Accepted Manuscript

Effectiveness and Safety of Cryotherapy after Arthroscopic Anterior Cruciate

Ligament Reconstruction. A Systematic Review of the Literature

Ana Luiza Cabrera Martimbianco, Brenda Nazaré Gomes da Silva, Alan Pedrosa
Viegas de Carvalho, Valter Silva, Maria Regina Torloni, Maria Stella Peccin

PII: S1466-853X(14)00012-1
DOI: 10.1016/j.ptsp.2014.02.008
Reference: YPTSP 601

To appear in: Physical Therapy in Sports

Received Date: 18 October 2013

Revised Date: 25 January 2014
Accepted Date: 27 February 2014

Please cite this article as: Martimbianco, A.L.C., Gomes da Silva, B.N., de Carvalho, A.P.V., Silva, V.,
Torloni, M.R., Peccin, M.S., Effectiveness and Safety of Cryotherapy after Arthroscopic Anterior Cruciate
Ligament Reconstruction. A Systematic Review of the Literature, Physical Therapy in Sports (2014), doi:
10.1016/j.ptsp.2014.02.008.

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TITLE PAGE

Effectiveness and Safety of Cryotherapy after Arthroscopic Anterior

Cruciate Ligament Reconstruction. A Systematic Review of the Literature

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Ana Luiza Cabrera Martimbiancoa

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Brenda Nazaré Gomes da Silvaa

Alan Pedrosa Viegas de Carvalhoa

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Valter Silvaa

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Maria Regina Torlonia
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Maria Stella Peccina
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a
Authors' affiliation address:
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Department of Internal Medicine, Federal University of Sao Paulo

Rua Botucatu, 740

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Postal Code: 04023-900

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São Paulo/SP

Brazil
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Corresponding author:

Ana Luiza Cabrera Martimbianco

E-mail: analuizacabrera@hotmail.com

Tel/Fax: + 55 (11) 5575 2970

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1 Effectiveness and Safety of Cryotherapy after Arthroscopic Anterior

2 Cruciate Ligament Reconstruction. A Systematic Review of the Literature

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24 ABSTRACT
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26 Cryotherapy is widely used in rehabilitation; however, its effectiveness

27 after anterior cruciate ligament (ACL) reconstruction remains uncertain. To

28 investigate the effectiveness and safety of cryotherapy following ACL

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29 reconstruction through a systematic review, randomized and quasi-randomized

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30 clinical trials were searched in the databases: MEDLINE, EMBASE, CENTRAL,

31 PEDro, SportDiscus, CINAHL, LILACS (June 2013). The primary outcomes

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32 measures were pain, edema and adverse events; the secondary outcomes

33 were knee function, analgesic medication use, range of motion, blood loss,

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hospital stay, quality of life and patient satisfaction. The methodological quality
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35 of studies was evaluated using the Cochrane Collaboration risk of bias tool. Ten
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36 trials (a total of 573 patients) were included. Results of meta-analysis showed

37 that the use of cold compression devices produced a significant reduction in

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38 pain scores 48 hours after surgery (p < 0.00001), compared to no cryotherapy.

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39 The risk for adverse events did not differ between patients receiving

40 cryotherapy versus no treatment (p = 1.00). The limited evidence currently

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41 available is insufficient to draw definitive conclusions on the effectiveness of

cryotherapy for other outcomes. There is a need for well designed, good quality
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42
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43 randomized trials to answer other questions related to this intervention and

44 increase the precision of future systematic reviews.

45 Key words: Anterior Cruciate Ligament, Anterior Cruciate Ligament

46 Reconstruction, Cryotherapy, Cold therapy.

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47 INTRODUCTION
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49 Rupture of the anterior cruciate ligament (ACL) of the knee is currently

50 one of the most common musculoskeletal injuries related to sports activities,

51 with an estimated 200,000 new cases per year in the United States (Gianotti,

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52 Marshall, Hume, & Bunt, 2009; Siegel, Vandenakker-Albanese, & Siegel, 2012).

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53 Arthroscopic ACL reconstruction surgery is the gold standard for treating ACL

54 tears (Adams, Logerstedt, Hunter-Giordano, Axe, & Snyder-Mackler, 2012;

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55 Lobb, Tumilty, & Claydon, 2012). However, the postoperative period is generally

56 associated with important clinical symptoms, including local pain, edema and

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reduced knee range of motion, which delay functional recovery time (van
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58 Grinsven, van Cingel, Holla, & van Loon, 2010; Yabroudi & Irrgang, 2013).
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59 The use of ice, or cryotherapy, is an easily available, low-cost and

60 popular intervention that has been widely used for acute musculoskeletal
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61 injuries. Cold reduces cellular metabolism, nerve conduction, edema formation

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62 and pain, thus helping injured tissues to recover (Nadler, Weingand, & Kruse,

63 2004; Ho, Coel, Kajawa, & Richardson, 1994; Warren, McCarty, Richardson,
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64 Michener, & Spindler, 2004). Cold has also been used in post-operative
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65 patients. By relieving acute symptoms including pain and edema, cryotherapy is

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66 believed to accelerate postoperative rehabilitation and the return to regular

67 activities. Several studies have tested the effects of cryotherapy in the relief of

68 post-operative pain after knee surgery (Martin, Spindler, Jeremy, Tarter,

69 Detwiler, & Petersen, 2001; Glenn, Spindler, Warren, McCarty, & Secic, 2004;

70 Lessard, Scudds, Amendola & Vaz, 1997; Woolf, Barfield, Merrill, & McBryde,

71 2008). It has been hypothesized that this effect may be due to decreased
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72 release of inflammatory mediators, such as prostaglandin E2, in the synovial

73 membranes (Stålman, Berglund, Dungnerc, Arner, & Felländer-Tsai, 2011).

74 Cold therapy can be applied through different methods, including cold

75 packs, ice massages, crushed-ice bags and cold compression devices. Up to

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76 the present, there is no consensus on which of these methods is most effective,

77 nor on what is the ideal duration of therapy or whether it should be used

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78 intermittently or continuously (Dykstra, Hill, Miller, Cheatham, Michael, & Baker,

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79 2009; Warren et al., 2004; Wilke & Weiner, 2003; Rupp, Herman, Hertel, &

80 Saliba, 2012). The safety of cryotherapy also needs to be considered, since ice

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81 can lead to skin burns (frostbite) and superficial nerve paralysis, as well as
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82 urticarial reactions and Raynaud’s phenomenon (Nadler et al., 2004; McGuire &

83 Hendricks, 2006).
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84 In 2005, a systematic review concluded that cryotherapy was effective in

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85 reducing post-operative pain after ACL reconstruction (Raynor, Pietrobon,

Guller, and Higgins, 2005). Since more trials have been published over the last
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87 years, we decided to update, critically appraise and synthesize the existing

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88 evidence on the effectiveness and safety of cryotherapy following arthroscopic

89 ACL reconstruction. This review will help to inform the clinical decisions of
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90 patients and physicians and to map existing controversies and research gaps in
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91 this area.

