The neonatal period is generally regarded as the first 28 days of extrauterine life. Anesthesia for the neonate is often required as the result of an urgent or life-threatening illness that requires surgical intervention. The normal human neonate is remarkably resilient and well equipped to survive in this hostile environment. The differences between the baby and the adult, however, are clearly greatest in the neonatal period, especially if birth occurs before term. The neonate that is born prematurely and ill is not as resilient as the full-term infant. Therefore, the neonatal anesthetist must have a thorough understanding of normal growth and development, the anatomic and physiologic differences during various stages of maturation, and how immature organ systems affect anesthetic pharmacokinetics and pharmacodynamics. Anesthetic management of the neonate requires integration of this specialized knowledge and refinement of acquired technical skills.
In the past, neonates and in particular preterm, sick neonates were anesthetized with the “Liverpool Technique,” which consisted of oxygen, nitrous oxide, and curare. Volatile anesthetics and opioids were not used, and the “stable” state that resulted was due to a sympathetic system in overdrive. However, in the last three decades, our understanding of neonatal physiology, particularly neurobiology, has led to an active program of research in the field of neonatal anesthesia. Neonates, term and preterm, respond to painful stimuli.1 Signs of distress are clearly evident when neonates are exposed to stimuli that are painful. The behavioral, physiologic, and humoral signs are similar to those seen in older children and adults.2 Therefore, all neonates require anesthesia for surgery except under extraordinary circumstances. Physiologic development is in a transitional state, and congenital anomalies may be present. Neonates and infants younger than 12 months old exhibit the highest rate of adverse events both intraoperatively and in the postanesthesia recovery room. Preterm infants are more prone to developing respiratory complications.3
The fetal circulatory system relies on the placenta for delivery of oxygen and transport of carbon dioxide (CO2). The chorionic villus is the functional unit of the placenta. Normally, fetal blood is separated from the maternal blood in the placenta by a thin layer of cells known as syncytial trophocytes. Oxygen, CO2, and small nonionized particles readily pass through this layer, whereas substances with a larger molecular weight are prevented from diffusing across the syncytial trophocytes. Fetal circulation is characterized by high pulmonary vascular resistance (uninflated atelectatic lungs and hypoxic vasoconstriction) and low systemic circulatory resistance (high flow and low impedance of the placental vessels). Fetal deoxygenated blood travels down the aorta and through the internal iliac arteries, arriving in the placenta via paired umbilical arteries. The umbilical arteries divide, forming the arterioles, capillaries, and venules of the intervillous placental space. Oxygenated blood is delivered to the fetus from the placenta via a single umbilical vein. This oxygenated blood bypasses the lungs by flowing through extracardiac (ductus arteriosus, ductus venosus) and intracardiac (foramen ovale) shunts, forming a parallel circulation. The ductus venosus routes oxygenated blood away from the sinusoids of the liver. The oxygenated blood in the inferior vena cava is directed by the eustachian valve toward the atrial septum and passes through the foramen ovale to enter the left side of the circulation. Oxygenated blood passes into the left ventricle and exits the aorta, supplying the coronary arteries. Blood entering the pulmonary artery from the right ventricle flows to the aorta via the ductus arteriosus. Only 5% to 10% of the combined ventricular output flows through the pulmonary circulation.
The transitional circulation is established at the time of birth. With the cessation of placental blood flow, aortic pressure increases. Clamping of the umbilical vein doubles systemic vascular resistance. Pulmonary vascular resistance falls with lung expansion, and increasing partial pressure of arterial oxygen (Pao2) produces pulmonary vasodilation, resulting in further decreases in pulmonary resistance. These changes in systemic and pulmonary blood flow produce corresponding changes in intracardiac pressure. Decreases in right atrial pressure with accompanying increases in left atrial pressure change the direction of blood flow through the foramen ovale, resulting in the closure of the foramen ovale as left atrial pressure increases. The foramen ovale may reopen if right atrial pressure is greater than left atrial pressure (e.g., pulmonary hypertension), permitting venous blood to flow from right to left. Within a period of 2 to 3 months, the foramen ovale will be permanently closed. Up to 25% of adult patients may demonstrate a probe patent foramen ovale at autopsy.4 Closure of the ductus arteriosus is precipitated in part by the increase in systemic vascular resistance and decrease in pulmonary vascular resistance. In utero prostaglandins maintain the patency of the ductus arteriosus. Within a few hours after birth, the muscular wall of the ductus arteriosus constricts, preventing the retrograde flow of blood from the aorta into the pulmonary artery. This functional closure (thrombosis) occurs within 1 to 8 days. Anatomic closure (fibrosis of the ductus arteriosus) requires 1 to 4 months. Ductus closure may be influenced by elevations in the systemic Pao2 that occur after birth. The majority of portal blood flow continues to enter the ductus venosus after interruption of umbilical vein blood flow. Although the cause of the initiating mechanisms of ductus venosus closure is unknown, the muscular wall of the ductus venosus begins to constrict 1 to 3 hours postnatally. Blood flow is directed into the liver, and portal venous pressure increases.
