy. Review of the literature revealed other cases with an association between the use of tocainide and the development of pulmonary complications such as pulmonary fibrosis and Interstitial pneumonitis, and suggested that clinical improvement occurs when the correct diagnosis is made early and tocainlde therapy Is stopped Immediately. Because tocainide is currently being Widely used for the treatment of ventricular arrhythmias, the pulmonary status of patients receiving tocalnide should be monitored closely. Hopefully, awareness of this potential complication of tocainide therapy will minimize the number of cases of serious pulmonary toxicity. AM REV RESPIR DIS 1990; 141:505-508
A
Case Report An 85-yr-old white woman with a long history of hypertension, congestive heart failure, and syncopal episodes, was started on 400 mg of toca inide every 8 h for ventricular arrhythmias. These arrhythmias had been treated with quinidine for the previous 5 yr. Her past medical histo ry was also remarkable for an episode of pneumonia requir ing a 2-wk hospitalization 7 yr previousl y. She was a nonsmoker. Her chest radiograph before starting tocainide treatment revealed card iomegaly and mild changes related to congestive heart failure (figu re IA). Her cardiac medications were diltiazem 60 mg every 8 h, digox in 0.125 mg daily, and nitroglycerin as needed. For osteoarthritis, she used ibuprofen and later indomethacin. She also was receiving ranitidine, and later cimetidine, and Maa lox for a previou s gastric ulcer. Tocainide, 400 mg every 8 h, was admin istered over a 14-month per iod during which her cardiac stat us was stab le with only mild perip heral edem a and no significant pulmonary signs or sym ptoms except for fine rales in her lung bases.
B
(Received in original form April 6. 1989 and in revised form July 20, 1989) I From the Mayo Medical School, Rochester, Minnesota, the Laboratory of Pathology, National Cancer Inst itute , and Ultrastructure Sect ion, Pathology Branch, National Heart, Lung , and Blood Institu te, and Internal Med icine, Suburban Ho spital , Beth esda , Maryland . , Request s for reprints should be addressed to William D. Travis, M.D., Laboratory o f Pathology, National Ca ncer Institute, National Inst itutes o f Heal th, Building 10, Room 2N212, Bethesda, MD 20892. J Food and Dr ug Admin istration: Adverse Drug Reporting System, 1988. Public Health Service, Rockville, Maryland.
Fig. 1. A. Chest radiographshortlybefore initiation of tocainide therapy shows strikingcardiomegaly. withnegligible pulmonaryinterstitial markings. B. Chest radiograph 15 months later shows extensive.bilateralretlculonodular interstitial infiltrates.
Several days before her final adm ission , the patient developed d yspnea without orthopnea, a mild productive cough, and night sweats. On admis sion, she was-afebrile and had bilateral, dr y rales from apex to base. Her ju gular venou s pressure was not
elevated, and she had slight pedal edema but no orga nomega ly. Ca rdiac examination revealed a Grade II/VI blowing systolic murmur, and an 5 J gallop. She had dyspnea at rest, relieved by 2 L/min o f oxygen by nasal cannula.
