In the absence of inborn metabolic dysfunction or birth trauma, the neonate is able to meet their physiologic needs when not under stress. However, neonatal physiology is characterized by decreased functional reserve. Increased physiologic demands may place a significant burden on organ systems that have not yet developed normal adult functional reserve.
Neonatal Physiology
Neonatal oxygen consumption is approximately 6 mL/kg per minute compared to 3 mL/kg per minute in the adult. The high metabolic rate of the neonate is the crucial determinant of cardiopulmonary function. Even under normal physiologic circumstances, the immature cardiac and respiratory systems operate near the edge of their functional reserve to support this metabolic demand. Immaturity of multiple neonatal organ systems creates important developmental differences in drug handling and response when compared to the older child and adults.1
Neonatal Cardiovascular Physiology
The newborn infant is in a state of transition from the fetal, intrauterine to the newborn, extrauterine circulatory pattern. As described in Chapter 45, the fetal circulation is characterized by high pulmonary vascular resistance, low systemic vascular resistance (including the placenta), and right-to-left cardiac shunting via the foramen ovale and ductus arteriosus. Expansion of the lungs at birth increases PO2 and causes a rapid decline in pulmonary vascular resistance and an increase in pulmonary blood flow. The decrease in pulmonary vascular resistance at birth is mediated by the endogenous production of nitric oxide. Increasing blood return to the heart via the pulmonary veins raises the pressure of the left atrium above that of the right, causing a functional closure of the foramen ovale. Anatomic closure of the foramen ovale usually occurs between 3 months and 1 year of age, but the foramen remains anatomically patent in 10% to 30% of people throughout life.2 These individuals are described as having a “probe patent” foramen ovale, meaning that a probe or other surgical instrument can be passed through the foramen ovale. In most of these individuals, the foramen is functionally closed by the lack of any significant pressure gradient between the left and right atria; however, in conditions where the pulmonary vascular resistance rises, significant right-to-left shunting can occur. Individuals with a probe patent foramen ovale are also at risk for systemic air embolism and resultant stroke when air emboli pass from the pulmonary to the systemic circulation. The functional closure of the ductus arteriosus is, in part, mediated by an increase in arterial oxygen partial pressure and is normally complete within the first 10 to 15 hours of life in the term neonate. However, anatomic closure does not occur until 2 months of age.
Because the foramen ovale and ductus arteriosus are only functionally closed in the neonatal period, the neonatal circulation is able to readily revert to the fetal pattern, particularly in response to physiologic stresses occasionally encountered in the perinatal period. The neonatal pulmonary circulation is very reactive. Hypoxemia, hypercarbia, or acidosis cause both pulmonary vasoconstriction and dilation of the ductus arteriosus. Increases in pulmonary vascular resistance result in right-to-left shunting across the foramen ovale and ductus arteriosus. Right-to-left shunting, by causing arterial hypoxemia, causes a further increase in pulmonary vascular resistance, thus creating a vicious cycle. Persistent pulmonary hypertension may be seen in premature neonates and those with diaphragmatic hernia, meconium aspiration, infection, congenital heart disease, and polycythemia.
The neonatal myocardium contains immature contractile elements and is less compliant than the adult myocardium. The Frank-Starling relationship is functional only within a very narrow range of left ventricular end diastolic pressure (Fig. 44-1).3 Thus, there is a limited increase in cardiac output to be gained from aggressive volume loading in the normovolemic newborn. However, if preload is reduced by hypovolemia or dehydration, normalization of volume status will generally restore cardiac output. However, because stroke volume cannot be significantly augmented by volume loading, and because contractile reserve is limited, neonatal cardiac output is exquisitely dependent on heart rate.
Although adrenergic receptors are thought to be mature at birth, sympathetic innervation is incomplete. After birth, neurotransmitter concentrations increase progressively, reflecting the maturation of sympathetic innervation. When compared to the adult, neonatal myocardium is more sensitive to norepinephrine.4 This phenomenon is a reflection of the relatively denervated status of neonatal myocardium. Dopamine is an indirectly acting inotrope that depends, in part, upon endogenous norepinephrine release for its action. Neonatal myocardium, being deficient in sympathetic innervation, is therefore less responsive to dopamine.
To meet the elevated metabolic demand, neonatal cardiac output, relative to body weight, is twice that of the adult. This is achieved with a relatively rapid heart rate (140 beats per minute) because as described earlier, stroke volume cannot be significantly increased. The neonatal circulation is characterized by centralization (increased peripheral vascular resistance and distribution of cardiac output primarily to vital organs), a situation comparable to an adult in compensated shock. Because neonatal baroreflex activity is impaired, the response to hemorrhage produces little increase in heart rate or change in total peripheral resistance. Thus, even a modest (10%) reduction in blood volume will cause a 15% to 30% decrease in mean blood pressure in the newborn infant. The structural and functional immaturity of the neonatal cardiovascular system severely limits the reserve that is available in the face of common perinatal and perioperative events such as hypovolemia, anesthetic-induced depression of contractility, relative bradycardia and positive pressure ventilation–induced decreases venous return. The marginal cardiovascular reserve of the neonate and leftward shift of the fetal hemoglobin dissociation curve are the rationale underlying the recommendation that the hematocrit be maintained at 30% or higher to prevent tissue ischemia in the newborn.
