Chapter 63. Anesthesia for Newborn Surgical Emergencies

1. Newborns require anesthesia for surgery. Newborns respond to noxious stimuli, and failure to provide analgesia and anesthesia increases perioperative morbidity and mortality

2. Pharmacokinetics and pharmacodynamics differ in newborns. Concentrations of albumin and alpha-1 acid glycoprotein are lower in newborns, and binding sites are fewer; thus, a greater proportion of active ("free") drug is available. Furthermore, the newborn cytochrome P450 system does not reach adult functionality until 1 to 2 months of life.

3. All potent inhalational anesthetics produce unacceptable hypotension in newborns. Thus, the risk of cardiovascular collapse during the induction of general anesthesia is much greater in newborn than in older children and adults.

4. Newborns have a fixed stroke volume and can increase cardiac output only by increasing heart rate. Atropine requirements in newborns (0.03-0.05 mg/kg intravenous [IV]) are almost three times greater than in adults, and total doses of less than 0.1 to 0.15 mg may produce paradoxical bradycardia, further contributing to hypotension.

5. Fentanyl (10-12.5 mcg/kg) produces insignificant hemodynamic changes and provides reliable anesthesia in newborns, provided the infants are preloaded with a balanced salt solution (20 mL/kg IV) and a vagolytic agent (eg, pancuronium or atropine) is administered.

6. Rapid-sequence induction with gentle cricoid pressure, rather than "awake" intubation, is usually the preferred method of securing the airway.

7. Newborns are at high risk for hypothermia during transport and in the operating room (OR). This is countered by wrapping the infant in plastic bags; using forced-air heating mattresses; increasing the OR temperature to or above 90°F, warming IV fluids; and using heated, humidified respiratory gases.

8. "Right-to-left" shunting of blood across the ductus arteriosus and the atrial septum is a catastrophic return to fetal circulation (ie, persistent fetal circulation or persistent pulmonary hypertension of the newborn); it occurs when pulmonary vascular resistance exceeds systemic vascular resistance. Treatment is directed at improving oxygenation and increasing pulmonary blood flow by the judicious use of muscle relaxants, analgesics (usually fentanyl), hyperventilation, ventilatory rates of greater than 100 breaths/min and low inflating pressures, preventing hypothermia, and correction of acidosis with IV bicarbonate therapy.

9. Accumulating data from animal studies suggest that some anesthetics, opioids, and related drugs (eg, benzodiazepines) may be neurotoxic in the developing brain, and there is some evidence of behavioral changes (eg, learning disabilities) in children who have had multiple anesthetic exposures. However, definitive evidence of neurotoxicity in newborns or children who have had single or limited exposures is lacking and is balanced by concerns about outcomes in newborns who are not anesthetized for painful procedures.

Except for extraordinary circumstances, all newborns require anesthesia for surgery.1-4 In the past, it had been assumed that newborn infants neither experienced nor perceived painful stimuli to the same degree that adults do. Indeed, it was thought that newborns did not have the neurologic substrate necessary for the perception of pain because of a lack of myelinization, incomplete pain pathways from the periphery to the cortex, or immaturity of the cerebral cortex. There is absolutely no evidence that any of this is true.2-5 Indeed, by the 24th week of gestation, newborn respond to noxious stimuli with behavioral, physiologic, metabolic, and hormonal responses suggestive of substantial stress.6 It is also clear that the neurophysiologic pathways for nociception from the peripheral receptors to the cerebral cortex are developed even in premature infants. Furthermore, the primary pathways of pain transmission involve unmyelinated C and A delta fibers, so postnatal myelination is not required for most pain perception.7-10 Finally, failure to provide anesthesia is associated with an increased incidence of circulatory, respiratory, and metabolic complications in newborns.11,12 Thus, the preponderance of evidence suggests that newborns not only respond to noxious stimuli but that the failure to provide analgesia and anesthesia significantly increases perioperative morbidity and mortality.

Newborns differ from adults and older children in the uptake, distribution, metabolism, and excretion of all drugs. During the first month of life (the "neonatal" period), newborns must function independently and adapt to extrauterine life. This involves anatomic, physiologic, and pharmacologic changes to maintain homeostasis and to ensure the infant's survival. Disease, congenital anomalies, surgery, and anesthesia may interfere with these adaptations and threaten survival. The important elements of the preoperative history and preanesthetic assessment, including review of systems, developmental physiology, and the transition from intra- to extrauterine life, are discussed in Chapter 18. This chapter discusses anesthetic pharmacology in neonates, an approach to intraoperative management, and the specific management of commonly encountered surgical problems. The general principles of pharmacokinetics and pharmacodynamics are discussed in detail in Chapter 40; the following focuses on the unique aspects that apply specifically to neonates.

When physicians administer drugs to patients of any age, they do so with the expectation that an anticipated therapeutic effect will occur. Unfortunately, other less desired results can also occur; the patient may derive inadequate or no therapeutic benefit from the administered drug, or worse yet, he or she may develop side effects or a toxic reaction. The aim of modern clinical pharmacology is to take the guesswork out of this process and to establish the relationship between the dose of a drug given and the response elicited. To attain this goal, clinicians need a working knowledge of the principles of drug absorption, distribution, and elimination and how these processes are related to intensity and duration of drug action. Additionally, they need a thorough understanding of the chemical and physical properties, physiologic effects, disposition, mechanisms of action, and therapeutic uses of the drugs that are used to provide anesthesia and analgesia in newborns.

An understanding of the factors that determine drug concentrations within the body is crucial to rational drug use in patients of any age and to achieving desirable plasma drug concentrations. Pharmacokinetics is the term used to describe the study of drug disposition within the body. It includes absorption, distribution, metabolism, and elimination of drug molecules from the body. Pharmacodynamics is the term used to describe the study of drug action within the body. It defines the relationship between the concentration of the drug at the site of action and the physiologic response. The relationship between pharmacokinetics and pharmacodynamics provides an understanding of the dose–response curves for the onset of action, magnitude of action, and duration of action of drugs used in treating patients.

Drug Distribution

How much drug reaches a receptor or effector site depends on the extent of protein binding, tissue volume, tissue solubility coefficients, and blood flow. Anatomic and maturational changes involving body composition, distribution of water, metabolism, protein binding, and organ function in health and in disease contribute to the unique responses of newborns to various drugs. In the blood, opioids (eg, fentanyl, morphine), amide local anesthetics (eg, bupivacaine, lidocaine), and muscle relaxants (eg, pancuronium, rocuronium) bind to albumin and other serum proteins, such as alpha-1 acid glycoprotein.13,14 The unbound or "free" drug is available to cross biological membranes, bind to receptors, and initiate a pharmacologic effect. Concentrations of both albumin and alpha-1 acid glycoprotein are lower in newborns than at any other moment in life. Additionally, the number of binding sites on these proteins and their affinity for drugs is less than in later life. Thus, a greater proportion of active, unbound (or "free") drug is available to penetrate the brain, heart, and other viscera. Furthermore, the membranes that separate target receptors from the blood (ie, the "blood–brain barrier") may also be immature at birth and thereby allow agonists with limited lipid solubility, such as morphine, greater access to the brain. Kupferberg and Way15 and Way et al16 demonstrated that morphine concentrations were 2 to 4 times greater in the brains of younger than older rats despite equal blood concentrations. On the other hand, decreased protein binding may contribute to the larger apparent volume of distribution (Vd) of many drugs as well. A large apparent Vd, in effect, dilutes the plasma concentrations of parenterally administered drugs and explains, in part, why some drugs must be given in larger doses (mg/kg basis) to achieve a therapeutic effect.17

Body composition also changes with age. About 80% to 90% of a newborn's body mass is composed of water (Table 63-1).18 In fact, in very-low-birth-weight premature infants (<2 kg), total body water can be estimated at 100% of body weight. This increase in total body water occurs primarily in the extracellular fluid (ECF) space, mostly in interstitial water, and explains the larger apparent Vd of most parenterally administered drugs in newborns. In newborns, interstitial water makes up 40% of the body weight but declines to10% to 15% in adults.

Blood flow determines how much drug reaches a target receptor. As in adults, a high proportion of cardiac output perfuses vessel-rich organs, such as the brain, kidney, and intestinal viscera. Very high brain concentrations are achieved after the administration of any lipophilic or inhalational anesthetic because the infant's brain receives almost 30% of the cardiac output versus only about 15% in adults. The very small muscle and fat mass of infants provides less of a reservoir to lower blood concentrations of drugs. Furthermore, the potent vapors are less soluble in neonatal blood than adults' blood. As a result, higher concentrations of an administered vapor anesthetic (eg, sevoflurane, isoflurane) are achieved more quickly than might be expected.19,20 Finally, the perinatal adaptation to extrauterine life produces rapid changes in the circulation. This process may be inhibited by congenital heart disease or any other condition that increases pulmonary vascular resistance more than systemic vascular resistance, such as hypoxia, hypercarbia, and acid–base problems. Uptake, distribution, metabolism, and excretion may be drastically affected when cardiovascular function is abnormal.

After administration, the disposition of a drug depends on distribution (t1/2α) and elimination. The terminal half-life of elimination (t1/2β) is directly proportional to the Vd and inversely proportional to the total body clearance (Cl) by the following formula:

Thus, prolongation of the t1/2β may be caused by either an increase in a drug's Vd or to a decrease in its clearance.

