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 Chapter 7, Pharmacology of Pediatric Anesthesia). Maturational changes in distribution of total body water, tissue composition, and organ function contribute to the unique response of the newborn and young infant to various drugs. In early fetal development, water constitutes approximately 94% of body weight. As gestation continues, the total body water decreases so that at 32 weeks, 80% to 90% of body weight is water, and at term, total body water is approximately 70% to 75% of body weight. Adult proportions of fluid to body weight (55%) are reached between the ages of 9 months and 2 years. The distribution of water between the extracellular and intracellular compartments also changes during fetal growth. Extracellular water (interstitial fluid plus plasma volume) decreases from 60% of body weight at the fifth month of fetal life to approximately 45% at term. Intracellular water increases from 25% in the fifth month of fetal life to 33% at birth; therefore, the extracellular fluid compartment of the newborn is equal to or greater than the intracellular fluid space. In adults, the intracellular and extracellular fluid compartments are approximately 40% and 20% of body weight, respectively. Because the plasma component of the extracellular fluid compartment remains at approximately 5% of body weight throughout life, it is the interstitial water that is greater in infancy (40%) and declines to 10% to 15% in the adult (Friis-Hansen, 1971).

Age-dependent changes in body composition also occur. At term, fat constitutes 11% of body weight. Fat content doubles by 6 months of age and is approximately 30% at 1 year. Teenage girls remain with approximately 20% to 30% fat, whereas fat in teenage boys decreases to 10% to 15% fat. Moreover, the composition of fat tissue changes with age. Fat of the newborn may contain as much as 57% water and 35% lipids; adults have 26% water and 71% lipids (Friis-Hansen, 1971). Skeletal muscle comprises 25% of total body mass in a 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 α₁-acid glycoprotein is lower in early infancy and reaches adult levels by approximately 1 year of age (Pacifica et al., 1986). Albumin primarily binds acidic drugs; α₁-acid glycoprotein binds basic drugs. The concentration of these two proteins and their binding affinities are deficient in the newborn (Piafsky and Woolner, 1982).

The primary organ for drug biotransformation is the liver, but the 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 (Niems et al., 1976). 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 (Arant, 1978; Hook and Bailie, 1979). Tubular secretory and reabsorptive capacity also mature postnatally (Fetterman et al., 1965).

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

Inhaled Anesthetic Agents

Infants have a higher incidence of cardiovascular instability and cardiac arrest during induction of inhalational anesthesia than do older persons (Rackow et al., 1961; Friesen and Lichtor, 1982, 1983; Morray, 2000, 2002; Murat et al., 2004). This untoward effect of potent inhalational agents can be attributed to several factors, including faster equilibration, rapid myocardial uptake in infants, the increased anesthetic requirement, and sensitivity of the neonatal myocardium. Infants attain a higher concentration of inhaled anesthetic agents in the heart and brain than do adults at the same inspired concentration. Moreover, the neonatal myocardium has 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 is the rate of rise of the alveolar concentration. This effect of alveolar ventilation is affected by the size of the functional residual capacity (FRC). Infants and children have an FRC similar to that of the adult, 30 mL/kg per minute. In contrast, alveolar ventilation is much higher in the infant (100 to 150 mL/kg per minute) 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 for the adult. Consequently, changes in concentrations of inspired gas are reflected rapidly in alveolar levels. In fact, it has been demonstrated that alveolar levels of inhalational anesthetic agents reach equilibrium faster in infants that in adults (see Chapter 7, Pharmacology of Pediatric Anesthesia).

The rise of the alveolar concentration of an inhaled anesthetic is opposed by uptake of the agent into lung tissue and more 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 is 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 3 to 6 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 the cardiac output is predominantly distributed to the vessel-rich group and because the muscle group is small, the arterial-venous partial pressure difference narrows quickly in the young and thereby decreases uptake.

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

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 (Malviya and Lerman, 1990). The blood-gas partition coefficient is an important determinant of solubility and therefore the rate of rise of the alveolar concentration of an inhaled agent.

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

Minimal alveolar concentration (MAC) is an estimate of anesthetic requirement and changes with age (Fig. 18-1) (Katoh and Ikeda, 1987, 1992; LeDez and Lerman, 1987). In the original study, Gregory et al. (1969) reported that infants in the first 6 months of life had the highest MAC. In a later study, newborns were noted to require approximately 25% less halothane at MAC compared with infants who are between 1 and 6 months of age (Lerman et al., 1983) (see Chapter 7, Pharmacology of Pediatric Anesthesia).

