Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.


PART THREE – Clinical Management of Special Surgical Problems

Chapter 16 – Anesthesia for Neonates and Premature Infants

Claire M. Brett,Peter J. Davis,
George Bikhazi



Neonatal Lesions Requiring Surgery, 521



Preanesthetic Assessment, 521



Medical History, 521



Physical Examination, 524



Review of Systems and Developmental Physiology,524



Anesthetic Pharmacology in the Neonate, 535



Inhaled Anesthetic Agents, 535



Intravenous Anesthetics and Analgesics,536



Muscle Relaxants, 537



General Preanesthetic Considerations, 537



Fluids, 537



Premedication, 538



General Approach to Intraoperative Management, 538



Thermal Protection, 538



Monitoring in the Operating Room,538



Induction of Anesthesia, 540



Anesthetic Systems, 540



Intraoperative Fluid Management, 541



Management of Commonly Encountered Surgical Lesions, 542



Abdominal Wall Defects: Gastroschisis/Omphalocele,542



Congenital Diaphragmatic Hernia, 545



Tracheoesophageal Fistula and Esophageal Atresia, 550



Necrotizing Enterocolitis, 552



Sacrococcygeal Teratoma, 555



Imperforate Anus (Anal Atresia), 556



Intestinal Obstruction, 557



Anesthesia for the Premature and Ex-Premature Infant, 559



Respiratory Problems of the Premature Infant and Ex-Premature Infant,559



Pulmonary Function in Premature and Ex-Premature Infants, 561



Neurologic Outcome of the Ex-Premature Infant, 563



Gastrointestinal Function in the Ex-Premature Infant, 563



Pain in the Neonate, 564



Delivering Anesthesia to Premature Infants, 564



Regional Anesthetic Techniques,564



Summary, 565

The neonatal period, which encompasses the first month of extrauterine life, challenges the newborn infant in several respects. Once separated from the placenta, the newborn infant must function independently to adapt to the new environment. This adaptation involves anatomic, physiologic, and pharmacologic changes to maintain homeostasis and to ensure the infant's survival. Disease states, anesthesia, and surgery can interfere with these developmental changes and threaten survival. The anesthesiologist must understand the principles of neonatal anesthesia and surgery, the normal course of development, the pathophysiology of neonatal disease states, and the glossary of terms used to describe the neonates and their diseases ( Box 16-1 ).

BOX 16-1 

Glossary of Abbreviations

AGA: Appropriate for gestational age, >5th percentile, <90th percentile for gestational age

BPD: Bronchopulmonary dysplasia

CDH: Congenital diaphragmatic hernia

CLD: Chronic lung disease

ELBW: Extremely low birth weight, <1000 g

GFR: Glomerular filtration rate

LBW: Low birth weight, <2500 g

LGA: Large for gestational age, >90th percentile for gestational age

NEC: Necrotizing enterocolitis

NICU: Neonatal intensive care unit

PDA: Patent ductus arteriosus

Premature: <37 Weeks gestation

SGA: Small for gestational age, <5th percentile for gestational age

TEF: Tracheoesophageal fistula

Term: >37 Weeks gestation

VLBW: Very low birth weight, <1500 g


Most neonatal lesions require emergency or urgent intervention. Infants born with congenital anomalies may have obvious malformations on physical examination or may show specific or nonspecific signs such as respiratory distress, gastrointestinal dysfunction, or temperature, hemodynamic, or metabolic instability. Of note, a neonate with one congenital anomaly may have coexisting anomalies that are not readily apparent. A detailed list of disease entities and coexisting anomalies has been described ( Jones and Pelton, 1976 ; Lynn, 1985 ) ( Box 16-2 ). An understanding of the congenital lesion(s) and its pathophysiology is essential to develop a logical and effective anesthetic plan. In addition, the general principles of care for all patients requiring surgery must be extrapolated to the newborn: positioning, blood loss, monitoring, fluid replacement, choice of anesthetic agents, and postoperative management.

BOX 16-2 

Commonly Encountered Lesions in the Neonate

Airway Lesions

Choanal atresia

Pierre Robin syndrome

Upper airway obstruction, for example:



Cystic hygroma



Upper airway cysts or webs



Laryngeal stenosis



Cleft lip and cleft palate

Thoracic Lesions

Tracheoesophageal fistula (TEF) and atresia

Congenital diaphragmatic hernia

Eventration of the diaphragm

Pneumomediastinum, pneumothorax, and pneumopericardium

Lobar emphysema

Congenital heart lesions

Mediastinal masses

Abdominal Lesions



Intestinal atresia or stenosis

Pyloric stenosis

Malrotation and volvulus

Necrotizing enterocolitis (NEC)

Imperforate anus

Exstrophy of the cloaca or bladder

Incarcerated hernia


Biliary atresia

Hirschsprung's disease

Neurosurgical Lesions




Intracranial masses

Skull fractures


Subdural hemorrhage

Spinal tumors

Copyright © 2008 Elsevier Inc. All rights reserved. -

Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier


Details of the newborn infant's perinatal course and delivery provide important information for the pediatric anesthesiologist. The preoperative assessment of the newborn should focus on the details of the labor and delivery and the infant's transition from fetal to newborn existence. Disease states, anesthetic agents, and surgical interventions can all influence the homeostatic mechanisms of adaptation.


The framework for developing an anesthetic plan for a newborn is centered on the specific medical history, current physical examination, and ongoing metabolic status. The medical history of a newborn requires a careful review of the mother's pregnancy ( Box 16-3 ), analysis of the labor and delivery, and the events of the first hours/days of life. After the first few weeks of life, the details of the labor and delivery become less relevant, except to account for and understand why any residual medical sequelae exist.

BOX 16-3 

Maternal Factors Associated With Increased Perinatal Risk






Prolonged rupture of membranes



Intravenous drug abuse






Collagen vascular disease






Infection, inflammation

Intrauterine Environment

The intrauterine environment has dramatic effects on the growth and the ability of the newborn to adapt to extrauterine life. Although this impact is most obvious over the first few hours, days, and, in some cases, weeks of life, some intrauterine events may have lifelong consequences. For example, the effect of drugs on the development of the fetus can cause well-described multisystem influences producing specific syndromes (e.g., Dilantin [phenytoin], thalidomide, alcohol) or less dramatic but easily identifiable effects on total somatic growth (e.g., smoking, steroids) or produce syndromes of drug dependence/withdrawal (e.g., opioids, amphetamines). The effects of such exposure can have direct effects on morphogenesis, resulting in anomalies of the heart, pulmonary circulation, brain, and other organs (e.g., cleft lip and palate). In other cases, asphyxia from effects of drugs on placental blood flow or as a result of embolic infarction may result in poor growth of the fetus or premature labor producing indirect effects secondary to stress response, ischemia, and asphyxia. Such newborns may require vigorous resuscitation in the immediate neonatal period and have significant metabolic derangements (e.g., hypoglycemia, hypocalcemia).

Such a sequence is of vital significance to the anesthesiologist, because asphyxiated infants can manifest neurologic problems (e.g., seizures), transient cardiac dysfunction (e.g., cardiomyopathy, tricuspid insufficiency, pulmonary hypertension), renal insufficiency (e.g., acute tubular necrosis), and/or gastrointestinal/hepatic dysfunctions (e.g., necrotizing enterocolitis, clotting abnormalities). Thus, prenatal and perinatal events often provide important insight into the status of a neonate who is headed to the operating room.

Labor and Delivery and Perinatal Events

The infant who was born after a complicated labor and delivery may have metabolic, cardiovascular, and respiratory instability for variable lengths of time. These events are of particular importance to the anesthesiologist evaluating such an infant in the first 1 to 2 days of life but takes on lesser significance as the infant is stabilized. The preoperative assessment should include review of acid-base status, glucose and calcium requirements, temperature stability, urine output/renal function, and clotting function (platelet count, prothrombin time/partial thromboplastin time).

After an asphyxial event at birth, an infant may have significant glucose instability, especially if the infant is premature, large-for-gestational-age (LGA), or small-for-gestational-age (SGA). The rate of glucose infusion required to produce normal serum glucose (60 to 100 mg/dL) is important to note (see later).

Similarly, calcium hemostasis can be challenging to achieve in the asphyxiated, SGA, LGA, or preterm infant. The dose required over the previous 12 to 24 hours should be calculated and the delivery method (intermittent bolus, constant infusion) noted. Infiltration of calcium into the subcutaneous space can produce skin sloughing and dehiscence. However, peripheral sites of infusion are difficult to observe when tiny infants are covered with surgical drapes. If an infusion of calcium is to be continued or delivery of a bolus is anticipated, the anesthesiologist must have reliable intravenous access in place.

For the first 2 to 3 hours of life, electrolyte levels of the newborn primarily reflect the mother's values as well as the perinatal events (e.g., asphyxia, placental or umbilical cord hemorrhage). If the newborn has required resuscitation, acidosis may persist for several hours, as perfusion to peripheral tissue is reestablished and gradually “washes out” lactate that had accumulated during the period of cardiovascular collapse. After the first few hours of life, lactate levels reflect a balance between oxygen delivery and normal metabolism (i.e., renal and hepatic function), ongoing metabolic derangements (e.g., sepsis, inherited metabolic diseases), or underlying congenital anomalies.

During the first 12 to 24 hours of life, sodium is generally not included in the intravenous fluid regimen. From day 2, the infusion of fluid is adjusted to reflect delivery of maintenance amounts of sodium (2 to 4 mEq/kg per day) as well as to replace any abnormal losses via the kidney or gastrointestinal tract, to compensate for abnormal water metabolism (e.g., syndrome of inappropriate antidiuretic hormone [ADH]), or to counter the effect of drugs (e.g., furosemide). In some cases where acidosis persists (e.g., inherited metabolic diseases, severe sepsis), an infusion of acetate (or even bicarbonate) is administered rather than chloride. Hyperkalemia and hyponatremia develop most commonly in the extremely low birth weight (ELBW) infant because of renal immaturity, asphyxia, and sepsis. In addition, premature infants tend to develop a mild metabolic acidosis and a renal tubular acidosis, because of their inability to absorb bicarbonate effectively in the proximal tubule.

Gestational Age

Perinatal problems can be related to an infant's gestational age and size. Full-term infants (37 to 42 weeks gestation) born weighing less than the 10th percentile for gestational age, possibly as a result of intrauterine malnutrition or infection, are considered SGA. SGA infants have different pathophysiologic problems from preterm infants (less than 37 weeks gestation) of the same weight ( Lubchenco et al., 1963 ). Birth weight must be interpreted in the context of gestational age.

The well-accepted definition of “prematurity” is an infant less than 37 weeks gestation. Although infants less than 37 weeks gestation tend to share some common features, the physiologic variability between 24 and 36 weeks of gestation is enormous. In fact, a 36-week-gestation infant is more similar to a term infant than to a 24-, 26-, or 28-week-gestation infant. To more accurately analyze the preoperative evaluation and intraoperative management of “newborns,” this age group is arbitrarily divided into more discrete subgroups based on gestational age.

Near-Term Infants (35 to 37 weeks gestation)

In the absence of congenital anomalies and without perinatal asphyxia, these infants usually have few of the major medical or surgical problems that are common in the more premature infant. A near-term infant may have some delay in establishing full feeds, whether breast or formula fed. Coincident with this, the incidence of nonhematologically based hyperbilirubinemia (e.g., not associated with positive Coombs or ABO/Rh incompatibility, etc.) is more common than in term infants. In the setting of the infant of a diabetic mother, pulmonary immaturity is common even at this late gestation. Otherwise, pulmonary function is similar to the term infant in most newborns born after 35 weeks gestation. Most surgical intervention in this developmental group is to treat congenital anomalies.

30 to 34 Weeks Gestation

For the sake of this general discussion, infants of 30 to 34 weeks gestation are considered to be similar. However, a 1200-g, 30-week-gestation infant has a greater incidence of the common problems of prematurity compared with a 2000-g, 34-week-gestation infant. Nonetheless, this range was chosen to simplify the specific discussion of preoperative evaluation.

Before exogenous pulmonary surfactant was introduced into clinical practice in 1990, this group of infants often developed respiratory distress syndrome (RDS), also known as hyaline membrane disease. Because of pulmonary immaturity, complications of respiratory supportive care developed, often in proportion to the severity of the RDS—pneumothorax, pulmonary interstitial emphysema, chronic lung disease, iatrogenic blood loss (sampling for blood analysis). With routine use of surfactant, the frequency and severity of classic RDS have decreased dramatically but have not been totally eliminated. The sequelae of pulmonary immaturity and its supportive care and the severity of subsequent chronic lung disease have changed from the presurfactant era. Nonetheless, the emergence of the “new bronchopulmonary dysplasia (BPD)” (see later) and the persistence of variations of chronic lung disease remain with an incidence as high as 20% to 25%.

Although uncommon in a 35-week-gestation infant, this age group of newborns may have marked temperature instability, especially if septic or asphyxiated. Feeding intolerance is common. Before enteral feeds are established, 30- to 34-week-gestation infants must be carefully monitored for metabolic problems, such as hypocalcemia and hypoglycemia. If total parenteral nutrition, either central or peripheral, is required for longer than 1 week, toxic effects (e.g., hepatic and renal) of intravenous alimentation may develop. The frequency of NEC is more common as gestational age decreases and when there is a coexisting patent ductus arteriosus (PDA).

The incidence of a PDA is high (20% to 30%) in these infants, but often the hemodynamic consequences are mild and spontaneous closure is common. In those infants with respiratory problems, the incidence of PDA is higher and more frequently requires either medical treatment (indomethacin) or surgical ligation. Similarly, the incidence of intracerebral bleeds increases with decreasing gestational age, and these intracranial hemorrhages are more common in the setting of other complications of prematurity'sepsis, asphyxia, or precipitous birth. Apnea is more frequent at this developmental stage and is most common in the presence of sepsis, temperature instability, metabolic abnormalities (hypoglycemia, hypocalcemia), and anemia.

27 to 29 Weeks Gestation

The complications of pulmonary, cardiovascular, gastrointestinal, and neurologic immaturity are magnified in this gestational age bracket in both incidence and severity. A key feature of these infants is the variability of diseases from one infant to another. Some infants are “growing preemies” after 1 to 2 weeks, whereas other infants develop multisystem dysfunction and poor growth.

In addition to the problems common in the greater-than-30-week-gestation infants, the impact of fragile skin and absence of subcutaneous tissue is increasingly important in infants of less than 30 weeks' gestation. Temperature instability, enormous caloric expenditure to maintain temperature, and significant transcutaneous fluid loss are of major significance when evaluating and planning for surgery at this developmental stage. Perioperative apnea is of major importance when planning for the postoperative monitoring and ventilatory support of such infants.

Less Than 26 Weeks Gestation

Infants of this gestational age are considered to be “on the edge of survivability.” Pulmonary, neurologic, and gastrointestinal sequelae are frequent and occur more often than in the 27- to 29-week-gestation infant. Variability in the rate of clinical progress, in the incidence and severity of complications, and in the frequency/urgency of surgical procedures, is enormous in infants of less than 26 weeks gestation.

The immature central nervous system is fragile. Intracranial hemorrhage correlates with the infant's neurologic status and, eventually, defines the infant's general clinical outcome. Apnea and perioperative pulmonary insufficiency are of major significance in these infants for months after birth. Especially for the first few weeks and months of life, most infants at this developmental stage require postoperative ventilatory support, even when the infant has been without such intervention in the neonatal intensive care nursery before surgery and even when the procedure seems “trivial.”

A history of perinatal resuscitation is not uncommon in both term and premature infants. Prolonged intubation is often necessary after meconium aspiration and hyaline membrane disease. In these infants, the airway should be evaluated for subglottic stenosis and lower airway obstruction.


Newborns are classified according to gestational age and weight. The simplest classification is to group all infants less than 2.5 kg as “low birth weight.” An infant of greater than 37 weeks gestational age is defined as “term.” However, both of these labels are far too simplistic to provide any useful clinical information. Of more importance, the infant should be grouped according to weight as a function of gestational age. Birth weight in the 10th to 90th percentiles for gestational age is termed appropriate-for-gestational age (AGA), those less than the 10th percentile are SGA, and those greater than the 90th percentile are LGA. This, too, is a simplistic analysis, because differences in fetal growth can be marked when different populations are studied. For example, term infants born in Denver tend to be smaller than those born at sea level. Nonetheless, although the absolute value for birth weight at each gestational age is variable depending on geography, nutritional state, and other factors, the pattern of fetal growth is similar in all populations. That is, between 20 and 38 weeks, fetal growth is linear. Near term, fetal weight gain decelerates. Maternal nutrition, multiple gestation, maternal chronic disease, high altitude, genotype (chromosomal abnormalities), birth order, and male sex all have been clearly identified as affecting rate of fetal growth.

Although the topics of fetal growth and metabolism generally are not of major interest or significance to the anesthesiologist, “SGA” and “LGA” infants are at higher risk for a variety of metabolic and structural abnormalities ( Box 16-4 ) that may be critical to analyze and understand before subjecting such a newborn to surgery and anesthesia. Monitoring such infants during surgery must be planned, because obtaining blood samples from infants under surgical drapes can be challenging. The assessment of the weight versus gestational age usually can be obtained from the patient's medical record or from the neonatologist. At other times, the pediatric anesthesiologist should be prepared to obtain this information via an abbreviated assessment such as that described by Ballard (1979) ( Table 16-1 ). This method combines a neurologic and physical assessment to generate a score that estimates gestational age. The primary focus of the anesthesiologist for the physical examination of a newborn in the presurgical period is on the airway and the cardiopulmonary status.

BOX 16-4 

Common Metabolic and Structural Problems in Small- and Large-for-Gestational-Age (SGA and LGA) Infants


Congenital anomalies
Chromosomal abnormalities
Chronic intrauterine infection
Heat loss
Metabolic abnormalities (hypoglycemia, hypocalcemia)


Birth injury (brachial, phrenic nerve, fractured clavicle)
Meconium aspiration
Metabolic abnormalities (hypoglycemia, hypocalcemia)


TABLE 16-1   -- Physical examination to determine gestational age









Gelatinous, red, transparent

Smooth, pink, visible veins

Superficial peeling &/or rash, few veins

Cracking, rare veins

Parchment, deep cracking, no vessels

Leathery, cracked, wrinkled





Bald areas

Mostly bald


Plantar Creases

No crease

Faint red marks

Anterior transverse crease only

Anterior crease 2/3

Creases cover entire sole



Barely present

Flat areola; no bud

Stippled areola, 1-2 mm bud

Raised areola, 3-4 mm bud

Full areola, 5-10 mm bud



Pinna flat, stays folded

Slightly curved pinna with slow recoil

Well-curved pinna; soft but ready recoil

Formed & firm with instant recoil

Thick cartilage; ear stiff


Genitals (male)

Scrotum empty; no rugae


Testes descending; few rugae

Testes down; good rugae

Testes pendulous; deep rugae


Genitals (female]

Prominent clitoris & labia minora


Majora & minora equally prominent

Majora large; minora small

Clitoris & minora completely covered



Gestational age (wks)





















For simplicity, the evaluation of neuromuscular maturity is not included. The maximum score for the physical maturity is 25, and the maximum for the neuro-muscular maturitys is also 25. Thus, 50 is correlated with the mature/postmature infant. In the setting of preoperative assessment, using only the physical maturity assessment, the correlation with gestational age will be estimated by multiplying by 2. From Ballarci JL, Novak KK, Driver M: A simplified score for assessment of fetal maturation of newly born infants. J Pediatr 95:769—774, 1979.




Head and Neck

Abnormal anatomy of the head and neck should alert the anesthesiologist to possible difficulties in managing the airway. Those anesthetizing the newborn should appreciate the anatomy and embryology of the pediatric airway. A small jaw (micrognathia), a receding jaw, or both, as is seen in Pierre Robin and Treacher Collins syndromes may eliminate any chance for a clear direct visualization of the upper airway. Intubation of the trachea often requires techniques beyond direct laryngoscopy.



Cleft lip with or without cleft palate occurs in 1:1000 live births. Associated congenital defects occur in up to 13% to 50% of patients with cleft palates and 7% to 13% of patients with cleft lips. Cleft palate may also complicate intubation.



Choanal atresia often is diagnosed in the delivery room when a catheter cannot be passed into the pharynx through the nostrils (see Chapter 23 , Anesthesia for Otolaryngologic Surgery).

A subset of patients with choanal atresia has the CHARGE association. These associations include

C: Colobomatous malformation

H: Heart defect

A: Atresia choane

R: Retardation

G: Growth deficiency, Genital hypoplasia

E: Ear abnormalities

The neonate has been described as an obligate nasal breather, so that if both nostrils are obstructed, respiratory distress may develop. Hemangiomas, lymphangiomas, and hygromas of the neck can produce upper airway obstruction and must be evaluated carefully before induction of anesthesia.

Respiratory System

Differentiation of the lung can be divided into five phases: (1) the embryonic phase (weeks 4 to 6 of gestation) involves early airways formation; (2) the glandular stage (weeks 7 to 16) includes the formation of the lower conduction airways; (3) the canalicular phase (weeks 17 to 28) includes the appearance of the acinus; (4) the terminal sac period (weeks 28 to 36) is characterized by the appearance of the first respiratory units for gas exchange (terminal air sacs and surrounding capillaries); and (5) the alveolar phase (begins at about 36 weeks' gestation and continues until at least 18 months of age) (Burri, 1974 ; Langston et al., 1984 ). The timing of various malformations in utero can be estimated with knowledge of these phases of lung maturation. For example, all malformations of the conduction airways take place before 16 weeks gestation. Upper airway abnormalities take place between conception and 6 weeks of gestation. Bronchial malformations occur between 6 and 16 weeks of gestation, and lung hypoplasia becomes evident after 16 weeks gestation. In general, extrauterine viability is first likely after 26 weeks, when the respiratory saccules have developed and vascularization by capillaries has occurred. Before this time, vascular and pulmonary surface area is often inadequate for sufficient gas exchange.

Alveoli develop mainly after birth, increasing from 20 million terminal air sacs in the newborn to about 300 million at 18 months of age. In early gestation, the epithelial cells are simple and columnar in type. Specific cell types are not recognizable until the canalicular stage of development (17 to 28 weeks gestation). During the last 10% to 20% of gestation, type II pneumocytes can be identified. Although these cells have been identified in the human fetus between 22 and 26 weeks of gestation, these cells are more prominent after 34 to 36 weeks of gestation. The major change distinguishing these cells is the appearance of “osmophilic lamellar bodies.” There is close correlation between the appearance of these lamellar bodies and the presence of surface-active material in lung extracts (i.e., surfactant).

By 16 weeks gestation, all subdivisions of the conducting airways have formed; that is, main stem bronchi as well as the conducting and terminal bronchioles are present. In the course of supportive care of a premature infant in an intensive care nursery, it is likely that oxygen, positive pressure ventilation, and infections each traumatizes and interferes with the normal but complex process of development of the immature airway. That the ex-premature infant has airway abnormalities consisting of increased resistance and reactivity is not surprising.

The first active inspiration after birth generates a negative intrapleural pressure as high as 70 to 80 cm H2O. This is essential for lung expansion to overcome surface tension ( Matoth et al., 1971 ). The volume of the first few breaths, ranging from 20 to 80 mL in full-term neonates, establishes the residual volume and the functional residual capacity (FRC) necessary for adequate gas exchange ( Avery, 1974 ) (also see Chapter 2 , Respiratory Physiology in Infants and Children).

The onset of breathing, marked by lung expansion and increased alveolar and arterial Po2, dilates the pulmonary arterial circulation, decreases pulmonary vascular resistance ( Strang, 1977 ), and increases pulmonary blood flow as well as arterial and mixed venous oxygen tensions. The perinatal increase in arterial oxygen tension (Pao2 >50 mm Hg) is the initial stimulus for constriction of the ductus arteriosus and its functional closure within 10 to 15 hours after birth in the full-term infant. Mechanisms involving nitric oxide (NO) and prostaglandins lead to anatomic closure that usually occurs in 2 to 3 weeks ( Born et al., 1956 ; Heymann and Rudolph, 1975 ; Seidner, 2001) .

Gas exchange in the lungs is maintained fully after successful removal of the lung fluid from the airways and alveoli. Increased pulmonary lymphatic flow for several hours to days after birth ( Humphreys et al., 1967 ) and the presence of surface-active phospholipids and surfactant specific proteins (surfactant) ( King, 1982 ) contribute to the clearance of alveolar fluid (∼30 mL/kg). Surfactant markedly reduces surface tension at the gas-liquid interface of the alveoli, maintaining the air spaces open even at end-expiration.

Immaturity of the respiratory control mechanisms can predispose the neonate, especially the premature infant, to life-threatening respiratory complications. The infant's response to hypoxia during the first 3 to 4 weeks of life is paradoxical ( Cross and Oppe, 1952 ; Brady and Ceruti, 1966 ) in that a brief hyperpnea develops initially in response to hypoxia but is followed by respiratory depression; this initial hyperpnea can be prevented by hypothermia ( Ceruti, 1966 ) ( Fig. 16-1 ). Moreover, hypoxia, which normally increases the respiratory drive in response to hypercapnia, depresses the neonate's response to carbon dioxide ( Rigatto et al., 1975 ). The sensitivity of an infant's ventilatory response to carbon dioxide increases with postnatal and gestational age ( Rigatto et al., 1975 ) (see Chapter 2 , Respiratory Physiology in Infants and Children).


FIGURE 16-1  Percentage change in ventilation with normoxia and hypoxia in warm and cool environments plotted against time.  (From Ceruti F: Pediatrics 37:556, 1966. Reproduced by permission of Pediatrics, copyright 1966 by AAP.)




The compliant rib cage of the newborn produces a mechanical disadvantage to effective ventilation. Negative intrapleural pressure of normal inspiratory effort tends to collapse the cartilaginous, compliant chest, which causes a paradoxical chest wall motion and limits air flow during inspiration ( Knill et al., 1976 ). The circular configuration of the rib cage (versus ellipsoid in adults) and the horizontal angle of insertion of the diaphragm (versus oblique in adults) cause distortion of the rib cage and inefficient diaphragmatic contraction ( Muller and Bryan, 1979 ).

Other factors also affect the infant's work and efficiency of breathing. Although the adult diaphragm contains 55% type I fibers (fatigue-resistant, slow-twitching, highly oxidative fibers), the diaphragm of the full-term infant has 25%, and that of the preterm infant, 10%. A lower proportion of type I fibers predisposes these primary respiratory muscles 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 intercostals may contribute to easier fatigability in the newborn/young infant ( Watchko and Sieck, 1993 ; Zhan et al., 1998 ). Less effective force-frequency ( Richards et al., 1991 ), length-tension ( Watchko and Sieck, 1993 ), and force-velocity relationships (Watchko et al., 1986 ) and mismatch of energy supply and demand characterize the immature muscle of the diaphragm and may predispose the newborn to fatigue, especially in the setting of decreased lung (e.g., RDS) or total chest wall compliance (e.g., total body edema).

Pulmonary surfactant effects dramatic changes in lung mechanics including distensibility and end expiratory volume stability. The development of RDS of the newborn correlates with insufficient (premature infants) or delayed (e.g., infants of diabetic mothers) synthesis of surfactant. A typical clinical feature of RDS is the early onset (within 6 hours) of symptoms that include tachypnea, retractions, grunting, and oxygen desaturation. The chest radiograph is also characteristic consisting of diffuse reticulogranular pattern with air bronchograms. A progressive worsening of symptoms with a peak severity by days 2 to 3 and recovery starting by 72 hours characterize the uncomplicated clinical course of RDS.

The discovery that surfactant deficiency is the primary pathophysiology of RDS eventually led to the development of commercially available surfactant. Delivery of surfactant either prophylactically or as a rescue technique has become the standard of care in the neonatal intensive care unit over the past two decades. In the neonatal intensive care unit, the usual practice is to deliver a dose of surfactant into the trachea of all newborns of less than 28 weeks gestational age. Another dose is given 12 hours later. If the infant remains mechanically ventilated, a third dose is administered about 12 hours after the second. If the trachea of a greater-than-28-week-gestation infant is intubated within the first several hours after birth, surfactant is given. Repeat doses are delivered if mechanical ventilation continues.

The sickest infants in the neonatal period are not always the ones who develop the most severe chronic lung disease. Due to the complexity of lung growth and development, chronic lung disease persists as a problem in about 20% of premature infants. This occurs even though artificial surfactant decreases the need for aggressive ventilatory support. Nonetheless, the most significant decrease in infant mortality observed in 20 years in the United States occurred in 1990, the year surfactant was released commercially. Surfactant therapy has been compared with vaccines from the standpoint of health economics ( Long et al., 1995 ).

Oxygen toxicity, barotrauma (volume trauma) of positive-pressure ventilation on immature lungs, and endotracheal intubation have been implicated as etiologic factors in the development of BPD ( Philip, 1975 ). Infants who develop BPD continue to need supplemental oxygen and often have severe lower airway obstruction and air trapping, carbon dioxide retention, atelectasis, recurrent bronchiolitis, and bronchopneumonia. Maintaining normal gas exchange during anesthesia in these infants requires careful monitoring and increased respiratory support. A knowledge of the infant's acid-base status (that is, Pco2, pH, Po2) before surgery is essential for managing the infant's ventilation during anesthesia. Increased peak inspiratory pressure (PIP) and positive end-expiratory pressure (PEEP) may be needed to maintain adequate oxygenation. Reactive airway disease involving small airways is also a common feature of infants with BPD. A pneumothorax, mediastinal air leak, or interstitial emphysema may occur during mechanical or manual ventilation and must be considered in the differential diagnosis of sudden cardiorespiratory deterioration during anesthesia.

Infants with a history of RDS and endotracheal intubation who manifest stridor or a weak cry may have developed subglottic stenosis or subglottic granulomas ( Hengerer, 1975) . These lesions can cause significant narrowing of the trachea. Induction of anesthesia in the setting of critical impingement of the cross-sectional area of the upper airway may precipitate acute airway obstruction. The intraoperative and postoperative courses may be drastically affected by upper airway obstruction. For example, if the trachea is narrowed, the appropriate-sized endotracheal tube usually is smaller than that predicted for the infant's age and size. Secretions may be more difficult to suction, and mechanical ventilatory support may require unusual settings. In addition, special endotracheal tubes may be required (e.g., a 3.0-mm endotracheal tube that is longer than the routine 3.0 tube).

If this diagnosis is suspected preoperatively, the infant should be evaluated by experts such as a pediatric pulmonologist, surgeon, or otolaryngologist to formulate an organized evaluation. To some degree, the level of evaluation depends on the surgery planned and the severity of the infant's symptoms and signs. For example, computed tomography (CT) scanning, magnetic resonance imaging (MRI), or both might be performed to have a clear definition of the airway anatomy. The role of a diagnostic bronchoscopy also needs to be considered. In some cases, the decision might be to perform a bronchoscopy without a prior imaging study or in other cases, in addition to the radiologic studies. Finally, the possibility of a tracheostomy should be considered during the preoperative evaluation. Such an intervention has drastic effects on long-term care and therefore must be discussed in detail with the infant's family before proceeding with any surgical treatment.

Circulatory System

Transitional Circulation

The fetal circulation is characterized by increased pulmonary vascular resistance, decreased pulmonary blood flow, decreased systemic vascular resistance, and right-to-left blood flow through the PDA and the foramen ovale ( Donovan, 1985 ). At birth, the onset of ventilation and the elimination of the placental circulation have dramatic effects on the relationship of systemic and pulmonary vascular resistances; that is, pulmonary vascular resistance decreases and pulmonary blood flow increases. Simultaneously, systemic vascular resistance increases, left atrial pressure increases, the foramen ovale closes functionally, and the right-to-left shunting ceases. However, bidirectional shunting through the ductus arteriosus may continue in the normal infant during the first 24 hours of life. If the ductus arteriosus remains patent, shunting eventually is predominantly left to right as pulmonary vascular resistance declines in the postnatal period. If anatomic closure is achieved and cardiac anatomy is normal, shunting through the ductus is eliminated.

On the other hand, arterial hypoxemia or acidosis in the newborn can precipitate return to a fetal pattern of circulation (i.e., pulmonary arterial vasoconstriction, pulmonary hypertension, reduced pulmonary blood flow). This combination leads to right atrial pressure increasing above left atrial pressure, resulting in right-to-left shunting through the foramen ovale and ductus arteriosus ( Rudolph and Yuan, 1966). This return to a fetal circulatory pattern, termed persistent fetal circulation (PFC) or persistent pulmonary hypertension of the newborn (PPHN), further exacerbates the hypoxemia and acidosis. The control of the pulmonary circulation, especially during the transition from fetal to postnatal life, is complex and dependent on the interaction of a variety of mediators and factors, receptors, and neurologic, endocrine, and vascular control mechanisms ( Kinsella and Abman, 1995 ) ( Table 16-2 ). Although numerous treatments (hyperventilation, vasoactive agents) have been proposed over the past two to three decades, a selective and effective vasodilator of the pulmonary circulation has not been identified. In addition, PPHN may be an isolated phenomenon or may be associated with a variety of clinical scenarios including meconium aspiration, sepsis, polycythemia, diaphragmatic hernia, hypoxemia, acidosis, and severe hypotension. An echocardiogram is routinely performed in infants manifesting signs and symptoms of PPHN to definitively exclude structural cyanotic heart disease ( Peckham and Fox, 1978 ; Murphy et al., 1981 ) (see Chapter 3 , Cardiovascular Physiology in Infants and Children).

TABLE 16-2   -- Factors that modulate pulmonary vascular resistance (PVR) in infants

Lowers PVR

Increases PVR

Endogenous Mediators and Mechanisms



Nitric oxide


PGI7, E2, D2


Adenosine, ATP, magnesium




Atrial natriuretic factor

Platelet-activating factor


Ca2+ channel activation

K+ channel activation

α-Adrenergic stimulation



Vagai nerve stimulation




β-Adrenergic stimulation


Mechanical Factors

Lung inflation

Overinflation or underinflation

Vascular cell structural changes

Excessive muscularization, vascular remodeling

Interstitial fluid and pressure changes

Altered mechanical properties of smooth muscle

Shear stress

Pulmonary hypoplasia Alveolar capillary dysplasia Pulmonary thromboemboli Main pulmonary artery distention Ventricular dysfunction, venous hypertension

PVR, pulmonary vascular resistance; PGI2, E2, D2, prostaglandins I2, E2, and D2; ATP, adenosine triphosphate; PGF2a, prostaglandin F2a. From KinsellaJP, Abman SH: J Pediatr 126:853, 1995, with permission.




Myocardial Ultrastructure

The ability of the fetal and adult myocardium to contract and relax depends on the same basic process; namely, with activation, the cytosolic calcium concentration increases, inducing force generation and, as the calcium concentration decreases, relaxation occurs ( Anderson, 1998 ). The membranes in the adult myocardium that control calcium flux and the contractile system that responds to calcium are present in the fetal heart; however, components of each system undergo qualitative and quantitative age-related changes. That is, progression toward adult myocardial function involves developmental changes in the sarcomere, myofibril, sarcoplasmic reticulum, extracellular matrix, membrane receptors, and sympathetic innervation.


The immature myocardium develops less force against a load compared with the adult myocardium ( Anderson et al., 1984 ). The premature and neonatal heart cannot maintain output against an arterial pressure that is “low” in the adult. In part, this reflects a smaller myocardial mass and a thinner-walled left ventricle. In addition, in the isolated immature myocyte, the velocity and quantity of sarcomere shortening are less than in the adult myocyte ( Nassar et al., 1987 ).

Postnatally, the number and size of ventricular cells increase. The myocyte changes from a spheroidal shape to one where the cell has tapered ends, which makes contraction more efficient. The neonatal period is characterized by a major development of the left ventricle as the heart shifts from right to left predominance, with marked increase in left ventricular work secondary to higher stroke volume, systolic arterial pressure, and wall tension. Simultaneously, right ventricular work decreases secondary to the decrease in right ventricular systolic pressure. Left ventricular weight in relation to body weight increases; right ventricular weight decreases in relation to body weight. The increase in myocytes is more pronounced in the left than in the right ventricle. By the second month of life, increase in cell size rather than cell number becomes the predominant developmental phenomenon. This has major implications in the setting of congenital heart disease, especially lesions that obstruct outflow from either ventricle ( Rudolph, 2000 ). Control of this postnatal development is not completely understood, but a role for α-agonist stimulation ( Simpson, 1985 ), cortisol ( Rudolph, 2000 ), thyroid hormone, and a variety of growth factors seems to be integral.

Isoforms of the sarcomeric proteins are expressed in developmental patterns, which, in part, determine myocardial function. For example, the activity of myosin ATPase has been correlated with the rate of cross-bridging, and a higher activity results in more efficient shortening velocity, a characteristic of the mature heart ( Pagani and Julian, 1984 ). The expression of actin isoforms also varies during development. Cardiac, not skeletal, α-actin is expressed during human fetal life but the reverse is seen postnatally. The increase in skeletal α-actin has been linked to an increase in cardiac contractility after birth ( Boheler et al., 1991 ). Another example of developmental importance of isoforms is the pattern of expression of tropomyosin, which has effects on diastolic relaxation; α-tropomyosin is the predominant isoform expressed in rapidly beating hearts ( Muthuchamy et al., 1995 ).

