Volume of Distribution

Volume of distribution (V_d) is a theoretic concept that relates the amount of drug in the body (dose) to the concentration (C) of drug that is measured (in blood, plasma, and unbound in tissue water). Volume of distribution is the volume of fluid “apparently” required to contain the total-body amount of drug homogeneously at a concentration equal to that in plasma (or blood) (Fig. 7-2):

FIGURE 7-2 Apparent volume of distribution. The real volume of the beaker is 5 L (V_d = 50 mg/10 mcg/mL = 5 L). However, based on measured concentrations in fluid and calculated according to the equation for V_d on p. 180, the volume of distribution may vary (thus apparent volume). It depends on significant tissue or plasma protein binding. Significant tissue binding (i.e., significant digoxin binding to myocardial Na⁺, K⁺-ATPase) increases volume of distribution (V_d = 10 L; see the text for explanation). Because routinely measured fluid concentration includes both free unbound and plasma protein bound drug, the increased protein binding reduces volume of distribution (V_d = 2.5 L).

The volume of distribution does not necessarily correspond to any specific physiologic volume or space. Drugs such as highly water-soluble compounds, which are confined intravascularly, have a small volume of distribution (approximately equal to intravascular volume), whereas lipophilic drugs that distribute to tissues have a large volume of distribution (that may be so large as to exceed total body water). For example, in adults the volume of distribution of gentamicin is 0.2 to 0.3 L/kg, whereas that of digoxin is 8 to 10 L/kg. Plasma protein binding of drugs decreases the apparent volume of distribution, and tissue binding increases the apparent volume of distribution. The major practical value of volume of distribution lies in the calculation of initial drug dosing (loading):

A major consequence of growth and maturational changes in body composition may be differences in volume of distribution. In general, neonates and infants have larger distribution volumes for water-soluble drugs and smaller volumes for lipophilic drugs. For example, the volume of distribution of gentamicin is 0.5 to 1.2 L/kg in neonates and infants compared with 0.2 to 0.3 L/kg in adults (Echeverrisa).

Clearance

Clearance is the fundamental parameter describing the ability to eliminate a drug. Clearance may refer to elimination from the body (systemic or total clearance) or by a specific organ (renal or hepatic clearance). Clearance is not the amount of drug actually eliminated, but rather represents the theoretic amount of biologic fluid (blood or plasma) from which the drug is completely removed per unit time (mL/min, L/hr). Systemic clearance represents the sum of hepatic clearance; renal clearance; and for some drugs, other routes of clearance (e.g., pulmonary elimination of volatile anesthetics, hydrolysis in blood, or dialysis).

where CL indicates clearance. Clearance is achieved through the processes of metabolism and excretion. A major practical value of understanding clearance is that at steady-state, total clearance is a primary determinant of dose and dosing interval (dose rate) when the desired steady-state plasma concentration (C_ss) is known:

Hepatic Clearance

For many drugs, including several used in anesthesia (e.g., sedative hypnotics, benzodiazepines, opioids, and neuromuscular blockers), hepatic clearance (CL_H in the following formulas) is a major route of elimination (Wilkinson, 1987). Hepatic clearance is the product of liver blood flow (Q_H) and the hepatic extraction ratio (E_H) of a drug.

E_H is defined as the fraction of drug entering the liver that is eliminated in one pass through the liver.

E_H depends on liver blood flow and the intrinsic clearance of the drug (CL_int), defined as the total capacity of the liver to eliminate drug in the absence of limitations from blood flow.

CL_int functionally represents drug biotransformation (the total activity of enzymes and transporters involved in metabolism and biliary secretion). Thus, combining the previous equation with the equation for hepatic clearance:

Since only an unbound drug is considered diffusible into liver cells (although in reality a simplification), E_H also depends on the fraction of unbound drug in the blood (f_u) (Baker and Parton, 2007). Therefore the three theoretic primary determinants of hepatic drug clearance are liver blood flow, intrinsic clearance (biotransformation), and plasma protein binding.

In reality, the important determinants of hepatic clearance are liver blood flow and the extraction ratio (Fig. 7-3). For drugs with a high extraction ratio (e.g., lidocaine, fentanyl, sufentanil, and propofol), hepatic clearance depends primarily on hepatic blood flow (because intrinsic clearance is so efficient, drug delivery to the liver becomes rate limiting). For low-extraction drugs (e.g., methadone, diazepam, and alfentanil), hepatic clearance is independent of hepatic blood flow and depends primarily on intrinsic clearance (metabolism).

FIGURE 7-3 Effect of increasing liver blood flow on the hepatic clearance of drugs with varying extraction ratios. Each curve represents a drug whose extraction ratio at 1.5 L/min is shown above that flow. For drugs with a low extraction ratio, an increase in liver blood flow within the physiologic range (arrow) produces very little change in hepatic clearance. For a drug with a high extraction ratio, however, increases in liver blood flow produce an almost proportional increase in hepatic clearance.

(From Wilkinson GR, Shank DG: Commentary: a physiological approach to hepatic drug clearance, Clin Pharmacol Ther 18:377, 1975.)

Absorption

Although the predominant route of drug administration in pediatric anesthesiology is intravenous, the oral route is the most commonly used in children. Changes in physiologic processes that accompany normal growth and development can affect drug absorption (Kearns et al., 2003; Abdel-Rahman et al., 2007). In general, neonates and small children absorb drugs more slowly than older children and adults, resulting in delayed and lower peak drug concentrations. Neonatal gastric pH is relatively high (greater than 4) compared with older children and adults, thus acid-labile drugs (such as penicillin G) are more efficiently absorbed and have greater bioavailability. Conversely, weak acids (such as phenobarbital) may require larger doses because of reduced bioavailability. In the first few months of life, gastric emptying, intestinal motility, and intestinal drug transport increase.

Parenteral drug absorption may also be affected by development. Transdermal bioavailability is increased in infants because there is a thinner strateum corneum in preterm neonates, better skin hydration and perfusion in small children, and a larger surface area-to-volume ratio. Intramuscular bioavailability is greater in neonates and infants than in older children because of a higher density of skeletal muscle capillaries. Rectal-drug bioavailability in drugs undergoing extensive first-pass metabolism is higher in neonates and infants, because hepatic metabolism is immature. Conversely, rectal formulations may be expelled more quickly in young children because of more frequent high-amplitude pulsatile contractions.

Distribution

The age-dependent changes in body composition described above can result in developmental differences in drug distribution. For hydrophilic drugs with relatively small volumes of distribution, greater total body water and larger extracellular fluid spaces result in larger volume of distribution, and hence lower intravascular drug concentrations. Lipophilic drugs with relatively large volumes of distribution are not similarly affected.

Plasma protein binding can exhibit developmental differences, although the clinical significance of protein binding in pharmacokinetics and pharmacodynamics remains unresolved (Benet and Hoener, 2002; Trainor, 2007). The primary binding proteins are albumin (for acidic drugs) and α₁-acid glycoprotein (for basic drugs). Decreased plasma albumin and α₁-acid glycoprotein concentrations in neonates may result in increased unbound (free) drug concentrations and hence pharmacologic effect.

Metabolism

Metabolism of a drug can result in bioactivation of an inactive prodrug, formation of an active or inactive metabolite, or occasionally a toxic metabolite. The liver is the primary site of drug metabolism, although the intestine can metabolize oral drugs before they reach the systemic circulation and extrahepatic metabolism (e.g., renal, blood, and other tissues) may be important for certain drugs (i.e., remifentanil and propofol). Phase I reactions (oxidation, reduction, and hydrolysis) chemically modify the drug structure to add, form, or uncover a functional group and render the molecule more water soluble. Phase II reactions (glucuronidation, sulphation, and glutathione conjugation) add an endogenous molecule to the drug or metabolite to render it even more water soluble for elimination. Typical pathways of drug metabolism are provided in Table 7-4.

TABLE 7-4 Pathways in Drug Metabolism

Modified from Tucker GT: Drug metabolism, Br J Anaesth 51:603, 1979.

Comprehensive reviews of human drug metabolism are available, but a generalized overview is instructive for understanding developmental changes in biotransformation (Kramer and Testa, 2008; Pelkonen et al., 2008; Zanger et al., 2008). Cytochrome P450 (CYP) is the main oxidative (phase I) metabolizing enzyme system, and more than 50 human P450s have been identified, although only a small fraction are responsible for the majority of drug metabolism (Fig. 7-4) (Paine et al., 2006; Zanger et al., 2008). Individual CYPs are classified by their sequence evolution and amino-acid similarities (Ingelman-Sundberg et al., 2007; Zanger et al., 2008). Those with greater than 40% sequence homology are grouped in a family (designated by an Arabic number, e.g., CYP3); those with more than 55% homology are in a subfamily (designated by a letter, e.g., CYP3A), and individual CYPs are identified by a third number (e.g., CYP3A4). The majority of drugs in humans are metabolized by CYPs 1, 2, and 3 (particularly CYPs 1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4, 3A5, and 3A7). CYPs can have numerous genetic variants, and there are several highly polymorphic CYPs. Allelic CYP variants are designated by an asterisk and number (e.g., CYP3A5*3, where the “wild-type” is always *1) (Ingelman-Sundberg et al., 2007; Zanger et al., 2008). CYPs can have varying degrees of substrate specificity, and some are very accommodating, like CYP3A, which metabolizes approximately one third to one half of all therapeutically used drugs.

FIGURE 7-4 Cytochrome P450 isoform content in human liver and intestine.

(Data from Rowland-Yeo K et al.: Abundance of cytochromes P450 in human liver: a metaanalysis, Br J Clin Pharmacol 57:687, 2004; Paine et al.: The human intestinal cytochrome P450 “pie,” Drug Metab Dispos 34:880, 2006.)

The developmental pattern of biotransformation activity generally follows a hyperbolic curve with age that begins in fetal development, with hepatic drug metabolism and very low clearance before and during the first month. It reaches near adult levels at approximately 1 year, becomes maximum before puberty, and declines slightly into adulthood (Johnson and Thomson, 2008). There are, however, enzyme and isoform-specific patterns of developmental maturation of drug-metabolizing enzymes (Blake et al., 2005; Hines, 2008). Several pertinent examples are in the following paragraphs.

The CYP3A family is the most important drug-metabolizing enzyme. The important isoforms are CYP3A4 (the major CYP present in the adult liver and the intestine), CYP3A5 (which metabolizes very many of the CYP3A4 substrates with equal or diminished activity and is polymorphically expressed), and CYP3A7 (a fetal form that is usually less active than 3A4 or 3A5). CYP3A undergoes a “developmental switch” with CYP3A7, the predominant CYP3A expressed in fetal liver (Stevens, 2006; Hines, 2008). Indeed it is the most abundant of any CYP and is thought to be important in fetal steroid metabolism and homeostasis (Fig. 7-5, A). CYP3A7 expression decreases during gestation, declines further after birth, and is typically undetectable after the first year. CYP3A4 expression is low during development and then increases after the first 6 months of age. CYP3A metabolizes many drugs of importance in anesthesiology, including all of the fentanyl series opioids (except remifentanil), most benzodiazepines, and local anesthetics. Although high in abundance, CYP3A7 has low activity toward many drugs (1% to 3% of the activity of CYP3A4 towards midazolam and alfentanil) (Björkman, 2006). Therefore, CYP3A-catalyzed drug metabolism and clearance increases with age. For example, the hepatic extraction of midazolam is only 0.04 in neonates, compared with 0.38 in adults (Björkman, 2006). Midazolam clearance is similarly very low in neonates, particularly in preterm infants. The age-dependent maturation of midazolam clearance is shown in Figure 7-5, B.

