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Craig Sims, Dana Weber and Chris Johnson (eds.) A Guide to Pediatric Anesthesiahttps://doi.org/10.1007/978-3-030-19246-4_2

2. Pharmacology of Anesthetic Agents in Children

Craig Sims¹ and John Thompson¹

(1)

Department of Anaesthesia and Pain Management, Perth Children’s Hospital, Nedlands, WA, Australia

Craig Sims (Corresponding author)

Email: craig.sims@health.wa.gov.au

John Thompson

Email: John.Thompson@health.wa.gov.au

Keywords

PharmacokineticsChildrenPharmacodynamic changesChildrenPharmacologyNeonatesDrug clearanceChildrenPediatric drug dosesPediatric anesthetic drugs

As children grow, absorption, distribution and clearance change because anatomical and physiological processes mature. Many drugs are poorly studied in children. Data is often extrapolated from adults as there are financial and ethical problems with clinical pediatric studies. These problems often mean newer drugs are not approved for use in children. Fortunately, the pharmacokinetics of many drugs commonly used as part of anesthesia have been studied, though less so their pharmacodynamics. This chapter focuses on the pharmacological differences between children and adults.

2.1 Factors Affecting Dosage in Children

Size and age are the most important determinants of drug dose in children. Size is most commonly dealt with by weight-based dosing but age affects organ function and body composition, which require more complex adjustments to dosage.

2.1.1 Size

Children can be less than a kilogram or more than 100 kg. There are three alternatives to allow for this. The first is weight-based dosing (mg/kg, up to a maximum equal to the adult dose). This is simple, accurate enough for most drugs and commonly used in anesthetic practice. Size and metabolism are not linearly related however, and the other two methods of dosing try to allow for this. Body surface area is one method. This requires complex calculations and is used for drugs with low therapeutic margins such as chemotherapy agents. The other alternative is to scale the dose using a non-linear, allometric power technique. Allometric scaling describes the nonlinear relationship between size and organ function. It also requires complex calculations and is not used clinically.

2.1.2 Age

Pharmacokinetic and pharmacodynamic differences between children and adults are maximal in the first 2 years of life, making neonates and young infants at high risk of side effects.

2.1.3 Pharmacokinetic Changes

The pharmacokinetics of drugs change with age due to several factors (Table 2.1). The two most important are differences in body composition and immature metabolic pathways.

Table 2.1

Pharmacokinetic differences in neonates and infants that affect their response to drugs

Absorption

Slow gastric emptying until 6–8 months and reduced gastric acidity in infancy

Thin neonatal skin, increasing absorption of EMLA and chlorhexidine antiseptic

Volume of distribution increased

Increased total body water (mostly as increased ECF)

Decreased fat and muscle as a proportion of body weight in neonate; increased and more sustained peak concentration of drugs that redistribute into fat and muscle

Decreased albumin (and affinity), decreased alpha-1 acid glycoprotein

Clearance

Decreased metabolism in neonate, especially if preterm. Varies with different P450 isoenzymes. Most conjugation enzymes also decreased

Renal function immature during first 6 months, adult level by 1–2 years

ECF extracellular fluid

Changes in body composition affect the physiological spaces into which drugs distribute. The high proportion of total body water (TBW) and extracellular fluid (ECF) in neonates (75% and 50% of body weight respectively) are the major factors, along with changes to fat, muscle, plasma protein levels and regional blood flow differences.

Keypoint

Neonates are ‘wet’ and ‘skinny’ at birth, increasing the apparent volume of distribution for many drugs.

Metabolic pathways are immature at term. The activity of most enzymes responsible for drug metabolism is low at birth and increases after birth, but may take 2 years to reach adult levels (Fig. 2.1). Drug metabolism begins developing even before birth, making the post menstrual age (PMA) more important than the age since birth for determining metabolism in former preterm children. Esterases are an exception to this pattern of development, and are fully developed at birth. As metabolism matures, clearance also increases and is highest at 1–2 years of age (Fig. 2.2). Clearance peaks at this age because of a mathematical artefact caused by expressing clearance in terms of weight. Clearance and weight are not linearly related (doubling weight does not double clearance), and there comes an age when clearance has increased more than weight. Renal excretion also develops with age. At term, the glomerular filtration rate (GFR) is about one quarter that of an adult, and reaches adult levels by 1–2 years.

