Gestational Age Assessment

The gestational age of an infant may be assessed in one of three ways. The most accurate means of assessing gestational age is by measuring the crown-rump length of the fetus during a first-trimester ultrasonographic examination. Another method involves calculating gestational age from the first day of the mother’s last menstrual period, but this is commonly inaccurate, leading to errors in estimation. Finally, the Dubowitz scoring system is a well-accepted method combining neurologic and physical criteria of the infant to provide an accurate assessment of gestational age.^1,2 A summary of the more significant neurologic and physical signs of maturity is presented in Table 2-3.

TABLE 2-3 Neurologic and External Physical Criteria to Assess Gestational Age

Weight and Length

Assessment of growth is measured by changes in weight, length, and head circumference. Percentile charts are valuable for monitoring the child’s growth and development. Deviation from growth within the same percentile for a child of any age is of greater significance than any single measurement (Figs. 2-1 and 2-2). Weight is a more sensitive index of well-being, illness, or poor nutrition than length or head circumference and is the most commonly used measurement of growth. Change in weight reflects changes in muscle mass, adipose tissue, skeleton, and body water and thus is a nonspecific measure of growth. Measurement of length provides the best indicator of skeletal growth because it is not affected by changes in adipose tissue or water content.

FIGURE 2-1 Postnatal growth curve (weight) for term male infants. This figure represents normal growth curves. Triangles indicate a normal child. Circles demonstrate failure to thrive in a child with severe renal failure.

FIGURE 2-2 Postnatal growth curve (weight) for preterm infants. This figure represents normal growth curves for preterm infants. Triangles indicate a normal preterm infant. Circles demonstrate failure to thrive in an infant with bronchopulmonary dysplasia.

Term infants may lose 5% to 10% of their body weight during the first 24 to 72 hours of life from loss of body water. Birth weight is usually regained in 7 to 10 days. A daily increase of 30 g (210 g/week) is satisfactory for the first 3 months. Thereafter, weight gain slows so that at 10 to 12 months of age it is 70 g each week (Table 2-4).

TABLE 2-4 Approximate Relationship of Age to Weight

When plotting the weight of a preterm infant on a growth chart, it is common to use the infant’s corrected gestational age (postmenstrual age; postconceptual age is taken from conception and is approximately 2 weeks shorter) instead of his or her chronologic age (postnatal age, i.e., from birth) during the first 2 years of the infant’s life in order to correct for prematurity.

Weight and length are important but changes affect the composition of the body itself, especially total body water, which decreases at the expense of the extracellular compartment, with adult levels attained at 1 year of age.^3,4 This finding has implications for drug dosing and distribution in the infant. Males have a greater percentage of water, whereas females have a slightly greater percentage of fat. The percentage decrease in extracellular water is greater than the decrease in total body water because of the simultaneous increase in intracellular water (Table 2-5).⁵

Another, more precise way to assess development is to calculate the body surface area (BSA).⁶

BSA can also be described using an allometric equation with an exponent of  (see Chapter 6):

Head Circumference

Head size reflects growth of the brain and correlates with intracranial volume and brain weight. Changing head circumference reflects head growth and is a part of the total body growth process; it may or may not indicate underlying involvement of the brain. An abnormally large or small head may indicate abnormal brain development, which must alert the anesthesiologist to possible underlying neurologic problems. A large head may indicate a normal variation, familial feature, or pathologic condition (e.g., hydrocephalus or increased intracranial pressure), whereas a small head may indicate a normal variant, familial feature, or pathologic condition such as craniosynostosis or abnormal brain development.

During the first year of life, head circumference normally increases 10 cm, and it increases 2.5 cm in the second year. By 9 months of age, head circumference reaches 50% of adult size, and by 2 years it is 75%. Head circumference is closely followed on standard percentile growth curves. As with weight, deviations of growth of the head within the same percentile are more significant than a single measurement.

The anterior fontanel should be palpated to assess whether it is sunken (dehydration) or bulging abnormally (suggesting increased intracranial pressure as in hydrocephalus, infection, hemorrhage, or increased partial pressure of carbon dioxide in the arterial blood [PaCO₂]). If it is bulging, the sutures should be palpated for abnormal separation as a result of increased intracranial pressure. The anterior fontanel closes between 9 and 18 months of age; the posterior fontanel closes by 2 to 4 months of age (Fig. 2-3). Cranial molding occurs particularly in LBW infants and is usually of no clinical importance.

FIGURE 2-3 Cranial development. A and B depict the skull of a neonate with wide-open suture. C and D depict the skull of a 7-year-old boy with fused sutures.

