Pediatric Pharmacology

Educational Objectives

The goal of this lecture is to improve the anesthetic management of neonates. After hearing and assimilating this lecture, the clinician will be better able to:

1. Explain the unique pharmacology of inhalation agents in infants.

2. Evaluate the role of propofol, ketamine, and neuromuscular agents in the anesthetic care of neonates and infants.

Summary

Physiology of children: respiratory — respiratory rate and minute ventilation higher in children because of increased oxygen consumption; relative to adults, children tend to desaturate more quickly because they have fewer alveoli, “floppy” airways with tendency to collapse, and smaller diameter of airways with higher resistance; cardiovascular — in children, stroke volume depends to great extent on heart rate; in infants, bradycardia occurs in times of stress because sympathetic nervous system immature; liver — in neonates, gluconeogenesis inefficient, so dextrose often included in fluid replenishment formulas; because fewer proteins available for binding of drugs, concentration of free fraction of drugs may be increased and effects possibly prolonged and potentiated; central nervous system — not fully mature (including blood-brain barrier) until age 12 yr; morphine often avoided in neonates and infants because peak concentration in brain 3 times higher than that in adults; children more sensitive to all sedatives, especially those with altered respiratory drive (eg, obstructive sleep apnea [OSA]); metabolism of glucose and oxygen twice that of adults because of rapid growth and synaptogenesis

Pharmacology of inhalation agents: minimum alveolar concentration (MAC) highest in infants 1 to 6 mo of age; wash-in effect — while functional residual capacity (FRC) remains static, alveolar ventilation changes with age; because neonatal ratio of alveolar ventilation to FRC 5:1 (vs 1.5:1 in adults), alveolar concentration in neonates approximates inspired concentration, thereby allowing faster inhalation induction; halothane — common side effects in children include breath holding, laryngospasm, and dysrhythmias; sevoflurane — toxicity less likely than with halothane; causes less hemodynamic variability; risk for emergence delirium increased; delirium treated with, eg, opioids, propofol, and (in severe cases) dexmedetomidine; delirium may be associated with pain (incidence of delirium 3 times less when ketorolac or caudal anesthesia administered)

Propofol: painful on injection; dose higher in children (350 μg/kg/min) than in adults because distribution and metabolic rate higher; propofol infusion syndrome — caused by accumulation of toxic metabolites; seen when given ≥2 days at doses of ≥70 μg/kg/min; manifested as severe metabolic acidosis, rhabdomyolysis, bradycardia, and cardiac arrest; mortality rate high; mortality reduced when dialysis initiated early and other substrates (eg, carbohydrates) administered

Benzodiazepines: midazolam (Versed) often given as premedication; may be given orally (bioavailability 15%-20%) or intranasally (bioavailability 50%); some patients exhibit paradoxical excitable response

Ketamine: has analgesic and hypnotic properties; at high doses (>2 mg/kg), can cause airway obstruction and hypotension, especially in the presence of adrenal insufficiency; exerts effects by inducing catecholamine secretion; causes increased secretions, so concomitant administration of antisecretory agent (eg, glycopyrrolate) should be considered

Opioids: immature blood-brain barrier in children increases risk for respiratory depression; fentanyl can quickly cause rigidity of chest wall and bradycardia secondary to immature sympathetic nervous system; remifentanil only medication that has increased clearance in neonates, compared with adults

Other medications: acetominophen may be given intravenously, usually over 10 to 15 min; ketorolac — previously not given to neonates and infants because of concern about renal injury; however, safe to give in healthy hydrated patients with adequate voiding; codeine — has fallen out of favor; neither O-demethylation, nor conversion to morphine, nor clinical effect seen in poor metabolizers, who lack cytochrome P450 2D6 enzyme; polymorphisms in enzyme also produce ultra-extensive metabolism, which can lead to respiratory depression (particularly dangerous in patients with OSA or disruptive sleep patterns, who have upregulated opioid receptors secondary to chronic nocturnal hypoxia); dexmedetomidine — increasing in popularity; has protective effects against apoptosis and neurobehavioral disorders

