DOI: 10.1542/peds.2013-3935; originally published online October 27, 2014;Pediatrics

Matute, María A. García-Casillas, Víctor Álvarez and Antonio Moreno-GaldóA.Indalecio Cano, María López, Francisco Hernández, Eduardo G. Pérez-Yarza, José

Claudia Marhuenda, Concepció Barceló, Inmaculada Fuentes, Gabriela Guillén,Multicenter Clinical Trial

Urokinase Versus VATS for Treatment of Empyema: A Randomized  

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located on the World Wide Web at: The online version of this article, along with updated information and services, is

 

of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2014 by the American Academy published, and trademarked by the American Academy of Pediatrics, 141 Northwest Pointpublication, it has been published continuously since 1948. PEDIATRICS is owned, PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

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Urokinase Versus VATS for Treatment of Empyema:A Randomized Multicenter Clinical Trial

WHAT’S KNOWN ON THIS SUBJECT: There are discrepanciesregarding which treatment is best in clinical practice for childrenwith parapneumonic empyema, with some authors favoringvideo-assisted thoracoscopy and others favoring intrapleuralfibrinolytic agents.

WHAT THIS STUDY ADDS: This study is one of the few randomizedclinical trials on this subject in children and the first multicentertrial. It exclusively included patients with septated empyema.Thoracoscopy and fibrinolysis with urokinase were equallyeffective for this condition.

abstractBACKGROUND AND OBJECTIVE: Parapneumonic empyema (PPE) isa frequent complication of acute bacterial pneumonia in children.There is limited evidence regarding the optimal treatment of this con-dition. The aim of this study was to compare the efficacy of drainageplus urokinase versus video-assisted thoracoscopic surgery in thetreatment of PPE in childhood.

METHODS: This prospective, randomized, multicenter clinical trial en-rolled patients aged ,15 years and hospitalized with septated PPE.Study patients were randomized to receive urokinase or thoracoscopy.The main outcome variable was the length of hospital stay after treat-ment. The secondary outcomes were total length of hospital stay, numberof days with the chest drain, number of days with fever, and treatmentfailures. The trial was approved by the ethics committees of all theparticipating hospitals.

RESULTS: A total of 103 patients were randomized to treatment andanalyzed; 53 were treated with thoracoscopy and 50 with urokinase.There were no differences in demographic characteristics or in themain baseline characteristics between the 2 groups. No statisticallysignificant differences were found between thoracoscopy and uroki-nase in the median postoperative stay (10 vs 9 days), median hospitalstay (14 vs 13 days), or days febrile after treatment (4 vs 6 days). Asecond intervention was required in 15% of children in the thoracoscopygroup versus 10% in the urokinase group (P = .47).

CONCLUSIONS: Drainage plus urokinase instillation is as effective asvideo-assisted thoracoscopic surgery as first-line treatment ofseptated PPE in children. Pediatrics 2014;134:e1301–e1307

AUTHORS: Claudia Marhuenda, MD,a Concepció Barceló,MD,a Inmaculada Fuentes, MD,b Gabriela Guillén, MD,a

Indalecio Cano, MD,c María López, MD,c FranciscoHernández, MD,d Eduardo G. Pérez-Yarza, MD, PhD,e,f,g

José A. Matute, MD,h María A. García-Casillas, MD,h VíctorÁlvarez, MD, PhD,i and Antonio Moreno-Galdó, MD, PhDj

Departments of aPediatric Surgery, bClinical Pharmacology, andjPediatric Pulmonology, Hospital Universitari Vall d’Hebron,Universitat Autònoma de Barcelona. Barcelona, Spain;cDepartment of Pediatric Surgery, Hospital 12 de Octubre,Madrid, Spain; dDepartment of Pediatric Surgery, Hospital La Paz,Madrid, Spain; eDepartment of Pediatrics, University of theBasque Country, UPV/EHU, San Sebastian, Spain; fDivision ofPediatric Respiratory Medicine, Hospital Universitario Donostia-Instituto Biodonostia, San Sebastián, España; gBiomedicalResearch Centre Network for Respiratory Diseases (CIBERES),San Sebastián, Spain; hDepartment of Pediatric Surgery, HospitalGregorio Marañón, Madrid, Spain; and iDepartment of PediatricSurgery, Hospital Central de Asturias, Oviedo, Spain

