Anesthesia for general surgery in neonates

Pharmacokinetics and pharmacodynamics

Pharmacokinetics and pharmacodynamics of drugs are affected by anatomic factors relating to body composition and distribution of water, as well as physiologic factors such as metabolism (i.e., hepatic biotransformation), protein binding, and pathologic factors (e.g., disease, anesthesia, and surgery) (see Part II, “Pharmacology”). Compared with older children and adults, neonates have significant body composition and physiologic differences. 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 9 months and 2 years of age. 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; therefore the extracellular fluid compartment of the newborn is greater than or equal to 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 ( ).

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 with approximately 20% to 30% fat, whereas in teenage boys it decreases to 10% to 15% fat. Moreover, the composition of fat tissue changes with age. Fat in the newborn may contain as much as 57% water and 35% lipids; adults have 26% water and 71% lipids ( ). Skeletal muscle comprises 25% of total body mass in a full-term newborn compared with 43% in an adult.

The binding of drugs to serum proteins depends on several factors, including 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 α ₁ -acid glycoprotein is lower in early infancy and reaches adult levels by approximately 1 year of age ( ). Albumin primarily binds acidic drugs; α ₁ -acid glycoprotein binds basic drugs. The concentration of these two proteins and their binding affinities are deficient in the newborn ( ).

The primary organ for drug biotransformation is the liver, but the kidneys, intestines, lungs, and skin also have minor roles. Hepatic oxidation, reduction, and hydrolysis (nonsynthetic, phase I reactions) mature rapidly, achieving adult rates by 6 months of age ( ). Drugs metabolized via this cytochrome P450–dependent monooxygenase 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 and GFR 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 ( ). (See Chapter 6 , “Regulation of Fluids and Electrolytes.”)

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.

Inhaled anesthetic agents

Infants have a higher incidence of cardiovascular instability and cardiac arrest during induction of inhalational anesthesia than do older persons ( ; ; ; ; ) (see Chapter 10 , “Inhaled Anesthetic Agents”). This untoward effect of potent inhalational 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. (See Chapter 10 , “Inhaled Anesthetic Agents,” Fig. 10.6 ). Moreover, the neonatal myocardium has a smaller fraction of 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 the rate of rise of the alveolar concentration ( Box 28.1 ). 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 minute. In contrast, alveolar ventilation is much higher in the infant (100 to 150 mL/kg) compared with the adult (60 mL/kg per minute). This difference parallels the greater oxygen consumption of the infant. Thus 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 that 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 than in adults (see Chapter 10 , “Inhaled Anesthetic Agents”).

The rise in alveolar concentration of an inhaled anesthetic is opposed by uptake of the agent into lung tissue and, more importantly, 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 the anesthetic uptake. The cardiac output of the newborn is 250 to 300 mL/kg per minute. By 8 weeks of age, the cardiac output has decreased to 150 mL/kg per minute. The cardiac output of young infants is approximately three to six times that of the normal adult (70 mL/kg per minute). 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 a smaller proportion to the muscle and fat group. The equilibrium between the inspired and alveolar concentrations of inhaled agent occurs more rapidly because uptake decreases faster.

Because 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.

Blood-gas partition coefficients of isoflurane, halothane, and sevoflurane did not differ in preterm infants compared with full-term infants but were lower than in adults. Only serum cholesterol correlated with the blood-gas partition coefficients ( ). 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 colleagues 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. 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 and changes with age ( Fig. 28.1 ) ( ; ; ). In the original study, Gregory and coworkers 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 were between 1 and 6 months of age ( ) (see Part II, “Pharmacology”).

Intravenous anesthetics and analgesics

Several studies have shown an increased sensitivity to and more prolonged effects of barbiturates and morphine in the neonate and young infant ( ; ). (See Chapter 12 , “Opioids.”) 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. (See Chapter 12 , “Opioids,” Fig. 12.2 ).

