Physiotherapy 104 (2018) 25–35

Systematic review

Active physiotherapy interventions following total knee

arthroplasty in the hospital and inpatient rehabilitation
settings: a systematic review and meta-analysis
Kate G. Henderson ∗ , Jason A. Wallis, David A. Snowdon
Eastern Health Physiotherapy Department, Box Hill Hospital, 8 Arnold Street Box Hill, VIC 3128, Australia

Abstract
Background Physiotherapy is a routine component of postoperative management following total knee arthroplasty (TKA). As the demand
for surgery increases it is vital that postoperative physiotherapy interventions are effective and efficient.
Objectives Determine the most beneficial active physiotherapy interventions in acute hospital and inpatient rehabilitation for improving pain,
activity, range of motion and reducing length of stay for adults who have undergone TKA.
Data sources Electronic databases MEDLINE, CINAHL, PUBMED and EMBASE.
Study eligibility criteria Randomised controlled trials investigating the effect of active physiotherapy interventions in the acute hospital or
inpatient rehabilitation setting for adults who have undergone TKA.
Study appraisal and synthesis methods Risk of bias for individual studies was assessed using the Physiotherapy Evidence Database (PEDro)
scale. Standardised Mean Differences (SMD) or Mean Differences (MD) and 95% confidence intervals were calculated and combined in
meta-analyses. Quality of meta-analyses was assessed using the Grades of Research, Assessment, Development and Evaluation approach.
Results Accelerated physiotherapy regimens were effective for reducing acute hospital length of stay (MD −3.50 days, 95% CI −5.70
to −1.30). Technology-assisted physiotherapy did not show any difference for activity (SMD −0.34, 95% CI −0.82 to 0.13). From high
quality individual studies pain, activity and range of motion improved with accelerated physiotherapy regimens and activity improved with
hydrotherapy.
Limitations Lack of blinding and small sample sizes across the included trials.
Conclusion After TKA, there is low level evidence that accelerated physiotherapy regimens can reduce acute hospital length of stay.
Systematic review registration number PROSPERO (Registration number CRD42014013414) http://www.crd.york.ac.uk/PROSPERO.
© 2017 Chartered Society of Physiotherapy. Published by Elsevier Ltd. All rights reserved.

Keywords: Total knee arthroplasty; Physiotherapy specialty; Physiotherapy techniques; Hydrotherapy; Rehabilitation

Introduction ple electing for TKA will continue to rise [3], consequently
placing an increasing burden on health care systems.
Total knee arthroplasty (TKA) is a cost effective inter- Physiotherapists play a role in the acute hospital and inpa-
vention for end-stage knee osteoarthritis, with demonstrable tient rehabilitation settings by facilitating independence in
benefits for improving pain, activity and quality of life [1,2]. transfers and ambulation, and achieving functional goals for
As the population ages, it is anticipated the number of peo- people after TKA. Despite trend to very early discharge after
TKA [4], the average hospital length of stay (LOS) fol-
lowing TKA is reported as 5.50 days (range 2.10 to 9.50
∗ Correspondence: Dandenong Hospital, Physiotherapy Department, days) in Australia [5] and 6.60 days in the United Kingdom
Allied Health Reception, 135 David Street, Dandenong, VIC 3175, Australia. [6]. It is therefore essential that physiotherapy interventions
Fax: +61 3 9554 9038. provided in the acute and inpatient rehabilitation settings
E-mail addresses: kate.henderson@monashhealth.org (K.G.
are worthwhile and efficient in producing these important
Henderson), jason.wallis@easternhealth.org.au (J.A. Wallis),
david.snowdon@easternhealth.org.au (D.A. Snowdon). patient outcomes, in order to further minimise LOS and health

https://doi.org/10.1016/j.physio.2017.01.002
0031-9406/© 2017 Chartered Society of Physiotherapy. Published by Elsevier Ltd. All rights reserved.
26 K.G. Henderson et al. / Physiotherapy 104 (2018) 25–35
care costs. However, there are currently no evidence-based
guidelines in these settings to advise the most effective phys-
iotherapy interventions following TKA, including the type,
timing, and dosage of interventions [3,7].
Two systematic reviews [8,9] investigating TKA rehabil-
itation in the outpatient setting have been conducted. The
first, a systematic review [8] and meta-analysis of six tri-
als demonstrated small to moderate benefits for activity
with physiotherapy interventions involving mostly functional
exercises (SMD 0.33, 95% CI 0.07 to 0.58). The second
systematic review [9] of 19 trials concluded physiotherapy
should comprise strengthening and intensive functional exer-
cises delivered via land-based or aquatic programs.
Therefore, the research question of this systematic review
was what are the most beneficial active physiotherapy
interventions and regimens in acute hospital and inpatient
rehabilitation for improving pain, activity, range of motion
(ROM) and reducing LOS for adults who have undergone
TKA?
Method
Search strategy
The electronic databases MEDLINE, CINAHL,
PUBMED and EMBASE were searched from earliest
available time until July 2014. The concepts of population,
intervention, outcome and design were combined with the
‘AND’ operator. Population was defined as participants
who had a TKA. Intervention was defined as any form
of active physiotherapy in an acute hospital or inpatient
rehabilitation setting following TKA. Primary outcomes
were pain, activity and LOS. Knee ROM was the secondary
outcome. The design was randomised controlled trials.
Synonyms were searched for each concept and combined
with the ‘OR’ operator (Appendix A).
All articles were imported to bibliographic software
and screened for duplicates. Two reviewers independently
screened title and abstract of each article using predetermined
eligibility criteria. Discrepancies were resolved via discus-
sion. Full text copies were retrieved for articles that were
not excluded based on title and abstract and eligibility crite-
ria applied by the same reviewers. Disagreements unable to
be resolved via discussion were taken to a third reviewer to
achieve consensus. Reference lists of included articles were
hand-searched and citation tracking applied using Google
Scholar to identify any further articles for inclusion.
Eligibility criteria
The review included randomised trials if at least 85%
of the sample had a primary TKA due to osteoarthritis, the
outcomes included at least one of pain, activity or LOS, and
the experimental intervention involved any form of active
physiotherapy intervention, such as strengthening or active
ROM, performed in an acute hospital or inpatient rehabil-
itation setting. Studies investigating the effects of passive
interventions such as continuous passive motion or manual
therapies, could only be included if the passive modality was
not the primary difference between the therapy provided to
experimental and control groups. Studies that included neu-
romuscular electrical stimulation were considered passive
if the participant was not required to produce a voluntary
contraction of the muscle prior to the device delivering elec-
trical stimulation. The comparison intervention was standard
physiotherapy, defined as usual physiotherapy management
in acute hospital or rehabilitation, or another form of active
physiotherapy intervention. Studies that compared two or
more different regimens of exercise were also included to
investigate the ideal intensity and postoperative commence-
ment of exercise. Studies were excluded if the samples
included participants who had a unicompartmental knee
arthroplasty or revision TKA. Studies that included partic-
ipants with total hip arthroplasty and TKA and did not report
outcomes separately were also ineligible. Studies written in
languages other than English were excluded.
Data collection and analysis
A predesigned data collection form was used to extract
data on participants, setting, interventions, outcome mea-
sures and results. Investigators were contacted to confirm
data where required. SMDs and 95% confidence intervals
were calculated from postintervention means and standard
deviations for pain and activity outcomes. Mean differences
(MD) and 95% confidence intervals were calculated for LOS
and ROM outcomes. P-values were used to estimate stan-
dard deviations where these data were not reported. Mean
values were extrapolated from graphs if not reported else-
where in the article. Medians were converted to means
where required [10]. Effect sizes of <0.20 were considered
small, 0.50 considered moderate and >0.80 considered a
large effect size [11]. A negative SMD or MD indicated
that the outcome favoured the intervention group for activ-
ity, pain and LOS measures. A positive MD indicated that
the outcome measure favoured the intervention group in
ROM. Studies were grouped according to similar interven-
tions for analysis purposes. ‘Accelerated physiotherapy’ was
defined as physiotherapy intervention commencing within
24 hours of surgery, and occurring more than 24 hours prior
to standard care. ‘Technology-assisted physiotherapy’ was
defined as physiotherapy intervention delivered via use of a
robotic training system or computer-based electronic device.
Meta-analyses were conducted if two or more studies were
clinically homogeneous, where common population, inter-
vention and outcome measures were used. Meta-analyses
were performed using the inverse variance method and ran-
dom effects model [12]. Studies that did not demonstrate
sufficient clinical homogeneity to be combined in meta-
analyses were reported in tables and descriptive format.
 K.G. Henderson et al. / Physiotherapy 104 (2018) 25–35 27

