Tranquilizers

The major effect of tranquilizers is to allay anxiety, but they also have the potential to produce sedation. This group of drugs includes the benzodiazepines, phenothiazines, and butyrophenones. Benzodiazepines are widely used in children, whereas phenothiazines and butyrophenones are infrequently used.

Benzodiazepines

Benzodiazepines calm children, allay anxiety, and diminish recall of perianesthetic events. At low doses, minimal drowsiness and cardiovascular or respiratory depression are produced.

Midazolam, a short-acting, water-soluble benzodiazepine with an elimination half-life of approximately 2 hours, is the most widely used premedication for children.^112,113 The major advantage of midazolam over other drugs in its class is its rapid uptake and elimination.¹¹⁴ It can be administered intravenously, intramuscularly, nasally, orally, and rectally with minimal irritation, although it leaves a bitter taste in the mouth or nasopharynx after oral or nasal administration, respectively.^115–121 Peak plasma concentrations occur approximately 10 minutes after intranasal midazolam administration, 16 minutes after rectal administration, and 53 minutes after oral administration.^114,121,122 The relative bioavailability of midazolam is approximately 90% after intramuscular injection, 60% after intranasal administration, 40% to 50% after rectal administration, and 30% after oral administration, compared with intravenous administration (see Chapter 6).^122,123 After oral or rectal administration, there is incomplete absorption and extensive hepatic extraction of the drug during the first pass through the liver—hence, the need for large doses through these routes. Most children are adequately sedated after receiving a midazolam dose of 0.025 to 0.1 mg/kg intravenously, 0.1 to 0.2 mg/kg intramuscularly, 0.25 to 0.75 mg/kg orally, 0.2 mg/kg nasally, or 1 mg/kg rectally.

Orally administered midazolam is effective in calming most children and does not increase gastric pH or residual volume.^124,125 The current formulation of oral midazolam (2 mg/mL) is a commercially prepared, strawberry-flavored liquid. Two multicenter studies yielded slightly different responses to this preparation of oral midazolam in children.^126,127 In one study, 0.25, 0.5, and 1.0 mg/kg all produced satisfactory sedation and anxiolysis within 10 to 20 minutes,¹²⁷ whereas in the other study, 1.0 mg/kg provided greater anxiolysis and sedation than 0.25 mg/kg.¹²⁶ These differing results may be attributed to the older ages of children in the former study.¹²⁶

Recent evidence suggests that the required dose of midazolam increases as age decreases in children, similar to that for inhaled agents and intravenous agents.¹²⁸ An increased clearance in younger children contributes to their increased dose requirement.¹²⁹ Thus, greater doses may be required in younger children to achieve a similar degree of sedation and anxiolysis. However, the formulation of the oral solution may also attenuate its effectiveness.^130,131 A number of medications that affect the cytochrome oxidase system, significantly affect the first-pass metabolism of midazolam, including grapefruit juice, erythromycin, protease inhibitors, and calcium-channel blockers that decrease CYP3A4 activity, which in turn increases the blood concentration of midazolam and prolongs sedation.^132–138 Conversely, anticonvulsants (phenytoin and carbamazepine), rifampin, St. John’s wort, glucocorticoids, and barbiturates induce the CYP3A4 isoenzyme, thereby reducing the blood concentration of midazolam and its duration of action.* The dose of oral midazolam should be adjusted in children who are taking these medications.

Concerns have been raised about possible delayed discharge after premedication with oral midazolam. Oral midazolam, 0.5 mg/kg, administered to children 1 to 10 years of age did not affect awakening times, time to extubation, postanesthesia care unit, or hospital discharge times, after sevoflurane anesthesia.¹³⁹ Similar results have been reported in children and adolescents after 20 mg of oral midazolam, however, detectable preoperative sedation in this group of children was predictive of delayed emergence.¹⁴⁰ In children aged 1 to 3 years undergoing adenoidectomy as outpatients, premedication with oral midazolam, 0.5 mg/kg, slightly delayed spontaneous eye opening by 4 minutes and discharge by 10 minutes compared with placebo; children who had been premedicated, however, exhibited a more peaceful sleep at home on the night after surgery.¹⁴¹

Likely the greatest effect of oral midazolam on recovery occurs with its use in children undergoing myringotomy and tube insertion, a procedure that normally takes 5 to 7 minutes. In this surgery, the use of this premedication must be carefully considered. Oral midazolam decreased the infusion requirements of propofol by 33% during a propofol-based anesthesia, although the time to discharge readiness was delayed.¹⁴² After oral midazolam premedication (0.5 mg/kg), induction of anesthesia with propofol, and maintenance with sevoflurane, emergence and early recovery were delayed by 6 and 14 minutes, respectively, in children 1 to 3 years of age compared with unpremedicated children, although discharge times did not differ.¹⁴³ Increased postoperative sedation may be attributed to synergism between propofol and midazolam on γ-aminobutyric acid (GABA) receptors.¹⁴⁴

One notable benefit of midazolam is anterograde amnesia; children who were amnestic about their initial dental extractions tolerated further dental treatments better than those who were not amnestic.¹⁴⁵ It appears that memory becomes impaired within 10 minutes and anxiolytic effects are apparent as early as 15 minutes after oral midazolam.¹⁴⁶

Although anxiolysis and a mild degree of sedation occur in most children after midazolam, a few develop undesirable adverse effects. Some children become agitated after oral midazolam.¹⁴⁷ If this occurs after intravenous midazolam (0.1 mg/kg), intravenous ketamine (0.5 mg/kg) may reverse the agitation.¹⁴⁸ Adverse behavioral changes have been reported in the postoperative period after midazolam premedication. One study found that oral midazolam suppresses crying during induction of anesthesia but may cause adverse behavioral changes (nightmares, night terrors, food rejection, anxiety, and negativism) for up to 4 weeks postoperatively compared with placebo¹⁴⁹; this finding has not been substantiated.⁵⁹ One undesirable effect associated with midazolam, independent of the mode of administration (rectal, nasal, or oral), is hiccups (approximately 1%); the etiology is unknown.

Anxiolysis and sedation usually occur within 10 minutes after intranasal midazolam,¹⁵⁰ although it may be less effective in children with an upper respiratory tract infection (URI) and excessive nasal discharge.¹²¹ Intranasal midazolam does not affect the time to recovery or discharge after surgical procedures at least 10 minutes in duration.^151,152 Although midazolam reduces negative behavior in children during parental separation, nasal administration is not well accepted because it produces irritation, discomfort, and a burning aftertaste that may overshadow its positive sedative effects.^153–155 Another theoretical concern for the nasal route of administration of midazolam is its potential to cause neurotoxicity via the cribriform plate.¹²¹ There are direct connections between the nasal mucosa and the central nervous system (CNS) (E-Fig. 4-2). Medications administered nasally reach high concentrations in the cerebrospinal fluid very quickly.^156–158 To date, no such sequelae have been reported. Because midazolam with preservative has been shown to cause neurotoxicity in animals, we recommend only preservative-free midazolam for nasal administration.^159,160

E-FIGURE 4-2 Anatomy of the nasal mucosa–cribriform plate interface. The nasal mucosa is the only location in the body that provides a direct connection between the central nervous system (CNS) and the atmosphere. Drugs administered to the nasal mucosa rapidly traverse through the cribriform plate into the CNS by three routes: (1) directly via the olfactory neurons, (2) through supporting cells and the surrounding capillary bed, and (3) directly into the cerebrospinal fluid.

(From Hilger PA. Fundamentals of otolaryngology: a textbook of ear, nose, and throat diseases. 6th ed. Philadelphia: Saunders; 1989, p. 184.)

Sublingual midazolam (0.2 mg/kg) has been reported to be as effective as, and better accepted than, intranasal midazolam.¹⁶¹ Oral transmucosal midazolam given in three to five small allotments (0.2 mg/kg total dose) placed on a child’s tongue (8 months to 6 years of age) was found to provide satisfactory acceptance and separation from parents in 95% of children.¹⁶²

There is another pharmacodynamic difference among benzodiazepines that is important to consider when these drugs are administered intravenously. Entry into the CNS is directly related to fat solubility.^163,164 The greater the fat solubility, the more rapid the transit into the CNS. The time to peak CNS electroencephalographic effect in adults is 4.8 minutes for midazolam but only 1.6 minutes for diazepam (see Fig. 47-7). Therefore, when administering intravenous midazolam, one must wait an adequate interval between doses to avoid excessive medication and oversedation.

