Intravenous Agents: Brian Blasiole and Peter J. Davis

8
Intravenous Agents
Brian Blasiole and Peter J. Davis
OUTLINE
Introduction, 186 Other Sedative Agents, 191
Barbiturates, 186 Etomidate, 191
Thiopental, 186 Propofol, 192
Methohexital, 187 Ketamine, 194
Pentobarbital, 187 Clonidine, 196
Benzodiazepines and Antagonists, 188 Dexmedetomidine, 197
Diazepam, 188 Summary, 199
Midazolam, 188
Flumazenil, 191
barbiturates develops rapidly and increases 30-fold during the first 3

INTRODUCTION
weeks of life (Brown, Zwelzin, and Burnett 1958). These agents are
Sedative hypnotic agents are an essential element in the care of pedi- used less commonly now because other short-acting sedative-hypnotic
atric patients. These drugs are used as premedicants, induction agents, agents have supplanted the short-acting barbiturates.
and adjuvants for the maintenance of anesthesia or sedation. They are
administered both as sole agents or in combination with other drugs. Thiopental
The multiple indications and routes of administration of intravenous Thiopental is an ultra-short-acting barbiturate used as an intrave-
induction agents require an understanding of the effect of age on the nous induction agent in anesthesia. It is also used in critical care
pharmacokinetics and pharmacodynamics for each of these drugs. settings as a continuous infusion for the treatment of intracranial
hypertension and status epilepticus. Hiccoughs, sneezing, and other
respiratory irregularities are rarely seen on induction, and there is
BARBITURATES no excitement or extrapyramidal activity associated with its use.
The sedative-hypnotic effect of barbiturates is thought to occur mainly It decreases cerebrospinal fluid pressure and intraocular pressure.
through interaction with CNS gamma-aminobutyric acid (GABA) Awakening is quiet, occasionally interrupted by shivering, and is
receptors, which causes a decreased rate of dissociation of the inhibi- associated with a low incidence of nausea (Smith, Bachman, and
tory of the inhibitory neurotransmitter GABA. These agents are Bougas 1955). Porphyria, seldom encountered in the United States,
administered intravenously for induction and maintenance of anesthe- is a specific contraindication to barbiturates (Dundee and Barron
sia, but oral, sublingual, intranasal, rectal, and, less commonly, intra- 1962). Thiopental requirements for induction of anesthesia reveal an
muscular routes are also used. inverse relation with age. Jonmarker and colleagues (1987) reported
Barbiturates have historically been classified as long, intermediate, that the ED50 of thiopental in infants is significantly greater (7 mg/
short, and ultrashort acting. Short-acting barbiturates (e.g., thiopental, kg) than that in adults (4 mg/kg) (Fig. 8-e1) (Table 8-1). Westrin and
methohexital, and pentobarbital) can be used to induce anesthesia in colleagues (1989) studied the dose of thiopental to achieve satisfac-
infants and children. These agents produce rapid induction of hypno- tory induction of 10 healthy, unpremedicated neonates who were
sis with minimal relaxation or analgesia. The pharmacokinetics of zero to 14 days old and 20 infants who were between 1 and 6 months
short-acting barbiturates in infants, children, and adults were studied old. In this study, the ED50 for thiopental induction was 3.4 ±
extensively by Brodie (1952), Dundee and Barron (1962), Mark (1963), 0.2 mg/kg in neonates and 6.3 ± 0.7 mg/kg in infants aged 1 to 6
Saidman and Eger (1966), and Lindsay and Shepherd (1969). The rapid months. In an in vitro study in which the free fraction of thiopental
recovery from a single IV dose of thiopental or methohexital reflects was measured in the serum of neonates and adult volunteers, Kings-
redistribution from the effect site of the brain to inactive tissues ton and colleagues (1990) noted that neonates had a free drug frac-
(Saidman 1974). tion that was 1.5 to 2 times greater than that of adults. After a single
Neonates have a decreased ability to metabolize barbiturates intravenous dose, clinical effect is mainly terminated by redistri
(Mirkin 1975). The longer-acting barbiturates, which are in part bution. When repetitive or larger doses are used, redistribution
excreted unmetabolized in the urine, would be expected to have pro- becomes less effective and metabolism plays a more important role,
longed or elevated blood levels (Knauer, Draffen, and Williams 1973; explaining the shorter recovery times in children when compared
Boreus, Jalling, and Kallberg 1975). Glucuronic acid conjugation of with adults.
186
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CHAPTER 8 Intravenous Agents 186.e1
ED50’ (mg/kg)
5
1–6 6–12 1–4 4–7 7–12 12–16 Age

Months Years
FIG 8-E1 Estimated ED50 ± SD for Thiopental in the Various

Age Groups. (From Jonmarker C, et al. Thiopental requirements for
induction of anesthesia in children. Anesthesiology. 1987;67:104.)
CHAPTER 8 Intravenous Agents 187
TABLE 8-1 Thiopental: Indications, Route TABLE 8-2 Methohexital: Indications,

of Administration, and Dosage Route of Administration, and Dosage
Recommendations Recommendations
Indication Route Dose Indication Route Dose
Induction (neonate) IV 3–4 mg/kg Induction (>1 month and children) IV 1–2 mg/kg (1% solution)
Induction (infants) IV 5–8 mg/kg Induction (>1 month and children) IM 6.6–10 mg/kg (5% solution)
Induction (age 1–12 years) IV 5–6 mg/kg Induction (>1 month and children) PR 25 mg/kg (1% or 10%
Induction (age >12 years) IV 3–5 mg/kg solution)
Sedation (age <6 months) PR 50 mg/kg
From McGhee B, et al. Pediatric drug therapy handbook and
Sedation (age 6–12 months) PR 35 mg/kg
formulary, 6th ed. Department of Pharmacy, Children’s Hospital of
Sedation (age 1–5 years) PR 25 mg/kg Pittsburgh of UPMC; 2011.
Seizures IV 2–3 mg/kg/dose (repeat prn)
Increased ICP IV 1.5–5 mg/kg/dose (repeat prn)

TABLE 8-3 Pentobarbital: Indications,
Pittsburgh of UPMC; 2011. Route of Administration, and Dosage
Reference: Beekman RP, Hoorntye TM, Beek FJA, et al. Sedation for Recommendations
children undergoing magnetic resonance imaging: Efficacy and safety
Indication Route Dose
of rectal thiopental. Eur J Pediatr. 1996;155:820.
Sedation IV 1–3 mg/kg (repeat q 5–10 min
prn)
Sedation IM 2–6 mg/kg (max 100mg/dose)
Methohexital
Barbiturate Coma IV 10–15 mg/kg load over 1–2 hours
Methohexital, a methylated oxybarbiturate, is more potent than thio- (Children and adults) 1–3 mg/kg/hour maintenance for
pental by a ratio of about 3 : 1, more rapidly eliminated, and produces EEG burst suppression
more undesirable side effects (Clarke et al. 1968). Greater speed of
recovery provides its principal indication, especially for outpatient care From McGhee B, et al. Pediatric drug therapy handbook and
or for when a very brief effect is wanted, such as cardioversion or formulary, 6th ed. Department of Pharmacy, Children’s Hospital of
electroconvulsive therapy. Beskow and colleagues (1995) compared Pittsburgh of UPMC; 2011.
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 2004a, 2004b; Table 8-3). The use of pentobarbital for sedation is
after methohexital was significantly shorter than it was for thiopental. waning due to increased adverse effects of vomiting, allergy, and pro-
The incidence of involuntary muscular movement, hiccoughs, and longed recovery when compared with the more favorable profile of
respiratory irregularity during induction is definitely greater with propofol (Mallory et al. 2009). Pentobarbital as a single agent was
methohexital than with thiopental. Methohexital can be administered associated with a longer time to arousal and time to discharge com-
via the intravenous, intramuscular, and rectal routes; however, some pared to propofol when the two drugs were used in a prospective trial
studies suggest that the high concentration of rectal methohexital can for sedation in MRI (Bloomfield et al. 1993). Pershad and colleagues
cause mucosal damage (Miller, Stoelting, and Dann 1961). (2007) found that propofol alone for MRI sedation resulted in faster
Forbes and colleagues (1989a) reported on the plasma concentra- onset and recovery time compared to a pentobarbital-based regimen
tions of 60 children after doses of 15, 20, 25, or 30 mg/kg of rectal consisting of midazolam and fentanyl, although efficacy was compa-
methohexital (Fig. 8-e2). The dose of 30 mg/kg resulted in significantly rable. Failed or inadequate sedations using pentobarbital ranges from
higher plasma concentrations for up to 20 minutes. In a separate study 1% to 16% (Karian et al. 1999; Greenberg, Adams, and Aspinall 2000;
of 12 patients premedicated with 25 mg/kg of 2% rectal methohexital, Malviya et al. 2000; Kienstra et al. 2004). Pentobarbital has also been
Forbes and colleagues (1989b) noted a significant increase in heart rate used to control increased intracranial pressure or for treatment of
but no change in cardiac index, stroke volume, ejection fraction, refractory status epilepticus (Shapiro et al. 1995). Use of pentobarbital
or blood pressure using pulsed Doppler and two-dimensional as a continuous infusion as a backup for failed sedation has been
echocardiography. described by Tobias and colleagues (1995), however subsequent studies
The intravenous dose for induction using methohexital dissolved describe a high incidence of complications related to continuous infu-
in a lipid emulsion was determined by Westrin (1992), who noted that sions (Yanay, Brogan, and Martin 2004).
the dose (adjusted by body weight) needed for induction in infants Pentobarbital is an oxy-analogue of thiopental and is primarily
younger than 5 months was almost twice that for older children metabolized in the liver with renal excretion of the metabolites,
(Fig. 8-e3). The recommended dose for intravenous use is 1 to 2 mg/ although a minority of the metabolic products are excreted in feces.
kg; in children younger than 5 years, 25 to 30 mg/kg can be adminis- The pharmacokinetics of pentobarbital has been well studied in adults,
tered rectally (Table 8-2). but the literature is limited in pediatrics. Zuppa and colleagues (2011)
studied the pharmacokinetics of intravenous pentobarbital in neo-
Pentobarbital nates, infants, and young children (age 3 days to 4.4 years) with con-
Pentobarbital is commonly used in pediatrics as a sedative drug for genital heart disease after open-heart surgery. In an allometrically
diagnostic imaging, with its effectiveness and relative safety having scaled model, they found total systemic clearance of 0.12 L/hr/kg,
been demonstrated in a number of studies (Strain et al. 1986, 1988; central compartment of 0.45 L/kg, and peripheral compartment of
Greenberg, Adams, and Aspinall 2000; Malviya et al. 2004; Mason et al. 0.98 L/kg, with an age effect on clearance for subjects younger than 12
PLASMA METHOHEXITONE CONCENTRATION

8
7 30 mg • kg–1
25 mg • kg–1
6 20 mg • kg–1
15 mg • kg–1
5
†
µg/mL
4
†
3
†
2
*
1 *
* *
0
15 30 45 60 90 120
Time (min)
FIG 8-E2 Plasma Methohexitone Concentrations After Rectal Administration of Methohexitone

