Early intervention (mobilization or active exercise) for critically ill patients in the intensive care unit

  • Protocol
  • Intervention



This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the effects of early intervention (mobilization or active exercise), commenced in the ICU, provided to critically ill participants who are, or were, mechanically ventilated, compared with usual care, on improving functional status, muscle strength and health-related quality of life.


Description of the condition

Critically ill patients are admitted to the intensive care unit (ICU) so that physiological responses to illness and injury can be monitored and stabilized in a sophisticated manner, and respiration can be assisted with mechanical ventilation if needed. Multiple factors, including haemodynamic instability, altered sleep patterns, the presence of vascular attachments and sedation to improve patient comfort during mechanical ventilation, can limit mobilization of these patients (Adler 2012). 

Survivors of critical illness often experience residual problems (Iwashyna 2010), including cognitive impairments (such as altered memory, attention and executive functioning); psychological difficulties (such as depression, anxiety and post-traumatic stress disorder); reduced physical function (as in activities of daily living) and decreased quality of life (Desai 2011). In addition, similar psychological difficulties may occur in families of patients with critical illness (Herridge 2011).               

Intensive care unit acquired weakness (ICUAW) may be described as clinically identified weakness with no likely cause other than ill-defined inflammation (Vincent 2009). ICUAW is a common complication for patients who are critically ill and is associated with extended duration of mechanical ventilation (DeJonghe 2002), sepsis, systemic inflammatory response syndrome, multi-organ failure and hyperglycaemia (Desai 2011). Critically ill patients sustain loss of muscle mass in the first two to three weeks when immobilized in the ICU (Gruther 2008), and this can develop as early as 7 days after a patient commences mechanical ventilation (DeJonghe 2002). ICUAW has also been related to a higher incidence of hospital mortality (Ali 2008).

Acute respiratory distress syndrome (ARDS) is "characterized by the presence of bilateral opacities consistent with pulmonary edema not fully explained by cardiac failure or fluid overload and a PaO2/FiO2 ratio of ≤300mmHg” (ARDS Definition Task Force 2012) and commonly produces respiratory failure in critically ill patients in the ICU (Rubenfeld 2005). A one-year follow-up of survivors of ARDS found that return to work was negatively impacted (Herridge 2003), and 64/109 (59 %) of this cohort reported persistent muscle weakness and decreased functional capacity at five years post-discharge from the ICU (Herridge 2011). 

In an attempt to improve outcomes for the survivors of critical illness, there have been efforts to interrupt sedation (Kress 2000), to allow patients to choose their own level of sedation (Chlan 2010), and to cease sedation (Strøm 2011) for patients who are mechanically ventilated. As patients become increasingly responsive, they are better able to participate in active exercise and to mobilize outside of bed, even when mechanically ventilated. Bailey 2007 demonstrated infrequent adverse events in participants who mobilized while mechanically ventilated and concluded that early mobility of patients in the intensive care unit is feasible and safe.

Description of the intervention

We will consider interventions that commenced early while the patient was in the ICU and may have included any of the following activities: cycle ergometer, active-assisted exercises, active range of motion exercises, bed mobility activities, activities of daily living, transfer training, pre-gait exercises and ambulation. (See Types of interventions for additional details.)

How the intervention might work

The consequences of bed rest are well understood and include adverse effects on the cardiovascular system (through decreased functional capacity), the respiratory system (through difficulty weaning from mechanical ventilation) and the neuromuscular system (through ICUAW) (Koo 2011). Beneficial effects of exercise training are widespread and can include improvements in skeletal muscle function, respiration (increased tidal volume and oxygen transport capacity) and cardiovascular function (including prevention of age-related diastolic dysfunction and decreased oxidative stress) (Gielen 2010). Winkelman 2012 found that mechanically ventilated participants who performed 20 minutes of low level exercise had a statistically significant increase in the anti-inflammatory cytokine IL-10 but no corresponding increase in the pro-inflammatory cytokine IL-6. In addition, this study noted a decreased length of stay for participants in the intervention group. Early mobilization and active exercise may contribute to prevention or reduction of the deleterious effects of critical illness on the cardiovascular, respiratory and neuromuscular systems, which, in turn, may contribute to improved functional performance and decreased length of stay.

