Pediatric Anesthesia: Pharmacological Differences

PHARMACOLOGICAL DIFFERENCES

Pediatric drug dosing is typically adjusted on a per-kilogram basis for convenience (Table 42–3). In early childhood a patient’s weight can be approxi-mated based on age:

50th percentile weight (kg) = (Age × 2) + 9

Weight-adjustment of drug dosing is incom-pletely effective because it does not take into account the disproportionately larger pediatric intravas-cular and extracellular fluid compartments, the immaturity of hepatic biotransformation pathways, increased organ blood flow, decreased protein for drug binding, or higher metabolic rate.

Neonates and infants have a proportionately greater total water content (70–75%) than adults (50–60%). Total body water content decreases while fat and muscle content increase with age. As a direct result, the volume of distribution for most intra-venous drugs is disproportionately greater in neo-nates, infants, and young children, and the optimal dose (per kilogram) is usually greater than in older children and adults. A disproportionately smaller muscle mass in neonates prolongs the clinical dura-tion of action (by delaying redistribution to muscle) of drugs such as thiopental and fentanyl. Neonates also have a relatively decreased glomerular filtration rate, hepatic blood flow, and renal tubular function, and immature hepatic enzyme systems. Increased intraabdominal pressure and abdominal surgery further reduce hepatic blood flow. All these factors may impair renal drug handling, hepatic metabo-lism, or biliary excretion of drugs in neonates and young infants. Neonates also have decreased protein binding for some drugs, most notably thiopental, bupivacaine, and many antibiotics. In the case of thiopental, increased free drug enhances potency and reduces the induction dose in neonates com-pared with older children. An increase in free bupi-vacaine might increase the risk of systemic toxicity.

Inhalational Anesthetics

Neonates, infants, and young children have relatively greater alveolar ventilation andreduced FRC compared with older children and adults. This greater minute ventilation-to-FRC ratio with relatively greater blood flow to vessel-rich organs contributes to a rapid increase in alveolar anesthetic concentration and speeds inhalation induction. Furthermore, the blood/gas coefficients of volatile anesthetics are reduced in neonates com-pared with adults, resulting in even faster induction times and potentially increasing the risk of acciden-tal overdosage.

The minimum alveolar concentration (MAC) for halogenated agents is greater in infantsthan in neonates and adults (Table 42–4). In con-trast to other agents, no increase in sevoflurane MAC can be demonstrated in neonates and infants. Nitrous oxide does not appear to reduce the MAC of desflurane or sevoflurane in children to the same extent as it does for other agents.

The blood pressure of neonates and infants appears to be especially sensitive to volatile anesthetics. This clinical observation has been attributed to less-well-developed compensatory mechanisms (eg, vasoconstriction, tachycardia) and greater sensitivity of the immature myocar-dium to myocardial depressants. Halothane (now much less commonly used) sensitizes the heart to catecholamines. The maximum recommended dose of epinephrine in local anesthetic solutions during halothane anesthesia is 10 mcg/kg. Cardiovascular depression, bradycardia, and arrhythmias are less frequent with sevoflurane than with halothane. Halothane and sevoflurane are less likely than other volatile agents to irritate the airway or cause breath holding or laryngospasm during induction . In general, volatile anesthetics appear to depress ventilation more in infants than in older children. Sevoflurane appears to produce the least respiratory depression. The risk for hal-othane-induced hepatic dysfunction appears to be much reduced in prepubertal children compared with adults. There are no reported instances of renal toxicity attributed to inorganic fluoride pro-duction during sevoflurane anesthesia in children.Overall, sevoflurane appears to have a greater ther-apeutic index than halothane and has become the preferred agent for inhaled induction in pediatric anesthesia.

Emergence is fastest following desflurane or sevoflurane, but both agents are associated with a greater incidence of agitation or delirium upon emergence, particularly in young children. Because of the latter, some clinicians switch to isoflurane for maintenance anesthesia following a sevoflurane induction .

Nonvolatile Anesthetics

After weight-adjustment of dosing, infants and young children require larger doses of propofol because of a larger volume of distribution compared with adults. Children also have a shorter elimina-tion half-life and higher plasma clearance for propofol. Recovery from a single bolus is not appre-ciably different from that in adults; however, recov-ery following a continuous infusion may be more rapid. For the same reasons, children may require increased weight-adjusted rates of infusion for maintenance of anesthesia (up to 250 mcg/kg/min). Propofol is not recommended for prolonged seda-tion of critically ill pediatric patients in the intensive care unit (ICU) due to an association with greater mortality than other agents. Although the “propofol infusion syndrome” has been reported more often in critically ill children, it has also been reported in adults undergoing long-term propofol infusion (>48 h) for sedation, particularly at increased doses (>5 mg/kg/h). Its essential features include rhabdo-myolysis, metabolic acidosis, hemodynamic insta-bility, hepatomegaly, and multiorgan failure.

Children require relatively larger doses of thio-pental compared with adults. The elimination half-life is shorter and the plasma clearance is greater than in adults. In contrast, neonates, appear to be more sensitive to barbiturates. Neonates have less pro-tein binding, a longer half-life, and impaired clear-ance. The thiopental induction dose for neonates is 3–4 mg/kg compared with 5–6 mg/kg for infants.

