- Email: [email protected]
A comparison: The efficacy of sevoflurane-nitrous oxide or propofol-nitrous oxide for the induction and maintenance of general anesthesia
ELSEVIER
A Comparison: The Efficacy of Sevoflurane-Nitrous Oxide or Propofol-Nitrous Oxide for th,e Induction and Maintenance of General Anesthesia Cynthia A. Lien, MD,* Hugh C. Hemmings, MD, PhD,* Matthew R. Belmont, MD,? Amy Abalos, RN,$ Charleen Hollmann, RN& Robert E. Kelly, MD” Department of Anesthesiology, New York, NY.
*Associate Professor of Anesthesiology jAssistant Professor of Anesthesiology IResearch Assistant in Anesthesiology aResearch Administrator
in Anesthesiology
“Associate Professor of Clinical
Anesthesiol-
09-y Address reprint Department of Hospital-Cornell 68th St., A-1045,
requests to Dr. Lien at the Anesthesiology, New York Medical Center, 525 East New York, r\iy 10021, USA.
Supported in part by Grant #SEVO 92-009 from Abbott Laboratories, Abbott Park, IL. Presented in part at the 69th Congress of the International Anesthesia Research Society, Honolulu, March 10-14, 1995. Received for publication July 20, 1995; revised manuscript accepted for publication ylarch 8, 1996.
New York Hospital-Cornell
Medical Center,
Study Objective: To compare sevoJurane-nitrous oxide with propofol-nitrous oxidefor the induction and maintenance of anesthesia, and to determine the rates of recovery following each anesthetic. Design: Randomized, controlled study. Setting: Teaching hospital. Patie:nts: 50 ASA physical status I and Npatients, ranging in age from 18 to 70 years. Interventions: General anesthesia was induced with either sevoflurane or propof and maintained with 60 % to 70 9%nitrous oxide and either sevojihrane or a propofol infusion and supplementalfentanyl. At the conclusion of surgery, the oxygen flow was increased to 6 L/m& and all anesthetics were discontinued simultaneously. Patients were monitoredfor the nature and speed of induction and emergencyfrom anesthesia. Measurements and Main Results: Induction of anesthesia was significantly slower in the sevoflurane group than in the propofol group (2.0 f 1.1 vs. 0.8 f 0.5 min, respectively). The ease of induction and the time required for emergencefrom anesthesia were the same in both study groups (eye opening: 9.0 * 4.4 min vs. 8.0 f 5.0 min; following commSands:11.2 + 5.0 min vs. 9.8 rt 6.9 min; extubation: 9.1 + 4.5 min vs. 8.6 vs. 5.1 min in the seuoflurane and propofol groups, respectively). Patients in the sevojkrane group experienced nausea and vomiting more frequently than patients in the propofol group (13 and 5 patients vs. 3 and 0 patients in the sevofurane and propofol groups, respectiveb), which were not related to the administration of neostigmine or intraoperative opioids. Conclusion: Sevoflurane allows for rapid inhalation induction of and emergence from, general anesthesia. 0 1996 by Elsevier Science Inc. Keywords:
Anesthesia:
emergence,
induction;
anesthetics,
volatile;
sevoflurane.
Introduction Halothane is commonly used for inhalation children. However, in addition to increasing
Journal of Clinical Anesthesia 8:639-643, 1996 0 1996 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
induction of general anesthesia in the sensitivity of the myocardium to
0952.8180/96/$15.00 PI1 SO952-8180(96)00172-9
Original Contributions
the arrhythmogenic effects of catecholamines, inhalation induction with halothane is relatively slow because of its blood:gas partition coefficient of 2.3.* While other volatile anesthetics may induce anesthesia more rapidly because of lower blood:gas partition coefficients (isoflurane (1.4) ’ and desflurane (0.42)l), they are generally not used for inhalation inductions because of patient intolerance of their odor. In fact, desflurane has been shown to cause an increased incidence of laryngospasm and bronchospasm in pediatric patients when used for inhalation induction.’ Sevoflurane, which is a fluorinated derivative of methyl isopropyl ether, has a minimum alveolar concentration (MAC) of approximately 2.3,4 It also has a low blood:gas partition coefficient of 0.69,5 which approaches that of desflurane and nitrous oxide (N,O) (0.46). This, as well as its pleasant odor, should allow for a rapid and smooth inhalation induction of and a rapid recovery from general anesthesia. Propofol, an alkylphenol, is a lipid-soluble intravenous (IV) anesthetic. Its onset time following an induction dose of 2.5 mg/kg IV is rapid, and approximates the time required for arm-brain circulation.6,7 Because of its lipid solubility, it has a large volume of distribution at steady state (2 to 10 L/kg) .*-12 Furthermore, it is rapidly conjugated to form inactive glucuronide and sulfate metabolites that are readily excreted by the kidney, which results in a short elimination half-life (4 to 7 hours) and rapid clearance (20 to 30 ml/kg/min).8-12 Studies have compared sevoflurane with other volatile to propofol-sevofluraneanesthetics,13 sevoflurane-N,O to propofol-N20.15 Because N@,14, and sevoflurane-N,O of their similar pharmacodynamic profiles, either sevoflurane or propofol could likely be used alone or in combination with N,O and small doses of opioids to rapidly induce and maintain anesthesia for ambulatory surgical procedures. This study was designed to directly compare sevoflurane-N,O with propofol-N,O for the induction and maintenance of anesthesia, and to determine the rates of recovery following each anesthetic.