Face

Although the cranial vault increases rapidly in size, the face and base of the skull develop at a slower rate. At birth, the mandible is small; but as a child develops, forward growth occurs, reducing the obliquity of the mandibular angle. Failure of prenatal development of the mandible may be associated with severe congenital defects (e.g., Pierre Robin, Treacher Collins, or Goldenhar syndromes). These syndromes often have other associated anomalies. After 2 years of age, the cranial vault increases only marginally in size, whereas the facial configuration undergoes substantive changes. The upper jaw grows rapidly to accommodate the developing teeth. In addition, the frontal sinuses develop by 2 to 6 years of age, and the maxillary, ethmoidal, and sphenoidal sinuses appear after 6 years of age.

Teeth

The first tooth, usually a lower incisor, erupts at approximately 6 months after birth (deciduous dentition). Eruption of all deciduous teeth is usually complete by 28 months of age. Permanent teeth appear at 6 years, with the shedding of the deciduous teeth; this process takes place during the next 6 to 8 years. Abnormally developed teeth occur with hereditary disorders, Down syndrome, cerebral palsy, medications (eg., tetracycline) and nutritional defects. Preterm infants may show severe enamel hypoplasia in their primary dentition.^7,8

Comportment and Behavior

The neurologic status and social acquisition of the child are part of the development assessment and will be described later in this chapter.

Upper Airway Development

During the course of development, the infant upper airways undergo deep anatomic modifications that include changes in size, shape, and interrelationship; this is particularly prominent during the first few years of life.

The face and the nasal chamber, the oropharynx with the tongue, and the laryngotracheal lumen are the three main parts of the upper airway involved. The development of the neurocranium will lead to the maturation of the cranial vault and skull base, and the development of the viscerocranium to the skeletal part of the face. The primordial areas involved in forming the covering of the tongue appear early in the second month of development.

The larynx is developed embryologically from ectodermal, endodermal, and mesodermal tissues that are derived from the third, fourth, and sixth branchial arch and pouch apparatus. The development of the larynx and airway in the neonate is outlined in detail in Chapter 12. The laryngeal opening (epiglottis and vocal cords) in a neonate and 2-year-old boy are shown in Figure 2-4. Note the omega-shaped long epiglottis and the pearly white vocal cords in the neonate.

FIGURE 2-4 Larynx development from neonate to 2 years old. The larynx in the neonate (A and B), with the long epiglottis (A) and the vocal cords (B, close-up). The larynx in a 2-year-old (C and D), with a shorter epiglottis (C) and the vocal cords (D, close up).

The skull base grows rapidly until age 6 years, with relatively slower growth thereafter. The cranial base flexes postnatally in a rapid growth trajectory that is complete by 2 years of age.

The depth of the nasopharynx increases due to remodeling of the palate as well as changes in the angulation of the skull base. During childhood, the soft tissues of the pharyngeal structures surrounding the upper airway grow proportionally to the skeletal structures. After birth, the dimensions of the nasal cavity increase very rapidly. During the first year of life, the total minimal cross-sectional area is increased by 67%, and the volume of the anterior 4 cm of the nasal airways by 36%.⁹

The volume of the oral cavity in the neonate is proportionally less than that in the adult, owing to a significantly shorter mandibular ramus. The volume of the oral cavity significantly increases during the first 12 months because of rapid growth in the height of the mandibular ramus.

Compared with the adult, the tongue in the neonate contains considerably less fat and soft tissue, but overall is large in size relative to the dimensions of the mouth, with relatively larger extrinsic musculature and a less developed superior longitudinal muscle resulting in a flat dorsal surface with poor lateral mobility (see also Chapter 12).

Respiratory System Development

The development of the respiratory system begins during week 4 of gestation. Three “laws” that describe the temporal development of the conducting airways, alveoli, and pulmonary vessels govern normal lung growth.

Transition to Air Breathing

Fetal breathing movements have been detected as early as 11 weeks of gestational age; they are interspersed with long periods of apnea and produce little tidal movement of lung fluid.^10,11 The critical event in the change from placental to pulmonary gas exchange is the first inspiration, which initiates pulmonary ventilation, promotes the clearance of lung fluid, and triggers the change from the fetal to the neonatal pattern of circulation.

The first breath is a gasp that generates a transpulmonary distending pressure of 40 to 80 cm H₂O.¹² This moves the tracheal fluid (100 times more viscous than air), overcomes surface forces that develop as the air−fluid interface reaches the small airways, and overcomes tissue resistance. In some children, the removal of lung fluid may be delayed, producing the syndrome called transient tachypnea of the newborn.¹³ Tachypnea lasts for 24 to 72 hours and is associated with a characteristic chest radiographic appearance consisting of increased perihilar markings, fluid in the interlobar fissures, and streaky linear opacities in the parenchyma.

