Neonatology for anesthesiologists

Brief history of modern neonatology

With origins in the 1960s to 1970s, neonatology remains a relatively young specialty. Fifty years ago, premature birth earlier than 3 to 4 weeks before term implied high risk for mortality, primarily from pulmonary insufficiency associated with immature lungs—the neonatal respiratory distress syndrome (RDS) ( ; ). Although in the 1960s premature infants had been ventilated with cumbersome devices that were developed to treat adults ( ), the report by Gregory and colleagues ( ) describing CPAP to treat premature infants with RDS or “hyaline membrane disease” ushered in the era of routine ventilatory support for premature infants. The role of surfactant in RDS was reported in 1959, but its clinical use did not occur until the 1990s.

At approximately the same time that ventilation of the newborn was introduced, reported the benefits to the premature infant of prenatal steroids delivered to the mother. By inducing lung maturity, betamethasone often eliminated or greatly reduced the severity of neonatal respiratory distress syndrome/hyaline membrane disease. Surprisingly, although included in obstetric care in some medical centers as early the late 1970s, prenatal steroids were not routinely and widely included in perinatal care until the late 1990s. Throughout the 1980s and 1990s, neonatal care emphasized nutrition, maintenance of a neutral thermal environment, ventilation, treating infections, and pharmacologic support of cardiovascular function. In addition to physical exam and ECG, monitoring of the critically ill newborn centered on directly measuring blood pressure via an umbilical arterial catheter, a device that also allowed an ability to intermittently measure blood gases. These innovative strategies for supportive care dramatically reduced mortality for premature infants ( Fig. 27.1 ).

Diagnosis and evaluation of intraventricular hemorrhage remained rudimentary until computed tomography and/or ultrasound were integrated into routine clinical care in the early mid-1980s. In the first decades of 2000, the advanced techniques of MRI exponentially expanded understanding of the neurologic sequelae of prematurity. At the same time, in the mid-2000s, gentle ventilatory strategies were adopted as a routine approach to supportive care in efforts to decrease the incidence of both bronchopulmonary dysplasia and neurologic injury that were frequent in extremely low-birth-weight infants.

Over the last 20 years, neonatal care has been revolutionized by advancements in technology, including extracorporeal membrane oxygenation (ECMO), cardiovascular and neurologic monitoring, routine bedside ultrasound, therapeutic hypothermia, and minimally invasive surgery. With these advances in diagnostic and therapeutic tools, coupled with ongoing developments in advanced clinical care and nutrition, survival has improved dramatically since the early days of neonatology (see the section Survival and Outcomes). Although morbidity has also decreased over the decades, consequences of prematurity remain significant, especially for the “micropremature” or the periviable newborn. Outcome clearly tracks gestational age, but even late preterm infants incur greater risk than those born full term. Currently, the edge of viability often extends to 22 to 23 weeks’ gestation, with this group of survivors consuming the most resources throughout a lifetime. As survival has improved dramatically, the goal of this young specialty has shifted to improving outcomes by minimizing morbidity, especially in the central nervous system. Over the last 50 years and in the current era, iatrogenic injury consistently contributed to morbidity. In fact, the concept that “less is more” requires vigilance and consistent reevaluation of guidelines and clinical practice ( ).

As the specialty advances, and because extreme prematurity is a leading cause of morbidity and mortality in the NICU, much effort has been generated to develop an artificial womb—a postnatal environment that mimics the uterine cavity. This system would allow for ongoing growth and development of all major organ systems without the common postnatal consequences of treating extreme prematurity, such as bronchopulmonary dysplasia and retinopathy of prematurity ( ; ; ; ; ). Challenges to implementation include fetal sepsis, umbilical vessel spasm, and heart failure due to imbalances in preload or afterload from the circuit oxygenator as well as medicolegal and ethical concerns ( ; ; ; ).

Developmental origins of adult disease

Over the last 50 years, the concept that the origin of adult diseases can be traced to intrauterine events has gained traction. Prematurity is included under the paradigm of fetal origins of adult diseases ( ; Barker 1990) and, more recently, developmental origins of health and disease (DOHaD) ( ; ; ). This concept exemplifies how early events can significantly influence cardiovascular, respiratory, central nervous, and renal function in later life. The foundation of DOHaD focuses on in utero reprogramming of development that has long-term effects. That is, a variety of perturbations from exogenous (environmental, nutritional, epigenetic) and endogenous factors (genetic) may impact fetal growth and development ( ; ).

Of particular relevance to the preterm infant, fetal and early postnatal events have been proposed to critically modify long-term pulmonary function ( ). This phenomenon is supported by two well-defined patterns ( ). First, parameters of lung function measured in the newborn establish a “tracking” that extends into adulthood ( ; ; ; ). In the setting of prematurity, disrupting normal fetal and early postnatal development predicts lifelong reduced lung function. In particular, these infants fail to achieve “maximal function,” which implies a more rapid decline in pulmonary function that normally accompanies aging ( Fig. 27.2 ). Second, noxious stimuli commonly encountered by the preterm infant (e.g., supplemental oxygen, ventilation, and inflammation) at critical stages of development induce a remodeling of a variety of cells, interrupting normal development. Thus injury and abnormal growth combine to result in lifelong pulmonary dysfunction ( ; ).

Development of the fetus and the intrauterine environment

The intrauterine environment dramatically affects growth and the ability of a newborn to adapt to extrauterine life. Although the impact of intrauterine events is most obvious during the first few hours and days of life, the effects of some of these events can last much longer. For example, phenytoin, thalidomide, alcohol, and other maternal drug use have caused well-described alterations in fetal and postnatal somatic growth and brain development ( ). Exposure to drugs during pregnancy has been associated with cardiac, craniofacial (cleft lip and palate), and central nervous system malformations and changes to the pulmonary vasculature ( ; ). Opioid, benzodiazepine, and/or amphetamine exposure in utero can lead to neonatal drug-dependence and withdrawal ( ).

During intrauterine life, fetuses expend minimal energy maintaining body temperature. The placental circulation provides needed substrates and eliminates waste products. The fetus’s primary activity is growth and development, which proceeds under hypoxic conditions. After the placental circulation is established, the saturation of blood perfusing the fetal brain and heart is approximately 60% ( ). A fetal Pa o ₂ of 20 to 30 mm Hg, a hemoglobin concentration of 18 to 20 g/dL, a left-shifted oxygen dissociation curve (P50, 18 mm Hg), and a higher cardiac output/kg (CO/kg) (approximately 2 to 3 times the level in adults) provide sufficient oxygen content in fetal blood to meet its oxygen demands.

However, the fetus is at a great disadvantage. The lungs are filled with fluid; no oxygen stores exist beyond that in the blood ( ). After only a minute of umbilical cord occlusion, the fetus’s Pa o ₂ is less than 5 mm Hg. At the same time oxygen decreases, the Pa co ₂ steadily rises and the pH rapidly declines. These changes are followed by bradycardia and a decrease in cardiac output (asphyxia). The effects of intrauterine asphyxia can be sudden and profound and may be associated with severe hypotension and acidosis ( Fig. 27.3 ) ( ).

Perinatal events

The physiology of transition from fetal to extrauterine life is important for understanding potential problems of the newborn ( ; ). A successful transition from fetal to postnatal life requires (see section Transitional Circulation): (1) increased pulmonary perfusion and increased systemic blood pressure, along with closure of the three fetal shunts (foramen ovale, ductus venosus, and ductus arteriosus); (2) expansion of the lung and establishment of a functional residual capacity (FRC); and (3) clearance of alveolar fluid.

Labor and delivery

Labor, fetal movements, and uterine contractions initiate removal of the 30 mL/kg of fluid normally present in fetal lungs ( ). After birth, breathing increases clearance of the lung fluid via the pulmonary capillaries and the lymphatics. Initiation of breathing further increases removal of fluid and helps establish the FRC ( ) (see also the pulmonary system). The specific mechanism that initiates breathing at birth remains unclear, but several factors are known to play critical roles. First, placental factors that inhibit breathing in utero are removed by clamping the umbilical cord ( ). Second, the sudden release of the circumferential pressure around the chest at birth allows the neonatal chest to recoil outward and draw gas into the lungs ( ). Third, tactile stimulation and changes in environmental temperature at birth stimulate breathing ( ). The effects of hypoxemia and hypercarbia on the chemosensors also stimulate breathing ( ). Poor respiratory effort at birth is associated with birth asphyxia.