The myocardial expression of isoforms of troponin I is of particular importance in the immature myocardium because this has been correlated with the relative resistance of the immature heart to acidosis (Solaro et al., 1988 ). The expression of slow skeletal muscle troponin I in fetal heart is linked to the newborn's ability to tolerate a greater degree of acidosis without myocardial depression. The response of the immature myocardium to sympathetic stimulation is similarly correlated with the expression of slow skeletal troponin I. Cardiac troponin is phosphorylated in response to β-stimulation. This phosphorylation decreases the sensitivity to calcium, facilitating diastolic relaxation. In the immature heart, the slow skeletal muscle isoform is not phosphorylated by β-adrenoceptor stimulation, which may have a negative effect on diastolic function ( Noland et al., 1995 ). Finally, troponin T is expressed in many isoforms, and this too has been correlated with the responsiveness of myofilaments to calcium. If the newborn and adult myocardium have different abilities to respond to calcium and calcium channel-mediated pharmacologic agents, this may have major implications concerning pharmacologic therapy in the presence of disease ( Anderson et al., 1995 ).


The myofilament content of the myocyte increases, and their arrangement becomes more highly organized during postnatal maturation. In the fetus, the pattern of the myofilaments is chaotic, compared with the long parallel rows of cells seen in the adult myocardium ( Nassar et al., 1987 ). The myofibrils are arranged in thin layers, which surround a collection of nuclei and mitochondria. This arrangement allows the trans-sarcolemmal movement of calcium, which is characteristic of the immature contractile process instead of an intracellular calcium release characteristic of contraction of the adult myocardium. The irregular arrangement of mitochondria in immature myocardium is likely to inhibit organized contractile activity, compared with the adult heart where the mitochondria alternate regularly within the sarcomere. In addition, the A and I bands of the sarcomere are irregular and the M band may be absent. The size of the Z band varies.

Sarcoplasmic Reticulum

The sarcoplasmic reticulum is the major intracellular organelle for controlling the cytosolic calcium during contraction. In the adult, only a small amount of extracellular calcium enters the myocyte and elicits the release of a larger amount of calcium from the sarcoplasmic reticulum. The immature heart has an underdeveloped sarcoplasmic reticulum. That is, the volume of sarcoplasmic reticulum within the cell and the ability to pump calcium increase with age. An increase in Ca2 +-ATPase activity has been linked to the increased function of the sarcoplasmic reticulum ( Mahony and Jones, 1986 ;Mahony, 1988 ). A significant finding is that the newborn heart requires a higher extracellular calcium concentration to achieve maximal contractility ( Jarmakani et al., 1982 ). Caffeine, which increases the release of calcium from the sarcoplasmic reticulum, has little effect on neonatal contractility, also suggesting that extracellular calcium, rather than intracellular calcium, has a primary role in control of contractility in the neonatal myocardium. With maturation, the quantity of sarcoplasmic reticulum, the number of specialized connections of the sarcoplasmic reticulum with other membranes, and the activity of Ca2 +-ATPase increases, as does the efficiency of pumping calcium.

Extracellular Matrix/Cytoskeleton

The immature myocardium is less compliant than that of the adult ( Romero et al., 1972 ). This age-related increase in compliance is secondary to changes in the extracellular matrix and the cytoskeleton. Because of the low compliance, the systolic pressure and diastolic pressure of the right ventricle can significantly alter left ventricular function in the newborn heart. That is, the higher the right ventricular end-diastolic pressure, the less the left ventricle fills in response to the same filling pressure. A similar pattern occurs in the right ventricle when the left ventricular end-diastolic pressure is increased (Pinson et al., 1987 ).

The various proteins in the extracellular space important in attaching cell surfaces may contribute to suboptimal shortening of contractile elements. The distribution of various proteins important in this process changes with maturation. For example, desmin, a protein important in linking Z bands of myofibrils, is distributed throughout the subsarcolemma area. As the myocardium develops, the organization of this protein improves the connection of myofibrils with mitochondria facilitating the mechanics of contraction. The distribution of various proteins in the cytoskeleton and extracellular matrix probably explains the irregular pattern of the A and I bands as well as the indistinct or absent M band. Integrins, which are important in linking cell surfaces to extracellular matrix proteins, are distributed differently in the immature heart. The amount and types of collagen also follow a developmental pattern that is based on changes in the expression of various isoforms that improve resting load and passive state of the myocardium. Many of the changes in the cytoskeleton and extracellular matrix occur rapidly after birth ( Robinson et al., 1983 ).

Membrane Receptors

Na+,K+-ATPase, the digitalis receptor, is a critical component of membrane function, regulating the cellular content of both sodium and calcium. The activity and quantity of this enzyme increase with maturation ( Khatter and Hoeschen, 1982 ). The α-subunits undergo developmental changes that correlate with its activity. Of clinical importance, the decreased inotropic effects of glycosides on the newborn myocardium have been explained by this maturational change. Although less well defined, a maturational difference in the role of the Na+-Ca2+ exchanger has been described, especially in species that are immature at birth (e.g., human, rat) ( Nakanishi et al., 1987 ). This exchanger may contribute to the sensitivity of the newborn myocardium to changes in extracellular calcium concentration. For example, in the clinical setting of surgery and rapid delivery of blood, serum calcium concentration may decrease, affecting myocardial dysfunction ( Sham et al., 1995 ).

Sympathetic Innervation

The sympathetic nervous system provides critical modulation of the developing myocardium at several levels: growth and differentiation of cells, regulation of calcium concentration, and response of contractile elements to calcium ( Anderson et al., 1998 ). This system also undergoes extensive postnatal development. Both innervation of the heart and availability of catecholamines increase during maturation ( Padbury et al., 1981 ; Nakanishi et al., 1987 ). On the subcellular level, the number and types of adrenoceptors and other membrane systems that are important in transmission of sympathetic stimuli are affected by maturational state but also vary from species to species. This emphasizes that caution is essential when extrapolating data from animals to clinical care of infants. For example, the fetal and neonatal myocardium of sheep has been shown to be more sensitive to norepinephrine ( Friedman, 1972 ) than the myocardium of older animals. The reported increased sensitivity of the neonatal myocardium to norepinephrine has been compared with denervation sensitivity. In contrast, developmental responses to isoproterenol are not evident in sheep.

The differences in uptake systems for adrenergic agents as the innervation of the myocardium develops may in part explain these findings. Differences in the relative number of α- and β-adrenoreceptors have been described, but, as with other developmental systems, the characteristics vary from species to species. For example, both dogs and sheep have a developmental decrease in the number of α-adrenoreceptors ( Wei and Sulakhe, 1979 ) and increase in β-receptors. In addition to changes in the population of receptors, the increase in adrenergic innervation of the myocardium and changes in the expression of isoforms of various G proteins (important in calcium current conduction) with development alters the response pattern to adrenergic stimuli.

Adrenergic stimuli are critical in normal growth and differentiation of the myocytes. The early high level of α-adrenoceptors may be critical in stimulating the left ventricular growth that develops in the early postnatal life. In fact, α1-blockade interrupts the increase in protein synthesis seen in cultured myocytes exposed to α-stimulation ( Robinson, 1996 ). Adenylate cyclase is an important enzyme that is involved in the intracellular transmission of β-stimulation. The activity of this system increases in concert with the increase in catecholamine levels. Similarly, developmental differences in the expression of isoforms of the regulatory subunit of G proteins have also been identified. The interaction of adrenergic innervation, catecholamine levels, and functional changes in multiple proteins that regulate responses to various agonists is complex and difficult to accurately extrapolate to clinical scenarios.

The newborn has the highest cardiac output per weight than any other age group (∼200 mL/kg per min). Teitel and others (1985) hypothesized that the greater increase in performance with adrenergic stimulation observed in the older lamb is due to a “lesser resting β-adrenergic tone”; that is, the baseline state of the newborn myocardium is at a higher level of “β-adrenergic tone.”

The fetus (i.e., preterm baby) may have impaired ventricular function secondary to decreased sympathetic innervation, decreased β-adrenoceptor concentration, immaturity of the sarcoplasmic reticulum structurally and functionally, and decreased number of myofibrils. This anatomy and physiology persist into the neonatal period, but cardiac output rapidly increases and cardiac performance is at a high level shortly after birth.

Myocardial Function

The major differences in myocardial function between the neonate and adult heart translate into important clinical applications (summarized in Box 16-5 ). The high content of collagen and high ratio of type I to type III collagen may account for the relative noncompliance of the neonatal heart and, consequently, its limited capacity to handle a volume load. Similarly, this nondistensible heart has limited capacity to increase stroke volume to augment cardiac output in response to increasing preload. The Frank-Starling response is considered to play a limited role and the heart rate a critical function in maintaining the cardiac output in the newborn. Over the first months of life, myocardial contractility gradually increases, which allows cardiac output to be maintained over a wider range of preload and afterload.

BOX 16-5 

Comparison of Neonatal and Adult Myocardial Functions




Cardiac output

Rate dependent

Stroke volume and rate




Starling response



Catecholamine response







The initial step in evaluating the cardiovascular system of the newborn is a careful physical examination. Evaluating skin color, capillary filling time, trends in the blood pressure, heart rate, intensity of the peripheral pulses, presence of a murmur or S3 or S4, and decreased urine output or metabolic acidosis may provide the initial hint of abnormal cardiovascular function and lead to early detection of a congenital heart lesion. Murmurs, abnormal heart sounds, dysrhythmias, and cardiomegaly are rarely innocuous findings in the newborn. For example, the femoral pulses are decreased with coarctation of the aorta, whereas they are bounding in patients with a large shunt or PDA. Cardiomegaly is associated with left heart outflow obstruction and with a variety of metabolic abnormalities, including hypoglycemia, hypocalcemia, and birth asphyxia. Infants with these conditions should have a thorough cardiac evaluation, including a chest radiograph, an electrocardiogram, and an echocardiogram, especially if a surgical intervention is urgent. The interpretation of these studies allows rational planning for intraoperative monitoring, selection of anesthetic agents, delivery of fluids, postoperative recovery, and the extent of the surgical procedure (e.g., total correction or staged procedure).


At birth, a full-term newborn normally has a hemoglobin concentration of 18 to 20 g/dL; a preterm infant usually has a lower hemoglobin concentration, ranging between 13 and 15 g/dL. Approximately 70% to 80% of the hemoglobin at birth is fetal hemoglobin (HgF), but the concentration of HgF decreases to physiologically insignificant levels by 3 to 6 months of age. The high affinity of HgF to oxygen shifts the hemoglobin-oxygen dissociation curve to the left, so that P50 (18 to 20 mm Hg) is less than in the adult value (27 mm Hg) ( Smith and Nelson, 1976 ). Although high oxygen affinity improves the fetus—ability for oxygen uptake from the mother at the placental interface ( Stern, 1973 ; Downes, 1974 ), after birth this same high affinity decreases the amount of oxygen released at tissue levels ( Pang and Mellins, 1975 ). In the normal newborn, higher hemoglobin levels, greater blood volume, and increased cardiac output (per unit weight) compensate adequately for HgF. Such normal-term infants tolerate the gradual decrease in hematocrit over the first few months of life with the nadir as low as 9 to 10 g/dL. By comparison, the concentration of hemoglobin in the very-low-birth-weight (VLBW)/ELBW infant at birth normally ranges between 13 to 15 g/dL. Of note, the nadir of a premature (<30 weeks gestation) infant's hemoglobin may be as low as 6 to 7 g/dL by 3 to 4 months of age. However, erythropoietin is routinely administered to infants in the neonatal intensive care unit, thereby avoiding such a profound anemia ( Soubasi et al., 1995 ; Al-Kharfy et al., 1996 ).

If a newborn is unstable secondary to congenital heart disease (especially cyanotic), sepsis, metabolic derangement, or other anomalies, the ability to compensate for HgF may be marginal. Such newborns with cardiovascular or respiratory instability often benefit from maintaining the hematocrit at greater than 40% to 45% to facilitate adequate oxygen delivery. Of note, after several transfusions with adult packed red blood cells (RBCs), the negative impact of HgF becomes less relevant. Blood loss exceeding 10% to 15% of the blood volume (or even less in some patients) may not be tolerated by newborns, especially the VLBW infants. Cross-matched blood should be available for any surgery, especially when blood loss is anticipated (see Chapter 2 , Respiratory Physiology in Infants and Children).

Assessing clotting function should be considered before major surgery in the newborn for several reasons. First, the synthesis of prothrombin and factors II, VII, and X in the liver is immature. Second, perinatal asphyxia and septicemia affect function and concentration of both clotting factors and platelet count, resulting in coagulopathies. Before surgical intervention, the availability of the requirements for fresh frozen plasma, fibrinogen, and/or platelets must be assessed (see Chapter 32 , Systemic Disorders in Infants and Children).

Renal Function

The fetal kidney is a passive organ, which at birth undergoes a transition to an active organ. Each day 200 to 1000 mL of urine is produced, depending on gestational age. Urine production increases from about 5 mL/hr at 20 weeks gestation, to 18 mL/hr at 30 weeks, and to 50 mL/hr at 40 weeks ( Rabinowitz et al., 1989 ). The fetal kidney handles a large volume load and produces large amounts of hypotonic urine. However, the kidney is not essential for maintaining the normal fluid and electrolyte balance of the fetus in utero. Production of urine is important to maintain normal amnionic fluid volume, and, in that way, urine volume contributes to normal pulmonary and urinary tract development. The term newborn kidney usually has fetal lobulations but the full number of nephrons (i.e., 1 ×106/kidney) found in the adult kidney ( McDonald and Emery, 1959 ) (see Chapter 4 , Regulation of Body Fluids and Electrolytes in Infants and Children).

The renal function of the newborn compared with the adult is characterized by a decreased glomerular filtration rate (GFR), decreased solid excretion, and decreased concentrating power. In the first 24 hours of life, GFR may be as low as 4 mL/min per 1.73 m2 in infants of less than 25 weeks gestational age. The GFR increases with gestational age, and by 34 to 36 weeks of gestation, values of 25 mL/min per 1.73 m2 are achieved, similar to those reported for full-term infants ( Svenningsen and Aronson, 1974 ). Over the first 3 months of life, GFR increases twofold to threefold. Thereafter, a slower rise is noted until adult values are reached by 12 to 24 months of life.

Renal function does respond to “demand” (solute exposure), and the newborn kidney improves its filtration and concentrating capacities if challenged. The high anabolic rate associated with growth does counteract the limited ability to excrete solute, because growth requires incorporation of calcium, nitrogen, sodium, phosphorus, and water into the new tissues. At 34 weeks gestational age, GFR increases markedly, whether the kidney is in utero or extrauterine. The GFR and tubular function of a 2-week-old 34-week-postconceptual age infant may be greater than a 1-day-old born at 34 weeks gestation. That is, the maturation of renal function in preterm infants after birth may be accelerated.

Maximum urinary osmolality after a DDAVP stimulation test was about 520 mOsm/kg in 30- to 35-week-gestation infants and 570 mOsm/kg in term infants at 4 to 6 weeks of age. In comparison, 1- to 2-year-old children responded to DDAVP by concentrating to 1300 to 1400 mOsm/kg ( Svenningson and Aronson, 1974 ). The majority of infants are still not able to concentrate as well as adults by 6 to 12 months of life. The therapeutic index for fluid and electrolytes is narrow in the newborn, especially the VLBW infant in the first days after birth when insensible water loss may be enormous. In healthy children and adolescents, evaporation accounts for approximately 40% of total baseline water losses. However, in premature neonates, insensible water evaporation is several magnitudes greater because of marked transepidermal permeability as well as relatively large body surface area. Exposed premature infants have a 15 times more evaporative losses than do naked term infants during the first few days after birth ( Hammarlund et al., 1983 ). An exposed VLBW infant can lose 10% of body weight during the first day of life by this route. Increased respiratory exchange in premature neonates can also contribute to water loss.

In addition to limited GFR, the tubular function of the neonatal kidney is immature. The discrepancy between the inner and the outer cortical nephrons is striking both anatomically and functionally. The inner nephrons (juxtamedullary) are more functional, as manifested by the length of the tubules when outer and inner cortical nephrons are compared. Because the site of filtering, the glomerulus, is uniform in its function, this leads to what is termed a “tubular/glomerular” imbalance. This imbalance in part explains why the urine of the newborn characteristically has a higher percentage of the filtered load (i.e., reabsorption at the proximal tubule has not occurred).

The limited tubular reabsorptive function of the kidney is the basis for the loss of bicarbonate and the “normal” acidosis that occurs in the newborn, particularly the premature ( Vanpee et al., 1988 ) (sometimes called renal tubular acidosis, type 4). The pH of the urine may be greater than 5 despite a serum total carbon dioxide of 15 to 18. At some point, the threshold for bicarbonate loss is reached, the urine pH is 5.0 and a mild-moderate metabolic acidosis persists.

Similarly, proximal tubular reabsorption of sodium increases with gestational age; the percentage of filtered sodium excreted in the urine is at least 5% in the less-than-30-week-gestation infant and about 0.2% in the term infant ( Vanpee et al., 1988 ). Of note, hypoxia, respiratory distress, and hyperbilirubinemia can increase fractional sodium excretion.

The distal tubular function also limits the ability of the kidney to excrete a sodium load. Until 34 weeks gestation, the level of aldosterone, the response to aldosterone, or both are low ( Aperia et al., 1979 ). The premature proximal tubule fails to reabsorb sodium effectively and delivers a high load of sodium to the distal tubule, which is also unable to salvage this electrolyte. Furthermore, the preterm infant has high levels of circulating atrial natriuretic peptide, prostaglandins, and progesterone, all of which contribute to a negative sodium balance ( Tulassay et al., 1986 ). High levels of ADH have been measured in the urine of both term and preterm infants in response to hypoxia, atelectasis, intraventricular hemorrhage, and BPD ( Wiriyathian et al., 1986 ). In part, this nonosmotic secretion of ADH accounts for the dilutional hyponatremia of the newborn, especially the premature. The limited urinary concentrating ability in the fetus and newborn can be correlated with the immature medullary concentration gradient, decreased response to ADH, and an immature aldosterone system.

Finally, plasma rennin activity (PRA) is inversely related to gestational age, increasing slightly at 3 to 6 days of postnatal life and then decreasing over the next 3 to 6 weeks. Thereafter, a gradual decline is noted. The physiologic significance of the high PRA levels in the neonatal period may be related to the renal salt wasting and negative salt balance that occur in the first few weeks of extrauterine life.

Serum potassium levels of greater than 5.0 mmol/L are not uncommon in newborns, particularly premature infants with a mild metabolic acidosis. In addition to a relative hyperkalemia secondary to metabolic acidosis, nonoliguric hyperkalemia has been described in the ELBW infant ( Mildenberger, 2002) . The disorder is characterized by a rapid rise of serum potassium, usually in the first day of life and not later than 72 hours after birth. The proposed mechanism is a rapid shift of potassium from intracellular to extracellular compartments, but the etiology of the phenomenon is unclear. Treatment has included the well-accepted regimen (insulin/glucose and calcium/bicarbonate, as well as diuretics and binding resins).

Central Nervous System

Common derangements of early brain development correlate with abnormalities in one of the two major structures of embryogenesis: neural tube and prosencephalon ( Volpe, 2001a ). Primary neural tube (3 to 4 weeks) and prosencephalon (2 to 3 months) development are complete early in gestation. Neural tube anomalies that are associated with these early events are dramatic and often fatal: anencephaly, craniorachischisis totalis, myeloshisis, and encephalocele. Less severe defects include myelomeningocele, a restricted version of abnormal neural tube closure. This defect is the most clinically important, because the affected infants frequently survive. Hydrocephalus frequently accompanies myelomeningocele—60% in occipital, cervical, thoracic, or sacral lesions and about 90% in thoracolumbar, lumbar, or lumbosacral lesions. The Arnold-Chiari malformation is common in this second group of patients and frequently contributes to the development of the hydrocephalus via obstruction of fourth ventricular outflow or aqueductal stenosis. Similar to neural tube defects, severe prosencephalic anomalies (holoprosencephalies) are often fatal, especially those associated with chromosomal abnormalities (e.g., trisomy 13-15, trisomy/ring/deletion 18).

Less severe disorders such as agenesis of the corpus callosum and of the septum pellucidum are less often fatal but are frequently associated with abnormal neuronal migration and, in those cases, are accompanied by significant clinical abnormalities. Isolated agenesis of the corpus callosum can be asymptomatic. Partial agenesis syndromes are likely to have occurred later in development and are associated with a range of clinical syndromes correlated with coexistent migrational and structural disorders.

After the primary structure of the neural tube and the prosencephalon are established during the first 2 to 3 months of gestation, development of the central nervous system entails proliferation and migration. These developmental processes are likely to have the greatest effect on prognosis for the preterm infant.

Proliferation of neurons proceeds from the ventricular and subventricular regions at every level of the developing nervous system. From the second to the fourth month of gestation, some glia is forming but the primary process is neuronal proliferation. From the fifth month of gestation forward into adult life, glial multiplication is the primary process. This developmental process of moving from ventricle to subventricular site is of particular relevance when considering the pathophysiology of the preterm infant. Glial development does occur to a limited degree during early gestation, as these cells are vital for normal migration. Arterial and venous supply is established during neuronal proliferation. The two neuropathologic diagnoses that define the pattern of injury in the preterm infant are periventricular hemorrhagic infarction and periventricular leukomalacia.

Intracranial Hemorrhage-Germinal Matrix/Intraventricular Hemorrhage

The pathophysiology of this lesion is related to the structure of the immature brain (Volpe, 2001b and 1997 [339] [340]; Lou et al., 2001 ). The proliferating region of the ventricular and subventricular areas of the developing nervous system is richly cellular and vascularized, and between 10 to 20 weeks of gestation is the site of origin of the neuroblasts. In the third trimester, this area is the source of glioblasts. The region is gelatinous in mid-gestation, but during the final 12 to 16 weeks of gestation, it gradually degenerates and is barely present in the term infant. The dense and well-developed vascular network at mid-gestation drains into a venous system that receives blood from the entire brain and terminates at the level of the head of the caudate nucleus, where the veins join the vein of Galen. The junction of capillaries with veins (rather than at arteries or arterioles) appears to be the site of bleeding in the premature brain. From 28 to 32 weeks gestation, the germinal matrix is most prominent at the level of the head of the caudate nucleus. This is the usual site of the germinal matrix hemorrhage.

Periventricular Leukomalacia

This bilaterally symmetrical, nonhemorrhagic lesion represents necrosis of white matter dorsal and lateral to the external angles of the lateral ventricles. More diffuse cerebral white matter injury has also been described. Periventricular leukomalacia is sometimes inappropriately described as a consequence of intraventricular hemorrhage, because both are frequently identified at the same time on the same scan. However, periventricular leukomalacia is a postischemic lesion, not a venous infarction ( Takashima, 1986) . Focal necrosis is seen pathologically. Tissue destruction may lead to formation of cavities and cysts. Eventually, with the loss of oligodendrocytes and abnormal myelination, the volume of white matter decreases and ventriculomegaly may develop. The most consistent clinical correlate of periventricular leukomalacia is spastic diplegia.

Autoregulation of Cerebral Blood Flow

Critically ill newborns often require mechanical ventilatory support, airway suctioning, and intravenous fluid boluses, all which may dramatically affect blood pressure, cardiac output, and heart rate. Episodes of metabolic instability (e.g., hypoglycemia, hypercarbia, hypocarbia, hypoxia, hyponatremia/hypernatremia, hypocalcemia) also can have dramatic effects on the hemodynamic status. Such fluctuation in blood pressure and cardiac output can have major impact on the central nervous system of the newborn, because the autoregulation of the cerebral blood flow is incomplete at this developmental stage compared with that seen in the adult. Autoregulation of cerebral blood flow seems to be intact over a wide range of arterial blood pressure of both preterm and term newborns ( Fig. 16-2 ), but the range is narrower for the preterm infant. Of particular significance, the normal blood pressure of the preterm is at the lower range of the autoregulatory limit. With decreasing gestational age, this lower limit is closer and closer to normal blood pressure. Similarly, the upper range of autoregulation may be approached during later gestational development when arterial pressure increases ( Papile et al., 1985 ). Furthermore, this normal range of autoregulation is disturbed or disrupted during hypoxia, acidosis, seizures, and with the low diastolic blood pressure of a PDA (Lou et al., 1979). A rapid increase in blood pressure may produce bleeding of the fragile vessels of the immature brain, whereas hypotension and low perfusion may produce ischemia (see Chapter 18 , Anesthesia for Pediatric Neurosurgery).


FIGURE 16-2  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, 2nd ed. New York, 1990, Churchill Livingstone, pp 341-362. After data of Hernandez MJ, Brennan RW, Vannucci RC, Bowman GS: Am J Physiol 234:R209-R215, 1978.)




Metabolic Requirements

Metabolic demands for growth are enormous in the newborn, especially the LBW infant. Adequate nutrition for growth and development must be analyzed from the viewpoint of both total calories and the appropriate ratio of fat, carbohydrate, and protein. These requirements vary enormously depending on gestational and postnatal age, cardiovascular status and perfusion, organ function (i.e., liver and kidney), infection, environmental temperature, metabolic rate, and other factors.

In addition, the major substrate to provide an adequate “energy source” varies from organ to organ. For example, brain and heart derive their energy from glucose metabolism. However, hepatic glycogen stores, the main source of glucose, are limited in the neonate, particularly those who are LGA or SGA. Thus, hypoglycemia in the neonatal period can be a major source of morbidity, causing apnea, hypotension, bradycardia, convulsions, and brain injury ( Senior, 1973 ).

Neonates are NPO for hours to days prior to and after undergoing surgery for a variety of reasons, such as nonspecific ileus, a primary gastrointestinal anomaly, and/or cardiovascular instability secondary to sepsis (e.g., necrotizing enterocolitis). These infants must receive their nutrition (120 kcal/kg per day) via intravenous alimentation. Delivery of total parenteral nutrition (TPN) requires meticulous monitoring of body weight, urine output, electrolytes (sodium, potassium, chloride, magnesium, calcium, total carbon dioxide, etc.), total protein, albumin, blood urea nitrogen, and creatinine. The daily calculation of TPN is often uncomplicated, if the basic “rules” for increasing glucose, maintaining the appropriate nonprotein-to-protein ratio, and maintaining the relative percentage of total calories from fat and carbohydrate, are followed.


Hypocalcemia is common in term infants who have not started oral feeds during the first day of life, have been asphyxiated, or have an underlying metabolic disorder (e.g., DiGeorge syndrome).

Slightly less than half of the total serum calcium is free or ionized, and most of the nonfree calcium is bound to protein (mostly albumin). The free calcium correlates with adequate cell function, so the ionized calcium concentration (1.0 to 1.3 mmol/L) is more physiologically relevant than the total calcium concentration. In older children and adults, the total calcium adequately estimates physiologic calcium. The serum calcium level in healthy full-term neonates averages 9 mg/dL during the first 40 hours of life ( Root and Harrison, 1976 ), which is within the range of normal adult levels (8.7 to 10.1 mg/dL). Each 1 g/dL of albumin in the serum binds about 0.8 mg/dL of calcium, so that a low total calcium concentration may not be abnormal in the setting of significant hypoalbuminemia. Because total protein and albumin values are normally lower in the newborn and even lower in the VLBW infant, total calcium is an unreliable estimate of calcium status in the newborn.

Neonatal hypocalcemia is linked to the sudden cessation of active transplacental delivery of calcium ( Tsang et al., 1973 ) (fetal levels are higher than those of the mother). Newborns may have a transient hypoparathyroidism secondary to the high fetal levels of calcium as well as refractoriness of the target cells to parathyroid hormone. Asphyxia elicits secretion of calcitonin, which also contributes to hypocalcemia of “sick” term or premature infants. The effect of these hormonal factors is further exacerbated by limited enteral intake by a “sick” and/or preterm infant. The incidence of hypocalcemia is inversely proportional to gestational age and birth weight and is common if adequate intake of calcium is not promptly established after birth. Infants of diabetic mothers have the additional factor of hypomagnesemia contributing to abnormal hypoparathyroid function (secondary hypoparathyroidism) and hypocalcemia. However, extrapolating these data to nonhealthy infants with abnormal blood volumes and multiorgan dysfunction is impossible. Other factors that contribute to neonatal hypocalcemia are abnormal intrauterine growth patterns (SGA, LGA), the administration of sodium bicarbonate, exchange transfusion with citrated blood, and alkalosis associated with hyperventilation ( Bergman et al., 1974 ). In general, signs and symptoms of hypocalcemia are nonspecific and include hypotension, irritability, jitteriness, twitching, seizures, and, rarely, cyanosis and vomiting.


SGA and LGA infants, especially those who are also preterm or have diabetic mothers, are at high risk for developing hypoglycemia. When enteral feeding is promptly established in the term infant, normal serum glucose levels range between 60 and 80 mg/dL. If the glucose level falls to less than 40 mg/dL, treatment should be initiated. Similar to hypocalcemia, hypoglycemia has nonspecific signs and symptoms—jitteriness, cyanosis, apnea, lethargy, hypotonia, and seizures. Hypoglycemic babies must be treated rapidly to prevent neurologic damage ( Koivisto et al., 1972 ). In some cases (e.g., stable term infants), this may simply involve increasing oral intake and remeasuring the glucose every 30 to 60 minutes until the value is greater than 60 mg/dL for several hours and oral feedings are well established. In high-risk infants (e.g., infant of a diabetic mother) or those who are not likely to establish full enteral feedings (e.g., cleft palate, asphyxiated infants), intravenous treatment is preferred. In some cases, nasogastric feeds might be initiated.

The etiology of hypoglycemia is often clear—perinatal hypoxemia, sepsis, high circulating levels of insulin ( Milner, 1972 ) in the infant of a diabetic mother, LGA or SGA, etc. In the preterm infant, inadequate glycogen stores and deficient gluconeogenesis are also important factors. In such high-risk infants, routine monitoring for hypoglycemia is critical because hypoglycemia is often asymptomatic or can be similar to symptoms and signs of other metabolic or systemic disorders. Treatment of hypoglycemia in LBW and critically ill infants consists of slow intravenous administration of a 250- to 500-mg/kg bolus of glucose as a D5 or D10 solution, followed by an infusion of 10% to 15% dextrose solution to deliver 4 to 6 mg/kg per min and titrated to maintain the serum glucose at greater than 40 mg/dL, preferably 80 to 120 mg/dL ( Box 16-6 ). Monitoring the glucose level is also critical to avoid hyperglycemia. A hyperosmolar state in a newborn, especially a VLBW infant, can result in intraventricular hemorrhage, osmotic diuresis, dehydration, and further release of insulin, leading to subsequent hypoglycemia.

BOX 16-6 

Common Intravenous Fluid and Electrolyte Requirements in the Newborn


Most newborns require 2 to 4 mg/kg per min.

Small-/large-for-gestational-age (SGA/LGA) infants may require >15 mg/kg per min on days 1 to 3 of life.

Glucose tolerance may fluctuate significantly in very low and extremely low birth weight (VLBW and ELBW) infants.


Most newborns require no sodium for the first 24 hours of life.

On day 2 and beyond, most newborns receive 2 to 4 mEq/kg per day.

Sodium requirement may change dramatically in response to gastrointestinal, genitourinary, or transcutaneous losses, drug or metabolic effects.

The ELBW infant may have huge transcutaneous fluid losses, requiring meticulous monitoring and replacement.


Requirements for potassium are minimal for the first 24 to 48 hours of life.

Subsequently, maintenance delivery is about 1 to 3 mEq/kg per day, always in the presence of a normal urine output.

Serum levels in the newborn, especially VLBW and ELBW, are higher than in older infants.

Replace gastrointestinal, genitourinary, or iatrogenic losses cautiously.


Requirements for calcium range between 200 and 400 mg/kg per day (calcium gluconate).

Requirements for calcium vary with gestational age, history of asphyxia, growth disturbances (SGA, LGA).

Serum levels can be obtained for total Ca2+ and/or ionized Ca2+.

Hyperinsulinism occurs infrequently in infants and is associated with erythroblastosis fetalis ( Barrett and Oliver, 1968 ), Beckwith-Wiedemann syndrome, insulin-secreting pancreatic tumors, and polycythemia ( Bedard and Kotagal, 1981 ).

Acid-Base Balance

Neonatal acid-base abnormalities can evolve from intrauterine problems (e.g., bleeding, infection, placental pathology) intrapartum events (e.g., umbilical cord prolapse, bleeding, prolonged or complicated labor), or intrinsic fetal anomalies (e.g., congenital heart disease, diaphragmatic hernia, upper airway or lung anomalies). A variety of etiologies may set the stage for cardiorespiratory depression in the newborn. Some neonatologists measure the pH, Po2, and Pco2 from the umbilical vein (from the placenta) immediately after birth to assess the severity of the birth asphyxia. The acid-base status of the depressed newborn must be monitored serially to guide treatment ( Table 16-3 ). Treatment and correction of acidosis (pH < 7.20) with intravenous sodium bicarbonate and glucose and mechanical ventilation can improve perfusion and oxygen delivery. Often acidosis clears as perfusion is established with neonatal resuscitation. Establishing effective ventilation of the lungs with or without intubation of the trachea is the critical maneuver, but crystalloid or colloid infusion may also be necessary. Rarely are chest compressions or vasoactive medications (e.g., epinephrine) necessary. Sodium bicarbonate should only be given after ventilation is established and the Pco2 is less than 35 mm Hg and the pH remains less than 7.20. Sodium bicarbonate is hyperosmolar and should be delivered slowly at a dose of 0.5 to 1 mEq/kg. Subsequent treatment with bicarbonate is based on frequent measurement of blood gases, serum electrolytes, and osmolality.

TABLE 16-3   -- Normal pH and blood gas values in umbilical arterial blood of the full-term neonate




5 minutes

1 hour

1 day

7 days


7.21 ± 0.05

7.33 ± 0.03

7.37 ± .03

7.37 ± .05

PaCO2 (mm Hg)

46 ± 7

36 ± 4

33 ± 3

36 ± 3

Base excess (mmol/L)

-8 ± 2

-6 ± 1

-5 ± 1

-3 ± 1

PaO2 (mm Hg)

50 ± 10

63 ± 11

73 ± 10

73 ± 10

Hematocrit (%)

53 ± 6

54 ± 5

55 ± 7

51 ± 8

From Koch G, Wendel H: Biol Neonate 12:136, 1968, with permission from S. Karger AG, Basel.

Value are given as mean ± SD.






The anesthesiologist must analyze the cardiorespiratory status, urine output, and laboratory values in the preoperative period to manage the neonate's fluid and electrolyte therapy. This is the framework for developing a rational plan for administering “maintenance fluid” during surgery.

Similar to the acid-base status, electrolyte abnormalities in the newborn are often secondary to intrauterine or intrapartum events or congenital anomalies that lead to asphyxia. That is, asphyxia is associated with hypocalcemia and hypoglycemia, renal failure (acute tubular necrosis), and myocardial depression. In addition, primary gastrointestinal malformations can lead to poor feeding and vomiting and dependence on intravenous fluids or TPN, predisposing to overhydration and other iatrogenic electrolyte problems.

Hypernatremia may occur in dehydrated infants if water loss is greater than sodium depletion, whereas hyponatremia occurs frequently in infants receiving salt-free solutions or water in excess of sodium. Inadequate or abnormal renal tubular function predisposes to serum sodium abnormalities. Hypokalemia can result from aggressive diuresis, respiratory alkalosis, and vomiting. Hyperkalemia may be caused by hypoperfusion states, massive blood transfusion, renal failure, or the administration of large amounts of potassium-containing solutions. Abnormalities in electrolyte balance may increase morbidity during anesthesia secondary to arrhythmias and, rarely, cardiac arrest.

Temperature Regulation

At birth, the newborn arrives abruptly into a cooler environment and loses thermal protection, and temperature regulation suddenly becomes an important and calorically expensive physiologic function. Once delivered, the infant loses heat via evaporation, convection, conduction, and radiation (see Chapter 5 , Thermoregulation: Physiology and Perioperative Disturbances).

Neonates are homeotherms whose compensatory mechanisms to maintain core body temperature operate within a narrow environmental temperature range. In addition, many factors increase the neonate's tendency to lose heat: large surface area-to-body weight ratio, reduced subcutaneous fat, and an underdeveloped ability to shiver in response to cold. The major compensatory mechanism in response to cold stress is to produce heat by nonshivering thermogenesis. Nonshivering thermogenesis involves the release of norepinephrine, which initiates triglyceride and fatty acid metabolism in the energy-rich brown fat deposits of the newborn ( Stern et al., 1965 ). Heat produced by this mechanism is extremely costly in the ill neonate because the energy available in brown fat is needed for growth and development.

Hypothermia increases oxygen consumption dramatically. The environmental temperature for the newborn in which oxygen consumption is minimal has been defined as the “neutral thermal environment.” Oxygen consumption is minimal when the newborn's skin temperature is 36°C, and the environment temperature is between 32° and 34°C ( Adamsons and Towell, 1965 ) (see Fig. 5-2 , Chapter 5 , Thermoregulation: Physiology and Perioperative Disturbances). Prematurity, hypoglycemia, and general anesthesia can exaggerate the neonate's metabolic responses to hypothermia ( Swyer, 1975 ). Prolonged exposure to a hypothermic environment can place increased demands that may exceed the neonatal cardiopulmonary capacity for compensation. This can result in hypoventilation, inadequate oxygen delivery, tissue acidosis, and cardiovascular collapse ( Gandy et al., 1965 ).