With the onset of pulmonary ventilation, pulmonary blood flow sharply increases. Decreased pulmonary vascular resistance (PVR) and increased peripheral systemic vascular resistance (loss of the umbilical circulation) are the two crucial events involved in the immediate transition from the fetal circulation to the normal postnatal pattern. The increase in systemic afterload causes an immediate closure of the flap valve mechanism of the foramen ovale and reverses the direction of shunt through the ductus arteriosus. Until these fetal shunt pathways close anatomically, the pattern of circulation is unstable. Increased pulmonary vascular reactivity in response to hypoxia and acidosis may precipitate a reversal to right-to-left shunting (“flip-flop” circulation).

In the first few minutes of life, a state of “normal” asphyxia exists as a result of impairment of placental blood flow during labor. The partial pressure of oxygen in arterial blood (PaO₂) and pH are low, whereas the PaCO₂ is increased immediately after birth, but these parameters change rapidly in the first hour of life. Extrapulmonary shunting through fetal channels and intrapulmonary shunting, probably through unexpanded regions of the lung, persist for some time after birth, so that in neonates the physiologic right-to-left shunt is about three times that in adults.¹⁴

Mechanics of Breathing

Total Lung Capacity

Adults have a markedly greater total lung capacity (TLC) than infants (Fig. 2-5). This difference reflects the fact that TLC is an effort-dependent parameter, depending on the strength and efficiency of the inspiratory muscles, which can be estimated by the maximum inspiratory pressure at functional residual capacity (FRC). An adult can generate negative pressures in excess of 100 cm H₂O; negative inspiratory pressures as high as 70 cm H₂O have been recorded for neonates, a surprisingly high value in view of their underdeveloped musculature and highly compliant chest wall. This may be a consequence of the small radius of curvature of an infant’s rib cage, which by the Laplace relationship converts a small tension into a large pressure difference.²¹

FIGURE 2-5 Lung volumes in infants and adults. Note that, in infants, tidal volume breathing occurs at the same volume as closing volume. CC, Closing capacity; FRC, functional residual capacity; VC, vital capacity.

(Modified from Nelson NM. Respiration and circulation after birth. In: Smith CA, Nelson NM editors. The physiology of the newborn infant. Springfield, Ill.: Charles C Thomas; 1976. p. 207.)

Functional Residual Capacity

FRC is similar on a per-kilogram basis at all ages, but the mechanical factors on which it is based are different in infants and adults.²² In adults, FRC is the same as the volume at which the elastic forces generated by the passive recoil of the chest wall are balanced by the recoil of the lung (Fig. 2-6); this is the volume attained at end-expiration with an open glottis.

FIGURE 2-6 Compliance curves for the chest wall, lungs, and thorax (combination of chest wall and lungs) in infants and adults.

(Modified and reproduced with permission from Pérez Fontán JJ, Haddad GG. Respiratory physiology. In: Behrman RE, Kliegman RM, Jenson HB, editors. Nelson textbook of pediatrics. 17th ed. Philadelphia: WB Saunders; 2003. p. 1363.)

An important clinical implication of the dynamic control of FRC is that an apneic infant has a disproportionately smaller reserve of intrapulmonary oxygen on which to draw than a similarly affected adult. This, combined with their increased metabolic rate, contributes to the rapid development of hypoxemia if the airway is lost in the anesthetized infant.

Airway Dynamics

Heart Rate

Autonomic control of the heart in utero is mediated predominantly through the parasympathetic nervous system. It is only shortly after birth that sympathetic control appears. In neonates, the heart rate may have a wide variation that is within normal limits.

In older children, a significant number of arrhythmias and conduction abnormalities are also encountered, with marked fluctuations in heart rate due to variations in autonomic tone. The mean heart rate in neonates in the first 24 hours of life is 120 beats per minute. It increases to a mean of 160 beats per minute at 1 month, after which it gradually decreases to 75 beats per minute at adolescence (Table 2-7).³²

TABLE 2-7 The Relationship of Age to Heart Rate*

^*Note that the heart rate will be lower during sleep.

Data from Hartman ME, Cheifetz IM. Pediatric Emergencies and Resuscitation. In: Kliegman RM, Stanton ST BF, Geme III JW, Schor NF, Behrman RE, editors. Nelson Textbook of Pediatrics. 19th ed. Philadelphia: Elsevier; 2011. p. 280.

