Thermal Environment

In a neutral thermal environment, neonates expend the least amount of energy to maintain their body temperature. The oxygen consumption (o₂) of normal neonates is 6 cc/kg per minute, twice that of resting adults. During the first week of life, o₂ increases to about 10 cc/kg per minute and may be twice that during heat-related stress. Because of their high oxygen consumption, greater CO, and smaller reserve of oxygen (i.e., smaller functional residual capacity [FRC]), neonates, especially preterm neonates, develop hypoxia more quickly than adults. In fact, hypoxia may develop in as few as 10 seconds in apneic neonates, whereas it takes several minutes for this to occur in adults (Peabody et al., 1978a, 1978b).

Sodium, Calcium, and Glucose

Box 17-2 contains common fluid and electrolyte requirements for neonatal infants. Because premature, large-for-gestational age (LGA), small-for-gestational-age (SGA), and asphyxiated neonates are often hyper- or hypoglycemic, intravenous glucose may be required to maintain normoglycemia (serum glucose concentration of 40 to 90 mg/dL; see Glucose Metabolism, p. 537) (Jain et al., 2008). Similarly, calcium homeostasis is often difficult to achieve in sick infants (Bass and Chan, 2006). Initial calcium administration is usually based on normal neonatal requirements and on need, as determined by serial ionized calcium measurements. Calcium should be infused into a well-functioning intravenous catheter to avoid extravasation of calcium into the tissues and severe tissue necrosis. During surgery the calcium infusion site is usually under the surgical drapes and hard to see. Therefore, calcium should be infused into a reliable intravenous catheter, preferably a central venous catheter.

For the first 2 to 3 hours of life, the neonate’s electrolyte concentrations reflect those of the mother and of perinatal events (e.g., asphyxia, or placental or umbilical cord hemorrhage). Afterward, the electrolyte concentrations reflect a balance between normal metabolism, renal and hepatic function, and ongoing metabolic derangements (e.g., sepsis, inherited metabolic diseases, hemolysis, or inborn errors of metabolism). Until tissue perfusion is adequate, resuscitated neonates usually have ongoing metabolic acidosis.

In full-term and near-term infants, sodium is seldom added to intravenous fluids during the first 24 hours of life. Urine output is low, despite the fact that 30 mL/kg of fluid must be removed from the lungs during and after birth (Herin and Zetterström, 1994). On the second day of life, maintenance sodium (2 to 4 mEq/kg per day) is added to the intravenous fluids to replace renal and gastrointestinal tract sodium losses, to compensate for abnormal fluid metabolism, or to counter the effect of diuretics (e.g., furosemide). In the extremely low-birth weight (ELBW) infant, fluid that contains sodium is often administered to maintain adequate intravascular volume, especially when transcutaneous fluid losses are excessive. After the first few days of life, an adequate sodium intake is essential for infants of all gestational ages to permit normal growth.

Development

Lung development is divided into the following five stages:

The latter stage begins at about 36 weeks’ gestation and continues until at least 18 months of age (Langston et al., 1984; Kotecha, 2000a, 2000b; Joshi and Kotecha, 2007). Knowledge of these phases of lung development allows estimation of when the 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 is increased 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 surface area in the lungs may be inadequate for gas exchange. However, in the past decade many babies have survived after 24 to 25 weeks’ gestation, usually with enormous effort and cost; these extremely premature infants often survive with severe CLD (Langston et al., 1984).

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 (Thurlbeck, 1982; Kotecha, 2000a, 2000b). Specific cell types are not recognizable in the lung until the canalicular stage of development (17 to 28 weeks’ gestation). During the last 10% to 20% of gestation, type II pneumocytes are more commonly identified. Although present in the human fetus by 22 weeks’ gestation, type II pneumocytes are more prominent after 34 to 36 weeks of gestation. The major distinguishing feature of type II cells is the presence of osmophilic lamellar bodies, which correlate closely with the presence of SAM in the lungs (Kotecha, 2000a, 2000b). The alveolar-capillary barrier is formed by type I pneumocytes (see Chapter 3, Respiratory Physiology in Infants and Children).

By 16 weeks’ gestation, all subdivisions of the conducting airways have formed, including the main-stem bronchi and the conducting and terminal bronchioles. Preterm infants often require mechanical ventilation or CPAP and supplemental oxygen, which interfere with the normal, complex process of lung and airway development. The barotrauma, oxidative stress, and inflammatory injury associated with these life-saving interventions and the effects of superimposed infections predispose preterm infants to airway and lung injury and to abnormal airway resistance and reactivity (Van Marter, 2005).

The diaphragm arises in part from the third through fifth cervical somites, and myoblasts from these somites migrate into the septum transversum to form diaphragmatic muscle (Mitchell and Sharma, 2009). The central tendon of the diaphragm arises from the mesoderm of the septum transversum. Somites of the lateral chest wall form the lateral portions of the diaphragm. The nerve supply of the diaphragm is from the third through fifth cervical somites. Bilateral pericardioperitoneal canals, located lateral to the developing diaphragm, cause a Bochdalek hernia if the canals fail to close. Complete closure of the diaphragm normally occurs at 10 to 12 weeks’ gestation, when the bowel is returning to the abdominal cavity from the amnion, where it resides in early gestation. If the diaphragm is incompletely formed, the returning bowel follows the path of least resistance and enters the chest. When this occurs lung growth ceases on the ipsilateral side. The mediastinum is then pushed into the opposite chest by the bowel and abdominal organs and contralateral lung growth is also reduced. Consequently, neonates who have a left-sided diaphragmatic hernia must survive with approximately two thirds of one lung or less (de Lorimier et al., 1967). In some cases, the amount of lung present is insufficient for survival (see Chapter 18, Anesthesia for General Surgery in the Neonate).

Failure of the lung buds to separate from the foregut causes a tracheal esophageal fistula (see Chapter 18, Anesthesia for General Surgery in the Neonate). The connection usually is found between the distal esophagus and the trachea, just above the carina. Failure of the distal and proximal ends of the esophagus to connect with each other results in esophageal atresia. Patients with esophageal atresia usually have copious secretions in the proximal esophageal pouch, and placing the patient flat without removing the secretions may cause aspiration of the secretions. Placing a suction catheter in the proximal esophageal pouch and connecting it to suction reduces this likelihood.

Early Postnatal Period: Changes in Oxygenation and Pulmonary Vascular Resistance

Although removal of fluid from the fetal lung begins during labor and delivery, the major transition to an air-filled lung occurs immediately after birth. The first active inspiration after birth produces a negative intrapleural pressure of 80 to 100 cm H₂O, which is required to overcome the high surface tension, low compliance, and high resistance of the liquid-filled lungs (Scarpelli and Mautone, 1984; Vyas et al., 2005). These pressures are not necessary when artificially ventilating neonatal lungs, however. In fact, delivering large tidal volumes and high airway pressures injure neonatal lungs (Bjorklund et al., 1997). In full-term neonates, the initial few spontaneous breaths are of 20 and 80 cc O₂ each. A small fraction of this volume is expired. The gas remaining in the lung forms the residual volume (RV) and the FRC, which are required for adequate gas exchange (Avery, 1974). If removal of lung fluid is delayed (e.g., with cesarean section) transient tachypnea of the newborn (TTN) develops (Guglani et al., 2008). Neonates with TTN breathe 60 to 150 times a minute and are often hypoxic and hypercarbic. Many of them require supplemental oxygen, and some require mechanical ventilation. Diuretics fail to induce a diuresis and improve lung function until a spontaneous diuresis occurs several days after birth (Lewis and Whitelaw, 2002).

Labor reduces pulmonary vascular resistance (PVR) by approximately 10%, but the most significant decrease occurs with the onset of breathing (Bland, 1983). Lung expansion increases alveolar and arterial Po₂, which dilates the pulmonary arterioles, decreases PVR and increases pulmonary blood flow (Dawes, 1974). These changes in PVR and blood flow are critical for conversion of the fetal circulation to the adult form of circulation (see Chapters 3, Respiratory Physiology, and 4, Cardiovascular Physiology). That is, transition to the gas-filled lung at birth, increased Fio₂ (air), and increased pH (decreased Paco₂) all interact to reduce PVR and increase pulmonary blood flow. Over the next 1 to 2 months, PVR decreases to adult levels. However, infants with cyanotic congenital heart disease (CHD) or large left-to-right shunts may have elevated PVR for months or longer (Rudolph, 2007).

The dramatic rise in pulmonary blood flow at birth increases the left atrial pressure and functionally closes the foramen ovale, preventing right-to-left shunting of deoxygenated blood through this structure. An increase in systemic vascular resistance that exceeds PVR dramatically reduces right-to-left blood flow through the ductus arteriosus. The rise in arterial oxygen tension at birth constricts and physiologically closes the ductus arteriosus in full-term but not in preterm neonates (Clyman et al., 1978). Nitric oxide (NO) and prostaglandins are important for anatomic closure of the ductus arteriosus, which usually occurs by 2 to 3 weeks of age (Born et al., 1956; Seidner et al., 2001; Clyman, 2006). If during this time hypoxia, acidosis, cold, or excessive airway pressures are present, the right atrial pressure increases and right-to-left shunting of blood can occur at both the atrial and the DA levels. When right-to-left shunting of blood occurs, hypoxemia ensues. The resulting pulmonary blood flow pattern mimics the pattern present in utero and is often referred to as persistent fetal circulation (PFC).

