Review
Apnea of prematurity – Perfect storm

https://doi.org/10.1016/j.resp.2013.05.026Get rights and content

Highlights

  • In premature infants, the respiratory network is “set” for fetal breathing.

  • Early birth does not hasten development of the respiratory network.

  • Early birth predisposes to mal development of the lung and respiratory network.

  • Apnea and hypoventilation are of little consequence if hypoxemia does not occur.

  • Immature lung development and injury combined with apnea of prematurity is the perfect storm causes CIH.

Abstract

With increased survival of preterm infants as young as 23 weeks gestation, maintaining adequate respiration and corresponding oxygenation represents a clinical challenge in this unique patient cohort. Respiratory instability characterized by apnea and periodic breathing occurs in premature infants because of immature development of the respiratory network. While short respiratory pauses and apnea may be of minimal consequence if oxygenation is maintained, they can be problematic if accompanied by chronic intermittent hypoxemia. Underdevelopment of the lung and the resultant lung injury that occurs in this population concurrent with respiratory instability creates the perfect storm leading to frequent episodes of profound and recurrent hypoxemia. Chronic intermittent hypoxemia contributes to the immediate and long term co-morbidities that occur in this population. In this review we discuss the pathophysiology leading to the perfect storm, diagnostic assessment of breathing instability in this unique population and therapeutic interventions that aim to stabilize breathing without contributing to tissue injury.

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

References (110)

  • E.B. Gauda et al.

    Inflammation in the carotid body during development and its contribution to apnea of prematurity

    Respiratory Physiology and Neurobiology

    (2013)
  • D.C. Givan

    Physiology of breathing and related pathological processes in infants

    Seminars in Pediatric Neurology

    (2003)
  • K. Gresham et al.

    Airway inflammation and central respiratory control: results from in vivo and in vitro neonatal rat

    Respiratory Physiology and Neurobiology

    (2011)
  • S. Hannam et al.

    A possible role for the Hering–Breuer deflation reflex in apnea of prematurity

    Journal of Pediatrics

    (1998)
  • A. Hislop

    Developmental biology of the pulmonary circulation

    Paediatric Respiratory Reviews

    (2005)
  • A.A. Hislop et al.

    The effects of preterm delivery and mechanical ventilation on human lung growth

    Early Human Development

    (1987)
  • A.G. Huxtable et al.

    Systemic inflammation impairs respiratory chemoreflexes and plasticity

    Respiratory Physiology and Neurobiology

    (2011)
  • N. Idiong et al.

    Airway closure during mixed apneas in preterm infants: is respiratory effort necessary?

    Journal of Pediatrics

    (1998)
  • J.A. Kitterman

    The effects of mechanical forces on fetal lung growth

    Clinics in Perinatology

    (1996)
  • J. Li et al.

    Chronic or high dose acute caffeine treatment protects mice against oleic acid-induced acute lung injury via an adenosine A2A receptor-independent mechanism

    European Journal of Pharmacology

    (2011)
  • R.J. Martin et al.

    Persistance of the biphasic ventilatory response to hypoxia in preterm infants

    Journal of Pediatrics

    (1998)
  • C.F. Poets

    Apnea of prematurity: what can observational studies tell us about pathophysiology?

    Sleep Medicine

    (2010)
  • S.H. Abman

    Impaired vascular endothelial growth factor signaling in the pathogenesis of neonatal pulmonary vascular disease

    Advances in Bladder Research

    (2010)
  • J.A. Adams et al.

    Hypoxemic events in spontaneously breathing premature infants: etiologic basis

    Pediatric Research

    (1997)
  • J.E. Alvarez et al.

    Sighs and their relationship to apnea in the newborn infant

    Biology of the Neonate

    (1993)
  • R.E. Alvaro et al.

    CO2 inhalation as a treatment for apnea of prematurity: a randomized double-blind controlled trial

    Journal of Pediatrics

    (2012)
  • E. Backstrom et al.

