Ibarz et al. Ann. Intensive Care (2020) 10:56 https://doi.org/10.1186/s13613-020-00672-w RESEARCH Open Access Sepsis at ICU admission does not decrease 30‑day survival in very old patients: a post‑hoc analysis of the VIP1 multinational cohort study Mercedes Ibarz1* , Ariane Boumendil2, Lenneke E. M. Haas3, Marian Irazabal4, Hans Flaatten5,28, Dylan W. de Lange6, Alessandro Morandi7,8, Finn H. Andersen9,10, Guido Bertolini11, Maurizio Cecconi12,13, Steffen Christensen14, Loredana Faraldi15, Jesper Fjølner14, Christian Jung16, Brian Marsh17, Rui Moreno18, Sandra Oeyen19, Christina Agwald Öhman20, Bernardo Bollen Pinto21, Ivo W. Soliman6, Wojciech Szczeklik22, Andreas Valentin23, Ximena Watson24, Tilemachos Zaferidis25, Bertrand Guidet2,26, Antonio Artigas1,4,27 and the VIP1 study Abstract Background: The number of intensive care patients aged ≥ 80 years (Very old Intensive Care Patients; VIPs) is grow- ing. VIPs have high mortality and morbidity and the benefits of ICU admission are frequently questioned. Sepsis incidence has risen in recent years and identification of outcomes is of considerable public importance. We aimed to determine whether VIPs admitted for sepsis had different outcomes than those admitted for other acute reasons and identify potential prognostic factors for 30-day survival. Results: This prospective study included VIPs with Sequential Organ Failure Assessment (SOFA) scores ≥ 2 acutely admitted to 307 ICUs in 21 European countries. Of 3869 acutely admitted VIPs, 493 (12.7%) [53.8% male, median age 83 (81–86) years] were admitted for sepsis. Sepsis was defined according to clinical criteria; suspected or demon- strated focus of infection and SOFA score ≥ 2 points. Compared to VIPs admitted for other acute reasons, VIPs admit- ted for sepsis were younger, had a higher SOFA score (9 vs. 7, p < 0.0001), required more vasoactive drugs [82.2% vs. 55.1%, p < 0.0001] and renal replacement therapies [17.4% vs. 9.9%; p < 0.0001], and had more life-sustaining treat- ment limitations [37.3% vs. 32.1%; p = 0.02]. Frailty was similar in both groups. Unadjusted 30-day survival was not significantly different between the two groups. After adjustment for age, gender, frailty, and SOFA score, sepsis had no impact on 30-day survival [HR 0.99 (95% CI 0.86–1.15), p = 0.917]. Inverse-probability weight (IPW)-adjusted survival curves for the first 30 days after ICU admission were similar for acute septic and non-septic patients [HR: 1.00 (95% CI 0.87–1.17), p = 0.95]. A matched-pair analysis in which patients with sepsis were matched with two control patients of the same gender with the same age, SOFA score, and level of frailty was also performed. A Cox proportional hazard regression model stratified on the matched pairs showed that 30-day survival was similar in both groups [57.2% (95% CI 52.7–60.7) vs. 57.1% (95% CI 53.7–60.1), p = 0.85]. Conclusions: After adjusting for organ dysfunction, sepsis at admission was not independently associated with decreased 30-day survival in this multinational study of 3869 VIPs. Age, frailty, and SOFA score were independently associated with survival. *Correspondence: mibarzvillamayor@gmail.com 1 Department of Intensive Care Medicine, Hospital Universitario Sagrat Cor, Viladomat 288, 08029 Barcelona, Spain Full list of author information is available at the end of the article © The Author(s) 2020. 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Intensive Care (2020) 10:56 Page 2 of 12 Keywords: Sepsis, Very old, Intensive care, Severity of illness, Outcome, Survival, Mortality Introduction the VIP1 study, we decided to analyse the cohort of VIPs The proportion of patients aged ≥ 80 years admitted to admitted for sepsis versus VIPs admitted for another intensive care units (ICU), so-called Very Old Intensive acute reason. Care Patients (VIPs), is growing fast due to ageing of the In brief, the VIP1 study was a prospective observational population [1]. Nowadays, VIPs represent 10% to 20% of study to measure outcomes in patients aged ≥ 80 years all ICU admissions [2–7]. in 311 ICUs in 21 European countries. Each participat- Infection is one of the most frequent reasons for acute ing ICU included the first consecutive 20 VIPs admitted ICU admission of older patients, with increasing inci- within a 3-month inclusion period; data were collected dences over the last decades [8–13]. Sepsis develops between October 2016 and May 2017. A website was when the host’s response to infection becomes dysregu- designed to provide information about the study and to lated and leads to life-threatening organ dysfunction enable data entry using an electronic case record form; [14]. Older patients account for a small proportion of the the electronic case record form and database ran on a overall population, but a large proportion of sepsis cases; secure server at Aarhus University, Denmark. The study about 60% of septic patients are aged > 65 years. The inci- was registered at ClinicalTRials.gov (ID: NCTO3134807). dence of sepsis increases with age and increases steeply in persons aged ≥ 80 years [8–10]. Very old persons are Participants at particularly high risk due to pre-existing comorbidi- From the original VIP1 study, only acute admissions in ties, impaired immune function (immunosenescence), patients ≥ 80 years of age were eligible. We excluded sarcopenia, decrease in reserve capacities related to age- patients admitted for postoperative care after planned ing, and many times malnutrition and polypharmacy surgery; all the other 11 reasons for acute ICU admis- [8–10, 15]. Moreover, mortality rates in VIPs with sepsis sions were accepted (Additional file 1: Table S1). are high, with an estimated ICU mortality of 50% to 60% [6], reaching 92% at 6 months in those with circulatory Study variables and data collection failure [16]. In addition, survivors are at increased risk of Demographic and clinical characteristics were recorded developing cognitive impairment and functional disabili- for all patients, including age, gender, hospital length of ties, estimated at 16% to 40% [17–19]. stay (LOS) prior to ICU admission, LOS in ICU, SOFA The relatively high risk of mortality and shorter life score at admission [22], and frailty measured with the expectancy amongst VIPs with sepsis, combined with Clinical Frailty Scale (CFS) [23]. increasing pressure on healthcare facilities including The main outcome variable was survival in the 30 days ICUs, result in uncertainty about the appropriateness of following ICU admission. We also recorded the use of the admitting VIPs with sepsis to ICUs, especially if they are following: invasive mechanical ventilation, non-invasive frail or have severe comorbidities. Given the goal of long- ventilation, vasoactive drugs, renal replacement therapies term survival with a satisfactory quality of life (QoL) (RRT), and orders to withhold or withdraw life-sustain- according to patients’ expectations, it is often difficult to ing treatment (LST). predict the benefits of ICU treatment in VIPs, [19, 20]. To determine whether VIPs with sepsis should be admit- ted to ICUs, healthcare providers need more information Definitions about outcomes and risk factors [21]. Admission categories We aimed to determine whether VIPs admitted with The most appropriate clinical reason for ICU admission sepsis had a different 30-day outcome than VIPs admit- was chosen by the site investigator from a predefined ted for other acute reasons and to identify potential prog- list of 11 acute categories (respiratory failure, circulatory nostic factors for 30-day