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93 METHODS
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95 This systematic review was conducted according to the

96 recommendations of the Cochrane Collaboration (Higgins & Green, 2011) and

97 the PRISMA reporting guidelines (Moher, Liberati, Tetzlaff, & Altman, 2010).

98

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99 Eligibility criteria

100 Types of studies: Randomized and quasi-randomized controlled trials

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101 (e.g. allocation by patient record number, date of birth).

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102 Participants: Skeletally mature patients (≥ 18 years old) submitted to

103 primary ACL arthroscopic reconstruction. Studies including patients with

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104 bilateral ACL reconstruction, re-rupture or concurrent knee ligament surgery
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105 were excluded.

106 Interventions: Any type of cold application around the knee (e.g. ice
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107 packs, cooling pads or cold compression devices) compared to any control
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108 group (e.g. placebo, no cold therapy, different types of cold therapy, other

clinical interventions – pharmacological or not). A cold compression device

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110 (CCD) is a cooling system that consists of a reservoir filled with cold water that
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111 is connected to two rubber plates or braces, via a rubber hose, which

112 completely involves the joint. The cold water circulates through the hose to the
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113 knee and temperature is controlled by the device’s control system (Nadler et al.,
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114 2004).

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116 Outcome measures

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117 Primary outcomes: (1) Pain intensity (measured by e.g. visual analogue

118 scale (VAS)), (2) Edema (e.g. knee circumference measured using tape) and

119 (3) Adverse events (thermal injury, such as burn, transient nerve palsy).

120 Secondary outcomes: (1) Function measured by knee scores (e.g.

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121 Lysholm score, IKDC score); (2) Post-operative analgesic medication use; (3)

122 Knee range of motion; (4) Blood loss (as measured from the intra-articular drain

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123 before removal); (5) Length of hospital stay; (6) Quality of life measures (e.g.

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124 SF-36 questionnaire); (7) Patient satisfaction.

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126 Search strategy
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127 The following databases were searched: MEDLINE (via Pubmed, 1966 to

128 June 2013); EMBASE (via Elsevier, 1980 to June 2013); Cochrane Central
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129 Register of Controlled Trials (The Cochrane Library, Issue 5, 2013); PEDro
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130 (1999 to June 2013); SportDiscus (1985 to June 2013); CINAHL (1982 to June

2013) and Literature of Latin America and the Caribbean: LILACS (1982 to June
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132 2013). We also searched ClinicalTrials.gov for ongoing and recently completed
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133 trials. No restrictions were placed on language of publication. The search was

134 complemented by screening the reference lists of the retrieved articles.

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135 The search strategies were based on the strategy developed for
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136 MEDLINE (via Pubmed), combined with the high-pass sensitivity filter

137 developed by the Cochrane Collaboration (Higgins & Green, 2011) to identify

138 randomized controlled trials. The following search terms were used: “Anterior

139 Cruciate Ligament” OR “Anterior Cruciate Ligament Reconstruction” OR “Bone-

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140 Patellar Tendon-Bone Graft” OR “Arthroscopy”, AND “Cryotherapy” OR “Cold

141 Therapy” and related terms adapted for each database (Appendix).

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143 Study selection

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144 Two reviewers (ALCM and BNGS) independently screened the titles and

145 abstracts retrieved through the search strategy. The full texts of all studies

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146 considered potentially relevant were obtained and read independently by the

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147 same two reviewers. The studies fulfilling the aforementioned selection criteria

148 were included in the review. Disagreements between the two reviewers were

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149 settled by a third reviewer (MSP).
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151 Data Extraction

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152 Two independent reviewers (ALCM and VS) extracted data from all
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153 included studies using a standardized extraction form especially created for this

review. The form collected information on participants, methodological aspects

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155 of the study, interventions, outcomes and results. The two individual forms were
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156 discussed by the reviewers until consensus was reached and merged into a

157 single extraction form. Persistent disagreements were settled by a third

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158 reviewer (MSP). When necessary, authors of the included studies were
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159 contacted for further information.

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161 Assessment of risk of bias in individual studies

162 Two reviewers (ALCM and APVC) independently assessed the

163 methodological quality of the included studies using The Cochrane

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164 Collaboration’s risk of bias tool (Higgins & Green, 2011). This tool assesses 7

165 study domains: sequence generation, allocation concealment, blinding of

166 participants, personnel and outcome assessors, incomplete outcome data,

167 selective reporting and other sources of bias. Each of these domains was

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168 classified by the reviewers as being at high, low or unclear risk of bias.

169 Disagreements between the two reviewers were settled by a third reviewer

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170 (MSP).

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172 Quantitative Data Synthesis and Analysis

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173 Measures of treatment effect
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174 For dichotomous outcomes, results were reported using risk ratio (RR) or

175 risk difference (RD). Outcomes presented as continuous data were reported
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176 using mean difference (MD); if different scales were used to measure the same
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177 outcome, standardized mean difference (SMD) was used. The 95% confidence

interval was calculated for all reported outcomes. If continuous outcome data
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179 were not reported and contacting trial authors was not successful, standard
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180 deviations were calculated using available standard errors, p-values or 95%

181 confidence intervals. Data presented only in graphs were extracted using the
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182 “Digitizelt” software (available from: http://www.digitizelt.de/). Whenever

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183 possible, meta-analyses were performed. (Higgins & Green, 2011; Levy,

184 Hubbard, & Eisenberg, 2009) using a review manager software (RevMan,

185 Version 5.2, The Nordic Cochrane Centre, Copenhagen, The Cochrane

186 Collaboration, 2011).

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188 Assessment of heterogeneity

189 Heterogeneity was assessed by visual inspection of the forest plots and

190 by using the I2 statistical test in fixed-effect meta-analyses; I2 values > 50%

191 were interpreted as indicative of significant heterogeneity. The Tau2 statistical

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192 test was used in random-effect meta-analyses: results > 1 were interpreted as

193 being suggestive of substantial statistical heterogeneity. Statistical significance

