Oxygen Consumption

The cardiopulmonary system of the neonate is driven by the need to deliver sufficient oxygen (O₂) to maintain a high metabolic rate. The O₂ consumption of an average neonate is 5 to 8 mL/kg/min, whereas that of an adult is 2 to 3 mL/kg/min (Table 36-1). It is this high rate of O₂ consumption that primarily leads to the rapid decrease in blood O₂ partial pressures in the neonate during periods of hypoventilation. Although ventilatory gas exchange volume is nearly 10-fold greater in adults than in neonates, the tidal volume relative to body weight for both is approximately equal (6 mL/kg). In neonates, increasing the respiratory rate facilitates the elimination of carbon dioxide (CO₂) generated by their relatively high metabolic processes; alveolar ventilation is approximately 130 mL/kg/min in the perinatal period, compared with 60 mL/kg/min in adulthood. In neonates, the thoracic gas volume on a weight basis is similar to that in adults. These metabolic and volume changes are consistent with those predicted by allometric scaling (see Chapter 6).¹

TABLE 36-1 Lung Function in Infants and Adults

Pulmonary Gas Exchange

Preterm neonates may have abnormalities in lung surfactant activity. Surfactant production by type II alveolar pneumocytes occurs predominantly after 32 weeks of gestation. Infants born prematurely may develop respiratory distress syndrome (RDS) because of surfactant deficiency. However, infants of mothers with gestational diabetes may develop RDS even when born near term. RDS is characterized by grunting respirations, nasal flaring, and chest retractions, developing soon after birth. Radiographic examination demonstrates decreased lung volume resulting from widespread atelectasis. The resultant intrapulmonary shunting of blood through atelectatic lung units causes intrapulmonary shunt and systemic hypoxemia and reduces O₂ delivery to the tissues. Judicious application of positive end-expiratory pressure (PEEP) and treatment with exogenous surfactant may reduce intrapulmonary shunting in RDS and decrease hypoxemia.^2–6 In addition, the incidence and severity of RDS has been decreased by the now routine treatment of mothers who are in preterm labor with glucocorticoids.

Atelectasis in neonates also might be caused by anatomic forces that decrease lung volume. For example, the relatively large abdomen in a neonate displaces the diaphragm cephalad, placing the lungs’ closing capacity within the expiratory reserve volume. Moreover, increases in intraabdominal pressure from gastric distention associated with overzealous assisted ventilation with a facemask, replacement of bowel in the abdomen during repair of gastroschisis or omphalocele, or surgical retraction or manipulation of the abdominal contents also might shift the closing capacity to within the infant’s expiratory reserve volume. The resulting atelectasis and intrapulmonary shunting may require controlled ventilation with PEEP to recruit closed lung units and improve oxygenation, emptying of the stomach, or changes in surgical maneuvers.

In the neonate, apnea decreases pulmonary gas exchange and can lead to hypoxemia and bradycardia. Conceptually, apnea is differentiated in terms of its cause: (1) central apnea, resulting from immaturity or depression of the respiratory drive; (2) obstructive apnea, caused by an infant’s inability to maintain a patent airway; and (3) mixed apnea, a combination of both central and obstructive apnea.⁷

Apnea of central origin may be secondary to the poor organization and integration of input from proprioceptive receptors, which are located in the diaphragm and intercostal muscles, and from medullary and peripheral chemoreceptors. Preterm infants are at greater risk for central apnea because chemoreceptor signaling is incompletely developed. Exaggerated responses to chemoreceptor signaling during periods of mild hypercarbia and hypoxia can cause apnea in preterm infants, in whom it might stimulate the respiratory rate in those born at term. Susceptibility to central apnea is also exacerbated by metabolic disturbances such as hypothermia, hypoglycemia, and hypocalcemia, even in full-term neonates. For these reasons, central apnea may be associated with anemia and sepsis in babies. Blood transfusions may decrease the incidence of apnea in preterm infants with a hematocrit less than 27%^8,9; however, data suggest a poor correlation between anemia and the incidence of apnea or bradycardia episodes.¹⁰ Central apnea resulting from immaturity of the respiratory drive center is often treated with xanthine derivatives, such as caffeine and theophylline (Table 36-2).^11–14 Of particular importance to the anesthesiologist is that central apnea in neonates can be exacerbated by opioids. In some cases, apnea in neonates exposed to opioids may be alleviated by treatment with naloxone. Because of these reasons, all neonates require careful continuous monitoring of blood O₂ saturations and heart rate in the postoperative period.