In 1981, Robinson and Gregory reported that after 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 patent ductus arteriosus (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 compared with those infants who did not receive analgesics ( ).

Plasma levels of fentanyl are lower in infants versus children versus adults (newborns were not studied) after similar intravenous doses ( ). Gauntlett and colleagues noted that clearance of fentanyl in newborns increased during the first few weeks of life ( ). Elimination half-life and volume of distribution did not change. In a study of newborns who were administered continuous fentanyl infusions, Saarenmaa and associates noted that plasma clearance correlated with maturity (gestational age) and weight ( ), whereas Santeiro and coworkers noted a correlation of clearance with postnatal age ( ) ( Fig. 28.2 A and B). Koehntop and colleagues showed a highly variable disposition and elimination of fentanyl in neonates ( ). In addition, infants with increased intraabdominal pressure (e.g., omphalocele, gastroschisis, or 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 associates noted that the clearance of alfentanil in newborn premature infants was markedly reduced compared with older children ( ) ( Fig. 28.3 ).

Koren and coworkers showed that the elimination half-life for morphine (13.9 hours) in human neonates is markedly 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.

Remifentanil is an ultra-short-acting opioid. Remifentanil is metabolized by plasma and tissue esterases, and its metabolism is independent of organ elimination. As a result, in neonates its pharmacokinetic profile is different from any other opioid. The remifentanil clearance rate in neonates is greater than in any other age group. Although its volume of distribution is large, its terminal elimination half-life does not change with age ( ). Because remifentanil is metabolized in tissues and plasma, it does not accumulate, and consequently its context-sensitive half-time is flat (i.e., the time for 50% reduction at the effect site is independent of drug duration). Thus remifentanil may be an ideal drug for anesthetic use in neonates.

Ketamine requirements are greater (mg per kg of body weight) in infants than in older children ( ). Ketamine has been shown to produce apnea in infants with increased intracranial pressure ( ). Ketamine produces hypertension and tachycardia, which some anesthesiologists have taken advantage of in caring for infants and children with congenital heart disease, cardiovascular instability, or both.

Propofol is commonly administered to infants. Propofol clearance is dependent on hepatic blood flow (high extraction coefficient) with subsequent metabolism and glucuronidation. In a population pharmacokinetic analysis, Allegaert and colleagues noted that postmenstrual age and postnatal age were predictive covariants for clearance and that developmental maturation occurs within the first 2 weeks of life ( ) ( Fig. 28.4 ).

Midazolam is an extensively used drug in both full-term and preterm infants and is metabolized by the P450 3A subfamily. Midazolam clearance in preterm infants is less than in children and older infants, and it may reflect the pattern of CYP3A4 ontogeny ( Fig. 28.5 A and B). In a study of 24 preterm infants De Wildt and associates found no relationship between age (postconceptual, gestational, or postnatal) and midazolam clearance ( ). Of note was that in infants exposed postnatally to indomethacin, plasma clearance was higher and the volume of distribution was larger than in those infants not exposed to indomethacin. Because CYP3A4 expression is actuated during the first week after birth regardless of gestational age at birth, the decrease in midazolam clearance probably represents a decrease in CYP3A activity.

Muscle relaxants

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. 28.6 ). 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 often correlate with surface area rather than with body weight. Neonates and infants have a higher sensitivity (lower ED ₅₀ and ED ₉₅ ) for most nondepolarizing blocking agents.

Fisher and coworkers studied infants’ 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 (mg per kg 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).

Studies of rocuronium in infants and children have shown that onset time in small infants is faster, and the occurrence of 100% block at lower doses compared with older children suggests a greater potency in infants. In addition, rocuronium has an age-dependent difference in duration of action and in recovery after 0.45 mg/kg and 0.6 mg/kg doses ( Fig. 28.7 ) ( ; ). Historically, medications that inhibit acetylcholinesterase, such as neostigmine or edrophonium, were administered to competitively reverse residual neuromuscular blockade ( ).

