Translational Stroke Research

, Volume 4, Issue 4, pp 462–475 | Cite as

Gender-Specific Differences in the Central Nervous System’s Response to Anesthesia

  • Lana J. Mawhinney
  • Davita Mabourakh
  • Michael C. Lewis
Original Article


Males and females are physiologically distinct in their responses to various anesthetic agents. The brain and central nervous system (CNS), the main target of anesthesia, are sexually dimorphic from birth and continue to differentiate throughout life. Accordingly, gender has a substantial impact on the influence of various anesthetic agents in the brain and CNS. Given the vast differences in the male and female CNS, it is surprising to find that females are often excluded from basic and clinical research studies of anesthesia. In animal research, males are typically studied to avoid the complication of breeding, pregnancy, and hormonal changes in females. In clinical studies, females are also excluded for the variations that occur in the reproductive cycle. Being that approximately half of the surgical population is female, the exclusion of females in anesthesia-related research studies leaves a huge knowledge gap in the literature. In this review, we examine the reported sex-specific differences in the central nervous system’s response to anesthesia. Furthermore, we suggest that anesthesia researchers perform experiments on both sexes to further evaluate such differences. We believe a key goal of research studying the interaction of the brain and anesthesia should include the search for knowledge of sex-specific mechanisms that will improve anesthetic care and management in both sexes.


Anesthesia Brain Central nervous system Gender differences Review 



The authors extend a note of appreciation to Eric Shaw and Dr. Dalton Dietrich for the critical review of this manuscript and helpful discussion. The authors regret space limitations that prevented the citation of many noteworthy and relevant studies. The support for the authors’ work and laboratories was from The Miami Project to Cure Paralysis and Department of Anesthesiology at the University of Miami Miller School of Medicine.

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    Holdcroft A. Females and their variability. Anaesthesia. 1997;52:931–4.PubMedCrossRefGoogle Scholar
  2. 2.
    Ciccone GK, Holdcroft A. Drugs and sex differences: a review of drugs relating to anaesthesia. Br J Anaesth. 1999;82:255–65.PubMedCrossRefGoogle Scholar
  3. 3.
    Howden L, Meyer J, U.S. Census Bureau. Age and Sex Composition. 2010. 2010.
  4. 4.
    Chen ML, Lee SC, Ng MJ, Schuirmann DJ, Lesko LJ, Williams RL. Pharmacokinetic analysis of bioequivalence trials: implications for sex-related issues in clinical pharmacology and biopharmaceutics. Clin Pharmacol Ther. 2000;68:510–21.PubMedCrossRefGoogle Scholar
  5. 5.
    Beery AK, Zucker I. Sex bias in neuroscience and biomedical research. Neurosci Biobehav Rev. 2011;35:565–72.PubMedCrossRefGoogle Scholar
  6. 6.
    Dhruva SS, Bero LA, Redberg RF. Gender bias in studies for Food and Drug Administration premarket approval of cardiovascular devices. Circ Cardiovasc Qual Outcomes. 2011;4:165–71.PubMedCrossRefGoogle Scholar
  7. 7.
    Phoenix CH, Goy RW, Gerall AA, Young WC. Organizing action of prenatally administered testosterone propionate on the tissues mediating mating behavior in the female guinea pig. Endocrinology. 1959;65:369–82.PubMedCrossRefGoogle Scholar
  8. 8.
    Ehrhardt AA, Meyer-Bahlburg HF. Prenatal sex hormones and the developing brain: effects on psychosexual differentiation and cognitive function. Annu Rev Med. 1979;30:417–30.PubMedCrossRefGoogle Scholar
  9. 9.
    Lombardo MV, Ashwin E, Auyeung B, Chakrabarti B, Taylor K, Hackett G, Bullmore ET, Baron-Cohen S. Fetal testosterone influences sexually dimorphic gray matter in the human brain. J Neurosci. 2012;32:674–80.PubMedCrossRefGoogle Scholar
  10. 10.
    Quadros PS, Wagner CK. Regulation of progesterone receptor expression by estradiol is dependent on age, sex and region in the rat brain. Endocrinology. 2008;149:3054–61.PubMedCrossRefGoogle Scholar
  11. 11.
    Weisz J, Ward IL. Plasma testosterone and progesterone titers of pregnant rats, their male and female fetuses, and neonatal offspring. Endocrinology. 1980;106:306–16.PubMedCrossRefGoogle Scholar
  12. 12.
    Quadros PS, Pfau JL, Goldstein AY, De Vries GJ, Wagner CK. Sex differences in progesterone receptor expression: a potential mechanism for estradiol-mediated sexual differentiation. Endocrinology. 2002;143:3727–39.PubMedCrossRefGoogle Scholar
  13. 13.
    Wagner EC, Prevolsek JS, Wynne-Edwards KE, Williams TD. Hematological changes associated with egg production: estrogen dependence and repeatability. J Exp Biol. 2008;211:400–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Scott WJ, Holson JF. Weight differences in rat embryos prior to sexual differentiation. J Embryol Exp Morpholog. 1977;40:259–63.Google Scholar
  15. 15.
    Pederson T. Chromatin structure and gene transcription: nucleosomes permit a new synthesis. Int Rev Cytol. 1978;55:1–21.PubMedCrossRefGoogle Scholar
  16. 16.
    Burgoyne PS. A Y-chromosomal effect on blastocyst cell number in mice. Development. 1993;117:341–5.PubMedGoogle Scholar
  17. 17.
    Thornhill AR, Burgoyne PS. A paternally imprinted X chromosome retards the development of the early mouse embryo. Development. 1993;118:171–4.PubMedGoogle Scholar
  18. 18.
    Burgoyne PS, Thornhill AR, Boudrean SK, Darling SM, Bishop CE, Evans EP. The genetic basis of XX-XY differences present before gonadal sex differentiation in the mouse. Philos Trans R Soc Lond B Biol Sci. 1995;350:253–60. discussion 260–1.PubMedCrossRefGoogle Scholar
  19. 19.
    Gilmore JH, Lin W, Prastawa MW, Looney CB, Vetsa YS, Knickmeyer RC, Evans DD, Smith JK, Hamer RM, Lieberman JA, Gerig G. Regional gray matter growth, sexual dimorphism, and cerebral asymmetry in the neonatal brain. J Neurosci. 2007;27:1255–60.PubMedCrossRefGoogle Scholar
  20. 20.
    Goldstein JM, Kennedy DN, Caviness Jr VS. Images in neuroscience. Brain development, XI: sexual dimorphism. Am J Psychiatry. 1999;156:352.PubMedGoogle Scholar
  21. 21.
    Giedd JN, Clasen LS, Lenroot R, Greenstein D, Wallace GL, Ordaz S, Molloy EA, Blumenthal JD, Tossell JW, Stayer C, Samango-Sprouse CA, Shen D, Davatzikos C, Merke D, Chrousos GP. Puberty-related influences on brain development. Mol Cell Endocrinol. 2006;254–255:154–62.PubMedCrossRefGoogle Scholar
  22. 22.
    De Bellis MD, Keshavan MS, Beers SR, Hall J, Frustaci K, Masalehdan A, Noll J, Boring AM. Sex differences in brain maturation during childhood and adolescence. Cereb Cortex. 2001;11:552–7.PubMedCrossRefGoogle Scholar
  23. 23.
    Sowell ER, Trauner DA, Gamst A, Jernigan TL. Development of cortical and subcortical brain structures in childhood and adolescence: a structural MRI study. Dev Med Child Neurol. 2002;44:4–16.PubMedCrossRefGoogle Scholar
  24. 24.
    Gogtay N, Giedd JN, Lusk L, Hayashi KM, Greenstein D, Vaituzis AC, Nugent 3rd TF, Herman DH, Clasen LS, Toga AW, Rapoport JL, Thompson PM. Dynamic mapping of human cortical development during childhood through early adulthood. Proc Natl Acad Sci U S A. 2004;101:8174–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Filipek PA, Richelme C, Kennedy DN, Caviness Jr VS. The young adult human brain: an MRI-based morphometric analysis. Cereb Cortex. 1994;4:344–60.PubMedCrossRefGoogle Scholar
  26. 26.
