Third Generation Cryotherapy Reduces Time to Surgery and Local Complication in Patients With Ankle Fractures: a Prospective Randomized Controlled Trial
Phase: NA
Conditions: Ankle Fractures
Sponsor: Azienda Ospedaliera San Camillo Forlanini

1 
 
Title of the study:  Third generation cryotherapy reduces time to surgery and local 
complication in patients with ankle fractures: a prospective randomized controlled trial. 
Type of the Paper: Randomized Controlled Trial.  
NCT number: not available 
Article ID: cryotherapy012021.n01 
Date of the document: 24/04/2024  
 
 
This is a RCT about the preoperatory use of third generation cryotherapy in patients hospitalized for 
ankle fracture. The aim of this study is to assess the effects of third generation cryotherapy on time 
to surgery, pain, opioids intake, and local skin complications. Although the use of cryotherapy is 
traditionally believed to reduce pain, swelling, local skin complications and the need of analgesia, the 
results on ankle surgery are not well reported and still contradictory. The working hypothesis is that 
third generation cryotherapy is a safe, reduces time to surgery and is useful in the surgical 
management of ankle fractures  
We confirm that each author of this article meets the journal's criteria for authorship. We confirm that 
the manuscript has not been submitted or is not simultaneously being submitted elsewhere, and that 
no portion of the data has been or will be published in proceedings or transactions of meetings or 
symposium volumes. 
Fiximed Italia, Rome, Italy, funded the APC, but the company had no role in the design of the study, 
in the collection, analyses, or interpretation of data, in the writing of the manuscript, and or in the 
decision to publish the results.  
The authors declare no external funding or other benefits from commercial sources for the work 
reported on in the manuscript, nor any other financial interests which could create a potential conflict 
of interest.   
Thank you 
Kind regards 
 
 
 
 
 

2 
 
Third generation cryotherapy reduces time to surgery and local complication in 
patients with ankle fractures: a prospective randomized controlled trial. 
 
Study protocol and statistical analysis 
 
We analyzed the prospectively collected data of 169 patients with ankle fracture, treated with open 
reduction and internal fixation (ORIF). Patients were randomized in two groups at the time of the 
diagnosis in the emergency department. The treatment group (T: 89 patients) were treated with a 
third-generation cryotherapy device (Z- One®, Zamar) which was applied daily for 2 hours two times 
a day up to the day of surgery. The leg was immobilized in a walking boot which was removed when 
the cryotherapy device was applied.  The control group (C: 80 patients) did not use cryotherapy before 
surgery, the leg was immobilized into a half cats and elevation of the injured limb was indicated. 
Patients were collected in two different hospitals (Azienda Ospedaliera San Camillo Forlanini -Roma 
and Ospedale San Paolo – Civitavecchia) between 2021 and 2023. All patients had signed a written 
consent, and the study was approved by the local ethic committee. 
 
Inclusion and exclusion criteria 
Patients admitted to the emergency department with an ankle fracture were included in the current 
study. Exclusion criteria were open fractures, fracture-dislocations which required external fixation, 
patients with one or more associated fractures, and patients with a diagnose of major trauma. Patients 
who were not able to complain with the pre and post-surgical indications were also excluded.  
 
Patients’ assessment  
A detailed physical examination was conducted in all patients, who were examined in the emergency 
department by local orthopedic surgeons. All patients underwent standard radiographs to diagnose 
the fracture, and computed tomography for the preoperatory planning if indicated. After the diagnosis 
was made and surgical treatment was indicated, the patient was hospitalized in the department of 
orthopedic and trauma surgery. Patients of group T were immobilized in a walking boot to allow the 
use of the cryotherapy device. Patients belong to group C were immobilized in a half cast. Pain was 
evaluated according to the Visual Analogue Scale (VAS) and the analgesic drug demand (including 
morphine or acetaminophen). The Body Mass Index (BMI), number of cigarettes smoked, presence 
of preoperative skin complications were assessed on a daily basis.  
 
Surgical technique 

3 
 
Under loco-regional anesthesia, the patient was positioned supine with a little rise under the buttock, 
or in prone decubitus if posterolateral surgical approach was indicated to reduce the posterior 
malleolus. A tourniquet was applied at the tight, and the lower limb was prepared and draped in the 
usual sterile fashion. Lateral malleolus was approached first, reduced and fixed with a plate and 
screws. Then, surgical technique varied depending on the pattern of fracture, distal tibiofibular 
syndesmosis injury or associated soft tissue injury, as deltoid ligament rupture.  
All patients received intraoperative antibiotic treatment, intravenous controlled analgesia for 24–48h 
after surgery, and standard thromboembolic prophylaxis with low molecular weight heparin (LMWE) 
for up to complete weight bearing. Passive motion of the ankle was encouraged from the first post-
operatory day.   
 
Statistical analysis 
A power analysis was performed to evaluate the sample size necessary to guarantee a power of at 
least 0.9 with a significance level of 0.05 using preliminary data on time to surgery. 
Univariate descriptive analysis of the variables under study was carried out by calculating the 
centrality and variability indices for the quantitative variables and frequency tables for the variables. 
The homogeneity of the control group and the treatment group for the variables sex, age, type of 
fracture, diabetes, hypercholesterolemia, venous insufficiency, and BMI class were checked. 
Depending on the nature of the variables, a t-test or a chi-square test was used. 
Any significant differences between the treatment and control groups were assessed using 
independent samples t-tests for quantitative variables and chi-square tests for qualitative variables. 
Where the sample size is not sufficient, the non-parametric Mann-Whitney test for independent 
samples was used. 
An alpha significance level of 0.05 was used in all analyses mentioned. For the statistical analysis of 
data, IBM SPSS Statistics software version 28 was used. 
 
  
 
 
 
 
 
 
 
 
 
 

4 
 
 
 
 
 
CONSORT 2010 Flow Diagram 
 
Assessed for eligibility (n=351) 
Excluded  (n=182) 
   Not meeting inclusion criteria (n=161) 
   Declined to participate (n=0) 
   Other reasons (n= 21) 
Analysed  (n=89) 
 Excluded from analysis (give reasons) (n=0) 
Lost to follow-up (give reasons) (n=0) 
Discontinued intervention (give reasons) (n=0) 
Allocated to third generation cryotherapy 
(n=89) 
 Received allocated intervention (n=89) 
 Did not receive allocated intervention (give 
reasons) (n=0) 
Lost to follow-up (give reasons) (n=0) 
Discontinued intervention (give reasons) (n=0) 
Allocated to control group (n=80) 
 Received allocated immobilization and 
elevation (n=80 ) 
 Did not receive allocated intervention (give 
reasons) (n=0) 
Analysed  (n=80) 
 Excluded from analysis (give reasons) (n=0) 
 
Allocation 
Analysis 
Follow-Up 
Randomized (n=169) 
Enrollment