Pulmonary Physiology of Neonatal Resuscitation

After completing this article, readers should be able to: The most important part of the transition from intrauterine to extrauterine life is the establishment of effective pulmonary gas exchange. Currently used techniques of resuscitation, although usually successful, are based on few physiologic studies and have come under critical review recently. This article reviews current understanding of pulmonary physiology during transition and resuscitation, based primarily on experimental animal studies, and relates it to clinical practices in neonatal resuscitation.The switch from placental to pulmonary gas exchange at birth requires rapid removal of lung liquid from the potential air space (Fig. 1 ) [multimedia-1]. This process is much more complex than simple mechanical compression of the chest at delivery that results in oral drainage of lung liquid, and it is controlled primarily by ion transport across the airway and pulmonary epithelium.During fetal life, the lungs are filled with liquid, and normal growth of the lungs depends in part on the balance between production and drainage of this fluid. The pulmonary epithelium actively transports chloride into the lung lumen, generating an osmotic gradient that causes liquid to flow from the microcirculation through the interstitium into potential air spaces. In fetal lambs, the hourly production of lung liquid increases from 2 mL/kg at midgestation to 5 mL/kg at term, and the total volume increases from 4 to 6 mL/kg at midgestation to more than 20 mL/kg near term.Secretion of lung liquid begins to decrease 2 to 3 days before spontaneous term or preterm labor, resulting in a 15 mL/kg reduction in lung water. Labor decreases extravascular lung water by 45%, with a further 38% reduction 6 hours after birth. At birth, several factors drive fluid from the lung lumen into the interstitium. First, the lung epithelium switches from a predominantly chloride-secreting membrane before birth to a predominantly sodium-absorbing membrane after birth. The expression and function of the epithelial sodium channels at the apical membrane and Na+, K+-ATPase at the basolateral membrane increase at birth. The causes of these changes are not clear but may be linked to alterations in the hormonal milieu associated with delivery. Second, the lung liquid contains almost no protein compared with 30 mg/mL of protein in the interstitial fluid, resulting in an osmotic pressure gradient. Third, inflation of the lungs with air establishes transpulmonary pressure, decreases hydrostatic pressure in the pulmonary circulation, and increases pulmonary blood flow, which in turn increases effective vascular surface area for fluid uptake. Under normal conditions, transepithelial liquid clearance requires 2 to 3 hours, and drainage from the interstitium into the circulation is complete by 6 hours. Most of the luminal fluid enters the pulmonary microcirculation, but about 10% exits the lungs through lymphatics. The process may be slower with preterm birth, delivery by cesarean section without prior labor, elevated lung microvascular pressure from hypoxemia or left heart failure, and conditions of low plasma protein concentration. Such circumstances often result in delayed establishment of final lung volumes.In spontaneously breathing term infants born vaginally, the first breath generates a mean negative intrathoracic pressure of 52.3±26.4 cm H2O during inspiration and a mean positive pressure of 71.3±32.8 cm H2O during expiration. The inspired volume averages 37.7±18.1 mL, with a functional residual capacity (FRC) of 15.1±7.9 mL. Babies delivered by cesarean section have similar inspiratory pressure and volume but lower expiratory pressure and develop FRC less frequently with the first breath.In contrast to spontaneously breathing newborns, an opening pressure must be exceeded before lung expansion occurs in asphyxiated infants. During resuscitation of infants who never have breathed, the median pressure on the first inflation to produce chest movement is 40 cm H2O, and the median first inspiratory volume achieved is 8.6 mL/kg. An inflation pressure of 25 to 30 cm H2O for 1 second achieves a tidal exchange of only 15 mL compared with 40 mL in spontaneously breathing babies. Furthermore, FRC is not formed for several breaths unless the baby exhibits a Head paradoxic reflex. By maintaining the first inflation for up to 5 seconds, a tidal volume similar to that seen in spontaneously breathing babies could be delivered and an FRC could be formed consistently. Thus, when