Long-Term Decreased Exercise Capacity of COVID-19 Patients Who Received Mechanical Ventilation in Japan

A Case Series

Abstract

The long-term exercise capacity of coronavirus disease 2019 patients with acute respiratory distress syndrome is not clear. The 6-min walking distance of four patients with coronavirus disease 2019–associated acute respiratory distress syndrome was followed for 6 mos after admission to the hospital. These four patients were admitted to the intensive care unit of our hospital and received mechanical ventilation. Rehabilitation therapy (positioning, postural drainage, and passive range-of-motion exercises) was started after intensive care unit admission. Mobilization therapy, including muscle power training, sitting on the edge of the bed, and endurance training, was performed after the end of sedation. The Medical Research Council sum scores and Barthel Indexes for the patients improved after intensive care unit discharge and completely recovered 6 mos after admission to the hospital. However, the 6-min walking distance of the four patients remained shorter than those of healthy persons of the same age at 6 mos after admission to the hospital. Furthermore, the minimum Spo₂ during the 6-min walking test remained less than 96%. It is possible that patients who receive mechanical ventilation due to coronavirus disease 2019–associated acute respiratory distress syndrome have decreased long-term exercise capacity, despite muscle power and activities of daily living recovering completely.

The effect of rehabilitation therapy in a severe novel coronavirus disease 2019 (COVID-19) patient receiving mechanical ventilation was recently reported.¹ The patient had muscle weakness in his limbs (Medical Research Council [MRC] sum score of 50 points) and decreased activity of daily living (ADL, Barthel Index of 15 points) after receiving mechanical ventilation for 19 days. Mobilization therapy was started immediately after sedation, and the MRC sum score and Barthel Index improved. However, the 6-min walking distance (6MWD) remained short (509 m) until 1 mo after discharge.

Most severe COVID-19 cases that require mechanical ventilation in the intensive care unit (ICU) are accompanied by acute respiratory distress syndrome (ARDS).² Pfoh et al.³ reported that 86% of ARDS survivors experienced long-term physical decline after hospital discharge. In a meta-analysis, Parry et al.⁴ reported that ICU survivors with ARDS had lower 6MWD after hospital discharge than survivors without ARDS. Li et al.⁵ also reported that patients who received mechanical ventilation due to ARDS caused by severe acute respiratory syndrome had decreased 6MWD at 12 mos after illness onset.

However, there is still no clarity on the long-term exercise capacity of patients who receive mechanical ventilation due to COVID-19–associated ARDS. This case series reports the 6MWD of four patients who received mechanical ventilation due to COVID-19–associated ARDS. The patients were followed up for 6 mos after admission to our hospital.

CASE DESCRIPTIONS

From February to October 2020, 21 patients admitted to the Yokohama City University Hospital with a diagnosis of COVID-19 were provided rehabilitation therapy and received mechanical ventilation. Of the 21 patients, 12 were discharged, 5 were transferred to another hospital, and 4 died. We followed up the discharged patients, and the four cases presented in this report are from the discharged patients who had been followed up for 6 mos until October 2020.

The patients received medical treatment based on World Health Organization recommendations for supportive care, including oxygen therapy, fluid management, and antibiotics for secondary bacterial infections.⁶ Therefore, there were no severe medical complications.

We collected patient characteristic data, including demographics, ventilator days, length of ICU stay, and length of hospital stay, using patient charts and an electronic database. Physical functions including MRC sum score, handgrip, gait speed, 6MWD, and the Barthel Index were measured at ICU discharge, hospital discharge, approximately 1 mo after admission, and 6 mos after admission repeatedly by a physical therapist.

The patients’ demographic characteristics are shown in Table 1.

TABLE 1 - Clinical characteristics and physical function assessments of the COVID-19 patients