15 mg/kg, 20 mg/kg, 25 mg/kg, or 30 mg/kg. Mean ± SEM. *P < 0.05, 15 mg/kg vs. 30 mg/kg; †P <
0.05, 20 mg/kg vs. 30 mg/kg. (From Forbes RB, et al. Pharmacokinetics of two percent rectal methohexitone
in children. Can J Anaesth. 1989;36:160.)
Not asleep
1–6 months
Asleep
Not asleep
7–11 months
Asleep
Not asleep
1–3 years
Asleep
Not asleep
4–7 years
Asleep
Not asleep
8–16 years
Asleep
1.0 1.1 1.3 1.4 1.6 1.8 2.0 2.2 2.5 2.8 3.2
Methohexital dose (mg/kg)
FIG 8-E3 Results of Injection of Different Doses of Methohexital. Each filled circle represents one
patient. The position of the circle below or above the line indicates whether induction was classified as
satisfactory or not satisfactory. (From Westrin P. Methohexital dissolved in lipid emulsion for intravenous
induction of anesthesia in infants and children. Anesthesiology. 1992;76:917.)
188 PART II Pharmacology
TABLE 8-4 Effect of Age (Percent) on TABLE 8-5 Diazepam: Indications, Route
Pentobarbital Clearance for Patients Less of Administration, and Dosage
Than 12 Months Old Recommendations
Age (Months) Percent Effect on Typical CL Indication Route Dose
0.1 33% Premedication PO 0.1–0.2 mg/kg (max 10 mg)
3 73% Sedation IV 0.05–0.3 mg/kg
6 85% Sedation IM 0.05–0.3 mg/kg
9 94%
12 100%
CL, Clearance. Pittsburgh of UPMC; 2011.
Data from Zuppa AF, Nicolson SC, Barret JS, et al. Population
pharmacokinetics of pentobarbital in neonates, infants, and children
after open heart surgery. J Pediatr. 2011;159:414.
Midazolam is metabolized in the liver, with less than 1% excreted
unchanged in the urine. Midazolam undergoes extensive metabolism
(involving CYP3A4, CYP3A5, and CYP3A7) to a major hydroxylated
months of age (Table 8-4). The recommended dose for intravenous use form, 1-OH-midazolam. Clearance of midazolam is age dependent,
is 1 to 3 mg/kg (to a maximum of 100 mg/dose) repeated every 5 to with the lowest clearance found in preterm infants compared to
10 minutes until the patient is asleep. older children and adults, reflecting the developmental immaturity of
CYP3A4 metabolism (de Wildt 1999, 2001, 2010; Ince et al. 2013) (Fig.
BENZODIAZEPINES AND ANTAGONISTS 8-1). Protein binding of midazolam is extensive, with a free fraction of
only 3% to 6%. Midazolam has an intermediate rate of absorption (0.5
Diazepam to 1.5 hours) and a bioavailability of 30% to 50%. The terminal elimi-
Benzodiazepines produce their sedative effect by enhancing the nation phase ranges from 1 to 4 hours (Smith, Eadie, and Brophy
affinity of the inhibitory neurotransmitter GABA for their receptors 1981).
(Goodchild 1993). Diazepam produces relatively pleasant sedation or The pharmacokinetics of midazolam has been reported in healthy
hypnosis with few side effects and prompt recovery. Its action is children (Payne et al. 1989; Jones, Chan, and Roulson 1993). However,
caused by depression of the amygdala in the limbic system and spinal comparisons between studies become difficult because the drug exhib-
internuncial neurons. It is a specific treatment of seizure disorders in its dose-related changes in clearance (Salonen, Kanto, and Iisalo 1987).
children (Lombroso 1966; Carter and Gold 1977; Chamberlain et al. Midazolam administered at 0.15 mg/kg and 0.5 mg/kg intravenously
2014). Intravenous administration of 0.2 to 0.3 mg/kg usually induces exhibited a volume of distribution at steady state between 1.29 and
hypnosis, but the requirement varies widely. Diazepam appears to 1.9 L/kg, respectively; an elimination half-life of 70 and 107 minutes,
cause less cardiac depression than do barbiturates (Muenster et al. respectively; and clearance of 9.1 and 15.4 mL/kg per minute, respec-
1967; Abel and Reis 1971; McCammon, Hilgenberg, and Stoelting tively. The kinetics of intravenous midazolam was consistent with a
1980). three-compartment model (Jones, Chan, and Roulson 1993).
Diazepam is metabolized by the CYP-linked monooxygenase The kinetics of midazolam has also been determined after intra-
system. In adults, the metabolite, desmethyldiazepam, is eliminated muscular, rectal, and oral administration. Payne and colleagues (1989)
more slowly (t 12 = 150 hours) than the parent compound ( t 1 = 20 to noted that times for peak serum concentrations after intramuscular,
2
30 hours) (Meberg et al. 1978). rectal, and oral administration were 15, 30, and 53 minutes, respec-
The plasma half-life of diazepam and the nature of the diazepam tively, whereas the drug clearance and bioavailability via these three
metabolites formed vary with maturity (Morselli et al. 1974). The pre- different routes were 10.4, 50.8, and 33.4 mL/kg per minute and 87%,
mature infant and the mature infant at term eliminate diazepam at a 18%, and 27%, respectively. The lower bioavailability after oral or
slower rate than older infants, children, and adults. A demethylated rectal administration is consistent with the commonly used oral dose
derivative of diazepam, N-desmethyldiazepam, could not be measured of 0.5 mg/kg, which is almost five times higher than intravenous
in plasma until 4 hours after injection in premature infants, compared dosing.
to only 1 hour in older infants and children. In adults, 71% of diaze- In a study involving pediatric patients aged 6 months to 16 years,
pam or its metabolites was excreted in the urine, and about 10% was Reed and colleagues (2001) characterized the pharmacokinetic profile
excreted in the feces. As an oral premedicant or intravenous induction of both oral and intravenous midazolam using noncompartmental
agent, the recommended dose of diazepam is listed in Table 8-5. The models. Midazolam absorption was rapid after oral administration,
local pain on injection intravenously has decreased its use in favor of with children younger than 12 years old absorbing the drug two times
other short-acting benzodiazepines (e.g., midazolam). faster than adolescents. Adolescents had a slower clearance and
longer half-life after intravenous administration compared to younger
Midazolam children.
Midazolam is a water-soluble, short-acting benzodiazepine that is two Population studies involving the pharmacokinetics of midazolam
to three times as potent as diazepam. Its chemical configuration confers in neonates have been reported by Burtin and colleagues (1994). Using
a pH-dependent ring phenomenon. At pH 4, the diazepine ring opens, NONMEM and a two-compartment model, 531 midazolam concen-
and a highly stable water-soluble compound results. At physiologic pH trations from 187 infants were analyzed. The clearance and the central
values, the ring closes and thereby increases the drug lipophilic activity. volume were noted to be 70 ± 13 mL/kg per hour (or 1.02 mL/kg per
Cardiovascular stability, transient mild respiratory depression, minimal minute) and 591 ± 65 mL/kg, respectively. Of interest was that the
venous irritation, amnesia, and short duration of action are reasons clearance was 1.6 times higher in full-term neonates with a gestational
why midazolam has replaced diazepam. age of more than 39 weeks than in neonates of fewer than 39 weeks’
1.000 100.0
Volume of distribution (L)

0.100 10.0
Clearance (L/min)
0.010
1.0
0.001
0.1
A 1 10 100 B 1 10 100
Body weight (Kg) Body weight (Kg)
FIG 8-1 The Major Change in Midazolam Clearance Occurs in the First Year of Life. Post hoc
estimates of cytochrome P450 3A4-mediated clearance of midazolam versus bodyweight. Open squares
preterm neonates, filled circles preterm neonates with respiratory distress syndrome, open circles children
after elective major craniofacial surgery, open triangles pediatric intensive care patients, open inverted tri-
angles pediatric oncology patients, and open diamonds male adults, with a black line as their post hoc popu-
lation predicted values. (From Ince I, de Wildt SN, Wang C, et al. A novel maturation function for clearance
of the cytochrome P450 3A substrate midazolam from preterm neonates to adults. Clin Pharmacokinet.
2013;52:555. Figure 1a [p. 559].)
gestation (Burtin et al. 1994). Peeters and colleagues (2006b) described 200
Range of coefficient of variation (%)
the clearance in nonventilated, critically ill children (16.7 mL/kg per 180

minute) as two to five times higher than clearance in ventilated criti-
160
cally ill children (3.1 mL/kg per minute as reported in Hughes et al.
140
1996; 5 mL/kg per minute in de Wildt 2003). The authors suggested
that mechanical ventilation affects hepatic blood flow, thus decreasing 120
midazolam clearance, and that nonventilated infants may need rela- 100
tively higher doses of midazolam after major surgery (Peeters et al. 80
2006b). Altamimi and colleagues (2015) found that interindividual 60
variation in midazolam clearance was greater than 50% in critically ill 40
pediatric patients, suggesting that inappropriate dosing of midazolam 20
is more likely in critically ill children than in noncritical patients 0
(Fig. 8-2).
8) tes
1) s
6)
)
57
50
67
22
23 te
=
11 na
= ona
The pharmacokinetics of midazolam in premature infants has been

=
=
(n
= eo
(n
(n
(n
(n ne
s(
described by de Wildt and colleagues (2001, 2002). At 24 to 34 weeks’

ts
(n m n
ts
en
nt
re
re
rm
en
gestational age and at 3 to 11 days of life, the apparent volume of
fa
sc
ild
ild
er
Te
sc
In
ole
et
Ch
Ch
distribution, clearance, and half-life of midazolam after a single

ole
Pr
Ad
Ad
0.1-mg/kg intravenous bolus dose were 1.1 L/kg, 1.8 mL/kg per

minute, and 6.3 hours, respectively. The low clearance rate was attrib- Critically ill Non-critically ill
uted to immature CYP3A4 activity, reflected by markedly reduced
FIG 8-2 Interindividual Variation in Midazolam Concentration
1-OH-midazolam metabolite compared with reports in older children.
Is Greater in Critically Ill Pediatric Patients. Range of coefficient
Notably, midazolam clearance was increased in infants exposed to of variation for midazolam in different patient groups. (From Altamimi
indomethacin (Fig. 8-3)(de Wildt et al. 2001). MI, Sammons H, Choonara I. Inter-individual variation in midazolam
The kinetics of midazolam is affected by the use of extracorporeal clearance in children. Arch Dis Chil. 2015;100:95 [Figure 2].)
membrane oxygenation (ECMO). Mulla and colleagues (2003) noted
that the volume of distribution and half-life of midazolam are signifi-
cantly increased in neonates requiring ECMO.
The cardiovascular and respiratory effects of midazolam have been reversed by naloxone, and independent of the rate of administration
reported in adults. Midazolam decreases systolic and diastolic blood of the drug (Forster, Morel, and Bachmann 1983; Alexander and Gross
pressures by 5% to 10%, decreases systemic vascular resistance by 15% 1988; Alexander, Teller, and Gross 1992).
to 30%, and increases heart rate by 20%. Right- and left-sided filling Midazolam is not as reliable as thiopental as an induction agent,
pressures are usually unaffected. even at doses as high as 0.6 mg/kg (Salonen, Kanto, and Iisalo 1987).
Respiratory depression is associated with midazolam administra- The most common pediatric use for intravenous midazolam other
tion, and this respiratory depression is poorly related to dose, not than as an anesthetic adjunct has been its use as a sedative for intensive
200 TABLE 8-6 Midazolam: Indications, Route

