The role of CO₂ and central chemoreception in the control of breathing in the fetus and the neonate

Abstract

Central chemoreception is active early in development and likely drives fetal breathing movements, which are influenced by a combination of behavioral state and powerful inhibition. In the premature human infant and newborn rat ventilation increases in response to CO₂; in the rat the sensitivity of the response increases steadily after ∼P12. The premature human infant is more vulnerable to instability than the newborn rat and exhibits periodic breathing that is augmented by hypoxia and eliminated by breathing oxygen or CO₂ or the administration of respiratory stimulants. The sites of central chemoreception active in the fetus are not known, but may involve the parafacial respiratory group which may be a precursor to the adult RTN. The fetal and neonatal rat brainstem-spinal-cord preparations promise to provide important information about central chemoreception in the developing rodent and will increase our understanding of important clinical problems, including The Sudden Infant Death Syndrome, Congenital Central Hypoventilation Syndrome, and periodic breathing and apnea of prematurity.

Introduction

There is common agreement that central respiratory chemoreception is in place early in development. In this review I will focus on the role of CO₂ and central chemoreception in the control of breathing in the fetus, preterm human infant and full term newborn rat based on the evidence that brainstem development in the newborn rat from P0 until P8–P10 is roughly equivalent to that in the third trimester human fetus. From studies of the rate of growth of the brain (Dobbing and Sands, 1979), functional studies of sleep and arousal (McNamara et al., 1998, Dauger et al., 2001, Karlsson and Blumberg, 2002, Durand et al., 2004, Blumberg et al., 2005, Seelke et al., 2005), control of breathing (Stunden et al., 2001, Putnam et al., 2005, Wong-Riley and Liu, 2005, Davis et al., 2006), the autonomic control of heart rate (Hofer and Reiser, 1969), and thermoregulation (Lagerspetz, 1966, Conklin and Heggeness, 1971, Mouroux et al., 1990), three periods during rat development can be recognized that are roughly comparable to stages of human development: (1) The period from P0 to P8–P10, roughly equivalent to the third trimester of pregnancy in the human, (2) a period from P10 to P15 roughly equivalent to early infancy in the human in which there is dramatic development of the autonomic control of heart rate, sleep, and thermoregulation, and (3) a period from P15 to P30, roughly equivalent to late infancy through young adulthood.

Rats are relatively immature at birth. They have no fur, their eyes are fused and ear ducts are sealed. In some respects they resemble premature infants at 24–26 weeks gestation. However, rats are born with more mature lungs and may not face the same challenges of the very premature infant including surfactant deficiency and poorly developed mechanisms to maintain lung volume. With respect to respiratory control and lung development, the full term newborn rat may be more like a late preterm infant at 32–36 weeks post menstrual age (gestational age + chronological age) (PMA).

Although it is well recognized that the neuronal and muscular components of the respiratory system, as well as the lungs, continue to develop after birth, even when delivered at term, a certain degree of development must occur in utero to assure adequate ventilation within minutes of birth. Even very immature human infants have the basic tools to breathe spontaneously and relatively continuously, albeit with significant disadvantages, including a highly compliant chest wall with difficulty maintaining functional residual capacity (FRC), a propensity for airway obstruction, difficulties with coordinating sucking, swallowing and breathing, and immature respiratory control mechanisms resulting in irregular and periodic breathing and apnea.