Establishing normal pulmonary blood flow and ventilation increases both arterial and mixed venous oxygen tensions. Although the transition to air breathing increases the oxygen content of blood, the Pao₂ of the neonate is usually 55 to 85 mm Hg for the first month of life, rather than the 95 to 100 mm Hg present after that. The lower Pao₂ is the result of a very compliant, cartilaginous neonatal chest wall that does not recoil outward at end-expiration, as it does in older children and adults (Koch and Wendel, 1968; Davis and Bureau, 1987). Failure to recoil outward produces a transpulmonary (intrapleural) pressure of 0 cm H₂O—not −5 cm H₂O pressure, as occurs in older patients. Because negative intrapleural pressures are important for maintenance of a normal FRC, neonates are predisposed to atelectasis and a lower Pao₂. In fact, application of sufficient negative pressure around the neonate’s chest to produce a pleural pressure of −5 cm H₂O, increases the Pao₂ from about 65 mm Hg to nearly 100 mm Hg, indicating that the negative intrapleural pressure expands the lungs, increases FRC, reduces atelectasis, and improves the match of ventilation to perfusion (Thibeault et al., 1968). Application of negative intrapleural pressure, positive end expiratory pressure (PEEP), or CPAP also reduces the amount of atelectasis and improves oxygenation (Gregory et al., 1975).

In addition to its effects on transpulmonary pressure, the newborn’s compliant rib cage has another unwanted effect on ventilation. That is, the cartilaginous, compliant chest wall tends to collapse inward (retract) during spontaneous inspiration, causing paradoxic chest-wall motion and limiting airflow (Knill et al., 1976). 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) also distort the rib cage and make the diaphragm less efficient (Muller and Bryan, 1979).

Other factors also affect the infant’s work and efficiency of breathing. For instance, the full-term infant’s diaphragm is comprised of only 25% fatigue-resistant, slow-twitch, highly oxidative type I fibers, and the preterm infant has only 10% (the adult diaphragm has 55%). The lower percentage of type I fibers predisposes the diaphragm to fatigue (Keens et al., 1978). The intercostal muscles show 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 (Watchko and Sieck, 1993; Zhan et al., 1998). Less effective force-frequency, length-tension, and force-velocity relationships and a mismatch of energy supply and demand characterize diaphragmatic muscle and predisposes these newborns to fatigue, especially when there is widespread atelectasis (e.g., RDS) or poor chest wall compliance (e.g., anasarca) (Watchko et al., 1986; Watchko and Sieck, 1993). Methylxanthines improve neonatal diaphragmatic function (Maycock et al., 1992).

Healthy neonates breathe 30 to 60 times per minute to maintain normal oxygenation and to remove the increased amount of CO₂ produced by an oxygen consumption of 6 to 10 cc/kg per minute. This respiratory rate also helps maintain the FRC by reducing the amount of time available for expiration and by trapping gas within the lung. At normal respiratory rates, the time constant of the lungs (compliance of lungs × airway resistance [C_• × R_aw]) is, on average, 0.25 seconds. A slow respiratory rate, apnea, or bradypnea can reduce the FRC, especially in preterm neonates (Fig. 17-3). A low level of PEEP (5 to 7 cm H₂O) should always be added to maintain the FRC of infants and young children, especially when slow ventilatory rates are used.

FIGURE 17-3 The change in FRC of a 1550 g infant that occurred with decreasing ventilator rates without PEEP. A PEEP of 5 cm H₂O maintained the FRC at about 25 mL/kg even at 5 breaths per minute (not shown).

Naturally occurring SAM or pulmonary surfactant is by far the most important mechanism for keeping alveoli of different sizes or diameters open. Initially, SAM appears in fetal lungs by 20 weeks’ gestation, even though no functional alveoli exist (Clements, 1961). At about 35 to 36 weeks’ gestation, the amount of SAM increases and is secreted onto the alveolar surface. The pulmonary surfactant monolayer creates a gas-liquid interface on the alveolar surface and drastically decreases surface tension during exhalation as the surface area decreases. During inspiration the monolayer is thinned, and the surface tension increases. SAM keeps the surface tension relatively constant regardless of the changes in the surface area and the radius of the alveoli. In neonates with RDS, there is loss of or inactivation of surfactant, and surface tension increases. The variability of surface tension normally occurring with changes in surface area is lost; alveoli develop higher pressures, collapse during exhalation, and remain collapsed (see Chapter 3, Respiratory Physiology in Infants and Children).

An additional mechanism that helps keep the alveoli open is 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 (Takishima and Mead, 1972). Millions of alveoli exerting this “pulling” effect help maintain FRC. Furthermore, blood-filled capillaries act as an exoskeleton for alveoli. If the pulmonary blood volume is inadequate, atelectasis develops. Increasing the blood volume increases FRC (Table 17-1) (Gregory, personal observation).

TABLE 17-1 Changes in FRC Associated with Blood Transfusion in Five Term Infants*

Gregory GA: Unpublished data.

* FRC was measured by helium dilution.

Thus, surfactant, intraalveolar forces, and pulmonary blood volume compensate for the lack of transpulmonary pressure at end expiration that is caused by the neonate’s extremely compliant chest wall and are responsible for maintaining the infant’s FRC, albeit smaller (30 cc/kg) than that of adults (50 cc/kg).

Surface Active Material

The demonstration by Avery and Mead (1959) that surfactant deficiency is the primary cause of RDS eventually led Phibbs et al. (1991) and Fujiwara et al. (1990) to use commercially available surfactant prophylactically after birth or in the rescue mode after the symptoms of RDS were apparent. Intubated infants of fewer than 28 weeks’ gestation often receive 1 or 2 doses of surfactant 12 hours apart. During preoperative evaluation of a newborn with RDS, it should be determined when the last dose of SAM was given and if an additional dose is required before surgery because of progressive atelectasis or worsening blood gases and oxygen requirement.

Pulmonary gas exchange is only possible after a significant portion of the lung fluid present in utero is removed from the airways and alveoli. Increased pulmonary lymphatic flow and surface-active phospholipids and proteins facilitate this process (Humphreys et al., 1967; King, 1982). Surfactant reduces the surface tension of the gas-liquid interface of the alveoli, keeping the air spaces open at end expiration. This reduction of surface tension is critical for the maintenance of FRC and gas exchange.

Type I pneumocytes account for more than 90% of the alveolar surface cells; type II pneumocytes, the SAM-storing cells, populate most of the remaining surface. The total weight of SAM consists of about 10% protein, 90% lipids, and 0.1% carbohydrates. The lipids lower the surface tension, but the proteins allow absorption and dispersion of the lipids in the air-liquid interface. Proteins are also necessary for reuptake of SAM by type II cells. Congenital absence of these proteins leads to a chronic RDS-like state (Yurdakök, 2004). During inspiration SAM is spread over the alveolar surface. During expiration it is compacted to lower the alveolar surface tension. SAM also stabilizes small airways and is important for pulmonary defense mechanisms (Jarstarand, 1984).

Respiratory Distress Syndrome

Neonatal RDS occurs when the quantity of SAM is insufficient or when there is delayed synthesis or release of surfactant (e.g., in infants of diabetic mothers). Giving betamethasone to the fetus, by way of the mother, before 36 weeks’ gestation accelerates the production and release of SAM from the type II alveolar epithelial cells and reduces the incidence of RDS (Liggins and Howie, 1972). Typical clinical features of RDS include: 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 shows a diffuse reticulogranular pattern and air bronchograms (Fig. 17-4). Unless SAM is given, the natural course of RDS includes worsening symptoms for 2 to 3 days, resulting in either improvement or death. In some cases, respiratory function may deteriorate, rather than improve, because of a superinfection or complications of ventilatory support. RDS-associated death is often the result of severe lung injury induced by mechanical ventilation, sepsis, renal or hepatic failure, or CNS injury. This severe clinical pattern occurs less commonly when pulmonary surfactant is provided early. About 5% of all babies with RDS are born at term.

FIGURE 17-4 RDS. Note the ground-glass appearance and the presence of air bronchograms.

(From Brozanski BS, Bogen DL: Neonatology. In Zitelli BJ, Davis HW, editors: Atlas of pediatric physical diagnosis, ed 4, Philadelphia, 2002, Mosby.)

