Review
Establishing functional residual capacity in the non-breathing infant

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Summary

The transition to newborn life critically depends upon lung aeration and the onset of air-breathing, which triggers major cardiovascular changes required for postnatal life, including increases in pulmonary blood flow. Recent imaging studies indicate that lung aeration and functional residual capacity (FRC) recruitment results from inspiratory efforts, which create transpulmonary pressure gradients. During inspiration, these pressure gradients drive airway liquid movement through the conducting and into the distal airways where it crosses the pulmonary epithelium and enters the surrounding tissue. Although this process can occur rapidly (within 3–5 breaths), liquid clearance from lung tissue is much slower, resulting in oedema and increased interstitial tissue pressures, facilitating liquid re-entry into the airways at FRC. Whereas this liquid may be cleared during the next inspiration, liquid re-entry at FRC can be opposed by Na+ reabsorption, oncotic pressures and expiratory braking manoeuvres. Recognition that transpulmonary pressure gradients mainly drive airway liquid clearance at birth has provided a clearer understanding of how this process may be facilitated in very preterm infants. In particular, it underpins the rationale for providing respiratory support that initially focuses on moving liquid through tubes (airways) rather than air. As the viscosity of liquid is much greater than air, the resistance to moving liquid is ∼100 times greater than air, necessitating the use of higher pressures or longer inflation times. Although it is unclear how this strategy could be safely applied clinically, it is clear that end-expiratory pressures are required to create and maintain FRC in preterm infants.

Introduction

As the lungs are liquid-filled before birth and gas exchange occurs across the placenta, the challenge of transitioning from fetal to newborn life begins with lung aeration and the onset of air-breathing [1]. Following an uncomplicated term birth, air entry into the lungs replaces lung liquid as the primary medium filling the airways, leading to the recruitment of a functional residual capacity (FRC) [2]. FRC gradually recruits with each breath, until eventually air penetrates down into the distal gas exchange regions of the lung, allowing pulmonary gas exchange to commence (Fig. 1). This process subsequently initiates major changes within the cardiovascular system that are critical for the successful transition to postnatal life. In particular, it stimulates a large increase in pulmonary blood flow, which underpins the increase in cardiac output and closure of vascular shunts that separate the systemic and pulmonary circulations [3], [4]. This review will focus on the factors that regulate lung aeration and the establishment of FRC at birth, as well as discussing issues that adversely influence these processes. As lung aeration results from airway liquid clearance, understanding how infants recruit and maintain FRC after birth requires an understanding of the factors that control this process. It is now apparent that airway liquid clearance is multi-dimensional and can occur via a number of mechanisms before, during and after birth [5], [6], with the relative contribution of each mechanism depending upon the mode and timing of delivery [7]. Furthermore, the physiologic changes associated with spontaneous air breathing during an uncomplicated birth may be quite different from those occurring in an apneic newborn who requires respiratory support immediately after birth.

Section snippets

Airway liquid clearance before birth

Although it is likely that some airway liquid clearance begins before labour [8], there is some debate as to how this is achieved [9], [10]. As airway liquid volumes in the fetus are controlled by a balance between the rate of liquid secretion and the rate of liquid loss via the trachea, reductions in airway liquid volumes before birth can only arise by altering one of these two variables [9], [10]. In late gestation, lung liquid secretion rates could be reduced in response to an increase in

Role of transpulmonary pressures

As only small increases in transpulmonary pressure are required to cause large reductions in fetal lung liquid volumes, the large forces applied to the fetus by uterine contractions during labour likely lead to substantial losses in lung liquid volume [9]. Indeed, the force required to expel a fetus through the cervix and vagina can produce high intrathoracic pressures, ranging from 88 to 265 cmH2O in human infants [21], [22]. This likely explains the frequent observation of large volumes of

Airway liquid clearance after birth

Although the volume of fetal lung liquid before birth is at least equivalent to FRC after birth, the volume of liquid remaining in the airways at birth will vary considerably among infants, depending on the timing and mode of delivery [7]. Nevertheless, after birth at least the distal airways remain liquid-filled before the infant takes its first breath. Recently, a series of studies has used phase contrast X-ray imaging to determine the temporal and spatial pattern of air entry into the lungs

Role of inspiration

As transepithelial pressures generated during inspiration persist after birth, inspiration likely continues as a mechanism for airway liquid clearance following lung aeration, particularly as liquid tends to re-enter the airways at rest during the newborn period [5]. Indeed, spontaneously breathing newborn rabbits continue to inspire more air than they expire (by ∼1 ml/kg) for at least the first 100 breaths after birth [5], [7]. This can only occur because FRC gradually decreases between

Facilitating FRC recruitment in preterm infants

Understanding the factors that regulate airway liquid clearance in spontaneously breathing infants has provided new insights into facilitating airway liquid clearance in preterm infants. Partial airway liquid retention and non-uniform ventilation of the lung is a frequent problem in preterm infants during the immediate newborn period, although the extent of the problem will vary markedly between infants. Whereas most infants will have a compliant chest wall and an immature liquid reabsorptive

Can expired CO2 levels indicate the degree of lung aeration?

Heart rate and transcutaneous oxygen (SpO2) saturation levels are the current ‘gold standard’ for assessing the success of the cardiopulmonary transition immediately after birth. However, these parameters are not sensitive indicators of the degree of lung aeration, ventilation efficiency or the degree of gas exchange, and provide limited feedback to guide clinical care when these cardiorespiratory indicators fail to improve. Recent studies [67] indicate that the level of CO2 in expired air is

Conclusion

The establishment of an FRC after birth is intrinsically linked with the clearance of airway liquid into the peri-alveolar interstitial tissue compartment, which is primarily driven by transepithelial hydrostatic pressures generated by inspiration. This knowledge has provided new insights into how the process of lung aeration can be facilitated in infants suffering respiratory failure immediately after birth, particularly very preterm infants. In particular, it indicates that the type of

Conflict of interest statement

None declared.

Funding sources

Supported by the SPring-8 synchrotron facility (Japan), which was granted under the approval of the SPring-8 Program Review Committee (proposal nos. 2006B0002, 2007A0002). All images were acquired at the SPring-8 synchrotron facility in Japan. The authors were supported by the Victorian Government's Operational Infrastructure Support Program.

Acknowledgements

The authors gratefully acknowledge the important contributions to this work made by M.J. Wallace, A. Fouras, R.A. Lewis, P.G. Davis, N. Yagi and K. Uesugi.

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