Can J Anesth/J Can Anesth (2022) 69:1390–1398 https://doi.org/10.1007/s12630-022-02304-2 REPORTS OF ORIGINAL INVESTIGATIONS Sex-specific treatment characteristics and 30-day mortality outcomes of critically ill COVID-19 patients over 70 years of age—results from the prospective COVIP study Caractéristiques des traitements en fonction du sexe et résultats de mortalité à 30 jours des patients atteints de COVID-19 gravement malades de plus de 70 ans—résultats de l’étude prospective COVIP Georg Wolff, MD . Bernhard Wernly, MD, PhD . Hans Flaatten, MD, PhD . Jesper Fjølner, MD Raphael Romano Bruno, MD . Antonio Artigas, MD, PhD . . Bernardo Bollen Pinto, MD . Joerg C. Schefold, MD . Malte Kelm, MD . Stephan Binneboessel, MD . Philipp Baldia, MD . Michael Beil, MD . Sigal Sivri, MD . Peter Vernon van Heerden, MD . Wojciech Szczeklik, MD, PhD . Muhammed Elhadi, MD . Michael Joannidis, MD . Sandra Oeyen, MD . Maria Flamm, MD, PhD . Tilemachos Zafeiridis, MD . Brian Marsh, MD . Finn H. Andersen, MD . Rui Moreno, MD, PhD . Ariane Boumendil, PhD . Dylan W. De Lange, MD, PhD . Bertrand Guidet, MD, PhD . Susannah Leaver, MD . Christian Jung, MD, PhD on behalf of the COVIP Study Group Received: 21 January 2022 / Revised: 6 May 2022 / Accepted: 6 May 2022 / Published online: 9 August 2022 Ó The Author(s) 2022 Abstract differences in treatment and outcome after intensive care Purpose Older critically ill patients with COVID-19 have unit (ICU) admission in this cohort. been the most vulnerable during the ongoing pandemic, Methods We performed a sex-specific analysis in with men being more prone to hospitalization and severe critically ill patients C 70 yr of age with COVID-19 who disease than women. We aimed to explore sex-specific were included in the international prospective multicenter COVIP study. All patients were analyzed for ICU admission and treatment characteristics. We performed a The COVIP study group (https://www.vipstudy.org; covip@med.uni- multilevel adjusted regression analysis to elucidate duesseldorf.de) is part of the Very Old Intensive Care Patients (VIP) associations of sex with 30-day mortality. project by the European Society of Intensive Care Medicine (ESICM). Results A total of 3,159 patients (69.8% male, 30.2% Supplementary Information The online version contains female; median age, 75 yr) were included. Male patients supplementary material available at https://doi.org/10.1007/s12630- were significantly fitter than female patients as determined 022-02304-2. G. Wolff, MD  R. R. Bruno, MD  M. Kelm, MD  H. Flaatten, MD, PhD S. Binneboessel, MD  P. Baldia, MD Department of Clinical Medicine, Department of Anaesthesia Department of Cardiology, Pulmonology and Vascular and Intensive Care, Haukeland University Hospital, University of Medicine, Heinrich-Heine-University Düsseldorf, Medical Bergen, Bergen, Norway Faculty, Düsseldorf, Germany J. Fjølner, MD B. Wernly, MD, PhD Department of Intensive Care, Aarhus University Hospital, Department of Anaesthesiology, Perioperative Medicine and Aarhus, Denmark Intensive Care Medicine, Paracelsus Medical University, Salzburg, Austria 123 Sex differences in older critically ill COVID-19 patients 1391 by the Clinical Frailty Scale (fit, 67% vs 54%; vulnerable, sexe et la mortalite´ à 30 jours. 14% vs 19%; frail, 19% vs 27%; P\0.001). Male patients Résultats Au total, 3159 patients (69,8 % d’hommes, 30,2 % more often underwent tracheostomy (20% vs 14%; odds de femmes; âge me´dian, 75 ans) ont e´te´ inclus. Les patients de ratio [OR], 1.57; P \ 0.001), vasopressor therapy (69% vs sexe masculin e´taient significativement plus en forme que les 62%; OR, 1.25; P = 0.02), and renal replacement therapy patientes, tel que de´termine´ par l’e´chelle de fragilite´ clinique (17% vs 11%; OR, 1.96; P \ 0.001). There was no (bonne sante´, 67 % vs 54 %; vulne´rables, 14 % vs 19 %; fragiles, difference in mechanical ventilation, life-sustaining 19 % vs 27 %; P\0,001). Les patients de sexe masculin ont plus treatment limitations, and crude 30-day mortality (50% souvent be´ne´ficie´ d’une trache´ostomie (20 % vs 14 %; rapport male vs 49% female; OR, 1.11; P = 0.19), which remained de cotes [RC], 1,57; P\0,001), d’un traitement vasopresseur true after adjustment for disease severity, frailty, age and (69 % vs 62 %; RC, 1,25; P = 0,02) et d’un traitement substitutif treatment limitations (OR, 1.17; 95% confidence interval, de l’insuffisance re´nale (17 % vs 11 %; RC, 1,96; P\0,001). Il 0.94 