Martin‑Loeches et al. Ann. Intensive Care (2019) 9:26 https://doi.org/10.1186/s13613-019-0495-x RESEARCH Open Access Risk factors for mortality in elderly and very elderly critically ill patients with sepsis: a prospective, observational, multicenter cohort study Ignacio Martin‑Loeches1,2,3,4*, Maria Consuelo Guia5, Maria Sole Vallecoccia1,6, David Suarez5, Mercedes Ibarz7, Marian Irazabal7, Ricard Ferrer8 and Antonio Artigas5,7 Abstract Background: Age has been traditionally considered a risk factor for mortality in elderly patients admitted to inten‑ sive care units. The aim of this prospective, observational, multicenter cohort study is to determine the risk factors for mortality in elderly and very elderly critically ill patients with sepsis. Results: A total of 1490 patients with ≥ 65 years of age were included in the study; most of them 1231 (82.6%) had a cardiovascular failure. The mean age (± SD) was 74.5 (± 5.6) years, and 876 (58.8%) were male. The patients were divided into two cohorts: (1) elderly: 65–79 years and (2) very elderly: ≥ 80 years. The overall hospital mortality was 48.8% (n = 727) and was significantly higher in very elderly compared to elderly patients (54.2% vs. 47.4%; p = 0.02). Factors independently associated with mortality were APACHE II score of the disease, patient location at sepsis diag‑ nosis, development of acute kidney injury, and thrombocytopenia in the group of elderly patients. On the other hand, in the group of very elderly patients, predictors of hospital mortality were age, APACHE II score, and prompt adher‑ ence of the resuscitation bundle. Conclusion: This prospective multicenter study found that patients aged 80 or over had higher hospital mortal‑ ity compared to patients between 65 and 79 years. Age was found to be an independent risk factor only in the very elderly group, and prompt therapy provided within the first 6 h of resuscitation was associated with a reduction in hospital mortality in the very elderly patients. Keywords: Elderly, Aging, ICU, Sepsis, Septic shock, Bundles, Critical care Introduction 5]. It accounts for more of 20% of ICU admissions with The increase in life expectancy in developed countries increasing severity over the last years [6]. Septic shock is has led to greater demand for the admission of the elderly a subcategory of sepsis associated with a greater risk of patients in hospital and in intensive care units (ICU). At mortality than sepsis alone [7]. least, more than half of the patients admitted to ICU are The incidence of sepsis increases with age, causing older than 65 years [1–3]. a sharp incidence in people older than 80 years, and is Sepsis is defined as life-threatening organ dysfunction associated with extremely high mortality rates [8, 9]. A caused by a dysregulated host response to infection [4, decade ago, Martin et al. showed that in patients admit- ted with sepsis, age was an independent predictor of *Correspondence: drmartinloeches@gmail.com mortality [8, 10–12]. For this reason, ICU physicians are, 1 Multidisciplinary Intensive Care Research Organization (MICRO), in general, reluctant to consider ICU admission to elderly St James’s Hospital/Trinity College Dublin TCD, James’s St, Ushers, patients, despite the presence of clinical criteria indicat- Dublin D03 VX82, Ireland Full list of author information is available at the end of the article ing that is appropriate [13]. © The Author(s) 2019, corrected publication 2019. This article is distributed under the terms of the Creative Commons Attribu‑ tion 4.0 International License (http://creat​iveco​mmons​.org/licen​ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Martin‑Loeches et al. Ann. Intensive Care (2019) 9:26 Page 2 of 9 Recent studies are showing that age is not a critical the Department of Intensive Care Medicine of the Parc determinant risk factor for survival in elderly patients. A Tauli/Hospital Sabadell, Barcelona. All participating recent study that included 2646 patients, with a median ICUs were medical–surgical; most of them (68%) were age of 87 years, found that predictors of in-hospital death university hospitals with residency training. Compliance were more related to immediate severity conditions was defined as national educational program based on (severity score, condition potentially warranting ICU the SSC guidelines could improve compliance with rec- admission, and decubitus ulcers) than the age itself [14]. ommended processes of care in sepsis in Spanish ICUs. This hypothesis was confirmed by another study involv- ing over 5000 patients older than 80 years (VIP1 study), where it was demonstrated that age had a smaller impact Patients on survival in ICU and other factors could predict better All ICU admissions from the emergency department or the risk of mortality among these patients [15]. This study medical and surgical wards and all ICU patients were included patients with elective and acute admission and, actively screened daily for the presence of sepsis, which unsurprisingly, patients admitted acutely had more organ included definitions of sepsis and organ dysfunction. failure and higher mortality. For this category of patients, The onset of sepsis (time zero) was determined accord- the evidence available still does not help the physicians to ing to the patient’s location within the hospital when decide if less intense settings could guarantee similar or sepsis was diagnosed. In patients diagnosed with sepsis better outcome [16]. in the emergency department, time zero was defined as There is no clear definition for elderly for patients the time of triage. For patients admitted to the ICU from admitted to an ICU. In this manuscript and following the medical and surgical wards or other nonemergency the World Health Organization (WHO) and the Organi- department units, time zero was determined by search- sation for Economic Co-operation and Development ing the clinical documentation for the time of diagnosis (OECD), “elderly” was considered for an age frame of of sepsis. This might include, for example, a physician’s 65 years or more [1, 2]. The aim of this manuscript was note or timed and dated orders, a timed and dated note to determine risk factors for mortality in elderly and very of a nurse’s discussion of sepsis with a physician, or timed elderly critically ill patients with sepsis. records initiating the referral to the ICU for sepsis. If no time and date could be found by searching the chart, the Methods default time of presentation was the time of admission to Study design and data source the ICU. Lastly, for patients who developed sepsis after We analyzed all the patients with 65 years or over admission to the ICU, the time of presentation was again enrolled in the multicenter Edusepsis Study group. Age determined on the basis of the clinical documentation. was determined in two categories based on the most Sepsis was defined as the combination of a known or often referred term to “elderly” as those aged 65–79. A suspected infection and acute organ dysfunction: (1) further analysis was conducted in very elderly patients respiratory dysfunction, bilateral pulmonary infiltrates over 80 years. Patients ≥ 65 years (including very elderly) with a ratio of PaO2 to FiO2 of less than 300 mm Hg; are referred to “patients aged 65 years or older." the worst PaO2/FiO2 at the time of diagnosis of sep- Edusepsis was a prospective, observational cohort sis was introduced entry in the database during the first study conducted across 77 ICU in Spain using a before- 24 h after ICU admission was recorded; (2) acute kid- and-after design to evaluate an educational program for ney injury (AKI), urine output of less than 0.5 mL/kg per patients with sepsis. The before period (pre-intervention) hour for at least 2 h or a serum creatinine level greater consisted of all consecutive patients with sepsis who were of 2.0 mg/dL (150 μmol/L); (3) coagulation abnormali- admitted to the participating ICUs 2 months before the ties, international normalized ratio greater than 1.5 or a educational program began. The intervention was intro- partial thromboplastin time greater than 60 s; (4) throm- duced over a 2-month period, during which no patient bocytopenia, platelet count of less than 100 × 103/μL; (5) data were collected. The post-intervention period con- hyperbilirubinemia, total plasma bilirubin level greater of sisted of all consecutive patients with sepsis (including 2.0 mg/dL (150 μmol/L); (6) hypoperfusion, lactate level organ dysfunction) admitted to the participating ICUs greater than lactate level of 2 mmol/L (18.2 mg/dL); or during a 4-month period. In addition, to determine the (7) hypotension, systolic blood pressure < 90 mm Hg, longevity of the effects of the educational program, a mean arterial pressure (MAP) < 65 mm Hg, or a reduc- third observation period, composed of all