Materials
and Methods
This study was approved by the Human Rights in Research Committee at The New York Hospital-Cornell Medical Center. After giving written informed consent, a total of 50 patients, ranging in age from 18 to 70 years, were enrolled randomly into one of two study groups. Patients who were randomized via sealed envelope assignment (Abbott) into study Group A received sevoflurane and those randomized in the same manner into Group B received propofol. All patients were ASA physical status I or II and were scheduled to undergo elective surgical procedures of 1 to 3 hours’ duration. Patients with a history of central nervous system disease or neuromuscular disease, including
“Yasuda N, Targ AG, Eger EI II: Solubility of I-653, sevoflurane, isoflurane, and halothane in human tissues [Abstract]. Anesthesiology 1988;69:A615. 640
J. Clin. Anesth., vol. 8, December 1996
malignant hyperthermia; patients scheduled for outpatient surgery; female patients who were pregnant or were nursing and any patients unsuitable for inhalation induction; patients who had received sevoflurane in the past, those who had received any other study drug during the previous 28 days, and those who had received general anesthesia in the previous 2 weeks, were excluded from the study. In the operating room (OR), routine monitors [electrocardiogram, automatic blood pressure (BP) cuff, capnograph, and pulse oximeter] were applied and IV access, appropriate for the nature of the surgery, was established. Sevoflurane was administered with an Ohmeda Sevotec 5 vaporizer, (Ohmeda, Madison, WI) and inspiratory and expiratory concentrations of sevoflurane were determined with a Datex model #ULT-l-27-02 gas monitor (Datex Instrumentarium, Helsinki, Finland). After induction of anesthesia, all patients were further monitored with peripheral nerve stimulators and esophageal temperature probes. While breathing 100% oxygen (0,) through a face mask attached to a semiclosed circuit for 2 to 3 minutes prior to induction of anesthesia, all patients received fentanyl 2 pg/kg IV. Patients in Group A then received 60% N,O and 0, (total gas flow of 6 L/min) and increasing concentrations of sevoflurane (up to 3.5%), while breathing spontaneously. Muscle relaxation with vecuronium, atracurium, or succinylcholine was established following loss of responsiveness to verbal stimulation. Ventilation was controlled and patients’ tracheas were intubated. Patients in Group B received propofol, 2 to 2.5 mg/kg as an IV injection over 60 seconds while breathing 100% 0,. With loss of responsiveness to verbal stimulation, a muscle relaxant was administered as in Group A, ventilation was controlled, and patients’ tracheas were intubated. Mechanical ventilation was adjusted to maintain normocapnia. Normothermia was maintained with warmed IV fluids and warming blankets. Anesthesia was maintained with 0, 1 L/min and N,O 1.5 to 2 L/min. Sevoflurane (Group A) or propofol (Group B) delivery was adjusted to maintain an adequate and stable depth of anesthesia as assessed by hemodynamic and pupillary responsiveness to surgical stimulation. Once this was achieved, delivery of either anesthetic was kept relatively constant. Patients in Group A received 0.3% to 1.8% sevoflurane and those in Group B received propofol infusions of 50 to 200 pg/kg/min. Fentanyl 1 to 3 pg/kg was administered as an IV bolus to supplement the other anesthetics as required intraoperatively. Droperidol 0.625 to 1.25 mg and/or midazolam 1 to 2 mg were administered intraoperatively if either were indicated clinically. Neuromuscular block was maintained, when required, with either vecuronium or atracurium. Residual neuromuscular block was pharmacologically antagonized at the end of surgery with neostigmine when necessary. At the conclusion of surgery, 0, flow was increased to 6 L/min, and N,O and either sevoflurane or propofol were discontinued simultaneously. No tapering of anesthetics near the end of the procedure was allowed in either study group. Immediately after discontinuation of the anesthetic and every minute thereafter, patients were assessed for
Efjcq
emergence from anesthesia by response to their name being called and verbal command to open their eyes. Patients’ tracheas were extubated and patients were transported to the postanesthesia care unit (PACU) following emergence from anesthesia. The end-tidal concentration of sevoflurane was noted every minute for 15 minutes and then every 5 minutes from induction of anesthesia to time of incision.. Following incision, it was recorded every minute for 5 minutes and then every 15 minutes until anesthesia was discontinued. Blood pressure was monitored and recorded before arrival in the OR (baseline), 1 minute prior to induction of anesthesia, every minute from induction to incision for up to 15 minutes, every minute for up to 5 minutes following incision, every 15 minutes until anesthetic was discontinued, and every 10 minutes while in the recovery room for up to 2 hours. Patients were monitored for the speed of induction of, and emergence from, anesthesia. Induction was defined as time from introduction of anesthetic to loss of response to verbal command, while emergence was defined as time from discontinuation of N,O and either sevoflurane or propofol to response to verbal command to open their eyes. The difficulty of induction of anesthesia with either anesthetic was determined by the incidence of excitement, coughing, or bronchospasm. Hemodynamic alterations (ie, atria1 or ventricular ectopy, relative bradycardia, tachycardia, hypertension, or hypotension) with either anesthetic technique were noted, as was the need to treat any hemodynamic changes. In the PACU, patients were monitored for a period of at least 2 hours during which their need for pain medications was assessed. The incidence and severity of nausea and/or vomiting prior to administration of opioid pain medication and the incidence of shivering were also recorded. Statistical significance was determined using Student’s two-tailed t-test for comparison of demographic variables and medication doses between study groups. Paired t-tests were used to compare BP and heart rate (HR.) changes. Chi-square was used to compare the incidence of nausea, vomiting, shivering, and pain postoperatively im the propofol and sevoflurane study groups. A p-value less than or equal to 0.05 was considered statistically significant. The Cochran-Mantel Haenszel Statistic was used to determine whether the incidence of nausea and vomiting was associated with administration of anticholinesterase (administered during reversal of neuromuscular blockade), intraoperative opioids, or the type of surgery.
Results The sevoflurane and propofol study groups were comparable in terms of demographic variables and types of surgical procedures done (Table I). The mean duration of surgery was similar in the two study groups (102 I 65.1 min VS. 95.3 + 47.4 min for the sevoflurane and propofol groups, respectively), while the mean duration of anesthesia was significantly longer in patients receiving sevoflu-
Table
1.
of swoflurane us. propofol: Lien et al.