    Murphy DG, DeCarli C, McIntosh AR, Daly E, Mentis MJ, Pietrini P, Szczepanik J, Schapiro MB, Grady CL, Horwitz B, Rapoport SI. Sex differences in human brain morphometry and metabolism: an in vivo quantitative magnetic resonance imaging and positron emission tomography study on the effect of aging. Arch Gen Psychiatry. 1996;53:585–94.PubMedCrossRefGoogle Scholar
  27. 27.
    Giedd JN, Castellanos FX, Rajapakse JC, Vaituzis AC, Rapoport JL. Sexual dimorphism of the developing human brain. Prog Neuropsychopharmacol Biol Psychiatry. 1997;21:1185–201.PubMedCrossRefGoogle Scholar
  28. 28.
    Paus T, Otaky N, Caramanos Z, MacDonald D, Zijdenbos A, D’Avirro D, Gutmans D, Holmes C, Tomaiuolo F, Evans AC. In vivo morphometry of the intrasulcal gray matter in the human cingulate, paracingulate, and superior-rostral sulci: hemispheric asymmetries, gender differences and probability maps. J Comp Neurol. 1996;376:664–73.PubMedCrossRefGoogle Scholar
  29. 29.
    Nopoulos P, Flaum M, O’Leary D, Andreasen NC. Sexual dimorphism in the human brain: evaluation of tissue volume, tissue composition and surface anatomy using magnetic resonance imaging. Psychiatry Res. 2000;98:1–13.PubMedCrossRefGoogle Scholar
  30. 30.
    Good CD, Johnsrude I, Ashburner J, Henson RN, Friston KJ, Frackowiak RS. Cerebral asymmetry and the effects of sex and handedness on brain structure: a voxel-based morphometric analysis of 465 normal adult human brains. NeuroImage. 2001;14:685–700.PubMedCrossRefGoogle Scholar
  31. 31.
    Luders E, Narr KL, Thompson PM, Woods RP, Rex DE, Jancke L, Steinmetz H, Toga AW. Mapping cortical gray matter in the young adult brain: effects of gender. NeuroImage. 2005;26:493–501.PubMedCrossRefGoogle Scholar
  32. 32.
    Luders E, Gaser C, Narr KL, Toga AW. Why sex matters: brain size independent differences in gray matter distributions between men and women. J Neurosci. 2009;29:14265–70.PubMedCrossRefGoogle Scholar
  33. 33.
    Savic I, Arver S. Sex dimorphism of the brain in male-to-female transsexuals. Cereb Cortex. 2011;21:2525–33.PubMedCrossRefGoogle Scholar
  34. 34.
    Neufang S, Specht K, Hausmann M, Gunturkun O, Herpertz-Dahlmann B, Fink GR, Konrad K. Sex differences and the impact of steroid hormones on the developing human brain. Cereb Cortex. 2009;19:464–73.PubMedCrossRefGoogle Scholar
  35. 35.
    Carne RP, Vogrin S, Litewka L, Cook MJ. Cerebral cortex: an MRI-based study of volume and variance with age and sex. J Clin Neurosci. 2006;13:60–72.PubMedCrossRefGoogle Scholar
  36. 36.
    McCarthy MM, Schwarz JM, Wright CL, Dean SL. Mechanisms mediating oestradiol modulation of the developing brain. J Neuroendocrinol. 2008;20:777–83.PubMedCrossRefGoogle Scholar
  37. 37.
    McCarthy MM, Arnold AP. Reframing sexual differentiation of the brain. Nat Neurosci. 2011;14:677–83.PubMedCrossRefGoogle Scholar
  38. 38.
    Matsumoto S, Sugiyama T, Hanai T, Ohnishi N, Park YC, Kurita T. A study of the clinical effect of estradiol transdermal therapeutic system alone on pollakisuria and urinary incontinence in postmenopausal woman. Nihon Hinyokika Gakkai Zasshi. 2000;91:501–5.PubMedGoogle Scholar
  39. 39.
    Wright DW, Hoffman SW, Virmani S, Stein DG. Effects of medroxyprogesterone acetate on cerebral oedema and spatial learning performance after traumatic brain injury in rats. Brain Inj. 2008;22:107–13.PubMedCrossRefGoogle Scholar
  40. 40.
    Wright CL, McCarthy MM. Prostaglandin E2-induced masculinization of brain and behavior requires protein kinase A, AMPA/kainate, and metabotropic glutamate receptor signaling. J Neurosci. 2009;29:13274–82.PubMedCrossRefGoogle Scholar
  41. 41.
    Mong JA, McCarthy MM. Ontogeny of sexually dimorphic astrocytes in the neonatal rat arcuate. Brain Res Dev Brain Res. 2002;139:151–8.PubMedCrossRefGoogle Scholar
  42. 42.
    Schwarz JM, Liang SL, Thompson SM, McCarthy MM. Estradiol induces hypothalamic dendritic spines by enhancing glutamate release: a mechanism for organizational sex differences. Neuron. 2008;58:584–98.PubMedCrossRefGoogle Scholar
  43. 43.
    Schwarz JM, McCarthy MM. The role of neonatal NMDA receptor activation in defeminization and masculinization of sex behavior in the rat. Horm Behav. 2008;54:662–8.PubMedCrossRefGoogle Scholar
  44. 44.
    Bao AM, Swaab DF. Sex differences in the brain, behavior, and neuropsychiatric disorders. Neuroscientist. 2010;16:550–65.PubMedCrossRefGoogle Scholar
  45. 45.
    Bao AM, Swaab DF. Sexual differentiation of the human brain: relation to gender identity, sexual orientation and neuropsychiatric disorders. Front Neuroendocrinol. 2011;32:214–26.PubMedCrossRefGoogle Scholar
  46. 46.
    Roof RL, Hall ED. Gender differences in acute CNS trauma and stroke: neuroprotective effects of estrogen and progesterone. J Neurotrauma. 2000;17:367–88.PubMedCrossRefGoogle Scholar
  47. 47.
    Bramlett HM, Dietrich WD. Neuropathological protection after traumatic brain injury in intact female rats versus males or ovariectomized females. J Neurotrauma. 2001;18:891–900.PubMedCrossRefGoogle Scholar
  48. 48.
    Roof RL, Duvdevani R, Stein DG. Gender influences outcome of brain injury: progesterone plays a protective role. Brain Res. 1993;607:333–6.PubMedCrossRefGoogle Scholar
  49. 49.
    O’Connor C, Heath DL, Cernak I, Nimmo AJ, Vink R. Effects of daily versus weekly testing and pre-training on the assessment of neurologic impairment following diffuse traumatic brain injury in rats. J Neurotrauma. 2003;20:985–93.PubMedCrossRefGoogle Scholar
  50. 50.
    Wagner AK, Willard LA, Kline AE, Wenger MK, Bolinger BD, Ren D, Zafonte RD, Dixon CE. Evaluation of estrous cycle stage and gender on behavioral outcome after experimental traumatic brain injury. Brain Res. 2004;998:113–21.PubMedCrossRefGoogle Scholar
  51. 51.
    Farace E, Alves WM. Do women fare worse? A metaanalysis of gender differences in outcome after traumatic brain injury. Neurosurg Focus. 2000;8:e6.PubMedCrossRefGoogle Scholar
  52. 52.
    Bazarian JJ, Wong T, Harris M, Leahey N, Mookerjee S, Dombovy M. Epidemiology and predictors of post-concussive syndrome after minor head injury in an emergency population. Brain Inj. 1999;13:173–89.PubMedCrossRefGoogle Scholar
  53. 53.
    Bazarian JJ, Blyth B, Mookerjee S, He H, McDermott MP. Sex differences in outcome after mild traumatic brain injury. J Neurotrauma. 2010;27:527–39.PubMedCrossRefGoogle Scholar
  54. 54.
    Wood RL. Understanding the ‘miserable minority’: a diasthesis-stress paradigm for post-concussional syndrome. Brain Inj. 2004;18:1135–53.PubMedCrossRefGoogle Scholar
  55. 55.