consecutive tion in systolic blood pressure of greater than 40 mm patients admitted to a subset of the participating ICUs Hg from baseline. Septic shock was defined as acute during a 2-month period 1 year later, was included [17]. circulatory failure (systolic blood pressure < 90 mm Briefly, the general coordinating center was located at Hg, MAP < 65 mm Hg, or a reduction in systolic blood Martin‑Loeches et al. Ann. Intensive Care (2019) 9:26 Page 3 of 9 pressure > 40 mm Hg from baseline) despite adequate observed. Each participating centers’ research and ethical volume resuscitation. review boards approved the study. Data collection We recorded demographic and clinical characteristics of Statistical analysis all patients included in the study. Age, sex, admission cat- Sample size calculation was not performed since this egory (medical, surgical and trauma), source of infection is a prospective observational study conducted during (pneumonia, urinary tract infection, abdominal infection, a limited time frame. Because the missing data rate in skin and soft tissue infections, catheter-associated blood- the study was low (the variable with the highest miss- stream infection, other infections, two or more infec- ing rate was an APACHE II score with a rate of 1.5%), tions), and patient location at the time of diagnosis of no imputation of missing data was performed. Statisti- sepsis (emergency department, medical or surgical ward, cal tests were two-tailed, and significance was set at a ICU) were collected at the time of presentation of sepsis. level of 0.05. We performed a descriptive analysis of the The level of severity at admission was assessed by a modi- sample by comparing the two age groups: (1) elderly: fied [18] Acute Physiology Chronic Health Evaluation II 65–79 years of age and (2) very elderly: ≥ 80 years of (APACHE II) score (in which the impact of age on the age. Categorical variables are expressed as frequencies APACHE score was eliminated) and the number of organ and percentages and analyzed with the Chi-squared failures. test or Fisher exact test, as appropriate. Continuous The initial treatment strategy was assessed applying variables are expressed as means and standard devia- the treatments recommended by the Surviving Sepsis tions (SD) and compared using the Student’s t test. A Campaign (SSC) guidelines [19] in the first 24 h after p-value < 0.05 was considered statistically significant. the diagnosis of sepsis, divided into two variables: (1) Multivariate logistic regression analysis was performed implementation of all measures of resuscitation in the to assess the impact of age on hospital mortality after first 6 h of sepsis (lactate measurement, collection of cul- adjusting the same models for the two populations: tures before starting an antibiotic treatment, adminis- 65–79 years and ≥ 80 years. Variables with p < 0.1 in tration of broad spectrum antibiotics, administration of the univariate analysis or clinically relevant were incor- fluids and vasopressors to achieve a systolic blood pres- porated as follows: Age, APACHE modified score, and sure > 90 mmHg or a MAP > 65 mmHg, central venous ICU LOS were included as continuous variables. Other pressure (CVP) equal to or greater than 8 mmHg, central covariates included were sex, patient location at sepsis venous saturation greater than or equal to 70%) and (2) diagnosis (emergency department, ward, ICU), type implementation of all measures of treatment within 24 h of infection (pneumonia, abdominal, urinary tract, (including consideration of low doses corticosteroids skin and soft tissue, catheter-related bacteraemia, in patients with septic shock, blood glucose control and other infections, two or more infections), hemody- control of the plateau pressure for protective mechanical namic failure, respiratory failure, AKI, hepatic failure, ventilation). The primary outcome of this study was hos- thrombocytopenia, coagulopathy, resuscitation, and pital mortality. Secondary outcomes were ICU mortality, implementation of resuscitation and treatment bun- 28-day mortality, hospital, ICU length of stay (LOS), and dles. To account for center effects in this multicenter bundle compliance variables. Bundle compliance vari- trial with a binary outcome, we fitted a generalized ables included ten tasks grouped in the sepsis resuscita- estimating equation model with a logit link and an tion bundle (six tasks that should