survival. failure, combined respiratory/circulatory failure, sepsis, severe trauma without head injury, severe trauma with head injury, isolated head injury, intoxication, non-trau- matic brain injury, postoperative care after emergency Materials and methods surgery, or other) (Additional file 1: Table S1). Study design and setting The present study is a post-hoc analysis of the VIP1 mul- tinational cohort study [1]. Patients with sepsis were Severe sepsis admission category identified as a group of interest and before the end of Patients were included in sepsis category according to clinical criteria. Ibarz et al. Ann. Intensive Care (2020) 10:56 Page 3 of 12 Clinical criteria adopted since 2015 are ¨suspected or Inverse probability weights (IPW) were used to produce documented infection and an acute increase of ≥ 2 SOFA survival curves adjusted for covariates [25]. The weights points (a proxy for organ dysfunction) ¨. It was updated were estimated using the same covariates included in the in 2016 in sepsis-3 criteria [14]: ¨Sepsis is a life-threat- Cox model, namely frailty, age, gender, type of admis- ening organ dysfunction caused by a dysregulated host sion (septic vs. non-septic), and SOFA score to estimate response to infection. For clinical operationalisation, the weights. Informally, each subject is weighted by the organ dysfunction can be represented by an increase in inverse of the probability of having sepsis or not condi- the Sequential [Sepsis-related] Organ Failure Assessment tionally on the covariates. (SOFA) score of 2 points or more, which is associated We also performed a matched-pair analysis. For each with a in-hospital mortality greater than 10%”. septic patient, we identified a non-septic patient of the same age, gender, level of frailty, and an SOFA score equal Frailty to that of the septic patient plus or minus 0.1. To estimate It was assessed according to the Clinical Frailty Scale associations between sepsis and survival at 30 days after [23]. This scale is composed of nine classes from very fit ICU admission in the matched sample, we used a Cox to terminally ill (Additional file 2: Figure S1). We deter- proportional hazard regression model stratified on the mined the frailty level present before hospital admission matched pairs. We plotted the Kaplan–Meier survival and not affected by the acute illness. Patients were classi- curves of septic and non-septic patients in the matched fied according to the CFS as “fit” (CFS ≤ 3), “vulnerable” sample and used the usual log-rank test to compare the (CFS = 4), or “frail” (CFS ≥ 5). curves [26]. P values less than 0.05 were considered statistically sig- Statistical analysis nificant. All analyses were performed with R software, No formal sample-size calculation was performed for version 3.2.2 (R foundation for Statistical computing). this observational study. Nevertheless, with the number of subjects included in our sample, to test whether the Results hazard ratio of septic vs non-septic patients is equal to Participants 1.5, the power is 99. To test whether survival of septic is The VIP1 study included 5132 VIPs; 5021 (98%) com- equivalent to that of non-septic patients, the power is 99. pleted the 30-day follow-up. Amongst patients who com- We compared baseline characteristics, treatment, pleted the 30-day follow-up, we excluded the 906 (18%) and outcomes between septic and non-septic VIPs. We admitted primarily for postoperative care after elec- expressed categorical variables as frequencies and per- tive surgery. Moreover, we excluded 246 (4.9%) patients centages, and continuous variables as medians and inter- with Sequential (Sepsis-related) Organ Failure Assess- quartile ranges. There are no missing values amongst the ment (SOFA) score < 2; thus, we analysed data from 3869 variables used in the analysis, except for 2 patients with patients (Fig. 1). Regions and countries of the included missing date of ICU discharge. To compare groups, we patients are listed (Additional file 3: Table S2). used Chi square tests for categorical variables and the Mann–Whitney U test for continuous variables. Patient characteristics To study 30-day survival, all patients were censored at We included 3869 VIPs [median age 84 (82–86) years; day 30. For patients discharged from the ICU and dead 2013 (52%) male; median SOFA score 8 (5–11); 47% at day 30, the precise date of death is unknown; for those, frail; 32.8% with limitations on LST] admitted as acute we assumed that the survival time was the middle of the patients to 307 ICUs in 21 countries in the context of the interval between date of discharge and day 30. This mid- multicentre VIP-1 study. LOS before ICU was 1 day (0–3) point imputation is a simple method to deal with inter- (see Table 1). val-censored data and has been shown to give similar The median number of patients recruited per coun- estimates than more advanced methods [24]. try was 143 (range 3–719), and the median number of Unadjusted survival curves were estimated using patients per ICU was 13 (range 1–67). the standard Kaplan–Meier estimator and compared between groups by means of a log-rank test. Comparison between VIPs admitted for sepsis and those To estimate associations between variables and survival admitted for other acute reasons 30 days after ICU admission, we used a Cox proportional Patients admitted for sepsis accounted for 12.7% hazard regression model. To check the proportional- (493/3869); there was no gender difference, but the sepsis ity assumption for each covariate, we plotted the scaled group were younger, had a higher SOFA score on admis- Schoenfeld residuals against time along with smooth sion, more often received vasoactive drugs and RRT, but curves and detected no violation of the assumption. were less frequently given mechanical ventilation and Ibarz et al. Ann. Intensive Care (2020) 10:56 Page 4 of 12 Fig. 1 Study flowchart. VIP1 study [1]. Septic patients: patients admitted to ICU for sepsis; non-septic patients: patients admitted to ICU for another acute reason. SOFA Sequential Organ Failure Assessment Table 1 Comparison of acute patients admitted for sepsis versus acute patients admitted for other reason Admission category All acute patients Other categories Sepsis p value N (%) 3869 (100%) 3376 (87.3%) 493 (12.7%) Age (years)a 84 (82–86) 84 (82–87) 83 (81–86) < 0.0001 Gender (male) 2013 (52%) 1748 (51.8%) 265 (53.8%) 0.4402 Hospital LOS before ICU (days)a 1 (0–3) 1 (0–3) 1 (0–3) 0.4600 SOFA score at ­admissiona 8 (5–11) 7 (5–11) 9 (6–12) < 0.0001 a ICU LOS (days) 2.96 (1.17–6.81) 2.88 (1.12–6.67) 3.54 (1.5–8) 0.0036 Frailty (CFS) Fit (CFS 1–3) 1331 (34.4%) 1166 (34.5%) 165 (33.5%) 0.0737 Vulnerable (CFS 4) 719 (18.6%) 643 (19%) 76 (15.4%) Frail (CFS 5–9) 1819 (47%) 1567 (46.4%) 252 (51.1%) Fit or vulnerable 2050 (53%) 1809 (53.6%) 241 (48.9%) 0.0568 Frail 1819 (47%) 1567 (46.4%) 252 (51.1%) Interventions in ICU At least 1 intervention 3196 (82.6%) 2760 (81.8%) 436 (88.4%) 0.0003 No interventions 673 (17.4%) 616 (18.2%) 57 (11.6%) Mechanical ventilation 2087 (53.9%) 1853 (54.9%) 234 (47.5%) 0.0024 Non-invasive ventilation 1047 (27.1%) 939 (27.8%) 108 (21.9%) 0.0069 Vasoactive drugs 2265 (58.5%) 1860 (55.1%) 405 (82.2%) < 0.0001 RRT​ 421 (10.9%) 335 (9.9%) 86 (17.4%) < 0.0001 Life-sustaining treatment limitations No LST limitations 2601 (67.2%) 2292 (67.9%) 309 (62.7%) 0.0243 LST limitations 1268 (32.8%) 1084 (32.1%) 184 (37.3%) Withholding 679 (17.5%) 571 (16.9%) 108 (21.9%) 0.0196 Withdrawing ± withholding 589 (15.2%) 513 (15.2%) 76 (15.4%) Outcome ICU mortality 1072 (27.7%) 918 (27.2%) 