    Rosamond W, Flegal K, Furie K, Go A, Greelund K, Hasse N, Halipern SM, Howard V, Kissela B, Kittner S, Lloyd-Jones D, McDermott M, Meigs J, Moy C, Nichol G, O’Donnell C, Roger V, Sorlie P, Steinberger J, Thom T, Wilson M, Hong Y. Heart disease and stroke statistics—2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2008; e25-e146.Google Scholar
  56. 56.
    Turtuzo LC, McCullough LD. Sex differences in stroke. Cerebrovasc Dis. 2008;26:462–74.CrossRefGoogle Scholar
  57. 57.
    Du L, Bayir H, Lai Y, Zhang X, Kochanek PM, Watkins SC, Graham SH, Clark RS. Innate gender-based proclivity in response to cytotoxicity and programmed cell death pathway. J Biol Chem. 2004;279:38563–70.PubMedCrossRefGoogle Scholar
  58. 58.
    Hagberg H, Wilson MA, Matsuchita H, Zhu C, Lange M, Gustavsson M, Poitras MF, Dawson TM, Dawson VL, Northington F, Hohston MT. PARP-1 gene disruption in mice preferentially protects males from perinatal brain injury. J Neurochem. 2009;90:1068–75.CrossRefGoogle Scholar
  59. 59.
    McCullough LD, Zeng Z, Blizzard KK, Debchoudhury I, Hurn PD. Ischemic nitric oxide and poly(ADP-ribose) polymerase-1 in cerebral ischemia: male toxicity, female protection. J Cereb Blood Flow Metab. 2005;25:502–12.PubMedCrossRefGoogle Scholar
  60. 60.
    Renolleau S, Fau S, Goyenvalle C, Loly LM, Chauvier D, Jacotot E, Mariani J, Charriaut-Marlangue C. Specific caspase inhibitor VD-OPh prevents neonatal stroke in P7 rat: a role for gender. JNeurochem. 2007;100:1062–71.CrossRefGoogle Scholar
  61. 61.
    Li J, McCullough LD. Sex differences in minocycline-induced neuroprotection after experimental stroke. J Cereb Blood Flow Metab. 2009;29:670–4.PubMedCrossRefGoogle Scholar
  62. 62.
    Liu J, Li Z, Li J, Siegel C, Yuan R, McCullough LD. Sex differences in caspase activation after stroke. Stroke. 2009;40:1842–8.PubMedCrossRefGoogle Scholar
  63. 63.
    Yuan M, Siegel C, Zeng Z, Li J, Liu F, McCullough LD. Sex differences in response to activation of poly(ADP-ribose) polymerase pathway after experimental stroke. Exp Neurol. 2009;217:210–8.PubMedCrossRefGoogle Scholar
  64. 64.
    Bazarian JJ, Atabaki S. Predicting postconcussion syndrome after minor traumatic brain injury. Acad Emerg Med. 2001;8:788–95.PubMedCrossRefGoogle Scholar
  65. 65.
    Martell R. Learning disabilities. Making history. Nurs Times. 2001;97:28–9.PubMedGoogle Scholar
  66. 66.
    Miller IN, Cronin-Golomb A. Gender differences in Parkinson’s disease: clinical characteristics and cognition. Mov Disord. 2010;25:2695–703.PubMedCrossRefGoogle Scholar
  67. 67.
    Shulman LM, Bhat V. Gender disparities in Parkinson’s disease. Expert Rev Neurother. 2006;6:407–16.PubMedCrossRefGoogle Scholar
  68. 68.
    Sadekov RA, Vendrova MI, Danilov AB. Gender dimorphism in Parkinson’s disease. Zh Nevrol Psikhiatr Im S S Korsakova. 2003;103:10–4.PubMedGoogle Scholar
  69. 69.
    Andersen K, Launer LJ, Dewey ME, Letenneur L, Ott A, Copeland JR, Dartigues JF, Kragh-Sorensen P, Baldereschi M, Brayne C, Lobo A, Martinez-Lage JM, Stijnen T, Hofman A. Gender differences in the incidence of AD and vascular dementia: the EURODEM studies. EURODEM Incidence Research Group. Neurology. 1999;53:1992–7.PubMedCrossRefGoogle Scholar
  70. 70.
    Brayne C, Gill C, Huppert FA, Barkley C, Gehlhaar E, Girling DM, O’Connor DW, Paykel ES. Incidence of clinically diagnosed subtypes of dementia in an elderly population. Cambridge Project for Later Life. Br J Psychiatry. 1995;167:255–62.PubMedCrossRefGoogle Scholar
  71. 71.
    Clarke D, Morgan K, Lilley J, Arie T, Jones R, Waite J, Prettyman R. Dementia and ‘borderline dementia’ in Britain: 8-year incidence and post-screening outcomes. Psychol Med. 1996;26:829–35.PubMedCrossRefGoogle Scholar
  72. 72.
    Fratiglioni L, Viitanen M, von Strauss E, Tontodonati V, Herlitz A, Winblad B. Very old women at highest risk of dementia and Alzheimer’s disease: incidence data from the Kungsholmen Project, Stockholm. Neurology. 1997;48:132–8.PubMedCrossRefGoogle Scholar
  73. 73.
    Morgan K, Lilley JM, Arie T, Byrne EJ, Jones R, Waite J. Incidence of dementia in a representative British sample. Br J Psychiatry. 1993;163:467–70.PubMedCrossRefGoogle Scholar
  74. 74.
    Yoshitake T, Kiyohara Y, Kato I, Ohmura T, Iwamoto H, Nakayama K, Ohmori S, Nomiyama K, Kawano H, Ueda K, et al. Incidence and risk factors of vascular dementia and Alzheimer’s disease in a defined elderly Japanese population: the Hisayama Study. Neurology. 1995;45:1161–8.PubMedCrossRefGoogle Scholar
  75. 75.
    Suzuki M, Edmonds Jr HL, Tsueda K, Malkani AL, Roberts CS. Effect of ketamine on bispectral index and levels of sedation. J Clin Monit Comput. 1998;14:373.PubMedGoogle Scholar
  76. 76.
    Torbati D, Ramirez J, Hon E, Camacho MT, Sussmane JB, Raszynski A, Wolfsdorf J. Experimental critical care in rats: gender differences in anesthesia, ventilation, and gas exchange. Crit Care Med. 1999;27:1878–84.PubMedCrossRefGoogle Scholar
  77. 77.
    Xue FS, Tong SY, Liao X, Liu JH, An G, Luo LK. Dose–response and time course of effect of rocuronium in male and female anesthetized patients. Anesth Analg. 1997;85:667–71.PubMedGoogle Scholar
  78. 78.
    Xue FS, Liao X, Liu JH, Tong SY, Zhang YM, Zhang RJ, An G, Luo LK. Dose–response curve and time-course of effect of vecuronium in male and female patients. Br J Anaesth. 1998;80:720–4.PubMedCrossRefGoogle Scholar
  79. 79.
    Donati F. Prolonged neuromuscular blockade with atracurium. Can Anaesth Soc J. 1986;33:683–5.PubMedCrossRefGoogle Scholar
  80. 80.
    Parker CJ, Hunter JM, Snowdon SL. Effect of age, sex and anaesthetic technique on the pharmacokinetics of atracurium. Br J Anaesth. 1992;69:439–43.PubMedCrossRefGoogle Scholar
  81. 81.
    Semple P, Hope DA, Clyburn P, Rodbert A. Relative potency of vecuronium in male and female patients in Britain and Australia. Br J Anaesth. 1994;72:190–4.PubMedCrossRefGoogle Scholar
  82. 82.
    MacLeod SM, Giles HG, Bengert B, Liu FF, Sellers EM. Age- and gender-related differences in diazepam pharmacokinetics. J Clin Pharmacol. 1979;19:15–9.PubMedCrossRefGoogle Scholar
  83. 83.
    Palva ES. Gender-related differences in diazepam effects on performance. Med Biol. 1985;63:92–5.PubMedGoogle Scholar
  84. 84.