Risk of bias

The risk of bias of each study was assessed by two

reviewers independently using the Physiotherapy Evidence
Database (PEDro) scale [13]. The 11 items of the scale were
scored ‘yes’ or ‘no’. The maximum score is 10 as the first
item of the scale is not counted. A score of six or more was
considered high quality [14]. Results of the reviewers were
compared and discrepancies resolved via discussion using the
PEDro operational definitions. Agreement between assessors
was calculated using kappa coefficient.
The quality of evidence of the meta-analyses performed
was assessed using the Grades of Research, Assessment,
Development and Evaluation (GRADE) approach [15]. This
approach specifies that a body of evidence can be downgraded
from high quality evidence, based on four criteria: (1) risk
of bias across studies (downgrade if average PEDro score
was <6 for studies included in the meta-analysis); (2) incon-
sistency of results (downgrade if I2 > 50% indicating high
statistical heterogeneity between the studies); (3) indirectness
of results (downgrade if indirect comparisons between inter-
ventions or outcomes); (4) imprecision of results (downgrade
if large confidence intervals, defined as > 0.80 for standard-
ised mean differences (SMD) or mean differences (MD)).

Results

Flow of studies through the review

The database search yielded 1019 trials. The eligibility

criteria were applied to title and abstract, excluding 978 trials.
Full texts of the remaining forty-one trials were retrieved. The
eligibility criteria were then applied to full texts. Twelve trials
fulfilled the inclusion criteria. No trials were identified from
reference lists of included articles or citation tracking. Two
trials reported results using the same data and were therefore
considered one trial in this review. The final yield was 11
trials (Fig. 1).
Fig. 1. Flow of studies through the review.
Participants
From 11 randomised controlled trials [16–27] 1197 par-
ticipants had undergone TKA, 98% due to osteoarthritis and
2% due to trauma and other pathologies. The mean age of
participants was 69 years, 67% were women and the average
body mass index was 30 kg/m2 from available data.

Characteristics of studies Interventions

Risk of bias
Eight trials were rated as having a low risk of bias and
the average PEDro score across all trials was 6/10 (range 3
to 8) [interrater agreement κ = 0.86 (95% CI 0.76 to 0.95)]
(Table 1). Most adhered to the items of random allocation,
between group comparison, measure of variability and spec-
ification of eligibility criteria. None adhered to the ‘blinded
participants’ or ‘blinded therapists’ items, which is to be
expected given the interventions in all trials involved exer-
cise. Eight used concealed allocation and four used blinded
assessors. Seven demonstrated baseline comparability. Seven
obtained at least one key outcome for more than 85% of
participants and seven analysed data according to intention-
to-treat.
The majority of trials were conducted in the acute hospital
setting (n = 8) and remaining trials conducted in the inpatient
rehabilitation setting (n = 3). The most common interven-
tion was accelerated physiotherapy compared with standard
physiotherapy in three trials [18,20,21]. Similarly another
trial [24] examined early hydrotherapy vs late hydrother-
apy protocols. One trial [26] investigated hydrotherapy vs
land-based physiotherapy. Three trials [16,17,25,27] investi-
gated the effects of the prescription of an additional exercise
(ergometer cycling, slide-board exercises and eccentric ham-
string exercises) to standard physiotherapy. One trial [22]
investigated twice daily physiotherapy vs once daily phys-
iotherapy. Two trials [19,23] compared technology-assisted
physiotherapy with standard physiotherapy. See Table 2 for
details of the interventions.
28 K.G. Henderson et al. / Physiotherapy 104 (2018) 25–35

