STUDY DESIGN
This is a multicentric, prospective, double-blind, randomized, placebo-controlled, phase IV clinical trial. Five pediatric intensive care units of hospitals located in Spain will participate in the study. The study protocol was developed in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist (Additional file 1). The study was registered with the European Clinical Trials Register under number 2009-016596-30 in May 2010.
STUDY POPULATION
The sample will include children between 1 month and 16 years of age admitted to the ICU who require intubation for more than 48 hours, regardless of their condition. Exclusion criteria were the presence of underlying airway disease (congenital malformations, surgery, infection), the administration of steroid therapy within the last seven days, or refusal to participate in the study.
RECRUITMENT
Study candidates will be identified by a study physician, who will explain the study to parents or guardians. Written informed consent will be obtained prior to inclusion in the study. CONSORT (Consolidated Standards of Reporting Trials) flow diagram is shown in Figure 1.
RANDOMIZATION AND MASKING
Patients will be assigned to one of the two therapy groups on a 1:1 ratio by simple randomization using a randomization table on EPIDAT 3.1 (Epidat: software package for epidemiological data analysis. 2006. Consellería de Sanidade, Xunta de Galicia, España; Organización Panamericana de la Salud; Universidad CES, Colombia). The Coordinating Center will send a table for sequential randomization of patients. This table will contain the number of medication that has been assigned to each patient. The treatment group will not be detailed in the randomization table. This table will also include a number of reserve medication for use in case of deterioration, loss, or if the drug is rendered unusable. The Pharmacy Unit of the Coordinating Center will send treatment-arm assignments labeled and blinded as established in the randomization table for each center.
The labeling and blinding of medication kits will be performed by the Pharmacy Unit of the Coordinating Center, which will keep an open record of these kits and their composition. This record will be coded and stored by the pharmacist of the Coordinating Center responsible for the labeling and submission of samples.
In case of severe or unexpected adverse events related to the medication, the Principal Investigator will require the responsible pharmacist to unblind the codes identifying the sample. The Principal Investigator will be informed so that timely action can be taken. The unblinding of any code will be recorded by the pharmacist responsible for sample blinding.
INTERVENTION
The treatment group will receive intravenous 0.25 mg/kg/dose (to a maximum of 8 mg) every 6 hours, for a total of 4 doses. The first dose will be administered between 6 and 12 hours prior to extubation. The placebo group will be administered saline 0.9%. The study medication will have the same aspect and characteristics than placebo and both will be administered in the same way. Dose adjustment, discontinuance or reinitiation of treatment will not be allowed. Inspections will be performed to ensure that the treatment is being administered adequately.
DATA COLLECTION AND ASSESSMENT OF EFFICACY
On inclusion, demographic (age, sex and weight) and clinical data will be collected, as follows:
- Diagnosis (six diagnostic groups will be established): surgery, lower airway obstruction, neurological disease, sepsis, trauma and other diagnosis.
- Assessment of severity: the clinical status of the patient will be assessed using PIM2, PRIMS 3 and PELOD scores prior to extubation.
- Size and type of endotracheal tube (cuffed or uncuffed).
- Route of intubation (oral, nasal).
- Previous need for endotracheal tube replacement.
- Previous airway endoscopies.
- Respiratory infection confirmed by endotracheal aspirate culture.
- Presence of blood in endotracheal aspirate.
- Duration of endotracheal intubation prior to extubation (days).
The primary endpoint is the occurrence of UAO symptoms within 48 hours after extubation.
A record of the following variables will be kept at 15 minutes, 1h, 2h, 6h, 12h, 24h and 48 hours after extubation:
- UAO Taussig score, a clinical scoring system for the assessment of UAO severity; evaluating stridor, retractions, inflow of air into the lungs, cyanosis and consciousness. Presence of inspiratory stridor.
- Need for and frequency of additional therapies for respiratory distress: adrenaline or nebulized budesonide, intravenous steroids, heliox or non-invasive ventilation.
- Hemodynamic (blood pressure, heart rate) and respiratory (peripheral oxygen saturation, respiratory rate) parameters.