Diazepam is only used for premedication of older children. In infants and especially preterm neonates, the elimination half-life of diazepam is markedly prolonged because of immature hepatic function (see Chapter 6). In addition, the active metabolite (desmethyldiazepam) has pharmacologic activity equal to that of the parent compound and a half-life of up to 9 days in adults.¹⁶⁵ The most effective route of administration of diazepam is intravenous, followed by oral and rectal. The intramuscular route is not recommended because it is painful and absorption is erratic.^166–170 The combination of oral midazolam 0.25 mg/kg and diazepam 0.25 mg/kg has been shown to provide better sedation at induction of anesthesia and less agitation during emergence than oral midazolam 0.5 mg/kg in children undergoing adenotonsillectomy.¹⁷¹ The average oral dose for premedicating healthy children with diazepam ranges from 0.1 to 0.3 mg/kg; however, doses as large as 0.5 mg/kg have been used.¹⁷² A rectal solution of diazepam is more effective and reliable than rectally administered tablets or suppositories.^170,173 The recommended dose of rectal diazepam is 1 mg/kg, and the peak serum concentration is reached after approximately at 20 minutes.¹⁷³ When compared with rectal midazolam, rectal diazepam is less effective.¹⁷⁴

Lorazepam (0.05 mg/kg) is reserved primarily for older children. Lorazepam causes less tissue irritation and more reliable amnesia than diazepam. It can be administered orally, intravenously, or intramuscularly and is metabolized in the liver to inactive metabolites. Compared with diazepam, the onset of action of lorazepam is slower and its duration of action is prolonged. Whereas these characteristics make it a suitable premedication for inpatients, there are disadvantages for outpatients. When given the night before surgery to children undergoing reconstructive burn surgery, oral lorazepam, 0.025 mg/kg, significantly decreased preoperative anxiety.¹⁷⁵ The intravenous formulation of lorazepam is avoided in neonates because it may be neurotoxic.^176,177

Barbiturates

Barbiturates are among the oldest medications used for premedication in children, but they are infrequently used for this purpose any longer. The advantages of barbiturates include minimal respiratory or cardiovascular depression, anticonvulsant effects, and a very low incidence of nausea and vomiting. The major disadvantage of barbiturates is hyperanalgesia. In some cases, a small dose administered to children with pain may intensify the pain and cause them to become uncooperative.

The relatively short-acting barbiturates thiopental and methohexital may be given rectally to premedicate young children who refuse other modes of sedation. These drugs are usually administered in the presence of the parents who may hold the toddler until he or she is sedated.¹⁷⁸ The usual dose of rectal thiopental is 30 mg/kg. This dose produces sleep in about two thirds of the children within 15 minutes.^179,180 The elimination half-life of intravenous thiopental (9 ± 1.6 hours) is almost threefold greater than that of methohexital (3.9 ± 2.1 hours) owing to a slower rate of hepatic metabolism.¹⁸¹ There are few data comparing the elimination kinetics of rectally administered barbiturates.

As in the case of thiopental, rectal methohexital is rarely used for premedication any longer. For rectal premedication, a 10% solution of 25 mg/kg or a 1% solution of 15 mg/kg administered via a shortened suction catheter provides effective sedation within 10 to 15 minutes.^182–184 In some cases, the sedation may be profound, resulting in airway obstruction and laryngospasm. Hence, all children should be closely monitored with a source of oxygen, suction, and a means for providing ventilatory support; rectally administered methohexital has been reported to cause apnea in children with meningomyelocele.^185,186 Children chronically treated with phenobarbital or phenytoin are more resistant to the effects of rectally administered methohexital, probably because of enzyme induction.^183,187

Recovery after methohexital is relatively rapid, but the time required to return to full consciousness after a 30-minute or shorter surgical procedure is slightly prolonged compared with the time needed after 5 mg/kg of intravenous thiopental for the induction of anesthesia.¹⁸⁸

Additional disadvantages of rectal methohexital include unpredictable systemic absorption, defecation after administration, and hiccups. Contraindications to methohexital include hypersensitivity, temporal lobe epilepsy, and latent or overt porphyria.^189–191 Rectal methohexital is also contraindicated in children with rectal mucosal tears or hemorrhoids because large quantities of the drug can be absorbed, resulting in respiratory or cardiac arrest.

Nonbarbiturate Sedatives

Chloral hydrate and triclofos are orally administered nonbarbiturate drugs that are used to sedate children; both have slow onset times and are relatively long acting. They are converted to trichloroethanol, which has an elimination half-life of 9 hours in toddlers (see Fig. 47-3).¹⁹² Chloral hydrate is frequently used by nonanesthesiologists to sedate children.^193–195 It is rarely used by anesthesiologists because it is unreliable, has a prolonged duration of action, is unpleasant to taste, and is irritating to the skin, mucous membranes, and gastrointestinal tract. An oral dose (50 to 100 mg/kg with a total maximum dose of 2 g) is most effective when administered 1.5 to 2 hours before anesthesia (see Chapters 6 and 47). Its use in neonates is not recommended because of impaired metabolism,^196,197 nor is chronic administration recommended because of the theoretical possibility of carcinogenesis.¹⁹⁸ Children with hepatic failure may have prolonged action of chloral hydrate, and greater doses can produce significant respiratory depression in children with liver disease. Commercially prepared chloral hydrate is no longer available in the USA but a powdered form can be reconstituted by the hospital pharmacy for oral administration.

Opioids

Opioids may be useful to provide analgesia and sedation in children who have pain preoperatively, but they also confer side effects including nausea, vomiting, respiratory depression, sedation, and dysphoria. Therefore, all children who receive an opioid premedication should be continuously observed and monitored with pulse oximetry.

Morphine sulfate, 0.05 to 0.1 mg/kg intravenously, may be given to children with preoperative pain. It is also effective when given orally; rectal administration is not recommended owing to erratic absorption. Neonates are more sensitive to the respiratory depressant effects of morphine, and it is rarely used to premedicate that age group.¹⁹⁹

Fentanyl was introduced in a “lollipop” delivery system known as oral transmucosal fentanyl citrate (OTFC) for premedication in children in the United States but is no longer available for that indication. Its current use is to treat breakthrough cancer pain. It is nonthreatening and more readily accepted by children than other routes as a premedicant and facilitates separation from parents.²⁰⁰ Fentanyl is strongly lipophilic, and OTFC is readily absorbed from the buccal mucosa, with an overall bioavailability of approximately 50%.^201,202 The optimal dose for premedication is 10 to 15 µg/kg with minimal desaturation and preoperative nausea.^203,204 The onset of sedation is within 10 minutes, although the blood concentrations of fentanyl continue to increase for up to 20 minutes after completion. Recovery from anesthesia after a premedication of 10 to 15 µg/kg of oral fentanyl is similar to that after 2 µg/kg intravenously.²⁰³ Doses greater than 15 µg/kg are not recommended because of opioid adverse effects, particularly respiratory depression. The incidence of the opioid-associated adverse effects is increased when the interval between completion of “lollipop” and induction of anesthesia is prolonged.^204–207 Ondansetron given after the induction of anesthesia does not affect the frequency of opioid-related nausea and vomiting.²⁰⁸ Fentanyl has also been administered nasally (1 to 2 µg/kg) but primarily after induction of anesthesia as a means of providing analgesia in children without intravenous access.²⁰⁹

Sufentanil is 10 times more potent than fentanyl and is administered nasally in a dose of 1.5 to 3 µg/kg. Children are usually calm and cooperative, and most separate with minimal distress from their parents.¹⁵⁰ In a study that compared the adverse effects of nasally administered midazolam and sufentanil, midazolam caused more nasal irritation, whereas sufentanil caused more postoperative nausea and vomiting and reduced chest wall compliance. In addition, children in the sufentanil group were discharged approximately 40 minutes later than those in the midazolam group.¹⁵⁴ The potential adverse effects and prolonged hospital stay after nasal sufentanil makes it an unpopular choice for premedication.