../images/467929_2_En_2_Chapter/467929_2_En_2_Fig1_HTML.png — Fig. 2.1

Maturation of clearance, expressed as a percentage of adult capacity. Glucuronide conjugation, responsible for paracetamol and morphine metabolism, matures slower than the cytochrome P450 isoenzymes responsible for l-bupivacaine metabolism. Cytochrome P450 isoenzymes also contribute to the metabolism of propofol during infancy, whereas propofol undergoes glucuronide conjugation in older children. Blood and tissue esterases which metabolise remifentanil and atracurium are fully active in term, and probably preterm, infants. Adapted from Anderson, Eur J Anaesthesiol 2012;29: 261–70

../images/467929_2_En_2_Chapter/467929_2_En_2_Fig2_HTML.png — Fig. 2.2

Schematic representation of weight-based clearance of many drugs during childhood. Clearance is generally lower in neonates compared with adults due to reduced metabolism, then increases in toddlers and decreases gradually during childhood to the adult level. Although the shape of this curve is helpful in the clinical setting, it is an artefact caused by the weight-based calculation of clearance

These pharmacokinetic changes combine to affect drug doses in different ways as age increases. For the first several months of life, and especially the first 3 months, reduced metabolism is the most important factor determining dose. Doses are therefore generally lower in neonates and infants. With age, metabolism matures, clearance is relatively high, but body water volumes are relatively large too. Doses expressed in mg/kg are then even higher than in adults (Fig. 2.3).

../images/467929_2_En_2_Chapter/467929_2_En_2_Fig3_HTML.png — Fig. 2.3

The dose in mg/kg of many drugs is larger in infants and young children

Keypoint

The speed of maturation of metabolism varies between children and increases inter-individual variability of drug effects in children.

Note

The doses of three anesthetic drugs do not change with age because they are metabolized by esterases which are fully active at birth: suxamethonium, remifentanil and atracurium.

2.1.4 Pharmacodynamic Changes

The neuromuscular junction is not fully developed in neonates, affecting muscle relaxant action. The CNS is not fully developed, affecting the MAC of volatile agents. Although end-organ maturation has an effect on the action of other drugs, it is the pharmacokinetic changes that are most important beyond infancy.

Keypoint

In general, drugs have longer duration of effect in neonates. Children aged 1–2 years need higher doses in mg/kg, and these doses are shorter in effect. The dose and effects of drugs in children beyond 2 years age gradually change to adult levels during childhood.

2.1.5 Pharmacogenomics

Genetic influences on drug metabolism is another factor affecting drug dosage. Genetic polymorphisms affect how a drug is used in an individual child, or what drug-drug interactions might occur. Phenotyping will become more available for children requiring treatment with drugs dependent on polymorphic enzymes for metabolism. The recent understanding of genetic influences on codeine metabolism has led to its removal from pediatric practice. Another example is the metabolism of tramadol.

2.2 Licensure of Drugs in Children

Many drugs commonly used in the care of children are not recommended for use in children by the drug’s manufacturer (Table 2.2). This off-label use has occurred due to the pharmaceutical companies balancing the costs of research and licensure against potential market increase in a small market segment. Strict adherence to the licensure would severely restrict access to safe and useful agents for children. The defensibility of using drugs off-label relies on following contemporary practice and using drugs that are supported by evidence. Related to licensure, many useful drugs do not have a commercially made oral liquid preparation. Work-arounds include preparation by a compounding pharmacy or using the IV preparation orally, both with uncertain bioavailability. Various strategies are used to improve taste and tolerability of oral preparations.