Persistent pulmonary hypertension of the newborn (PPHN) is the result of an abnormal early adaptation to the perinatal circulatory transition. PPHN is characterized by a sustained elevation of pulmonary vascular resistance (PVR); decreased perfusion of the lungs; and continued right-to-left shunting of blood through the fetal channels (foramen ovale and ductus arteriosus). When PVR remains high after birth, right (and sometimes left) ventricular function and cardiac output are depressed. Moderate or severe PPHN is believed to affect up to 2 to 6 per 1000 live births, and complicates the course of 10% of all infants admitted to neonatal intensive care. These circulatory abnormalities are also responsible for an 8% to 10% risk of death and a 25% risk of long-term neurodevelopmental morbidity. Significant pulmonary hypertension also may develop in neonates and young infants as a result of bronchopulmonary dysplasia (BPD) or cardiac disease. Pulmonary hypertension affects roughly one third of infants with moderate-to-severe BPD.5-7
During fetal development, PVR is high but rapidly decreases at birth to near-normal levels, allowing the lungs to become a gas-exchanging organ. Before anatomic closure of the extracardiac and intracardiac shunts, fetal circulation may be reestablished and persist. Persistent PPHN is manifest by increases in PVR and accompanying pulmonary hypertension, which produces a right-to-left shunt across the foramen ovale and the ductus arteriosus, with resultant cyanosis. The presence of congenital cardiovascular or pulmonary disease inhibits functional and anatomic closure of these aforementioned fetal shunts. Persistent fetal circulation is common in preterm infants and infants with metabolic derangements (e.g., asphyxia, sepsis, meconium aspiration, congenital diaphragmatic hernia). Hypoxemia, acidosis, pneumonia, and hypothermia are primary precipitating factors of PPHN. Oxygenation, the avoidance of acidosis, and maintenance of normothermia will attenuate the increase in pulmonary vascular resistance. Continual increases in pulmonary vascular pressure and resistance will precipitate the development of right ventricular hypertrophy (cor pulmonale). Although pulmonary vasodilators may have some utility in decreasing pulmonary vascular resistance, concurrent reductions in systemic vascular resistance can occur and may worsen the shunt.
The primary aim of PPHN therapy is selective pulmonary vasodilation. Treatment of pulmonary hypertension includes optimization of lung function, oxygen delivery, and support of cardiac function. Optimal lung inflation is essential because PVR is increased when the lungs are underexpanded or overexpanded, independent of lung disease. The use of lung recruitment strategies, such as high-frequency ventilation and exogenous surfactant administration, is particularly important in infants with PPHN associated with parenchymal disease, but has limited impact in infants with primary vascular disease. Correction of severe acidosis and avoidance of hypoxemia are important because they both stimulate pulmonary vasoconstriction. Maintaining a normal hematocrit is also important to ensure adequate oxygen-carrying capacity while avoiding polycythemia, because hyperviscosity can increase PVR.
The myocardium of the newborn is immature. The neonatal heart contains the essential structural elements of the adult heart; however, there is cellular disorganization and fewer myofibrils. Although the ventricles are of equal size and shape, the contractile components (sarcoplasmic reticulum and T-tubule system) are immature. Accordingly, the neonatal heart is less capable of generating a response to an increase in resistive load (increase in stroke volume) and is dependent on free ionized calcium for contractility. Despite this immaturity, the neonatal heart is capable of limited increases in stroke volume up to left atrial pressures of 10 to 12 mmHg when afterload remains low. This information suggests that the neonatal heart is operating near the peak of the Frank-Starling curve because there is a limited reserve to increases in both preload and afterload.
During maturation, the left ventricle will hypertrophy through an increase in the number and size of myofibrils. This maturation is a consequence of left ventricular contraction against a higher postnatal systemic pressure. Acute increases in afterload (e.g., acidosis, hypothermia, pain) will produce further reductions in cardiac output. In the immediate postnatal period, left ventricular compliance is low. The neonate may develop congestive heart failure because the stiff left ventricle will not stretch to accommodate large fluid loads. Left ventricular distention from volume overload compresses the adjacent right ventricle, producing additional embarrassment to cardiac output. Likewise, ventilation with high peak pressure will produce left ventricular dysfunction and overload of the right ventricle.
Owing to the immaturity of the contractile elements of the neonatal myocardium, the belief is that pediatric cardiac output is solely dependent on heart rate. Atropine is frequently administered for the treatment of decreased cardiac output. However, marked increases in heart rate fail to a large extent to produce further increases in cardiac output. Although the neonatal myocardium will develop less stretch with volume loading than the older child or adult, volume expansion remains important, albeit to a smaller extent than in the adult, in increasing cardiac output. The combination of hypovolemia and bradycardia produce dramatic decreases in cardiac output that threaten organ perfusion. Epinephrine rather than atropine increases contractility and heart rate and is now advocated for the treatment of bradycardia and decreased cardiac output in pediatric patients. The baroreceptor reflex is not completely developed, limiting the neonate’s ability to compensate for hypotension with the reflex tachycardia expected in the older child and adult.
Autonomic innervation of the neonatal heart is predominantly controlled by the parasympathetic nervous system; the sympathetic nervous system is immature at birth. Parasympathetic dominance produces bradycardia with minor clinical interventions such as pharyngeal suctioning and laryngoscopy. Marked variation in the newborn heart rate and rhythm occur secondary to changes in autonomic tone. The electrocardiogram (ECG) recording in the newborn reflects the immaturity of the conduction system. The ECG axis is shifted to the right but shifts to the left with maturation and accompanying hypertrophy of the left ventricle. The P wave is evident; the PR is less than 0.12 second and increases until adolescence. T waves are upright in the recorded chest leads, reflecting right ventricular domination. The newborn heart rate averages 120 beats per minute (bpm) during the first day of life, increasing to 160 bpm at 1 month of age, then steadily decreasing to an average of 75 beats by the adolescent period. Sleep may produce heart rates lower than 100 bpm, whereas pain increases the rate up 200 bpm.
Blood pressure increases immediately after birth, rising to a mean systolic pressure of 70 to 75 mmHg within the first 48 hours. Blood pressure is lower in the preterm infant. As the heart rate decreases with maturation, there is an accompanying increase in blood pressure. Hypotension in an anesthetized newborn is defined as a systolic blood pressure of less than 60 mmHg. In a 1-year-old child, hypotension is defined as systolic pressure less than 70 mmHg. In the older child, hypotension is determined as a systolic pressure of 70 mmHg plus twice the child’s age in years. Table 47-1 shows values for heart rate and blood pressure at different ages.
