Prophylactic "Xymedon" in Abdominal Surgery


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Abstract

Importance. Surgical procedures have a lot of stress, causing significant violation of the non specific defense mechanisms of the body and the immune system, which requires the use of different pharmacological agents in order to increase natural resistance to infection.
Purpose. An analytical review of experimental and clinical research in the direction of studying the effectiveness of the impact of enteral xymedon on reparative process of surgical wounds and tissue non-specific resistance of the organism to infection for the prevention of inflammatory wound complications.
Materials and methods. The analysis of experimental and clinical data, dealing with the question of studying the effect of enteral and topical xymedon to repair tissue in the area of the surgical wound and the non-specific resistance to infection. The criteria for the effectiveness of the drug were clinical and laboratory parameters, and statistic methods.
Results and their discussion. The analysis of experimental and clinical studies have shown that enteral and topical use xymedon in surgical patients stimulates wound healing surgical site and increases nonspecific resistance to infection by increasing the functional activity of neutrophils, their backup potentials normalize the concentration of a bioactive and immunoreactive fibronectin in blood plasma, improve antimicrobial activity of wound.
Conclusions. Xymedon is recommended as an effective means of pharmacological support of wound healing in surgical patients to prevent postoperative wound complications.

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Surgical interventions exert severe stress, causing significant disorders of the mechanisms of non-specific protection of the body and immune system [1-3]. Possible methods of increasing the body 's natural resistance to infection are carried out mainly by means of various pharmacological agents, while isolating specific immunoprophylaxis (active and passive) and non-specific [4, 5]. Non-glycoside analogs of pyrimidine nucleosides, in particular domestic preparation - xymedone 1- (-oxyethyl) -4,6-dimethyl-1,2-dihydro-2-oxypyrimidine, are used in the general complex program for combating postoperative intraspital infection. By Order of the Ministry of Health of the Russian Federation No. 287 of 17.12.93, Ksimedon was entered into the Register of Medicines of the Russian Federation for the Treatment of Burn Patients [6].

The theoretical prerequisites for the use of xymedone to stimulate the healing of surgical wounds and the prevention of purulent-inflammatory wound complications were the presence of a powerful regenerative, anti-inflammatory and antibacterial action in the given preparation. These properties were confirmed by the results of numerous experimental and clinical studies [7-16].

Purpose.
An analytical review of experimental and clinical research in the direction of studying the effectiveness of the impact of enteral xymedon on reparative process of surgical wounds and tissue non-specific resistance of the organism to infection for the prevention of inflammatory wound complications.
Materials and methods.

 

Efficiency of enteral application of xymedone on repair process of tissues of postoperative wounds and non-specific resistance of organism to infection is studied in model of acute inflammation [17-22]. To this end, 240 patients aged between 15 and 54 years, inclusive, were examined, operated openly for various forms of acute appendicitis. Males were 90 (37.5%) and females 150 (62.5%). The main group (102 patients) from the first day after surgery received xymedone 0.5 g 4 times a day for 10-20 days [23]. The control group (138 patients) was operated in parallel with the main and received methyluracil 0.5 g 3 times a day. Patients were representative of the form of acute appendicitis, age, sex, and concomitant diseases.

Clinical effectiveness of xymedone was assessed by such indicators as general condition and subjective sensations of patients, time (in days) of normalization of general body temperature and elements of local inflammatory signs in the wound area (pain, swelling, hyperemia), dynamics of peripheral blood indicators, time of suturing and stay of patients in hospital, number of postoperative nudities and infiltrations from the side of the operative wound.

Functional activity of neutrophils of venous blood of patients was studied by the reaction of reduction of nitrosine tetrazolium [24]. Determination of concentration of immunoreactive fibronectin in blood plasma was carried out by rocket immunoelectrrophoresis using monospecific antiserum [25], and biologically active fibronectin - by agglutination reaction of gelatinized microparticles on laser nephelometer [26]. The activity of Factor XIII in blood plasma was determined by the method of B.P. Baluda et al. [27].

he analysis of postoperative local complications in the discussed patient groups was carried out according to Clavien-Dindo Classification of Surgical Complications (2004) [28] and depending on the degree of contamination of the operation.

