The importance of amiodarone pulmonary toxicity in the differential diagnosis of a patient with dyspnea awaiting a heart transplant

Abstracts

Amiodarone is a class III antiarrhythmic medication used extensively to treat ventricular arrhythmias¹. It is pharmacologically classified as a cationic amphiphilic drug due to its polar and apolar components. During the past few years, amiodarone has proved to be an effective treatment therapy for patients with ventricular dysfunctions, regardless of the etiology, and in particular ventricular arrhythmia associated with Chagas disease². Nevertheless, despite its hemodynamic and electrophysiological benefits, amiodarone produces serious collateral effects such as a bluish skin discoloration, photosensitivity, thyroid dysfunction, corneal deposit, peripheral neuropathy, bone marrow suppression, hepatitis, heart blocks, pneumonitis, among others³. The objective of this case report is to discuss one of the most serious complications related to amiodarone, pulmonary toxicity, which is described as a differential diagnosis for a chagasic patient that was on the waiting list for a heart transplant. Amiodarone pneumonitis is a relevant differential diagnosis for heart failure (HF) patients using amiodarone that are admitted to the emergency ward with dyspnea.

Amiodarone; pulmonary toxicity; heart failure

A amiodarona é um antiarrítmico da classe III, amplamente utilizado em arritmias ventriculares¹. Farmacologicamente é classificado como uma drogra ampifílica catiônica, pelos seus constituintes polares e apolares. Nos últimos anos, a amiodarona obteve destaque pelo seu uso em portadores de disfunção ventricular por qualquer etiologia, em especial a chagásica, quando ocorrem arritmias ventriculares². Entretanto, a despeito de seus benefícios hemodinâmicos e eletrofisiológicos, a amiodarona produz efeitos colaterais relevantes, como coloração azulada da pele, fotossensibilidade, disfunção tireoidiana, depósito corneal, neuropatia periférica, supressão da medula óssea, hepatite, bloqueios cardíacos, pneumonites e outros³. Este relato de caso se propõe a abordar uma de suas mais sérias complicações, a toxicidade pulmonar, aqui especialmente descrita como diagnóstico diferencial em um paciente chagásico que aguardava em fila de transplante cardíaco. Pneumonite por amiodarona constitui-se em um importante diagnóstico diferencial entre os pacientes que se apresentam na sala de emergência com dispnéia, quando estes são portadores de insuficiência cardíaca (IC) e estão em uso dessa droga.

Amiodarona; toxicidade pulmonar; insuficiência cardíaca

CASE REPORT

The importance of amiodarone pulmonary toxicity in the differential diagnosis of a patient with dyspnea awaiting a heart transplant

Christiano Pereira Silva; Fernando Bacal; Philippe Vieira Pires; Luciano F. Drager; Germano Emílio Conceição Souza; Ginny Michele G. Fajardo; Léa Maria Macruz F. Demarchi; Edimar Alcides Bocchi

Instituto do Coração do Hospital das Clínicas – FMUSP - São Paulo, SP - Brazil

^{Mailing Address}

ABSTRACT

Amiodarone is a class III antiarrhythmic medication used extensively to treat ventricular arrhythmias¹. It is pharmacologically classified as a cationic amphiphilic drug due to its polar and apolar components. During the past few years, amiodarone has proved to be an effective treatment therapy for patients with ventricular dysfunctions, regardless of the etiology, and in particular ventricular arrhythmia associated with Chagas disease². Nevertheless, despite its hemodynamic and electrophysiological benefits, amiodarone produces serious collateral effects such as a bluish skin discoloration, photosensitivity, thyroid dysfunction, corneal deposit, peripheral neuropathy, bone marrow suppression, hepatitis, heart blocks, pneumonitis, among others³. The objective of this case report is to discuss one of the most serious complications related to amiodarone, pulmonary toxicity, which is described as a differential diagnosis for a chagasic patient that was on the waiting list for a heart transplant. Amiodarone pneumonitis is a relevant differential diagnosis for heart failure (HF) patients using amiodarone that are admitted to the emergency ward with dyspnea.

Key words: Amiodarone, pulmonary toxicity, heart failure.