Patient Demographics Sevoflurme (n = 25)
Gender (male:female) (%) Race (Caucasian:Black: Hispanic:Asian) (%) ASA classification (1:II) (%) Smoking history (%) Age (ys)* Weight (kg) * Type of surgery Abdominal hTeurosurgica1 Urologic Breast
Propofol (n = 25)
24:76
36:64
68:8:16:8 52:48 16 43.2 t 10.8 69.8 i 15.8
80:12:4:4 60:40 16 38.2 f 11.2 69.7 f 15.8
13 6
11 10
5
3 0
*= Data are presented as means k SD. rane anesthesia (132.2 + 72.6 min vs. 123.0 + 47.5 min in the sevoflurane and propofol groups, respectively; p = 0.043). Three patients in the sevoflurane group had anesthesia and surgical procedures that lasted longer than 3 hours (342 and 300 min, 304 and 244 min, 276 and 245 min, respectively). Induction of anesthesia with sevoflurane was significantly slower (2.0 f 1.1 min vs. 0.8 + 0.5 min for the sevoflurane and propofol groups, respectively). The nature of induction was similar in that the incidence of bronchospasm, excitement, and coughing was not significantly different between the two groups. One patient in the sevoflurane group developed bronchospasm and coughing on induction of anesthesia, which required no specific therapy and resolved with increasing his depth of anesthesia. This patient had a history of asthma that had never required treatment. In both study groups there was marked variability in HR and mean arterial pressure (MAP) over the course of anesthesia and surgery. The nature and extent of hemodynamic changes were similar in the two study groups (mean maximal increase in MAP: 12.1 i 14.3 mmHg and 19.1 + 19.2 mmHg in the sevoflurane and propofol groups, respectively; mean maximal decrease in MAP: 33.9 + 10.8 mmHg and 34.3 + 8.0 mmHg in the sevoflurane and propofol groups, respectively; mean maximal increase in HR: 16.2 f 15.0 bpm and 24.0 + 25.7 bpm and mean maximal decrease in HR: 33.4 + 1.7 bpm and 26.0 ir 12.1 bpm in the sevoflurane and propofol, respectively). Four patients in the sevoflurane group received ephedrine and two patients in the propofol group received labetalol for BP alterations. Two patients in the sevoflurane group developed premature ventricular contractions, which had no effect on BP, were self-limited, and required no therapy. Patients in the propofol group received more fentanyl intraoperatively (135 + 146 pg ZIS. 108 i- 93 pg for the propofol and sevoflurane groups, respectively). Similar numbers of patients in each group received droperidol (3 patients in each group) and/or midazolam (18 patients in each group) intraoperatively and the average doses of these drugs were similar in each study group (0.625 f 0 mg J. Clin. Anesth., vol. 8, December 1996
641
Original
Cmhbutions
vs. 0.842 i 0.354 mg droperidol in the sevoflurane and propofol groups, respectively, and 1.5 -+ 0.5 mg z/s. 1.8 + 0.4 mg midazolam in the sevoflurane and propofol groups, respectively), There was no difference in the number of patients who received nondepolarizing neuromuscular blockers (atracurium: 1 VS. 2 patients in the sevoflurane and propofol groups, respectively; vecuronium: 16 patients in each of the groups). Similarly, there was no difference in the number of patients in each group who required neostigmine and glycopyrrolate for antagonism of residua1 neuromuscular block (20 US. 18 patients in the sevoflurane and propofol groups, respectively). The average dose of neostigmine was similar in each of the study groups (3.3 i- 1.4 mg US. 3.2 + 0.7 mg in the sevoflurane and propofol groups, respectively). The times required for emergence from anesthesia as defined by eye opening, ability to follow verbal commands, and tracheal extubation were the same in both study groups (Table 2). Patients in the sevoflurane group experienced nausea and vomiting more frequently in the postoperative period than did patients in the propofol group (Table 3). The nausea and vomiting were not related to the administration of neostigmine or intraoperative opioids. The incidence of postoperative pain and shivering were similar in the two study groups.
Discussion General anesthesia with the combination of sevoflurane and N,O allows for rapid and smooth induction, easy maintenance, and prompt emergence. The induction time of 2.0 1. 1.1 minutes does not appear to be markedly different from that previously reported by Smith et al. (1.8 + 0.4 min)16 or Fredman et al. (2.6 + 1.7 min) .I5 Patients in this as well as the Smith el al. and Fredman et al. studies received fentanyl prior to induction of anesthesia (1.5 pg/ kg in our study, 2 pg/kg in the Smith et al. study and 1 to 2 pg/kg in the Fredman et al. study). The administration of additional opioids is not expected to affect time to induction with propofol, which occurred in under one minute in this study, because speed of onset of propofol anesthesia has been shown to be related primarily to the dose and speed of administration and is not affected by ‘,* The difference in time to inducopioid premeditation. tion with sevoflurane-N20 or propofol (2.0 US. 0.8 min)
Table 2.
Emergence from Anesthesia Anesthetic
Time to (min): Eye opening Following commands Extubation Able to say name Able to say birthdate NS
Sevoflurane 9.0 14.4 11.2 k 5.0 9.1 _+4.5 12.8 I 5.6 13.2 iz 5.7
Propofol 8.0 i: 5.0 9.8 * 6.9 8.6 + 5.1 11.0 i- 6.9 11.3 f 6.8
= not statistically significant.
642
1. Clin. Anesth., vol. 8, December 1996
p-value
NS NS NS NS NS
Table 3. Recovery from Anesthesia Anesthetic Symptom
Sevoflm-ane (No. of Patients)
Propofol (No. of Patients)
p-value
Pain Shivering Nausea Vomiting
21 4 13 5
18 4 3 0
NS NS 0.002 0.018
NS = not statistically significant.