154 (31.2%) 0.0686 30-day mortality 1577 (40.8%) 1357 (40.2%) 220 (44.6%) 0.0687 LOS length of stay, SOFA Sequential Organ Failure Assessment, CFS Clinical Frailty Scale, RRT​ renal replacement therapy, LST Life-sustaining treatment a Expressed as median, IQR No missing values except for length of ICU stay; 2 patients had a missing date of discharge Ibarz et al. Ann. Intensive Care (2020) 10:56 Page 5 of 12 NIV. Limitations of life-sustaining treatment (LST) were had only one match and 55 could not be matched— more frequently performed, and LOS was increased in Table 3) was similar in septic and non-septic VIPs [57.2% patients admitted with sepsis (Table 1). (95% CI 52.7–60.7) vs. 57.1% (95% CI 53.7–60.1); HR: 1.02 (95% CI 0.85–1.22), p = 0.854] (Fig. 2c). Unmatched analysis No significant differences between groups were observed Prognostic factors of survival in all acute admitted patients in survival after ICU admission (p = 0.1); survival at day 4 In the multivariate analysis, age, frailty, and SOFA score was 78.2% (95% CI 74.6–82.0) in septic patients vs. 82.8% were independently associated with survival, but sepsis (95% CI 81.5–84.1) in non-septic patients and survival at was not (Table 2A). day 30 was 54.8% (95% CI 50.5–59.5) in septic patients Separate analyses for septic and non-septic patients vs. 57.8% (95% CI 56.1–59.5) in non-septic VIPs; HR for yielded similar results (Table 2B, C). septic vs. non-septic patients was 1.13 (95% CI 0.98–1.3), A possible centre effect was assessed comparing the p = 0.0986. After adjustment for age, frailty, gender, and log partial likelihood of a model including only sepsis SOFA score, sepsis had no effect on survival after ICU and that of the same model integrating a random centre admission [HR: 0.99 (95% CI 0.86–1.15), p = 0.917] effect. The p value for the random effect was < 0.001 sug- (Table 2A). gesting a significant random effect across centre. We thus Inverse-probability weight (IPW)-adjusted survival built a Cox model using the same variables and integrat- curves for the first 30 days after ICU admission were sim- ing a random centre effect. The coefficients and degree of ilar for septic and non-septic patients [HR: 1.00 (95% CI significance of the parameters are comparable to those 0.87–1.17), p = 0.947] (Fig. 2b). of the model without random effect (Additional file 5: Inverse-probability weight (IPW) survival curves for Table S3). quartiles of the SOFA score in septic and non-septic patients showed no significant differences (Additional Discussion file 4: Figure S2). We found that the 30-day survival rate in patients with sepsis was similar to the survival of patients admitted for Matched analysis another acute reason. Sepsis, after adjusting for organ Likewise, 30-day survival in the matched sample (443 dysfunction, did not significantly influence. Age, frailty, septic patients vs. 824 patients without sepsis, 62 patients and SOFA score were the independent factors associated Table 2 Factors affecting 30-day survival of ICU patients aged ≥ 80 years with SOFA ≥ 2 at admission, multivariate analysis HR (95% CI) p value A. Results of the Cox analysis considering all acutely admitted patients (n = 3869) Sepsis 0.99 (0.86–1.15) p = 0.9173 Age (per 5-year increase) 1.16 (1.09–1.25) p < 0.0001 Frailty: vulnerable vs. fit 1.16 (1–1.35) p = 0.0556 Frailty: frail vs. fit 1.47 (1.31–1.66) p < 0.0001 Male vs. female 1.16 (1.05–1.28) p = 0.0043 SOFA score (per one-point increase) 1.13 (1.12–1.14) p < 0.0001 B. Results of the Cox analysis considering only acute patients admitted for sepsis (n = 493) Age (per 5-year increase) 1.33 (1.1–1.61) p = 0.0029 Frailty: vulnerable vs. fit 1.54 (1.02–2.34) p = 0.0416 Frailty: frail vs. fit 1.47 (1.07–2.02) p = 0.0182 Male vs. female 1.12 (0.85–1.47) p = 0.4202 SOFA score (per one-point increase) 1.13 (1.1–1.17) p < 0.0001 C. Results of the Cox analysis considering only acute patients admitted for other reason than sepsis (n = 3376) Age (per 5-year increase) 1.14 (1.06–1.23) p = 0.0005 Frailty: vulnerable vs. fit 1.11 (0.95–1.31) p = 0.1939 Frailty: frail vs. fit 1.48 (1.31–1.68) p < 0.0001 Male vs. female 1.16 (1.04–1.3) p = 0.0064 SOFA score (per one-point increase) 1.13 (1.12–1.14) p < 0.0001 Ibarz et al. Ann. Intensive Care (2020) 10:56 Page 6 of 12 Fig. 2 Kaplan–Meyer survival curves in septic and acute non-septic patients. a Non-adjusted. b Inverse-probability weight (IPW)-adjusted overall survival (the weights were estimated using frailty, age, gender, type of admission, and SOFA score). c Matched cohort survival analysis Ibarz et al. Ann. Intensive Care (2020) 10:56 Page 7 of 12 Table 3 Description of the matched sample study the occurrence of frailty and to assess its impact Admission category Other categories Sepsis p value on 30-day mortality in patients 80 years of age or older admitted to European ICUs. The secondary objective was N 824 443 to report the intensity of care and treatment restrictions Age (years)a 82 (81–85) 83 (81–85) 0.5618 whilst in the ICU in this patient group. The original VIP-1 Gender (male) 435 (52.8%) 233 (52.6%) 0.9941 study demonstrated an inverse relation between frailty Hospital LOS before ICU 1 (0–3) 1 (0–3) 0.28 and 30-day mortality and high mortality rates for VIPs admission (days)a admitted to the ICU with sepsis. We studied and better SOFA score at 8 (6–11) 8 (6–12) 0.5468 ­admissiona characterised the subgroup of very old septic patients, identifying the variables associated with outcome, rein- ICU LOS (days)a 3.29 (1.33–7.85) 3.88 (1.67–8.53) 0.2454 forcing that frailty and severity of illness (SOFA) as well Frailty (CFS) 0.6963 as age, and are the determinant factors affecting outcome Fit (CFS 1–3) 273 (33.1%) 144 (32.5%) in VIPs admitted for sepsis. Moreover, we confirmed that Vulnerable (CFS 4) 105 (12.7%) 64 (14.4%) sepsis at admission was not a determinant factor on out- Frail (CFS 5–9) 446 (54.1%) 235 (53%) come in this population with the analysis of a matched Therapeutic interventions in ICU sample with septic and non-septic patients. At least one 723 (87.7%) 389 (87.8%) 0.999 Our results are important because relatively few well- Mechanical ventilation 480 (58.3%) 202 (45.6%) < 0.0001 designed studies have addressed the impact of sepsis in Non-invasive ventilation 239 (29%) 100 (22.6%) 0.0164 older patients. Reported ICU-survival rates amongst Vasoactive drugs 500 (60,7%) 361 (81.5%) < 0.0001 octogenarians with sepsis vary widely [6, 16, 27, 28], and RRT​ 115 (14%) 77 (17.4%) 0.1238 the risk factors for mortality in these patients have not Life-sustaining treatment limitations been completely elucidated. A recent systematic review No LST limitations 568 (68.9%) 286 (64.6%) 0.1284 including 4256 patients aged ≥ 80 years from 18 stud- LST limitations 256 (31.1%) 157 (35.4%) ies [29] reported mortality rates of 43% in the ICU, 47% Withholding 128 (15.5%) 98 (22.1%) 0.0124 in the hospital, and 68% 1 year after ICU admission. Withdrawing ± with- 128 (15.5%) 59 (13.3%) holding Reported rates for 30-day mortality range from 30 [27] to ICU mortality 239 (29%) 126 (28.4%) 0.8841 50% [6, 29]. 