Cardiovascular System

The cardiovascular system undergoes dramatic physiologic and maturational changes during the first year of life. In utero, most of the cardiac output is directed from the placenta across the foramen ovale into the ascending aorta (oxygenated blood), whereas superior vena cava blood (deoxygenated) is directed to both the pulmonary artery and the ductus arteriosus (see also Chapter 78 ). This pattern of circulation results in minimal intrauterine pulmonary blood flow. At birth, a number of events change hemodynamic interactions such that the fetal circulation adapts to the postuterine environment. Specifically, the placenta is removed from the circulation; portal blood pressure falls, which causes the ductus venosus to close; and blood becomes oxygenated through the lungs. Exposure of the ductus arteriosus to oxygenated blood induces ductal closure. As a result of the combined effects of lung expansion, exposure of blood to oxygen, and loss of low resistance through placental blood flow, pulmonary vascular resistance decreases while peripheral vascular resistance rapidly rises. The decrease in pulmonary vascular resistance occurs on the first day of life and continues to decrease gradually during the next several years as the architecture of the pulmonary vessels changes. An increase in pressure on the left side of the heart (caused by the increase in peripheral vascular resistance) induces mechanical closure of the foramen ovale. As a result, all three connections between the right and left sides of the circulation close. Although closure of the ductus arteriosus probably occurs primarily from an increase in arterial oxygen concentration, successful completion requires arterial muscular tissue; that such tissue is less prevalent in preterm infants may partly account for the frequent incidence of patent ductus arteriosus in preterm infants. True mechanical closure of the ductus by fibrosis does not occur until 2 to 3 weeks of age.

During this critical period, the infant can readily revert from the adult type of circulation to a fetal type of circulation; this state is called transitional circulation . Many factors (e.g., hypoxia, hypercapnia, anesthesia-induced changes in peripheral or pulmonary vascular tone) can affect this precarious balance and result in a sudden return to the fetal circulation. When such a flip-flop occurs, pulmonary artery pressure increases to systemic levels, blood is shunted past the lungs via the patent foramen ovale, and the ductus arteriosus may reopen and allow blood to shunt at the ductal level. A rapid downhill spiral may occur and lead to severe hypoxemia. In this situation, the hypoxemia may be prolonged, despite adequate pulmonary ventilation with 100% oxygen. In most cases, simple hyperventilation with resultant reduction in arterial partial pressure of carbon dioxide (Pa CO ₂ ) will cause the pulmonary artery pressure to return to normal.

Risk factors increasing the likelihood of prolonged transitional circulation include prematurity, infection, acidosis, pulmonary disease resulting in hypercapnia or hypoxemia (aspiration of meconium), hypothermia, and congenital heart disease. Care must be directed to keeping the infant warm, maintaining normal arterial oxygen and carbon dioxide tensions, and minimizing the effects of anesthetic-induced myocardial depression for those newborns requiring anesthesia.

The myocardial structure of the heart, particularly the volume of cellular mass devoted to contractility, is significantly less developed in neonates than in adults. This difference, as well as developmental changes in contractile proteins, produce a leftward displacement of the cardiac function curve and less compliant ventricles. As a result of these differences, cardiac output is strongly dependent on heart rate; bradycardia is poorly tolerated because the infant cannot easily compensate for the decreased heart rate by increasing stroke volume to maintain normal cardiac output.

The most frequently encountered arrhythmia in pediatric populations is hypoxia-induced bradycardia that can lead to asystole, if not appropriately handled. Ventricular fibrillation is extremely rare in infants and children.

Generally, myocardial function is usually adequate in most infants and children including those with congenital heart disease. Rare exceptions from this rule are individuals with congenital neuromuscular and metabolic diseases where the myocardium can be seriously compromised. In neonates and infants, cardiac calcium stores are reduced because of the immaturity of the sarcoplasmic reticulum; consequently, these populations have a greater dependence on exogenous (blood-ionized) calcium and probably increased susceptibility to myocardial depression by volatile anesthetics that have calcium channel–blocking activity.

Respiratory System

The pulmonary system is not capable of sustaining life until both the lungs and the vascular system have sufficiently matured to allow the exchange of oxygen from air to the bloodstream across the pulmonary alveolar-vascular bed. The lung bud septates from the foregut during the first trimester and the gas exchanging portions of the airway are formed during the second trimester. Alveolar ductal development starts at gestation week 24 while the septation of the air sacs begins around gestational week 36. Alveoli then increase in number and size until a child is approximately 8 years old. Further growth is manifested as an increase in size of the alveoli and airways. At term, complete development of surface-active proteins helps maintain patency of the airways. If a child is prematurely born and these proteins are insufficient, then respiratory failure (e.g., respiratory distress syndrome) may occur.

Respiration is less efficient in infants than adults. The airway of infants is highly compliant and poorly supported by the surrounding structures. The chest wall is also highly compliant; therefore the ribs provide little support for the lungs; that is, negative intrathoracic pressure is poorly maintained. The small diameter of the airways increases resistance to airflow. Thus functional airway closure accompanies each breath. Dead space ventilation is proportionally similar to that in adults; however, oxygen consumption is two to three times higher. In preterm infants, the work of breathing is approximately three times that of adults. This increased work of breathing can increase significantly by cold stress (i.e., increased metabolic demand for oxygen) or any degree of airway obstruction. Another important factor is the composition of the diaphragmatic and intercostal muscles. These muscles do not achieve the adult configuration of type I muscle fibers until the child is approximately 2 years old ( Fig. 77.2 ). Because type I muscle fibers provide the ability to perform repeated exercise, any factor that increases the work of breathing contributes to early fatigue of the respiratory muscles of infants; this partially explains why the infant’s respiratory rate and hemoglobin desaturation is so rapid, and their propensity to develop fatigue and apnea with airway obstruction.

The composition of the diaphragm and intercostal muscles significantly changes during the first 2 years of life. The number of type I muscle fibers is inversely related to age and may account, in part, for the ease of inducing respiratory fatigue as the work of breathing increases.

Data from Keens TG, Bryan AC, Levison H, et al. Developmental pattern of muscle fiber types in human ventilatory muscles. J Appl Physiol. 1978;44:909–913.

Differences in airway anatomy explain the more likely potential for technical airway difficulties in infants than in teenagers or adults. Typically, the airway of infants differs from adults in five ways : (1) The relatively large size of the infant’s tongue, in relation to the oropharynx, suggests that the infant is more likely to sustain airway obstruction and technical difficulties during induction of anesthesia and laryngoscopy. Recently, however, magnetic resonance imaging (MRI) studies have called this into question by showing that soft tissues surrounding the upper airway grow proportionally to the skeletal structures during childhood. (2) Other anatomic differences may account for some of the airway management challenges in children. The larynx is located higher (more cephalic) in the neck, thus making straight blades more useful than curved blades. (3) The epiglottis is shaped differently, being short, stubby, omega shaped, and angled over the laryngeal inlet. Control with the laryngoscope blade is therefore more difficult. (4) The vocal cords are angled; consequently, a blindly passed tracheal tube may easily lodge in the anterior commissure rather than slide into the trachea. (5) Finally, the infant larynx is funnel shaped, the narrowest portion occurring at the cricoid cartilage ( Fig. 77.3 ). While classic teaching is that the adult larynx is cylindrical and the infant larynx is funnel shaped, it is now recognized that the narrowest portion of the airway in approximately 70% of adults is also in the same subglottic region at the level of the cricoid cartilage as it is in children. Nonetheless, the challenges of tracheal tube placement in children are different than they are in adults. For adult patients, the airway size is much larger, so the commonly used tracheal tubes are usually easy to advance past the glottic opening. In infants or young children, a tracheal tube that easily passes the vocal cords may be tight in the subglottic region because of the relatively greater proportional narrowing at the level of the cricoid cartilage.