FIGURE 18-1 Effect of age on MAC of anesthetic gases. The MAC of anesthetic gases is dependent on age. MAC is higher at birth than in adults and increases until peaking at 3 to 6 months. The values at 1 year of age are closer to the adult values.

(From Greeley WJ: Pediatric anesthesia, In Miller RD, editor: Atlas of anesthesia, vol 7, Philadelphia, 1999, Churchill Livingstone.)

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 (Kupferberg and Way, 1963; Way et al., 1965). These features have been attributed in part to the immaturity of the blood-brain barrier, allowing faster and greater penetration and therefore higher concentration of these drugs in the brain.

In 1981, Robinson and Gregory reported that 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 (Anand et al., 1987).

Plasma levels of fentanyl are lower in infants vs. children vs. adults (newborns were not studied) after similar intravenous doses (Singleton et al., 1987). Gauntlett and others (1988) 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 others (2000) noted that plasma clearance correlated with maturity (gestational age) and weight, whereas Santeiro and others (1997) noted a correlation of clearance with postnatal age (Fig. 18-2). Koehntop et al. (1986) have shown 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 others (1989) noted that the clearance of alfentanil in newborn premature infants was markedly reduced compared with older children (Fig. 18-3).

FIGURE 18-2 Plasma clearance of fentanyl correlates with A, gestational age (r = 0.46, P < 0.01), and B, birth weight (r = 0.48, P < 0.01).

(From Saarenmaa et al.: Gestational age and birth weight effects of plasma clearance of fentanyl in newborn infants, J Pediatr 136:767, 2000.)

FIGURE 18-3 Age-related changes in alfentanil pharmacokinetics for premature infants, children, and adults.

(From Davis CM, Brando M: Pediatric pharmacology. In Greeley W, editor: Atlas of anesthesiology, vol 7, Philadelphia, 1999, Churchill Livingstone.)

Koren and others (1985) have shown that the elimination half-life for morphine (13.9 hours) in human neonates is 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 ultrashort-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 (Ross et al., 2001). 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.

Animal studies have shown a decreased median effective dose (ED₅₀) for thiopental in the early weeks of life. Also, arousal in newborn rats occurred at lower brain levels of thiopental than in adult rats (Mirkin, 1975). Although this may suggest that lower doses of thiopental are needed in young neonates, studies by Jonmarker and others (1987) suggest the contrary. Similarly, ketamine requirements are greater (mg per kg of body weight) in infants than in older children (Lockhart and Nelson, 1974). Ketamine has been shown to produce apnea in infants with increased intracranial pressure (Lockhart and Jenkins, 1972). Ketamine produces hypertension and tachycardia, which some 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 population pharmacokinetic analysis, Allegaert et al. (2007) noted that postmenstrual age and postnatal age were predictive covariants for clearance and that developmental maturation occurs within the first two weeks of life (Fig. 18-4).

FIGURE 18-4 Simulated population propofol concentrations (line) in neonates aged 27, 38, and 43 weeks’ gestation, with a postnatal age (PNA) of 10 days or less, after a bolus dose of 9 mg in 10 seconds.

(From Allegaert et al.: Interindividual variability in propofol pharmacokinetics in preterm and term neonates, Br J Anaesth 99:864, 2007.)

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. 18-5). DeWildt et al. (2001), in a study of 24 preterm infants, 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.

FIGURE 18-5 Developmental aspects of CYP3A activity. A, Clearance of the CYP3A4 probe midazolam. B, CYP3A7 and CYP3A4 expression. GA, Gestational age; MDZ, midazolam.

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

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. 18-6). 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 ED₅₀ and ED₉₅) for most nondepolarizing blocking agents.

FIGURE 18-6 Tracings of the frequency sweep electromyogram (FS-EMG).

(From Crumrine RS, Yodlowski EH: Assessment of neuromuscular function in infants, Anesthesiology 54:29, 1981.)

Fisher et al. (1982) 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 (CP_ss50) and noted that infants had a lower CP_ss50 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 following 0.45 mg/kg and 0.6 mg/kg doses (Fig. 18-7) (Driessen et al., 2000; Rapp et al., 2004).

FIGURE 18-7 Recovery of twitch to 10%, 25%, 50%, and 75% of baseline value (min) in infants after single-dose relaxation with rocuronium bromide (n=61, mean ± SE). Note significant differences between 0 and 1 month and between 5 and 12 months. P = 0.05 (0.45 mg • kg^-1) and P = 0.05 (0.6 mg • kg^-1).

(From Rapp et al.: Neuromuscular recovery following rocuronium bromide single dose in infants, Pediatr Anesth 14:329, 2004.)

