Edited by: Graziamaria Corbi, University of Molise, Italy
Reviewed by: Renato Gorga Bandeira De Mello, Federal University of Rio Grande do Sul, Brazil; Fiammetta Monacelli, Università degli Studi di Genova, Italy
This article was submitted to Geriatric Medicine, a section of the journal Frontiers in Medicine
†These authors have contributed equally to this work
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Sepsis is common and is associated with a high morbidity and mortality (
This risk is of great importance for intensive care medicine as old and very old patients are among the fastest-growing subgroups of all patients admitted to the intensive care unit (ICU) (
These issues result in ongoing conflict for the intensive care physician: There are increasingly older and frailer patients, more and more intensive care treatments available, but at the same time a decreasing overall capacity due to economic constraints and more recently the covid pandemic.
However, in reality, in situations, such as a pandemic, the chronological age often serves as a key factor used to estimate the predicted outcome for a critically ill patient and thus whether they are admitted to ICU (
Therefore, this study aimed to investigate and compare the mortality of old and very old patients with sepsis. Furthermore, we compared the rates of organ support and the length of stay between these two groups. We conducted this analysis using the multi-center eICU Collaborative Research Database (
The eICU-Database was originally drawn from the eICU telehealth system. This system complemented on-site ICU teams with remote support. This multi-center ICU database, comprised over 200,000 admissions to 335 ICUs from 208 hospitals across the USA in 2014 and 2015 (
Septic patients in this study were identified
We extracted baseline characteristics and management strategies (defined as use of vasopressors and mechanical ventilation) on day one. The (pre-defined) site of primary infection and the ethical background were extracted. The database was released under the Health Insurance Portability and Accountability Act (HIPAA) safe harbor provision. The re-identification risk was certified as meeting safe harbor standards by Privacert (Cambridge, MA) (HIPAA Certification no. 1031219-2).
Continuous data are expressed as median ± interquartile range. We assessed differences between independent groups using Kruskal-Wallis equality-of-populations rank test. We expressed categorical data as numbers (percentage) and used the Chi-square test to calculate univariate differences between groups.
The primary exposure was the age dichotomised in two age strata: old patients, i.e., patients aged 65–79 years (
We conducted all analyses in the total cohort of 9,385 patients diagnosed with sepsis and a sub-group of patients with septic shock (
Additionally, we performed stratified sensitivity analyses, stratifying patients receiving above and below 30 ml/kg/h of fluid, creatinine above and below 2.0 mg/dl (arbitrary cut-off), lactate above and below 2.0 mmol/L (arbitrary cut-off), SOFA > 1 (Sepsis-3 criteria) and SOFA > 6 (median SOFA score), with and without mechanical ventilation, with and without the vasopressor use, and patients with a primary pulmonary focus vs. non-pulmonary (all other foci), and Caucasian patients (being the most frequent ethnic group) vs. non-Caucasian patients. We performed the stratified sensitivity analyses using model-1. Length of stay was divided into <72, 72–168, and >168 h.
All tests were two-sided, and a
In the total cohort of 9,385 patients, 6,184 were old patients (aged 65–79 years), and 3,201 were very old patients (aged 80 years and older). The baseline characteristics of old vs. very old patients are shown in
Baseline characteristics in the total cohort
Age (years); median (IQR) | 72 (8) | 84 (4) | <0.001 | 72 (8) | 84 (4) | <0.001 |
male; |
3,221 (52) | 1,638 (51) | 0.40 | 384 (53) | 177 (55) | 0.54 |
