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 with the name “Steroids in the prevention of upper airway postextubation complications in critically ill children”.
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. Patients with airway malformations, suspected or confirmed croup syndrome, tracheitis or epiglottitis and those who had previously underwent any surgery involving upper or lower airway will be excluded. Furthermore, other exclusion criteria were the administration of steroid therapy within the last seven days, patients who had a previous extubation failure during the stay 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 from parents or guardians 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 reduction of the incidence of moderate to severe UAO symptoms within 48 hours after extubation. Moderate-severe UAO symptoms will be considered if stridor or Taussig score >5 are present. The secondary endpoints are the presence of reintubation and the potential secondary effects associated with dexamethasone.
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[13], a clinical scoring system for the assessment of UAO severity; evaluating stridor, retractions, inflow of air into the lungs, cyanosis and consciousness (table 1). 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 2.
All interventions that patients require for their treatment are allowed but those that could affect the upper airway (respiratory tract infections, reintubations, etc.), will be recorded and will be taken into account in the statistical analysis
A co-investigator will be appointed as responsible for each participating center in order to verify the correct adherence to the study protocol, checking in every 8 hour shift that the medication is prescribed in the treatment and that it has been administered. This investigator will also be responsible of complete follow up of every patient.
Monthly communication newsletter regarding recruitment activity will be sent by email to all researchers. In this newsletter, researchers will also be encouraged to continue recruiting.
|
|
Score
|
|
|
0
|
1
|
2
|
3
|
Clinical parameters
|
Color
|
Normal
|
Normal
|
Normal
|
Cyanotic
|
Air entry
|
Normal
|
Mildly diminished
|
Moderately diminished
|
Substantially diminished
|
Retractions
|
None
|
Mild
|
Moderate
|
Severe
|
Level of consciousness
|
Normal
|
Restlessness if disturbed
|
Restlessness at rest
|
Lethargy
|
Stridor
|
None
|
Mild
|
Moderate
|
Severe (or no stridor if severe obstruction)
|
Table 2 Modified Taussig score. Upper airway obstruction is considered mild if score is less than 5 points, moderate-severe with ≥5 points. Modified of Taussig LM. Treatment of Laryngotracheobronchitis (Croup). Am J Dis Child 1975;129:790.
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 2. 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. All patients will be monitored until hospital discharge, including those who discontinue their participation in the study. 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 consider 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-severe UAO symptoms is approximately 33% [1–3]. We consider a clinically relevant result the reduction of moderate to severe UAO symptoms incidence by 50% in the treatment group.
To calculate the minimum sample size, a two-sample two-proportion two-tiled comparison test was used, using arcsine approximation for proportions (Cohen's method). To detect a 50% reduction of incidence (0.33 UAO symptoms proportion in the placebo group, 0.16 expected proportion in the treatment group, i.e. Cohen's h effect size=0.4) with 80% statistical power and 5% significance level, 110 subjects per arm will be needed. A follow-up loss rate of 10% has been estimated.
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.
To compare the primary endopoint of outcome between the group receiving dexamethasone and the group receiving placebo Z-test statistics will be used. Per protocol analysis will be performed. An intention-to-treat analysis will be also performed to guarantee the effect of randomization.
The association between other 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. Additional subgroup analysis according to age and pathologies 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 AND AUDITING
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. An interim analysis will be performed by an independent Data Monitoring Committee (DMC) comprised of members of Central Unit of Clinical Research Support and Clinical Trials (UCAICEC) of the Gregorio Marañón Research Institute. 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.
UCAICEC will be responsible for auditing the trial independently from investigators yearly.