Early Rehabilitation Interventions by Physical Therapists for Severe COVID-19 Patients Were Associated With Decreased Incidence of Post-ICU Physical Impairment

Shinya Oku; Junji Hatakeyama; Keibun Liu; Kentaro Tojo; Masafumi Idei; Shigeaki Inoue; Kazuma Yamakawa; Takeshi Nishida; Shinichiro Ohshimo; Satoru Hashimoto; Shuhei Maruyama; Yoshitaka Ogata; Daisuke Kawakami; Hiroaki Shimizu; Katsura Hayakawa; Yuji Fujino; Taku Oshima; Tatsuya Fuchigami; Hironori Yawata; Kyoji Oe; Akira Kawauchi; Hidehiro Yamagata; Masahiro Harada; Yuichi Sato; Tomoyuki Nakamura; Kei Sugiki; Takahiro Hakozaki; Satoru Beppu; Masaki Anraku; Noboru Kato; Tomomi Iwashita; Hiroshi Kamijo; Yuichiro Kitagawa; Michio Nagashima; Hirona Nishimaki; Kentaro Tokuda; Osamu Nishida; Kensuke Nakamura

doi:10.5535/arm.240066

Ann Rehabil Med > Volume 49(1); 2025 > Article

Oku, Hatakeyama, Liu, Tojo, Idei, Inoue, Yamakawa, Nishida, Ohshimo, Hashimoto, Maruyama, Ogata, Kawakami, Shimizu, Hayakawa, Fujino, Oshima, Fuchigami, Yawata, Oe, Kawauchi, Yamagata, Harada, Sato, Nakamura, Sugiki, Hakozaki, Beppu, Anraku, Kato, Iwashita, Kamijo, Kitagawa, Nagashima, Nishimaki, Tokuda, Nishida, and Nakamura: Early Rehabilitation Interventions by Physical Therapists for Severe COVID-19 Patients Were Associated With Decreased Incidence of Post-ICU Physical Impairment

Original Article

Annals of Rehabilitation Medicine 2025;49(1):49-59.

Published online: February 28, 2025

DOI: https://doi.org/10.5535/arm.240066

Early Rehabilitation Interventions by Physical Therapists for Severe COVID-19 Patients Were Associated With Decreased Incidence of Post-ICU Physical Impairment

Shinya Oku, MD¹

, Junji Hatakeyama, MD^2,³

, Keibun Liu, MD, PhD^4,^*

, Kentaro Tojo, MD, PhD⁵

, Masafumi Idei, MD, PhD⁵

, Shigeaki Inoue, MD, PhD^6,^†

, Kazuma Yamakawa, MD, PhD³

, Takeshi Nishida, MD⁷

, Shinichiro Ohshimo, MD, PhD⁸

, Satoru Hashimoto, MD, PhD⁹

, Shuhei Maruyama, MD¹⁰

, Yoshitaka Ogata, MD, PhD¹¹

, Daisuke Kawakami, MD, PhD¹²

, Hiroaki Shimizu, MD¹³

, Katsura Hayakawa, MD¹⁴

, Yuji Fujino, MD, PhD¹⁵

, Taku Oshima, MD, PhD¹⁶

, Tatsuya Fuchigami, MD, PhD¹⁷

, Hironori Yawata, MD¹⁸

, Kyoji Oe, MD¹⁹

, Akira Kawauchi, MD²⁰

, Hidehiro Yamagata, MD²¹

, Masahiro Harada, MD, PhD²²

, Yuichi Sato, MD²³

, Tomoyuki Nakamura, MD, PhD²⁴

, Kei Sugiki, MD²⁵

, Takahiro Hakozaki, MD, PhD²⁶

, Satoru Beppu, MD, PhD²⁷

, Masaki Anraku, MD, PhD²⁸

, Noboru Kato, MD, PhD²⁹

, Tomomi Iwashita, MD, PhD³⁰

, Hiroshi Kamijo, MD, PhD³¹

, Yuichiro Kitagawa, MD³²

, Michio Nagashima, MD, PhD^33,³⁴

, Hirona Nishimaki, MD³⁵

, Kentaro Tokuda, MD, PhD³⁶

, Osamu Nishida, MD, PhD²⁴

, Kensuke Nakamura, MD, PhD⁵

¹Department of Anesthesiology, Yokohama City University Hospital, Yokohama, Japan

²Department of Emergency and Critical Care Medicine, National Hospital Organization Tokyo Medical Center, Tokyo, Japan

³Department of Emergency and Critical Care Medicine, Osaka Medical and Pharmaceutical University, Osaka, Japan

⁴Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia

⁵Department of Critical Care Medicine, Yokohama City University Hospital, Yokohama, Japan

⁶Department of Disaster and Emergency Medicine, School of Medicine, Kobe University, Kobe, Japan