KEY WORDSchildren, empyema, fibrinolytics, parapneumonic effusions,randomized clinical trial, urokinase, VATS, video-assistedthoracoscopic surgery

ABBREVIATIONSIQR—interquartile rangeUK—urokinaseVATS—video-assisted thoracoscopic surgery

Drs Marhuenda, Fuentes, and Moreno-Galdó were responsiblefor the study concept and design, data acquisition, data analysisand interpretation, and drafting of the manuscript; Dr Barcelówas responsible for the study concept and design andacquisition of data; Drs Guillén, López, and García-Casillas wereresponsible for data acquisition; Drs Cano, Hernández,Pérez-Yarza, Matute, and Álvarez were responsible for andcoordinated data acquisition at 1 of the 6 sites. All authorsagreed to be accountable for all aspects of the work in ensuringthat questions related to the accuracy or integrity of any part ofthe work are appropriately investigated and resolved; they wereall responsible for critical revision of the manuscript forimportant intellectual content; and all approved the finalmanuscript as submitted.

The trial was registered with the European Clinical TrialsDatabase (2007-003416-61) before enrolling patients in thisstudy.

www.pediatrics.org/cgi/doi/10.1542/peds.2013-3935

doi:10.1542/peds.2013-3935

Accepted for publication Aug 5, 2014

(Continued on last page)

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Empyema is the most frequent suppura-tive complication of bacterial pneumoniain childhood.1 As a parapneumonic ef-fusion progresses, fibrin and cellulardetritus accumulate, the purulent fluidbecomes septated, and a thick peelforms over the visceral and parietalpleura. Parapneumonic pleural effu-sion is thus classified into 3 stages ofprogression: exudative (stage 1), fibri-nopurulent (stage 2), and organiza-tional (stage 3).2

An estimated 0.6% to 2% of pneumoniacases in children are complicated byempyema.3 Since the 1990s, there hasbeen a considerableworldwide increasein the incidence of empyema, with ratesreaching 28.3% to 53% of all patientshospitalized for pneumonia.4–7 In Spain,an increase from 1.7 to 8.5 cases/100 000 children has been documented.8

The 2 historical pillars of treatment ofempyemaareantibioticsanddrainageofthe purulent fluid by chest tube place-ment. However, in advancedstages of thecondition, this approach is associatedwith lengthy hospital stays and highfailure rates.9–11 In addition to thoracot-omy,9–12 2 less invasive treatments havebeen examined: fibrinolytic agents in-stilled into the pleural space and video-assisted thoracoscopic surgery (VATS).The aim of both these approaches is tobreak up the septa, extract or fluidizethe fibrin and cellular detritus, and thusrestore normal function of the mecha-nisms of pleural reabsorption, makinga quick recovery possible.13

Two randomized controlled pediatricclinical trials have been publishedcomparing the effectiveness of fibrino-lyticagentsversussalineserum.Thomsonet al14 found that administration ofurokinase significantly reduced hospi-tal stay and was associated with a lowfailure rate (7%), whereas Singhet al15 found no clinical benefit. Inseveral pediatric series of empyema,VATS has been successfully used assalvage therapy16–18 or as the initial

treatment,19–22 resulting in earlier andmore complete resolution of empyemaand shorter hospitalization than withchest tube drainage alone.23,24

The small numbers of pediatric studiescomparing VATS and fibrinolytic agentsas the initial therapy for parapneumonicempyema have concluded that the 2treatments are equivalent.25–27 One ofthese studies, however, was a retrospec-tive review of a hospital experience,25

and the other 2 are clinical trials thatincluded some patients with empyemawithout septations.26,27 In another clinicaltrial, which included children with em-pyema originating from various causes,VATS was compared with streptokinasetreatment.28 The authors reported simi-lar success rateswith the 2methods andsome advantages with the use of VATS.