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194 (P < .10) was also assessed. When heterogeneity was detected, possible

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195 reasons were investigated and reported. (Higgins & Green, 2011)

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197 RESULTS
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The electronic search resulted in a total of 341 references which were

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200 reduced to 255 after the exclusion of duplicates. At first screening (titles and
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201 abstracts) 239 studies were excluded because they were outside the scope of
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202 this review and 16 were selected as potentially relevant. After reading these 16

203 full-texts, 6 studies were excluded (5 because of different participant selection

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204 criteria (Fang, Hung, Wu, Fang, & Stocker, 2012; Zaffagnini, Iacono, Petitto,

205 Loreti, Fu, & Marcacci, 1998; Ling-li, Ning, Xiao-ling, Hong, Jia-li, & Zhong-lan,
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2010; Lessard et al., 1997; Whitelaw, DeMuth, Demos, Schepsis, & Jacques,
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207 1995) and 1 due to study design (Daniel, Stone, Arendt, 1994)) and 10 studies

208 were included in the review (FIGURE 1).

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210 Characteristics of included studies

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211 Table 1 presents the main characteristics and results of the studies

212 included in the review. The 10 studies included recruited a total 573

213 participants. Seven were randomized clinical trials (Edwards, Rimmer, & Keene,

214 1996; Konrath, Lock, Goitz, & Scheidler, 1996; Brandsson, Rydgren, Hedner,

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215 Eriksson, Lundin, Sward, & Karlsson, 1996; Cohn, Draeger, & Jackson, 1989;

216 Schröder & Pässler, 1994; Dambros, Martimbianco, Polachini, Lahoz,

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217 Chamlian, & Cohen, 2012; Waterman, Walker, Swaims, Shortt, Todd, Machen,

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218 & Owens, 2012) and three were quasi-randomized clinical trials (Dervin, Taylor,

219 Keene, 1998; Ohkoshi, Ohkoshi, Nagasaki, Ono, Hashimoto, & Yamane, 1999;

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220 Barber, McGuire, & Click, 1998). All studies involved patients diagnosed with
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221 ACL rupture who underwent arthroscopic ACL reconstruction and were treated

222 with cryotherapy in hospital settings during the post-operative period, before
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223 discharge. In two studies (Waterman et al., 2012; Barber et al., 1998) the
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224 participants were instructed to continue cryotherapy after discharge for a total of

6 weeks and 1 week, respectively.

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225

226 Most of the participants were men (69%) with a mean age ranging from
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227 22 to 34 years. One study (Dambros et al., 2012) compared the use of knee ice

228 packs versus no treatment, while the other nine studies reported the use of a
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229 cold compression device (CCD) versus ice packs (Cohn et al., 1989; Konrath et
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230 al., 1996; Schröder & Pässler, 1994; Waterman et al., 2012), CCD versus

231 placebo (CCD filled with water at room temperature) (Konrath et al., 1996;

232 Edwards et al., 1996; Konrath et al., 1996) and CCD versus no cold therapy

233 (Konrath et al., 1996; Edwards et al., 1996; Brandsson et al., 1996; Ohkoshi et
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234 al., 1999; Barber et al., 1998). All the authors reported that occlusive dressings

235 had been used on the surgical incision prior to applying the cooling device.

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237 Assessment of risk of bias

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238 The methodological quality of the 10 studies is described in Figure 2. We

239 contacted the authors of all 10 studies via e-mail to clarify details related to the

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240 risk of bias and to obtain additional information; only four authors responded

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241 (Dervin et al., 1998; Ohkoshi et al., 1999; Waterman et al., 2012; Dambros et

242 al., 2012). Three studies (Dervin et al., 1998; Ohkoshi et al., 1999; Barber et al.,

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243 1998) were quasi-randomized trials (patients were allocated according to the
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244 number of their medical record or date of birth) and were categorized as being

245 at high risk of bias for two domains — random sequence generation and
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246 allocation concealment (risk of selection bias). All trials were classified as being
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247 at high risk of bias for blinding of participants and personnel because, given the

nature of the intervention, patients could not be blinded, thus introducing

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249 potential bias. Two studies (Dervin et al., 1998; Dambros et al., 2012) were
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250 classified as having an unclear risk of bias for incomplete outcome data

251 reporting because they did not provide information on excluded participants.
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252 This fact may cause imbalance between the groups thus influencing the results.
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253 Based on the recommendations of the Cochrane Collaboration, all 10 studies

254 were judged to be at high risk of bias because at least one of the first three

255 domains were scored as being at high risk of bias (Higgins & Green, 2011).

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257 Effects of interventions (Quantitative analysis)

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258 Continuous outcomes

259 Given the lack of data and the unsuccessful contact with trial authors, we

260 were able to obtain outcome data for pooling in meta-analyses from only two

261 studies (Brandsson et al., 1996; Ohkoshi et al., 1999) which reported one of our

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262 primary outcomes (pain intensity). These two studies compared the use of a

263 cold compression device (CCD) versus no cold therapy. Pooling of results

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264 indicated a significant reduction in pain intensity (VAS pain score 48 hours after

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265 ACLR) in the group receiving the intervention: mean difference (MD) -1.41, 95%

266 CI -1.66 to -1.17, p < 0.00001], with low heterogeneity (Figure 3).

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267 Results of the outcomes that could not be pooled in a meta-analysis
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268 (individual clinical trials) are described in Table 1. Edwards et al., (1996),

269 Barber et al., (1998) and Konrath et al., (1996) reported no statistical
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270 differences with or without cold therapy for pain intensity. When comparing CCD
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271 with cold water against CCD with room temperature water (placebo), Dervin et

al., (1998), Edwards et al., (1996) and Konrath et al., (1996) did not find
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273 statistically significant differences for the pain measured 24 and 48 hours after
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274 ACL reconstruction. Two studies which compared the use of CCD versus ice

275 pack reported significant improvement favoring CCD after the 1st week (p <
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276 0.01) (Schröder & Pässler, 1994) and after 6 weeks after surgery (p < 0.0001)
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277 (Waterman et al., 2012).

278 Despite the difficulty in comparing the different drugs prescribed in each

279 study, the same clinical trials (Cohn et al., 1989; Ohkoshi et al., 1999; Barber et

280 al., 1998; Schröder & Pässler, 1994; Waterman et al., 2012; Brandsson et al.,

281 1996) that reported improvement in pain intensity, also showed a statistically
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282 significant reduction in the amount of medication taken by the patients after the

283 use of CCD, when compared to both ice pack and control (no cold therapy).

