Sevoflurane in Pediatric Anesthesia

Sevoflurane is the first ether anesthetic to rival halothane as the anesthetic of choice for infants and children. Among its characteristics, the combination of nonirritation of the upper airway and low blood and tissue solubilities sets sevoflurane apart from other inhalational anesthetics. Unfortunately, sevoflurane falls short of the "ideal anesthetic," as it is metabolized in vivo and degraded in vitro in the presence of carbon dioxide absorbants. The following review summarizes the current experience with sevoflurane in pediatric anesthesia. Pharmacology Solubility The solubility of sevoflurane in blood is low, 0.69 in adults [1] and 0.66 in newborns [2]. The adult value is intermediate between that of desflurane (0.42) [3] and that of isoflurane (1.38) [2]. The very small difference in the blood solubility of sevoflurane with age may reflect the attenuated signal/noise ratio of less-soluble anesthetics when they are compared with moresoluble anesthetics [4]. The tissue/gas solubility of sevoflurane is also low, approximately half that of isoflurane [5]. Comparable data in the tissues of children are lacking. However, based on our knowledge of the effect of age on the solubility of anesthetics in human tissues [6], the solubility of sevoflurane in the tissues of infants and children should be similar to or possibly less than that in adult tissues. Pharmacokinetics The rate of increase of alveolar to inspired partial pressures of sevoflurane in adults is intermediate between that of desflurane and that of isoflurane [7]. This relatively rapid wash-in of sevoflurane may be attributed in part to its low solubilities in blood and tissues [1,2,5]. Age is an important determinant of the wash-in of halothane in infants and children. Salanitre and Rackow [8] demonstrated that the wash-in of halothane in infants and children was more rapid than it was in adults. This difference has been attributed to four factors: 1) greater alveolar ventilation; 2) greater cardiac output directed to the vessel-rich group; 3) lower tissue solubility [6]; and 4) lower blood solubility [4]. Although the wash-in of sevoflurane in infants and children has not been reported, the rate of wash-in of sevoflurane in infants and children may be predicted using the four factors listed above. Alveolar ventilation accounts for most of the difference in the wash-in of halothane between children and adults. Since changes in alveolar ventilation affect more-soluble anesthetics to a greater extent than they affect less-soluble anesthetics [9], the wash-in of sevoflurane should be as rapid in children as it is in adults. If this speculation holds true, administration of less-soluble anesthetics such as sevoflurane will provide an added margin of safety during inhalational inductions in young infants. The wash-out of sevoflurane is rapid and similar to that of desflurane [7], and the wash-out of both is more rapid than that of isoflurane or halothane. In infants and children, greater FA/FAO ratios (where FA is the alveolar fraction of anesthetic and FAO is the alveolar fraction of anesthetic at the beginning of the wash-out) at 2 and 5 min after sevoflurane indicate a slower elimination than after desflurane [10,11]. Nonetheless, the difference in elimination of these two anesthetics is small and unlikely to be of clinical significance. These data indicate that decreases in the inspired concentration of sevoflurane will result in rapid decreases in its alveolar concentration, a more rapid response than will occur with isoflurane and halothane. A right-to-left shunt (at the level of either the heart or lungs) delays the rate of increase of the partial pressure of an inhalational anesthetic in arterial blood [9,12]. In dogs, right-to-left shunts delay the wash-in of less-soluble anesthetics to a greater extent than more-soluble anesthetics [12]. This may be attributed to the rapid equilibration of alveolar to inspired partial pressures of less-soluble anesthetics and the greater effect of alveolar ventilation on the wash-in of more-soluble anesthetics as illustrated in a lung model [13]. Thus, a right-to-left shunt slows the wash-in and delays the time to equilibration of alveolar and inspired partial pressures, effects that are exaggerated in the presence of sevoflurane compared with the more soluble anesthetic halothane. Pharmacodynamics 1. Minimum alveolar anesthetic concentration (MAC). The relationship between the MAC of sevoflurane and age is important for a clear understanding of the pharmacology of and physiologic responses to sevoflurane. The MAC of sevoflurane was first measured in newborn swine and found to be 2.12% [14]. The MAC of sevoflurane in infants and children between birth and 12 yr is 3.3% in neonates, 3.2% in infants aged 1-6 mo, and approximate 2.5% in infants and children aged 6 mo to 12 yr Figure 1[10]. The data for children 1-6 yr of age are consistent with a previous report [15].Figure 1: Minimum