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Recovery and pharmacokinetic parameters of desflurane, sevoflurane, and isoflurane in patients undergoing urologic procedures
Original Contributions Recovery and Pharmacokinetic Parameters of Desflurane, Sevoflurane, and Isoflurane in Patients Undergoing Urologic Procedures Michael Behne, MD,* Hans-Joachim Wilke, MD,† Volker Lischke, MD‡ Klinik fuer Anaesthesiologie, Intensivmedizin und Schmerztherapie, Klinikum der Johann Wolfgang Goethe-Universitaet, Frankfurt am Main, Germany
*Associate Professor of Anaesthesiology †Attending Anaesthesiologist ‡Assistant Professor of Anaesthesiology Address correspondence to Dr. Behne at the Zentrum der Anaesthesiologie und Wiederbelebung, Klinikum der Johann Wolfgang Goethe-Universitaet, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. E-mail: [email protected]
Study Objective: To compare the pharmacokinetics and the speed of recovery after inhalation anesthesia with desflurane, sevoflurane, and isoflurane in elective surgery. Design: Prospective, randomized study. Setting: University medical center. Patients: 30 ASA physical status I and II adults presenting for elective surgery. Interventions: Anesthesia was induced with etomidate and maintained with desflurane (n ⫽ 10), sevoflurane (n ⫽ 10), or isoflurane (n ⫽ 10) and nitrous oxide. The inhalation drugs were titrated until an adequate clinical depth of anesthesia was reached. At the end of anesthesia, the patients breathed oxygen via the endotracheal tube and after extubation via a face mask. Measurements and Main Results: The groups were similar with respect to age, weight, duration of anesthesia, and mean arterial pressure. Mean end-tidal concentration (FA ⫽ FA0) at the end of anesthesia was 6.34 ⫾ 1.15% after desflurane, 1.85 ⫾ 0.42% after sevoflurane, and 1.10 ⫾ 0.24% after isoflurane. FA/FA0 decreased significantly faster with desflurane than with isoflurane, while there was little difference between desflurane and sevoflurane. As for the terminal half-life (t1/2), there were no differences among the groups (8.16 ⫾ 3.15 min after desflurane, 9.47 ⫾ 4.46 min after sevoflurane, and 10.0 ⫾ 5.57 min after isoflurane). The time until a command was followed for the first time was the same in all three groups (13.0 ⫾ 4.7 min after desflurane, 13.4 ⫾ 4.4 min after sevoflurane, and 13.6 ⫾ 3.4 min after isoflurane). There was no significant correlation between duration of anesthesia and the time until recovery. Conclusions: There are only minor differences with regard to the recovery phase in premedicated patients who receive clinically titrated inhalation anesthesia with desflurane, sevoflurane, or isoflurane. © 1999 by Elsevier Science Inc. Keywords: Anesthetics, inhalational; desflurane; isoflurane; sevoflurane.
Received for publication March 2, 1999; revised manuscript accepted for publication June 28, 1999. Journal of Clinical Anesthesia 11:460 – 465, 1999 © 1999 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
0952-8180/99/$–see front matter PII S0952-8180(99)00082-3
Kinetics of inhalation anesthetics: Behne et al.
Introduction The inhalation anesthetics sevoflurane and desflurane were introduced into clinical practice because of their more rapid pharmacokinetics compared with isoflurane or halothane, as a result of their low blood solubilities.1–3 It is postulated that recovery from anesthesia is faster with these new drugs. The pharmacokinetics of the two substances in humans were examined by the same group of investigators based on a five-compartment model and compared with halothane and isoflurane in two different studies.4,5 To make a direct comparison possible, data for sevoflurane and desflurane from the two different studies were used and evaluated. A study comparing the pharmacokinetics of sevoflurane and desflurane in humans is not yet available. Moreover, to date, the clinical superiority of sevoflurane and desflurane has been proven mainly through separate studies comparing the two drugs to halothane or isoflurane, respectively. A direct comparison of the recovery time after anesthesia with sevoflurane and desflurane in adult patients was done in only four studies.6 –9 Nathanson et al.6 found only slight and clinically insignificant differences after short surgical procedures. Tarazi and Philip7 found recovery indices marginally but not significantly better with sevoflurane than desflurane. In two other studies carried out by Eger et al.8,9 with healthy volunteers, a significantly faster recovery after anesthesia with desflurane was found. However, in these studies, sevoflurane and desflurane were administered in fixed, predetermined concentrations based on the minimum alveolar concentration (MAC) values of the two substances. Thus, the differences that were noted cannot prove the clinical superiority of desflurane because under clinical conditions the concentration applied is titrated as needed. The present study seeks to analyze, under controlled, randomized conditions, the pharmacokinetics and the speed of recovery after anesthesia with desflurane, sevoflurane, and isoflurane in patients undergoing elective surgery.
