Published ahead of print on May 4, 2006, doi:10.1164/rccm.200601-027OC
© 2006 American Thoracic Society doi: 10.1164/rccm.200601-027OC
Comparison of Urokinase and Video-assisted Thoracoscopic Surgery for Treatment of Childhood EmpyemaDepartment of Respiratory Medicine, Department of Cardio-Thoracic Surgery, and Department of Radiology, Great Ormond Street Hospital for Children NHS Trust; Portex Anaesthesia, Intensive Therapy and Respiratory Unit, Institute of Child Health; and Department of Public Health and Policy, London School of Hygiene and Tropical Medicine, London, United Kingdom Correspondence and requests for reprints should be addressed to Samatha Sonnappa, M.D., D.Ch., M.R.C.P., F.R.C.P.Ch., Portex Anaesthesia, Intensive Therapy and Respiratory Unit, Level 6, Cardiac Wing, Institute of Child Health, 30, Guilford Street, London WC1N 1EH, UK. E-mail:s.sonnappa{at}ich.ucl.ac.uk
Background: Despite increasing incidence and morbidity, little evidence exists to inform the best management approach in childhood empyema. Aim: To compare chest drain with intrapleural urokinase and primary video-assisted thoracoscopic surgery (VATS) for the treatment of childhood empyema. Methods: Children were prospectively randomized to receive either percutaneous chest drain with intrapleural urokinase or primary VATS. The primary outcome was the number of hospital days after intervention. Secondary end points were number of chest drain days, total hospital stay, failure rate, radiologic outcome at 6 mo, and total treatment costs. Results: Sixty children were recruited. The two groups were well matched for demographics; baseline characteristics; and hematologic, biochemical, and bacteriologic parameters. No significant difference was found in length of hospital stay after intervention between the two groups: VATS (median [range], 6 [3–16] d) versus urokinase (6 [4–25] d) (p = 0.311; 95% confidence interval, –2 to 1). No difference was demonstrated in total hospital stay: VATS versus urokinase (8 [4–17] d and 7 [4–25] d) (p = 0.645); failure rate: 5 (16.6%); and radiologic outcome at 6 mo after intervention in both groups. The mean (median) treatment costs of patients in the urokinase arm $9,127 ($6,914) were significantly lower than those for the VATS arm $11,379 ($10,146) (p < 0.001). Conclusions: There is no difference in clinical outcome between intrapleural urokinase and VATS for the treatment of childhood empyema. Urokinase is a more economic treatment option compared with VATS and should be the primary treatment of choice. This study provides an evidence base to guide the management of childhood empyema.
Key Words: intrapleural urokinase • primary video-assisted thoracoscopic surgery • prospective randomized trial The incidence of empyema is increasing worldwide, causing significant childhood morbidity with an estimated 0.6% of childhood pneumonia progressing to empyema (1–4). The aim of treatment in empyema is to sterilize the pleural cavity, reduce fever, and ensure full expansion of the lung and return to normal function. Many treatment options are available, including antibiotics alone or in combination with thoracocentesis, chest-drain insertion, chest drain and fibrinolytics, mini-thoracotomy, open decortication, and video-assisted thoracoscopic surgery (VATS). However, treatment is not standardized and currently patient care is dependent on local practice and physician preference. These issues were recently highlighted by the British Thoracic Society (3) (www.brit-thoracic.org.uk) in the publication of guidelines on the management of pleural infection in children, which states that there is a lack of grade A evidence available to inform the best management approach (5). Urokinase has been demonstrated as safe in several uncontrolled studies, and has been found to play an important role in the treatment of empyema (6–8). Some centers use fibrinolytics such as urokinase, and in the event of failure patients will undergo either open decortication or VATS (9). In a large controlled trial, administration of intrapleural streptokinase in adults with empyema was not found to reduce mortality, rate of