Significant Sex-Based Outcome Differences in Severely Injured Chinese Trauma Patients
Yang, Kai-Chao*; Zhou, Min-Jie*; Sperry, Jason L.†; Rong, Liu*; Zhu, Xiao-Guang*; Geng, Lei*; Wu, Wei*; Zhao, Gang*; Billiar, Timothy R.†; Feng, Qi-Ming*
*Department of Emergency Medicine, Shanghai Jiao Tong University Affiliated Sixth People’;s Hospital, Shanghai, China; and †Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
Received 12 Jan 2014; first review completed 5 Feb 2014; accepted in final form 5 Mar 2014
Address reprint requests to Qi-Ming Feng, MD, Department of Emergency Medicine, Shanghai Jiao Tong University Affiliated Sixth People’;s Hospital, No. 600 Yishan Rd, Xuhui District, Shanghai 200233, China. E-mail: firstname.lastname@example.org.
This study was supported by the Shanghai Committee of Science and Technology, China (grant no. 12410710700).
ABSTRACT: A body of experimental evidence suggests that the female sex is associated with a lower risk of mortality after trauma-hemorrhage. However, controversy remains regarding the mechanism responsible for these differences and if basic science findings correspond to clinical differences. Racial disparities in trauma outcomes have also been increasingly described. Until now, research on the association between sex and trauma patient outcomes mainly focused on patients in Europe and the United States. Our research attempted to determine whether the female sex is associated with a survival advantage among severely injured Chinese trauma patients. A retrospective analysis of data derived from the Emergency Intensive Care Unit of the Shanghai Sixth People’;s Hospital Acute Trauma Center during 2010 to 2013 was performed to characterize differences in sex-based outcomes after severe blunt trauma. The patient study cohort (858 Asian subjects) was then stratified by age and injury severity (using the Injury Severity Score [ISS]). Crude and adjusted odds ratios (ORs) were calculated to evaluate the association between sex and nosocomial infection rate and hospitalized mortality, both overall and by age and ISS category subgroups. Among all trauma patients, females had a significantly lower risk of in-hospital mortality compared with males (OR, 0.41; 95% confidence interval [95% CI], 0.20 – 0.85). This difference was most apparent for patients younger than 50 years (OR, 0.31; 95% CI, 0.12 – 0.82) and the group with ISS scores of 25 or higher (OR, 0.39; 95% CI, 0.17 – 0.91). No differences in the development of nosocomial infections between sexes were seen among the overall patient group and subgroups. This study revealed a statistically significant association between sex and mortality among severe blunt trauma patients, particularly those patients younger than 50 years and with ISSs of 25 or higher. Women had significantly lower mortality than men after severe blunt trauma. These results highlight the important role of sex hormones and sex-based outcome differences after severe traumatic injury in the Chinese population.
The role of sex (male versus female) and its potential impact on mortality after blunt trauma have been debated for many years. Laboratory studies have confirmed that the female sex is associated with an obvious survival advantage after trauma-hemorrhage (1–8). However, clinical studies have yielded conflicting results. Several articles have revealed that females have a lower overall mortality after blunt trauma (9–13). However, other studies have failed to show an association between sex and mortality risk in injured patients (14–17). Ethnic differences have been documented in other diseases (18–21). Recently, racial disparities have also been increasingly described for postinjury functional outcomes (22–25). However, until now, studies on the association between sex and outcomes after traumatic injury mainly focused on patients in Europe and the United States; few articles have focused on trauma in other regions. We recently reported (23) that sex-based outcome differences postinjury were varied when stratified by race. The relatively small cohort of trauma patients of Asian descent in our previous US-based study was shown to have an exaggerated sexual dimorphism for the risk of mortality as compared with whites, blacks, and Hispanics. In this study, however, the racial demographic data collection lacked specificity. The Asian demographic represents many different racial groups, which may influence the outcomes of the analysis. Here we extended our previous analysis by comparing outcomes in terms of mortality and development of nosocomial infections (NIs) in 858 trauma patients composed of Han Chinese. We show that female sex is associated with an independent lower risk of mortality among Chinese trauma patients who were significantly injured. These findings confirm the strong association between sex and outcomes in trauma in an Asian population.
MATERIALS AND METHODS
We retrospectively analyzed data derived from the Emergency Intensive Care Unit of the Shanghai Sixth People’;s Hospital Acute Trauma Center during the 2010 to 2013 period and characterized sex-based outcome differences after severe blunt trauma and investigated potential mechanisms responsible for these differences. We first selected injured adults (aged >16 years) who experienced significant blunt trauma (Injury Severity Score [ISS], ≥16) who survived beyond 24 h from the time of injury. Pregnant women and patients who received hormone replacement therapy were excluded from the study. The study cohort was further characterized after being stratified by age (<50 vs. ≥50 years) and ISS (16 ≤ ISS < 25 vs. ISS ≥ 25).
The collected demographics and injury characteristics included sex, age, body mass index (BMI), injury mechanism, injury severity (ISS), Abbreviated Injury Scale (AIS) scores of all anatomy sites, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, presenting systolic blood pressure (SBP), presenting Glasgow Coma Scale (GCS) score, presence of hypotension on arrival (SBP, ≤90 mmHg), initial base excess, blood transfusion at 12 h, the requirement of emergency operation intervention, and preinjury comorbidities (diabetes and cardiac, pulmonary, liver, and kidney). Outcomes of interest included the rate of NI and in-hospital mortality. The definition of preinjury comorbidities corresponded with related chronic disease diagnostic guidelines or patients who had any history of chronic diseases and received the appropriate drug treatment.
