Quantifying infant respiratory variability: how to capture complexity

Respiratory control is a complex  eld. The magnitude and timing of each breath result from spontaneous rhythms of brainstem respiratory neurons, and are  netuned by input from peripheral and central chemoreceptors as well as by lung and airway receptors. Breathing pattern is further modi ed by sleep-waking state and is interrupted momentarily by actions such as sighing, yawning and swallowing. These factors, as well as their interplay, may be subject to maturational changes for weeks or months after the  rst, crucial breath. In this issue of Acta Paediatrica, Al-Hathlol and coworkers (1) present a study in which breathing pattern and respiratory variability during quiet sleep are compared in healthy preterm and term infants and adults. Total respiratory variability decreased from preterm to term to adult. The higher respiratory variability in preterms resided largely in variations in expiratory time and was paralleled by larger  uctuations in end-tidal pCO2 and SaO2. The study contributes importantly to an already extensively studied  eld, mainly because of its design: the need for similar experimental conditions when comparing infants and adults is emphasized by the authors. Their call for standardized protocols in studies of infant respiratory control is understandable. For obvious reasons, such studies have often been performed in a clinical setting, e.g. in preterm infants, or with a focus on apnea of prematurity, apparent life-threatening events, sudden infant death syndrome, or rare conditions such as central hypoventilation syndrome (“Ondine’s curse”). The clinical, emotional and academic motivation to study high-risk or “special-problem” populations is obvious. However, breathing patterns that characterize selected high-risk populations often have low predictive value as a screening tool (2), and the  ndings may not be easily extrapolated to a more general population. Numerous studies have also addressed respiratory physiology and maturation in healthy infants, and in most recent work important factors such as sleep-waking state and body position are controlled. Still, in spite of detailed knowledge of many aspects of infant respiratory control and recent insights at the molecular and neuronal network level, the complex interplay between different sources of respiratory variability is yet not fully understood. Al-Hathlol and co-workers (1) attempt to capture the total variability of breaths using group mean coef cient of variation for each ventilatory variable as a measure. As expected, the preterm group displayed the most variable ventilation, and the study showed that this increased variability was closely related to variation in expiratory time. The authors suggest that this may have resulted from post-inspiratory diaphragmatic and airway muscle activity, a breathing strategy that augments functional residual lung volume and thereby prevents lung collapse. This strategy is seen in healthy term infants, but is much more important in preterm infants, since they have a very pliant chest wall and breathe at or near closing volume. Given the authors’ hypothesis, it would have been interesting to know how the variability in expiratory time was distributed among the preterm infants, whose gestational ages spanned 8 wk, re ecting differences in both body size and maturation. Only compound data for each age group were presented, and obviously a much larger material would be necessary to explore this matter in depth. Still, the paper leaves us curious of the physiological sources of the reported respiratory variability. Infant breathing is inherently variable; sometimes the term ‘instability’ is used. In an attempt to increase our understanding of the developing respiratory control system, it is crucial to distinguish between seemingly random, unpredictable variation in ventilation, and periodic variations that can at least partially be explained by central nervous rhythms, re ex feedback loops and circulation times. Some distinctive breathing patterns are known to contribute to the higher respiratory variability in infants compared to adults. Oscillations in infant breathing have been demonstrated with  ltering and spectral analysis techniques for ventilation, tidal volume and respiratory rate (3, 4) also in preterm infants (5). Tidal volume oscillations are most often out of phase with those for respiratory rate (3); they may be apparent in a respiratory tracing and constitute a major source of variability. Importantly, the amplitude of ventilatory oscillations was found to be higher in preterm than in term infants (5). The wider distribution of respiratory rate and tidal volume values in preterm infants reported in this issue (1) may partially have resulted from this. Periodic breathing occurs not only in preterm infants but throughout the  rst year of life (6–8). Some work has indicated that periodic breathing represents exaggerations of low-frequency ventilatory oscillations (9), tidal volume and respiratory rate oscillating in phase (3) (Fig. 1). The periodicity may result from