TABLE 36-2 Primary Categories of Apnea in Infants

Apnea of an obstructive or mixed origin is responsible for the majority of apneic episodes in preterm infants.^15–17 Obstructive apnea may be due to incomplete maturation and poor coordination of upper airway musculature. These forms of apnea often respond to changes in head position, insertion of an oral or nasal airway, or placing the infant in a prone position. Application of continuous positive airway pressure (CPAP) also may reduce obstructive apnea.¹⁸

Postoperative apnea is a common morbidity associated with anesthesia in neonates with a history of prematurity, apnea, or chronic lung disease.¹⁹ Nearly 20% of such infants have apnea exacerbated by anesthesia or surgery in the postoperative period. Apnea may result from prolonged action of anesthetic agents, a shift of CO₂ response curve, immaturity of respiratory control, or fatigue of respiratory muscles.²⁰ Early studies suggested that preterm infants who were younger than 46 weeks postconceptional age (PCA*) at the time of general anesthesia require continuous cardiopulmonary monitoring in the hospital afterward until they are apnea-free.¹⁵ Kurth and colleagues²¹ extended these recommendations to include monitoring for premature infants younger than 60 weeks PCA for at least 12 apnea-free hours after surgery. Although several studies suggest that regional anesthesia techniques reduce the incidence of postoperative apnea, others reported that apnea may still occur if the regional technique is supplemented with a sedative (e.g., ketamine).^22–25 An analysis of several hundred former preterm infants studied prospectively from four centers over 6 years revealed the following²⁶:

Apnea also might be associated with nasal obstruction in infants. Although most neonates prefer to breathe through their nose, a few are obligate nasal breathers and do not overcome nasal airway obstruction by changing to mouth breathing.^32,33 In such neonates, nasal obstruction caused by choanal stenosis or atresia or a nasogastric tube may lead to apnea and cyanosis. Obstruction resulting from nasal edema may be relieved by instillation of saline or phenylephrine nose drops.

The work of breathing comprises compliance and resistive components. Although the work of breathing from compliance is 20- to 40-fold greater in the adult than in the neonate, the compliance work relative to tidal volume is nearly the same. However, the resistive work of breathing in the neonate is nearly 6 times greater than in the adult because of the relatively small airways in the neonate. Breathing through a tracheal tube especially increases resistive work in neonates because the airway resistance is inversely proportional to the fifth power of the radius of the tube and directly proportional to the length of the tracheal tube. The relatively narrow and long tracheal tubes through which neonates breathe can greatly increase their work of breathing (see Fig. 12-7). The work is also increased when a neonate breathes spontaneously through a circle system because of the inspiratory force required to open the one-way valves in the system. Although valveless ventilatory circuits, such as the Mapleson D systems, are recommended for spontaneously breathing neonates, studies suggest that a circle system may be used in these patients provided compensation is arranged for the problems associated with this circuit; that is, a neonate requires assisted ventilation and adequate inflation pressures to reduce the work of breathing and ensure adequate ventilation (see Chapter 51).^34–36