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Copyright © 2005 Mosby, An Imprint of Elsevier


Increasing evidence indicates that the physiologic response of neonates to painful stimuli is similar to that of adults (see Chapter 13 , Pain Management in Infants and Children). The response of the sympathetic nervous system to noxious stimulation includes tachycardia and hypertension, which in the setting of abnormal cerebral autoregulation predisposes the LBW infant to intraventricular hemorrhage and possibly pulmonary hypertension. The goal during anesthesia is to avoid pain and its cardiovascular and neurologic consequences. The response of newborns to narcotics and potent inhalation agents is variable, and meticulous titration is critical for neonates undergoing surgery to avoid cardiovascular collapse and to maintain acid-base balance but to eliminate awareness and pain.

Drug pharmacokinetics and pharmacodynamics are affected by anatomic factors relating to body composition and distribution of water as well as physiologic factors (metabolism [i.e., hepatic biotransformation], protein binding, and pathologic factors [disease, anesthesia, and surgery]). Maturational changes in distribution of total body water, in tissue composition, and in organ function contribute to the unique response of the newborn and young infant to various drugs. In early fetal development, water constitutes approximately 94% of body weight. As gestation continues, the total body water decreases so that at 32 weeks, 80% to 90% of body weight is water, and at term, total body water is approximately 70% to 75% of body weight. Adult proportions of fluid to body weight (55%) are reached between the age of 9 months and 2 years. The distribution of water between the extracellular and intracellular compartments also changes during fetal growth. Extracellular water (interstitial fluid plus plasma volume) decreases from 60% of body weight at the fifth month of fetal life to approximately 45% at term. Intracellular water increases from 25% in the fifth month of fetal life to 33% at birth. So, the extracellular fluid compartment of the newborn is equal to or greater than the intracellular fluid space. In adults, the intracellular and extracellular fluid compartments are approximately 40% and 20% of body weight, respectively. Because the plasma component of the extracellular fluid compartment remains at approximately 5% of body weight throughout life, it is the interstitial water that is greater in infancy (40%) and declines to 10% to 15% in the adult ( Friis-Hansen, 1971 ).

Age-dependent changes in body composition also occur. At term, fat constitutes 11% of body weight. Fat content doubles by 6 months of age and is approximately 30% at 1 year. Teenage girls remain at approximately 20% to 30% fat, whereas teenage boys decrease to 10% to 15%. Moreover, the composition of fat tissue changes with age. Fat of the newborn may contain as much as 57% water and 35% lipids; adults have 26% water and 71% lipids ( Friis-Hansen, 1971 ). Skeletal muscle comprises 25% of total body mass in a term newborn compared with 43% in an adult.

The binding of drugs to serum proteins depends on several factors, such as the concentration of protein, the number of binding sites on these proteins, and the affinity of the binding sites. The concentration of total serum protein, albumin, and α1-acid glycoprotein is lower in early infancy and reaches adult levels by approximately 1 year ( Pacifica and others, 1986) . Albumin primarily binds acidic drugs; α1-acid glycoprotein binds basic drugs. The concentration of these two proteins and their binding affinities are deficient in the newborn ( Piafsky and Woolner, 1982 ).

The primary organ for drug biotransformation is the liver, but the kidney, intestine, lung, and skin also have minor roles. Hepatic oxidation, reduction, and hydrolysis (nonsynthetic, phase I reactions) mature rapidly, achieving adult rates by 6 months ( Niems et al., 1976 ). Drugs metabolized via this cytochrome P450-dependent mono-oxygenase system include phenobarbital and phenytoin. Conjugation reactions (synthetic, phase II reactions) convert drugs into more polar compounds to facilitate renal excretion. These systems also mature postnatally.

The renal excretion of drugs is a function of glomerular filtration rate (GFR), active secretion, and passive reabsorption. GFR and secretion increase in an age-dependent manner. Renal blood flow ( Hook and Bailie, 1979 ) and GFR ( Arant, 1978 ) increase dramatically during the first postnatal week and more gradually during the next several months, and adult performance is achieved at approximately 6 to 12 months of age. Tubular secretory and reabsorptive capacity also mature postnatally ( Fetterman et al., 1965 ).

Cardiac output and its distribution to various organs contribute to drug elimination. The perinatal adaptation to extrauterine life demands rapid changes in the circulation. This process may be inhibited as a result of congenital heart disease or acid-base problems. Drug metabolism and elimination may be drastically affected when cardiovascular function is abnormal.


Infants have a higher incidence of cardiovascular instability and cardiac arrest during induction of inhalation anesthesia than do older persons ( Rackow et al., 1961 ; Friesen and Lichtor, 1982, 1983 [85] [86]; Morray, 2000, 2002 [203] [204]; Murat et al., 2004 ). This untoward effect of potent inhalation agents can be attributed to several factors, including faster equilibration, rapid myocardial uptake in infants, increased anesthetic requirement, and sensitivity of the neonatal myocardium. Infants attain a higher concentration of inhaled anesthetic agents in the heart and brain than do adults at the same inspired concentration. Moreover, the neonatal myocardium has decreased contractile mass, and the magnitude and velocity of fiber shortening are less than in the adult myocardium. These factors and the increased anesthetic requirement, which is inversely related to age, all produce a higher incidence of adverse cardiovascular effects in infants.

The rate of rise of the alveolar concentration of an inhaled anesthetic depends on several factors: the inspired concentration, alveolar ventilation, and uptake. The greater the alveolar ventilation, the faster is the rate of rise of the alveolar concentration. This effect of alveolar ventilation is affected by the size of the functional residual capacity (FRC). Infants and children have an FRC similar to that of the adult: 30 mL/kg per min. In contrast, alveolar ventilation is much higher in the infant (100 to 150 mL/kg per min) compared with the adult (60 mL/kg per min). This difference parallels the greater oxygen consumption of the infant. So, in the normal term newborn who weighs 3.0 kg, the ratio of alveolar ventilation to FRC is approximately 5:1, compared with the adult, in whom the same ratio is 1.5:1. As a result of this difference, the time constant of the inhaled anesthetic equilibrium for infants is much shorter than for the adult. Consequently, changes in concentrations of inspired gas are reflected rapidly in alveolar levels. In fact, it has been demonstrated that alveolar levels of inhalational anesthetic agents reach equilibrium faster in infants that in adults (see Chapter 6 , Pharmacology of Pediatric Anesthesia).

The rise of the alveolar concentration of an inhaled anesthetic is opposed by uptake of the agent into lung tissue and, more important, blood. Three factors determine inhaled anesthetic uptake: cardiac output, the alveolar-to-mixed venous anesthetic partial pressure difference, and solubility. Each of these factors has unique aspects in the infant, compared with in the adult, and consequently affects the pharmacology of the uptake of inhaled agents.

The greater the cardiac output, the greater is the anesthetic uptake. The cardiac output of the newborn is 250 to 300 mL/kg per min; by 8 weeks, the cardiac output has decreased to 150 mL/kg per min. The cardiac output of young infants is approximately 3 to 6 times that of the normal adult (70 mL/kg per min). By itself, this high cardiac output should significantly decrease the rate of rise of the alveolar concentration of the soluble anesthetic agents. However, the newborn distributes a greater proportion of this cardiac output to the vessel-rich group of organs and less to the muscle and fat group. The equilibrium between the inspired and alveolar concentration of inhaled agent occurs more rapidly because uptake decreases faster.

Because the cardiac output is predominantly distributed to the vessel-rich group and because the muscle group is small, the arterial-venous partial pressure difference narrows quickly in the young and thereby decreases uptake.

Both left-to-right and right-to-left shunting occurs in infants. A left-to-right shunt results in an increase in total cardiac output. However, the shunted blood does not lose anesthetic to tissue; instead it returns to the lung with the same anesthetic partial pressure. This recycled blood cannot accept more anesthetic agent unless the alveolar partial pressure has risen. Thus, a left-to-right shunt has no effect on anesthetic uptake. A right-to-left shunt slows the rate of rise of the alveolar concentration of an inhaled anesthetic. The anesthetic-deficient-shunted blood dilutes the concentration of the anesthetic in the blood, decreasing the partial pressure of anesthetic in the arterial circulation. This slows the rate of rise of the anesthetic by slowing tissue uptake and equilibration.

Lerman and others ( Lerman et al., 1984 ; Malviya and Lerman, 1990 ) reported that the blood-gas partition coefficient in newborns was consistently lower than that in adults by 18%. They also found that two or more serum constituents (albumin, globulin, triglyceride, cholesterol) are required to predict the blood-gas partition coefficient of isoflurane, enflurane, halothane, and methoxyflurane in all age groups. However, in a later study, blood-gas partition coefficients of isoflurane, halothane, and sevoflurane did not differ in preterm compared with term infants but were lower than in adults. Only serum cholesterol correlated with the blood-gas partition coefficients ( Malviya and Lerman, 1990 ). The blood-gas partition coefficient is an important determinant of solubility and, therefore, the rate of rise of the alveolar concentration of an inhaled agent.

The effect of age on the solubility of the inhaled agents in tissue is also important in determining the rate of rise of the alveolar concentration of the agent—the rate of anesthetic induction. Data by Lerman and others (1986) are consistent with earlier work documenting that anesthetic solubility in brain, heart, liver, and muscle increases with age. An increase in solubility may prolong uptake, delay equilibration of the tissue partial pressure of anesthetic, and prolong the time of induction. Lerman and others found that the rate of increase in tissue anesthetic partial pressure, and, therefore alveolar anesthetic partial pressure, is approximately 30% more rapid in newborns than in adults.

Minimal alveolar concentration (MAC) is an estimate of anesthetic requirement. In the original study, Gregory and others (1969) reported that infants in the first 6 months of life had the highest MAC. In a later study, newborns were noted to require approximately 25% less halothane at MAC compared with infants who are between 1 and 6 months of age ( Lerman et al., 1983 ) (see Chapter 6 , Pharmacology of Pediatric Anesthesia).


Several studies have shown an increased sensitivity to and more prolonged effects of barbiturates and morphine in the neonate and young infant ( Kupferberg and Way, 1963 ; Way et al., 1965 ). These features have been attributed in part to the immaturity of the blood-brain barrier, allowing faster and greater penetration and therefore higher concentration of these drugs in the brain.

In 1981, Robinson and Gregory reported that, following a 10-mL/kg bolus of lactated Ringer's solution, 30 to 50 mcg/kg of fentanyl was a safe anesthetic for premature infants undergoing ligation of a PDA. Several years later, evidence was presented that infants who received fentanyl in combination with d-tubocurarine and nitrous oxide in oxygen had an improved perioperative course ( Anand et al., 1987 ).

Plasma levels of fentanyl are lower in infants versus children versus adults (newborns were not studied) after similar intravenous doses ( Singleton et al., 1987 ). Gauntlett and others (1988) noted in newborns that clearance of fentanyl increased during the first few weeks of life. Elimination half-life and volume of distribution did not change. In a study of newborns administered continuous fentanyl infusions, Saarenmaa and others (2000) noted that plasma clearance correlated with maturity (gestational age), whereas Santeiro and others (1997) noted a correlation of clearance with postnatal age.Koehntop and others (1986) have shown a highly variable disposition and elimination of fentanyl in neonates. In addition, infants with increased intra-abdominal pressure (omphalocele, gastroschisis, septic ileus) appeared to have a further increase in the elimination half-life compared with infants undergoing repair of a PDA or myelomeningocele. Davis and others (1989) noted that the clearance of alfentanil in newborn premature infants was markedly reduced compared with older children ( Fig. 16-3 ).


FIGURE 16-3  Age-related changes in alfentanil pharmacokinetics for premature infants, children, and adults.  (From Davis CM, Brando M: Pediatric pharmacology. In Greely W, volume editor: Atlas of anesthesiology, vol. 7. Philadelphia, 1999, Churchill Livingstone.)




Koren and others (1985) have shown that the elimination half-life for morphine (13.9 hours) in human neonates is prolonged compared with that in older children and adults (2 hours). They also showed reduced clearance and higher serum concentration in neonates compared with those seen in older children after morphine infusion. Because of the large variability in clearance among neonates of different ages, the dose of opioids needs to be carefully titrated for each patient and each clinical setting.

Animal studies have shown a decreased ED50 for thiopental in the early weeks of life. Also, arousal in newborn rats occurred at lower brain levels of thiopental than in adult rats ( Mirkin, 1975 ). Although this may suggest that lower doses of thiopental are needed in young neonates, studies by Jonmarker and others (1987) suggest the contrary. Similarly, ketamine requirements are greater (milligrams per kilogram of body weight) in infants than in older children ( Lockhart and Nelson, 1974 ). Ketamine has been shown to produce apnea in infants with increased intracranial pressure ( Lockhart and Jenkins, 1972 ). Ketamine produces hypertension and tachycardia, which some anesthesiologist have taken advantage of in caring for infants and children with congenital heart disease, cardiovascular instability, or both.


Developmental pharmacologic changes influence the requirements for muscle relaxants in infants and older children. Synaptic transmission is slow at birth, the rate at which acetylcholine is released during repetitive stimulation is limited, and neuromuscular reserve is reduced ( Fig. 16-4 ). In addition, the reported sensitivity of infants to the effects of neuromuscular blocking agents has differed depending on whether drug administration was indexed to body weight or to body surface area. Because most neuromuscular blocking agents are distributed in the extracellular space and the extracellular space is related to the body surface area, dosage requirements for neuromuscular blocking agents frequently correlate with surface area rather than with body weight.


FIGURE 16-4  Tracings of the frequency sweep electromyogram (FS-EMG).  (From Crumrine RS, Yodlowski EH: Assessment of neuromuscular function in infants. Anestesiology 54:29-32, 1981.)




Fisher and others (1982) studied the infant's sensitivity to nondepolarizing muscle relaxants using the pharmacodynamic and pharmacokinetic properties of d-tubocurarine. These investigators determined the steady-state plasma concentration associated with 50% neuromuscular blockade (CPss50) and noted that infants had a lower CPss50 than older children. Because the volume of distribution of d-tubocurarine in infants is significantly larger than that in older children, the dose (milligrams per kilogram of body weight) required to achieve the same degree of neuromuscular blockade appeared the same for infants and older children. Although the pharmacokinetic data reveal similar clearance values for infants and older children, the infant's larger volume of distribution and consequently longer elimination half-life suggest that infants need less frequent and smaller supplemental doses for continued neuromuscular relaxation. Although these data are specific for d-tubocurarine, the general principles can be extrapolated to other hydrophilic compounds that are primarily distributed to the “central compartment” (i.e., small volume of distribution).

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Copyright © 2005 Mosby, An Imprint of Elsevier



To devise a rational plan for administering fluid to the newborn during surgery requires the anesthesiologist to consider the same four components that are always relevant when analyzing what intravenous fluids are required: (1) estimating deficit, (2) calculating maintenance, (3) replacing ongoing losses, and (4) considering special losses/deficits/needs.

During the preoperative assessment, deficits should be recognized, and by the time surgery begins, dehydration or electrolyte imbalance should be reversed; that is, acidosis, low hemoglobin, poor urine output, poor perfusion, or other cardiovascular instability will have been treated appropriately. In some cases, acidosis and cardiorespiratory instability are the indications for surgery (e.g., necrotizing enterocolitis [NEC]), so that at some point, proceeding with the surgery even with continuing acidosis or instability is the logical decision.

Neonates undergoing elective surgery can be fed until 4 hours before anesthesia and then given clear fluids until 2 hours before surgery. Formula is in the same category as solid food. Breast milk has been considered a “solid” by some and somewhere between a clear liquid and a solid by others. Many anesthesiologists chose an NPO range based on the frequency of routine feeding. That is, an infant feeding every 2 hours only needs to be NPO for 2 hours but another who is fed every 4 hours should be NPO for 4 hours. Few would emphasize replacing this amount of fluid before surgery.

Maintenance fluids for some infants include TPN. The anesthesiologist must note the amount of glucose/kg per minute as well as the amount of sodium, calcium, and potassium currently required by the infant (see Box 16-6 ) and ensure a reliable system to continue this regimen during surgery. If the TPN must be discontinued, a system for monitoring serum glucose must be incorporated into the anesthetic plan.

Third-space deficits should be replaced with infusions of an iso-osmotic solution, such as normal saline, lactated Ringer's, or Plasma-Lyte solution. That is, to avoid hyperglycemia, neither TPN nor any solution containing dextrose should be used to replace the ongoing fluid losses during surgery.

The point at which colloid should replace crystalloid varies with the patient, the surgical procedure, the anesthesiologist, and the surgeon. Most would infuse packed red blood cells after 10% to 20% of blood volume loss (10% to 20% of 100 mL/kg) or when hematocrit is less than 30% to 35% in a stable newborn. In the setting of continued instability, ongoing blood loss, and/or cyanotic heart disease, most would start blood replacement earlier. Other colloid (fresh frozen plasma, albumin, platelets) should be considered when laboratory or clinical evidence indicates that such therapy is required.

Defining what is “stable/normal” for each infant is essential before surgery. The anesthesiologist must know what the trends have been in blood pressure, heart rate, urine output, electrolytes, and ventilatory support and what interventions have been required to achieve stability. What is “stable/normal” may vary from patient to patient and from one point in time to another.


Most newborns do not receive premedication before surgery. Some anesthesiologists might elect to premedicate certain infants—those with increased morbidity associated with transient bradycardia (e.g., cyanotic heart disease) or infants with marked airway secretions—with intravenous atropine (10 to 30 mcg/kg). The vagolytic effect of atropine has been reported to counteract the bradycardia and hypotensive effects of potent inhalation agents ( Friesen and Lichtor, 1982 ). However, a relative overdose of inhaled agent is the most likely cause of bradycardia and hypotension during halothane anesthesia, and eliminating halothane, not delivering atropine, is the appropriate response. Careful titration of inhalational agents and relying on narcotic-based anesthesia, especially in the infant who will be mechanically ventilated postoperatively, have made this indication for atropine less relevant. The antisialagogue action of atropine also may be advantageous if copious secretions are noticed, because secretions can obstruct small endotracheal tubes and airways.

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Copyright © 2005 Mosby, An Imprint of Elsevier


Safe and effective intraoperative management of the newborn depends on understanding basic principles of physiology and pharmacology, as well as understanding technical aspects of monitoring and the anesthesia equipment.


As already described, the newborn infant loses thermal protection after birth so that measures must be taken to protect against heat loss during surgery:



Transport the baby in a heated “isolette.”



Warm the operating room to greater than 27°C (80°F).



Use a warming mattress (water temperature of 40°C).



Heat and humidify gases to 36°C (at the trachea).



Use a radiant heat warmer with a servocontrol mechanism.



Wrap noninvolved areas with plastic.



Warm intravenous fluids and blood.



Warm scrubbing and irrigation solutions.


Attention must be paid to fine, seemingly insignificant details in the care of a sick neonate because the margin of safety is narrow. Although advanced electronic monitoring has contributed significantly to the safety of these babies, the anesthesiologist's clinical skills, judgment, and evaluation remain indispensable.

General Observation

Color (cyanosis, pallor), chest mobility (bilateral expansion, respiratory pattern, chest compliance), and palpation (warmth, pulses, peripheral perfusion) are often difficult to assess because of the patient's position and draping on the operating room bed. The use of specific monitors depends on the planned surgical intervention and the underlying disease state.

Circulatory Monitoring

A precordial stethoscope is a simple and effective means to assess the quality of heart sounds, rate, and rhythm. A change in the intensity of heart sounds indicates a decrease in blood pressure and possibly cardiac output. Depending on the surgical procedure and the airway management (mask versus LMA versus endotracheal tube), an esophageal stethoscope is an alternative monitor for noninvasive beat-to-beat cardiovascular monitoring. Although the sensitivity of the “stethoscope” has been discussed ( Hubmayr, 2004 ), the simplicity and accuracy of the precordial and esophageal device to monitor heart tones and breath sounds during surgery involving pediatric patients cannot be denied.

The primary role for continuous electrocardiography during anesthesia for the newborn is to detect arrhythmias, especially in the setting of electrolyte disturbance or as evidence of adverse effects of various drugs. Simple monitoring of heart rate is available via the pulse oximeter, now a routine monitor for all patients in the operating room.

In most cases, the blood pressure can be accurately monitored with an automated device based on oscillometry (e.g., Dinamap) or ultrasonic flow (e.g., Arteriosonde) if the appropriate-sized cuff is available. Cuff inflation of the automatic devices should cycle no more frequently than every 3 to 4 minutes to avoid ischemia to the arm ( Waugh and Johnson, 1984 ). Systolic blood pressure measurements correlate with the circulating blood volume and therefore are essential to monitor and guide fluid and blood replacement. Another alternative system is a Doppler ultrasonic transducer, which has a characteristic sound that decreases in intensity with a decrease in blood pressure.

An indwelling arterial cannula allows frequent blood sampling for cardiopulmonary and biochemical evaluation. A 22- or 24-gauge cannula can be inserted percutaneously or by cutdown into a variety of sites including the radial, dorsalis pedis, or posterior tibial artery. The adequacy of circulation to the hand should be assessed before the insertion of the catheter by applying a modified Allen's test (Brodsky, 1975 ). Rarely, the axillary artery is cannulated. In general, the umbilical artery can be cannulated in the first 4 to 7 days of life, but this is generally avoided after the first 2 days of life because of the risks of infection and vascular emboli. The umbilical catheter tip must be above the bifurcation of the aorta and below the level of the renal arteries. The placement of the catheter must be confirmed by a radiograph demonstrating the catheter tip to be between L4 and L5.

The risk for retinopathy of prematurity necessitates meticulous monitoring of oxygen saturation in the neonate, especially the VLBW infant. Most neonatologists would recommend adjusting the inspired oxygen to maintain oxygen saturation between 90% and 95%, depending on the underlying medical status, gestational age, hemoglobin, and postnatal age (i.e., quantity of HgF). Of importance, if blood is shunting right-to-left through a PDA, the oxygen saturation measured in the lower extremities or umbilical artery (postductal site) does not reflect the oxygen saturation in the retinal vessels (preductal site). To enable simultaneous monitoring of both preductal and postductal oxygen saturation, two pulse oximeters are placed, one on the right hand (preductal) and one on a lower extremity (postductal). During right-to-left shunting through the PDA, the preductal oxygen saturation is higher than the postductal value, and the difference depends on the amount of shunting. If blood is shunting right-to-left only via the foramen ovale or other intracardiac sites (e.g., ventriculoseptal defect), the preductal and postductal oxygen saturation are equal (see Chapters 2 , 3 , and 19 , Respiratory Physiology in Infants and Children, Cardiovascular Physiology in Infants and Children, and Anesthesia for General Abdominal, Thoracic, Urologic, and Bariatric Surgery).

An arterial cannula must be connected to a pressure transducer and slowly and continuously infused with a small volume of dilute heparin solution (0.1 to 1 U/mL) at the rate of 0.5 to 1 mL/hr. In the ELBW infant, the flush volume should be measured and included in calculating the total daily fluid intake. In addition, extreme caution is critical while flushing an arterial cannula because retrograde embolization into the cerebral circulation is possible in the small infant, especially with a patent foramen ovale or ductus arteriosus.

A central venous catheter may be indicated to administer blood, fluid, TPN, and medications and to monitor central venous pressure (CVP). Using the Seldinger technique, a catheter can be inserted percutaneously into the subclavian, internal jugular, external jugular, or femoral vein. An indwelling umbilical vein catheter is not recommended because of its association with portal vein thrombosis. All central venous catheters are associated with significant morbidity including thrombosis, emboli, and infection. Central venous catheters in the LBW infant have additional risks, from malpositioning and from the disruption of venous flow (ratio of the size of vessel to the size of the catheter is low).

Ventilatory Monitoring

The combination of immature and fragile central nervous and cardiorespiratory systems coupled with unstable chest wall mechanics and variable responses to anesthetic agents frequently leads to mechanical ventilatory support both during and after surgery for the newborn. For each patient and for each procedure, the anesthesiologist must evaluate the needs and the requirements for mechanical ventilation. For some infants, the ventilatory status might be so precarious that using the ventilator from the neonatal intensive care unit intraoperatively might offer additional options for responding to intraoperative events affecting ventilatory status. Of note, if an infant is requiring a specific mode of ventilatory support such as high frequency or oscillation, the operating room strategy should be coordinated with the critical care team.

Manual ventilation has been proposed as a technique to allow the anesthesiologist to continuously sense changes in compliance of the chest and airways. However, Spears and others (1991) noted that manual ventilation can be extremely unreliable in sensing airway compliance changes. In addition to monitoring heart sounds, the precordial or esophageal stethoscope is a simple system to monitor ventilation and quality of breath sounds. Peak airway and end-expiratory pressure should also be measured. End-tidal carbon dioxide (mass spectrometers or infrared analyzers) devices are now the “standard of care” to continuously monitor the adequacy of respiratory exchange. These devices provide a breath-to-breath level of carbon dioxide tension, and the waveform of this measurement can provide information about rebreathing, ventilator disconnection, suspected air embolism, and hypermetabolic states (see Chapter 9 , Anesthesia Equipment and Monitoring).

The pulse oximeter provides a precise, continuous readout of the hemoglobin oxygen saturation. During the first 1 to 2 weeks of life and without transfusion of autologous blood, the oxygen dissociation curve of HgF is shifted to the left of the adult curve so that hemoglobin saturation of 95% to 97% corresponds to Pao2of 52 to 77 mm Hg, assuming a P50 of 19. The hemoglobin saturation should be correlated with an arterial Po2 measurement to ensure valid interpretation of oxygen saturation data in the operating room (see Chapter 2 , Respiratory Physiology in Infants and Children).

Monitoring of the Neuromuscular Junction

Neuromuscular blockade can be monitored with a battery-operated nerve stimulator. The simple twitch and train-of-four are elicited by stimulating the ulnar nerve at the wrist or the posterior tibial nerve at the ankle. The neonate's neuromuscular response to nerve stimulation allows the anesthesiologist to titrate further doses of a muscle relaxant and avoid excessive neuromuscular blockade. However, neuromuscular monitoring is technically challenging for VLBW infants because of the small size of their muscles. Accurate data from the transcutaneous devices are often impossible to obtain. Inserting needles into a tiny infant's extremity should be justified because such trauma may cause bleeding or infection. Furthermore, even with needles in place, obtaining a reliable response using the standard battery-operated devices is unpredictable. Of significance, most of these infants require mechanical ventilation postoperatively, so that documenting full recovery to neuromuscular blockade is often unnecessary immediately after surgery.

Monitoring Urine Output

Devices that collect urine during surgery (specifically, Foley catheters or modifications) are helpful because, in the absence of glycosuria, urine output is a good indicator of hydration, circulating volume, and renal function. The desirable range of urine output in the neonate under anesthesia is 0.5 to 2.0 mL/kg per hr. Note that for a 1-kg infant, 0.5 to 2 mL of urine per hour is difficult to reliably collect in the setting of surgical drapes, lack of direct access to the patient, and easy kinking of drainage tubing secondary to pressure and positioning. Thus, in actual practice, accurately assessing urine output is difficult.


The techniques for induction of anesthesia in the newborn vary with the infant's size, gestational age, medical status, surgical lesion, and the skill and experience of the anesthesiologist. For example, neonates with a full stomach should have tracheal intubation either “awake” or via a rapid sequence technique. Awake intubation has been associated with significant morbidity, including increased intracranial pressure, bradycardia, desaturation, breath holding ( Raju et al., 1980 ; Hinkle, 1983 ; Marshall et al., 1984 ), apnea, and mechanical trauma to the airway. The use of an oxyscope (see Fig. 9-18), a laryngoscope designed to administer oxygen during laryngoscopy, can help to prevent hypoxemia during awake intubation ( Hinkle, 1983 ). Titrating tiny intravenous doses of fentanyl (0.1 to 0.2 mcg/kg) or morphine sulfate (0.02 to 0.03 mg/kg) may diminish the trauma of awake intubation.

A rapid sequence induction in the premature infant is challenging. First, the small size of the face/mandible/upper airway and easily compressible trachea predispose to mechanical upper airway obstruction. Second, the inspired concentration of oxygen cannot be increased to 1.0 without introducing a risk for retinopathy of prematurity. This risk is constantly being weighed against the risk of hypoxemia. Even a short period of apnea can result in immediate oxygen desaturation. Of note, the “rapid sequence” technique is particularly risky in neonates with abdominal distention (i.e., low FRC) because any period of apnea promptly induces hypoxemia and positive pressure ventilation with a mask may be ineffective and may induce regurgitation. That is, abdominal distention may displace the diaphragm cephalad, decreasing lung volume (FRC) and compliance. This combination of factors prevents effective manual ventilation of the lungs via a mask and, at the same time, dilates the stomach (further compressing the diaphragm and lungs) and increases the risk for regurgitation, creating a cycle of events that can be disastrous as the anesthesiologist attempts to intubate the trachea.

Neonates with a high risk for a difficult visualization of the airway (micrognathia, macroglossia, protruding maxilla, cleft palate, or cysts obstructing the airway) must not be paralyzed until the ability to ventilate the infant's lungs with a mask is ensured. In such infants, an initial attempt at direct laryngoscopy with minimal sedation and the infant breathing spontaneously should be made before anesthetic agents or muscle relaxants are administered. In infants in whom direct laryngoscopy does not allow the larynx to be visualized, other techniques, such as bronchoscopy, must be considered (see Chapter 9 , Anesthesia Equipment and Monitoring).

Direct laryngoscopy and endotracheal intubation of the neonate's trachea require head and neck positioning different from that recommended for the adult. The prominent occiput of the newborn results in an “automatic sniffing position” without the additional support of towels or blankets under the head/neck. The larynx of the newborn is one or two vertebral bodies cephalad to that of the adult, so that extension of the neck may impede visualizing the vocal cords. Gentle pressure (with the pinky finger, for example) can assist in moving the larynx into view during direct laryngoscopy. The Miller-0 straight laryngoscope blade is probably the most commonly recommended device for visualizing the airway of a tiny neonate (preterm or of low birth weight), and the Miller-1 is used in the full-term neonate. The Wis-Hipple 1.5 blade may be preferred in infants greater than 4 kg. Uncuffed 3.0- or 3.5-mm (inner diameter [ID]) Magill disposable endotracheal tubes with a Murphy eye are commonly the appropriate size to intubate the trachea in neonates. A 2.5-mm (ID) tube is usually used in infants less than 1200 g. To ensure that the endotracheal tube is not too large, inspired gas should leak around the endotracheal tube while delivering a manual positive breath (20 to 25 cm H2O pressure). A tightly fitting tube can damage the subglottic mucosa, causing edema and postoperative stridor or possibly subglottic stenosis. The low perfusion pressure of the newborn may contribute to the higher risk for development of subglottic pressure necrosis in response to an endotracheal tube “pressing” on the tracheal mucosa in the infant.

Ensuring that the endotracheal tube is at the appropriate depth in the trachea of the LBW infant also requires attention. The distance from the vocal cords to the carina in the term infant is about 4 cm. One algorithm recommends that the 1-, 2-, 3-, and 4-kg infant should have an endotracheal tube taped with the 7-, 8-, 9-, and 10-cm mark, respectively, at the alveolar ridge. In VLBW infants, a chest radiograph may be needed to confirm the position of the endotracheal tube at the midtracheal level (see Chapters 8 and 9 , Preoperative Preparation, and Anesthesia Equipment and Monitoring).


Several anesthetic delivery systems are safe and readily available for the care of neonates during surgery. Disposable, humidified pediatric circle systems have low compliance and thereby eliminate the problems previously described with the older, nondisposable, highly compliant circuits. Lightweight plastic valves have replaced the metal structures and eliminated the high resistance and “stickiness” associated with the older anesthesia machines. Because neonates are mechanically ventilated during surgery, the work of breathing associated with spontaneous ventilation is eliminated. The valveless, humidified, lightweight Mapleson D or E (Jackson Rees) systems are modifications of the Ayre T-piece or the Bain circuit ( Bain and Spoerel, 1973 ).

All anesthetic delivery systems should incorporate a mechanism to heat and humidify the inspired gas mixture. The heating system must be regulated by a thermistor at the endotracheal tube connection to avoid hyperthermia and airway burns. The gas temperature at the monitoring site at the endotracheal tube must range from 36° to 37°C ( Bain and Spoerel, 1973 ). Warm gases minimize damage to the tracheal mucosal cells associated with cold, dry gases. Heated inspired gases also decrease heat loss from the respiratory system. Alternatively, heat and moisture exchangers, known also as artificial noses, can be placed at the endotracheal tube connection to provide partial humidification and warming of the inspired gases. However, these artificial noses may be less efficient than devices incorporated in the anesthetic circuit.

During neonatal anesthesia, the anesthesia machine must be equipped to deliver air when nitrous oxide is contraindicated. In addition, the anesthesia machine should have a mechanism to prevent the delivery of hypoxic gas mixtures and a monitor to measure inspired oxygen concentrations.


Calculating fluid requirements for newborns is an inexact science. Historically, caloric expenditure at rest has been the basis for calculating “maintenance” fluid requirements ( Shires et al., 1961 ; Winters, 1973 ; Furman, 1987 ). Fluid requirements are based on the metabolic rate expressed in terms of caloric requirements ( Holliday and Segar, 1957 ); that is, the energy requirements of a neonate are usually estimated to be 100 kcal/kg per 24 hours and 100 mL of fluid are consumed for every 100 calories metabolized per day. However, in some cases, during the first 2 to 3 days of life, the fluid requirements are considerably less. First, approximately 30 mL/kg of fluid is mobilized from the lungs into the extracellular fluid space. Second, urine output is often low in the first 24 hours after birth (see Chapter 4 , Regulation of Body Fluids and Electrolytes in Infants and Children). On the other hand, these factors are countered by increased insensible loss through the highly permeable skin of the VLBW infant. The estimate for “maintenance” fluid in the newborn cannot be viewed as a simple calculation. Great variability among individual neonates related to gestational age, ambient temperature, exposure to radiant warmth, humidity, sepsis, physical activity, feeding pattern, disease, physiologic immaturity, and positive-pressure ventilation can dramatically alter fluid requirements.

These data for metabolic rate (100 kcal/kg per day and 100 mL/kg per day) are valid for infants weighing less than 10 kg. The metabolic rate decreases gradually with age such that an average adult consumes about 35 cal/kg per day. The important extension of the interaction of metabolic rate with fluid requirements gradually evolved to our current practice of estimating “maintenance” fluid as 4 mL/kg per hr for the first 10 kg, 2 mL/kg per hr for the next 10 kg, and 1 mL/kg for each kg over 20.

Maintenance electrolyte requirements are based on data from studies of basal metabolic rates. The requirements for sodium and potassium (chloride salts) have been reported to range between 2.5 to 3.0 mmol/100 kcal per 24 hr ( Winters, 1973 ). Since chloride is included with both sodium and potassium, neonates may have an “extra” load of chloride. In addition, the tubular immaturity of the newborn allows renal loss of bicarbonate, exacerbating the metabolic acidosis associated with hyperchloremia. In some clinical settings, the hyperchloremia and associated metabolic acidosis are treated by infusing sodium acetate instead of sodium chloride.

Intraoperative fluid therapy has the same four components described for any clinical setting where intravenous treatment is considered: (1) maintenance fluid, (2) replacement of fluid deficit, (3) replacement of third-space loss, and (4) replacement of other losses.

Maintenance Fluids

Normal fluid losses consist primarily of insensible water loss from the respiratory system and evaporation from the skin. The average fluid loss from both lungs and skin can vary from 45 to 70 mL/100 cal. Changes in the respiratory rate and duration of crying can increase this value significantly ( Zweymuller and Preining, 1970 ). Insensible water loss may be increased during phototherapy or when a radiant heater is used ( Wu and Hodgman, 1974 ). Premature infants, especially those weighing less than 1500 g, have insensible water loss ( Fanaroff et al., 1972 ) that can be as much as 3 times the loss in full-term infants secondary to a highly permeable epidermis and reduced subcutaneous fat. On the other hand, the mobilizing of fluid from the lungs over the first day of life decreases free water requirements over the first 24 hours of life.

Urinary losses are variable in the newborn but generally range between 45 to 65 mL/100 cal, depending on the solute load and fluid intake, as well as renal and cardiovascular function. Fecal loss of water and water expended for growth contributes a very small percentage (5 to 10 mL/100 kcal) to the total daily fluid loss. In summary, the variability for maintenance fluid over the first few days of life is enormous, but a total fluid loss of 95 to 145 mL/100 cal is a reasonable estimate.

Fluid Deficits

Fluid deficits are caused primarily by preoperative fasting or excessive gastrointestinal losses without parenteral replacement. Infants receiving adequate preoperative maintenance (and who have no additional fluid requirements) have no deficit. The volume of deficit is calculated by multiplying the hourly maintenance requirement by the number of hours since the last fluid intake. One algorithm recommends that intraoperative replacement of the fluid deficit be delivered over a period of 3 hours: 50% of the deficit volume is given in the first hour, 25% in the second hour, and 25% in the third hour (Furman et al., 1975 ). In some clinical settings (e.g., central nervous system injury), none or a fraction of the deficit is replaced. Deficit replacement may be carried into the postoperative period and is added to the regular hourly maintenance fluid.