BMI; median (IQR) | 28 (10) | 25 (8) | 0.001 | 27 (10) | 25 (8) | <0.001 |
BMI <18.5 | 289 (14) | 217 (15) | 0.48 | 29 (12) | 24 (15) | 0.31 |
BMI > 30 | 2,243 (56) | 740 (40) | <0.001 | 255 (54) | 75 (36) | <0.001 |
SOFA score; median (IQR) | 6 (5) | 6 (5) | 0.66 | 10 (5) | 9 (4) | 0.007 |
Creatinine (mg/dl); median (IQR) | 1.4 (1.5) | 1.5 (1.3) | 0.005 | 2.1 (1.6) | 1.9 (1.5) | 0.13 |
Creatinine >2.0mg/dl | 1,809 (31) | 911 (31) | 0.82 | 369 (52) | 142 (46) | 0.052 |
Lactate (mmol/L); median (IQR) | 1.8 (1.8) | 2.0 (1.9) | 0.02 | 3.8 (3.5) | 3.7 (3.1) | 0.18 |
UTI; |
1,490 (24) | 887 (28) | <0.001 | 158 (21) | 90 (28) | 0.03 |
Pulmonary; |
2,407 (39) | 1,264 (40) | 0.60 | 261 (36) | 102 (32) | 0.18 |
GI; |
730 (12) | 382 (12) | 0.85 | 142 (20) | 50 (15) | 0.12 |
Cutaneous; |
477 (8) | 160 (5) | <0.001 | 32 (4) | 16 (5) | 0.69 |
Unknown; |
704 (11) | 328 (10) | 0.10 | 95 (13) | 44 (14) | 0.80 |
Gynaecologic; |
7 (<1) | 0 (0) | 0.06 | 1 (<1) | 0 (0) | 0.51 |
Other; |
369 (6) | 180 (6) | 0.50 | 41 (6) | 22 (7) | 0.46 |
The median length of stay was shorter (50 ± 67 h vs. 56 ± 72; <0.001), and the rate of short-term stay (<72 h; 65 vs. 62%;
ICU-Mortality of the total cohort
Length of stay and amount of fluid in in the total cohort
Length of stay (h); median (IQR) | 56 (72) | 50 (67) | <0.001 | 71 (110) | 64 (84) | 0.01 |
<72 h; |
3,805 (62) | 2,093 (65) | <0.001 | 374 (51) | 181 (56) | 0.17 |
72–168 h; |
1,612 (26) | 814 (25) | 0.50 | 193 (26) | 105 (32) | 0.05 |
>168 h; |
767 (12) | 294 (9) | <0.001 | 163 (22) | 38 (12) | <0.001 |
Total amount of fluid (ml); median (IQR) | 2,570 (2,890) | 2,430 (2,608) | 0.03 | 3,270 (3,815) | 3,405 (3,258) | 0.99 |
Amount of fluid per kg bodyweight; median (IQR) | 32 (38) | 33 (39) | 0.10 | 40 (51) | 47 (55) | 0.15 |
Amount of fluid per kg BW > 30ml/kg/h; |
1,581 (52) | 865 (54) | 0.17 | 235 (61) | 110 (69) | 0.10 |
The rate of vasopressor use was comparable (33 vs. 34%;
Associations of old vs. very old septic patients with mortality and management strategies in three multi-level logistic regression models.
ICU mortality | 692 (11) | 412 (13) | 1.21 (1.06–1.38; 0.005) | 1.28 (1.06–1.54; 0.01) | 1.32 (1.09–1.59; 0.004) |
Management | – | – | – | – | – |
Mechanical ventilation | 1,418 (23) | 562 (18) | 0.72 (0.64–0.81; <0.001) | 0.72 (0.61–0.85; <0.001) | – |
Vasopressor use | 2,075 (34) | 1,045 (33) | 0.99 (0.90–1.10; 0.91) | 0.99 (0.86–1.14; 0.86) | – |
ICU-mortality was higher in the very old (13 vs. 11%,
Length of stay in the total cohort
In the sensitivity analyses, being very old was associated with a higher odds of ICU mortality in female patients (aOR 1.40 95%CI 1.16-1.70), non-ventilated patients (aOR 1.50 95% CI 1.26–1.78) and patients without vasopressor use (aOR 1.30 95% CI 1.06–1.60;
Forest plot of aOR of old vs. very old septic patients for different subgroups according to model-1 (aOR 95% CI). SOFA, Sepsis-related organ failure assessment.
In the sub-group of patients with septic shock, according to Sepsis-3, 730 patients were old and 324 very old. The very old patients evidenced lower median BMI values (27 ± 10 vs. 25 ± 8;
The length of stay was lower in the very old patients (64 ± 84 vs. 71 ± 110 h;
Mortality was higher in the very old patients (38 vs. 36%) and being very old remained associated with a higher odds of ICU mortality after adjustments in model-1 (aOR 1.10 95% CI 0.84–1.45;
Association of old vs. very old septic shock patients with mortality and management strategies in three multi-level logistic regression models.
ICU mortality | 260 (36) | 122 (38) | 1.10 (0.84–1.45; 0.49) | 1.46 (1.07–1.99; 0.02) | 1.50 (1.10–2.06; 0.01) |
Management | – | – | – | – | – |
Mechanical ventilation | 404 (55) | 136 (42) | 0.60 (0.46–0.79; <0.001) | 0.68 (0.49–0.93; 0.02) | – |
Vasopressor use | 730 (100) | 324 (100) | – | – | – |
Forest plot of aOR of old vs. very old septic shock patients for different subgroups according to model-1 (aOR 95% CI). SOFA, Sepsis-related organ failure assessment.