Table 1
PEDro scores of included studies.
Study Random Concealed Groups Participant Therapist Assessor <15% Intention- Between- Point Total
alloca- alloca- similar blind- blind- blind- dropouts to-treat group estimate (0 to
tion tion at ing ing ing analy- differ- and vari- 10)
base- sis ence ability
line reported reported
Beaupre et al. 2001 [27] & Y Y Y N N Y Y Y Y Y 8
Davies et al. 2003 [17]
Codine et al. 2004 [16] Y N N N N N N N Y Y 3
den Hertog et al. 2012 [18] Y Y Y N N N Y Y Y Y 7
Eisermann et al. 2004 [19] Y N Y N N N N N Y Y 4
Labraca et al. 2011 [20] Y Y N N N Y Y N Y Y 6
Larsen et al. 2008 [21] Y Y N N N N Y Y Y Y 6
Lenssen et al. 2006 [22] Y Y Y N N Y Y Y Y Y 8
Li et al. 2014 [23] Y N N N N N N N Y Y 3
Liebs et al. 2010 [25] Y Y Y N N N Y Y Y Y 7
Liebs et al. 2012 [24] Y Y Y N N N Y Y Y Y 7
Rahmann et al. 2009 [26] Y Y Y N N Y N Y Y Y 7

Outcomes A high quality individual trial [24] comparing early com-

The most common outcomes to measure pain and activity
included Western Ontario and McMaster Universities Arthri-
tis Index (WOMAC) (n = 6 trials), Bodily Pain and Physical
Function subscales of Short Form 36 Health Survey (SF-
36) (n = 3 trials), Knee Society Score (KSS) (n = 3 trials) and
Visual Analogue Scale (VAS) (n = 2 trials). LOS was mea-
sured in seven trials and knee ROM was measured in six
trials.
Effect of interventions
Hydrotherapy vs land-based physiotherapy
A high quality individual trial [26] investigated the
effect of two different hydrotherapy interventions combined
with standard physiotherapy vs standard physiotherapy and
additional land-based therapy. Both hydrotherapy groups
demonstrated a statistically significant improvement in activ-
ity compared to the standard physiotherapy and additional
land-based physiotherapy group at day 14 postoperatively,
however neither demonstrated any difference for LOS
(Table 3). Knee ROM outcomes were not separated from total
hip arthroplasty data and therefore could not be analysed.
Accelerated physiotherapy vs standard physiotherapy
Meta-analysis of three trials with 447 participants pro-
vided low quality evidence that accelerated physiotherapy
compared to standard physiotherapy was effective for reduc-
ing acute hospital LOS (MD −3.50 days, 95% CI −5.70 to
−1.30) (Fig. 2, Table 4). Meta-analysis of activity was unable
to be performed due to differences in reporting methods.
One high quality individual trial [18] demonstrated improved
activity at 5 to 7 days, 6 weeks and 3 months postoperatively.
Another high quality individual trial [20] did not provide
sufficient data to determine the effect on activity. One high
quality trial [20] demonstrated a significant improvement in
pain and knee ROM at time of discharge from acute hospital.
mencing hydrotherapy to late commencing hydrotherapy did
not demonstrate any differences for pain or activity from 3 to
24 months postoperatively (Table 3).
Technology-assisted physiotherapy vs standard
physiotherapy
Meta-analysis of two trials with 196 participants provided
very low quality evidence that technology-assisted physio-
therapy compared to standard physiotherapy did not show any
difference for activity approximately one month following
TKA (SMD −0.34, 95% CI −0.82 to 0.13) (Fig. 3, Table 4).
The two individual low quality trials [19,23] did not report
outcomes of pain. The one trial [19] that reported LOS and
knee ROM provided insufficient data for analysis (Table 3).
Standard physiotherapy and an additional exercise vs
standard physiotherapy
Three trials investigating the effect of specific phys-
iotherapy exercises in addition to standard physiotherapy
[16,17,25,27] vs standard physiotherapy alone could not be
combined in meta-analysis due to heterogeneity. None of
these trials, two high quality [17,25,27] and one low quality
[16], demonstrated any significant difference for measures
of pain, activity or LOS. One high quality individual trial
[17,27] did not demonstrate any significant differences in
knee ROM. A lesser quality individual trial [16] demon-
strated an improvement in knee extension ROM in favour
of the standard physiotherapy group day 10 postoperatively,
however no significant differences in knee ROM at day 30
postoperatively (Table 3).
Twice daily physiotherapy vs once daily physiotherapy
A high quality individual trial [22] of twice daily physio-
therapy vs once daily physiotherapy did not demonstrate any
 K.G. Henderson et al. / Physiotherapy 104 (2018) 25–35 29

Table 2
Summary of included studies.
Study Participants Setting Intervention Comparison Outcome Follow-up
measures
Beaupre et al. Exp (n = 40), Acute Slide-board Exs + standard Standard PT: Pain = WOMAC 3 mo
2001 [27] mean age 68 yrs, hospital PT: D1 sit out of bed. D2 (pain), SF-36 (BP) 6 mo
Davies et al. 50% female, D2 additional Kn ROM commence walking. D3 Activity = WOMAC
2003 [17] OA = 95%. slide-board Exs to Pt’s walking in parallel bars or (function), SF-36
Con (n = 40), tolerance. with gait aid, Kn ROM (PF)
mean age 69 yrs, Dosage: minimum of slide-board Exs & quads ROM = active
30% female, 2 × 10 minutes sessions in strength Exs. D4 SLR & stair Flex/Ext
OA = 90%. addition to standard PT. climbing. Ice applied before LOS = days
& after Exs.
Dosage: 30 minutes Ex
sessions.
Codine et al. Exp (n = 30), Inpatient Eccentric hams + standard PT: Standard PT: Activity = KSS D40
2004 [16] mean age 75 yrs, rehabilita- Submaximal eccentric Kn mobilisation (function & knee)
53% female. tion isokinetic strength Exs (10◦ (manual + CPM), isometric ROM = active
Con (n = 30), of movement per seconds). strengthening of Kn muscle Flex/Ext
mean age 71 yrs, Monitored with groups, proprioceptive
70% female. dynamometer. Ice applied enhancement, walking Exs.
after Exs.
Dosage: 15 minutes 5 days/w,
for 3 w.
den Hertog Exp (n = 74), Acute Accelerated pathway: Standard pathway: Activity = WOMAC D5 to 7
et al. 2012 mean age 67 yrs, hospital First mobilisation D0. Stair First mobilisation D2. Exs: (total), AKSS D15 to 23
[18] 69% female, mean climbing commenced D2. walking, passive Flex/Ext, LL LOS = days 6w
BMI 31, Exs: as per standard pathway. muscle strengthening, 3 mo
OA = 97%. Use of positive messages “yes respiratory training.
Con (n = 73), you can” & comparison of Type: daily 1 hour individual
mean age 68 yrs, progress to fellow Pts. PT sessions.
73% female, mean Type: daily 2 hours PT Discharge planning: occurred
BMI 30, sessions, focus on ADLs in a when Pt felt ready, Pts not
OA = 99%. living room environment. informed of intended LOS.
Discharge planning: Pts
informed discharge scheduled
for D6.
Eisermann Exp (n = 68), Inpatient Computer-assisted Standard PT: Activity = FIM, Discharge
et al. 2004 mean age 70 yrs, rehabilita- PT + standard PT: Exs performed with or HSS, FFbH 6 mo
[19] 66% female, tion Exs (as per standard PT) without equipment (such as ROM = Flexa
22 days since provided to Pt via “Training balls or rubber bands). LOS = days
surgery. Assistant” device (includes 30 minutes group PT sessions
Con (n = 68), movement descriptions, video with 8 to 10 Pts.
mean age 70 yrs, animations & feedback Dosage: 3 to 5 days/w for
79% female, devices—movement sensors duration of inpatient rehab
24 days since & webcams). stay (3 to 4 w).
surgery. Dosage: 30 minutes session
instructing use of device.
Then as per standard PT.
Labraca et al. Exp (n = 138), Acute Early rehabilitation: Standard PT: Activity = Barthel Discharge
2011 [20] mean age 66 yrs, hospital Commenced within 24 hours Remained at rest in bed or Index, Tinetti
73% female. of surgery. chair for first 24 hours with Balancea
Con (n = 135), D1: Kn ROM 0 to 40◦ , no treatment. Commenced 48 Pain = VAS
mean age 66 yrs, isometric quads/hams. D2: to 72 hours postop. Then as ROM = Flex/Ext
81% female. transfer chair, standing & per early rehabilitation. LOS = days
walking, seated ROM, Dosage: daily 45 minutes
isotonic muscle Exs. D3: sessions.
progressed gait aid, walking,
ADLs & D2 Exs. D4:
increased walking distance,
strength Exs, stair climbing &
ADL practice.
Dosage: daily 45 minutes
sessions.
30 K.G. Henderson et al. / Physiotherapy 104 (2018) 25–35

