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Abstract
Rationale: Frailty in critically ill patients is associated with higher mortality and prolonged length of stay; however, little is known about the impact on the duration of mechanical ventilation.
Objectives: To identify the relationship between frailty and total duration of mechanical ventilation and the interaction with patients’ age.
Methods: This retrospective population-based cohort study was performed using data submitted to the Australian and New Zealand Intensive Care Society Adult Patient Database between 2017 and 2020. We analyzed adult critically ill patients who received invasive mechanical ventilation within the first 24 hours of intensive care unit admission.
Results: Of 59,319 available patients receiving invasive mechanical ventilation, 8,331 (14%) were classified as frail. Patients with frailty had longer duration of mechanical ventilation compared with patients without frailty. Duration of mechanical ventilation increased with higher frailty score. Patients with frailty had longer intensive care unit and hospital stay with higher mortality than patients without frailty. After adjustment for relevant covariates in multivariate analyses, frailty was significantly associated with a reduced probability of cessation of invasive mechanical ventilation (adjusted hazard ratio, 0.57 [95% confidence interval, 0.51–0.64]; P < 0.001). Sensitivity and subgroup analyses suggested that frailty could prolong mechanical ventilation in survivors, and the relationship was especially strong in younger patients.
Conclusions: Frailty score was independently associated with longer duration of mechanical ventilation and contributed to identifying patients who were less likely to be liberated from mechanical ventilation. The impact of frailty on ventilation time varied with age and was most apparent for younger patients.
Prolonged mechanical ventilation is a major problem for critically ill patients and associated with an increased risk of death, longer intensive care unit (ICU) and hospital stays, and increased resource utilization and healthcare costs. These patients are more likely to be dependent on health care at discharge with an increased likelihood of discharge to chronic care/nursing home (1, 2). Historically, age, ICU admission diagnosis, degree of physiologic derangement, and prior patient residential location have been identified as risk factors for prolonged mechanical ventilation (3). The importance of nonpulmonary factors that lead to prolonged mechanical ventilation, however, tends to be underestimated (4). In particular, it is unclear how functional status in daily life should be taken into consideration.
Frailty is a multidimensional state that includes poor functional status, sarcopenia, muscle weakness, decreased physiological reserve, poor nutritional status, and diminished cognitive function, all of which lead to increased vulnerability to stress (5). Frailty is common among critically ill older patients, presenting in 40% of those aged at least 80 years in Australian and New Zealand ICUs (6). Younger patients with comorbidities such as advanced malignancy, chronic respiratory disease, and cirrhosis may also have frailty. Frailty at ICU admission is associated with adverse outcomes, including higher mortality and prolonged length of ICU stay (6–8).
A retrospective review of a large cohort of critically ill patients reported that frailty was associated with intense organ support, including the need for mechanical ventilation (9). In contrast, four prospective observational studies to investigate the relationship between frailty and health service utilization reported that there was no difference between patients with and without frailty in the necessity of invasive mechanical ventilation (8, 10–12). The relationship between frailty and invasive mechanical ventilation is complex, as invasive mechanical ventilation for patients with frailty may be preferentially avoided by patients, their family, or clinicians, while the vulnerability to illness paradoxically may increase the requirement for organ support and resource use (13). Therefore, it is unclear if frailty is independently associated with the duration of mechanical ventilation (7).
We hypothesized that the duration of invasive mechanical ventilation would be affected by frailty independent of other relevant factors, such as diagnosis and chronic respiratory conditions. Our study aimed to identify the relationship between frailty and duration of mechanical ventilation and determine whether this differed with patients’ age in critically ill patients.
This was a retrospective population-based cohort study, analyzing the Australian and New Zealand Intensive Care Society (ANZICS) Adult Patient Database between July 1, 2017, and June 30, 2020. This database includes more than 90% of patients admitted to Australian and New Zealand ICUs.