Why it is important to do this review

Early mobilization and active exercise of critically ill patients are increasingly being provided in some ICUs. Emerging research evidence suggests that this is safe and may improve functional and health-related quality of life outcomes. This review will guide clinicians and intensive care unit policy makers regarding the timing of mobilization and active exercise for critically ill patients.


To assess the effects of early intervention (mobilization or active exercise), commenced in the ICU, provided to critically ill participants who are, or were, mechanically ventilated, compared with usual care, on improving functional status, muscle strength and health-related quality of life.


Criteria for considering studies for this review

Types of studies

We will include all randomized controlled trials (RCTs) or quasi-randomized controlled trials that compare early intervention (mobilization or active exercise) of critically ill participants who are, or were, mechanically ventilated in the ICU with usual care (see Types of interventions). We will include in the review a list of studies that do not meet inclusion criteria (and the main reason(s) for their exclusion).

Types of participants

We will include adults who have been admitted to an ICU and are, or were, mechanically ventilated. We will exclude patients who have pre-existing or rapidly developing neuromuscular disease, spinal cord injury, cardiopulmonary arrest, raised intracranial pressure, advanced dementia or irreversible disorders with expected six-month mortality.

Types of interventions


The intervention must have been mobilization and/or active exercise (as described later) that was designed to commence earlier than the care received by the control group.

Any combination of one or more of the following will be considered:

  • Cycle ergometer;

  • Active-assisted exercises;

  • Active range of motion (ROM) exercises;

  • Bed mobility activities (e.g. bridging, rolling, lying to sitting);

  • Activities of daily living (ADLs) or exercises related to increasing independence with functional tasks;

  • Transfer training;

  • Pre-gait exercises (including marching on the spot);

  • Ambulation; and

  • Any other type of active exercise modality that commenced while the participant was in the ICU.


The comparator will be usual care, which may have consisted of:

  • Mobilization or active exercise that commenced only once the patient had left the ICU; or

  • Mobilization or active exercise that commenced later than in the early treatment group but while the participant was in the ICU; or

  • Exercise or training that consisted only of inspiratory or respiratory muscle training.

Types of outcome measures

Primary outcomes
  • Functional status (the ability to perform everyday activities such as walking, transfers and basic ADLs).

  • Adverse events (falls, accidental dislodgement of attachments, haemodynamic instability, oxygen desaturation or any other adverse events stated by trial authors).

Secondary outcomes
  • Length of stay (ICU and hospital).

  • Muscle strength (Medical Research Council (MRC) score, cross-sectional diameter).

  • Health-related quality of life or well-being (e.g. The MOS 36-item Short-Form Health Survey(SF-36) questionnaire (Ware 1992), Acute Physiology And Chronic Health Evaluation (APACHE) score, Sequential Organ Failure Assessment (SOFA) score).

  • Delirium.

  • Death from any cause.

  • Hospital costs.

Search methods for identification of studies

Electronic searches

We will search the Cochrane Anaesthesia Group Register of Trials, the current issue of the Cochrane Central Register of Controlled Trials (CENTRAL),The Cochrane Library, MEDLINE (Ovid SP, 1966 to date), EMBASE (Ovid SP, 1974 to date), CINAHL (EBSCO, 1981 to date), PEDro (1980 to date) and OTseeker (1951 to date).

Please see Appendix 1 for the MEDLINE search terms that will be used in this review. We will adopt the MEDLINE search strategy in searching other databases.

Searching other resources

We will search the controlled trial registry http://www.controlled-trials.com/ for studies that may have been missed or unpublished and will review relevant conference proceedings and abstract presentations of important symposia, We will correspond with authors of studies that have been completed but not published and with content experts to identify unpublished research and trials still under way. We will not impose a publication or language restriction. We will conduct translations if required.

Data collection and analysis

Selection of studies

Two review authors (KAD and TH) will independently assess for inclusion all studies identified as a result of the search strategy. We will resolve any disagreement through discussion or consultation with a third review author (EMB) if required.

