Kaplan-Meier time-to-event analysis revealed that sex-based differences in mortality occurred early after injury (log-rank = 0.007) (Fig. 1).
An increasing amount of data from laboratory studies suggests sex-related outcome differences after severe trauma. Clinical studies investigating differences in sex and trauma outcomes have produced mixed results. Several studies have shown that women have a significantly lower risk of death and were less likely than men to develop life-threatening complications such as acute respiratory distress syndrome, pneumonia, sepsis, and multiple organ failure (9–13, 26, 27). However, other studies (14–17) revealed that there were no sex-based differences with respect to the development of serious complications or decreased mortality after blunt trauma. The explanation for these conflicting results in clinical studies is still unknown. One possible contribution to variability is race-based differences. We show here in an Asian population within China that mortality is significantly lower in young females after severe trauma when compared with males.
Studies that characterize race-based differences after trauma are limited. A study of functional outcome differences among pediatric traumatic brain injury patients in a national US database suggested that black children had worse clinical and functional outcomes at discharge when compared with equivalently injured white children (24). A study to identify the effect of race and insurance status on trauma mortality demonstrated that race and insurance status each independently predict outcome disparities after trauma (22). This study concluded that, even without considering insurance status, race is still an independent factor influencing prognosis in trauma patients. We recently reported (23) the strength of sex-based outcome differences across different racial groups, which suggested that an exaggerated survival advantage was afforded to Asian females relative to Asian males when compared with whites, Hispanics, and blacks in a US population study. The results reported here confirm these preliminary results and show an even more exaggerated sexual dimorphism after severe trauma than that found in our initial study when studying a Chinese cohort of Asian patients. Chinese females exhibited a 62% reduction in mortality compared with equivalent males. Although NI rates did not vary between the sexes, our results further show a possible racial specificity in sex-based outcome differences in trauma patients. One explanation is that the different immune responses to infections associated with sex-related polymorphisms and the different sex hormone levels and effects in men and women might potentially alter the outcomes of infections (28).
The present study showed that only females younger than 50 years had a statistically significant survival advantage compared with males younger than 50 years and that there was no significant difference in patients older than 50 years. This is consistent with previous clinical studies (10, 11). At approximately 50 years old, most women will have experienced changes consistent with menopause. Therefore, these results suggest a contribution of sex hormones for the observed differences in mortality. After menopause, a marked reduction of serum estrogen levels occurs in women (29). Administration of 17β-estradiol, the primary circulating estrogen, has been shown to improve the hepatocellular and cardiovascular organ depression in males after trauma-hemorrhage (30–33). Laboratory studies also show that only proestrus (when estrogen levels are at the peak) animals experience a protective effect against mortality after trauma-hemorrhage (34, 35). Age also influences the levels of testosterone (36–38). This is important because laboratory studies indicated that testosterone or its derivatives exert an adverse effect after injury and lead to worse outcomes for males (39). Males have a significantly higher mortality after injury and are more susceptible to develop subsequent sepsis than females under such conditions (34). Castration or administration of a testosterone receptor antagonist also prevents suppression in immune, hepatocellular, and cardiovascular functions (40, 41). Interestingly, clinical studies (42) revealed that estradiol was significantly elevated in nonsurvivors compared with survivors. Similar research by May et al. (43) also showed that an estradiol level of 100 pg/mL was associated with a 4.6 times greater mortality after severe trauma compared with a reference estradiol level of 45 pg/mL. However, these two studies tested sex hormones only at one time point (48 h after injury) and did not address dynamic changes in hormone levels. We also did not measure hormone levels and therefore can only speculate that hormonal status is one of the factors.
Although ours was a single-center study, the patients studied had high homogeneity and comparability. This analysis is limited by its relative small sample size; therefore, our ability to conduct further comparisons between sexes based on other subgroups is limited. In addition, patients with isolated head injury were not excluded in this analysis, and this may have influenced the final outcomes. However, isolated head injury accounted for only a small proportion of all trauma patients.