To further evaluate the relativemerits ofthese treatment modalities, the presenttrial was conducted to compare VATSversus urokinase instillation in a cohortof patients with septated empyema.

METHODS

The project was approved by the ethicscommittees of all the participating hos-pitals, as well as the Spanish Agency ofMedicinesandMedical Devices. Parentalwritten informed consent, and consentof the children when applicable, wasobtained from all participants.

Study Design and Sample Size

This study was a randomized, multi-center, open-label, parallel-group, pilotclinical trial, performed over 2 years at6 Spanish university hospitals (Table 1).

The study compared 2 treatments forparapneumonic empyema.

Sample size was first calculated basedon preliminary results from a previousseriesofpatientstreatedbytheprincipleinvestigator in Hospital Universitari Valld’Hebron (Barcelona, Spain) between2001 and 2005. During that period, 58patientswith complicated effusion weretreated: 33 with the use of VATS and 25by using urokinase instillation. Meanpostoperative hospital stay was 12.7267.04 days in the VATS group and 14.1667.19 days in the urokinase group. Thesedata suggested that there would beno significant differences in the du-ration of hospitalization between thegroups. However, an equivalence testof means by using 2 one-sided tests ondata from a parallel-group design toachieve 80% power at a 5% signifi-cance level, and considering equiva-lence limits of –1.50 and 1.50, wouldhave had to include 378 patients ineach group. We considered it unfeasibleto recruit such a large number of chil-dren; hence, a pilot clinical trial withoutformal calculation of the sample sizewas conducted. Also based on our pre-vious experience, the recruitment pe-riod was established at 2 years underthe assumption that that period of timewould suffice to enroll a larger numberof patients than had been included inprevious studies.

Inclusion and Exclusion Criteria

Previously healthy patients aged ,15years with community-acquired pneu-monia, a diagnosis of parapneumonicpleural effusion requiring chest tube

TABLE 1 Number of Patients Per Participating Center

Center No. of PatientsAssessed

No. of Patients Randomizedto Treatment

Hospital Vall d’Hebron (Barcelona) 75 66Hospital Doce de Octubre (Madrid) 29 20Hospital La Paz (Madrid) 11 7Hospital Gregorio Marañón (Madrid) 10 4Hospital Donostia (San Sebastián) 6 5Hospital Central de Asturias (Oviedo) 18 3Total 149 105

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drainage (Table 2), and sonographicfeatures of complicated effusion wereconsidered candidates for enrollment.Complicated effusion was defined ashyperechoic fluid with fibrinous septa(sonographic stage 2) or hyperechoicloculations with or without thick pari-etal peel (sonographic stage 3).10,28

Exclusion criteria are summarized inTable 3. Diagnostic thoracentesis withno attempt at evacuating the effusionwas not a reason for exclusion.

Determinations

All patients underwent determinationof hemoglobin, white blood cell count,platelets, and C-reactive protein inblood, and white blood cell count, pH,lactate dehydrogenase, and glucose inpleural fluid. Blood and pleural fluidcultures were performed, and Strepto-coccus pneumoniae was investigated inpleural fluid by using antigen detectionor polymerase chain reaction assay.

Patients were followed up for 3 monthsafter hospital discharge, with chest

radiographs at each visit. In each cen-ter, chest radiographs were assessedby a radiologist blinded to the outcomeparameters. The radiographs were clas-sifiedasnormal,showingsmallchanges,or showing considerable pleural thick-ening.

