Amiodarone-Induced Pulmonary Toxicity

Amiodarone induced pulmonary toxicity is lung injury from the antiarrhythmic drug amiodarone, which causes interstitial pneumonitis, organising pneumonia, acute respiratory distress, pleural disease or lung masses. It occurs in about 1 to 5% of treated patients and up to 10 to 15% at doses over 400 mg daily.

Risk rises with a daily dose over 400 mg, a long duration of treatment, age over 60 years, pre-existing lung disease and exposure to high inspired oxygen or thoracic surgery. Toxicity can appear within weeks or after years, and it persists after stopping because of the long tissue half life (about 50 days).

Pathophysiology. The drug and its metabolite accumulate in alveolar macrophages and type II cells as phospholipid laden inclusions (phospholipidosis). Direct cytotoxicity and an immune mediated reaction cause alveolar and interstitial inflammation, with fibrosis in some. Iodine content makes affected lung dense on CT.

Subacute cough, exertional dyspnoea, pleuritic chest pain, fever and weight loss over weeks to months. Acute presentations resemble acute respiratory distress syndrome, particularly after surgery with high oxygen. Examination may show bibasal crackles.

Rapid hypoxaemia, fever with new infiltrates or respiratory failure needs urgent assessment, since pneumonia and heart failure look similar.

• A clinical diagnosis after exclusion of other causes, in a patient on amiodarone with new respiratory symptoms and new lung abnormalities.
• High resolution CT: patchy or diffuse ground glass, reticulation, organising pneumonia pattern, or high attenuation consolidation (over 82 Hounsfield units) from iodine, usually in the periphery and upper zones, sometimes with pleural thickening.
• Lung function: restrictive defect, with a fall in DLCO of 15 to 20% or more from baseline.
• Bronchoalveolar lavage: lymphocytosis and foamy macrophages (these indicate drug exposure and not toxicity on their own).
• Exclude infection (including Pneumocystis), heart failure (echocardiography, natriuretic peptide), pulmonary embolism and malignancy.
• Thyroid function and liver tests, since toxicity in other organs often coexists.

Differential diagnosis.

• Cardiogenic pulmonary oedema
• Pneumonia and opportunistic infection
• Pulmonary embolism
• Organising pneumonia from another cause
• Lung cancer or metastases
• Idiopathic interstitial pneumonia
• Radiation pneumonitis

• Stop amiodarone if possible, in agreement with cardiology, and replace with another rate or rhythm strategy: a beta blocker, flecainide in structurally normal hearts, sotalol, or catheter ablation. If the arrhythmia is life threatening and no alternative exists, use the lowest dose that controls it (100 to 200 mg daily).
• Corticosteroid for moderate to severe disease: prednisolone 0.5 to 1 mg/kg daily (usually 40 to 60 mg) for 4 to 8 weeks, then tapered slowly over 3 to 6 months because of the long drug half life and the risk of relapse.
• Acute respiratory failure: methylprednisolone 500 to 1000 mg intravenously daily for 3 days, then prednisolone, with supportive ventilation and lung protective settings.
• Supportive care: oxygen with a target saturation of 92 to 96%, but the lowest oxygen concentration that works, and avoid unnecessary high oxygen exposure.
• Prophylaxis against Pneumocystis when prednisolone is 20 mg or more daily for over 4 weeks: co-trimoxazole 960 mg three times weekly.
• Prevention: baseline chest radiograph, spirometry with DLCO, thyroid, liver function and eye review before starting, a chest radiograph every 6 to 12 months, and the lowest effective dose.
• Do not rechallenge after pulmonary toxicity.

Complications and prognosis. Most patients improve after withdrawal, with or without steroids. Mortality is about 10% for chronic disease and up to 50% for the acute respiratory distress form, and fibrosis can persist.

Monitoring. Review at 2 weeks, 4 weeks and 3 months, with oxygen saturation, spirometry and DLCO, and a CT at 3 months, then at 6 and 12 months. Review thyroid and liver function every 6 months.

Referral and escalation. Refer to cardiology for an alternative antiarrhythmic, and to a respiratory physician for severe or persisting disease. Refer urgently for respiratory failure.