All preinjury disease information was obtained from patient medical records, which contained information from referring physician reports, patient and family interviews, or past medical records. The diagnosis of NI was based on the CDC Definitions of Nosocomial Infections. All patients were treated by an attending physician according to Advanced Trauma Life Support guidelines and standard treatment protocol of critically ill patients.
Student t test was used to compare continuous variables, and chi-square or Fisher exact test was used for categorical variables. Multivariable logistic regression model was used to determine the independent risks of mortality associated with sex (female versus male) after controlling for important confounders in the cohort. In addition to sex, our regression model included and controlled for differences in age, BMI, injury mechanism, ISS, head/neck AIS, APACHE II score, presenting GCS, hypotension on arrival (SBP, ≤90 mmHg), preinjury comorbidities, initial base excess, blood transfusion at 12 h, and the requirement of operative intervention. A stratified analysis using the same regression models was then performed to characterize differences in the strength of the sexual dimorphism across age and injury severity groups. Finally, Kaplan-Meier time-to-event analysis and log-rank comparison for mortality were conducted to characterize the time course for which these events occurred across females and males. Data were recorded as mean ± SD or percentage. The logistic regression analysis results are presented as odds ratios (ORs) with 95% confidence intervals (95% CIs). Outcomes were considered statistically significant at a value of P ≤ 0.05. Statistical analyses were performed using SPSS 19.0 (IBM SPSS).
A total of 858 patients met inclusion criteria and represent the study cohort. Of the 858 patients during the period of the study, 73.7% of patients were male (n = 616). The mean age for males was 45.4 ± 14.3 years and 45.9 ± 16.4 years for females, and all were ethnically of Asian descent. This patient cohort had significant injuries, with a mean ISS of 24.6 ± 8.0. Traffic accidents accounted for the injuries in 62.9% of the patients and falls in 33.6%, and the mean blood transfusion within the first 12 h postinjury were 3.0 ± 2.5 units of packed red blood cells. An emergency operation was performed in 14.6% of patients. Males and females were clinically similar in age, BMI, injury mechanism, presenting SBP, APACHE II score, initial base excess, presenting GCS score, and presence of hypotension on arrival (Table 1). The overall mortality and NI rates were 7.7% and 15.4%, respectively. Among patients who developed NI, pneumonia represented the most common, accounting for 6.7% (n = 58) of all trauma patients, followed by wound infection and urinary tract infection; both were 3.5%. When males and females were compared across the entire cohort (Table 1), females were more likely to have preinjury comorbidities (women, 18.2% vs. men, 12.7%; P < 0.05). Injury severity was similar for both sexes, but women had lower head and abdominal abbreviated injury component scores and higher face component scores. However, the blood transfusion within the first 12 h and the requirement of emergency operation intervention were similar for both men and women.
When clinical outcomes were compared between sexes (Table 2), overall length of stay (LOS) and ICU LOS were similar. Males had greater ventilator requirements (12.7% vs. 7.4%, P < 0.05), but the number of days required on a ventilator was similar between men and women. Crude analysis of all patients revealed that men had a significantly higher mortality rate compared with women (9.1% vs. 4.1%, P < 0.05). However, there was no statistically significant difference in the NI rate (15.9% vs. 14.0%, P = 0.53). We next stratified results based on age and injury severity. Table 3 demonstrates trauma patient outcomes by sex for each age group in the study. In the 50-year-old or older group, women had a longer total LOS than men. Women had a significantly lower mortality than men in patients younger than 50 years (3.9% vs. 9.8%, P = 0.025) but not in patients older than 50 years (4.4% vs. 8.0%, P = 0.295). Similar results were seen in the ISS 25 or higher group; here, again, men had a higher rate of ventilator need. In trauma patients with moderate injury (16 ≤ ISS < 25), male and female patients did not significantly differ in hospitalized mortality (3.5% vs. 1.6%, P = 0.373). However, in the severe injury group (ISS, >25), male trauma patients had a significantly increased mortality (16.3% vs. 6.8%, P = 0.011) (Table 4). There was still no statistically significant difference in the NI rate for both age-stratified and ISS-stratified group. Multivariable logistic regression revealed that sex was an independent risk factor for mortality. Female sex was significantly associated with a 59% lower risk of mortality (OR, 0.41; 95% CI, 0.20 – 0.85) after severe trauma as compared with their male counterparts. In a subgroup analysis, sex remained an independent risk factor for these outcomes in those younger than 50 years (OR, 0.31; 95% CI, 0.12 – 0.82) and the severe injury group (OR, 0.39; 95% CI, 0.17 – 0.91) but not in the 50-year-old or older group (OR, 0.42; 95% CI, 0.16 – 1.48) and the moderate injury group (OR, 0.34; 95% CI, 0.07 – 1.69). Again, sex was not a significant risk factor for NI rate in either the overall or age-stratified and ISS-stratified group (Table 5).
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.
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Blunt trauma; sex; injury severity; sex hormone; nosocomial infection; mortality
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