After redistribution, the major processes that lead to the termination of a drug's effect are biotransformation, metabolism, and excretion. Many anesthetic-related drugs (eg, opioids, muscle relaxants, hypnotics) are biotransformed in the liver before excretion. Many of these reactions are catalyzed in the liver by microsomal mixed-function oxidases that require the cytochrome P450 (CYP450) system, NADPH (nicotinamide adenine dinucleotide phosphate), and oxygen. The CYP450 system is very immature at birth and does not reach adult functionality until the month 1 or 2 of life. This immaturity of this hepatic enzyme system may explain the prolonged clearance or elimination of some drugs in the first few days to weeks of life and the inability of the liver to convert a precursor into its active form (eg, codeine into morphine).21,22 However, the CYP450 system can be induced by various drugs (eg, phenobarbital) and substrates, and this enzyme system matures regardless of gestational age. Thus, it is the age from birth, not the duration of gestation, that determines how premature or full-term infants metabolize many drugs. Greeley and de Bruijn23 demonstrated that sufentanil is more rapidly metabolized and eliminated in 2- to 3-week-old infants than newborns less than 1 week of age. Elimination may be further prolonged by abnormal or decreased liver blood flow, which may occur after an acute illness or abdominal surgery. Certain conditions that may raise intra-abdominal pressure (eg, closure of an abdominal wall defect, such as an omphalocele or gastroschisis) may further decrease liver blood flow by shunting blood away from the liver via the still patent ductus venosus.24,25 Finally, in all newborns, excretion may be reduced compared with in older children and adults because both glomerular and tubular renal function, which are responsible for active secretion and passive resorption, are reduced in newborns.26

Inhalational Anesthetics

At equipotent doses, all of the potent inhalational anesthetics (eg, sevoflurane, desflurane, and isoflurane) produce unacceptable hypotension in newborns requiring emergency surgery. Thus, the risk of cardiovascular collapse during the induction of general anesthesia is much greater in newborns than in older children and adults.27-32 This greater decrease in blood pressure is attributable to differences in uptake and distribution of the anesthetic, anesthetic dose requirements, vascular actions of the anesthetics, and sensitivity of the newborn's myocardium to these agents.33-36 Newborns attain a greater absolute concentration of halothane (or any of the potent vapors) in the brain and heart and at a faster rate than adults do at the same inspired concentration. If the inspired concentration of an inhaled agent is kept constant, the ratio of the inspired to the alveolar concentration (FA/FI) is significantly greater in the newborn compared with adults because of differences in ventilation and anesthetic uptake. Infants have three to four times the minute ventilation of older children and adults but the same functional residual capacity on an mL/kg basis (Table 63-2). Thus, inhalational anesthetics wash in (and wash out) rapidly because the time constant of the lung is so markedly reduced compared with in adults (0.19 min in infants vs 0.73 min in adults). Controlled ventilation further exacerbates this phenomenon.

The uptake of a potent vapor is very rapid in newborns as well. Because the mass of vessel rich organs is so small, the uptake of inhalational agents by the tissues is rapid, and tissue concentrations saturate quickly. Venous blood returning to the lung arrives at a relatively high anesthetic partial pressure compared with the case in adults, and this further reduces the FA/FI ratio and increases the amount of potent agent in the alveolus. This allows a higher concentration of inhalational agent to be taken up by the blood for delivery to the major organs. End-tidal gas monitoring may help prevent inadvertent overdosage. Finally, both left-to-right and right-to-left shunting occur in infants. A left-to-right shunt has little to no effect on anesthetic uptake, but a right-to-left shunt may slow the rate of rise of the arterial concentration of an inhaled anesthetic.

The minimum alveolar concentration (MAC) of all vapor anesthetics is also significantly lower in newborns than in infants 1 to 6 months of age. Furthermore, premature infants have lower MAC requirements than full-term infants. Thus, some of the hypotension associated with the inhalational agents may result from relative anesthetic overdose. Nevertheless, even at "true" MAC concentrations in newborns, heart rate and blood pressure decrease by 12% and 30%, respectively, with all vapor anesthetics. This can be partially attenuated by pretreating the infant with an intravenous (IV) anticholinergics such as atropine immediately before the induction of anesthesia.37 Atropine requirements in newborns are greater than in adults (0.03-0.05 mg/kg vs 0.01-0.02 mg/kg, respectively). Additionally, IV doses of atropine less than 0.1 to 0.15 mg may produce paradoxical bradycardia.

Characteristics of the myocardium in newborns also contribute to hypotension; newborns' myocardium are less compliant than those of older children and adults.38 Indeed, newborns have a fixed stroke volume and can increase cardiac output only by increasing heart rate. Additionally newborns' myocardium have decreased contractile mass and a decreased velocity of shortening. The negative inotropic and chronotropic effects associated with the inhaled anesthetics are therefore poorly tolerated. Furthermore, the baroreceptor reflexes are blunted or obliterated by these agents.27,39 Reflex tachycardia, which is vital in supporting blood pressure and cardiac output, may not occur.

Fentanyl(s)

Fentanyl and its structurally related relatives, sufentanil, alfentanil, and remifentanil, are highly lipophilic drugs that rapidly penetrate all membranes, including the blood-brain barrier. After an IV bolus, fentanyl is rapidly eliminated from plasma as the result of its extensive uptake by body tissues. The fentanyls are highly bound to alpha-1 acid glycoproteins in the plasma, but these are reduced in newborns.40,41 The fraction of free unbound sufentanil is significantly increased in neonates and children younger than 1 year of age (19.5% ± 2.7% and 11.5% ± 3.2%, respectively) compared with older children and adults (8.1% ± 1.4% and 7.8% ± 1.5%, respectively), and this correlates to levels of alpha-1 acid glycoproteins in the blood.41,42

Fentanyl pharmacokinetics differ among newborn infants, children, and adults. The total body clearance of fentanyl is greater in infants 3 to 12 months of age than in children older than 1 year of age or adults (18.1 ± 1.4, 11.5 ± 4.2, and 10.0 ± 1.7 mL/kg/min, respectively), and the half-life of elimination is longer (233 ± 137, 244 ± 79, and 129 ± 42 min, respectively).41,42 The prolonged elimination half-life of fentanyl from plasma has important clinical implications. Repeated doses lead to accumulation of fentanyl and resulting ventilatory depressant effects. Very large doses (0.05-0.10 mg/kg) may be expected to induce long-lasting respiratory depression because plasma fentanyl levels will not fall below the threshold level at which spontaneous ventilation occurs during the distribution phases.43

Robinson and Gregory44 reported the first use of fentanyl, 30 to 50 mcg/kg, as the principal anesthetic in neonates undergoing ductus ligation surgery. Using heart rate and blood pressure responses as an index of adequate anesthesia, they demonstrated that the combination of fentanyl, oxygen, and pancuronium could provide anesthesia with minimal hemodynamic consequences, and these findings have been confirmed by several other investigators.11,45 In all reported studies, both hypotension and bradycardia are rare as long as the infant is preloaded with a fluid bolus of a balanced salt solution (20 mL/kg) and a vagolytic agent (either pancuronium or atropine) is administered concomitantly. Furthermore, in newborn lambs, fentanyl does not significantly affect heart rate, blood pressure, cardiac output, or the regional distribution of blood flow to the major organs (eg, the brain and gastrointestinal tract) when it was administered in doses ranging between 30 and 3000 mcg/kg.46 However, the safety of "fentanyl" anesthesia may be diminished when other anesthetics, such as nitrous oxide, barbiturates, or benzodiazepines are administered concomitantly.47,48

Yaster45 extended the observations of Robinson and Gregory44 in a prospective study of premature and full-term infants younger than 7 days of age undergoing a variety of thoracic, abdominal, and genitourinary emergency operations. In Yaster's45 study, fentanyl in doses of 10 to 12.5 mcg/kg produced insignificant hemodynamic changes and provided reliable anesthesia for at least 75 minutes. There are reasons for the discrepancies in fentanyl requirements in these studies. Whereas Robinson and Gregory44 studied premature infants varying in age from 1 day to 6 weeks undergoing thoracic surgery, Yaster's45 patients were younger (the majority were "newly born," ie, less than 24 hours old). Analgesic requirements reduced in the first few days of life, perhaps because endogenous opioids are released in response to birth or to fetal and neonatal distress. As mentioned, the blood–brain barrier is immature in the first few days of life, and this may allow more fentanyl to reach the μ-opioid receptors within the central nervous system, although this is more important for less lipid-soluble agonists such as morphine. Alternatively, the increased fraction of free, unbound fentanyl in newborns may allow more drug to penetrate into the brain. Additionally, fentanyl clearance increases markedly in the first weeks of life, probably as a result of increasing activity of the CYP450 system and increasing hepatic blood flow after closure of the ductus venosus. Thus, the increased fentanyl metabolism that occurs in older newborns may increase their anesthetic (fentanyl) requirements. Finally, many of the patients in Yaster's study underwent abdominal surgery or had significant abdominal pathology such as necrotizing enterocolitis (NEC). Fentanyl clearance as well as analgesic requirements may be significantly decreased in these situations, particularly if intra-abdominal pressure is increased. Increased intra-abdominal pressure (>15-20 mmHg) markedly reduces liver and splanchnic blood flow and has been documented to occur after closure of abdominal wall defects such as omphalocele or gastroschisis.24,25 This decreased liver blood flow reduces fentanyl biotransformation and thereby anesthetic requirements. Thus fentanyl dose may depend on the neonate's postnatal age; on the type of surgery being performed; and on patient factors such as acidosis, hypoxia, and circulatory instability.