		Case 1	Case 2	Case 3	Case 4
Age, yr		65	67	61	30
Sex		Male	Male	Male	Male
Height, cm		174	178	168	169
Body weight, kg		84.4	79.9	79.2	71.2
Body mass index, kg/m2		27.9	25.2	28.1	24.9
Race		Asian	Asian	Asian	Asian
Ethnicity		Japanese	Japanese	Japanese	Japanese
Home/social support		Yes	Yes	Yes	Yes
Socioeconomic status		Work with income	Work with income	Work with income	Work with income
Ventilator days, d		19	13	15	16
Length of ICU stay, d		21	16	17	20
Length of hospital stay, d		31	34	34	29
MRC sum score, point	ICU discharge	50	50	56	53
	Hospital discharge	53	59	58	57
	1 mo	60	60	58	60
	6 mos	60	60	60	60
Grip right/left, kg	ICU discharge	NC	16.3/22.9	NC	NC
	Hospital discharge	28.1/25.2	12.9/26.9	NC	NC
	1 mo	34.9/30.4	9.8/23.2	28.1/24.6	22.5/21/2
	6 mos	42.0/40.5	33.2/30.1	30.9/31/7	29.4/24.1
Gait speed, m/sec	ICU discharge	NC	0.53	0.91	0.49
	Hospital discharge	1.3	0.88	0.95	0.83
	1 mo	1.5	1.29	1.26	1.50
	6 mos	1.4	1.56	2.77	2.97
6MWD, m	ICU discharge	NC	NC	NC	NC
	Hospital discharge	360	570	NC	NC
	1 mo	509	543	448	462
	6 mos	567	564	537	501
Baseline Spo 2/minimum Spo 2 during 6MWT, %	ICU discharge	NC	NC	NC	NC
	Hospital discharge	98/93	98/93	NC	NC
	1 mo	98/95	97/93	96/92	99/95
	6 mos	98/95	98/96	96/94	98/95
Barthel Index, point	ICU discharge	15	15	30	55
	Hospital discharge	90	100	95	95
	1 mo	100	100	100	100
	6 mos	100	100	100	100

The MRC sum is scored from 0 to 60. Scores of less than 48 are considered to indicate ICU-acquired weakness.

Average grip value in the Japanese male patients (30–34 yrs), 47.14 ± 7.25 kg; (60–64 yrs), 43.16 ± 6.00 kg; and (65–69 yrs), 39.68 ± 6.04 kg.

Average gait speed in the Japanese male patients (30–39 yrs), 2.0 m/sec, and (60–69 yrs), 1.92 m/sec.

Average 6MWD value in the Japanese elderly male patients (65–69 yrs), 626.36 ± 87.68 m.

The Barthel Index is scored from 0 to 100. Scores of less than 20 indicate total dependency and scores of greater than 70 indicate independence.

1 mo, approximately 1 mo after admission to hospital; 6 mos, approximately 6 mos after admission to hospital; NC, not completed.

The four patients provided written consent for the publication of this case report. This study conforms to all case reports guidelines and reports the required information accordingly (see Supplemental Checklist, Supplemental Digital Content 1, https://links.lww.com/PHM/B312).

Intervention

The following rehabilitation protocol was followed for all cases. Rehabilitation therapy was started with pulmonary physical therapy (positioning and postural drainage) and passive range-of-motion exercises. This was advanced to active range-of-motion exercises, muscle power training, sitting on the edge of the bed, standing, stepping, gait exercises, and endurance training (cycle ergometer exercise) until hospital discharge. The rehabilitation therapy was provided in one session for 40 mins/d by a physical therapist from ICU admission to hospital discharge. The criteria for starting mobilization (sitting) were maintenance of the fraction of inspiratory oxygen at 60% or less, positive expiratory end pressure of 10 cmH₂O or less, maintenance of oxygen saturation (Spo₂) during posture change at 90%, and a Richmond agitation sedation score of −1 to 0. No cases experienced major complications during rehabilitation therapy. After hospital discharge, we advised patients to engage in home exercises, such as walking, lower limb muscle strength training using a closed kinetic chain, upper limb strength training using the Thera-Band (Hygenic, Akron, OH), and balance training. Moreover, after hospital discharge, we checked that all patients continued home exercises up until 6 mos after admission to the hospital.

Case 1

The patient was a 65-yr-old man with a history of hypertension. Eight days after the patient developed a fever of 38°C, his respiratory condition worsened. Therefore, he was admitted to the ICU of our hospital, where mechanical ventilation was started. Axial computed tomography (CT) showed bilateral ground-glass opacities (GGOs) in his peripheral regions (Fig. 1). Coronavirus disease 2019 was diagnosed by polymerase chain reaction 6 days after admission to our hospital. Rehabilitation therapy was started 6 days after ICU admission. Mechanical ventilation was needed for 19 days, and mobilization was started 14 days after starting mechanical ventilation. The lengths of the ICU and hospital stays were 21 and 31 days, respectively. Physical function improved from ICU discharge to hospital discharge (Table 1). However, the 6MWD (360 m) remained short and minimum percutaneous Spo₂ during the 6-min walking test (6MWT) was low (93%; the normal ranges of Spo₂ are more than 95%, and healthy persons do not exhibit a significant decrease in Spo₂ during the 6MWT⁷) at hospital discharge (31 days after admission to hospital; Table 1). At 212 days after admission to the hospital, his 6MWD and minimum Spo₂ during the 6MWT increased to 567 m and 95%, respectively. However, these variables remained lower than those of healthy persons of the same age. Therefore, the patient was discharged without achieving his previous level of activity. The GGOs in the peripheral regions of his axial CT images were improved but were not completely cleared until 177 days after admission to the hospital (Fig. 1).