to 1.45; P = 0.16). n’y avait aucune diffe´rence en matie`re de ventilation Conclusion In this analysis of sex-specific treatment me´canique, de limites des traitements de maintien en vie et de characteristics and 30-day mortality outcomes of mortalite´brute à 30 jours (50 % d’hommes vs 49 % de femmes; critically ill patients with COVID-19 C 70 yr of age, we RC, 1,11; P = 0,19), ce qui est demeure´le cas apre`s ajustement found more tracheostomy and renal replacement therapy in pour tenir compte de la gravite´de la maladie, de la fragilite´, de male vs female patients, but no significant association of l’âge et des limites du traitement (RC, 1,17 ; intervalle de patient sex with 30-day mortality. confiance à 95 %, 0,94 à 1,45; P = 0,16). Study registration www.ClinicalTrials.gov (NCT04321 Conclusion Dans cette analyse des caracte´ristiques de 265); registered 25 March 2020). traitement spe´cifiques au sexe et des re´sultats de mortalite´ à 30 jours des patients gravement malades atteints de Résumé COVID-19 de C 70 ans, nous avons note´ un nombre plus Objectif Les patients âge´s gravement malades atteints de e´leve´ de trache´otomies et de traitements substitutifs de la COVID-19 ont e´te´ les plus vulne´rables pendant la l’insuffisance re´nale chez les hommes vs les femmes, mais pande´mie actuelle, les hommes e´tant plus sujets à aucune association significative entre le sexe des patients l’hospitalisation et aux maladies graves que les femmes. et la mortalite´ à 30 jours. Nous avons cherche´ à explorer les diffe´rences spe´cifiques Enregistrement de l’étude zwww.ClinicalTrials.gov (NCT- au sexe dans le traitement et les devenirs apre`s l’admission 04321265); enregistre´ le 25 mars 2020. à l’unite´ de soins intensifs (USI) dans cette cohorte. Méthode Nous avons effectue´ une analyse spe´cifique au Keywords COVID  COVIP  critical illness  elderly  sexe chez des patients gravement malades âge´s de C 70 ans mortality  sex atteints de COVID-19 qui ont e´te´ inclus dans l’e´tude prospective multicentrique internationale COVIP. Tous les patients ont e´te´ analyse´s pour connaıˆtre les de´tails de leur The ongoing COVID-19 pandemic poses serious admission à l’USI et les caracte´ristiques de leur traitement. challenges to patients and healthcare systems worldwide. Nous avons re´alise´ une analyse de re´gression ajuste´e à Older patients C 70 yr of age have been disproportionally plusieurs niveaux pour e´lucider les associations entre le A. Artigas, MD, PhD P. V. van Heerden, MD Department of Intensive Care Medicine, CIBER Enfermedades Department of Anesthesia, Intensive Care and Pain Medicine, Respiratorias, Corporacion Sanitaria Universitaria Parc Tauli, Hadassah Medical Center and Faculty of Medicine, Hebrew Autonomous University of Barcelona, Sabadell, Spain University of Jerusalem, Jerusalem, Israel B. B. Pinto, MD W. Szczeklik, MD, PhD Department of Acute Medicine, Geneva University Hospitals, Department of Intensive Care and Perioperative Medicine, Geneva, Switzerland Jagiellonian University Medical College, Kraków, Poland J. C. Schefold, MD M. Elhadi, MD Department of Intensive Care Medicine, Inselspital, Faculty of Medicine, University of Tripoli, Tripoli, Libya Universitätsspital, University of Bern, Bern, Switzerland M. Joannidis, MD M. Beil, MD  SigalSivri, MD Division of Intensive Care and Emergency Medicine, Department of Medical Intensive Care, Hadassah Medical Department of Internal Medicine, Medical University Innsbruck, Center and Faculty of Medicine, Hebrew University of Innsbruck, Austria Jerusalem, Jerusalem, Israel 123 1392 G. Wolff et al. affected by COVID-19 with severe disease courses and a on 19 March 2020, and recruited COVID-19 patients C 70 yr high risk of mortality.1 admitted to an ICU. The COVIP study was conducted by the Since the beginning of the pandemic, data from across Very Old Intensive Care Patients (VIP) project within the the world have identified patient characteristics associated European Society of Intensive Care Medicine (www. with risk for adverse clinical outcomes of COVID-19. Age, vipstudy.org) in 376 ICUs in 44 countries, where the study male sex, comorbidities,2 and severity of disease course3 protocol and case report forms are available to download. have been identified as prognostic factors. Nevertheless, Ethical approval by an institutional review board was data on their validity in older patients with critical illness mandatory for study participation in each