Table 2 (Continued)
Study Participants Setting Intervention Comparison Outcome Follow-up
measures
Larsen et al. Exp (n = 15), Acute Accelerated pathway: Standard pathway: LOS = days Discharge
2008 [21] mean age 68 yrs, hospital Information session 1 w Admitted day before
60% female, pre-op. Admitted day of surgery. D1: Exs in bed,
OA = 100%. surgery. D0 first first mobilisation. Days
Con (n = 12), mobilisation. D1: 4 hours following: Pt in hospital
mean age 67 yrs, out of bed doing PT & OT gown, mobilisation
58% female, training. Days following: increased to meet
OA = 92%. 8 hours mobilisation per discharge criteria, care
day, Pt wears own clothes, given in response to Pt’s
work towards set daily needs.
goals.
Lenssen et al. Exp (n = 21), Acute Twice daily PT: Once daily PT: Pain = WOMAC D4
2006 [22] mean age 70 yrs, hospital Exs: active/passive Kn Exs: as per twice daily PT (pain), VAS 6w
71% female. mobilisation, quads group. Activity = WOMAC 3 mo
Con (n = 22), strengthening, functional Dosage: 1 × 20 minutes (function), KSS
mean age 67 yrs, Exs (supine to sit to stand daily PT sessions. (function)
77% female. transfers, walking, stair ROM = active &
climbing). passive Flex/Ext
Dosage: 2 × 20 minutes LOS = days
daily PT sessions.
Li et al. 2014 Exp (n = 30). Acute Robot-assisted Standard PT: Activity = HSS, 1w
[23] Con (n = 30). hospital rehab + standard PT: CPM 1 hour daily. Berg balance, 2w
CPM & NMES as per Peri-knee NMES 6 minute walking 1 mo
standard PT. 30 minutes 2× daily. distance 3 mo
Early exoskeleton rehab Isometric quads & hams, 6 mo
with robotic assistance ankle pumps, bed-aided 12 mo
(simulates normal standing & walker-aided
walking in a partial gait training 30 minutes
weight support condition, 2× daily.
speed 45 to Dosage: 5 days/w, for 2 w.
70 m/minutes).
30 minutes 2× daily.
Dosage: 5 days/w, for 2 w.
Liebs et al. Exp (n = 85), Inpatient Ergometer Standard PT: Pain = WOMAC 3 mo
2010 [25] mean age 70 yrs, rehabilita- cycling + standard PT: Exs to improve ROM, (pain) 6 mo
73% female, mean tion Bicycle ergometer muscle strength, venous Activity = WOMAC 12 mo
BMI 30, commenced 2 w postop. return, balance, (function), SF-36 2 yrs
OA = 98%. Initial session with PT, coordination & gait. (PCS), Lequesne
Con (n = 74), minimum resistance to Practice of ADLs, Hip and Knee
mean age 70 yrs, target muscular transfers, walking, stairs Score
70% female, mean coordination, & uneven surfaces.
BMI 29, proprioception & ROM Dosage: daily for 3 w.
OA = 100%. (not cardio).
Dosage: 3 days/w for 3 w.
Liebs et al. Exp (n = 87), Acute Early aquatic therapy: Late aquatic therapy: Pain = WOMAC 3 mo
2012 [24] mean age 69, 70% hospital Aquatic Exs commenced Aquatic therapy Exs (pain) 6 mo
female, mean BMI D6. Wound covered with commenced D14 (when Activity = WOMAC 12 mo
29, OA = 99%. waterproof dressing wound healed). (function), SF-36 2 yrs
Con (n = 98), (Op-site). Aquatic Exs: (PCS), Lequesne
mean age 71, 73% Aquatic & land Exs as per proprioception, Hip and Knee
female, mean BMI late aquatic therapy coordination & strength Score
29, OA = 98%. group. with floats & kickboards.
Dosage: 30 minutes Land Exs: ROM, muscle
3 days/w, 5 w postop. strength, balance,
coordination & gait,
ADLs, transfers, walking,
stairs.
Dosage: 30 minutes
3 days/w, 5 w postop.
 K.G. Henderson et al. / Physiotherapy 104 (2018) 25–35 31

