Pleural Empyema
Conditions
Keywords
Randomized controlled trial, Pleural Empyema, tPA, DNase
Brief summary
Bacterial pneumonia can be complicated by the development of excess fluid and pus (pleural empyema) around the lungs in children. The incidence of pleural empyema in children has increased significantly in the last 10 years. Short term morbidity for this condition is substantial, but unlike in adults, the long term outcome of this condition for children in developed countries is favourable. Inserting a chest drain and then adding a medicine (tissue plasminogen activator - tPA) to break down organized pus has been shown to be an effective therapy for reducing the duration of illness. However, this treatment is still suboptimal and prolonged hospitalization is common. Recent data from adults suggests that adding an additional medicine (DNase) to decrease the viscosity (thickness) of the fluid improves drainage and leads to better patient outcomes; however, there are no published studies on children. This is a multi-centre randomized controlled trial comparing the time to discharge from hospital after chest drain insertion in previously well children who present with pleural empyema, treated with intrapleural DNase and tissue plasminogen activator (tPA) by chest drain for three doses over 48 hours compared with three doses over 48 hours of tPA alone. Other outcomes related to effectiveness, safety and cost will be assessed as well.
Interventions
DRUGTPA (Tissue Plasminogen Activator)
Intrapleural administration of tPA 4 mg in 10 ml (≤10 kg) or 20 ml (\>10 kg) normal saline once daily for 3 days
DRUGDNase
Intrapleural administration of DNase 5 mg diluted to 10 ml (≤10 kg) or 20 ml (\>10 kg) normal saline once daily for 3 days
OTHERPlacebo
Intrapleural administration of normal saline 10 ml (≤10 kg) or 20 ml (\>10 kg)
Sponsors
Canadian Institutes of Health Research (CIHR)
Children's Hospital of Eastern Ontario
St. Justine's Hospital
Unity Health Toronto
The Physicians' Services Incorporated Foundation
McMaster Children's Hospital
British Columbia Children's Hospital
The Hospital for Sick Children
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Months to 18 Years
Healthy volunteers
No
Inclusion criteria
1. age 6 months to 18 years 2. hospitalized with diagnosis of pleural empyema requiring chest tube drainage with fibrinolytics as judged by the attending physician with the following criteria: 1. pneumonia with pleural effusion as documented on ultrasound of the chest; AND 2. need for further intervention in addition to antibiotics based on clinical criteria \[persistent fever despite on antibiotics for at least 48 hours OR significant respiratory distress tachypnea, hypoxia) as a result of the pleural fluid collection\]
Exclusion criteria
1. empyema as a result of tuberculosis, fungus or non-infectious causes (e.g. malignancy) 2. known coagulation impairment 3. suspected or proven allergy to tPA or DNase 4. chronic lung disease or other chronic illnesses (e.g. immunodeficiency or neurologic impairment) 5. child has already undergone a drainage procedure (e.g. chest drain or VATS). 6. recent administration of an investigational drug (within previous 30 days) 7. pregnancy 8. breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Hospital Discharge | up to 4 months | Time from insertion of the chest drain to discharge from hospital. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Meeting Discharge Criteria | up to 4 months | Time from insertion of the chest drain to meeting discharge criteria. Discharge criteria: * Chest tube removed * No fever \[temperature less than 38°C\] * Normal respiratory rate forage * No hypoxia * Drinking fluids wel |
| Time to Drain Removal | up to 4 months | Time from drain insertion to drain removal. |
| Duration of Fever After Intervention | up to 4 months | Duration of fever (defined as temperature \>38 degrees celsius taken by any method) from insertion of the chest drain until resolution. |
| Number of Participants With Need for Ventilatory Support or Non-invasive Ventilation Following the Intervention | up to 4 months | Number of Participants with need for any kind of ventilatory support or any kind of non-invasive ventilation right after the intervention. |
| Number of Participants With Further Interventions | up to 4 months | Number of participants who needed further intervention such as placement of another chest drain (by any technique) or surgical intervention such as thoracotomy and decortication, video-assisted thorascopic surgery, or pneumonectomy. |
| Number of Participants With Hospital Readmission | 3 months post-discharge | Number of Participants who had any hospital readmission after discharge from hospital for initial treatment for pleural empyema within three months related to pleural empyema or its treatment. |
| Cost of the Hospitalization | up to 4 months | An economic evaluation will compare the relative costs of DNase-tPA with tPA alone in previously well children who present with pleural empyema, using patient-level data from the trial. |
| Mortality | up to 4 months | Mortality from any cause during the hospitalization for empyema. |
| Number of Participants With Serious Bleeding | up to 4 months | Number of Participants who had intrapleural bleeding resulting in a drop in hemoglobin of greater than 20 g/L or needing a transfusion. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Chest Radiography | 7 days after drain removal | The radiograph closest to the time of drain removal will be reviewed by a blinded study radiologist to determine the percentage of hemithorax occupied using a 5 point ordinal scale utilized in previous studies ranging from no fluid present to fluid occupying \>75% of the most affected hemithorax. |
Countries
Canada
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Intervention (tPA & DNase) Intrapleural tPA, 4 mg, followed by DNase (Roche), 5 mg | 49 |
| Placebo (tPA & Placebo) Intrapleural tPA (Roche), 4 mg, followed by 5 mL of normal saline | 48 |
| Total | 97 |
Baseline characteristics
| Characteristic | Intervention (tPA & DNase) | Placebo (tPA & Placebo) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 49 Participants | 48 Participants | 97 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 58.4 Months STANDARD_DEVIATION 43.3 | 64.1 Months STANDARD_DEVIATION 44.2 | 61.3 Months STANDARD_DEVIATION 45.6 |
| Race/Ethnicity, Customized Race/ethnicity African | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Race/ethnicity Asian/Pacific Islander | 14 Participants | 13 Participants | 27 Participants |
| Race/Ethnicity, Customized Race/ethnicity First nations | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Race/ethnicity Hispanic | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race/ethnicity Middle Eastern | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race/ethnicity Missing | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Race/ethnicity Prefer not to answer | 5 Participants | 4 Participants | 9 Participants |
| Race/Ethnicity, Customized Race/ethnicity South Asian | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race/ethnicity White | 26 Participants | 26 Participants | 52 Participants |
| Region of Enrollment Canada | 49 Participants | 48 Participants | 97 Participants |
| Sex: Female, Male Female | 24 Participants | 21 Participants | 45 Participants |
| Sex: Female, Male Male | 25 Participants | 27 Participants | 52 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 49 | 0 / 48 |
| other Total, other adverse events | 8 / 49 | 13 / 48 |
| serious Total, serious adverse events | 6 / 49 | 8 / 48 |
Outcome results
Primary
Time to Hospital Discharge
Time from insertion of the chest drain to discharge from hospital.