⁷Division of Trauma and Surgical Critical Care, Osaka General Medical Center, Osaka, Japan

⁸Department of Emergency and Critical Care Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

⁹Non-Profit Organization ICU Collaboration Network (ICON), Tokyo, Japan

¹⁰Department of Emergency and Critical Care Medicine, Kansai Medical University Medical Center, Osaka, Japan

¹¹Department of Critical Care Medicine, Yao Tokushukai General Hospital, Osaka, Japan

¹²Department of Anesthesia and Critical Care, Kobe City Medical Center General Hospital, Kobe, Japan

¹³Acute Care Medical Center, Hyogo Prefectural Kakogawa Medical Center, Kakogawa, Japan

¹⁴Department of Emergency and Critical Care Medicine, Saitama Red Cross Hospital, Saitama, Japan

¹⁵Department of Anesthesiology and Intensive Care Medicine, Osaka University Graduate School of Medicine, Osaka, Japan

¹⁶Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, Chiba, Japan

¹⁷Intensive Care Unit, University of the Ryukyus Hospital, Okinawa, Japan

¹⁸Department of Emergency and Critical Care Medicine, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan

¹⁹Department of Intensive Care Medicine, Asahi General Hospital, Chiba, Japan

²⁰Japanese Red Cross Maebashi Hospital, Advanced Medical Emergency Department and Critical Care Center, Maebashi, Japan

²¹Advanced Critical Care and Emergency Center, Yokohama City University Medical Center, Yokohama, Japan

²²Department of Emergency and Critical Care, National Hospital Organization Kumamoto Medical Center, Kumamoto, Japan

²³Critical Care and Emergency Center, Metropolitan Tama General Medical Center, Tokyo, Japan

²⁴Department of Anesthesiology and Critical Care Medicine, Fujita Health University School of Medicine, Nagoya, Japan

²⁵Department of Intensive Care Medicine, Yokohama City Minato Red Cross Hospital, Yokohama, Japan

²⁶Department of Anesthesiology, Fukushima Medical University, Fukushima, Japan

²⁷Department of Emergency and Critical Care Medicine, National Hospital Organization Kyoto Medical Center, Kyoto, Japan

²⁸Department of Thoracic Surgery, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan

²⁹Department of Emergency and Critical Care Medicine, Yodogawa Christian Hospital, Osaka, Japan

³⁰Department of Emergency and Critical Care Center, Nagano Red Cross Hospital, Nagano, Japan

³¹Department of Emergency and Critical Care Medicine, Shinshu University Hospital, Nagano, Japan

³²Emergency and Disaster Medicine, Gifu University School of Medicine Graduate School of Medicine, Gifu, Japan

³³Department of Intensive Care Medicine, Tokyo Medical and Dental University, Tokyo, Japan

³⁴Department of Anesthesiology and Pain Medicine, Juntendo University, Tokyo, Japan

³⁵Department of Anesthesiology, Tohoku University Hospital, Sendai, Japan

³⁶Intensive Care Unit, Kyushu University Hospital, Fukuoka, Japan

Correspondence: Kensuke Nakamura Department of Critical Care Medicine, Yokohama City University Hospital, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
Tel: +81-45-787-2918 Fax: +81-45-787-2918 E-mail: mamashockpapashock@yahoo.co.jp

^*Current affiliation: Non-Profit Organization ICU Collaboration Network (ICON), Tokyo, Japan.

^†Current affiliation: Department of Emergency and Critical Care Medicine, Wakayama Medical University, Wakayama, Japan.

Received July 8, 2024 Revised November 22, 2024 Accepted January 7, 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Objective

To implement early rehabilitation interventions by physical therapists is recommended. However, the effectiveness of early rehabilitation for severe coronavirus disease 2019 (COVID-19) patients in the prevention of post-intensive care syndrome (PICS) is unclear. We analyzed a multicenter prospective observational study (Post-Intensive Care outcomeS in patients with COronaVIrus Disease 2019) to examine the association between early rehabilitation interventions and PICS physical impairment.

Methods

An analysis was performed on COVID-19 patients who were admitted to intensive care units (ICUs) between March 2020 and March 2021, and required mechanical ventilation. The primary outcome was the incidence of PICS physical impairment (Barthel Index≤90) after one year. Multivariate logistic regression analysis was used to estimate the association between early rehabilitation interventions and PICS physical impairment by adjusting ICU mobility scale (IMS) during seven-day following ICU admission, and clinically relevant risk factors.

Results

The analysis included 259 patients, 54 of whom developed PICS physical impairment one year later. In 81 patients, physical therapists intervened within seven days of ICU admission. There was no significant difference in mean IMS by day seven of admission between the early and non-early rehabilitation patients (0.70 and 0.61, respectively). Multivariate logistic regression analysis showed that early rehabilitation interventions were significantly associated with a low incidence of PICS physical impairment (odds ratio, 0.294; 95% confidence interval, 0.123–0.706; p=0.006).