surgery, or length of hospital stay (10). However, in the only randomized prospective study in children comparing the instillation of urokinase through percutaneous chest drains to normal saline, the urokinase group had a significantly reduced hospital stay after intervention (7.4 d vs. 9.5 d; ratio of geometric means 1.28; confidence interval [CI], 1.16–1.41) (11). This study also found shorter hospital stay with small percutaneous chest drain insertion compared with large bore chest drains (7.2 d vs. 9.4 d). Conversely, the only other randomized controlled study of fibrinolytics that compared instillation of streptokinase with normal saline in Indian children found no difference between all outcome measures in both groups (12). Interest in using primary VATS in the treatment of empyema in children has increased over the past few years (13). Kern and Rodgers were the first to use VATS for the treatment of empyema in children in 1993 (14). Since then there have been various case series reports of its success in children (14–23). Subramaniam and coworkers reported a postoperative hospital stay of 4.63 d ± 0.33 d (20), and Grewal and colleagues reported one of 4.9 d ± 2.7 d (24). The single randomized controlled study comparing fibrinolytics (streptokinase) to VATS in adults found that the VATS group had a higher primary success, fewer days in hospital, and fewer days with a chest drain (25). There has been no such study in an equivalent pediatric group, and adult data cannot be extrapolated to children as empyema has an estimated mortality of 20% in adults (26), whereas in children death rarely occurs. The only study in children to compare urokinase and early VATS was a retrospective review of clinical practice which showed that patients who received VATS had a significant reduction in total length of hospital stay (15). Our study is the first randomized prospective trial to compare chest drain with intrapleural urokinase against primary VATS for the treatment of empyema in children. Some of the results of this study have been previously reported in the form of an abstract (27).
We hypothesized that patients with empyema treated with primary VATS had a shorter postoperative hospital stay than patients receiving percutaneous chest drain insertion with intrapleural urokinase.
Study Design This study was a prospective, randomized trial performed over 3 yr at Great Ormond Street Hospital for Children (GOSH) (London, UK). The study subjects were recruited from patients referred to GOSH, a tertiary respiratory center, for further management of parapneumonic effusions. Patients were included if they were under the age of 16 yr and had radiographic evidence of empyema (i.e., pleural fluid on chest X-ray [CXR] and ultrasound). Indications for drainage were a persistent fever of 38°C (100°F) or greater after more than 24 h of parenteral antibiotic treatment or respiratory distress (tachypnea and/or oxygen requirement) caused by the pleural collection. Patients were excluded from the study if thoracocentesis or chest drain insertion was performed or attempted at the referring hospital, if there was a history of an underlying cardiac disease or previous cardiac surgery or known immunodeficiency. Each patient had blood culture, hemoglobin, white blood cell (WBC) and differential counts, platelet count, coagulation profile, C-reactive protein (CRP), electrolytes, albumin, lactate dehydrogenase (LDH), CXR, and chest ultrasound scan (USS) performed on entry into the study. Those with low platelets or abnormal clotting received VATS even if assigned to the urokinase arm, and were analyzed on the basis of intention to treat. Empyema was categorized into three stages based on the appearance of pleural fluid on USS: Stage 1, anechoic nonseptated fluid; Stage 2, hyperechoic fluid with fibrinous septation; and Stage 3, hyperechoic loculations with or without thick parietal peel (28, 29). Following the intervention pleural fluid was sent for culture, broad range16S rDNA polymerase chain reaction (PCR), WBC, albumin, and LDH. Broad range 16S rDNA PCR was performed on pleural fluid using a previously described technique (30).