Bronchopulmonary dysplasia (BPD) is an important chronic lung disease of neonates born prematurely.³⁷ Although the use of antenatal steroids, exogenous surfactant treatment, and advanced ventilator therapies has decreased the incidence of BPD, it still afflicts nearly 10,000 premature infants in the United States every year and is a significant contributor to infant morbidity and mortality. BPD is identified in preterm infants with abnormal chest radiographs that require supplemental O₂ at 36 weeks postmenstrual age (PMA). Other factors that increase the risk for developing BPD include chorioamnionitis and the persistence of a patent ductus arteriosus (PDA).³⁸ Lung injury in the preterm infant decreases pulmonary maturation; infants who have died from BPD have impaired pulmonary alveolar and disrupted microvascular development.³⁹ BPD is most often seen in preterm infants who are subjected to high levels of O₂ and ventilation therapy and may be caused by lung injury–induced increase in cytokine activation.⁴⁰ Decreased lung development in infants with BPD diminishes the surface area for pulmonary gas exchange that increases O₂ requirements. Moreover, some infants with BPD have reduced lung compliance and increased airway resistance and hence have prolonged pulmonary time constants. Some infants with severe BPD have abnormal muscularization of the vessels in the periphery of their lungs, pulmonary hypertension, and right ventricular hypertrophy.

Pulmonary disease in infants with BPD is associated with abnormal pulmonary function tests and chest radiograph findings (small radiolucent cysts and hyperexpanded lungs), hypercarbia, chronic hypoxemia, and reactive airway disease.^41–46 Nitric oxide (NO) is a free radical gas formed in endothelial cells and diffuses into subjacent smooth muscle cells, where it stimulates cyclic guanosine monophosphate (cGMP) production and mediates vasorelaxation (Fig. 36-1). Inhaled NO decreases abnormal cell proliferation in the injured developing lung^47,48 and improves alveolar development in preterm animal models of BPD.^49,50 Given the biologic plausibility and the results from animal studies, clinical trials have examined whether preterm neonates would benefit from NO. However, 14 randomized controlled trials of inhaled NO in preterm infants 34 weeks gestational age or younger failed to demonstrate benefit in survival or pulmonary or neurodevelopmental outcomes.⁵¹ It is likely that decreased NO signaling enzyme activity in the injured newborn lung reduces the effectiveness of inhaled NO in protecting pulmonary development. Emerging laboratory studies suggest that modulating cytokine signaling might improve the development of the injured lung and decrease BPD. For example, investigations in newborn animal models suggest that lung injury increases cytokine signaling. Moreover, in a mouse pup model of BPD, antibody-mediated inhibition of excess transforming growth factor-beta (TGF-β) activity was observed to improve NO signaling and pulmonary alveolar and microvascular development.⁵² Studies are under way to examine the mechanisms through which TGF-β modulates injured lung development.

FIGURE 36-1 Nitric oxide (NO) produced by nitric oxide synthase (NOS) in endothelial cells (EC) diffuses into subjacent smooth muscle cells (SMC), interacts with soluble guanylate cyclase (sGC ), and increases the concentration of cyclic guanosine monophosphate (cGMP) to cause vascular relaxation. The effect of NO is decreased by metabolism of cGMP by specific phosphodiesterases (PDE). l-arg, l-Arginine.

The treatment of BPD in neonates often requires ventilatory and medical therapies.⁵³ Early and aggressive CPAP may eliminate the need for positive-pressure ventilation. Air trapping during assisted ventilation is associated with the long lung time constants in babies with BPD and may be reduced by using a prolonged expiratory time. Respiratory infection (e.g., Ureaplasma urealyticum) may contribute to the inflammatory response. Bronchodilators such as aminophylline, albuterol, or ipratropium may be beneficial in reducing airway resistance in some infants with BPD.

Infants with BPD are often treated with diuretics. As a result of chronic furosemide treatment, metabolic abnormalities may exist. Hypercalciuria may occur from the action of furosemide on the ascending loop of Henle, leading to secondary hyperparathyroidism and nephrocalcinosis in some infants. Hydrochlorothiazide and spironolactone produce less severe metabolic abnormalities. Finally, large doses of steroids, especially dexamethasone, have been shown to provide relief for some infants with severe BPD that is refractory to other medical and ventilator therapies.^54,55 However, dexamethasone treatment may result in systemic hypertension, hyperglycemia, hypertrophic cardiomyopathy, and alteration of neurologic and pulmonary development in some children.^56,57 Preoperative evaluation of infants with BPD requires a very careful history and physical examination, particularly focused on the pulmonary and cardiovascular systems.

