Pharmacology of Pediatric Anesthesia - Smith's Anesthesia for Infants and Children

Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

PART ONE – Basic Principles in Pediatric Anesthesia

Chapter 6 – Pharmacology of Pediatric Anesthesia

Peter J. Davis,Jerrold Lerman,
Stevan P. Tofovic,
D. Ryan Cook

Developmental Pharmacology, 177

Pharmacokinetic Parameters, 178

		Hepatic Clearance,179
		Renal Clearance, 181

Nonlinear Pharmacokinetics, 181

Compartment Models, 182

Offset of Drug Effect and Context-Sensitive Half-Time Concept, 184

Intravenous Drugs, 185

		Sedative-Hypnotic Agents, 185
		Opioids, 193
		Local Anesthetics, 202
		Commonly Administered Anesthetic Adjuncts,203

Inhalation Anesthetics, 206

		Nitrous Oxide, 206
		Sevoflurane, 207
		Desflurane, 208
		Isoflurane, 209
		Halothane, 209
		Uptake and Distribution,210

Neuromuscular Blocking Agents, 213

		Neuromuscular System, 213
		Types of Neuromuscular Blocking Agents: Succinylcholine,215
		Nondepolarizing Neuromuscular Blocking Drugs, 220

Summary, 227

▪ DEVELOPMENTAL PHARMACOLOGY

Pharmacokinetics and pharmacodynamics in the pediatric population are significantly different from those in adults. As recognized by Dr. Abraham Jacobi more than a century ago, children should not be regarded as “little adults.” He wrote that, “Pediatrics does not deal with miniature men and women, with reduced doses and the same class of disease in smaller bodies” but rather “has its own independent range and horizon” ( Kearns et al., 2003 ; Halpern, 1988 ). The physical growth and major physiologic changes that occur during the child's maturation (i.e., from preterm newborn to adolescence) may substantially affect drug disposition ( Table 6-1 ). However, the pharmacologic maturation and rapid changes in factors that govern the drug absorption, distribution, redistribution, metabolism, and excretion occur mainly during the first 12 months of life. The factors that influence different phases of drug disposition, their differences in various pediatric age groups, and basic pharmacokinetic concepts for intravenously administered drugs important for pediatric anesthesia are presented in this chapter.

TABLE 6-1 -- Changes in organ weights with age (percentage of body weight)

Organ System	Fetus	Full-Term Newborn	Adult
Skeletal muscle	25.0	25.0	40.0
Skin	13.0	4.0	6.0
Skeleton	22.0	18.0	14.0
Heart	0.6	0.5	0.4
Liver	4.0	5.0	2.0
Kidneys	0.7	1.0	0.5
Brain	13.0	12.0	2.0

Reproduced with permission from Widdowson EM: Scientific foundations of paediatrics, ed 2. Baltimore, 1982, University Park Press.

Distribution of drugs is the process by which a drug leaves the bloodstream and enters the extracellular fluids (ECFs) and tissues. The rate and extent of distribution of a drug are determined by body composition, permeability of tissue membranes for drugs, cardiac output and regional blood flow, and relative distribution of the drug between tissue and blood. The latter is dependent on the binding of the drug in blood and tissues, the lipid solubility of the drug, and, for ionizable drugs, the pK_a and the pH of the environment.

Body composition (i.e., body water and fat content) undergoes dramatic changes during the maturation process ( Table 6-2 ). Because drug distribution between ECF and fat tissue depends on its lipid-water partition coefficient, the changes in body composition affect drug disposition in the pediatric population. The fetus has high total body water, which at birth accounts for about 75% of the body weight in the full-term newborn infant and 80% in the preterm newborn. The total body water decreases during the first year of life to about 60% of body weight and remains at that level until puberty ( Friis-Hansen, 1961 ). Importantly, there is a dramatic shift in ECF content versus intracellular fluid (ICF) content during the first year of life. The newborn infants have a much higher ECF volume, which in premature infants constitutes 50%, and in full-term, 45%, of body weight. The postnatal diuresis induces an immediate decrease in ECF volume and by 1 year of age, the ratio of ECF volume (20% to 25%) to ICF volume (35% to 40%) approaches adult levels. In contrast to water content, the fat content gradually increases with maturation, from 3% in premature infants and 12% in full-term newborns, to 30% at 1 year of age and about 18% in the average adult. These changes result in a relatively higher volume of distribution of water-soluble drugs and a relatively smaller volume of distribution of liposoluble drugs in neonates and infants. The volume of distribution of water-soluble gentamicin is 0.5 to 1.2 L/kg in neonates and infants compared with 0.2 to 0.3 L/kg in adults ( Echeverria et al., 1975 ), and in neonates the volume of distribution of sulfisoxazole is twice as large as that in adults ( Morselli, 1976 ). Also, the volume of distribution of liposoluble drugs such as diazepam and flunitrazepam has been reported to be smaller in infants than in adults (Treluyer et al., 1997). Table 6-3 gives developmental estimates of gas and tissue volumes and tissue blood flow derived from physiologic studies and autopsies of normal tissue (Altman and Dittmer, 1971; Widdowson, 1974 ; Guignard et al., 1975 ; Smith and Nelson, 1976 ).

TABLE 6-2 -- Body composition during growth

Body Compartment	Premature Infant (1.5 kg)	Full-Term Infant (3.5 kg)	Adult (70 kg)
Total body water (% body weight)	83	73	60
Extracellular fluid (% body weight)	62	44	20
Blood volume (mL/kg)	60	85–105	70
Intracellular water (% body weight)	25	33	40
Muscle mass (% body weight)	15	20	50
Fat (% body weight)	3	12	18

From Cook DR, Marcy JH: Neonatal anesthesia. Pasadena, CA, 1988, Appleton Davies.

TABLE 6-3 -- Age-related estimates of gas and tissue volumes and blood flow

	GAS AND TISSUE VOLUME (mL/kg)		TISSUE BLOOD FLOW (% CO)
Tissue Volume	*Adult*	*Infant*	*Adult*	*Infant*
Tidal volume (V_T)	7	7	—	—
Functional residual capacity (FRC)	40	25	—	—
Blood volume	70	90	—	—
Brain	21	90	14.3	34
Heart	4	4.5	4.3	3
Abdominal viscera	57	70	28.6	25
Kidney	6	10	25.7	18
Muscle	425	180	11.4	10
Fat	150	100	5.7	5
Poorly perfused tissue	270	270	10.0	5

From Cook DR, Marcy JH: Neonatal anesthesia. Pasadena, CA, 1988, Appleton Davies.

The membrane permeability changes during the maturation period. It is particularly high in immature neonates, and the penetration of drugs into the central nervous system (CNS) should be considered in preterm infants. In full-term infants, the myelinization (which counteracts drug passage) continues, and due to the immature blood-brain barrier, the distribution of drugs into the CNS should be expected. In infants, administration of first-generation histamine type 1 receptor (H₁) antagonists was reported to be associated with marked central adverse effects, suggesting significant CNS distribution of these lipophilic drugs (Yokoyoma et al., 1993; Simons et al., 1996 ). The CNS permeability decreases as a function of age, as evidenced by decreased brain/plasma ratio of anticonvulsant agents in infants compared with that in neonates ( Benedetti and Baltes, 2003 ).

Plasma protein binding is another factor that determines drug distribution and elimination. Pharmacologic response may also be altered, because it is the free (unbound) fraction of drug that is available at the site of action (receptor) and is pharmacologically active. In general, acidic drugs mainly bind to albumin, whereas basic drugs bind to α₁-acid glycoprotein and, to a lesser extent, to globulins and lipoproteins. The clinical pharmacokinetic profile of weak acid drugs that significantly (>90%) bind to albumin may be affected by changes in binding affinity/capacity and the amount of circulating albumin. In neonates, the reduced amount of total plasma protein (including the albumin), the presence of fetal albumin that has reduced binding affinity for weak acids, and the increased concentrations of endogenous substances (i.e., bilirubin and free fatty acids) that reduce binding capacity of albumin may contribute to a higher free-unbound fraction of highly protein-bound drugs (phenytoin, valproic acid, salicylates) ( Ehrnebo et al., 1971 ; Kurz et al., 1977 ; Wallace, 1977 ).

Basic drugs, including propranolol, lidocaine, imipramine, and carbamazepine, bind with high affinity to α₁-acid glycoprotein. The plasma levels of this high-affinity, low-capacity globulin range from 40 to 100 mg/L, and because plasma levels are relatively low, it may be saturated over the therapeutic plasma concentration range of the binding drug. This protein behaves as an acute-phase reactant, and plasma levels of α₁-acid glycoprotein are increased during acute myocardial infarction, burns, cancer, inflammatory disease, surgery, and trauma. This increase in protein level may lead to increased binding of basic drugs. In contrast, severe liver disease, including cirrhosis and nephrotic syndrome, leads to decreased plasma levels of α₁-acid glycoprotein and increased free-unbound fraction of basic drugs. The concentrations of α₁-acid glycoprotein are low at birth but reach adult levels over the first year of life. It has been reported that the free-unbound (i.e., pharmacologically active) fraction of sufentanil decreases with age (i.e., 20% in neonates, 12% in infants, and 8% in children and adults). It seems that the lower α₁-acid glycoprotein levels in neonates and infants are responsible for the decrease in protein binding of sufentanil in these age groups compared with adults ( Meistelman et al., 1990 ).

Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

▪ PHARMACOKINETIC PARAMETERS

Volume of distribution is one of the basic pharmacokinetic parameters, and it describes disposition of the drug in the body. It is defined as a space in the body where the drug is uniformly distributed. It is an important pharmacokinetic parameter that relates the amount of the drug in the body (A_B) to the concentration of drug in plasma (C_p) or other measured fluid:

6.1

This volume does not necessarily correlate with any anatomic space or physiologic volume in the body. It is defined as a fluid of volume that would be required to contain all of the drug in the body at the same C_p as the measured one. This theoretical or fictitious space is also called the apparent volume of distribution. Tissue binding increases the volume of distribution, whereas binding to plasma proteins reduces the volume of distribution ( Fig 6-1 ). Water-soluble drugs have a relatively smaller volume of distribution, whereas lipophilic drugs have a larger volume of distribution. A volume of distribution greater than the total body water volume (>40 L) suggests extensive tissue binding of drug. For example, due to high binding for myocardial Na⁺,K⁺-ATPase, digoxin concentrations in the adult heart are 50 times higher than concentrations in plasma, and volume of distribution in adults is up to 700 L (6 to 10 L/kg). In the pediatric population there is an even greater binding affinity for myocardial Na⁺,K⁺-ATPase, and neonates (10 L/kg) and infants and toddlers (16 L/kg) have a larger volume of distribution digoxin than do adults.



FIGURE 6-1 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 Eq. 1, the volume of distribution (V_d) may vary (i.e., 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 V_d (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 V_d (V_d = 2.5 L).

This fictitious volume helps clinicians to estimate the loading dose of a drug that would be required to achieve a desired C_p. For drugs administered intravenously, the loading dose (L_Dor A_B from Eq. 6.1) would depend on volume of distribution:

6.2

Clearance (CL) is the intrinsic ability of the body to eliminate the drug. Clearance is not an indicator of the amount of drug eliminated but rather represents the theoretical volume of biologic fluid (blood or plasma) that is completely cleared of drug per unit of time (mL/min; L/hr). The amount of drug removed depends on the plasma concentration of the drug and clearance. At the steady state, when the rate of administration (R_A) is equal to the rate of elimination, CL can be considered as the proportionality constant that defines the rate of administration (or maintenance dose) for given steady-state plasma concentrations (C_ss) to be maintained.

6.3

The drugs are eliminated or cleared unchanged by the kidney, metabolized in the liver or other organs, or both. The total systemic clearance represents the sum of all of these separate clearances.

6.4

▪ HEPATIC CLEARANCE

The principal determinants of hepatic clearance (CL_H) are the metabolizing and excretory capacity (intrinsic clearance, CL_int), hepatic blood flow (Q_H), and plasma protein binding (i.e., fraction of unbound drug in the plasma [f_u]) of the liver.

The relation of these factors is defined by the following equation:

6.5

The CL_int can be referred to as the extraction ratio (E), which is equal to the differences in arterial blood concentration presented to the liver (C_A) and concentration of drug in the venous blood leaving the liver (C_V), divided by the arterial blood drug concentration:

6.6

For drugs that exhibit a high (i.e., lidocaine, propofol, ketamine, fentanyl, sufentanil) or intermediate (methohexital, midazolam, alfentanil) hepatic extraction ratio, hepatic clearance depends mainly on hepatic blood flow. The elimination of drugs with low hepatic extraction ratios (diazepam) depends on enzymatic activity of the liver and is independent of hepatic blood flow ( Fig 6-2 ). Hepatic blood flow is decreased in patients with congestive heart failure, volume depletion, hypocapnia, circulatory shock, and β-adrenergic blockade. Based on similar systemic clearance values for lidocaine in infants and adults, it seems not that hepatic blood flow is a limiting factor for drug metabolism in infants but rather that the immature metabolizing enzyme systems and inefficient excretory function are major limiting factors for hepatic clearance of drugs in infants (infra vide). Protein binding may also alter drug clearance. In contrast to highly extracted drugs where protein binding does not influence clearance, for drugs with low extraction ratios, protein binding inversely affects the clearance. That is, increased protein binding results in reduced clearance, whereas decreased protein binding and subsequent increase in free-unbound fraction augment the hepatic clearance of the drug.



FIGURE 6-2 Effect of increasing liver blood flow on the hepatic clearance of drugs with varying extraction ratios. Each curve represents a drug whose extraction ratio (E.R.) at 1.5 L/min is shown above that flow. For drugs with a low extraction ratio, increase in liver blood flow within the physiologic range (indicated by arrow) produces very little change in hepatic clearance. For a drug with a high E.R., however, increases in liver blood flow produce an almost proportional increase in hepatic clearance. (With permission from Wilkinson GR, Shank DG: Clin Pharmacol Ther 18:377, 1975.)

Regardingdrug metabolism, hepatic biotransformation is a main route of elimination for many drugs. In general, hepatic metabolism increases the hydrophilicity of drugs and allows their renal elimination and termination of their pharmacologic and toxicologic activity. Drug metabolism that takes place in the liver involves various pathways that are generally categorized as phase I and phase II reactions (Table 6-4 ). Although the phase I and phase II reactions are well characterized in adults, there is limited information on the ontogeny of these important metabolic pathways.

TABLE 6-4 -- Pathways in drug metabolism

Reaction	Examples
Phase I
Oxidation Reactions	Thiopental, methohexital
Aliphatic hydroxylation	Pentazocine, meperidine, glutethimide, doxapram, ketamine, chlorpromazine
Aromatic	Lidocaine, bupivacaine, mepivacaine, meperidine, glutethimide, fentanyl, propranolol
Expoxidation	Phenytoin
O-Dealkylation	Pancuronium, vecuronium, codeine, phenacetin, methoxyflurane
N-Dealkylation	Morphine, meperidine, fentanyl, diazepam, amide local anesthetics, ketamine, codeine, atropine, methadone
N-Oxidation	Meperidine, normeperidine, morphine, tetracaine
S-Oxidation	Chlorpromazine
Oxidative deamination	Amphetamine, epinephrine
Desulfuration	Thiopental
Dehalogenation	Halogenated anesthetics
Dehydrogenation	Ethanol
Reduction Reactions
Axoreduction	Fazadinium
Nitroreduction	Nitrazepam, dantrolene
Carbonyl reduction	Prednisolone
Alcohol dehydrogenation	Ethanol, chloral hydrate
Hydrolysis Reactions
Ester hydrolysis	Ester local anesthetics, succinylcholine, acetylsalicyclic acid, propanidid
	Amide local anesthetics
Phase II: Conjugation Reactions
Glucuronamide	Oxazepam, lorazepam, morphine, nalorphine, codeine, fentanyl, naloxone
Sulfate	Paracetamol, morphine, isoproterenol, cimetidine
Methylation	Norepinephrine
Acetylation	Procainamide
Amino acid	Salicyclic acid
Mercapturic acid	Sulfobromophthalein
Glutathione	Paracetamol

Adapted from Tucker GT: Br J Anaesth 51:603, 1979.

The phase I reactions (oxidation, reduction, and hydrolysis) that result in addition, formation, or uncovering of a functional group on the drug molecule are mediated mainly by cytochrome P450 enzymes (CYPs). The CYP enzymes are a superfamily of heme-containing enzymes that catalyze the oxidative metabolism of a variety of exogenous and endogenous compounds, including many lipophilic drugs. At least 12 CYP gene families have been identified in humans. Based on amino acid sequence similarities, CYPs are divided into families when the amino acid sequence possesses more than 40% homology (denoted by Arabic number) and grouped into subfamilies (>55% homology; designated by letter). Individual enzymes (labeled by Arabic letter) may have up to 97% homology between the sequences. Only families 1 through 4 play an important role in drug metabolism. In general, CYP enzymes have broad substrate specificity for both exogenous and endogenous compounds. However, some CYPs have narrow substrate specificity with little overlapping activity. The presence of constitutive and inducible forms and documented genetic polymorphism for several CYPs may affect the metabolic clearance and have significant clinical ramification ( Leeder and Kearns, 1997 ; Rane, 1999 ). Oxidation is the phase I reaction most deficient in neonates, whereas reduction is less affected and hydroxylation is almost equally effective as in adults. Parturition triggers the dramatic development of CYP enzymes.

The fetal liver and liver in infants exhibit significant differences in CYP mRNA and protein level and enzyme activity compared with adults. CYP1A2, the only member of the CYP1A subfamily present in the liver, is responsible for metabolism of caffeine and theophylline, two methylxanthines used frequently in pediatrics. The CYP1A2 is practically absent in the fetal liver and has very low activity in neonates, with 85% of a caffeine dose being excreted unchanged by the kidney in neonates ( Cazeneuve et al., 1994 ). It reaches adult levels by the age of 4 to 6 months ( Besunder et al., 1988 ; Cazeneuve et al., 1994 ; Hakkola et al., 1994 ; Yang et al., 1995 ; Leeder, 2001 ). The metabolism of caffeine in neonates primarily depends on CYP3A4 and not, as in the case of infants and adults, on CYP1A2 activity ( Cazeneuve et al., 1994 ). The CYP3A subfamily (CYP3A4, CYP3A5, and CYP3A7) is the most important group of CYPs in regard to hepatic drug metabolism. The CYP3A4 isoform is the major isoenzyme (30% to 40% of the total CYP content) present in the adult liver and in the intestinal wall, where it markedly participates in the first-pass metabolism of midazolam ( Thummel et al., 1996 ). In addition to midazolam, it metabolizes important drugs for pediatric anesthesiology such as alfentanil, fentanyl, lidocaine, diazepam, and methadone. The CYP3A5, which is 83% homologous with CYP3A4, is less expressed in the liver but is the main CYP3A in the kidney and has similar substrate specificity to CYP3A4 ( Yang et al., 1994 ). The CYP3A7 is 90% homologous to CYP3A4 and is a major highly active isoform present in fetal liver, with maximal activity in the early neonatal period and with progressive, and almost complete, loss of the activity within the first months after birth ( Leeder and Kearns, 1997 ; Leeder, 2001 ). Only a few substrates have been studied with respect to the CYP3A7 activity, and it has minor contribution in metabolism of midazolam, carbamazepine, and cisapride ( Thummel et al., 1996 ; de Wildt et al., 1999 ). CYP2D6 is another important isoenzyme involved in the metabolism of up to 25% of drugs (antidepressants, antipsychotics, antiarrhythmics, β-blockers, and opioids). This includes the metabolism of codeine and tramadol, which are converted by CYP2D6 to their respective pharmacologically active entities, morphine and O-desmethyl tramadol. In vitro studies suggest limited fetus CYP2D6 activity that reaches 20% of adult activity by 1 month of age ( Treluyer et al., 1991 ). Both CYP2C19 (diazepam) and CYP2C9 (fluoxetine, phenytoin, torsemide) are absent in the fetal liver, and they reach the activity seen in adults by 6 months of age.

Phase II reactions catalyze the conjugation (glucuronidation, sulfation, glutathione conjugation) of a water-soluble endogenous molecule to the drug compound and further enhance the water solubility of drugs and their renal or biliary excretion. Glucuronidation, glutathione conjugation, and acetylation are deficient in the neonate, whereas sulfate conjugation is an effective pathway at birth ( Cappiello et al., 1991 ). Uridine 5′-diphosphate-glucuronosyltransferase (UGT) catalyzes the conjugation of glucuronic acid to their substrates. Like the CYPs, the UGTs are a gene superfamily of enzymes that, according to the sequence homologues, are divided into two families (UGT1A and UGT2B) with more than 18 different enzymes. The conjugation of bilirubin (UGT1A1) is practically undetectable in the fetal liver but increases immediately after birth and reaches adult levels by the age of 6 to 9 months. The glucuronidation of morphine (a UGT2B7 substrate) in the fetal liver in vitro is 10% to 20% of that in the adult liver ( Anderson et al., 1997 ). Clinical studies suggest deficient morphine glucuronidation in young infants with adult values reached by 6 to 30 months of age, depending on the method used to calculate clearance (clearance corrected by body weight or body surface area) ( Choonara et al., 1989 ; Balistreri, 1983 ).

▪ RENAL CLEARANCE

The kidney is the most important organ for elimination of drugs, and renal clearance contributes to the elimination of a significant number of water-soluble drugs and their metabolites. Glomerular filtration rate (CL_GFR), tubular secretion (CL_tub-sec), and tubular reabsorption (CL_tub-abs) mainly govern renal clearance. Their relationship is defined by the following equation:

6.7

The renal clearance mechanisms are also subject to maturational changes, with each renal clearance process exhibiting a different rate and pattern of development. Changes in renal clearance of digoxin (which includes glomerular filtration and tubular excretion) from 0.6 L/hr per 1.73 m² and 2.0 L/hr per 1.73 m² in premature and full-term infants, respectively, to 5.3 L/hr per 1.73 m² and 8.7 L/hr per 1.73 m² in 3-month-old infants and 18-month-old children, respectively, are representative of renal growth and maturation processes ( Halkin et al., 1978 ; Ng et al., 1981 ).

The nephrogenesis that begins in the eighth week of gestation is completed by 36 weeks of age. At that time, for the full complement of nephrons, GFR is only 5% of the adult values ( Haycock, 1998 ). Measurements of renal plasma flow (para-aminohippuric acid) and GFR (inulin or mannitol) that are normalized for the body surface area indicate that adult values are reached between 6 and 12 months of age ( Rubin et al., 1949 ; Heilbron et al., 1991 ). Notably, if clearance numbers are related to body weight, the adult values for plasma flow and GFR are reached much earlier (i.e., within weeks to a month). Both anatomic and functional immaturity of renal tubules is present at birth and both passive reabsorption and active secretion are diminished. The maturation of renal tubular function has a more protracted time course and reaches the adult renal tubular function values by 12 to 18 months of age ( Alcorn and McNamara, 2002 ). The reduced GFR in the perinatal period seems to be due to the active vasoconstriction of the renal microvasculature, and diminished renal blood flow accounts mainly for the differences in GFR between full-term infants and adults. The low GFR at birth seems to protect the immature proximal tubules from an overload of electrolytes and other solutes. Parturition triggers dramatic increase in renal blood flow, with a 10-fold increase of para-aminohippuric acid clearance in the first year of life. For most drugs eliminated predominantly by the kidney, there is prolonged half-life in the first 1 to 3 weeks of life, with a significantly shorter half-life by 4 weeks and adult values for t ₁ _/2reached by 6 months of age.

Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

▪ NONLINEAR PHARMACOKINETICS

For some drugs, an increase in dose is not followed by proportional increase in steady-state plasma concentrations (C_ss) and area-under-the-plasma-concentration curve (AUC). Instead, the C_ss and AUC increase more than expected. The explanation for this nonlinear pharmacokinetics is that enzymes responsible for metabolism and elimination of the drug may be saturated. The nonlinear pharmacokinetics, also called Michaelis-Menten kinetics, occur when the maximum rate of metabolism (Vmax) for the drug is approached. The Michaelis-Menten-type pharmacokinetics describe the rate of production of molecules (drug metabolites) produced by enzymatic chemical reactions. Enzymes can perform up to several million catalytic reactions per second. To determine the maximum rate of an enzymatic reaction, the substrate (plasma drug) concentration should be increased until a constant rate of product (drug metabolite) formation is achieved. This is the maximum velocity (V _max) of the enzyme, and at this point the active sites of the enzymes are saturated with drug and a constant amount of drug begins to be eliminated per unit of time (“zero-order” kinetics). Because the substrate (drug plasma) concentration at V_max cannot be measured exactly, the metabolism of drug can be characterized by Michaelis-Menten constant (K _m), i.e., the drug plasma concentration at which the rate of metabolism is half of its maximum (K _m = V _max/2). For practical purposes, the K _m is the plasma concentration at which, when the dose is increased, the nonproportional increase in C_ss and AUC start to occur.

For most of drugs that are metabolized by hepatic enzymes and eliminated by the liver, the K _m is above the required therapeutic range and they follow linear kinetics. However, when the therapeutic range is above the K _m, nonlinear kinetics occurs. For example, the average K _m and therapeutic range for phenytoin are 4 mg/L and 10 to 20 mg/L, respectively, and many patients on phenytoin experience nonlinear pharmacokinetics.

The nonlinear pharmacokinetics may also be seen in low-clearance drugs for which elimination is significantly influenced by the binding of the drug to plasma proteins. In this scenario, after increasing the dose of drug, a less-than-expected increase in C_ss and AUC occurs. This would suggest that the plasma protein binding sites have been saturated and that the free fraction of low-clearance drug has increased. The latter would result with increased clearance and a less-than-expected increase C_ss occurs. However, if measured, the free fraction of the low-clearance drug increases proportionally. Both valproic acid and disopyramide follow this type of nonlinear pharmacokinetics ( Bowdle et al., 1980 ; Lima et al., 1991 ).

Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

▪ COMPARTMENT MODELS

For many drugs, after intravenous administration, the process of distribution throughout plasma and tissues occurs rapidly and simultaneously, and the whole body could be thought of as a single compartment. In this single-compartment model, after bolus intravenous administration of the drug, there is a monoexponential decrease in plasma concentration. The latter is due to the elimination process that allows a constant portion of the drug (not amount) in the body to be eliminated per unit of time. In this case, the drug follows the first-order kinetic. The first order elimination of a drug from the body or plasma (C_p) is defined as follows:

6.8

A_B^o is the initial amount in the body and C_p ⁰ plasma concentration immediately after the bolus; t is the time since bolus and K _d is the rate constant of elimination. The e^-Kdt represents the fraction of the A_B ⁰ remaining at time t. The drug elimination rate constant (K _d) is an index of the body's capacity to remove the drug. The elimination rate constant K _d is the fraction of the total amount of drug in the body that is removed per unit of time. It is a function of clearance and volume of distribution:

6.9

The elimination rate constant (K _d) can be also thought of as the fraction of the volume of distribution that is effectively cleared of drug per unit of time. Because the drug plasma concentration diminishes monoexponentially, a graph plot of the logarithm of the plasma concentrations versus time yields a straight line. The elimination rate constant defines the slope of this curve ( Fig 6-3 ), and two plasma concentrations measured during the decay or elimination phase can be used to calculate the K _d:



FIGURE 6-3 Single-compartment model. The initial plasma (body) drug concentration (C_p ⁰) produced by single loading dose diminishes monoexponentially (left). The semilogarithmic graph of concentration versus time yields a straight line (right).

6.10

The elimination rate constant is often expressed in terms of a time required for half of the total amount of drug in the body to be eliminated, or the plasma concentrations to decrease by one half, that is, by the half-life of the drug (t_½). If plasma concentrations drop by 50% and C_p1= 2C_p2, then in Eq. 5, t₂ - t₁=t_½and

6.11

6.12

The half-life, like K _d, is dependent on volume of distribution and clearance, and this relationship is shown in Eq. 13,

6.13

The half-life is a variable that determines (1) the time needed (5 × t_½) to reach plasma steady-state concentrations of the drug after initiation of an infusion, (2) the time needed to reach new steady-state concentrations after increasing or decreasing the infusion rate, (3) the time needed for drug to disappear from plasma after the infusion is stopped, and (4) the time it takes for all drug from the body to be eliminated after cessation of the drug infusion ( Fig 6-4 ). The short half-life is an obvious advantage for drugs given by intravenous infusion: it allows for drug effects to be easily and dynamically titrated; a relatively shorter time is required for steady-state concentrations to be achieved; and if toxicity occurs, it is easier to handle. For drugs used by intermittent administration (oral or parenteral), a short half-life is a disadvantage because multiple doses are needed; it is difficult to keep the plasma concentration within the therapeutic window; and a missed dose could drop plasma concentrations below the minimal therapeutic level. It should be emphasized that V_d and CL may change independent of one another and alter the half-life in the same or opposite directions. For the given clearance, drugs with smaller V_dhave a shorter t_½and a faster recovery after the infusion of an anesthetic agent. Reduced clearance, with no changes in volume of distribution, increases the half-life and recovery time after intravenous infusion.



FIGURE 6-4 Changes in plasma concentration and steady-state level after intravenous infusion are in the function of half-life.

Most of the drugs used in anesthesia do not follow the simple, one-compartment pharmacokinetics but rather behave like a two- or even three-compartment model. Distribution of anesthetic drugs into and out of peripheral tissues determines the pharmacokinetic profile and the time course of the anesthetic drug effect. For the two-compartment model, the central compartment includes the blood and organs or tissues that have high blood flow and can be thought of as a rapidly equilibrating volume. The second compartment has a volume (V_t) that equilibrates at a much slower pace. After bolus administration of a drug that follows the two-compartment model, two distinct phases can be distinguished—distribution phase and terminal elimination—and the decay of plasma concentration over time is defined by the biexponential equation ( Fig 6-5 ). Changes in plasma and the site of action concentrations would depend on drug elimination and on the equilibrium between central and peripheral tissue compartments.



FIGURE 6-5 Two-compartment model. For many drugs, after an intravenous bolus, there is no “instantaneous” and even distribution of the drug throughout the body (as in the one-compartment model). Drugs distribute with different paces between the initial/central (V_c) compartment (i.e., circulation and well-perfused organs, including the brain) and the tissue/peripheral compartment (V_t). The changes in plasma concentrations follow the biexponential decay.

For many anesthetic drugs, even three phases can be distinguished after intravenous bolus administration. This three-compartment model is composed of the central compartment and two additional compartments that include the respective rapid and slow equilibrating tissues and organs ( Fig 6-6 ). Likewise, the three-compartment model is characterized by the triexponential plasma concentration equation, three volumes of distribution, and five rate constants of distribution and terminal elimination (K ₁₂, K ₂₁, K ₁₃, K ₃₁, and K ₁₀).



FIGURE 6-6 Three-compartment model. After intravenous administration, for many anesthetic drugs three phases in distribution can be distinguished. After immediate distribution into central compartment (i.e., bloodstream and highly perfused organs), there is redistribution of drugs (i.e., from the brain) back into circulation (K₂₁) and to peripheral tissue with rapid equilibrium (K₁₂). Drug also diffuses at very slow pace into and out from the poorly perfused tissues (K₁₃, K₃₁). The triexponential decay describes the changes in plasma concentrations.

After an intravenous bolus, the anesthetic/hypnotic drug dilutes almost immediately, within the single circulation time, into the central compartment (i.e., in the bloodstream and in the highly perfused organs such as brain and spinal cord). The central volume of distribution can be used to calculate the loading dose. Subsequently, there is a redistribution of drug out from the CNS back into the blood and to the peripheral compartments with rapid equilibrium (muscles viscera; V_d _rapid). Finally, the drug diffuses into poorly perfused tissues (fat) that slowly equilibrate with the central compartment. The initial redistribution, rather than metabolic clearance, determines the termination of the effect of single boluses of parenteral anesthetics. If prolonged anesthesia is required, the maintenance infusion rate should compensate not only for the drug clearance but initially also for the transient loss of anesthetic by redistribution to the peripheral compartments that are governed by “intercompartmental clearance” and elimination rate constants (K ₁₂, K ₂₁, K ₁₃, and K ₃₁).

Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

▪OFFSET OF DRUG EFFECT AND CONTEXT-SENSITIVE HALF-TIME CONCEPT

Traditionally, clearance, volume of distribution, and half-life are standard pharmacokinetic parameters used to characterize the drug offset of action. As presented earlier, they are derived from one- and two-compartment models or, through the use of computer simulation programs, from multicompartment models. These pharmacokinetic parameters can be relatively easy to apply to calculate the infusion rate and predict the offset of action of water-soluble drugs with small V_d and relatively “simple pattern of disposition” (i.e., muscle relaxants).

For the anesthesiologist, pharmacokinetic factors are frequently used for the routine selection and use of various intravenous anesthetic agents. Drugs with short elimination half-lives are frequently selected for brief procedures, whereas drugs with longer half-lives are selected for lengthier procedures. Drugs with small volumes of distribution tend to decrease the time required for recovery after intravenous infusion, and agents with decreased plasma clearances may increase the time for recovery. In general, formulas for the calculation of continuous infusions incorporate knowledge of these pharmacokinetics. For bolus administration of drug, the volume of distribution and the desired plasma concentration are needed. Table 6-5 lists plasma concentrations in adults for some of the opioids. The bolus dose is calculated as the product of the volume of distribution (V_d) and the desired plasma concentration (C_p):

TABLE 6-5 -- Opioid concentrations that ablate responsiveness to intraoperative noxious stimuli and permit adequate ventilation on emergence^[*]

	Fentanyl	Alfentanil	Sufentanil
Induction and intubation
Thiopental	3 to 5	250 to 400	0.4 to 0.6
O₂/N₂O only	8 to 10	400 to 750	0.8 to 1.2
Maintenance
N₂O/potent vapor	1.5 to 4	100 to 300	0.25 to 0.5
O₂/N₂O only	1.5 to 10	100 to 750	0.25 to 1.0
O₂ only	15 to 60	1000 to 4000	10 to 60
Adequate ventilation on emergence	1.5	125	0.25

^*	Opioid concentration given in ng/mL.

6.14

The maintenance infusion rate (MIR) is calculated as the product of the desired plasma concentration (C_p) and the clearance (CL):

6.15

Although these formulas work well, Shafer and Varvel (1991) and Hughes and others (1992) have demonstrated the complex interactions that occur with prolonged infusions, especially in drugs that are lipid soluble.

The offset of drug effect depends on reduction of the plasma concentrations and the withdrawal of drug from the site of action, that is, for anesthetic from the receptor site in the CNS. If steady state is achieved and all compartments are saturated, then the half-life of elimination phase, which is a function of the first-order processes of elimination, would correlate with decrease in the site-of-action drug concentrations and with the offset of drug action. However, after infusion of a highly lipophilic anesthetic agent, when steady state is not achieved and not all compartments are saturated, the decline in concentrations (i.e., the offset of action and recovery from anesthesia) depends on complex interaction between the duration of the infusion and initial distribution, redistribution, and metabolic/elimination first-order processes. The classic descriptors of a drug's pharmacokinetics and offset of action (terminal half-time) are of little help to anesthesiologists in predicting the offset of action and recovery from anesthesia for the intravenous anesthetic drugs. Fortunately, with the help of pharmacokinetic/pharmacodynamic simulation models, new predictors of offset of drug effect have evolved ( Shafer and Varvel, 1991 ; Huges et al., 1992 ; Youngs and Shafer, 1994 ).

Using a pharmacokinetic/pharmacodynamic model and basic pharmacokinetics profile of commonly used synthetic opioid analogs, Shafer and Varel (1991) were the first to construct the offset of action (recovery) curves as a function of the duration of infusion for fentanyl, alfentanil, and sufentanil ( Fig 6-7 ). Huges and others (1992) introduced the term “context-sensitive half-time” (context refers to the duration of infusion) as a time required for a drug concentration to decrease to half of its value after drug infusion of a given duration. Of importance is that for any given drug, its context-sensitive half-time varies with the duration of the drug infusion. Thus, a 2-hour context-sensitive half-time is a time required for the plasma or effects site concentrations to decrease by 50% after termination of a 2-hour infusion. Because for most intravenous anesthetic drugs the 50% fall in concentration is not sufficient for recovery from anesthesia, other decrement times have been introduced ( Youngs and Shafer, 1994 ). For example, 1-hour 80% and 3-hour 90% decrement times describe the time needed for concentrations to decrease by 80% and 90% after the cessation of the 1- and 3-hour infusions, respectively.



FIGURE 6-7 Context-sensitive half-time: the time required for drug concentration to decrease by half of its value (Y axis) after cessation of infusion of given duration (X axis) for fentanyl and its congeners, sufentanil, alfentanil, and remifentanil (see the text for explanation). (Adapted from Shafer SL, Varvel MD: Pharmacokinetics, pharmacodynamics and rational opioid selection. Anesthesiology 74:53, 1991; and Egan TD: Clin Pharmacokinet 29:80, 1995.)

After a short intravenous infusion (>10 to 15 minutes), fentanyl and other synthetic opioid analogs have similar context-sensitive half-times (see Fig. 6-7 ). However, after prolonged infusion (>1 hour), there is a marked difference among four synthetic opioid analogs (fentanyl, sufentanil, alfentanil, and remifentanil), and these differences do not correlate with their classic pharmacokinetic parameters (Table 6-6 ). In contrast to its older congeners, remifentanil has a short and steady context-sensitive half-life of 3 minutes, which does not change with the increasing duration of infusion ( Egan et al., 1996 ). This contrasts with alfentanil, with a context-sensitive half-time that increases to 1 hour after a 4-hour infusion ( Ebling et al., 1990 ; Scholz et al., 1996 ). This difference is due to the unique pharmacokinetic profile of remifentanil. It is a highly liposoluble (volume of distribution at steady state [Vd_ss], 30 L) opioid analog that undergoes widespread metabolism (deesterification), including metabolism in the circulation. Unlike other opioids, the termination of action of remifentanil does not depend on redistribution but rather on extremely rapid metabolic clearance. Kapila and others (1995) demonstrated that the context-sensitive half-times of remifentanil (3 minutes) and alfentanil (50 to 55 minutes) derived from computer modeling are similar to measured context-sensitive half-times (3.2 and 47 minutes for remifentanil and alfentanil, respectively), and both correlate with measured pharmacodynamic offset (recovery of minute ventilation). The latter confirms the value and clinical applicability of this new pharmacokinetic/pharmacodynamic parameter in predicting the offset of anesthetic drugs.

TABLE 6-6 -- Pharmacokinetic parameters of synthetic opioids after single intravenous bolus administration

	Volume of Distribution (Vd_ss; L/kg)	Elimination Half-Life (t_½α; min)	Distribution Half-Life (t_½β; min)	Total Body Clearance (mL/min per kg)	Context-Sensitive Half-Time (3-hr infusion)
Fentanyl	4	2 to 3	220 to 300	10 to 20	100
Sufentanil	1.7	1.4	160	10 to 15	30
Alfentanil	0.75	0.6 to 12	90 to 120	8	50
Remifentanil	0.3 to 0.4	1 to 1.5	6 to 14	50	3

Data from Egan et al., 1996 ; Ebling et al., 1990 ; and Scholz et al., 1996 .

The context-sensitive half-time curves provide a better, clinically more relevant comparison of the pharmacokinetic profiles of anesthetic drugs than the traditional pharmacokinetic parameters ( Fig 6-8 ). After a single intravenous dose, commonly used anesthetic/hypnotic drugs have a short duration of action. However, after prolonged infusions, the context-sensitive half-times and duration of action increase. For some drugs (propofol, ketamine), this increase is modest, whereas for others (diazepam, thiopental), it is quite dramatic. In the case of midazolam, the rapid increase in its context-sensitive half-time with prolonged duration of infusion occurs in the presence of a relatively short elimination half-life (t_½β), and this is most likely due to the low clearance of midazolam.



FIGURE 6-8 Context-sensitive half-time for commonly used general anesthetics. (From Reves JG, Glass PSA, Lubarsky DA: Non-barbiturate intravenous anesthetics. In Miller RD, editor: Anesthesia, 5th ed. New York, 2000, Churchill Livingstone, p 228, Fig. 9-5 .)

The data regarding the context-sensitive half-times and other decrement times of anesthetic agents in the pediatric population are limited, at best. In children aged 3 to 11 years, longer context-sensitive half-times than in adults were reported for propofol. After a 1-hour infusion in children and adults, the context-sensitive half-times for propofol are 10.4 and 6.6 minutes, respectively, and after a 4-hour infusion, they are 19.6 and 9.5 minutes, respectively ( McFarlan et al., 1999 ). This is probably due to the altered compartment volumes and may lead to slower recovery from a propofol infusion in children than in adults ( Short et al., 1994 ). In contrast, the shorter context-sensitive half-time of fentanyl was determined in pediatric population (2 to 11 years old) compared with published data in adults ( Ginsberg et al., 1996 ; Reves et al., 1994).

Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

▪ INTRAVENOUS DRUGS

▪ SEDATIVE-HYPNOTIC AGENTS

A variety of sedative-hypnotic agents can be used for premedication or induction of anesthesia. Most commonly these agents are administered intravenously, but oral, rectal, or intramuscular routes are occasionally used.

On a milligram-per-kilogram basis, barbiturates are more lethal to newborns than to more mature animals (Carmichael, 1938, 1947; Weatherall, 1960 ; Goldenthal, 1971 ). The sleeping times of newborn animals are markedly prolonged at sublethal doses given on an equal milligram-per-kilogram basis ( Weatherall, 1960 ). Greater penetration of the blood-brain barrier by barbiturates has been found in neonates as opposed to older animals ( Domek et al., 1960 ).

Neonates have a decreased ability to metabolize barbiturates ( Mirkin, 1975 ). The longer-acting barbiturates, which are in part excreted unmetabolized in the urine, would be expected to have prolonged or elevated blood levels ( Knauer et al., 1973 ; Boreus et al., 1975 ). Glucuronic acid conjugation of barbiturates develops rapidly and increases 30-fold during the first 3 weeks of life ( Brown et al., 1958 ).

Short-acting barbiturates (e.g., methohexital, thiamylal, and thiopental) can be used to induce anesthesia in infants and children. These agents produce rapid induction of hypnosis with minimal relaxation or analgesia. The pharmacokinetics of short-acting barbiturates in infants, children, and adults were studied extensively by Brodie (1952), Dundee and Barron (1962), Mark (1963), Saidman and Eger (1966), and Lindsay and Shepherd (1969). Because of the child's proportionately greater amount of vessel-rich tissue, the uptake of short-acting barbiturates should be more rapid ( Eger, 1974 ), the effect more quickly achieved, and metabolism, excretion, and recovery more prompt unless retarded by supplementary agents.

Thiopental

Thiopental is a commonly administered intravenous induction agent. Hiccoughs, sneezing, and other irregularities are rarely seen on induction, and there is no excitement or extrapyramidal activity. Cerebrospinal fluid pressure is reduced, making the agent useful for diagnostic and operative neurologic procedures ( Dawson et al., 1971 ), and intraocular pressure also is decreased. Awakening is quiet, occasionally interrupted by shivering ( Smith et al., 1955 ), and associated with a low incidence of nausea. 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 and others (1987) reported that the ED₅₀ of thiopental in infants is significantly greater (7 mg/kg) than that in adults (4 mg/kg) ( Jonmarker et al., 1987 ) ( Fig 6-9 ). Westrin and others (1989) determined the dose of thiopental needed for satisfactory induction of 10 healthy, nonpremedicated neonates, 0 to 14 days old, and 20 infants, 1 to 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 and others (1990) noted that neonates had a free drug fraction 1.5×to 2×greater than that of adults. The increased free fraction of thiopental may explain the decreased induction dose required by the neonate. Sorbo and others (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 Vd_ss was approximately 2.0 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 12.0 ± 6.0 hours and 3.1 ± 0.5 mL/kg per minute, respectively, observed in adults.



FIGURE 6-9 Estimated ED₅₀ ± SE for thiopental in the various age groups. (With permission from Jonmarker C, Westrin P, Larsson S, et al.: Anesthesiology 67:104, 1987.)

Methohexital

Methohexital, a methylated oxybarbiturate, is more potent than thiopental by a ratio of about 3:1 ( Clarke et al., 1968 ), is more rapidly eliminated, and produces more undesirable side effects. Greater speed of recovery provides its principal indication, especially for outpatient care or for situations where very brief effect is wanted, as for cardioversion or electroconvulsive therapy. The incidence of involuntary muscular movement, hiccough, 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 ( Miller et al., 1961 ), some studies suggest that the high concentration of rectal methohexital can cause mucosal damage. Administration of 10% methohexital to rats via the rectal route produces minor, self-limiting 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 and others (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, Khalil and others 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 ( Goresky and Steward, 1979 ), which coincided with peak serum levels ( Letty et al., 1985 ).