Fetal hemoglobin is the predominant hemoglobin species in the newborn, contributing between 70% and 90% of the total. This amounts to a hemoglobin of between 18 and 20 g/dL at birth. Fetal hemoglobin has a higher affinity for oxygen than adult hemoglobin. In utero, this increased oxygen affinity facilitates oxygen uptake as fetal blood circulates through the placenta, increasing the binding of oxygen to fetal hemoglobin and allowing the fetus to exist in a relatively low Pao2 environment. There is a rapid change in the fetal hematopoietic physiology in the oxygen-rich extrauterine environment. The increased arterial oxygen content after birth results in a decrease in erythroid activity, and hematopoiesis ceases. A decrease in erythropoiesis and decreased life span of the newborn’s red blood cells (RBCs) produces a progressive decrease in hemoglobin, reaching a nadir by age 3 months. This “physiologic anemia of infancy” does not compromise the delivery of oxygen, because the oxyhemoglobin dissociation curve shifts to the right and RBC concentrations of 2,3-diphosphoglycerate increase (Figure 47-1). Fetal hemoglobin is replaced by adult hemoglobin during the first 3 to 6 months, producing a rightward shift of the oxyhemoglobin dissociation curve.
FIGURE 47-1 Schematic representation of oxyhemoglobin dissociation curves with different oxygen affinities. Top arrows, Direction of rightward shifting of the oxyhemoglobin dissociation curve (and P50) after birth. By 10 weeks of age, the adult position of the curve is reached. (From Davis PJ, Cladis FP, Motoyama EK. Smith’s Anesthesia for Infants and Children. 8th ed. Philadelphia: Mosby; 2011:62.)
It is important to note that the premature infant may experience a dramatic fall in hemoglobin because of insufficient body stores of iron. Newborns should receive vitamin K prophylaxis, because the concentration of vitamin K–dependent clotting factors (II, VII, IX, and X) are 20% to 50% of adult levels. Premature infants generally have lower levels of vitamin K–dependent clotting factors. Maternally ingested drugs such as warfarin and isoniazid may precipitate the development of a coagulopathy.
The newborn’s blood volume is dependent on the time of cord clamping (transfusion from the placenta). Blood volume is approximately 80 to 90 mL/kg but may be as high as 100 mL/kg in the premature neonate. The intravascular volume decreases 25% in the immediate postnatal period with the loss of intravascular fluid. Blood volume increases over the next 2 months, peaking at 2 months of age. Table 47-2 provides an estimate of circulating blood volume development.
In utero, fetal lung development beings with the formation of lung buds, which occurs during the first few weeks after conception. During organogenesis in the second trimester, distinct bronchi and bronchopulmonary segment proliferation that extends downward to the terminal bronchioles is created. There are 10 to 20 million terminal sacs, which, after elongation, begin to develop into alveoli after birth. The process of alveolar formation is accelerated between 12 to 18 months postnatally and increases to 200 to 300 million between 8 to 10 years of age.
Type II pneumocytes are responsible for the production and secretion of surfactant, which begins between 22 and 26 weeks, and concentrations peak between 35 and 36 weeks’ gestation. Surfactant decreases surface tension within the alveoli to decrease alveolar collapse. This relationship can be explained by the Law of Laplace as shown below. In the absence of adequate pulmonary surfactant such as in a premature neonate, alveoli become stiff and noncompliant as depicted in Figure 47-2. Severe atelectasis decreases alveolar surface area available for oxygen and carbon dioxide exchange. Increased physiologic dead space and ventilation perfusion mismatch cause hypoxia and hypercarbia, necessitating mechanical ventilation. The treatment for infantile respiratory distress syndrome includes synthetic surfactant, continuous positive airway pressure, and mechanical ventilation.8
FIGURE 47-2 An idealized state showing the reciprocal relationship between resistance and compliance; gas flow is preferentially delivered to the most compliant regions, regardless of the rate of inflation. Static and dynamic compliance are equal. (From Davis PJ, Cladis FP, Motoyama EK. Smith’s Anesthesia for Infants and Children. 8th ed. Philadelphia: Mosby; 2011:354.)
At birth the neonatal larynx is small compared with the mouth and pharynx. The epiglottis is short and small, and the vallecula is shallow so that the tongue approximates the epiglottis. The larynx is pointed toward the nasopharynx, facilitating nasal breathing. The arytenoids are large in proportion to the lumen of the larynx. The subglottic region is smaller than the glottic opening with the cartilages telescoping into one another, forming a conical shape.9 The cricoid cartilage is the narrowest portion of the airway, and the cricoid lumen is not a round but mostly an ellipsoid structure. It is lined with a pseudostratified epithelium that is easily injured, resulting in significant edema and stridor. A recent study questions this traditional teaching. Video bronchoscopic images and magnetic resonance spectrographs were obtained in 135 children, aged 6 months to 13 years. Measurement of laryngeal dimensions, including cross-sectional area, anteroposterior, and transverse diameters at the level of the glottis and the cricoid were performed. They found that the glottis rather than cricoid was the narrowest portion of the pediatric airway. They also noted that like adults, the pediatric airway is more cylindrical than funnel shaped.10
The newborn tongue is large and difficult to manipulate because of the position of the hyoid. In addition, a smaller potential submental space is present, in which it is possible to displace the tongue during laryngoscopy. The anterior position of the larynx and the large tongue increase the potential difficulty of mask ventilation.
The larynx is located more cephalad and anterior, extending from the second to the fourth cervical vertebrae (C2 to C4). The anesthetic implication of the more cephalad location is that placing a neonate in the “sniffing position” for laryngoscopy and intubation will only move the larynx in an anterior direction.