180 of Administration, and Dosage
Midazolam concentration (ng/mL)
160
Recommendations
140 Indication Route Dose
120 Premedication PO 0.25–0.5 mg/kg (max 20 mg)
Premedication Intranasal 0.2–0.3 mg/kg
100
Premedication IV 0.05 mg/kg
80 Sedation Intranasal 0.2–0.3 mg/kg (max 10 mg/
60 dose)
40 Sedation IM 0.1–0.15 mg/kg
Sedation (age 6 IV 0.05–0.1 mg/kg (max 6 mg)
20
months to 5 years)
0
Sedation (age 5 to 12 IV 0.025–0.05 mg/kg (max
-20 10 20 30 years) 10 mg)
Time (h) Sedation PR 1 mg/kg
Sedation SL 0.5–0.75 mg/kg
FIG 8-3 Effect of Postnatal Indomethacin Exposure on Mid- Sedation (neonates IV infusion 0.03 mg/kg/hour
azolam Disposition in Preterm Infants. Midazolam concentration less than 32 weeks)
versus time curve after a single intravenous dose (0.1 mg/kg) to preterm
Sedation (neonates IV infusion 0.06 mg/kg/hour
infants with (n = 11, red circles) and without (n = 13, blue circles) post-
more than 32 weeks)
natal indomethacin exposure. Each dot represents mean ± SD concen-
tration at each time point. (Redrawn from de Wildt SN, et al. Sedation IV infusion 0.06–0.12 mg/kg/hour
Pharmacokinetics and metabolism of intravenous medazolam in titrate to effect
preterm infants. Clin Pharmacol Ther. 2001;70:525-531.) From McGhee B, et al. Pediatric drug therapy handbook and
Pittsburgh of UPMC; 2011.
References:
care patients (Rosen and Rosen 1991). However, others have noted
Davis PJ, Stiller RL, McGowan Jr FX, et al. Preanesthetic medication
reversible neurologic abnormalities associated with prolonged intrave- with intranasal midazolam for brief surgical procedures: effect on
nous midazolam infusions (Engstrom and Cohen 1989; Sury, Billing- recovery and hospital discharge times. Anesthesiology. 1992;82:2.
ham, and Russell 1989; Bergman, Steeves, and Burckart 1991). Spear RM, Yaster M, Berkowitz ID. Preinduction of anesthesia in
Most of the pediatric experience with midazolam is derived from children with rectally administered midazolam. Anesthesiology.
its use as a preanesthetic medication delivered via the oral, intramus- 1991;74:670.
cular, rectal, intranasal, and sublingual routes of administration (Table Khalil S, Philbrook L, Rabb M, et al. Sublingual midazolam
8-6). More than 85% of anesthesiologists responding to a survey of premedication in children: A dose response study. Paediatr Anaesth.
premedication practices indicated that they prescribe midazolam 1998;8:461.
(Kain et al. 1997). In children, midazolam has been shown to produce
tranquil and calm sedation, reduce separation anxiety, facilitate induc-
tion of anesthesia, and enhance antegrade amnesia (Twersky, Hartung, colleagues (2001) in a study of 88 children having outpatient surgery
and Berger 1993). Kain and colleagues (2000) showed that 0.5 mg/kg reported a lower incidence of emergence agitation after a sevoflurane/
of oral midazolam can produce significant anterograde amnesia at 10 N2O/O2 anesthetic when oral midazolam 0.2 mg/kg was given.
and 20 minutes and anxiolysis as early as 15 minutes after administra- Oral midazolam has been associated with prolonged recovery times
tion. Numerous studies have documented the efficacy of orally admin- in some studies, but others, using BIS and measured end-tidal gases,
istered midazolam (Feld, Negus, and White 1990; Weldon, Watcha, and did not find this problem (Viitanen et al. 1999; Brosius and Bannister
White 1992; Levine, Spahr-Schopfer, and Hartley 1993). The appropri- 2001, 2002). In a multicenter study involving 455 children, Coté and
ate dose appears to range between 0.5 and 1 mg/kg, and time of onset colleagues (2002) reported on the effectiveness of commercially pre-
ranges from 15 to 30 minutes. Oral midazolam can also be safely pared midazolam syrup. In this study, oral midazolam was effective for
administered to children with cyanotic heart disease without affecting sedation and anxiolysis at a dose as low as 0.25 mg/kg. Doses as high
oxygen saturation (Levine, Hartley, and Macpherson 1993). Serious as 1 mg/kg had minimal effects on respiration and oxygen saturation
side effects of midazolam are uncommon. However, several postopera- (Fig. 8-e4).
tive behavioral problems (fearfulness, nightmares, food rejection) were Rectal administration of midazolam has also been successfully used
observed in children premedicated with oral midazolam (0.5 mg/kg) to sedate patients. Saint-Maurice and colleagues (1986) showed that
(McGraw 1993). In addition, McMillan and colleagues (1992) noted after a dose of 0.3 mg/kg, a maximum plasma concentration of 100 ng/
loss of balance, dysphoria, and blurred vision in some patients receiv- mL was achieved with levels of sedation as judged by mask acceptance,
ing 0.75 and 1 mg/kg orally. Hiccups have been associated with mid- with patient cooperation being satisfactory in all 16 patients. However,
azolam administration via the rectal, nasal, and oral routes (Marhofer Spear and colleagues (1991) noted that the optimum dose of rectal
et al. 1999). One major disadvantage of oral midazolam is its bitter midazolam was 1 mg/kg and that doses of 0.3 mg/kg resulted in patient
taste. Almenrader and colleagues (2007) reported that 14% of children struggling during anesthesia induction.
refused oral midazolam in a study comparing oral clonidine with oral Nasal and sublingual transmucosal routes of administration have
midazolam premedication. They also reported a trend toward an also been used for midazolam preanesthesia medications. Wilton and
increased incidence of emergence agitation in the midazolam group, colleagues (1988) and Davis and colleagues (1995) demonstrated the
with parental satisfaction favoring clonidine. Alternatively, Ko and usefulness of preanesthetic sedation of preschool children with 0.2 to
DOSE OF ORAL MIDAZOLAM SYRUP (n = 397)

45
0.25 mg/kg
35 0.5 mg/kg
Anxious patients (%)
1.0 mg/kg
25 Overall
15
−5
Baseline 0–10 min 11–20 min 21–30 min
Time after premedication
FIG 8-E4 Percentage of Patients Exhibiting Anxiety from Base-

line to Time Elapsed After Administration of Oral Midazolam.
There was a positive association between dose and onset of anxiolysis
(P = 0.01); a larger proportion of children achieved satisfactory anxiolysis
within 10 minutes at the higher doses. (From Coté CJ, et al. A com-
parison of three doses of commercially prepared oral midazolam syrup
in children. Anesth Analg. 2002;94:37.)
0.3 mg/kg of intranasal midazolam. Walbergh and colleagues (1991)