Table 2 (Continued)
Study Participants Setting Intervention Comparison Outcome Follow-up
measures
Rahmann Exp 1 (n = 18), Acute Aquatic PT (Exp1) + standard Additional ward PT + standard Activity = WOMAC D14
et al. 2009 mean age 69 yrs, hospital ward PT: ward PT: (total), 10MWT 6 mo
[26] 44% female, mean Fast pace (80 to 88 bpm). Standard ward PT: as clinically ROM = Flexa
BMI 28, TKA Standing at xiphisternal level determined by treating PT for LOS = days
(n = 8). 30% WB (progressed to waist first 3 days postop. D4 onwards
Exp 2 (n = 19), level 50% WB) walking forward, once daily (standard
mean age 69, 63% back & side, Hip orthopaedic clinical pathway).
female, mean BMI Abd/Add/Flex/Ext, squats, heel Additional ward PT Exs:
28, TKA (n = 7). raises, lunges on step, step-ups, transfer, gait & stairs practice
Con (n = 17), mean bilateral arm swing. On plinth circulation & deep breathing
age 70, 80% scissors, Hip Ext, kicking, Exs. Bed Exs inner range
female, mean BMI cycling. Seated Kn Flex/Ext. quads, active Hip & Kn Flex,
29, TKA (n = 12). Dosage: 40 minutes daily D4 bridging, SLR. Seated active
until discharge. Kn Flex/Ext. Standing Hip
Water exercise (Exp2) + standard Abd, Hip/Kn Flex/Ext,
ward PT: mini-squats, heel raises, calf
Slow pace (50 to 58 bpm). stretches, Hams curls.
Standing at neck level 10% WB Dosage: 40 minutes daily D4
walking forwards, single leg until discharge.
balance non-operative leg, march
on spot, hand claps, elbow
Flex/Ext. On plinth scissors,
cycling, Kn Flex/Ext. Supine
(neck, Hip & Kn floats) lateral
trunk Flex, sculling, lumbar spine
mobilisations.
Dosage: 40 minutes daily D4
until discharge.
Exp = experimental, Con = control, yrs = years, OA = osteoarthritis, PT = physiotherapy or physical therapy, Exs = exercises, D = postoperative day, Kn = knee,
Ext = extension, Flex = flexion, Pt = patient, x = times, postop = postoperative, ROM = range of motion, Quads = quadriceps, reps = repetitions, SLR = straight
leg raise, LOS = length of stay, WOMAC = Western Ontario and McMaster Universities Arthritis Index, SF-36 = Short Form 36 Health Survey (BP = Bodily
Pain, PF = Physical Function, PCS = Physical Health Composite Score), Hams = hamstrings, mo = months, w = weeks, CPM = continuous passive motion,
KSS = Knee Society Score, BMI = body mass index, ADLs = activities of daily living, LL = lower limb, AKSS = American Knee Society Score, FIM = Functional
Independence Measure, HSS = Hospital for Special Surgery Score, FFbH = Hanover Functional Ability Questionnaire, PF = plantarflexion, DF = dorsiflexion,
VAS = Visual Analogue Scale, pre-op = pre-operative, OT = Occupational Therapy, m = metres, NMES = neuromuscular electrical stimulation, bpm = beats per
minute, Abd = Abduction, Add = Adduction, WB = weight bearing, 10MWT = 10 Metre Walk Test.
a Unable to report postintervention scores, SMD or MD due to insufficient data provided by authors.

Fig. 2. MD (95% CI) of effect of accelerated physiotherapy vs standard physiotherapy on acute hospital length of stay (days).

Fig. 3. SMD (95% CI) of effect of technology-assisted physiotherapy vs standard physiotherapy on activity one month postoperatively.
32 K.G. Henderson et al. / Physiotherapy 104 (2018) 25–35

Table 3
Postintervention scores and SMD (95% CI) between groups for activity and pain or MD (95% CI) between groups for length of stay and range of motion.
Outcome Study Groups Difference between groups

Hydrotherapy and Land-based Hydrotherapy and land-based

land-based physiotherapy physiotherapy minus
physiotherapy land-based physiotherapy
Activity Rahmann et al. 2009 37.10 (6.60) 48.40 (5) −1.91 (−3.02 to −0.80)$
[26]—Aquatic PT
Rahmann et al. 2009 32.40 (7.10) 48.40 (5) −2.62 (-3.94 to −1.30)$
[26]—Water exercise
Length of stay Rahmann et al. 2009 7.40 (1.60) 8.30 (1.90) −0.90 (−2.07 to 0.27)
[26]—Aquatic PT
Rahmann et al. 2009 8.10 (1.70) 8.30 (1.90) −0.20 (−1.38 to 0.98)
[26]—Water exercise

Early hydrotherapy Late hydrotherapy Early minus late

hydrotherapy
Activity Liebs et al. 2012 [24] 21.90 (19.40) 26.80 (20.70) −0.24 (−0.55 to 0.06)
Pain Liebs et al. 2012 [24] 20.10 (20) 22.50 (21.70) −0.11 (−0.42 to 0.19)

Accelerated Standard Accelerated physiotherapy

physiotherapy physiotherapy minus standard physiotherapy
Activity den Hertog et al. 2012 [18] 1.85 (1.20) 2.35 (1.20) −0.41 (−0.74 to −0.09)$
Pain Labraca et al. 2011 [20] 3.01 (2.35) 5.36 (2.50) −0.96 (−1.21 to −0.71)$
ROM—Flexion Labraca et al. 2011 [20] 88.11 (2.35) 71.82 (16.81) 16.29 (13.43 to 19.15)$
ROM— Extension Labraca et al. 2011 [20] 0.68 (1.84) 2.80 (1.10) −2.12 (−2.48 to −1.76)$

Twice daily Once daily Twice daily minus once daily

physiotherapy physiotherapy physiotherapy
Activity Lenssen et al. 2006 [22] 73.40 (14.90) 78 (11.30) −0.34 (−0.95 to 0.26)
Length of stay Lenssen et al. 2006 [22] 4.10 (0.90) 4.50 (1.30) −0.40 (−1.07 to 0.27)
Pain Lenssen et al. 2006 [22] 15.20 (3) 16.20 (2.40) −0.36 (−0.97 to 0.24)
ROM—Flexion Lenssen et al. 2006 [22] 103.70 (13) 105.10 (15) −1.40 (−9.78 to 6.98)
ROM—Extension Lenssen et al. 2006 [22] 5.30 (5.10) 8.30 (5.50) −3.00 (−6.17 to 0.17)

