Randomised Controlled Trial to Study the Effect of Nasal Continuous Positive Airway Pressure (NCPAP) Cycling on Successful Weaning When Compared With Nasal Continuous Positive Airway Pressure (NCPAP) in Premature Infants of 25-28 Weeks Gestation

Randomized Controlled Trial to Study the Effect of Nasal Continuous Positive Airway Pressure (NCPAP) Cycling on Successful Weaning when Compared with Continuous Nasal Positive Airway Pressure (NCPAP) in Premature Infants of 25-28 weeks gestations Background: In Canada, preterm babies of < 28 weeks gestation constitute 12% of all newborn admissions and their survival has increased from 65% to 72%. In Alberta, the premature birth rate has been increasing over the past several years and although these preterm infants make up a small percentage of births, they add disproportionately to the mortality, morbidity and cost of medical care. Their rate of long-term neurodevelopmental disability is also disproportionately high. Advances in neonatal ventilation and neonatal care including increased use of antenatal steroids, postnatal surfactant, improved mechanical ventilation and early use of total parenteral nutrition have improved survival of extremely low birth weight (ELBW) premature infants. Despite these advances, the incidence of Bronchopulmonary Dysplasia (BPD) in these infants remains high in Southern Alberta.

Perinatal risk factors and the duration of mechanical ventilation, including high inspired oxygen, high peak inspiratory pressure, lower positive end-expiratory pressure, higher ventilation rate and hypocarbia (Partial pressure of carbon dioxide < 40 cm of water at 48 to 96 hours) are associated with later development of BPD in these premature infants. Although pressure-induced injury might play a role in the injury leading to 'new' BPD, alveolar over distention is likely to be a more important contributing factor. Atelectasis also contributes to BPD as ventilation of the atelectatic lung leads to pulmonary parenchymal injury through the sheer stress of repeatedly reinflating collapsed alveoli. Despite various preventive and treatment strategies including permissive hypercapnia, high frequency ventilation, antioxidants, indomethacin, fluid restriction and use of diuretic, the prevalence of BPD continues to be unacceptably high. It is unclear whether minimum ventilator pressure exposure to premature lungs could prevent increasing incidence of BPD with the use of nasal continuous positive airways pressure (NCPAP) cycling ( NCPAP for a few hours alternating with continuous nasal flow) when compared with continuous NCPAP. High pressure on the ventilator or continuous NCPAP possibly remains an underlying mechanism for pressure and volume induced injury to the lungs and exhaustion of the respiratory muscle.

Prolonged ventilation may predispose diaphragmatic myofibrils to disuse atrophy or failure of normal growth, which contributes, to difficulties in weaning infants from mechanical ventilator support including Nasal continuous positive airways pressure (NCPAP). Age and gestation dependent changes in contractile function of the diaphragm include decreased fatigue resistance with advancing maturation and Ventilator Induced Diaphragmatic Dysfunction (VIDD). The combination of high work, rapid breathing, and low-oxidative capacity suggests respiratory muscle fatigue in the infant with respiratory disease. Even short-term controlled mechanical ventilation produces significant remodeling and functional alterations of the diaphragm, which could impede efforts at discontinuing ventilator support.