The correct diagnosis of the etiology of dyspnea in patients with left ventricular dysfunction is decisive for the success of treatment. Several pathologies have to be differentiated from pulmonary congestion under the risk of adopting inadequate procedures. In this case report, the authors approach amiodarone pulmonary toxicity as yet another diagnosis to be investigated especially in patients with Chagasic cardiomiopathy awaiting a heart transplant. The clinical-radiological picture is similar to a picture of decompensated heart failure and the specific use of medication to treat complex arrhythmias contribute to make the correct diagnosis more difficult and therefore make the therapeutic approach more difficult as well.

CASE REPORT

A 44-year-old male suffering from heart failure for ten years due to a chagasic etiology, had been on the waiting list for a heart transplant for one year. Drug therapy included furosemide (40 mg per day), spironolactone (25 mg per day) and losartan (50 mg per day), as well as amiodarone (400 mg per day), due to a three year episode of sustained ventricular tachycardia. Patient follow-up was conducted on a bi-weekly basis and his condition was classified as functional class III in accordance with the guidelines of the New York Heart Association (NYHA). A radioistopic ventriculography revealed a left ventricular ejection fraction (LVEF) of 14%, and the patient’s last hospitalization had been three months earlier.

Upon admission at the emergency ward of the Heart Institute (InCor) the patient’s general appearance was normal, he had a non-productive cough, dyspnea and fever (37.6ºC). There was no previous history of infection, pulmonary disease, ischemia, abuse or incorrect use of medication. Blood pressure was 110 x 60 mmHg, breath sounds were normal with a respiratory rate of eighteen cycles per minute. There were no signs of respiratory failure. The electrocardiogram showed a classic Chagas disease pattern: right bundle block of the His bundle with a left anterior hemiblock. The chest x-ray showed an asymmetrical distribution pattern of bilateral alveolar infiltrates (fig.1).

Treatment for decompensated heart failure was initiated, without improvement in the clinical picture. Ceftriaxone (2 grams per day) was administered for pulmonary infection. There was no improvement with this treatment. A high resolution CT was conducted that showed irregular areas with diffused "dull glass" opacities and interlobular septal thickening. Alterations in the pleura were not identified (fig.2). Arterial blood gas saturation was normal and a pulmonary function test revealed a moderate restrictive disorder. The laboratory tests also revealed a nonspecific increase of leukocytes (12,300/mm³), normal lactic acid dehydrogenase (LDH) and a erythrocyte sedimentation rate of 32 mm (normal up to 6 mm). A negative Gallium-67 scintillography discarded the presence of an active pulmonary inflammatory process, however, despite this finding, the patient was submitted to a transbronchial biopsy that showed non-specific chronic interstitial pneumonia, with moderate inflammatory mononuclear cell infiltrates in the alveolar septum and a large number of macrophages in the alveolar spaces (fig. 3).

These histopathological findings are described as a common pattern for amiodarone induced pulmonary disease⁴. Foamy macrophages are considered a classic sign of amiodarone exposure⁴. Hyaline membranes outlining the alveoli and alveolar spaces, filled with small quantities of erythrocytes and fibrin, were also observed in focal areas. These lesions are found in a small number of patients that develop amiodarone pulmonary toxicity. Foamy cells with relatively small nuclei and clear cytoplasm were observed in the bronchoalveolar lavage (BAL) which are very similar to those found in the BAL fluid of patients with amiodarone pulmonary disease. These cells are not usually found in the BAL of healthy patients⁵. Bacteria, fungi and bacilli were not shown in appropriate colorations in either the pulmonary biopsy or the BAL.

The amiodarone treatment was immediately interrupted and replaced with prednisone (40 mg per day). After fourteen days of cortisone therapy the patient’s clinical and radiological condition improved. After three months of treatment there was a complete resolution of the disease (fig.4), and the patient could once again be placed on the heart transplant waiting list. Sotalol was prescribed as an antiarrhythmic medication and an implantable defibrillator was indicated. Eight months after returning to the waiting list, the patient was transplanted without intercurrences. The transplant surgery was performed more than one year ago, the patient remains asymptomatic and has regular medical follow-up at the InCor heart transplant clinic on a monthly basis.

DISCUSSION

Amiodarone toxicity was first described by Rotmensch et al⁶ Amiodarone pulmonary toxicity (APT) affects 5% to 7% of patients and has a higher correlation with the total cumulative dose than with the serum level of the drug⁷. The clinical symptoms can vary from a dry cough and discrete dyspnea to classic respiratory failure however the most common clinical picture is fatigue upon exertion. Associated symptoms such as fever are also common⁸. The appearance of pulmonary masses and nodes is also reported⁹. Cutaneous vasculitis is rarely present⁹.

