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Gender-Based Differences in Outcome in Patients With Sepsis
Soumitra R. Eachempati, MD;
Lynn Hydo, RN;
Philip S. Barie, MD, FCCM, FCCS
Arch Surg. 1999;134:1342-1347.
ABSTRACT
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Hypothesis Among factors postulated to affect outcome in sepsis is the gender of the patient, with a suggestion that females may have lower mortality. This study tested the hypothesis that female patients admitted to the surgical intensive care unit with a documented infection have a lower mortality rate.
Design Retrospective analysis of a prospectively collected data set.
Setting Surgical intensive care unit of a university hospital medical center.
Methods Analysis of a consecutive series of 1348 patients who had signs of systemic inflammatory response syndrome on admission to a surgical intensive care unit. A cohort of 443 patients (32.9%) admitted with documented infection—and who therefore had sepsis, severe sepsis, or septic shock—constituted the study population. For each patient, APACHE (Acute Physiology and Chronic Health Evaluation) II and III scores, systemic inflammatory response syndrome score, gender, age, and hospital mortality were recorded.  2 With Fisher exact test was performed to compare mortality rates between males and females. Univariate analysis of variance was used to compare continuous variables in discrete populations. Multivariate analysis of variance was used to determine which factors independently predicted mortality.
Primary Outcome Measures Mortality, intensive care unit length of stay, hospital length of stay, and maximal multiple organ dysfunction score. Outcomes stratified by gender.
Results Patients had mean±SEM age of 67±1 years; mean±SEM APACHE II and III scores of 20.1±0.4 and 67.7±1.0 points, respectively. There were no demographic differences between genders. Overall, 104 (23.5%) of 443 patients with sepsis died. The difference in mortality rates between female and male patients was not significant, except in octogenarians (P = .05). Multivariate analysis of variance, APACHE III (P<.001), maximal multiple organ dysfunction score (P<.001), and female gender (P=.02) predicted mortality. In females, APACHE III (P=.03) and maximal multiple organ dysfunction score (P<.001) predicted mortality, but age did not.
Conclusion Female gender is an independent predictor of increased mortality in critically ill surgical patients with documented infection.
INTRODUCTION
SEPSIS REMAINS a primary cause of morbidity and mortality in hospitalized patients. Among many factors postulated to affect outcome in sepsis is the gender of the patient. Females have a more active humoral and cell-mediated response than males.1-2 In 1898, Calzolari et al3 showed that adult male rabbits developed increased thymic mass after castration. In more recent studies,4 castrated animals developed thymic hypertrophy and splenic enlargement, the latter largely caused by expansion of the B-cell population.
Results of studies5-6 of the immunologic effects of sex steroids demonstrate altered production of sex steroids under stress. With a model of chronic intraperitoneal sepsis in male mice, Sharma et al7 showed that sepsis significantly decreased levels of testosterone at 24 and 48 hours compared with control animals. Progesterone levels were also significantly increased at 12 hours in infected and sham-operated mice but not in control (nonoperated) mice.
Androgens may have immunosuppressive effects; administration hindered the development of fatal autoimmune disease in NZB/NZW F1 hybrid mice.8 In a trauma-hemorrhage model, androgens had an immunosuppressive role, independent of changes in corticosterone release.9 In a skin allograft rejection model, Graff et al10 observed that female mice had significantly shorter rejection times, and the time to rejection was shortened in males after castration.
Responses to noxious agents are also gender-specific in animal models. Human females exert an increased primary and secondary antigen response to poliovirus administration.11 Zellweger et al12 found that female mice had a significantly higher survival rate after similar infectious challenges compared with males. Splenocyte proliferative capacity and splenocyte interleukin 1 (IL-1) and IL-2 release were also decreased only in male mice with sepsis.12
The immunosuppressive effects of androgens may be reversed by administration of antiandrogens. Angele et al13 demonstrated in a murine hemorrhage and infection model that male mice had depressed splenocyte and macrophage function. Treatment with flutamide, an androgen receptor blocker, resulted in improved splenocyte macrophage IL-1 and IL-6 release, and increased survival.