Randomization

Patients were randomly allocated toreceive 1 of the 2 treatments. Thecomputer-generated randomization se-quence was stratified according tocenter and had varying block sizes toensure balance in the number of pa-tients per group. Once the informedconsent was signed, the attending phy-sician accessed a Web platform andobtained the treatment assigned to eachnew patient. Allocation was carried outat a 1:1 ratio. Treatmentwas not blinded.

Treatment Protocol

Patients were randomized to receiveeither VATS debridement or urokinaseinstillation. It was recommended thatVATS be conducted by experiencedsurgeons or by a resident under thedirect supervision of a senior surgeon.The aim of VATS was to break the fibrinseptations, aspirate the purulent fluid,and abundantly irrigate the empyemacavity. After the procedure, 1 or 2 chesttubes were left in place.

In patients receiving urokinase treat-ment, 12F to 14F chest tubeswere used,and the insertion site was previouslyselected by using sonography. Thepleural fluid was first drained, andurokinase was then instilled into thepleuralcavity throughthechest tube. Tenmilliliters of a 1000-IU/mL solution ofurokinase in children aged,1 year and40 mL in older children was adminis-tered every 12 hours for 3 days.14,26 Afterinstillation, the chest tube was clampedfor 4 hours. It was then unclamped andconnected to a suction systemat–20 cmH2O for 8 hours, until the next dose ofurokinase was administered. In both

treatment groups, chest tubes wereremoved when the drainage volumewas,40 to 60 mL/24 h.

Antibiotic treatment recommendationswerenot included in the studyprotocol. Itwasassumedthatpatientswouldreceiveempiric treatment with antibiotics cov-ering the spectrum of the most commonmicroorganisms in our setting, withsubsequent treatmentadjustmentbasedonmicrobiology results. After removal ofthechest tube, antibiotic treatmentcouldbe administered orally, provided that thepatient had been afebrile (#37.5°C) for24 hours. Patients could be discharged ifthey had been afebrile for at least 24hours with oral treatment (suggesteddischarge criteria).

Persistent fever ($38°C) for .4 daysafter either of the study treatments,associated with persistent purulentpleural collections on ultrasound, wasconsidered treatment failure. In casesof failure, salvage treatment was per-formed, which was individually de-termined by the attending physicianaccording to the needs of each patient.

Outcome Measures

The postoperative length of hospitali-zation was the primary outcome vari-able, defined as the number of dayshospitalized, starting from the day ofthe intervention to discharge. The sec-ondary outcomes were the total num-ber of days hospitalized (including thedays before initiating treatment), daysthe chest tube was in place, days thepatient had fever after treatment, fail-ure rate of the assigned treatment, andtreatment-related complications.

Statistical Analysis

Due to the multicenter nature of thestudy,demographiccharacteristicsof thechildren in the 2 treatment groups werecompared by using the Wilcoxon rank-sum stratified test (van Elteren test) forquantitative variables and the Cochran-Mantel-Haenszel test for categorical

TABLE 2 Indications for Chest TubeDrainage of Pleural Effusion

Fever and ultrasound-proven complicated effusionEffusion .1 cm and fever $38°C after 24 h of

appropriate intravenous antibiotic treatmentTachypneaOxygen requirement as a consequence of the

effusionIncrease in the size of the effusion during the

observation period

TABLE 3 Exclusion Criteria

Anechoic, nonseptated effusionPreexisting conditionsCerebral paralysisCongenital cardiopathyPrevious cardiac or thoracic surgery in the

affected hemithoraxImmunodeficiencySignificant thoracic trauma in the last 2 mo

Thrombocytopenia or abnormal clottingSevere arterial hypertensionTuberculous empyemaPneumothorax before treatmentPatients treated with chest tube placement at

the referring hospital

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variables. Differences between medianresults with their confidence intervalswere calculated by using the Hodges-Lehmann method, adjusting for centerclustering. Statistical significance wasset at a P value of ,.05. Data were an-alyzed by using SAS version 9.2 (SASInstitute, Inc, Cary, NC) and Stata version13.1 (StataCorp, College Station, TX). Anintention-to-treat analysis was applied,including all randomized patients whoreceived the assigned treatment.