Data extraction and management

Please see Appendix 2 for the data extraction form that will be used in this review.

We will examine trials that meet the inclusion criteria and will record the following information:

  • Methods - a description of study design, randomization and treatment setting;

  • Participants - number of participants, age, gender, race/ethnicity, body mass index, inclusion and exclusion criteria, ICU days before inclusion, primary presenting diagnosis, biochemical data, health and well-being status scores and functional scale scores;

  • Interventions - description of experimental and comparator interventions and relevant co-interventions (e.g. medications);

  • Outcomes - baseline and end of study measurement of functional status (functional independence measure (FIM), Barthel Index (Mahoney 1965)), health-related quality of life or well-being (The MOS 36-item Short-Form Health Survey(SF-36) questionnaire (Ware 1992), APACHE score, SOFA score) and muscle strength, as well as adverse events, length of stay (ICU and hospital), delirium, death from any cause and hospital costs; and

  • Notes - language of the study and any other information relevant to this review.

We will comment briefly about the reasons for exclusion of studies identified in the search strategy but not subsequently included.

Assessment of risk of bias in included studies

Two review authors (EMB and KAD) will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreement by discussion or by involving a third review author (TH). We will assess the risk of bias according to the following domains:

  • Allocation sequence generation;

  • Concealment of allocation;

  • Blinding of study participants and personnel;

  • Incomplete outcomes data;

  • Selective outcomes reporting; and

  • Other biases.

We will grade each potential source of bias as yes, no or unclear according to whether the potential for bias was high, low or unknown.

We will consider a trial as having a high risk of bias if either of the domains of concealment of allocation or blinding of study participants and personnel is assessed as inadequate or unclear.

We will include a 'Risk of bias' table as part of the 'Table of characteristics of included studies' and a 'Risk of bias summary' figure, which will detail all of the judgements made for all included studies in the review.

Measures of treatment effect

Primary outcomes

Functional status: Where studies report this on a dichotomous scale (e.g. return to independent functional status at hospital discharge), we will combine these studies using the risk ratio to compare the intervention group with the control group. We anticipate that studies will report ADL composite measures and functional component measures using continuous scales (e.g. Barthel Index (Mahoney 1965), Six -Minute Walk Distance (Crapo 2002)) and will report these results using standardized mean difference.

Adverse events: We will use the proportion of participants experiencing any adverse event of treatment and will combine studies using the risk ratio. We will also report descriptively the numbers of adverse events of particular types.

Secondary outcomes

Length of stay will be reported using time, and we will therefore use mean difference.

Health-related quality of life, muscle strength and hospital costs: We expect that these outcomes will be reported using continuous scales and therefore will use standardized mean difference or mean difference as appropriate.

Delirium: We will use risk ratio to report this outcome.

Death from any cause: We will use risk ratio to report this outcome.

Unit of analysis issues

It is unlikely that any studies in this review will be cross-over trials or cluster-randomized trials. Therefore the unit of analysis will be the individual participant.

If there are studies of multiple treatment groups, we will consider only the interventions specified in the review. We will compare them only with the usual care group and will ignore the results of any other intervention groups.

Dealing with missing data

We will write to investigators to verify key study characteristics and to obtain missing outcomes data as needed. We will report participant drop-out and will conduct intention-to-treat (ITT) analysis where possible. We will apply the methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) to impute missing standard deviations if few in number.

Assessment of heterogeneity

We will use the I² statistic to measure heterogeneity among the trials in each analysis. If we identify substantial heterogeneity (greater than 50%) we will explore it by subgroup analysis that aims to identify plausible contributing factors.

If the subgroup analysis does not identify the potential source of heterogeneity, we will look at study and participant characteristics and will decide whether it is appropriate to combine these studies in a meta-analysis.

Assessment of reporting biases

Where we suspect reporting bias, we will contact investigators to request the missing outcomes data. Where this is not possible, and the missing data may introduce serious bias, we will explore the impact of including these studies in the overall assessment of results by a sensitivity analysis.

If at least 10 studies are found, we will create a funnel plot to investigate potential publication bias (Egger 1997).

