After comparing the variables between 1-year survivors and non-survivors in the univariate analysis (see Table 4), we chose to input sex, race, first ICU service, marital status, insurance, admission location, SAPS and SOFA scores but not admission type into the Cox proportional hazards regression model (see Fig. 2). Our multivariate regression model revealed relations between sex and 1-year mortality; the risk of death within 1 year in men was 0.083-times higher than that in women (P = 0.031, OR = 1.083, 95% CI 1.007–1.167). In addition, advanced age and higher admission SAPS and SOFA score were correlated with increased mortality risk within 1 year (P < 0.001).
At present, there are many studies on the relationship between sex and clinical outcomes in patients with sepsis, but the results are still controversial. Hence, it is necessary to further study this problem using a database. All data in the MIMIC database are directly imported by the medical record system or recorded by the medical staff. We then extracted the relevant data according to our research requirements; the only inclusion criterion was an adult patient diagnosed with sepsis, irrespective of his or her primary disease, disease severity, and special treatment. Data storage and assessment were performed by different teams. Since data were already recorded in the database before we formed the research plan, our subjective consciousness did not interfere with patient inclusion and treatment, which ensures that our data are true and that our results are credible. However, selection bias or subjective interference were difficult to avoid in previous retrospective studies and may affect the research results to some extent. In addition, the population number in our research study is four times or more than that in previous studies, and our study duration was also longer. Therefore, some of the confounding factors are more balanced among the two groups of men and women. Animal studies have also indicated that females appear to have a survival advantage in terms of both immunologic and cardiovascular responses (15).
After comprehensive analysis of our data and related literature, we concluded that the difference in 1-year mortality between men and women may be due to postintensive care syndrome (PICS). PICS describes new or worse health problems after critical illness that remain after patients leave the hospital (21). These problems can be related to the body, thoughts, feelings, or mind of patients and may cause physical weakness and affect disease recovery, further influencing the long-term survival rate of patients. Some surveys have shown that the incidence of PICS in males is significantly higher than that in females (22). Sepsis, mechanical ventilation, and invasive operation are high-risk factors for PICS occurrence (23). As mentioned above, male patients are more likely to receive more aggressive treatment in the ICU, including mechanical ventilation, deep venous and artery puncture, and dialysis, than female patients. These treatments also increase the risk of PICS occurrence in male patients.
At present, the clinical interpretation of sex differences in the outcome of sepsis is still undetermined. The mainstream view regards the difference in the outcome of sepsis based on sex to be caused by different levels of hormones in the body (24, 25). Animal studies have confirmed that oestrogen, especially oestradiol, can inhibit the inflammatory response and regulate the immune system to achieve a balance of inflammatory and anti-inflammatory reactions and promote the repair of damaged tissues, thereby protecting the organs (26, 27). Oestrogen has also been proven to have a direct protective effect on vascular endothelial cells (VECs), which play an important role in microcirculation. It was reported that oestrogen can promote the growth of VECs and protect the normal function of blood vessels (28). Oestrogen can also inhibit endothelial cell apoptosis, induce endothelial cell proliferation and migration, and promote microvessel regeneration (29). In addition to the effect of oestrogen on the inflammatory response, whether the protective effect of oestrogen on endothelial cells underlies the differences in sex-based sepsis outcomes requires more scientists to investigate.
Although our research is based on a large, diverse population, this is actually a retrospective single-center study. Limited by our current capabilities and the extent to which the database can be used, our research discovered a phenomenon but cannot fully explain its pathophysiological mechanism. The inflammatory response has a strong effect on the pathogenesis of sepsis and is closely related to the mortality rate. However, in this study, we did not extract indicators of the inflammatory response, such as the level of inflammatory factors, in patients. Therefore, we cannot directly compare the inflammatory response between male and female patients. In patients with sepsis, the indicators of VEC function are not routinely tested. Thus, we should focus on whether there is a difference in endothelial cell function between male and female patients with sepsis in a future study.
The mechanism of the relationship between sex and clinical outcomes in patients with sepsis also requires further study. A large number of animals and molecular experiments must be carried out to discover the relevant mechanisms, as an understanding of these mechanisms will be of great significance for the prevention and treatment of sepsis.
The clinical outcome in women with sepsis is better than that in men with sepsis in terms of mortality and the length of hospitalization and ICU stay.
1. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Crit Care Med
45 3:486–552, 2017.
2. Vincent JL, Marshall JC, Namendys-Silva SA, Francois B, Martin-Loeches I, Lipman J, Reinhart K, Antonelli M, Pickkers P, Njimi H, et al. Assessment of the worldwide burden of critical illness: The intensive care over nations (ICON) audit. Lancet Respir Med
2 5:380–386, 2014.
3. Sakr Y, Moreira CL, Rhodes A, Ferguson ND, Kleinpell R, Pickkers P, Kuiper MA, Lipman J, Vincent JL. The impact of hospital and ICU
organizational factors on outcome in critically ill patients: Results from the Extended Prevalence of Infection in Intensive Care study. Crit Care Med
43 3:519–526, 2015.
4. van Vught LA, Klein Klouwenberg PM, Spitoni C, Scicluna BP, Wiewel MA, Horn J, Schultz MJ, Nurnberg P, Bonten MJ, Cremer OL, et al. Incidence, risk factors, and attributable mortality
of secondary infections in the intensive care unit
after admission for sepsis. JAMA
315 14:1469–1479, 2016.
5. Geurs TL, Hill EB, Lippold DM, French AR. Sex differences in murine susceptibility to systemic viral infections. J Autoimmun
38 (2–3):J245–J253, 2012.
