HYPERBARIC OXYGENATION IN PREVENTION OF AMPUTATIONS OF DIABETIC FOOT HIPERBARIČNA OKSIGENACIJA U PREVENCIJI AMPUTACIJA DIJABETIČNOG STOPALA

Background/Aim. Diabetic foot is the term for the pathological changes on foot in patients with diabetes. It is caused by diabetic angiopathy, polyneuropathy and osteoarthropathy. The treatment is complex and long-term and often leads to the loss of the extremity. The appliance of hyperbaric oxygen therapy (HBOT) has a lot more important place in adjuvant treatment of this disease. The aim of this study was to determine the influence of HBOT on the wound healing in comparison with the conventional treatment, the possibility of shortening the time of the treatment in patients with diabetic foot. Methods. In a fiveyear period a retrospective-prospective multicentric study, involving 60 patients with diabetic foot divided into two groups, was performed. The first group (group A) consisted of 30 patients treated by combined therapy (with medications, surgical therapy and HBOT). All the patients were receiving HBOT in the Special Hospital for Hyperbaric Medicine, CHM Hollywell-Neopren in Belgrade. The control group (group B) also consisted of 30 patients treated with medications and surgical therapy, but without HBOT. Results. The demographic data, the types of diabetes, as well as the Wagner classification stage of diabetic ulcers and radiography scans of changes in bones were equal in both groups. The median healing time of the Wagner grade III ulcer in the group A was 37.36 days [mean ? standard deviation (SD) = 65.6 ? 45.8 days], and in the group B 99.78 days (mean ? SD = 134.8 ? 105.96 days) and it was statistically significant (p = 0.074). The median time of recovery in patients of the group A with the Wagner grade IV was 48.18 days (mean ? SD = 49.7 ? 33.8 days), and in the group B 85.05 days (mean ? SD = 86.7 ? 71.6 days) and that was statistically significant (p = 0.121). The foot amputations were performed in both groups in 3 (10%) patients. In the group A there were no high amputations, whereas in the group B there were 4 (13.33%) below-knee amputations and 4 (13.33%) above-knee amputations which was highly statistically significant (p < 0.0001). Conclusion. In this study, HBOT definitely showed positive adjuvant role in the treatment of diabetic foot. For the good treatment result it is essential the timely and successful surgical treatment of the ulcer and the use of bandage with the healing dressings. In case of the clear signs of local infection, the antibiotic therapy according to the antibiogram is necessary.


ABSTRACT
Diabetic foot is the term for the pathological changes on foot in patients with diabetes and is caused by diabetic angiopathy, polyneuropathy and osteoarthopathy.The treatment is complex and long-term and often leads to the loss of the extremity.The appliance of hyperbaric oxygen therapy (HBOT) has a lot more important place in adjuvant treatment of this disease.
The aim of this paper is to determine the influence of HBOT on the wound healing in comparison with the conventional treatment, the possibility of shortening the time of treatment and the reduction of the treatment cost of patients with diabetic foot.
In a five-year period a retrospective-prospective multicentric study was carried out which involved 60 patients divided into two groups.The first group (Group A) consisted of 30 patients treated by combined therapy (with medications, surgical therapy and HBOT).
All the patients were receiving HBOT in Special Hospital for Hyperbaric Medicine, CHM Hollywell-Neopren in Belgrade.The control group (Group B) was of 30 patients with diabetic foot as well and was treated with medications and surgical therapy, but without HBOT.
The demographic data, the types of diabetes, as well as the Wagner classification stage of diabetic ulcers and the X ray scans of changes in bones were statistically equal in both groups.
The average healing time of Wagner grade III ulcer in Group A was 37.36 days (65.6±45.8),and in Group B 99.78 days (134.8±105.96)and it is statistically significant (p=0.074).
The patients in grade IV in the Wagner classification in group A had the average time of recovery 48.18 days (49.7±33.8),and in Group B 85.05 days (86.7±71.6)and that is statistically significant (p=0.121).
The foot amputations were performed in both groups on 3 patients (10%).The most significant parameter of success in the treatment is high amputation that showed that in group A was not perfomed a single one high amputation, whereas in group B there were made 4 below-knee amputations (13.33%) and 4 above-knee amputations (13.33%) which is highly significant (p<0.0001).
In this study, as with many other authors, HBOT has definitely shown positive adjuvant role in the treatment of diabetic foot.For the good treatment result it is essential the opportune and successive surgical ulcer treatment and the use of bandage with the healing dressings.In case of showing the clear signs of local infection, the antibiotic therapy according to the antibiogram is necessary.Key words: Diabetic foot, Hyperbaric oxygene therapy, High amputations APSTRAKT Dijabetičnim stopalom nazivamo patološke promene na stopalu kod pacijenata koji boluju od šećerne bolesti, a uzrokovane su dijabetičnom angiopatijom, polineuropatijom i osteoartropatijom.Lečenje je kompleksno i dugotrajno i često dovodi do gubitka esktremiteta.Primena hiperbarične oksigene terapija (HBOT) ima sve značajnije mesto u adjuvantnom lečenju ovog oboljenja.CiIj ovog rada je utvrĎivanje uticaja HBOT na efikasnije zarastanje rane u poreĎenju sa konvencijalnim lečenjem, mogućnost skraćenja vremena lečenja i smanjenje troškova lečenja bolesnika sa dijabetičnim stopalom.