Before the development of commercially available surfactant, lung injury (e.g., pneumothorax, pulmonary interstitial emphysema, or BPD), blood loss from repeated blood sampling, and sepsis and its secondary effects (e.g., renal and hepatic dysfunction) were relatively common. Since 1990, exogenous SAM administration has significantly reduced the need for mechanical ventilation and oxygen therapy in preterm infants because of its effects on lung mechanics, including distensibility of the lung and end-expiratory volume stability (Morley et al., 2008). However, volutrauma (high tidal volume), and barotrauma (high airway pressure) persist in causing lung injury despite recent decreases in the incidence and severity of classic RDS and a reduction in the complications of pulmonary immaturity and supportive care. Despite all of these changes, the incidence of BPD has remained stable at about 20% (higher in ELBW infants) over the last 20 years (Bancalari and del Moral, 2001). But the BPD now seen in surfactant-treated lungs is different from classic BPD and is called new BPD. New BPD most commonly develops in ELBW infants, is characterized by a more uniform pattern of injury, and seems to represent an arrest of lung growth. Persistence of BPD, in spite of surfactant, suggests that other factors beside SAM deficiency contribute to BPD (Bancalari, 2001). Inflammatory and oxidative injury caused by infection, oxygen therapy, and “gentle” ventilation during periods of rapid lung growth and development, especially in the ELBW infants, seem to cause long-term pulmonary dysfunction (Kramer et al., 2009). The increased number of survivors has enlarged the number of patients (with and without BPD) requiring surgical treatment for coexisting long-term sequelae of prematurity.

Recent efforts to minimize lung injury caused by mechanical ventilation of premature infants have included introducing nasal CPAP (nCPAP) in the delivery room to prevent or treat RDS (Morley et al., 2008). This tactic avoids endotracheal intubation in patients and has markedly reduced the use of SAM. On the other hand, some infants with RDS (especially those weighing less than 1000 g) often fail a trial of nCPAP and require endotracheal intubation. They are usually treated with surfactant when their trachea are intubated.

Oxidative Injury in the Newborn

Although the role of oxygen in ROP is well established, oxygen toxicity of other organs, especially those of more mature newborns, is being increasingly recognized. Despite its widespread use for more than a century and the recognition that oxygen can be toxic for at least 50 years, the precise molecular mechanism of oxygen toxicity remains unknown (Tin, 2002). The severity of BPD has been correlated with oxygen exposure and with the oxygen saturation level used. In addition, greater oxidative injury to the heart, brain, and kidneys has been reported when neonatal resuscitation is accomplished with supplemental oxygen (Munkeby et al., 2004; Martín et al., 2007).

ROP is a multifactorial disease, but two main factors are associated with its development—prematurity and oxygen (see Chapter 27, Anesthesia for Ophthalmic Surgery). As stated, the neonate is exposed in utero to an oxygen tension of 20 to 30 mm Hg. Birth raises the Pao₂ to 55 to 85 mm Hg that may represent hyperoxia, especially for preterm neonates. The retinal vessels grow radially outward from the center of the optic disc from about 16 to 40 weeks’ gestation. Neonates born before term have incompletely developed retinal vessels (Roth, 1977). Two phases of ROP have been described. The initial phase, which occurs between 30 and 32 weeks’ gestation, is associated with inhibition of growth and loss of retinal vessels. Growth of the retina under these circumstances leads to retinal hypoxia. The second phase of ROP is associated with effusive retinal neovascularization and occurs between 32 and 34 weeks’ gestation. New vessels form in the avascular regions and send up fibrous bands to the vitreous gel and lens. These strands are responsible for retinal detachment in some premature infants (Chen and Smith, 2007). Vascular endothelial cell growth factor (VEGF) is required for new vessel growth in utero and afterwards. Administering oxygen after birth decreases VEGF during the first phase of ROP, which decreases vessel growth. In the second phase of ROP, retinal hypoxia increases VEGF expression, which causes exuberant vessel overgrowth. Insulin-like growth factor-1 (IGF-1) is required for VEGF to have its maximal effect. During gestation, serum concentrations of IGF-1 increase, and the severity of ROP is directly correlated with the level of IGF-1. In utero, IGF-1 is supplied by both the placenta and the amniotic fluid. This is withdrawn at birth, decreasing the effectiveness of VEGF, and vessel growth decreases. Excessive amounts of oxygen turn off VEGF. Thus, both VEGF and IGF-1, under appropriate circumstances, inhibit vessel growth and cause vessel regression. Because of the severe retinal hypoxia in phase I of ROP, VEGF and IGF-1 concentrations increase. Retinal vessels’ growth causes the severe problems seen in the later stages of ROP. Avoidance of excessive oxygen concentrations in the operating room is therefore necessary (Betts et al., 1977).

Because there is evidence that supplemental oxygen causes a significant amount of injury, the use of supplemental oxygen should be limited to that required to maintain the oxygen saturation between 85% and 93%, both during resuscitation at birth and during the entire neonatal period (Rabi et al., 2007).

BPD in the Surgical Patient

Infants with moderate to severe BPD often require supplemental oxygen beyond 36 weeks’ postconceptual age and often have evidence of lower-airway obstruction. Chest x-rays usually show hyperinflation or atelectasis and, on occasion, bronchopneumonia. Recurrent upper airway infections are common. If BPD is severe, hypercarbia and treatment with diuretics (e.g., furosemide) may complicate management of fluids, electrolytes, and nutrition. Maintaining normal pulmonary gas exchange in infants with BPD during anesthesia and surgery may be difficult. Consequently, many infants require increased respiratory support (including PIP, PEEP, and oxygen) to maintain baseline oxygenation and ventilation; however, use of these modalities also increases the risk of lung injury. Analyzing the infant’s current and recent ventilatory history, including severity and treatment of airway reactivity, is necessary to guide intraoperative care. Imitating the care established in the NICU can minimize exposure to excessive pressures, tidal volumes, and oxygen concentrations. To minimize the risk of a pneumothorax, pneumomediastinum, or interstitial emphysema, high peak airway pressures should be avoided, and adequate expiratory times should be allowed, especially if a patient has obstructive lung disease. All of these factors can cause sudden deterioration of hemodynamic and respiratory function. Hyperreactivity of the small airways is a common feature of BPD, and bronchodilation should be maximized preoperatively. Stimulation of the airways by tracheal intubation and surgical manipulation can induce severe bronchospasm, even at surgical planes of anesthesia.

Perioperative nutritional deficits and increased fluid requirements during surgery affect pulmonary function and ventilatory management, especially during and after major surgery (e.g., laparotomy for NEC). Assessing an infant’s acid-base status (Paco₂, pH, base deficit) and preoperative hepatic and renal function is essential for determining what kind and how much fluid to administer during surgery. Vigorous intravenous crystalloid and colloid administration during anesthesia and surgery, as well as postoperative hemodynamic instability, can dramatically affect pulmonary function, especially if the lungs were injured by BPD.

Preoperative Evaluation of the Pulmonary System

Evaluation of the pulmonary system begins with a review of the gestation, birth, and neonatal course. Was the infant hypoxic or asphyxiated in utero or at birth? Did the infant require artificial ventilation or other resuscitation at birth? If so, are there residual, active pulmonary symptoms, signs, or laboratory abnormalities? Does the infant presently require mechanical ventilation? If so, what are the current requirements for Fio₂, peak airway pressures, end-expiratory pressure, tidal volume, and ventilator rates? Have the ventilator settings increased or decreased over the previous 24 hours? What is the targeted oxygen saturation? What are the pH_a and Paco₂? If present, is hypercarbia chronic or acute, and is it intentional?

Transitional Circulation

The fetal circulation is characterized by increased PVR, decreased pulmonary blood flow, decreased systemic vascular resistance, and right-to-left blood flow through a PDA and foramen ovale (Rudolph, 2007). At birth, the onset of ventilation and the elimination of the placental circulation have dramatic effects on systemic and PVRs (see Chapters 4, Cardiovascular Physiology, and 21, Congenital Cardiac Anesthesia: Non-Bypass Procedures). Pulmonary vascular resistance (PVR) decreases and pulmonary blood flow increases. Simultaneously, systemic vascular resistance increases, and the left atrial pressure rises. This functionally closes the foramen ovale and stops right-to-left shunting at this level. However, bidirectional shunting through the ductus arteriosus often continues for the first 24 hours of extrauterine life in healthy infants. If the ductus arteriosus fails to close, blood is shunted left-to-right into the pulmonary circulation as the PVR declines after birth. Anatomic closure of the ductus arteriosus occurs after several days, and shunting of blood through this structure ceases. The neonate now has the circulation of an adult.

If arterial hypoxemia or acidosis occurs during the first few days of life, the neonate’s circulation may revert to the fetal pattern (i.e., pulmonary arterial vasoconstriction, pulmonary hypertension, and reduced pulmonary blood flow). The resultant increase in right atrial pressure reestablishes right-to-left shunting of deoxygenated blood through the foramen ovale and ductus arteriosus, producing arterial hypoxemia (Rudolph and Yuan, 1966). This return to the fetal circulatory pattern, called PFC or persistent pulmonary hypertension of the newborn (PPHN), further exacerbates the hypoxemia and acidosis. Although numerous treatments for PPHN (e.g., hyperventilation or vasoactive agents) have been used, a selective and highly effective vasodilator of the pulmonary circulation has not been identified. PPHN may be an isolated phenomenon, or it may be associated with a variety of clinical conditions, including meconium aspiration, sepsis, polycythemia, diaphragmatic hernia, hypoxemia, acidosis, and severe hypotension. An echocardiogram should be performed to exclude structural cyanotic heart disease (Peckham and Fox, 1978; Murphy et al., 1981). The primary treatment of PPHN is aggressive hemodynamic support, including 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 greater than 7.5) and hyperoxia to more gentle approaches, including maintenance of normal oxygenation, Paco₂, and pH with either conventional or high-frequency mechanical ventilators. Vasodilatory agents such as NO are often used, but the protocols vary from institution to institution. NO has significantly reduced the need for extracorporeal membrane oxygenation to treat PPHN (Field et al., 2007).