505
506
CASE REPORT
Her admission chest radiograph showed cardiomegaly with diffuse bilateral nodular and interstitial pulmonary infiltrates (figure IB) greater on the right than on the left side . While receiving 2 Llmin of oxygen, her arterial blood had a pH of 7.48, a Po, of 62 mm Hg, and a Pco, of 28 mm Hg . Two days later, her dyspnea worsened, and prednisone 60 mg per day and isoniazid 300 mg per day were started. While receiving 5 L/min of oxygen , her arterial blood had a pH of 7.45, a Po, of 58 mm Hg, and a Pco, of 36 mm Hg without improvement in symptoms. Eleven days after admission, an open lung biopsy of the lingula was performed. Histologic sections of lung showed severe inter stitial fibrosi s characterized by extensive areas of advanced fibrosis with remodeling of lung architecture (figure 2A). In addition, areas of loo se, intraluminal and interstitial fibrosis were seen (figure 28 and C). Interstitial chronic inflammation was mild and consisted primarily of lymphocytes with occasional plasma cells and rare eosinophils. Cuboidal change of Type II pneumocytes was focally present. Alveolar macrophages were prominent adjacent to areas of fibrosis, and some showed foamy cytoplasm. The pathologic findings shared many features with those seen in idiopathic pulmonary fibrosis . Postoperatively the patient became febrile to 38.4 0 C. After 4 days, her dyspnea worsened, and she developed pulmonary edema with moderate pedal edema . While receiving 4 L/min of oxygen, the arterial blood had a pH of 7.45, a Po, of 35.5 mm Hg, and a Pco, of 39.1 mm Hg. She was treated with 100070 oxygen and furosemide 40 mg intravenously, with improvement of her Po, to 50.2 mm Hg , She continued to be severely dyspneic and was unresponsive to high doses of intravenous steroids. She died 3 days later from respiratory failure. At autopsy, gross examination of the lung s revealed very firm parenchyma, with marked interstitial thickening and focal honeycomb changes. The lung weights were increased: right, 900 g; left, 570 g. A right lower lobe bronchopneumonia was evident by white-tan areas of consolidation. Histologically, in addition to the bronchopneumonia, there was an extensive background of advanced interstitial fibrosis . Death was attributed to respiratory failure secondary to bilateral lower lobe acute bronchopneumonia superimposed on severe interstitial fibrosis.
Discussion Pulmonary toxicity has been previously recognized as a complication of tocainide therapy (5, 11-14). The product label approved by the Food and Drug Administration (FDA) includes a precaution that pulmonary fibrosis, interstitial pneumonitis, and other pulmonary conditions have occurred in patients receiving tocainide (15). However, only a few reports (table 1) have drawn attention to this potential side effect (5, 11-14). These reports provide little pathologic details about the pulmonary toxic effects of tocainide. Data presented to the FDA indicate the incidence of tocainide-associated pulmonary fibrosis to be 0.30/0 in the Emergency Use Program (5). Pulmonary toxicity usually occurs in seriously ill patients, with onset 3 to 18 wk after initiation of therapy (5). Since tocainide's approval, approximately 40 reports of pulmonary toxicity have been received by the FDA's adverse drug reaction reporting system. 3 Tocainide is being used with increasing frequency for the treatment of ventriculararrhyth-
Fig. 2. A. Open lung biopsy shows severe interstitial fibrosis characterized by prominent cystic remodeling of lung architecture, bronchiolar proliferation, and mild interstitial chronic inflammation. Hernatoxynn-eosln stain; magnification: x15. B. This area shows bronchiolar proliferation, and extensive interstitial fibrosis character ized by prominent intraluminal loose fibrosiswithareas ofmuralincorporation. Hematoxylin-eosin stain; magnification: x60. C. Higher power reveals a nodular focus of loose, edematous fibrosis protruding into an alveolar space and showing features of mural incorporation into the adjacent interstitium. Reactive alveolar liningcells line the surface on this intraluminal bud. Macrophages and lymphocytes are present in the adjacent alveolar space. Hematoxylin-eosin stain; magnification: x250.
