Amiodarone pulmonary toxicity
Section snippets
Pharmacokinetics of amiodarone
The distinctive chemical structure and pharmacokinetics of Am impact on the clinical, imaging, and pathologic features of APT, as well as on its outcome. Am and its quantitatively-relevant metabolite, desethyl-amiodarone (DEAm), are cationic amphiphilics, which accumulate in tissues, including the lung. In addition to sequestering into the lung, Am and DEAm infiltrate into the liver, skin (particularly the discolored skin of patients who receive Am on a continual basis [10]), thyroid, and eye.
Epidemiology and risk factors
There is some link between indexes of exposure to Am (a composite of daily dosage and duration of treatment) and the likelihood of developing APT [27], [28], [29]. Thus, Am should be titrated to the lowest possible effective dosage [30].
Am pneumonitis is more frequent in men and is unusual in patients who are younger than 40 [31]. Rare reports described its occurrence in children or adolescents [32]. The risk of developing APT increases with age, and, on average, with daily dosage of the drug
Clinical imaging patterns of amiodarone pulmonary toxicity
Am pneumonitis can develop at any time from a few days after an initial loading dose of Am [33], [39], [45] to more that a decade into treatment. Most cases, however, develop at some point during the first 1 or 1.5 years of treatment. Time to onset of pneumonitis tends to be shorter in patients who take elevated dosages of Am [46]. In a few patients, APT developed up to 3 months after cessation of treatment [47]; this may reflect the extended storage of Am in lung.
Signs and symptoms of APT are
Pulmonary function testing
Patients who receive Am often have a background of exposure to tobacco, emphysema, or heart failure, which can impact of pulmonary functions. For that reason, it was suggested to repeat three or four determinations of pulmonary function in the first months of treatment with Am [33]; this will serve as a baseline to which further changes can be compared. The earliest abnormality in APT is a consistent decrease in the diffusing capacity for carbon monoxide (CO) [33]. Chronic left heart failure
Bronchoalveolar lavage
The contribution of BAL to the diagnosis of Am-related lung disease is controversial. An increase in the numbers of CD8+ lymphocytes used to be considered of diagnostic value. Other studies, however, indicated that a wide range of abnormalities can be found in the BAL in Am pneumonitis, including a normal distribution or an increase in neutrophils or lymphocytes or lymphocytes and neutrophils [81], [83], [84]. The time to onset of the pneumonitis tends to be shorter in patients who have
Histopathologic evaluation
A lung biopsy specimen of significant size is required to establish confidently the diagnosis of APT; however, it is not indicated in every patient. The histopathologic appearances of Am pneumonitis and of subpleural masses include septal thickening, interstitial edema, nonspecific inflammation and fibrosis, as well as the presence of lipids within interstitial and endothelial cells and lying free in alveolar spaces [5], [8], [25], [81], [85]. Free foamy intra-alveolar macrophages also are
Work-up in patients who are suspected of having amiodarone pulmonary toxicity
In addition to taking drug history, patients should undergo detailed imaging, pulmonary function testing, BAL, and diuresis as a first step in evaluation. Results of these tests may establish a presumptive diagnosis of APT, especially if pretherapy imaging and pulmonary function tests, including the diffusing capacity, were normal. If there is sufficient confidence in the diagnosis of APT, Am should be discontinued (under cardiologic guidance) and the patient should be observed until
Outcome
Clinical improvement and clearing of pulmonary opacities typically require 1 to 3 months [25]. Discontinuation of Am as the sole therapeutic measure may be sufficient, if disease extent is limited; however, unless corticosteroid drugs are added, discontinuation of Am rarely is followed by convincing improvement in patients who have more advanced disease [13].
Despite the lack of controlled studies, clinical evidence has accumulated that supports the beneficial effects of corticosteroid
Pleural effusion
An exudative pleural effusion develops in up to one third of patients who have Am pneumonitis [20], although it is considered unusual [8]. The effusion is often unilateral, of moderate volume, and can cause chest pain.
The development of lone pleural effusion during treatments with Am is unusual. On imaging, a free-flowing effusion is present that often is accompanied by pleural thickening. Bilateral exudates developed in one patient who was placed on high-dose Am (1600 mg/day, decreased to 1200
Prevention and early detection of amiodarone pulmonary toxicity
Given the frequency and potential severity of Am pneumonitis, early detection is desirable; however, no consensus exists in that area. Earlier diagnosis of APT may simplify management and improve prognosis, but this is unproved. Patients who should benefit from Am should be carefully selected; a go-low attitude regarding Am dosage is warranted, where possible.
Pulmonary evaluation, including plain chest radiograph, and pulmonary function, including diffusion capacity for CO are recommended when
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