FUNCTIONAL STATUS OF LOCAL MICROCIRCULATION IN EXPLOSIVE INJURY AND ITS EXPERIMENTAL CORRECTION

FUNCTIONAL STATUS OF LOCAL MICROCIRCULATION IN EXPLOSIVE INJURY AND ITS EXPERIMENTAL CORRECTION

Shperling I.A., Shulepov A.V., Bazhenov M.V., KourоvA.S., Rostovtsev S.O., Shperling N.V. 

State Scientific Research Test Institute of Military Medicine,
Saint-Petersburg Research Institute of Emergency Medicine named after I.I. Dzhanelidze, Saint Petersburg, Russia

Explosive trauma is the result of the impact on the human body of high-energy mechanisms that cause deep and extensive tissue damage, significantly limiting the range of therapeutic measures and the possibilities of restorative treatment. The relevance of this type of combat surgical pathology over the past five years has acquired a new round in connection with the ongoing local military conflicts, terrorism and injuries received during work [1, 2].
In this category of victims, a primary or secondary defect of the skin and underlying tissues naturally occurs, which largely determines the nature of the course of the wound process [3]. The tactics of treating traumatic soft tissue defects consists in the open management of the wound until it is completely healed by secondary intention. The result of secondary wound healing is the development of chronic wound infection, the formation of rough scars and contractures [4]. In addition to soft tissue defects arising immediately after an explosive injury or after its surgical treatment, wound defects can also form in the long-term post-traumatic (postoperative) period, which are mainly caused by microcirculation disorders and disorders of oxidative metabolism in tissues [5, 7].
For the last decade, one of the promising methods for the treatment of acute and chronic pathological processes caused by impaired local microcirculation and tissue trophism is the use of drugs with antihypoxant action [8, 9]. One of them is deproteinized calf blood extract (DCBE), which belongs to the clinical and pharmacological group of drugs that activate metabolism, which improves tissue trophism and stimulates the regeneration process due to antihypoxic and antioxidant effects [10]. DCBE is highly effective in vascular and metabolic disorders of the brain, diseases of peripheral (arterial and venous) vessels, trauma, diabetic polyneuropathy and trophic lesions of soft tissues [11, 12]. The high efficiency of local administration of an aqueous solution of DCBE for the correction of microrheological and metabolic disorders in traumatic muscle ischemia has been proven [9]. In this regard, it seems important to study the effectiveness of local paravulnar administration of DCBE in soft tissue damage as a result of the combined effect of explosion factors.
Objective - to evaluate the effect of local intramuscular injection of an aqueous solution of deproteinized calf blood extract (DCBE) on microcirculation and metabolism of skeletal muscles of the damaged area in experimental explosive limb injury.

MATERIALS AND METHODS

The studies were carried out in the laboratory of the State Research and Testing Institute of Military Medicine of the Ministry of Defense of the Russian Federation on 70 sexually mature male Wistar rats aged 4-4.5 months, weighing 320 ± 20 g, grown in the Rappolovo nursery (Leningrad region, Russia). Before the start of the experiment, all animals were quarantined for 14 days. The study was approved by the local Ethics Committee (protocol No. 13 of June 22, 2020), conducted in accordance with Directive 2010/63/ EC.
All animals were divided into 3 groups: main (n = 30), comparison group (n = 30), and intact (n = 10). The blast wound was modeled according to the original patented technique (Patent RU2741238) developed at the State Research and Testing Institute of Military Medicine of the RF Ministry of Defense [13]. The sequence of modeling an explosive wound included the following stages: anesthesia; preparation of the site of damage; installation of a firecracker in the intermuscular space of the thigh of the hind (pelvic) limb of the animal; setting the firecracker into action by igniting the fuse. One hour after the application of the explosive wound, the animals of the main group and the comparison group underwent primary surgical treatment (PST), which included bleeding arrest, removing foreign bodies and non-viable tissues, followed by applying an aseptic dressing to the wound. 3 hours after the damage was inflicted to the rats of the main group, an aqueous solution of deproteinized hemoderivative of the blood of calves (drug "Actovegin" ™ produced by "Takeda Pharmaceuticals", Russia) in a total volume of 0.2 ml (drug concentration 40 mg/ml) was introduced. Animals of the comparison group were injected with a 0.9 % sodium chloride solution in the same volume in the similar way (Fig. 1a). Within 7 days, all animals of the main group and the comparison group received standard treatment: daily wound dressing was performed using an ointment for external use "Levomekol", a solution of gentamicin sulfate was injected intramuscularly at a dose of 5 mg/kg/day into the opposite limb of the injured one, in accordance with the recommendations of the national guidelines for military field surgery [14]. The death of animals in the studied groups was not revealed.
7, 14 and 28 days after injury, the rats were assessed for microcirculation and oxidative metabolism in the skeletal muscles of the damaged area using the laser blood flow analyzer "LAKK-M" (NPP "Lazma", Russia). The animals were preliminarily anesthetized with a mixture of zoletil and xylazine (intramuscularly at 10 mg/kg of animal weight of each drug, respectively). Then a skin flap of 5-7 mm wide was removed around the explosive wound of the rat's thigh to the muscle layer, the wound surface was treated with a sterile napkin moistened with 0.9 % sodium chloride solution, the measuring probe was installed paravulnarly, retreating 1-2 mm from the edge of the wound, on the tail fixed the pulse oximeter sensor (Fig. 1b).