Tramadol is a weak µ-opioid receptor agonist whose analgesic effect is mediated via inhibition of norepinephrine reuptake and stimulation of serotonin release. Tramadol is devoid of action on platelets and does not depress respirations in the clinical dose range.²¹⁰ Serum concentrations peak by 2 hours after oral dosing with clinical analgesia maintained for 6 to 9 hours. Tramadol is metabolized by CYP2D6 and is subject to variable responses based on polymorphisms of this enzyme.²¹¹ When oral tramadol (1.5 mg/kg) was given to children who had been premedicated with oral midazolam (0.5 mg/kg), it provided good analgesia after multiple dental extractions with no adverse respiratory or cardiovascular effects.²¹² Intravenous tramadol (1.5 mg/kg) given before induction of general anesthesia has been compared with local infiltration of 0.5% bupivacaine (0.25 mL/kg) for ilioinguinal and iliohypogastric nerve blocks. Tramadol was as effective as the regional blocks in terms of pain control, although the incidence of nausea and vomiting was greater in the tramadol group. Time to discharge was similar in both groups.²¹³

Butorphanol is a synthetic opioid agonist-antagonist with properties similar to those of morphine that can be administered nasally.²¹⁴ It is as effective as equipotent doses of intramuscular meperidine and morphine, with an onset of analgesic action in about 15 minutes and peak activity within 1 to 2 hours in adults. The most frequent adverse effect is sedation that resolves approximately 1 hour after administration. A dose of 0.025 mg/kg administered nasally immediately after the induction of anesthesia was shown to provide good analgesia after myringotomy and tube placement at the expense of an increased incidence of emesis at home compared with nonopioid analgesics such as acetaminophen.²¹⁵

When fentanyl or other opioids are combined with midazolam, they produce more respiratory depression than opioids or midazolam alone.²¹⁶ If opioids are used in combination with other sedatives such as benzodiazepines, the dose of each drug should be appropriately reduced to avoid serious respiratory depression. For example, if fentanyl is indicated to control pain in a child who has already received midazolam, the fentanyl dose should be titrated in small increments (0.25 to 0.5 µg/kg) to prevent hypoxemia and hypopnea or apnea.

Codeine is a commonly prescribed oral opioid that must undergo O-demethylation in the liver to produce morphine to provide effective analgesia. Between 5% and 10% of children lack the cytochrome isoenzyme (CYP2D6) required for this conversion and therefore do not derive analgesic benefit. On the other hand, a very small percentage of children are ultrarapid metabolizers who rapidly convert this prodrug to morphine (see Chapter 6 for further discussion). As a result, they may experience the more severe adverse effects and complications associated with morphine (the codeine metabolite) in addition to analgesia, particularly if excessive or frequent doses of codeine are prescribed. If these same children have been sensitized to opioids because of intermittent or chronic hypoxia, the adverse events may result in respiratory and cardiac arrest.²¹⁷

Codeine can be administered orally or intramuscularly but should not be administered intravenously because of the risk of seizures.^217a The usual oral dose of oral codeine is 0.5 to 1.5 mg/kg with an onset of action within 20 minutes and a peak effect between 1 and 2 hours. The elimination half-life of codeine is 2.5 to 3 hours. The combination of codeine with acetaminophen is effective in relieving mild to moderate pain. This combination was found to provide superior analgesia compared with acetaminophen alone after myringotomy and placement of pressure-equalizing tubes.^218,219 Codeine, like all opioids, may result in nausea and vomiting (see Chapter 6).

Ketamine

Ketamine is a phencyclidine derivative that produces dissociation of the cortex from the limbic system, producing reliable sedation and analgesia while preserving upper airway muscular tone and respiratory drive.²¹⁸ Ketamine may be administered by intravenous, intramuscular, oral, nasal transmucosal, and rectal routes. The disadvantages of ketamine include sialorrhea, nystagmus, an increased incidence of postoperative emesis, and possible undesirable psychological reactions such as hallucinations, nightmares, and delirium, although to date no psychological reactions have been reported after oral ketamine. Concomitant administration of midazolam may eliminate or attenuate these emergence reactions.^220,221 The addition of atropine or glycopyrrolate is recommended to decrease the sialorrhea caused by ketamine.²²²

Intramuscular ketamine is an effective means of sedating combative, apprehensive, or developmentally delayed children who are otherwise uncooperative and refuse oral medication. A low dose of 2 mg/kg is sufficient to adequately calm most uncooperative children in 3 to 5 minutes so that they will accept a mask for inhalation induction of anesthesia and does not prolong hospital discharge times even after brief procedures.¹¹⁰ However, the combination of intramuscular ketamine (2 mg/kg) and midazolam (0.1 to 0.2 mg/kg) significantly prolongs recovery and discharge times, making the ketamine-midazolam combination inappropriate for brief ambulatory procedures.²²³

Larger doses of intramuscular ketamine are particularly useful for the induction of anesthesia in children in whom there is a desire to maintain a stable blood pressure and in whom there is no venous access, such as those with congenital heart disease. Larger doses (4 to 5 mg/kg) sedate children within 2 to 4 minutes, and very large doses (10 mg/kg) induce deep sedation that may last from 12 to 25 minutes. Larger doses and repeated doses may be associated with hallucinations, nightmares, vomiting, and unpleasant, as well as prolonged, recovery from anesthesia.^110,224 Concentrations of ketamine of 100 mg/mL are available in the United States and several other countries for intramuscular injection. It is imperative to label these syringes to avoid a syringe swap with syringes containing more dilute concentrations of ketamine. Oral ketamine alone and in combination with oral midazolam is an effective premedication and has been used to alleviate the distress of invasive procedures (e.g., bone marrow aspiration) in pediatric oncology patients.^225,226 In a dose of 5 to 6 mg/kg, oral ketamine alone sedates most children within 12 minutes and provides sufficient sedation in more than half of the children to permit establishing intravenous access.^223,227 A larger dose of 8 mg/kg prolongs recovery from anesthesia, although by 2 hours the recovery was no different from that after 4 mg/kg.²²⁸ Doses of up to 10 mg/kg have been described as a premedicant for children having procedures for burns; the relative bioavailability was 45%, and absorption was slow with an absorption half-life of 1 hour in this cohort.²²⁹

The combination of oral midazolam and ketamine provides more effective preoperative sedation than either drug alone. This oral lytic cocktail is a good alternative for children who were not adequately sedated with oral midazolam alone. The combination of oral ketamine (3 mg/kg) and midazolam (0.5 mg/kg) did not prolong recovery after surgical procedures that lasted more than 30 minutes.²³⁰

Nasal transmucosal ketamine in a dose of 6 mg/kg is also an effective premedication for children, with sedation developing by 20 to 40 minutes.²³¹ In theory, nasally administered ketamine could cause neural tissue damage if it reaches the cribriform plate (see E-Fig. 4-2). Because the preservative in ketamine is neurotoxic, preservative-free ketamine may be safer to administer by the nasal route, although this has not been established.²³² If ketamine is given by this route, we recommend the 100 mg/mL concentration to minimize the volume that must be instilled.

Rectal ketamine (5 mg/kg) produces good anxiolysis and sedation within 30 minutes of administration.²³³ However, the rectal route does not provide reliable absorption.

α₂-Agonists

Clonidine, an α₂-agonist, causes dose-related sedation by its effect in the locus ceruleus.²³⁴ After oral administration, the plasma concentration peaks at approximately 60 minutes,²³⁵ similar to rectal administration, which peaks at about 50 minutes.²³⁶ An oral dose of 3 µg/kg given 45 to 120 minutes before surgery produces comparable sedation to that of diazepam or midazolam.²³⁷ Oral clonidine combined with 0.15 mL/kg of apple juice 100 minutes before the induction of anesthesia does not affect the gastric fluid pH and volume in children.²³⁸ Clonidine acts both centrally and peripherally to reduce blood pressure, and therefore it attenuates the hemodynamic response to intubation.²³⁹ It appears to be devoid of respiratory depressant properties, even when administered in an overdose.²³⁴ The sedative and CNS properties of clonidine reduce the dose of intravenous barbiturate required for induction of anesthesia²³⁹ as well as the minimum alveolar concentration (MAC) of sevoflurane for tracheal intubation²⁴⁰ and the concentration of inhaled anesthetic required for the maintenance of anesthesia, as evidenced by the hemodynamic stability.^241–243 Oral clonidine (2 or 4 µg/kg) reduces MAC for tracheal extubation (MAC-ex) for sevoflurane by 36% and 60%, respectively. These doses neither prolonged emergence from anesthesia nor led to airway-related complications.²⁴⁴

