RU2153879C1 - Method of prophylaxis of implantation syndrome in cement articulation endoprosthesis - Google Patents

Abstract

FIELD: medicine, traumatology, orthopedics. SUBSTANCE: method involves preliminary puncture and catheterization of femoral vein of limb to be operated. After administration of osseous cement into marrowy channel infusion of 0.03% sodium hypochlorite solution is carried out through femoral catheter. Infusion rate is 50-60 drops per 1 min for the first hour and then rate is 30-40 drops per 1 min for 3 h, not less. The total volume of infusion is 400 ml. Method ensures to decrease toxic effect of methylmethacrylate monomer. EFFECT: improved method of prophylaxis and treatment of implantation syndrome. 3 tbl, 2 dwg, 1 ex

Description

 The invention relates to medicine, in particular to traumatology and orthopedics, and can find application in arthroplasty of large joints of the lower extremities with cement fixation of components of the arthroplasty.

 Performing a joint replacement operation in some cases (pronounced osteoporosis, anatomical features, the need for quick activation after surgery in old age) is possible only with the use of bone cement (CC). With an intervention accompanied by the introduction of polymerizable bone cement into the bone marrow wound, the risk of implantation syndrome, which develops as a result of various types of embolic complications, as well as the toxic effect of methyl methacrylate monomer (MMA), is high. The latter is one of the components in the preparation of CC. In an amount of 3-5% of the used dose, MMA can penetrate into the general bloodstream and lead to acute respiratory failure, severe hypotension, changes in heart rate up to a stop of blood circulation, myocardial infarction (1). Mortality in cemented joint arthroplasty of large joints is significantly higher than in case of cementless endoprosthesis placement (2). However, to date in clinical practice there is no alternative to bone cement based on methyl methacrylate. The ongoing drug prophylaxis and treatment methods for the implantation syndrome are largely symptomatic.

 Closest to the proposed method is the prevention of intraoperative complications by prophylactic administration of sufficiently high doses of corticosteroids to reduce the toxic effects of MMA, as well as drugs that prevent the development of embolic complications (3). This method reduces the severity of the implantation syndrome, affecting the severity of fatty hyperglobulinemia, disorders of the aggregate state of the blood, as well as changes in the cardiovascular system caused by hypovolemia and a decrease in vascular tone. However, the toxic effect of MMA does not eliminate this method.

 The technical result of the present invention is to prevent the toxic effects of MMA due to the regional use of a solution of sodium hypochlorite.

 This result is achieved by the fact that in the known method, including intravenous administration of corticosteroids and means of preventing embolic complications, according to the invention, the femoral vein of the operated limb is punctured and catheterized beforehand, and after bone cement has been introduced into the bone marrow canal, sodium hypochlorite is infused 0.03 % concentration at a speed of 50-60 cap. 1 min for the first hour, and then at a speed of 30-40 drops. in 1 min for at least 3 hours with a total infusion volume of 400 ml.

 Having been professionally dealing with the complications of cement arthroplasty of large joints for several years and using the literature on this issue (4), we suggested that one of the triggers for the development of implantation syndrome may be penetration of MMA initially into the regional bloodstream.

 In this regard, the regional introduction of funds that contribute to the reduction of MMA, in our opinion, can prevent or reduce the severity of this complication.

 Since the implementation of extracorporeal detoxification methods during traumatic surgery is excluded, we decided to study the possibility of MMA degradation by oxidizing it using sodium hypochlorite (GN) solution.

 The use of this drug for detoxification in various endo- and exogenous intoxications is known from the literature, based on the oxidizing ability of sodium hypochlorite with respect to xenobiotics (5, 6). However, based on these data, it was impossible to unequivocally count on the positive effect of this drug in cement endoprosthetics, given the specific nature of surgical aggression. It was also unclear whether the enhancement of the effect would give the regional nature of the use of GN.

To assess the possibility of oxidation of MMA and its destruction using sodium hypochlorite, we conducted a number of experimental studies:
1). chemical assessment of in vitro the possibility of destruction of MMA under the influence of GN and the study of the rate of release of MMA from Polacris cement,
2). assessment of the protective effect of GN under the influence of MMA on human fibroblasts in culture,
3). study of the protective effect of GN with the introduction of MMA to experimental animals.

 1). Chemical grade. It was revealed that the introduction of an equimolar amount of GN into a physiological solution containing MMA leads to instant destruction of the latter. Moreover, oxidation goes to organic acids, which are metabolites of the human body.

 To determine the rate of introduction of GN for the purpose of oxidative destruction of MMA, the rate of MMA release from polymerizable bone cement was determined (Table 1).

A cement sample weighing 6.200 g was prepared from a serial cement sample according to the instructions for use. The surface area of the sample is 40.0 cm ² , the thickness is 2.0-3.5 mm. A sample of cement was introduced into physiological saline 4 minutes after the start of mixing cement (room temperature 23 + 1 ^o C). The temperature of the physiological saline during the test was maintained within 36 ± 1 ^o C.

