Acute Crit Care.  2024 May;39(2):207-213. 10.4266/acc.2024.00591.

Sex or gender differences in treatment outcomes of sepsis and septic shock

• Min SY
• Yong HJ
• Kim D

• KMID: 2557236
• DOI: http://doi.org/10.4266/acc.2024.00591

Abstract

Gender disparities in intensive care unit (ICU) treatment approaches and outcomes are evident. However, clinicians often pay little attention to the importance of biological sex and sociocultural gender in their treatment courses. Previous studies have reported that differences between sexes or genders can significantly affect the manifestation of diseases, diagnosis, clinicians' treatment decisions, scope of treatment, and treatment outcomes in the intensive care field. In addition, numerous reports have suggested that immunomodulatory effects of sex hormones and differences in gene expression from X chromosomes between genders might play a significant role in treatment outcomes of various diseases. However, results from clinical studies are conflicting. Recently, the need for customized treatment based on physical, physiological, and genetic differences between females and males and sociocultural characteristics of society have been increasingly emphasized. However, interest in and research into this field are remarkably lacking in Asian countries, including South Korea. Through this review, we hope to enhance our awareness of the importance of sex and gender in intensive care treatment and research by briefly summarizing several principal issues, mainly focusing on sex and sex hormone-based outcomes in patients admitted to the ICU with sepsis and septic shock.

Keyword

intensive care units; sepsis; septic shock; sex

Reference

1. Canadian Institutes of Health Research. How to integrate sex and gender into research [Internet]. Canadian Institutes of Health Research;2019. [cited 2024 Apr 1]. Available from: https://cihr-irsc.gc.ca/e/50836.html.

2. Shannon G, Jansen M, Williams K, Cáceres C, Motta A, Odhiambo A, et al. Gender equality in science, medicine, and global health: where are we at and why does it matter? Lancet. 2019; 393:560–9.

3. Mauvais-Jarvis F, Bairey Merz N, Barnes PJ, Brinton RD, Carrero JJ, DeMeo DL, et al. Sex and gender: modifiers of health, disease, and medicine. Lancet. 2020; 396:565–82.

4. Regitz-Zagrosek V, Gebhard C. Gender medicine: effects of sex and gender on cardiovascular disease manifestation and outcomes. Nat Rev Cardiol. 2023; 20:236–47.

5. National Institutes of Health. NIH policy and guidelines on the inclusion of women and minorities as subjects in clinical research [Internet]. NIH Central Resource for Grants and Funding Information;2001. [cited 2024 Apr 1]. Available from: https://grants.nih.gov/policy/inclusion/women-and-minorities/guidelines.htm.

6. National Institutes of Health. Consideration of sex as a biological variable in NIH-funded research [Internet]. National Institutes of Health;2015. [cited 2024 Apr 1]. Available from: https://grants.nih.gov/grants/guide/notice-files/not-od-15-102.html.

7. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 2003; 348:1546–54.

8. Campanelli F, Landoni G, Cabrini L, Zangrillo A. Gender differences in septic intensive care unit patients. Minerva Anestesiol. 2018; 84:504–8.

9. Thompson KJ, Finfer SR, Woodward M, Leong RN, Liu B. Sex differences in sepsis hospitalisations and outcomes in older women and men: a prospective cohort study. J Infect. 2022; 84:770–6.

10. Dias SP, Brouwer MC, van de Beek D. Sex and gender differences in bacterial infections. Infect Immun. 2022; 90:e0028322.

11. Grimaldi CM, Hill L, Xu X, Peeva E, Diamond B. Hormonal modulation of B cell development and repertoire selection. Mol Immunol. 2005; 42:811–20.

12. Cui J, Shen Y, Li R. Estrogen synthesis and signaling pathways during aging: from periphery to brain. Trends Mol Med. 2013; 19:197–209.