Table 2.2

Commonly used drugs and minimum age recommended by manufacturer

Drug	License age
Propofol	Over 3 years
Fentanyl	Over 2 years
Remifentanil	Over 1 year
Oxycodone	Adults
Ropivacaine	Term neonate
Atracurium	Over 1 month
Ondansetron	Over 2 years
Dolasetron, Tropisetron	Adults
Sugammadex	Over 2 years

2.3 Drug Errors

Drug errors are common in pediatric anesthesia. The dose has to be calculated and taken from an adult-sized ampoule. Pediatric doses may not be a whole number and misplacing decimal places and trailing zeroes are risks. Medication errors are twice as common in children compared with adults, most commonly at the prescribing stage. The commonest error is a dosing error, and the commonest (and classic pediatric error) is a ten times overdose. Drug infusions are a high risk for errors because of the complexities of variable weight and concentration. Oral drugs have the added risk of different strengths (such as paracetamol elixir 120 mg or 250 mg per 5 mL). Finally, small amounts of drug remaining in a three-way tap, injection port or IV line can be enough to cause serious complications in children. A running IV does not remove residual drug traces, and each injected dose must be followed with a saline flush through the same injection site. Techniques to reduce errors specific to children are listed in Table 2.3.

Table 2.3

Reducing drug errors in children

Techniques to reduce drug errors in children
Have another person in theater check unusual doses, unusual drugs, or difficult calculations
Have another person in theater check the preparation of infusions
Label drugs carefully. Do not rely on color of a drug or memory
Avoid diluting drugs if possible, or always use the same or a standard dilution for each drug
For drugs that are not titrated to effect such as antibiotics, draw up only the dose to be given
Cross check by comparing the dose with an adult dose—“If an adult dose is for 50 kg and the child is 10 kg, how does the dose I’m about to give compare?”
Prescribe practical doses for postop use that are not complex for staff to calculate (such as 110 mg of paracetamol rather than 113 mg); or use increments of dose that match the strength of the drug preparation—paracetamol 24 mg/mL for example
Write ‘micrograms’ in full to prevent one thousand times overdose from misreading abbreviation
Flush the IV injection point after every dose of drug

2.4 Local Anesthetic Creams

Local anesthetic creams are used to reduce the pain of venipuncture. However, children still often fear needles and do not believe the cream will work. EMLA ^® is a eutectic mixture of lidocaine, prilocaine and excipients. It takes 45–60 min to work, although a longer duration is more effective. The larger the needle, the more likely it is to be felt. The cream continues to penetrate deeper and work better for at least the first few hours, though the skin can become ‘soggy’ if the cream is left on more than 3 or 4 h. It works for 1–2 h after removal, depending on duration of application. It vasoconstricts micro vessels which may make larger veins more obvious against a pale background. Prilocaine toxicity (methemoglobinemia ) is a concern in neonates. Absorption of EMLA through their thin skin is increased, and methemoglobin reductase activity is reduced. During the first 3 months, application to only one site for up to 1 h in a 24 h period is recommended.

Tetracaine (amethocaine ) gel (‘Ametop’ or ‘AnGEL’ cream) is faster in onset (30 min) and penetrates better than EMLA for IV insertion. It vasodilates microvessels and makes the skin red. Local skin reactions are rare, but more common than after EMLA. It should be left on no longer than 60 min and continues to work for 2 or 3 h after removal. Four percent of lidocaine cream (LMX-4) also takes 30 min to have a similar efficacy to EMLA.

2.5 IV Induction Agents

2.5.1 Propofol

Propofol is particularly useful in children because it suppresses airway reflexes and reduces emergence delirium.

2.5.1.1 Pharmacokinetics

Children have a central volume of distribution almost twice that of adults and an increased rate of clearance (Table 2.4). They need larger doses to achieve the same plasma concentrations as adults, mainly because of increased distribution from plasma to peripheral compartments. After its administration, more propofol remains in the body for any given plasma concentration, increasing the context sensitive half time and slowing recovery. Rapid awakening is not a feature of TIVA with propofol in children. Neonates and infants have lower clearance of propofol as glucuronidation, which is the major metabolic pathway for propofol metabolism. The immature glucuronidation is partially offset by the faster maturing P450 system. However, neonates remain at an increased risk for accumulation during either intermittent bolus or continuous administration of propofol.

