RU2539385C2 - Method of treating diabetic foot syndrome - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to surgery, and can be used for treating trophic ulcers and purulonecrotic involvements of lower extremities in diabetic patients. That requires a baseline therapy and a regional fibrinolytic therapy. Conducting the regional fibrinolytic therapy following applying a rubber bandage on the lower one-third of the shin is accompanied by administering Urokinase medac in a dose of 100 thousand units into the heel bone once a day within 5 days.

EFFECT: in the setting of reducing the total dosage of the preparation, the invention enables providing the high concentration of Urokinase medac in a pathological centre, improving microcirculation and metabolic processes in the involved tissues, accelerating the wound healing and reducing the length of hospital admission of the patients suffering from diabetic foot syndrome.

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Description

The invention relates to medicine, namely to the treatment of trophic ulcers and purulent-necrotic lesions of the lower extremities in patients with diabetes mellitus.

It is known that the most important direction in the treatment of complicated forms of diabetic foot syndrome (SDS) is the use of drugs that improve macro- and microcirculation. The generally accepted treatment is mainly antispasmodic in nature and with obstruction of the arterioles and capillaries does not lead to a significant clinical effect. Preparations with thrombolytic properties allow the dissolution of small blood clots in small-caliber arteries and arterioles, thereby improving trophism and tissue oxygenation.

The effectiveness of urokinase in treatment in patients against the background of atherosclerotic changes in the vascular bed of diabetic origin is known. In addition to basic treatment, patients received the drug intravenously slowly dropwise at a dosage of 300 thousand ME for 1.5-2 hours, after diluting it in 200 ml of 0.9% NaCl solution (Koryba K.A. Thrombolytics in the complex treatment of diabetic foot syndrome // Actual issues of diagnosis, treatment and prevention of diabetic foot syndrome: Materials of the IV All-Russian scientific-practical conference with international. - Kazan, 2012. - P.79-82).

The disadvantage of this method is the following: the intravenous route of administration of urokinase used, quickly creating high concentrations of the drug in the blood, which are transported to various oranges and tissues, accumulating mainly in excretory organs (kidneys and liver). In such a situation, drugs are rapidly excreted from the body and do not allow a sufficiently high concentration of the drug in the inflammation zone to be created, therefore, to maintain their high therapeutic concentrations, it is necessary to continuously administer maintenance doses of the drug.

The technical result consists in reducing the treatment time for patients with diabetic foot syndrome due to more pronounced and faster positive dynamics of the wound process, hemostasis, free radical oxidation and endogenous intoxication.

The essence of the invention lies in the fact that in a method of treating diabetic foot syndrome, which includes basic therapy and regional fibrinolytic therapy, in the implementation of which medac urokinase is administered in the calcaneus of the affected limb at a dose of 100 thousand units, 1 time per day for 5 days.

The method is as follows. To assess the effectiveness of therapy, patients were divided into 2 groups.

The first group consisted of 35 patients with diabetic foot syndrome who received traditional treatment (comparison group). The main group consisted of 30 patients, in the complex treatment of which included regional intraosseous in the calcaneus of the affected limb, the introduction of medoc urokinase in a dose of 100 thousand units, for 5 days. To control the laboratory parameters, a group of practically healthy individuals (30 people) was examined. The indicators were examined when patients were admitted to the hospital on the 5th, 10th and 20th days of treatment in both groups.

Traditional treatment was carried out taking into account complications and concomitant diseases. Patients were prescribed a diet, subcutaneous administration of adequate doses of short-acting insulin (actrapid, humulin R, insuman rapid) and ultra-short action (novorapid, humalog) in combination with medium-duration insulins (protofan, humulin N, insuman basal), taking into account the type of diabetes, energy consumption as well as ascorbic and nicotinic acid, B vitamins, cocarboxylase, ATP, xanthinol nicotinate. Surgical treatment was combined with active antibiotic therapy, which was carried out using broad-spectrum antibiotics or by combining antibiotics with a different mechanism and range of action. The treatment was carried out taking into account the sensitivity to seeded microflora. Angioprotectors (trental, prodectin), vasodilators (papaverine, no-spa), antiplatelet drugs (acetylsalicylic acid), direct-acting anticoagulants (heparin) were used. Blood substitutes were poured (reopoliglyukin).