Thermal Protection

As already described, the newborn infant loses thermal protection after birth, so measures must be taken to protect against heat loss during surgery (Box 18-1):

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 [LMA] 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 (Hubmayr, 2004).

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 OR.

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

An indwelling arterial cannula allows repeated blood sampling for cardiopulmonary and biochemical evaluation. A 22- or 24-gauge cannula can be inserted percutaneously or by cutdown into a variety of sites, including the radial, dorsalis pedis, or posterior tibial arteries. Before the insertion of the catheter, the adequacy of circulation to the hand should be assessed by applying a modified Allen’s test (Brodsky, 1975). 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 risks of 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). The placement of the catheter must be confirmed by a radiograph (Fig. 18-8).

FIGURE 18-8 Umbilical artery-vein x-ray image. A, AP view. B, Lateral view. UA and UV catheters have different courses on plain films. The UV catheter goes directly up to the right atrium from the umbilicus, whereas the UA catheter goes down into the external iliac artery and up into the aorta.

The risk for retinopathy of prematurity 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 HgF). Of importance, if blood is shunting right-to-left through a PDA, the oxygen saturation measured in the lower extremities or umbilical artery (postductal site) does not reflect the oxygen saturation in the retinal vessels (preductal site). To enable simultaneous monitoring of both preductal and postductal oxygen saturation, two pulse oximeters are placed—one on the right hand (preductal) and one on a lower extremity (postductal). During right-to-left shunting through the PDA, the preductal oxygen saturation is higher than the postductal value, and the difference depends on the amount of shunting. If blood is shunting right-to-left only via the foramen ovale or other intracardiac sites (e.g., ventriculoseptal defect), the preductal and postductal oxygen saturation are equal (see Chapters 34, and 23, Respiratory Physiology in Infants and Children, Cardiovascular Physiology, and Anesthesia for General Abdominal, Thoracic, Urologic, and Bariatric Surgery).

An arterial cannula must be connected to a pressure transducer and slowly and continuously infused with a small volume of 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) infant, the flush volume should be measured and included in calculating the total daily fluid intake. In addition, extreme caution is critical while flushing an arterial cannula, because retrograde embolization into the cerebral circulation is possible in the small infant, especially with a patent foramen ovale or 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 catheter can be inserted and passed into the right atrium (Fig. 18-8). Its location must be verified by x-ray 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 LBW infant have additional risks, from malpositioning and from the disruption of venous flow (ratio of the size of vessel to the size of the catheter is low).

Laparoscopy Background

The cardiorespiratory effects of laparoscopy are often difficult to separate from those of anesthesia, surgery, and intraoperative positioning (e.g., Trendelenberg or reverse Trendelenberg). Although the enormous amount of data accumulated for adults, children, and older infants cannot be directly extrapolated to newborns, some of the trends noted in these studies are worth considering in the context of neonatal surgery and anesthesia.

In adults, intraoperative pulmonary catheter monitoring determined the hemodynamic effects of general anesthesia, the reverse Trendelenberg position, peritoneal insufflation, and their combined effects during laparoscopic cholecystectomy. After induction of anesthesia, mean arterial pressure and cardiac index decreased from baseline. Adding the reverse Trendelenberg position further decreased right atrial and pulmonary capillary wedge pressures, cardiac index, and mean arterial pressure. After peritoneal insufflation with CO₂ while in the reverse Trendelenberg position, mean arterial pressure increased as systemic and pulmonary vascular resistances increased. Right atrial and pulmonary capillary wedge pressures increased, and cardiac index decreased beyond the level associated with positioning.

These hemodynamic changes from insufflation, positioning, and hypercarbia are of minimal significance in a euvolemic, healthy adult, but the risks may become significant in patients with underlying cardiac disease (Grabowski and Talamini, 2009). Data documenting cardiorespiratory responses to laparoscopy in infants have been reported, but only about studies involving the use of noninvasive tools, and they differ from some of the results reported in healthy adults.

Using a transesophageal ultrasonic probe inserted after induction of general anesthesia in 12 healthy boys (23 ± 5 months of age), Gueugniaud et al. (1998) noted that pneumoperitoneum (10 mm Hg) decreased aortic blood flow and stroke volume and increased systemic vascular resistance. No effects on mean arterial pressure or end-tidal CO₂ were noted. Of importance, these patients remained supine (no reverse Trendelenberg positioning).

