Physical Therapy in Sport 49 (2021) 243e249

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Physical Therapy in Sport

journal homepage: www.elsevier.com/ptsp

Review Article

Effectiveness of cryotherapy on pain intensity, swelling, range of

motion, function and recurrence in acute ankle sprain: A systematic
review of randomized controlled trials
Júlio Pascoal Miranda a, Whesley Tanor Silva a, Hytalo Jesus Silva b,
Rodrigo Oliveira Mascarenhas a, Vinícius Cunha Oliveira c, *
a
Department of Physiotherapy, Universidade Federal dos Vales do Jequitinhonha e Mucuri (UFVJM), Diamantina, Brazil
b
Postgraduate Program in Health Sciences, Universidade Federal dos Vales do Jequitinhonha e Mucuri, Diamantina, Brazil
c
Postgraduate Program in Rehabilitation and Functional Performance, Postgraduate Program in Health Sciences, Universidade Federal dos Vales do
Jequitinhonha e Mucuri (UFVJM), Diamantina, Brazil

a r t i c l e i n f o a b s t r a c t

Article history: Objective: Investigate effectiveness of cryotherapy on pain intensity, swelling, range of motion, function
Received 8 February 2021 and recurrence in acute ankle sprain.
Received in revised form Methods: Searches were conducted on six databases for randomized or quasi-randomized controlled
17 March 2021
trials (RCTs) evaluating effectiveness of cryotherapy for pain intensity, swelling, range of motion, function
Accepted 21 March 2021
and recurrence in acute ankle sprain. Selection of trials, data extraction and methodological quality
assessment of included trials were conducted independently by two reviewers with discrepancies
Keywords:
resolved by a third reviewer. Estimates were presented as mean differences (MDs) with 95% confidence
Acute ankle sprain
Cryotherapy
intervals (CIs). The quality of the evidence was assessed using the Grading of Recommendations
Systematic review Assessment (GRADE) approach.
Results: Two RCTs with high risk of bias were included. Both evaluated the additional effects of cryo-
therapy, comparing cryotherapy combined with other intervention versus other intervention stand-
alone. Uncertain evidence shows that cryotherapy does not enhance effects of other intervention on
swelling (MD ¼ 6.0; 95%CI: 0.5 to 12.5), pain intensity (MD ¼ 0.03; 95%CI: 0.34 to 0.28) and range of
motion (p > 0.05).
Conclusions: Current literature lacks evidence supporting the use of cryotherapy on management of
acute ankle sprain. There is an urgent call for larger high-quality randomized controlled trials.
© 2021 Elsevier Ltd. All rights reserved.

1. Introduction
Ankle sprain is a common condition in the general population
and athletes (Gribble et al., 2016). The ankle sprain incidence is
estimated in seven sprains per 1000 expositions in athletes, being
higher in young women (bib_Doherty_et_al_2014,Doherty et al.,
* Corresponding author. Postgraduate Program in Rehabilitation and Functional
Performance Universidade Federal dos Vales do Jequitinhonha e Mucuri (UFVJM),
Campus JK - Rodovia MGT 367 e Km 583, nº 5000. Bairro Alto da Jacuba, CEP 39100-
000, Diamantina, Brazil.
E-mail addresses: juliopascoal09@gmail.com (J.P. Miranda), whesleytanor@
gmail.com (W.T. Silva), hytalo-silva@hotmail.com (H.J. Silva), rdmasc@gmail.com
(R.O. Mascarenhas), vcunhaoliveira@gmail.com, vinicius.oliveira@ufvjm.edu.br
(V.C. Oliveira).
2014). After a new episode of ankle sprain, there is a high fre-
quency of chronic ankle instability and recurrence (Gribble et al.,
2016). Moreover, it is a musculoskeletal injury that causes direct
(expenses with medical consultations and medicines) and indirect
costs (absence from work, reducing productivity) (Gribble et al.,
2016). Effective therapies to improve pain intensity, swelling,
range of motion and decrease recurrence are important for this
health condition.
Available treatment options after an acute ankle sprain comprise
cryotherapy (Bleakley et al., 2010; Van Dijk, 1999), surgical treat-
ment (Doherty, Bleakley, Delahunt, & Holden, 2017) joint mobili-
zation (Cosby, Koroch, Grindstaff, Parente, & Hertel, 2011),
kinesiotherapy (Bleakley et al., 2010; Cleland et al., 2013), brace
(Beynnon, Renstro € m, Haugh, Uh, & Barker, 2006), acupuncture
(Doherty et al., 2017), among others. Cryotherapy has often been