TABLE 8-7 Etomidate: Indications, Route
determined plasma concentrations after administration of 0.1 mg/kg
of intranasal midazolam, with peak plasma concentrations ranging
of Administration, and Dosage
from 43 to 106 ng/mL within 10 minutes. In this study, plasma mid- Recommendations
azolam concentrations exceeded threshold sedation values for adults Indication Route Dose
(40 ng/mL) as early as 3 minutes after its nasal administration and Induction IV 0.2–0.6 mg/kg
exceeded this level for as long as 30 minutes. Because intranasal mid- Sedation IV 0.1–0.3 mg/kg, repeat as needed
azolam can irritate the nasal mucosa, its use is limited by the volume
of drug to be administered. The sublingual mucosa has a rich vascular From McGhee B, et al. Pediatric Drug Therapy Handbook and
supply, and drugs are absorbed systemically, thereby eliminating Formulary, 6th ed. Department of Pharmacy, Children’s Hospital of
hepatic first-pass metabolism. Karl and colleagues (1993), in a com- Pittsburgh of UPMC.
parative study of intranasal and sublingual midazolam administration,
demonstrated the two routes to be equally effective but that the sub-
lingual route of administration had better patient acceptance. population analysis of etomidate in children aged 6 months to 13 years
using NONMEM with results allometrically scaled (to a standard of
Flumazenil 70 kg). Forty-nine children with a median age of 4 years and weight
Flumazenil blocks the effects of benzodiazepines on the GABA-ergic of 15.7 kg received a single bolus dose of etomidate 0.3 mg/kg for
inhibition pathway in the CNS. Flumazenil does not have significant anesthesia induction with arterial samples collected 2 hours after injec-
agonist activity of its own and does not appear to reverse the effects of tion. Using a three-compartment model and standardizing parameters
opioids. Flumazenil has a short duration of action. Its plasma half-life to a 70-kg adult, clearance was 1.50, 1.95, and 1.23 L/min for C1, C2,
is between 0.7 and 1.3 hours. It is metabolized and cleared by the liver and C3, respectively, while central volume was 9.51, 11.0, and 79.2 L
and excreted in the urine (Rocari, Ziegler, and Guentert 1986). Adverse for V1, V2, and V3, respectively. In this study, etomidate clearance was
effects of flumazenil include nausea, vomiting, blurred vision, sweat- influenced by both weight and age, with younger children having
ing, anxiety, and emotional lability. Serious adverse effects include higher clearance after scaling for weight. Su and colleagues (2014)
seizures and cardiac dysrhythmias; these events have been associated performed a population pharmacokinetic study of single-dose etomi-
with patients physically dependent on benzodiazepines, patients with date in neonates and infants with congenital heart disease, for
epilepsy, and patients having taken multiple drug ingestions or over- which a two-compartment model best fit the data. Clearance was
doses. Clinical trials in adults suggest using flumazenil in reversing the 0.624 L/min per 70 kg, intercompartmental clearance was 0.44 L/min
effects of conscious sedation, general anesthesia in benzodiazepine per 70 kg, central volume was 9.47 L/70 kg, and peripheral volume was
overdose, and hepatic encephalopathy. 22.8 L/70 kg. The lower clearance in the study by Su and colleagues
Flumazenil use in pediatric patients has been reported as a treat- (2014) compared to Lin and colleagues (2012) was attributed to a
ment for benzodiazepine overdose and for paradoxical reaction to younger average patient studied and relative immature liver function.
midazolam, as well as a reversal agent for benzodiazepine in anesthesia For induction of anesthesia, the recommended intravenous dose of
(Roald and Dohl 1989; Jones, Lawson, and Andrew 1991; Jackson, etomidate is 0.3 mg/kg (see Table 8-7).
Beck, and Losek 2015). Doses of flumazenil varied between 0.005 and Etomidate causes little change in cardiovascular function in either
0.1 mg/kg, with 0.01 mg/kg being the most commonly used dose. In a healthy or compromised patients (Guldner et al. 2003). In a study of
study of 107 children undergoing procedural sedation, Shannon and children with atrial septal defects undergoing cardiac catheterization,
colleagues (1997) noted that a mean dose of 0.017 mg/kg of flumazenil Sarkar and colleagues (2005) noted that induction doses of intrave-
was used to reverse a mean midazolam dose of 0.18 mg/kg. Because of nous etomidate had no significant effect on the hemodynamics or on
its short half-life relative to the half-life of most benzodiazepines, rese- the shunt fraction.
dation is a common finding after flumazenil use. Consequently, repeat Etomidate has both anticonvulsant and proconvulsant qualities. In
administrations and careful patient observations are necessary (Jones, patients with known seizure disorders, etomidate can produce epilep-
Chan, and Roulson 1993). tiform activity (Ebrahim et al. 1986; Modica, Pempelhoff, and White
1990). Myoclonic movements that are not associated with epileptiform
OTHER SEDATIVE AGENTS electroencephalographic activity occur in 30% to 75% of patients after
induction with etomidate (Ghonheim and Yamanda, 1977). Pain at the
Etomidate injection site is a common side effect. A formulation of etomidate
Etomidate is a potent, short-acting, nonbarbiturate sedative-hypnotic dissolved in a fat emulsion of medium and long-chain triglycerides
agent without analgesic properties. After a single intravenous bolus studied in children reported a low incidence (5%) of pain at injection;
injection, it has a rapid onset (5 to 15 seconds) with a peak effect at 60 however, a higher incidence of myoclonic movements (85%) is
seconds and a short duration of action (3 to 5 minutes) that is termi- reported as well (Nyman et al. 2006).
nated by redistribution. It produces a central depressant effect through A major side effect limiting etomidate use is its suppression of
GABA-mimetic action. Administered intravenously, etomidate has adrenal steroid synthesis and reports of increased mortality after its
been used for induction and maintenance of anesthesia (Table 8-7); use (Ledingham and Watt 1983). Etomidate blocks adrenal steroid
use for prolonged sedation in critically ill patients has become very synthesis through inhibition of two mitochondrial enzymes dependent
uncommon because of its inhibitory effects on steroid-synthesis on CYP: cholesterol side-chain cleavage enzyme and 11β-hydroxylase
effects. (Wagner et al. 1984). The inhibition of steroid synthesis occurs with
Etomidate is rapidly metabolized in the liver, with only 2% of the both prolonged continuous infusions and with single induction doses
drug detected unchanged in the urine. Etomidate pharmacokinetics in (Longnecker 1984; Wagner and White 1984). Dönmez and colleagues
adults has been described using a two- or three-compartment model (1998) noted in a randomized prospective study of 30 children under-
(Van Hamme and Ghoneim 1978; Hebron et al. 1983; Davis and Cook going cardiopulmonary bypass that when etomidate (0.3 mg/kg) was
1986; Kaneda et al. 2010). Lin and colleagues (2012) published a used as an induction agent, it significantly suppressed the increased
cortisol levels associated with the stress responses of surgery and car- 10 years, Marsh and colleagues (1991) noted the volume of the central
diopulmonary bypass. In critically ill children, a single bolus dose has compartment to be 0.34 L/kg and the clearance of the drug to be
shown impaired adrenal function associated with increased mortality 34.3 mL/kg per minute. Kataria and colleagues (1994), using three
(den Brinker et al. 2008). In adult trauma patients, single-dose etomi- different pharmacokinetic modeling approaches, analyzed the kinetics
date administration for rapid-sequence intubation was associated with of single-bolus and continuous infusions of propofol in children. In
chemical evidence of adrenal suppression, increased length of stay in all three models, the pharmacokinetics were well described by a three-
the intensive care unit (ICU), and an increased number of days using compartment model, with a central compartment of 0.52 L/kg and a
a ventilator (Hildreth et al. 2008). However, other studies of adults clearance of 34 mL/kg per minute. The pharmacokinetics of propofol
suggest that for ICU patients receiving etomidate for induction, their in neonates (4 to 25 days postnatal) was described by Allegaert and
clinical outcome and therapy were no different from patients induced colleagues (2007) and found after appropriate allometric scaling to
with other sedative hypnotic agents (Ray and McKeown 2007), and 70 kg that clearance and volume of distribution was 32% and 44%,
mortality was not increased in ICU patients with sepsis (McPhee et al. respectively, of values reported in infants. They found that scaled pro-
2013; Gu et al. 2015). These studies suggest that etomidate should pofol clearance reaches adult values within the first 3 months to 1 year
be avoided in patients with adrenally suppressed states. Interestingly, of life, reflecting development of hepatic metabolic enzymes.
work on modifications of etomidate have identified analogs that Peeters and colleagues (2006a) studied propofol pharmacokinetics
undergo ultra rapid metabolism, maintain the drug’s sedative proper- and pharmacodynamics in unventilated infants after craniofacial
ties, and have no adrenal suppression (Cotton et al. 2009; Pejo et al. surgery. Twenty-two infants, aged 1 month to 2 years, received propofol
2012, 2014; Campagna et al. 2014). at 33 to 66 mcg/kg per minute in the ICU, based on Comfort-B scores
and bispectral index (BIS) monitoring. Population kinetic analysis
Propofol using NONMEM showed propofol kinetics was best described by a
Propofol is an alkylphenol derivative that is formulated as an oil/water two-compartment model. Body weight was a significant covariate (i.e.,
emulsion using 10% soybean oil, 2.25% glycerol, and 1.2% purified use of body weight made the model fit the measured concentrations
egg phosphatide. This form of reconstitution is used because of ana- more closely). Clearance was 0.169 L/min (or 77 mL/min per kilo-
phylactic reactions that occurred when propofol was reconstituted gram), steady-state volume of distribution 144 L (or 16.1 L/kg), and
with polyethoxylated castor oil (Cremophor-EL). The rapid redistribu- central volume 20.3 L (or 2.3 L/kg). These values are much higher than
tion and metabolism of propofol result in a short duration of action those reported in children receiving ventilation. The importance of
and allow the drug to be administered via repeated injections or con- dose titration was emphasized by the great interpatient variability in
tinuous infusions with minimal accumulation. Kinetic studies in both propofol effect on Comfort-B scores or BIS readings.
adults and children reveal a drug with a large steady-state volume of The pharmacokinetics of propofol was studied in a small number
distribution, a slow elimination half-life, and a rapid clearance. Gluc- of children after cardiac surgery. When propofol was used to provide
uronidation of propofol is a major route of elimination. Uridine sedation for 6 hours, Knibbe and colleagues (2002), using population
5-diphosphate-glucuronosyltransferases (UGTs) are the drug metabo- kinetics, reported propofol to fit a two-compartment model with a
lizing enzymes for phase II. Because the clearance of propofol exceeds clearance of 35 mL/kg per minute and a central compartment of
the capacity of the liver blood supply, extrahepatic sites of metabolism 0.78 L/kg. In addition, the authors suggested that children may have a
appear to be involved with drug clearance. These extrahepatic sites of lower pharmacodynamic sensitivity to propofol in that higher plasma
metabolism were suggested in studies of patients undergoing liver concentrations were needed to maintain sedation than those reported
transplantation where propofol metabolites were detected when pro- in adults.
pofol was administered only during the anhepatic phase of the opera- The effect of obesity on propofol pharmacokinetics has been rela-
tion. Conjugation of propofol at these extrahepatic sites is governed tively well characterized in adults, while studies in obese children have
by different exons than in the liver (Takahashi et al. 2008), and muta- been limited. Servin and colleagues (1993) found that both volume of
tions in these locations can markedly affect glucuronidation. In radio- distribution and clearance were significantly correlated with total body
labeled isotope studies, 88% of the radioactivity is excreted in the weight (TBW) in adults. The result of simultaneously increased volume
urine, 2% is excreted in the feces, and the remainder is excreted as 1- of distribution and clearance was that the elimination half-life of pro-
and 4-glucuronides and 4-sulfate conjugates. In patients with hepatic pofol was similar between obese and nonobese adults. Population
and renal impairments, no statistically significant alterations occur in pharmacokinetic studies in obese adults found that clearance was best
the pharmacokinetics. The effect of fentanyl on propofol clearance is described with an allometric function using TBW. Cortinez and col-
not clear. In studies by Cockshott and colleagues (1987), fentanyl leagues (2010) reported a scaling factor of 0.75, and van Kralingen and
decreased propofol clearance, whereas in other studies, no effect was colleagues (2011) reported a factor of 0.72 in obese adults, which is in
noted (Saint-Maurice et al. 1989; Gill, Wright, and Reilly 1990). accordance to the factor of 0.71 reported in lean adults (Schüttler and
Another important aspect of propofol pharmacokinetics is that the Ihmsen 2000). Diepstraten and colleagues (2012) found that TBW was
drug can limit its own clearance. Propofol is eliminated by hepatic the most significant determinant for clearance in a prospective study
conjugation to inactive metabolites, which are excreted by the kidneys. of propofol pharmacokinetics in morbidly obese children and adoles-
A 2-mg/kg bolus dose of propofol for the induction of anesthesia cents (Fig. 8-4). The effect of obesity on induction doses of propofol
can reduce blood flow to the liver by 14%. Bolus doses of propofol in children and adolescents was studied by Olutoye and colleagues
may cause a small but persistent change in blood flow to the liver, (2012). This study found that the ED95 of propofol for loss of lash reflex
resulting in decreased clearance and higher than predicted plasma was significantly lower in obese compared to nonobese children aged
concentrations. 3 to 17 years (2.0 mg/kg vs. 3.2 mg/kg, respectively).
The pharmacokinetics of propofol in children has been described The pharmacodynamics of propofol has been well described and
by numerous investigators (Saint-Maurice et al. 1989; Jones, Chan, and reviewed (Shafer 1993). Because of the pharmacokinetic properties of
Andrew 1990; Marsh, White, and Morton 1991; Kataria, Ved, and Nico- propofol, infusions allow for more rapid decreases in plasma concen-
demus 1994; Knibbe et al. 2002; Zuppa, Helfaer, and Adamson 2003). trations and faster patient recoveries from anesthesia (Fig. 8-5) (Mira-
In computer-controlled infusions of propofol in children younger than khur 1988; Borgeat, Popovic, and Meier 1990; Watcha, Simeon, and
They found concentrations were higher than predicted in the first 30

5 r = 0.721 (p < 0.001) minutes (7.1 mcg/mL vs. 6.6 mcg/mL), but the differences at 30, 50,
and 70 minutes were not significant, and no child needed rescue doses
of propofol.
4 The use of a propofol infusion to maintain deep sedation or anes-
thesia is commonly used to facilitate a motionless patient for MRI
Clearance (L/min)
(Pershad, Wan, and Anghelescu 2007; Machata et al. 2008; Heard et al.
3 2008; Bryan et al. 2009; Pedersen et al. 2013). Heard and colleagues
(2015) found a lower incidence of adverse airway events in children
anesthetized for an MRI with a propofol infusion using an open airway
2 compared to isoflurane/nitrous oxide with an LMA. All children (n =
75 in both groups) successfully completed the MRI, but the children
receiving propofol recovered to eye opening and wakefulness in the
1
postanesthesia care unit faster than the isoflurane group.
In general, blood pressure and systemic vascular resistance decrease
0 with induction doses of propofol, changes in heart rate are variable,
75 100 125 150 175 200 and cardiac output decreases slightly. In patients with congenital heart
Total body weight (kg) disease, Gozal and colleagues (2001) demonstrated that despite lower
systemic and pulmonary pressures, propofol did not modify the char-
FIG 8-4 Total Body Weight Plays a Significant Role in Clearance acteristics of the patient’s underlying intracardiac shunts.
of Propofol in Obese Pediatric Patients. Total body weight plays a In normal children aged 1 to 6 years, Karsli and colleagues (2002),
significant role in clearance of propofol in obese pediatric patients. using transcranial Doppler, noted that propofol decreases cerebral
Individual post hoc estimates for clearance of propofol versus total body blood flow velocity in a dose-dependent relationship. In addition,
weight in 20 obese and morbidly obese children and adolescents with
Wilson-Smith and colleagues (2003) noted that the effects of nitrous
Pearson’s correlation coefficient (r). (From Diepstraten J, Chidambaran
oxide on cerebral blood flow velocity were preserved in healthy chil-
V, Sadhasivam S, et al. Propofol clearance in morbidly obese children
and adolescents. Clin Pharmakinet. 2012;51:543. [Figure 1a, p. 547].) dren who were given propofol for their elective surgery.
In studies evaluating propofol requirements for induction of anes-
thesia in children, Manschot and colleagues (1992) noted age-related
RECOVERY CURVES differences in propofol. Children aged 10 to 15 years required 1.5 mg/
120 kg of propofol for sufficient induction of sleep, while children aged 3
50% decrease in concentration
Propofol to 9 years required a dose of 2.5 mg/kg. In this study, propofol was