could have been further reduced by the use of higher gas flows (a total gas flow of 6 L/min was used for induction in this study) or by delivering higher concentrations of sevoflurane during induction. Currently, the maximum delivery of sevoflurane by the Sevotec vaporizer is limited to 5%. Regardless, a difference of 1 minute is unlikely to be of clinical importance. Patients were comfortable during inhalation induction with sevoflurane, and there was no sense of a need to rush the induction. A clinical setting in which this difference could be clinically significant is in rapid induction of anesthesia, although these patients would be unlikely candidates for inhalation induction. The relative ease with which anesthesia could be induced with either anesthetic is indicated by the speed with which anesthesia was obtained in both study groups. Furthermore, once a stable depth of anesthesia was obtained, frequent alteration of anesthetic delivery was not necessary. The use of N,O in both study groups contributed to this end. WhiIe the study can be criticized for use of N,O as an adjunct anesthetic, the study was designed to be clinically relevant and, in the majority of cases where sevoflurane or propofol are used to maintain anesthesia, N,O will likely also be used. The administration of greater doses of fentanyl to patients receiving propofol may be indicative of the poor analgesic properties of propofol.16 Despite the different anesthetics given to each group of patients, the speed of emergence from anesthesia was similar. Three patients in the sevoflurane group had a duration of surgery and anesthesia that exceeded 3 hours. Because they were tolerating the longer anesthetic without apparent difficulty and because surgical closure was always imminent, their participation in the study was not discontinued. Despite the prolonged administration of sevoflurane, their recovery from anesthesia did not differ from other patients receiving sevoflurane for a shorter period of time, as shown by their average time to eye opening of 9 * 5 minutes, extubation of 11 f 3.6 minutes, following commands of 10.6 + 5.5 minutes, and ability to say their names and birthdates of 15.0 _+5.5 and 15.6 + 6.0 minutes, respectively. Nausea and vomiting have been reported to prolong a patient’s recovery room stay and necessitate admission to the hospita1.l’ The incidence of vomiting following general anesthesia without prophylactic treatment with antiemetics has been reported to be between 39% and
Efficaq
7()%."W9
In a retrospective study, Dexter and Tinker*’ demonstrated that the 8% of patients requiring antiemetits after general anesthesia had a longer stay in the recovery room. With the exception of propofol,‘i choice of anesthetic has little effect on incidence of postoperative nausea and vomiting. ” The 20% incidence of vomiting in this study is lower than that which has been generally reported. That no patients in the propofol group experienced vomiting and only 12% experienced nausea may well be the result of the antiemetic effect of laropofo1.23 In conclusion, sevoflurane allows for rapid inhalation induction of and emergence from general anesthesia for cases of 1 to 3 hours’ duration.
Acknowledgments The authors would like to thank Dr. Thomas J.J. Blanck for his critical review of and comments regarding the study design and manuscript, Irusia Kocka for her editorial assistance in the preparation of this manuscript, and Larissa Eppich, Nathaniel Zoneraich, and Maria Siambekos for assistance in data collection.
References 1. Eger EI 2d: Partition coefficients of I-653 in human blood, saline, and olive oil. An&h Analg 1987;66:971-3. 2. Zwass MS, Fisher DM, Welborn LG, et al: Induction and maintenance characteristics of anesthesia with desflurane and nitrous oxide in infants and children. Anesthesiology 1992;76:373-8. 3. Scheller MS, Saidman LJ, Partridge BL: MAC of sevoflurane in humans and the New Zealand white rabbit. CanJAnaesth 1988; 35:153-6. 4. Katoh T, Ikeda K: The minimum alveolar concentration (MAC) of sevoflurane in humans. Anesthesiology 1987;66:301-3. 5. Strum DP, Eger EI 2d: Partition coefficients for sevoflurane in human blood, saline, and olive oil. An&h Analg 1987;66:654-6. 6. Major E, Verniquet AJW, Waddell TK, Savege TM, Hoffler DE, Aveling W: A study of three doses of ICI 35 868 for induction and maintenance of anaesthesia. BrJAnaesth 1981;53:267-72. 7. Rolly G, Versichelen L, Huyghe L, Mungroop H: Effect of speed of injection on induction of anaesthesia using propofol. BrJAna&h 1985:57:743-6.
“Monk TG, White PF, Lemon D: Ondansetron reduces nausea and vomiting following outpatient lithotripsy [Abstract]. Anesthesioloa 1992;77:819.
of sevojlurune
us. propofol:
Lien et al.
8. Adam HK Briggs LP, Bahar M, Douglas EJ, Dundee JW: Pharmacokinetic evaluation of ICI 35 868 in man. Single induction doses with different rates of injection. BrJ Anaesth 1983;55:9’7103. 9. Kay NH, Sear JW, Upington J, Cockshott ID, Douglas EJ: Disposition of propofol in patients undergoing surgery. A comparison in men and women. BrJAnaesth 1986;58:1075-9. 10. Gepts E, Camu F, Cockshott ID, Douglas EJ: Disposition of propofol administered as constant rate intravenous infusions in humans. Anesth An&g 1987;66:1256-63. 11. Kirkpatrick T, Cockshott ID, Douglas EJ, Nimmo WS: Pharmacokinetics of propofol (diprivan) in elderly patients. BrJ Anaesth 1988;60:146-50. 12. Shafer A, Doze VA, Shafer SL, White PF: Pharmacokinetics and pharmacodynamics of propofol infusions during general anesthesia. Anesthesiology 1988;69:348-56. 13. Frink EJ Jr, Malan TP, Atlas M, Dominguez LM, DiNardo JA, Brown BR Jr: Clinical comparison of sevoflurane and isoflurane in healthy patients. An&h An&g 1992;74:241-5. 14. Smith I, Ding Y, White PF: Comparison of induction, maintenance, and recovery characteristics of sevoflurane-N,O and propofol-sevoflurane-N,O with propofol-isoflurane-r\‘,O anesthesia. Anesth Analg 1992;74:253-9. 15. Fredman B, Nathanson MH, Smith I, Wang J, Klein K, White PF: Sevoflurane for outpatient anesthesia: a comparison with propofol. Anesth Analg 1995;81:823-8. 16. Briggs LP, Dundee JW, Bahar M, Clarke RS: Comparison of the effect of diisopropyl phenol (ICI 35, 868) and thiopentone in response to somatic pain. Br JAnaesth 1982;54:307-11. 17. Korttila K, &tman P, Faure E, et al: Randomized comparison of recovery after propofol-nitrous oxide versus thiopentoneisoflurane-nitrous oxide anaesthesia in patients undergoing ambulatory surgery. Acta Anaesthesiol &and 1990;34:400-3. 18. Ferrari LR, DonlonJV: Metoclopramide reduces the incidence of vomiting after tonsillectomy in children. Anesth An&g 1992;75: 351-4. 19. Khalil SN, Berry JM, Howard G, et al: The antiemetic effect of lorazepam after outpatient strabismus surgery in children. Anesthesiolog) 1992;77:915-9. 20. Dexter F, Tinker JH: Analysis of strategies to decrease postanesthesia care unit costs. Anesthesioloa 1995;82:94-101. 21. McCollum JS, Milligan KR, Dundee JW: Has propofol an antiemetic action? Br JAnaesth 1987;59(Suppl) :654P-5P. 22. MuirJ, Warner MA, Offard KP, Buck CF, HarperJV, Kunkel SE: Role of nitrous oxide and other factors in postoperative nausea and vomiting: a randomized and blinded prospective study. Anesthesiology 1987;66:513-8. 23. Borgeat A, Wilder-Smith OH, Saiah M, Rifat IQ Subhypnotic doses of propofol possess direct antiemetic properties. Anesth Analg 1992;74:539-41.