The placenta: In utero function and umbilical cord clamping

The critical role of the placenta centers on ensuring health and well-being of the fetus. The placenta has regulatory function for both the mother (e.g., preeclampsia) and the fetus (prematurity, intrauterine growth restriction). By studying regulatory genes and other factors associated with mechanisms that regulate the intense, complex interaction of mother and fetus ( ) that define fetal growth, immune competence, and in utero cardiovascular and hormonal/endocrine function, investigators have provided a preliminary framework for intervening early in gestation to improve outcome ( ).

Of more immediate clinical relevance, the timing of clamping of the umbilical cord—the event that terminates the relationship of the fetus with the placenta—has been the subject of numerous investigations, clinical trials, and meta-analyses. The goals of these efforts center on optimally utilizing this organ during the neonatal transition from fetal to extrauterine cardiovascular physiology.

The volume of blood available for transfusion to the newborn varies depending on gestation. At 20 to 32 weeks’ gestation, the placenta receives approximately 33% of the fetal combined ventricular output or 110 to 120 mL/kg/min ( ). After 32 weeks, this distribution decreases to approximately 20% ( ). At birth, the blood remaining in the placenta may be a critical resource for a smooth transition from fetus to newborn. At term, 20 to 35 mL/kg ( ), but only 11 to 15 mL/kg in the premature infant ( ) are available to transfuse at birth. But, the volume of blood transfused correlates with the timing of clamping the umbilical cord. As much as 50% of the transfusion is complete within 1 minute and mostly completed by 5 minutes ( ; ).

Initially, “delayed clamping” and/or “milking” of the umbilical cord was recognized as a safe method to deliver the significant placental volume of red blood cells to the newborn. Although the data are not totally consistent among studies, delaying cord clamping until after adequate pulmonary ventilation has been established is associated with a wide range of improved short and long-term outcomes, especially in preterm infants. These include decreased mortality, higher hematocrit, and improved perinatal cardiovascular function/less need for inotropes ( ; ). Advantages related to a lower incidence of sepsis ( ) and necrotizing enterocolitis ( ) and intraventricular hemorrhage ( ; ; ) are less consistently documented.

Clamping of the umbilical cord decreases venous return to the heart (preload) abruptly by as much as 40% to 50% ( ; ; ) while simultaneously increasing the afterload to the left ventricle and decreasing cardiac output.

At birth, expanding and aerating the lungs are the primary triggers for decreasing pulmonary vascular resistance, leading to increased pulmonary blood flow. This pulmonary blood flow replaces umbilical venous return as preload to the left ventricle. The interrelated cascade of hemodynamic events at birth (i.e., closure of fetal vascular shunts, increased systemic and decreased pulmonary vascular resistances) separates the pulmonary and systemic circulations of the newborn, enabling the right ventricle output to be the sole source for pulmonary blood flow. Pulmonary blood flow becomes the sole source for preload for the left ventricle. Thus effective ventilation (spontaneous crying or assisted support) expands the fluid-filled fetal lung, increases pulmonary blood flow (secondary to the dramatic decrease in pulmonary vascular resistance), and preserves filling of the left atrium and left ventricular output. The interdependence of ventilation, establishing pulmonary blood flow, and timing of clamping of the umbilical cord directly defines care during the third stage of labor ( ).

In theory, delayed clamping of the umbilical cord may allow a more physiologic transition to postnatal physiology by maintaining preload by transfusion and by allowing pulmonary blood flow to increase before eliminating umbilical venous flow.

However, publications on the benefits of delayed cord clamping are inconclusive ( ; ; ; ; ; ; ; ; ).

Neonatal asphyxia

Neonatal asphyxia (see also section Hypoxic-Ischemic Injury) is due to impaired gas exchange or inadequate blood flow and leads to persistent hypoxemia and can occur in utero (prior to labor and delivery) or perinatally, during labor and delivery. Neonatal signs consistent with an acute perinatal asphyxia include an Apgar score of <5 at 5 and 10 minutes; a fetal umbilical artery pH <7.0 or base deficit ≥12 mmol/L, or both; brain injury seen on magnetic resonance imaging consistent with acute hypoxia-ischemia; and multisystem organ failure (“Executive Summary” 2014). Prompt evaluation and treatment of infants with neonatal asphyxia is necessary to optimize outcomes and prevent death (also see section Hypoxic-Ischemic Encephalopathy).

Chronic intrauterine asphyxia affects placental flow, and placental infarction adversely affects fetal growth. In cases of chronic intrauterine asphyxia, labor is often poorly tolerated and neonatal resuscitation is necessary. Even with effective neonatal resuscitation, primary or secondary consequences of asphyxia may evolve during the postnatal period, including acidosis, seizures, transient cardiac dysfunction (e.g., cardiomyopathy or tricuspid insufficiency), pulmonary hypertension, renal insufficiency (e.g., acute tubular necrosis), gastrointestinal/hepatic injuries (e.g., necrotizing enterocolitis [NEC]), or clotting abnormalities ( ) .

Postnatal asphyxia may develop as a continuum of intrauterine events but is most commonly related to events that occur shortly before birth, during labor and delivery (see section Hypoxic-Ischemic Encephalopathy). Life-threatening responses to asphyxia are associated with immature control of respiration, especially in the premature infant. With the onset of asphyxia, the newborn’s respiratory rate increases briefly ( Fig. 27.3 ), but primary apnea develops quickly and persists for variable amounts of time. Primary apnea is followed by slow gasping respirations and eventually by terminal apnea and death, unless effective resuscitation is initiated ( ).

During the respiratory events of asphyxia, heart rate and arterial blood pressure initially increase moderately, but bradycardia and hypotension soon develop. Because the cardiac output of the fetus and newborn is highly dependent on heart rate, the asphyxia-induced reduction in heart rate significantly reduces CO ( ). To compensate for the decrease in total cardiac output, blood flow is centralized to maintain flow and oxygen delivery to the brain, heart, and adrenal glands. Arterial blood pressure increases during gasping respirations but decreases markedly during terminal apnea. Heart rate, CO, and arterial blood pressure quickly improve with resuscitation. Despite the increase in CO, the metabolic component of acidosis may worsen as effective flow is reestablished because fixed acids are washed out of peripheral tissues by the improved perfusion. If perfusion and pH do not improve with ventilation, therapy with sodium bicarbonate might be considered. However, treatment with sodium bicarbonate results in increased CO ₂ production, requiring increased ventilation. To avoid adverse effects and because evidence is lacking for its effectiveness, sodium bicarbonate is not recommended, especially if CPR is brief. If the arrest is prolonged and resistant to other interventions (e.g., epinephrine, boluses of fluid), a slow infusion (<1 mEq/kg/min) of 1 to 2 mEq/kg (4.2% solution) may be administered ( ). Serial blood gases should guide cardiorespiratory support, including delivery of bicarbonate. The use of therapeutic hypothermia (33° C to 34° C) for the treatment of birth asphyxia in patients >34 weeks’ gestation is a proven neuroprotective strategy (see section Hypoxic-Ischemic Encephalopathy) ( ).

Apgar score

The Apgar score was initially proposed as a means of rapidly assessing the status of newborns 1 minute after birth to determine whether they required respiratory support ( ; ) ( Table 27.1 ). As noted, “Every baby born in a modern hospital in the world is looked at first through the eyes of Virginia Apgar.” Five variables (heart rate, respiratory effort, muscle tone, reflex irritability, and color) are assessed and scored between 0 to 2; the healthiest infants have a score of 10. Scoring is performed at 1 and 5 minutes. If continued resuscitative efforts are required, scoring continues for as long as 20 minutes.

Apgar scoring may predict the risk of death, although this function was not included in the original purpose. reported a mortality rate of 24.4% in full-term infants whose 5-minute Apgar scores were 1 to 3 and 0.02% when scores were 7 to 10. The mortality rate of preterm infants of 26 to 36 weeks’ gestation was 31.5% when the 5-minute Apgar score was 0 to 3 but 0.5% with a score of 7 to 10. Thus the rate of neonatal death was highest when the 5-minute Apgar score was 3 or lower, independent of gestational age. Death most commonly occurred during the first day of life; the majority of infants died before 3 days of age. Similar data from over 1 million newborns was recently reported, documenting the persistent correlation of death, both neonatal and infant, associated with a low 5-minute Apgar score (i.e., 0 to 3) ( ).