country. Patients remain limited. Frailty and associated factors might have were included after informed consent and consented to an additional important impact on prognosis.4 publication upon study inclusion. The study was registered at Prior to the COVID-19 pandemic, patient sex had not been www.ClinicalTrials.gov (ID: NCT04321265; 25 March associated with mortality in large observational registries of 2020) and adhered to the European Union General Data unselected critically ill patients.5,6 Nevertheless, studies Privacy Regulation directive, which is implemented in most focusing on older patient populations found that male sex participating countries. The study intentionally allowed for was a risk factor for adverse outcomes,7,8 as is also the case in coenrolment of study patients in other COVID-19 studies. COVID-19.9 Exploring patient sex as a risk factor in older Other analyses have been previously published from the critically ill patients with COVID-19 may thus have COVIP database (e.g., the impact of frailty on survival4). implications for treatment and prognosis of the most Study population vulnerable patient subgroup. We hypothesized that older male patients with severe COVID-19 may have a worse Each participating center included consecutive patients aged prognosis than females. 70 yr or older with COVID-19 (confirmed by a positive The COVIP study is an international prospective SARS-CoV-2 polymerase chain reaction result) at admission multicenter study of critically ill patients C 70 yr of age to the ICU. Each patient was only included once in the study, with COVID-19 treated in an intensive care unit (ICU). In regardless of possible readmission, transfer to another ICU, this analysis from its database, we aimed to explore sex- etc. In case of a patient transfer or readmission, data were specific treatment characteristics and clinical outcomes in summed up within a single case, which resulted in a unique critically ill patients with COVID-19 and hypothesized that electronic database record per patient. Other than duration of there are sex-specific differences in treatment and lower symptoms and duration of hospitalization, pre-ICU disease mortality in female patients in this population. course and possible pre-ICU triage due to resource shortage during pandemic surges were not specifically recorded. The reference date was day 1 of the first ICU admission with all Methods consecutive time points relative to this date. Study design Data collection This work is a secondary analysis of the international Centers collected data on patient baseline characteristics, prospective multicenter COVIP study, which was initiated ICU admission characteristics, ICU disease course, and S. Oeyen, MD Department of Circulation and Medical Imaging, Norwegian Department of Intensive Care 1K12IC, Ghent University University of Science and Technology, Trondheim, Norway Hospital, Ghent, Belgium R. Moreno, MD, PhD M. Flamm, MD, PhD Unidade de Cuidados Intensivos Neurocrı́ticos e Trauma, Institute of General Practice, Family Medicine and Preventive Hospital de São José, Centro Hospitalar Universitário de Lisboa Medicine, Paracelsus Medical University, Salzburg, Austria Central, Faculdade de Ciências Médicas de Lisboa, Nova Médical School, Lisbon, Portugal T. Zafeiridis, MD Intensive Care Unit General Hospital of Larissa, Larissa, Greece A. Boumendil, PhDB. Guidet, MD, PhD Sorbonne Universités, UPMC Univ Paris, Institut Pierre Louis B. Marsh, MD d’Epidémiologie et de Santé Publique, Equipe: épidémiologie Mater Misericordiae University Hospital, Dublin, Ireland hospitalière qualité et organisation des soins, Paris, France, Assistance Publique - Hôpitaux de Paris, Hôpital Saint-Antoine, F. H. Andersen, MD Service de Réanimation Médicale, Paris, France Department of Anesthesia and Intensive Care, Ålesund Hospital, Ålesund, Norway 123 Sex differences in older critically ill COVID-19 patients 1393 clinical outcomes using a uniform electronic case report treatments, which were documented according to form (eCRF). No direct patient identifying characteristics international recommendations.12 like name or other ID were registered in the database. As described previously,10 the eCRF and database runs on Statistical analysis secure servers composed and stored in Aarhus University, Denmark. These servers were operated in cooperation All statistical computations were performed using Stata/BE between the Information Technology Department and the 17.0 