In 2015 the U.S. Food and Drug Administration (FDA) approved sugammadex as the first noncompetitive antagonist for the reversal of neuromuscular blockade for clinical use in adults ( ). Sugammadex has a completely different mechanism of action compared with acetylcholinesterase inhibitors; it encapsulates rocuronium or vecuronium, providing rapid and complete recovery of neuromuscular blockade. The reported adverse effect profile of sugammadex has included minor and self-limited issues (nausea, vomiting, hypotension, etc). During a preclinical trial, severe adverse effects such as bradycardia and anaphylactoid reactions were noted ( ). Sugammadex has not received FDA approval for use in children. Published neonatal data on sugammadex use are relatively sparse with three case reports and one open-label trial. However, these studies reflect the overall safety profile of sugammadex in the pediatric population ( ).

Thermal protection

Perioperative hypothermia is a challenge when caring for neonates outside the NICU. In these patients, hypothermia is associated with increased morbidity ( ). Measures must be taken to protect against heat loss during surgery ( Box 28.2 ).

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 anesthesiologists’ clinical skills, judgment, and evaluation remain indispensable.

Monitoring in the operating room

Circulatory monitoring

A precordial stethoscope is a simple and effective means to assess the quality of heart sounds, rate, and rhythm, as well as breath sounds. 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 method of airway management (mask vs. laryngeal mask airway vs. 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, the simplicity and accuracy of the precordial and esophageal devices 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 ( ). Systolic blood pressure measurements correlate with the circulating blood volume and therefore are essential to monitor and guide fluid and blood replacement. Normal values of blood pressure change with age, gestational age, and anesthetic conditions. See Fig. 5.17 in Chapter 5 , “Cardiovascular Physiology,” and Fig. 21.7 in Chapter 21 , “Induction, Maintenance, and Recovery.” 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 repeated blood sampling for cardiopulmonary and biochemical evaluation. A 24-gauge cannula can be inserted percutaneously or by cutdown into a variety of sites, including the radial, dorsalis pedis, or posterior tibial arteries. Percutaneous insertion aided by two-dimensional ultrasound has shown higher first-attempt success rate, fewer overall needle passes, and faster time to cannulation ( ). The axillary artery is rarely cannulated. In general, the umbilical artery can be cannulated in the first 4 to 7 days of life, but this is usually avoided after the first 2 days of life because of the risk for infection and vascular emboli. The umbilical catheter tip can be placed high (T10 to T12) or low, above the bifurcation of the aorta and below the level of the renal arteries (L4, L5). If an umbilical vein catheter is placed for long-term access, the line should be advanced into the inferior vena cava just beneath the right atrium. This is usually 10 to 12 cm in a full-term neonate. The placement of the catheter must be confirmed by a radiograph ( Fig. 28.8 ).

The risk for retinopathy of prematurity (ROP) necessitates meticulous monitoring of oxygen saturation in the neonate, especially the very low-birth-weight (VLBW) infant. Most neonatologists 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 fetal hemoglobin HgbF) (see Chapter 27 , “Neonatology for Anesthesiologists”). 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 Chapter 3 , “Respiratory Physiology,” and Chapter 5 , “Cardiovascular Physiology.”)

An arterial catheter must be connected to a pressure transducer and slowly and continuously infused with a small volume of diluted heparin solution (0.1 to 1 units/mL) at the rate of 0.5 to 1 mL/hr. In the extremely low-birth-weight (ELBW) neonate, 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 neonate, especially with a patent foramen ovale or PDA.