Third-Space Fluid Loss

Surgical trauma can result in translocation of extracellular fluid from the intravascular space into the interstitial space ( Shires et al., 1961 ) producing edema in the bowel wall and mesentery during intra-abdominal surgery (or pathology) or in the subcutaneous tissues and muscle following administration of large amounts of intravenous fluid. The magnitude of third-space loss depends on the site and extent of the surgical manipulation, is increased by inflammatory processes such as peritonitis, and occurs mostly during the first few hours of surgery. Guidelines for replacement of third-space losses include the following:



During peripheral or superficial surgery: 1 to 3 mL/kg per hr



During abdominal, chest, or hip surgery: 3 to 4 mL/kg per hr



During extensive intra-abdominal surgery: 6 to 10 mL/kg per hr (or more)

Third-space loss must be replaced with an isotonic or iso-osmotic solution such as normal saline solution, lactated Ringer's solution, or other balanced salt solution such as Plasma-Lyte without dextrose. Neonates with severe peritonitis or a congenital lesion such as gastroschisis may need 25 to 100 mL/kg per hr for replacement of third-space losses. The state of hydration and degree of third-space loss should be reassessed continually by observing the status of fontanels, dryness of mucosa, and periorbital edema, as well as hemodynamic stability, CVP, and urine output.

Other Fluid Losses

Other fluid losses include those from suction or removal of gastric, intestinal, or pancreatic fluids, drainage of an ileostomy, diarrhea, or excessive sweat losses. In these cases, the electrolyte content of the fluid losses should be measured to determine replacement fluids.

Monitoring of Intraoperative Fluid Therapy

Although clinically assessing the volume status of the newborn during surgery is critical, supplemental data are often essential. Although neonates have limited renal concentrating and diluting capacities, they can excrete “concentrated” urine when dehydrated or dilute urine when overhydrated. Thus, in addition to measuring the total volume of urine (∼0.5 to 2 mL/kg per hr is normal), urine osmolality and specific gravity add reliable data to assess the state of hydration and the needs for solute therapy. Urine osmolality in the neonate varies from 50 to 800 mOsm/L, with an average of 270 mOsm/L. Osmolality should be maintained between 200 to 400 mOsm/L, and specific gravity between 1.006 to 1.012.

Serum osmolality is also a useful monitor of electrolyte and fluid therapy. Increased osmolality reflects either reduced intake of water or increased intake of solute, chiefly sodium. A decrease in serum osmolality suggests an infusion of water in excess of sodium or insufficient delivery of, or excess loss of, sodium. Normal serum osmolality in the neonate ranges between 270 and 280 mOsm/kg ( Rowe et al., 1974 ). Hyperosmolar states are particularly dangerous to the neonate because of the high risk for cerebral hemorrhage, kidney damage, or both. Hyperosmolarity can occur with rapid infusion of large quantities of sodium bicarbonate, tris(hydroxymethyl)aminomethane, hypertonic glucose, or hypertonic saline solution. Serum electrolytes must be measured concurrently with serum osmolality to guide electrolyte replacement.

Standard hemodynamic intraoperative monitoring contributes to assessing the adequacy of fluid therapy. Hypotension, diminished heart sounds, or tachycardia suggests compromised circulation and possibly inadequate fluid administration. If invasive monitors (i.e., indwelling arterial catheter or a CVP catheter) have been inserted, careful observation of their traces, in addition to the specific numerical readout, can provide valuable information about intravascular volume status. For example, if a patient is euvolemic, the arterial pressure tracing has a dicrotic notch in the middle third of the downstroke. If a patient is hypovolemic, the area under the arterial pressure curve decreases (i.e., waveform is narrow) and the dicrotic notch changes position. Similarly, when properly placed in the superior vena cava, the CVP catheter provides valuable data about volume status by monitoring right ventricular filling pressure, which is useful in guiding crystalloid and colloid infusions. Large variation in the CVP trace during positive pressure ventilation is common with hypovolemia. The balloon-tipped, flow-directed (Swan-Ganz) catheter, although not often used in the neonate, measures pulmonary arterial and left atrial pressures, which are reliable guides to adjusting fluid and pharmacologic therapy in critically ill infants.

Blood Replacement

Similar to older infants and children, the decision to deliver blood during surgery depends on the underlying and current cardiorespiratory status, ongoing blood loss, anticipated further blood loss, and baseline hemoglobin. In general, the hematocrit of a critically ill newborn undergoing surgery should be maintained at greater than 40% by delivering packed RBCs. Transfusion of other components of blood—platelets, fibrinogen, fresh frozen plasma'should be guided by a combination of laboratory studies and the clinical status.

Copyright © 2008 Elsevier Inc. All rights reserved. -

Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier



Abdominal wall defects are rare, with an incidence of 0.3 to 2:10,000 births ( Baird and MacDonald, 1981 ). Omphaloceles are more common (1:5000 to 1:7000). The diagnosis of an abdominal wall defect may first be suspected if the maternal serum α-fetoprotein is elevated. This laboratory value prompts an evaluation that includes a fetal ultrasound, which often confirms the presence of a lesion. With the frequency of fetal ultrasonography, an in utero definition of the anatomic defect can be made in about 95% of cases. The in utero diagnosis allows planned delivery at a medical center with resources for high-risk obstetric, surgical/anesthetic, and neonatal care.

Although omphalocele and gastroschisis appear to be similar on gross physical appearance, these lesions are distinct from each other. An omphalocele is a central defect of the umbilical ring, and the abdominal contents are within a sac, unless the sac ruptures in utero ( Fig. 16-5 ). The umbilical cord is inserted into the sac, which is peritoneal membrane internally and amniotic membrane externally. The lesion has a fascial defect greater than 4 cm (<4 cm is often considered an umbilical hernia) and often as large as 10 to 12 cm. The sac often contains the stomach, loops of small and large intestine, and, in about 30% to 50%, the liver. A gastroschisis is an abdominal wall defect usually to the right of the umbilical cord ( Fig. 16-6 ). This lesion is usually 2 to 5 cm in diameter and, in most cases, with only small and large bowel present. In rare cases, the liver may exit through the abdominal wall defect. The bowel is exposed to the intrauterine environment with no sac, so that the loops are matted, thickened, and often covered with an inflammatory coating or peel. Whether this exudative peel is secondary to a specific inflammatory pathway or just an effect of amniotic fluid is unclear. The umbilical cord is normal and separate from the defect. Cryptorchidism occurs with gastroschisis when the testes exit with the bowel through the abdominal wall ( Weber et al., 2002 ).


FIGURE 16-5  Newborn with large omphalocele, sac intact. Umbilical cord is seen emerging from mass. The major problem will be replacing the viscera in the small abdominal cavity.




FIGURE 16-6  Gastroschisis, sometimes called ruptured omphalocele, but umbilical cord is intact. Heat loss, rapid dehydration, and infection are added to problems of omphalocele.




Although experimental models have been described ( Correia-Pinto et al., 2001 ), the embryologic etiology of these lesions is not completely understood. Omphalocele has been described as a failure of the cephalic, lateral, and caudal folds to fuse (closure of the exocelomic space) and abnormal fusion and differentiation of myotomes to form abdominal wall musculature (7 to 12 weeks of gestation); the abdominal cavity is primarily underdeveloped. During weeks 7 to 12 of development, the midgut elongates and herniates into the umbilical cord. By week 12, the abdominal cavity is large enough for the developing gut to exit the cord and reenter the abdomen. Some believe that the simple failure of this return to the abdomen is a developmental arrest that results in an omphalocele and a small abdominal cavity. The abdominal cavity is small only because the gut remains in the umbilical sac.

Gastroschisis is considered to be an earlier embryologic event, resulting from an abnormality of the right omphalomesenteric artery or right umbilical vein development that results in ischemia to the right paraumbilical area. Abdominal wall defects have been ascribed to an abnormal relationship between cell proliferation and planned cell death (apoptosis) at the critical embryonic folding period. Inadequate mesoderm development may contribute to dysplastic abdominal wall growth. This underdeveloped site is commonly just to the right of the umbilicus and, with increased pressure of the growing intra-abdominal organs, ruptures. Similar defects in other areas may produce other lesions, such as exstrophy of the bladder.

Gastroschisis is usually an isolated lesion. The association of in utero exposure to acetaminophen, aspirin, and pseudoephedrine and the increased incidence of gastroschisis have been described ( Werler et al., 2002 ; Baerg et al., 2003 ). In the case of either an omphalocele or gastroschisis, rotation of the gut is incomplete in utero. This results in various “malrotation” phenotypes. Intestinal atresias are common, especially in patients with gastroschisis.

Although neither gastroschisis nor omphaloceles are considered to be “familial,” reports raise the possibility of familial occurrence ( Yang et al., 1992 ; Torfs et al., 1994 ), and 50% to 75% of infants with an omphalocele have other anomalies and 20% to 30% have chromosomal abnormalities ( Robinson and Abuhamad, 2000 ; Weber et al., 2002 ). For example, Beckwith-Wiedemann, Reiger, and prune belly syndromes are associated with omphaloceles, as are trisomy 13, 15, 18, and 21. If the omphalocele contains only bowel and if oligo- or polyhydramnios is present, the likelihood of an associated chromosomal abnormality increases. Syndromes of midline defects often include an omphalocele. One syndrome, pentalogy of Cantrell, includes an omphalocele, diaphragmatic hernia, sternal abnormalities, an ectopic and anomalous heart, and gene abnormalities at Xq25 to q26.1. Another syndrome involving the lower abdomen includes omphalocele, bladder or cloacal exstrophy, imperforate anus, colonic atresia, sacrovertebral anomalies, and meningomyelocele. No environmental or teratogenic associations have been proposed as etiologic causes.

Preoperative Management

The preoperative management of abdominal wall defects is concerned primarily with fluid resuscitation, minimizing heat loss, treating sepsis, and avoiding direct trauma to the herniated organs. Normothermia should be maintained or achieved by preventing heat loss from the exposed viscera. A bowel bag may be used for this purpose ( Towne et al., 1980 ). Decompression of the stomach with an orogastric or nasogastric tube is important to prevent regurgitation, aspiration pneumonia, and further bowel distention. Broad-spectrum antibiotics are started, and intravenous fluid therapy, 2 to 4 times “maintenance,” is infused to ensure adequate hydration and to compensate for a combination of peritonitis, edema, ischemia, protein loss, and significant third-space loss. Without such vigorous fluid resuscitation, hypovolemic shock, hemoconcentration, and metabolic acidosis may develop. A balanced salt solution (lactated Ringer's solution or 5% albumin) is used, and urine output is monitored. A urine output of 1 to 2 mL/kg per hr indicates adequate hydration. Because of the large fluid requirements, acid-base status and electrolyte levels should be monitored carefully by serial arterial or venous blood gas measurements. If severe metabolic acidosis develops despite fluid delivery, sodium bicarbonate, colloids, ventilatory support, and vasopressors may be administered in order to maintain the pH greater than 7.20.

Intraoperative Management

Surgical management is aimed at repairing the abdominal wall defect and reducing the protruded viscera. If primary closure is not possible, a staged repair is planned, including the use of the silo chimney or Silastic silo prosthesis ( Schuster, 1967 ). The “silo” consists of a Silastic or Teflon mesh that is sutured to the fascia of the defect. The synthetic material used to cover the lesion and the specific mechanism for placing the organs into the abdomen (e.g., umbilical tapes, umbilical cord clamps) vary from center to center. After the silo is in place, the extra-abdominal organs are then gradually returned to the peritoneal cavity over 3 to 10 days ( Fig. 16-7 ). Improved outcome has been claimed using the delayed repair approach after the nonoperative placement of a spring-loaded silo ( Schlatter et al., 2003). These authors state that this procedure is accomplished in the neonatal intensive care nursery or delivery room and requires “no anesthesia.” These authors claim that the time to both first and full feeds was shorter in the infants who underwent delayed closure. The prosthesis is then removed or reduced under general anesthesia, and eventually the defect is closed.


FIGURE 16-7  A silo is used to aid in the reduction of the abdominal contents when the abdominal cavity is too small. Over time the intestinal contents are gradually reduced back into the abdominal cavity.



Forcing the viscera into an underdeveloped abdominal cavity that cannot accommodate the herniated bowel and tight closure of the skin can restrict diaphragmatic excursion and possibly compress the lungs. The result is impaired ventilation and reduced return of vena caval blood. During abdominal closure, the anesthesiologist must monitor airway pressures and watch for decreased pulmonary compliance. The surgeon and the anesthesiologist should cooperate to assess the feasibility of a primary closure. Yaster and others (1988) noted that increases in intragastric pressure greater than 20 mm Hg and increases in CVP of greater than 4 mm Hg above baseline were frequently associated with reductions in venous return and cardiac index, requiring surgical decompression of the abdomen.

An arterial catheter facilitates blood sampling and continuous monitoring of blood pressure. A CVP catheter is probably more important than the arterial catheter, however, for evaluation of changes in blood volume and the degree of visceral compression during abdominal closure ( Yaster et al., 1988 ). Metabolic monitoring is also important. Serial intraoperative glucose monitoring, especially in infants with Beckwith-Wiedemann syndrome, may be indicated. Fluid therapy consists of 5% to 10% dextrose in 0.2% saline at the maintenance rates stated earlier and lactated Ringer's solution (8 to 15 mL/kg, or more, per hour) for third-space loss. A warm environment must be maintained, as well as vigilant efforts at preventing heat loss (see Chapter 5 , Thermoregulation: Physiology and Perioperative Disturbances).

After decompression of the stomach, anesthesia may be induced with inhalation or intravenous agents. Because it distends the bowel, nitrous oxide is avoided. The infant is paralyzed and ventilated with an air (or nitrogen) and oxygen mixture with low concentrations of an inhalation anesthetic. The inspired oxygen concentration must be adjusted to maintain oxygen saturation between 95% and 97% (the physiologic range of Pao2in the newborn, 50 to 70 mm Hg). Vane and others (1994) demonstrated that spinal anesthesia can be an effective anesthetic for the repair of gastroschisis in selected patients.

Postoperative Care

Postoperatively, except in infants with a small defect, mechanical ventilation should be maintained for 24 to 48 hours, or longer; thereafter, respiratory compliance usually improves dramatically (Nakayama et al., 1989, 1991 [216] [217]). Infants with a small defect sometimes can be extubated at the conclusion of surgery. All of these patients must be carefully monitored for respiratory complications in an intensive care unit. Inferior vena caval compression, evident as “blue” lower limbs, or bowel ischemia (necrotizing enterocolitis) can occur as a result of increased abdominal pressure and may require surgical treatment. These infants are also at high risk for developing sepsis in the postoperative period.

The onset of peristalsis after repair of omphalocele or gastroschisis is usually delayed, and the resulting ileus may be prolonged ( O'Neil and Grosfeld, 1974 ) so that TPN is generally required for days to weeks in the postoperative period. Anticipating this, most infants with large lesions, especially gastroschisis, should have appropriate intravenous access established in the operating room to facilitate early postoperative nutritional support, which is essential for healing and recovery.


Survival of infants born with anterior abdominal wall defects has improved dramatically secondary to prenatal diagnosis, improved surgical, anesthetic, and perioperative intensive care, and nutritional support. The advent of accurate prenatal imaging has allowed termination of a pregnancy when a fetus with multiple anomalies, chromosomal lesions, or a huge defect is identified. When the defect is isolated, 95% to 97% survival is expected. Mortality and long-term outcome are related to associated anomalies (e.g., cardiac, intestinal atresia, etc.), complications of treatment (bowel perforation, NEC, sepsis, short bowel syndrome), and the side effects of intravenous alimentation (liver failure, sepsis). Although specific data have been collected to stratify and predict outcome of patients with abdominal wall defects, the general pattern is that infants with a “simple” defect (no atresias, no extraintestinal anomalies, <5 to 6 cm) and no postoperative complications (obstruction, NEC, short gut syndrome) have a better prognosis than those with a “complex” lesion or postoperative course ( Molik et al., 2001 ).

In a follow-up study of 23 infants (>16 years old) born with gastroschisis between 1972 and 1984 and who survived longer than 1 year, Davies and Stringer (1997) reported that 22 of these 23 infants were in good health and overall growth was normal. About one third of patients with gastroschisis had undergone surgery for adhesions, bowel obstruction, or scar complications related to their defect. Of note was that in 25% to 60% ( Tunell, 1995 ; Davies and Stringer, 1997 ) of patients with anterior wall defects, the absence of an umbilicus was a distressing physical sign, especially during adolescence.

Other studies involving shorter follow-up periods have noted patients with chronic abdominal pain and gastroesophageal reflux ( Fasching et al., 1996 ). An economic analysis of care of infants with gastroschisis emphasized that the cost of care is high and that on average 47 days of hospitalization were needed in to establish full feeds ( Sydorak et al., 2002 ).


Congenital diaphragmatic hernia (CDH) is a defect in the diaphragm that develops early in gestation and is associated with extrusion of intra-abdominal organs into the thoracic cavity ( Fig. 16-8 ). The incidence of CDH ranges between 1:2500 and 1:3000 live births. The most common defect is posterolateral (Bochdalek) (90%), of which 75% are left-sided. Morgagni (anteromedial) and paraesophageal hernia and eventrations make up the remainder ( Fig. 16-9 ). The anomaly is much more than a hole in the diaphragm. CDH is associated with



Varying degrees of bilateral lung hypoplasia



Pulmonary hypertension and arteriolar reactivity



Congenital anomalies (e.g., cardiac, chromosomal anomalies)



High mortality (30% to 50%)



Significant morbidity, both short and long term


FIGURE 16-8  Diaphragmatic hernia at postmortem examination showing obliteration of left pleural cavity and severe compression of heart and right lung.  (Courtesy Dr. Arnold Colodny, Boston, MA.)



FIGURE 16-9  Diagram (from below) showing sites of congenital diaphragmatic hernia.



In addition to the marked abnormalities in both airway and vascular pulmonary development, striking dysfunction of the left ventricle has been noted. Karamanoukian and others (1995) noted that left ventricular mass and ventricular compliance may have a predictive value for outcome.

Prenatal diagnosis of CDH has increased from about 10% in 1985 to more than 50% at present. The most frequent findings include displacement of the heart and a fluid-filled stomach in the thorax. Of note, prenatal ultrasound evaluation can have a high incidence of false-negative results ( Lewis et al., 1997 ).


The diaphragm, lungs, and gastrointestinal tract develop synchronously. The lungs begin as a ventral bud of the foregut. Airway development and branching begin between the fourth and fifth weeks of gestation and progress until the terminal bronchioles are formed by the 17th week. The ventral (membranous) component of the diaphragm is formed between the third and fourth weeks of gestation. At about the eighth week of gestation, this portion envelops the esophagus, inferior vena cava, and aorta and fuses with the foregut mesentery to form the posterior and medial (membranous) portions of the diaphragm. The lateral margins of the diaphragm are derived from the muscular components of the body wall. The pleuroperitoneal canals close when all the membranous portions of the diaphragm fuse together, and by the ninth week of gestation, diaphragmatic closure is usually complete ( Wells, 1954 ). If the closure (obliteration) of the pleuroperitoneal canals is delayed beyond the 9th to 10th weeks of development or if the normal rotation and settling of the midgut occur before the 10th week or before the obliteration of the pleuroperitoneal canals, the midgut (abdominal viscera) herniates into the thoracic (pleural) cavity.

In the past, the defect has been attributed to an abnormal closure of the pleuroperitoneal canal, but investigation using the nitrofen-induced CDH model in the rat has allowed an innovative approach to reexamining the etiology of this lesion. CDH seems to be linked to a disordered formation of the pleuroperitoneal fold, a much earlier event (fourth week of gestation). The findings of an abnormal formation of the framework of mesenchyme, inhibiting muscular development of the diaphragm, has been linked to abnormalities in retinoid signaling pathway, suggesting that vitamin A may play a role in the pathophysiology of CDH ( Greer et al., 2003 ).

Stillborn babies with CDH have a 95% incidence of other anomalies. Live-born infants have a 20% incidence of associated cardiovascular defects, most commonly PDA ( Johnson et al., 1967 ). Others (Fauza and Wilson, 1994 ) have reported that hypoplastic left heart syndrome was the most frequently associated cardiac defect. Rarely, CDH is a part of a complex set of anomalies, Cantrell's pentalogy (Wesselhoeft and DeLuca, 1984 ), consisting of omphalocele, sternal cleft, ectopia cordis, and an intracardiac defect (ventricular septal defect or diverticulum of left ventricle). Although uncommon, CDH has been identified in the context of several syndromes including Fryns ( Fryns et al., 1979 ), Goldenhar ( Rollnick and Kaye, 1983 ), Brachmann-deLange ( Jelsema et al., 1993 ), and Beckwith-Weidemann ( Thornburn et al., 1970 ). From 5% to 18% of infants with CDH have associated chromosomal abnormalities ( Cunniff et al., 1990 ; Bollman et al., 1995 ).

Preoperative Assessment


In the most common presentation, the herniated abdominal viscera, which include the midgut but may also include the stomach, parts of the descending colon, the left kidney, and the left lobe of the liver, occupy the left thoracic cavity and interfere with the development of the lung. In most cases, this produces some degree of pulmonary hypoplasia, the severity of which is related to how early in fetal development the herniation and compression occurred. The herniation of abdominal contents shifts the mediastinum to the right, which can cause compression and hypoplasia of the contralateral lung.

Several structural abnormalities of the pulmonary vasculature correlate with the pathophysiology of CDH. The low number of airways, the simple arterial branching pattern, the increase in smooth muscle mass at the level of the resistance vessels, and left ventricular abnormalities add to the cardiorespiratory dysfunction ( Schwartz et al., 1994 ) produced by the hernia itself. Lung growth (alveolar) does occur postnatally, but growth at the preacinar level is limited in that the number of airway generations remains constant after mid-gestation ( Geggel and Reid, 1984 ). Vascular remodeling provides larger and less muscular arteries, so that the pathology present at birth has been documented to reverse to some degree ( Beals et al., 1992 ). The degree of pulmonary hypoplasia is predictive not only of survival but also of the development of chronic lung disease in the survivor.

Although the anatomic abnormalities of CDH are consistent with the phenomenon of persistent pulmonary hypertension, other factors are critical in determining the physiology of the pulmonary circulation of the newborn. For example, the fall in pulmonary vascular resistance and rise in pulmonary blood flow that are essential for the transition from the placental circulation to the postnatal pattern is dependent on adequate function of the endothelial cell. Imbalance in the production, release, and/or circulating levels of vasoconstrictors (leukotrienes C4 and D4, thromboxane A2, platelet-activating factor) and vasodilators seems to be central to the right-to-left shunting observed with pulmonary hypertension associated with CDH ( Furchgott and Zawadzki, 1980 ). Similarly, endothelins have taken a central role in defining and treating the newborn with pulmonary hypertension. These peptides are vasoconstrictors that are produced in response to inflammation, ischemia, and other stimuli. Multiple receptors have been localized both in the vascular smooth muscle and in the vascular endothelial cell. Of note, elevated levels of endothelin 1 have been described in infants with CDH ( Rosenberg et al., 1993 ; Kobayashi and Puri, 1994 ). The release of these vasoactive agents appears to be the result of an inflammatory cascade produced in part by ventilator-induced epithelial and endothelial damage from hyperinflation of the hypoplastic lungs.

Clinical Presentation

Infants born with bilateral lung hypoplasia or severe unilateral hypoplasia exhibit symptoms in the first minutes to hours of life. Babies with less severe hypoplasia of the lung whose herniation occurred late in gestation generally present symptoms within 24 hours after birth. The classic triad of CDH consists of cyanosis, dyspnea, and apparent dextrocardia. Physical examination reveals a scaphoid abdomen, bulging chest, decreased breath sounds, distant or right-displaced heart sounds, and bowel sounds in the chest. Radiographic examination of the chest shows a bowel gas pattern in the chest, mediastinal shift and little lung tissue at the right costophrenic sulcus ( Fig. 16-10 ).


FIGURE 16-10  Diaphragmatic hernia. Radiograph shows loops of intestine in the left side of the chest, displacement of the heart to the right, and compression of the right lung.



Clinical presentation is related to survival. Infants with symptoms severe enough to require endotracheal intubation immediately after birth have a very poor prognosis. Infants weighing less than 1000 g, who are born at less than 33 weeks' gestation, or who have an Pao2-Pao2gradient greater than 500 seldom survive ( Raphaely and Downes, 1973 ). Antenatal diagnosis, neonatal stabilization and delayed surgery, and, most important, the avoidance of ventilator-induced lung injury have resulted in significant improvement in morbidity and mortality of infants with severe CDH.

Ultrasonography has made antenatal diagnosis of CDH possible. Sonographic determination of lung-to-head ratio and the presence or absence of liver herniation into the chest have been reported to correlate with postnatal outcome. Fetuses with liver herniation and a low lung-to-head ratio have high mortality and morbidity despite maximum care (NO, extracorporeal membrane oxygenation [ECMO], high-frequency ventilation [HFV], and delayed operative repair) ( Albanese et al., 1998 ; Desfrere et al., 2000 ; Cacciari et al., 2001 ; Muratore et al., 2001a and b; Boloker et al., 2002 ; Stege et al., 2003 ). The reported survival rates for this lesion range from 40% to 90%, but these rates may be falsely elevated. Harrison (1978, 1994) [114] [115] noted that mortality may be “hidden” when in utero deaths and early postnatal deaths from extreme prematurity are not included in calculating mortality. The survival rate for all cases of isolated CDH approaches 70% in those without fetal surgery and 80% in those who do not require ECMO ( Reickert et al., 1998 ).

In Utero Treatment

Because the fundamental pathophysiology of CDH is pulmonary hypoplasia, various fetal surgical techniques to improve the growth of hypoplastic lungs in utero have been reported (Harrison et al., 1990, 1993, 1997 [113] [114] [115]). Starting with animal models in the 1980s, Harrison and others gradually perfected the fetal surgical procedures, improved the treatment of preterm labor with tocolytics, and fine-tuned the anesthetic management to the point of establishing selection criteria for intervention in the human. Initially, a hysterotomy was performed and the fetus was partially exteriorized. The fetal circulation and, therefore, oxygenation were maintained via the placental circulation (ex utero intrapartum treatment [EXIT procedure]). The herniated viscera in the chest were reduced into the abdominal cavity by push-and-pull technique. The procedure was eventually drastically modified to a minimally invasive operation using fetoscopy to surgically occlude the trachea. Tracheal occlusion served to manipulate the physiology of fetal lung development. That is, the fetal lung development is physiologically accelerated by the airway expansion that results from accumulation of the lung fluid while the glottis is occluded. This tracheal occlusion technique has marginally improved the survival of the affected fetus but is associated with significant complications, including premature labor and delivery (Harrison et al., 2003 ). Meanwhile, the survival of the infants with CDH with conventional postnatal management (see later) had improved in the latter half of the 1990s. The National Institutes of Health-sponsored, controlled, comparative study did not show any increased survival after surgical treatment of fetuses with CDH ( Harrison et al., 2003 ). Consequently, fetal surgery for the repair of CDH was suspended in 2001.

Timing of Surgery

CDH was considered a neonatal emergency and the infant with CDH was operated on as soon as possible after birth. The infant's lungs were hyperventilated with 100% oxygen circulation in an attempt to produce pulmonary vasodilation from hyperoxia and respiratory alkalosis. Although this combination of hyperoxia and respiratory alkalosis may produce transient pulmonary vasodilation, repetitious overdistention of the lung tissues results in damage to the alveolar and capillary membranes (barotrauma or, more accurately, volutrauma) and induces an inflammatory reaction and the associated release of vasoactive mediators, eventually producing pulmonary vasoconstriction and pulmonary hypertension.

The goal of the initial management of CDH is to avoid a surgical intervention when the infant is hypoxic and acidotic ( Levin, 1987 ). Instead, medical management is directed to stabilizing the cardiorespiratory status by improving oxygenation, correcting metabolic acidosis, reducing the right-to-left shunting, and increasing pulmonary perfusion ( Miyasaka et al., 1984 ; Hazebroek et al., 1988 ).Sakai and others (1987) reported that the postoperative compliance of the respiratory system (Crs), as measured with a noninvasive, passive mechanics technique ( Lesouef et al., 1984 ), immediately decreased 10% to 77% from the preoperative value. The four infants with more than 50% decrease in compliance died after increased hypoxemia and acidosis. Respiratory mechanics in CHD, rather than improving, frequently deteriorate after repair of the hernia. Studies such as these prompted a revaluation of the practice of urgent surgery in this malformation.

Nakayama and others (1991) evaluated pulmonary function and outcome of 22 infants with severe CDH treated either with emergency repair or with preoperative stabilization for 2 to 11 days. Nine of 13 infants who underwent immediate repair of CDH received ECMO support postoperatively, and 6 of 13 infants (2 after ECMO) survived (46% survival). Six of nine infants whose surgery was delayed for preoperative stabilization immediately received ECMO support for 4 to 10 days; one died before surgery after an intraventricular hemorrhage. All other eight infants survived after surgery (89% survival). Seven days after surgery, respiratory system compliance (Crs) for those infants operated on in the immediate repair group did not improve from the preoperative (immediate neonatal) values. In contrast, Crsincreased more than 60% from their baseline values in these infants who underwent preoperative stabilization. Although the duration of mechanical ventilation was similar in the survivors of the two groups, the preoperative stabilization group had higher postductal Pao2, lower respiratory rates, lower peak and mean airway pressures, and lower Fio2. Based on the physiologic and clinical evidence, these researchers concluded that preoperative stabilization is beneficial before the repair of CDH ( Nakayama et al., 1991 ).

Preoperative Supportive Care

Preoperative care of an infant with severe CDH should start in the delivery room. Establishing effective ventilation in newborn infants often requires peak airway pressure greater than 30 cm H2O.Bjorklund and others (1997) found that six manual inflations with a tidal volume of 35 to 40 mL/kg in preterm lambs resulted in persistent respiratory failure and pneumothorax despite surfactant treatment.Wada and others (1997) also found that ventilation of premature lambs at birth with a tidal volume of 20 mL/kg for only 30 minutes resulted in marked decreases in Crs along with the development of poor gas exchange. In comparison, premature lambs ventilated with a tidal volume of 5 or 10 mL/kg maintained high Crs and normal gas exchange. Although most infants with CDH are born at term or near term, these data from preterm lambs and the high incidence of chronic lung disease in survivors of CDH suggest that minimizing the barotrauma from positive pressure ventilation may be an important tactic from the first ventilatory intervention. In fact, some neonatologists advocate not only preoperative stabilization but also endotracheal intubation and high-frequency oscillatory ventilation (HFOV) immediately at birth. Preoperative stabilization is followed at least for several days. With this “lung protective” approach, Uezono (2003) reported a 90% survival rate after the repair of severe CDH.

Positive pressure ventilation by mask and bag is particularly risky for infants with CDH, because attempting to expand the noncompliant lungs may distend the stomach and intestines, which are in the left hemithorax, further decreasing chest compliance. Early intubation of the trachea and decompression of the stomach are important initial steps to prevent further distention of, and pulmonary compression by, the displaced abdominal viscera.

In the perioperative period, some infants exhibit a “honeymoon period,” which is then followed by a sudden, often unexplained return to a state of persistent pulmonary hypertension and clinical deterioration (acidosis, hypoxemia, hypercapnia, pulmonary hypertension, and right-to-left shunting through the foramen ovale and the ductus arteriosus). Numerous efforts at manipulating the pulmonary vascular resistance have been used with varying degrees of success (or no success). In the 1970s/early 1980s, such measures included hyperventilation (often maintaining the pH > 7.50 and the Pco2 < 25 mm Hg), ligation of the PDA, and pharmacologic therapy (e.g., isoproterenol, tolazoline). During the 1980s, other pharmacologic therapies were introduced, including prostacyclin, prostaglandins, NO, and ECMO ( Goetzman et al., 1976 ; Clyman et al., 1977 ; Collins et al., 1977 ; Levy et al., 1977 ; Moodie et al., 1978 ; Soifer et al., 1982 ; Bohn et al., 1987 ; Langham et al., 1987 ; Pappert et al., 1995 ;Zwissler et al., 1995 ; Clark et al., 1998 ). More recently, therapeutic aims have been directed toward NO and ECMO.

Nitric Oxide (NO)

The role of NO in the treatment of CDH is a logical extension from the use of NO for infants with pulmonary hypertension, sepsis, and congenital heart disease ( Kinsella et al., 1992 ; Roberts et al., 1992 ). NO diffuses across the alveolar capillary membranes and stimulates cyclic guanylate cyclase, which increases cyclic GMP, thereby causing vascular smooth muscle to relax (see Chapter 2 , Respiratory Physiology in Infants and Children). At the present, a limited number of patients with CDH treated with NO have been reported. In a case report of premature infants with CDH, Lévêque and others (1994)noted that NO was a significant factor in the infants—survival. In a small series, Shah and others (1994) noted that patients with CHD may be more resistant to the effects of inhaled NO, whereasKaramanoukian and others (1994) reported that NO was effective in patients with hypoplastic lungs only after extracorporeal membrane oxygenation.

Extracorporeal Membrane Oxygenation

Frequently, infants with CDH for whom conservative medical management fails receive cardiorespiratory support with ECMO, which is similar to cardiopulmonary bypass ( German et al., 1977 ; Hardesty et al., 1981 ; Bohn et al., 1987 ; Langham et al., 1987 ; Redmond et al., 1987 ). Several types of ECMO have been developed based on site of cannulation and the design of the ECMO circuit. The most common setup is a venoarterial circuit where the patient's internal jugular vein and common carotid artery are cannulated. In this system, blood is drained via gravity from the right atrium, oxygenated through the membrane oxygenator, and returned to the patient through the arterial cannulas. In patients who have undergone venovenous bypass, the patient's blood returns to the membrane oxygenator by gravity, is oxygenated in the membrane oxygenator, and then is returned to the venous system. In venovenous ECMO, adequate systemic oxygen delivery depends on the effective cardiac output, whereas in infants undergoing venoarterial ECMO, the bypass system can compensate for both pulmonary and myocardial dysfunction. Significant risks are associated with ECMO, including bleeding at surgical or chest tube insertion sites, intracranial hemorrhage, sepsis, hypertension, and brain death. Outcome data for neonates who have been supported with ECMO have been far more promising than the data from adults. Clearly, the underlying disease process influences the success rates of ECMO ( Dalton, 1992) ( Table 16-4 ). In general, because the mortality is higher and the likelihood of intracranial hemorrhage is higher in LBW infants, ECMO is limited to infants weighing more than 2.0 kg and of greater than 35 weeks' gestation.

TABLE 16-4   -- International neonatal ECMO patient population (1973–1990)





Patients Entered

3662 (83%)

769 (17%)



Meconium aspiration syndrome

1575 (93%)

123 (7%)

1698 (38%)


551 (84%)

107 (16%)

658 (15%)


478 (61%)

306 (39%)

784 (18%)


433 (77%)

133 (23%)

566 (13%)

Air leak syndrome

12 (63%)

7 (23%)

19 (0.4%)

Pulmonary hypertension of the newborn

502 (88%)


573 (13%)


111 (83%)

22 (17%)

133 (3%)

From Dalton HI, Thompson AE: Extracorporeal membrane oxygenation. In Fuhrman BP, Zimmerman J, editors: Pediatric critical care. St Louis, 1992, Mosby—Year Book. Reprinted with permission fromNeonatal ELSO (Extracorporeal Lift Support Organization) Registry Report, Ann Arbor, MI, January 1991.




In centers where ECMO support is available and entry criteria are followed, it is not surprising that survival in infants who do not require ECMO is higher than in those who do. For example, in one series of 30 infants with CDH who were surgically treated within the first day of life, the survival rate of the 18 who did not require ECMO was 83%. Of the 12 infants who underwent ECMO therapy for severe respiratory failure, 7 (58%) were weaned from ECMO and mechanical ventilation, and 6 (50%) were long-term survivors ( Redmond et al., 1987 ). In a multicenter (n = 19) study including 93 infants with severe CDH who were treated with ECMO between 1983 and 1987, overall long-term survival was 58% ( Langham et al., 1987 ).

The criteria for instituting ECMO vary and often are vague (failure of medical therapy, failure to respond to “maximal treatment,” acute clinical deterioration making death appear likely). However, in most centers, stricter, specific guidelines are followed, including Pao2-Pao2 greater than 600 mm Hg for 8 hours, oxygen index ([Fio2×mean airway pressure]/Pao2) of 51 for 5 hours, and cardiac arrest ( Langham et al., 1987 ; Heiss et al., 1989 ; Norden et al., 1994 ; Steimle et al., 1994 ). Nonetheless, no selection criteria appear accurate in predicting which infants, if any, have sufficient pulmonary parenchyma to survive ( Newman et al., 1990 ; Van Meurs, 1990 ; Charlton, 1993 ; Steimle et al., 1994 ). Steimle and others (1994) have shown that the application of ECMO to all patients resulted in overall decreased patient survival and only a modest (27%) survival rate for patients with severe cardiorespiratory compromise. In contrast, a multicenter study enrolled 632 of 730 neonates from the CDH Registry from January 1995 to November 1997. These infants had a complete data set and were eligible for ECMO by the weight criterion of greater than 2.0 kg. Of importance, the mortality risk of these infants was stratified according to previously validated independent predictors of survival: birth weight and 5-minute Apgar score. Five groups were defined based on increasing predictive mortality risk. ECMO significantly improved survival rates for those CDH neonates with a predictive mortality risk greater than or equal to 80%. Generally, the more critically ill the infant with CDH, the more likely that ECMO improves survival. Thus, before an intervention such as ECMO is considered, strict entry criteria must be followed. These criteria are not static, and as various modes of therapy are refined, the basis for initiating various therapies is likely to evolve ( The Congenital Diaphragmatic Hernia Study Group, 1999 ).

