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rehabilitation following intensive care unit discharge for recovery
from critical illness: executive summary of a Cochrane Collaboration
systematic reviewBronwen Connolly1,2,3,*, Lisa Salisbury4, Brenda O'Neill5, Louise Geneen6, Abdel Douiri3,7, Michael P. W. Grocott8,9,10, Nicholas Hart1,2,3, Timothy S. Walsh11, Bronagh Blackwood12
Version of Record online: 16 SEP 2016
muscle wasting and weakness are major complications of critical illness
and underlie the profound physical and functional impairments
experienced by survivors after discharge from the intensive care unit
(ICU). Exercise-based rehabilitation has been shown to be beneficial
when delivered during ICU admission. This review aimed to determine the
effectiveness of exercise rehabilitation initiated after ICU discharge
on primary outcomes of functional exercise capacity and health-related
quality of life. We sought randomized controlled trials,
quasi-randomized controlled trials, and controlled clinical trials
comparing an exercise intervention commenced after ICU discharge vs. any
other intervention or a control or ‘usual care’ programme in adult
survivors of critical illness. Cochrane Central Register of Controlled
Trials, Medical Literature Analysis and Retrieval System Online
(MEDLINE), Excerpta Medica Database, and Cumulative Index to Nursing and
Allied Health Literature databases were searched up to February 2015.
Dual, independent screening of results, data extraction, and quality
appraisal were performed. We included six trials involving 483 patients.
Overall quality of evidence for both outcomes was very low. All studies
evaluated functional exercise capacity, with three reporting positive
effects in favour of the intervention. Only two studies evaluated
health-related quality of life and neither reported differences between
intervention and control groups. Meta-analyses of data were precluded
due to variation in study design, types of interventions, and selection
and reporting of outcome measurements. We were unable to determine an
overall effect on functional exercise capacity or health-related quality
of life of interventions initiated after ICU discharge for survivors of
critical illness. Findings from ongoing studies are awaited. Future
studies need to address methodological aspects of study design and
conduct to enhance rigour, quality, and synthesis.
improving standards of care and improved patient selection for
admission to the intensive care unit (ICU) are reducing rates of
mortality amongst critically ill patients. However, as a consequence,
the prevalence of impairment and disability among survivors has
significantly increased. A substantial volume of longitudinal
observational follow-up data has now characterized the profound
impairments that survivors of critical illness experience for many years
following ICU discharge across multiple domains including physical,[1-4] cognitive,[5-7] psychological,[8, 9] and health-related quality of life.[10, 11] In addition, critical illness impacts on healthcare utilization and socioeconomic status[1, 12, 13] and can result in notable burden for family and caregivers.[14-16]
Recently, an international multi-disciplinary stakeholder consensus
assigned the term ‘post-intensive care syndrome’ to encompass the
multi-faceted sequelae following critical illness.
care unit-acquired weakness, stemming from the deleterious effects of
peripheral skeletal muscle dysfunction secondary to critical illness,
contributes to the persistent deficits observed in physical function.
Significant muscle wasting has been observed to occur early, rapidly,
and most severely in patients in multi-organ failure and is one example of how peripheral skeletal muscle architecture can be affected.
Rehabilitation is the cornerstone of management of post-critical illness morbidity,
and exercise-based interventions are advocated to target physical and
functional disability. Ideally, rehabilitation should be delivered in a
seamless pathway from ICU admission, transitioning to the ward, and
following hospital discharge.
In the ICU, physical rehabilitation is typically characterized by early
mobilization encompassing an increasingly functional hierarchy of
activities ranging from bed-based exercises, sitting over the edge of
the bed, standing, and ultimately walking. Adjunctive technologies
including electrical muscle stimulation and cycle ergometry may also be employed. The safety and feasibility of early mobilization have been well documented,[24-28]
and its efficacy has been examined in a number of systematic reviews
demonstrating significant benefit in health-related quality of life,
physical function, respiratory and peripheral skeletal muscle strength,
length of ICU and hospital stay, and duration of mechanical
However, the post-ICU discharge stages of recovery have been relatively
under-examined, and given the residual impairments in physical function
evident in ICU survivors, there is rationale for the ongoing delivery
of exercise-based rehabilitation interventions.