A central venous catheter may be indicated to administer blood, fluid, total parenteral nutrition (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 veins. In emergencies or situations of difficult venous access, the umbilical vein catheter can be inserted and passed into the right atrium (see Fig. 28.8 ). Its location must be verified by radiograph or by a CVP tracing. Umbilical vein catheters have been associated with portal vein thrombosis. All central venous catheters are associated with significant morbidity, including thrombosis, emboli, and infection. Central venous catheters in the low-birth-weight (LBW) neonate have additional risks, from malpositioning and from the disruption of venous flow (ratio of the size of the vessel to the size of the catheter is low).

Laparoscopy and thoracoscopy in the neonate

Although the range of procedures managed by minimally invasive surgery has expanded dramatically in the newborn over the last 2 decades, morbidity in this age group continues to be considerable because of the neonate’s unique cardiorespiratory physiology. Specifically, the transitional circulation may predispose the newborn to exaggerated risks secondary to insufflation pressure and enhanced absorption of carbon dioxide during laparoscopy and thoracoscopy. Kalfa and colleagues noted that hemodynamic, respiratory, and/or thermal stability was disrupted in 12% of newborns during either laparoscopy or thoracoscopy ( ).

Increasing intrathoracic or intraabdominal pressure (e.g., >8 mm Hg) may decrease venous return and therefore cardiac output and blood pressure. In most cases, temporarily interrupting insufflation, limiting the peak pressure, and/or delivering volume expansion promptly alleviates hypotension, with a low incidence of converting to an open technique ( ). In fact, only 20% of patients encounter significant hypotension ( ). Although exceedingly rare, the newborn maintains a higher risk for cardiovascular collapse secondary to paradoxical emboli via the PDA/foramen ovale during laparoscopy ( ; ). Gas entry probably occurs through a transversed umbilical vein by the trocar.

Interfering with ventilation of the lungs during insufflation may induce hypoxia and/or hypercarbia, which can profoundly influence the transitional circulation ( ; ). As expected, these effects are more common during thoracoscopy ( ) and are proportional to the pressure, flow rates, and duration of insufflation. The low quantity of peritoneal fat serves a buffer, since CO ₂ is soluble in fat, and the higher permeability of the relatively thin surface allows the CO ₂ to be absorbed more efficiently from the peritoneum as a function of decreasing age ( ), exacerbating the direct and indirect effects of insufflation on respiratory function. Beyond the newborn period in hemodynamically stable patients, hypercarbia is not associated with major clinical side effects, and the Pco ₂ is usually controlled to acceptable levels (e.g., Pco ₂ <45 to 50 torr) by increasing minute ventilation. However, in the setting of major developmental anomalies (e.g., tracheoesophageal atresia or CDH), hypercarbia may cause more hemodynamic changes, especially on the central nervous system. Bishay and associates noted that cerebral oxygenation decreased during insufflation, and it was associated with hypercarbia and acidosis ( ). These authors suggest that this finding should prompt reassessing the risks associated with thoracoscopic repair of these lesions. In addition, increasing peak airway pressure/minute ventilation and fraction of inspired oxygen (Fio ₂ ) are associated with a higher risk for long-term morbidity in the immature lung (see Chapter 27 , “Neonatology for Anesthesiologists”).

In some cases, in spite of increased minute ventilation, hypercarbia persists and only returns to baseline levels approximately 15 minutes after desufflation ( ). For unclear reasons, younger patients often demonstrate a period of increased CO ₂ elimination after desufflation, which may be related to increased venous return and/or minute ventilation after the decrease in intraabdominal pressure. On the other hand, this postinsufflation phenomenon is not universal, implying a persistent risk for hypercarbia in some patients into the postoperative period.

Of concern, end-tidal CO ₂ may less accurately reflect arterial levels during laparoscopy ( ), especially in the presence of cyanotic heart disease ( ; ). That is, the alveolar-arterial difference may be greater in the newborn during insufflation with CO ₂ .

Delivering gas into body cavities can decrease core body temperature, but the incidence of hypothermia varies. For example, in one study, 50% of newborns developed a postoperative core temperature less than 36° C, especially in the setting of a prolonged operative time (insufflation time longer than 100 minutes) ( ), but severe hypothermia (<34.5° C) is uncommon (12%). With improved warming techniques and shorter times for insufflation, postoperative hypothermia (<34.9° C) was noted in less than 2% of newborns ( ).