Intraoperative and Postoperative Management

Usually, surgical repair is approached through an abdominal incision, but a transthoracic or thoracoabdominal approach is also possible. Infants with large defects may not tolerate primary closure of the abdomen after the hernia is reduced. In such a case, a chimney prosthesis or Silastic pouch is placed. In these infants, venous access in the lower extremities should be avoided because the inferior vena cava may be compressed after reduction of the hernia, limiting venous return. An internal jugular cannula provides more reliable access. This access allows CVP monitoring both intraoperatively and postoperatively and may be essential to deliver TPN postoperatively.

With rare exceptions, infants with a moderate or large CHD require ventilatory support preoperatively and most receive neuromuscular blockade. The goals of ventilation in the operating room are the same as preoperatively—to optimize pH and pulmonary blood flow with minimal barotrauma. Hyperventilation is reserved to initially treat an acute episode of pulmonary hypertension. If a sudden deterioration occurs in ventilation, hemodynamic status, or both, pulmonary hypertension must be quickly differentiated from a contralateral pneumothorax, because the treatment for a pneumothorax is needle thoracostomy and chest tube placement rather than hyperventilation.

All newborns deserve meticulous attention to temperature in the operating room, but infants with a CDH have dramatic risks associated with hypothermia ( Nielson and Jorgensen, 1978 ), including an increase in pulmonary vascular resistance, which may increase right-to-left shunting through a PDA or the foramen ovale. Hypothermia increases oxygen consumption, and in the setting of marginal cardiorespiratory function, may result in inadequate oxygen delivery and acidosis, which then further increases pulmonary vasoconstriction and worsens arterial desaturation.

The selection of specific anesthetic agents must be based on cardiorespiratory status, the site for surgical repair (e.g., neonatal intensive care nursery or operating room), and the plans for intraoperative ventilatory support. Nitrous oxide is avoided in infants with CDH because most require high, inspired oxygen concentrations and because nitrous oxide can diffuse inside the viscera and exaggerate lung compression. If an anesthesia machine is available, low concentrations of inhalation anesthetics (sevoflurane or isoflurane) can be administered and increased if the patient is hemodynamically stable. In most cases, high-dose narcotics (usually, fentanyl) are administered and the narcotic infusion is continued into the postoperative period ( Vacanti et al., 1984 ).


Early reports of outcome in survivors of CDH noted a decreased total lung capacity and an increased residual volume ( Reid and Hutcherson, 1976 ), as well as hyperinflation and reduced pulmonary perfusion on the affected side ( Wohl et al., 1977 ). Imai and others (1994) noted a high incidence (>75%) of lower airway obstruction, air trapping, and reactive airway disease in those infants with severe CDH who required prolonged mechanical ventilation in the neonatal period. In addition, successful repair of CDH may be associated with gastroesophageal reflux ( Nagaya et al., 1994 ; Sigalet et al., 1994). In a study by Lund and others (1994) on high-risk CDH survivors, 45% had developmental delay, 39% were below the fifth percentile for weight, 18% required a fundoplication, and 21% had a significant hearing loss.


The incidence of this lesion is 1:4000 live births. Approximately 20% to 25% of these infants also have a congenital heart disease (ventricular septal defect, atrial septal defect, tetralogy of Fallot, atrioventricular canal, or coarctation of the aorta). Another 20% to 30% of infants with tracheoesophageal fistula (TEF) are premature, weighing less than 2000 g. Mortality associated with TEF generally depends on the severity of the underlying lung disease and associated anomalies. Improvements in anesthetic and surgical techniques allow greater than 90% survival in otherwise healthy full-term infants (Choudhury et al., 1999 ). In high-risk infants (<1800 g or with pneumonia) with TEF, mortality ranges from 15% to 60%.

In addition to cardiac anomalies, anorectal, genitourinary, vertebral, skeletal, and craniofacial abnormalities can occur with TEF. The VATER syndrome, described in 1973, is an association of the following anomalies: V, vertebral defects; A, anal defects; T, TEF; E, esophageal atresia; and R, radial or renal anomalies ( Quan and Smith, 1973 ). Another acronym includes a “C” and “L” because cardiac and limb anomalies are also common. As many as 20% to 25% of infants with esophageal atresia have at least three of the lesions included in VACTERL ( Rittler et al., 1996 ). Between 50% and 65% of infants with esophageal atresia with or without a TEF have at least one additional anomaly. Anomalies are more common in the isolated esophageal atresia type and least common in the H-type fistula.

Some infants may also have other anomalies as part of a generalized chromosomal syndrome. Clearly, the spectrum of presentation from an isolated TEF to a multisystem or chromosomal disorder has major implications for treatment options and surgical and anesthetic management.


The embryogenesis of this set of lesions is not completely defined, but several aspects of the recent investigations are relevant to clinicians. The trachea and esophagus develop from a common site, the foregut, in the first 4 to 5 weeks of gestation. The high incidence of associated lesions within the trachea and the gastrointestinal tract is well known. For example, anomalies of the tracheobronchial tree occur in almost 50% of patients with TEF. The most common lesion is an ectopic right upper bronchus, but other lesions include congenital bronchial stenosis, congenital tracheal stenosis, tracheal web, and the absence of the right upper bronchus. Duodenal or ileal atresia, malrotation, and imperforate anus are common associated anomalies of the gastrointestinal system ( Dave et al., 1999 ).

Both the esophagus and the trachea originate from the median ventral diverticulum of the primitive foregut. The TEF lesion results from failure of the two structures to separate during division of the endoderm. Esophageal atresia results when the tracheal structures assume most of the endoderm, and TEF results when the esophageal and tracheal ridges fail to develop, leaving a communication between the two structures.

An Adriamycin (doxorubicin)-induced TEF model in rats has allowed a careful examination of the distal esophageal development. This model results in the most common anatomic TEF: blind esophageal pouch and fistula between the trachea and the distal esophagus. The distal esophagus has been identified as being of tracheal origin by examining the expression of thyroid-transcription factor-1 (TTF-1), known to be specific to the respiratory tract. TTF-1 expression localizes to the lung bud but not to the esophagus early in gestation. TTF-1 was expressed in the fistula tract all through gestation. The distal “esophagus” appears to be of embryonic lung origin. This discovery is of major clinical relevance, explaining the pathophysiology and clinical findings of this disorder: poor esophageal motility, gastroesophageal reflux, esophageal stenosis, and pseudostratified columnar (respiratory epithelium) rather than squamous epithelium (esophageal epithelium) (Crisera et al., 1999a, 1999b [58] [59]). These same investigators have reported abnormal signaling of a glycoprotein (Sonic hedgehog) involved in embryologic processes including foregut development in human TEF tissue ( Spilde et al., 2003 ).

Anatomy of Tracheoesophageal Fistula

The anatomic variations of TEF have been well described ( Fig. 16-11 , classification of Gross) and, in most cases (types B, C, and E), TEF and esophageal atresia occur together. The most common lesion (>90%) is type C, in which a fistula exists between the trachea and the lower esophageal segment at a point slightly above the carina, whereas the upper esophageal segment ends blindly in the mediastinum at the level of the second or third thoracic vertebra.


FIGURE 16-11  Types of congenital abnormalities of the esophagus. A, Esophageal atresia, no esophageal communication with the trachea. B, Esophageal atresia, upper segment communicating with the trachea. C, Esophageal atresia, lower segment communicating with the back of the trachea. More than 90% of all esophageal malformations fall into this group. D, Esophageal atresia, both segments communicating with the trachea. E, Esophagus has no disruption of its continuity but has a tracheoesophageal fistula. F, Esophageal stenosis. (From Gross RE:The surgery of infancy and childhood. Philadelphia, 1953, WB Saunders.)


Clinical Presentation

TEF should be suspected in cases of maternal polyhydramnios and premature labor. Both conditions may result from esophageal obstruction that prevents the swallowing of amniotic fluid. The newborn infant exhibits excessive salivation, drooling, cyanotic spells, and coughing relieved by suctioning. The diagnosis of esophageal atresia can be confirmed in the delivery room by the inability to pass a catheter down the esophagus into the stomach. When a radiopaque catheter is used, a radiograph reveals the catheter in the blind upper pouch. If a TEF is present, a plain radiograph of the chest and abdomen reveals air or gas bubbles in the stomach and intestines that have entered through the fistula ( Fig. 16-12 ). Ultrasonography is important to evaluate for any associated cardiac, renal, or genitourinary abnormalities.


FIGURE 16-12  Gastric distention, in type C lesion, may require prompt relief. Note blindly ending esophagus on lateral view.  (Courtesy Dr. Arnold Colodny, Boston, MA.)


Preoperative Management

The ligation of a TEF is urgent. Preoperatively, several interventions are undertaken promptly to protect the lungs from aspiration pneumonia, including



Avoidance of feedings (NPO)



Upright positioning of the infant to prevent gastroesophageal reflux



Intermittent suctioning of the upper pouch



Antibiotic therapy and physiotherapy in babies with contaminated lungs

Intraoperative Management

Optimally, a total repair can be accomplished as a one-stage procedure, in which the fistula is ligated and the esophagus is primarily anastomosed. In infants with significant associated anomalies or sepsis, a thoracotomy may be considered too risky and, instead, a palliative procedure, a gastrostomy, is performed under local or general anesthesia. Despite the lower morbidity associated with a gastrostomy, many anesthesiologists prefer to intubate the trachea to minimize the risks from aspiration during surgical manipulation. The definitive repair is performed within 24 to 72 hours, when the extent of other anomalies is defined, cardiovascular stability is established, and a clear surgical plan has been defined. The gastrostomy tube is kept patent to decompress the stomach and to minimize regurgitation into the lungs.

Unless the aortic arch is right-sided, the surgical approach for definitive repair is through a right thoracotomy using a posterolateral extrapleural approach. On occasion, the distal portion of the esophagus is either absent or too short to reach the proximal segment. In such cases, some surgeons may ligate the fistula and exteriorize the upper pouch through an esophagostomy. The infant is then fed via the gastrostomy until a weight of about 9 to 10 kg (20 lb) or 1 year of age has been reached. At that time, the two esophageal segments are surgically bridged with an interposed bowel segment or gastric tube graft.

A technique of “awake intubation” is generally considered as the safest approach to secure the airway in infants with TEF. This allows the appropriate positioning of the endotracheal tube without positive-pressure ventilation, as well as minimizing the risk of gastric distention from inspired gases passing through the fistula. Titrating small doses of fentanyl (0.2 to 0.5 mcg/kg) or morphine (0.02 to 0.05 mg/kg) before intubation is ideal, but this must be considered from the perspective of the infant's clinical status at the time of the procedure. An alternative induction technique includes an inhalation anesthetic with or without muscle relaxation with cautious, gentle positive-pressure ventilation.

After the endotracheal tube is in place, end-tidal carbon dioxide and oxygen saturation must be monitored, and the stomach and chest should be ausculated to ensure that the lungs are adequately ventilated and the stomach is not distended with inspired gases. If the endotracheal tube is positioned so that ventilation is entering the stomach via the fistula, or if the fistula itself has been intubated, the stomach may become distended and impair ventilation. Salem and others (1973) suggest distal positioning of the endotracheal tube, with the bevel facing anteriorly and the posterior wall of the endotracheal tube occluding the fistula, but this maneuver is challenging to achieve and maintain.

In patients with a gastrostomy, proper positioning of the endotracheal tube can be monitored by submerging the gastrostomy tube in a container of water so that gas bubbles are evident during ventilation of the fistula. If gas bubbling occurs, the endotracheal tube must be repositioned. Alternatively, the gastrostomy tube can be connected to a capnograph. When the endotracheal tube is proximal to the fistula, carbon dioxide is detected. When the endotracheal tube is distal to the fistula, no expiratory gases are detected.

Even with adequate positioning of the endotracheal tube, in some patients ventilation through the fistula still occurs. In patients without a gastrostomy, gastric distention may impair ventilation. Filston and others (1982) have suggested occluding the fistula with a Fogarty catheter placed through a bronchoscope. However, bronchoscopy, even without the challenge of precise positioning of a Fogarty, can be a difficult procedure in the newborn, especially if pulmonary compliance is abnormal.

In patients with a gastrostomy, gastric decompression may serve as a low resistance vent through which most of the tidal volume escapes. If this occurs, the gastrostomy tube should be clamped or, as Karl (1985) has reported, a retrograde Fogarty catheter can be inserted. Although theoretically possible, this technique is often impractical in the setting of small infants. Precisely positioning a Fogarty catheter so that the balloon is occluding only the fistula is difficult to achieve, and even if the positioning is perfect on initial attempt, maintaining this exact position of the catheter for any length of time is almost impossible. Furthermore, displacement of the balloon can be disastrous (e.g., occluding the trachea). The balloon is a high-pressure device that may impinge on small pulmonary vessels and/or airways compromising pulmonary blood flow or ventilation.

Once satisfactory ventilation is ensured, the chest is opened and the lungs are retracted. Lung retraction impairs ventilation, especially in infants with respiratory dysfunction from immature lungs, pneumonia, or congenital heart disease. Intermittent release of pressure by the surgeon to allow inflation of the right lung often improves oxygenation and ventilation. Blood clots or secretions may block the endotracheal tube, and frequent endotracheal suctioning may be required. Because the trachea is a soft structure in the newborn, surgical manipulation may kink the airway and further obstruct ventilation. Thus, interference with adequate oxygenation can occur as a result of the patient's anatomy, operative positioning, and surgical manipulations. Inspired concentration of oxygen must be closely monitored and adjusted, balancing the risks of oxygen toxicity with those of hypoxia. Close communication between the surgeon and anesthesiologist is essential.

After the TEF is ligated, the anesthesiologist is asked to pass a catheter through the nose or mouth into the blind upper pouch to identify the upper esophageal structure. The surgeon passes a catheter into the lower part of the esophagus, and the anastomosis is made over the catheter. When the anastomosis is complete, the catheter is withdrawn just above the suture line, and the proximal end of the catheter is marked at the mouth. The distance from the mouth to the distal tip is noted. Only catheters of this length should be used for suction in the postoperative period.

Intraoperative monitoring must be carefully planned. The precordial stethoscope is repositioned after induction of anesthesia into the left axilla. In infants with an unstable cardiorespiratory status or congenital heart disease, an arterial catheter (umbilical or right radial) should be placed. If an arterial catheter is not available, a noninvasive device is used. Other monitoring consists of an electrocardiogram, pulse oximetry, and end-tidal gas monitoring. In some infants, both preductal and postductal pulse oximeters are placed. The patient's temperature must also be monitored, and efforts must be made to prevent hypothermia.

Postoperative Management

Some term infants can be extubated after simple ligation of a TEF, but this is rare. Tracheomalacia or a defective tracheal wall at the site of the fistula can cause collapse of the airway and require reinsertion of the endotracheal tube. These specific problems with TEF, as well as the host of other cardiorespiratory problems of the newborn, generally require a period of postoperative ventilation for these infants, often for at least 24 to 48 hours. In addition, most surgeons request that ventilation with a mask and bag be avoided for at least several days postoperatively. Infants who have had repair of a “long-gap” atresia require postoperative ventilatory support for a longer (5 to 7 days) postoperative period. Neuromuscular blocking agents are administered during this time to eliminate any spontaneous ventilation. Postoperative ventilation is also planned for an infant whose lungs were contaminated, whose intraoperative course was complicated (e.g., tracheal perforation), or who has underlying lung disease associated with prematurity.


TEF cannot be considered a simple anatomic problem cured by a surgical intervention. Many patients have anatomic narrowing of the esophagus either at the site of anastomosis or the fistula ligation, and this narrowing may progress to a severe stricture. Esophageal dysmotility and reflux are common, and may also lead to esophageal stricture. Recurrent upper and lower respiratory infections occur in 35% to 75% of patients ( Dudley and Phelan, 1976 ). Pulmonary function studies 7 to 18 years after repair show a high incidence of obstructive and restrictive forms of lung disease ( Milligan and Levison, 1979 ).


Necrotizing enterocolitis (NEC) is a gastrointestinal emergency primarily affecting premature infants of gestational age less than 32 weeks; 80% of affected patients are preterm. The severity of the symptoms, complications, and mortality are inversely related to gestational age. Although centered in the gastrointestinal tract, NEC is a systemic process primarily related to the sepsis that accompanies the intestinal necrosis and increased mucosal permeability.

The etiology of NEC is considered to be multifactorial. The incidence of NEC (10% to 20%, in infants <1500 g) has not decreased and overall mortality has not improved over the past two to three decades. As the survival of the premature, especially the ELBW, infant has improved, the incidence of NEC has increased in some populations. The increased number of susceptible infants may explain the lack of improved overall survival in infants with NEC.

Bell and others (1978) described three stages of NEC. Stage 1 refers to mild disease with the infant having only nonspecific symptoms (vomiting, gastric residuals, apnea, bradycardia, guaiac-positive stools). There is no definitive radiologic evidence for NEC, and the state of the bowel is completely unknown. Stage 2 includes infants with definitive NEC. They have clinical symptoms similar to the infants in stage I, but on radiographs these infants have pneumatosis intestinalis or portal venous air (Figs. 16-13 and 16-14 [13] [14]). These infants are suitable for medical management. Stage 3 includes infants with advanced disease. These infants have evidence of intestinal necrosis and/or perforation along with clinical signs of hemodynamic, respiratory, and/or hematologic instability. Although these three stages are not distinct and are actually a continuum of clinical disease, the three-stage concept helps define management strategies.


FIGURE 16-13  Air pattern in the portal venous system of the liver in an infant with necrotizing enterocolitis.  (From Rowe MI: Necrotizing enterocolitis. In Welch KJ, Randolph JG, Ravitch MM, et al., editors: Pediatric surgery, 4th ed. Chicago, 1986, Year Book Medical Publishers.)





FIGURE 16-14  Pneumatosis intestinalis in an infant with necrotizing enterocolitis.  (From Rowe MI: Necrotizing enterocolitis. In Welch KJ, Randolph JG, Ravitch MM, et al., editors: Pediatric surgery, 4th ed. Chicago, 1986, Year Book Medical Publishers. Reproduced with permission.)





NEC is a paradoxical disease. Classically, it occurs in premature infants and in infants with LBW. Most infants with NEC weigh less than 2500 g and are less than 37 weeks gestational age at birth. However, NEC can also occur in full-term infants on the first day of life or months after birth. It can occur in fed or unfed infants, in a single patient, or as a nursery epidemic. Of note, term infants develop symptoms by day 2 to 3 of life, whereas the ELBW infants are more likely to develop NEC in the second week of life.

NEC is frequently linked to intestinal mucosal injury from ischemia caused by reduced mesenteric blood flow. Mesenteric blood flow may be compromised by a decreased cardiac output in the presence of fetal asphyxia, a PDA, postnatal apnea, heart failure, arrhythmia, or severe bradycardia and hypoxemia. Other factors that may contribute to the pathogenesis of NEC include enteral feeding of small preterm infants, use of a hyperosmolar formula, bacterial infection, intestinal dysfunction, gram-negative endotoxemia, polycythemia, congenital heart disease, and a history of umbilical arterial catheterization or exchange transfusion.

The most common anatomic site for NEC is the ileocolic region. However, NEC is frequently discontinuous, with patchy occurrence in both the small and large intestine in as many as 50% of cases. Large bowel involvement is most common in the term infant. Perforations often are multiple and commonly identified at the junction of a site of necrosis with more normal bowel but are also found within the affected areas.

The primary pathologic finding in NEC is coagulative or ischemic necrosis, but inflammation is prominent. The inflammatory response seems to be unique in that abscesses do not form, as seen in inflammatory bowel disease or infectious colitis or as a result of acute arterial occlusion. The combination of ischemia and bacteria seems to be essential. For example, NEC does not evolve after an episode of vascular injury in utero, when the bowel is sterile ( Musemeche et al., 1986 ). Instead, an intestinal atresia or stenosis may develop. The formation of the gas bubbles (pneumatosis intestinalis) reflects fermentation of intraluminal substrate by bacteria. However, NEC is not associated with a specific organism or with particularly virulent bacteria. A wide range of organisms have been identified in the stool of infants with NEC, some who also have a bacteremia with the same organism—Escherichia coli, various strains of Enterobacter, Klebsiella, and Pseudomonas, and coagulase-negative staphylococci, and others.

Several “models” of NEC, emphasizing the role of inflammatory/vasoactive mediators, platelet-activating factor (PAF), and tumor necrosis factor (TNF) α have been developed ( Fong et al., 1990 ; Sun and Hsueh, 1991 ; Sun et al., 1996 ; Wand et al., 1997 ; Tan et al., 2000 ). PAF is released by inflammatory cells as well as by bacteria and in high concentrations can induce hypotension and shock as well as increase gut permeability ( Tan et al., 2000 ).

Elevated levels of PAF have been measured in infants with NEC ( Rabinowitz et al., 2001 ). In addition, premature infants have low levels of PAF-degrading enzyme, acetylhydrolase ( Caplan et al., 1990 ). Other mechanisms included in the pathogenesis of NEC include immature immunologic mechanisms, abnormal patterns of bacterial overgrowth, and deficient mesenteric blood flow regulation. Differences in the content of sialic acid and N-acetylglucosamine residues of the mucosa may affect anatomy and function of the microvilli, leading to certain types of bacterial colonization, bacterial adhesion, and, eventually, permeation of the gastrointestinal tract ( Claud and Walker, 2001 ) ( Fig. 16-15 ).


FIGURE 16-15  Schematic representation of the pathophysiology of necrotizing enterocolitis.



Preoperative Management

A typical infant with NEC is a preterm baby weighing less than 2500 g. These infants commonly have had perinatal asphyxia or other respiratory complications in the early postnatal period. Prenatal complications associated with NEC include premature rupture of the membranes, placenta previa, maternal sepsis, and toxemia of pregnancy ( Touloukian, 1976 ; Uauy et al., 1991 ). A history of breech delivery or cesarean section are associated with 15% to 20% of NEC cases ( Santulli et al., 1975 ). Infants with NEC may be acidotic, hypoxic, hypothermic, and in shock. The gastrointestinal signs appear between the 1st and 10th days of life in more than 90% of these babies ( Touloukian, 1976 ). They include abdominal distention, retained gastric secretions (may be bile-tinged), vomiting, bloody or mucoid diarrhea, and occult blood loss in the stools. Bowel necrosis and perforation follow, and sepsis occurs, with thermal instability, lethargy, metabolic acidosis, jaundice, disseminated intravascular coagulation, and generalized bleeding. Most infants with NEC have a decreased platelet count (50,000 to 75,000/mm3) and prolonged prothrombin and partial thromboplastin times. Abdominal radiographs may reveal dilated, fixed (adynamic ileus) loops of bowel, pneumatosis (intramural air in the intestine), gas in the portal venous system, and pneumoperitoneum. These are pathognomonic signs of NEC.

Unless there is evidence of intestinal necrosis or perforation, the initial treatment for NEC is nonoperative. Decompression of the stomach; cessation of feeding; broad-spectrum antibiotics; fluid and electrolyte therapy, including parenteral nutrition; and correction of hematologic abnormalities are the main components of medical therapy. Supportive therapy, including inotropic agents and steroids, may be used to treat endotoxic shock. Bowel perforation is the most important indication for surgery. Other relative indications include peritonitis, air in the portal system, bowel wall edema, ascites, and a progressively deteriorating cardiorespiratory status ( Box 16-7 ).

BOX 16-7 

Indications for Operation

Absolute Indications


Intestinal gangrene (positive results of paracentesis)

Relative Indications

Clinical deterioration



Metabolic acidosis



Ventilatory failure



Oliguria; hypovolemia






Leukopenia; leukocytosis

Portal vein gas

Erythema of abdominal wall

Fixed abdominal mass

Persistently dilated loop


Severe gastrointestinal hemorrhage

Abdominal tenderness

Intestinal obstruction

Gasless abdomen with ascites

The role for primary peritoneal drainage is not well defined. The effectiveness of peritoneal lavage in “buying time” for an infant to achieve hemodynamic, acid-base, and hematologic stability is actively debated. This procedure seems to be “palliative” because most infants eventually require surgery. The ELBW infant may benefit from such a temporizing procedure that would allow resuscitation and stabilization. If surgery is performed after the hemodynamic status improves, adequate gut perfusion to marginal segments of bowel might be established and, consequently, less bowel is resected. This might avoid excessive bowel resection and short gut syndrome ( Ahmed et al., 1998 ).

The preoperative assessment of infants with NEC should focus on evaluating and correcting the respiratory, circulatory, metabolic, and hematologic disorders. Laboratory testing includes analysis of blood gases, glucose, electrolytes, and coagulation status, including platelet count. Increased fluid and crystalloid therapy may be needed in hypovolemic infants with massive third-space fluid losses. During fluid resuscitation, these infants must be monitored carefully for signs of PDA or congestive heart failure.

Intraoperative Management

Intraoperative monitoring should include arterial and central venous cannulas for continuous pressure monitoring, blood gas analysis, and other metabolic tests. Fresh frozen plasma, platelets, and red blood cells may be administered early in surgery in response to clinical and laboratory evidence of coagulopathy. Inspired oxygen concentration should be adjusted to produce an arterial oxygen tension of 50 to 70 mm Hg (Spo2, 90% to 95%). Nitrous oxide must be avoided, especially in the presence of free air in the gastrointestinal and portal venous systems.

Potent inhalation agents are often poorly tolerated and often are only introduced in low concentrations to supplement narcotics or ketamine. Fentanyl or remifentanil combined with low-dose, inhaled anesthetic agents can provide infants with analgesia and amnesia as well as cardiovascular stability. Neuromuscular blocking agents facilitate surgical exposure. Inotropic agents occasionally are needed to support the cardiovascular system when fluid therapy alone fails to maintain adequate perfusion.

Because of the large fluid requirements, hypothermia is a frequent intraoperative complication. Usually the operating room and infused fluids are warmed to assist in maintaining adequate body temperature. In the surgical treatment of NEC, necrotic bowel is resected, and, usually, the marginally viable ends are exteriorized. The cardinal principles of surgery for NEC are to excise all necrotic bowel but preserve as much bowel length as possible by leaving “marginal” appearing bowel in place, decompressing the bowel, and removing pus, stool, and necrotic debris from the peritoneal cavity. Preserving bowel may require multiple segmental resections and second-look operations to reassess bowel viability. Selected patients may tolerate resection and primary reanastomosis. Bowel strictures often develop within days to months after the initial surgery, frequently necessitating further surgical intervention. In patients with enterostomies, closure can be attempted 4 weeks to 4 months later.

Postoperative Management

Postoperatively, mechanical ventilation and cardiovascular support are usually continued in the neonatal intensive care unit. Central venous parenteral nutrition is essential after sepsis is controlled and metabolic stability is established.


Mortality from NEC is high, ranging between 10% and 30% (or higher in severely affected ELBW infants), depending on the gestational age, coexisting morbidity, and severity of the process. Infants who initially respond to medical management may eventually require surgery to treat bowel obstruction secondary to strictures or another episode of NEC. Similarly, those who initially respond to placement of an intraperitoneal drain for lavage may eventually require surgery. Infants who develop a spontaneous localized intestinal perforation are probably distinct from those with NEC and usually have a more benign course. The hospital course for preterm infants with NEC can be prolonged and characterized by repeated episodes of sepsis and long-term requirements for intravenous alimentation as enteral feedings are introduced slowly. A devastating complication in survivors of NEC is short bowel syndrome. In these cases, the extent of bowel resection is so extensive that the infant is unable to establish enteral feedings and inevitably develops hepatic failure secondary to intravenous alimentation.

Breast milk has been used in the preterm infant to prevent or at least decrease the incidence of NEC and its complications. The role for treatment with probiotics ( Millar et al., 2003 ), nonspecific (steroids, indomethacin, magnesium, copper) and specific anti-inflammatory agents (e.g., PAF receptor blockers), growth factors (erythropoietin), or antibiotics remains speculative.


Sacrococcygeal teratomas are the most common congenital neoplasm, occurring in 1:40,000 infants. Approximately 95% of infants are female.


The tumor is derived from pleuripotential cell lines and contains components consisting of all three germ layers. Perinatal mortality is high when the tumor is diagnosed antenatally. Postulated mechanisms of death include high output cardiac failure, preterm delivery secondary to polyhydramnios, anemia from hemorrhage into the tumor, dystocia, and tumor rupture.

Sacrococcygeal teratomas receive their blood supply from the middle sacral artery and branches of the internal iliac artery. A steal syndrome can shunt blood from the placenta and lead to high output cardiac failure and hydrops. Approximately 2% to 10% of sacrococcygeal tumors are malignant before the infant reaches 2 months of age, and 50% are malignant by 1 year of age. Serum α-fetoprotein levels are elevated in 70% of children with malignant tumors.

Sacrococcygeal tumors generally arise from the tip of the coccyx and vary with the amount of internal and/or external extension. These tumors are classified into four types according to their location ( Box 16-8 ; Figs. 16-16 and 16-17 [16] [17]).

BOX 16-8 

Sacral Coccygeal Tumor Types

Type I

External with minimal pressure component

Type II

External considerable intrapelvic extension

Type III

External with pelvic and intra-abdominal extension

Type IV

Presacral;no external presentation


FIGURE 16-16  Sacrococcygeal teratoma type.




FIGURE 16-17  In utero diagnosis by magnetic resonance imaging.  (From Auni et al.: Am J Radiol 178:179, 2002.)




Intraoperative Management

Surgical treatment involves complete resection of both the tumor and coccyx. Failure to remove the coccyx completely can result in local recurrence. Treatment options in utero include open fetal surgery (Bullard and Harrison, 1995 ), endoscopic laser ablation ( Hecher and Hackeloer, 1996 ), and radiofrequency ablation ( Paek et al., 2001 ).

Anesthetic management for removal of tumors in the neonatal period requires an understanding of neonatal physiology and an appreciation for the possibility of cardiovascular instability, massive blood transfusion requirements, hypothermia, and coagulation dysfunction. Death during resection is often related to hemorrhage, hypothermia, coagulopathy, and the inability to provide adequate cardiopulmonary support during the intraoperative manipulation of the tumor. For large tumors, adequate venous access, central venous access, and invasive arterial pressure monitoring are essential.


Predictors of poor outcome have been associated with (1) diagnosis before 20 weeks' gestation, (2) delivery before 30 weeks, (3) development of hydrops, (4) low birth weight, and (5) 5-minute Apgar score less than 7 ( Chisholm et al., 1999 ).


The incidence of anorectal malformations is 1:5000 live births. “Imperforate” anus can range from a mild stenosis to a complex syndrome with other associated congenital anomalies. The higher the anatomic relation of the terminal bowel to the puborectalis sling of the levator musculature, the greater is the incidence of associated anomalies. The frequency of additional genitourinary abnormalities is 48% but ranges from 14% in infants with perineal fistulas to 90% in infants with bladder fistulas. Twenty-four percent of infants have a tethered spinal cord ( Levitt et al., 1997 ). Male infants with imperforate anus may require an operation soon after birth for relief of obstruction. In female infants, a rectovaginal fistula usually prevents total bowel obstruction so that surgical treatment is not an emergency.

Intraoperative Management

Anesthetic requirements vary depending on the severity of the abdominal distention and complexity of the surgery—a simple perineal anoplasty, a temporary colostomy, or an extensive abdominoperineal repair. Anorectal malformation can be classified by the presence or absence of a fistula and by the fistula's location ( Pena and Hong, 2000 ) ( Box 16-9 ). Perineal fistulas in both male and female infants represent the simplest defect, and treatment generally consists of an anoplasty performed in the neonatal period. Imperforate anus with no fistula is the least common presentation, whereas rectourethral fistulas are the most common with the exception of the perineal fistula. The standard surgical approach has generally involved three steps: (1) a diverting colostomy performed in the neonatal period, (2) the main repair done during infancy, and (3) a take-down colostomy performed later in infancy. Surgical trends, however, have been aimed at performing the primary repair without a colostomy. The primary repair involves a posterior surgical approach. Laparoscopic techniques have been used to assist in the pull-through technique ( Georgeson, 2000) .

BOX 16-9 

Therapeutic Classification of Anorectal Malformations



Cutaneous fistula

No colostomy required

Anal stenosis


Anal membrane


Rectourethral fistula

Colostomy required





Rectovesical fistula


Anorectal agenesis without fistula


Rectal atresia




Cutaneous (perineal) fistula

No colostomy required

Vestibular fistula

Colostomy required

Vaginal fistula


Anorectal agenesis without fistula


Rectal atresia


Persistent cloaca



Anesthetic considerations for neonates with intestinal obstruction from any etiology include airway management of a “full stomach,” assessment of fluid status, correction of electrolyte disturbances, treatment of sepsis, and cardiorespiratory evaluation. Marked abdominal distention secondary to intestinal obstruction can impede diaphragmatic excursion and impair ventilation. Gastric (or lower intestinal) contents often are incompletely emptied with nasogastric suction, so that the risk of aspiration is significant, especially in the setting of induction of general anesthesia.

Intubation of the trachea of infants with an apparently normal upper airway can be accomplished with an “awake” or rapid sequence technique. If the anesthesiologist suspects that the upper airway will be difficult to visualize, the usual airway precautions should be followed. That is, neuromuscular blocking agents, deep sedation, and general anesthesia are avoided and an “awake” technique is attempted. Supplemental support systems for the difficult airway (e.g., neonatal bronchoscopes, light wand, LMA) should be available (see Chapter 9 , Anesthesia Equipment and Monitoring).

Anesthesia during the surgery can include potent inhalation anesthetics, narcotics, or both. In general, nitrous oxide is avoided because of the risk for increasing bowel distention. Intermediate- or long-acting nondepolarizing muscle relaxants often improve surgical conditions at lower inhaled anesthetic concentrations. If early postoperative extubation is planned, narcotics should be judiciously administered, but in many cases postoperative mechanical ventilation is required.

Imperforate anus is usually recognized early in the postnatal period, and in the group of infants without total bowel obstruction, massive distention may not develop and, therefore, the complications associated with intestinal obstruction are minimized, as are the complications from bowel ischemia, third-space fluid loss, electrolyte disturbances, and sepsis. Imperforate anus without a fistula can be associated with the development of total intestinal obstruction in utero, leading to severe abdominal distention, bowel perforation, sepsis, or a combination. In addition, other congenital anomalies often have a dramatic effect on the management of these infants. For example, imperforate anus is associated with tracheoesophageal fistula, renal anomalies, and heart disease.

During surgery, the management of fluids, blood replacement, and electrolyte delivery are similar to the principles discussed for NEC and for intestinal obstruction. As with any intra-abdominal surgery in the newborn, a major challenge is maintaining an adequate intravascular volume. The presence of radiopaque contrast agents, bowel manipulation, and peritonitis increases third-space fluid requirements. In such cases, 10 mL/kg per hr (or more) of isotonic saline solution or colloid is frequently needed intraoperatively. Monitoring urine output, quality of heart tones, heart rate, and blood pressure is a basic requirement to assess continuing fluid needs. Invasive monitors such as an arterial catheter and a CVP catheter generally are reserved for those with marked cardiorespiratory instability.

Postoperative Management

The preoperative and intraoperative courses and the effects of associated congenital anomalies set the stage for the postoperative course. Many infants require postoperative ventilatory support, total parenteral alimentation, cardiovascular support, and treatment of sepsis. The function and recovery of the gastrointestinal system vary enormously among infants with imperforate anus and seem to be related to whether the lesion is isolated and whether the complications of total bowel obstruction have developed.


Intestinal obstruction has been one of the major causes of death after neonatal surgery. With more skilled pediatric management and the development of parenteral alimentation, mortality is now limited primarily to infants whose condition is diagnosed late and who require extensive excision of the small and large bowel. Long-term complications from anorectal malformations, especially a high imperforate anus, can be lifelong and involve sequelae related to fecal soiling, constipation, and sexual inadequacy.


Intestinal obstruction is a surgical emergency in the newborn, requiring swift intervention after diagnosis. Bowel obstruction presents with symptoms and signs similar to those seen at other ages—vomiting, abdominal distention, decreased bowel sounds, and radiologic evidence of gas-filled loops of bowel. However, in the newborn the list of etiologies includes a unique set of congenital anomalies.

Delay in the diagnosis and treatment of such lesions may lead to various complications that can increase morbidity and mortality. As described for the infant with imperforate anus, delay in diagnosis leads to disturbance of fluid and electrolyte balance and increased abdominal distention, with subsequent respiratory embarrassment and high risk for aspiration pneumonitis. Intestinal perforation, necrosis of the bowel, and septicemia are other secondary consequences if intestinal obstruction is not managed promptly.

Distended bowel forces the diaphragm into a high, fixed position, limiting excursion, causing severe ventilatory compromise, and increasing the risk of aspiration. Although prompt surgical repair is imperative, optimizing the patient's metabolic status is critical before surgery. Initiation of corrective fluid and electrolyte therapy should precede the induction of anesthesia. Nasogastric suction may decrease gastric distention and the risk for aspiration, but, if the site of obstruction is below the duodenum, the abdominal distention is not drastically affected.

Although the underlying etiologies of intestinal obstruction are variable (annular pancreas, intestinal atresia or stenosis, duplication of intestine, meconium ileus, tumors, enterocolitis), the problems of anesthetic management for surgical correction of these lesions are similar.

Duodenal Obstruction

The incidence of duodenal obstruction in the neonate is 1:10,000 to 1:40,000 births and is frequently associated with other congenital anomalies such as Down syndrome, cystic fibrosis, renal anomalies, intestinal malrotation, and, especially, midline defects such as esophageal atresia and imperforate anus. An intraluminal diaphragm, a membranous web, or an annular pancreas can also be associated with obstruction of the duodenum. The degree of obstruction varies from severe or complete atresia to incomplete obstruction or stenosis. Air contrast films reveal a dilated stomach and a dilated proximal duodenum, resulting in the “double-bubble” appearance.