Blood Pressure

Mean systolic blood pressure in neonates and infants increases from 65 mm Hg in the first 12 hours of life to 75 mm Hg at 4 days and 95 mm Hg at 6 weeks. There is little change in mean systolic pressure between 6 weeks and 1 year of age; between 1 year and 6 years, there is only a slight change, followed by a gradual increase.^33,34 These measurements apply to infants and children who are awake and quiet. The blood pressure in preterm infants in the first 12 hours is less than that in full-term infants; a gradual increase in blood pressure occurs after birth—68/43 mm Hg on day 1 of life compared with 90/55 mm Hg on day 90 of life (Table 2-8).^35,36 It has also been noted that infants with birth asphyxia and those who require mechanical ventilation have reduced blood pressures.³⁷ Blood pressure measured in the lower leg is less than in the upper arm.³⁸

TABLE 2-8 The Relationship of Age to Blood Pressure*

^*Note that the blood pressure will be lower during sleep or during anesthesia.

Data from Hartman ME, Cheifetz IM. Pediatric Emergencies and Resuscitation. In: Kliegman RM, Stanton ST BF, Geme III JW, Schor NF, Behrman RE, editors. Nelson Textbook of Pediatrics. 19th ed. Philadelphia: Elsevier; 2011. p. 280.

Blood pressure in adolescents and adults who were born preterm is greater than in those who were born full-term. However, the slower fetal growth in preterm, LBW infants was not identified as an independent predictor of this greater blood pressure later in life.³⁹

Cardiac Output

Determination of cardiac output and blood pressure allows calculation of systemic vascular resistance. It provides important information relating to the left ventricular afterload and allows rational application of vasoactive (e.g., vasoconstrictor, vasodilator) and inotropic drugs. Measurement of cardiac output may be carried out by the Fick method (using oxygen extraction) or thermodilution using a pulmonary artery flow-directed catheter. In neonates, the latter technique is rarely used because shunts at the atrial and ductal level introduce errors when interpreting the results.

Pulsed Doppler determinations of cardiac output provide reasonable noninvasive estimates of cardiac output for clinical application in neonates. Cardiac output, normalized for body weight, in neonates between 780 and 4740 g at birth, remains fairly constant, changing approximately 10% over the weight range.⁴⁰ The range of cardiac output in both full-term and preterm neonates is 220 to 350 mL/kg/min, two- to threefold greater than in adults.^40,41 Between birth and the end of the first year, mean cardiac output normalized for body weight (or surface area), remains fairly constant at 204 ± 45 mL/kg/min.⁴² The relatively large cardiac output (mL/min/kg) in neonates reflects their greater metabolic rate (expressed per kilogram) and oxygen consumption compared with adults. Basal metabolic rate has been shown to increase as size decreases in all species⁴³ (see Chapter 6).

Pulsed Doppler estimation of cardiac output has also been found useful in assessing left ventricular myocardial dysfunction in neonates after perinatal asphyxia and acidosis, as well as its response to therapy.^35,44,45 In older children, measurements of cardiac output are necessary in circulatory shock.⁴⁶ New noninvasive techniques using changes in impedance may be useful in the future (see Chapter 51).

Normal Electrocardiographic Findings From Infancy to Adolescence

The P wave reflects atrial depolarization and varies little with age. The PR interval increases with age (mean value for the first year is 0.10 second, increasing to 0.14 second at 12 to 16 years).⁴⁷ The duration of the QRS complex increases with age, but prolongation greater than 0.10 second is abnormal at any age.

At birth, the QRS axis is right sided, reflecting the predominant right ventricular intrauterine development. It moves leftward in the first month as left ventricular muscle hypertrophies. Thereafter, the QRS follows a gradual change away from the initial marked right-sided axis.

In addition, T waves are upright in all chest leads. Within hours, they become isoelectric or inverted over the left chest; by the seventh day, the T waves are inverted in V_4R (V₄ position under the right clavicle), V₁, and across to V₄; from then on, the T waves remain inverted over the right chest until adolescence, when they become upright over the right side of the chest again. Failure of T waves to become inverted in V_4R and V₁ to V₄ by 7 days may be the earliest electrocardiographic evidence of right ventricular hypertrophy.^48,49

Hepatic System

Development of the liver and bile ducts begins as an outgrowth of the foregut; by 10 weeks of gestation, the biliary tract has completed its development. The vitelline veins give rise to the portal and hepatic veins. Hepatic sinusoids form the ductus venosus, the bridge between the hepatic vein and the inferior vena cava. Most umbilical venous blood from the placenta passes through the ductus venosus to the inferior vena cava. The remainder passes via the portal vein through the liver to the hepatic veins. The portal venous drainage to the left lobe is less than to the right lobe, leading to a relative underdevelopment of the left lobe. The ductus venosus closes soon after birth.

