RESPIRATORY FUNCTION OF THE UPPER AIRWAYS –
FROM PHYLOGENY AND ONTOGENY TO PHYSIOLOGY
Jean-Paul Praud
Departments of Pediatrics and Physiology
Université de Sherbrooke
Corresponding author:
Jean-Paul Praud MD PhD
Tel: (819) 346-1110, ext. 14851
Departments of Pediatrics and Physiology
Fax: (819) 564-5215
Université de Sherbrooke
email: Jean-Paul.Praud@USherbrooke.ca
J1H 5N4, QC Canada
Acknowledgments
Jean-Paul Praud is the holder of the Canada Research Chair in Neonatal Respiratory Physiology.
His research is supported by the Canadian Institutes for Health Research, the Fonds de la
recherche en santé du Québec and the Foundation of Stars.
INTRODUCTION
The upper airways exert an important influence on breathing. In addition to participating in fetal
lung growth, in the successful transition towards air breathing at birth and in the maintenance of
optimal lung ventilation thereafter, the larynx is also involved in swallowing and protection of
the lower airways. Furthermore, neural immaturity in the newborn is often responsible for
reflexes originating from the laryngeal region, the laryngeal chemoreflexes, which are inhibitory
to cardiorespiratory function. This short review will use phylogenetic and ontogenetic
background to introduce a few aspects of postnatal upper airway function related to apneas,
laryngeal chemoreflexes and swallowing-breathing coordination.
PHYLOGENY: UPPER AIRWAYS AND RESPIRATION
A pharyngeal pump and a laryngeal closing valve for initial air-breathing in vertebrates
Early lungfishes acquired the ability to use environmental air to fulfill their metabolic
requirements more than 370 million years ago. As bimodal breathers, they were capable for the
first time of ventilating a primitive lung intermittently, in addition to water breathing. The
simultaneous appearance of a closing valve, the primitive larynx, was critical to this evolutionary
step to protect the lungs from flooding during feeding and water breathing.
Amphibians were the first to become dependent on air breathing. Air breathing was
accomplished by filling the oral cavity with air through the nares by passive recoil of the
pharyngeal wall, then forcing air into the lungs by pharyngeal muscle contraction and holding air
in the lungs by laryngeal closure, much as the lungfish. With evolution, modern amphibians
acquired a well-developed larynx homologous to those of higher vertebrates, with a cartilage
skeleton and strong, paired dilator muscles in addition to muscles that close the glottal aperture
(1).
Disappearance of pharyngeal pump mechanism for breathing with vertebrate evolution
A significant problem with the pharyngeal pump mechanism of filling the lungs is that tidal
volume is constrained by the size of the pharynx. Evolution towards vertebrates with large
bodies and small heads such as reptiles was only made possible by adding a thoracic aspiratory
system, i.e., inspiratory thoracic muscles. Contraction of the latter, especially the diaphragm, has
remained of crucial importance for lung breathing in mammals. Still, while the pharyngeal
contraction phase has disappeared from the breathing cycle, active laryngeal closure remains
prominent in today’s vertebrates in certain conditions. Indeed, though absent in most adult
terrestrial mammals, active post-inspiratory laryngeal closure remains a basic component of the
breathing cycle in many lower vertebrates and in diving mammals, even on land (2). In addition,
active post-inspiratory laryngeal closure represents a mechanism of major importance for early
postnatal breathing in terrestrial mammals (see below).
ONTOGENY: FROM FLUID-FILLED AIRWAYS TO AERIAL BREATHING
While the nasal airway originates from invagination of the ectoderm, the skeleton and muscles of
the mouth, pharynx and larynx develop from pharyngeal arches and clefts in the embryo.
Following anatomical and functional development, the pharynx and larynx are actively engaged
in swallowing and breathing movements in the fetus.
Respiratory function of the larynx in fetal life
In the fetal mammal, the larynx is actively closed when fetal breathing movements are absent,
reminiscent of the lungfish during diving. Fetal lung growth relies heavily on the high pressure
present in the liquid-filled airways generated by this glottal closure, which opposes continuous
secretion of lung liquid by the airway epithelium. In addition, coordinated contraction of
pharyngeal/laryngeal dilator muscles and diaphragm is observed during bursts of fetal breathing
movements (3). However, these fetal breathing movements do not entrain amniotic liquid into
the trachea. Indeed, when necessary, laryngeal constrictor muscles contract to defend the
entrance of the trachea against influx of amniotic fluid filled with debris (lanugo, vernix caseosa)
via reflex glottal closure. Such laryngeal chemoreflexes are due to laryngeal receptors sensitive
to the lower chloride concentration of the amniotic fluid (4). Finally, breathing-swallowing
coordination develops in the fetus, allowing oral feeding around 35 weeks of gestation in the
newborn infant born prematurely.
Respiratory function of the upper airways at birth and in the early postnatal period
At birth, complete, active glottal closure throughout the very first expirations is vital for
establishing an end-expiratory lung volume of air, i.e. the initial functional residual capacity. In
the first hours and days after birth, an active post-inspiratory laryngeal closure is frequently
observed. By decreasing lung emptying, this expiratory airflow braking mechanism defends
functional residual capacity against low lung compliance present at that age (5).