During the first 12 hours after surgery, oral clonidine (4 µg/kg) reduced the postoperative pain scores and the requirement for supplementary analgesics.^245,246 In children scheduled for tonsillectomy, those who received oral clonidine (4 µg/kg) exhibited more intense anxiety on separation and during induction than those who received oral midazolam (0.5 mg/kg). However, those who received clonidine had reduced mean intraoperative blood pressures; reduced duration of surgery, anesthesia, and emergence; and decreased need for supplemental oxygen during recovery but greater postoperative opioid requirements, greater pain scores, and greater excitement. Parenthetically, these observations are not consistent with previously reported analgesic and anesthetic properties of clonidine. Even though discharge readiness, postoperative emesis, and 24-hour analgesic requirements were similar in both groups, midazolam was judged to be the better premedicant for children undergoing tonsillectomy.²⁴⁷ Oral clonidine (4 µg/kg) reduces the incidence of vomiting after strabismus surgery compared with a placebo, clonidine (2 µg/kg), and oral diazepam (0.4 mg/kg).²⁴⁸

Although oral clonidine offers several desirable qualities as a premedication, particularly sedation and analgesia, the need to administer it 60 minutes before induction of anesthesia makes its use impractical in many busy outpatient settings.²⁴⁷ One study found that an oral dose of 4 µg/kg attenuated the hyperglycemic response to a glucose infusion and the surgical stress in children undergoing minor surgery, possibly by inhibiting the surgical stress release of catecholamines and cortisol. Children who were involved in surgeries that lasted 1.7 hours did not develop hypoglycemia, but in the absence of intraoperative glucose infusions, there is a risk of hypoglycemia during operations of prolonged duration.²⁴⁹

Dexmedetomidine is a sedative with properties that are similar to those of clonidine except that it has an eightfold greater affinity for the α₂-adenoreceptors than clonidine. Based on bioavailability studies in adults,²⁵⁰ it is well absorbed through the oral mucosa. In a study of 13 children aged 4 to 14 years, of whom 9 had neurobehavioral disorders, an oral dose of 2 µg/kg of dexmedetomidine provided adequate sedation for a mask induction within 20 to 30 minutes of administration. It was postulated that a larger dose of 3 to 4 µg/kg might be more effective.²⁵¹

Intranasal administration of 1 and 1.5 µg/kg dexmedetomidine produced significant sedation after 45 minutes with a peak effect at 90 to 150 minutes as compared with placebo. In addition, decreases in systolic blood pressure and heart rate were reported.²⁵²

In children with burns, both 2 µg/kg intranasal dexmedetomidine and 0.5 mg/kg oral midazolam administered 30 to 45 minutes before induction of anesthesia provided adequate conditions for induction of anesthesia and emergence, although dexmedetomidine produced more sleep preoperatively.²⁵³ Oral midazolam (0.5 µg/kg given 30 minutes before surgery), oral clonidine (4 µg/kg given 90 minutes before surgery), and transmucosal dexmedetomidine (1 µg/kg given 45 minutes before surgery) all produced similar preanesthetic sedation and response to separation from parents in a comparative trial, although children who received dexmedetomidine and clonidine experienced attenuated mean arterial pressure and heart rate preoperatively and reduced pain scores postoperatively compared with midazolam.²⁵⁴

Antihistamines

Antihistamines are rarely used for premedication in children, in part because their sedative effects are quite variable. They are very rarely given to infants but may occasionally be indicated for older children, especially those who are hyperkinetic.

Hydroxyzine is mainly administered for its tranquilizing properties^255,256; it also has antiemetic, antihistaminic, and antispasmodic properties, with minimal respiratory and circulatory effects. It is commonly administered with other classes of drugs as an intramuscular “cocktail” in a dose of 0.5 to 1.0 mg/kg.

Diphenhydramine is an H₁ blocker with mild sedative and antimuscarinic effects. The dose in children is 2.5 to 5 mg/kg/day (maximum 300 mg/day) in four divided doses orally, intravenously, or intramuscularly. Although the duration of action is 4 to 6 hours, it does not appear to interfere with recovery from anesthesia.²⁵⁷ The combination of oral diphenhydramine (1.25 mg/kg) and oral midazolam (0.5 mg/kg) has been used to provide sedation for healthy children undergoing MRI.²⁵⁸ The combination was more effective than midazolam alone without a delay in discharge and recovery times.

Anticholinergic Drugs

In the past, anticholinergic agents were used (1) to prevent the undesirable bradycardia associated with some anesthetic agents (halothane and succinylcholine), (2) to minimize the autonomic vagal reflexes manifested during surgical manipulations (e.g., laryngoscopy, strabismus repair), and (3) to reduce secretions. The most commonly used anticholinergic drugs are atropine, scopolamine, and glycopyrrolate. Anticholinergics also provide undesirable effects including tachycardia, dry mouth, skin erythema, and hyperthermia due to inhibition of sweating. Atropine and scopolamine cross the blood-brain barrier and may cause CNS excitation manifested as agitation, confusion, restlessness, ataxia, hallucinations, slurred speech, and memory loss if given in excessive doses.

Because most modern inhalational anesthetics are not associated with bradycardia and succinylcholine is infrequently used in children, the routine use of an anticholinergic drug is not generally warranted. Most anesthesiologists administer these agents only when indicated, such as before intravenous succinylcholine, combined with ketamine, before laryngoscopy and intubation in neonates, and when surgery stimulates vagal reflexes, such as during strabismus repair. In the majority of cases, anticholinergics need not be given preoperatively but rather should be given after intravenous access is established.

The recommended doses of anticholinergics are atropine, 0.01 to 0.02 mg/kg, and scopolamine, 0.005 to 0.010 mg/kg. Atropine is more commonly used and blocks the vagus nerve more effectively than scopolamine, whereas scopolamine is a better sedative, antisialagogue, and amnestic. Infants who are at risk for or show early evidence of a slowing of the heart rate should receive the atropine before the heart rate actually decreases to ensure a prompt onset of effect to maintain cardiac output.²⁵⁹ Glycopyrrolate is a synthetic quaternary ammonium compound that does not cross the blood-brain barrier. It is twice as potent as atropine in decreasing the volume of oral secretions, and its duration of effect is three times greater. The recommended dose of glycopyrrolate (0.01 mg/kg) is half that of atropine. The routine use of an anticholinergic drug for the sole purpose of drying secretions is probably unwarranted, because a dry mouth can be a source of extreme discomfort for a child. Therefore, it is best to reserve the use of glycopyrrolate for specific indications such as to limit sialorrhea associated with ketamine.

Topical Anesthetics

The child’s exaggerated fear of the needle makes topical anesthetic creams an attractive alternative to intradermal infiltration and intramuscular injections. There are several needleless methods to minimize procedural pain, each with its own limitations.

EMLA cream (eutectic mixture of local anesthetic, Astra Zeneca, Wilmington, Del.) is a mixture of two local anesthetics (2.5% lidocaine and 2.5% prilocaine). One-hour application of EMLA cream to intact skin with an occlusive dressing provides adequate topical anesthesia²⁶⁰ for a variety of superficial procedures, including intravenous catheter insertion, lumbar puncture, vaccination, laser treatment of port-wine stains, and neonatal circumcision.^261–266 However, EMLA causes venoconstriction and skin blanching, both of which obscure superficial veins, making intravenous cannulation more difficult.²⁶⁷ The prilocaine in EMLA may cause methemoglobinemia,²⁶⁸ although, a 1-hour application at a maximum dose of 1 gram did not induce methemoglobinemia when applied to intact skin in full-term neonates and infants younger than 3 months of age.²⁶⁹ Lidocaine toxicity has been reported when EMLA was applied to mucosal membranes for extended periods.²⁷⁰

Ametop is a topical local anesthetic (4% tetracaine) that is available in the United Kingdom, Europe, and Canada (Smith and Nephew, Lachine, Quebec) but not in the United States. Its indications are identical to those of EMLA, but its properties are different. When applied to intact skin under an occlusive dressing, it anesthetizes the skin within 30 to 40 minutes, and it produces no venoconstriction or skin blanching and zero risk of methemoglobinemia.