The study of the antimicrobial action of xymedone with a view to its inclusion in the developed wound tread was carried out by serial dilutions on a liquid nutrient medium [20-22].

Clinical efficacy of the proposed tread was assessed in 45 patients, of which acute appendicitis was in 23 (51.1%). The control group includes 84 patients operated in parallel with the main group with similar acute abdominal diseases, which during the operation used a traditional method of protection with a gauze napkin. The evaluation of the degree of effectiveness of practical application of the tread was carried out on the basis of the results of microbiological studies, electrothermometry method and study of antimicrobial activity of wound separated by the method S.A. Paevsky. Method is based on inhibition of growth of culture Micrococcus Lysodeicticus in contact with disk of filter paper impregnated with wound contents.

Processing and statistical analysis of the obtained data was carried out using Microsoft Office Excel and Statistica 6.0 computer programs. Descriptive statistics for groups are represented as mean ± standard error. Welch 's t-test was used to compare the average. The differences were considered statistically significant at p < 0.05.

 

Results and their discussion

Clinical results of treatment of patients with acute appendicitis with enteral application of xymedone showed that in the first days after surgery patients of the main group behaved more calmly, slept better, were active, temperature response was considerably less expressed and in a shorter period of time there were external signs of inflammation of the operative wound (Table 1).

 

Table 1. Days normalization of temperature (T) and the regression of local inflammatory signs (B) in the wound area in patients with acute appendicitis after enteral xymedon and methyluracil (М ± m)

Group

 endoappendicitis

Phlegmonous appendicitis

Т

В

Т

В

Control

3,42±0,42

5,04±0,21

3,61±0,27

4,91±0,21

Main

2,20±0,21

2,87±0,15

2,36±0,14

2,69±0,12

P-value

< 0,05

< 0,001

< 0,001

< 0,001

 

 

 

In the main group patients, the total temperature normalized 1.2 days earlier compared to control. The failure of local signs of the inflammatory process in the operating wound in the main group was faster than the patients who did not receive xymedone. This indicated an improvement in the course of the whole postoperative period, a rapid resolution of the entire inflammatory process, an increase in the protective forces of the body in patients treated with xymedone. Visual control showed a sufficiently strong growth of wound edges, which was the basis (taking into account experimental data) [29.30] to remove skin sutures in earlier time than in the control (Table 2).

 

Table 2. Time of removal of sutures and duration of post-operative period (in days) in patients with acute appendicitis with enteral xymedon (Group 1) and methyluracil (Group 2) (M ± m)

Appendicitis

Time of removal of sutures

Duration of post-operative period

1-st group

2-nd group

1-st group

22-nd group

Endoapendicitis

4,77±0,14

6,19±0,06

5,90±0,1

6,60±0,1

P-value

< 0,01

-

< 0,001

-

Phlegmonous

4,86±0,12

6,09±0,02

5,98±0,09

6,54±0,08

 P-value

< 0,001

-

< 0,001

-

 

 

In no case was there a divergence of wound edges during the early suturing period. It should be noted that early suturing had a beneficial effect on the repair capacity of tissues in the wound area and thus created optimal conditions for the aseptic course of the wound process [31-33].

Examining the peripheral blood values in dynamics it was stated (Table 3) that in the main group of patients there is a significant increase of lymphocytes by the 4th-5th day after operation with simultaneous normalization of the ratio of segmentonuclear neutrophils, eosinophils and monocytes. Patients treated with xymedone showed the most favorable ratio between lymphocytes (LF) and segmentonuclear neutrophils (CH), indicating increased resistance of the body 's protective forces to postoperative infection.

