Developmental physiology describes the bodily changes that take place during early development. Anesthesiologists must be familiar with these changes as they pertain to the different organ systems. Developmental pharmacology describes the changes in pharmacokinetics and pharmacodynamics during early life. In pediatric anesthesia, this is especially important because it influences the administration of intravenous and inhaled anesthetic agents in young children.
Respiratory Physiology
A term newborn will have near full functionality of the lungs within several hours after birth. Its lung contains approximately 50 million alveoli, which grow during early childhood until reaching the adult level of approximately 500 million sometime before adolescence.
Healthy term newborns have a well-developed biochemical and reflex control of ventilation. Although they may demonstrate episodes of periodic breathing that last 5 seconds or more, in the healthy infant, these episodes of central apnea are self-limited and are not associated with clinically significant bradycardia, which may occur in preterm infants. Periodic breathing after the first month of life is not normal and should warrant further investigation.
One of the ways that respiratory physiologists measure ventilatory drive is to note the increase in ventilation when a subject inhales carbon dioxide (CO 2 ). The newborn’s ventilatory response to breathing CO 2 will be less than that of older children. The newborn’s response to breathing a hypoxic mixture is more unique and includes an immediate increase in ventilation that lasts about 1 minute, followed by a decrease in ventilation that lasts about 5 minutes. This reflects carotid body immaturity, and differs from older children in whom the initial protective phase of ventilatory stimulation has a longer duration. This shortened phase of ventilatory depression is even more prominent during hypercarbia, acidosis, or hypothermia.
Newborns demonstrate maladaptive respiratory depression (including apnea) in response to certain provocations that would normally result in stimulation of respiratory function in older infants. These stimuli may include lung inflation (Hering-Breuer reflex), stimulation of the carina or superior laryngeal nerve, and upper airway obstruction. Taken together, all these observations demonstrate the relatively weaker ability of newborns to adapt to acute hypoxemia.
The most important differences in respiratory function between children and adults are anatomically based, related to the growth and maturity of the chest wall during the first 2 years of life. These differences directly influence the mechanism by which functional residual capacity (FRC) is maintained. The newborn infant’s FRC is established in the first several breaths after birth. In unanesthetized infants and adults, FRC is approximately the same, although the mechanisms by which FRC is attained are different in these two populations. However, when anesthetized, these differences impart substantial effects on FRC.
In neonates and small infants, the orientation of the ribs is more parallel than angled ( Fig. 2.1 ). This results in a relative inefficiency of movement because the volume of the rib cage is not increased by raising the ribs as in older children and adults. At about 2 years of age, when the child spends more time in the upright position, the effect of gravity causes the ribs to be angled downward, and the rib cage then becomes more adult-like, thus providing an advantage to maintaining FRC while anesthetized. During early childhood development, the structure of the ribs becomes bonier and less cartilaginous and provides an inherent stiffness to the thoracic cavity. This stiffness imparts a tendency for the chest wall to expand outward, which counteracts the tendency for the lungs to collapse inward. The opposing tendencies between lungs and chest wall generate a slightly negative intrapleural pressure at the end of exhalation, and serve to maintain FRC in older children and adults, but this mechanism does not exist in infants.
The chest wall of neonates and small infants is primarily cartilaginous because it has not yet developed its bony components. It is highly compliant and tends to collapse inward along with the lungs. As a consequence, infants must maintain their negative intrathoracic pressure (and negative intrapleural pressure) by active recruitment of accessory muscles of respiration, such as the intercostal muscles. In addition, the adductor muscles of the larynx of the neonate act as a valve; they contract during exhalation to maintain positive end-expiratory pressure and contribute to the maintenance of FRC. This phenomenon is called laryngeal braking . Newborns commonly demonstrate prominent abdominal excursions during normal breathing because of their reliance on diaphragmatic contraction for development of a sufficiently negative intrapleural pressure during inspiration. Despite the above-mentioned intrinsic mechanisms that attempt to maintain lung volumes, neonates may develop small airway collapse during normal tidal breathing.
These differences explain the marked changes in FRC in infants after the onset of general anesthesia that is normally not observed in older children and adults. After the administration of sedatives or anesthetics, older children and adults tend to maintain FRC. However, sedated or anesthetized infants will rapidly develop hypoxemia because their tonic muscular contraction that maintains FRC is lost. This loss of FRC can be remedied by application of continuous positive airway pressure (CPAP) or institution of positive-pressure breathing.
