Neonatal Management and Outcome in Extreme Prematurity

Introduction

Neonatology is a fairly new field of medicine which has emerged over the past 50 years. Rapid technological progress over recent decades and major advances in perinatal treatment and neonatal intensive care have led to a significant improvement in survival after premature birth, particularly at extremely low gestations (<28 weeks of gestation). Improvement in survival rates has also led to a gradual decrease in limits of viability, which nowadays vary between 22 and 24 weeks of gestation in most Western countries.

Despite improvement in perinatal survival, significant rates of neonatal morbidity and severe long-term impairments continue to be observed in extreme preterm neonates. Further improvement in the medical care and short- and long-term outcome in this highly vulnerable group of infants requires, among others, close collaboration among neonatologists, fetal medicine specialists and high-risk obstetric services. Optimal collaboration starts with sharing the knowledge and changes in management among the various specialists in the fields of perinatal medicine.

In this chapter, we discuss the management and outcome in extreme preterm neonates and summarise the recent improvements in the field of neonatal medicine, focussing on the transition at birth, strategies for respiratory support to reduce the risk for lung injury and the improved role of neuroimaging in detecting cerebral injury. The focus on lung injury and cerebral injury was selected because both are major determinants of long-term outcome. The results of recent cohort studies reporting on long-term neurodevelopmental outcome in extreme preterm neonates are finally summarised at the end of this chapter.

Delivery Room Management

Although in the past decades, much progress has been made in the clinical care of preterm infants in the neonatal intensive care unit (NICU), very little attention has been paid on the management in the first 10 minutes of life after birth. International guidelines for neonatal resuscitation were based on very little scientific data, and our understanding of the physiology of transition was mostly based on animal studies and extrapolation from human fetal data from the 1970s. However, recent animal and human studies have challenged some of the prevailing concepts of transition as well as the causes and consequences for when this transition fails.

To allow gas exchange at birth, the airways must be cleared of liquid to allow the entry of air into the distal gas-exchange regions, and blood flow through the lungs must markedly increase. Recent studies have shown that a transpulmonary pressure generated by the infant or applied by the caregiver is primarily responsible for the lung liquid clearance and air entry. For adequate gas exchange, after lung aeration, a sufficient amount of air has to remain in the lung at the end of expiration (functional residual capacity). However, the accumulation of lung liquid in the interstitial tissue leads to a positive pressure, and lung liquid can potentially move back into the airways. To prevent this, infants create a positive pressure in the airways by breathing with expiratory braking patterns. Also, the activated epithelial sodium channels play a role in keeping the airways clear from lung liquid.

It is now well established that lung aeration also triggers a decrease in pulmonary vascular resistance and increase in pulmonary blood flow. The exact mechanisms that sense and mediate this event remain unclear. Increased oxygenation, mediated by nitric oxide release, is one component of the response, but mechanisms that are independent of oxygen are also involved. Clamping the umbilical cord before pulmonary blood flow increases reduces venous return and thus preload for the left heart, reducing cardiac output. Thus, if ventilation onset is delayed after cord clamping, the infant is at risk for an ischaemic insult because of low cardiac output.

The management in the first minutes after birth can severely impact morbidities associated with prematurity, such as bronchopulmonary dysplasia (BPD) and cerebral injury. To minimise injury, intubation and mechanical ventilation in the delivery room are now avoided, and the focus of respiratory care has shifted to noninvasive ventilation (positive pressure support of breathing, ventilation via facemask or both). In apnoeic or insufficiently breathing infants, international guidelines recommend that lung aeration can be achieved by applying intermittent positive pressure ventilation with initial higher pressures. Alternatively, recent animal and clinical studies demonstrated a beneficial effect in applying a positive pressure for longer duration (sustained inflation). Applying positive end-expiratory pressure (PEEP) during ventilation is then essential to maintain lung volume by preventing airways to collapse and interstitial lung liquid return to the airways. Applying continuous positive airway pressure (CPAP) to support the spontaneously breathing infants during the transition has similar effects and is now universally adopted as an alternative for endotracheal intubation and mechanical ventilation.