With open wound management, its cavity was loosely tamponized with gauze drains with a hypertonic sodium chloride solution or antiseptic solutions. To accelerate the cleansing of the wound from necrotic tissue used chymotrypsin, trypsin. After cleansing the wound, dressings with ointments were used: iruxol, levosin, levomecol, dioxicol.

Against the background of traditional treatment, patients received regional intraosseous injection of medac urokinase into the calcaneus of the affected limb according to the following procedure.

In compliance with aseptic rules, a rubber bandage was applied at the level of the lower third of the lower leg of the affected limb in order to compress the superficial veins of the lower leg. For intraosseous infusions, a diagnostic and medullary marrow needle with a diameter of 1.5 mm with a mandrin was used. The skin on the outer surface of the calcaneus and the periosteum of the affected limb were anesthetized with 5-10 ml of 0.5% novocaine solution. Then, a needle to a depth of 1-1.5 cm was introduced into the spongy substance of the bone with rotary movements, at moderate pressure along the axis. Medoc urokinase was injected at a dose of 100 thousand units, diluted in 10 ml of a 0.9% sodium chloride solution 1 time per day daily for 5 days. After the end of the intraosseous injection, the rubber bandage remained at the level of the lower third of the leg for 15 minutes. The needle was left in the bone tissue for subsequent intraosseous infusions.

The following indicators were identified as criteria for evaluating the effectiveness of therapy:

1) the effectiveness of treatment was evaluated clinically by the growth rate of granulation tissue, the appearance of marginal epithelization.

2) assessment of the course of reparative processes was carried out according to the cytological study of wound exudate obtained by surface wound biopsy according to the method of M.F. Kamaeva (1970). Smears were stained and fixed according to the Romanovsky method.

3) the dynamics of hemostasis indicators were evaluated by blood coagulation time, activated partial thromboplastin time (APTT), thrombin time, plasma fibrinogen content, RFMK and prothrombin index level, antithrombin III.

4) the dynamics of indicators of oxidative reactions and antioxidant protection - malondialdehyde (MDA), plasma catalase and red blood cells.

Clinical criteria for intraosseous administration of urokinase in the complex treatment of complicated forms of diabetic foot testified to an improvement in the course of the wound process, since in group 2 the appearance of full-blooded granulations and marginal epithelization occurred 2, 3, and 4 days earlier than in the control group.

Prior to treatment, a moderate amount of unchanged polymorphonuclear leukocytes (15-20 in the field of view) was noted in the cytogram of the surface layers of the wound. The number of polyblasts and macrophages reached 1-3 in the field of view, a meager amount of microflora. Filaments of fibrin.

On days 12-14, in patients with traditional treatment, polymorphic-nuclear unchanged white blood cells up to 8-10 in the field of vision were observed in the cytogram. The number of macrophages and polyblasts was observed up to 7–9 in the field of view.

In the group of patients where the regional introduction of urokinase was carried out by 12-14 days of treatment, the favorable course of the wound process was a decrease in the number of polymorphonuclear leukocytes (3-5 in the field of view), microflora was absent. Single macrophages were noted. The number of polyblasts increased to 12-15 in the field of view, occurring singly and in groups of 2-3 cells. The transformation of polyblasts into profibroblasts was observed, which indicated the activation of the wound regeneration process.

Upon admission, coagulation hemostasis with severe fibrinogenemia was noted in patients. An increase in the level of RFMC by 68% was observed (P <0.001). The presence in the plasma of RFMCs with anticoagulant activity led to an extension of thrombin time by 11% (P <0.001). The increased coagulating ability of the blood led to a significant consumption of antithrombin III. At the same time, a decrease in the level of antithrombin III by 39.1% (P <0.001) and a shortening of the time characterizing plasma tolerance to heparin by 1.4 times (P <0.001), compared with the control, which contributes to the occurrence of ischemic and thrombotic phenomena , especially in the area of peripheral blood flow.

On the 5th day, despite adequate traditional therapy, the changes in the hemostasiogram shifted towards hypercoagulation, which was due to the activation of tissue thromboplastin and the accumulation of plasma thromboplastin in the postoperative period, caused by mechanical tissue injury. By the 10-12th day of traditional therapy, a tendency toward a slight decrease in blood coagulation activity was determined, which persisted by the 20-22th day.