Randomization
Treatment Protocol VATS was performed under general anesthesia with either one or both lungs ventilated, depending on the size of the child. Two or three ports were made in the chest, with the child in the lateral decubitus position. One port was used for the camera and the others for grasping instruments. The chest cavity was insufflated with carbon dioxide to aid collapse of the lung for better visualization. The free fluid was evacuated and loculations drained, the fibrinous adhesions were separated, and the pleural debris removed from the pleural lining using endoscopic grasping forceps or by extensive irrigation and suction. If on inspecting the pleural cavity and trial of thoracoscopic decortication the surgeon deemed VATS to be inappropriate (thick peel preventing lung expansion), the procedure was converted to a mini-thoracotomy. This was deemed as a failure of VATS for our trial purpose. After the procedure, one or two chest drains were placed in the portholes on negative suction pressure of 10–20 cm of H2O to facilitate further drainage. Adverse events related to treatment were recorded. In both treatment groups the chest drains were removed when there was minimal drainage (40–60ml/24 h), and the patients were discharged home if they remained afebrile for 24 h after drain removal and at the attending pediatrician's discretion. Duration of hospital stay after intervention was calculated from the date of procedure to the date of discharge. All patients initially received intravenous cefuroxime and oral azithromycin, which were subsequently rationalized according to microbiological results.
Outcome Measures CXRs (postero-anterior views) were performed at 6 mo after intervention. CXRs were scored in separate sessions by two observers (radiologists at different levels of seniority) blinded to treatment and outcome parameters. The CXRs were assessed for the following five parameters: pleural thickening, parenchymal changes, bronchial wall dilatation and thickening, lung expansion, and lung attenuation. If any one of these parameters were found to be abnormal, then the CXRs were classified as abnormal. Interobserver reliability was calculated using a Kappa statistic.
Sample Size and Data Analysis
Baseline characteristics were compared between the two groups using
Cost Analysis
Ethical Aspects The project was approved by the local ethics committee. The trial is fully registered with clinicaltrials.gov (ID: NCT00144950).
Patients From January 2002 to February 2005, 80 children were referred to GOSH for further management of pleural effusions from secondary care centers. Of these, 60 patients were randomized, 30 into each treatment arm (Figure 1). Of the 30 patients randomized to VATS, 25 had VATS only, 4 had VATS and mini-thoracotomy due to the presence of thick peel preventing full lung expansion, and 1 patient had VATS performed twice. Of the 30 patients randomized to the urokinase arm, 28 had urokinase and 2 had VATS, as they had prolonged clotting. The two groups were well matched for demographics and baseline characteristics including duration of illness before intervention, hematologic, biochemical, and bacteriologic parameters (Table 2).
Primary End Point We did not find a clinically significant difference in hospital stay after intervention between the two treatment groups (p = 0.311, 95% CI of the median difference, –2 to 1). Patients with VATS had a median post-intervention hospital stay of 6 d (range, 3–16 d) compared with children who received urokinase (6 d; range, 4–25 d).
Secondary End Points A total of 16 patients were lost to follow-up at 6 mo, and CXRs at 6 mo after intervention were performed in 44 patients (24 in the VATS arm and 20 in the urokinase arm). Thirty-nine (88.6%) of the patients had abnormal CXRs (21 in the VATS arm and 18 in the urokinase arm). There was moderate agreement between the two radiologists in classifying the CXRs as normal or abnormal using our devised scoring system (Kappa = 0.54). There was no significant difference in the radiologic outcome between the two groups (p = 0.27). When assessed for USS staging at entry into the study 16 (10 in the urokinase group and 6 in the VATS group) had Stage 1 disease, 21 (8 in the urokinase group and 13 in the VATS group) had Stage 2 disease, and 23 (12 in the urokinase group and 11 in the VATS group) had Stage 3 disease. When the treatment groups were compared depending on USS staging, the VATS group had a reduced hospital stay of borderline statistical significance noted in the USS Stage 1 patients: VATS versus urokinase (5 [3–5] d vs. 6 [4–25] d; p = 0.056). However, this result is likely to be skewed by an outlier in the urokinase group who had a hospital stay of 25 d. When this outlier was omitted from analysis, the effect disappeared (p = 0.088). We did not find a difference in postintervention hospital stay between the two groups in USS Stage 2: VATS versus urokinase (6 [3–16] d vs. 5 [5–9] d; p = 0.86) and USS Stage 3 (7 [4–12] d vs. 7 [5–19] days; p = 0.83).