13. Cooke PS, Nanjappa MK, Ko C, Prins GS, Hess RA. Estrogens in male physiology. Physiol Rev. 2017; 97:995–1043.

14. Nilsson S, Mäkelä S, Treuter E, Tujague M, Thomsen J, Andersson G, et al. Mechanisms of estrogen action. Physiol Rev. 2001; 81:1535–65.

15. Lösel R, Wehling M. Nongenomic actions of steroid hormones. Nat Rev Mol Cell Biol. 2003; 4:46–56.

16. Revankar CM, Cimino DF, Sklar LA, Arterburn JB, Prossnitz ER. A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science. 2005; 307:1625–30.

17. Giannoni E, Guignard L, Knaup Reymond M, Perreau M, Roth-Kleiner M, Calandra T, et al. Estradiol and progesterone strongly inhibit the innate immune response of mononuclear cells in newborns. Infect Immun. 2011; 79:2690–8.

18. Pelekanou V, Kampa M, Kiagiadaki F, Deli A, Theodoropoulos P, Agrogiannis G, et al. Estrogen anti-inflammatory activity on human monocytes is mediated through cross-talk between estrogen receptor ERα36 and GPR30/GPER1. J Leukoc Biol. 2016; 99:333–47.

19. Dupuis ML, Conti F, Maselli A, Pagano MT, Ruggieri A, Anticoli S, et al. The natural agonist of estrogen receptor β silibinin plays an immunosuppressive role representing a potential therapeutic tool in rheumatoid arthritis. Front Immunol. 2018; 9:1903.

20. Rider V, Li X, Peterson G, Dawson J, Kimler BF, Abdou NI. Differential expression of estrogen receptors in women with systemic lupus erythematosus. J Rheumatol. 2006; 33:1093–101.

21. Harding AT, Heaton NS. The impact of estrogens and their receptors on immunity and inflammation during infection. Cancers (Basel). 2022; 14:909.

22. Zellweger R, Wichmann MW, Ayala A, Stein S, DeMaso CM, Chaudry IH. Females in proestrus state maintain splenic immune functions and tolerate sepsis better than males. Crit Care Med. 1997; 25:106–10.

23. Knöferl MW, Angele MK, Schwacha MG, Bland KI, Chaudry IH. Preservation of splenic immune functions by female sex hormones after trauma-hemorrhage. Crit Care Med. 2002; 30:888–93.

24. Diodato MD, Knöferl MW, Schwacha MG, Bland KI, Chaudry IH. Gender differences in the inflammatory response and survival following haemorrhage and subsequent sepsis. Cytokine. 2001; 14:162–9.

25. Xerri A, Gallardo F, Kober F, Mathieu C, Fourny N, Tran TT, et al. Female hormones prevent sepsis-induced cardiac dysfunction: an experimental randomized study. Sci Rep. 2022; 12:4939.

26. Xu Z, Mu S, Liao X, Fan R, Gao W, Sun Y, et al. Estrogen protects against liver damage in sepsis through inhibiting oxidative stress mediated activation of pyroptosis signaling pathway. PLoS One. 2020; 15:e0239659.

27. Trigunaite A, Dimo J, Jørgensen TN. Suppressive effects of androgens on the immune system. Cell Immunol. 2015; 294:87–94.

28. Angele MK, Pratschke S, Hubbard WJ, Chaudry IH. Gender differences in sepsis: cardiovascular and immunological aspects. Virulence. 2014; 5:12–9.

29. Ongaro L, Castrogiovanni D, Giovambattista A, Gaillard RC, Spinedi E. Enhanced proinflammatory cytokine response to bacterial lipopolysaccharide in the adult male rat after either neonatal or prepubertal ablation of biological testosterone activity. Neuroimmunomodulation. 2011; 18:254–60.

30. Rettew JA, Huet-Hudson YM, Marriott I. Testosterone reduces macrophage expression in the mouse of toll-like receptor 4, a trigger for inflammation and innate immunity. Biol Reprod. 2008; 78:432–7.