https://doi.org/10.1016/j.ptsp.2021.03.011
1466-853X/© 2021 Elsevier Ltd. All rights reserved.
J.P. Miranda, W.T. Silva, H.J. Silva et al.
recommended by clinical practice guidelines and used by health
professionals in acute ankle sprain management because it has low
cost, easy application, and is considered potentially effective in
clinical practice settings (Doherty et al., 2017; Van Dijk, 1999;
Vuurberg et al., 2018). However, current evidence supporting
cryotherapy is still unclear.
Previous systematic reviews (Bleakley, McDonough, &
MacAuley, 2004; bib_van_den_Bekerom_et_al_2012,van den
Bekerom et al., 2012; Doherty et al., 2017) that investigated the
efficacy of cryotherapy in acute ankle sprain, included trials
without appropriate comparator to isolate effects of therapies (i.e.,
placebo, sham, waiting list or no intervention) or to investigate
whether cryotherapy enhances effects of other intervention (i.e.,
cryotherapy combined with other active intervention compared
with the other active intervention stand-alone). Besides, these re-
views had methodological limitations that could have impacted on
the estimates, which in some cases rendered them misleading (e.g.,
unclear inclusion criteria for the population of interest, lack of
heterogeneity investigation and inclusion of non-randomized
controlled trials). Thus, a new systematic review addressing these
issues is necessary to inform clinicians and patients about current
quality of the evidence for the effectiveness of cryotherapy in
management of acute ankle sprain. Our systematic review aims to
investigate the effectiveness of cryotherapy on pain intensity,
swelling, range of motion, function and recurrence in people with
an acute episode of ankle sprain.
2. Methods
2.1. Study design
This systematic review of randomized or quasi-randomized
controlled trials is reported following the PRISMA checklist
(Liberati et al., 2009) and some stages were conducted according to
the Cochrane recommendations (Higgins et al., 2020). Protocol was
prospectively registered in PROSPERO (CRD42020166411) and
Open Science Framework (https://osf.io/x6p23) (Miranda, Silva,
Mascarenhas, & Oliveira, 2020).
2.2. Eligibility criteria
We included trials that investigated the efficacy of cryotherapy
in people of both sexes, regardless of age, from any health care
setting, diagnosed with a new episode of ankle sprain, with dura-
tion of the injury up to seven days
(bib_Bleakley_et_al_2007,Bleakley et al., 2007; van Den Bekerom
et al., 2016). Cryotherapy was considered any conservative inter-
vention which includes low temperature components such as the
combination of protection, rest, ice, compression and elevation
(PRICE) and rest, ice, compression and elevation (RICE) (Bleakley
et al., 2007; Hing, Lopes, Hume, & Reid, 2011), protection, opti-
mum load, ice, compression and elevation (POLICE) (Salim, Umar, &
Shaharudin, 2018), ice pack therapy (Bleakley, McDonough, &
MacAuley, 2006; bib_Enwemeka_et_al_2002,Enwemeka et al.,
2002), whole body immersion therapy (Banfi, Lombardi,
Colombini, & Melegati, 2010). The comparators of interest to
investigate the isolated effect of cryotherapy were no intervention,
waiting list, placebo or sham. In addition, we included trials that
evaluated whether combination of cryotherapy with other active
intervention could enhance effects of the other investigated active
intervention stand-alone. Our outcomes of interest were pain in-
tensity, swelling, function, range of motion and recurrence assessed
using any valid instrument such as Visual Analog Scale - VAS
(Bleakley et al., 2007) and Numerical Rating Scales - NRS (Cohen
et al., 2017) - for pain intensity; volumetry
244
Physical Therapy in Sport 49 (2021) 243e249
(bib_Nunes_et_al_2015,Nunes et al., 2015), perimeter and the figure
of eight technique for swelling (Bleakley et al., 2007); Lower Ex-
tremity Functional Scale - LEFS (Bleakley et al., 2010), Foot & Ankle
Disability Index - FADI (Cosby et al., 2011), American Orthopaedic
Foot & Ankle Society - AOFAS (bib_Prado_et_al_2014,Prado et al.,
2014), Foot and Ankle Outcome Score - FAOS (Brison et al., 2016)
for function; goniometry (Weerasekara, Tennakoon, & Suraweera,
2016), and weight bearing lunge test (Gogate, Satpute, & Hall,
2020) for range of motion; and self-reported occurrence for
recurrence (Hupperets, Verhagen, & Van Mechelen, 2009).
2.3. Search strategy and study selection
Search strategies were conducted in MEDLINE, COCHRANE,
EMBASE, AMED, PSYCINFO and PEDRO, without language or date
restrictions, up to January 25th, 2021. Search terms were related to
“randomized controlled trials”, “ankle sprain” and “cryotherapy”.
Detailed search strategy was presented in Appendix 1. In addition,
we hand searched identified systematic reviews published in the
field for potentially relevant full texts. After searches, retrieved