INTRODUCTION
Diabetic foot is the term for the pathological changes on foot ensued due to ischaemia as a consequence of microangiopathy, the late notice of soft tissue damage and slow ulcer healing as a result of polyneuropathy as well as the uneven pressure of footwear due to the deformation of foot because of diabetic osteoarthropathy [1].The curing demands complex multimodal treatment, including the regulation of glycaemia, the antibiotic therapy, the local treatment of the ulcer, as well as surgical or endovascular revascularization in patients with macro-occlusive artery disease.The healing of diabetic foot ulcer is long-term and in 60% of patients it lasts about one year.All this is accompanied by high treatment costs and additional social problems [3].In the most of European countries 10% of health care costs is expended on diabetes treatment, and 68% of that is spent on the curing the disease complications.
In the newer literature hyperbaric oxygen therapy has a lot more significant place in adjuvant treatment of this disease [4].HBOT is breathing 100% oxygen in a special chamber, in higher ambient pressure conditions (2.0-2.9Kpa), determined by the particular protocols.The oxygen contents in plasma increases from 0.3 to 5.62 volume percents.The average number of treatments is 20 (from 15 to 30).In normal conditions haemoglobinbound oxygen is transported to the cells in erythrocytes.In the hyperbaric pressure conditions, according to the laws of physics, there is the increased dissolution of molecular oxygen in plasma which enables the oxygen supply even there where the blood vessels are narrowed (the capillary lumen is smaller than the erythrocytes' diameter) or occlusive [5,6].To those patients HBOT ameliorates the peripheral tissue oxygen supply, and in addition to that oxygen has antibacterial (for anaerobic flora it is bactericidal), antiinflamatory and imunosuppressive effects [7,8].These effects are made by the inhibition of prostaglandin gamma interferons (IFNG), interleukin-1 and interleukin-2 [9].The hyperbaric oxygenation is beneficial for wound healing due to stimulation of fibroblast proliferation and differentiation and rapid collagen synthesis [10].The neovascularization is stimulated and the energy metabolism of peripheral cells is increased.
The aim of this paper is to determine the significance of HBOT as the adjuvant therapy that may influence on: the efficient healing of diabetic foot ulcer in comparison to conventional type of treatment (with medications and surgical treatment); the possibility of shortening the time of diabetic foot healing and reducing the treatment costs in patients with diabetic foot.