284 Three studies assessed knee edema (Waterman et al., 2012; Schröder &

285 Pässler, 1994; Barber et al., 1998) and only one (Schröder & Pässler, 1994)

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286 reported a small but statistically significant improvement in this outcome in

287 patients using CCD compared to those randomized to receive ice packs

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288 (p<0.035). Among the studies that assessed the amount of blood drained after

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289 surgery (Schröder & Pässler, 1994; Edwards et al., 1996; Konrath et al., 1996;

290 Ohkoshi et al., 1999; Dervin et al., 1998), only Ohkoshi et al., (1999) reported

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291 significant reduction in the volume of blood drained immediately after surgery
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292 (48 hours) with the use of CCD at 5°C, compared to CCD at 10°C and no

293 cryotherapy (control group) (p <0.01).

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294 Five studies assessed knee range of motion (Schröder & Pässler, 1994;
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295 Dambros et al., 2012; Barber et al., 1998; Edwards et al., 1996; Konrath et al.,

1996) and only one (Schröder & Pässler, 1994) reported statistically significant
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297 results favoring the intervention group (CCD) versus ice pack group (p < 0.01).
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298 Schröder & Pässler, (1994) and Waterman et al., (2012) evaluated knee

299 function. Only Schröder & Pässler, (1994) reported a small but statistically
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300 significant improvement favoring the CCD group when compared to the ice pack
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301 group (p < 0.025). Brandsson et al., (1996) analyzed patient satisfaction and

302 reported a statistically significant difference in favor of the CCD group when

303 compared with no treatment (p < 0.05). The individual clinical trials did not

304 detect significant differences in duration of hospital stay (Edwards et al., 1996;
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305 Konrath et al., 1996; Cohn et al., 1989; Brandsson et al., 1996; Dervin et al.,

306 1998) and quality of life (Waterman et al., 2012).

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308 Dichotomous outcomes

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309 All the included studies assessed the safety of cryotherapy by evaluating

310 the occurrence of adverse events. Only one study (Cohn et al., 1989), that

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311 compared the use of a cold compression device (CCD) versus ice pack,

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312 reported the occurrence of transient peroneal nerve palsy in one patient who

313 received the ice pack. Results of meta-analysis for adverse events showed no

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314 statistically significant difference between comparison groups: CCD versus ice
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315 pack (risk difference (RD) -0.01, 95% CI -0.06 to 0.04, p = 0.66); CCD versus

316 no treatment (risk difference (RD) -0.00, 95% CI -0.04 to 0.04, p = 1.00) and
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317 CCD versus CCD placebo (risk difference (RD) -0.01, 95% CI -0.06 to 0.04, p =
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318 0.66).
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319 DISCUSSION
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321 Cryotherapy after arthroscopic anterior cruciate ligament (ACL)

322 reconstruction significantly reduced immediate post-surgery pain and did not
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increase the risk of adverse events, in the short-term (up to 48 hours after
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324 surgery). The limited evidence currently available from randomized trials is

325 insufficient to draw definitive conclusions on the effectiveness of cryotherapy for

326 other outcomes such as edema, knee function, postoperative blood loss,

327 duration of hospital stay, range of motion, post-operative analgesic medication

328 use, patient satisfaction or quality of life. Observational studies suggest that
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329 cryotherapy may produce immediate benefits by reducing pain and edema

330 during the inflammatory response after surgery, decreasing muscle spasm and

331 improving knee function, thereby accelerating the postoperative rehabilitation

332 and the return to routine activities. (Rashkovska, Trobec, Avbelj & Veselko,

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333 2013; Dykstra, Hill, Miller, Cheatham, Michael, & Baker, 2009; Osbahr, Cawley,

334 & Speer, 2002)

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335 Our meta-analysis indicates that CCD, compared to no cold therapy,

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336 leads to a significant reduction in knee pain measured 48 hours after

337 arthroscopic ACL reconstruction (p < 0.00001). Based on the existing evidence,

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338 it was not possible to determine what are best type, frequency and duration of
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339 cryotherapy to reduce pain after ACL reconstruction. The use of CCD can

340 reduce pain by compression or by cold therapy; therefore it is difficult to

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341 separate the actual effects of each component. Some investigators question the
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342 effectiveness of the compression produced by CCD, claiming that it might not

have much influence on pain relief as the cooling itself (Dervin et al., 1998;
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344 Morsi, 2002; Raynor et al., 2005).

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345 Knee edema can also be influenced by cryotherapy associated with

346 compression (Kullenberg, Ylipää, Söderlund, & Resch, 2006; Morsi, 2002).
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347 Some investigators consider this outcome as somewhat subjective, since it is

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348 difficult to obtain a precise measurement of the edema (Dervin et al., 1998;

349 Edwards et al., 1996); this could help to explain the lack of data on this

350 outcome. Low temperatures might reduce post-surgery blood loss, thus helping

351 to reduce swelling (Adie, Kwan, Naylor, Harris, & Mittal, 2012).
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352 All the included studies investigated the occurrence of adverse events

353 related to cold therapy. The results from the meta-analysis indicate that cold

354 therapy after ACL reconstruction is safe. Cohn et al., (1989) reported that one

355 patient in the ice pack group developed transient peroneal nerve palsy, after the

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356 pack had been left in place for nearly 40 minutes. According to these authors,

357 this type of complication could be avoided by using ice packs for no longer than

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358 30 minutes and by protecting superficial nerves with knee bandages prior to

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359 applying the intervention.

360 The evidence provided partial answers to the core questions raised in

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361 this review. In most trials, assessment of outcomes was limited to a short
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362 period, between 24 to 48 hours after surgery. Only one study (Waterman et al.,

363 2012) assessed results of the intervention in the long term (6 weeks after the
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364 surgery).
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365 A recent systematic review assessed the effectiveness of cryotherapy

after total knee arthroplasty, and reported that it is associated with a small but
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367 statistically significant reduction in pain and blood loss, as well as improvement
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368 in the range of motion (Adie et al., 2012). As in the present study, the authors of

369 that review noted methodological limitations in the included studies, which could
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370 have influenced most of the outcomes assessed. According to a systematic

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371 review on cryotherapy for acute soft tissues injuries (Bleakley, McDonough, &

372 MacAuley, 2004), there was small but statistically significant effect of

373 compression combined with cryotherapy (CCD) compared to ice packs.

374 However, as in our review, the studies included in that review were limited to

375 interventions carried out before hospital discharge. Those authors recommend
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376 caution when interpreting the results due to the heterogeneity and poor

377 methodological quality of the included studies.

