Video-assisted thoracoscopy with pleurodesis as treatment of amiodarone induced recurrent pleural effusion

Abstract

53-year-old male with recurrent right pleural effusion secondary to chronic use of amiodarone. The patient required multiple thoracenteses, and despite amiodarone dose reduction effusion recurred. Video-assisted thoracoscopy with unilateral mechanical pleurodesis and decortication were done, with complete resolution and no recurrence of the effusion even with the amiodarone on board. Surgical approach for unilateral pleural effusion due to amiodarone that is resistant to the standard treatment, may be a strategy in patients where amiodarone cannot be discontinued.

1. Introduction

Amiodarone is a class III antiarrhythmic. It exerts its action by inhibiting the potassium rectifier currents, which are responsible to repolarize the heart in the phase 3 of the cardiac action potential, but also affects the beta-adrenergic receptors, such as beta-1 and calcium channel blockers, leading to a decrease in the automaticity of the sinoatrial node [1]. It is known that amiodarone has multiple side effects, especially in organs such as lungs, thyroid, liver, skin, nerves and cornea. The frequency of amiodarone adverse effects can reach 15% throughout the first year and up to 50% in patients with long-term usage [1]. Changes in the corneal epithelium is seen in around 98% of individuals on this medication, being the most prevalent adverse effect [2].

Among these adverse events, pleural disease due to amiodarone therapy is uncommon, even more rare is to find isolated pleural effusion without parenchymal involvement. The typical natural history of pleural abnormalities due to amiodarone involves parenchymal changes in patients receiving more than 400 mg daily for over 2 months. However, cases have also been reported with lower doses taken for more than 2 years [[3], [4], [5]]. Chest imaging findings more commonly show pleural thickening, and the typical pleural fluid analysis is consistent with a lymphocytic exudate [6].

When pulmonary toxicity related to amiodarone is suspected, it's imperative to stop or reduce the dose when possible. Nevertheless, as amiodarone is a drug with a long half-life, the resolution of the effects can take days to weeks. The cornerstone of treatment is glucocorticoids with usually a good prognosis if detected early [7,8].

Herein, we present a case of recurrent amiodarone induced pleural effusion, without parenchymal involvement successfully treated with Video-assisted thoracoscopy (VATS) mechanical pleurodesis and decortication.

2. Case report

53-year-old male former smoker with a medical history of diabetes mellitus type II, hypertension, end-stage renal disease on hemodialysis, and atrial flutter. Patient underwent radiofrequency ablation for the atrial flutter, which initially improved his condition; however, due to recurrence, he required a repeat ablation with pulmonary vein isolation one year later. He continued to progress, now developing atypical atrial flutter, leading to a left-sided flutter ablation in the next year. During this period, he was on amiodarone intermittently for at least 4 years, even after the multiple ablations, with an average dose of 200 mg daily. Additionally, the patient has been on Apixaban 5 mg twice a day, Amlodipine 5 mg daily and morphine as needed for severe pain.

Five months after resuming amiodarone after his ablation, he presented to our office complaining of increasingly progressive dyspnea on exertion. Physical examination was significant for decreased bilateral breath sounds in the lung bases. Laboratory workup was unremarkable, including a normal BNP and BUN (controlled due to dialysis sessions), as well as inflammatory markers like C-reactive protein and erythrocyte sedimentation rate. An echocardiogram performed 1 year ago showed mild left ventricular hypertrophy, normal left ventricular cavity size, a left ventricular ejection fraction 55-60% and Grade II diastolic dysfunction, with no significant valvular disease, no new echocardiograms were obtained. Chest computerized tomography (CT) scan showed cardiomegaly, mildly dilated main pulmonary artery and a moderate right pleural effusion without any parenchymal involvement or pleural abnormalities including thickening. (Fig. 1).

Fig. 1.

Chest computed tomography scan.

Chest CT scan showing moderate right pleural effusion with adjacent right lower lobe atelectasis/consolidation.

Because the etiology of the pleural effusion was unclear and the patient was symptomatic, a diagnostic and therapeutic thoracentesis was performed. The first thoracentesis revealed a pleural protein of 4.2 g/dL, serum protein 6.6 g/dL, with a ratio of 0.6, and pleural LDH of 129 U/L, consistent with exudative effusion. Additionally, Gram stain, as well as bacterial, fungal, and acid-fast bacilli cultures of the pleural fluid, were negative. Cytology showed mesothelial cells and lymphocytes without any malignant cells.

Given the possibility of amiodarone-induced pleural effusion, the decision was made to reduce the dose to 100 mg daily. Immediately after the thoracentesis and dose reduction, there was radiologic and symptomatic improvement. However, two months later, the patient returned with the same symptoms. A chest CT was performed, revealing a large right-sided pleural effusion. Thoracentesis was performed, draining 1.5 L of yellowish fluid; however, no studies were conducted.

Two weeks later, the symptoms returned, and a chest X-ray showed recurrence of the right-sided pleural effusion. A third thoracentesis was performed. After discussion with the treatment team, thoracic surgery was consulted. The decision to perform a video-assisted thoracoscopy with right parietal pleurectomy, partial lung decortication and mechanical pleurodesis was made, especially because discontinuation of amiodarone was not possible at that time given the patient's history of difficult-to-control atrial flutter. During surgery, over 2.5 L of serous pleural effusion and fibrinous material were drained. Exploration showed a thickened parietal pleura, and the lung was contracted with a small amount of visceral pleural peel. Pleurodesis and decortication was performed, and a pleural biopsy was taken. Histopathological examination of the right parietal pleural biopsy revealed fibrosis, focal mesothelial proliferation, chronic inflammation, and lymphoid aggregates, with no evidence of malignancy.