6. Berletch JB, Yang F, Xu J, Carrel L, Disteche CM. Genes that escape from X inactivation. Hum Genet
130 2:237–245, 2011.
7. Arck PC, Hecher K. Fetomaternal immune cross-talk and its consequences for maternal and offspring's health. Nat Med
19 5:548–556, 2013.
8. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med
348 16:1546–1554, 2003.
9. Nachtigall I, Tafelski S, Rothbart A, Kaufner L, Schmidt M, Tamarkin A, Kartachov M, Zebedies D, Trefzer T, Wernecke KD, et al. Gender
-related outcome difference is related to course of sepsis on mixed ICUs: a prospective, observational clinical study. Crit Care
15 3:R151, 2011.
10. Nasir N, Jamil B, Siddiqui S, Talat N, Khan FA, Hussain R. Mortality
in Sepsis and its relationship with Gender
. Pak J Med Sci
31 5:1201–1206, 2015.
11. van Vught LA, Scicluna BP, Wiewel MA, Hoogendijk AJ, Klein Klouwenberg PMC, Ong DSY, Cremer OL, Horn J, Franitza M, Toliat MR, et al. Association of gender
with outcome and host response in critically ill sepsis patients. Crit Care Med
45 11:1854–1862, 2017.
12. Johnson AE, Pollard TJ, Shen L, Lehman LW, Feng M, Ghassemi M, Moody B, Szolovits P, Celi LA, Mark RG. MIMIC
-III, a freely accessible critical care database. Sci Data
13. Goldberger AL, Amaral LA, Glass L, Hausdorff JM, Ivanov PC, Mark RG, Mietus JE, Moody GB, Peng CK, Stanley HE. PhysioBank, PhysioToolkit, and PhysioNet: Components of a new research resource for complex physiologic signals. Circulation
101 23:E215–E220, 2000.
14. Johnson AE, Stone DJ, Celi LA, Pollard TJ. The MIMIC
Code Repository: enabling reproducibility in critical care research. J Am Med Inform Assoc
25 1:32–39, 2018.
15. Kuebler JF, Jarrar D, Toth B, Bland KI, Rue L 3rd, Wang P, Chaudry IH. Estradiol administration improves splanchnic perfusion following trauma-hemorrhage and sepsis. Arch Surg
137 1:74–79, 2002.
16. Sakr Y, Elia C, Mascia L, Barberis B, Cardellino S, Livigni S, Fiore G, Filippini C, Ranieri VM. The influence of gender
on the epidemiology of and outcome from severe sepsis. Crit Care
17 2:R50, 2013.
17. Samuelsson C, Sjoberg F, Karlstrom G, Nolin T, Walther SM. Gender
differences in outcome and use of resources do exist in Swedish intensive care, but to no advantage for women of premenopausal age. Crit Care
18. Adrie C, Azoulay E, Francais A, Clec’h C, Darques L, Schwebel C, Nakache D, Jamali S, Goldgran-Toledano D, Garrouste-Orgeas M, et al. Influence of gender
on the outcome of severe sepsis: A reappraisal. Chest
132 6:1786–1793, 2007.
19. 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
? J Crit Care
29 3:e7–e11, 2014.
20. Esper AM, Moss M, Lewis CA, Nisbet R, Mannino DM, Martin GS. The role of infection and comorbidity: Factors that influence disparities in sepsis. Crit Care Med
34 10:2576–2582, 2006.
21. Needham DM, Davidson J, Cohen H, Hopkins RO, Weinert C, Wunsch H, Zawistowski C, Bemis-Dougherty A, Berney SC, Bienvenu OJ, et al. Improving long-term outcomes after discharge from intensive care unit
: report from a stakeholders’ conference. Crit Care Med
40 2:502–509, 2012.
22. Hogue CW Jr, Sundt T 3rd, Barzilai B, Schecthman KB, Dávila-Román VG. Cardiac and neurologic complications identify risks for mortality
for both men and women undergoing coronary artery bypass graft surgery. Anesthesiology
95 5:1074–1078, 2001.
23. Weinert CR, Sprenkle M. Post-ICU
consequences of patient wakefulness and sedative exposure during mechanical ventilation. Intensive Care Med
34 1:82–90, 2008.
24. Sharawy N, Pavlovic D, Wendt M, Cerny V, Lehmann C. Evaluation of the effects of gender
and estradiol treatment on the intestinal microcirculation during experimental sepsis. Microvasc Res
82 3:397–403, 2011.
25. Plackett TP, Cory RD, Jessica LP, Richard LG, Elizabeth JK. Effects of estrogen on bacterial clearance and neutrophil response after combined burn injury and wound infection. J Burn Care Res
37 5:328–333, 2016.
26. Hwang TL, Yang YM. Sex differences in response to immunonutrition in sepsis. Nutrition
24 (7–8):761–766, 2008.
27. Jia YL, Liu X, Yan JY, Chong LM, Li L, Ma AC, Zhou L, Sun ZY. The alteration of inflammatory markers and apoptosis on chronic prostatitis induced by estrogen and androgen. Int Urol Nephrol
47 1:39–46, 2015.
28. Knowlton AA, Lee AR. Estrogen and the cardiovascular system. Pharmacol Ther
135 1:54–70, 2012.
29. Montt-Guevara MM, Palla G, Spina S, Bernacchi G, Cecchi E, Campelo AE, Shortrede JE, Canu A, Simoncini T. Regulatory effects of estetrol on the endothelial plasminogen pathway and endothelial cell migration. Maturitas