RESULTS

Over the study period (July 1, 2008–June30, 2010), 149 patientswere assessed ascandidates for the trial. Forty-fourpatients were excluded before ran-domization for the following reasons:declined to participate (n = 20), did notmeet selection criteria (n = 12), andother reasons (n = 12). Thus, 105 pa-tientswere randomized to treatment: 53in the VATS group and 52 in the uroki-nase group. All patients in the VATSgroup received the allocated interven-tion. One patient in the urokinase groupwas found to have pleural tuberculosisafter randomization and did not receivethe study treatment. Another patientwas erroneously randomized twice andreceived the first treatment assigned(VATS). Thus, 53 patients in the VATSgroup and 50 patients in the urokinasegroup were analyzed. The 2 populationswere comparable in terms of baselinecharacteristics (Table 4).

Primary End Point

The median length of postinterventionhospitalization was 10 days in patientsundergoing VATS (interquartile range[IQR]: 7–13) and 9 days in those un-dergoing urokinase instillation (IQR: 8–12). There were no significant differ-ences between groups (Table 5).

Secondary End Points

Nosignificantdifferenceswere found fortotal hospital stay, with a median of 14days (IQR: 10–16) in the VATS group and

13 days (IQR: 10–18) in the urokinasegroup (P = .60), or duration of fever af-ter treatment (4 days [IQR: 2–7] withVATS versus 6 days [IQR: 3–7) with uro-kinase; P = .62) (Table 5). The chest tubewas retained longer in patients re-ceiving urokinase (5 days) than in thoseundergoing VATS (4 days) (P , .001).

Eight (15.1%) patients treatedwith VATSand 5 (10%) treated with urokinaserequired another procedure to resolveempyema and were considered treat-ment failures; these differences werenot significant. Analysis of potentialfactors predisposing to failure (gender,

age, duration of symptoms, and days ofantibiotic treatment before the pro-cedure) yielded no predisposing fac-tors in either group. Reinterventionsare shown in Table 6.

Microbiology Findings

In 40 (75%) patients from the VATSgroup and 34 (68%) from the urokinasegroup, S pneumoniae was identified asthe cause of pneumonia (P = .51).

Adverse Events

Forty-three (81.1%) patients in the VATSgroup and 41 (82%) in the urokinase

TABLE 4 Baseline Characteristics of the Participants

Characteristic VATS (n = 53) Urokinase (n = 50) P

Male gender, n (%) 32 (60.3) 29 (58.0) .80Age, mean (range), y 4.14 (1.1–13.7) 4.63 (1.0–12.2) .46Symptoms before diagnosis, median (IQR), d 6 (5–7) 6 (4–9) .84Symptoms before intervention, median (IQR), d 7 (5–9) 7 (5–9) .95Oxygen requirement, n (%) 46 (86.8) 39 (78.0) .22Blood parametersHemoglobin, median (IQR), g/dL n = 53 n = 48

10.8 (10.4–11.4) 10.9 (10.1–11.8) .82WBC, median (IQR), 3109/L n = 53 n = 49

17.9 (13.1–22.4) 17.4 (11.9–23.5) .88Platelets, median (IQR), 3109/L n = 53 n = 48

407.5 (284.8–529.0) 398.4 (277.0–527.0) .58CRP, median (IQR), mg/dL n = 48 n = 45

30.03 (20.2–40.4) 26.7 (15.4–33.7) .25Pleural fluid characteristicsWBC, median (IQR), 3109/L n = 15 n = 22

2.42 (0.6–13.0) 1.70 (0.9–7.0) .77LDH, median (IQR), IU/L n = 43 n = 45

4027 (1859–7287) 3951 (996–9990) .94pH, median (IQR) n = 32 n = 38 .84

6.96 (6.90–7.22) 7.03 (6.90–7.27)pH ,7.1, n (%) 21 (65.6%) 23 (60.5%) .85

Glucose, median (IQR), mg/dL n = 46 n = 44 .9815.20 (2.1–49.0) 5.3 (2.5–56.4)

Transfer from another hospital, n (%) 36 (67.9) 33 (66.0) .93Days hospitalized before transfer, median (IQR) 2.0 (1.0–3.5) 1.0 (0.0–4.0) .85

CRP, C-reactive protein; LDH, lactate dehydrogenase; WBC, white blood cell count.

