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

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Ann Rehabil Med. 2025;49(1):49-59

Publication date (electronic) : 2025 February 28

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

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, PhD^,5

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 2024 July 8; Revised 2024 November 22; Accepted 2025 January 7.

Abstract

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

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.

Fig. 1.

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

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).

Table 1.

Overall information

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.

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 2.

Outcomes one year after ICU admission of patients

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.

Table 3.

Differences in Barthel Index

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.

Table 4.

Univariable logistic regression analyses of PICS and each element in patients

Table 5.

Multivariable logistic regression analyses of PICS and each element in patients

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.

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