Nitrous Oxide (N ₂ O)

N ₂ O is commonly used in pediatric anesthesia to speed and facilitate induction and to provide analgesia/amnesia during maintenance. It may also be administered to sedate and to provide analgesia before intravenous induction of anesthesia. N ₂ O is odorless and insoluble (blood/gas partition coefficient (λ _b/g ) is 0.47) with a MAC of 104% in adults. In large concentrations, it enhances the rate of uptake of the inhaled anesthetics into the alveoli, accelerating induction of anesthesia (second-gas effect). The analgesic effects of N ₂ O may complement the anesthetic regimen during maintenance. The effects of N ₂ O on ventilation appear to equal those of equipotent concentrations of halothane. N ₂ O mildly depresses cardiac output and systemic blood pressure in infants, but it has little effect on pulmonary artery pressure or pulmonary vascular resistance, even in those with pulmonary vascular disease. In infants and small children, the cardiovascular effects of N ₂ O combined with either halothane or isoflurane to 1.5 MAC are similar to those of equipotent (1.5 MAC) concentrations of either halothane or isoflurane in oxygen. N ₂ O rapidly diffuses into any gas-containing space within the body; this contraindicates its use in those with lung cysts, pneumothorax, lobar emphysema, necrotizing enterocolitis, bowel obstruction, and any other gas filled cavity. N ₂ O (70%) doubles the size of a pneumothorax in 12 minutes and that of gas containing bowel in 120 minutes. The tenfold difference in doubling time is the result of the shrinking blood supply to the bowel, as the lumen of the bowel expands, and unchanged blood flow to the chest wall/pleura with expansion of the pneumothorax. N ₂ O also diffuses into the middle ear and may displace the graft during tympanoplasty. In some children with a normal ear and an intact eardrum, postoperative absorption of N ₂ O from the middle ear results in atelectasis of the drum and a later complaint of earache. N ₂ O does not appear to increase postoperative vomiting in children. However, when treating children for procedures that are associated with a high incidence of PONV, it may be prudent to avoid nitrous oxide.

Sevoflurane

In the past decade, sevoflurane has become the agent of choice for inhalational induction in children. A fluorinated methyl isopropyl ether, it has a low solubility in blood (λ _b/g is 0.68), a not-unpleasant odor, and is the least irritating to the airway of the inhaled anesthetics. Thus it is the ideal agent for inhalational induction. Induction of anesthesia can most rapidly be achieved by administering the maximum deliverable initial concentration (8%); it is not necessary to introduce sevoflurane in slow stepwise increases in inspired concentration except as a means of reducing its pungency for the child. Slowly increasing the inspired concentration of sevoflurane only prolongs the excitement period. To minimize the response to 8% sevoflurane during induction, the mask should be flavored and 70% N ₂ O in oxygen administered first until the child stops responding. For older, cooperative children, the so called “single breath induction” (i.e., a vital capacity breath) using an anesthesia circuit primed with 8% sevoflurane in 66% nitrous oxide and fitted with a large reservoir bag will induce anesthesia rapidly and smoothly. The effect of age on the MAC of sevoflurane differs from that of the other anesthetics: it is 2.4% in children 6 months to 10 years and 3.2% in neonates up to 6 months of age. The large MAC limits the magnitude of the overpressure technique that is possible with an 8% vaporizer. The addition of 60% N ₂ O to sevoflurane in children only decreases the MAC by 23%. Attempts at intravenous cannulation should not be made until the child is adequately anesthetized and unresponsive. Satisfactory conditions for endotracheal intubation without neuromuscular blocking agents can be achieved quite rapidly as anesthesia is deepened especially if a single dose of propofol is administered before intubation or ventilation is controlled for a brief period.

During sevoflurane anesthesia there is a dose related decrease in tidal volume, respiratory frequency, and minute ventilation, which is reversed by surgical stimulation. In practice, the addition of nitrous oxide to sevoflurane decreases the MAC of the latter and thus minimizes respiratory depression in the spontaneously ventilating child.