30-day mortality 337 (40.9%) 187 (42.2%) 0.6942 To our knowledge, this is the first study to compare frequencies of therapeutic interventions, limitations on 443 patients with sepsis were matched to 824 patients without sepsis life-supporting treatments, risk factors for mortality, and 62 patients had only one match and 55 could not be matched Survival was similar; sepsis HR 1.02 (95% CI 0.85–1.22), p = 0.854 outcomes between VIPs admitted with sepsis and those LOS length of stay, SOFA Sequential Organ Failure Assessment, CFS Clinical Frailty admitted for other acute reasons. In the present study, Score, RRT​renal replacement therapy, LST life-sustaining treatment elective surgical patients were excluded because various a Expressed in median, IQR other publications [23, 28–32] demonstrated that such patients have a better outcome with much lower mortal- ity rates. with 30-day survival in patients admitted to ICU for sep- Previous studies reported that limitations on life- sis, similar to all acute VIPs with SOFA ≥ 2. This prob- sustaining treatment were applied more frequently and ably indicates that severity of illness (as expressed by the earlier in aged patients than in younger patients [27], SOFA score) is the factor that predicts survival indepen- and moreover, limitations on LST often preceded VIPs’ dently of whether it is due to sepsis or to other reasons. death in the ICU [27, 33, 34]. However, the intensity Therefore, admission for sepsis should not be a factor to of treatment in VIPs has increased over time, and this limit an ICU admission in this old population. increase has been associated with a decrease in mor- We collected data from a large cohort in 307 ICUs from 21 European countries. Sepsis was the main rea- tality adjusted for severity [3]. The incidence of LST limitations reported in recent studies ranges from 10 to son for admission in 12.7% of the VIPs, a rate similar to 27%, being higher in aged patients and reaching 41.6% those reported in previous studies (9–12%) [8, 15, 19, in very old, frail patients [33–36]. Guidet et al. [37] 20, 27]. Our sample was slightly different to the one ana- studied decisions to limit LST in the VIP-1 cohort and lysed in the original VIP1 study, because we excluded demonstrated that acute admission, frailty, age, SOFA the subgroup of patients admitted after planned surgery score at admission, and country were associated with and compared all acute admissions with the sepsis sub- the application of limitations. We found that patients group. This might explain changes in the results, and in admitted for sepsis received more therapeutic interven- the significance of the lack of variable gender in the pre- tions, mainly vasoactive drugs and RRT. Decisions to sent analysis. The original VIP1 paper was designed to Ibarz et al. Ann. Intensive Care (2020) 10:56 Page 8 of 12 limit LST (mainly as withholding therapy) were more Conclusion common in septic patients (22% vs 17%) and this could Mortality 30 days after ICU admission is high in very old be explained because they were frailer and had more patients admitted with sepsis. However, we did not find organ dysfunction. admission for sepsis to be an independent risk factor for Our study’s strengths include its large prospective decreased survival. Frailty, older age, and higher SOFA sample, multicentre design, international participa- score at admission were the significant factors associated tion, and acutely admitted non-septic control group. with decreased 30-day survival in this population. There- Furthermore, recruiting all patients prospectively in a fore, sepsis at admission should not be the only determin- period of 8 months reduced time bias. ing factor either in the decision of admission to the ICU Our study, however, has several limitations. First, or in the establishment of LST in very elderly patients. data in VIP1 study were prospectively collected [1] but Future research is required to optimise care for these the data analysis on septic patients was retrospectively patients. We also need more information about long- done after closure of the database of the original study. term survival and quality of life in VIPs admitted for sep- Second, admission categories were mutually exclusive sis and a reliable risk prediction model. and the site investigator in every centre decided to include the patient in one or another category accord- Supplementary information ing to the main diagnosis. Severe sepsis was defined Supplementary information accompanies this paper at https​://doi. according to clinical criteria [14] and we must assume org/10.1186/s1361​3-020-00672​-w. that the individual ICUs appropriately used this defi- nition. However, we cannot fully exclude that some Additional file 1: Table S1. Admission acute categories SOFA ≥ 2. patients may have been misclassified, for example as Additional file 2: Figure S1. Clinical Frailty Scale (CFS). acute circulatory or respiratory failure. In other words, Additional file 3: Table S2. Information about region and country of the patients with acute or respiratory failure may also have included patients. had a sepsis. Additional file 4: Figure S2. Inverse probability weighted survival curves for quartiles of the SOFA SCORE. Third, we were not able to analyse the subgroup of patients with septic shock since lactate levels were not Additional file 5: Table S3. Results of the Cox analysis integrating a random centre effect. available in the registry. Anyhow, 82.2% of the septic patients received vasopressors to maintain a mean arte- Abbreviations rial pressure of 65 mmHg and mean SOFA at admission ICU: Intensive care unit; VIPs: Very Old Intensive Care Patients; RRT​: Renal was 9. Fourth, the focus of infection was not registered replacement therapy; SOFA: Sequential Organ Failure Assessment; CFS: Clinical and occurrence of sepsis after ICU admission was nei- Frailty Scale; LOS: Length of stay; LST: Life-sustaining treatment; QoL: Quality of life. ther reported. Fifth, we have no data about patients who were not admitted to the ICU due to triage deci- Acknowledgements sions. Sixth, we did not analyse reasons for LST limi- VIP1 study contributors: René Schmutz, B5, Hospital of St. John of God Vienna, Austria; Franz Wimmer, Interne Intensiv, Kardinal Schwarzenberg´sches tations, because it was not the aim of the study, it is Krankenhaus, Austria; Philipp Eller, Intensivstation der Univ.-Klinik für Innere fully analysed in another article [36]. Seventh, the only Medizin, Medical University Graz, Austria; Michael Joannidis, MICU, University datum about prior health status recorded was frailty, so Hospital Innsbruck, Austria; Pieter De Buysscher, Department of Intensive Care, AZ Sint-Lucas Ghent, Belgium; Nikolaas De Neve, Department of Intensive no information about comorbidities or previous cogni- Care, O.L.Vrouwhospital Aalst, Belgium; Sandra Oeyen, Department of tive status was available. And last, no follow-up of the Intensive Care, Ghent University Hospital, Belgium; Walter Swinnen, patients was performed. Department of Intensive Care Medicine, AZ Sint-Blasius Dendermonde, Belgium; Bernardo Bollen Pinto, Peri-Interventional Intermediate Care (SINPI), Nevertheless, our results provide insight into the out- Geneva University Hospitals, Switzerland; Paul Abraham, Adult Intensive Care come and factors associated with 30-day survival in VIPs (SIA), Geneva University Hospitals, Switzerland; Leila Hergafi, Service des Soins admitted for sepsis in comparison to VIPs admitted for intensifs, Hôpital Fribourgeois, Fribourg, Switzerland; Joerg C. Schefold, Universitätsklinik für Intensivmedizin, Inselspital, Bern University Hospital, other acute reasons. The fact that sepsis at admission, University of Bern, Switzerland; Ewelina Biskup, Medical ICU, University after adjusting for organ dysfunction, was not indepen- Hospital Basel, Switzerland; Petr Piza, KARIP, IKEM, Czech Republic.; Ioannis dently associated with survival suggests that the best Taliadoros, CY001, Nicosia General Hospital, Cyprus; Jesper