Forbes and others (1989a) reported on the plasma concentrations of 60 children after doses of 15, 20, 25, or 30 mg/kg of rectal methohexital ( Fig 6-10 ). 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 and others (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 6-10 Plasma methohexitone concentrations following 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 versus 30 mg/kg; †P < 0.05 20 mg/kg versus 30 mg/kg. (Redrawn from Forbes RB, Murray DJ, Dillman JB, et al.: Can J Anaesth 36:160-164, 1989.)*

Audenaert and others (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 occurred usually in 6 minutes. Sleep was less likely to occur in patients with myelomeningocele or in patients on phenobarbital or Dilantin (phenytoin) therapy. Side effects of defecation after administration occurred in 10% of patients and hiccups occurred in 13% ( Audenaert et al., 1995 ). The intravenous dose for induction using methohexital dissolved in a rapid emulsion was determined by Westrin (1992). Westrin 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 6-11 ).



FIGURE 6-11 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. (Redrawn from Westrin P:Anesthesiology 76:917-921, 1992.)

Beskow and others (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 for thiopental.

Benzodiazepines and Antagonists

Diazepam

Diazepam produces relatively pleasant sedation or hypnosis with few side effects and prompt recovery. Its action is due to 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 mono-oxygenase system. In adults, the metabolite (desmethyldiazepam) is eliminated slower (t_½= 150 hours) than the parent compound (t_½= 20 to 30 hours) (Meberg, 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 do older infants, children, and adults. In premature infants, a demethylated derivative of diazepam, N-demethyldiazepam, could not be measured in plasma until 4 hours after injection, in comparison to older infants and children, in whom, N-demethyldiazepam 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.

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, retrograde 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 (CYP3A4, CYP3A5, 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 were reported. Payne and others (1989) noted that in healthy children administered 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 and others (1993) have also reported on the kinetics of intravenous midazolam (0.5 mg/kg) in 12 healthy Chinese 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 ( Salonen et al., 1987 ), comparisons between studies become difficult. The kinetics of midazolam have also been determined after intramuscular, rectal, and oral administration. Payne and others (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.

In a study involving pediatric patients aged 6 months to 16 years, Reed and others (2001) characterized the pharmacokinetic profile of both oral and intravenous midazolam using noncompartment models. After oral administration, midazolam absorption was rapid with adolescents absorbing the drug at half that seen with children younger than 12 years. 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 little effect of age on volume of distribution or clearance and the half-life was slightly shorter in children ( Reed et al., 2001 ).

The pharmacokinetics of rectally administered midazolam in children were reported by Saint-Maurice and others (1986). In this study of 16 children administered 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 ( Lammers et al., 2002 ; Goho, 2001 ) of midazolam.

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 and 591 ± 65 mL/kg, respectively. Of interest was that the clearance was 1.6×higher in neonates with a gestational age of more than 39 weeks than in neonates of less than 39 weeks ( Burtin et al., 1994 ).

The pharmacokinetics of midazolam in premature infants after both oral and intravenous administration were described by de Wildt and others (2002, 2001). In premature infants, 24 to 34 weeks' gestational age and 3 to 11 days of age, de Wildt and others 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 ( de Wildt et al., 2001 ) ( Fig 6-12 ).



FIGURE 6-12 Effect of postnatal indomethacin exposure on midazolam disposition in preterm infants. Midazolam concentration versus 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, Kearns GL, Hop WCJ, et al.: Clin Pharmacol Ther 70:525-531, 2001.)

In a separate study of preterm infants who were administered oral midazolam, de Wildt and others (2002) noted that midazolam clearance was markedly decreased and 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 and others (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 and others (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 ( Lebowitz et al., 1982 ), no significant difference was found in the hemodynamic effects of induction doses of 0.25 mg/kg midazolam and 4 mg/kg thiopental.

Respiratory depression is frequently 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 4.0 mg/kg per minute, 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 and others (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 1.0 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, potential postoperative behavior problems (fearfulness, nightmares, food rejection) were observed in children premedicated with oral (0.5 mg/kg) midazolam ( McGraw, 1993 ). In addition, McMillan and others (1992) have noted loss of balance, dysphoria, and blurred vision in some patients receiving 0.75 and 1.0 mg/kg orally. Hiccups have been associated with midazolam administration via the rectal, nasal, and oral routes ( Marhofer et al., 1999 ). The major disadvantage of oral midazolam is its bitter taste; it has to be administered in a flavored syrup or drink; however, a commercially available liquid preparation is now available.

Oral midazolam has been associated with prolonged recovery times in some children (Viitanen and others (1999), but studies by Brosius and Bannister (2001, 2002) using bispectral index and measured end-tidal gases refute this.

In a multicenter study involving 455 children, Coté and others (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 1.0 mg/kg had minimal effect on respiration and oxygen saturation ( Fig 6-13 ).



FIGURE 6-13 Percentage of patients exhibiting anxiety from baseline to time after 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. (Redrawn from Coté CJ, Cohen IT, Suresh S, et al.: Anesth Analg 94:374, 2002.)

Rectal administration of midazolam has been successfully used to sedate patients. Saint Maurice and others (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 and others (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 and others (1991) noted that the optimum dose of rectal midazolam was 1.0 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 and others (1988) and Davis and others (1995a) demonstrated the usefulness of preanesthetic sedation of preschool children with 0.2 to 0.3 mg/kg of intranasal midazolam. Walbergh and others (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/kg) 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 and others (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 and others (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 and others (1998) noted that in children aged 12 to 129 months who received either placebo or one of three doses of midazolam, none of the 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 much 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 events include seizures and cardiac dysrhythmias; these serious 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 midazolam 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 frequently used dose. In a study of 107 children undergoing procedural sedation, Shannon and others (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 ( Shannon et al., 1997 ). Because of its short half-life relative to the half-life of most benzodiazepines, resedation is a frequent finding after flumazenil use. Consequently, repeat administrations and careful patient observations are necessary (Jones, et al., 1993).

Nonbarbiturate Nonbenzodiazepines

Etomidate

Etomidate is a potent, short-acting, nonbarbiturate sedative-hypnotic agent without analgesic properties. It produces a central depressant effect through γ-aminobutyric acid (GABA) mimetic action. Administered intravenously, it has been used for induction and maintenance of anesthesia as well as for prolonged sedation in critically ill patients. Little information is available about 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 ASDs undergoing cardiac catheterizaion, Sarkar and others (2005) noted that induction doses of intravenous etomidate had no significant effect on the hemodynamics or on the shunt fraction ( p: s). Myoclonic movements that are not associated with ipileptiform electroencephalographic activity ( Ghonheim and Yamanda, 1977 ) occur in 30% to 75% of patients after induction with etomidate.

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 ). The major side effect regarding etomidate is it can suppress adrenal steroid synthesis and increase mortality (Ledinham 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 ( Wagner and White, 1984 ; Longnecker, 1984 ). In 30 children undergoing cardiopulmonary bypass, Donmez and others (1998) in a randomized prospective study noted that when etomidate (0.3 mg/kg) was used as an induction agent, it significantly suppressed the increased cortisol levels associated with the stress response of surgery and cardiopulmonary bypass. For induction of anesthesia, the recommended intravenous dose is 0.3 to 0.4 mg/kg.

Propofol

Propofol is an alkyl phenol 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 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, a slow elimination half-life, and a rapid clearance. 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 impairment, 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 and others (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 were 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 and others (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 and others (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 and others (2002), using population kinetics, reported propofol to have 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.

The pharmacodynamics of propofol have been well described and reviewed (Glass, 1993). Because of the pharmacokinetic properties of propofol, infusions allow for more rapid decreases in plasma concentrations ( Shafer, 1993 ) ( Fig 6-14 ) and allow for faster patient recoveries from anesthesia ( 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 ).



FIGURE 6-14 Curves showing time required for a 50% decrease in propofol and thiopental concentration after discontinuation of a continuous infusion. (With permission from Shafer SL: J Clin Anesth 5:145, 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 and others (1992) noted that in children aged 3 to 15 years receiving 5 mg/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 and others (1991) in which alfentanil was not administered, the ED₅₀ and ED₉₅ for loss of eyelash reflex were 1.3 and 2.0 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 3.0 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.

In patients with congenital heart disease, Gozal and others (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 and others (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 and others (2003) noted that in healthy children administered 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 and others (1992) demonstrated that 10 mg of propofol administered in the recovery room was effective in reducing the incidence of nausea and vomiting. In pediatric patients, Watcha and others (1991) noted that in patients undergoing strabismus surgery, propofol alone effectively decreases the incidence of postoperative emesis compared with a similar group of patients anesthetized with halothane and nitrous oxide and supplemented with prophylactic droperidol 23% versus 50%. However, in patients who received propofol and nitrous oxide, Watcha and others (1991) noted that the incidence of emesis increased significantly (60%). Weil and others (1993) also noted the antiemetic effect in pediatric strabismus patients 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 and others (1993) noted no difference in the incidence of emesis between pediatric patients undergoing strabismus repair 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 ( Borgeat et al., 1990 ) and ambulatory surgical procedures (Martin et al., 1993 ).

In patients undergoing radiofrequency ablation, a procedure that is associated with emesis as frequently as 60%, Erb and others (2002) noted that propofol-based anesthesia was associated with a markedly decreased incidence of nausea (21%) and emesis (6%) compared with a rate 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 on 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 on injection occurred more frequently in the infants (50%) than in the older children (18%). The addition of 5 mg/kg of alfentanil, 1% xylocaine (1 mg), or 0.1 mg/kg xylocaine can markedly attenuate the pain on injection ( Valtonen et al., 1989 ; Manschot et al., 1992 ). The addition of thiopental ( Cox, 2002 ) and the use of inhaled nitrous oxide ( Beh et al., 2002 ) also have been shown to attenuate the pain on injection.

Involuntary motor movements have been associated with propofol ( Reynolds and Koh, 1993 ), and these spontaneous movement disorders appear to occur in the absence of epileptic form activity on electroencephalography ( Borgeat et al., 1993 ). Anaphylactic reactions have also been reported. Initial studies with propofol using 10% Cremophor EL as a solubilizing agent had reported instances of anaphylactic reactions ( Briggs et al., 1982 ). Laxenaire and others (1992) have reported on 14 patients with life-threatening reactions within minutes after receiving propofol in its current preparation. In some patients, these anaphylaxis 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% EDTA or metabisulfite was added to the formulation by different manufacturers. In a study comparing propofol with and without EDTA, Cohen and others (2001) noted no differences in clinical profiles between the two drugs and noted that both formulations lower ionized calcium without any apparent clinical effect.

Ketamine

Ketamine is a racemic nonbarbiturate cyclohexamine derivative that produces dissociation of the 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 frequently is electroencephalographic seizure activity, particularly in the limbic system and cortex, without clinical manifestations ( Schwartz et al., 1974) . Clinically ketamine anesthetic produces effective analgesia, but patients may keep their eyes open. Many reflexes are preserved. Preservation of gag reflex, laryngeal irritability, and continued muscle tension occur. Two mg/kg produces 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 and others (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 6-7 ). In infants younger than 3 months, 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.

TABLE 6-7 -- Pharmacokinetics of ketamine: effect of age

Age	t_½β (min)	Vd_ss (L/kg)	CL (mL/min per kg)
< 3 mo	184.7	3.46	12.9
4 to 12 mo	65.1	3.03	35.0
4 yr	31.6	1.18	25.1
Adult	107.3	0.75	20.0

Modified from Lake CL: Pediatric anesthesia. East Norwalk, CT, 1988, Appleton & Lange.

t_½β, Elimination half-life; Vd_ss, volume of distribution at steady state; CL, clearance.

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 ; Murray et al., 1984).

The mechanism of cardiorespiratory stimulation has not been entirely clarified. Dowdy and Kaya (1968), Traber and others (1970), and other groups have shown that there is a direct negative inotropic action on 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 at all ages. This serves as a most valuable adjunct in 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 ( Gardner et al., 1971 ; Lockhart and Jenkins, 1972 ), but as shown by Dawson and others (1971), the increase may be held within acceptable limits by pretreatment with thiopental. 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 movements limit its usefulness in eye surgery.

With the present concern over toxicity of anesthetic agents, ketamine has the advantage of a clean record with no known toxic effects on liver, kidney, or other organ systems. The major drawback to ketamine administration 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 metabolic norketamine. Gutstein and colleagues compared oral premedication with ketamine at either 3 or 6 mg/kg. With 3 mg, 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 ).

▪ OPIOIDS

To avoid the major adverse hemodynamic effects caused by potent inhalation anesthetic agents, the use of narcotic anesthesia has reemerged. Relative potencies of the various narcotics are listed in Table 6-8 . Initially, meperidine (0.5 to 1.0 mg/kg) and morphine (0.05 to 0.1 mg/kg) were used to reinforce nitrous oxide anesthesia in the neonate. However, concerns regarding the toxicity and increased sensitivity of neonates to narcotics were raised. Way and others (1965) have demonstrated that morphine depresses newborn respiration more than does meperidine and that these decreases in respiration occur at a dose one third (on a milligram-per-kilogram basis) of that administered to adults. In laboratory animals, narcotics are more toxic to newborn animals than to older animals ( Goldenthal, 1971 ). For morphine and dihydromorphine, the blood-brain barrier is more permeable in newborn animals than in older animals. The brain concentration of morphine several hours after injection was two to four times greater in brains of younger rats despite equal blood concentration. This finding may be related to greater perfusion, to greater permeability, or to both in the newborn. Such developmentally increased permeability is not seen with meperidine ( Kupferberg and Way, 1963 ); this is not surprising because the lipid solubility of meperidine is quite high.

TABLE 6-8 -- Comparative narcotic potencies

Drug	Potency
Morphine	1
Meperidine	0.1
Alfentanil	40
Fentanyl	150
Sufentanil	1500

Studies involving opiate receptor-binding sites in rats have suggested that changes in receptor ontogeny also may be responsible for the respiratory depressant and analgesic effects observed in newborns. Zhang and others (1981) have shown that both low-affinity and high-affinity opiate receptors are present in rats. Low-affinity receptors are associated with respiratory depression, whereas high-affinity receptors are associated with analgesia. In the rat model, low-affinity receptors are present in large numbers at birth, and the number remains constant to 18 days of life. By contrast, high-affinity receptors are scarce at birth and do not reach significant proportions (50% of the adult value) until 15 days of life. Respiratory depression in infants may be a function not only of the lipophilicity of opioids but also of the maturational changes in the opiate receptor pool. In addition to age-related changes in opioid receptor pools, genetic factors may affect the OPRMJ opioid receptor. Single nucleotide polymorphisms, resulting in a single amino acid change, can have effects on opioid side effects and analgesia ( Matthes et al., 1996 ; Klepstad et al., 2004 ; Romberg et al., 2004 , 2005).

Clinical studies on opioid sensitivity have been conflicting. Early reports by Kupferberg and Way suggested neonates had more respiratory depression after opioid administration than did adults. However, Lynn and others (1993) evaluated the respiratory depressant effects of intravenous morphine infusions in 30 patients aged 2 to 570 days and noted no evidence of a relationship of any given morphine concentration with respiratory depression and age.

Nichols and others (1993) studied the extent and duration of respiratory depression after intrathecal administration of 0.02 mg/kg of morphine to 10 patients aged 4 months to 15 years. Although intrathecal morphine depresses ventilation for at least 18 hours, there was no relationship of age and ventilatory depression.

Age-related sensitivities have also been studied after intravenous fentanyl administration. Hertzka and others (1989) determined that fentanyl-induced ventilatory depression as assessed by skin surface Pco₂and ventilatory patterns was not greater in infants older than 3 months than in children or adults. In addition to age sensitivities, Zhou and others (1993) demonstrated ethnic differences in the disposition and effects of morphine.

Morphine

The pharmacology of morphine has been studied in both adults and children. In adults, morphine is 30% to 35% protein bound, while in neonates, it is 18% to 22% bound ( Bhat et al., 1990 ). Morphine is a drug with a high hepatic extraction coefficient; consequently, morphine clearance is determined by hepatic blood flow. Increases in hepatic blood flow can further increase morphine clearance, whereas decreases in hepatic blood flow can lower drug clearance. Morphine is inactivated by N-demethylation and glucuronidation. The two major metabolic products are morphine 6-glucuronide and morphine 3-glucuronide, which are mainly excreted by the kidney. In adults, sulfate metabolism accounts for 5% to 10% of the drug metabolism. Although in neonates the enzymes for glucuronide metabolism are immature and the role of sulfation in morphine metabolism may be more pronounced, Choonara and others (1989) demonstrated that in the neonate sulfation contributes little to morphine metabolism.

As with other drugs, morphine appears to undergo age-related changes in its pharmacokinetic profile ( Table 6-9 ). The presence of age-related changes in the neonatal period appears somewhat controversial. Bhat and others (1990) studied the pharmacokinetics in 20 newborn infants less than 5 days of age after a single bolus administration of intravenous morphine. In this study, they concluded that with increasing gestational age, drug clearance increases by 0.9 mL/kg per minute per week gestation and that with increasing gestational age, both distribution and elimination half-life also decreased. Compared with term infants, Bhat and others noted that infants less than 30 weeks' gestation had a longer elimination half-life (50 versus 19 minutes) and slower clearances (3.4 versus 15 mL/kg per minute). However, Chay and others (1992) reported no difference in the pharmacokinetics of continuous morphine infusions in preterm and term infants. There was no reported correlation of gestational age or conceptual age with drug clearance or elimination half-life. In addition, these investigators noted that a plasma concentration of 125 ng/mL was necessary to provide adequate sedation in 50% of the neonates. These values are quite high compared with analgesic values of 12 ng/mL needed after cardiac surgery ( Lynn et al., 1984 ).

TABLE 6-9 -- Morphine age-related pharmacokinetics

Reference	Age	No. of Patients	V_d (L/kg)	CL (mL/kg per min)	t_½β (min)
Dahlstrom et al. (1979)	1 to 7 yr	8	1.13	6.17	183
Dahlstrom et al. (1979)	7 to 15 yr	8	1.36	6.71	202
Lynn and Slattery (1987)	2 to 4 days	7	3.3	6.3	408
Lynn and Slattery (1987)	17 to 65 days	4	5.15	23.8	234
Barret et al. (1991)	1 to 37 days	26	2.7	3.6	534

V_d, Volume of distribution; CL, clearance; t_½β, elimination half-life.

In addition to age, morphine pharmacokinetics can be influenced by disease. Patients with renal failure were reported to be sensitive to narcotic intoxication after morphine administration. Chauvin and others (1987b) studied the pharmacokinetics of morphine in adult patients with renal insufficiency. For morphine, they found that patients with chronic renal failure have similar rates of clearance and half-lives but significantly smaller steady-state volumes of distribution compared with age- and weight-matched control patients. Although chronic renal failure did not alter the elimination of unchanged morphine, metabolites of morphine accumulated at higher plasma levels for longer periods of time in the patients with chronic renal failure ( Chauvin et al., 1987b ). In studies of patients with renal failure, Osbourne and others (1993) noted that morphine metabolism is impaired and that the metabolites of morphine (morphine 3-glucuronide and morphine 6-glucuronide) accumulate in the plasma ( Fig 6-15 ). Hanna and others (1993) have also demonstrated abnormal kinetics of morphine metabolites in patients with renal failure. Patients with renal failure had a prolonged elimination half-life and decreased clearance in the pharmacokinetic profile of morphine 6-glucuronide. In patients with renal impairment, the increased opioid sensitivity may be a function of decreased morphine metabolism coupled with impaired clearance of the metabolites.



FIGURE 6-15 (A) Morphine and metabolite levels in normal volunteers (mean ± SEM; data correction to 10 mg/70 kg). (B) Pharmacokinetics of morphine and morphine glucuronides in patients with kidney failure. (With permission from Osborne R, Joel S, Grebenik K:Clin Pharmacol Ther 54:158, 1993.)

In patients with liver disease, the effects of disease can be unpredictable. Patwardhan and others (1981) described the effects of liver disease on morphine kinetics in adult patients with cirrhosis and healthy adult volunteers. Compared with healthy subjects, patients with moderate-to-severe cirrhosis had a normal elimination and disposition of morphine but a prolonged elimination half-life and decreased clearance of indocyanine. Because morphine is a highly extracted drug and its clearance depends on hepatic blood flow, the investigators postulated that morphine has extrahepatic sites of metabolism in the gastrointestinal tract and kidneys.

In a limited study of 21 children aged 6 months to 10 years who underwent cardiopulmonary bypass for repair of their underlying heart defects, Dagan and others (1993) noted that morphine clearance in the postbypass period for patients requiring inotropic support was 50% less than that reported for other children.

In addition to intravenous infusions, intraspinal axis administration of opioids has been studied. In adults, Nordberg and others (1984) noted that after 0.5 mg of intrathecally (L2-4) administered morphine, the cerebrospinal fluid kinetics revealed a terminal half-life of 175 minutes, volume of cerebrospinal fluid distribution of 0.88 mL/kg, and a clearance of 2.8 mL/kg per minute. In pediatric patients undergoing craniofacial surgical repairs, Nichols and others (1993) noted that the cerebrospinal fluid concentrations at 6, 12, and 18 hours after 0.02 mg/kg intrathecal administration were 2860, 640, and 220 mg/mL, respectively.

In children, Attia and others (1986) demonstrated that the pharmacokinetics of epidural morphine were similar to values reported in adults. After a 50-mg/kg epidural bolus, the volume of distribution was 7.9 L/kg, the elimination half-life was 74 minutes, and the clearance was 28 mL/kg per minute. In addition to morphine pharmacokinetics, Attia and others noted that the onset and duration of analgesia were 30 minutes and 19 hours, respectively, and that respiratory depression as evidenced by changes in the slope of the ventilatory response to CO₂ was impaired for 22 hours after epidural administration.

Fentanyl

Fentanyl is a synthetic opiate with a clinical potency 50×to 100×that of morphine. It is metabolized by dealkylation, hydroxylation, and amide hydrolysis to inactive metabolites. It has a high hepatic extraction coefficient and a high pulmonary uptake ( Roerig et al., 1987 ). In adults, Heberer noted that cirrhosis had no effect on fentanyl kinetics. Fentanyl has relatively minimal hemodynamic effects and is used both as an adjunct to nitrous oxide anesthesia and as a sole anesthetic agent. Bradycardia and chest wall rigidity are potential features of high-dose fentanyl anesthesia. The cardiovascular effects of fentanyl at doses of 30 to 75 mcg/kg fentanyl (with pancuronium) are minimal ( Hickey et al., 1984 ). Modest decreases in mean arterial pressure and systemic vascular resistance index were noted by Hickey and others (1985).

In neonates, Murat and others (1988) have shown that although baroreceptor control of heart rate is present, fentanyl anesthesia (10 mcg/kg) can significantly depress the baroreceptor response to both hypotension and hypertension. Respiratory depression is probably concentration related as well. In adult comparative studies of opioid-induced respiratory depression with sufentanil and fentanyl administration, Bailey and others (1990) noted that ventilatory depression (both magnitude and duration) was less after sufentanil administration. In addition, although the two drugs have similar half-lives, analgesia lasted longer after sufentanil administration.

The dose of fentanyl needed to ensure satisfactory anesthesia for infants varies with the surgical stress. Hickey and Retzack (1993) have shown that in a pediatric patient with reactive pulmonary vasculature, 25 mcg/kg of fentanyl was needed to prevent an acute episode of right ventricular failure secondary to pulmonary hypertension in the patient who was undergoing upper airway instrumentation and manipulation. Ellis and Steward (1990) have shown that in children undergoing hypothermic cardiopulmonary bypass or profound hypothermia with circulatory arrest anesthetized with fentanyl, a dose of at least 50 mcg/kg of fentanyl was needed to blunt the hyperglycemic response to hypothermia and circulatory arrest. Yaster (1987) noted that in neonates anesthetized with fentanyl, metocurine, and oxygen who were undergoing a wide variety of surgical procedures, fentanyl (10 to 12.5 mcg/kg) provided reliable hemodynamic stability for 75 minutes ( Yaster, 1987 ).

In a study of children aged 6 months to 6 years undergoing cardiac surgery with cardiopulmonary bypass, Pirat and others (2002) compared three groups of patients. One group received intravenous fentanyl, the second group received intrathecal fentanyl, and the third group received both intravenous and intrathecal fentanyl. In this study, intrathecal fentanyl offered no advantage over intravenous fentanyl with regard to hemodynamic stability or suppression of the biochemical stress response. However, the combination of intrathecal and intravenous fentanyl was associated with better hemodynamic stability in the prebypass period compared with either group alone.

Duncan and others (2000) reported a dose-ranging study of 40 pediatric patients undergoing cardiac surgery using one of five intravenous fentanyl doses: 2, 25, 50, 100, and 150 mcg/kg. In this study, patients in the 2 mcg/kg group had significant rises in prebypass glucose, prebypass and postbypass cortisol, and prebypass and postbypass norepinephrine. No significant rise occurred in glucose, cortisol, and catecholamines in any of the higher dosage groups. Patients in the 2 mcg/kg group had significantly higher mean systolic blood pressure and heart rate. Higher doses of fentanyl (100 and 150 mcg/kg) offered little advantage over 50 mcg/kg.

Age-related differences in the kinetics and sensitivity to fentanyl and changes in kinetics associated with pathophysiologic conditions and types of surgery create variability and make generalizations difficult ( Johnson et al., 1984 ; Collins et al., 1985 ; Koehntop et al., 1986 ; Singleton et al., 1987 ; Koren, et al., 1984). In the neonate, fentanyl clearance seems comparable to that of the older child or adult, whereas in the premature infant, fentanyl clearance is markedly reduced. In premature infants, fentanyl half-life was reported as 6 to 32 hours ( Collins et al., 1985 ). In infants and children, fentanyl plasma concentrations were less than those in adults after similarly administered intravenous doses (milligrams per kilogram) ( Singleton et al., 1987 ) ( Fig 6-16 ). These marked variations in kinetics reflect age differences and perhaps differences in anesthetic, dose, and duration of sampling.



FIGURE 6-16 Fentanyl concentration-versus-time curves for adults (top curve), children (middle curve), and infants (bottom curve). (With permission from Singleton MA, Rosen JI, Fisher DM: Can Anaesth Soc J 34:152, 1987.)

Fentanyl pharmacokinetics after continuous infusions for less than 24 hours in critically ill children have demonstrated increased steady-state volume of distribution (15.2 L/kg), prolonged terminal elimination half-life (24 hours), and normal clearances ( Katz and Kelly, 1993 ). The pharmacokinetics after 48 hours of continuous fentanyl infusion in newborns were reported in 12 neonates. In these infants (mean gestational age, 32 weeks; mean weight, 1.88 kg; mean postnatal age, 6 ± 9 days), the volume of distribution was noted as 17 ± 9 L/kg, total body clearance was 1154 mL/kg per hour, and the half-life was 9.5 ± 2.6 hours ( Santeiro et al., 1997 ). In addition, the relatively high total body clearance was noted to correlate with postnatal age, suggesting that hepatic blood flow increases with age. Gauntlett and others (1988) found that fentanyl clearance increased with postnatal age, with most of the increase occurring by 2 weeks of age.

In a study of nonsurgical neonates, Saarenmaa and others (2000) studied the fentanyl clearance in the first few days of life of 38 infants who were at 26 to 42 weeks gestation and had birth weights of 835 to 3550 g. This study reported a correlation of fentanyl clearances with gestational age and birth weight ( Fig 6-17 ).



FIGURE 6-17 Plasma clearance of fentanyl correlates with gestational age and birth weight. (Redrawn with permission from Saarenmaa E, Neuvonen P, Fellman V: Gestational age and birth weight effects on plasma clearance of fentanyl in newborn infants. J Pediatr136:767-770, 2000.)

Prolonged fentanyl infusions, however, were associated with tolerance. In neonates sedated with fentanyl via continuous infusion while undergoing ECMO, Arnold and others (1991) noted that the daily infusion rates and plasma concentrations required to keep the infant sedated increased over time. Although prolonged continuous infusions of fentanyl may increase the volume of distribution, prolong the elimination half-life of the drug, and consequently prolong recovery on discontinuation, the development of tolerance may minimize this pharmacologic consequence.

In addition to intravenous administration, fentanyl has been administered transmucosally as a means of providing sedation to children. The pharmacokinetics and bioavailability of oral transmucosal fentanyl citrate (OTFC) were studied by Streisand and others (1991) using adult volunteers studied on three separate occasions ( Fig 6-18 ). Plasma levels of fentanyl were determined after either the intravenous, transmucosal, or gastrointestinal (oral) route of administration. Regardless of the mode of administration, the terminal elimination half-life was similar in all three groups (425 to 469 minutes). Compared with the oral group, peak plasma concentrations of fentanyl occurred earlier (22 versus 101 minutes) and were higher (30 versus 1.6 ng/mL) in the OTFC groups. The bioavailability of OTFC was 50% compared with 30% in the oral group. This difference in the bioavailability probably relates to the first-pass (hepatic extraction) effect observed with orally administered drugs ( Streisand et al., 1991 ).



FIGURE 6-18 Plasma concentrations of fentanyl following oral transmucosal (OTFC), intravenous (IV), and oral administration. (With permission from Streisand JB, Varvel JR, Stanski DR: Anesthesiology 75:226, 1991.)

Intranasal administration of fentanyl has also been used to provide postoperative analgesia for pediatric patients ( Galinkin et al., 2000 ; Manjushree et al., 2002 ). After 2 mcg/kg of intranasal fentanyl, Galinkin and others noted the mean fentanyl concentrations at 10 and 34 minutes were 0.8 and 0.6 ng/mL, respectively. In a study comparing intranasal fentanyl with intravenous fentanyl, Manjushree and others noted that onset time to analgesia after 1 mcg/kg of fentanyl was slower (13 minutes) for the intranasal route than for the intravenous route of administration (8 minutes).

Sufentanil

With the supposition that increase in potency is associated with increased opiate effects and decreased nonspecific cardiovascular effects, other fentanyl congeners have been developed. Sufentanil, a potent synthetic opioid, is an N-4 substituted derivative of fentanyl. It is a highly lipophilic compound that is distributed rapidly and extensively to all tissues. Sufentanil is approximately 5 to 10 times more potent than fentanyl and has an extremely high margin of safety. The major pathways for sufentanil metabolism involve O-demethylation and N-dealkylation; minimal amounts are excreted unchanged in urine. Desmethyl sufentanil, the major metabolite of sufentanil, possess about 10% the activity of the potent compound.

Pharmacokinetic and pharmacodynamic studies of sufentanil were conducted in infants, children, and adults. In adults, compared with fentanyl, the smaller volume of distribution (2.48 L/kg) and high clearance rate (11.3 mL/kg per minute) of sufentanil contribute to its short terminal elimination half-life (149 minutes). Meuldermans and others (1982) demonstrated that sufentanil is more protein bound (92%) than fentanyl (84%) and that pH affects protein binding. Decreasing pH from 7.4 to 7.0 increased protein binding by 28%; conversely, increasing pH from 7.4 to 7.8 decreased protein binding by 28%.

Clinical studies assessing the hemodynamic and endocrine stress response of sufentanil have been done in adults undergoing cardiopulmonary bypass ( deLange et al., 1982 ; Sebel and Bovill, 1982 ). Sufentanil appears to block some of the stress responses to cardiac surgery. Stress-induced increases in antidiuretic hormone (ADH) and growth hormone (GH) appear to be blocked before, during, and after cardiopulmonary bypass, whereas the catecholamines (norepinephrine, epinephrine, and dopamine) show a large surge during the bypass and postbypass periods ( deLange et al., 1982 ; Bovill et al., 1983 ). In a double-blind study, Rosow and others (1984) found the drugs, fentanyl and sufentanil, to be comparable with regard to hemodynamic stability.

The pharmacokinetic and pharmacodynamic effects of sufentanil in children were studied. Hickey and others (1984) compared the hemodynamic response of 5 and 10 mcg/kg of sufentanil to 50 to 75 mcg/kg of fentanyl in patients with complex congenital heart disease. Although heart rate and blood pressure changed slightly, they noted marked improvement in the patient's oxygenation with both fentanyl and sufentanil. They concluded that both sufentanil and fentanyl were safe anesthetics in high doses and that both agents favorably decreased pulmonary vascular resistance and thereby increased pulmonary blood flow and systemic oxygenation in patients with cyanotic heart disease. Davis and others (1987) examined both the pharmacodynamics and pharmacokinetics of high-dose sufentanil (15 mcg/kg) and oxygen in infants and children undergoing cardiac surgery. Sufentanil provided marked hemodynamic stability after an infusion and during the stress periods of incision and sternotomy ( Table 6-10 ). The hemodynamic responses to sufentanil were similar to those noted by Hickey and others (1984) but differed from the increases in blood pressure and heart rate occurring after intubation, sternotomy, and incision observed in older children having repair of their congenital heart defect ( Moore et al., 1985 ).

TABLE 6-10 -- Hemodynamics during sufentanil anesthesia in infants and children undergoing open-heart surgery

Variable	Baseline	1 min	5 min	Incision	Sternotomy
Heart rate	140 ± 14	129 ± 25	118 ± 23^[*]	116 ± 20^[*]	123 ± 32
Systolic blood pressure	101 ± 9	86 ± 15^[*]	74 ± 11^[*]	99 ± 15	106 ± 13
Diastolic blood pressure	65 ± 10	48 ± 9^[*]	46 ± 12^[*]	65 ± 14	67 ± 13

Reprinted with permission from the International Anesthesia Research Society from Davis PJ, Cook DR, Stiller RL, Davin-Robinson KA: Pharmacodynamics and pharmacokinetics of high-dose sufentanil in infants and children undergoing cardiac surgery. Anesth Analg 66:203, 1987.

Values are mean ± SD.

^*	P < .01 compared with baseline.

Greeley and others (1987) investigated age-related changes in the pharmacokinetics of sufentanil in pediatric patients undergoing cardiothoracic surgery. They noted that sufentanil best fit a three-compartment model and that neonates had significantly smaller clearance rates, larger volumes of distribution at steady state, and longer elimination half-lives than infants, children, and adolescents ( Table 6-11 ). The developmental pharmacokinetic changes of improved clearance and elimination for sufentanil were further substantiated in another report in which infants were studied within the first 8 days of life and then again at 3 to 4 weeks of age ( Greeley and de Bruijn, 1988 ).

TABLE 6-11 -- Age-related pharmacokinetic values for sufentanil

Age	N	t_½α (min)	t_½β (min)	CL (mL/kg per min)	Vd_ss (L/kg)
Neonates (0 to 8 days)	3	20.5	635	4.2	2.7
Neonates (20 to 28 days)	3	8.8	217	17.3	3.4
0 to 1 mo	9	23.4	737	6.7	4.15
1 mo to 2 yr	7	15.8	214	18.1	3.09
2 to 12 yr	7	19.6	140	16.9	2.73
12 to 16 yr	5	20.4	209	13.1	2.75

Reprinted with permission from the International Anesthesia Research Society from Greeley WJ, de Bruijn NP: Sufentanil pharmacokinetics in pediatric cardiovascular patients. Anesth Analg 67:86, 1988.

t_½α, Distribution phase half-life; t_½β, elimination phase half-life; CL, clearance; Vd_ss, volume of distribution at steady state.

Guay and others (1992) studied the pharmacokinetics of sufentanil in 20 healthy pediatric patients aged 2 to 8 years. After intravenous administration of 1 to 3 mcg/kg of sufentanil, the elimination half-life was 97 minutes, the volume of distribution at steady state was 2.9 L/kg, and the plasma clearance was 30.5. It is unclear whether the doubling of the plasma clearance value in healthy children was a function of the study design or the patient's underlying disease.

In addition to its use as an anesthetic agent, sufentanil has been used as a preanesthetic medication in children. Pharmacokinetic studies in adults after intravenous and intranasal administration show that the area under the curve from 0 to 120 minutes after intranasal dosing was 78% of that after intravenous injection ( Helmers et al., 1989 ). By 30 minutes after drug administration, plasma sufentanil concentrations were identical for the two routes of administration.

The role of the kidney in sufentanil elimination and metabolism has not been well defined. The effects of renal failure in sufentanil kinetics were assessed in adolescent patients with chronic renal failure (Davis et al., 1988 ). Although there was no statistical difference in apparent volume of distribution, elimination, and clearance between patients with renal failure and control patients, patients with renal failure demonstrated more variability in clearance and half-life ( Table 6-12 ). In patients with renal failure, sufentanil must be administered carefully on the basis of responses elicited in individual patients.

TABLE 6-12 -- Pharmacokinetics of sufentanil in adolescent patients with chronic renal failure (group 1) and in patients without renal disease (group 2)

Group	Vd₁₈₀ (L/kg)	t_½α (min)	t_½ β₁₈₀	CL (mL/kg per min)
1	1.65±0.6	2.85±1.7	89.7±15.7	16.4±6.1
2	1.28±0.62	2.5±0.73	76.0±32.8	12.8±12.0

Reprinted with permission from the International Anesthesia Research Society from Davis PJ, Stiller RL, Cook DR, et al: Effects of cholestatic hepatic disease and chronic renal failure on alfentanil pharmacokinetics in children. Anesth Analg 67:268, 1988.

Values are mean ± SD. Vd₁₈₀, Volume of distribution at 180 min; t_½α, distribution phase half-life; t_½β₁₈₀, elimination phase half-life at 180 min; CL, clearance.

The pharmacodynamics of sufentanil were also evaluated in neurosurgical patients. The effects of opioids on intracranial pressure (ICP) and cerebral perfusion pressure have been controversial. In intubated patients with severe head injuries (Glasgow Coma Scale GCS < 8), sufentanil administration was associated with an increase in ICP, a decrease in mean arterial blood pressure, and a decrease in cerebral perfusion pressure ( Albanese et al., 1993 ). The effects of sufentanil in the EEG of premature infants was reported by Nguyen and others (2003). Bolus injection and continuous infusion increased EEG discontinuity, decreased burst suppression, and increased interburst intervals.

In adult patients undergoing nonintracranial neurosurgical procedures, Trindle and others (1993) noted that cerebral blood flow velocity (as assessed by transcranial Doppler) increased after sufentanil infusion. This increase in velocity was similar for equipotent doses of fentanyl ( Trindle et al., 1993 ).

In a study of adult head trauma patients, Scholz and others (1994) noted that sufentanil bolus (2 mcg/kg), combined with a sufentanil continuous infusion (150 mcg/hr) and midazolam continuous infusion (9.0 mg/hr), resulted in a decrease in both ICP and mean arterial pressure. Perfusion pressure was noted to be stable.

Alfentanil

Alfentanil, a potent, short-acting analog of fentanyl, is rapidly distributed to the brain and central organs and then rapidly redistributed to more remote sites. It is about one fourth as potent as fentanyl and has one third the duration of action. Following a single bolus injection, the drug's decreased volume of distribution results in a significantly shorter elimination half-life. Its low lipid solubility allows less penetration of the blood-brain barrier. The concentration in brain tissue is markedly less than that in plasma. The duration of narcotic effect appears to be governed by redistribution and elimination. The redistribution principle operates in a small single-dose infusion, whereas elimination determines the effect of a large single bolus, a multiple small-bolus infusion, or a continuous infusion. Alfentanil is metabolized in the liver by oxidative N-dealkylation and O-demethylation in the CYP3A4 system ( Yun et al., 1992 ). The pharmacologically inactive metabolites are excreted in the urine ( Camu et al., 1982 ), with the major metabolite being noralfentanil. Alfentanil metabolism is catalyzed by CYP3A3/4 and CYP3A5 ( Klees et al., 2005 ). Interindividual differences in the expression of this cytochrome and its susceptibility to inducers and inhibitors may account for the clinical variability in alfentanil kinetics and dynamics ( Kharasch and Thummel, 1993 ). Although gender differences in CYP activity can affect drug metabolism, Kharasch and others (1997), in a study of young women, could find no differences in alfentanil clearance on different days of the menstrual cycle. Differences in CYP activity can markedly influence the pharmacokinetics of alfentanil, specifically its context-sensitive half-time. Using normal, low, and high CYP3A4 activity, Kharasch and others (1997b) have postulated through computer simulations that alfentanil can behave similarly to remifentanil (high CYP3A4 activity) or fentanyl (low CYP3A4 activity) ( Fig 6-19 ).



FIGURE 6-19 Effect of P450 3A4 activity on the time required for a 50% decrease in alfentanil venous plasma concentration after targeted infusions of variable durations. Half-times for fentanyl and remifentanil in normal participants were calculated using reported kinetic parameters. (Redrawn from Kharasch E, Russell M, Mautz D, et al.: The role of cytochrome P450 3A4 in alfentanil clearance: implications for interindividual variability in disposition and perioperative drug interactions. Anesthesiology 87:36-50, 1997.)

Protein binding has a significant influence on the pharmacokinetics of alfentanil. Alfentanil is 88% to 95% protein bound in the plasma and is independent of concentration and blood pH. The plasma protein most responsible for binding of alfentanil is α₁-acid glycoprotein. In adults, changes in the binding and in the pharmacokinetics of alfentanil occur during and after cardiopulmonary bypass ( Hug, 1984 ). Disease states including end-stage kidney or liver failure can alter protein binding of opioids in children. Davis and others (1989b) studied the effects of liver disease and kidney disease on the binding characteristics of alfentanil. Compared with the healthy children, patients with kidney disease had a significant decrease in protein binding (89.2 ± 5.4% versus 93.1 ± 3.2%), an increase in α₁-acid glycoprotein concentration (108.8 ± 44.3 versus 71.8 ± 30.7 mg/dL), and no change in albumin concentration (3910 ± 754 versus 4555 ± 524 mg/dL), whereas patients with liver disease had a significant decrease in protein binding (85.9 ± 6.2% versus 93.1 ± 3.2%), no change in α₁-acid glycoprotein concentration (65.8 ± 31.8 versus 71.8 ± 30.7 mg/dL), and a decrease in albumin concentration (3045 ± 1255 versus 4555 ± 524 mg/dL). Alfentanil binding has been studied in adult burn patients and noted to be increased from 90% to 94% protein bound ( Macfie et al., 1992 ). Because alfentanil is highly protein bound, even small changes in the drug's free fraction could have marked pharmacodynamic effects in patients with kidney or liver failure.

The pharmacokinetics of alfentanil have been studied in both adults and children, but limited information is available for children of different ages. The limited, age-related, developmental pharmacokinetic data for alfentanil are presented in Table 6-13 . In a study by Meistelman and others (1987), children aged 5 ± 1.1 years had a significantly smaller volume of distribution and shorter elimination half-life but similar clearance values compared with young adult patients aged 31 ± 4 years. Gorskey and others (1987) noted no difference in volume of distribution, elimination half-life, or clearance in infants aged 3 to 12 months compared with children aged 1 to 14 years. Roure and others (1987), on the other hand, noted that children aged 33 ± 18 months had faster clearance rates and elimination half-lives but similar volumes of distribution compared with those of adults. As Maitre and others (1987) noted in population studies of alfentanil pharmacokinetics in adults, differences in the pharmacokinetic profiles among the pediatric studies may be related to the large interpatient variability of alfentanil. Davis and others (1989a) have studied the pharmacokinetics of a single bolus of alfentanil in newborn premature infants and older children. In their study, newborn premature infants had considerably longer elimination half-lives (525 ± 305 versus 60 ± 11 minutes), slower clearance rates (2.2 ± 2.4 versus 5.6 ± 2.4 mL/kg per minute), and larger volumes of distribution (1.0 ± 0.39 versus 0.48 ± 0.19 L/kg) than those observed in the older children ( Fig 6-20 ).

TABLE 6-13 -- Alfentanil age-related pharmacokinetics

Reference	Age	No. of Patients	V_d (L/kg)	CL (mL/min per kg)	t_½β (min)
Meistelman et al. (1987)	4 to 8 yr	8	0.163	4.7	40
Meistelman et al. (1987)	25 to 40 yr	5	0.457	4.2	97
Goresky et al. (1987)	4 to 12 mo	5	0.500	8.3	76
Goresky et al. (1987)	1 to 14 yr	8	0.416	7.7	84
Davis et al. (1989a)	1 to 3 days (premature, 26 to 35 wk)	5	0.840	1.35	455
Killian et al. (1990)	1 to 3 days (term)	5	0.820	1.7	328

V_d, Volume of distribution; CL, clearance; t_½β, elimination half-life.



FIGURE 6-20 Alfentanil concentration-versus-time curves in newborn premature infants and older children. Both groups received 25 mcg/kg of alfentanil. (With permission from Davis PJ, Killian A, Stiller RL, et al.: Dev Pharmacol Ther 13:21, 1989.)

In a report on the influence of gestational age on the pharmacokinetics of alfentanil in neonates, Killian and others (1990) noted no change in alfentanil kinetics between preterm and term infants. Wiest and others (1991) studied the kinetics of alfentanil in neonates after a loading dose and variable continuous infusion route. Noncompartmental analysis revealed a clearance rate of 3.24 mL/kg per minute, a volume of distribution of 0.54 L/kg, and an elimination half-life of 4.1 hours. However, they noted an effect of alfentanil plasma concentration and plasma clearance.