The ANZICS Adult Patient Database prospectively collects deidentified information on patients admitted to adult ICUs in Australia and New Zealand. This high-quality binational database records patient admission diagnosis, chronic health status, physiological and biochemical variables within the first 24 hours of admission, required for the acute physiology and chronic health evaluation (APACHE) II and III-j illness severity scores systems and Australian and New Zealand risk of death, as well as ICU and hospital outcomes.
All adult patients (age ⩾16 yr) who received invasive mechanical ventilation within the first 24 hours of ICU admission were included, with only the first ICU admission per hospitalization considered. Patients were excluded if they were admitted for the purposes of organ donation or palliative care. Patients were also excluded if there were no data about invasive mechanical ventilation hours or frailty score was not documented.
Frailty was identified using the Canadian Study of Health and Aging clinical frailty scale (CFS), a nine-point assessment tool to quantify frailty based on the deficit accumulation approach (14). This measurement has been validated among critically ill patients (6, 8), with good interrater reliability (15, 16), and reported to be correlated with the other comprehensive frailty scales (17, 18). In the ANZICS Adult Patient Database, the CFS is modified to eight categories without a CFS of 9 (terminally ill). Patients with a CFS of 4 or lower were considered nonfrail, and those with a score of 5 or higher were considered frail. CFS was assigned by data collectors in participating ICUs based on the patient’s level of physical function in the 2 months preceding ICU admission (19).
Based on previous literature (3, 20–22), admission diagnosis, prior patient location, elective or emergency admission, acute physiology score (APS) for APACHE III-j, and chronic medical comorbidities (cardiovascular, lung, and renal) were investigated as risk factors for prolonged mechanical ventilation. No information was available on ventilator settings or patients’ respiratory parameters.
The primary outcome of interest was the total duration of mechanical ventilation. This was defined as the time from connection to positive pressure ventilation via an invasive artificial airway (either an endotracheal tube or a tracheostomy) to the cessation of mechanical ventilation, including all episodes of invasive mechanical ventilation during the same ICU admission period. Secondary outcomes included ICU length of stay, ICU mortality, readmission to ICU during the hospitalization, hospital length of stay, and in-hospital mortality.
Between dichotomized categories (frail vs. nonfrail), continuous normally distributed variables were compared using Student’s t tests and reported as means (standard deviation), while nonnormally distributed variables were compared using Wilcoxon rank-sum tests and reported as medians (interquartile range). Categorical data were compared using chi-square tests and reported as n (%). The duration of mechanical ventilation was compared among CFS categories (1–8) using the Kruskal-Wallis test. As definitive analysis of duration of mechanical ventilation could be confounded by the competing risk of ICU death, we assumed that true duration of mechanical ventilation was truncated for all patients who died in the ICU while receiving ventilation or within 48 hours after the end of ventilation (23). Therefore, we have treated ICU death in these patients as a competing risk, modeling duration of mechanical ventilation with the Fine and Gray proportional subdistribution hazard regression (see Figure E1 in the online supplement). This model was adjusted for age, chronic respiratory disease, cardiovascular disease, renal disease, APS, elective admission, ICU admission source, and diagnosis, with patients clustered by hospital site and site treated as a random effect. To investigate the impact of age on the relationship between frailty and duration of mechanical ventilation, interaction terms between frailty and age were fitted to the models. To ensure robustness of findings, the sensitivity analyses were performed, including the Fine and Gray test, using age as a categorical variable and separately examining ventilator-free days at Day 30. Duration of mechanical ventilation was also reported by age groups for each frailty level and displayed as tabular heat maps. As the duration of mechanical ventilation was found to be well approximated by a log-normal distribution, for increased transparency to present the impact of frailty, multivariate linear regression for a log-transformed duration of mechanical ventilation was also conducted, adjusting for the previously described covariates, with results stratified by survival status and reported as geometric means (95% confidence interval [CI]). All analyses were performed using R version 3.6.1 (R Foundation for Statistical Computing). A two-sided P < 0.05 was considered statistically significant.