coadministered with alfentanil 5 mcg/kg to decrease the pain of pro-
Minutes required for a
90 Thiopental
pofol injection. In a study by Hannallah and colleagues (1991) in which
alfentanil was not administered, the ED50 and ED95 for loss of eyelash
60 reflex were 1.3 and 2 mg/kg, respectively, 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
35 aged 10 to 16 years, noted that the ED50 of propofol was 3 mg/kg for
infants and 2.4 mg/kg for the older children. In all three of these
0 studies, propofol was administered over 10 to 30 seconds. However,
0 120 240 360 480 600 as with most hypnotic agents, propofol also demonstrates a rate-
dependent induction. Stokes and Hutton (1991) demonstrated that
Infusion duration with the use of slower infusion rates, induction time for anesthesia
FIG 8-5 Curves Showing Time Required for 50% Decreases in increases, but smaller doses could be used (Table 8-8).
Propofol and Thiopental Concentrations After Discontinuation In addition to its anesthetic action, propofol appears to have anti-
of a Continuous Infusion. (From Shafer SL. Advances in propofol emetic properties. In adult patients, Borgeat and colleagues (1992)
pharmacokinetics and pharmacodynamics. J Clin Anesth. 1993;5:14S.) demonstrated that 10 mg of propofol administered in the recovery
room was effective in reducing the incidence of nausea and vomiting.
White 1991; Larsson, Asgeirsson, and Magnusson 1992; Lebovic, Reich, Watcha and colleagues (1991) noted that in pediatric patients under-
and Steinberg 1992; Nightingale and Lewis 1992; Reimer, Montgomery, going strabismus surgery, propofol alone effectively decreased the inci-
and Bevan 1993; Shafer 1993). McFarlan and colleagues (1999) dence of postoperative emesis (23%) compared with a similar group
reported a propofol infusion simulation to keep blood concentration of patients anesthetized with halothane and nitrous oxide and supple-
of propofol at 3 mcg/mL in children aged 3 to 11 years. After a bolus mented with prophylactic droperidol (50%). However, the incidence
of 2.5 mg/kg, infusions rates were 250 mcg/kg per minute for 15 of emesis increased significantly (60%) when nitrous oxide was used
minutes, then 216 mcg/kg per minute for 15 minutes, 183 mcg/kg per in patients that received propofol (Watcha, Simeon, and White 1991).
minute for 30 minutes, 166 mcg/kg per minute for 1 hour, and Weir and colleagues (1993) also noted the antiemetic effect in pediatric
150 mcg/kg per minute for the second and fourth hours. The predicted patients with strabismus who were anesthetized with propofol and
context-sensitive half-life in children was 10.4 minutes (for a 1-hour nitrous oxide compared with patients anesthetized with halothane and
infusion) to 19.6 minutes (4-hour infusion), compared with values of nitrous oxide. This antiemetic effect of propofol was even more pro-
6.7 to 9.5 minutes in adults. Engelhardt and colleagues (2008) prospec- nounced in patients who received no opioids. Reimer and colleagues
tively used this changing infusion schema to reach predicted propofol (1993) noted no difference in the incidence of emesis between pediat-
concentrations in 17 healthy children between 1 and 6 years of age. ric patients undergoing strabismus repair who were anesthetized with
kg lidocaine can markedly attenuate the pain on injection (Valtonen,