Additional specific Standard Additional specific exercise

exercise and standard physiotherapy and standard physiotherapy
physiotherapy minus standard physiotherapy
Activity Beaupre et al. 2001 [27] 72 (17) 72 (17) 0.00 (−0.48 to 0.48)
Codine et al. 2004 [16] 70.71 (16.85) 66.92 (15.26) 0.23 (−0.28 to 0.74)
Liebs et al. 2010 [25] 25.40 (17.70) 24.90 (16.90) 0.03 (−0.31 to 0.37)
Length of stay Davies et al. 2003 [17] 7.20 (2.60) 7.50 (3) −0.30 (−1.53 to 0.93)
Pain Beaupre et al. 2001 [27] 75 (19) 73 (18) 0.11 (−0.38 to 0.59)
Liebs et al. 2010 [25] 22.40 (17.70) 23.80 (20.50) −0.07 (−0.41 to 0.27)
ROM—Flexion Beaupre et al. 2001 [27] 96 (14) 91 (11) 5.00 (−1.44 to 11.44)
Codine et al. 2004 [16] 102.32 (7.75) 104.64 (7.80) −2.32 (−6.25 to 1.61)
ROM—Extension Beaupre et al. 2001 [27] 4 (3) 3 (6) 1.00 (−1.36 to 3.36)
Codine et al. 2004 [16] 2.67 (3.72) 1.25 (2.20) 1.42 (−0.13 to 2.97)
Statistically significant (p < 0.05) difference between intervention and control groups.
$ Significant difference between intervention and control groups.

