Implementation of Early Rehabilitation in Severe COVID-19 Respiratory Failure

A Scoping Review

Abstract

Purpose: 

The purpose of this scoping review is to describe current clinical practice guidelines (CPGs) for early rehabilitation for individuals hospitalized in an intensive care unit with COVID-19 and examine practice patterns for implementation of mobility-related interventions.

Methods: 

PubMed, EMBASE, and CINAHL databases were searched from January 1, 2020, through April 1, 2022. Selected studies included individuals hospitalized with severe COVID-19 and provided objective criteria for clinical decision making for mobility interventions. A total of 1464 publications were assessed for eligibility and data extraction. The PRISMA-ScR Checklist and established guidelines for reporting for scoping reviews were followed.

Results: 

Twelve articles met inclusion criteria: 5 CPGs and 7 implementation articles. Objective clinical criteria and guidelines for implementation of early rehabilitation demonstrated variable agreement across systems. No significant adverse events were reported.

Conclusions: 

Sixty percent (3/5) of CPGs restrict mobility for individuals requiring ventilatory support of more than 60% Fio₂ (fraction of inspired oxygen) and/or positive end-expiratory pressure (PEEP) greater than 10-cm H₂O (positive end-expiratory pressure). Preliminary evidence from implementation studies may suggest that some individuals with COVID-19 requiring enhanced ventilatory support outside of established parameters may be able to safely participate in mobility-related interventions, though further research is needed to determine safety and feasibility to guide clinical decision making.

SARS-CoV-2, the virus responsible for the syndrome COVID-19, has caused many paradigm shifts in health care and rehabilitation.^1–3 The strains on the health care system during a pandemic characterized by an increased incidence of severe respiratory failure have meant that paradigm shifts are especially profound in the intensive care unit (ICU).^4,5 Patients with COVID-19 often experience respiratory failure but may have additional symptoms including anorexia, nausea and diarrhea, myocarditis, skeletal muscle myopathy, and generalized debility.^6–14 These patients are at risk of substantial deconditioning as they are confined to bed from systemic symptoms as well as profound hypoxemia. Early rehabilitation and mobility-related interventions for critically ill patients are a necessary paradigm shift to improve patient outcomes and reduce the duration of hospitalization.^15,16

Patients admitted to an ICU with COVID-19 are at high risk of developing intensive care unit acquired weakness (ICUAW).¹⁰ The exact incidence of ICUAW in individuals with COVID-19 requiring ICU-level of care is unknown; however, recent studies suggest that it may range between 27% and 72%.^10,17 Intensive care unit acquired weakness has been correlated with increased length of ICU stay, difficulty weaning from mechanical ventilation, impaired mobility performance, diminished exercise tolerance, decreased independence with activities of daily living at discharge, and lower quality of life.^8,17 A recent prospective observational study of 75 patients with COVID-19 admitted to the ICU for more than 72 hours found that bed rest time was independently associated with the development of ICUAW.¹¹

The physiologic processes underlying the pathogenesis of ICUAW are not fully understood. The etiology is likely multifactorial and may be attributable to myogenic processes resulting in critical illness myopathy, neurogenic processes resulting in critical illness polyneuropathy, or a combination resulting in mixed critical illness neuromyopathy.^18,19 The clinical picture is further complicated by systemic inflammation, as well as the effects of glucocorticoids and hyperglycemia, neuromuscular blocking agents, superinfections and sepsis, and catabolism of skeletal muscle from immobility and bed rest.¹⁸

Critical illness is associated with significant loss of muscle mass, which begins as early as the first week following admission to the ICU.¹⁹ A recent study of 32 patients with critical illness due to COVID-19 assessed muscle integrity via ultrasonography and grip strength dynamometry and found that by ICU day 10, the cross-sectional area of the rectus femoris decreased by 30.1% and grip strength decreased by 22.3%.⁸

Identifying and addressing modifiable risk factors is essential to decrease the effects of ICUAW. Aggressive symptom management, adequate nutrition (including early artificial enteric nutrition if needed),¹⁹ maintenance of euglycemia,^17,19 and minimizing deep sedation^18,20 and paralysis²¹ are all beneficial in decreasing ICUAW. Early rehabilitation programs to address impairments and promote mobility and strength are intuitively beneficial, but current evidence is limited to small studies of variable quality.^19,22–24 The evidence that exists suggests that in the acute phase of critical illness, early rehabilitation is safe and may improve strength and mobility-related outcomes in individuals with ICUAW.^19,25–28

The purpose of this scoping review is to describe current clinical practice guidelines (CPGs) and examine practice patterns for implementation of early rehabilitation programs and mobility-related interventions for individuals hospitalized in an ICU with COVID-19.

METHODS

Data Sources and Searches

The methodology for scoping reviews described by Arksey and O΄Malley²⁹ and Levac and colleagues³⁰ was used to provide an analysis of current literature with regard to early rehabilitation in individuals with severe illness due to COVID-19. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) Checklist was completed and the established guidelines for reporting were followed to promote transparency of the methodological rigor used for the development of this review.