Materials and Methods After obtaining Klinikum der Johann Wolfgang Goethe University institutional human investigation committee approval and written, informed consent from the patients, 30 ASA physical status I or II patients (18 to 85 years) scheduled for elective general surgical and urological procedures were enrolled in this study. As a rule, procedures were transurethral, urological procedures; in all groups, there were three major procedures such as nephrectomies. Patients were randomly assigned to three groups. One group (n ⫽ 10) received desflurane (Pharmacia & Upjohn GmbH, Erlangen, Germany), the second group (n ⫽ 10) received sevoflurane (Abbott GmbH, Wiesbaden, Germany), and the third group (n ⫽ 10) received isoflurane (Abbott GmbH, Wiesbaden, Germany). Patients with a history of cardiovascular disease,
anaphylactic reactions, or contraindications for inhalation anesthesia were excluded from the study. A standard anesthetic protocol was rigidly followed and the usual noninvasive monitoring was used. On the morning of surgery, each patient was given 7.5 mg midazolam orally. Anesthesia was induced intravenously (IV) with 10 mg atracurium, 1 to 2 g/kg fentanyl, 0.3 mg/kg etomidate, and 1 mg/kg succinylcholine, and was maintained by inhalation of 50% nitrous oxide (N2O) in oxygen (O2) with desflurane, sevoflurane, or isoflurane added as needed using a fresh gas flow of 2 L/min. Desflurane, isoflurane, and sevoflurane were titrated in such a way that in all patients heart rate (HR) and arterial blood pressure (BP) did not exceed or fall below preoperative base line values by more than 20%. Supplemental atracurium was administered to maintain relaxation. During anesthesia, patients were ventilated at a rate of 12 breaths/min and end-tidal carbon dioxide tension (ETCO2) was maintained at 35 mmHg. Hemodynamic parameters, ventilation parameters, inspiratory and expiratory concentrations of CO2, N2O, and respective anesthetic drugs were monitored throughout the anesthesia in 20-second intervals. The data obtained were stored in the electronic memory of the anesthetic apparatus (Modulus CD, Ohmeda GmbH, Erlangen, Germany). The precision of the infrared analysis was verified once per week by calibration with room air and calibration gas. During the last 15 minutes of the procedure, the end-expiratory concentration of the inhalation drug was maintained constant. On completion of the procedure, the supply of inhalation drug and of N2O was stopped and the patients were ventilated at a fresh gas flow of 8 L/min O2 and an end-expiratory CO2 of 35 mmHg. After the onset of spontaneous ventilation, patients were extubated and they breathed spontaneously via a face mask until the 15th minute after discontinuation of the anesthetic. The times when spontaneous ventilation, eyelid reflex, and cough reflex set in were noted. The patients were asked to open their eyes in 30-second intervals. Calculation of uptake of anesthetic drug and exposure to the drug (MAC-h) was based on a MAC of 6.0% for desflurane,10 2.05% for sevoflurane,11 and 1.15% for isoflurane.12 After linear and logarithmic evaluation of the end-expiratory concentrations (FA) by way of a graph for each individual patient, a biphasic concentration course could be found in all three groups. The quotient FA/FA0 was determined by FA and the alveolar concentration at the stop of administration of drug (FA0) and shown in a graph. The time was determined when FA decreased to 10% of FA0 (t10). The logarithmic graph obtained showed for all 30 patients a rapid decrease of the alveolar concentration and a monophasic decrease of the concentration from the 2nd through the 15th minute. Using the pharmacokinetic and pharmacodynamic data analysis program TOPFIT 2.0,13 data analysis was performed by noncompartmental analysis for all patients. The parameter of the noncompartmental analysis was the terminal half-life (t1/2). Data are expressed as mean values ⫾ standard deviation (SD), unless otherwise indicated. Statistical analysis J. Clin. Anesth., vol. 11, September 1999
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Table 1. Demographic Data and Drug Requirements
Age (yrs) Weight (kg) Height (cm) Gender (M/F) Duration of anesthesia (min) Total dose of inhalation anaesthetic ⫽ MAC 䡠 h (hrs) Total dose of fentanyl (g) Total dose of infusion (ml)
Desflurane (n ⴝ 10)
Sevoflurane (n ⴝ 10)
Isoflurane (n ⴝ 10)
56.3 ⫾ 21.9 85 ⫾ 14 178 ⫾ 7 10/0 117 ⫾ 83
53.5 ⫾ 16.1 80 ⫾ 7 177 ⫾ 9 10/0 109 ⫾ 80
55.3 ⫾ 13.7 80 ⫾ 20 175 ⫾ 8 8/2 111 ⫾ 66
1.99 ⫾ 1.42
1.60 ⫾ 1.41
1.69 ⫾ 1.28
135 ⫾ 53
175 ⫾ 68
165 ⫾ 75
1,550 ⫾ 798
1,180 ⫾ 518
1,200 ⫾ 483
Note: Data are reported as means ⫾ SD. There where no significant differences among groups.
consisted of H-test of Kruskal and Wallis (three groups) and also U-Test (Wilcoxon, Mann and Whitney test) for all data. A p-value less than 0.05 was required for statistical significance. Using the Spearman rank correlation test and linear regression analysis, we tested whether there was a correlation between duration of anesthesia and recovery time and uptake of anesthetic drug.
Results The two groups were comparable with respect to age, weight, height, and gender ratio (Table 1). They were also comparable with respect to duration of anesthesia and the total amount of crystalloids infused (Table 1). None of the patients received blood products. There was no significant difference with regard to hemodynamic parameters during anesthesia or in the recovery phase (Figure 1).
Table 2. Indices of Recovery Desflurane Sevoflurane Isoflurane (n ⴝ 10) (n ⴝ 10) (n ⴝ 10) Spontaneous 6.0 ⫾ 2.6 ventilation (min) Cough reflex (min) 6.2 ⫾ 2.9* Tracheal extubation (min) 8.5 ⫾ 3.1 Eyelid reflex (min) 8.7 ⫾ 4.1 Eye opening to 13.0 ⫾ 4.7 command (min)
9.5 ⫾ 7.0
6.9 ⫾ 4.6
11.5 ⫾ 5.3 8.8 ⫾ 3.5 12.0 ⫾ 5.0 10.1 ⫾ 3.7 12.0 ⫾ 4.7 10.1 ⫾ 2.7 13.4 ⫾ 4.4 13.6 ⫾ 3.4
Note: Data are reported as mean ⫾ SD. *p ⬍ 0.05 between desflurane and sevoflurane.
Pharmacodynamic Analysis There was no difference among the three groups with regard to the moment when spontaneous ventilation, extubation, and eyelid reflex set in and the moment of first reaction to a command (“open your eyes”) (Table 2). In all three groups, the patients followed a command after an average of 13 minutes. After desflurane the cough reflex set in significantly earlier as compared to sevoflurane (p ⬍ 0.05). Table 3 shows for all three anesthetic drugs the alveolar concentration when the patients followed a command for the first time (MACAWAKE). In relation to the MAC of the respective inhalation anaesthetic (MACAWAKE/MAC), this was true at a lower FA with desflurane and sevoflurane than with isoflurane. The difference between desflurane and isoflurane was significant (p ⬍ 0.05).
Pharmacokinetic Analysis Table 3 shows the values for FA at the time when the supply of the anesthetic drug was stopped (FA0). In relation to the MAC of the respective inhalation drug, the value FA0/ MAC of 1.05 ⫾ 0.19 for desflurane was higher than for sevoflurane (0.90 ⫾ 0.20) or for isoflurane (0.95 ⫾ 0.21). The difference was not significant. In all three groups 1 Table 3. Pharmacokinetic Data Desflurane (n ⴝ 10)
Sevoflurane (n ⴝ 10)
Isoflurane (n ⴝ 10)
FA0 (%) 6.34 ⫾ 1.15 1.85 ⫾ 0.42 1.10 ⫾ 0.24 1.05 ⫾ 0.19 0.90 ⫾ 0.20 0.95 ⫾ 0.21 FA0/MAC 8.16 ⫾ 3.15 9.47 ⫾ 4.46 10.0 ⫾ 5.57 t1/2 (min) 10.6 ⫾ 3.53 11.9 ⫾ 5.30 13.3 ⫾ 2.36* t10 (min) 0.57 ⫾ 0.22 0.21 ⫾ 0.09 0.14 ⫾ 0.05 MACAWAKE (%) MACAWAKE/MAC 0.094 ⫾ 0.037 0.102 ⫾ 0.043 0.121 ⫾ 0.045*
Figure 1. Mean arterial pressure (MAP) during the first 90 minutes of anesthesia and in the recovery period. 462
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Note: Data are reported as mean ⫾ SD. FA0 ⫽ alveolar concentration at the stop of administration; FA0/ MAC ⫽ FA0 related to MAC; t1/2 ⫽ terminal half-life; t10 ⫽ time required for endexpiratory concentration to decrease to 10% of FA0; MACAWAKE ⫽ alveolar concentration when patients woke up. *p ⬍ 0.05 between isoflurane and desflurane.