Oxygen Uptake and Circulation

Uptake of O₂ in the pulmonary microvasculature of neonates is facilitated by the greater hemoglobin concentration in the neonate and the increased amount of fetal hemoglobin. Fetal hemoglobin has a reduced affinity for 2,3-diphosphoglycerate and hence a greater affinity for O₂. Although this affinity facilitates fetal hemoglobin O₂ uptake in the placenta, it can reduce O₂ release from hemoglobin to the tissues. Red blood cells containing fetal hemoglobin have an average life span of 100 days, compared with 120 days for those containing adult hemoglobin. The higher hematocrit in neonates causes an increased bilirubin load for an immature hepatic clearance pathway. However, preterm infants frequently experience anemia of prematurity, a normocytic, normochromic hypoproliferative anemia with the hallmark of inadequate production of erythropoietin.⁵⁸

The O₂ delivery to systemic tissues in neonates is facilitated by a cardiac output greater than in adults on a per–kilogram body-weight basis. The relationships among myocardial preload, contractility, afterload, and heart rate determine cardiac output. Passive myocardial fiber tension is reflective of myocardial compliance, which is significantly reduced in the perinatal period.⁵⁹ Active myocardial tension, reflecting contractility, is also significantly reduced in the neonate.⁵⁹ At smaller end-diastolic volumes, mild increases in preload in the neonate are associated with increased cardiac output. At greater end-diastolic volumes, as a result of poor ventricular compliance in the neonatal heart, this positive effect is soon overcome and cardiac output becomes more dependent on heart rate (see Chapters 14 and 16).^60–62 The heart rate of a term neonate is approximately 120 beats/min; it increases to 160 beats/min by 1 month of age.⁶³ Parasympathetic control of heart rate in lambs, and probably in developing humans, matures earlier in gestation and to a greater extent than β-adrenergic control.^64,65 For this reason, neonates tend not to respond to adrenergic signaling associated with hypovolemia or an inadequate depth of anesthesia with tachycardia. Additionally, the vagotonic response caused by succinylcholine or its metabolites (succinylmonocholine) and synthetic opioids may lead to bradycardia. These cardiac reflexes can be offset by the vagolytic effects of pancuronium or atropine.^66,67

Preterm infants may have pulmonary hypertension. In utero, the lungs are not required for gas exchange; the placenta performs this function. Thus the fetal circulatory pattern consists of atria and ventricles working as units in parallel (see Fig. 16-1). As little as 10% of the fetal right ventricular output may circulate through the lungs.⁶⁸ Most of the blood returned from the lower extremities and a portion of the umbilical venous blood supply passes into the pulmonary arteries and subsequently through the PDA into the systemic circulation (see Chapters 14 and 16). The superior vena caval blood supply circulates through the patent foramen ovale (PFO) into the left atria and subsequently into the systemic circulation. With expansion of the lungs during the first breath, pulmonary vascular resistance decreases and blood flow to the lungs increases, matching perfusion with new ventilation.^68,69 Any factor that increases pulmonary vascular resistance, (e.g., hypoxia, hypercarbia, or acidosis) may cause the circulation to revert to a fetal circulatory pattern with shunting of deoxygenated blood from the right to the left side of the heart via the PFO or PDA. This right-to-left shunting of blood explains in part why some infants remain hypoxemic despite ventilation with 100% O₂ after severe desaturation.

The ductus arteriosus may remain patent in neonates, especially in those born prematurely.⁷⁰ Bounding peripheral pulses, a harsh systolic ejection murmur at the left sternal border, and widened pulse–pressure difference, suggest the presence of a PDA. The presence of a PDA and of right-to-left shunting of blood may contribute to ventilation-perfusion () mismatch as deoxygenated blood is shunted from the pulmonary arteries to the systemic circulation through the PDA and differential upper and lower extremity O₂ saturations result. Later, as the pulmonary vascular resistance decreases, left-to-right shunting of blood from the systemic to pulmonary circulation across the PDA may cause flow-mediated endothelial cell injury and abnormal pulmonary artery remodeling and hypertension. Infants with a PDA often require increased ventilatory support.