Because many of the strategies to affect single-lung ventilation (e.g., double-lumen endotracheal tubes, endobronchial blockers) are not available for the newborn, adequate surgical exposure for thoracoscopy relies heavily on insufflation to collapse the lung. Thus single-lung ventilation is challenging to achieve and at times is not tolerated by a newborn. Many pediatric surgeons suggest that insufflation of the chest with a low flow of CO ₂ (1 to 2 L/min, peak pressure of 4 to 6 mm Hg) in the 30- to 45-degree prone position induces adequate lung collapse ( ; ). Lungs with abnormal distribution of ventilation impede uniform collapse with insufflation, so the newborn with abnormal lung function may not be eligible for thoracoscopic surgery.

In spite of the myriad of critical physiologic challenges, endoscopic procedures have been conducted successfully in high-risk infants with conditions such as hypoplastic left heart syndrome, complex cyanotic heart disease, and patients with single-ventricle physiology ( ; ; ). With increasing expertise among surgeons and anesthesiologists, risk factors are successfully managed with close collaboration and preoperative planning so that MAS has become the standard for complex surgery in the newborn.

Abdominal wall defects: Gastroschisis and omphalocele

Gastroschisis and omphalocele are the most common abdominal wall defects, but they are still rare. The National Birth Defects Prevention Network (NBDPN) examined a 5-year birth cohort (birth years 2012–2016) using data from 30 population-based birth defect surveillance programs in the United States and found the overall prevalence estimates (per 10,000 live births) were 4.3 (95% confidence interval [CI]: 4.1–4.4) for gastroschisis and 2.1 (95% CI: 2.0–2.2) for omphalocele ( ). An ultrasound easily confirms the presence of these lesions in approximately 95% to 100% of cases at the time of the nuchal scan at 10 to 13 weeks of gestation ( ; ). In some cases, an elevated level of α-fetoprotein may initially suggest an in utero abnormality; this marker is elevated more often in gastroschisis than in omphalocele ( Box 28.3 ). According to some reports, the increasing prevalence of gastroschisis has been allocated to younger women ( ; ; ), but others suggest that the phenomenon is not restricted to those younger than 20 years of age ( ). In the cohort of births studied by the NBDPN, mothers of neonates with gastroschisis were more likely to be underweight/normal weight prior to pregnancy. Little evidence points to a significant genetic link. However, in utero exposure to acetaminophen, aspirin, and pseudoephedrine has been associated with an increased incidence of gastroschisis ( ; ). Furthermore, a recent ecologic analysis found a higher prevalence of gastroschisis in areas where opioid prescription rates were high, supporting epidemiologic data suggesting an association between opioid use during pregnancy and gastroschisis ( ).

In contrast to gastroschisis, the prevalence of omphalocele has been stable. Genetic factors have a major role ( ). In fact, the in utero diagnosis should prompt further noninvasive prenatal testing, because this lesion is commonly associated (50% to 80%) with chromosomal abnormalities or other complex syndromes (e.g., cloacal exstrophy, Donnai-Barrow syndrome, pentalogy of Cantrell, Beckwith-Wiedemann syndrome); 30% to 40% of omphaloceles are associated with trisomy 21, 18, or 13. Multiple associated anomalies are identified in 65% to 88% of cases ( ; ; ; ). These anomalies are more common with nongiant omphaloceles (<4 cm) than with giant omphaloceles (55% vs. 36%) ( ). If the omphalocele contains only bowel and if oligohydramnios or polyhydramnios are present, the likelihood of an associated chromosomal abnormality increases. Mann and colleagues noted that omphaloceles that contain liver and other viscera are more likely to have cardiac, renal, or limb anomalies, whereas the smaller omphaloceles are more likely to have gastrointestinal or central nervous system malformations ( ). Syndromes of midline defects often include an omphalocele, and this lesion also has been included in the nonsyndromic multiple congenital anomalies (MCA) complex.

