Hemodynamic significance and clinical relevance of deferred cord clamping and umbilical cord milking

Airway liquid clearance

In utero, the fetus grows and develops in a liquid environment, with gas exchange occurring across the placenta. The future airways are filled with a liquid that is produced by the lung and plays a vital role in stimulating fetal lung growth and development. This liquid is actively retained within the airways by the fetus and keeps the lungs under a constant state of distension, resulting in a resting lung volume that is larger than the functional residual capacity of the newborn lung. This constant state of distension provides a mechanical stimulus for lung growth, which, if absent, results in severe lung hypoplasia that is either lethal or causes significant morbidity in the newborn. ^, However, while airway liquid is essential for fetal lung growth, its presence prevents the entry of air and the onset of pulmonary gas exchange after birth. As such, it is important that the airways are cleared as rapidly as possible during the birth process to ensure that air can enter the terminal gas exchange regions of the lung and facilitate the onset of gas exchange.

Much interest has focused on the mechanisms of airway liquid clearance at birth, as reduced or variable airway liquid clearance is a major cause of perinatal morbidity, particularly in premature infants or term infants born by cesarean section. There are potentially three mechanisms that can contribute to airway liquid clearance at birth, which depend upon the timing and mode of birth: (i) expulsion of liquid with uterine contractions after rupture of membranes, (ii) increased circulating adrenaline levels during labor which activate amiloride-sensitive Na ⁺ channels and stimulate liquid reabsorption, and (iii) trans-epithelial hydrostatic pressures generated during initial inspirations or mechanical inflations after birth.

As the fetal respiratory system is highly compliant, small increases in transthoracic pressure, for example, due to postural changes, can greatly reduce the volume of airway liquid. It is well established that the loss of amniotic fluid and uterine contractions increase fetal spinal flexion, which in turn increases both abdominal and intrathoracic pressures, resulting in lung liquid loss. ^, While this mechanism can account for large reductions in airway liquid at birth, it does not explain how residual volumes of liquid are cleared from the airways after birth. It has been proposed that increased circulating adrenaline levels during labor activate amiloride-sensitive Na ⁺ channels located on the apical surface of pulmonary epithelial cells. ^, The resulting uptake of Na ⁺ from the lung lumen and its transport across the epithelium into the pulmonary interstitium also increases the electropotential gradient for Cl ^– ion flux in the same direction. This reverses the osmotic gradient driving fetal lung liquid secretion, leading to liquid reabsorption from the airway lumen. While this mechanism has been extensively studied and described, it only develops late in gestation and requires very high levels of circulating adrenaline, and at maximally stimulated rates (30 mL/h), it would take hours to clear all airway liquid. ^{, ,} As a result, this mechanism likely accounts for only a small proportion (<5%) of airway liquid clearance at birth. ^,

Phase contrast X-ray imaging has allowed researchers to visualize the entry of air onto the lungs at birth in both spontaneously breathing and mechanically ventilated term and preterm rabbits. These studies clearly show that the air-liquid interface only moves distally during inspiration or during positive pressure inflations ( Figure 6.1 ). Between breaths or inflations, the air-liquid interface either remains stationary or moves proximally, indicating that some airway liquid re-entry may occur between breaths. ^{, ,} Based on these results, it was concluded that after birth, airway liquid clearance primarily results from trans-epithelial hydrostatic pressures generated during inspiration/inflation. ^, That is, inspiration-induced hydrostatic pressure gradients between the airways and surrounding tissue drive the movement of liquid out of the airways across the pulmonary epithelium. This process was found to be extraordinarily rapid, with some newborn rabbits completely aerating their lungs in 3–5 breaths, generating an FRC of 15–20 mL/kg in that time (∼30 seconds). ^, Similarly, in spontaneously breathing term newborns delivered via cesarean section without labor, 90% had aerated lungs (measured by ultrasound), and 100% had detectable exhaled carbon dioxide within 7 breaths after birth. This confirms a dominant role for inspirations in airway liquid clearance as a single mechanism. ^,

Increase in pulmonary blood flow at birth in response to lung aeration

At birth, lung aeration increases PBF 20- to 30-fold, which not only enhances pulmonary gas exchange capacity but also plays a critical role in taking over the supply of preload for the left ventricle from umbilical venous return. ^, Numerous mechanisms are believed to mediate the pulmonary vasodilation in response to lung aeration, including increased oxygenation leading to the release of vasodilators such as nitric oxide, a reduction in lung distension caused by the formation of surface tension, and a vagal-mediated vasodilation caused by the movement of liquid out of the airways into the surrounding tissue. The latter mechanism was identified using simultaneous phase contrast X-ray imaging and angiography, designed to examine the spatial relationship between ventilation and perfusion during transition. While the imaging was expected to show that partial lung aeration would increase PBF in only aerated lung regions, unexpectedly, the imaging unequivocally demonstrated that partial lung aeration caused a global increase in PBF ( Figure 6.2 ). As ventilation with 100% nitrogen was able to produce a similar response as well as an increase in heart rate, it appears that increased oxygenation is not a prerequisite for pulmonary vasodilation at birth, which is a consistently reported finding. ^, Nevertheless, ventilation with 100% oxygen enhanced the increase in PBF, but only in ventilated lung regions, indicating that the increase in PBF in response to lung aeration is multifactorial, with different mechanisms working independently. As vagal nerve section abolished the increase in PBF induced by partial lung ventilation with 100% nitrogen, it was suggested that the movement of airway liquid into lung tissue activated receptors (possibly J receptors), which signaled via the vagus to stimulate a global increase in PBF.

While the global increase in PBF that is stimulated by partial lung aeration causes a large ventilation/perfusion mismatch after birth, this is not necessarily problematic. Indeed, as lung aeration is usually quite heterogeneous, restricting the overall increase in PBF by only increasing PBF in aerated lung regions will reduce pulmonary venous return and may affect cardiac output. This is because, following UCC, pulmonary venous return becomes the primary source of preload for the left ventricle and restricting the increase in PBF restricts cardiac output. As a result, the importance of clamping the umbilical cord at the appropriate time within this physiological sequence (lung aeration followed by PBF increase) becomes self-evident.