Effectiveness of Intrapleural Tissue Plasminogen Activator and Dornase Alfa vs Tissue Plasminogen Activator Alone in Children with Pleural Empyema: A Randomized Clinical Trial | Pediatrics | JAMA Pediatrics | JAMA Network
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Figure 1.  Trial Profile
Trial Profile

DNase indicates dornase alfa; tPA, tissue plasminogen activator.

Figure 2.  Mean Pleural Drainage Volume Following Chest Tube Insertion by Treatment Group
Mean Pleural Drainage Volume Following Chest Tube Insertion by Treatment Group

The error bars indicate standard deviation. DNase indicates dornase alfa; tPA, tissue plasminogen activator.

aOverall volume includes all drainage from chest tube insertion until removal.

Table 1.  Baseline Characteristics
Baseline Characteristics
Table 2.  Outcomes
Outcomes
Table 3.  Adverse Events
Adverse Events
1.
Bradley  JS, Byington  CL, Shah  SS,  et al; Pediatric Infectious Diseases Society and the Infectious Diseases Society of America.  The management of community-acquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America.  Clin Infect Dis. 2011;53(7):e25-e76. doi:10.1093/cid/cir531PubMedGoogle ScholarCrossref
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Balfour-Lynn  IM, Abrahamson  E, Cohen  G,  et al; Paediatric Pleural Diseases Subcommittee of the BTS Standards of Care Committee.  BTS guidelines for the management of pleural infection in children.  Thorax. 2005;60(suppl 1):i1-i21. doi:10.1136/thx.2004.030676PubMedGoogle ScholarCrossref
3.
Chibuk  T, Cohen  E, Robinson  J, Mahant  S, Hartfield  D; Canadian Paediatric Society.  Paediatric complicated pneumonia: diagnosis and management of empyema.  Paediatr Child Health. 2011;16(7):425-429.PubMedGoogle ScholarCrossref
4.
Islam  S, Calkins  CM, Goldin  AB,  et al; APSA Outcomes and Clinical Trials Committee, 2011-2012.  The diagnosis and management of empyema in children: a comprehensive review from the APSA Outcomes and Clinical Trials Committee.  J Pediatr Surg. 2012;47(11):2101-2110. doi:10.1016/j.jpedsurg.2012.07.047PubMedGoogle ScholarCrossref
5.
Moreno-Pérez  D, Andrés Martín  A, Tagarro García  A,  et al.  Community acquired pneumonia in children: treatment of complicated cases and risk patients: consensus statement by the Spanish Society of Paediatric Infectious Diseases (SEIP) and the Spanish Society of Paediatric Chest Diseases (SENP)  [in Spanish].  An Pediatr (Barc). 2015;83(3):217.e1-217.e11. doi:10.1016/j.anpede.2015.08.002PubMedGoogle ScholarCrossref
6.
Strachan  RE, Gulliver  T, Martin  A,  et al. Paediatric empyema thoracis: recommendations for management: position statement from the Thoracic Society of Australia and New Zealand. https://www.thoracic.org.au/journal-publishing/command/download_file/id/24/filename/PaediatricEmpyemaThoracisPositionStatementTSANZFINAL.pdf. Accessed April 9, 2019.
7.
Kelly  MM, Coller  RJ, Kohler  JE,  et al.  Trends in hospital treatment of empyema in children in the United States.  J Pediatr. 2018;202:245-251.e1. doi:10.1016/j.jpeds.2018.07.004PubMedGoogle ScholarCrossref
8.
Nath  S, Thomas  M, Spencer  D, Turner  S.  Has the incidence of empyema in Scottish children continued to increase beyond 2005?  Arch Dis Child. 2015;100(3):255-258. doi:10.1136/archdischild-2014-306525PubMedGoogle ScholarCrossref
9.
Deceuninck  G, Quach  C, Panagopoulos  M,  et al.  Pediatric pleural empyema in the province of Quebec: analysis of a 10-fold increase between 1990 and 2007.  J Pediatric Infect Dis Soc. 2014;3(2):119-126. doi:10.1093/jpids/pit075PubMedGoogle ScholarCrossref
10.
Mahon  C, Walker  W, Drage  A, Best  E.  Incidence, aetiology and outcome of pleural empyema and parapneumonic effusion from 1998 to 2012 in a population of New Zealand children.  J Paediatr Child Health. 2016;52(6):662-668. doi:10.1111/jpc.13172PubMedGoogle ScholarCrossref
11.
Liese  JG, Schoen  C, van der Linden  M,  et al.  Changes in the incidence and bacterial aetiology of paediatric parapneumonic pleural effusions/empyema in Germany, 2010-2017: a nationwide surveillance study.  Clin Microbiol Infect. 2019;25(7):857-864. doi:10.1016/j.cmi.2018.10.020PubMedGoogle ScholarCrossref
12.
Saxena  S, Atchison  C, Cecil  E, Sharland  M, Koshy  E, Bottle  A.  Additive impact of pneumococcal conjugate vaccines on pneumonia and empyema hospital admissions in England.  J Infect. 2015;71(4):428-436. doi:10.1016/j.jinf.2015.06.011PubMedGoogle ScholarCrossref
13.
Avansino  JR, Goldman  B, Sawin  RS, Flum  DR.  Primary operative versus nonoperative therapy for pediatric empyema: a meta-analysis.  Pediatrics. 2005;115(6):1652-1659. doi:10.1542/peds.2004-1405PubMedGoogle ScholarCrossref
14.