for Mac (Intel 64-bit; StataCorp LLC, College Station, Department of Clinical Medicine at the University. TX, USA). Patients included in the COVIP study between Prior diagnoses of diabetes (any type), ischemic heart 19 March 2020, and 4 February 2021, were analyzed and disease, chronic renal insufficiency (creatinine clearance grouped into male or female. Patients with missing data for \ 60 mLmin-1), arterial hypertension (any grade), sex or 30-day mortality were excluded, and other missing pulmonary disease (any type), and chronic heart failure data were handled using listwise deletion (Electronic (any type) were recorded. The frailty level prior to hospital Supplementary Material [ESM], eTable 1). Sex-subgroup admission for COVID-19 was assessed using the English differences regarding baseline characteristics, ICU version of the Clinical Frailty Scale (CFS),11 classifying admission characteristics, ICU disease course, and patients into nine classes from very fit to terminally ill. clinical outcomes were analyzed. Continuous variables Patients were grouped as fit (CFS of 1–3), vulnerable (CFS are reported as medians with interquartile range (IQR), and of 4), and frail (CFS of 5–9) for data analysis. The categorical variables as counts with % of total or respective Sequential Organ Failure Assessment (SOFA) score on sex subgroup. Normal distribution of continuous variables ICU admission was calculated either manually or using an was empirically tested using the Shapiro–Wilk and online calculator in the eCRF as described previously.10,11 Kolmogorov–Smirnov tests. Comparisons were performed Type and duration of organ support were recorded in detail using Mann–Whitney U tests (for non-normally distributed regarding noninvasive and invasive mechanical ventilation, variables) and Student’s t tests (normally distributed prone positioning, tracheostomy, vasopressor therapy, and variables). Categorical variables were compared using renal replacement therapy. Chi-square tests. Three sequential multilevel logistic regression models Clinical outcome assessment were used to evaluate the associations of patient sex with ICU disease course and clinical outcomes. Included The primary endpoint was survival assessed at 30 days variables were selected based on previous literature and after ICU admission, which was either assessed directly our own clinical experience—a detailed description is from the hospital administration system, or in follow-up by given in ESM eTable 1. First, a baseline model with male telephone. Secondary outcomes were disease-specific sex as a fixed effect and effects of the singular specific ICU variables of noninvasive ventilation, intubation, site as a random effect (model 1) was fitted, which tracheostomy, prone positioning, vasopressor therapy, corrected for possible bias (recruitment/treatment) on an renal replacement therapy, and limitation of life- ICU level that may have occurred between the many sustaining therapies such as withholding or withdrawing countries/ICUs that participated in COVIP. An additional analysis of model 1 was performed to analyze subgroups for sex differences (ESM eFig. 1) on data only adjusted for ICU effects (model 1). Second, adjustment for patient and D. W. De Lange, MD, PhD ICU admission characteristics (age, SOFA score, and Department of Intensive Care Medicine, University Medical frailty; model 2) were added to model 1. Third, adjustment Center, University Utrecht, Utrecht, The Netherlands for management strategies (treatment withhold/withdrawal; S. Leaver, MD model 3) were added to model 2. Model 1 and model 2 General Intensive care, St Georges University Hospitals NHS were used to evaluate the subgroup-specific primary and Foundation Trust, London, UK secondary outcomes, whereas model 3 was only used to evaluate the primary outcome. Odds ratios (ORs) with 95% C. Jung, MD, PhD (&) Department of Cardiology, Pulmonology and Vascular Medicine, confidence intervals (CIs) are reported. Sex-specific Heinrich-Heine-University Düsseldorf, Medical Faculty, marginal predicted means for 30-day mortality according Düsseldorf, Germany to SOFA and CFS scoring at ICU admission were e-mail: christian.jung@med.uni-duesseldorf.de calculated and graphically analyzed. All statistical tests Division of Cardiology, Department of Internal Medicine, were two-sided, and P \ 0.05 was considered statistically Pulmonology and Vascular Medicine, Heinrich-Heine- significant. University, Moorenstr. 