The narrowest part of the adult larynx and the pediatric larynx is at the level of the cricoid cartilage. Traditionally, the adult larynx was thought to be cylindrically shaped, but autopsy data suggest that the narrowing in adults (A) is not as pronounced as it is in infants (B). The narrowest part of the infant larynx occurs at the level of the cricoid cartilage; the normal adult configuration of the larynx is not achieved until the teenage years. This anatomic difference is one of the reasons uncuffed tracheal tubes have been traditionally preferred for children younger than 6 years of age. A, Anterior; P, posterior.

From Coté CJ, Lerman J, Anderson BJ, eds. A Practice of Anesthesia for Infants and Children. 5th ed. Philadelphia: Saunders; 2013.

Although neonates and infants are considered as obligate nasal breathers, they can also utilize the oral airway to maintain ventilation both spontaneously and in response to complete nasal obstruction. Even in preterm infants, the prevalence of spontaneous oral breathing has been reported to be as high as 50% during sleep, and oral breathing could be consistently initiated in this population upon nasal obstruction.

The Kidneys

Renal function is diminished in neonates with even less function in preterm infants as a result of lower renal perfusion pressures and immature glomerular and tubular function ( Table 77.3 ) ( Fig. 77.4 ). In full-term infants, maturation of glomerular filtration and tubular function is nearly complete by approximately 20 weeks after birth, although delayed in preterm infants. Complete maturation of renal function occurs at approximately 2 years of age. As a result of the delayed development, newborns have reduced ability to excrete free water and solute loads; the half-life of medications excreted by means of glomerular filtration will be prolonged (e.g., antibiotics). Dosing intervals should be longer in neonates.

Glomerular filtration rate (GFR) in the first month of life in preterm infants. The ability of the kidney to regulate large amounts of solutes and water is also limited during the first several months of life. These developmental changes have significant implications for drug excretion and fluid therapy, particularly during the first 4 weeks of life. Maturation of renal function may be delayed in sick and preterm neonates. Data are means ± SEM.

From Vieux R, Hascoet JM, Merdariu D, et al. Glomerular filtration rate reference values in very preterm infants. Pediatrics. 2010;125(5):e1186–e1192.

The Liver

At term, the functional maturity of the liver is incomplete. Most enzyme systems for drug metabolism are developed, but not yet induced (stimulated) by the material that they metabolize. As the infant grows, the ability to metabolize medications rapidly increases for two reasons: (1) hepatic blood flow increases and hence more drug is delivered to the liver, and (2) the enzyme systems develop and are induced. The cytochrome P450 system is responsible for phase I drug metabolism of lipophilic compounds. This system reaches approximately 50% of adult levels at birth. The capacity for drug metabolism (e.g., caffeine) is reduced. However, this is not true for all lipophilic medications. The ability of neonates to metabolize some drugs is dependent on specific individual drug cytochromes. CYP3A (cytochrome P450, family 3, subfamily A) is generally present at adult values at birth, whereas other cytochromes are absent or reduced. Phase II reactions involve conjugation that makes the drug more water-soluble to facilitate renal excretion. These reactions are often impaired in neonates and result in jaundice (decreased bilirubin breakdown) and long drug (and their active metabolites) half-lives (e.g., the half-life of morphine and benzodiazepines is several days). Some of these reactions do not achieve adult activity until after 1 year of age.

A preterm infant’s liver has minimal glycogen stores and is unable to manage large protein loads. These differences account for the neonate’s tendency toward hypoglycemia and acidemia and for the failure to gain weight when the diet contains too much protein. Additionally, plasma levels of albumin and other proteins necessary for the binding of drugs are lower in full-term newborns (and are even lower in preterm infants) than in older infants ( Fig. 77.5 ). This condition has clinical implications regarding neonatal coagulopathy (e.g., need for vitamin K at birth), as well as for drug binding and its pharmacodynamic effects; the lower the albumin value, the less protein binding of some drugs with resultant greater levels of unbound drug (i.e., unbound drug is the portion available to cross biologic membranes). In addition, the binding of some drugs to albumin may be altered in the presence of hyperbilirubinemia in the neonatal period; this effect is more important for drugs with high protein binding because a greater fraction of unbound drug will occur.

Total serum protein and albumin values change with maturation.

Total protein and albumin are less in preterm infants than in term infants and less in term infants than in adults. The result may be pharmacokinetic and pharmacodynamic alterations for drugs with a high degree of protein binding because less drug is protein bound and more is available for clinical effect.

From Ehrnebo M, Agurell S, Jalling B, et al. Age differences in drug binding by plasma proteins: studies on human foetuses, neonates and adults. Eur J Clin Pharmacol. 1971;3:189–193; Coté CJ, Lerman J, Anderson BJ, eds. A Practice of Anesthesia for Infants and Children. 5th ed. Philadelphia: Saunders; 2013.

Gastrointestinal System

At birth, gastric pH is alkalotic; by the second day of life, pH is in the normal physiologic range for older children. The ability to coordinate swallowing with respiration does not fully mature until infants are 4 to 5 months of age, resulting in a high incidence of gastroesophageal reflux, particularly in preterm newborns. If a developmental problem exists within the gastrointestinal system, then symptoms will generally occur within 24 to 36 hours of life. Upper intestinal abnormalities are exhibited as vomiting and regurgitation, whereas lower intestinal abnormalities produce abdominal distention and a failure to pass meconium.

Hematology and Coagulation System

The fetus uses two compensatory mechanisms to assure adequate oxygen delivery in the relatively hypoxemic in utero environment. One of them is the increased red blood cell production resulting from increased fetal renal erythropoietin secretion in response to hypoxemia. The other compensatory mechanism is the production of fetal hemoglobin. Fetal hemoglobin has a high affinity for oxygen, causing a leftward shift in the oxyhemoglobin dissociation curve, increasing oxygen uptake at the lower oxygenated placental vascular bed. Hemoglobin levels are high at birth (160-240 g/L) but rapidly decrease during the first 3 months of life because of decreased renal erythropoietin production in the normoxic ex utero environment. Fetal hemoglobin will be progressively replaced by adult hemoglobin during the first 6 months of postnatal life. The extent of this physiologic anemia is more important in premature infants and may contribute to the need for perioperative blood transfusion.

The hemostatic system of the neonate and infant has many unique features compared to adults. At birth, levels of vitamin K-dependent coagulation factors are low. They reach adult levels by 6 months of age. Fibrinogen levels are comparable between newborns and adults. However, fibrinogen polymerization does not reach its full capacity during the first few postnatal months, thereby leading to prolonged thrombin time. Platelet number at birth is also comparable to adults, but platelet function is impaired during early life. Despite these apparent deficits, the postnatal period represents a hypercoagulable state, since inhibitors of coagulation are also decreased by 30% to 50% in the newborn. Antithrombin III and protein S levels reach maturity by 3 months of age whereas protein C and plasminogen levels reach adult levels after 6 months of life. The overall results of this hypercoagulable state are higher risks of thrombotic complications in neonates and infants. Children between 1 and 16 years of age have a 25% lower ability to form thrombin compared to adults, and the incidence of venous thrombosis in this population is estimated to be very low (0.05%-0.08%). At adolescence, the physiology of the coagulation system matures. In the adolescent population, additional factors such as smoking, obesity, pregnancy, and use of oral contraceptives become relevant. As a result of some of these factors, recent guidelines recommend considering thromboprophylaxis in postpubertal adolescents.

In utero, the immune system of the fetus remains tolerant to maternal alloantigens. After birth, exposure to myriads of environmental antigens, including those derived from intestinal bacteria, leads to a rapid development of the immune system. However, full maturation of both the innate and adaptive immune systems is achieved after several years of life. Therefore young children are at increased risk from many pathogenic viruses, bacteria, fungi, and parasites when compared to adults.

