Abstract
[Purpose] To examine the association between intensive care unit-acquired weakness and functional disability, specifically hospitalization-associated disability. [Participants and Methods] This post-hoc analysis of an investigation of the physical activity of mechanical ventilated patients in intensive care units involved nine hospitals. Consecutive patients, intubated in the intensive care unit for >48 h, were eligible. The exposure variable was intensive-care-unit-acquired weakness. The primary outcomes were the Barthel Index and incidence of hospitalization-associated disability. Multiple logistic regression analysis was used to analyze the association between intensive-care-unit-acquired weakness and both outcomes. [Results] Of the 121 patients, 46 were assigned to the intensive-care-unit-acquired weakness group and 75 to the non-intensive-care-unit-acquired weakness group. The Barthel Index scores were consistently different between intensive care unit discharge and hospital discharge. No significant difference in the incidence of hospitalization-associated disability was found from intensive care unit discharge to 28 days post-ICU discharge. A significant difference between the two groups was observed only at the time of hospital discharge. The Medical Research Council score correlated linearly with the Barthel Index at 7, 14, and 28 days and with hospital discharge. [Conclusion] Intensive-care-unit-acquired weakness is significantly associated with functional disability and hospitalization-associated disability in critically ill patients admitted with acute illness.
Keywords: Intensive care unit-acquired weakness, Hospitalization-associated disability, Rehabilitation
INTRODUCTION
Although short-term mortality among critically ill patients has improved recently, functional impairment after intensive care unit (ICU) discharge has become a growing concern1). ICU-acquired muscle weakness (ICU-AW), a physical dysfunction of post-intensive care syndrome, is an acute symmetrical limb muscle weakness syndrome that develops after ICU admission2). Unlike disuse syndrome, ICU-AW results from factors such as inflammation, leading to muscle weakness and atrophy3, 4), ICU-AW prolongs hospital stays, extends the duration of mechanical ventilation5), increases healthcare costs, and contributes to long-term muscle weakness in both limb and respiratory muscles, ultimately reducing quality of life5, 6).
Regarding the course of subsequent physical dysfunction associated with the occurrence of ICU-AW, a relationship between survival rate and physical dysfunction after 5 years has been reported7). Approximately 75% of patients who survived the ICU have been reported to experience persistent physical dysfunction8). Once ICU-AW develops, few effective treatments exist, with rehabilitation being the most promising intervention9). Although ICU-AW has long been associated with short-term mortality, such as in-hospital mortality10), its impact on the course of physical dysfunction and hospitalization-associated disability (HAD) during hospitalization remains unclear11).
Insights into the course of ICU-AW development and daily functioning during hospitalization for patients to return home may help optimize in-hospital rehabilitation for critically ill patients. However, the relationship between ICU-AW onset and the course of daily life function and physical dysfunction after ICU discharge remains unclear. We hypothesized that patients who develop ICU-AW may experience greater difficulty with subsequent activities of daily living. A post hoc analysis of the Investigating Physical Activity of Mechanical Ventilation Patients in the ICU (IPAM) Study12), a prospective, multicenter study of rehabilitation dose and daily living function in patients in the ICU, was conducted to investigate the association between the occurrence of ICU-AW, physical dysfunction, and HAD.
PARTICIPANTS AND METHODS
This was a post-hoc analysis of the IPAM Study (UMIN ID: 000047578)12). This study was approved by the Ethics Committee of Gifu University of Health Science (202204) and eight other participating hospitals. Informed consent was obtained from all patients. Patients aged <18 years, those with a loss of walking independence before hospitalization, those with neurological complications, those with communication difficulties due to preexisting mental diseases, and those in a terminal state were excluded. Patients with coronavirus disease were also excluded from this study.