Kinetics of inhalation anesthetics: Behne et al.
minutes the quotient FA/FA0 was lower with sevoflurane than with isoflurane (p ⬍ 0.05). For all 30 patients, the semilogarithmic graph showed a monophasic decrease of FA from minutes 1 to 15 after the supply inhalation drug was stopped. With regard to t1/2 during this phase, there was no difference among the three groups (Table 3). The values obtained for t10 were significantly greater after isoflurane than after desflurane. There was no difference between desflurane and sevoflurane. Figure 3 shows a linear relation between duration of anesthesia and total uptake of the inhalation drug in all groups. However, there was no correlation in any of the three groups between the duration of anesthesia and the time until recovery.
Figure 2. In all three groups, FA/FA0 ratio (mean ⫾ SD) decreased 1 minute after discontinuation to less than 0.4. At any time, FA/FA0 was significantly lower after desflurane than after isoflurane (p ⬍ 0.05). # p ⬍ 0.05 between isoflurane and sevoflurane. *p ⬍ 0.05 between sevoflurane and desflurane.
minute after discontinuation of anesthetic drug, the quotient FA/FA0 decreased to less than 0.4 (Figure 2). At any time, FA/FA0 was significantly lower in the desflurane group than in the isoflurane group (p ⬍ 0.05). Only at 4 minutes, 9 minutes, and 14 minutes was the quotient FA/FA0 lower with desflurane than with sevoflurane (p ⬍ 0.05). At 4 minutes, 5 minutes, and 13
Discussion In all three groups, FA decreased rapidly within 1 minute to 30% to 40% of the FA0 after start of elimination of inhalational drug. During the following 14 minutes, there was a monoexponential decrease of FA. Desflurane was eliminated significantly faster than isoflurane. There was no significant difference between desflurane and sevoflurane. The recovery time until the moment when the patient first followed a command was not shorter after desflurane or sevoflurane than it was after isoflurane. In previous tests, the clinical superiority of sevoflurane and desflurane was studied only in comparison to isoflurane, halothane, and enflurane. A direct comparison of the new inhalation drugs in adults was done in only three studies. Nathanson et al. compared the recovery character-
Figure 3. In all three groups there was a significant correlation between the duration of anesthesia and the uptake of the volatile drug (Spearman rank correlation rs ⫽ 0.9394 for sevoflurane, 0.8788 for isoflurane, and 0.8788 for desflurane). In none of the three groups was a correlation seen between the duration of anesthesia and the time to initial response to command (rs ⫽ ⫺0.7052 for sevoflurane, 0.1166 for isoflurane, and ⫺0.1785 for desflurane). J. Clin. Anesth., vol. 11, September 1999
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istics and discharge times in young healthy women undergoing short outpatient gynecological procedures. In this study, the inhalation drugs were administered according to hemodynamic response with the goal of maintaining mean arterial pressure within 20% of baseline values. The only significant result found was a faster wake up (“open eyes”) after desflurane than sevoflurane; the difference was 3 minutes. Although this result was certainly significant, it cannot be considered clinically relevant. There was no difference between the two groups with regard to the patient performance tested in the later recovery phase up to discharge. Furthermore, Tarazi and Philip,7 in a double-blinded design, found a slightly more rapid awakening with sevoflurane as compared to desflurane in outpatient anesthetics. Eger et al.,8,9 however, carrying out anesthesia in 28 healthy young volunteers for 2, 4, or 8 hours at 1.25 MAC, found a pronounced and significantly faster recovery at the end of anesthesia with desflurane as compared to sevoflurane (14 ⫾ 4 min vs. 28 ⫾ 8 min after anesthesia for 8 hrs). An important difference between the studies carried out by Eger et al.,8,9 the present study, and Nathanson et al.6 lies in the dosage of the inhalational drugs. Eger et al. applied desflurane and sevoflurane in a predetermined fixed dosage ratio (3.02:1), derived from the MAC of the two drugs as reported in the literature. However, the dosage ratio chosen by Eger et al. is not supportable by a careful review of the references on which it is based. The MAC of desflurane was found by Rampil et al.10 to be 7.25% in 18- to 30-year-old volunteers. The determination of the MAC of sevoflurane, which was done by Scheller et al.11 is not comparable for several reasons. Scheller et al. carried out their studies in only 16 volunteers between 30 and 48 years of age. In the age group from 19 to 27 years, only four volunteers were tested and the authors refrained from calculating the MAC for this subgroup. It seems as if Eger et al. took the average of the results shown in the table of the study of Scheller et al. and arrived at their figure of 2.4%. We mention this fact because a calculation of a pharmacodynamic quantity such as the MAC is not valid for statistical reasons when the number of volunteers is so small. Therefore, it appears questionable to us to choose a dosage ratio taken from these studies as a basis for a pharmacodynamic study. In our study, sevoflurane and desflurane were not applied in a fixed dosage ratio, but the dosing was done clinically, as in the Nathanson et al. study, according to the hemodynamic reactions of the patients. At the end of the surgical procedure in the steady state we found an F0 of 6.34% for desflurane and an F0 of 1.85% for sevoflurane. Related to the MAC of the respective age groups, this finding corresponds to the 1.05-fold of the MAC of desflurane and to the 0.90-fold of the MAC of sevoflurane. Furthermore, it corresponds to a dosage ratio of 3.42:1. Hence, in the present study in which the dosage followed clinical considerations, desflurane was administered in a concentration about 15% higher than by Eger et al.8,9 However, our study (as with the studies of Eger et al. and Nathanson et al.) was not carried out in a blinded design. In the study by Nathanson et al.,6 as well as the present 464
