Skip Navigation LinksHome > November 2003 - Volume 99 - Issue 5 > Women Have the Same Desflurane Minimum Alveolar Concentratio...
Anesthesiology:
Clinical Investigations

Women Have the Same Desflurane Minimum Alveolar Concentration as Men: A Prospective Study

Wadhwa, Anupama M.D.*; Durrani, Jaleel M.D.†; Sengupta, Papiya M.D.‡; Doufas, Anthony G. M.D., Ph.D.*; Sessler, Daniel I. M.D.§

Free Access
Article Outline
Collapse Box

Author Information

Collapse Box

Abstract

Background: Women generally report greater sensitivity to pain than do men, and healthy young women require 20% more anesthetic than healthy age-matched men to prevent movement in response to noxious electrical stimulation. In contrast, minimum alveolar concentration (MAC) for xenon is 26% less in elderly Japanese women than in elderly Japanese men. Whether anesthetic requirement is similar in men and women thus remains in dispute. The authors therefore tested the hypothesis that the desflurane concentration required to prevent movement in response to skin incision (MAC) differs between men and women.
Methods: Using the Dixon “up and down” method, the authors determined MAC for desflurane in 15 female and 15 male patients (18–40 yr old) undergoing surgery.
Results: MAC was 6.2 ± 0.4% desflurane for women versus 6.0 ± 0.3% for men (P = 0.31), a difference of only 3%. These data provide 90% power to detect a 9% difference between the groups.
Conclusions: The MAC of desflurane did not differ between young men and women undergoing surgery with a true surgical incision. Although pain sensitivity may differ in women versus men, MAC of desflurane does not.
THE minimum alveolar concentration (MAC) is the alveolar (i.e., end-tidal) concentration of an inhaled anesthetic at which 50% of patients move in response to surgical incision. 1,2 A key element of this definition is that skin incision is a supramaximal stimulus that fully activates pain pathways. Movement in response to skin incision is an unconscious spinal reflex. 3,4
Goto et al.5 report that xenon MAC for elderly Japanese women is 26% less than xenon MAC for elderly Japanese men. This would seem to conflict with the finding that women experience more pain than men after comparable noxious stimuli. 6–9 This difference in pain sensitivity is pharmacodynamic rather than kinetic 10,11 and therefore implies the existence of complex, sex-based differences in the circuitry that modulates pain perception.
Consistent with increased pain sensitivity, we previously found that women required approximately 20% more desflurane than men to suppress movement in response to 100 Hz, 65- to 70-mA stimulation applied bilaterally for 10 s. 12 Although such electrical current is unbearable without anesthesia, it is probably not supramaximal, because anesthetic requirement as determined by this method may be less than that obtained using skin incision. 13 In view of these apparently conflicting data, we tested the hypothesis that MAC for desflurane in women would differ from that in men.
Back to Top | Article Outline