At each participating site, ICU physicians or physiotherapists used a five-level mobility protocol to determine each patient’s rehabilitation level based on their condition13, 14). All ICUs implemented standardized early rehabilitation following the 2017 expert consensus on early rehabilitation by the Japanese Society of Intensive Care Medicine15). Background information on participating ICUs and patients are shown in Supplementary Table 1. In this study, rehabilitation was primarily provided by physiotherapists and occupational therapists, with nurses playing a supporting role in mobilization and bedside activities. The degree of nurse involvement varied from facility to facility depending on institutional policy and staff availability. After ICU discharge, physical or occupational therapists provided rehabilitation, including muscle strengthening, balance, walking, and stair exercises for more than 20 minutes on weekdays, in line with the rehabilitation policies of each hospital’s general ward. Although ICU care protocols were not unified across sites, they adhered to recent standard guidelines, including the 2018 Pain, Agitation/Sedation, Delirium, Immobility, and Sleep guidelines16), nutrition guidelines17), and mechanical ventilation management guidelines18), tailored to each ICU’s characteristics.
The exposure variable in this study was the occurrence of ICU-AWs upon ICU discharge. ICU-AW was defined by a Medical Research Council (MRC) score (assessed by a physiotherapist) of <48 upon discharge from the ICU19).
The primary outcomes were the Barthel Index (BI) and HAD incidence. Each evaluation was performed at five time points: ICU discharge (T1), 7th day of ICU discharge (T2), 14th day of ICU discharge (T3), 28th day of ICU discharge (T4), and hospital discharge (T5) (Supplementary Fig. 1). HAD was defined as a decrease in the discharge BI score of at least 5 points compared to the prehospital BI score (T0)20). Prehospitalization BI scores were assessed at the time of admission to the ICU based on information from the family or patients if they were conscious.
The following basic patient information was recorded at the time of ICU admission: age, sex, body mass index, acute physiology and chronic health evaluation score, sequential organ failure assessment score, Charlson Comorbidity Index, BI before hospitalization, and ICU admission diagnosis. Other variables/parameters included ICU and hospital length of stay, mechanical ventilation duration, discharge to home, and hospital mortality.
Patient characteristics are expressed as median (interquartile range) or number of cases (%) in the data. A multiple logistic regression model was used as the main model to assess whether the occurrence of ICU-AW affected the dependent variables, BI and HAD incidence, during hospitalization. Covariates for multivariate analysis included age, sex, Charlson Comorbidity Index, acute physiology and chronic health evaluation score, sequential organ failure assessment score at ICU admission, and use of steroids and neuromuscular blockers. To analyze secondary and other outcomes, we performed multiple logistic regression analyses on log-transformed continuous and categorical variables, respectively, using the same covariates used to analyze the primary outcome. BI scores of the two defined groups (patients who developed ICU-AW and those who did not develop ICU-AW) at different time points (T1, T2, T3, T4, and T5) were compared using one-way analysis of variance. Pearson’s correlation coefficient was used to assess the correlation between the MRC score at ICU discharge and the BI score at T2–T5.
All analyses were performed using JMP (version 13.0; SAS Institute, Cary, NC, USA). Statistical tests were two-tailed, and p-values <0.05 were considered statistically significant.
RESULTS
A total of 671 patients were admitted to the ICU, of which 121 were included in the study after excluding patients aged <18 years, those with loss of walking independence before hospitalization, those with neurological complications, those with communication difficulties, and those with terminal conditions (Supplementary Fig. 2). ICU-AW was observed in 46 patients (ICU-AW) but not in 75 patients (No ICU-AW).
Table 1 shows the baseline characteristics of patients in the entire study cohort, as well as in the ICU-AW and No ICU-AW groups. Intergroup comparisons revealed significant differences (Table 1) in age (p=0.002), Charlson Comorbidity Index (p=0.029), mechanical ventilation duration (p=0.003), ICU length of stay (p=0.018), and discharge to home (p=0.006).
Table 1. Baseline characteristics at the time of intensive care unit admissions.