Mahant  S, Cohen  E, Weinstein  M, Wadhwa  A.  Video-assisted thorascopic surgery vs chest drain with fibrinolytics for the treatment of pleural empyema in children: a systematic review of randomized controlled trials.  Arch Pediatr Adolesc Med. 2010;164(2):201-203. doi:10.1001/archpediatrics.2009.271PubMedGoogle ScholarCrossref
15.
Kurt  BA, Winterhalter  KM, Connors  RH, Betz  BW, Winters  JW.  Therapy of parapneumonic effusions in children: video-assisted thoracoscopic surgery versus conventional thoracostomy drainage.  Pediatrics. 2006;118(3):e547-e553. doi:10.1542/peds.2005-2719PubMedGoogle ScholarCrossref
16.
St Peter  SD, Tsao  K, Spilde  TL,  et al.  Thoracoscopic decortication vs tube thoracostomy with fibrinolysis for empyema in children: a prospective, randomized trial  [published correction appears in J Pediatr Surg. 2009;44(9):1865].  J Pediatr Surg. 2009;44(1):106-111. doi:10.1016/j.jpedsurg.2008.10.018PubMedGoogle ScholarCrossref
17.
Sonnappa  S, Cohen  G, Owens  CM,  et al.  Comparison of urokinase and video-assisted thoracoscopic surgery for treatment of childhood empyema.  Am J Respir Crit Care Med. 2006;174(2):221-227. doi:10.1164/rccm.200601-027OCPubMedGoogle ScholarCrossref
18.
Marhuenda  C, Barceló  C, Fuentes  I,  et al.  Urokinase versus VATS for treatment of empyema: a randomized multicenter clinical trial.  Pediatrics. 2014;134(5):e1301-e1307. doi:10.1542/peds.2013-3935PubMedGoogle ScholarCrossref
19.
Cohen  E, Weinstein  M, Fisman  DN.  Cost-effectiveness of competing strategies for the treatment of pediatric empyema.  Pediatrics. 2008;121(5):e1250-e1257. doi:10.1542/peds.2007-1886PubMedGoogle ScholarCrossref
20.
Zhu  Z, Hawthorne  ML, Guo  Y,  et al.  Tissue plasminogen activator combined with human recombinant deoxyribonuclease is effective therapy for empyema in a rabbit model.  Chest. 2006;129(6):1577-1583. doi:10.1378/chest.129.6.1577PubMedGoogle ScholarCrossref
21.
Dentice  R, Elkins  M.  Timing of dornase alfa inhalation for cystic fibrosis.  Cochrane Database Syst Rev. 2016;(7):CD007923. doi:10.1002/14651858.CD007923.pub4PubMedGoogle Scholar
22.
Rahman  NM, Maskell  NA, West  A,  et al.  Intrapleural use of tissue plasminogen activator and DNase in pleural infection.  N Engl J Med. 2011;365(6):518-526. doi:10.1056/NEJMoa1012740PubMedGoogle ScholarCrossref
23.
Livingston  MH, Mahant  S, Ratjen  F,  et al.  Intrapleural Dornase and Tissue Plasminogen Activator in Pediatric Empyema (DTPA): a study protocol for a randomized controlled trial.  Trials. 2017;18(1):293. doi:10.1186/s13063-017-2026-0PubMedGoogle ScholarCrossref
24.
Livingston  MH, Cohen  E, Giglia  L,  et al.  Are some children with empyema at risk for treatment failure with fibrinolytics? a multicenter cohort study.  J Pediatr Surg. 2016;51(5):832-837. doi:10.1016/j.jpedsurg.2016.02.032PubMedGoogle ScholarCrossref
25.
Cohen  E, Mahant  S, Dell  SD,  et al.  The long-term outcomes of pediatric pleural empyema: a prospective study.  Arch Pediatr Adolesc Med. 2012;166(11):999-1004. doi:10.1001/archpediatrics.2012.1055PubMedGoogle ScholarCrossref
26.
Maffey  A, Colom  A, Venialgo  C,  et al.  Clinical, functional, and radiological outcome in children with pleural empyema.  Pediatr Pulmonol. 2019;54(5):525-530. doi:10.1002/ppul.24255PubMedGoogle ScholarCrossref
27.
de Benedictis  FM, Carloni  I, Osimani  P,  et al.  Prospective evaluation of lung function in children with parapneumonic empyema.  Pediatr Pulmonol. 2019;54(4):421-427. doi:10.1002/ppul.24204PubMedGoogle ScholarCrossref
28.
Bishwakarma  R, Shah  S, Frank  L, Zhang  W, Sharma  G, Nishi  SP.  Mixing it up: coadministration of tPA/DNase in complicated parapneumonic pleural effusions and empyema.  J Bronchology Interv Pulmonol. 2017;24(1):40-47. doi:10.1097/LBR.0000000000000334PubMedGoogle ScholarCrossref
29.
Innabi  A, Surana  A, Alzghoul  B, Meena  N.  Rethinking the doses of tissue plasminogen activator and deoxyribonuclease administrated concurrently for intrapleural therapy for complicated pleural effusion and empyema.  Cureus. 2018;10(2):e2214. doi:10.7759/cureus.2214PubMedGoogle Scholar
30.
Majid  A, Kheir  F, Folch  A,  et al.  Concurrent intrapleural instillation of tissue plasminogen activator and DNase for pleural infection: a single-center experience.  Ann Am Thorac Soc. 2016;13(9):1512-1518. doi:10.1513/AnnalsATS.201602-127OCPubMedGoogle ScholarCrossref
31.
Zwarenstein  M, Treweek  S.  What kind of randomized trials do we need?  CMAJ. 2009;180(10):998-1000. doi:10.1503/cmaj.082007PubMedGoogle ScholarCrossref
32.
Thorpe  KE, Zwarenstein  M, Oxman  AD,  et al.  A Pragmatic-Explanatory Continuum Indicator Summary (PRECIS): a tool to help trial designers.  CMAJ. 2009;180(10):E47-E57. doi:10.1503/cmaj.090523PubMedGoogle ScholarCrossref
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    Original Investigation
    February 3, 2020