FIGURE 7-5 Developmental aspects of hepatic CYP3A expression and activity. A, Content of hepatic CYP3A4, CYP3A5, and CYP3A7 proteins as a function of age. B, Clearance of the CYP3A substrate midazolam. EGA, Estimated gestational age; PNA, postnatal age.

(A From Stevens JC: New perspectives on the impact of cytochrome P450 3A expression for pediatric pharmacology, Drug Discov Today 11:440, 2006; B, Redrawn from de Wildt SN et al.: Cytochrome P450 3A: ontogeny and drug disposition, Clin Pharmacokinet 37:485, 1999.)

Other hepatic CYP isoforms also demonstrate maturation of expression. CYPs 1A2, 2C9, 2C19, 2D6, and 2E1 are expressed minimally or not at all in the fetus, but substantial increases occur after birth. CYP2D6 metabolizes about one fourth of all drugs, including antidepressants, antipsychotics, β-blockers, and numerous orally administered opioids, most notably catalyzing bioactivation of the inactive prodrugs codeine and tramadol (to the pharmacologically active metabolites morphine and O-desmethyltramadol, respectively) (Ingelman-Sundberg et al., 2007; Madadi and Koren, 2008). Isoform-dependent maturation of CYP enzymes in infants is exemplified by the development of tramadol metabolism and disposition, which shows that CYP2D6-catalyzed O-demethylation matures faster than CYP3A-catalyzed N-demethylation (Fig. 7-6). CYP1A2 metabolizes caffeine and theophylline, two methylxanthines that are commonly used in pediatrics. CYP1A2 is essentially absent in fetal liver and minimally active in neonates, such that 85% of caffeine is eliminated unchanged renally in neonates (Cazeneuve et al., 1994). CYP1A2 activity matures rapidly thereafter, reaching adult values by age 6 months, and caffeine clearance in these children reflects primarily hepatic demethylation (Kearns et al., 2003).

FIGURE 7-6 Age-dependent and cytochrome P450 (CYP) isoform-dependent development of tramadol metabolism and disposition. Tramadol is a relatively inactive prodrug. Tramadol undergoes CYP2D6-catalyzed O-demethylation to the active analgesic metabolite O-desmethyltramadol, and CYP3A4-catalyzed N-demethylation to the inactive metabolite N-desmethyltramadol. The O-desmethyltramadol/tramadol concentration ratio represents a bioactivation pathway and reflects CYP2D6 activity. The N-desmethyltramadol/tramadol concentration ratio represents an inactivation pathway, and reflects CYP3A4 activity. The figure shows the influence of age on metabolite/tramadol concentration ratios in 24-hour urine collections in neonates and infants after administration of intravenous tramadol. Maturation of CYP2D6 activity is faster than that of CYP3A4.

(Redrawn from Allegaert K et al.: Determinants of drug metabolism in early neonatal life, Curr Clin Pharmacol 2:23, 2007.)

Compared with hepatic CYP enzymes, the ontogeny of CYPs in the intestine is far less understood. CYPs 3A4, 3A5, and 2C9 are the predominant intestinal isoforms, accounting for approximately 80% (3As) and 15% (2C9) of the total, respectively, with the remainder comprising CYPs 1A1, 1A2, 2C19, 2J2, and 2D6 (Paine et al., 2006). CYP3A expression declines from the proximal to distal intestine, with 75% occurring in the duodenum and jejunum (Paine et al., 1997). In the intestine, like in the liver, CYP3A4 is the predominant CYP3A isoform, and CYP3A5 is polymorphically expressed in 20% to 70% of adults (Paine et al., 1997). In otherwise histologically normal duodenal biopsies from a population of 74 children, CYP3A4 protein expression increased steadily with age (Fig. 7-7) (Johnson and Thomson, 2008). In fetal duodenum it was essentially absent, and in neonates it was expressed at about half the level seen in mature children. Intestinal CYP3A enzyme activity followed the same pattern as enzyme expression (Johnson and Thomson, 2008).

FIGURE 7-7 Developmental aspects of duodenal CYP3A4 expression and activity (mean ± SD). The number of patients in each group is given in brackets. CYP3A protein expression was measured by Western blotting. Statistically significant differences were observed between the fetus group and all of the other groups and between neonates and children older than 5 years (p < 0.05). The age-related pattern of duodenal CYP3A activity was similar to that of CYP3A protein expression (not shown).

(From Johnson TN et al.: Enterocytic CYP3A4 in a paediatric population: developmental changes and the effect of coeliac disease and cystic fibrosis, Br J Clin Pharmacol 51:451, 2001.)

Other phase I enzymes are important in drug metabolism. Ester hydrolysis is a ubiquitous reaction catalyzed by a diverse array of esterases in blood and tissue. Esterase activity is important in the hydrolysis of remifentanil to an inactive metabolite, resulting in termination of clinical effect. Remifentanil is hydrolyzed by nonspecific esterases in plasma and (more so) tissue, but not by plasma cholinesterase (Manullang and Egan, 1999). In contrast, and unlike most ester drugs, red-cell rather than plasma esterases metabolize esmolol. Whereas CYPs mostly mature in the first months to year of life, esterase activity in neonates is already at levels nearly equivalent to those in adults (Allegaert et al., 2008). For example, remifentanil clearance in children from the ages of 1 month to 9 years old resembles that in adults (Sumpter and Anderson, 2009).

Phase II drug-metabolizing enzymes include glucuronosyltransferases (UGTs), sulfotransferases (SULTs), acetyltransferases, and glutathione transferases, all catalyzing conjugation reactions with multiple isoforms of each enzyme, often with isoform-dependent ontogeny (Blake et al., 2005; Hines, 2008). The two main UGT families are UGT1 and UGT2. UGT1A1, the major enzyme responsible for bilirubin conjugation, is not detectable in fetal liver, increases immediately after birth, and reaches adult levels by 3 to 6 months of age. UGT2B7 is of particular interest, because it conjugates morphine. UGT2B7 activity in fetal liver is present at 10% to 20% of adult values and increases in neonates to reach adult values by 2 to 3 months after birth. Morphine clearance is very low in premature infants and increases substantially over the first year of life. SULT ontogeny is isoform-specific, with SULT1E1 activity highest in the fetus and declining thereafter, SULT2A1 activity is barely detectable in neonates and increases in neonates, whereas SULT1A1 activity is constant from fetal age to adulthood.

Elimination

Elimination refers to all processes that remove a drug from the body, including drug metabolism (biotransformation) and excretion. Returning to the concept of drug elimination in general, it is now appreciated that several elements affect the development of drug elimination from fetus to adult, including patient size, organ maturation, organ function, and coexisting disease. Developmental patterns of drug clearance are shown for several drugs in Figure 7-8. For drugs in which renal elimination largely determines systemic clearance, the age-dependence of such clearance approximates that of GFR. In contrast, when hepatic metabolism predominates, the pattern differs.

FIGURE 7-8 Clearance maturation, expressed as a percentage of mature clearance. Maturation profiles for acetaminophen, morphine, and dexmedetomidine, in which glucuronidation and renal excretion play a major role, resemble that for renal function (GFR). For propofol, cytochrome P450 enzymes also contribute to biotransformation and elimination, thus causing faster maturation than that predicted from renal excretion alone. The maturation half-time (TM₅₀) and Hill coefficient are shown for each drug.

(From Sumpter A, Anderson BJ: Pediatric pharmacology in the first year of life, Curr Opin Anaesthesiol 22:469, 2009.)

The complexity of developmental pharmacokinetics can be appreciated using a drug such as propacetamol. Propacetamol is an N, N-diethylglycine ester prodrug of acetaminophen (paracetamol), which is hydrolyzed by plasma esterases after intravenous administration to the active metabolite acetaminophen. Acetaminophen in turn undergoes both phase I, and more so phase II metabolism, to glucuronic acid, sulfate, cysteine, and glutathione conjugates. Figure 7-9 shows the developmental aspects of propacetamol pharmacokinetics (Anderson et al., 2005). Consistent with the relative age invariance of esterase expression, ester hydrolysis to the active metabolite, acetaminophen, was also age invariant. The central compartment volume of distribution was also age invariant, whereas the peripheral compartment volume was somewhat decreased in neonates. Clearance increased markedly with age in the first year, from 12% of adult values at 27 weeks’ PCA to 84% of its mature value by 1 year. Importantly, PCA was more important than PNA, as described above.

FIGURE 7-9 Developmental aspects of intravenous propacetamol disposition. A, Lack of effect of age on the half-life of propacetamol hydrolysis to acetaminophen. B, Influence of age on the peripheral compartment volume of distribution (V₃) of acetaminophen, standardized to a 70-kg person. The solid line represents the nonlinear relation between V₃ and age. Peripheral volume of distribution decreased from 27 weeks’ postconceptional age to reach 110% of the value in older children by 6 months. The central volume of distribution did not change with age. C, Influence of age on acetaminophen’s apparent systemic clearance, standardized to a 70-kg person. The solid line represents the nonlinear relation between clearance and age. Clearance increased from 27 weeks’ postconceptional age to reach 84% of the value in older children by 1 year. Data are from a meta-analysis, with different symbols representing different individual studies.

(From Anderson BJ et al.: Pediatric intravenous paracetamol (propacetamol) pharmacokinetics: a population analysis, Pediatr Anesth 15:282, 2005.)

Scaling Pediatric Dosing

Ideal clinical practice would be informed by age-specific clinical pharmacokinetic data for every drug used in children. As this remains an unattained ideal, considerable effort has been expended to establish pharmacokinetic models to predict age-dependent dosing based on adult data (Anderson and Holford, 2008; Johnson, 2008 Tod et al., 2008; Sumpter and Anderson, 2009). Several principles are now apparent, some of which have been described previously in this chapter. Loading doses depend on concentration and central volume of distribution. For central volumes, allometric modeling (p. 195) suggests that the volume of distribution scales with a power of 1, such that

where W_i is the weight of any individual and V_std is the volume of a standardized 70-kg adult. Because maintenance dosing equals the product of concentration and clearance, the fidelity of clearance models is important. Historically, the linear per-kilogram model, the body-surface area model, and the allometric three-fourths power model have been used. There is a nonlinear relationship between clearance and size. The linear per-kilogram model, although widely used, is the most inaccurate of the three models, because clearance (per kg) is larger in children than in adults. It leads to underprediction by more than 10% at body weights less than 47 kg, and approaches 50% for a 3.5-kg newborn. The body-surface area model, which assumes that adults and children are geometrically similar (although they in fact are not), over-predicts clearance by more than 10% at body weights below 20 kg. The allometric model, which is based on physiologic principles and has been well-validated clinically, is the most accurate.