In a prospective study of 52 patients with surgical sepsis, Schröder et al14 examined gender-related differences in outcomes and certain mediator levels. Hospital mortality was 70% in males but only 26% in females. Males had higher tumor necrosis factor  levels and lower IL-10 levels than women. Lower testosterone levels occurred in male patients compared with male controls, whereas higher estradiol levels were noted in postmenopausal female patients compared with controls of similar age.
Although gender may affect the experimental septic response, it is unclear whether this biological feature is relevant to the outcome of critically ill patients. To our knowledge, no large study has analyzed gender-related outcomes after sepsis in critically ill patients. We tested the hypothesis that a gender-specific difference in morbidity and mortality, specifically, lower mortality and other improved outcomes in females, exists for critically ill patients with sepsis.
METHODS
A retrospective review was performed of the database of a single tertiary surgical intensive care unit (ICU) between 1994 and 1998. All data were collected prospectively. Patients admitted to the surgical ICU with systemic inflammatory response syndrome (SIRS) and a diagnosis of infection were identified. All admissions were emergent; patients admitted electively for monitoring purposes were excluded from this analysis. Patients were considered to have sepsis by having a SIRS score of 2 or greater and a documented diagnosis of infection. Location of the primary infection was also recorded in 1 of 8 categories: pulmonary, central nervous system, abdominal, skin and soft tissue, blood, genitourinary, multiple sources, or other.
For each patient, APACHE (Acute Physiology and Chronic Health Evaluation) II and III scores and SIRS score were determined, based on the worst values obtained within the first 24 hours of admission to the ICU.15-16 Age and gender were recorded. Defined end points included length of stay in the ICU, length of stay in the hospital, maximal multiple organ dysfunction score,17-18 and hospital mortality. Patients were stratified by gender and by location of the primary infection.
Categorical variables (eg, gender and infection site) were analyzed using 2 with Fisher exact test. Coordinate variables were analyzed by univariate analysis of variance (ANOVA). Multivariate ANOVA was performed to determine factors having an independent effect on mortality. Data are expressed as mean±SEM. Statistical significance was accepted at P=.05.
RESULTS
During the study, 3490 consecutive patients were admitted to the surgical ICU. Of these, 1348 patients (38.6%) met the criteria for SIRS on admission ( 2 points). Of 1348 patients, 443 (32.9%) admitted with SIRS proved to have an infection and, therefore, were given a diagnosis of sepsis. Overall, 104 (23.5%) of 443 patients with sepsis died.
Descriptive statistics for the patients are presented in Table 1. Mean age was 67±1 years, with no difference between males and females. Age distribution of the gender cohorts is shown in Figure 1. Patients had a SIRS score of 3.3±0.1 points, an APACHE II score of 20.1±0.4 points, and an APACHE III score of 67.7±1.6 points; again, there were no differences between males and females. The distribution of infections by gender is shown in Figure 2. Abdominal infections composed two thirds of the cases, whereas multiple sites of infection were identified in 8.6% of cases. There were no differences between groups with respect to case mix.
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Table 1. Demographics and Descriptive Statistics of the Patient Cohorts (N = 443)*
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Figure 1. Age distributions for females (top) and males (bottom). Age distributions were comparable but reflect a preponderance of older patients in both groups.
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Figure 2. Preponderance of intra-abdominal infections among patients with sepsis admitted to the surgical intensive care unit. However, there was no difference in case mix between males and females.
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Patient outcomes are summarized in Table 2. By univariate ANOVA, there were no differences in predefined outcomes between males and females. As expected, nonsurvivors presented with more severe illness and a higher SIRS score, irrespective of gender, spent substantially more time in the ICU, and developed significantly greater organ dysfunction (P<.001) (Table 3). However, age did not affect mortality.