Central Nervous System

In humans, the neural tube is formed between the third and fourth week of pregnancy and is followed by an active phase of cell proliferation and migration during the second trimester. With particular relevance to neonatal and pediatric perioperative care, the most intense phase of brain development takes place between the beginning of the third trimester of pregnancy and the first few years of postnatal life. During this period, also called the brain growth spurt, the nervous system undergoes important differentiation, including the formation of myriads of synaptic contacts between neurons. Neural activity plays a preponderant role in these events especially during critical periods of development when the nervous system is particularly sensitive to and relies on external stimuli to drive differentiation of neuronal networks. Pharmacologic interference with physiologic activity patterns during this period may lead to impaired brain development.

Both premature and term newborns show strong pain behavior that is more diffuse and untuned when compared to older children and adults. The first functional and reflex responses to tactile and noxious stimuli are aimed to protect the individual from tissue damage and can trigger a range of physiologic responses throughout the whole organism. The onset of pain awareness or “feelings” in humans remains undefined and largely debated. Nevertheless, there is evidence that early painful experiences, even if nonconscious, might alter subsequent central nervous system (CNS) function and that adequate pain relief can improve outcome.

Thermoregulation

Infants are especially vulnerable to hypothermia because of the large ratio of body surface area to weight, the thinness of the skin, and a limited ability to cope with cold stress. Cold stress causes increased oxygen consumption and a metabolic acidosis, particularly in preterm infants because of even thinner skin and limited fat stores. The infant compensates by shivering and nonshivering (cellular) thermogenesis (metabolism of brown fat); however, the minimal ability to shiver during the first 3 months of life makes cellular thermogenesis the principal method of heat production. As a result of these issues, managing heat loss is vital for newborns undergoing anesthesia and surgery. Placing the baby on a warming mattress and warming the surgical unit (80°F or warmer) will reduce heat lost by conduction. Keeping the infant in an incubator and covered with blankets minimizes heat lost through convection. The head should also be covered, since heat loss from the scalp is significant. Heat lost from radiation is decreased with the use of a double-shelled isolette during transport. Heat lost through evaporation is lessened by humidification of inspired gases, the use of plastic wrap to decrease water loss through the skin, and warming of skin disinfectant solutions. Hot air blankets are the most effective means of warming children; at the same time, especially in neonates, overheating must be avoided. Anesthetics also impact thermoregulation, particularly nonshivering thermogenesis in neonates.

Body Composition

The body compartments (e.g., fat, muscle, water) change with age ( Fig. 77.6 ). Total body water content is significantly higher in preterm infants than in term infants and in term infants than in 2-year-olds. Neonates and infants have a substantially greater extracellular fluid volume compared to intracellular fluid volume. Fat and muscle content increases with age. These alterations in body composition have several clinical implications for neonates. First, a drug that is water soluble has a large volume of distribution and usually requires a large initial dose (mg/kg) to achieve the desired blood level (e.g., most antibiotics, succinylcholine). Second, because the neonate has less fat and muscle, a drug that depends on the redistribution into fat or muscle for the termination of its action will have a long clinical effect (e.g., fentanyl, propofol, and thiopental).

Body composition rapidly changes in preterm and term infants during the first 12 months of life.

Their high water content provides a large volume of distribution for water-soluble medications, whereas their low fat and muscle content provides a small reservoir for drugs that depend on redistribution into these tissues for the termination of the drug effect. Thus body composition may significantly affect pharmacokinetics and pharmacodynamics.

Data from Friis-Hansen B. Body composition during growth. In vivo measurements and biochemical data correlated to differential anatomical growth. Pediatrics. 1971;47:264; Coté CJ, Lerman J, Anderson BJ, eds. A Practice of Anesthesia for Infants and Children. 5th ed. Philadelphia: Saunders; 2013.

Protein Binding

Neonates have reduced total plasma protein levels, including lower levels of albumin (which binds acidic drugs such as diazepam and barbiturates) and α ₁ acid glycoprotein (which binds lidocaine and alfentanil). Reduced protein levels mean that drugs that are highly protein bound will have a higher free fraction and hence a greater drug effect; however it is important to note that this is only clinically relevant for drugs that have a very high degree of protein binding, a high extraction ratio, and a narrow therapeutic index (such as lidocaine). Some drugs, such as caffeine and ceftriaxone, may also displace bilirubin from plasma proteins increasing the risk of kernicterus in sick neonates.

Clearance

Clearance is the fundamental parameter in predicting drug elimination. It is also an important characteristic for determining duration of effect, dosing interval, and infusion rate. Drugs are cleared through a combination of metabolism and excretion. Clearance changes with age in a complex manner. Clearance (expressed as L/h/kg) is greater in a toddler than it is for an older child. The difference is related to a nonlinear relationship between many aspects of organ function and size. This nonlinear relationship is not related to organ maturity and is surprisingly constant across different aspects of organ function, age, and species. It is known as allometry and can be expressed as

Using body surface instead of body mass results in an allometric exponent of approximately 2/3 and is a reasonable predictor of clearance. Other pediatric pharmacologists argue that an allometric exponent of 3/4 better reflects actual function.

Allometry alone, however, does not explain changes to clearance in the infant and neonate.

For these infants, organ maturity has a substantial impact. A sigmoid hyperbolic or Hill model, in addition to allometry, is needed to predict clearance in this age group. Using postmenstrual age provides a better fit than chronologic age, consistent with organ maturity being on a continuum from fetal to postnatal life. The time to full maturation of renal and hepatic clearance varies between drugs. In general the slope is steepest in the neonatal period and full maturity is achieved by 2 years of age ( Fig. 77.7 ).

Clearance maturation, expressed as a percentage of mature clearance, of drugs in which glucuronide conjugation plays a major role.

From Sumpter A, Anderson BJ. Pediatric pharmacology in the first year of life. Curr Opin Anaesthesiol. 2009;22:469–475.

Many drugs such as succinylcholine, atracurium, and remifentanil undergo clearance independent of the liver or kidney. The nonspecific esterases that metabolize remifentanil are mature at birth. The clearances for these drugs do not require an adjustment for maturation and can be predicted largely through allometry alone.

For drugs that require hepatic or renal clearance, neonates and infants will have a lower clearance resulting in longer elimination half-times, and hence infrequent dosing and lower infusion rates at steady state. In older children, elimination half-times may appear to be shorter, but this difference tends to disappear with allometric (body mass) scaling.

In addition to the differences in drug pharmacokinetics in neonates, other factors will have influence on drug dosing and clearance. Some of the critical factors include sepsis, congestive heart failure, and increases in intraabdominal pressure affecting renal and hepatic function.

Pharmacodynamic Differences

In older children pharmacodynamic properties of most anesthetic agents are probably similar to those in adults, albeit with some notable exceptions such as anticoagulants. In infants and neonates much less is known about the pharmacodynamics of anesthetic agents. The lack of data are partly due to the lack of robust and validated measures of various aspects of anesthetic effect in the infant and neonatal population. For example, fundamental anesthesia endpoints such as pain, memory, and even unconsciousness can be difficult to assess in infants. Surrogate measures of anesthesia effect, such as the EEG, are also unreliable in infants. With increasing understanding of the developmental neurobiology of pain and consciousness it is likely that we will identify other clinically significant pharmacodynamic differences in infants.

Potency of Inhaled Anesthetics in Children

The expired minimum alveolar concentration (MAC) of an inhaled anesthetic required in children changes with age ( Fig. 77.8 ). Anesthetic requirement is smaller for preterm than for term neonates and smaller for term neonates than for 3-month olds. Infants have a higher MAC than that of older children or adults; the reasons for these age-related differences in MAC are not known. When considering the impact of age on MAC, it must be noted that the evidence is limited; the number of studies and the number of children in each study are small.