    Ochs HR, Otten H, Greenblatt DJ, Dengler HJ. Diazepam absorption: effects of age, sex, and Billroth gastrectomy. Dig Dis Sci. 1982;27:225–30.PubMedCrossRefGoogle Scholar
  85. 85.
    Greenblatt DJ, Abernethy DR, Locniskar A, Harmatz JS, Limjuco RA, Shader RI. Effect of age, gender, and obesity on midazolam kinetics. Anesthesiology. 1984;61:27–35.PubMedGoogle Scholar
  86. 86.
    Shafer SQ, Hauser WA, Annegers JF, Klass DW. EEG and other early predictors of epilepsy remission: a community study. Epilepsia. 1988;29:590–600.PubMedCrossRefGoogle Scholar
  87. 87.
    Ward DS, Norton JR, Guivarc’h PH, Litman RS, Bailey PL. Pharmacodynamics and pharmacokinetics of propofol in a medium-chain triglyceride emulsion. Anesthesiology. 2002;97:1401–8.PubMedCrossRefGoogle Scholar
  88. 88.
    Puri A, Medhi B, Panda NB, Puri GD, Dhawan S. Propofol pharmacokinetics in young healthy Indian subjects. Indian J Pharmacol. 2012;44:402–6.PubMedCrossRefGoogle Scholar
  89. 89.
    Loryan I, Lindqvist M, Johansson I, Hiratsuka M, van der Heiden I, van Schaik RH, Jakobsson J, Ingelman-Sundberg M. Influence of sex on propofol metabolism, a pilot study: implications for propofol anesthesia. Eur J Clin Pharmacol. 2012;68:397–406.PubMedCrossRefGoogle Scholar
  90. 90.
    Kotani K, Tokunaga K, Fujioka S, Kobatake T, Keno Y, Yoshida S, Shimomura I, Tarui S, Matsuzawa Y. Sexual dimorphism of age-related changes in whole-body fat distribution in the obese. Int J Obes Relat Metab Disord. 1994;18:207–2.PubMedGoogle Scholar
  91. 91.
    Lovejoy JC, Sainsbury A. Sex differences in obesity and the regulation of energy homeostasis. Obes Rev. 2009;10:154–67.PubMedCrossRefGoogle Scholar
  92. 92.
    Macotela Y, Boucher J, Tran TT, Kahn CR. Sex and depot differences in adipocyte insulin sensitivity and glucose metabolism. Diabetes. 2009;58:803–12.PubMedCrossRefGoogle Scholar
  93. 93.
    Power ML, Schulkin J. Sex differences in fat storage, fat metabolism, and the health risks from obesity: possible evolutionary origins. Br J Nutr. 2008;99:931–40.PubMedCrossRefGoogle Scholar
  94. 94.
    Wajchenberg BL. Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev. 2000;21:697–738.PubMedCrossRefGoogle Scholar
  95. 95.
    Brodie BB, Mark LC, Lief PA, Bernstein E, Papper EM. Acute tolerance to thiopental. J Pharmacol Exp Ther. 1951;102:215–8.PubMedGoogle Scholar
  96. 96.
    Maynert EW, Losin L. The metabolism of butabarbital (butisol) in the dog. J Pharmacol Exp Ther. 1955;115:275–82.PubMedGoogle Scholar
  97. 97.
    Chen TL, Wu CH, Chen TG, Tai YT, Chang HC, Lin CJ. Effects of propofol on functional activities of hepatic and extrahepatic conjugation enzyme systems. Br J Anaesth. 2000;84:771–6.PubMedCrossRefGoogle Scholar
  98. 98.
    Tontisirin N, Muangman SL, Suz P, Pihoker C, Fisk D, Moore A, Lam AM, Vavilala MS. Early childhood gender differences in anterior and posterior cerebral blood flow velocity and autoregulation. Pediatrics. 2007;119:e610–5.PubMedCrossRefGoogle Scholar
  99. 99.
    Kashuba AD, Nafziger AN. Physiological changes during the menstrual cycle and their effects on the pharmacokinetics and pharmacodynamics of drugs. Clin Pharmacokinet. 1998;34:203–18.PubMedCrossRefGoogle Scholar
  100. 100.
    Kinirons MT, O’Shea D, Kim RB, Groopman JD, Thummel KE, Wood AJ, Wilkinson GR. Failure of erythromycin breath test to correlate with midazolam clearance as a probe of cytochrome P4503A. Clin Pharmacol Ther. 1999;66:224–31.PubMedCrossRefGoogle Scholar
  101. 101.
    Zambricki EA, Dalecy LG. Rat sex differences in anesthesia. Comp Med. 2004;54:49–53.PubMedGoogle Scholar
  102. 102.
    Vuyk J, Oostwouder CJ, Vletter AA, Burm AG, Bovill JG. Gender differences in the pharmacokinetics of propofol in elderly patients during and after continuous infusion. Br J Anaesth. 2001;86:183–8.PubMedCrossRefGoogle Scholar
  103. 103.
    Myles PS, McLeod AD, Hunt JO, Fletcher H. Sex differences in speed of emergence and quality of recovery after anaesthesia: cohort study. BMJ. 2001;322:710–1.PubMedCrossRefGoogle Scholar
  104. 104.
    Mead J. Dysanapsis in normal lungs assessed by the relationship between maximal flow, static recoil, and vital capacity. Am Rev Respir Dis. 1980;121:339–42.PubMedGoogle Scholar
  105. 105.
    McClaran SR, Harms CA, Pegelow DF, Dempsey JA. Smaller lungs in women affect exercise hyperpnea. J Appl Physiol. 1998;84:1872–81.PubMedGoogle Scholar
  106. 106.
    Harms CA, McClaran SR, Nickele GA, Pegelow DF, Nelson WB, Dempsey JA. Exercise-induced arterial hypoxaemia in healthy young women. J Physiol. 1998;507(Pt 2):619–28.PubMedCrossRefGoogle Scholar
  107. 107.
    Kilbride E, McLoughlin P, Gallagher CG, Harty HR. Do gender differences exist in the ventilatory response to progressive exercise in males and females of average fitness? Eur J Appl Physiol. 2003;89:595–602.PubMedCrossRefGoogle Scholar
  108. 108.
    Morelli C, Badr MS, Mateika JH. Ventilatory responses to carbon dioxide at low and high levels of oxygen are elevated after episodic hypoxia in men compared with women. J Appl Physiol. 2004;97:1673–80.PubMedCrossRefGoogle Scholar
  109. 109.
    Reckelhoff JF, Hennington BS, Moore AG, Blanchard EJ, Cameron J. Gender differences in the renal nitric oxide (NO) system: dissociation between expression of endothelial NO synthase and renal hemodynamic response to NO synthase inhibition. Am J Hypertens. 1998;11:97–104.PubMedCrossRefGoogle Scholar
  110. 110.
    Nishiyama M, Hashitani H, Fukuta H, Yamamoto Y, Suzuki H. Potassium channels activated in the endothelium-dependent hyperpolarization in guinea-pig coronary artery. J Physiol. 1998;510(Pt 2):455–65.PubMedCrossRefGoogle Scholar
  111. 111.
    Gorski JC, Jones DR, Haehner-Daniels BD, Hamman MA, O’Mara Jr EM, Hall SD. The contribution of intestinal and hepatic CYP3A to the interaction between midazolam and clarithromycin. Clin Pharmacol Ther. 1998;64:133–43.PubMedCrossRefGoogle Scholar
  112. 112.
    Gandhi M, Aweeka F, Greenblatt RM, Blaschke TF. Sex differences in pharmacokinetics and pharmacodynamics. Annu Rev Pharmacol Toxicol. 2004;44:499–523.PubMedCrossRefGoogle Scholar
  113. 113.
    Gilman AG, Hardman JG, Limbird LE. Goodman and Gilman’s the pharmacological basis of therapeutics. New York: McGraw-Hill; 1996.Google Scholar
  114. 114.
    Clewell HJ, Teeguarden J, McDonald T, Sarangapani R, Lawrence G, Covington T, Gentry R, Shipp A. Review and evaluation of the potential impact of age- and gender-specific pharmacokinetic differences on tissue dosimetry. Crit Rev Toxicol. 2002;32:329–89.PubMedCrossRefGoogle Scholar
  115. 115.