Manner et al. (1998) reported the pulmonary effects of pneumoperitoneum in 10 patients between the ages of 1 and 15 years who were undergoing a variety of laparoscopic procedures (intraperitoneal pressure, 12 mm Hg). In this study, the patients’ pulmonary compliance decreased (17% with the reverse Trendelenberg position, 28% with the reverse Trendelenberg position plus insufflation); peak inspiratory pressure increased (25% with the reverse Trendelenberg position, 30% with the reverse Trendelenberg position plus insufflation) and end-tidal CO₂ tension (Petco₂) concentration increased from 33 to 42 mm Hg at maximum insufflation pressure. In 17 infants (younger than 10 months) who were undergoing a variety of procedures that required at least 30 minutes of laparoscopy but experienced no change in position, Bannister et al. (2003) reported similar findings. Patients were divided into two groups: those weighing less than 5 kg (intraabdominal pressure less than 12 mm Hg), and those weighing more than 5 kg (intraabdominal pressure, less than 15 mm Hg). Again, peak inspiratory pressure increased (18%) and correlated with insufflation pressure, and dynamic compliance decreased (48%). Tidal volume decreased 33% and oxygen saturation fell 2% to 11% in 41% of the patients. Ventilation was adjusted to maintain Petco₂ within 10% of baseline, and 20 adjustments were reported. Neither heart rate nor blood pressure changed with insufflation or ventilatory adjustments, and significant changes from baseline status were noted at insufflation pressures of 10 mm Hg and greater but not at pressures of 5 mm Hg. Similar minimal hemodynamic effects of low-pressure pneumoperitoneum have been documented in young children elsewhere (DeWaal and Kalkman, 2003).

Of note, inducing a pneumoperitoneum in the Tredelenburg position during gynecologic surgery in adults decreases the distance between the endotracheal tip and the carina as well as the tracheal length (Kim et al., 2007). Because the distance between the larynx and the carina is markedly less in the infant, this phenomenon may be of critical importance in the newborn undergoing laparoscopy.

Renal function is affected by pneumoperitoneum. However, data have primarily been acquired in the adult population. In adults, decreased urine production has been attributed to the decreased glomerular filtration rate and renal perfusion from the direct effects of pneumoperitoneum (e.g., compression of the renal artery, the inferior vena cava, or the parenchyma) or from secondary effects (e.g., decreased cardiac output and release of mediators) (Rosin et al., 2002). Renal blood flow and renal function decrease during pneumoperitoneum; the effects on blood flow are pressure dependent and exacerbated in the head-up position, but they return to normal after deflation (Demyttenaere et al., 2007).

The effect of pneumoperitoneum on intracranial pressure has been studied in adults. Although the newborn’s cerebrovascular physiology and autoregulatory responses differ from those of the adult, newborns with limited autoregulatory responses may have more profound cerebral vascular responses from increased intraabdominal pressure. In adult animals, intraabdominal pressures of 15 and 25 mm Hg—but not 5 mm Hg—affected intracranial pressure, similar to findings by Rosenthal et al. (1998) (Rosin et al., 2002). Bloomfield et al. (1997) created models that linked intraabdominal, intrathoracic, and intracranial pressures. As with other studies, pleural, peak inspiratory, right atrial, and pulmonary arterial pressures increased as intraabdominal pressure increased above 10 mm Hg. The increases became especially significant at intraabdominal pressures of 25 mm Hg. At the same time cardiac index decreased, but systemic vascular resistance increased and blood pressure remained stable. Increased intracranial pressure accompanied the rise in intraabdominal pressure; however, these changes reversed when the abdomen was decompressed. Of significance, the increase in pleural and intracranial pressures with increased intraabdominal pressure was prevented in a group of swine with the chest opened (e.g., median sternotomy and pleuropericardotomy). However, in spite of the open chest, cardiac index decreased and systemic vascular resistance increased. The investigators suggested that the acuity of the increase in intrathoracic pressure secondary to an abrupt rise in intraabdominal pressure acutely increased central venous pressure, preventing cerebral venous outflow. When they prevented the effect of intraabdominal pressure on the pleural pressure (open chest), venous and intracranial pressures did not change.

The absence of predictable autoregulation of cerebral perfusion in the newborn combined with the significant risk of injury secondary to oxygen and positive pressure ventilation may have unique implications for the anesthetic management of the newborn during either laparoscopy or thoracoscopy. Although indirect monitoring of cerebral blood flow is available (e.g., near-infrared spectroscopy, or NIRS), ideally a reliable, continuous method to accurately monitor cerebral perfusion pressure would be of critical benefit in this setting (Brady et al., 2007).

In summary, pneumoperitoneum in infants affects ventilation as well as cardiovascular, renal, and cerebrovascular function. With pneumoperitoneum, the upward displacement of the diaphragm affects intrathoracic pressure and lung volumes, ultimately affecting compliance, peak airway pressure, tidal volume, and effective minute ventilation. All of these changes result in a decrease in functional residual capacity, which can promote atelectasis and worsen the ventilation/perfusion mismatch abnormalities.

