EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Postoperative pleural effusions are common in patients who undergo cardiac surgery and orthotopic heart transplant. Postoperative pleural effusions may also occur as postcardiac injury syndrome. Most of these effusions are nonspecific and develop as a harmless complication of the surgical procedure itself and generally have a benign course. Here, we investigated the cause and clinical and laboratory features of postoperative early and late pleural effusions in orthotopic heart transplant patients.

Materials and Methods: We retrospectively reviewed the medical records of 50 patients who underwent orthotopic heart transplant between 2004 and 2015 at Baskent University. Patient demographics and clinical and laboratory data, including cause of heart failure, presence of pleural effusions at chest radiography in the first year after transplant, timing of onset, microbiologic and biochemical analyses of pleural effusions, and treatment strategies were noted.

Results: Mean age of patients was 39.22 ± 13.83 years (39 men, 11 women). Reason for heart failure was dilated cardiomyopathy in most patients (76%). Nineteen patients (38%) had postoperative pleural effusions, with 15 patients (78.9%) with pleural effusion during the first week after transplant. Of these, 4 patients had recurrent pleural effusion. A diagnostic thoracentesis was performed in 10 patients, with 4 showing transudative effusion and 6 showing exudative effusion secondary to infection (2 patients), postcardiac injury syndrome (1 patient), and hemothorax (3 patients). Aspergillus fumigatus was detected by quantitative culture from pleural effusion in 1 patient. Tube thoracoscopy drainage was performed in 10 patients (25%), and 2 patients received antibiotic therapy.

Conclusions: Pleural effusions are frequent after cardiac transplant. Complications may occur in a small portion of patients, with most effusions being nonspecific and having a benign course with spontaneous resolution. Early diagnostic thoracentesis could improve postoperative outcomes in these patients.

Key words : Complication, Postoperative, Transplantation

Pleural effusion (PE) is a common medical problem with more than 50 recognized causes, including disease local to the pleura or underlying lung, systemic conditions, organ dysfunction, surgical procedures, and drugs.^1,2

Pleural effusion is a frequent outcome in the early (≤ 30 d) and late (> 30 d) postoperative course after cardiac surgery. The causes of PE are generally cardiac cooling, surgical interruption of mediastinal lym-phatic channels, and pleural injury by pleurotomy and postpericardiotomy syndrome in the early postoperative period. Most postoperative pleural effusions are small and are not associated with increased mortality or prolonged hospital stay.^3-6

Cardiac transplant is a surgical treatment per-formed on patients with end-stage heart failure or severe coronary artery disease.⁷ Respiratory com-plications are reported to be frequent in heart transplant recipients^8-10; however, these complications are self-limiting and did not result in worse mortality in most patients.

Although there are several studies reporting PE prevalence after cardiac transplant, limited know-ledge exists about the causes and the treatment of PE after heart transplant.^3-6 The aim of this study was investigate the causes and clinical and laboratory features of postoperative early and late PE in patients after orthotopic heart transplant (OHT).

Materials and Methods

This study was conducted at Baskent University Hospital and was approved by the Ethical Review Committee of the Institute. Written informed consent was not required due to the retrospective nature of the study.

In this study, we retrospectively collected data from medical records of 50 consecutive patients who underwent OHT from January 2004 to December 2015. Patients younger than 18 years old, who died during surgery, or died during the first postoperative day were excluded from the study. Patient demographics and clinical and laboratory data were obtained, including cause of heart failure, presence of PE on chest radiography at time of onset, microbiologic and biochemical analysis results, treatment strategies of PE, and survival rates during the first year after transplant. The mean duration of postoperative mechanical ventilation and intensive care unit stay were also recorded in all patients.

The presence of PE was obtained from chest radiography, thoracic ultrasonography, and thoracic computed tomography scans. Pleural effusion was defined as an abnormal blunting of sharp lateral costophrenic angle on the chest posteroanterior view and a blunting of the sharp posterior costophrenic angle on the lateral radiography,¹¹ an echo-free (anechoic) space between the visceral and parietal pleura in ultrasonography,¹²and a sickle-shaped opacity in the most dependent part of the thorax posteriorly on chest computed tomography.¹³

An ultrasonographic-guided thoracentesis was performed in all patients. A green needle (21G) and 50-mL syringe were used for all thoracentesis. All samples were analyzed for pleural fluid pH and underwent microbiologic, biochemical, and cytologic analyses. Microscopic examination of Gram- and Wright-stained pleural sediment and aerobic, anaerobic, tuberculous mycobacteria, and fungi cultures were obtained from all patients who underwent thoracentesis.