Cardiovascular Function in the Newborn

In spite of the intense age-related changes in myocardial physiology and function, the qualitative characteristics of the fetal and neonatal heart are similar to those of the adult in that blood pressure is directly proportional to CO and systemic vascular resistance (Table 17-3). The primary determinants of CO are heart rate and stroke volume. Preload, afterload, and myocardial contractility interact to determine ventricular performance. At all times, oxygen delivery and oxygen demands are interdependent; oxygen delivery (CO) is regulated by oxygen consumption (metabolism).

TABLE 17-3 Comparison of Neonatal and Adult Myocardial Functions

The high collagen content and high ratio of Type I collagen to Type III collagen may be responsible for the relative noncompliance of the neonatal heart and its limited capacity to respond to volume loading (Klopfenstein and Rudolph,1978). This nondistensible heart has limited capacity to increase stroke volume and augment CO when faced with an increased preload. Thus, the Frank-Starling response appears to have a limited role, and heart rate is the primary means of increasing CO in the newborn. Over the first months of life, myocardial contractility gradually increases, which allows CO to be maintained over a wider range of preloads and afterloads. Similarly, the increase in contractile proteins and the shift in the expression of various isoforms; the development of sarcoplasmic reticulum and T tubules, adrenergic innervation, calcium recruitment and transport; and the overall response of the myocardium to stress or increased demands all contribute to complex changes in force development.

The newborn’s CO per unit weight is the highest of any age group (approximately 200 mL/kg per minute). Teitel (1985) hypothesized that the greater increase in myocardial performance with adrenergic stimulation in older lambs is to the result of a “lesser resting β-adrenergic tone” in the older animals. That is, the baseline state of the newborn myocardium is at higher level of “β-adrenergic tone,” and the high resting CO of the newborn limits its ability to further increase CO in response to increased demand or to adapt to wide variations in preload or afterload. Because the newborn’s normal heart rate is high, increasing the heart rate has limited effect on CO, but decreasing the heart rate dramatically decreases output.

Volume loading of the immature ventricle increases CO, but the effect is less than that that seen at older ages (Klopfenstein and Rudolph, 1978). Similarly, the tolerance of the immature myocardium to increases in afterload is less than it is at older ages. Thus, the impaired ventricular function of the fetus (i.e., preterm baby) and newborn are the result of fewer myofibrils; decreased sympathetic innervation; decreased β-adrenoreceptor concentration; immaturity of the structure and function of the sarcoplasmic reticulum; maturation-specific mechanisms for calcium uptake, release, and storage; and a specific spectra of expression of various isoforms of contractile and noncontractile proteins, channels, exchangers, and enzymes.

Cardiovascular Evaluation

Preoperative evaluation of the newborn should focus on understanding “normal,” because infants of the same gestational age can vary significantly in their baseline heart rates and blood pressures (Fig. 17-5). Acid-base status (electrolytes, pH, Paco₂), urine output, and rates of fluid administration must be interpreted in the context of “normal” blood pressure and heart rate and the interventions required to maintain normalcy. Trends in these data over the hour, 6 hours, and 12 to 48 hours prior to examination help clarify the infant’s cardiac function. It is necessary to understand whether there were responses to fluid boluses and inotropic intervention, and if so, what those responses were with respect to maintenance of cardiovascular stability. This critical insight is important when developing a rational anesthetic plan. Finally, evaluation of the current level of sedation and the response to various agents also helps determine which drugs (e.g., morphine, fentanyl) and the amounts of each drug that are required to achieve the desired effect. This knowledge will guide the anesthesiologist in determining which drugs may be most effective during surgery.

FIGURE 17-5 A, Linear regressions (broken lines) and 95% confidence limits (solid lines) of systolic (top) and diastolic (bottom) aortic blood pressures on birth weight in 61 healthy newborn infants during the first 12 hours after birth. For systolic pressure, y = 7.13x + 40.45; r = 0.79. For diastolic pressure, y = 4.81x + 22.18; r = 0.71. For both, n = 413 and P < 0.001. B, SBP and DBP are plotted for first 5 days of life with each day subdivided into 8-hour periods. Infants are categorized by gestational age into the following four groups: ≤28 weeks (n = 33); 29 to 32 weeks (n = 73); 33 to 36 weeks (n = 100); and ≥37 weeks (n = 110). C, Blood pressure ranges in premature infants during the first week of life, with a gestational age of 31.4 ± 2.6 weeks.

(A From Versmold HT, et al.: Aortic blood pressure during the first 12 hours of life in infants with birth weight 610 to 4220 grams, Pediatrics 67:607, 1981; B From Zubrow AB, Hulman S, Kushner H, et al.: Determinants of blood pressure in infants admitted to neonatal intensive care units: a prospective multicenter study. Philadelphia Neonatal Blood Pressure Study Group, J Perinatol 15:470, 1995; C From Hegyi T, Anwar M, Carbone MT, et al.: Blood pressure ranges in premature infants: II. The first week of life, Pediatrics 97:336, 1996.)

Autoregulation of Cerebral Blood Flow

Critically ill newborns often require mechanical ventilation, airway suctioning, and intravenous fluid boluses, all of which can affect blood pressure, CO, heart rate, and cerebral blood flow. Hypoglycemia, hypercarbia, hypocarbia, hypoxia, hypo- or hypernatremia, and hypocalcemia can also dramatically affect the neonate’s hemodynamic status. Fluctuations in blood pressure and CO often affect the newborn’s CNS, since cerebral blood flow may change as a result of absent or attenuated cerebrovascular autoregulation. Cerebral blood flow autoregulation is present in both preterm and full-term newborns, but it is tenuous (Fig. 17-9). Also, the range of pressures over which blood flow is regulated is narrower for preterm infants. Cerebrovascular autoregulation is easily disrupted in neonates, and the normal blood pressure of preterm infants is close to the lower autoregulatory limit (Lou et al., 1979; Versmold et al., 1981; Tweed et al., 1983;Lou 1998). With decreasing gestational age, the lower limit approaches normal blood pressure. Similarly, the upper range of autoregulation may be approached during later gestational development (Papile et al., 1985). Furthermore, the normal range of autoregulation can be disturbed or disrupted by hypoxia, acidosis, seizures, and by the low diastolic blood pressures of patients with a PDA (Lou et al., 1979; Tweed et al., 1983; Lou, 1998). Rapid increases in arterial blood pressure can rupture the fragile vessels of the immature brain, while hypotension and low perfusion pressures may cause ischemia.

FIGURE 17-9 Autoregulation of cerebral circulation in neonates (curve B) and adults (curve A).

(Redrawn from Harris MM: Pediatric neuroanesthesia. In Berry FA, editor: Anesthetic management of difficult and routine pediatric patients, ed 2, New York, 1990, Churchill Livingstone. Data from Hernandez MJ, Brennan RW, Vannucci RC, Bowman GS: Cerebral blood flow and oxygen consumption in the newborn dog, Am J Physiol 234:R209, 1878).

Apgar Score

The Apgar score was initially proposed as a means of rapidly assessing the status of newborns at 1 minute after birth and as a means of determining whether a neonate required respiratory support (Apgar, 1953) (Table 17-4). As Casey and others (2001) recently suggested, “Every baby born in a modern hospital in the world is looked at first through the eyes of Virginia Apgar.” The Apgar score includes five variables with a range of scores from 0 to 2 (for a maximum of 10 points): heart rate, respiratory effort, muscle tone, reflex irritability, and color. Currently, the score is applied at 1 and 5 minutes, but in some cases the evaluation continues for as long as 20 minutes if continued resuscitative efforts are required.

The Apgar score has been demonstrated recently to be a predictor of mortality (Casey et al., 2001). In full-term infants, these authors found a mortality rate of 244 per 1000 (24.4%) for infants with 5-minute Apgar scores of 1 to 3, compared with 0.2 per 1000 (0.02%) for infants with 5-minute Apgar scores of 7 to 10. Similarly, in preterm infants of 26 to 36 weeks’ gestation, the mortality rate was 315 per 1000 (31.5%) for infants with 5-minute Apgar scores of 0 to 3 and 5 per 1000 (0.5%) for infants with 5-minute Apgar scores of 7 to 10. Thus, the incidence of neonatal death was highest when the 5-minute Apgar scores were 3 or lower, independent of gestational age. Neonatal death most commonly occurred during the first day of life, with the majority of infants dying before 3 days of age. These data indicate that the Apgar score is a valid predictor of neonatal mortality. In fact, the Apgar score better predicted outcome than umbilical-artery 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 increased the risk of death in both preterm and full-term infants. An Apgar score of 0 for longer than 10 minutes suggests that resuscitative efforts should be suspended (Jain et al., 1991). Papile (2001) stated, “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, with the etiology of neonatal depression, and with other factors, effective resuscitation of infants with low Apgar scores resulted in survival of about 40% to 60% of the patients and, approximately two thirds of survivors had normal neurologic function (Leuthner and Das, 2004). In 1964, the Collaborative Study on Cerebral Palsy reported a stronger relationship between the 5-minute Apgar score and neonatal mortality than the 1-minute score (Drage et al., 1964). Controversy about the Apgar score arises when people try to use the Apgar score to predict neurologic outcome. Dr. Apgar did not intend that the score be used to establish the diagnosis of asphyxia, to measure the severity of perinatal asphyxia, or to predict long-term neurologic outcome. In fact, 75% of children with cerebral palsy had normal Apgar scores at 5 minutes (Nelson and Ellenberg, 1981).