Infants with complete obstruction exhibit copious vomiting of bile or bile-stained gastric contents and minimal abdominal distention. The infant may or may not pass meconium in the first day of life. Infants who have incomplete obstruction have intermittent bile-stained vomiting and usually pass meconium. A delay in the treatment of this condition can result in dehydration, weight loss, and hypochloremic alkalosis.

Jejunoileal Atresia

Jejunoileal atresia causes complete obstruction in 1:5000 live births. In contrast to duodenal atresias, jejunoileal atresias are associated with few other anomalies. Prematurity is associated with 50% of cases, polyhydramnios with 25%, and cystic fibrosis with 20%.

The etiology of jejunoileal atresia is uncertain but is thought to involve intrauterine vascular accidents. Four types of atresia have been identified ( Fig. 16-18 ). Type I is not a true atresia but actually is a membranous obstruction of the lumen in an intestine of otherwise normal length and diameter. Type II, a true atresia, consists of two blind ends frequently connected by a fibrous strand with slightly shortened intestinal length. Type IIIa lesions have blind ends separated by a mesenteric defect. The type IIIb lesion is also called “apple peel” or “Christmas tree” deformity, consisting of a long jejunal atresia with a very short remaining ileum. The superior mesenteric artery is missing, and the blood supply to the ileum is by retrograde flow via a branch of the ileocolic artery. Type 3b lesions are rare but have a very high mortality. Type IV lesions involve multiple intestinal atresias.


FIGURE 16-18  The various types of jejunal atresia.  (With permission from Grosfeld JL: Jejunoileal atresia and stenosis. In Welch KJ, Randolph JG, Ravitch MM, et al., editors: Pediatric surgery, 4th ed. Chicago, 1986, Year Book Medical Publishers.)




Meconium Ileus

Meconium ileus is a luminal obstruction of the distal small bowel by abnormal meconium. Meconium ileus is found almost exclusively in patients with cystic fibrosis, but only 20% of patients with cystic fibrosis have meconium ileus. Because meconium ileus presents in the neonatal period, respiratory symptoms of cystic fibrosis generally are not present. Both surgical and nonsurgical therapies are used to relieve the obstruction. The nonsurgical approach involves diatrizoate meglumine (Gastrografin) enemas, which can be both diagnostic and therapeutic. Diatrizoate meglumine, a water-soluble contrast agent, loosens and softens the meconium, thereby facilitating its evacuation. When medical management does not succeed, surgery is performed. After the peritoneal cavity is entered and the obstruction is located, diatrizoate meglumine or acetylcysteine is injected into the bowel lumen and allowed to mix with the meconium. When the meconium has loosened, it is massaged into the colon. If this is unsuccessful, an enterostomy is performed, and the sterile meconium is evacuated from the small bowel.

Malrotation and Volvulus

Malrotations are rare and generally result from abnormalities in the rotation of the bowel, which usually occur during the 10th to 12th weeks of gestation. Consequently, areas of ischemia and atresia develop, along with volvulus, resulting in strangulation of bowel, bloody stools, abdominal distention, peritonitis, and hypovolemic shock. Nonrotation or malrotation is twice as common in boys as in girls and frequently produces symptoms of intestinal obstruction in the first 1 to 2 months after birth. In other cases, symptoms do not appear until later, even adulthood. Malrotations are often associated with duodenal stenosis or atresia or small intestinal atresia, as well as with cardiac, esophageal, urinary, and anal anomalies. Major anatomic defects of the abdominal wall (gastroschisis, omphalocele) and CDH universally have intestinal malrotation or nonrotation.

The operative procedure for a nonrotation complicated by volvulus consists of untwisting of the intestine and then a short intraoperative period of observation to evaluate recovery of vascular perfusion to the involved intestine. Areas of frank necrosis are excised, and a primary anastomosis is performed. If the patient has peritonitis or poor perfusion of the remaining bowel, proximal and distal enteral stomas are formed.

Children with less than 30 to 40 cm of small bowel generally develop short-gut syndrome and ultimately require total parenteral nutrition. If marginal areas of intestinal viability are present at operation, they may be left unresected in the hope that postoperative resuscitation improves their perfusion. Under these circumstances, a “second-look” operation usually is performed 24 to 48 hours later.

Copyright © 2008 Elsevier Inc. All rights reserved. -

Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier


Since the 1980s, vast improvement in prenatal care and better understanding of neonatal medicine have increased the survival of premature babies. Consequently, more premature infants or neonatal intensive care nursery graduates require surgical procedures.

Comparing mortality and short-term outcome among three time periods of 1987-1988, 1993-1994, and 1999-2000 provides a perspective on the impact of advances in obstetric and neonatal care since the 1980s ( Fanaroff et al., 2003 ). Infants between 500 and 1500 g were studied, with separate emphasis on the 501- to 800-g infants. Although mortality decreased progressively from 1987 through 2000 for each gestational age bracket, survival without major morbidity (chronic lung disease, NEC, grade III/IV intraventricular hemorrhage) did not. Of note, these findings exist even with the administration of prenatal steroids increasing from 16% to 79%. Surfactant was given to 57% of all the infants in the 1999-2000 births and in 87% of those weighing 501 to 800 g. Inhaled nitric oxide did not affect mortality or BPD incidence, but it may improve developmental outcome in premature infants (Meurs et al., 2005; Van Mestan et al., 2005 ).


The degree of pulmonary immaturity at birth depends on many factors but is primarily dependent on the gestational age. Anatomic and biochemical development are both essential for successful extrauterine adaptation of the respiratory system. In human fetuses, the alveoli develop from the primitive terminal air sacs after 36 weeks gestation; pulmonary surfactant in sufficient quantities normally is not produced in the type 2 pneumocytes and secreted onto the surface of the airspace until 32 to 34 weeks gestation, and this process depends on many factors (e.g., stress, cortisol, thyroid). Insufficient levels of surfactant result in alveolar wall instability and alveolar collapse at end-expiration.

Preterm infants are unable to maintain adequate rhythmic breathing after birth, and apneic episodes may be frequent. Moreover, preterm infants have increased work of breathing compared with full-term infants because a greater force is required to expand their alveoli and prevent collapse. The highly compliant thoracic cage prevents chest wall fixation during inspirations, so that negative intrathoracic pressure causes inward motion of the thorax and less effective expansion of the lung.

Full-term neonates respond to hypercapnia by increasing ventilation similar to adults. Although preterm babies initially hyperventilate, this response is transitory and overall they have a depressed carbon dioxide response curve ( Frantz et al., 1976 ). The sensitivity to carbon dioxide increases with gestational age and postnatal age. A brief exposure to hypoxia is similar, and can result in transient hyperventilation but is followed by hypoventilation, periodic breathing, or apnea ( Rigatto et al., 1975 ; Gerhardt and Bancalari, 1984 ).

The Hering-Breuer reflex (inflation of the lung resulting in apnea) is more prominent in preterm than in full-term infants. Transient apnea, lasting 5 to 10 seconds, is common, and prolonged apnea, exceeding 20 seconds, also occurs. Periodic breathing occurs in most preterm babies but becomes less frequent after 36 weeks gestation ( Kelly and Shannon, 1981 ) (see Chapter 2 , Respiratory Physiology in Infants and Children). Premature infants spend much of their time in rapid eye movement (REM) sleep, during which respiratory muscles relax and paradoxical movements of the rib cage and diaphragm develop. However, periodic breathing or apneic spells are more frequent during non-REM sleep. Even when they are awake, preterm infants have a large dead space-to-tidal volume (VD/VT) ratio because of uneven distribution of ventilation and capillary perfusion.

A high incidence of RDS (i.e., hyaline membrane disease) occurs among preterm infants because of an inadequate amount of pulmonary surfactant in immature lungs. Infants with RDS have increased Paco2, resulting in respiratory acidosis, and ventilation-perfusion imbalance, causing hypoxemia. Shunting through a PDA or foramen ovale may exaggerate hypoxemia. If congestive heart failure develops metabolic acidosis may follow. These infants often need respiratory support, including oxygen, and continuous positive airway pressure (CPAP) or intermittent positive-pressure ventilation (IPPV) with PEEP. The complications that occur during treatment of these infants include pneumothorax, pneumomediastinum, pulmonary interstitial emphysema, subglottic stenosis, and chronic lung disease. Although chronic lung disease is uncommon among term infants, disorders that require supplemental oxygen and mechanical ventilation, such as meconium aspiration and tracheoesophageal fistula, can produce a clinical picture similar to that seen in the ex-premature infant.

For the most part, chronic lung disease of infancy is a disorder that results from injury, repair, and abnormal development of premature lungs. Most infants who develop sequelae secondary to RDS are less than 30 weeks' gestation and require mechanical ventilatory support during the first week of life. The infant born at less than 26 weeks' gestation is at very high risk for the development of chronic lung disease.

Chronic Lung Disease Versus the “New Bronchopulmonary Dysplasia”

In 1967, Northway and others (1967) first described BPD, a chronic lung disease that developed in some preterm infants exposed to oxygen and positive pressure ventilation. In the original group of infants described by Northway and others, none were less than 31 weeks' gestation and only one weighed less than 1500 g.

Traditionally, the definition of BPD is based on the clinical and radiographic criteria proposed by Bancalari and others (1979) , as follows:



Mechanical ventilation during more than 3 days in the first week of life



Persistence of oxygen dependence after 28 days



Radiographic abnormalities characterized by patchy density with areas of hyperlucency

The term “chronic lung disease” continues to evolve as the mortality of the less-than-28-week-gestation infant improves, as the physiology and pathology of the “new BPD” are defined, and as the use of oxygen is standardized for the ex-premature ( Shennan et al., 1988 ).

The simplest strategy is to consider chronic lung disease of infancy as abnormal lung function with an abnormal chest radiograph identified in the first 3 to 4 months after birth. This definition includes BPD. Classically, BPD was considered to be caused by RDS and to evolve as a consequence of the repair process. This repair process resulted in parenchymal fibrosis, chronic inflammation, airway epithelial metaplasia, and smooth muscle hypertrophy. The chest radiographs typically had areas of overinflation as well as areas of volume loss consistent with fibrosis ( Fig. 16-19 ).


FIGURE 16-19  The pathologic description of classic chronic disease or “old BPD” is a fibroproliferative process with epithelial metaplasia, interstitial fibrosis, and air space obliteration from the fibrosis. This correlates with the radiologic findings of nonhomogeneity of the lung parenchyma with densities secondary to volume loss from fibrosis extending to the periphery coexisting with cystic emphysema (note cysts in both lung bases, right > left) and hyperinflation (note the flattened diaphragms). This is a pattern of repair of and response to injury.



Current evidence confirms that a variety of factors interact synergistically to disrupt normal lung growth and development—genetics, hypoxia, hyperoxia, mechanical ventilation, steroids, and, unequivocally, inflammatory mediators. Chronic lung disease is the cumulative outcome of these multiple exposures ( Jobe and Bancalari, 2001 ). As survival of ELBW infants has increased, and as the respiratory support of these infants has evolved in the era of surfactant therapy, a “new BPD” has been recognized both clinically and pathologically. First, these infants born after 1990 often are much less mature at birth than were the infants born in the 1970s and 1980s. That is, lung development at 24 to 27 weeks gestation is in the canalicular stage, and that at 31 to 34 weeks, the saccular stage. Second, because of artificial surfactant and prenatal glucocorticoids (betamethasone administered to the mother), the acute respiratory disease of the premature newborn is less severe. In fact, some infants who have never had classic RDS develop chronic lung disease. These infants develop oxygen dependency later and, in some cases, progress to require ventilatory support. Third, the characteristic fibroproliferative pattern of BPD is not seen in those surfactant-treated infants who have less severe acute pulmonary disease. Instead, the pathology in these infants is one of abnormal growth of both alveoli and vasculature ( Hussain et al., 1998 ; Jobe and Bancalari, 2001 ). Alveoli are large and fewer in number, and the elastic tissue is abundant. Airways are free of epithelial metaplasia, and lung inflation is more uniform. This pattern has been documented in animal models and human infants ( Chambers and Van Velzen, 1989 ; Coalson et al., 1999 ). The chest radiograph characteristically shows a uniform pattern, unlike that of “classic BPD” where there are areas of patchy density with areas of hyperlucency.

The striking effects on alveolar growth in the “new BPD” imply a fundamental interference with a signaling pathway that is essential for normal lung development ( Fig. 16-20 ). These signaling pathways can be affected by genetics, inflammation, infection, mechanical ventilation, and oxygen toxicity. The role of genetics has not been clearly defined, but fibroblast growth factor 10, transforming growth factor β, surfactant proteins, TNF-α converting enzyme, hoxa5 gene, ENaC, cytochrome P450 1A2, and glucocorticoid receptors have all been associated with the disease ( Nogee et al., 1994 ; Ramet et al., 2000 ; Copland and Post, 2002 ; Hallman and Haataja, 2003 ).


FIGURE 16-20  The abnormal pathology in the “new BPD” is abnormal growth of alveoli and vasculature, dilation of distal sites of gas exchange (alveolar ducts) but without prominent fibrosis. This correlates with a fine, hazy uniform parenchymal pattern with modest hyperinflation but no cysts. This is a pattern of arrested development.



Infection and inflammation seem to play a critical role in the etiology of preterm delivery as well as subsequent chronic lung disease. Chorioamnionitis has been associated with preterm delivery, but its role in the subsequent development of chronic lung disease in this high-risk population has only been recently hypothesized ( Gomez et al., 1998 ; Yoon et al., 1999 ; Schmidt et al., 2001 ). In addition to the high levels of interleukin (IL)-1 and IL-6 in fetal cord blood and a significant presence of inflammatory cells, IL-8 mRNA has been detected in the fetal lung of infants who later develop chronic lung disease ( Schmidt et al., 2001 ).

Yoon and others (1999) noted that chorioamnionitis was easily detected in 92% of the placentas from preterm infants who developed BPD and 62% of those who did not. IL-1β, IL-6, and IL-8 were in the amniotic fluid within 5 days of preterm delivery and were predictive of subsequent development of BPD. Similar findings have been reported with TNF-α ( Hitti et al., 1997 ). Chorioamnionitis may play a role in fetal lung injury as a result of systemic effects as well as direct effects on the lungs, as supported by the detection of such mediators in cord blood. Thus, chorioamnionitis may induce lung maturation in the fetus but simultaneously sets the stage for chronic lung disease ( Shimoya et al., 2000 ).

In addition to the data relating chorioamnionitis to chronic lung disease, reports have proposed that proinflammatory cytokines are critical in the initial postnatal response to lung injury in the preterm infant ( Groneck et al., 1994 ; Tullus et al., 1996 ; Jonsson et al., 1997 ). For example, in one report, TNF-α and several interleukins (IL-1β, IL-6, and IL-8) were measured daily in tracheobronchial aspirate fluid of 28 infants born at less than 34 weeks' gestation ( Jonsson et al., 1997 ). Infants meeting appropriate criteria were treated with surfactant. In the 17 infants who developed chronic lung disease, significant increases in concentrations of TNF-α, IL-6, and IL-8 were obtained on days 2 and 3. TNF-α, IL-6, and IL-8 concentrations were significantly related to gestational age and duration of supplemental oxygen as well as to time receiving ventilatory support. IL-8 concentration decreased in infants with resolving RDS, whereas the infants who developed chronic lung disease had a sustained secretion of IL-8 (Groneck et al., 1994 ; Tullus et al., 1996 ; Jonsson et al., 1997 ). Other cytokine actors identified in high concentrations in the airways of infants with BPD include anaphylatoxin C5a, leukotriene C4, platelet-activating factor, intercellular adhesion molecule-1 (ICAM-1), fibronectin, elastin degradation products, 5-hydroxyeicosatetranoic acid, IL-16, monocyte chemotactic protein, and macrophage inflammatory protein-1α.

Mechanical ventilation itself influences the development of chronic lung disease. Even after surfactant administration, mechanical ventilation initiates and sustains an inflammatory reaction. For example, the normal preterm lung is populated with few white cells (either macrophages or granulocytes). The influx of granulocytes into the alveoli of preterm infants after mechanical ventilation has been measured as soon as 1 hour of age; these infants have a higher incidence of BPD ( Ferreira et al., 2000 ). Neutrophils release cytokines and initiate an inflammatory cascade that is associated with a higher incidence of BPD.

Hyperoxia produces lung injury at any stage of development but may be particularly insulting to the immature lung because of insufficiency of several systems that are important in protecting tissues from oxygen toxicity. This inadequate antioxidant state, coupled with exposure to higher oxygen concentrations than in the intrauterine environment, presents the premature infant with an excessive physiologic oxygen load. The resultant excess free radicals induce inflammation and damage to cellular lipids, proteins, and carbohydrates. Clearly, the preterm infant is predisposed to an oxidant/antioxidant imbalance. Of particular importance, antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase) develop on a time scale similar to surfactant, so that the level of these antioxidants normally rises rapidly just before birth ( Frank and Sosenko, 1987 ). In addition to its effects on antioxidant systems, hyperoxia inhibits surfactant synthesis, normal protein synthesis ( Jornot et al., 1987 ), and DNA synthesis ( Clement et al., 1985 ), as well as producing pulmonary vascular reactivity ( Newman et al., 1983 ).


Prematurity with or without RDS and with or without chronic lung disease is associated with long-term pulmonary sequelae. In addition to spirometric pulmonary assessments, exercise tolerance and diffusion of gases during exercise have helped define the functional impact of residual respiratory abnormalities in the ex-premature ( Jacob, 1997) . Seven- to 8-year-old children who had BPD after preterm birth had lower gas transfer compared with children who had been born at term or had been born prematurely but had no chronic lung disease ( Mitchell et al., 1998 ). During exercise, only survivors of BPD had wheezing or oxygen desaturation. In a study by Jacob and others (1997) , ex-premature infants with a history of severe BPD, ex-premature infants who had had RDS but no BPD, and healthy term infants were studied at ages 9 to 12 years. The BPD group used a greater percentage of their “ventilatory reserve” (VEmax/40 forced expiratory volume in 1 second [FEV1]) during exercise, especially those children with the lowest FEV1( Jacob et al., 1997 ). Other studies ( Bader et al., 1987 ; Parat et al., 1995 ; Santuz et al., 1995 ) have documented that children with a history of mild BPD do not have decreased exercise capacity compared with other survivors of neonatal mechanical respiratory support but that the BPD groups did have a greater incidence of oxygen desaturation during exercise.

Postmortem assessment of morphometric lung development has confirmed the drastic restriction in the number of alveoli in survivors of BPD compared with that in normal infants. The total number of alveoli in a 22-month-old (31.1 million) and a 28-month-old (40.4 million) was less than that in a normal 1-week-old (67.2 million) ( Margraf et al., 1991 ). Of course, infants who die from chronic lung disease may have more dramatic morphometric abnormalities than the less severely affected survivors.

These postmortem studies of infants with chronic lung disease also documented an abnormal architecture of elastic fibers, the framework on which new alveoli develop. Elastic fiber damage is primarily linked to oxygen damage and an increased activity of elastase ( Bruce et al., 1985 ). With damage to the cellular matrix, further deposition of collagen and elastin is erratic. Although the effects of prematurity on the molecular mechanisms of lung growth are not clearly defined, the consequences of decreased alveolar surface area and airway hyperreactivity have significant clinical implications.

Pulmonary Function During the First 2 Years After Preterm Birth

Chronic lung injury secondary to prematurity characteristically includes decreased vital capacity, obstruction of small airways, chest hyperinflation, and reactive airway disease. Over the first 1 to 2 years of life, the ex-premature infant often has respiratory compromise. Reactive airway disease is common and is exacerbated by frequent infections ( Greenough et al., 1990 ; Parat et al., 1995 ; Smyth et al., 1995 ;Tarpy and Celi, 1995 ; Walther et al., 1995 ; Tait et al., 2001 ). Oxygen therapy may be necessary for months to years in order to maintain oxygen saturation between 90% and 95%. Bronchodilators and diuretics are often mainstays of therapy for these infants. Significant hypoxemia often accompanies respiratory infections, and hospital admission and readjustment of medications are frequently needed. Finally, aspiration associated with gastroesophageal reflux can lead to acute/recurrent pulmonary deterioration ( Greenough et al., 1990 ; Radford et al., 1996 ).

Function in School-Aged and Older Ex-Premature Infants

In 1990, Northway and others (1990) presented follow-up of 26 patients from their original cohort ( Northway et al., 1967 ). These patients were ( Northway et al., 1990 ) between the ages of 14 and 23 years. None of these patients had been less than 1500 g or less than 30 weeks' gestation. Seventy-six percent had pulmonary dysfunction (i.e., abnormalities on pulmonary function tests or reactive airway disease, or both). Airway obstruction was noted in 68%, with 24% having fixed airway obstruction. Although all were “leading normal lives” and usually asymptomatic, the patients who had had BPD had more episodes of wheezing and pneumonia, limitation of exercise, and long-term medication use.

Now, 10 years after the introduction of surfactant and with improved modes of ventilation, studies have examined the pulmonary function of school-aged ex-premature infants. These infants can be divided into two groups: surfactant-treated ex-premature infants and non-surfactant-treated ex-premature infants. The pulmonary function tests in school-aged ex-premature infants with chronic lung disease who did not receive surfactant at birth were measured serially between 6 and 10 years of age and at 11 and 18 years of age. At the final testing period, pulmonary function tests revealed normal total lung capacity (TLC) and vital capacity (VC), but these values had improved over the time course of the repeated pulmonary function studies. Residual volume (RV) and RV/TLC decreased over time, suggesting gradual improvement in air trapping ( Koumbourlis et al., 1996 ). The peak expiratory flow rate (PEFR), FEV1, and the ratio FEV1/FVC remained at or above the normal range in all patients. FEF25-75(forced expiratory flow), FEF50, and FEF75 were decreased in 50% of these patients. The lower values are suggestive of relatively small airways obstruction. Regardless, most children in both groups responded to inhaled bronchodilator treatment.

Lung volume abnormalities gradually normalized in this group of ex-premature infants with chronic lung disease, and this process continued well into adolescence. Chronic airflow obstruction is common but not present in all ex-premature infants with the diagnosis of chronic lung disease. That school-aged ex-premature infants who had the diagnosis of BPD as neonates have severe functional abnormalities is well established ( Bertrand et al., 1985 ; MacLusky et al., 1986 ). What is of particular note is that prematurely born infants who had no significant lung disease in the newborn period may develop obstructive airway disease that persists into early childhood ( MacLusky, 1986) .

The pulmonary function tests in school-aged ex-premature infants who received surfactant at birth reveal that FVC, FEV1, and FRC are within normal limits (similar to values obtained in a group who had not received surfactant). Airway resistance (Raw) was slightly elevated, and MEF25(maximum expiratory flow, 25% lung volume) was slightly decreased, suggestive of mild lower airway obstruction. In addition, similar to studies in non-surfactant-treated VLBW infants, exercise challenge elicited bronchial reactivity. These data reveal little effect of surfactant on VLBW infants (25 to 30 weeks gestation) from the viewpoint of long-term pulmonary function at 6 to 7 years of age ( Gappa et al., 1999 ).

In summary, (1) greater than 90% of children who had been diagnosed with chronic lung disease at 36 weeks postconceptual age had documented airway obstruction at follow-up; (2) the incidence of β-agonist responsive airway obstruction in ex-preterm infants is striking: 45% in surfactant-treated and 67% in the placebo group, compared with 0% in children who had been born at term; (3) the incidence of chronic lung disease was not different after surfactant treatment; and (4) the duration of intubation and oxygen therapy, with or without surfactant therapy, correlated with pulmonary outcome ( Pelkonen et al., 1998 ).

Postanesthetic Apnea

Preterm and ex-premature infants (“ex-premies”) undergoing elective surgery are more likely to encounter perioperative apnea ( Gregory, 1981 ; Steward, 1982 ) than are term infants. Many such infants have a history of idiopathic apnea in the neonatal intensive care nursery, and this has been correlated with a higher susceptibility to life-threatening apnea in the postoperative period ( Liu et al., 1983 ). Apnea (cessation of breathing for 20 seconds or longer) resulting in cyanosis and bradycardia occurs in 20% to 30% of preterm infants during the first month of life ( American Academy of Pediatrics, 1978) . Steward (1982) reported an 18% incidence of apnea in preterm infants (gestational age <38 weeks; postnatal age 3 to 28 weeks) during the first 12 hours after surgery.

A prospective study by Liu and others (1983) demonstrated that a history of apnea and a postconceptual age of less than 44 weeks were associated with prolonged postanesthetic apnea. Kurth and others (1987) found a 37% incidence of postanesthetic apnea (defined as cessation of breathing for longer than 15, rather than 20, seconds) in ex-premature infants whose postconceptual age varied from 32 to 55 weeks. The initial episode of apnea was found to occur as late as 12 hours after anesthesia. Kurth and others recommended that monitoring be continued in infants who develop apnea until they are apnea free for at least 12 hours if their postconceptual age is less than 60 weeks.

Welborn and others (1986) failed to demonstrate apnea in a group of healthy premature infants of less than 44 weeks postconceptual age undergoing general anesthesia for herniorrhaphy. They did find a 63.6% incidence of periodic breathing. Malviya and others (1993) noted that ex-premature infants younger than 44 weeks postconceptual age were at significantly greater risk for apnea than were infants older than 44 weeks. In the latter, Malviya and others determined the risk to be 3%. Coté and others (1995) , in a combined analysis of 255 patients taken from previously published studies, noted that with logistic regression the incidence of apnea decreased to 1% at 55 to 56 weeks postconceptual age. In addition, in this meta-analysis of neonates with postoperative apnea, Coté and others (1995) noted that the incidence of apnea was inversely related to both gestational age and postconceptual age. Infants who are 55 weeks postconceptual age and younger are at greatest risk, and anemia further increases the risk ( Fig. 16-21 ).


FIGURE 16-21  Predicted probability of apnea for all patients, by gestational age and weeks of postconceptual age. Patients with anemia are shown as the horizontal hatched line. Bottom marks indicate the number of data points by postconceptual age. The shaded boxes represent the overall rates of apnea for infants within that gestational age range. The probability of apnea was the same regardless of postconceptual age or gestational age for infants with anemia (horizontal hatched line).  (Redrawn from Coté CJ, Zaslavsky A, Downes JJ, et al.: Postoperative apnea in former preterm infants after inguinal herniorrhaphy: A combined analysis. Anesthesiology 82:807, 1995.)




Other factors predisposing an infant, especially a premature, to apnea include hypoglycemia, hypoxia, hyperoxia, sepsis, anemia, hypocalcemia, and environmental temperature changes ( Schute, 1977 ). Postoperative apnea occurring in preterm infants may also be related to the pharmacologic effects of general anesthesia and the immaturity of the central nervous system, including the respiratory center. In low concentrations, halothane can depress the chemoreceptor response to hypoxia ( Knill and Gelb, 1978 ) and depress intercostal muscle preferentially, thus reducing the functional residual capacity and increasing the risk of hypoxemia ( Tusiewicz et al., 1977 ; Motoyama et al., 1982 ). This, coupled with an immature response to hypoxia and hypercarbia, predisposes the premature infant to erratic respiratory responses in the perioperative period ( Rigatto, 1982 ).

Residual anesthesia may be an important contributing factor to the occurrence of apnea in preterm infants in the postoperative period. Moreover, the cartilaginous upper airway of the preterm infants predisposes these infants to upper airway obstruction ( Dransfield et al., 1983 ), which can be aggravated by the impact of residual anesthesia on the pharyngeal muscles. Elective surgery should be delayed, if possible, until the former preterm infant is older than 44 weeks postconceptual age ( Gregory and Steward, 1983 ). Infants younger than 44 weeks postconceptual age who need surgery must be individually evaluated. The type of surgery and the patient's gestational age and postconceptual age, hematocrit, and current cardiorespiratory function (oxygen and/or diuretic dependent, chronic lung disease, neurologic status) are all factors that must be considered when developing a perioperative plan for the ex-premature infant—in particular, admission for 24 to 36 hours for postoperative monitoring.


As an initial overview, neurologic morbidity associated with preterm birth can be divided into major and minor dysfunctions. The major impairments include “cerebral palsy,” mental retardation, sensorineural hearing loss, and visual abnormalities. Hydrocephalus or seizures often accompany serious neurologic dysfunction. These major disorders are apparent before the age of 2 years and often earlier if the deficit is profound and occur 2 to 5 times more frequently in VLBW infants. Data document that approximately 50,000 infants who weigh less than 1500 g are born in the United States annually ( Hack et al., 1996 ). At least 5% to 15% of these have spastic motor dysfunction, and intellectual abnormalities frequently accompany the motor problems. An additional 25% to 50% of VLBW infants have less significant (“minor”) developmental abnormalities, such as isolated intellectual or cognition problems, speech and language disorders, learning disabilities, difficulties with balance and coordination, perceptual problems, emotional instability, social competence, and selective attention deficits ( Volpe, 1997 ). In fact, these minor dysfunctions become more prevalent beyond infancy and with long-term follow-up are increasingly obvious.

From another viewpoint, 40% of all children with spastic motor deficits were born prematurely. In particular, spastic diplegia (with the legs more affected than the arms) is the most common syndrome of cerebral palsy seen in the ex-premature infant. About 70% of infants with spastic diplegia were born prematurely.

Discussing neurodevelopmental and functional outcome of the preterm infant without dividing this population into subgroups based on gestational age at birth provides limited insight into this important topic. Although follow-up data are limited and are available primarily for infants who are only 18 to 24 months past birth, these studies suggest that the group of infants born at the edge of survival (<500 to 600 g and 23 to 24 weeks gestational age) is at marked risk for neurologic and developmental problems.

The National Institute of Child Health and Human Development (NICHD) reported outcome studies at 18 to 22 months corrected age of 1480 ELBW infants according to 100-g weight categories (401 to 500, 501 to 600, 601 to 700, 701 to 800, 801 to 900, and 901 to 1000). For the entire cohort, 25% had an abnormal neurologic examination, 37% had a Bayley II Mental Developmental Index (MDI) of less than 70, and 29% had a Psychomotor Developmental Index (PDI) of less than 70 ( Vohr, 2000) .

In the many outcome studies across multiple developmental and behavioral domains, a consistent finding is that groups of premature children are less competent and score less well than do groups of full-term children ( Piecuch, 1998 ; Vohr, 2000) . On the other hand, individual premature children are not invariably less capable than individual full-term children; that is, individual developmental outcome remains difficult to accurately predict based on a type of neonatal course. Although the concept of “neurologic and developmental outcome” of the premature infant is extremely difficult to pinpoint during infancy, these developmental abnormalities are much more common when the birth weight of the AGA survivor moves further and further below 1000 g.


Gastroesophageal reflux is a common event in infants but usually resolves by 4 months to 1 year of age. Since the 1980s, gastroesophageal reflux has been recognized more frequently because of an increased awareness and because of improved diagnostic techniques. Normal gastroesophageal function is complex and depends on effective esophageal motility, coordinated relaxation and contractility of the lower esophageal sphincter, intraluminal pressure of the stomach, and effective contractility, allowing emptying of the stomach. Patients with neurologic disorders appear to have a high incidence of autonomic neuropathy, which delays esophagogastric transit and gastric emptying. In fact, esophageal dysmotility has been recognized in approximately one third of children with severe gastroesophageal reflux. Another high-risk group of infants is those with congenital anomalies of the esophagus. Symptomatic gastroesophageal reflux is estimated to occur in 30% to 80% of infants who have required surgical repair of esophageal atresia.

The symptoms of gastroesophageal reflux often are related to esophagitis (emesis, irritability), but a wide spectrum of manifestations have been described. For example, if the refluxed material contacts the upper or lower airway, laryngospasm, stridor, laryngitis, recurrent laryngotracheitis, apnea, chronic cough, otitis media, asthma, recurrent bronchitis, pneumonia, or a combination may occur. Infants often present with “failure to thrive.” Severe dental caries is an unusual, but not uncommon, presentation. Reflux occurs most commonly in the supine position, and thus is most common during sleep.

Neurologically impaired children are at high risk for having symptomatic gastroesophageal reflux, especially when the patient is fed via nasogastric tube or gastrostomy. In addition, delayed gastric emptying has been documented in infants and children with neurologic disorders and symptoms of gastroesophageal reflux. Although patients with upper airway obstruction and proximal gastroesophageal reflux can usually be managed successfully with medical therapy, some infants require fundoplication ( Conley et al., 1995 ). Most who require surgery were either premature or developmentally delayed, or both. In another study, 75% of children with symptomatic gastroesophageal reflux and delayed gastric emptying were neurologically impaired ( Papaila, 1989 ). Because of neurologic immaturity of the premature infant and higher incidence of neurologic abnormalities in the ex-premature infant, the incidence of gastroesophageal reflux is high in these groups and should be treated aggressively to minimize upper and lower respiratory complications in these populations who are already predisposed to pulmonary dysfunction.

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Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier


The neonate's ability to experience pain has become a topic frequently discussed by anesthesiologists, pediatricians, and other scientists. Those involved with neonatal anesthesia have witnessed clinical evidence of increased sympathetic discharge (tachycardia and elevation of blood pressure) after surgical stimulation in an inadequately anesthetized infant. Moreover, facial grimacing and motor movements have been observed in the absence of paralysis.

Available evidence suggests that the cortical and peripheral centers necessary for pain perception, as well as the pain pathways, are well developed late in gestation ( Anand and Hickey, 1987 ). Moreover, a neonate has an intact neuroendocrine response to stressful stimulation that is reflected in hormonal and metabolic changes. In a randomized, controlled trial of nitrous oxide-fentanyl (10 mcg/kg) anesthesia versus nitrous oxide alone in preterm neonates undergoing PDA ligation, the infants with nitrous oxide alone had a greater change in hormonal and fuel substrate levels in response to stress than did those treated with fentanyl ( Anand et al., 1987 ). Moreover, the group without fentanyl was more likely to have postoperative circulatory or metabolic complications, such as bradycardia, hypotension, glycosuria, metabolic acidosis, the need for ventilatory support, and intraventricular hemorrhage. Alterations in sleep-wake patterns and behavior (e.g., irritability) have also been documented by different investigators during circumcision ( Emde et al., 1971 ) or heel lancing ( Field and Goldson, 1984 ) performed without anesthesia. These behavioral changes may have prolonged effects on the neurologic and psychological development of neonates. In VLBW preterm infants at risk for BPD, developmental outcomes were improved when the intensity of stressful stimulation and sensory input were reduced in the intensive care unit ( Als et al., 1986 ).

Because of increased medical and public awareness regarding the adequacy of anesthetic techniques for premature infants and the physiologic alterations (increased right-to-left shunting, hypoxemia, acidosis, intraventricular hemorrhage) associated with stress and light anesthesia, anesthetic practices for neonates have been better defined. Consequently, several committees and sections of the American Academy of Pediatrics have proposed that anesthesia and analgesia be provided for neonates undergoing surgery. In moribund infants hemodynamically unable to tolerate anesthesia, the decision to withhold anesthetics should be based on the same medical criteria used for critically ill older patients ( Poland et al., 1987 ).

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Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier


Potent inhalation anesthetics can rarely be delivered to neonates, especially preterm infants, at a dose equivalent to or greater than MAC without producing unacceptable hemodynamic depression ( Yaster, 1987 ), even when decreasing the dose to compensate for the lower MAC values in preterm infants ( LeDez and Lerman, 1987 ; Lerman, 1988 ). In preterm infants who require postoperative ventilatory support, fentanyl, from 10 ( Yaster, 1987 ) to 50 mcg/kg (Robinson and Gregory, 1981 ), has been a safe and effective anesthetic.

In the early days of intensive care of newborns (1970s), infants sometimes received only nitrous oxide with or without low doses of other inhaled anesthetics during surgical procedure. Furthermore, the trachea of an awake infant often was intubated without sedation or after the infant received only a neuromuscular blocker. These techniques do not provide adequate anesthesia to ablate the stress response to surgery ( Booker, 1987 ; Hatch, 1987 ) or to other painful procedures. Premature and ex-premature infants may have dramatic responses to narcotics and potent inhaled anesthetics. Clearly, the benefit of providing adequate anesthesia and analgesia must be carefully balanced against the significant risk of cardiorespiratory depression in this fragile population. Titration of anesthetics to a desired effect, while carefully monitoring the cardiorespiratory status, is the goal. Developing and publishing simple protocols defining and recommending specific doses of drugs for this high-risk group of patients are impossible. These infants have wide variability in their responses to anesthetics and sedatives, and frequently experience exaggerated and unpredictable effects not observed in older infants and children.


Since the 1990s, caudal epidural block with bupivacaine has been accepted as an effective and safe option to provide intraoperative and postoperative analgesia after lower abdominal surgery, particularly in preterm and ex-premature infants who had been treated for chronic respiratory failure in the neonatal intensive care unit ( Booker, 1988 ; Rice et al., 1988 ; see also Chapter 13 , Pain Management). Typically, such an infant undergoes an inhalational induction consisting of nitrous oxide and sevoflurane (low inhaled concentrations, titrated as tolerated) delivered by mask. After intravenous access is established, some anesthesiologists administer an intermediate-acting, nondepolarizing muscle relaxant in order to facilitate intubation of the trachea and to avoid high doses of a potent inhaled agent. For a noninvasive surgical procedure such as a hydrocele repair or an inguinal herniorrhaphy, routine monitors are adequate. After the trachea is intubated and the endotracheal tube is properly positioned and secured, anesthesia is maintained with nitrous oxide (60% to 70%) and a potent inhaled anesthetic in a concentration that preserves hemodynamic stability. The infant can then be placed in the lateral position and a caudal block placed using a 22-gauge “block” needle or an angiocath. In most cases, 1 mL/kg of 0.25% or 0.125% bupivacaine (1.25 to 2.5 mg/kg) is given as a bolus. An addition of epinephrine (5 mcg/mL) prolongs the analgesic effect to up to 3.5 hours.