The Apgar score better predicts outcomes than an umbilical artery blood pH of 7.0 or less. Combining a 5-minute Apgar of 0 to 3 with an umbilical artery blood pH of 7.0 or less provides a more accurate prediction of death in both preterm and full-term infants. An Apgar score of 0 for more than 10 minutes suggests that resuscitative efforts should be suspended ( ). In 2001, Papile said (p. 519), “At present, there is no single measure of the fetal or neonatal condition that accurately predicts later neurodevelopmental disability, . . . but few will deny the Apgar score’s application at 1 minute of age accomplishes Dr. Apgar’s goal of focusing attention on the condition of the infant immediately after birth.” Although outcomes vary with gestational age, the cause of neonatal depression, and other factors, providing effective resuscitation for infants with low Apgar scores resulted in survival of 40% to 60% of infants. Approximately two-thirds of the survivors had normal neurologic function ( ).

In 1964, the Collaborative Study on Cerebral Palsy reported a stronger relationship between the 5-minute Apgar score and neonatal death than the 1-minute score ( ). However, Apgar scores do not accurately predict neurologic outcomes. The score was not intended to establish the diagnosis of asphyxia, to measure the severity of perinatal asphyxia, or to predict long-term neurologic outcomes. In fact, 75% of children with cerebral palsy had a normal 5-minute Apgar score ( ). In a group of term infants with a 5-minute Apgar score of <3, only 6.8% (16/292) developed cerebral palsy ( ).

Gestational age

The premature infant

Prematurity is defined as birth before 37 weeks of gestation. In the United States approximately 550,000 preterm births occur each year, with an incidence of 9.57%; 2.7% of all infants are born at less than 34 weeks ( ) (see section Incidence of Preterm Birth). Although premature infants share common features, the physiologic variability between 24 and 36 weeks’ gestation is enormous. An infant at 36 weeks’ gestation is more similar to a term infant than to infants born before 30 weeks’ gestation. For this discussion, premature infants are divided into subgroups based on gestational age.

Metabolic status: Early postnatal period

Thermal environment and regulation

Newborns are abruptly born into an environment that is approximately 20° C cooler than that in utero. Exposure to this new colder environment markedly increases caloric expenditure required to regulate body temperature; oxygen consumption and cell metabolism increase two- to threefold. Newborns lose heat by evaporation, convection, conduction, and radiation. Extremely preterm infants lose about 15 times more heat by transdermal water loss than full-term babies ( ) (see Fig. 27.24 ). To compensate for increased heat losses, the sympathetic nervous system constricts skin blood vessels to centralize blood flow and conserve body heat ( ).

In addition to the cooler environment, other factors contribute to heat loss, including a high ratio of surface area to body weight, reduced subcutaneous fat, and an underdeveloped or absent ability to shiver in response to cold. In part, shivering is limited by the newborn’s smaller muscle mass (25% vs. 45% in the adult). As a result, nonshivering thermogenesis (NST) is the major compensatory mechanism for cold stress. Norepinephrine and thyroid hormone stimulate triglyceride and fatty acid metabolism of energy-rich brown fat ( ). Brown fat, which is mostly deposited during the third trimester of pregnancy, is stored between the scapulae and around major abdominal organs. Infants born before the third trimester are less able to generate heat by NST and are therefore more prone to hypothermia. The SGA newborn also has limited NST compared with AGA term infants.

Hypothermia (body temperature <36° C) increases oxygen consumption and predisposes to metabolic acidosis, increased pulmonary and peripheral vascular resistance, and reduced cardiac output ( ). Infants admitted to the NICU with temperatures of 35.5° C had a Pa o ₂ that was approximately 18 mm Hg lower than those of newborns with a body temperature of 36.5° C; warming cold infants to 36.5° C or higher increased the Pa o ₂ (Stephenson et al., 1970). A neutral thermal environment (i.e., the environmental temperature associated with minimal oxygen consumption) normally corresponds to a skin temperature of 36° C and an environmental temperature of 32° C to 34° C (see Chapter 7 : Thermoregulation: Physiology and Perioperative Disturbances, Fig. 7.4 ) ( ). Prematurity, hypoglycemia, and general anesthesia exaggerate the newborn’s metabolic response to hypothermia ( ). Because preterm and asphyxiated or neurologically injured full-term newborns have limited ability to maintain a normal body temperature, the environmental temperature must be carefully controlled with forced-air warming devices, isolettes, and warm operating rooms.

If the staff in the NICU must adjust the environmental temperature to maintain a normal body temperature, the infant has temperature instability. Preterm infants usually require servocontrolled devices to maintain normal body temperatures. Although infants cared for in incubators have less insensible fluid loss (and, therefore, require less fluid intake) and lower body temperatures on the first 2 days of life, no differences in weight gain, maximum serum sodium, or serious complications (e.g., NEC, IVH, Periventricular leukomalacia (PVL), or ROP) were noted in these infants compared with those treated with overhead warmers ( ). Neurologically intact term infants usually require minimal assistance to maintain stable body temperatures (e.g., clothing and a blanket). AGA infants who have difficulty maintaining body temperature are commonly septic or have neurologic injury. Avoiding hypothermia is crucial to prevent increasing pulmonary vascular resistance, decreasing pulmonary blood flow, and inducing right-to-left shunting of blood through the foramen ovale or PDA (see section Transitional Circulation and Chapter 7 : Thermoregulation: Physiology and Perioperative Disturbances) ( ; Stephenson et al. 1970). Infants exposed to hypothermia for prolonged periods of time may develop hypoventilation, inadequate oxygen delivery, acidosis, and cardiovascular collapse ( ).

Wrapping the trunk and extremities with plastic wrap, using hats, and utilizing a forced-air warming device helps maintain normal body temperatures during surgery (Vora et al., 1999; ). To avoid overheating, the temperature must be monitored when actively warming patients ( ). When evaluating newborns for surgery, anesthesia providers must consider that patients cared for under overhead warmers may be predisposed to hypovolemia secondary to increased insensible loss of fluid.

Newborns expend the least amount of energy to maintain body temperature in a neutral thermal environment. The oxygen consumptions (V o ₂ ) of a normal newborn is approximately 6 cc/kg per minute, twice that of resting adults. During the first week of life, V o ₂ increases to nearly 10 cc/kg per minute and may be twice that during heat-related stress. Because of high oxygen consumption, greater cardiac output, and smaller reserve of oxygen (i.e., smaller functional residual capacity/kg [FRC]), newborns, especially the preterm, develop hypoxemia more quickly than adults. Hypoxemia may develop in as few as 10 seconds in apneic newborn; in adults, under the same circumstances, several minutes may elapse before hypoxemia develops ( ). Consequently, maintaining normal temperature in a neonate is imperative ( ; ).

Apnea of the newborn

The immaturity of respiratory control (e.g., reduced sensitivity to CO ₂ and hypoxia) and the mechanical properties of the newborn’s respiratory system (e.g., small airways, compliant chest wall) predispose to disorders of breathing, such as neonatal apnea. That is, immaturity of both the autonomic and central nervous system as well as peripheral and central chemoreceptors fail to accurately regulate respiratory muscles and the upper airway. Finally, separate from imperfect neural input, a compliant chest wall and upper airway tend to collapse, leading to airway obstruction/apnea. Because of greater maturity of both the central nervous and respiratory systems, the term infant is physiologically equipped to adapt to postnatal life. Thus apnea in the term infant should be considered pathologic and deserves an in-depth evaluation to identify a specific etiology. That is, in the full-term infant, apnea is more likely to imply a significant underlying condition such as brain disorders (e.g., hemorrhage, stroke, trauma, malformations, seizures, congenital central hypoventilation), metabolic instability (e.g., glucose, calcium, sodium, temperature), inherited errors in metabolism, lesions that predispose to airway obstruction (e.g., craniofacial anomalies, upper airway anomalies, masses/tumors), anemia, or infection. Although these pathologies also apply to and are relevant to evaluating the preterm infant, apnea of prematurity (AOP) deserves additional analysis.

Apnea of prematurity (AOP) can be thought of as a developmental disorder because, at birth, especially in the extremely low-birth-weight infant, the central and peripheral mechanisms for control of ventilation remain oriented to fetal life, when breathing is characterized by frequent pauses. These imperfect regulatory mechanisms coupled with the immature parenchyma and vascular bed of the lung in the setting of a compliant chest wall create the “perfect storm” for AOP ( ).

The definition of apnea of prematurity varies, but most commonly the disorder refers to a pause in breathing for greater than 20 seconds or shorter accompanied by clinical evidence of hypoxia such as cyanosis or bradycardia ( ; ). In fact, this well-accepted definition is not evidence based ( ), and experts have not developed a consensus statement for a clinically significant event based on length of a pause in respiration ( ). For example, apneic events <20 seconds in duration can lead to clinical signs of hypoxia; conversely, apneic events up to 30 seconds may be observed in healthy term babies. Thus the clinical consequences (desaturation and bradycardia) in the context of gestational/postnatal age rather than simply the length of apnea may be more relevant to long-term risk and, in that context, contribute to developing guidelines for initiating and discontinuing treatment as well as monitoring after discharge from the intensive care nursery.