Already on the 5th day of intraosseous administration of urokinase, in comparison with traditional treatment, there was a clear shift in the coagulation link of hemostasis towards its improvement, by 10-12 days the recalcification time lengthened by 10% (P <0.001), APTT by 9 % (P <0.05), shortening of thrombin time was observed by 6% (P <0.001), a decrease in fibrinogen level by 6% (P <0.05), prothrombin index decreased by 8.6% (P <0.001), fibrin-stabilizing factor activity increased by 11% (P <0.001).

When admitted in patients with diabetic angiopathy of the lower extremities, significant activation of lipid peroxidation processes was observed against the background of depression of the antioxidant system. There was an increase in the content of MDA in plasma by 3.53 times. In red blood cells in patients, an increase in lipid peroxidation processes was also recorded. During spontaneous oxidation of lipids, the content of malondialdehyde increased by 92%, and during Fe-induced oxidation, by 90.15% (P <0.001) relative to normal values. Plasma catalase activity decreased by 69.3%, erythrocyte catalase activity decreased by 66.7%. These results indicate the important role of increasing lipid peroxidation processes in the pathogenesis of purulent-necrotic complications of the diabetic foot and taking into account the literature (Balabolkin MI, Klebanova EM, 2000; Ceriello A., 2003, etc.), we can say on the development of oxidative stress in the studied group of patients

Traditional treatment helped to reduce lipid peroxidation processes and to a certain extent stimulated the production of catalase in plasma and red blood cells, however, a significant difference in the studied parameters was observed only by 20-22 days of treatment. By this time, the content of MDA in blood plasma decreased by 18.53%, of Fe-MDA plasma - by 7.88%. The level of MDA in erythrocytes decreased by 10.48%, Fe-MDA in erythrocytes by 10.16% in relation to the data at admission. The rate of catalase activity in plasma and red blood cells increased by 24.56 and 33.55%.

Thus, traditional therapy contributed only to 20-22 days a slight decrease in the intensity of lipid peroxidation processes and stimulation of antioxidant defense of the body, which indicates the advisability of including in the complex therapy drugs that target these processes.

Against the background of intraosseous use of urokinase, by the 14th day of treatment, a marked decrease in the indicators characterizing the processes of lipid peroxidation was recorded. The values of the MDA of plasma and red blood cells decreased by 36.23 and 15.67% (P <0.001). The rate of catalase activity of plasma and erythrocytes increased by 73.33 and 91.74% (P <0.001), relative to the data for conventional treatment.

By 20-22 days of complex treatment using intraosseous administration of urokinase urokinase, plasma MDA and erythrocytes decreased by 42.59 and 25%, respectively. Against the background of a decrease in the intensity of lipid peroxidation processes, there was an increase in the level of catalase in plasma and erythrocytes by 69.44 and 83.8% (P <0.001) relative to the data for conventional treatment. From the data obtained it follows that a direct consequence of membrane-stabilizing processes is an improvement in microcirculation and increased delivery of oxygen to tissues.

Clinical example 1.

Patient K., 69 years old, was admitted to the purulent surgery department of GBUZ RM "MRKB" on 12.09.12. Clinical diagnosis: Type 2 diabetes mellitus, severe course, insulin-requiring form. Diabetic angiopathy, polyneuropathy of the lower extremities. Trophic ulcer of the stump of the first toe of the left foot. Ischemic heart disease. Angina pectoris II FC. Atherosclerotic cardiosclerosis, atherosclerosis of the aorta, coronary and cerebral vessels. Hypertension of the III degree, very high risk. CHF IIA.

Received complaints of the presence of a long non-healing trophic ulcer of the stump of the first toe of the left foot, pain in the ulcer area. From the anamnesis: diabetes has been suffering from 1992. Correction of glycemia with the use of sugar-lowering drugs (mannyl). In 2008, the amputation of the first toe of the left foot was performed at the level of the middle third of the main phalanx. A trophic ulcer of the stump of the first toe of the left foot exists for 3 months. She was treated by a surgeon at a polyclinic without significant positive dynamics. Objectively: there is no swelling of the left foot, ripple on a. dorsalis pedis and a.tibialis posterior are absent. The first toe of the left foot is amputated at the level of the middle third of the main phalanx; the stump has a trophic ulcer 1 × 2 cm in size with moderate perifocal edema. On the periphery, the wound is made by soft tissue necrosis, in the center is a granulation tissue covered with a coating of fibrin. According to the VAT data of the arteries of the lower extremities: atherosclerosis of the arteries of the lower extremities with stenosis of OBA by 20%, PBA by 30-40%, PKA on the left by 50%, on the right by 40%, ZBA and PBA on the left up to 60%. In the study of smear imprint revealed necrotic type of cytogram. The patient was prescribed a course of complex conservative therapy in combination with regional intraosseous administration of medoc urokinase at a dose of 100 thousand units once a day for 5 days.