5, 40225 Düsseldorf, Germany 123 1394 G. Wolff et al. Results ICU treatment characteristics Patient population Sex-specific differences in treatment characteristics were recorded (Table 2). While there was no difference in A total of 3,159 critically ill COVID-19 patients were noninvasive ventilation, the following were significantly included in this analysis of the COVIP study (Table 1). more frequent in male patients: mechanical ventilation Details on missing data are provided in ESM eTable 1. (1,574/2,205, 72% vs 640/954, 67%; P = 0.01), Patients were more frequently male (n = 2,205; 69.8%). tracheostomy (439/2,205, 20% vs 130/954, 14%; P \ Median [IQR] age at admission was 75 [72–78] yr and did 0.001), and prone positioning (852/2,205, 55% vs 301/954, not differ by sex (P = 0.52). 48%; P = 0.01). Additionally, male patients were more The following comorbidities were present: arterial often given vasopressor therapy (1,513/2,205, 69% vs hypertension (2,112/3,159; 67%), diabetes mellitus 588/954, 62%; P \ 0.001) and renal replacement therapy (1,162/3,159; 37%), cardiovascular disease (733/3,159; (382/2,205, 17% vs 100/954, 11%; P \ 0.001). 23%), chronic pulmonary disease (700/3,159; 22%), Regarding limitation of life-sustaining treatments, there chronic kidney disease (541/3,159; 17%), and chronic was no difference between male and female patients in heart failure (455/3,159; 14%). Male patients had treatment withholding (631/2,205, 29% vs 254/954, 27%; significantly more often cardiovascular disease (27% vs P = 0.22); however, treatment withdrawal was significantly 15%; P \ 0.001) and chronic heart failure (16% vs 12%; more common in male patients (427/2,205, 20% vs P = 0.02). 154/954, 16%; P = 0.03). ICU admission characteristics Clinical outcomes The median SOFA score at ICU admission was 5 (IQR Thirty-day mortality (Table 2) was 50% in male and 49% 3–8), and there was a small but statistically significant in female patients (P = 0.75). difference in SOFA score distribution (P = 0.01) with more Marginal predicted means of 30-day mortality (ESM severe disease in males. Male patients were significantly eFig. 2) according to SOFA and CFS scoring at ICU fitter at ICU admission than female patients according to admission showed a linear increase in mortality with CFS (fit: 67% vs 54%; vulnerable 14% vs 19%; frail 19% increasing SOFA or CFS. vs 27%; P \ 0.01). Duration of COVID-19 associated symptoms before ICU admission was longer in male Multilevel adjusted regression analysis patients (7 (IQR 4–10) days vs 6 (IQR 3–9) days; P = 0.02). There was no difference in duration of hospitalization Details on 30-day mortality and adjustment variables before ICU admission between sexes (Table 2). included in the models are given in Table 3 and ESM eTable 2: When adjusting the analysis for the ICU level Table 1 Patient characteristics Male patients Female patients P value (N = 2,205; 69.8%) (N = 954; 30.2%) Age (yr) 75 [72–78] 75 [72–79] 0.52 70–79 1,768/2,205 (80%) 728/954 (76%) 0.008 80–89 422/2,205 (19%) 210/954 (22%) [ 90 15/2,205 (1%) 15/954 (2%) Arterial hypertension 1,458/2,205 (66%) 654/954 (69%) 0.16 Diabetes mellitus 807/2,205 (37%) 355/954 (38%) 0.67 Cardiovascular disease 590/2,205 (27%) 143/954 (15%) \ 0.001 Chronic pulmonary disease 498/2,205 (16%) 202/954 (21%) 0.38 Chronic kidney disease 389/2,205 (18%) 152/954 (16%) 0.24 Chronic heart failure 339/2,205 (16%) 116/954 (12%) 0.02 Patient characteristics of male vs female patients. Data are presented as median [interquartile range] or n/total N (%). Age was tested as a continuous variable (Mann–Whitney U test) and categorized in arbitrary groups, which were tested for their distribution (Chi square test). 123 Sex differences in older critically ill COVID-19 patients 1395 Table 2 ICU admission, treatment characteristics, and 30-day mortality outcomes Male patients Female patients P value (N = 2,205; 69.8%) (N = 954; 30.2%) ICU admission SOFA score 5 [3–8] 5 [3–8] 0.01 0–4 915/2,205 (42%) 449/954 (48%) 5–9 980/2,205 (45%) 373/954 (40%) [9 287/2,205 (13%) 122/954 (13%) Clinical Frailty Scale 3 [2–4] 3 [3–5] \ 0.001 Fit 1,331/2,205 (67%) 459/954 (54%) Vulnerable 274/2,205 (14%) 162/954 (19%) Frail 369/2,205 (19%) 226/954 (27%) Duration of symptoms before ICU admission (days) 7 [4–10] 6 [3–9] 0.02 Duration of hospitalization before ICU admission (days) 2 [1–5] 2 [1–5] 0.93 Treatment characteristics Noninvasive ventilation 571/2,205 (26%) 243/954 (26%) 0.76 