Conclusion

Early rehabilitation interventions by physical therapists were an independent factor associated with the decreased development of PICS physical impairment at one year, even though early rehabilitation had no significant effect on IMS.

Keywords: Critical illness, Rehabilitation, Post-intensive care syndrome, COVID-19

GRAPHICAL ABSTRACT

INTRODUCTION

Post-intensive care syndrome (PICS) is a syndrome consisting of impairment of physical, mental, and cognitive function that occurs during or after intensive care unit (ICU) stay and affects the patient’s prognosis after discharge [1,2]. It has been reported that 40%–60% of patients admitted to an ICU develop PICS [1]. PICS decreases quality of life (QOL) of patients after discharge and makes it challenging for them to return to society. The prevention of PICS is a critical issue for medical staff in ICUs [1-3].

Early rehabilitation interventions to prevent PICS have been recommended [4-6]. It has been reported to decrease ICU-acquired weakness [7] and improve ICU Medical Council Scores within 48 hours after ICU discharge [7,8]. While early rehabilitation improves early PICS physical impairment in the short term after ICU discharge [8-10], the recent large randomized controlled trials (RCTs) showed that early rehabilitation did not improve PICS physical impairment in the late term after ICU discharge [9,11-13]. However, the effectiveness of early rehabilitation is controversial for long-term PICS physical impairment because of differing definitions of rehabilitation, target populations, and outcome assessments. Furthermore, the efficacy of early rehabilitation interventions for long-term PICS physical impairment may vary depending on the contents of the rehabilitation program and the professional composition of the healthcare providers involved. In Japan, numerous hospitals have integrated physical therapists specializing in critical care into the early rehabilitation process. Nevertheless, the association between the participation of physical therapists specializing in critical care in early rehabilitation interventions and the resultant long-term PICS physical impairment attributed to PICS remains unclear.

It had been difficult for physical therapists to provide rehabilitation interventions for severe coronavirus disease 2019 (COVID-19) patients. Severe COVID-19 patients were also isolated due to the risk of spreading COVID-19, limiting the quality and quantity of rehabilitation interventions by physical therapists [14-16] .Many patients required mechanical ventilation and extracorporeal membrane oxygenation (ECMO) during COVID-19 pandemic, which had overwhelmed medical resources. These factors may have made effective rehabilitation interventions difficult. Therefore, it is also unclear for severe COVID-19 patients whether early rehabilitation interventions by physical therapists are associated with improved long-term prognosis related to PICS physical impairment.

In this study, we analyzed part of a multicenter prospective observational study (Post-Intensive Care outcomeS in patients with COronaVIrus Disease 2019, PICSCOVID) [17,18] to determine whether early rehabilitation interventions by physical therapists of severe COVID-19 patients were associated with PICS physical impairment at one year.

METHODS

Study design and settings

This study was conducted as part of the PICSCOVID [17,18] study, an exploratory prospective multicenter observational study that investigated the long-term outcomes of patients with severe COVID-19 infection. Thirty-two Japanese ICUs participated in this study. The study was approved by the Ethics Committees of the Tokyo Medical Center (approval number: R20-133, approval date: November 26, 2020) and each participating institution. The study protocol was registered in the UMIN network (UMIN000041276). The study complied with the Helsinki guidelines.

Study participants

Participants in this study were COVID-19 patients aged 20 years or older who required mechanical ventilation and were admitted to an ICU between March 2020 and March 2021. The PICSCOVID study initially planned to recruit patients between March and December 2020. However, owing to the increase in the number of patients following the spread of COVID-19 in Japan, the recruitment period was extended to March 2021. The decision regarding the indication for mechanical ventilation induction was made at the discretion of each institution. Participants were treated in isolated units in ICUs. Confirmation of infection by COVID-19 was made by polymerase chain reaction test. Patients who did not give consent for the study or who were unable to walk unaccompanied with or without assistive devices at the time of admission were excluded. Patients with COVID-19 requiring mechanical ventilation are promptly registered in the CRoss Icu Searchable Information System (CRISIS) registry upon admission to the ICUs of each participating institution, following national policy. Those patients included in the CRISIS registry were enrolled in PICSCOVID if they met the specified inclusion criteria. Written informed consent was obtained from all patients in the analysis.

Patients were divided into two groups. In the early rehabilitation intervention (ERI) group, patients received therapeutic intervention by a physical therapist within 7 days; in the non-early rehabilitation intervention (NERI) group, patients received no therapy within 7 days. The physical therapists were dedicated to the ICU with at least five years of experience in acute care. The rehabilitation intervention by physical therapists was defined as the development of a plan with both physicians and nurses, after understanding and evaluating the patients’ situation, of specific support measures to maintain, improve, or reacquire various functions, including motor, respiratory, feeding and swallowing, digestion and absorption, and excretory functions. In addition, the efforts made based on the plan were periodically evaluated and revised based on the patients’ condition.