During the course of treatment, a clear positive clinical dynamics was achieved. Purification of the wound surface occurred 4 days after the start of treatment, foci of granulation tissue in the wound appeared on the 7th day. According to fingerprints: on day 14, a regenerative type of cytogram was detected. The patient was discharged to the outpatient stage of aftercare on September 28, 2012.

Clinical example 2.

Patient C, 42 years old, was admitted to the purulent surgery department of GBUZ RM "MRKB" on 20.11.12. Clinical diagnosis: Type 1 diabetes mellitus, severe course. Diabetic angiopathy of the lower extremities, polyneuropathy. Diabetic osteoarthropathy of the right foot. Putrid-necrotic phlegmon of the right foot. Exarticulation of I-II toes of the right foot with resection of the metatarsal bones, necrectomy from 11.23.12. Amputation stump of the left tibia. Diabetic nephropathy. Arterial hypertension II Art., Risk III. CHF I. Anemia of moderate severity.

Received complaints of general weakness, pain in the right foot. He suffers from diabetes since 1981. In 1998, the amputation of the left lower limb was performed at the level of the upper third of the lower leg due to putrefactive necrotic phlegmon of the left foot. In August 2012, she injured her right foot. For a long time it was treated on an outpatient basis, without effect.

Upon admission, the right foot and lower third of the leg are swollen. The rear of the foot is hyperemic, on the plantar surface of the I metatarsophalangeal joint, a wound of 3 * 4 cm with copious purulent discharge. The bottom of the wound is the articular surfaces of the 1st metatarsophalangeal joint destroyed by a purulent-destructive process. The left lower limb is amputated at the level of the upper third of the leg.

X-ray of the right foot from 12/21/12: The destruction of adjacent sections of the articulating bones of the 1st metatarsophalangeal joint is determined: the proximal phalanx to the border of the lower third and middle third of the diaphysis, metatarsal bone to the distal metaphysis, without clear contours. The surrounding soft tissue is thickened, heterogeneous, due to the presence of free gas, along the plantar surface of the marginal defect. In bones pronounced osteoporosis. Conclusion: Osteomyelitis of the articulating bones of the I metatarsophalangeal joint. RVG of the lower extremities from 11.22.12: Right foot: pulse blood supply is significantly reduced, the tone of the leading vessels is moderately increased, the tone of the arterioles and precapillaries is moderately increased, venous outflow is preserved, peripheral vascular resistance is slightly increased; right lower leg: pulse blood supply is significantly reduced. The tone of the leading vessels is moderately increased. The tone of arterioles and precapillaries is moderately increased, venous outflow is slightly difficult, peripheral vascular resistance is moderately increased.

Traditional therapy has been prescribed taking into account complications and concomitant diseases. 11/23/12, performed exarticulation of I-II toes of the right foot with resection of the metatarsal bones, necrectomy. The wound was conducted openly. An intraosseous needle is installed in the calcaneus of the right foot. Once a day for 5 days, regional intraosseous administration of medoc urokinase at a dose of 100 thousand units was carried out.

The postoperative period was uneventful. Necrolysis and cleansing of the wound surface occurred on the 3rd day, foci of granulation tissue in the wound appeared on the 5th day. On the 7th day, according to the data of fingerprints, a regenerative type of cytogram was revealed, secondary sutures were applied. The patient in satisfactory condition was discharged on the 20th day.

Compared with the known solution, the proposed solution allows to create a high concentration of medoc urokinase in the pathological focus, reduce microcirculation and metabolic processes in the affected tissues, accelerate wound healing and shorten the time of inpatient treatment of patients with diabetic foot syndrome amid a decrease in the total dosage of the drug.

Claims (1)

A method of treating diabetic foot syndrome, including basic therapy and regional fibrinolytic therapy, characterized in that when regional fibrinolytic therapy is applied after applying a rubber bandage to the lower third of the lower leg, a medication urokinase is administered in a dose of 100 thousand units, 1 time per day, to the calcaneus of the affected limb within 5 days.