The use of fentanyl in newborns may result in the need for postoperative intubation and ventilation independent of the infant's medical or surgical condition. All opioids produce profound respiratory depression in newborns. A number of studies suggest that the respiratory depression and analgesia produced by μ-opioid agonists involve different receptor subtypes. These receptors change in number in an age-related fashion and can be blocked by naloxone. Zhang and Pasternak49 and Pasternak et al50 showed that 14-day-old rats are 40 times more sensitive to morphine analgesia than 2-day-old rats and that morphine decreases the respiratory rate to a greater extent in the 2-day-old animals. Thus, newborns may be particularly sensitive to the respiratory depressant effects of the commonly administered opioids.

The need for early extubation and minimal residual respiratory depression has led to the increased use of remifentanil in newborn anesthesia practice.51,52 Remifentanil is primarily metabolized by plasma esterases. The pharmacokinetics of remifentanil are characterized by small distribution volumes, rapid clearances, and low variability compared with other IV anesthetic drugs.53,54 The drug has a rapid onset of action (half-time for equilibration between blood and the effect compartment, 1.3 min) and a short context-sensitive half-life (3-5 min). The latter property is attributable to hydrolytic metabolism of the compound by nonspecific tissue and plasma esterases. Virtually all (99.8%) of an administered remifentanil dose is eliminated during the "half-life (0.9 min) and $half-life (6.3 min). The pharmacokinetics of remifentanil suggest that it will reach nearly steady state within 10 minutes of starting an infusion, so changing its infusion rate will produce rapid changes in drug effect. The rapid metabolism and small Vd mean that remifentanil will not accumulate. Discontinuing the drug rapidly terminates its effects regardless of how long it was being administered.43,55 Finally, the primary metabolite has little biologic activity, making it safe even in patients with renal disease. Collectively, these properties are especially advantageous for opioid administration in newborns.

Muscle Relaxants

The structural and functional development of the neuromuscular system is incomplete at birth.56 In fact, newborns have decreased neuromuscular reserve compared with older children and adults. At a stimulation rate of 20 Hz, many neonates demonstrate tetanic fade, and premature infants demonstrate posttetanic exhaustion.57,58 At a higher stimulation rate (50 Hz), all newborns demonstrate posttetanic exhaustion. The train-of-four ratio and the magnitude of posttetanic facilitation all increase with age. Based on these findings and on clinical criteria, it has been suggested that newborns are more "sensitive" to nondepolarizing muscle relaxants than older patients and should theoretically require less drug to produce neuromuscular blockade.56

However, this is counterbalanced by an increased ECF space and a larger apparent Vd.17 Thus, a first dose of a paralytic agent may on a mg/kg basis have the same effect and duration of action in the newborn as it does in older children and adults. However, subsequent doses may have a prolonged duration of paralysis.

At appropriate doses, all of the nondepolarizing muscle relaxants are effective paralytics in newborns, and the choice of which to use is more often based on their duration, side effects, and elimination profiles. Because pancuronium is a potent vagolytic, it remains one of the most commonly used agents in newborns.59 Unlike in adults, tachycardia is often a desired side effect because infants respond to a variety of stimuli, such as hypoxia, intubation, and fentanyl administration, with bradycardia. Because newborns' cardiac output is heart rate dependent, bradycardia can potentially be catastrophic. Occasionally, other relaxants (eg, cis-atracurium) are selected because end-organ pathology (liver or kidney) may interfere with drug elimination or because the onset or duration of paralysis is inappropriate for the surgery being performed.

Interestingly, newborns are relatively resistant to succinylcholine even though plasma cholinesterase levels are reduced after birth. IV doses of 1 to 2 mg/kg, rather than 0.5 mg/kg, are required for complete paralysis. IV succinylcholine produces myriad arrhythmias, including sinus bradycardia, sinus arrest, nodal rhythms, and ventricular ectopy, even with a first dose. Furthermore, several neonates have developed pulmonary edema and hemorrhage in the absence of upper airway obstruction after IV use of succinylcholine.60 Other well-known complications of succinylcholine include malignant hyperthermia, hyperkalemia, myoglobinemia, and increased intraocular (?intracranial) pressure. Because of these effects, increasing numbers of pediatric anesthesiologists are discouraging the routine use of this drug. Nevertheless, succinylcholine "remains one of the most rapidly acting neuromuscular blocking agents available, and despite the problems associated with its use, there is no substitute for it when "full stomach" precautions are required or when laryngospasm occurs. Thus, the authors' practice is to "always have it; rarely use it."

Ketamine, General Anesthetics, Sedatives, and the Developing Brain

As pointed out in Chapter 25, most studies of anesthetic and analgetic drugs (in any age group) have been short-term evaluations, often tied to the perioperative interval only. However, 10 years of accruing data from animal studies suggest that almost all of the commonly used anesthetic and sedative agents used in general anesthesia can be neurotoxic and that young developing brains may be particularly vulnerable to such injury.57 Furthermore, it is increasingly clear that many anesthetic and sedative agents are agonists at the gamma-aminobutyric acidA (GABAA) receptor and as antagonists at glutamic acid (glutamate) receptors such as the N-methyl-D-aspartate (NMDA) receptors.58-65 When anesthetic or sedative drugs bind to these receptors in vulnerable periods in brain development, programmed cell death (apoptosis) may occur with potentially catastrophic consequences.

In brief, the GABAA receptor is a ligand-gated ion channel that selectively conducts chloride ion through its pore, resulting in hyperpolarization of neurons.66,67 This inhibits neurotransmission and diminishes the occurrence of action potentials. The active site of the GABAA receptor is the binding site for GABA and several drugs such as bicuculline. The protein also contains a number of different allosteric binding sites that modulate the activity of the receptor indirectly and increase the efficiency of chloride conductance. These allosteric sites are the targets of various drugs, including the benzodiazepines, barbiturates, ethanol, neuroactive steroids, and the inhaled vapor general anesthetics, among others.66-68 Mild inhibition of neuronal firing at the GABAA receptor causes a reduction of anxiety or amnesia in patients, and more pronounced inhibition induces an anticonvulsant effect, sleep, and general anesthesia.

The NMDA receptor (NMDAR) is the predominant molecular device for controlling synaptic plasticity and memory function.69-71 The NMDAR is a specific type of ionotropic glutamate receptor.72,73 Activation of NMDA receptors results in the opening of an ion channel that is nonselective to cations. A unique property of the NMDA receptor is its voltage-dependent activation, a result of ion channel block by extracellular magnesium (Mg2+) ions. This allows voltage-dependent flow of sodium (Na+) and small amounts of calcium (Ca2+) ions into the cell and potassium (K+) out of the cell. A positive change in transmembrane potential will make it more likely that the ion channel in the NMDA receptor will open by expelling the Mg2+ ion. This allows more Ca2+ flux through NMDARs and is thought to play a critical role in synaptic plasticity, a cellular mechanism for learning and memory. The NMDAR is distinct in 2 ways: First, it is both ligand gated and voltage dependent; second, it requires coactivation by 2 excitatory ligands, glutamate and glycine.

NMDAR antagonists such as ketamine, phencyclidine (PCP), nitrous oxide, xenon, and ethanol have general anesthetic and analgesic properties.67,69,74,75 In addition, some opioids, particularly methadone, are also NMDAR antagonists, and it is this property that makes methadone so effective in treating neuropathic pain. Of the NMDAR antagonists, ketamine is the most commonly used as a general anesthetic. It is a hallucinogen that produces an altered or "dissociative" level of consciousness. Ketamine has many salutary properties that make it an ideal anesthetic in patients with congenital heart disease, those who are hemodynamically unstable, and those who have asthma. It increases both systemic and pulmonary vascular resistance and is often used in newborns with known congenital heart disease and in newborns in whom the ductus arteriosus and the foramen ovale are still open.