The effects of renal failure and cirrhosis on alfentanil kinetics were studied in adult and in pediatric patients. Chauvin and others (1987a) have studied the pharmacokinetics of alfentanil in adult patients with chronic renal failure. The clearance and half-life values for alfentanil were similar in patients with renal failure and in control patients, but the steady-state volumes of distribution of alfentanil were significantly greater in patients with renal disease than in control patients. However, when the kinetic values for alfentanil were corrected for protein binding, the steady-state volumes of distribution and rates of clearance of unbound drug were similar in both groups of patients.

The effects of cirrhosis on alfentanil pharmacokinetics in adults were demonstrated by Ferrier and others (1985). Cirrhotic patients have lower total plasma clearance (1.60 versus 3.06 mL/kg per minute) and prolonged terminal elimination half-life (219 versus 97 minutes) but similar volume of distribution (0.390 versus 0.355 L/kg) compared with control patients.

By contrast to the studies in adults, the pharmacokinetics of alfentanil in children with cholestatic liver disease or end-stage kidney disease who are about to undergo either liver or kidney transplantation appear to be unaffected by the disease process ( Davis et al., 1989b ). Whether this difference is related to age or to the underlying pathophysiology of the disease states remains unanswered.

As do other narcotics, alfentanil produces a shift to the right in the ventilatory response curve. Although this shift is dose dependent, the ventilatory depressant effects dissipate by 30 to 50 minutes after the dose is given ( Kay and Pleuvry, 1980 ; Kay and Stephenson, 1980 ).

Goldberg and others (1992) noted that in healthy adult patients, prolonged alfentanil administration sometimes resulted in arterial oxygen desaturation and depression of the hypercapneic respiratory drive even though the patients were easily arousable. Muscle rigidity can occur with rapid-acting opiates such as fentanyl, sufentanil, and alfentanil. Pokela and others (1992) have reported that rigidity occurs in neonates after alfentanil administration.

The cardiovascular effects of alfentanil were assessed during both low- and high-dose infusions ( Kay and Pleuvry, 1980 ; Kay and Stephenson, 1980 ). At doses of 150 mcg/kg, heart rate, mean arterial pressure, and systemic vascular resistance were noted to decrease. Pulmonary capillary wedge pressure, pulmonary vascular resistance, right atrial pressure, and pulmonary artery pressure increased slightly ( Kramer et al., 1983 ).

The neuroendocrine stress response with alfentanil has been studied in adults. Alfentanil incompletely suppresses the stress response. High-dose alfentanil can blunt the GH, ADH, and cortisol response to bypass. Epinephrine and norepinephrine concentrations are increased with the onset of bypass (Stanley, et al., 1983; deLange, et al., 1982).

In children, Meretoja and Rautiainen (1990) noted that in children aged 1 month to 2 years, oral flunitrazepam premedication and alfentanil bolus of 20 mcg/kg followed by a continuous infusion of 0.5 mcg/kg per minute provided adequate sedation for patients spontaneously breathing room air who were undergoing cardiac catheterization. In these patients, hemodynamic variables changed less than 11%.

In adults, Ausems and Hug (1986) have defined the Cp₅₀ values of alfentanil for various surgical and anesthetic stimulations ( Fig 6-21 ). Using these adult Cp₅₀ plasma values, initial bolus and infusion rates can be estimated for children.



FIGURE 6-21 Relationship between the alfentanil plasma concentrations (with 66% nitrous oxide) and their effects for three specific events of short duration (intubation, skin incision, and skin closure). (With permission from Ausems ME, Hug C, Stanski DR, et al.:Anesthesiology 65:362, 1986.)

Remifentanil

Remifentanil is the hydrochloride salt of 3-[4-methoxy-carbonyl]-4-[(1-oxopropyl) phenylamino]-1-piperidine] propanoic acid, methyl ester. Because of its ester linkage, remifentanil is susceptible to metabolism by blood and tissue esterases. Its primary metabolic pathway is through deesterification to form a carboxylic acid metabolite, which is only one-300th to one-1000th the potency of the parent compound. In adult studies, the pharmacokinetic profile of remifentanil is best described by a biexponential decay curve, with a small volume of distribution (0.39 L/kg), a rapid distribution phase (0.94 minute), and an extremely short elimination half-life (10 minutes) ( Egan et al., 1993 ; Glass et al., 1993 ; Westmoreland et al., 1993 ).

In addition, computer simulations show that the duration of remifentanil infusion has no effect on the time to decrease the plasma or effect site concentration by 50%. The t_½ keo, or half-time for equilibration between plasma and the effect compartment, is 1.3 minutes. Thus, the context-sensitive half-time is a flat line.

For opioids, which undergo organ elimination, the neonatal profile of opioids demonstrates prolonged clearances, large volume of distributions, and markedly prolonged half-lives. However, in neonates remifentanil has a rapid clearance, a large volume of distribution, and a half-life that does not change with age. In an age-related study of remifentanil pharmacokinetics, Ross and others (2001) noted that the volume of distribution was largest in the infants younger than 2 months (mean, 452 mL/kg) and decreased to mean values of 223 to 308 mL/kg in the older patients. There was a more rapid clearance in the infants younger than 2 months (90 mL/kg per minute) and infants aged 2 months to 2 years (92 mL/kg per minute) than in the other groups (mean, 46 to 76 mL/kg per minute). The half-life was similar in all age groups, with mean values of 3.4 to 5.7 minutes. Because the redistribution phase and elimination half-life are so rapid, a bolus injection prior to a continuous infusion of remifentanil is unnecessary.

Another unique feature of remifentanil kinetics in children is that its pharmacokinetic profile is unchanged by cardiopulmonary bypass. For opioids, which undergo organ elimination, cardiopulmonary bypass prolongs drug clearance, increases volume of distribution, and increases half-life. The pharmacokinetic profile of remifentanil appears to be unaffected by cardiopulmonary bypass ( Davis et al., 1999 ) ( Fig 6-22 ).



FIGURE 6-22 Prebypass (filled circles) and postbypass (open circles) pharmacokinetic decay curves of remifentanil were constructed from the average concentrations of the 12 patients. (Redrawn with permission from Davis PJ, Wilson AS, Siewers RD, et al.: The effects of cardiopulmonary bypass on remifentanil kinetics in children undergoing atrial septal defect repair. Anesth Analg 89:904-908, 1999.)

The pharmacodynamics of remifentanil were studied in children and infants. Multiple case reports of remifentanil use in neonates and infants suggest its usefulness ( Wee and Stokes, 1999 ; Chiaretti et al., 2000; German et al., 2000 ; Doönmez et al., 2001; Foubert et al., 2002 ). In a multicenter trial of infants younger than 2 months who were undergoing pyloromyotomy, Galinkin and others (2001) and Davis and others (2001) noted that remifentanil provides stable hemodynamic conditions and that new onset of postoperative apnea, as detected by pneumograms, did not occur with remifentanil.

In older children, pharmacodynamic studies suggest that the short duration of remifentanil can be used to promote faster emergence times ( Davis et al., 1997 , 2000). As with other opioids, the issue of tolerance is a concern with remifentanil. Acute tolerance to remifentanil has been suggested in the nonblinded studies of Guignard and others (2000) and Vinik and others (1998) but not in the studies of Gustorff and others (2002) and Schraag and others (1999). The incidence of postoperative nausea and vomiting appears similar to the incidence seen with other opioids ( Eltzschig et al., 2002 ).

Methadone

Methadone is a synthetic narcotic analgesic. It is a racemic mixture with the L-isomer 10 to 50 times more potent than the D-isomer. Methadone has an oral bioavailability of 80% with a range of 41% to 99%. It is 60% to 90% protein bound, and α₁-acid glycoprotein is the main determinant of the free factor of methadone. After an intravenous dose in adults, the pharmacokinetic profile fits a two-compartment model with a distribution half-life of 6 minutes and an elimination half-life of 35 hours ( Gourlay et al., 1982 ). Findings of the pharmacokinetics of methadone in children suggest that it has a large volume of distribution (7.1 L/kg), a high plasma clearance (5.4 mL/kg per minute), and a long half-life (19.2 hours) ( Berde et al., 1991 ).

Although methadone is metabolized in the liver, little information is available with respect to its pK profile in end-stage liver or kidney failure. Urinary pH is another important determinant of the elimination half-life of methadone. Acidifying the urine markedly decreases the half-life of methadone and increases its renal clearance ( Bellward et al., 1977 ).

Clinical use in children is somewhat limited. Berde and others (1991), in a randomized, double-blind study of morphine and methadone, noted that the children receiving methadone had significantly less opioid requirements and better pain scores in the postoperative period than did children receiving equipotent doses of morphine. Recommended doses of perioperative methadone include a loading dose of 0.1 to 0.2 mg/kg with 0.05 mg/kg supplemental dose every 4 to 12 hours.

▪ LOCAL ANESTHETICS

Local anesthetics are divided into two types: esters (tetracaine, chlorprocaine, procaine) and amides (lidocaine, bupivacaine, ropivacaine, and levobupivacaine). The ester compounds are metabolized by plasma cholinesterase, and the amide class of drugs undergoes hepatic biotransformation and clearance. Local anesthetic agents work by blocking voltage-gated sodium channels.

Local toxicity involves the spinal cord and peripheral nerves and usually occurs at the site of injection. General or systemic toxicity involves either the central nervous system or the heart. In general, there is a direct relationship between local anesthetic potency and systemic toxicity, and, in general, central nervous system toxicity occurs at lower plasma concentrations than for cardiac toxicity. The systemic effects of local anesthetics are a function of dose rapidity of injection and site of injection. Highly vascular areas are prone to local anesthetic uptake and, consequently, toxicity. The order of site absorption from highest to lowest is intercostal, intratracheal > caudal, epidural > brachial plexus > subcutaneous.

The amide local anesthetics are bound to serum proteins. Alpha₁-acid glycoprotein is the major binding protein. The free drug fraction for lidocaine ranges from 30% to 40%, and for both ropivacaine and bupivacaine it ranges from 4% to 7%. Metabolism of amides is by the liver's cytochrome P450 system. CYP3A4 metabolizes bupivacaine while CYP1A2 is mostly involved with ropivacaine's metabolism. Lidocaine has a high hepatic extraction ratio, and its clearance is dependent on hepatic blood flow. In addition, the metabolic product of lidocaine metabolism (ME6X) may inhibit the intrinsic enzyme involved with its degradation. Lidocaine has a longer elimination half-life and larger volume of distribution in children than in adults after either intratracheal or caudal anesthsia ( Eyres et al., 1978 ;Ecoffey et al., 1984 ). Bokesch and others (1985) demonstrated higher plasma lidocaine levels in the systemic circulation in animals with right-to-left shunts.

Bupivacaine

Bupivacaine and ropivacaine have a low hepatic extraction ratio. Thus, protein binding and CYP enzyme activity effect drug clearance (Lonnqvist et al., 2000). Bupivacaine is a racemic mixture of equiosmolar amounts of R-(+)-bupivacaine and S-(-)-bupivacaine. Drug clearance is low at birth and increases throughout the first year of life. Pharmacokinetic studies have demonstrated age-related differences between infants and children ( Ecoffey et al., 1985 ; Desparmet et al., 1987 ; Mazoit et al., 1988 ; Mazoit and Dalens, 2004 ; Eyres et al., 1983 ). Extrapolation of pharmacokinetic data after single-bolus bupivacaine administration for infants and children suggests that for continuous caudal/epidural infusions, rates of 0.2 to 0.4 mg/kg per hour for infants and 0.2 to 0.75 mg/kg per hour for children would provide efficacious and safe plasma concentrations ( McCloskey et al., 1992 ) ( Table 6-14 ).

TABLE 6-14 -- Pharmacokinetics of bolus caudal-epidural bupivacaine in infants and children

	C_max (mcg/mL)	t_½β (hr)	V_d (L/kg)	CL (mL/min per kg)
Infants^[*] (2.5 mg/kg)	0.97±0.42	7.7 ± 2.4	3.9 ± 2.0	7.1 ± 3.2
Children^[†] (2.5 mg/kg)	1.25 ± 0.09	4.6 ± 0.5	2.7 ± 0.2	10.0 ± 0.7

C_max, Maximal serum concentration; t_½β, elimination half-life; V_d, volume of distribution; CL, clearance.

^*	Expressed as value ± SD ( Mazoit et al., 1988 ).
^†	Expressed as value ± SEM ( Ecoffey et al., 1985 ).

Ropivacaine

Ropivacaine is a long-acting amide, local anesthetic agent with fewer cardiac and CNS toxicities. It is thought to provide a greater separation of sensory and motor effects. Compared with bupivacaine, Karmakar and others (2002) have shown that after 2.0 mg/kg of either caudal ropivacaine or bupivacaine, ropivacaine undergoes slower systemic absorption from the caudal space but with comparable peak venous plasma concentrations. In comparative studies of caudal blocks with ropivacaine and bupivacaine, Khalil and others (1999) and Ivani and others (1998) noted that for children the quality and duration of postoperative pain relief, motor and sensory effects, and time to first micturition were similar.

In infants and children, the pharmacokinetics of ropivacaine have been reported after caudal, epidural, and ilioinguinal blocks (Hansen, 2000, 2001; Loönnqvist et al., 2000; Wulf et al., 2000 ; Dalens, 2001). Hansen and others (2001) have shown that infants 0 to 3 months of age have higher to medium maximum free ropivacaine concentrations than infants 3 to 12 months of age, and for both these groups of infants the free drug concentrations were within the concentrations reported for adults. However, Wulf and others (2000) noted that in infants less than one year of age and toddlers 1 to 5 years of age, infants had higher peak plasma concentrations than toddlers, with the peak concentration occurring at 60 minutes in both groups. In a dosing study of children 4 to 12 years of age, Bosenberg and others (2001) noted that single shot caudals in doses of 1 to 3 mg/kg resulted in peak plasma levels of free ropivacaine that increased proportionately to the increase in dose.

McCann and others (2001) reported on the pharmacokinetics of epidural ropivacaine (1.7 mg/kg) in infants and young children. In this study, they noted that ropivacaine has a biphasic absorption. As with bupivacaine, ropivacaine shows age-related clearance changes with infants having slower clearance than children, but in both groups the peak plasma concentrations were well below the maximum tolerated venous concentration (2100 mcg/mL for adults).

The pharmacodynamics of ropivacaine after caudal blocks have been shown to be similar to bupivacaine with regard to onset time, efficacy, duration of analgesia, and incidence of motor block. Local anesthetic supplements can also affect ther duration of action. Ropivacaine's duration of action can be prolonged with neostigmine, clonidine, or ketamine supplementation (Da Conceicao et al., 1998; Ivani et al., 1998 , 1999-2000; Khalil et al., 1999 ; Morton, 2000 ; Turan et al., 2003 ).

Levobupivacaine

Levobupivacaine is one of the enantiomers of bupivacaine. Information regarding its use in children is less than with the other local anesthetics ( Locatelli et al., 2005 ; DeNegri et al., 2004 ; Chalkiadis et al., 2004 ; Kokki et al., 2004 ; Lerman et al., 2003 ; Ivani et al., 2003 ; Gunter et al., 1999 ; Ivani et al., 2005 ).

In studies of children 1 to 7 years of age, Ivani and others (2002) noted that caudal bupivacaine, levobupivacaine, and ropivacaine were thought to be clinically comparable. Locatelli and others (2005) reported that caudal bupivacaine was associated with more motor block and longer analgesic block. In pediatric patients with continuous infusions of epidurals, DeNegri and others (2004) noted that ropivacaine and levobupivacaine were associated with less motor block than bupivacaine.

In a dose-response study by Ivani and others (2003) in children undergoing caudal block for subumbilical surgical procedures, three concentrations (0.125%, 0.20%, and 0.25%) of levobupivacaine were compared. A dose-response relationship was observed with median duration of postoperative analgesia and with motor blockade ( Fig 6-23 ). Based on these relationships, they noted the optimal concentration to be 0.2% (Ivani, 2003). More information on local anesthetics is given in Chapter 14 , Regional Anesthesia.



FIGURE 6-23 Fraction of patients without a need for supplemental analgesia in relation to various concentrations of levobupivacaine. (Redrawn with permission from Ivani G, Pasquale De Negri, et al.: A comparison of three different concentrations of levobupivacaine for caudal block in children. Anesth Analg 97:368-371, 2003.)

▪ COMMONLY ADMINISTERED ANESTHETIC ADJUNCTS

Atropine

Strong cholinergic stimulation such as occurs from halothane and succinylcholine can produce profound bradycardia and reduce cardiac output in infants. The primary purpose of atropine in pediatric anesthesia is to protect against cholinergic stimulation; its secondary purpose is to inhibit the production of secretions.

If atropine is administered intravenously in incremental doses, more atropine on weight basis is needed to accelerate the heart rate in children younger than 2 years; however, acceleration uniformly occurs with 14.3 mcg/kg ( Dauchot and Gravenstein, 1971 ). Infants need higher doses of atropine to increase heart rate compared with adults ( Palmisano et al., 1991 ). The onset of the chronotopic effects of atropine appears to be related to the underlying heart rate at the time of administration of atropine. Children with slower heart rates have longer onset times than do children with faster heart rates (Zimmerman and Steward, 1986 ). Although atropine can increase heart rate and cardiac output, it does not appear to change the neuromuscular blocking onset time of atracurium ( Simhi et al., 1997 ). A dose of 30 mg/kg appears to be vagolytic in infants, children, and adults. This dose provides adequate protection against a cholinergic challenge. In a study of 20 healthy children aged 1 to 36 months undergoing elective surgery, McAuliffe and others (1997) noted that 20 mcg/kg intravenously caused a variable increase in heart rate and cardiac output in anesthetized children. In 40 children, 2 to 6 years of age, intratracheal atropine (20 mcg/kg) produced only a modest increase in heart rate after 5 minutes (Jorgensen et al., 1997). However, 50 mcg/kg increased heart rate rapidly (Howard et al., 1990). The site of injection has a role in the onset time of atropine effect. In a randomized study of children 1 to 10 years of age anesthetized with nitrous oxide, oxygen, and halothane, Sullivan and others (1997) noted that a subglossal injection resulted in a faster onset time than either a deltoid or vastus lateralis intramuscular injection.

In all age groups, 5 to 10 mcg/kg atropine minimally decreases salivation ( Gaviotaki and Smith, 1962 ). Children with Down syndrome may have an increased sensitivity to atropine; the pupils dilate in response to atropine, and large increases in heart rate occur after repeated doses of atropine ( Berg et al., 1960 ; Priest, 1960 ; Harris and Goodman, 1968 ). In retrospective study by Kobel and others (1982), however, patients with Down syndrome were no more sensitive to intravenous atropine than were other patients.

Ketorolac

Ketorolac is a nonsteroidal anti-inflammatory drug (NSAID). The analgesic properties of NSAIDs are thought to be related to their ability to attenuate the hyperalgesic state caused by prostaglandins as opposed to producing analgesia directly. Ketorolac may act both peripherally and centrally. Ketorolac is an enantiomeric compound. The pharmacokinetics of ketorolac were described after single and continuous infusion (Olkkola et al., 1991; Hamunen et al., 1999 ; Kauffman et al., 1999 ; Dsida et al., 2002 ; Kokki et al.; 2002; Gillis et al., 1997).

In a study of 43 pediatric surgical patients, Dsida and others (2002) noted no age-related differences in the pharmacokinetics, and the kinetic profile was similar to that reported for adults. In a pharmacokinetic study of the stereoisomers of ketorolac in children, Kauffman and others (1999) noted that concentrations of the (S)-(-)-enantiomer were lower than those of the (R)-(+)-enantiomer and that the (S)-(-)-enantiomer had a shorter half-life, greater clearance, and larger volume of distribution. These differences in the enantiomer kinetic profile appear similar for children, adolescents, and adults (Hamunen et al., 1999 ) ( Fig 6-24 ). In addition to its analgesic properties, ketorolac may have antiemetic properties ( Munro et al., 1994 ), and in children undergoing ureteral reimplantation procedures, ketorolac can decrease the incidence and severity of postoperative bladder spasms ( Park et al., 2000 ).



FIGURE 6-24 Concentrations (mean ± SD) of (S)-ketorolac (filled circles) and (R)-ketorolac (shaded circles) in plasma following intravenous administration of 0.5 mg/kg of racemic ketorolac tromethamine to 18 children, 28 adolescents, and 18 adults. (Redrawn with permission from Hamunen K, Maunuksela EL, Sarvela J, et al.: Stereoselective pharmacokinetics of ketorolac in children, adolescents and adults. Acta Anaesthesiol Scand 43:1041-1046, 1999.)

Tramadol

Tramadol is a centrally acting agent with two distinct mechanisms of action: opioid and nonopioid. Tramadol acts as an opioid agonist. Tramadol also acts on monoamine systems to inhibit the reuptake of norepinephrine and serotonin. Tramadol is structurally related to codeine. It is metabolized by liver CYP2D6; about 0.8% of the white population is deficient in this enzyme. Its metabolite, O-demethyl metabolic intermediate has some analgesic effect. Tramadol is a stereoisomer. The (+)-stereoisomer form provides similar analgesia as the racemic form. The bioavailability of tramadol in adults is 68%, and it is 20% protein bound. In 14 children aged 1 to 12 years, the intravenous tramadol pharmacokinetic profile demonstrated a volume of distribution, clearance, and half-life of 3.1 L/kg, 6.1 mL/kg per minute, and 6.4 hours, respectively. In the same study, the kinetics of tramadol after caudal administration revealed a volume of distribution, clearance, and half-life of 2.06 L/kg, 6.6 mL/kg per minute, and 3.7 hours, respectively. Of note was that the ratio of caudal and intravenous AUC was 0.83, suggesting there is extensive systemic absorption of caudal tramadol ( Murthy et al., 2000 ) ( Fig 6-25 ).



FIGURE 6-25 (A) Mean (SD) serum concentrations of total tramadol after intravenous (IV) or caudal injection of tramadol 2 mg/kg. (B) Mean (SD) serum concentrations of O-dimethyl tramadol (M1) after IV or caudal injection of tramadol 2 mg/kg. (Redrawn from Murthy BVS, Pandya KS, Booker PD, et al.: Pharmacokinetics of tramadol in children after IV or caudal epidural administration. Br J Anaesth 84:346-349, 2000.)

The clinical efficacy of tramadol has been reviewed in adults and children by Scott and Perry (2000); in summary, the overall efficacy of tramadol is comparable to equianalgesic doses of parenteral opioids. In children, tramadol has been administered orally, intravenously, intramuscularly, and caudally. Its major advantage is its lack of respiratory depression after its administration ( Scott and Perry, 2000 ;Ozcengiz et al., 2001 ; Viitanen and Annila, 2001 ; Finkel et al., 2002 ; Engelhardt et al., 2003 ; Rose et al., 2003 ).

5-HT₃ Receptor Antagonists

Ondansetron is a 5-hydroxytryptamine₃ (serotonin) (5-HT₃) receptor antagonist. The mechanism of action, although not totally elucidated, appears to block the effects of serotonin on 5-HT₃receptors on vagal afferents. Ondansetron is well absorbed orally and has an oral bioavailability of 60%. Ondansetron is metabolized in the liver by the CYPIA2, CYP2D6, and CYP3A4 (Gregory et al., 1998; Sweetland et al., 1992 ). After oral administration, peak plasma levels occur in 1 to 2 hours. In adults after oral, intramuscular, or intravenous administration, the volume of distribution and half-life are 140 L/kg and 3.5 hours. In children, the half-life ranged from 2.5 to 3.0 hours, the volume of distribution ranged from 1.9 to 2.4 L/kg, and the clearance ranged from 6.6 to 15.6 mL/kg per minute ( Bryson et al., 1991 ;Spahr-Schopfer et al., 1995 ). The major clinical use in anesthesia has been for prophylaxis and treatment of postoperative nausea and vomiting. Both large-scale studies and meta-analyses noted ondansetron to be a superior prophylactic drug compared with placebo, droperidol, and metaclopramide ( Patel et al., 1997 ; Domino et al., 1999 ; Lim et al., 1999 ). The addition of dexamethasone to prophylactic ondansetron further increases the antiemetic efficacy of the drugs (Splinter et al., 1998). When used for treatment of postoperative nausea and vomiting, ondansetron (0.1 mg/kg, maximum 4.0 mg) appears to be superior to placebo ( Khalil et al., 1996 ; Culy et al., 2001 ).

Granisetron, with an elimination half-life of 9 to 12 hours, has been reported to be effective at a dose of 40 mcg/kg when administered either orally or intravenously ( Fujii et al., 1998 , 1999a, 1999b, 2001;Fujii and Tanaka, 1999 , 2001, 2002).

Tropisetron is another 5-HT₃receptor antagonist whose half-life is two to three times longer than that of ondansetron. In studies of children, doses ranging from 0.1 to 0.2 mg/kg were found to be effective for postoperative nausea and vomiting ( Ang et al., 1998 ; Holt et al., 2000 ; Jensen et al., 2000 ).

Dolasetron, a highly potent and selective 5-HT₃ receptor antagonist, appears to provide prophylactic antiemetic efficiency similar to that of ondansetron ( Sukhani et al., 2002 ; Olutoye et al., 2003 ). Dolasetron appears to have an active metabolite that has a half-life of about 8 hours. In a pharmacokinetic study of 30 children, the kinetics of the metabolite were similar after both intravenous and oral administration. The volume of distribution, clearance, and half-life were 5.2 L/kg, 22.1 mL/kg per minute, and 5.7 hours, respectively. Bioavailability has been estimated at 59% ( Lerman et al., 1996 ).

Dexmedetomidine

Alpha₂-adrenoreceptor agonists are being used increasingly in anesthesia and critical care because they not only decrease sympathetic tone and attenuate the stress responses to anesthesia and surgery, but also cause sedation and analgesia. They are used as adjuvants during regional anesthesia. Clonidine, which was initially introduced as an antihypertensive, is the most commonly used alpha₂ agonist by anesthesiologists. Dexmedetomidine is the most recent agent in this group, approved by the FDA in 1999 for use in humans for analgesia and sedation. It is used to sedate ICU patients. In addition to its sedative properties, dexmedetomidine also acts synergistically with other sedative drugs to lower the overall analgesic and sedative doses of the other agents. Although clonidine, another alpha₂-adrenoreceptor agonist, has been used in pediatric patients to promote sedation and reduce anesthetic requirements, dexmedetomidine differs from clonidine in that dexmedetomidine possesses selective alpha₂-adrenoreceptor activity, especially for the 2A subtype of this receptor. Dexmedetomidine is 8 to 10 times more specific than clonidine. This selectivity, coupled with its pharmacokinetic profile, allows the drug to be administered as a continuous infusion with a relatively quick onset and offset of action.

The hemodynamic effects of dexmedetomidine are similar to clonidine and vary depending on the dose rate and route of administration ( Dyck et al., 1993 ; Ebert et al., 2000 ). Its use in pediatric anesthesia has been limited, but its ability to provide sedation for pediatric patients has been reported in case reports and small series (Tobias et al., 1997; Serlin, 2004 ; Finkel and Elretai, 2004; Tobias et al., 2003 ;Ard et al., 2003 ; Dyck et al., 1993 ; Ebert et al., 2000 ; DeRuiter and Crawford, 2001; Meretoja et al., 1995 ). Ibacache and others (2003) have noted that as an adjunct to sevoflurane, a single-dose of dexmedetomidine (0.3 μg/kg) markedly attenuated the incidence of sevoflurane-associated emergence agitation.

Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

▪ INHALATION ANESTHETICS

Sevoflurane, isoflurane, and nitrous oxide are the most widely used inhalational anesthetics in the practice of pediatric anesthesia. During the 1990s, sevoflurane displaced halothane as the pediatric induction agent of choice. Where economic issues prevail, halothane continues to dominate the pediatric anesthetic practice. Desflurane has not established itself as a widely used maintenance/emergence agent in children, although this role is under review.

▪ NITROUS OXIDE

Nitrous oxide reduces the anesthetic requirements for the more potent inhalational anesthetics, speeds uptake of the more potent agents, and serves to dilute the inspired oxygen concentration. Nitrous oxide expands gas-containing spaces because it is 34×more soluble in blood (blood/gas partition coefficient, 0.47) than nitrogen (blood gas partition coefficient, 0.014). Assuming a trivial quantity of nitrogen diffuses out of the space while ventilating the lungs with nitrous oxide, then the maximum multiple expansion of the original space that can occur is as follows ( Eger, 1974 ):

6.16

Using this equation, if 75% nitrous oxide is inspired, then the space volume may expand up to threefold. The rate at which the space expands varies with the site: a pneumothorax may double in size in 12 minutes, whereas a small bowel obstruction may double in 120 minutes ( Eger, 1974 ). This 10-fold difference in the rate of expansion is determined in part by the reduction in (mural) blood flow to the bowel as the gas volume within the lumen expands. The same limitation of blood flow does not occur with a pneumothorax. Other cavities that may expand in the presence of nitrous oxide include the middle ear, gas within the ocular globe, and CNS air from a pneumoencephalogram. In situations where oxygenation (either inspired oxygen concentration or tissue oxygenation) must be maximized, the use of nitrous oxide, particularly in concentrations in excess of 50%, must be judiciously reviewed. The potency of nitrous oxide is affected by barometric pressure, being less effective at high altitude than at sea level or below.

Once believed to be entirely nontoxic, nitrous oxide has aroused increasing suspicion of cellular and atmospheric toxicity on several counts. Lymphocyte depression, miscarriage (first trimester), cancer, defects in spermatogenesis, apoptosis, and others have raised concerns about health risks after prolonged exposure ( Brodsky et al., 1984 ; Rowland et al., 1995 ; Jevtovic-Todorovic et al., 2003 ). The half-life of nitrous oxide, an oxygen-free radical scavenger, in the troposphere is approximately 150 years compared with the half-lives of the polyhalogenated inhalational anesthetics, which are 5 to 10 years. Although less than 5% of the nitrous oxide released into the atmosphere originates from medical sources, limiting the waste of nitrous oxide through the use of low fresh gas flows and smoke stack scrubbers curbs the depletion of the ozone layer.

Potent inhalational anesthetics are sevoflurane, isoflurane, halothane, and desflurane. Sevoflurane and isoflurane have become the dominant maintenance anesthetics in children, displacing halothane because of their “forgiving” qualities; that is, they are less soluble in blood and tissues than is halothane. The pharmacology of available inhalational anesthetics is summarized in Table 6-15 .

TABLE 6-15 -- The pharmacology, solubility, and minimum alveolar concentration (MAC) of five potent inhalational anesthetics

	Halothane	Isoflurane	Sevoflurane	Desflurane
Pharmacology
Chemical structure
Molecular weight	197.4	184.5	200.1	168
Boiling point (°C)	50.2	48.5	58.6	23.5
Vapor pressure (mm Hg)	244	240	185	664
Odor	Mild, pleasant	Etheral	Pleasant	Etheral
Metabolized (%)	15–25	0.2	5	0.02
Solubility
λ_b/g adults	2.4	1.4	0.66	0.42
λ_b/g neonates	2.1	1.2	0.66	–
λ_fat/b adults	51	45	48	27
MAC
MAC_adults	0.75	1.2	2.05	7.0
MAC_neonates	0.87	1.60	3.3	9.2

With permission from Lerman J: Anesth Clin North Am 9:764, 1991.

b/g, Blood/gas; fat/b, fat/blood.

Note that the boiling point of desflurane is close to room temperature and that the solubilities of the anesthetics in blood and fat decrease from left to right across the table, whereas MAC increases from left to right.

▪ SEVOFLURANE

Sevoflurane is a polyfluorinated methyl isopropyl ether anesthetic that is the first ether anesthetic to be widely used for induction of anesthesia in children. Its low blood solubility, half that of isoflurane, speeds the equilibration of alveolar and inspired anesthetic partial pressures ( Fig 6-26 ). However, the tissue/blood solubilities of sevoflurane and isoflurane in the vessel-rich group (brain, heart, liver, kidneys, and endocrine glands), muscle, and fat groups are indistinguishable. Because the wash-in of inhalational anesthetics is increased by use of the overpressure technique, these physicochemical differences affect the wash-in of the anesthetics to a lesser extent than they do the rate of washout and the rate of emergence from anesthesia. In terms of the pharmacokinetics of inhaled anesthetics, changes in alveolar ventilation and cardiac output affect the wash-in of more-soluble anesthetics (halothane and methoxyflurane) more than that of the less-soluble anesthetic agents (sevoflurane and desflurane) (Eger, 1974 ). In contrast, increases in the right-to-left shunt (as in an intrapulmonary or intracardiac shunt) affect the wash-in of the less-soluble anesthetics (sevoflurane) compared with the more-soluble anesthetics (halothane and methoxyflurane) ( Lerman, 2002 ). Because of the low blood and tissue solubilities of sevoflurane, its elimination in infants and children is rapid.



FIGURE 6-26 (A) In unstimulated human volunteers, the increase in the alveolar concentration (F_A) toward the inspired concentration (F_I) is more rapid with the least soluble potent inhaled anesthetic (desflurane) and slowest with the most soluble potent inhaled anesthetic (halothane). Only nitrous oxide has a more rapid increase in F_A/F_I than desflurane. Nitrous oxide enjoys a still more rapid increase because of its low solubility in blood and tissues, and because of the employment of a greater inspired concentration (i.e., its rise is influenced by the concentration effect). (B) Elimination, as defined by the decrease in alveolar concentration relative to the last alveolar concentration found during anesthesia (F_AO), is most rapid with desflurane, less rapid with sevoflurane, and slowest with isoflurane and halothane. Despite its greater solubility, the decrease with halothane is as rapid as the decrease with isoflurane because halothane is metabolized and thus is cleared from the body by both lungs and liver, whereas isoflurane is cleared only by the lungs.

Sevoflurane is a far less potent anesthetic than isoflurane and halothane, as reflected by the minimum alveolar concentration (MAC) of sevoflurane. The MAC of sevoflurane is twice that of isoflurane and three times that of halothane ( Lerman et al., 1994 ). The relationship between age (in the pediatric range) and the MAC of sevoflurane differs from the relationships for isoflurane and halothane in two respects: first, the MAC of sevoflurane does not increase steadily as age decreases, and second, the contribution of nitrous oxide to the MAC of sevoflurane in children is less than that of halothane. MAC of sevoflurane in neonates and infants younger than 6 months (3.2%) and in infants older than 6 months and children up to 12 years (2.5%) is constant. Why the MAC of sevoflurane does not increase as age decreases as it does with the other inhalational anesthetics is unclear. Although nitrous oxide reduces the MAC of inhalational anesthetics in proportion to its concentration, the same does not hold true for sevoflurane in children. In the case of sevoflurane in children aged 1 to 3 years, nitrous oxide (inspired concentration, 60%) decreases the MAC of sevoflurane by only 25%. The explanation for the blunted effect of nitrous oxide on the MAC of sevoflurane in children also remains unclear.

Sevoflurane is unique among the currently used ether anesthetics in that in nonpremedicated children, it is well tolerated when administered for induction of anesthesia, even without nitrous oxide. The incidences of breath holding, coughing, laryngospasm, and desaturation during induction of anesthesia with sevoflurane and halothane are infrequent and similar with the two anesthetics (Black et al., 1996;Lerman et al., 1996 ). However, induction of anesthesia with sevoflurane is not always uneventful. Although exceedingly rare, electroencephalographic and epileptiform activities were reported during inhalational inductions with sevoflurane in children (Komatsu et al., 1994; Vakkuri et al., 2001 ; Jaaskelainen et al., 2003 ). Investigations failed to identify a cause for these episodes ( Constant et al., 1999). Rare instances of twitching of the face or limb usually dissipate rapidly as the depth of anesthesia is increased. If the inspired concentration of sevoflurane is increased slowly (i.e., in 0.5% to 1% increments every few breaths), a protracted excitement phase may ensue during the induction. This can be obviated by increasing the inspired concentration of sevoflurane very quickly, without inducing airway reflex responses. Administering 60% to 70% nitrous oxide for approximately 1 minute and then adding 8% (inspired concentration) sevoflurane to the nitrous oxide makes the induction rapid and smooth. Recall of the odor of sevoflurane is rare, and excitement during the induction of anesthesia is minimal. Other techniques for rapid induction of anesthesia in children with sevoflurane have included a single breath (vital capacity) induction with 8% sevoflurane, which is 40% more rapid than a single breath induction with 5% halothane ( Agnor et al., 1998 ). Whichever technique is used to induce anesthesia, clinicians continue to be surprised by anesthetized children who withdrew on attempted cannulation of a vein. This results not from a flaw in the anesthetic, sevoflurane, but rather in the combination of its pharmacology and delivery. Compared with halothane, the modestly increased maximum vaporizer concentration of sevoflurane is overshadowed by the 250% greater MAC. This limits the alveolar concentration that can be achieved in the first few minutes of anesthesia. This may reduce the probability of circulatory depression during induction of anesthesia with sevoflurane, but it also prevents clinicians from inducing a deep level of anesthesia quickly and thereby preventing a response to stimulation.

Like halothane, sevoflurane is a potent respiratory depressant. At concentrations greater than 1.5 MAC, sevoflurane is a more potent respiratory depressant than halothane. Indeed, apnea may occur in the nonstimulated child breathing 8% inspired sevoflurane. Premedication with midazolam or other medications may potentiate the respiratory depression with sevoflurane. After an inhalational induction with sevoflurane, spontaneous ventilation usually resumes after a brief period of apnea or manual ventilation of the lungs and a reduction in the inspired concentration of sevoflurane. Sevoflurane maintains cardiovascular homeostasis in infants and children. At 1 MAC sevoflurane, heart rate is usually maintained in infants and children even when they are not pretreated with atropine ( Lerman et al., 1994 ), although rare instances of a slowing of the heart rate have been reported, particularly at concentrations exceeding 1 MAC. Systolic pressure is usually reduced 20% to 25% from awake values. These responses to 1 MAC sevoflurane are similar to those after other inhalational anesthetics. Arrhythmias during sevoflurane anesthesia are infrequent; the incidence of arrhythmias during sevoflurane anesthesia after exogenous epinephrine is similar to that during isoflurane anesthesia. In infants and children with congenital heart disease undergoing cardiac surgery, hypotension and desaturation in cyanotic children after sevoflurane anesthesia occurred less frequently than they did after halothane anesthesia ( Russell et al., 2001 ). In parallel with the rapid elimination of sevoflurane, the recovery profile for sevoflurane is rapid compared with that for halothane. Transient agitation and involuntary movements during emergence from anesthesia have been reported. Emergence agitation occurs primarily in preschool age children, lasts 10 to 20 minutes, and is often self-limiting. Although agitation has been attributed to pain, pain as the sole explanation was dispelled when agitation was noted in children after lower abdominal surgery with a working caudal block in situ and after sevoflurane for magnetic resonance imaging procedures, where no pain occurs ( Aono et al., 1997 ; Cravero et al., 2000). One of the most difficult problems has been defining emergence agitation, which could not previously be assessed with any scale or measurement ( Sikich and Lerman, 2004 ). It is important to note that emergence agitation is not unique to sevoflurane; it also occurs after other anesthetic agents, including isoflurane and desflurane.

Sevoflurane is degraded both in vivo (to inorganic fluoride and hexafluoroisopropanol) and in vitro (via alkaline hydrolysis in the presence of soda lime or Baralyme [barium hydroxide lime] to five compounds: A to E [ Hanaki et al., 1987 ; Morio et al., 1992 ]). In vivo, sevoflurane is metabolized by microsomal CYP IIE1 isozyme in both the liver and kidney ( Kharasch et al., 1995a , 1995b). The peak plasma concentration of inorganic fluoride is proportional to the duration of exposure to sevoflurane in children. However, there have been no instances of sevoflurane-induced nephrotoxicity after several million anesthetic procedures. Two plausible explanations for the absence of nephrotoxicity are the rapid elimination of sevoflurane and the small extent of intrarenal metabolism of sevoflurane, the putative source of inorganic fluoride-induced nephrotoxicity ( Kharasch et al., 1995a ). In vitro, sevoflurane is both absorbed and degraded in the presence of soda lime and Baralyme, yielding only compound A in significant concentrations; up to 20 to 40 ppm in closed circuits in humans ( Liu et al., 1991 ). Alkaline hydrolysis of sevoflurane is enhanced by high temperatures, decreased water content in the absorbent, increased inspired concentration of sevoflurane, and new absorbent. In infants and children, compound A concentrations during sevoflurane anesthesia in a closed circuit increase in parallel with increasing in age ( Frink et al., 1996 ). In concentrations up to 100 ppm for 3 hours, compound A causes histopathologic changes in the kidneys of rats ( Gonsowski et al., 1994a , 1994b), although no evidence of histopathologic or pathophysiologic renal changes have been reported in humans. In the presence of desiccated soda lime and Baralyme, sevoflurane is degraded to only an extremely small extent to carbon monoxide ( Fang et al., 1995 ; Wissing et al., 2001 ). When both potassium hydroxide and sodium hydroxide are eliminated from the absorbent (i.e., Amsorb), sevoflurane produces only minute concentrations of carbon monoxide ( Murray et al., 1999 ; Versichelen et al., 2001 ). The combination of high-dose sevoflurane with desiccated Baralyme has resulted in instances of extreme heat and fire within the absorbent canister.

▪ DESFLURANE

Desflurane is a potent polyfluorinated methyl ethyl ether anesthetic available for use in infants and children. The single substitution of a fluorine atom for a chlorine atom on the carbon atom of isoflurane dramatically changes the physicochemical properties of this anesthetic (see Table 6-15 ). Blood/gas and tissue/blood solubilities are only fractions of those of halothane and isoflurane ( Yasuda et al., 1989 ). As a result, the wash-in of desflurane is the fastest of all of the available potent inhalational anesthetics (see Fig 6-26 ). As in the case of sevoflurane, changes in alveolar ventilation and cardiac output exert small effects on the pharmacokinetics of this anesthetic, whereas changes in right-to-left shunting exert a large effect ( Eger, 1974 ; Lerman, 2002 ). Just as the wash-in of desflurane is extremely fast, so, too, the washout of desflurane is extremely rapid. Of the potent inhalational anesthetics, the elimination of desflurane is most rapid (Yasuda, 1991) (see Fig. 6-26 ).

The MAC of desflurane in infants and children is least in neonates, increasing throughout infancy and reaching a zenith of 9.9% in infants aged 6 to 12 months. MAC decreases thereafter with increasing age through adolescence (Taylor and Lerman, 1991). Nitrous oxide (60%) decreases the MAC of desflurane by only 26% in children ( Fisher and Zwass, 1992 ), an effect similar to that of sevoflurane.

Inhalational inductions with desflurane are not recommended because upper airway reflexes are frequently triggered (50% incidence of breath holding, 40% incidence of laryngospasm) ( Taylor and Lerman, 1992 ; Zwass et al., 1992 ). If anesthesia is induced by either the intravenous or inhalational route, desflurane may be used to maintain anesthesia ( Taylor and Lerman, 1992 ; Zwass et al., 1992 ). Like sevoflurane, desflurane maintains cardiovascular homeostasis at 1 MAC ( Taylor and Lerman, 1991 ). At this concentration, heart rate and systolic blood pressure are depressed 20% to 25% compared with awake values ( Taylor and Lerman, 1991 ). Arrhythmias and bradycardia are uncommon with this anesthetic.

The rate of recovery after desflurane anesthesia parallels the extremely rapid washout of this anesthetic ( Taylor and Lerman, 1992 ; Davis et al., 1994 ). Early experience with the rapid recovery after discontinuation of desflurane resulted in the precipitous onset of excruciating surgical pain. A strategy to prevent pain on emergence must be considered and the intervention instituted before discontinuation of this anesthetic.

Desflurane resists metabolism both in vivo (0.02%) ( Smiley et al., 1991 ) and in vitro (in the presence of soda lime and Baralyme). In vivo, insignificant blood concentrations of inorganic fluoride are produced after desflurane anesthesia. However, in vitro degradation of desflurane may be problematic. If the carbon dioxide absorbent becomes desiccated and is incubated with desflurane, then desflurane may react with the constituents to release carbon monoxide into the inspired limb of the breathing circuit ( Fang et al., 1995 ; Wissing et al., 2001 ). Other ether anesthetics, including isoflurane and enflurane, all difluoromethyl ethyl ether anesthetics (including desflurane), undergo a similar path of degradation to carbon monoxide in the presence of desiccated absorbent, albeit to a lesser extent than desflurane ( Baxter et al., 1998 ). Absorbent becomes desiccated by circulating fresh gas through an absorbent canister for a prolonged period of time without a reservoir bag in place. In some anesthetic machines, this continuous fresh gas flow desiccates the absorbent by flowing retrograde through the canister, exiting where the reservoir bag usually is attached. Without the ability to detect carbon monoxide in the breathing circuit, contamination of the breathing circuit with carbon monoxide might present a serious risk to patients, particularly those anesthetized after the anesthetic machine has not been used for a prolonged period (i.e., Monday mornings). To preclude this complication, the fresh gas flow should be discontinued when the anesthetic machine is not in use, the reservoir bag should never be removed from the canister, and, most important, the anesthetic machine should be turned off when not in use. If one suspects that the absorbent has been desiccated, the absorbent must be replaced before any anesthetic is administered. There are no guidelines for rehumidifying desiccated absorbents. Not all absorbents produce carbon monoxide when they are exposed to the desflurane. Those absorbents that lack both potassium hydroxide and sodium hydroxide (i.e., Amsorb) do not produce carbon monoxide.