references were exported to an Endnote® file and duplicates were
removed. Then, two independent reviewers (JPM and WTS)
screened titles and abstracts and assessed potential full texts. Trials
fulfilling our eligibility criteria were included in our review.
Between-reviewer discrepancies were resolved by a third reviewer
(VCO).
2.4. Data extraction
Two independent reviewers (JPM and WTS) extracted charac-
teristics and outcome data from the included trials and any dis-
crepancies was resolved by a third reviewer (VCO). Characteristics
extracted from trials included: study design; source of participants;
age; description of cryotherapy and control groups; outcomes; in-
strument measurements; and time points. For our outcomes of
interest, we extracted post-intervention means (first option) or
within-group mean changes over time, standard deviations (SDs)
and sample sizes for each of our groups of interest to investigate
effects at short-, medium- and long-term. Short-term effects were
considered follow-up up three months after baseline, medium-
term effects were considered follow-up over three months but
less than twelve months after baseline, and long-term effects were
considered follow-up of at least twelve months after baseline. If
more than one-time point was available within the same follow-up
period, the one closer to the end of the intervention was consid-
ered. When outcome data was not reported, authors were con-
tacted to provide the non-reported data. When authors did not
respond, we imputed mean and SD from individual scores, p-value
and sample size. When contacted authors did not answer or im-
putations were not possible, the trial was excluded from the
quantitative analysis. All procedures followed recommended
methods (Higgins et al., 2020; Wan, Wang, Liu, & Tong, 2014).
2.5. Risk of bias assessment
Two independent reviewers (JPM and WTS) assessed method-
ological quality of included trials using the 0e10 PEDro scale
(http://www.pedro.org.au/) (bib_Macedo_et_al_2010,Macedo et al.,
2010). A third reviewer (VCO) resolved between-reviewer dis-
crepancies. When available, we used scores already rated on the
PEDro database.
2.6. Data analysis
Planned meta-analysis using a random-effects model was not
J.P. Miranda, W.T. Silva, H.J. Silva et al.
possible because of the small number of included trials. Mean dif-
ferences (MDs) with 95% confidence intervals (CIs) were presented.
All analyses were conducted using the Comprehensive Meta-
analysis software, version 2.2.04 (Biostat, Englewood, NJ).
Two independent reviewers (JPM and WTS) assessed the quality
of the current evidence using the Grading of Recommendations
Assessment (GRADE) approach (Balshem et al., 2011; Guyatt et al.,
2008). According to the four-level GRADE system, evidence may
range from high to very-low quality, with low levels indicating that
future high-quality trials are likely to change estimated effects. In
the current review, evidence began from high quality and was
downgraded in one point for each of the following issues: serious
imprecision when analyzed sample less than 400 (Mueller,
Montori, Bassler, Koenig, & Guyatt, 2007); serious risk of bias
when more than 25% of the analyzed participants were from trials
with a high risk of bias (i.e., PEDro score less than 6 out of 10) (Foley,
Teasell, Bhogal, & Speechley, 2003); and serious inconsistency of
results when I2 statistics was higher than 50% or when pooling was
not possible (Higgins et al., 2020). Publication bias was not assessed
Fig. 1. Flow of studies through the review. *Articles could be excluded for more than one reason; RCT: randomized controlled trial.
245
Physical Therapy in Sport 49 (2021) 243e249
because of the small number of included trials, i.e., less than ten
trials (Guyatt et al., 2011; Ioannidis & Trikalinos, 2007). Between-
reviewer discrepancies were resolved by a third reviewer (VCO).
We planned subgroup analyzes to investigate the impact of
different types/dosages of cryotherapy and of different character-
istics of participants. Besides, sensitivity analyzes were planned to
investigate whether high risk of bias impacted on the estimates. For
subgroup and sensitivity analyzes, we intended to use meta-
regression, if it was possible (i.e., at least 10 trials analyzed);
otherwise, qualitative analysis could have been used, following
recommendations (Higgins et al., 2020).
3. Results
We retrieved 377 records from our searches, 134 duplicates
were removed, and the remaining 243 titles and abstracts were
screened. Then, 19 potential full texts were assessed and two ran-
domized controlled trials were included (Laba & Roestenburg,
1989; Sloan, Hain, & Pownall, 1989). Flow of studies in the review
J.P. Miranda, W.T. Silva, H.J. Silva et al. Physical Therapy in Sport 49 (2021) 243e249