 As can be seen from the table, the largest amount of MMA is released in the first hour, in the next 3 hours - 2 times less. After 4 hours from the moment of the introduction of cement, its intake into the body becomes insignificant.

 2). Cell culture experiment.

 In order to assess the prospects of the method of electrochemical detoxification in the prevention of the toxic effects of MMA, we also conducted an in vitro study using a model of human embryo fibroblasts. When CC was introduced into the medium, the development of oxidative stress was revealed as a result of depletion of the endogenous antioxidant system and cellular hypoxia caused by the suppression of the total activity of respiratory enzymes. The total activity of respiratory enzymes was determined spectrophotometrically in a microtetrazolium test by the ability of mitochondrial enzymes to restore nitrosine tetrazolium to formazan. The results of the study are presented in table. 2. As can be seen from it, the introduction into the environment of MMA in the amount that can enter the bloodstream during operations of cement arthroplasty led to a decrease in the activity of mitochondrial enzymes compared to the level of intact cells by 42.9%. A dose-dependent effect of MMA was noted, which was consistent with clinical observations of an increase in the severity of manifestations of the implantation syndrome with an increase in the amount of bone cement used for surgery.

 It was found that the toxic effect of MMA also depends on the time of exposure. It was found that the most pronounced destructive changes in the cells occurred within 1-2 hours of incubation of fibroblasts with CC from the moment of polymerization. It was shown that the replacement of the incubation medium during this period (i.e., modeling of detoxification) led to a significant weakening of destructive disorders in fibroblasts, estimated 18 hours after the start of the experiment. Thus, the concentration of lactate dehydrogenase (LDH) in the incubation medium, reflecting the degree of damage to cell membranes, decreased by 9.36 times when changing the medium after the first hour of incubation compared to the control. This is probably due to both the removal of MMA released during the polymerization of CC and pathological metabolic products of damaged fibroblasts.

 To study the protective effect of sodium hypochlorite, its freshly prepared 0.06% solution was used. For testing, 50 μl of MMA with GN were mixed in the following ratios: 1: 1, 1: 2.5, 1: 5, 1:10. The mixture with periodic vigorous shaking was left at room temperature for 15-20 minutes. Next, each sample was adjusted with Eagle medium to 5 ml. To the culture of fibroblasts incubated in Eagle’s medium with the addition of 10% cattle serum for two days to form a confluent monolayer, 100 or 200 μl of each of the mixtures was added (final monomer concentration 0.05 and 0.1 mg / L, respectively, which is comparable with the amount of MMA, entering the bloodstream when using one portion of cement for surgery). Fibroblasts served as a control, which were incubated in the medium a) without any additives and b) in the presence of one MMA of the corresponding concentration. The exposure time of these compounds to the cells was 18 hours, after which the cell viability was assessed by the change in the total activity of respiratory enzymes in the microtetrazolium test. The results of the study are presented in table. 3.

 As follows from the table, with a ratio of MMA and GN of 1: 1, 1: 2.5, 1: 5, the mixture did not cause a decrease in the activity of cellular respiration, the suppression of which is clearly seen when exposed to the same monomer concentration as in the mixture. The most pronounced protective effect was detected when the ratio of the introduction of such an amount of 0.06% solution of GN, which was 2.5-5 times higher than the content of MMA. Inhibition of cellular respiration was detected only on exceeding the permissible pharmacopoeial doses of sodium hypochlorite.

 The increase in the amount of sodium hypochlorite compared with that required for oxidation in a purely chemical experiment is apparently due to the buffering properties of serum. The study was performed to determine the amount of GN necessary for the oxidation of methyl methacrylate monomer, the rate of entry of which into the bloodstream was found in the chemical experiment N1.

 Thus, the rate of introduction of a 0.03% solution of GN 60 cap. per minute (a solution of this concentration practically does not affect the endothelium) is sufficient for the oxidation of the methyl methacrylate monomer, which can come from 5-6 servings of used cement, but is within the limits allowed by the pharmacopoeia.

 3). Animal experiment.

 To assess the effectiveness and safety of GN in preventing the toxic effects of MMA, we conducted an experimental study in animals. For the experiment, we selected sexually healthy healthy chinchilla rabbits, males weighing 2.5–3 kg, obtained from the Rappolovo laboratory animal nursery and passed the necessary quarantine. The tests were carried out in strict accordance with the State Pharmacopoeia of the USSR XI ("MU for toxicological and hygienic research of polymer filling materials and products for endoprosthetics" MZ, USSR, 11.27.1985).

 In the experiment, 6 rabbits were used. MMA was injected into the ear vein at a dosage of 0.3 g / kg (3 control and 3 experimental animals). A dosage of 0.3 g / kg (0.9 ml / kg) corresponds to the amount of MMA that can enter the bloodstream when using 10 servings of cement for surgery (on average, 1 to 5-6 servings are used), so this is obviously more pronounced than you have to experience sick exposure. Experimental animals at the same time as MMA were injected with GN 1.8 ml of 0.06% concentration.