F
77
14
Idiopathic congestive cardiomyopathy; ventricular ectopy
400 mg q.i.d. 6 months
400 mg t.i.d. 2 months
High grade ventricular ectopy; IHD
M
72
12
400 mg q.i.d. 2 months
F
67
13
200-400 mg t.i.d. 8 months
200 mg t.i.d. 12 wk
Dose Duration
Refractory ventricular arrhythmias; Post-AMI
Refractory ventricular arrhythmias; AMI x 2
F
13
58
55
11
History of acute myocardial infarction (AMI)
Cardiac Problem
M
Reference Age No. (yr) Sex
1/369 7
1/72
Incidence
Dyspnea; decreased exercise tolerance; afebrile
Pulmonary Function Tests
New diffuse bilateral infiltrates
Decreased interstitial markings
New diffuse bilateral infiltrates; CT-thin section: interstitial thickening
Stopped tocainide; corticosteroids
Treatment
BAL: PMN, 21 %; normal microbiology. Open lung biopsy: active alveolitis with chronic diffuse interstitial pneumonitis and early fibrosis Interstitial pneumonia; focal intra-alveolar macrophages and fibrin deposition
Pao2 = 52; Peo 2 = 32; pulmonary capillary wedge == 9 mm Hg; right atrial pressure = 2 mm Hg; VC = 1.9 L; TLC = 3.3 L; OLeo = 9.6 ml/min/mm Hg; gallium scan: markedly t activity in lung bases and moderately t in upper lung fields
None
Stopped tocainide; prednisone 60 mg every day
Stopped tocainide; prednisone 60 mg/day for 4 wk then tapered over 2 wk
Stopped tocainide
Transtracheal biopsy: organizing Stopped tocainide; pneumonia suggestive of prednisone hypersensitivity rxn; organizing 80 mg/day, alveolar interstitial fibrosis tapered over 6 wk with moderate alveolar infiltrate
None
Pathology Findings
Increased alveolar ventilation; t AaPo2; + diffusing capacity; t TLC; gallium scan: diffusely positive
Severe hypoxemia Severe + diffusing capacity
Severe hypoxia; severe + diffusing capacity (AaPo2 = 65)
Pulmonary edema Pao2 = 55; Peo 2 = 33 Moderate restrictive defect; + transfer factor; + lung volume
Chest Radiograph
Progressive dyspnea; Diffuse infiltrates decreased exercise tolerance
Rapid onset of dyspnea
Dyspnea
Dyspnea on exertion
Symptoms
SUMMARY OF LITERATURE REPORTS
TABLE 1
Improved over 2 months
Improved symptoms and CXR cleared; improved PFT; + PMN in BAL gallium scan clear 12 wk after stopping tocainide
CXR markedly resolved 1-2 wk after drug stopped; PFT improved
Improved; infiltrate cleared; remains asymptomatic
Improved without tocainide; lung function normalized after steroids
Outcome
....
Q
en
~
~
::u m
Sm
508
mias, as indicated by survey information cited by Arrowsmith and coworkers (16) that 762,000 prescriptions were written in 1986, up from 473,000 in 1985. Thus, it is likely that an increasing number of cases of tocainide pulmonary toxicity will occur, and it is important for clinicians using this drug to be aware of this potential adverse side effect. The pathologic and radiographic findings in our patient, with a normal pretherapy chest radiograph, clearly demonstrate the onset of pulmonary fibrosis while receiving tocainide. These findings confirm previous reports indicating that tocainide is associated with pulmonary toxicity (5, 11-14). The onset of pulmonary symptoms after the initiation of tocainide therapy in the previously reported cases was 1.5 to 8 months (median, 2 months) (table 1). In our patient, pulmonary symptoms first presented 14 months after initiation of tocainide therapy. There is nothing specific about the lung disease or the clinical presentation in our case to prove that the pulmonary fibrosis was caused by tocainide administration, but our patient had no other known predisposing conditions, and to our knowledge she used no other medications associated with the development of pulmonary fibrosis. Pulmonary complications associated with antiarrhythmic medications have become well known in recent years with the widespread use of amiodarone (17). Alveolar "foamy" macrophages are a characteristic finding associated with amiodarone therapy. Interstitial fibrosis may also occur, and in some cases it can be severe. Some alveolar macrophages in the lung biopsy from our patient had foamy cytoplasm, as did some alveolar lining cells. Unfortunately, tissue was not set aside for electron microscopy from either the open lung biopsy or the autopsy. Thus, we were not able
CASE REPORT
to investigate the presence of the characteristic lamellar lysosomal inclusions described in association with amiodarone (17). However, the question of whether tocainide induces similar effects could be studied in future cases using ultrastructural analysis on cells from bronchoalveolar lavage, as has been done with patients receiving amiodarone therapy. The development of severe, irreversible pulmonary fibrosis in our case contrasts with the previous reports of reversible pulmonary toxicity associated with tocainide (table 1). The preceding reports described a shorter duration of therapy and resolution of symptoms after cessation of tocainide treatment, usually in conjunction with steroid therapy (11-14). Unfortunately, in our patient, pulmonary fibrosis was irreversible by the time it was first detected. This case emphasizes the importance of detecting pulmonary changes associated with tocainide as early as possible while they are still potentially reversible. The goal of this report is to alert physicians that patients receiving tocainide should be monitored periodically with chest radiographs for onset of pulmonary fibrosis. Hopefully, awareness of this potential complication of tocainide will reduce the number of cases of serious pulmonary toxicity.