The use of spinal anesthesia for herniorrhaphy in premature infants less than 36 weeks gestational age recovering from RDS is reportedly a safe and satisfactory alternative to general anesthesia. Respiratory problems occurred in 2 of 20 patients, however, and “intensive postoperative monitoring” was recommended ( Harnik et al., 1986 ). The use of combined spinal and epidural anesthesia for major abdominal surgery in infants has also been reported by Williams and others (1997).

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Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier


For newborns to survive the transition from fetal to extrauterine life, critical multisystem developmental adaptation must occur. Congenital anomalies and acquired disease states requiring anesthetic and surgical intervention may deter this orderly physiologic transition. Those involved with anesthetic care of neonates must acquire and maintain an in-depth knowledge of developmental physiology as well as an understanding of the effects of immaturity on anesthetic and monitoring requirements. The pediatric anesthesiologist must assimilate this information and thoughtfully apply it to the practice of neonatal anesthesia.

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Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier


Adamsons and Towell, 1965. Adamsons Jr K, Towell ME: Thermal homeostasis in the fetus and newborn.  Anesthesiology  1965; 26:531.

Ahmed et al., 1998. Ahmed T, Ein S, Moore A: The role of peritoneal drains in treatment of perforated necrotizing enterocolitis: recommendations from recent experience.  J Pediatr Surg  1998; 33:1468-1470.

Albanese et al., 1998. Albanese CT, Lopoo J, Goldstein RB, et al: Fetal liver position and perinatal outcome for congenital diaphragmatic hernia.  Prenat Diagn  1998; 18:1138-1142.

Al-Kharfy et al., 1996. Al-Kharfy T, Smyth JA, Wadsworth L, et al: Erythropoietin therapy in neonates at risk of having bronchopulmonary dysplasia and requiring multiple transfusions.  J Pediatr  1996; 129:89-96.

Als et al., 1986. Als H, Lawhon G, Brown E, et al: Individualized behavioral and environmental care for the very low birth weight preterm infant at high risk for bronchopulmonary dysplasia: Neonatal intensive care unit and developmental outcome.  Pediatrics  1986; 78:1123.

American Academy of Pediatrics Task Force on Prolonged Apnea, 1978. American Academy of Pediatrics Task Force on Prolonged Apnea : Prolonged apnea.  Pediatrics  1978; 61:651.

Anand and Hickey, 1987. Anand KJS, Hickey PR: Pain and its effects in the human neonate and fetus.  N Engl J Med  1987; 317:1321.

Anand et al., 1987. Anand KJS, Sippel WG, Aynsley-Green A: Randomized trial of fentanyl anaesthesia in preterm babies undergoing surgery: Effects on the stress response.  Lancet  1987; 1:243.

Anderson, 1998. Anderson PAW: Physiology of the fetal, neonatal, and adult heart.   In: Polin RA, Fox WW, ed. Fetal and neonatal physiology,  Philadelphia: WB Saunders; 1998:837.

Anderson et al., 1984. Anderson PAW, Glick KL, Manring A, Crenshaw Jr C: Developmental changes in cardiac contractility in fetal and postnatal sheep: In vitro and in vivo.  Am J Physiol  1984; 247:H371-H379.

Anderson et al., 1995. Anderson PAW, Greig A, Mark TM, et al: Molecular basis of human cardiac troponin T isoforms expressed in the developing, adult, and failing heart.  Circ Res  1995; 76:681-686.

Anderson et al., 1998. Anderson PAW, Kleinman CS, Lister G, Talner NS: Fetal and neonatal physiology.   In: Polin RI, Fox WW, ed. Fetal and neonatal physiology,  Philadelphia: WB Saunders; 1998:856.

Aperia et al., 1979. Aperia A, Broberger O, Herin P, Zetterstrom R: Sodium excretion in relation to sodium intake and aldosterone excretion in newborn pre-term and full-term infants.  Acta Paediatr Scand  1979; 68:813-817.

Arant, 1978. Arant Jr BS: Developmental patterns of renal functional maturation compared in human neonates.  J Pediatr  1978; 92:705-712.

Avery, 1974. Avery ME: The lung and its disorders in the newborn infant,  ed 3. Philadelphia, WB Saunders, 1974.

Bader et al., 1987. Bader D, Ramos AD, Lew CD, et al: Childhood sequelae of infant lung disease: Exercise and pulmonary function abnormalities after bronchopulmonary dysplasia.  J Pediatr  1987; 110:693-699.

Baerg et al., 2003. Baerg J, Kaban G, Tonita J, et al: Gastroschisis: A sixteen-year review.  J Pediatr Surg  2003; 38:771-774.

Bain and Spoerel, 1973. Bain JA, Spoerel WE: Flow requirements for a modified Mapleson D system during controlled ventilation.  Can Anaesth Soc J  1973; 20:629.

Baird and MacDonald, 1981. Baird PA, MacDonald EC: An epidemiologic study of congenital malformations of the anterior abdominal wall in more than half a million consecutive live births.  Am J Hum Genet  1981; 33:470-478.

Ballard et al., 1979. Ballard JL, Novak KK, Driver M: A simplified score for assessment of fetal maturation of newly born infants.  J Pediatr  1979; 95:769-774.

Bancalari et al., 1979. Bancalari E, Abdenour G, Feller R, Gannon J: Bronchopulmonary dysplasia: Clinical presentation.  J Pediatr  1979; 95:819-823.

Barrett and Oliver, 1968. Barrett CT, Oliver Jr TK: Hypoglycemia and hyperinsulinism in infants with erythroblastosis fetalis.  N Engl J Med  1968; 278:1260.

Beals et al., 1992. Beals DA, Schloo BL, Vacanti JP, et al: Pulmonary growth and remodeling in infants with high-risk congenital diaphragmatic hernia.  J Pediatr Surg  1992; 27:997-1002.

Bedard and Kotagal, 1981. Bedard MP, Kotagal UR: Hypoglycemia in association with polycythemia.  Perinatol Neonatal  1981; 5:83.

Bell et al., 1978. Bell MJ, Ternberg JL, Geigin RD, et al: Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging.  Ann Surg  1978; 187:1-7.

Bergman et al., 1974. Bergman L, Kjellmer I, Selstam U: Calcitonin and parathyroid hormone: Relation to early neonatal hypocalcemia in infants of diabetic mothers.  Biol Neonate  1974; 24:151.

Bertrand et al., 1985. Bertrand JM, Riley SP, Popkin J, Coates AL: The long-term pulmonary sequelae of prematurity: The role of familial airway hyperreactivity and the respiratory distress syndrome.  N Engl J Med  1985; 312:742-745.

Bjorklund et al., 1997. Bjorklund LJ, Ingimarsson J, Curstedt T, et al: Manual ventilation with a few large breaths at birth compromises the therapeutic effect of subsequent surfactant replacement in immature lambs.  Pediatr Res  1997; 42:348-355.

Boheler et al., 1991. Boheler KR, Carrier L, de la Bastie D, et al: Skeletal actin mRNA increases in the human heart during ontogenic development and is the major isoform of control and failing adult hearts.  J Clin Invest  1991; 88:323-330.

Bohn et al., 1987. Bohn D, Tamura M, Perrin D, et al: Ventilatory predictors of pulmonary hypoplasia in congenital diaphragmatic hernia, confirmed by morphologic assessment.  J Pediatr  1987; 111:423.

Bollman et al., 1995. Bollman R, Kalache K, Mau H, et al: Associated malformations and chromosomal defects in congenital diaphragmatic hernia.  Fetal Diagn Ther  1995; 10:52-59.

Boloker et al., 2002. Boloker J, Bateman DA, Wung JT, Stolar CJ: Congenital diaphragmatic hernia in 120 infants treated consecutively with permissive hypercapnia/spontaneous respiration/elective repair.  J Pediatr Surg  2002; 37:357-366.

Booker, 1988. Booker PD: Management of postoperative pain in infants and children.  Curr Opin Anaesth  1988; 1:1-7.

Booker, 1987. Booker PD: Postoperative analgesia for neonates.  Anaesthesia  1987; 42:343.

Born et al., 1956. Born GVR, Dawes GS, Mott JC, et al: The constriction of the ductus arteriosus caused by oxygen and by asphyxia in newborn lambs.  J Physiol (Lond)  1956; 132:304.

Brady and Ceruti, 1966. Brady JP, Ceruti E: Chemoreceptor reflexes in the newborn infant: Effects of varying degrees of hypoxia on heart rate and ventilation in warmer environment.  J Physiol  1966; 184:631.

Brodsky, 1975. Brodsky JB: A simple method to determine patency of the ulnar artery intraoperatively prior to radial-artery cannulation.  Anesthesiology  1975; 42:626.

Bruce et al., 1985. Bruce MC, Wedig KE, Jentoft N, et al: Altered urinary excretion of elastin cross-links in premature infants who develop bronchopulmonary dysplasia.  Am Rev Respir Dis  1985; 131:568-572.

Bullard and Harrison, 1995. Bullard KM, Harrison MR: Before the horse is out of the barn: Fetal surgery for hydrops.  Semin Perinatol  1995; 19:462-473.

Burri, 1974. Burri PH: The postnatal growth of the rat lung. III. Morphology.  Anat Rec  1974; 178:711.

Cacciari et al., 2001. Cacciari A, Ruggeri G, Mordenti M, et al: High-frequency oscillatory ventilation versus conventional mechanical ventilation in congenital diaphragmatic hernia.  Eur J Pediatr Surg  2001; 11:3-7.

Caplan et al., 1990. Caplan M, Hsueh W, Kelly A, Donovan M: Serum PAF acetylhydrolase increases during neonatal maturation.  Prostaglandins  1990; 39:705-714.

Ceruti, 1966. Ceruti E: Chemoreceptor reflexes in the newborn infant: Effect of cooling on the response to hypoxia.  Pediatrics  1966; 37:556.

Chambers and Van Velzen, 1989. Chambers H, Van Velzen D: Ventilator-associated pathology in the extremely immature lung.  Pathology  1989; 21:79-83.

Charlton, 1993. Charlton AJ: The management of congenital diaphragmatic hernia without ECMO (review).  Paediatr Anaesth  1993; 3:201.

Chisholm et al., 1999. Chisholm CA, Heider AL, Kuller JA, et al: Prenatal diagnosis and perinatal management of fetal sacrococcygeal teratoma.  Am J Perinatol  1999; 16:89-92.

Choudhury et al., 1999. Choudhury SR, Ashcraft KW, Sharp RJ, et al: Survival of patients with esophageal atresia: Influence of birth weight, cardiac anomaly and late respiratory complications.  J Pediatr Surg  1999; 34:70-74.

Clark et al., 1998. Clark RH, Hardin Jr WD, Hirschl RB, et al: Current surgical management of congenital diaphragmatic hernia: A report from the Congenital Diaphragmatic Hernia Study Group.  J Pediatr Surg  1998; 33:1004-1009.

Claud and Walker, 2001. Claud EC, Walker WA: Hypothesis: Inappropriate colonization of the premature intestine can cause neonatal necrotizing enterocolitis.  FASEB J  2001; 15:1398-1403.

Clement et al., 1985. Clement A, Hubscher U, Junod AF: Effects of hyperoxia on DNA synthesis in cultured porcine aortic endothelial cells.  J Appl Physiol  1985; 59:1110-1116.

Clyman et al., 1977. Clyman RI, Heymann MA, Rudolph AM: Ductus arteriosus responses to prostaglandin E1 at high and low oxygen concentrations.  Prostaglandins  1977; 13:219.

Coalson et al., 1999. Coalson JJ, Winter VT, Siler-Khodr T, Yoder BA: Neonatal chronic lung disease in extremely immature baboon.  Am J Respir Crit Care Med  1999; 160:1333-1346.

Collins et al., 1977. Collins DL, Pomerance JJ, Travis KW, et al: A new approach to congenital posterolateral diaphragmatic hernia.  J Pediatr Surg  1977; 12:149.

Conley et al., 1995. Conley SF, Werlin SL, Beste DJ: Proximal pH-metry for diagnosis of upper airway complications of gastroesophageal reflux.  J Otolaryngol  1995; 24:295-298.

Copland and Post, 2002. Copland IB, Post M: Understanding the mechanisms of infant respiratory distress and chronic lung disease.  Am J Respir Cell Mol Biol  2002; 26:261-265.

Correia-Pinto et al., 2001. Correia-Pinto J, Tavares ML, Baptista MJ, et al: A new fetal rat model of gastroschisis: Development and early characterization.  J Pediatr Surg  2001; 36:213-216.

Coté et al., 1995. Coté CJ, Zaslavsky A, Downes JJ, et al: Postoperative apnea in former preterm infants after inguinal herniorrhaphy: A combined analysis.  Anesthesiology  1995; 82:807.

Crisera et al., 1999a. Crisera CA, Connelly PR, Marmureanu AR, et al: Esophageal atresia with tracheoesophageal fistula: Suggested mechanism in faulty organogenesis.  J Pediatr Surg  1999; 34:204-208.

Crisera et al., 1999b. Crisera CA, Connelly PR, Marmureanu AR, et al: TTF-1 and HNF-3β in the developing tracheoesophageal fistula: Further evidence for the respiratory origin of the ‘distal esophagus’.  J Pediatr Surg  1999; 34:1322-1326.

Cross and Oppe, 1952. Cross KW, Oppe TE: The effect of inhalation of high and low concentrations of oxygen on the respiration of premature infants.  J Physiol  1952; 117:38.

Cunniff et al., 1990. Cunniff C, Jones KL, Jones MC: Patterns of malformation in children with congenital diaphragmatic defects.  J Pediatr  1990; 116:258-261.

Dalton and Thompson, 1992. Dalton HJ, Thompson AE: Extracorporeal membrane oxygenation.   In: Fuhrman BP, Zimmerman JJ, ed. Pediatric critical care,  St Louis: Mosby–Year Book; 1992.

Dave et al., 1999. Dave S, Bajpai M, Gupta DK, et al: Esophageal atresia and tracheo-esophageal fistula: A review.  Indian J Pediatr  1999; 66:759-772.

Davies and Stringer, 1997. Davies BW, Stringer MD: The survivors of gastroschisis.  Arch Dis Child  1997; 77:158-160.

Desfrere et al., 2000. Desfrere L, Jarreau PH, Dommergues M, et al: Impact of delayed repair and elective high-frequency oscillatory ventilation on survival of antenatally diagnosed congenital diaphragmatic hernia: First application of these strategies in the more “severe” subgroup of antenatally diagnosed newborns.  Intensive Care Med  2000; 26:934-941.

Donovan, 1985. Donovan EF: Perioperative care of the surgical neonate.  Surg Clin North Am  1985; 65:1061.

Downes, 1974. Downes JJ: Respiratory care of the newborn: ASA refresher course.  Anesthesiology  1974; 2:65.

Dransfield et al., 1983. Dransfield DA, Spitzer AR, Fox WW: Episodic airway obstruction in premature infants.  Am J Dis Child  1983; 137:441.

Dudley and Phelan, 1976. Dudley NE, Phelan PD: Respiratory complications in long term survivors of esophageal atresia.  Arch Dis Child  1976; 51:279.

Emde et al., 1971. Emde RN, Harmon RJ, Metcalf D, et al: Stress and neonatal sleep.  Psychosom Med  1971; 33:491.

Fanaroff et al., 2003. Fanaroff AA, Hack M, Walsh MC: The NICHD Neonatal Research Network: Changes in practice and outcomes during the first 15 years.  Semin Perinatol  2003; 27:281-287.

Fanaroff et al., 1972. Fanaroff AA, Wald M, Gruber HS, Klaus MH: Insensible water loss in low birth weight infants.  Pediatrics  1972; 50:236.

Fasching et al., 1996. Fasching G, Huber A, Uray E, et al: Late follow-up in patients with gastroschisis.  Pediatr Surg Int  1996; 11:103-106.

Fauza and Wilson, 1994. Fauza DO, Wilson JM: Congenital diaphragmatic hernia and associated anomalies: Their incidence, identification, and impact on prognosis.  J Pediatr Surg  1994; 29:1113.

Ferreira et al., 2000. Ferreira PJ, Bunch TH, Albertine KH, Carlton DP: Circulating neutrophil concentration and respiratory distress in premature infants.  J Pediatr  2000; 136:466-472.

Fetterman et al., 1965. Fetterman GH, Shuplock NA, Philip FJ, Gregg HS: The growth and maturation of human glomeruli and proximal convolutions from term to childhood.  Pediatrics  1965; 35:601-619.

Field and Goldson, 1984. Field T, Goldson F: Pacifying effects of nonnutritive sucking on term and preterm neonates during heelstick procedures.  Pediatrics  1984; 74:1012.

Filston et al., 1982. Filston HC, Chitwood Jr WR, Schkolne B, Blackmon LR: The Fogarty balloon catheter as an aid to management of the infant with esophageal atresia and tracheoesophageal fistula complicated by severe RDS or pneumonia.  J Pediatr Surg  1982; 17:149.

Fisher et al., 1982. Fisher DM, O'Keefe C, Stanski DR, et al: Pharmacokinetics and pharmacodynamics of d-tubocurarine in infants, children, and adults.  Anesthesiology  1982; 57:203.

Fong et al., 1990. Fong YM, Marano MA, Moldawer LL, et al: The acute splanchnic and peripheral tissue metabolic response to endotoxin in humans.  J Clin Invest  1990; 85:1896-1904.

Frank and Sosenko, 1987. Frank L, Sosenko IR: Prenatal development of lung antioxidant enzymes in four species.  J Pediatr  1987; 110:106-110.

Frantz et al., 1976. Frantz III ID, Adler SM, Thach BT, et al: Maturational effects on respiratory responses to carbon dioxide in premature infants.  J Appl Physiol  1976; 41:41.

Friedman, 1972. Friedman WF: Neuropharmacologic studies of perinatal myocardium.  Cardiovasc Clin  1972; 4:43-57.

Friesen and Lichtor, 1983. Friesen RH, Lichtor JL: Cardiovascular effects of inhalation induction with isoflurane in infants.  Anesth Analg  1983; 62:411.

Friesen and Lichtor, 1982. Friesen RH, Lichtor LJ: Cardiovascular depression during halothane anesthesia in infants: A study of three induction techniques.  Anesth Analg  1982; 61:42.

Friis-Hansen, 1971. Friis-Hansen B: Body composition during growth: In vivo measurements and biochemical data correlated to differential anatomical growth.  Pediatrics  1971; 47(suppl):264-274.

Fryns et al., 1979. Fryns JP, Moerman F, Goddeeris P, et al: A new lethal syndrome with cloudy cornea, diaphragmatic defects and distal limb deformities.  Hum Genet  1979; 50:65-70.

Furchgott and Zawadzki, 1980. Furchgott RF, Zawadzki JV: The obligatory role of endothelial cells in relaxation of arterial smooth muscle by acetylcholine.  Nature  1980; 288:373-376.

Furman, 1987. Furman EB: Pediatric fluid management during anesthesia.  ASA Refresher Course Lectures  1987;226.

Furman et al., 1975. Furman EB, Roman DG, Lemmer LAS, et al: Specific therapy in water, electrolyte, and blood-volume replacement during pediatric surgery.  Anesthesiology  1975; 42:187.

Gandy et al., 1965. Gandy GM, Adamsons K, Cunningham N, et al: Thermal environment and acid-base homeostasis in human infants during the first few hours of life.  Arch Dis Child  1965; 40:465.

Gappa et al., 1999. Gappa M, Berner MM, Hohenschild S, et al: Pulmonary function at school-age in surfactant-treated preterm infants.  Pediatr Pulmonol  1999; 27:191-198.

Gauntlett et al., 1988. Gauntlett IS, Fisher DM, Hertzka RE, et al: Pharmacokinetics of fentanyl in neonatal humans and lambs: effects of age.  Anesthesiology  1988; 69:683-687.

Geggel and Reid, 1984. Geggel Rl, Reid LM: The structural basis of PPHN.  Clin Perinatol  1984; 2:525-549.

Georgeson et al., 2000. Georgeson KE, Inge TH, Albanese CT: Laparoscopically assisted anorectal pull-through for high imperforate anus—A new technique.  J Pediatr Surg  2000; 35:927-930.

Gerhardt and Bancalari, 1984. Gerhardt T, Bancalari E: Apnea of prematurity. I. Lung function and regulation of breathing.  Pediatrics  1984; 74:58.

German et al., 1977. German JC, Gazzaniga AB, Amlie R, et al: Management of pulmonary insufficiency in diaphragmatic hernia using extracorporeal circulation with a membrane oxygenator (ECMO).  J Pediatr Surg  1977; 12:905.

Goetzman et al., 1976. Goetzman BW, Sunshine B, Johnson JD, et al: Neonatal hypoxia and pulmonary vasospasm: Response to tolazoline.  J Pediatr  1976; 89:617.

Gomez et al., 1998. Gomez R, Romero R, Ghezzi F, et al: The fetal inflammatory response syndrome.  Am J Obstet Gynecol  1998; 179:194-202.

Greenough et al., 1990. Greenough A, Maconochie E, Yuksel B: Recurrent respiratory symptoms in the first year of life following preterm delivery.  J Perinat Med  1990; 18:489-494.

Greer et al., 2003. Greer JJ, Babiuk RP, Thebaud B: Etiology of congenital diaphragmatic hernia: the retinoid hypothesis.  Pediatr Res  2003; 53:726-730.

Gregory, 1981. Gregory GA: Outpatient anesthesia.   In: Miller RD, ed. Anesthesia,  New York: Churchill Livingstone; 1981.

Gregory et al., 1969. Gregory GA, Eger EI, Munson ES: The relationship between age and halothane requirements in man.  Anesthesiology  1969; 30:488-491.

Gregory and Steward, 1983. Gregory GA, Steward DJ: Life-threatening perioperative apnea in the ex-“premie.”.  Anesthesiology  1983; 59:495.

Groneck et al., 1994. Groneck P, Gotze-Speer B, Oppermann M, et al: Association of pulmonary inflammation and increased microvascular permeability during the development of bronchopulmonary dysplasia: A sequential analysis of inflammatory mediators in respiratory fluids of high-risk preterm neonates.  Pediatrics  1994; 93:712-718.

Hack et al., 1996. Hack M, Friedman H, Avroy A, Fanaroff MB: Outcomes of extremely low birth weight infants.  Pediatrics  1996; 98:931-937.

Hallman and Haataja, 2003. Hallman M, Haataja R: Genetic influences and neonatal lung disease.  Semin Neonatol  2003; 8:19-27.

Hammarlund et al., 1983. Hammarlund K, Sedin G, Stromberg B: Transepidermal water loss in newborn infants. VIII. Relation to gestational age and postnatal age in appropriate and small for gestational age infants.  Acta Paediatr Scand  1983; 72:721-728.

Hardesty et al., 1981. Hardesty RL, Griffith BP, Debski RF, et al: Extracorporeal membrane oxygenation. Successful treatment of persistent fetal circulation following repair of congenital diaphragmatic hernia.  J Thorac Cardiovasc Surg  1981; 81:556.

Harnik et al., 1986. Harnik EV, Hoy GR, Potolicchio S, et al: Spinal anesthesia in premature infants recovering from respiratory distress syndrome.  Anesthesiology  1986; 64:95.

Harrison et al., 1997. Harrison MR, Adzick NS, Bullard KM, et al: Correction of congenital diaphragmatic hernia in utero. VII. A prospective trial.  J Pediatr Surg  1997; 32:1637-1642.

Harrison et al., 1994. Harrison MR, Adzick NS, Estes JM, Howell LJ: A prospective study of the outcome for fetuses with diaphragmatic hernia.  JAMA  1994; 271:382-384.

Harrison et al., 1990. Harrison MR, Adzick NS, Longaker MT, et al: Successful repair in utero of a fetal diaphragmatic hernia after removal of herniated viscera from the left thorax.  N Engl J Med  1990; 322:1582-1584.

Harrison et al., 1978. Harrison MR, Bjordal RI, Langmork F, Knutrud O: Congenital diaphragmatic hernia: The hidden mortality.  J Pediatr Surg  1978; 13:227-230.

Harrison et al., 2003. Harrison MR, Keller RL, Hawgood SB, et al: A randomized trial of fetal endoscopic tracheal occlusion for severe fetal congenital diaphragmatic hernia.  N Engl J Med  2003; 349:1224-1916.

Harrison et al., 1993. Harrison MR, Langer JC, Adzick NS: Correction of congenital diaphragmatic hernia in utero. VI. Hard-earned lessons.  J Pediatr Surg  1993; 28:1411-1417.

Hatch, 1987. Hatch DJ: Analgesia in the neonate.  Br Med J  1987; 294:920.

Hazebroek et al., 1988. Hazebroek FWJ, Tibboel D, Bos AP, et al: Congenital diaphragmatic hernia: Impact of preoperative stabilization. A prospective pilot study in 13 patients.  J Pediatr Surg  1988; 23:1139.

Hecher and Hackeloer, 1996. Hecher K, Hackeloer BJ: Intrauterine endoscopic laser surgery for fetal sacrococcygeal teratoma.  Lancet  1996; 347:470.

Heiss et al., 1989. Heiss K, Manning P, Oldham KT, et al: Reversal of mortality for congenital diaphragmatic hernia with ECMO.  Ann Surg  1989; 209:225.

Hengerer et al., 1975. Hengerer AS, Strome M, Jaffe BF: Injuries to the neonatal larynx from long-term endotracheal tube intubation and suggested tube modification for prevention.  Ann Otol Rhinol Laryngol  1975; 84:764.

Heymann and Rudolph, 1975. Heymann MA, Rudolph AM: Control of the ductus arteriosus.  Physiol Rev  1975; 55:62.

Hinkle, 1983. Hinkle AJ: Awake neonatal laryngoscopy: Pre-oxygenation alone versus continuous oxygenation.  Anesthesiology  1983; 59:A437.

Hitti et al., 1997. Hitti J, Krohn MA, Patton DL, et al: Amniotic fluid tumor necrosis factor-alpha and the risk of respiratory distress syndrome among preterm infants.  Am J Obstet Gynecol  1997; 177:50-56.

Holliday and Segar, 1957. Holliday MA, Segar WE: The maintenance need for water in parenteral fluid therapy.  Pediatrics  1957; 19:823.

Hook and Bailie, 1979. Hook JB, Bailie MD: Perinatal renal pharmacology.  Annu Rev Pharmacol Toxicol  1979; 19:491-509.

Hubmayr, 2004. Hubmayr RD: The times are a-changin.  Anesthesiology  2004; 100:1-2.

Humphreys et al., 1967. Humphreys PW, Normand ICS, Reynolds EOR, et al: Pulmonary lymph flow and the uptake of liquid from the lungs of the lamb at the start of breathing.  J Physiol  1967; 193:1.

Hussain et al., 1998. Hussain AN, Siddiqui NH, Stocker JT: Pathology of arrested acinar development in postsurfactant BPD.  Hum Pathol  1998; 29:710-717.

Imai et al., 1994. Imai T, Kurland G, Wiener E, et al: Lung function in children after repair of severe neonatal congenital diaphragmatic hernia (CDH) and mechanical ventilation.  Am Rev Respir Dis  1994; 149:A547.

Jacob et al., 1997. Jacob SV, Lands LC, Coates AL, et al: Exercise ability in survivors of severe bronchopulmonary dysplasia.  Am J Respir Crit Care Med  1997; 155:1925-1929.

Jarmakani et al., 1982. Jarmakani JM, Nakanishi T, Gerorge BL, Bers D: Effect of extracellular calcium ion myocardial mechanical function in the neonatal rabbit.  Dev Pharmacol Ther  1982; 5:1-13.

Jelsema et al., 1993. Jelsema RD, Isada NB, Kazzi NJ, et al: Prenatal diagnosis of congenital diaphragmatic hernia not amenable to prenatal or neonatal repair: Brachmann-de-Lange syndrome.  Am J Med Genet  1993; 47:1022-1023.

Jobe and Bancalari, 2001. Jobe AH, Bancalari E: Bronchopulmonary dysplasia.  Am J Respir Crit Care Med  2001; 163:1723-1729.

Johnson et al., 1967. Johnson DG, Deamer RM, Koop CE: Diaphragmatic hernia in infancy: Factors affecting the mortality rate.  Surgery  1967; 62:1082.

Jones and Pelton, 1976. Jones EP, Pelton DA: An index of syndromes and their anaesthetic implications.  Can Anaesth Soc J  1976; 23:207-225.

Jonmarker et al., 1987. Jonmarker C, Westrin P, Larsson S, Werner O: Thiopental requirements for induction of anesthesia in children.  Anesthesiology  1987; 67:104.

Jonsson et al., 1997. Jonsson B, Tullus K, Brauner A, et al: Early increase of TNF and IL-6 in tracheobronchial aspirate fluid indicator of subsequent chronic lung disease in preterm infants.  Arch Dis Child  1997; 77:F198-F201.

Jornot et al., 1987. Jornot L, Mirault ME, Junod AF: Protein synthesis in hyperoxic endothelial cells: Evidence for translational defect.  J Appl Physiol  1987; 63:457-464.

Karamanoukian et al., 1994. Karamanoukian HL, Click PL, Zayek M, et al: Inhaled nitric oxide in congenital hypoplasia of the lungs due to diaphragmatic hernia or oligohydramnios.  Pediatrics  1994; 94:715.

Karamanoukian et al., 1995. Karamanoukian HL, Glick PL, Wilcox DT, et al: Pathophysiology of congenital diaphragmatic hernia: XI. Anatomic and biochemical characterization of the heart in the fetal lamb CEH model.  J Pediatr Surg  1995; 30:925-928.

Karl, 1985. Karl HW: Control of life-threatening air leak after gastrostomy in an infant with respiratory distress syndrome and tracheoesophageal fistula.  Anesthesiology  1985; 62:670.

Keens et al., 1978. Keens TG, Bryan AC, Levison H, et al: Developmental pattern of muscle fiber types in human ventilatory muscles.  J Appl Physiol Respir Environ Exerc Physiol  1978; 44:909.

Kelly and Shannon, 1981. Kelly DH, Shannon DC: Treatment of apnea and excessive periodic breathing in the full-term infant.  Pediatrics  1981; 68:183.

Khatter and Hoeschen, 1982. Khatter JC, Hoeschen RJ: Developmental increase of digitalis receptors in guinea pig heart.  Cardiovasc Res  1982; 16:80-85.

King, 1982. King RJ: Pulmonary surfactant.  J Appl Physiol  1982; 53:1.

Kinsella and Abman, 1995. Kinsella JP, Abman SH: Recent developments in the pathophysiology and treatment of persistent pulmonary hypertension of the newborn.  J Pediatr  1995; 126:853.

Kinsella et al., 1992. Kinsella JP, Neish SR, Shaffer F, et al: Low-dose inhaled nitric oxide in persistent pulmonary hypertension of the newborn.  Lancet  1992; 340:819.

Knill et al., 1976. Knill R, Andrews W, Bryan AC, et al: Respiratory load compensation in infants.  J Appl Physiol  1976; 40:357.

Knill and Gelb, 1978. Knill RL, Gelb AW: Ventilatory responses to hypoxia and hypercapnia during halothane sedation and anesthesia in man.  Anesthesiology  1978; 49:244.

Kobayashi and Puri, 1994. Kobayashi H, Puri P: Plasma endothelin levels in congenital diaphragmatic hernia.  J Pediatr Surg  1994; 29:1258-1261.

Koch and Wendel, 1968. Koch G, Wendel H: Adjustment of arterial blood gases and acid base balance in the normal newborn infant during the first week of life.  Biol Neonate  1968; 12:136.

Koehntop et al., 1986. Koehntop DE, Rodman JH, Brundage DM, et al: Pharmacokinetics of fentanyl in neonates.  Anesth Analg  1986; 65:227.

Koivisto et al., 1972. Koivisto M, Blanco-Sequeiros M, Krause H: Neonatal symptomatic and asymptomatic hypoglycemia: A follow-up study of 151 children.  Dev Med Child Neurol  1972; 14:603.

Koren et al., 1985. Koren G, Butt W, Chinyanga H, et al: Post-operative morphine infusion in newborn infants: Assessment of disposition characteristics and safety.  J Pediatr  1985; 107:963.

Koumbourlis et al., 1996. Koumbourlis AC, Motoyama EK, Mutich RL, et al: Longitudinal follow-up of lung function from childhood to adolescence in prematurely born patients with neonatal chronic lung disease.  Pediatr Pulmonol  1996; 21:28-34.

Kupferberg and Way, 1963. Kupferberg HJ, Way EL: Pharmacologic basis for the increased sensitivity of the newborn rat to morphine.  J Pharmacol Exp Ther  1963; 141:105.

Kurth et al., 1987. Kurth CD, Spitzer AR, Broennle AM, Downes JJ: Postoperative apnea in preterm infants.  Anesthesiology  1987; 66:483.

Langham et al., 1987. Langham MR, Krummel TM, Bartlett RH, et al: Mortality with extracorporeal membrane oxygenation following repair of congenital diaphragmatic hernia in 93 infants.  J Pediatr Surg  1987; 22:1150.

Langston et al., 1984. Langston C, Kida K, Reed M, Thurlbeck WM: Human lung growth in later gestation and in the neonate.  Am Rev Respir Dis  1984; 129:607.

LeDez and Lerman, 1987. LeDez KM, Lerman J: The minimum alveolar concentration (MAC) of isoflurane in preterm neonates.  Anesthesiology  1987; 67:301.

Lerman, 1988. Lerman J: Anaesthesia in preterm and ex-preterm infants.  Curr Opin Anaesth  1988; 1:11.

Lerman et al., 1984. Lerman J, Gregory GA, Willis MM, Eger II EI: Age and solubility of volatile anesthetics in blood.  Anesthesiology  1984; 61:139-142.

Lerman et al., 1983. Lerman J, Robinson S, Willis MM, Gregory GA: Anesthetic requirements for halothane in young children 0–1 months and 1–6 months of age.  Anesthesiology  1983; 59:421-424.

Lerman et al., 1986. Lerman J, Schmitt-Bantel BI, Gregory GA, et al: Effect of age on solubility of volatile anesthetics in human tissues.  Anesthesiology  1986; 65:307-311.

Lesouef et al., 1984. Lesouef PN, England SJ, Bryan AC: Passive respiratory mechanics in newborns and children.  Am Rev Respir Dis  1984; 129:552-556.

Lévêque et al., 1994. Lévêque C, Hamza J, Berg AE, et al: Successful repair of a severe left congenital diaphragmatic hernia during continuous inhalation of nitric oxide.  Anesthesiology  1994; 80:1171.

Levin, 1987. Levin DL: Congenital diaphragmatic hernia: A persistent problem.  J Pediatr  1987; 111:390-392.

Levitt et al., 1997. Levitt MA, Patel M, Rodriguez G, et al: The tethered spinal cord in patients with anorectal malformations.  J Pediatr Surg  1997; 32:462.

Levy et al., 1977. Levy RJ, Rosenthal A, Freed MD, et al: Persistent pulmonary hypertension in a newborn with congenital diaphragmatic hernia: Successful management with tolazoline.  Pediatrics  1977; 60:740.

Lewis et al., 1997. Lewis DA, Reickert C, Bowerman R, Hirschl RB: Prenatal ultrasonography frequently fails to diagnose congenital diaphragmatic hernia.  J Pediatr Surg  1997; 32:352-356.

Liu et al., 1983. Liu LMP, Coté CJ, Goudsouzian NG, et al: Life-threatening apnea in infants recovering from anesthesia.  Anesthesiology  1983; 59:506.

Lockhart and Jenkins, 1972. Lockhart CH, Jenkins JJ: Ketamine-induced apnea in patients with increased intracranial pressure.  Anesthesiology  1972; 37:92.

Lockhart and Nelson, 1974. Lockhart CH, Nelson WL: The relationship of ketamine requirement to age in pediatric patients.  Anesthesiology  1974; 40:507.

Long et al., 1995. Long W, Zucker J, Kraybill E: Symposium on synthetic surfactant. II: Perspective and commentary.  J Pediatr  1995; 126:S1-S4.

Lou et al., 1979A. Lou HC, Lassen NA, Friis-Hansen B: Impaired autoregulation of cerebral blood flow in the distressed newborn infant.  J Pediatr  1979; 94:118-121.

Lou et al., 1979B. Lou HC, Lassen NA, Tweed WA: Pressure passive cerebral blood flow changes and breakdown of the blood-brain barrier in experimental fetal asphyxia.  Acta Paediatr Scand  1979; 68:57-63.

Lou et al., 2001. Lou HC, Lassen NA, Tweed WA, Volpe JJ: Intracranial hemorrhage: Germinal matrix-intraventricular hemorrhage of the premature infant.  Neurology of the newborn,  4th ed.. Philadelphia, WB Saunders, 2001. chap 11.

Lubchenco et al., 1963. Lubchenco L, Hansman C, Dressler M: Intrauterine growth as estimated from liveborn birth-weight data at 24 to 42 weeks of gestation.  Pediatrics  1963; 32:793.

Lund et al., 1994. Lund DP, Mitchell J, Kharasch V, et al: Congenital diaphragmatic hernia: The hidden morbidity.  J Pediatr Surg  1994; 29:258.