Figure 7-10 compares the accuracy of the linear per-kilogram, the body-surface area, and the allometric three-fourths power models.

FIGURE 7-10 Relative differences in clearance determined by the dose per surface area and the dose per kilogram of weight models when compared with the allometric ¾-power weight model.

(From Anderson BJ, Holford NH: Mechanism-based concepts of size and maturity in pharmacokinetics, Ann Rev Pharmacol Toxicol 48:303, 2008.)

Clearance, however, depends on not just growth (size), but also on maturation of organ clearance processes (i.e., PCA). It is also influenced by concomitant diseases and potentially by drug interactions, which can influence organ function. While allometry alone provides reasonable estimates of clearance in older children using adult data, it alone is insufficient to predict clearance in infants and young children (Sumpter and Anderson, 2009). Therefore, the most parsimonious model for prediction drug clearance is as follows:

where MF is the maturation function (with a value from 0 to 1), and OF is organ function (also with a value from 0 to 1). The only major exception to this rule is in neonates, where organ maturation is relatively uninitiated, and the practical relationship is best approximated by the linear per-kilogram model.

For practical purposes, size models have been simplified for clinical use. This is also influenced by regulatory considerations, which sort children into the categories of neonates (younger than 1 month), infants (1 month to 2 years), children (2 to 12 years), and adolescents (12 to 18 years). Table 7-5 presents age-specific dose adjustments. An even simpler method suggests 1 month, 1 year, 7 years, and 12 years, respectively for doses that are one eighth, one fourth, one half, and three fourths of the adult doses (Anderson and Holford, 2008). It is important to remember that these dose adjustments are for drug disposition only, and they do not take into account any age-dependent differences in pharmacodynamic response.

Body Size and Maturation Adjustments

Two major features of children that are not seen in adults are growth and development, and these unique characteristics of the pediatric population can be studied by using size and age as covariates. PPK studies in children cover a population with much wider range in body size than similar studies in adults, and body weight can vary in the pediatric population up to 200-fold (i.e., 0.5 to 100 kg). Even when only one particular age group is studied, it is not uncommon that tenfold differences in body weight are reported. Both primary pharmacokinetic parameters, clearance, and volume of distribution are functions of body size. Therefore, to identify the potential effects of other covariates in predicting pharmacokinetic parameters, it is necessary to use size as a primary covariate and standardized clearance and volume of distribution to appropriate body size.

In adults, to account for impact of body size, pharmacokinetic parameters are traditionally adjusted to body weight or body surface area. However, these empirical approaches, although appropriate when adjusting for dose, clearance, or volume of distribution in adults, may be inappropriate for scaling small children to adults (Holford, 1996). The body-weight adjustments may underpredict clearance, whereas the body surface area model may overpredict clearance in children (and the error increases with decreasing weight) (Mitchell et al., 1971; Holford, 1996; Anderson et al., 2006). Measurement of body surface area, which can be calculated from height and weight by DuBois formula:

where BSA represents body surface area, W is weight, and H is height. It may also be calculated by using several very similar formulas; however, all formulas may be inaccurate, especially in younger pediatric patients (Holford, 1996; Anderson et al., 2006). Infants are not morphologically similar to adults (they have short legs, relatively big heads, and large body trunks), and direct photometric measurement has been suggested to be an inaccurate prediction of body surface area in children younger than 12 years old, or BSA greater than 1.3 m² (Mitchell et al., 1971).

A method for body-size adjustment that has begun to be used regularly in PPK studies in children is allometric size adjustment. Allometry is a methodology used to relate morphology and body function to the size of an organism. This methodology had found wide application in drug development to predict pharmacokinetic parameters in humans based on data from different animal species. Gillooly and colleagues (2001) have shown that in almost all species, including humans, when the log of the basal metabolic rate is plotted against the log of body weight, a straight line with a slope of 0.75 is produced (Fig. 7-17).

FIGURE 7-17 A comparison of the temperature-standardized relation for whole-organism metabolic rate (W) as a function of the body mass (kg). Data points represent unicells, plants, ectotherms, and endotherms, all standardized to 20° C. The three lines indicate that the “allometric 0.75 power model” fits for unicells, poikilotherms and homeotherms.

(From Gillooly JF et al.: Effects of size and temperature on metabolic rate, Science 293:2248, 2001.)

In the allometric size adjustment model, pharmacokinetic parameters are studied by body weight of an individual by power model:

where F_size is a factor for size, W is a body weight of an individual, W_adult is body weight of an adult of standard 70-kg size, and PWR is allometric power exponent.

The allometric “0.25 power” model can be used to predict the pharmacokinetic estimates in children with PWRs of 0.75, 0.25, and 1 for clearance, half-life, and volume of distribution, respectively (West et al., 1997, 1999; Anderson et al., 2006). Using the fixed power exponent allows investigators to delineate secondary covariate effects from the effects of size. The allometric scaling also allows direct comparison of pediatric and adult pharmacokinetic estimates and can be used to predict the pediatric dose based on the adult dose (Table 7-5).

Age is used as a covariate to describe the maturation process in the pediatric population. Several quantitative models that describe the maturation of clearance have been developed, and they vary depending on age group studied (Allegaert et al., 2006; Anderson et al., 2000). Rhodin and colleagues (2009) have studied the effects of size and maturation on GFR in 923 individuals from eight studies, from 22 weeks’ PMA to 31 years of age. They demonstrated that PMA is a better descriptor of maturation changes than PNA and that a sigmoid hyperbolic model describes the nonlinear relationship between GFR and PMA. Half of the adult values are reached at 48 weeks PMA, and at 1 year PNA the predicted GFR is 90% of the adult GFR (Rhodin et al., 2009).

Data Modeling

There are three main approaches to modeling data collected from a group of subjects: naïve pooled data, the standard two-stage approach, and mixed-effects models. In the naïve pooled-data approach, time-concentration data pooled together from different subjects are treated as if all doses and all observations pertain to a single subject. This approach does not allow information about the magnitude and the causes of between-subject variability to be collected, and it is adequate only if data are extensive for each subject and if there is only minor between-subject variability. In the standard two-stage approach, individual time-concentration profiles are analyzed, and the individual parameters (i.e., volume of distribution and clearance) are estimated in the first stage by separately fitting each subject’s data. In the second stage, individual estimates are used as variables and combined to obtain summary measures. If data are sparse, misrepresentation may occur easily.

In contrast to the naïve pooled-data and the two-stage approaches that use dense data from a small group of subjects, the mixed-effects models study the variability in drug response in the population of interest, using sparse data (often only two or three samples) from a large number of subjects. The mixed-effects modeling approach, similar to the naïve pooled-data approach, analyzes the data of all individuals at once, but it takes into consideration the interindividual effects. The modeling is “mixed” because it describes the data using a mixture of fixed effects (parameters’ differences predicted by covariates) and random effects (between subject and residual or unexplained variability). In their seminal work in the early 1980s, by using phenytoin data collected from therapeutic monitoring in epileptic patients, Sheiner and Beal showed not only how estimates of PPK could be obtained from few samples per patient, but they also demonstrated that the naïve pooled-data and the two-stage approaches may both result in biased parameter estimates. The advantages of this approach are that in addition to sparse data, it can handle the imbalance in data per individual and it can estimate the between-observation variability. Obviously, the use of sparse data and imbalanced data allows many ethical concerns and practical problems related to frequent sampling to be overcome. The disadvantage is that this approach needs advanced training for the use of specialized software such as NONMEM, and fitting complicated models can be time consuming.

Thiopental

Thiopental is an ultra short-acting barbiturate used as an intravenous induction agent in anesthesia. It has been also used in critical care settings as a continuous infusion for the treatment of intracranial hypertension and status epilepticus. Hiccoughs, sneezing, and other respiratory irregularities are rarely seen on induction, and there is no excitement or extrapyramidal activity associated with its use. It decreases cerebrospinal fluid pressure, making it useful for diagnostic and operative neurologic procedures (Dawson et al., 1971). Intraocular pressure also is decreased. Awakening is quiet, occasionally interrupted by shivering, and associated with a low incidence of nausea (Smith et al., 1955). Porphyria, seldom encountered in the United States, is a specific contraindication to barbiturates (Dundee and Barron, 1962). Thiopental requirements for induction of anesthesia reveal an inverse relation with age. Jonmarker et al. (1987) reported that the ED₅₀ of thiopental in infants is significantly greater (7 mg/kg) than that in adults (4 mg/kg) (Fig. 7-18). Westrin et al. (1989) determined the dose of thiopental needed for satisfactory induction of 10 healthy, unpremedicated neonates who were 0 to 14 days old and 20 infants who were between 1 and 6 months old. In this study, the ED₅₀ for thiopental induction was 3.4 ± 0.2 mg/kg in neonates and 6.3 ± 0.7 mg/kg in infants aged 1 to 6 months. In an in-vitro study in which the free fraction of thiopental was measured in the serum of neonates and adult volunteers, Kingston et al. (1990) noted that neonates had a free drug fraction that was 1.5 to two times greater than that of adults. The increased free fraction of thiopental may explain the decreased induction dose required by the neonate. Sorbo et al. (1984) studied the pharmacokinetics of thiopental in 24 surgical patients aged 5 months to 13 years. The volume of distribution of the central compartment ranged from 0.3 to 0.4 L/kg. The steady-state volume of distribution was approximately 2 L/kg and did not differ statistically from values previously measured in adults. The elimination half-time and clearance of thiopental in these infants and children were 6.1 ± 3.3 hours and 6.6 ± 2.2 mL/kg per minute, respectively. These values were significantly different from the values of 12 ± 6 hours and 3.1 ± 0.5 mL/kg per minute, respectively, observed in adults. After a single intravenous dose, clinical effect is mainly terminated by redistribution. When repetitive or larger doses are used, redistribution becomes less effective and metabolism plays a more important role, explaining the shorter recovery times in children when compared with adults.

FIGURE 7-18 Estimated ED₅₀ ± SD for thiopental in the various age groups.

(From Jonmarker C et al.: Thiopental requirements for induction of anesthesia in children, Anesthesiology 67:104, 1987.)

Methohexital

Methohexital, a methylated oxybarbiturate, is more potent than thiopental by a ratio of about 3:1, is more rapidly eliminated, and produces more undesirable side effects (Clarke et al., 1968). Greater speed of recovery provides its principal indication, especially for outpatient care or for situations where very brief effect is wanted, such as for cardioversion or electroconvulsive therapy. The incidence of involuntary muscular movement, hiccoughs, and respiratory irregularity during induction is definitely greater with methohexital than with thiopental. Although methohexital has been used via the intramuscular or rectal route without tissue damage, some studies suggest that the high concentration of rectal methohexital can cause mucosal damage (Miller et al., 1961). Administration of 10% methohexital to rats via the rectal route produces minor, self-limited lesions in the rectal mucosa (Hinkle and Weinlander, 1989). The recommended dose for intravenous use is 1 to 2 mg/kg, and in children younger than 5 years, 25 to 30 mg/kg can be administered rectally.