The occiput of the newborn’s head is large and prominent. The placement of a rolled towel under the shoulders aids in the visual alignment of the oral, pharyngeal, and laryngeal axes during laryngoscopy (Figure 47-3 and Table 47-3).
|Narrowest location of airway||Cricoid||Glottis|
|Shape of epiglottis||Longer, more narrow||V-shaped|
|Right mainstem bronchus||Less vertical||More vertical|
The neonate’s chest wall is pliable for lack of developed musculature and a skeletal structure primarily composed of cartilage. The ribs are horizontal in orientation, providing minimal assistance in the expansion of the chest wall with inspiration. During inspiration the compliant chest wall is noted to collapse inward during respiration (paradoxical breathing). To maintain negative intrathoracic pressure in the face of a compliant chest wall, the neonate and infant actively recruit accessory muscles of respiration (i.e., intercostal muscles). Additionally, exhalation is limited by the adductor muscles of the larynx, which contract and serve as an expiratory valve or brake to maintain end-expiratory pressure. These structural differences are responsible for the decrease in functional residual capacity (FRC) with administration of general anesthesia in the neonate and infant. The previously cited muscular activity responsible for maintaining FRC is lost with the administration of sedatives, inhalation anesthetics, and neuromuscular relaxants. Rapid hypoxemia follows the loss of FRC. FRC may be restored with the application of continuous positive airway pressure or controlled ventilation. The premature infant has an even more pliable chest wall, and paradoxical chest movement may occur with breathing during rest.
The diaphragm contributes to the differences in respiratory function of the neonate and infant. Unlike the adult diaphragm, which is dome shaped, the diaphragm of the neonate and infant is relatively flat. Accordingly, its anterior insertion on the chest wall fails to contribute any mechanical advantage with contraction. Primarily the diaphragm and to a lesser extent the intercostal muscles allow for expansion of the thoracic cavity and the associated increase in negative intrathoracic pressure. As a result, during inspiration, air is drawn into the lungs, and with relaxation of these muscles, air passively exits the lungs due to the elastic recoil. Two types of muscle fibers are present in muscle tissue—specifically, the diaphragm and intercostals. Type 1 muscle fibers are slow twitch muscle fibers and are resistant to fatigue. These fibers are essential for sustained ventilatory activity. Type 2 muscle fibers, also known as fast twitch muscle fibers, are fast twitch but fatigue rapidly. A newborn infant’s diaphragm is composed of 25% type 1 muscle fibers as compared to 55% type 1 muscle fibers in the adult diaphragm. Also, type 2 muscle fibers are predominant within the intercostals. Therefore, newborns and young infants are at risk of muscle fatigue, respiratory distress, and respiratory arrest. The anesthetist must assess for respiratory compromise resulting from the depressant effects of residual anesthetic agents, airway obstruction, and postoperative pain. Assisting with respirations and relieving airway obstruction during the perioperative period will promote adequate gas exchange and decrease the degree of atelectasis.
The control of breathing is dependent on the Pao2 sensed via the peripheral chemoreceptors (carotid and aortic bodies), the partial pressure of arterial CO2 (Paco2), and pH, which influence the central chemoreceptors within the respiratory control center of the medulla. Increases in Paco2 produce corresponding increases in tidal volume and respiratory rate, although this response is not as vigorous as in the adult. Increases in Pao2 will depress the ventilatory response in the newborn, whereas a decreased Pao2 will increase the ventilatory response. The ventilatory response to hypoxemia produces two distinctly different responses. Initially hypoxemia stimulates an increase in ventilation for the first minute but produces ventilatory depression with a decreasing response for the next 3 to 5 minutes. This response is more robust in the premature infant than in the newborn. Ventilatory depression is more profound in the hypothermic, acidotic, or hypercarbic neonate.
Respiratory depression and/or apnea may develop in the newborn after stimulation of the carina and/or the superior laryngeal nerve, following upper airway obstruction or following lung inflation (Hering-Breuer reflex). The newborn may exhibit periodic breathing with inspiratory pauses lasting 10 seconds, followed by abrupt increases in ventilation. Periodic breathing is more common in the premature infant and occurs more often during rapid eye movement sleep. Apneic episodes are not uncommon in the premature infant; such episodes produce arterial desaturation. Bradycardia and cardiac arrest may follow these apneic episodes. The suspected causes of apnea in premature infants include immature responses of the respiratory control center to hypercarbia or hypoxic stimuli and respiratory fatigue. Infants who have experienced apneic or bradycardic episodes are at risk for these episodes after general anesthesia.
The mean values for pulmonary function in the newborn and adult are shown in Table 47-4. The infant’s metabolic rate and oxygen consumption are approximately twice those of the adult. The decreased reservoir for oxygen (decreased FRC), coupled with the increased demand for oxygen (increased metabolic rate), results in rapid desaturation when ventilation is interrupted. Airway closure produces a mismatching of ventilation and perfusion. The volume of these poorly ventilated alveoli that contribute to intrapulmonary shunting is greater in neonates than in adults. In addition, increased pulmonary vascular resistance can produce a right-to-left shunt through the foramen ovale or a patent ductus arteriosus, resulting in the rapid development of cyanosis.
Airway resistance is greater in neonates and declines markedly with growth from 19 to 28 cm H2O/L/sec to less than 2 cm H2O/L/sec in adults.11-13 According to Poiseuille’s law, airway resistance is inversely proportional to the fourth power of the radius of the airway during laminar flow. A neonate must overcome the resistance to airflow, as well as the elastic recoil of the lungs and chest wall. The rate of ventilation that uses the least amount of muscular energy and generates a satisfactory tidal volume has been found to be 37 breaths per minute in the healthy newborn.