is available in Fig. 1.
3.1. Characteristics of included trials and assessment of risk of bias
No study has evaluated the effectiveness of cryotherapy
compared with placebo, sham, waiting list or no intervention. The
two included trials evaluated the additional effects of cryotherapy
on pain intensity and swelling (Laba & Roestenburg, 1989; Sloan
et al., 1989), and one trial assessed range of motion (Sloan et al.,
1989). Both trials investigated outcomes at short-term. None of
the included trials assessed effects of cryotherapy on function and
recurrence. The form of cryotherapy used in both trials was ice pack
with the duration of application varying from 20 to 30 min as
adjunct of non-steroidal medication, elevation and rest (Sloan et al.,
1989) or ultrasound therapy, standardized exercise program and
support (Laba & Roestenburg, 1989). Detailed description of in-
terventions is in Table 1.
The two included trials had high risk of bias, scoring three out of
10 on the PEDro scale. Main reasons for increasing risk of bias were
not performing concealed allocation (2 trials [100%]); not blinding
therapists and subjects (2 trials [100%]); not adequate follow-up (2
trials [100%]); and not performing an intention-to-treat analysis (2
trials [100%]). Detailed characteristics of the included trials are
presented in Table 1.
3.2. Effects of cryotherapy on swelling, pain intensity, and range of
motion in acute ankle sprain
It was not possible to perform a meta-analysis due to the het-
erogeneity and missing data. Authors were contacted by e-mail to
provide mean and SD data, but one of them did not respond (Sloan
et al., 1989) and the other (Laba & Roestenburg, 1989) reported that
was not possible to provide the missing data because it has been a
long time since the trial was completed. For the results of individual
studies, mean and SD were imputed from individual scores and
sample size for pain intensity (Laba & Roestenburg, 1989), and SD
from mean, p-value and sample size for swelling (Sloan et al., 1989).
Summary of findings with GRADE recommendations are reported
in Table 2.
3.3. Swelling
In one trial (Sloan et al., 1989), swelling was assessed by the ratio
between the swelling and the intermalleolar distance calculated
from X-ray image. There was a within-group improvement of 46%
when cryotherapy was combined with the other active interven-
tion and of 40% when applied the other active intervention stand-
alone after seven days. There was no between-group difference
(MD ¼ 6, 95%IC: 0.5 to 12.5, p ¼ 0.07). In the trial conducted by Laba
and Roestenburg (1989), swelling was assessed by volumetry
through the percentage of increase on volume compared with the
contralateral limb. Participants were classified in three levels cat-
egories: 15-10%; 10-5%; and 5-0%. All the participants in both
groups improved up to 10% when compared with the contralateral
limb, but there was no between-group difference (p > 0.05).
3.4. Pain intensity
Sloan et al. (1989) showed no between-group difference on pain
intensity but did not report outcome data or how it was measured.
In Laba and Roestenburg (1989), pain intensity was assessed using a
5-point Likert scale that ranged from “no pain” to “very severe
pain”. Mean post-intervention scores were 0.21 (SD: 0.41) on the 5-
point scale for combination of cryotherapy with the other active