    Effectiveness of Intrapleural Tissue Plasminogen Activator and Dornase Alfa vs Tissue Plasminogen Activator Alone in Children with Pleural Empyema: A Randomized Clinical Trial

    Author Affiliations
    • 1McMaster Children’s Hospital, McMaster University, Hamilton, Ontario, Canada
    • 2Golisano Children’s Hospital, University of Rochester Medical Center, Rochester, New York
    • 3Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
    • 4Image-Guided Therapy, Department of Diagnostic Imaging, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
    • 5Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada
    • 6Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada
    • 7British Columbia’s Children’s Hospital, Division of Respiratory Medicine, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada
    • 8Health Sciences Centre, Winnipeg, Manitoba, Canada
    • 9Alberta Children’s Hospital, University of Calgary, Calgary, Alberta, Canada
    • 10Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
    • 11Applied Health Research Centre, Li Ka Shing Knowledge Institute, St Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada
    • 12Li Ka Shing Centre for Healthcare Analytics Research and Training, St Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada
    • 13Centre for Excellence in Economic Analysis Research (CLEAR), The HUB Health Research Solutions, St Michael’s Hospital, Toronto, Ontario, Canada
    • 14Li Ka Shing Knowledge Institute, St Michael’s Hospital, Toronto, Ontario, Canada
    JAMA Pediatr. 2020;174(4):332-340. doi:10.1001/jamapediatrics.2019.5863
    Key Points

    Question  Is intrapleural tissue plasminogen activator (tPA) and dornase alfa (DNase) beneficial in pediatric empyema compared with tPA alone?

    Findings  In this multicenter randomized clinical trial of 97 children with pleural empyema, there were no significant differences between those treated with tPA and DNase and those treated with tPA and placebo.

    Meaning  Guidelines should continue to support the use of chest tube insertion and intrapleural fibrinolytics alone as first-line treatment for pediatric empyema.

    Abstract

    Importance  Clinical guidelines recommend that children with pleural empyema be treated with chest tube insertion and intrapleural fibrinolytics. The addition of dornase alfa (DNase) has been reported to improve outcomes in adults but remains unproven in children.

    Objective  To determine if intrapleural tissue plasminogen activator (tPA) and DNase is more effective than tPA and placebo at reducing hospital length of stay in children with pleural empyema.

    Design, Setting, and Participants  This multicenter, parallel-group, placebo-controlled, superiority randomized clinical trial included children diagnosed as having pleural empyema requiring drainage aged 6 months to 18 years treated at 6 tertiary Canadian children’s hospitals. A total of 379 children were assessed for eligibility; 281 were excluded and 98 were randomized. One child was excluded after randomization for not meeting the inclusion criteria. Data were collected from March 4, 2013, to December 13, 2017.