References 1. Holmes B, Brogden RN, Heel RC, Speight TM, Avery GS. Tocainide, a review of its pharmacological properties and therapeutic efficacy. Drugs 1983; 26:93-123. 2. Kutalek SP, Morganroth J, Horowitz LN. Tocainide: a new oral antiarrhythmic agent. Ann Intern Med 1985; 103:387-91. 3. Roden DM, Woosley RL. Drug therapy: tocainide. N Engl J Med 1986; 315:41-5. 4. Hohnloser SH, Lange HW, Raeder EA, Podrid PJ, Lawn B. Short- and long-term therapy with to-
cainide for malignant ventricular tachyarrhythmias. Circulation 1986; 73:143-9. 5. Horn HR, Hadidian Z, Johnson JL, Vassallo HG, Williams JH, Young MD. Safety evaluation of tocainide in the American emergency use program. Am Heart J 1980; 100:1037-40. 6. Mohiuddin SM, Esterbrooks D, Mooss AN, Dahl JM, Hilleman DF. Efficacy and tolerance of tocainide during long-term treatment of malignant ventricular arrhythmias. Clin Cardiol 1987; 10: 457-62. 7. Vermeij P, Hulshof JH. Dose finding of tocainide in the treatment of tinnitus. Int J Clin Pharmacol Ther Toxicol 1986; 24: 207-12. 8. Gertz MA, Garton JP, Jennings WHo Aplastic anemia due to tocainide. N Engl J Med 1986; 314:583-4. 9. Soff GA, Kadin ME. Tocainide-induced reversible agranulocytosis and anemia. Arch Intern Med 1987; 147:598-9. 10. Volosin K, Greenberg RM, Greenspon AJ. Tocainide associated agranulocytosis. Am Heart J 1985; 109:1392-3. 11. Bastian BC, Macfarlane PW, McLauchlan JH, et al. Prospective randomized trial of tocainide in patients following myocardial infarction. Am Heart J 1980; 100:1017-22. 12. Braude AC, Downar E, Chamberlain DW, Rebuck AS. Tocainide-associated interstitial pneumonitis. Thorax 1982; 37:309-10. 13. Perlow GM, Jain BP, Pauker SG, Zarren HS, Wistran DC, Epstein RL. Tocainide-associated interstitial pneumonitis. Ann Intern Med 1981; 94: 489-90. 14. Stein MG, Demarco T, Gamsu G, Finkbeiner W, Golden JA. Computed tomography: pathologic correlation in lung disease due to tocainide. Am Rev Respir Dis 1988; 137:458-60. 15. 1988 Physicians' Desk Reference. Oradell, NJ: Medical Economics Co., 1988; 1398. 16. Arrowsmith JB, Creamer Jl, Bosco L. Severe dermatologic reactions reported after treatment with tocainide. Ann Intern Med 1987; 107:693-6. 17. Martin WJ, Rosenow EC. Amiodarone pulmonary toxicity. Recognition and pathogenesis. Parts I and II. Chest 1988; 93:1067-75 and 1242-8.
LAURIE FEINBERG, WILLIAM D. TRAVIS, VICTOR FERRANS, NORIKO SATO, and HORACE F. BERNTON
Introduction 'L>cainide is a new, oral Class I an tiarrhythmic used for treating ventricu lar arrhythmias (1-3). It was approved for marketing in the United States in November 1984, but it has been used in thiscountry in clinical trials since the mid-1970s. Tocainide is a primary amine analogue of lidocaine and has similar electrophysiologic properties, but it differs in its oral bioavailability and plasma half-life of about 15 h (1-3). The use of tocainide has been associated with a variety of side effects, most commonly, dizziness, tremor, paresthesia, and vomiting (4-7), but also with a low incidence of agranulocytosis (8-10) and pulmonary toxicity (5, 11-14). Wereport the clinical and pathologic featur es of a case of severe pulmonary fibrosis tha t developed after 14months of tocain ide therapy.