A PDA in the neonate may be treated with indomethacin or ibuprofen. If the PDA persists despite medical treatment, surgical ligation may be required.^71–73 Treatment with indomethacin is associated with renal and platelet dysfunction. Although experience suggests that infants who have received large volumes of intravascular fluid have a greater incidence of PDA,⁷⁴ the mechanism behind this is unknown, and the relationship may not be causal. In fact, if the PDA is associated with ventricular dysfunction and poor organ perfusion, it is imperative to provide adequate intravascular volume and to improve cardiac output rather than expose the infant to hypotension mediated by left-to-right shunting across the PDA. Occasionally, systemic perfusion in infants with PDA may be improved with a dopamine infusion and judicious intravenous fluid administration.

In neonates, increased pulmonary vascular resistance causes shunting of desaturated blood through the PFO and PDA and thereby causes severe systemic hypoxemia. Although the cause of persistent pulmonary hypertension of the newborn (PPHN) is incompletely understood, it is associated with increased muscularization of pulmonary arterial vessels⁷⁵ and sepsis and aspiration syndromes.⁷⁶ PPHN is suspected in severely hypoxic neonates who do not have a significant increase in postductal O₂ saturation when they breathe 100% O₂. A difference in preductal and postductal O₂ saturations supports the diagnosis because it reflects the extrapulmonary right-to-left shunting of deoxygenated blood via the PDA. PPHN is diagnosed when pulmonary hypertension and no other structural heart lesions are observed by cardiac ultrasound.

Treatment of PPHN is directed at decreasing pulmonary vascular resistance and the extrapulmonary shunting of deoxygenated blood. In cases of pneumonia and aspiration syndromes, in which airway disease can lead to atelectasis and intrapulmonary shunt, PEEP and exogenous surfactant are sometimes used to recruit alveoli. To treat the pulmonary vasoconstriction that is pathognomonic of PPHN, hyperoxia and alkalosis therapies have been used. Although inspired O₂ is a potent vasodilator, maximum dilation of the pulmonary vasculature is achieved by relatively low levels of O₂. For this reason, increasing the Fio₂ often does not improve gas exchange in PPHN. Through a mechanism that is incompletely understood, alkalosis causes pulmonary vasodilation. In many infants with PPHN, alkalosis induced by hyperventilation or the infusion of base decreases pulmonary vascular resistance and increases systemic O₂ partial pressures. In general, the vasodilation induced by alkalosis occurs when the arterial pH is 7.55 or greater. With the advent of inhaled NO, alkalosis has been largely replaced with avoiding acidemia, but not inducing marked alkalosis. Intravenous vasodilator drugs cause inconsistent vasodilation in infants with pulmonary hypertension.⁷⁷ Unfortunately, because these agents dilate the systemic as well as the pulmonary vasculature, they often cause severe systemic hypotension.

Inhaled NO selectively decreases pulmonary vascular resistance and increases systemic O₂ partial pressures in infants with PPHN.^78–80 NO is a gas that is synthesized by NO synthase from l-arginine and O₂ in endothelial cells and diffuses into subjacent smooth muscle cells, where it stimulates soluble guanylate cyclase to increase cGMP levels. It is probably through cGMP’s stimulation of cGMP-dependent protein kinase I and the phosphorylation of several cytoplasmic targets that regulate intracellular calcium levels and vasomotor protein function that NO causes vascular relaxation (see Fig. 36-1). Inhaling small concentrations of NO caused selective pulmonary vasodilation, decreased right-to-left shunting of blood, and increased systemic O₂ partial pressures in neonate animals and infants with pulmonary hypertension.^81–83 Acutely breathing up to 80 parts per million (ppm) by volume of NO rapidly and selectively decreases pulmonary vascular resistance and increases systemic O₂ partial pressures by decreasing extrapulmonary shunting of deoxygenated blood. Although methemoglobin is produced during the metabolism of NO, no important increases in methemoglobin were observed in infants breathing low concentrations of NO. Large multicenter studies suggest that breathing 20 ppm NO decreases the requirement for extracorporeal membrane oxygenation (ECMO). Although ECMO can be lifesaving for severely hypoxemic neonates,^84–86 it is expensive and invasive, sometimes causes important complications, and is not available at most hospitals. For these reasons, inhaled NO is used in most intensive care nurseries to treat the severe hypoxemia associated with PPHN.