Literature searches were performed using PubMed, EMBASE, and CINAHL databases to identify English language publications with full text availability published between January 1, 2020, and April 1, 2022, which was the date of the last search. All study designs were included in the database searches. In the 3 databases identified, we used multiple combinations of the following terms: “COVID-19,” “SARS-CoV-2,” “coronavirus,” “critical illness,” “intensive care unit,” “early mobility,” “rehabilitation,” “physiotherapy,” “physical therapy,” “mobilization,” “mobility,” “progressive mobility,” and “exercise” combined with the Booleans “OR” and “AND.” The final search strategies are described in Appendix A. In addition to these search strategies, the references cited in selected articles were also reviewed.

Study Selection

The titles and abstracts of all articles were screened to identify and remove duplicates and screen for eligibility based on inclusion and exclusion criteria. Inclusion criteria: Selected studies included patients hospitalized with respiratory failure and severe or critical illness due to COVID-19 and provided objective, measurable, system-based criteria for clinical decision making for mobility-related interventions and early rehabilitation. As described in the Figure, articles were excluded if they were not focused on ICU management of individuals with COVID-19 or failed to provide objective criteria for clinical decision making related to mobility.

FIGURE.: Flow Diagram of Studies in the Selection Process. ICU indicates intensive care unit.

Data Extraction and Quality Assessment

A data extraction form was developed by the authors to identify important data points to extract from implementation papers and CPGs. Authors extracted data independently for all full text articles included in this review. For the mobility intervention implementation papers, data were collected regarding study design, country of origin, patient demographics, levels of oxygen support during rehabilitation interventions, levels of mobility achieved on the highest levels of ventilatory support, adverse events, and primary findings. For the CPGs included, data were collected regarding objective clinical criteria for clinical decision making for implementation of mobility-related interventions for each of the major systems: respiratory, circulatory/cardiovascular, neurological, and other.

RESULTS

Study Selection

As shown in the flow diagram in the Figure, the initial literature search yielded 1440 publications. An additional 24 publications were obtained from the references and citations of selected articles. A total of 1464 records were screened for inclusion.

Two reviewers (D.M. and K.S.) reviewed and screened the titles, abstracts, and texts to identify articles specific to hospital management of individuals with COVID-19, which provided objective clinical criteria for decision making related to implementation of early rehabilitation or mobility-related interventions for individuals with severe respiratory failure. In cases of disagreement, consensus was reached through discussion and consultation with a third reviewer (J.P.). A total of 187 duplicate records were excluded. Of the 59 articles initially meeting inclusion criteria, 13 were excluded because of insufficient focus on hospital management of individuals with COVID-19, 32 were excluded because of insufficient or lack of objective clinical criteria for clinical decision making with regard to mobility-related interventions with this population, and 2 were excluded because of not being focused on ICU/critical care.

Characteristics of Included Studies

Clinical Practice Guidelines

Table 1 provides a summary of the objective clinical criteria for implementation of early rehabilitation and mobility-related interventions recommended by the 5 CPGs included in this review. Three of the 5 CPGs included in this review restrict mobility for individuals requiring more than 60% Fio₂ and/or positive end-expiratory pressure (PEEP) more than 10 cm H₂O,^31–33 1 article allows mobility for individuals requiring Fio₂ support up to 85% and PEEP up to 15 cm H₂O,³⁴ and one of the guidelines does not provide guidance regarding level of ventilatory support but advocates maintaining oxygen saturation (Spo₂) within a target range during mobility interventions.³⁵ There is significant variability in the termination criteria for mobility interventions with regard to Spo₂ values one guideline suggesting termination with Spo₂ less than 85%,³¹ another suggesting Spo₂ less than 90%,³² and a third indicating that mobility should be terminated with Spo₂ less than 93%.³³ Two of the 5 guidelines recommend that mobility interventions be terminated with a decrease in Spo₂ more than 4% from baseline.^32,33 Two of the 5 CPGs advocate that mobility interventions be terminated if an individual΄s respiratory rate exceeds 40 breaths/min^31,32; however, 1 CPG recommends a cutoff of 30 breaths/min.³³

TABLE 1. - Summary of System-Based Clinical Criteria for Clinical Practice Guidelines for Mobility in Severe or Critical COVID-19 Disease