Olney and colleagues have shown that even a brief exposure to NMDAR antagonists or GABAA receptor agonists during vulnerable developmental ages in rats can cause apoptotic neurodegeneration ("Olney lesions").57,58,61,63,65,76-78 These studies in combination with a few epidemiologic studies in older children who were exposed to these agents as newborns and infants have fueled concern regarding the safety of general anesthesia in infants and young children.79,80 Wilder and colleagues79 performed a retrospective analysis based on the educational and medical records of all children who were born to mothers living in Olmsted County, Minnesota, from 1976 to 1982, and who remained in that community at age 5 years. They found that the risk of developing a learning disability increased with the number of exposures to anesthesia (greater than one exposure) before age 4 years. A single anesthetic exposure was not associated with increased risk. Furthermore, the longer the cumulative duration of anesthetic exposure, the greater the risk of learning disability. It is unclear if it is the anesthesia exposure that is the risk factor for the development of these learning disabilities or if multiple and prolonged anesthetic exposures are a marker of other comorbidities and causative factors. DiMaggio et al81 retrospectively reviewed the New York State Medicaid program data from 1999 to 2002. They found that in children younger than age 3 years, there was an association between surgery and anesthesia for inguinal hernia and subsequent behavioral and developmental learning disorders in children. The extrapolation of the results from experimental animal studies combined with the newer epidemiologic studies in children has aroused concern regarding the safety of general anesthetics in children with developing brains. It is somewhat reassuring that the greatest risks for anesthetic-related neurodegeneration involve multiple anesthetic exposures,82-86 the use of a combination of anesthetic drugs, high doses of specific drugs (higher than commonly used in clinical practice), and prolonged drug administration.87

Nonetheless, we are left with the dilemma: Are these and other drugs that we routinely use in newborns to provide anesthesia safe?88 The animal studies showing deleterious neurologic effects of anesthetic drugs have been in the absence of surgery, but pain in newborn rats and young children has also been shown to cause neuroapoptosis and memory impairment. So, there may be serious consequences to developing brains when not providing analgesia and anesthesia for surgery as well. Further study in this area is needed and will likely influence future pediatric anesthesia practice.

Local Anesthetics

All currently available local anesthetics work by blocking sodium ion flux through open, voltage-gated sodium channels and are of 2 classes: amino amides and amino esters.89,90 The amino amides, lidocaine, bupivacaine, and ropivacaine, are metabolized in the liver by the CYP450 (CYP linked) isoenzymes. Details of local anesthetic pharmacology are provided in Chapter 45. These metabolic pathways are markedly diminished in function in the neonatal period and therefore clearance of these drugs will be greatly reduced.91,92 As mentioned, these drugs are bound to plasma proteins, which are reduced in newborns. Thus, more unbound or free drug is available, and the potential for severe toxicity is increased. In contrast, the amino esters are metabolized by plasma esterases. These enzymes are also reduced in quantity and function in newborns, but the clearance of amino esters is much less impaired than that of amino amides.

Critically ill neonates undergoing emergency surgery require as much, if not more, monitoring than do critically ill adults because the margin of error is so small and because disaster can strike so quickly. Unfortunately, compromises are often made because of the technical difficulty in monitoring small children and because, after they are positioned and draped on the operating room (OR) table, observation, palpation, and even auscultation are often difficult, if not impossible. Meticulous attention to detail is absolutely necessary; no machine can replace a vigilant anesthesiologist who constantly evaluates analyzes, interprets, and acts on the patient's condition.

One of the simplest and most effective monitors in newborn anesthesia is the precordial or esophageal stethoscope. Stethoscopy provides beat-to-beat, breath-by-breath information on the patient's condition. For example, the first indication of cardiovascular deterioration in children may be a change in heart sounds, from brisk and close to muffled and distant. Loss of breath sounds may indicate a mechanical disconnection or an endobronchial intubation well before a mechanical alarm sounds. Despite its historical importance, this simple, effective, and inexpensive monitor is rapidly becoming as extinct as the slide rule and rotary dial telephone.

Only slightly less important than the precordial stethoscope is the pulse oximeter. This noninvasive, beat-to-beat monitor has revolutionized anesthesia monitoring and should be used not only in the OR but also in transport to and from the OR as well.93 In neonates, the probe is preferentially placed to measure preductal oxygen saturation because in the presence of intracardiac shunting, it best reflects what the brain is "seeing." This is easily accomplished by placing the probe on the right hand, ear lobe, or buccal mucosa and is used to maintain an oxygen saturation between 90% and 95% (PaO2 of 50-70 mm Hg). Higher oxygen saturations may produce retinopathy of the premature (ROP). Indeed, because of intracardiac shunting, many anesthesiologists use 2 pulse oximeters, one on the right hand and one on the lower extremity, to measure pre- and postductal flow. Preductal arterial oxygen saturation reflects coronary and cerebral oxygen saturation, and the cerebral oxygenation affects the eyes and is responsible for ROP. Nevertheless, in our zeal to protect the eyes, we must never compromise oxygen delivery to the neonate's brain!

The next most important monitor is blood pressure. Newborns, particularly premature newborns weighing less than 1.5 kg, may have normal systolic blood pressures of only 40 to 50 mm Hg. Blood pressure measurement and control become Herculean tasks. Indeed, this explains in part why many pediatric anesthesiologists prefer fentanyl-based anesthetics to inhalational agents when providing anesthesia for surgery in newborns. In most cases, blood pressure can be adequately measured with an appropriately sized blood pressure cuff and commonly available noninvasive automatic blood pressure devices. Occasionally, a Doppler ultrasonic transducer or a strategically placed oxygen saturation probe can help in blood pressure measurement. However, for most major operations, continuous intra-arterial monitoring is indicated for the safe conduct of anesthesia. Catheterization of preferably the radial artery is accomplished either percutaneously or by surgical access. The temporal arteries must be avoided for intra-arterial cannulation because catastrophic brain injury, presumably from embolization of clot and debris, has been associated with its use. Alternative catheterization sites include the dorsalis pedis, the posterior tibial, and the umbilical artery. The arterial catheter provides beat-to-beat monitoring and access to sample blood gases, hematocrit, and glucose, and it is an extremely sensitive guide of the intravascular volume status. Finally, meticulous attention to detail and technique is needed when flushing these catheters. We recommend high-pressure, low-volume tubing and after aspiration of blood for sampling flushing the tubing with 0.5 to 1 mL of saline to minimize the risk of embolization into the cerebral circulation.

Judging intravascular volume clinically is extremely difficult in neonates. During abdominal surgery (eg, NEC) third-space fluid losses may approach 100 to 200 mL/kg. Analysis of the arterial wave form from an indwelling intra-arterial catheter is one of the best methods of evaluating and detecting early intravascular volume losses (Fig. 63-1). One looks for either a change in the shape of the wave form (decreased area under the curve) or the development of respiratory variation in the wave form. During positive-pressure ventilation, decreased venous return causes a decease in the arterial wave form with each breath; this decrease is dramatically more evident when the intravascular volume has been depleted.

In adults, the more commonly used monitors for measuring (or estimating) intravascular volume include either a central venous or a pulmonary artery catheter. Historically, central venous pressure (CVP) measurements in newborns have been considered both technically difficult and insensitive to volume status. Experiments done in the 1960s during exchange transfusions demonstrated little correlation between blood losses of as much as 20% of the estimated blood volume (EBV) and CVP as measured by umbilical central venous catheters.94 Unfortunately, these experiments have never been repeated with central venous catheters placed in the internal or external jugular veins and pressure transduced with modern equipment. In our experience, measurement of the CVP is very useful, particularly in surgery involving major blood or third-space loss or shock or when intra-abdominal pressure is elevated.24,25 Furthermore, because these are large-bore catheters securely inserted within the vascular tree, usually the internal jugular vein, they supply a reliable means of administering fluids and vasoactive drugs.

One of the mainstays in the assessment of volume status of the newborn is the measurement of urine output (or lack thereof). Bladder catheterization is easily accomplished using a 5-Fr feeding tube (not a balloon-tipped Foley catheter). The catheter is secured to the skin with tape and connected to a calibrated urinometer by low-volume tubing. Minimum acceptable urine outputs range between 0.5 and 1.0 mL/kg/h.26,95 Unfortunately, in very small children, this small volume of urine may take hours to travel under the surgical drapes to the urinometer. Additionally, the drainage tubing is usually not easily accessible to the anesthesiologist, making identification of kinks and disconnects almost impossible. Because of this, measurement of urine output during surgery may be of marginal value.

Because neonatal anesthesia is virtually always performed with controlled mechanical ventilation, respiratory monitoring with capnography is essential. Despite the many technical problems involved in measuring end-tidal carbon dioxide concentrations through small uncuffed endotracheal tubes, it is a "standard of care" and is a mandatory monitor for the provision of safe anesthesia.96,97

Last, but not least, is temperature monitoring. All newborns are at extraordinarily high risk of becoming cold during transport to and from the OR and while in the OR. To minimize this risk, we routinely wrap children in plastic bags; use forced-air heating mattresses; increase the ambient temperature of the OR (usually above 90°F); and use warm IV fluids and heated, humidified respiratory gases.98,99 Temperature is routinely monitored with either a rectal or a nasopharyngeal temperature probe. We strive to maintain core temperature at 36°C to avoid the consequences of hypothermia. These include hypoventilation or even apnea, relative anesthetic overdose (reduced MAC at lower temperatures), metabolic acidosis, norepinephrine secretion, and increased oxygen demand. Increased oxygen demand to maintain normal core temperature and increased norepinephrine secretion may cause pulmonary and peripheral vasoconstriction, right-to-left shunting, anaerobic metabolism, and increased acidosis and oxygen consumption, all of which may exacerbate preexisting cardiopulmonary insufficiency.

Intraoperative IV fluid therapy provides infants with maintenance requirements of water, electrolytes, and glucose to replace preoperative deficits and ongoing intraoperative "third-space" and blood losses. Maintenance fluid requirements are calculated based on the assumption that 100 mL of water is required for every 100 calories consumed. The newborn's energy requirements are 100 calories/kg/24 h. Thus, fluid requirements are 100 mL/kg/24 h or approximately 4 mL/kg/h.100 Although basal caloric requirements are significantly reduced under general anesthesia, we continue to provide maintenance fluid, usually with 5% to 10% (50-100 mg/mL) glucose, at a rate of 4 mL/kg/h delivered by an infusion pump.