Studies also suggest that chronic NO inhalation protects the neonatal lung from injury.⁴⁷ In cell cultures, NO has been observed to decrease pulmonary smooth muscle cell proliferation and increase programmed cell death (apoptosis). Inhaled NO has been observed to decrease pulmonary artery neomuscularization in animals with lungs injured by breathing gases with low concentrations of inspired O₂. Although inhaled NO may decrease lung artery remodeling by preventing hypoxic pulmonary vasoconstriction, studies suggest that it prevents abnormal pulmonary artery remodeling in injured lungs without hypertension.⁷⁸ Although the protective mechanism of inhaled NO is unknown, it does decrease smooth muscle cell proliferation in vitro,⁸⁷ possibly by altering the expression of transcriptional regulators and the progression of the cell cycle.^88–90 It is likely that studies that identify the protective mechanisms of NO/cGMP signaling will guide the development of novel therapies to prevent pulmonary disease in the injured lung.

Appreciation has been increasing of the potential harmful effects of even brief periods of hyperoxia.⁹¹ Six randomized controlled clinical studies have shown no apparent advantage of initiating resuscitation of neonates with 100% supplemental O₂ instead of 21% O₂. In fact, some studies suggest slightly greater mortality rates with 100% O₂. In light of these findings, the 2010 Neonatal Resuscitation Program has been updated to recommend initiating resuscitation of full-term neonates with 21% O₂ and that pulse oximetry be used if supplemental O₂ is needed.⁹²

Renal Function

The placenta acts as an excretory organ for the fetus. A neonate’s kidneys are not fully developed at birth, and development is closely related to PCA.^98,99 At full-term birth, the glomerular filtration rate (GFR) is only 30% of normal adult rates (see Chapter 6).¹⁰⁰ The GFR reaches adult values at approximately 1 year of age (see Figs. 6-10 and 6-11). The kidneys’ tubular function, and hence sodium-retaining ability, does not develop until about 32 weeks of gestation.^101,102 The immaturity of the kidney at birth also affects the metabolism of many drugs in the neonate The renal excretion of medications such as penicillin, gentamicin, and some neuromuscular blocking drugs (NMBDs), such as pancuronium, may be prolonged, resulting in increased duration of action or the development of excessive blood concentrations. This effect is particularly important when administering medications to an extremely preterm infant. Thus the use of NMBDs that do not require renal function are most advantageous (e.g., cisatracurium).

The total body water content in neonates is greater than it is in infants, children, or adults. In the preterm infant 75% to 85% of body weight is water; in general, the less the PCA of the neonate, the greater the percentage of water. In a term infant, 70% of body weight is water.¹⁰³ By 6 to 12 months of age, 50% to 60% of body weight is water (see also Figs. 6-7 and 6-8). Differences between the total body water, renal maturity, and serum protein concentrations (see also Fig. 6-6) in a neonate affect the volume of distribution of many medications. Because of the increase in the volume of distribution of drugs confined to the extracellular fluid, the initial doses of some medications (e.g., NMBDs, aminoglycosides) may be greater on a weight basis in neonates than for adults to achieve the desired blood concentration. In contrast, because of immaturity of renal function, the interval between doses of these drugs may be increased (see also E-Fig. 6-4).