Apnea is classified according to the mechanism of dysfunction: obstructive (no air flow associated with respiratory effort; usually obstruction is at the pharyngeal level), central (no respiratory effort without obstruction), and—the most common— mixed apnea, with features of both obstruction and pauses in respiratory effort ( ). The incidence of recurrent apnea increases as gestational age decreases: 100% of infants <28 weeks gestational age, 54% at 30 to 31 weeks, 15% at 32 to 34 weeks, and 7% at 34 to 35 weeks. By 40 weeks’ postmenstrual age, 98% of infants no longer have apnea ( ). Of note, apnea persists beyond 38 weeks postmenstrual age more commonly in infants born at 24 to 26 weeks’ gestation and in those who develop BPD. In most cases, episodes of severe apnea (requiring intervention) decrease in frequency earlier than less severe apnea (i.e., spontaneously resolves) ( ). In conjunction with nasal continuous positive airway pressure, caffeine has evolved as a treatment for apnea. For more information see Chapter 27 online, section Apnea of the Newborn.

Apnea may be accompanied by bradycardia (so-called As and Bs)—with or without hemoglobin desaturation, suggesting that a common pathway (e.g., vagal inhibition) may contribute to both phenomena ( ). With hemoglobin desaturation, direct effects on the carotid body may lead to further bradycardia; the net result is reduced oxygen delivery ( Fig. 27.e1 ). The common thread of inflammation/oxidative stress that characterizes the diverse abnormalities associated with prematurity (e.g., sepsis, intracerebral hemorrhage, anemia, patent ductus arteriosus, neurologic abnormalities, airway anomalies, and other systemic illness) has been proposed to play a modulating role in AOP. The chronic intermittent hypoxia (CIH) that frequently accompanies AOP, not the respiratory pauses per se, has been linked to significant complications, including prolonged respiratory support, higher incidence of ROP, delayed establishment of oral feeds, and a higher risk for abnormal neurodevelopmental outcome ( ; ). Infants with BPD have been reported to have a higher incidence of AOP ( ). Systemic or local inflammation has been shown to upregulate inflammatory gene expression in the central nervous system (in the rat), inducing vagally mediated responses associated with apnea and CIH ( ; ). Studies involving epigenetic mechanisms (e.g., DNA methylation) associated with CIH in the newborn (rat) contribute to altered sensitivity of the carotid body. Of significance, this neonatal “reprogramming” is associated with autonomic dysfunction in adulthood. For example, adults who had apnea of prematurity exhibit higher incidences of sleep-disordered breathing ( ; ).

End-expiratory lung volume (FRC) contributes to preventing prompt and severe desaturation in response to apnea. However, the compliant chest wall and pulmonary insufficiency can decrease FRC. In addition, activating chest wall muscles contributes to maintaining FRC by maintaining chest wall stability. However, the sleep pattern of preterm infants includes >80% of time in active sleep when chest wall muscle activity is inhibited ( ), thereby interfering with FRC. Because the prone position stabilizes the chest wall, sleep in this position may stabilize FRC, and therefore oxygen saturation, especially in patients with BPD ( ; ). As evidence for the critical role of FRC in allowing oxygen uptake to continue in the setting of apnea (i.e., prevent/delay desaturation), the decrease in FRC during apnea has been shown to correlate with the rate of desaturation. That is, the greater loss of FRC mirrors rapid desaturation. Thus the premature infant is predisposed to a low FRC that increases the risk for severe desaturation in response to apnea ( ). Finally, titrating supplemental oxygen in extremely low-birth-weight infants to achieve oxygen saturation of 85% to 95% to avoid hyperoxia (see section Oxygen Toxicity) may add to the risk for incurring CIH in this fragile group.

In conjunction with nasal continuous positive airway pressure (4 to 6 cm H ₂ O), caffeine has evolved as the primary pharmacologic agent to treat apnea of prematurity. Although caffeine (and other xanthines) is known to have a multitude of CNS effects, a role in inhibiting adenosine receptors seems to be most relevant to treating apnea of prematurity. By blocking inhibitory A ₁ and A _2A receptors, caffeine produces excitatory neural output, manifested clinically by increased minute ventilation, improved carbon dioxide sensitivity, decreased periodic breathing, and decreased hypoxic hypoventilation. Of note, hypoxic ventilatory depression is thought to be mediated in the pons, with significant modulation via adenosine receptors.

Because of a long half-life, absence of side effects (tachycardia, dysrhythmias), and lack of need for monitoring with drug levels, caffeine has evolved as the preferred agent (usually, 20 mg/kg IV loading dose, 5 to 10 mg/kg/day IV maintenance). The Caffeine for Apnea of Prematurity (CAP) randomized controlled trial (and other studies) established a broad experience, defined a safety profile, and documented improved short-term outcomes (e.g., decreased duration of respiratory support, lower rate of BPD, less frequent use of corticosteroids, and increased survival without neurodevelopmental disability at 21 months). However, therapy with caffeine did not significantly reduce the combined rate of academic, motor, and behavioral impairments at 5 and 11 years but was associated with a reduced risk of motor impairment ( ; ; ). In spite of these data, long-term cellular and molecular effects of caffeine on brain development in the setting of prematurity are unknown ( ).

A recent review and meta-analysis noted (observational studies, low quality of evidence) a significant benefit of early treatment (less than 3 days of age) in decreasing the risk for BPD ( ). Similarly, at follow-up at 11 years (CAP study), expiratory flow rates in those treated with caffeine were higher compared with the control group. That is, fewer children (11%) in the caffeine group had FVC below the fifth percentile compared with those who received placebo (28%) ( ). Although some have recommended higher doses of caffeine, no clear-cut advantages have been identified ( ). Discontinuing caffeine may be timed to when an infant no longer has clinically significant apnea/bradycardia and is weaned from positive pressure for 5 to 7 days or at 33 to 34 weeks’ PMA, whichever comes first ( ; ).

AOP should be differentiated from other breathing patterns of the newborn. For example, periodic breathing is a common physiologic pattern that includes short pauses in respiration interspersed with high-frequency ventilation attributed to discoordination in the feedback control mechanisms of the respiratory control center. It generally resolves by 1 month of age in the term neonate ( ; ).

Apnea associated with anesthesia and surgery in the preterm, term, and ex-premature infant remains a controversial topic with “more questions than answers” ( ) and, over the last 30 years, little new evidence-based data has been acquired to develop specific guidelines for time of surgery, optimal anesthetic agents, and predictors for perioperative complications ( ). The “historical risk” in ex-preterm infants ( Fig. 27.4 ) ranges from 5% to 49% ( ; ; ; ). However, more recently, a randomized controlled trial reported that overall the incidence of apnea (0 to 12 hours) was similar in ex-premature infants less than 60 weeks postconceptual age who underwent inguinal hernia repair under regional anesthesia (3%) compared with the group who received general anesthesia (4%). In this study, the incidence of early apnea (0 to 30 minutes) was higher in the general anesthesia group (3%) compared with the regional anesthesia group (1%) ( ). Consistent with earlier data, this study confirmed that, although the incidence is low, life-threatening apnea occurs in both the PACU and later on the ward. This data is consistent with a Cochrane review that found insufficient evidence to recommend regional anesthetics in place of general anesthesia ( ).

Although most experts have emphasized the critical relevance of gestational and postconceptual age in analyzing perioperative risk, comorbidities also deserve scrutiny. In a study that compared two groups—<45 weeks’ postconceptual age vs. those between 45 to 60 weeks—infants younger than 45 weeks’ PCA were more prone to apnea (4.7%) than the older 45- to 60-week PCA infants (0.8%). However, comorbidities created a predisposition to apnea. Specifically, in the absence of comorbidities, no patients in the older group encountered apnea ( ).

Developmental physiology airway

Anatomy of the head and neck of the newborn present challenges for managing the airway ( ). Differences in nasal and airway morphology significantly affect the pressure drop across the airway, which determines distribution of water (inspired humidified gases) and bronchodilators during breathing ( ).

