Effect of Patient Sex on Intensive Care Unit Survival

ORIGINAL INVESTIGATION Effect of Patient Sex on Intensive Care Unit Survival

Hugo Romo, MD; Andre´ Carlos Kajdacsy-Balla Amaral, MD; Jean-Louis Vincent, MD, PhD

Background: Human observations have shown differ- female patients older than 50 years (OR, 1.33; 95% CI, ent mortality rates between men and women with vari- 1.12-1.58) but not in the younger age group. The sub- ous pathological conditions, but this issue has not been group of medical admissions had a higher mortality widely studied in a heterogeneous population of criti- (24.4% vs 7.4%, PϽ.001) and a higher female propor- cally ill patients. tion (37.9% vs 34.2%, P=.01) than surgical admissions. In multivariate analysis, female sex remained an impor- Methods: Retrospective analysis of all patients admit- tant predictor of mortality (OR, 1.54; 95% CI, 1.25-1.89). ted to a mixed medical-surgical, 31-bed intensive care Women had a higher mortality than men in the sub- unit (ICU) during 2 different years (1983 and 1995) to group of cardiovascular diseases. The highest mortality evaluate possible differences in mortality between male in female patients was present in the first days after ad- and female patients and between medical and surgical admission and decreased over time, showing a covariance missions and variations in these differences over time. of time and sex.

Results: From a total of 4420 admissions (1587 women, Conclusions: In a mixed medical-surgical ICU, older 2833 men), women showed a higher mortality, with an women have a higher mortality rate than men. This dif- odds ratio (OR) of 1.18 (95% confidence interval [CI], ference is not apparent for patients staying longer in the 1.02-1.38). This pattern was the same for the 2 periods, ICU. and all patient data were therefore analyzed together. Af- ter age stratification, the differences were significant for Arch Intern Med. 2004;164:61-65

ECENTLY, THERE HAS BEEN sex hormones, with women and men increased interest in the treated with estrogens developing a more possible influences of sex marked proinflammatory response22-24 and on disease development having improved cardiac and hepatic func- and intensive care unit tion compared with men.25 These changes (ICU) survival. Women have a lower in- are influenced by the female reproduc- R 26 cidence of coronary heart disease (CHD), tive cycle, and the cytokine response is an effect that is blunted with aging.1 Af- reversed when older animals with de- ter an acute myocardial infarction (AMI), creased hormonal levels are compared.27 women have a higher rate of early mor- Indeed, higher male mortality rates have tality,2-5 although long-term mortality af- been observed,28,29 and treatment of sep- ter AMI is not different between the sexes.5 tic male animals with dehydroepiandros- Higher mortality rates in men have been terone resulted in improved outcome.30 observed in some situations, including Whether these experimental findings can congestive heart failure6,7 and trauma,8,9 but be translated to the clinical arena, how- in other areas, including sepsis,10-16 me- ever, remains unclear. The objective of this chanical ventilation,17,18 and burns,19-21 the study was to observe if there were any dif- literature is conflicting. ferences in mortality rates and length of The reasons behind possible sex dif- ICU stay between men and women in a ferences have been explored in several ex- mixed medical-surgical ICU population. From the Department of Intensive Care, Erasme perimental models, mainly focusing on the Hospital, Free University of possible immunological effects of sex hor- METHODS Brussels, Brussels, Belgium. mones. Numerous studies have shown that The authors have no relevant the immune response, including that as- Records for all consecutive admissions to the financial interest in this article. sociated with sepsis, may be modulated by ICU of Erasme University Hospital, Brussels,

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Downloaded From: https://jamanetwork.com/ on 09/24/2021 Table 1. Demographic Data of 4420 Patients Admitted to the Intensive Care Unit During 2 Study Periods

1983 1995

Variable Women Men Women Men P Value Patients, % 33.5 66.5 38.0 62.0 .004 Age, mean ± SD, y 54.3 ± 20.2 54.5 ± 16.6 56.5 ± 19.8 56.7 ± 18.6 .006* Patients older than 65 y, % 33.9 27.7 42.7 42.4 Ͻ.001† Length of stay, mean ± SD, d 4.1 ± 5.3 3.9 ± 5.5 3.5 ± 7.1 3.7 ± 6.1 .20* Surgical patients, % 58.6 67.4 64.6 64.5 .007† Survivors, % 85.6 87.6 84.7 87.2 .34†

*General linear model. †Mantel-Haenszel test.