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study, sevoflurane and desflurane were administered according to clinical parameters. In both studies either minimal, clinically irrelevant or no differences with regard to the speed of recovery are found. In both studies, desflurane was administered in higher concentrations than in the study of Eger et al. We conclude from this fact that the MAC values taken as a basis by Eger et al. either underestimate the MAC of desflurane or overestimate the MAC of sevoflurane. This finding agrees with the results of a meta-analysis that estimated the MAC of sevoflurane at 1.80% and the MAC of desflurane at 6.6% (for the 40-year age).14 Yasuda et al.4,5 tested the pharmacokinetics of sevoflurane and desflurane in identical studies using a fivecompartment-model. With the help of gas chromatographic methods, traces of the inhalation drugs could be detected in the expired air of volunteers for up to 5 days. Under these conditions, it could be demonstrated that elimination of desflurane is significantly more rapid than for sevoflurane. In clinical practice, however, it is primarily the decrease of the plasma level of an inhalation drug in the immediate postoperative phase that is of interest. The beginning of spontaneous ventilation, the appearance of the eye reflex, and the ability to follow a command are the clinical signs that determine the best moment of extubation and discharge of the patient to the recovery room. More rapid pharmacokinetics and a shorter recovery phase would be beneficial for clinical and economical reasons. We found that in all patients, 1 minute after stopping the supply of the drug, the alveolar concentration FA had decreased to about 30% of the F0 (39% for isoflurane). With regard to the model taken as a basis by Yasuda et al., this corresponds to the elimination from the pulmonary compartment, i.e., functional residual capacity. In the subsequent 14 minutes, all patients showed a monoexponential decrease of FA, which can be described with one single half-life regardless of the model. Here we found practically identical results with a mean t1/2 ⫽ 8.16 ⫾ 3.15 minutes for desflurane, t1/2 ⫽ 9.47 ⫾ 4.46 minutes for sevoflurane, and t1/2 ⫽ 10.0 ⫾ 5.57 minutes for isoflurane. In addition, with regard to the time in which FA decreases to 10% of the F0 (t10), no differences could be found between sevoflurane and desflurane, whereas isoflurane was eliminated significantly more slowly, with a mean t10 of 13.3 minutes. This phase corresponds to elimination from organs with high perfusion including the brain. Furthermore, we found that in the early postoperative phase that we investigated, recovery time is not dependent on either the duration of anesthesia or on total amount taken up of the inhalation drugs. Other investigators found that in humans the time for emergence is dependent on the duration of anaesthesia for isoflurane,15,16 but not for sevoflurane.16,17 In contrast, Eger et al.8,9 found more rapid awakening after a 2- and 4-hour anesthetic with sevoflurane as compared to one of 8 hours. However, these differences were not statistically significant. Thus, we believe that in the early postoperative phase in which only elimination from the lungs and from organs well supplied with blood takes place, a difference between desflurane,
Kinetics of inhalation anesthetics: Behne et al.
sevoflurane, and isoflurane cannot be proven because the observation period is too short. As customary in our institution, patients were premedicated with midazolam and they received etomidate and fentanyl for induction of anesthesia. While the effect of these substances probably had worn off after longer procedures, it is possible that with short procedures the recovery was delayed. Our results confirm those of Ebert et al.,18 who studied the time to emergence after sevoflurane and isoflurane in 1,417 patients. They found a statistically significant, however clinically irrelevant, difference of 3 minutes. Furthermore, despite the large population studied, there was no interdependence between the time to emergence and the duration of anesthesia. The important point to be recorded is that for the first 15 minutes of elimination of a volatile drug the pharmacokinetic data cannot prove any definite advantages of sevoflurane or desflurane over isoflurane. There was no difference with regard to the speed of recovery until the ability to follow a command. Economic advantages in the initial period until the patient is transferred to the recovery room cannot be derived from the results of our study. Future studies should be aimed at clarifying whether there are differences in the later periods of elimination, e.g., up to the complete psychomotoric recovery or the ability to participate in traffic. In summary, we found that with premedicated patients who receive a titrated inhalation anesthesia according to clinical parameters, there are only minor advantages to using desflurane and sevoflurane over isoflurane. With regard to the speed of recovery, the three drugs can be judged as equal.
References 1. Eger EI 2nd: New inhaled anesthetics. Anesthesiology 1994;80:906 – 22. 2. Strum DP, Eger EI 2nd: Partition coefficients for sevoflurane in human blood, saline, and olive oil. Anesth Analg 1987;66:654 – 6. 3. Eger EI 2nd: Uptake and distribution. In: Miller RD (ed): Anesthesia, 4th ed. (Vol. 1.) New York: Churchill Livingstone, 1994:101–23. 4. Yasuda N, Lockhart SH, Eger EI 2d, et al: Comparison of kinetics of sevoflurane and isoflurane in humans. Anesth Analg 1991;72: 316 –24.
5. Yasuda N, Lockhart SH, Eger EI 2nd, et al: Kinetics of desflurane, isoflurane, and halothane in humans. Anesthesiology 1991;74:489 – 98. 6. Nathanson MH, Fredman B, Smith I, White PF: Sevoflurane versus desflurane for outpatient anesthesia: a comparison of maintenance and recovery profiles. Anesth Analg 1995;81:1186 – 90. 7. Tarazi EM, Philip BK: A comparison of recovery after sevoflurane or desflurane in ambulatory anesthesia. J Clin Anesth 1998;10: 272–7. 8. Eger EI 2nd, Bowland T, Ionescu P, et al: Recovery and kinetic characteristics of desflurane and sevoflurane in volunteers after 8-h exposure, including kinetics of degradation products. Anesthesiology 1997;87:517–26. 9. Eger EI 2nd, Gong D, Koblin DD, et al: The effect of anesthetic duration on kinetic and recovery characteristics of desflurane versus sevoflurane, and on the kinetic characteristics of compound A, in volunteers. Anesth Analg 1998;86:414 –21. 10. Rampil IJ, Lockhart SH, Zwass MS, et al: Clinical characteristics of desflurane in surgical patients: minimum alveolar concentration. Anesthesiology 1991;74:429 –33. 11. Scheller MS, Saidman LJ, Partridge BL: MAC of sevoflurane in humans and the New Zealand white rabbit. Can J Anaesth 1988;35:153– 6. 12. Stevens WC, Dolan WM, Gibbons RT, et al: Minimum alveolar concentrations (MAC) of isoflurane with and without nitrous oxide in patients of various ages. Anesthesiology 1975;42:197–200. 13. Heinzel G, Woloszczak R, Thomann P: Pharmacokinetic and Pharmacodynamic Data Analysis System. Stuttgart: Gustav Fischer, 1993. 14. Mapleson WW: Effect of age on MAC in humans: a meta-analysis. Br J Anaesth 1996;76:179 – 85. 15. Carpenter RL, Eger EI 2nd, Johnson BH, Unadkat JD, Sheiner LB: Does the duration of anesthetic administration affect the pharmacokinetics or metabolism of inhaled anesthetics in humans? Anesth Analg 1987;66:1– 8. 16. Frink EJ Jr, Malan TP, Atlas M, Dominguez LM, DiNardo JA, Brown BR Jr: Clinical comparisons of sevoflurane and isoflurane in healthy patients. Anesth Analg 1992;74:241–5. 17. Wiesner G, Wild K, Merz M, Hobbhahn J: Awakening periods (emergence times), hemodynamics and adverse experiences with sevoflurane and enflurane: a phase III, open-label, randomised comparative study. Anaesthesiol Intensivmed Notfallmed Schmerzther 1995;30:290 – 6. 18. Ebert TJ, Robinson BJ, Uhrich TD, Mackenthun A, Pichotta PJ: Recovery from sevoflurane anesthesia. Anesthesiology 1998;89: 1524 –31.