| Baseline characteristics | All patients | ICU-AW | No ICU-AW |
| n=121 | n=46 | n=75 | |
| Age (years), median [IQR] | 74 [64–80] | 78 [68–84] | 71 [64–77] |
| Gender (male), n (%) | 72 (60) | 24 (52) | 48 (64) |
| BMI (kg/m2), median [IQR] | 21 [18–24] | 20 [17–24] | 22 [19–25] |
| CCI, median [IQR] | 1 [1–3] | 2 [1–4] | 1 [0–3] |
| BI before hospitalization (T0), n (%)a | 100 [100–100] | 100 [95–100] | 100 [100–100] |
| ICU admission diagnosis, n (%) | |||
| Acute respiratory failure | 24 (20) | 11 (24) | 13 (17) |
| Cardiovascular disease | 50 (41) | 13 (28) | 37 (50) |
| Gastric or colonic surgery | 25 (21) | 12 (26) | 13 (17) |
| Other diagnoses | 22 (18) | 10 (22) | 12 (16) |
| APACHE II score, median [IQR] | 22 [16–26] | 23 [17–29] | 21 [15–25] |
| SOFA at ICU admission, median [IQR] | 7 [4–10] | 8 [5–10] | 7 [4–10] |
| The use of continuous vasopressor during ICU stay, n (%) | 80 (66) | 31 (67) | 49 (65) |
| The use of steroids during ICU stay, n (%) | 10 (8) | 6 (13) | 4 (5) |
| The use of neuromuscular blocking agent during ICU stay, n (%) | 12 (10) | 5 (10) | 7 (9) |
| Duration of mechanical ventilation, median [IQR] | 5 [3–9] | 7 [4–15] | 5 [3–8] |
| ICU length of stay, median [IQR] | 8 [6–12] | 10 [7–19] | 7 [5–11] |
| Hospital length of stay, median [IQR] | 37 [23–57] | 42 [30–69] | 34 [20–53] |
| Discharge to home, n (%) | 71 (58) | 15 (32) | 56 (75) |
| Hospital mortality, n (%) | 5 (4) | 5 (11) | 0 (0) |
Data are presented as median [interquartile range] or number (%).
IQR: interquartile range; BMI: Body mass index; CCI: Charlson comorbidity index; BI: Barthel index; ICU: Intensive Care Unit; APACHE: Acute Physiology and Chronic Health Evaluation; SOFA: Sequential Organ Failure Assessment.
The BI and HAD scores and incidence rates for both groups are shown in Table 2. BI scores were always significantly different (T1; adjusted p=0.028, T2; adjusted p<0.001, T3; adjusted p=0.006, T4; adjusted p=0.021, and T5; adjusted p<0.001). No significant difference was observed in the incidence of HAD from T1 to T4. A significant difference between the two groups was observed only at T5 (ICU-AW 84% vs. No ICU-AW 52%, adjusted p=0.007). Early discharge from the hospital did not allow us to follow up 10 patients on the 7th, 27 patients on the 14th and 52 patients on the 28th days after ICU discharge, respectively.
Table 2. Comparison of clinical outcomes.
| Baseline characteristics | ICU-AW | No ICU-AW |
| n=46 | n=75 | |
| Barthel index at ICU discharge (T1), median [IQR] | 10 [5–21] | 25 [5–50] |
| Barthel index at 7 days after ICU discharge (T2), median [IQR] | 20 [0–39] | 60 [20–85] |
| Barthel index at 14 days after ICU discharge (T3), median [IQR] | 25 [0–55] | 65 [20–90] |
| Barthel index at 28 days after ICU discharge (T4), median [IQR] | 30 [0–60] | 68 [35–85] |
| Barthel index at hospital discharge (T5), median [IQR] | 53 [0–90] | 95 [75–100] |
| HAD at ICU discharge (T1), n (%) | 46 (100) | 75 (100) |
| HAD at 7 days after ICU discharge (T2), n (%) | 43 (97) | 65 (90) |
| HAD at 14 days after ICU discharge (T3), n (%) | 37 (95) | 46 (78) |
| HAD at 28 days after ICU discharge (T4), n (%) | 29 (94) | 40 (97) |
| HAD at hospital discharge (T5), n (%) | 39 (84) | 39 (52) |
Data are presented as median [interquartile range] or number (%).
aThe covariates in the multivariable analysis included age, male, Charlson comorbidity index, Acute Physiology and Chronic Health Evaluation, use of neuromuscular blocking agent and steroid.
Early discharge from the hospital did not allow us to follow up eight and 5 patients on the 7th, 38 patients on the 14th and 52 patients on the 28th days after extubation, respectively. IQR: interquartile range; ICU-AW: Intensive care unit acquired weakness; HAD: Hospitalization-associated disability.
We also examined the temporal patterns of the BI scores. Patients who did not develop ICU-AW had significantly higher scores than those who developed ICU-AW (F=62,15, p<0.001) (Supplementary Fig. 3).