31. Yu HP, Yang S, Choudhry MA, Hsieh YC, Bland KI, Chaudry IH. Mechanism responsible for the salutary effects of flutamide on cardiac performance after trauma-hemorrhagic shock: upregulation of cardiomyocyte estrogen receptors. Surgery. 2005; 138:85–92.

32. Hsieh YC, Yang S, Choudhry MA, Yu HP, Bland KI, Schwacha MG, et al. Flutamide restores cardiac function after trauma-hemorrhage via an estrogen-dependent pathway through upregulation of PGC-1. Am J Physiol Heart Circ Physiol. 2006; 290:H416–23.

33. Shimizu T, Yu HP, Hsieh YC, Choudhry MA, Suzuki T, Bland KI, et al. Flutamide attenuates pro-inflammatory cytokine production and hepatic injury following trauma-hemorrhage via estrogen receptor-related pathway. Ann Surg. 2007; 245:297–304.

34. Lakbar I, Einav S, Lalevée N, Martin-Loeches I, Pastene B, Leone M. Interactions between gender and sepsis-implications for the future. Microorganisms. 2023; 11:746.

35. Kim J, Kim K, Lee H, Ahn S. Epidemiology of sepsis in Korea: a population-based study of incidence, mortality, cost and risk factors for death in sepsis. Clin Exp Emerg Med. 2019; 6:49–63.

36. Prajapati C, Koivumäki J, Pekkanen-Mattila M, Aalto-Setälä K. Sex differences in heart: from basics to clinics. Eur J Med Res. 2022; 27:241.

37. Chyou JY, Qin H, Butler J, Voors AA, Lam CS. Sex-related similarities and differences in responses to heart failure therapies. Nat Rev Cardiol. 2024; Mar. 8. [Epub]. https://doi.org/10.1038/s41569-024-00996-1.

38. Merdji H, Long MT, Ostermann M, Herridge M, Myatra SN, De Rosa S, et al. Sex and gender differences in intensive care medicine. Intensive Care Med. 2023; 49:1155–67.

39. Molanorouzi K, Khoo S, Morris T. Motives for adult participation in physical activity: type of activity, age, and gender. BMC Public Health. 2015; 15:66.

40. Białas AJ, Kumor-Kisielewska A, Górski P. Ageing, sex, obesity, smoking and COVID-19: truths, myths and speculations. Adv Respir Med. 2020; 88:335–42.

41. Ghazeeri G, Abdullah L, Abbas O. Immunological differences in women compared with men: overview and contributing factors. Am J Reprod Immunol. 2011; 66:163–9.

42. García-Gómez E, González-Pedrajo B, Camacho-Arroyo I. Role of sex steroid hormones in bacterial-host interactions. Biomed Res Int. 2013; 2013:928290.

43. Vázquez-Martínez ER, García-Gómez E, Camacho-Arroyo I, González-Pedrajo B. Sexual dimorphism in bacterial infections. Biol Sex Differ. 2018; 9:27.

44. Park DW, Chun BC, Kim JM, Sohn JW, Peck KR, Kim YS, et al. Epidemiological and clinical characteristics of community-acquired severe sepsis and septic shock: a prospective observational study in 12 university hospitals in Korea. J Korean Med Sci. 2012; 27:1308–14.

45. Pietropaoli AP, Glance LG, Oakes D, Fisher SG. Gender differences in mortality in patients with severe sepsis or septic shock. Gend Med. 2010; 7:422–37.

46. Nachtigall I, Tafelski S, Rothbart A, Kaufner L, Schmidt M, Tamarkin A, et al. Gender-related outcome difference is related to course of sepsis on mixed ICUs: a prospective, observational clinical study. Crit Care. 2011; 15:R151.

47. Sakr Y, Elia C, Mascia L, Barberis B, Cardellino S, Livigni S, et al. The influence of gender on the epidemiology of and outcome from severe sepsis. Crit Care. 2013; 17:R50.

48. Sunden-Cullberg J, Nilsson A, Inghammar M. Sex-based differences in ED management of critically ill patients with sepsis: a nationwide cohort study. Intensive Care Med. 2020; 46:727–36.