The present study also demonstrates that sexual dimorphism was only found in patients with an ISS of 25 or higher and not in patients with an ISS less than 25. Sperry et al. (23) also showed that protection of female trauma patients against mortality was strongest in those with severe injury. We speculate that minor trauma does not typically lead to exaggerated or sustained immune alterations and sex-based outcome differences may be more obvious in severe blunt trauma patients.
In conclusion, the current study showed an exaggerated sexual dimorphism in severely injured Chinese patients. Moreover, this difference only exists in those patients younger than 50 years and with ISS of 25 or higher. These results show a possible strong racial influence on the injury response in humans. One potential contributor to the higher survival rates in females could be the role of sex hormones; however, other genetic factors cannot be excluded. Gene association studies and future investigation of circulating biomarkers comparing Asian with non-Asian populations could lead to insights on factors that determine sex-based differences on trauma outcomes.
1. Angele MK, Knöferl MW, Ayala A, Bland KI, Chaudry IH: Testosterone and estrogen differently effect Th1 and Th2 cytokine release following trauma-haemorrhage. Cytokine
16 (1): 22–30, 2001.
2. Jarrar D, Wang P, Cioffi WG, Bland KI, Chaudry IH: The female reproductive cycle is an important variable in the response to trauma-hemorrhage. Am J Physiol Heart Circ Physiol
279 (3): H1015–H1021, 2000.
3. Diodato MD, Knöferl MW, Schwacha MG, Bland KI, Chaudry IH: Gender differences in the inflammatory response and survival following haemorrhage and subsequent sepsis. Cytokine
14 (3): 162–169, 2001.
4. Angele MK, Schwacha MG, Ayala A, Chaudry IH: Effect of gender and sex hormones on immune responses following shock. Shock
14 (2): 81–90, 2000.
5. Knoferl MW, Jarrar D, Angele MK, Ayala A, Schwacha MG, Bland KI, Chaudry IH: 17 beta-Estradiol normalizes immune responses in ovariectomized females after trauma-hemorrhage. Am J Physiol Cell Physiol
281 (4): C1131–C1138, 2001.
6. Jarrar D, Wang P, Knoferl MW, Kuebler JF, Cioffi WG, Bland KI, Chaudry IH: Insight into the mechanism by which estradiol improves organ functions after trauma-hemorrhage. Surgery
128 (2): 246–252, 2000.
7. Deitch EA, Feketeova E, Lu Q, Zaets S, Berezina TL, Machiedo GW, Hauser CJ, Livingston DH, Xu DZ: Resistance of the female, as opposed to the male, intestine to I/R-mediated injury is associated with increased resistance to gut-induced distant organ injury. Shock
29 (1): 78–83, 2008.
8. Knoferl MW, Angele MK, Diodato MD, Schwacha MG, Ayala A, Cioffi WG, Bland KI, Chaudry IH: Female sex hormones regulate macrophage function after trauma-hemorrhage and prevent increased death rate from subsequent sepsis. Ann Surg
235 (1): 105–112, 2002.
9. Haider AH, Crompton JG, Oyetunji T, Stevens KA, Efron DT, Kieninger AN, Chang DC, Cornwell EE 3rd, Haut ER: Females have fewer complications and lower mortality following trauma than similarly injured males: a risk adjusted analysis of adults in the National Trauma Data Bank. Surgery
146 (2): 308–315, 2009.
10. Wohltmann CD, Franklin GA, Boaz PW, Luchette FA, Kearney PA, Richardson JD, Spain DA: A multicenter evaluation of whether gender dimorphism affects survival after trauma. Am J Surg
181 (4): 297–300, 2001.
11. Haider AH, Crompton JG, Chang DC, Efron DT, Haut ER, Handly N, Cornwell EE 3rd: Evidence of hormonal basis for improved survival among females with trauma-associated shock: an analysis of the National Trauma Data Bank. J Trauma
69 (3): 537–540, 2010.