The concept of an “isolated omphalocele” must be considered from the perspective of recent data suggesting that 30% of the fetuses allocated to the category of “isolated cases” are then found to have multiple defects. Only 14% of omphaloceles were truly isolated lesions ( ). Similarly, Porter and colleagues noted that 26% of cases classified prenatally as “isolated” had significant anomalies (e.g., cardiac) identified postnatally. In addition, one-third of these infants were premature, and the mortality rate was 50% ( ). In contrast to omphalocele, only 15% to 20% of neonates with gastroschisis have associated malformations, and only rarely is a complex pattern of malformation identified ( ).

Whether isolated or part of a more complex disorder, an in utero diagnosis of an abdominal wall defect implies delivery at a medical center with resources for high-risk obstetric, surgical, anesthetic, and neonatal care. In general, it is the associated lesions (both extraintestinal and intraintestinal) as opposed to the abdominal defect itself that contributes to short-term and long-term outcomes of patients with gastroschisis or omphalocele. Because prognosis correlates with the severity of associated anomalies, identifying a structural or karyotypic abnormality is critical in predicting outcome and counseling parents.

Although similar in gross physical appearance, omphalocele and gastroschisis are distinct lesions. An omphalocele is a central defect of the umbilical ring; the abdominal contents herniate into the intact umbilical sac, and the bowel remains protected throughout gestation unless the sac ruptures in utero ( Fig. 28.10 ). The umbilical cord inserts into the sac, which contains an internal peritoneal membrane, Wharton jelly, and an external amniotic membrane. By definition, the lesion has a fascial defect of more than 4 cm (<4 cm is considered an umbilical hernia) and often as large as 10 to 12 cm. The sac often contains the stomach, loops of the small and large intestines, and in about 30% to 50% of cases, the liver.

A gastroschisis is a full-thickness abdominal wall defect usually 2 to 5 cm in diameter, almost always to the right of the umbilical cord, with evisceration of bowel (usually only small and large bowel, rarely liver) through the defect, and without a covering membrane ( Fig. 28.11 ). The bowel is exposed to the intrauterine environment with no sac, predisposing the loops to become matted, thickened, and often covered with an inflammatory coating or peel. Whether this exudative peel is secondary to a specific inflammatory pathway or simply an effect of amniotic fluid is unclear. The umbilical cord is normal and separate from the defect. Cryptorchidism coexists when the testes exit along with the bowel ( ; ). Although “simple gastroschisis” is not commonly associated with other anomalies, the presence of a complex intestinal disorder such as an atresia (5% to 15%) or volvulus increases morbidity. In the setting of atresia, Kronfli and colleagues noted that prolonged feeding intolerance, recurrent sepsis, short bowel syndrome/intestinal failure, and mortality were higher ( ).

With either omphalocele or gastroschisis, the rotation of the gut is incomplete in utero. This results in various “malrotation” phenotypes.

Postoperative care

Unless the lesion is small, postoperatively after an uncomplicated primary closure of an abdominal wall defect, mechanical ventilation is often required for 24 to 48 hours or longer; thereafter, respiratory compliance usually improves dramatically ( ). Clearly, neonates undergoing a gradual reduction after placement of a silo ( Fig. 28.12 ) or similar device usually require mechanical ventilatory support during this process. Neonates with a small defect can sometimes be extubated at the conclusion of surgery. All patients must be carefully monitored for respiratory and infectious complications in an intensive care unit after closure of an abdominal wall defect. Inferior vena caval compression (evident by blueish lower limbs) or bowel ischemia (necrotizing enterocolitis [NE]) can occur as a result of increased abdominal pressure and may require surgical decompression.

