Bouros 1999.

Methods	Double‐blind, placebo controlled, parallel group RCT.
Participants	24 male, 7 female, age 21 to 78 years Participants received antibiotics which were appropriate for the organisms cultured, or broad spectrum antibiotics to cover gram‐positive, gram‐negative and anaerobic organisms. Eligibility criteria: parapneumonic effusion as defined by the following criteria: purulent fluid with evidence of bacteria on Gram stain or culture, pH < 7.0, lactate dehydrogenase > 1000 IU/L, pleural fluid glucose < 40 mg/dL with multi‐loculation of pleural fluid on CT or ultrasound, or with an empyema with frank pus on thoracocentesis and multiple locules. The patients also had clinical features of systemic sepsis and chest infection. Exclusion criteria: bronchopleural fistula, known sensitivity to urokinase, bleeding diathesis, and contraindication to thrombolytic therapy such as a history of haemorrhagic stroke, intracranial neoplasm, cranial surgery or head trauma within the previous 14 days, recent major surgery within 10 days, or disease making survival greater than 2 months unlikely.
Interventions	Daily intrapleural urokinase 100,000 IU for 3 days versus saline Intervention group: intrapleural urokinase 100,000 IU via a 28 to 32 French intercostal catheter in 100 mL normal saline on 3 consecutive days. Control group: 100 mL normal saline. The drain was then clamped for 3 hours. Continuous suction of −20 cmH₂O was applied for 18 hours after each instillation. The intercostal catheter was removed after the 4th instillation and when the amount of fluid drained was < 50 mL in 24 hours. Follow‐up period: assessment of chest radiograph at between 7 and 28 months (mean 14).
Outcomes	Primary treatment outcomes: Treatment failure, as defined by death or requirement for surgical intervention. Any patient in the control (saline alone) arm who was deemed to have failed saline therapy alone was then given intrapleural urokinase before being reassessed for surgery. This group were considered to have failed primary treatment for the purposes of this meta‐analysis. Secondary and surrogate treatment outcomes: Improvement in chest radiography (see Discussion) Improvement in CT and/or chest ultrasound Duration and total volume of pleural drainage Subjective clinical improvement (score 1 for symptom improvement, 2 for no change and 3 for deterioration) Time in days to defervescence Time to leucocytes < 10 × 10⁹/L Evidence for coagulapathy at day 0, 3 and at discharge Withdrawal from the trial by continuing with fibrinolytic therapy or proceeding to surgery was made by the attending physician on the basis of "substantial" (unspecified) residual pleural fluid and persistent sepsis. Treatment success was defined as pleural fluid drainage < 50 mL in 24 hours after 3 days' treatment, without residual pleural fluid collection on chest imaging. Follow‐up by chest radiograph and/or chest ultrasound or thoracic CT ranged from 7 to 28 months (mean 14 months).
Notes	Parapneumonic effusion and empyema. Funding "Supported in part by a grant from ASTRA Hellas" — i.e. drug company funding. No additional statements made.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated randomisation sequence.
Allocation concealment (selection bias)	Unclear risk	Information not available.
Blinding (performance bias and detection bias) All outcomes	High risk	The solutions were prepared by the hospital nursing staff, and neither the treating physicians nor the participant were aware of the identity of the treatment. It appears that nursing staff not blinded with potential for unblinding physicians and participant.
Blinding of outcome assessment (detection bias) All outcomes	High risk	Chest radiographs were evaluated independently by 2 experts without knowledge of the randomisation group of the participant. Chest radiographs properly blinded but other measures including observations appear to be made by possibly unblinded nurses or clinicians with high risk of inadvertent unblinding.
Incomplete outcome data (attrition bias) All outcomes	Low risk	No dropouts.
Selective reporting (reporting bias)	Unclear risk	All outcomes described in methods fully reported. Original protocol unavailable to confirm original primary outcomes.
Other bias	Low risk	Partial cross‐over design. In the case of treatment failure the codes were broken and further instillation was undertaken with 3 days of instillation of UK in the control group and VATS in case of UK failure in both groups. Usage of UK after breaking codes has been assumed to be treatment failure equivalent to referral for surgery.