The patient was discharged on a 100 mg of amiodarone and was symptom-free. Since then, there has been no recurrence of symptoms, and no radiographic evidence of a recurrent pleural effusion. The patient is currently awaiting a kidney transplant.

3. Discussion

The first description of amiodarone pulmonary toxicity was by Rotmensch in 1980 [3], interstitial lung disease is the most common pulmonary complications that could also be described as organizing pneumonia, acute respiratory distress syndrome (ARDS), diffuse alveolar hemorrhage, and less common a pleural effusion [1].

Amiodarone pulmonary toxicity is more closely associated with the total cumulative dose than with serum drug levels, with the toxicity often arising several months following the initiation of therapy. Doses of ≥400 mg per day, duration of more than two months, and age >60 years have each been noted as primary risk factors. Notably, the risk of amiodarone-induced pulmonary toxicity increases threefold for every 10-year increment in age among patients over 60 years old, compared to those under 60 years old. Preexisting lung disease also makes one susceptible [9]. Evidence shows that the rate of pulmonary toxicity rises with time on therapy—4.2% with 1 year, 7.8% with 3 years, and 10.6% with 5 years of treatment [10,11].

The precise mechanism of pulmonary toxicity is not fully elucidated but is thought to be due to direct cytotoxic effect and immune-mediated injury. On the latter, research has demonstrated that amiodarone induces an immune-mediated hypersensitivity, with histopathological characteristics of hypersensitivity pneumonitis, showing an organizing pneumonia-like reaction, and intra-alveolar foamy macrophages [[11], [12], [13]].

The second hypothesis refers to amiodarone's active metabolite, monodesethylamiodarone [14], with higher power of accumulation in the lung, leading to enhanced direct cytotoxic activity, via interference in phospholipid metabolism, and mitochondrial injury, leading to apoptosis of alveolar type II pneumocytes, and subsequent fibrotic response [[15], [16], [17]].

Pleural involvement is usually unilateral, with small-to-moderate volume. Pleuritic chest pain, and a pleuritic rub are the most common signs and symptoms. Pericarditis, pneumonitis or even drug-induced lupus can also be associated with the pleural disease [11,18].

Pleural effusions are usually exudative and can be associated with amiodarone pneumonitis in up to one third of patients. However, cases of recurrent unilateral amiodarone pleural effusion without lung parenchyma involvement are rare [4].

Amiodarone induced pleural effusion is a diagnosis of exclusion. It is confirmed once the fluid is drained, the amiodarone dose is reduced or stopped, and the fluid does not reaccumulate [19]. Due to the long half-life of amiodarone, side effects may continue for several weeks, even after the discontinuation of the medication. Additionally, amiodarone also tends to accumulate in skeletal muscle, adipose tissue and lungs, which makes it difficult to clear [1,6]. A few case reports have documented pleural effusion secondary to amiodarone use; however, the majority of cases have parenchymal involvement. During our literature review we did not find any cases that used a surgical approach in a patient with a recurrent pleural effusion, despite dose reduction and multiple thoracentesis.

Surgical interventions in exudative pleural effusions are commonly reserved for recurrent or complicated cases, typically in resistant malignant pleural effusions [20]. Pleurodesis is performed to obliterate the pleural space. It can be achieved in two ways: either chemically, using a sclerosing agent, or mechanically during surgery. Our patient underwent mechanically pleurodesis through VATS with complete resolution. Literature around mechanical pleurodesis in recurrent amiodarone induced pleural effusion is scarce. The decision to proceed with VATS was made after considering that the patient was symptomatic, with recurrent effusions, and the inability to stop amiodarone. Additionally, he had been placed on hold on the kidney transplant list because of this condition. After evaluating the risks versus benefits, the surgical approach was chosen as a faster and definitive treatment of the illness, with great outcomes.

This case report may serve as a precedent, demonstrating that in patients with a similar clinical presentation where initial medical management fails, pleurodesis with decortication through VATS is a viable option for definitive treatment in patients that need to continue the amiodarone.

4. Conclusion

The initial and most critical step in the management of an isolated pleural effusion is determining its underlying etiology. This requires a detailed history, a thorough physical examination, and the exclusion of the most common causes. In our patient, multiple thoracenteses and diagnostic studies were necessary. However, the onset of symptoms, the history of amiodarone use, and the improvement observed upon dose reduction were pivotal in establishing the diagnosis. The cornerstone of pleural effusion management is addressing the underlying cause, with surgical pleurodesis typically reserved for complicated or recurrent effusions. Our case demonstrates that when dose reduction amiodarone does not resolve the effusion and discontinuation is not feasible, surgical intervention may be a viable option.

CRediT authorship contribution statement

Diego Cedano: Writing – review & editing, Writing – original draft, Investigation, Conceptualization. Daria Ovcharuk: Writing – review & editing, Writing – original draft. Faiz Bhora: Writing – review & editing, Writing – original draft. Carlos Remolina: Writing – review & editing, Writing – original draft, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.