The metabolic cost of breathing in the neonate is similar to an adult, approximately 0.5 mL per 0.5 L of ventilation. This is equivalent to 1% of their metabolic energy. The premature neonate’s metabolic cost of breathing is 0.9 mL/0.5 L, almost double the metabolic price. If the neonate has pulmonary problems, the cost could go even higher.14
Airway resistance changes with age. Although the larger airway resistance remains constant, airway resistance in the smaller airways is increased. The increase in airway resistance increases the work of breathing in the neonate. Small airway disease (e.g., pneumonia) produces additional increases in the work of breathing.
The central nervous system in the newborn differs from the older child in the degree of myelination, muscle tone and reflexes, and development of the cerebral cortex. In the peripheral nervous system, myelination begins in the motor roots and progresses to the sensory roots. In contrast, the myelination in the cerebral sensory systems precedes that of the central motor systems. This incomplete myelination is associated with those reflexes that are used to measure neural development, the Moro and grasp reflexes. Myelination of the nervous system is not complete until age 3.
The neuromuscular junction (NMJ) undergoes developmental changes during the first 2 months of life. During the maturation process, the NMJ differs in several ways. There is a difference in the maturity, density, sensitivity, and distribution of the postsynaptic acetylcholine receptors; in the rapidity of neuromuscular transmission; and in muscle fiber type.15 What differentiates the immature receptors from the developed ones is a functional difference that is due to a prolonged opening of the ionic channels. This prolonged channel opening allows the immature muscles to be more easily depolarized. These receptors also have a greater affinity for depolarizing agents and a lower affinity for nondepolarizing muscle relaxants (NDMRs). The clinical implication of these maturational changes is that neonates can have a greater variability in their responses to nondepolarizing muscle relaxants and in the monitoring of the NMJ via a peripheral nerve stimulator. Neuromuscular immaturity may be demonstrated with the appearance of fade after tetanic stimulation in the absence of neuromuscular blocking drugs. It is also worth noting that the type I fibers are more sensitive to NDMRs when compared with type II fibers. The clinical relevance of this difference is that the diaphragm of a neonate has fewer type I fibers as compared to a diaphragm of a toddler or an adult. This makes the diaphragm of a neonate more responsive to NDMRs than his or her peripheral musculature.16
Pathways required for pain perception can be traced from sensory receptors in the skin to sensory areas in the cerebral cortex of newborn infants. These pain pathways have been demonstrated in the perioral area as early as 7 weeks’ gestation. With positron emission tomography scans, neonates demonstrate maximal metabolic activity in the regions associated with sensory perception, such as the cortex, thalamus, and midbrain-brainstem regions. Neonatal anesthesia providers have seen newborns exhibit signs of increased sympathetic activity (e.g., tachycardia and hypertension) in response to surgical stimulation with inadequate anesthesia. The risks associated with inadequate or absent pain control expose the neonate to noxious stimulation that can have significant physiologic consequences. Those consequences in the presence of abnormal cerebral autoregulation could result in intraventricular hemorrhage and pulmonary hypertension.17
Lack of development of inhibitory tracts may actually increase the intensity and duration of the painful stimulus. It has been suggested that newborn infants may develop prolonged responses to painful procedures that far outlast the stimuli by hours or days. This is illustrated by several examples. Premature infants mount a metabolic stress response that can be blocked with opioids, increased crying, and interrupted sleep patterns; behavioral changes have been shown to occur for days after circumcision,18 and with repeated heel lancing, there appeared to be a hyperalgesic response to injury.19 Other physiologic alterations that have been demonstrated are increased right-to-left shunting, hypoxemia, acidosis, and intraventricular hemorrhage.17
Sensory nerve distribution is formed by 20 weeks’ gestational age. Pain pathways and receptors are present within the central nervous system at birth. Physiologic stimulation from anesthesia management and surgery dramatically increase circulating catecholamines and other stress hormones. As in adults, during the perioperative experience, pediatric patients exhibit tachycardia and hypertension if light anesthesia is coupled with significant surgical stimulation. Due to the lack of cerebral vascular autoregulation, increased blood pressure can cause intracerebral bleeding, especially in premature neonates. The pain threshold for infants and children may be lower than in older children and adults, possibly because of increased pain sensitivity, behavioral factors, or both. Preoperative and postoperative signs of pain in patients that are preverbal include tachycardia, elevated blood pressure, crying, restlessness, and grimacing.
In recent years, the safety of anesthetic medications and their effect on the developing brain have been questioned. In animal studies, agents that either antagonize N-methyl-D-aspartate (NMDA) receptors or potentiate the neurotransmission of γ-aminobutyric acid (GABA) agents) have been implicated, and no safe doses or durations of exposure of these agents have been defined.20 One proposed mechanism of action for these effects is by inhibition of brain-derived neurotrophic factor, which stimulates neural development.21 Neurotoxicity resulting in neuroapoptosis, interference with nerve pathway, and nerve cell development can result in long-term neurocognitive deficits.20,22–24 The most damage occurs during maturation periods when synaptogenesis rapidly occurs.25 The Food and Drug Administration (FDA) is addressing this issue by forming a public-private partnership with the International Anesthesia Research Society called SmartTots (Strategies for Mitigating Anesthesia-Related Neuro-Toxicity in Tots). This partnership will seek to mobilize the scientific community, stimulate dialogue among thoughtful leaders in the anesthesia community, and work to raise funding for the necessary research. SmartTots is a multi-year collaborative effort designed to increase the safety of anesthetic drugs for the millions of infants and children who undergo anesthesia each year. Findings from these studies will help establish new practice guidelines. Data, outcomes, and best practices generated by SmartTots will be placed in the public domain.