resuscitating asphyxiated neonates, lung volume similar to the first breath of spontaneously breathing babies can be accomplished either by maintaining a pressure of 25 to 30 cm H2O for at least 3 seconds or by using higher pressure (up to 50 cm H2O) for much shorter periods that is guided by chest wall movement. Although physiologic studies have demonstrated that lung inflation requires high or sustained inflation pressures, clinical trials have not been performed to validate this concept.The amount of pressure needed to resuscitate preterm babies remains controversial. In physiologic studies, inflation pressures of 27.3±4.8 cm H2O produced adequate tidal exchange (ie, twice the anatomic dead space) in fewer than one third of preterm infants in the first three breaths. Other data suggested the median pressure to achieve chest wall movement was 22.8 (range, 14 to 30) cm H2O in infants younger than 36 weeks’ gestation and could establish no correlation between the inflating pressure and either birthweight or gestational age. In a recent study of extremely low-birthweight infants, inflation pressures of 20 to 25 cm H2O sustained for 15 seconds followed by continuous positive airway pressure seemed effective in establishing FRC and avoided unnecessary intubation. Further clinical trials of various strategies to establish lung volumes and FRC in preterm infants are needed to examine both short-term outcome (oxygenation, ventilation, spontaneous breathing) and long-term measures of severity of respiratory distress and lung injury.The response of an infant to resuscitation is primarily a product of physiologic reflexes. Infants are more vulnerable to cardiopulmonary compromise because the autonomic nervous system and the pulmonary mechanics are immature. Without an understanding of the physiologic reflexes, attempts at resuscitation actually may worsen apnea, bradycardia, and hypoxemia.Chemical stimulation of the laryngeal receptors with water, saline, or milk and mechanical stimulation with a suction catheter induce bradycardia and apnea. The afferent pathway from laryngeal chemoreceptors is the superior laryngeal nerve, which transmits impulses to the nucleus tractus solitarius and dorsal nucleus of the medulla. The motor limb originates from the nucleus ambiguus and nucleus retroambigualis in the medulla, reaching the larynx via the recurrent laryngeal nerve. Sedation with reduced respiratory drive before stimulation is associated with more prolonged apnea. Pre-existing hypoxemia also enhances the laryngeal reflex. Therefore, in asphyxiated infants, vigorous attempts to suction the pharynx or intubate the larynx superimposed on the effects of maternal sedation may lead to profound apnea and bradycardia.The carotid bodies are peripheral chemoreceptors located near the bifurcation of the common carotid arteries. When stimulated by hypoxemia, they send afferent impulses via the glossopharyngeal nerve to the nucleus tractus solitarius and then to the respiratory neurons in the medulla. The efferent response includes hyperventilation, vagal bradycardia, bronchoconstriction, dilation of the upper airway, and alpha-adrenergic peripheral vasoconstriction with increased blood pressure. The increase in ventilation is enhanced by hypercapnia. However, newborns, especially preterm infants, respond to hypoxia with an initial increase followed by a later decrease in ventilation with worsening hypoxemia, which can lead to periodic breathing or apnea. On the other hand, a single breath of 100% oxygen causes a decrease in minute ventilation or even apnea in neonates during quiet sleep, with preterm infants showing a greater response. Stimulation of the laryngeal chemoreflex inhibits the carotid body respiratory reflex and facilitates the carotid body cardioinhibitory reflex, which may lead to temporary cardiac arrest. Thus, the carotid body reflex in the newborn can mediate apnea and bradycardia through several pathways.Lung inflation stimulates stretch receptors located within the smooth muscle of large and small airways, transmitting afferent impulses via large myelinated fibers in the vagus into the dorsal respiratory neurons, the apneustic center, and the pneumotaxic center in the brainstem. The reflex includes slowing of ventilatory frequency or even apnea and bronchodilation. In addition, lung inflations cause a decrease in vagal tone with an increase in heart rate and vasoconstriction, which may reverse the marked bradycardia and hypotension elicited by stimulation of the laryngeal and carotid body reflexes. The strength of