SUMMARY A report is presented of an 85-yr-old woman who developed severe pulmonary fibrosis while receiving tocainide for treatment of ventricular arrhythmias. Severe bilateral interst itial fibrosis was documented in this patient by open lung biopsy and at autopsy. Review of the literature revealed other cases with an association between the use of tocainide and the development of pulmonary complications such as pulmonary fibrosis and Interstitial pneumonitis, and suggested that clinical improvement occurs when the correct diagnosis is made early and tocainlde therapy Is stopped Immediately. Because tocainide is currently being Widely used for the treatment of ventricular arrhythmias, the pulmonary status of patients receiving tocalnide should be monitored closely. Hopefully, awareness of this potential complication of tocainide therapy will minimize the number of cases of serious pulmonary toxicity. AM REV RESPIR DIS 1990; 141:505-508
A
Case Report An 85-yr-old white woman with a long history of hypertension, congestive heart failure, and syncopal episodes, was started on 400 mg of toca inide every 8 h for ventricular arrhythmias. These arrhythmias had been treated with quinidine for the previous 5 yr. Her past medical histo ry was also remarkable for an episode of pneumonia requir ing a 2-wk hospitalization 7 yr previousl y. She was a nonsmoker. Her chest radiograph before starting tocainide treatment revealed card iomegaly and mild changes related to congestive heart failure (figu re IA). Her cardiac medications were diltiazem 60 mg every 8 h, digox in 0.125 mg daily, and nitroglycerin as needed. For osteoarthritis, she used ibuprofen and later indomethacin. She also was receiving ranitidine, and later cimetidine, and Maa lox for a previou s gastric ulcer. Tocainide, 400 mg every 8 h, was admin istered over a 14-month per iod during which her cardiac stat us was stab le with only mild perip heral edem a and no significant pulmonary signs or sym ptoms except for fine rales in her lung bases.
B
(Received in original form April 6. 1989 and in revised form July 20, 1989) I From the Mayo Medical School, Rochester, Minnesota, the Laboratory of Pathology, National Cancer Inst itute , and Ultrastructure Sect ion, Pathology Branch, National Heart, Lung , and Blood Institu te, and Internal Med icine, Suburban Ho spital , Beth esda , Maryland . , Request s for reprints should be addressed to William D. Travis, M.D., Laboratory o f Pathology, National Ca ncer Institute, National Inst itutes o f Heal th, Building 10, Room 2N212, Bethesda, MD 20892. J Food and Dr ug Admin istration: Adverse Drug Reporting System, 1988. Public Health Service, Rockville, Maryland.
Fig. 1. A. Chest radiographshortlybefore initiation of tocainide therapy shows strikingcardiomegaly. withnegligible pulmonaryinterstitial markings. B. Chest radiograph 15 months later shows extensive.bilateralretlculonodular interstitial infiltrates.
Several days before her final adm ission , the patient developed d yspnea without orthopnea, a mild productive cough, and night sweats. On admis sion, she was-afebrile and had bilateral, dr y rales from apex to base. Her ju gular venou s pressure was not
elevated, and she had slight pedal edema but no orga nomega ly. Ca rdiac examination revealed a Grade II/VI blowing systolic murmur, and an 5 J gallop. She had dyspnea at rest, relieved by 2 L/min o f oxygen by nasal cannula.
