Increasing pulmonary blood flow at birth: the nerve of the baby

The transition from a fetus to a newborn infant is one of the most dramatic and important physiological changes in an individual’s life. With the cutting of the umbilical cord, the fetus must almost instantly convert to newborn physiology, which relies on efficient gas exchange in the lungs, energy metabolism in the liver, and thermoregulation through brown fat (Hillman et al. 2012). The most crucial of these physiological shifts at birth is the transition from the fetal circulator pattern to normal dual ventricular physiology (Hooper et al. 2015). In utero, the pulmonary vascular resistance (PVR) is high and the majority (80–90%) of the blood return from the placenta is shunted through the foramen ovale and ductus arteriosus into the systemic circulation. With minimal blood return from the pulmonary vasculature, the left ventricular preload is highly dependent on the atrial shunt. With removal of the placenta at birth, the systemic vascular resistance rapidly increases, leading to increased left atrial pressures and closure of the foramen ovale. The pulmonary blood flow must simultaneously increase, through a decrease in PVR, to provide adequate preload to the left ventricle. Failure to decrease PVR leads to decreased cardiac output and the hypertension seen in the newborn condition – persistent pulmonary hypertension of the newborn. Closure of the ductus arteriosus completes the transition to newborn. The majority of normal newborns have rapid decreases of PVR in the first minutes after birth with recruitment of the lung, but up to 10% of infants will require some assistance at birth with the conversion to a newborn physiology. Aeration of the lung is essential for clearing the airways of fetal lung fluid and increasing pulmonary blood flow (Hillman et al. 2012). Infants generate large, negative pressure breaths at birth to force the fluid out of the airways and allow for gas exchange. By using a unique phase-contrast X-ray system on slightly preterm rabbit pups (kittens), Hooper et al. have studied the lung recruitment at birth (Hooper et al. 2007, 2016). They demonstrated that fetal lung fluid is cleared into the interstitial space only during inspiration. The use of positive end-expiratory pressure during ventilation at birth improves the uniformity of lung recruitment and decreases the back-flow of interstitial fluid into airways during exhalation (Hooper et al. 2016). Simultaneous decrease in PVR occurs with airway clearance. The aeration of the alveoli increases transmural pressures on the capillaries to increase capillary diameter and increase pulmonary blood flow (PBF) (Hooper et al. 2016). Pulmonary stretch also causes prostacyclin (PGI2) release from vascular endothelial cells to relax arterial smooth muscle. Increased oxygen tension after birth increases nitric oxide production in the endothelial cells to relax vessels. With the addition of iodine angiography to the phase contrast X-ray rabbit model, Lang and colleagues have been able to simultaneously evaluate airway recruitment and pulmonary blood flow. They previously demonstrated that unilateral ventilation of one lung with 100% nitrogen increased pulmonary blood flow to both the inflated lung and the unventilated lung (Lang et al. 2016). Ventilation with 100% oxygen increased the dilator effects in both lungs compared with nitrogen or air. In this issue of The Journal of Physiology, Lang et al. (2017) further explore the role of the vagal stimulation on pulmonary blood flow increases at birth. Prior to the initiation of ventilation, the preterm rabbit kittens received either bilateral sectioning through the vagus nerves or sham operation. With the breathing tube occluded, kittens were assigned to single lung ventilation with 100% nitrogen, air, or 100% oxygen. After 2 min of ventilation (X-rays and angiography obtained throughout), the rabbit kittens were converted to single lung ventilation with air and then to bilateral lung ventilation. Lang et al. (2017) confirmed previous findings that pulmonary blood flow increases on the contralateral side of the single lung inflation with 100% nitrogen at birth, and demonstrated this increase was blocked in kittens with vagotomies. Vagotomy also decreased the heart rate increase normally found with ventilation. The use of oxygen for initial breaths caused vasodilatation on both sides of lung, irrespective of cutting the vagus nerves. The authors suggest that the C-fibres of the vagus nerve are stimulated by the increased pressure within the pulmonary interstitial tissues after clearance of the fetal lung liquid from the airways. The additive effects of oxygen confirms that multiple, overlapping stimuli exist to insure the critical decrease in PVR occurs. The presence of the vagal nerve response is especially important for preterm infants, who have heterogeneous lung expansion due to surfactant deficiency and need a rapid increase in pulmonary blood flow through both lungs to maintain cardiac output. This study supports the stress placed by the newborn resuscitation guidelines on establishing adequate ventilation prior to proceeding to more advanced cardiopulmonary resuscitation. Understanding the physiology of transition at birth is crucial for developing guidelines for newborn resuscitation. Cutting the umbilical cord immediately at birth, prior to a decrease in PVR and increase in PBF, causes a rapid decrease in the left ventricular preload and shifts in systemic blood pressure (Hooper et al. 2015). The reduced left ventricular output leads to alterations in cerebral blood flow that may influence the intra-ventricular haemorrhage seen in extremely preterm infants. Initiation of ventilation prior to removing the placenta maintains cerebral blood flow in preterm sheep, and human studies have recently begun recruiting (Hooper et al. 2015). The current study underscores the importance of lung aeration, partially through vagal nerve stimulation, on the critical decrease in PVR at birth needed for the most dramatic transition in one’s life.