At 12 weeks of gestation there is evidence of gluconeogenesis and protein synthesis; at 14 weeks, glycogen is found in liver cells. Although by late gestation liver cell morphology is similar to that of adults, the functional development of the liver is immature in neonates and more so in preterm infants. The liver has a major role in metabolism, controlling carbohydrate, protein, and lipid delivery to the tissues. Toward the end of pregnancy, large amounts of glycogen appear in the liver, and, as a result, preterm and small-for-gestational-age (SGA) infants with smaller stores of glycogen may develop hypoglycemia. Bile acid secretion in neonates is reduced, and malabsorption of fat occurs.

The liver is the site for the synthesis of proteins; this process is active in fetal and neonatal life. In fetal life, the main serum protein is alpha-fetoprotein. This protein first appears at 6 weeks of gestation and reaches a peak at 13 weeks. Albumin synthesis starts at 3 to 4 months of gestation and approaches adult values at birth; in preterm infants, the level is reduced. Proteins involved in clotting are also formed in the liver but their concentrations in preterm and full-term neonates are less than normal for the first few days after birth. Hematopoiesis occurs in the fetal liver, with peak activity at 7 months of gestation. After 6 weeks of age, hematopoiesis is confined to the bone marrow except under pathologic conditions, such as hemolytic anemia (see Chapter 28).

The capacity to enzymatically break down proteins is reduced at birth. This is particularly important in preterm infants, when the intake of a large protein load can result in dangerous levels of serum amino acid concentrations. In the first weeks of life, drug metabolism is less efficient than in later life. In addition to less effective hepatic metabolism, altered drug binding by serum proteins and immature renal function contribute to the problem (see Chapter 6).

Gastrointestinal Tract

In an embryo, the digestive tract consists of the developing foregut and hindgut. These rapidly elongate so that a loop of gut is forced into the yolk sac. At 5 to 7 weeks, this loop twists around the axis of the superior mesenteric artery and returns to the abdominal cavity. Maturation occurs gradually from the proximal to the distal end. Blood vessels and nerves (Auerbach and Meissner plexuses) are developed by 13 weeks of gestation, and peristalsis begins. The pancreas arises from two outgrowths of the foregut; a diverticulum of the foregut gives rise to the liver.

Enzyme levels of enterokinase and lipase increase with gestational age but are lower at birth compared with older children. Full-term neonates and preterm infants handle protein loads reasonably well, although preterm infants may have difficulty with large loads. Fat digestion is limited, particularly in preterm infants, who absorb only 65% of adult levels. Neonatal duodenal motility undergoes marked maturational changes between 29 and 32 weeks of gestation. This is one factor limiting tolerance of enteral feeding before 29 to 30 weeks of gestation. Central nervous system abnormalities will delay these maturational changes.⁶⁶

Swallowing is a complex process that is under central and peripheral control. The reflex is initiated in the medulla, through cranial nerves to the muscles that control the passage of food through the pharyngoesophageal sphincter. In the process, the tongue, soft palate, pharynx, and larynx all are smoothly coordinated. Any pathologic condition of these structures can interfere with normal swallowing. Neuromuscular incoordination, however, is more likely to be responsible for any dysfunction. This is particularly evident when the central nervous system has sustained damage either before or during delivery.

Lower esophageal pressures are reduced at birth but increase steadily reaching adult values 3 to 6 weeks postnatally. Daily vomiting or “spitting up” may be seen in half of all infants between 0 and 3 months of age and up to two-thirds of 4- to 6-month-old infants.⁶⁷ Most of these infants suffer no ill effect (“happy spitters”) and grow well.⁶⁸ This condition usually begins in the first weeks of life and resolves spontaneously by 9 to 24 months of age as solid food is introduced and the child assumes the upright position. Between 1 : 300 and 1 : 1000 infants have reflux that is significant enough to warrant treatment to prevent complications.⁶⁹

Meconium is the material contained in the intestinal tract before birth. It consists of desquamated epithelial cells from the intestinal tract, bile, pancreatic and intestinal secretions, and water (70%). Meconium is usually passed in the first few hours after birth; virtually all term neonates pass their first stool by 48 hours. However, passage of the first stool is usually delayed in LBW neonates, probably because of immaturity of bowel motility and lack of gut hormones due to delayed enteral feeding. Meconium ileus occurs in cystic fibrosis or Hirschsprung disease.

The gastrointestinal transit time in the infant is less than that of an adult and increases with age. The normal physiologic range of stool frequency varies greatly (from 10 times a day to 1-2 times a week⁷⁰ and more often in breastfed infants. The frequency of bowel movements gradually declines over the first years of life, reaching adult habits at about 4 years of age.