Procedures

To evaluate PICS, questionnaires were sent to consenting patients between 10 and 15 months after discharge from the ICU. We included patients who returned the questionnaire. The questionnaire consisted of simple questions on PICS. The Barthel Index (BI) score was used to assess physical function, the Short-Memory Questionnaire (SMQ) to assess cognitive function, the Hospital Anxiety and Depression Scale (HADS) to assess mental health, anxiety, and depression, and the EuroQol 5 Dimension 5 Level (EQ-5D-5L) to assess QOL. Patients completed the questionnaires alone or were assisted by a family member or acquaintance. Patients who returned the questionnaires were eligible to receive a gift of JPY 1,000.

Outcomes

The primary outcome was the incidence of PICS physical impairment one year after discharge from the ICU. PICS physical impairment was defined as 90 points or less based on BI score [19]. The secondary outcomes were other items of the questionnaire, particularly the incidence of PICS, cognitive impairment, mental disorder, and QOL. Cognitive impairment was defined as a SMQ score of 40 or less [20,21], and HADS score of eight or more on the mental disorder as an anxiety or depression scale [22-24]. PICS onset was defined by PICS physical, cognitive, or mental impairment onset. QOL was evaluated using EQ-5D-5L [25].

Statistical analysis

Patient demographic characteristics and long-term health outcomes were presented as medians (interquartile range) for continuous variables and as absolute values and percentages for categorical variables. Continuous patient characteristic variables were compared using the Mann–Whitney U-test, and categorical variables were compared using the chi-square test. Univariate logistic regression analysis was used to evaluate the associations among early rehabilitation interventions by physical therapists and mean ICU mobility scale (IMS) within seven days of ICU admission and outcomes related to PICS at one year later. Multivariate logistic regression analysis was used to estimate the association of early rehabilitation by physical therapists on the incidence of PICS physical impairment by adjusting by the mean IMS during ICU admission for seven days and clinically relevant factors. The following clinically relevant factors were incorporated: age [26], sex [26,27], body mass index (BMI) [28], Clinical Frailty Scale before hospitalization [29], Sequential Organ Failure Assessment (SOFA) score [27], delirium [30], mechanical ventilation duration [27], ECMO [29], continuous muscle relaxant administration [27], maximum daily steroid dose (prednisolone equivalent dose) [31], and prone position [32]. The mean IMS within seven days of ICU admission was analyzed by calculating mean IMS on days 3, 5, and 7 after ICU admission. Mean IMS was redefined as an ordinal variable, with a score of zero for zero, two for four or more, and one for others. Odds ratios (ORs) were presented as means and 95% confidence intervals (CIs). Missing values were excluded from the analysis. Significance was set at p-values<0.05 (two-tailed) using Python, version 3.10.9.

RESULTS

An outline of the study is shown in Fig. 1. Between March 2020 and March 2021, 673 severe COVID-19 patients required mechanical ventilation in participating ICUs. Of these, 508 patients were enrolled in the study. Of 401 patients who were discharged, 270 responded to the questionnaire. Eleven patients were excluded due to missing clinical information. Finally, 259 patients were evaluated for PICS outcomes. Eighty-one patients received early rehabilitation by physical therapists and 178 patients did not.

Patient backgrounds are shown in Table 1. Patients in ERI group had higher SOFA scores than those in NERI group (p=0.01). There were no patients with malignancy complications in ERI group, but there were 13 (7.3%) patients in the NERI group (p=0.03). Both ERI and NERI groups also had lower IMS on days three, five, and seven after ICU admission (Fig. 2). There was no significant difference in IMS on days three and seven; however, it was significantly higher in ERI group on day five (p=0.004).

In Table 2, the PICS outcomes for the ERI and NERI patient groups are summarized. On the other hand, looking at the continuous variables, there was no significant difference because many people had high BI scores, but the incidence of PICS physical impairment after 1 year, which was the primary endpoint, was significantly lower in the ERI group (10 cases [12.3%] vs. 44 cases [24.7%], p=0.04). In contrast, there were no significant differences in the incidences of PICS cognitive impairment (38 [46.9%] vs. 87 [50.3%]), mental impairment (21 [25.9%] vs. 49 [27.7%]), and PICS (42 [51.9%] vs. 110 [62.5%]) between ERI and NERI groups. There was no significant difference in EQ-5D-5L between ERI (0.87 [0.76, 1.00]) and NERI group (0.85 [0.77, 1.00]).

