Sex Differences in Mortality, Multidimensional Morbidity, and Health Care Utilization: A Secondary Analysis of the Canadian RECOVER Study

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Herridge This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6717946/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 22 Jan, 2026 Read the published version in Intensive Care Medicine → Version 1 posted 4 You are reading this latest preprint version Abstract Purpose We assessed for differences in sex and disability group membership in ICU mortality, longitudinal Functional Independence Measure (FIM) scores, Beck Depression Inventory-II (BDI-II), Impact of Event Scale - Revised (IES-R), and healthcare utilization to 1-year after intensive care unit (ICU) discharge. Methods Secondary analysis of medical/surgical patients in the Canadian Towards RECOVER study. Results Of 463 (185 females, 278 males) participants, significantly more males 45 (16.2%) versus females 20 (10.8%) died in the ICU [Hazard Ratio (HR) 1.8 (1.1, 3.1); p = 0.03]. Of 398 (165 females, 233 males) ICU survivors, 391 had FIM scores. Median FIM scores were significantly higher for male (versus female) survivors at 3-months (117 versus 106 points; p = 0.005), 6-months (119 versus 111.5 points; p = 0.005), and 12-months (121 versus 115 points; p = 0.003). Conversely, female (versus male) survivors had significantly higher BDI-II scores at 3-months [12.50 (7.0, 18.0) versus 9.0 (5.3, 14.8); p = 0.036], 6-months [11.8 (6.0, 17.8) versus 7.2 (3.0, 14.0); p = 0.009], 12-months [10.0 (4.0, 19.0) versus 11 (3.0, 26.3); p = 0.036] and higher IES-R scores at 3-months. Female survivors also experienced significantly more moderate (versus mild) [OR 6.9 (3.5, 13.7); p < 0.0001] and severe (versus moderate)[OR 40.9 (17.1, 98.2); p < 0.0001] depression. Whereas female ICU survivors had more rheumatology and nephrology specialty visits, males had more cardiology, endocrinology, surgical, and rehabilitation visits. There were no sex by time or sex by disability group interactions. Conclusions Although male ICU survivors experienced significantly higher ICU mortality, females experienced significantly lower longitudinal FIM scores and more frequent and severe depression. sex gender sex and gender based analysis critical illness functional independence depression Figures Figure 1 Figure 2 Key points Take Home Messages: Male (versus female) Canadian RECOVER patients experienced significantly higher ICU mortality. Male patients started with higher median FIM scores and their longitudinal FIM scores were persistently higher than females up to 1-year after ICU discharge. Female ICU survivors experienced more frequent and severe depression and had significantly higher IES-R scores at 3-months compared to male survivors. Tweet Males had significantly higher ICU mortality but female ICU survivors ventilated for at least 7-days had a higher burden of illness. Introduction Several international studies support that critical illness generates new and clinically important functional and neurocognitive disabilities that are additive to underlying organ dysfunction. ( 1 – 7 ) Moreover, return to functional independence for intensive care unit (ICU) survivors is multidimensional and complex. ( 8 ) Transparent reporting of long-term ICU outcomes is necessary to ensure accountability for the human and financial costs of outcomes in ICU survivors. Differences in health status and health inequities may worsen these outcomes. ( 9 ) Although several studies have highlighted the low representation of females and women as research participants in basic and clinical research ( 10 – 12 ), few studies have examined how sex (a biologic attribute) or gender (social roles) impact treatment responses and outcomes in critically ill patients. ( 10 , 13 ) Sex- and gender-based analyses (SGBA) evaluate the assumption that a standardized approach to summarizing combined treatment effects and adverse event profiles of male and female (alternatively, men and women) research participants is sufficient. ( 14 , 15 ) The 2016 Sex and Gender Equity in Research (SAGER) guideline provided a comprehensive procedure for reporting of sex and gender information in trials. ( 16 ) This guideline applies to all research involving humans, animals, materials originating from humans and animals, and disciplines whose results may be applied to humans. ( 16 ) A systematic review of acute care trials published in leading medical journals identified that only a quarter of trials (26.1%) reported a SGBA. ( 17 ) Lack of disaggregation of data by sex or gender may lead to erroneous assumptions that treatment effects are similar in study participants. ( 14 – 16 ) Previous studies have assessed for sex and age differences in ICU care provision and outcomes. A large cohort study identified that fewer women than men were admitted to ICU. ( 18 ) Additionally, older women were not only less likely to receive both care in an ICU setting and invasive ventilation but had an increased risk of ICU and hospital mortality. ( 18 ) For Canadian RECOVER (hereafter RECOVER) participants who were invasively ventilated for at least 7 days ( 19 ), we evaluated differences in sex and disability risk group membership on outcomes including ICU mortality, longitudinal Functional Independence Measure (FIM) scores, Beck Depression Inventory-II (BDI-II), Impact of Event Scale - Revised (IES-R) and healthcare utilization (disposition, readmission, specialty visits) up to 1-year after hospital discharge. We hypothesized that males would have higher FIM scores and females would have higher BDI-II and IES-R scores and lower healthcare utilization. Methods Participants RECOVER was a multicenter, prospective cohort study conducted between February 2007 and March 2014 at 9 university-affiliated medical/surgical ICUs in Vancouver, Hamilton, Toronto (4 sites), Ottawa, Montreal, and Sherbrooke, Canada. For patients who met eligibility criteria, written informed consent for follow-up to 7-days was obtained from substitute decision-makers. At 3-month follow-up, first person written informed consent was obtained to extend follow-up to 1-year from patients who had decision-making capacity. The study protocol was approved by the Research Ethics Boards at University Health Network (no. 06-0157-AE, April 7, 2006) and by the ethics committees of participating ICUs. Potentially eligible patients were at least 16 years of age with dependence on invasive ventilation for ≥ 7-days. Detailed exclusion criteria have been summarized elsewhere. ( 19 ) Patients were evaluated (physical exam, outcome measures) at 7-day and longitudinally at 3, 6, and 12-months after ICU discharge. ( 19 ) Outcome Measures We assessed for sex differences in ICU mortality. In ICU survivors, we assessed longitudinal disability, using the FIM scale score that reflected participant’s level of independence with activities of daily living (e.g., eating, bathing, toileting, using stairs). ( 20 ) The FIM includes 18-items (13 motor tasks, 5 cognitive tasks) rated on a 7-point ordinal scale ranging from complete assistance to total independence; FIM motor subscale score ranged from 13–91 with higher scores indicating greater functional independence. ( 20 ) Recovery trajectories were based on membership in 4 disability risk groups based on participant age and ICU length of stay (LOS) [Group 1 (Young, Short ICU LOS), Group 2 (Mixed age, Variable LOS), Group 3 (Older, Long ICU LOS) or Group 4 (Oldest, Long ICU LOS)]. ( 19 ) We assessed for depressive symptoms using the BDI-II, a 21-question multiple-choice self-reported inventory with scores ranging from 0–63. Higher BDI- II scores represented worse depressive symptoms. Depression severity was rated as mild (score 0–13), minimal ( 14 – 19 ), moderate ( 20 – 28 ), or severe (29–63). ( 21 ) We assessed for post-traumatic stress disorder (PTSD) symptoms using the IES-R, a 22-question self-reported questionnaire with scores ranging from 0–88. Higher IES-R scores represented worse PTSD with scores greater than 24 being clinically concerning. ( 22 ) Finally, we assessed for differences in healthcare utilization (ICU and hospital readmission and mortality, disposition, and specialist visits) to 1-year after hospital discharge. Statistical Analysis Categorical variables were reported as counts and percentages, and group comparisons were performed using the Chi-squared test. Continuous variables were reported as medians with interquartile ranges (IQR). Group comparisons were performed using the Mann-Whitney U test. We generated Kaplan-Meier survival curves to compare time to ICU mortality by sex, and evaluated survival probabilities using the log-rank test. Sex differences in longitudinal outcomes, including FIM score ( 20 ), BDI-II scores ( 21 ), and