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While the neuronal and musculoskeletal
components of the respiratory system mature postnatally, the systems
governing respiratory control in general, and more specifically
rhythmogenesis, must be mature and functional by birth to enable
the successful transition from fetus to infant. The respiratory
controllers must have the necessary components to generate a rhythm
that allows gas exchange in a highly compliant chest wall and to integrate swallowing,
crying, vocalization, and other behaviors with breathing. Neonatal
intensive care units are a frequent place where pediatricians are
daily confronted with immature respiratory control systems. Premature
infants display deficiencies of central respiratory rhythmogenesis
or of activation of respiratory musculature. However, such problems are
not restricted to this particular stage of life, and alterations
in the control of breathing may play a role in many conditions that
become apparent throughout childhood and adolescence, particularly
during sleep. During sleep, the clinical manifestations of many
diseases of respiratory control as well as other conditions affecting
the respiratory system in general are more likely to emerge. Thus,
understanding the pathogenesis of breathing problems is an important
component of the clinical evaluation of any child with respiratory
symptoms.
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Development
of Respiratory Control and Normal Function
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Current understanding of the mechanisms governing control of respiration
has undergone multiple iterations and progress in the last century.
While we cannot deny that breathing is an important and vital function,
and as such should be prioritized during evolution, it has become
apparent that at least in mammals, and more particularly in humans,
the respiratory control system undergoes substantial maturation
during the first few years of life. There is, however, substantial
uncertainty on the exact anatomical locations and function of specific
neural respiratory pathways. Furthermore, the complexities of neuronal
firing activities, the multitude of neurotransmitters within each brainstem
nucleus, and the frequently nucleus-dependent opposing roles played
by these neurotransmitters on respiratory function make integration
of all these elements a difficult and sometimes confusing task. The progress
in our understanding of the intricate neural networks of respiration
has been tremendous, and the identity of several of the genes that
control the development and maturation of multiple neurally controlled
respiratory functions is now emerging.1-10
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The Respiratory
Rhythm Generator
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The presumed neural region underlying the generation of respiratory
rhythmic activity has now been recognized,11 and
specific markers such as neurokinin and opioid receptors in these
neurons have revealed that this uniquely important neural center
consists of a small cluster of only 150 to 200 neurons in the brainstem
region designated as pre-Bötzinger complex.12 These
relatively few rhythmically firing neurons appear both necessary
and sufficient to generate most of the complex normal respiratory
behaviors that we currently recognize, such as eupnea, sigh, and
gasping.13-15 The development of several elegant
models, ranging from highly reductionistic (brainstem slice) to less
reductionistic approaches (whole brainstem-heart-lung preparation),
will undoubtedly permit extensive characterization of the network
connectivity and responses and the functional neurotransmitters ...