378 A similar review was published by Raynor et al., (2005) eight years ago

379 and, in concordance with our findings; it concluded that cryotherapy after ACL

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380 surgery significantly reduced immediate post-surgery pain, without significant

381 improvement in postoperative blood loss or range of motion. However, there are

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382 several differences between our reviews. Raynor et al., (2005) included only

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383 seven studies and 420 participants, while we included ten studies and 573

384 participants. Although two studies included in our review were published

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385 recently (Dambros et al., 2012; Waterman et al., 2012), we also included two
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386 studies which had already been published at the time of that previous review

387 (Cohn et al., 1989; Schröder & Pässler, 1994) but were not included by those
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388 authors. This was in part due to our more sensitive search and to the fact that
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389 we ran our search in three additional electronic databases that had not been

included by those investigators (EMBASE, LILACS and PEDro). Due to different

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390

391 selection criteria, our review excluded one study (Daniel et al., 1994) which was
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392 included by Raynor et al., (2005). Contrary to Raynor´s review, we assessed

393 the methodological quality (risk of bias) of the included studies which is an
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394 important step in systematic reviews of the literature (Higgins & Green, 2011).
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395 Finally, besides the outcomes evaluated by Raynor et al., (2005) (pain,

396 postoperative drainage and range of motion), our review included additional

397 clinically relevant outcomes such as knee edema and function, use of post-

398 operative analgesics, length of hospital stay, quality of life, patient satisfaction,

399 and safety of cryotherapy.

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400 All studies included in our review were at high risk of bias, recruited a

401 small number of participants and provided sparse data on most of our pre-

402 established outcomes of interest, thus precluding pooling of their results into

403 meta-analyses. These studies were heterogeneous in several aspects: they

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404 compared different forms of cryotherapy (Cold Compression Device (CCD) x ice

405 pack; CCD x CCD placebo (with water at room temperature); CCD x no cold

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406 therapy; ice pack x no cold therapy), different frequencies and durations of

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407 sessions, and different follow-up periods. The main methodological limitations of

408 the included studies were the lack of description of random sequence

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409 generation and allocation concealment, as well as difficulties in blinding of
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410 participants and outcome assessors due to the nature of the intervention. This

411 may in part be explained by the fact that most of these studies (8 /10) were
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412 published in the 80s and 90s, a period when most trials did not follow the
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413 internationally accepted standard recommendations for reporting clinical trials

(CONSORT -Consolidated Standards of Reporting Trials) and did not have

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414

415 published protocols. We admit the possibility that relevant studies may have
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416 been missed, despite our rigorous and ample search strategy without language

417 or date restrictions. Another potential limitation of this review is the lack of
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418 success in obtaining additional information from the trial authors, precluding
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419 additional meta-analyses. According to GRADE system (The Grades of

420 Recommendation, Assessment, Development and Evaluation Working Group)

421 (Higgins & Green, 2011), the general analysis of the quality of the evidence

422 (internal validity) was moderate, since most information was obtained from

423 studies that presented “unclear risk of bias”.

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424

425 CONCLUSION
426

427 There is moderate quality evidence that cryotherapy is safe and effective

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428 in reducing pain after ACL reconstruction, in the first 48 hours after surgery. The

limited evidence currently available is insufficient to draw definitive conclusions

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429

430 on the effectiveness of this intervention for other important outcomes, such as

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431 knee edema and function, use of post-operative analgesic medication, knee

432 range of motion, blood loss, duration of hospital stay, quality of life measures

433
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and patient satisfaction. There is a need for more, well designed, good quality
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434 randomized trials to answer several remaining questions related to this

intervention and increase the precision of future systematic reviews.

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435

436
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437 Ethical Approval

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438 This study was approved by the Ethics Committee of Federal University

439 of Sao Paulo (CEP 0142/11).

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440

441 Funding
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There are no sources of funding.

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442

443

444 Conflict of interest

445 The authors have no conflicts of interest or financial support to declare

446 (including research funding) or involvement with any commercial organization

447 that has a direct financial interest in any matter included in this manuscript.
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448

449 REFERENCES
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APPENDIX

Search strategies

MEDLINE (via Pubmed)

#A ("Anterior Cruciate Ligament"[Mesh]) OR (Cruciate Ligament, Anterior) OR (Anterior

Cruciate Ligaments) OR (Cruciate Ligaments, Anterior) OR (Ligament, Anterior Cruciate) OR
(Ligaments, Anterior Cruciate) OR (Anterior Cruciate Ligament Injury) OR (Anterior Cruciate
Ligament Injuries) OR (Anterior Cruciate Ligament Repair) OR (Anterior Cruciate Ligament

PT
Tears) OR (“Anterior Cruciate Ligament Reconstruction”[Mesh]) OR ("Bone-Patellar Tendon-
Bone Graft"[Mesh]) OR (Bone Patellar Tendon Bone Graft) OR (Bone-Patellar Tendon-Bone
Grafts) OR (Graft, Bone-Patellar Tendon-Bone) OR (Grafts, Bone-Patellar Tendon-Bone) OR

RI
("Knee"[Mesh]) OR Knees OR ("Knee Joint"[Mesh]) OR (Joint, Knee) OR (Joints, Knee) OR
(Knee Joints) OR ("Knee Injuries"[Mesh]) OR (Knee injuries) OR (Knee Injury) OR (Injuries,
Knee) OR (Injury, Knee) OR (Knee Instability) OR (Knee Reconstruction) OR (Knee Repair)

SC
OR (Knee Damage) OR (Knee Impingement) OR (Knee Ligament Injury) OR (Acutely Injured
Knee) OR (Cruciate Knee Surgery) OR ("Arthroscopy"[Mesh]) OR Arthroscopies OR
(Arthroscopic Surgical Procedures) OR (Arthroscopic Surgical Procedure) OR (Procedure,
Arthroscopic Surgical) OR (Procedures, Arthroscopic Surgical) OR (Surgical Procedure,

U
Arthroscopic) OR (Surgery, Arthroscopic) OR (Surgical Procedures, Arthroscopic) OR
(Arthroscopic Surgery) OR (Arthroscopic Surgeries) OR (Surgeries, Arthroscopic) OR
AN
(Arthroscopic Lateral Retinacular Release) OR (Knee Joint Arthroscopy) OR (Knee Joint
Arthroscopies) OR (Arthroscopic Knee Surgery) OR (Arthroscopic Knee Surgeries) OR (Knee
Arthroscopy) OR (Knee Arthroscopies)
M