Respiratory Physiology of the Newborn
The respiratory system of a term neonate at birth is immature and postnatal development continues through early childhood. Although the conducting airways are fully developed by 16 weeks of gestation, the number of alveoli is reduced at birth. A premature infant born at 24 to 28 weeks of gestation is just beginning to develop alveoli from the distal saccules of the lung.5 Complete alveolar maturation does not occur until 8 to 10 years of age. Thus, the ratio of alveolar surface area to body surface area is one-third that of the adult. At birth, the infant possesses approximately one-tenth of the adult population of alveoli. To satisfy increased oxygen demand, neonatal alveolar minute ventilation is twice that of the adult. Increasing respiratory rate rather than tidal volume is the most efficient means to increase alveolar ventilation in the newborn. The diaphragm is the primary muscle of respiration in the neonate but has fewer high-oxidative muscle fibers and is thus less fatigue-resistant than in the adult. Ventilation-perfusion imbalance occurs as a result of distal airway closure during normal tidal breathing in the neonate. This phenomenon is responsible for an increase in the alveolar-arterial oxygen tension gradient compared to adults.
Adequate gas exchange depends on adequate alveolar recruitment and thus surfactant function. Production of surfactant begins by 23 to 24 weeks of gestation and reaches maturity at approximately 35 weeks of gestation. Surfactant-deficient preterm infants have decreased lung compliance and are at risk for the development of respiratory distress syndrome (RDS).5 Administration of corticosteroids to mothers in preterm labor may accelerate lung maturation in the fetus. Furthermore, the instillation of intratracheal exogenous surfactant in preterm babies has considerably improved the prognosis for premature infants. Infants born to mothers with intrauterine infection have a paradoxical increase in pulmonary maturation. The enhancement in lung maturation can be mimicked with lipopolysaccharide, suggesting that the effect is due to local inflammatory mediators rather than a downstream effect of corticosteroids.6 In humans, the effect of inflammation on lung maturation is not enhanced by corticosteroid administration.7
The neonatal chest wall is more compliant and has less outward recoil than that of the adult. Thus, the neonatal lung has a greater tendency to collapse and the infant is obliged to utilize active mechanisms to maintain normal lung volumes (Table 44-1). First, by breathing at a relatively rapid rate, the duration of expiration is limited. In this way, inspiration is initiated before the lung has completed recoiling to its end-expiratory volume. Second, the neonate utilizes intercostal muscle activity during expiration to stabilize the chest wall, thus retarding the decline in lung volume during expiration. Last, the neonate exhales through a partially closed glottis, also retarding expiratory flow and maintaining end-expiratory lung volume. The awake neonate has a functional residual capacity (FRC) that is similar, when normalized to body weight, to that of an adult. However, because neonatal alveolar ventilation is twice that of an adult, the ratio of alveolar ventilation to FRC in the neonate is twice that of the adult. The high ratio of minute ventilation to FRC causes a much more rapid wash-out or wash-in of oxygen and anesthetic drugs in response to changes in inspired concentrations.
The active mechanisms utilized by the newborn to protect lung volume are exquisitely sensitive to the effects of general anesthesia. Therefore, the neonatal FRC may decrease significantly during anesthesia, particularly during periodic breathing and apnea. The combination of increased oxygen consumption and a reduced ratio of alveolar ventilation to FRC in the newborn explains why apnea and hypoventilation are associated with marked and rapid arterial oxygen desaturation.
Although the peripheral chemoreceptors are active from 28 weeks of gestation, their function is immature until several days after birth. Therefore, the neonate and preterm infant exhibit an altered response to hypoxia and hypercarbia. When challenged with hypoxic inspired gas mixtures, both the term and preterm infant have an initial 1- or 2-minute period of hyperventilation followed by sustained hypoventilation. As postnatal age increases, the hyperventilatory response becomes sustained. However, this protective response develops more slowly in the preterm infant and the ventilatory response to hypercarbia is impaired. The impaired neonatal ventilatory responses to hypoxia and hypercarbia are contributing factors to the development of life-threatening apnea and hypoventilation in the postoperative period.8
Although airway resistance is relatively low in infants, in absolute terms, the airways are very narrow. Relatively minor quantities of secretions or trivial inflammatory disease can produce serious respiratory embarrassment in small infants.