The minimum alveolar concentrations (MACs) of four commonly used inhaled anesthetics are plotted versus age.

From references 37–44.

It is also important to note that MAC measures only one aspect of anesthesia effect and reflects primarily a spinal cord reflex. Compared to adults, older children have a similar relationship between MAC and other measures of anesthetic effect. The ratio of MAC to MAC _awake , MAC _intubation , MAC _{LMA insertion} , MAC _extubation , and MAC _BAR are similar in children to adults. The relationship between MAC and the EEG, and hence most anesthesia depth monitors, is not as consistent in children and adults. Children have a higher BIS (bispectral index) for a specific fraction of MAC. The significance of this is unclear. In infants and neonates there are no data to determine how MAC relates to other aspects of anesthetic effect. It is clear that the relationship between MAC and the EEG is substantially different in infants compared to adults, but once again the clinical significance of this is unclear.

Halothane, sevoflurane, isoflurane, and desflurane all produce a dose-dependent reduction in systemic blood pressure. It is unclear if this is a direct effect on myocardial contractility and vascular smooth muscle or an indirect effect via autonomic or neurohumoral reflexes. The myocardial depressant effect is greater in neonates compared to older children. All of these agents also have a dose-dependent effect on ventilator drive and response to carbon dioxide.

Pharmacokinetics of Inhaled Anesthetics in Children

The rate of rise of inhalational anesthetic concentration depends on rate of delivery determined by the inspired concentration, minute ventilation, and ratio of minute ventilation to residual functional capacity; it also depends on the rate of uptake that is determined by the cardiac output, tissue/blood solubility, and alveolar to venous partial pressure gradient.

Attainment of steady state, where the alveolar and inspired fractions equilibrate, is faster in children than adults. This difference is due to a greater minute ventilation relative to functional residual capacity as well as a lower tissue/blood solubility. This effect in children is greater for more soluble agents such as halothane and less for sevoflurane and desflurane.

The faster attainment of steady state in neonates can increase the risk of overdose during induction of anesthesia, particularly if a high inspired concentration is used for an excessively long period. The risk may be greater for agents when greater MAC multiples can be delivered by the vaporizer; for example, a halothane vaporizer can deliver up to 5.75 MAC multiples versus 2.42 MAC multiples for a sevoflurane vaporizer ( Table 77.4 ).

Halothane

Halothane is now rarely, if ever, used in the United States and many other countries; however, it is still widely used in developing countries. Halothane is a relatively potent agent, but has a greater blood solubility and slower induction and emergence if similar MAC multiples of inspired concentrations are used. It does not have a noxious smell and hence, prior to the use of sevoflurane, was the agent of choice for inhalational inductions in children. Halothane, being a polyhalogenated alkane, has subtle differences in pharmacodynamic properties compared to the other ether inhalational anesthetics. Halothane has more “analgesic” properties than the ethers and has a higher BIS at equivalent MAC multiples. The MAC of halothane is low in neonates, highest in infants, and then steadily declines with age.

Halothane is a potent myocardial depressant that can have profound effects on neonates and children. Halothane also causes sensitization of the myocardium to arrhythmias. The first Pediatric Perioperative Cardiac Arrest (POCA) registry study reported that halothane was a major cause for perioperative cardiac arrest. It was thought to be particularly dangerous with the use of controlled ventilation without reducing the inspired concentration after induction. The decline in cardiac events in subsequent POCA audits has been attributed to the decline in use of halothane in the United States. At the same time, halothane may be used safely, but care should be exercised particularly if the anesthesiologist is not experienced with its use.

Sevoflurane

Sevoflurane is a polyhalogenated ether. It has a low blood solubility facilitating a relatively rapid inhalational induction. Sevoflurane is less pungent than isoflurane and desflurane and has become the agent of choice for inhaled induction of anesthesia in children. Unlike other inhalational agents, the MAC is similar with neonates and infants, but like other agents becomes lower with age after infancy: 3.3% for neonates, 3.2% for infants 1 to 6 months old, and 2.5% for children older than 6 months. Sevoflurane is associated with a greater incidence of emergence delirium compared to halothane (see later). Sevoflurane is also reported to cause epileptiform changes in the EEG when delivered at high concentrations in children. The clinical significance of these EEG changes is not clear.

Isoflurane

Isoflurane, a polyhalogenated ether, has a blood solubility between halothane and sevoflurane. As with sevoflurane, it has a relatively lower MAC in neonates, peaks in infancy, and then declines with age. It is more potent than sevoflurane but has a relatively more noxious smell, which makes an inhalational induction with it unacceptable for most children.

Desflurane

Desflurane is another polyhalogenated ether, with a blood solubility lower than isoflurane or sevoflurane. Similar to sevoflurane and isoflurane, desflurane’s MAC peaks in infancy, is lower in neonates, and declines with age after infancy. The low solubility facilitates a more rapid emergence. It is however not suitable for inhalational induction in children because of its pungent odor and an unacceptable incidence of laryngospasm (∼50%). It is however suitable for maintenance of anesthesia in children although the package insert indicates that it is not recommended for maintenance in children without tracheal tubes.

Nitrous Oxide

Nitrous oxide is an odorless gas that has a low solubility in blood, but is relatively nonpotent. The MAC of nitrous oxide has not been accurately determined in children. When nitrous oxide is used with an inhaled anesthetic, it reduces the concentration required for the more potent inhalational agents. It may speed the uptake of more potent anesthetics, but the underlying theory behind this “second gas” effect has been challenged. This characteristic is probably of limited clinical relevance. Nitrous oxide is a weak analgesic; it can be used alone or in conjunction with other agents for procedural sedation and analgesia for children. Since it is odorless, it is also commonly used for an inhalational induction in cooperative children. For example, breathing high concentrations for a short period can provide considerable sedation prior to adding sevoflurane. In many institutions the routine use of nitrous oxide during maintenance of anesthesia has declined since it is associated with an increased risk of postoperative nausea and vomiting in adults; however studies have shown little evidence that nitrous oxide has any impact on postoperative nausea and vomiting in children.

Xenon

Xenon is another odorless anesthetic gas that has a relatively low potency. While it is currently not routinely used, it has some potential advantages over other anesthetic agents. The MAC in children is unknown. In adults it has remarkably little cardiovascular effect. It has thus been proposed as a potentially superior anesthetic for children with significant congenital heart disease but only preliminary studies have evaluated this to date. Its high cost mandates the use of either very low fresh gas flows or complex scavenging and recycling systems. This may reduce the practicality of its use in many pediatric settings.

Emergence Agitation and Delirium

Children can become agitated on emergence or shortly after arrival in the postanesthesia care unit (PACU). The reported incidence of agitation varies enormously, reflecting the variety of definitions of agitation and delirium used in various studies. The potential list of causes or associated factors is long. Agitation may be due to many factors including pain, cold, full bladder, presence of restrictive casts, fear, anxiety due to parental separation, or simply having a “tantrum.” Agitation is best measured with the Cravero scale. The initial management of agitation is to try to identify or rule out likely causes. In some cases agitation may be due to delirium. Delirium is characterized by reduced awareness of the environment and altered cognition or perceptual disturbances. Typically the child is disoriented and does not respond to parents or staff. There is generally no eye contact and the child cannot be consoled. If the delirium is associated with thrashing around or violent movement, this is known as “emergence delirium.” Emergence delirium occurs most frequently in preschool children. It is distressing to staff and parents. It may also lead to self injury, and dislodging dressings, drains, and intravenous lines. In most cases, emergence delirium may persist for 10 to 20 minutes but is self-limiting. Delirium may also be hypoactive; in this situation, the child has a delirium, but is inactive and not agitated, and thus is at less risk of doing harm to themselves.