TABLE 8-8 Propofol: Indications, Route of
Iisalo, and Kanto 1989; Manschot, Meuring, and Axt 1992; Kwak et al.
Administration, and Dosage 2009). The addition of thiopental and the use of inhaled nitrous oxide
Recommendations also have been shown to attenuate the pain on injection (Beh, Splinter,
Indication Route Dose and Kim 2002; Cox 2002).
Induction (age more IV 2.5–3.5 mg/kg Involuntary motor movements have been associated with propofol,
than 3 years) and these spontaneous movement disorders appear to occur in the
Induction (obese; age IV 2 mg/kg absence of epileptic form activity on electroencephalography (Borgeat,
3 to 7 years) Wilder-Smith, and Despland 1993; Reynolds and Koh 1993). Anaphy-
Induction (adults) IV 2–2.5 mg/kg lactic reactions have also been reported. Initial studies with propofol
Sedation (infusion) IV 125–150 mcg/kg/minute using 10% polyethoxylated castor oil as a solubilizing agent had
Emergence Delirium IV 1–3 mg/kg (at end anesthesia) reported instances of anaphylactic reactions (Briggs, Clarke, and
Watkins 1982). Laxenaire and colleagues (1992) reported on 14 patients
From McGhee B, et al. Pediatric drug therapy handbook and with life-threatening reactions within minutes after receiving propofol.
formulary, 6th ed. Department of Pharmacy, Children’s Hospital of In some patients, these anaphylactic reactions occurred during the
Pittsburgh of UPMC; 2011. patient’s first exposure to propofol. Propofol is formulated as an emul-
References:
sion using soybean oil and egg lecithin. It has been suggested that
Aouad MT, Yazbeck-Karam VG, Nasr VG, et al. A single dose of
propofol at the end of surgery for the prevention of emergence
egg-allergic patients not be administered propofol, but there has not
agitation in children undergoing strabismus surgery during been a confirmed report of propofol-induced anaphylaxis by allergy
sevoflurane anesthesia. Anesthesiology. 2007;107:733. testing. Patients with egg allergies are generally hypersensitive to the
Costi D, Ellwood J, Wallace A, et al. Transition to propofol after proteins from egg whites, whereas lecithin is from the egg yolk. In
sevoflurane anesthesia to prevent emergence agitation: a randomized addition, propofol need not be contraindicated in children with soy
controlled trial. Pediatr Anesth. 2015 (Epub ahead of print). allergies because the soy oil used in propofol is refined, thereby elimi-
Olutoye OA, Yu X, Govindan K, et al. The effect of obesity on the nating the allergenic proteins (Bradley, Tober, and Brown 2008).
ED95 of propofol for loss of consciousness in children and Because of its lipid base, propofol has been associated with bacterial
adolescents. Anesth Analg. 2012;115:147. growth and patient infection if strict aseptic techniques during han-
dling are not observed. Because of patient safety concerns, 0.005%
ethylenediaminetetraacetate (EDTA) or metabisulfite was added to the
halothane and nitrous oxide and those receiving propofol in oxygen or formulation by different manufacturers. In a study comparing propo-
propofol with nitrous oxide. Differences between studies with regard fol with and without EDTA, Cohen and colleagues (2001) noted no
to the antiemetic effect of propofol may be a function of the basic differences in clinical profiles between the two drugs and noted that
design of each study. Variations in premedications, opioid administra- both formulations lower ionized calcium without any apparent clinical
tion, and postoperative fluid intake may be factors that make compari- effect.
sons of the studies difficult. A major concern with propofol administration is the development
In patients undergoing radiofrequency ablation, a procedure that of the propofol infusion syndrome (PRIS). PRIS has been defined as
is associated with an incidence of emesis as high as 60%, Erb and col- bradycardia during the infusion plus one or more of the following:
leagues (2002) noted that propofol-based anesthesia was associated lipemic plasma, hepatomegaly, metabolic acidosis with or without an
with a markedly decreased incidence of nausea (21%) and emesis (6%) increase in serum lactate, or rhabdomyolysis with myoglobinuria (Bray
compared with rates of nausea and vomiting of 63% and 55%, respec- 1998). The occurrence of deaths in infants, children, and adults has
tively, in children anesthetized with isoflurane. The antiemetic effects raised concerns regarding the safety of propofol infusions for ICU-
of propofol have also been demonstrated in pediatric patients under- patient sedations. The pathogenesis of PRIS is unclear, though it is
going short ear, nose, and throat surgical procedures and ambulatory thought that propofol disrupts mitochondrial fatty acid metabolism
surgical procedures (Borgeat, Popovic, and Meier 1990; Martin, Nicol- (Kam and Cardone 2007) or directly inhibits the mitochondrial respi-
son, and Bargas 1993). ratory chain by inhibition of coenzyme Q at complex II, cytochrome
Propofol has also been reported to be efficacious in reducing the c, or aa3 at complex IV (Vanlander et al. 2015). The rare occurrence
incidence of emergence delirium. In a study of pediatric patients of PRIS suggests a genetic susceptibility. PRIS is associated with con-
undergoing strabismus surgery, propofol bolus of 1 mg/kg at the end comitant catecholamine and steroid administration with high-dose
of sevoflurance anesthesia reduced the incidence of emergence delir- propofol infusion (>4 mg/kg/hr) over a prolonged amount of time
ium to 19.5 % compared to 47.2% with saline (Aouad et al. 2007). (>48 hrs). Although monitoring of biochemical markers has been pro-
Costi and colleagues (2015) found a reduced incidence of emergence posed to detect the development of PRIS, it may result in a false sense
delirium when propofol is administered as a 3 mg/kg bolus over 3 of security (Veldhoen, Hartman, and van Gestel 2009).
minutes at the end of sevoflurane anesthesia, but there was a slight
delay in recovery time. Ketamine
Side effects from propofol include tolerance to the drug, pain on Ketamine is a racemic, nonbarbiturate cyclohexamine derivative that
injection, spontaneous excitatory movements, and anaphylactic reac- produces dissociation of the cerebral cortex from the limbic system.
tions. Tolerance has been reported in a pediatric patient undergoing Ketamine noncompetitively antagonizes the N-methy-D-aspartate glu-
numerous exposures for radiation therapy (Deer and Rich 1992). Pain tamate (NMDA) receptor blocking afferent impulses in the diencepha-
from injection is a common problem with propofol administration lon and associated pathways of the cortex, sparing the reticular
and may be related to the size of the vein in which it is administered. formation of the brainstem (Domino, Chodoff, and Corssen 1965).
Westrin (1991) noted that pain during the injection occurred more There is often electroencephalographic seizure activity, particularly in
often in the infants (50%) than in the older children (18%). The addi- the limbic system and cortex, without clinical manifestations (Schwartz,
tion of 5 to 15 mcg/kg of alfentanil, 1% lidocaine (1 mg), or 0.1 mg/ Virden, and Scott 1974). Ketamine may also interact at other sites,
including monoaminergic receptors (cocaine effect), opioid receptors, Respiration and blood pressure are usually well maintained in the
muscarinic receptors, and voltage-sensitive sodium and L-type calcium anesthetic state associated with ketamine. At the high doses required
channels (Hirota and Lambert 1996; Wagner et al. 2001). Clinically, for lack of movement, ketamine has been associated with respiratory
ketamine produces a “dissociative anesthetic” with effective sedation depression and apnea in infants (Eng et al. 1975). Generalized extensor
and analgesia, but patients may keep their eyes open. Many reflexes are spasm with opisthotonos also has been seen in infants (Radney and
preserved, including the gag reflex, laryngeal irritability, and continued Badola 1973). Studies suggest that pulmonary vascular resistance is not
muscle tension. Intravenous doses of 2 mg/kg produce a highly pre- changed by ketamine in infants with either normal or elevated pulmo-
dictable response in children (Table 8-9). On a milligram-per-kilogram nary vascular resistance, as long as the airway and ventilation are
basis, the amount of ketamine required to prevent gross movements is maintained (Hickey, Hansen, and Cramolini 1984; Morray et al. 1984).
four times greater in infants younger than 6 months than in 6-year-old In a study of 60 children with congenital heart disease randomized to
children (Lockhart and Nelson 1974). receive propofol infusion or propofol with ketamine 0.5 mg/kg during
White and colleagues (1980) compared both the l- and d-isomers cardiac catheterization, Akin and colleagues (2005) reported that
of ketamine in adult surgical patients with respect to the efficacy and hypotension and bradycardia were higher in the group that received
side effects of these isomers. In this study, they noted that the d-isomer propofol alone. Williams and colleagues (2007) studied ketamine
produced the most satisfactory anesthetic state and the lowest inci- 2 mg/kg bolus over 5 minutes, followed by infusion at 10 mcg/kg per
dence of negative emergence reactions, whereas the l-isomer produced minute in 15 children with pulmonary hypertension having cardiac
the least satisfactory anesthesia and the highest incidence of emergence catheterization with sevoflurane (1 MAC decreased to 0.5 M AC after
reactions. ketamine) and spontaneous ventilation. No changes in pulmonary
The pharmacokinetics of ketamine in patients of different ages were artery pressure or resistance index were found. A retrospective review
determined (Table 8-10). In infants younger than 3 months old, the of the anesthetic records of 68 children with pulmonary hypertension
volume of distribution was similar to that in older infants, but who had ketamine administered during 149 procedures did not dem-
the elimination half-life was prolonged. Clearance was reduced in the onstrate increased complications associated with ketamine (Williams,
younger infants; reduced metabolism and renal excretion in the young Maan, and Ramamoorthy 2010).
infant are the likely causes. Ketamine is metabolized in the liver, and The mechanism of cardiorespiratory stimulation has not been
its major metabolite is norketamine. Norketamine has about 30% of entirely clarified. Dowdy and Kaya (1968), Wilson and colleagues
the clinical activity of ketamine. (1970) and other groups have shown that there is a direct negative
inotropic action on the denervated heart. In the presence of intact
sympathetic and autonomic nervous systems, however, a pressor effect
TABLE 8-9 Ketamine: Indications, Route of causes increased blood pressure, heart rate, and cardiac output, a
Administration, and Dosage response present in all ages. This serves as a most valuable adjunct in
Recommendations the management of poor-risk patients but is a contraindication in the
Indication Route Dose presence of hypertension or tachycardia. In their investigation of ket-
amine, Dowdy and Kaya (1968) also found evidence of antiarrhythmic
Premedication PO 6–10 mg/kg
activity.
Premedication IM 3–7 mg/kg
Ketamine increases cerebrospinal fluid pressure significantly for 5
Sedation IV 0.5–2 mg/kg per dose
to 15 minutes, but as shown by Dawson and colleagues (1971), the
Induction IV 1–2 mg/kg
increase may be held within acceptable limits by pretreatment with
Analgesic IV 0.1 mg/kg
thiopental (Gardner, Olson, and Lichtiger 1971; Lockhart and Jenkins
Analgesic (infusion) IV 0.1–0.3 mg/kg/hr
1972). Elevation of intraocular pressure also occurs after ketamine
From McGhee B, et al. Pediatric drug therapy handbook and administration. In a group of 15 children, Yoshikawa and Murai (1971)
formulary, 6th ed. Department of Pharmacy, Children’s Hospital of noted an average pressure increase of 30% that peaked within 15
Pittsburgh of UPMC; 2011. minutes and persisted for approximately 30 minutes after administra-
References: tion of ketamine. In addition to the elevation of intraocular pressure,
Gutstein HB, Johnson KL, Heard MB, et al. Oral ketamine nystagmus limits its usefulness in eye surgery.
preanesthetic medication in children. Anesthesiology 1992;76:28.
Although ketamine has no known toxic effects on the liver, kidneys,
Finkel JC, Pestieau SR, Quezado ZMN. Ketamine as an adjunct for
treatment of cancer pain in children and adolescents. J Pain.
or other organ systems, it has been associated with neuronal apoptosis
2007;8:515. after exposure in newborn animal model studies (Slikker et al. 2007;
Zou et al. 2009a, 2009b; Soriano et al. 2010; Liu et al. 2011; Paule et al.
2011). A major drawback to ketamine administration in older children
TABLE 8-10 Pharmacokinetics of is the high incidence of hallucinations and bad dreams. In adults, this
Ketamine: Effect of Age occurs in 30% to 50% of patients, and in prepubescent children, the
CL (mL/min
incidence is noted at 5% to 10%. Hallucinations were uncommon in
Age t1/2β (min) Vdss (L/kg) per kg)
children, but the awakening phase may entail considerable excitement
(Wilson, Traber, and Evans 1970).
Less than 3 months 184.7 3.46 12.9 Ketamine can be administered orally, and part of its effect is sec-
4 to 12 months 65.1 3.03 35 ondary to its metabolite norketamine. Gutstein and colleagues (1992)
4 years 31.6 1.18 25.1 compared oral premedication with ketamine at either 3 or 6 mg/kg.
Adult 107.3 0.75 20 With 3 mg/kg, 73% of the children were sedated within 30 minutes,
Modified from Lake CL. Pediaric anesthesia. East Norwalk, CT: while 100% of the patients were sedated and 67% tolerated intrave-
Appleton & Lange; 1988. nous cannulation at the 6 mg/kg dose (see Table 8-9). Onset times for
t1/2β, Elimination half-life; Vdss, volume of distribution at steady state; the 3- and 6-mg/kg dose groups were 19.6 and 11.2 minutes,
CL, clearance. respectively.
Use of low-dose ketamine as an analgesic adjunct has been shown The combination group had fewer patients needing rescue propofol
to decrease postoperative pain and opioid requirements in adults (Elia (83% vs. 100%) or fentanyl (43% vs. 75%) and showed more stable
and Tramer 2005; see Table 8-9). A meta-analysis by Dahmani and hemodynamics. However, 40% of the combination group had agita-