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Table 2. Outcomes of the Patient Cohorts*
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Table 3. Descriptive and Outcome Statistics of Survivors Compared With Nonsurvivors Irrespective of Gender*
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Gender-specific mortality as a function of primary infection site is shown in Figure 3. Although there were no site-related differences in mortality between genders, the comparisons might be affected by small sample sizes (except for abdominal infections).
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Figure 3. Mortality rates as a function of primary source of infection. No differences between females and males. Sample sizes for each source cohort obtainable from Figure 2.
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The interactions of age and gender with respect to mortality are depicted in Figure 4, expressed by decile of age. There was 0 mortality for patients aged 20 to 29 years so the data are omitted. There was no difference in mortality by multiple-group 2 for males with respect to age (P=.45) or for females compared with males within age strata, except for higher mortality for octogenarian females (P = .05). Data suggest no survival advantage for female patients with sepsis and indeed, that females may be disadvantaged. Moreover, the lack of an age-related mortality effect in females implies that the effect of estrus cycle or menopausal status on mortality may be discounted.
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Figure 4. Mortality rates as a function of age and gender. No change in mortality rate as a function of age in males or females. For gender differences within given age groups, increased mortality occurred only in octogenarian females (P<.05).
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The independence of effects of various variables on mortality was tested using multivariate ANOVA (Table 4). Within the overall cohort, independent effects on mortality were exerted only by severity of illness on ICU admission (APACHE III score, P<.001), degree of organ dysfunction (maximal multiple organ dysfunction score, P<.001), and notably, female gender (P=.02). Because female gender was independently associated with mortality, a multivariate ANOVA was performed for the cohort of female patients to determine concurrence with the overall model, specifically, to assess the effect of age on mortality. Whereas severity of illness (P=.03) and magnitude of organ dysfunction (P<.001) again predicted mortality, there was no impact of age on mortality in females (P=.14), lending further support to the idea that neither estrus cycle nor menopausal status affected the results in females.
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Table 4. Multivariate Analysis of Independence of Effects on Mortality*
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COMMENT
Many factors affect outcome in sepsis.19-22 Noting the presence of an accentuated proinflammatory cytokine response in sepsis, investigators23 have tried adjunctive therapies for sepsis targeting several different cytokines. These strategies have not shown benefit in clinical settings.24-25 The importance of "gender-specific physiological mechanisms" has been recognized for a variety of disease states.26 In animal models, investigators3-4,6-10,12 have demonstrated that gender-specific differences exist in immune function. In humans, gender-specific differences have been noted for many disease processes,27-29 including gastrointestinal tract,30 psychiatric,31-32 pulmonary,33-34 and cardiac diseases.35-38
Male and female patients demonstrate different sex steroid hormone responses to infection.39-40 Fourrier et al41 observed high estrogen levels in males and females with sepsis and septic shock. Schröder et al14 demonstrated that male patients had consistently lower testosterone levels than controls, and that postmenopausal female patients had higher estradiol levels than expected. Owing to the previously demonstrated immunosuppressive characteristics of androgens, several researchers12-14 have hypothesized that differences in sex steroid hormone concentrations in patients with sepsis might represent a mechanism by which male patients may have higher mortality in sepsis.
Although data from animal studies strongly suggest that male gender is a risk factor for an adverse outcome from infection, clinical data are conflicting. A meta-analysis42 of 122 trials of community-acquired pneumonia demonstrated an odds ratio of 1.3 for mortality in male patients. However, trials43 in patients with nosocomial pneumonia that acknowledged male gender as a risk factor and examined specifically for such an effect did not demonstrate the phenomenon. A review44 of 18,792 patients with blunt trauma, stratified by age, gender, and injury severity, found no relationship between gender and mortality. Female trauma patients had a higher incidence of urinary tract infection, whereas older, more seriously injured male patients had a higher incidence of pneumonia; neither difference affected outcome.44
Results of the present study suggest that critically ill female surgical patients with sepsis may have slightly increased mortality compared with their male counterparts. Similar results were observed by McLauchlan et al45 in a cohort of critically ill patients who also had predominantly intra-abdominal infection. They observed significantly higher mortality in females; the severity of illness reported was even higher in that study (mean APACHE II score, 23; incidence of shock, 80%; hospital mortality, 63%) than in ours.