Light criteria were used to differentiate transudates and exudates by analyzing the levels of protein and lactate dehydrogenase (LDH) levels in the pleural fluid and serum.^2,14 According to Light criteria, exudative pleural effusions must meet at least 1 of the following criteria, whereas transudative pleural effusions meet none: (1) pleural fluid protein/serum protein ratio greater than 0.50, (2) pleural fluid LDH/serum LDH ratio greater than 0.60, and (3) pleural fluid LDH greater than two-thirds of the upper normal limit for serum. If a patient showed none of these criteria, the patient was considered to have a transudative pleural effusion in our study.

Empyema was considered when PE in an infectious setting was associated with the presence of pus in the pleural cavity or pleural fluid showed a positive Gram stain or culture.^2,14 A hemothorax was defined as pleural fluid hematocrit level > 50% of the patient’s peripheral blood hematocrit level.¹⁵

Statistical analyses
Data analyses were performed with SPSS software (SPSS: An IBM Company, version 20.0, IBM Corporation, Armonk, NY, USA). Continuous variables are expressed as means ± standard deviation. Frequencies are expressed as both numbers and percentages. Chi-squared tests were used to compare parameters. The level of significance was set at P < .05.

Our study included 50 patients (11 female and 39 male) with mean age of 39 ± 14 years. Clinical characteristics of the patients are presented in Table 1. All patients were treated with tacrolimus, mycophenolate mofetil, and steroids after transplant.

Preexisting pulmonary disease or any other comorbidity, except for their primary heart disease, was not observed in any of the patients. Underlying heart disease was dilated cardiomyopathy in most of the patients (76%) (Table 2).

Nineteen patients had PE in postoperative period. Recurrent PE was detected in 4 of the patients in the follow-up period (Table 3). Most patients (9/50 patients; 18%) had PE in early postoperative period (within 7 days after transplant). Four patients (12%) had PE 30 days after surgery.

A diagnostic thoracentesis was needed in 10 patients with PE. The primary reasons for diagnostic thoracentesis were prolonged fever, pleuritic pain, and an increase in amount of PE despite systemic anti-inflammatory treatment. Because we did not observe any clinical findings or symptoms of complicated PE, diagnostic thoracentesis was not performed in 9 of the patients.

Results of biochemical and cellular examinations of pleural specimens are presented in Table 4. Microbiologic culture was obtained in all patients who underwent diagnostic thoracentesis (10 patients). Aspergillus fumigatus grew in 1 patient’s PE, but no other microbiologic agents were detected in the remaining patients.

Chest tube insertion was performed in 4 patients with PE, with 2 of these patients requiring antibiotics. The antibiotic regimen consisted of 2 × voriconazole at 6 mg/kg intravenously for the first 24 h, then twice daily at 4 mg/kg intravenously for 10 days, and finally twice daily at 200 mg orally for 90 days; meropenem 3 times per day at 500 mg intravenously for 14 days; and ciprofloxacin twice daily at 400 mg intravenously for 14 days (Table 5). Ultrafiltration dialysis was performed because of hypervolemia and acute renal failure in 1 patient.

Pleural effusion resolved spontaneously in 10 of 19 patients (52.6) in the follow-up. There was no relation between presence or absence of PE and recipient age, sex, underlying cardiac disease, and smoking history (P < .36). No correlation was found between survival rate and presence of PE in our patients (P = .46).

Although PE after coronary artery bypass graft surgery and other cardiac surgeries has been well established in the literature, there are limited studies about the prevalence, composition, and cause of PE following OHT in recipients.

The incidence of postoperative PE in adult heart transplant recipients has been reported to be 6.2%.9 In this previous study by Lenner and associates, 90% (9/10) of PEs were detected within the first 6 months after cardiac surgery. In our study, 11 of the 19 patients (79%) developed PE in the first 6 months after OHT, which is consistent with the literature. A recent study by Camkiran Firat and associates from our center reported a similar rate for PE after OHT.8 They studied the occurrence of a variety of pulmonary complications, including the development of pleural effusions, after OHT in 83 patients. They found the prevalence rate of pleural effusion after transplant to be 22.8% (n = 19 patients). No data about composition of the effusions were reported in the studies from Lenner and associates and Camkiran Firat and associates, highlighting the uniqueness of our present study.

Pleural effusions after OHT may develop due to the surgical procedure, infections, hypervolemia, or adverse effects of immunosuppressive drugs. Most incidences of PE are bilateral, and up to 85% of heart transplant recipients develop PE in the first year after surgery.¹⁰ In our study, PE developed in 38% of adult cardiac transplant recipients during the 1-year follow-up. Consistent with the literature, pleural effusion was unilateral in less than 20% of patients in our study.