begin immediately and exchangeable correlation structure. be accomplished within the first 6 h of presentation) and the sepsis management bundle (four tasks that should begin immediately and be completed within 24 h of pres- Results entation). Time (0 to 12 h) was also recorded from sep- Patient characteristics sis presentation to the process of care variables of serum A total of 1490 patients with ≥ 65 years of age were lactate measurement, blood culture collection, admin- included in the study; most of them 1231 (82.6%) had a istration of broad spectrum antibiotics, achievement of cardiovascular failure. The mean age (± SD) was 74.5 CVP of 8 mm Hg or greater, and central venous oxygen (± 5.6) years, and 876 (58.8%) were male. The mean saturation of 70% or greater. As in the Edusepsis study, APACHE II score and modified APACHE II score were we controlled the quality of the data gathered, checking 22.6 (± 7.0) and 17.1 (± 7.0) points, respectively. Com- for completeness, accuracy, and uniformity. Also, a ran- pliance with the SSC recommendations was 7.8% for the dom sample of 10% of patients was re-evaluated and reli- sepsis resuscitation bundle (6 h) and 13.2% for the sepsis ability of 96.5% of all variables per case report form was management bundle (24 h) (Fig. 1). Martin‑Loeches et al. Ann. Intensive Care (2019) 9:26 Page 4 of 9 2,319 paents with sepsis 1,490 paents with ≥ 65 years of age Elderly, n = 1193 (80.1%) Very elderly , n = 297 (19.9%) Pneumonia N=223 (57%) Pneumonia N=42 (61.8%) Peritonitis N=183 (45.7%) Peritonis N=77 (57%) Urinary tract infec n N=36 (26.3%) Urinary tract infecon N=14 (36.8%) So and skin ei s N=19 (33.9%) So‰ and skin ssue infecons N=4 (40%) Catheter-related bacteraemia N=12 (40%) Catheter-related bacteraemia N=1 (50%) Other N=72 (49%) Other N=21 (53.8%) Sepsis resuscitaon bundle N=42 (41.2%) Sepsis resuscitaon bundle N=45 (28.6%) Sepsis management bundle N=72 (43.6%) Sepsis management bundle N=75 (46.9%) Fig. 1 Flow chart for the study Comparison between cohorts 11.5 ± 20.4 days, p = 0.014). Further demographic and As displayed in Table 1, patients were divided into clinical characteristics of patients are shown in Table 1. two cohorts: (1) elderly: 65–79 years and (2) very elderly: > 80 years. The two groups were similar in Mortality and age in patients with sepsis and septic shock terms of number of organ failures (2.9 vs. 2.9, p = 0.88), The overall hospital mortality was 48.8% (n = 727) and invasive mechanical ventilation (59.3% vs. 62.0%, was significantly higher in very elderly compared to p = 0.428), and modified APACHE II score (17.2 vs. elderly patients (54.2% vs. 47.4%; p = 0.02). The 28-day 16.7, p = 0.374). mortality was 39.6% (n = 590) and was significantly Conversely, we found that very elderly patients had higher in very elderly compared to elderly patients (46.8% more intra-abdominal infections (46.5%, vs. 34.7%, vs. 37.8%; p = 0.005). Risk factors for hospital mortality in p < 0.001) and, consequently, more urgent diagnostic elderly and very elderly patients are displayed in Table 2. surgical pathology (49.3% vs. 30.4%, p < 0.001) (data not According to the univariate analysis, independent vari- shown in tables). Otherwise, the group of elderly had ables significantly associated with hospital mortality were an increased number of medical admissions (60.2% vs. the following: modified APACHE II, number of organ 46.6%, p < 0.001), and while the major source of infection failures, type of organ failure (respiratory failure, AKI, was peritonitis, it was less frequent than in very elderly thrombocytopenia, and coagulopathy), source of infec- patients (33.2% vs. 45.5%, p = 0.001). In addition, this tion, and patient location at sepsis diagnosis in the elderly group had more male patients (60.3% vs. 52.9%, p = 0.02), cohort. On the other hand, in the very elderly cohort, the an increased use of sepsis resuscitation bundles (8.5% vs implementation of all measures of resuscitation within 4.7%, p = 0.027), a longer ICU LOS (14.5 ± 18.8 days vs. 6 h of diagnosis of sepsis and the location of the patient Martin‑Loeches et al. Ann. Intensive Care (2019) 9:26 Page 5 of 9 Table 1 Comparison of baseline characteristics between elderly and very elderly patients Elderly (n = 1193) Very elderly (n = 297) Overall (n = 1490) p (80.1%) (19.9%) Age (years) mean (SD) 72.4 (4.1) 82.8 (2.7) 74.5 (5.6) < 0.001 Ç APACHE II modified score mean (SD) 17.2 (7.0) 16.7 (7.2) 17.1 (7.0) 0.374 Ç Number of organs involved on admission mean (SD) 2.9 (1.4) 2.9 (1.4) 2.9 (1.4) 0.888 Ç ICU LOS mean (SD) 14.5 (18.8) 11.5 (20.4) 13.9 (19.2) 0.014 Ç Median 7.7 5.4 7.2 0.012 Median in survivors 7.8 7.5 7.4 0.7 Median in nonsurvivors 5.8 5.3 7.8 0.5 Mortality N (%)* 727 (48.8) 161 (54.2) 727 (48.8) 0.027* Sex (male) N (%)* 719 (60.3) 157 (52.9) 876 (58.8) 0.020* Admission category N (%) Medical 715 (60.2) 138 (46.6) 853 (57.2) < 0.001* Urgent surgery 361(30.4) 146 (49.3) 507 (34.0) Elective surgery 97 (8.2) 10 (3.4) 107 (7.2) Trauma 14 (1.2) 2 (0.7) 16 (1.1) Source of infection N (%) Pneumonia 391 (32.8) 68 (22.9) 459 (30.8) < 0.001* Peritonitis 396 (33.2) 135 (45.5) 531 (35.6) UTI 137 (11.5) 38 (12.8) 175 (11.7) SSTI 56 (4.7) 10 (3.4) 66 (4.4) Catheter-related bacteraemia 30 (2.5) 2 (0.7) 32 (2.1) Other 147 (12.3) 39 (13.1) 186 (12.5) Patient location at sepsis diagnosis N (%) ED 469 (39.3) 127 (42.8) 596 (40.0) 0.023* Ward 547 (45.9) 144 (48.5) 691 (46.4) ICU 177 (14.8) 26 (8.8) 203 (13.6) Baseline acute organ dysfunction N (%) Cardiovascular 1023 (85.8) 245 (82.5) 1268(85.1) 0.158* Pulmonary 250 (21.0) 62 (20.9) 312 (20.9) 0.976* Renal 940 (78.8) 241 (81.1) 1181(79.3) 0.371* Hepatic 191 (16.0) 50 (16.8) 241 (16.2) 0.730* Thrombocytopenia 263 (22.0) 60 (20.2) 323 (21.7) 0.490* Coagulopathy 415 (34.8) 104 (35.0) 519 (34.8) 0.941* Sepsis resuscitation bundle N (%)$ 102 (8.5) 14 (4.7) 116 (7.8) 0.027* Sepsis management bundle N (%)$ 165 (13.8) 32 (10.8) 197 (13.2) 0.164* APACHE II acute physiology and chronic health evaluation II, ICU intensive care unit, LOS length of stay, UTI urinary tract infection, SSTI soft and skin tissue infections, ED emergency department * χ2 tests; Ç Student’s t tests; $ sepsis resuscitation bundle (six tasks that should begin immediately and be accomplished within the first 6 h of presentation) and the sepsis management bundle (four tasks that should begin immediately and be completed within 24 h of presentation) at the time of diagnosis were associated with mortality and thrombocytopenia (aOR 1.5, [95% CI 1.1–2.1], (Table 2). p  ≤ 0.01). In the very elderly cohort, age (aOR 1.1 [95% In the multivariable analysis, several risk factors CI 1.1–1.2], p < 0.04), modified APACHE II score (aOR remained independently associated with hospital 1.1 [95% CI 1.1–1.1], p  ≤ 0.001), and the compliance mortality in the elderly cohort such as the modified in sepsis resuscitation bundle (6 h) according to the APACHE II score (aOR 1.1 [95% CI 1.1–1.1], p ≤ .001), SSC recommendations (aOR 0.214 [95% CI 0.1–0.9], patient location at sepsis diagnosis (ward: aOR 1.5 [95% p < 0.05) were independent risk factors associated CI 1.1–2] p = 0.002, ICU: aOR 2.6 [95% CI 1.7–3.9] with hospital mortality (further details are shown in p  ≤ .001), AKI (aOR 1.4 [95% CI 1.0–2.0], p = 0.01), Table 3). Martin‑Loeches et al. Ann. Intensive Care (2019) 9:26 Page 6 of 9 Table 2 Risk factors for hospital mortality between elderly and very elderly patients Elderly N = 566 p Very elderly N = 161 p Age (years) mean (SD) 72.4 (4.1) 0.412Ç 83.0 (2.8) 0.329 Ç APACHE II modified score mean (SD) 19.3 (7.2) < 0.001Ç 18.4 (7.4) 0.012 Ç Number of organs mean (SD) 3.2 (1.5) < 0.001* 3.0 (1.5) 0.547* Sex (male) n (%) 356 (49.5) 0.078* 86 (54.8) 0.835* Admission category n (%) Medical 337 (47.1) 0.594* 66 (47.8) 0.056* Urgent surgery 168 (46.5) 85 (58.2) Elective surgery 48 (49.5) 8 (80.0) Trauma 9 (64.3) 2 (100.0) Source of infection n (%) Pneumonia 223 (57.0) < 0.001* 42 (61.8) 0.249* Peritonitis 183 (45.7) 77 (57.0) UTI 36 (26.3) 14 (36.8) SSTI 19 (33.9) 4 (40.0) Catheter-related bacteraemia 12 (40.0) 1 (50.0) Other 72 (49.0) 21 (53.8) Patient location at sepsis diagnosis n (%) ED 188 (40.1) < 0.001* 58 (45.7) 0.038* Ward 271 (49.5) 87 (60.4) ICU 107 (60.5) 16 (61.5) Baseline acute organ dysfunction n (%) Cardiovascular 494 (48.3) 0.151* 133 (54.3) 0.954* Pulmonary 145 (58.0) < 0.001* 38 (61.3) 0.208* Renal 472 (50.2) < 0.001* 132 (54.8) 0.686* Hepatic 106 (55.5) 0.015* 25 (50.0) 0.512* Thrombocytopenia 150 (57.0) < 0.001* 31 (51.7) 0.658* Coagulopathy 229 (55.2) < 0.001* 64 (61.5) 0.063* Sepsis resuscitation bundle N (%)$ 42 (41.2) 0.185* 45 (28.6) 0.049* Sepsis management bundle N (%)$ 72 (43.6) 0.291* 75 (46.9) 0.378* APACHE II acute physiology and chronic health evaluation II, ICU intensive care unit, LOS length of stay, UTI urinary tract infection, SSTI soft