#B ("Cryotherapy"[Mesh]) OR Cryotherapies OR (Therapy, Cold) OR (Cold Therapies) OR

(Therapies, Cold) OR (Cold Therapy) OR (Ice Therapy) OR (Ice Therapies) OR (Cubed Ice)
OR (Crushed Ice) OR (Ice Packs) OR (Ice Pack) OR (Cold Packs) OR (Ice Bag) OR (Ice Bags)
D

OR (Cold Pack) OR (Cooling Pads) OR (Cooling Pad) OR (Cold Compression) OR (Cooled

Water) OR (Cold Bags) OR (Cold Bag) OR (Cold Gel Packs) OR (Ice Massage) OR (Cold
TE

Water) OR (Ice Bath) OR (Cold Gel) OR (Cold Therapy Gel) OR (Cold Application) OR (Cold
Applications) OR (Cold Water Immersion) OR (Cryokinetic) OR (Cryotherapeutic Agents) OR
(Local Cooling) OR (Therapeutic Cooling) OR (Continuous Cryotherapy) OR (Cryocuff) OR
(Thermal Therapy) OR (Cryotherapy Device) OR Hypothermia OR Thermotherapy OR
EP

(Continuous Flow Cold Therapy) OR (Ice Pack Therapy) OR (Cold Gel Pack) OR (Cold
Compressive Dressing) OR (Cold Compressive Devices) OR (Thermal Modalities) OR (Ice
Treatment) OR (Chipped Ice) OR (Ice Machines) OR (Ice Submersion) OR (Wetted Ice)
C

#C ((randomized controlled trial [pt]) OR (controlled clinical trial [pt]) OR (randomized [tiab]) OR
AC

(placebo [tiab]) OR (drug therapy [sh]) OR (randomly [tiab]) OR (trial [tiab]) OR (groups [tiab]))
AND (humans [mh])
EMBASE (via Elsevier)

#1 'anterior cruciate ligament'/exp OR ‘anterior cruciate knee ligament’ OR ‘anterior cruciate

ligament knee’ OR ‘cruciate knee ligament anterior’ OR ‘ligament anterior cruciate knee’ OR
'anterior cruciate ligament reconstruction'/exp OR 'ACL reconstruction' OR 'ACL repair' OR
'ACL surgery' OR 'anterior cruciate ligament repair' OR 'anterior cruciate ligament surgery' OR
'bone patellar tendon bone graft'/exp OR bone-patellar tendon-bone graft OR 'knee'/exp OR
'articulatic genus'/exp OR 'genopathy'/exp OR 'joint knee'/exp OR 'knee compartment'/exp OR
'knee joint'/exp OR 'knee movement'/exp OR 'knee stiffness'/exp OR 'knee injury'/exp OR
'injury knee'/exp OR 'knee injuries'/exp OR 'knee joint injury'/exp OR 'knee joint trauma'/exp OR
'knee open injury'/exp OR 'knee trauma'/exp OR 'trauma knee'/exp OR 'soft tissue injury'/exp
 ACCEPTED MANUSCRIPT
OR 'soft tissue injuries'/exp OR 'soft tissue trauma'/exp OR 'soft tissue wound'/exp OR
'arthroscopy'/exp OR 'arthroendoscopy'/exp OR 'arthroscopic procedure'/exp OR 'arthroscopic
procedures'/exp
#2 'cryotherapy'/exp OR ‘bath cold’ OR ‘bath hypothermal’ OR ‘cold bath’ OR ‘cold therapy’
OR ‘cryogenic therapy’ OR ‘cryothermy’ OR ‘cryotreatment’ OR ‘therapy cryogenic’
CENTRAL

#1 MeSH descriptor Anterior Cruciate Ligament explode all trees

#2 MeSH descriptor Anterior Cruciate Ligament Reconstruction explode all trees
#3 MeSH descriptor Knee explode all trees

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#4 MeSH descriptor Knee Joint explode all trees
#5 MeSH descriptor Knee Injuries explode all trees
#6 MeSH descriptor Arthroscopy explode all trees

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#7 (#1 OR #2 OR #3 OR #4 OR #5 OR #6)
#8 MeSH descriptor Cryotherapy explode all trees
#9 (#7 AND #8)

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PEDro

Using the 'Advanced search' option, each term in the ‘Abstract & Title’ field will be combined
with each term in the ‘Subdiscipline’ field in separate searches.

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Abstract & Title: Cryotherapy
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Body part: lower leg or knee
Subdiscipline:
Method: clinical trial
When searching: match all search terms (AND)
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SPORTDISCUS

#1 DE "ANTERIOR cruciate ligament" OR “Cruciate Ligament, Anterior” OR “Anterior Cruciate

D

Ligaments” OR “Cruciate Ligaments, Anterior” OR “Ligament, Anterior Cruciate” OR

“Ligaments, Anterior Cruciate” OR “Anterior Cruciate Ligament Injury” OR “Anterior Cruciate
TE

Ligament Injuries” OR “Anterior Cruciate Ligament Repair” OR “Anterior Cruciate Ligament

Tears” OR “Anterior Cruciate Ligament Reconstruction” OR “Bone-Patellar Tendon-Bone Graft”
OR “Bone Patellar Tendon Bone Graft” OR “Bone-Patellar Tendon-Bone Grafts” OR “Graft,
EP

Bone-Patellar Tendon-Bone” OR “Grafts, Bone-Patellar Tendon-Bone” OR “Knee” OR “Knees”

OR “Knee Joint” OR “Joint, Knee” OR “Joints, Knee” OR “Knee Joints” OR “Knee Injuries” OR
“Knee injuries” OR “Knee Injury” OR “Injuries, Knee” OR “Injury, Knee” OR “Knee Instability”
OR “Knee Reconstruction” OR “Knee Repair” OR “Knee Damage” OR “Knee Impingement” OR
C

“Knee Ligament Injury” OR “Acutely Injured Knee” OR “Cruciate Knee Surgery” OR

“Arthroscopy” OR “Arthroscopies” OR “Arthroscopic Surgical Procedures” OR “Arthroscopic
AC

Surgical Procedure” OR “Procedure, Arthroscopic Surgical” OR “Procedures, Arthroscopic