- Arterial pCO2 and pO2 and glycemia. Blood samples will not be routinely collected, they will be drawn only for clinical purpose.
- Need for reintubation, time point and cause.
- Presence of digestive bleeding.
- Occurrence of infection.
The timing of parameter recording is shown in Table 1.
Tests
|
Screening
|
First visit prior to extubation
|
Visits
2 to 8
|
Assessment of eligibility
|
|
|
|
Informed consent
|
X
|
|
|
Inclusion and exclusion criteria
|
X
|
|
|
Anamnesis
|
X
|
|
|
Assessment of safety
|
|
|
|
Physical examination
|
X
|
X
|
X
|
Vital signs
|
X
|
X
|
X
|
Assessment of adverse events
|
|
X
|
X
|
Previous and current medications
|
X
|
X
|
X
|
Assessment of efficacy a
|
|
|
|
Vital signs
|
X
|
X
|
X
|
Stridor
|
X
|
X
|
X
|
Taussig scale
|
X
|
X
|
X
|
Reintubation
|
|
X
|
X
|
Other assessments
|
|
|
|
Other medications
|
|
X
|
X
|
Deliveries of medication
|
|
|
|
Randomization and dispensing of the medication
|
|
X
|
X
|
Contact with the randomized-dispensing center
|
X
|
X
|
X
|
Table 1. SPIRIT Schedule of Events Timeline: enrolment, assessment of safety, assessment of efficacy, and dispensing of the medicine. Visits 2 to 8, respectively: 15 minutes following extubation, 1 h, 2 h, 6 h, 12 h, 24 h and 48 h after extubation.
EVALUATION OF SAFETY
The occurrence of adverse events from inclusion to study completion will be recorded for all patients. Severe adverse events during hospital stay will be reported to the Study Coordinator and Promotor. In case of occurrence of severe adverse events, follow-up will be performed until remission or until a diagnosis is made and its association with the study medication is established.
A severe adverse event is defined as any adverse event that the patient's treating physician considers to require treatment on the basis of the characteristics and clinical status of the patient. Severe hyperglycemia is any glycemia > 200 mg/dl that persists for more than 6 hours and/or physicians considers to require treatment on the basis of the clinical status of the patient.
Any unused medication will be disposed in accordance with the protocol established by the Pharmacy Unit in collaboration with the Unit of Environmental Management of the Coordinating center, in compliance with ISO 14.001. Upon study completion, any unused or partially used medication will be sent back to the Coordinating Center.
SAMPLE SIZE
The estimated incidence of moderate-to-severe UAO symptoms is approximately 30%. To detect a 25-to-10% reduction of breathing distress secondary to UAO with a statistical power of 80% and an alpha risk of 5%, we estimated that 100 patients would be needed in each study arm.
STATISTICS
Categorical variables will be expressed as frequencies and percentages. Normality of continuous data will be assessed by the Kolmogorov-Smirnov test. Continuous variables will be expressed as mean values and SD, or as median values and interquartile range.
The association between categorical variables will be assessed by Chi-squared test or Pearson's coefficient, or by Fisher's exact test, as appropriate, based on the sample size.
Continuous variables will be compared by Student's t-test or Mann-Whitney U test. In comparisons of values with respect to time, Student's t-test of repeated measures or Wilcoxon test will be performed, as appropriate. Per protocol analysis will be performed.
Bilateral statistical tests will be used at a 5% level of significance. Statistical analysis will be performed using SPSS version 20 (SPSS Inc, Chicago, USA).
DATA PROCESSING
Data from each patient will be collected and anonymized by a study member in a data log. Each study center will send their data logs to the Coordinating Center. The Principal Investigator will enter data from data logs into a single database for all study patients. A preliminary study will be performed when 50% of the required sample has been reached. Only the Principal Investigator will have access to unmasked data and preliminary study results. The study will only be interrupted if the incidence of UAO or the incidence of severe adverse events is significantly higher in the steroid treatment group as compared to the placebo group.
The final analysis will be carried out when the sample size has been reached.