ReviewApnea of prematurity – Perfect storm☆
Introduction
Breathing is an essential, involuntary and dynamic process that is modulated by a multitude of central and peripheral inputs such that oxygen and metabolic demands of cells and tissues can be met. Since the fetus does not rely on ventilation to oxygenate tissues, it is not necessary for breathing to be sustained even though it can be modulated by arterial oxygen tension and blood glucose levels. The primary function of fetal breathing is to provide intermittent stretch for structural development of the lung (Kitterman, 1996, Sanchez-Esteban et al., 2001). For the infant who is born prematurely, central and peripheral mechanisms that control breathing are still “set” for intra-uterine life and breathing is both unsustained and punctuated by frequent respiratory pauses. These respiratory pauses are of minimal consequence to the fetus but can be problematic for the premature infant for which breathing is a prerequisite for life. Apnea of prematurity, therefore, is a developmental disorder that occurs in infants born before 34 weeks gestational age and usually resolves by term gestation (Henderson-Smart, 1981). However, for infants born less than 28 weeks gestation, apnea can often persist past term gestation (Eichenwald et al., 1997, Hofstetter et al., 2008). While short respiratory pauses should be of little consequence provided that adequate oxygenation is maintained, these apneic pauses can be problematic if associated with intermittent hypoxemia.
Chronic intermittent hypoxia (CIH) increases free radical production and contributes to the pathogenesis of adverse outcomes associated with obstructive apnea in adults (Sunderram and Androulakis, 2012) and children (Bass et al., 2004). As we have reported, CIH frequently occurs in premature infants (Di Fiore et al., 2010a, Di Fiore et al., 2010b). Infants with a high frequency of apnea associated with CIH need prolonged respiratory support, take longer to achieve oral feeds, have a greater incidence of retinopathy of prematurity (Di Fiore et al., 2010a, Di Fiore et al., 2010b), and have greater risk of adverse neurodevelopmental outcomes (Martin et al., 2011, Pillekamp et al., 2007). Thus, it is not the apnea per se that is of concern but the associated hypoxemia and/or bradycardia that often accompanies the apnea and compromises oxygenation and perfusion to vital organs and tissues. Paradoxically, the frequency and severity of apnea of prematurity (Miller et al., 1959) and associated CIH often progressively increases during the first weeks of life (Di Fiore et al., 2010a, Di Fiore et al., 2010b). Thus, the most significant clinical challenge is to understand the physiological basis for this paradox – why hypoxemia occurs – and develop therapeutic strategies to prevent CIH associated with apnea of prematurity.
Premature infants are also born with underdeveloped lungs that are vulnerable to injury. The concurrent occurrence of an “immature respiratory network” and immature lung development creates the perfect storm for apnea of prematurity associated with CIH. In fact, infants with the most severe apnea often have worse lung disease (Eichenwald et al., 1997). While providing supplemental oxygen to premature infants reduces the severity and frequency of apnea and CIH (Weintraub et al., 1992), determining the optimal level of arterial oxygen that prevents CIH without increasing the risk of retinopathy of prematurity remains a clinical challenge. In order to begin to address these challenges, here we review the (1) current understanding of the unique physiology of the developing premature infant that creates the perfect storm, (2) techniques that most accurately assess CIH and its temporal relationship with cardiorespiratory events (apnea and bradycardia), and (3) lastly, the current therapies that target this unique physiology to reduce apnea and associated CIH.
Section snippets
Integrated respiratory network
The structure and function of all components (sensors, controls and effectors) of the integrated respiratory network are undergoing significant modification during early development such that ventilation progresses from sporadic fetal breathing to more sustained breathing seen in infants born at term gestation (Givan, 2003). The current hypothesis states that respiratory rhythm is generated from the central pattern generator within the ventral brainstem. Inspiration is driven by the
Diagnostic challenges
Cardiorespiratory monitoring is a vital component of clinical care of the neonate. Accurate measurements of respiration, oxygen saturation and heart rate are imperative in detection of clinical apnea during both spontaneous breathing and respiratory support. Continuous measurements of oxygen saturation are needed for both detection of intermittent hypoxemia events and to maintain infants within a safe oxygen saturation target range while uninterrupted ECG waveforms are necessary to document
Biologic basis for therapeutic interventions
The aggressiveness with which therapy is pursued in apneic preterm infants must weigh the potential consequences of apnea and resultant desaturation and bradycardia, with the natural history which favors spontaneous resolution of these episodes with advancing maturation. For the most widely used therapies, namely continuous positive airway pressure (CPAP) and methyl xanthines, we are still gaining knowledge of their precise mechanisms of action. While these two approaches are both effective and
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This paper is part of a special issue entitled “Clinical Challenges to Ventilatory Control”, guest-edited by Dr. Gordon Mitchell, Dr. Jan-Marino Ramirez, Dr. Tracy Baker-Herman and Dr. Dr. David Paydarfar.