Pathophysiology of Hypoxic-Ischemic Injury

Asphyxia-related insults follow a pattern of early energy depletion and failure of the Na⁺, K⁺-ATPase pump, which disrupts normal transmembrane ion gradients. This loss of these gradients causes the release of excitatory neurotransmitters, such as glutamate, dopamine, serotonin, and aspartate. Although glutamate is important for normal brain development, excessive excitation of glutamate receptors (e.g., N-methyl-d-aspartate [NMDA], α-3-amino-hydroxy-5-methyl-4-isoxazole propionic acid [AMPA], and kainite) leads to excessive intracellular calcium concentrations and activation of a variety of phospholipases and proteases that cause the release of arachadonic acid and other mediators. Downstream production of xanthine and prostaglandins generates free radicals, in part via the NO synthase system. Although this is a condensed and simplified version of some of the pathways for cellular injury, the basic schema of hypoxic-ischemic injury is clearly one of disruption of membrane and intracellular function (Volpe, 2001). The clinical correlates of this intense cellular injury include seizures, abnormal mental status, eventual cell death, and long-term CNS deficits.

Neuroprotection

Gonzalez and Ferriero (2008) emphasized that treatment of neonatal brain injury should focus on both neuroprotection and after injury treatment. Optimal therapy may require intervening at multiple pathways to both prevent cell death and to induce cell growth and differentiation (Gonzalez and Ferriero, 2008). In general, therapies under evaluation attempt to decrease oxidative stress (e.g., inhibition of NO, melatonin, allopurinol, or deferoxamine), inflammation (e.g., minocycline), and excitotoxicity pathways (e.g., magnesium, MK-801, topiramate, or memantine). Other strategies include administering various growth factors, such as erythropoietin, a glycoprotein that has diverse CNS functions. These include vasogenic and immune responses that may provide neuroprotection during hypoxia and ischemia and modulate neurogenesis and neural differentiation. Primarily studies of VEGF in animals have shown that VEGF regulates both angiogenesis and neurogenesis. Cortical neurons are the primary site of VEGF-A activity early in development, but later its primary effect is on glial cells. VEGF seems to enhance the survival of neurons after hypoxia and after exposure to glutamate. Generating new neurons could play a major role in recovery after injury that results from perinatal stroke or hypoxia and ischemia.

Hypothermia is being used more often as a method of treating brain injury. It is hypothesized that hypothermia modifies apoptosis and necrosis of injured neurons by reducing their metabolic demands and by decreasing the release of excitotoxic mediators. Several studies have shown a significant reduction in CNS injury with cooling to 33° to 34° C for about 72 hours. Preliminary results suggested decreased mortality and improved neurodevelopmental outcome, although the differences in neurodevelopment after cooling are not large (Shankaran et al., 2005; 2008). Hypothermia plus another form of therapy may have greater therapeutic effect than either treatment alone (Alkan et al., 2001).

Seizures

Seizures occur commonly in neonates, especially after asphyxia (Silverstein and Jensen, 2007). Neonates with encephalopathy, stroke, intracranial hemorrhage, CHD, inborn errors of metabolism, and some syndromes are prone to develop seizures. Without an EEG, it may be difficult to tell if a neonate is having a seizure, because non–seizure-induced, repetitive movements are common. Cerebral palsy, low intelligence quotient (IQ), and epilepsy often accompany seizures and receptor expression, and neonatal seizures alter synaptic plasticity (Holden et al., 1982; Mellits et al., 1982; Swann and Hablitz, 2000 Stafstrom et al., 2006). Phenobarbital, diazepam, phenytoin, and valproate are commonly used drugs for the treatment of seizures, but these drugs can increase apoptotic neuronal death (Pereira de Vasconcelos et al., 1990; Schroeder et al., 1995). Furthermore, they fail to block neonatal seizures in as many as 50% of patients (Sankar and Painter, 2005). Hypoglycemia and hypocalcemia are other causes of seizures, and correcting these abnormalities usually terminates the seizures. The neonate’s Paco₂ should be maintained within the normal preoperative range (not reduced), because alkalosis lowers the seizure threshold and may induce a seizure. Anesthesia obscures overt seizure activity, especially when paralytic drugs are used.

Perinatal Stroke

Perinatal stroke has been more commonly recognized during the past few years because of improved neuroimaging. The incidence is 1:2300 to 1:5000 infants born at term and 7:1000 in those born prematurely (Raju et al., 2007; Benders et al., 2008). Infants with CHD have significantly more ischemic perinatal strokes than other neonates (Sherlock et al., 2009). Approximately 40% of neonates with transposition of the great vessels (TGV) show evidence of preoperative stroke; an additional one third has evidence of a new stroke after cardiac surgery. Many of the patients who had a stroke before surgery underwent balloon septostomy to improve oxygen—the incidence of stroke is high after this procedure (McQuillen et al., 2006). Strokes are either detected in the first few days of life or after 28 days of age. Those detected early are found because patients have seizures or undergo an MRI. Despite the evidence of a stroke, many neonates have no signs of neurologic dysfunction. They may not show signs of focal lesions or encephalopathy (Miller, 2000). Perinatal strokes are classically located within the boundary of the area perfused by the middle cerebral artery, usually the left cerebral artery (Schulzke et al., 2005). The incidence of arterial perinatal stroke is similar in preterm neonates to that of term infants (de Veber et al., 1998). Cerebral venous thrombosis is another cause of perinatal strokes and is usually detected when the neonate develops seizures (Wu et al., 2003). Venous infarctions often become hemorrhagic.

Many infants with perinatal strokes show no evidence of injury in the neonatal period. The diagnosis is only made at 4 to 8 months of age when hemiplegia, seizures, or difficulty with locomotion or handedness are detected. Again, most of these injuries are the result of middle cerebral-artery occlusion.

The cause of a stroke in a given patient is almost never known. However, possible maternal factors include chorioamnionitis, prolonged rupture of the membranes, preeclampsia, and intrauterine growth retardation (Wu et al., 2004b). Twenty percent to 68% of infants with arterial ischemic stroke had prothrombotic states (Golomb et al., 2001). Polycythemia is also a cause of neonatal stroke, and suggested factors related to perinatal stroke include infection, inflammation, and hypoglycemia (Günther, et al., 2000; Benders et al., 2007).

Preoperative Neurologic Evaluation

Neurologically injured newborns often require surgery to treat CNS abnormalities (e.g., insertion of a ventriculoperitoneal shunt), to provide supportive care (e.g., insertion of a gastrostomy tube or central venous catheter for intravenous alimentation), or to treat associated anomalies and problems (e.g., repair of congenital diaphragmatic hernia [CDH], laparotomy to treat an intraabdominal crisis, repair of a meningomyelocele, or insertion of a vetriculoperitoneal shunt).

There are some important questions to answer as part of the preoperative evaluation of the nervous system of neonates. Does the neonate breathe spontaneously and is the heart rate relatively stable and normal (120 to 160 beats per minute)? Is the fontanel normal (i.e., skin even with the outer table of the skull), bulging (from increased intracranial pressure), or sunken (from dehydration or volume depletions)? Is the muscle tone normal for the infant’s age? Differences in tone between the upper and lower extremities or between one side of the body or the other may suggest the presence of a neonatal stroke (Ibrahim et al., 2008). Does the infant bring his hands and arms together in front of the chest (Moro reflex) when the arms are raised and suddenly released? Is the Moro reflex equal bilaterally? Does the infant grasp the examiner’s finger when it is placed in a hand? When a finger is placed on the anterior sole of the foot, do the toes curl in a grasping motion? Is the Babinski reflex normal? Without experience it may be difficult to elicit deep tendon reflexes in neonates, especially preterm neonates. Do the eyes move normally when a flashlight is moved in different directions? The pupils should constrict to light, and there should be evidence of a gag reflex and a suck. A complete neurologic examination should be documented in the patient’s chart to note neurologic abnormalities that predate surgery and anesthesia.