    Interventions  Participants underwent chest tube insertion and 3 daily administrations of intrapleural tPA, 4 mg, followed by DNase, 5 mg (intervention group), or 5 mL of normal saline (placebo; control group). Participants, families, clinical staff, and members of the study team were blinded to allocation.

    Main Outcomes and Measures  The primary outcome was hospital length of stay from chest tube insertion to discharge. Secondary outcomes included time to meeting discharge criteria, time to chest tube removal, mean fever duration, additional pleural drainage procedures, hospital readmissions, and total health care cost.

    Results  Of the 97 analyzed children with pleural empyema, 52 (54%) were male, and the mean (SD) age was 5.1 (3.6) years. A total of 49 children were randomized to tPA and DNase and 48 were randomized to tPA and placebo. Treatment with tPA and DNase was not associated with decreased hospital length of stay compared with tPA and placebo (mean [SD] length of stay, 9.0 [4.9] vs 9.1 [5.3] days; mean difference, −0.1 days; 95% CI, −2.0 to 2.1; P = .96). Similarly, no significant differences were observed for any of the secondary outcomes. Of the 14 adverse events in the tPA and DNase group, 6 (43%) were serious; of the 21 adverse events in the tPA and placebo group, 8 (38%) were serious. There were no deaths.

    Conclusions and Relevance  The addition of DNase to intrapleural tPA for children with pleural empyema had no effect on hospital length of stay or other outcomes compared with tPA with placebo. Clinical practice guidelines should continue to support the use of chest tube insertion and intrapleural fibrinolytics alone as first-line treatment for pediatric empyema.

    Trial Registration  ClinicalTrials.gov identifier: NCT01717742

    Introduction

    Up to 50% of children admitted to a hospital with community-acquired pneumonia develop an associated parapneumonic effusion.1 While the underlying infection often improves with antibiotics alone, some effusions becomes purulent and/or loculated, a condition known as pleural empyema.1-6 Recent estimates suggest a rate of 2.0 hospital discharges related to empyema per 100 000 children in the United States.7 Similar estimates have been reported in other countries.8-12

    Clinical practice guidelines recommend that children with empyema undergo pleural drainage if they have moderate to large pleural effusions or significant respiratory compromise.1-6 Pleural drainage options include decortication and drainage via video-assisted thoracoscopic surgery (VATS) or insertion of a chest tube with instillation of intrapleural fibrinolytics, such as tissue plasminogen activator (tPA).4,13 Systematic reviews of small randomized clinical trials of children with empyema have reported similar outcomes with these 2 approaches but increased costs associated with upfront VATS.14-19

    Dornase alfa (DNase) has been shown in vitro to decrease viscosity by cleaving free DNA and liquefying pus in the pleural space.20 The nebulized formulation is approved for use in children with cystic fibrosis to facilitate airway clearance.21 A factorial randomized clinical trial of 210 adults with pleural empyema22 reported improved outcomes with the use of DNase and tPA compared with tPA alone, DNase alone, or normal saline flushes only. This included greater resolution of pleural opacity on chest radiography, decreased rate of referral for surgical debridement, and shorter length of stay in hospital. However, it remains unclear whether these findings can be extrapolated to children.

    We designed the Intrapleural DNase and Tissue Plasminogen Activator in Pediatric Empyema (DTPA) trial to assess the efficacy and safety of tPA and DNase in children with pleural empyema compared with tPA alone. Since the combination of tPA and DNase has been shown to improve outcomes in adults, we hypothesized that this treatment strategy would result in shorter lengths of stay in hospital for children compared with tPA alone. We also compared a variety of secondary and exploratory outcomes between the 2 treatment groups related to efficacy, safety, and cost.

    Methods
    Study Design

    The DTPA trial was a multicenter, parallel-group, placebo-controlled, superiority randomized clinical trial involving 6 Canadian children’s hospitals (Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montreal, Quebec; Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario; The Hospital for Sick Children, University of Toronto, Toronto, Ontario; McMaster Children’s Hospital, McMaster University, Hamilton, Ontario; Alberta Children’s Hospital, University of Calgary, Calgary, Alberta; and British Columbia’s Children’s Hospital, University of British Columbia, Vancouver, British Columbia). The study protocol was registered at ClinicalTrials.gov (NCT01717742) and published in full previously23 and is available in Supplement 1. Ethics approval was obtained from the institutional review board at the Hospital for Sick Children and at each participating hospital. Potential participants were approached for consent after the child’s medical team had decided to proceed with chest tube insertion but prior to the actual procedure. Written informed consent was obtained from each participant’s parent or legal guardian. Assent was obtained from the child whenever possible. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.