	Respiratory	Circulatory	Neurologic	Other
Felten-Barentsz et al31 (2020)	Red flags: Oxygen desaturation (Spo 2 <90%) Fio 2 ≥ 0.6 PEEP ≥ 10 cm H2O RR >40 breaths/min Termination criteria: RR >40 breaths/min Spo 2 <85% Physical therapy is not indicated for individuals with deep sedation (RASS <−4) or on neuromuscular blocking agents When sedation is reduced (RASS ≥−2) during weaning from mechanical ventilation, detaching the ventilation system for respiratory muscle training or breathing exercises is not recommended because of risk for virus transmission Multidisciplinary team should discuss risk/benefit of respiratory muscle training for patients who fail >3 weaning attempts or require >7 d of weaning after first spontaneous breathing trial	Red flags: Recent myocardial ischemia HR <40 and >130 bpm MAP <60 mm Hg and >110 mm Hg High inotrope doses (eg, dopamine ≥ 10 μg/kg/min, noradrenaline/adrenaline ≥ 0.1 μg/kg/min) Termination criteria: HR <40 and >130 bpm MAP <65 and >110 mm Hg new cardiac arrhythmia	Red flags: RASS=−5, −4, 3, or 4 Decreased level of awareness/consciousness Neurologic instability (eg, ICP ≥ 20 cm H2O) Termination criteria: Decreased level of awareness/consciousness No therapeutic goals if the patient is unconscious, RASS <−4, or patient is mechanically ventilated in prone position with neuromuscular blockade	Red flags: Temperature ≥ 38.5°C or ≤36°C Sweating at rest Abnormal face color Pain Fatigue Unstable fractures Presence of lines that make mobilization unsafe Termination criteria: New clinical symptoms (eg, decreased level of awareness/consciousness, sweating, abnormal face color, pain, fatigue, discomfort)
Kurtais Aytur et al32 (2020)	Initiation criteria: Fio 2 ≤ 0.6 Spo 2 ≥ 90% on oxygen therapy Respiratory rate ≤ 40 breaths/min PEEP ≤ 10 cm H2O Absence of ventilator resistance Termination criteria: Progression in chest imaging >50% within 24-48 h Spo 2<90% or decrease by 4% from baseline Respiratory rate >40 breaths/min Ventilator resistance Artificial airway dislodgement or migration Pulmonary rehabilitation is not appropriate or safe for ARDS patients in respiratory distress who meet any of the following criteria: Pao 2/Fio 2<300 mm Hg on ventilator or CPAP settings >5 cm H2O Temperature >38°C RR >40 breaths/min Spo 2<90% despite oxygen support Prone positioning to improve oxygenation	Initiation criteria: BP ≥ 90/60 or ≤180/90 mm Hg HR ≥ 40 and ≤ 120 bpm Absence of new arrhythmia or myocardial ischemia Absence of shock with lactic acid level ≥4 mmol/L Absence of new unstable DVT or PE Termination criteria: BP < 90/60 (MAP = 70) or >180/90 (MAP = 120) mm Hg, or >20% change compared with baseline HR <40 or >120 bpm New arrhythmia and myocardial ischemia Pulmonary rehabilitation is not appropriate or safe for ARDS patients in respiratory distress who meet any of the following criteria: HR <40 or >120 bpm Variable arrhythmia on EKG BP <90/60 or >180/90	Initiation criteria: Able to cope with the rehabilitation program regarding consciousness and cognitive status Termination criteria: Loss of consciousness Irritability Unable to cope with the program or follow instructions Pulmonary rehabilitation is not appropriate or safe for ARDS patients in respiratory distress who meet the following criterion: Deep sedation	Initiation criteria: Absence of new progressively worsening hepatic/renal impairment Temperature ≤38°C Termination criteria: Body temperature >38°C Indication of clinical worsening and general contraindication for exercise Discontinuation of any treatment or removal of monitoring tube connected to the patient Patient-perceived heart palpitations Exacerbation of dyspnea or shortness of breath Intolerable fatigue
Schallom et al34 (2020)	Oxygen stability Fio 2 <0.85 on mechanical ventilation PEEP < 15 cm H2O No unsecured airway (no unstable or difficult airway)	Myocardial stability No active cardiac ischemia within past 12-24 h No dysrhythmia requiring new antidysrhythmic agent or electrical therapy within past 12-24 h Vasopressor use/vascular access No new or increase of any vasopressor × 2 h No femoral sheath/introducer	Neurological stability ICP <15 No acute or uncontrolled intracranial event No spine instability No unclamped lumbar drain Engages to voice Responds to verbal stimulation RASS <+3	No pelvic/lower extremity fractures that are non–weight-bearing No unstable surgical incision
Thomas et al35 (2020)	Therapy not indicated for airway clearance for individuals who meet the following criteria: mild symptoms without significant respiratory compromise; pneumonia with low-level oxygen (≤5 L/min for Spo 2≥ 90%), nonproductive cough, or patient able to clear secretions independently Therapy may be indicated for airway clearance in individuals with mild symptoms and/or pneumonia with coexisting respiratory or neuromuscular comorbidity and current/anticipated difficulty with secretion clearance, or evidence of exudative consolidation and difficulty/inability to clear secretions independently For patients presenting with severe respiratory distress, hypoxemia or shock, Spo 2>94% is targeted. Once a patient is stable, the Spo 2 target is >90% in nonpregnant adults and 92%-95% in pregnant patients. In adults with COVID-19 and acute hypoxemic respiratory failure, the Spo2 target should not be maintained >96%. Therapy may be indicated for airway clearance in individuals with severe symptoms of pneumonia or lower respiratory tract infection with increasing oxygen requirements, dyspnea, productive cough, with chest imaging consistent with consolidation	Any patient at significant risk of developing or with evidence of significant functional limitations (eg, frail, multiple comorbidities, ICU patient with functional decline and/or at risk or ICU-acquired weakness should be referred to physical therapy	Any patient at significant risk of developing or with evidence of significant functional limitations (eg, frail, multiple comorbidities, ICU patient with functional decline, and/or at risk or ICU-acquired weakness should be referred to physical therapy	Any patient at significant risk of developing or with evidence of significant functional limitations (eg, frail, multiple comorbidities, ICU patient with functional decline and/or at risk, or ICU-acquired weakness should be referred to physical therapy
Zhu et al33 (2020)	Fio 2 ≤ 60% Spo 2 ≥ 93% at rest, Spo 2 target is 95%-100%, but in patients at risk of hypercapnia, Spo 2 target of 88%-89% is acceptable; terminate therapy with Spo 2<93% or with >4% decrease from baseline Respiratory rate ≤30 breaths/min; terminate therapy if RR >30 breaths/min PEEP ≤10 cm H2O Therapy contraindicated with severe dyspnea Terminate therapy with severe sudden dyspnea	Systolic BP ≥ 90 mm Hg and <180 mm Hg; terminate therapy if SBP <90 mm Hg or >180 mm Hg; therapy contraindicated for SBP <90/60 mm Hg or >140/90 mm Hg MAP ≥ 65 mm Hg and ≤110 mm Hg; terminate therapy if MAP <65 mm Hg or >110 mm Hg or more than 20% change from baseline HR ≥ 40 bpm and ≤120 bpm; therapy contraindicated for resting HR > 120 bpm No new arrhythmia or signs of myocardial ischemia No new unstable DVT or PE No aortic stenosis	Terminate therapy with increased anxiety or fatigue	Temperature <38.5°C No severe hepatorenal disease or new/progressive impairment of liver and kidney function