The unique anatomic insertion of the infant diaphragm affects respiratory function. At the initiation of inhalation, the newborn diaphragm is relatively flat. Its anterior insertion onto the internal surface of the rib cage confers a mechanical disadvantage during inspiration compared with the high-domed structure of the adult diaphragm. The muscular composition of the newborn’s diaphragm is also unique. In contrast to the adult diaphragm, which has a high proportion (50%–60%) of slow-twitch, high-oxidative, fatigue-resistant (type 1) fibers, the newborn diaphragm is made up of only 10% to 30% type 1 fibers. This characteristic predisposes the newborn diaphragm to fatigue, and may contribute to the inherent instability of the chest wall and apnea and respiratory failure in the face of increased ventilatory demands or work of breathing.
On a per-kilogram basis, tidal volume is the same for both neonates and adults and ranges from 7 to 9 mL/kg. Because oxygen consumption is relatively high in neonates and small infants (7–9 mL/kg versus 3 mL/kg for the adult), minute ventilation must be increased to deliver a sufficient amount of oxygen into the lungs (nearly three times that of the adult). As a consequence, small children have a relatively increased ratio of minute volume to FRC. This results in more rapid oxyhemoglobin desaturation during ventilatory depression or apnea.
The generalities are mentioned for discussion purposes only. Research studies demonstrate that respiratory function indices in children are primarily influenced by age, height, gender, stage of puberty, ethnicity, and coexisting disease. Therefore, it would be impossible to predict with any accuracy a given child’s tidal volume, FRC, or any other ventilatory function without sophisticated testing.
Hematologic Physiology
At birth, the hemoglobin concentration is approximately 19 g/dL, of which 70% is fetal hemoglobin (Hgb F). This relatively high hemoglobin concentration is needed to offset the leftward shift of the oxyhemoglobin dissociation curve, which causes oxygen to be held tightly by Hgb F. During the first year of life Hgb F is progressively replaced by adult hemoglobin (Hgb A). Production of erythropoietin is absent until hemoglobin levels drop to the physiologic nadir of about 9 to 11 g/dL, between approximately 6 to 9 weeks of age. This is referred to as physiologic anemia of infancy . Although this relative anemia may decrease oxygen delivery to the peripheral tissues, it is offset by the increased production of Hgb A and increase in red-cell 2,3-diphosphoglycerate, both of which shift the oxyhemoglobin dissociation curve to the right, which facilitates unloading of oxygen to the peripheral tissues.
Coagulation factors are relatively low at birth and normalize within the first year of life ( Table 2.1 ).
| Test | 25–31 Weeks Gestation | 30–36 Weeks Gestation | Full-Term Newborn | 1–10 Years | 11–18 Years |
|---|---|---|---|---|---|
| Prothrombin time (s) | 15.4 (I5–17) | 13 (11–16) | 15 (14–16) | 12 (11.4–13.7) | 12.6 (11.4–13.8) |
| Partial thromboplastin time (s) | 108 (80–168) | 54 (28–79) | 41 (32–47) | 37 (31–44) | 36 (30–43) |
| Bleeding time (s) | 207 ± 105 | 157 ± 68 | 107 ± 38 | 420 (180–780) | 300 (180–480) |
a Values are mean, approximate normal range in parentheses, and standard deviations for bleeding times for neonatal ages
Cardiovascular Physiology
Substantial cellular and structural changes occur in the heart in the first several months of life. Neonatal cardiac muscle cells contain all the normal structural elements of the adult heart but are qualitatively and quantitatively different. The pattern of myofilaments is described as chaotic, compared with the long parallel rows of the mature heart. More specifically, the elements of the myocyte that are responsible for contraction are less able to function properly when challenged with a resistive load. Thus, force development is impaired compared with the adult heart, and cardiac output is relatively less in response to changes in preload and afterload. This makes intuitive sense when one considers that during fetal life the left side of the heart had little responsibility against a low-pressure systemic circuit, but in the postnatal period must adapt to a higher stroke volume and increased wall tension.
The postnatal left ventricle develops into a thick organ capable of contracting against higher systemic pressures by increasing the size and number of myocytes. In addition, the shape of the myocyte changes from spheroidal to one with more tapered edges, to increase efficiency of contraction. Factors that increase systemic vascular resistance (e.g., acidosis, cold, pain) in the newborn may lead to a decrease in cardiac output. Therefore, it is possible that intraoperative cardiovascular stability can be enhanced in the newborn by preventing hypothermia and adequately blunting the stress response by titration of opioids. Indeed, a well-publicized, yet controversial, study in newborn cardiac anesthesia suggested that an opioid-based anesthetic technique is associated with improved postoperative cardiac function.