With a boiling point close to room temperature, a heated pressurized vaporizer was developed to deliver a predictable concentration of desflurane. This vaporizer requires electrical current to maintain a predictable temperature and pressure that are independent of ambient conditions.

▪ ISOFLURANE

The pharmacology of isoflurane is very similar to that of desflurane with a few exceptions. As mentioned, the chemical structure of isoflurane is identical to that of desflurane except that isoflurane has a chlorine atom instead of a fluoride atom on the carbon atom (see Table 6-15 ). Because isoflurane is more soluble in blood and tissues than desflurane, the wash-in and washout of isoflurane are slower than those of desflurane (see Fig. 6-26 ) ( Yasuda et al., 1991 ). The MAC of isoflurane is intermediate between those of halothane and sevoflurane, as described previously (see Table 6-15 ) ( Cameron et al., 1984 ).

Like desflurane, isoflurane triggers airway reflex responses during inhalational inductions and is not suited for this purpose. Although numerous attempts were made to ameliorate the airway responses to an inhalational induction, clinicians abandoned the notion of using it for this purpose. Isoflurane is used similarly to desflurane for the maintenance phase of anesthesia.

Once anesthesia is induced, whether the airway is instrumented or not, children and adults breathe isoflurane without difficulty. Similarly, they emerge from isoflurane anesthesia without difficulty.

Isoflurane, like desflurane, does not depress the circulation in children. In fact, heart rate often increases during isoflurane anesthesia and blood pressure is well maintained. Unlike in the adult, rapid increases in the inspired concentration of isoflurane do not trigger a central sympathetic (tachycardia and hypertension) response that requires intervention with an opioid or other agent.

The in vivo metabolism of isoflurane, 0.2%, yields very small concentrations of inorganic fluoride in the blood without significant intrarenal production. Nephrotoxicity after isoflurane anesthesia is not a substantive risk. However, in the presence of desiccated soda lime and Baralyme, isoflurane can produce carbon monoxide, as discussed earlier.

▪ HALOTHANE

Halothane has been the standard of practice against which all other inhalational anesthetics were compared until the introduction of sevoflurane. Halothane is the only nonether anesthetic that is used today, being an alkane in structure. The wash-in of halothane is the slowest of the currently used anesthetic agents because it is the most soluble (see Table 6-15 ). This means that the time to equilibration of inspired and alveolar (or brain) partial pressures of halothane is the greatest of the anesthetics. Although this may be viewed as a safety factor, the potency of halothane is the greatest of the anesthetic agents. These two factors, together with the ability to deliver a maximum inspired concentration of 5% halothane with all vaporizers, resulted in numerous episodes of cardiorespiratory instability that included hypotension and bradycardia/arrhythmias. In particular, concern was expressed in the 1980s about the ability of neonates to tolerate halothane anesthesia because of the hemodynamic consequences. Based on our current understanding of the pharmacology of halothane, several conclusions may be made about the past experience with this anesthetic in pediatric anesthesia:

	1.	The MAC for halothane in neonates is less than that in older infants.
	2.	Halothane depresses both the circulation and respiration in infants and children.
	3.	With the design of the vaporizer and given the potency of halothane, it is easier to overdose children with halothane than with other anesthetic agents.

Halothane is metabolized approximately 15% to 20% in humans. Immunologic responses including hepatitis have been documented after repeat halothane anesthesia even in children ( Kenna et al., 1989 ). With the declining use of this agent in clinical practice, it is unlikely to pose a serious threat to children.

▪ UPTAKE AND DISTRIBUTION

The uptake and distribution of inhaled anesthetics are more rapid in infants and small children than in adults ( Salanitre and Rackow, 1969 ; Steward and Creighton, 1978 ; Gallagher and Black, 1985 ). Studies have shown inspired and expired partial pressures of nitrous oxide equilibrate in infants in 25 minutes, in children in 30 minutes, and in adults in 60 minutes ( Salanitre and Rackow, 1969 ). However, the differences in uptake between children and adults are magnified as the solubility of the agents increases. In the case of halothane, the wash-in in infants and children is more rapid than it is in adults ( Fig 6-27 ).



FIGURE 6-27 The observed ratio of expired to inspired halothane (FE/FI) in infants demonstrates their more rapid uptake of halothane compared with adults. \|—○—\|, Infant observed (mean ± SD); —□—, infant predicted; \|—•—\|, adult observed (mean ± SD); x- - -x, adult predicted. (Observed data from adults from Sechzer PH, Linde HW, Dripps RD, et al.: Anesthesiology 24:779, 1963; Eger EI II, Bahlman SH, Munson ES: Anesthesiology 35:365, 1971a. Predicted curves generated from a computerized model. Reprinted with permission from the International Anesthesia Research Society from Brandom BW, Brandom RB, Cook DR: Anesth Analg 62:404, 1983.)

Four factors explain the more rapid wash-in of alveolar to inspired anesthetic partial pressures in children compared with adults:

	1.	Increased alveolar ventilation-to-functional residual capacity (FRC) ratio
	2.	Increased cardiac output
	3.	Decreased blood/gas partition coefficient ( Lerman et al., 1984 )
	4.	Decreased tissue/blood partition coefficients ( Lerman et al., 1986 )

The alveolar ventilation-to-FRC ratio in infants (5:1) is about threefold greater than it is in adults (1.5:1). Because the time to achieve 63% equilibration of alveolar to inspired anesthetic partial pressures (one time constant) is the ratio of the volume to the flow through the volume, the greater the ratio of alveolar ventilation to FRC, the faster is the time to equilibration. This effect is more pronounced for soluble anesthetics than it is for less-soluble anesthetics.

Although an increased cardiac output should delay the equilibration of alveolar to inspired anesthetic partial pressures ( Eger, 1974 ), an increased cardiac output in infants actually speeds the equilibration of partial pressures. This paradoxical effect may be attributed to the vessel-rich group (VRG) (brain, heart, liver, kidneys, and endocrine glands) representing 18% of body weight in infants compared with 8% in adults. This effect is compounded by the limited muscle and fat mass in the infant. An increased cardiac output distributed primarily to the VRG in infants speeds the equilibration of anesthetic partial pressures in the VRG.

The lower solubilities of inhalational anesthetics in blood and tissues in neonates and infants ( Lerman et al., 1984 , 1986) compared with those in adults speed the equilibration of alveolar to inspired anesthetic partial pressures. The time constant for equilibration of inspired and alveolar anesthetic partial pressures in tissues is similar to that for the lungs, but this equation includes the tissue solubility, as follows:

6.17

Hence, if the tissue/blood solubility in infants is one half that in adults, then the time constant is reduced by one half and the time to 95% equilibration (four time constants) is one half that in adults. This effect is augmented by the reduced mass of the neonatal myocardium compared with that of the adult ( Fig 6-28 ).



FIGURE 6-28 (A) Predicted concentration of halothane in the brain. Values were derived from a computerized model of anesthetic uptake and distribution. (B) Predicted concentration of halothane in the heart. (Reprinted with permission from the International Anesthesia Research Society from Brandom BW, Brandom RB, Cook DR: Anesth Analg 62:404, 1983.)

Effect of Shunting

Intracardiac and intrapulmonary shunts can affect the uptake of inhalational anesthetics ( Stoelting and Longnecker, 1972 ; Tanner et al., 1985 ; Huntington et al., 1999 ). A right-to-left shunt slows the uptake of anesthetic as the partial pressure in arterial blood increases more slowly. The effect of the shunt is more pronounced with less soluble anesthetics than it is with more soluble anesthetics ( Lerman, 2002 ) ( Fig 6-29 ). Induction of anesthesia is protracted in the presence of an insoluble anesthetic with a right-to-left shunt. Evidence suggests that when anesthetizing children with congenital heart disease, sevoflurane may better preserve cardiovascular homeostasis than halothane ( Russell et al., 2001 ). Care must be taken to avoid an inadvertent overdose of a soluble inhaled anesthetic as removal of the anesthetic in the presence of a right-to-left shunt may be prolonged. The effect of a left-to-right shunt depends on the magnitude of the shunt and on whether there is a coincidental right-to-left shunt. A large (>80%) left-to-right shunt increases the rate of uptake of anesthetic from the FRC to the arterial blood: smaller shunts (<50%) have a negligible effect on uptake.



FIGURE 6-29 When no ventilation-perfusion abnormalities exist, the alveolar (P_A or P_ET) and arterial a) anesthetic partial pressures rise together (solid lines) toward the inspired partial pressure P_a). When 50% of the cardiac output is shunted through the lungs, the rate of rise of the end-tidal partial pressure (dashed lines) is accelerated, whereas the rate of rise of the arterial partial pressure (dotted lines) is retarded. The greatest retardation is found with the least soluble anesthetic, cyclopropane. (Redrawn from Eger EI II: Anesthetic uptake and action. Baltimore, 1974, Williams & Wilkins. ©1974, El Eger II, MD.)

Anesthetic Requirements and Minimum Alveolar Concentration

The MACs for various inhalation anesthetics generally are inversely related to age ( Gregory et al., 1969 ; Lerman et al., 1983 ; LeDez and Lerman, 1987 ; Taylor and Lerman, 1991 ; Lerman et al., 1994 ). Anesthetic requirement is usually quantified by the MAC, at which 50% of the subjects move in response to a surgical stimulus. Alternatively, the MAC for an individual subject can be estimated as an intermediate concentration between a concentration associated with movement and one associated with no movement. To prevent a sympathetic response to a surgical stimulus, the end-tidal concentration must exceed the MAC by 30%.

In the first months of life, the relationship between age and MAC is complex. The neurologic connections are intact beginning about 24 weeks' gestation. Gregory and others (1983) noted that MAC in lambs increased during gestation and in the first few hours of postnatal life. Several plausible explanations have been proposed to explain the age-related change in MAC, including change in progesterone levels, endorphin levels, and enkephalin levels; however, none of these have been substantiated.

Equally perplexing is the change in MAC with age in humans. In this case, MAC increases throughout gestation from 24 weeks' gestation, reaching a peak during infancy ( LeDez and Lerman, 1987 ). For isoflurane and halothane, MAC reaches its zenith in infants aged 1 to 6 months ( Lerman et al., 1983 ; Cameron et al., 1984 ). For desflurane, MAC reaches its zenith in infants aged 6 to 12 months ( Taylor and Lerman, 1991 ). In the case of sevoflurane, MAC does not peak in infancy but rather is constant in neonates and infants younger than 6 months ( Lerman et al., 1994 ). After reaching its peak, MAC decreases with increasing age to adulthood.

Although MAC additivity has been widely accepted, two exceptions were reported in children. The contribution of the MAC of nitrous oxide to the MAC of sevoflurane and desflurane in children appear to be less than additive. In both of these instances, 60% nitrous oxide reduced the MAC values of these two anesthetics in children by only 26% ( Fisher and Zwass, 1992 ; Lerman et al., 1994 ). The explanation for this attenuated effect remains unclear.

Frei and others (1997) reported that the MAC of halothane in cognitively challenged children was reduced. In particular, they noted a 25% decrease in the MAC in those challenged children who were not receiving seizure medication and a further 15% reduction in the MAC if they had been taking seizure medication. Although the cognitively challenged children had a heterogeneous group of disorders, this is the first evidence of a reduced anesthetic requirement in these children.

Respiration

All inhalational anesthetics depress respiration in a dose-dependent manner. In general, tidal volume and the response to carbon dioxide decrease and respiratory rate increases as the anesthetic concentration increases. These effects are most pronounced in the neonate and young infant because the mechanics of respiratory effort are compromised due to the child's immature chest wall (bones) and lungs (lack of elastin). In the case of sevoflurane, the extent of respiratory depression is similar to that of halothane up to 1.4 MAC, but thereafter respiratory depression may be greater with sevoflurane. It is important to note that compared with halothane, sevoflurane decreases intercostal muscle tone to a lesser extent. If hypopnea or apnea should occur during sevoflurane or desflurane anesthesia, it is important to recognize that their low solubilities in blood and tissues should facilitate a rapid reduction in anesthetic concentration and resolution of the respiratory depression.

Circulation

The incidence of bradycardia, hypotension, and cardiac arrest during induction of anesthesia is greater in infants and children than in adults ( Leigh and Belton, 1960 ; Rackow et al., 1961 ; Keenan and Boyan, 1985 ; Cohen et al., 1990 ). This has been attributed in part to the administration of excessive concentrations of inhalational anesthetics to neonates ( Lerman et al., 1983 ) and to an increased sensitivity of the myocardium in neonates to inhalational anesthetics. Inhalational anesthetics depress contractility of the myocardium in neonatal rats and rabbits compared with adult animals (Rao et al., 1986; Krane and Su, 1987 ; Murat et al., 1990 ; Palmisano et al., 1994 ). This may result from structural or functional differences, or both, in the myocardium of neonates and adults. In particular, there is a paucity of contractile elements and decreased sarcoplasmic reticulum in neonatal myocardium. The latter increases the neonate's dependency on the influx of extracellular calcium to support contractility. Current evidence suggests that inhalational anesthetics decrease the calcium flux by their actions on the calcium channels themselves, Na⁺-Ca² ⁺ exchange pumps, and the sarcoplasmic reticulum (Baum and Palmisano, 1997). Further evidence now suggests that inhalational anesthetics may attenuate contractility of ventricular myocytes via voltage-dependent L-type calcium channels (which release large amounts of calcium from the sarcoplasmic reticulum) ( Baum and Wetzel, 1994 ). This may explain why neonates are more sensitive to the cardiodepressant effects of inhalational anesthetics than are adults. To clearly define the issue of age-related cardiovascular sensitivity, it is necessary to measure simultaneously the determinants of cardiac output in anesthetized subjects (or animals) at known end-tidal concentrations of anesthetic and at known MAC multiples. In addition, it is necessary to define the sensitivity of cardiovascular “protective” reflexes (baroreceptor reflexes) at MAC multiples of the anesthetic. Direct measurement of cardiac output, contractility, preload, and afterload involves invasive techniques, although the application of an indirect measurement of these variables using noninvasive techniques such as echocardiography has provided some evidence of age-related effects of inhalational anesthetics in humans in early infancy. This, together with neonatal animal data, has clarified these effects in this age group.

The cardiovascular effects of 1.0 and 1.5 MAC halothane and isoflurane were compared in healthy neonates and infants with the use of two-dimensional echocardiography ( Murray et al., 1992 ). Depression of the cardiovascular system was dose dependent and similar with both anesthetics (>30% decrease in ejection fraction and stroke volume at 1.5 MAC) in the two age groups. Atropine (0.02 mg/kg) increased heart rate and cardiac output up to 20% at 1.5 MAC for both anesthetics in both age groups ( Barash et al., 1978 ). In a previous study that included infants and children between 9 days and 32 months old, 15 mL/kg lactated Ringer's solution decreased the stroke volume index at 1.25 MAC halothane, whereas it increased the stroke volume index with isoflurane ( Murray et al., 1987 ). Interpretation of the latter study is difficult in view of the large age range of the infants studied.

Halothane depresses cardiovascular function in direct proportion to the depth of anesthesia (MacGregor et al., 1958; Reynolds, 1962 ; Barash et al., 1978 ). This depression results from direct myocardial depression, dromotropic (cardiac slowing), and a reduction in peripheral resistance ( Goldberg, 1968 ; Skovsted et al., 1969 ; Eger et al., 1970 , 1971). This cardiovascular depression can be attenuated by the use of atropine ( Barash et al., 1978 ; Murray et al., 1992 ).

Isoflurane has a direct negative inotropic effect on myocardium and causes a marked reduction in peripheral resistance. It is considered to have a less depressant effect than halothane on the cardiovascular system, however, because cardiac output is more adequately sustained during hypotension by a compensatory increase in heart rate. In normal adults, both drugs cause reduced blood pressure with increasing depth of agent when used without supplementation, with the hypotension with halothane being greater.

Sevoflurane and desflurane confer similar cardiodepressant activity as isoflurane at equipotent concentrations. At approximately 1 MAC sevoflurane and desflurane, heart rate and blood pressure are similarly reduced in neonates, infants, and children as they are with isoflurane.

Metabolism

Inhalational anesthetics are metabolized to varying degrees in vivo. The extent of metabolism in adults is as follows: methoxyflurane (50%) > halothane (15% to 25%) > sevoflurane (5%) > enflurane (2.4%) > isoflurane (0.2%) > desflurane (0.02%). Metabolism of inhalational anesthetics in vivo in neonates is less than that in adults. This may be attributed to several factors, including reduced activity of the hepatic microsomal enzyme activities, reduced fat stores, and more rapid elimination of inhalational anesthetics in neonates compared with adults. Halothane and, more recently, enflurane have been suspected of causing liver dysfunction. Several cases of postoperative liver failure have been attributed to “halothane hepatitis” in children ( Kenna et al., 1989 ). The exact mechanism that leads to this response remains unclear, although some have speculated that it may be caused by a specific metabolite of halothane. This putative toxic substance may be produced when the reductive pathway for halothane biotransformation in the liver microsomes is active as, for example, when hepatic blood flow is impaired and liver enzyme induction has occurred. Because the reductive metabolic pathways in the liver are poorly developed in infants and children, this may account for the very low incidence of halothane hepatitis in children. Perioperative liver dysfunction has been associated with the use of halothane, isoflurane, enflurane, and desflurane (Carrigan et al., 1987; Martin et al., 1995 ). Transient hepatic dysfunction has been reported after administration of halothane and sevoflurane in children (Kenna et al., 1989 ; Ogawa et al., 1991; Watanabe et al., 1993 ).

In vivo metabolism of inhalational anesthetics to inorganic fluoride has been discussed for each anesthetic. Similarly, the propensity of these anesthetics to undergo in vitro degradation to compound A in the case of sevoflurane and carbon monoxide in the cases of desflurane, isoflurane, and enflurane has also been discussed.

Malignant Hyperthermia

All inhalational anesthetics can trigger malignant hyperthermia (MH) reactions. However, whether the probability of triggering a reaction or the severity of a reaction, were it to occur, differs among these anesthetics is less clear. For example, the relative capability of these anesthetics to augment a caffeine-induced contracture in vitro follows the order of halothane > enflurane > isoflurane > methoxyflurane. The onset of an MH reaction in susceptible swine differs among the anesthetics: halothane > isoflurane > desflurane ( Wedel et al., 1993 ). MH is discussed in further detail in Chapter 31 , Malignant Hyperthermia.

Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

▪ NEUROMUSCULAR BLOCKING AGENTS

Neuromuscular blocking agents are frequently used to facilitate endotracheal intubation, to provide surgical relaxation, and to facilitate controlled mechanical ventilation in both the operating room and the intensive care unit (ICU). Neuromuscular blocking agents have no sedative, hypnotic, or analgesic side effects, but they may indirectly decrease metabolic demand, prevent shivering, decrease nonsynchronous ventilation, decrease ICP, and improve chest wall compliance. The purposes of this section are to review (1) the growth and development of the neuromuscular junction and (2) the age-related pharmacologic characteristics of neuromuscular blocking agents.

▪ NEUROMUSCULAR SYSTEM

Throughout infancy, the neuromuscular junction matures physically and biochemically, the contractile properties of skeletal muscle change, and the amount of muscle in proportion to body weight increases; as a result, the neuromuscular junction is variably sensitive to relaxants. In addition, there are changes in the apparent volume of distribution of relaxants, their redistribution and excretion (clearance), and possibly their rate of metabolism. These factors influence the dose-response relationship of relaxants (i.e., ED₅₀ and ED₉₅) and the duration of neuromuscular blockade. The ED₉₅, which is the mean dose that produces a maximal effect of 95% twitch suppression or neuromuscular blockade, of a neuromuscular blocking agent can be viewed conceptually as proportional to both the volume of distribution (the bucket size) and the concentration of the blocker at its effect site. Both factors have major age-related differences. Although the concentration of drug at the neuromuscular junction in vivo is inaccessible, the drug concentration in plasma that produces 95% twitch suppression at steady-state conditions (C_ss95) provides a means of comparing drug potencies and the factors that affect them. The volume of distribution of neuromuscular blocking agents is highly correlated with (but not equal to) the ECF volume. The ECF of the volume of the infant is significantly greater than that of the older child and adult on a weight basis. ECF volume and surface area, by contrast, bear a nearly constant relationship throughout life (6 to 8 L/m²). Major organ failure, upregulation of acetylcholine (ACh) receptors, poor nutrition, electrolyte and acid-base abnormalities, hypothermia drug interactions, and muscle atrophy can also profoundly influence both the kinetics and dynamics of relaxants ( Fiamengo and Savarese, 1991 ; Klessig et al., 1992 ; Magorian and Lynam, 1992 ; Martyn et al., 1992 ; Rupp, 1987 ; Viby-Mogensen, 1993 ; Fleming, 1994 ; Watling and Dasta, 1994 ; Elliot and Bion, 1995 ; Kim et al., 1995 ; Lee, 1995 ; Miller, 1995 ).

Neuromuscular Junction and Neuromuscular Transmission

The general anatomy, age-related physiology, and pharmacology of the neuromuscular junction have been well defined ( Meakin et al., 1992 ; Wareham et al., 1994 ; Calakos and Scheller, 1996 ; Prince and Since, 1998 ; Sanes and Lichtman, 1999 ). The neuromuscular system is incompletely developed at birth. The conduction velocity of motor nerves increases throughout gestation as nerve fibers are myelinated. The myotubules connect to mature muscle fibers in the latter part of intrauterine life and in the first several weeks after birth ( Table 6-16 ). Some slow-contracting muscle (e.g., intrinsic muscles of the hand) is progressively converted to fast-contracting muscle, with a concomitant change in the force-velocity relationship. Both the diaphragm and the intercostal muscles increase their percentage of slow muscle fibers in the first months of life. Synaptic transmission is relatively slow at birth but, more important, the rate at which ACh is released during repeated nerve stimulation is limited in the infant. The margin of safety for neurotransmissions is smaller in infants than in adults. Age-related changes in the ACh receptor may also contribute to the reduced margin of safety of neurotransmission. See Box 6-1 .

TABLE 6-16 -- Development of skeletal muscle fibers

Age	Development
4 wk	Mesenchymal cells become syncytial; myoblasts become myotube.
5 wk	Syncytial myotube grows in length.
9 wk	Primitive muscle fibers with myofilaments appear.
5 mo	More myofilaments appear and grow in length.
Birth	Nuclei are centralized.
Adult	Muscle fibers become thicker and longer; myofilaments multiply; myofilaments differentiate into actin and myosin; nuclei move more peripherally; myofilaments aggregate into bundles and form myofibrils; muscle fibers grow still thicker and longer; nuclei have shifted peripherally; muscle fibers are thick and mature; alternating actin and myosin myofilaments aggregate into longitudinal bundles.

BOX 6-1

Characteristics of neonatal neuromuscular junction

	•	Acetylcholine receptors change in function and distribution.
	•	Slow twitch fibers (type I increase severalfold in first 6 months).
	•	Infants younger than 2 months have lower train-of-four ratio.
	•	Infants younger than 2 months have increased fade.
	•	Differences more pronounced in premature infants than in term infants.

Acetylcholine Receptors

Prejunctional, postjunctional, and extrajunctional ACh receptors are involved with neuromuscular transmission. The postjunctional ACh receptor is organized into five subprotein units, forming a rosette with a central pit at the mouth of the ion channel, a so-called doughnut hole ( Fig 6-30 ). Each rosette is made up of two α₁ units and a β₁, ε, and δ unit. These subunits are arranged in a specific order (counterclockwise α₁*-ε-α₁-δ-β₁). The α*-subunit has a higher affinity binding site for d-tubocurarine. The binding sites for ACh and neuromuscular blocking drugs are at the α₁/δ interface ( Blount and Merlie, 1989 ; Gu et al., 1990 ; Pederson and Cohen, 1990). Fetal ACh receptor subtypes differ in the structure of one subunit from the adult subtype (i.e., a γ subunit is present in the fetal ACh receptor instead of the ε subunit present in the adult ACh receptor). One presumes that neonates have a mix of both adult and fetal receptors, but at term the adult subtypes are more common. Functional differences exist between these two forms of ACh receptors ( Table 6-17 ; Fig 6-31 ). These differences appear to contribute to the sensitivity of fetal ACh muscle receptors to nondepolarizing and depolarizing neuromuscular blocking drugs. Some uncertainty exists concerning these observations ( Martyn et al., 1992 ; Yost and Dodson, 1993 ; Paul et al., 2002 ).



FIGURE 6-30 Structure of the nicotinic acetylcholine receptor and a description of the requirements to activate and competitively antagonize receptor function. The five subunits (2α, β, γ, and δ with apparent molecular masses of 40, 50, 60, and 65 kDa, respectively), which are partly homologous in sequence, are arranged to form the perimeter of an internal cavity, which is believed to be the ion channel. Each of the subunits has an extracellular and a cytoplasmic exposure, with the bulk of the peptide chain existing on the extracellular side. The α subunits each carry a recognition site for agonists and competitive antagonists. (With permission from Taylor P: Are neuromuscular blocking agents more efficacious in pairs? Anesthesiology 63:1, 1985.)

TABLE 6-17 -- Distinguishing features of mature and fetal receptors

Mature Receptors	*Fetal Receptors^[]**
ε Subunit	γ Subunit
Localized to end-plate region	Junctional and extrajunctional sites
Metabolically stable (half-life 2 wk)	Metabolically unstable (half-life ≈24 hr)
Larger single-channel conductance	Smaller single-channel conductance
Shorter mean open time	Twofold to 10-fold longer mean open time
Agonists depolarize less easily	Agonists depolarize more easily
Competitive agents block more easily	Competitive agents block less easily^[†]

Data from Martyn JA, White DA, Gronert GA, et al.: Anesthesiology 76:822, 1992.

Fetal receptors are more sensitive to pancuronium, vecuronium, mivacurium, and rocuronium but not to d-tubocurarine or gallamine.

^*	Immature junctional receptors have the same characteristics as upregulated extrajunctional receptors.
^†	Recent data conflict with this statement (M. Paul, C. H. Kindler, R. M. Fokt, et al.: 2002).



FIGURE 6-31 Acetylcholine receptor (AChR) channels with the subunits (α, β, ε, and δ or α, β, γ, and δ) arranged around the central cation channel. Binding of acetylcholine to the two α subunits induces the conformational change that converts the channel from closed to open, although the mean channel open times differ between the two types of AChRs depicted here. (With permission from Martyn JAJ, White DA, Gronert GA, et al.: Anesthesiology 76:822, 1992.)

Prejunctional receptors (α₃ subunits) modulate both ACh mobilization and release. They have different binding characteristics and possibly different channel characteristics than the postjunctional receptors ( Bowman, 1980 ). Antagonism of the prejunctional receptor results in diminished release of ACh from neurons stimulated at high frequency. These prejunctional receptors increase ACh mobilization to readily releasable stores and provide feedback control during high-frequency stimulation. The ontogeny of α₃ subunits is not known.

A limited number of extrajunctional ACh receptors (i.e., fetal or upregulated receptors) are also loosely incorporated in the muscle membrane of older infants, children, or adults. Nerve activity inhibits the biosynthesis of ACh receptors at extrajunctional sites. Neurologic motor defects, direct muscle trauma, thermal injury, disease atrophy, sepsis, and prolonged use of relaxants can markedly increase the number of normal ACh receptors and, more important, the number of extrajunctional ACh receptors (i.e., upregulation of receptors) ( Martyn et al., 1992 ).

Neuromuscular Transmission

The issues of ACh transfer, release, or reformation in the nerve terminal have been well reviewed ( Lee, 1987 ; Naguib et al., 2002 ). Mobilization of ACh during tetanic stimulation may be limited in the neonate and particularly in the premature infant. Unanesthetized newborns appear to have less neuromuscular reserve during tetanic stimulation than do adults. In neonates, there is no fade of twitch height with repeated stimulation at rates of 1 to 2 Hz; at 20 Hz, however, there is significant fade. Premature infants may show posttetanic exhaustion for 15 to 20 minutes. Goudsouzian (1980) noted slower contraction times of the thumb after slow and rapid rates of stimulation in term infants (aged 1 to 10 days, anesthetized with halothane) than in older children. The percentage of fade at 20, 50, or 100 Hz did not differ between the infants and the older children, but the tetanic stimulus was applied for only 5 seconds. The train-of-four (TOF) ratio (the ratio of the amplitude of the fourth evoked response to the amplitude of the first response in the same train), the degree of posttetanic facilitation, and the tetanus/twitch ratio increase with age. Crumrine and Yodlowski (1981) noted a decrease in the amplitude of the frequency sweep electromyogram (FS-EMG) at frequencies of 50 to 100 Hz in infants younger than 12 weeks ( Fig 6-32 ). The FS-EMG is a recording of the action potential from an electrical stimulus rate that increases exponentially from one pulse per second to 100 Hz during a stimulation period of 10 seconds. The exponential increase in frequency allows assessment of neuromuscular transmission at tetanic rates without inducing fatigue. In older infants and children, Crumrine and Yodlowski found little or no decrement in the FS-EMG at the high frequencies of stimulation.



FIGURE 6-32 Tracings of the frequency sweep electromyographic (FS-EMG) responses from the tibialis anterior muscles of a 1-day-old infant (A) and a 4-month-old infant (B) premedicated with methohexital. (From Crumrine RS, Yodlowski EH: Anesthesiology 54:29, 1981.)

▪ TYPES OF NEUROMUSCULAR BLOCKING AGENTS: SUCCINYLCHOLINE

Succinylcholine, the only depolarizing relaxant that is used, produces two different types of blockade: phase 1 and phase 2 ( Fig 6-33 ). During phase 1, succinylcholine binds to ACh receptors, causing membrane ionic channels to open in the same fashion as does ACh. The molecules remain bound to the receptor for an extended period and cause the membrane to remain depolarized and unable to trigger any further muscle action potentials. With prolonged exposure, a succinylcholine-induced blockade begins to assume the characteristics of a nondepolarizing blockade. This is referred to as phase 2, desensitization, or dual blockade ( Sutherland et al., 1980 ; Donati and Bevan, 1983 ; Goudsouzian and Liu, 1984 ; Lee, 1986 ). Nondepolarizing agents competitively bind to the α units of the ACh receptor and may also physically block the ion channel in the motor end-plate. Channel blockade can also occur.



FIGURE 6-33 During continuous infusion of succinylcholine chloride, a phase I block—characterized by reduced neuromuscular response, little fade of train-of-four (TOF), and increased blockade with edrophonium—is seen initially. During phase II, there is a fade on TOF, increasing reversibility of the block by edrophonium, and accumulation of the slowly recovering residual block.

Dose-Response Relationships

Several multiples of the ED₉₅ (e.g., 2×ED₉₅)—the so-called intubating dose—are usually administered to ensure adequate neuromuscular blockade and to minimize the time to maximum neuromuscular blockade (the onset time) ( Kopman et al., 2001 ). Table 6-18 gives the relative potencies and duration of effect of various neuromuscular blocking agents in infants and children. By current convention,onset is defined as the time to maximum effect, and duration is defined as the time for return to 25% neuromuscular transmission after a 2×ED₉₅ dose ( Bedford, 1995 ). In general, the ED₉₅ of relaxants was determined on the intrinsic muscles of the hand (e.g., adductor pollicis muscle of the thumb) under steady-state anesthetic conditions. The response to neuromuscular blocking agents and the time to achieve a given degree of blockade (i.e., degree of neuromuscular blockade) vary somewhat with the nerve motor unit being monitored ( Law and Cook, 1990 ). When neuromuscular blocking drugs are used to facilitate tracheal intubation, the goal is to produce relaxation of laryngeal, jaw, abdominal, and intercostal muscles. Diaphragmatic relaxation is of less concern during intubation, but ideally, coughing, bucking, or pushing are not wanted ( Table 6-19 ). The laryngeal adductors are less sensitive than the adductor pollicis to nondepolarizing relaxants, and that response is similar in intensity and time course to the orbicularis oculi ( Fig 6-34 ). This means that thumb twitch may cease before relaxation of the vocal cords; the opposite is true for succinylcholine ( Donati et al., 1991 ; Meistelman et al., 1991 , 1992; Ungureanu et al., 1993; Iwasaki et al., 1994a , 1994b; Plaud et al., 1996 ). Alternatively, small priming doses of the nondepolarizing relaxant (<ED₅ _- ₁₀) can be given to partially occupy the receptor ( Kopman et al., 2001 ). Larger, top-up doses (total dose, 2×ED₉₅) given several minutes later seem to accelerate the onset time. This approach avoids potential cardiovascular changes from even higher multiples of the ED₉₅ (i.e., 6×to 8×ED₉₅) and still provides rapid onset time of neuromuscular blockade.

TABLE 6-18 -- Time course of neuromuscular blockade with various drugs^[*]

Drug	Dose (mg/kg)	Time to Complete Neuromuscular Blockade (min)	Recovery Time to T₂₅ (min)
Succinylcholine	2.0	1.0	4
Mivacurium	0.3	1.5	6
Rocuronium	0.6	1.3	27
Atracurium	0.5	1.5	33
Vecuronium	0.1	1.3	24
Pancuronium	0.4	0.7	75
Doxacurium	0.1	2.5	NA
cis-Atracurium	0.05	5.3	51

Adapted from Gronert BJ, Brandom BW: Pediatr Clin North Am 41:73–92, 1994.

In general, maintenance dose (one-fourth that in table) is given when one palpable twitch is present with train-of-four monitoring.

^*	Drug dose (∼2× ED₉₅) represents so-called intubating dose.

TABLE 6-19 -- Degrees of neuromuscular blockade

Neuromuscular Blockade (%)	Clinical Relaxation	Ventilation
0	None; train-of-four >0.70; tetanus sustained at 50 Hz	Normal; vital capacity normal; inspiratory force >50 cm H₂O
25	Poor; head lift inadequate; leg flexion inadequate	Slightly to moderately diminished vital capacity
50	Fair	Moderately to markedly diminished vital capacity; tidal volume may be adequate
75	Good	Tidal volume diminished
90	Good	Tidal volume inadequate
95	Very good—adequate for tracheal intubation under light anesthesia	Some diaphragmatic motion possible
100	Excellent; very good for tracheal intubation	Apnea



FIGURE 6-34 First twitch height (T1) against time for vocal cords and adductor pollicis, after vecuronium 0.07 mg/kg. Bars indicate SEM. (With permission from Donati F, Meistelman C, Plaud B: Anesthesiology 74:833, 1991.)

As neuromuscular transmission recovers to 25% of control twitch height (T₂₅), the patient may require an additional top-up dose of relaxant ( Fig 6-35 ). Published T₁₀ or T₂₅ indexes of recovery provide some prediction of the expected duration of effect, but monitoring of neuromuscular transmission is preferable. Traditional long-acting relaxants such as pancuronium or intermediate ones such as atracurium, vecuronium, or rocuronium provide about 0.5 to 1 hour of clinical relaxation (1×to 1.5×ED₉₅).



FIGURE 6-35 Spontaneous recovery of neuromuscular function after a dose of rocuronium (1×ED₉₅) in children and infants.

Intermittent administration of neuromuscular blocking agents for prolonged periods may be inconvenient, and administration via infusion appears to be a practical alternative. The goal of such infusion techniques is to maintain a constant plasma concentration of relaxant and a constant degree of neuromuscular blockade. The steady-state infusion rate (I_ss) is proportional to the required plasma concentration (C_ss95) and clearance rate and, thus, the removal rate (R_ss).

6.18

Although traditional long-acting agents (e.g., pancuronium) have been used via infusion, there are drawbacks such as recurrent cardiovascular effects and accumulation. It may be more prudent to infuse agents with an intermediate duration (e.g., atracurium, cis-atracurium, rocuronium, or vecuronium) for prolonged periods. Short-acting agents (e.g., mivacurium) may be even more preferable. Shorter-acting agents may allow more rapid recovery of neuromuscular transmission and are more easily titrated but are clearly more expensive ( Table 6-20 ). Monitoring of neuromuscular blockade with a nerve-muscle stimulator or clinical indicators diminishes the likelihood of prolonged neuromuscular blockade. Additional boluses of relaxant should not be administered until there is reappearance of a single twitch in the TOF-evoked response. Infusion rates can be adjusted to maintain a perceptible single twitch or a level that just abolishes the twitch.

TABLE 6-20 -- Comparison of neuromuscular blocking agents by infusion

	Loading Dose (mcg/kg)	Infusion Rate (mcg/kg per min)	$/mg	$/HR
Pancuronium	50 to 100	0.5 to 1.0	0.42	4.70
Vecuronium	80 to 100	1.0 to 1.5	0.96	2.77
Pipecuronium	40 to 80	0.2 to 0.3	0.44	30.15
Atracurium	200 to 500	5 to 8	1.06	16.32
Doxacurium	25 to 50	0.2 to 0.35	4.06	20.20
Mivacurium	250 to 300	10 to 15	0.92	77.15
Succinylcholine	2000	5.0	0.005	0.86

Modified from Fleming NW: Semin Anesth 13:255, 1994.

^*Based on 70-kg adult.

Characteristics of Specific Agents

The sensitivity of the postjunctional cholinergic receptor to neuromuscular blocking agents may vary with age. When allowance is made for differences in the volume of distribution, infants appear as sensitive to succinylcholine as adults but more sensitive to nondepolarizing relaxants.

Succinylcholine

Succinylcholine, a rapid-acting and ultrashort-duration depolarizing muscle relaxant, is useful when given as a bolus to facilitate endotracheal intubation. The onset times (i.e., time to maximum neuromuscular blockade) at so-called intubating doses are listed in Table 6-21 . Succinylcholine is metabolized by butyrylcholinesterase. Markedly prolonged neuromuscular blockade can result from atypical or abnormally low enzyme concentrations.

TABLE 6-21 -- Variation in onset time at different epochs for various relaxants

	RESPONDERS (%)
Onset Time (sec)	*Succinyl-choline*	Rapacuronium^[*]	*Rocuronium*	*Mivacurium*
<30	0	0	0	0
31 to 60	90	62	50	27
61 to 90	10	19	25	45
91 to 120	0	14	17	9
121 to 150	0	0	0	9
151 to 180	0	0	8	9
>180	0	5	0	0

Data from various studies by the author.

Onset times from 2× ED₉₅.

^*	Not commercially available.

Butyrylcholinesterase activity is reduced in neonates, but there is little change in butyrylcholinesterase activity between 3 months and 12 years of age (B. Gronert, B. W. Brandom, D. R. Cook, unpublished data).

When differences in volume of distribution and concentration of anesthesia are taken into account, infants and small children (<2 years old) appear relatively resistant to succinylcholine, have a faster clearance, and have a shorter onset time (at equal multiples of the ED₉₅) than do older children and adults. Most of the side effects of succinylcholine were described within years of its introduction: dysrhythmias, increased intraocular pressure, prolonged apnea, injured muscle membranes with associated hyperkalemia, association with masseter spasm and malignant hyperthermia, and death. Infants and small children have a high incidence of such complications. Intractable, unexpected cardiac arrest (ventricular fibrillation or asystole) associated with a 40% to 50% mortality has been reported after the use of succinylcholine in children with undiagnosed Duchenne's muscular dystrophy. In these patients, succinylcholine may cause rhabdomyolysis and massive hyperkalemia ( Tang et al., 1992 ; Hopkins, 1995 ; Gronert, 2001 ). This series of case reports created a small firestorm that culminated in the Food and Drug Administration issuing a “box” warning against the elective use of succinylcholine.

Age-Related Responses

Neonates and infants require about twice as much succinylcholine on a weight basis as do older children or adults to depress respiration or neuromuscular transmission or to produce apnea. In infants, 1 mg/kg succinylcholine produces neuroblockade about equal to that produced by 0.5 mg/kg in children aged 6 to 8 years ( Cook and Fischer, 1975 ). At these equipotent doses, there is no statistically significant difference between the times to recover to 50% and 90% (T₉₀) neuromuscular transmission in the two groups. Complete neuromuscular blockade develops in children given 1 mg/kg of succinylcholine. Cook and Fischer (1975) estimated the ED₉₅ of succinylcholine to be 2.2 mg/kg. Estimates of the ED₉₅ of succinylcholine were made in additional age groups by Meakin and others (1989) ( Table 6-22 ; Fig 6-36 ). Neonates and infants may require 2 to 3 mg/kg and children may require 1 to 2 mg/kg of succinylcholine to achieve comparable intubation conditions seen in adults who are given 1 to 1.5 mg/kg of succinylcholine. In view of the marked variability in neuromuscular block produced by small doses of succinylcholine, it would seem advisable to select doses at the upper end of these ranges. Spontaneous recovery from succinylcholine-induced apnea may not occur sufficiently quickly to prevent hemoglobin desaturation in patients whose ventilation is not assisted ( Heir et al., 2001 ).

TABLE 6-22 -- Calculated ED₅₀ and ED₉₅ for succinylcholine as a function of age

Age Group	ED₅₀ (mcg/kg)	ED₉₅ (mcg/kg)	ED₅₀ (mcg/m²)	ED₉₅ (mcg/m²)
Neonates	250	625	3952	9881
Infants	317	729	6277	14,436
Children	184	423	4416	10,154
Adults	—	290	—	11,940

Data from Meakin G, McKiernan EP, Morris P, et al.: Dose-response curves for suxamethonium in neonates, infants and children. Br J Anaesth 62:655, 1989.



FIGURE 6-36 Log dose-probit response regression lines for succinylcholine for neonates (N), infants (I), and children (C). Points along the lines represent mean responses from subgroups of five patients. (With permission from Meankin G, McKiernan EP, Morris P, et al.: Br J Anaesth 62:655, 1989.)

Goudsouzian and Liu (1984) found that a threefold higher infusion rate of succinylcholine (milligrams per kilogram per hour) was needed to maintain a 90% twitch depression in young infants compared with older infants or children. A slightly larger dose of succinylcholine was needed in infants than in the other age groups to achieve phase II block. Differences in butyrylcholinesterase activity, receptor sensitivity, or volume of distribution may explain these age-related differences in succinylcholine requirements. The neonate has about one half the butyrylcholinesterase activity of the older child or adult; it is unlikely that augmented butyrylcholinesterase activity is responsible for the infant's resistance to succinylcholine. When succinylcholine was given on a surface area basis (40 mg/m²), no difference existed between infants and adults in the times to recover to 10%, 50%, or 90% neuromuscular transmission; this dose of succinylcholine produced complete neuromuscular blockade in all patients. A linear relationship occurs between the log dose on a milligram-per-meter squared basis and the maximum intensity of neuromuscular blockade for infants, children, and adults. They also observed a linear relationship between the logarithm of the dose on a milligram-per-meter squared basis and either 50% or 90% recovery time for infants and children as a combined group. Similar findings were noted by others (see Table 6-22 ). Because of the small molecular size of succinylcholine, it is rapidly distributed throughout the ECF. The blood volume and ECF volume of the infant are significantly greater than those of the child and adult on a weight basis. On a weight basis (milligram per kilogram), twice as much succinylcholine is needed in infants as in adults to produce a given degree of neuromuscular blockade.

Because ECF volume and surface area bear a nearly constant relationship throughout life, it is not surprising that there is a good correlation between succinylcholine dose (micrograms per meter squared) and response throughout life. The data of Goudsouzian and Liu (1984) suggest that relative resistance to succinylcholine persists in some infants even when the dose is transformed to micrograms per meter squared per minute. These data suggest that the ACh receptor matures with age, or that butyryl cholinesterase activity is high in infants. Indeed, butyryl cholinesterase activity is quite high in infants compared with adults.

Side Effects

Succinylcholine can have profound cardiovascular effects; increase intraocular, intragastric, and intracranial pressures; and be associated with hyperkalemia, myoglobinemia, and malignant hyperthermia.

Dysrhythmias.

Succinylcholine exerts variable and seemingly paradoxical effects on the cardiovascular system. Typically, intravenous succinylcholine produces initial bradycardia and hypotension, followed after 15 to 30 seconds by tachycardia and hypertension. In the infant and small child, profound sustained sinus bradycardia (rates of 50 to 60 beats/min) commonly is observed; rarely, asystole occurs. Nodal rhythm and ventricular ectopic beats are seen in about 80% of children given a single intravenous injection of succinylcholine; such dysrhythmias are rarely seen after an intramuscular injection of succinylcholine. The incidence of bradycardia and other dysrhythmias is higher after a second dose of succinylcholine.

Atropine (0.1 mg) appears to offer adequate protection against these bradyarrhythmias in all age groups of infants and children. (In infants, vagolytic doses of 0.03 mg/kg are required for protection; in older children, adequate protection is provided by doses of 0.005 mg/kg.)

Pulmonary Edema and Pulmonary Hemorrhage.

Cook and others (1981) have described several young infants in whom fulminant pulmonary edema developed only minutes after intramuscular injection of succinylcholine (4 mg/kg). The edema responded to ventilation with continuous positive airway pressure.

