Amiodarone pulmonary toxicity

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Hardik Patel, M.D.; Sapan Patel M.B.B.S

Overview

Amiodarone is an antiarrhythmic drug which is commonly used to treat ventricular and supraventricular arrhythmias, in particular following pulmonary and cardiac surgery, due to a higher incidence of postoperative atrial fibrillation in these patients. It is an iodine-containing compound that tends to accumulate in several organs, including the lungs. It has been associated with a variety of adverse effects. Most individuals administered amiodarone on a chronic basis will experience at least one side effect. The most serious adverse effect is amiodarone-induced pulmonary toxicity. It occurs mostly in patients receiving large doses of the drug over prolonged periods.

Amiodarone Pulmonary Toxicity

Pulmonary toxicity is the most serious adverse effect of amiodarone, which may occur in up to 5–10% of treated patients.

Types

Acute Pulmonary Toxicity

• Acute respiratory distress syndrome:

The rare but the most dangerous form of pulmonary toxicity is a sudden, life-threatening, diffuse lung involvement called acute respiratory distress syndrome (ARDS). Patients with ARDS rapidly develop severe dyspnea and hypoxia. They usually must be placed on mechanical ventilators, and their mortality rate even with intensive therapy approaches 50%. ARDS related to amiodarone is seen most often following major surgical procedures, especially cardiac surgery, but it can be seen at any time and without any obvious precipitating causes.

Intermediate Pulmonary Toxicity

• Diffuse alveolar hemorrhage
• Pneumonia

Chronic Pulmonary Toxicity

• Chronic interstitial pneumonitis:

The most common presentation of amiodarone-induced pulmonary toxicity is the chronic interstitial pneumonitis. It has an insidious and gradual onset. It is characterized by the slowly progressing dyspnea, cough, weight loss, and easy fatigue. These symptoms are easy to mistaken for heart disease or the effects of aging, as many patients taking amiodarone have a history of heart disease.

Pulmonary fibrosis induced by amiodarone.

Copyleft image obtained courtesy of http://en.wikipedia.org/wiki/File:IPF_amiodarone.JPG; James Heilman, MD.

• Solitary lung mass

Pathogenesis

The pathogenesis of amiodarone-induced pulmonary toxicity is incompletely understood.

There are 2 major hypotheses:

• Cytotoxicity- a direct toxic injury to lung cells : Amiodarone may induce the production of toxic O2 radicals, which can directly damage cells . It also appears to promote the accumulation of phospholipids in tissues.
• Hypersensitivity- an indirect immunologic reaction which is supported by the finding of cytotoxic T cells in bronchoalveolar lavage (BAL) fluid from patients with diagnosed toxicity.

Risk Factors

Anyone taking amiodarone is at risk. Patients on higher doses and one who have been taking the drug for a long period of time appear to have a higher risk, and some evidence suggests that individuals with underlying lung disease are also more likely to develop toxicity with amiodarone.

• High cumulative dose (more than 400 milligrams per day)
• Duration over two months
• Increased age
• Preexisting pulmonary disease

Some individuals were noted to develop pulmonary fibrosis after a week of treatment, while others did not develop it after years of continuous use. Common practice is to avoid the drug if possible in individuals with decreased lung function.

Diagnosis

The diagnosis of amiodarone-induced pulmonary toxicity is one of exclusion. Conditions to be ruled out are following:

• Heart failure
• Infectious pneumonia
• Pulmonary embolism
• Malignancy

Clinical Presentation

Typically, patients who have been on amiodarone for months or even several years develop progressive dyspnea, nonproductive cough, malaise, fever, and occasionally pleuritic chest pain. However, clinicians evaluating patients with possible amiodarone-induced pulmonary toxicity must obtain a thorough drug exposure history, maintain a high index of suspicion, and use a systematic diagnostic approach to make the correct and firm diagnosis. Any new pulmonary symptom in patient taking amiodarone should raise the suspicion of toxicity. Physical examination may be unremarkable in milder cases, but in more severely affected individuals, following findings may be noted:

• Bilateral inspiratory crackles
• Hypoxemia
• Respiratory distress

These findings frequently must be distinguished from heart failure.Unexplained pulmonary conditions for which no other likely cause can be identified should be judged as probable amiodarone lung toxicity.

Laboratory Findings

• Chest imaging like chest x-ray and CT scan
• Pulmonary function testing
• Bronchoalveolar lavage
• Lung biopsy

Treatment

• Stop the drug as soon as possible.
• Use the alternative medications and procedures to treat supraventricular arrhythmias, and the implantable cardioverter-defibrillator for potentially life-threatening ventricular arrhythmias.
• Pulse systemic glucocorticoid therapy (eg, prednisone 40 to 60 mg per day) with gradual tapering of the dose.
• [[Polymyxin B]-immobilized fiber column direct hemoperfusion.

Prevention and Monitoring

Prevention

Currently there are no proven measures to prevent toxicity. The only strategy that appears to be efficacious is that of using the smallest dose possible for any particular patient.

Monitoring

Patients who are to begin amiodarone therapy should be informed about potential adverse effects and told to report any new respiratory symptoms promptly. They should have an initial chest x-ray and pulmonary function test, including a DLCO for the baseline reference points.

Current guidelines for monitoring are:

• Annual chest x-ray should be obtained as long as patients remain on amiodarone treatment.
• An immediate chest x-ray and pulmonary function testing should be performed if there is clinical suspicion of pulmonary toxicity.
• There are recommendations for monitoring for extrapulmonary toxicity. These include thyroid function testing, monitoring liver enzymes and function, as well as protective measures for skin photosensitivity.

Prognosis

It is usually favorable in most of the patients after withdrawal of drug with or without treatment. The mortality rate of amiodarone pulmonary toxicity is 10% of the reported cases but may have higher mortality rate in patients with ARDS.