The cause for delirium is not precisely known. It may relate to the mode of awakening. It is intriguingly similar to night terrors in children. It is more common when maintenance anesthesia included either sevoflurane or desflurane. It is unusual after total intravenous anesthesia (TIVA) with propofol. Many agents have been found to reduce the incidence. The most effective is using TIVA or giving 2 to 3 mg/kg of propofol before emergence. Fentanyl and α ₂ agonists have also been found to be effective. Propofol, clonidine, and midazolam have all been described as useful in management. When managing delirium other causes for agitation should be considered, particularly pain. Emergence delirium may occur after painless procedures; however there is also some evidence that pain may increase the risk of emergence delirium. Other physiologic changes, including hypoxia, metabolic derangement, and hyponatremia, may also cause agitation or delirium, so must be ruled out, particularly if the delirium is prolonged.

Propofol

The pharmacokinetics of propofol have been well described in children. In children the volume of distribution is greater than in adults and there is a more rapid redistribution. Clearance is similar in children to adults; however clearance is longer in preterm neonates. The dose for induction increases with decreasing age. The median effective dose (ED ₅₀ ) for loss of eyelash reflex is 3 mg/kg in infants aged 1 to 6 months, and 1.3 to 1.6 mg/kg in children aged 1 to 12 years. The pharmacokinetics of propofol in neonates has not been as well described; however, the induction dose is generally less than for older infants. Use of propofol has been associated with profound hypotension in neonates. A potential drawback is pain on injection. Numerous strategies have been described to reduce this pain. The most effective is probably using a large vein, or adding lidocaine (0.5-1.0 mg/kg) to the propofol, or injecting lidocaine before the propofol. Propofol is not contraindicated in children with egg allergy.

A major concern with propofol is the potential for propofol infusion syndrome (lipemia, metabolic acidosis, rhabdomyolysis, and hyperkalemia followed by refractory cardiovascular collapse), which is generally associated with high-dose infusions for an extended period (usually days in an intensive care unit [ICU] environment). The onset may be subtle and unnoticed followed by rapid demise. The mechanism underlying propofol infusion syndrome remains unclear. It may be related to mitochondrial lipid metabolism.

Total Intravenous Anesthesia in Children

TIVA is becoming increasingly popular in pediatric anesthesia. Propofol and remifentanil are the main agents used. In children TIVA has been suggested to have many advantages including reduced emergence agitation and emergence delirium, faster recovery, reduced postoperative vomiting, and fewer airway complications on emergence. These advantages are all plausible; however there are few well-designed studies to test these assertions. One limitation of TIVA in children is the need for specific and well-validated pediatric algorithms. Adult target-controlled infusion models are not best suited for children. The Paedfusor model is one pediatric-specific algorithm that is widely used for children.

Thiopental

In most countries, propofol has largely replaced thiopental in pediatric anesthesia. The ED ₅₀ of thiopental is 3.4 mg/kg in neonates, 6 mg/kg in infants, 4 mg/kg in preschool children, 4.5 mg/kg in children aged 4 to 7 years, 4.3 mg/kg in children aged 7 to 12 years, and 4.1 mg/kg in older children. Clearance is slower in neonates. Limiting the total dose to 10 mg/kg or less in older children minimizes the possibility of prolongation of anesthesia caused by residual barbiturate sedation.

Ketamine

Ketamine has a similar volume of distribution in children compared to adults, but the clearance is reduced in infants. Ketamine has a number of niche uses in pediatric anesthesia. Ketamine may be used for induction of anesthesia (1-3 mg/kg intravenously and 5-10 mg/kg intramuscularly). The intramuscular route is well described for larger uncooperative children where intravenous and inhalational induction are impossible and other forms of premedication are refused. The intramuscular dose may have a benzodiazepine added to reduce the risk of hallucinations and an anticholinergic agent to reduce the risk of hypersecretion. For relatively brief procedures a large intramuscular dose may lead to significantly delayed emergence.

Compared to equipotent doses of other intravenous anesthetics, ketamine causes relatively little cardiovascular or respiratory depression and is less likely to result in airway obstruction. It is thus favored as a safer drug in resource poor settings. However, although spontaneous respirations and a patent airway are usually maintained, apnea and laryngospasm may still occur. It is also frequently used in the pediatric emergency department for brief painful procedures. Ketamine may be used alone or in combination with other agents as an effective premedication. Given its cardiovascular stability it may be the optimal premedication for children with significant cardiovascular disease such as children with congenital heart disease. Ketamine is increasingly used as a postoperative analgesic, either alone or in combination with other agents.

Etomidate

Clearance is similar in children to adults; however the volume of distribution is larger in children and hence a larger initial bolus is required. Concerns regarding anaphylactoid reactions and suppression of adrenal function have limited widespread use of this anesthetic in children. As with propofol, the incidence of pain on intravenous administration is frequent. Etomidate has minimal cardiovascular suppression and thus it is useful in children who are critically ill and those with a head injury. Etomidate has gained increasing popularity for airway management in the emergency department.

Clonidine

Clonidine is increasingly used for premedication. To be optimally effective 4 mcg/kg clonidine should be given orally 45 to 60 minutes prior to induction. There is some evidence that clonidine is superior to midazolam as a premedicant in terms of sedation, postoperative agitation, and postoperative pain. Similar to many other drugs, the clearance of clonidine is reduced in neonates; however it rises to 82% of adult levels by 1 year of age.

Dexmedetomidine

Dexmedetomidine has greater selectivity for the α ₂ adrenoreceptor than clonidine, and hence produces less hypotension and bradycardia compared to clonidine. It also has minimal respiratory depressive effects. The sedation provided by dexmedetomidine is similar to natural sleep. Thus with stimuli, children may be more easily aroused from dexmedetomidine sedation compared to other sedative agents. Dexmedetomidine has been widely used as a sedative in the intensive care setting. It has also been used as a sole sedative for medical imaging in children. The loading dose of 1 to 2 μg/kg is typically given over 10 minutes followed by an infusion of 0.5 to 1 μg/kg/h. This may however produce a more prolonged recovery compared to other regimens. Dexmedetomidine has also been used for cardiac catheterization, awake-craniotomies, and to facilitate opioid withdrawal. Dexmedetomidine may produce a biphasic hemodynamic response with a bolus producing an initial increase in blood pressure before a mild reduction in blood pressure. The clearance is reduced in neonates.

Dexmedetomidine is increasingly used intranasally for premedication where it has a bioavailability of 80%. A dose of 1 to 2 μg/kg is usually used for intranasal premedication, taking 30 to 40 minutes for peak effect. Several studies have found intranasal dexmedetomidine to be superior to midazolam for premedication in children.

Morphine

Morphine is frequently used for postoperative analgesia. In children, as in adults, there is also a large variability in pharmacodynamic and pharmacokinetic profile and thus doses should be titrated to effect. Morphine is metabolized by both glucuronidation and sulfation. In adults sulfation is a minor pathway; however in neonates it is relatively more dominant. The clinical significance of this is unclear. Clearance is low in neonates but reaches adult levels at 6 to 12 months of age. The most worrisome adverse effect of morphine is respiratory depression. In animal models neonates are more susceptible to respiratory depression compared to older animals, perhaps due to an immature blood-brain barrier. There is some evidence that human neonates are also more susceptible to the respiratory depressive effects of morphine; however the mechanism remains unclear. Nevertheless it should be used cautiously in infants, especially preterm infants.

