BENEFITS OF OZONE THERAPY IN THE TREATMENT OF FOOT ULCERS IN PEOPLE WITH DIABETES MELLITUS

Objective: To identify the benefits of ozone therapy in the treatment of foot ulcers in people with diabetes mellitus. Method: Literature review carried out in the CINAHL, Cochrane Library, LILACS, PUBMED, SciELO, SCOPUS and Web of Science databases in the period between April and May 2020. In each database, the controlled descriptors were delimited in the Science Descriptors of Health and Medical Subject Headings, keywords defined: Ozone (Ozone), Diabetic Foot (Diabetic foot), with the help of the Boolean operator AND. Results: 14 primary studies were selected. Most studies have level II evidence, published in English, in different journals, from different parts of the world. 15 benefits of ozone therapy for the treatment of foot ulcers were identified, with a predominance of increased granulation tissue and intensification in the progress of tissue repair. Conclusion: The use of ozone therapy has shown several benefits in the progress in tissue repair of foot ulcers in people with diabetes, increased granulation tissue, promoted antiseptic and bactericidal activities, preventing oxidative stress. DESCRIPTORS: Ozone. Diabetic foot. Therapeutics. Stomatherapy.


INTRODUCTION
Ozone therapy is a therapeutic resource that uses the ozone molecule as its main component, and its application can be combined with oxygen in different concentrations. Manipulated since World War II, ozone has been touted as an adjuvant therapy for wound care 1 . The Federal Council of Nursing (Conselho Federal de Enfermagem-COFEN),through Normative Opinion No. 001 of 2020, it recognized and regularized ozone therapy as a complementary practice that can be carried out by nurses, under the condition that they are qualified. The agency guides professionals to reach 120 hours in courses on the subject. In nursing, technology can be applied to improve outcomes to treat injuries of different etiologies, thus raising the quality of care for patients affected with skin lesions 4 .
A class of injury that can be treated with this type of adjuvant therapy is foot ulcers in people with diabetes mellitus (DM), which can involve several sensory, motor and foot deformities, which can aggravate and condition necrosis and/or serious infections, the result of incorrect and deficient actions in the prevention of this clinical condition 5 .
Foot ulcers are the main cause of hospital admissions within the group of people affected with DM, therefore, it is the disease that promotes higher costs to health services, and the risk of non-traumatic amputations and even death 6 . The estimated number of deaths from diabetes and its complications in 2019 is 4.2 million people. Scary index that expresses the equivalence of one death every 8 seconds 7 .
Thus, the treatment of foot ulcers in people with DM can benefit from the adjuvant action of ozone therapy, since the technology has oxidizing and disinfecting properties1. Clinical studies carried out in Iran and Russia identified a reduction in infection and amputations in the feet of people with DM who underwent treatment with ozone 8,9 . Knowing the benefits of new technologies and improving existing protocols can contribute to reducing the rates of amputations caused by DM complications, with the diabetic foot being one of the most relevant causes. Ozone therapy as an adjunct technology is an important milestone for health. Knowing its benefits and the best way to apply it to foot ulcers is essential. This generates optimization in the handling of technology, better quality assistance and significantly important advances for the scientific field, arousing curiosity and epistemological considerations to be investigated by the scientific community. This study aims to identify the benefits of ozone therapy in the treatment of foot ulcers in people with DM.

Type of study
This is a Literature Integrative Review (IR). In this type of study, a methodological approach is used, in which it is intended to carry out a review to fully understand the phenomenon examined. A combination of data from the literature and other deliberations is carried out, such as: definition, review of theories and analysis of questions about problems of peculiar models 10 . The textual corpus was built through scientific productions that report benefits of the application of ozone therapy in the treatment of diabetic foot ulcers.

Methodological framework
The integrative review followed six steps: I) Construction of the research problem; II) Sample screening from descriptors; III) Collection of relevant information; IV) Analysis of information related to the researched topic; V) Appreciation and interpretation of the collected results; and VI) Data exposure 11 .

