Non-invasive Respiratory Support
Preterm infants with respiratory distress syndrome (RDS) have low pulmonary compliance and high thoracic-cage compliance. Thus, to avoid loss of lung volume and atelectasis they need gentle support of functional residual capacity (FRC) and surfactant replacement. The aim of the respiratory treatment of RDS is to oxygenate and ventilate the premature infants using these two elements of treatment while preventing death, BPD, and neurological morbidity.32
Bronchopulmonary dysplasia has a complex pathophysiology, based on arrest of maturation and multi-heat phenomena.33
Thus, there is no magic bullet, and the prevention of BPD warrants the implementation of a comprehensive approach.34
Even few breaths by positive pressure ventilation were found to be harmful to the lungs.35,36 Furthermore, endotracheal ventilation was found to be associated with cerebral palsy and low mental developmental index (MDI).37 Thus, to achieve the goals of respiratory support we try to avoid endotracheal ventilation.
If endotracheal ventilation is needed in premature infants with RDS, there is no preference of conventional ventilation or high-frequency ventilation when assessing death or BPD or severe adverse neurological outcomes.38 If conventional ventilation is used, volume-targeted ventilation is preferred over pressure-limited ventilation in order to reduce death or BPD, pneumothoraxes, hypocarbia, severe cranial ultrasound pathologies, and duration of ventilation.39 However, innovative modes of ventilation and the use of surfactant did not reduce substantially the incidence of BPD. The rate of BPD was found to correlate with the use and length of endotracheal mechanical ventilation.40 Furthermore, BPD in itself is associated with adverse neurodevelopmental outcome.41
Allowing nasal respiratory support as a safe and efficient alternative to endotracheal ventilation and surfactant in the most premature infants was the result of a thorough evaluation by two large RCTs. Morley et al.42 randomly assigned 610 infants who were born at 25–28 weeks’ gestation to nasal continuous positive airway pressure (NCPAP) or intubation and ventilation at 5 minutes after birth. They concluded that early NCPAP did not significantly reduce the rate of death or BPD, as compared with intubation. The SUPPORT trial43 was a randomized, multicenter trial, involving infants who were born at 24.0–27.6 weeks’ gestation. Infants were randomly assigned to intubation and surfactant treatment (within 1 hour after birth) or to NCPAP treatment initiated in the delivery room. A total of 1,316 infants were enrolled in the study. This study supported consideration of NCPAP as an alternative to intubation and surfactant in preterm infants. The primary outcome (death or BPD) rates did not differ significantly between the two groups. However, infants in the NCPAP group required less frequent intubation or postnatal corticosteroids for BPD (P<0.001), required fewer days of mechanical ventilation (P=0.03), and were more likely to survive and be free from mechanical ventilation by day 7 (P=0.01).
These studies allow the consideration of NCPAP as an alternative to intubation and surfactant in extremely preterm infants and reveal a small but significant benefit in long-term outcomes. A meta-analysis44 including these studies and a total of 3,289 infants found that the combined odds ratio (95% confidence interval) of death or BPD was 0.83 (0.71–0.96) using NCPAP versus intubation and surfactant. The number needed to treat was 35 infants. Avoiding endotracheal mechanical ventilation had no influence on the incidence of severe IVH. They concluded that strategies aimed at avoiding endotracheal mechanical ventilation in infants <30 weeks’ gestational age have a small but significant beneficial impact on preventing BPD.