FIGURE 1: Chest CT images taken on the day of admission to our hospital (A), hospital discharge (B), approximately 1 mo after hospital admission (C), and approximately 6 mos after hospital admission (D).

Case 2

The patient was a 67-yr-old man with no medical history. Nine days after the patient developed a fever of 38°C, his respiratory condition worsened. Therefore, he was admitted to the ICU of our hospital. On the next day, mechanical ventilation was started, and COVID-19 was diagnosed by polymerase chain reaction. Axial CT images showed bilateral GGOs in his peripheral regions (Fig. 1). Rehabilitation therapy was started 2 days after ICU admission. Mechanical ventilation was needed for 13 days, and mobilization was started 8 days after starting mechanical ventilation. The lengths of the ICU and hospital stays were 16 and 34 days, respectively. Physical function improved from ICU discharge to after hospital discharge (Table 1). However, the 6MWD (543 m) remained short and the Spo₂ during the 6MWT low (93%) at hospital discharge (49 days after admission to hospital; Table 1). At 235 days after admission to the hospital, his 6MWD and minimum Spo₂ during the 6MWT increased to 564 m and 96%, respectively. However, these variables remained lower than those of healthy persons of the same age. Therefore, the patient was discharged without achieving his previous level of activity. The GGOs in the peripheral regions of the axial CT image at ICU discharge improved but were not completely cleared until 179 days after admission to the hospital (Fig. 1).

Case 3

The patient was a 61-yr-old man with a history of hypertension, type 2 diabetes mellitus, and bullous pemphigoid. Seven days after the patient developed a fever of 37°C, his respiratory condition worsened. Therefore, he was admitted to the ICU of our hospital, where mechanical ventilation was started. Axial CT images showed bilateral GGOs in his peripheral regions (Fig. 1). Coronavirus disease 2019 was diagnosed by polymerase chain reaction on the day of admission to our hospital. Rehabilitation therapy was started 2 days after ICU admission. Mechanical ventilation was needed for 15 days, and mobilization was started 9 days after starting mechanical ventilation. The lengths of the ICU and hospital stays were 17 and 34 days, respectively. Physical function improved from ICU discharge to hospital discharge (Table 1). However, the 6MWD (448 m) remained short and the Spo₂ during 6MWT low (92%) 48 days after admission to the hospital (Table 1). At 171 days after admission to the hospital, his 6MWD and minimum Spo₂ during the 6MWT increased to 537 m and 94%, respectively. However, these variables remained lower than those of healthy persons of the same age. Therefore, the patient was discharged without achieving his previous level of activity. The GGOs in the peripheral regions of the axial CT image at ICU discharge improved but were not completely cleared until 171 days after admission to the hospital (Fig. 1).

Case 4

The patient was a 30-yr-old man with no medical history. Fifteen days after the onset of cold symptoms, his respiratory condition worsened. Therefore, he was admitted to the ICU of our hospital, and mechanical ventilation was started the next day. Axial CT showed bilateral GGOs in his peripheral regions (Fig. 1). He was diagnosed with COVID-19 by polymerase chain reaction a day before admission to our hospital. Rehabilitation therapy was started 3 days after ICU admission. Mechanical ventilation was needed for 16 days, and mobilization was started 10 days after starting mechanical ventilation. The lengths of the ICU and hospital stays were 20 and 29 days, respectively. Physical function improved from ICU discharge to hospital discharge (Table 1). However, 6MWD (426 m) remained short and Spo₂ during the 6MWT low (95%) at 44 days after admission to the hospital (Table 1). At 167 days after admission to the hospital, his 6MWD increased to 501 m but remained shorter than that of healthy people of the same age. Furthermore, the minimum Spo₂ during the 6MWT remained at 95%. Therefore, the patient was discharged without achieving his previous level of activity. The GGOs in the peripheral regions of his axial CT image at ICU admission were improved, but the GGOs remained until 44 days after admission to the hospital. In this case, the GGOs were almost cleared until 167 days after admission to the hospital (Fig. 1).

DISCUSSION

In this case series, the 6MWDs of all four patients were shorter than those of healthy individuals of the same age until 6 mos after admission to the hospital. Furthermore, the minimum Spo₂ during the 6MWT was less than 96%. On the other hand, the MRC sum score and Barthel Index of the four patients had completely recovered at 6 mos after admission to the hospital. Based on these cases, we intimate that patients who receive mechanical ventilation due to COVID-19–associated ARDS have decreased long-term exercise capacity, although muscle power and ADL are completely recovered. We consider a need for long-term (over 6 mos after onset) follow-up and continuation of cardiopulmonary exercise after hospital discharge for severe COVID-19 patients with ARDS.