Table 2. Differences Between Medical and Surgical Patients

Medical Surgical

Variable Women Men Women Men P Value Patients, No. (%) 601 (37.9) 968 (34.2) 986 (62.1) 1865 (65.8) .01 Age, mean ± SD, y 56.5 ± 20.9 55.3 ± 19.8 55 ± 19.4 55.9 ± 16.6 .57* Length of stay, mean ± SD, d 4.0 ± 6.8 4.2 ± 5.4 3.5 ± 6.2 3.6 ± 6.0 .03* Mortality, % 24.1 24.6 9.3 6.4 Ͻ.001†

*General linear model. †Mantel-Haenszel test.

Belgium, during 2 different years, 1983 and 1995, were From the total number of patients, 595 (13.5%) retrieved by searching the unit databases. These years were died during their ICU stay. Survivors were younger than chosen because they were readily available from our databases nonsurvivors (55±18 years vs 61±18 years, P=.006), and allowed a comparison of mortality rates over time. Erasme and they had a significantly shorter length of ICU stay University Hospital is a 900-bed, academic, adult hospital with (3.5±5.7 days vs 5.4±7.6 days, PϽ.001). Mortality a multidisciplinary, mixed medical and surgical, 31-bed intensive care department. Patients with acute, uncomplicated coro- increased with age from 9.9% in patients younger than nary disease are admitted to a separate coronary care unit. 45 years, 11.8% in patients aged 45 to 65 years, and 2 Patients admitted several times during these years were 18.1% in patients older than 65 years (␹ trend=40.5, included as new admissions. Demographic data, including sex, PϽ.001). Women had a higher mortality rate than men admission diagnosis, medical or surgical status, age, length of (15% vs 13%; odds ratio [OR], 1.18; PϽ.05). When the ICU stay, and ICU outcome, were collected. Univariate and sample was stratified according to age, women older multivariate analyses were performed to determine predictors than 50 years showed the highest risk of mortality (OR, of mortality in this population using statistical software (SPSS 1.33; PϽ.001). The crude OR and the Mantel-Haenszel version 10.0.5; SPSS Inc, Chicago, Ill). Categorical variables adjusted OR were not significantly different, showing no were assessed with the ␹2 test. The 2-tailed t test and Mann- Whitney U test were used as appropriate for continuous vari- evidence of confounding. However, the homogeneity ables. Stratified analysis was performed using the Mantel- test across strata confirmed the presence of a significant Haenszel test. General linear model and time-dependent Cox interaction between sex and mortality when age was regression model were also applied. The actuarial method was controlled (PϽ.001). used to assess cumulative differences in survival. PϽ.05 was Medical patients represented 35.9% of the popula- considered statistically significant unless a Bonferroni correc- tion; differences between the medical and surgical tion was applied to evaluate multiple comparisons. Data are groups are depicted in Table 2. There were no differ- presented as mean±SD, excepted where stated otherwise. ences in age between the medical and surgical groups as a whole or when stratified according to diagnosis or sex. RESULTS There were more female than male medical patients (37.9% vs 34.2%, P=.01). Surgical patients had a shorter Demographic data for the 2 years are summarized in mean length of stay than medical patients (3.6±6.1 days Table 1. There were 4420 admissions (1587 women, vs 4.1±5.9 days, P=.04). The mortality rate was higher 2833 men), 1950 admitted in 1983 and 2470 in 1995. in medical vs surgical patients (24.4% vs 7.4%, PϽ.001). The proportion of female patients increased throughout Cardiovascular problems were the most frequent source the 12-year period. There were no significant differ- of admission to the ICU for the medical group, account- ences in the mean ICU length of stay when both years ing for 29% of admissions. The mortality rate of female were compared. Since mortality rates were similar in the patients with cardiovascular disease was higher than that 2 different periods, data from the 2 years were analyzed of their male counterparts (23% vs 12%; OR, 2.07; 95% collectively. CI, 1.50-2.87; PϽ.001) (Table 3).