Intragastric Pressure.

Succinylcholine may increase intragastric pressure. The increase in intragastric pressure is directly related to the intensity of muscle fasciculations. In adults, pressures as high as 40 cm H₂O have been recorded after violent fasciculations. When the intragastric pressure exceeds 20 cm H₂O, the cardioesophageal valve (“sphincter”) mechanism may become incompetent; regurgitation and aspiration may occur. Because of limited muscle mass, the infant or small child, in contrast to the adult, seldom has strong fasciculations. Salem and others (1972) observed only a 4 cm H₂O increase in intragastric pressure after intravenous administration of succinylcholine in infants; in some patients, the intragastric pressure decreased

Intraocular Pressure.

Intravenous or intramuscular administration of succinylcholine increases intraocular pressure in infants and adults. Although dilation of choroidal vessels by succinylcholine is a contributory factor, the increase in intraocular pressure is primarily the result of contraction of extraocular muscles. Typically after intravenous succinylcholine administration, the intraocular pressure begins to increase within 60 seconds, peaks at 2 to 3 minutes, and then returns to control levels 5 to 7 minutes after injection. A succinylcholine-induced increase in intraocular pressure in the presence of a penetrating wound of the eye can result in extrusion of vitreous humor through the site of injury and possibly loss of vision. The transient increase in intraocular pressure may be misinterpreted and lead to unnecessary surgery in a patient with glaucoma if tonometry is performed within 5 to 7 minutes of the injection of succinylcholine

Increased Intracranial Pressure.

Minton and others (1986) suggested that succinylcholine per se may increase ICP. Increases in ICP after the administration of succinylcholine are produced by cerebral metabolic stimulation and increases in cerebral blood flow. These effects are attenuated by prior administration of a nondepolarizing agent and by treatment with thiopental or lidocaine

Hyperkalemia and Myoglobinemia.

In normal patients, succinylcholine increases plasma levels of potassium by 0.3 to 0.5 mEq/L. Alarming levels of potassium, as high as 11 mEq/L, along with cardiovascular collapse, were frequently reported with succinylcholine in a variety of conditions, including burns, massive trauma, stroke, spinal cord injury, and muscle diseases ( Delphin et al., 1987 ; Rosenberg and Gronert, 1992 ; Schow et al., 2002 ). The common denominator appears to be either massive tissue destruction or CNS injury with muscle wasting. Strong fasciculations are not necessary to produce hyperkalemia in susceptible patients. There are no data to suggest that the infant is any less vulnerable than the adult to massive potassium flux from the listed conditions ( Henning and Bush, 1982 ; Dierdorf et al., 1984 ). A seemingly high incidence of myoglobinemia occurs after succinylcholine (1 mg/kg) in prepubertal patients, especially those anesthetized with halothane. Myoglobinemia rarely results from succinylcholine administration in adults. Plasma levels of creatine phosphokinase, an indicator of muscle injury, have been shown to be significantly increased after succinylcholine administration in children. Myoglobinemia and increased plasma levels of creatine phosphokinase occurred without strong fasciculations. The tendency of muscle in children to release myoglobin after depolarization with succinylcholine is not readily explained. Such changes seem to be rare in infants

Masseter Spasm, Trismus, and Malignant Hyperthermia.

Most clinicians are well aware of the association of succinylcholine with malignant hyperthermia (MH). Typically, MH develops as a profound rigidity or violent fasciculations, a rapid increase in temperature, an increase in pulse rate, and an increase in end-tidal carbon dioxide tension. These are the classic signs, but occasionally the only manifestation of MH is trismus ( Flewellen and Nelson, 1984; Schwartz et al., 1984 ). The rigid jaw can be forced open but only with considerable difficulty. Only about half of the patients in whom trismus follows administration of succinylcholine have a predisposition to MH ( Flewellen and Nelson, 1984 ). Resting tension or stiffness in the masseter muscle increases in a dose-related manner as succinylcholine blocks neuromuscular function ( DeCook and Goudsouzian, 1980 ; Plumley et al., 1990 ; Sadler et al., 1990; Van Der Spek et al., 1989 , 1988). These changes can make laryngoscopy difficult. Perhaps masseter spasm is an extreme case of the apparently normal dose-related increase in resting tension observed in some studies. A more complete evaluation of the force required to open the mouth is necessary to clarify this issue. Perhaps masseter spasm is not only quantitatively different from the changes in resting tension but also qualitatively different. If so, the identifying features of masseter spasm have yet to be described in sufficient detail to allow differentiation of masseter spasm from an extreme instance of the normal increase in resting tension of the masseter after the administration of succinylcholine. It is not possible to define susceptibility to MH solely on the basis of trismus. Creatine phosphokinase measurement and muscle biopsy may be of some help, but most centers are reluctant to perform major muscle biopsies in children younger than 8 to 10 years. The diagnosis is extraordinarily difficult to make on clinical grounds alone. See Chapter 31 , Malignant Hyperthermia.

Decreasing Use

Rumors of the total withdrawal from use of succinylcholine have become more common in the past several years. Many have suggested that succinylcholine be eliminated from clinical use; others have demanded that succinylcholine be eliminated altogether. Both the “box” warning against the elective use of succinylcholine and increased availability of alternative agents have contributed to the markedly diminished use of this agent ( Cook, 2000 ). Many of the profound cardiovascular complications of succinylcholine were described within 5 to 15 years of its introduction: the hazards of the use of succinylcholine in patients with neural injuries, neuromuscular disease, burns, and massive trauma were established; and the hazards of succinylcholine as a “triggering” agent for myotonia, masseter spasm, and MH were established. Despite these hazards, succinylcholine remained popular to facilitate endotracheal intubation because there was no reasonable alternative. The clinical introduction of the new short-acting and intermediate-acting relaxants and the development of the so-called priming principle and other clinical strategies to minimize the onset time of relaxants have minimized the need for succinylcholine. Priming or administration of 8×to 10×the ED₉₅ of a relaxant can be used to accelerate the onset of neuromuscular blockade. Infants and small children rarely demonstrate histamine release after relaxants are administered; thus large top-up doses can be used after the priming dose or initial megadoses of relaxants. Such uses convert atracurium, cis-atracurium, rocuronium, and vecuronium from intermediate-acting to long-acting relaxants.

▪ NONDEPOLARIZING NEUROMUSCULAR BLOCKING DRUGS

Nondepolarizing neuromuscular blocking agents can be categorized by the time to maximum blockade (onset time) and by the clinical duration of effect (i.e., time to return of neuromuscular transmission to 25% of control) after a 2×ED₉₅ dose during a standard anesthetic technique ( Bedford, 1995 ) ( Table 6-23 ).

TABLE 6-23 -- Definitions of adjectives describing nondepolarizing neuromuscular blocking agents

	TIME (min)
Adjective	*Minimum*	*Maximum*
Onset
Ultrarapid	Not needed	<1
Rapid	1	2
Intermediate	2	4
Slow	4	Not needed
Duration
Ultrashort	Not needed	8
Short	8	20
Intermediate	20	50
Long-acting	>50	Not needed

From Bedford RF: Anesthesiology 82:33A, 1995.

There is a clear trend to use short-duration and intermediate-duration relaxants rather than long-acting relaxants for most surgical patients. There also is a thought that more rapid-acting relaxants are preferable to those of longer onset. In general, at equal multiples of the ED₉₅, the less potent agents have more rapid onset times than the more potent agents (i.e., rocuronium has a more rapid onset time than vecuronium). The coefficient of variation in onset time for various relaxants is listed in Table 6-24 . Long-acting relaxants are probably reserved for long surgical procedures and procedures in which postoperative ventilation is anticipated.

TABLE 6-24 -- Coefficient of variation in onset time of intubating doses of relaxants in infants and children^[*]

	COEFFICIENT OF VARIATION (%)
Drug	*Infants*	*Children*
Atracurium	45.9	46.5
Vecuronium	40.0	58.3
Mivacurium	53.3	42.8
Succinylcholine	36.4	22.2
cis-Atracurium	NA	53.5

^*	Intubating dose = 2× ED₉₅.

There are four routes of elimination of nondepolarizing muscle relaxants: renal excretion; hepatic uptake, storage and excretion; biotransformation (including Hofmann elimination); and tissue binding (Table 6-25 ). Nondepolarizing muscle relaxants filter freely through the glomerulus, and the renal clearance of these drugs does not exceed the GFRe (1 to 2 mL/kg per minute). The degree of metabolism that nondepolarizing muscle relaxants undergo varies widely. Hofmann elimination and ester hydrolysis are largely responsible for the breakdown of atracurium and cis-atracurium; butyrylcholinesterase is primarily associated with the metabolism of mivacurium. Hepatic biodegradation has been demonstrated for steroidal relaxants ( Savage et al., 1980 ; Bencini et al., 1983). A small fraction (20% to 30%) of pancuronium undergoes metabolism. The metabolism of vecuronium is significant ( Savage et al., 1980 ; Marshall et al., 1983). Spontaneous deacetylation occurs in the liver, and the byproducts are 3-hydroxy and 17-hydroxy derivatives. The metabolism of steroidal relaxants is not mediated by CYP systems but by nonspecific esterases (personal observations). The 3-OH metabolites of both vecuronium and pancuronium are roughly one half to equally potent at the neuromuscular junction as the parent compounds. The 17-OH and 3,17-OH metabolites are far less active (Marshall et al., 1983).

TABLE 6-25 -- Elimination routes of muscle relaxants

Agent	Hepatobiliary Metabolism in Plasma	Uptake and Metabolism	Renal Excretion
Mivacurium	XX	—	—
Atracurium	XX	—	—
cis-Atracurium	XX	—	—
Vecuronium	—	XX	X
Rocuronium	—	XX	X
Pancuronium	—	XX	X
Pipecuronium	—	XX	X
Doxacurium	—	—	XX

XX, major route; X, alternative route.

Short-Acting Agents

Mivacurium

Mivacurium, a nondepolarizing muscle relaxant with a short duration of action, is metabolized by butyrylcholinesterase, which clearly influences the duration of action ( Beaufort et al., 1998 ; Ostergaard et al., 2000 ; Gatke et al., 2001 ). Mivacurium is a mixture of three optical isomers. The two active isomers of mivacurium (trans-trans and cis-trans) have a short half-life and rapid clearance because of rapid enzymatic hydrolysis. The cis-cis isomer has minimal neuromuscular blocking effects but is slowly hydrolyzed ( Cook et al., 1992a , 1992b; Head-Rapson et al., 1994 ; Lien et al., 1994 ). The ED₉₅ of mivacurium during halothane anesthesia in infants and children is 85 and 89 mcg/kg, respectively ( Woelfel et al., 1993 ; Meretoja et al., 1994 ). Mivacurium is metabolized by butyrylcholinesterase more slowly than is succinylcholine. In infants, mivacurium produces complete neuromuscular blockade as quickly as succinylcholine, but at that time the intubating conditions were less desirable after mivacurium (i.e., a higher incidence of coughing and diaphragmatic movement) ( Gronert et al., 1995 ). In children, mivacurium produces complete neuromuscular blockade more slowly than does succinylcholine. During halothane anesthesia increasing the dose of mivacurium from 0.2 mg/kg to 0.3 mg/kg does not shorten the time to complete paralysis after mivacurium administration (1.5 minutes) (Gronert and Brandom, 1994 ). After administration of 0.3 mg/kg of mivacurium during halothane anesthesia, hypotension or cutaneous flushing was not observed in children. Mivacurium can induce histamine release when large bolus doses (e.g., 0.4 mg/kg) are administered rapidly. The most common manifestation of histamine release is transient cutaneous flushing and mild decreases in blood pressure. Recovery to T₂₅ was faster in infants (6.3 minutes) compared with children (10 minutes). Increasing the dose of mivacurium given to children from 0.2 to 0.3 mg/kg did not significantly prolong the time to spontaneous recovery of neuromuscular function to 25% of baseline ( Gronert et al., 1995 ). Mivacurium (0.3 mg/kg) has little or no effect on lung mechanics (flow-volume loops) ( Fine et al., 2002 ).

It is remarkable that the duration of action of mivacurium is so short in children. Mivacurium is one of the few neuromuscular blocking agents that are cleared in the plasma rather than by the kidneys or liver. This may be the reason why infants recover from this drug at least as rapidly as do children and why children recover more rapidly than do adults. There have been several studies of the kinetics of mivacurium in infants and children ( Ostergaard et al., 2002 ; Markakis et al., 1998 ; Meretoja, et al., 1994) ( Table 6-26 ). The volume of distribution of mivacurium is seemingly greater in the infant than in the child, and the clearance in infants and children is faster than that of the adult. These conclusions are indirectly supported by the observations that the infusion rate of mivacurium to maintain constant neuromuscular block (˜95% twitch depression) is about twice as great in infants and children as in adults ( Markakis et al., 1998 ). An advantage of mivacurium is that it can be given via infusion for hours without accumulation or prolongation of recovery once the infusion is stopped ( Brandom et al., 1990 ; Goudsouzian et al., 1994 ).

TABLE 6-26 -- Pharmacokinetic parameters for the three isomers of mivacurium in children

	*trans-trans*	*cis-trans*	*cis-cis*
AUC (ng/mL per min)	4032 ± 1095	1768 ± 569^[*]	1502 ± 414^[*]
MRT (min)	2.2 ± 1.1	1.5 ± 1.0	7.7 ± 2.4^[*][†]
V_d (mL/kg)	85.1 ± 53.5	83.9 ± 67.8	83.9 ± 15.7
CL (mL/min per kg)	38.5 ± 10.9	56.3 ± 17.9^[*]	11.6 ± 4.0^[*][†]
t_½β (min)	1.2 ± 0.2	0.8 ± 0.2	4.5 ± 1.6^[*][†]

AUC, area-under-the-plasma-concentration curve; MRT, mean residence time; V_d, volume of distribution; CL, clearance; t_½β, elimination half-life.

Analysis of variance with Student-Newman-Keuls test.

Unpublished data of the author.

^*	Different from trans-trans.
^†	Different from cis-trans.

In adults with renal or hepatic failure and subsequently reduced butyrylcholinesterase activity, the duration of mivacurium-induced neuromuscular blockade is increased by renal and hepatic failure. Similar studies in children have not been performed. In adults given 0.15 mg/kg, the duration of block was approximately three times normal in those with liver failure (Cook et al., 1992; Head-Rapson et al., 1994 , 1995; Levy, 1994 ). There was a significant nonlinear, negative correlation between butyrylcholinesterase and time to spontaneous recovery of neuromuscular function to 25% of baseline in these patients.

Intermediate-Acting Agents

Atracurium

Atracurium, a muscle relaxant of intermediate duration, is metabolized by nonspecific esters and spontaneously decomposed by Hofmann degradation. Both processes are sensitive to pH and temperature. Under physiologic conditions, the breakdown of atracurium is mainly by ester hydrolysis; Hofmann elimination plays a minor role. Deficient or abnormal butyryl cholinesterases have little or no effect on atracurium degradation. The effects of both age and potent inhaled anesthetics on the dose-response relationships of atracurium in infants, children, and adolescents have been studied ( Brandom et al., 1985; Goudsouzian et al., 1983 , 1985; Stiller et al., 1985a , 1985b; Meretoja, et al., 1994). On the basis of weight (micrograms per kilogram), the ED₉₅ for atracurium was similar in infants aged 1 to 6 months and in adolescents, whereas children had a higher dose requirement. On the basis of surface area (micrograms per meter squared), the ED₉₅ for atracurium was similar in children and adolescents, and the ED₉₅ (milligrams per meter squared) for atracurium in infants was much lower. At equipotent doses (1×ED₉₅), the duration of effect (time from injection to 95% recovery) was 23 minutes in infants and 29 minutes in children and adolescents, compared with 44 minutes in adults. The time from injection to T₂₅ (i.e., 25% neuromuscular transmission) was 10 minutes in infants, 15 minutes in children and adolescents, and 16 minutes in adults. At T₂₅, supplemental doses are needed to maintain relaxation for surgery. At higher multiples of the ED₉₅, the duration of effect is longer, but the times from T₅ to T₂₅are the same. The shorter duration of effect in the infant may represent a difference in pharmacokinetics. The pharmacokinetics of atracurium differ among infants, children, and adults. The volume of distribution is larger, clearance is more rapid, and the elimination half-life is seemingly shorter in infants than in children or adults ( Table 6-27 ).

TABLE 6-27 -- Age-related pharmacokinetics of atracurium

Variable	Children	Infants
t_½α (min)	2.1 ± 0.56	1.04 ± 0.34^[*]
t_½β (min)	19.1 ± 4.5	13.6 ± 1.4^[*]
V_d (mL/kg)	139.0 ± 23.48	176.6 ± 22.2^[*]
CL (mL/kg per min)	5.1 ± 0.56	9.0 ± 1.65^[*]

From Cook DR, Marcy JH: Neonatal anesthesia. Pasadena, CA, 1988, Appleton Davies.

Values are mean ± SEM. t_½α, half-life of the distribution phase; t_½β, elimination half-life; V_d, volume of distribution; CL, clearance.

^*	P < 0.5 in infants compared with values in children.

Brandom and others (1985) used a continuous infusion of dilute atracurium (200 mcg/mL) after a bolus infusion to maintain neuromuscular blockade at 95 ± 5%. To maintain this degree of steady-state blockade, 8 to 10 mcg/kg per minute was required with nitrous oxide, thiopental, and narcotic anesthesia after an initial bolus. No accumulation was seen with prolonged infusion; recovery of neuromuscular transmission was prompt. The recovery of neuromuscular transmission from the same degree of blockade was similar if potent anesthetics were used (i.e., halothane). With these data the removal of atracurium can be estimated. At steady state, the infusion rate (I_ss) equals the removal rate (R_ss) of atracurium. Removal is directly related to the clearance and the C_ss95. In children, during so-called balanced anesthesia, C_ss95 is about 2 mcg/mL. Atracurium infusion requirements in children during nitrous oxide and narcotic anesthesia can be compared with those noted in several age groups of adults during similar anesthetic administrations. d—Hollander and others (1983) noted that in patients aged 16 to 85 years, the steady-state atracurium infusion rate averaged 14.4 mg/kg per hour; this corresponds to 240 mg/m² per minute. This value is similar to the 226 mg/m² per minute rate we noted. Atracurium does not depend on the kidney or the liver for elimination because it is biodegraded by Hofmann elimination and ester hydrolysis. However, the parent compound and its metabolites are normally found in bile and urine ( Neill and Chapple, 1983 ). Because atracurium does not depend on the kidney for excretion, its elimination half-life and duration of action are not prolonged in patients with renal failure ( Hunter et al., 1982 ; Ward and Neill, 1983; Fahey et al., 1984 ) ( Table 6-28 ). Fahey and others (1984) found no change in the kinetics or the duration of action and rate of recovery from atracurium in these patients. Hunter and others (1982) also found no difference in duration of action.

TABLE 6-28 -- Pharmacokinetic parameters in normal and organ failure patients

	NORMAL PATIENTS			HEPATIC PATIENTS			RENAL FAILURE PATIENTS
Drug	*Vd_SS (L/kg)*	t_½β (hr)	*CL (mL/kg per min)*	*Vd_SS (L/kg)*	t_½β (hr)	*CL (mL/kg per min)*	Vd_SS (L/kg)	t_½β (hr)	*CL (mL/kg per min)*
d-Tubocurarine	0.3 to 0.5	2 to 5.8	1 to 2.7	NA	NA	NA	0.25	2.2	1.5
Pancuronium	0.14 to 0.4	1.7 to 2.4	1 to 2	0.21 to 0.42	3.4 to 5.1	0.6 to 1.5	0.29	4.3	0.9
Vecuronium	0.18 to 0.26	0.5 to 1.3	3	0.23	1.2	2.7	0.19	0.8	5.3
Atracurium	0.18	0.33	5 to 6	0.16	0.35	5.2	0.22	0.4	5.3
Rocuronium	0.20	1.5	3.7 to 5	0.25	2.5	2.6	0.20	1	2.5
cis-Atracurium	0.16	—	5.7	0.20	—	6.6	—	—	—

The cis-atracurium is a mixture of 10 optical and geometric isomers ( Welch et al., 1995 ). The R-R¹ optical isomer in the cis-cis configuration, cis-atracurium, is about 1.5×more potent than atracurium and does not liberate histamine at very high doses ( Tobias et al., 2001 ). Seemingly cis-atracurium is primarily degraded by Hofmann elimination, pH-dependent chemical degradation, with the initial formation of laudanosine and a monoquaternary acrylate. Plasma esterases hydrolyze the monoquaternary acrylate to a monoquaternary alcohol; further Hofmann elimination can form another molecule of laudanosine. Renal failure or liver disease has minimal effect on the pharmacodynamics of cis-atracurium ( Prielipp et al., 1995 ; DeWolf et al., 1996 ). Because cis-atracurium is more potent than atracurium, less laudanosine accumulates in patients after a bolus of prolonged infusion. Dhonneur and others (2001) infused cis-atracurium for 0.5 to 8 days in patients with adult respiratory distress syndrome. Clearance ofcis-atracurium was little different from that seen in normal patients, and laudanosine plasma concentrations were less than 1200 ng/mL. Reich and others (2002) infusedcis-atracurium in infants after congenital heart surgery. The clearance ofcis-atracurium was quite high and the duration of residual blockade was low. Laudanosine plasma concentrations were less than 2000 ng/mL.

DeRuiter and Crawford (2001) have noted that cis-atracurium is equipotent in infants and children. During nitrous oxide-narcotic thiopentone administration, the ED₅₀ and ED₉₅ values for infants (29 ± 3 μg/kg and 43 ± 9 μg/kg, respectively) were similar for children (29 ± 2 μg/kg and 47 ± 7 μg/kg) (DeRuiter and Crawford, 2001).

Using halothane anesthesia, Meretoja noted that the rate of recovery following a dose of 1 to 2×the ED₉₅ was rapid with a recovery index of 9 to 11 minutes and a time from 5% to 95% recovery of 25 to 30 minutes. In a separate study of infants and children anesthetized with nitrous oxide and opioids, Taivainen and others (2000) noted that following 0.1 mg/kg of cis-atracurium, the mean (SD) onset time of maximum blockade was more rapid in infants (2.0 ± 0.8 min) than in children (3.0 ± 1.2 min). The clinical duration of action of cis-atracurium (recovery of evoked response to 25% of control) was significantly longer in infants (43.3 ± 6.2 min) than in children (36.0 ± 5.4 min). Once neuromuscular function started to recover, the rate was similar in both age groups. It appears that liver disease and renal failure do not alter cis-atracurium's pharmacologic profile.

Laudanosine is the major end-product of atracurium orcis-atracurium degradation (Stiller et al., 1985; Eddleston et al., 1989 ). The byproducts of atracurium metabolism have no neuromuscular blocking effect, and they are excreted by the liver and the kidney ( Neill and Chapple, 1983 ; Parker et al., 1988 ). Laudanosine accumulates in patients with liver or renal failure, and its serum concentration remains elevated for a prolonged period ( Fahey et al., 1985 ). In large doses, laudanosine has been shown to cause CNS stimulation in dogs and rabbits but not in cats ( Babel, 1989 ; Ingram et al., 1986). It also increases the MAC of halothane in rabbits ( Shi et al., 1985 ), and in dogs it causes electroencephalographic changes of arousal during halothane anesthesia ( Lanier et al., 1985 ).

Adverse effects observed with laudanosine accumulation may be partially attributed to an interaction with neuronal nicotinic receptors (e.g., α₄β₂ and α₃β₄ receptors) ( Chiodini et al., 2001 ). The clinical importance of laudanosine in patients with renal failure, particularly after repeated doses of atracurium, has not been determined. Atracurium has been infused in patients for 22 to 106 hours, however, without adverse effect ( Parker et al., 1988 ).

Vecuronium

The ED₉₅ for vecuronium is somewhat higher in children than in infants and adults (d—Hollander et al., 1982; Fisher and Miller, 1983 ). At equipotent doses (2×ED₉₅) of vecuronium, the duration of effect (time from injection to 90% recovery) was longest in infants (73 minutes) compared with that in children (35 minutes) and adults (53 minutes). Thus vecuronium does not have intermediate duration in infants. An infusion rate of 2.4 mcg/kg per minute (60 mg/m² per minute) vecuronium is generally required to maintain approximately 95% neuromuscular blockade in children during narcotic and nitrous oxide anesthesia. These infusion rates are several times higher than those noted by d—Hollander and others (1982) in adults (aged 18 to 85 years). Young adults required 0.9 mcg/kg per minute (45 mcg/m²per minute) to maintain 95% neuromuscular blockade. Children recover more rapidly from vecuronium infusion than do adults. Several groups have noted long-term vecuronium infusion requirements in adults with multiple organ failure in the ICU ( Segredo et al., 1992 ). Infusion rates of about 1.6 mcg/kg per minute are required, and the degree of block may gradually increase, a sign of accumulation. Increasing vecuronium infusion requirements, by contrast, may be seen during very prolonged infusions (i.e., lasting 3 to 14 days). These increased requirements could not be clearly associated with various pathophysiologic states, concurrent drug administration, or biochemical abnormalities. Proliferation of extrajunctional cholinergic receptors resulting from prolonged nondepolarizing blockade has also been offered as an explanation.

Fisher and others (1983) determined the pharmacodynamics and pharmacokinetics of vecuronium in infants and children (Tables 6-29 and 6-30 [29] [30]). The volume of distribution and the mean residence time were greater in infants than in children. Clearance was similar in the two groups; the C_ss50 was lower in infants than in children. The combination of a large volume of distribution in infants and fixed clearance results in a longer mean residence time. After a single dose of relaxant, recovery of neuromuscular transmission depends on both distribution and elimination. The combination of a longer mean residence time and a lower sensitivity for vecuronium explains the prolongation of neuromuscular blockade in infants. Little or no 3-OH vecuronium is seemingly formed after a single dose of vecuronium (0.1 to 0.2 mg/kg).

TABLE 6-29 -- Age-related potency and time course for vecuronium

	POTENCY			TIME COURSE (70 mcg/kg)
*Age Group*	*ED₅₀ (mcg/kg)*	*ED₉₅ (mcg/kg)*	*ED₉₅ (multiple)*	*Onset Time (min)*	*Duration (min)*
Infants	16.5	27.7	2.5	4.5 ± 0.6	73 ± 27
Children	19.0	45.5	1.5	2.4 ± 1.4	35 ± 6
Adults	15.0	33.8	2	2.9 ± 0.2	53 ± 21

From Cook DR, Marcy JH: Neonatal anesthesia. Pasadena, CA, 1988, Appleton Davies.

Values are mean ± SD. ED₅₀, effective dose for 50% twitch depression; ED₉₅, estimated dose needed to produce 95% neuromuscular blockade.

TABLE 6-30 -- Pharmacokinetics and pharmacodynamics of vecuronium

Age Group	t_½β (min)	CL (mL/kg per min)	Vd_ss (mL/kg)	Cp_ss50 (ng/mL)
Infants	64.7 ± 30.2	5.6 ± 1.0	357 ± 70	57.3 ± 17.7
Children	41.0 ± 15.1	5.9 ± 24	204 ± 116	109.8 ± 28.1
Adults	70.7 ± 20.4	5.2 ± 0.7	269 ± 42	93.7 ± 33.5

From Cook DR, Marcy JH: Neonatal anesthesia. Pasadena, CA, 1988, Appleton Davies.

Values are mean ± SD. t_½β, elimination half-life; CL, clearance; Vd_ss, volume of distribution at steady state; Cp_ss50, steady-state plasma concentration associated with 50% neuromuscular blockade.

Lebrault and others (1985) studied the pharmacokinetics and pharmacodynamics of vecuronium in patients with cirrhosis compared with normal subjects. The volume of distribution in patients with cirrhosis was normal, but the clearance was reduced by roughly 50%. The time interval between the administration of vecuronium and 50% recovery of twitch height was 130 minutes in patients with cirrhosis versus 62 minutes in normal subjects. The time to recovery from 25% to 75% of control twitch height was 68 minutes in patients with cirrhosis versus 21 minutes in normal subjects. Plasma concentration of vecuronium at 50% twitch recovery (CP₅₀) was similar in both groups. This similarity suggests that patients with cirrhosis have normal sensitivity to vecuronium. Despite the prolongedduration of action of vecuronium in cirrhotic patients, it was still shorter than that of pancuronium in patients free of liver disease.

Vecuronium is only slightly dependent on renal elimination (10% to 30%), and its elimination should be minimally affected by renal failure. Although some found no change in volume of distribution, clearance, elimination half-life, or recovery time with vecuronium in patients with renal failure, subsequent studies demonstrated that the duration of neuromuscular blockade was longer in patients with renal failure than in those with normal renal function ( Lynam et al., 1988 ). This increased duration of effect may be related to both a decreased plasma clearance and a prolonged elimination half-life of vecuronium in the renal failure group. Similarly, Bencini and others (1983) found a 50% decrease in clearance, an increase in volume of distribution, and a 50% increase in elimination half-life. The duration of action was not reported. Metabolites of vecuronium were not measured in these studies. Reich and others (2002) infused vecuronium in infants after congenital heart surgery. The clearance of vecuronium was low, significant amounts of 3-OH vecuronium were noted, and return of neuromuscular transmission was quite slow.

Rocuronium

Rocuronium (ORG-9426) is a nondepolarizing, steroidal neuromuscular blocking drug similar to vecuronium but with one-eighth to one-tenth the potency. It is similar in many ways to vecuronium, but the lesser potency of rocuronium produces a more rapid onset of paralysis in comparison with equipotent doses of other drugs (i.e., equal multiples of the ED₉₅) ( Kopman, 1989 ). Bolus administration of 0.6 mg/kg of rocuronium, twice the ED₉₅, is associated with a transient increase in heart rate of about 15 beats/min (O—Kelly et al., 1994). Bolus intravenous administration of 0.6 mg/kg of rocuronium produces complete neuromuscular blockade (at the adductor pollicis) in infants and children in 50 and 80 seconds, respectively ( Woelfel et al., 1992 ). Increasing the dose to 0.8 mg/kg in children shortens this time to an average of 30 seconds (O—Kelly et al., 1994). The time to recovery of neuromuscular function to T₂₅ after a dose of 0.6 mg/kg is almost twice as long in infants younger than 10 months compared with children aged 1 to 5 years (45.1 versus 26.7 minutes, respectively). This age-related difference is similar to that observed with vecuronium ( Meretoja, 1989 ). Its rapid onset of action with minimal tachycardia and intermediate duration of action makes it an attractive neuromuscular blocking drug for use in pediatric patients. The role of rocuronium in ICU patients is unclear. Hepatic uptake and biliary excretion are the dominant mechanisms for its clearance; hepatobiliary clearance is about 75% and renal clearance is about 9% ( Khuenl-Brady et al., 1990 ). The effects of rocuronium are prolonged in patients with renal disease ( Cooper et al., 1993 ). Little or no metabolism of rocuronium takes place (i.e., about 3%).

Long-Acting Agents

d-Tubocurarine

Although d-tubocurarine is no longer commercially available, studies of its dose-response relationships and kinetics were the prototypes for future studies with other nondepolarizing relaxants and have helped provide key concepts ( Goudsouzian et al., 1981 , 1984; Cook, 1981 ; Fisher et al., 1982 ). The volume of distribution for d-tubocurarine is quite high in the newborn infant compared with that in the older child or adult, but plasma clearance of d-tubocurarine does not differ with age. The volume of distribution for d-tubocurarine appears relatively constant on a liter-per-meter squared basis (estimated by author). Adults and children require about 7 to 8 mg/m² of d-tubocurarine, 6- to 9-month-old infants require about 5 to 6 mg/m², and neonates require only about 4 mg/m². These differences suggest that the neonate and, to a lesser degree, the infant are quite sensitive to d-tubocurarine if compensation is made for the wide variation in volumes of distribution. More important, the steady-state plasma concentration associated with 50% neuromuscular blockade (C_ss50) was age related; C_ss50 in neonates was about one third that noted for adults. The largest variability in elimination half-lives and volumes of distribution was seen in the data from neonates.

Pancuronium

Pancuronium, a steroidal bisquaternary muscle relaxant, has been used frequently for infants and children because of its rather predictable neuromuscular blocking action and associated cardiovascular stimulating properties. The dose-response relationships for pancuronium were determined in infants and children by Goudsouzian and others (1981) and by Blinn and others (1992). Older children require a higher dose on a weight basis (micrograms per kilogram) than do infants and small children ( Table 6-31 ).

TABLE 6-31 -- Cumulative dose-response relationship of pancuronium

Age	ED₅₀ (mg/kg; mg/m²)	ED₉₅ (mg/kg; mg/m²)
3 to 6 mo	24 ± 7; 448 ± 136	45 ± 7; 849 ± 151
7 to 12 mo	30 ± 5; 602 ± 90	52 ± 9; 1050 ± 175
1 to 3 yr	34 ± 9^[*]; 753 ± 198	62 ± 18^[*]; 1394 ± 401
4 to 6 yr	29 ± 8; 1022 ± 524^[*]	62 ± 13^[]; 2136 ± 855^[]

Data from Blinn A, Woefel SK, Cook DR, et al.: 1992.

^*	Statistically significant difference from the 3- to 6-month age group (analysis of variance).

Within 24 hours after administration of pancuronium, Duvaldestin and others (1982) recovered 67% of the drug in the urine in the form of the parent compound and its metabolites. In other studies, about 25% of the injected pancuronium appeared in the urine in the form of the 3-OH metabolite and less than 5% each appeared in the form of the 17-OH and 3,17-dehydroxy metabolites. Approximately 11% of the pancuronium was excreted in the bile as the parent compound and its metabolites.

Pancuronium has been studied extensively in patients with hepatic dysfunction or renal dysfunction ( Duvaldestin et al., 1982 ; Lavine and Hindein, 1983 ) (see Table 6-28 ). The studies demonstrate that different types of liver disease have different effects on the disposition of muscle relaxants. Studies show prolonged elimination half-life and delayed recovery from pancuronium in patients with cholestasis. Duvaldestin and others (1982) studied the pharmacokinetics of pancuronium in patients with cirrhosis and found a prolonged distribution half-life, an almost twofold increase in elimination half-life, and a 20% decrease in clearance. These effects are related primarily to an increase in ECF and in volume of distribution (see Table 6-28 ). On the basis of these observations, one would predict that, in cirrhotic patients, resistance and increased sensitivity to pancuronium exist at the same time. On one hand, the onset time of pancuronium would be prolonged because of an increase in the volume of distribution, suggesting resistance to the drug; on the other hand, recovery would be delayed because of the prolonged elimination half-life, suggesting increased sensitivity.

If pancuronium is given to a patient in renal failure, it may cause prolonged paralysis. The clearance of pancuronium is reduced by one half to two thirds, whereas the volume of distribution is only minimally affected (see Table 6-28 ). The metabolites accumulate in renal failure because they normally depend on renal excretion. The metabolites, especially 3-hydroxy pancuronium, have some neuromuscular blocking activity, and they further prolong paralysis. A twofold to fourfold increase in elimination half-life results.

Pipecuronium

Pipecuronium, an analog of pancuronium, is free of cardiovascular side effects. It is a long-acting neuromuscular blocking drug with duration of action similar to pancuronium. After administration of an ED₉₅ dose, complete recovery of neuromuscular function occurs in approximately 1 hour in children. The ED₉₅ of pipecuronium in children is 80 mcg/kg during nitrous oxide/fentanyl anesthesia ( Pittet et al., 1989 ) and 50 mcg/kg during nitrous oxide/halothane anesthesia ( Sarner et al., 1990 ). The ED₉₅ of pipecuronium in infants is only about 35 mcg/kg during nitrous oxide/halothane anesthesia, but spontaneous recovery is not prolonged in infants relative to older patients after a dose titrated to produce close to maximal effect (i.e., not overdose) ( Pittet et al., 1989 ). Prolonged recovery is to be expected when multiples of the ED₉₅ are administered.

Pipecuronium is largely excreted by the kidneys. In adults with renal failure, mean duration of neuromuscular blockade after one dose of 70 mcg/kg was similar to that in patients with normal renal function, but there was more variability in duration of action in the renal failure group ( Caldwell et al., 1989 ). Prolonged neuromuscular blockade in an adult with renal failure has been reported ( Caballero and Johnson, 1992 ). It is to be expected that a dose of pipecuronium administered to facilitate rapid endotracheal intubation in children with no renal function lasts at least several hours. Pipecuronium is not easily removed through peritoneal dialysis.

Doxacurium

Doxacurium has a duration of action similar to that of pancuronium. Unlike pancuronium, doxacurium has minimal cardiovascular side effects. In children, Sarner and others (1988) noted that the ED₅₀ and ED₉₅ of doxacurium in children during halothane/nitrous oxide/oxygen anesthesia are 14.8 mcg/kg and 27.3 mcg/kg, respectively. These values are comparable to the requirements seen in adults administered nitrous oxide/oxygen narcotic anesthesia. In addition, at equipotent doses of doxacurium, the investigators noted age-related differences with respect to the time of recovery of neuromuscular transmission to T₂₅ and time of onset to maximal blockade; the children anesthetized with halothane had a shorter onset time to maximal block and shorter recovery times compared with adults anesthetized with nitrous oxide/oxygen and narcotic. Doxacurium is eliminated largely unchanged in the urine ( Dresner et al., 1990 ). At equal doses of doxacurium, patients with hepatic failure achieve a lesser and more variable degree of neuromuscular blockade than do normal patients; the onset time and clinical duration tended to be longer in patients with hepatic failure ( Cook et al., 1991 ).

Selection of Nondepolarizing Relaxant

At appropriate doses, all nondepolarizing relaxants produce neuromuscular blockade; at equipotent doses, each relaxant produces the same degree of relaxation as any other. Potency is important not only to the drug concentration in the vial but perhaps also to the disparity between neuromuscular blocking effects and autonomic side effects. In addition, onset time is markedly reduced with relaxants with high ED₉₅ values, a mass effect. Potent inhaled anesthetic agents may decrease the onset time of neuromuscular blocking agents (i.e., mivacurium) and duration in a concentration-dependent manner ( Jalkanen and Meretoja, 1997 ). However, this has not been studied in a systematic fashion for a variety of relaxants. In selecting one relaxant over another, one should consider its onset time, duration of effect, side effects, and routes of elimination (renal, liver, or spontaneous). In addition, one should consider how the age or the pathologic condition of the patient may have an influence on the kinetics of the relaxant. The side effects of the nondepolarizing relaxants are primarily cardiovascular; these cardiovascular effects are related to the magnitude of histamine release, ganglionic blockade, and vagolysis. In addition, the cardiovascular effects appear to be age related. In infants and children, minimal cardiovascular effects are seen after administration of atracurium or vecuronium at several multiples of the ED₉₅ (Brandom et al., 1983 , 1984; Fisher and Miller, 1983 ; Goudsouzian et al., 1983 ). In adults, atracurium at 3×ED₉₅ causes slightly less histamine release than 2×ED₉₅ of metocurine and less than half as much histamine release as the ED₉₅ of d-tubocurarine ( Tullock et al., 1990 ). Vecuronium (at any multiple of ED₉₅) is not associated with histamine release ( Tullock et al., 1990 ). Infants and children appear to be less susceptible than adults to histamine release after administration of relaxants. In a small series of infants, 5×ED₉₅ of atracurium did not elicit flushing or alter heart rate or blood pressure (Brandom et al., 1984 ; Goudsouzian et al., 1985 ). However, local signs of histamine release after direct intravenous injection of atracurium in infants and children have been described; rarely, flushing with or without mild hypotension is seen at high multiples of the ED₉₅ ( Nightingale and Bush, 1983 ). At high doses, d-tubocurarine may cause hypotension and histamine release in children. The different pattern of tryptase release by the various types of relaxants suggests different mechanisms of mast cell activation ( Koppert et al., 2001 ). Bronchospasm may be related to histamine release or release of leukotrienes. Some relaxants may block prejunctional muscarinic receptors in the airway.

At 2×ED₉₅, increases in heart rate are seen with pancuronium and rocuronium in children; in contrast, both have minimal effect on heart rate in infants. Because the infant responds with bradycardia to a variety of stimuli (hypoxia, tracheal intubation), the “potential” vagolytic effects of pancuronium or rocuronium may be desired side effects.

Priming Principle

The priming principle, or the judicious use of a subparalyzing dose of a nondepolarizing muscle relaxant several minutes before an intubating dose is given, has been used in attempts to achieve a shorter onset time of neuromuscular blocking agents for endotracheal intubation. The priming principle is based on the concept that neuromuscular junction has a large margin of safety. When 75% to 80% of the receptors are blocked, seemingly normal neuromuscular transmission still occurs. Consequently, the pharmacodynamic effects of neuromuscular blocking agents are seen when the remaining 20% to 25% of unoccupied ACh receptors bind the drug. Because the initial dose is subtherapeutic and binds to less than 75% of the available receptors, no apparent pharmacologic or clinical effect is observed. When the second dose or intubating dose is administered, it interacts with the remainder of the unoccupied receptors. Because the second dose exerts its effect on the remaining 25% of the receptor pool, the pharmacologic effect (i.e., onset of a clinical neuromuscular block) occurs faster. Certain cautions need to be emphasized when using the priming principle: (1) the time interval between the initial dose and the second intubating dose needs to be of sufficient length such that the initial dose has time to occupy the receptors and (2) the dose-response curve for any given muscle relaxant has significant patient variability. For some patients, the initial dose may not be sufficient and the intubating dose does not have a rapid onset time. Conversely, for other patients, the initial dose may be too much and consequently those patients may be unable to protect their airways.

Synergism (supra-additivity) has been demonstrated between some neuromuscular blocking drugs of different molecular structures (Satwicz and Martyn, 1984; Naguib, 1994 ; Rautoma et al., 1995a , 1995b; Erkola et al., 1996 ; Naguib et al., 1997 , 1998). For example, in children the amount of an equipotent combination of atracurium and vecuronium that produces 95% block is only 60% of the amount of either atracurium or vecuronium administered alone that would produce the same effect ( Meretoja et al., 1993 ). When ED₅₀ (the dose expected to cause 50% neuromuscular block) of pancuronium was given simultaneously with one half of an ED₅₀ dose of mivacurium, 97% depression of neuromuscular function occurred ( Meretoja et al., 1993 ). When children receive a long-acting muscle relaxant (pancuronium) followed by a short-acting muscle relaxant (mivacurium) ( Brandom et al., 1993 ), the duration of neuromuscular blockade is prolonged beyond what would be expected with mivacurium alone ( Fig 6-37 ).



FIGURE 6-37 Onset of paralysis induced either by 200 mcg/kg of mivacurium preceded by saline solution (M₂₀₀) or 15 mcg/kg of pancuronium (P₁₅M₂₀₀), or by 170 mcg/kg of mivacurium preceded by 15 mcg/kg of pancuronium (P₁₅M₁₇₀). A small dose of pancuronium did shorten the onset significantly. (With permission from Brandom BW, Meretoja OA, Taivaninen T, et al: Anesth Analg 76:998, 1993.)

Modes of Evaluation of Neuromuscular Transmission

Restoration of complete skeletal muscle strength is essential to ensure that patients are able to sustain adequate ventilation, to cough, and to maintain a patent airway after chronic administration of relaxants. Peripheral nerve stimulation (usually the ulnar nerve) adequately measures recovery from nondepolarizing neuromuscular blockade. Peripheral nerve stimulation (e.g., TOF, double burst or tetanic stimulation) is often used in preference to tests of ventilation. Nerve stimulators used for neuromuscular monitoring in the ICU may need to deliver at least 100 mA to generate supramaximal stimulation (Harper et al., 2001 ). TOF stimulation has been established as the pattern of stimulation for clinical monitoring of neuromuscular blockade. This stimulation mode allows for convenient and reliable tactile evaluation of moderate degrees of nondepolarizing blockade without undue discomfort accompanying tetanic bursts (i.e., 50 to 100 Hz for 5 seconds). However, several studies suggest that these rigorous criteria for adequacy of neuromuscular transmission are indeed needed. The rationale for this approach is the following: first, the diaphragm recovers from the effects of nondepolarizing neuromuscular blocking drugs more rapidly than does the adductor pollicis; and second, at a TOF ratio of 0.9, vital capacity returns to normal (>15 to 20 mL/kg), pharyngeal muscle strengthens with recovery of swallowing, diplopia disappears, and maximum inspiratory and expiratory force are only slightly depressed (-50 cm H₂O). Intense neuromuscular blockade of the peripheral muscles is indicated by disappearance of the response to TOF and single-twitch stimulation ( Pavlin et al., 1989 ). It is possible, however, to quantify part of this period of no response by applying tetanic stimulation (50 Hz for 5 seconds), followed by 1-Hz stimulation and observing the posttetanic single-twitch response (posttetanic count). The posttetanic count is highly correlated with recovery from intense blockade caused by relaxants and with antagonism less than or equal to the neuromuscular blockade.