Time frame: up to 4 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intervention | Time to Hospital Discharge | 9.0 days | Standard Deviation 4.9 |
| Control | Time to Hospital Discharge | 9.1 days | Standard Deviation 5.3 |
Secondary
Cost of the Hospitalization
An economic evaluation will compare the relative costs of DNase-tPA with tPA alone in previously well children who present with pleural empyema, using patient-level data from the trial.
Time frame: up to 4 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intervention | Cost of the Hospitalization | 11329 2018 US $ | Standard Deviation 7139 |
| Control | Cost of the Hospitalization | 10760 2018 US $ | Standard Deviation 5071 |
Secondary
Duration of Fever After Intervention
Duration of fever (defined as temperature \>38 degrees celsius taken by any method) from insertion of the chest drain until resolution.
Time frame: up to 4 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intervention | Duration of Fever After Intervention | 2.8 days | Standard Deviation 3.4 |
| Control | Duration of Fever After Intervention | 3.3 days | Standard Deviation 3.4 |
Secondary
Mortality
Mortality from any cause during the hospitalization for empyema.
Time frame: up to 4 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Mortality | 0 Participants |
| Control | Mortality | 0 Participants |
Secondary
Number of Participants With Further Interventions
Number of participants who needed further intervention such as placement of another chest drain (by any technique) or surgical intervention such as thoracotomy and decortication, video-assisted thorascopic surgery, or pneumonectomy.
Time frame: up to 4 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Number of Participants With Further Interventions | 4 Participants |
| Control | Number of Participants With Further Interventions | 2 Participants |
Secondary
Number of Participants With Hospital Readmission
Number of Participants who had any hospital readmission after discharge from hospital for initial treatment for pleural empyema within three months related to pleural empyema or its treatment.
Time frame: 3 months post-discharge
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Number of Participants With Hospital Readmission | 2 Participants |
| Control | Number of Participants With Hospital Readmission | 0 Participants |
Secondary
Number of Participants With Need for Ventilatory Support or Non-invasive Ventilation Following the Intervention
Number of Participants with need for any kind of ventilatory support or any kind of non-invasive ventilation right after the intervention.
Time frame: up to 4 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Number of Participants With Need for Ventilatory Support or Non-invasive Ventilation Following the Intervention | 9 Participants |
| Control | Number of Participants With Need for Ventilatory Support or Non-invasive Ventilation Following the Intervention | 8 Participants |
Secondary
Number of Participants With Serious Bleeding
Number of Participants who had intrapleural bleeding resulting in a drop in hemoglobin of greater than 20 g/L or needing a transfusion.
Time frame: up to 4 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Number of Participants With Serious Bleeding | 2 Participants |
| Control | Number of Participants With Serious Bleeding | 4 Participants |
Secondary
Time to Drain Removal
Time from drain insertion to drain removal.
Time frame: up to 4 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intervention | Time to Drain Removal | 6.9 days | Standard Deviation 4.3 |
| Control | Time to Drain Removal | 6.9 days | Standard Deviation 5.3 |
Secondary
Time to Meeting Discharge Criteria
Time from insertion of the chest drain to meeting discharge criteria. Discharge criteria: * Chest tube removed * No fever \[temperature less than 38°C\] * Normal respiratory rate forage * No hypoxia * Drinking fluids wel
Time frame: up to 4 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intervention | Time to Meeting Discharge Criteria | 8.2 days | Standard Deviation 4.5 |
| Control | Time to Meeting Discharge Criteria | 8.5 days | Standard Deviation 5.4 |
Other Pre-specified
Chest Radiography
The radiograph closest to the time of drain removal will be reviewed by a blinded study radiologist to determine the percentage of hemithorax occupied using a 5 point ordinal scale utilized in previous studies ranging from no fluid present to fluid occupying \>75% of the most affected hemithorax.
Time frame: 7 days after drain removal
Population: Degree of opacification on chest radiography prior to chest tube removal
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Intervention | Chest Radiography | <=25% | 33 Participants |
| Intervention | Chest Radiography | >75% | 2 Participants |
| Intervention | Chest Radiography | 26-50% | 10 Participants |
| Intervention | Chest Radiography | Missing | 3 Participants |
| Intervention | Chest Radiography | 51-75% | 1 Participants |
| Control | Chest Radiography | Missing | 7 Participants |
| Control | Chest Radiography | <=25% | 25 Participants |
| Control | Chest Radiography | 51-75% | 4 Participants |
| Control | Chest Radiography | >75% | 1 Participants |
| Control | Chest Radiography | 26-50% | 11 Participants |