This is a parallel, two-arm, non-blinded, randomized controlled trial in the single center.
The study will be conducted in the city of Imperatriz, Maranhão in diabetic patients with chronic foot ulcers (classified as grade 2, 3 and 4 of Wagner  and persisting for more than one month). The outpatient follow-up for diabetic foot patients will be done at the SUS (Unified Health System - a public health service for the entire Brazilian population), with HBOT sessions being held in the CicatrizAR Clinic.
Sample and Study Period
The sample will consist of diabetic patients with chronic foot ulcers treated with standard methods, i.e. dressings, debridement, antibiotics, and load relief (control group), and to the other group will be added HBOT (HBOT group). The study will be conducted from 2019 to 2020.
The sample size has been calculated based on the formula for comparing two independent groups according to qualitative variables , with 95% confidence interval and 80% power. A wound healing rate of 90% was considered for the case group and the control group had less than 20% wound healing rate. Thus, the sample size comprised of 60 patients per group.
Registration number RBR-7bd3xy. Registered 17 July 2019. The first recruitment was held on 04 July 2019 and the last recruitment is foreseen on 31 August 2020.
The inclusion criteria of the study are adult patients (age > 18 years), stable clinical presentation, diabetes type 1 and 2, Wagner Grade 2, 3, and 4 foot ulcers, ulcers persisting for more than one month without cure, authorisation for the study, and patients of the SUS (Unified Health System).
Exclusion criteria of the study are failure to meet one of the inclusion criteria, patients with macroangiopathy (absent distal pulses), and patients with contraindications for HBOT, absolute or relative, patients on bleomycin chemotherapy, with chronic obstructive pulmonary disease, previous spontaneous pneumothorax, chronic sinusitis, chronic otitis media, unstable angina, severe congestive heart failure, claustrophobia, severe dementia, depression, and history of seizures.
The data collection will be performed in the diabetic foot outpatient clinic of the SUS and in the CicatrizAR clinic, using a standardised questionnaire provided in the Supporting Information, as well as with photographic recording of the ulcers, according to the timeline described in Figure 1.
Figure1. The schedule of enrolment, interventions, and assessments.
This is a parallel, two-arm, non-blinded, randomized controlled trial in which an randomization will be performed using a simple draw 1:1 by the research coordinator.
The patients of the HBOT group will be evaluated upon admission, after 10, 20, 30 and 35 HBOT sessions and after six months and one year; and the control group will also be assessed at equivalent periods (upon admission, after 2, 4, 6 and 7 weeks, six months and one year) to clinically evaluate the ulcers and perform specific measures using the software ImageJ, developed at the National Institutes of Health (NIH, Bethesda, Maryland). The progression of the wounds and specific treatment such as appropriate bandage, antibiotic therapy, or need for some surgical intervention will be evaluated on a weekly basis. The HBOT sessions will be conducted five days a week, being carried out with patients in a multiplace chamber at 2.5 atmospheres absolute (ATA) and 100% O2, with 10 minutes for compression and decompression, effective sessions of 90 minutes, with intervals of 5 minutes for each 30 minutes of treatment. The dressings will be done in both groups with Exufiber foam Ag ® (Molnlycke, Gotemburgo, Suécia) or Mepilex® (Molnlycke, Gotemburgo, Suécia), which will be chosen according to the characteristics of wounds, with silver dressings for the infected injuries and a foam with polyurethane protective layer for wounds in which granulation tissue has formed. The progression of the wounds and specific treatment, such as appropriate bandage, antibiotic therapy, or need of some surgical intervention will be evaluated on a weekly basis.
The SF-36 quality of life questionnaire will be filled upon admission and after three months of follow-up in both the groups. On admission, the patients of both groups will undergo arterial Doppler ultrasound, and patients with macroangiopathy will be excluded from the research. Laboratory examinations, such as a haemogram, erythrocyte sedimentation rate, levels of C-reactive protein, creatinine, fasting blood glucose, and glycosylated haemoglobin will also be estimated only on admission.
Wound healing will be assessed by evaluating the diameter of the lesions by specific software and periods, as described in the interventions.
Amputation rates will be assessed, with an evaluation of statistical significance between the groups. The evaluation of the domains of the SF-36 quality of life questionnaire will also be done in both groups. The data from this questionnaire upon admission and after three months of follow-up will be compared.
The collected data will be stored in a Microsoft Excel 2016 spreadsheet format. After checking for errors and inconsistencies, descriptive examinations will be performed by means of absolute and relative frequencies and measures of central tendency and variability. We will only analyze the data of patients who follow the intervention, those who do not continue the intervention will be considered sample loss. Blinding will be done for the researcher who will evaluate the final data and for the statistician.
The chi-square test or an equivalent test will be used to assess associations between the categorical variables, odds ratios (ORs), and confidence intervals will be calculated by means of logistic regression. Student's t-test or a similar non-parametric method will be used for the analysis of continuous variables. All examinations will be performed at 5% significance in the IBM SPSS® program, Version 24.0, 2016 (IBM, Armonk, New York, USA).
This study will be based on the principles of Resolution 466/12 of the National Health Council that regulates the research involving human subjects. The patients involved shall be duly informed and clarified about the importance and purpose of the study; if patients accept to participate, they will sign an informed consent form (see supporting information). The non-participation in the study or waiver, privacy, reliability, and anonymity of the participants will be guaranteed.
The study was initiated after approval by the Research Ethics Committee of the ABC University. It is registered with the Brazilian Registry of Clinical Trials (ReBEC) under the number RBR-7bd3xy.
This study is being conducted in accordance with the guidelines of the Brazilian Society of Hyperbaric Medicine (SBMH) and Undersea & Hyperbaric Medical Society (UHMS), and if adverse events occur (such as dizziness, seizure, pneumothorax, pneumomediastinum, nauseas, middle ear barotrauma, seizure, ear pain, confinement anxiety, hypoglycemic event and shortness of breath), these will be conducted according to these guidelines, as well as be documented and published later.