During recovery of neuromuscular transmission, it is difficult, however, to estimate the TOF ratio with sufficient certainty to exclude residual paralysis ( Viby-Mogensen et al., 1985 ). In this situation it may be more reliable to ascertain the ability to sustain tetanus (50 Hz) for 5 seconds or to evaluate double burst stimulation (DBS). DBS is a new pattern of stimulation that was developed to reveal residual neuromuscular blockade ( Drenck et al., 1989 ). DBS consists of two short tetanic bursts separated by 750 milliseconds. A DBS with three impulses (200-microsecond square-wave impulses) in each of two tetanic bursts of 50 Hz (DBS 3.3) is most suitable for clinical work. Fade in the response results from residual neuromuscular blockade as is seen with TOF stimulation. However, DBS is more sensitive than TOF in the manual detection of residual neuromuscular blockade. Absence of fade in response to DBS 3.3 normally excludes severe residual neuromuscular blockade but does not necessarily indicate adequate clinical recovery. Sustained tetanus (50 Hz) correlates with a TOF ratio of at least 0.85 ( Kopman et al., 2001 ; Dahaba et al., 2002 ).

Myoneuropathies (Critical Illness Polyneuropathy)

Unexpectedly prolonged duration of paralysis after the administration of muscle relaxants to ICU patients has seemingly reached epidemic proportions ( Segredo et al., 1992 ; Tobias et al., 1995 ). Individual patients with so-called ICU neuromuscular syndrome have had a variety of relaxants administered for variable times, have had a variety of underlying critical diseases and coexisting conditions, and have had a spectrum of muscle weakness. Unfortunately, there is considerable overlap by this syndrome, disuse atrophy, polyneuropathy of critical illness, and steroid myopathy. Multiorgan dysfunction, corticosteroid administration, prolonged immobilization, and female sex have been suggested as key risk factors. Some cases appear to represent a pharmacologic overdose (i.e., pharmacokinetic category), but other cases seemingly represent specific pathology of the neuromuscular structures ( Lee, 1995 ; Watling and Dasta, 1994 ; De Jonghe et al., 2002). The pathology includes marked atrophy of type I and type II muscle fibers, destruction of muscle, relatively little inflammation, and relatively intact motor and sensory nerves ( Lee, 1995 ). This syndrome may be related in part to synergistic dysfunctional upregulation of ACh receptors from both a critical illness and the administration of muscle relaxants ( Lee, 1995 ). It has been suggested that reducing the amount of relaxants used (i.e., dose over time) by monitoring neuromuscular transmission may decrease the risk of prolonged paralysis ( Fine et al., 2001 ). Lee suggests that periodic interruption of relaxant administration, pharmacodynamic studies, and neurologic and electrophysiologic studies may be useful in the early detection of this complication. Prolonged neuromuscular blockade in infants and small children may interfere with normal growth and development of muscle and result in moderate to severe residual weakness for months. Immobilization-induced atrophy may not be reversible in developing muscle. Recovery of muscle function thus may be more likely in older infants and children, in whom neuromuscular development has already progressed to a fair degree, than in newborns and especially premature newborns immobilized shortly after birth ( Shear, 1981 ).

Reversal of Neuromuscular Blockade

Because of the increased potential for respiratory inadequacy from residual neuromuscular blockade in infants, most anesthesiologists routinely antagonize nondepolarizing relaxants. The rule has been always to reverse neuromuscular blockade. Large doses of neostigmine (70 mcg/kg) are usually used. In infants, as in adults, neurotransmission returns promptly if few receptors are blocked at the time of reversal. Proper choice of relaxant and careful timing and titration of the dose of relaxant usually ensure that some motor tone is present by the time antagonism is attempted. Certain antibiotics, hypotension, hypothermia, acidosis, or hypocalcemia can prolong or potentiate neuromuscular blockade from nondepolarizing relaxants. Hypothermia, deep sedation, or narcosis per se can also lead to respiratory depression in infants.

The use of intermediate-acting relaxants forces one to reexamine the dictum to “always reverse blockade.” Clearly, the margin of safety of relaxants is increased by using objective criteria to judge the adequacy of neuromuscular transmission. As stated in the preceding section, these criteria include a TOF ratio greater than 0.9, the ability to sustain tetanus at 50 Hz, a vital capacity of 15 to 20 mL/kg, the ability to flex the arms and legs, and an inspiratory force greater than 50 cm H₂O. If the infant or child can meet several of these criteria without reversal, no reversal is needed. When there is doubt, however, a drug should be given to antagonize blockade.

Fisher and others (1983, 1984) examined the dose of neostigmine and edrophonium required in infants, children, and adults to reverse a 90% blockade from a continuous d-tubocurarine infusion. In infants and children, 15 mcg/kg of neostigmine produced a 50% antagonism of the d-tubocurarine blockade; in adults, 23 mcg/kg was required. It was claimed that the duration of antagonism was equal in all three groups, although the elimination half-life was clearly shorter in infants. A larger dose than that seemingly recommended would give a higher sustained blood concentration; whether this is of pharmacologic benefit in the absence of a continuous infusion or relaxant is doubtful. The dissociation between the elimination half-life and the duration of antagonism may result from the carbamylation of cholinesterase by neostigmine. In infants, 145 mcg/kg of edrophonium produced a 50% antagonism of the d-tubocurarine blockade; in children, 233 mcg/kg was required; and in adults, 128 mcg/kg was required. The volume of distribution of edrophonium was similar in all age groups. The elimination half-life of edrophonium was shorter in infants than in children or adults; hence, clearance was more rapid in infants. Because the molecular interaction between edrophonium and cholinesterase is readily reversible, Fisher and others (1983, 1984) suggest that the shorter elimination half-life for edrophonium might limit its value in pediatric patients. This is doubtful.

Meakin and others (1983) compared the rate of recovery from pancuronium-induced neuromuscular blockade after various doses of neostigmine (0.036 or 0.07 mg/kg) or edrophonium (0.7 or 1.43 mg/kg) in infants and children. In the first 5 minutes, recovery of neuromuscular transmission was more rapid after edrophonium than after neostigmine in all age groups; recovery was more rapid in infants and children than in adults. By 10 minutes, there was no difference in neuromuscular transmission achieved in infants and children with either reversal agent (at either dose); adults had lower neuromuscular transmission at the lower dose (0.036 mg/kg) of neostigmine. If speed of initial recovery is a critical issue, edrophonium is better than neostigmine, and a high dose of neostigmine is better than a low dose. At 30 minutes after injection of either reversal agent (at any dose), there was no difference between neuromuscular transmission among age groups.

Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

▪ SUMMARY

To provide appropriate anesthesia care for pediatric surgical patients, the anesthesiologist should have not only an appreciation of the pathophysiology of the child's disease but also a firm understanding of how developmental changes affect the pharmacology of anesthetic agents. As the child's cardiac output becomes less rate dependent, hemodynamic stability occurs with inhalational anesthetics. For the infant, anesthetics that decrease heart rate and myocardial contractility can have a profound cardiovascular effect. Because infants—baroreceptors are less mature, compensatory mechanisms for the inhalational anesthetics cannot compensate. In addition to inhalational anesthetics, intravenous agents are also offered by pharmacokinetic parameters; that is, volume distribution, clearance, and elimination half-life also develop. Consequently, drug dosages need to be individualized. The anesthetic management of the infant and child requires a careful approach; knowledge of pharmacologic and physiologic development is essential for optimum patient management.

Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

REFERENCES

Abel and Reis, 1971. Abel RM, Reis RL: Intravenous diazepam for sedation following cardiac operations: Clinical and hemodynamic assessments. Anesth Analg (Cleve) 1971; 50:244.

Agnor et al., 1998. Agnor RC, Sikich N, Lerman J: Single breath vial capacity rapid inhalation induction in children: 8% Sevoflurane versus 5% halothane. Anesthesiology 1998; 89:379.

Albanese et al., 1993. Albanese J, Durbec O, Viviand X: Sufentanil increases intracranial pressure in patients with head trauma. Anesthesiology 1993; 79:493.

Alcorn and McNamara, 2002. Alcorn J, McNamara PJ: Ontogeny of hepatic and renal systemic clearance pathways in infants. Part I. Clin Pharmacokinet 2002; 41:959-998.

Alexander and Gross, 1988. Alexander CM, Gross JB: Sedative doses of midazolam depress hypoxic ventilatory responses in humans. Anesth Analg 1988; 67:377.

Alexander et al., 1992. Alexander CM, Teller LE, Gross JB: Slow injection does not prevent midazolam-induced ventilatory depression. Anesth Analg 1992; 74:260.

Anderson et al., 1997. Anderson BJ, McKee AD, Holford NH: Size, myths and the clinical pharmacokinetics of analgesia in paediatric patients. Clin Pharmacokinet 1997; 33:313-327.

Ang et al., 1998. Ang C, Habre W, Sims C: Tropisetron reduces vomiting after tonsillectomy in children. Br J Anaesth 1998; 80:761-763.

Aono et al., 1997. Aono J, Ueda W, Mamiya K, et al: Greater incidence of delirium during recovery from sevoflurane anesthesia in preschool boys. Anesthesiology 1997; 87:1298.

Ard et al., 2003. Ard J, Doyle W, Bekker A: Awake craniotomy with dexmedetomidine in pediatric patients. J Neurosurg Anesthesiol 2003; 15:263.

Arnold et al., 1991. Arnold JH, Truog RD, Scavone JM: Changes in the pharmacodynamic response to fentanyl in neonates during continuous infusion. J Pediatr 1991; 119:639.

Attia et al., 1986. Attia J, Ecoffey C, Sandouk P: Epidural morphine in children: Pharmacokinetics and CO2 sensitivity. Anesthesiology 1986; 65:590.

Audenaert et al., 1995. Audenaert SM, Montgomery CL, Thompson DE, et al: A prospective study of rectal methohexital: Efficacy and side effects in 648 cases. Anesth Analg 1995; 81:957-961.

Ausems et al., 1986. Ausems ME, Hug Jr C, Stanski DR, et al: Plasma concentrations of alfentanil required to supplement nitrous oxide anesthesia for general surgery. Anesthesiology 1986; 65:362.

Babel, 1989. Babel A: Etude comparative de la laudanosine et de la papaverine au point de vue pharmacodynamique. Rev Med Suisse Romande 1989; 19:657.

Bailey et al., 1990. Bailey PL, Stresand JB, East KA: Differences in magnitude and duration of opioid-induced respiratory depression and analgesia with fentanyl and sufentanil. Anesth Analg 1990; 77:708.

Balistreri, 1983. Balistreri WF: Immaturity of hepatic excretory function and the ontogeny of bile acid metabolism. J Pediatr Gastroenterol Nutr 1983; 2(Suppl 1):S207-S214.

Barash et al., 1978. Barash PG, Glanzz S, Katz JD, et al: Ventricular function in children during halothane anesthesia: An echocardiographic evaluation. Anesthesiology 1978; 49:79.

Baum and Plamisano, 1997. Baum VC, Plamisano BW: The immature heart and anesthesia. Anesthesiology 1997; 87:1529.

Baum and Wetzel, 1994. Baum VC, Wetzel GT: Sodium-calcium exchange in neonatal myocardium: Reversible inhibition by halothane. Anesth Analg 1994; 78:1105.

Baxter et al., 1998. Baxter PJ, Garten K, Kharasch ED: Mechanistic aspects of carbon monoxide formation from volatile anesthetics. Anesthesiology 1998; 89:929-941.

Beaufort et al., 1998. Beaufort TM, Nigrovic V, Proost JH, et al: Inhibition of the enzymic degradation of suxamethonium and mivacurium increases the onset time of submaximal neuromuscular block. Anesthesiology 1998; 89:707-714.

Bedford, 1995. Bedford RF: The FDA protects the public by regulating the manufacture of anesthetic agents and the production devices used in anesthetic practice. Anesthesiology 1995; 82:33A.

Beh et al., 2002. Beh T, Splinter W, Kim J: In children, nitrous oxide decreases pain on injection of propofol mixed with lidocaine. Can J Anesth 2002; 49:1061-1063.

Bellward et al., 1977. Bellward GD, Warren PM, Howald W, et al: Methadone maintenance: Effect of urinary pH on renal clearance in chronic high and low doses. Clin Pharmacol Ther 1977; 22:92.

Bencini, 1983. Bencini A, et al: Clinical pharmacokinetics of vecuronium. In: Agoston S, et al ed. Clinical experiences with Norcuron (Org NC 45 vecuronium bromide), Amsterdam: Excerpta Medica; 1983.

Benedetti and Baltes, 2003. Benedetti SM, Baltes EL: Drug metabolism and disposition in children. Fundam Clin Pharmacol 2003; 17:281-299.

Berde et al., 1991. Berde CB, Beyer JE, Bournaki M-C, et al: Comparison of morphine and methadone for prevention of postoperative pain in 3- to 7-year-old children. J Pediatr 1991; 119:136-141.

Berg et al., 1960. Berg JM, Brandon MWG, Kirwan BH: Atropine in mongolism. Cancer 1960; 2:441.

Bergman et al., 1991. Bergman I, Steeves M, Burckart G: Reversible neurologic abnormalities associated with prolonged intravenous midazolam and fentanyl administration. J Pediatr 1991; 119:644.

Beskow et al., 1995. Beskow A, Werner O, Westrin P: Faster recovery after anesthesia in infants after intravenous induction with methohexital instead of thiopental. Anesthesiology 1995; 83:976-979.

Besunder et al., 1988. Besunder JB, Reef MD, Blumer JL: Principles of drug biodisposition in the neonate. A critical evaluation of the pharmacokinetic-pharmacodynamic interface. Clin Pharmacokinet 1988; 14:189-216.

Bhat et al., 1990. Bhat R, Chari G, Golati A: Pharmacokinetics of a single dose of morphine in preterm infants during the first week of life. J Pediatr 1990; 117:477.

Black, 1996. Black A: A comparison of the induction characteristics of sevoflurane and halothane in children. Anaesthesia 1996; 51:539.

Blinn et al., 1992. Blinn A, Woelfel SK, Cook DR, et al: Pancuronium dose-response revisited. Paediatr Anesth 1992; 2:153.

Blount and Merlie, 1989. Blount P, Merlie JP: Molecular basis of the two nonequivalent ligand binding sites of the muscle nicotinic acetylcholine receptor. Neuron 1989; 3:349.

Bokesch et al., 1985. Bokesch PM, Ziemer G, Castaneda AR, et al: Arterial lidocaine concentrations in intracardiac right-to-left shunts. Anesthesiology 1985; 63:468.

Boreus et al., 1975. Boreus LO, Jalling B, Kallberg N: Clinical pharmacology of phenobarbital in the neonatal period. In: Morselli PL, Garatini S, Sereni F, ed. Basic and therapeutic aspects of perinatal pharmacology, New York: Raven Press; 1975:331.

Borgeat et al., 1990. Borgeat A, Popovic V, Meier D: Comparison of propofol and thiopental/halothane for short-duration ENT surgical procedures in children. Anesth Analg 1990; 71:511.

Borgeat et al., 1993. Borgeat A, Wilder-Smith OHG, Despland PA: Spontaneous excitatory movements during recovery from propofol anaesthesia in an infant: EEG evaluation. Br J Anaesth 1993; 70:459.

Borgeat et al., 1992. Borgeat A, Wilder-Smith OHG, Saiah M, et al: Subhypnotic doses of propofol possess direct antiemetic properties. Anesth Analg 1992; 74:539.

Bosenberg et al., 2001. Bosenberg AT, Thomas J, Lopez T, et al: Plasma concentrations of ropivacaine following a single-shot caudal block of 1, 2 or 3 mg/kg in children. Acta Anaesthesiol Scand 2001; 45:1276-1280.

Bovill et al., 1983. Bovill J, Sebel P, Fiolet J, et al: The influence of sufentanil on endocrine and metabolic responses to cardiac surgery. Anesth Analg 1983; 62:391.

Bowdle et al., 1980. Bowdle TA, Patel IH, Levy RH, et al: Valproic acid dosage and plasma protein binding and clearance. Clin Pharmacol Ther 1980; 28:486-492.

Bowman, 1980. Bowman WC: Prejunctional and postjunctional cholinoreceptors at the neuromuscular junction. Anesth Analg 1980; 59:935.

Brandom et al., 1985. Brandom BW, Cook DR, Woelfel SK, et al: Atracurium infusion in children during fentanyl, halothane, and isoflurane anesthesia. Anesth Analg 1985; 64:471.

Brandom et al., 1993. Brandom BW, Meretoja OA, Taivainen T, et al: Accelerated onset and delayed recovery of neuromuscular block induced by mivacurium preceded by pancuronium in children. Anesth Analg 1993; 76:998.

Brandom et al., 1983. Brandom BW, Rudd GD, Cook DR: Clinical pharmacology of atracurium in pediatric patients. Br J Anaesth 1983; 55:117S.

Brandom et al., 1990. Brandom BW, Sarner JB, Woelfel SK, et al: Mivacurium infusion requirements in pediatric surgical patients during nitrous oxide-halothane and during nitrous oxide-narcotic anesthesia. Anesth Analg 1990; 71:16.

Brandom et al., 1984. Brandom BW, Woelfel SK, Cook DR, et al: Clinical pharmacology of atracurium in infants. Anesth Analg 1984; 63:309.

Briggs et al., 1982. Briggs LP, Clarke RSJ, Watkins J: An adverse reaction to the administration of disoprofol (Diprivan). Anaesthesia 1982; 37:1099.

Brodie, 1952. Brodie BB: Physiological disposition and chemical fate of thiobarbiturates in the body. Fed Proc 1952; 11:632.

Brodsky et al., 1984. Brodsky JB, Baden JM, Serra M, et al: Nitrous oxide inactivates methionine synthetase activity in rat testis. Anesthesiology 1984; 61:66-68.

Brosius and Bannister, 2001. Brosius KK, Bannister CF: Effect of oral midazolam premedication on the awakening concentration of sevoflurane, recovery times and bispectral index in children. Paediatr Anaesth 2001; 11:585-590.

Brosius and Bannister, 2003. Brosius KK, Bannister CF: Midazolam premedication in children: A comparison of two oral dosage formulations on sedation score and plasma midazolam levels. Anesth Analg 2003; 96:392-395.

Brosius and Bannister, 2002. Brosius KK, Bannister CF: Oral midazolam premedication in preadolescents and adolescents. Anesth Analg 2002; 94:31-36.

Brown et al., 1958. Brown AK, Zwelzin WW, Burnett HH: Studies on the neonatal development of the glucuronide conjugating system. J Clin Invest 1958; 37:332.

Bryson et al., 1991. Bryson JC, Pritchard JF, Shurin S, et al: Efficacy, pharmacokinetics (PK), and safety of ondansetron (OND) in pediatric chemotherapy patients [abstract]. Clin Pharmacol Ther 1991; 49:161.

Burtin et al., 1994. Burtin P, Jacqz-Aigrain E, Girard P, et al: Population pharmacokinetics of midazolam in neonates. Clin Pharmacol Ther 1994; 56:615.

Caballero and Johnson, 1992. Caballero PA, Johnson RE: Long-lasting neuromuscular blockade from pipecuronium. Anesthesiology 1992; 76:154.

Calakos and Scheller, 1996. Calakos N, Scheller RH: Synaptic vesicle biogenesis, docking, and fusion: A molecular description. Physiol Rev 1996; 76:1-29.

Caldwell et al., 1989. Caldwell JE, Canfell PC, Castagnoli KP, et al: The influence of renal failure on the pharmacokinetics and duration of action of pipecuronium bromide in patients anesthetized with halothane and nitrous oxide. Anesthesiology 1989; 70:7.

Cameron et al., 1984. Cameron CB, Robinson S, Gregory GA: The minimum anesthetic concentrations of isoflurane in children. Anesth Analg 1984; 63:418.

Camu et al., 1982. Camu F, Gepts E, Rucquoi M, et al: Pharmacokinetics of alfentanil (R39709) in man. Anesth Analg 1982; 61:657.

Cappiello et al., 1991. Cappiello M, Giuliani L, Rane A, et al: Dopamine sulphotransferase is better developed than p-nitrophenol sulphotransferase in the human fetus. Dev Pharmacol Ther 1991; 16:83-88.

Carmichael, 1947. Carmichael EB: The median lethal dose (LD50) of pentothal sodium for both young and old guinea pigs and rats. Anesthesiology 1947; 8:589.

Carrigan and Straughen, 1987. Carrigan TW, Straughen WJ: A report of hepatic necrosis and death following isoflurane anesthesia. Anesthesiology 1987; 67:581.

Carter and Gold, 1977. Carter S, Gold AP: Status epilepticus. In: Smith CA, ed. The critically ill child, 2nd ed.. Philadelphia: WB Saunders; 1977.

Cazeneuve et al., 1994. Cazeneuve C, Pons G, Rey E, et al: Biotransformation of caffeine in human liver microsomes from foetuses, neonates, infants and adults. Br J Clin Pharmacol 1994; 37:405-412.

Chalkiadis et al., 2004. Chalkiadis GA, Eyers RI, Cranswick N, et al: Pharmacokinetics of levobupivacaine 0.25% following caudal administration in children under 2 years of age. Br J Anaesth 2004; 92:218-222.

Chauvin et al., 1987a. Chauvin M, Lebrault C, Levron JC, et al: Pharmacokinetics of alfentanil in chronic renal failure. Anesth Analg 1987; 66:53.

Chauvin et al., 1987b. Chauvin M, Sandouk P, Schermann JM, et al: Morphine pharmacokinetics in renal failure. Anesthesiology 1987; 66:327.

Chay et al., 1992. Chay PCW, Duffy BJ, Walker JS: Pharmacokinetic-pharmacodynamic relationships of morphine in neonates. Clin Pharmacol Ther 1992; 51:334.

Chiaretti and Pietrini, 2000. Chiaretti A, Pietrini D, et al: Safety and efficacy of remifentanil in craniosynostosis repair in children less than 1 year old. Pediatr Neurosurg 2000; 33:83-88.

Chiodini et al., 2001. Chiodini F, Charpantier E, Muller D, et al: Blockade and activation of the human neuronal nicotinic acetylcholine receptors by atracurium and laudanosine. Anesthesiology 2001; 94:643-651.

Choonara et al., 1989. Choonara IA, McKay P, Hain R, et al: Morphine metabolism in children. Br J Clin Pharmacol 1989; 28:599-604.

Clarke et al., 1968. Clarke RS, Dundee JW, Barron DW, et al: Clinical studies of induction agents. XXVI. The relative potencies of thiopentone, methohexitone and propanidid. Br J Anaesth 1968; 40:593.

Cockshott et al., 1987. Cockshott ID, Briggs IP, Douglas EJ, et al: Studies using single bolus injection. Br J Anaesth 1987; 59:1103.

Cohen et al., 1990. Cohen MM, Cameron CB, Duncan PG: Pediatric anesthesia morbidity and mortality in the perioperative period. Anesth Analg 1990; 70:160.

Cohen et al., 2001. Cohen IT, Hannallah RS, Goodale DB: The clinical and biochemical effects of propofol infusion with and without EDTA for maintenance anesthesia in healthy children undergoing ambulatory surgery. Anesth Analg 2001; 93:106-111.

Collins et al., 1985. Collins G, Koren G, Crean P, et al: Fentanyl pharmacokinetics and hemodynamic effects in preterm infants ligation of patent ductus arteriosus. Anesth Analg 1985; 64:1078.

Constant et al., 1999. Constant I, Dubois MC, Piat V, et al: Changes in electroencephalogram and autonomic cardiovascular activity during induction of anesthesia with sevoflurane compared with halothane in children. Anesthesiology 1999; 91:1604.

Cook, 2000. Cook DR: Can succinylcholine be abandoned?. Anesth Analg 2000; 90:S24-S28.

Cook, 1981. Cook DR: Sensitivity of the newborn to tubocurarine. Br J Anaesth 1981; 53:320.

Cook et al., 1992a. Cook DR, Chakravorti S, Brandom BW, et al: Effects of neostigmine, edrophonium and succinylcholine on the in vitro metabolism of mivacurium: Clinical correlates. Anesthesiology 1992; 77:A948.

Cook and Fischer, 1975. Cook DR, Fischer CG: Neuromuscular blocking effects of succinylcholine in infants and children. Anesthesiology 1975; 42:662-665.

Cook et al., 1992b. Cook DR, Freeman JA, Lai AA, et al: Pharmacokinetics of mivacurium in normal patients and in those with hepatic or renal failure. Br J Anaesth 1992; 69:580.

Cook et al., 1991. Cook DR, Freeman JA, Lai AA, et al: Pharmacokinetics and pharmacodynamics of doxacurium in normal patients and in those with hepatic or renal failure. Anesth Analg 1991; 72:145.

Cook et al., 1981. Cook DR, Westman HR, Rosenfeld L, et al: Pulmonary edema in infants: Possible association with intramuscular succinylcholine. Anesth Analg 1981; 60:220.

Cooper et al., 1993. Cooper RA, Maddineni VR, Mirakhur RK, et al: Time course of neuromuscular effects and pharmacokinetics of rocuronium bromide (ORG 9426) during isoflurane anesthesia in patients with and without renal failure. Br J Anaesth 1993; 71:222.

Coté et al., 2002. Coté CJ, Cohen IT, Suresh S, et al: A comparison of three doses of a commercially prepared oral midazolam syrup in children. Anesth Analg 2002; 94:37-43.

Coventry et al., 1991. Coventry DM, Martin CS, Burke AM: Sedation for paediatric computerized tomography—a double-blind assessment of rectal midazolam. Eur J Anaesth 1991; 8:29.

Cox, 2002. Cox RG: Are children just little adults when it comes to propofol injection pain?. Can J Anesth 2002; 49:1016-1020.

Cravero et al., 2000. Cravero J, Surgenor S, Whalen K: Emergence agitation in paediatric patients after sevoflurane anaesthesia and no surgery: A comparison with halothane. Paediatr Anaesth 2000; 10:419-424.

Crumrine and Yodlowski, 1981. Crumrine RS, Yodlowski EH: Assessment of neuromuscular function in infants. Anesthesiology 1981; 54:29.

Culy et al., 2001. Culy CR, Bhana N, Plosker GL: Ondansetron. A review of its use as an antiemetic in children. Paediatr Drugs 2001; 3:441-479.

DaConceicao and Coelho, 1998. DaConceicao MJ, Coelho L: Caudal anaesthesia with 0.375% ropivacaine or 0.375% bupivacaine in paediatric patients. Br J Anaesth 1998; 80:507.

Dagan et al., 1993. Dagan O, Klein J, Bohn D, et al: Morphine pharmacokinetics in children following cardiac surgery: Effects of disease and inotropic support. J Cardiothorac Vasc Anesth 1993; 7:396-398.

Dahaba et al., 2002. Dahaba AA, von Klobucar F, Rehak PH, et al: The neuromuscular transmission module versus the relaxometer mechanomyograph for neuromuscular block monitoring. Anesth Analg 2002; 94:591-596.

Dalens et al., 2001. Dalens B, Ecoffey C, Joly A, et al: Pharmacokinetics and analgestic effect of ropivacaine following illioinguinal/iliohypogastric nerve block in children. Pediatr Anaesth 2001; 11:415.

Dauchot and Gravenstein, 1971. Dauchot P, Gravenstein JS: Effects of atropine on the electrocardiogram in different age groups. Clin Pharmacol Ther 1971; 12:274.

Davis et al., 1994. Davis PJ, Cohen RT, McGowan Jr FX, et al: Recovery characteristics of desflurane versus halothane for maintenance of anesthesia in pediatric ambulatory patients. Anesthesiology 1994; 80:298.

Davis et al., 1987. Davis PJ, Cook DR, Stiller RL, et al: Pharmacodynamics and pharmacokinetics of high-dose sufentanil in infants and children undergoing cardiac surgery. Anesth Analg 1987; 66:203.

Davis et al., 2000. Davis PJ, Finkel JC, Orr RJ, et al: A randomized, double-blinded study of remifentanil versus fentanyl for tonsillectomy and adenoidectomy surgery in pediatric ambulatory surgical patients. Anesth Analg 2000; 90:863-871.

Davis et al., 2001. Davis PJ, Galinkin J, McGowan FX, et al: A randomized multicenter study of remifentanil compared with halothane in neonates and infants undergoing pyloromyotomy. I. Emergence and recovery profiles. Anesth Analg 2001; 93:1380-1386.

Davis et al., 1997. Davis PJ, Lerman J, Suresh S, et al: A randomized multicenter study of remifentanil compared with alfentanil, isoflurane, or propofol in anesthetized pediatric patients undergoing elective strabismus surgery. Anesth Analg 1997; 84:982-989.

Davis et al., 1989a. Davis PJ, Killian A, Stiller RL, et al: Pharmacokinetics of alfentanil in newly born premature infants and older children. Dev Pharmacol Ther 1989; 13:21.

Davis et al., 1989b. Davis PJ, Stiller RL, Cook DR, et al: Effects of cholestatic hepatic disease and chronic renal failure on alfentanil pharmacokinetics in children. Anesth Analg 1989; 68:568.

Davis et al., 1988. Davis PJ, Stiller RL, Cook DR, et al: Pharmacokinetics of sufentanil in adolescent patients with chronic renal failure. Anesth Analg 1988; 67:268.

Davis et al., 1993. Davis PJ, Stiller RL, McGowan Jr FX: Decreased protein binding of alfentanil in plasma from children with kidney or liver failure. Paediatr Anaesth 1993; 3:19.

Davis et al., 1995. Davis PJ, Stiller RL, McGowan Jr FX, et al: Preanesthetic medication with intranasal midazolam for brief surgical procedures: Effect on recovery and hospital discharge times. Anesthesiology 1995; 82:2.

Davis et al., 1999. Davis PJ, Wilson AS, Siewers RD, et al: The effects of cardiopulmonary bypass on remifentanil kinetics in children undergoing atrial septal defect repair. Anesth Analg 1999; 89:904-908.

Dawson et al., 1971. Dawson B, Michenfelder JD, Theye RA: Effects of ketamine on canine cerebral blood flow and metabolism: Modification by prior administration of thiopental. Anesth Analg (Cleve) 1971; 50:443.

De Ruiter and Crawford, 2001. De Ruiter J, Crawford MW: Does-response relationship and infusion requirement of cisatracurium besylate in infants and children during nitrous oxide-narcotic anesthesia. Anesthesiology 2001; 94:790-792.

de Wildt et al., 2002. de Wildt SN, Kearns GL, Hop WCJ, et al: Pharmacokinetics and metabolism of oral midazolam in preterm infants. Br J Clin Pharmacol 2002; 53:390-392.

de Wildt et al., 2001. de Wildt SN, Kearns GL, Hop WCJ, et al: Pharmacokinetics and metabolism of intravenous midazolam in preterm infants. Clin Pharmacol Ther 2001; 70:525-531.

de Wildt et al., 1999. de Wildt SN, Kearns GL, Leeder JS, et al: Cytochrome P4503A: Ontogeny and drug disposition. Clin Pharmacokinet 1999; 37:486-505.

DeCook and Goudsouzian, 1980. DeCook TH, Goudsouzian NG: Tachyphylaxis and phase II block development during infusion of succinylcholine in children. Anesth Analg 1980; 59:639.

Deer and Rich, 1992. Deer TR, Rich GF: Propofol tolerance in a pediatric patient. Anesthesiology 1992; 77:828.

DeJonghe et al., 2002. DeJonghe B, Sharshar T, Lefaucheur JP, et al: Paresis acquired in the intensive care unit. JAMA 2002; 288:2859-2867.

deLange et al., 1982. deLange S, Boscoe M, Stanley T, et al: Comparison of sufentanil-oxygen and fentanyl-oxygen for coronary artery surgery. Anesthesiology 1982; 56:112.

Delphin et al., 1987. Delphin E, Jackson D, Rothstein P: Use of succinylcholine during elective pediatric anesthesia should be reevaluated. Anesth Analg 1987; 66:1190.

DeNegri et al., 2004. DeNegri P, Ivani G, Tirri T, et al: A comparison of epidural bupivacaine, levobupivacaine, and ropivacaine on postoperative analgesia and motor blockade. Anesth Analg 2004; 99:45-48.

Desparmet et al., 1987. Desparmet J, Meistelman C, Barre J, et al: Continuous epidural infusion of bupivacaine for postoperative pain relief in children. Anesthesiology 1987; 67:108.

DeWolf et al., 1996. DeWolf AM, Freeman JA, Scott VL, et al: Pharmacokinetics and pharmacodynamics of cisatracurium in patients with end-stage liver disease undergoing liver transplantation. Br J Anesth 1996; 76:624.

d'Hollander et al., 1982. d'Hollander A, Massaux F, Nevelsteen M, et al: Age-dependent dose-response relationship of ORG NC45 in anesthetized patients. Br J Anaesth 1982; 54:653.

d'Hollander et al., 1983. d'Hollander AA, Luyckx C, Barvais L, et al: Clinical evaluation of atracurium besylate requirement for a stable muscle relaxation during surgery: Lack of age-related effects. Anesthesiology 1983; 59:237.

Dhonneur et al., 2001. Dhonneur G, Cerf C, Lagneau F, et al: The pharmacokinetics of cisatracurium in patients with acute respiratory distress syndrome. Anesth Analg 2001; 93:400-404.

Dierdorf et al., 1984. Dierdorf SF, McNiece WL, Wolfe TM, et al: Effect of thiopental and succinylcholine on serum potassium concentrations in children. Anesth Analg 1984; 63:1136.

Doenicke et al., 1973. Doenicke A, Lorenz W, Beigl R, et al: Histamine release after intravenous application of short-acting hypnotics. Br J Anesth 1973; 45:1097.

Domek et al., 1960. Domek NS, Batlow CF, Roth LJ: An ontogenetic study of phenobarbital C-14 in cat brain. J Pharmacol Exp Ther 1960; 130:285.

Domino et al., 1999. Domino KB, Anderson EA, Polissar NL, et al: Comparative efficacy and safety of ondansetron, droperidol, and metoclopramide for preventing postoperative nausea and vomiting: A meta-analysis. Anesth Analg 1999; 88:1370-1379.

Domino et al., 1965. Domino EF, Chodoff P, Corssen G: Pharmacologic effects of CI-581, a new dissociative anesthetic, in man. Clin Pharmacol Ther 1965; 6:279.

Donati and Bevan, 1983. Donati F, Bevan DR: Long-term succinylcholine infusion during isoflurane. Anesthesiology 1983; 58:6.

Donati et al., 1991. Donati F, Meistelman C, Plaud B: Vecuronium neuromuscular blockaded at the adductor muscles of the larynx and adductor pollicies. Anesthesiology 1991; 74:833-837.

Dönmez et al., 1998. Dönmez A, Kaya H, Haberal A, et al: The effect of etomidate induction on plasma cortisol levels in children undergoing cardiac surgery. J Cardiothorac Vasc Anesth 1998; 12:182-185.

Dönmez et al., 2001. Dönmez A, Kizilkan A, Berksun H, et al: One center's experience with remifentanil infusions for pediatric cardiac catheterization. J Cardiothorac Vasc Anesth 2001; 15:736-739.

Dowdy and Kaya, 1968. Dowdy EG, Kaya K: Studies of mechanism of cardiovascular responses to CI-581. Anesthesiology 1968; 29:931.

Drenck et al., 1989. Drenck NE, Ueda N, Olsen NV, et al: Manual evaluation of residual curarization using double burst stimulation: A comparison with train-of-four. Anesthesiology 1989; 70:578.

Dresner et al., 1990. Dresner DL, Basta SJ, Ali HA, et al: Pharmacokinetics and pharmacodynamics of doxacurium in young and elderly patients during isoflurane anesthesia. Anesth Analg 1990; 71:498.

Dsida et al., 2002. Dsida RM, Wheeler M, Birmingham PK, et al: Age-stratified pharmacokinetics of ketorolac tromethamine in pediatric surgical patients. Anesth Analg 2002; 94:266-270.

Duncan et al., 2000. Duncan HP, Cloote PM, Weir I, et al: Reducing stress responses in the pre-bypass phase of open heart surgery in infants and young children: A comparison of different fentanyl doses. Br J Anaesth 2000; 84:556-564.

Dundee and Barron, 1962. Dundee JW, Barron DW: The barbiturates. Br J Anaesth 1962; 34:240.

Duvaldestin et al., 1982. Duvaldestin P, Saada J, Berger JL, et al: Pharmacokinetics, pharmacodynamics, and dose-response relationships of pancuronium in control and elderly subjects. Anesthesiology 1982; 56:36.

Dyck et al., 1993. Dyck JB, Maze M, Haack C, et al: The pharmocokinetics and hemodynamic effects of intravenous and intramuscular dexmedetomidine hydrochloride in adult human volunteers. Anesthesiology 1993; 78:813-820.

Ebert et al., 2000. Ebert TJ, Hall JE, Barney JA, et al: The effects of increasing plasma concentrations of dexmedetomidine in humans. Anesthesiology 2000; 93:382-394.

Ebling et al., 1990. Ebling WF, Lee EN, Stanski DR: Understanding pharmacokinetics and pharmacodynamics through computer simulation: I. The comparative clinical profiles of fentanyl and alfentanil. Anesthesiology 1990; 72:650-658.

Ebrahim et al., 1986. Ebrahim ZY, DeBoer GE, Luders H, et al: Effect of etomidate on the electroencephalogram of patients with epilepsy. Anesth Analg 1986; 65:1004-1006.

Echeverria et al., 1975. Echeverria P, Siber GR, Paisley J, et al: Age-dependent dose response to gentamicin. Pediatrics 1975; 87:805-808.

Ecoffey et al., 1985. Ecoffey C, Desparmet J, Berdeaux A, et al: Bupivacaine in children: Pharmacokinetics following caudal anesthesia. Anesthesiology 1985; 63:447.

Ecoffey et al., 1984. Ecoffey C, Desparmet J, Berdeaux A, et al: Pharmacokinetics of lignocaine in children following caudal anesthesia. Br J Anaesth 1984; 56:1399.

Eddleston et al., 1989. Eddleston JM, Harper NJ, Pollard BJ, et al: Concentrations of atracurium and laudanosine in cerebrospinal fluid during intracranial surgery. Br J Anaesth 1989; 63:525.

Egan et al., 1993. Egan TD, Lemmens HJM, Fiset P: The pharmacokinetics of the new short-acting opioid remifentanil (GI87084B) in healthy adult male volunteers. Anesthesiology 1993; 79:881.

Egan et al., 1996. Egan TD, Minto CF, Hermann DJ, et al: Remifentanil versus alfentanil: Comparative pharmacokinetics and pharmacodynamics in healthy adult male volunteers. Anesthesiology 1996; 84:821-833.

Eger, 1974. Eger II EI: Anesthetic uptake and action, Baltimore, Williams & Wilkins, 1974.

Eger et al., 1971. Eger II EI, Smith NT, Cullen DJ, et al: A comparison of cardiovascular effects of halothane, fluroxene, ether and cyclopropane in man. Anesthesiology 1971; 34:325.

Eger et al., 1970. Eger II EI, Smith NT, Stoeling RK, et al: Cardiovascular effects of halothane in man. Anesthesiology 1970; 32:396.

Ehrnebo et al., 1971. Ehrnebo M, Agurell S, Jalling B, et al: Age differences in drug binding by plasma proteins: Studies on human foetuses, neonates and adults. J Eur Clin Pharmacol 1971; 3:189-193.

Elliot and Bion, 1995. Elliot JM, Bion JF: The use of neuromuscular blocking drugs in intensive care practice. Acta Anaesthesiol Scand 1995; 39:70.

Ellis and Steward, 1990. Ellis DJ, Steward DJ: Fentanyl dosage is associated with reduced blood glucose in pediatric patients with hypothermic cardiopulmonary bypass. Anesthesiology 1990; 72:812.

Eltzschig et al., 2002. Eltzschig HK, Schroeder TH, Eissler BJ, et al: The effect of remifentanil or fentanyl on postoperative vomiting and pain in children undergoing strabismus surgery. Anesth Analg 2002; 94:1173-1177.

Eng et al., 1975. Eng M, Bonica JJ, Akamatsu TJ, et al: Respiratory depression in newborn monkeys at cesarean section following ketamine administration. Br J Anaesth 1975; 47:917.

Engelhardt et al., 2003. Engelhardt T, Steel E, Johnston G, et al: Tramadol for pain relief in children undergoing tonsillectomy: A comparison with morphine. Paediatr Anaesth 2003; 13:249-252.

Engstron and Cohen, 1989. Engstron RH, Cohen SE: A complication associated with the use of midazolam [letter]. Anesthesiology 1989; 70:719.

Erb et al., 2002. Erb TO, Hall JM, Ing RJ, et al: Postoperative nausea and vomiting in children and adolescents undergoing radiofrequency catheter ablation: A randomized comparison of propofol- and isoflurane-based anesthetics. Anesth Analg 2002; 95:1577-1581.

Erkola et al., 1996. Erkola O, Rautoma P, Meretoja OA: Mivacurium when preceded by pancuronium becomes a long-acting muscle relaxant [comment]. Anesthesiology 1996; 84:562-565.

Eyres et al., 1983. Eyres RL, Bishop W, Brinn TCK: Plasma bupivacaine concentrations in children during caudal epidural analgesia. Anesth Intensive Care 1983; 11:20.

Eyres et al., 1978. Eyres RL, Kidd J, Oppenheim R, et al: Local anaesthestic plasma levels in children. Anaesth Intensive Care 1978; 6:243.

Fahey et al., 1985. Fahey MR, Rupp SM, Canfell C, et al: The effect of renal failure on laudanosine excretion in man. Br J Anaesth 1985; 57:1049.

Fahey et al., 1984. Fahey MR, Rupp SM, Fisher DM, et al: The pharmacokinetics and pharmacodynamics of atracurium in patients with and without renal failure. Anesthesiology 1984; 61:699.

Fang et al., 1995. Fang ZX, Eger 2nd EI, Laster MJ, et al: Carbon monoxide production from degradation of desflurane, enflurane, isoflurane, halothane and sevoflurane by soda lime and Baralyme. Anesth Analg 1995; 80:1187.

Feld et al., 1990. Feld LH, Negus JB, White PF: Oral midazolam preanesthetic medication in pediatric outpatients. Anesthesiology 1990; 73:831.

Ferrier et al., 1985. Ferrier C, Marty J, Bouffard Y, et al: Alfentanil pharmacokinetics in patients with cirrhosis. Anesthesiology 1985; 62:480.

Fiamengo and Savarese, 1991. Fiamengo SA, Savarese JJ: Use of muscle relaxants in intensive care units. Crit Care Med 1991; 19:1457.

Fine et al., 2001. Fine GF, Brandom BW, Yellon RF: Unmasked residual neuromuscular block after administration of vecuronium for days. Anesth Analg 2001; 93:345-347.

Fine et al., 2002. Fine GF, Motoyama EK, Brandom BW, et al: The effect on lung mechanics in anesthetized children with rapacuronium: A comparative study with mivacurium. Anesth Analg 2002; 95:56-61.

Finkel and Elrefai, 2004. Finkel JC, Elrefai A: The use of dexmedetomidine to facilitate opioids and benzodiazepine detoxification in an infant. Anesth Analg 2004; 98:1658-1659.

Finkel et al., 2002. Finkel JC, Rose JB, Schmitz ML, et al: An evaluation of the efficacy and tolerability of oral tramadol hydrochloride tablets for the treatment of postsurgical pain in children. Anesth Analg 2002; 94:1469-1473.

Fisher et al., 1983. Fisher DM, Cronnelly R, Miller RD, et al: The neuromuscular pharmacology of neostigmine in infants and children. Anesthesiology 1983; 59:220.

Fisher et al., 1984. Fisher DM, Cronnelly R, Sharma M, et al: Clinical pharmacology of edrophonium in infants. Anesthesiology 1984; 61:428.

Fisher and Miller, 1983. Fisher DM, Miller RD: Neuromuscular effects of vecuronium (ORG NC45) in infants and children during N2O-halothane anesthesia. Anesthesiology 1983; 58:519.

Fisher et al., 1982. Fisher DM, O'Keeffe C, Stanski DR, et al: Pharmacokinetics and pharmacodynamics of d-tubocurarine in infants, children, and adults. Anesthesiology 1982; 57:203.

Fisher and Zwass, 1992. Fisher DM, Zwass MS: MAC of desflurane in 60% nitrous oxide in infants and children. Anesthesiology 1992; 76:354.

Fleming, 1994. Fleming NW: Neuromuscular blocking drugs in the intensive care unit: Indications, protocols, and complications. Semin Anesth 1994; 13:255.

Flewellen and Nelson, 1984. Flewellen EH, Nelson TE: Halothane-succinylcholine induced masseter spasm: Indicative of malignant hyperthermia susceptibility. Anesth Analg 1984; 63:693.

Forbes et al., 1989a. Forbes RB, Murray DJ, Dillman JB, et al: Pharmacokinetics of two percent rectal methohexitone in children. Can J Anaesth 1989; 36:160-164.

Forbes et al., 1989b. Forbes RB, Murray DJ, Dull KL, et al: Haemodynamic effects of rectal methohexitone for induction of anaesthesia in children. Can J Anaesth 1989; 36:526-529.

