To the best of our knowledge, this is the first local study looking at the outcomes of intrapleural alteplase as the choice of IPFT for complex pleural effusion compared to surgical intervention. There are other studies/case reports in our country on different regiments of alteplase with/out dornase alfa [20,21,22,23,24].
There were more patients in the IPFT group compared to the surgical intervention group (n = 40 vs. n = 18). The smaller number in the surgical intervention group could be due to the total usage of IPFT. In 2017, IPFT was first introduced in our centre, as the first-line treatment for complex pleural effusion. Since 2017, none of the patients who underwent IPFT required surgical intervention.
Surgical intervention has been reported to have higher success rates compared to IPFT . The IPFT used in that study was streptokinase. Local data for outcomes of alteplase compared to surgery is limited.
Our study found that the post-intervention chest radiograph changes in IPFT were lower than in the surgical intervention group. The baseline chest radiographs in IPFT were worse than in the surgical intervention group. We excluded patients who had undergone pneumonectomy and lobectomy from our radiographic analysis as post intervention (surgical) chest radiographs have been reported to show more pleural effusion . Twenty-two per cent of surgical patients were converted to pneumonectomy on the table.
The success rate for IPFT was 57.9% which is lower than various studies, between 80 and 90%. [11, 16,17,18, 27,28,29] This is due to the patient profile difference and the smaller sample size. In addition, we encountered missing data, for the post IPFT radiological improvement. Between the years 2017 to 2018, there was a problem with the radiology PAX server in UKMMC, resulting in some files being corrupted. Some patients did not repeat chest radiographs at weeks 4 to 8. These patients defaulted on their follow-up or chose to be followed up at another hospital.
There was no statistical difference in the median length of stay between IPFT (21.5 (3–73) days) and the surgical intervention group (26.5 (7–68) days). Our study’s median duration of intravenous antibiotics was 33.5 (33–75) days. The median duration of intravenous antibiotics may not reflect treatment duration for pleural infection as data collected included total antibiotics used for other indications. Most patients developed nosocomial infections (hospital-acquired pneumonia, thrombophlebitis, urinary tract infection) requiring antibiotics therapy.
Generally, our patients had relatively low white cell count and CRP. This can be explained by two possible reasons: (1) The values were measured prior to intervention and not on day 1 of admission. Hence, some of the patients had already received intravenous antibiotics which may have reduced the white cell count. (2) Patients with tuberculosis (TB) were also included, and patients with pleural TB have relatively low white cell count to begin with."
The significant difference in post-intervention complications (hypotension and bleeding) was because the cases in the surgical intervention arm were more complicated than the cases in the IPFT group. 4 cases out of 18 were converted from decortication to pneumonectomy and lobectomy. The 4 cases were 24, 40, 42, and 75 years old with multiple comorbidities.
MPE was diagnosed either by findings of metastases at the pleura on CT scan or pleuroscopy, pleural fluid cytology, or pleural biopsy histopathology. [30,31,32] There were 4 newly diagnosed lung carcinoma with three confirmed by lung biopsy (2 adenocarcinoma, 1 neuroendocrine carcinoma) and another patient was diagnosed by CT thorax imaging as he declined lung biopsy. Other underlying cancers that came with malignant pleural effusion were two breast cancers, two lung adenocarcinomas, and one each for oesophageal and cervical carcinoma. This finding was similar to previous studies that found the most common primary for malignant pleural effusion was from the lungs, followed by the breast. [33, 34].
Patients with malignant pleural effusion were not referred to surgery due to the advanced stage of cancer, while in pleural infection, there was significant improvement of pleural effusion after fibrinolysis. Longer duration of a chest tube in situ was seen in MPE (median 20 days (11.5–23)) as some of the patients had an indwelling pleural catheter (IPC). The mean duration of the chest drain was long as it was measured from day 1 insertion and not the mean duration of chest drain after intervention. These patients were managed by general medical team and it took few days before referral to the respiratory team was made.
The length of stay was similar between infective (median 20.5 days (15–34.75)) and MPE (median 21.5 days (16.5–26)) partly because of the antibiotics initiated to cover for infection, as evidenced by a high total white cell count. Patients usually have intravenous antibiotics for at least 2–3 weeks. In addition, some patients developed nosocomial infection. The administration of intravenous home antibiotics via peripherally inserted central catheter (PICC) line is not available locally.
While no cases recorded more than 50% reduction in pleural effusion on chest radiograph at week 1, there was a mean reduction of 30.14% ± 14.25, which was not statistically different compared to pleural infection hence the role of the IPFT as a means of reducing the accumulation of pleural fluid in complex pleural effusion. The success rate of IPFT in MPE improved to 50% in weeks 4 to 8, likely due to spontaneous resolution of pleural effusion or initiation of pleurodesis that stopped the re-accumulation of pleural fluid [34, 35]. The prolonged used of antibiotics in the pleural infection group may have contributed to further improvement of pleural opacity.
Our study's most common alteplase regime was 10 mg × 5 doses (52.5%). The decision to use different dosages was dependent on the amount of pleural effusion on chest radiograph and underlying diseases such as liver disease, kidney disease, and anaemia; as well as the concurrent use of anticoagulant.
The improvement of success rate in our study at weeks 4 to 8 (27% to 56%) was due to delayed radiological changes post-intervention. The delayed radiological changes were similar in both surgical intervention and MPE groups.
TB is prevalent in Malaysia, and loculated pleural effusions are a known complication. The etiology is likely due to a delayed hypersensitivity response. Fibrosis of the pleural cavity leads to pleural thickening, and this can compromise pulmonary function . There were 12 patients with tuberculous complex pleural effusion who received IPFT. Of the 12, 1 patient had residual pleural thickening (8%). There is no available data on the role of alteplase in reducing residual pleural thickening, though Cao et al. showed good results with intrapleural urokinase. .
Two cases (3%) in the MPE group developed bleeding (intrapleural haemorrhage, haematuria) after IPFT requiring packed cells transfusion. Both patients developed bleeding after completing 5 doses of 10 mg and 5 mg intrapleural alteplase, respectively. None had a hemodynamic compromise. According to the literature, the incidence of bleeding post-IPFT ranges from 1 to 8%. [11, 17, 18, 27,28,29] Other complications found in our study were fever (17.5%) and chest pain (10%), with the latter being more common in malignant pleural effusion, probably due to non-expandable lung, however, it did not result in early termination of IPFT.
We did not achieve the required number of cases in the surgical intervention arm. Fifteen patients were excluded from radiographic analysis due to corrupted files due to a problem with the PAX server. Another limitation was the inability to differentiate pleural effusion from pleural thickening from chest radiographs alone on follow-up. Furthermore, it would be ideal to have multiple radiologists analyze the images to mitigate bias. We also recognized that in our study, surgical patients were younger. The higher likelihood of comorbidities that comes with increased age may determine outcomes and treatment responses.