Methodological path
In this process, the PICO strategy was used: where P refers to the population, patient or problem (people with diabetic foot ulcers), I intervention (treatment with ozone therapy), element O refers to the outcome (beneficial effects of ozone therapy in the treatment of the lesion of interest in this study), whereas element C, of comparison between intervention or group, was not used due to the type of review 12 . Therefore, the guiding question of this study, based on the PICO method, is: "What are the benefits of ozone therapy in the treatment of diabetic foot ulcers?".

Data extraction source
The bibliographic survey took place between April and May 2020. To search for primary studies, seven databases were SciELO databases, the search strategy used was "Ozônio AND Pé diabético". In the CINAHL, COCHRANE, PUBMED, SCOPUS and Web of Science databases, the strategy used was "Ozone AND Diabetic foot".

Data collection
There was no delimitation in the dates of publication of the studies, which followed in a timeless search. The delimited eligibility criteria were primary studies, which addressed therapeutic procedures in the treatment of diabetic foot ulcers with ozone therapy, available free of charge in full and published in Spanish, English and Portuguese. Publications that did not meet the guiding question of the study, studies with lesions of other etiologies, review articles, studies with animal species or in vitro, repeated theses, dissertations, letters to the editor or articles unavailable in the databases were excluded. The extraction of data from primary studies was performed with the subsidy of an instrument developed and submitted to face and content validation 13 .
The level of evidence was defined according to the classification: level I -meta-analysis of controlled and randomized studies; level II -experimental study; level III -quasi-experimental study; level IV -descriptive/non-experimental study or with a qualitative approach; level V -case report or experience; level VI -consensus and expert opinions 14 . Data analysis of the integrative review was elaborated descriptively. Each study included was analyzed in detail by the authors and two summary tables were prepared, containing the following information: the first table contains the title of the articles, source database, author citation, year and country of production, purpose of the study, sample, type of study and level of study; in the second, the organization is done by name of author(s), year of publication, frequency of application of ozone therapy, form of application and main result found by the research.

Ethical aspects
All scientific productions used in the research were duly cited and referenced, respecting copyright.

RESULTS
The initial search identified 210 records in the selected databases. After reading the title and abstract, 168 articles that did not meet the eligibility criteria were excluded, as they presented a different theme.
42 articles were selected for reading the title and abstract. There were 14 articles excluded due to duplication and, thus, 28 articles were selected for full reading. Among the 28 studies evaluated as fully eligible, 12 were incomplete and/or inaccessible, 1 article was carried out with an animal model and another was inconsistent with the study's guiding question, which were excluded. Thus, 14 primary studies comprised the sample of this IR, according to the flowchart described in Fig. 1.

Benefits of ozone therapy in the treatment of foot ulcers in people with diabetes mellitus
The final analysis included 14 studies with 1,148 people with diabetic foot ulcers, which aimed to identify the safety and/or efficacy of ozone therapy in the treatment of foot ulcers. Most studies have level II evidence, published in English (n = 9) in different journals, from different parts of the world, which are described in Table 1.   Table 2 shows the application protocols for ozone therapy and the results achieved with the use of this therapy. The application frequency varied according to the assessment of the lesion; the application time ranged from two weeks to months.
Different methods of application of ozone therapy were used, such as local application, intravenous, rectal insufflation and intralesional injection, in different concentrations of ozone.
The most used method was the local application, through bagging of ozone in the lesion. Only in the intralesional injection method were there negative results. In other studies, there was an improvement in the tissue repair process, granulation, epithelialization, pain reduction, antisepsis, reduction in the need for major and minor amputations, improvement in blood glucose levels, in addition to bactericidal and fungicidal effects. Table 3 shows the 16 benefits of ozone therapy reported in the studies analyzed. The most frequent benefits were progress in tissue repair and granulation, antiseptic and bactericidal effects, prevention or inhibition of oxidative stress, and improvement in vascularization and glycemic control.
Benefits of ozone therapy in the treatment of foot ulcers in people with diabetes mellitus

Application frequency Form of application Main result
Fathi; Mawsoufn; Viebahn-  Multiplies collagen fibers 8 Increases the expression of VEGF, TGF-β and PDGF proteins. 8 Reduces the percentage of platelet aggregation 15 VEGF = vascular endothelial growth factor; TGF-β = transforming growth factor beta; PDGF = platelet-derived growth factor.