Abbreviations: ARDS, acute respiratory distress syndrome; BMAT, Bedside Mobility Assessment Tool; BP, blood pressure; CPAP, continuous positive airway pressure; DVT, deep vein thrombosis; EKG, electrocardiogram; Fio₂, fraction of inspired oxygen; H₂O, water, l/min = liters per minute; HR, heart rate; ICP, intracranial pressure; ICU, intensive care unit; MAP, mean arterial pressure; PE, pulmonary embolism; PEEP, positive end-expiratory pressure; RASS, Richmond Agitation Sedation Scale; RR, respiratory rate; SBP, systolic blood pressure; Spo₂, oxygen saturation.

There is limited agreement with regard to cardiovascular/circulatory criteria for clinical decision making for initiation of mobility interventions. Regarding blood pressure values, 2 guidelines advocate terminating mobility interventions for a mean arterial pressure of less than 65 or greater than 110 mm Hg^31,33; 1 guideline recommends termination of mobility for mean arterial pressure of less than 70 or greater than 120 mm Hg.³² Two of the 5 CPGs recommend termination of mobility interventions with more than 20% change from baseline blood pressure.^32,33 Three of the 5 CPGs agree that mobility interventions are not indicated for individuals with bradycardia with a heart rate less than 40 beats per minute.^31–33 Two guidelines agree that mobility interventions should be terminated for heart rates that exceed 120 beats per minute^32,33; however, 1 guideline recommends 130 beats per minute as the upper limit.³¹

There is limited agreement with regard to neurologic criteria for safe initiation of mobility. However, 2 of the 5 guidelines advocate the use of the Richmond Agitation Sedations Scale (RASS) as an objective measure to identify those who may be appropriate for early mobility.^31,34 In addition, 2 of the 5 guidelines also suggest that any new or worsening hepatic or renal function may be an important indicator that an individual may not be appropriate for mobility-related interventions.^32,33

Early Rehabilitation Implementation Studies

Table 2 provides a description of the characteristics of the 7 articles selected for inclusion in this scoping review, which describe practice patterns for the implementation of early rehabilitation and mobility-related interventions in individuals with severe COVID-19. The 7 mobility intervention implementation articles reviewed include 3 case reports,^36–38 1 case series report,³⁹ 1 retrospective chart review,¹⁶ and 2 observational cohort studies.^40,41 The comprehensive search did not identify any randomized clinical trials in this patient population.