12. Sperry JL, Nathens AB, Frankel HL, Vanek SL, Moore EE, Maier RV, Minei JP: Characterization of the gender dimorphism after injury and hemorrhagic shock: are hormonal differences responsible? Crit Care Med
36 (6): 1838–1845, 2008.
13. Magnotti LJ, Fischer PE, Zarzaur BL, Fabian TC, Croce MA: Impact of gender on outcomes after blunt injury: a definitive analysis of more than 36,000 trauma patients. J Am Coll Surg
206 (5): 984–991, 2008.
14. Rappold JF, Coimbra R, Hoyt DB, Potenza BM, Fortlage D, Holbrook T, Minard G: Female gender does not protect blunt trauma patients from complications and mortality. J Trauma
53 (3): 436–441, 2002.
15. Bowles BJ, Roth B, Demetriades D: Sexual dimorphism in trauma? A retrospective evaluation of outcome. Injury
34 (1): 27–31, 2003.
16. Napolitano LM, Greco ME, Rodriguez A, Kufera JA, West RS, Scalea TM: Gender differences in adverse outcomes after blunt trauma. J Trauma
50 (2): 274–280, 2001.
17. Coimbra R, Hoyt DB, Potenza BM, Fortlage D, Hollingsworth-Fridlund P: Does sexual dimorphism influence outcome of traumatic brain injury patients? The answer is no! J Trauma
54 (4): 689–700, 2003.
18. Pathak EB, Sloan MA: Recent racial/ethnic disparities in stroke hospitalizations and outcomes for young adults in Florida, 2001–2006. Neuroepidemiology
32 (4): 302–311, 2009.
19. Bertoni AG, Goonan KL, Bonds DE, Whitt MC, Goff DC Jr, Brancati FL: Racial and ethnic disparities in cardiac catheterization for acute myocardial infarction in the United States, 1995–2001. J Natl Med Assoc
97 (3): 317–323, 2005.
20. Lucas FL, Stukel TA, Morris AM, Siewers AE, Birkmeyer JD: Race and surgical mortality in the United States. Ann Surg
243 (2): 281–286, 2006.
21. Ghafoori B, Barragan B, Tohidian N, Palinkas L: Racial and ethnic differences in symptom severity of PTSD, GAD, and depression in trauma-exposed, urban, treatment-seeking adults. J Trauma Stress
25 (1): 106–110, 2012.
22. Haider AH, Chang DC, Efron DT, Haut ER, Crandall M, Cornwell EE 3rd: Race and insurance status as risk factors for trauma mortality. Arch Surg
143 (10): 945–949, 2008.
23. Sperry JL, Vodovotz Y, Ferrell RE, Namas R, Chai YM, Feng QM, Jia WP, Forsythe RM, Peitzman AB, Billiar TR: Racial disparities and sex-based outcomes differences after severe injury. J Am Coll Surg
214 (6): 973–980, 2012.
24. Haider AH, Efron DT, Haut ER, DiRusso SM, Sullivan T, Cornwell EE 3rd: Black children experience worse clinical and functional outcomes after traumatic brain injury: an analysis of the National Pediatric Trauma Registry. J Trauma
62 (5): 1259–1262, 2007.
25. Young MF, Hern HG, Alter HJ, Barger J, Vahidnia F: Racial differences in receiving morphine among prehospital patients with blunt trauma. J Emerg Med
45 (1): 46–52, 2013.
26. Gannon CJ, Pasquale M, Tracy JK, McCarter RJ, Napolitano LM: Male gender is associated with increased risk for postinjury pneumonia. Shock
21 (5): 410–414, 2004.
27. Frink M, Pape H-C, van Griensven M, Krettek C, Chaudry IH, Hildebrand F: Influence of sex and age on MODS and cytokines after multiple injuries. Shock
27 (2): 151–156, 2007.