Table 1
Characteristics of included trials and assessment of risk of bias (n ¼ 2).

STUDY PARTICIPANTS INTERVENTION OUTCOME MEASURES PEDRO SCALE (0e10)

Sloan (1989) People with diagnosis of acute
ankle sprain within the
previous 24 h from Accident
and Emergency Department of
the University Hospital,
Nottingham;
Exclusion criteria: history of
asthma or upper
gastrointestinal disturbance;
chronic relapsing injuries;
fracture (excluded by
radiological examination);
n ¼ 116; age ¼ 16e50 years;
gender: 79% M/21% F
Laba (1989) People from Accident and
Emergency Department of
Dunedin Hospital.
Inclusion criteria: Diagnosis of
acute ankle sprain within the
previous 2 days; 3 and 4 grade
of injury classification (Hocutt
et al., 1982); and fracture
discarded by X-ray
examination.
n ¼ 30 (IG: 14; NI: 16); Grade of
injury: Grade 3: 19 (IG: 8; NI:
11); Grade 4: 11 (IG: 6; NI: 5)
Experimental group: Non-
steroidal
medication þ Rest þ Ice pack
with ankle elevation during
30 min.
Control group: Non-steroidal
medication þ Rest þ Ankle
brace with no ice pack and no
elevation for 30 min.
Experimental Group: Ice
pack þ Ultrasound
therapy þ Exercises.
Control Group: Ultrasound
therapy þ Exercises.
Swelling: Ratio between the 3/10a
swelling and the intermalleolar
distance calculated from X-ray
image;
Pain Intensity: Not reported.
Ankle range of motion:
Purpose-built goniometer;
Follow up: 7 days.
Swelling: Volumetry . 3/10b
Pain intensity: 5-point Likert
scale varying from ‘No Pain’ to
‘Very severe pain’
Follow-up: Participants were
discharged when they reached
grade of injury 1 or 2. No time
from the enrollment until
discharge was reported

Age in years; n ¼ sample size; M ¼ male; F ¼ female; IG ¼ Ice group; NI ¼ No Ice.

a
Random allocation: Yes, concealed allocation: No, baseline comparability: Yes, blind subjects: No, blind therapists: No, blind assessors: No, adequate follow-up: No,
intention-to-treat analysis: No, between-group comparisons: No, point estimates and variability: Yes.
b
Random allocation: Yes, concealed allocation: No, baseline comparability: No, blind subjects: No, blind therapists: No, blind assessors: Yes, adequate follow-up: No,
intention-to-treat analysis: No, between-group comparisons: Yes, point estimates and variability: No.

246
J.P. Miranda, W.T. Silva, H.J. Silva et al. Physical Therapy in Sport 49 (2021) 243e249

intervention and 0.25 (SD: 0.44) for the other intervention stand-
alone. There was no between-group difference on pain intensity
at short-term (MD ¼ 0.03, 95%CI: 0.34 to 0.28, p ¼ 0.84).
3.5. Range of motion
Sloan et al. (1989) showed no between-group difference at
short-term on range of motion assessed by goniometry (p > 0.05).
Outcome data was not provided in the trial.
4. Discussion
Our findings show that literature lacks evidence supporting the
effectiveness of cryotherapy for the management of acute ankle
sprain. Very-low quality of evidence from two randomized
controlled trials suggests that efficacy of cryotherapy on acute
ankle sprain is uncertain. The findings of this systematic review is
of great importance as it is a “call to action” for more appropriate
larger high-quality trials to investigate the efficacy of cryotherapy
on acute ankle sprain.
Previous systematic reviews reported that cryotherapy is
effective in acute ankle sprain (Bleakley et al., 2004) or recommend
its use in clinical practice if this decision is based on national
clinical practice guidelines or on expert decision (van den Bekerom
et al., 2012). However, their conclusions based on basic research
and expert opinion are biased and do not inform reliable estimates
of effect sizes for cryotherapy on different outcomes at different
time points. Moreover, previous reviews included non-randomized
controlled trials (Basur, Shephard, & Mouzas, 1976; Cote , Prentice Jr,
Hooker, & Shields, 1988; Hocutt, Jaffe, Rylander, & Beebe, 1982;
Wilkerson & Horn-Kingery, 1993), did not compare cryotherapy
with an appropriate comparator to isolate the effects of cryo-
therapy (Arde vol, Bolíbar, Belda, & Argilaga, 2002; Bleakley et al.,
2010; bib_Cote _et_al_1988,Cote , Prentice, Hooker, & Shields,
1988; Esch, Gerngross, & Fabian, 1989; Green, Refshauge, Crosbie,
& Adams, 2001; Hocutt et al., 1982; Prado et al., 2014; Wilkerson
& Horn-Kingery, 1993). Our systematic review is the first to eval-
uate the effectiveness of cryotherapy for the management of acute
ankle sprain. The adoption of appropriate inclusion and exclusion
criteria allowed us to inform the current evidence on the efficacy of
cryotherapy, and whether it enhances effects of other active
intervention in this health condition.
There are recommendations for the use of cryotherapy on
management of acute ankle sprain from clinical practice guidelines
(Van Dijk, 1999; Vuurberg et al., 2018), but these recommendations
are not based on high-quality clinical research from randomized
controlled trials. Vuurberg et al. (2018) recommend cryotherapy to
enhance effects of other active intervention, based on a randomized
controlled trial (Bleakley et al., 2010); however, comparators of this
trial were not appropriate to clarify it (i.e., compared cryotherapy
stand-alone with cryotherapy combined with exercise).
Clinicians have used cryotherapy in acute ankle sprain man-
agement based on findings from basic research, suggesting that
cryotherapy might decrease inflammatory processes by reducing
the macrophage infiltration, and the accumulation of TNF-a, NF-k B,
TGF-b and MMP-9 mRNA levels (bib_Nemet_et_al_2009,Nemet
et al., 2009; bib_Takagi_et_al_2011,Takagi et al., 2011); hypothe-
sizing that it might also lead to improvement on clinical outcomes.
However, this hypothesis is controversial because other basic
research hypothesizes that cryotherapy might delay migration of