Necrotizing enterocolitis is an acquired gastrointestinal disease associated with significant morbidity and mortality in prematurely born neonates. The disease affects about 10% of preterm neonates weighing less than 1500 g or 1% to 5% of all neonatal intensive care unit admissions (see also Chapters 35 and 36). Combined with enteral feeds and bacterial colonization, inflammatory mediators are released, leading to a propagated inflammatory response with both pro- and antiinflammatory influences.⁷¹

Pancreas

The placenta is impermeable to both insulin and glucagon. The islets of Langerhans in the fetal pancreas, however, secrete insulin from week 11 of fetal life; the amount of insulin secretion increases with age. After birth, insulin response is related to gestational and postnatal age and is more mature in term infants.

Maternal hyperglycemia, particularly when uncontrolled, results in hypertrophy and hyperplasia of the fetal islets of Langerhans. This leads to increased levels of insulin in the fetus, affecting lipid metabolism and giving rise to a large, overweight infant characteristic of a mother with poorly controlled diabetes (infant of a diabetic mother, IDM). Hyperglycemia alone is not instrumental in this effect; IDM may also be the result of an increase in serum amino acids found in diabetic mothers. Hyperinsulinemia of the fetus persists after birth and may lead to rapid development of serious hypoglycemia. In addition to severe hypoglycemia, these infants have an increased incidence of congenital anomalies.

Infants who are SGA are frequently hypoglycemic, and this may be the result of malnutrition in utero. In addition, hepatic glycogen stores are inadequate, and deficient gluconeogenesis exists. Preterm infants may be hypoglycemic without demonstrable symptoms, necessitating close monitoring of blood glucose levels.

Full-term neonates undergo a metabolic adjustment postnatally with regard to glucose. Studies have defined values for glucose levels that should be cause for concern: plasma glucose levels less than 35 mg/dL in the first 3 hours of life; less than 40 mg/dL between 3 and 24 hours; and less than 45 mg/dL after 24 hours.⁷² Others have defined hypoglycemia in full-term infants as a plasma glucose concentration of less than 30 mg/dL in the first day of life or less than 40 mg/dL in the second day of life.⁷³ It is important to recognize that infants may develop serious hypoglycemia that could lead to irreversible central nervous system damage, even though they demonstrate no symptoms. Other infants may present with convulsions, but signs may also be subtle (e.g., lethargy, somnolence, and jitteriness).

Hyperglycemia (plasma glucose 150 mg/dL or greater) occurs in stressed neonates, particularly LBW infants infused with glucose-containing solutions. Hyperglycemia commonly occurs in infants undergoing elective surgery under general anesthesia; infusion of glucose-containing solutions may increase the risk of hyperglycemia. Thus it is advisable that intraoperative glucose levels be monitored. A study in infants undergoing surgery under general anesthesia showed that postsurgical plasma glucose values were significantly greater than postinduction values; insulin changes were minimal.⁷⁴ The risk of hyperglycemia is considerably greater in infants weighing less than 1000 g compared with infants of 2000 g or more.⁷³ Hyperglycemia may also lead to osmotic diuresis and dehydration and has been associated with an increased incidence of intraventricular hemorrhage and a neurologic handicap.

Hemoglobin

The normal hemoglobin range in the neonate is between 14 and 20 g/dL. The site of sampling must be considered when interpreting these values for the diagnosis of neonatal anemia or hyperviscosity syndrome. Capillary sampling (e.g., heel stick) generally overestimates the true hemoglobin concentration because of stasis in peripheral vessels that results in a loss of plasma and produces hemoconcentration. The net effect may be an increase in hemoglobin by as much as 6 g/dL As a result, venipuncture is preferred over capillary sampling. In 1% of infants, fetal-maternal transfusion before the umbilical cord is cut may explain many of the “lower normal” hemoglobin values reported.

Erythropoietic activity from the bone marrow decreases immediately after birth in both full-term and preterm infants. The cord blood reticulocyte count of 5% persists for a few days and declines below 1% by 1 week. This is followed by a slight increase to 1% to 2% by the 12th week, where it remains throughout childhood. Preterm infants have greater reticulocyte counts (up to 10%) at birth. Abnormal reticulocyte values reflect hemorrhage or hemolysis.