Because the majority of newborns presenting for emergency surgery are in neonatal intensive care units (NICUs) and are receiving IV fluids before surgery, the logical presumption is that preoperative deficits are nonexistent. Unfortunately, this is rarely true. Most newborns are fluid restricted in the NICU despite the presence of a surgical emergency and third-space fluid losses. Furthermore, infants are rarely given solutions containing electrolytes even though the newborn's kidney cannot tolerate a water load and will waste sodium even when water overloaded. Indeed, the maximum urine osmolality achievable by the neonatal kidney is only 800 mOsm/L. When combined with anesthetic drugs, unsuspected hypovolemia can be catastrophic. Thus, before the induction of general anesthesia in neonates requiring emergency surgery, we routinely provide a fluid bolus of 20 mL/kg of Ringer lactate solution in an attempt to ensure an adequate preload. An additional 10 to 20 mL/kg may be necessary if there is evidence of hemodynamic instability (eg, tachycardia, hypotension).

Surgical trauma and manipulation or inflammation of the bowel results in internal sequestration of functional ECFs and is often referred to as "third-space" losses. The fluid and salt within the third space acts as sequestered fluid and is nonfunctional in terms of the duties of the ECF. Replenishment of this interstitial water and salt loss with balanced salt solutions ("isotonic crystalloid solutions"), such as Ringer lactate or normal saline, is essential. The magnitude of the third-space loss depends on the site and extent of injury. Abdominal surgery, particularly if there is extensive bowel pathology or manipulation, may require third-space replacement therapy of 10 to 20 (or more) mL/kg/h, whereas, peripheral or thoracic surgery may require only 3 to 5 mL/kg/h.

All blood loss must be replaced with a balanced salt solutions, 5% albumin, or blood. Normally, infants are born with high hematocrits (>50%), which decrease to 30% over the first 3 months of life. Additionally, these red blood cells (RBCs) are made primarily of hemoglobin F (HbF), which has a greater affinity for oxygen than adult hemoglobin (HbA). Indeed, the partial pressure at which 50% of hemoglobin is saturated (P50) is 19 for HbF versus 27 for HbA. Because newborns have limited stores of iron and limited ability to replace lost RBCs, the hematocrit (Hct) should not be allowed to fall below 35% during surgery. The allowable blood loss before transfusing can be estimated at 20 mL/kg or can be calculated by the following formula:

As an example, assume a 3-kg, full-term infant with a 45% (0.45) starting hematocrit is undergoing surgery. The EBV would be 90 mL/kg (see Table 63-1), or 270 mL, and we would allow a blood loss to a hematocrit of 35% (0.35). Because the hematocrit of the blood lost is not constant, we use an average to estimate it. In this example, it would be 40% (45 + 35 = 80/2 = 40). Thus, the allowable blood loss is 67.5 mL (3 × 90 × 0.1/0.4). Ideally, blood would be replaced with fresh whole blood because it contains platelets and clotting factors as well as RBCs. Unfortunately, this is rarely, if ever, available. Packed (PRBCs) are usually used instead. This blood product typically has a hematocrit of 60% to 70%; high potassium concentration; and little, if any, of factors V and VIII. Large blood losses and massive RBC cell transfusion (2-3 times the EBV) often produce a secondary coagulopathy and hyperkalemia.97 This bleeding is often caused by either dilutional or consumptive thrombocytopenia. Platelets can be transfused based on the following formula:

Fresh-frozen plasma is rarely necessary and should be given only when a legitimate indication exists, such as a documented factor deficiency or intraoperative bleeding with massive blood transfusion. All blood products, including fresh-frozen plasma, may be contaminated with viruses. Additionally, newborns should be considered immune compromised hosts. Therefore, one should consider irradiating any blood product that may contain white blood cells before transfusion because of the possibility of producing a graft-versus-host reaction. Finally, all banked blood (especially older blood) contains significant amounts of potassium.101 Life-threatening hyperkalemia has occurred after large-volume blood transfusions in newborns and may be prevented with washed RBCs or fresh whole blood.102

Understanding the anatomic differences among infants, children, and adults is crucial for successful airway management in normal children and children with congenital anomalies (Fig. 63-2). Infants younger than 3 to 6 months of age are obligate nose breathers. Anatomic (eg, choanal atresia), physical (eg, nasogastric tube), or infectious obstruction of the nasopharynx rapidly causes respiratory distress or failure. The abundant and friable lymphoidal tissue of the nasopharynx also precludes the routine placement of nasopharyngeal airways in this age group when treating upper airway obstruction.

The tongue is relatively large in relation to the mandible in children younger than 2 years of age, making visualization of the larynx difficult. Indeed, the tongue most commonly obstructs the upper airway when consciousness is lost after the induction of anesthesia. The larynx is also difficult to visualize because it is anterior and more cephalad in the newborn. It is located at C2-C3 vertebrae in infants and C4-C5 in adults. The vocal cords are also different in their appearance. In infants, they are 40% ligament and 60% arytenoid cartilage. These ratios are reversed in adults.

In infants, the epiglottis is omega-shaped floppy, and has a 45-degree angle of entry into the pharyngeal wall. Visualization of the larynx requires lifting the epiglottis directly with an appropriately sized straight laryngoscope blade ("0" or "1" Miller blade). In contrast, in adults, the epiglottis is stiff, flat, and parallel to the tracheal wall. Visualization of the larynx can be made indirectly by placing the laryngoscope blade in the vallecula (Fig. 63-3). The trachea is different as well. The narrowest part of the airway in children younger than 8 to 10 years of age is the cricoid ring. Uncuffed endotracheal tubes, usually 2.5 to 3.5 mm in diameter, are used in neonates to prevent damage to the mucosa underlying this structure. Furthermore, the trachea in infants may be only 4 to 5 cm in total length. This makes inadvertent endobronchial intubation extremely likely even by very experienced practitioners. To minimize this risk, we use the "1-2-3 … 7-8-9" rule to assist in correct endotracheal tube positioning. The "1-2-3" refers to the patient's weight in kilograms, and the "7-8-9" refers to the position of the endotracheal tube in centimeters at the patient's lip. An alternative estimation is: "6 + weight in kg = Position of the endotracheal tube in centimeters at the patient's lip." Thus, a 1-kg infant would have the tip of the endotracheal tube taped at the 7-cm mark at the lip. Proper positioning of the endotracheal tube can be made by auscultation (return of breath sounds after a deliberate right main stem intubation), palpation of the tip of the endotracheal tube in the sternal notch, inspection of the distal line marker at the level of the vocal cords, and by chest radiography. After being positioned, the endotracheal tube must be secured in place with adhesive tape in a way that minimizes the likelihood of dislodgement or accidental extubation. The "fishmouth" technique is the authors' preferred technique (Fig. 63-4).

Because of the anatomic considerations listed above and because newborns rapidly desaturate after only 15 to 20 seconds of apnea or breath holding, in the past, many anesthesiologists believed it was safer to intubate newborns' tracheas "awake." This is no longer true. Increasing evidence indicates that awake intubation may cause intraventricular hemorrhage in fragile, premature newborns.103,104 Furthermore, awake intubations are technically more difficult to accomplish and often result in trauma to the vocal cords, hemorrhage, bradycardia, and desaturation secondary to breath holding. The authors prefer to use a "rapid sequence" induction in infants requiring "full stomach" precautions, that is, infants who are at risk of aspirating their gastric contents (eg, intestinal obstruction, NEC) and who on physical examination have a normal airway. After fluid volume resuscitation (10-40 mL/kg of Ringer lactate), preoxygenation, and pretreatment with atropine (0.15 mg), gentle cricoid pressure is applied to occlude the esophagus.105,106 If cricoid pressure is applied too vigorously, the position of the larynx may be distorted or the trachea itself occluded. In hemodynamically stable patients, a rapid-sequence IV induction can be accomplished by bolus administration of 4 to 7 mg/kg of thiopental, 2 to 3 mg/kg of propofol, 2 to 4 mg/kg of ketamine, or 12.5 mcg/kg of fentanyl immediately followed by 2 mg/kg of succinylcholine or 0.9 to 1.2 mg/kg of rocuronium.107,108 Newborns not requiring full-stomach precautions are in the minority (eg, myelomeningocele or bladder exstrophy), and in these patients, anesthesia can be induced by inhalational agents delivered by mask or IV without cricoid pressure.

The spectrum of surgical emergencies that may occur in the first few weeks of life is extensive; the following discussion focuses on the most common ones, but the basic principles provided can be applied to conditions that are not specifically discussed.