In contrast, Schröder et al14 reported that mortality in male patients was higher in a small cohort of 52 patients, 45 of whom had intra-abdominal infection and only 19 of whom were male. Compared with the present study, patients studied by Schröder et al14 were younger (mean age, 54 years because patients 75 years were excluded) and less severely ill (mean APACHE II score, 18), but had substantially more organ dysfunction, as assessed by the Marshall score (mean, 10.4 points). Despite the careful descriptions of sex steroid hormone concentrations provided, mortality in males was implausibly high (70%, despite a mean APACHE II score of only 18), and their results are likely spurious. Moreover, Schröder et al14 did not perform a multivariate ANOVA to determine whether gender independently affected mortality in their study.
Why might female gender impart an adverse outcome from infection? Severe infection stimulates both a proinflammatory and an anti-inflammatory response.46 Recent hypotheses47 suggest that the development of organ dysfunction, which is invariably associated with death from infection, may arise from dysregulated proinflammatory and anti-inflammatory responses. Which temporal sequence and magnitude of countervailing responses are optimal for survival is a matter of conjecture because anti-inflammatory responses are difficult to quantitate, especially at the bedside.
Patients in septic shock have high concentrations of the anti-inflammatory mediator IL-10. It is possible that a relative degree of immmunosuppression might be advantageous in some circumstances. For example, Stroud et al48 found female gender to be an independent predictor of mortality in patients with nosocomial enterococcal bacteremia, along with severity of illness, type of antibiotic drug used for therapy, and age. Invasive enterococcal infections have a tendency to occur in debilitated, immunosuppressed patients.49
Nonimmunologic factors might contribute to worse outcomes for women during serious illness. Males might have better access to preventive health care, and maintain a superior baseline health status.50-52 A gender-related difference in access to emergency care might also exist.53 Data might also suggest that men are admitted to the hospital with a less severe pattern of illness.54 However, studying only ICU patients, as we did, obviates that concern.
Results of the present study demonstrate that women might have worse outcomes to sepsis than men, but there are several limitations. The study is retrospective, but the data were collected prospectively. Gender cohorts were well-matched at baseline in our study, which should have minimized any pre-existing patient bias. Inclusion of only ICU patients may have omitted less severely ill patients who were destined to avoid organ failure. However, our outcome data reveal that our patients had a relatively low mortality rate for their severity of illness.
Our findings do not support the hypothesis that females are superior to males in responding to infection. Prospective multicenter studies are necessary to resolve the discrepancy. Before studies are undertaken to evaluate the effect of hormonal manipulation in patients with sepsis, clearer demonstration of the roles of sex steroid hormones in the pathogenesis of sepsis is needed. Study may be especially needed to determine whether differential signaling or other mechanisms regulate a gender-specific proinflammatory and anti-inflammatory responses in patients with sepsis.
AUTHOR INFORMATION
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Presented at the 19th Annual Meeting of the Surgical Infection Society, Seattle, Wash, April 30, 1999.
| Statement of Clinical Relevance
Whether males and females respond differently to infection, either in terms of the host response or the eventual outcome, is critically important for both clinical care and the design of future clinical trials of anti-infective therapies or biological response modifiers. Equal access to clinical trials for males and females is currently mandated. If differences do indeed exist, it is possible that future studies might have to stratify for gender and for infection source, severity of illness, and immunologic phenotype. At the bedside, recognizing that males and females might need different types or schedules of therapy could become a fundamental issue.
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Reprints: Soumitra R. Eachempati, MD, Department of Surgery, New York Presbyterian Hospital, 525 E 68th St, Room 2010, New York, NY 10021 (e-mail: seachempati{at}surgery.med.cornell.edu).
From the Department of Surgery, Weill Medical College of Cornell University; and Anne and Max A. Cohen Surgical Intensive Care Unit, New York Presbyterian Hospital, New York, NY.
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