Chapter 508

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.

### Development of Respiratory Control and Normal Function

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

#### The Respiratory Rhythm Generator

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 ...

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