    Jevtovic-Todorovic V, Hartman RE, Izumi Y, Benshoff ND, Dikranian K, Zorumski CF, Olney JW, Wozniak DF. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci. 2003;23:876–82.PubMedGoogle Scholar
  116. 116.
    Loepke AW, Istaphanous GK, McAuliffe 3rd JJ, Miles L, Hughes EA, McCann JC, Harlow KE, Kurth CD, Williams MT, Vorhees CV, Danzer SC. The effects of neonatal isoflurane exposure in mice on brain cell viability, adult behavior, learning, and memory. Anesth Analg. 2009;108:90–104.PubMedCrossRefGoogle Scholar
  117. 117.
    Young C, Jevtovic-Todorovic V, Qin YQ, Tenkova T, Wang H, Labruyere J, Olney JW. Potential of ketamine and midazolam, individually or in combination, to induce apoptotic neurodegeneration in the infant mouse brain. Br J Pharmacol. 2005;146:189–97.PubMedCrossRefGoogle Scholar
  118. 118.
    Rizzi S, Carter LB, Ori C, Jevtovic-Todorovic V. Clinical anesthesia causes permanent damage to the fetal guinea pig brain. Brain Pathol. 2008;18:198–210.PubMedCrossRefGoogle Scholar
  119. 119.
    Slikker Jr W, Zou X, Hotchkiss CE, Divine RL, Sadovova N, Twaddle NC, Doerge DR, Scallet AC, Patterson TA, Hanig JP, Paule MG, Wang C. Ketamine-induced neuronal cell death in the perinatal rhesus monkey. Toxicol Sci. 2007;98:145–58.PubMedCrossRefGoogle Scholar
  120. 120.
    Fredriksson A, Archer T, Alm H, Gordh T, Eriksson P. Neurofunctional deficits and potentiated apoptosis by neonatal NMDA antagonist administration. Behav Brain Res. 2004;153:367–76.PubMedCrossRefGoogle Scholar
  121. 121.
    Fredriksson A, Ponten E, Gordh T, Eriksson P. Neonatal exposure to a combination of N-methyl-d-aspartate and gamma-aminobutyric acid type A receptor anesthetic agents potentiates apoptotic neurodegeneration and persistent behavioral deficits. Anesthesiology. 2007;107:427–36.PubMedCrossRefGoogle Scholar
  122. 122.
    Pesic V, Milanovic D, Tanic N, Popic J, Kanazir S, Jevtovic-Todorovic V, Ruzdijic S. Potential mechanism of cell death in the developing rat brain induced by propofol anesthesia. Int J Dev Neurosci. 2009;27:279–87.PubMedCrossRefGoogle Scholar
  123. 123.
    Satomoto M, Satoh Y, Terui K, Miyao H, Takishima K, Ito M, Imaki J. Neonatal exposure to sevoflurane induces abnormal social behaviors and deficits in fear conditioning in mice. Anesthesiology. 2009;110:628–37.PubMedCrossRefGoogle Scholar
  124. 124.
    Viberg H, Ponten E, Eriksson P, Gordh T, Fredriksson A. Neonatal ketamine exposure results in changes in biochemical substrates of neuronal growth and synaptogenesis, and alters adult behavior irreversibly. Toxicology. 2008;249:153–9.PubMedCrossRefGoogle Scholar
  125. 125.
    Paule MG, Li M, Allen RR, Liu F, Zou X, Hotchkiss C, Hanig JP, Patterson TA, Slikker Jr W, Wang C. Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys. Neurotoxicol Teratol. 2011;33:220–30.PubMedCrossRefGoogle Scholar
  126. 126.
    Flick RP, Katusic SK, Colligan RC, Wilder RT, Voigt RG, Olson MD, Sprung J, Weaver AL, Schroeder DR, Warner DO. Cognitive and behavioral outcomes after early exposure to anesthesia and surgery. Pediatrics. 2011;128:e1053–61.PubMedCrossRefGoogle Scholar
  127. 127.
    Rothstein S, Simkins T, Nunez JL. Response to neonatal anesthesia: effect of sex on anatomical and behavioral outcome. Neuroscience. 2008;152:959–69.PubMedCrossRefGoogle Scholar
  128. 128.
    Soldin OP, Chung SH, Mattison DR. Sex differences in drug disposition. J Biomed Biotechnol. 2011; 187103.Google Scholar
  129. 129.
    Lauer MS, Anderson KM, Larson MG, Levy D. A new method for indexing left ventricular mass for differences in body size. Am J Cardiol. 1994;74:487–91.PubMedCrossRefGoogle Scholar
  130. 130.
    de Simone G, Devereux RB, Kizer JR, Chinali M, Bella JN, Oberman A, Kitzman DW, Hopkins PN, Rao DC, Arnett DK. Body composition and fat distribution influence systemic hemodynamics in the absence of obesity: the HyperGEN Study. Am J Clin Nutr. 2005;81:757–61.PubMedGoogle Scholar
  131. 131.
    Cain PA, Ahl R, Hedstrom E, Ugander M, Allansdotter-Johnsson A, Friberg P, Marild S, Arheden H. Physiological determinants of the variation in left ventricular mass from early adolescence to late adulthood in healthy subjects. Clin Physiol Funct Imaging. 2005;25:332–9.PubMedCrossRefGoogle Scholar
  132. 132.
    Grandi AM, Ricordi L, Rossi M, Marti G, Fratino P, Finardi G, Bernardi L. Noninvasive assessment of the relationship between cardiac and autonomic function in diabetes. Acta Cardiol. 1992;47:77–85.PubMedGoogle Scholar
  133. 133.
    Chung AK, Das SR, Leonard D, Peshock RM, Kazi F, Abdullah SM, Canham RM, Levine BD, Drazner MH. Women have higher left ventricular ejection fractions than men independent of differences in left ventricular volume: the Dallas Heart Study. Circulation. 2006;113:1597–604.PubMedCrossRefGoogle Scholar
  134. 134.
    Legato MJ. Gender and the heart: sex-specific differences in normal anatomy and physiology. J Gend Specif Med. 2000;3:15–8.PubMedGoogle Scholar
  135. 135.
    Sarangapani R, Gentry PR, Covington TR, Teeguarden JG, Clewell 3rd HJ. Evaluation of the potential impact of age- and gender-specific lung morphology and ventilation rate on the dosimetry of vapors. Inhal Toxicol. 2003;15:987–1016.PubMedGoogle Scholar
  136. 136.
    Pfaff DW, McEwen BS. Actions of estrogens and progestins on nerve cells. Science. 1983;219:808–14.PubMedCrossRefGoogle Scholar
  137. 137.
    Goldfien A. The gonadal hormones and inhibitors. In: Katzung BG, editor. Basic and clinical pharmacology. Stamford: Appleton & Lange; 1998. p. 653–83.Google Scholar
  138. 138.
    Yoshimi T, Lipsett MB. The measurement of plasma progesterone. Steroids. 1968;11:527–40.PubMedCrossRefGoogle Scholar
  139. 139.
    Stricker R, Eberhart R, Chevailler MC, Quinn FA, Bischof P. Establishment of detailed reference values for luteinizing hormone, follicle stimulating hormone, estradiol, and progesterone during different phases of the menstrual cycle on the Abbott ARCHITECT analyzer. Clin Chem Lab Med. 2006;44:883–7.PubMedCrossRefGoogle Scholar
  140. 140.
    Evans PW, Wheeler T, Anthony FW, Osmond C. A longitudinal study of maternal serum vascular endothelial growth factor in early pregnancy. Hum Reprod. 1998;13:1057–62.PubMedCrossRefGoogle Scholar
  141. 141.
    Paul SM, Purdy RH. Neuroactive steroids. FASEB J. 1992;6:2311–22.PubMedGoogle Scholar
  142. 142.
    Manber R, Armitage R. Sex, steroids, and sleep: a review. Sleep. 1999;22:540–55.PubMedGoogle Scholar
  143. 143.