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Downloaded From: https://jamanetwork.com/ on 09/24/2021 Table 3. Admission Diagnoses With Corresponding Mortality Rates

Mortality Rate, No. (%)

Cause of Admission Patients, No. Admissions, % All Men Women Surgical Neurosurgery 891 20.2 158 (17.7) 90 (19.3) 68 (16.0) Cardiac surgery 323 7.3 10 (3.1) 8 (4.4) 2 (1.4) Thoracic surgery 163 3.7 6 (3.7) 5 (4.4) 1 (2.0) Vascular surgery 94 2.1 3 (3.2) 1 (1.4) 2 (8.0) Abdominal surgery 87 2.0 13 (14.9) 4 (8.9) 9 (21.4) Urology 15 0.3 0 0 0 Polytrauma 299 6.8 44 (14.7) 24 (12.1) 20 (20.0) Gynecology-obstetrics 21 0.5 0 0 Medical Cardiovascular 1284 29.0 191 (14.9) 118 (12.1) 73 (22.5)* Respiratory 510 11.5 72 (14.1) 49 (14.3) 23 (13.8) Gastrointestinal 309 7.0 47 (15.2) 28 (13.2) 19 (19.6) Neurology 165 3.7 33 (20.0) 22 (24.4) 11 (14.7) Nephrology 86 1.9 5 (5.8) 4 (7.7) 1 (2.9) Intoxications 64 1.4 5 (7.8) 3 (10.0) 2 (2.9) Internal medicine 48 1.1 5 (10.4) 2 (8.0) 3 (13.0) Psychiatry 19 0.4 1 (5.3) 0 1 (7.7) Endocrinology 16 0.4 0 0 0 Oncology 10 0.2 0 0 0 Others 16 0.4 2 (12.5) 0 2 (28.6)

*PϽ.001.

Using the actuarial method, life tables were used to Table 4. Cumulative Survival of Patients assess the median length of stay in the ICU until death. The median length of stay was 26 days for surgical pa- Cumulative Survival, % tients and 14 days for medical patients (PϽ.001). Dif- Time P ferences in mortality were observed from days 3 through Interval, d Men Women Value 6, favoring men (Table 4), but after this initial period, 1 95 92 .11 the mortality rate was lower for women, although not sig- 2 91 89 .05 nificantly, suggesting that survival for men and women 38985Ͻ.001 is not constant over time. The plot of survival curves (Fig- 48782Ͻ.001 Ͻ ure) shows the cumulative proportion of patients stay- 58677.001 68174Ͻ.001 ing in the ICU until death. The curves eventually cross 7 78 71 .12 each other due to interaction of sex with length of ICU 14 60 54 .07 stay; therefore, a time-dependent Cox regression model 21 48 50 .72 was used to assess the joint effects of prognostic factors, 28 33 43 .23 such as age, sex, and medical-surgical status, on length 35 30 43 .42 of stay in the ICU until death. The model showed mortality for women to be associated with an OR of 1.54 (95% CI, 1.25-1.89) overall and an OR of 0.95 (95% CI, 0.92- had a higher mortality rate. So why do our results and 0.98) for each day of increase in length of stay, suggest- those from other clinical studies14,19 differ from what we ing a reduction in the OR for longer stays (Table 5). would expect from these experimental observations? First, This confirms the significant interaction of sex and time experimental data are generally based on young women that was already found with the stratified analysis. in their proestrus state. Clinical studies usually involve populations of mixed ages, with some women in the pro- COMMENT estrus state and others in the postmenopausal state; thus, the hormonal milieu will be different from the con- More male patients are admitted to the ICU than female trolled animal experiment.26 The difference in ages may patients, with men accounting for approximately two not only be important because of decreased estrogen lev- thirds of admissions.13,31 Our study confirms this pro- els in older women, but, as shown by Kahlke et al27 in portion, although suggests a slight increase in the pro- mice, the cytokine response is reversed so that older male portion of female admissions in more recent years. mice show a better proinflammatory response than fe- In experimental studies,28,29,32 mortality rates have male mice. This factor could explain why, in our results consistently been shown to be higher in male than fe- as well as others,14 differences were noted only in older male animals in various disease models, yet our study patients and why women fared worse. Second, it is pos- showed no significant differences in mortality rates be- sible that a female sex advantage may prevent women from tween sexes, except in women older than 50 years, who developing a more severe state to the same insult. Wich-