Surgical” OR “Surgical Procedure, Arthroscopic” OR “Surgery, Arthroscopic” OR “Surgical
Procedures, Arthroscopic” OR “Arthroscopic Surgery” OR “Arthroscopic Surgeries” OR
“Surgeries, Arthroscopic” OR “Arthroscopic Lateral Retinacular Release” OR “Knee Joint
Arthroscopy” OR “Knee Joint Arthroscopies” OR “Arthroscopic Knee Surgery” OR “Arthroscopic
Knee Surgeries” OR “Knee Arthroscopy” OR “Knee Arthroscopies”

#2 DE “COLD (Temperature) -- Therapeutic use” OR “Cryotherapy” OR “Cryotherapies” OR

“Therapy, Cold” OR “Cold Therapies” OR “Therapies, Cold” OR “Cold Therapy” OR “Ice
Therapy” OR “Ice Therapies” OR “Cubed Ice” OR “Crushed Ice” OR “Ice Packs” OR “Ice Pack”
OR “Cold Packs” OR “Ice Bag” OR “Ice Bags” OR “Cold Pack” OR “Cooling Pads” OR “Cooling
Pad” OR “Cold Compression” OR “Cooled Water” OR “Cold Bags” OR “Cold Bag” OR “Cold
 ACCEPTED MANUSCRIPT
Gel Packs” OR “Ice Massage” OR “Cold Water” OR “Ice Bath” OR “Cold Gel” OR “Cold
Therapy Gel” OR “Cold Application” OR “Cold Applications” OR “Cold Water Immersion” OR
“Cryokinetic” OR “Cryotherapeutic Agents” OR “Local Cooling” OR “Therapeutic Cooling” OR
“Continuous Cryotherapy” OR “Cryocuff” OR “Thermal Therapy” OR “Cryotherapy Device” OR
“Hypothermia” OR “Thermotherapy” OR “Continuous Flow Cold Therapy” OR “Ice Pack
Therapy” OR “Cold Gel Pack” OR “Cold Compressive Dressing” OR “Cold Compressive
Devices” OR “Thermal Modalities” OR “Ice Treatment” OR “Chipped Ice” OR “Ice Machines”
OR “Ice Submersion” OR “Wetted Ice”

PT
CINAHL

S1 (MH "Anterior Cruciate Ligament") OR

S2 (MH "Anterior Cruciate Ligament Injuries") OR

RI
S3 (MH "Knee") OR (MH "Knee Joint") OR
S4 (MH "Arthroscopy")
S5 (S1 OR S2 OR S3 OR S4)

SC
S6 (MH "Cryotherapy")
S7 (S5 AND S6)
LILACS

U
((Anterior Cruciate Ligament) OR (Ligamento Cruzado Anterior) OR (Ex A02.513.514.100) OR
(Anterior Cruciate Ligament Reconstruction) OR (Reconstrucción del Ligamento Cruzado
AN
Anterior) OR (Reconstrução do Ligamento Cruzado Anterior) OR (E02.718.050) OR
(E04.555.085) OR (E04.555.110.026) OR (E04.680.051) OR (knee) OR (joelho) OR (Rodilla)
OR (Ex A01.378.610.450) OR (Knee Injuries) OR (Traumatismos de la Rodilla) OR
(Traumatismos do Joelho) OR (Lesões do Joelho) OR (Ex C21.866.558.554) OR (Arthroscopy)
M

OR (Artroscopía) OR (Artroscopia) OR (E01.370.388.250.070) OR (E04.555.113) OR

(E04.800.250.070)) AND ((cryotherapy) OR (crioterapia) OR (terapia a frio) OR (terapia por
frio) OR (Ex E02.258)) AND ((Pt randomized controlled trial OR Pt controlled clinical trial OR
D

Mh randomized controlled trials OR Mh random allocation OR Mh double-blind method OR Mh

single-blind method) AND NOT (Ct animal AND NOT (Ct human and Ct animal)) OR (Pt clinical
TE

trial OR Ex E05.318.760.535$ OR (Tw clin$ AND (Tw trial$ OR Tw ensa$ OR Tw estud$ OR

Tw experim$ OR Tw investiga$)) OR ((Tw singl$ OR Tw simple$ OR Tw doubl$ OR Tw doble$
OR Tw duplo$ OR Tw trebl$ OR Tw trip$) AND (Tw blind$ OR Tw cego$ OR Tw ciego$ OR
Tw mask$ OR Tw mascar$)) OR Mh placebos OR Tw placebo$ OR (Tw random$ OR Tw
EP

randon$ OR Tw casual$ OR Tw acaso$ OR Tw azar OR Tw aleator$) OR Mh research design)

AND NOT (Ct animal AND NOT (Ct human and Ct animal)) OR (Ct comparative study OR Ex
E05.337$ OR Mh follow-up studies OR Mh prospective studies OR Tw control$ OR Tw
C

prospectiv$ OR Tw volunt$ OR Tw volunteer$) AND NOT (Ct animal AND NOT (Ct human and
Ct animal)))
AC
 1
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1 Acknowledgements

2 We would like to thank Dr. Alvaro Nagib Atallah and the Brazilian

3 Cochrane Centre team for methodological support.

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 ACCEPTED MANUSCRIPT
TABLE 1: Main characteristics and findings of ten studies on cryotherapy after

anterior cruciate ligament reconstruction.

STUDY PARTICIPANTS INTERVENTION OUTCOMES MEASURED AND RESULTS

DESIGN
Cohn et al., 54 patients G1: CCD (10°C) 1. Use of analgesic medication (total doses, mg/Kg) of IM
1989 (continuously up to meperidine, oral hydroxyzine and hydrocodone, measured 48
G1 (n = 26) hospital discharge) hours after surgery

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RCT 17 M / 9 W 2. Length of hospital stay
mean age 22.9 y G2: Ice bags 3. Adverse events
(applied once – 30
G2 (n = 28) minutes) G1 patients used significantly less IM meperidine and oral

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15 M / 13 W hydroxyzine (p < 0.01). One G2 patient had transient peroneal
mean age 25.1 y nerve palsy.
Schröder & 44 patients G1: CCD 1. Pain intensity (VAS)

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Passler, (continuously up to 2. Edema (knee circumference measured using tape)
1994 G1 (n = 21) hospital 3. Range of motion-ROM (in degrees)
15 M / 6 W 4. Knee function (knee score of Noyes and McGinniss)
RCT mean age 24.2 y G2: Ice bags (three 5. Use of analgesic medication (total doses, mg/Kg) of oral

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times/day) tilidine, IM pethidine and piritramide
G2 (n = 23) 6. Blood loss (in ml)
18 M / 5 W 7. Adverse events
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mean age 24.8 y Outcomes were measured on days: 1, 2, 3, 6, 14, 28.