Fjølner, ITA, Randers Regional Hospital, Denmark; Nilanjan Dey, Intensiv Herning, Regions Hospital option today is assessing very old patients according to Herning, Denmark; Christoffer Sølling, I-25, Regionshospital Viborg, Denmark; their age, frailty, and severity of illness, independently of Bodil Steen Rasmussen, ICU, Aalborg University Hospital, Denmark; Steffen their diagnostic category. Once admitted to ICU, we can Christensen, OPI Ost, Aarhus University Hospital Skejby, Denmark; Xavier Forceville, Réanimation médico chirurgical, Centre Hospitalier de Meaux, establish goals of care and reassess the intensity of thera- France; Guillaume Besch, Département d´Anesthésie Réanimation Chirurgi- peutic interventions after a reasonable period of time, cale, Centre Hospitalier Régional Universtaire de Besançon, France; Herve according to response to treatment, expected outcomes, Mentec, Service de Réanimation Polyvalente, Centre Hospitalier Victor Dupouy Argenteuil, France; Philippe Michel, Réanimation médico-chirurgicale, CH and patient/family wishes [38]. Carnelle - Portes de l’Oise, France; Philippe Mateu, Réanimation Polyvalente, Ibarz et al. Ann. Intensive Care (2020) 10:56 Page 9 of 12 CH de Charleville-Mézières, France; Philippe Michel, Réanimation médico- Unit di Terapia Intensiva del Serio di Anestesia, Asiana Ospedaliera Universi- chirurgicale, CH René Dubos, France; Lucie Vettoretti, Réanimation Médicale, taria Sant Anna (Ferrara), Italy; Guisepepe Nattino, Rianimazione generale, CHRU de Besançon, France; Jeremy Bourenne, Reanimation des Urgences et ASST Lecco - Ospedale A.Manzoni (Lecco), Italy; Matteo Pedeferri, Rianimazi- Médicale, CHU Marseille - Timone, France; Nathalie MARIN, reanimation one, AO della Provincia di Lecco - Presidio Ospedaliero S.Leopoldo Mandic, médicale, hopital cochin, France; Max Guillot, Réanimation médicale, Hôpital Merate, Italy; Annalisa Boscolo, Giustiniani I e II (Istar), Azienda Ospedaliera di de Hautepierre, France; Nadia Aissaoui, Réanimation médicale, hopital Padova (Padova), Italy; Simona Rossi, Servizio Anestesia Rianimazione, Azienda européen georges pompidou, France; Cyril Goulenok, Réanimation Médicale, Ospedaliera G.Salvini - Presidio Ospedaliero di Rho, Italy; Giuseppe Calicchio, Hopital Privé Jacques CARTIER, France; Nathalie Thieulot-Rolin, Intensive care Centro di Rianimazione, Azienda Ospedaliera Universitaria San Giovanni di Dio medicine department, Hospital Marc Jacquet 77,000 Melun, France; Jonathan e Ruggi d’Aragona, Italy; Lucia Cubattoli, Rianimazione Generale, Azienda Messika, Réanimation Médico-Chirurgicale, Louis Mourier, France; Lionel Ospedaliera Universitaria Senese (Siena), Italy; Gabriella Di Lascio, Terapia Lamhaut, Polyvalente adult ICU, Necker (APHP), France; Bertrand Guidet, Intensiva di Emergenza, Azienda Ospedaliero Universitaria Careggi (Firenze), Réanimation médicale, Saint Antoine, France; Cyril Charron, Medical-surgical Italy; Maria Barbagallo, UO 2 Anestesia Rianimazione Terapia Intensiva, Azienda ICU, University Hospital Ambroise Paré, de Paris Boulogne-Billancourt, France, Ospedaliero-Universitaria di Parma (Parma), Italy; Francesco Berruto, France; Alexander Lauten, 1) Department of Cardiology, 2) DZHK Berlin partner rianimazione, Ospedale E. Agnelli (Pinerolo), Italy; Daniela Codazzi, Unità side, Charité Universitaetsmedizin Berlin, Germany; Anna Lena Sacher, Terapia Intensiva, Fondazione IRCCS Istituto Nazionale dei Tumori (Milano), Department of Anesthesiology, Charité Universitaetsmedizin Berlin, Germany; Italy; Andrea Bottazzi, Rianimazione 2, Fondazione IRCCS Policlinico S.Matteo Thorsten Brenner, Department of Anesthesiology, Heidelberg University (Pavia), Italy; Paolo Fumagalli, Rianimazione 1, Fondazione Policlinico San Hospital, Germany; Marcus Franz, Department of Internal Medicine, Jena Matteo (Pavia), Italy; Giancarlo Negro, Anestesia e Rianimazione 1, Ospedale University Hospital, Friedrich-Schiller University, Germany; Frank Bloos, Francesco Ferrari (Casarano), Italy; Giuseppe Lupi, Servizio Anestesia e Department of Anesthesiology, Jena University Hospital, Friedrich-Schiller Rianimazione, Ospedale Maggiore (Cremona), Italy; Flavia Savelli, Anestesia e University, Germany; Henning Ebelt, Department for Medicine II, Catholic Rianimazione - TI 2, Ospedale Maurizio Bufalini (Cesena), Italy; Giuseppe A. Hospital “St. Johann Nepomuk”, Germany; Stefan J Schaller, Department of Vulcano, Terapia Intensiva, Ospedale Civile Nicola Giannettasio (Rossano), Italy; Anesthesiology, Klinikum rechts der Isar, Technical University of Munich, Roberto Fumagalli, Anestesia e Rianimazione 1, Ospedale Niguarda Ca’ Granda Munich, Germany; Kristina Fuest, Department of Anesthesiology, Klinikum (Milano), Italy; Andrea Marudi, Rianimazione Neurorianimazione, Nuovo rechts der Isar, Technical University of Munich, Munich, Germany, Germany; Ospedale Civile Sant Agostino Estense (Modena), Italy; Ugo Lefons, Terapia Christian Rabe, Department Of Clinical Toxicology, Klinikum rechts der Isar, intensiva, Ospedale Alta Val d’Elsa (Poggibonsi), Italy; Rita Lembo, Rianimazi- Technical University of Munich, Munich, Germany, Germany; Thorben Dieck, one generale, Ospedale Castelli di Verbania (Verbania), Italy; Maria Babini, Department of Anaesthesiology and Intensive Care, Medical School Hospital Servizio Anestesia e Rianimazione, Ospedale Civile Lugo (Lugo), Italy; Hannover, Germany; Stephan Steiner, Department of Cardiology, Pneumology Alessandra Paggioro, Struttura Semplice di Rianimazione e Terapia Intensiva, and Intensive Care, St. Vincenz Krankenhaus Limburg, Germany; Tobias Graf, Ospedale degli Infermi di Biella - ASL BI (Biella), Italy; Vieri Parrini, Anestesia e Department of Cardiology, University Heart Center Luebeck, Germany; Amir M Rianimazione, Ospedale del Mugello (Borgo San Lorenzo), Italy; Maria Zaccaria, Nia, Division of Cardiology and Intensive Care, University Hospital Düsseldorf, Rianimazione e Terapia Intensiva, Ospedale di Ciriè (Torino), Italy; Stefano Heinrich-Heine University, Germany; Christian Jung, Division of Cardiology and Clementi, terapia intensiva polivalente, Ospedale di Sesto San Giovanni (Sesto Intensive Care, University Hospital Düsseldorf, Heinrich-Heine University, San Giovanni), Italy; Carmelo Gigliuto, Rianimazione, Ospedale di Vigevano Germany; Rolf Alexander Janosi, Department of Cardiology and Vascular - AziendaOspedaliera della Provincia di Pavia (Vigevano), Italy; Francesca Diseases, University Hospital Essen, Germany; Patrick Meybohm of the Facondini, Reparto di Rianimazione e Terapia Intensiva, Ospedale Infermi Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, (Rimini), Italy; Simonetta Pastorini, Servizio Anestesia-Rianimazione, Ospedale Frankfurt University Hospital, Frankfurt, Germany; Philipp Simon, Department P. Cosma-AUSL 15 Alta padovana (Camposampiero), Italy; Susanna Munaron, of Anaesthesiology and ICM, University Hospital of Leipzig, Germany; Stefan Unità di Terapia Intensiva, Ospedale San Giacomo (Castelfranco Veneto), Italy; Utzolino, Department of General and Visceral Surgery, Universitätsklinikum Italo Calamai, Rianimazione, Ospedale San Giuseppe (Empoli), Italy; Anna Freiburg, Germany; Tim Rahmel, Department of Anaesthesiology, Intensive Bocchi, Terapia Intensiva, Ospedale San Luca (Trecenta), Italy; Adele Adorni, Care Medicine, University Hospital Knappschaftskrankenhaus Bochum, Unità di Terapia Intensiva Rianimatoria, Ospedale Valduce (Como), Italy; Maria Germany; Eberhard Barth, Department of Anaesthesiology, University of Ulm, Grazia Bocci, Centro di