 

Table 3.Peripheral blood counts in main (with enteral xymedon) and control groups of patients after appendectomy, on the 5th day after surgery операции (M± m)

Research group

Lymphocytes,%

Segmented neutrophils,%

СН/Ratio

Main

29,9±1,3

58,9±1,2

29,5/58,9

Control

19,9±2,0

69,3±2,1

19,9/69,3

P-value

<0,001

<0,001

-

 

The control group of patients showed significantly less lymphocyte content as well as a less favorable LF/CH ratio.

Lymphopenia is known to serve as one of the tests for developing complications. It is believed, for example, that a decrease in lymphocyte content to 5-7% indicates that nudity should be expected. Therefore, lymphopenia can be attributed to prognostically important indicators indicating the possibility of wound nagging in the postoperative period [34]. Therefore, in order to prevent the development of the infectious process in the wound, it is necessary to administer preparations that contribute to the increase of lymphocyte content in the blood and prevent their fall to 7-10%. One such drug, according to our research, is xymedone.

The results of ksimedon treatment of patients with acute appendicitis showed that the preparation stimulates wound healing processes and increases non-specific body resistance to infection [20, 35]. Thus, in the main group (using xymedone), on the 2nd day after the operation, the relative activity of Factor XIII was below the 9.5% norm. The treatment with xymedone contributed to a statistically significant increase in the activity of Factor XIII on the 5th day after 53% surgery, which should be considered as a manifestation of the positive effect of the drug on liver function. In the control group of patients (using methyluracil) on day 5, there was a statistically slight increase in the relative activity of Factor XIII compared to day 2 of the study.

The patients treated with xymedone showed changes in the neutrophilic phagocytosis system: the spontaneous and induced HST test was much lower than the control group patients. Patients in both groups were found to have a 4.3 and 2.0 fold increase in spontaneous and induced HCT test variants compared to healthy individuals before surgery. On the 2nd day after surgery in patients of the control group, the spontaneous version of the HST test was statistically significantly increased by 2.3 times (58, 4 ± 8.6%) compared to pre-surgery data (25, 6 ± 4.7%). On the 5th day since the surgery, a decrease in NST-positive neutrophils was observed 2.1 times compared to the 2nd day of the study and approached the indicators observed in patients prior to the surgery. Compared to the norm, the spontaneous version of the NST test on day 5 of the study remained 3.5 times larger. A similar pattern is found in the dynamics of the induced version of the HST test.

On the 2nd day of the postoperative period, patients in the main group showed a decrease in both spontaneous (on average up to 8, 3 ± 2.1%) and induced (on average up to 32, 4 ± 7.5%) NST tests compared to patients before surgery (respectively, 23, 7 ± 2.3% and 74, 5 ± 3.0%, P < 0.05). The spontaneous version of the NST test approached normal with subsequent normalization on the 5th day of surgery (6, 0 ± 1.5%). The induced version of the HST test was statistically significantly lower than the norm (averaged 29, 4 ± 0.2%) and statistically significantly different from the control group of patients (P < 0.001).

The neutrophil activation index (ratio of induced test to spontaneous test) in healthy individuals was 5-fold, and in patients of the control group did not exceed 2.8, which indicated a decrease in the reserve of oxygen-dependent metabolism of blood neutrophils. Neutrophil activation index (IAN) in patients of the main group is higher than control and accordingly on the days of the study this indicator approached the norm.

The detected effect is explained by the membrane stabilising effect of xymedone on leukocytes, which is manifested in the decrease of spontaneous HST-test by 3 times with simultaneously high potential of killer activity of leukocytes, which is expressed in the increase of IAN on the 2nd day after operation to 3.9 compared to the non-treated group - 1.5. Due to membrane stabilization, the release of lysosomal enzymes from leukocytes into the wound is reduced, thereby reducing proteolysis of fibrin, collagen and other tissue proteins and creating favorable conditions for wound healing by primary tension.

