The Ventilatory Effects of Sevoflurane

Sevoflurane (fluoromethyl 2,2,2-trifluoro-1-[trifluoromethyl])ethyl ether is a potent inhaled anesthetic that provides rapid induction of anesthesia, control of anesthetic depth, and recovery due to its low solubility reflected by a blood:gas distribution coefficient of 0.60 +/- 0.07 [1]. The solubility of sevoflurane, like desflurane, approaches that of nitrous oxide, which has a blood:gas distribution coefficient of 0.46. Early trials in humans [2] and studies in dogs [3] indicate sevoflurane depresses ventilatory function, as shown by a moderate increase in PaCO2 and lower minute ventilation. To further delineate the effects of sevoflurane on respiratory physiology, Doi and Ikeda [3] conducted a comparative study of sevoflurane and halothane in 14 patients scheduled to undergo minor head and neck procedures. To avoid the effects of surgical stimulation on respiration, measurements were made of resting ventilation and responses to carbon dioxide after the completion of surgery. Sevoflurane is a more potent ventilatory depressant than halothane. Depression of carbon dioxide response curves is similar with halothane and sevoflurane at a minimum alveolar anesthetic concentration (MAC) equivalent of 1.1, but at a MAC of 1.4, sevoflurane produces more severe depression [3]. No difference in PaCO2 was seen with sevoflurane and halothane at a MAC of 1.1, but at a MAC of 1.4, PaCO2 was higher and minute ventilation lower in spontaneously ventilated patients receiving sevoflurane than in those receiving halothane. Tidal volume with sevoflurane decreases with increasing depth of anesthesia as it does with halothane. At 1.4 MAC, tidal volumes are similar with the two agents. However, respiratory frequency in patients given sevoflurane was found to increase, but not enough to compensate for the reduction in tidal volume. The result is the reduction in minute ventilation seen with sevoflurane. This decrease in minute ventilation differs from halothane anesthesia, in which the increase in respiratory frequency is enough to offset the reduction in tidal volume. Both sevoflurane and halothane show similar increases in carbon dioxide elimination and dead space to tidal volume ratio with increasing depth of anesthesia. Additional ventilatory effects of sevoflurane in combination with nitrous oxide and surgical stimulation were evaluated by Doi et al. [4]. They studied 10 patients undergoing minor surgery of the head and neck. Patients received either 1.3 MAC sevoflurane, 1.5 MAC sevoflurane, 0.9 MAC sevoflurane with 0.4 MAC nitrous oxide, or 1.1 MAC sevoflurane with 0.4 MAC nitrous oxide. Hypercapnia was again found to be a function of or related to anesthetic depth. PaCO2 decreases when a 0.4 MAC sevoflurane is replaced with an equivalent MAC of nitrous oxide. As had been demonstrated in patients without surgical stimulation, tidal volume decreases with increasing depth of anesthesia. However, replacement of sevoflurane with 0.4 MAC nitrous oxide leads to an increase in tidal volume toward unanesthetized control values. No significant difference in respiratory rate was found in any of the treatment groups. In all treatment groups, respiratory rate was more rapid during anesthesia than when the patients were awake. With increasing depth of anesthesia, minute ventilation decreases. Replacement of sevoflurane with 0.4 MAC nitrous oxide results in an increase in minute ventilation toward control values. Nishino and Kochi [5] have looked at the effect of sevoflurane and surgical stimulation on the apneic threshold, the carbon dioxide off-switch threshold below which controlled hyperventilation produces hypocapneic apnea. Previous work had shown that apnea occurred when PaCO2 was decreased an average 4.6 torr below the PaCO2 seen with spontaneous ventilation during anesthesia [6]. There was no difference between inhaled anesthetics. In anesthetized individuals, surgical stimulation has been demonstrated to shift the ventilatory response curve to the left [7]. Nishino and Kochi [5] measured the end-tidal carbon dioxide partial pressures (PETCO2) at three points: resting, apneic threshold, and on-switch threshold. The apneic threshold was significantly less than the resting PETCO2. The on-switch threshold, the PETCO2 at which the respiratory drive reappears after posthyperventilation apnea, was also found to be significantly greater than resting PETCO2. Surgical