TABLE 5 Results for the Primary and Secondary Study Outcomes

Outcome VATS(n = 53)

Urokinase(n = 50)

Median Difference(95% CI)

P

Primary outcomePO hospital stay, median (IQR), d 10 (7–13) 9 (8–12) 0 (–1 to 1) .45

Secondary outcomesTotal hospital stay, median (IQR), d 14 (10–16) 13 (10–18) 0 (–2 to 2) .60Chest tube in place, median (IQR), d 4 (3–5) 5 (4–6) 21 (–2 to –1) ,.001PO fever, median (IQR), d 4 (2–7) 6 (3–7) 21 (–2 to 1) .62Failure rate, n (%) 8 (15.1) 5 (10) .47

CI, confidence interval; PO, postoperative.

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grouphadno treatment- or pneumonia-related complications.

The treatment-related complications en-counteredwereminor, except foraseverebronchospasm requiring tracheal in-tubation and mechanical ventilation in 1urokinase-treated patient and a broncho-pleuralfistula in 1patientwhounderwentVATS. There were no bleeding complica-tions in the urokinase group. Complica-tions considered to be related to thepatients’ pneumonia included 2 bron-chopleural fistulas in the VATS group and1 bronchopleural fistula in the urokinasegroup, all occurring in patients who hadnecrotizing pneumonia or a pulmonaryabscess (Table 7). There were no deaths.

Follow-up

Clinical and radiologic follow-up for3 months after hospital discharge waspossible in 36 (67.9%) patients in theVATS group and 42 (84%) in the uroki-nase group (P= .28). At the 3-month visit,radiologists considered chest radio-graphs normal or showing only small

changes in 66.7% (24 of 36) of VATS-treated patients and 59.5% (25 of 42)of those receiving urokinase (P = .40).

DISCUSSION

Thepresentstudy is thethirdrandomizedclinical trial in children that comparedVATS and fibrinolytic agents as alter-native treatments for parapneumonicempyema. In addition, it is the firstmulticenter study and the first to ex-clusively include patients with septatedempyema.

The results show that urokinase in-stillation is as effective as VATS as theinitial therapy for treating septatedpleural empyema. There were no sig-nificant differences between the 2groups in the length of postoperativehospitalization (ie, the main outcomemeasure). Furthermore, the only dif-ference found among all the variablesstudied was the fact that the chest tubewas in place longer in the urokinasegroup. The study design, which requiredurokinase instillation through the tubefor 3 days, may have resulted in biasregarding this variable. Nonetheless,this requiredusedidnot lead to lengthierpostoperative hospitalization in the uro-kinase group. The treatment failure ratesand requirements for additional proce-dureswerealso found tobesimilar in the2 treatment groups.

Ourresultssupport thenotion that initialtreatment of purulent pleural effusion inchildren with VATS or urokinase in-stillation speeds pus drainage and re-covery and, therefore, shortens hospitalstay and duration of chest tube place-ment. In a meta-analysis by Avansinoet al,29 the mean hospital stay of 3418children undergoing chest tube drain-age alone was 20 6 8.3 days; patientsrequired drainage a mean of 10.66 3.4days; and treatment failure occurred in23.6% of patients. These results are veryunfavorable compared with those fromstudies in which the initial treatmentwas VATS or urokinase.