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Downloaded From: https://jamanetwork.com/ on 09/24/2021 of women may allow more of them to reach the hospital 1.2 Female alive, giving a biased population of more severely ill fe- Male male patients. These data are suggested by 2 studies42,43 1.0 that confirm a higher AMI prehospital mortality for men, higher hospital mortality for women, and, subse- 0.8 quently, the same overall mortality. Our study is, to our knowledge, the first report of 0.6 differences in mortality in a large population derived from a mixed medical-surgical ICU rather than in specific patient groups. We observed a significantly higher mortal- Cumulative Survival 0.4 ity in women older than 50 years and in the subgroup admitted for cardiovascular diseases. Although more 0.2 women were admitted for medical reasons, and this subgroup had a higher mortality, in multivariate analysis fe- 0.0 –10 010 20 30 40 male sex remained an important predictor of mortality. Length of Stay in ICU, d Importantly, patients with uncomplicated acute coronary syndromes were not included but have relatively low Cumulative survival curves for female and male sex according to length of mortality rates; thus, for differences in mortality to be intensive care unit (ICU) stay (n=595 patients). shown, large patient populations may be required. The ICU mortality rates are more valuable when controlled for severity of illness; unfortunately, one of the limita- Table 5. Time-Dependent Cox Regression Model tions of our study was the lack of a severity score, not widely used in 1983, to further explore our data and per- Variable OR (95% CI) P Value haps provide some explanations for the observed differ- Sex 1.54 (1.25-1.89) Ͻ.001 ences in mortality. Age 1.02 (1.01-1.02) Ͻ.001 Survival analysis showed that women’s survival Medical patients 2.94 (2.46-3.45) Ͻ.001 Ͻ chances improve with longer length of stay, as shown by Time covariate with sex 0.95 (0.92-0.98) .001 a decreasing hazard function for female patients, which Abbreviations: CI, confidence interval; OR, odds ratio. crossed over the male hazard function. This finding is in parallel with studies that compare mortality in men and women after coronary events, which showed an in- mann et al13 studied the development of severe sepsis and crease in early mortality in women.2,44 This result could septic shock in the postoperative state. These authors ob- also be due to an enhanced initial proinflammatory re- served that the mortality from severe sepsis and septic action in women, as demonstrated in animal experi- shock was similar for men and women, but more men ments,22-25 followed by a more balanced reaction later, needed ICU care, and in this subgroup, more men de- as indicated by a higher interleukin 10 level in women veloped severe sepsis and septic shock. Male sex has also after 10 days.10 Hence, the timing of observations may been observed as a risk factor for sepsis and multiple or- be important when studying sex-related differences in gan dysfunction after burns33 and trauma,34 as well as for mortality. infections after surgery.35 This fact may limit the detec- In conclusion, ICU survival depends on the effects tion of any direct sex-related differences in mortality if of several predictors interacting with each other and with patients are studied only in the ICU. time. Clinical trials should consider that men and women The greatest paradox is seen in CHD, because fe- respond differently to noxious stimuli, although the pos- male sex protects against its development but still car- sible female advantages described in animals have not yet ries a greater mortality risk for acute events. Several fac- been confirmed in humans. Additional prospective stud- tors can account for this finding. First, the most important ies observing not only sex but also hormonal status (in- difference is observed for the younger groups3; thus, cluding exogenous hormone use), associated with a bet- younger women may have a more severe form of CHD, ter stratification according to age and disease state and as manifested by a greater tendency to show eroded severity of illness, are needed to further characterize these plaques,36 higher platelet reactivity,37 fewer collateral ves- differences. sels,38 and a higher incidence of AMI with normal an- giogram.39 Second, women have been shown to have more Accepted for publication January 31, 2003. complications, such as arrhythmia, acute pulmonary Corresponding author and reprints: Jean-Louis Vin- edema, and cardiogenic shock,3-5,39 as well as more co- cent, MD, PhD, Department of Intensive Care, Erasme Hos- morbid disease processes, such as congestive heart fail- pital, Route de Lennik, 808, B-1070 Brussels, Belgium ure, arterial hypertension, and type 2 diabetes mellitus (e-mail: [email protected]). 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