505
506
CASE REPORT
Her admission chest radiograph showed cardiomegaly with diffuse bilateral nodular and interstitial pulmonary infiltrates (figure IB) greater on the right than on the left side . While receiving 2 Llmin of oxygen, her arterial blood had a pH of 7.48, a Po, of 62 mm Hg, and a Pco, of 28 mm Hg . Two days later, her dyspnea worsened, and prednisone 60 mg per day and isoniazid 300 mg per day were started. While receiving 5 L/min of oxygen , her arterial blood had a pH of 7.45, a Po, of 58 mm Hg, and a Pco, of 36 mm Hg without improvement in symptoms. Eleven days after admission, an open lung biopsy of the lingula was performed. Histologic sections of lung showed severe inter stitial fibrosi s characterized by extensive areas of advanced fibrosis with remodeling of lung architecture (figure 2A). In addition, areas of loo se, intraluminal and interstitial fibrosis were seen (figure 28 and C). Interstitial chronic inflammation was mild and consisted primarily of lymphocytes with occasional plasma cells and rare eosinophils. Cuboidal change of Type II pneumocytes was focally present. Alveolar macrophages were prominent adjacent to areas of fibrosis, and some showed foamy cytoplasm. The pathologic findings shared many features with those seen in idiopathic pulmonary fibrosis . Postoperatively the patient became febrile to 38.4 0 C. After 4 days, her dyspnea worsened, and she developed pulmonary edema with moderate pedal edema . While receiving 4 L/min of oxygen, the arterial blood had a pH of 7.45, a Po, of 35.5 mm Hg, and a Pco, of 39.1 mm Hg. She was treated with 100070 oxygen and furosemide 40 mg intravenously, with improvement of her Po, to 50.2 mm Hg , She continued to be severely dyspneic and was unresponsive to high doses of intravenous steroids. She died 3 days later from respiratory failure. At autopsy, gross examination of the lung s revealed very firm parenchyma, with marked interstitial thickening and focal honeycomb changes. The lung weights were increased: right, 900 g; left, 570 g. A right lower lobe bronchopneumonia was evident by white-tan areas of consolidation. Histologically, in addition to the bronchopneumonia, there was an extensive background of advanced interstitial fibrosis . Death was attributed to respiratory failure secondary to bilateral lower lobe acute bronchopneumonia superimposed on severe interstitial fibrosis.
Discussion Pulmonary toxicity has been previously recognized as a complication of tocainide therapy (5, 11-14). The product label approved by the Food and Drug Administration (FDA) includes a precaution that pulmonary fibrosis, interstitial pneumonitis, and other pulmonary conditions have occurred in patients receiving tocainide (15). However, only a few reports (table 1) have drawn attention to this potential side effect (5, 11-14). These reports provide little pathologic details about the pulmonary toxic effects of tocainide. Data presented to the FDA indicate the incidence of tocainide-associated pulmonary fibrosis to be 0.30/0 in the Emergency Use Program (5). Pulmonary toxicity usually occurs in seriously ill patients, with onset 3 to 18 wk after initiation of therapy (5). Since tocainide's approval, approximately 40 reports of pulmonary toxicity have been received by the FDA's adverse drug reaction reporting system. 3 Tocainide is being used with increasing frequency for the treatment of ventriculararrhyth-
Fig. 2. A. Open lung biopsy shows severe interstitial fibrosis characterized by prominent cystic remodeling of lung architecture, bronchiolar proliferation, and mild interstitial chronic inflammation. Hernatoxynn-eosln stain; magnification: x15. B. This area shows bronchiolar proliferation, and extensive interstitial fibrosis character ized by prominent intraluminal loose fibrosiswithareas ofmuralincorporation. Hematoxylin-eosin stain; magnification: x60. C. Higher power reveals a nodular focus of loose, edematous fibrosis protruding into an alveolar space and showing features of mural incorporation into the adjacent interstitium. Reactive alveolar liningcells line the surface on this intraluminal bud. Macrophages and lymphocytes are present in the adjacent alveolar space. Hematoxylin-eosin stain; magnification: x250.