Two previous randomized clinical trialsinvolving fibrinolytic agents and VATShave been conducted in children. Thefirst of these, reported by Sonnappa et alin 2006, included 60 patients and com-pared VATS with urokinase instillation,26

whereas the second, reported by St Pe-ter in 2009 and including 36 patients,27

compared VATS with instillation of alte-plase. Both studies were performed ina single center and had similar designs.Our results are in keeping with thefindings from these previous studies inthat fibrinolytic instillation and VATS areequally effective for treating patientswith more severe empyema. The resultsof a protocol using fibrinolysis to treatempyema have recently replicated thefindings of these previous trials.30

Although the design of the present studyis very similar to the study of Sonnappaet al,26 there are 2 main differences.First, our study included patients withparapneumonic pleural effusion in sono-graphic stages 2 and 3 but not those withanechoic, nonseptated effusion (stage 1),who accounted for 16 patients in thestudy of Sonnappa et al. The second dif-ference was that our trial was a multi-center study. As noted by Sonnappa et al,the results of multicenter studies can bemore reliably extrapolated to the generalpopulation.

The duration of postoperative hospitalstay was longer in both our patientgroups than in the earlier studies: 10days for VATS and 9 days for urokinaseversus 6 and 6 days in the study bySonnappa et al26 and 6.9 and 6.8 days inthe study by St Peter et al,27 respectively.These differences are not attributable toa delay in transferring our patients fortreatment, as the interval was similar tothat reported in the study by Sonnappaet al. The lengthier hospitalization inour study may be due, in part, to thefact that children with anechoic, non-septated effusions were not includedin our series, but we believe the mainreason is possible differences in pediatric

TABLE 6 Reinterventions According toTreatment Group

Reintervention VATS Group Urokinase Group

VATS 2 2Urokinase 4 1Chest drain 1 2Thoracotomy 1 0Total 8 5

TABLE 7 Treatment and Pneumonia-RelatedComplications

Complication VATS(n = 53)

UK(n = 50)

Treatment-relatedPneumothorax 3 5Subcutaneous emphysema 1 0Bronchopleural fistula 1 0Bronchospasm 0 1Extravasation 0 1Dyspnea and pain 0 1

Pneumonia relatedLung abscess 2 0Necrotizing pneumonia 5 2Mechanical ventilation 1 2Renal insufficiency/nephritic

syndrome1 0

Bronchopleural fistula 2 1Pericardial effusion 1 0

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management between countries. In ourhospitals, the drain was not withdrawnuntil drainage volume was minimal(,40–60 mL/24 h), and patients werenot discharged until they had beenafebrile for 24 hours. This practice mayhave differed in the previous studiesreporting a shorter hospital stay.

Thetreatmentfailureratesweresimilarinthe 2 groups (15% for VATS and 10% forurokinase) and were comparable tothe values reported by the studies ofSonnappa et al and St Peter et al (16.6%for fibrinolysis).26,27 Among the 13 pa-tients in whom the initial treatmentfailed, only 5 subsequently underwentsurgery; the remaining 8 patients weretreated by drain placement or uroki-nase instillation.

Of note, only 1 patient of the 103 subjectsanalyzed in our study needed a thora-cotomy, as compared with 4 of 30 in theVATS group and an unspecified numberin the urokinase group in the trial bySonnappa et al.26 All 4 patients in thatstudy were converted to thoracotomyduring the initial VATS procedure, basedon the surgeon’s perception that thepleural peel would impede proper expan-sion of the lung. Because the radiologicand functional course of our previouslytreated patients had demonstrated thatresidual pleural thickening resolvesspontaneously over follow-up,25 oursurgical protocol in the present studydid not include debridement of pleuralpeel on the lung. Debridement is not

performed in patients undergoing fi-brinolytic treatment, and the risk ofparenchymal injury is higher whenattempts are made to remove the fibrinlayer. In our series, findings on radio-graphic follow-up at 3 months afterhospital discharge were considerednormal in 66.7% of patients in the VATSgroup and 59.5% of those receivingurokinase. There were no later hospitalreferrals for “trapped lung.” Therefore,we believe that the surgeon’s subjectiveperception of lung distensibility duringthe acute phase of empyema should notguide the surgery performed.