the Hering-Breuer reflex is greater at 36°C than at 24°C ambient temperature in newborn rats, suggesting that newborns exposed to a warm environment are more susceptible to inhibitory inputs, and hyperthermia may predispose to respiratory depression.Lung inflation also can stimulate stretch receptors in the lungs, followed by afferent transmission via the vagus, causing very deep inspirations. This reflex is present as early as 25 weeks of gestation, but generally persists only in the first 5 days postnatally. It may be involved in the sigh response to prevent atelectasis and in generating the first breath of the newborn.When a newborn is deprived of oxygen, respirations cease after a few rapid breaths, and heart rate drops. This primary apnea usually resolves with stimulation. However, if oxygen deprivation continues, the baby will develop several irregular gasping respirations followed by a period of secondary apnea, which is associated with significant bradycardia and hypotension (Fig. 2 ) [multimedia-2]. This secondary apnea cannot be relieved by stimulation alone; it can be reversed only by positive-pressure ventilation. Suctioning and attempts at intubation may stimulate laryngeal reflexes and worsen the apnea, bradycardia, hypotension, and hypoxemia. Face mask pressure and cold air over the face can stimulate the trigeminal reflex, also causing bradycardia. Adequate inflation of the lungs is of utmost importance. Stimulation of the pulmonary stretch receptors immediately mediates an increase in heart rate and blood pressure, inhibits laryngeal and carotid body reflexes, and induces the paradoxic reflex of Head, with initiation of spontaneous respirations. Lung inflation also gradually establishes FRC and improves pulmonary blood flow and gas exchange.During fetal life, pulmonary vascular resistance (PVR) is high and pulmonary blood flow is low. Several potential factors contribute to the high pulmonary vascular tone in the fetus. Small pulmonary arteries are compressed by the fluid-filled alveolar space. Low estrogen production and low oxygen tension promote the synthesis of vasoconstrictors such as endothelin-1 and inhibit the production of vasodilators such as nitric oxide and prostacyclin. Decreased concentrations of cyclic guanosine monophosphate and cyclic adenosine monophosphate, which are second messengers mediating vasorelaxation, also potentiate the effects of vasoconstrictors.In the fetus, most of the blood from the right side of the heart flows through the ductus arteriosus into the aorta (Fig. 3 ) [multimedia-3]. At birth, clamping the umbilical vessels removes the low-resistance placental circuit and increases systemic blood pressure, while blood vessels in the lungs relax. As a result, pulmonary blood flow increases immediately by 8- to 10-fold, and the flow through the ductus arteriosus decreases (Fig. 4 ) [multimedia-4]. The most important stimuli for increasing pulmonary blood flow are ventilation of the lungs and an increase in oxygen tension. Intrauterine ventilation of the fetal lamb without changing the arterial tension of carbon dioxide or oxygen increases pulmonary blood flow to about two thirds of that observed following birth; breathing hyperbaric oxygen without ventilating the lungs increases pulmonary blood flow to levels comparable to those after birth. The largest effects are seen when ventilation and increases in arterial oxygen tension occur simultaneously.The fall of PVR is due to mechanical and chemical factors. Inflation of the lungs dilates and recruits the pulmonary circulation, resulting in a rapid fall in PVR within the first 30 seconds. Establishment of gas-liquid interphase and absorption of lung fluids also may contribute. The basic mechanism by which increased oxygenation affects the pulmonary circulation is not well understood, but it may be related to the release of various vasodilators, which possibly account for the slower decline of PVR over the subsequent 10 to 20 minutes.Nitric oxide and arachidonic acid metabolites play an essential role in inducing pulmonary vasodilatation at birth. Expression of endothelial nitric oxide synthase (eNOS) peaks during mid- to late gestation and decreases postnatally in rats and lambs. Rhythmic distention of the lung without changing oxygen tension increases eNOS mRNA expression, and oxygen ventilation further increases its mRNA and protein expression. In addition, increased shear stress from increasing pulmonary blood flow induces eNOS expression. Nitric oxide also suppresses endothelin-1 synthesis, thus further contributing to