Prolonged use of mechanical ventilation has also been associated with infections, subglottic stenosis and aspiration. Therefore, clinicians strive to wean early from the ventilator and avoid reintubation once infants are extubated. Clinical signs of respiratory failure after extubation include apnea (prolonged cessation of respiration for 20 seconds or more and/or associated with cyanosis; abrupt, marked pallor or hypotonia; bradycardia), respiratory acidosis or increasing oxygen requirements. These problems may lead to reintubation and ventilation with their attendant morbidity and economic costs. NCPAP appears to stabilize the upper airway, improve lung function and reduce apnea. Randomized trials have shown that NCPAP, applied prophylactically after extubation, reduces the need for additional ventilatory support and is associated with a lower incidence of BPD compared to mechanical ventilation. NCPAP supports the compliant chest wall of the neonate by providing a pneumatic splint to counteract the tendency to move paradoxically during inspiration or to collapse upon expiration. NCPAP has been used to prevent extubation failure and as an alternative to intubation and ventilation for respiratory distress syndrome in very preterm infants. The optimal method of weaning infants from NCPAP remains unanswered. Although some Neonatal intensive care units try abrupt discontinuation of NCPAP, most wean on an ad hoc basis by gradually decreasing either time spent on the Infant Flow Driver (IFD) or the NCPAP pressure. Early discontinuation of NCPAP may carry the risk of pulmonary atelectasis, apnea and bradycardia. The most common reason for failure to wean on NCPAP is respiratory acidosis, apneas, bradycardias, and increasing oxygen requirements above 60%. Similarly, the most common reason for re-ventilation is respiratory acidosis. In a prospective study in 2011 on preterm infants with resolving respiratory distress syndrome, NCPAP impeded systemic and pulmonary venous return but did not compromise systemic arterial pressure or heart rate. The important issue, therefore, is the rationale of continuing NCPAP when supplemental oxygen requirement have ended, in the absence of moderate-to-severe apnea. Mechanical ventilation and NCPAP both tend to cause barotraumas and possibly BPD in premature infants. It is unclear whether preterm infants who undergo NCPAP cycling with free flow of oxygen are at less risk for BPD compared to those who are dependent on continuous NCPAP. In a randomized controlled trial of discontinuation of NCPAP in 2011, authors found that almost all preterm infants breathing room air tolerated a 6 hour pause in NCPAP with no increase in apnea and bradycardia. A reduction in the subsequent use of NCPAP was also observed. These findings led to the development of a strategy to further reduce ventilator induced trauma and thus BPD. This strategy used non-invasive intermittent continuous positive airway pressure ventilation by alternating NCPAP with continuous nasal flow (CNF) via nasal prongs for ELBW infants. This method of ventilation is termed cycling of NCPAP. In our subjective clinical experience, cycling of NCPAP with CNF reduces the duration of respiratory support and therefore would be expected to reduce the incidence of BPD. Cycling reduces duration of NCPAP and dependency, trauma and or deviation of nasal septum, feed intolerance due to gastric distension, agitation from pain/discomfort and nosocomial infection. The benefits of cycling NCPAP in comparison to continuous NCPAP in premature infants have not been studied in clinical trials. The aim of this pilot study is to establish the ability of NCPAP cycling to prevent reintubation, decrease the duration of respiratory support and thereby, the incidence of BPD.

Rationale for this study: There is no evidence in the literature that premature infants who are treated with NCPAP cycling alternating with continuous nasal air flow (CNF) versus NCPAP without alternating CNF do better or worse in the immediate newborn period. We speculate that NCPAP cycling or weaning will gradually shift the work of breathing from the supportive intervention to the baby without producing fatigue of respiratory muscles and trauma to the developing lungs. Currently, this mode of respiratory support is being used in our Neonatal intensive care unit. It is largely determined by personal preferences with little clinical data, only experimental or anecdotal evidence without any long-term outcomes data. A retrospective study to confirm benefits of cycling NCPAP with CNF versus continuous NCPAP is not feasible since duration of this alternative therapy has varied in infants of different gestational ages. There is equipoise regarding the role of cycling NCPAP with CNF versus continuous NCPAP without CNF in premature infants. Therefore, it would be prudent to study the benefits of NCPAP cycling versus continuous NCPAP in premature infants. Our pilot study will address the importance of NCPAP cycling as a useful weaning mode in ELBW infants. Results of this pilot study will inform future power and sample size calculations for a larger randomized controlled trial. Information obtained from this study will also fill gaps in the existing knowledge in neonatal medicine and will resolve current controversies concerning the use of NCPAP cycling with CNF versus continuous NCPAP in ELBW infants.