Sevoflurane causes less myocardial depression than halothane, isoflurane, or desflurane and arrhythmias are uncommon, even when epinephrine-containing solutions are injected. An increase in heart rate and a slight decrease in blood pressure usually occur after induction of anesthesia. Occasionally bradycardia occurs during induction of anesthesia in infants and particularly in children with trisomy 21, but this may be prevented by pretreatment with an anticholinergic. Compared with halothane, sevoflurane causes less hypotension in children with congenital heart disease and less desaturation in those with cyanotic CHD.

Epileptiform EEG activity and myoclonic jerking movements have been reported exceedingly rarely during sevoflurane anesthesia in children. The combination of high concentrations of sevoflurane and hyperventilation appear to increase the epileptiform activity, although frank seizures are exceedingly rare. Epileptiform EEG activity during sevoflurane may cause paradoxical readings on “depth of anesthesia” monitors (e.g., the BIS monitor). Caution should be exercised when interpreting BIS values during sevoflurane anesthesia at higher concentrations.

Emergence from sevoflurane anesthesia is smooth and rapid, although emergence agitation may occur in some children, especially preschool-age children (see page 216 ). This transient phenomenon is characterized by restless and inconsolable behavior, inability to establish eye contact, lack of purposeful movement, and lack of interaction with their surroundings. To reduce the incidence of agitation, care must be taken to ensure adequate analgesia during emergence by means of a regional block or systemic analgesics. Antinociceptive strategies combined with midazolam premedication, propofol, or an alpha ₂ agonist (e.g., dexmedetomidine) all reduce the risk of emergence agitation. There is some evidence that recovery of fine coordination over the first few hours after sevoflurane is more complete than it is after isoflurane or halothane.

Sevoflurane is metabolized (5%) in vivo by CYP450 2E1 releasing inorganic fluoride; maximum plasma concentrations occur within 2 hours of terminating the anesthetic. Although large plasma inorganic fluoride concentrations after methoxyflurane were associated with nephrotoxicity, this does not occur after sevoflurane. Nephrotoxicity depends on the affinity of renal CYP450 2E1 for the ether anesthetic, which locally releases inorganic fluoride that may impair renal tubular function. In the case of CYP450 2E1, the affinity for sevoflurane is one fifth that of methoxyflurane, hence nephrotoxicity does not occur with the former despite similar plasma concentrations of inorganic fluoride to those after methoxyflurane. Sevoflurane is also degraded in vitro in the presence of some carbon dioxide absorbents (baralyme > soda lime>>Amsorb Plus). The extent of degradation in vitro increases at low fresh gas flows and in desiccated absorbent. Degradation of sevoflurane in vitro yields five compounds, the most common being Compound A, a potentially nephrotoxic vinyl compound. Compound A production varies directly with the weight of the child. Absorbents that are free of KOH and NaOH such as Amsorb Plus do not degrade sevoflurane. In some countries, a minimum fresh gas flow and concentration-time exposure have been recommended for sevoflurane although there is limited evidence that very low fresh gas flows present any risk to humans. The combination of desiccated baralyme and sevoflurane resulted in an absorber fire (the result of hydrogen production from degradation of sevoflurane in the presence of desiccated baralyme at temperatures >200 °C) that led to the withdrawal of baralyme from the market. To date, neither sevoflurane nor its degradation products have been shown to be toxic in humans.

Isoflurane

Isoflurane is a polyhalogenated methyl ethyl ether. It is a stable compound that is metabolized less than 0.2% in vivo, although it is degraded to carbon monoxide in the presence of some desiccated CO ₂ absorbents. It is eliminated almost completely unchanged via the lungs; therefore recovery should be very complete.

The λ _b/g of 1.43 dictates that wash-in to the alveoli is slower than that of sevoflurane. In addition, isoflurane is not suited as an induction agent because its pungent odor irritates airway reflexes (coughing, laryngospasm, and breath holding). Nonetheless, isoflurane can be successfully introduced after an intravenous induction, provided the concentration is increased slowly. Alternatively, for more prolonged surgery, anesthesia may be maintained with isoflurane after induction has been successfully completed with sevoflurane. Recovery after isoflurane anesthesia is slower than after sevoflurane although emergence agitation appears to be less of a problem. The incidence of laryngospasm during extubation and emergence is similar to that with halothane (see later discussion). Isoflurane depresses the respiratory system to a similar extent as sevoflurane.