Opioids appear to be more potent in neo-nates than in older children and adults. Unproven (but popular) explanations include “easier entry” across the blood–brain barrier, decreased metabolic

capability, or increased sensitivity of the respiratory centers. Morphine sulfate, particularly in repeated doses, should be used with caution in neonates because hepatic conjugation is reduced and renal clearance of morphine metabolites is decreased. The cytochrome P-450 pathways mature at the end of the neonatal period. Older pediatric patients have relatively greater rates of biotransformation and elimination as a result of high hepatic blood flow. Sufentanil, alfentanil, and, possibly, fentanyl clear-ances may be greater in children than in adults. Remifentanil clearance is increased in neonates and infants but elimination half-life is unaltered com-pared with adults. Neonates and infants may be more resistant to the hypnotic effects of ketamine, requiring slightly higher doses than adults (but the “differences” are within the range of error in studies); pharmacokinetic values do not appear to be signifi-cantly different from those of adults. Etomidate has not been well-studied in pediatric patients younger than 10 years of age; its profile in older children is similar to that in adults. Midazolam has the fastest clearance of all the benzodiazepines; however, mid-azolam clearance is significantly reduced in neonates compared with older children. The combination of midazolam and fentanyl can cause hypotension in patients of all ages.

Muscle Relaxants

For a wide variety of reasons (including pharmacol-ogy, convenience, case mix, and convenience), muscle relaxants are less commonly used during induction of anesthesia in pediatric than in adult patients. Many children will have a laryngeal mask airway (LMA) or endotracheal tube placed after receiving a sevoflurane inhalation induction, placement of an intravenous catheter, and administration of various combinations of propofol, opioids, or lidocaine.

All muscle relaxants generally have a faster onset (up to 50% less delay) in pediatric patients because of shorter circulation times than adults. In both children and adults, intravenous succinyl-choline (1–1.5 mg/kg) has the fastest onset . Infants require significantly larger doses of succinylcholine (2–3 mg/kg) than older children and adults because of the relatively larger volume of distribution. This discrepancy disappears

if dosage is based on body surface area. Table 42–5 lists commonly used muscle relaxants and their ED₉₅ (the dose that produces 95% depression of evoked twitches). With the notable exclusion of succinyl-choline and possibly cisatracurium, infants require significantly smaller muscle relaxant doses than older children. Moreover, based on weight, older children require larger doses than adults for some neuromuscular blocking agents (eg, atracurium). As with adults, a more rapid intubation can be achieved with a muscle relaxant dose that is twice the ED ₉₅ dose at the expense of prolonging the duration of action.

The response of neonates to nondepolarizing muscle relaxants is variable. Popular (and unproven) explanations for this include “immaturity of the neuromuscular junction” (in premature neonates), tending to increase sensitivity (unproven), counter-balanced by a disproportionately larger extracellular compartment, reducing drug concentrations (proven). The relative immaturity of neonatal hepatic function prolongs the duration of action for drugs that depend primarily on hepatic metabolism (eg, pancuronium, vecuronium, and rocuronium). Atracurium and cisatracurium do  not depend on hepatic biotransformation and reliably behave as intermediate-acting muscle relaxants.

Children are more susceptible than adults to cardiac arrhythmias, hyperkalemia, rhabdomyolysis, myoglobinemia, masseter spasm, and malignant hyperthermia  associated with succinylcholine. When a child experiences cardiac arrest following administration of succinylcho-line, immediate treatment for hyperkalemia should be instituted. Prolonged, heroic (eg, potentially including cardiopulmonary bypass) resuscitative efforts may be required. For this reason, succinylcho-line is avoided for routine, elective paralysis for  intubation in children and adolescents. Unlike adults, children may have profound bradycardia and sinus node arrest following the first dose of succinylcholine without atropine pretreatment. Atropine (0.1 mg minimum) must therefore always be administered prior to succinylcholine in children. Generally accepted indications for intravenous suc-cinylcholine in children include rapid sequence induction with a “full” stomach and laryngospasm that does not respond to positive-pressure ventila-tion. When rapid muscle relaxation is required prior to intravenous access (eg, with inhaled inductions in patients with full stomachs), intramuscular succinyl-choline (4–6 mg/kg) can be used. Intramuscular atropine (0.02 mg/kg) should be administered with intramuscular succinylcholine to reduce the likeli-hood of bradycardia. Some clinicians advocate intra-lingual administration (2 mg/kg in the midline to avoid hematoma formation) as an alternate emer-gency route for intramuscular succinylcholine.

Many clinicians consider rocuronium (0.6 mg/ kg intravenously) to be the drug of choice (when a relaxant will be used) during routine intubation in pediatric patients with intravenous access because it has the fastest onset of nondepolarizing neuro-muscular blocking agents . Larger doses of rocuronium (0.9–1.2 mg/kg) may be used for rapid sequence induction but a prolonged dura-tion (up to 90 min) will likely follow. Rocuronium is the only nondepolarizing neuromuscular blocker that has been adequately studied for intramuscular administration (1.0–1.5 mg/kg), but this approach requires 3–4 min for onset.

Atracurium or cisatracurium may be preferred in young infants, particularly for short procedures, because these drugs consistently display short to intermediate duration.

As with adults, the effect of incremental doses of muscle relaxants (usually 25–30% of the initial dose) should be monitored with a peripheral nerve stimulator. Sensitivity can vary significantly between patients. Nondepolarizing blockade can be reversed with neostigmine (0.03–0.07 mg/kg) or edropho-nium (0.5–1 mg/kg) along with an anticholinergic agent (glycopyrrolate, 0.01 mg/kg, or atropine, 0.01– 0.02 mg/kg). Sugammadex, a specific antagonist for rocuronium and vecuronium, has yet to be released in the United States.