Codeine

Codeine is a morphine-like opioid with approximately 10% the potency of morphine. It has rapid oral absorption and 90% bioavailability. These features resulted in it previously being used extensively as an oral analgesic (1 mg/kg). Approximately 10% of codeine is metabolized to morphine and thus a considerable amount of its analgesic action is through this mechanism of metabolism. There is considerable variation in this metabolism with poor, rapid, and ultra-rapid metabolizers. About 10% of Caucasians and 30% of Hong Kong Chinese are poor metabolizers in whom codeine provides only poor analgesia. In contrast, 1% of some Caucasian groups and 30% of Ethiopians are ultra-rapid metabolizers. Ultra-rapid metabolizers are at risk of increased clinical response including profound respiratory depression that has been associated with death in children. For this reason, codeine is increasingly being used infrequently. The U.S. Food and Drug Administration (FDA) issued a “black box” warning against its use in children after tonsillectomy.

Meperidine

The use of meperidine is declining because of concerns over the accumulation of the metabolite normeperidine with multiple doses, which may cause seizures. Meperidine has a potency of approximately one tenth that of morphine and a shorter time to peak effect. The elimination of meperidine is reduced in neonates.

Fentanyl

Fentanyl is commonly used in pediatric anesthesia for intraoperative analgesia. It has greater hemodynamic stability than morphine. High doses of 10 μg/kg or greater can be used to maintain cardiovascular stability. The clearance is markedly reduced in preterm infants but rises to 80% of adult values by term. Adult levels of clearance are achieved within the first few weeks post term. The volume of distribution is greatest in neonates (5.9 L/kg) and steadily declines with age to 1.6 L/kg in adults.

Alfentanil

The clearance of alfentanil in preterm neonates is markedly reduced and the volume of distribution is greater than older infants. Pharmacokinetic data are generally sparse and somewhat contradictory but volume of distribution and elimination half-life are similar between infants aged 3 to 12 months and older children.

Sufentanil

Sufentanil is used mainly for pediatric cardiac surgery. Like other similar agents, in neonates sufentanil has a greater volume of distribution, reduced clearance, and longer elimination half-life.

Remifentanil

The main advantage of remifentanil is its extremely brief half-life. The elimination half-life is 3 to 6 minutes and is independent of dose and duration. Remifentanil is degraded by nonspecific plasma and tissue esterases and metabolism is not affected by butyrylcholinesterase deficiency. The importance of maturation of renal and hepatic function is minimal and the drug has great utility in infants with hepatic or renal failure. The differences in remifentanil’s half-life among neonates, infants, and adults are minimal.

One study examined its pharmacokinetic effects in children and found age-related differences in the volume of distribution and clearance but not in half-life with volume of distribution being greater in infants compared to older children ( Fig. 77.9 ). Contrary to the pharmacokinetics of most drugs, neonates are able to clear the drug more rapidly than older children. Of further interest is the very small patient-to-patient variability in pharmacokinetic parameters when compared with similar studies examining other opioids, particularly in infants and neonates. The particularly favorable pharmacokinetics in neonates allows the provision of a deep opioid-induced plane of anesthesia while avoiding cardiovascular depression and the need for postoperative ventilation.

Remifentanil is the newest potent opioid available for the care of neonates.

Unlike virtually all other medications, its clearance is more rapid in neonates than it is in older children, probably because of elimination of remifentanil by nonspecific plasma and tissue esterases, as well as the larger volume of distribution in neonates. The importance of this observation is that developmental immaturity of liver and renal function does not affect the pharmacokinetics of remifentanil.

Data abstracted from Ross AK, Davis PJ, del Dear G, et al. Pharmacokinetics of remifentanil in anesthetized pediatric patients undergoing elective surgery or diagnostic procedures. Anesth Analg. 2001;93:1393–1401.

An initial dose of remifentanil may be required prior to infusion; however, a rapid large bolus may produce hypotension and bradycardia. A combination of 3 μg/kg remifentanil with 3 to 4 mg/kg propofol is an alternative to succinylcholine to facilitate endotracheal intubation. An acute tolerance similar to that occurring in adults has also been described in children. If postoperative pain is anticipated, adequate long-acting analgesia should be given well before the remifentanil infusion is discontinued.

Tramadol

Tramadol is a relatively weak opioid with less respiratory depressant effects. Two enantiomers provide analgesia; one is an opioid mu receptor agonist and the other inhibits uptake of serotonin and noradrenaline. Clearance is less in premature neonates but in children is similar to adults if standard allometric scaling is applied. Tramadol is metabolized by various pathways including via CYP2D6 to 0-desmethyltramadol. This metabolite has mu-receptor affinity approximately 200 times greater than tramadol. The genetic polymorphism of CYP2D6 produces fast and slow metabolizers that may produce a variable response among children. The FDA has warned against using tramadol after tonsillectomy in children with obstructive sleep apnea. One oral formulation of tramadol for children has a concentration of 100 mg/mL and is administered in drops. This may increase the risk of errors in administration if milliliters are mistakenly given rather than drops, resulting in a potentially 10-fold overdose. This formulation has been replaced in some countries by an elixir of 10 mg/mL.

Succinylcholine

Succinylcholine is highly water soluble and rapidly redistributes into the extracellular fluid volume. For this reason, the dose required for intravenous administration of this depolarizing muscle relaxant in infants (2.0 mg/kg) is approximately twice that for older children (1.0 mg/kg). Succinylcholine is also effective when given intramuscularly; reliable muscle relaxation occurs within 3 to 4 minutes after 5 mg/kg in infants and 4 mg/kg in children older than 6 months. The skeletal muscle relaxation produced by intramuscular administration may last up to 20 minutes. In an emergency situation, succinylcholine may be administered intralingually (via a submental approach), which will further speed the onset of relaxation because the drug is more rapidly absorbed from the tongue than from peripheral skeletal muscle.

Cardiac arrhythmias may follow intravenous administration. Prior intravenous administration of atropine (but not intramuscular administration of atropine as a premedication) reduces the incidence of arrhythmias. Cardiac sinus arrest may follow the first dose of succinylcholine but is more common after repeated bolus administrations; such arrest may occur in children of any age. Therefore a vagolytic drug should probably be intravenously administered just before the first dose of succinylcholine in all children, including teenagers, unless a contraindication to tachycardia (e.g., a cardiomyopathy) exists.

Succinylcholine has received significant attention because of the severity of its possible complications. The potential for rhabdomyolysis and hyperkalemia (particularly in boys younger than 8 years of age who have unrecognized muscular dystrophy), as well as the risk for malignant hyperthermia, suggests that succinylcholine should not be routinely used in children. Increased jaw muscle tone (masseter spasm) after succinylcholine has been observed, particularly when halothane is used. Masseter tetany (“jaws of steel”), which prevents any mouth opening, is an extreme variation in increased masseter muscle tone. Such tetany may be an early sign of malignant hyperthermia, but certainly not all cases of tetany progress to malignant hyperthermia.

Succinylcholine is still used for emergency airway management including the management of severe laryngospasm and as part of a rapid sequence induction (RSI) where the child has a full stomach. High-dose nondepolarizing neuromuscular blockers such as rocuronium or a large dose of propofol and remifentanil have been proposed as alternatives to succinylcholine for RSI. Large-dose rocuronium produces adequate intubating conditions almost as quickly as succinylcholine in adults. The advent of sugammadex has enabled the rapid reversal of large-dose rocuronium if needed. High-dose propofol and remifentanil may also produce timely adequate intubating conditions; however significant hypotension may occur.

Nondepolarizing Muscle Relaxants

A comparison of infants with older children and adults regarding responses to nondepolarizing muscle relaxants shows that infants are generally more sensitive to these drugs and that their responses vary to a greater degree. Although the initial dose per kilogram needed for neuromuscular blockade is often similar for children of all ages, the greater volume of distribution and reduced renal or hepatic function of neonates result in a slower rate of excretion and a prolongation of effect. Neuromuscular blockade occurs at a lower blood concentration in infants.