Congenital Diaphragmatic Hernia

One of he most challenging of all neonatal surgical emergencies, this malformation involves herniation of the abdominal viscera into the thorax; it has a high (20%-50%) mortality rate regardless of the method of treatment.109-111 Even early prenatal ultrasound diagnosis and attempts at in utero, fetal surgical correction, has done little, if anything, to affect outcome. The incidence of this devastating problem, which has significant short- and long-term morbidity, is reported to be 1 in 2000 to 5000 live births.111,112

In its most common presentation, the abdominal viscera, including the small bowel and colon, liver, and occasionally the kidneys, herniates into the left hemithorax during the first or second trimester of affected pregnancies and interferes with the development of both the lung parenchyma and its blood supply. Infants born with this anomaly present with the classic triad of dyspnea, cyanosis, and apparent dextrocardia. Physical examination reveals a scaphoid abdomen, bowel sounds in the chest, distant or displaced heart sounds, and absent breath sounds in the affected chest. Chest radiography demonstrates loops of gas-filled bowel or a gastric tube in the affected chest; mediastinal shift; absent lung markings in the affected chest; and most ominously, a contralateral pneumothorax. Pneumothorax is an iatrogenic complication that usually occurs as a result of vigorous attempts at ventilation, oxygenation, or resuscitation. The major differential diagnosis is a cystic adenomatoid malformation of the lung or congenital lobar emphysema. Approximately 20% of patients with congenital diaphragmatic hernia have associated congenital heart disease.

Surgical decompression of the herniated abdominal viscera (which may consist of midgut, stomach, colon, kidney, or liver) from the affected hemithorax and repair of the diaphragmatic defect, although essential in the management of this malformation, does not determine ultimate survival. Rather, outcome depends on the pulmonary vasculature and whether it will respond in an exaggerated, hyperreactive fashion to the stimuli that vasoconstrict and elevate pulmonary artery pressure.113,114 Histologic studies of the lungs of children born with this anomaly reveal decreased number and size of the bronchi, lung saccules, and alveoli and abnormalities of the pulmonary vascular bed. The numbers of pulmonary blood vessels are reduced, and the arterial muscularis and media are hypertrophied. Hyperactive pulmonary arterial vasoconstriction caused by hypoxia, hypercarbia, acidosis, pain, or positive-pressure ventilation can set in motion a catastrophic cycle of events in which desaturated blood returning to the lung is preferentially shunted across the still patent ductus arteriosus and atrial septum into the systemic circulation. This "right-to-left" shunting of blood across the ductus and atrial septum is a return of the circulation to the pattern that existed in utero and is referred to as persistent fetal circulation (PFC) or persistent pulmonary hypertension of the newborn (PPHN). The goal of anesthetic management is to prevent this catastrophic cascade from occurring by maximizing arterial oxygenation and preventing pain and metabolic or respiratory acidosis.

The most severely affected infants require immediate intubation and decompression of the stomach as soon as the diagnosis is suspected. This usually takes place in the delivery room or in the NICU before surgery. Medical management is directed at improving oxygenation and increasing pulmonary blood flow. This may be accomplished by the judicious use of muscle relaxants, analgesics, usually fentanyl (1-10 mcg/kg as an initial bolus followed by a continuous infusion of 3-10 mcg/kg/h), hyperventilation using rapid rates (> 100 breaths/min) and low inflating pressures, preventing hypothermia, and correction of acidosis with IV bicarbonate therapy. Interestingly, this is also the basis of intraoperative anesthetic management. Nevertheless, aggressive proactive management may be harmful; barotrauma and volume trauma from too vigorous ventilation may induce alveolar and capillary damage and induce a catastrophic inflammatory cascade. Inhalational anesthetic agents are mostly avoided because of their hypotensive and cardiac depressant effects, and nitrous oxide is contraindicated because it can diffuse into the bowel and further compromise lung function. The importance of inadequate cardiac output in PFC should not be overlooked. Decreased cardiac output leads to decreased pulmonary perfusion and further hypoxemia. Blood returning to the heart from poorly perfused organs arrives with a lower oxygen content that potentiates the hypoxemia caused by right-to-left shunting.

Bohn et al115 advocated the avoidance of the "mad dash" to the OR and recommend instead a 24- to 48-hour period of stabilization.116 Furthermore, they contend that infants who do not respond to this therapy will fail to survive with surgery or any other therapy, including extracorporeal membrane oxygenation (ECMO). Bohn et al117 also suggested a nomogram to predict the extent of pulmonary hypoplasia present in these infants and their chance of survival. They used the preoperative PaCO2 and correlated it and an index of ventilation that is determined by the mean airway pressure times the respiratory rate. If the PaCO2 could be reduced to less than 40 mm Hg and the ventilatory index was less than 1000, survival was almost universal. On the other hand, if PaCO2 and the ventilatory index were greater than 40 mm Hg and 1000, respectively, death was virtually inevitable. Interestingly, these latter infants were found at autopsy to have less than 10% of the normal number of alveoli bilaterally.

Others have approached newborns with congenital diaphragmatic hernia with a different perioperative management strategy.118 They work to stabilize these newborns preoperatively and bring them through their period of PPHN with a strategy of "gentle ventilation." Using low peak inflating pressures and permissive hypercapnia, they are careful to avoid iatrogenic damage from barotrauma to the already hypoplastic lungs of these newborns. After a period of stabilization, during which pulmonary arterial pressure falls, the patient is electively taken to the OR for surgical repair.

Blood loss is minimal during the surgical repair of this problem, and third-space losses can be assumed to average 8 to 10 mL/kg/h. Aside from routine monitoring, these patients require an intravascular arterial and central venous catheter for continuous blood pressure monitoring and for blood gas, hemoglobin, and blood chemistry sampling. Central venous access is obtained either via an umbilical vein or from the jugular or subclavian veins. If the latter approach is attempted, it is essential to avoid a pneumo- or hemothorax in the normal lung. A precordial stethoscope placed in the unaffected right axilla may help alert the anesthesiologist to one of the most feared intraoperative catastrophes, namely, the development of a contralateral pneumothorax. This is heralded by sudden hypoxia, hypotension, or both. Placement of a chest tube when this occurs may be lifesaving. In fact, some authors have suggested the insertion of a prophylactic chest tube on the contralateral side because this complication is so catastrophic.

Vasodilator therapy has also been advocated for perioperative control of the increased pulmonary artery pressures. IV agents suggested include isoproterenol, nitroglycerin, tolazoline, adenosine, and adenosine triphosphate. These are rarely effective because the pulmonary vasodilation produced is matched by an equal decrease in systemic vascular resistance. These have been largely replaced by inhaled nitric oxide (NO).119-121 NO diffuses across alveolar capillary membranes and stimulates cyclic guanylate cyclase, which increases cyclic GMP (cGMP). cGMP is a potent dilator of vascular smooth muscle. Because NO is rapidly metabolized by RBCs, it has a potent local effect and should preferentially dilate only the pulmonary vascular musculature. NO can be used anytime during the perioperative or intraoperative period as needed. Finally, the anesthesiologist should anticipate the possibility of a cardiac arrest during this operation, and vasopressors, including dopamine (4-10 mcg/kg/min) and epinephrine (0.1-1.0 mcg/kg/min) should always be available for emergency intraoperative administration.

The most recent and important innovation in the treatment of infants with congenital diaphragmatic hernia is the perioperative use of ECMO.122,123 Infants who either would not survive by Bohn's criteria or who develop a PFC pattern after a "honeymoon" period may be placed on ECMO to allow the infant's lungs time to develop and restructure. Unfortunately, decisions pathways about when to initiate ECMO therapy (either before or after surgery), when to operate if an infant is on ECMO, and when to withdraw ECMO support are not well defined; they remain parochial decisions that may differ even among physicians within the same institution.

Omphalocele or Gastroschisis

Abdominal wall defects are rare and although at first glance appear to be similar, they are in fact quite different. An omphalocele is a central, midline defect and is always associated with other congenital anomalies. It occurs because of failure of the gut to return to the abdominal cavity at the 10th week of gestation. The herniated bowel is covered by the amnion, which protects it from fluid loss; infection; and a chemical, amniotic fluid burn. The apex of the herniated sac is the umbilical cord. A gastroschisis, on the other hand, is not a midline defect and is therefore rarely associated with other defects. It results from an intrauterine vascular accident that results in the interruption of the abdominal wall and musculature. The herniated bowel is not covered by any membrane, is "burned" by the amniotic fluid, and is covered by an inflammatory coating or peel. It is subject to tremendous postnatal evaporative fluid losses as well as infection. In gastroschisis, the umbilical cord is found to the side of the herniated bowel.

The optimal method for operative management of infants with congenital abdominal wall defects remains controversial. Two options exist, either primary fascial closure with or without intra- and postoperative muscle paralysis or a staged repair using either a silicone elastomer silo or a primary skin closure. Primary fascial closure of omphalocele or gastroschisis carries the risk of placing the abdominal contents under pressure, which may produce a reduction in cardiac output, hypotension, bowel ischemia, venous stasis, and postoperative respiratory and renal failure.24,25,124 When primary fascial closure cannot be achieved, either because of the large size of the defect or because it critically compromises respiratory or cardiovascular function, the alternative approach is a staged repair using either a silicone elastomer silo or a skin closure with secondary fascial closure. When using the silo, the defect is reduced over several days until a stable infant with a small defect can be taken to the OR for final repair. The staged silicone elastomer repair carries an increased risk of infection.

Traditional criteria for deciding on which course to choose have been based on the size of the defect; the presence of associated congenital anomalies; or clinical observations of the infant's respiratory rate, pulmonary compliance, blood pressure, skin color, and peripheral perfusion during fascial approximation. Unfortunately, these clinical observations may not be reliable, particularly in paralyzed, anesthetized infants.

