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ORIGINAL ARTICLE

The Impact of Time of Mobilization After Split


Thickness Skin Graft on Lower Extremity Wound
Healing—Systematic Review and Meta-analysis
Helene Retrouvey, MDCM*,†, Annie Wang, BSc‡,
Joseph Corkum, MD||,$, and Shahriar Shahrokhi, MD, FRCSC, FACS*,†

Following split-thickness skin grafting (STSG), surgeons have used different postoperative
care protocols. One area of contention is the timing of mobilization of the grafted area after
STSG. The aim of this systematic review and meta-analysis is to summarize the evidence for
timing of mobilization in the extremities after STSG. MedLine, Embase, and the Cochrane
Library were searched to conduct a systematic review and meta-analysis evaluating the
impact of early versus late mobilization after STSG in adult patients with wounds in the
upper extremity (UE) or lower extremity (LE). Outcomes evaluated were graft healing,
postoperative morbidity, and length of stay in hospital. A fixed-effect model was used to
calculate pooled odds ratio and mean difference with 95% confidence intervals (CI). A total
of seven full texts (five randomized trials and two observational studies) were included
in the analysis. All wounds were in the LE. Odds of graft loss, infection, and hematoma
were 0.55 (CI: 0.12–2.54), 1.66 (CI: 0.54–5.10), and 0.98 (CI: 0.25–3.85), respectively,
for early versus late mobilization (n = 2). Deconditioning was more common in the late
mobilization group (n = 3). Hospital length of stay was shorter in the early mobilization
group (n = 3). We conclude that early mobilization may be the preferred strategy for
patients treated with STSG to the LE as it provides good graft healing and prevents
morbidity. High-quality studies are needed to provide more robust recommendations
on mobilization in the LE. Studies are needed to provide evidence in the UE.

Systematic Review registration: Prospero CRD42017070990.

Different postoperative care protocols have been found results favoring early mobilization, suggesting
proposed to optimize the take of split-thickness skin that prolonged bed rest may increase postoperative
grafting (STSG) and to minimize complications. One risks related to patient immobility and contribute to
area of contention is the timing of mobilization of the higher healthcare costs associated with prolonged hos-
newly grafted area. In 1971, Bodenham et  al ques- pitalization.2–5 Despite these findings, the traditional
tioned the tradition of prolonged bed rest following approach of bed rest after STSG remains popular, as
STSG and found that while early mobilization did not this strategy is thought to optimize wound healing.2–8
facilitate “quicker” or “better” graft healing, avoiding The aim of this systematic review and meta-analysis
prolonged confinement in bed did prevent “lowering was to summarize the evidence for early versus late
of morale.”1 This article led to subsequent studies that mobilization of adult patients after STSG of the upper
extremities (UEs) and lower extremities (LEs). We
From the *Division of Plastic and Reconstructive Surgery, †Ross hypothesized that early mobilization results in similar
Tilley Burn Centre, Sunnybrook Health Sciences Centre, and wound healing outcomes but decreased morbidity.