Fluid Management

The basic principles of fluid maintenance in neonates are similar to those in older children and adults. The highly variable body fluid composition, degree of renal maturity,¹⁰⁴ neuroendocrine control of intravascular fluid status, and insensible fluid loss with age¹⁰⁵ make precise estimates of fluid requirements in neonates very difficult (see Chapter 8). Urine volume and concentration may be difficult to determine intraoperatively and may not always correlate with volume status. Moreover, blood pressure and heart rate may not correlate with intravascular volume status in preterm infants, and anesthetics may mask subtle cardiovascular changes that occur with changes in intravascular volume. Increased insensible fluid loss, which often occurs in the operating room environment, requires judicious titration of intravenous fluids. Congenital abnormalities (e.g., gastroschisis, omphalocele) may markedly increase insensible fluid loss through exposure of large mucosal surfaces. The use of humidified gas mixtures reduces insensible fluid loss through the respiratory tract. However, overzealous intraoperative administration of fluids can result in pulmonary complications and worsened third-spacing of fluids.

Methods of Intravenous Access and Monitoring

Infants who are dehydrated after a prolonged period of fasting or vomiting or because of increased insensible fluid losses may require special procedures for intravenous access. With severe hypovolemia, scalp and peripheral veins may be difficult to cannulate. Many of the superficial veins may be thrombosed from prior use. Fiberoptic light sources or ultrasound may help visualize deeper veins and peripheral arteries. Femoral and axillary veins may be accessed percutaneously or via a surgical approach for the delivery of fluids and medications.^106–108 Knowledge of femoral artery and vein anatomy decreases the incidence of accidental injury of the femoral head joint and possible septic arthritis (see Fig. 48-5).¹⁰⁹ The external or internal jugular veins can also provide alternative sites for venous access.

In neonates, fluids and many medications may be infused through the umbilical vessels. The tip of umbilical arterial lines should be placed either in a “low” position, at the level of the bifurcation of the femoral arteries (L3-4), or in a “high” position, in the descending aorta above the diaphragm (T6-9). The catheter tip of the umbilical artery catheter should not be left in the descending aorta in the area of the renal or mesenteric arteries (L1-2) because renal or mesenteric artery thrombosis might result (see Figs. 48-8 and 48-9). Aortic thrombosis occurs in approximately 1% of umbilical artery catheterizations, although thrombi can be detected with radiologic techniques in 20% to 95% of infants.^110–112 Infants with renal artery thrombosis may present with hypertension, oliguria, hematuria, and elevated blood creatinine concentrations. The tip of an umbilical venous catheter should rest in the inferior vena cava above the level of the ductus venosus and hepatic veins so that solutions are not directly infused into the liver parenchyma. The delivery of hypertonic solutions into the liver might result in liver damage and portal cirrhosis. Aspiration of arterial oxygenated blood suggests that the venous catheter has entered the left atrium through the foramen ovale. Catheters in the left atrium should be pulled back to the level described earlier.

Some drugs may be delivered through the tracheal tube. Rapid uptake and minimal effects on gas exchange or the pulmonary parenchyma occur with epinephrine, atropine, and lidocaine (see Chapter 39). The doses of some drugs administered through the tracheal tube are increased in comparison with that delivered intravenously (e.g., epinephrine 0.05 to 0.1 mg/kg via the tracheal tube versus 0.01 to 0.03 mg/kg intravenously).⁹² It is important to understand that administration of solutions via the endotracheal tube can cause adverse effects. For example, complications associated with the tracheal administration of exogenous surfactant include occasional transient hypoxia and bradycardia and are likely due to the relatively large volume of fluid (2.5 to 6 mL/kg) associated with the proper dose of surfactant.

Intraosseous cannulation of the tibia with a special intraosseous infusion needle (e.g., Easy-IO, Vidacare, San Antonio, Tex.) or a styleted spinal needle provides a rapid route for emergency fluid and drug administration and can be lifesaving (see Fig. 48-6 and E-Fig. 48-1, A through E).

