Melissa L. Siew

Imaging lung aeration and lung liquid clearance at birth

Aeration of the lung and the transition to air‐breathing at birth is fundamental to mammalian life and initiates major changes in cardiopulmonary physiology. However, the dynamics of this process and the factors involved are largely unknown, because it has not been possible to observe or measure lung aeration on a breath‐by‐breath basis. We have used the high contrast and spatial resolution of phase contrast X‐ray imaging to study lung aeration at birth in spontaneously breathing neonatal rabbits. As the liquid‐filled fetal lungs provide little absorption or phase contrast, they are not visible and only become visible as they aerate, allowing a detailed examination of this process. Pups were imaged live from birth to determine the timing and spatial pattern of lung aeration, and relative levels of lung aeration were measured from the images using a power spectral analysis. We report the first detailed observations and measurements of lung aeration, demonstrating its dependence on inspiratory activity and body position; dependent regions aerated at much slower rates. The air/liquid interface moved toward the distal airways only during inspiration, with little proximal movement during expiration, indicating that trans‐pulmonary pressures play an important role in airway liquid clearance at birth. Using these imaging techniques, the dynamics of lung aeration and the critical role it plays in regulating the physiological changes at birth can be fully explored.—Hooper S. B., Kitchen, M. J., Wallace, M. J., Yagi, N., Uesugi, K., Morgan M. J., Hall, C., Siu, K. K. W., Williams, I. M., Siew, M., Irvine, S. C., Pavlov, K., Lewis R. A. Imaging lung aeration and lung liquid clearance at birth. FASEB J. 21, 3329–3337 (2007)

Effect of Sustained Inflation Length on Establishing Functional Residual Capacity at Birth in Ventilated Premature Rabbits

The effect of inflation length on lung aeration pattern, tidal volumes, and functional residual capacity (FRC) immediately after birth was investigated. Preterm rabbits (28 d), randomized into four groups, received a 1-, 5-, 10-, or 20-s inflation (SI) followed by ventilation with 5 cm H2O end-expiratory pressure. Gas volumes were measured by plethysmography and uniformity of lung aeration by phase contrast x-ray imaging for 7 min. The first inspiratory volume significantly (p < 0.001) increased with inflation duration from a median (IQR) of 0.2 (0.1–3.1) mL/kg for 1-s inflation to 23.4 (19.3–30.4) mL/kg for 20-s SI. The lung was uniformly aerated, and the FRC and tidal volume fully recruited after 20-s SI. A 10-s SI caused a higher FRC (p < 0.05) at 7 min, and a 20-s SI caused a higher FRC (p < 0.05) at 20 s and 7 min than a 1- or 5-s SI. The mean (SD) time for 90% of the lung to aerate was 14.0 (4.1) s using 35 cm H2O peak inflation pressure. In these rabbits, 10- and 20-s SI increased the inspiratory volume and produced a greater FRC, and a 20-s SI uniformly aerated the lung before ventilation started.

Positive end-expiratory pressure enhances development of a functional residual capacity in preterm rabbits ventilated from birth

The factors regulating lung aeration and the initiation of pulmonary gas exchange at birth are largely unknown, particularly in infants born very preterm. As hydrostatic pressure gradients may play a role, we have examined the effect of a positive end-expiratory pressure (PEEP) on the spatial and temporal pattern of lung aeration in preterm rabbit pups mechanically ventilated from birth using simultaneous phase-contrast X-ray imaging and plethysmography. Preterm rabbit pups were delivered by caesarean section at 28 days of gestational age, anesthetized, intubated, and placed within a water-filled plethysmograph (head out). Pups were imaged as they were mechanically ventilated from birth with a PEEP of either 0 cmH(2)O or 5 cmH(2)O. The peak inflation pressure was held constant at 35 cmH(2)O. Without PEEP, gas only entered into the distal airways during inflation. The distal airways collapsed during expiration, and, as a result, the functional residual capacity (FRC) did not increase above the lungs anatomic dead space volume (2.5 +/- 0.8 ml/kg). In contrast, ventilation with 5-cmH(2)O PEEP gradually increased aeration of the distal airways, which did not collapse at end expiration. The FRC achieved in pups ventilated with PEEP (19.9 +/- 3.2 ml/kg) was significantly greater than in pups ventilated without PEEP (-2.3 +/- 3.5 ml/kg). PEEP greatly facilitates aeration of the distal airways and the accumulation of FRC and prevents distal airway collapse at end expiration in very preterm rabbit pups mechanically ventilated from birth.