Faculty of Medicine, University of Toronto, Ontario, Canada;
||
Division of Plastic and Reconstructive Surgery and $Queen
Elizabeth II Health Sciences Centre, Halifax Infirmary Site,
Dalhousie University, Halifax, Nova Scotia, Canada METHODS
Address correspondence to Helene Retrouvey, MDCM, Division of
Plastic and Reconstructive Surgery, University of Toronto, 149 This review followed guidance published by
College Street, Suite 508, ON M5T 1P5, Canada. Email: helene. the Centre for Reviews and Dissemination and
retrouvey@mail.utoronto.ca
the Cochrane Collaboration  and  the Preferred
© American Burn Association 2018. All rights reserved.
For permissions, please e-mail: journals.permissions@oup.com Reporting Items for Systematic Reviews and Meta-
doi:10.1093/jbcr/iry003 Analyses (PRISMA) guidelines.9–11 A  protocol
1
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for this systematic review was registered using the 3) blinding of participants and personnel, 4) blind-
International Prospective Register of Systematic ing of outcome assessment, 5) incomplete outcome
Reviews (PROSPERO CRD42017070990). data, 6) selective reporting, and 7) other biases. Each
domain was assessed as having a “low,” “unclear,” or
Study Eligibility Criteria “high” risk of bias. For our study, the EPOC RoB
The study population was defined as adults tool was modified by removing the domain of blind-
(>18 years old) with wounds in the UE or LE from ing of participants, as blinding of participants was not
any etiology treated with STSG. The intervention possible due to the nature of the intervention. On
and comparator were early versus late mobilization the other hand, the New Castle Ottawa Scale is used
after STSG. Early mobilization was defined as mo- to evaluate three domains in observational studies:
bilization prior to postoperative day (POD) 3, while 1) the selection of the study groups (maximum four
late mobilization was defined as postoperative bed stars), 2) the comparability of the groups (maximum
rest or immobilization until at least POD 4. The pri- two stars), and 3) the ascertainment of either the ex-
mary outcome evaluated was graft healing from 5 posure or outcome (maximum three stars). Each do-
to 7 days postoperatively. The secondary outcomes main is scored using a star system, with a maximum
were graft site pain, postoperative complications, of nine stars possible, which represents the lowest
and length of stay in hospital. Included study designs risk of bias in an observational study. Publication bias
consisted of randomized control trials (RCTs) or using a funnel plot could not be evaluated due to the
observational studies, whereas editorials, commen- small number of studies but is hypothesized to be
taries, letters, conference abstracts, dissertations, low or absent.
reviews, case reports, and case series were excluded. The Grades of Recommendation, Assessment,
Development and Evaluation (GRADE) approach
was used to score the quality of the evidence for each
Search Strategy
outcome.14–23 For the assessments of outcomes from
A comprehensive, electronic search strategy was pooled RCT data, evidence was downgraded from
used to identify studies indexed in MedLine, Embase, “high quality” if serious study limitations, indirect-
and Cochrane databases. The search strategy was ness of evidence, serious inconsistency, imprecision of
developed by a medical librarian in collaboration effect estimates, or publication biases were present.
with the first author (H.R.) and peer reviewed by a Data from the observational studies started at “low
second medical librarian. Articles were not restricted quality” and could be upgraded if appropriate.
based on language or year of publication. The search
strategy focused on 1)  skin grafts, 2)  mobilization,
and  3)  adult patients (search strategy in Appendix Data Extraction
1). Citations from key papers were hand searched Data extraction was performed using Microsoft
and added if relevant. The first 200 citations output- Excel (Office 2010; Microsoft Corporation,
ted by Google Scholar were reviewed and included Redmond, Washington, United States). The data ex-
if appropriate. All articles retrieved were independ- traction form was created by the first author (H.R.)
ently assessed by two reviewers (H.R. and A.W.): first with guidance from the Cochrane Data Collection
through title and abstract screen and then through Form.12 It was pilot tested with the first two stud-
full-text review. Disagreements were resolved through ies and modified based on identified discrepancies.
consensus or discussion with the senior author (S.S.). The key data extracted included study characteristics
(year of publication, study design, country of publi-
Quality Assessment cation, and sample size), study population character-
istics, wound characteristics (etiology of wound and
The quality of the included studies was independ-
location of wound), and outcomes of the study (graft
ently evaluated by two authors (H.R. and A.W.). The
healing, postoperative complications, and length of
two reviewers were not blinded to study authors,
stay in hospital). The number of events per group was
institution, or journal when performing quality
extracted for binary outcomes. For continuous out-
assessment.
comes, raw data for each group (mean and standard
Bias was evaluated using the Cochrane Effective
deviation or median and range) were extracted.
Practice and Organisation of Care (EPOC) RoB Tool
for randomized studies and the New Castle Ottawa
Scale for observational studies.12,13 The EPOC RoB Data Synthesis
tool is used to assess seven domains: 1)  random The extracted data were analyzed in a qualita-
sequence generation, 2)  allocation concealment, tive fashion for all studies. The RCTs were further