Forster et al., 1983. Forster A, Morel D, Bachmann M: Respiratory depressant effects of different doses of midazolam and lack of reversal with naloxone—a double-blind randomized study. Anesth Analg 1983; 62:920.

Foubert et al., 2002. Foubert L, Reyntjens K, De Wolf D, et al: Remifentanil infusion for cardiac catheterization in children with congenital heart disease. Acta Anesthiol Scand 2002; 46:355-360.

Frei et al., 1997. Frei FJ, Haemmerle MH, Brunner R, et al: Minimum alveolar concentration for halothane in children with cerebral palsy and severe mental retardation. Anaesthesia 1997; 52:1056.

Friis-Hansen, 1961. Friis-Hansen B: Body water compartments in children: Changes during growth and related changes in body composition. Pediatrics 1961; 28:169-181.

Frink et al., 1996. Frink Jr EJ, Green Jr WB, Brown EA, et al: Compound A concentrations during sevoflurane anesthesia in children. Anesthesiology 1996; 84:566.

Fujii et al., 2001. Fujii Y, Saitoh Y, Kobayashi N: Prevention of vomiting after tonsillectomy in children: Granisetron versus ramosetron. Laryngoscope 2001; 111:255-258.

Fujii et al., 1999a. Fujii Y, Saitoh Y, Tanaka H, et al: Preoperative oral antiemetics for reducing postoperative vomiting after tonsillectomy in children: Granisetron versus perphenazine. Anesth Analg 1999; 88:1298-1301.

Fujii et al., 1999b. Fujii Y, Saitoh Y, Tanaka H, et al: Prevention of postoperative vomiting with granisetron in paediatric patients with and without a history of motion sickness. Paediatr Anaesth 1999; 9:527-530.

Fujii and Tanaka, 2001. Fujii Y, Tanaka H: Comparison of granisetron, droperidol, and metoclopramide for prevention of postoperative vomiting in children with a history of motion sickness undergoing tonsillectomy. J Pediatr Surg 2001; 36:460-462.

Fujii and Tanaka, 1999. Fujii Y, Tanaka H: Granisetron reduces postoperative vomiting in children: A dose-ranging study. Eur J Anesthesiol 1999; 16:62-65.

Fujii and Tanaka, 2002. Fujii Y, Tanaka H: Preoperative oral granisetron for the prevention of vomiting following paediatric surgery. Paediatr Anaesth 2002; 12:267-271.

Fujii et al., 1998. Fujii Y, Toyooka H, Tanaka H: A granisetron-droperidol combination prevents postoperative vomiting in children. Anesth Analg 1998; 87:761-765.

Galinkin et al., 2001. Galinkin JL, Davis PJ, McGowan FX, et al: A randomized multicenter study of remifentanil compared with halothane in neonates and infants undergoing pyloromyotomy. II. Perioperative breathing patterns in neonates and infants with pyloric stenosis. Anesth Analg 2001; 93:1387-1392.

Galinkin et al., 2000. Galinkin JL, Fazi LM, Cuy RM, et al: Use of intranasal fentanyl in children undergoing myringotomy and tube placement during halothane and sevoflurane anesthesia. Anesthesiology 2000; 93:1378-1383.

Gallagher and Black, 1985. Gallagher TW, Black GW: Uptake of volatile anaesthetics in children. Anaesthesia 1985; 40:1073.

Gardner et al., 1971. Gardner AE, Olson BE, Lichtiger M: Cerebrospinal fluid pressure during dissociative anesthesia with ketamine. Anesthesiology 1971; 35:226.

Gatke et al., 2001. Gatke MR, Ostergaard D, Bundgaard JR, et al: Response to mivacurium in a patient compound heterozygous for a novel and a known silent mutation in the butyrylcholinesterase gene: Genotyping by sequencing. Anesthesiology 2001; 95:600-606.

Gauntlett et al., 1988. Gauntlett IS, Fisher DM, Hertzka RE, et al: Pharmacokinetics of fentanyl in neonatal humans and lambs: Effects of age. Anesthesiology 1988; 69:683-687.

Gaviotaki and Smith, 1962. Gaviotaki A, Smith RM: Use of atropine in pediatric anesthesia. Int Anesthesiol Clin 1962; 1:97.

German et al., 2000. German JW, Aneja R, Heard C, et al: Continuous remifentanil for pediatric neurosurgery patients. Pediatr Neurosurg 2000; 33:227-229.

Ghonheim and Yamanda, 1977. Ghonheim M, Yamanda T: Etomidate: A clinical and electroencephalographic comparison with thiopental. Anesth Analg 1977; 56:479.

Gill et al., 1990. Gill SS, Wright EM, Reilly CS: Pharmacokinetic interaction of propofol and fentanyl: Single bolus injection study. Br J Anaesth 1990; 65:760.

Gillis and Brogden, 1997. Gillis JC, Brogden RN: Ketorolac. A reappraisal of its pharmacodynamic and pharmacokinetic properties and therapeutic use in pain management. Drugs 1997; 53:139-188.

Ginsberg et al., 1996. Ginsberg B, Scott H, Glass PSA, et al: Pharmacokinetic model-driven infusion of fentanyl in children. Anesthesiology 1996; 85:1268-1275.

Glass et al., 1993. Glass PSA, Hardman D, Kamiyama Y: Preliminary pharmacokinetics and pharmacodynamics of an ultra-short-acting opioid: Remifentanil (GI87084B). Anesth Analg 1993; 77:1031.

Goho, 2001. Goho C: Oral midazolam-grapefruit juice drug interaction. Pediatr Dent 2001; 23:365-366.

Goldberg, 1968. Goldberg AH: Effects of halothane on force-velocity, length-tension, and stress-strain curves of isolated heart muscle. Anesthesiology 1968; 29:192.

Goldberg et al., 1992. Goldberg ME, Torjman M, Bartkowski RR: Time-course of respiratory depression after an alfentanil infusion-based anesthetic. Anesth Analg 1992; 75:965.

Goldenthal, 1971. Goldenthal EI: A compilation of LD50 values in newborn and adult animals. Toxicol Appl Pharmacol 1971; 18:185.

Gonsowski et al., 1994a. Gonsowski CT, Laster MJ, Eger II EI, et al: Toxicity of compound A in rats: Effect of a 3-hour administration. Anesthesiology 1994; 80:556.

Gonsowski et al., 1994b. Gonsowski CT, Laster MJ, Eger II EI, et al: Toxicity of compound A in rats. Anesthesiology 1994; 80:566.

Goresky et al., 1987. Goresky GV, Koren G, Sabourin MA, et al: The pharmacokinetics of alfentanil in children undergoing surgery. Anesthesiology 1987; 67:654.

Goresky and Steward, 1979. Goresky GV, Steward DJ: Rectal methohexitone for induction of anaesthesia in children. Can Anaesth Soc J 1979; 26:213.

Goudsouzian et al., 1994. Goudsouzian N, Chakravorti S, Denman W, et al: Lack of accumulation of the cis-cis isomer of mivacurium in patients with low butyryl cholinesterase activity. Anesthesiology 1994; 81:1060.

Goudsouzian et al., 1985. Goudsouzian N, Liu LM, Gionfriddo M, et al: Neuromuscular effect of atracurium in infants and children. Anesthesiology 1985; 62:75.

Goudsouzian et al., 1983. Goudsouzian NG, Liu LM, Cote CJ, et al: Safety and efficacy of atracurium in adolescents and children anesthetized with halothane. Anesthesiology 1983; 59:459.

Goudsouzian et al., 1981. Goudsouzian NG, Liu LMP, Cote CJ: Comparison of equipotent doses of non-depolarizing muscle relaxants in children. Anesth Analg 1981; 60:862.

Goudsouzian and Liu, 1984. Goudsouzian NG, Liu LMP: The neuromuscular response of infants to a continuous infusion of succinylcholine. Anesthesiology 1984; 60:97.

Goudsouzian et al., 1984. Goudsouzian NG, Martyn JJA, Liu LMP: The dose response effect of long-acting non-depolarizing neuromuscular blocking agents in children. Can J Anaesth 1984; 3:246.

Goudsouzian, 1980. Goudsouzian NG: Maturation of neuromuscular transmission in the infant. Br J Anaesth 1980; 52:205.

Gourlay et al., 1982. Gourlay GK, Wilson PR, Glynn CJ: Pharmacodynamics and pharmacokinetics of methadone during the perioperative period. Anesthesiology 1982; 57:458.

Gozal et al., 2001. Gozal D, Rein AJJT, Nir A, et al: Propofol does not modify the hemodynamic status of children with intracardiac shunts undergoing cardiac catheterization. Pediatr Cardiol 2001; 22:488-490.

Greeley and de Bruijn, 1988. Greeley WJ, de Bruijn NP: Changes in sufentanil pharmacokinetics within the neonatal period. Anesth Analg 1988; 67:86.

Greeley et al., 1987. Greeley WJ, de Bruijn NP, Davis DP: Sufentanil pharmacokinetics in pediatric cardiovascular patients. Anesth Analg 1987; 66:1067.

Gregory et al., 1969. Gregory GA, Eger II EI, Munson ES: The relationship between age and halothane requirement in man. Anesthesiology 1969; 30:488.

Gregory et al., 1983. Gregory GA, Wade JG, Beihl DR, et al: Fetal anesthetic requirement (MAC) for halothane. Anesth Analg 1983; 62:9-14.

Gregory and Ettinger, 1998. Gregory RE, Ettinger DS: 5-HT3 receptor antagonists for the prevention of chemotherapy-induced nausea and vomiting: A comparison of their pharmacology and clinical efficacy. Drugs 1998; 55:173-189.

Gronert and Brandom, 1994. Gronert BJ, Brandom BW: Neuromuscular blocking drugs in infants and children. Pediatr Clin North Am 1994; 41:73.

Gronert et al., 1995. Gronert BJ, Woelfel SK, Cook DR: Comparison of the neuromuscular effects of mivacurium and succinylcholine in infants and children. Acta Anaesthesiol Scand 1995; 39:35.

Gronert, 2001. Gronert GA: Mortality greater with rhabdomyolysis than receptor upregulation. Anesthesiology 2001; 94:523-529.

Gu et al., 1990. Gu Y, Franco Jr A, Gardner PD, et al: Properties of embryonic and adult muscle acetylcholine receptors transiently expressed in COS cells. Neuron 1990; 5:147.

Guay et al., 1992. Guay J, Gaudreault P, Tang A: Pharmacokinetics of sufentanil in normal children. Can J Anaesth 1992; 39:14.

Guignard et al., 2000. Guignard B, Bossard AE, Coste C, et al: Acute opioid tolerance: Intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology 2000; 93:409-417.

Guignard et al., 1975. Guignard JP, Torrado A, Cunha OD, et al: Glomerular filtration rate in the first three weeks of life. J Pediatr 1975; 87:268.

Guldner et al., 2003. Guldner G, Schultz J, Sexton P, et al: Etomidate for rapid-sequence intubation in young children: hemodynamic effects and adverse events. Acad Emerg Med 2003; 10:134-139.

Gunter et al., 1999. Gunter JB, Gregg T, Varughese AM, et al: Levobupivacaine for ilioinguinal/iliohypogastric nerve block in children. Anesth Analg 1999; 89:647-649.

Gustorff et al., 2002. Gustorff B, Nahlik G, Hoerauf KH, et al: The absence of acute tolerance during remifentanil infusion in volunteers. Anesth Analg 2002; 94:1223-1228.

Gutstein et al., 1992. Gutstein HB, Johnson KL, Heard MB, et al: Oral ketamine preanesthetic medication in children. Anesthesiology 1992; 76:28-33.

Hakkola et al., 1994. Hakkola J, Pasanen M, Purkunen R, et al: Expression of xenobiotic-metabolizing cytochrome P450 forms in human adult and fetal liver. Biochem Pharmacol 1994; 48:59-64.

Halkin et al., 1978. Halkin H, Radomsky M, Millman P, et al: Steady state serum concentrations and renal clearance of digoxin in neonates, infants and children. Eur J Clin Pharmacol 1978; 13:113-117.

Halpern, 1988. Halpern SA: American pediatrics: The social dynamic of professionalism, 1880–1980, Berkeley, University of California Press, 1988.

Hamunen et al., 1999. Hamunen K, Maunuksela EL, Sarvela J, et al: Stereoselective pharmacokinetics of ketorolac in children, adolescents and adults. Acta Anaesthesiol Scand 1999; 43:1041-1046.

Hamza et al., 1989. Hamza J, Ecoffey C, Gross JB: Ventilatory response to CO2 following intravenous ketamine in children. Anesthesiology 1989; 70:422-425.

Hanaki et al., 1987. Hanaki C, Fujii K, Morio M, et al: Decomposition of sevoflurane by soda lime. Hiroshima J Med Sci 1987; 36:61.

Hanna et al., 1993. Hanna MH, D'Costa F, Peat SJ: Morphine-6-glucuronide disposition in renal impairment. Br J Anaesth 1993; 70:511.

Hannallah et al., 1991. Hannallah RS, Baker SB, Casey W: Propofol: Effective dose and induction characteristics in unpremedicated children. Anesthesiology 1991; 74:217.

Hansen et al., 2000. Hansen TG, Ilett KF, Lim SI, et al: Pharmacokinetics and clinical efficacy of long-term epidural ropivacaine infusion in children. Br J Anaesth 2000; 85:347-353.

Hansen et al., 2001. Hansen TG, Ilett KF, Reid C, et al: Caudal ropivacaine in infants. Anesthesiology 2001; 94:579-584.

Harper et al., 2001. Harper NJ, Greer R, Conway D: Neuromuscular monitoring in intensive care patients: Milliamperage requirements for supramaximal stimulation. Br J Anaesth 2001; 87:625-627.

Harris and Goodman, 1968. Harris WS, Goodman PM: Hyperactivity to atropine in Down's syndrome. N Engl J Med 1968; 279:407.

Haycock, 1998. Haycock GB: Development of glomerular filtration and tubular sodium reabsorption in the human fetus and newborn. Br J Urol 1998; 81(Suppl 2):33-38.

Head-Rapson et al., 1995. Head-Rapson AG, Devlin JC, Parker CJ, et al: Pharmacokinetics and pharmacodynamics of the three isomers of mivacurium in health, in end-stage renal failure and in patients with impaired renal function. Br J Anaesth 1995; 75:31-36.

Head-Rapson et al., 1994. Head-Rapson AG, Devlin JC, Parker CJ, et al: Pharmacokinetics of the three isomers of mivacurium and pharmacodynamics of the chiral mixture in hepatic cirrhosis. Br J Anaesth 1994; 73:613-618.

Heilbron et al., 1991. Heilbron DC, Holliday MA, al-Dahwi A, et al: Expressing glomerular filtration rate in children. Pediatr Nephrol 1991; 5:5-11.

Heir et al., 2001. Heir T, Feiner JR, Lin J, et al: Hemoglobin desaturation after succinylcholine-induced apnea. Anesthesia 2001; 94:754-759.

Helmers et al., 1989. Helmers JH, Noorduin H, Van Peer A: Comparison of intravenous and intranasal sufentanil absorption and sedation. Can J Anaesth 1989; 36:494.

Henning and Bush, 1982. Henning RD, Bush GH: Plasma potassium after halothane suxamethonium induction in children. Anaesthesia 1982; 37:802.

Hertzka et al., 1989. Hertzka RE, Gauntlett IS, Fisher DM: Fentanyl-induced ventilatory depression: Effects of age. Anesthesiology 1989; 70:213.

Hickey et al., 1984. Hickey PR, Hansen DD, Cramolini GM: Pulmonary and systemic hemodynamic responses to ketamine in infants with normal and elevated pulmonary vascular resistance. Anesthesiology 1984; 61:A438.

Hickey et al., 1985. Hickey PR, Hansen DD, Wessel DL: Pulmonary and systemic hemodynamic responses to fentanyl in infants. Anesth Analg 1985; 64:483.

Hickey and Retzack, 1993. Hickey PR, Retzack SM: Acute right ventricular failure after pulmonary hypertensive responses to airway instrumentation: Effect of fentanyl dose. Anesthesiology 1993; 78:372.

Hinkle and Weinlander, 1989. Hinkle AJ, Weinlander CM: The effects of 10% methohexital on the rectal mucosa in mice. Anesthesiology 1989; 71:550.

Holt et al., 2000. Holt R, Rask P, Coulthard KP, et al: Tropisetron plus dexamethasone is more effective than tropisetron alone for the prevention of postoperative nausea and vomiting in children undergoing tonsillectomy. Paediatr Anaesth 2000; 10:181-188.

Hopkins, 1995. Hopkins PM: Use of suxamethonium in children. Br J Anaesth 1995; 75:675-677.

Howard and Bingham, 1990. Howard RF, Bingham RM: Endotracheal compared with intravenous administration of atropine. Arch Dis Childhood 1990; 65:449-450.

Hug, 1984. Hug C: Alfentanil: Pharmacology and uses in anaesthesia, Auckland, New Zealand, Adis Press, 1984.

Huges et al., 1992. Huges MA, Glass PS, Jacobs JR: Context-sensitive half-time in multi-compartment pharmacokinetic models for intravenous anesthetic drugs. Anesthesiology 1992; 76:334-341.

Hunter et al., 1982. Hunter JM, Jones RS, Utting JE: Use of atracurium in patients with no renal function. Br J Anaesth 1982; 54:1251.

Huntington et al., 1999. Huntington JH, Malviya S, Voepel-Lewis T, et al: The effect of right-to-left intracardiac shunt on the rate of rise of arterial and end-tidal halothane in children. Anesth Analg 1999; 88:759-762.

Ibacache et al., 2004. Ibacache ME, Munoz HR, Brandes V, Morales AL: Single-dose dexmedetomidine reduces agitation after sevoflurane anesthesia in children. Anesth Analg 2004; 98:60.

Ingram, 1986. Ingram MD, et al: Cardiovascular and electroencephalographic effects of laudanosine in “nephrectomized” cats. Br J Anaesth 1986; 58:14S.

Ivani et al., 2002. Ivani G, DeNegri P, Conio A, et al: Comparison of racemic bupivacaine, ropivacaine, and levobupivacaine for pediatric caudal anesthesia: Effects on postoperative analgesia and motor block. Reg Anesth Pain Med 2002; 27:157-161.

Ivani et al., 2000. Ivani G, DeNegri P, Conio A, et al: Ropivacaine-clonidine combination for caudal blockade in children. Acta Anaesth Scand 2000; 44:446.

Ivani et al., 2005. Ivani G, DeNegri P, Lonngvist PA, et al: Caudal anesthesia for minor pediatric surgery: a prospective randomized comparison of ropivacaine 0.2% vs levobupivacaine 0.2%. Paediatr Anaesth 2005; 15:491.

Ivani et al., 2003. Ivani G, DeNegri P, Lonqvist PA, et al: A comparison of three different concentrations of levobupivacaine for caudal block in children. Anesth Analg 2003; 97:368-371.

Ivani et al., 1999. Ivani G, Lampugnani E, DeNegri P, et al: Ropivacaine vs bupivacaine in major surgery in infants. Can J Anaesth 1999; 46:467.

Ivani et al., 1998. Ivani G, Lampugnani E, Torre M, et al: Comparison of ropivacaine with bupivacaine for paediatric caudal block. Br J Anaesth 1998; 81:247-248.

Iwasaki et al., 1994a. Iwasaki H, Igarashi M, Namiki A, et al: Differential neuromuscular effects of vecuronium on the adductor and abductor laryngeal muscles and tibialis anterior muscle in dogs. Br J Anaesth 1994; 72:321-323.

Iwasaki et al., 1994b. Iwasaki H, Igarashi M, Omote K, et al: Vecuronium neuromuscular blockade at the cricothyroid and posterior cricoarytenoid muscles of the larynx and at the adductor pollices muscle in humans. J Clin Anesth 1994; 6:14-17.

Jaaskelainen et al., 2003. Jaaskelainen SK, Kaisti K, Suni L, et al: Sevoflurane is epileptogenic in healthy subjects at surgical levels of anesthesia. Neurology 2003; 61:1073-1078.

Jalkanen and Meretoja, 1997. Jalkanen L, Meretoja OA: The influence of the duration of isoflurane anesthesia on neuromuscular effects of mivacurium. Acta Anesthesiol Scand 1997; 41:248-251.

Jalkanen et al., 1994. Jalkanen L, Meretoja OA, Taivainen T, et al: Synergism between atracurium and mivacurium compared with that between vecuronium and mivacurium [comment]. Anesth Analg 1994; 79:998-1002.

Jensen et al., 2000. Jensen AB, Christiansen DB, Coulthard K, et al: Tropisetron reduces postoperative vomiting in children undergoing tonsillectomy. Paediatr Anaesth 2000; 10:69-75.

Jevtovic-Todorovic et al., 2003. Jevtovic-Todorovic V, Beals J, Benshoff N, et al: Prolonged exposure to inhalational anesthetic nitrous oxide kills neurons in adult rat brain. Neuroscience 2003; 122:609-616.

Johnson et al., 1984. Johnson KL, Erickson JP, Holley FO, et al: Fentanyl pharmacokinetics in the pediatric population. Anesthesiology 1984; 61:A441.

Jones et al., 1990. Jones RDM, Chan K, Andrew LJ: Pharmacokinetics of propofol in children. Br J Anaesth 1990; 65:661.

Jones et al., 1993. Jones RDM, Chan K, Roulson CJ: Pharmacokinetics of flumazenil and midazolam. Br J Anaesth 1993; 70:286.

Jones et al., 1991. Jones RDM, Lawson AD, Andrew LJ: Antagonism of the hypnotic side effects of midazolam in children: A randomized double-blind study of placebo and flumazenil administered after midazolam-induced anesthesia. Br J Anaesth 1991; 66:660.

Jonmarker et al., 1987. Jonmarker C, Westrin P, Larsson S, et al: Thiopental requirements for induction of anesthesia in children. Anesthesiology 1987; 67:104.

Jorgensen and Ostergaard, 1997. Jorgensen BG, Ostergaard D: Tracheal administration of atropine in children–effect on heart rate. Paed Anaesth 1997; 7:461-463.

Kain et al., 2000. Kain ZN, Hofstadter MB, Mayes L, et al: Midazolam: Effects on amnesia and anxiety in children. Anesthesiology 2000; 93:676-684.

Kain et al., 1997. Kain ZN, Mayes LC, Bell C, et al: Premedication in the United States: A status report. Anesth Analg 1997; 84:427-432.

Kapila et al., 1995. Kapila A, Glass PS, Jacobs JR, et al: Measured context-sensitive half-times of remifentanil and alfentanil. Anesthesiology 1995; 83:968-975.

Karl et al., 1993. Karl HW, Rosenberger JL, Larach MG: Transmucosal administration of midazolam for premedication of pediatric patients: Comparison of nasal and sublingual routes. Anesthesiology 1993; 78:885.

Karmakar et al., 2002. Karmakar MK, Aun CST, Wong ELY, et al: Ropivacaine undergoes slower systemic absorption from the caudal epidural space in children than bupivacaine. Anesth Analg 2002; 94:259-265.

Karsli et al., 2002. Karsli C, Luginbuehl I, Farrar M, et al: Propofol decreases cerebral blood flow velocity in anesthetized children. Can J Anesth 2002; 49:830-834.

Kataria et al., 1994. Kataria BK, Ved SA, Nicodemus HF: The pharmacokinetics of propofol in children using three different data analysis approaches. Anesthesiology 1994; 80:104.

Katz and Kelly, 1993. Katz R, Kelly HW: Pharmacokinetics of continuous infusions of fentanyl in critically ill children. Crit Care Med 1993; 21:995.

Kauffman et al., 1999. Kauffman RE, Lieh-Lai MW, Uy HG, et al: Enantiomer-selective pharmacokinetics and metabolism of ketorolac in children. Clin Pharmacol Ther 1999; 65:382-388.

Kay and Pleuvry, 1980. Kay B, Pleuvry B: Human volunteer studies of alfentanil (R39209), a new short-acting narcotic analgesic. Anaesthesia 1980; 35:952.

Kay and Stephenson, 1980. Kay B, Stephenson D: Alfentanil (R34209) initial clinical experience with a new narcotic analgesic. Anaesthesia 1980; 35:1182.

Kearns et al., 2003. Kearns GL, Abdel-Rahman SM, Alander SW, et al: Drug therapy: Developmental pharmacology: Drug disposition, action, and therapy in infants and children. N Engl J Med 2003; 349:1157-1167.

Keenan and Boyan, 1985. Keenan RL, Boyan CP: Cardiac arrest due to anesthesia. JAMA 1985; 253:2372.

Kenna et al., 1989. Kenna JG, Neuberger J, Mieli-Vergani G, et al: Halothane hepatitis in children. Br Med J 1989; 294:1209.

Khalil et al., 1999. Khalil S, Campos C, Farag AM, et al: Caudal block in children. Anesthesiology 1999; 91:1279-1284.

Khalil et al., 1998. Khalil S, Philbrook L, Rabb M, et al: Sublingual midazolam premedication in children: A dose response study. Paediatr Anaesth 1998; 8:461-465.

Khalil et al., 1996. Khalil S, Rodarte A, Wildon BC, et al: Intravenous ondansetron in established postoperative emesis in children. S3A-381 Study Group. Anesthesiology 1996; 85:270-276.

Khalil et al., 1990. Khalil SN, Florence FB, Van den Nieuwenhuyzen MCO, et al: Rectal methohexital: Concentration and length of the rectal catheters. Anesth Analg 1990; 70:645-649.

Kharasch et al., 1997b. Kharasch E, Russell M, Mautz D, et al: The role of cytochrome P450 3A4 in alfentanil clearance: Implications for interindividual variability in disposition and perioperative drug interactions. Anesthesiology 1997; 87:36-50.

Kharasch et al., 1995a. Kharasch ED, Armstrong AS, Gunn K, et al: Clinical sevoflurane metabolism and disposition: II. The role of cytochrome P450 2E1 in fluoride and hexafluoroisopropanol formation. Anesthesiology 1995; 82:1379.

Kharasch et al., 1995b. Kharasch ED, Hankins DC, Thummel KE: Human kidney methoxyflurane and sevoflurane metabolism: Intrarenal fluoride production as a possible mechanism of methoxyflurane nephrotoxicity. Anesthesiology 1995; 82:689.

Kharasch et al., 1997. Kharasch ED, Russell M, Garton K, et al: Assessment of cytochrome P450 3A4 activity during the menstrual cycle using alfentanil as a noninvasive probe. Anesthesiology 1997; 87:26-35.

Kharasch and Thummel, 1993. Kharasch ED, Thummel KE: Human alfentanil metabolism by cytochrome P450 3A3/4. An explanation for the interindividual variability in alfentanil clearance?. Anesth Analg 1993; 76:1033-1039.

Khuenl-Brady et al., 1990. Khuenl-Brady K, Castagnoli KP, Canfell C, et al: The neuromuscular blocking effects and pharmacokinetics of ORG 9426 and ORG 9616 in the cat. Anesthesiology 1990; 72:669-674.

Killian et al., 1990. Killian A, Davis PJ, Stiller RL: Influence of gestational age on pharmacokinetics of alfentanil in neonates. Dev Pharmacol Ther 1990; 15:82.

Kim et al., 1995. Kim C, Hirose M, Martyn JAJ: d-Tubocurarine accentuates the burn-induced upregulation of nicotinic acetylcholine receptors at the muscle membrane. Anesthesiology 1995; 83:309-315.

Kingston et al., 1990. Kingston HGG, Kendrick A, Sommer KM: Binding of thiopental in neonatal serum. Anesthesiology 1990; 72:428.

Klees et al., 2005. Klees TM, Sheffels P, Thummel KE, Kharasch ED: Pharmacogenetic determinants of human liver microsomal alfentanil metabolism and the role of cytochrome P450 3A5. Anesthesiology 2005; 102(3):550-556.

Klepstad et al., 2004. Klepstad P, Rakvag TT, Kaasa S, et al: The 118A>G polymorphism in the human microopioid receptor gene may increase morphine requirements in patients with pain caused by malignant disease. Acta Anaesthesiol Scand 2004; 48:1232.

Klessig et al., 1992. Klessig HT, Geiger HJ, Murray MJ, et al: A national survey on the practice patterns of anesthesiologist intensivists in the use of muscle relaxants. Crit Care Med 1992; 20:1341.

Knauer et al., 1973. Knauer B, Draffen GA, Williams FM: Elimination kinetics of amobarbital in mothers and their newborn infants. Clin Pharmacol Ther 1973; 14:442.

Knibbe et al., 2002. Knibbe CAJ, Melenhorst-de Jong G, Mestrom M, et al: Pharmacokinetics and effects of propofol 6% for short-term sedation in paediatric patients following cardiac surgery. Br J Clin Pharmacol 2002; 54:415-422.

Kobel et al., 1982. Kobel M, Creighton RE, Steward DJ: Anaesthetic considerations in Down's syndrome: Experience with 100 patients and a review of the literature. Can Anaesth Soc J 1982; 29:593.

Koehntop et al., 1986. Koehntop DE, Rodman JH, Brundage DM, et al: Pharmacokinetics of fentanyl in neonates. Anesth Analg 1986; 65:227.

Kokki et al., 2004. Kokki H, Ylonen P, Heikkinen M, Reinikainen M: Levobupivacaine for pediatric spinal anesthesia. Anesth Analg 2004; 98:64-67.

Kokki et al., 2002. Kokki H, Karvinen M, Jekunen A: Pharmacokinetics of a 24-hour intravenous ketoprofen infusion in children. Acta Anaesthesiol Scand 2002; 46:194-198.

Komatsu, 1994. Komatsu H, et al: Electrical seizures during sevoflurane anesthesia in two pediatric patients with epilepsy. Anesthesiology 1994; 81:1535.

Kopman, 1989. Kopman A: Pancuronium, gallamine, and d-tubocurarine compared: Is speed of onset inversely related to drug potency?. Anesthesiology 1989; 70:915.

Kopman et al., 2001. Kopman AF, Khan NA, Neuman GG: Precurarization and priming: A theoretical analysis of safety and timing. Anesth Analg 2001; 93:1253-1256.

Kopman et al., 2001. Kopman AF, Klewicka MM, Neuman GG: Reexamined: The recommended endotracheal intubating dose for nondepolarizing neuromuscular blockers of rapid onset. Anesth Analg 2001; 93:954-959.

Kopman et al., 2001. Kopman AF, Kumar S, Klewicka MM, et al: The staircase phenomenon: Implications for monitoring of neuromuscular transmission. Anesthesiology 2001; 95:403-407.

Koppert et al., 2001. Koppert W, Blunk JA, Petersen LJ: Different patterns of mast cell activation by muscle relaxants in human skin. Anesthesiology 2001; 95:659-667.

Koren et al., 1984. Koren G, Goresky G, Crean P: Pediatric fentanyl dosing based on pharmacokinetics during cardiac surgery. Anesth Analg 1984; 63:577.

Kramer et al., 1983. Kramer M, Kling D, Walter P, et al: Alfentanil: A new short acting opioid: Haemodynamic and respiratory aspects. Anaesthetist 1983; 32:265.

Krane and Su, 1987. Krane EJ, Su JY: Comparison of the effects of halothane on newborn and adult rabbit myocardium. Anesth Analg 1987; 66:1240.

Kupferberg and Way, 1963. Kupferberg HI, Way EL: Pharmacologic basis for the increased sensitivity of the newborn rat to morphine. J Pharmacol Exp Ther 1963; 141:105.

Kurz et al., 1977. Kurz H, Michels H, Stickel HH: Differences in the binding of drugs to plasma proteins from newborn to adult man. Eur J Clin Pharmacol 1977; 11:469-472.

Lammers et al., 2002. Lammers CR, Rosner JL, Crockett DE, et al: Oral midazolam with an antacid may increase the speed of onset of sedation in children prior to general anaesthesia. Paediatr Anaesth 2002; 12:26-28.

Lanier et al., 1985. Lanier WL, Milde JH, Michenfelder JD: The cerebral effects of pancuronium and atracurium in halothane-anesthetized dogs. Anesthesiology 1985; 63:589.

Larsson et al., 1992. Larsson S, Asgeirsson B, Magnusson J: Propofol-fentanyl anesthesia compared with thiopental-halothane with special reference to recovery and vomiting after pediatric strabismus surgery. Acta Anaesthesiol Scand 1992; 36:182.

Lavine and Hindein, 1983. Lavine LM, Hindein BI: Hemodialysis as treatment for prolonged neuromuscular blockade in anephric patients. Anesthesiology 1983; 59:264.

Law and Cook, 1990. Law SC, Cook DR: Monitoring the neuromuscular junction. In: Lake CL, ed. Clinical monitoring, Philadelphia: WB Saunders; 1990:719-755.

Laxenaire et al., 1992. Laxenaire M-C, Mata-Bermejo E, Moneret-Vautrin DA: Life-threatening anaphylactoid reactions to propofol (Diprivan®). Anesthesiology 1992; 77:275.

Lebovic et al., 1992. Lebovic S, Reich DL, Steinberg LG: Comparison of propofol versus ketamine for anesthesia in pediatric patients undergoing cardiac catheterization. Anesth Analg 1992; 74:490.

Lebowitz et al., 1982. Lebowitz P, Cote E, Daniels A, et al: Comparative cardiovascular effects of midazolam and thiopental in healthy patients. Anesth Analg 1982; 61:77.

Lebrault et al., 1985. Lebrault C, Berger JL, D'Hollander AA, et al: Pharmacokinetics and pharmacodynamics of vecuronium (ORG NC45) in patients with cirrhosis. Anesthesiology 1985; 62:601-605.

LeDez and Lerman, 1987. LeDez KM, Lerman J: The minimum alveolar concentration (MAC) of isoflurane in preterm neonates. Anesthesiology 1987; 67:301.

Ledingham and Watt, 1983. Ledingham I, Watt I: Influence of sedation on mortality in critically ill multiple trauma patients. Lancet 1983; 1:1270.

Lee, 1995. Lee C: Intensive care unit neuromuscular syndrome?. Anesthesiology 1995; 83:237.

Lee, 1986. Lee C: Self antagonism: Possible mechanism of tachyphylaxis in suxamethonium-induced neuromuscular block in man. Br J Anaesth 1986; 48:1097.

Lee, 1987. Lee C: Structure, conformation, and action of neuromuscular blocking drugs. Br J Anaesth 1987; 5:755-769.

Leeder, 2001. Leeder JS: Pharmacogenetics and pharmacogenomics. Pediatr Clin North Am 2001; 48:765-781.

Leeder and Kearns, 1997. Leeder JS, Kearns GL: Pharmacogenetics in pediatrics. Implications for practice. Pediatr Clin North Am 1997; 44:55-77.

Leigh and Belton, 1960. Leigh MD, Belton MK: Pediatric anesthesiology, 2nd ed.. New York, Macmillan, 1960.

Lerman, 1996. Lerman J: Induction, recovery and safety characteristics of sevoflurane in children undergoing ambulatory surgery: A comparison with halothane. Anesthesiology 1996; 84:1332.

Lerman, 2002. Lerman J: Inhalational agents. In: Bissonnette B, Dalens BJ, ed. Pediatric anesthesia: Principles and practice, New York: McGraw-Hill Professional; 2002.Chapter 13

Lerman, 1994. Lerman J: Pharmacokinetics of inhalational anesthetic agents. In: Bowdle TA, Horita A, Kharasch ED, ed. The pharmacologic basis of anesthesiology, New York: Churchill Livingstone; 1994.

Lerman et al., 1984. Lerman J, Gregory GA, Eger II EI: Age and the solubility of volatile anesthetics in blood. Anesthesiology 1984; 61:139.

Lerman et al., 2003. Lerman J, Nolan J, Eyers R, et al: Efficacy, Safety, and pharmacokinetics of levobupivacaine with and without fentanyl after continuous epidural infusion in children: a multicenter trial. Anesthesiology 2003; 99:1166-1174.

Lerman et al., 1983. Lerman J, Robinson S, Willis MM, et al: Anesthetic requirements for halothane in young children 0–1 month and 1–6 months of age. Anesthesiology 1983; 59:421.

Lerman et al., 1986. Lerman J, Schmitt BI, Willis MM, et al: Effect of age on the solubility of volative anesthetics in human tissues. Anesthesiology 1986; 65:63.

Lerman et al., 1994. Lerman J, Sikich N, Kleinman S, et al: The pharmacology of sevoflurane in infants and children. Anesthesiology 1994; 80:814.

Lerman et al., 1996. Lerman J, Sims C, Sikich N, et al: Pharmacokinetics of the active metabolite (MDL 74,156) of dolasetron mesylate after oral or intravenous administration to anesthetized children. Clin Pharmacol Ther 1996; 60:485-492.

Letty et al., 1985. Letty MP, Gaudreault P, Friedman PA: Methohexital plasma concentrations in the child following rectal administration. Anesthesiology 1985; 62:567.

Levine et al., 1993a. Levine MF, Hartley EJ, Macpherson BA: Oral midazolam premedication for children with congenital cyanotic heart disease undergoing cardiac surgery. Can J Anaesth 1993; 40:934.

Levine et al., 1993b. Levine MF, Spahr-Schopfer I, Hartley E: Oral midazolam premedication in children. Can J Anaesth 1993; 40:726.

Levy, 1994. Levy G: Effect of hepatic cirrhosis on the pharmacodynamics and pharmacokinetics of mivacurium in humans. Pharmaceut Res 1994; 11:772-773.

Lien et al., 1994. Lien CA, Schmith VD, Embree PB, et al: The pharmacokinetics and pharmacodynamics of the stereoisomers of mivacurium in patients receiving nitrous oxide/opioid/barbiturate anesthesia. Anesthesiology 1994; 80:1296.

Lim et al., 1999. Lim L-Y, Dear KBG, Heller RF: A systematic review of the antiemetic efficacy of prophylactic ondansetron compared with droperidol and with metoclopramide in children. Clin Res Regul Aff 1999; 16:59-70.

Lima et al., 1991. Lima JJ, Boudonlans H, Blanford M: Concentration dependence of disopyramide binding to plasma protein and its influence kinetics and dynamics. J Pharmacol Exp Ther 1991; 219:741-747.

Lindsay and Shepherd, 1969. Lindsay WA, Shepherd J: Plasma levels of thiopentone after premedication with rectal suppositories in young children. Br J Anaesth 1969; 41:977.

Liu et al., 1991. Liu J, Laster MJ, Eger 2nd EI, et al: Absorption and degradation of sevoflurane and isoflurane in a conventional anesthetic circuit. Anesth Analg 1991; 72:785.

Locatelli et al., 2005. Locatelli B, Ingelmo P, Sonzogni V, et al: Randomized, double-blind, phase III, controlled trial comparing levobupivacaine 0.25%, ropivacaine 0.25% and bupivacaine 0.25% by the caudal route in children. Br J Anaesth 2005; 94:366-371.

Lockhart and Jenkins, 1972. Lockhart CH, Jenkins JJ: Ketamine-induced apnea in patients with increased intracranial pressure. Anesthesiology 1972; 37:92.

Lockhart and Nelson, 1974. Lockhart CH, Nelson WL: The relationship of ketamine requirements to age in pediatric patients. Anesthesiology 1974; 40:507.

Lombroso, 1966. Lombroso CT: Treatment of status epilepticus with diazepam. Neurology 1966; 16:629.

Longnecker, 1984. Longnecker DR: Stress free: To be or not to be?. Anesthesiology 1984; 61:643.

Lönnqvist et al., 2000. Lönnqvist PA, Westrin P, Larsson BA, et al: Ropivacaine pharmacokinetics after caudal block in 1–8 year old children. Br J Anaesth 2000; 85:506-511.

Lynam et al., 1988. Lynam DP, Cronnelly R, Castagnoli KP, et al: The pharmacodynamics and pharmacokinetics of vecuronium in patients anesthetized with isoflurane with normal renal function or with renal failure. Anesthesiology 1988; 69:227.

Lynn et al., 1993. Lynn AM, Nespeca MK, Opheim KE: Respiratory effects of intravenous morphine infusions in neonates, infants, and children after cardiac surgery. Anesth Analg 1993; 77:695.

Lynn et al., 1984. Lynn AM, Opheim KE, Tyler DC: Morphine infusion after pediatric cardiac surgery. Crit Care Med 1984; 12:863.

Macfie et al., 1992. Macfie AG, Magides AD, Reilly CS: Disposition of alfentanil in burn patients. Br J Anaesth 1992; 69:447.

Magorian and Lynam, 1992. Magorian T, Lynam DP: Clinical use of muscle relaxants in patients with hepatic disease. In: Rupp SM, ed. Problems in anaesthesia: Neuromuscular relaxants, Philadelphia: JB Lippincott; 1992.

Maitre et al., 1987. Maitre PO, Vozeh S, Heykants J, et al: Population pharmacokinetics of alfentanil. Anesthesiology 1987; 66:3.

Manjushree et al., 2002. Manjushree R, Lahiri A, Ghosh BR, et al: Intranasal fentanyl provides adequate postoperative analgesia in pediatric patients. Can J Anaesth 2002; 49:190-193.

Manschot et al., 1992. Manschot HJ, Meuring AEE, Axt P: Propofol requirements for induction of anesthesia in children of different age groups. Anesth Analg 1992; 75:876.

Marhofer et al., 1999. Marhofer P, Glaser C, Krenn CG, et al: Incidence and therapy of midazolam induced hiccups in paediatric anaesthesia. Paediatr Anaesth 1999; 9:295-298.

Mark, 1963. Mark LC: Thiobarbiturates. In: Papper EM, Kitz RJ, ed. Uptake and distribution of anesthetic agents, New York: McGraw-Hill; 1963.

Markakis et al., 1998. Markakis DA, Lau M, Brown R, et al: The pharmacokinetics and steady state pharmacodynamics of mivacurium in children. Anesthesiology 1998; 88:978-983.

Marsh et al., 1991. Marsh B, White M, Morton N: Pharmacokinetic model driven infusion of propofol in children. Br J Anaesth 1991; 67:41.

Martin et al., 1995. Martin JL, Plevak DJ, Flannery KD, et al: Hepatotoxicity after desflurane anesthesia. Anesthesiology 1995; 83:1125.

Martin et al., 1993. Martin TM, Nicolson SC, Bargas MS: Propofol anesthesia reduces emesis and airway obstruction in pediatric outpatients. Anesth Analg 1993; 76:144.

Martyn et al., 1992. Martyn JAJ, White DA, Gronert GA, et al: Up-and-down regulation of skeletal muscle acetylcholine receptors. Anesthesiology 1992; 76:822-843.

Matthes et al., 1996. Matthes HW, Maldonado R, Simonin F, et al: Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioid-receptor gene. Nature 1996; 383:819.

Mazoit et al., 1988. Mazoit JX, Denson DD, Samil K: Pharmacokinetics of bupivacaine following caudal anesthesia in infants. Anesthesiology 1988; 68:387.

Mazoit and Dalens, 2004. Mazoit JX, Dalens BJ: Pharmacokinetics of local anaesthetics in infants and children. Clin Pharmacokinet 2004; 43:17-32.

McAuliffe et al., 1997. McAuliffe G, Bissonnette B, Cavallé-Garrido T, et al: Heart rate and cardiac output after atropine in anaesthetized infants and children. Can J Anaesth 1997; 44:154-159.

McCann et al., 2001. McCann ME, Sethna NF, Mazoit JX, et al: The pharmacokinetics of epidural ropivacaine in infants and young children. Anesth Analg 2001; 93:893-897.

McCloskey et al., 1992. McCloskey JJ, Haun SE, Deshpande JK: Bupivacaine toxicity secondary to continuous caudal epidural infusion in children. Anesth Analg 1992; 75:287.

McFarlan et al., 1999. McFarlan CS, Anderson BJ, Timothy SG: The use of propofol infusion in pediatric anesthesia: A practical guide. Pediatr Anaesth 1999; 9:209-216.

McGraw, 1993. McGraw T: Oral midazolam and postoperative behaviour in children. Can J Anaesth 1993; 40:682.

McGregor et al., 1958. McGregor M, Davenport HT, Jegier W, et al: The cardiovascular effects of halothane in normal children. Br J Anaesth 1958; 30:398.

McMillan et al., 1992. McMillan CO, Spahr-Schopfer IA, Sikich N: Premedication of children with oral midazolam. Can J Anaesth 1992; 39:545.

Meakin et al., 1989. Meakin G, McKiernan EP, Morris P, et al: Dose-response curves for suxamethonium in neonates, infants and children. Br J Anaesth 1989; 62:655.

Meakin et al., 1992. Meakin G, Morton RH, Wareham AC: Age-dependent variation in response to tubocurarine in the isolated rat diaphragm. Br J Anaesth 1992; 68:161-163.

Meakin et al., 1983. Meakin G, Sweet PT, Bevan JC, et al: Neostigmine and edrophonium as antagonists of pancuronium in infants and children. Anesthesiology 1983; 59:316.