The choice of nondepolarizing muscle relaxant depends on the side effects and the duration of the desired muscle relaxation. If tachycardia is desired (e.g., with fentanyl anesthesia), then pancuronium may be an appropriate choice. Vecuronium, atracurium, rocuronium, and cisatracurium are useful for shorter procedures in infants and children; they may also be administered as a constant infusion. The method of excretion of atracurium and cisatracurium (Hofmann elimination and ester hydrolysis) makes these relaxants particularly useful in newborns and children with immature or abnormal hepatic or renal function. Vecuronium is valuable because no histamine is released; however, its duration of action is prolonged in newborns.

Rocuronium has a clinical profile similar to that of vecuronium, cisatracurium, and atracurium. Rocuronium can be administered intramuscularly. One study observed that acceptable conditions for intubation are produced by rocuronium within 3 to 4 minutes after 1 mg/kg intramuscularly in infants and 1.8 mg/kg intramuscularly in children older than 1 year of age; these effects were more dependable with deltoid than with quadriceps muscle injection. Table 77.5 provides commonly recommended guidelines for doses. Routine pharmacologic antagonism of neuromuscular blockade is recommended in all children, even if they have clinically recovered. Recovery times vary between subjects and residual blockade may be difficult to detect, and may be associated with increased postoperative complications.

Sugammadex

Sugammadex is a cyclodextrin that rapidly encapsulates rocuronium, and to a lesser extent, vecuronium, forming a stable complex that prevents any further action of the muscle relaxant. The complex is excreted by the kidney. There are few data in children; however one study found that 2 mg/kg reversed moderate rocuronium-induced block in children and adolescents in a time that was similar to that seen in adults.

Animal data

There is substantial preclinical evidence that many general anesthetics have the capacity to cause morphological and functional changes to the developing brain. These changes have been demonstrated in a wide variety of species, ranging from the nematode to the nonhuman primate. A variety of different morphological changes have been seen. Accelerated neuronal apoptosis is the most widely recognized. Changes to dendritic morphology have also been described. Apoptosis has also been described in glial cells. Several mechanisms have been identified, and mitochondrial dysfunction may be important. The effects are greatest with larger doses and longer exposure; however, it is difficult to identify the upper limit of duration of exposure that has no effect. The effect also varies with age at the time of exposure. Generally the effects are greater in the more immature brain—which may translate to the late trimester of pregnancy or early infancy in humans, but some effects are also seen in older animals. The area of the brain affected may also vary with age of exposure. Effects are greatest with γ-aminobutyric acid agonists and N-methyl-D-aspartate antagonists and have been seen with propofol, benzodiazepines, volatile anesthetics, and ketamine. There is contradictory evidence for an effect with α ₂ agonists. Functional experiments have demonstrated that animals, including nonhuman primates exposed to anesthesia in early life, may have deficits in learning and altered behavior; however not all experiments have demonstrated functional deficits and it is unclear if the functional deficits are a function of the observed morphologic changes.

Translating the Animal Data to Humans

There are considerable problems translating animal data to humans in general, and more challenging when considering age. Translating dose ranges is problematic as is understanding exactly how a particular age of animal correlates to the age of a human. In small animals, homeostasis may be deranged during anesthesia and few models examine the impact of concurrent surgery. Human brains are complex and develop over a longer period. The impact of an injury in humans will depend on the type of injury and timing of the injury. Human brains can be extraordinarily vulnerable to injuries of a specific type at particular times, or demonstrate considerable plasticity and recovery. Importantly, genetic and environmental factors have a huge impact on resilience and recovery or vulnerability.

Human Study Outcomes

The human studies can be broadly grouped according to their design and the outcomes at which they look. So far there is only one prospective trial with published results. All other studies are observational. This is a crucial point that will be explained later. Various study designs have been used.

The design of observational studies broadly consist of:

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  Data linkage population-based studies. These studies use existing datasets that can be linked. They are inherently retrospective and limited by the outcomes and exposure variables that have already been collected. They can however be very large, examining whole country or whole state populations. The outcomes commonly used are some form of preschool test for school readiness, or school grades.

  
  
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  Use of existing birth cohorts or longitudinal studies. These studies use existing data in longitudinal cohorts that have usually been set up for other purposes. They often include access to more detailed outcome measures including some psychometric outcomes; they may also include diagnoses of disability and school grades. While often large, they are not as big as the population linkage studies. The details of exposure may be limited but there are usually good data about other factors that may contribute to outcome.

  
  
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  Purpose built cohort studies. These studies recruit children that have been exposed to anesthesia and match them to those that have not, and then test the children for a range of psychometric outcomes. These studies enable researchers to focus on neurodevelopmental areas of greatest interest but logistically it is difficult to recruit large numbers of children. Children may be recruited in various ways including from existing longitudinal studies.

Various outcome measures have also been used.

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  School grades or school readiness tests. These are of great interest and importance to families but they are coarse measures of neurodevelopment. A deficit may however exist in one aspect of neurodevelopment that is not reflected in school grades; conversely many other factors influence school grades, diluting any possible “injury” effect. Their advantage is not only their importance to families, but also that they are easy to obtain in very large numbers.

  
  
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  Diagnosis of a learning disorder or specific neurodevelopmental disorder. These are also of great importance to the families and the community. A major problem is that the diagnosis may not always be clear and definitions of disorders vary between jurisdictions and over time. Another potential disadvantage is that these disorders are not common enough to be able to produce precise results except in very large studies.

  
  
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  Psychometric testing. Many tests are available to test a wide range of neurodevelopmental domains. Apical tests, such as intelligence quotient (IQ), are composite scores that pool results from several domains. Apical tests have the best value as far as predicting future function, but using apical tests may miss deficits in some subdomains. Looking at multiple domains raises the problem of type 1 error (finding a “significant” association due to multiple testing). The psychology literature abounds with studies that are not replicable—partly because of this issue. If a “deficit” is found in only one or two of many subdomains tested then the results must be interpreted very cautiously until they are replicated in following studies. Performing psychometric testing is labor intensive and must be done to a high standard to be useful.

  
  
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  Imaging. MRI may provide some insight; however, these studies are usually small due to logistic problems and, similar to psychometric testing, many outcomes are usually measured that increase the risk of type 1 error. Our understanding of MRI is rapidly increasing but there is still a degree of disconnect between what is seen on the MRI and functional relevance.

In all these studies, it is important to consider the subject’s age at testing. Some aspects of neurodevelopment such as higher executive function cannot be tested until the child is older. Also, after an injury children will usually “grow into their deficit.” An injury in a particular aspect of brain function will become more apparent as the child develops and lacks that function. This is contrary to the idea that the brain will always have plasticity and recovery.

Results From Studies That Look at Specific Developmental Disorders

Most, but not all, studies that identify a diagnosis of a learning or developmental disorder found evidence for an association between anesthesia in early childhood and an increased risk of a diagnosis of a behavioral disorder or learning disability. Most of these studies also note that this association is greater with multiple exposures.

The Child With an Upper Respiratory Tract Infection

Upper respiratory tract infections (URIs) are very frequent in childhood with an annual incidence of up to 6 to 8 episodes in infants and preschool children. They usually last for 7 to 10 days, but symptoms may persist for up to 3 weeks. More than 200 viruses have been shown to be associated with URI. The viral invasion of the respiratory mucosa leads to an inflammatory response that results in airway edema and increased secretions. Bronchial hyperreactivity, resulting primarily from the impact of the viral infection on the autonomic nervous system, may persist for up to 6 weeks or longer, well beyond the disappearance of clinical symptoms. Therefore a child with a URI is a major challenge for pediatric anesthesia. The most common perioperative respiratory adverse events (PRAEs) associated with URI are: laryngospasm, bronchospasm, breath holding, atelectasis, arterial oxygen desaturation, bacterial pneumonia, and unplanned hospital admission. Fortunately, the incidence of serious PRAEs in children with “common cold” is low.