APT risk factors include a daily dosage higher than 400 mg (toxic reactions from the drug are more common in patients with amiodarone serum levels higher than 2.5 mg/l), preexisting pulmonary disorder, therapy duration of more than two months, advanced age and previous pulmonary surgery¹⁰. The occurrence of pulmonary toxicity has also been confirmed in patients using lower dosages of the drug¹¹.

The mechanisms involved in APT have not been entirely established. Two hypotheses have been proposed: toxicity directly to the pulmonary cells and an indirect immunological reaction¹². Patients treated with amiodarone present with different types of pulmonary disease including chronic interstitial pneumonitis (most common), organizing pneumonia (with or without bronchiolitis obliterans), acute respiratory distress syndrome¹³, and solitary pulmonary nodule (rare)¹⁴.

In this case, APT affected a chagasic patient awaiting a heart transplant. This special situation has serious clinical implications: patients on a transplant waiting list can be called at any time for a surgical procedure, depending on organ availability; the appearance of a pulmonary inflammation could jeopardize a transplant opportunity; conducting this procedure under these conditions raises serious doubts such as the possibility of a worse post-operative prognosis, the appearance of respiratory failure or acute respiratory distress syndrome¹⁵. In addition, there is not enough information about immunosuppression and infection incidence in these cases.

Another important consideration is the differential diagnosis between this clinical picture and pulmonary congestion secondary to heart failure. Various similar clinical symptoms are present in addition to the chest x-ray. In this case, due to the questionable diagnosis at first, furosemide was administered. The treatment did not improve the clinical or radiological symptoms. It is difficult to differentiate between the two entities and further testing is required to determine the diagnosis. The increase of gallium lung uptake is an important test to detect inflammatory processes such as amiodarone pneumonitis, due to its high sensitivity¹⁶. Nevertheless, in this case the scintillography was negative. Another accurate radiological exam is the high resolution CT scan, mainly to improve the specificity of nuclear medicine¹⁷. This test revealed nonspecific alterations that could be related to APT. Since the clinical assumption was almost certain and there were no symptoms that suggested other disorders such as pulmonary embolism or bacterial pneumonia, a complementary investigation was conducted that included a transbronchial pulmonary biopsy that produced results compatible with amiodarone induced pulmonary damage. The anatomicopathologic study helps to determine the diagnosis and also to define the amiodarone induced pneumonopathy pattern¹⁸.

Recently, a new diagnostic method has been proposed. Research of KL-6, a high molecular weight mucin glycoprotein that is secreted by pneumocytes, can predict the presence of interstitial pneumonitis, reinforcing the APT diagnosis¹⁹.

APT treatment for most patients consists in discontinuing the use of amiodarone. Corticosteroid therapy (40 to 60 mg per day of prednisone with a gradual reduction in two to six months) is safe and effective in severe cases and accelerates the resolution process when the simple withdrawal of amiodarone is not sufficient⁹. In patients who develop respiratory failure, inhalation of nitric oxide in conjunction with mechanical ventilator support improves hypoxemia and offers a better prognosis. Nevertheless, approximately 30% of the patients develop irreversible pulmonary fibrosis²⁰. Experimental reports demonstrate the effectiveness of vitamin E in the reduction of amiodarone induced pulmonary fibrosis²¹.

Amiodarone is the drug of choice for ventricular arrhythmia treatment in chagasic patients with ventricular dysfunction. Despite the collateral effects demonstrated here , its use is totally justified in this case. New studies have recommended, mainly in the case of ischemia²², the use of implantable defibrillators²³ for patients with severe ventricular arrhythmia²⁴, syncope or an elevated risk of sudden death²⁵. This recommendation is supported by influential clinical studies²⁶.

CONCLUSION

Amiodarone pulmonary toxicity should be considered a differential diagnosis in patients that present with dyspnea in emergency wards. Usually prescribed in high dosages, the drug is widely used and can cause pulmonary toxicity that has a clinical picture very similar to pulmonary congestion. Complementary methods that are more differentiated are useful for the diagnosis of this condition.

Potencial Conflict of Interest

No potential conflict of interest relevant to this article was reported.

REFERENCES

Received on 04/27/05

Accepted on 07/01/05

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Publication Dates

• Publication in this collection
  16 Oct 2006
• Date of issue
  Sept 2006

History

• Accepted
  01 July 2005
• Received
  27 Apr 2005