stimulation does not have a linear effect on these three points. Resting PETCO2 was decreased under sevoflurane anesthesia. Likewise, the apneic threshold was decreased with the apneic threshold significantly less than resting PETCO2. However, after surgical stimulus there was no significant difference between on-switch threshold and resting PETCO2. To determine whether the effects of halothane and sevoflurane on central respiratory centers are similar, Kochi et al. [8] studied the effects of the two anesthetics at 1 MAC in patients undergoing minor gynecologic procedures. The duration of the respiratory cycle was found to be longer with sevoflurane than with halothane. Occlusion pressure waveforms also differed Figure 1, indicating that sevoflurane and halothane affect the muscles of the diaphragm and rib cage differently. As a result of these differences, the authors postulated that sevoflurane and halothane have different effects on the central respiratory centers.Figure 1: Occlusion pressure (-Pocc) waveforms of halothane- and sevoflurane-anesthetized subjects. Pressure was measured in 100-ms intervals and averaged for seven subjects in each group. Values are mean +/- SEM. fill circle, halothane; open circle, sevoflurane; t(s), time measured in seconds. [From Kochi et al. [8] with permission.]The effect of sevoflurane on diaphragm function has been assessed in dogs. Ide et al. [9] studied the effects of three sevoflurane concentrations (1, 1.5, and 2 MAC) on diaphragmatic function by measuring transdiaphragmatic pressure after phrenic nerve stimulation at 0.5, 10, 20, 30, 50, and 100 Hz. Sevoflurane exposure at the three concentrations did not have a significant effect on transdiaphragmatic pressure at 0.5, 10, 20, 30, and 50 Hz, which are in the physiologic range of intrinsic neural firing. However, at 2.0 MAC with a supraphysiologic stimulation of 100 Hz, a decrease in transdiaphragmatic pressure was observed Figure 2[9]. In contrast, halothane has no effect on diaphragmatic function, while at the other extreme, enflurane causes a very pronounced decrease in force generation by the diaphragm [10].Figure 2: Force-frequency relationships of the diaphragm at three levels of sevoflurane anesthesia (n = 6 dogs). Each point represents average data and bars indicate 1 SEM. ???? represents statistical difference (P < 0.05 vs 1 MAC, 1.5 MAC). Pdi, transdiaphragmatic pressure; MAC, minimum alveolar anesthetic concentration. [From Ide et al. [9] with permission.]Ide et al. [10] further evaluated the effect of sevoflurane (0, 1.0, or 1.5 MAC) on diaphragmatic contractility in dogs. In addition to transdiaphragmatic pressure (Pdi), integrated electrical activity (Edi) of the crural (Edi cru) and costal (Edi cost) parts of the diaphragm were evaluated. Measurements were made at the start of stimulation and at the end of a 2-s period. No significant difference was found among treatment groups in arterial pH, PaCO2, or PaO2. No significant difference was found in Pdi, Edi cru, or Edi cost in the three concentration exposures to sevoflurane at 10-and 20-Hz stimulation. It is interesting to note that a small increase in Pdi was seen at 1 MAC anesthesia at the physiologic frequencies of 10 and 20 Hz. This could be a result of reduced functional residual capacity enabling the shortened muscle to develop more tension or the result of increased PaCO2 in the anesthetized state. However, at 50- and 100-Hz stimulation, Pdi and Edi cru decreased significantly during 1.0 and 1.5 MAC sevoflurane exposure compared with 0 MAC. Pdi and Edi cru also showed a fade phenomenon at 1.5 MAC at 100-Hz stimulation that was not present at 1.0 MAC Table 1[11]. There was no increase in Edi cost with increasing depth of anesthesia with sevoflurane at 50 and 100 Hz. Increasing depth of anesthesia also resulted in a decrease in mean arterial pressure, while mean arterial pressure in the control group was unchanged after a 2-h period. Ide et al. [11] concluded that there is probably a different sensitivity to sevoflurane in the crural and costal parts of the diaphragm, and that the decrease in diaphragmatic contraction after exposure to sevoflurane was secondary to its depressant effect on the crural portion of the diaphragm Figure 3[11].Table 1: Pdi at the End of a 2-s Period During Sevoflurane Anesthesia at MAC 0, 1, and 1.5 at the Tetanic Stimulation of the Phrenic NervesFigure 3: The relationships between transdiaphragmatic