Data synthesis

We will use a random-effects model because of the varying nature of potential interventions in this review. If studies are insufficient (e.g. fewer than 3) for completion of a meta-analysis, we will descriptively report the results of included studies.

Subgroup analysis and investigation of heterogeneity

If heterogeneity of studies is observed, we will investigate possible sources of heterogeneity such as age group, cause of ICU stay, length of mechanical ventilation, co-morbidities such as diabetes and use of corticosteroids, and will report on these descriptively, unless sufficient studies are identified for subgroup analysis to be performed.

Sensitivity analysis

If studies are sufficient for completion of a sensitivity analysis, we will perform this by omitting the high risk of bias studies defined as lack of concealment of allocation and blinding of study participants and personnel.

Summary of findings

We will use the principles of the GRADE system (Guyatt 2008) to assess the quality of the body of evidence associated with specific outcomes (functional status, adverse events and length of stay in the ICU and hospital) in our review and will construct a summary of findings (SoF) table using the GRADE software. The GRADE approach appraises the quality of a body of evidence based on the extent to which one can be confident that an estimate of effect or association reflects the item being assessed. The quality of a body of evidence considers within-study risk of bias (methodological quality), the directness of the evidence, the heterogeneity of the data, the precision of effect estimates and the risk of publication bias.


We would like to thank Karen Hovhannisyan,Trials Search Co-ordinator, the Cochrane Anaesthesia Review Group (CARG), and Sarah Thorning,Trials Search Co-ordinator, Cochrane Acute Respiratory Infections Group, for their assistance in identifying search terms for this review.

We would like to thank Matthew Zacharias (content editor), Cathal Walsh (statistical editor), Andrea Lemos, Andrezza L Bezzera, Linda Denehy and Sue Berney (peer reviewers) for their help and editorial advice during the preparation of this protocol for the systematic review.


Appendix 1. MEDLINE (Ovid SP) search strategy

1. exp Respiration, Artificial/ or (mechanical* adj3 ventila*).af.
2. exp Exercise Therapy/ or exp Physical Therapy Modalities/ or exp Occupational Therapy/ or mobilizat*.mp. or mobilisat*.mp. or mobility.mp or exercis*.mp. or (therap* adj3 (physical or exercise or occupational)).mp. or ((bed or daily living) adj3 activit*).mp. or training.mp. or pre?gait.mp. or walk*.mp. or ADL*.ti,ab. or physiotherap*.mp.
3. exp Intensive Care Units/ or ICU.mp. or exp Critical Illness/ or exp Critical Care/ or (critical* adj3 (ill* or care)).mp. or intensive care.mp. or ICUAW.mp.
4. 1 and 2 and 3

Appendix 2. Data extraction form

Review title or ID


Study ID (surname of first author and year first full report of study was published e.g. Smith 2001)


Report IDs of other reports of this study (e.g. duplicate publications, follow-up studies)






1.     General Information


Date form completed (dd/mm/yyyy)     
Name/ID of person extracting data



Report title

(title of paper/abstract/report that data are extracted from)



Report ID

(ID for this paper/abstract/report)



Reference details




Report author contact details



Publication type

(e.g. full report, abstract, letter)



Study funding sources

(including role of funders)



Possible conflicts of interest

(for study authors)






2.     Study Eligibility


Study Characteristics

Eligibility criteria

(Insert eligibility criteria for each characteristic as defined in the Protocol)


Location in text

(pg & ¶/fig/table)

Type of studyRandomized controlled trial        

Controlled clinical trial

(quasi-randomized trial)


Participants (inclusion criteria)


 Admitted to intensive care unit    
 Mechanically ventilated    
Participants (exclusion criteria)Pre-existing or rapidly developing neuromuscular disease    
 Cardiopulmonary arrest    
 Raised intracranial pressure    
 Advanced dementia    
 Spinal cord injury    
 Irreversible disorders with expected six-month mortality    

Types of interventions:

(Any combination of any of the following)