Neonatal Thermoregulation
The neonate tends to become hypothermic during general anesthesia much more rapidly than the adult. Accelerated heat loss in the neonate is related to its relatively large surface area compared to body mass, thinner layer of insulating subcutaneous fat, and a limited capability for thermogenesis. The neonate primarily relies on nonshivering or chemical thermogenesis in brown adipose tissue for heat production. Thermogenesis in brown fat is mediated by the sympathetic nervous system and is stimulated by norepinephrine, resulting in triglyceride hydrolysis. The thermoregulatory range is the ambient temperature range within which an unclothed subject can maintain normal body temperature. The lower limit of the thermoregulatory range (ambient temperature at which core temperature can be maintained) is 1¼°C for an adult, but is as high as 23°C and 28°C for the full-term infant and premature infant, respectively. Therefore, the thermoregulatory range of the neonate is much narrower than that of the adult. During anesthesia and surgery, heat loss in the pediatric patient is further enhanced by decrease in the thermoregulatory threshold due to anesthesia, low ambient temperatures of the operating suite (20°C to 22°C), preparation of skin with cold solutions, infusion of cold solutions, anesthesia-induced vasodilatation, and use of dry anesthetic gases in high flow, nonrebreathing systems. Intraoperative hypothermia will markedly delay emergence. Furthermore, with the return of the thermostatic reflexes, oxygen consumption increases by three- to fourfold as the metabolic rate is increased in an attempt to generate heat. This additional demand on an immature cardiorespiratory system that is already compromised due to the residual effects of anesthesia and surgery may precipitate cardiorespiratory failure. However, the loss of heat during anesthesia and surgery can be prevented by a number of simple measures, such as raising operating room temperature to 28°C to 30°C, radiant heat lamps, wrapping the extremities with insulating material, using nonvolatile warmed solutions for skin preparation, and administration of warmed intravenous fluids and blood products. Inhaled gases should be heated and humidified. Forced air warming devices are also effective in maintaining perioperative normothermia in neonates.
Neonatal Fluid, Electrolyte, and Renal Physiology
The neonate is characterized by an increased total body water, increased extracellular fluid volume, increased water turnover rate, and reduced glomerular filtration rate. The neonatal renal tubules have a decreased ability to absorb sodium, bicarbonate, glucose, amino acids, and phosphates. Neonates are obligate sodium wasters and require sodium supplementation. All of these factors contribute to the potential for overhydration, dehydration, metabolic acidosis, and hyponatremia, necessitating meticulous attention to intraoperative fluid therapy. Although third-space translocation of fluids is relatively similar in neonates and adults, neonatal insensible losses vary greatly. Fever, radiant warmers, phototherapy, increased ambient temperature, and decreased humidity all increase insensible loss.
Neonates have decreased glycogen stores and are prone to hypoglycemia after relatively brief periods of starvation. The preterm infant is at even greater risk for hypoglycemia. Glucose is therefore an essential element of the intraoperative fluid plan. The term neonate requires 3 to 5 mg/kg per minute and preterm neonates 5 to 6 mg/kg per minute of glucose to maintain serum glucose between 35 and 125 mg/dL.
Neonatal Neurophysiology
EEG rhythms that are mediated by subcortical integration of cortical and subcortical processes are present from 20 weeks’ gestation.9 Somatosensory evoked potentials can be recorded from the fetal cerebral cortex at 29 weeks’ gestation.10 As such, the functional circuitry required for sensation of pain is likely to be present between 20 and 30 weeks’ gestation. Although myelination is incomplete, and nerve conduction velocity may be diminished, the shorter conduction distances found in the neonate facilitate rapid transmission of nociceptive impulses to the brain.11 As in adults, most nociceptive impulses are transmitted by unmyelinated C fibers and by poorly myelinated Aδ fibers. Painful stimuli produce withdrawal, autonomic stimulation, and neuroendocrine stress responses. The concept of plasticity of the nervous system has important implications for the management of pain in newborns. The failure to provide analgesia for neonates leads to changes in nociceptive pathways in the dorsal horn of the spinal cord and in the brain. As a result, future painful insults result in exaggerated pain perception. Indeed, in human newborns, the failure to provide adequate anesthesia or analgesia for circumcision is associated with long-term changes, including an increased response to immunization later in childhood.12 The adequate treatment of pain in the neonatal period is challenging because of the fear of respiratory depression associated with opioid administration. Fortunately, several nonpharmacologic behavioral interventions have analgesic effects in infants.13 Analgesia may be induced by the administration of sucrose and by suckling. These effects are mediated via descending endogenous opioid and nonopioid mechanisms originating in the brainstem and may be partially reversed by the administration of naloxone.14
The germinal matrix has a rich blood supply, thin vessel walls, and scant vascular supporting tissue, causing the vessels of this region to be susceptible to rupture. With increasing gestational age, the germinal matrix involutes and is absent in the full-term infant. Intraventricular hemorrhage in the premature infant and in the fetus originates predominantly in the germinal matrix and occasionally in the choroid plexus. Periventricular-intraventricular hemorrhage occurs in 40% to 50% of premature infants and is a major cause of neonatal morbidity and mortality. The factors in the pathogenesis of intraventricular hemorrhage include abrupt changes in cerebral hemodynamics, changes in intracranial pressure, disturbances in osmotic equilibrium, and coagulopathy. Preterm infants are also at risk for retinopathy of prematurity (ROP) in which abnormal growth of retinal vessels can lead to scarring and blindness. Although gestational age is the primary etiologic factor in the development of ROP, hyperoxia, hypocarbia, vitamin E deficiency, and acidemia have also been implicated as contributing factors. The neonatal brain is comparatively large at birth compared to the adult. Myelination is incomplete at birth and is typically accomplished before the third year of age.
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