Mechanical ventilation 1,574/2,205 (72%) 640/954 (67%) 0.01 Tracheostomy 439/2,205 (20%) 130/954 (14%) \ 0.001 Prone positioning 852/2,205 (39%) 301/954 (32%) 0.01 Vasopressor therapy 1,513/2,205 (69%) 588/954 (62%) \ 0.001 Renal replacement therapy 382/2,205 (17%) 100/954 (11%) \ 0.001 Treatment withholding 631/2,205 (29%) 254/954 (27%) 0.22 Treatment withdrawal 427/2,205 (20%) 154/954 (16%) 0.03 30-day mortality 1,100/2,205 (50%) 470/954 (49%) 0.75 ICU admission characteristics, treatment characteristics, and 30-day mortality outcomes; crude data without adjustment. Data are presented as median [interquartile range] or n/total N (%). CFS = clinical frailty scale (CFS was recoded as CFS 1–3 = fit, CFS 4 = vulnerable, CFS 5–9 = frail); ICU = intensive care unit; SOFA = Sequential Organ Failure Assessment only (model 1), we found significantly higher odds for Discussion tracheostomy (OR, 1.57; 95% CI, 1.27 to 1.95; P \ 0.001), vasopressor therapy (OR, 1.25; 95% CI, 1.04 to 1.51; We present here an analysis of sex-specific treatment P = 0.02) and renal replacement therapy (OR, 1.96; 95% characteristics and clinical outcomes in critically ill CI, 1.57 to 2.25; P \ 0.001) in male vs female patients. In COVID-19 patients C 70 yr of age from the international additional subgroup analyses (ESM eFig. 1), there was a multicenter COVIP database. We found (1) a higher higher risk for mortality (OR C 1) in male vs female prevalence of male sex and slightly greater severity of patients who were classified as fit (OR, 1.35; 95% CI, 1.09 illness at ICU admission; (2) more tracheostomy and renal to 1.69), who were \ 80 yr of age (OR, 1.22; 95% CI, 1.03 replacement therapy in male patients; and (3) no difference to 1.43) and in patients with [ seven days after symptom between sexes in 30-day mortality. onset (OR, 1.51; 95% CI, 1.20 to 2.06). When adjusting the Patient factors including age, comorbidities,2,13,14 and model (model 2) for age, disease severity at ICU admission frailty4,10 as well as disease severity3,15,16 are drivers of (SOFA score), and patient frailty (CFS), only tracheostomy short-term mortality in critical illness—with and without (OR, 1.49; 95% CI, 1.17 to 1.88; P = 0.001) and renal COVID-19. Differentiating sex-specific effects in this replacement therapy (OR, 1.94; 95% CI, 1.49 to 2.51; conundrum of interdependent factors has been P \ 0.001) were significantly associated with male sex. challenging in the past: Valentin et al. found no Additionally, the model found higher 30-day mortality difference in illness-adjusted mortality rates between (OR, 1.24; 95% CI, 1.03 to 1.49; P = 0.03) in male vs 25,998 critically ill male (58%) vs female patients6 from female patients; however, when additionally adjusting for Austria, despite more intensive ICU treatment in male treatment limitations (Table 3, model 3), this difference in patients. At an age cut-off of 45 yr, Samuelsson et al. found 30-day mortality was no longer statistically significant no difference in prognosis between sexes in 127,254 (OR, 1.17; 95% CI, 0.94 to 1.45; P = 0.16). 123 1396 G. Wolff et al. Table 3 Multilevel logistic regression models for male vs female patients Male Female Model 1 Model 2 Model 3 patients patients (OR with 95% CI) (OR with 95% CI) (OR with 95% CI) Treatment characteristics Noninvasive ventilation 26% 26% 1.08 (0.82–1.41; P = 0.60) 1.22 (0.90–1.64; P = 0.20) Mechanical ventilation 72% 67% 1.15 (0.95–1.39; P = 0.16) 0.82 (0.65–1.03; P = 0.08) Tracheostomy 20% 14% 1.57 (1.27–1.95; P \ 0.001) 1.49 (1.17–1.88; P = 0.001) Prone positioning 55% 48% 1.22 (0.96–1.56; P = 0.11) 1.21 (0.96–1.53; P = 0.10) Vasopressor therapy 69% 62% 1.25 (1.04–1.51; P = 0.02) 1.03 (0.83–1.27; P = 0.78) Renal replacement therapy 17% 11% 1.96 (1.57–2.25; P \ 0.001) 1.94 (1.49–2.51; P \ 0.001) Treatment withholding 29% 27% 1.04 (0.87–1.25; P = 0.66) 1.10 (0.90–1.33; P = 0.36) Treatment withdrawal 20% 16% 1.14 (0.91–1.42; P = 0.27) 1.09 (0.85–1.40; P = 0.49) 30-day mortality 50% 49% 1.11 (0.95–1.31; P = 0.19) 1.24 (1.03–1.49; P = 0.03) 1.17 (0.94–1.45; P = 0.16) Multilevel logistic regression models for the association of treatment characteristics and mortality outcomes in male vs female patients. Data are presented as OR with 95% CI. Columns 2 and 3 show unadjusted treatment characteristics for comparison. Model 1 = univariate analysis only corrected for singular ICU level effects Model 2 = model 1 plus adjustment for SOFA score, age, and frailty Model 3 = model 2 plus adjustment for treatment limitations (only for mortality). CI = confidence interval; ICU = intensive care unit; OR = odds ratio; SOFA = Sequential Organ Failure Assessment patients (57% male) from Sweden, but men also used more This increased severity of illness in male patients with ICU resources than women did.5 COVID-19 may be reflected in the recruitment of critically Nevertheless, more advanced age may have impact on ill patients in the COVIP study (70% male). We recognized sex-specific prognosis of critical illness, as studies focusing more cardiovascular comorbidities in male patients on older (rather than unselected) patients in the ICU found (Table 1), which was found to be associated with other results. In an analysis from combined data from the mortality.2 We also found more tracheostomy and renal VIP1 and VIP2 studies, Wernly et al.8 found higher 30-day replacement therapy in male patients than in female mortality in male vs female patients over 80 yr of age after patients. Even though the crude differences are small matching and adjusting for baseline characteristics and between sexes, these findings confirm previous data on ICU management. In the FROG-ICU (French and treatment intensity in male compared with female critically European Outcome reGistry in Intensive Care Units) ill elderly patients, and extend them to COVID-19, without study, Hollinger et al. found a survival advantage in a showing an association with 30-day mortality. Thus, no subgroup analysis of female patients [ 63 yr of age, while significant effect of sex on mortality from COVID-19 was there was no difference between sexes in the overall detectable during ICU treatment of patients C 70 yr of age. cohort.7 These data hint at an age-dependent effect of This could be because the excess mortality from COVID- patient sex on outcome of critical illness. 19 in males was determined prior to ICU admission, which In studies of critically ill older patients with COVID-19, highlights the importance of preventive measures and 60–70% of patients were male4,17—despite females effective early treatments prior to critical illness, especially accounting for a majority of the elderly patients in in men. developed countries. An analysis of over three million Frailty is recognized as an important prognostic factor in global cases of COVID-19 by Peckham et al.9 found a critically ill older patients with and without COVID-19. In strong worldwide association of male sex with need for the VIP2 study, frailty was independently associated with ICU treatment (OR, 2.84) and risk of death from COVID- short-term mortality.11 Similarly, six-month mortality in 19 (OR, 1.39), despite no difference in the sex-specific risk patients [ 80 yr with sepsis was predicted by age, SOFA of contracting COVID-19. In a propensity-score matched score, and frailty.19,20 In a recent analysis from the COVIP analysis of 14,712 patients from the multinational TriNetX study,4 we confirmed frailty to be associated with lower network,18 male sex was significantly associated with death survival also in COVID-19. Hewitt et al. found frailty to from COVID-19, independent of the level of comorbidities. predict COVID-19 outcomes better than either age or comorbidities.21 In the COVIP study, frailty correlated just 123 Sex differences in older critically ill COVID-19 patients 1397 as well with 30-day mortality as the initial SOFA score at primary statistical analyses; Georg Wolff, Bernhard Wernly, and admission (ESM eFig. 2) in both sexes; interestingly, Christian Jung analyzed and interpreted the data and drafted the manuscript; all authors interpreted the data and critically revised the frailty was slightly but significantly lower in male vs manuscript. All authors read and approved the submitted version of female patients, despite worse outcomes in male patients. the manuscript. This is certainly a point that deserves more research. This is the first and largest primary analysis of sex- Disclosures All authors declare no support from any industry for the submitted work; no financial relationships with any organizations specific therapy and 30-day mortality in patients with that might have an interest in the submitted work in the previous three COVID-19 C 70 yr of age, as the patient group most years; and no other relationships or activities that could appear to severely challenged by the ongoing pandemic. A large have influenced the submitted work. Joerg C. Schefold reports