Laparoscopy and Thoracoscopy in the Newborn

The effects of insufflation during both laparoscopy and thoracoscopy are dramatic in the newborn. The impact of increased intrathoracic pressure and hypercarbia can profoundly influence the transitional circulation. Changes in patient oxygen saturation, hypotension, interruption of the procedure, and hypercarbia are common in the newborn (Kalfa et al., 2005, 2007; Krosnar and Baxter, 2005).

Insufflation in the newborn also decreases core body temperature. In 50% of newborns, the postoperative core temperature was less than 36° C. A long operative time (insufflation for more than 100 minutes) was associated with lower postoperative core body temperature (Kalfa et al., 2005).

Inaccurate end-tidal CO₂ values are common during laparoscopy, especially in the setting of cyanotic heart disease (Laffon et al., 1998; Wulkan and Vasudevan, 2001). At the same time, absorption of CO₂ from the peritoneum seems to be age-dependent (McHoney et al., 2003). The total amount of insufflated CO₂ and elimination of CO₂ correlated with age. Younger patients also demonstrated a short period of increased CO₂ elimination after desufflation, which may be related to increased venous return after the decrease in intraabdominal pressure.

Because one-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 low flow of CO₂ (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 (Rothenberg, 2002; 2005b; Holcomb et al., 2005).

Because many of the strategies to affect one-lung ventilation are not available for the newborn, adequate surgical exposure for thoracoscopy relies heavily on insufflation to collapse the lung. 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. The effect of pneumoperitoneum on tracheal length implies that the risk for inadvertent endobronchial intubation may be increased in the newborn.

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 (Mariano et al., 2005; Rice-Townsend et al., 2007; Slater et al., 2007).

Abdominal Wall Defects: Gastroschisis and Omphalocele

Gastroschisis and omphaloceles are the most common abdominal wall defects (ectopia cordis and cloacal and bladder extrophy are less common), but they are still rare, with an incidence of approximately 1:10,000 and 1:4000 to 7000 births (Paidas et al., 1994). Some have suggested that both ethnic and geographic origins affect the incidence, but overall the lesions seem sporadic (Mann et al., 2008).

Currently, fetal ultrasounds are routinely conducted to screen for high-risk conditions. For example, nuchal translucency and biochemical markers (free β-subunit of human chorionic gonadotropin and pregnancy-associated plasma protein A) are now measured to screen for aneuploidy or cardiac and other anomalies (Souter and Nyberg, 2001; Weiner et al., 2007). An abnormal value on screening prompts an evaluation that includes a detailed fetal ultrasound; in the case of abdominal wall defects, ultrasound confirms the presence of a lesion in approximately 95% of cases after as few as 10 to 14 weeks’ gestation (Mann et al., 2008). The in utero diagnosis allows planned delivery at a medical center with resources for high-risk obstetric, surgical and anesthetic, and neonatal care.

Although omphalocele and gastroschisis appear to be similar in gross physical appearance, these lesions are distinct from each other. An omphalocele is a central defect of the umbilical ring; the abdominal contents herniate into the intact umbilical sac unless the sac ruptures in utero (Fig. 18-10). The umbilical cord is also inserted into the sac, which contains an internal peritoneal membrane and external amniotic membrane. The lesion has a fascial defect of more than 4 cm (fewer than 4 cm is often considered an umbilical hernia) and often as large as 10 to 12 cm. The sac often contains the stomach, loops of the small and large intestines, and in about 30% to 50% of cases, the liver. A gastroschisis, on the other hand, is an abdominal wall defect that usually occurs to the right of the umbilical cord, with evisceration of bowel through the defect (Fig. 18-11). This lesion is usually 2 to 5 cm in diameter, and in most cases there are only small and large bowel present. In rare cases the liver may exit through the abdominal wall defect as well. The bowel is exposed to the intrauterine environment with no sac, causing its 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 just an effect of amniotic fluid is unclear. The umbilical cord is normal and separate from the defect. When the testes exit along with the bowel, cryptorchidism occurs with gastroschisis (Lawson and de La Hunt, 2001; Weber et al., 2002).

FIGURE 18-10 Newborn with large omphalocele, sac intact. Umbilical cord is seen emerging from mass. The major problem will be replacing the viscera in the small abdominal cavity.

FIGURE 18-11 Gastroschisis, sometimes called ruptured omphalocele, with umbilical cord intact. Heat loss, rapid dehydration, and infection are added to problems of omphalocele.