Cycle ergometer        
 Active-assisted exercises    
 Active range of motion (ROM) exercises    
 Bed mobility activities (bridging, rolling, lying to sitting)    
 Activities of daily living (ADLs) or exercises related to increasing independence with functional tasks    
 Transfer training    
 Pre-gait exercises (including marching on the spot)    
 Any other type of active exercise modality that commenced while the patient was in the ICU (specify)    
ComparatorsMobilization or active exercise that commenced only once the patient had left the ICU    
 Usual care where the exercise or training consisted only of inspiratory or respiratory muscle training    

Reason for exclusion







3.     Population and Setting




Include comparative information for each group (i.e. intervention and controls) if available

Location in text

(pg & ¶/fig/table)

Population description

(from which study participants are drawn)



(including location and social context)

Inclusion criteria          
Exclusion criteria          
Method/s of recruitment of participants          

Informed consent obtained


 Yes No Unclear                 


4.     Methods



Descriptions as stated in report/paper


Location in text

(pg & ¶/fig/table)

Aim of study           
Design (e.g. parallel, cross-over, cluster)          

Unit of allocation

(by individuals, cluster/groups or body parts)

Start date



End date



Total study duration           
Protocol violations  
Time spent performing intervention  
Median time to commencement of intervention  
% of treatments delivered from the protocol (feasibility)   
Ethical approval needed/obtained for study  Yes No Unclear          


5.     Risk of Bias Assessment

See Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).



Risk of bias


Support for judgement


Location in text

(pg & ¶/fig/table)

Low riskHigh riskUnclear

Random sequence generation

(selection bias)


Allocation concealment

(selection bias)


Blinding of participants and personnel

(performance bias)


Outcome group: All/     



Blinding of outcomes assessment

(detection bias)


Outcome group:    

Functional status


Outcome group:      

Adverse events   


Outcome group:

Length of stay (ICU and hospital)


Outcome group:

Muscle strength (MRC score, cross-sectional diameter)


Outcome group:

Health-related quality of life or well-being


Outcome group:



Outcome group:

Death from any cause


Outcome group:

Hospital costs


Incomplete outcome data

(attrition bias)  


Selective outcome reporting?

(reporting bias)

Other bias             


6.     Participants

Provide overall data and, if available, comparative data for each intervention or comparison group.



Description as stated in report/paper


Location in text

(pg & ¶/fig/table)

Total no. randomly assigned

(or total pop. at start of study for NRCTs)



(if applicable, no., type, no. people per cluster)

Baseline imbalances          

Withdrawals and exclusions

(if not provided below by outcome)

Body mass index (kg/m2)  
Acute Physiology and Chronic Health Evaluation (APACHE) score          
Sequential Organ Failure Assessment (SOFA) score  
SF-36 Health Survey questionnaire  
Richmond Agitation Sedation Scale (RASS)  
Confusion Assessment Method (CAM)  
Barthel Index ( Mahoney 1965 )  
Functional Independence Measure (FIM)  
Other functional scale (specify)  
Primary diagnosis on admission to intensive care  
ICU stay before inclusion (days)  
Duration of mechanical ventilation (days)  
C-reactive protein  
Co-morbidities (medical and surgical)           
Other treatment received (additional to study interventionmedications, dialysis etc)        

Other relevant sociodemographics


Subgroups measured           
Subgroups reported           


7.     Intervention Groups

Copy and paste table for each intervention and comparison group.


Intervention Group 1


Description as stated in report/paper


Location in text

(pg & ¶/fig/table)

Group name           

No. randomly assigned to group

(specify whether no. people or clusters)

Theoretical basis for choice of intervention (include key references)           
Description (include sufficient detail for replication, e.g. content, dose, components)          
Duration of treatment period          
Timing (e.g. frequency, duration of each episode)          
Delivery (e.g. mechanism, medium, intensity, fidelity)          


(e.g. no., profession, training, ethnicity etc. if relevant)

Economic variables
(i.e. intervention cost, changes in other costs as result of intervention)

Resource requirements to replicate intervention

(e.g. staff numbers, cold chain, equipment)



8.     Outcomes

Copy and paste table for each outcome.