Postintensive care patients who experience long-term bed rest due to mechanical ventilation are at a high risk of developing postintensive care syndrome, including ICU-acquired weakness, and are prone to decreased physical function.⁸ These postintensive patients need acute phase mobilization to improve their physical function.⁹ All our patients also had muscle weakness in their limbs (decreased MRC sum scores) and low levels of ADL (low Barthel Index score) on the day of ICU discharge. The acute phase mobilization was performed, and muscle weakness and ADL significantly improved by the day of hospital discharge. Moreover, 1 mo after discharge, daily activities had returned to normal (100 points on the Barthel Index). Therefore, rehabilitation therapy starting from the acute phase is necessary to improve the muscle power and ADL of severe COVID-19 patients with ARDS who require intensive care. Alternatively, at 6 mos after admission to the hospital, the patients’ 6MWDs were low compared with healthy people of the same age and the decrease in Spo₂ during 6MWT persisted for all of our patients. The desaturations with exercise of chronic lung disease patients were defined as a drop of greater than 4% in Spo₂ to less than 90% by an official systematic review of the European Respiratory Society/American Thoracic Society,¹⁰ and it has been reported that chronic obstructive pulmonary disease patients without resting hypoxia experience exercise-induced hypoxia due to low pulmonary functions.¹¹ In addition, healthy persons do not exhibit a significant decrease in Spo₂ during the 6MWT.⁷ Some studies indicate that although 6MWD was lower for patients with severe acute respiratory syndrome than for healthy persons, Spo₂ during 6MWT at 3 and 6 mos was not decreased.^12,13 We considered that the decrease in Spo₂ during 6MWT of all our patients indicates abnormal response and low exercise capacity. Therefore, the four patients continued to display low exercise capacities (low 6MWD and decreased Spo₂ during 6MWT) at 6 mos after admission to the hospital, despite the complete muscle power and ADL recovery, and that all patients continued home exercises after hospital discharge. This suggests that the cause of decreased long-term exercise capacity may be both the effect of the intensive care and bed rest and the specific pathology of severe COVID-19 with ARDS. However, because we did not collect objective data for adherence to home exercise after hospital discharge, low activity after hospital discharge could be the cause of low exercise capacity.

The main cause of decreased long-term exercise capacity in severe COVID-19 patients was assumed to be impaired respiratory function due to ARDS. In China, COVID-19 patients with severe pneumonia were reported to have a low diffusing capacity of the lungs for carbon monoxide, total lung capacity, and residual volume at hospital discharge.¹⁴ In three of our cases, the GGOs remained on the axial CT images until 6 mos after hospital admission. The minimum Spo₂ during 6MWT remained less than 96% in all our patients. This suggests that lung injury persists in patients who receive mechanical ventilation due to COVID-19–associated ARDS.

High inflammation caused by COVID-19 has been reported to affect cardiac function. In addition, the same report also suggested that severe acute respiratory syndrome coronavirus 2 directly damaged cardiac muscle and caused hypoxia due to respiratory failure–effected cardiac dysfunction.¹⁵ Although we did not evaluate cardiac function in our cases, it is possible that long-term decreased exercise capacity after severe COVID-19 was caused not only by lung injury but also by cardiac dysfunction.

After recovering from COVID-19, some patients exhibit long-term effects, such as dyspnea, fatigue, loss of smell, and considerable depression.¹⁶ It is possible that the long-term decreased exercise capacity of the four patients in our study was not only a characteristic of postintensive care syndrome but also one of the long-term effects of COVID-19. In addition, we believed that the muscle weakness of all our COVID-19 patients with ARDS on the day of ICU discharge was smaller than that in patients with other ARDS-causing etiologies, despite experiencing the same long-term bed rest and sedation. Therefore, the etiology of physical dysfunction of severe COVID-19 patients with ARDS might be different from other etiologies causing ARDS. We will continue to evaluate more COVID-19 patients with ARDS for long periods to clarify the pathology of long-term decreased exercise capacity.

CONCLUSIONS

We evaluated the physical functions of four patients who received mechanical ventilation due to COVID-19–associated ARDS. They were followed up for 6 mos after admission to the hospital. All four patients had short 6MWD and a decreased Spo₂ during 6MWT until 6 mos after admission to the hospital. However, muscle power and ADL were completely recovered. Patients who receive mechanical ventilation due to COVID-19–associated ARDS may have decreased long-term exercise capacity.