IES-R scores ( 22 ), were depicted with spaghetti plots. To examine for sex differences in ICU mortality, we used univariable and multivariable Cox proportional hazards models and included sex, the presence of one, two, or three or more comorbidities, corticosteroid use, slope of multiple organ dysfunction score (MODS) from 1 to 7-days ( 23 ) and Acute Physiology and Chronic Health Evaluation (APACHE) II score ( 24 ) as potential predictor variables. We report our findings using hazard ratios (HR) and 95% confidence intervals (CI). For longitudinal outcomes, univariable and multivariable linear mixed-effects regression models were used to assess for sex differences in FIM scores ( 20 ), BDI-II scores ( 21 ), and IES-R scores ( 22 ). Univariable and multivariable ordinal logistic mixed-effects models were used to assess for sex differences in BDI-II severity (mild, moderate, severe). Univariable and multivariable logistic mixed-effects models were used to evaluate sex differences in IES-R scores, categorized as above or below 30.5. ( 25 ) In these models, we evaluated interaction effects (sex and time, sex and disability group) using the 7-day FIM score (alternatively, 3-month BDI-II or IES-R score) and the mixed age, variable LOS disability group (Group 2) as reference categories. Results Baseline and Day-7 After ICU Discharge Characteristics Of 463 RECOVER participants (185 females, 278 males), 20 (10.8%) females and 45 (16.2%) males died in the ICU. Of 398 (165 females, 233 males) ICU survivors, 7 patients survived to ICU discharge but died before 7-day assessment. Of 391 remaining patients, 345 had 7-day, 206 had 3-month, 207 had 6-month, and 211 had 12-month follow-up FIM assessments. In descending order, participants were in disability risk groups; Group 3 (Old, Long ICU LOS; 67 (40.6%) females, 81 (34.8%) males], Group 2 (Mixed age, Variable ICU LOS; 47 (28.5%) females, 89 (38.2%) males], and Group 4 (Oldest, Long ICU LOS; 43 (26.1%) females, 49 (21.0%) males. Group 1 (Young, Short ICU LOS) had the fewest participants [8 (4.0%) females, 14 (6.1%) males; p = 0.18). We present the baseline and day-7 characteristics by sex in Table 1. Sex Differences in ICU Mortality In eFigure 1, we depict the ICU mortality of RECOVER participants (n = 463) by sex using a Kaplan-Meier survival curve. After adjusting for number of comorbidities, MODS slope in the first 7-days of ICU, use of corticosteroids, and APACHE II score in a multivariable Cox Proportional Hazards model of ICU mortality, we identified significantly higher ICU mortality in male (versus females) [Hazard Ratio (HR) 1.8 (1.1, 3.1); p = 0.03] RECOVER participants. Higher ICU mortality was significantly associated with increasing MODS slope (1 to 7)[HR 1.1 (1.0, 1.2); p = 0.01], participants with a single (versus no) comorbidity [HR 2.7 (1.2, 6.1); p = 0.02], and 3 or more (versus no) comorbidities [HR 6.1 (2.5, 14.7); p < 0.0001]. (Table 2) Sex Differences in Median FIM Scale Scores, Disability Risk Group Membership, and ICU Stay For male and female ICU survivors, the median FIM score was lowest at 7-day and increased over time with the largest improvement in median FIM scores occurring between 7-day and 3-months. Although there were no differences in median FIM scores between males and females at 7-day (56.0 versus 61.0; p = 0.17), FIM scores were significantly higher for male versus female ICU survivors at 3-months (117 versus 106; p = 0.005), 6-months (119 versus 111.5; p = 0.005), and 12-months (121 versus 115; p = 0.003). (eTable 1) Male and female ICU survivors had similar ICU LOS (20 versus 19 days; = p = 0.75) and were similarly represented across the four disability risk groups. (e Table 1) Sex Differences in Longitudinal FIM scales. Compared to 7-day FIM measurements, FIM scores in males versus females survivors were higher by 37.4 points (34.3, 40.6); p < 0.0001 at 3-months, 42.2 points (39.0, 45.4); p < 0.0001 at 6-months, and 45.9 points (42.8, 49.1); p < 0.0001 at 12-months. A Spaghetti plot illustrates that male ICU survivors started out with higher median FIM scores and the FIM scale score slope remained consistently higher and parallel to that of female ICU survivors over 1-year of follow-up. (Fig. 1) In a multivariable linear mixed effects model, male (versus female) sex was associated with 6.2 higher longitudinal FIM points in regression models [univariable [4.6 (-0.2, 9.7); p = 0.08]; multivariable [6.2 (0.2, 12.2); p = 0.04]. (Table 3) Compared to Group 2, there was a significant positive association between male sex and longitudinal FIM scores in the young, short ICU LOS Group [18.0 (5.5, 30.6); p < 0.01], and conversely a significant negative associations between male sex and longitudinal FIM scores in the older, long ICU LOS Group [-10.6 (-17.3, -4.0); p < 0.01] and the oldest, long ICU LOS Group [-20.6 (-28.4, -12.9); p < 0.0001]. (Table 3) Sex Differences in Depression Scores Of 398 ICU survivors, 166 had 3-month, 170 had 6-month, and 175 had 12-month BDI-II scores. Female (versus male) survivors had significantly higher BDI-II scores at 3-months [12.50 (7.0, 18.0) versus 9.0 (5.3, 14.8); p = 0.036], 6-months [11.8 (6.0, 17.8) versus 7.2 (3.0, 14.0); p = 0.009], and 12-months [10.0 (4.0, 19.0) versus 11 (3.0, 26.3); p = 0.036]. (Fig. 2; panel A) Although longitudinal BDI scale scores were significantly lower (3.5 points) in males (versus females) in both univariable [-3.6 (-5.8, -1.4); p < 0.01] and multivariable [-3.5 (-5.7, -1.4); p < 0.01] regression models (eTable 3), we did not find significant sex differences in slopes over time. Most BDI-II scores were in the mild depressive symptom range. Univariable ordinal logistic mixed effects identified that male (versus female) ICU survivors were as likely to experience mild (versus minimal) depression [OR 1.47 (0.8, 2.7); p = 0.21] but were significantly less likely to be experience moderate (versus mild) [OR 6.9 (3.5, 13.7); p < 0.0001] and severe (versus moderate)[OR 40.9 (17.1, 98.2); p < 0.0001] depression with nonsignificant sex by time and sex by disability group interactions. Sex Differences in Impact Event Scale-R Scores Of 398 ICU survivors, 164 had 3-month, 170 had 6-month, and 174 had 12-month IES-R scores. Although IES-R scores were significantly higher in females (versus males) at 3-months [19.0 (8.25, 29.5) versus 11.0 (3.0, 26.3); p = 0.036], these differences did not persist at 6-months [15.0 (6.0, 28.5) versus 12.5 (3.0 and 27.5); p = 0.38] and 12-months [13.1 (3.75, 28.0) versus 11.0 (4.0 and 23.0); p = 0.37]. (Fig. 2, panel B) However, longitudinal IES-R scores were significantly lower by 4.2 points for males (versus females) in regression models [univariable [-4.5 points (-8.4, -0.6); p = 0.025]; multivariable [-4.2 points (-8.1, -0.20); p = 0.04}]. (eTable 4). Ordinal linear mixed effects models did not reveal sex differences in IES-R scores above and below 30.5. Interactions There were no significant sex by time or sex by disability group interactions in longitudinal FIM (eTable 2), BDI-II, or IES-R scores. Sex Differences in Healthcare Utilization of ICU Survivors after Hospital Discharge Although, we did not find sex differences in ICU and hospital readmission rates, disposition, or total specialist visits after ICU discharge, we found that whereas female ICU survivors had more rheumatology and nephrology specialist visits, males had more cardiology, endocrinology, surgical, and rehabilitation visits after hospital discharge. There were no sex by time or sex by disability group interactions. (eTable 5) Discussion Of 463 RECOVER participants who received invasive ventilation for at least 7-days, significantly more males versus females died in the ICU. Among 398 ICU survivors, median longitudinal FIM scores were significantly higher for male (versus female) participants up to 1-year after ICU discharge. Conversely, female ICU survivors had significantly higher BDI-II scores at all follow-up time points, were significantly more likely to experience moderate (versus mild) and severe (versus moderate) depression, and had significantly higher IES-R scores at 3-months after ICU discharge. Whereas, female survivors had more specialty visits with a rheumatologist and nephrologist, male ICU survivors had more specialty visits with a cardiologist, endocrinologist, surgeon, or rehabilitation specialist after hospital discharge. There were no sex by time or sex by disability group interactions for any outcome. Literature regarding sex differences in ICU outcomes remain sparse. ( 26 ) The impact of sex on short-term mortality in critically ill patients is inconsistent with studies suggesting higher ICU mortality in males ( 27 ), higher morality in older women ( 18 ), and no between-sex differences. ( 28 , 29 ) However, sex differences in outcomes may not only