In term infants, the hemoglobin concentration decreases during the 9th to 12th week to reach a nadir of 10 to 11 g/dL (hematocrit 30% to 33%) and then increases. This decrease in hemoglobin concentration is due to a decrease in erythropoiesis and to some extent due to a shortened life span of the red blood cells. In preterm infants, the decrease in the hemoglobin level is greater and is directly related to the degree of prematurity; also, the nadir is reached earlier (4 to 8 weeks).⁷⁷ In infants weighing 800 to 1000 g, the decrement may reach a very small concentration, 8 g/dL. This “anemia” (physiologic anemia of the newborn) is a normal physiologic adjustment to extrauterine life. Despite the reduction in hemoglobin, the oxygen delivery to the tissues may not be compromised because of a shift of the oxygen-hemoglobin dissociation curve (to the right), secondary to an increase of 2,3-diphosphoglycerate.⁷⁸ In addition, fetal hemoglobin is replaced by adult-type hemoglobin, which also results in a shift in the same direction. In neonates, especially preterm infants, reduced hemoglobin concentrations may be associated with apnea and tachycardia.⁷⁹ Vitamin E administration does not prevent anemia of prematurity; no significant difference was noted between vitamin E–supplemented and unsupplemented groups in terms of hemoglobin concentration, reticulocyte and platelet counts, or erythrocyte morphology in infants at 6 weeks of age.⁸⁰ Infants with anemia of prematurity have been found to have an inadequate production of erythropoietin (the primary regulator in erythropoiesis). Some centers are now using recombinant human erythropoietin in VLBW infants to stimulate erythropoiesis and decrease the need for transfusions.^81,82

After the third month, the hemoglobin concentration stabilizes at 11.5 to 12 g/dL, until about 2 years of age. The hemoglobin values of full-term and preterm infants are comparable after the first year. Thereafter, there is a gradual increase in the hemoglobin concentration to mean values at puberty of 14 g/dL for females and 15.5 g/dL for males.

Leukocyte and Immunology

The white blood cell count may normally reach 21,000/mm³ in the first 24 hours of life and 12,000/mm³ at the end of the first week, with the number of neutrophils equaling the number of lymphocytes. It then decreases gradually, reaching adult values at puberty. At birth, neutrophil granulocytes predominate but rapidly decrease in number so that during the first week of life and through 4 years of age the lymphocyte is the predominant cell. After the fourth year, the values approximate an adult’s. Neonates have an increased susceptibility to bacterial infection, which is related in part to immaturity of leukocyte function. Sepsis may be associated with a minimal leukocyte response or even with leukopenia. Spurious increases in the white blood cell content may be due to drugs (e.g., epinephrine). The incidence of neonatal sepsis correlates inversely with gestational age and may be as great as 58% in VLBW infants.⁸³

Platelets

Thrombocytopenia is a common hematologic finding in neonates, occurring in 1% to 2% of healthy term neonates.⁸⁴ Mechanical ventilation has been associated with a significant decrease in the platelet count in neonates.⁸⁵ There appears to be an inverse correlation between gestational age or birth weight and the severity of platelet reduction. A study of neonatal thrombocytopenia and its impact on hemostatic integrity showed that thrombocytopenic infants are at greater risk for bleeding than equally sick nonthrombocytopenic infants (see Chapter 18).

Coagulation

At birth, vitamin K–dependent factors (i.e., II, VII, IX, and X) are 20% to 60% of adult values; in preterm infants, the values are even less. The result is prolonged prothrombin times, normally encountered in full-term and preterm infants. Synthesis of vitamin K–dependent factors occurs in the liver, which, being immature, leads to relatively lower levels of the coagulation factors, even with the administration of vitamin K. It takes several weeks for the levels of coagulation factors to reach adult values; the deficit is even more pronounced in preterm infants. Vitamin K prophylaxis has been evaluated,⁸⁶ and the findings show that the majority of cases of neonatal vitamin K deficiency occur in normal neonates. Thus, all neonates should receive prophylactic vitamin K soon after birth to prevent hemorrhagic disease of the neonate. Its omission could lead to serious and life-threatening consequences, especially if surgery is undertaken. However, in theory, the increasing risk of bleeding is balanced by the protective effects of physiologic deficiencies of coagulation inhibitors, as well as by the decreased fibrinolytic capacity. Developmental hemostasis should be considered, as well as laboratory variations of coagulation tests that may render any diagnosis of bleeding disorder in infants difficult to establish.⁸⁷

Infants of mothers who have received anticonvulsant drugs during pregnancy may develop a serious coagulopathy similar to that encountered with vitamin K deficiency.⁸⁸ Vitamin K₁ administered to neonates usually reverses this bleeding tendency, but deaths have occurred despite therapy. Other risk factors include maternal use of drugs such as warfarin, rifampin, and isoniazid. Breastfeeding may also be associated with severe vitamin K deficiency.

Polycythemia

Neonatal polycythemia (central hematocrit greater than 65%) occurs in 3% to 5% of full-term neonates.⁸⁹ Using M-mode echocardiography, a study of neonates demonstrated an increase in PVR with hyperviscosity.⁹⁰ Partial exchange transfusion to reduce the hematocrit and decrease the blood viscosity improves systemic and pulmonary blood flow and oxygen transport, although one review questioned the efficacy when the exchange transfusion was conducted after 6 hours of life in asymptomatic infants.⁹¹ The increased organ blood flow should prevent the cardiovascular and neurologic symptoms associated with the hyperviscosity syndrome.