In addition to the above questions, infants with neurologic injury who are undergoing preoperative assessment are usually divided into three categories:

Preoperative evaluation of neurologically stable infants with no evidence of acute cardiorespiratory, hepatic, or renal problems and who require an elective surgical or diagnostic procedure should focus on determining what is normal for each patient. That is, what is the range of an infant’s normal blood pressure, heart rate, respiratory rate, oxygen saturation (and Fio₂), urine output, and nutritional status. These variables should be kept within this normal range if possible. The neurologic status should be documented, including evidence for gastroesophageal reflux and its treatment, as well as the incidence of seizures (if any) and their treatment. If available, electrolyte and calcium concentrations and liver function studies should be reviewed. If the neonate’s course is stable and the procedure proposed is noninvasive, the most relevant laboratory value is a hematocrit.

Infants whose condition is stable except for ongoing neurologic problems (e.g., encephalopathy or seizures) require review of their vital signs, laboratory values, and medications, and they must have an appropriate physical examination. The hemodynamic responses to sedatives and analgesics and to painful procedures should be reviewed so the anesthesiologist can develop an anesthetic plan that will minimize wide variations in blood pressure. It should be determined whether the intravascular volume is adequate. Rapid administration of intravenous fluid during induction of anesthesia should be avoided because doing this may suddenly increase arterial and intracranial pressures, which can cause intracranial hemorrhage, especially in preterm neonates. The intracranial hypertension and increased intracranial volumes occur because cerebrovascular autoregulation is abnormal or absent. Both hypertension and hypotension can exacerbate neurologic injury. If available, near-infrared spectroscopy (NIRS) or EEG data should be reviewed. Do feeding, suctioning the trachea, medications (e.g., sedation), and fluid therapy alter cerebral oxygenation (Baserga et al., 2003)? If the patient is mechanically ventilated, understanding how oxygenation and ventilation are affected by various interventions may provide clues to the best ventilatory strategy to employ during surgery.

Finally, if the surgery is urgent or emergent, the overwhelming focus must be on the lesion that is making the surgery urgent, but the trends in cardiorespiratory and metabolic status must also be evaluated so that intraoperative management will have the least effect on the CNS injury and not make it worse.

Postanesthetic Apnea

Preterm and expremature infants undergoing elective surgery are prone to develop postoperative apnea (Steward, 1982; Gregory and Steward, 1983). Apnea is usually defined as cessation of breathing for 20 seconds or more. The likelihood of life-threatening postoperative apnea increases if the patient had apneic spells in the NICU (Liu et al., 1983). Twenty percent to 30% of preterm infants have apnea with cyanosis and bradycardia during the first month of extrauterine life. Steward (1982) reported the presence of apnea in 18% of preterm infants (with a gestational age of fewer than 38 weeks or a postnatal age of 3 to 28 weeks) during the first 12 hours after surgery.

A prospective study by Liu et al. (1983) found that a history of apnea and a postconceptual age of fewer than 44 weeks often resulted in apnea after surgery. Kurth and LeBard (1991) reported that postanesthetic apnea (defined as cessation of breathing for more than 15 seconds, not longer than 20 seconds) occurred commonly in expremature infants whose postconceptual ages varied from 32 to 55 weeks. The initial episode of apnea occurred as late as 12 hours after the termination of anesthesia. These authors recommended that infants who whose postconceptual age was younger than 60 weeks and who developed apnea after surgery be continuously monitored in the hospital until they were apnea free for at least 12 hours.

Welborn et al. (1986) found no evidence of apnea in a group of healthy premature infants who had a postconceptual age of 44 weeks or more at the time of surgery and who underwent general anesthesia for herniorrhaphy. Although many of these patients did not have apnea, 63.6% of the them had periodic breathing, a common finding in premature infants that is characterized by repetitive apneas of short duration (fewer than 5 to 10 seconds) without oxygen desaturation or cyanosis and is usually harmless. Malviya et al. (1993) noted that expremature infants younger than a postconceptual age of 44 weeks had significantly more apnea than older infants. Coté et al. (1995), using data from 255 patients garnered from previously published studies, found an incidence of apnea of 1% in infants of 55 to 56 weeks’ postconceptual age. They also found an inverse relationship between postconceptional age and the incidence of apnea. Those who were 56 weeks’ postconceptual age or younger had the greatest risk for apnea. Anemia (Hct < 30%) was also an important risk factor for apnea (Fig. 17-10).

FIGURE 17-10 Predicted probability of apnea for all patients, by gestational age and weeks of postconceptual age. Patients with anemia are shown as the horizontal line. The bottom marks indicate the number of data points by postconceptual age. The shaded boxes represent the overall rates of apnea for infants within that range of gestational ages. The probability of apnea was the same regardless of postconceptual age or gestational age for infants with anemia.

(Redrawn from Coté CJ, et al.: Postoperative apnea in former preterm infants after inguinal herniorrhaphy: a combined analysis, Anesthesiology 82:807, 1995.)

Nearly all patients in these studies of postoperative apnea in prematurely born infants in the past were anesthetized with halothane or isoflurane, drugs that have higher blood-gas solubility coefficients than newer inhaled anesthetics such as sevoflurane and desflurane. These less soluble agents have been associated with a lower incidence of apnea in patients who do not have a history of preoperative apnea (William et al., 2001).

Other factors that predispose infants, especially premature infants, to apnea include hypoglycemia, hypoxia, hyperoxia, sepsis, anemia, hypocalcemia, and changes in the environmental temperature (Schulte, 1977). Postoperative apnea may also be the result of the interaction of general anesthesia with an immature CNS (including the respiratory center). For example, in low concentrations, halothane depressed the chemoreceptor responses to hypoxia (Knill and Gelb, 1978). Inhaled anesthetics also depressed intercostal muscles function, thus reducing the FRC and increasing the risk of hypoxemia (Tusiewicz et al., 1977). These differences, coupled with an immature response to hypoxia and hypercarbia, predispose premature infants to erratic respiratory responses in the perioperative period (Rigatto et al., 1982).

Residual anesthesia in the postoperative period may also be an important factor in the development of apnea in preterm babies. This may be especially true when halothane, with its high lipid solubility, was the standard anesthetic in pediatric anesthesia. The cartilaginous upper airway of preterm infants may also predispose them to upper airway obstruction, and this obstruction may be made worse by the effects of residual anesthesia on pharyngeal muscles (Dransfield et al., 1983). Elective surgery should be delayed, if possible, until former preterm infants are beyond 44 weeks’ postconceptual age (Gregory and Steward, 1983). Infants younger than 44 weeks’ postconceptual age who require surgery must be individually evaluated. The type of surgery, the patient’s gestational and postconceptual age, hematocrit, current cardiorespiratory function (i.e., oxygen or diuretic dependence, CLD, neurologic status) are all factors that must be taken into consideration when developing a perioperative plan for the expremature infant. These patients should be admitted to hospital for 24 to 36 hours for postoperative monitoring.

Glucose Metabolism

The fetal supply of glucose is abruptly interrupted at birth, requiring neonates to meet their glucose needs by glucose intake, by converting glycogen (which is stored in the liver and heart during the third trimester of pregnancy) to glucose, and by glycogenolysis. Glycogen breakdown is under the control of catecholamines and glucagon. The liver of infants born at term has a greater store of glycogen than the adult (Kalhan and Parimi, 2000). Glycogenolysis allows full-term infants to maintain normal serum glucose concentrations during a 10 to 12 hour fast. Since glycogen storage and the capacity for degradation mostly occur during the last trimester of pregnancy, preterm infants are predisposed to hypoglycemia. Gluconeogenesis is not active in fetal liver, but a variety of hepatic enzymes that are important in gluconeogenesis (e.g., glucose-6-phosphatase) undergo rapid development after birth (Kalhan and Parimi, 2000; Kalhan et al., 2001).

Preoperatively, most newborns receive an intravenous infusion containing 5% to 10% dextrose. In general, an infusion rate for dextrose of 4 to 7 mg/kg per minute (e.g., 10% dextrose at 4 mL/kg per hour equals 6.6 mg/kg per minute of dextrose) maintains normoglycemia in both full-term and preterm infants. Normal glucose levels are between 40 and 60 mg/dL. A blood sugar concentration of less than 40 mg/dL is defined as hypoglycemia. The symptoms of hypoglycemia are nonspecific and include jitteriness, cyanosis, apnea, lethargy, seizures, and hypotonia. The common causes of hypoglycemia include hypoxemia, sepsis, and high levels of circulating insulin. During a preoperative visit, the serum glucose concentration achieved with the current rate of intravenous glucose administration should provide the information needed to determine what glucose infusion rate is required during surgery. Occasionally administering this amount of glucose produces hyperglycemia, and the infused concentration of glucose must be reduced, usually to 2.5% dextrose.

Biotransformation

The liver is the primary site for metabolism of drugs and other xenobiotics, as well as for detoxification of nontherapeutic and environmental compounds. Because of this vital function, the liver is vulnerable to the toxic effects of these compounds. Because degradation pathways are immature, infants (especially newborns) may metabolize drugs and toxins less efficiently than older patients. Three main categories of hepatic-drug metabolizing systems include phase I (oxidation-reduction and hydrolysis), phase II (conjugation with glucuronic acid, glycine, acetate, or sulfate), and phase III (transport from liver) reactions. In general, the neonatal liver has less capacity to metabolize and excrete drugs because there are deficiencies of many of the enzymes involved in oxidation, reduction, hydrolysis, and conjugation.