be attributed to biologic differences but also to factors that reflect access to care. ( 30 ) Moreover, bias in observational studies may arise due to indication bias, time-varying treatment and time-dependent confounding, and non-uniform treatment effects over time. ( 31 ) We found that male (versus female) participants were significantly more likely to die in ICU; however, male survivors had significantly better longitudinal FIM scores – raising the possibility of a survival bias. However, to mitigate the effect of the highest mortality in the first week of ventilation ( 30 ), we only included patients who were invasively ventilated at day 7. Similar to others ( 27 , 32 ), we included fewer invasively ventilated females (versus males). Contrary to a previous study that identified similar survival in males and females who received one or more organ supports ( 27 ), we found significantly higher ICU mortality in males ventilated for at least 7-days. Female sex has been consistently identified as a risk factor for ICU-acquired weakness in multicenter studies ( 33 ) and meta-analyses ( 34 ). In 95 patients who received invasive ventilation, De Jonghe and colleagues found that 25.3% of patients had ICU-acquired paresis with an odds ratio (OR) of 4.66. ( 33 ) Similarly, a meta-analysis of 32 studies identified increased disease severity (OR = 2.54), older age (OR = 2.19), and female sex (OR = 1.96) as risk factors for development of physical impairment. ( 34 ) Compared to 7-day FIM measurements, we found that FIM scores in male versus female RECOVER participants were 37.4, 42.2, and 45.9 points higher at 3, 6, and 12-months respectively. Multivariable regression models revealed a between-sex difference in longitudinal FIM scores of 6.2 points. Although the minimally clinically important difference (MCID) in FIM scores for ICU survivors at follow-up has not been characterized, a FIM change score of 22 points was identified as the MCID for stroke patients at hospital discharge ( 35 ) and for hip fracture patients after rehabilitation. ( 36 ) Following critical illness, females may be at increased risk for new mental health diagnoses. ( 34 ) A meta-analysis of 33 studies identified 3 significant risk factors for development of mental health diagnoses after critical illness including previous mental health problems (OR = 9.45), female sex (odds ratio [OR] = 3.37), and negative ICU experiences (OR = 2.59). ( 34 ) Herridge and coworkers, described that depressive symptoms (17%) and PTSD (18%) persisted up to 1-year after ICU discharge. ( 37 ) Hamilton and colleagues described that nearly a quarter (27.2%) of ICU survivors experienced moderate or severe depression symptom scores (BDI-II ≥ 20) to 1-year of follow-up. ( 38 ) Our data add to this literature by identifying sex differences in depression, with female ICU survivors experiencing both significantly higher BDI-II scores at all follow-up time points and more moderate and severe depression. We also found significantly higher IES-R scores in female ICU survivors at 3-months after ICU discharge. We did not identify sex differences in ICU and hospital readmission rates or in disposition. Similar to Garland et al, we found a hospital readmission rate of 40%; however, our cohort had a higher ICU readmission rate (10% versus 17%) likely reflecting different populations. ( 39 ) We noted that female ICU survivors had more rheumatology and nephrology specialty visits after hospital discharge, and males had more cardiology, endocrinology, surgical, and rehabilitation visits. (eTable 5) Strengths of our study include its multicenter prospective design, focus on patients invasively ventilated for ≥ 7-days, rigorous follow-up to 1-year after hospital discharge, and the application of SGBA. FIM change score accuracy was enhanced by the use of individual 7-day FIM score anchors as opposed to a sample measurement. ( 35 ) Finding lower longitudinal FIM scores in female ICU survivors has important implications for understanding their ability to recover functional independence, navigate care transitions, and resume prior roles at work and at home. ( 34 ) Importantly, disaggregation of our data by sex revealed novel information regarding sex differences in outcomes that was masked by aggregate analysis. These findings are hypothesis generating and warrant elucidation and confirmation in future research. Our study also has limitations. First, as an observational study, our findings may be subject to considerations and biases. Differences in ICU mortality may be influenced by sex differences in ICU admission rates, receipt of invasive ventilation, withholding/withdrawal practices, and consent rates. Similarly, differences in depression and PTSD may be confounded by sex-differences in treatment ( 40 ) or participant’s ability to access and participate in (social roles, caregiving responsibilities) longitudinal follow-up. ( 26 ) Healthcare utilization may be influenced by underlying comorbidities, development of new illnesses, referral bias/gender roles. For example, male survivors had more specialty visits with rehabilitation specialists despite having higher FIM scale scores at all follow-up time points. Second, although RECOVER was conducted in 9 ICUs (4 provinces), additional power to ascertain sex differences would have necessitated inclusion of more patients. Third, study centers were all urban, academic ICUs. Consequently, care practices and outcomes may not reflect those in other ICUs. Fourth, we lacked information regarding other determinants of health (gender, ethnicity, religion, language) that may influence treatment decisions, care delivery and processes, and outcomes. Finally, disposition data were not available for approximately 20% of our cohort. Declarations Acknowledgement: The authors wish to thank the members of the Canadian Critical Care Trials Group for their contributions to the trial methodology and implementation. The authors wish to thanks the patients and families for participating in the Canadian RECOVER study. Conflicts of Interest: Dr. Burns held a Physician Services Incorporated Mid-Career Research Award at the time of study design and initiation. Dr. Herridge holds a Canada Research Chair in Critical Illness Outcomes and the Recovery Continuum. Ethics Approval: The study protocol was approved by the Research Ethics Boards at University Health Network (no. 06-0157-AE, April 7, 2006) and by the ethics committees of participating ICUs. Consent: Informed consent was obtained from all individual participants or their substitute decision makers to participate in the study. Funding : This work was unfunded. Data Access, Responsibility, and Analysis EH and QL had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Requests for data access can be made in writing to Dr. Burns. Author Contributions: All authors contributed to the study conception and design. Material preparation [Margaret Herridge, Qixuan Li], data collection [Margaret Herridge], study design [Karen Burns, Margaret Herridge, Ella Huszti] and analysis were performed by [Qixuan Li, Ella Huszti]. 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Herridge MS, Chu LM, Matte A, Tomlinson G, Chan L, Thomas C, Friedrich JO, Mehta S, Lamontagne F, Levasseur M, Ferguson ND, Adhikari NK, Rudkowski JC, Meggison H, Skrobik Y, Flannery J, Bayley M, Batt J, Santos CD, Abbey SE, Tan A, Lo V, Mathur S, Parotto M, Morris D, Flockhart L, Fan E, Lee CM, Wilcox ME, Ayas N, Choong K, Fowler R, Scales DC, Sinuff T, Cuthbertson BH, Rose L, Robles P, Burns S, Cypel M, Singer L, Chaparro C, Chow CW, Keshavjee S, Brochard L, Hebert P, Slutsky AS, Marshall JC, Cook D, Cameron JI; RECOVER Program Investigators (Phase 1: Towards RECOVER); Canadian Critical Care Trials Group. (2016) The RECOVER Program: Disability Risk Groups and 1-Year Outcome after 7 or More Days of Mechanical Ventilation. Am J Respir Crit Care Med;194(7):831-44. doi: 10.1164/rccm.201512-2343OC. Oczkowski WJ, Barreca S. (1993) The functional independence measure: its use to identify rehabilitation needs in stroke survivors. Arch Phys Med Rehabil;74(12):1291-94. doi: 10.1016/0003-9993(93)90081-k. Beck AT, Steer RA, Brown GK. (1996) BDI-II, Beck Depression Inventory: Manual. San Antonio, TX: Psychological Corp. Weiss, D.S., & Marmar, C.R. (1997). The Impact of Event Scale-Revised. In J.P. Wilson, & T.M. Keane (Eds.), Assessing Psychological Trauma and PTSD: A Practitioner’s Handbook (pp. 399-411). New York: Guilford Press. Marshall JC, Cook DJ, Christou NV, Bernard GR, Sprung CL, Sibbald WJ. (1995) Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome. Crit Care Med;23:1638–52. doi: 10.1097/00003246-199510000-00007. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. (1985) APACHE II: a severity of disease classification system. Crit Care Med;13(10):818-29. PMID: 3928249. Ali AM, Al-Dossary SA, Mofdy Almarwani A, Atout M, Al-Amer R, Alkhamees AA. (2023) The Impact of Event Scale Revised: Examining Its Cutoff Scores among Arab Psychiatric Patients and Health Adults within the Context of COVID-19 as a Collective Traumatic Event. Healthcare;11:892. PMID: 36981549. Merdji H, Long MT, Ostermann M, Herridge M, Myatra SN, De Rosa S, et al. (2023) Sex and gender differences in intensive care medicine. Intensive Care Med;49(10):1155–67. doi: 10.1007/s00134-023-07194-6. Modra LJ, Higgins AM, Pilcher DV, Bailey MJ, Bellomo R. (2022) Sex differences in mortality of ICU patients according to diagnosis-related sex balance. Am J Respir Crit Care Med;206(11):1353–60. doi: 10.1164/rccm.202203-0539OC. Hollinger A, Gayat E, Feliot E, Paugam-Burtz C, Fournier MC, Duranteau J, et al. (2019) Gender and survival of critically ill patients: results from the FROG-ICU study. Ann Intensive Care;9(1):43. doi: 10.1186/s13613-019-0514-y. Kaufmann M, Perren A, Cerutti B, et al; (2020) Swiss Society of Intensive Care Medicine: Severity-adjusted ICU mortality only tells half the truth-the impact of treatment limitation in a nationwide database. Crit Care Med; 48:e1242–e1250. doi: 10.1097/CCM.0000000000004658. Kaplan V, Angus DC, Griffin MF, Clermont G, Watson RS, Linde-Zwirble WT. Hospitalized Community-acquired Pneumonia in the Elderly. (2002) Age- and Sex-related Patterns of Care and Outcome in the United States.Am J Respir Crit Care Med; 165: 766–72. doi: 10.1164/ajrccm.165.6.2103038. del Junco DJ, Fox EE, Camp EA, Rahbar MH, Holcomb JB on behalf of the PROMMTT Study Group. (2013) Seven Deadly Sins in Trauma Outcomes Research: An Epidemiologic Post-Mortem for Major Causes of Bias. J Trauma Acute Care Surg; 75(1 0 1): S97–S103. doi: 10.1097/TA.0b013e318298b0a4. Hessey E, Montgomery C, Zuege DJ, Rolfson D, Stelfox HT, Fiest KM, Bagshaw SM. (2020) Sex-specific prevalence and outcomes of frailty in critically ill patients. Journal of Intensive Care;8:75. doi: 10.1186/s40560-020-00494-9. De Jonghe B, Sharshar T, Lefaucheur JP, Authier FJ, Durand-Zaleski I, Boussarsar M, Cerf C, Renaud E, Mesrati F, Carlet J, Raphael JC, Outin H, Bastuji-Garin S, Groupe de Réflexion et d'Etude des Neuromyopathies en Réanimation. (2002) Paresis acquired in the intensive care unit: a prospective multicenter study. JAMA;288:2859-67. doi: 10.1001/jama.288.22.2859. Lee M, Kang J, Jeong YJ. (2020) Risk factors for post-intensive care syndrome: a systematic review and meta-analysis. Aust Crit Care;33:287–94. doi: 10.1016/j.aucc.2019.10.004. Beninato M, Gill-Body, Salles S, Stark PC, Black-Schaffer RM, Stein J. (2006) Determination of the Minimal Clinically Important Difference in the FIM Instrument in Patients With Stroke. Arch Phys Med Rehabil;87:32-9. doi: 10.1016/j.apmr.2005.08.130. Arcolin I, Godi M, Giardini M, Guglielmetti S, Bellotti L, Corna S. (2024) Minimal clinically important difference of the functional independence measure in older adults with hip fracture, Disability and Rehabilitation;46:4, 812-19. doi: 10.1080/09638288.2023.2175386. Herridge MS, Cheung AM, Tansey CM, Matte-Martyn A, Diaz-Granados N, Al-Saidi F, Cooper AB, Guest CB, Mazer CD, Mehta S, et al. (2003) Canadian Critical Care Trials Group. One-year outcomes in survivors of the acute respiratory distress syndrome. N Engl J Med;348:683–693. doi: 10.1056/NEJMoa022450. Hamilton M, Tomlinson G, Chu L, Robles P, Matte A, Burns S, Thomas C, Lamontagne F, Adhikari NKJ, Ferguson N, Friedrich JO, Rudkowski JC, Skrobik Y, Meggison H, Cameron J, Herridge M. for the RECOVER Program Investigators* and the Canadian Critical Care Trials Group. (2019) Determinants of Depressive Symptoms at 1-year Following ICU Discharge in Survivors of $ 7 Days of Mechanical Ventilation: Results From the RECOVER Program, a Secondary Analysis of a Prospective Multicenter Cohort Study. Chest;156(3):466-76. doi: 10.1016/j.chest.2019.04.104. Garland A, Olafson K, Ramsey CD, Yogendran M, Fransoo R.(2015) A Population-Based Observational Study of Intensive Care Unit–Related Outcomes With Emphasis on Post-Hospital Outcomes. Ann Am Thorac Soc;12: 202–8. doi: 10.1513/AnnalsATS.201405-201CME. Hauer D, Kaufmann I, Strewe C, Briegel I, Campolongo P, Schelling G. (2014) The role of glucocorticoids, catecholamines and endocannabinoids in the development of traumatic memories and posttraumatic distress symptoms in survivors of critical illness. Neurobiol Learn Mem;112:68–74. doi: 10.1016/j.nlm.2013.10.003. Tables Tables are available in the Supplementary Files section. Supplementary Files STROBEchecklistcohort3.docx SupplementaryTablesandFigures.docx Tables.docx Cite Share Download PDF Status: Published Journal Publication published 22 Jan, 2026 Read the published version in Intensive Care Medicine → Version 1 posted Reviewers agreed at journal 01 Jun, 2025 Reviewers invited by journal 28 May, 2025 Editor assigned by journal 24 May, 2025 First submitted to journal 21 May, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6717946","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":463212400,"identity":"96290805-729c-40b4-90e6-74a5aa552d6f","order_by":0,"name":"Karen E Burns","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABDklEQVRIiWNgGAWjYBACCQh1AEQwPgDzQUIPICIEtTAbAPkSYKGEhAMMPERoYZMACxDSItl+9uHjAoY7idtntz+r5t1hUWdwu/ngh8Qfdxjs2RuwapHmSTc2nsHwLHHOnTNmt3nPSEgY3DmWLJGQ8IyBhwe7f+QY0tikeRgOJ86QyGG7zdsG1HIjxwCo5TADj0QCdi38z9h/Q7SkPyuGaMn//AOfFmmJNDZmiJYEM2aoLWx4bZGc8YxZmsfgmTHQYcaSc9skJGfeSDOzSEg7zMNzBrtfJM6nMX7mqbgjC3TYww9v2+r4+W4kP77xweawHHs79hCDAAMktgLUbFzRggXI4zN7FIyCUTAKRiQAAMyYXEywkYI+AAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-9967-5424","institution":"St. Michael's Hospital","correspondingAuthor":true,"prefix":"","firstName":"Karen","middleName":"E","lastName":"Burns","suffix":""},{"id":463212401,"identity":"f521be42-ed5b-4ec6-ada5-8021e14edae6","order_by":1,"name":"Ella Huszti","email":"","orcid":"","institution":"Biostatistics Research Unit, Toronto General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ella","middleName":"","lastName":"Huszti","suffix":""},{"id":463212402,"identity":"b7ccaf38-f2b9-476e-b485-7de77a3d096b","order_by":2,"name":"Qixuan Li","email":"","orcid":"","institution":"Biostatistics Research Unit, Toronto General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Qixuan","middleName":"","lastName":"Li","suffix":""},{"id":463212403,"identity":"6f24d553-a805-458d-92fa-5e1320d27739","order_by":3,"name":"Margaret S. Herridge","email":"","orcid":"","institution":"University Health Network","correspondingAuthor":false,"prefix":"","firstName":"Margaret","middleName":"S.","lastName":"Herridge","suffix":""}],"badges":[],"createdAt":"2025-05-21 15:33:59","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6717946/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6717946/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00134-025-08267-4","type":"published","date":"2026-01-22T15:57:16+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":83837666,"identity":"cd12eee4-a8ee-4d61-af16-077ffcea3e76","added_by":"auto","created_at":"2025-06-03 13:25:54","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1209202,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFIM Scores of Male and Female RECOVER Participants Over Time\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure1WordKBurns.png","url":"https://assets-eu.researchsquare.com/files/rs-6717946/v1/8d63aceb0730f3dc4c8740f7.png"},{"id":83836537,"identity":"e9fba8a7-38e4-481e-b62f-069bb418daea","added_by":"auto","created_at":"2025-06-03 13:17:54","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1101777,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSex Differences in BDI-II and IES-R Scores Over Time\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure2WordKBurns.png","url":"https://assets-eu.researchsquare.com/files/rs-6717946/v1/98df7c389a9abc06eecd166f.png"},{"id":101151788,"identity":"453ac883-346a-410f-92a0-d9c5bfa34016","added_by":"auto","created_at":"2026-01-26 16:05:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3459468,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6717946/v1/2765bf19-84fb-4ac7-9357-f2025b455932.pdf"},{"id":83837665,"identity":"5ffff7f3-dcee-4c99-a040-82dd2f219e21","added_by":"auto","created_at":"2025-06-03 13:25:54","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":53288,"visible":true,"origin":"","legend":"","description":"","filename":"STROBEchecklistcohort3.docx","url":"https://assets-eu.researchsquare.com/files/rs-6717946/v1/57db2aae89320ce00288f99a.docx"},{"id":83836527,"identity":"aef9d99d-625c-456f-a58a-8a6b7db8c17e","added_by":"auto","created_at":"2025-06-03 13:17:54","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":111949,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTablesandFigures.docx","url":"https://assets-eu.researchsquare.com/files/rs-6717946/v1/2313eacef27cf820c6b966bd.docx"},{"id":83837668,"identity":"051ccc35-37d5-4d23-9945-c3677735f6da","added_by":"auto","created_at":"2025-06-03 13:25:54","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":22636,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-6717946/v1/10e403f845c6e35f2a6c96fb.docx"}],"financialInterests":"","formattedTitle":"Sex Differences in Mortality, Multidimensional Morbidity, and Health Care Utilization: A Secondary Analysis of the Canadian RECOVER Study","fulltext":[{"header":"Key points","content":"\u003cp\u003e\u003cstrong\u003eTake Home Messages:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMale (versus female) Canadian RECOVER patients experienced significantly higher ICU mortality.