pressure (Pdi) and the electrical activity of the crural and costal parts of the diaphragm (Cru and Cost, respectively) for phrenic nerve stimulation at 50 Hz (left) and 100 Hz (right). Open symbols, at the start of stimulation: closed symbols, at the end of a 2-s period. Circles, 0 minimum alveolar anesthetic concentration (MAC); squares, 1.0 MAC; triangles, 1.5 MAC. [From Ide et al. [11] with permission.]Animal studies have shown induction with sevoflurane to be rapid and without airway irritation [12]. Airway irritation due to sevoflurane exposure in humans was assessed by Doi and Ikeda [13], using respiratory plethysmography. Changes in respiratory frequency, tidal volume, and end-expiratory volume due to inhalation of various anesthetics were evaluated. In general, inhalation of anesthetics caused an increase in respiratory frequency, decrease in tidal volume, and decrease in end-expiratory volume. A 30% change in tidal volume or respiratory frequency for 10 or longer or a 30% change in end-expiratory volume constituted a significant change. Isoflurane was associated with the most frequent number of changes, followed by enflurane, halothane, then sevoflurane. Sevoflurane had the least effect on tidal volume, had no effect on respiratory rate, and did not initiate a cough reflex. The severity of subjective airway irritation is shown in Table 2[13]. A four-point scale was used, with 1 being the least irritation and 4 the most.Table 2: Severity of Subjective Airway Irritation in Human Volunteers Exposed to Sevoflurane, Halothane, Enflurane, and Isoflurane at MAC 1 and 2Sevoflurane appears to be effective in reversing bronchospasm. This finding is not surprising, considering that the three other inhaled anesthetics in widespread use at this time--halothane, enflurane, and isoflurane--are effective in preventing and reversing vagal reflex-induced bronchoconstriction [14]. Hirshman and Bergman [14] have demonstrated in dogs that the attenuation of bronchoconstriction with inhaled anesthetics is not a direct effect. Halothane and isoflurane only slightly attenuated bronchoconstriction in methacholine-treated Basenji greyhounds. Mitsuhata and colleagues [15] have successfully demonstrated that anaphylaxis-induced increase in pulmonary resistance is attenuated by sevoflurane anesthesia at 1 MAC. Furthermore, no significant difference in attenuation was found between sevoflurane and isoflurane. No data are available as to whether sevoflurane inhibits methacholine-induced bronchoconstriction. Therefore, the mechanism of sevoflurane attenuation of histamine-induced bronchoconstriction remains unknown. Is it a direct effect or is it the result of inhibited vagal reflexes as appears to be the case with the other inhaled anesthetics? Sevoflurane has been found to be quite appropriate for use in inhalational induction techniques. Its use was especially amenable to the vital capacity rapid inhaled induction of anesthesia [16]. When sevoflurane was used in this technique, induction took half the time of conventional inhalational induction (54 s vs 108 s) and was not associated with cardiovascular instability. When compared with halothane, the anesthetic most often used in an inhaled induction of anesthesia, sevoflurane has a more rapid induction and fewer complications, such as coughing and movement, using the vital capacity rapid inhaled induction technique [17]. Volunteers subjected to sevoflurane induction found the smell of the anesthetic to be more acceptable than did those subjected to halothane [17]. Sevoflurane is a potent inhaled anesthetic that provides rapid induction of anesthesia, rapid recovery, and control of anesthetic depth. Sevoflurane, like the other inhaled anesthetics, is a ventilatory depressant. With increasing depth of anesthesia, a decrease in minute ventilation and PaCO2 has been observed. However, when 0.4 MAC nitrous oxide was substituted for sevoflurane in the presence of surgical stimulation, a decrease in PaCO2 and an increase in tidal volume were seen. While sevoflurane's depressant effects are more pronounced than those of halothane, they are quite similar to those of isoflurane [18]. Because sevoflurane causes less airway irritation than other inhaled anesthetics, it would appear to be an excellent anesthetic. It does not irritate the airway or induce the cough reflex, and is therefore a good candidate for inhaled induction of anesthesia in children [19].