The study was approved by the Alfred Hospital Ethics Committee (Project no. 584/18). Access to the ANZICS Adult Patient Database was granted by the ANZICS Centre for Outcome and Resource Evaluation Management Committee in accordance with standing protocols.
Among 524,124 patients, 145,060 received invasive mechanical ventilation within the first 24 hours of ICU admission. Excluding patients with missing ventilation hours or CFS, 59,319 patients were included in this study analysis (Figure 1). There were some differences in the baseline demographics between patients with complete data and those with either missing mechanical ventilation data or CFS score who were excluded, although magnitude of differences was small with similar severity score (APACHE III-j 60.1 vs. 59.8) and mechanical ventilation time (18 h vs. 17 h) (Tables E1 and E2).
Figure 1. Study flow. ANZICS = Australian and New Zealand Intensive Care Society; APD = adult patient database; CFS = clinical frailty scale; ICU = intensive care unit.
[More] [Minimize]Overall, 14% (8,331/59,319) of patients were classified as frail. Patients with frailty were older, had a higher proportion of females, higher prevalence of chronic medical conditions (cardiovascular, lung, and renal), and higher illness severity scores (APACHE II, APACHE III-j, ANZROD), and were more likely to be admitted emergently (Table 1).
| Characteristics | Frail | Nonfrail |
|---|---|---|
| N = 8,331 | N = 50,988 | |
| Age, mean (SD), years | 68.0 (15.0) | 58.5 (17.5) |
| Male sex, n (%) | 4,543 (54.5) | 34,024 (66.7) |
| Diagnosis in ICU admission, n (%) | ||
| Cardiac | 1,470 (17.6) | 6,785 (13.3) |
| Cardiovascular surgery | 1,110 (13.3) | 18,322 (35.9) |
| Gastrointestinal | 1,749 (21.0) | 4,895 (9.6) |
| Neurological disease | 924 (11.1) | 4,673 (9.2) |
| Respiratory disease | 1,421 (17.1) | 4,009 (7.9) |
| Sepsis | 696 (8.4) | 1,735 (3.4) |
| Trauma | 249 (3.0) | 3,762 (7.4) |
| Other | 712 (8.5) | 6,807 (13.4) |
| ICU admission source, n (%) | ||
| Operating theater or recovery room | 4,082 (49.0) | 30,718 (60.2) |
| Accident and emergency | 2,292 (27.5) | 13,123 (25.7) |
| Hospital ward | 1,174 (14.1) | 2,928 (5.7) |
| Other hospital | 758 (9.1) | 4,122 (8.1) |
| Other | 25 (0.3) | 96 (0.2) |
| Elective admission, n (%) | 1,717 (20.6) | 21,142 (41.5) |
| Chronic medical condition, n (%) | ||
| Cardiovascular system | 1,411 (16.9) | 4,507 (8.8) |
| Lung | 1,531 (18.4) | 2,210 (4.3) |
| Renal | 584 (7.0) | 937 (1.8) |
| APACHE II, mean (SD) | 22.7 (8.4) | 17.3 (7.6) |
| APACHE III-j score, mean (SD) | 74.2 (28.7) | 57.5 (25.7) |
| ANZROD, mean, median (IQR), % | 23.1, 11.6 (3.2–35.7) | 9.7, 1.6 (0.5–8.2) |
| Duration of mechanical ventilation, median (IQR), h | 27 (13–-81) | 16 (7–44) |
| New tracheostomy performed during ICU stay, n (%) | 287 (3.4) | 1,545 (3.0) |
| ICU length of stay, median (IQR), h | 87 (45–165) | 51 (28–110) |
| ICU mortality, n (%) | 1,483 (17.8) | 3,815 (7.5) |
| ICU readmission, n (%) | 565 (6.8) | 2,097 (4.1) |
| Hospital length of stay, median (IQR), d | 13.0 (6.7–23.3) | 9.6 (5.9–16.0) |
| Hospital mortality, n (%) | 2,078 (25.1) | 4,694 (9.2) |
Patients with frailty had longer duration of mechanical ventilation than patients without frailty (27 [13–81] h vs. 16 [7–44] h; P < 0.001). Figure E2 shows the duration of mechanical ventilation by individual CFS category, with duration of mechanical ventilation increasing with higher CFS score (P < 0.001). Patients with frailty receiving invasive mechanical ventilation had longer ICU and hospital length of stay, with higher ICU and hospital mortality than patients without frailty.