In a study of 85 children, Khalil et al. (1990) compared 25 mg/kg of rectal methohexital in a 10% and a 1% concentration. In this study, 1% was associated with a better success rate, faster onset time, high plasma concentration, and longer recovery time than the 10% concentration. In addition, they noted that the length of the rectal catheter had no effect on the pharmacodynamics of the drug. A 10% solution of methohexital at a dose of 25 mg/kg usually produced sleep in 6 to 10 minutes, which coincided with peak serum levels (Goresky and Steward, 1979; Letty et al., 1985).

Forbes et al. (1989a) reported on the plasma concentrations of 60 children after doses of 15, 20, 25, or 30 mg/kg of rectal methohexital (Fig. 7-19). The dose of 30 mg/kg resulted in significantly higher plasma concentrations for up to 20 minutes. In addition, in a separate study of 12 patients who were premedicated with 25 mg/kg of 2% rectal methohexital, Forbes et al. (1989b), using pulsed Doppler and two-dimensional echocardiography, noted a significant increase in heart rate but no change in cardiac index, stroke volume, ejection fraction, or blood pressure.

FIGURE 7-19 Plasma methohexitone concentrations after rectal administration of methohexitone 15 mg/kg, 20 mg/kg, 25 mg/kg, or 30 mg/kg. Mean ± SEM. ^*P < 0.05, 15 mg/kg vs. 30 mg/kg; ^†P < 0.05, 20 mg/kg vs. 30 mg/kg.

(From Forbes RB et al.: Pharmacokinetics of two percent rectal methohexitone in children, Can J Anaesth 36:160, 1989a.)

Audenaert et al. (1995) prospectively reviewed the effects of rectal methohexital in 648 patients. They noted that after a 30 mg/kg dose of 10% methohexital, children fell asleep 85% of the time. Sleep usually occurred in 6 minutes. Sleep was less likely to occur in patients with myelomeningocele or in patients receiving phenobarbital or phenytoin therapy. Side effects of defecation after administration occurred in 10% of patients, and hiccoughs occurred in 13% (Audenaert et al., 1995). The intravenous dose for induction using methohexital dissolved in a lipid emulsion was determined by Westrin (1992), who noted that the dose (adjusted by body weight) needed for induction in infants younger than 5 months was almost twice that for older children (Fig. 7-20).

FIGURE 7-20 Results of injection of different doses of methohexital. Each filled circle represents one patient. The position of the circle below or above the line indicates whether induction was classified as satisfactory or not satisfactory.

(From Westrin P: Methohexital dissolved in lipid emulsion for intravenous induction of anesthesia in infants and children, Anesthesiology 76:917, 1992.)

Beskow et al. (1995) compared intravenous induction of methohexital (3 mg/kg) and thiopental (7.3 mg/kg) in 41 infants aged 1 month to 1 year. In this study of short surgical procedures, recovery as measured by spontaneous eye opening after methohexital was significantly shorter than it was for thiopental.

Diazepam

Diazepam produces relatively pleasant sedation or hypnosis with few side effects and prompt recovery. Its action is caused by depression of the amygdala of the limbic system and spinal internuncial neurons. It is a specific treatment of seizure disorders in children (Lombroso, 1966; Carter and Gold, 1977). Intravenous administration of 0.2 to 0.3 mg/kg usually induces hypnosis, but the requirement varies widely. Diazepam appears to cause less cardiac depression than do barbiturates (Muenster et al., 1967; Abel and Reis, 1971).

Diazepam is metabolized by the CYP-linked monooxygenase system. In adults, the metabolite, desmethyldiazepam, is eliminated more slowly (t_½ = 150 hours) than the parent compound (t_½ = 20 to 30 hours) (Meberg et al., 1978).

The plasma half-life of diazepam and the nature of the diazepam metabolites formed vary with maturity (Morselli et al., 1974). The premature infant and the mature infant at term eliminate diazepam at a slower rate than older infants, children, and adults. In premature infants, a demethylated derivative of diazepam, N-desmethyldiazepam, could not be measured in plasma until 4 hours after injection, in comparison with older infants and children, in whom N-desmethyldiazepam was measured in the plasma by 1 hour and had peaked by 24 hours. In adults, 71% of diazepam or its metabolites was excreted in the urine, and about 10% was excreted in the feces. As an oral premedicant or intravenous induction agent, the recommended dose of diazepam is 0.1 to 0.2 mg/kg. The local pain on injection intravenously has decreased its current use, along with the availability of other short-acting benzodiazepines (e.g., midazolam).

Midazolam

Midazolam is a water-soluble, short-acting benzodiazepine. Its chemical configuration confers a pH-dependent ring phenomenon. At pH 4, the diazepine ring opens, and a highly stable water-soluble compound results. At physiologic pH values, the ring closes and thereby increases the drug lipophilic activity. Cardiovascular stability, transient mild respiratory depression, minimal venous irritation, amnesia, and short duration of action are reasons why midazolam has replaced diazepam.

Midazolam is metabolized in the liver; less than 1% is excreted unchanged in the urine. Midazolam undergoes extensive metabolism (involving CYP3A4, CYP3A5, and CYP3A7) to a major hydroxylated form, 1-OH-midazolam. The protein binding of midazolam is extensive, with a free fraction of only 3% to 6%. Midazolam has an intermediate rate of absorption (0.5 to 1.5 hours) and a bioavailability of 30% to 50%. The terminal elimination phase ranges from 1 to 4 hours (Smith et al., 1981).

In children, the pharmacokinetics of midazolam have been reported. Payne et al. (1989) noted that in healthy children, midazolam administered at 0.15 mg/kg intravenously, the volume of distribution at steady state, the elimination half-life, and the clearance were 1.29 L/kg, 70 minutes, and 9.1 mL/kg per minute, respectively. Jones et al. (1993) have also reported on the kinetics of intravenous midazolam (0.5 mg/kg) in 12 healthy children and noted that the kinetics were consistent with a three-compartment model with a volume of distribution of 1.9 L/kg, t_½β of 107 minutes, and a clearance of 15.4 mL/kg per minute. However, because the drug exhibits dose-related changes in clearance, comparisons between studies become difficult (Salonen et al., 1987). The kinetics of midazolam have also been determined after intramuscular, rectal, and oral administration. Payne et al. (1989) noted that times for peak serum concentrations after intramuscular, rectal, and oral administration were 15, 30, and 53 minutes, respectively, whereas the drug clearance and bioavailability via these three different routes were 10.4, 50.8, and 33.4 mL/kg per minute and 87%, 18%, and 27%, respectively. The lower bioavailability after oral or rectal administration is consistent with the commonly used oral dose of 0.5 mg/kg, which is almost five times higher than intravenous dosing.

In a study involving pediatric patients aged 6 months to 16 years, Reed et al. (2001) characterized the pharmacokinetic profile of both oral and intravenous midazolam using noncompartmental models. After oral administration, midazolam absorption was rapid, with adolescents absorbing the drug at half the rate seen in children younger than 12 years old. In young children, the volumes of distribution were larger; the largest volume of distribution was observed in children, whereas adolescents had a slower clearance and longer half-life after intravenous administration. There was great variability between patients in oral bioavailability, which averaged 36% (with a range of 9% to 71%) and in metabolism. An oral dose of 0.2 to 0.3 mg/kg was suggested as adequate in most children for sedation. The authors emphasized the importance of titrating intravenous dosing in the individual patient (Reed et al., 2001).

The pharmacokinetics of rectally administered midazolam in children were reported by Saint-Maurice and colleagues (1986). In this study of 16 children who were administered midazolam at 0.3 mg/kg, the terminal half-life and clearance were 106 minutes and 42.5 mL/kg per minute, respectively. Differences in the plasma clearance rates between pharmacokinetic studies involving rectal, oral, and intramuscular forms of administration were probably related to changes in drug bioavailability. Decreases in bioavailability increase the apparent drug clearance.

Commercially prepared solutions for oral midazolam are available. Literature on the pharmacokinetics and pharmacodynamics of oral midazolam has been hindered by the fact that studies have used different vehicles for administering the drug. Different vehicles affect drug absorption and, consequently, onset time and drug bioavailability (Brosius and Bannister, 2003). In addition, concurrent antacid use and grapefruit juice may increase the onset time and drug bioavailability of midazolam (Goho, 2001; Lammers et al., 2002).

Population studies involving the pharmacokinetics of midazolam in neonates have been reported. Using NONMEM and a two-compartment model, 531 midazolam concentrations from 187 infants were analyzed. The clearance and the central volume were noted to be 70 ± 13 mL/kg per hour (or 1.02 mL/kg per minute) and 591 ± 65 mL/kg, respectively. Of interest was that the clearance was 1.6 times higher in full-term neonates with a gestational age of more than 39 weeks than in neonates of fewer than 39 weeks’ gestation (Burtin et al., 1994).

The pharmacokinetics of midazolam in premature infants after both oral and intravenous administration were described by de Wildt and colleagues (2001, 2002). In premature infants with 24 to 34 weeks’ gestational age and at 3 to 11 days of life, de Wildt et al. noted the apparent volume of distribution, clearance, and half-life were 1.1 L/kg, 1.8 mL/kg per minute, and 6.3 hours, respectively, after a single 0.1-mg/kg bolus dose. In addition, the metabolite 1-OH midazolam was markedly reduced compared with reports in older children. Also of note was that in those infants exposed to indomethacin, midazolam clearance was increased (Fig. 7-21) (de Wildt et al., 2001).

FIGURE 7-21 Effect of postnatal indomethacin exposure on midazolam disposition in preterm infants. Midazolam concentration vs. time curve after a single intravenous dose (0.1 mg/kg) to preterm infants with (n = 11, open circles) and without (n = 13, solid circles) postnatal indomethacin exposure. Each dot represents mean ± SD concentration at each time point.

(Redrawn from de Wildt SN et al.: Pharmacokinetics and metabolism of intravenous medazolam in preterm infants, Clin Pharmacol Ther 70:525-531, 2001.)

In a separate study of preterm infants who were administered oral midazolam, de Wildt et al. (2002) noted that midazolam clearance was markedly decreased and that the bioavailability was 0.4. The decrease in clearance was thought to mirror the pattern of CYP3A4 intestinal and hepatic activity (de Wildt et al., 2002). The kinetics of midazolam are affected by the use of extracorporeal membrane oxygenation (ECMO); Mulla et al. (2003) noted that the volume of distribution and half-life of midazolam are significantly increased in neonates requiring ECMO.

The cardiovascular and respiratory effects of midazolam have been reported in adults. Midazolam decreases systolic and diastolic blood pressures by 5% to 10%, decreases systemic vascular resistance by 15% to 30%, and increases heart rate by 20%. Right- and left-sided filling pressures are usually unaffected. Reeves et al. (1979) observed that 0.2 mg/kg midazolam was a safe agent for induction of anesthesia in patients with compromised myocardial function. In healthy patients, no significant difference was found in the hemodynamic effects of induction doses of 0.25 mg/kg midazolam and 4 mg/kg thiopental (Lebowitz et al., 1982).