One of the most important clinical correlations of these morphologic differences in the neonate is a decrease in compliance of the left ventricle. The newborn, therefore, is more prone to development of congestive heart failure during periods of fluid overload because the left ventricle is less able to stretch in response to this increase in stroke volume. Also, because of this stiffness, distention of either ventricle will result in compression and dysfunction of the contralateral ventricle, thus further decreasing cardiac function. Newborns with respiratory disease who require high inspiratory pressures may develop left ventricular dysfunction with right ventricular overload. Perhaps more importantly, the newborn left ventricle has an impaired ability to shorten normally, and the heart is less able to increase left ventricular stroke volume during periods of hypovolemia or bradycardia. Thus, episodes of hypovolemia or bradycardia can significantly decrease cardiac output in the neonate, and will endanger end organ perfusion.
Because of these differences in neonatal cardiac function it is often taught that increases in heart rate are needed to increase cardiac output. This should be done with caution, however. Cardiac output will fail to increase substantially if heart rate is increased to levels significantly above normal. Volume expansion also remains an effective method to increase blood pressure and cardiac output during, especially periods of hypovolemia.
Sympathetic innervation of the heart and production of catecholamines, which are not fully developed at birth, increase during postnatal maturation. In contrast, the parasympathetic system appears to be fully functional at birth. Thus, neonates and small infants will demonstrate an imbalance whereby seemingly minor stimuli (e.g., suctioning of the pharynx) result in an exaggerated parasympathetic or vagal response that results in bradycardia. For this reason, pediatric anesthesiologists may administer atropine before airway manipulation in small infants. The belief that bradycardia will result from too small a dose of atropine (<0.1 mg) was ultimately proven erroneous.
These structural and physiologic differences in the cardiovascular system explain why neonates and infants under 6 months of age appear to be more sensitive to the depressant effects of volatile anesthetics. Isoflurane, sevoflurane, and desflurane appear to depress myocardial contractility equally.
The normal heart rate of the newborn ranges from 120 to 160 beats per minute (bpm). Lower rates (e.g., 85 bpm) are frequently observed during sleep, and higher rates (>200 bpm) are common during anxiety or pain. Heart rates tend to decrease with age and parallel decreases in oxygen consumption. Many children have a noticeable variation in heart rate that varies with respiration (i.e., sinus arrhythmia).
Blood pressure increases gradually throughout childhood and has a positive relationship with height. Taller children have higher blood pressure. These reference values have been retrospectively determined for anesthetized children. Blood pressure ranges in premature infants have been defined and will vary depending on the health status of the infant and mother. One of the most important current topics in pediatric anesthesia is defining the safe limits of blood pressure in young infants. As Mary Ellen McCann points out in her important paper on the topic, these limits have not been delineated. However, there is accumulating evidence that low blood pressures may not be as safe as once thought.
In most children, careful auscultation of the heart reveals a soft, vibratory, systolic flow murmur. A heart murmur is considered abnormal when it is louder than II/VI or has a diastolic component. Peripheral pulses in children of all ages should be clearly palpable. Absence of femoral pulses may indicate an aortic arch abnormality. Capillary refill in the distal extremities should be brisk (less than 2 seconds), but may be slightly delayed in the first few hours of life. Distal limb cyanosis (acrocyanosis) is normal in the first few hours of life.
As described in Chapter 1 , the fetal heart is characterized by right-sided dominance that gradually abates in the first few months of life as pulmonary pressures decrease toward normal adult values. The normal newborn ECG ( Fig. 2.2 ) demonstrates a preponderance of right-sided forces with a mean QRS axis of +110 degrees (range +30 to +190 degrees), and decreasing R wave size from leads V1 to V6. T waves are normally inverted in lead AVR and the right-sided precordial leads. This gradually shifts to left-sided dominance during early childhood as the left ventricle hypertrophies to its normal size and the ECG becomes more like that of an adult.
The newborn cardiac output (about 350 mL/kg/min) falls over the first 2 months of life to about 150 mL/kg/min and then more gradually to the normal adult cardiac output of about 75 mL/kg/min.