The obtained results are consistent with the data of determination of bioactive and immunoreactive fibronectin in blood [35]. Most patients in the control group were found to have moderate hypofibronectinemia in the early postoperative period, reaching 214, 9 ± 29.0 μg/ml on the 3rd day after surgery and 234, 6 ± 27.8 μg/ml on the 5th day (P > 0.05). The dynamics of the immunoreactive fibronectin plasma content in the main group patients was identical and the fibronectin concentration was 223, 6 ± 19.3 μg/ml and 253, 4 ± 23.4 μg/ml (P > 0.05), respectively, on the days of the study. The opposite data were obtained by determining the concentration of bioactive blood fibronectin.

The concentration of bioactive blood fibronectin in patients of both groups prior to surgery was on average 204, 3 ± 32.1 μg/ml (at a rate of 300 μg/ml). In patients in the control group, the fibronectin level on day 1 after surgery was 267, 4 ± 23.8 μg/ml (P > 0.05). On the third day its concentration decreased statistically significantly compared to the 1st day of the study to 129, 3 ± 8.8 μg/ml (P < 0.001) and on the 5th day it increased again to 232, 0 ± 6.1 μg/ml (P < 0.05) without reaching the initial values. This decrease in fibronectin level is related to its consumption in the center of inflammation, as one of the mechanisms of fibronectin action, which in recent years is considered to be a group of non-specific opsonins of wide spectrum effect, is its participation in antimicrobial protection measures of the "first line" [36-38].

In the main group, the concentration of fibronectin in the blood on day 1 after the operation was 280, 0 ± 37.6 μg/ml, on day 3 - 298, 0 ± 25.7 μg/ml and on day 5 - 275, 7 ± 23.0 μg/ml. The observed decrease in fibronectin levels on day 3 of the study was not in control in patients treated with xymedone. Difference of average values between groups is statistically significant (P < 0.001). The results obtained proved for the first time that the use of xymedone in the postoperative period equalizes the concentration of plasma bioactive fibronectin to the norm. The revealed effect of the preparation is explained by the fact that xymedone, being an adaptogen, enhances protein synthesis and stimulates fibronectin formation in the liver with its subsequent entry into the blood channel. This is most significant on the 3rd day after surgery. It should be noted that the decrease in the concentration of bioactive fibronectin in blood below 100 μg/ml is an adverse factor in the development of complications [39]. Thus, our studies have proved that xymedone increases the body 's non-specific resistance to infection by enhancing the functional activity of neutrophils, their reserve potentials, fibronectin synthesis and Factor XII.

Early postoperative complications from postoperative wounds occurred in 23 (9.6%) of 240 patients (Table 4). In the main group of patients, wound postoperative complications were 3.9%, in the control group - 13.8% (p < 0.05). Wound postoperative complications had II, IIIA of severity (severity grade). Complications of the II degree of severity (infiltration) did not require wound inspection and regressed independently against the background of increased length of antibacterial therapy. Removal of skin sutures through one, use of alcohol bandages and physiotherapeutic procedures were sufficient to reduce the inflammatory process. In case of complications of the degree of severity (nagging), an autopsy was performed, the purulent cavities were drained without general anesthesia. It should be noted that in patients of both groups, purulent foci were localized within subcutaneous fat and had no tendency to spread. Removal of sutures and reduction of complications in patients of the main group resulted in reduction of time of their stay in hospital after operation.

Table 4.Structure of wound postoperative complications in the main group of patients (with enteral xymedon) and control group depending on severity grade according to Clavien-Dindo classification (2004).

Wound complications

Main group

Control group

Total

II

IIIа

II

IIIа

Infiltrate

1

 

8

 

9

Wound infection

 

3

 

11

14

Total

n1=4  n2=19

1

3

8

11

23

Note: II, IIIa - severity of complications; n1 and n2 are the total number of complications in the main group of patients and the comparison group, respectively. Explanations in the text.

The positive results obtained from the use of xymedone in emergency surgical patients allowed us to successfully apply it in a planned manner. To this end, the preparation is used in patients operated for chronic calculous cholecystitis, inguinal, postoperative hernia and chronic appendicitis. The scheme of ksimedon administration to scheduled patients was as follows [32]. For 3-5 days before surgery, xymedon is orally administered at a dose of 0.5 g 4 times a day. After the operation, starting from day 1, administration of the preparation in the same dose is continued orally until the moment of discharge from the hospital. The total course of ksimedon therapy averaged 10-20 days.