Rianimazione, Policlinico Agostino Gemelli (Roma), Germany; Christian Jung, University Hospital Düsseldorf, Heinrich-Heine- Italy; Andrea Cortegiani, Unità di Terapia Intensiva Polivalente, Policlinico P. University Düsseldorf, Medical Faculty, Division of Cardiology, Pulmonology Giaccone. University of Palermo, Italy; Tariana Casalicchio, Terapia Intensiva, and Vascular Medicine, Düsseldorf, Germany, Germany; Michael Schuster, Hopedale San Giovanni Bosco (Torino), Italy; Serena Melia, Unità di Terapia Department of Anaesthesiology, University Hospital Mainz, Germany; Zoi Intensiva, Ospedale Santa Maria della Misericordia (Perugia), Italy; Elia Graziani, Aidoni, ICU, UGHT AHEPA, Greece; Stavros Aloizos, ICU, Army Share Fund Unità Operativa Anestesia e Rianimazione, Santa Maria delle Croci (Ravenna), Hospital, Athens, Greece; Polychronis Tasioudis, ICU, G. Gennimatas hospital of Italy; Massimo Barattini, Rianimazione, Ospedale Santa Maria Nuova (Firenze), Thessaloniki, Greece; Kleri Lampiri, ICU, General Hospital Of Kavala, Greece; Italy; Elisabetta Brizio, Servizio di Rianimazione, Ospedale SS Annunziata, Italy; Vasiliki Zisopoulou, ICU1, General Hospital Of Larissa, Greece; Ifigenia Ravani, Maurizio Rossi, UO Anestesia e Rianimazione, Zenda Ospedaliera Sant’Anna ICU, General hospital of Patras, Greece; Evmorfia Pagaki, ICU, General hospital Como – Presidio di Manage, Italy; Michael Hahn, ICU, Augend hospital, of Trikala, Greece; Angela Antoniou, ICU, Volos General Hospital, Greece; Norway; Hans Flattens, General ICU, Haukeland University Hospital, Norway; Theodoros A. Katsoulas, ICU, “Ag Anargyroi” General Hospital, Greece; Aikaterini Nicolai Kemmerer, ICU, Kongsberg hospital, Norway; Hans Frank Streiter, ICU, Kounougeri, ICU, Konstantopouleion General Hospital, Athens, Greece; George Kristiansund Hospital, Norway; Knut Dybwik, ICU, Nordlandssykehuset Bodo, Marinakis, ICU, “Korgialenio-Benakio” G. Hospital of Athens, Greece; Fotios Norway; Terje Legernaes, ICU, Hamar hospital, Norway; Pål Klepstad, Dept Tsimpoukas, ICU, Lamia General Hospital, Greece; Anastasia Spyropoulou, ICU, Intensive Care Medicine, St Olavs University Hospital, Norway; Even Braut Panarkadian General Hospital of Tripolis, Greece; Paris Zygoulis, General ICU, Olaussen, ICU, Stavanger University Hospital, Norway; Knut Inge Olsen, ICU, University hospital of Larisa, Greece; Aikaterini Kyparissi, ICU, “HIPPOCRATEIO” Namsos Hospital, Norway; Ole Marius Brresen, ICU, Telemark Hospital, Skien, General Hospital of Athens, Greece; Manish Gupta, MICU, MAX SUPER Norway; Geir Bjorsvik, ICU, University Hospital Tromso, Norway; Finn H. SPECIALTY HOSPITAL, Vaishali, India; Mohan Gurjar, Department of Critical Care Andersen, ICU, Ålesund hospital, Norway; Sameer Maini, Medical ICU, Medicine, Sanjay Gandhi Postgraduate Institute of Medical Sciences, India; Aalesund Hospital, Norway; Lutz Fehrle, ICU, Molde hospital, Norway; Mirosław Ismail M Maji, MICU, St Johns Medical Colleg Hospital, Bangaluri, India; Ivan Czuczwar, 2nd Department of Anesthesiology and Intensive Care Medical Hayes, CUH GICU, Cork University Hospital, Ireland; Brian Marsh, Department of University of Lublin, Poland; Paweł Krawczyk, Department of Anaesthesiology Critical Care Medicine, Mater Misericordiae University Hospital, Ireland; and Intensive Care Medicine, Jagiellonian University Medical College, Poland; Yvelynne Kelly, General ICU, St. Jamess Hospital, Ireland; Andrew Westbrook, Mirosław Ziętkiewicz, Department of Anaesthesiology and Intensive Care ICU, St. Vincents University Hospital, Ireland; Gerry Fitzpatrick, Tallaght intensive Medicine, Jagiellonian University Medical College & Thoracic Anaesthesia and Care, Tallaght Hospital, Ireland; Darshana Maheshwari, UHG ICU, University Respiratory ICU, John Paul II Hospital, Poland; Łukasz R. Nowak, Maria hospital galway, Ireland; Catherine Motherway, ICU, University Hospital Skłodowska-Curie Memorial Institute of Oncology, Cancer Centre, Poland; limerick, Ireland; Giovanni Negri, Rianimazione, A.S.S.T. Covets Milanese Katarzyna Kotfis,Department of Anesthesiology, Intensive Therapy and Acute - Presidio Di Magenta - Rosedale G. Forwardly (Magenta), Italy; Savino Spadaro, Intoxications, University Hospital No. 2, Pomeranian Medical University in Ibarz et al. Ann. Intensive Care (2020) 10:56 Page 10 of 12 Szczecin, Poland; Katarzyna Cwyl, Anesthesia and Intensive Care Unit, Regional Medical Center, Russia; Boris Boskholov, Dept of intensive care, Zhadkevich Health Center in Lubin, Poland; Ryszard Gajdosz, Faculty of medicine and Clinical Hospital, Russia; Enver Rodriguez, UCI, General Universitario de Health Sciences Krakow University A.F. Modrzewski &St.Raphael Hospital, Castellón, Spain; Sergio Rebollo, ICU, HGU Santa Lucia,Cartagena, Murcia, Department of Anaesthesiology and Intensive Care, Poland; Jowita Spain; Gerardo Aguilar, Unidad de Reanimación - Surgical ICU, Hospital Clínico Biernawska, Pomeranian Medical University SPSK 1, Clinical Anesthesiology Universitario de Valencia, Spain; Gaspar Masdeu, Servei Medicina Intensiva, and Intensive Therapy PUM, Poland; Romuald Bohatyrewicz, Pomeranian Hospital de Tortosa Verge de la Cinta, Spain; Marián Irazábal Jaimes, Critical Medical University SPSK 1, Clinical Anesthesiology and Intensive Therapy PUM, Care Unit, Hospital General de Catalunya, Spain; Ángela Prado Mira, Medicina Poland; Ryszard Gawda, Department of Anesthesiology and Intensive Care, Intensiva, Hospital General Universitario de Albacete, Spain; Maria A. Bodi, Opole University Hospital, Poland; Paweł Grudzień, Department of Anaesthesi- General ICU, Hospital Universitari de Tarragona Joan XXIII, Spain; Jesus A. Barea ology and Intensive Therapy, Edward Szczeklik Specialist Hospital in Tarnów, Mendoza, Servicio de Medicina Intensiva, Hospital Universitario 12 de Octubre, Poland; Paweł Nasiłowski, Department of Anaesthesiology and Intensive Spain; Sonia López-Cuenca, Servicio de Medicina Intensiva y Grandes Therapy, Department of Anaesthesiology and Intensive Care, Gabriel Quemados, Hospital Universitario de Getafe, Spain; Marcela Homez Guzman, Narutowicz Specialist Hospital in Kraków, Poland; Natalia Popek, Department ICU, Hospital Universitario del Henares, Spain; Jesús Rico-Feijoo, Postoperative of Anaesthesiology and Intensive Therapy, Stefan Żeromski Specialist Hospital Critical Care Unit and Reanimation, Hospital Universitario Río Hortega de in Kraków, Poland; Waldemar Cyrankiewicz, Department of Anaesthesiology Valladolid, Spain; Mercedes Ibarz, ICU Hospital Universitario Sagrado Corazon, and Intensive Therapy, Antoni Jurasz University Hospital No. 1 in Bydgoszcz, Barcelona, Spain; Josep Trenado Alvarez, Intensive Care Department. Poland; Katarzyna Wawrzyniak, Department of Anaesthesiology and Intensive UCI-Semicritics, Hospital Universitario Mutua Terassa, Spain; Rafael Kawati, Therapy, Antoni Jurasz University Hospital No. 1 in Bydgoszcz, Poland; Marek central ICU, Akademiska sjukhuset, Sweden; Joakim Sivik, IVA Alingsås Lasarett, Wnuk, Department of Aanesthesiology and Intensive Therapy, John Paul II Alingsås Lasarett, Sweden; den; Joakim Sivik, IVA Alingsås Lasarett, Sweden; Memorial Hospital in Bełchatów, Poland; Dariusz Maciejewski, Faculty of Health Jessica Nauska, Intensivvårdsavdelning 31, Blekingesjukhuset Karlskrona, Science, ATH Bielsko-Biała & Department of Anaesthesiology and Intensive Sweeden; Daniel Smole, IVA, Centralsjukhuset i Karlstad, Sweden; Fredric Therapy, Regional Hospital in Bielsko-Biała, Poland; Dorota Studzińska, Parenmark, IVA, Gävle sjukhus, Sweden; Johanna