Most PEs are described as harmless in the literature, with only a small number of patients requiring diagnostic analyses and treatment. Nevertheless, various infectious agents, including viruses, bacteria, mycobacteria, fungi, and protozoa, may cause pneumonia and pleural effusion in immunocompromised patients. These may be related to the pneumonia or may be seen as isolated. Few studies have reported on the bacterial causes of PE in heart transplant recipients. In 3 of our patients, the cause of PE was parapneumonic, with 1 patient diagnosed with empyema and the other 2 showing uncomplicated exudates due to early nosocomial pneumonia.

Invasive fungal infections are common in transplant recipients, especially in those with prolonged neutropenia. However, pleural involvement is uncommon in OHT recipients. It has been shown that fungal infections are associated with empyema, requiring decortication and chest tube drainage in cardiac recipients.¹⁶ In 1 study, no relation was found between the mortality and the presence of PE, although a higher mortality rate (75%) was observed in patients with Aspergillus infection.⁹In the present study, Aspergillus fumigatus was detected in 1 of our patients with PE who died after a chest tube drainage and effective medical treatment with voriconazole. We suggest that microbiologic examination of pleural fluid samples for fungi should be performed routinely in heart transplant recipients with exudative PE to decrease mortality of the patients.

In our study, 9 of the 50 patients examined died after transplant (4 patients died within 1 year after and 5 patients died 2 years after OHT). No relation was detected between survival rates and the presence of PE. This result could be explained by 3 reasons: (1) PE following OHT is not generally harmful and does not affect the outcome of transplant; (2) our study reported on the first year after transplant and our year 1 mortality rate was also lower than reported in the literature (8%); and (3) the major causes of mortality were organ rejection, cardiac problems, and other system infections (89%) in our study group. Only 1 patient died due to PE (empyema) in our population, which did not affect our statistical results.

Tacrolimus is a calcineurin inhibitor of choice for maintenance immunosuppression in heart recipients. Fluid and sodium retention, hypervolemia, and PE have been reported to occur in the posttransplant period.¹⁷ Mycophenolate mofetil is the morpholino ethyl ester of mycophenolic acid with potent immunosuppressive properties in patients who have had solid-organ transplant procedures. Mycophenolate mofetil has a potential adverse effect for hypervolemia and edema similar to that shown with tacrolimus. Tacrolimus also has a potential adverse effect for developing PE (5%-36%).^18,19 Symptoms of drug-induced PE are nonspecific and include pleuritic chest pain, cough, dyspnea, and occasional fever. The latency between the development of PE from first drug exposure is several months.²⁰ Approximately 25 drugs have been implicated in the development of PE, and other drugs likely have the potential to cause PE. Nevertheless, immunosuppressive agents may cause PE with potentially harmful effects.¹⁷ We believe that further studies are needed to outline the role of immunosuppressive drugs and PE.

In our study, 11 patients had PE in the early period (≤ 30 d), whereas 4 patients had PE in the late period (< 30 d). Pleural effusion resolved in 1 patient after cessation of tacrolimus therapy. Pleural effusion was transudative, and eosinophilia was not detected in pleural fluid analysis in this patient. We suggest that drug-induced PE should be considered in the differential diagnosis of late postoperative PE, even if the PE is not reflecting the well-known characteristics of drug-induced PE in heart recipients.

In our study, most patients with PE were detected in the first week after surgery and no relation was found between presence of PE and mortality. In nearly one-third of patients with PE, the effusions were observed as a result of pleural infection despite many PEs being reported to be harmless in these patients.21 Moreover, in our study, Aspergillus was detected in the culture in 1 patient with PE. Therefore, we suggest that diagnostic thoracentesis and a fungal culture should be conducted in patients with PE if there is any clinical suspicion.

Most PEs have been described as harmless in the literature, with diagnostic analyses and treatment required in a small number of patients. However, if the patient is febrile and has pleuritic chest pain, if the effusion shows progression on chest radiographic images, or if the patient shows worsened clinical status, a diagnostic thoracentesis should be performed without any delay. Drug-induced PE should always be considered in the differential diagnosis of PE to avoid overtreatment and unnecessary diagnostic procedures in these patients. Microbiologic examination of pleural fluid samples for fungi should be performed routinely in heart transplant recipients with exudative PE to decrease mortality of the recipients.

Volume: 14 Issue: 3 November 2016 - Supplement - 3

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