and skin tissue infections, ED emergency department *χ2 tests; ÇStudent’s t tests, $sepsis resuscitation bundle (six tasks that should begin immediately and be accomplished within the first 6 h of presentation) and the sepsis management bundle (four tasks that should begin immediately and be completed within 24 h of presentation) Discussion According to the results of the 2017 revision of the This prospective multicenter study found that mortal- world population prospects, Europe is today facing ity in old ages due to sepsis is high. Patients aged 80 or unprecedented demographic change: 25% of the popula- over had higher hospital mortality compared to patients tion is already aged 60 years or over and that proportion between 65 and 79 years, and age represents an inde- is projected to reach 35% in 2050, while the number of pendent mortality-associated risk factor in this very persons aged 80 or over is going to triple by 2050 [20]. elderly cohort while it is not in the younger popula- Therefore, the mean age of patients admitted to the hos- tion cohort. Interestingly, there are elements identified pital and ICU has also increased. Almost two out of three that would improve hospital survival, in very elderly patients admitted to our study for sepsis were “patients patients, such as the resuscitation bundle provided in aged 65 years or older.” Martin et al. [10] reported a simi- the first hours of hospital admission. Despite the high lar percentage, showing that age is associated with the mortality associated with this very elderly population development of sepsis and with the outcome. Angus et al. (54.2%), appropriate and prompt medical management reported a steadily increased mortality with patients’ age, in ICU ultimately impacts in patients’ survival. with a significant peak of almost 40% in patients older Martin‑Loeches et al. Ann. Intensive Care (2019) 9:26 Page 7 of 9 Table 3 Multivariate analysis for risk factors associated with hospital mortality between elderly and very elderly patients Elderly N = 566 aOR (CI 95%) p Very elderly N = 161 aOR (CI p 95%) Age (years)a 1.1 (0.9–1.0) 0.683 1.1 (1.0–1.2) 0.04 Sex (male) 0.8 (0.6–1.1) 0.231 1.1 (0.7–1.7) 0.710 APACHE II modified scoreb 1.1 (1.1–1.1) 0.000 1.1 (1.1–1.2) < 0.001 ICU LOS 0.9 (0.989–1.003) 0.235 1.031 (1.0–1.0) 0.009 Patient location at sepsis diagnosisc Ward 1.5 (1.1–2.0) 0.002 1.5 (0.8–2.7) 0.130 ICU 2.6 (1.7–3.9) 0.000 0.6 (0.2–2.1) 0.507 ED (reference) 1.0 1.0 Source of infectiond Peritonitis 0.6 (0.4–0.8) 0.005 0.9 (0.4–1.9) 0.856 UTI 0.3 (0.1–0.4) 0.000 0.3 (0.1–1.0) 0.059 SSTI 0.4 (0.2–0.8) 0.009 0.4 (0.1–2.1) 0.307 Catheter-related bacteremia 0.4 (0.2–1.0 0.055 0.9 (0.1–5.1) 0.243 Other 0.6 (0.4–1.4) 0.080 1.1 (0.4–2.7) 0.864 Pneumonia (reference) 1.0 1.0 Baseline acute organ dysfunction Cardiovascular 1.0 (0.7–1.4) 0.886 0.6 (0.3–1.4) 0.316 Pulmonary 1.3 (0.9–1.8) 0.076 1.1 (0.5–2.3) 0.621 Renal 1.4 (1.0–2.0) 0.018 0.8 (0.4–1.7) 0.648 Hepatic 1.1 (0.8–1.7) 0.337 0.7 (0.3–1.6) 0.466 Thrombocytopenia 1.5 (1.1–2.1) 0.009 0.9 (0.4–2.1) 0.955 Coagulopathy 1.2 (0.9–1.7) 0.077 1.492 (0.8–2.6) 0.171 Sepsis resuscitation bundle N (%)$ 0.8 (0.5–1.3) 0.437 0.214 (0.1–0.9) 0.031 Sepsis management bundle N (%)$ 0.9 (0.6–1.3) 0.730 0.780 (0.3–1.8) 0.562 Elderly: 65–79 years of age and (2) very elderly ≥ 80 years of age aOR adjusted odds ratio, APACHE II acute physiology and chronic health evaluation II, ICU intensive care unit; LOS length of stay, UTI urinary tract infection, SSTI soft and skin tissue infections a Per age b Per point c Compared with the ED department d Compared with pneumonia $ Sepsis resuscitation bundle (six tasks that should begin immediately and be accomplished within the first 6 h of presentation) and the sepsis management bundle (four tasks that should begin immediately and be completed within 24 h of presentation) than 85 years [8]. In a historical cohort study compar- prompt therapy provided within the first 6 h of resuscita- ing middle-aged (45–64 years), old (65–74 years), and tion was associated with a reduction in hospital mortality very old ICU patients (> 75 years), Blot et al. [21] found in this subgroup of patients. that mortality rates increased with age: 42.9%, 49.1%, In our study, as age can contribute up to 6 points, the and 56.0% for middle-aged, old, and very old patients, level of severity at admission was assessed by a modi- respectively. fied APACHE II score, in which