Adverse Events
Cost Analysis
Microbiology
This prospective study is the first to demonstrate that there is no significant clinical difference in duration of hospital stay after intervention between percutaneous chest drain with intrapleural urokinase and primary VATS for the treatment of empyema in children. While there have been many case series comparing surgical interventions with fibrinolytics, none were properly controlled randomized studies. The aim of instillation of fibrinolytics into the pleural cavity is to lyse the fibrinous strands and clear lymphatic pores, thus improving drainage (11). There have been more than 10 published reports on the use of fibrinolytics in children (6, 7, 12, 31–42), but only two are randomized controlled trials, neither of which compared fibrinolytics to surgical treatment. The case series reports describe management of empyema in more than 300 children using streptokinase, urokinase, alteplase, or tissue plasminogen activator, but each used different protocols and hence is not comparable. In these series, the success rates were approximately 80–90%, and it was clearly demonstrated that the use of fibrinolytics is safe in children. One surgical concern is that patients may be more likely to fail rescue VATS treatment following urokinase, as it is suggested that urokinase causes intrapleural loculations to become very adhesive, and increases the difficulty of the VATS procedure (43, 44), although this may simply be a result of operating at a later stage. VATS for the primary treatment of empyema in children has been gaining popularity over the past decade. Proponents of VATS suggest that it has the potential advantage over open surgery of limiting the morbidity to skin, muscles, nerves, and supporting structures that occurs after a large surgical incision (13) and that entails pain, infection, limitation of movement, and cosmetic scarring (45). Furthermore, VATS may reduce cytokine responses compared with conventional surgery (46). However, these statements are based on clinical experience rather than carefully conducted trials. The major limitation of VATS is that it is highly dependent on the skill of the operator; poor results in some centers have been reported (16), and surgical expertise to perform pediatric VATS is limited to a few major centers in the United Kingdom (47, 48). Our study was not designed as an equivalence study, as we based our hypothesis on previously reported results and expected patients randomized to VATS to have a shorter hospital stay. We chose our primary outcome measure as length of hospital stay after intervention rather than as total hospital stay, as we were evaluating the effect of the two different management approaches. The two treatment groups in the study were well matched for baseline characteristics. We did not find a difference in hospital stay after intervention between the two groups. The precision of the estimates (95% CI) suggests that the true difference in the hospital stay between the two groups ranges from two fewer days to one extra day for the VATS group. This suggests that there is no clinically significant difference of more than two hospital days between these two treatment groups. Alternatively, an equivalence study to determine no difference between the two treatments with a precision of less than 1 d would have required over 1,000 patients. Even if a multicentered trial was conducted, recruiting such a large number of patients into the study would be logistically difficult and is unlikely ever to be performed, particularly as pediatric VATS expertise is limited to a few specialist centers in the United Kingdom. It has been suggested that ultrasound is useful to stage the disease in childhood empyema (28). We did not find USS staging to be useful in evaluating the success of treatment. However, our study was not designed to evaluate this outcome and therefore may have lacked the power to detect a difference between the groups. A study of adult patients also found that ultrasound was unable to accurately identify the stage of the disease, using Light's criteria as the gold standard (49). Light's criteria (50) have not been fully evaluated in children, and it is difficult to know whether they are applicable to the pediatric population. There was no statistically significant difference in all the secondary outcome measures except costs between the two groups. Although there was a borderline statistical difference in the number of chest drain in situ days between the two groups in favor of the VATS group, no significant clinical difference was demonstrated, as this did not have an impact on the hospital stay after intervention. The protocol is biased against the urokinase group, because intrapleural urokinase is administered over 3 d.