Several major pediatric centers and subspecialty organizations with specific interest in this matter are part of this research consortium. Some ongoing clinical trials assessing the effects of anesthetics on neurocognitive development are noted in Table 47-5.
|Ongoing Clinical Trials||Study|
|Odense University Hospital (Denmark) and the Danish Registry Study Group||A nationwide epidemiologic study comparing the educational achievements of all children who have undergone a surgical procedure before the age of 1 year with that of a general-population control group|
|Columbia University||A prospective cohort study of children who have exposure to an anesthetic before the age of 3 years and their siblings who were not exposed; the two groups will be followed for neurodevelopmental outcomes|
|International Collaboration of Institutions from Australia, Canada, Italy, Netherlands, United Kingdom, and United States||Prospective, randomized, investigator-blinded, controlled clinical trial to assess the effects of general anesthesia using sevoflurane versus neuraxial anesthesia using bupivacaine on neurocognitive function in infants over 26 weeks’ gestational age; children will be followed with evaluations of neurocognitive development at 2 and 5 years of age|
Adapted from Rappaport B, et al. Defining safe use of anesthesia in children. N Engl J Med. 2011;364(15):1386-1390.
The most significant neurologic growth and development occurs in utero. The neural tube is nearly completely formed by 3 to 4 weeks’ gestational age. It further differentiates over the next 4 to 12 weeks to create other anatomic structures that include the forebrain, facial bones, and spinal cord. Neurogenesis proceeds during weeks 12 to 20, followed by synaptogenesis and increased myelination. Increased density of synaptic connections and glial cells continues to develop until 2 years of age and is estimated to be 50% greater than in the adult brain.26
After birth, there is continued rapid functional and structural brain development. The brain doubles in weight within the first 6 months of life and triples in weight within 1 year. At 1 year of age, maturation of the cerebral cortex and brainstem is nearly complete. Myelination of nerve cells continues until 3 years of age. By age 2 years, the child’s brain is 80% of the adult weight and 90% by age 5 years. Because of this rapid growth, fontanelles and supple cranial bones allow the skull to accommodate for this increased cerebral volume without increasing intracranial pressure. In 96% of children, the anterior fontanelle closes by 2 years of age. The posterior fontanelle closes at approximately 4 months. The anterior fontanelle can be used to assess increased intracranial pressure (bulging anterior fontanelle) and also dehydration (sunken anterior fontanelle). The blood-brain barrier is immature until approximately 1 year of age. Therefore, higher concentrations of medications and toxins that would be impermeable to the adult brain can result in higher cerebral concentrations throughout infancy. There are two major fontanelles, anterior and posterior, as shown in Figure 47-4.27 Nerve cells within the spinal cord mature until completion at 6 to 7 years of age. As the pediatric patient grows, the conus medullaris and the dural sac migrates cephalad. Although the exact vertebral level of these structures varies slightly, the conus medullaris terminates between L2 and L3 in neonates. The dural sac ends between S2 and S3 until approximately 6 years of age. Being mindful of this information is imperative to providing safe anesthesia during placement of a spinal or caudal anesthetic. By age 8, the spinal cord approximates the adult and ends at L1.27 Figure 47-5 depicts a comparison between the adult and infant spinal anatomy.
Figure 47-4 Cranial sutures and fontanelles in neonates and infants. (Modified from Davis PJ, Cladis FP, Motoyama EK. Smith’s Anesthesia for Infants and Children. 8th ed. Philadelphia: Mosby; 2011:714.)
Because of the rapid maturation of the central nervous system (CNS) during infancy and childhood, proper nutrition is essential to ensure normal development. With maturation, there is an increase in the metabolic demands of the CNS. The primary fuel for the brain is glucose, and in the neonate, there are decreased stores of glycogen, making hypoglycemia a major source of morbidity causing apnea, hypotension, bradycardia, convulsions, and brain injury.
Cerebral blood flow (CBF) is closely coupled with cerebral metabolic rate of oxygen consumption (CMRO2). CBF in the premature infant is 40 mL/100 g/minute, and in older children approaches the adult level of 100 mL/100 g/minute. Autoregulation of CBF refers to the ability of the CNS to regulate CBF over a wide range of cerebral perfusion pressures. CBF autoregulation is thought to take place in the neonate, but the specific limits are unknown. Complete loss of cerebral autoregulation may occur with hypoxia, severe hypercapnia (greater than 80 mmHg), blood-brain barrier disruption after head trauma, subarachnoid or intracerebral hemorrhage, or cerebral ischemia, or after the administration of high concentrations of potent inhalation anesthetics and vasodilators (nitroprusside). Changes in CBF will parallel changes in cerebral blood volume, except when cerebral perfusion decreases and autoregulation produces vasodilation to maintain a constant flow. The cerebral vessels are very fragile in preterm and low-birth-weight infants. This fragility predisposes neonates to intracranial hemorrhage. Intracranial hemorrhage may be precipitated by hypoxia, hypercarbia, hyperglycemia, hypoglycemia, hypernatremia, and wide swings in arterial or venous pressure. The intravenous administration of hypertonic solutions may damage these fragile vessels. Therefore, adult-strength sodium bicarbonate should not be administered to neonates.
At birth, the autonomic nervous system is developed but not mature as in an adult. The sympathetic nervous system innervation to the heart and vasculature is less responsive compared with parasympathetic nervous system innervation. As a result, physiologic stress can cause severe and rapid cardiovascular collapse. As the pediatric patient ages, the child’s sympathetic response becomes pronounced, and the child is able to compensate for stress by increasing heart rate and blood pressure. If bradycardia occurs, the anesthetist should focus first on hypoxia as possible cause. Rapid assessment and treatment is essential. Specific causes that could lead to bradycardia and cardiac arrest are included in Box 47-1.