The MRC score at ICU discharge correlated linearly with the BI scores at 7 days (r=0.468, p<0.001), 14 days (r=0.479, p<0.001), 28 days (r=0.560, p<0.001), and at hospital discharge (r=0.669, p<0.001) (Fig. 1).
Fig. 1.
Correlation of medical research council score and Barthel index.
a: 7th day after ICU discharge, b: 14th day after ICU discharge, c: 28th days after ICU discharge, d: hospital discharge. ICU: Intensive care unit.
DISCUSSION
In this study, we investigated the association between ICU-AW occurrence in critically ill patients admitted to the ICU and the course of BI and HAD incidence during hospitalization. ICU-AW was consistently associated with lower BI scores during hospitalization. The incidence of HAD was significantly higher in patients who developed ICU-AW than in those who did not develop ICU-AW only at the time of discharge. MRC scores at ICU discharge also showed a greater correlation with BI as the time of discharge approached. To our knowledge, this is the first report on ICU-AW occurrence during hospitalization and its association with the BI and HAD incidence.
A previous study on the functional prognosis of patients with ICU-AW reported that during MRC follow-up, the ICU-AW group recovered muscle strength after discharge compared to the No ICU-AW group, without significant differences21). However, the activities of daily living and quality of life during the same period were significantly lower in the ICU-AW group. Similarly, in a study on acute lung injury by Fan et al., muscle strength gradually recovered in all patients, but physical function continued to decline even after 2 years6). Since the development of other functional scales, the BI has been considered too simple and unresponsive. However, studies on patients with traumatic brain injury suggest that the BI is non-inferior to the Functional Independence Scale and can be applied more quickly22). It has been suggested that the BI masks reactivity when the patient’s function is too low23). Nearly all the patients in the study population had low scores at ICU discharge. However, before discharge, the patients consistently showed significant differences in functional status. Furthermore, the correlation coefficient between the MRC and BI scores increased as the time of discharge approached. BI was able to detect this. In this study, the patients were evaluated until discharge. This suggests that patients who develop ICU-AW have consistently impaired physical function up to the time of discharge and, therefore, require a higher level of support after discharge from the ICU.
Hospitalization for acute illness is a significant risk factor for functional decline, and HAD can jeopardize clinical outcomes and post-discharge recovery in critically ill patients24). Previous studies have shown that functional decline during hospitalization in older adult patients significantly increases hospital length of stay, mortality risk, and healthcare costs25). Additionally, decreased grip strength has been identified as a significant predictor of mortality in hospitalized patients, with muscle weakness during hospitalization linked to adverse clinical outcomes26). The clinical impact of ICU-AW on critically ill patients may have been underestimated, as many patients were already weak and frail due to disuse muscle atrophy. Therefore, the HAD incidence may be reduced before discharge in patients who did not develop ICU-AW compared to those who did develop ICU-AW, as in-hospital rehabilitation may have improved the disuse syndrome.
This study was conducted in nine ICUs in Japan and included both large and small ICUs in urban areas, ensuring the external validity of our findings. However, this study had some limitations. First, the small number of patients limited the scope of our findings, particularly for subgroup analyses. Second, unadjusted confounding factors may have significantly impacted the results. Third, the study’s follow-up period was short. Fourth, the provision of rehabilitation by nurses and on weekdays and weekends varied between facilities depending on facility policy and staff availability. Fifth, some patients were lost to follow-up on the 7th, 14th, and 28th days after discharge from the ICU due to early discharge, which may have influenced the results. Finally, we included patients with various medical and surgical conditions to increase generalizability. A multicenter randomized controlled trial with more patients is needed to validate these findings further and investigate causality.
ICU-AW is significantly associated with functional decline and HAD incidence in critically ill patients admitted with acute illnesses. This highlights the urgent need for early and targeted rehabilitation strategies in ICU settings to mitigate the impacts of ICU-AW on patients’ long-term recovery and quality of life. However, to validate these findings further, interventional studies are needed to examine the causal relationship between muscle weakness associated with ICU admission and clinical outcomes.
Conflict of interest
The authors declare no conflicts of interest in relation to the work presented in the manuscript.
Supplementary Material
Acknowledgments
The authors acknowledge the participants for their voluntary involvement in this study (Supplementary Table 2).
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