The onset of peristalsis after repair of omphalocele or gastroschisis is usually delayed, and the resulting ileus may be prolonged so that TPN is generally required for days to weeks postoperatively ( ). Bowel hypomotility is most common in neonates with gastroschisis, especially those with an atresia or volvulus. In anticipation of this, most neonates with large lesions and/or gastroschisis should have appropriate intravenous access established in the operating room to facilitate early postoperative nutritional support, which is essential for healing and recovery. Prolonged feeding intolerance should precipitate an evaluation for an associated intestinal atresia or other intestinal lesion.

Congenital diaphragmatic hernia

With an incidence between 1:2500 and 1:3000 live births, CDH ( Video 28.1 ) results when intraabdominal organs extrude into the thoracic cavity secondary to failure of development of the diaphragm early in gestation ( Fig. 28.13 ). With the thorax containing variable quantities of intestine/stomach/liver, this disorder represents much more than an anatomic abnormality of a hole in the diaphragm. That is, in utero, CDH evolves into a disorder of lung development, including pulmonary hypoplasia and abnormal vasculature.

The normal patterns of postnatal transition from intrauterine to extrauterine physiology (the “transitional circulation”) seem to occur in the newborn with CDH, but the process may be protracted ( ; ). This constitutes the primary physiologic basis for delaying surgery for several days. Some have suggested that failure of improvement in the postnatal cardiorespiratory status in the setting of CDH correlates with a degree of pulmonary hypoplasia that is incompatible with life ( ; ). Finally, surfactant deficiency and left ventricular function may contribute to the postnatal clinical dysfunction in the newborn with CDH ( ; ).

CDH may be an isolated lesion, but approximately 40% of cases are associated with other anomalies, including 20% with congenital heart disease ( ). CDH imparts morbidity to a variety of syndromes, such as Beckwith-Wiedemann, CHARGE (coloboma, heart, atresia choanae, retardation, genital, and ear anomalies), Cornelia de Lange, and Denys-Drash syndromes. Trisomies 13, 18, 21, and 45X are the most common aneuploidies associated with CDH ( ). Chromosomal microarray analysis has become a “first-tier diagnostic test” in some institutions ( ). In addition to karyotype abnormalities, copy number variants (e.g., microdeletions, microduplications) have been diagnosed in 3.5% to 13% of isolated CDH patients ( ). In spite of recognizing a genetic basis for a greater number of CDHs, genetic evaluation in the setting of this lesion is usually normal. If the family history is negative, the risk for recurrence is minimal ( ).

The most common defect is posterolateral (Bochdalek hernia), accounting for more than 95% of cases, of which 80% to 87% are left-sided ( ; ). In approximately 2%, CDH is bilateral. Morgagni (anteromedial) and paraesophageal hernias and eventrations define the rarer versions ( Fig. 28.14 ). Of interest, trisomy 21 is the most frequent aneuploidy identified in Morgagni hernia ( ). Of major clinical relevance, CDH is associated with the following:

• Varying degrees of bilateral lung hypoplasia

• Pulmonary hypertension and arteriolar reactivity

• Congenital anomalies (e.g., cardiac, gastrointestinal, genitourinary, skeletal, neural, and trisomic)

Since the 1980s, the overall survival of neonates with CDH has improved dramatically from 40% to 60% in the 1980s to 70% to 80% in subsequent years (1990 to 2000) ( ), with survival of patients who required extracorporeal membrane oxygenation (ECMO) of about 50%. Although some have reported no change in survival rates ( ; ), others have suggested that overall survival is as high as 85% to 95% ( ; ) and 55% to 85% when ECMO is required ( ; ). In summary, rates for mortality continue to vary widely, depending on how the cohort is analyzed.