In the past, the larynx of those younger than 5 years old was described as cone shaped, rather than cylindrical ( ). However, this concept has been challenged ( ; ). These studies suggest that the shape of the newborn and young infant’s larynx is cylindrical like that of an adult’s. Although the true vocal cords are the narrowest point in both adults and infants, the functionally narrowest point of the upper airway in newborns is the fixed cricoid ring. The cricoid ring is “unyielding,” whereas the vocal cords are somewhat distensible ( ).

In adults, the diameter of the inlet and outlet of the cricoid ring are similar. In young infants the posterior tilt of the cricoid lamina results in an oval inlet and a circular outlet. Thus the posterior larynx is more cephalad than the anterior larynx, and when looking from above, the rigid cricoid ring is slightly elliptical and not circular ( ). By 5 years of age, the posterior larynx descends, the cricoid ring is circular, and the vocal cords are now functionally the narrowest portion of the airway. Compared with later in life, these anatomic differences place the neonatal larynx in a more cephalad position.

Although relatively large compared with older age groups, the newborn’s epiglottis is a small structure. Repeated attempts to lift the epiglottis with a laryngoscope blade can cause injury. In the newborn, a straight laryngoscope blade can be used like a curved blade by placing the tip into the vallecula and then pulling up and out at a 45-degree angle to view the glottic opening. The cephalad larynx and a relatively large tongue contribute to difficulty maintaining an airway during bag-and-mask ventilation and tracheal intubation. The neonate’s large occiput naturally places the head (when looking straight forward) in the “sniffing” position (the optimal position for ventilating the lungs and intubating the trachea). Both extension and flexion of the head interfere with establishing a clear view of the larynx. A small jaw (micrognathia) or receding jaw (e.g., Pierre-Robin sequence, Treacher-Collins syndrome) may make it difficult or impossible to directly visualize the vocal cords. A large tongue (hypothyroidism, Down syndrome, or Beckwith-Wiedemann syndrome) can also contribute to a difficult or impossible oral tracheal intubation. Techniques other than direct laryngoscopy may be required to intubate the trachea of these infants (see Chapter 4 : Airway Physiology and Development and Chapter 19 : Normal and Difficult Airway Management) ( ).

With or without a cleft palate, cleft lip occurs in 1:600 to 1:1000 live births (1:500 in Asians, 1:1000 in white Americans, and 1:2500 in African Americans) and is associated with other congenital defects in 13% to 50% of patients (see Chapter 35 : Anesthesia for Plastic Surgery) ( ; ). The distorted external anatomy caused by a cleft lip may impede the usual positioning of the laryngoscope during intubation that is necessary to gain a clear view of the glottis, as the tongue may flop over the laryngoscope blade and block the view of the glottis.

Choanal atresia occurs in 1:7000 to 1:8000 live births and is often diagnosed in the delivery room when a catheter cannot be passed through a nostril into the pharynx. In some cases, especially when the mouth is closed, the newborn cannot breathe secondary to obstructed nasal passages, leading to apnea, cyanosis, and bradycardia ( ). Often an oral airway allows effective ventilation with a bag-mask. The incidence of a difficult airway in a newborn with bilateral choanal atresia approaches 30% ( ). Some patients who have choanal atresia have the CHARGE association: C, colobomatous malformation; H, heart defect; A, atresia choanae; R, retardation; G, growth deficiency/genital hypoplasia; and E, ear anomalies ( ).

Hemangiomas, lymphangiomas, and hygromas of the neck can produce airway obstruction. Ultrasound or MRI images of the fetus during pregnancy may reveal the extent of the airway lesions. A multidisciplinary evaluation should occur prior to delivery to determine whether an ex-utero intrapartum therapy (EXIT) procedure is needed for delivery to secure the airway ( ; ) (see Chapter 29 : Fetal Surgery). Once the infant is born, repeat imaging may be needed to further define the anatomy and the risk for an airway crisis, such as during surgery and general anesthesia. Unanesthetized patients with these lesions may sustain spontaneous ventilation without airway obstruction, but the same patient may have severe obstruction during general anesthesia. In addition, these lesions may prevent direct visualization of the larynx. Patients with laryngeal or tracheal hemangiomas are of special concern because injuring the hemangioma during tracheal intubation may produce hemorrhage and airway obstruction and aspiration of blood.

Fortunately, most infantile hemangiomas are localized and benign and do not involve the airway or major organs. These hemangiomas commonly enlarge over the first 5 to 6 months of life and then regress. Although first-line treatment includes propranolol, further laser treatment or surgery may be necessary ( ). Larger, segmental lesions are sometimes associated with multifocal anomalies. For example, in addition to h emangiomas, the neurocutaneous syndrome, PHACES, includes malformations in the p osterior fossa, c ardiac/ a ortic coarctation and e ye anomalies, and s ternal defects. Of importance, a risk for progressive neurovascular disease is increased secondary to the anomalous vasculature ( ; ; ). In most cases, extensive imaging to delineate the extent of the disease and to monitor response to therapy (e.g., propranolol) is recommended. If the patient has respiratory distress or stridor, an LMA or endotracheal tube may be indicated. In these cases, the advantages of imaging that requires invasive support of the airway must be weighed against the risks secondary to possibly traumatizing a lesion. Especially in the patient with respiratory distress, a pediatric otolaryngologist should be consulted before considering general anesthesia.

The pulmonary system

The pulmonary system is arguably the most sensitive organ system to the effects of prematurity. An understanding of the embryologic development of the pulmonary system, as well as normal and abnormal neonatal pulmonary physiology, is important to the anesthesiologist. The impact of interventions such as oxygen delivery, continuous positive airway pressure (CPAP), and mechanical ventilation are essential to understand in order to minimize further pulmonary injury during anesthetic care.

Development

Lung development is divided into the following five stages ( Fig. 27.5 ):

• 1.

  The embryonic stage (weeks 4 to 6 of gestation), when early upper airways appear.

• 2.

  The pseudoglandular stage (weeks 7 to 16), when the lower conducting airways form.

• 3.

  The canalicular phase (weeks 17 to 28), when acini and capillaries develop.

• 4.

  The saccular phase (weeks 28 to 36), when the first respiratory units for gas exchange (terminal air sacs and surrounding capillaries) make their appearance.

• 5.

  The alveolar phase, when alveoli develop.

The latter stage begins at about 36 weeks’ gestation and continues until at least 18 months of age ( ; ; ; ). Knowledge of these phases of lung development allows for the estimation of when various lung malformations occur in utero. For example, malformations of the conducting airways (e.g., cystic adenomatoid malformation) occur before 16 weeks’ gestation. Upper airway abnormalities occur by 6 weeks’ gestation, bronchial malformations between 6 and 16 weeks of gestation, and lung hypoplasia after 16 weeks’ gestation. In general, extrauterine viability increases after 26 weeks’ gestation because the respiratory saccules have developed, and the capillaries are in close approximation to the developing distal airways. Before this time, both the vascular network and the surface area of the lungs may be inadequate for gas exchange. Surprisingly, some infants born after only 24 to 25 weeks’ gestation have minimal pulmonary symptoms at birth. Others have severe lung disease that is often exacerbated by the interventions used to treat respiratory insufficiency (e.g., mechanical ventilation, elevated inspired oxygen concentrations). In general, infants who survive after only 23 to 25 weeks’ gestation incur severe lung injury and dysfunction (see section Bronchopulmonary Dysplasia) ( ; ) with enormous effort and cost.

Most alveoli develop after birth, increasing from 20 million terminal air sacs at term to about 300 to 400 million alveoli at 18 months of age ( ; ). Specific cell types are not recognized in the lung until the canalicular stage of development (17 to 28 weeks’ gestation). The alveolar-capillary barrier is formed by type I pneumocytes (see Chapter 3 : Respiratory Physiology in Infants and Children). Type II cells contain osmophilic lamellar bodies that secrete surface-active material (SAM) ( ; ; ). The lamellar bodies and enzymes required for synthesis and secretion of SAM are present between 23 and 24 weeks’ gestation ( ; ) but are more commonly identified during the last 10% to 20% of gestation. In preparation for birth, SAM is normally secreted into the alveoli at 34 to 36 weeks of gestation.

Because the main-stem bronchi, conducting airways, and terminal bronchioles are formed by 18 weeks of gestation, mechanical ventilation, CPAP, or the use of supplemental oxygen may cause irreparable injury to these structures in extremely premature infants. The barotrauma, oxidative stress, and inflammatory/infectious injury associated with these life-saving interventions frequently interfere with lung and airway development, predisposing these infants to long-term abnormal airway resistance and reactivity ( ; ) (see section Bronchopulmonary Dysplasia).

