Relevance of the problem
Chronic wounds have been a major global health problem for many years.
Many Russian and foreign authors have studied it, adopting various definitions of this concept and offering many treatment methods for this pathology [1, 3, 6, 9]. Despite the mass of scientific works on this topic and hundreds of proposed innovative treatment methods, the problem of treating chronic wounds is still acute for surgeons all over the world [2–4, 11, 12]. The annual cost of treating chronic wounds reaches $9 billion and requires a lot of time and effort from medical personnel to organize long-term adequate monitoring of this category of patients [5, 6, 8, 10, 12]. In 1996, the European Society for Tissue Repair at a special meeting adopted the definition: “a wound should be considered chronic if it does not heal within a period that is normal for wounds of this type or location.” Domestic authors have supplemented this definition and describe a chronic wound as a wound whose repair is impaired due to unfavorable background conditions. The concept of “chronic wound” is very broad and also includes trophic ulcers, chronic anal fissure and other long-term non-healing wound defects. The reasons behind the formation of chronic wounds are also very diverse. The etiological factors leading to the development of trophic ulcers have been well studied. They can be venous against the background of chronic lymphovenous insufficiency, arterial, with chronic ischemia of the lower extremities, against the background of diabetic polyneuropathy, micro- and macroangiopathy, hypertensive (Martorell syndrome), with systemic diseases (blood diseases, metabolism, collagenosis, vasculitis), neurotrophic, scar-trophic; congestive (against the background of circulatory failure), pyogenic, specific and infectious, malignant, with Lyell's syndrome, with congenital malformations of the vascular system, radiation, artificial [2, 3, 7]. The genesis of most chronic wounds is polyetiological, involving various pathogenetic mechanisms affecting cellular and tissue metabolism, microvascular endothelium [7, 9, 11]. In this regard, it is important to use therapeutic techniques using, in particular, pharmacological drugs that affect various stages of pathogenesis. The drug Actovegin, which has pleiotropic effects, has shown its therapeutic potential in patients with diabetes mellitus and chronic ischemia of the lower extremities, accompanied by ulcerative necrotic complications [1, 3, 4, 7]. Taking into account the above, the goal of our work was to evaluate the effects of the drug Actovegin in the complex treatment of chronic wounds of various etiologies.
Material and methods
Under our supervision were 118 patients aged from 52 to 80 years old, hospitalized in the department of vascular surgery and surgery for purulent complications of diabetes mellitus of City Clinical Hospital No. 81. All patients were treated due to the presence of chronic wound defects. The patients were divided according to the etiological factor into three groups, which included pathological conditions that cause the formation of 90% of long-term non-healing wound defects. Group 1 included 54 patients who suffered from long-term non-healing trophic ulcers of the lower extremities due to chronic venous insufficiency. In all patients, duplex ultrasound scanning (USD) of the veins of the lower extremities diagnosed the incompetence of the saphenous vein valves and the presence of long-term (from 2 to 48 months) non-healing wound defects in the lower and middle thirds of the legs. All patients underwent etiopathogenetic treatment: after a course of antibacterial therapy, taking into account the microbial landscape and cleaning of wound defects, crossectomy was performed in combination with Linton's operation. In the postoperative period, the patients were divided into 27 patients into two groups - the main and control groups, identical in gender, age and severity of concomitant pathology. The patients received drug therapy and local treatment in full. In addition to traditional treatment, patients of the main group received Actovegin intravenously (1200 mg once a day for 14 days) and topically in the form of a gel, ointment or cream, depending on the stage of the wound process:
- in the exudation stage, Actovegin 20% in the form of a gel was used in a thick layer, followed by the application of a compress with Actovegin 5% in the form of an ointment;
- in the proliferation stage, a bandage with Actovegin 5% in cream form was used;
- At the granulation stage, a bandage with Actovegin 5% in gel form was applied.
After discharge, patients were prescribed the drug Actovegin, 1 tablet (200 mg) 3 times a day for 30 days. In the control group, local treatment was carried out with ointment dressings (Betadine, methyluracil, Levosin).
Group 2 included 36 patients with symptoms of chronic arterial ischemia of the lower extremities, as well as long-term non-healing wound defects at various levels of the feet against the background of obliterating atherosclerosis and endarteritis. Ultrasound scanning of the arteries of the lower extremities revealed occlusions of the femoral-popliteal-tibial segment at various levels. All patients underwent correction of the main blood flow according to indications: femoral-distal bypass with autologous or synthetic prostheses, conservative hemorheological (reopolyglucin, dextran, etc.), anticoagulant (heparin, Plavix, Wessel Due F), antiplatelet (pentoxifylline, acetylsalicylic acid) full therapy. In the postoperative period, patients were divided into 18 people into the main and control groups, identical in gender, age and severity of concomitant pathology. In addition to standard treatment, patients in the main group received Actovegin intravenously 1200 mg once a day for 14 days, as well as locally in various dosage forms depending on the stage of the wound process:
- in the exudation stage, Actovegin 20% in the form of a gel was used in a thick layer, followed by the application of a compress with Actovegin 5% in the form of an ointment;
- in the proliferation stage, a bandage with Actovegin 5% in cream form was used;
- At the granulation stage, a bandage with Actovegin 5% in gel form was applied.