\u003c/p\u003e\n\u003cp\u003eMale patients started with higher median FIM scores and their longitudinal FIM scores were persistently higher than females up to 1-year after ICU discharge. \u003c/p\u003e\n\u003cp\u003eFemale ICU survivors experienced more frequent and severe depression and had significantly higher IES-R scores at 3-months compared to male survivors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTweet\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMales had significantly higher ICU mortality but female ICU survivors ventilated for at least 7-days had a higher burden of illness. \u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eSeveral international studies support that critical illness generates new and clinically important functional and neurocognitive disabilities that are additive to underlying organ dysfunction. (\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5 CR6\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) Moreover, return to functional independence for intensive care unit (ICU) survivors is multidimensional and complex. (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) Transparent reporting of long-term ICU outcomes is necessary to ensure accountability for the human and financial costs of outcomes in ICU survivors. Differences in health status and health inequities may worsen these outcomes. (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) Although several studies have highlighted the low representation of females and women as research participants in basic and clinical research (\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e), few studies have examined how sex (a biologic attribute) or gender (social roles) impact treatment responses and outcomes in critically ill patients. (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eSex- and gender-based analyses (SGBA) evaluate the assumption that a standardized approach to summarizing combined treatment effects and adverse event profiles of male and female (alternatively, men and women) research participants is sufficient. (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) The 2016 Sex and Gender Equity in Research (SAGER) guideline provided a comprehensive procedure for reporting of sex and gender information in trials. (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) This guideline applies to all research involving humans, animals, materials originating from humans and animals, and disciplines whose results may be applied to humans. (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) A systematic review of acute care trials published in leading medical journals identified that only a quarter of trials (26.1%) reported a SGBA. (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) Lack of disaggregation of data by sex or gender may lead to erroneous assumptions that treatment effects are similar in study participants. (\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e)\u003c/p\u003e \u003cp\u003ePrevious studies have assessed for sex and age differences in ICU care provision and outcomes. A large cohort study identified that fewer women than men were admitted to ICU. (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e) Additionally, older women were not only less likely to receive both care in an ICU setting and invasive ventilation but had an increased risk of ICU and hospital mortality. (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e) For Canadian RECOVER (hereafter RECOVER) participants who were invasively ventilated for at least 7 days (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e), we evaluated differences in sex and disability risk group membership on outcomes including ICU mortality, longitudinal Functional Independence Measure (FIM) scores, Beck Depression Inventory-II (BDI-II), Impact of Event Scale - Revised (IES-R) and healthcare utilization (disposition, readmission, specialty visits) up to 1-year after hospital discharge. We hypothesized that males would have higher FIM scores and females would have higher BDI-II and IES-R scores and lower healthcare utilization.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eParticipants\u003c/h2\u003e \u003cp\u003eRECOVER was a multicenter, prospective cohort study conducted between February 2007 and March 2014 at 9 university-affiliated medical/surgical ICUs in Vancouver, Hamilton, Toronto (4 sites), Ottawa, Montreal, and Sherbrooke, Canada. For patients who met eligibility criteria, written informed consent for follow-up to 7-days was obtained from substitute decision-makers. At 3-month follow-up, first person written informed consent was obtained to extend follow-up to 1-year from patients who had decision-making capacity. The study protocol was approved by the Research Ethics Boards at University Health Network (no. 06-0157-AE, April 7, 2006) and by the ethics committees of participating ICUs.\u003c/p\u003e \u003cp\u003ePotentially eligible patients were at least 16 years of age with dependence on invasive ventilation for \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;7-days. Detailed exclusion criteria have been summarized elsewhere. (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e) Patients were evaluated (physical exam, outcome measures) at 7-day and longitudinally at 3, 6, and 12-months after ICU discharge. (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e)\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eOutcome Measures\u003c/h3\u003e\n\u003cp\u003eWe assessed for sex differences in ICU mortality. In ICU survivors, we assessed longitudinal disability, using the FIM scale score that reflected participant\u0026rsquo;s level of independence with activities of daily living (e.g., eating, bathing, toileting, using stairs). (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) The FIM includes 18-items (13 motor tasks, 5 cognitive tasks) rated on a 7-point ordinal scale ranging from complete assistance to total independence; FIM motor subscale score ranged from 13\u0026ndash;91 with higher scores indicating greater functional independence. (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) Recovery trajectories were based on membership in 4 disability risk groups based on participant age and ICU length of stay (LOS) [Group 1 (Young, Short ICU LOS), Group 2 (Mixed age, Variable LOS), Group 3 (Older, Long ICU LOS) or Group 4 (Oldest, Long ICU LOS)]. (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eWe assessed for depressive symptoms using the BDI-II, a 21-question multiple-choice self-reported inventory with scores ranging from 0\u0026ndash;63. Higher BDI- II scores represented worse depressive symptoms. Depression severity was rated as mild (score 0\u0026ndash;13), minimal (\u003cspan additionalcitationids=\"CR15 CR16 CR17 CR18\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e), moderate (\u003cspan additionalcitationids=\"CR21 CR22 CR23 CR24 CR25 CR26 CR27\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e), or severe (29\u0026ndash;63). (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) We assessed for post-traumatic stress disorder (PTSD) symptoms using the IES-R, a 22-question self-reported questionnaire with scores ranging from 0\u0026ndash;88. Higher IES-R scores represented worse PTSD with scores greater than 24 being clinically concerning. (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) Finally, we assessed for differences in healthcare utilization (ICU and hospital readmission and mortality, disposition, and specialist visits) to 1-year after hospital discharge.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eCategorical variables were reported as counts and percentages, and group comparisons were performed using the Chi-squared test. Continuous variables were reported as medians with interquartile ranges (IQR). Group comparisons were performed using the Mann-Whitney U test.