New insights in neonatal apnea

Apnea of prematurity (AOP) remains a major clinical problem requiring frequent evaluations and challenging therapeutic strategies. The exact mechanisms responsible for AOP are still undefined. Immaturity of breathing responses in preterm infants affects all levels of respiratory control, including central and peripheral chemosensitivity, and inhibitory pulmonary afferents. This immaturity is manifested by impaired ventilatory responses to hypoxia, hypercapnia and an exaggerated inhibitory response to stimulation of airway receptors. Noteworthy, recent findings suggest an effect of genetic variability on regulation of breathing and apnea.
There are several open issues in the management of AOP. First, animal studies suggest that some proteins, such as cytokines, may enhance vulnerability of neonatal respiratory control via prostaglandin mediated pathways. While this finding has not a therapeutic significance at this time, it may provide new insights in AOP mechanisms. Another issue being studied is the role of gastroesophageal reflux (GER). Despite the frequent coexistence of apnea and GER in preterm infants, there is no current evidence that GER prolongs the concurrent apnea. This may also raise doubts about the efficiency of widespread anti-reflux medication use in AOP infants.
Continuous positive airway pressure (CPAP) and methylxanthines are the mainstay for AOP therapy. CPAP at 4-6 cm H2O has proven a relatively safe and effective therapy for over 35 years. Because longer episodes of apnea frequently involve an obstructive component, CPAP appears to be effective by splinting the upper airway and decreasing the risk of pharyngeal or laryngeal obstruction. CPAP also benefits apnea by increasing functional residual capacity, thus improving oxygenation status. Recently, high-flow nasal cannula therapy has been suggested as an equivalent treatment modality that may allow CPAP delivery while enhancing infant mobility. However, some questions have been raised about the safety and efficacy of devices providing a relatively unregulated high flow as a means of CPAP delivery.
For what concerns methylxanthines, caffeine and theophylline have been the mainstay of pharmacological treatment of apnea of prematurity for over 30 years. This therapy increases minute ventilation, improves CO2 sensitivity, decreases hypoxic depression of breathing, enhances diaphragmatic activity, and decreases periodic breathing. On the other hand, methylxanthines have some acute adverse effects, such as mild diuresis tachycardia, cardiac dysrhythmias, feeding intolerance and, infrequently, seizures, although these effects are seen less commonly with caffeine at the usual therapeutic doses. Xanthine therapy increases the metabolic rate and oxygen consumption by 20%: this suggests that the caloric demands may be increased with this therapy at a time when nutritional intake already is compromised. A large international multicenter placebo-controlled trial investigating the short-term and long-term safety of caffeine therapy has now been completed. The study showed that caffeine provides a significant reduction in the incidence of bronchopulmonary dysplasia and a significantly better neurodevelopmental outcome.  
AOP generally resolves by about 36-40 weeks' post-conceptional age. However, in more immature infants, it frequently persists beyond this time. Available data indicate that cardiorespiratory events in such infants return to the baseline' level at about 43-44 weeks' postconceptional age. It is important to remember that AOP can have a serious impact on long-term neurodevelopmental outcomes: therefore, further studies are required to fully elucidate the different aspects of this condition.

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