The failure rates were similar in both the treatment arms; that is, five patients in the urokinase arm did not respond to conservative management and had to proceed to have secondary VATS with or without mini-thoracotomy, and four patients in the VATS arm had the operation converted to a mini-thoracotomy. Interestingly, four of the five urokinase failures were from "Winter 2003," which may reflect a change in virulence of pathogens from winter to winter. These results ( The commonest causative organism isolated in our study was fully penicillin-sensitive S. pneumoniae, suggesting that the increase in the incidence of empyema is not due to the emergence of penicillin-resistant strains. There was no impact of the causative organism on the length of hospital stay. We acknowledge that there are some limitations to this study. The study reflects single-center practice; however, patients are diverse and representative of the United Kingdom as a whole, as referrals are from the south-east of England and VATS was performed by three different surgeons trained in three different institutions. Radiologic follow-up at 6 mo was somewhat arbitrary, as no validated CXR scoring systems for evaluation of radiologic resolution of empyema exist. However, the CXR changes that were evaluated in our study were the common changes looked for on radiographic assessment after infection, and there was considerable agreement between our two radiologists. The commonest abnormality noted was pleural shadowing, which was seen in 38 (86%) of the 44 CXRs assessed.
No functional outcome measures were included in the data analysis, although spirometry and ventilation perfusion ( An important observation is that VATS is $2,250, or 25% more expensive than intrapleural urokinase at our center without including additional start up costs for provision of VATS service. The main limitations of this analysis are that it only considers costs and not effectiveness; each cost estimate is based on only 30 patients; and the prices used are from a single institution in the United Kingdom. However, it is unlikely that there is a significant cost differential between the two treatments in other developed countries. All patients undergoing VATS were assumed to have a CT chest scan, as most surgeons request a preoperative CT chest scan and it is not our practice to routinely request CT chest scans for treatment with intrapleural urokinase. Even if costs of CT chest scans were omitted from the analysis, VATS was still significantly more expensive than intrapleural urokinase. The cost analysis does strongly suggest that VATS will only be less expensive if the probability of treatment success is much lower with urokinase than with VATS. Our study has shown that both intrapleural urokinase and primary VATS are equally effective for the treatment of childhood empyema, and therefore VATS is unlikely to be less expensive. There have been no reports addressing the financial burden to health services, should VATS be the favored approach for the treatment of empyema in children. The incidence of childhood pneumonia is in the order of 10–15 cases per 1,000 children (52). There were an estimated 12 million children aged 0–16 yr in the United Kingdom (www.statistics.gov.uk) and 74 million children in the United States (www.childstats.gov) in mid-2005. If 0.6% of the pneumonias progressed to empyemas, this would mean 1,080 and 6,660 cases of childhood empyema per year in the United Kingdom and the United States, respectively. This broadly would indicate a saving of $2.5 million and $15 million per annum to the UK and U.S. health services, respectively, if intrapleural urokinase is the first line of treatment for childhood empyema compared with VATS. In conclusion, we have provided an evidence base to guide the management of childhood empyema. Intrapleural urokinase should be the primary treatment of choice in the treatment of uncomplicated empyemas in children. This will have further implications on reducing the financial burden of costs to the health services.
The authors thank Dr. Robert Dinwiddie, Dr. Colin Wallis, Dr. Paul Aurora (Respiratory Pediatricians); Dr. John Hartley, Dr. Kathryn Harris (Microbiologists); Dr. Alistair Calder (Radiologist); Ms. Deborah Ridout (Statistical Support); and Ms. Moranti Falade (Service Agreement and Costing).
Research at the Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust benefits from Research and Development funding received from the NHS Executive. Originally Published in Press as DOI: 10.1164/rccm.200601-027OC on May 4, 2006 Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Received in original form January 6, 2006; accepted in final form April 28, 2006
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ABSTRACT
Hypothesis
38.0°C (100°F), 4 d after intervention associated with persistence of fluid on pleural USS. Those who failed urokinase treatment had secondary VATS. 
2, t tests, and Mann-Whitney U tests where appropriate. All data were analyzed according to the intention-to-treat principle. A p value of 
0.05 was considered statistically significant. 
16% failure rate) reflect the failure rates reported in various other studies: 6–15% for chest drains with fibrinolytics (
/
) scan at 6 mo after intervention were included in the study design, with ethical approval. Significant proportions (71%) of the recruited patients were under 6 yr of age, and it would have been difficult to measure lung function by standard spirometry. We were unable to perform