Attempts to enhance NCPAP to achieve a better outcome for nasal respiratory support led to the use of nasal intermittent positive pressure ventilation (NIPPV), defined as a method of augmenting NCPAP by delivering ventilator breaths via nasal prongs. The rationale for using NIPPV is the administration of “sigh” to the infant, thus opening microatelectasis and recruiting more ventilation units. Synchronized NIPPV compared with NCPAP has been found to activate the respiratory drive,45 improves thoraco-abdominal synchrony,46 stabilizes the chest wall,46 improves lung mechanics,46 and decreases the breathing effort in premature infants.47
In clinical studies, early NIPPV appears to be superior to NCPAP for reducing respiratory failure and the need for endotracheal tube ventilation among preterm infants with RDS.48 However, infants randomized to NIPPV have comparable risk of BPD. For the initial therapy of RDS high-flow nasal cannula (HFNC) compared with NCPAP in 564 infants with gestational age ≥28 weeks was associated with significantly higher rates of treatment failure within 72 hours. “Rescue” NCPAP use resulted in similar intubation rates in the two treatment groups.49 Kugelman et al. in infants >1,000 g found no difference between HFNC and NIPPV, but that study included only 76 infants.50
For post-extubation, a meta-analysis showed that synchronized NIPPV reduces the incidence of extubation failure and the need for re-intubation within 48 hours–1 week more effectively than NCPAP; however, the rate of BPD or mortality was not changed. The number needed to treat was 3 infants.51 High-flow nasal cannula post-extubation in 303 infants <32 weeks’ gestation was found to be non-inferior to the use of NCPAP, with treatment failure occurring in 34% of the infants in the nasal-cannula group and in 25% of the infants in the NCPAP group.52 Almost half the infants in whom treatment with HFNC failed were successfully treated with NCPAP without re-intubation. The incidence of nasal trauma was significantly lower in the nasal-cannula group than in the CPAP group (P=0.01).
Surfactant was a major breakthrough in the treatment of premature infants with RDS. A crucial question was whether surfactant should be given as a preventive therapy or only as rescue therapy. This is important if we try to avoid endotracheal ventilation, as surfactant traditionally is given via the endotracheal tube. The Cochrane Review53
concluded that recent large trials that reflect current practice (including greater utilization of antenatal steroids and routine post-delivery stabilization on NCPAP) demonstrate less risk of BPD or death when using early stabilization on NCPAP with selective surfactant administration to infants requiring intubation.
While non-invasive ventilation seems to be safe, its success depends on gestational age.42,43,54 There is still a significant role for surfactant in the treatment of RDS, especially in extremely low-birth-weight infants (~50% will need intubation and surfactant). In the last decade, few methods of gentle administration of surfactant were developed to allow the infant to benefit from both, surfactant and nasal respiratory support. The INSURE approach (INtubation SURfactant Extubation; in which surfactant is administered during brief intubation followed by immediate extubation to NCPAP), when compared with later selective surfactant administration, continued mechanical ventilation, and extubation from low respiratory support, was associated with less need for mechanical ventilation, lower incidence of BPD (at 28 days), and fewer air-leak syndromes.55 Gopel et al.56 showed that the application of surfactant via a thin catheter to spontaneously breathing preterm infants receiving NCPAP reduces the need for mechanical ventilation. This method is called LISA (less invasive surfactant administration) or MIST (minimal invasive surfactant therapy). A recent meta-analysis showed that, among preterm infants, LISA use was associated with the lowest likelihood of the composite outcome of death or BPD at 36 weeks’ postmenstrual age.57 A new approach that is under investigation, which will allow avoidance of direct instillation of surfactant to the trachea, would be aerosolization of the surfactant.58
Non-invasive Ventilation and Surfactant Treatment
To summarize, a lot of effort is invested in the non-invasive ventilation approach. The outcomes of that approach in the long run are still to be investigated. A recent study did not find benefits, concluding that despite substantial increases in the use of less invasive ventilation after birth, there was no significant decline in oxygen dependence at 36 weeks and no significant improvement in lung function in childhood over time.59
The results of that study could have different interpretations.60,61
The recent cohorts in that study, 1997 and 2005, showed no significant difference in the rate of endotracheal ventilation. It has been shown that even short exposure to endotracheal positive pressure ventilation is harmful.35,36
Thus, it is possible to conclude from the study of Doyle et al.59
that every effort should be made to minimize the use of endotracheal ventilation by using more non-invasive ventilation. At the same time, there was a striking decrease in the use of postnatal glucocorticoids between these cohorts, from 46% in 1997 to 23% in 2005. The differences between these periods could explain the surprising results found by Doyle et al.59
To overcome the possible effect of the decreased use of glucocorticoids, it is possible that we should consider other policies of using postnatal glucocorticoids that do not adversely affect the neurodevelopmental outcome. These could include inhaled glucocorticoids,62
or intratracheal glucocorticoids with surfactant.64
Considering the complex nature of BPD,33 a comprehensive approach34 will be needed to show its reduction. Beyond understanding the biologic and physiologic rationale of such an approach, studying it in RCTs seems to be an impossible mission with the current knowledge due to ethical constraints.