grants sample size and high-quality data from prospective (full departmental disclosure) from Orion Pharma, Abbott Nutrition International, B. Braun Medical AG, CSEM AG, Edwards assessment in the international COVIP study allowed Lifesciences Services GmbH, Kenta Biotech Ltd, Maquet Critical multilevel adjusted analyses for detection of small sex- Care AB, Omnicare Clinical Research AG, Nestle, Pierre Fabre dependent effects on treatment intensity and outcomes. Pharma AG, Pfizer, Bard Medica S.A., Abbott AG, Anandic Medical Nevertheless, several study limitations of the design need Systems, Pan Gas AG Healthcare, Bracco, Hamilton Medical AG, Fresenius Kabi, Getinge Group Maquet AG, Dräger AG, Teleflex to be considered. The COVIP study does not provide data Medical GmbH, Glaxo Smith Kline, Merck Sharp and Dohme AG, on pre-ICU triage and admission decisions, which may Eli Lilly and Company, Baxter, Astellas, Astra Zeneca, CSL Behring, have introduced bias due to patient selection for ICU Novartis, Covidien, Philips Medical, Phagenesis Ltd, Prolong admission. Treatment characteristics were recorded as Pharmaceuticals, and Nycomed outside the submitted work. The money went into departmental funds. No personal financial gain binary variables (yes/no), which may not reflect disease applied. course in all patients appropriately. Standards of care including pharmacological therapies (antivirals, Funding statement The study is supported in France by a grant immunomodulators, vaccines, etc.) may have changed from Fondation Assistance Publique-Hôpitaux de Paris pour la during the time of the study; however, this was not assessed recherche. In Norway, the study is supported by a grant from the Health Region West. In addition, the study was supported by a grant in COVIP. Also, no information on ICU recruitment from the European Open Science Cloud (EOSC). EOSCsecretariat.eu characteristics, occurrence and length of COVID-19 waves has received funding from the European Union’s Horizon Programme with impact on pre-ICU triage, healthcare capacity and call H2020-INFRAEOSC-05-2018-2019, grant agreement number healthcare use, data quality, treatment quality, treatment 831644. The first author was supported by the Forschungskommission of the Medical Faculty of the Heinrich-Heine-University Düsseldorf intensity, etc., was available for inclusion in the models. In (No. 2018-32 for a Clinician Scientist Track). model 2 and model 3, including the SOFA score as a covariate to adjust for disease severity bears risk for Editorial responsibility This submission was handled by Dr. overfitting of treatment variables included in the score Donald E. G. Griesdale, Associate Editor, Canadian Journal of Anesthesia/ Journal canadien d’anesthe´sie. (vasopressors, ventilation, renal failure). Because of the design of this analysis, P values were not adjusted for Data availability statement Additional data and materials are multiple testing. available upon request to the corresponding author. Funding Open Access funding enabled and organized by Projekt DEAL. Conclusion Open Access This article is licensed under a Creative Commons In this analysis of sex-specific treatment characteristics and Attribution-NonCommercial 4.0 International License, which permits 30-day mortality outcomes of critically ill patients with any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give COVID-19 C 70 yr of age, we found a higher prevalence of appropriate credit to the original author(s) and the source, provide a male sex and more tracheostomy and renal replacement link to the Creative Commons licence, and indicate if changes were therapy in male patients than in female patients, but no made. The images or other third party material in this article are significant association of patient sex with 30-day mortality. included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not Author contributions The COVIP study group is part of the Very permitted by statutory regulation or exceeds the permitted use, you Old Intensive Care Patients (VIP) project by the European Society of will need to obtain permission directly from the copyright holder. To Intensive Care Medicine (ESICM) and is conducted by an view a copy of this licence, visit http://creativecommons.org/licenses/ international steering committee, in which all authors contribute to by-nc/4.0/. study conduct and Christian Jung serves as principal investigator. 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