the impact of age on the In our study, the very elderly cohort had a lower imple- APACHE score was eliminated. The overall mortality of mentation of resuscitation bundles after sepsis diagnosis. our study is 48.8%. This is high if compared to the VIP1 Interestingly, this finding is in agreement with previous study, a prospective multinational study involving 5132 studies, showing that age is an independent factor for the very old intensive care patients with a median age of limitation of treatment in critically ill patients. Does it 84 years from 311 ICUs. In the VIP 1 study, the 30-d mor- reflect a poor encouragement from the attending physi- tality is, respectively, 43% for the subgroup of acute medi- cian to change patients’ outcome? Therefore, the older is cal admission (n = 3245 patients admitted) and 26.4% for the patient; the lower is the implementation of therapy. the acute surgical admission (n = 382 patients) and 47% However, and despite of this common clinical sense, for trauma admission (n = 228 patients). However, the Martin‑Loeches et al. Ann. Intensive Care (2019) 9:26 Page 8 of 9 reason for admission was not only sepsis/septic shock the time of the study and now outdated. However, the and, according to the multivariate analysis, but only the important message is that prompt management in the acute admissions have the strongest impact on survival, first hours of sepsis is beneficial also in the patients that while age has a smaller impact. The strength of the study are usually considered for a less intense treatment. This is that is focused on the septic subgroup (sepsis and sep- is in line with recent studies that are proving that the tic shock): 83% of them with septic shock and with a intensity of care in elderly patients is increasing with median LOS in ICU of 13.9 days, wherein the VIP 1 study beneficial effects in these patients [15, 23, 24]. Similarly, the median ICU LOS was much shorter (2.3 days) and we should study the long-term survival and the quality included more than 3000 acute patients. In addition, our of life at 6 months after discharge from the hospital, in study is in line with other studies about elderly patients order to create predictive models to guide the decision- with sepsis and septic shock, where the mortality rates making for admitting elderly and very elderly patients are around 50–60% [2, 10, 12]. We have to acknowledge in ICU. Another important concept that should be that in our manuscript, we incorporated bundles before further investigated as a predictor of outcome in the the new update of SSC guidelines, as the largest reduc- elderly patients is the frailty that measures the suscep- tions in mortality have been associated with early iden- tibility from the age-associated decline in reserve and tification of sepsis, initiation of a 3-h care bundle, and function in a wide range of physiological systems [25]. prescription and administration of broad spectrum anti- Recently, frailty was associated with an increased risk biotics within the first hour. Despite current extraordi- of mortality in critically ill patients older than 80 years nary investment in sepsis implementation awareness and [15] and generally in the elderly patients [26]. management, there is still a lack of progress in mortality reduction in sepsis treatment that underscores the vari- ability in patients with sepsis. Conclusion Life-sustaining treatment (LST) limitations before and This prospective multicenter study about elderly criti- during ICU admission related to comorbidities, ventilator cally ill patients with sepsis shows that patients aged support time, noninvasive mechanical ventilation, quality 80 or over had higher hospital mortality compared to of life, frailty, and/or functional status were not recorded patients between 65 and 79 years. Age was found to and are major limitations in our study. Additionally, be an independent risk factor only in the very elderly the lack of a well-known organ failure score such as the group, and prompt therapy provided within the first 6 h sequential organ failure assessment (SOFA) score could of resuscitation was associated with a reduction in hos- be used for comparison of results with other similar stud- pital mortality in the very elderly patients. ies. Only 20% of patients admitted to ICU for sepsis or Authors’ contributions cardiovascular failure were 80 years or over and a minor- IML, MCG, MIb, MIr, RF, AA