The muscular pharyngeal tube, which is so important for glossopharyngeal respiration in
amphibians, however does not retain any respiratory advantage in mammals after birth. On the
contrary, its collapsible characteristics render phasic contraction of pharyngeal dilator muscles
necessary just before diaphragm inspiratory contraction to prevent unwanted pharyngeal
narrowing secondary to decreased intraluminal pressure (6).
Upper airways and apneas
Premature infants born before 27 weeks are virtually all affected by apneas of prematurity, which
are responsible for bradycardia and desaturation and carry the potential of neurological sequelae.
Complete, active laryngeal closure during central apneas in the newborn. Our group has
shown that complete, active glottal closure with maintenance of a high apneic lung volume
throughout apneas was consistently noted during periodic breathing (7), as well as during most
post-sigh apneas in preterm lambs. Such observations were concordant with previous reports in
dog pups, newborn opossums and human newborns. Maintenance of a high lung volume during
central apneas increases alveolar O2 stores and limits post-apneic arterial O2 desaturation (8).
Such active inspiratory breath-holding has phylogenetic and ontogenetic correlations (see above)
and is not related to reflexes originating from laryngeal receptors, e.g., laryngeal chemoreflexes.
Of note, while prominent in newborns, closure of the laryngeal valve during central apneas has
also been observed in adult humans.
Passive pharyngeal collapse during central apneas. Loss of central respiratory drive induces
passive pharyngeal narrowing during central apneas. Insufficient pharyngeal dilator muscle
contraction at breathing resumption can cause pharyngeal closure, i.e., a mixed apnea. The latter
is frequently seen in newborns, as well as in older children and adults with obstructive sleep
disordered breathing. In fact, pharyngeal lumen size during breathing results from interaction
between anatomical and neural mechanisms. Any anatomical imbalance between soft tissue
volume (increased with macroglossia, peripharyngeal fat pads, adenotonsillar hypertrophy, …)
and bony enclosure size (decreased with microretrognathia, syndromic malformations,
orthodontic anomalies, …) favors pharyngeal closure. In addition, any neural imbalance between
the collapsing force of inspiratory thoracic muscle contraction and dilating force of pharyngeal
dilator muscles (decreased by prematurity, REM sleep, sedation, …) favors pharyngeal closure
(9).
Laryngeal chemoreflexes
Laryngeal chemoreflexes represent another prominent manifestation of the original, protective
valve function of the vertebrate larynx. Laryngeal chemoreflexes (LCR) are triggered by the
contact between liquids - especially acid or with low chloride content - and receptors of the
laryngeal mucosa in mammals. These lung protective reflexes consist primarily of swallowing,
coughing and arousal in mature mammals, thus limiting larynx penetration and tracheal
aspiration (4). However, in the immature, newborn mammal, LCR are composed of both a vagal
component, which includes laryngospasm, apnea, oxygen desaturation and bradycardia, and a
sympathetic component, which includes systemic hypertension and redistribution of blood flow
to vital organs (4). Clinical relevance of LCR stems from the observation that they are often
triggered by gastric reflux, bottle-feeding or oral intake of liquid medications in preterms. In
addition, they can be responsible for apparent life-threatening events and probably some cases of
sudden infant death syndrome (10). Abnormal conditions, such as respiratory syncytial virus
infection in young infants or laryngopharyngeal reflux during sleep in older children, exacerbate
the potentially dangerous cardiorespiratory components of the LCR.
SWALLOWING AND BREATHING ACTIVITY: THE DANGEROUS LIAISONS
The pharynx was involved in feeding long before the emergence of air breathing in lungfishes.
With air breathing, however, breathing and swallowing became competing functions at the
pharyngeal level. Swallowing activity involves the coordinated contraction of more than 25 pairs
of upper airway muscles in a sequence designed and coordinated by the brainstem swallowing
center. In addition, a precise swallowing-breathing coordination, which includes an obligatory
respiratory pause, is a necessity to prevent both prolonged apnea and tracheal aspiration (11).
Thus, while forceful contraction of pharyngeal constrictor muscles propels the food bolus into
the esophagus, the tensor and elevator veli palatini and the laryngeal constrictor muscles contract
to prevent entry of food into the nasopharynx and the trachea respectively. In humans, phonation
modifies upper airway anatomy and adds further complexity to breathing-swallowing interaction
(1). In the newborn, before development of phonation, the larynx is cephalad, and the
overlapping epiglottis and soft palate establish a nasal airway for respiration during milk
swallowing. This anatomical configuration explains that human infants are preferential nose
breathers for the first 6 weeks to 6 months. Postnatal modifications of the upper airways to allow
sound production lead to descent of the larynx in the neck and loss of epiglottis-soft palate
contact. Increased risks of tracheal aspiration are then prevented by elevation of the larynx
during swallowing, by the shape of the epiglottis, which directs food laterally into the pyriform
fossae, and by the aryepiglottic folds + arytenoids, which act as ramparts to prevent laryngeal
penetration. In the meantime, maturation of the swallowing and respiratory centers in the
brainstem ensures an optimal swallowing-breathing coordination. Conversely, immaturity,
neuromuscular disorders, laryngeal inflammation or upper airways malformations, for example,
can be responsible for inadequate swallowing-breathing coordination and tracheal aspiration in
children.
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