Respiratory depression is commonly associated with midazolam administration, and this respiratory depression is poorly related to dose, not reversed by naloxone, and independent of the rate of administration of the drug (Forster et al., 1983; Alexander and Gross, 1988; Alexander et al., 1992).

As an intravenous induction agent in children, midazolam in doses as high as 0.6 mg/kg was not as reliable as thiopental (Salonen et al., 1987). The most common pediatric use for intravenous midazolam other than as an anesthetic adjunct has been its use as a sedative for intensive care patients. Rosen and Rosen (1991) demonstrated the usefulness of continuous midazolam in critically ill pediatric patients. In their retrospective report of patients sedated for 4 to 72 hours who received a slow intravenous bolus (0.25 mg/kg) followed by a continuous infusion at 0.4 to 4 mg/kg per hour, they noted that all of their patients were adequately sedated, their patients’ oxygen consumption was significantly reduced, and enteral feedings were successful in all of those in whom it was attempted. However, others have noted reversible neurologic abnormalities associated with prolonged intravenous midazolam infusions (Engstrom and Cohen, 1989; Sury et al., 1989; Bergman et al., 1991).

Even with the extensive experience of intravenous midazolam in adult patients and volunteers, most of the pediatric experience with midazolam is derived from its use as a preanesthetic medication delivered via the intramuscular, oral, rectal, intranasal, and sublingual routes of administration. More than 85% of anesthesiologists responding to a survey of premedication practices indicated that they prescribe midazolam (Kain et al., 1997). In children, midazolam has been shown to produce tranquil and calm sedation, reduce separation anxiety, facilitate induction of anesthesia, and enhance antegrade amnesia (Twersky et al., 1993). Kain et al. (2000) have shown that 0.5 mg/kg of oral midazolam can produce significant anterograde amnesia at 10 and 20 minutes and anxiolysis as early as 15 minutes after administration. Numerous studies have documented the efficacy of orally administered midazolam (Feld et al., 1990; Weldon et al., 1992; Levine et al., 1993b). The appropriate dose appears to range between 0.5 and 1 mg/kg. Its time of onset ranges from 15 to 30 minutes. Oral midazolam can also be safely administered to children with cyanotic heart disease without affecting oxygen saturation (Levine et al., 1993a). Serious side effects of midazolam are uncommon. However, several postoperative behavioral problems (fearfulness, nightmares, food rejection) were observed in children premedicated with oral midazolam (0.5 mg/kg) (McGraw, 1993). Postoperative dysphoria and crying can be very difficult for families when it occurs; a duration of 15 to 20 minutes sounds short but may seem very long for those caring for such a child. In addition, McMillan et al. (1992) have noted loss of balance, dysphoria, and blurred vision in some patients receiving 0.75 and 1 mg/kg orally. Hiccups have been associated with midazolam administration via the rectal, nasal, and oral routes (Marhofer et al., 1999). One major disadvantage of oral midazolam is its bitter taste. It should be administered in a flavored syrup or drink; however, a commercially available liquid preparation is now available. Almenrader et al. (2007) reported that 14% of children refused oral midazolam in a study comparing oral clonidine with oral midazolam premedication. They also reported a trend toward an increased incidence of emergence agitation in the midazolam group, with parental satisfaction favoring clonidine. Alternatively, Ko et al. (2001) in a study of 88 children having outpatient surgery, reported a lower incidence of emergence agitation after a sevoflurane/N₂O/O₂ anesthetic when oral midazolam 0.2 mg/kg was given.

Oral midazolam has been associated with prolonged recovery times in some studies, but others, using BIS and measured end-tidal gases, did not find this problem (Viitanen et al., 1999; Brosius and Bannister 2001, 2002).

In a multicenter study involving 455 children, Coté et al. (2002) reported on the effectiveness of commercially prepared midazolam syrup. In this study, oral midazolam was effective for sedation and anxiolysis at a dose as low as 0.25 mg/kg. Doses as high as 1 mg/kg had minimal effects on respiration and oxygen saturation (Fig. 7-22).

FIGURE 7-22 Percentage of patients exhibiting anxiety from baseline to time elapsed after administration of oral midazolam. There was a positive association between dose and onset of anxiolysis (P = 0.01); a larger proportion of children achieved satisfactory anxiolysis within 10 minutes at the higher doses.

(From Coté CJ et al.: A comparison of three doses of a commercially prepared oral midazolam syrup in children, Anesth Analg 94:37, 2002.)

Rectal administration of midazolam has also been successfully used to sedate patients. Saint-Maurice et al. (1986) have shown that after a dose of 0.3 mg/kg, a maximum plasma concentration of 100 ng/mL was achieved with levels of sedation as judged by mask acceptance, with patient cooperation being satisfactory in all 16 patients. Coventry et al. (1991), in a double-blind study of pediatric patients requiring sedation for computed tomography evaluations, noted that 0.3 and 0.6 mg/kg of rectal midazolam was ineffective in providing satisfactory sedation. Spear et al. (1991) noted that the optimum dose of rectal midazolam was 1 mg/kg and that doses of 0.3 mg/kg resulted in patient struggling during anesthesia induction.

Nasal and sublingual transmucosal routes of administration have also been used for midazolam preanesthesia medications. Wilton et al. (1988) and Davis et al. (1995) demonstrated the usefulness of preanesthetic sedation of preschool children with 0.2 to 0.3 mg/kg of intranasal midazolam. Walbergh et al. (1991) determined plasma concentrations after administration of 0.1 mg/kg of intranasal midazolam. In these patients, peak plasma concentrations of midazolam occurred within 10 minutes after its administration, with peak plasma concentrations ranging from 43 to 106 ng/mL. In this study, plasma midazolam concentrations exceeded threshold sedation values for adults (40 ng/mL) as early as 3 minutes after its nasal administration and exceeded this level for as long as 30 minutes. Because intranasal midazolam can irritate the nasal mucosa, its use is limited by the volume of drug to be administered. The sublingual mucosa has a rich vascular supply and drugs are absorbed systemically, thereby eliminating hepatic first-pass metabolism. Karl et al. (1993), in a comparative study of intranasal and sublingual midazolam administration, demonstrated the two routes to be equally effective but that the sublingual route of administration had better patient acceptance.

Pandit et al. (2001) demonstrated that when aliquots of midazolam dissolved in strawberry syrup were placed on the anterosuperior aspect of the child’s tongue, 0.2 mg of midazolam was effective in 95% of patients for parental separation. When midazolam was administered sublingually, Khalil et al. (1998) noted that in children aged 12 to 129 months who received either placebo or 1 of 3 doses of midazolam (with none of these children receiving placebo), 28% of those receiving 0.25 mg/kg, 52% of those receiving 0.5 mg/kg, and 64% of those receiving 0.75 mg/kg of midazolam showed satisfactory sedation (drowsy) 15 minutes after drug administration. Children receiving the two higher doses of midazolam (0.5 and 0.75 mg/kg) accepted mask induction willingly, whereas the group receiving 0.25 mg/kg resembled the placebo group.

Flumazenil

Flumazenil blocks the effects of benzodiazepines on the GABAergic inhibition pathway in the CNS. Flumazenil does not have significant agonist activity of its own and does not appear to reverse the effects of opioids. Flumazenil has a short duration of action. Its plasma half-life is between 0.7 and 1.3 hours. It is metabolized and cleared by the liver and excreted in the urine (Rocari et al., 1986). Adverse effects of flumazenil include nausea, vomiting, blurred vision, sweating, anxiety, and emotional lability. Serious adverse effects include seizures and cardiac dysrhythmias; these events have been associated with patients physically dependent on benzodiazepines, patients with epilepsy, and patients having taken multiple drug ingestions or overdoses. Clinical trials in adults suggest a use of flumazenil in reversing the effects of conscious sedation, general anesthesia in benzodiazepine overdose, and hepatic encephalopathy.

Use of flumazenil in pediatric patients has been related to clinical situations requiring benzodiazepine reversal in anesthesia and for the treatment of benzodiazepine overdose (Roald and Dohl, 1989; Jones et al., 1991). Doses of flumazenil varied between 0.005 and 0.1 mg/kg, with 0.01 mg/kg being the most commonly used dose. In a study of 107 children undergoing procedural sedation, Shannon et al. (1997) noted that a mean dose of 0.017 mg/kg of flumazenil was used to reverse a mean midazolam dose of 0.18 mg/kg. Because of its short half-life relative to the half-life of most benzodiazepines, resedation is a common finding after flumazenil use. Consequently, repeat administrations and careful patient observations are necessary (Jones et al., 1993).

Etomidate

Etomidate is a potent, short-acting, nonbarbiturate sedative-hypnotic agent without analgesic properties. After a single intravenous bolus injection, it has a rapid onset (5 to 15 seconds) with a peak effect at 60 seconds and a short duration of action (3 to 5 minutes) that is terminated by redistribution. It produces a central depressant effect through GABA mimetic action. Administered intravenously, it has been used for induction and maintenance of anesthesia; use for prolonged sedation in critically ill patients has become very uncommon because of steroid-synthesis effects. Little information is available about the use of etomidate in infants and small children.

Etomidate is metabolized in the liver. Only 2% of the drug appears unchanged in the urine. Etomidate causes little change in cardiovascular function in either healthy or compromised patients (Guldner et al., 2003). In a study of children with atrial septal defects (ASDs) undergoing cardiac catheterization, Sarkar et al. (2005) noted that induction doses of intravenous etomidate had no significant effect on the hemodynamics or on the shunt fraction. Myoclonic movements that are not associated with epileptiform electroencephalographic activity occur in 30% to 75% of patients after induction with etomidate (Ghonheim and Yamanda, 1977). Pain at the injection site is a common side effect. A new formulation of etomidate dissolved in a fat emulsion of medium and long-chain triglycerides is available. A study in children using this formulation reported a low incidence (5%) of pain at injection; however, a higher incidence of myoclonic movements (85%) is reported as well (Nyman et al., 2006).

Etomidate has both anticonvulsant and proconvulsant qualities. In patients with known seizure disorders, etomidate can produce epileptiform activity (Ebrahim et al., 1986; Modica et al., 1990). A major side effect limiting etomidate use is its suppression of adrenal steroid synthesis and reports of increased mortality after its use (Ledingham and Watt, 1983). Etomidate blocks adrenal steroid synthesis through inhibition of two mitochondrial enzymes dependent on CYP: cholesterol side-chain cleavage enzyme and 11β-hydroxylase (Wagner et al., 1984). The inhibition of steroid synthesis occurs with both prolonged continuous infusions and with single induction doses (Longnecker, 1984; Wagner and White, 1984). Dönmez et al. (1998) noted in a randomized prospective study of 30 children undergoing cardiopulmonary bypass that when etomidate (0.3 mg/kg) was used as an induction agent, it significantly suppressed the increased cortisol levels associated with the stress responses of surgery and cardiopulmonary bypass. In critically ill children a single bolus dose has shown impaired adrenal function associated with increased mortality (den Brinker et al., 2008). In adult trauma patients, single-dose etomidate administration for rapid-sequence intubation was associated with chemical evidence of adrenal suppression, increased length of stay in the intensive care unit (ICU), and an increased number of days using a ventilator (Hildreth et al., 2008). However, other studies of adults suggest that for ICU patients receiving etomidate for induction, their clinical outcome and therapy were no different from patients induced with other sedative hypnotic agents (Ray and McKeown, 2007). For induction of anesthesia, the recommended intravenous dose is 0.3 to 0.4 mg/kg. Recent studies by Cotton et al. (2009) with an etomidate analog suggests that the analog undergoes ultra rapid metabolism, maintains the drug’s sedative properties, and has no adrenal suppression. It is probably best to avoid etomidate use in patients with adrenally suppressed states.