contributed to the recognition of the need ity (0.4%) were 90 or over. However, a French prospec- to undertake this work. IML, MSV, AA, DS took part in preparation of the tive, observational multicenter cohort study about the manuscript. IML, MSV, MCG, MIb, MIr, RF, AA contributed to revision of the manuscript. All authors read and approved the final manuscript. admission of patients older than 80 years to ICU showed that not only emergency physicians were unlikely to refer Author details 1 octogenarian patients, but also intensivists were reluctant Multidisciplinary Intensive Care Research Organization (MICRO), St James’s Hospital/Trinity College Dublin TCD, James’s St, Ushers, Dublin D03 VX82, to admit them despite the presence of criteria indicat- Ireland. 2 Pulmonary Intensive Care Unit, Respiratory Institute, Hospital Clinic ing an appropriate admission [22]. Therefore, this might of Barcelona, IDIBAPS, Barcelona, Spain. 3 University of Barcelona, Barcelona, explain why the number of patients included in the very Spain. 4 Centro de Investigación Biomédica en Red-Enfermedades Res‑ piratorias (CIBERES CB06/06/0028), Barcelona, Spain. 5 Critical care Center, elderly cohort was low, and might justify the inequal- Corporacion Sanitaria Universitaria Parc Tauli, CIBER Enfermedades Respira‑ ity of sample size between the two cohorts (elderly and torias, Autonomous University of Barcelona, Sabadell, Spain. 6 Department very elderly). However, this selection bias would be mini- of Intensive Care and Anaesthesiology, Università Cattolica del Sacro Cuore - Fondazione Policlinico Universitario A.Gemelli, Rome, Italy. 7 Servicio de mized since there were no significant differences between Medicina Intensiva, Hospitales Universitarios Sagrado Corazon y General the groups in any of the weighted variables: modified de Cataluña, Barcelona, Spain. 8 Intensive Care Department, Vall d’Hebron APACHE II score and baseline acute organ dysfunction, University Hospital, Shock Organ Dysfunction and Resuscitation Research Group, Vall d’ Hebron Research Institute, Passeig de la Vall d’Hebron, 119‑129, number and incidence of organ failures. Considering the 08035 Barcelona, Spain. differences between the two groups in sample size, in clinical characteristics and in the univariate analysis of Acknowledgements Nil. mortality, we performed a multivariate analysis for each cohort, adjusted to the same logistic regression model. Competing interests The initial treatment strategy followed the treatments The authors certify that there is no competing interests with any financial organization regarding the material discussed in the manuscript. recommended by the SSC guidelines [19] available at Martin‑Loeches et al. Ann. Intensive Care (2019) 9:26 Page 9 of 9 Availability of data and materials 11. Yang Y, Yang KS, Hsann YM, Lim V, Ong BC. The effect of comorbidity and The datasets analyzed during the current study are available from the cor‑ age on hospital mortality and length of stay in patients with sepsis. J Crit responding author on reasonable request. Care. 2010;25(3):398–405. 12. Nasa P, Juneja D, Singh O, Dang R, Arora V. Severe sepsis and its impact on Consent for publication outcome in elderly and very elderly patients admitted in intensive care Not applicable. unit. J Intensive Care Med. 2012;27(3):179–83. 13. Boumendil A, Somme D, Garrouste-Orgeas M, Guidet B. Should elderly Ethics approval and consent to participate patients be admitted to the intensive care unit? Intensive Care Med. Each participating center’s Research and Ethical Review Board approved the 2007;33(7):1252. study, and patients remained anonymous. 14. Boumendil A, Angus DC, Guitonneau AL, Menn AM, Ginsburg C, Takun K, et al. Variability of intensive care admission decisions for the very elderly. Funding PLoS One. 2012;7(4):e34387. Nil. 15. Flaatten H, De Lange DW, Morandi A, Andersen FH, Artigas A, Berto‑ lini G, et al. The impact of frailty on ICU and 30-day mortality and the level of care in very elderly patients (≥ 80 years). Intensive Care Med. Publisher’s Note 2017;43(12):1820–8. Springer Nature remains neutral with regard to jurisdictional claims in pub‑ 16. Guidet B, De Lange DW, Christensen S, Moreno R, Fjolner J, Dumas lished maps and institutional affiliations. G, et al. Attitudes of physicians towards the care of critically ill elderly patients—a European survey. 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