Table 3 shows the scores for each item of the BI for the patients in ERI and NERI groups. The score for the transfer item is significantly higher in the ERI group (14.8±1.0) compared to the NERI group (14.3±2.9), with a p-value of 0.04.

The results of the univariate and multivariate logistic regression analyses of PICS outcomes are shown in Tables 4 and 5, respectively. Univariate logistic regression analysis showed that early rehabilitation interventions by physical therapists within seven days of ICU admission was significantly correlated with a low incidence of PICS physical impairment one year later (OR, 0.429; 95% CI, 0.204–0.903; p=0.03). Adjusted for age, sex, BMI, CFS, SOFA score, delirium, duration of mechanical ventilation, ECMO, continuous muscle relaxant administration, maximum daily steroid dose, prone position, and mean IMS within seven days of ICU admission, early rehabilitation was significantly correlated with a low incidence of PICS physical impairment one year later (OR, 0.294; 95% CI, 0.123–0.706; p=0.006). It was significantly correlated with a low incidence of PICS (OR, 0.542; 95% CI, 0.301–0.979; p=0.04), but not significantly correlated with the incidence of PICS cognitive impairment (OR, 0.809; 95% CI, 0.454–1.441) or PICS mental impairment (OR, 0.731; 95% CI, 0.380–1.404). Mean IMS within seven days of ICU admission was not significantly correlated with the incidence of PICS physical impairment (OR, 0.691; 95% CI, 0.337–1.419) by multivariate logistic regression analysis.

DISCUSSION

In this post-hoc analysis of the PICSCOVID study, we found that early rehabilitation interventions by physical therapists in severe COVID-19 patients associated with a decreased incidence of PICS physical impairment after one year, even after adjustment for confounding factors. IMS during the first seven days of ICU stay in patients with severe COVID-19 that required mechanical ventilation was low, and there was no clinical difference between ERI and NERI group.

Our results showed early rehabilitation intervention by physical therapists may be associated with a decreased incidence of PICS physical impairment after one year despite the low level of patient activity in ICU. Surprisingly, our logistic regression multivariate analysis showed that early rehabilitation intervention by physical therapists was significantly associated with a decreased incidence of PICS physical impairment after one year, even after adjusting IMS score within first ICU admission seven days. This may suggest that rehabilitation interventions planned by physical therapists within the first seven ICU admission days may improve incidence of PICS physical impairment beyond improvement in physical activity level in ICUs. Electric muscle stimulation (EMS) has been reported to maintain muscle strength in patients with low activity levels [33-35], although EMS is not considered for IMS. Respiratory rehabilitation has been also reported to be associated with a better score of BI scores in long term in mild COVID-19 patients, and it may be effective in severe COVID-19 patients. Early involvement of the physical therapist with the patient may have made it possible to provide various treatments such as EMS and respiratory rehabilitation other than increasing the patient’s activity in ICU.

The recent large RCTs showed that early rehabilitation improved PICS physical impairment in short term after ICU discharge, but did not in late term [9,11-13]. The TEAM Study Investigators and the ANZICS Clinical Trials Group reported that there is no difference between the early rehabilitation and usual care groups in 6-month BI scores, which used in our definition of PICS physical impairment. There are several possible reasons why the results of our study and the previous RCTs differed. First, it was difficult for the control group in our study to receive rehabilitation interventions from other medical staff such as nurses, because of the isolation ward. The usual care group in previous RCTs received standard-protocol [9,11-13]. Our study suggests that the lack of intervention by physical therapists in the early phase of treatment might be associated with the increased incidence of PICS physical impairment [9,11-13]. Second, the population of our study was older and had a longer duration of ventilator use than previous RCTs [9,11-13]. The population in our study was at high risk of PICS physical impairment due to these factors. Therefore, it is possible that this high-risk population was more likely to benefit from early rehabilitation [9,11-13,36]. Third, the pathophysiology of COVID-19 and non-COVID-19 patients is different, which may explain the difference in effectiveness. Although some reports indicate that early rehabilitation in COVID-19 patients improves physical impairment at discharge from the hospital [37,38], no reports within the scope of our study were reported in the late term. Early rehabilitation may reduce PICS physical impairment in the long term by selecting an appropriate population and rehabilitation methods. However, the mechanism by which early rehabilitation reduces PICS physical impairment is unknown. Further research is needed to elucidate its effectiveness and mechanism.