During the preanesthesia visit, the anesthesiologist should assess the patient for an underlying respiratory illness and identify the risk factors associated with PRAE. These risk factors can be related to the child itself, the specific risks of the anesthesia procedure, or surgery specific factors. Children presenting with signs of serious URI, including fever, productive cough, green runny nose, or otitis media, are at increased risk for PRAE. Infants with respiratory syncytial virus infection present a particularly high-risk group during perioperative management. The anesthesiologist should also elicit any history or signs of primary pulmonary morbidity, such as bronchial asthma, prematurity, and bronchopulmonary dysplasia, cystic fibrosis, and pulmonary hypertension. Passive smoke exposure should also be considered. The anesthesia- and surgery-specific risk factors are most important with instrumental manipulation of the airway such as with bronchoscopy and endotracheal intubation. Ear, nose and throat, and eye surgery as well as upper abdominal and thoracic surgeries also increase the risk of PRAE.

The question of whether to cancel a procedure in a child with URI and, if so for how long, is difficult to answer and is influenced by many factors ( Fig. 77.10 ). There is now an increasing expert consensus that it is not necessary to postpone a surgical procedure for 6 weeks after any URI in children. Indeed, given the high annual incidence of URI in children, such an approach could even lead to postponing surgery indefinitely. Recent recommendations emphasize an approximately 2-week-long time lag between the resolutions of clinical symptoms and anesthesia.

Proposal for decision algorithm for a child with a “cold.”

ENT, Ear, nose, and throat; LMA, laryngeal mask airway.

From Becke K. Anesthesia in children with a cold. Curr Opin Anaesthesiol. 2012;25[3]:333–339.

Several approaches can be taken to decrease the incidence of PRAE in children with URI. Premedication with an aerosol of salbutamol has been shown to be effective in both the prevention and treatment of perioperative bronchospasm in children with bronchial hyperreactivity. While intravenous lidocaine (1 mg/kg) has also been proposed to decrease the incidence of PRAE, current evidence does not support this approach. Induction of anesthesia through an intravenous approach with propofol has been suggested to result in a lower incidence of PRAE in children with URI when compared to inhalational induction. Endotracheal intubation in patients with bronchial hyperreactivity has been shown to be associated with a higher incidence of PRAE when compared with ventilation via a face mask or LMA. Last but not least, several lines of investigations point to the anesthesiologist’s experience as an important factor to prevent PRAE.

Airway Management

Preoperative evaluation of the airway should be based on both the child’s medical record and clinical evaluation. A wide range of syndromic and genetic conditions and congenital malformations are associated with potential airway problems, especially those involving facial dysmorphias. History of birth complications, obstructive sleep apnea, head and neck trauma, previous surgery, and related airway management must also be considered. During the physical examination, the anesthesiologist should check for facial dysmorphias, signs of stridor, dysphonia, swallowing disorders, difficulty in breathing, difficulty in speaking, and hoarseness. There are a large number of difficult airway predictors in children but their applicability, sensitivity, and specificity vary greatly in the clinical setting. Among them, mandibular protrusion, Mallampati’s classification, movement of atlantooccipital joint, reduced mandibular space, and increased tongue thickness have all been shown to be good predictors of airway problems. Other reported risk factors are age less than 1 year, ASA II-IV status, obesity, and maxillofacial and cardiac surgery.

Appropriately performed mask ventilation is a critical component of pediatric airway management. Anesthetized children are particularly prone to upper airway collapse; it can be easily relieved by a combination of moderate head tilt, chin lift, jaw thrust, and the application of continuous positive airway pressure. The combination of these maneuvers with lateral decubitus position can further improve airway patency. Additionally, both oropharyngeal and nasopharyngeal airway devices can be used during spontaneous or positive pressure mask ventilation to further relieve airway obstruction caused by the posterior displacement of the tongue in anesthetized children.

A large variety of supraglottic airway devices are now commonly used in pediatric anesthesia. The two most popular among these are the classic laryngeal mask airway (LMA) and the LMA ProSeal. Both devices have comparable safety and efficacy profiles in pediatric populations. Increasing evidence suggests that the use of the LMA in children is associated with a decreased incidence of perioperative respiratory complications when compared to endotracheal tube insertion.

Direct laryngoscopy is still the most frequently used technique for intubation in children. Because of the diverse ages and size of the pediatric patient population, any hospital that cares for children must have a full selection of both curved and straight laryngoscope blades to ensure that the blade most appropriate for the child is readily available. In general, since the epiglottis is more “U” shaped in young children and it may lie across the glottic opening, straight blades are routinely used in neonates and toddlers to directly elevate the epiglottis and visualize the vocal cords. Older children can be managed with either curved or straight blades. An ever-increasing number of devices have been developed over the past decade to facilitate endotracheal intubation. Among them, videolaryngoscopy has been initially introduced as an aid for difficult airway management, and it may even replace the use of flexible fibroscopy in an increasing number of indications. The use of videolaryngoscopy in everyday routine airway management is also increasing. Indeed, these devices enable a better and faster glottic visualization thereby reducing the time of intubation, the number of attempts, as well as dental trauma. It is, however, important to note that each type of videolaryngoscope requires a particular technique, and that technique can vary considerably between devices. While awake fiberoptic intubation is generally considered as the gold standard for the known or anticipated difficult airway in adults, this option is usually not feasible in children due to the need for significant cooperation during the procedure. Most pediatric anesthesiologists prefer the use of inhalational induction in the case of predicted difficult airway and perform flexible fibroscopy-aided intubation under spontaneous ventilation in the anesthetized child.

The use of cuffed endotracheal tubes has become increasingly common in neonates, infants, and young children. Historically, uncuffed endotracheal tubes were recommended in children less than 8 years of age, because it was thought that the narrowest part of the airway was the cricoid ring and to minimize potential cuff-induced damage of the tracheal mucosa as well as to allow reduction of air flow resistance by inserting a larger size tube. Airway trauma can also occur when using an uncuffed tube with acceptable leak pressures. Moreover, a higher incidence of laryngospasm with the use of uncuffed tubes has also been reported, and there is no data of increased subglottic airway trauma when cuffed versus uncuffed tubes are used. A cuffed tube with no leak may also allow a more accurate estimate of end tidal carbon dioxide (CO ₂ ) concentrations and avoid pollution of the operating room. Last but not least, the relatively frequent need for changing the endotracheal tubes due to significant leak associated with insertion of an uncuffed tube is also virtually eliminated by using cuffed tubes. Repeat laryngoscopy is avoided since inflating the cuff may allow insertion of a smaller tube and using the cuff to occlude the airway without the need for replacing the tube with a larger tube. At the same time, care must be exercised when using a cuffed tube since smaller diameter tracheal tubes may become more easily kinked or obstructed by secretions.

The incidence of an unexpected difficult pediatric airway is low compared to adults but may still result in major morbidity and mortality. As a result, although sparse high-quality evidence is available on pediatric airway management, there is a general expert consensus that adult guidelines are not designed for use in young children. The recent international guidelines for the management of unanticipated difficult airway in pediatric practice is the result of a Delphi panel expert discussion and is focusing on airway management in children between 1 year and 8 years of age. Three scenarios are identified: (a) difficult mask ventilation, (b) difficult tracheal intubation, and (c) cannot intubate and cannot ventilate in paralyzed anesthetized children. Detailed guidance for each of these scenarios is provided ( Fig. 77.11 ). These guidelines were developed specifically for the nonspecialist anesthesiologist and can be adapted to the specificities of the anesthesia service taking care of children. Most importantly, each area for anesthetizing children should have access to a specific difficult airway trolley with appropriate equipment as well as a written plan of difficult airway algorithms along with a plan for whom to call for help, should an anesthesiologist need additional help in managing an unanticipated difficult pediatric airway.

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