Maturation of peripheral arterial chemoreceptors in relation to neonatal apnoea

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Abstract

Apnoea and periodic breathing are the hallmarks of breathing for the infant who is born prematurely. Sustained respiration is obtained through modulation of respiratory-related neurons with inputs from the periphery. The peripheral arterial chemoreceptors, uniquely and reflexly change ventilation in response to changes in oxygen tension. The chemoreflex in response to hypoxia is hyperventilation, bradycardia and vasoconstriction. The fast response time of the peripheral arterial chemoreceptors to changes in oxygen and carbon dioxide tension increases the risk of more periodicity in the breathing pattern. As a result of baseline hypoxaemia, peripheral arterial chemoreceptors contribute more to baseline breathing in premature than in term infants. While premature infants may have an augmented chemoreflex, infants who develop bronchopulmonary dysplasia have a blunted chemoreflex at term gestation. The development of chemosensitivity of the peripheral arterial chemoreceptors and environmental factors that might cause maldevelopment of chemosensitivity with continued maturation are reviewed in an attempt to help explain the physiology of apnoea of prematurity and the increased incidence of sudden infant death syndrome (SIDS) in infants born prematurely and those who are exposed to tobacco smoke.

Introduction

Advances in perinatal and neonatal care have allowed premature infants born at little more than half of term gestation to survive.1, 2 As might be expected, fetal physiology predominates many biological processes in premature neonates and is frequently disadvantageous to the neonate in an ex-uterine environment. For example, fetal breathing is characterized by periodicity—short bursts of breathing and apnoeic pauses, which are state dependent and modulated by oxygen tension and glucose levels. In premature infants, periodic breathing and apnoea of prematurity are commonly observed respiratory patterns that resemble fetal breathing. These respiratory patterns are inversely related to gestational age with the youngest infants having the more significant apnoeic events and with advancing maturity, apnoea decreases in frequency.3, 4, 5 Although not proven, apnoea of prematurity may be associated with long-term morbidity. The associated bradycardia and haemoglobin (Hb) desaturations, particularly when recurrent, may increase the risk of gastrointestinal and neurological morbidity; probably related to hypoperfusion–reperfusion mechanisms. Furthermore, intermittent hypoxic exposure without ischaemia (a paradigm used to experimentally mimic recurrent apnoea) disrupts the development of mesotelencephalic pathways that modulate sleep, wakefulness, locomotion and executive functioning in newborn rat models.6 Thus, breathing punctuated with periods of apnoea and Hb-desaturations in premature infants has the potential to increase cognitive morbidity.

The major neuronal networks controlling ventilation are located within the brainstem. These networks are modulated by many neural inputs from the upper airway, lungs and peripheral arterial and aortic chemoreceptors. This review focuses on the contribution of peripheral arterial chemoreflexes alone and in combination with stimulation of upper airway and lung receptors on apnoea, bradycardia and Hb-desaturations, which all occur frequently in the premature infant during the neonatal period. In addition, possible biological mechanisms involving plasticity-induced changes in peripheral arterial chemoreceptors, which may account for the epidemiological association between prematurity, tobacco smoke exposure and sudden infant death syndrome (SIDS), will be discussed.

Respiratory rhythmogenesis has been the focus of several recent, excellent reviews.7, 8 Here, an overview of the respiratory network in the brainstem, obtained from studies in the cat and rat, will be presented to provide a framework for how the peripheral arterial chemoreceptors modulate breathing during development. In brief, respiratory rhythm is generated by a network of brainstem neurons. A group of cells in the rostral ventral lateral medulla form the pre-Bötzinger complex that exhibits bursting pacemaker properties. This complex is believed to be the ‘kernel’ responsible for the generation of respiratory rhythm.7, 8, 9, 10, 11 Experiments that lesion or block the activity of this group of cells abolish respiratory rhythm giving strong support to this model of respiratory rhythm generation.12, 13, 14 Pre-Bötzinger neurons synapse onto two main groups of respiratory-related neurons that form the ventral respiratory group (VRG) located in the ventral lateral medulla, and the dorsal respiratory group (DRG), located in the nucleus tractus solatari (nTS).15 Neurons from the VRG and DRG form synapses with the phrenic motoneuron pool, which innervate the diaphragm.16 However, in the newborn rat, only the VRG, in contrast to both the VRG and DRG in the adult cat, appears to be essential for respiratory rhythmogenesis.17

Second to second changes in ventilation are the result of the integration of peripheral inputs in the respiratory network. Information in response to activation or inhibition of sensory fibres from peripheral arterial chemoreceptors, upper airway and lungs (to be described below) is integrated and processed in the nTS. Thus, the nTS is commonly known as a relay station for afferent influences that modulate respiration.18, 19, 20 Central and peripheral influences indirectly modulate the muscles of respiration via axonal projections from the nTS that synapse onto upper airway motoneurons and phrenic motoneuron pools.21, 22 Thus, respiratory rhythmogenesis is a complex physiological function that is precisely regulated from second to second to provide unobstructed, regular breathing during wakefulness and sleep.