Anesthetic Management

Infants are transported to the OR by placing the exposed bowel in a bag designed for this purpose. It helps maintain normothermia and reduces evaporative fluid losses. Patients are fluid resuscitated with a balanced salt solution; preoxygenated; anesthetized with fentanyl (10-12.5 mcg/kg), pancuronium, and oxygen; and intubated. In addition to routine monitoring, we routinely place catheters in the right radial artery, an internal jugular vein, and in the stomach. An oral or nasal gastric tube both decompresses the abdomen and allows measurement of intragastric pressure by fluid filling the tube. Yaster et al24,25 suggested that successful management of omphalocele or gastroschisis can be successfully and reliably determined by the intraoperative measurement of intragastric and CVPs (Fig. 63-5). In this treatment algorithm, primary repair is always attempted. However, if the intragastric pressure rises above 20 mm Hg or the CVP increases by 4 mm Hg or more after closure of the abdominal fascia, the primary repair is abandoned and a staged repair with a silicone elastomer chimney is performed. This algorithm avoids the consequences of acutely elevating intra-abdominal pressure. After surgery, the patient is taken to the NICU intubated and placed on controlled mechanical ventilation. Infants treated with a staged repair have their chimneys gradually reduced over 5 to 10 days. Central venous and intragastric pressure can be used to guide this therapy as well.

Newborn infants with abdominal wall defects have significantly increased fluid requirements because of the increase in insensible losses that occur when eviscerated bowel is exposed to the environment. Additionally, they have enormous "third-space" losses because of the traumatized, inflamed bowel and adynamic ileus that develops perioperatively. Fluid requirements are even greater in gastroschisis patients because the herniated viscera lack a protective covering, resulting in a chemical burn preoperatively.

Intestinal Obstruction, Necrotizing Enterocolitis, and Pyloric Stenosis

Intestinal obstruction is among the most common surgical emergencies encountered in newborns and is characterized by feeding intolerance, bilious or projectile vomiting, and abdominal distension. Common sites of obstruction include the pylorus; duodenum; jejunum–ileum, particularly the terminal ileum; and the anus. NEC, on the other hand, is caused by a bacterial invasion of previously injured or ischemic bowel wall.125-127 It is characterized by intestinal obstruction, gangrene, perforation, intramural air ("pneumatosis intestinalis"), and peritonitis. Patients are usually premature and are often septic, hypotensive, thrombocytopenic, and in respiratory failure. Metabolic and respiratory acidosis and electrolyte disturbances are also common. Although the initial management is nonoperative and supportive (eg, decompression, antibiotics, correction of hematologic abnormalities), evidence of intestinal gangrene (eg, positive results of paracentesis), pneumoperitoneum, and clinical deterioration results in the need for emergency exploratory laparotomy.

Duodenal obstruction typically presents within the first hours of life and is extremely common in children with trisomy 21 (Down syndrome). An abdominal radiograph will show the classic "double bubble" sign or a dilated, air-filled stomach and proximal duodenum. Because these children present so early in life, usually within the first 12 hours, they are rarely dehydrated or hypochloremic. Small and large bowel obstructions typically present later, usually 2 to 7 days after birth, and are often associated with hemodynamic compromise and metabolic disturbances. Jejunal or ileal atresias are thought to be caused by intrauterine vascular accidents. Meconium ileus is an obstruction of the small bowel caused by inspissated, abnormal meconium and is pathognomic of cystic fibrosis. At the time of presentation, these infants do not have the lung disease associated with this devastating disease. Malrotations of the bowel also present with obstruction and are very common in patients with congenital diaphragmatic hernia and omphalocele or gastroschisis. Infants with Hirschsprung disease have a functional distal obstruction caused by a lack of ganglia in the rectum and distal colon. Imperforate anus, which should be readily obvious in the delivery room, requires special attention because of the many anomalies associated with it. At one time called the VATER syndrome for vertebral, anal, tracheoesophageal fistula (TEF), esophageal atresia (see below), and renal anomalies, this syndrome also has a 20% incidence of significant congenital heart disease. Patients diagnosed with it should have an echocardiogram obtained before surgery.

Finally, despite being a congenital defect, pyloric stenosis usually does not present until 2 to 6 weeks of age. This is one of the most common surgical emergencies in newborns. Infants with pyloric stenosis have prolonged, repeated projectile nonbilious vomiting that results in a hypochloremic, hypokalemic metabolic alkalosis and profound dehydration. Interestingly, one would expect that the body's response to this alkalosis would be to eliminate bicarbonate in the urine. However, the sodium losses in pyloric stenosis are so great and the dehydration so profound that hydrogen ion is wasted in the urine in place of sodium with a resultant "paradoxical aciduria." Although it is considered to be an urgent surgical procedure, pyloric stenosis never requires immediate emergency surgical correction. Rather, patients require fluid resuscitation, restoration of an effective circulating volume, and correction of metabolic derangements. Only when this is done should surgery and anesthesia be performed. An easy way to assess successful resuscitation is to measure urine pH. When the urine pH is no longer acidotic (pH >6), it is usually safe to proceed with anesthesia and surgery.

Regardless of the underlying pathology, the major anesthetic challenge with this entire group of surgical patients is maintaining an adequate circulating blood volume and preventing the pulmonary aspiration of gastric contents. Virtually all newborns presenting for emergency abdominal surgery are intravascularly depleted secondary to the enormous ongoing third-space losses. Sepsis, bowel manipulation, peritonitis, the use of contrast agents, and the release of vasoactive peptides significantly deplete the circulating blood volume and ECF space of water and electrolytes. In the presence of NEC, third-space fluid replacement therapy in the perioperative period may exceed 100 to 200 mL/kg/h. Fresh-frozen plasma, platelets, and PRBCs are often needed and should be used early in surgery in response to clinical and laboratory evidence of coagulopathy. Additionally, critically ill, septic patients may not be able to tolerate these enormous fluid shifts, and 4 to 10 mcg/kg/min of dopamine should be infused to help maintain blood pressure and blood flow. Both arterial and CVP monitors are required to monitor intravascular volume in these situations.

All newborns presenting for emergency abdominal surgery may aspirate their abdominal contents at the induction of anesthesia. Therefore, methods that minimize these risks, such as an awake intubation or a rapid sequence induction with cricoid pressure, must be used. We prefer to maintain anesthesia with the fentanyl, pancuronium, and oxygen technique for this group of patients. Potent inhalational anesthetics are often poorly tolerated in this group of infants. Nitrous oxide is almost never used in these patients because it will further distend the bowel and complicate intestinal perfusion and fascial closure.

Esophageal Atresia and Tracheoesophageal Fistula

Ninety percent of infants born with a TEF have a blind esophageal pouch and a fistula connecting the distal esophagus and the distal trachea, usually within 1 to 2 cm of the carina (Fig. 63-6).128,129 About 30% to 50% of these infants have the associated anomalies of the VATER syndrome (see above). The most common associated defect is cardiac and necessitates an echocardiogram before surgery.130 Often suspected prenatally by polyhydramnios, infants present with excessive salivation ("mucousy mouth"), choking, coughing, aspiration pneumonia, and cyanosis. Attempts at feeding are met with explosive vomiting, and it is impossible to pass an oral (nasal) gastric tube. Indeed, a chest radiograph of a coiled oral gastric tube in the cervical esophageal pouch is diagnostic of TEF. Because of the potential for aspiration, contrast media should not be instilled to confirm this diagnosis.

The tracheal to distal esophageal fistula aerates the gastrointestinal tract and allows for regurgitation of gastric juice up the fistula into the lung. Thus, pulmonary aspiration occurs by 2 methods. The first involves aspiration of saliva or attempted feedings from the blind esophageal pouch and the second by gastric juice contamination via the fistula tract. If significant aspiration pneumonia occurs, definitive corrective surgery is deferred, and a decompressing gastrostomy is placed under local or caudal anesthesia.131

As soon as the diagnosis is confirmed, the child is placed in a head-up position, and the upper pouch is decompressed with a large-bore sump (Replogle) tube. After the diagnostic workup the child is transported to the OR for corrective repair, which has historically been performed through a right-sided thoracotomy. Increasingly, thoracoscopic surgical repair is being performed with excellent results.132,133 Routine monitors are placed. The authors highly recommend the use of a strategically placed precordial stethoscope during this surgical repair. The precordial stethoscope is placed in the left axilla and carefully secured in place with both a "double-stick" and clear plastic adhesive dressing. This immediately alerts the anesthesiologist to a change in the endotracheal tube position from the juxtacarinal position to the right mainstem bronchus. Adequate IV access and a radial artery catheterization complete the preinduction preparation.

Immediately before intubation, the infant is given 0.15 mg IV of atropine, and the esophageal pouch is suctioned. Then with the infant in a semi-sitting position, the trachea is intubated while the patient is awake. This allows the appropriate positioning of the endotracheal tube without positive-pressure ventilation, which can cause gastric distension through the fistula. Then, in the classic technique, with the infant spontaneously breathing sevoflurane, the endotracheal tube is positioned below the fistula but above the carina by deliberately intubating the right mainstem bronchus and then slowly pulling back the tube until breath sounds are heard in the left axilla and not in the stomach. Isolation of the fistula is possible because in most cases, the fistula is approximately 0.5 to 1.0 cm above the carina on the posterior surface of the trachea. If the endotracheal tube has a side ("Murphy eye") hole, it should be turned to the left, opposite to its normal orientation, to maximize left lung ventilation. Even if the endotracheal tube does not have a side hole, it is helpful to turn the bevel of the tube 180 degrees, so that the curve of the tube faces forward. This will reduce ventilation into the fistula and stomach. After being positioned, the endotracheal tube is secured with the "fishmouth" technique to avoid displacement of the endotracheal tube down the right main stem bronchus or, more ominously, into the fistula tract itself (see Fig. 63-4). Indeed, this is why the precordial stethoscope is so securely placed in the left axilla.