49. Adrie C, Azoulay E, Francais A, Clec'h C, Darques L, Schwebel C, et al. Influence of gender on the outcome of severe sepsis: a reappraisal. Chest. 2007; 132:1786–93.

50. Xu J, Tong L, Yao J, Guo Z, Lui KY, Hu X, et al. Association of sex with clinical outcome in critically ill sepsis patients: a retrospective analysis of the large clinical database MIMIC-III. Shock. 2019; 52:146–51.

51. Thompson K, Venkatesh B, Hammond N, Taylor C, Finfer S; on behalf of the ADRENAL Investigators, sex-disaggregated analysis Steering Committee. Sex differences in response to adjunctive corticosteroid treatment for patients with septic shock. Intensive Care Med. 2021; 47:246–8.

52. Banta JE, Joshi KP, Beeson L, Nguyen HB. Patient and hospital characteristics associated with inpatient severe sepsis mortality in California, 2005-2010. Crit Care Med. 2012; 40:2960–6.

53. Madsen TE, Simmons J, Choo EK, Portelli D, McGregor AJ, Napoli AM. The DISPARITY Study: do gender differences exist in Surviving Sepsis Campaign resuscitation bundle completion, completion of individual bundle elements, or sepsis mortality? J Crit Care. 2014; 29:473.

54. van Vught LA, Scicluna BP, Wiewel MA, Hoogendijk AJ, Klein Klouwenberg PM, Ong DS, et al. Association of gender with outcome and host response in critically ill sepsis patients. Crit Care Med. 2017; 45:1854–62.

55. Antequera A, Lopez-Alcalde J, Stallings E, Muriel A, Fernández Félix B, Del Campo R, et al. Sex as a prognostic factor for mortality in critically ill adults with sepsis: a systematic review and meta-analysis. BMJ Open. 2021; 11:e048982.

56. Zhang MQ, Macala KF, Fox-Robichaud A, Mendelson AA, Lalu MM; Sepsis Canada National Preclinical Sepsis Platform. Sex- and gender-dependent differences in clinical and preclinical sepsis. Shock. 2021; 56:178–87.

57. Frink M, Pape HC, van Griensven M, Krettek C, Chaudry IH, Hildebrand F. Influence of sex and age on mods and cytokines after multiple injuries. Shock. 2007; 27:151–6.

58. May AK, Dossett LA, Norris PR, Hansen EN, Dorsett RC, Popovsky KA, et al. Estradiol is associated with mortality in critically ill trauma and surgical patients. Crit Care Med. 2008; 36:62–8.

59. Tsang G, Insel MB, Weis JM, Morgan MA, Gough MS, Frasier LM, et al. Bioavailable estradiol concentrations are elevated and predict mortality in septic patients: a prospective cohort study. Crit Care. 2016; 20:335.

60. Feng JY, Liu KT, Abraham E, Chen CY, Tsai PY, Chen YC, et al. Serum estradiol levels predict survival and acute kidney injury in patients with septic shock: a prospective study. PLoS One. 2014; 9:e97967.

61. Reade MC, Yende S, D'Angelo G, Kong L, Kellum JA, Barnato AE, et al. Differences in immune response may explain lower survival among older men with pneumonia. Crit Care Med. 2009; 37:1655–62.

62. Wang HE, Shapiro NI, Griffin R, Safford MM, Judd S, Howard G. Inflammatory and endothelial activation biomarkers and risk of sepsis: a nested case-control study. J Crit Care. 2013; 28:549–55.

63. Modra LJ, Higgins AM, Abeygunawardana VS, Vithanage RN, Bailey MJ, Bellomo R. Sex differences in treatment of adult intensive care patients: a systematic review and meta-analysis. Crit Care Med. 2022; 50:913–23.

64. Todorov A, Kaufmann F, Arslani K, Haider A, Bengs S, Goliasch G, et al. Gender differences in the provision of intensive care: a Bayesian approach. Intensive Care Med. 2021; 47:577–87.