    Developmental stage is a major determinant of lung injury in a murine model of bronchopulmonary dysplasia

    Pediatric Research

    (2011)
  • T.M. Baird et al.

    Optimal electrode locationa for monitoring the ECG and breathing in neonates

    Pediatric Pulmonology

    (1992)
  • K.J. Barrington et al.

    Periodic breathing and apnea in preterm infants

    Pediatric Research

    (1990)
  • M.T. Bashambu et al.

    Evidence for oxygen use in preterm infants

    Acta Paediatrica

    (2012)
  • J.L. Bass et al.

    The effect of chronic or intermittent hypoxia on cognition in childhood: a review of the evidence

    Pediatrics

    (2004)
  • G.M. Blain et al.

    Peripheral chemoreceptors determine the respiratory sensitivity of central chemoreceptors to CO2

    Journal of Physiology

    (2010)
  • E. Bloch-Salisbury et al.

    Stabilizing immature breathing patterns of preterm infants using stochastic mechanosensory stimulation

    Journal of Applied Physiology

    (2009)
  • B. Bohnhorst et al.

    Detection of hyperoxaemia in neonates: data from three new pulse oximeters

    Archives of Disease in Childhood. Fetal and Neonatal Edition

    (2002)
  • V.R. Chavez et al.

    Correlation between serum caffeine levels and changes in cytokine profile in a cohort of preterm infants

    Journal of Pediatrics

    (2011)
  • C.M. Chen et al.

    Protective effects of adenosine A2A receptor agonist in ventilator-induced lung injury in rats

    Critical Care Medicine

    (2009)
  • N. Claure et al.

    Multicenter crossover study of automated control of inspired oxygen in ventilated preterm infants

    Pediatrics

    (2011)
  • L. Corvaglia et al.

    Gastro-oesophageal reflux increases the number of apnoeas in very preterm infants

    Archives of Disease in Childhood. Fetal and Neonatal Edition

    (2009)
  • P.G. Davis et al.

    Caffeine for apnea of prematurity trial: benefits may vary in subgroups

    Journal of Pediatrics

    (2010)
  • P. Dejours

    Chemoreflexes in breathing

    Physiological Reviews

    (1962)
  • J. Di Fiore et al.

    Characterization of cardiorespiratory events following gastroesophageal reflux in preterm infants

    Journal of Perinatology

    (2010)
  • J.M. Di Fiore et al.

    The relationship between patterns of intermittent hypoxia and retinopathy of prematurity in preterm infants

    Pediatric Research

    (2012)
  • J.M. Di Fiore et al.

    Low oxygen saturation target range is associated with increased incidence of intermittent hypoxemia

    Journal of Pediatrics

    (2012)
  • P.A. Easton et al.

    Ventilatory response to sustained hypoxia after pretreatment with aminophylline

    Journal of Applied Physiology

    (1988)
  • E.C. Eichenwald et al.

    Apnea frequently persists beyond term gestation in infants delivered at 24 to 28 weeks

    Pediatrics

    (1997)
  • S.J. Erickson et al.

    Hypocarbia in the ventilated preterm infant and its effect on intraventricular haemorrhage and bronchopulmonary dysplasia

    Journal of Paediatrics and Child Health

    (2002)
  • J.L. Feldman et al.

    Understanding the rhythm of breathing: so near, yet so far

    Annual Review of Physiology

    (2013)
  • J.S. Garland et al.

    Hypocarbia before surfactant therapy appears to increase bronchopulmonary dysplasia risk in infants with respiratory distress syndrome

    Archives of Pediatrics and Adolescent Medicine

    (1995)
  • E.B. Gauda et al.

    Developmental maturation of chemosensitivity to hypoxia of peripheral arterial chemoreceptors – invited article

    Advances in Experimental Medicine and Biology

    (2009)
  • E.B. Gauda et al.
  • Cited by (0)

    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.

    View full text