ELA-Max (4% lidocaine) is another topical anesthetic cream that decreases the pain associated with dermatologic procedures²⁷¹ and intravenous catheter insertion after only a 30-minute application.²⁷² ELA-Max causes some blanching of the skin, like EMLA cream but to a lesser extent, and dilates the veins better than EMLA cream.²⁷³

The S-Caine Patch (ZARS, Inc., Salt Lake City) is a eutectic mixture of lidocaine and tetracaine (70 mg of each per patch) that uses a controlled heating system to accelerate delivery and effectiveness of the local anesthetic. After 20 minutes of application, the pain associated with venipuncture is reduced. This patch causes mild and transient local erythema and edema and no blanching of the skin.²⁷⁴ Other noninvasive topical anesthetic delivery systems are available, such as lidocaine iontophoresis using an impregnated electrode, a current generator, and a return pad to carry ionized lidocaine through the stratum corneum.²⁷⁵ This technique provides similar pain relief for insertion of intravenous catheters in children as EMLA cream but requires extra equipment and training for proper application.²⁷⁶ Lidocaine iontophoresis also causes a stinging pain that some children experience during current application, and potential skin burns from the electrodes.²⁷⁷ Needle-free injection systems for lidocaine are also available for pain free insertion of intravenous cannulae or other needle-based procedures.^277a,277b

Nonopioid Analgesics

Acetaminophen is the most common nonopioid analgesic used for treatment of postoperative pain in children. It can be administered orally preoperatively, rectally immediately after induction of anesthesia but before the start of surgery, or intravenously (where available) once intravenous access has been established.

The oral doses of acetaminophen for antipyresis,10 to 15 mg/kg, are as effective as ketorolac, 1 mg/kg,²⁷⁸ given 10 or more minutes postoperatively for myringotomies and tube placement.²⁷⁹ Oral acetaminophen is very rapidly absorbed with a bioavailability of 0.9-1.²⁷⁹ Neonates may have a lower incidence of hepatotoxicity because the immature hepatic enzyme systems in neonates produce less toxic metabolites than in older children.^280–282 When given preemptively, acetaminophen has opioid-sparing properties that enhance analgesia in children after tonsillectomy.^283,284 Preoperative oral acetaminophen and codeine provided superior analgesia to acetaminophen alone after myringotomy and tube placement.²¹⁹ However, in children undergoing tonsillectomy, there was no difference in the level of pain control provided by acetaminophen and acetaminophen with codeine. Postoperative oral intake was significantly higher in children treated with acetaminophen alone.²⁸⁵ A relationship between concentration and analgesic effect for pain relief after tonsillectomy has been observed in children. An effect compartment concentration of 10 mg/L was associated with a reduction of pain by 2.6 units (using a visual analogue scale ranging from 0 to 10).²⁸⁶

The time to the peak blood concentration of acetaminophen after rectal administration of 10, 20, and 30 mg/kg ranges between 60 and 180 minutes after administration. In addition, the equilibration half-time between plasma and effect compartment is approximately 1 hour.²⁸⁶ This slow absorption and delayed effect site concentrations require acetaminophen administration immediately after induction of anesthesia to provide sufficient time to achieve therapeutic blood concentrations by the end of surgery (primarily for operations that will take 1 hour or longer).²⁸⁷ Furthermore, doses of 10 to 30 mg/kg rectal acetaminophen may not achieve peak or sustained blood concentrations that ensure effect (Fig. 4-2). Thus, an initial dose of rectal acetaminophen of 40 mg/kg has been recommended, followed by 20 mg/kg rectally every 6 hours. This dosing regimen was subsequently confirmed.²⁸⁸ After 45 mg/kg rectal acetaminophen, the mean maximum blood concentration was 13 µg/mL (range 7 to 19), and the mean time to that maximum concentration was approximately 200 minutes.²⁸⁹ Several other single-dose rectal administration studies reported similar results.^289,290

FIGURE 4-2 Acetaminophen concentrations after rectal administration of 10, 20, or 30 mg/kg were recorded. Values for serum concentration of acetaminophen (solid circles, teal lines) are plotted against time for each child. Thick (magenta) lines indicate “average” values. Note that only children who received 30 mg/kg achieved the antipyretic threshold of 10 to 20 µg/mL, but that even at this dose that range was not sustained. These data suggest the need to use a larger loading dose (approximately 40 mg/kg) followed by subsequent doses of 20 mg/kg every 6 hours; see text for details.

(From Birmingham PK, Tobin MJ, Henthorn TK, et al. Twenty-four-hour pharmacokinetics of rectal acetaminophen: an old drug with new recommendations. Anesthesiology 1997;87:244-52.)

For children undergoing tonsillectomy, a preoperative oral dose of 40 mg/kg plus 20 mg/kg rectally 2 hours later was associated with satisfactory pain scores for about 8 hours after administration.²⁷⁹ With doses of 40 to 60 mg/kg rectally administered after induction of anesthesia but before surgery, children required less rescue morphine postoperatively and less analgesia at home than children who received either a placebo or 20 mg/kg of acetaminophen rectally.²⁸⁴ In addition, the children who received larger doses of acetaminophen experienced less postoperative nausea and vomiting. However, until further safety data are developed, the initial dose of acetaminophen should not exceed 40 to 45 mg/kg with a total 24-hour dose of not more than 100 mg/kg in order to avoid hepatic toxicity. Acetaminophen administered rectally in a loading dose of 40 mg/kg and then 20 mg/kg either orally or rectally every 6 hours after elective craniofacial surgery yielded greater plasma concentrations and lower pain scores than those who received oral acetaminophen; this was in part related to some children vomiting the oral acetaminophen.²⁹¹ Note that these are excessive oral doses which cannot be recommended.

Excessive fasting, a very large loading dose of acetaminophen, and sevoflurane anesthesia may deplete glutathione stores and thus contribute to the development of hepatic failure.²⁹² The coadministration of antiepileptic drugs has also been implicated in hepatotoxicity from acetaminophen.²⁹³ Because hepatic toxicity is a real and potentially fatal complication of an acetaminophen overdose, a complete medication history of acetaminophen consumption and concomitant drugs should be completed preoperatively, and the recommended maximum daily dose should not be exceeded.

There are two different intravenous formulations of acetaminophen available in some countries.²⁹⁴ One is a prodrug of acetaminophen (propacetamol) with a bioavailability of 50%. It may be administered in a dose of 30 mg/kg (15 mg/kg acetaminophen) every 6 hours to children 2 to 15 years of age. In a placebo-controlled trial in febrile children, this dose of propacetamol was superior to placebo.²⁹⁵ Pharmacokinetic studies indicate that such a dose of propacetamol maintains mean steady-state blood concentrations of acetaminophen of 10 µg/mL.²⁹⁶ Therapeutic blood concentrations are achieved in neonates 10 days of age or younger with 15 mg/kg of propacetamol four times daily, but neonates older than 10 days require twice the dose, or 30 mg/kg at the same frequency.²⁹⁷ Hemostatic effects of large (60 mg/kg) doses of propacetamol in adult volunteers showed transient but reversible inhibition of platelet aggregation as well as decreased thromboxane activity. Although these effects were less than those after ketorolac (0.4 mg/kg), the combination of acetaminophen and ketorolac may prolong these effects.²⁹⁸

A new intravenous formulation of paracetamol (15 mg/kg) was introduced and compared with propacetamol, 30 mg/kg, for postoperative pain relief after inguinal hernia repair. The outcomes were similar, but intravenous paracetamol was better tolerated at the injection site.²⁹⁹

In a study of 50 children, ages 2 to 5 years, undergoing elective adenoidectomy or adenotonsillectomy, intravenous acetaminophen 15 mg/kg or rectal acetaminophen 40 mg/kg resulted in equivalent pain scores. The time to the first rescue analgesic in the rectal acetaminophen group (median 10 hours, attributed to its slow absorption) was greater than in the intravenous acetaminophen group (median 7 hours), although few children in either group required any rescue analgesics during the first 6 hours.³⁰⁰ Intravenous acetaminophen (15 mg/kg) has been compared with intramuscular meperidine 1 mg/kg in children undergoing tonsillectomy. When compared with meperidine, intravenous acetaminophen resulted in comparable analgesia but less sedation and earlier readiness for discharge.³⁰¹ In children undergoing dental restoration with the same medications and doses, children in the acetaminophen group had greater pain scores but earlier readiness for recovery room discharge.³⁰²