28. Combes A, Luyt C-E, Trouillet J-L, Nieszkowska A, Chastre J: Gender impact on the outcomes of critically ill patients with nosocomial infections. Crit Care Med
37 (9): 2506–2511, 2009.
29. Judd HL: Hormonal dynamics associated with the menopause. Clin Obstet Gynecol
19 (4): 775–788, 1976.
30. Knoferl MW, Diodato MD, Angele MK, Ayala A, Cioffi WG, Bland KI, Chaudry IH: Do female sex steroids adversely or beneficially affect the depressed immune responses in males after trauma-hemorrhage? Arch Surg
135 (4): 425, 2000.
31. Mizushima Y, Wang P, Jarrar D, Cioffi WG, Bland KI, Chaudry IH: Estradiol administration after trauma-hemorrhage improves cardiovascular and hepatocellular functions in male animals. Ann Surg
232 (5): 673–679, 2000.
32. Kher A, Wang M, Tsai BM, Pitcher JM, Greenbaum ES, Nagy RD, Patel KM, Wairiuko GM, Markel TA, Meldrum DR: Sex differences in the myocardial inflammatory response to acute injury. Shock
23 (1): 1–10, 2005.
33. Ba ZF, Hsu JT, Chen J, Kan WH, Schwacha MG, Chaudry IH: Systematic analysis of the salutary effect of estrogen on cardiac performance after trauma-hemorrhage. Shock
30 (5): 585–589, 2008.
34. Choudhry MA, Schwacha MG, Hubbard WJ, Kerby JD, Rue LW, Bland KI, Chaudry IH: Gender differences in acute response to trauma-hemorrhage. Shock
24 (Suppl 1): 101–106, 2005.
35. Krausz MM, Bashenko Y, Hirsh M: Improved survival in uncontrolled hemorrhagic shock induced by massive splenic injury in the proestrus phase of the reproductive cycle in the female rat. Shock
20 (5): 444–448, 2003.
36. Leifke E, Gorenoi V, Wichers C, Von Zur Mühlen A, Von Büren E, Brabant G: Age-related changes of serum sex hormones, insulin-like growth factor-1 and sex-hormone binding globulin levels in men: cross-sectional data from a healthy male cohort. Clin Endocrinol
53 (6): 689–695, 2000.
37. Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR: Longitudinal effects of aging on serum total and free testosterone levels in healthy men. J Clin Endocrinol Metab
86 (2): 724–731, 2001.
38. Matsumoto AM: Andropause clinical implications of the decline in serum testosterone levels with aging in men. J Gerontol A Biol Sci Med Sci
57 (2): M76–M99, 2002.
39. Schneider CP, Nickel EA, Samy AT, Schwacha MG, Cioffi WG, Bland KI, Chaudry IH: The aromatase inhibitor, 4-hydroxyandrostenedione, restores immune responses following trauma-hemorrhage in males and decreases mortality from subsequent sepsis. Shock
14 (3): 347–353, 2000.
40. Chaudry IH, Samy T, Schwacha MG, Wang P, Rue LW, Bland KI: Endocrine targets in experimental shock. J Trauma Injury Infect Crit Care
54 (5): S118–S125, 2003.
41. Samy AT, Schwacha MG, Cioffi WG, Bland KI, Chaudry IH: Androgen and estrogen receptors in splenic T lymphocytes: effects of flutamide and trauma-hemorrhage. Shock
14 (4): 465–470, 2000.
42. Dossett LA, Swenson BR, Heffernan D, Bonatti H, Metzger R, Sawyer RG, May AK: High levels of endogenous estrogens are associated with death in the critically injured adult. J Trauma
64 (3): 580, 2008.
43. May AK, Dossett LA, Norris PR, Hansen EN, Dorsett RC, Popovsky KA, Sawyer RG: Estradiol is associated with mortality in critically ill trauma and surgical patients. Crit Care Med
36 (1): 62, 2008.