 With the introduction of deliberately higher average doses of MMA (0.3 g / kg), all control animals died in cases of acute respiratory failure. Of the experimental animals, everyone survived. Manifestations of respiratory failure in them were practically not expressed.

 A pathomorphological study of animals in the control group revealed changes in the lungs. During their macroscopic examination, a bluish-red uneven staining of lung tissue and a decrease in airiness were observed. Microscopic examination revealed gross violations: extensive hemorrhage fields with ruptured capillary walls and interalveolar septa; foci of swelling and desquamation of endotheliocytes were found in arterial vessels. The vessels of the interalveolar septa are unevenly full-blooded, in some cases the red blood cells both outside and inside the vessels had fuzzy contours, which indicated their hemolysis. In significant areas, the picture of hemorrhage resembled hemorrhagic pulmonary infarction (Fig. 1). The subpleural location of the foci of hemorrhages attracted attention. In addition to erythrocytes, accumulation of edematous fluid was noted in significant areas of the alveoli, there were foci of lung tissue decline — distelectase. Changes in the epithelium of the bronchi were not detected.

 In animals of the experimental group, to which sodium hypochlorite was introduced simultaneously with MMA, the morphological picture in the lungs was different. Macroscopically, the lungs had the usual color, were airy. This was confirmed by microscopic examination: in all animals hemorrhages into the lumen of the alveoli were completely absent, no accumulation of edematous fluid in the lumens of the alveoli was observed, which testified to the preservation of the integrity of the alveolar-capillary barrier (Fig. 2).

 Thus, a series of experiments made it possible, in our opinion, to consider the protective effect of sodium hypochlorite solution in the prevention of the toxic effects of methyl methacrylate monomer as proven. This served as the basis for the clinical use of this method.

 Clinical example.

 The claimed method was used in the surgical treatment of patient S., 53 years old, medical history N 4414 for 1999. He was admitted to the RNIITO named after P.P. Harmful 06/16/1999 with complaints of pain in the area of the left hip joint at rest and during exercise, walking only with support on crutches. Sick since 1976, treated conservatively. The deterioration of the condition, which led to walking with support, has been noted since December 1996. An objective examination revealed adducing contracture of the left thigh, a sharp restriction of movements in the joint. The diagnosis of left-sided deforming coxarthrosis of the 3rd degree. The X-ray diagnosis was confirmed: a cystic restructuring of the nadacetular region and the isthmus was determined, the femoral head was with dystrophic changes in the neck. Marked thinning of the bone bottom of the acetabulum, a pronounced narrowing of the joint cavity. The diagnosis was an indication for surgical treatment. On June 29, 1999, under total spinal anesthesia, an operation was performed on total endoprosthetics of the left hip joint. Before the operation under aseptic conditions, the femoral vein of the operated limb was punctured and catheterized. The catheter is fixed with sutures to the skin at a distance of 1 cm from the puncture site and a plaster to the skin of the abdomen on the right. The catheter area is covered with a sealed aseptic sticker. Before the introduction of sodium hypochlorite solution, physiological saline was infused at an insignificant rate (to maintain venous catheter patency). After the introduction of two portions of Polacris bone cement, when the surgeon ascertained the final hemostasis, the introduction of 0.03% sodium hypochlorite solution at a rate of 60 cap. per minute for the first hour. Surgical blood loss amounted to 1 liter, which corresponds to the average for such an operation. In the next 3 hours, the rate of sodium hypochlorite administration was 40 cap. per minute. After this period, the catheter is removed. When the hemostasis system was monitored after the end of GN administration, there were signs of normocoagulation (in contrast to commonly detected hypercoagulation). No complications of the operation and the immediate postoperative period were noted.

 The proposed method is currently applied in 5 patients. Complications during the operation and the postoperative period in these patients were also not detected.

 As studies have shown, the proposed method of using sodium hypochlorite prevents the development of implantation syndrome. This method in comparison with the known for the first time makes it possible to prevent the cytotoxic effect of MMA by destroying it, which does not allow the use of any of the known methods for the prevention and treatment of implantation syndrome.

 The method is developed in the clinic and laboratories RNIITO them. P.P. Harmful. After conducting in vitro tests and on experimental animals, it was applied with a positive result in operations of cement hip arthroplasty in 5 patients.

Claims (1)

 A method for the prevention of implantation syndrome in case of cement joint arthroplasty of the lower extremities, including intravenous administration of corticosteroids and means for the prevention of embolic complications, characterized in that the femoral vein of the operated limb is punctured and catheterized before, and after bone cement is introduced into the bone marrow canal through the femoral catheter sodium hypochlorite solution of 0.03% concentration at a rate of 50-60 cap. in 1 min for the first hour, and then at a speed of 30 - 40 cap. in 1 min for at least 3 hours with a total infusion volume of 400 ml.

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