Fluid balance is not a concern for the fetus because water and electrolytes equilibrate across the placenta in response to growth and metabolic demands. The fetal kidneys make urine that passes into the amniotic cavity to compose one half of the amniotic fluid, which is then swallowed and absorbed in the gut. Structurally the kidney is different in the neonate. Nephrons are still being formed up to 35 weeks’ gestation. The resulting glomerular filtration rate is much lower in a preterm (0.55 mL/min/kg) than a full-term baby (up to 1.6 mL/min/kg) or a 2-year-old child (2 mL/min/kg). Decreased systemic arterial pressure, increased renal vascular resistance, and decreased permeability of the glomerular capillaries contribute to the low glomerular filtration rate (GFR). In addition to the stiff, noncompliant myocardium, the neonate is unable to tolerate fluid overload because of the lower GFR. GFR reaches adult levels by 6 to 12 months of age. The renal medulla is not completely mature, and the potential effect of antidiuretic hormone is diminished. However, all of the hormones that affect the kidney are active even in a very immature infant, albeit with reduced potency. Neonates are obligate sodium excreters because of their inability to conserve sodium, even in cases of severe sodium depletion. The renin-angiotensin-aldosterone system (RAAS) acts to reduce sodium loss from the distal tubule, but the immature renal tubules fail to respond. In addition, the renal tubules have a limited ability to reabsorb glucose. Increasing plasma glucose concentrations may elicit an osmotic diuresis, depleting intravascular volume. Table 47-6 lists the daily electrolyte requirements for the newborn. Renal tubular function is immature until the age of 2 to 3 years. The neonate has a limited ability to concentrate urine compared with an adult (700 vs 1200 mOsm/L). Overall, the neonate has a tendency to accumulate sodium because it is essential for growth. Atrial natriuretic peptide is present, but its effects are blunted. In effect, the neonatal kidney is able to excrete water and sodium but cannot conserve them like the kidney of an older child.28
Neonates have a high turnover of fluid. After the first week, a baby needs 150 mL/kg/day of fluid (equivalent to 20 pints a day for an adult). This is because milk has a low concentration of energy compared with solid food, and the neonate cannot physiologically reduce urine output below 1 mL/kg/hr. Neonates also have high insensible losses, particularly from evaporation, as a result of a high surface area/body-weight ratio (four times higher than an adult) and immature skin. These problems are accentuated for the preterm baby. Thirst mechanisms are poorly developed and are affected by sepsis or respiratory distress syndrome. Also, a surge of antidiuretic hormone at birth causes oliguria over the first few days. Table 47-7 summarizes indicators of fluid balance.
|Body weight||Should fall by up to 10% below birth, by 1 week, then increase|
|Hematocrit||Increases (without transfusion) suggest dehydration|
|Creatinine||Should fall from maternal levels to less than 50 µmol/L after 5 days|
The liver begins to develop at 10 weeks’ gestation, and by 12 weeks’ gestation, it has already begun to function. Gluconeogenesis and protein synthesis are under way, and by 14 weeks glycogen is found in liver cells. The fetal liver has the ability to synthesize glycogen. Glycogen storage capacity is greatly increased just before birth. Approximately 98% of this stored glycogen is released from the liver within the first 48 hours of life, and glycogen levels are not restored to adult levels until the third week of life. Glycogen stores are not as large in preterm or small-for-gestational-age (SGA) infants. Therefore preterm and SGA infants should be monitored for the development of hypoglycemia.
The synthetic function of the liver is decreased, and the capability for biotransformation is decreased, with oxidative activities approximately one quarter to one half of adult values.29 The capacity to enzymatically break down proteins is depressed at birth as a result of a decrement in quantity and quality of hepatic enzymes. Albumin, an essential protein that regulates colloidal osmotic pressure, is produced beginning at 3 to 4 months of gestation, approaching 75% to 80% of adult levels at the time of birth. Plasma levels of albumin and other necessary proteins for binding of drugs are lower in newborns and even lower in premature infants. The lower ability of the newborn to bind drug to plasma proteins results in greater levels of free drug. At approximately 1 year of age, its activity reaches adult levels.
There is little glucuronyl transferase activity in the fetal liver. This enzyme is responsible for the metabolic breakdown of bilirubin. Hyperbilirubinemia may develop in term infants within the first days of life. Bilirubin production as a result of the breakdown of RBCs and enterohepatic circulation is increased because of the aforementioned depressed activity of glucuronyl transferase that is required for hepatic conjugation. Bilirubin levels of 6 to 8 mg/100 mL are not uncommon in term infants. However, premature infants may have levels as high as 10 to 12 mg/mL on the third day of life. Phototherapy and, in rare cases, exchange transfusion are used to avoid the development of encephalopathy (kernicterus). In infants with hyperbilirubinemia, it is imperative that a determination of physiologic versus pathologic jaundice be determined.
Concentrations of clotting factors in the premature infant and the newborn are low; however, hepatic synthesis of essential clotting factors reaches adult levels during the first week after birth. In utero, the liver is the organ responsible for hematopoiesis, but by 4 to 6 weeks after birth, this function is assumed by the bone marrow.
The neonate is decidedly disadvantaged in the ability to regulate body temperature. Large surface area, poor insulation, a small mass from which heat is generated, and the inability to shiver all contribute to the problem of thermoregulation.
The neonate has a minimal ability to shiver, so sympathetic stimulation of brown fat metabolism (nonshivering thermogenesis [NST]) increases heat production. NST is the neonate’s defense against hypothermia. It is metabolically driven heat production that does not involve muscular work. Brown fat stores located in the scapulae, axillae, the mediastinum, and in the retroperitoneal space surrounding the kidneys are metabolically active and contain a high density of mitochondria. Hypothermia stimulates the release of norepinephrine, which acts on brown fat to uncouple oxidative phosphorylation.30 Heat production follows an increase in the basal metabolic rate stimulated through the release of anterior pituitary hormones.