    Participants

    Children with pleural empyema aged 6 months to 18 years were eligible for inclusion if they were referred for pleural drainage by their attending physician and had evidence of pleural effusion on ultrasonography and needed further intervention based on clinical criteria (ie, persistent fever despite antibiotics for at least 48 hours, significant respiratory distress, tachypnea, or hypoxia as a result of the pleural effusion). We excluded children with pleural empyema from tuberculosis, fungus, or noninfectious causes of pleural effusion; with known coagulation impairment; with allergy to tPA or DNase; with chronic lung disease (other than asthma); with other chronic or neurologic disorders; with a previous pleural drainage procedure (eg, chest tube already in place); who were recently administered an investigational drug (within the previous 30 days); who were pregnant; who were breastfeeding; or who had pneumothorax present prior to chest tube insertion.

    Randomization and Masking

    Randomization was stratified by study site. Participants were randomized into treatment groups using a random allocation sequence facilitated by an off-site data coordination center (Applied Health Research Centre, Toronto, Ontario, Canada). An allocation ratio of 1:1 with random permuted blocks of size 2 and 4 was used within each site to ensure that the treatment groups were approximately the same size within each site and throughout the trial overall. A computer-based pseudorandom number generator was used to create treatment allocation tables.

    After participant eligibility was confirmed and consent was obtained, the site coordinator assigned a unique study identification number in sequential order. The study identification number corresponded with the randomization table held in each hospital’s research pharmacy for dispensing open-label tPA and either blinded DNase or placebo. The biostatistician at the data coordination center maintained a secure master list of randomization codes and assigned treatments.

    Participants, families, clinicians, outcome assessors, research assistants, study investigators, and those who administered study medications were blinded to treatment assignment. Study medications were formulated by research pharmacists as clear liquids in identical polyethylene syringes (ie, with the same packaging, color, and volume) to maintain blinding.

    Procedures

    Participants were randomized to either (1) intrapleural tPA (Roche), 4 mg, followed by 5 mL of normal saline (ie, placebo; control group) or (2) intrapleural tPA, 4 mg, followed by DNase (Roche), 5 mg (intervention group). Study drugs were administered once daily for 3 days. The first dose was typically given within 1 hour of chest tube insertion.

    Safety data on DNase in children is derived from its currently licensed indication (nebulization at a dose of 2.5 to 5 mg once or twice daily) for the reduction of sputum viscosity in patients with cystic fibrosis.21 Since the stability of tPA-DNase admixture is unknown, medications were administered sequentially with a 1-hour dwell time after each drug.23

    In the tPA and DNase group, participants received tPA, 4 mg (dissolved in 20 mL of normal saline if the participant weighed 10 kg or more or in 10 mL of normal saline if less than 10 kg), followed by a normal 5-mL saline flush. The chest tube was clamped for 1 hour and then allowed to drain for another hour while on −20 cm H2O suction with underwater seal. The child then received DNase, 5 mg (dissolved in 20 mL of normal saline if the participant weighed 10 kg or more or in 10 mL of normal saline if less than 10 kg), followed by a normal 5-mL saline flush. The chest tube was again clamped for 1 hour and finally left to drain on −20 cm H2O suction with underwater seal until the next dose the following day. Similarly, in the tPA and placebo group, participants received tPA, 4 mg, followed by 5 mL of placebo (ie, normal saline) instead of DNase. The same procedures were followed for treatment volume, saline flushes, and dwell time.

    Outcomes

    The primary outcome was length of stay in hospital (measured in days) from chest tube insertion to discharge. Secondary outcomes included time from chest tube insertion to meeting discharge criteria (defined after chest tube removal as having no fever [temperature less than 38°C], normal respiratory rate for age, no hypoxia, and drinking fluids well), time from chest tube insertion to removal, fever duration, additional pleural drainage procedures (eg, additional chest tube insertion or rescue VATS), ventilatory support (including both invasive and noninvasive positive-pressure ventilation), hospital readmissions up to 3 months postdischarge, and cost. Estimates of total health care costs were based on the perspective of the public health care payer and incorporated charges for all medications, hospital stay (general ward and/or intensive care unit), and readmissions within 3 months of discharge from baseline. Data are reported in 2018 US dollars. We also reported serious adverse events. Serious bleeding was defined a priori as intrapleural bleeding resulting in a hemoglobin drop of greater than 2 g/dL (to convert to grams per liter, multiply by 10) or requiring a transfusion of packed red blood cells.

    Exploratory outcomes included degree of opacification of the affected hemithorax on chest radiography closest to time of chest tube removal. We also reported total pleural drainage volume from chest tube insertion to removal as well as cumulative drainage at 24 hours and 48 hours after chest tube insertion.