Lyrén, Intensivvårdsavdeln- Department of Anaesthesiology and Intensive Care, St. John Grande Hospital, ing, Hudiksvalls sjukhus, Gävleborg,, Sweden; Katalin Rockstrohm, IVA, Kalmar Poland; Maciej Żukowski, Department of Anesthesiology, Intensive Therapy Länssjukhus, Sweden; Sara Rydén, Karolinska ICU Huddinge, Karolinska and Acute Intoxications, University Hospital No. 2, Pomeranian Medical University Hospital, Sweden; Martin Spångfors, Intensiven, Kristianstad, University in Szczecin, Poland; Szymon Bernas, Department of Anaesthesiol- Sweden; Morten Strinnholm, ICU KungälvsHospital, Sweden; Sten Walther, ogy and Intensive Therapy Centre for Artificial Extracorporeal Kidney and Liver Cardiothoracic ICU, Linköping University Hospital, Sweden; Lina De Geer, ICU, Support, Dr Władysław Biegański Regional Specialist Hospital in Łódź, Poland; Linköping University Hospital, Sweden; Peter Nordlund, OP/IVA Kliniken, Mariusz Piechota, Department of Anaesthesiology and Intensive Therapy Länssjukhuset Ryhov, Sweden; Staffan Pålsson, Intensivvårdsavdelningen, Centre for Artificial Extracorporeal Kidney and Liver Support, Dr Władysław Norrtälje, Sweden; Harald Zetterquist, IVA, Nyköpings lasarett, Sweden; Annika Biegański Regional Specialist Hospital in Łódź, Poland; Centre for Artificial Nilsson, IVA, Örnsköldsviks hospital, Sweden; Karin Thiringer, ICU, Sahlgrenska Extracorporeal Kidney and Liver Support, Poland; Wojciech Szczeklik, University Hospital Mölndal, Sweden; Mårten Jungner, ICU SUS Malmö, Skane Department of Intensive Care and Perioperative Medicine, Jagiellonian University Hospital, Sweden; Björn Bark, IVA Lund, Skåne University Hospital, University Medical College, Poland; Ilona Nowak-Kózka, Department of Sweden; Berit Nordling, IVA Sundsvall, Sweden; Hans Sköld, ICU, Torsby Intensive Care and Perioperative Medicine, Jagiellonian University Medical Sjukhus, Sweden; Camilla Brorsson, ICU University Hospital Northern Sweden, College, Poland; Jakub Fronczek, Department of Intensive Care and Sweden; Stefan Persson, Intensivvårsdavdelningen USÖ, University hospital Perioperative Medicine, Jagiellonian University Medical College, Poland; Marta Örebro, Sweden; Anna Bergström, ICU Vrinnevi hospital, Sweden; Johan Serwa, Anaesthesia and Intensive Care Clinic, Central Clinical Hospital CKD, Berkius, ICU Västerviks hospital, Sweden; Johanna Holmström, ICU Västerås, University Medical College in Łódź, Poland; Waldemar Machała, Anaesthesia Västmanlands hospital, Sweden; I. van Dijk, Intensive Care, Alrijne Ziekenhuis, and Intensive Care Clinic, Central Clinical Hospital CKD, University Medical The Netherlands; Lenneke E.M. Haas, Intensive Care, Diakonessenhuis Utrecht, College in Łódź, Poland; Jan Stefaniak, Department of Anaesthesiology and The Netherlands; D.Ramnarain, Intensive Care, Elisabeth Tweesteden Hospital Intensive Therapy, Medical University of Gdańsk, Faculty of Medicine, Poland; Tilburg, The Netherlands; Tim Jansen, Intensive Care, HagaZiekenhuis, The Maria Wujtewicz, Department of Anaesthesiology and Intensive Therapy, Netherlands; Fleur Nooteboom, IC LZR, Laurentius Ziekenhuis, The Nether- Medical University of Gdańsk, Faculty of Medicine, Poland; Małgorzata lands; Peter HJ van der Voort, ICU OLVG, OLVG, The Netherlands; Dylan de Szymkowiak, Department of Anaesthesiology and Intensive Therapy, Józef Lange, Department of Intensive Care Medicine, UMC Utrecht, The Netherlands; Struś Specialist Hospital in Poznań, Poland; Barbara Adamik, Department of Willem Dieperink, Department of Critical Care, University Medical Center Anesthesiology and Intensive Therapy, Wrocław Medical University, Poland; Groningen, The Netherlands; Monique C. de Waard, Intensive Care Adults, VU Kamil Polok, Department of Intensive Care and Perioperative Medicine, University Medical Center Amsterdam, The Netherlands; Annemarie GE de Jagiellonian University Medical College, Poland; Anna Włudarczyk, Depart- Smet, Intensive Care Unit, University Medical Centre, University of Groningen, ment of Intensive Care and Perioperative Medicine, Jagiellonian University The Netherlands; Laura Bormans, Intensive Care, Zuyderland Medical Centrer, Medical College, Poland; Jacek Górka, Department of Intensive Care and Heerlen, The Netherlands; Tom Dormans, Intensive Care, Zuyderland Medical Perioperative Medicine, Jagiellonian University Medical College, Poland; Center, Heerlen, The Netherlands; Ged Dempsey, Critical Care Unit, Aintree Natalia Kozera, Department of Anesthesiology and Intensive Therapy, Wroclaw University Hospital NHS Foundation Trust, UK; Shiju J Mathew, ICU, Alexandra Medical University, Poland; Waldemar Goździk, Department of Anesthesiology Hospital, UK; Ashok S Raj, ICU, Barts Health NHS Trust, Whipps Cross Hospital, and Intensive Therapy, Wroclaw Medical University, Poland; Nuno Catorze, UK; Irina Grecu, ITU/HDU, Basingstoke and North Hampshire Hospital, UK; UCIP, C. H. Médio TEJO, Portugal; Miguel Castelo Branco, Unidade de Cuidados Jason Cupitt, Critical Care Unit, Blackpool Teaching Hospitals NHS Foundation Intensivos, Centro Hospitalar Cova da Beira, EPE, Portugal; Inês Barros, Unidade Trust, UK; Tom Lawton, Critical Care Unit, Bradford Royal Infirmary, UK; Richard de Cuidados Intensivos Polivalente, Centro Hospitalar Tondela-Viseu, Portugal; Clark, ICU, Central Manchester Foundation Trust, UK; Monica Popescu, ICU, Nelson Barros, Serviço Medicina Intensiva, Centro Hospitalar Trás-os-Montes e Chelsea and Westminster Foundation Trust, West Middlesex University Alto Douro, Portugal; Andriy Krystopchuk, Intensive Care and Emergency Hospital, UK; Nick Spittle, ICU, Chesterfield Royal Hospital, UK; Maria Faulkner, Department, Centro Hospitalar do Algarve-Hospital de Faro, Portugal; Teresa ICU, Countess of Chester Hospital NHS Foundation Trust, UK; Amanda Cowton, Honrado, Unidade Cuidados INtensivos Polivalente, Hospital de São João, ICU, Darlington memorial Hospital (CDDFT), UK; Esme Elloway, ICU, Derriford Portugal; Cristina Sousa, UCI, Hospital da Luz, Portugal; Francisco Munoz, UMI, Hospital, UK; Patricia Williams, Critical Care Unit, Dorset County Hospital, UK; Hospital do SAMS, Portugal; Marta Rebelo, UCIP, Hospital de Egas Moniz, Michael Reay, Critical Care Unit, Dudley Group of Hospitals NHSFT, Russells Hall Portugal; Rui Gomes, UCI, Hospital Garcia de Orta, Portugal; Jorge Nunes, Hospital, UK; Srikanth Chukkambotla, Critical Care Unit, East Lancashire Unidade de Cuidados Intensivos, Hospital Lusiadas Lisboa, Portugal; celeste Hospitals NHS Trust, UK; Ravi Kumar, CCU, East Surrey Hospital, UK; Nawaf dias, Neurocritical ICU, Hospital de São João, Portugal; Ana Margarida Al-Subaie, ICU, Espsom and St Helier University Hospitals, UK; Linda Kent, Fernandes, UCI Neurocríticos, Hospital S. José - CHLC EPE, Portugal; Cristina Critical Care Unit, Fairfield General Hospital, UK; Tiina Tamm, ICU, Frimley Petrisor, Anaesthesia and Intensive Care 1, Clinical Emergency County Hospital Health, Wexham Park Hospital, UK; Istvan Kajtor, ICU, Frimley Park Hospital, UK; Cluj, Portugal; Bodolea Constantin, ATI, Municipal Hospital, Portugal; Vladislav Karen Burns, ICU, Furness General, UK; Richard Pugh, Critical Care Unit, Glan Belskiy, Department of Anesthesiology and Intensive Care, Privolzhskiy District Clwyd Hospital, UK; Marlies Ostermann, ICU, Guys and St Thomas Hospital, UK; Ibarz et al. Ann. Intensive Care (2020) 10:56 Page 11 of 12 Elisa Kam, ICU, Hillingdon Hospital, UK; Helen Bowyer, Critical Care Centre, study but in some countries given its non-interventional nature, informed Hinchingbrooke Healthcare NHS