    Bitran D, Shiekh M, McLeod M. Anxiolytic effect of progesterone is mediated by the neurosteroid allopregnanolone at brain GABAA receptors. J Neuroendocrinol. 1995;7:171–7.PubMedCrossRefGoogle Scholar
  144. 144.
    Soderpalm AH, Lindsey S, Purdy RH, Hauger R, de Wit H. Administration of progesterone produces mild sedative-like effects in men and women. Psychoneuroendocrinology. 2004;29:339–54.PubMedCrossRefGoogle Scholar
  145. 145.
    Nadeson R, Goodchild CS. Antinociceptive properties of neurosteroids III: experiments with alphadolone given intravenously, intraperitoneally, and intragastrically. Br J Anaesth. 2001;86:704–8.PubMedCrossRefGoogle Scholar
  146. 146.
    Carl P, Hogskilde S, Nielsen JW, Sorensen MB, Lindholm M, Karlen B, Backstrom T. Pregnanolone emulsion: a preliminary pharmacokinetic and pharmacodynamic study of a new intravenous anaesthetic agent. Anaesthesia. 1990;45:189–97.PubMedCrossRefGoogle Scholar
  147. 147.
    Lancel M, Faulhaber J, Holsboer F, Rupprecht R. Progesterone induces changes in sleep comparable to those of agonistic GABAA receptor modulators. Am J Physiol. 1996;271:E763–72.PubMedGoogle Scholar
  148. 148.
    Lancel M, Faulhaber J, Schiffelholz T, Romeo E, Di Michele F, Holsboer F, Rupprecht R. Allopregnanolone affects sleep in a benzodiazepine-like fashion. J Pharmacol Exp Ther. 1997;282:1213–8.PubMedGoogle Scholar
  149. 149.
    Friess E, Tagaya H, Trachsel L, Holsboer F, Rupprecht R. Progesterone-induced changes in sleep in male subjects. Am J Physiol. 1997;272:E885–91.PubMedGoogle Scholar
  150. 150.
    Datta S, Migliozzi RP, Flanagan HL, Krieger NR. Chronically administered progesterone decreases halothane requirements in rabbits. Anesth Analg. 1989;68:46–50.PubMedCrossRefGoogle Scholar
  151. 151.
    Erden V, Yangin Z, Erkalp K, Delatioglu H, Bahceci F, Seyhan A. Increased progesterone production during the luteal phase of menstruation may decrease anesthetic requirement. Anesth Analg. 2005;101:1007–11. table of contents.PubMedCrossRefGoogle Scholar
  152. 152.
    Buchanan FF, Myles PS, Cicuttini F. Effect of patient sex on general anaesthesia and recovery. Br J Anaesth; 106: 832–9.Google Scholar
  153. 153.
    Tanifuji Y, Mima S, Yasuda N, Machida H, Shimizu T, Kobayashi K. Effect of the menstrual cycle on MAC. Masui. 1988;37:1240–2.PubMedGoogle Scholar
  154. 154.
    Katoh T, Ikeda K. The effects of fentanyl on sevoflurane requirements for loss of consciousness and skin incision. Anesthesiology. 1998;88:18–24.PubMedCrossRefGoogle Scholar
  155. 155.
    Katoh T, Nakajima Y, Moriwaki G, Kobayashi S, Suzuki A, Iwamoto T, Bito H, Ikeda K. Sevoflurane requirements for tracheal intubation with and without fentanyl. Br J Anaesth. 1999;82:561–5.PubMedCrossRefGoogle Scholar
  156. 156.
    Eger 2nd EI, Laster MJ, Gregory GA, Katoh T, Sonner JM. Women appear to have the same minimum alveolar concentration as men: a retrospective study. Anesthesiology. 2003;99:1059–61.PubMedCrossRefGoogle Scholar
  157. 157.
    Wadhwa A, Durrani J, Sengupta P, Doufas AG, Sessler DI. Women have the same desflurane minimum alveolar concentration as men: a prospective study. Anesthesiology. 2003;99:1062–5.PubMedCrossRefGoogle Scholar
  158. 158.
    Palahniuk RJ, Shnider SM, Eger 2nd EI. Pregnancy decreases the requirement for inhaled anesthetic agents. Anesthesiology. 1974;41:82–3.PubMedCrossRefGoogle Scholar
  159. 159.
    Gin T, Chan MT. Decreased minimum alveolar concentration of isoflurane in pregnant humans. Anesthesiology. 1994;81:829–32.PubMedCrossRefGoogle Scholar
  160. 160.
    Chan MT, Gin T. Postpartum changes in the minimum alveolar concentration of isoflurane. Anesthesiology. 1995;82:1360–3.PubMedCrossRefGoogle Scholar
  161. 161.
    Succari M, Foglietti MJ, Percheron F. Microheterogeneity of alpha 1-acid glycoprotein: variation during the menstrual cycle in healthy women, and profile in women receiving estrogen-progestogen treatment. Clin Chim Acta. 1990;187:235–41.PubMedCrossRefGoogle Scholar
  162. 162.
    Walle UK, Fagan TC, Topmiller MJ, Conradi EC, Walle T. The influence of gender and sex steroid hormones on the plasma binding of propranolol enantiomers. Br J Clin Pharmacol. 1994;37:21–5.PubMedCrossRefGoogle Scholar
  163. 163.
    Tuck CH, Holleran S, Berglund L. Hormonal regulation of lipoprotein(a) levels: effects of estrogen replacement therapy on lipoprotein(a) and acute phase reactants in postmenopausal women. Arterioscler Thromb Vasc Biol. 1997;17:1822–9.PubMedCrossRefGoogle Scholar
  164. 164.
    Blok LJ, de Ruiter PE, Brinkmann AO. Androgen receptor phosphorylation. Endocr Res. 1996;22:197–219.PubMedCrossRefGoogle Scholar
  165. 165.
    Haram K, Augensen K, Elsayed S. Serum protein pattern in normal pregnancy with special reference to acute-phase reactants. Br J Obstet Gynaecol. 1983;90:139–45.PubMedCrossRefGoogle Scholar
  166. 166.
    Aquirre C, Rodriguez-Sasiain JM, Navajas P, Calvo R. Plasma protein binding of penbutolol in pregnancy. Eur J Drug Metab Pharmacokinet. 1988;13:23–6.PubMedCrossRefGoogle Scholar
  167. 167.
    Wood SM, Hytten FE. The fate of drugs in pregnancy. Clin Obstet Gynaecol. 1981;8:255–9.PubMedGoogle Scholar
  168. 168.
    Chu CY, Singla VP, Wang HP, Sweet B, Lai LT. Plasma alpha 1-acid glycoprotein levels in pregnancy. Clin Chim Acta. 1981;112:235–40.PubMedCrossRefGoogle Scholar
  169. 169.
    Notarianni LJ. Plasma protein binding of drugs in pregnancy and in neonates. Clin Pharmacokinet. 1990;18:20–36.PubMedCrossRefGoogle Scholar
  170. 170.
    Hill MD, Abramson FP. The significance of plasma protein binding on the fetal/maternal distribution of drugs at steady-state. Clin Pharmacokinet. 1988;14:156–70.PubMedCrossRefGoogle Scholar
  171. 171.
    Perucca E, Crema A. Plasma protein binding of drugs in pregnancy. Clin Pharmacokinet. 1982;7:336–52.PubMedCrossRefGoogle Scholar
  172. 172.
    Wadelius M, Darj E, Frenne G, Rane A. Induction of CYP2D6 in pregnancy. Clin Pharmacol Ther. 1997;62:400–7.PubMedCrossRefGoogle Scholar
  173. 173.
    Suzuki M, Inagaki K, Kihira M, Matsuzawa K, Ishikawa K, Ishizuka T. Maternal liver impairment associated with prolonged high-dose administration of terbutaline for premature labor. Obstet Gynecol. 1985;66:14S–5S.PubMedGoogle Scholar
  174. 174.
    Van Le L, Pizzuti DJ, Greenberg M, Reid R. Accidental use of low-dose 5-fluorouracil in pregnancy. J Reprod Med. 1991;36:872–4.PubMedGoogle Scholar
  175. 175.
