Parapneumonic effusion is the filling of the pleural cavity with exudative pleural fluid, which develops secondary to pneumonia. Although the majority of parapneumonic effusion is improved with antibiotic treatment, some of this condition progress from uncomplicated parapneumonic effusion to complicated parapneumonic effusion (CPPE) or even to empyema. The basic principle of treating CPPE includes an appropriate antibiotic treatment and adequate drainage of the infected fluid collection1. Percutaneous catheter drainage is the main interventional modality to decrease the amount of CPPE; however, this approach is not always successful owing to a thick layer of fibrin deposit and loculated nature of effusions. Therefore, intrapleural fibrinolytic treatment has been widely employed to lyse the fibrinous structures in pleural space2-5.

Urokinase is one of the most widely used fibrinolytic agents3; however, its proper dosage remains entirely empiric. Because most previous studies used more than 100,000 IU for single fibrinolysis, conventional single dose has been thought to be 100,000 IU6. Fibrinolysis inherently accompanies the risk of hemorrhagic complications and is relatively expensive treatment; therefore, the concept of lower dose urokinase was raised by some physicians. The authors have taken lower dose strategy for several years to reduce side effects and enhance cost-effectiveness. However, there has been no evidence of low dose fibrinolytic treatment. We herein sought to investigate the treatment efficacy of half dose urokinase compared with conventional dose urokinase.

Among 1,250 patients diagnosed as having pneumonia, 92 patients with CPPE or empyema who need intrapleural urokinase treatment were enrolled in this study, of whom 44 were treated with daily half dose urokinase 50,000 IU and 48 received daily conventional dose urokinase 100,000 IU. Both groups were homogeneous with regard to clinical and pleural fluid characteristics (Tables 1, 2), although pre/post-urokinase serum white blood cell count and the prevalence of empyema were higher in the half dose group. The radiologic findings suggestive of severe involvement did not show statistical differences in the both groups (Table 3).

Table 4 shows the clinical outcomes of patients treated with intrapleural urokinase. The treatment success rate was not different between two groups (p=0.048). There were eight failures (18.2%) in the half dose group and eight failures (16.7%) in the conventional dose group. Each one patient in the both group died during hospitalization. Each two patients received surgical treatment owing to ineffective intrapleural urokinase treatment. Six patients in the half dose group and five patients in the conventional dose group were transferred to local convalescent hospitals without clinical improvement. As shown in Table 5, a significantly smaller amount of urokinase was administered in the half dose group, although the number of fibrinolysis, total amount of drained effusion through percutaneous catheter, and indwelling catheter duration was not different between the two groups. There was no clinically relevant bleeding event in both groups. In the multivariate logistic regression analysis, urokinase dose was not a factor to predict treatment success or failure. Only severe radiologic involvement was a significant predictor for treatment failure (odds ratio, 6.204; 95% confidence interval, 1.247-30.871; p=0.026).

In this retrospective observational series enrolling patients from real-world clinical practice, half dose urokinase 50,000 IU is equally as effective as conventional dose 100,000 IU to treat patient with CPPE with or without empyema who need percutaneous drainage. The results of this study demonstrated the following. First, there were no significant differences in the rate of treatment success between two groups. Second, the rate of in-hospital death or surgical treatment were also not significantly different. Third, intrapleural urokinase fibrinolysis was a useful therapeutic approach for the majority of patients irrespective of the dose.

Since the successful fibrinolysis using streptokinase8, there have been numerous reports of fibrinolysis to treat patients with CPPE. Fibrinolysis using urokinase was first reported by Moulton et al.9. In their study, the empirical urokinase doses of 80,000-150,000 IU were used without specific explanation for choosing such doses. In the following studies, urokinase dose varied from 100,000 IU to 250,000 IU10-13. Recently, streptokinase and urokinase are the most widely used fibrinolytic agents and guideline recommend 250,000 IU for streptokinase and 100,000 IU for urokinase as usual dose6. However, recommended urokinase dose is mainly based on small observational studies, and dose is frequently to change in real clinical practice. Bouros et al.14 firstly reported a study regarding the clinical applicability of fibrinolysis using lower dose urokinase, in which patients with CPPE and empyema were successfully treated with urokinase 50,000 IU. However, the number of enrolled patients was only 20 and this half dose was not compared with conventional higher dose 100,000 IU. To the best of our knowledge, our study is the first study to compare the fibrinolysis outcomes between half dose urokinase and conventional dose. Our study showed high treatment success rate and low surgical treatment rate. The need for surgical treatment has been an important endpoint in previous studies regarding intrapleural fibrinolysis and recent meta-analysis concluded that fibrinolysis alone may prevent the need of surgical drainage15. What is notable in our study is that a minority of patients in the half dose group (4.5%) as well as in the conventional dose group (4.2%) underwent surgical treatment. These values are in contrast to the 16% of patients requiring surgical referral within 3 months of having received streptokinase in the MIST1 study (first multicenter intrapleural sepsis trial)16. Recent advances in treatment other than intrapleural fibrinolysis for CPPE patients may contribute to these low surgical treatment rates. Another notable point in our study is that the total amount of drained effusion during catheter indwelling time was not statistically different between the both groups. This result supports that the lower dosage of the UK shows the same clinical and radiologic recovery under the similar severity of CPPE.

Intrapleural fibrinolysis with lower dose urokinase is reasonable in several aspects. Urokinase is an expensive drug, therefore, the lower urokinase dose would result in a reduction of medical expense. In addition, although the incidence is low, intrapleural fibrinolysis accompanies the possibility of bleeding complications17,18, so lower urokinase dose might decrease bleeding events in vulnerable patients. Since increased dose and interval of fibrinolysis was associated with increased treatment efficacy in previous experimental study19, further prospective randomized clinical trial is warranted to reveal unknown benefit and pitfall of fibrinolysis using half dose urokinase.

This study has a few limitations. First, our study was a retrospective observational study. Therefore, the possibility of selection bias and/or residual confounding from unknown or unmeasured covariates cannot be excluded. However, we included relatively a large number of patients from two tertiary hospitals. Second, urokinase dose was unequally distributed by the participating hospitals. However, participating two hospitals had similar treatment policy except for the urokinase dose. In addition, both groups were relatively well-matched with regard to baseline clinical and laboratory characteristics. Even though serum white blood cell count and the prevalence of empyema, which might be poor prognostic factors, were higher in the half dose group, treatment success rate was not different between both groups. Furthermore, urokinase dose was not a predictor of treatment success in the multivariate analysis. Third, there is a possibility that our study included relatively milder patients compared to the MIST. Therefore, our results may not be applicable to patients with severe CPPE or empyema who need prior surgical treatment without fibrinolysis. Fourth, there were several patients whose final clinical outcomes were not confirmed because these patients were transferred to local hospitals without clinical improvement. Finally, long-term clinical outcomes were not evaluated in this study.

In conclusion, intrapleural fibrinolysis with half dose urokinase is equally as effective as conventional dose to treat patients with CPPE with or without empyema at possible lower cost.