2. Volume of drug distribution
b) There is a greater adipose content and a higher ratio of water to lipid. Fat content is approximately 12% at birth, doubling by 6 months of age and reaching 30% at 12 months of age.
c) These factors lower plasma drug concentrations when water-soluble drugs are administered according to weight.
3. Protein binding
a) Total plasma protein is decreased in infants, reaching equivalent adult concentrations by childhood.
4. Metabolism
a) Phase II reactions, which are immature at birth, consist of conjugation or synthesis. Conjugation couples the drug with an endogenous substrate (glucuronidation, methylation, acetylation, and sulfation) to facilitate excretion.
b) Newborns lack the capacity to efficiently conjugate bilirubin (decreased glucuronyl transferase activity), and metabolize acetaminophen, chloramphenicol, and sulfonamides.
5. Rectal and oral drug administration
b) Midazolam may be administered orally for premedication, and the rectal route may be selected for the administration of acetaminophen, opioids, barbiturates, and benzodiazepines.
c) Both routes rely on passive diffusion for drug absorption. The resulting plasma drug concentration depends on the molecular weight, degree of drug ionization, and lipid solubility.
d) Orally administered drugs are generally reserved for older children because gastric pH is elevated in neonates at birth (pH 6 to 8), and although decreased to a pH level of 1 to 3 within 24 hours, adult gastric pH values are not consistent until age 2 years.
e) Gastric absorption is reduced after oral administration of acidic drugs in infants. Gastric emptying time reaches adult values by 6 months of age. Although gastric emptying time does not affect drug absorption, it may alter peak drug concentration.
f) Acetaminophen, a metabolite of phenacetin, is a popular and safe analgesic and antipyretic commonly administered to children during the perioperative period.
g) The analgesic and antipyretic effects of acetaminophen are equivalent to those of aspirin when the drugs are administered in equipotent dosages.
h) Suppositories should not be divided in an attempt to provide the exact calculated dose because the suspended acetaminophen is distributed unevenly within the suppository. Recommended acetaminophen doses have been based on the age of the child, weight, body surface area calculations, and fractions of adult dosages.
i) Currently recommended oral and rectal doses of acetaminophen range from 10 to 15 mg/kg every 4 hours. Because of the variable absorption of acetaminophen suppositories, some practitioners have advocated the administration of larger initial rectal dosages. It should be emphasized that subsequent rectal doses should be decreased (20 mg/kg), and the dosing interval should be extended to every 6 to 8 hours.
j) After acetaminophen administered during the perioperative period, the parents should be informed as to the time of administration and be advised of appropriate acetaminophen dosages (60-65 mg/kg/day).
k) The daily acetaminophen dosage administered either rectally or orally should be limited to 100 mg/kg/day for children and 75 mg/kg/day for infants.
l) Sedation with nasally administered midazolam (0.2 mg/kg) may be achieved in as little as 10 to 20 minutes and is explained in part through drug absorption via the olfactory mucosa. Nasal administration is unpleasant because midazolam produces a burning of the nasal mucosa.
m) Oral fentanyl, although effective in producing significant sedation, has been plagued by significant side effects, including facial pruritus (up to 80%) and postoperative nausea and vomiting, seven times greater than when a child receives an oral meperidine, midazolam, or atropine premedicant.
Inhalation agents
1. Introduction
a) Although tidal volume is similar between children and adults (5-7 mL/kg), children have greater minute ventilation and a higher ratio of tidal volume to functional residual capacity (5:1) compared with adults (1.5:1).
b) The greater minute ventilation and higher cardiac output in infants and children are responsible for rapid inhalation anesthetic uptake and rapidly increasing alveolar anesthetic concentration. In addition, their decreased distribution of adipose tissue and decreased muscle mass affect the rate of equilibration among the alveoli, blood, and brain.
c) The percentage of blood flow to the vessel-rich organs is greater than in adults, and the blood-gas partition coefficients are lower in infants and children.
d) Anesthetic requirements are known to change with age. Neonates have a somewhat lower minimum alveolar concentration (MAC) than infants, which peaks at around 30 days of age.
e) MAC is higher in infants from age 1 to 6 months of age; thereafter, MAC values are known to decrease with increasing age.
f) Myocardial depression may be exaggerated when inhalation anesthetics are administered to pediatric patients. A more rapid rise FA/FI ratio, the greater percentage of blood flow to the vessel-rich organs, and higher administered anesthetic concentrations are central to the cause of myocardial depression.
2. Isoflurane
b) Inhalation induction with isoflurane produces more adverse respiratory events (breath-holding, coughing, and laryngospasm with copious secretions) than sevoflurane.
c) Administration of isoflurane to adults produces dose-dependent decreases in peripheral vascular resistance, but increases in heart rate maintain blood pressure. This touted advantage (e.g., increase in heart rate to maintain blood pressure) does not occur in infants.
3. Desflurane
b) Desflurane has the lowest blood-gas partition coefficient of all the inhalation anesthetics (0.42), which facilitates a rapid induction, rapid alterations in anesthetic depth, and emergence.
c) Similar to isoflurane, desflurane is pungent and is associated with more adverse respiratory events during inhalation induction, including breath-holding, laryngospasm, coughing, and increased secretions with accompanying hypoxia.
d) After inhalation induction with sevoflurane, desflurane is appropriate for the maintenance of general anesthesia with face mask, ETT, or laryngeal mask airway (LMA).
4. Sevoflurane
a) The MAC of sevoflurane in oxygen is 3% for infants up to 6 months of age, decreasing to 2.5% to 2.8% up to 1 year of age. The MAC of sevoflurane in oxygen is 2% to 3%.
b) Sevoflurane produces a more rapid induction and emergence than halothane because of its low blood-gas partition coefficient.
c) Sevoflurane is readily accepted for mask induction, and its safe cardiovascular profile (compared with halothane) is responsible for the increasing popularity of sevoflurane in pediatric anesthesia.