Materials and Methods

In our previous study, 12 we found that the SD of the anesthetic requirement for desflurane was 0.5% desflurane with n = 10 subjects. We thus estimated that a total of 30 patients would provide an 85% power for detecting a 10% difference in MAC between the sexes.
After obtaining approval from the Institutional Review Board and written informed consent, we enrolled 34 American Society of Anesthesiologists physical status I and II patients 18–40 yr old undergoing general anesthesia for elective surgery. We enrolled patients scheduled to have a skin incision greater than 3 cm (e.g., we excluded laparoscopic procedures).
Candidates having a history of chronic pain and those taking analgesic or sedative medications were excluded, as were those having a contraindication to an inhalation induction of anesthesia. We restricted enrollment to surgeries scheduled between 8 am and noon to minimize the circadian influence on anesthetic requirement. 14 We did not select patients on the basis of their menstrual cycle.
Back to Top | Article Outline
Protocol
Patients were not given preoperative medications. Routine anesthetic monitors were applied. Anesthesia was induced by inhalation of 6–8% sevoflurane in 100% oxygen. The end-tidal concentration of the inhalational agent was measured with a Datex-AS-3 monitor (Datex-Engstrom, Ohmeda, Helsinki, Finland) with an accuracy of 0.1%. A neuromuscular monitor was attached to the ulnar nerve to monitor “train-of-four” response. After loss of the lash reflex, succinylcholine was given intravenously. The patients’ lungs were ventilated with 80% oxygen, the balance nitrogen, and high concentrations of desflurane until all four twitches were lost. This time was used to remove sevoflurane from the lungs and replace it with desflurane. The trachea was then intubated.
An esophageal temperature probe was inserted. Forced air was used to maintain normothermia because MAC for volatile anesthetics decreases by 4–5% per degree centigrade decrease in core temperature. 15,16 The patients were maintained at their assigned end-tidal desflurane concentration for at least 10 min before skin incision with a fresh-gas flow of 3 l/min. Stimulation to the patient was avoided until incision. Patients’ lungs were ventilated with a tidal volume of 5–8 ml/kg. Before skin incision, we confirmed that the patient had recovered four full twitches in response to supramaximal stimulation of the ulnar nerve at the wrist and that residual sevoflurane concentration was <0.1%. The first male and female patients studied were assigned to an end-tidal desflurane concentration of 6%. If this patient moved in response to surgical skin incision, the concentration was increased by 0.5% desflurane in the subsequent patient of that sex. In contrast, the desflurane concentration in the subsequent patient in that group was decreased by 0.5% if skin incision did not provoke movement. This paradigm is referred to as the “Dixon up-and-down” method. 17
Back to Top | Article Outline
Measurements
Two independent investigators blinded to the end-tidal concentration of desflurane determined patient response to skin incision (movement or no movement). One investigator observed the upper extremities and head of the patient, and the other investigator observed the lower extremities. A positive response to skin incision was defined by a purposeful movement of one or more extremities or the head. 3 Grimacing and coughing were not considered purposeful responses. Patients were observed for movement for 1 min after skin incision.
Back to Top | Article Outline
Data Analysis
Our primary outcome was MAC, defined as the concentration of desflurane required to prevent movement in 50% of patients in response to skin incision. MAC was calculated as the average desflurane in each group for independent pairs of patients in which one patient moved and the next did not.
Results in men and women were compared by unpaired Student's t test. Data are presented as mean ± SD; a value of P < 0.05 was considered statistically significant. We considered differences in anesthetic requirement differing by less than 10% to be clinically unimportant.
Back to Top | Article Outline

Results

We enrolled 17 male and 17 female patients in the study. Data from two men and two women were deleted because of protocol violations: incision was made before the end of an adequate (10-min) equilibration period in three patients, and opioid was inadvertently given before the incision in one patient. Analysis was thus restricted to the data obtained from the remaining 30 patients.
Table 1
Table 1
Image Tools
Demographic and morphometric characteristics did not differ between groups except for height, which was greater for men (table 1). We had data on the menstrual cycle phases of 10 of the 15 women: these were equally divided between premenstrual, periovulatory, and luteal phases of menstruation. The average time from induction of anesthesia to incision was 24 min in each group, which allowed us to maintain steady end-tidal desflurane concentrations for at least 10 min before incision. Core temperature and hemodynamic responses were similar in each group at the time of incision.
Fig. 1
Fig. 1
Image Tools
The average desflurane concentration required to prevent movement in 50% of the patients did not differ between women and men (fig. 1). The MAC of desflurane was 6.2 ± 0.4% in women and 6.0 ± 0.3% in men (P = 0.31), a difference of 3%. These data provide 85% power to detect a 10% difference between the groups.
Back to Top | Article Outline