Section snippets

Anatomy and histology of peripheral arterial chemoreceptors

The peripheral arterial chemoreceptors are located within the carotid body, positioned between the internal and external carotid arteries. The carotid body is an intricate structure that contains a rich supply of blood vessels, nerve fibres from the carotid sinus nerve (a branch of the 9th cranial nerve), parasympathetic and sympathetic nerve fibres, glial-like type II cells and specialized type I cells that contain the oxygen sensor. Type I cells depolarize in response to hypoxia, hypercapnia

The effect of development on peripheral chemoreceptor function

Peripheral arterial chemoreceptors do not contribute much to fetal breathing in the healthy fetus although the level of hypoxia is approximately 25 torr,26 and the activity of peripheral chemoreceptors is not necessary for establishing rhythmic breathing at birth.27 However, multiple studies, in numerous mammalian models, support a role for peripheral arterial chemoreceptors in contributing to stable ventilation at a critical period of development during early postnatal life, which establishes

Development of peripheral arterial chemoreceptor function

Much knowledge has been gained from animal studies that characterize the development of hypoxic and hypercapnic sensitivity of peripheral arterial chemoreceptors during postnatal development (for reviews see Carroll34 and Gauda and Lawson35). For the most part, these animal studies support the findings shown in human infants. Two significant and distinct physiological responses characterize the developmental profile of hypoxic chemosensitivity at birth and during early postnatal development: an

Assessment of hypoxic chemosensitivity in human infants

Assessing the absolute contribution of peripheral arterial chemoreceptors to ventilation in vivo involves directly measuring carotid sinus nerve activity and, thus, can only be done in anaesthetized animals. Therefore, indirect tests of peripheral chemoreceptor function are done in human infants and unanaesthetized animals by measuring ventilatory responses to short exposures to hypoxic and hyperoxic gas mixtures. Since the peripheral arterial chemoreceptors can rapidly sense changes in O2

Periodic breathing is another marker of enhanced peripheral chemoreceptor function in premature infants

Further support for increased peripheral arterial chemoreceptor activity in premature infants is the high prevalence of periodic breathing that uniformly occurs in the most immature infants. Periodic breathing is a respiratory pattern consisting of cycles of hyperventilation followed by short apnoeic pauses. The hyperventilatory phase of periodic breathing reduces arterial PCO2, which decreases the central drive to breathe, resulting in short apnoeic pauses. Similar to apnoea, the prevalence of

Ventilatory and cardiovascular components of the peripheral arterial chemoreflex

Although the ventilatory response of the chemoreflex is most often described, the reflex response to hypoxic exposure that is mediated by the peripheral arterial chemoreceptors also includes bradycardia and peripheral vasoconstriction.66 The cardiovascular responses are compensatory mechanisms to maintain cerebral blood flow during periods of prolonged hypoxia and asphyxia. This reflex is commonly known as the diving reflex in marine mammals and can be easily elicited in the fetus,67 newborn

Chemoreflexes in combination with upper airway reflexes

In addition to the central mechanisms that inhibit breathing in premature infants, peripheral afferents from upper airway reflexes, particularly the laryngeal chemoreflex (LCR), a potent airway protective reflex, are strongly inhibitory. Sensory fibres in the larynx, which innervate ‘taste buds’ on the epiglottis, are activated by fluids with a low chloride content.71, 72 In response to water in the larynx, LCR is elicited to prevent inadvertent aspiration.73, 74 The physiological components of

Duration of hypoxic exposure can either increase or decrease chemoreflexes in response to acute hypoxic exposure

Acute hypoxic exposure is defined as exposure of less than 60 min, whereas sustained hypoxic exposure is from hours to days and chronic hypoxic exposure is from weeks to months. Acute, sustained and chronic hypoxic exposures can elicit different physiological responses, which are mediated by the peripheral arterial chemoreceptors. Thus, an exaggerated hypoxic chemosensitivity response may be present in premature infants (discussed above) during early postnatal development followed by an abnormal

A reduction in peripheral chemoreceptor function may contribute to the increased incidence of SIDS in infants who were born premature

Apnoea of prematurity is a normal physiological event and sudden infant death syndrome (SIDS) is hypothesized to be a pathological event of cardiorespiratory control. Therefore, it is no surprise that premature infants with apnoea of prematurity are not at greater risk of dying of SIDS than premature infants without significant apnoea of prematurity.94 However, in the USA, Sweden and Japan premature infants are at higher risk of dying of SIDS than term infants.95, 96, 97 Infants at greatest

Association between premature birth and tobacco smoke exposure

Premature infants are at increased risk of dying of SIDS; they are also at increased risk of being exposed to tobacco smoke pre- and postnatally. Smoking during pregnancy accounts for 15% of all preterm births and 20–30% of all low birthweight infants.117 A dose–response relationship between premature birth and number of cigarettes smoked daily during pregnancy has been reported. Adjusted odds ratio (OR) for an infant to be born prematurely at <32 weeks' gestation was 1.4 (95% confidence

Conclusion

Normal and abnormal functional development of arterial chemoreceptors and its possible role in apnoea of prematurity in the neonatal period and later in SIDS has been reviewed (see Fig. 1). Peripheral chemoreceptor activity is more probably increased than decreased in premature infants (because of their relative hypoxaemia) placing them at increased risk for periodic breathing, short and long apnoeic pauses associated with bradycardia and Hb-desaturations. However, over time, chronic hypoxia

Acknowledgements

The authors would like to thank Dr Edward Lawson for his critique of the manuscript and helpful suggestions. E.B.G. is a recipient of National Institute on Drug Abuse Grant RO1 DA13940, which also supports G.L.M.

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