DISCUSSION
The analysis of the results of the studies included in the review allowed the identification of compliance regarding the use of ozone therapy as an adjuvant for the treatment of foot ulcers in people with DM.
Ozone therapy proved to be a beneficial therapy, with a predominant outcome of increased granulation tissue and advances in the tissue repair process. Furthermore, studies suggest that ozone therapy has antiseptic and bactericidal properties, acts to prevent or inhibit oxidative stress, improves the level of pain, tissue vascularization and glycemic control.
Cuban studies report that such characteristics can significantly contribute to the reduction of hospital admissions 16,19,25 .
Ozone therapy also showed signs of systemic improvement and promoted physiological benefits in the user's body as a whole. A study in Iran identified as a benefit of ozone therapy the reduction in sedimentation of erythrocytes, c-reactive protein and reduced fasting blood glucose 8 .This data demonstrates that the therapy under study can provide the patient with secondary outcomes that help in conducting foot ulcer healing.
Studies in Russia, Ukraine and Egypt corroborate the beneficial results of the use of ozone not only for ulcers, since this therapy secondarily induces the normalization of the white blood cell count, with a reduction in segmented leukocytes, an increase in the number of lymphocytes and monocytes, and characteristic of immunomodulation, which is documented as a transition from degenerative to regenerative inflammatory effect 9,17,21 .
Systemic ozone therapy also reduced reports of complaints of thirst, dry mouth sensation, polyuria, and increased catalase activity, in addition, there is a record of clinical cardiac improvement 17,21 27 . These data demonstrate the effectiveness of ozone use in tissue repair time.
There was a predominance of local application of ozone, with ozone in bags (bagging). The use of ozone in this way was successfully used by researchers from China, Israel and Cuba, through an occluded chamber, with a mixture of oxygen and ozone 15,16,20,22 . The greatest preference for local application in bagging may lie in the fact that it requires simple, low-cost, safe and minimally invasive techniques, and, thus, it is more acceptable to patients.
However, there is variability in application frequency, formulation type and ozone/oxygen concentration. This reason can be related to the fact that there is a variability of protocols, but none has been disseminated as the most suitable for use in diabetic foot. Another point that can explain this situation is the fact that ozone therapy is considered a contemporary technology, which can generate the existence of a variability of tests and studies that are still in progress.
The safety of handling ozone therapy and its effects is a factor that has stimulated research in the area. Knowing innovative adjuvant techniques is an evolutionary milestone for each field, investigating and elaborating questions is also a function that brings implementation of care, each process that generates research, produces science and entails several welcome conditions in the user's life. Despite having limitations, such as the unavailability of some studies in their entirety, this review presents promising data regarding the benefits of using ozone therapy in the treatment of foot ulcers in people with DM. The data found in this review may contribute to evidence-based practice, innovation in nursing care for people with DM and foot ulcers.
New studies are expected to show increasingly promising results on the use of ozone in the treatment of diabetic foot, frequency of application, type of formulation and ozone/oxygen concentration to validate the efficacy and safety data demonstrated in this review.

CONCLUSION
The use of ozone therapy in the treatment of diabetic foot has the benefit of progress in tissue repair, increase in granulation tissue, antiseptic and bactericidal properties, prevention or inhibition of oxidative stress, improvement in tissue vascularization, improvement in glycemic control, improvement in pain , decreased amputation rates, reduced hospital stay, reduced edema, multiplication of collagen fibers, reduced percentage of platelet aggregation and increased expression of vascular endothelial growth factor (VEGF) proteins, transforming growth factor beta (TGF-β) and platelet-derived growth factor (PDGF). It is noteworthy that ozone therapy points to an arsenal of therapeutic resources to accelerate the healing of foot ulcers in diabetic individuals and at a lower cost than conventional treatments.