Figure. Method of administration of the studied drugs (a) and measurement of microcirculation parameters in the muscle of the damaged area (b)

  

The state of microcirculation and oxygen consumption in injured muscles was assessed by laser doppler flowmetry (LDF) and optical tissue oximetry (OTO). Using LDF, the intensity of microcirculation was assessed in terms of the constant (M, perfusion units) and variable (σ, p.u.) perfusion components, the value of the coefficient of variation (Kv), which is calculated in the device program according to the formula: Kv (%) = σ / M × 100. The Kv coefficient reflects the state of microcirculation in the studied tissue, and its increase indicates an improvement in microcirculation mainly due to an increase in σ as a result of activation of neurogenic, myogenic and endothelial mechanisms of tissue blood flow modulation.
The OTO method was used to measure the value of the oxygen saturation index of blood in the microvasculature of the probed biological tissue (SO2,%), and in the program of the device the index of perfusion oxygen saturation in the microcirculation was calculated using the formula: Sm (c.u.) = SO2 / M. The value of Sm characterizes the relationship between perfusion and the amount of unused oxygen by tissues, and its increase indicates a decrease in oxygen consumption by tissues. The same method was used to determine the level of oxygen saturation of arterial blood (SpO2,%), followed by software calculation using the formula for the index of specific oxygen consumption in tissue: U (c.u.) = SpO2 / SO2. The U value shows the total amount of oxygen consumed by the tissues per unit volume of circulating blood, and its increase indicates an active uptake of oxygen by the tissues.
Evaluation of the metabolic status of tissues was carried out by the method of laser fluorescence diagnostics (LFD), with the help of which data were obtained for the fluorescence amplitudes of oxidative (AFAD, c.u.) and reductive (ANAD, c.u.) of natural coenzymes nicotinamide adenine dinucleotide (NAD) and flavin adenine dinucleotide (FAD), which play an important role in cellular energy exchange. By the intensity of the fluorescence of these coenzymes, one can judge the metabolic status of tissues. On the basis of the obtained values of NAD and FAD in the manual mode, the fluorescent oxygen consumption index (FOCI) was calculated using the formula: FOCI, c.u. = ANAD / AFAD. When interpreting the data, we took into account the fact that the bulk of FAD is formed during oxidative phosphorylation with the participation of oxygen, and NAD − during anaerobic glycolysis. For a comprehensive assessment of the state of microcirculation, oxygen consumption by tissues, as well as their metabolic activity in the manual mode, the effective oxygen metabolism was calculated using the formula: EOM, rel. units = M × U × FOCI. An increase in the values of FOCI and EOM indicated an increase in oxygen consumption by skeletal muscles and the activation of redox processes in them [15]. The data obtained from intact animals were used as the norm.
Statistical analysis of research results. The obtained data were processed using the Microsoft Excel 2013 software package and their subsequent processing in the Statistica 10.0 environment of the StatSoft Inc. (USA). After testing the hypothesis for normality using the Kolmogorov-Smirnov and Shapiro-Wilk tests, the median (Me) and the upper/lower quartiles (LQ-UQ) were calculated; when comparing the data, the nonparametric Mann-Whitney U test was used; differences between values were considered significant if the probability of their identity was less than 5 % (p < 0.05). 