significant difference for measures of pain, activity, hospital
LOS or knee ROM (Table 3).
Discussion
The results of this systematic review demonstrate acceler-
ated physiotherapy regimens, where the patient is mobilised
within 24-hours of surgery, are the most beneficial active
physiotherapy interventions during the acute hospital stay
following TKA. Activity and ROM were significantly
improved whilst LOS was reduced by 3.50 days. Physio-
therapy regimens involving the addition of specific exercises
did not demonstrate significant improvements in patient out-
comes. Most of the impairment-based trials were conducted
more than ten years ago, whilst the most recently conducted
trials are focused towards activity-based interventions with
early mobilisation. This is likely a reflection of the shift in
physiotherapy management of this patient population, where
the focus is on achieving functional independence early
 K.G. Henderson et al. / Physiotherapy 104 (2018) 25–35
Table 4
Summary of meta-analyses.
Intervention No. of trials No. of Outcome
participants
Accelerated 3[18,20,21] 447 No. of days (length of Discharge
physiotherapy hospital stay)
Technology-assisted 2[19,23] 196 Hospital for special
physiotherapy surgery score
GRADE = GRADE working group grades of evidence (see reasons for downgrade).
a Reasons for downgrade: statistical heterogeneity (I2 = 75%), large confidence interval (>0.80).
b Reasons for downgrade: all trials rated lesser quality (PEDro <6), statistical heterogeneity (I2 = 58%), indirectness of results (different types of technology),
large confidence interval (>0.80).
postoperatively to facilitate rehabilitation in the home envi-
ronment. Therefore, our findings indicate that physiotherapy
interventions post-TKA should be focused on activity-based
interventions in the inpatient setting.
A defining aspect of physiotherapy management across
the three trials [18,20,21] that investigated accelerated phys-
iotherapy was mobilisation within 24 hours of surgery. This
is consistent with the results of a systematic review that
demonstrated early mobilisation of patients following hip and
knee arthroplasty reduced acute hospital LOS by 1.80 days
[28]. The findings of our meta-analysis must not be solely
attributed to the physiotherapy intervention alone, as the tri-
als were primarily investigating the effect of an ‘enhanced
recovery’ pathway which entails a multidisciplinary and
multimodal approach. Previous literature also attributes the
success of enhanced recovery pathways being due to the pro-
cess itself rather than the individual interventions it comprises
[29]. Implementation of a pathway requires an organised and
logistical framework, standardised procedures and a mul-
tidisciplinary approach to all aspects of patient care [30].
Consequently, this would necessitate a significant change to
practice for all disciplines involved. Enhanced recovery path-
ways have been shown to improve patient satisfaction [31]
and cost efficiency as a result of a reduced hospital LOS [32].
Therefore implementation of an enhanced recovery path-
way incorporating an early mobilisation regimen would be
a worthwhile change to practice and investment of resources.
There is limited literature to direct physiotherapists as to
which types of exercise are most beneficial or considered
‘best practice’ following TKA. For this reason current phys-
iotherapy regimens have been described as being based on
traditional practices rather than scientific evidence [7]. Three
studies in this review [16,17,25,27] investigated the effect of
an additional specific exercise to standard physiotherapy. The
additional exercises in all three trials were directed towards
addressing impairment, such as joint ROM [17,25,27], pro-
prioception [25] and muscle function [16,25], however the
results did not demonstrate improvements in knee ROM,
pain, activity or LOS. Given that knee ROM one year post-
operatively correlates directly with activity and functional
restriction [33], addressing ROM impairment appears to be a
necessary component of exercise regimens following TKA.
However further research is required to determine whether
33
Timeframe SMD (95% MD (95% CI), Quality of evidence
CI), I2 I2 (GRADE)
−3.47 [−5.67, Lowa
−1.27], 75%
1 month post- −0.34 [−0.82, Very lowb
operatively 0.13], 58%
this is sufficiently addressed through functional retraining
and early mobilisation regimes, or if specific ROM exercises
are required.
A high quality trial [26] in this review suggests that
hydrotherapy combined with land-based therapy may be
more effective in improving activity than land-based therapy
alone. This may be explained by a number of theories, such as
reduced joint loading due to buoyancy [34] or changes to the
cardiovascular and autonomic nervous systems [35], result-
ing in reduced pain and lower limb oedema. Hydrotherapy has
been found to be safe to commence as early as day four pos-
torthopaedic surgery, with no increase in wound infection risk
provided an appropriate water-proof dressing is applied [36].
With the mean hospital LOS reported as 5 to 6 days [5,6], it
would be impractical to implement hydrotherapy in the acute
setting. Therefore patients who are transferred to a rehabil-
itation facility would be more likely to benefit from early
hydrotherapy. Further high quality research is required to
establish if early commencement of hydrotherapy can reduce
LOS in the inpatient rehabilitation setting.
Currently the evidence for technology-assisted physio-
therapy interventions in enhancing patient activity following
TKA does not justify its utilisation in the acute hospital and
rehabilitation settings compared to standard physiotherapy
[19,23]. The use of technology in rehabilitation of people
with TKA has also been investigated in the community set-
ting. A recent randomised controlled trial concluded that
the use of Nintendo Wii Fit [37] for balance retraining was
equally effective in improving patient outcomes as standard
community-based physiotherapy interventions. However, to
justify the additional expense of technology-assisted phys-
iotherapy interventions it is pivotal that the intervention
produces improved outcomes for patients when compared
to standard physiotherapy.
The majority of trials included in this systematic review
had a low risk of bias. However there was a consistent lack of
participant and therapist blinding across the trials, therefore
introducing a high risk of performance and detection bias.
This has been identified as a common difficulty when eval-
uating the effects of non-pharmacological treatments [38].
Additionally, two of the 11 trials contained less than 50 par-
ticipants, which is a concern because small sample sizes lead
to low statistical power [39] and inflated confidence intervals
34 K.G. Henderson et al. / Physiotherapy 104 (2018) 25–35
Key messages
• The most important role of physiotherapists in the
management of patients following TKA is facilitating
mobilisation within 48 hours of surgery, as part of an
accelerated pathway.
• Physiotherapy in the hospital and inpatient rehabili-
tation settings following TKA should be focused on
activity-based interventions.
• Further research is required to establish the effect of
impairment-based interventions in the hospital and
inpatient rehabilitation settings following TKA.
around the effect sizes. Due to insufficient reporting only five
of the 11 trials [18–21,23] were able to be included in meta-
analyses, and each meta-analysis contained only two to three
trials. There was also a degree of subjectivity in determining if
the trials were sufficiently homogenous in their interventions
to combine in meta-analysis. However decisions were made
with careful clinical consideration and analysis conducted
with the more conservative random effects model. Further-
more, the meta-analyses were rated low in quality, therefore
reducing confidence in these findings.
The most beneficial active physiotherapy intervention
in the acute hospital setting following TKA is accelerated
physiotherapy regimens involving early mobilisation, most
commonly delivered as a component of an enhanced recovery
pathway. This is a clinically significant finding, with hospital
LOS reduced by an average of 3.50 days.
Acknowledgement
Thank you to Nick Taylor for his guidance and contribu-
tion to this systematic review.
Conflict of interest: None declared.
Appendix A.
Medline Search Strategy (n = 252)
Population
S1. (MH “Arthroplasty, Replacement, Knee”) OR “knee
arthroplasty” S2. (MH “Arthroplasty, Replacement, Knee”)
OR “knee replacement”
S3 = S1OR S2
Intervention
S4. “physiotherapy*” S5. (MH “Physical Therapy”) OR