After discharge, Actovegin was prescribed 1 tablet (200 mg) 3 times a day for 30 days. In the control group, Actovegin was not used, and local treatment was carried out with Betadine solution, Levomekol ointment, and methyluracil ointment.
Group 3 included 28 patients who had suffered from type 2 diabetes mellitus for a long time, with clinical signs of polyneuropathy and long-term wound defects of the lower extremities, not associated with chronic arterial or venous insufficiency. These patients underwent correction of carbohydrate metabolism (insulin therapy), local treatment including necrectomy (according to indications), hemorheological and neurotropic therapy (Octolipen, Berlition), ultrasonic cavitation of wounds in regeneration mode every other day, dressings with Hydrosorb gel, Betadine solution. These patients were also divided into 14 people into the main and control groups, identical in gender, age and severity of concomitant pathology.
In the main group, in addition to standard treatment, patients received the drug Actovegin intravenously 1200 mg once a day for 14 days, as well as locally in various dosage forms depending on the stage of the wound process:
- in the exudation stage, Actovegin 20% in the form of a gel was used in a thick layer, followed by the application of a compress with Actovegin 5% in the form of an ointment;
- in the proliferation stage, a bandage with Actovegin 5% in cream form was used;
- At the granulation stage, a bandage with Actovegin 5% in gel form was applied.
After discharge, Actovegin was prescribed 1 tablet (200 mg) 3 times a day for 30 days.
In all nosological groups of patients, before and after courses of complex therapy, visual monitoring of wounds was carried out using the MEASURE system [11], and microcirculation studies were also performed using laser Doppler flowmetry. The sensor was located at the bottom of the wound defects. In addition, all patients underwent histological examination of wound biopsies throughout the entire period of hospital treatment in dynamics. Biopsy specimens were fixed in 10% neutral formalin and, according to the generally accepted method, embedded in paraffin blocks. Histological sections 4–5 μm thick made from paraffin blocks were stained with hematoxylin and eosin.
Results and its discussion
In patients of group 1, who were treated for chronic wounds caused by chronic venous insufficiency, a decrease in the area of wound defects (calculated from the linear dimensions of the wounds) in the main group was noted on days 4–5, in the control group – on days 7–9 -e postoperative period.
In both groups, on the 3rd–4th day of the postoperative period, the amount of exudate decreased from moderate to scanty, and we qualitatively assessed the exudate as serous or serous-hemorrhagic. The bottom of the wounds was represented by granulation tissue in both groups. In the main group, pain decreased significantly on days 2–3 of the postoperative period, while in the control group its intensity decreased only on days 5–6. No wound destruction was observed in both groups. Epithelization of the wound edges in the main group was observed on days 3–4, while in the control group – on days 6–7. At the time of discharge, chronic wounds had completely healed in 10 (37%) patients in the main group and in 5 (18.5%) in the control group. 3 weeks after discharge, the wounds healed in all (100%) patients in the main group, and in 15 (55.5%) patients in the control group.
In patients of group 2, who received treatment for chronic wounds caused by chronic arterial insufficiency, a decrease in the area of wound defects was noted in both groups, however, in the main group it occurred on days 4–5, and in the control group on days 7 –8th day after surgery. The amount of exudate decreased from scanty to absent in both groups on the 3rd–4th day of the postoperative period; we assessed the exudate qualitatively as serous-hemorrhagic. The bottom of the wounds was represented by granulation tissue on days 6–7 in 11 (61%) patients of the main group and 6 (33%) of the control group. In the remaining patients, the wounds were completely covered with hard and dry scab. In the main group, the pain syndrome decreased significantly on the 3rd–4th day of the postoperative period, while in the control group its intensity decreased only on the 6th–7th day. No wound destruction was observed in both groups. Epithelization of the wound edges in the main group was noted on days 4–6 and on days 8–10 in the control group. At the time of discharge, chronic wounds had completely healed in 7 (38.8%) patients in the main group and in 3 (16.6%) patients in the control group. During the first 3 weeks after discharge, wounds healed in 12 (66.6%) patients in the main group and in 8 (44.4%) patients in the control group.