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*Associate Professor of Anaesthesiology †Attending Anaesthesiologist ‡Assistant Professor of Anaesthesiology Address correspondence to Dr. Behne at the Zentrum der Anaesthesiologie und Wiederbelebung, Klinikum der Johann Wolfgang Goethe-Universitaet, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. E-mail: [email protected]
Study Objective: To compare the pharmacokinetics and the speed of recovery after inhalation anesthesia with desflurane, sevoflurane, and isoflurane in elective surgery. Design: Prospective, randomized study. Setting: University medical center. Patients: 30 ASA physical status I and II adults presenting for elective surgery. Interventions: Anesthesia was induced with etomidate and maintained with desflurane (n ⫽ 10), sevoflurane (n ⫽ 10), or isoflurane (n ⫽ 10) and nitrous oxide. The inhalation drugs were titrated until an adequate clinical depth of anesthesia was reached. At the end of anesthesia, the patients breathed oxygen via the endotracheal tube and after extubation via a face mask. Measurements and Main Results: The groups were similar with respect to age, weight, duration of anesthesia, and mean arterial pressure. Mean end-tidal concentration (FA ⫽ FA0) at the end of anesthesia was 6.34 ⫾ 1.15% after desflurane, 1.85 ⫾ 0.42% after sevoflurane, and 1.10 ⫾ 0.24% after isoflurane. FA/FA0 decreased significantly faster with desflurane than with isoflurane, while there was little difference between desflurane and sevoflurane. As for the terminal half-life (t1/2), there were no differences among the groups (8.16 ⫾ 3.15 min after desflurane, 9.47 ⫾ 4.46 min after sevoflurane, and 10.0 ⫾ 5.57 min after isoflurane). The time until a command was followed for the first time was the same in all three groups (13.0 ⫾ 4.7 min after desflurane, 13.4 ⫾ 4.4 min after sevoflurane, and 13.6 ⫾ 3.4 min after isoflurane). There was no significant correlation between duration of anesthesia and the time until recovery. Conclusions: There are only minor differences with regard to the recovery phase in premedicated patients who receive clinically titrated inhalation anesthesia with desflurane, sevoflurane, or isoflurane. © 1999 by Elsevier Science Inc. Keywords: Anesthetics, inhalational; desflurane; isoflurane; sevoflurane.
Received for publication March 2, 1999; revised manuscript accepted for publication June 28, 1999. Journal of Clinical Anesthesia 11:460 – 465, 1999 © 1999 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
0952-8180/99/$–see front matter PII S0952-8180(99)00082-3
Kinetics of inhalation anesthetics: Behne et al.
Introduction The inhalation anesthetics sevoflurane and desflurane were introduced into clinical practice because of their more rapid pharmacokinetics compared with isoflurane or halothane, as a result of their low blood solubilities.1–3 It is postulated that recovery from anesthesia is faster with these new drugs. The pharmacokinetics of the two substances in humans were examined by the same group of investigators based on a five-compartment model and compared with halothane and isoflurane in two different studies.4,5 To make a direct comparison possible, data for sevoflurane and desflurane from the two different studies were used and evaluated. A study comparing the pharmacokinetics of sevoflurane and desflurane in humans is not yet available. Moreover, to date, the clinical superiority of sevoflurane and desflurane has been proven mainly through separate studies comparing the two drugs to halothane or isoflurane, respectively. A direct comparison of the recovery time after anesthesia with sevoflurane and desflurane in adult patients was done in only four studies.6 –9 Nathanson et al.6 found only slight and clinically insignificant differences after short surgical procedures. Tarazi and Philip7 found recovery indices marginally but not significantly better with sevoflurane than desflurane. In two other studies carried out by Eger et al.8,9 with healthy volunteers, a significantly faster recovery after anesthesia with desflurane was found. However, in these studies, sevoflurane and desflurane were administered in fixed, predetermined concentrations based on the minimum alveolar concentration (MAC) values of the two substances. Thus, the differences that were noted cannot prove the clinical superiority of desflurane because under clinical conditions the concentration applied is titrated as needed. The present study seeks to analyze, under controlled, randomized conditions, the pharmacokinetics and the speed of recovery after anesthesia with desflurane, sevoflurane, and isoflurane in patients undergoing elective surgery.
Materials and Methods After obtaining Klinikum der Johann Wolfgang Goethe University institutional human investigation committee approval and written, informed consent from the patients, 30 ASA physical status I or II patients (18 to 85 years) scheduled for elective general surgical and urological procedures were enrolled in this study. As a rule, procedures were transurethral, urological procedures; in all groups, there were three major procedures such as nephrectomies. Patients were randomly assigned to three groups. One group (n ⫽ 10) received desflurane (Pharmacia & Upjohn GmbH, Erlangen, Germany), the second group (n ⫽ 10) received sevoflurane (Abbott GmbH, Wiesbaden, Germany), and the third group (n ⫽ 10) received isoflurane (Abbott GmbH, Wiesbaden, Germany). Patients with a history of cardiovascular disease,