In this retrospective multi-center study of old (65–79 years) vs. very old (aged 80 and older) critically ill patients with sepsis admitted to ICU, we found a slightly higher ICU mortality in the very old. Recently, in Europe during the Covid-19 pandemic, as part of triage, numerous ICUs set an age cut-off for ICU admission (
Sepsis is a common acute illness associated with a high mortality–some authors estimate that sepsis is the third leading cause of death in the Western world (
Our results are at odds with previous analyses, which demonstrated an effect of age on mortality in septic patients (
In our analysis, very old patients were intubated and ventilated significantly less frequently than “old only” patients. This may indicate that in these very old patients–even after adjusting for numerous confounders–the decision to limit therapy was made more frequently on the basis of age. In fact, we found a significantly lower rate of mechanical ventilation in the very old, although the median SOFA and the numbers with a pulmonary focus for sepsis were similar in both the old and the very old. These findings indicate a less intensive approach to treatment in the very old and support previous analysis. Boumendil et al. (
It is interesting that, despite the fact that the very old patients received less intensive care treatment than the old patients, even after adjustment for severity of illness, the mortality is only marginally higher. If could be that the more aggressive treatment in the old (the younger patients) may not have been indicated, and therefore it was not associated with an improved outcome. Alternatively, the very old patients may have received less intensive care and been discharged from the ICU for further palliative treatment–making them formally ICU survivors as their mortality would not have been captured in our analysis. If we had looked at longer term follow up, mortality may have been much higher in this patient group. In support of this, Biston et al. (
Due to the absolute mortality difference of 2% points in both groups, the number needed to “harm” would be 50. Therefore, based on these data, for patients with a chronological age over 80 years, we would not consider a generic withholding of intensive medical therapy to be justified. However, there may be other reasons or scenarios when withholding and “rationing” intensive care treatment may be deemed appropriate, especially for old people (
This study aimed to look at mortality as the primary outcome. However, for older people who are close to their natural end of life, functional outcomes, such as quality of life are of equal or greater importance (
Intensive care medicine requires robust and reliable parameters which enable us to predict outcomes in intensive care, particularly when treatment is deemed futile. Established scores, such as SOFA, biomarkers, such as lactate and novel developments including machine learning algorithms are helpful (
Of note, in some subgroups we found a pronounced association between being very old and ICU mortality. In very old patients, mortality was higher in female patients and in those who did not receive mechanical ventilation or vasopressors. We are aware of the limitations of subgroup analyses (
Although we found a higher mortality in the subgroup of patients with septic shock and numerically a higher mortality in the very old patients, even in this subgroup, the absolute difference between old and very old patients was 2%points, a level that we would not consider clinically relevant. In this subgroup, the functional outcomes would be of particular interest as after prolonged intubation and immobilization very old patients may suffer from significant morbidity resulting in the inability to lead an independent life. Unfortunately, we do not have data on this, another relevant limitation of our data.
Interestingly, and in contrast to previous studies, such as Heyland et al. (
It is open to debate to what extent this effect of chronological age on mortality, although statistically significant and detectable even after multi-variable correction, is clinically relevant. The absolute differences were, in our opinion, relatively small both in the total cohort of septic patients (13 vs. 11%), and in the subgroup of patients with septic shock (38 vs. 36%). From the clinicians' point of view, we interpret our data along with other preliminary studies in very old intensive care patients that the blanket denial of intensive care treatment based on the calendar age alone does not seem justifiable. From our perspective, a combination of pre-admission risk factors (such as frailty), markers of disease severity on admission (such as acute organ failure) and solid clinical judgement should be used to assess patients in all age categories in order to formulate a bespoke and realistic clinical plan. In the (frequent) case of ambiguity, an “ICU trial” is an opportunity to gain further information or at least time to consider the individual patient's prognosis (
From a scientific perspective, the association of chronological age and intensive care outcomes seems less robust than perhaps intuitively assumed. However, due to the retrospective nature of this study these data do not allow for any generalization of the findings. With this analysis, we hope to gain a better understanding and to propose suggestions for future prospective studies evaluating this issue. Future studies should focus on different aspects of aging, such as frailty, and on different outcome measures, such as independent daily living or quality of life.
This study found a 2% absolute difference in mortality between old and very old septic patients, which translates into a relative risk difference of ~20% in a vulnerable patient population. This finding is statistically significant but probably clinically irrelevant. This study underlines the pivotal importance of concepts, such as frailty that involve the biological age of patients and not the chronological age alone for outcome prediction. Based on these data, being old or very old alone are insufficient to define therapeutic goals.
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
The study was an analysis of two third-party anonymized publicly available databases with a pre-existing institutional review board (IRB) approval. The database was released under the Health Insurance Portability and Accountability Act (HIPAA) safe harbor provision.
RB, BW, CJ, and BM analyzed the data and wrote the first drought of the manuscript. SL, HF, and VO contributed to statistical analysis and improved the paper. RR, SB, PB, GW, MK, BG, DDL, DD, AK, TD, WS, SS, PvH, and MB gave guidance and improved the paper. All authors read and approved the final manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.