This paper provides an executive summary of a recent Cochrane Collaboration systematic review,
which synthesizes evidence for exercise-based rehabilitation initiated
after ICU discharge. The aim was to determine the effectiveness of
exercise-based rehabilitation, compared with usual care, on primary
outcomes of functional exercise capacity and health-related quality of
life in survivors of critical illness.
for review entry were randomized controlled trials, quasi-randomized
controlled trials, and controlled clinical trials that compared any
exercise intervention initiated after ICU discharge vs. any other
intervention or a control or ‘usual care’ programme in adult (≥18 years
of age) survivors of critical illness who had been mechanically
ventilated for 24 h or longer during an ICU admission.
outcomes were functional exercise capacity (with physical objective
and/or subjective assessment) and health-related quality of life
measured by reliable assessment scales. Secondary outcomes included
rates of withdrawal, adherence and mortality, loss to follow-up, and
strategies were based on a combination of controlled vocabulary and
free-text terms related to the population and intervention. The
following databases were searched from inception until 15 May 2014:
Cochrane Central Register of Controlled Trials, Ovid SP Medical
Literature Analysis and Retrieval System Online, Ovid SP Excerpta Medica
Database, and the Cumulative Index to Nursing and Allied Health
Literature. Searches were re-run in February 2015. Ongoing and studies
pending classification were identified for inclusion in the update of
the full review (scheduled 2017). We identified ongoing studies by using
Clinical Trials (www.clinicaltrials.gov) and Current Controlled Trial (www.controlled-trials.com.isrctn/)
registries and additionally searched the reference lists of included
studies and the personal libraries of the review authors for additional
potentially relevant studies. We contacted authors of studies where data
were only available in abstract form to determine full publication
Data collection and analysis
lead author (BC) initially screened results for de-duplication and
removal of non-relevant subject material. Subsequently, two review
authors (BC, and BO'N) independently screened firstly titles and
abstracts, and then full-text versions of potentially relevant studies,
and independently determined final eligibility by joint agreement by
using a bespoke standardized form. Two review authors (LG and LS)
independently extracted data pertaining to study design, participants,
trial characteristics, intervention detail, and outcomes. Original
authors were contacted for missing data. Two review authors (BB and LS)
independently assessed risk of bias by using criteria outlined by the
Cochrane Handbook for Systematic Reviews of Interventions.
Where a review author was the primary author of an included study (LS),
data extraction and risk of bias were conducted by a different review
Data management was performed by using RevMan, and
the GRADE approach was used to assess the quality of the total body of
evidence. Data were reported descriptively. Insufficient study numbers
and heterogeneity across those included, precluded meta-analyses,
subgroup and sensitivity analyses.
We identified 4298 results of which 276 underwent title and abstract screening (Figure 1).
Twenty two of these were reviewed in full-text format. Six studies were
identified as eligible for inclusion in the qualitative synthesis,
involving 483 participants.[35-40] Three studies were identified as ongoing[41-43] and a further three awaiting classification.[44-46]
Flow diagram of study selection.
Risk of bias was variable for all domains across all included trials (Figure 2).
Risk of performance bias was high in all studies. For remaining
domains, at least half of the studies demonstrated low risk of bias. One
study was at high risk of selection bias, attrition bias, and other
sources of bias. Risk of bias was unclear for the remaining studies
Cochrane Risk of Bias summary.
interventions in included studies were delivered on the ward in two
studies: both on the ward and in the community in one study and in the
community in three studies, and were of variable duration. Control group
participants in all included studies were documented as receiving
standard practice care for post-critical illness management, albeit
exact descriptions were limited (Table 1).Table 1. Summary of interventions evaluated in included studies
were unable to undertake meta-analyses of data due to variability in
study design, type and nature of interventions, outcome measures and
associated metrics, and data reporting across included studies and
therefore presented a narrative description of findings for individual
studies for each outcome.
All six studies assessed functional
exercise capacity. Overall quality of the evidence was very low.
Individually, three studies reported positive results in favour of the
intervention. Batterham et al. found a small short-term benefit in anaerobic threshold [mean difference (MD) 1.8 mL O2/kg/min, 95% confidence interval (CI) 0.4 to 3.2; P value = 0.02]. In a second study, both incremental (MD 4.7, 95% CI 1.69 to 7.75 W; P value = 0.003) and endurance (MD 4.12, 95% CI 0.68 to 7.56 min; P value = 0.021) exercise testing results were improved with intervention. Finally, self-reported physical function increased significantly following use of a rehabilitation manual (P value = 0.006). Remaining studies found no effect of the intervention.
two studies evaluated health-related quality of life, and neither study
reported differences between intervention and control groups.[35, 36]. Overall quality of the evidence was very low.
studies reported rates of withdrawal, which ranged from 0% to 26.5% in
control groups and from 8.2% to 27.6% in intervention groups.[35-37, 39]
The quality of evidence for the effect of the intervention on
withdrawal was low. Intervention adherence did not apply to control
participants, and only one study made some reference to adherence rates
in the intervention group,
and quality of evidence was very low. Quality of evidence for mortality
was low, with mortality reported by all studies and ranging from 0% to
18.8%. Loss to follow-up, also reported in all studies and with low
quality of evidence, ranged from 0% to 14% across all participants. Only
one non-mortality adverse event was reported across all participants in
all studies (a minor musculoskeletal injury), and the quality of the
evidence was low.
aim of this Cochrane Review was to evaluate the effectiveness of
exercise-based rehabilitation initiated after ICU discharge on
functional exercise capacity and health-related quality of life in
survivors of critical illness. We identified six completed and fully
published trials for inclusion in the current review and six further
pending trials that will be subsequently evaluated when the review is
updated, indicating an expanding evidence base for this clinical field.