The central two-thirds of the diaphragm arise from the third through fifth cervical somites. Myoblasts from these somites migrate into the septum transversum to form diaphragmatic muscle ( ). The central tendon of the diaphragm arises from the mesoderm of the septum transversum. Somites of the chest wall migrate inward to form the lateral portions of the diaphragm. The nerve supply of the diaphragm also arises from the third through fifth cervical somites. Located lateral to the developing diaphragm are the bilateral pericardioperitoneal canals that, when they fail to close, are the site of a Bochdalek diaphragmatic hernia. Complete closure of the diaphragm normally occurs at 10 to 12 weeks’ gestation. At this time the bowel is also returning to the abdominal cavity from the amnion. If the diaphragm is incompletely formed, the returning bowel follows the path of least resistance and enters the chest. As a consequence, lung growth ceases on the ipsilateral side. The bowel and abdominal organs now residing in the chest push the mediastinum into the opposite chest, which reduces growth of that lung. However, a defect in lung development may also affect lung growth as well as lung vascular development in these patients ( ). Regardless of the underlying cause, infants born with left-sided diaphragmatic hernias must survive with approximately two-thirds (or less) of one lung. In some cases, these infants have insufficient lung for survival (see Chapter 28 : Anesthesia for General Surgery in the Neonate).

Tracheoesophageal fistulas (TEFs) are caused by failure of the lung buds to separate from the foregut (see Chapter 28 : Anesthesia for General Surgery in the Neonate). The usual TEF (Gross type C) includes a connection between the distal esophagus and trachea that usually is located just above the carina. Esophageal atresia occurs when the distal and proximal ends of the esophagus fail to connect.

The early postnatal period

Pulmonary blood flow

During late gestation, the pulmonary vascular resistance (PVR) is approximately five times higher and the pulmonary arterial pressure three times higher than in term newborns. At the same time, fetal pulmonary arterial blood flow is only 25% (lambs) ( ) to 50% (humans) ( ) of that of newborns. Because the Pa o ₂ of pulmonary arterial blood is low (~18 mm Hg, Sa o ₂ ~50%) in utero, the pulmonary vessels are constricted, which limits blood flow to <10% of combined cardiac output. PVR rapidly decreases after birth and normally reaches adult levels by 6 to 8 weeks of extrauterine life. Although the fetal PVR decreases during maternal hyperoxygenation late in the third trimester of pregnancy, the pulmonary vasculature of a midgestation fetus is much less responsive to oxygen ( ; ). Consequently, the pulmonary vascular response to oxygen of infants born during the second trimester may be blunted.

Labor reduces PVR by approximately 10%, but the onset of breathing is responsible for most of the decrease ( ). Lung expansion and the transition from a fluid-filled to gas-filled structure at birth increases alveolar and arterial P o ₂ , which dilates the pulmonary arterioles, decreases PVR, and increases pulmonary blood flow ( ). These changes in PVR and blood flow are critical for converting the circulation from the fetal to the adult pattern ( ) (see section Transitional Circulation). A variety of vasoactive agents (endothelium-derived nitric oxide, prostacyclin, endothelin-1, platelet-activating factors) also contribute to this complex process by decreasing PVR and increasing pulmonary blood flow postnatally. Persistent pulmonary hypertension can occur with underdevelopment (as seen in congenital diaphragmatic hernia (CDH), congenital pulmonary airway malformation (CPAM), and intrauterine growth restriction (IUGR)), maldevelopment (as seen in meconium aspiration syndrome or premature closure of the PDA), or maladaptation (as seen in pulmonary parenchymal diseases or pneumonia) ( ). Infants with some types of cyanotic congenital heart disease or large left-to-right shunts may maintain elevated PVRs for months or longer ( ).

The increased arterial oxygen tension at birth constricts and physiologically closes the ductus arteriosus of full-term but not of preterm neonates ( ). Prostaglandins and prostacyclin also reduce flow through the ductus arteriosus ( ; ). The oxygen saturation during the first 10 minutes of life increases from approximately 70% to 99% in the normal full-term infant ( Table 27.2 ).

TABLE 27.2

Comparison of SpO ₂ Values from the 1st to the 10th Minute After Birth for Full-Term Births

Lu, Y.-C., Wang, C.-C., Lee, C.-M., et al. [2014]. Revaluating reference ranges of oxygen saturation for healthy full-term neonates using pulse oximetry. Pediatr Neonatol, 55 (6), 459–465. IQR, Interquartile range.

Time After Birth	SpO 2 , Median (IQR – interquartile range), % All infants
1st min 2nd min 3rd min 4th min 5th min 6th min 7th min 8th min 9th min 10th min	67 (59–78) 75 (65–84) 83 (74–87) 89 (82–94) 94 (86–96) 96 (91–97) 97 (91–98) 98 (95–99) 98 (96–99) 99 (97–99)

Ventilation

In utero, the lung produces about 4 mL/kg/hour of a filtrate of interstitial fluid that fills the lungs ( ) and is essential for normal lung growth and development. The volume of fluid in the lung decreases from about 25 mL/kg to 18 mL/kg before the onset of labor ( ) and then decreases further during labor.

Transition to an air-filled lung begins with the first active inspiration. This produces a negative intrapleural pressure of 80 to 100 cm H ₂ O, which is required to overcome the high surface tension, low compliance, and high resistance of the fluid-filled lungs ( ). In term infants, clearance of lung fluid is usually complete within 4 hours of birth ( ). Transport of sodium through epithelial sodium channels is the principle mechanism for reabsorption of fetal lung fluid ( ). Delayed removal of lung fluid (e.g., with cesarean section) may lead to transient tachypnea of the newborn (TTN) ( ; ; ), characterized by tachypnea (60 to 150 respirations per minute) and, in some cases, hypoxemia and hypercarbia. The incidence of TTN following cesarean section is approximately twice that of infants born vaginally ( ; ). Following cesarean section, CPAP can alleviate the symptoms of TTN ( ). The volume of the initial few spontaneous breaths taken by full-term neonates ranges between 20 to 80 mL. A small fraction of this volume is expired. Gas remaining within the lungs forms the residual volume (RV) and FRC, which are necessary for adequate gas exchange and for reducing PVR.

Establishing normal pulmonary blood flow and ventilation increases both arterial and mixed venous oxygen tensions. However, the Pa o ₂ usually ranges between 65 and 85 mm Hg, which is lower than that of normal older infants, children, and adults (95 to 100 mm Hg) ( ). In part, the lower Pa o ₂ results from a compliant, cartilaginous neonatal chest wall that does not recoil outward at end expiration as it does in older children and adults ( ; ). Failure to recoil outward produces a transpulmonary (intrapleural) pressure of 0 cm H ₂ O—not the −5 cm H ₂ O pressure characteristically present in older infants, children, and adults. Because a negative intrapleural pressure is important for maintaining a normal FRC, newborns are predisposed to atelectasis and a lower Pa o ₂ . In fact, applying sufficient negative pressure around the newborn’s chest to produce a pleural pressure of −5 cm H ₂ O increases the Pa o ₂ from about 65 mm Hg to nearly 100 mm Hg. The negative intrapleural pressure expands the lungs, increases FRC, reduces atelectasis, and improves the match of ventilation to perfusion ( ). Application of positive end expiratory pressure (PEEP) or CPAP also reduces atelectasis and improves oxygenation ( ).

The newborn’s compliant rib cage allows the chest wall to collapse inward (retract) during spontaneous inspiration, which causes paradoxical chest-wall motion that limits air flow ( ; ). The circular configuration of the rib cage (rather than the ellipsoid rib cage of adults) and the horizontal angle of insertion of the diaphragm (rather than the oblique angle in adults) negatively affect diaphragmatic function ( ).

Other factors also affect the infant’s work and efficiency of breathing. For example, the full-term infant’s diaphragm has 25% fatigue-resistant, slow-twitch, highly oxidative type I fibers, whereas preterm infants have only 10%. At approximately 1 year of age, infants have the adult complement of type I fibers (50% to 55%). Having a lower percentage of type I fibers predisposes the diaphragm to fatigue ( ). The intercostal muscles have a similar developmental pattern. Expression of various isoforms of the myosin heavy chains in muscle fibers of the diaphragm and the intercostal muscles of newborn and young infants may contribute to easier fatigability ( ; ), which probably contributes to the bouts of apnea so common in premature infants. Less effective force-frequency, length-tension, and force-velocity relationships and a mismatch of energy supply and demand characterize diaphragmatic muscle and predispose newborns to fatigue, especially in the face of widespread atelectasis (e.g., RDS) or poor chest wall compliance (e.g., anasarca) ( ; ). Methylxanthines (e.g., caffeine) often improve neonatal diaphragmatic function ( ).