RESULTS

Explosive trauma to the hind limb of the animals led to impaired microcirculation in the skeletal muscles of the damaged area. So, 7 days after injury, the Kv coefficient in muscles in animals of the control group was reduced by an average of 18.2 % (p = 0.005) relative to intact rats. With further observation, the Kv coefficient increased, but by the end of the observation period it was 9.1 % less (p = 0.004) than the values in intact animals. Local paravulnar administration of DCBE at the appropriate time was accompanied by a significant increase in Kv by 4.4-7.0 % (p < 0.05) relative to animals in the control group.
Disturbance of microcirculation in rats with experimental explosive limb trauma in the control group was accompanied by a decrease in tissue oxygen consumption. The Sm parameter in the muscles of rats for 7-14 days was increased by 48.3-68.9 % (p < 0.05) compared with intact animals. In the subsequent periods of the study, the Sm indicator remained increased by 24.1 % (p = 0.006) relative to the values in intact rats. Local administration of DCBE promoted a decrease in Sm in the period of 7-14 days by 16.3-23.3 % (p < 0.05), compared with animals of the control group, with its subsequent restoration to normal values by the 28th day. During the observation, the opposite dynamics of the U indicator was noted relative to the Sm indicator. The U value in animals of the control group during all periods of observation decreased by 27.3-39.4 % (p < 0.05) as compared to intact animals. The use of DCBE promoted an increase in U by 13.6-35.0 % (p < 0.05) relative to the animals of the control group during the entire observation period (7-28 days). Complete recovery of U to values in intact animals was not revealed (Table 1).

Table 1. Indicators of microcirculation and oxygen consumption in the area of a damage to muscles of the thigh in rats after a single local injection of solution of DCBE 3 hours after application of an explosive wound (Me (LQ; UQ))

Study groups

Observation period after drug administration, days

Kv,
%

Sm,
усл. ед./c.u.

U,
усл. ед./c.u.

Intact group
(n = 10)

13.2
(13.1; 13.6)

2.9
(2.7; 3.0)

3.3
(3.0; 3.4)

(n = 10)

Main group (deproteinized calf blood hemoderivative)
(n = 30)

7

11.31,2
(11.0; 11.5)

4.11,2
(4.0; 4.2)

2.71,2
(2.7; 2.8)

(n = 10)

14

12.81,2
(12.1; 13.0)

3.31,2
(3.2; 3.4)

2.51,2
(2.4; 2.6)

(n = 10)

28

12.71,2
(12.3; 13.1)

2.92
(2.7; 3.0)

2.91,2
(2.8; 3.1)

(n = 10)

Control group
(0.9% sodium chloride solution)
(n = 30)

7

10.81
(10.4; 11.0)

4.91
(4.7; 5.1)

2.01
(1.8; 2.1)

(n = 10)

14

11.91
(11.5; 12.1)

4.31
(4.1; 4.6)

2.21
(2.0; 2.3)

(n = 10)

28

12.01
(11.8; 12.3)

3.61
(3.4; 3.7)

2.41
(2.2; 2.5)

(n = 10)

Note: 1p < 0.05 - differences with indicators in intact animals; 2p < 0.05 - differences with indicators in animals of the control group; Kv is the coefficient of variation; Sm - perfusion oxygen saturation in the microcirculation; U - the index of specific oxygen consumption by tissues; Me -the median; LQ/UQ - upper/lower quartiles; n - the number of animals.

Experimental explosive trauma led to disruption of redox processes in the muscles of the damaged area, which was reflected in the dynamics of FOCI and EOM index.
7 days after the explosive injury, there was a 44.8 % decrease in FOCI (p = 0.003) compared with intact animals. In the subsequent periods (days 14-28), there was a recovery of FOCI, which by the end of the observation period was 1.84 (1.78; 1.87) c.u., which is 25.8 % (p = 0.008) lower than the values of intact rats. Local perifocal administration of DCBE led to a significant increase in FOCI in the muscles of the damaged area (by 63.5-74.2 %, at p ≤ 0.05) relative to animals in the control group at all periods of observation. There were no significant differences in FOCI in the main and intact groups after 14-28 days, which indicated the restoration of skeletal muscle metabolism in the area of damage after local application of DCBE.
In animals of the control group, a decrease in the integral EOM index was observed during the entire observation period with a maximum decrease in its value 14 days after the explosive injury (46.4 % lower, at p = 0.004) relative to intact rats. Local intramuscular injection of DCBE into the area of injury promoted an increase in EOM by 56.2 % (p = 0.002) compared with animals from the control group, mainly on the 7th day after the explosive injury. Further observation of the animals receiving DCBE revealed the restoration of EOM to normal values and the absence of significant differences between the animals of the main and intact groups (Table 2).

Table 2. Metabolic parameters in the area of a damage to the thigh muscles in rats after a single local injection of a DCBE solution 3 h after application of an explosive wound (Me (LQ; UQ))

Study groups

Observation period after drug administration, days

FOCI, c.u.