Cumulative incidences of ventilator dependence and mortality after ICU admission are presented in Figure 2. Patients with frailty had higher proportion of ventilator dependence despite higher mortality throughout their ICU stay. After adjustment for relevant covariates in multivariate analyses (Table 2), frailty was significantly associated with a reduced probability of cessation of invasive mechanical ventilation (adjusted hazard ratio [HR], 0.57 [95% CI, 0.51–0.64]; P < 0.001). In this model, the interaction term between frailty and age was significant and indicated that the nature of relationship between frailty and ventilation hours differed with age. Figure 3 describes the median duration of mechanical ventilation based on CFS categories and age. In patients younger than 60 years, invasive mechanical ventilation was prolonged for patients with higher CFS, while older patients had less difference among CFS categories. Among ICU survivors, younger patients with frailty received longer invasive mechanical ventilation, whereas in deceased patients, mechanical ventilation tended to be prolonged for younger patients with frailty and older patients without frailty.
Figure 2. Cumulative incidence of ventilator dependence and mortality. Cumulative incidence in patients with and without frailty are shown as dashed and solid lines, respectively.
[More] [Minimize]| Hazard Ratio | 95% CI | P Value | |
|---|---|---|---|
| Basic demographics | |||
| Age (per 10 yr) | 0.94 | 0.94–0.95 | <0.001 |
| Frailty | 0.57 | 0.51–0.64 | <0.001 |
| Interaction (frailty and age) | 1.06 | 1.05–1.08 | <0.001 |
| Chronic respiratory disease | 0.91 | 0.87–0.94 | <0.001 |
| Chronic cardiovascular disease | 0.92 | 0.89–0.95 | <0.001 |
| Chronic renal disease | 1.02 | 0.96–1.08 | 0.57 |
| Elective admission | 1.56 | 1.51–1.61 | <0.001 |
| Physiological data | |||
| Acute physiology score (APACHE III-j) (per 10 points) | 0.81 | 0.81–0.81 | <0.001 |
| ICU admission source (reference; operating theater or recovery room) | |||
| Accident and emergency | 0.91 | 0.89–0.94 | <0.001 |
| Hospital ward | 0.81 | 0.78–0.85 | <0.001 |
| Other hospital | 0.79 | 0.76–0.82 | <0.001 |
| Others | 0.90 | 0.74–1.10 | 0.30 |
| Diagnosis (reference; others) | |||
| Cardiac | 0.64 | 0.61–0.66 | <0.001 |
| Cardiovascular surgery | 1.13 | 1.08–1.17 | <0.001 |
| Gastrointestinal | 0.81 | 0.78–0.84 | <0.001 |
| Neurological disease | 0.53 | 0.51–0.56 | <0.001 |
| Respiratory disease | 0.54 | 0.52–0.56 | <0.001 |
| Sepsis | 0.55 | 0.52–0.58 | <0.001 |
| Trauma | 0.46 | 0.44–0.48 | <0.001 |
Figure 3. Heat map of mechanical ventilation hours by frailty category and age group. The values in each area present median and interquartile range of mechanical ventilation hours. ICU = intensive care unit. *The number of patients is less than 50.
[More] [Minimize]A regression model using age as categorical variable (grouped as <50 yr, 50–59 yr, 60–69 yr, 70–79 yr, and ⩾80 yr) indicated that frailty was associated with a prolonged duration of mechanical ventilation. There was a significant interaction between frailty and age (Table E3). In patients with frailty, the probability of cessation of invasive mechanical ventilation (i.e., shorter ventilation duration) increased with every additional decade of age by 4% (HR, 1.04 [95% CI, 1.02–1.06]; P < 0.001); however, in patients without frailty, this relationship decreased by 6% (HR, 0.94 [95% CI, 0.93–0.95]; P < 0.001). Ventilator-free days at Day 30 in patients with frailty were fewer than in those without frailty (28.4 [22.4–29.4] d vs. 29.3 [27.7–29.7] d; P < 0.001).