Glucose Homeostasis

Although the placenta allows the delivery of glucose from the maternal circulation to the fetus, the development of significant glycogen stores does not occur until late in gestation. Various conditions may lead to hypoglycemia in a neonate. Preterm and small-for-gestational-age (SGA) infants have very high glucose requirements; they require glucose infusion rates of 8 to 10 mg/kg/min. In full-term infants, a glucose infusion rate of 5 to 8 mg/kg/min prevents hypoglycemia. Full-term infants who have been excessively fasted, SGA infants, and infants of diabetic mothers are all prone to develop hypoglycemia. Although hypoglycemia may result in respiratory distress, apnea, cyanosis, seizures, tremors, high-pitched cry, irritability, limpness, lethargy, eye-rolling, poor feeding, temperature instability, and sweating, the signs and symptoms in infants are often blunted and nonspecific.^113,114 In infants younger than 24 hours old, a plasma glucose concentration of less than 40 mg/dL is a cause for concern and should be treated.¹¹⁵ After 24 hours of life, plasma glucose values less than 45 mg/dL should be considered abnormally low. Although hypertonic glucose administration has been used to treat hypoglycemia in neonates, studies reveal that administration of hypertonic sodium bicarbonate solutions increases the incidence of intraventricular hemorrhage in preterm infants.¹¹⁶ For this reason, it is prudent to avoid bolus administration of hypertonic glucose to treat hypoglycemia to prevent sudden changes in blood tonicity and hyperglycemia. A bolus of 2 to 4 mL/kg of D₁₀W (0.2 to 0.4 g/kg of glucose) and an increase in the basal glucose infusion are prudent measures to treat hypoglycemia. It is extremely important to reassess the blood glucose concentration after these treatments to determine the effectiveness of the therapy.

Infants undergoing surgical procedures often require less glucose supplementation.¹¹⁷ This reduced need may be attributed to hormonal responses that decrease glucose uptake as a result of catecholamine release in excess of insulin activity, as well as a decrease in metabolic demand from the effects of the anesthetic agents.^118–120 Nevertheless, it is important to administer glucose-containing solutions using a constant-infusion device to avoid large fluctuations in blood glucose values and monitor blood glucose values in critically ill neonates. All other fluids (e.g., to replace third-space losses, blood loss, and fluid deficits) should be glucose-free to avoid hyperglycemia.¹¹⁷ Infants treated with high levels of glucose via total parental nutrition (TPN) may develop severe hypoglycemia if the infusion rate is abruptly lowered; thus it is important to continue these infusions (possibly at a slightly reduced rate) during surgery and to check the serum glucose concentrations.

Calcium Homeostasis

Calcium exists in the serum in three fractions: (1) protein bound; (2) chelated to bicarbonate, phosphate, and citrate; and (3) free or ionized calcium (iCa²⁺). The ionized fraction is the physiologically active component. The serum calcium concentration is mainly regulated by the action of parathyroid hormone (PTH) and vitamin D metabolites. PTH acts directly in the bone and kidneys and indirectly through calciferol in the gut.¹²¹

Hypocalcemia has been observed in nearly 40% of critically ill neonates.¹²² Causes of hypocalcemia include (1) PTH insufficiency and peripheral resistance to PTH, (2) inadequate calcium supplementation, and (3) altered calcium metabolism caused by transfusion with citrated blood products (see also Fig. 10-9), bicarbonate administration, or diuretics (furosemide). Hypocalcemia may be asymptomatic or accompanied by nonspecific symptoms (e.g., seizures and tremors). Thus the diagnosis rests on the determination of total and iCa²⁺ levels. In critically ill children, total calcium concentrations do not accurately reflect the iCa²⁺ concentrations; therefore the diagnosis of hypocalcemia in these infants should be determined by direct measurement of iCa²⁺ with an ion-specific electrode.¹²³ Neonatal hypocalcemia may be defined as a serum iCa²⁺ less than 1 mmol/L in full-term infants and less than 0.75 mmol/L in preterm infants. Persistent hypocalcemia necessitates determination of magnesium, phosphorus, PTH, and vitamin D concentrations.

Treatment of hypocalcemia is not effective in the presence of hypomagnesemia. In this situation, administration of supplemental magnesium and calcium and treatment of the underlying cause of hypocalcemia are necessary.¹²² Symptomatic hypocalcemia is treated with 100 mg/kg calcium gluconate (10%) by slow intravenous infusion (5 minutes) in a patent intravenous line. Thereafter, maintenance calcium is administered at 100 to 200 mg/kg/day elemental calcium and the clinical response and serum iCa²⁺ levels are carefully monitored.