Both ERI and NERI groups in our study had low IMS for up to 7 days after ICU admission. Furthermore, both ERI and NERI groups had clinically similar IMS courses for up to 7 days after ICU admission, because the difference of IMS on day 5 was lower than the clinically meaningful IMS difference of 1.4 to 3 reported in previous studies [39]. Hodgson et al. [7] reported that non-COVID-19 patients requiring mechanical ventilation who received early rehabilitation had a higher incidence of IMS after ICU admission than those who received usual care. These results suggest that early rehabilitation interventions with physical therapists in COVID-19 patients did not have improved physical activity level in early phase in ICUs. One possible reason for the very low IMS in our study was the influence of the COVID-19 pandemic, which limited human health care resources and staff due to the high levels of critically ill patients. Inadequate staffing levels have been reported as a factor preventing adequate rehabilitation [40]. Furthermore, the quality and quantity of rehabilitation that could be provided were limited due to patients being in an isolated environment to prevent the spread of the virus to medical staff [14-16]. Therefore, early rehabilitation interventions may fail to increase ICU activity in patients during the early phase.

There are several limitations to this study. First, there are some potential biases due to observational study. The delay in the initiation of rehabilitation in the NERI group could not be fully clarified, this potential factor may have affected the outcome. Second, rehabilitation protocols were not standardized and were conducted on a facility-specific basis. Especially, it has not been observed whether EMS or respiratory rehabilitation was performed. Furthermore, we did not measure rehabilitation interventions after ICU discharge. As the length of hospital after ICU discharge was longer in early rehabilitation group, there was possibility that they were given more rehabilitation in longer hospital days after ICU discharge. However, it was likely challenging for physical therapists to be involved in rehabilitation on general wards. Previous reports indicate that only 19% of ICUs had physical therapist involvement during the ICU stay [14], suggesting limited availability. After ICU discharge, it is probable that even fewer patients had access to physical therapist-led rehabilitation in general wards. Additionally, no physical therapist involvement occurred following discharge from each facility. Therefore, the presence or absence of post-ICU physical therapy likely had minimal impact on the results of this study. Third, PICS physical impairment was assessed by BI scores. No assessment was made using objective measures such as the 6-minute walk. Fourth, IMS was assessed only up to the seventh day of admission to ICU. The approach of averaging IMS scores across 7 days might not be a clinically meaningful measure of patient mobility. It is possible that there were differences regarding the physical activities not evaluated by IMS. Fifth, this study is based on COVID-19 patients who require mechanical ventilation. These results may not be applicable to COVID-19 patients who do not require ventilation or to non-COVID patients.

Conclusions

In this analysis, we found that early rehabilitation interventions by physical therapists were associated with a decreased incidence of PICS physical impairment after one year in severe COVID-19 patients with low physical activity. Our results may indicate that early rehabilitation interventions by physical therapists are possible to prevent PICS physical impairment when the patients’ activities cannot be adequately increased in ICU.

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

FUNDING INFORMATION

This research was funded by the Nestlé Health Science Company of Nestlé Japan. The funder of this study had no role in the study design, data collection, data analysis, data interpretation, and writing of the report. The funds were used to conduct the electronic data capture for the study, operate the central office, pay for questionnaire postage, and provide honoraria to patients.

AUTHOR CONTRIBUTION

Conceptualization: Nakamura K, Hatakeyama J. Methodology: Nakamura K, Oku S. Formal analysis: Oku S. Investigation: Hatakeyama J, Liu K, Inoue S, Yamakawa K, Nishida T, Ohshimo S, Hashimoto S, Maruyama S, Ogata Y, Kawakami D, Shimizu H, Hayakawa K, Fujino Y, Oshima T, Fuchigami T, Yawata H, Oe K, Kawauchi A, Yamagata H, Harada M, Sato Y, Nakamura T, Sugiki K, Hakozaki T, Beppu S, Anraku M, Kato N, Iwashita T, Kamijo H, Kitagawa Y, Nagashima M, Nishimaki H, Tokuda K, Nishida O, Nakamura K. Funding acquisition: Nakamura K, Hatakeyama J. Project administration: Nakamura K, Hatakeyama J. Writing – original draft: Oku S. Writing – review and editing: Nakamura K, Tojo K, Idei M. Approval of final manuscript: all authors.