Cytochrome P450 (CYP) enzymes are responsible for phase I processes. More than 50 CYP enzymes have been identified, and they are classified according to their nucleotide sequence (Wilkinson, 2005). Although the full clinical relevance of the relative expression of these enzymes in fetus and neonates is yet to be defined, their primary expression is in the liver, and their developmental expression has a major role in the pharmacokinetics and pharmacodynamics of drugs, including those used during anesthesia. The CYP3A family is responsible for metabolism of about 50% of all drugs (Hines and McCarver, 2002). Multiple patterns of developmental expression have been reported (Figs. 17-11 and 17-12). For example, although CYP3A7 is present in utero, its expression is negligible 1 week after birth. On the other hand, the concentration of CYP3A4 is low during fetal life but is about 50% of adult levels by 6 months of age. CYP2D6 has a multitude of polymorphisms and may be of particular relevance in the metabolism of psychotropic (and anesthetic) drugs (Blake et al., 2005). Clearly, as the ontogeny of metabolizing enzymes and transporters is understood, the dosing of drugs will be better adjusted for age-related differences, toxicity may be avoided, and clinical effectiveness will be improved.

FIGURE 17-11 Changes in metabolic capacity. The activity of many cytochrome P-450 (CYP) isoforms and a single glucuronosyltransferase (UGT) isoform is markedly diminished during the first 2 months of life. In addition, the acquisition of adult activity over time is enzyme- and isoform-specific.

(From Kearns GL, et al.: Developmental pharmacology-drug disposition, action, and therapy in infants and children, N Engl J Med 349:1157, 2003.)

FIGURE 17-12 Ontogeny of cytochrome P450 (CYP) 3A4 and 3A7 activity expressed as activity measured using isoform-specific probes in human liver microsomes.

(From de Wildt SN, et al.: Cytochrome P450 3A: ontogeny and drug disposition, Clin Pharmacokinet 37:485, 1999.)

Fewer data are available concerning the ontogeny of phases II and III. However, the uridine glucuronosyltransferases (UGTs) function at much lower levels in neonates than they do in adults. For example, glucuronidation of morphine reaches adult levels only at 2 to 6 months of age (de Wildt et al., 1999). Other conjugating enzymes with major roles in drug metabolism have been less well characterized (glutathione S-transferases, N-acetyltransferases, glucuronosyl transferases), but they are likely to play important roles in the unique drug handling commonly seen in the newborn.

Although the clinical implications of the genetic variability and developmental changes of hepatic metabolizing processes are not clearly identified, examples of age-related differences in drug responses are well documented. For example, the age-related pharmacokinetics of various muscle relaxants and narcotics were described more than 20 years ago (Cook, 1981; Fisher et al., 1982; Gauntlett et al., 1988). Caffeine and theophylline are metabolized by CYP1A2, which is expressed at low levels in the newborn and requires age-related considerations for therapeutic dosing (Hakkola et al., 1994). More recently, both postnatal age and postconceptual age were correlated with decreased and variable propofol clearance in preterm and full-term infants. Of note, multiple cytochrome P450 enzymes are required for metabolism of this drug. Consequently, altered expression of phases I and II hepatic metabolic enzymes may be responsible for these pharmacokinetic findings (Allegaert et al., 2007).

The preoperative evaluation of a newborn should include a review of current medications and determination of unexpected durations of action, toxicity, or side effects. In general, prolonged effects of these drugs can be expected in neonates because the enzymes of metabolism and elimination are immature.

Coagulation

The fetus produces coagulation factors because they inefficiently cross the placenta. Plasma levels of some coagulation proteins and factors and laboratory tests of clotting function (e.g., prothrombin time [PT] and activated partial thromboblastin time [APTT]) are markedly different in healthy full-term and preterm infants than in adults (Table 17-5).

Plasma concentrations of vitamin K–dependent proteins (e.g., factors II, VII, IX, and X), as well as factors XI and XII, prekallikrein, and kininogen, are about 50% lower than those of adults, but the concentrations of fibrinogen, factor V, and factor VIII are similar to those of adults (Andrew et al., 1987; 1988).

Disturbances in clotting caused by liver dysfunction correlate with decreased synthesis of both clotting and fibrinolytic factors and with abnormal platelet function. Hepatocytes synthesize factors 1 (fibrinogen), II (prothrombin), V, VII, IX, and X, and abnormal production of these factors is reflected in a prolonged PT. The PT mostly reflects availability of factor VII. Thrombin levels of newborns are about 50% those of adults. APTT primarily reflects the amount of thrombin generated (Green et al., 1976).

In spite of differences between newborn and adult liver function, clinically significant bleeding is uncommon in normal neonates who have adequate vitamin K levels. The association of vitamin K deficiency and hemorrhage in the newborn was initially described in 1894, is secondary to inadequate activity of vitamin K–dependent coagulation factors (i.e., II, VII, IX, and X), and is corrected by vitamin K replacement (Sutor et al., 1999). On the other hand, the newborn is predisposed to bleeding by infections and asphyxia, which may cause DIC. DIC is associated with prolonged PT and APTT that are caused by depletion of certain coagulation factors (e.g., fibrinogen and factors V and VIII), with increased fibrin degradation products, and thrombocytopenia.

Preoperative evaluation should initially focus on whether or not there is a history of bleeding. If no clinical bleeding has been noted and the PT and PTT are normal for age, no further preoperative evaluation or treatment is indicated. Since many infants requiring surgery have significant physiologic derangements and nutritional deficiencies, laboratory studies, including a PT and APTT and a platelet count, should be obtained. If bleeding has occurred or if the laboratory studies are abnormal and there is clinical instability (e.g., sepsis or NEC), aggressive treatment is indicated. Preoperatively, interpretation of responses to fresh frozen plasma (FFP) (which contains adult levels of all coagulation proteins) or cryoprecipitate (which contains high levels of fibrinogen and factor VIII) will aid in planning to maintain intraoperative hemostasis. FFP is used sometimes for intraoperative volume repletion if hemostasis is also abnormal. However, rapid administration of FFP can cause hypotension because of the high concentrations of histamine present in some FFP and because of decreased ionized calcium concentrations caused by citrate. If large volumes of intravenous fluids are not needed, cryoprecipitate may be used to correct the fibrinogen and factor VIII deficiencies associated with DIC. Cryoprecipitate does not correct other clotting deficiencies.

Hyperbilirubinemia

Increased serum bilirubin concentrations are almost universal during the first postnatal week. (Kahlan and Parini, 2000). In most cases, hyperbilirubinemia is transient and has been labeled physiologic. The primary source of bilirubin is hemoglobin, but other heme-containing proteins (e.g., cytochromes, catalases, and myoglobin) also contribute. Infants produce more bilirubin per kg of body mass than older patients because they have higher red cell masses and their red blood cells have shorter life spans. Bilirubin is the end product of hemoglobin breakdown and has also been reported to be an antioxidant and a free-radical scavenger (Sedlak and Snyder, 2004).

Because of its large nonpolar structure, bilirubin is lipophilic and requires biotransformation for excretion. Binding of bilirubin to albumin facilitates its delivery to the liver, and uptake of bilirubin into hepatocytes for conjugation requires glucuronic acid (i.e., organic anion transporter, [OATP2]) (Cui et al., 2001). Uridine diphosphate glucuronic acid provides the glucuronic acid. Most bilirubin is excreted in bile as bilirubin diglucuronides. Upon entry into the intestinal lumen, a variety of pathways exist for further disposal of bilrubin. As occurs in adults, bacteria metabolize bilirubin to urobilinogens for excretion in feces. Since the neonatal gastrointestinal tract lacks the same bacterial flora as adults, bilirubin may be reabsorbed and raise the serum bilirubin concentration. Beta-glucuronidase is also important for bilirubin metabolism, because it deconjugates bilirubin. Although this enzyme clears unconjugated bilirubin from the placenta, it increases bilirubin reabsorption from the gut after birth. Breast milk contains high level of β-glucuronidase and is partly responsible for “breast-milk jaundice” (Gourley and Arend, 1986).

Even if significant hemolysis occurs in utero, the normal placenta efficiently clears the bilirubin, and the newborn is seldom jaundiced. However, after birth the same bilirubin production would cause jaundice in most infants. With increasing bilirubin concentrations, the skin becomes progressively yellow (icteric) in a cephalocaudad pattern (Knudsen, 1990). The term physiologic jaundice refers to the common, transient, indirect (unconjugated) hyperbilirubinemia in normal newborns. However, jaundice should be considered abnormal if it is present in the first 36 hours of life, persists beyond 10 days of life, is greater than 12 mg/dL, and the direct (conjugated) bilirubin is greater than 2 mg/dL or more than 30% of the total bilirubin concentration. Multiple disorders of increased bilirubin production (e.g., hemolysis secondary to maternal-fetal blood group incompatibility, other hemoglobinopathies, reabsorption of red blood cells from a hematoma, and polycythemia) or decreased excretion (e.g., as with genetic diseases, hypothyroidism, or infants of diabetic mothers) are recognized. Preterm infants more commonly develop elevated levels of bilirubin and are more vulnerable to bilirubin-induced CNS toxicity. CNS toxicity, or kernicterus, results from hyperbilirubinemia. Neuronal necrosis is the predominant feature and occurs mostly in the basal ganglia, brainstem, occulomotor nuclei, and cochlear nuclei.