Neuromuscular agents: nondepolarizing — when evaluating return of strength and function in infants <6 mo of age, hip flexion more useful than head lift, but function of orbicularis oculi best correlates with recovery of diaphragm and vocal cords; for rapid sequence intubation, rocuronium (1.2 mg/kg) may be used in place of succinylcholine if no difficulty in intubation anticipated

Succinylcholine: should be reserved for emergency intubation or when immediate securing of airway necessary (eg, laryngospasm, difficult airway, full stomach); may cause increase in intraocular or intracranial pressure, potassium release, induction of masseter spasm, and triggering of malignant hyperthermia (MH); when concerned about these side effects, consider whether risks outweigh those associated with substituting rocuronium (ie, possibility of losing airway); risk for MH — only 3 diagnoses have 100% susceptibility (King-Denborough syndrome, central core myopathy, and multiminicore disease with RYR1 mutation); Duchenne and Becker muscular dystrophies also associated with elevated risk

Local anesthetics: free fraction higher in children because less protein available for binding; rate of systemic absorption higher; uptake greater with, eg, intercostal injection, compared with peripheral sites; anesthetic blocks usually effective because of incomplete myelination in children

Inhalation induction: negative feedback — if patient allowed to breathe spontaneously, respiratory center automatically tempers alveolar and minute ventilation; positive feedback — if overpressure used (eg, vaporizer dialed to 8%, which consistently delivers dose of agent with each breathe), alveolar fraction reached quickly; this can lead to hemodynamic compromise

Laryngospasm: risk factors in young children include recent illness or fever, findings on lung examination, otolaryngologic procedures, history of OSA, and exposure to tobacco or environmental pollutants; early detection and rapid intervention crucial; apply sustained jaw thrust and positive-pressure ventilation; can be treated with high-dose propofol or succinylcholine; in younger children, positive pressure tends to insufflate stomach and result in tight spasm

Apoptosis: defined as scheduled cell death triggered by intrinsic or extrinsic cellular events; risk highest during period of rapid brain growth (ie, from third trimester of pregnancy to age 3 yr); imbalance in apoptosis can lead to atrophy or cancer; most medications used in anesthesia implicated in causing neurodegeneration; however, opioids, nondepolarizing muscle relaxants, dexmedetomidine, and xenon have little or no effect

Readings

Karuparthy V et al: Chewing gum: a potential cause of airway obstruction. J Anesth 2009;23(1):168-9; Kearns GL et al: Developmental pharmacology — drug disposition, action, and therapy in infants and children. N Engl J Med 2003 Sep;349:1157-1167; LeDez KM, Lerman J: The minimum alveolar concentration (MAC) of isoflurane in preterm neonates. Anesthesiology 1987 Sep;67(3):301-7; Mayer J et al: Desflurane anesthesia after sevoflurane inhaled induction reduces severity of emergence agitation in children undergoing minor ear-nose-throat surgery compared with sevoflurane induction and maintenance. Anesth Anal 2006 Feb;102(2):400-4; Tetelbaum M et al: Back to basics: understanding drugs in children: pharmacokinetic maturation. Pediatr Rev 2005 Sep;26(9):321-8; Wolf AR, Potter F: Propofol infusion in children: when does an anesthetic tool become an intensive care liability? Paediatr Anaesth 2004 Jun;14(6):435-8.

Disclosures

For this lecture, members of the faculty and planning committee reported nothing to disclose. In her lecture, Dr. Rodriguez presents information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Rodriguez spoke at the 2015 Comprehensive Anesthesiology Review, presented March 23-28, 2015, in Cleveland, OH, by the Cleveland Clinic Anesthesiology Institute. For information on upcoming CME meetings from the Cleveland Clinic Anesthesiology Institute, please visit clevelandclinicmeded.com, or visit our website, Audio-Digest.org, and click on “Upcoming Meetings.” The Audio Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this lecture.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

AN580301

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.