TABLE 2. - Implementation of Mobility Interventions in Severe COVID-19

Study and Country of Origin	Design	Quality	Participant Demographics	Highest Level of Oxygen Support During Rehabilitation Interventions	Level of Mobility on Highest Level of Oxygen Support	Adverse Events	Main Findings
Andersen, et al36 (2022) United States of America	Case report	n/a	38-y-old man; BMI = 35.6 kg/m2; active (triathlete)	Full mechanical ventilation (PCV+); Fio 2 = 60%-100%, PEEP: 10-14 cm H2O; ECMO Fio 2= 100%; sweep gas flow = 2-5 L/min	Sit to Stand with 3-person assist	Oxygen desaturation to 78%-82% with activity	Discharged home on hospital day 29, received 23 PT sessions, required 2 L/min O2 via NC at discharge; 30-s Sit to Stand Test = 16 reps; gait speed = 1.9 m/s
Kinoshita, et al37 (2021) Japan	Case report	CARE checklist	71-y-old man, COPD, diabetes mellitus, Pao 2/Fio 2 = 196, pH = 7.379, Pao 2 = 98.1 mm Hg, PaCO2 = 61.4 mm Hg; SOFA = 3	Full mechanical ventilation (PCV), frequency = 28, Fio 2 = 50%, PEEP = 10 cm, H2O; following extubation: high-flow nasal cannula; 40 L/min and Fio 2 80%.	Sitting edge of bed; Sit to stand	None reported	Patients with severe COVID-19 requiring mechanical ventilation are at a higher risk for developing ICUAW and exercise tolerance. Patient-specific early mobility rehabilitation interventions are safe necessary to optimize outcomes.
Li et al39 (2021) China	Observational case series	NIHa = 6	N = 16; age range = 43-87 y; N = 3 patients on mechanical ventilation; n = 13 patients on HFNC or NC; Pao 2/Fio 2 range at initiation of rehabilitation = 114-452; Pao 2/Fio 2 range at discharge = 236-624	If on mechanical ventilation: Fio2 ≤60%, PEEP <12 cm H2O, Spo 2 ≥ 88% Respiratory rate: 18-35 breaths/min	Mechanically ventilated group was limited to transferring from the bed to chair, but were lower-level nursing home residents at baseline	None reported	Early mobility is safe and helps improve respiratory and mobility function in individuals with COVID-19. Interdisciplinary care for mobility-related interventions is critical to success of early mobility programs. Mobility interventions were progressed on the basis of oxygen saturation (Spo2) stability, and rated of perceived exertion on the Modified Borg Dyspnea Scale (encouraged patients to rest and recover for scores >4/10)
Mark et al38 (2021) United States of America	Case report	n/a	27-y-old woman; 23 wk and 6 d pregnant	Mechanical ventilation (VC); Fio 2 = 30%, RR = 10, PEEP = 16 cm H2O	Sit to stand, 2 reps	Transient orthostatic hypotension	Early mobility interventions are safe and feasible with individuals with COVID-19 requiring ECMO but require interdisciplinary care coordination
McWilliams, et al40 (2021) United Kingdom	Single-center, prospective, noninterventional, observational study	NIHb = 9	N = 177; N = 110 ICU survivors (aged 53 ± 12 y, 75% male, 87% with BMI >25 kg/m2, 45% with HTN, 31% with diabetes mellitus), N = 67 died in ICU	Excluded from mobility if mechanically ventilated with Fio 2>0.8 and/or PEEP >12 or acutely worsening respiratory failure Restricted to sitting edge of bed if mechanically ventilated with Fio 2>0.6 and/or PEEP >10	Not reported, patients were mobilized within 24 h of stopping sedation. Patients were mobilizing with nursing and rehabilitation at least 5 d before weaning of mechanical ventilation	A single patient (1%) died in the hospital following ICU discharge, following a cardiac arrest on the ward. Two (2%) patients were readmitted to the ICU before discharge, both as a result of respiratory deterioration secondary to newly diagnosed hospital-acquired pneumonia	ICU rehabilitation with mechanically ventilated patients with COVID-19 is feasible and led to improved mobility-related outcomes; 50% of patients were able to stand and step transfer to a chair by the time of discharge from ICU
Stolboushkin, et al16 (2022) United States	Single-center, retrospective chart review	NIHb = 8	N = 77; median age = 58 y; 36 female, 41 male; median ICU length of stay = 13 d; median days on ventilator = 10; median P/F ratio when initiating mobility = 280 (lowest = 82.8); median Fio 2 when initiating mobility = 40% (highest= 100%); median PEEP when initiating mobility = 8 cm H2O (highest= 15 cm H2O)	N = 9 patients required Fio 2>60%; N = 16 patients required PEEP >10 cm H2O; N = 3 patients required Fio 2 up to 100%	N = 2 patients requiring Fio 2 100% were able to ambulate up to 5 ft; N = 1 patient requiring Fio 2 95% was able to ambulate >5 ft	None reported	Current established parameters for early mobility may be too restrictive and exclude patients with critical illness who may benefit from mobility related interventions. Patients with COVID-19 on mechanical ventilation requiring high Fio 2 and PEEP have the potential to safely stand and/or ambulate with appropriate interdisciplinary ICU rehabilitation
Ozyemisci Taskiran et al41 (2021) Turkey	Observational cohort study	NIHb = 7	N = 18 standard ICU care + Rehabilitation group; median age = 73 y (range: 55-91); N = 11 male, N = 7 female; median BMI = 24.8; N = 5 with CAD, N = 6 with DM, N = 7 with HTN, N = 8 with COPD, N = 6 with CA, N = 4 with neurologic disease	All patients required fraction of inspired oxygen (Fio 2) ≤0.6; PEEP ≤10 cm H2O; oxygen saturation >92%;	Patients requiring invasive mechanical ventilation received PROM exercises only Patients with NIV, HFNC, or NC performed AAROM/AROM bed exercises; Mobility interventions not initiated until transfer out of ICU	None reported	Early rehabilitation in the ICU is safe, but the results of this study did not support the beneficial effects of early rehabilitation for improving muscle strength. It should be noted that the primary intervention was use of unsupervised neuromuscular electrical stimulation to the quadriceps and tibialis anterior, mobility interventions were not initiated until transfer out of the ICU.