ACKNOWLEDGMENTS

We thank to Yasushi Nakamori (Kansai Medical University Medical Center), Masanari Hamaguchi (Department of Critical Care Medicine, Yao Tokushukai General Hospital), Kentaro Motoda (Clinical Research Center, Yao Tokushukai General Hospital), Asase Yamaguchi (Department of Emergency and Critical Care Medicine, Osaka Medical and Pharmaceutical University), Jiro Ito (Department of Anesthesiology and Critical Care, Kobe City Medical Center General Hospital), Kazuya Kiyota (Department of Emergency and Critical Care Medicine, Saitama Red Cross Hospital), Aiko Tanaka (Department of Anesthesiology and Intensive Care Medicine, Osaka University Graduate School of Medicine), Akinori Uchiyama (Department of Anesthesiology and Intensive Care Medicine, Osaka University Graduate School of Medicine), Haruhiko Hirata (Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine), Jiro Fujita (Department of Infectious, Respiratory, and Digestive Medicine, Control and Prevention of Infectious Diseases, Graduate School of Medicine, University of the Ryukyus), Masaki Yamasaki (Department of Anesthesiology and Intensive Care Medicine, Kyoto Prefectural University of Medicine), Masahito Horiguchi (Department of Emergency and Critical Care Medicine, Japanese Red Cross Kyoto Daiichi Hospital), Mitsunobu Nakamura (Japanese Red Cross Maebashi Hospital, Advanced Medical Emergency and Critical Care Center, Intensive Care Unit and Department of Emergency & Critical Care Medicine), Hayato Taniguchi (Advanced Critical Care and Emergency Center, Yokohama City University Medical Center), Takahiro Inagawa (Department of Emergency and Critical Care Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University), Hiroshi Ono (Department of Infectious Diseases, National Hospital Organization Kumamoto Medical Center), Toshihiro Sakurai (Department of Emergency and Critical Care, National Hospital Organization Kumamoto Medical Center), Isao Nagata (Department of Intensive Care Medicine, Yokohama City Minato Red Cross Hospital), Kosuke Yoshida (Department of Emergency & Critical Care Medicine, National Hospital Organization Kyoto Medical Center), Masayoshi Nishijima (Department of Respiratory Medicine, Yodogawa Christian Hospital), Kuraishi Hiroshi (Nagano Red Cross Hospital, Department of Respiratory Medicine), Kengo Hiwatashi (Department of Emergency and Critical Care Medicine, Hitachi General Hospital), Takuya Shiga (Department of Intensive Care, Tohoku University Hospital), Yoshiaki Iwashita (Department of Emergency and Critical Care Medicine, Faculty of Medicine, Shimane University) and Hiroaki Watanabe (Department of Acute Care Surgery, Shimane University Faculty of Medicine) for collecting the data. We also thank to Non-profit Organization Japan ECMO Network ant the Cross ICU Searchable Information System study group for providing the data for this study.

Fig. 1.

Outline of the study. COVID-19, coronavirus disease 2019; ICUs, intensive care units; PICS, post-intensive care syndrome.

Fig. 2.

Intensive care unit (ICU) mobility scale up to 7 days after ICU admission for patients with and without rehabilitation interventions (RIs) by physical therapists within 7 days. The bars show median values, and the error bars show quartile ranges.

Table 1.

Overall information

	Rehabilitation interventions within 7 days of ICU admission (n=81)	No rehabilitation interventions within 7 days of ICU admission (n=178)	p-value
Age (yr)	64.5±12.3	65.7±11.3	0.66
Sex			0.9
Male	65 (80.2)	140 (78.7)
Female	16 (19.8)	38 (21.3)
Body mass index (kg/m²)	25.7±4.6	25.7±4.2	0.98
SOFA score on the day of ventilation start	6.0 (4.0, 8.0)	5.0 (3.0, 7.0)	0.01
Clinical Frailty Scale before hospitalization	2.0 (1.0, 3.0)	2.0 (1.0, 2.0)	0.09
Delirium	19 (23.5)	35 (19.7)	0.6
Duration of delirium within 1 week of ICU admission (day)	0.8±1.7	0.5±1.3	0.31
Duration of invasive mechanical ventilation (day)	15.2±18.0	12.3±10.0	0.19
Length of ICU stay (day)	16.1±16.9	16.0±10.8	0.97
Length of hospital stay (day)	38.3±42.6	30.1±26.0	0.11
Length of hospital stay after ICU discharge (day)	22.2±29.0	14.1±21.1	0.03
Rehabilitation interventions by physical therapists in ICU	81 (100)	58 (32.6)	<0.01
Comorbidity
Hypertension	40 (49.4)	87 (48.9)	>0.99
Diabetes	34 (42.0)	56 (31.5)	0.13
Cardiac disease	12 (14.8)	21 (11.8)	0.64
Chronic kidney disease	2 (2.5)	5 (2.8)	>0.99
Autoimmune diseases	1 (1.2)	7 (3.9)	0.44
Malignant tumors	0 (0)	13 (7.3)	0.03
COPD	7 (8.6)	14 (7.9)	>0.99
Immunodeficiency	0 (0)	8 (4.5)	0.12
Maximum prednisolone dose (mg/day)	40.0 (20.0, 82.5)	44.0 (30.0, 100.0)	0.34

Values are presented as mean±standard deviation for normally distributed continuous variables or median (interquartile range) for non-normally distributed continuous variables. Categorical variables are presented as number (%).

ICU, intensive care unit; SOFA, Sequential Organ Failure Assessment; COPD, chronic obstructive pulmonary disease.

Table 2.