“physical therap*” S6. (MH “Exercise”) OR “exercise*”
S7. “mobilis*” S8. “mobiliz*” S9. “ambulat*” S10. (MH
“Walking”) OR “walk*” S11. (MH “Electric Stimulation”)
OR “electrical stimulation” S12. (MH “Hydrotherapy”)
OR “hydrotherapy*” S13. (MH “Aquatic Exercises”) OR
“aquatic therap*” S14. (MH “Pilates”) OR “Pilates” S15.
“balance training” S16. (MH “Biofeedback”) OR “biofeed-
back” S17. (MH “Resistance Training”) OR “resist* training”
S18. “strength training”
S19 = S4 OR S5 OR S6 OR S7 OR S8 OR S9 OR S10
OR S11 OR S12 OR S13 OR S14 OR S15 OR S16 OR S17
OR S18
Outcome
S20. (MH “Pain”) OR “pain” S21. “function*” S22. (MH
“Length of Stay”) OR “length of stay”
S23 = S20OR S21 OR S22
Design
S24. (MH “Randomised Controlled Trials”) OR “ran-
domis*” S25. “randomiz*” S26. “control* trial”
S27 = S24OR S25 OR S26
S28 = S3AND S19 AND S23 AND S27
References
[1] Skou ST, Roos EM, Laursen MB, Rathleff MS, Arendt-Nielsen L,
Simonsen O, et al. A randomized, controlled trial of total knee replace-
ment. N Engl J Med 2015;373(17):1597–606.
[2] Carr AJ, Robertsson O, Graves S, Price AJ, Arden NK, Judge A, et al.
Knee replacement. Lancet 2012;379(9823):1331–40.
[3] Naylor J, Harmer A, Fransen M, Crosbie J, Innes L. Status of phys-
iotherapy rehabilitation after total knee replacement in Australia.
Physiother Res Int 2006;11(1):35–47.
[4] Sibia US, King PJ, MacDonald JH. Who is not a candidate for a 1-day
hospital-based total knee arthroplasty. J Arthroplasty 2016;32(1):16–9.
[5] National Health Performance Authority. Hospital performance:
length of stay in public hospitals in 2011–12 [Internet]. Sydney
(AU): National Health Performance Authority; 2013 [Nov.]. Avail-
able from: http://www.myhospitals.gov.au/docs/default-source/our
-report-pdfs/HP LengthOfStay 2011-12 RPT.pdf.
[6] National Joint Registry. National joint registry for England
and Wales. 7th annual report 2010 [Internet]. Hertford-
shire, UK: National Joint Registry; 2010 [Sep.]. Available
from: http://www.njrcentre.org.uk/njrcentre/portals/0/njr%207th
%20annual%20report%202010.pdf.
[7] Bandholm T, Kehlet H. Physiotherapy exercise after fast-track total
hip and knee arthroplasty: time for reconsideration? Arch Phys Med
Rehabil 2012;93(7):1292–4.
[8] Minns Lowe CJ, Barker KL, Dewey M, Sackley CM. Effectiveness of
physiotherapy exercise after knee arthroplasty for osteoarthritis: sys-
tematic review and meta-analysis of randomised controlled trials. BMJ
2007;335(7624):812.
[9] Pozzi F, Snyder-Mackler L, Zeni J. Physical exercise after knee arthro-
plasty: a systematic review of controlled trials. Eur J Phys Rehabil Med
2013;49(6):877–92.
[10] Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance
from the median, range, and the size of a sample. BMC Med Res
Methodol 2005;5:13.
[11] Cohen J. Statistical power analysis for the behavioural sciences. 2nd
ed. Hillsdale, NJ: Lawrence Erlbaum Associates; 1988.
[12] Review Manager (RevMan). 5.3 ed. Copenhagen: The Nordic Cochrane
Centre: The Cochrane Collaboration; 2014.
[13] de Morton NA. The PEDro scale is a valid measure of the methodolog-
ical quality of clinical trials: a demographic study. Aust J Physiother
2009;55(2):129–33.
 K.G. Henderson et al. / Physiotherapy 104 (2018) 25–35
[14] Hahne AJ, Ford JJ, McMeeken JM. Conservative management of lum-
bar disc herniation with associated radiculopathy: a systematic review.
Spine 2010;35(11):E488–504.
[15] Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S, et al.
Grading quality of evidence and strength of recommendations. BMJ
2004;328(7454):1490.
[16] Codine P, Dellemme Y, Denis-Laroque F, Herisson C. The use of
low velocity submaximal eccentric contractions of the hamstring for
recovery of full extension after total knee replacement: a randomized
controlled study. Isokinet Exerc Sci 2004;12(3):215–8.
[17] Davies DM, Johnston DWC, Beaupre LA, Lier DA. Effect of adjunctive
range-of-motion therapy after primary total knee arthroplasty on the use
of health services after hospital discharge. Can J Surg 2003;46(1):30–6.
[18] den Hertog A, Gliesche K, Timm J, Mühlbauer B, Zebrowski S.
Pathway-controlled fast-track rehabilitation after total knee arthro-
plasty: a randomized prospective clinical study evaluating the recovery
pattern, drug consumption, and length of stay. Arch Orthop Trauma
Surg 2012;132(8):1153–63.
[19] Eisermann U, Haase I, Kladny B. Computer-aided multimedia
training in orthopedic rehabilitation. Am J Phys Med Rehabil
2004;83(9):670–80.
[20] Labraca NS, Castro-Sanchez AM, Mataran-Penarrocha GA, Arroyo-
Morales M, Sanchez-Joya Mdel M, Moreno-Lorenzo C. Benefits of
starting rehabilitation within 24 hours of primary total knee arthro-
plasty: randomized clinical trial. Clin Rehabil 2011;25(6):557–66.
[21] Larsen K, Sorensen OG, Hansen TB, Thomsen PB, Soballe K. Accel-
erated perioperative care and rehabilitation intervention for hip and
knee replacement is effective: a randomized clinical trial involving 87
patients with 3 months of follow-up. Acta Orthop 2008;79(2):149–59.
[22] Lenssen AF, Crijns YHF, Waltjé EMH, van Steyn MJA, Geesink RJT,
van den Brandt PA, et al. Efficiency of immediate postoperative inpa-
tient physical therapy following total knee arthroplasty: an RCT. BMC
Musculoskelet Disord 2006;7:71.
[23] Li J, Wu T, Xu Z, Gu X. A pilot study of post-total knee replacement
gait rehabilitation using lower limbs robot-assisted training system. Eur
J Orthop Surg Traumatol 2014;24(2):203–8.
[24] Liebs TR, Herzberg W, Rther W, Haasters J, Russlies M, Hassenpflug
J. Multicenter randomized controlled trial comparing early versus late
aquatic therapy after total hip or knee arthroplasty. Arch Phys Med
Rehabil 2012;93(2):192–9.
[25] Liebs TR, Herzberg W, Ruther W, Haasters J, Russlies M, Hassenpflug
J. Ergometer cycling after hip or knee replacement surgery: a random-
ized controlled trial. J Bone Joint Surg Am 2010;92(4):814–22.
[26] Rahmann AE, Brauer SG, Nitz JC. A specific inpatient aquatic physio-
therapy program improves strength after total hip or knee replacement
Available online at www.sciencedirect.com
ScienceDirect
35
surgery: a randomized controlled trial. Arch Phys Med Rehabil
2009;90(5):745–55.
[27] Beaupre LA, Davies DM, Jones CA, Cinats JG. Exercise combined
with continuous passive motion or slider board therapy compared with
exercise only: a randomized controlled trial of patients following total
knee arthroplasty. Phys Ther 2001;81(4):1029–37.
[28] Guerra ML, Singh PJ, Taylor NF. Early mobilization of patients who
have had a hip or knee joint replacement reduces length of stay in
hospital: a systematic review. Clin Rehabil 2014;29(9):844–54.
[29] Antrobus JD, Bryson GL. Enhanced recovery for arthroplasty: good for
the patient or good for the hospital? Can J Anaesth 2011;58(10):891–4.
[30] Wainwright T, Middleton R. An orthopaedic enhanced recovery path-
way. Curr Anaesth Crit Care 2010;21(3):114–20.
[31] Husted H, Holm G, Jacobsen S. Predictors of length of stay and patient
satisfaction after hip and knee replacement surgery: fast-track experi-
ence in 712 patients. Acta Orthop 2008;79(2):168–73.
[32] Lovald ST, Ong KL, Malkani AL, Lau EC, Schmier JK, Kurtz SM,
et al. Complications, mortality, and costs for outpatient and short-stay
total knee arthroplasty patients in comparison to standard-stay patients.
J Arthroplasty 2014;29(3):510–5.
[33] Devers BN, Conditt MA, Jamieson ML, Driscoll MD, Noble
PC, Parsley BS. Does greater knee flexion increase patient func-
tion and satisfaction after total knee arthroplasty? J Arthroplasty
2011;26(2):178–86.
[34] Hinman RS, Heywood SE, Day AR. Aquatic physical therapy for hip
and knee osteoarthritis: results of a single-blind randomized controlled
trial. Phys Ther 2007;87(1):32–43.
[35] Becker BE, Hildenbrand K, Whitcomb RK, Sanders JP. Biophysiologic
effects of warm water immersion. IJARE 2009;3(1):24–37.
[36] Villalta EM, Peiris CL. Early aquatic physical therapy improves func-
tion and does not increase risk of wound-related adverse events for
adults after orthopedic surgery: a systematic review and meta-analysis.
Arch Phys Med Rehabil 2013;94(1):138–48.
[37] Fung V, Ho A, Shaffer J, Chung E, Gomez M. Use of Nintendo Wii Fit
in the rehabilitation of outpatients following total knee replacement:
a preliminary randomised controlled trial. Physiotherapy 2012;98(3):
183–8.
[38] Boutron I, Tubach F, Giraudeau B, Ravaud P. Blinding was judged more
difficult to achieve and maintain in nonpharmacologic than pharmaco-
logic trials. J Clin Epidemiol 2004;57(6):543–50.
[39] Button KS, Ioannidis JPA, Mokrysz C, Nosek BA, Flint J, Robin-
son ESJ, et al. Power failure: why small sample size undermines the
reliability of neuroscience. Nat Rev Neurosci 2013;14(5):365–76.