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Volume XX, Number XX Retrouvey et al  3

analyzed quantitatively through meta-analysis if het- Study Characteristics


erogeneity was low. The clinical assessment and I2 The seven eligible studies (five RCTs and two ob-
statistic were reviewed to determine study hetero- servational studies) were published between 1979 and
geneity. Fixed effects model were generated using 2014 (Table 1). Studies were published in Australia
Review Manager 5.3 (Version 5.3.5; Copenhagen: (n  =  1), England (n  =  3), New Zealand (n  =  1),
The Nordic Cochrane Centre, The Cochrane Sweden (n = 1), and the United States (n = 1). All
Collaboration, 2014)  to statistically compare out- studies evaluated outcomes after mobilization in
comes, with odds ratios presented for binary out- patients with LE STSG.7,8,24–28 The specific location
comes and mean differences for continuous data. of the wound was defined as LE (n  =  3), pretibial
Forrest plots were computed to present the results. (n = 2), shin (n = 1), and area below the inguinal lig-
ament (n = 1). Wound size varied between each study
RESULTS and is presented in Table 1. There were no included
studies that evaluated UE wounds. In all studies, the
The literature review process is shown in Figure 1 in grafted site was dressed using a conventional dressing
a Prisma diagram. The searches identified 4172 articles with splinting as needed if the graft crossed a joint.
of which 1108 duplicates were removed. The title and None of the included patients received negative pres-
abstract of the remaining 3064 articles were screened, sure wound therapy dressings. Early mobilization was
and 42 articles were deemed to be potentially relevant. defined as mobilization on the day of the operation or
A full-text review based on study design, study popu- the first day postoperatively (n = 5), the second POD
lation, and selection of comparator and intervention (n = 1), and prior to POD 3 (n = 1). Late mobiliza-
groups further eliminated 35 articles. The resulting tion was defined as mobilization postoperatively after
seven articles were included in the quantitative analysis. 4 days of bed rest (n = 2), on POD 5 (n = 1), POD

Figure 1. Prisma diagram.

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Table 1. Included study characteristics


Year of Country of Location of
Author publication Study design publication Patient age (y) wound Wound etiology Wound size

 Budny24 1993 RCT EnglandEM: 77.5 (47–93) pretibial – EM: 28.5 (6–99) cm3
LM: 74.2 (50–92) LM: 38.8 (2–99) cm3

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4  Retrouvey et al

 Gaze25 1979 Retrospective cohort England 55–89 shin – 3 × 4 cm to 10 × 16 cm


EM: 35.4 (SD: 16.4) EM: 3.56 (SD: 2.06) % TBSA
 Lorello26 2014 RCT United States LM: 43.6 (SD: 14.8) lower extremity Burn LM: 4.07 (SD: 4.18) % TBSA
Sharp trauma, blunt trauma, infection,
 Luczak8 2012 Retrospective cohort Australia EM: 42 LM: 55.7 lower limb burn, excision of lesion –
EM: 915 (210–2025) mm2
 Tallon27 2009 RCT New Zealand EM: 78.3 LM: 78.0 lower leg – LM: 716 (180–2250) mm2
Skin cancer, trauma, venous wound,
area below the arterial wound, diabetic wound,
 Wallenberg28 1999 RCT Sweden 69 (20–85) inguinal ligament erysipelas, unspecified –
 Wood7 1994 RCT England EM: 74.3 (SD: 14.2) pretibial — EM: 48.4 (SD: 40.8) cm2
LM: 73.3 (SD: 12.9) LM: 51.7 (SD: 37.5) cm2

Wound healing Wound evaluation


Author EM definition LM definition Dressing Sample size evaluation timing Other outcomes

 Budny POD 0–1 POD7 Conventional with below knee 61 Percent skin graft POD7 and 21 Any complication
plaster backslab in LM group EM: 21 take
LM: 40
30
EM: 16
 Gaze POD1 – Conventional LM: 14 – POD7 –
31

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Conventional with immobilization EM: 17
 Lorello POD1 POD5 splint for grafts crossing joints LM: 14 Percent graft loss POD5 –
48
Conventional with plaster of Paris EM: 25 Hematoma, infection,
 Luczak <POD3 POD4 backslab in 35 patients for 5 d LM: 23 Percent graft take POD5 deconditioning
42
EM: 18 Number of grafts
 Tallon POD2 POD7 Conventional LM: 24 loss POD7 Any complication
50 Healing of graft
EM: 25 using four
 Wallenberg POD1 POD4 Conventional LM: 25 codes POD14 –
 Wood POD1 POD10 Conventional 75 Percent graft take POD 7, 10, and 14 Date discharge,
EM: 36 complications
LM: 39
XXXX/XXXX 2018
Journal of Burn Care & Research

RCT, randomized controlled trials; EM, early mobilization; LM, late mobilization; %TBSA, percent total body surface area; POD, postoperative day.