Non-invasive CO2 Monitoring
The non-invasive approach is seen also in seeking methods of non-invasive continuous monitoring of carbon dioxide (CO2
) in the NICU. Hypercarbia and hypocarbia are to be avoided in premature infants because of possible neurological and respiratory deleterious effects.65–67
Carbon dioxide can be monitored by capnography68,69
and by transcutaneous CO2
Kugelman et al.71 showed that continuous distal end tidal CO2 monitoring improved control of CO2 levels within a safe range during conventional ventilation in NICUs. The prevalence of IVH or periventricular leukomalacia rate was lower in the monitored group. However, the number of extremely premature infants was small, and these results should be interpreted with caution. Larger studies in the vulnerable population are needed in order to show short- and long-term clinical benefits of continuous CO2 monitoring. We should probably perform continuous non-invasive monitoring of ventilation (CO2) similarly to what we do for oxygenation by using continuous pulse oximetry. This can be done by capnography and TcCO2. Capnography and TcCO2 monitoring should be viewed as complementary technologies in various clinical scenarios in the NICU.
“Kangaroo Care” and Newborn Individualized Developmental Care and Assessment Program (NIDCAP)
“Kangaroo care” and Newborn Individualized Developmental Care and Assessment Program (NIDCAP) are adopted by the modern neonatology.
Kangaroo mother care (KMC) was defined as “skin-to-skin contact between a mother and her newborn, frequent and exclusive or nearly exclusive breastfeeding, and early discharge from hospital.”72 A Cochrane Review72 aimed to determine whether evidence is available to support the use of KMC in low-birth-weight infants as an alternative to conventional neonatal care before or after the initial period of stabilization with conventional care. Their updated review supports use of KMC in low-birth-weight infants as an alternative to conventional neonatal care, mainly in resource-limited settings.
The immaturity of their organ systems causes preterm infants to experience a range of morbidities. There is concern that a non-gentle or an un-comfortable environment in the NICU may have an unfavorable effect on this morbidity or result in iatrogenesis. Environmental modification can minimize the iatrogenic effects. Developmental care represents a broad category of interventions designed to minimize NICU environmental stress. Such interventions may include control of external stimuli (vestibular, auditory, visual, tactile), clustering of nursery care activities, and positioning or swaddling of the preterm infant. Individual strategies have also been combined to form programs, such as the NIDCAP. A Cochrane Review73 looking at the effect of NIDCAP concluded that determination of the effect of any single intervention is difficult because of the inclusion of multiple interventions in most studies. Although the evidence indicates a limited benefit for developmental care interventions overall, and no data suggest harmful effects, there have been a large number of outcomes with debatable effects. For each intervention there is only support by single small studies which were not repeated. The interventions have an economic impact that needs to be considered. A more recent systematic review of preterm infants (n=627) found no evidence that NIDCAP improves long-term neurodevelopmental or short-term medical outcomes.74 The composite primary outcomes of death or major sensorineural disability at 18 months corrected age or later in childhood (RR 0.89 [95% CI 0.61 to 1.29]) and survival free of disability at 18 months corrected age or later in childhood (RR 0.97 [95% CI 0.69 to 1.35]) were not significantly different between the NIDCAP and control groups.