Propofol

Propofol is an alkylphenol that is formulated in 10% soybean oil, 2.25% glycerol, and 12% purified egg phosphatide. This form of reconstitution is used because of anaphylactic reactions that occurred when propofol was reconstituted with polyethoxylated castor oil (Cremophor-EL). The rapid redistribution and metabolism of propofol result in a short duration of action and allow for the drug to be administered via repeated injections or continuous infusions with minimal accumulation. Kinetic studies in both adults and children reveal a drug with a large steady-state volume of distribution, a slow elimination half-life, and a rapid clearance. Glucuronidation of propofol is a major route of elimination. Uridine 5-diphosphate-glucuronosyltransferases (UGTs) are the drug metabolizing enzymes for phase II. Extrahepatic metabolism of propofol occurs, and at these extrahepatic sites, conjugation is governed by different exons than in the liver (Takahashi, 2008). Mutations in these locations can markedly affect glucuronidation. In radiolabeled isotope studies, 88% of the radioactivity is excreted in the urine, 2% is excreted in the feces, and the remainder is excreted as 1- and 4-glucuronides and 4-sulfate conjugates. In patients with hepatic and renal impairments, no statistically significant alterations occur in the pharmacokinetics. Because the clearance of the drug exceeds the capacity of the liver blood supply, extrahepatic sites of metabolism appear to be involved with the clearance of propofol. These extrahepatic sites of metabolism were suggested in studies of patients undergoing liver transplantation where metabolic products of propofol metabolism were produced when propofol was administered only during the anhepatic phase of the operation. The effect of fentanyl on propofol clearance is not clear. In studies by Cockshott et al. (1987), fentanyl decreased propofol clearance, whereas in other studies, no effect was noted (Saint-Maurice et al., 1989; Gill et al., 1990).

Another important aspect of propofol pharmacokinetics is that the drug can limit its own clearance. Propofol is eliminated by hepatic conjugation to inactive metabolites, which are excreted by the kidneys. A 2-mg/kg bolus dose of propofol for the induction of anesthesia can reduce blood flow to the liver by 14%. Bolus doses of propofol may cause a small but persistent change in blood flow to the liver, resulting in decreased clearance and higher-than-predicted plasma concentrations.

The pharmacokinetics of propofol in children have been described by numerous investigators (Saint-Maurice et al., 1989; Jones et al., 1990; Marsh et al., 1991; Kataria et al., 1994; Knibbe et al., 2002; Zuppa et al., 2003). In computer-controlled infusions of propofol in children younger than 10 years, Marsh et al. (1991) noted the volume of the central compartment to be 0.34 L/kg and the clearance of the drug to be 34.3 mL/kg per minute. Kataria et al. (1994) using three different pharmacokinetic modeling approaches, analyzed the kinetics of single-bolus and continuous infusions of propofol in children. In all three models, the pharmacokinetics were well described by a three-compartment model with a central compartment of 0.52 L/kg and a clearance of 34 mL/kg per minute.

The pharmacokinetics of propofol were studied in a small number of children after cardiac surgery. When propofol was used to provide sedation for 6 hours, Knibbe et al. (2002), using population kinetics, reported propofol to fit a two-compartment model with a clearance of 35 mL/kg per minute and a central compartment of 0.78 L/kg. In addition, the authors suggested that children may have a lower pharmacodynamic sensitivity to propofol in that higher plasma concentrations were needed to maintain sedation than those reported in adults.

The pharmacodynamics of propofol have been well described and reviewed (Shafer, 1993). Because of the pharmacokinetic properties of propofol, infusions allow for more rapid decreases in plasma concentrations and faster patient recoveries from anesthesia (Fig. 7-23) (Mirakhur, 1988; Borgeat et al., 1990; Watcha et al., 1991; Larsson et al., 1992; Lebovic et al., 1992; Nightingale and Lewis, 1992; Reimer et al., 1993; Shafer, 1993). One of the newer pharmacokinetic terms is context-sensitive half-life, used to describe the time to decrease drug concentration by 50% after variable infusion durations. Such values can show how long a drug’s effects may persists after discontinuing infusions, based on how long it has been infused. McFarlan et al. (1999) reported a propofol infusion simulation to keep blood concentration of propofol at 3 mcg/mL in children aged 3 to 11 years. After a bolus of 2.5 mg/kg, infusions rates were 250 mcg/kg per minute for 15 minutes, then 216 mcg/kg per minute for 15 minutes, 183 mcg/kg per minute for 30 minutes, 166 mcg/kg per minute for 1 hour, and 150 mcg/kg per minute for the second and fourth hours. The predicted context-sensitive half-life in children was 10.4 minutes (for a 1-hour infusion) to 19.6 minutes (4-hour infusion), compared with values of 6.7 to 9.5 minutes in adults. Engelhardt et al. (2008) prospectively used this changing infusion schema to reach predicted propofol concentrations in 17 healthy children between 1 and 6 years of age. They found concentrations were higher than predicted in the first 30 minutes (7.1 mcg/mL vs. 6.6 mcg/mL) but the differences at 30, 50, and 70 minutes were not significant and no child needed rescue doses of propofol.

FIGURE 7-23 Curves showing time required for 50% decreases in propofol and thiopental concentrations after discontinuation of a continuous infusion.

(From Shafer SL: Advances in propofol pharmacokinetics and pharmacodynamics, J Clin Anesth 5:14S, 1993.)

In general, with induction doses of propofol, blood pressure decreases, as does systemic vascular resistance. Changes in heart rate are variable, and cardiac output decreases slightly. In studies evaluating propofol requirements for induction of anesthesia in children, Manschot et al. (1992) noted that in children aged 3 to 15 years receiving 5 mcg/kg of alfentanil to reduce the pain of propofol injection, age-related differences in propofol requirements were demonstrated. In children aged 10 to 15 years, 1.5 mg/kg of propofol was sufficient to induce sleep, whereas in children aged 3 to 9 years, a dose of 2.5 mg/kg was needed. In a study by Hannallah et al. (1991) in which alfentanil was not administered, the ED₅₀ and ED₉₅ for loss of eyelash reflex were 1.3 and 2 mg/kg, whereas the ED₅₀ and ED₉₅ for induction of anesthesia were 1.5 and 2.3 mg/kg, respectively. Westrin (1991), in a study of infants aged 1 to 6 months and children aged 10 to 16 years, noted that the ED₅₀ of propofol was 3 mg/kg for infants and 2.4 mg/kg for the older children. In all three of these studies, propofol was administered over 10 to 30 seconds. However, as with most hypnotic agents, propofol also demonstrates a rate-dependent induction. Stokes and Hutton (1991) demonstrated that with the use of slower infusion rates, induction time for anesthesia increases but smaller doses could be used.

Peeters et al., (2006) studied propofol pharmacokinetics and pharmacodynamics in unventilated infants after craniofacial surgery. Twenty-two infants, aged 1 month to 2 years, received propofol at 33 to 66 mcg/kg per minute in the ICU, based on Comfort-B scores and bispectral index (BIS) monitoring. Population kinetic analysis using NONMEM showed propofol kinetics was best described by a two-compartment model. Body weight was a significant covariate (i.e., use of body weight made the model fit the measured concentrations more closely). Clearance was 0.169 L/min (or 77 mL/min per kilogram), steady-state volume of distribution 144 L (or 16.1 L/kg) and central volume 20.3 L (or 2.3 L/kg). These values are much higher than those reported in children receiving ventilation. The importance of dose titration was emphasized by the great interpatient variability in propofol effect on Comfort-B scores or BIS readings.

In patients with congenital heart disease, Gozal et al. (2001) demonstrated that despite lower systemic and pulmonary pressures, propofol did not modify the characteristics of the patient’s underlying intracardiac shunts.

In normal children aged 1 to 6 years, Karsli et al. (2002), using transcranial Doppler, noted that propofol decreases cerebral blood flow velocity and that there is a relationship between cerebral blood flow velocity and propofol dosing. In addition, Wilson-Smith et al. (2003) noted that in healthy children who were given propofol for their elective surgery, the effects of nitrous oxide on cerebral blood flow velocity were preserved.

In addition to its anesthetic action, propofol appears to have antiemetic properties. In adult patients, Borgeat et al. (1992) demonstrated that 10 mg of propofol administered in the recovery room was effective in reducing the incidence of nausea and vomiting. Watcha et al. (1991) noted that in pediatric patients undergoing strabismus surgery, propofol alone effectively decreased the incidence of postoperative emesis (23%) compared with a similar group of patients anesthetized with halothane and nitrous oxide and supplemented with prophylactic droperidol (50%). However, in patients who received propofol and nitrous oxide, Watcha et al. (1991) noted that the incidence of emesis increased significantly (60%). Weil et al. (1993) also noted the antiemetic effect in pediatric patients with strabismus who were anesthetized with propofol and nitrous oxide compared with patients anesthetized with halothane and nitrous oxide. This antiemetic effect of propofol was even more pronounced in patients who received no opioids. Reimer et al. (1993) noted no difference in the incidence of emesis between pediatric patients undergoing strabismus repair who were anesthetized with halothane and nitrous oxide and those receiving propofol in oxygen or propofol with nitrous oxide. Differences between studies with regard to the antiemetic effect of propofol may be a function of the basic design of each study. Variations in premedications, opioid administration, and postoperative fluid intake may be factors that make comparisons of the studies difficult.

The antiemetic effects of propofol have also been demonstrated in pediatric patients undergoing short ear, nose, and throat surgical procedures and ambulatory surgical procedures (Borgeat et al., 1990; Martin et al., 1993).

In patients undergoing radiofrequency ablation, a procedure that is associated with an incidence of emesis as high as 60%, Erb et al. (2002) noted that propofol-based anesthesia was associated with a markedly decreased incidence of nausea (21%) and emesis (6%) compared with rates of nausea and vomiting of 63% and 55%, respectively, in children anesthetized with isoflurane.

Side effects from propofol include tolerance to the drug, pain on injection, spontaneous excitatory movements, and anaphylactic reactions. Tolerance has been reported in a pediatric patient undergoing numerous exposures for radiation therapy (Deer and Rich, 1992). Pain from injection is a common problem with propofol administration and may be related to the size of the vein in which it is administered. Westrin (1991) noted that pain during the injection occurred more often in the infants (50%) than in the older children (18%). The addition of 5 to 15 mcg/kg of alfentanil, 1% lidocaine (1 mg), or 0.1 mg/kg lidocaine can markedly attenuate the pain on injection (Valtonen et al., 1989; Manschot et al., 1992; Kwak et al., 2009). The addition of thiopental and the use of inhaled nitrous oxide also have been shown to attenuate the pain on injection (Beh et al., 2002; Cox, 2002).