G1 had significant differences in: ROM on all days (p < 0.01);

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VAS pain scale on the 6 day (p < 0.01); knee edema on the
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3 and 6 days (p<0.035), knee function (p < 0.025) and used
less oral tilidine and IM piritramide (p < 0.04).
There were no adverse events.
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Konrath et 100 patients G1: CCD with cold 1. Use of analgesic medication (total doses, mg/kg) of IM
al., 1996 water (10°C) meperidine and hydroxyzine; and oral hydrocodone
G1 (n = 27) (continuously up to 2. ROM (in degrees)
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RCT 21M/6W hospital discharge) 3. Length of hospital stay

mean age 27 y 4. Blood loss (in ml)
G2: CCD water at 5. Adverse events
G2 (n = 23) room temperature All outcomes were measured before hospital discharge
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13M/10W (25°C)
mean age 25 y (continuously up to There were no significant differences between the groups.
hospital discharge) There were no adverse events.
G3 (n = 23)
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17M/6W G3: ice packs

mean age 26 y changed every 4
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hours (up to
G4 (n = 27) hospital discharge)
16M/11W
mean age 26 y G4: no cold therapy
Brandsson 50 patients G1: CCD 1. Pain intensity (VAS), measured 1, 2, 4, 6, 24 and 48 hours
et al., (continuously - first after surgery.
1996 G1 (n = 20) 24 hours) + IA 2. Use of analgesic medication (total doses , mg/Kg) of codeine
G2 (n = 20) injection of and morphine measured 24 and 48 hours after surgery.
RCT G3 (n = 10) physiological saline. 3. Length of hospital stay (measured in days)
4. Patient satisfaction
31 M / 19 W G2: CCD 5. Adverse events
mean age 26 y (continuously - first
24 hours) + IA G1 had significantly less pain (p < 0.05) and use of analgesic
injection of medication (p < 0.05), compared with G3. In G1, 80% were
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morphine satisfied with their pain relief, compared with 30% in G3 (p <
hydrochloride and 0.05). There were no adverse events.
bupivacaine.

G3: IA injection of
physiological saline.
Edwards et 71 patients G1: CCD cold water 1. Pain intensity (VAS)
al., 1996 (continuously - first 2. Use of analgesic medication (total doses, mg/Kg) of
G1 (n = 26) 36 hours) injectable morphine, oral paracetamol and codeine
RCT 18 M / 8 W 3. ROM (in degrees)
mean age 28.7 y G2: CCD water at 4. Blood loss (in ml)

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room temperature 5. Adverse events
G2 (n = 21) (continuously - first Outcomes measurement: 24 and 48 hours after surgery
17 M / 4 W 36 hours)

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mean age 26 y There were no significant differences between groups. There
G3: no cold therapy were no adverse events.
G3 (n = 24)
15 M / 9 W

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mean age 28 y
Dervin et 78 patients G1: CCD with cold 1. Pain intensity (VAS)
al., water (continuously 2. Use of analgesic medication; total doses, (mg/Kg) of
1998 G1 (n = 40) up to hospital morphine and number of codeine tablets (30 mg)

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27 M / 13 W discharge) 3. Length of hospital stay (in days)
Quasi-RCT mean age 30.6 y 4. Blood loss (ml)
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G2: CCD with water 5. Adverse events
G2 (n = 38) at room Outcomes measurement: 24 hours after surgery.
27 M / 11 W temperature
mean age 26.9 y (continuously up to There were no significant differences between the groups.
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hospital discharge) There were no adverse events.

Barber et 100 patients G1: CCD 1. Pain intensity (VAS and Likert categorical pain score)
al., continuously 2. Edema (knee circumference measured using tape)
1998 G1 (n = 51) 3. ROM (in degrees)
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34 M / 17 W G2: no cold therapy 4. Use of analgesic medication (total doses, mg/Kg) of

Quasi-RCT mean age 34 y oxycodone/paracetamol and hydrocodone
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Outcomes measurement: 1, 2, and 8 hours, and daily

evaluations lasting up to 1 week after surgery.
G2 (n = 49)
40 M / 9 W G1 had marginally significant pain reduction, 24 hours after
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mean age 34 y surgery (p =0.059) and significant reduction in hydrocodone

use (p =0.013). There were no adverse events.
Ohkoshi et 21 patients G1: continuous 1. Pain intensity (VAS)
al., 1999 CCD (5°C) 2. Use of analgesic medication : total doses of 25 mg of
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G1 (n = 7) diclofenac sodium consumed, via suppository.

Quasi-RCT G2 (n = 7) G2: continuous 3. Blood loss (ml)
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G3 (n = 7) CCD (10°C) Outcomes measurement: 48 hours after surgery

10 M / 11 W G3: no cold therapy G2 had significantly lower VAS pain scores and fewer number
mean age 22.1 y of analgesic doses than G3 (p <0.05). Blood loss was
significantly lower in G1 than in G3 (p <0.01).
There were no adverse events.
Dambros et 19 patients G1: ice packs 20 1. Pain intensity (VAS)
al., minutes, twice a 2. ROM (in degrees)
2012 G1 (n = 10) day Outcomes measurement: 24 hours after surgery.
G2 (n = 9)
RCT 19 M / 0 W G2: no cold therapy There were no significant differences between groups. There
mean age 29.5 y were no adverse events.
Waterman 36 patients G1: CCD (3 1. Pain intensity (VAS)
et al., sessions (30 2. Edema (knee circumference measured using tape)
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2012 G1 (n = 18) minutes) / day for 6 3. Use of analgesic medication (not reported)
15 M / 3 W weeks) 4. Knee function (Lysholm score)
RCT mean age 28.7 y 5. Quality of life (SF-36)
G2: Conventional Outcomes measurement: 1, 2, and 6 weeks after surgery
G2 (n = 18) ice pack therapy (3
15 M / 3 W sessions (30 G1 had significantly lower VAS pain scores (p < 0.0001) and
mean age 30.9 y minutes) / day for 6 discontinued use of pain medications, by 6 weeks (p = 0.0008).
weeks) There were no adverse events.
CCD, Cold compression device; G1, group 1; G2, group 2; G3 group 3; G4 group 4; IM, intramuscular; IA, intra-
articular; M, men; ml, milliliters; mg/Kg, milligrams/kilograms; Quasi-RCT, quasi-randomized controlled trial; RCT,

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randomized clinical trial; ROM, range of motion; VAS, visual analogue scale; W, women; y, years.

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