After the endotracheal tube has been positioned, anesthetic management is based on the presence or absence of a decompressive gastrostomy and by the preferential flow of gases down the path of least resistance, namely through the fistula tract into the stomach. Positive-pressure ventilation may allow oxygen and other gasses to bypass the lungs and acutely dilate the stomach. This interferes with ventilation and venous return and can lead to cardiopulmonary arrest and gastric rupture; if this occurs, an emergency decompressive gastrostomy may be lifesaving. Unfortunately, the insertion of a gastrostomy may substitute one problem for another. Airflow resistance through the fistula–stomach–gastrostomy may be so low that ventilation of the lungs becomes impossible. The gastrostomy may need to be intermittently clamped and unclamped or left partially clamped through the procedure. Some have advocated the use of a Fogarty catheter placed either through a bronchoscope or through a gastric endoscope to occlude the fistula tract if this becomes a problem.134 Great caution must be exercised when using a Fogarty catheter alongside an endotracheal tube; if the catheter slips out of the fistula tract into the trachea, it can completely occlude the end of the endotracheal tube. Thus, because of these myriad problems with positive-pressure ventilation, many anesthesiologists recommend an anesthetic technique that uses spontaneous ventilation with sevoflurane. Alternatively, others believe that paralysis may be a safe and effective alternative as long as the fistula can be effectively isolated by careful positioning of the endotracheal tube.

Unfortunately, in the authors' experience, it is rarely possible to have a spontaneously breathing newborn sufficiently anesthetized with sevoflurane without compromising blood pressure and oxygenation. This is particularly true in the repair of an esophageal atresia with TEF because this surgery is performed in the lateral position. An intriguing option, which is our preferred technique, is to supplement spontaneous ventilation with a potent vapor general anesthetic with a caudally placed thoracic epidural anesthetic.135,136

The caudal approach to the epidural space is remarkably easy to perform in newborns and does not require specialized equipment even though small-diameter Crawford needles (17-20 gauge) and catheters (19-24 Fr) are now commercially available. The epidural space of young children and infants is filled with loosely packed fat and blood vessels, making it possible to advance a caudally placed catheter as far as the thorax. Typically, either 0.5 to 1 mL/kg of 0.25% bupivacaine with epinephrine (5 mcg/mL) or 0.5 mL/kg of 3% chloroprocaine (15 mg/kg) with epinephrine is administered, and the inspired sevoflurane concentration is significantly reduced.132 Using this combination technique, patients can be adequately anesthetized and hemodynamically stable even while breathing spontaneously. Analgesia can be maintained with this technique postoperatively as well.

Surgery is performed in the left lateral decubitus position. During the surgical repair, the right lung is compressed and packed away, which may result in hypoxia. Additionally, the infant may become hypoxemic if the trachea or endotracheal tube is compressed and occluded by the surgeon. Alternatively, the endotracheal tube can become obstructed by blood clots or may migrate into the fistula tract. Thus, to provide a greater margin of safety, the authors routinely use 100% oxygen during these anesthetics even in premature infants who are at risk of developing retinopathy of prematurity.

Meningomyelocele

Failure of neural tube closure early in intrauterine development results in a spectrum of abnormalities ranging from spina bifida occulta, a relatively benign process, to myelomeningocele, an abnormality involving vertebral bodies, the spinal cord, and the brainstem. The brainstem lesion (ie, Arnold-Chiari malformation) may be the cause of rather than the effect of the failure of neural tube closure. Ninety percent of infants with myelomeningocele have Arnold-Chiari malformation, which consists of downward displacement of the brainstem and cerebellar tonsils through the cervical spinal canal. This together with an obliteration of the foramina of the fourth ventricle blocks the normal circulation of cerebrospinal fluid (CSF) and leads to progressive hydrocephalus. Associated skeletal anomalies, particularly of the lower extremities, and urodynamic problems are common, and patients born with this defect undergo multiple corrective surgical procedures in their lifetimes.137 Thus, fetal corrective surgery has been proposed and has shown some preliminary positive results.138,139

Infants with a meningomyelocele are transported to the OR in the prone position. The defect is covered with moist, sterile dressings, and great care is taken to avoid contamination and infection. If the meningocele is ruptured, Ringer lactate solution is used to replace CSF losses milliliter for milliliter or at an approximate rate of 4 to 6 mL/kg/h.

The infant must be turned supine for intubation, and positioning is crucial to facilitate this maneuver. A foam head ring or OR towels folded into a ring is covered with a sterile drape or towel. The baby is then turned to the supine position with the defect resting in the pocket of the ring. Towels are then placed under the child's back to build up a level platform for intubation (Fig. 63-7). Anesthesia is induced with either inhalational or IV agents (thiopental or propofol). Virtually any anesthetic technique is possible for this operation as long as it allows for rapid extubation after surgery. Succinylcholine does not cause catastrophic hyperkalemia in patients with this defect.140 After the trachea has been intubated, the endotracheal tube is secured with a "fishmouth" technique (see Fig. 63-4), and the infant is turned to the prone position for surgery.

Spinal anesthesia may be used alone or in combination with general anesthesia for this surgery. When combined with a general anesthetic, the patient is induced as described above. After being turned prone and surgery starts, the surgeon drops 0.5 to 0.7 mg/kg of hyperbaric tetracaine (5 mg/mL) directly into the open meningomyelocele sac.142 Within minutes, the concentration of inhaled general anesthetic is reduced to a level that provides immobility and allows the child to tolerate the endotracheal tube. Less commonly, spinal anesthesia may be used as the sole anesthetic for this repair. Using a small-gauge needle, 0.5 to 0.7 mg/kg of hyperbaric tetracaine (5 mg/mL) with epinephrine is injected into the most inferior region of the meningomyelocele sac. Supplemental doses are administered as described above for the combined approach.

The decision to place a ventricular-peritoneal (VP) shunt at the time of the initial surgery or several days later is a surgical one. Some surgeons defer placement of the VP shunt because they fear that the drain will become infected. Additionally, because 5% to 10% of these patients do not develop hydrocephalus, some surgeons prefer to wait until it develops rather than treating it expectantly.

Patent Ductus Arteriosus

After birth, the increase in arterial oxygen that occurs by breathing room air results in the closure of the ductus arteriosus. In premature infants, this may not occur and often results in a large left-to-right shunt, heart failure, pulmonary edema, and an inability to be weaned from mechanical ventilation. Medical management consists of fluid restriction, diuretic therapy, digoxin, and 0.2 mg/kg of the cyclooxygenase (COX) inhibitor indomethacin. Other COX inhibitors, such as ibuprofen, may also be effective.142,143 When they are not effective, surgical correction becomes essential if the child is to be weaned from mechanical ventilation. Unfortunately, in the smallest of premature infants (<1000 g), indomethacin is often unsuccessful because it significantly impairs renal function.

Because these infants have been fluid restricted and are intravascularly volume depleted before surgery, volume expansion with Ringer lactate solution is essential to prevent profound hypotension during the induction of anesthesia even when a fentanyl anesthetic is used. Fentanyl (10-50 mcg/kg has become the most common anesthetic technique used.8,46 Obviously, nitrous oxide must be avoided and 100% oxygen is often required to maintain oxyhemoglobin concentrations above 90%, especially after the chest is opened and the lung is retracted. Lung retraction, which is necessary to provide surgical exposure, may result in vagal stimulation, and if the infant has not been pretreated with atropine or pancuronium, bradycardia and hypotension results. During closure of the ductus, hemorrhage and exsanguination may occur if this fragile structure is inadvertently torn by the surgeon. Thus, typed and crossmatched blood should always be available before the start of surgery. Additionally, closure of the ductus is associated with an abrupt increase in diastolic blood pressure, which may contribute to the development of intraventricular hemorrhage in this patient population.

Recently, epidural anesthesia has been used to treat postoperative pain in these infants and to reduce intraoperative anesthetic requirements. Both local anesthetics and epidurally administered opioids are effective. Typically, opioids are administered via a caudal approach, and local anesthetics are administered via a caudally placed catheter that has been advanced to the thorax. Finally, because these infants are so fragile, many centers advocate the closure of a patent ductus in NICU rather than transporting the infant to the OR.144

Except for extraordinary circumstances, all newborns require anesthesia and analgesia for surgery. During the first month of life, newborns must function independently and adapt to extrauterine life. This involves anatomic, physiologic, and pharmacologic changes to maintain homeostasis and to ensure the infant's survival. Disease, congenital anomalies, surgery, and anesthesia may interfere with these adaptations and threaten survival. This chapter has attempted to provide an in-depth review of developmental physiology, pathophysiology, and pharmacology and common management techniques that are essential to provide safe, effective anesthesia care to newborns.

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