    Sample Size Calculation

    In previous trials of pediatric empyema, the mean time to discharge following pleural drainage ranged from 6 to 15 days.15-18 A randomized clinical trial using tPA dosing identical to the DTPA trial reported a mean (SD) length of stay after chest tube insertion of 6.8 (2.9) days.16

    Based on discussions with clinical experts, hospital administrators, and parents of children with pleural empyema, a 2-day difference in length of stay between treatment groups was selected as representing a minimal clinically important difference. This threshold has been used in a previous trial of pleural empyema in children comparing chest tube insertion and intrapleural fibrinolytics with primary VATS.17 Assuming a type 1 error rate of .05 (2-sided), power (1 − β) of 90%, and an SD of 2.9 days for each group, this trial required at least 46 participants in each group (92 individuals total) to detect a difference in length of stay of 2 days.

    Statistical Analysis

    We performed hypothesis testing on the basis of intention to treat for the primary, secondary, and exploratory outcomes. The primary outcome (length of stay in hospital after chest tube insertion) was reported as the mean difference (with 95% CIs), and the independent t test was used to compare the 2 treatment groups. For secondary outcomes, χ2 tests were used for dichotomous variables and independent t tests for continuous variables. Costing differences were assessed with the Mann-Whitney rank sum test.

    A secondary analysis was conducted adjusting for potentially important baseline covariates of the primary outcome with multivariable regression, including admission to the intensive care unit, bacterial identification in blood, and study site.24 An interim analysis was performed after 25 and 50 participants were recruited for safety review by the study’s independent data monitoring committee.

    All P values were 2-tailed, and significance was set at a P value less than .05. Analyses were conducted using SAS version 9.4 (SAS Institute) and R version 3.5.1 (The R Foundation).

    Results
    Recruitment

    Between March 4, 2013, and December 13, 2017, 379 children with pleural empyema were screened across 6 study sites (Figure 1). A total of 281 children were excluded. The most common reasons for exclusion were not requiring chest tube insertion (n = 128), having already undergone a pleural drainage procedure (n = 42), other chronic or neurologic disorders (n = 64), or the parent or guardian declining to participate (n = 34).

    Of the 98 children randomized, 1 individual was included erroneously, as this participant never met study inclusion criteria (ie, chest tube was not required) and was excluded from further analysis. Of the remaining 97 participants, 49 were assigned to the tPA and DNase group and 48 to the tPA and placebo group. All were included in the analysis in accordance with the intention-to-treat approach. Seven participants (2 assigned to tPA and DNase and 5 assigned to tPA and placebo) did not complete all 3 study treatments. Reasons for stopping treatment early were based on the decision of the attending physician (1 in the tPA and DNase group and 2 in the tPA and placebo), family preference (1 in the tPA and DNase group), or adverse events (3 in the tPA and placebo group).

    Baseline Characteristics

    Baseline characteristics are summarized in Table 1. The participants were a median (interquartile range) age of 52 (36-66) months with similar proportions of male participants (54% [52 of 97]) and female participants (46% [45 of 97]). The groups were similar in terms of demographic characteristics (age, sex, and race/ethnicity), previous health (asthma, prematurity, and weight), clinical baseline features (days in hospital prior to chest tube insertion, fever days, exposure to antibiotics prior to chest tube insertion, admission to the intensive care unit, pleural effusion size, radiographic opacification, and bacterial identification in blood or pleural fluid), and chest tube characteristics (mode of insertion, type of chest tube, and size). Most participants in both groups had greater than 50% opacification of the affected hemithorax.

    Primary Outcome

    The mean (SD) length of stay in hospital following chest tube insertion was 9.0 (4.9) days among participants assigned to the tPA and DNase group compared with 9.1 (5.3) days in the tPA and placebo group (Table 2). This corresponded to a mean difference of −0.1 days (95% CI, −2.0 to 2.1; P = .96). The results did not change after adjusting for admission to the intensive care unit, positive blood culture, and study site (eTables 1 and 2 in Supplement 2).

    Secondary Outcomes

    Analysis of the secondary outcomes is presented in Table 2. There were no differences in time from chest tube insertion to meeting discharge criteria, time to chest tube removal, fever duration, frequency of needing invasive or noninvasive ventilatory support, need for additional pleural drainage procedures, or hospital readmission. Total costs were also comparable between the 2 groups (eTable 3 in Supplement 2).

    Most participants in both groups (91 of 97 [94%]) were successfully managed with a single chest tube insertion followed by intrapleural tPA and either DNase or placebo. Only 6 participants required additional pleural drainage procedures. In the tPA and DNase group, 1 participant underwent rescue VATS, 2 participants underwent a second chest tube insertion alone, and 1 participant underwent insertion of a second and then a third chest tube. In the tPA and placebo group, 1 participant underwent rescue VATS alone and another underwent rescue VATS followed by chest tube insertion as a third procedure. Differences between treatment groups were not statistically significant.