\u003c/p\u003e \u003cp\u003eWe generated Kaplan-Meier survival curves to compare time to ICU mortality by sex, and evaluated survival probabilities using the log-rank test. Sex differences in longitudinal outcomes, including FIM score (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e), BDI-II scores (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e), and IES-R scores (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e), were depicted with spaghetti plots. To examine for sex differences in ICU mortality, we used univariable and multivariable Cox proportional hazards models and included sex, the presence of one, two, or three or more comorbidities, corticosteroid use, slope of multiple organ dysfunction score (MODS) from 1 to 7-days (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e) and Acute Physiology and Chronic Health Evaluation (APACHE) II score (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e) as potential predictor variables. We report our findings using hazard ratios (HR) and 95% confidence intervals (CI).\u003c/p\u003e \u003cp\u003eFor longitudinal outcomes, univariable and multivariable linear mixed-effects regression models were used to assess for sex differences in FIM scores (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e), BDI-II scores (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e), and IES-R scores (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Univariable and multivariable ordinal logistic mixed-effects models were used to assess for sex differences in BDI-II severity (mild, moderate, severe). Univariable and multivariable logistic mixed-effects models were used to evaluate sex differences in IES-R scores, categorized as above or below 30.5. (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) In these models, we evaluated interaction effects (sex and time, sex and disability group) using the 7-day FIM score (alternatively, 3-month BDI-II or IES-R score) and the mixed age, variable LOS disability group (Group 2) as reference categories.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\"\u003e\n \u003ch2\u003eBaseline and Day-7 After ICU Discharge Characteristics\u003c/h2\u003e\n \u003cp\u003eOf 463 RECOVER participants (185 females, 278 males), 20 (10.8%) females and 45 (16.2%) males died in the ICU. Of 398 (165 females, 233 males) ICU survivors, 7 patients survived to ICU discharge but died before 7-day assessment. Of 391 remaining patients, 345 had 7-day, 206 had 3-month, 207 had 6-month, and 211 had 12-month follow-up FIM assessments. In descending order, participants were in disability risk groups; Group 3 (Old, Long ICU LOS; 67 (40.6%) females, 81 (34.8%) males], Group 2 (Mixed age, Variable ICU LOS; 47 (28.5%) females, 89 (38.2%) males], and Group 4 (Oldest, Long ICU LOS; 43 (26.1%) females, 49 (21.0%) males. Group 1 (Young, Short ICU LOS) had the fewest participants [8 (4.0%) females, 14 (6.1%) males; p\u0026thinsp;=\u0026thinsp;0.18). We present the baseline and day-7 characteristics by sex in Table 1.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\"\u003e\n \u003ch2\u003eSex Differences in ICU Mortality\u003c/h2\u003e\n \u003cp\u003eIn eFigure 1, we depict the ICU mortality of RECOVER participants (n\u0026thinsp;=\u0026thinsp;463) by sex using a Kaplan-Meier survival curve. After adjusting for number of comorbidities, MODS slope in the first 7-days of ICU, use of corticosteroids, and APACHE II score in a multivariable Cox Proportional Hazards model of ICU mortality, we identified significantly higher ICU mortality in male (versus females) [Hazard Ratio (HR) 1.8 (1.1, 3.1); p\u0026thinsp;=\u0026thinsp;0.03] RECOVER participants. Higher ICU mortality was significantly associated with increasing MODS slope (1 to 7)[HR 1.1 (1.0, 1.2); p\u0026thinsp;=\u0026thinsp;0.01], participants with a single (versus no) comorbidity [HR 2.7 (1.2, 6.1); p\u0026thinsp;=\u0026thinsp;0.02], and 3 or more (versus no) comorbidities [HR 6.1 (2.5, 14.7); p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001]. (Table 2)\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eSex Differences in Median FIM Scale Scores, Disability Risk Group Membership, and ICU Stay\u003c/h3\u003e\n\u003cp\u003eFor male and female ICU survivors, the median FIM score was lowest at 7-day and increased over time with the largest improvement in median FIM scores occurring between 7-day and 3-months. Although there were no differences in median FIM scores between males and females at 7-day (56.0 versus 61.0; p\u0026thinsp;=\u0026thinsp;0.17), FIM scores were significantly higher for male versus female ICU survivors at 3-months (117 versus 106; p\u0026thinsp;=\u0026thinsp;0.005), 6-months (119 versus 111.5; p\u0026thinsp;=\u0026thinsp;0.005), and 12-months (121 versus 115; p\u0026thinsp;=\u0026thinsp;0.003). (eTable 1) Male and female ICU survivors had similar ICU LOS (20 versus 19 days;\u0026thinsp;=\u0026thinsp;p\u0026thinsp;=\u0026thinsp;0.75) and were similarly represented across the four disability risk groups. (e Table\u0026nbsp;1)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSex Differences in Longitudinal FIM scales.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCompared to 7-day FIM measurements, FIM scores in males versus females survivors were higher by 37.4 points (34.3, 40.6); p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 at 3-months, 42.2 points (39.0, 45.4); p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 at 6-months, and 45.9 points (42.8, 49.1); p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 at 12-months. A Spaghetti plot illustrates that male ICU survivors started out with higher median FIM scores and the FIM scale score slope remained consistently higher and parallel to that of female ICU survivors over 1-year of follow-up. (Fig. 1) In a multivariable linear mixed effects model, male (versus female) sex was associated with 6.2 higher longitudinal FIM points in regression models [univariable [4.6 (-0.2, 9.7); p\u0026thinsp;=\u0026thinsp;0.08]; multivariable [6.2 (0.2, 12.2); p\u0026thinsp;=\u0026thinsp;0.04]. (Table 3) Compared to Group 2, there was a significant positive association between male sex and longitudinal FIM scores in the young, short ICU LOS Group [18.0 (5.5, 30.6); p\u0026thinsp;\u0026lt;\u0026thinsp;0.01], and conversely a significant negative associations between male sex and longitudinal FIM scores in the older, long ICU LOS Group [-10.6 (-17.3, -4.0); p\u0026thinsp;\u0026lt;\u0026thinsp;0.01] and the oldest, long ICU LOS Group [-20.6 (-28.4, -12.9); p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001]. (Table 3)\u003c/p\u003e\n\u003ch3\u003eSex Differences in Depression Scores\u003c/h3\u003e\n\u003cp\u003eOf 398 ICU survivors, 166 had 3-month, 170 had 6-month, and 175 had 12-month BDI-II scores. Female (versus male) survivors had significantly higher BDI-II scores at 3-months [12.50 (7.0, 18.0) versus 9.0 (5.3, 14.8); p\u0026thinsp;=\u0026thinsp;0.036], 6-months [11.8 (6.0, 17.8) versus 7.2 (3.0, 14.0); p\u0026thinsp;=\u0026thinsp;0.009], and 12-months [10.0 (4.0, 19.0) versus 11 (3.0, 26.3); p\u0026thinsp;=\u0026thinsp;0.036]. (Fig.\u0026nbsp;2; panel A) Although longitudinal BDI scale scores were significantly lower (3.5 points) in males (versus females) in both univariable [-3.6 (-5.8, -1.4); p\u0026thinsp;\u0026lt;\u0026thinsp;0.01] and multivariable [-3.5 (-5.7, -1.4); p\u0026thinsp;\u0026lt;\u0026thinsp;0.01] regression models (eTable 3), we did not find significant sex differences in slopes over time.\u003c/p\u003e\n\u003cp\u003eMost BDI-II scores were in the mild depressive symptom range. Univariable ordinal logistic mixed effects identified that male (versus female) ICU survivors were as likely to experience mild (versus minimal) depression [OR 1.47 (0.8, 2.7); p\u0026thinsp;=\u0026thinsp;0.21] but were significantly less likely to be experience moderate (versus mild) [OR 6.9 (3.5, 13.7); p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001] and severe (versus moderate)[OR 40.9 (17.1, 98.2); p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001] depression with nonsignificant sex by time and sex by disability group interactions.\u003c/p\u003e\n\u003cdiv id=\"Sec11\"\u003e\n \u003ch2\u003eSex Differences in Impact Event Scale-R Scores\u003c/h2\u003e\n \u003cp\u003eOf 398 ICU survivors, 164 had 3-month, 170 had 6-month, and 174 had 12-month IES-R scores. Although IES-R scores were significantly higher in females (versus males) at 3-months [19.0 (8.25, 29.5) versus 11.0 (3.0, 26.3); p\u0026thinsp;=\u0026thinsp;0.036], these differences did not persist at 6-months [15.0 (6.0, 28.5) versus 12.5 (3.0 and 27.5); p\u0026thinsp;=\u0026thinsp;0.38] and 12-months [13.1 (3.75, 28.0) versus 11.0 (4.0 and 23.0); p\u0026thinsp;=\u0026thinsp;0.37]. (Fig.