    Adamus M, Gabrhelik T, Marek O. Influence of gender on the course of neuromuscular block following a single bolus dose of cisatracurium or rocuronium. Eur J Anaesthesiol. 2008;25:589–95.PubMedCrossRefGoogle Scholar
  176. 176.
    Smith CE, van Miert MM, Parker CJ, Hunter JM. A comparison of the infusion pharmacokinetics and pharmacodynamics of cisatracurium, the 1R-cis 1′R-cis isomer of atracurium, with atracurium besylate in healthy patients. Anaesthesia. 1997;52:833–41.PubMedCrossRefGoogle Scholar
  177. 177.
    Apfelbaum JL, Grasela TH, Hug Jr CC, McLeskey CH, Nahrwold ML, Roizen MF, Stanley TH, Thisted RA, Walawander CA, White PF. The initial clinical experience of 1819 physicians in maintaining anesthesia with propofol: characteristics associated with prolonged time to awakening. Anesth Analg. 1993;77:S10–4.PubMedGoogle Scholar
  178. 178.
    Gan TJ, Glass PS, Sigl J, Sebel P, Payne F, Rosow C, Embree P. Women emerge from general anesthesia with propofol/alfentanil/nitrous oxide faster than men. Anesthesiology. 1999;90:1283–7.PubMedCrossRefGoogle Scholar
  179. 179.
    Glass PS, Bloom M, Kearse L, Rosow C, Sebel P, Manberg P. Bispectral analysis measures sedation and memory effects of propofol, midazolam, isoflurane, and alfentanil in healthy volunteers. Anesthesiology. 1997;86:836–47.PubMedCrossRefGoogle Scholar
  180. 180.
    Greenblatt DJ, Ehrenberg BL, Gunderman J, Locniskar A, Scavone JM, Harmatz JS, Shader RI. Pharmacokinetic and electroencephalographic study of intravenous diazepam, midazolam, and placebo. Clin Pharmacol Ther. 1989;45:356–65.PubMedCrossRefGoogle Scholar
  181. 181.
    Miners JO, Attwood J, Birkett DJ. Influence of sex and oral contraceptive steroids on paracetamol metabolism. Br J Clin Pharmacol. 1983;16:503–9.PubMedCrossRefGoogle Scholar
  182. 182.
    Walle T, Walle UK, Cowart TD, Conradi EC. Pathway-selective sex differences in the metabolic clearance of propranolol in human subjects. Clin Pharmacol Ther. 1989;46:257–63.PubMedCrossRefGoogle Scholar
  183. 183.
    Sandin RH, Enlund G, Samuelsson P, Lennmarken C. Awareness during anaesthesia: a prospective case study. Lancet. 2000;355:707–11.PubMedCrossRefGoogle Scholar
  184. 184.
    Myles PS, Williams DL, Hendrata M, Anderson H, Weeks AM. Patient satisfaction after anaesthesia and surgery: results of a prospective survey of 10,811 patients. Br J Anaesth. 2000;84:6–10.PubMedCrossRefGoogle Scholar
  185. 185.
    Sebel PS, Bowdle TA, Ghoneim MM, Rampil IJ, Padilla RE, Gan TJ, Domino KB. The incidence of awareness during anesthesia: a multicenter United States study. Anesth Analg. 2004;99:833–9.PubMedCrossRefGoogle Scholar
  186. 186.
    Domino KB, Posner KL, Caplan RA, Cheney FW. Awareness during anesthesia: a closed claims analysis. Anesthesiology. 1999;90:1053–61.PubMedCrossRefGoogle Scholar
  187. 187.
    Hoymork SC, Raeder J, Grimsmo B, Steen PA. Bispectral index, serum drug concentrations and emergence associated with individually adjusted target-controlled infusions of remifentanil and propofol for laparoscopic surgery. Br J Anaesth. 2003;91:773–80.PubMedCrossRefGoogle Scholar
  188. 188.
    Buchanan FF, Myles PS, Leslie K, Forbes A, Cicuttini F. Gender and recovery after general anesthesia combined with neuromuscular blocking drugs. Anesth Analg. 2006;102:291–7.PubMedCrossRefGoogle Scholar
  189. 189.
    Buchanan FF, Myles PS, Cicuttini F. Effect of patient sex on general anaesthesia and recovery. Br J Anaesth. 2011;106:832–9.PubMedCrossRefGoogle Scholar
  190. 190.
    Monk TG, Saini V, Weldon BC, Sigl JC. Anesthetic management and one-year mortality after noncardiac surgery. Anesth Analg. 2005;100:4–10.PubMedCrossRefGoogle Scholar
  191. 191.
    Kertai MD, Pal N, Palanca BJ, Lin N, Searleman SA, Zhang L, Burnside BA, Finkel KJ, Avidan MS. Association of perioperative risk factors and cumulative duration of low bispectral index with intermediate-term mortality after cardiac surgery in the B-Unaware Trial. Anesthesiology. 2010;112:1116–27.PubMedCrossRefGoogle Scholar
  192. 192.
    Lindholm ML, Traff S, Granath F, Greenwald SD, Ekbom A, Lennmarken C, Sandin RH. Mortality within 2 years after surgery in relation to low intraoperative bispectral index values and preexisting malignant disease. Anesth Analg. 2009;108:508–12.PubMedCrossRefGoogle Scholar
  193. 193.
    Moller DH, Glass PS. Should a patient’s gender alter the anesthetic plan? Curr Opin Anaesthesiol. 2003;16:379–83.PubMedGoogle Scholar
  194. 194.
    Pleym H, Spigset O, Kharasch ED, Dale O. Gender differences in drug effects: implications for anesthesiologists. Acta Anaesthesiol Scand. 2003;47:241–59.PubMedCrossRefGoogle Scholar
  195. 195.
    Davis C, Fattore L, Kaplan AS, Carter JC, Levitan RD, Kennedy JL. The suppression of appetite and food consumption by methylphenidate: the moderating effects of gender and weight status in healthy adults. Int J Neuropsychopharmacol. 2012;15:181–7.PubMedCrossRefGoogle Scholar
  196. 196.
    Taenzer AH, Clark C, Curry CS. Gender affects report of pain and function after arthroscopic anterior cruciate ligament reconstruction. Anesthesiology. 2000;93:670–5.PubMedCrossRefGoogle Scholar
  197. 197.
    Harmon D, O’Connor P, Gleasa O, Gardiner J. Menstrual cycle irregularity and the incidence of nausea and vomiting after laparoscopy. Anaesthesia. 2000;55:1164–7.PubMedCrossRefGoogle Scholar
  198. 198.
    Myles PS, Hunt JO, Moloney JT. Postoperative ‘minor’ complications. Comparison between men and women. Anaesthesia. 1997;52:300–6.PubMedCrossRefGoogle Scholar
  199. 199.
    Beattie WS, Lindblad T, Buckley DN, Forrest JB. The incidence of postoperative nausea and vomiting in women undergoing laparoscopy is influenced by the day of menstrual cycle. Can J Anaesth. 1991;38:298–302.PubMedCrossRefGoogle Scholar
  200. 200.
    Edwards DJ, Brickley MR, Horton J, Edwards MJ, Shepherd JP. Choice of anaesthetic and healthcare facility for third molar surgery. Br J Oral Maxillofac Surg. 1998;36:333–40.PubMedCrossRefGoogle Scholar
  201. 201.
    Culley DJ, Baxter M, Yukhananov R, Crosby G. The memory effects of general anesthesia persist for weeks in young and aged rats. Anesth Analg. 2003;96:1004–9.PubMedCrossRefGoogle Scholar
  202. 202.
    Culley DJ, Baxter MG, Crosby CA, Yukhananov R, Crosby G. Impaired acquisition of spatial memory 2 weeks after isoflurane and isoflurane-nitrous oxide anesthesia in aged rats. Anesth Analg. 2004;99:1393–7.PubMedCrossRefGoogle Scholar
  203. 203.
    Culley DJ, Baxter MG, Yukhananov R, Crosby G. Long-term impairment of acquisition of a spatial memory task following isoflurane-nitrous oxide anesthesia in rats. Anesthesiology. 2004;100:309–14.PubMedCrossRefGoogle Scholar
  204. 204.