    Adverse events are summarized in Table 3. Similar numbers of participants experienced at least 1 adverse event in the 2 treatment groups (24% [12 of 49] vs 29% [14 of 48]; P = .64). The most common serious adverse event was serious bleeding. One participant assigned to the tPA and DNase group experienced a tension pyothorax, and another developed a bronchopleural fistula. One of the participants assigned to the tPA and placebo group experienced septic shock. There were no deaths in either group.

    Exploratory Outcomes

    In both the tPA and DNase group and tPA and placebo group, most participants had opacification of the affected hemithorax less than or equal to 50% on chest radiography closest to time of chest tube removal (35 of 49 [71%] vs 43 of 48 [90%]; P = .42). The mean (SD) overall volume of pleural drainage following chest tube insertion was also similar (1524 [909] mL vs 1733 [1029] mL; mean difference, −208.7 mL; 95% CI, −602.3 to 185.0; P = .30) and was also similar after 24 hours (741 [545] mL vs 809 [577] mL; mean difference, −67.6 mL; 95% CI, −300.0 to 164.9; P = .56) and 48 hours (957 [572] mL vs 1067 [674] mL; mean difference, −110.5 mL; 95% CI, −364.0 to 143.1; P = .39). These results are summarized in Table 2 and Figure 2.

    Discussion

    To the best of our knowledge, this study is the first randomized clinical trial to explore the efficacy, safety, and cost of intrapleural DNase in children with pleural empyema. We found that treatment with tPA and DNase compared with tPA and placebo was not associated with an improvement in the primary outcome, length of stay in hospital. Furthermore, the confidence limits around the estimated difference between groups was within what we considered a clinically meaningful difference (ie, 2 days). We also found comparable results for all secondary and exploratory outcomes.

    These findings contrast with the factorial randomized clinical trial of adults with pleural empyema,22 which reported improved outcomes with the use of tPA and DNase compared with tPA alone, DNase alone, or normal saline flushes only. These included greater resolution of pleural opacity on chest radiography, decreased rate of referral for surgical debridement, and shorter length of stay in hospital.

    There are several possible explanations for the different findings in the adult trial and the current study. First, empyema is a different disease in children compared with adults. Children with empyema are often previously healthy with few or no preexisting comorbidities. They have lower rates of needing rescue surgical therapy, and their long-term outcomes are almost always complete recovery with a near-zero rate of mortality.25-27 In the current study, this difference was further amplified by the fact that we specifically excluded children with serious long-term comorbidities. Participants in the adult trial had a variety of comorbidities, and the mortality rate was 11% after 12 months of follow-up.22 Another difference between these studies was the dosing regimen. While both studies administered tPA and DNase separately and sequentially with identical dwell times, medications in the adult study were administered twice per day for 3 days (ie, a total of 6 doses each), and the dosing of tPA differed (4 mg in the current trial vs 10 mg in the adult trial), although the dosing of DNase was identical. We elected to administer drugs once daily for 3 days at the prescribed dose to conform with standard practice and clinical trial evidence for the use of tPA in children.4 There have been some recent reports of administering both medications simultaneously with no apparent effect on outcomes.28-30

    Limitations

    This study has some important limitations. First, our standard deviation for length of stay in hospital was larger in the study than what was predicted based on the results of previous studies. In the study protocol, we estimated an SD of 2.9 days, whereas in the actual trial, the value was 5.1 days. This finding may have decreased our ability to detect a difference (if one actually existed). Nevertheless, given the nearly identical lengths of stay between the 2 treatment groups, our limit of confidence was within the predefined threshold for a minimally clinically important difference of 2 days. Second, we designed this trial using a pragmatic approach.31 While this design has a number of benefits by simulating real-world applicability, it weakens our ability to attribute the lack of difference between the groups as being due to DNase as opposed to systematic differences in the use of cointerventions across the 2 groups.32 Although participating hospitals received suggestions for standard care, we made no attempt to ensure that suggestions for chest tube size, length or type of antibiotic treatment, or other aspects of routine care were implemented.23 This explanation for our null observation, while possible, is unlikely given the similarities in the 2 groups at baseline, rigorous blinding and randomization procedures, and the lack of effect on the primary outcome when adjusted for study site and other confounders. Third, some participants withdrew from the study before completing all 3 study treatments.

    Fourth, while we collected a wide variety of measures, we did not assess some potentially important outcomes, such as pain, patient satisfaction, and degree of resolution on chest radiography for each participant. Radiographic resolution was a primary outcome in the adult trial of tPA and DNase vs tPA and placebo, defined by changes in radiography from baseline to day 7 and validated using a computed tomography digital measurement model.22 Our study team felt it would be ethically inappropriate to expose children to additional ionizing radiation beyond their routine clinical care and so did not include standardized radiography in the protocol. Nevertheless, the degree of opacification for all available chest radiography at baseline and again prior to chest tube removal was similar in both groups.