Current dosing recommendations for intravenous paracetamol in children and adolescents 2 to 12 years old weighing less than 50 kg is 15 mg/kg every 6 hours with a maximum of 75 mg/kg/day. In infants 1 month to 2 years of age, dosing from the pharmacokinetic data suggests a dose reduction of 33%, 10 mg/kg every 4 hours or 12.5 mg/kg every 6 hours with a maximum dose of 50 to 60 mg/kg/day. In full-term neonates up to 28 days of age, the dose of intravenous acetaminophen should be reduced by 50% to 7.5 mg/kg every 6 to 8 hours with a maximum daily dose of 30 mg/kg. This dosing regimen produces a similar pharmacokinetic profile as in children older than 2 years of age.^303,304 The major concern in this age group is accidental overdose of acetaminophen and hepatic toxicity. Three near-fatal cases of infants who received 10- and 20-fold overdoses of intravenous acetaminophen have been reported.^305,306 Careful documentation of the dose of intravenous acetaminophen is warranted in infants.³⁰⁷

Combinations of nonsteroidal antiinflammatory drugs (NSAIDs) can be more effective in pain management than single-agent therapy.³⁰⁸ Children undergoing suboccipital craniotomy who received a combination of oral acetaminophen (10 mg/kg) and ibuprofen (10 mg/kg) alternating every 2 hours had better pain scores and decreased opioid and antiemetic interventions compared with those who received analgesic medications only when requested.³⁰⁹

Ibuprofen is a commonly used NSAID. In children undergoing a variety of surgical procedures, rectal ibuprofen (40 mg/kg/day in divided doses) was given for up to 3 days supplemented with intravenous or intramuscular morphine as clinically indicated. The need for supplemental morphine during the 3-day study period was less for those who received the rectal ibuprofen than for those without ibuprofen.³¹⁰ Children undergoing bilateral myringotomy who were given either oral ibuprofen (10 mg/kg) or acetaminophen (15 mg/kg) demonstrated similar pain scores.³¹¹ Rectal ibuprofen alone provided insufficient analgesia for children undergoing ambulatory adenoidectomy.³¹²

A combination of acetaminophen and codeine provides superior analgesia to ibuprofen after tonsillectomy. Furthermore, the children who received ibuprofen had a significant increase in bleeding time.³¹³ In an unblinded study, ibuprofen provided similar postoperative analgesia as acetaminophen with codeine after tonsillectomy with less nausea and vomiting and no increase in bleeding.³¹⁴ The combination of acetaminophen with ibuprofen, but not with rofecoxib, reduced the need for early analgesia by 50% in children undergoing tonsillectomy compared with acetaminophen alone.³¹⁵ Ibuprofen provides analgesia superior to placebo and equal to acetaminophen in children undergoing dental procedures.³¹⁶ Ibuprofen should not be used in children with impaired renal function or in those who are hypovolemic because of the increased risk of renal toxicity.^317,318

Ketorolac is an NSAID that can be administered parenterally or orally, intraoperatively, or postoperatively. Ketorolac has an opioid-sparing effect, reducing the incidence of adverse effects of opioids such as respiratory depression, nausea, and vomiting. Features that may limit the usefulness of this drug include gastrointestinal irritation, antiplatelet effects, and limited safety data. In children, small cohort pharmacokinetic studies failed to demonstrate any age-related differences in pharmacokinetics.³¹⁹ However, stereospecific pharmacokinetics of ketorolac in infants and toddlers aged 6 to 18 months showed differences in pharmacokinetics between the R(+) and S(−) isomers with more rapid elimination of the analgesic S(−) isomer. Thus, smaller dose intervals of 4 hours rather than 6 hours may be needed in infants older than 6 months to achieve serum concentrations comparable to the adult effective concentration (EC₅₀).³²⁰

Ketorolac diminishes emergence agitation and pain when given intravenously after induction for myringotomy and tube insertion.³²¹ However, ketorolac (1 mg/kg) provided no better pain relief than rectal acetaminophen (35 mg/kg) in children undergoing tonsillectomy with or without adenoidectomy.³²² Ketorolac (1 mg/kg) intramuscularly or intravenously before tonsillectomy increased intraoperative and postoperative blood loss compared with codeine (1.5 mg/kg) intramuscularly³²³ or morphine (0.1 mg/kg) intravenously.^324,325 In the same study, there was no difference in awakening time or readiness for discharge among the treatment groups. In contrast, when ketorolac was given as a single dose at the end of tonsillectomy there was no increase in posttonsillectomy hemorrhage, although duration of hospitalization and the likelihood of overnight admission decreased.³²⁶ Ketorolac is a useful adjunct when given intravenously to supplement the local anesthesia infiltrated by the surgeon during inguinal herniorrhaphies.³²⁷ Ketorolac (0.9 mg/kg) is an effective alternative to morphine (0.1 mg/kg), with less nausea and vomiting³²⁸ and less postoperative morphine requirement if continued at a dose of 0.5 mg/kg intravenously every 6 hours in infants and children.³²⁹ This has also been confirmed in orthopedic surgery with the added benefit of decreased length of stay.³³⁰ Single doses of ketorolac (0.8 mg/kg) are opioid sparing and decrease the frequency of urinary retention in orthopedic surgery when combined with patient-controlled analgesia with morphine.³³¹ In children undergoing strabismus surgery, ketorolac provides equivalent analgesia to fentanyl (1 µg/kg) and morphine (0.1 mg/kg), with less postoperative nausea and vomiting.^332,333 In children undergoing ureteral reimplantation, ketorolac decreases the incidence and severity of postoperative bladder spasms with no decrease in hematocrit or increase in serum creatinine.^334,335

Because ketorolac can increase bleeding time, we recommend discussing its use with the surgeon and administering the drug only after achieving hemostasis and completion of surgery. The safe use of this drug in infants younger than 6 months of age has been questioned, although a review of 53 infants who received ketorolac 48 hours after cardiac surgery that was continued for 3 days showed a minimal increase in serum creatinine and blood urea nitrogen at 48 hours after institution of the therapy but no increase in bleeding episodes.^336,337 This is too small a sample to forecast the safety of ketorolac in the entire population of surgical children. Furthermore, creatinine and blood urea nitrogen are too insensitive as indices of renal function. Despite the varied doses described earlier, the recommended dose should be limited to 0.5 mg/kg, with a maximal dose of 15 mg for children who weigh less than 50 kg and 0.5 mg/kg up to 30 mg every 6 hours for those who weigh more than 50 kg. A new metered nasal formulation may simplify administration.

Rofecoxib, an NSAID cyclooxygenase-2 (COX-2) inhibitor, offers the advantages of minimal effects on renal, gastrointestinal, and platelet functions.^338–341 However, the use of COX-2 inhibitors is currently under reevaluation owing to the increased risk of myocardial and neurologic sequelae after their long-term use in adults³⁴²; risks in the pediatric population have not been described.

Antiemetics

Antiemetic administration should be considered in children undergoing high-risk procedures such as tonsillectomy and strabismus repair as well as those who have a history of motion sickness or prior history of postanesthesia nausea and vomiting. The uses of these medications are presented elsewhere in the text (see Chapters 6, 31, and 32).

Corticosteroids

Children who have been taking chronic corticosteroid therapy (e.g., for asthma, Crohn disease, lupus, acute lymphocytic leukemia) and those who have discontinued chronic corticosteroid therapy in the last 6 months may suffer from suppression of the hypothalamic-pituitary-adrenal axis.³⁴³ There is a paucity of evidence to support the need for supplemental corticosteroids in children in the perioperative period who have been taking chronic corticosteroid therapy. In the past, hypotension was reported in those who were taking chronic corticosteroid therapy and underwent general anesthesia or another stress. This may be attributed to hypovolemia. Nonetheless, many endocrinologists continue to recommend a dose of supplemental corticosteroids before or shortly after induction of anesthesia for “stress” corticosteroid coverage. The usual recommended dose is 1 to 2 mg/kg of hydrocortisone intramuscularly or intravenously or an equivalent dose of dexamethasone (0.05 to 0.1 mg/kg) approximately 1 hour before the induction of anesthesia or as soon as intravenous access is established. For more complicated operations, the corticosteroid dose may be repeated every 6 hours for up to 72 hours (see Chapter 25).

