In this randomized controlled trial we included intubated infants with birth weight ≤ 1,250 grams. Infants with congenital abnormalities of the upper airway tract, acquired nasal septum injury and major congenital or chromosomal abnormalities were excluded. The study was conducted at a tertiary care NICU, Mount Sinai Hospital, Toronto, Ontario, Canada, during the period from April 2006 to November 2008.
Parents of eligible infants were approached for participation in the trial and written informed consent was obtained prior to extubation. A marker was then placed at the bedside of eligible infants whose parents had given consent. Randomization cards were generated using a computer generated random numbers list. The cards were sealed in sequentially marked opaque envelopes and opened immediately prior to the first extubation. Infants were randomized to one of two groups: BP-NCPAP or NCPAP delivered by the Infant Flow® SiPAP™ (Viasys Healthcare, Yorba Linda, CA, USA). The assigned mode of support was continued until the infant was ready to be placed in room air or supplemental oxygen. The study was approved by the local Research Ethics Board.
Preset criteria were used to guide extubation using a consensus approach amongst neonatologists in our NICU. For conventional ventilation the criteria included: a ventilator rate of < 20 breaths per minute (bpm), peak inspiratory pressure (PIP) ≤ 16 cm H2O and fractional inspired oxygen (FiO2) of ≤ 0.35. For high frequency ventilation the criteria were: frequency of 9-13 Hz, amplitude < 20 percent, mean airway pressure (MAP) of ≤ 8 cm H2O and FiO2 ≤ 0.35. Once an infant reached these preset criteria, the medical team was approached for consideration of extubation. In the event of accidental extubation in eligible consented infants, face mask CPAP was applied for no more than 15 minutes until a decision was made either to reintubate based on the clinical condition or to randomize to the study group. All infants had the appropriate bonnet, nasal prong interface and Cannulaide® (Beevers Manufacturing Inc., McMinnville, OR, USA) applied.
In the BP-NCPAP arm the respiratory rate was set at 20 bpm with an inspiratory time of 1.0 second. The upper level of CPAP was set 3 cm above the lower (baseline) level of CPAP. In both modes the lowest baseline CPAP was set at 5 cm H2O and the CPAP was titrated according to the infant's FiO2 needs based on an algorithm (Table ). Neither mode of NCPAP was synchronised with the infant's respiratory effort. Weaning in both groups was left at the discretion of the attending neonatologist. If the infant remained clinically stable in FiO2 ≤ 0.25 with no evidence of increased work of breathing and/or apnea of prematurity, then attempt was made to trial off CPAP.
Guidelines for use of biphasic nasal continuous positive airway pressure (BP-NCPAP) and nasal continuous positive airway pressure (NCPAP)
Criteria for reintubation included: presence of severe apnea (defined as need for positive pressure ventilation), ≥ 4 minor apneic episodes per hour requiring moderate stimulation, required supplemental oxygen of > 60% to maintain oxygen saturation > 88%, developed uncompensated respiratory acidosis (defined a pH < 7.25) or a combination of the above. Apnea was defined as cessation of respiration for > 20 seconds or a shorter pause if associated with bradycardia (heart rate < 100 beats per minute) or desaturation (< 85%). Reintubation was also allowed at the discretion of the attending medical team for other reasons, e.g., concerns regarding sepsis. Data were collected for the duration of their in-hospital stay. Other medical therapy and interventions were provided at the discretion of the medical team.
In our unit, caffeine is usually commenced in the first week of life even if the infant requires positive pressure ventilation via endotracheal tube. A loading dose of 10 mg/kg followed by maintenance dose of 2.5 mg/kg is administered within 24-36 hours. Based on the clinical response the maximum dose of maintenance caffeine used is 5 mg/kg.
Data were collected on maternal characteristics including age, gravidity, parity, pregnancy induced hypertension, essential hypertension, preterm prolonged rupture of the membranes (> 18 hours), antenatal steroids (complete and partial course), and clinical and histological diagnosis of chorioamnionitis from maternal health records and placental pathology.
The primary outcome was the incidence of sustained extubation for 7 days. Secondary outcomes included incidence of adverse events such as: nasal septal injury/erythema, eyelid edema, abdominal distension, feeding intolerance and pneumothorax. Nasal septal injury/erythema and eyelid edema were monitored and recorded every 4 hours by the respiratory therapists and the nursing staff. Data on feeding intolerance (defined as aspirates of ≥ 30% of a single feed administered) and abdominal distension (defined as > 10% increase in abdominal girth) were recorded by the nursing staff every 4 hours and/or prompted by clinical concerns. Data on the other clinical outcomes including the incidence of BPD [oxygen dependency at 36 weeks post menstrual age (PMA)], patent ductus arteriosus (PDA) (diagnosed clinically or by ECHO and treated with indomethacin ± surgery), necrotizing enterocolitis (NEC) (Bell's stage 2 or greater) [15
], grade 3/4 intraventricular hemorrhage (IVH) [16
] or periventricular leucomalacia (PVL) and retinopathy of prematurity (ROP) were abstracted from the chart. Retinopathy of prematurity was classified according to the international classification [17
]. Infants who died were excluded from the analysis for ROP and for BPD if they died before they reached 36 weeks PMA. In our unit, PDA is treated pharmacologically (with indomethacin) based on the presence of clinical symptoms and signs. Prior to administration of a second course of indomethacin or referral for surgical ligation, infants undergo echocardiography. Both caregivers administering the interventions and research assistants were not blinded to the group assignment.
The sample size calculation was based on the results obtained from a previous study that compared the rate of sustained extubation using NCPAP vs. high flow oxygen in our unit. The rate of sustained extubation with NCPAP was 85% [18
]. To demonstrate a clinically significant increase in the rate of sustained extubation by 10% between groups (i.e. from 85% to 93.5%) with 80% power and an alpha value of 0.05, we estimated a sample size of 141 patients in each arm for a total of 282 patients.
The analysis was performed using the intention-to-treat principle. Baseline maternal and infant characteristics and outcomes of the infants randomized to both modes were compared using χ2 test for categorical data and Student's t test for continuous data. The Wilcoxon rank sum test was used to compare continuous data with highly skewed distributions. All reported P values are two sided. A planned secondary analysis examined the predictors of successful extubation using multivariate logistic regression to control for possible confounders including birth weight, sex, age at the time of first extubation, accidental extubation and use of antenatal steroids. All statistical analyses were performed using the computer program Statistical Package for the Social Sciences v.12™ (Chicago, IL, USA). A P value of 0.05 was considered significant.