J. Clin. Anesth., vol. 8; December
1996
643
A Comparison: The Efficacy of Sevoflurane-Nitrous Oxide or Propofol-Nitrous Oxide for th,e Induction and Maintenance of General Anesthesia Cynthia A. Lien, MD,* Hugh C. Hemmings, MD, PhD,* Matthew R. Belmont, MD,? Amy Abalos, RN,$ Charleen Hollmann, RN& Robert E. Kelly, MD” Department of Anesthesiology, New York, NY.
*Associate Professor of Anesthesiology jAssistant Professor of Anesthesiology IResearch Assistant in Anesthesiology aResearch Administrator
in Anesthesiology
“Associate Professor of Clinical
Anesthesiol-
09-y Address reprint Department of Hospital-Cornell 68th St., A-1045,
requests to Dr. Lien at the Anesthesiology, New York Medical Center, 525 East New York, r\iy 10021, USA.
Supported in part by Grant #SEVO 92-009 from Abbott Laboratories, Abbott Park, IL. Presented in part at the 69th Congress of the International Anesthesia Research Society, Honolulu, March 10-14, 1995. Received for publication July 20, 1995; revised manuscript accepted for publication ylarch 8, 1996.
New York Hospital-Cornell
Medical Center,
Study Objective: To compare sevoJurane-nitrous oxide with propofol-nitrous oxidefor the induction and maintenance of anesthesia, and to determine the rates of recovery following each anesthetic. Design: Randomized, controlled study. Setting: Teaching hospital. Patie:nts: 50 ASA physical status I and Npatients, ranging in age from 18 to 70 years. Interventions: General anesthesia was induced with either sevoflurane or propof and maintained with 60 % to 70 9%nitrous oxide and either sevojihrane or a propofol infusion and supplementalfentanyl. At the conclusion of surgery, the oxygen flow was increased to 6 L/m& and all anesthetics were discontinued simultaneously. Patients were monitoredfor the nature and speed of induction and emergencyfrom anesthesia. Measurements and Main Results: Induction of anesthesia was significantly slower in the sevoflurane group than in the propofol group (2.0 f 1.1 vs. 0.8 f 0.5 min, respectively). The ease of induction and the time required for emergencefrom anesthesia were the same in both study groups (eye opening: 9.0 * 4.4 min vs. 8.0 f 5.0 min; following commSands:11.2 + 5.0 min vs. 9.8 rt 6.9 min; extubation: 9.1 + 4.5 min vs. 8.6 vs. 5.1 min in the seuoflurane and propofol groups, respectively). Patients in the sevojkrane group experienced nausea and vomiting more frequently than patients in the propofol group (13 and 5 patients vs. 3 and 0 patients in the sevofurane and propofol groups, respectiveb), which were not related to the administration of neostigmine or intraoperative opioids. Conclusion: Sevoflurane allows for rapid inhalation induction of and emergence from, general anesthesia. 0 1996 by Elsevier Science Inc. Keywords:
Anesthesia:
emergence,
induction;
anesthetics,
volatile;
sevoflurane.
Introduction Halothane is commonly used for inhalation children. However, in addition to increasing
Journal of Clinical Anesthesia 8:639-643, 1996 0 1996 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
induction of general anesthesia in the sensitivity of the myocardium to
0952.8180/96/$15.00 PI1 SO952-8180(96)00172-9
Original Contributions
the arrhythmogenic effects of catecholamines, inhalation induction with halothane is relatively slow because of its blood:gas partition coefficient of 2.3.* While other volatile anesthetics may induce anesthesia more rapidly because of lower blood:gas partition coefficients (isoflurane (1.4) ’ and desflurane (0.42)l), they are generally not used for inhalation inductions because of patient intolerance of their odor. In fact, desflurane has been shown to cause an increased incidence of laryngospasm and bronchospasm in pediatric patients when used for inhalation induction.’ Sevoflurane, which is a fluorinated derivative of methyl isopropyl ether, has a minimum alveolar concentration (MAC) of approximately 2.3,4 It also has a low blood:gas partition coefficient of 0.69,5 which approaches that of desflurane and nitrous oxide (N,O) (0.46). This, as well as its pleasant odor, should allow for a rapid and smooth inhalation induction of and a rapid recovery from general anesthesia. Propofol, an alkylphenol, is a lipid-soluble intravenous (IV) anesthetic. Its onset time following an induction dose of 2.5 mg/kg IV is rapid, and approximates the time required for arm-brain circulation.6,7 Because of its lipid solubility, it has a large volume of distribution at steady state (2 to 10 L/kg) .*-12 Furthermore, it is rapidly conjugated to form inactive glucuronide and sulfate metabolites that are readily excreted by the kidney, which results in a short elimination half-life (4 to 7 hours) and rapid clearance (20 to 30 ml/kg/min).8-12 Studies have compared sevoflurane with other volatile to propofol-sevofluraneanesthetics,13 sevoflurane-N,O to propofol-N20.15 Because N@,14, and sevoflurane-N,O of their similar pharmacodynamic profiles, either sevoflurane or propofol could likely be used alone or in combination with N,O and small doses of opioids to rapidly induce and maintain anesthesia for ambulatory surgical procedures. This study was designed to directly compare sevoflurane-N,O with propofol-N,O for the induction and maintenance of anesthesia, and to determine the rates of recovery following each anesthetic.