Insulin

Optimal management of diabetic children undergoing surgery entails maintaining glucose homeostasis, avoiding hyperglycemia with resultant osmotic diuresis, impaired wound healing, and increased infection rate, and avoiding hypoglycemia. Anesthesiologists should work together with the endocrinologist or primary care physician to design a plan for each child’s specific diabetes treatment regimen, glycemic control, intended surgery, and anticipated postoperative care. Diabetes mellitus is the most common endocrine problem encountered in children. The preoperative fasting time should be the same as that recommended for nondiabetic children. Every attempt should be made to schedule these children as the first case of the day to minimize the fasting period. Preoperative laboratory tests generally include hematocrit, serum electrolytes, and glucose levels; blood glucose concentrations should be measured at frequent intervals during the perianesthetic period. Several protocols have been crafted to control the blood sugar in children who are diabetic³⁴⁴; these are described in more detail in Chapter 25 (see also Figs. 25-1 to 25-9, which describe a variety of management strategies).

Antibiotics

Antibiotics are frequently administered to prevent or reduce infection in surgical patients. The appropriate timing of antibiotics is now a source of performance benchmarking for some insurance carriers, making communication with surgeons essential for the success of this anesthesiology-directed quality assessment measure. For prophylaxis against endocarditis in children with structural heart disease, antibiotics should ideally be administered either intravenously 30 to 60 minutes or orally 1 hour before the induction of anesthesia and surgery. In reality, in children these antibiotics are usually administered after induction of anesthesia and establishment of intravenous access (see also Tables 14-2 and 14-3).³⁴⁵

Antacids, H₂ Antagonists, and Gastrointestinal Motility Drugs

The risk of aspiration during induction of or emergence from anesthesia is increased in children who are developmentally delayed, have gastroesophageal reflux, experienced previous esophageal surgery, had a difficult airway, were obese, or had undergone a traumatic injury. Preanesthetic administration of drugs that reduce gastric fluid volume and acidity may decrease the risk of pulmonary acid aspiration syndrome (Table 4-4).^1,346 Gastric fluid pH may be increased by drinking a nonparticulate antacid such as sodium citrate; particulate antacids should be avoided because they can cause severe pneumonitis if aspirated.

TABLE 4-4 Doses of Antacids, H₂ Antagonists, and Gastrointestinal Motility Drugs

Cimetidine and ranitidine are H₂-receptor antagonists that decrease gastric acid secretion, increase gastric fluid pH, and reduce gastric residual volume.^347,348 These drugs can be given orally, intravenously, or intramuscularly.

Metoclopramide is often administered with an H₂-receptor antagonist to increase lower esophageal sphincter tone, relax the pyloric sphincter and the duodenal bulb, and promote gastric emptying by increasing peristalsis of the duodenum and jejunum. The drug effect is apparent 30 to 60 minutes after oral administration and 1 to 2 minutes after intravenous administration.³⁴⁹ Adverse effects such as extrapyramidal signs relate to the effect of metoclopramide on the CNS through blockade of dopaminergic receptors.

Inhalation with Sevoflurane

The traditional mask induction of anesthesia is accomplished by placing the mask lightly on the child’s face and administering a mixture of N₂O in O₂ (2 : 1) for 1 or 2 minutes until the full effect of N₂O is achieved. Offering children the choice of a scented mask or “sleepy air,” such as bubble gum or strawberry flavor, applied to the inside of the face mask may disguise the odor of the plastic. Sevoflurane is then introduced and can be rapidly increased to 8% in a single stepwise increase, without significant bradycardia or hypotension in otherwise healthy children. After anesthesia is induced, the sevoflurane concentration should be maintained at the maximum tolerable concentration until intravenous access is established, but this concentration should be reduced if controlled ventilation is initiated so as to avoid overdose. The reason for maintaining delivery of a high concentration of sevoflurane is to minimize the risk of awareness during the early period of the induction sequence. Data from unmedicated children (aged ≥3 years) indicate that sevoflurane is associated with small increases in heart rate, although heart rate does decrease to 80 to 100 beats per minute in some children after breathing sevoflurane for a period of time.³⁵⁰ In contrast to halothane,³⁵¹ sevoflurane does not increase the myocardial sensitivity to epinephrine.³⁵² In a study of three techniques for delivering sevoflurane for induction of anesthesia, minimal differences were detected among the three: incremental increases in sevoflurane (2%, 4%, 6%, and 7%) in oxygen, a high concentration of sevoflurane (7%) in oxygen, and a high concentration of sevoflurane in a 1 : 1 mixture of N₂O and O₂.³⁵³ When N₂O was added, there was a decreased time to loss of the eyelash reflex and a decreased incidence of excitement during the induction. Agitation or excitement in early induction (shortly after loss of eyelash reflex) with sevoflurane has been observed; this is discussed in detail in Chapter 6.

Inhalation Induction with Halothane

Halothane has largely been replaced by sevoflurane for inhalation induction of anesthesia because of halothane’s slower wash-in and emergence and greater incidence of bradycardia, hypotension, and arrhythmias. When anesthesia is induced with halothane, the inspired concentration is gradually increased by 0.5% every two to three breaths up to 5%. Alternatively, a single-breath induction of anesthesia with 5% halothane can yield a rapid induction of anesthesia without triggering airway reflex responses.³⁵⁴

The inspired concentration of halothane should be decreased as soon as anesthesia is established to avoid heart rate slowing and myocardial depression. The child will autoregulate the depth of anesthesia as long as he or she is allowed to breath spontaneously; however, if respirations are controlled, then anesthetic overdose may easily occur (see Chapter 6).^355,356 Halothane sensitizes the heart to catecholamines, and ventricular arrhythmias may commonly be seen, especially during periods of hypercapnia or light anesthesia.³⁵⁷

If vital signs become abnormal during induction, the concentration of halothane should be reduced or discontinued and the circuit flushed with 100% oxygen. If bigeminy or short bursts of ventricular tachycardia occur, then the following strategies should be considered: (1) hyperventilation (to reduce the arterial carbon dioxide tension [Paco₂]) (2) deepening of the halothane anesthesia, or (3) changing to an alternate potent inhalation agent.³⁵⁷ There is no role for intravenous lidocaine to treat these arrhythmias.

During inhalation induction with either sevoflurane or halothane, if the oxygen saturation decreases (and there is no mechanical cause for the desaturation such as partial dislodgement of the oximeter probe, patient clenching of fingers or toes, or blood pressure cuff inflating), 100% oxygen should be administered until the oxygen saturation returns to normal while the cause of the desaturation is addressed. If the cause of the desaturation is not related to upper airway obstruction, the most common cause in a healthy child is a ventilation-perfusion mismatch due to segmental atelectasis. Recruitment of alveoli may be achieved by applying a sustained inflation of the lungs to 30 cm H₂O for 30 seconds or as tolerated.³⁵⁸ This may be difficult to complete before tracheal intubation, because the stomach may inflate. In such a case, recruitment should be abandoned. Alternatively, mild to moderate upper airway obstruction from collapse of the hypopharyngeal structures or the development of mild laryngospasm causes hypoventilation and desaturation. In general, this upper airway obstruction is readily relieved by gently applying a tight mask fit, closing the pop-off valve sufficiently to generate 5 to 10 cm of positive end-expiratory pressure, and allowing the distending pressure of the bag to stent open the airway until the child is adequately anesthetized to tolerate the placement of an oral airway (see Fig. 12-10 and Fig. 31-6). Cephalad pressure should be applied to the superior pole of the condyle of the mandible to sublux the temporomandibular joint. because this maneuver opens the mouth and pulls the tongue off the posterior and nasopharyngeal walls, opening the laryngeal inlet (Video 4-3, A and B).³⁵⁹ This maneuver may supplant the need for an oral airway. It is very important to avoid applying digital pressure to the soft tissues of the submental triangle, because this pushes the tongue and soft tissues into the hypopharynx, occluding the oropharynx and nasopharynx. If the child develops symptomatic bradycardia, then oxygenation and ventilation must first be established, followed by intravenous atropine (0.02 mg/kg) and, if necessary, chest compressions and intravenous epinephrine (see Chapter 39).

Inhalation Induction with Desflurane

Desflurane is very pungent, as evidenced by severe laryngospasm (49%), coughing, increased secretions, and hypoxemia during induction.³⁶⁰ Therefore, desflurane is not recommended for inhalation induction in children but may be used safely for maintenance of general anesthesia after the trachea has been intubated.