Ksimedon was included in the program we developed to prevent purulent-inflammatory complications of postoperative wounds. A major role in the complex program was assigned to the protection of postoperative wounds from microbial contamination and mechanical damage by the tread (consisting of polyethylene film, porolone impregnated with 10% xymedone solution), wound treatment and method of their suturing [20-22].

Experimental studies in vitro allowed us to find for the first time that 5-10% solution of xymedone has antimicrobial activity towards intestinal stick and staphylococcus, which are the main agents in the occurrence of wound complications [20, 21, 40, 41]. The xymedone solutions had a bacteriostatic and bactericidal effect on the corresponding micro-organisms, which was the basis for its inclusion in the scheme of using the tread developed by us [42] and the wound treatment device [43]. A tread made of a hygroscopic material coated with a polyethylene film is characterized in that the hygroscopic material is porolone impregnated with a 10% xymedone solution. Antibacterial and wound healing properties have other dosage forms of xymedone (filling, ointment), the use of which reduces the duration of inflammatory and accelerates the onset of the proliferative phase of the wound process [44-48].

Analysis of the studies showed significant advantages of the new method of wound protection compared to traditional methods of protection. Thus, the obtained results of thermometry of surgical wounds in patients of the main and control groups showed that the tread isolates the wound from mechanical damage, helps to normalize the temperature in the cross-linked tissues, thus creating optimal conditions for the course of the local repair process, as reported by other authors [49, 50].

Impregnation of the powder sponge with a 10% solution of xymedone, had a local antimicrobial effect on the pathogenic microflora during the whole operation and stimulated local repair processes. Microbiological studies have shown that in the control group of patients the degree of bacterial contamination of 1 g of wound wall tissue towards the end of "contaminated" and "dirty" operations was on average 3, 4 ± 0.4 '104 CFU/g. Application of the disclosed tread allowed reducing the number of microbes to 0, 8 ± 0.02 '102 CFU/g (P < 0.05) and thus reducing the total number of complications on the wound side from 29, 8 ± 4.2 to 6, 7 ± 1.7% (P < 0,001).

The study of the antimicrobial activity of the wound separable revealed (Table 5) that the growth retardation zone of the test culture in the patients of the main group is 1.8 times greater than that of the control 2 hours after the operation (P < 0.05), 1.3 times more on the 1st day (P < 0.001) and 1.1 times more on the 3rd day after the operation (P > 0.05). The maximum peak of increase of disinfecting activity of the wound separated was observed on the 1st day after surgery in both groups of patients. A statistically significant increase in the antimicrobial activity of the wound release in patients using the proposed tread in the first hours and days after surgery can be attributed to the activation of local metabolic processes in the wound. This may be due to the improvement of microcirculation in the wound tissues and the local action of the xymedone solution, which restores the repair capacity of the paravulnar tissues [51].

Table 5. Antimicrobial activity of wound discharge depending on the size zones of growth suppression test culture (mm) of the patients in the control and main groups (M± m)

Research group

Two hours of post-operative period

Days of post-operative period

1-й/1-st

3-й/3-rd

Control

6,2±1,6

18,7±0,4

16,4±0,9

m=Main

10,9±0,9

23,5±0,4

18,1±0,2

P-value

<0,05

<0,001

>0,05

 

Purulent-inflammatory complications of postoperative wounds in the control group occurred in 25 people (29.8%). After "clean-contaminated" operations, the percentage of wound complications was 12.5, "contaminated" - 27.1 and "dirty" - 75%.

In the main group, wound complications were observed in 3 patients (6.7%). Of these, after "contaminated" operations, complications occurred in 1 patient (4%), after "dirty" - in 2 (16.7%). After "pure-contaminated" surgical interventions, there were no wound complications, while in the control group, purulent-inflammatory complications after "pure-contaminated" operations were 12.5%. The use of the wound tread reduced the total number of complications on the side of the wound from 29, 8 ± 4.2 to 6, 7 ± 1.7% (P < 0,001).