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Volume XX, Number XX Retrouvey et al  5

7 (n = 2), POD 10 (n = 1), or unspecified (n = 1). Secondary Outcomes


Graft healing was evaluated at POD 5 (n = 2), POD Graft Pain. Graft pain was evaluated by one RCT
7 (n = 4), POD 10 (n = 1), POD 14 (n = 2), or 3 (Lorello et al).26 At rest, pain rated on a scale of 1
weeks postoperatively (n = 1). The total study sample to 10 was 1.3 (SD: 2.0) for the early group and 3.5
size varied between 30 and 75 patients, with 16 to 36 (SD: 3.1) for the late group (P = 0.02). With ambula-
patients in the early mobilization group and 14 to 39 tion, pain rating was 1.8 (SD: 2.3) in the early group
in the late mobilization group. versus 3.5 (SD: 2.9) in the late group (P = 0.08).26
Study quality as evaluated by the modified Local Complications. Infection and hematoma
Cochrane EPOC RoB Tool for RCTs and the New were the two local complications reported. There
Castle Ottawa Scale for observational studies is was no statistically significant difference in infection
presented in Tables 2 and 3.  All RCTs had bias, rate between early mobilization and late mobiliza-
with random sequence generation, allocation con- tion (2 RCTs24,27, 103 participants; OR: 1.66, 95%
cealment, and blinding of outcome being the most CI: 0.54–5.10; I2 = 0% and P = 0.61; Table 4 and
common sources of bias identified.7,24,26–28 The Figure 4). One observational study also reported this
quality of included observational studies was vari- outcome and found no difference between groups
able; Gaze et al scored three out of nine stars due (P = 0.22; Figure 4).8
to poor selection, comparability and outcome re- There was no statistically significant difference in
porting, whereas Luczak et  al scored nine out of hematoma rate between early mobilization and late
nine stars.8,25 mobilization (2 RCTs24,27, 103 participants; OR:
0.98, 95% CI: 0.25–3.85; I2  =  0% and P  =  0.97;
Primary Outcome Table 4 and Figure 4). One observational study by
Graft Healing. There was no statistically signifi- Luczak et  al reported no difference between these
cant difference in percent graft take between early comparator groups (P = 1; Figure 4).8 Quality of the
mobilization and late mobilization (2 RCTs7,24, 136 evidence presented in these RCTs was downgraded
participants, mean difference −2.16%; 95% con- to “low” due to bias and inconsistencies in outcome
fidence intervals [CI]: −9.05–4.72%; I2  =  0 and reporting.
P  =  0.56; Table  4 and Figure  2). An observational Systemic Complications. Deconditioning defined
study by Wallenberg et  al reported no difference by decreased ease of mobilization was reported by
at POD 14, with 80% in the early group and 88% two studies, including one observational study and
in the late group with primary healing of the graft one RCT. Luczak et  al defined deconditioning as
(P = 0.7).28 Quality of the RCT evidence was down- “delay of discharge after the immobilization period
graded to “moderate” due to the presence of bias secondary to poor mobility, requiring rehabilita-
(poor random sequence generation and the possi- tion.” Budny et al defined it as “diminished ease of
bility of allocation concealment bias). activity.”8,24 Quantitative analysis reveals lower rates
In addition, there was no statistically significant of deconditioning in patients treated with early mo-
difference in number of grafts lost (2 RCTs26,27, 73 bilization (Figure 5).8,24
participants, OR: 0.55, 95% CI: 0.12–2.54; I2 = 0% Three studies reported other systemic complica-
and P  =  0.86; Table  4 and Figure  3). Two obser- tions in a heterogenous manner that did not allow for
vational studies also evaluated this outcome and quantitative assessments, hence only qualitative anal-
found no difference between the comparator groups ysis is performed for this outcome. Budny et  al re-
(Figure 3).8,28 The quality of the RCT evidence was ported no systemic complications in the early group
graded as “moderate” due to sparce data. and one severe complication related to the heparin

Table 2. Modified Cochrane Effective Practice and Organisation of Care (EPOC) RoB Tool assessing bias for the five ran-
domized clinical trials
Adequate Incomplete Free of selective
sequence Allocation Blinding of outcome outcome Free of other
generation concealment outcome assessment reporting bias

Budny24 High High High Low Low Low


Lorello26 Unknown Unknown Low Low Low Low
Tallon27 Unknown Unknown Unknown Low Low Low
Wallenberg28 Low High Low Low Low Low
Wood7 Unknown Unknown High Unknown Low Low

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Figure 2. Forrest plot of results of meta-analysis of percent graft healed at POD7.