Discussion

Estrogen and progesterone play a pivotal role in establishing the pain threshold during pregnancy and parturition, 18–20 perhaps because female sex hormones modulate neuronal excitability via effects on the ion channels responsible for spinal and supraspinal neurotransmission. 21,22 It is therefore unsurprising that there appear to be sex differences in endogenous pain-inhibitory circuitry in men and women. For example, women report both temporary and persistent pain more frequently than men 8 and report greater pain in response to a given stimulus. 7,9,23–25
The results of previous work from this laboratory found that women required 20% more desflurane than men to block reflex movement in response to electrical stimulation. 12 However, desflurane MAC did not differ in the male and female participants in the present study. MAC values in both cases were approximately 6%, a value similar to that previously reported for patients of this age. 26 These present results have a high degree of statistical power, indicating that there is less than a 10% chance that anesthetic requirements in men and women differ by more than 9%. It is thus unlikely that we simply failed to detect a true sex difference in MAC. Instead, differences between our previous and current protocols presumably explain the contrasting results.
The critical difference appears to be that Greif et al.12 used tetanic electrical shocks as the noxious stimulus rather than surgical skin incision. Although tetanic current at 65 mA is unbearable without anesthesia, anesthetic requirement, as determined by this method, is consistently less than that obtained by formal MAC testing. 13 For example, the average desflurane requirement in the study by Greif et al. was 5%, whereas it was 6% in the present study, a difference of 20%. The key distinction here is that skin incision is a supramaximal stimulus that fully activates pain receptors and pathways. Electrical stimulation is not, and therefore, it provides graded activation of pain pathways.
It is worth noting, however, that there is little evidence that pain pathways are interrupted by volatile anesthetics. For example, MAC-BAR (MAC of inhalation agent that blocks adrenergic responses to skin incision) considerably exceeds MAC. 27 Furthermore, small concentrations of opioids substantially decrease MAC. And finally, the increase in ventilation prompted by skin incision is similar with either 1 or 2 MACs of isoflurane or halothane anesthesia. 28 We must thus consider the possibility that our previous results are wrong. 12
It remains unclear why our results differ so markedly from those reported recently by Goto et al.5 in which elderly Japanese women were found to require 26% less xenon than elderly Japanese men. Possibly the effects of xenon and desflurane on anesthetic requirement for men and women are dissimilar. Alternatively, there may be a sex difference for Japanese women versus men but not for Caucasian women versus men. Age-related pharmacokinetic differences could also account for the discrepancy. 26,29,30 MAC for inhalation anesthetics consistently decreases with age 26; this age-related change could be different in men than women, because hormonal levels probably affect the efficacy of inhalation anesthetics. For example, women in early pregnancy have a decreased MAC for isoflurane, halothane, and enflurane compared with nonpregnant women. 31 Thus, the altered hormonal milieu in the postmenopausal women may alter the response to inhalation anesthesia as well.
The pain threshold varies as a function of the menstrual cycle. 32 Women have a higher pain threshold in the follicular phase than in the periovulatory, luteal, or premenstrual phases. Women are most sensitive to ischemic, thermal, and pressure pain during the luteal phase. 33,34 It is thus a limitation of our study that we included women in all phases of their menstrual cycles. Doing so may have increased response variability in the women. Nonetheless, the SD in the women was relatively small, and the study was well powered to detect even small differences in anesthetic requirement. There remains a 10% chance that anesthetic requirements in men and women differ by as much as 9%. However, such small differences are of little clinical or physiologic importance. Finally, the work of Tanifuji et al.35 suggests that the phase of the menstrual cycle is irrelevant to MAC, despite its effect on the perception of pain.
In summary, the MAC of desflurane did not differ in young, healthy men and women. This result contrasts with previous results in which anesthetic requirement was based on the response to electrical stimulation. It also differs from studies showing that women report more pain than men. We thus conclude that although pain sensitivity is augmented in women, anesthetic requirement may not be.
The authors appreciate the assistance of Keith Hanni, M.D. (Medical Student, University of Louisville School of Medicine); Grigory Chernyak, M.D. (Research Fellow, outcomes research™ Institute, University of Louisville); Rainer Lenhardt, M.D. (Assistant Director, outcomes research™ and Assistant Professor, Department of Anesthesiology, University of Louisville); and Yunus Shah, M.D. (Resident, Department of Anesthesiology, University of Louisville). The authors thank Edmond Eger II, M.D. (Professor and Vice-Chair, Department of Anesthesia, University of California, San Francisco, California) for his insightful comments and suggestions.
Back to Top | Article Outline

References

1. Eger EI, Saidman IJ, Brandstater B: Minimum alveolar anesthetic concentration: A standard of potency. A nesthesiology 1965; 26: 756–63

2. Saidman LJ, Eger EI II: Effect of nitrous oxide and of narcotic premedication on the alveolar concentration of halothane required for anesthesia. A nesthesiology 1964; 25: 302–6

3. Rampil IJ: Anesthetic potency is not altered after hypothermic spinal cord transection in rats. A nesthesiology 1994; 80: 606–10

4. Antognini JF, Schwartz K: Exaggerated anesthetic requirements in the preferentially anesthetized brain. A nesthesiology 1993; 79: 1244–9

5. Goto T, Nakata Y, Morita S: The minimum alveolar concentration of xenon in the elderly is sex-dependent. A nesthesiology 2002; 5: 1129–32

6. Fillingham R, Ness T: Sex-related hormonal influences on pain and analgesic responses. Neurosci Biobehav Rev 2000; 24: 485–501

7. Berkley KJ: Sex differences in pain. Behav Brain Sci 1997; 20: 371–80; discussion 435–513

8. Unruh AM: Gender variations in clinical pain experience. Pain 1996; 65: 123–67

9. Sarlani E, Greenspan JD: Gender differences in temporal summation of mechanically evoked pain. Pain 2002; 97: 163–9

10. Gear RW, Gordon NC, Heller PH, Paul S, Miaskowski C, Levine JD: Gender difference in analgesic response to the kappa-opioid pentazocine. Neurosci Lett 1996; 205: 207–9