F
77
14
Idiopathic congestive cardiomyopathy; ventricular ectopy
400 mg q.i.d. 6 months
400 mg t.i.d. 2 months
High grade ventricular ectopy; IHD
M
72
12
400 mg q.i.d. 2 months
F
67
13
200-400 mg t.i.d. 8 months
200 mg t.i.d. 12 wk
Dose Duration
Refractory ventricular arrhythmias; Post-AMI
Refractory ventricular arrhythmias; AMI x 2
F
13
58
55
11
History of acute myocardial infarction (AMI)
Cardiac Problem
M
Reference Age No. (yr) Sex
1/369 7
1/72
Incidence
Dyspnea; decreased exercise tolerance; afebrile
Pulmonary Function Tests
New diffuse bilateral infiltrates
Decreased interstitial markings
New diffuse bilateral infiltrates; CT-thin section: interstitial thickening
Stopped tocainide; corticosteroids
Treatment
BAL: PMN, 21 %; normal microbiology. Open lung biopsy: active alveolitis with chronic diffuse interstitial pneumonitis and early fibrosis Interstitial pneumonia; focal intra-alveolar macrophages and fibrin deposition
Pao2 = 52; Peo 2 = 32; pulmonary capillary wedge == 9 mm Hg; right atrial pressure = 2 mm Hg; VC = 1.9 L; TLC = 3.3 L; OLeo = 9.6 ml/min/mm Hg; gallium scan: markedly t activity in lung bases and moderately t in upper lung fields
None
Stopped tocainide; prednisone 60 mg every day
Stopped tocainide; prednisone 60 mg/day for 4 wk then tapered over 2 wk
Stopped tocainide
Transtracheal biopsy: organizing Stopped tocainide; pneumonia suggestive of prednisone hypersensitivity rxn; organizing 80 mg/day, alveolar interstitial fibrosis tapered over 6 wk with moderate alveolar infiltrate
None
Pathology Findings
Increased alveolar ventilation; t AaPo2; + diffusing capacity; t TLC; gallium scan: diffusely positive
Severe hypoxemia Severe + diffusing capacity
Severe hypoxia; severe + diffusing capacity (AaPo2 = 65)
Pulmonary edema Pao2 = 55; Peo 2 = 33 Moderate restrictive defect; + transfer factor; + lung volume
Chest Radiograph
Progressive dyspnea; Diffuse infiltrates decreased exercise tolerance
Rapid onset of dyspnea
Dyspnea
Dyspnea on exertion
Symptoms
SUMMARY OF LITERATURE REPORTS
TABLE 1
Improved over 2 months
Improved symptoms and CXR cleared; improved PFT; + PMN in BAL gallium scan clear 12 wk after stopping tocainide
CXR markedly resolved 1-2 wk after drug stopped; PFT improved
Improved; infiltrate cleared; remains asymptomatic
Improved without tocainide; lung function normalized after steroids
Outcome
....
Q
en
~
~
::u m
Sm
508
mias, as indicated by survey information cited by Arrowsmith and coworkers (16) that 762,000 prescriptions were written in 1986, up from 473,000 in 1985. Thus, it is likely that an increasing number of cases of tocainide pulmonary toxicity will occur, and it is important for clinicians using this drug to be aware of this potential adverse side effect. The pathologic and radiographic findings in our patient, with a normal pretherapy chest radiograph, clearly demonstrate the onset of pulmonary fibrosis while receiving tocainide. These findings confirm previous reports indicating that tocainide is associated with pulmonary toxicity (5, 11-14). The onset of pulmonary symptoms after the initiation of tocainide therapy in the previously reported cases was 1.5 to 8 months (median, 2 months) (table 1). In our patient, pulmonary symptoms first presented 14 months after initiation of tocainide therapy. There is nothing specific about the lung disease or the clinical presentation in our case to prove that the pulmonary fibrosis was caused by tocainide administration, but our patient had no other known predisposing conditions, and to our knowledge she used no other medications associated with the development of pulmonary fibrosis. Pulmonary complications associated with antiarrhythmic medications have become well known in recent years with the widespread use of amiodarone (17). Alveolar "foamy" macrophages are a characteristic finding associated with amiodarone therapy. Interstitial fibrosis may also occur, and in some cases it can be severe. Some alveolar macrophages in the lung biopsy from our patient had foamy cytoplasm, as did some alveolar lining cells. Unfortunately, tissue was not set aside for electron microscopy from either the open lung biopsy or the autopsy. Thus, we were not able
CASE REPORT
to investigate the presence of the characteristic lamellar lysosomal inclusions described in association with amiodarone (17). However, the question of whether tocainide induces similar effects could be studied in future cases using ultrastructural analysis on cells from bronchoalveolar lavage, as has been done with patients receiving amiodarone therapy. The development of severe, irreversible pulmonary fibrosis in our case contrasts with the previous reports of reversible pulmonary toxicity associated with tocainide (table 1). The preceding reports described a shorter duration of therapy and resolution of symptoms after cessation of tocainide treatment, usually in conjunction with steroid therapy (11-14). Unfortunately, in our patient, pulmonary fibrosis was irreversible by the time it was first detected. This case emphasizes the importance of detecting pulmonary changes associated with tocainide as early as possible while they are still potentially reversible. The goal of this report is to alert physicians that patients receiving tocainide should be monitored periodically with chest radiographs for onset of pulmonary fibrosis. Hopefully, awareness of this potential complication of tocainide will reduce the number of cases of serious pulmonary toxicity.