Involuntary motor movements have been associated with propofol, and these spontaneous movement disorders appear to occur in the absence of epileptic form activity on electroencephalography (Borgeat et al., 1993; Reynolds and Koh, 1993). Anaphylactic reactions have also been reported. Initial studies with propofol using 10% polyethoxylated castor oil as a solubilizing agent had reported instances of anaphylactic reactions (Briggs et al., 1982). Laxenaire et al. (1992) have reported on 14 patients with life-threatening reactions within minutes after receiving propofol in its current preparation. In some patients, these anaphylactic reactions occurred during the patient’s first exposure to propofol.

Because of its lipid base, propofol has been associated with bacterial growth and patient infection if strict aseptic techniques during handling are not observed. Because of patient safety concerns, 0.005% ethylenediaminetetraacetate (EDTA) or metabisulfite was added to the formulation by different manufacturers. In a study comparing propofol with and without EDTA, Cohen et al. (2001) noted no differences in clinical profiles between the two drugs and noted that both formulations lower ionized calcium without any apparent clinical effect.

A major concern with propofol administration is the development of the propofol infusion syndrome (PRIS). PRIS has been defined as arrhythmias during the infusion plus one or more of the following: lipemic plasma, hepatomegaly, metabolic acidosis with or without an increase in serum lactate, or rhabdomyolysis with myoglobinuria. The occurrence of deaths in infants, children, and adults has raised concerns regarding the safety of propofol infusions for ICU-patient sedations. The pathogenesis of PRIS is unclear. Proposed mechanisms include enzyme block steps in mitochondrial fatty acid oxidation and inhibition of β-adrenergic receptors and calcium channel function. The rare occurrence of PRIS suggests a genetic susceptibility. PRIS is associated with concomitant catecholamine and steroid administration and high-dose infusion. Although monitoring of biochemical markers has been proposed to detect the development of PRIS, it may result in a false sense of security (Veldhoen et al., 2009).

Ketamine

Ketamine is a racemic, nonbarbiturate cyclohexamine derivative that produces dissociation of the cerebral cortex from the limbic system. Ketamine appears to block afferent impulses in the diencephalon and associated pathways of the cortex, sparing the reticular formation of the brain stem. This may be the mechanism of its action. It may also act on the brain stem (Domino et al., 1965). There is often electroencephalographic seizure activity, particularly in the limbic system and cortex, without clinical manifestations (Schwartz et al., 1974). Clinically, a ketamine anesthetic produces effective sedation and analgesia, but patients may keep their eyes open. Many reflexes are preserved. Preservation of gag reflex, laryngeal irritability, and continued muscle tension occur. Intravenous doses of 2 mg/kg produce a highly predictable response in children. On a milligram-per-kilogram basis, the amount of ketamine required to prevent gross movements is four times greater in infants younger than 6 months than in 6-year-old children (Lockhart and Nelson, 1974).

White et al. (1980) compared both the l- and d-isomers of ketamine in adult surgical patients with respect to the efficacy and side effects of these isomers. In this study, they noted that the d-isomer produced the most satisfactory anesthetic state and the lowest incidence of negative emergence reactions, whereas the l-isomer produced the least satisfactory anesthesia and the highest incidence of emergence reactions.

The pharmacokinetics of ketamine in patients of different ages were determined (Table 7-8). In infants younger than 3 months old, the volume of distribution was similar to that in older infants but the elimination half-life was prolonged. Clearance was reduced in the younger infants; reduced metabolism and renal excretion in the young infant are the likely causes. Ketamine is metabolized in the liver, and its major metabolite is norketamine. Norketamine has about 30% of the clinical activity of ketamine.

In the anesthetic state associated with ketamine, respiration and blood pressure are usually well maintained. The use of ketamine in infants, particularly at the high doses required for lack of movement, has been associated with respiratory depression and apnea (Eng et al., 1975). Generalized extensor spasm with opisthotonos also has been seen in infants (Radney and Badola, 1973). In addition, acute increases in pulmonary artery pressure have occasionally occurred in infants with congenital heart disease during ketamine anesthesia for cardiac catheterization. Studies suggest that pulmonary vascular resistance is not changed by ketamine in infants with either normal or elevated pulmonary vascular resistance, as long as the airway and ventilation are maintained (Hickey et al., 1984; Morray et al., 1984). In a study of 60 children with congenital heart disease randomized to receive propofol infusion or propofol with ketamine 0.5 mg/kg during cardiac catheterization, Akin et al. (2005) reported that hypotension and bradycardia were higher in the group that received propofol alone. Williams et al. (2007) studied ketamine 2 mg/kg bolus over 5 minutes followed by infusion at 10 mcg/kg per minute in 15 children with pulmonary hypertension having cardiac catheterization with sevoflurane (1 MAC decreased to 0.5 MAC after ketamine) and spontaneous ventilation. No changes in pulmonary artery pressure or resistance index were found.

The mechanism of cardiorespiratory stimulation has not been entirely clarified. Dowdy and Kaya (1968), Traber et al. (1970), and other groups have shown that there is a direct negative inotropic action on the denervated heart. In the presence of intact sympathetic and autonomic nervous systems, however, a pressor effect causes increased blood pressure, heart rate, and cardiac output, a response present in all ages. This serves as a most valuable adjunct in the management of poor-risk patients but is a contraindication in the presence of hypertension or tachycardia. In their investigation of ketamine, Dowdy and Kaya (1968) also found evidence of antiarrhythmic activity.

Ketamine increases cerebrospinal fluid pressure significantly for 5 to 15 minutes, but as shown by Dawson et al. (1971), the increase may be held within acceptable limits by pretreatment with thiopental (Gardner et al., 1971; Lockhart and Jenkins, 1972). Elevation of intraocular pressure also occurs after ketamine administration. In a group of 15 children, Yoshikawa and Murai (1971) noted an average increase of 30% that was maximum within 15 minutes after administration of ketamine and evident for approximately 30 minutes. In addition to the elevation of intraocular pressure, nystagmus limits its usefulness in eye surgery.

Ketamine had the advantage of a clean record with no known toxic effects on the liver, kidneys, or other organ systems. However, it has been the most thoroughly studied anesthetic/sedative agent implicated in causing neuronal apoptosis after exposure in newborn animal model studies.

A major drawback to ketamine administration in older children is the high incidence of hallucinations and bad dreams. In adults, this occurs in 30% to 50% of patients, and in prepubescent children, the incidence is noted at 5% to 10%. Hallucinations were uncommon in children, but the awakening phase may entail considerable excitement (Wilson et al., 1970).

Ketamine can be administered orally, and part of its effect is secondary to its metabolite norketamine. Gutstein and colleagues (1992) compared oral premedication with ketamine at either 3 or 6 mg/kg. With 3 mg/kg, 73% of the children were sedated within 30 minutes. At the 6 mg/kg dose, 100% of the patients were sedated, and 67% tolerated intravenous cannulation. Onset times for the 3- and 6-mg/kg dose groups were 19.6 and 11.2 minutes, respectively (Gutstein et al., 1992).

Use of low-dose ketamine as an analgesic adjunct has emerged in select populations in recent work. Aouad et al. (2008) conducted a prospective randomized double-blind comparison of propofol alone (1 mg/kg) to propofol and ketamine (0.5 mg/kg of each) in 63 children undergoing anesthesia for oncologic procedures. The combination group had fewer patients needing rescue propofol (83% vs. 100%) or fentanyl (43% vs. 75%) and showed more stable hemodynamics. However, 40% of the combination group had agitation during recovery (vs. 6% with propofol alone). Slavik and Zed (2007) reviewed studies of ketamine and propofol for procedural sedation and anesthesia using MEDLINE, EMBASE, and the Cochrane databases and found eight clinical trials to include. They found that the ideal ratio of ketamine to propofol was unclear; better clinical efficacy of the combination over propofol alone was not shown; better hemodynamic and respiratory status was demonstrated in some studies; and at higher ketamine doses, greater adverse effects were apparent (Slavik and Zed, 2007).

Several investigators have studied low dose-ketamine given intravenously or into the tonsillar bed in children undergoing tonsillectomy with conflicting results (O’Flaherty et al., 2003; Conceicao et al., 2006; Batra et al., 2007; Dal et al., 2007; Erk et al., 2007; Abu-Shahwan, 2008; Honarmand et al., 2008). Most studies involved 60 to 100 children and compared the perioperative course looking at pain scores, rescue analgesics, and side effects compared with patients in a control group (receiving saline). Ketamine at doses less than 0.25 mg/kg were ineffective, and at 0.5 mg/kg results were positive in some studies and negative in others. The addition of low-dose ketamine infusions in 11 children with advanced cancer and pain that was inadequately treated with high doses of opiates (0.1 to 0.2 mg/kg per hour titrated up to 0.5 mg/kg per hour in 3 of 11 patients) improved pain control and allowed decreases in opiate pain medications in 8 (Finkel et al., 2007).

Clonidine

Clonidine is an α₂-adrenergic agonist that has been used as a premedication, anesthetic adjunct, extender for postoperative analgesic duration, and to prolong the analgesia associated with regional anesthetic blocks. In one prospective, randomized, blinded study, 60 children (aged 5 to 11 years) received placebo, 2 mcg/kg or 4 mcg/kg oral clonidine 100 minutes before inhalation induction of anesthesia with halothane/N₂O/O₂ (Nishina et al., 1996). Sedation, separation from family, and tolerance to mask application were better in the 4 mcg/kg clonidine group. Halothane was titrated to maintain blood pressure and heart rate within 20% of baseline, and the 4-mcg/kg group used 45% less halothane. No delay in transfer to ward postoperatively was found (15 to 17 minutes). Heart rates were slower in the group receiving 4 mcg/kg, but bradycardia did not occur, although all children received atropine 30 mcg/kg with the premedication.

Bergendahl et al., (2006) reviewed clonidine use in pediatric anesthesia both as premedication and for intraoperative use. Rectal absorption is rapid, and clonidine shows high bioavailability. Some studies included in this review found improved postoperative analgesia with oral clonidine, decreased vomiting, and shivering. Postoperative confusion and agitation in young children receiving clonidine compared with children receiving placebo or midazolam was reported by some. Persistence of postoperative sedation (or calmness) is a desirable feature to some assessors.

Addition of clonidine to local anesthetics for caudal blocks has been successful in extending duration of analgesia in most studies, although some increases in side effects have occurred in some studies. Two case reports of caudal blocks with clonidine in formerly premature infants with the appearance of postoperative apnea have limited its use in this population.

Atropine use is often recommended to minimize heart rate decreases, and this extra step may be a partial explanation for the lack of more extensive use of this agent.