anaphylactic reactions, or contraindications for inhalation anesthesia were excluded from the study. A standard anesthetic protocol was rigidly followed and the usual noninvasive monitoring was used. On the morning of surgery, each patient was given 7.5 mg midazolam orally. Anesthesia was induced intravenously (IV) with 10 mg atracurium, 1 to 2 g/kg fentanyl, 0.3 mg/kg etomidate, and 1 mg/kg succinylcholine, and was maintained by inhalation of 50% nitrous oxide (N2O) in oxygen (O2) with desflurane, sevoflurane, or isoflurane added as needed using a fresh gas flow of 2 L/min. Desflurane, isoflurane, and sevoflurane were titrated in such a way that in all patients heart rate (HR) and arterial blood pressure (BP) did not exceed or fall below preoperative base line values by more than 20%. Supplemental atracurium was administered to maintain relaxation. During anesthesia, patients were ventilated at a rate of 12 breaths/min and end-tidal carbon dioxide tension (ETCO2) was maintained at 35 mmHg. Hemodynamic parameters, ventilation parameters, inspiratory and expiratory concentrations of CO2, N2O, and respective anesthetic drugs were monitored throughout the anesthesia in 20-second intervals. The data obtained were stored in the electronic memory of the anesthetic apparatus (Modulus CD, Ohmeda GmbH, Erlangen, Germany). The precision of the infrared analysis was verified once per week by calibration with room air and calibration gas. During the last 15 minutes of the procedure, the end-expiratory concentration of the inhalation drug was maintained constant. On completion of the procedure, the supply of inhalation drug and of N2O was stopped and the patients were ventilated at a fresh gas flow of 8 L/min O2 and an end-expiratory CO2 of 35 mmHg. After the onset of spontaneous ventilation, patients were extubated and they breathed spontaneously via a face mask until the 15th minute after discontinuation of the anesthetic. The times when spontaneous ventilation, eyelid reflex, and cough reflex set in were noted. The patients were asked to open their eyes in 30-second intervals. Calculation of uptake of anesthetic drug and exposure to the drug (MAC-h) was based on a MAC of 6.0% for desflurane,10 2.05% for sevoflurane,11 and 1.15% for isoflurane.12 After linear and logarithmic evaluation of the end-expiratory concentrations (FA) by way of a graph for each individual patient, a biphasic concentration course could be found in all three groups. The quotient FA/FA0 was determined by FA and the alveolar concentration at the stop of administration of drug (FA0) and shown in a graph. The time was determined when FA decreased to 10% of FA0 (t10). The logarithmic graph obtained showed for all 30 patients a rapid decrease of the alveolar concentration and a monophasic decrease of the concentration from the 2nd through the 15th minute. Using the pharmacokinetic and pharmacodynamic data analysis program TOPFIT 2.0,13 data analysis was performed by noncompartmental analysis for all patients. The parameter of the noncompartmental analysis was the terminal half-life (t1/2). Data are expressed as mean values ⫾ standard deviation (SD), unless otherwise indicated. Statistical analysis J. Clin. Anesth., vol. 11, September 1999
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Table 1. Demographic Data and Drug Requirements
Age (yrs) Weight (kg) Height (cm) Gender (M/F) Duration of anesthesia (min) Total dose of inhalation anaesthetic ⫽ MAC 䡠 h (hrs) Total dose of fentanyl (g) Total dose of infusion (ml)
Desflurane (n ⴝ 10)
Sevoflurane (n ⴝ 10)
Isoflurane (n ⴝ 10)
56.3 ⫾ 21.9 85 ⫾ 14 178 ⫾ 7 10/0 117 ⫾ 83
53.5 ⫾ 16.1 80 ⫾ 7 177 ⫾ 9 10/0 109 ⫾ 80
55.3 ⫾ 13.7 80 ⫾ 20 175 ⫾ 8 8/2 111 ⫾ 66
1.99 ⫾ 1.42
1.60 ⫾ 1.41
1.69 ⫾ 1.28
135 ⫾ 53
175 ⫾ 68
165 ⫾ 75
1,550 ⫾ 798
1,180 ⫾ 518
1,200 ⫾ 483
Note: Data are reported as means ⫾ SD. There where no significant differences among groups.
consisted of H-test of Kruskal and Wallis (three groups) and also U-Test (Wilcoxon, Mann and Whitney test) for all data. A p-value less than 0.05 was required for statistical significance. Using the Spearman rank correlation test and linear regression analysis, we tested whether there was a correlation between duration of anesthesia and recovery time and uptake of anesthetic drug.
Results The two groups were comparable with respect to age, weight, height, and gender ratio (Table 1). They were also comparable with respect to duration of anesthesia and the total amount of crystalloids infused (Table 1). None of the patients received blood products. There was no significant difference with regard to hemodynamic parameters during anesthesia or in the recovery phase (Figure 1).
Table 2. Indices of Recovery Desflurane Sevoflurane Isoflurane (n ⴝ 10) (n ⴝ 10) (n ⴝ 10) Spontaneous 6.0 ⫾ 2.6 ventilation (min) Cough reflex (min) 6.2 ⫾ 2.9* Tracheal extubation (min) 8.5 ⫾ 3.1 Eyelid reflex (min) 8.7 ⫾ 4.1 Eye opening to 13.0 ⫾ 4.7 command (min)
9.5 ⫾ 7.0
6.9 ⫾ 4.6
11.5 ⫾ 5.3 8.8 ⫾ 3.5 12.0 ⫾ 5.0 10.1 ⫾ 3.7 12.0 ⫾ 4.7 10.1 ⫾ 2.7 13.4 ⫾ 4.4 13.6 ⫾ 3.4
Note: Data are reported as mean ⫾ SD. *p ⬍ 0.05 between desflurane and sevoflurane.
Pharmacodynamic Analysis There was no difference among the three groups with regard to the moment when spontaneous ventilation, extubation, and eyelid reflex set in and the moment of first reaction to a command (“open your eyes”) (Table 2). In all three groups, the patients followed a command after an average of 13 minutes. After desflurane the cough reflex set in significantly earlier as compared to sevoflurane (p ⬍ 0.05). Table 3 shows for all three anesthetic drugs the alveolar concentration when the patients followed a command for the first time (MACAWAKE). In relation to the MAC of the respective inhalation anaesthetic (MACAWAKE/MAC), this was true at a lower FA with desflurane and sevoflurane than with isoflurane. The difference between desflurane and isoflurane was significant (p ⬍ 0.05).
Pharmacokinetic Analysis Table 3 shows the values for FA at the time when the supply of the anesthetic drug was stopped (FA0). In relation to the MAC of the respective inhalation drug, the value FA0/ MAC of 1.05 ⫾ 0.19 for desflurane was higher than for sevoflurane (0.90 ⫾ 0.20) or for isoflurane (0.95 ⫾ 0.21). The difference was not significant. In all three groups 1 Table 3. Pharmacokinetic Data Desflurane (n ⴝ 10)
Sevoflurane (n ⴝ 10)
Isoflurane (n ⴝ 10)
FA0 (%) 6.34 ⫾ 1.15 1.85 ⫾ 0.42 1.10 ⫾ 0.24 1.05 ⫾ 0.19 0.90 ⫾ 0.20 0.95 ⫾ 0.21 FA0/MAC 8.16 ⫾ 3.15 9.47 ⫾ 4.46 10.0 ⫾ 5.57 t1/2 (min) 10.6 ⫾ 3.53 11.9 ⫾ 5.30 13.3 ⫾ 2.36* t10 (min) 0.57 ⫾ 0.22 0.21 ⫾ 0.09 0.14 ⫾ 0.05 MACAWAKE (%) MACAWAKE/MAC 0.094 ⫾ 0.037 0.102 ⫾ 0.043 0.121 ⫾ 0.045*
Figure 1. Mean arterial pressure (MAP) during the first 90 minutes of anesthesia and in the recovery period. 462
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Note: Data are reported as mean ⫾ SD. FA0 ⫽ alveolar concentration at the stop of administration; FA0/ MAC ⫽ FA0 related to MAC; t1/2 ⫽ terminal half-life; t10 ⫽ time required for endexpiratory concentration to decrease to 10% of FA0; MACAWAKE ⫽ alveolar concentration when patients woke up. *p ⬍ 0.05 between isoflurane and desflurane.