Trust, UK; Neil Smith, HICU 1&2, Hull Royal consent was waived. Infirmary, UK; Maie Templeton, Critical Care UNIT, Imperial College Healthcare NHS Trust, UK; Jeremy Henning, ICU2&3, James Cook Univeristy Hospital, UK; Consent for publication Kelly Goffin, ICU, James Paget University Hospital, UK; Ritoo Kapoor, K&C ITU, Not applicable. Kent and Canterbury Hospital, UK; Shondipon Laha, CrCU, Lancashire Teaching Hospitals NHS Foundation Trust, UK; Phil Chilton, Critical Care Unit, Leighton Competing interests Hospital, UK; Waqas Khaliq, ITU/HDU, Lewisham and Greenwich NHS Trust, UK; None of the authors have competing interests; all authors have read the Alison Crayford, ITU/HDU, Maidstone, UK; Samantha Coetzee, ICU, Medway current “Instructions to authors” and accept the conditions posed therein. NHS Foundation Trust, UK; Moira Tait, Adult ICU, Musgrove Park, UK; Wendy This manuscript is original and has not been and will not be simultaneously Stoker, ICU, Northumbria Specialist Emergency Care Hospital, UK; Marc submitted elsewhere for publication. None of the material from this study is Gimenez, ICU, Papworth Hospital NHS Foundation Trust, UK; Alan Pope, Critical included in another manuscript, has been published previously, or has been Care Unit, Peterborough City Hospital, UK; Julie Camsooksai, Critical Care Unit, posted on the internet. Poole Hospital NHS Trust, UK; David Pogson, Department of Critical Care, Queen Alexandra Hospital Portsmouth, UK; Kate Quigley, ICU, Queen Elizabeth Author details 1 Hospital, UK; Jenny Ritzema, Critical Care Department, Queen Elizabeth Department of Intensive Care Medicine, Hospital Universitario Sagrat Cor, Hospital, Gateshead, UK; Anil Hormis, Critical Care Unit, Rotherham NHS Viladomat 288, 08029 Barcelona, Spain. 2 Assistance Publique-Hôpital de Paris, Foundation Trust, UK; Carole Boulanger, ICU, Royal Devon and Exeter NHS Hôpital Saint-Antoine, Service de Réanimation Médicale, 75012 Paris, France. 3 Foundation Trust, UK; M. Balasubramaniam, ICU and HCU, Royal Bolton NHS Department of Intensive Care Medicine, Diakonessenhuis Utrecht, Utrecht, hospital trust, UK; Luke Vamplew, Critical Care Unit, Royal Bournemouth The Netherlands. 4 Department of Intensive Care Medicine, Hospital Universi- Hospital, UK; Karen Burt, Critical Care Unit, Royal Cornwall Hospital NHS Trust, tario General de Cataluña, Sant Cugat del Valles, Spain. 5 Department of Anaes- UK; Daniel Martin, ICU, Royal Free London NHS Foundation Trust, UK; Irina thesia and Intensive Care, Haukeland University Hospital, Bergen, Norway. 6 Grecu, ICU, Royal Hampshire County Hospital, UK; Jayne Craig, ICU, Royal Department of Intensive Care Medicine, University Medical Center, University Lancaster Infirmary, UK; John Prowle, Adult Critical Care Unit, Royal London of Utrecht, Utrecht, The Netherlands. 7 Department of Rehabilitation Hospital Hospital, UK; Nanci Doyle, ICU, Royal Surrey County Hospital, UK; Jonathon Ancelle di Cremona, Cremona, Italy. 8 Geriatric Research Group, Brescia, Italy. 9 Shelton, Ward 38 ICU, Royal Victoria Infirmary, UK; Carmen Scott, Ward 18 ICU, Department of Anaesthesia and Intensive Care, Ålesund Hospital, Ålesund, Royal Victoria Infirmary, UK; Phil Donnison, ICU, Salisbury District Hospital, UK; Norway. 10 NTNU, Department of Circulation and Medical Imaging, Trondheim, Sarah Shelton, ICU, Sherwood Forest Hospitals NHS Foundation Trust, UK; Norway. 11 Laboratorio di Epidemiologia Clinica, Centro di Coordinamento Christian Frey, ITU/HDU, South Tyneside District Hospital, UK; Christine Ryan, GiViTI Dipartimento di Salute Pubblica, IRCCS - Instituto di Ricerche Farma- GICU, St Georges Hospital, UK; Dominic Spray, Cardiothoracic ICU, St Georges cologiche “Mario Negri” Ranica, Bergamo, Italy. 12 Department of Anesthesia Hospital, UK; Christine Ryan, Acute Dependency Unit, St Georges Hospital NHS and Intensive Care Medicine, Humanitas Clinical and Research Center - IRCCS, Trust London, UK; Veronica Barnes, Neuro ICU, St Georges University Hospital Via Alessandro 13 Manzoni, 56, 20089 Rozzano, MI, Italy. 13 Department of Bio- NHS Foundation Trust, UK; Kerry Barnes, ITU, st helier hospital, UK; Stephanie medical Sciences, Humanitas University, Pieve Emanuele, MI, Italy. 14 Depart- Ridgway, Critical Care Unit, NHS Foundation Trust, Tameside General Hospital, ment of Anaesthesia and Intensive Care Medicine, Aarhus University Hospital, UK; Rajnish Saha, Critical Care Unit, The Princess Alexandra NHS Hospital, UK; Aarhus, Denmark. 15 ASST Grande Ospedale Metropolitano Niguarda, Milan, Linda Kent, ICU, The Royal Oldham Hospital, UK; Thomas Clark, ICU, Torbay Italy. 16 Department of Cardiology, Pulmonology and Angiology, University Hospital, UK; James Wood, ICU, Tunbridge Wells Hospital, UK; Clare Bolger, Hospital, Düsseldorf, Germany. 17 Mater Misericordiae University Hospital, General Intensive Care, Univeristy Hospital Southampton NHS Foundation Dublin, Ireland. 18 Unidade de Cuidados Intensivos Neurocríticos e Trauma, Trust, UK; Christopher Bassford, General Critical Care, University Hospital Hospital de São José, Centro Hospitalar de Lisboa Central, Faculdade de Ciên- Coventry, UK; Amanda Cowton, ICU, University hospital of North Durham, UK; cia Médicas de Lisboa, Nova Médical School, Lisbon, Portugal. 19 Department john lewandowski, Critical Care Unit, University Hospital of North Tees, UK; of Intensive Care 1K12IC, Ghent University Hospital, Ghent, Belgium. 20 Karo- Xiaobei Zhao, ICU (Level 6), Watford General Hospital/West Hertfortshire NHS linska University Hospital, Stockholm, Sweden. 21 Department of Anaesthesiol- trust, UK; Sally Humphreys, Critical Care, West Suffolk NHS Foundation Trust, ogy, Pharmacology and Intensive Care, Geneva University Hospitals, Geneva, UK; Susan Dowling, Ward 4E Critical Care unit, Whiston, UK; Neil Richardson, Switzerland. 22 Intensive Care and Perioperative Medicine Division, Jagiellon- ICU, William Harvey Hospital, Ashford, UK; Andrew Burtenshaw, Critical Care ian University Medical College, Kraków, Poland. 23 Kardinal Schwarzenberg Unit, Worcestershire Royal Hospital, UK; Carl Stevenson, ICU, Wye Valley NHS Hospital, Schwarzach, Austria. 24 St George’s University Hospital, London, UK. 25 Trust, UK; Danielle Wilcock, Critical Care Unit, York Teaching Hospital NHS Intensive Care Unit General Hospital of Larissa, Larissa, Greece. 26 Sor- Foundation Trust, UK; Yuiry Nalapko, Anaesthesia and Intensive Care, Lugansk bonne Université, INSERM, Institut Pierre Louis d’Epidémiologie et de Santé State Medical University, Ukraine. Publique, AP-HP, Paris, France. 27 Department of Intensive Care Medicine, CIBER Enfermedades Respiratorias, Corporacion Sanitaria Universitaria Parc Tauli, Authors’ contributions Autonomous University of Barcelona, Sabadell, Spain. 28 Department of Clini- MI and AA designed the study. MI, AB, LH, BG, and AA performed the analyses cal Medicine, University of Bergen, Bergen, Norway. and drafted and coordinated the manuscript. AB performed the statistical analyses and helped with interpreting the results and writing the manuscript. Received: 9 October 2019 Accepted: 4 May 2020 HF was principal investigator of the VIP-1 study, provided his expertise, and made substantial contributions to the interpretation of the results and to drafting and revising the manuscript for important intellectual content. JF run the database and the eCRF. All other authors were country coordinators and validated the manuscript. All authors read and approved the final manuscript. References 1. 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