Neurologic Development

Reduction of perinatal mortality during the past decade has not resulted in the expected reduction in the prevalence of cerebral palsy (1 : 500 live births). The most common etiologies of cerebral palsy are perinatal ischemic stroke, white matter disorder, and intrauterine inflammation.⁹² Less than 5% of cerebral palsy results from perinatal asphyxia. The strongest predictors of cerebral palsy appear to be congenital anomaly, low birth weight, low placental weight, multiple fetuses, or abnormal fetal position before labor and delivery.⁹³

The nervous system is anatomically complete at birth; functionally it remains immature with the continuation of myelination and synaptogenesis. Myelination is usually complete by 7 years of age. An infant’s normal mental development depends on the maturation of the central nervous system. This development may be affected by physical illness, inadequate psychosocial support, or bad nutrition conditions in preterm babies. In a randomized trial of diet in preterm babies, a suboptimal diet resulted in reduced intelligence quotients 7 to 8 years later.⁹⁴

Recent controversies concerning the potential adverse effects of anesthesia on the developing brain show how delicate this organ is and how its development may be affected by environmental agents^95,96 (see Chapter 23).

The rate of brain growth is different from the growth rate of other body systems. The brain has two growth spurts, neuronal cell multiplication between 15 and 20 weeks of gestation, and glial cell multiplication commencing at 25 weeks and extending into the second year of life. Myelination continues into the third year. Malnutrition during this phase of neural development may have profound handicapping effects.

Plasma membrane transport selectively promotes the passage of essential substrates such as glucose, organic acids, and amino acids across the blood-brain barrier. Hypoxemia and ischemia may lead to a breakdown in this barrier, with resulting edema and increased intracranial pressure. Injury to the blood-brain barrier may result from abnormal entry of calcium or formation of free radicals. Further studies of the mechanism of this breakdown will lead to rational approaches to therapy. In preterm infants stressed by hypoxia, the blood-brain barrier may become particularly permeable to the water-soluble unbound bilirubin, with possible damage to the brain.⁹⁷

Normal neonates show various primitive reflexes, which include the Moro response and grasp reflex. Milestones of development are useful indicators of mental development and possible deviations from normal. It should be appreciated, however, that these milestones represent the average, and infants can vary in their rates of maturation of different body functions and still be within the normal range.⁹⁸ The Denver Developmental Screening Test is useful for assessing these milestones. The test focuses on four areas: (1) gross motor function, (2) fine motor and adaptive skills, (3) language, and (4) personal and social skills. Developing infants rapidly acquire motor skills. For effective movement, an infant needs postural control, which develops in a cephalocaudal direction. It starts with head control and progresses to sitting, standing, walking, and finally running (Table 2-11).

TABLE 2-11 Relationship of Motor Milestones to Age

Adaptive skills are performed through well-coordinated fine motor movements (Table 2-12). Abnormal development may be reflected in a delay in appearance of a particular milestone or in its pathologic persistence with maturation in a child. For example, at 20 weeks, a child reaches and retrieves objects, frequently placing them in his or her mouth. As an infant matures, however, this behavior pattern usually ceases at 12 to 13 months of age; in infants with a developmental delay, this practice may continue much longer.

TABLE 2-12 Relationship of Fine Motor/Adaptive Milestones to Age

Language development correlates closely with cognitive skills (Table 2-13). Personal and social skills are modified by environmental factors and cultural patterns (Table 2-14). Development of walking, speech, and sphincter control are most important. For appropriate evaluation consider familial patterns, level of intelligence, and physical illness. Deafness may cause delayed speech.

TABLE 2-13 Relationship of Language Milestones to Age

TABLE 2-14 Relationship of Personal-Social Milestones to Age

Developmental Issues

Children with developmental issues are delayed in many aspects of both cognitive and motor development. Smiling, vocalization, sitting, walking, speech, and sphincter control are delayed. When there is a delay in the eye following an object and the head turning in response to sound, blindness and deafness may erroneously be diagnosed. Drooling, common in young infants, is frequently prolonged for years in neurologically delayed children. Initially, a mentally handicapped infant appears to be inactive and may be seen as a “good child.” The child later demonstrates constant and sometimes uncontrollable overactivity. In diagnosing a developmental abnormality, anesthesiologists must be aware of possible pitfalls: Infants born prematurely will be delayed and should be assessed in terms of their conceptional age. Infants with cerebral palsy or sensory deficits (auditory and visual) may have normal mental development, but the handicap may interfere with assessment of mental status. The effects of drugs should be considered (e.g., barbiturates for epilepsy).

Acknowledgment

The author wishes to acknowledge the prior contributions of Robert M. Insoft and I. David Todres to this chapter.