\u0026nbsp;2, panel B) However, longitudinal IES-R scores were significantly lower by 4.2 points for males (versus females) in regression models [univariable [-4.5 points (-8.4, -0.6); p\u0026thinsp;=\u0026thinsp;0.025]; multivariable [-4.2 points (-8.1, -0.20); p\u0026thinsp;=\u0026thinsp;0.04}]. (eTable 4). Ordinal linear mixed effects models did not reveal sex differences in IES-R scores above and below 30.5.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\"\u003e\n \u003ch2\u003eInteractions\u003c/h2\u003e\n \u003cp\u003eThere were no significant sex by time or sex by disability group interactions in longitudinal FIM (eTable 2), BDI-II, or IES-R scores.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\"\u003e\n \u003ch2\u003eSex Differences in Healthcare Utilization of ICU Survivors after Hospital Discharge\u003c/h2\u003e\n \u003cp\u003eAlthough, we did not find sex differences in ICU and hospital readmission rates, disposition, or total specialist visits after ICU discharge, we found that whereas female ICU survivors had more rheumatology and nephrology specialist visits, males had more cardiology, endocrinology, surgical, and rehabilitation visits after hospital discharge. There were no sex by time or sex by disability group interactions. (eTable 5)\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eOf 463 RECOVER participants who received invasive ventilation for at least 7-days, significantly more males versus females died in the ICU. Among 398 ICU survivors, median longitudinal FIM scores were significantly higher for male (versus female) participants up to 1-year after ICU discharge. Conversely, female ICU survivors had significantly higher BDI-II scores at all follow-up time points, were significantly more likely to experience moderate (versus mild) and severe (versus moderate) depression, and had significantly higher IES-R scores at 3-months after ICU discharge. Whereas, female survivors had more specialty visits with a rheumatologist and nephrologist, male ICU survivors had more specialty visits with a cardiologist, endocrinologist, surgeon, or rehabilitation specialist after hospital discharge. There were no sex by time or sex by disability group interactions for any outcome.\u003c/p\u003e \u003cp\u003eLiterature regarding sex differences in ICU outcomes remain sparse. (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e) The impact of sex on short-term mortality in critically ill patients is inconsistent with studies suggesting higher ICU mortality in males (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e), higher morality in older women (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e), and no between-sex differences. (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e) However, sex differences in outcomes may not only be attributed to biologic differences but also to factors that reflect access to care. (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e) Moreover, bias in observational studies may arise due to indication bias, time-varying treatment and time-dependent confounding, and non-uniform treatment effects over time. (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e) We found that male (versus female) participants were significantly more likely to die in ICU; however, male survivors had significantly better longitudinal FIM scores \u0026ndash; raising the possibility of a survival bias. However, to mitigate the effect of the highest mortality in the first week of ventilation (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e), we only included patients who were invasively ventilated at day 7. Similar to others (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e), we included fewer invasively ventilated females (versus males). Contrary to a previous study that identified similar survival in males and females who received one or more organ supports (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e), we found significantly higher ICU mortality in males ventilated for at least 7-days.\u003c/p\u003e \u003cp\u003eFemale sex has been consistently identified as a risk factor for ICU-acquired weakness in multicenter studies (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e) and meta-analyses (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). In 95 patients who received invasive ventilation, De Jonghe and colleagues found that 25.3% of patients had ICU-acquired paresis with an odds ratio (OR) of 4.66. (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e) Similarly, a meta-analysis of 32 studies identified increased disease severity (OR\u0026thinsp;=\u0026thinsp;2.54), older age (OR\u0026thinsp;=\u0026thinsp;2.19), and female sex (OR\u0026thinsp;=\u0026thinsp;1.96) as risk factors for development of physical impairment. (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e) Compared to 7-day FIM measurements, we found that FIM scores in male versus female RECOVER participants were 37.4, 42.2, and 45.9 points higher at 3, 6, and 12-months respectively. Multivariable regression models revealed a between-sex difference in longitudinal FIM scores of 6.2 points. Although the minimally clinically important difference (MCID) in FIM scores for ICU survivors at follow-up has not been characterized, a FIM change score of 22 points was identified as the MCID for stroke patients at hospital discharge (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e) and for hip fracture patients after rehabilitation. (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eFollowing critical illness, females may be at increased risk for new mental health diagnoses. (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e) A meta-analysis of 33 studies identified 3 significant risk factors for development of mental health diagnoses after critical illness including previous mental health problems (OR\u0026thinsp;=\u0026thinsp;9.45), female sex (odds ratio [OR]\u0026thinsp;=\u0026thinsp;3.37), and negative ICU experiences (OR\u0026thinsp;=\u0026thinsp;2.59). (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e) Herridge and coworkers, described that depressive symptoms (17%) and PTSD (18%) persisted up to 1-year after ICU discharge. (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e) Hamilton and colleagues described that nearly a quarter (27.2%) of ICU survivors experienced moderate or severe depression symptom scores (BDI-II\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;20) to 1-year of follow-up. (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e) Our data add to this literature by identifying sex differences in depression, with female ICU survivors experiencing both significantly higher BDI-II scores at all follow-up time points and more moderate and severe depression. We also found significantly higher IES-R scores in female ICU survivors at 3-months after ICU discharge.\u003c/p\u003e \u003cp\u003eWe did not identify sex differences in ICU and hospital readmission rates or in disposition. Similar to Garland et al, we found a hospital readmission rate of 40%; however, our cohort had a higher ICU readmission rate (10% versus 17%) likely reflecting different populations. (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e) We noted that female ICU survivors had more rheumatology and nephrology specialty visits after hospital discharge, and males had more cardiology, endocrinology, surgical, and rehabilitation visits. (eTable 5)\u003c/p\u003e \u003cp\u003eStrengths of our study include its multicenter prospective design, focus on patients invasively ventilated for \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;7-days, rigorous follow-up to 1-year after hospital discharge, and the application of SGBA. FIM change score accuracy was enhanced by the use of individual 7-day FIM score anchors as opposed to a sample measurement. (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e) Finding lower longitudinal FIM scores in female ICU survivors has important implications for understanding their ability to recover functional independence, navigate care transitions, and resume prior roles at work and at home. (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e) Importantly, disaggregation of our data by sex revealed novel information regarding sex differences in outcomes that was masked by aggregate analysis. These findings are hypothesis generating and warrant elucidation and confirmation in future research. Our study also has limitations. First, as an observational study, our findings may be subject to considerations and biases. Differences in ICU mortality may be influenced by sex differences in ICU admission rates, receipt of invasive ventilation, withholding/withdrawal practices, and consent rates. Similarly, differences in depression and PTSD may be confounded by sex-differences in treatment (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e) or participant\u0026rsquo;s ability to access and participate in (social roles, caregiving responsibilities) longitudinal follow-up. (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e) Healthcare utilization may be influenced by underlying comorbidities, development of new illnesses, referral bias/gender roles. For example, male survivors had more specialty visits with rehabilitation specialists despite having higher FIM scale scores at all follow-up time points. Second, although RECOVER was conducted in 9 ICUs (4 provinces), additional power to ascertain sex differences would have necessitated inclusion of more patients. Third, study centers were all urban, academic ICUs. Consequently, care practices and outcomes may not reflect those in other ICUs. Fourth, we lacked information regarding other determinants of health (gender, ethnicity, religion, language) that may influence treatment decisions, care delivery and processes, and outcomes. Finally, disposition data were not available for approximately 20% of our cohort.