During isoflurane anesthesia, blood pressure decreases although heart rate does not change substantively. The decrease in blood pressure is due in part to myocardial depression, but also to peripheral vasodilation. Infusion of intravenous fluids tends to restore the blood pressure. The vasodilating effect of isoflurane may be useful to control blood pressure, such as during induced hypotension. Isoflurane depresses the baroreflex in the neonate. This impairs the ability to compensate for changes in arterial blood pressure and for hypovolemia. Isoflurane does not sensitize the myocardium to the effects of catecholamines or theophylline.

Isoflurane potentiates nondepolarizing neuromuscular blocking drugs to a greater extent than sevoflurane or halothane, thus allowing reduced doses of relaxant drugs to be used. The neuromuscular effects of isoflurane are reversible when isoflurane is withdrawn, thereby facilitating reversal of neuromuscular blockade.

Halothane

Halothane was considered to be an ideal anesthetic for children, although its popularity in pediatric anesthesia has waned since the introduction of sevoflurane into clinical practice. Indeed, many recent North American trainees have never used halothane in children, unless they have administered anesthesia overseas. Nonetheless, halothane is inexpensive and is still used in some parts of the world where more expensive anesthetics are less available. Pediatric anesthesiologists familiar with halothane consider that it may have some advantages over sevoflurane when a more prolonged emergence is needed to facilitate endoscopy with spontaneous ventilation (e.g., for laryngoscopy, bronchoscopy), or when managing a difficult airway. Its use will therefore be discussed.

With a λ _b/g of 2.3 the wash-in of halothane is slow compared with sevoflurane. However, with a 5% maximum inspired concentration and a MAC in children of approximately 1%, greater MAC-multiples of halothane can be delivered than of sevoflurane. The MAC in children who are cognitively challenged may be 25% less than in children who are not challenged. Halothane provides a smooth inhalation induction with minimal irritation of the airways.

During halothane anesthesia, a dose-dependent depression of spontaneous ventilation occurs; there is usually an increase in respiratory rate, but tidal volume and minute ventilation decrease considerably. This increases the end-tidal carbon dioxide concentration but prevents anesthetic overdose as long as respirations are not assisted or controlled (see later discussion). Alveolar ventilation returns toward normal during surgical stimulation but is variable throughout anesthesia. Halothane inhibits intercostal muscle activity. Diaphragmatic ventilation predominates, and paradoxical movement of the chest wall may occur. Even very low blood levels of halothane severely depress the ventilatory response to hypoxia in young adult volunteers. It is likely that this effect also occurs in children of all ages. Laryngospasm may occur during light planes of halothane anesthesia, especially during extubation of the trachea. This effect can be avoided by extubating the trachea while the child is either still deeply anesthetized or completely awake. Lidocaine (1 to 2 mg/kg IV) given slowly before extubation may reduce coughing but will not prevent laryngospasm. Halothane is a potent bronchodilator and is very useful in children with asthma.

Halothane depresses myocardial contractility, especially in small infants. It also produces bradycardia and thus causes a decrease in cardiac output. Atropine prevents the bradycardia and tends to maintain cardiac output, but does not reverse the reduced myocardial contractility. Neonates are especially sensitive to the myocardial depressant effects of halothane. Severe hypotension may ensue if large concentrations of halothane are administered to infants and children, particularly when ventilation is controlled. This is a result of myocardial depression and, with the subsequent decreased cardiac output, the concentration of halothane rapidly increases in the child’s myocardium, leading to electromechanical dissociation/cardiac arrest.