Table 2.4

Pharmacokinetic data for propofol at different ages

Age group	Vd (L/kg)	Clearance (mL/min/kg)
Neonates	5.6	20
Child <3 years	9.5	53
Child >3 years	9.7	34
Adult	4.7	28

2.5.1.2 Clinical Use

The induction dose is often stated as 2.5–3.5 mg/kg in unpremedicated children. However, doses of 4–5 mg/kg are routinely used in younger children to reduce spontaneous movements and facilitate instrumentation of the airway (Table 2.5). Lower doses are required in neonates, after sedative premedication, and if there is hypovolemia. Many children have food allergies to eggs and although propofol can still be used, more information should be sought if the history is of anaphylaxis to egg. Stinging with injection is a problem in children, as small veins on the dorsum of the hand are commonly used for induction. Lidocaine 0.2 mg/kg for every 3 mg/kg of propofol is effective. Propofol induction in children causes more hypotension than thiopentone, but propofol causes less hypotension in children than in adults. However in some neonates a bolus dose causes significant hypotension lasting up to an hour (Fig. 2.4). Propofol causes apnea of more than 20 s in up to 50% of children and depresses pharyngeal and laryngeal reflexes (making a bolus of 1–2 mg/kg useful to avert coughing or laryngospasm). A propofol bolus or transition technique at the end of sevoflurane anesthesia, or TIVA are effective methods to prevent emergence delirium (see Chap. 1, Sect. 1.8.1).

Table 2.5

Summary of IV induction agent doses

	Age group
Agent (dose mg/kg)	Neonates	Infants and children
Propofol	3	3–5
Thiopentone	3	5–7
Ketamine	1–2	1–3

../images/467929_2_En_2_Chapter/467929_2_En_2_Fig4_HTML.png — Fig. 2.4

A propofol bolus may cause a prolonged fall in blood pressure in neonates. Based on Welzing et al., Pediatr Anesth 2010;21: 605–11

2.5.1.3 Propofol Infusions in Children

Propofol infusions reduce airway responsiveness, emergence delirium and nausea and vomiting in children. Children do not usually wake quickly after propofol anesthesia due to the high doses needed and long context-sensitive half time. They tend to sleep for a period in recovery but then usually wake in a calmer and less distressed manner if analgesia is adequate. Starting an infusion at some point after an inhalational induction is quite acceptable, and most of the benefits of propofol are still gained. The propofol dose is reduced by the concomitant use of remifentanil or alfentanil, and to a lesser extent by nitrous oxide (Table 2.6).

Table 2.6

Initial target propofol concentration in adolescents during maintenance with propofol given with analgesic agents

Intraoperative analgesic	Target concentration propofol (μg/mL)
Propofol alone	4–6
Remifentanil or regional block	3–4
Nitrous oxide	4–5

Titration of dose according to observed anesthetic depth is critical. Adapted from McCormack, Curr Anesth Crit Care 2008;19:309–14

2.5.1.4 Target Controlled Infusions (TCI)

There are two TCI models licensed in some countries for children—the Paedfusor and Kataria . Both have minimum age and weight settings and target plasma rather than effect site concentration. Age however is ignored as a variable by both models, although the Paedfusor does adjust assumed volumes when the when age is more than 12 years. In general, TCI pumps give children a bolus dose about 50% higher and a maintenance rate 25% higher compared to adult TCI models.

TCI propofol is a useful technique in children, but the algorithms can’t entirely allow for the marked inter-individual variability of propofol in children and for the pharmacokinetic changes over a broad range of ages. These issues and some practical points are given in Table 2.7.

Table 2.7

Problems and practical points of propofol TCI in children

Propofol TCI in children	Comments
Problems	Pump algorithms use averaged pharmacokinetic variables. Titration of the dose is still needed to allow for interindividual differences
	Target concentration in children is probably the same as in adults, but it is not known why this is the case when MAC for volatiles varies with age
	Induction slower than manual propofol bolus which may prolong induction process in unhappy or uncooperative child
Practical points	If gas induction, start TCI target 1–2 μg/mL then increase as sevoflurane washes out. Closely observe depth of anesthesia and watch for hypotension
	Always add an analgesic component to reduce propofol dose: An effective regional block; remifentanil infusion; alfentanil infusion if short anesthesia; even just nitrous
	If propofol used alone, need target about 6 μg/mL or more to prevent involuntary movement. Huge dose and PACU recovery is prolonged
	Wake-up concentration reported as 1.3–1.8 μg/mL

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