Dynamic measures of regional lung air volume using phase contrast x-ray imaging

Phase contrast x-ray imaging can provide detailed images of lung morphology with sufficient spatial resolution to observe the terminal airways (alveoli). We demonstrate that quantitative functional and anatomical imaging of lung ventilation can be achieved in vivo using two-dimensional phase contrast x-ray images with high contrast and spatial resolution (<100 microm) in near real time. Changes in lung air volume as small as 25 microL were calculated from the images of term and preterm rabbit pup lungs (n = 28) using a single-image phase retrieval algorithm. Comparisons with plethysmography and computed tomography showed that the technique provided an accurate and robust method of measuring total lung air volumes. Furthermore, regional ventilation was measured by partitioning the phase contrast images, which revealed differences in aeration for different ventilation strategies.

Inspiration regulates the rate and temporal pattern of lung liquid clearance and lung aeration at birth

At birth, the initiation of pulmonary gas exchange is dependent on air entry into the lungs, and recent evidence indicates that pressures generated by inspiration may be involved. We have used simultaneous plethysmography and phase-contrast X-ray imaging to investigate the contribution of inspiration and expiratory braking maneuvers (EBMs) to lung aeration and the formation of a functional residual capacity (FRC) after birth. Near-term rabbit pups (n = 26) were delivered by cesarean section, placed in a water plethysmograph, and imaged during the initiation of spontaneous breathing. Breath-by-breath changes in lung gas volumes were measured using plethysmography and visualized using phase-contrast X-ray imaging. Pups rapidly (1-5 breaths) generate a FRC (16.2 +/- 1.2 ml/kg) by inhaling a greater volume than they expire (by 2.9 +/- 0.4 ml.kg(-1).breath(-1) over the first 5 breaths). As a result, 94.8 +/- 1.4% of lung aeration occurred during inspiration over multiple breaths. The incidence of EBMs was rare early during lung aeration, with most (>80%) occurring after >80% of max FRC was achieved. Although EBMs were associated with an overall increase in FRC, 34.8 +/- 5.3% of EBMs were associated with a decrease in FRC. We conclude that lung aeration is predominantly achieved by inspiratory efforts and that EBMs help to maintain FRC following its formation.

IMAGING LUNG AERATION AND LUNG LIQUID CLEARANCE AT BIRTH USING PHASE CONTRAST X‐RAY IMAGING

1 The transition to extra‐uterine life at birth is critically dependent on airway liquid clearance to allow the entry of air and the onset of gaseous ventilation. We have used phase contrast X‐ray imaging to identify factors that regulate lung aeration at birth in spontaneously breathing term and mechanically ventilated preterm rabbit pups. 2 Phase contrast X‐ray imaging exploits the difference in refractive index between air and water to enhance image contrast, enabling the smallest air‐filled structures of the lung (alveoli; < 100 µm) to be resolved. Using this technique, the lungs become visible as they aerate, allowing the air–liquid interface to be observed as it moves distally during lung aeration. 3 Spontaneously breathing term rabbit pups rapidly aerate their lungs, with most fully recruiting their functional residual capacity (FRC) within the first few breaths. The increase in FRC occurs mainly during individual breaths, demonstrating that airway liquid clearance and lung aeration is closely associated with inspiration. We suggest that transpulmonary pressures generated by inspiration provide a hydrostatic pressure gradient for the movement of water out of the airways and into the surrounding lung tissue after birth. 4 In mechanically ventilated preterm pups, lung aeration is closely associated with lung inflation and a positive end‐expiratory pressure is required to generate and maintain FRC after birth. 5 In summary, phase contrast X‐ray imaging can image the air‐filled lung with high temporal and spatial resolution and is ideal for identifying factors that regulate lung aeration at birth in both spontaneously breathing term and mechanically ventilated preterm neonates.