Kinetics of inhalation anesthetics: Behne et al.
minutes the quotient FA/FA0 was lower with sevoflurane than with isoflurane (p ⬍ 0.05). For all 30 patients, the semilogarithmic graph showed a monophasic decrease of FA from minutes 1 to 15 after the supply inhalation drug was stopped. With regard to t1/2 during this phase, there was no difference among the three groups (Table 3). The values obtained for t10 were significantly greater after isoflurane than after desflurane. There was no difference between desflurane and sevoflurane. Figure 3 shows a linear relation between duration of anesthesia and total uptake of the inhalation drug in all groups. However, there was no correlation in any of the three groups between the duration of anesthesia and the time until recovery.
Figure 2. In all three groups, FA/FA0 ratio (mean ⫾ SD) decreased 1 minute after discontinuation to less than 0.4. At any time, FA/FA0 was significantly lower after desflurane than after isoflurane (p ⬍ 0.05). # p ⬍ 0.05 between isoflurane and sevoflurane. *p ⬍ 0.05 between sevoflurane and desflurane.
minute after discontinuation of anesthetic drug, the quotient FA/FA0 decreased to less than 0.4 (Figure 2). At any time, FA/FA0 was significantly lower in the desflurane group than in the isoflurane group (p ⬍ 0.05). Only at 4 minutes, 9 minutes, and 14 minutes was the quotient FA/FA0 lower with desflurane than with sevoflurane (p ⬍ 0.05). At 4 minutes, 5 minutes, and 13
Discussion In all three groups, FA decreased rapidly within 1 minute to 30% to 40% of the FA0 after start of elimination of inhalational drug. During the following 14 minutes, there was a monoexponential decrease of FA. Desflurane was eliminated significantly faster than isoflurane. There was no significant difference between desflurane and sevoflurane. The recovery time until the moment when the patient first followed a command was not shorter after desflurane or sevoflurane than it was after isoflurane. In previous tests, the clinical superiority of sevoflurane and desflurane was studied only in comparison to isoflurane, halothane, and enflurane. A direct comparison of the new inhalation drugs in adults was done in only three studies. Nathanson et al. compared the recovery character-
Figure 3. In all three groups there was a significant correlation between the duration of anesthesia and the uptake of the volatile drug (Spearman rank correlation rs ⫽ 0.9394 for sevoflurane, 0.8788 for isoflurane, and 0.8788 for desflurane). In none of the three groups was a correlation seen between the duration of anesthesia and the time to initial response to command (rs ⫽ ⫺0.7052 for sevoflurane, 0.1166 for isoflurane, and ⫺0.1785 for desflurane). J. Clin. Anesth., vol. 11, September 1999
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istics and discharge times in young healthy women undergoing short outpatient gynecological procedures. In this study, the inhalation drugs were administered according to hemodynamic response with the goal of maintaining mean arterial pressure within 20% of baseline values. The only significant result found was a faster wake up (“open eyes”) after desflurane than sevoflurane; the difference was 3 minutes. Although this result was certainly significant, it cannot be considered clinically relevant. There was no difference between the two groups with regard to the patient performance tested in the later recovery phase up to discharge. Furthermore, Tarazi and Philip,7 in a double-blinded design, found a slightly more rapid awakening with sevoflurane as compared to desflurane in outpatient anesthetics. Eger et al.,8,9 however, carrying out anesthesia in 28 healthy young volunteers for 2, 4, or 8 hours at 1.25 MAC, found a pronounced and significantly faster recovery at the end of anesthesia with desflurane as compared to sevoflurane (14 ⫾ 4 min vs. 28 ⫾ 8 min after anesthesia for 8 hrs). An important difference between the studies carried out by Eger et al.,8,9 the present study, and Nathanson et al.6 lies in the dosage of the inhalational drugs. Eger et al. applied desflurane and sevoflurane in a predetermined fixed dosage ratio (3.02:1), derived from the MAC of the two drugs as reported in the literature. However, the dosage ratio chosen by Eger et al. is not supportable by a careful review of the references on which it is based. The MAC of desflurane was found by Rampil et al.10 to be 7.25% in 18- to 30-year-old volunteers. The determination of the MAC of sevoflurane, which was done by Scheller et al.11 is not comparable for several reasons. Scheller et al. carried out their studies in only 16 volunteers between 30 and 48 years of age. In the age group from 19 to 27 years, only four volunteers were tested and the authors refrained from calculating the MAC for this subgroup. It seems as if Eger et al. took the average of the results shown in the table of the study of Scheller et al. and arrived at their figure of 2.4%. We mention this fact because a calculation of a pharmacodynamic quantity such as the MAC is not valid for statistical reasons when the number of volunteers is so small. Therefore, it appears questionable to us to choose a dosage ratio taken from these studies as a basis for a pharmacodynamic study. In our study, sevoflurane and desflurane were not applied in a fixed dosage ratio, but the dosing was done clinically, as in the Nathanson et al. study, according to the hemodynamic reactions of the patients. At the end of the surgical procedure in the steady state we found an F0 of 6.34% for desflurane and an F0 of 1.85% for sevoflurane. Related to the MAC of the respective age groups, this finding corresponds to the 1.05-fold of the MAC of desflurane and to the 0.90-fold of the MAC of sevoflurane. Furthermore, it corresponds to a dosage ratio of 3.42:1. Hence, in the present study in which the dosage followed clinical considerations, desflurane was administered in a concentration about 15% higher than by Eger et al.8,9 However, our study (as with the studies of Eger et al. and Nathanson et al.) was not carried out in a blinded design. In the study by Nathanson et al.,6 as well as the present 464
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study, sevoflurane and desflurane were administered according to clinical parameters. In both studies either minimal, clinically irrelevant or no differences with regard to the speed of recovery are found. In both studies, desflurane was administered in higher concentrations than in the study of Eger et al. We conclude from this fact that the MAC values taken as a basis by Eger et al. either underestimate the MAC of desflurane or overestimate the MAC of sevoflurane. This finding agrees with the results of a meta-analysis that estimated the MAC of sevoflurane at 1.80% and the MAC of desflurane at 6.6% (for the 40-year age).14 Yasuda et al.4,5 tested the pharmacokinetics of sevoflurane and desflurane in identical studies using a fivecompartment-model. With the help of gas chromatographic methods, traces of the inhalation drugs could be detected in the expired air of volunteers for up to 5 days. Under these conditions, it could be demonstrated that elimination of desflurane is significantly more rapid than for sevoflurane. In clinical practice, however, it is primarily the decrease of the plasma level of an inhalation drug in the immediate postoperative phase that is of interest. The beginning of spontaneous ventilation, the appearance of the eye reflex, and the ability to follow a command are the clinical signs that determine the best moment of extubation and discharge of the patient to the recovery room. More rapid pharmacokinetics and a shorter recovery phase would be beneficial for clinical and economical reasons. We found that in all patients, 1 minute after stopping the supply of the drug, the alveolar concentration FA had decreased to about 30% of the F0 (39% for isoflurane). With regard to the model taken as a basis by Yasuda et al., this corresponds to the elimination from the pulmonary compartment, i.e., functional residual capacity. In the subsequent 14 minutes, all patients showed a monoexponential decrease of FA, which can be described with one single half-life regardless of the model. Here we found practically identical results with a mean t1/2 ⫽ 8.16 ⫾ 3.15 minutes for desflurane, t1/2 ⫽ 9.47 ⫾ 4.46 minutes for sevoflurane, and t1/2 ⫽ 10.0 ⫾ 5.57 minutes for isoflurane. In addition, with regard to the time in which FA decreases to 10% of the F0 (t10), no differences could be found between sevoflurane and desflurane, whereas isoflurane was eliminated significantly more slowly, with a mean t10 of 13.3 minutes. This phase corresponds to elimination from organs with high perfusion including the brain. Furthermore, we found that in the early postoperative phase that we investigated, recovery time is not dependent on either the duration of anesthesia or on total amount taken up of the inhalation drugs. Other investigators found that in humans the time for emergence is dependent on the duration of anaesthesia for isoflurane,15,16 but not for sevoflurane.16,17 In contrast, Eger et al.8,9 found more rapid awakening after a 2- and 4-hour anesthetic with sevoflurane as compared to one of 8 hours. However, these differences were not statistically significant. Thus, we believe that in the early postoperative phase in which only elimination from the lungs and from organs well supplied with blood takes place, a difference between desflurane,
Kinetics of inhalation anesthetics: Behne et al.