Abbreviations: AAROM, active-assisted range of motion; AROM, active range of motion; BMI, body mass index; CA, cancer; CAD, coronary artery disease; CARE, case report guidelines (www.carestatement.org/checklist); COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; ECMO, extracorporeal membrane oxygenation; Fio₂, fraction of inspired oxygen; HFNC, high-flow nasal cannula; HTN, hypertension; ICU, intensive care unit; ICUAW, intensive care unit acquired weakness; n/a, not applicable; NC, nasal cannula; NIV, noninvasive ventilation; Pao₂, partial pressure of oxygen; PCV, pressure-controlled ventilation; PEEP, positive end-expiratory pressure; PT, physical therapy; RR, respiratory rate; SOFA, Sequential Organ Failure Assessment Score; Spo₂, oxygen saturation; VC, volume control

^aNIH: National Institutes of Health Quality Assessment Tool for Case Series Studies.

^bNIH: National Institutes of Health Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies.

Four of the 7 implementation-based studies included in this scoping review adhere to established clinical criteria outlined in CPGs for early rehabilitation.^37–39,41 Ozyemisci Taskiran and colleagues⁴¹ limited their intervention to bed-level range of motion exercises and neuromuscular electrical stimulation to the quadriceps and tibialis anterior and did not initiate mobility interventions until patients had transferred out of the ICU.⁴¹

In the United States, Stolboushkin et al¹⁶ developed a clinical decision-making algorithm based on a retrospective chart review of 77 individuals admitted to the ICU with COVID-19. The proposed algorithm advocates for initiation of mobility for individuals requiring 75% Fio₂ and less and/or PEEP 15 cm H₂O and less who have maintained stable vital signs and stable requirements for ventilatory support.¹⁶ In this study, at least 9 patients who engaged in mobility-related interventions required Fio₂ more than 60%, including 2 patients who were able to ambulate up to 5 ft on 100% Fio₂, and 1 patient who ambulated more than 5 ft on 95% Fio₂. No adverse events were reported.

Finally, Andersen et al³⁶ presented a case report of a 38-year-old man who successfully participated in a progressive mobility intervention while mechanically ventilated on pressure-control ventilation with Fio₂ from 60% to 100% and PEEP 10 to 14 cm H₂O and extracorporeal membrane oxygenation (ECMO) with Fio₂ 100% and sweep gas flow of 2 to 5 L/min. The patient had a transient decrease in oxygen saturation (Spo₂) to 78% to 82% with activity but recovered and was able to successfully wean off of ECMO and mechanical ventilation and discharged home at hospital day 29 on 2 L/min of supplemental oxygen via nasal cannula and a gait speed of 1.9 m/s.³⁶

As noted in Table 2, there is significant variability in the clinical criteria used to determine whether or not patients were eligible for mobility-related interventions. Two studies, an observational case series of 16 patients³⁹ and an observational cohort study of 18 patients,⁴¹ restricted mobility for individuals requiring Fio₂ greater than 60%.^39,41 In the United Kingdom, McWilliams et al⁴⁰ conducted a single-center, prospective, noninterventional observational study of 110 ICU survivors with severe COVID-19, mobility was restricted to sitting edge of bed if patients were mechanically ventilated and required Fio₂ greater than 60%, and mobility was restricted for individuals who were mechanically ventilated and required Fio₂ greater than 80%.⁴⁰ No adverse events were attributed to mobility-related interventions in the ICU.⁴⁰

Three individual case reports failed to show any consistency in parameters and clinical criteria for initiation of mobility interventions. One patient required Fio₂ 100% and support of VV-ECMO,³⁶ another with multiple comorbidities including chronic obstructive pulmonary disease and diabetes mellitus required Fio₂ 80% at 40 L/min via heated high-flow nasal cannula,³⁷ and a third required veno-venous extracorporeal membranous oxygenation (VV-ECMO) support and mechanical ventilation with Fio₂ 30% despite being pregnant.³⁸ All were able to safely participate in early rehabilitation without any adverse events.