In patients of the 3rd group who were treated for chronic wounds against the background of a neuropathic form of diabetic foot syndrome, a decrease in the area of wound defects in the main group was noted on days 2–3, in the control group – on days 4–5 after start of treatment. The amount of exudate decreased from moderate to scanty in the main group on days 1–2, in the control group on days 2–3, and we qualitatively assessed the exudate as serous-hemorrhagic. The bottom of the wounds was represented by granulation tissue in both groups. In the main group, pain decreased significantly on days 2–3 of the postoperative period, while in the control group its intensity decreased only on days 5–6. No wound destruction was observed in both groups. Epithelization of the wound edges in the main group was observed on days 3–4 and on days 5–6 in the control group. At the time of discharge, chronic wounds had completely healed in 12 (85%) patients in the main group and in 8 (57%) patients in the control group. During the first 3 weeks after discharge, wounds healed in all patients of the main group (100%) and in 12 (85.7%) patients in the control group.
Particular attention is paid to the dynamics of ulcer healing in the study groups as one of the most important indicators of the effectiveness of therapy. The results of the study showed that when using Actovegin for external use and intravenous infusions in combination, a month after the start of treatment, epithelization of the ulcer was observed in more than half (53%) of the patients, which is statistically significant.
When using Actovegin externally in the form of a gel, cream and ointment, the average time for cleansing wounds from purulent and necrotic masses, the appearance of granulations was on average less than the time in the control groups for 3-4 days (Table 1). A month after the start of therapy, epithelization of the ulcer defect was observed in 29 patients of the main group and 16 of the control group. In 9 patients of the main group, flaccid granulations with fibrin deposits were observed, in the control group - in 20 patients (Table 2).
The results of studying microcirculation using laser Doppler flowmetry are presented in table. 3.
Histological analysis of biopsy samples from wounds after a period of hospital treatment in all patients receiving Actovegin, compared with patients in the control groups, showed normalization of the processes of proliferation and differentiation of granulation tissue (collagen formation and neovascularization), less pronounced leukocyte infiltration, active processes of epidermization of skin lesions ( growth of the epithelial layer at the border with granulation tissue).
To illustrate the effects of complex therapy, we provide a clinical example.
Patient V., 67 years old, with diabetic foot syndrome, neuropathy of the 2nd degree according to Wagner, trophic ulcer of the plantar surface of the resected right foot against the background of a corn for three months (Fig. 1). The patient was treated as an outpatient at the clinic; as prescribed by the surgeon, dressings with levomekol ointment were used for one month without effect. The patient was sent to the department of purulent surgery and purulent complications of diabetes mellitus as planned. During the examination: clinical and biochemical parameters were within normal limits; ultrasound scanning of the arteries of the lower extremities revealed occlusion of the distal parts of the anterior and posterior tibial arteries.
Upon admission, the patient took a biopsy from the wound (Fig. 2), normalized carbohydrate metabolism, and prescribed local treatment: ultrasonic cavitation in regeneration mode every other day, bandages with Hydrosorb gel. Along with traditional treatment, the patient was prescribed a course of Actovegin 1200 mg intravenously once a day for 14 days. On the 6th day after cleansing the wound, Actovegin gel was used in a thick layer under a bandage. During treatment, positive dynamics were noted: the size of the wound decreased, perifocal inflammation disappeared (Fig. 3). Upon discharge, the patient underwent a wound biopsy (Fig. 4). After discharge, the patient was recommended to take Actovegin on an outpatient basis, 1 tablet (200 mg) 3 times a day for 30 days, and to use Actovegin topically in gel form. On the 28th day from the start of treatment, pronounced positive dynamics were noted (Fig. 5), and on the 42nd day from the start of treatment, the patient developed a connective tissue scar at the site of the trophic ulcer of the resected right foot. The treatment result was assessed as satisfactory (Fig. 6).
In conclusion, it is worth noting that the prescription of the drug Actovegin was not accidental and is due to its pharmacological properties: pronounced metabolic and endothelial protective effects at the level of the microvascular bed. Actovegin improves collateral blood flow, trophic oxygen supply to tissues during chronic ischemia, as well as vascular and neuropathic complications of diabetes mellitus [1–3, 7]. The results obtained allowed us to draw the following conclusions and recommendations:
In the complex treatment of chronic wounds, the leading role belongs to pathogenetic treatment.
For the treatment of chronic wounds of various etiologies, the use of Actovegin as part of complex therapy reliably increases its effectiveness. When using Actovegin, the size of chronic wounds decreases 3-4 days earlier, and pain syndrome decreases 2-3 days earlier compared to patients in the control group.
The administration of Actovegin can significantly improve microcirculation in a chronic wound (the average microcirculation indicator is on average 0.2 pF higher in the group of patients receiving Actovegin).
We recommend including the drug Actovegin in the complex treatment regimen for patients with chronic wounds of various etiologies according to the following scheme: 1200 mg intravenously once a day for 14 days. Next, switch to the tablet form: 1 tablet (200 mg) 3 times a day for 30 days.
For local treatment of clean chronic wounds of various etiologies, we recommend using Actovegin in gel form once a day until complete healing.