Meberg et al., 1978. Meberg A, Langslet A, Bredesen JE, et al: Plasma concentration of diazepam and N-desmethyldiazepam in children after a single rectal or intramuscular dose of diazepam. Eur J Clin Pharmacol 1978; 14:273-276.

Meistelman et al., 1991. Meistelman C, Plaud B, Donati F: Neuromuscular effects of succinylcholine on the vocal cords and adductor pollicis muscles. Anesth Analg 1991; 73:278-282.

Meistelman et al., 1992. Meistelman C, Plaud B, Donati F: Rocuronium (ORG 9426) neuromuscular blockade at the adductor muscles of the larynx and adductor pollicies in humans. Can J Anesth 1992; 39:665-669.

Meistelman et al., 1990. Meistelman C, Benhamou D, Barre J, et al: Effects of age on plasma protein binding of sufentanil. Anesthesiology 1990; 72:470-473.

Meistelman et al., 1987. Meistelman C, Saint-Maurice C, Lepaul M, et al: A comparison of alfentanil pharmacokinetics in children and adults. Anesthesiology 1987; 66:13.

Meretoja and Rautiainen, 1990. Meretoja OA, Rautiainen P: Alfentanil and fentanyl sedation in infants and small children during cardiac catheterization. Can J Anaesth 1990; 37:624.

Meretoja et al., 1993. Meretoja OA, Brandom BW, Taivainen T, et al: Synergism between atracurium and vecuronium in children. Br J Anaesth 1993; 71:440-442.

Meretoja et al., 1994. Meretoja OA, Taivainen T, Jalkanen L, et al: Synergism between atracurium and vecuronium in infants and children during nitrous oxide-oxygen-alfentanil anaesthesia. Br J Anaesth 1994; 73:605-607.

Meretoja et al., 1994. Meretoja OA, Taivainen T, Wirtavuori K: Pharmacodynamics of mivacurium in infants. Br J Anaesth 1994; 73:490.

Meretoja, 1989. Meretoja OA: Is vecuronium a long-acting neuromuscular blocking agent in neonates and infants?. Br J Anaesth 1989; 62:184.

Meretoja et al., 1995. Meretoja OA, Taivainen T, Wirtavuori K: Pharmacodynamic effects of 51 W89, an isomer of atracurium, in children during halothane anaesthesia. Br J Anaesth 1995; 74:6-11.

Meuldermans et al., 1982. Meuldermans W, Hurkmans R, Heykants J: Plasma protein binding and distribution of fentanyl, sufentanil and lofentanil in blood. Arch Int Pharmacol Ther 1982; 25:4.

Miller et al., 1961. Miller JR, Stoelting VK, Dann MW: A preliminary report on the use of intramuscular methohexital sodium (Brevital) for pediatric anesthesia. Anesth Analg (Cleve) 1961; 40:573.

Miller, 1995. Miller RD: Use of neuromuscular blocking drugs in intensive care unit patients. Anesth Analg 1995; 81:1-2.

Minton et al., 1986. Minton MD, Grosslight K, Stirt JA, et al: Increases in intracranial pressure from succinylcholine: Prevention by prior nondepolarizing blockade. Anesthesiology 1986; 65:165.

Mirakhur, 1988. Mirakhur RK: Induction characteristics of propofol in children. Anaesthesia 1988; 43:593.

Mirkin, 1975. Mirkin BL: Developmental pharmacology. Anesthesiology 1975; 43:156.

Modica et al., 1990. Modica PA, Pempelhoff R, White PF: Pro-and anticonvulsant effects of anesthetics (Part II). Anesth Analg 1990; 70:433-444.

Moore et al., 1985. Moore RA, Yang SS, McNicholas KW, et al: Hemodynamic and aesthetic effects of sufentanil as the sole anesthetic for pediatric cardiovascular surgery. Anesthesiology 1985; 62:725.

Morio et al., 1992. Morio M, Fugii K, Satoh N, et al: Reaction of sevoflurane and its degradation products with soda lime. Anesthesiology 1992; 77:1155.

Morselli, 1974. Morselli PL, et al: Drug interactions in the human fetus and in the newborn infant. In: Morselli PL, Cohen SN, ed. Drug interactions, New York: Raven Press; 1974:320.

Morselli, 1976. Morselli PL: Clinical pharmacokinetics in neonates. Clin Pharmacokinet 1976; 1:81-98.

Morton, 2000. Morton NS: Editorial. II. Ropivacaine in children. Br J Anaesth 2000; 85:344-346.

Muenster, 1967. Muenster JJ, et al: Comparison between diazepam and sodium thiopental during D.C. countershock. JAMA 1967; 199:758.

Mulla et al., 2003. Mulla H, McCormack P, Lawson G, et al: Pharmacokinetics of midazolam in neonates undergoing extracorporeal membrane oxygenation. Anesthesiology 2003; 99:275.

Munro et al., 1994. Munro HM, Riegger LQ, Reynolds PI, et al: Comparison of the analgesic and emetic properties of ketorolac and morphine for paediatric outpatient strabismus surgery. Br J Anaesth 1994; 71:624-628.

Murat et al., 1988. Murat I, Levron J-C, Berg A: Effects of fentanyl on baroreceptor reflex control of heart rate in newborn infants. Anesthesiology 1988; 68:717.

Murat et al., 1990. Murat I, Hoerter J, Ventura-Clapier R: Developmental changes in effects of halothane and isoflurane on contractile properties of rabbit cardiac skinned fibers. Anesthesiology 1990; 73:137.

Murray et al., 1987. Murray D, Vandewalker G, Matherne GP, et al: Pulsed Doppler and two-dimensional echocardiography: Comparison of halothane and isoflurane on cardiac function in infants and small children. Anesthesiology 1987; 67:211.

Murray et al., 1992. Murray DJ, Forbes RB, Mahoney LT: Comparative hemodynamic depression of halothane versus isoflurane in neonates and infants: An echocardiographic study. Anesth Analg 1992; 74:329.

Murray et al., 1999. Murray JM, Renfrew CW, Bedi A, et al: Amsorb: A new carbon dioxide absorbent for use in anesthetic breathing systems. Anesthesiology 1999; 91:1342.

Murray, 1984. Murray JP, et al: Hemodynamic effects of ketamine in children with congenital heart disease. Anesth Analg 1984; 63:895.

Murthy et al., 2000. Murthy BVS, Pandya KS, Booker PD, et al: Pharmacokinetics of tramadol in children after IV or caudal epidural administration. Br J Anaesth 2000; 84:346-349.

Naguib et al., 2002. Naguib M, Flood P, McArdle JJ, et al: Advances in neurobiology of the neuromuscular junction. Anesthesiology 2002; 96:202-231.

Naguib et al., 1998. Naguib M, Samarkandi AH, Ammar A, et al: Comparative clinical pharmacology of rocuronium, cis-atracurium, and their combination. Anesthesiology 1998; 89:1116-1124.

Naguib et al., 1997. Naguib M, Samarkandi AH, Ammar A, et al: Comparison of suxamethonium and different combinations of rocuronium and mivacurium for rapid tracheal intubation in children. Br J Anaesth 1997; 79:450-455.

Naguib, 1994. Naguib M: Neuromuscular effects of rocuronium bromide and mivacurium chloride administered alone and in combination. Anesthesiology 1994; 91:388-395.

Neill and Chapple, 1983. Neill EAM, Chapple DJ: Metabolic studies in the cat with atracurium: neuromuscular blocking agent designed for non-enzymatic inactivation at physiological pH. Xenobiotica 1983; 12:203.

Ng et al., 1981. Ng PK, Cote J, Schiff D, et al: Renal clearance of digoxin in premature neonates. Res Commun Chem Pathol Pharmacol 1981; 34:207-216.

Nguyen et al., 2003. Nguyen TTS, Vecchierini MF, Debillon T, Pereon Y: Effects of sufentanil on electroencephalogram in very and extremely peterm neonates. Pediatrics 2003; 11:123-128.

Nichols et al., 1993. Nichols DG, Yaster M, Lynn AM: Disposition and respiratory effects of intrathecal morphine in children. Anesthesiology 1993; 79:733.

Nightingale and Bush, 1983. Nightingale DA, Bush GH: Atracurium in paediatric anesthesia. Br J Anaesth 1983; 55:115S.

Nightingale and Lewis, 1992. Nightingale JJ, Lewis IH: Recovery from day-case anesthesia. Br J Anaesth 1992; 68:356.

Nordberg et al., 1984. Nordberg G, Hedner T, Mellstrand T: Pharmacokinetic aspects of intrathecal morphine analgesia. Anesthesiology 1984; 60:448.

Ogawa, 1991. Ogawa M, et al: Drug-induced hepatitis following sevoflurane anesthesia in a child. Masui 1991; 40:1952.

O'Kelly et al., 1994. O'Kelly B, Fiset P, Meistelman C, et al: Pharmacokinetics of rocuronium in pediatric patients. Eur J Anesth Suppl 1994; 9:57-58.

Olkkola and Maunuksela, 1991. Olkkola KT, Maunuksela EL: The pharmacokinetics of postoperative intravenous ketorolac tromethamine in children. Br J Clin Pharmac 1991; 31:182-184.

Olutoye et al., 2003. Olutoye O, Jantzen EC, Alexis R, et al: A comparison of the costs and efficacy of ondansetron and dolasetron in the prophylaxis of postoperative vomiting in pediatric patients undergoing ambulatory surgery. Anesth Analg 2003; 97:390-396.

Osbourne et al., 1993. Osbourne R, Joel S, Grebenik K: The pharmacokinetics of morphine and morphine glucuronides in kidney failure. Clin Pharmacol Ther 1993; 54:158.

Ostergaard et al., 2002. Ostergaard D, Gatke MR, Rasmussen BH, et al: The pharmacodynamics and pharmacokinetics of mivacurium in children. Acta Anaesthesiol Scand 2002; 46:512-518.

Ostergaard et al., 2000. Ostergaard D, Rasmussen SN, Vib-Mogensen J, et al: The influence of drug-induced low butyryl cholinesterase activity on the pharmacokinetics and pharmacodynamics of mivacurium. Anesthesiology 2000; 92:1581-1587.

Ozcengiz et al., 2001. Ozcengiz D, Gunduz M, Ozbek H, et al: Comparison of caudal morphine and tramadol for postoperative pain control in children undergoing inguinal herniorrhaphy. Paediatr Anaesth 2001; 11:459-464.

Palmisano et al., 1994. Palmisano BW, Mehner RW, Stowe DF, et al: Direct myocardial effects of halothane and isoflurane. Anesthesiology 1994; 81:718.

Palmisano et al., 1991. Palmisano BW, Setlock MA, Brown MP, et al: Dose-response for atropine and heart rate in infants and children anesthetized with halothane and nitrous oxide. Anesthesiology 1991; 75:238-242.

Pandit et al., 2001. Pandit UA, Collier PJ, Malviya S, et al: Oral transmucosal midazolam premedication for preschool children. Can J Anesth 2001; 48:191-195.

Park et al., 2000. Park JM, Houck CS, Sethna NF, et al: Ketorolac suppresses postoperative bladder spasms after pediatric ureteral reimplantation. Anesth Analg 2000; 91:11-15.

Parker et al., 1988. Parker CJR, Jones JE, Hunter JM: Disposition of atracurium and its metabolite, laudanosine, in patients in renal and respiratory failure in an ITU. Br J Anaesth 1988; 61:531.

Patel et al., 1997. Patel RI, Davis PJ, Orr RJ, et al: Single-dose ondansetron prevents postoperative vomiting in pediatric outpatients. Anesth Analg 1997; 85:538-545.

Patwardhan, 1981. Patwardhan RV, et al: Normal metabolism of morphine in cirrhosis. Gastroenterology 1981; 81:1006.

Paul et al., 2002. Paul M, Folt DM, Kindler CH, et al: Characterization of the interactions between volatile anesthetics and neuromuscular blockers at the muscle nicotinic acetylcholine receptor. Anesth Analg 2002; 95:362-367.

Paul et al., 2002. Paul M, Kindler CH, Fokt RM, et al: The potency of new muscle relaxants on recombinant muscle-type acetylcholine receptors. Anesth Analg 2002; 94:597-603.

Pavlin et al., 1989. Pavlin EG, Halle RH, Schaene R: Recovery of airway protection compared with ventilation in humans after paralysis with curare. Anesthesiology 1989; 70:381.

Payne, 1989. Payne K, et al: The pharmacokinetics of midazolam in paediatric patients. Eur J Clin Pharmacol 1989; 37:267.

Pedersen and Cohen, 1990. Pedersen SE, Cohen JB: d-Tubocurarine binding sites are located at alpha-gamma and alpha-delta subunit interfaces of the nicotinic acetylcholine receptor. Proc Natl Acad Sci USA 1990; 87:2785.

Pirat et al., 2002. Pirat A, Akpek E, Arslan G: Intrathecal versus IV fentanyl in pediatric cardiac anesthesia. Anesth Analg 2002; 95:1207-1214.

Pittet et al., 1989. Pittet JF, Tassonyi E, Morel DR, et al: Pipecuronium-induced neuromuscular blockade during nitrous oxide-fentanyl, isoflurane, and halothane anesthesia in adults and children. Anesthesiology 1989; 71:210.

Plaud et al., 1996. Plaud B, Debaine B, Lequean F, et al: Mivarcurium neuromuscular block at the adductor muscles of the larynx and adductor pollicis in humans. Anesthesiology 1996; 85:77-81.

Plumley et al., 1990. Plumley MH, Bevan JC, Saddler JM, et al: Dose-related effects of succinylcholine on the adductor pollicis and masseter muscles in children. Can J Anaesth 1990; 37:15.

Pokela et al., 1992. Pokela M-L, Ryhanen PT, Koivisto ME: Alfentanil-induced rigidity in newborn infants. Anesth Analg 1992; 75:252.

Prielipp et al., 1995. Prielipp RC, Coursin DB, Scuderi PE, et al: Comparison of the infusion requirements and recovery profiles of vecuronium and cisatracurium 51W89 in intensive care unit patients. Crit Care Trauma 1995; 81:3.

Priest, 1960. Priest JH: Atropine response of the eyes to mongolism. Am J Dis Child 1960; 100:869.

Prince and Since, 1998. Prince RJ, Since SM: The ligand binding domains of the nicotinic acetylcholine receptor. In: Barrantes FJ, ed. The nicotinic acetylcholine receptor: Current views and future trends, Berlin/New York: Springer-Verlag; 1998.

Rackow et al., 1961. Rackow H, Salinitre E, Green LT: Frequency of cardiac arrest associated with anesthesia in infants and children. Pediatrics 1961; 28:697.

Radney and Badola, 1973. Radney PA, Badola RP: Generalized extensor spasm in infants following ketamine anesthesia. Anesthesiology 1973; 39:459.

Rane, 1999. Rane A: Phenotyping of drug metabolism in infants and children: Potentials and problems. Pediatrics 1999; 104:640-645.

Rao, 1986. Rao CC, et al: Increased sensitivity of the isometric contraction of the neonatal isolated rat atria to halothane, isoflurane, and enflurane. Anesthesiology 1986; 64:13.

Rautoma et al., 1995a. Rautoma P, Erkola O, Meretoja OA: Potency and maintenance requirement of atracurium and vecuronium given alone or together. Acta Anaesthesiol Scand 1995; 39:220-223.

Rautoma et al., 1995b. Rautoma P, Erkola O, Meretoja OA: Synergism between mivacurium and pancuronium in adults. Acta Anaesthesiol Scand 1995; 39:733-737.

Reed et al., 2001. Reed MD, Rodarte A, Blumer JL, et al: The single-dose pharmacokinetics of midazolam and its primary metabolite in pediatric patients after oral and intravenous administration. J Clin Pharmacol 2001; 41:1359-1369.

Reeves et al., 1979. Reeves J, Samuelson P, Lewis S: Midazolam maleate induction in patients with ischemic heart disease: Hemodynamic observation. Can Anaesth Soc J 1979; 26:402.

Reimer et al., 1993. Reimer EJ, Montgomery CJ, Bevan JC: Propofol anaesthesia reduces early postoperative emesis after paediatric strabismus surgery. Can J Anaesth 1993; 40:927.

Reich et al., October 2002. Reich DL, Hollinger I, Harrington DJ, et al: Pharmacokinetic comparison of cisatracurium and vecuronium infusions in neonates and infants following congenital heart surgery. Anesthesiology October 2002;

Reves et al., 2000. Reves JG, Glass PSA, Lubarsky DA: Non-barbiturate intravenous anesthetics. In: Miller RD, ed. Anesthesia, 5th ed.. New York: Churchill Livingstone; 2000:228-272.

Reynolds and Koh, 1993. Reynolds LM, Koh JL: Prolonged spontaneous movement following emergence from propofol/nitrous oxide anesthesia. Anesth Analg 1993; 76:192.

Reynolds, 1962. Reynolds RN: Halothane in pediatric anesthesia. Int Anesthesiol Clin 1962; 1:209.

Roald and Dohl, 1989. Roald OK, Dohl V: Flunitrazepam intoxication in a child successfully treated with the benzodiazepine antagonist flumazenil. Crit Care Med 1989; 17:1355.

Rocari et al., 1986. Rocari G, Ziegler WH, Guentert TW: Pharmacokinetics of the new benzodiazepine antagonist Ro 15–788 in man following intravenous and oral administration. Br J Clin Pharmacol 1986; 22:421.

Roerig et al., 1987. Roerig DL, Kotrly KJ, Vucins EJ: First pass uptake of fentanyl, meperidine, and morphine in the human lung. Anesthesiology 1987; 67:466.

Romberg et al., 2004. Romberg R, Olofsen E, Sarton E, et al: Pharmacokinetic-pharmacodynamic modeling of morphine-6-glucuronide-induced analgesia in healthy volunteers: Absence of sex differences. Anesthesiology 2004; 100:120.

Romberg et al., 2005. Romberg RR, Olofsen E, Bijl H, et al: Polymorphism of mu-opioid receptor gene (OPRM1:c.118A>G) does not protect against opioid-induced respiratory depression despite reduced analgesic response. Anesthesiology 2005; 102:522.

Rose et al., 2003. Rose JB, Finkel JC, Arquedas-Mohs A, et al: Oral tramadol for the treatment of pain of 7–30 days' duration in children. Anesth Analg 2003; 96:78-81.

Rosen and Rosen, 1991. Rosen DA, Rosen KR: Midazolam for sedation in the pediatric intensive care unit. Intens Care Med 1991; 17(Suppl 1):515.

Rosenberg and Gronert, 1992. Rosenberg H, Gronert GA: Intractable cardiac arrest in children given succinylcholine. Anesthesiology 1992; 77:1054.

Rosow et al., 1983. Rosow C, Philbin D, Moss J, et al: Sufentanil vs. fentanyl: I Suppression of hemodynamic responses. Anesthesiology 1983; 59:A323.

Rosow et al., 1984. Rosow CE, Philbin DM, Keegan CR, Moss J: Hemodynamics and histamine release during induction with sufentanil or fentanyl. Anesthesiology 1984; 60:489.

Ross and Davis, 2001. Ross AK, Davis PJ, et al: Pharmacokinetics of remifentanil in anesthetized pediatric patients undergoing elective surgery or diagnostic procedures. Anesth Analg 2001; 93:1392-1401.

Roure et al., 1987. Roure P, Jean N, Leclerc A-C, et al: Pharmacokinetics of alfentanil in children undergoing surgery. Br J Anaesth 1987; 59:1437.

Rowland et al., 1995. Rowland AS, Baird DD, Shore DL, et al: Nitrous oxide and spontaneous abortion in female dental assistants. Am J Epidemiol 1995; 141:531-538.

Rubin et al., 1949. Rubin M, Bruck E, Rapoport M: Maturation of renal function in childhood: Clearance studies. J Clin Invest 1949; 28:1144-1162.

Rupp, 1987. Rupp SM: Muscle relaxants and the patient with renal and/or hepatic failure. In: Azar I, ed. Muscle relaxants, New York: Dekker; 1987.

Russell et al., 2001. Russell IA, Miller Hance WC, Gregory G, et al: The safety and efficacy of sevoflurane anesthesia in infants and children with congenital heart disease. Anesth Analg 2001; 92:1152-1158.

Saarenmaa et al., 2000. Saarenmaa E, Neuvonen P, Fellman V: Gestational age and birth weight effects on plasma clearance of fentanyl in newborn infants. J Pediatr 2000; 136:767-770.

Sadler, 1990. Sadler JM, et al: Jaw tension after succinylcholine in children undergoing strabismus surgery. Can J Anaesth 1990; 37:21.

Saidman and Eger, 1966. Saidman LJ, Eger II EI: The effect of thiopental metabolism on duration of anesthesia. Anesthesiology 1966; 27:118.

Saint-Maurice, 1989. Saint-Maurice C, et al: Pharmacokinetics of propofol in young children after a single dose. Br J Anaesth 1989; 63:667.

Saint-Maurice, 1986. Saint-Maurice C, et al: The pharmacokinetics of rectal midazolam for premedication in children. Anesthesiology 1986; 65:536.

Salanitre and Rackow, 1969. Salanitre E, Rackow H: The pulmonary exchange of nitrous oxide and halothane in infants and children. Anesthesiology 1969; 30:388.

Salem et al., 1972. Salem MR, Wong AY, Lin YH: The effect of suxamethonium on the intragastric pressure in infants and children. Br J Anaesth 1972; 44:166.

Salonen et al., 1987. Salonen M, Kanto J, Iisalo E: Midazolam as an induction agent in children. Anesth Analg 1987; 66:625.

Sanes and Lichtman, 1999. Sanes JR, Lichtman JW: Development of vertebrate neuromuscular junction. Annu Rev Neurosci 1999; 22:389-442.

Santeiro et al., 1997. Santeiro ML, Christie J, Stromquist C, et al: Pharmacokinetics of continuous infusion fentanyl in newborns. J Perinatol 1997; 17:135-139.

Sarkar et al., 2005. Sarkar M, Laussen PC, Zurakowski D, et al: Hemodynamic responses of etomidate on induction of anesthesia in pediatric patients. Anesth Analg 2005;(in press).

Sarner et al., 1988. Sarner JB, Brandom BW, Cook DR, et al: Clinical pharmacology of doxacurium chloride (BW A938U) in children. Anesth Analg 1988; 67:303-306.

Sarner et al., 1990. Sarner JB, Brandom BW, Dong ML, et al: Clinical pharmacology of pipecuronium in infants and children during halothane anesthesia. Anesth Analg 1990; 71:362.

Satwicz et al., 1984. Satwicz PR, Martyn JA, Szyfelbein SF, et al: Potentiation of neuromuscular blockade using a combination of pancuronium and dimethyltubocurarine. Studies in children following acute burn injury or during reconstructive surgery. Br J Anaesth 1984; 56:479-484.

Savage et al., 1980. Savage DS, Sleigh T, Carlyle I: The emergence of ORG NC 45 from the pancuronium series. Br J Anaesth 1980; 52:3S.

Scholz et al., 1994. Scholz J, Bause H, Schulz M, et al: Pharmacokinetics and effects on intracranial pressure of sufentanil in head trauma patients. Br J Clin Pharmacol 1994; 38:369-372.

Scholz et al., 1996. Scholz J, Steinfath M, Shultz M: Clinical pharmacokinetics of alfentanil, fentanyl and sufentanil. An update. Clin Pharmacokinet 1996; 31:275-292.

Schow et al., 2002. Schow AJ, Lubarsky DA, Olson RP, et al: Can succinylcholine be used safely in hyperkalemic patients?. Anesth Analg 2002; 95:119-122.

Schraag et al., 1999. Schraag S, Checketts MR, Kenny GN: Lack of rapid development of opioid tolerance during alfentanil and remifentanil infusions for postoperative pain. Anesth Analg 1999; 89:753-757.

Schwartz et al., 1984. Schwartz L, Rockoff MA, Koka BV: Masseter spasm with anesthesia: incidence and implications. Anesthesiology 1984; 61:772.

Schwartz, 1974. Schwartz MS, et al: Effects of ketamine on the electroencephalograph. Anaesthesia 1974; 29:135.

Scott and Perry, 2000. Scott LJ, Perry CM: Tramadol. A review of its use in perioperative pain. Drugs 2000; 60:139-176.

Sebel and Bovill, 1982. Sebel P, Bovill J: Cardiovascular effects of sufentanil anesthesia. Anesth Analg 1982; 61:115.

Segredo et al., 1992. Segredo V, Caldwell JE, Matthay MA, et al: Persistent paralysis in critically ill patients after long-term administration of vecuronium. N Engl J Med 1992; 327:524.

Serlin, 2004. Serlin S: Dexmedetomidine in pediatrics: controlled studies needed. Anesth Analg 2004; 98:1814.

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

Shafer and Varvel, 1991. Shafer SL, Varvel JR: Pharmacokinetics, pharmacodynamics and rational opioid selection. Anesthesiology 1991; 74:53-63.

Shannon et al., 1997. Shannon M, Albers G, Burkhart K: Safety and efficacy of flumazenil in the reversal of benzodiazepine-induced conscious sedation. The Flumazenil Pediatric Study Group. J Pediatr 1997; 131:582-586.

Shear, 1981. Shear CR: Effects of disuse on growing and adult chick skeletal muscle. J Cell Sci 1981; 48:35.

Shi et al., 1985. Shi WZ, Fahey MR, Fisher DM, et al: Laudanozine (a metabolite of atracurium) increases the minimum alveolar concentration of halothane in rabbits. Anesthesiology 1985; 63:584.

Short et al., 1994. Short TC, Aun CS, Tan P: A prospective evaluation of pharmacokinetic model controlled infusion of propofol in pediatric patients. Br J Anesth 1994; 72:302-306.

Sikich and Lerman, 2004. Sikich N, Lerman J: Development and psychometric evaluation of the pediatric anesthesia emergence delirium scale. Anesthesiology 2004; 100:1138-1145.

Simhi et al., 1997. Simhi E, Brandom BW, Lloyd ME, Woelfel SK: Administration of atropine and onset of neuromuscular block produced by atracurium in infants. Paediatr Anaesth 1997; 7:375-378.

Simons et al., 1996. Simons FE, Fraser TG, Reggin JD, et al: Adverse central nervous system effects of older antihistamines in children. Pediatr Allergy Immunol 1996; 7:22-27.

Singleton et al., 1987. Singleton MA, Rosen JI, Fisher DM: Plasma concentrations of fentanyl in infants, children and adults. Can J Anaesth 1987; 34:152.

Skovsted et al., 1969. Skovsted P, Price ML, Price HL: The effects of halothane on arterial pressure, preganglionic sympathetic activity and barostatic reflexes. Anesthesiology 1969; 31:507.

Smiley et al., 1991. Smiley RM, Ornstein E, Pantuck EJ, et al: Metabolism of desflurane and isoflurane to fluoride ion in surgical patients. Can J Anaesth 1991; 38:965.

Smith and Nelson, 1976. Smith CA, Nelson NM: The physiology of the newborn infant, ed 4. Springfield, IL: Charles C Thomas, Publisher; 1976:179.

Smith et al., 1981. Smith M, Eadie M, Brophy T: The pharmacokinetics of midazolam in man. Eur J Clin Pharmacol 1981; 19:271.

Smith et al., 1955. Smith RM, Bachman L, Bougas T: Shivering following thiopental sodium and other anesthetic agents. Anesthesiology 1955; 16:655.

Sorbo et al., 1984. Sorbo RM, Hudson RJ, Loomis JC: The pharmacokinetics of thiopental in pediatric surgical patients. Anesthesiology 1984; 61:666.

Spahr-Schopfer et al., 1995. Spahr-Schopfer IA, Lerman J, Sikich N, et al: Pharmacokinetics of intravenous ondansetron in healthy children undergoing ear, nose and throat surgery. Clin Pharmacol Ther 1995; 58:316-321.

Spear et al., 1991. Spear RM, Yaster M, Berkowitz ID: Preinduction of anesthesia in children with rectally administered midazolam. Anesthesiology 1991; 74:670.

Splinter and Rhine, 1998. Splinter WM, Rhine EJ: Low-dose ondansetron with dexamethasone more effectively decreases vomiting after strabismus surgery in children than does high-dose ondansetron. Anesthesiology 1998; 88:72-75.

Stanley et al., 1983. Stanley T, Pace N, Liu W, et al: Alfentanil-N2O vs fentanyl-N2O balanced anesthesia: Comparison of plasma hormonal changes, early postoperative respiratory function and speed of postoperative recovery. Anesth Analg 1983; 62:285.

Steward and Creighton, 1978. Steward DJ, Creighton RE: The uptake and excretion of nitrous oxide in the newborn. Can Anaesth Soc J 1978; 25:215.

Stiller et al., 1985a. Stiller RL, Brandom BW, Cook DR: Determination of atracurium by high-performance liquid chromatography. Anesth Analg 1985; 64:58.

Stiller et al., 1985b. Stiller RL, Cook DR, Chakravorti S: In vitro degradation of atracurium in human plasma. Br J Anaesth 1985; 57:1085.

Stoelting and Longnecker, 1972. Stoelting RK, Longnecker DE: The effect of right-to-left shunt on the rate of increase of arterial anesthetic concentration. Anesthesiology 1972; 36:352.

Stokes and Hutton, 1991. Stokes DN, Hutton P: Rate-dependent induction phenomena with propofol: Implications for the relative potency of intravenous anesthetics. Anesth Analg 1991; 72:578.

Streisand et al., 1991. Streisand JB, Varvel JR, Stanski DR: Absorption and bioavailability of oral transmucosal fentanyl citrate. Anesthesiology 1991; 72:223.

Sukhani et al., 2002. Sukhani R, Pappas AL, Lurie J, et al: Ondansetron and dolasetron provide equivalent postoperative vomiting control after ambulatory tonsillectomy in dexamethasone-pretreated children. Anesth Analg 2002; 95:1230-1235.

Sullivan et al., 1997. Sullivan KJ, Berman LS, Koska J, et al: Intramuscular atropine sulfate in children: Comparison of injection sites. Anesth Analg 1997; 84:54-58.

Sury et al., 1989. Sury MRJ, Billingham I, Russell GN: Acute benzodiazepine withdrawal syndromes after midazolam infusions in children (letter). Crit Care Med 1989; 17:301.

Sutherland et al., 1980. Sutherland GA, Bevan JC, Bevan DR: Neuromuscular blockade in infants following intramuscular succinylcholine in two or five percent solution. Can J Anaesth 1980; 30:342.

Sweetland et al., 1992. Sweetland J, Lettis S, Fowler PA, et al: Duration of the inhibitory effect of intravenous ondansetron on intradermal 5-HT-induced flare. Br J Clin Pharmacol 1992; 33:565P.

Taivainen et al., 2000. Taivainen T, Meakin GH, Meretoja OA, et al: The safety and efficacy of cisatracurium 0.15 mg.kg(-1) during nitrous oxide-opioid anaesthesia in infants and children. Anaesthesia 2000; 55:1047.

Tang et al., 1992. Tang TT, Oechler HW, Siker D, et al: Anesthesia-induced rhabdomyolysis in infants with unsuspected Duchenne dystrophy. Acta Paediatr 1992; 81:716-719.

Tanner et al., 1985. Tanner GE, Angers DG, Barash PG, et al: Effect of left-to-right, mixed left-to-right, and right-to-left shunts on inhalational anesthetic induction in children: a computer model. Anesth Analg 1985; 64:101.

Taylor, 1985. Taylor P: Are neuromuscular blocking agents more efficacious in pairs?. Anesthesiology 1985; 63:1.

Taylor and Lerman, 1992. Taylor RH, Lerman J: Induction and recovery characteristics for desflurane in children. Can J Anaesth 1992; 39:6.

Taylor and Lerman, 1991. Taylor RH, Lerman J: Minimum alveolar concentration (MAC) of desflurane and hemodynamic responses in neonates, infants and children. Anesthesiology 1991; 75:975.

Thummel et al., 1996. Thummel KE, O'Shea D, Paine MF, et al: Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A-mediated metabolism. Clin Pharmacol Ther 1996; 59:491-502.

Tobias and Berkenbosch, 1997. Tobias JD, Berkenbosch JW: Sedation during mechanical ventilation in infants and children: Dexmedetomidine versus midazolam. South Med J 1997; 97(5):451-455.

Tobias et al., 2003. Tobias JD, Berkenbosch JW, Russo P: Additional experience with dexmedetomidine in pediatric patients. South Med J 2003; 96:871-875.

Tobias et al., 2001. Tobias JD, Johnson JO, Sprague K, et al: Effects of rapacuronium on respiratory function during general anesthesia. Anesthesiology 2001; 95:908-912.

Tobias et al., 1995. Tobias JD, Lynch A, McDuffee A, et al: Pancuronium infusion for neuromuscular block in children in the pediatric intensive care unit. Anesth Analg 1995; 81:13.

Traber et al., 1970. Traber DL, Wilson RD, Priano LL: Blockade of the hypertensive response to ketamine. Anesth Analg (Cleve) 1970; 49:420.

Treluyer et al., 1991. Treluyer JM, Jacqz-Aigrain E, Alvarez F, et al: Expression of CYP2D6 in developing human liver. Eur J Biochem 1991; 202:583-588.

Trindle et al., 1993. Trindle MR, Dodson BA, Rampil IJ: Effects of fentanyl versus sufentanil in equianesthetic doses on middle cerebral artery blood flow velocity. Anesthesiology 1993; 78:454.

Tullock et al., 1990. Tullock WC, Diana P, Cook DR, et al: Neuromuscular and cardiovascular effects of high-dose vecuronium. Anesth Analg 1990; 70:80-90.

Turan et al., 2003. Turan A, Memis D, Basaran UN, et al: Caudal ropivacaine and neostigmine in pediatric surgery. Anesthesiology 2003; 98:719-722.

Twersky et al., 1993. Twersky RS, Hartung J, Berger BJ: Midazolam enhances anterograde but not retrograde amnesia in pediatric patients. Anesthesiology 1993; 78:51.

Urgureanu et al., 1993. Urgureanu D, Meistelman C, Frossard J, et al: The arbicularis oculi and the adductor pollicis muscles as monitors of atracurium block of laryngeal muscles. Anesth Analg 1993; 77:775-779.

Vakkuri et al., 2001. Vakkuri A, Yli-Hankala A, Sarkela M, et al: Sevoflurane mask induction of anaesthesia is associated with epileptiform EEG in children. Acta Anaesthesiol Scand 2001; 45:805-811.

Valtonen et al., 1989. Valtonen M, Iisalo E, Kanto J: Propofol as an induction agent in children: Pain on injection and pharmacokinetics. Acta Anaesthesiol Scand 1989; 33:152.

Van der Spek et al., 1988. Van der Spek AF, Fang WB, Ashton-Miller JA, et al: Increased masticatory muscle stiffness during limb muscle flaccidity associated with succinylcholine administration. Anesthesiology 1988; 69:11.

Van der Spek et al., 1989. Van der Spek AF, Reynolds PI, Ashton-Miller JA, et al: Differing effect of agonist and antagonist muscle relaxants on cat jaw muscles. Anesth Analg 1989; 69:76.

Versichelen et al., 2001. Versichelen LFM, Bouche M-PLA, Georges R, et al: Only carbon dioxide absorbents free of both NaOH and KOH do not generate compound A during in vitro closed-system sevoflurane evaluation of five absorbents. Anesthesiology 2001; 95:750-755.

Viby-Mogensen et al., 1985. Viby-Mogensen J, Jensen NH, Engbaek J, et al: Tactile and visual evaluation of the response to train-of-four stimulation. Anesthesiology 1985; 63:440.

Viby-Mogensen, 1993. Viby-Mogensen J: Monitoring neuromuscular function in the intensive care unit. Intensive Care Med 1993; 19(Suppl):S74.

Viitanen and Annila, 2001. Viitanen H, Annila P: Analgesic efficacy of tramadol 2 mg kg-1 for paediatric day-case adenoidectomy. Br J Anaesth 2001; 86:572-575.

Viitanen et al., 1999. Viitanen H, Annila P, Viitanen M, et al: Premedication with midazolam delays recovery after ambulatory sevoflurane anesthesia in children. Anesth Analg 1999; 89:75-79.

Vinik and Kissin, 1998. Vinik HR, Kissin I: Rapid development of tolerance to analgesia during remifentanil infusion in humans. Anesth Analg 1998; 86:1307-1311.

Wagner et al., 1984. Wagner R, White P, Kan P, et al: Inhibition of adrenal steroidogenesis by the anesthetic etomidate. N Engl J Med 1984; 310:1415.

Wagner and White, 1984. Wagner R, White P: Etomidate inhibits adrenocortical function in surgical patients. Anesthesiology 1984; 61:647.

Walbergh et al., 1991. Walbergh EJ, Wills RJ, Eckhert J: Plasma concentrations of midazolam in children following intranasal administration. Anesthesiology 1991; 74:233.

Wallace, 1977. Wallace S: Altered plasma albumin in the newborn infant. Br J Clin Pharmacol 1977; 4:83-85.

Ward and Neil, 1983. Ward S, Neil EAM: Pharmacokinetics of atracurium in acute hepatic failure (with acute renal failure). Br J Anaesth 1983; 55:1169.

Wareham et al., 1994. Wareham AC, Morton RH, Meakin GH: Low quantal content of the endplate potential reduces safety factor for neuromuscular transmission in the diaphragm of the newborn rat. Br J Anaesth 1994; 72:205-209.

Watanabe et al., 1993. Watanabe K, Hatakenaka S, Ikemune K, et al: A case of suspected liver dysfunction induced by sevoflurane anesthesia. Masui 1993; 42:902.

Watcha et al., 1991. Watcha MF, Simeon RM, White PF: Effect of propofol on the incidence of postoperative vomiting after strabismus surgery in pediatric outpatients. Anesthesiology 1991; 75:204.

Watling and Dasta, 1994. Watling SM, Dasta JF: Prolonged paralysis in intensive care unit patients after the use of neuromuscular blocking agents: A review of the literature. Crit Care Med 1994; 22:884.

Way et al., 1965. Way WL, Costley EC, Way EL: Respiratory sensitivity of the newborn infant to meperidine and morphine. Clin Pharmacol Ther 1965; 6:454.

Weatherall, 1960. Weatherall JA: Anaesthesia in newborn animals. Br J Pharmacol 1960; 15:454.

Wedel et al., 1993. Wedel DJ, Gammel SA, Milde JH, et al: Delayed onset of malignant hyperthermia induced by isoflurane and desflurane compared with halothane in susceptible swine. Anesthesiology 1993; 78:1138.

Wee and Stokes, 1999. Wee L, Stokes MA: Bladder extrophy in a neonate at risk of transient myasthenia gravis: A role for remifentanil and epidural analgesia. Br J Anaesth 1999; 82:774-776.

Weil et al., 1993. Weil PM, Munro HM, Reynolds PI: Propofol infusion and the incidence of emesis in pediatric outpatient strabismus surgery. Anesth Analg 1993; 76:760.

Welch et al., 1995. Welch RM, Brown A, Ravitch J, et al: The in vitro degradation of cisatracurium, the R, cis-R′-isomer of atracurium, in human and rat plasma. Clin Pharmacol Ther 1995; 58:132.

Weldon et al., 1992. Weldon BC, Watcha MF, White PF: Oral midazolam in children: Effect of time and adjunctive therapy. Anesth Analg 1992; 75:51.

Westmoreland et al., 1993. Westmoreland CL, Hoke JF, Sebel PS: Pharmacokinetics of remifentanil (GI87084B) and its major metabolite (GI90291) in patients undergoing elective inpatient surgery. Anesthesiology 1993; 9:893.

Westrin, 1991. Westrin P: The induction dose of propofol in infants 1–6 months of age and in children 16 years of age. Anesthesiology 1991; 74:455.

Westrin, 1992. Westrin P: Methohexital dissolved in lipid emulsion for intravenous induction of anesthesia in infants and children. Anesthesiology 1992; 76:917-921.

Westrin et al., 1989. Westrin P, Jonmarker C, Werner O: Thiopental requirements for induction of anesthesia in neonates and infants one to six months of age. Anesthesiology 1989; 71:344.

White et al., 1980. White PF, Ham J, Way WL, Trevor AJ: Pharmacology of ketamine isomers in surgical patients. Anesthesiology 1980; 52:231.

Widdowson, 1974. Widdowson EM: Changes in body proportions and composite during growth. In: Davis JA, Dobbing J, ed. Scientific foundations of pediatrics, Philadelphia: WB Saunders Co; 1974:153.

Wiest et al., 1991. Wiest DB, Oyning BL, Garner SS: The disposition of alfentanil in neonates with respiratory distress. Pharmacotherapy 1991; 11:308.

Wilson et al., 1970. Wilson RD, Traber DL, Evans BL: Correlation of psychologic and physiologic observations from children undergoing repeated ketamine anesthesia. Anesth Analg (Cleve) 1970; 48:995.

Wilson-Smith et al., 2003. Wilson-Smith E, Karsli C, Luginbuehl IA, et al: The effect of nitrous oxide on cerebral blood flow velocity in children anesthetized with propofol. Acta Anaesthesiol Scand 2003; 47:307-311.

Wilton et al., 1988. Wilton NCT, Leigh J, Rosen DR: Preanesthetic sedation of preschool children using intranasal midazolam. Anesthesiology 1988; 69:972.

Wissing et al., 2001. Wissing H, Kuhn I, Warnken U, et al: Carbon monoxide production from desflurane, enflurane, halothane, isoflurane and sevoflurane in dry soda lime. Anesthesiology 2001; 95:1205-1212.

Woelfel et al., 1992. Woelfel SK, Brandom BW, Cook DR, et al: Effects of bolus administration of ORG-9426 in children during nitrous oxide-halothane anesthesia. Anesthesiology 1992; 76:939.

Woelfel et al., 1993. Woelfel SK, Brandom BW, McGowan FX, et al: Clinical pharmacology of mivacurium in pediatric patients less than two years old during nitrous oxide-halothane anesthesia. Anesth Analg 1993; 77:713.

Wulf et al., 2000. Wulf H, Peters C, Behnke H: The pharmacokinetics of caudal ropivacaine 0.2 in children. Anaesthesia 2000; 55:560-575.

Yang et al., 1994. Yang HY, Lee QP, Rettie AR, et al: Functional cytochrome P4503A isoforms in human embryonic tissues: Expression during organogenesis. Mol Pharmacol 1994; 46:922-928.

Yang et al., 1995. Yang HYL, Namkung MJ, Juchau MR: Expression of functional cytochrome P4501A1 in human embryonic hepatic tissues during organogenesis. Biochem Pharmacol 1995; 49:717-726.

Yaster, 1987. Yaster M: The dose response of fentanyl in neonatal anesthesia. Anesthesiology 1987; 66:433.

Yasuda et al., 1991. Yasuda N, Lockhart SH, Eger II, et al: Kinetics of desflurane, isoflurane, and halothane in humans. Anesthesiology 1991; 74:489.

Yasuda et al., 1989. Yasuda N, Targ AG, Eger II EI: Solubility of I–653, sevoflurane, isoflurane, and halothane in human tissues. Anesth Analg 1989; 69:370.

Yokoyama et al., 1993. Yokoyama H, Iinuma K, Yanai K, et al: Proconvulsant effect of ketotifen, a histamine H1-antagonist, confirmed by the use of d-chlorpheniramine with monitoring electroencephalography. Methods Fundam Exp Clin Pharmacol 1993; 15:183-188.

Yoshikawa and Murai, 1971. Yoshikawa K, Murai Y: The effect of ketamine on intraocular pressure in children. Anesth Analg (Cleve) 1971; 50:199.

Yost and Dodson, 1993. Yost CS, Dodson BA: Inhibition of the nicotinic acetylcholine receptor by barbiturates and by procaine: Do they act at different sites?. Cell Mol Neurobiol 1993; 13:159.

Youngs and Shafer, 1994. Youngs EJ, Shafer SL: Pharmacokinetic parameters relevant to recovery from opioids. Anesthesiology 1994; 81:833-842.

Yun et al., 1992. Yun C-H, Wood M, Wood AJJ, et al: Identification of the pharmacogenetic determinants of alfentanil metabolism: Cytochrome P-450 3A4. Anesthesiology 1992; 77:467.

Zhang and Pasternak, 1981. Zhang AZ, Pasternak GW: Ontogeny of opioid pharmacology and receptors. High and low affinity site differences. Eur J Pharmacol 1981; 73:29.

Zhou et al., 1993. Zhou HH, Sheller JR, Nu H, et al: Ethnic differences in response to morphine. Clin Pharmacol Ther 1993; 54:507.

Zimmerman and Steward, 1986. Zimmerman G, Steward DJ: Bradycardia delays the onset of action of intravenous atropine in infants. Anesthesiology 1986; 65:320.

Zuppa et al., 2003. Zuppa AF, Helfaer MA, Adamson PC: Propofol pharmacokinetics. Pediatr Crit Care Med 2003; 4:124-125.

Zwass et al., 1992. Zwass MS, Fisher DM, Welborn LG, et al: Induction and maintenance characteristics of anesthesia with desflurane and nitrous oxide in infants and children. Anesthesiology 1992; 76:373

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