References 1. Holmes B, Brogden RN, Heel RC, Speight TM, Avery GS. Tocainide, a review of its pharmacological properties and therapeutic efficacy. Drugs 1983; 26:93-123. 2. Kutalek SP, Morganroth J, Horowitz LN. Tocainide: a new oral antiarrhythmic agent. Ann Intern Med 1985; 103:387-91. 3. Roden DM, Woosley RL. Drug therapy: tocainide. N Engl J Med 1986; 315:41-5. 4. Hohnloser SH, Lange HW, Raeder EA, Podrid PJ, Lawn B. Short- and long-term therapy with to-
cainide for malignant ventricular tachyarrhythmias. Circulation 1986; 73:143-9. 5. Horn HR, Hadidian Z, Johnson JL, Vassallo HG, Williams JH, Young MD. Safety evaluation of tocainide in the American emergency use program. Am Heart J 1980; 100:1037-40. 6. Mohiuddin SM, Esterbrooks D, Mooss AN, Dahl JM, Hilleman DF. Efficacy and tolerance of tocainide during long-term treatment of malignant ventricular arrhythmias. Clin Cardiol 1987; 10: 457-62. 7. Vermeij P, Hulshof JH. Dose finding of tocainide in the treatment of tinnitus. Int J Clin Pharmacol Ther Toxicol 1986; 24: 207-12. 8. Gertz MA, Garton JP, Jennings WHo Aplastic anemia due to tocainide. N Engl J Med 1986; 314:583-4. 9. Soff GA, Kadin ME. Tocainide-induced reversible agranulocytosis and anemia. Arch Intern Med 1987; 147:598-9. 10. Volosin K, Greenberg RM, Greenspon AJ. Tocainide associated agranulocytosis. Am Heart J 1985; 109:1392-3. 11. Bastian BC, Macfarlane PW, McLauchlan JH, et al. Prospective randomized trial of tocainide in patients following myocardial infarction. Am Heart J 1980; 100:1017-22. 12. Braude AC, Downar E, Chamberlain DW, Rebuck AS. Tocainide-associated interstitial pneumonitis. Thorax 1982; 37:309-10. 13. Perlow GM, Jain BP, Pauker SG, Zarren HS, Wistran DC, Epstein RL. Tocainide-associated interstitial pneumonitis. Ann Intern Med 1981; 94: 489-90. 14. Stein MG, Demarco T, Gamsu G, Finkbeiner W, Golden JA. Computed tomography: pathologic correlation in lung disease due to tocainide. Am Rev Respir Dis 1988; 137:458-60. 15. 1988 Physicians' Desk Reference. Oradell, NJ: Medical Economics Co., 1988; 1398. 16. Arrowsmith JB, Creamer Jl, Bosco L. Severe dermatologic reactions reported after treatment with tocainide. Ann Intern Med 1987; 107:693-6. 17. Martin WJ, Rosenow EC. Amiodarone pulmonary toxicity. Recognition and pathogenesis. Parts I and II. Chest 1988; 93:1067-75 and 1242-8.