Excessive oxygen exposure leads to oxidative stress and tissue injury and should be avoided during stabilisation at birth. Current guidelines now recommend the judicious use of oxygen in preterm infants. On the other hand, hypoxia immediately after birth will cause a weakened or absent respiratory drive, and it is not known when the switch from respiratory suppression to stimulation occurs in response to hypoxia. Nomograms of saturation of peripheral oxygen (SpO ₂ ) percentiles based on pulse oxymetry (PO) measurements have been developed to guide the caregiver in titrating the oxygen between the acceptable reference ranges. The optimal inspired oxygen content required to avoid hypoxia as well because hyperoxia remains unclear.

Because mask ventilation is the cornerstone in neonatal resuscitation, an optimal mask-holding technique is one of the most important skills of neonatal caregivers. Mask ventilation in infants can be difficult and is often hampered by leak and airway obstruction, resulting in low tidal volumes and thereby inadequate ventilation. Mask technique should be incorporated into all local training in neonatal resuscitation. For pressure delivery, a T-piece ventilator seems the best device available. In contrast to a self-inflating of flow-inflating bag, the pressure is set and not generated manually, which leads to more consistent pressures and thus less variation in volumes. In addition, sustained inflations, PEEP and CPAP can easily be delivered with a T-piece ventilator, but when using a self-inflating bag, it is very difficult to apply a sustained inflation, and PEEP and CPAP cannot be delivered.

Respiratory Support in the Neonatal Intensive Care Unit

Next to antenatal corticosteroids and surfactant therapy, mechanical ventilation is one of the major interventions that led to improved neonatal survival in preterm infants. However, mechanical ventilation can also cause lung injury. As a result, there is continuous effort in improving the respiratory care with the aim of providing strategies to maintain adequate gas exchange while minimising lung damage.

Noninvasive ventilation strategies are now increasingly used as initial respiratory support. Meta-analyses have demonstrated the beneficial effect of CPAP as primary treatment of respiratory distress syndrome in preterm infants. This decreased the need for mechanical ventilation but unfortunately did not decrease the incidence of BPD. Usually CPAP levels of 5 to 6 cm H ₂ O are used, but this can vary among centres. In a large randomised trial, higher levels up to 12 cm H ₂ O were used, but a higher incidence of pneumothorax was reported.

Respiratory distress syndrome in very preterm neonates is primarily caused by surfactant deficiency. Traditionally, surfactant was given after the infant was intubated and mechanical ventilated. The time point of extubating, immediately after surfactant administration (INtubation-SURfactant-Extubation [INSURE] approach) or later on, varied among centres. Recent studies have demonstrated the safety of administering surfactant on spontaneously breathing infants receiving noninvasive support. Surfactant is then given via a feeding tube or endovascular catheter placed endotracheally. Trials are underway investigating the efficacy of the less invasive surfactant administration.

Other noninvasive ventilation strategies are available, although most of them are used after mechanical ventilation to prevent extubation failure. Most modes are available in a nonsynchronised mode (nasal intermittent positive-pressure ventilation, bilevel CPAP). It has been shown that these modes are not very effective in transmitting the pressure to the lung during the inflation because the vocal cords can be closed, while a synchronised mode could be more effective. Nevertheless, the beneficial effect can also be attributed to increasing the mean airway pressure, and a similar effect could be reached by increasing the CPAP pressure.

The most commonly used ventilator is time controlled, pressure limited and with a continuous flow in the circuit to allow the infants to breathe at any time. Synchronising the inflations of the ventilator to the breaths of the infants (triggered ventilation) is now used in most neonatal centres and has shortened the duration of ventilation. For synchronisation, a flow sensor is placed proximal of the patient at the endotracheal tube. New technology and the use of microprocessors has led to the availability of many different modes that are more sophisticated and could potentially reduce the ventilation-induced lung injury. Volume-guaranteed ventilation, in which the pressure is automatically adjusted as needed to ensure the targeted volume, has been shown to reduce duration of ventilation, the occurrence of air leak, BPD and cerebral injury.