No significant adverse events were reported in any of the studies included in this scoping review. The only mildly adverse events reported related to mobility interventions included transient oxygen desaturation to 78% to 82% with activity³⁶ and transient orthostatic hypotension.³⁸

DISCUSSION

Implementation of Early Rehabilitation for Individuals With COVID-19

The 7 implementation studies of early rehabilitation interventions included in this scoping review include a total of 224 ICU survivors of respiratory failure due to COVID-19. The quality of these studies was limited to case reports, observational case series, retrospective chart reviews, and prospective observational studies. The early rehabilitation interventions for these patients ranged from simple passive range of motion (PROM) exercises to mobility-related interventions including sit to stand transfers and limited distance ambulation. The available reports are primarily descriptive; therefore, there is limited evidence to guide clinicians with clinical decision making for initiation and progression of early rehabilitation interventions.

Intensive care unit CPGs advocate for implementation of early rehabilitation and early mobility interventions to mitigate the debilitating effects of prolonged bed rest and complications associated with ICUAW. A recent systematic review of 16 studies, including a total of 607 ICU patients, investigated the activity level of patients in the ICU using actigraphy.⁴² Actigraphy is a method for measuring an individual΄s level of activity using patient-worn accelerometers.^42,43 One of the primary findings of the systematic review was that patients in the ICU are profoundly inactive.⁴² These findings are supported by a prospective observational study, which used actigraphy to study the activity level of 34 patients in a medical ICU who reported that even those individuals who were young, nonsedated, and nonrestrained were profoundly inactive.⁴³

To date, there have not been any actigraphy studies conducted to report on the activity level of individuals admitted to the ICU due to complications associated with COVID-19. However, based on studies of other ICU patient populations, there is no reason to assume that implementation of mobility interventions is any higher in individuals admitted to the ICU due to COVID-19.^42,43 Based on the limited evidence for individuals with COVID-19, ICUAW continues to be concerning and prevalent in this population.^10,11,17

Current Mobility Guidelines for Early Rehabilitation for Individuals With COVID-19

The 2018 Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU, or PADIS Guidelines,⁴⁴ are the most widely adopted guidelines and provide the current best evidence to inform clinical decision making for mobility interventions in the ICU. Although they are not specific to individuals with COVID-19, these guidelines provide guidance for safe mobilization for patients with critical illness. Intensive care unit management of patients with severe COVID-19 has presented unique challenges as these individuals frequently require enhanced ventilatory and hemodynamic support, which is not clearly addressed in the PADIS guidelines. Individuals with severe COVID-19 who require enhanced ventilatory support are frequently excluded from mobility interventions as the PADIS guidelines restrict mobility for anyone requiring a Fio₂ greater than 60% and/or a PEEP greater than 10 cm H₂O.⁴⁴

Since the onset of the COVID-19 global pandemic, several expert-based CPGs and consensus documents have been published to guide clinicians in implementation of early rehabilitation and mobility-related interventions for individuals with COVID-19.^{31–33,35,45} However, the unique challenges presented by individuals with respiratory failure due to COVID-19 have illuminated areas where current CPGs do not provide sufficient guidance for clinical decision making with regard to early rehabilitation.

Because of the high mortality of individuals with COVID-19 requiring invasive ventilatory support via mechanical ventilation, the National Institutes of Health has advocated for an increase in the use of noninvasive methods of delivering enhanced ventilatory support.^46–48 Following the National Institutes of Health guidance, there has been increased use of enhanced oxygen support systems, including heated high-flow nasal cannula capable of delivering oxygen at 30 to 60 L/min with Fio₂ up to 100%, and non-invasive positive pressure ventilation (NIPPV) systems delivering Fio₂ up to 100%.⁴⁸ These noninvasive methods of delivering-enhanced ventilatory support are not addressed clearly in recently published guidelines. Most current guidelines are based on cutoff values for vital signs and levels of ventilatory support and restrict mobility interventions for individuals who require Fio₂ greater than 60% and/or PEEP greater than 10 cm H₂O, regardless of the method of delivery.^{31,32,35,44,45} If therapeutic targets for ventilation and perfusion are not met through enhanced oxygen support systems, individuals with critical illness may require the addition of supplemental pulmonary artery vasodilators such as inhaled nitric oxide (iNO) or inhaled epoprostenol (iEpo). Current mobility guidelines do not provide recommendations to inform early rehabilitation or mobility-related interventions for individuals requiring support of inhaled pulmonary artery vasodilators.

Many individuals with COVID-19 on mechanical ventilation or noninvasive enhanced ventilatory support require Fio₂ support up to 100%. Given that current guidelines do not make a distinction between different delivery methods of enhanced ventilatory support or provide guidance for clinical decision making for individuals requiring supplemental pulmonary artery vasodilators, individuals receiving these therapies are often excluded from participation in early rehabilitation and mobility interventions.

It is important to note that the cutoff values for Fio₂ and PEEP were established prior to the global pandemic and relate to the severity of acute respiratory distress syndrome (ARDS) indicated by the P/F ratio (Horowitz Index for Lung function: arterial pO₂ divided by Fio₂).⁴⁹ If individuals require Fio₂ support greater than 60%, there is a significant likelihood that the P/F ratio is in the moderate (P/F= 101-200) to severe (P/F=≤ 100) range of the ARDS severity score.⁴⁹ Prior to the COVID-19 global pandemic, individuals with ARDS in the moderate to severe range were considered too critically ill to safely participate in mobility-related interventions.