11. Kepler KL, Standifer KM, Paul D, Kest B, Pasternak GW, Bodnar RJ: Gender effects and central opioid analgesia. Pain 1991; 45: 87–94

12. Greif R, Laciny S, Mokhtarani M, Doufas AG, Bakhshandeh M, Dorfer L, Sessler DI: Transcutaneous electrical stimulation of an auricular acupuncture point decreases anesthetic requirement. A nesthesiology 2002; 96: 306–12

13. Sebel PS, Glass PS, Fletcher JE, Murphy MR, Gallagher C, Quill T: Reduction of the MAC of desflurane with fentanyl. A nesthesiology 1992; 76: 52–9

14. Halberg J, Halberg E, Halberg FEM: Chronobiologic monitoring and analysis for anesthesiologists: Another look at a chronoanesthetic index, Advances in Chronobiology Part B. Edited by Puly JE, Scheving LE. New York, Alan R. Liss, 1985, 315–22

15. Regan MJ, Eger EI II: Effect of hypothermia in dogs on anesthetizing and apneic doses of inhalation agents: Determination of the anesthetic index (apnea/MAC). A nesthesiology 1967; 28: 689–700

16. Eger EI II: Age, minimum alveolar anesthetic concentration, and minimum alveolar anesthetic concentration-awake. Anesth Analg 2001; 93: 947–53

17. Dixon WJ: Quantal-response variable experimentation: The up-and-down method, Statistics in Endocrinology. Edited by McArthur JW, Colton T. Cambridge, MIT Press, 1970, pp 251–67

18. Ginzler A: Endorphin-mediated increases in pain threshold during pregnancy. Nature 1980; 210: 193–6

19. Fletcher JE, Thomas TA, Hill RG: Beta-endorphin and parturition (letter). Lancet 1980; 1: 310

20. Genazzani AR, Facchinetti F, Ricci-Danero MG, Parrini D, Petraglia F, La Rosa R, D'Antona N: Beta-lipotropin and beta-endorphin in physiological and surgical menopause. J Endocrinol Invest 1981; 4: 375–8

21. Moss RL, Gu Q, Wong M: Estrogen: Nontranscriptional signaling pathway. Recent Prog Horm Res 1997; 52: 33–68; discussion 68–9

22. Wong M, Thompson TL, Moss RL: Nongenomic actions of estrogen in the brain: Physiological significance and cellular mechanisms. Crit Rev Neurobiol 1996; 10: 189–203

23. Fillingham R, Maixner W: Gender differences in response to noxious stimuli. Pain Forum 1995; 4: 209–21

24. Berkley K, Holdcroft A: Sex and gender differences in pain, Textbook of Pain, 4th Edition. Edited by Wall PD, Melzack R. Edinburgh, Churchill Livingstone, 1999, pp 951–65

25. Riley JL III, Robinson ME, Wise EA, Myers CD, Fillingim RB: Sex differences in the perception of noxious experimental stimuli: A meta-analysis. Pain 1998; 74: 181–7

26. Mapleson WW: Effect of age on MAC in humans: A meta-analysis. Br J Anaesth 1996; 76: 179–85

27. Roizen MF, Horrigan RW, Frazer BM: Anesthetic doses blocking adrenergic (stress) and cardiovascular responses to incision: MAC BAR. A nesthesiology 1981; 54: 390–8

28. France CJ, Plumer MH, Eger EI II, Wahrenbrock EA: Ventilatory effects of isoflurane (Forane) or halothane when combined with morphine, nitrous oxide and surgery. Br J Anaesth 1974; 46: 117–20

29. Nishiyama T, Matsukawa T, Hanaoka K: The effects of age and gender on the optimal premedication dose of intramuscular midazolam. Anesth Analg 1998; 86: 1103–8

30. Eger EI II: Desflurane animal and human pharmacology: Aspects of kinetics, safety, and MAC. Anesth Analg 1992; 75: S3–7; discussion S8–9

31. Chan MT, Mainland P, Gin T: Minimum alveolar concentration of halothane and enflurane are decreased in early pregnancy. A nesthesiology 1996; 85: 782–6

32. Riley JL III, Robinson ME, Wise EA, Price DD: A meta-analytic review of pain perception across the menstrual cycle. Pain 1999; 81: 225–35

33. Veith JL, Anderson J, Slade SA, Thompson P, Laugel GR, Getzlaf S: Plasma beta-endorphin, pain thresholds and anxiety levels across the human menstrual cycle. Physiol Behav 1984; 32: 31–4

34. Pfleeger M, Straneva PA, Fillingim RB, Maixner W, Girdler SS: Menstrual cycle, blood pressure and ischemic pain sensitivity in women: A preliminary investigation. Int J Psychophysiol 1997; 27: 161–6

35. Tanifuji Y, Mima S, Yasuda N, Machida H, Shimizu T, Kobayashi K: Effect of the menstrual cycle on MAC [in Japanese]. Masui 1988; 37: 1240–2

Cited By:

This article has been cited 12 time(s).