Healthy newborns breathe 30 to 60 times per minute to maintain normal oxygenation and to remove the increased CO ₂ secondary to high oxygen consumption (6 to 10 cc/kg per minute). This respiratory rate also helps to maintain the FRC by reducing the amount of time available for expiration. At normal respiratory rates, the lung’s time constant (compliance of lungs × airway resistance [C. × R _aw ]) is about 0.25 seconds. Slow respiratory rate during mechanical ventilation or during bradypnea or apnea (e.g., narcotics) is often associated with reduced FRCs, especially in preterm neonates ( Fig. 27.6 ). Low levels of PEEP (5 to 7 cm H ₂ O) should be added to maintain the FRC of mechanically ventilated infants and young children, especially when the ventilator rates are slow.

SAM, also known as pulmonary surfactant, is of primary importance for maintaining alveoli of different diameters open. Produced by type II alveolar cells, SAM initially appears in fetal lungs at about 20 weeks’ gestation, even though no functional alveoli are present ( ). At about 35 to 36 weeks’ gestation, the amount of SAM increases and forms a monolayer on the potential gas-liquid interface. SAM is composed of 10% protein, 90% lipids, and 0.1% carbohydrates. Lipids lower surface tension; proteins allow lipids to be absorbed and dispersed in the air-liquid interface and are important for reuptake of SAM into type II cells.

During the inspiratory phase of normal breathing, SAM is spread over the alveolar surface, the monolayer thins, and the surface tension increases. During expiration, SAM is compacted, drastically decreasing alveolar surface tension, which is critical for maintaining FRC and gas exchange. SAM also stabilizes small airways and plays a role in pulmonary defense mechanisms ( ).

An additional mechanism to maintain open alveoli includes the interdependence among alveoli, small airways, and lung parenchyma. Because the alveoli are attached to each other by connective tissues, the tendency of one alveolus to collapse during expiration pulls its neighbor open ( ). In fact, millions of alveoli exerting this “pulling” effect helps to maintain FRC. Furthermore, blood-filled capillaries act as an exoskeleton for alveoli. Atelectasis can develop with inadequate pulmonary blood volume.

Thus surfactant, intraalveolar forces and pulmonary blood volume compensate for the lack of transpulmonary pressure at end expiration associated with the extremely compliant chest wall of the newborn. These factors maintain the infant’s FRC, albeit smaller (30 cc/kg) than that of adults (50 cc/kg). Positive end-expiratory pressure contributes to maintaining FRC during assisted ventilation.

Respiratory distress syndrome

An insufficient quantity of SAM leads to RDS, resulting in alveolar collapse at end expiration. Without the surface tension provided by SAM, FRC is not maintained and gas exchange is compromised. The alveoli encounter higher pressures during inspiration and collapse during expiration. Lung compliance is decreased and reopening of the alveoli from “collapse” may injure the terminal bronchioles and other small airways during both spontaneous and mechanical ventilation (see Chapter 3 : Respiratory Physiology in Infants and Children). Atelectasis, V-Q mismatch, and pulmonary inflammation lead to hypoxemia. Deficiency of SAM can be due to premature birth, delayed synthesis, or delayed release (e.g., infants of diabetic mothers).

Preterm infants have a defect in both the quantity and quality of surfactant produced and therefore are at risk for RDS ( ). Administering prenatal betamethasone prior to 36 weeks’ gestation accelerates the production and release of SAM and reduces the incidence of RDS ( ). Typical clinical features of RDS include the early onset of tachypnea; intercostal, sternal, and suprasternal retractions; grunting respirations; oxygen desaturation; respiratory and metabolic acidosis; and death if not treated. A chest radiograph reveals a diffuse reticulogranular pattern and air bronchograms ( Fig. 27.7 ). Unless SAM is administered, RDS typically worsens for 2 to 3 days until endogenous surfactant production increases, and then, in most cases, the respiratory status improves. In some cases, respiratory function deteriorates because of prolonged ventilatory support, oxygen toxicity, sepsis, renal or hepatic failure, or CNS injury.

In the past, preterm infants were intubated and given a dose of surfactant after delivery, but current data do not support this as a first-line intervention for newborns with RDS. Instead, to initially stabilize such infants, gentle respiratory support that reduces or prevents atelectasis is introduced, with intubation and administration of surfactant reserved for infants with persistent hypoxemia, apnea, or acidosis ( ; ). This approach, supported by the American Academy of Pediatrics (AAP), the American Heart Association (AHA), the International Liaison Committee on Resuscitation (ILOR) guidelines, and the European Consensus Guidelines ( ; ; ; ), reduces the risk of bronchopulmonary dysplasia (BPD), which is the main long-term complication associated with RDS, often seen following endotracheal intubation and mechanical ventilation ( ). Alternative methods of surfactant delivery, including as a nebulized solution as well as delivery of surfactant via a supraglottic airway, have been shown to be effective. However, these routes have not yet been directly compared with endotracheal intubation ( ; ).

In spite of the dramatic changes in clinical care over the past 2 to 3 decades, the incidence of bronchopulmonary dysplasia has declined only slightly ( ). However, the new BPD that develops in the ELBW infant differs from classic BPD (see section Outcomes of Ex-Premature Patients After Neonatal Pulmonary Injury) ( ; ). The persistence of BPD despite surfactant suggests that other factors besides SAM deficiency contribute to BPD ( ).

During preoperative evaluation of a newborn with RDS, the role of SAM in the current ventilatory status should be determined (e.g., number and timing of doses). If progressive atelectasis, worsening blood gas values, and/or increased oxygen or ventilator requirements (unrelated to the need for surgery—e.g., abdominal distension) are noted, administering an additional dose of SAM should be discussed with the neonatologists.

Oxidative injury in the newborn

Although the role of oxygen in retinopathy of prematurity (ROP) is well established, the role of oxygen toxicity to other organs, even in the more mature newborns, is increasingly recognized. Reactive oxygen species (ROS) are generated with hyperoxia; newborns are particularly prone to ROS because of their limited antioxidant defense systems ( ). The severity of BPD has been correlated with the extent of oxygen exposure. Oxygen-induced injury to the heart, brain, and kidneys has been reported following neonatal resuscitation with supplemental oxygen ( Table 27.3 ) ( ; ; ). Current literature supports targeting an oxygen saturation of 90% to 95% in the neonatal period, as lower targets (85% to 89%) have been associated with higher risk of death and necrotizing enterocolitis. Data about the risk for ROP remain controversial (see sections Outcomes of Ex-Premature Patients After Neonatal Pulmonary Injury and Outcome of Ex-Premature Patients After Neonatal Neurologic Injury) ( ; ; ).

TABLE 27.3

Neonatal Diseases Related to Oxygen Supplementation and Oxidative Stress

Source: Kayton, A., Timoney, P., Vargo, L., & Perez, J. A. (2018). A review of oxygen physiology and appropriate management of oxygen levels in premature neonates. Adv Neonatal Care, 18 (2), 98–104.

Condition	Characteristics
Retinopathy of prematurity 16 , 20	Primarily occurs in premature infants Abnormal vascularization of the retina Range of vision impairment, including blindness Goal of oxygen therapy; avoid high oxygen saturation levels and alternating hypoxia/hyperoxia
Chronic lung disease or bronchopulmonary dysplasia 16 , 17 , 21-23	Involves all tissues of the developing lung Develops in stages Associated with prolonged use of supplemental oxygen at high concentrations (80%–100%), suggesting a pathogenic role of ROS Other factors also may be involved in pathogenesis
Intraventricular hemorrhage 24	Serious and complex neurologic disorder High mortality and morbidity with cognitive disability and cerebral palsy Enhanced oxidative stress Gene studies implicate inflammatory, coagulation, and vascular pathways; also environment
Periventricular leukomalacia 17 , 25	Associated with sustained hyperoxia and formation of ROS Major precursor for adverse neurologic outcomes
Cancer 26-28	Increased incidence among neonates resuscitated with oxygen for >3 min Lymphatic leukemia is the most common cancer type (consistent with age group)

ROS, reactive oxygen species.

Retinopathy of prematurity is a disorder of retinal vascularization that can lead to severe visual impairment. Because retinal vessels grow radially outward from the center of the optic disc from about 16 to 40 weeks’ gestation, the retina of the premature newborn is incompletely developed ( ). The incidence of ROP correlates with intrauterine growth restriction, and inversely with gestational age; 30% to 45% of infants born at less than 28 weeks develop ROP ( ; ).