pulmonary vasodilatation.Prostacyclin, formed by the action of cyclooxygenase on arachidonic acid, increases dramatically during late gestation and early postnatal life, accompanied by an upregulation of cyclooxygenase expression. Prostacyclin participates in reduction of PVR accompanying ventilation, but not in response to oxygenation, and its effect is more marked in the preterm than in the near-term fetus. Prostaglandin D2 lowers pulmonary artery pressure in the fetus and newborn during the first 2 to 3 days after birth, but it is a primary vasoconstrictor in older animals. It is possible that prostaglandin D2 also has a physiologic role in producing vasodilatation at birth. Bradykinin is released transiently from fetal lungs following ventilation with oxygen. It increases prostacyclin production and stimulates endothelial cells to release nitric oxide. Thus, bradykinin also may have a physiologic role during transition.The normal pulmonary vascular transition at birth is based on the complex structural and biochemical development of the lungs. This process can be disrupted easily by prematurity, intrauterine hypoxia, and parenchymal lung disease. Adequate ventilation and oxygenation through mechanical and humoral pathways are the most important resuscitative measures for achieving normal pulmonary circulation.Hypoxia in the fetus leads to cessation of breathing movement; hyperoxia initiates a continuous breathing pattern. Therefore, supplemental oxygen may be therapeutic to initiate spontaneous respiration. However, hyperoxia may turn off aortic chemoreceptors, leading to hypotension, or it may turn off carotid chemoreceptors and cause hypopnea. Hyperoxia may increase the work of breathing, metabolic rate, and oxygen consumption, and it has been shown to decrease cerebral blood flow in preterm infants. Using 100% oxygen may lead to formation of more oxygen free radicals during the reperfusion/reoxygenation period after ischemia/hypoxia, causing more extensive tissue damage, especially in preterm infants who have limited antioxidant defenses.A series of experiments in piglets subjected to severe neonatal hypoxia demonstrated that room air resuscitation normalized blood pressure, acid-base variables, hypoxanthine in plasma and brain microdialysate, cerebral blood flow, somatosensory evoked potentials, PVR, and cerebral membrane Na+, K+-ATPase activity as efficiently as resuscitation with 100% oxygen. Brain morphologic changes 4 days after the hypoxic insult were similar in both groups of piglets. Two clinical trials showed that resuscitation of asphyxiated newborns with room air was as effective as 100% oxygen, and room air-resuscitated infants seem to recover more quickly, with earlier first breaths and higher Apgar scores.Although biochemical evidence and preliminary clinical evidence suggest the benefits of resuscitation with lower oxygen concentrations, current clinical data are insufficient to justify adopting this as routine practice. Long-term neurodevelopmental effects are unknown, and room air resuscitation may be inadequate in certain circumstances. However, when 100% oxygen is not available, resuscitation can be initiated effectively with room air. Furthermore, it seems prudent to use oxygen judiciously and to avoid prolonged and unnecessarily high concentrations.Although based primarily on experimental data, understanding of the complex physiologic changes involved in transition at birth is increasing. These concepts are incorporated into the most recent recommendations for resuscitation. Clearing fluid in the lungs, establishing adequate lung expansion, and increasing pulmonary blood flow are key factors in successful pulmonary gas exchange. In asphyxiated newborns, optimal lung inflation and ventilation can increase heart rate and blood pressure promptly via reflex mechanisms, and it can hasten lung liquid clearance and decrease PVR, thereby improving oxygenation. Oxygen should be used to correct hypoxemia, and prolonged hyperoxia should be avoided. Further physiologic and clinical trials are needed to refine the techniques for establishing effective pulmonary gas exchange in infants who require resuscitation at birth.Electronic assets (illustrations, photographs, videos, virtual reality animations) were developed for the Neonatal Resuscitation Program under the direction of Dana A.V. Braner, MD, at the Media Lab of Doernbecher Children’s Hospital, Portland, OR.The quality of the electronic assets may vary, depending on the presentation format (CD-ROM versus Internet) and the system used for viewing.