Renal Physiology
By the 36th week of gestation, the formation of nephrons in the kidney is complete. However, the nephrons are small, and the glomerular filtration rate (GFR) is only 25% of adult values at birth. GFR reaches adult levels gradually during the first year of life. Tubular function is also immature; there is a decreased ability to concentrate and dilute the urine in the immediate newborn period. The maximal concentrating ability of the full-term newborn is 400 mOsm/L; the adult value of 1200 mOsm/L is attained by 1 year of age. Therefore, intraoperative evaporative fluid losses may result in development of hypernatremia in the neonate.
In newborn infants, daily fluid intake is gradually increased from 80 mL/kg on the first day of life to 150 mL/kg by the third or fourth day of life. It is adjusted based on additional factors, such as extreme prematurity or use of a radiant warmer, in which evaporative losses from the skin are increased. Neonates who are unable to ingest enteral feeds should receive supplementation of electrolytes (sodium, potassium, and calcium) on the second day of life ( Table 2.2 ).
| Electrolyte | Average Daily Requirement a |
|---|---|
| Sodium | 2–3 mEq/kg |
| Potassium | 1–2 mEq/kg |
| Calcium b | 150–200 mg/kg |
a Adjusted to normal values on a daily basis.
Central Nervous System Physiology
The skull and CNS undergo substantial postnatal maturation. At birth, the brain is encased within several pieces of the skull that are separated by strong, fibrous, elastic tissues called cranial sutures . The anterior fontanel, located at the junction of the frontal and parietal bones, is formed by the intersection of the metopic, coronal, and sagittal sutures. Fusion of these sutures and closure of the anterior fontanel normally closes by 20 months of age. The posterior fontanel, located at the junction of the parietal and occipital bones, is formed by the intersection of the lambdoid and sagittal sutures. The posterior fontanel usually closes by 3 months of age.
The metabolic demand of the brain increases throughout the first year of life and then decreases gradually throughout childhood. The average cerebral metabolic rate of oxygen consumption (CMRO 2 ) of the child’s brain (5.2 mL/min of oxygen per 100 g of brain tissue) is greater than the adult’s brain (3.5 mL/min/100 g) and greater than that of anesthetized newborns and infants (2.3 mL/min/100 g).
Cerebral blood flow (CBF) is closely coupled to the CMRO 2 . Whereas in adults the CBF is 50 to 60 mL/min per 100 g of brain tissue, the CBF of term newborns is approximately 40 mL/min/100 g and may be <5 mL/min/100 g in premature infants; in older children the CBF may reach 100 mL/min/100 g.
Autoregulation of CBF is based on systemic blood pressure. While it is thought that autoregulation does occur in newborns its limits are unknown. Extrapolation from animal studies indicates an approximate range of 20 to 80 mm Hg, in contrast to the adult whose autoregulatory limits lie between 60 and 150 mm Hg. Extremely premature infants may have largely pressure-passive CBF that predisposes to brain injury in the face of hypotension or hypertension.
Developmental Pharmacology
The broad subject of pharmacology encompasses the study of pharmacokinetics (the body’s influence on the drug) and pharmacodynamics (the drug’s influence on the body). Each of these two components is influenced by age and developmental stage. Major differences in pharmacology between adults and children exist because of differences in body composition that influence pharmacokinetics and pharmacodynamics. This section will review the ways in which these factors influence the pharmacology of intravenous and inhaled anesthetics in children.
Pharmacokinetics of Intravenous Anesthetics
The term pharmacokinetics describes the physiologic processes that alter a drug’s disposition after entering the body. Pharmacokinetic processes determine the amount of drug that arrives at the effect site (the central nervous system for general anesthetic agents) at a given point in time (i.e., the “effect site” concentration) and the speed at which it arrives. The two general pharmacokinetic processes of interest are those that determine the rate and amount of drug that initially reaches the effect site, and those that determine the rate and amount of drug that leave the effect site. These two processes, which are of prime importance to anesthesiologists, are determined by a drug’s unique combination of pharmacokinetic parameters: volume of distribution, distribution clearance, protein binding, and elimination clearance (metabolism and excretion). Each of these parameters will be discussed, with an emphasis on the changes that occur during development.
Volume of Distribution
The total (or steady-state) volume of distribution is the calculated amount of plasma into which the drug appears to have distributed at a specified interval after administration. It is not a discrete body compartment but rather is calculated by dividing the dose administered by the plasma concentration. Put another way, the dose of an intravenously administered drug is determined by multiplying the volume of distribution and the desired effect site concentration:
Dose(mgkg)=VolumeofDistribution(Lkg)×DesiredEffectSiteConcentration(mgL)
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