MATERIALS AND METHODS
In a five-year period it was conducted a retrospective-prospective multicentric study, which involved 60 patients divided into two groups.The first group (Group A), which consisted of 30 patients, was treated by combined therapy (with medications, surgical therapy and HBOT).There were 25 patients from The Clinic for Surgery, Zvezdara and the rest 5 of them were from The Clinic for the Vascular and Endovascular Surgery, Clinical Center of Serbia.All the patients were receiving HBOT in Special Hospital for Hyperbaric Medicine, CHM Hollywell-Neopren in Belgrade.
The control group (Group B) was of 30 patients with diabetic foot as well and it was treated with medications and surgical therapy, but without HBOT.23 patients were treated in The Clinic for Surgery, Zvezdara and the rest 7 of them in The Clinic for the Vascular and Endovascular Surgery, Clinical Center of Serbia.
In this study were included only the patients with diabetic foot with whom it was by non-invasive examination (Color duplex sonography -CDS, Ankle brachial index -ABI) concluded that the magistral arteries were passable and that surgical or endovascular revascularization were not indicated.Before the treatment, the X-ray scans were made to all the patients and the wound smear was taken for the bacteriological examination.The complete recovery considered the state of full epithelialization of the wound or recovery of inflammatory changes (soft tissue and the bone).In patients with the amputation the recovery considered the full healing of the amputation stump.
In Tables 1 and 2 the whole patients' material is shown (  and Medians with the corresponding 95% confidence intervals were estimated.Analyses were performed using SPSS for Windows version 22 (SPSS, Inc., Chicago, IL).

RESULTS
The Group A was treated by combined therapy (with medications, surgical therapy and HBOT), and the Group B was treated in the same way, but without HBOT.In Table 3 is demonstrated that there are no statistically significant difference in demographic data in both groups, as well as in gender and age (p=ns).
In Group A there were 11 patients with type 1 diabetes and 19 of them with type 2.
In control group there were 12 patients with type 1 and 18 of them with type 2 diabetes.
There is no statistically significant difference in representation of diabetes type (p=ns).
Among 30 patients in Group A, 12 of them were with Wagner grade III ulcers and 18 of them with Wagner grade IV ulcers.In control group (Group B) there were 10 patients with ulcers grade III in the Wagner classification system, and 20 with Wagner grade IV ulcers (Table 4).
Based on the X-ray foot results, the patients were divided into the subgroups with osteoporosis, osteoarthropathy, osteomyelitis and the normal X-ray results on foot bones.In Group A the normal result was in 50% of cases, and 60% in Group B (Table 5).
The most frequent pathological result was osteomyelitis, which is diagnosed in 30% in Group A and in 26.67% of patients in Group B (p=0.262).This kind of the X-ray result of foot bones does not differ significantly among groups.
The type of surgical intervention depended on the local result (Table 5).Incision and drainage were performed in 5 patients in total, in Group A in 3 (10%), whereas in Group B in 2 patients (6.7%).
Necrectomy was the most frequent intervention in Group A (in 17 patients or in 56.7%) while in Group B just in 3 patients (10%).The finger amputations were conducted in 23.3% (7 patients) of Group A and in 46.7% (14 patients) of Group B. The foot amputations (transmetatarsal, in Chopart and Lisfranc's joint line) were performed in 3 patients in both groups (10%).There were no high amputations in Group A, but there were 4 below-knee (13.3%) and 4 above-knee amputations (13.3%) (p<0.0001).
In this study the average healing time of Wagner grade III ulcer in Group A was 65.6 days (±45.8)whereas in Group B it was 134.8 days (±105.96)and it is statistically important (p=0.074).
In Group A the patients with Wagner grade IV ulcers had the average time of healing 49.7 days (±33.8), and in Group B 86.7 days (±71.6) and it is statistically significant (p=0.121)(Table 6,Table 7).
The first control examination was carried out immediately after the healing process was finished, the second one was after a month and later on the examinations were carried out in three months.In case of deterioration of the local result the examinations were carried out more frequently.
Ten patients from Group A had some problems after healing of diabetic foot laesion which are:

DISCUSSION
The reasons for the bad outcomes of the healing of diabetic foot ulcer are combined influences of ischaemia with hypoxia of soft tissues, prolonged wound healing due to existing polyneuropathy and propensity to infection [12].Many authors talk about positive influence of oxygen therapy in hyperbaric conditions on the healing or reducing the major complications of diabetic foot ulcer.In this study there are compared the results of treatment of two groups of patients with ulcus changes with Wagner grade 3 and Wagner grade 4 ulcer, within the entity diabetic foot [13].The first group of 30 patients was treated both with HBOT and medication and surgical methods (the experimental group), whereas the other group (the control group) was treated with medication and surgical methods in the same way, but without HBOT.
In regards to significant parameters, this study has shown the positive influence of HBOT on the obtained results, especially in regard with the most important result -high amputation.Moreover, there were no above-knee and below-knee amputations whereas there were 8 amputations in the control group and that is highly significant (p<0.0001).
In patients treated with HBOT the most common side effects were discomfort and ear pain (17-20%) and after that was claustrophobia (13%).The cases of pneumothorax neurological disturbances were not noticed.
Baroni was among the first who published his treatment outcomes with HBOT.
When comparing the two groups of patients (the group treated with HBOT and the group without receiving HBOT) the statistical analysis using chi-square test demonstrated highly significant difference (p=0.001) in favour of HBOT.In regards to the most significant parameter, the limb amputation, HBOT drastically reduced the percentage of amputations [14].These results coincide with our experience.
Kalani and contributors from Karolinska Hospital, Stockholm in their study observed the treatment results of two groups in a follow-up time of 3 years.76% of patients treated with HBOT had healed ulcer lesion and intact skin, whereas in the group of patients treated conventionally that value was 48%.The amputation had to be performed just in 12% in the HBOT group and in conventionally treated control group that value was 33% [15].
The mechanisms that HBOT uses to act positively on healing of diabetic foot ulcer are the reducing of wound exudate and stimulation of granulation process.The values of partial oxygen pressure in the wound surrounding during HBOT may indicate the future treatment outcome.Thus there is positively correlation between TcPO2 and the speed of the wound size reduction and the reducing of wound exudate and the fastness of epithelialization [16].Negative correlation between TcPO2 is determined in the group of patients whose treatment ended with high amputations [17].
The authors who compared the patients with Wagner grade III diabetic foot ulcer and Wagner grade IV ulcer could conclude that HBOT after 30 sessions greatly contributed to prevent of amputations and the healing of the wound by epithelialization Antibiotic therapy has its significant place [18].
Comparing our results with the results of Fedorko and contributors [19]

CONCLUSION
On our material and with many other authors, HBOT definitely has positive adjuvant role in managing diabetic foot.For the optimal treatment results successive surgical ulcer treatment is necessary and the use of bandage with the healing dressings, as well as the treatment of HBOT in patients.In case of showing the clear signs of local infection, the antibiotic therapy according to the antibiogram is necessary.
The medical practitioners, the patients and policy creators should define good clinical practice guidelines of Shared Decision Making for appliance of hyperbaric oxygen therapy as the additional treatment for diabetic foot management.The future researches should be aimed at the improvement of methods for choosing patients, testing various protocols of treatment and improvement of trust in those assessments.The routine implementation of transcutaneous oximetry imposes itself as a simple, cheap and reliable method for early assessment of HBOT efficacy and the patients are not needlessly exposed to the efforts which exist at some degree (arrival from their home to Centre for baromedicine or organizing transport from their hospital to the Centre).The special problem is the treatment cost which should be payed by the Health Insurance Fund without interference with ethical principles that every patient should have the same right on treatment if that treatment is a proper one.All the patients in the control group were admitted to the hospital, and the duration of their stay depended on the healing period.
THE CRITERIA FOR THE STUDY  Palpable pedal pulses  ABI higher than 0.75  Three-phase spectrogram on pedal arteries The surgical interventions were performed in both groups depending on the type of diabetic foot laesion and with:  ulcers -necrectomy  phlegmons -incisions, contra-incisions, drainages  osteomyelitis -incisions, contra-incisions, sequestrectomies  gangrenes -necrectomies or amputations.The transplantation of skin (Thiersch) was performed in a few patients with the amputation of foot in the joint line (Chopart or Lisfranc) in order to shorten the healing period.

o 1 patient
-foot pain and discomfort during walking o 5 patients -ulcer appearing at the different place on the same foot, or ulcer appearing on the other foot o 4 patients -foot deformation after the surgical interventions and discomfort during walking o 4 patients died within a year o 7 patients did not come for the control examination and their state is not known

Table 2 )
1, Statistical Methodology Descriptive statistics were used for the base processing of demographic and clinical characteristics and symptoms, in two groups.Categorial variables were compared by using chi-square test.Continuous variables were compared by ANOVA test, or Median test (for variables without normal distribution).A significance of 0.05 was required.Means (SD)

TABLE 1 , GROUP A PATIENTS
, 24 patients were treated as the inpatients, whereas 6 of patients were treated outpatiently.The number of HBO treatments depended on the Wagner classification stage of ulcers as well as on the approval of extension of treatment by National Health Insurance Fund.