Potts et al. (2007) recently reported a population analysis of clonidine in children using NONMEM and reporting their results using allometric scaling (to a standard of 70 kg). Published data from four studies (two intravenous, one rectal, and one epidural clonidine) were combined with an open-label group of children who received clonidine 1 to 2 mcg/kg after cardiac surgery (380 observations). The mean age was 4 years, and the mean weight was 17.8 kg. Clearance was 14.6 L/hr per 70 kg, central volume was 62.5 L/70 kg, and peripheral volume was 119 L/70 kg with the distribution half-life of 12 minutes and elimination half-life of 9 hours. At birth, clearance was low at 3.8 L/hr per 70 kg, reaching 82% of adult values by age 1 year. Absorption was slower from epidural sites than the rectum (Fig. 7-24; Table 7-9). Simulations showed context-sensitive half-lives increased with infusion duration (1, 3, 6, and 10 hours) and decreased with increasing age (Table 7-10). The relatively long elimination half-life and importance of intact renal function for clearance may be features explaining the current preference for the newer α₂-agonist dexmedetomidine.

FIGURE 7-24 Typical time-concentration profiles for a 5-year-old child (20 kg) given intravenous, epidural, and rectal clonidine (2.5 mcg/kg⁻¹).

(From Potts AL et al.: Clonidine disposition in children: a population analysis, Pediatr Anesth 17:924, 2007.)

Dexmedetomidine

One of the newer additions to the list of intravenous sedative and anesthetic drugs is dexmedetomidine. It is a selective α₂-agonist with sedative and analgesic properties. Dexmedetomidine is more selective for the α₂-adrenoreceptor with a reported ratio of α₂ to α₁ of 1600:1, which is seven to eight times higher than that reported for clonidine. Its sedative effect is attributed to hyperpolarization of noradrenergic neurons in the locus coeruleus (Carollo et al., 2008). This suppression of locus coeruleus neurons is similar to normal sleep. It provides respiratory stability, with no ventilatory depression accompanying its sedative, anxiolytic, and analgesic effects in adults. Mahmoud et al. (2009) have shown dexmedetomidine to be a useful anesthetic agent for magnetic resonance imaging (MRI) evaluations of airways in children with obstructive sleep apnea (OSA). Although hemodynamic effects of hypotension or bradycardia are less commonly seen than with clonidine, they have been reported. Dexmedetomidine has also been suggested as a novel treatment for atrial and junctional tachyarrhythmias (Chrysostomou et al., 2008). Tobias and Berkenbosch (2004) reported early experience with dexmedetomidine infusions in 30 ventilated infants and children, comparing it with midazolam. Decreases in morphine use were found in the high-dose dexmedetomidine group (0.5 mcg/kg per hour) compared with those receiving midazolam (0.1 mg/kg per hour). Heart rates were slower in the dexmedetomidine group, but hypotension was not seen. In pediatric cardiac surgical patients, Chrysostomou et al. (2009) suggest that higher doses may be needed in the younger patients.

In neurosurgeries requiring an intraoperative “awake” period to assess patient responses during deep brain stimulation for Parkinson’s disease, or in surgeries near speech areas, or in surgery for epilepsy, dexmedetomidine has proved very useful to allow anesthesia without intubation (Mack et al., 2004).

Koroguli et al. (2005) noted that in children aged 1 to 7 years undergoing MRI that dexmedetomidine was superior to midazolam. However, in a separate study, Koroguli et al. (2006), also noted that dexmedetomidine has slower recovery and discharge compared with propofol. The slower recovery times with dexmedetomidine compared with propofol have also been observed by Heard and others (2008).

Hammer and colleagues (2008) reported dexmedetomidine effects on cardiac electrophysiology in 12 children (aged 5 to 17 years). One mcg/kg administered over 10 minutes and then 0.7 mcg/kg per hour for 10 minutes led to decreased heart rates, increased blood pressure, and depressed sinus and atrioventricular (AV) node function. Respiratory rate and end-tidal CO₂ during spontaneous ventilation were unchanged (Hammer et al., 2008). Caution in dexmedetomidine use for patients who are poorly tolerant of bradycardia or at risk for AV nodal block was emphasized. Jooste and others (2010) demonstrated in post-cardiac transplant patients that a rapid IV bolus dose had a transient increase in systemic and pulmonary pressures, as well as a decrease in heart rate. These transient changes were more pronounced in the systemic system as opposed to the pulmonary circulation.

Because dexmedetomidine has pharmacolytic properties that simulate normal sleep, Mahmoud et al. (2009) have demonstrated its usefulness in patients with sleep apnea.

Pharmacokinetics for dexmedetomidine in adults demonstrate desirable characteristics for use as titrated intravenous infusions for sedation and anxiolysis. Its elimination half-life is 2 hours (8 hour for clonidine), and its distribution half-life is 6 minutes (Carollo et al., 2008). Several groups have reported pharmacokinetics in children of dexmedetomidine. Petroz et al. (2006) studied 36 children, 18 from Canada and 18 from South Africa, in an open-label study. Blood was sampled for 24 hours after 10-minute infusions of 2, 4, or 6 mcg/kg per hour and analyzed by NONMEM. Concentrations were below detection after 6 hours; a two-compartment model central volume of distribution of 0.8 L/kg was constructed with a systemic clearance of 0.013 L/kg per minute and an elimination half-life of 110 minutes. Table 7-11 lists the pharmacokinetic values from this and other studies; a puzzling finding was dexmedetomidine concentrations that were consistently 30% higher in Canadian children, which was thought to have occurred because of a handling problem with specimens. Context-sensitive decrement times did not increase after 90- to 120-minute infusions with the context-sensitive half-life, plateauing at about 70 minutes and the 80% decrement time at about 220 minutes. Heart rate and blood pressure decreased over the hour after the infusion and decreased with higher infusion doses, whereas respiration and oximetry were stable. Sedation lasted less than 1 hour. Vilo et al. (2008) studied eight children (aged 2 to 11 years) and eight infants (aged 1 to 23 months) after receiving dexmedetomidine at 1 mcg/kg. Analysis of blood samples used noncompartmental methods. Data are summarized in Table 7-11. Clearance was similar in the two age groups, but volume of distribution (steady state) was larger in the younger group, making the half-life longer. Interindividual variation was large, especially in the infants. All were sedated by the dexmedetomidine but easily aroused, and five of the eight children needed extra sedation during MRIs. Based on the volume at steady state, younger children would be predicted to need larger initial dexmedetomidine doses with similar maintenance rates to older children or adults.

Potts et al. (2008) looked at population pharmacokinetics in 45 children after cardiac surgery aged 4 days to 14 years (mean age of 3.4 years). Population parameter estimates for a two-compartment model using NONMEM were reported using allometric scaling to 70 kg. In Table 7-11 the results are corrected for comparison with others’ work. Clearance increased from 15.5 L/hour per 70 kg at birth to reach 72% adult values at 6 months and 87% by 1 year (Table 7-12). Clearance in children at 39.2 L/hour per 70 kg is slightly less than adult values of 44.8 to 52.5 L/hour per 70 kg. Volumes of distribution were 103.5 to 126 L/70 kg, and half-lives were 12 minutes (α, distribution) and 2.3 hours (β, elimination), similar to adult reports. Context-sensitive half-lives after infusions of 1, 3, and 10 hours were longer in neonates (1.24 for 1 hour to 2.07 for 10 hours) than at age 1 year (0.49 to 1.09 hours) or in adults (0.49 to 1.45 hours). Large intersubject variability was attributed to age and size differences (Fig. 7-25).

FIGURE 7-25 Simulated dexmedetomidine concentration-time profile after a dosage regimen of 1 mcg/kg⁻¹ for 10 minutes and a maintenance infusion of 0.7 mcg/kg⁻¹ per hour⁻¹ for 50 minutes in a 5-year-old child (20 kg), with 95% prediction interval simulated using 1000 children with an age range of 2.4 to 14.5 years. Pharmacokinetic parameters for the simulation are those determined from this study. A concentration of 0.304 mcg/L⁻¹ is associated with recovery from sedation (return to baseline alertness) and is represented by the dashed line.

(From Potts AL et al.: Dexmedetomidine disposition in children: a population analysis, Pediatr Anesth 18:722, 2008.)

In addition to intravenous administration, dexmedetomidine can also be administered intramuscularly and intranasally. Dyck et al. (1993) demonstrated a 73% bioavailability after intramuscular administration in adult volunteers and that intramuscular injection did not result in the biphasic hemodynamic response observed with intravenous administration. Intranasal doses of 1 to 2 mcg/kg have been shown to induce sedation in children (Yuen et al., 2007, 2008; Talon et al., 2009). Transmucosal dexmedetomidine has a bioavailability of 80% (Anttila et al., 2003).

In addition to its use as a sedative agent, dexmedetomidine has been demonstrated to decrease the incidence of postoperative emergence agitation and effectively treat postemergence shivering. Ibacache et al. (2004) noted that a single dose of dexmedetomidine (0.3 mcg/kg) markedly attenuated the incidence of sevoflurane-associated emergence agitation, while Easley et al. (2007) reported that 0.5 mcg/kg of dexmedetomidine effectively stopped postoperative shivering in children within 5 minutes.

Nalbuphine

Nalbuphine is a phenanthrene opioid derivative, structurally similar to oxymorphone and naloxone. It has an analgesic potency equivalent to morphine with a respiratory depressant and analgesic ceiling effect between 150 and 300 mcg/kg (Beaver and Feise, 1978; Romagnoli and Keats., 1980; Gal and DiFazio, 1982; Julien, 1982). After intravenous administration in adults, it has an elimination half-life of 135.5 ± 55.4 minutes with a clearance of 217.6 mL/min (Sears et al., 1987). After intramuscular and subcutaneous administration, bioavailability is high, with mean values of 83% and 79%, respectively. Absorption is rapid with a C_max of 59.96 ± 9.52 ng/mL and 56.14 ± 14.48 ng/mL after intramuscular and subcutaneous injection of 20 mg in adults (Lo et al., 1987). After oral administration the bioavailability is low at 11.8% because of the high clearance rate (Aitkenhead et al., 1988). In children the distribution is similar to adults, but the elimination half-life is shorter (57 ± 14 minutes) (Jaillon et al., 1989). In a study in children receiving 0.3 mg/kg of nalbuphine rectally, the maximum plasma concentration achieved was 24 ± 15 ng/mL in a mean time of 25 ± 11 minutes with an elimination half-life of 162 ± 42 minutes (Bessard et al., 1997).

Nalbuphine has been used for treatment of opioid-induced pruritus. In adults, studies show similar effects to naloxone (Penning et al., 1988; Kendrick et al., 1996). However, one study in pediatrics did not have a similar finding, suggesting that nalbuphine may not be as effective in treating opioid-induced pruritus in children (Nakatsuka et al., 2006). Nalbuphine has also been used to decrease the incidence of emergence delirium after general anesthesia with sevoflurane as the sole agent for nonpainful procedures in children. Dalens et al. (2006) report that administration of a single dose of 0.1 mg/kg of nalbuphine before extubation decreases by 30% the development of emergence delirium without prolonging the postanesthesia recovery time when compared with placebo. The use of nalbuphine as a sole agent for postoperative pain treatment is scarce. There are two studies describing its use with positive reports after tonsillectomy and adenoidectomy procedures (Habre and McLeod, 1997; Van den Berg et al., 1999). However, the ceiling analgesic effect makes its use difficult for moderate to severe pain treatment.