Expired CO2 Levels Indicate Degree of Lung Aeration at Birth

As neonatal resuscitation critically depends upon lung aeration at birth, knowledge of the progression of this process is required to guide ongoing care. We investigated whether expired CO2 (ECO2) levels indicate the degree of lung aeration immediately after birth in two animal models and in preterm infants. Lambs were delivered by caesarean section and ventilated from birth. In lambs, ECO2 levels were significantly (p<0.0001) related to tidal volumes and CO2 clearance/breath increased exponentially when tidal volumes were greater than 6 mL/kg. Preterm (28 days of gestation; term = 32 days) rabbits were also delivered by caesarean section and lung aeration was measured using phase contrast X-ray imaging. In rabbit kittens, ECO2 levels were closely related (p<0.001) to lung volumes at end-inflation and were first detected when ∼7% of the distal lung regions were aerated. ECO2 levels in preterm infants at birth also correlated with tidal volumes. In each infant, ECO2 levels increased to >10 mmHg 28 (median) (21–36) seconds before the heart rate increased above 100 beats per minute. These data demonstrate that ECO2 levels can indicate the relative degree of lung aeration after birth and can be used to clinically assess ventilation in the immediate newborn period.

Auditing resuscitation of preterm infants at birth by recording video and physiological parameters

OBJECTIVE To evaluate compliance with neonatal resuscitation guidelines during resuscitation of preterm infants by video recording of delivery room management and monitoring physiologic parameters. METHODS The delivery room management of preterm infants at birth was recorded by an independent researcher. Physiological parameters (airway pressures, gas flow, tidal volume, heart rate and oxygen saturation) were measured, use of supplemental oxygen was noted and a video of the resuscitation was recorded. All signals were digitised and recorded using specially designed software. The delivery room management was then evaluated and compared with the local resuscitation guidelines. RESULTS Thirty-four infants were included with a mean (SD) gestational age of 30.6 (3.2) weeks and birth weight of 1292 (570) g. Time from birth to initial evaluation was longer than recommended (65 (15) s). Respiratory support was started at 70 (23) s. In 7/34 infants (21%), interventions were performed according to guidelines. In 25/34 infants (74%), one or more respiratory interventions were not performed according to guidelines. In 10/34 infants (29%), one or more non-respiratory interventions (mainly related to the prevention of heat loss) were not performed according to guidelines. The presence and adequacy of spontaneous breathing was difficult to judge clinically. In almost all occasions (96%) the information from the respiratory function monitor was not used. CONCLUSIONS Neonatal caregivers often deviate from resuscitation guidelines. Respiratory function monitoring parameters were often not used during resuscitation. A difficult part of neonatal resuscitation is subjectively assessing spontaneous breathing.

Establishing functional residual capacity in the non-breathing infant.

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.

Measuring Physiological Changes during the Transition to Life after Birth

The transition to life after birth is characterized by major physiological changes in respiratory and hemodynamic function, which are predominantly initiated by breathing at birth and clamping of the umbilical cord. Lung aeration leads to the establishment of functional residual capacity, allowing pulmonary gas exchange to commence. This triggers a significant decrease in pulmonary vascular resistance, consequently increasing pulmonary blood flow and cardiac venous return. Clamping the umbilical cord also contributes to these hemodynamic changes by altering the cardiac preload and increasing peripheral systemic vascular resistance. The resulting changes in systemic and pulmonary circulation influence blood flow through both the oval foramen and ductus arteriosus. This eventually leads to closure of these structures and the separation of the pulmonary and systemic circulations. Most of our knowledge on human neonatal transition is based on human (fetal) data from the 1970s and extrapolation from animal studies. However, there is renewed interest in performing measurements directly at birth. By using less cumbersome techniques (and probably more accurate), our previous understanding of the physiological transition at birth is challenged, as well as the causes and consequences for when this transition fails to progress. This review will provide an overview of physiological measurements of the respiratory and hemodynamic transition at birth. Also, it will give a perspective on some of the upcoming technological advances in physiological measurements of neonatal transition in infants who are unable to make the transition without support.