In 2020, the American Association of Critical-Care Nurses published an early progressive mobility protocol advocating early mobility for individuals requiring mechanical ventilation with Fio₂ less than 85% and PEEP less than 15 cm H₂O.³⁴ In addition, Bitzer and colleagues¹⁵ published a clinical perspective paper to suggest that decisions regarding appropriateness for initiation of mobility-related interventions be based primarily on stable ventilator settings over the past 12 hours, a RASS score of −2 to +1, appropriate biomarkers and laboratory values, and appropriate pH and blood gas trends.

Although we acknowledge that mobilizing patients requiring enhanced ventilatory support due to respiratory failure with severe to critical COVID-19 is complex and challenging, the potential benefits may outweigh the potential risks.

Clinical Decision Making and Risk Mitigation for Early Rehabilitation in the ICU

Decisions regarding risk versus benefit of early rehabilitation and mobility programs are complex for individuals with respiratory failure due to COVID-19. Mobility-related interventions for patients with respiratory failure due to severe COVID-19 are not without risk; however, it is possible that the risks associated with prolonged bed rest are more severe.^18,20,50,51 Evidence suggests that mobility interventions are more effective for airway clearance than other bed exercise or airway clearance techniques.⁵²

Three out of the 5 CPGs for mobilizing individuals with COVID-19 who are mechanically ventilated included in this review state that mobility is contraindicated for individuals requiring Fio₂ greater than 60% and PEEP greater than 10 cm H₂O. However, 1 guideline³⁴ permits mobility for individuals requiring up to Fio₂ 85% and PEEP 15 cm H₂O, and another guideline³⁵ does not have any definitive cutoff regarding level of ventilatory support, provided Spo₂ is maintained more than 90%.

As suggested by current CPGs, individuals who require Fio₂ greater than 60% may be at high risk for complications with early rehabilitation and mobility. To mitigate the risks associated with early rehabilitation in a medically complex patient population, interdisciplinary teams should consider what options are available to provide an escalation of care due to any unforeseen adverse events that may occur. For example, individuals receiving noninvasive ventilatory support via high-flow nasal cannula or NIPPV with Fio₂ greater than 100% may require an escalation in care via intubation and mechanical ventilation if they experience an unexpected deterioration in respiratory status during early rehabilitation.

Fio₂ and PEEP values may be increased for individuals with ARDS in an effort to improve oxygenation to address pathology-related hypoxia; however, increased PEEP values may result in decreased cardiac output and decreased tolerance for early rehabilitation.^53,54 Individuals with ARDS who do not respond to mechanical ventilation with increased Fio₂ and PEEP may require VV-ECMO for escalation of care.⁵⁵ Therefore, interdisciplinary teams considering the risk versus benefit of early rehabilitation for individuals who are mechanically ventilated with Fio₂ greater than 60% and/or PEEP greater than 10 cm H₂O should consider the availability of ECMO to provide an escalation in care with any unexpected adverse event.

Limitations

There are currently no randomized clinical trials to objectively inform clinical decision making with regard to implementation of mobility-related interventions for individuals with respiratory failure due to severe COVID-19. To date, no studies have systematically examined the physiological effects or safety of mobilizing or exercising individuals with COVID-19 requiring enhanced ventilatory support. Current CPGs and consensus recommendations are extrapolated from research on other patient populations. Published case reports and case series have based the implementation of interventions on different guidelines making it impossible to determine the optimal metrics on which to base clinical decisions. Future research should investigate the safety of implementing symptom-limited early progressive mobility interventions for individuals with COVID-19 who require Fio₂ greater than 60% and/or PEEP greater than 10 cm H₂O and have a RASS score of +1 to −2. Future studies should also examine the most appropriate clinical criteria, which indicate that early rehabilitation interventions should be terminated to minimize risk for adverse events.

CONCLUSION

There is some variability in objective clinical criteria reported in current CPGs, which inform clinical decision making for implementation of early rehabilitation programs in individuals with respiratory failure due to COVID-19. The majority, 60%, of current CPGs restrict mobility for individuals requiring ventilatory support of greater than 60% Fio₂ and/or PEEP greater than 10 cm H₂O but do not differentiate their recommendations based on invasive versus noninvasive methods of ventilatory support. Some individuals with respiratory failure due to COVID-19 requiring enhanced ventilatory support outside of established parameters may be able to safely participate in early rehabilitation and mobility-related interventions; however, preliminary evidence is derived from low-quality case reports, observational case series, retrospective chart reviews, and prospective observational studies. Further research is needed to determine safety and feasibility of early rehabilitation in this medically complex patient population. Increased access and implementation of early rehabilitation may help optimize outcomes and minimize the negative effects of bed rest for individuals with respiratory failure due to severe COVID-19.