Amiodarone pulmonary toxicity

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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

Synonyms and Keywords: Amiodarone lung toxicity; APT

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.

Pathophysiology

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 lung tissue with direct effect on alveolar-capillary membrane.[1]
  • 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.[2][1][3]

Microscopic Pathology

Copyleft image obtained courtesy of http://en.wikipedia.org/wiki/File:Usual_interstitial_pneumonia_%281%29.JPG, http://en.wikipedia.org/wiki/File:Hyaline_membranes_-_very_high_mag.jpg, http://en.wikipedia.org/wiki/File:Masson_body_-_high_mag.jpg.

Differentiating Amiodarone Pulmonary Toxicity from other Diseases

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

Epidemiology and Demographics

Pulmonary toxicity is the most serious adverse effect of amiodarone. It may occur in up to 5–10% of treated patients.[2]

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 mg/d)[2]
  • Duration over two months
  • Increased age
  • Preexisting pulmonary disease
  • Major surgical procedures
  • Pulmonary angiography

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.

Natural History, Complications, and Prognosis

Amiodarone pulmonary toxicity can manifest itself in several ways:

Acute Respiratory Distress Syndrome

  • Rare but the most dangerous form of pulmonary toxicity
  • Sudden, life-threatening, and having diffuse lung involvement
  • Most often following major surgical procedures, especially cardiac surgery and pulmonary angiography, but it can be seen at any time and without any obvious precipitating causes.[4][5][6]
  • Surgical patients develop symptoms 1-4 days post-extubation and patients who have undergone pulmonary angiography may develop symptoms within 30 minutes of procedure which include severe dyspnea and hypoxia.[7]
  • Patients usually must be placed on mechanical ventilators, and their mortality rate even with intensive therapy approaches 50%.[8]
  • Chest x ray shows bilateral diffuse pulmonary infiltrates.
Chest x ray showing bilateral diffuse pulmonary infiltrates.

Diffuse Alveolar Hemorrhage

Bronchiolitis Obliterans Organizing Pneumonia (BOOP)

CT slide of biopsy-proven bronchiolitis obliterans organizing pneumonia.

Copyleft image obtained courtesy of http://en.wikipedia.org/wiki/File:CT_BOOP.jpg

Chronic Interstitial Pneumonitis

  • Most common presentation of amiodarone-induced pulmonary toxicity
  • Insidious and gradual onset over weeks to months in patients on therapy >2 months
  • 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.
  • Chest x ray shows focal or diffuse interstitial opacities
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

Prognosis

Prognosis is usually favorable in about 75% of the patients after withdrawal of the drug with or without treatment.[18] The mortality rate of amiodarone pulmonary toxicity is 10% of the reported cases but may have higher mortality rate in patients with ARDS.[8]

Diagnosis

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.[19][2][20] 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. Symptoms can persist or worsen despite drug withdrawal as elimination half-life averages 40-55 days. 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:

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

Diagnostic Criteria

The diagnosis of amiodarone-induced pulmonary toxicity is one of exclusion. Once other diagnoses are excluded, then the clinical diagnosis is suggested when ≥ 3 of the following are present:[2]

  1. Decrease in TLC of ≥ 15% or in DLCO of ≥ 20%
  2. New abnormal finding on chest imaging
  3. New or worsening signs or symptoms
  4. Phospholipidosis in lung cells
  5. CD8+ lymphocytosis on BAL
  6. Lung biopsy with interstitial pneumonitis, BOOP, ARDS, or pulmonary fibrosis.
  7. Improvement in symptoms with drug discontinuation.

Treatment

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:

References

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