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgement:\u0026nbsp;\u003c/strong\u003eThe authors wish to thank the members of the Canadian Critical Care Trials Group for their contributions to the trial methodology and implementation. The authors wish to thanks the patients and families for participating in the Canadian RECOVER study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDr. Burns held a Physician Services Incorporated Mid-Career Research Award at the time of study design and initiation. Dr. Herridge holds a Canada Research Chair in Critical Illness Outcomes and the Recovery Continuum.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval:\u003c/strong\u003e The study protocol was approved by the Research Ethics Boards at University Health Network (no. 06-0157-AE, April 7, 2006) and by the ethics committees of participating ICUs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent:\u003c/strong\u003e Informed consent was obtained from all individual participants or their substitute decision makers to participate in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: This work was unfunded.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Access, Responsibility, and Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEH and QL had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Requests for data access can be made in writing to Dr. Burns.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u0026nbsp;\u003c/strong\u003eAll authors contributed to the study conception and design. Material preparation [Margaret Herridge, Qixuan Li], data collection [Margaret Herridge], study design [Karen Burns, Margaret Herridge, Ella Huszti] and analysis were performed by [Qixuan Li, Ella Huszti]. The first draft of the manuscript was written by [Karen Burns] and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eIwashyna TJ, Ely EW, Smith DM, Langa KM. (2010) Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA;304:1787-94. doi: 10.1001/jama.2010.1553.\u003c/li\u003e\n\u003cli\u003eEhlenbach WJ, Hough CL, Crane PK, et al. 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N Engl J Med;348:683\u0026ndash;693. doi: 10.1056/NEJMoa022450.\u003c/li\u003e\n\u003cli\u003eHamilton M, Tomlinson G, Chu L, Robles P, Matte A, Burns S, Thomas C, Lamontagne F, Adhikari NKJ, Ferguson N, Friedrich JO, Rudkowski JC, Skrobik Y, Meggison H, Cameron J, Herridge M. for the RECOVER Program Investigators* and the Canadian Critical Care Trials Group. (2019) Determinants of Depressive Symptoms at 1-year Following ICU Discharge in Survivors of $ 7 Days of Mechanical Ventilation: Results From the RECOVER Program, a Secondary Analysis of a Prospective Multicenter Cohort Study. Chest;156(3):466-76. doi: 10.1016/j.chest.2019.04.104.\u003c/li\u003e\n\u003cli\u003eGarland A, Olafson K, Ramsey CD, Yogendran M, Fransoo R.(2015) A Population-Based Observational Study of Intensive Care Unit\u0026ndash;Related Outcomes With Emphasis on Post-Hospital Outcomes. 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Neurobiol Learn Mem;112:68\u0026ndash;74. doi: 10.1016/j.nlm.2013.10.003.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are available in the Supplementary Files section.\u003c/p\u003e\n"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"intensive-care-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"icme","sideBox":"Learn more about [Intensive Care Medicine](http://link.springer.com/journal/134)","snPcode":"134","submissionUrl":"https://www.editorialmanager.com/icme/default2.aspx","title":"Intensive Care Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"sex, gender, sex and gender based analysis, critical illness, functional independence, depression","lastPublishedDoi":"10.21203/rs.3.rs-6717946/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6717946/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003ePurpose\u003c/b\u003e\u003c/p\u003e \u003cp\u003eWe assessed for differences in sex and disability group membership in ICU mortality, longitudinal Functional Independence Measure (FIM) scores, Beck Depression Inventory-II (BDI-II), Impact of Event Scale - Revised (IES-R), and healthcare utilization to 1-year after intensive care unit (ICU) discharge.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eSecondary analysis of medical/surgical patients in the Canadian Towards RECOVER study.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eOf 463 (185 females, 278 males) participants, significantly more males 45 (16.2%) versus females 20 (10.8%) died in the ICU [Hazard Ratio (HR) 1.8 (1.1, 3.1); p\u0026thinsp;=\u0026thinsp;0.03]. Of 398 (165 females, 233 males) ICU survivors, 391 had FIM scores. Median FIM scores were significantly higher for male (versus female) survivors at 3-months (117 versus 106 points; p\u0026thinsp;=\u0026thinsp;0.005), 6-months (119 versus 111.5 points; p\u0026thinsp;=\u0026thinsp;0.005), and 12-months (121 versus 115 points; p\u0026thinsp;=\u0026thinsp;0.003). Conversely, female (versus male) survivors had significantly higher BDI-II scores at 3-months [12.50 (7.0, 18.0) versus 9.0 (5.3, 14.8); p\u0026thinsp;=\u0026thinsp;0.036], 6-months [11.8 (6.0, 17.8) versus 7.2 (3.0, 14.0); p\u0026thinsp;=\u0026thinsp;0.009], 12-months [10.0 (4.0, 19.0) versus 11 (3.0, 26.3); p\u0026thinsp;=\u0026thinsp;0.036] and higher IES-R scores at 3-months. Female survivors also experienced significantly more moderate (versus mild) [OR 6.9 (3.5, 13.7); p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001] and severe (versus moderate)[OR 40.9 (17.1, 98.2); p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001] depression. Whereas female ICU survivors had more rheumatology and nephrology specialty visits, males had more cardiology, endocrinology, surgical, and rehabilitation visits. There were no sex by time or sex by disability group interactions.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusions\u003c/b\u003e\u003c/p\u003e \u003cp\u003eAlthough male ICU survivors experienced significantly higher ICU mortality, females experienced significantly lower longitudinal FIM scores and more frequent and severe depression.\u003c/p\u003e","manuscriptTitle":"Sex Differences in Mortality, Multidimensional Morbidity, and Health Care Utilization: A Secondary Analysis of the Canadian RECOVER Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-03 13:17:49","doi":"10.21203/rs.3.rs-6717946/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2025-06-01T19:57:09+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-05-28T16:31:47+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-05-24T11:16:39+00:00","index":"","fulltext":""},{"type":"submitted","content":"Intensive Care Medicine","date":"2025-05-21T11:33:11+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"intensive-care-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"icme","sideBox":"Learn more about [Intensive Care Medicine](http://link.springer.com/journal/134)","snPcode":"134","submissionUrl":"https://www.editorialmanager.com/icme/default2.aspx","title":"Intensive Care Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"f23c2880-7245-4ffe-afdf-f52f401e4b85","owner":[],"postedDate":"June 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-26T16:01:46+00:00","versionOfRecord":{"articleIdentity":"rs-6717946","link":"https://doi.org/10.1007/s00134-025-08267-4","journal":{"identity":"intensive-care-medicine","isVorOnly":false,"title":"Intensive Care Medicine"},"publishedOn":"2026-01-22 15:57:16","publishedOnDateReadable":"January 22nd, 2026"},"versionCreatedAt":"2025-06-03 13:17:49","video":"","vorDoi":"10.1007/s00134-025-08267-4","vorDoiUrl":"https://doi.org/10.1007/s00134-025-08267-4","workflowStages":[]},"version":"v1","identity":"rs-6717946","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6717946","identity":"rs-6717946","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}