Multivariate linear regression in ICU survivors indicated that the adjusted geometric mean duration of mechanical ventilation was significantly longer in patients with frailty than patients without frailty (24.9 [95% CI, 22.8–27.2] h vs. 21.2 [95% CI, 19.4–23.1] h; P < 0.001). In contrast, among deceased patients, there was no difference in duration of mechanical ventilation according to frailty status (frail, 44.3 [95% CI, 36.5–53.7] h vs. nonfrail, 53.4 [95% CI, 44.0–64.8] h; P = 0.09) (Table 3).
| Clinical Frailty Scale (CFS) | ICU Survivors | ICU Deceased Patients | ||
|---|---|---|---|---|
| Unadjusted Geometric, Mean (95% CI), h | Adjusted Geometric, Mean* (95% CI), h | Unadjusted Geometric, Mean (95% CI), h | Adjusted Geometric, Mean* (95% CI), h | |
| Nonfrail (CFS 1–4) | 17.7 (17.5–17.9) | 21.2 (19.4–23.1) | 53.9 (51.5–56.3) | 53.4 (44.0–64.8) |
| 1 | 17.5 (16.7–18.2) | 18.8 (17.0–20.7) | 59.0 (48.9–71.1) | 60.4 (43.8–83.2) |
| 2 | 17.2 (16.9–17.6) | 19.9 (18.3–21.8) | 60.6 (55.5–66.2) | 59.6 (48.1–73.9) |
| 3 | 16.6 (16.3–16.9) | 20.9 (19.2–22.8) | 52.5 (48.9–56.4) | 54.1 (44.1–66.2) |
| 4 | 20.7 (20.2–21.3) | 23.2 (21.2–25.3) | 49.6 (45.7–53.8) | 52.8 (43.2–64.5) |
| Frail (CFS 5–8) | 29.1 (28.2–30.0) | 24.9 (22.8–27.2) | 39.8 (37.1–42.8) | 44.3 (36.5–53.7) |
| 5 | 27.1 (26.0–28.4) | 24.6 (22.4–27.0) | 42.6 (37.8–48.0) | 46.3 (37.3–57.5) |
| 6 | 29.4 (27.9–31.0) | 24.8 (22.5–27.3) | 39.7 (35.4–44.6) | 45.7 (36.9–56.6) |
| 7 | 36.1 (33.2–39.2) | 25.3 (22.7–28.2) | 39.7 (33.7–46.7) | 44.0 (34.5–55.9) |
| 8 | 33.3 (26.6–41.7) | 20.4 (16.5–25.1) | 28.1 (21.2–37.3) | 33.1 (23.7–46.2) |
In this large retrospective cohort study analyzing almost 60,000 patients receiving invasive mechanical ventilation within 24 hours of ICU admission, 14% of patients were classified as frail. These patients received invasive mechanical ventilation for longer and had increased mortality when compared with patients without frailty. Multivariate competing risk analysis demonstrated that frailty was independently associated with a reduced probability of cessation of invasive mechanical ventilation. The impact of frailty differed with age, with younger patients with advanced frailty being more likely to receive longer mechanical ventilation. In linear regression, frailty was associated with prolonged mechanical ventilation in ICU survivors, but not in deceased patients.