Figure 3. Forrest plot of quantitative analysis of graft loss at POD5-14.

Figure 4. Forrest plot of results of the quantitative analysis for local complications including infections and hematomas.

Figure 5. Forrest plot of the quantitative analysis for deconditioning.

Figure 6. Forrest plot of the quantitative analysis for length of stay in hospital.

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Table 3. New Castle Ottawa Scale for bias assessment for included in the review. The percent graft take and
the two observational studies the number of grafts lost were not statistically dif-
Selection Comparability Outcome Total ferent between the early and late groups in the LE
based on moderate-quality evidence.7,24,26,27 Graft
Gaze 25
** * 3/9
pain, both at rest and with ambulation, was improved
Luczak8 **** ** *** 9/9
in the early mobilization group, although this was
reported in only one study.26 The pooled odds for
local complications (infection or hematoma) demon-
administration (hematuria with diffuse intravascular
strated no statistical difference between early and late
coagulopathy) in the late group.24 Tallon et  al and
mobilization groups.24,27 No systemic complications
Wood et  al reported no systemic complications (ve-
related to the graft procedure were reported in either
nous thromboembolism or chest infections) in either
group.7,24,27 Deconditioning was more severe in the
group.7,27
late group as compared with the early mobilization
Length of Stay in Hospital. Four of the included
group. Lastly, length of stay tended to be lower in
studies discussed length of stay. These were not
the early mobilization group.7,24–26
meta-analyzed because of high clinical heterogeneity
Our findings are mostly consistent with the ex-
between studies, specifically different discharge proto-
isting literature. In fact, a meta-analysis published
cols and variable reporting of the length of stay out-
in 2012 evaluated graft take after STSG for pretibial
come. Lorello et al’s criteria for discharge consisted of
lacerations and found no difference in skin graft heal-
independent ambulation and ability to change dress-
ing between early mobilization and bed rest (OR:
ings at home.26 Budny et al and Wood et al allowed
0.74, 95% CI: 0.31–1.79).2 Since the publication of
patients in the early group to be discharged on the day
this 2012 meta-analysis, Lorello et  al published an
of the operation, whereas patients in the late group
RCT that found statistically significant lower rates
were hospitalized for the duration of their immobili-
of graft loss in the early mobilization group.26 Our
zation.7,24 Although Budney et al and Wood et al had
meta-analysis pooled this new data with the previous
similar discharge protocols, they had different mea-
literature, confirming the 2012 findings that no dif-
surements of the length of stay outcome. Budny et al
ference between the groups existed with regard to
captured overall length of stay, whereas Wood et al de-
wound healing and more comprehensively assessed
fined length of stay as the period following initiation
patient outcomes such as graft site pain, local, and
of mobilization.4,29
systemic complications as well as length of stay in
Quantitative analysis of these three RCTs suggests
hospital.
that length of stay is equivalent or shorter in patients
Our findings support the assertion that early mo-
treated with early mobilization (Figure  6).7,24,26
bilization of the LE does not impact wound healing
Gaze reported a shorter length of stay in the early
if appropriate wound bed preparation, proper sur-
mobilization group but did not specify the number
gical technique, and adequate wound dressing are
of days in each group.25 Quality of the evidence in
performed. Furthermore, as expected, confinement
these RCTs is “low” due to high heterogeneity and
of a patient to bed rest may lead to increased mor-
the presence of biases (poor allocation concealment
bidity, including deconditioning, systemic complica-
and poor blinding of outcome).
tions, and prolonged length of stay in hospital.
DISCUSSION This review is significant as it highlights a gap
in evidence with regard to the optimal postopera-
Seven articles describing LE STSG procedures and tive mobilization protocol for patients with UE
no articles describing UE STSG procedures were STSG, as no UE studies have been conducted to
date. Although some authors suggest that early UE

Table 4. Summary of meta-analysis findings


Number of Mean difference
Outcome studies I2 P-value (95% CI) Odds ratio (95% CI) P-value GRADE

Graft take 2 7,24


0 0.56 −2.16% (−9.05–4.72) 0.54 Moderate
Graft loss 226,27 0 0.86 0.55 (0.12–2.54) 0.44 Moderate
Infection 224,27 0 0.61 1.66 (0.54–5.10) 0.37 Low
Hematoma 224,27 0 0.97 0.98 (0.25–3.85) 0.98 Low

GRADE, Grades of Recommendation, Assessment, Development and Evaluation.