Our study has some limitations thatshould be mentioned. First, it was con-ducted without previous calculation ofthe sample size because of the unfea-sibly large number of patients whowould be needed to perform an equiv-alencestudy.Nonetheless, thenumberofpatients ultimately randomized for thistrial is the largest among the existingprospective studies having the sameobjective. Second, the diagnostic sono-graphic images did not undergo cen-tralized review, and there is a possibilityof variability between the readers in thedifferent centers.

The present study has some practicalimplications. Many second-level pediat-ric hospitals have the capability to per-form ultrasound diagnosis of severeempyema and image-guided chest tubeplacement, enabling treatment with fi-brinolytic drugs. Surgical treatment

would not be possible in these centers;children requiring surgery must betransferred to third-level hospitals withsurgeons trained to treat them. Second,VATS is a procedure lasting ∼1 hourthat requires general anesthesia andinvolves considerable aggressiveness ina severely ill patient, as was noted in therecent review by Islam et al.23 Urokinaseinstillation is much less invasive. Lastly,although we did not perform a compar-ative cost study between the 2 treat-ments, previous trials have shown thatthe surgical option is more costly thanfibrinolytic therapy.26,27

CONCLUSIONS

Initial treatment of septated para-pneumonic empyema with fibrinolyticagents isaseffectiveasVATS inchildren.This multicenter study adds strength tocurrent recommendations23,24 to usechemical debridement as first-linetherapy in these patients.

ACKNOWLEDGMENTSTheauthors aregrateful to themembersof the Departments of Pediatric Surgery,Pediatrics, and Radiology of the partici-pating hospitals, whose invaluable helpcontributed tomake this study possible.We thank Xavier Vidal (Department ofClinical Pharmacology, Hospital Valld’Hebron, Barcelona) for his help withthe statistical analysis and Celine Cavallofor English language support.

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(Continued from first page)

Address correspondence to Claudia Marhuenda, MD, Servicio de Cirugía Pediátrica, Hospital Universitari Son Espases, Carretera de Valldemossa, 79, 07010 Palmade Mallorca, Spain. E-mail: claudia.marhuenda@ssib.es

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2014 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

FUNDING: This clinical trial was funded by a Health Research Fund grant (EC07/90385) from the Institute of Health Carlos III, under the Spanish Ministry of Scienceand Innovation. The funding within the program of support for research unrelated to commercial interests was essential for completion of this study.

POTENTIAL CONFLICT OF INTEREST: Dr Moreno-Galdó has been an advisory board member of and has received institutional research funding from AbbVie Inc; hasreceived funding for travel to conferences by Actelion, Novartis, Gilead, Bayer Pharma AG, and Ferrer Laboratories; and received a fee for speaking from MerckSharp & Dohme. Dr Pérez-Yarza is an advisory board member of AbbVie Inc, has received institutional research funding from AbbVie Inc, and has received fees forspeaking from Merck Sharp & Dohme. The other authors have indicated they have no potential conflicts of interest to disclose.

ARTICLE

PEDIATRICS Volume 134, Number 5, November 2014 e1307 at Instituto Catala De La Salut on October 27, 2014pediatrics.aappublications.orgDownloaded from

DOI: 10.1542/peds.2013-3935; originally published online October 27, 2014;Pediatrics

Matute, María A. García-Casillas, Víctor Álvarez and Antonio Moreno-GaldóA.Indalecio Cano, María López, Francisco Hernández, Eduardo G. Pérez-Yarza, José

Claudia Marhuenda, Concepció Barceló, Inmaculada Fuentes, Gabriela Guillén,Multicenter Clinical Trial

Urokinase Versus VATS for Treatment of Empyema: A Randomized  

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