Table 2
Summary of findings for cryotherapy and GRADE recommendations.

Additional effects of cryotherapy for acute ankle sprain

Patient or population: Participants with acute ankle sprain previous 24h (one study); participants with acute ankle sprain previous 48h (one study)
Setting: Accident and Emergency Department
Intervention: Ice pack applied for 20e30 min (two studies);
Comparison: Same interventions of experimental group but without the ice pack (two studies).

Outcomes WMD or MD (95% IC) Nº of Certainty of the Comments

participants evidence (GRADE)
(studies)

Swelling 6.0 (0.5 to 12.5) 143 (1 RCT) 222 The difference is not statistically significant.
Ratio (%) between the swelling and intermalleolar P-value ¼ 0.07 VERY LOWa,b,c
distance calculated from X-ray image;
Follow up: 7 days.
Swelling Not estimated 30 (1 RCT) 222 The difference is not statistically significant.
Volumetry VERY LOWa,b,c
Follow-up: Until discharge
Pain Intensity Not estimated 143 (1 RCT) 222 The outcome measure was not clearly stated. The
Follow up: 7 days. VERY LOWa,b,c difference is not statistically significant.
Pain intensity 0.03 (0.34 to 0.28) 30 (1 RCT) 222 The difference is not statistically significant.
Pain after treatment rated in 0e4 p-value ¼ 0.84 VERY LOWa,b,c
Follow-up: Until discharge
Ankle range of motion Not estimated 143 (1 RCT) 222 The difference is not statistically significant
Goniometry VERY LOWa,b,c
Follow up: 7 days.
GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is
substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Explanations.
a
Downgraded owing to imprecision: less than 400 participants included in the analysis (sample of less than 200 was considered serious imprecision and downgraded in
two levels).
b
Downgraded owing to inconsistency: I2 statistic was higher than 50% or pooling was not possible or poor overlap between the confidence intervals of the effects of the
included studies in the meta-analysis.
c
Downgraded owing to risk of bias: analysis were from trials with a high risk of bias (i.e., PEDro score <6 of 10).

247
J.P. Miranda, W.T. Silva, H.J. Silva et al.
macrophages in the injured area and the secretion of growth factors
such as TGF-b 1 and IGF-I expression, bringing harmful effects for
muscle regeneration (Ramos et al., 2016; Takagi et al., 2011). We
acknowledge the importance of basic research to identify potential
mechanisms of action to be tested in the biopsychosocial context of
clinical practice, but informed clinical decision should be supported
by clinical research. Clinical research is important to clarify efficacy
and potential harms. Some trials reported adverse events because
of cryotherapy such as superficial skin burn (Mutlu & Yılmaz, 2020;
Selfe et al., 2014), itching (Mutlu & Yılmaz, 2020) and cold-induced
peroneal nerve palsy for 24h (Bassett, Kirkpatrick, Engelhardt, &
Malone, 1992; Cohn, Draeger, & Jackson, 1989).
This systematic review has some potential limitations. We
investigated efficacy on our five outcomes of interest chosen
because they are frequently considered in clinical practice; how-
ever, there are other outcomes to be assessed. In this context, we
believe that clinicians should avoid surrogate outcomes. Besides,
we were unable to assess publication bias, planned subgroup and
sensitivity analyses because of the small number of included trials.
Future investigations should explore their potential impact.
5. Conclusions
The findings of this study conclude that current literature lacks
evidence supporting the use of cryotherapy on management of
acute ankle sprain. There is an urgent call for larger high-quality
randomized controlled trials to clarify the evidence on efficacy of
cryotherapy in this condition.
Ethical approval
None
The manuscript is a systematic review.
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Declaration of competing interest
None.
Acknowledgments
None.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.ptsp.2021.03.011.
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