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motion is safe and prevents stiffness and contracture, care workers and tolerance of early mobilization by
no observational study or RCT has been performed patients would provide useful information prior to
to validate these claims.30,31 Furthermore, this meta- making recommendations on the use of this strategy.
analysis underscores the paucity of high-quality stud-
ies evaluating mobilization protocols in the LE.
This review has a number of limitations. First, CONCLUSION
studies included in the qualitative and the quantita-
tive analysis have small sample sizes ranging between This comprehensive summary combines the ev-
30 and 75 patients. Therefore, despite pooling of idence for early versus late mobilization of adult
the study results, our conclusions are based on small patients after STSG in the LEs. Graft healing was
sample sizes. Larger RCTs are needed to further con- found to be similar between interventions in the LE
firm our conclusions. The estimates presented in our based on moderate-quality evidence. Local complica-
meta-analysis can serve as a guide for sample size cal- tions were also similar based on low-quality evidence.
culations during the design of these future studies. Graft pain was decreased, deconditioning was pre-
Second, the studies included were published over a vented, and length of stay was shortened in the early
long period, between 1979 and 2014. Care provided mobilization group, based on low-quality evidence
to patients during this long time period is likely to and heterogenous study results. No studies evaluated
have changed over time. Third, wound evaluation the effect of mobilization in UE STSG. We conclude
was performed in a heterogenous manner, with dif- that early mobilization may be the preferred strategy
ferent metrics for wound evaluation conducted at for patients treated with STSG to the LE, as it pro-
varying time points. In fact, the included studies vides similar graft healing compared with late mobi-
evaluated wounds with criteria ranging from percent lization but prevents morbidity. High-quality studies
graft take, percent graft loss, number of grafts lost to are needed to evaluate the impact of mobilization on
categorizing wounds into four levels of healing. The UE STSG and to make stronger recommendations for
timing of these wound evaluations was even more LE STSG.
diverse, being performed at POD 5, POD 7, POD
10, 2 weeks postoperatively, or 3 weeks postopera-
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APPENDIX 1.  MEDLINE SEARCH STRATEGY (PERFORMED ON MAY 23, 2017)


# Searches Results

1 Skin transplantation/and graft*.af. 16,898


2 (skin* adj6 graft*).mp. 17,187
3 “split thickness”.mp. 2929
4 split skin graft.mp. 378
5 stsg.mp. 189
6 (skin* adj6 autograft*).mp. 524
7 1 or 2 or 3 or 4 or 5 or 6 24,483
8 Early ambulation/ 2487
9 ambulat*.mp. 149,346
10 (mobilis* or mobiliz*).mp. 68,444
11 exp Immobilization/ 25,674
12 immobili*.mp. 103,546
13 splint*.mp. 17,002
14 cast*.mp. 101,129
15 bed rest/ 3787
16 bed rest*.mp. 890
17 rest/ 15,668
18 rest???.mp. 269,961
19 exp walking/ 44,313
20 walk*.mp. 89,304
21 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 786,150
22 7 and 21 1302
23 exp animals/not (exp humans/ and exp animals/) 4,399,007
24 22 not 23 1146
limit 24 to (“all adult (19 plus years)” or “young adult (19 to 24 years)” or “adult (19 to 44 years)” or “young adult
and adult (19–24 and 19–44)” or “middle age (45 to 64 years)” or “middle aged (45 plus years)” or “all aged (65
25 and over)” or “aged (80 and over)”) 710
limit 24 to (“all infant (birth to 23 months)” or “all child (0 to 18 years)” or “newborn infant (birth to 1 month)”
or “infant (1 to 23 months)” or “preschool child (2 to 5 years)” or “child (6 to 12 years)” or “adolescent (13 to
26 18 years)”) 400
27 24 not 26 746
28 25 or 27 1012
29 remove duplicates from 28 998

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