colleagues (2011) reviewed 35 randomized, blinded controlled trials of tion during recovery (vs. 6% with propofol alone). Coulter and col-
ketamine used systemically, locally, or by epidural routes for manage- leagues (2014) determined that the ratio of ketamine to propofol
ment of pediatric postoperative pain. They found that systemic ket- needed to be adjusted based on the proposed procedure so as not to
amine decreased pain intensity and analgesic requirements in the unduly prolong recovery. They suggested a ratio of ketamine to pro-
PACU, but these effects were limited in the early postoperative period pofol 1 : 5 for 30-minutes of anesthesia and 1 : 6.7 for 90 minutes of
(from 6 to 24 hours postoperatively). The use of ketamine as an adjunct anesthesia.
in caudal anesthesia increased the duration of sensory block and
decreased the PACU analgesic requirement without impacting pain Clonidine
intensity scores in the PACU. Overall, the meta-analysis found that Clonidine is an α2-adrenergic agonist that has been used as a premedi-
ketamine failed to exhibit a postoperative opioid-sparing effect cation, anesthetic adjunct, extender for postoperative analgesic
(Dahmani et al. 2011). Supporting this result, Pestieau and colleagues duration, and for prolonging the analgesia associated with regional
(2014) prospectively studied the use of a continuous perioperative anesthetic blocks. In one prospective, randomized, blinded study, 60
infusion of low-dose ketamine for scoliosis surgery and found similar children (aged 5 to 11 years) received placebo, 2 mcg/kg or 4 mcg/kg
postoperative opioid use, pain scores, and sedation score measure- oral clonidine 100 minutes before inhalation induction of anesthesia
ments compared to placebo. with halothane/N2O/O2 (Nishina et al. 1996). Sedation, separation
The effect of ketamine on chronic pain may differ from acute post- from family, and tolerance to mask application were better in the
operative pain. The addition of low-dose ketamine infusions in 11 4 mcg/kg clonidine group. Halothane was titrated to maintain blood
children with advanced cancer and pain that was inadequately treated pressure and heart rate within 20% of baseline, and the 4-mcg/kg
with high doses of opiates (0.1 to 0.2 mg/kg per hour titrated up to group used 45% less halothane. No postoperative delay in transfer to
0.5 mg/kg per hour in 3 of 11 patients) improved pain control and ward was found (15 to 17 minutes). Heart rates were slower in the
allowed decreases in opiate pain medications in 8 (Finkel, Pestieau, and group receiving 4 mcg/kg, but bradycardia did not occur, although all
Quezado 2007). children received atropine 30 mcg/kg with the premedication. Atro-
Several investigators have studied low-dose ketamine given intra- pine use is often recommended to minimize heart rate decreases, and
venously or into the tonsillar bed in children undergoing tonsillectomy, this extra step may be a partial explanation for the lack of more exten-
with conflicting results (O’Flaherty and Lin 2003; Conceicao, Brug- sive use of this agent.
gemann, and Carneiro 2006; Batra et al. 2007; Dal et al. 2007; Erk et al. Bergendahl and colleagues (2006) reviewed clonidine use as
2007; Abu-Shahwan 2008; Honarmand, Safavi, and Jamshidi 2008). premedication in pediatric anesthesia. Some studies reviewed found
Most studies involved 60 to 100 children and compared the periopera- improved postoperative analgesia with oral clonidine, decreased vom-
tive course in regard to pain scores, rescue analgesics, and side effects iting, and shivering. Postoperative confusion and agitation in young
to a control group (receiving saline). Ketamine at doses less than children receiving oral clonidine compared to placebo or midazolam
0.25 mg/kg were ineffective, and at 0.5 mg/kg results were positive in were reported by some. Persistence of postoperative sedation (or calm-
some studies and negative in others. A meta-analysis by Dahmani and ness) was a desirable feature to some assessors. A meta-analysis of
colleagues (2011) found that ketamine administered locally during a premedication with oral clonidine versus benzodiazepines found that
tonsillectomy decreased PACU and early postoperative (6- to 24-hour) clonidine was superior to midazolam in producing sedation, decreas-
pain scores, and decreased the PACU analgesic requirement without ing emergence agitation, and relieving postoperative pain (Dahmani
affecting the early postoperative analgesic requirement. Tong and col- et al. 2010). The papers evaluated for the meta-analysis only studied
leagues (2014) performed a meta-analysis on peritonsillar infiltration minor and short-duration procedures, however, and did not account
of ketamine versus placebo during tonsillectomy in pediatric patients for the effect of clonidine or benzodiazepines on recovery and readi-
and found that postoperative pain was relieved at 1 hour but not at 2 ness for discharge. The dose of oral clonidine commonly used for
hours. premedication in these studies was 4 mcg/kg.
Ketamine is frequently used for procedural sedation in children. Addition of clonidine to local anesthetics for caudal blocks has been
Because ketamine is distributed in a variety of different concentrations, successful in extending duration of analgesia in most studies, although
medication overdose can easily occur. Green and others (1999) reported increases in side effects have occurred in some studies. Two case reports
on healthy children undergoing procedural sedation that received 5 to of caudal blocks with clonidine in formerly premature infants with the
100 times the intended dose. Prolonged sedation was common, and appearance of postoperative apnea have limited its use in this popula-
brief respiratory depression occurred in some. tion. Concerns about the developing spinal cord being susceptible to
Ketamine can be safely combined with other drugs for anesthesia drug-related toxicity, coupled with the lack of minimal preclinical
and sedation (Topsun et al. 2007; Roelofse 2010). Slavik and Zed testing standards for neuraxial administered drugs, raises the question
(2007) reviewed studies of ketamine and propofol for procedural of whether these drugs should continue to be administered without
sedation and anesthesia using MEDLINE, EMBASE, and the Cochrane proper testing (Walker and Yaksh 2012).
databases and found eight clinical trials to include. They found that Hünseler and colleagues (2014) evaluated the effects of clonidine
the ideal ratio of ketamine to propofol was unclear; better clinical infusion on fentanyl and midazolam requirements during sedation for
efficacy of the combination over propofol alone was not shown; mechanical ventilation in neonates and infants. They found that cloni-
better hemodynamic and respiratory status was demonstrated in dine infusion at 1 ug/kg per hour decreased the fentanyl and mid-
some studies; and at higher ketamine doses, greater adverse effects azolam demand in ventilated neonates (aged 1 to 28 days) but not in
were apparent (Slavik and Zed, 2007). Aouad and colleagues (2008) older infants. The lack of effect in older infants was likely related to
conducted a prospective randomized double-blind comparison of the lower measured clonidine plasma concentrations compared to the
propofol alone (1 mg/kg) to propofol and ketamine (0.5 mg/kg of neonates. They did not find an increase in side effects with clonidine
each) in 63 children undergoing anesthesia for oncologic procedures. infusion.
Potts and colleagues (2007) conducted a population analysis of hemodynamic effects of hypotension or bradycardia are less com-
clonidine in children using NONMEM and reported their results using monly seen than with clonidine, they have been reported. The sedative
allometric scaling (to a standard of 70 kg). Published data from four effect of dexmedetomidine is attributed to hyperpolarization of nor-
studies (two intravenous, one rectal, and one epidural clonidine) were adrenergic neurons in the locus coeruleus (Carollo, Nossaman, and
combined with an open-label group of children who received clonidine Ramadhyani 2008). This suppression of locus coeruleus neurons is
1 to 2 mcg/kg after cardiac surgery (380 observations). The mean age similar to normal sleep. It provides respiratory stability, with no ven-
was 4 years, and the mean weight was 17.8 kg. Clearance was 14.6 L/ tilatory depression accompanying its sedative, anxiolytic, and analgesic
hr per 70 kg, central volume was 62.5 L/70 kg, and peripheral volume effects in adults. In neurosurgeries requiring an intraoperative “awake”
was 119 L/70 kg, with the distribution half-life of 12 minutes and period to assess patient responses during deep brain stimulation for
elimination half-life of 9 hours. At birth, clearance was low at 3.8 L/hr Parkinson’s disease, in surgeries near speech areas, or in surgery for
per 70 kg, reaching 82% of adult values by age 1 year. Absorption was epilepsy, dexmedetomidine has proved very useful to allow anesthesia
slower from epidural sites than the rectum (Fig. 8-e5) (Table 8-11). without intubation (Mack et al. 2004). Mahmoud and colleagues
Simulations showed that context-sensitive half-lives increased with (2009) have shown dexmedetomidine to be a useful anesthetic agent
infusion duration (1, 3, 6, and 10 hours) and decreased with increasing for magnetic resonance imaging (MRI) evaluations of airways in chil-
age (Table 8-12). The relatively long elimination half-life and impor- dren with obstructive sleep apnea (OSA). A promising finding is that
tance of intact renal function for clearance may be features explaining dexmedetomidine may exert a neuroprotective role: Sanders and col-
the preference for the α2-agonist dexmedetomidine. leagues (2009) showed that dexmedetomidine protects against
isoflurane-induced apoptosis in an in vivo and in vitro neonatal rat
Dexmedetomidine model. Dexmedetomidine has also been suggested as a novel treatment
Dexmedetomidine is a selective α2-agonist with sedative and analgesic for atrial and junctional tachyarrhythmias (Chrysostomou et al. 2008).
properties. Dexmedetomidine is more selective for the α2- Tobias and Berkenbosch (2004) reported early experience with dexme-
adrenoreceptor with a reported ratio of α2 to α1 of 1600 : 1, which is detomidine infusions in 30 ventilated infants and children, comparing
seven to eight times higher than that reported for clonidine. Although it with midazolam. Decreases in morphine use were found in the high-
dose dexmedetomidine group (0.5 mcg/kg per hour) compared with
those receiving midazolam (0.1 mg/kg per hour). Heart rates were
TABLE 8-11 Age-Related Clonidine slower in the dexmedetomidine group, but hypotension was not seen.
Clearances Described Using Both the In pediatric cardiac surgical patients, Chrysostomou and colleagues
(2009) suggested that higher doses may be needed in the younger ages
Allometric “3/4 Power” Model (70kg−1) and
groups. Achuff and colleagues (2015) showed that inclusion of dexme-
the Linear per Kilogram Models (kg−1)* detomidine bolus around the time of sternal closure was significantly
Age Weight (kg) CLstd (L/h per 70 kg) CL (L/h/kg) associated with decreased odds of requiring postoperative mechanical
0 3.5 3.83 0.116 ventilation in pediatric cardiac surgical patients, which was thought to
1 Month 4.5 4.93 0.14 be due to the decreased need for opioids.
3 Months 6 6.8 0.18 Dexmedetomidine has also been shown to reduce intraocular pres-
6 Months 7.5 8.96 0.224 sure (IOP), suggesting it may be a useful adjunct in ophthalmic surgery.
1 Year 10 12 0.278 Jaakola and colleagues (1992) found that a 0.6 mcg/kg bolus 10
2 Years 12 13.9 0.31 minutes prior to anesthesia induction decreased IOP by 34%. Increased
4 Years 16 14.6 0.273 IOP associated with laryngoscopy and tracheal intubation was also
10 Years 30 14.6 0.258 found to be attenuated by premedication with dexmedetomindine, an
effect partly explained by its hemodynamic effects (Scheinin et al.
From Potts AL, et al. Clonidine disposition in children: A population 1992; Mowafi et al. 2008).
analysis. Pediatr Anesth. 2007;17:924. Koroguli and colleagues (2005) noted in children aged 1 to 7 years
*Residual errors were similar between data from children undergoing undergoing MRI that dexmedetomidine was superior to midazolam.
cardiac surgery (additive error 0.02 mcg/L, proportional error 0.09%)
However, in a separate study, Koroguli and colleagues (2006) also
and those undergoing general surgery (additive error 0.03 mcg/L,
proportional error 0.11%).
noted that dexmedetomidine had slower recovery and discharge com-
pared with propofol. The slower recovery times with dexmedetomi-
dine compared with propofol have also been observed by Heard and
others (2008). The dosage of dexmedetomidine for sedation during
TABLE 8-12 Changes in Context-Sensitive noninvasive procedures and diagnostic imaging such as MRI typically
Half-Life with Age After an Infusion of consists of a 1- to 2-mcg/kg intravenous loading dose over 10 minutes
0.3 mcg/kg hr−1 followed by a continuous infusion at 0.5 to 1 mcg/kg/hr (Phan and
Age 1 Hour 3 Hours 6 Hours 10 Hours Nahata 2008).
Administration of dexmedetomidine results in a biphasic hemody-
Neonate 8 10.75 11.5 11.75
namic response with a transient increase in blood pressure followed
3 Months 5.5 8 8.25 8.5
by a decrease in blood pressure combined with a sustained decrease in
6 Months 4.25 6.5 7 7.25
heart rate. Hammer and colleagues (2008) reported dexmedetomidine
1 Year 3.3 5.25 6 6.25
effects on cardiac electrophysiology in 12 children (aged 5 to 17 years).
5 Years 2.8 5.25 6 6.25
Administration of 1 mcg/kg over 10 minutes followed by 0.7 mcg/kg
10 Years 2.75 5.75 6.25 6.75
per hour led to decreased heart rates, increased blood pressure, and
Adult 2.5 6.5 7.5 8.25
depressed sinus and atrioventricular (AV) node function. Respira-
From Potts AL et al. Clonidine disposition in children: A population tory rate and end-tidal CO2 during spontaneous ventilation were
analysis. Pediatr Anesth. 2007;17:924. unchanged (Hammer et al. 2008). The authors emphasized caution
2.5
IV Cardiac surgery
IV General surgery
Concentration (µg • l–1)
2
Epidural
Rectal
1.5
0.5
0
0 1 2 3 4
Time (h)
FIG 8-E5 Typical Time-Concentration Profiles for a 5-Year-Old