Anesthesia and Analgesia
Increased progesterone production during the luteal phase of menstruation may decrease anesthetic requirement
Erden, V; Yangin, Z; Erkalp, K; Delatioglu, H; Bahceci, F; Seyhan, A
Anesthesia and Analgesia, 101(4): 1007-1011.
10.1213/01.ane.0000168271.76090.63
CrossRef
Anesthesia and Analgesia
Neuromuscular Block Differentially Affects Immobility and Cortical Activation at Near-Minimum Alveolar Concentration Anesthesia
Doufas, AG; Komatsu, R; Orhan-Sungur, M; Sengupta, P; Wadhwa, A; Mascha, E; Shafer, SL; Sessler, DI
Anesthesia and Analgesia, 109(4): 1097-1104.
10.1213/ANE.0b013e3181af631a
CrossRef
Anaesthesist
Pharmacokinetic-pharmacodynamic models for inhaled anaesthetics
Kreuer, S; Bruhn, J; Wilhelm, W; Bouillon, T
Anaesthesist, 56(6): 538-556.
10.1007/s00101-007-1188-7
CrossRef
Journal of Veterinary Medical Science
Effect of Age on Minimum Alveolar Concentration (MAC) of Sevoflurane in Dogs
Yamashita, K; Iwasaki, Y; Umar, MA; Itami, T
Journal of Veterinary Medical Science, 71(): 1509-1512.

Journal of Anesthesia
Desflurane requirements for laryngeal mask airway insertion during inhalation induction
Shin, HY; Lim, JA; Kim, SH; Baek, SW; Kim, DK
Journal of Anesthesia, 23(2): 209-214.
10.1007/s00540-008-0730-3
CrossRef
Anesthesia and Analgesia
Molecular properties important for inhaled anesthetic action on human 5-HT3A receptors
Stevens, RJN; Rusch, D; Davies, PA; Raines, DE
Anesthesia and Analgesia, 100(6): 1696-1703.
10.1213/01.ANE.0000151720.36988.09
CrossRef
Journal of Pharmacology and Experimental Therapeutics
Modulation of human 5-hydroxytryptamine type 3AB receptors by volatile anesthetics and n-alcohols
Stevens, R; Rusch, D; Solt, K; Raines, DE; Davies, PA
Journal of Pharmacology and Experimental Therapeutics, 314(1): 338-345.
10.1124/jpet.105.085076
CrossRef
British Journal of Anaesthesia
Progesterone decreases sevoflurane requirement in male mice: a dose-response study
Shimizu, T; Inomata, S; Tanaka, M
British Journal of Anaesthesia, 104(5): 603-605.
10.1093/bja/aeq068
CrossRef
Translational Stroke Research
Gender-Specific Differences in the Central Nervous System's Response to Anesthesia
Mawhinney, LJ; Mabourakh, D; Lewis, MC
Translational Stroke Research, 4(4): 462-475.
10.1007/s12975-012-0229-y
CrossRef
Anesthesiology
Association of Ethnicity with the Minimum Alveolar Concentration of Sevoflurane
Ezri, T; Sessler, D; Weisenberg, M; Muzikant, G; Protianov, M; Mascha, E; Evron, S
Anesthesiology, 107(1): 9-14.
10.1097/01.anes.0000267534.31668.62
PDF (312) | CrossRef
Anesthesiology
Anesthetic Requirement Is Increased in Redheads
Liem, EB; Lin, C; Suleman, M; Doufas, AG; Gregg, RG; Veauthier, JM; Loyd, G; Sessler, DI
Anesthesiology, 101(2): 279-283.

PDF (203)
Anesthesiology
Advances in and Limitations of Up-and-down Methodology: A Précis of Clinical Use, Study Design, and Dose Estimation in Anesthesia Research
Pace, NL; Stylianou, MP
Anesthesiology, 107(1): 144-152.
10.1097/01.anes.0000267514.42592.2a
PDF (889) | CrossRef
Back to Top | Article Outline

© 2003 American Society of Anesthesiologists, Inc.

Publication of an advertisement in Anesthesiology Online does not constitute endorsement by the American Society of Anesthesiologists, Inc. or Lippincott Williams & Wilkins, Inc. of the product or service being advertised.
Login

Article Tools

Images

Share