    Mawhinney LJ, de Rivero Vaccari JP, Alonso OF, Jimenez CA, Furones C, Moreno WJ, Lewis MC, Dietrich WD, Bramlett HM. Isoflurane/nitrous oxide anesthesia induces increases in NMDA receptor subunit NR2B protein expression in the aged rat brain. Brain Res. 2011;1431:23–34.PubMedCrossRefGoogle Scholar
  205. 205.
    Eckenhoff RG, Johansson JS, Wei H, Carnini A, Kang B, Wei W, Pidikiti R, Keller JM, Eckenhoff MF. Inhaled anesthetic enhancement of amyloid-beta oligomerization and cytotoxicity. Anesthesiology. 2004;101:703–9.PubMedCrossRefGoogle Scholar
  206. 206.
    Kvolik S, Glavas-Obrovac L, Bares V, Karner I. Effects of inhalation anesthetics halothane, sevoflurane, and isoflurane on human cell lines. Life Sci. 2005;77:2369–83.PubMedCrossRefGoogle Scholar
  207. 207.
    Loop T, Dovi-Akue D, Frick M, Roesslein M, Egger L, Humar M, Hoetzel A, Schmidt R, Borner C, Pahl HL, Geiger KK, Pannen BH. Volatile anesthetics induce caspase-dependent, mitochondria-mediated apoptosis in human T lymphocytes in vitro. Anesthesiology. 2005;102:1147–57.PubMedCrossRefGoogle Scholar
  208. 208.
    Wei H, Kang B, Wei W, Liang G, Meng QC, Li Y, Eckenhoff RG. Isoflurane and sevoflurane affect cell survival and BCL-2/BAX ratio differently. Brain Res. 2005;1037:139–47.PubMedCrossRefGoogle Scholar
  209. 209.
    Matsuoka H, Kurosawa S, Horinouchi T, Kato M, Hashimoto Y. Inhalation anesthetics induce apoptosis in normal peripheral lymphocytes in vitro. Anesthesiology. 2001;95:1467–72.PubMedCrossRefGoogle Scholar
  210. 210.
    Xie Z, Tanzi RE. Alzheimer’s disease and post-operative cognitive dysfunction. Exp Gerontol. 2006;41:346–59.PubMedCrossRefGoogle Scholar
  211. 211.
    Xie Z, Dong Y, Maeda U, Moir R, Inouye SK, Culley DJ, Crosby G, Tanzi RE. Isoflurane-induced apoptosis: a potential pathogenic link between delirium and dementia. J Gerontol A Biol Sci Med Sci. 2006;61:1300–6.PubMedCrossRefGoogle Scholar
  212. 212.
    Xie Z, Dong Y, Maeda U, Moir RD, Xia W, Culley DJ, Crosby G, Tanzi RE. The inhalation anesthetic isoflurane induces a vicious cycle of apoptosis and amyloid beta-protein accumulation. J Neurosci. 2007;27:1247–54.PubMedCrossRefGoogle Scholar
  213. 213.
    Brambrink AM, Evers AS, Avidan MS, Farber NB, Smith DJ, Zhang X, Dissen GA, Creeley CE, Olney JW. Isoflurane-induced neuroapoptosis in the neonatal rhesus macaque brain. Anesthesiology. 2010;112:834–41.PubMedCrossRefGoogle Scholar
  214. 214.
    Culley DJ, Xie Z, Crosby G. General anesthetic-induced neurotoxicity: an emerging problem for the young and old? Curr Opin Anaesthesiol. 2007;20:408–13.PubMedCrossRefGoogle Scholar
  215. 215.
    Bianchi SL, Tran T, Liu C, Lin S, Li Y, Keller JM, Eckenhoff RG, Eckenhoff MF. Brain and behavior changes in 12-month-old Tg2576 and nontransgenic mice exposed to anesthetics. Neurobiol Aging. 2008;29:1002–10.PubMedCrossRefGoogle Scholar
  216. 216.
    Tang JX, Mardini F, Caltagarone BM, Garrity ST, Li RQ, Bianchi SL, Gomes O, Laferla FM, Eckenhoff RG, Eckenhoff MF. Anesthesia in presymptomatic Alzheimer’s disease: a study using the triple-transgenic mouse model. Alzheimers Dement. 2011;7:521–531 e1.PubMedCrossRefGoogle Scholar
  217. 217.
    Le Freche H, Brouillette J, Fernandez-Gomez FJ, Patin P, Caillierez R, Zommer N, Sergeant N, Buee-Scherrer V, Lebuffe G, Blum D, Buee L. Tau phosphorylation and sevoflurane anesthesia: an association to postoperative cognitive impairment. Anesthesiology. 2012;116:779–87.PubMedCrossRefGoogle Scholar
  218. 218.
    Ghirlanda G, Hilcove SA, Pidikiti R, Johansson JS, Lear JD, Degrado WF, Eckenhoff RG. Volatile anesthetic modulation of oligomerization equilibria in a hexameric model peptide. FEBS Lett. 2004;578:140–4.PubMedCrossRefGoogle Scholar
  219. 219.
    Dong Y, Wu X, Xu Z, Zhang Y, Xie Z. Anesthetic isoflurane increases phosphorylated tau levels mediated by caspase activation and Aβ generation. PLoS One. 2012;7:e39386.PubMedCrossRefGoogle Scholar
  220. 220.
    Tang JX, Eckenhoff MF, Eckenhoff RG. Anesthetic modulation of neuroinflammation in Alzheimer’s disease. Curr Opin Anaesthesiol. 2011;24:389–94.PubMedCrossRefGoogle Scholar
  221. 221.
    Monk TG, Weldon BC, Garvan CW, Dede DE, van der Aa MT, Heilman KM, Gravenstein JS. Predictors of cognitive dysfunction after major noncardiac surgery. Anesthesiology. 2008;108:18–30.PubMedCrossRefGoogle Scholar
  222. 222.
    Chan MT, Cheng BC, Lee TM, Gin T. BIS-guided anesthesia decreases postoperative delirium and cognitive decline. J Neurosurg Anesthesiol. 2012. doi: 10.1097/ANA.0b013e3182712fba.
  223. 223.
    Steinmetz J, Funder KS, Dahl BT, Rasmussen LS. Depth of anaesthesia and post-operative cognitive dysfunction. Acta Anaesthesiol Scand. 2010;54:162–8.PubMedCrossRefGoogle Scholar
  224. 224.
    An J, Fang Q, Huang C, Qian X, Fan T, Lin Y, Guo Q. Deeper total intravenous anesthesia reduced the incidence of early postoperative cognitive dysfunction after microvascular decompression for facial spasm. J Neurosurg Anesthesiol. 2011;23:12–7.PubMedCrossRefGoogle Scholar
  225. 225.
    Farag E, Chelune GJ, Schubert A, Mascha EJ. Is depth of anesthesia, as assessed by the Bispectral Index, related to postoperative cognitive dysfunction and recovery? Anesth Analg. 2006;103:633–40.PubMedCrossRefGoogle Scholar
  226. 226.
    Leslie K, Myles PS, Forbes A, Chan MT. The effect of bispectral index monitoring on long-term survival in the B-aware trial. Anesth Analg. 2010;110:816–22.PubMedCrossRefGoogle Scholar
  227. 227.
    Kertai MD, Palanca BJ, Pal N, Burnside BA, Zhang L, Sadiq F, Finkel KJ, Avidan MS. Bispectral index monitoring, duration of bispectral index below 45, patient risk factors, and intermediate-term mortality after noncardiac surgery in the B-Unaware Trial. Anesthesiology. 2011;114:545–56.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Lana J. Mawhinney
    • 1
  • Davita Mabourakh
    • 2
  • Michael C. Lewis
    • 3
  1. 1.The Miami Project to Cure Paralysis, Department of Neurological SurgeryUniversity of Miami Miller School of MedicineMiamiUSA
  2. 2.College of Arts and ScienceUniversity of MiamiMiamiUSA
  3. 3.Graduate Medical EducationUniversity of Miami Miller School of MedicineMiamiUSA

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