Meta-analyses of findings were precluded due to quantity of data, and
wide variability in characteristics of interventions and metrics of
outcome measure selection and reporting, and hence, we were able to
report a qualitative description of findings only. Consequently, we were
unable to conclude the efficacy of post-ICU discharge exercise-based
rehabilitation on our selected outcomes. Most included studies failed to
show a significant difference between intervention and control groups.
Where significant differences were evident, these were noted only in
physiological outcomes following specific types of exercise training
programmes, and which were non-generalizable. Methodological variation
in intervention ‘dose’ and outcomes used for evaluating effectiveness
was considered contributing factors to the non-significant differences
seen between groups in the remaining studies.
The quality of the
evidence was inconsistent. For most domains, low risk of bias ranged
from 50% to 75%. All included studies demonstrated high risk of bias for
blinding on participants and trial personnel, although it is
acknowledged, such blinding in therapeutic rehabilitation trials can be
pragmatically challenging. Notably, several studies reporting
non-significant findings failed to meet intended sample size or were
intended as pilot, feasibility studies to provide data to inform
larger-scale trials; hence, these results could be attributable to type
II error. Examination of screening and enrolment rates highlighted the
challenges associated with recruitment into post-critical illness
was insufficient evidence to determine an overall effect on functional
exercise capacity or health-related quality of life of an exercise-based
intervention initiated after ICU discharge for survivors of critical
illness. The degree of heterogeneity across included studies precluded a
meta-analysis of data, and individual study findings were inconsistent
with regards a beneficial effect on functional exercise capacity. No
effect on health-related quality of life was reported. The
methodological rigour of included studies was variable with risk of bias
present in several domains. Results of ongoing studies, and those
awaiting classification, will contribute to a further update of this
Cochrane Collaboration systematic review. Future studies must address
methodological aspects of identifying the target population, optimum
dose of intervention, detailed characterization of usual care, and
standardization of outcomes and reporting to enhance methodological
rigour of investigations.
would like to thank Karen Hovhannisyan, Cochrane Search Trials
Co-ordinator, and Jane Cracknell, Managing Editor, Cochrane Anaesthesia,
Critical and Emergency Care Review Group (ACE), for their assistance
provided during the conduct and review of the original Cochrane
Collaboration review, and Anna Lee (content editor), Vibeke E Horstmann
(statistical editor), Tom J Overend, Sue Berney and Terri Hough (peer
reviewers), and Janet Wale (consumer editor) for the editorial advice
for the original review.
The Enhanced Recovery After Critical
Illness Programme Group additionally includes Stephen Brett, David
Griffith, Stephen Shepherd, Judith Merriweather, Nazir Lone, Simon
Baudouin, Stephen Bonner, Kathryn McDowell, Dorothy Wade, Natalie
Pattison, Danielle Bear, Sallie Lamb, Rebecca Cusack, Daniel F McAuley,
Robert Hatch, David Parkin, Mark Foster, Laura Price, Liesl Wandrag, and
The authors certify that they comply with the
ethical guidelines for authorship and publishing of the Journal of
Cachexia, Sarcopenia, and Muscle.
AD and NH are supported by the National Institute for Health Research
(NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS
Foundation Trust and King's College London. The views expressed are
those of the review author(s) and are not necessarily those of the NHS,
the NIHR or the Department of Health.
Conflict of interest
B.C. is lead author of one study awaiting classification, which may be included in a future update of the full review. L.S. is lead author of one included study.
L.S. did not extract data from this study nor check interpretation
against the study report. L.S. is also a co-author of one study awaiting
classification, which may be included in a future update of this review. B.O'N. is lead author of one currently ongoing study,
which may be included in a future update of this review. L.G., A.D.,
M.P.W.G.: none known. N.H. is senior author for one study awaiting
classification, which may be included in a future update of this review. T.S.W. is senior author for one included study.
T.S.W. did not extract data from this study nor check interpretation
against the study report. T.S.W. is also lead author for one study
awaiting classification, which may be included in a future update of this review. B.B. is co-author of a currently ongoing study, which may be included in a future update of the full review.