Outcome 1


Description as stated in report/paper


Location in text

(pg & ¶/fig/table)

Outcome name            
Time points measured          
Time points reported          
Outcome definition (with diagnostic criteria if relevant)          
Person measuring/reporting          

Unit of measurement

(if relevant)


Scales: upper and lower limits (indicate whether high or low score is good)          
Is outcome/tool validated?Yes No Unclear                    
Imputation of missing data
(e.g. assumptions made for ITT analysis)

Assumed risk estimate

(e.g. baseline or population risk noted  in Background)


9.     Results

Copy and paste the appropriate table for each outcome, including additional tables for each time point and subgroup as required.


Dichotomous outcome


Description as stated in report/paper


Location in text

(pg & ¶/fig/table)

Time point
(specify whether from start or end of intervention)
Results Intervention Comparison     
No. eventsNo. participantsNo. eventsNo. participants
No. missing participants and reasons               
No. participants moved from other group and reasons               
Any other results reported          
Unit of analysis (by individuals, cluster/groups or body parts)           
Statistical methods used and appropriateness of these methods (e.g. adjustment for correlation)          
Reanalysis required? (specify)Yes No Unclear            
Reanalysis possible?Yes No Unclear          
Reanalysed results          


Continuous outcome


Description as stated in report/paper


Location in text

(pg & ¶/fig/table)

Time point
(specify whether from start or end of intervention)
Post-intervention or change from baseline?          
Results Intervention Comparison 
MeanSD (or other variance)No. participantsMeanSD (or other variance)No. participants     
No. missing participants and reasons               
No. participants moved from other group and reasons               
Any other results reported           

Unit of analysis

(individuals, cluster/groups or body parts)

Statistical methods used and appropriateness of these methods (e.g. adjustment for correlation)          
Reanalysis required? (specify) Yes No Unclear               
Reanalysis possible?Yes No Unclear            
Reanalysed results          


10. Applicability


Have important populations been excluded from the study? (consider disadvantaged populations and possible differences in the intervention effect)  Yes No Unclear         
Is the intervention likely to be aimed at disadvantaged groups? (e.g. lower socioeconomic groups)Yes No Unclear          

Does the study directly address the review question?

(any issues of partial or indirect applicability)

Yes No Unclear 


11. Other Information



Description as stated in report/paper


Location in text

(pg & ¶/fig/table)

Key conclusions of study authors           
References to other relevant studies           
Correspondence required for further study information (from whom, what and when)     

Contributions of authors

Conceiving the review: Katherine A Doiron (KAD), Tammy Hoffmann (TH).

Co-ordinating the review: KAD, TH.

Undertaking manual searches: KAD.

Screening search results: KAD, TH.

Organizing retrieval of papers: KAD.

Screening retrieved papers against inclusion criteria: KAD, TH.

Appraising quality of papers: KAD, TH.

Abstracting data from papers: KAD, TH.

Writing to authors of papers for additional information: KAD.

Providing additional data about papers: KAD, TH.

Obtaining and screening data on unpublished studies: KAD, TH.

Providing data management for the review: KAD, TH, Elaine M Beller (EMB).

Entering data into Review Manager (RevMan 5.1): KAD, TH.

Entering RevMan statistical data: EMB, KAD.

Performing other statistical analysis not using RevMan (RevMan 5.1): KAD, EMB.

Interpreting data: KAD, EMB.

Making statistical inferences: KAD, EMB.

Writing the review: KAD, TH, EMB.

Securing funding for the review: KAD, TH.

Performing previous work that was the foundation of the present study: KAD, TH.

Serving as guarantor for the review (one author): KAD.

Taking responsibility for reading and checking the review before submission: KAD.

Declarations of interest

Katherine A Doiron: none known.

Tammy Hoffmann: none known.

Elaine M Beller: see Sources of support.

Sources of support

Internal sources

  • No sources of support supplied, Not specified.

External sources

  • National Health and Medical Research Council (NHMRC), Australia.

    Elaine M Beller's work on this review was supported by an Australia Fellowship Grant from the NHMRC, Australia, to the Centre for Evidence-Based Practice, Bond University.