sevoflurane, and isoflurane cannot be proven because the observation period is too short. As customary in our institution, patients were premedicated with midazolam and they received etomidate and fentanyl for induction of anesthesia. While the effect of these substances probably had worn off after longer procedures, it is possible that with short procedures the recovery was delayed. Our results confirm those of Ebert et al.,18 who studied the time to emergence after sevoflurane and isoflurane in 1,417 patients. They found a statistically significant, however clinically irrelevant, difference of 3 minutes. Furthermore, despite the large population studied, there was no interdependence between the time to emergence and the duration of anesthesia. The important point to be recorded is that for the first 15 minutes of elimination of a volatile drug the pharmacokinetic data cannot prove any definite advantages of sevoflurane or desflurane over isoflurane. There was no difference with regard to the speed of recovery until the ability to follow a command. Economic advantages in the initial period until the patient is transferred to the recovery room cannot be derived from the results of our study. Future studies should be aimed at clarifying whether there are differences in the later periods of elimination, e.g., up to the complete psychomotoric recovery or the ability to participate in traffic. In summary, we found that with premedicated patients who receive a titrated inhalation anesthesia according to clinical parameters, there are only minor advantages to using desflurane and sevoflurane over isoflurane. With regard to the speed of recovery, the three drugs can be judged as equal.
References 1. Eger EI 2nd: New inhaled anesthetics. Anesthesiology 1994;80:906 – 22. 2. Strum DP, Eger EI 2nd: Partition coefficients for sevoflurane in human blood, saline, and olive oil. Anesth Analg 1987;66:654 – 6. 3. Eger EI 2nd: Uptake and distribution. In: Miller RD (ed): Anesthesia, 4th ed. (Vol. 1.) New York: Churchill Livingstone, 1994:101–23. 4. Yasuda N, Lockhart SH, Eger EI 2d, et al: Comparison of kinetics of sevoflurane and isoflurane in humans. Anesth Analg 1991;72: 316 –24.
5. Yasuda N, Lockhart SH, Eger EI 2nd, et al: Kinetics of desflurane, isoflurane, and halothane in humans. Anesthesiology 1991;74:489 – 98. 6. Nathanson MH, Fredman B, Smith I, White PF: Sevoflurane versus desflurane for outpatient anesthesia: a comparison of maintenance and recovery profiles. Anesth Analg 1995;81:1186 – 90. 7. Tarazi EM, Philip BK: A comparison of recovery after sevoflurane or desflurane in ambulatory anesthesia. J Clin Anesth 1998;10: 272–7. 8. Eger EI 2nd, Bowland T, Ionescu P, et al: Recovery and kinetic characteristics of desflurane and sevoflurane in volunteers after 8-h exposure, including kinetics of degradation products. Anesthesiology 1997;87:517–26. 9. Eger EI 2nd, Gong D, Koblin DD, et al: The effect of anesthetic duration on kinetic and recovery characteristics of desflurane versus sevoflurane, and on the kinetic characteristics of compound A, in volunteers. Anesth Analg 1998;86:414 –21. 10. Rampil IJ, Lockhart SH, Zwass MS, et al: Clinical characteristics of desflurane in surgical patients: minimum alveolar concentration. Anesthesiology 1991;74:429 –33. 11. Scheller MS, Saidman LJ, Partridge BL: MAC of sevoflurane in humans and the New Zealand white rabbit. Can J Anaesth 1988;35:153– 6. 12. Stevens WC, Dolan WM, Gibbons RT, et al: Minimum alveolar concentrations (MAC) of isoflurane with and without nitrous oxide in patients of various ages. Anesthesiology 1975;42:197–200. 13. Heinzel G, Woloszczak R, Thomann P: Pharmacokinetic and Pharmacodynamic Data Analysis System. Stuttgart: Gustav Fischer, 1993. 14. Mapleson WW: Effect of age on MAC in humans: a meta-analysis. Br J Anaesth 1996;76:179 – 85. 15. Carpenter RL, Eger EI 2nd, Johnson BH, Unadkat JD, Sheiner LB: Does the duration of anesthetic administration affect the pharmacokinetics or metabolism of inhaled anesthetics in humans? Anesth Analg 1987;66:1– 8. 16. Frink EJ Jr, Malan TP, Atlas M, Dominguez LM, DiNardo JA, Brown BR Jr: Clinical comparisons of sevoflurane and isoflurane in healthy patients. Anesth Analg 1992;74:241–5. 17. Wiesner G, Wild K, Merz M, Hobbhahn J: Awakening periods (emergence times), hemodynamics and adverse experiences with sevoflurane and enflurane: a phase III, open-label, randomised comparative study. Anaesthesiol Intensivmed Notfallmed Schmerzther 1995;30:290 – 6. 18. Ebert TJ, Robinson BJ, Uhrich TD, Mackenthun A, Pichotta PJ: Recovery from sevoflurane anesthesia. Anesthesiology 1998;89: 1524 –31.
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