OEE, c.u.

Intact group
(n = 10)

2.48
(2.41; 3.04)

53.2
(45.1; 58.3)

(n = 10)

Experimental group (deproteinized calf blood hemoderivative)
(n = 30)

7

2.391,2
(2.34; 2.5)

74.21,2
(69.3; 76.3)

(n = 10)

14

3.162
(2.33; 3.32)

44.92
(42.8; 48.7)

(n = 10)

28

3.012
(2.13; 3.24)

54.82
(52.1; 55.3)

(n = 10)

Control group
(0.9% sodium chloride solution)
(n = 30)

7

1.371
(1.22; 1.40)

47.51
(38.1; 68.5)

(n = 10)

14

1.791
(1.56; 2.00)

28.51
(26.6; 31.2)

(n = 10)

28

1.841
(1.78; 1.87)

37.31
(36.2; 38.2)

(n = 10)

Note: 1p < 0.05 – differences with indicators in intact animals; 2p < 0.05 – differences with indicators in animals of the control group; FOCI – fluorescent oxygen consumption index; OEE – oxygen exchange efficiency; Me – the median; LQ/UQ – upper/lower quartiles; n – number of animals.

DISCUSSION

Pathomorphological changes in soft tissues in the area of action of the damaging factors of the explosion, namely, a shock wave, fragments, gas jets, high temperature, flame and toxic products, correspond to the general laws of a gunshot wound and are characterized by the presence of three zones: a zone of destruction (separation) of a segment, a zone of primary necrosis tissues and areas of secondary necrosis. The last zone is a dynamic area of damage, which is characterized by parabiotic changes caused by impaired microcirculation, hypoxia of damaged tissues and a decrease in metabolic processes in them. Ultimately, a demarcation line is formed in this zone, along the border of which it is possible to estimate an array of "uncertain" tissues. It is this area that is the point of application for pathogenetically based treatment aimed at creating favorable conditions for restoring tissue perfusion, providing them with sufficient oxygen, which contributes to the restoration of metabolic processes at the cellular and tissue levels [16].
The study showed that the local perifocal injection of an aqueous solution of DCBE into the area of damaged skeletal muscles promotes the restoration of microcirculation mainly in the area of parabiotically altered tissues, improves oxygen delivery to them and promotes its active consumption. The greatest efficiency of DCBE is observed with minor and moderate violations of the structural integrity of the capillaries [17]. Restoration of microcirculation in explosive injury is mediated by the cytoprotective effect of DCBE on the vascular endothelium, which leads to normalization in the system of regulation of vascular tone and blood rheology [18]. Possessing pleiotropic action, DCBE has a modulating effect on various pathological mechanisms in trauma (hypoxia, inflammation, apoptosis, oxidative stress, etc.) [19]. DCBE plays an important role in enhancing the reaction of macrophages, the activity of which contributes to the timely cleansing of the wound from tissue detritus and bacterial infection [20].
Local administration of DCBE leads to the activation of redox processes in the muscles of the damaged area, which are most pronounced in the early post-traumatic period (7 days). Many metabolic effects of DCBE are due to the presence in its composition of substances of inorganic and organic nature, which are actively involved in many intracellular processes and affect the specific pathways of cell metabolism. Inositolphosphooligosaccharides, included in its composition, modulate the activity of insulin-dependent enzymes and increase the ability of cells to capture glucose with its subsequent transport into the cell [21]. Superoxide dismutase with magnesium ions contained in DCBE activates the reduction potential of the glutathione system, which acts as an acceptor of reactive oxygen species (ROS) and activator of enzymes of the detoxification and antioxidant systems [22]. The ability of DCBE to restore ischemic nerve fibers (neuroprotective effect) contributes to the normalization of the central nervous regulation of metabolic processes in damaged tissues [23].

CONCLUSION

The study showed that in case of explosive injury to the hind limb of rats, a single local injection of an aqueous solution of deproteinized hemoderivative of the blood of calves in the early stages after injury (3 hours after its application) improves microcirculation in the skeletal muscles of the damaged area, increases oxygen consumption by cells and activates their metabolism. The results of this study substantiate the advisability of including an aqueous solution of deproteinized hemoderivative of calves' blood in a complex scheme of emergency care for patients with explosive injury in order to correct microcirculatory and metabolic disorders in skeletal muscles subjected to explosive injury.

Funding information and conflicts of interest

The study was not sponsored.
The authors declare no obvious and potential conflicts of interest related to the publication of this article.

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