 

Conclusions.

Thus, the analysis of experimental-clinical studies showed that enteral and local use of xymedone in surgical patients stimulates wound healing processes and increases non-specific resistance of the body to infection by increasing functional activity of neutrophils, their reserve potentials, normalizing concentration of bioactive and immunoreactive fibronectin in blood plasma, increasing antimicrobial activity of the wound separated.

The obtained clinical-laboratory material makes it possible to offer scientifically based indications for a wide enteral preventive use of xymedone in patients with various surgical diseases of organs of different localisation in order to intensify recovery processes and increase non-specific resistance of the organism to infection, as well as to recommend further study of local use of xymedone in the form of various dosage forms.

A special role in the optimization of therapeutic measures should be played by ksimedone in the complex treatment of elderly and senile patients with severe concomitant diseases (diabetes mellitus, atherosclerosis, anemia, peripheral nervous system lesions, etc.). In this category of patients, along with pronounced microcirculatory disorders, there is a sharp suppression of non-specific body resistance to trauma and infection, as well as inhibition of the processes of repair. Therefore, in order to create the necessary conditions for successful surgical treatment, reduce operational risk, prevent the development of purulent-inflammatory complications on the part of postoperative wound, preventive enteral use of xymedone is justified by experimental-clinical studies [22].

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About the authors

Nikita A. Koloshein

State Budgetary Institution of public health "City clinical hospital №7 of the Leninsky District of Nizhny Novgorod named after E.L. Berezova",

Author for correspondence.
Email: predator-94@mail.ru
ORCID iD: 0000-0002-4563-5478
SPIN-code: 8542-6969

surgeon

Russian Federation, st. October Revolution 66a, Nizhny Novgorod, 603011, Russia.

Sergei G. Izmailov

State Budgetary Institution of public health "City clinical hospital №7 of the Leninsky District of Nizhny Novgorod named after E.L. Berezova",

Email: izi28082009@yandex.ru
ORCID iD: 0000-0001-7998-9277
SPIN-code: 3984-2070

surgical consultant
Russian Federation, st. October Revolution 66a, Nizhny Novgorod, 603011, Russia.

Egor Е. Lukoianychev

State Budgetary Institution of public health "City clinical hospital №7 of the Leninsky District of Nizhny Novgorod named after E.L. Berezova"

Email: egor-lukoyanychev@yandex.ru
ORCID iD: 0000-0001-6392-2692
SPIN-code: 7896-4581

surgical consultant

Russian Federation, st. October Revolution 66a, Nizhny Novgorod, 603011, Russia.

Andrey Е. Leontev

State Budgetary Institution of public health "City clinical hospital №7 of the Leninsky District of Nizhny Novgorod named after E.L. Berezova"

Email: leontjeff@mail.ru
ORCID iD: 0000-0001-6510-3391
SPIN-code: 3253-6406

surgical consultant

Russian Federation, st. October Revolution 66a, Nizhny Novgorod, 603011, Russia

Alexey А. Bodrov

State Budgetary Institution of public health "City clinical hospital №7 of the Leninsky District of Nizhny Novgorod named after E.L. Berezova"

Email: sl.on2014@yandex.ru
ORCID iD: 0000-0002-1163-2199
SPIN-code: 8596-9597

surgical consultant

Russian Federation, st. October Revolution 66a, Nizhny Novgorod, 603011, Russia

Andrey I. Rotkov

State Budgetary Institution of public health "City clinical hospital №7 of the Leninsky District of Nizhny Novgorod named after E.L. Berezova"

Email: 3959400@mail.ru
ORCID iD: 0000-0002-6678-8422
SPIN-code: 3904-4379

surgeon

Russian Federation, st. October Revolution 66a, Nizhny Novgorod, 603011, Russia

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