Materials
and Methods
This study was approved by the Human Rights in Research Committee at The New York Hospital-Cornell Medical Center. After giving written informed consent, a total of 50 patients, ranging in age from 18 to 70 years, were enrolled randomly into one of two study groups. Patients who were randomized via sealed envelope assignment (Abbott) into study Group A received sevoflurane and those randomized in the same manner into Group B received propofol. All patients were ASA physical status I or II and were scheduled to undergo elective surgical procedures of 1 to 3 hours’ duration. Patients with a history of central nervous system disease or neuromuscular disease, including
“Yasuda N, Targ AG, Eger EI II: Solubility of I-653, sevoflurane, isoflurane, and halothane in human tissues [Abstract]. Anesthesiology 1988;69:A615. 640
J. Clin. Anesth., vol. 8, December 1996
malignant hyperthermia; patients scheduled for outpatient surgery; female patients who were pregnant or were nursing and any patients unsuitable for inhalation induction; patients who had received sevoflurane in the past, those who had received any other study drug during the previous 28 days, and those who had received general anesthesia in the previous 2 weeks, were excluded from the study. In the operating room (OR), routine monitors [electrocardiogram, automatic blood pressure (BP) cuff, capnograph, and pulse oximeter] were applied and IV access, appropriate for the nature of the surgery, was established. Sevoflurane was administered with an Ohmeda Sevotec 5 vaporizer, (Ohmeda, Madison, WI) and inspiratory and expiratory concentrations of sevoflurane were determined with a Datex model #ULT-l-27-02 gas monitor (Datex Instrumentarium, Helsinki, Finland). After induction of anesthesia, all patients were further monitored with peripheral nerve stimulators and esophageal temperature probes. While breathing 100% oxygen (0,) through a face mask attached to a semiclosed circuit for 2 to 3 minutes prior to induction of anesthesia, all patients received fentanyl 2 pg/kg IV. Patients in Group A then received 60% N,O and 0, (total gas flow of 6 L/min) and increasing concentrations of sevoflurane (up to 3.5%), while breathing spontaneously. Muscle relaxation with vecuronium, atracurium, or succinylcholine was established following loss of responsiveness to verbal stimulation. Ventilation was controlled and patients’ tracheas were intubated. Patients in Group B received propofol, 2 to 2.5 mg/kg as an IV injection over 60 seconds while breathing 100% 0,. With loss of responsiveness to verbal stimulation, a muscle relaxant was administered as in Group A, ventilation was controlled, and patients’ tracheas were intubated. Mechanical ventilation was adjusted to maintain normocapnia. Normothermia was maintained with warmed IV fluids and warming blankets. Anesthesia was maintained with 0, 1 L/min and N,O 1.5 to 2 L/min. Sevoflurane (Group A) or propofol (Group B) delivery was adjusted to maintain an adequate and stable depth of anesthesia as assessed by hemodynamic and pupillary responsiveness to surgical stimulation. Once this was achieved, delivery of either anesthetic was kept relatively constant. Patients in Group A received 0.3% to 1.8% sevoflurane and those in Group B received propofol infusions of 50 to 200 pg/kg/min. Fentanyl 1 to 3 pg/kg was administered as an IV bolus to supplement the other anesthetics as required intraoperatively. Droperidol 0.625 to 1.25 mg and/or midazolam 1 to 2 mg were administered intraoperatively if either were indicated clinically. Neuromuscular block was maintained, when required, with either vecuronium or atracurium. Residual neuromuscular block was pharmacologically antagonized at the end of surgery with neostigmine when necessary. At the conclusion of surgery, 0, flow was increased to 6 L/min, and N,O and either sevoflurane or propofol were discontinued simultaneously. No tapering of anesthetics near the end of the procedure was allowed in either study group. Immediately after discontinuation of the anesthetic and every minute thereafter, patients were assessed for
Efjcq
emergence from anesthesia by response to their name being called and verbal command to open their eyes. Patients’ tracheas were extubated and patients were transported to the postanesthesia care unit (PACU) following emergence from anesthesia. The end-tidal concentration of sevoflurane was noted every minute for 15 minutes and then every 5 minutes from induction of anesthesia to time of incision.. Following incision, it was recorded every minute for 5 minutes and then every 15 minutes until anesthesia was discontinued. Blood pressure was monitored and recorded before arrival in the OR (baseline), 1 minute prior to induction of anesthesia, every minute from induction to incision for up to 15 minutes, every minute for up to 5 minutes following incision, every 15 minutes until anesthetic was discontinued, and every 10 minutes while in the recovery room for up to 2 hours. Patients were monitored for the speed of induction of, and emergence from, anesthesia. Induction was defined as time from introduction of anesthetic to loss of response to verbal command, while emergence was defined as time from discontinuation of N,O and either sevoflurane or propofol to response to verbal command to open their eyes. The difficulty of induction of anesthesia with either anesthetic was determined by the incidence of excitement, coughing, or bronchospasm. Hemodynamic alterations (ie, atria1 or ventricular ectopy, relative bradycardia, tachycardia, hypertension, or hypotension) with either anesthetic technique were noted, as was the need to treat any hemodynamic changes. In the PACU, patients were monitored for a period of at least 2 hours during which their need for pain medications was assessed. The incidence and severity of nausea and/or vomiting prior to administration of opioid pain medication and the incidence of shivering were also recorded. Statistical significance was determined using Student’s two-tailed t-test for comparison of demographic variables and medication doses between study groups. Paired t-tests were used to compare BP and heart rate (HR.) changes. Chi-square was used to compare the incidence of nausea, vomiting, shivering, and pain postoperatively im the propofol and sevoflurane study groups. A p-value less than or equal to 0.05 was considered statistically significant. The Cochran-Mantel Haenszel Statistic was used to determine whether the incidence of nausea and vomiting was associated with administration of anticholinesterase (administered during reversal of neuromuscular blockade), intraoperative opioids, or the type of surgery.
Results The sevoflurane and propofol study groups were comparable in terms of demographic variables and types of surgical procedures done (Table I). The mean duration of surgery was similar in the two study groups (102 I 65.1 min VS. 95.3 + 47.4 min for the sevoflurane and propofol groups, respectively), while the mean duration of anesthesia was significantly longer in patients receiving sevoflu-
Table
1.
of swoflurane us. propofol: Lien et al.
