ReviewThe role of CO2 and central chemoreception in the control of breathing in the fetus and the neonate☆
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.
Section snippets
Role of CO2 in the control of fetal breathing movements
It is likely that mechanisms designed to maintain oxygenation and acid base balance in the fetus are largely focused on the cardiovascular system and the placenta, since the lungs play no role in gas exchange. On the other hand, a rapid adaptation must take place at birth to survive in a new and different environment that requires the lungs to become the organ of gas-exchange immediately after birth. Thus the discovery of fetal breathing movements in the late 1960s generated interest in
The premature human infant
Breathing in premature human infants is characterized by irregularity, periodic breathing, and frequent apnea. Breathing irregularity is largely dependent on sleep/behavioral state and is most common in active or REM sleep (AS), whereas breathing is more regular during quiet or NREM sleep (QS). In the human infant from 30 to 40 weeks PMA, breathing irregularity appears to increase slightly from 30 to 36 weeks and then steadily decreases. Breathing is irregular approximately 60–70% of the time
Conclusions
In conclusion, central chemoreception is active early in development and likely drives fetal breathing movements, which are essential for maintaining fetal lung volume and lung growth and development and in preparation for continuous breathing required after birth. In the fetus breathing is influenced by the combination of behavioral state and powerful inhibition from sources including prostaglandins, adenosine, and neurons located in the upper lateral pons. Inhibition increases during hypoxia
Acknowledgements
The author is supported by an NIH grant 5P01 HD036379-12 and thanks Don Bartlett for reviewing the manuscript.
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This paper is part of a special issue entitled “Central Chemoreception”, guest-edited by Drs. E.E. Nattie and H.V. Forster.