Child (20 kg) Given Intravenous, Epidural, and Rectal Clonidine
(2.5 mcg/kg−1). (From Potts AL, et al. Clonidine disposition in children:
A population analysis. Pediatr Anesth. 2007;17:924.)
TABLE 8-13 Dexmedetomidine Pharmacokinetic Studies

Author N Age Analysis CL mL/min/kg Vd L/kg t 12 b (min) Protein Binding
Petroz 36 2–12 yr Population 13 1 110 92.6% (n = 11)
Vilo 8 <2 yr Traditional 17.4 3.8 139
8 2–11 yr 17.3 1.2 96
Potts 45 4d–14 yr Population 7.8–13.6 0.97
Diaz 10 4 mo–7.9 yr Traditional 9.5 1.53 159
Chrysostomou 42 ≥28 wk Traditional 5 2.7–3.9 3.2–7.6 192–456
≤44 wk
Data from Petroz GC, Sikich N, James M, et al. A phase 1, two-center study of the pharmacokinetics and pharmacodynamics of
dexmedetomidine in children. Anesthesiol. 2006;105:1098; Vilo S, Rautiainen P, Kaisti K, et al. Pharmacokinetics of intravenous
dexmedetomidine in children under 11 years of age. Br J Anaesth. 2008;100:697; Potts AL, Warman GR, Anderson BJ. Dexmedetomidine
dispostion in children: A population analysis. Pediatr Anesth. 2008;18:722; Diaz SM, Rodarte A, Foley J. Pharamacokinetics of dexmedetomidine
in postsurgical pediatric intensive care patients: Preliminary study. Ped Crit Care Med. 2007;8:419-424; Chrysostomou C, Schulman S,
Castellanos MH, et al. A phase II/III multicenter, safety, efficacy, and pharmacokinetic study of dexmedetomidine in preterm and term neonates.
J Pediatr. 2014;164:276-282.
for dexmedetomidine use in patients who are poorly tolerant of bra- TABLE 8-14 Age-Related
dycardia or at risk for AV nodal block. Jooste and colleagues (2010)
Dexmedetomidine Clearances Described
demonstrated in pediatric postcardiac transplant patients that a rapid
IV bolus 0.5 mcg/kg of dexmedetomidine resulted in a decreased
Using Both the Allometric “3/4 Power”
heart rate and increases in systolic and diastolic blood pressure, pul- Model (per 70 kg) and the Linear per
monary artery pressure, pulmonary wedge pressure, and systemic vas- Kilogram Model (per kg)
cular resistance. All values other than heart rate returned to baseline CL std
after 5 minutes. These transient changes were more pronounced in the Age Weight (kg) (L/h/70 kg) CL (L/h/kg)
systemic system as opposed to the pulmonary circulation. In a study
0 3.5 15.56 0.47
of 400 patients undergoing tonsillectomy with and without adenoid-
1 Month 4.5 18.1 0.51
ectomy, Hauber and colleagues (2015) observed similar biphasic
3 Months 6 22.62 0.6
hemodynamic responses following a rapid injection of dexmedetomi-
6 Months 7.5 28.45 0.71
dine. Although bradycardia is a known side effect of dexmedetomi-
1 Year 10 34.09 0.79
dine, intravenous treatment with glycopyrrolate has resulted in an
2 Years 12 37.58 0.83
exaggerated hypertensive response (Mester et al. 2008; Mason et al.
3 Years 14 38.49 0.82
2009; Subramanyam et al. 2015).
4 Years 16 38.83 0.8
The pharmacokinetics of dexmedetomidine in adults provide
8 Years 25 39.13 0.72
desirable characteristics for use as titrated intravenous infusions for
12 Years 38 39.18 0.65
sedation and anxiolysis. Its elimination half-life is 2 hours (8 hours
for clonidine), and its distribution half-life is 6 minutes (Carollo, From Potts AL, et al. Dexmedetomidine disposition in children: A
Nossaman, and Ramadhyani 2008). Several groups have reported population analysis. Pediatr Anesth. 2008;18:722-730.
dexmedetomidine pharmacokinetics in children. Petroz and colleagues
(2006) studied 36 children, 18 from Canada and 18 from South Africa,
in an open-label study. Blood was sampled for 24 hours after 10-minute larger in the younger group, making the half-life longer. Interindivid-
infusions of 2, 4, or 6 mcg/kg per hour and analyzed by NONMEM. ual variation was large, especially in the infants. Chrysostomou and
Concentrations were below detection after 6 hours; a two-compartment colleagues (2014) studied the pharmacokinetic profile of dexmedeto-
model central volume of distribution of 0.8 L/kg was constructed with midine in intubated and mechanically ventilated preterm (28 weeks to
a systemic clearance of 0.013 L/kg per minute and an elimination half- less than 36 weeks) and full-term neonates (36 to 44 weeks). Data are
life of 110 minutes. Table 8-13 lists the pharmacokinetic values from summarized in Table 8-13. Preterm neonates, more so than full-term
this and other studies; a puzzling finding was dexmedetomidine con- neonates, had a lower clearance, larger volume of distribution, and
centrations that were consistently 30% higher in Canadian children, longer elimination t1/2 in this study compared to values previously
which was thought to have occurred because of a handling problem reported in older children and adults (see Table 8-13). Chrysostomou
with specimens. Context-sensitive decrement times did not increase and colleagues (2014) reported that only 10% of patients required
after 90- to 120-minute infusions, plateauing at about 70 minutes and more sedation, and 40% required more analgesia. Other than potential
the 80% decrement time at about 220 minutes. Heart rate and blood withdrawal, long-term use of dexmedetomidine for sedation in criti-
pressure decreased over the hour after the infusion and decreased with cally ill neonates and children appears to be safe, while providing
higher infusion doses, whereas respiration and oximetry were stable. opioid-sparing effects (Chrysostomou et al. 2006; Whalen et al. 2014).
Sedation lasted less than 1 hour. Potts and colleagues (2008) looked at population pharmacokinetics
Vilo and colleagues (2008), using noncompartmental pharmacoki- in 45 children after cardiac surgery aged 4 days to 14 years (mean age
netic models, studied eight children (aged 2 to 11 years) and eight of 3.4 years). Population parameter estimates for a two-compartment
infants (aged 1 to 23 months) after receiving dexmedetomidine at model using NONMEM were reported using allometric scaling to
1 mcg/kg. Data are summarized in Table 8-14. Clearance was similar 70 kg. In Table 8-13, the results are corrected for comparison with
in the two age groups, but volume of distribution (steady state) was others’ work. Clearance increased from 15.5 L/hour per 70 kg at birth
2.5 TABLE 8-15 Dexmedetomidine:

95% Prediction interval Indications, Route of Administration, and
Dosage Recommendations
Concentration (µg • l–1)
2 Mean concentration for

a 5-year-old child
Indication Route Dose
1.5
Premedication IM 1–2 mcg/kg
Premedication IN 2 mcg/kg (max 100 mcg/dose)
1
Repeat as needed in 5–15 minutes
Premedication IV 0.5 mcg/kg
0.5 Sedation (infusion) IV 1–2 mcg/kg over 10 minutes, then
0.5–1 mcg/kg/hr (children age <1
0 year may require up to 1.5 mcg/
0 1 2 3 4 5 6 kg/hr)
Time (h) Shivering IV 0.5 mcg/kg
Emergence Delirium IV 0.3 mcg/kg
FIG 8-6 Simulated Dexmedetomidine Concentration-Time
Profile After a Dosage Regimen of 1 mcg/kg−1 for 10 Minutes From McGhee B, et al. Pediatric drug therapy handbook and
and a Maintenance Infusion of 0.7 mcg/kg−1 per Hour−1 for 50 formulary, 6th ed. Department of Pharmacy, Children’s Hospital of
Minutes in a 5-Year-Old Child (20 kg), with 95% Prediction Inter- Pittsburgh of UPMC; 2011.
val Simulated Using 1000 Children with an Age Range of 2.4 References:
to 14.5 Years. Pharmacokinetic parameters for the simulation are Ibacache ME, Munoz HR, Brandes V, et al. 2004 Single-dose
those determined from this study. A concentration of 0.304 mcg/L−1 is dexmedetomidine reduces agitation after sevoflurane anesthesia in
associated with recovery from sedation (return to baseline alertness) children. Anesth Analg. 2004;98:60.
and is represented by the dashed line. (From Potts AL, et al. Dexme- Blaine Easley R, Brady KM, Tobias JD. Dexmedetomidine for the
detomidine disposition in children: A population analysis. Pediatr treatment of postanesthesia shivering in children. Paediatr Anaesth.
Anesth. 2008;18:722.) 2007;17:341.
to reach 72% adult values at 6 months and 87% by 1 year, indicating incidence of sevoflurane-associated emergence agitation, while Hauber
that age-specific dosing may be important (see Table 8-14). Clearance and colleagues (2015) demonstrated that a rapid bolus dose (over 2 to
in children at 39.2 L/hour per 70 kg is slightly less than adult values of 3 seconds) could be administered with minimal hemodynamic effect
44.8 to 52.5 L/hour per 70 kg. Volumes of distribution were 103.5 to and was also effective in decreasing the incidence of emergence agita-
126 L/70 kg, and half-lives were 12 minutes (α, distribution) and 2.3 tion in a study of 440 patients undergoing tonsillectomy with or
hours (β, elimination), similar to adult reports. Context-sensitive half- without adenoidectomy. Blaine Easley and colleagues (2007) reported
lives after infusions of 1, 3, and 10 hours were longer in neonates (1.24 that 0.5 mcg/kg of dexmedetomidine effectively stopped postoperative
for 1 hour to 2.07 for 10 hours) than at age 1 year (0.49 to 1.09 hours) shivering in children within 5 minutes. The postoperative clinical ben-
or in adults (0.49 to 1.45 hours). Large intersubject variability was efits of analgesia, reduced emergence agitation, and postoperative shiv-
attributed to age and size differences (Fig. 8-6). ering after dexmedetomidine premedication are supported by the data
In addition to intravenous administration, dexmedetomidine can summarized in the meta-analyses by Sun and colleagues (2014) and
also be administered transmucosally, intramuscularly, and intranasally Pasin and colleagues (2015), but decreased heart rate and blood pres-
(Table 8-15). Transmucosal dexmedetomidine has a bioavailability of sure, as well as prolonged duration, should be considered with dexme-
80% (Anttila et al. 2003). Dyck and colleagues (1993) demonstrated a detomidine premedication.
73% bioavailability after intramuscular administration in adult volun-
teers and that intramuscular injection did not result in the biphasic
hemodynamic response observed with intravenous administration.
SUMMARY
Intranasal doses of 1 to 2 mcg/kg have been shown to induce sedation
in children (Yuen et al. 2007, 2008; Talon et al. 2009). Sheta and col- Intravenous anesthetic agents can be administered for a variety of
leagues (2014) found that as a premedication, intranasal dexmedeto- clinical indications. Depending on the route administered and the dose
midine provided superior sedation compared to midazolam, but onset given, these agents can produce sedation or a state of general anesthe-
of effective sedation was longer with dexmedetomidine. Two separate sia. Their underlying pharmacokinetic properties, coupled with their
meta-analyses comparing premedication with dexmedetomidine to known side effects, are the major factors that influence their use.
midazolam via multiple routes of administration found that sedation Understanding the developmental differences in their pharmacology is
for separation from parents and mask acceptance was superior with essential for the safe practice of anesthesia.
dexmedetomidine (Sun et al. 2014; Pasin et al. 2015). Intranasal dex-
medetomidine premedication has also been shown to reduce the For questions and answers on topics in this chapter, go to “Chapter Ques-
minimum alveolar concentration of sevoflurane for laryngeal mask tions” at ExpertConsult.com.
insertion, with the additional benefit of reduced incidence of emer-
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dose of dexmedetomidine (0.3 mcg/kg) markedly attenuated the ExpertConsult.com.
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8

barbiturates develops rapidly and increases 30-fold during the first 3

1–6 6–12 1–4 4–7 7–12 12–16 Age

FIG 8-E1 Estimated ED50 ± SD for Thiopental in the Various

TABLE 8-1 Thiopental: Indications, Route TABLE 8-2 Methohexital: Indications,

From McGhee B, et al. Pediatric drug therapy handbook and

PLASMA METHOHEXITONE CONCENTRATION

FIG 8-E2 Plasma Methohexitone Concentrations After Rectal Administration of Methohexitone

Volume of distribution (L)

the clearance in nonventilated, critically ill children (16.7 mL/kg per 180

The pharmacokinetics of midazolam in premature infants has been

described by de Wildt and colleagues (2001, 2002). At 24 to 34 weeks’

distribution, clearance, and half-life of midazolam after a single

0.1-mg/kg intravenous bolus dose were 1.1 L/kg, 1.8 mL/kg per

200 TABLE 8-6 Midazolam: Indications, Route

DOSE OF ORAL MIDAZOLAM SYRUP (n = 397)

FIG 8-E4 Percentage of Patients Exhibiting Anxiety from Base-

0.3 mg/kg of intranasal midazolam. Walbergh and colleagues (1991)

They found concentrations were higher than predicted in the first 30

Propofol to 9 years required a dose of 2.5 mg/kg. In this study, propofol was

kg lidocaine can markedly attenuate the pain on injection (Valtonen,

FIG 8-E5 Typical Time-Concentration Profiles for a 5-Year-Old

TABLE 8-13 Dexmedetomidine Pharmacokinetic Studies

2.5 TABLE 8-15 Dexmedetomidine:

2 Mean concentration for

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the clearance in nonventilated, critically ill children (16.7 mL/kg per 180

0.1-mg/kg intravenous bolus dose were 1.1 L/kg, 1.8 mL/kg per

0.3 mg/kg of intranasal midazolam. Walbergh and colleagues (1991)

Propofol to 9 years required a dose of 2.5 mg/kg. In this study, propofol was