Patient Demographics Sevoflurme (n = 25)
Gender (male:female) (%) Race (Caucasian:Black: Hispanic:Asian) (%) ASA classification (1:II) (%) Smoking history (%) Age (ys)* Weight (kg) * Type of surgery Abdominal hTeurosurgica1 Urologic Breast
Propofol (n = 25)
24:76
36:64
68:8:16:8 52:48 16 43.2 t 10.8 69.8 i 15.8
80:12:4:4 60:40 16 38.2 f 11.2 69.7 f 15.8
13 6
11 10
5
3 0
*= Data are presented as means k SD. rane anesthesia (132.2 + 72.6 min vs. 123.0 + 47.5 min in the sevoflurane and propofol groups, respectively; p = 0.043). Three patients in the sevoflurane group had anesthesia and surgical procedures that lasted longer than 3 hours (342 and 300 min, 304 and 244 min, 276 and 245 min, respectively). Induction of anesthesia with sevoflurane was significantly slower (2.0 f 1.1 min vs. 0.8 + 0.5 min for the sevoflurane and propofol groups, respectively). The nature of induction was similar in that the incidence of bronchospasm, excitement, and coughing was not significantly different between the two groups. One patient in the sevoflurane group developed bronchospasm and coughing on induction of anesthesia, which required no specific therapy and resolved with increasing his depth of anesthesia. This patient had a history of asthma that had never required treatment. In both study groups there was marked variability in HR and mean arterial pressure (MAP) over the course of anesthesia and surgery. The nature and extent of hemodynamic changes were similar in the two study groups (mean maximal increase in MAP: 12.1 i 14.3 mmHg and 19.1 + 19.2 mmHg in the sevoflurane and propofol groups, respectively; mean maximal decrease in MAP: 33.9 + 10.8 mmHg and 34.3 + 8.0 mmHg in the sevoflurane and propofol groups, respectively; mean maximal increase in HR: 16.2 f 15.0 bpm and 24.0 + 25.7 bpm and mean maximal decrease in HR: 33.4 + 1.7 bpm and 26.0 ir 12.1 bpm in the sevoflurane and propofol, respectively). Four patients in the sevoflurane group received ephedrine and two patients in the propofol group received labetalol for BP alterations. Two patients in the sevoflurane group developed premature ventricular contractions, which had no effect on BP, were self-limited, and required no therapy. Patients in the propofol group received more fentanyl intraoperatively (135 + 146 pg ZIS. 108 i- 93 pg for the propofol and sevoflurane groups, respectively). Similar numbers of patients in each group received droperidol (3 patients in each group) and/or midazolam (18 patients in each group) intraoperatively and the average doses of these drugs were similar in each study group (0.625 f 0 mg J. Clin. Anesth., vol. 8, December 1996
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Cmhbutions
vs. 0.842 i 0.354 mg droperidol in the sevoflurane and propofol groups, respectively, and 1.5 -+ 0.5 mg z/s. 1.8 + 0.4 mg midazolam in the sevoflurane and propofol groups, respectively), There was no difference in the number of patients who received nondepolarizing neuromuscular blockers (atracurium: 1 VS. 2 patients in the sevoflurane and propofol groups, respectively; vecuronium: 16 patients in each of the groups). Similarly, there was no difference in the number of patients in each group who required neostigmine and glycopyrrolate for antagonism of residua1 neuromuscular block (20 US. 18 patients in the sevoflurane and propofol groups, respectively). The average dose of neostigmine was similar in each of the study groups (3.3 i- 1.4 mg US. 3.2 + 0.7 mg in the sevoflurane and propofol groups, respectively). The times required for emergence from anesthesia as defined by eye opening, ability to follow verbal commands, and tracheal extubation were the same in both study groups (Table 2). Patients in the sevoflurane group experienced nausea and vomiting more frequently in the postoperative period than did patients in the propofol group (Table 3). The nausea and vomiting were not related to the administration of neostigmine or intraoperative opioids. The incidence of postoperative pain and shivering were similar in the two study groups.
Discussion General anesthesia with the combination of sevoflurane and N,O allows for rapid and smooth induction, easy maintenance, and prompt emergence. The induction time of 2.0 1. 1.1 minutes does not appear to be markedly different from that previously reported by Smith et al. (1.8 + 0.4 min)16 or Fredman et al. (2.6 + 1.7 min) .I5 Patients in this as well as the Smith el al. and Fredman et al. studies received fentanyl prior to induction of anesthesia (1.5 pg/ kg in our study, 2 pg/kg in the Smith et al. study and 1 to 2 pg/kg in the Fredman et al. study). The administration of additional opioids is not expected to affect time to induction with propofol, which occurred in under one minute in this study, because speed of onset of propofol anesthesia has been shown to be related primarily to the dose and speed of administration and is not affected by ‘,* The difference in time to inducopioid premeditation. tion with sevoflurane-N20 or propofol (2.0 US. 0.8 min)
Table 2.
Emergence from Anesthesia Anesthetic
Time to (min): Eye opening Following commands Extubation Able to say name Able to say birthdate NS
Sevoflurane 9.0 14.4 11.2 k 5.0 9.1 _+4.5 12.8 I 5.6 13.2 iz 5.7
Propofol 8.0 i: 5.0 9.8 * 6.9 8.6 + 5.1 11.0 i- 6.9 11.3 f 6.8
= not statistically significant.