alveolar anesthetic concentration (MAC) of sevoflurane versus age. The mean (+/- SD) end-tidal concentration of sevoflurane in oxygen for neonates, infants, and children. Data for the MAC at 30 yr of age were obtained from [47]. With permission from [10].Sixty percent nitrous oxide decreases the MAC of sevoflurane in children 1-3 yr of age by 25% [10], an effect similar to that reported with desflurane [16]. However, this effect is only half that published previously for the effect of 60% nitrous oxide on the MAC of halothane and isoflurane in children [17,18]; the explanation for this remains unclear. Nonetheless, it is important to recognize this diminished effect of nitrous oxide in order to ensure that adequate levels of anesthesia are provided for infants and children anesthetized with sevoflurane. The MAC of sevoflurane for endotracheal intubation in children 1-9 yr of age is 2.7%, with a MAC for skin incision of 2.0% [19]. The MAC for skin incision, however, is 25% less than that reported previously in children [10,15]. The difference in the MAC of sevoflurane for skin incision between studies may be explained in part by the use of 0.5% increments in the inspired concentration of sevoflurane between patients [19] rather than 0.2% as reported previously [10,15]. Further investigation is required to fully explain these differences. 2. Induction of anesthesia. Although induction of anesthesia with sevoflurane is rapid, the rate of induction should be no more rapid than with other inhaled anesthetics. The low solubility of sevoflurane provides for a rapid wash-in of alveolar to inspired partial pressures that is faster than with halothane [7]. However, the factors that determine the rate of induction of anesthesia depend not only on the wash-in of the anesthetic, but also on its MAC value, the maximum deliverable inspired concentration (based on the vaporizer design), and the rate of increase of the inspired concentration. To provide a rapid induction of anesthesia with an inhaled anesthetic such as halothane, clinicians increase the inspired concentration to values that are severalfold greater than the MAC for that age group. This is termed the overpressure technique [9]. If the overpressure technique were applied to all anesthetics similarly, then the rate of induction of anesthesia would be similar for all inhaled anesthetics [20-22]. In two recent studies, however, the time to loss of the eyelash reflex was less during sevoflurane anesthesia than during halothane anesthesia [23,24]. Although the rapid loss of the eyelash reflex with sevoflurane in these studies implies that induction of anesthesia is more rapid with sevoflurane than it is with halothane, it is more likely that this reflects differences in experimental design or practice. For example, in the study by Taivainen et al. [24], the maximum inspired concentrations of sevoflurane and halothane were 7.0% and 3.5%, respectively. These concentrations provide for a greater overpressure effect for sevoflurane than for halothane. Based on published data, we estimated that the maximum inspired concentration of 7% sevoflurane corresponds to 4.5% halothane. A second explanation for the difference in induction times is the notion that halothane is a slow induction agent and sevoflurane is a fast one. Clinicians may have increased the inspired concentrations of sevoflurane at a faster rate than they used for halothane with the knowledge that sevoflurane is suited for inhalational inductions in children. Sevoflurane is well tolerated by infants, children, and adults when it is administered by mask [10,15,20,21,23]. Coughing and breath holding occur infrequently during inhalational anesthesia with sevoflurane; laryngospasm and bronchospasm are exceedingly rare events. In 68 infants and children aged 1 mo to 12 yr who were anesthetized by inhalation of sevoflurane in 95% oxygen, the incidence of coughing during induction of anesthesia was 1.5% [10]. In a subsequent multicenter comparison of sevoflurane and halothane (both in 66% nitrous oxide), the incidence of coughing in 250 children anesthetized with sevoflurane was 3%, compared with 7% in 125 children anesthetized with halothane [23]. In a third study, the incidence of coughing during induction of anesthesia with sevoflurane in 95% oxygen was 15%, compared with 10% for sevoflurane in 66% nitrous oxide and 17% for halothane in 66% nitrous oxide [23]. These data are consistent with published data on the airway irritability of inhalants in adults [25]. Breath holding occurs infrequently (approximate 2.5%) during sevoflurane anesthesia [21,23]. Induction of anesthesia with sevoflurane with or without nitrous oxide is well tolerated in unmedicated children, with an incidence of airway complications that is similar to or less than that with halothane. Although sevoflurane does not irritate the upper airway, it may cause transient involuntary movements (excitement) and agitation during induction of anesthesia [26]. These spontaneous movements vary between random movements of one extremity (most frequent occurrence) to flexion movements of all four extremities requiring restraint (rare occurrence). Episodes of agitation have been regarded as minor or moderate adverse events by investigators [10,21,23]. The incidence of agitation during sevoflurane anesthesia appears to depend on the presence of nitrous oxide. When anesthesia is induced with sevoflurane in 95% oxygen, the incidence of agitation is 20%-35% [10,23], which is fivefold greater than the 5%-7% incidence with sevoflurane in 66% nitrous oxide [21,23]. Since most inhalational inductions include nitrous oxide, agitation is unlikely to complicate induction of anesthesia with sevoflurane in the clinical setting. Isolated instances of transient apnea have been reported during sevoflurane anesthesia in children. A 3-yr-old male who was scheduled for circumcision developed 3 min of apnea during an inhalational induction with sevoflurane and 66% nitrous oxide [23]. This event followed administration of a caudal block. When apnea occurred, the inspired concentration of sevoflurane was decreased and, after a period of manual ventilation, spontaneous ventilation resumed. This example serves to remind us that sevoflurane, like all inhalants, is a potent respiratory depressant and, in the absence of pain or other stimulation, deep sevoflurane anesthesia may induce hypoventilation and apnea. In adults, the carbon dioxide response to sevoflurane concentrations in excess of 1.4 MAC is attenuated compared with the response to similar concentrations of halothane [27]. However, owing to the rapid elimination of sevoflurane, respiratory depression dissipates more rapidly after sevoflurane than it does after halothane [28]. 3. Hemodynamic responses. The hemodynamic responses to 0.5-1.5 MAC sevoflurane were first compared with equipotent concentrations of halothane and isoflurane in newborn swine [14]. Systolic arterial blood pressure and cardiac index at 1.0 and 1.5 MAC decreased to a lesser extent during sevoflurane anesthesia than they did with both halothane and isoflurane. Limited data are available for the hemodynamic responses to sevoflurane in infants and children. Systolic blood pressure decreases 20% to 30% at 1 MAC sevoflurane in all age groups compared with awake values; fluid resuscitation or inotropic support has not been required Figure 2. The hemodynamic responses to >1 MAC sevoflurane in infants and children have not been quantitated, although blood pressure and heart rate responses during inhalational inductions with inspired concentrations up to 7% sevoflurane have been unremarkable [10,21,23,29]. Heart rate is unchanged at 1 MAC sevoflurane compared with awake values in infants and children up to 3 yr of age but increases >or=to10% above awake values in children older than 3 yr of age Figure 3[10]. Similar or greater increases in heart rate (15% to 25% above baseline measurements) have been reported after both sevoflurane in 95% oxygen and sevoflurane in 66% nitrous oxide, although these lasted only 2-5 min and resolved spontaneously [23,29]. Arrhythmias are uncommon during sevoflurane anesthesia [10,15,20,21,23]. The incidence of nodal rhythms during induction of anesthesia with sevoflurane is 0.5%-3% [10,23]. Premature ventricular contractions that lasted more than 1 h occurred in 1 of 250 children anesthetized with sevoflurane (0.4%) [23]. All arrhythmias resolved spontaneously.Figure 2: Systolic blood pressure responses to 1 minimum alveolar anesthetic concentration (MAC) sevoflurane in seven groups of infants and children. Systolic blood pressure was measured when subjects were awake, at 1 MAC sevoflurane preincision, and at 1 MAC sevoflurane postincision. Anesthesia consisted of sevoflurane and 95% oxygen for all groups except one, children "1-3 yr and N2 O," in which sevoflurane anesthesia also included 60% nitrous oxide. Systolic blood pressure at 1 MAC decreased 14% from awake values (P < 0.05), although it did not change significantly for either children 1-3 yr with N2 O or children 5-12 yr compared with awake values. With permission from [10].Figure 3: Heart rate responses to 1 minimum alveolar anesthetic concentration (MAC) sevoflurane. Heart rate was measured when subjects were awake, at 1 MAC sevoflurane preincision, and at 1 MAC sevoflurane postincision for seven groups of infants and children. Anesthesia consisted of sevoflurane in 95% oxygen for all groups except one, children "1-3 yr and N2 O," in which sevoflurane anesthesia included 60% nitrous oxide. Heart rate at 1 MAC was unchanged compared with awake values for all infants and children except children 3-5 and 5-12 yr of age, in whom heart rate increased (P < 0.017) compared with awake values. With permission from [10].4. Emergence. The rapid elimination of inhaled anesthetics is associated with rapid recovery in animals [30] and humans. Emergence from sevoflurane anesthesia after either brief (