During the preoperative visit, levels of total and direct bilirubin and their trends should be determined, as these levels and trends may reflect either normal postnatal development or sepsis and other anomalies. Hyperbilirubinemia, in association of other laboratory values, may provide an estimate of possible hepatic dysfunction and suggest the need for additional laboratory studies. Various tests evaluate direct injury to the liver; alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and bilirubin concentrations may be increased as a result of asphyxia-ischemia-hypoxia (“shock liver”), sepsis, toxin-induced injury, or hepatitis. Direct bilirubin concentrations contribute to the hyperbilirubinemia that occurs with sepsis. Abnormalities in alkaline phosphatase, γ-glutamyltransferase (GGT), and 5-nucleotidase (5-NT) are more often to the result of impaired bile flow or cholestasis. Specific clearances of substances, such as indocyanine green and paraaminobenzoic acid (PABA), are measures of hepatic excretory function. While albumin is synthesized only in the liver, abnormal serum albumin levels may also result from protein lost in the gastrointestinal track or kidney or from chronic infection. Finally, abnormal ammonia concentrations should suggest the presence of specific urea-cycle defects. During preoperative assessment, the goal is to understand the functional status of the liver and to estimate the effect of current liver function on drug metabolism, blood loss, surgical trauma, and the need for coagulation factors.

Renal Tubular Function

Maintenance of normal extracellular fluid volume, water balance, sodium, and other electrolyte concentrations are interrelated and undergo significant postnatal changes. In addition to the marked changes in nephron number, glomerular function, and renal blood flow, developmental changes occur in the renal tubules throughout fetal and postnatal life. Coupled with tubular immaturity, metabolic demands of rapid growth and illnesses make managing fluids and providing nutritional support complicated in the newborn. The following factors should be considered:

FIGURE 17-13 Scattergram demonstrating the inversion correlation between fractional sodium excretion and gestational age.

(From Siegel SR, et al.: Renal function as a marker of human renal fetal maturation, Acta Paediatr Scand 65:481, 1976.)

All renal tubular cells are polarized. The apical membrane faces the lumen of the tubule, and the basal membrane faces the capillaries. Sodium is actively reabsorbed along the entire tubular system. Most sodium-coupled transporters required to salvage amino acids, glucose, phosphate, and lactate are located on the apical membrane of the proximal tubules. The Na⁺, K⁺-ATPase pump, which is responsible for approximately 70% of renal oxygen consumption, is located on the basolateral membrane and is important for active transport of sodium. About 60% to 80% of sodium reabsorption occurs in the proximal tubules. Another 10% to 15% occurs in the distal (i.e., aldosterone responsive) and collecting tubules (antidiuretic hormone [ADH] determines water permeability). The amount of sodium in fluid presented to the distal tubules depends in part on the efficiency of the proximal tubules.

After birth, reabsorption of sodium in the proximal tubules increases five- to tenfold in response to increased Na⁺, K⁺ -ATPase activity (Holtbäck and Aperia, 2003). Glucocorticoid hormones increase messenger ribonucleic acid (mRNA) for both subunits of this enzyme, and prenatal administration of betamethasone to mature the lungs may also mature renal function. Similarly, developmental changes in the Na⁺–H⁺ exchanger (NHE) may be responsible for differences in acid-base balance among newborns, older children, and adults. The kidneys both reabsorb bicarbonate and excrete fixed acids. Bicarbonate reabsorption occurs primarily in the proximal tubules, but it also occurs in the loop of Henle and the collecting ducts. Hydrogen is actively secreted, and the secreted hydrogen reacts with bicarbonate to produce carbonic acid and carbon dioxide. These substances enter the tubular cells through the action of carbonic anhydrase. Bicarbonate again forms and exits the cell via another transport mechanism. Several isoforms of NHE have been identified, and impaired function of this transporter has been described (Rodríguez-Soriano, 2000; Holtbäck and Aperia, 2003). Immature carbonic anhydrase activity and impaired NHE function explain in part the normal metabolic acidosis found in newborns.

Distribution of total body water changes throughout fetal life (Friis-Hansen, 1983; Brans, 1986). At 16 weeks’ gestation, the total body water makes up 94% of the fetus’ weight; at about 32 weeks’ gestation it is 82%, and at term it is approximately 75%. The size of the extracellular compartment decreases from 65% at 16 weeks’ gestation to about 60% at 24 to 25 weeks’ gestation, to about 50% at term. At the same time the intracellular compartment increases from 34% in early gestation to 50% at term. Of note, most extracellular water is in the interstitial space (i.e., an extracellular compartment). This is exaggerated in preterm neonates, especially ELBW neonates, whose extracellular water compartments are very large.

During the first 3 to 7 days of extrauterine life, healthy term infants lose about 5% to 10% of their body weight, primarily through contraction of the extracellular water space (Fig. 17-14). Preterm infants follow a similar pattern, but they may lose more than 15% of their body weight; premature infants also take longer to establish steady growth than full-term infants do. Cardiorespiratory abnormalities and their treatment, infections and their side effects, and pharmacologic interventions so alter growth patterns that it is difficult to define normal growth patterns in preterm neonates.

FIGURE 17-14 Extrauterine growth chart according to gestational age in weeks.

(Data from Schaffer SG, Quimiro CL, Anderson JR, Hall RT: Postnatal weight changes in low–birth-weight infants, Pediatrics 79:702, 1987; Gleason CA, Taeusch HW, Ballard RA, editors: Avery’s diseases of the newborn, ed 8, Philadelphia, 2005, Saunders, p. 1575.)

Hormonal control of neonatal fluid and electrolyte homeostasis is complex, and some of its features are unique. The renin-angiotensin-aldosterone, atrial natriuretic peptide (ANP), vasopressin, and catecholamine (i.e., dopamine and noradrenalin) systems affect regulation of electrolytes and water balance. However, the overall effectiveness of each of these systems is less than it is later in development. For example:

Based on the complex interactions of renal development, illness, prematurity, and therapy, fluid and electrolyte management in the newborn should take the following factors into account:

FIGURE 17-15 A, The effects of gestation on transepidermal water loss. Measurements were made from abdominal skin and carried out in the first few days of life. B, Insensible water loss (IWL) as a function of birth weight in premature infants nursed under radiant warmers. C, Transepidermal water evaporation from the skin of premature neonates with gestational ages of 25 to 40 weeks, followed longitudinally from birth over the first month of life. Dehydration is the most dangerous in the first week of life for the most immature babies of less than 28 weeks’ gestation, before skin keratinization occurs.

(A, From Hammarlund K, et al.: Transepidermal water loss in newborn infants, III: relation to gestational age, Acta Paediatr Scand 68:795, 1979. B, Adapted from Costarino AT, Baumgart S: Controversies in fluid and electrolyte therapy for the premature infant, Clin Perinatol 15:863, 1988. C, From Sedin G, et al.: Measurements of transepidermal water loss in newborn infants, Clin Perinatol 12:79, 1985.)

The high anabolic rate associated with growth makes the neonate’s limited ability to excrete solute a problem. Moreover, this increased solute load occurs at a time when the therapeutic index for fluid and electrolytes is narrow (especially in VLBW infants), when insensible water losses are enormous, when there is renal immaturity or insufficiency, and when multiorgan effects of prematurity and infection are common.

Preoperative Hematologic Evaluation

Several important questions must be answered during the preoperative evaluation. Is there evidence of bleeding? Are there petechiae or skin hemorrhages? Is there, or has there been, recent active bleeding into the bowels, lungs, or the brain? What is the platelet count, and has it decreased over the previous 24 hours? Were platelet transfusions required to maintain the desired platelet count, usually greater than 100,000/mm³? Are PT and PTT normal? If not, has the patient been treated with FFP? How many times? How much did FFP improve the PT, PTT, and international normalized ratio (INR)? For how long does it remain improved (normal)? When was FFP last administered? What is the WBC count? Is it increased or decreased from normal? Does an increase or decrease in the WBC count occur with sepsis? What are the patient’s hemoglobin concentration and hematocrit value? Are they high? If so, is this because of overtransfusion or dehydration? Is the hematocrit value low? If so, is the low hematocrit value caused by bleeding or by excessive blood drawing? Is blood available for the patient in the blood bank? How many units have been cross-matched against the child? How old is the blood? Blood that has been in the blood bank for more than a few days has an elevated potassium concentration, often in excess of 10 mEq/L. If this blood is administered rapidly to replace blood loss in neonates, a potassium-induced cardiac arrest may occur, which may be difficult to treat (Brown et al., 1990). Because many infants have potassium concentrations of 5 mEq/L or more, rapid addition of potassium during blood transfusion may be disastrous or lethal.