642
1. Clin. Anesth., vol. 8, December 1996
p-value
NS NS NS NS NS
Table 3. Recovery from Anesthesia Anesthetic Symptom
Sevoflm-ane (No. of Patients)
Propofol (No. of Patients)
p-value
Pain Shivering Nausea Vomiting
21 4 13 5
18 4 3 0
NS NS 0.002 0.018
NS = not statistically significant.
could have been further reduced by the use of higher gas flows (a total gas flow of 6 L/min was used for induction in this study) or by delivering higher concentrations of sevoflurane during induction. Currently, the maximum delivery of sevoflurane by the Sevotec vaporizer is limited to 5%. Regardless, a difference of 1 minute is unlikely to be of clinical importance. Patients were comfortable during inhalation induction with sevoflurane, and there was no sense of a need to rush the induction. A clinical setting in which this difference could be clinically significant is in rapid induction of anesthesia, although these patients would be unlikely candidates for inhalation induction. The relative ease with which anesthesia could be induced with either anesthetic is indicated by the speed with which anesthesia was obtained in both study groups. Furthermore, once a stable depth of anesthesia was obtained, frequent alteration of anesthetic delivery was not necessary. The use of N,O in both study groups contributed to this end. WhiIe the study can be criticized for use of N,O as an adjunct anesthetic, the study was designed to be clinically relevant and, in the majority of cases where sevoflurane or propofol are used to maintain anesthesia, N,O will likely also be used. The administration of greater doses of fentanyl to patients receiving propofol may be indicative of the poor analgesic properties of propofol.16 Despite the different anesthetics given to each group of patients, the speed of emergence from anesthesia was similar. Three patients in the sevoflurane group had a duration of surgery and anesthesia that exceeded 3 hours. Because they were tolerating the longer anesthetic without apparent difficulty and because surgical closure was always imminent, their participation in the study was not discontinued. Despite the prolonged administration of sevoflurane, their recovery from anesthesia did not differ from other patients receiving sevoflurane for a shorter period of time, as shown by their average time to eye opening of 9 * 5 minutes, extubation of 11 f 3.6 minutes, following commands of 10.6 + 5.5 minutes, and ability to say their names and birthdates of 15.0 _+5.5 and 15.6 + 6.0 minutes, respectively. Nausea and vomiting have been reported to prolong a patient’s recovery room stay and necessitate admission to the hospita1.l’ The incidence of vomiting following general anesthesia without prophylactic treatment with antiemetics has been reported to be between 39% and
Efficaq
7()%."W9
In a retrospective study, Dexter and Tinker*’ demonstrated that the 8% of patients requiring antiemetits after general anesthesia had a longer stay in the recovery room. With the exception of propofol,‘i choice of anesthetic has little effect on incidence of postoperative nausea and vomiting. ” The 20% incidence of vomiting in this study is lower than that which has been generally reported. That no patients in the propofol group experienced vomiting and only 12% experienced nausea may well be the result of the antiemetic effect of laropofo1.23 In conclusion, sevoflurane allows for rapid inhalation induction of and emergence from general anesthesia for cases of 1 to 3 hours’ duration.
Acknowledgments The authors would like to thank Dr. Thomas J.J. Blanck for his critical review of and comments regarding the study design and manuscript, Irusia Kocka for her editorial assistance in the preparation of this manuscript, and Larissa Eppich, Nathaniel Zoneraich, and Maria Siambekos for assistance in data collection.
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8. Adam HK Briggs LP, Bahar M, Douglas EJ, Dundee JW: Pharmacokinetic evaluation of ICI 35 868 in man. Single induction doses with different rates of injection. BrJ Anaesth 1983;55:9’7103. 9. Kay NH, Sear JW, Upington J, Cockshott ID, Douglas EJ: Disposition of propofol in patients undergoing surgery. A comparison in men and women. BrJAnaesth 1986;58:1075-9. 10. Gepts E, Camu F, Cockshott ID, Douglas EJ: Disposition of propofol administered as constant rate intravenous infusions in humans. Anesth An&g 1987;66:1256-63. 11. Kirkpatrick T, Cockshott ID, Douglas EJ, Nimmo WS: Pharmacokinetics of propofol (diprivan) in elderly patients. BrJ Anaesth 1988;60:146-50. 12. Shafer A, Doze VA, Shafer SL, White PF: Pharmacokinetics and pharmacodynamics of propofol infusions during general anesthesia. Anesthesiology 1988;69:348-56. 13. Frink EJ Jr, Malan TP, Atlas M, Dominguez LM, DiNardo JA, Brown BR Jr: Clinical comparison of sevoflurane and isoflurane in healthy patients. An&h An&g 1992;74:241-5. 14. Smith I, Ding Y, White PF: Comparison of induction, maintenance, and recovery characteristics of sevoflurane-N,O and propofol-sevoflurane-N,O with propofol-isoflurane-r\‘,O anesthesia. Anesth Analg 1992;74:253-9. 15. Fredman B, Nathanson MH, Smith I, Wang J, Klein K, White PF: Sevoflurane for outpatient anesthesia: a comparison with propofol. Anesth Analg 1995;81:823-8. 16. Briggs LP, Dundee JW, Bahar M, Clarke RS: Comparison of the effect of diisopropyl phenol (ICI 35, 868) and thiopentone in response to somatic pain. Br JAnaesth 1982;54:307-11. 17. Korttila K, &tman P, Faure E, et al: Randomized comparison of recovery after propofol-nitrous oxide versus thiopentoneisoflurane-nitrous oxide anaesthesia in patients undergoing ambulatory surgery. Acta Anaesthesiol &and 1990;34:400-3. 18. Ferrari LR, DonlonJV: Metoclopramide reduces the incidence of vomiting after tonsillectomy in children. Anesth An&g 1992;75: 351-4. 19. Khalil SN, Berry JM, Howard G, et al: The antiemetic effect of lorazepam after outpatient strabismus surgery in children. Anesthesiolog) 1992;77:915-9. 20. Dexter F, Tinker JH: Analysis of strategies to decrease postanesthesia care unit costs. Anesthesioloa 1995;82:94-101. 21. McCollum JS, Milligan KR, Dundee JW: Has propofol an antiemetic action? Br JAnaesth 1987;59(Suppl) :654P-5P. 22. MuirJ, Warner MA, Offard KP, Buck CF, HarperJV, Kunkel SE: Role of nitrous oxide and other factors in postoperative nausea and vomiting: a randomized and blinded prospective study. Anesthesiology 1987;66:513-8. 23. Borgeat A, Wilder-Smith OH, Saiah M, Rifat IQ Subhypnotic doses of propofol possess direct antiemetic properties. Anesth Analg 1992;74:539-41.
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