Lynn, 1985. Lynn A: Unusual conditions in paediatric anaesthesia.  Clin Anesthesiol  1985; 3:741.

MacLusky et al., 1986. MacLusky IB, Stringer D, Zarfen J, et al: Cardiorespiratory status in long-term survivors of prematurity with and without hyaline membrane disease.  Pediatr Pulmonol  1986; 2:94-102.

Mahony, 1988. Mahony L: Maturation of calcium transport in cardiac sarcoplasmic reticulum.  Pediatr Res  1988; 24:639-643.

Mahony and Jones, 1986. Mahony L, Jones LR: Developmental changes in cardiac sarcoplasmic reticulum in sheep.  J Biol Chem  1986; 261:15257-15265.

Malviya and Lerman, 1990. Malviya S, Lerman J: The blood/gas solubilities of sevoflurane, isoflurane, halothane, and serum constituent concentrations in neonates and adults.  Anesthesiology  1990; 72:793-796.

Malviya et al., 1993. Malviya S, Swartz J, Lerman J: Are all preterm infants younger than 60 weeks postconceptual age at risk for postanesthetic apnea?.  Anesthesiology  1993; 78:1076.

Margraf et al., 1991. Margraf LR, Tomashefski JF, Bruce MC, Dahms BB: Morphometric analysis of the lung in bronchopulmonary dysplasia.  Am Rev Respir Dis  1991; 143:391-400.

Marshall et al., 1984. Marshall TA, Deeder R, Pai S, et al: Physiologic changes associated with endotracheal intubation in preterm infants.  Crit Care Med  1984; 12:501.

Matoth et al., 1971. Matoth Y, Zaizov R, Varsano I: Postnatal chances in some red cell parameters.  Acta Paediatr Scand  1971; 60:317.

McDonald and Emery, 1959. McDonald MS, Emery JL: The later intrauterine and postnatal development of human glomeruli.  J Anat  1959; 93:331-340.

Metkus et al., 1995. Metkus AP, Esserman L, Sola A, et al: Cost per anomaly: What does a diaphragmatic hernia cost?.  J Pediatr Surg  1995; 30:226.

Mestan et al., 2005. Mestan KK, Marks JD, Hecox K, et al: Neurodevelopmental outcomes of premature infants treated with inhaled nitric oxide.  N Engl J Med  2005; 353:23-32.

Mildenberger and Versmold, 2002. Mildenberger E, Versmold HT: Pathogenesis and therapy of non-oliguric hyperkalaemia of the premature infant.  Eur J Pediatr  2002; 161:415-422.

Millar et al., 2003. Millar M, Wilks M, Costeloe K: Probiotics for preterm infants?.  Arch Dis Child Fetal Neonatal Ed  2003; 88:F354-F358.

Milligan and Levison, 1979. Milligan DWA, Levison H: Lung function in children following repair of tracheoesophageal fistula.  J Pediatr  1979; 95:24.

Milner, 1972. Milner RDG: Neonatal hypoglycemia: A critical reappraisal.  Arch Dis Child  1972; 47:679.

Mirkin, 1975. Mirkin BL: Perinatal pharmacology.  Anesthesiology  1975; 43:156.

Mitchell et al., 1998. Mitchell SH, Teague WG, Robinson A: Reduced gas transfer at rest and during exercise in school-age survivors of bronchopulmonary dysplasia.  Am J Respir Crit Care Med  1998; 157:1406-1412.

Miyasaka et al., 1984. Miyasaka K, Sankawa H, Nakajo T, Akiyama H: Congenital diaphragmatic hernia: Is emergency radical surgery really necessary.  Jpn J Pediatr Surg  1984; 16:1417.

Molik et al., 2001. Molik KA, Gingalewski CA, West KW, et al: Gastroschisis: A plea for risk categorization.  J Pediatr Surg  2001; 36:51-55.

Moodie et al., 1978. Moodie DS, Telander RL, Kleinberg F, Feldt RH: Use of tolazoline in newborn infants with diaphragmatic hernia and severe cardiopulmonary disease.  J Thorac Cardiovasc Surg  1978; 75:725.

Morray, 2002. Morray JP: Anesthesia-related cardiac arrest in children. An update.  Anesthesiol Clin North Am  2002; 20:1-28.

Morray et al., 2000. Morray JP, Geiduschek JM, Ramamoorthy C, et al: Anesthesia-related cardiac arrest in children: initial findings of the Pediatric Perioperative Cardiac Arrest (POCA) Registry.  Anesthesiology  2000; 93:6-14.

Motoyama et al., 1982. Motoyama EK, Brinkmeyer SD, Mutich RL, et al: Reduced FRC in anesthetized infants: Effect of low PEEP.  Anesthesiology  1982; 57:A418.

Muller and Bryan, 1979. Muller NL, Bryan AC: Chest wall mechanics and respiratory muscles in infants.  Pediatr C/in North Am  1979; 26:503.

Murat et al., 2004. Murat I, Constant I, Maud'huy H: Perioperative anaesthetic morbidity in children: a database of 24,165 anaesthetics over a 30-month period.  Paediatr Anaesth  2004; 14:158-166.

Muratore et al., 2001. Muratore CS, Kharasch V, Lund DP, et al: Pulmonary morbidity in 100 survivors of congenital diaphragmatic hernia monitored in a multidisciplinary clinic.  J Pediatr Surg  2001; 36:133-140.

Muratore et al., 2001a. Muratore CS, Utter S, Jaksic T, et al: Nutritional morbidity in survivors of congenital diaphragmatic hernia.  J Pediatr Surg  2001; 36:1171-1176.

Muratore et al., 2001b. Muratore CS, Utter S, Jaksic T, et al: Pulmonary morbidity in 100 survivors of congenital diaphragmatic hernia monitored in a multidisciplinary clinic.  J Pediatr Surg  2001; 36:133-140.

Murphy et al., 1981. Murphy ID, Rabinovitch M, Goldstein ID, Reid LM: The structural basis of persistent pulmonary hypertension of the new-horn infant.  J Pediatr  1981; 98:962.

Musemeche et al., 1986. Musemeche CA, Kosloske AM, Bartow SA, Umland ET: Comparative effects of ischemia, bacteria and substrate on the pathogenesis of intestinal necrosis.  J Pediatr Surg  1986; 21:536-538.

Muthuchamy et al., 1995. Muthuchamy M, Grupp II, Grupp G, et al: Molecular and physiological effects of overexpressing striated muscle β-tropomyosin in the adult murine heart.  J Biol Chem  1995; 270:30593-30603.

Nagaya et al., 1994. Nagaya M, Akatsuka H, Kato J: Gastroesophageal reflux occurring after repair of congenital diaphragmatic hernia.  J Pediatr Surg  1994; 29:1447.

Nakanishi et al., 1987. Nakanishi T, Okuda H, Kamata K, et al: Development of myocardial contractile system in the fetal rabbit.  Pediatr Res  1987; 22:201-207.

Nakayama et al., 1991. Nakayama DK, Motoyama EK, Tagge EM: Effect of preoperative stabilization on respiratory system compliance and outcome in newborn infants with congenital diaphragmatic hernia.  J Pediatr  1991; 118:793.

Nakayama et al., 1989. Nakayama DK, Mutich R, Rowe MI, Motoyama EK: Pulmonary function following primary closure of abdominal wall defects in the newborn and its improvement with bronchodilators.  Surg Forum  1989; 40:571.

Nassar et al., 1987. Nassar R, Reedy MC, Anderson PA: Developmental changes in the ultrastructure and sarcomere shortening of the isolated rabbit ventricular myocyte.  Circ Res  1987; 61:465-483.

Newman et al., 1983. Newman JH, Loyd JE, English DK, et al: Effects of 100% oxygen on lung vascular function in awake sheep.  J Appl Physiol  1983; 54:1379-1386.

Newman et al., 1990. Newman KD, Anderson KD, Van Meurs K, et al: Extracorporeal membrane oxygenation and congenital diaphragmatic hernia: Should any infant be excluded?.  J Pediatr Surg  1990; 25:1048.

Nielson and Jorgensen, 1978. Nielson OH, Jorgensen AF: Congenital posterolateral diaphragmatic hernia: Factors affecting survival.  Z Kinderchir  1978; 24:201.

Niems et al., 1976. Niems AH, Warner M, Loughnan PM, Aranda JV: Developmental aspects of the hepatic cytochrome P450 mono-oxygenase system.  Annu Rev Pharmacol Toxicol  1976; 16:427-445.

Nogee et al., 1994. Nogee LM, Garnier H, Dietz HC, et al: A mutation in the surfactant protein B gene responsible for fatal neonatal respiratory disease in multiple kindreds.  J Clin Invest  1994; 93:1860-1863.

Noland et al., 1995. Noland Jr TA, Guo X, Raynor RL, et al: Cardiac troponin I mutants: Phosphorylation by protein kinases C and A and regulation of Ca2+-stimulated MgATPase of reconstituted actomysin S-1.  J Biol Chem  1995; 270:25445-25454.

Norden et al., 1994. Norden MA, Butt W, McDougall P: Predictors of survival for infants with congenital diaphragmatic hernia.  J Pediatr Surg  1994; 29:1442.

Northway et al., 1990. Northway Jr WH, Moss RB, Carlisle KB, et al: Late pulmonary sequelae of bronchopulmonary dysplasia.  N Engl J Med  1990; 323:1793-1799.

Northway et al., 1967. Northway WH, Rosan RC, Porter DY: Pulmonary disease following respirator therapy of hyaline membrane disease.  N Engl J Med  1967; 276:357-368.

O'Neil and Grosfeld, 1974. O'Neil JA, Grosfeld JL: Intestinal malfunction after antenatal exposure of viscera.  Am J Surg  1974; 127:129.

Pacifica et al., 1986. Pacifica GM, Biani A, Teddeucci-Brunelli G, et al: Effects of development, aging, and renal and hepatic insufficiency as well as hemodialysis on the plasma concentrations of albumin and alpha 1 acid glycoprotein: Implications for binding of drugs.  Ther Drug Monit  1986; 8:259-263.

Padbury et al., 1981. Padbury JF, Diakomanolis ES, Lam RW, et al: Ontogenesis of tissue catecholamines in fetal and neonatal rabbits.  J Dev Physiol  1981; 3:297-303.

Paek et al., 2001. Paek BW, Jennings RW, Harrison MR, et al: Radiofrequency ablation of fetal sacrococcygeal teratoma.  Am J Obstet Gynecol  2001; 184:503-507.

Pagani and Julian, 1984. Pagani ED, Julian FJ: Rabbit papillary muscle myosin isozymes and the velocity of muscle shortening.  Circ Res  1984; 54:586-594.

Pang and Mellins, 1975. Pang LM, Mellins RB: Neonatal cardiorespiratory physiology.  Anesthesiology  1975; 43:171.

Papaila, 1989. Papaila JG: Increased incidence of delayed gastric emptying in children with gastroesophageal reflux. A prospective evaluation.  Arch Surg  1989; 124:933-936.

Papile et al., 1978. Papile L, Burnstein J, Burnstein R, et al: Incidence and evolution of subependymal and intraventricular hemorrhage: A study of infants with birth weights less than 1500 grams.  J Pediatr  1978; 92:529.

Papile et al., 1985. Papile LA, Rudolph AM, Heymann MA: Autoregulation of cerebral blood flow in the preterm fetal lamb.  Pediatr Res  1985; 19:159-161.

Pappert et al., 1995. Pappert D, Busch T, Gerlach H, et al: Aerosolized prostacyclin versus inhaled nitric oxide in children with severe acute respiratory distress syndrome.  Anesthesiology  1995; 82:1507.

Parat et al., 1995. Parat S, Moriette G, Delaperche M-F, et al: Long-term pulmonary functional outcome of bronchopulmonary dysplasia and premature birth.  Pediatr Pulmonol  1995; 20:289-296.

Peckham and Fox, 1978. Peckham CJ, Fox WW: Physiologic factors affecting pulmonary artery pressure in infants with persistent pulmonary hypertension.  J Pediatr  1978; 93:1005.

Pelkonen et al., 1998. Pelkonen AS, Hakulinen AL, Turpeinen M, Hallman M: Effect of neonatal surfactant therapy on lung function at school age in children born very preterm.  Pediatr Pulmonol  1998; 25:182-190.

Pena and Hong, 2000. Pena A, Hong A: Advances in the management of anorectal malformations.  Am J Surg  2000; 180:370-376.

Philip, 1975. Philip AGS: Oxygen plus pressure plus time: The etiology of bronchopulmonary dysplasia.  Pediatrics  1975; 55:44.

Piafsky and Woolner, 1982. Piafsky KM, Woolner M: The binding of basic drugs to α1-acid glycoprotein in cord serum.  J Pediatr  1982; 100:820-823.

Piecuch and Leonard, 1998. Piecuch RE, Leonard CH: Outcome of very preterm infants.  Contemp Rev Obstet Gynecol  1998; June:115-120.

Pinson et al., 1987. Pinson CW, Morton MJ, Thornburg KL: An anatomic basis for fetal right ventricular dominance and arterial pressure sensitivity.  J Dev Physiol  1987; 9:253-269.

Poland et al., 1987. Poland RL, Roberts RJ, Gutierrez-Mazorra JF, Fonkalsrud EW: Neonatal anesthesia.  Pediatrics  1987; 80:446.

Quan and Smith, 1973. Quan L, Smith DW: The VATER association: Vertebral defects, anal atresia, tracheoesophageal fistula with esophageal atresia, radial dysplasia.  Birth Defects  1973; 8:75.

Quinn et al., 1981. Quinn GE, Betts EK, Diamond GR, Schaeffer DB: Neonatal age (human) at retinal maturation.  Anesthesiology  1981; 55:A326.

Rabinowitz et al., 1989. Rabinowitz R, Peters MT, Vyas S, et al: Measurement of fetal urine production in normal pregnancy by real-time ultrasonography.  Am J Obstet Gynecol  1989; 161:1264-1268.

Rabinowitz et al., 2001. Rabinowitz SS, Dzakpasu P, Piecuch S, et al: Platelet-activating factor in infants at risk for necrotizing enterocolitis.  J Pediatr  2001; 138:81-86.

Rackow et al., 1961. Rackow H, Salanitre E, Green LT: Frequency of cardiac arrest associated with anesthesia in infants and children.  Pediatrics  1961; 28:697.

Radford et al., 1996. Radford PJ, Stillwell PC, Blue B, Hertel G: Aspiration complications in bronchopulmonary dysplasia.  Chest  1996; 107:185-188.

Raju et al., 1980. Raju TNK, Vidyasagar D, Torres C, et al: Intracranial pressure during intubation and anesthesia in infants.  J Pediatr  1980; 96:860.

Ramet et al., 2000. Ramet M, Haataja R, Marttila R, et al: Association between the surfactant protein A (SP-A) gene locus and respiratory-distress syndrome in the Finnish population.  Am J Hum Genet  2000; 66:1569-1579.

Raphaely and Downes, 1973. Raphaely RC, Downes Jr JJ: Congenital diaphragmatic hernia: Prediction of survival.  J Pediatr Surg  1973; 8:815.

Redmond et al., 1987. Redmond C, Heaton J, Calix J, et al: A correlation of pulmonary hypoplasia, mean airway pressure, and survival in congenital diaphragmatic hernia treated with extracorporeal membrane oxygenation.  J Pediatr Surg  1987; 22:1143.

Reickert et al., 1998. Reickert CA, Hirschl RB, Atkinson JB, et al: Congenital diaphragmatic hernia survival and use of extracorporeal life support at selected level III nurseries with multimodality support.  Surgery  1998; 123:305-310.

Reid and Hutcherson, 1976. Reid IS, Hutcherson RJ: Long-term follow-up of patients with congenital diaphragmatic hernia.  J Pediatr Surg  1976; 11:939.

Rice et al., 1988. Rice LJ, Pudimat MA, Hannallah RS: Timing of caudal block placement does not affect duration of postoperative analgesia in pediatric ambulatory surgical patients.  Anesthesiology  1988; 69:A771.

Richards et al., 1991. Richards IS, Kulkarni A, Brooks SM: Human fetal tracheal smooth muscle produces spontaneous electromechanical oscillations that are Ca2+ dependent and cholinergically potentiated.  Dev Pharmacol Ther  1991; 16:22-28.

Rigatto, 1982. Rigatto H: Apnea.  Pediatr Clin North Am  1982; 29:1105-1116.

Rigatto et al., 1975. Rigatto H, Brady JP, Verduzco R: Chemoreceptor reflexes in preterm infants. II. The effect of gestational and postnatal age on the ventilatory response to inhaled carbon dioxide.  Pediatrics  1975; 55:614.

Rigatto et al., 1975. Rigatto H, Verduzco RT, Cates DB: Effects of O2 on the ventilatory response to CO2 in preterm infants.  J Appl Physiol  1975; 39:896.

Rittler et al., 1996. Rittler M, Paz JE, Castilla EE: VACTERL association, epidemiologic definition and delineation.  Am J Med Gen  1996; 63:529-536.

Roberts et al., 1992. Roberts JD, Polaner DM, Lang P, et al: Inhaled nitric oxide in persistent pulmonary hypertension of the newborn.  Lancet  1992; 340:818.

Robinson and Abuhamad, 2000. Robinson JN, Abuhamad AZ: Abdominal wall and umbilical cord anomalies.  Clin Perinatol  2000; 27:947-978.

Robinson, 1996. Robinson RB: Review: Autonomic receptor-effector coupling during post-natal development.  Cardiovasc Res  1996; 31:E68-E76.

Robinson and Gregory, 1981. Robinson S, Gregory GA: Fentanyl-air-oxygen anesthesia for ligation of patent ductus arteriosus in preterm infants.  Anesth Analg  1981; 60:331-334.

Robinson et al., 1983. Robinson TF, Cohen-Gould L, Factor SM: Skeletal framework of mammalian heart muscle: arrangement of inter- and pericellular connective tissue structures.  Lab Invest  1983; 49:482-498.

Rollnick and Kaye, 1983. Rollnick BR, Kaye CI: Hemifacial microsomia and variants: Pedigree data.  Am J Med Genet  1983; 15:233-253.

Romero et al., 1972. Romero T, Covell J, Friedman WF: A comparison of pressure-volume relations of the fetal, newborn, and adult heart.  Am J Physiol  1972; 222:1285-1290.

Root and Harrison, 1976. Root AW, Harrison HE: Recent advances in calcium metabolism. I. Mechanism of calcium homeostasis.  J Pediatr  1976; 88:177-199.

Rosenberg et al., 1993. Rosenberg AA, Kennaugh J, Koppenhafer SL, et al: Elevated immunoreactive endothelin-1 levels in newborn infants with persistent pulmonary hypertension.  J Pediatr  1993; 123:109-114.

Rowe et al., 1974. Rowe MI, Lankau C, Newmark S: Clinical evaluation of methods to monitor colloid oncotic pressure in the surgical treatment of children.  Surg Gynecol Obstet  1974; 139:889.

Rudolph, 2000. Rudolph AM: Myocardial growth before and after birth: Clinical implications.  Acta Paediatr  2000; 89:129-133.

Rudolph and Yuan, 1966. Rudolph AM, Yuan S: Response of the pulmonary vasculature to hypoxia and H+ ion concentration changes.  J Clin Invest  1966; 45:399.

Saarenmaa et al., 2000. Saarenmaa E, Neuvonen PJ, Fellman V: Gestational age and birth weight effects on plasma clearance of fentanyl in newborn infants.  J Pediatr  2000; 136:767.

Sakai et al., 1987. Sakai H, Tamura M, Hosokawa Y, et al: Effect of surgical repair on respiratory mechanics in congenital diaphragmatic hernia.  J Pediatr  1987; 111:432-438.

Salem et al., 1973. Salem MR, Wong AY, Lin YH, et al: Prevention of gastric distention during anesthesia for newborns with tracheoesophageal fistulas.  Anesthesiology  1973; 38:82-83.

Santeiro et al., 1997. Santeiro ML, Christie J, Stromquist C, et al: Pharmacokinetics of continuous infusion fentanyl in newborns.  J Perinatol  1997; 17:135-139.

Santulli et al., 1975. Santulli TV, Schullinger JN, Heird WC, et al: Acute necrotizing enterocolitis in infancy: A review of 64 cases.  Pediatrics  1975; 55:376.

Santuz et al., 1995. Santuz P, Baraldi E, Zaramella P, et al: Factors limiting exercise performance in long-term survivors of bronchopulmonary dysplasia.  Am J Respir Crit Care Med  1995; 152:1284-1289.

Schlatter et al., 2003. Schlatter M, Norris K, Uitvlugt N, et al: Improved outcomes in the treatment of gastroschisis using a preformed silo and delayed repair approach.  J Pediatr Surg  2003; 38:459-464.

Schmidt et al., 2001. Schmidt B, Cao L, Mackensen-Haen S, et al: Chorioamnionitis and inflammation of the fetal lung.  Am J Obset Gynecol  2001; 194:173-177.

Schuster, 1967. Schuster SR: A new method for staged repair of large omphaloceles.  Surg Gynecol Obstet  1967; 125:837.

Schute, 1977. Schute FJ: Apnea.  Clin Perinatol  1977; 4:65.

Schwartz et al., 1994. Schwartz SM, Vermillion RP, Hirschl RB: Evaluation of left ventricular mass in children with left-sided congenital diaphragmatic hernia.  J Pediatr  1994; 125:447-451.

Seidner et al., 2001. Seidner SR, Chen YQ, Oprysko PR, et al: Combined prostaglandin and nitric oxide inhibition produces anatomic remodeling and closure of the ductus arteriosus in the premature newborn baboon.  Pediatr Res  2001; 50:365-373.

Senior, 1973. Senior B: Neonatal hypoglycemia.  N Engl J Med  1973; 289:790.

Shah et al., 1994. Shah N, Jacob T, Exler R, et al: Inhaled nitric oxide in congenital diaphragmatic hernia.  J Pediatr Surg  1994; 29:1010.

Sham et al., 1995. Sham JS, Hatem SN, Morad M: Species differences in the activity of the Na(+)-Ca2+ exchanger in mammalian cardiac myocytes.  J Physiol  1995; 488:623-631.

Shennan et al., 1988. Shennan AT, Dunn MS, Ohlsson A, et al: Abnormal pulmonary outcomes in premature infants: Prediction from oxygen requirement in the neonatal period.  Pediatrics  1988; 82:527-532.

Shimoya et al., 2000. Shimoya K, Taniguchi T, Matsuzaki N, et al: Chorioamnionitis decreased incidence of respiratory distress syndrome by elevating fetal interleukin-6 serum concentration.  Hum Reprod  2000; 15:2234-2240.

Shires et al., 1961. Shires T, Williams J, Brown F: Acute change in extracellular fluids associated with major surgical procedures.  Ann Surg  1961; 154:803.

Sigalet et al., 1994. Sigalet DL, Nguyen LT, Laberge JM, et al: Gastroesophageal reflux associated with large diaphragmatic hernias.  J Pediatr Surg  1994; 29:1262.

Simpson, 1985. Simpson P: Stimulation of hypertrophy of cultured neonatal rat heart cells through an α1-adrenergic receptor and induction of beating through an α1-β1-adrenergic receptor interaction: evidence for independent regulation of growth and beating.  Circ Res  1985; 56:884-894.

Singleton et al., 1987. Singleton MA, Rosen JI, Fisher DM: Plasma concentrations of fentanyl in infants, children, and adults.  Can J Anaesth  1987; 34:152-155.

Smith and Nelson, 1976. Smith CA, Nelson NM: The physiology of the newborn infant,  4th ed.. Springfield, IL, Charles C Thomas, Publisher, 1976.

Smyth et al., 1995. Smyth J, Allen A, MacMurray B, et al: Double-blind, randomized, placebo-controlled Canadian multicenter trial of two doses of synthetic surfactant or air placebo in 224 infants weighing 500–749 gm with respiratory distress syndrome.  J Pediatr  1995; 126:S81-S89.

Soifer et al., 1982. Soifer SJ, Morin III FC, Heymann MA: Prostaglandin D2 reverses induced pulmonary hypertension in the newborn lamb.  J Pediatr  1982; 100:458.

Solaro et al., 1988. Solaro RJ, Lee JA, Kentish JC, Allen DG: Effects of acidosis on ventricular muscle from adult and neonatal rats.  Circ Res  1988; 63:779-786.

Soubasi et al., 1995. Soubasi V, Kremenopoulos G, Diamanti E, et al: Follow-up of very low birth weight infants after erythropoietin treatment to prevent anemia prematurity.  J Pediatr  1995; 127:291-297.

Spears et al., 1991. Spears Jr RS, Yeh A, Fisher DM, Zwoss MS: The “educated hand.” Can anesthesiologists assess changes in neonatal pulmonary compliance manually?.  Anesthesiology  1991; 75:693.

Spilde et al., 2003. Spilde T, Bhatia A, Ostlie D, et al: A role for sonic hedgehog signaling in the pathogenesis of human tracheoesophageal fistula.  J Pediatr Surg  2003; 38:465-468.

Stege et al., 2003. Stege G, Fenton A, Jaffrey B: Nihilism in the 1990s: The true mortality of congenital diaphragmatic hernia.  Pediatrics  2003; 112:532-535.

Steimle et al., 1994. Steimle CN, Meric F, Hirschl RB, et al: Effect of extracorporeal life support on survival when applied to all patients with congenital diaphragmatic hernia.  J Pediatr Surg  1994; 29:997.

Stern et al., 1965. Stern L, Lees MH, Leduc J: Environmental temperature, oxygen consumption, and catecholamine excretion in newborn infants.  Pediatrics  1965; 36:367.

Stern, 1973. Stern L: The use and misuse of oxygen in the newborn infant.  Pediatr Clin North Am  1973; 20:447.

Steward, 1982. Steward DJ: Preterm infants are more prone to complications following minor surgery than are term infants.  Anesthesiology  1982; 56:304.

Strang, 1977. Strang LB: Neonatal respiration: Physiological and clinical studies,  Oxford, Blackwell Scientific Publications, 1977.

Sun and Hsueh, 1991. Sun X, Hsueh W: Platelet-activating factor produces shock, in vivo complement activation, and tissue injury in mice.  J Immunol  1991; 147:509-514.

Sun et al., 1996. Sun XM, Qu XW, Huang W, et al: Role of leukocyte beta 2-integrin in PAF-induced shock and intestinal injury.  Am J Physiol  1996; 270:G184-G190.

Svenningsen and Aronson, 1974. Svenningsen NW, Aronson AS: Postnatal development of renal concentration capacity as estimated by DDAVP-test in normal and asphyxiated neonates.  Biol Neonate  1974; 25:230-241.

Swyer, 1975.   Swyer PR: The intensive care of the newly born. Physiological principles and practice. Monographs in Pediatrics, vol 6. Basel, 1975, S Karger.

Sydorak et al., 2002. Sydorak RM, Nijagal A, Sbragia L, et al: Gastroschisis: Small hole, big cost.  J Pediatr Surg  2002; 37:1669-1672.

Tait et al., 2001. Tait AR, Malviya S, Voepel-Lewis T, et al: Risk factors for perioperative adverse respiratory events in children with upper respiratory tract infections.  Anesthesiology  2001; 95:299-306.

Takashima et al., 1986. Takashima S, Mito T, Ando Y: Pathogenesis of periventricular white matter hemorrhages in preterm infants.  Brain Dev  1986; 8:25-30.

Tan et al., 2000. Tan XD, Chang H, Qu XW, et al: PAF increases mucosal permeability in rat intestine via tyrosine phosphorylation of E-cadherin.  Br J Pharmacol  2000; 129:1522-1529.

Tarpy and Celi, 1995. Tarpy SP, Celi BR: Long-term oxygen therapy.  N Engl J Med  1995; 333:710-714.

Teitel et al., 1985. Teitel DF, Sidi D, Chin T, et al: Developmental changes in myocardial contractile reserve in the lamb.  Pediatr Res  1985; 19:948-955.

The Congenital Diaphragmatic Hernia Study Group, 1999. The Congenital Diaphragmatic Hernia Study Group : Does extracorporeal membrane oxygenation improve survival in neonates with congenital diaphragmatic hernia?.  J Pediatr Surg  1999; 34:720-724.

Thornburn et al., 1970. Thornburn MJ, Wright ES, Miller CG, Smith-Read E: Exomphalos-macroglossia-gigantism syndrome in Jamaican infants.  Am J Dis Child  1970; 119:316-321.

Torfs et al., 1994. Torfs CP, Velie EM, Oechsli FW, et al: A population based study of gastroschisis: Demographic, pregnancy and lifestyle risk factors.  Teratology  1994; 50:44-53.

Touloukian, 1976. Touloukian RJ: Neonatal necrotizing enterocolitis: An update on etiology, diagnosis, and treatment.  Surg Clin North Am  1976; 56:281.

Towne et al., 1980. Towne BH, Peters G, Chang JHT: The problem of “giant” omphalocele.  J Pediatr Surg  1980; 15:543.

Tsang et al., 1973. Tsang RC, Light IJ, Sutherland JM, Kleinman LI: Possible pathogenetic factors in neonatal hypocalcemia of prematurity. The role of gestation, hyperphosphatemia, hypomagnesemia, urinary calcium loss, and parathormone responsiveness.  J Pediatr  1973; 82:423-426.

Tulassay et al., 1986. Tulassay T, Rascher W, Seyberth HW, et al: Role of atrial natriuretic peptide in sodium homeostasis in premature infants.  J Pediatr  1986; 109:1023-1027.

Tullus et al., 1996. Tullus K, Noack G, Burman L, et al: Elevated cytokine levels in tracheobronchial aspirate fluids from ventilator treated neonates with bronchopulmonary dysplasia.  Eur J Pediatr  1996; 155:112-116.

Tunell et al., 1995. Tunell WP, Puffinbarger NK, Tuggle DW, et al: Abdominal wall defects in infants: Survival and implications for adult life.  Ann Surg  1995; 221:525-530.

Tusiewicz et al., 1977. Tusiewicz K, Bryan AC, Froese AB: Contributions of changing rib cage-diaphragm interactions to the ventilatory depression of halothane anesthesia.  Anesthesiology  1977; 47:327.

Uauy et al., 1991. Uauy RD, Fanaroff AA, Korones SB, et al: Necrotizing enterocolitis in very low birth weight infants: Biodemographic and clinical correlates.  J Pediatr  1991; 119:630.

Uezono, 2003.   Uezono S: Presented at the Joint Meeting of the Society of Pediatric Anesthesia and the Japanese Society of Pediatric Anesthesiologists. San Francisco, October 10, 2003.

Vacanti et al., 1984. Vacanti JP, Crone RK, Murphy JD, et al: The pulmonary hemodynamic response to perioperative anesthesia in the treatment of high-risk infants with congenital diaphragmatic hernia.  J Pediatr Surg  1984; 19:672.

Van Meurs et al., 1990. Van Meurs KP, Newman KD, Anderson KD, Short B: Effect of extracorporeal membrane oxygenation on survival of infants with congenital diaphragmatic hernia.  J Pediatr  1990; 117:954.

Van Meurs et al., 2005. Van Meurs KP, Wright LL, Ehrenkranz RA, et al: Inhaled nitric oxide for premature infants with severe respiratory failure.  N Engl J Med  2005; 353:13-22.

Vane et al., 1994. Vane DW, Abajian JC, Hong AR: Spinal anesthesia for primary repair of gastroschisis: A new and safe technique for selected patients.  J Pediatr Surg  1994; 29:1234.

Vanpee et al., 1988. Vanpee M, Herin P, Zetterstrom R, Aperia A: Postnatal development of renal function in very low-birth-weight infants.  Acta Paediatr Scand  1988; 77:191-197.

Vohr et al., 2000. Vohr BR, Wright LL, Dusick AM, et al: Neurodevelopmental and functional outcomes of extremely low birth weight infants in the National Institute of Child Health and Human Development Neonatal Research Network, 1993–1994.  Pediatrics  2000; 105:1216-1226.

Volpe, 1997. Volpe JJ: Brain injury in the premature infant: From pathogenesis to prevention.  Brain Dev  1997; 19:519-534.

Volpe, 2001b. Volpe JJ: Intracranial hemorrhage: Germinal matrix-intraventricular hemorrhage of the premature infant.  Neurology of the newborn,  4th ed.. Philadelphia, WB Saunders, 2001. chap 11.

Volpe, 2001a. Volpe JJ: Neural tube formation and prosencephalic development.  Neurology of the newborn,  4th ed.. Philadelphia, WB Saunders, 2001. chap 1.

Wada et al., 1997. Wada K, Jobe Ah, Ikegami M: Tidal volume effects on surfactant treatment responses with the initiation of ventilation in preterm lambs.  J Appl Physiol  1997; 83:1054-1061.

Walther et al., 1995. Walther FJ, Mullett M, Schumacher R, et al: The American Exosurf Neonatal Study Group I: One-year follow-up of 66 premature infants weighing 500 to 699 grams treated with a single dose of synthetic surfactant or air placebo at birth: Results of a double-blind trial.  J Pediatr  1995; 126:S13-S19.

Wand et al., 1997. Wand H, Tan X, Chang H, et al: Regulation of platelet-activating factor receptor gene expression in vivo by endotoxin, platelet-activating factor, and endogenous tumour necrosis factor.  Biochem J  1997; 322:603-608.

Watchko et al., 1986. Watchko JF, Mayock DE, Standaert TA, Woodrum DE: Postnatal changes in transdiaphragmatic pressure in piglets.  Pediatr Res  1986; 20:658-661.

Watchko and Sieck, 1993. Watchko JF, Sieck GC: Respiratory muscle fatigue resistance relates to myosin phenotype and SDH activity during development.  J Appl Physiol  1993; 75:1341-1347.

Waugh and Johnson, 1984. Waugh R, Johnson GG: Current considerations in neonatal anaesthesia.  Can Anaesth Soc J  1984; 31:700.

Way et al., 1965. Way WL, Costley EC, Way EL: Respiratory sensitivity of the newborn infant to meperidine and morphine.  Clin Pharmacol Ther  1965; 6:454.

Weber et al., 2002. Weber TR, Au-Fliegner M, Downard CD, Fishman SJ: Abdominal wall defects.  Curr Opin Pediatr  2002; 14:491-497.

Wei and Sulakhe, 1979. Wei JW, Sulakhe PV: Regional and subcellular distribution of beta- and alpha-adrenergic receptors in the myocardium of different species.  Gen Pharm  1979; 10:263-267.

Welborn et al., 1986. Welborn LG, Ramirez N, Oh TH, et al: Postanesthetic apnea and periodic breathing in infants.  Anesthesiology  1986; 65:658.

Wells, 1954. Wells LJ: Development of the human diaphragm and pleural sacs.  Contrib Embryol  1954; 35:109.

Werler et al., 2002. Werler MM, Sheehan JE, Mitchell AA: Maternal medication use and risks of gastroschisis and small intestinal atresia.  Am J Epidemiol  2002; 155:26-31.

Wesselhoeft and DeLuca, 1984. Wesselhoeft CW, DeLuca FG: Neonatal septum transversum diaphragmatic defects.  Am J Surg  1984; 147:481.

Williams et al., 1997. Williams RK, McBride WJ, Abajian JC: Combined spinal and epidural anaesthesia for major abdominal surgery in infants.  Can J Anaesth  1997; 44:511-514.

Winters, 1973. Winters RW: Maintenance fluid therapy.   In: Winters RW, ed. The body fluids in pediatrics,  Boston: Little, Brown & Co.; 1973.

Wiriyathian et al., 1986. Wiriyathian S, Rosenfeld CR, Arant Jr BS, et al: Urinary arginine vasopressin: Pattern of excretion in the neonatal period.  Pediatr Res  1986; 20:103-108.

Wohl et al., 1977. Wohl MEB, Griscom NT, Strieder DJ, et al: The lung following repair of congenital diaphragmatic hernia.  J Pediatr  1977; 90:405.

Wu and Hodgman, 1974. Wu PYK, Hodgman JE: Insensible water loss in preterm infants: Changes with postnatal development and non-ionizing radiant energy.  Pediatrics  1974; 54:704.

Yang et al., 1992. Yang P, Bealy TH, Khoury MJ, et al: Genetic-epidemiologic study of omphalocele and gastroschisis: Evidence for heterogeneity.  Am J Med Genet  1992; 44:668-675.

Yaster, 1987. Yaster M: Analgesia and anesthesia in neonates.  J Pediatr  1987; 111:394.

Yaster et al., 1988. Yaster M, Buck JR, Dudgeon DL, et al: Hemodynamic effects of primary closure of omphalocele/gastroschisis in human newborns.  Anesthesiology  1988; 69:84.

Yoon et al., 1999. Yoon BH, Romero R, Kim KS, et al: A systemic fetal inflammatory response and the development of bronchopulmonary dysplasia.  Am J Obstet Gynecol  1999; 181:773-779.

Zhan et al., 1998. Zhan W-Z, Watchko JF, Prakash YS, Sieck GC: Isotonic contractile and fatigue properties of developing rat diaphragm muscle.  J Appl Physiol  1998; 84:1260-1268.

Zweymuller and Preining, 1970. Zweymuller E, Preining O: The insensible water loss of the newborn infant.  Acta Paediatr Scand  1970;205.

Zwissler et al., 1995. Zwissler B, Rank N, Jaenicke U, et al: Selective pulmonary vasodilation by inhaled prostacyclin in a newborn with congenital heart disease and cardiopulmonary bypass.  Anesthesiology  1995; 82:1512.