Outcomes one year after ICU admission of patients

	Rehabilitation interventions within 7 days of ICU admission (n=81)	No rehabilitation interventions within 7 days of ICU admission (n=176)	p-value
Barthel Index	100 (100.0, 100.0)	100 (95.0, 100.0)	0.08
Short-Memory Questionnaire	40.0 (34.0, 43.0)	39.0 (36.0, 43.0)	0.96
Hospital Anxiety and Depression Scale	7.0 (2.0, 12.0)	7.0 (3.0, 12.0)	0.82
EuroQol 5 Dimension 5-level	0.87 (0.76, 1.00)	0.85 (0.77, 1.00)	0.87
PICS	42.0 (51.9)	110 (62.5)	0.14
PICS-physical	10.0 (12.3)	44 (25.0)	0.04
PICS-cognitive	38.0 (46.9)	87 (49.4)	0.71
PICS-mental	21.0 (25.9)	49 (27.8)	0.89
Visual analog scale
Physical condition	7.5 (5.5, 8.6)	7.5 (6.2, 8.7)	0.32
Cognitive condition	8.3 (6.7, 9.9)	8.9 (7.4, 9.9)	0.19
Mental condition	8.0 (5.9, 9.2)	8.2 (6.7, 9.3)	0.55
Dyspnea	41 (50.6)	74 (42.0)	0.2
Walking difficulty	20 (24.7)	50 (28.4)	0.66
Weight loss	24 (29.6)	59 (33.5)	0.7
Memory impairment	23 (28.4)	51 (29.0)	>0.99
Execution disability	38 (46.9)	77 (43.8)	0.74
Depression	35 (43.8)	71 (40.3)	0.66
Anxiety	36 (44.4)	94 (53.4)	0.27
Sleeping disorder	36 (44.4)	75 (42.6)	0.83

Values are presented as median (interquartile range) for non-normally distributed continuous variables. Categorical variables are presented as number (%).

ICU, intensive care unit; PICS, post-intensive care syndrome.

Table 3.

Differences in Barthel Index

	Rehabilitation interventions within 7 days of ICU admission	No rehabilitation interventions within 7 days of ICU admission	p-value
Feeding	9.9±0.6	9.8±1.4	0.17
Transfers	14.8±1.0	14.3±2.9	0.04
Grooming	4.9±0.6	4.8±0.9	0.24
Toilet use	9.8±1.1	9.5±2.1	0.19
Bathing	4.6±1.4	4.6±1.4	0.86
Mobility	14.4±2.3	14.2±3.1	0.46
Stairs	9.3±2.3	9.3±2.2	0.91
Dressing	9.7±1.2	9.4±2.2	0.13
Bowels	9.4±1.8	9.2±2.5	0.31
Bladder	9.3±2.1	9.1±2.6	0.44

Values are presented as mean±standard deviation for normally distributed continuous variables.

ICU, intensive care unit.

Table 4.

Univariable logistic regression analyses of PICS and each element in patients

	Physical impairment			Cognitive impairment			Mental impairment			PICS
	OR	95% CI	p-value	OR	95% CI	p-value	OR	95% CI	p-value	OR	95% CI	p-value
Rehabilitation interventions within 7 days of ICU admission	0.429	0.204–0.903	0.03	0.858	0.515–1.481	0.62	0.914	0.504–1.660	0.77	0.646	0.379–1.100	0.11
Mean IMS for 7 days	0.616	0.344–1.101	0.1	1.008	0.628–1.619	0.97	1.083	0.598–1.699	0.98	0.98	0.611–1.573	0.93

PICS, post-intensive care syndrome; OR, odds ratio; CI, confidence interval; ICU, intensive care unit; IMS, ICU Mobility Scale.

Table 5.

Multivariable logistic regression analyses of PICS and each element in patients

	Physical impairment			Cognitive impairment			Mental impairment			PICS
	OR	95% CI	p-value	OR	95% CI	p-value	OR	95% CI	p-value	OR	95% CI	p-value
Rehabilitation interventions within 7 days of ICU admission	0.294	0.123–0.706	0.006	0.809	0.454–1.441	0.47	0.731	0.380–1.404	0.34	0.542	0.301–0.979	0.04
Mean IMS for 7 days	0.691	0.337–1.419	0.31	1.166	0.593–1.738	0.96	1.155	0.633–2.168	0.64	1.156	0.672–1.990	0.52

Adjusted by age, BMI, CSF, SOFA, delirium, duration of ventilation, presence, or absence of ECMO, continuous muscle relaxant administration, maximum daily steroid dose, prone position, and IMS.

PICS, post-intensive care syndrome; OR, odds ratio; CI, confidence interval; ICU, intensive care unit; IMS, ICU Mobility Scale; BMI, body mass index; CFS, Clinical Frailty Scale; SOFA, Sequential Organ Failure Assessment; ECMO, extracorporeal membrane oxygenation.

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