Although ROP is a multifactorial disease, prematurity and oxygen (hypoxia and hyperoxia) are clearly associated with its development (see also Chapter 37 : Anesthesia for Ophthalmic Surgery). Human retinal blood vessels develop normally in a “hypoxic” intrauterine environment (oxygen tensions of 25 to 30 mm Hg). In this environment, hypoxia-inducible factors (HIFs) and various growth factors (e.g., insulin growth factor [IGF-1], vascular endothelial growth factor [VEGF]) are produced. When the Pa o ₂ of premature infants increases to 55 to 85 mm Hg after birth, normal retinal vascularization is delayed. Removal of the placenta and amniotic fluid eliminates a rich source of IGF-1, which is required for VEGF to have its maximal effect. Phase I of ROP occurs between 30 and 32 weeks’ gestation and is characterized by both inhibition of growth and loss of retinal vessels. Phase II ROP evolves at 32 to 34 weeks’ gestation when the avascular and therefore hypoxic retina stimulates expression of various growth factors (e.g., VEGF). Oxidative damage also contributes to this process ( ). The retina responds to these factors with overgrowth of abnormal vessels that includes fibrous bands that extend to the vitreous gel and lens, which can lead to retinal detachment ( ; ; ). The specific “dose” of oxygen (saturation, Pa o ₂ ) that increases the risk for ROP is not clear ( ; ; ).

The cardiovascular system

Transitional circulation

The umbilical vein enters the hilum of the liver where it divides into three branches: vessels that provide flow directly to the left lobe, a large arcuate branch that joins the portal vein to supply the right lobe, and the ductus venosus that proceeds cephalad to join the inferior vena cava ( Fig. 27.8 ). Umbilical venous blood flowing into the inferior vena cava is preferentially directed across the foramen ovale into the left atrium and then the left ventricle. Thus highly oxygenated blood exits the placenta, bypasses the liver, and flows directly to the myocardium and brain. Desaturated blood from the superior vena cava and the abdominal vena cava enters the right atrium and ventricle and then returns to the placenta after crossing the ductus arteriosus to enter the descending aorta and eventually the umbilical arteries. A variety of anatomic features of the atrial septum (e.g., crista dividens, eustachian valve) and the angle of entry of the ductus venosus into the inferior vena cava facilitate this preferential streaming ( ).

The hallmarks of the fetal circulation include increased pulmonary vascular resistance (PVR), decreased pulmonary blood flow, decreased systemic vascular resistance, and blood flow from right to left through a patent ductus arteriosus (PDA) and the foramen ovale ( Fig. 27.9 ) ( ) (see Chapter 5 : Cardiovascular Physiology). Thus, in utero, flow to the heart is derived both from the systemic and placental circulations. Because the cardiac output is distributed to the fetal organs and the placenta from both the right and left ventricles, the term “combined ventricular output” (CVO) more accurately describes the fetal cardiac output. In late gestation (sheep), the output from the right ventricle (300 mL/kg/min or 66% of the CVO) is double that from the left ventricle (150 mL/kg/min or 33% of the CVO) ( ). Estimated by Doppler ultrasound, the CVO in humans is similar (410 to 503 mL/kg/min) ( ), with at least one study suggesting that the output from the right (approximately 59%) compared with the left (approximately 41%) remains stable throughout gestation ( ). Other experts have reported changes in the relative output of each ventricle throughout gestation, with more closely matched output early in gestation, until near term when, similar to the sheep, the right ventricular output doubles that of the left ventricle ( ). Although lower than postnatally, pulmonary blood flow increases from approximately 13% (midgestation) to 25% (30 weeks’ gestation) of the combined ventricular output; the pulmonary vascular resistance decreases 1.5-fold between 20 to 30 weeks’ gestation ( ). At the same time, in both sheep and humans, the responsiveness of the pulmonary vascular bed to both hypoxia and hyperoxia increases in late gestation ( ; ).

At birth, after eliminating the placental circulation and with the onset of breathing, pulmonary blood flow increases dramatically as PVR decreases ( ). The increased pulmonary blood flow raises both the volume returning to and pressure of the left atrium, which closes a flap valve, functionally eliminating the right-to-left shunting of blood through the foramen ovale. Simultaneously, systemic vascular resistance increases, contributing to eliminating right-to-left flow not only through foramen ovale but also via the ductus arteriosus. In healthy term infants, some bidirectional shunting through the ductus arteriosus may continue for the first 24 to 48 hours of extrauterine life. Normally, the ductus arteriosus closes anatomically after several days. If the ductus arteriosus fails to close after birth, blood flow into the pulmonary circulation increases due to left-to-right shunting (i.e., postnatal higher SVR and lower PVR) and may cause congestive heart failure, especially in the premature infant. After the ductus arteriosus and foramen ovale close and as the PVR decreases and SVR increases, distinct and separate pulmonary and systemic circulations exist, and the anatomic transition to the adult circulation is established. Of note, physiologic transition to the adult state is gradual. For example, compared with the adult, pulmonary vascular resistance of the infant remains high for at least the first 2 months of postnatal life ( Fig. 27.10 ). Blood pressure, heart rate, and cardiac output mature more gradually over the first 1 to 2 years of life.

Because of the higher and more reactive pulmonary vascular resistance of the newborn compared with the adult, during the early postnatal period arterial hypoxemia, acidosis ( Fig. 27.11 ), or exposure to cold may abruptly increase the pulmonary vascular resistance further, inducing the circulation to revert to the fetal pattern of blood flow. That is, high pulmonary vascular resistance increases right atrial and pulmonary arterial pressures, which reestablishes the right-to-left shunting of deoxygenated blood through the foramen ovale and ductus arteriosus, decreasing pulmonary blood flow ( ). This return to the fetal circulatory pattern, known as persistent fetal circulation or persistent pulmonary hypertension of the newborn (PPHN), further exacerbates the initial hypoxemia and may worsen acidosis ( ).

Although a variety of mediators and factors; receptors; and neurologic, endocrine, and vascular control mechanisms interact to regulate the pulmonary circulation ( ; ), nitric oxide (NO) seems to play a critical role in mediating the vasodilating effect of oxygen ( ) via the (NO)-cyclic guanosine monophosphate pathway ( ). In addition, the prostacyclin-cyclic adenosine monophosphate pathway also contributes to maintaining predictable pulmonary vascular function ( ). Both systems mediate this activity by decreasing the concentration of intracellular calcium. Other less well-defined systems (e.g., oxygen-sensitive K ⁺ channels in pulmonary vascular smooth muscle) ( ) also influence the complex activities of the pulmonary circulation.

PPHN may be an isolated phenomenon or associated with a variety of clinical conditions, including hypoxemia/acidosis/severe hypotension (e.g., birth asphyxia), meconium aspiration, sepsis, polycythemia, and diaphragmatic hernia ( ). The disorder has been divided into three types: maladaptation (structurally normal but abnormally constricted vessels due to parenchymal disease such as meconium aspiration, respiratory distress syndrome, pneumonia); maldevelopment (excessive muscular development in the pulmonary vessels); and underdevelopment (hypoplasia, as with congenital diaphragmatic hernia) ( ). An echocardiogram is routinely performed in infants manifesting signs and symptoms of persistent pulmonary hypertension to definitively exclude structural cyanotic heart disease ( ; ).

Higher oxygen tension and expansion of the lungs at the onset of breathing directly decrease PVR and increase pulmonary blood flow. The shear stress associated with increased blood flow distends the vessels, flattening the endothelium and smooth muscle cells; this promotes the release of various mediators ( ). The balance between the effects of vasodilators (e.g., nitric oxide and prostacyclin) and vasoconstrictors (e.g., ET-1 and leukotrienes) determines pulmonary blood flow. The primary treatment of PPHN includes hemodynamic support by maintaining intravascular volume, initiating inotropic support (especially if PPHN is associated with sepsis or asphyxia), correcting acidosis and electrolyte disturbances, and administering antibiotics when appropriate. Ventilatory strategies have moved away from hyperventilation (pH >7.5) and hyperoxia to “gentler approaches” with conventional or, when needed, high-frequency mechanical ventilation. Vasodilatory agents (e.g., nitric oxide, sildenafil, and other agents) are often administered, with protocols and results varying among institutions. Treatments for PPHN have included nitric oxide, phosphodiesterase inhibitors, PDE5, PDE3, prostacyclin, and vasoconstrictor antagonizing agents (see Fig. 27.12 ).

For more information, see the section Nitric Oxide at Chapter 27 online.