Perioperative hypothermia has many contributing causes, including a cold operating room environment, anesthetic-induced vasodilation, the infusion of room-temperature intravenous fluids, evaporative heat loss from opened body cavities, use of cool irrigating solutions, and the inspiration of cool/dry anesthetic gases.
It is well recognized that the thermoregulatory response is inhibited by anesthetic agents. Core body temperature may decrease as much as 1° C to 3° C. Heat loss occurs as a result of the internal redistribution of heat, reduced metabolism and heat production, increased heat loss to the environment, and the effects of anesthetic agents on thermoregulatory control. Heat loss occurs more rapidly in neonates because of limited heat production (NST) and the body surface/body weight ratio. The skin (particularly of the premature neonate) is thinner and has less subcutaneous tissue, increasing the rate of evaporative heat loss.31-34
Radiant heat loss is responsible for the majority of heat loss.28 It occurs with the transfer of heat to the environment and is dependent on the temperature differences between the neonate and the environment. Radiant heat loss may be minimized by wrapping the neonate in a warm blanket and isolating the skin from the cold operating table, effectively decreasing the transfer of heat. Radiant heat lamps may be used to maintain temperature during surgical positioning and preparation. Radiant heat lamps increase the temperature of the air between the neonate and the lamps, thereby minimizing radiant heat loss. However, radiant heat lamps are ineffective when operating room personnel or large objects are placed between the lamp and the patient. In addition, the placement of a radiant heat lamp in close proximity to the neonate may produce thermal injury.
An example of conductive heat loss includes placing the neonate on a cold operating table, resulting in heat transfer from the neonate to the table and thereby causing a decrease in core body temperature. Conductive heat loss is minimized with the use of warmed irrigating solutions, the use of warm blankets or heated forced-air blankets to cover the nonoperative areas of the patient, and the prewarming of the operating room. Covering the head with a stockinette or reflective cap dramatically decreases conductive heat loss. The neonate’s head may account for up to 60% of the total heat loss during the perioperative period.
Convective heat loss is precipitated by moving air currents. The operating room air circulation is changed 6 to 12 times per hour and, in conjunction with cool ambient temperatures, increases heat loss. The air surrounding the body is warmed and subsequently rises, being replaced by the cooler ambient air. To minimize convective heat loss, the ambient air temperature must be increased. Prudent practice is to preheat the operating room to 26° C for premature and neonatal surgical patients. The premature infant or neonate arrives in the operating room in a heated Isolette and is immediately covered with a warm blanket before being transferred to the operating table. Convective heat loss may be increased when wet cloth is in contact with the infant. Wet diapers and blankets soiled with preparation solutions must be replaced and not allowed to remain in contact with the skin.
Evaporative heat loss occurs through the vaporization of liquid from body cavities and the respiratory tract. Evaporative heat loss is either sensible loss (the evaporation of sweat) or insensible loss (the evaporation of water through the skin). The thin-skinned premature infant is particularly susceptible to insensible evaporative heat loss. Sensible evaporative heat loss may be prevented by removing wet clothing or blankets and thoroughly drying the neonate. Insensible evaporative heat loss may be mitigated by increasing the relative humidity of the operating room, covering the patient with a plastic barrier, and using warmed irrigating solutions. Insensible respiratory tract evaporative heat loss may be prevented with humidification of the inspired gases, which requires attentive temperature monitoring to avoid superheating of airway gases and subsequent airway burns. The addition of in-line humidifiers to the patient breathing circuit adds to the complexity and weight, perhaps increasing the likelihood of unintended tracheal extubation. These humidifiers also may contribute to unintended increases in core body temperature during lengthy surgical procedures. The use of a passive heat and moisture exchanger, added between the patient circuit and endotracheal tube, has been of questionable efficacy.35,36
Iatrogenic increases in core body temperature also may occur. Attentiveness in covering the neonate may result in progressive increases in core temperature during prolonged surgical procedures. These steady increases in core temperature may be aggravated by the previous administration of atropine. Surgical procedures also may affect thermoregulation.
Physiologic characteristics that modify the pharmacokinetic (what the body does to the drug) and pharmacodynamic (what the drug does to the body) activity in the neonate include differences in total body water (TBW) composition; immaturity of metabolic degradation pathways; reduced protein binding; immaturity of the blood-brain barrier; greater proportion of blood flow to the brain, heart, liver, and lungs; reduced glomerular filtration; smaller functional residual capacity; and increased minute ventilation.
Several age-related differences in absorption, distribution, metabolism, and elimination effect pharmacologic responses in the neonate. Absorption and distribution are increased via an increased cardiac output per kilogram of body weight, protein binding limits, body composition, and the immaturity of the blood-brain barrier. Elimination is decreased due to immature metabolic pathways and renal immaturity.
Resting cardiac output in the newborn is approximately 200 mL/kg/min. This means faster circulation times that are capable of delivering and removing drugs from their sites of action at a higher rate.
Total body water and extracellular fluid (ECF) are increased in neonates and fall proportionately with postnatal age. The percentage of body weight contributed by fat is 3% in a 1.5-kg premature neonate, 12% in a term neonate. The proportion of fat further doubles by 4 to 5 months of age. These body component changes affect volumes of distribution of drugs. Water-soluble drugs such as neuromuscular blocking drugs (NMBDs) distribute rapidly into the ECF, but enter cells more slowly. The initial dose of water-soluble drugs is consequently higher in the neonate than in the child or adult. Delayed awakening occurs because central nervous system (CNS) concentration remains higher than that observed in older children as a consequence of this reduced redistribution.37 Table 47-8 illustrates the changes in TBW, intracellular fluid (ICF), and extracellular fluid (ECF) during stages of maturation.