Institution-based reports that only include data about live-born infants cared for in an NICU may underestimate the total mortality of CDH and the incidence and severity of associated anomalies. Two decades ago, survival rates associated with an isolated CDH approached 80% in those who did not require ECMO ( ; ). In the 1970s, Harrison and colleagues first noted that mortality may be “hidden” when in utero and that early postnatal deaths were not included in calculating mortality associated with CDH ( ). In fact, combining improved prenatal diagnosis with deliberate delivery at medical institutions equipped to provide the appropriate level of obstetric and neonatal care has eliminated some of the “hidden mortality” associated with CDH.

However, the impact of “hidden mortality” persists and should be analyzed when examining reports of increased survival. The Congenital Diaphragmatic Hernia Study Group reviewed outcomes from their international CDH registry (January 1995 to January 2010, 4390 patients). One notable result of this report was that if only surgical patients were included in the analysis (i.e., eliminate preoperative mortality, exclude patients who were not considered surgical candidates, stillbirths, spontaneous/therapeutic abortions), survival was high for those undergoing a minimally invasive approach (98.7%), as well as for those who had an open repair (82.9%). The higher survival among those undergoing minimally invasive surgery implies selection bias for patients with the requirement for less severely deranged cardiorespiratory status for this approach ( ; ).

Stillborn babies with CDH have a 95% incidence of other anomalies. A severe cardiac malformation combined with CDH implies a lethal outcome ( ; ). Various series rank the incidence of associated malformations differently. Stege and colleagues reported that cardiovascular lesions were most common, followed by chromosomal, skeletal, facial dysmorphism (cleft palate, ear deformity), gastrointestinal, and syndromal ( ). CDH is sometimes part of a complex set of anomalies: pentalogy of Cantrell (omphalocele, sternal cleft, ectopia cordis, and an intracardiac defect [ventricular septal defect or diverticulum of the left ventricle]) ( ). CDH has also been associated with Fryns syndrome, Goldenhar syndrome, Brachmann–de Lange syndrome, and Beckwith-Weidemann syndrome ( ; ; ; ).

The improved operative survival rate of CDH stems from the strategy of delaying surgery to ensure stabilization of the transitional circulation, adopting a lung-protective, or “gentle ventilatory,” strategy using small tidal volumes and as low as possible positive end-expiratory pressure (PEEP), and accepting higher Pco ₂ (permissive hypercapnia) ( ; ; ). The lung-protective approach aims to avoid barotrauma and volutrauma ( ; ) (see the “Timing of Surgery” section later in the chapter).

CDH outcomes are a function of the underlying pulmonary hypoplasia and pulmonary hypertension. Dillon and colleagues correlated pulmonary artery pressure (measured via echocardiogram) with survival in a cohort of 47 full-term neonates treated with delayed surgery and gentle ventilatory approaches such as high-frequency oscillatory ventilation (HFOV), permissive hypercarbia, nitric oxide (NO), or ECMO. All 23 infants with estimated normal (i.e., less than 50% of systemic) pulmonary artery pressure within the first 3 weeks of life (49% of the study) survived. In contrast, none of the eight patients with persistent systemic (or higher) pulmonary artery pressure survived. Of the remaining 16 patients with pulmonary artery pressure between these two extremes, 12 (75%) of the 16 survived ( ). Similarly, proposed that preoperative pulmonary pressure greater than 90% of systemic pressure predicted an overwhelming risk for mortality. Clearly, the severity of pulmonary hypertension contributes significantly to mortality. Optimal in utero and postnatal strategies for infants with CDH, especially those with pulmonary hypertension, remain incompletely defined ( ).

The overall mortality (23.6%) among those recruited for the DHREAMS (Diaphragmatic Hernia Research and Exploration, Advancing Molecular Science) study ( ) correlates with other data. Morbidity and mortality strongly correlated with degree of pulmonary hypertension. In turn, other markers (e.g., prenatal diagnosis, need for a patch for repair, support with ECMO, nonisolated CDH) that track severity of pulmonary hypertension also predicted survival.