Hypnotic Induction

Hypnosis can reduce anxiety and pain in children with chronic medical problems and those undergoing painful procedures^361,362 as well as reduce preoperative anxiety. Hypnosis is an altered state of consciousness with highly focused attention, based on the principle of dissociation.³⁶³ Hypnosis results in a state of inner absorption that leads to a reduction in awareness of immediate physical surroundings and experiences. Children are more likely to be absorbed in fantasy, and their natural power of play making them more hypnotizable than adults.³⁶⁴ Although an anesthesiologist may not have training in hypnosis, he or she can use hypnotic suggestions to help children even though an actual trance state is not induced. It may be helpful to engage children in age-appropriate scenarios, such as going to the zoo, a fancy tea party, a baseball game, or flying a jet. Words should be spoken slowly and rhythmically with descriptions of sights and sounds that are familiar to the child as well as repeated suggestions of “feeling good.” The hypnotic suggestions distract the child so that the smell of anesthetic agent becomes the scent of the zoo animals, the tea brewing, the aviation fuel, and so on. Any number of stories can be told with the same result as long as one remembers to repeatedly say things that can be identified by the child and that fit with what the child is experiencing at the time of induction.

When hypnosis was administered 30 minutes before surgery, it significantly reduced preoperative anxiety at the time of face mask application and the frequency of behavior disorders postoperatively when compared with oral midazolam, 0.5 mg/kg.³⁶⁵ Hypnosis provided a relaxed state of well-being and enabled children to actively participate in anesthesia, thus leaving them with a pleasant memory. Unlike the anterograde amnesia associated with midazolam, hypnosis offers the benefit of maintaining a pleasant memory to prevent fear during future anesthetics.

Modified Single-Breath Induction

The single-breath induction is especially appealing to children who desire to fall asleep “really fast” with a face mask, because loss of consciousness is achieved much more rapidly than with a traditional escalating dose technique. It works best with older children, although some as young as 3 years of age can be anesthetized with this technique if they are cooperative. Before beginning, the child should be coached through a mock induction by instructing him or her to “breathe in the biggest breath, possible” through the mouth (not the nose) and then “breathe all the way out until there is no more air in the lungs.” If the child is used to swimming and holding the breath underwater, this makes the exercise much easier. Once this has been practiced a few times, then a practice run is repeated with only the mask (no circuit) on the face.

Before induction, the circuit and reservoir bag are primed with 70% N₂O in O₂ and the maximum concentration of concentration of halothane or sevoflurane the vaporizer can deliver. This is achieved by running modest fresh gas flows through the circuit and intermittently emptying the reservoir bag manually into the scavenger system (i.e., with the circuit Y-connector occluded). Once the circuit is primed with the maximum concentration of inhalation agent, the mask is placed on the Y-connector, then the distal end of the circuit is occluded (to avoid contaminating the operating room), and the child is instructed to take a deep breath of room air and to exhale all the air and hold expiration. The face mask is then placed securely over the child’s mouth and nose while he or she is instructed to take in the “deepest breath ever through their mouth” and “hold it, now just breathe normally.” Loss of consciousness, as noted by loss of the eyelash reflex, occurs within 15 to 30 seconds after this vital capacity breath (Fig. 4-4, A, B and C, and Video 4-4).^354,366

FIGURE 4-4 A single-breath induction is another useful method that is most appropriate for children 5 to 10 years of age. It is important to practice several times without the mask attached to the circuit before the actual induction (see text for details of preparing the circuit). This allows the child to become familiar with the feel of the mask as it is applied to the face and to properly time the sequence of events. A and B, Typically, we ask the child to take “the biggest breath possible and hold it.” Then we ask the child to “breathe all the way out until you have no more air in your lungs and hold it” and place the face mask on the child’s face. C, We then ask the child to take in “the biggest breath you have ever taken, hold it, then breathe normally.” If a full vital capacity breath is taken with a good mask seal around the mouth and nose, most children will lose their lid reflex within 15 to 30 seconds, which is similar to intravenous induction agents.

Thiopental

Thiopental (sodium pentothal) has been replaced by propofol as the most commonly used intravenous induction agent. The recommended induction dose of thiopental in healthy, unpremedicated children is 5 to 6 mg/kg³⁶⁷; neonates require a smaller dose (3 to 4 mg/kg).³⁶⁸ Debilitated or severely ill patients, those who are hypovolemic, and those who have been premedicated may also require a smaller dose for induction of anesthesia. The beta-elimination half-life of thiopental in neonates is twice that in their mothers (15 versus 7 hours), so a single dose may produce excessively prolonged effect in neonates.³⁶⁹ This drug is no longer available in the United States.

Methohexital

Methohexital is an ultra-short-acting oxybarbiturate that is infrequently used for induction. The induction dose for unpremedicated children ranges from 1.0 to 2.5 mg/kg³⁷⁰; premedicated children require a smaller dose. Recovery after intravenous administration is more rapid than after thiopental.³⁷¹ Larger doses cause skeletal muscle hyperactivity, myoclonic movements, and hiccups.³⁷⁰ Pain at the injection site is common, necessitating pretreatment with intravenous lidocaine.

Propofol

Propofol is the most commonly used nonbarbiturate intravenous induction agent in children. The induction dose of propofol varies with age: the median effective dose (ED₅₀) for a satisfactory induction in healthy infants 1 to 6 months old is 3.0 ± 0.2 mg/kg, and in healthy children 10 to 16 years old it is 2.4 ± 0.1 mg/kg.³⁷² The 95% effective dose (ED₉₅) in healthy unpremedicated children 3 to 12 years of age is 2.5 to 3.0 mg/kg.³⁷³ The early distribution half-life is about 2 minutes, and the terminal elimination half-life is about 30 minutes.³⁷⁴ Clearance is very large (2.3 ± 0.6 L/min) and exceeds liver blood flow.³⁷⁴ Advantages to propofol for induction of anesthesia include a reduced incidence of airway-related problems (e.g., laryngospasm, bronchospasm), more rapid emergence,^375,376 and a reduced incidence of nausea and vomiting.^377,378 The major disadvantage of propofol is pain at the site of injection, especially when administered in small veins (e.g., the back of the hand).³⁷² The administration of lidocaine (0.5 to 1.0 mg/kg) while applying tourniquet pressure proximal to the injection site (mini-Bier block) for 30 to 60 seconds before injecting the propofol effectively eliminates the pain in more than 90% of patients. However, younger children may not tolerate even the discomfort from the Bier block, which is the reason to consider using nitrous oxide to as an alternative and equally effective strategy (see Chapter 6). Other techniques reported to attenuate the pain include mixing lidocaine (0.5 to 1 mg/kg) with the propofol (but this should be done within 60 seconds of administration of the propofol), mixing thiopental with the propofol, refrigerating the propofol, pretreating with an opioid or ketamine, and diluting propofol to a 0.5% solution.^379–388

In addition to its use as an induction agent, propofol can be administered by infusion for total intravenous anesthesia (see Chapter 7) because of its relatively low context-sensitive half-life. It is especially useful for pediatric patients undergoing non–operating room procedures such as CT, MRI, radiotherapy, bone marrow biopsy, upper and lower gastrointestinal endoscopy, and lumbar puncture.

Etomidate

Etomidate is a hypnotic induction agent that provides marked cardiovascular stability. Etomidate is available for use in the United States and several other countries, but it is not available in many others due to concern for adrenal suppression. It is indicated for the induction of anesthesia in children with sepsis, cardiac instability, cardiomyopathy, or hypovolemic shock. The recommended induction dose is 0.2 to 0.3 mg/kg depending on the cardiovascular status of the child. Etomidate causes pain and myoclonic movements when injected intravenously³⁸⁹ and may suppress adrenal steroid synthesis (see also Chapter 6).³⁹⁰

Ketamine

Ketamine is a very useful induction agent for children with cardiovascular instability, especially in hypovolemic states, or for those who cannot tolerate a reduction in systemic vascular resistance, such as those with aortic stenosis or congenital heart disease in whom the balance between pulmonary and systemic blood flow is vital for maintaining cardiovascular homeostasis. In children whose circulation is already maximally compensated by endogenous catecholamines, ketamine is a myocardial depressant that can result in systemic hypotension.³⁹¹ The induction dose of ketamine in healthy children is 1 to 2 mg/kg. The dose should be reduced in the presence of severe hypovolemia. Smaller doses of intravenous ketamine (0.25 to 0.5 mg/kg) have also been used successfully for procedural sedation.

Ketamine causes sialorrhea, psychomimetic side effects (hallucinations, nightmares), and postoperative nausea and vomiting. The administration of an antisialagogue and midazolam is recommended to attenuate these side effects.