    Conclusions

    Taken together, the results of this multicenter randomized clinical trial provide no evidence of a difference in outcomes between children treated with 3 doses of sequentially administered tPA and DNase compared with tPA and placebo. Guidelines should continue to support the use of chest tube insertion and intrapleural fibrinolytics alone as first-line therapy for children with empyema and should not recommend the routine use of DNase. This study also serves as a cautionary reminder that children are not just little adults and that extrapolating evidence from adult trials to children may be problematic, particularly when the same disease may have different epidemiology, risk factors, and outcomes.

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    Article Information

    Accepted for Publication: October 20, 2019.

    Corresponding Author: Eyal Cohen, MD, MSc, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, 555 University Ave, Toronto, ON M5G 1X8, Canada (eyal.cohen@sickkids.ca).

    Published Online: February 3, 2020. doi:10.1001/jamapediatrics.2019.5863

    Author Contributions: Mr Thorpe and Dr Cohen had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Study concept and design: Mahant, Laberge, Brindle, Mamdani, Ratjen, Cohen.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Livingston, Ratjen, Chan, Cohen.

    Critical revision of the manuscript for important intellectual content: Livingston, Mahant, Connolly, MacLusky, Laberge, Giglia, Yang, Roberts, Shawyer, Brindle, Parsons, Stoian, Walton, Thorpe, Chen, Zuo, Mamdani, Loong, Isaranuwatchai, Ratjen, Cohen.

    Statistical analysis: Livingston, Thorpe, Chen, Zuo, Mamdani, Loong, Isaranuwatchai.

    Obtained funding: Mahant, Ratjen, Cohen.

    Administrative, technical, or material support: Livingston, MacLusky, Laberge, Parsons, Walton, Mamdani, Loong, Isaranuwatchai, Chan, Cohen.

    Study supervision: Laberge, Yang, Brindle, Walton, Isaranuwatchai, Ratjen, Cohen.

    Conflict of Interest Disclosures: Drs Mahant and Cohen have received grants from the Canadian Institutes of Health Research and the PSI Foundation. Drs Giglia and Roberts have received grants from the Canadian Institutes of Health Research. Dr Mamdani has received honorariums for 1-day expert consultations from Allergan and Novo Nordisk. Dr Ratjen has received personal fees for consulting from Genentech during the conduct of the study as well as grants from Genome Canada, Cystic Fibrosis Canada, Cystic Fibrosis Foundation, and Vertex Pharmaceuticals and personal fees for consulting from Vertex Pharmaceuticals, Proteostasis Therapeutics, Boehringer Ingelheim, Vectura Group, Calithera Biosciences, and Actelion Pharmaceuticals outside the submitted work. No other disclosures were reported.

    Funding/Support: This study was funded by operating grants from the Canadian Institutes of Health Research and PSI Foundation. Dr Livingston was supported by the Clinician Investigator Program at McMaster University (funded by the Ontario Ministry of Health and Long-term Care). Dr Brindle was supported by the Brian and Brenda MacNeill Chair in Pediatric Surgery at the University of Calgary.

    Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Disclaimer: The opinions, results, and conclusions reported in this article are those of the authors and are independent from the funding sources.

    Meeting Presentation: This article was presented at the 2019 Pediatric Academic Societies Annual Meeting; April 28, 2019; Baltimore, Maryland.

    Data Sharing Statement: See Supplement 3.

    Additional Contributions: We thank the study project managers, Jodi Tiffany Shim, BSc(Hons) (Applied Health Research Centre, St Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada), and Olivia Chan, MSc (University Health Network, Toronto, Ontario, Canada), as well as research staff, Lynda Hoey (Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada), Hélène Gagnon, RN (Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada), Lauré-Anne Parent, BA (Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal), Adam Pow, BSc (MCI Management Center Innsbruck, Innsbruck, Austria), Ali MacRobie (O’Brien Institute for Public Health, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada), and Shamini Selvakumar, MD (Department of Pediatrics, McMaster Children’s Hospital, McMaster University, Hamilton, Ontario, Canada). We also acknowledge the efforts of Ashna Jinah, MSc (Centre for Excellence in Economic Analysis Research [CLEAR], The HUB Health Research Solutions, St Michael’s Hospital, Toronto, Ontario, Canada), in conducting health economic analyses as well as our data monitoring committee, including Michael Weinstein, MD, Michael Temple, MD, and Reshma Amin, MD (The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada). Drs Weinstein, Temple, and Amin were not compensated for their work. All other contributors were compensated for their contributions.

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