Frailty is an important consideration reflecting how a patient lived prior to ICU admission, including their physical performance, mobility, and malnutrition, which could adversely affect respiratory reserve and other fitness. However, limited literature has examined associations with mechanical ventilation time and frailty. A prospective French observational study of 196 patients aged at least 65 years presented no difference in duration of invasive mechanical ventilation between patients with and without frailty (24), which were not adjusted for possible competing risk owing to increased mortality in patients with frailty. A recent Canadian retrospective study of a prospectively collected registry indicated patients with frailty had more adverse outcomes following invasive mechanical ventilation including increased hospital mortality, disposition to long-term care, failure of first extubation attempt, and need for tracheostomy, which could lead to prolonged ventilation (25). Our findings further reinforced the impact of frailty on adverse outcomes following invasive mechanical ventilation with a much greater number of patients and provided novel perspective in terms of associated complications and resource use owing to longer duration of mechanical ventilation. Frailty would be useful for clinicians to discuss the prognosis with patients receiving invasive mechanical ventilation and their family and make a decision on goals of care in the ICU.
Our study found that the effect of frailty on ventilation time varied with age. Mechanical ventilation was prolonged for younger patients with frailty, but not for older patients, which would suggest that intensivists are willing to devote intensive healthcare resources, including mechanical ventilation, to support younger patients with frailty in ICU. Coupled with the result that invasive mechanical ventilation was prolonged for patients with advanced frailty among ICU survivors, younger patients with advanced frailty could be considered a group to target for longer duration of mechanical ventilation, in achieving more favorable outcomes in ICU. In the clinical setting, frailty and advanced age could affect patients’, families’, or clinicians’ decision making, potentially prompting palliative extubation or moving to end-of-life care management, which may result in shorter ventilation time in older patients with frailty.
Prolonged ventilation has been associated with worse outcomes in critical illness, although premature extubation may lead to the requirement for reintubation with associated complications (21, 26). Several studies reported that spontaneous breathing trials and protocolized ventilator weaning could contribute to rapid and reliable extubation in critically ill adult patients (27, 28). More importantly, identification of high-risk patients at ICU admission could provide clinicians with time to initiate rehabilitation and weaning programs earlier and more intensively (29). Mobilization and respiratory muscle training have an important role in preventing dependent airway closure, pulmonary atelectasis, pneumonia, and ICU-acquired weakness, which may reduce hospital length of stay (30–32). Predicting the risk of prolonged ventilation, considering frailty, allowing early intervention, may improve the outcomes for critically ill patients dependent on invasive mechanical ventilation.
One of the strengths of this study is the inclusion of multiple ICUs throughout Australia and New Zealand, providing a comprehensive overview of total duration of mechanical ventilation stratified by frailty at the population level. In the present study, competing risk analyses were applied to assess the impact of frailty on ventilation time to address the confounding factors. Our findings about frailty and its effect in the whole cohort, as well as within specific age subgroups, were consistent across multiple different types of analyses, providing a comprehensive understanding of the impact of frailty on mortality and prolonged mechanical ventilation.
Our study has several limitations. First, due to the retrospective study design, we assessed total duration of invasive mechanical ventilation via an endotracheal tube or a tracheostomy and could not assess whether reintubation was offered for each patient. Second, detailed information about ventilation mode or other managements and treatment was unavailable in our dataset. Third, missing data for mechanical ventilation hours and CFS were 38% and 34%, respectively. There were only small differences, however, between patients included and those excluded because of missing values. Finally, although registry data were generally collected by trained data collectors, the assignment of CFS did not require individualized training, other than the instructions for scoring contained in the data dictionary. Future studies are required to clarify the impact of frailty on reintubation and noninvasive ventilation, and on how age and frailty independently affect decision-making processes about delivery and cessation of ventilation.
Frailty is independently associated with longer duration of mechanical ventilation, particularly in younger patients with advanced frailty. These findings provide new insights into the prognosis for patients with different frailty degrees receiving invasive mechanical ventilation. The CFS offers important information to identify high-risk patients requiring longer invasive mechanical ventilation, which should be measured on patient admission and considered in ventilator weaning assessment in the ICU.
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Author Contributions: S.O. and D.V.P. have full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. S.O., A.S., J.N.D., R.U., M.B., and D.V.P. contributed substantially to the study design, data analysis and interpretation, and writing of the manuscript and approved this submission.
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