The infant’s blood pressure is very sensitive to changes in cardiac output. Vasoconstriction is less effective than in the adult. Halothane also depresses reflex baroresponses. Inspired halothane concentrations are usually limited to 0.5% to 1% during controlled ventilation, and the blood pressure should be carefully monitored. In children with cardiac failure, the myocardial depressant effects of halothane are prominent, and severe hypotension may occur.

Arrhythmias also occur during halothane anesthesia. Ventricular premature beats are common, especially during spontaneous ventilation in the presence of hypercarbia. If they occur, ventilation should be assisted or controlled; if they persist, another inhalational anesthetic (e.g., isoflurane) should be substituted for halothane. Junctional rhythm and wandering pacemaker also occur during halothane anesthesia. This is usually of little consequence but might compromise the child with congenital heart disease. Halothane sensitizes the myocardium to exogenous catecholamines, and arrhythmias may occur when these compounds are injected (e.g., to infiltrate the skin). Studies indicate that children tolerate greater doses of injected epinephrine than adults. Epinephrine in doses up to a maximum of 10 μg/kg mixed with local anesthetic or saline and injected into the tissues of healthy children appears to be safe. Serious arrhythmias may occur if halothane is administered to children who have been receiving theophylline medication chronically; other agents should be used.

Halothane, like most other inhalational anesthetics, increases cerebral blood flow and therefore may increase ICP. At small concentrations, this effect is minimal, and if hyperventilation is employed, the increase is insignificant even in those with intracranial space-occupying lesions.

Shivering and muscle rigidity are common during emergence from halothane anesthesia. These effects may be of concern after orthopedic surgery and in children in whom the additional oxygen demands of shivering might be detrimental. In such cases, an alternative anesthetic technique may be more appropriate.

Halothane is metabolized 15% to 20% in adults in vivo, but the extent of metabolism is less in infants and small children. Occasional cases of hepatic failure have been reported in adults, but many fewer have been reported in children, despite its wide and often repeated use in the latter age group. These rare cases of halothane hepatitis in children have been confirmed by the presence of halothane-related antibodies. Most episodes of halothane hepatitis in children run a less fulminant course than in adults. The reason for the reduced susceptibility of prepubertal children to halothane hepatitis is not known. Contraindications to halothane include a history of unexplained postoperative jaundice.

Desflurane

Desflurane is a fluorinated ether with a boiling point of 23 °C and the smallest λ _b/g , 0.42. In addition, it is the least soluble anesthetic in all tissues. It is a very stable compound, with less than 0.02% metabolized in vivo, although it is degraded to carbon monoxide in the presence of some desiccated absorbents. Desflurane is a less potent anesthetic agent with a MAC of 7% to 9.5% in children. MAC increases with decreasing age, peaking in infants 6 to 12 months of age. The effects of desflurane on the cardiovascular system at 1 MAC anesthesia are similar to those of other ether inhalational anesthetics, although bradycardia is rare. In adults, when desflurane is the sole anesthetic agent, sudden increases in the inspired concentration can lead to profound central sympathetic discharge, resulting in sudden increases in blood pressure and heart rate.

Desflurane is very pungent and causes airway irritation; breath holding and laryngospasm are very common and for these reasons desflurane is not recommended for inhalational inductions in children. It can, however, be safely used for maintenance after induction with other agents in children whose airways are intubated. There are limited data on airway responses to desflurane in children managed with either a mask or an LMA. Emergence is very rapid as a result of its limited solubility. To prevent the sudden onset of acute pain, analgesics should be administered before emergence. Emergence agitation has also been reported after desflurane, particularly if pain is present. The very rapid recovery may be useful in some children (e.g., small infants at risk for postoperative apnea, although this does not eliminate this risk).

Desflurane increases intracranial pressure more than isoflurane and sevoflurane, although this effect may be attenuated by hyperventilation before introducing the desflurane.

Desflurane is less convenient to use than other agents because its low boiling point demands a specially designed, electrically heated vaporizer. A greater concentration is required to maintain anesthesia (because of its greater MAC), necessitating small fresh gas flows to limit the cost.

Enflurane

This inhaled agent has several disadvantages compared with other agents and, as a result, is not commonly administered to children.