Intoxication of the body: symptoms and diagnosis

Intoxication of the body almost always accompanies severe trauma and in this sense is a universal phenomenon, which, from our point of view, has not always received enough attention. In addition to the word "intoxication", the term "toxicosis" is often found in literature, which includes the concept of the accumulation of toxins in the body. However, in a strict interpretation, it does not reflect the body's reaction to toxins, i.e. poisoning.

Even more controversial from the semantic point of view is the term "endotoxicosis", meaning the accumulation of endotoxins in the body. If we take into account that endotoxins, according to a long-standing tradition, are called toxins secreted by bacteria, it turns out that the concept of "endotoxicosis" should be applied only to those types of toxicosis that are of bacterial origin. Nevertheless, this term is used more widely and is applied even when it comes to toxicosis due to the endogenous formation of toxic substances, not necessarily associated with bacteria, but appearing, for example, as a result of metabolic disorders. This is not entirely correct.

Thus, to describe poisoning accompanying severe mechanical trauma, it is more correct to use the term “intoxication”, which includes the concept of toxicosis, endotoxicosis and the clinical manifestations of these phenomena.

Extreme intoxication can lead to the development of toxic or endotoxin shock, which occur as a result of exceeding the adaptive capabilities of the body. In practical resuscitation, toxic or endotoxin shock most often ends in crush syndrome or sepsis. In the latter case, the term "septic shock" is often used.

Intoxication in severe shockogenic trauma manifests itself early only in cases where it is accompanied by large crushing of tissues. However, on average, the peak of intoxication occurs on the 2nd-3rd day after the injury and it is at this time that its clinical manifestations reach their maximum, which together constitute the so-called intoxication syndrome.

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Causes bodily intoxication

The idea that intoxication always accompanies severe trauma and shock appeared at the beginning of our century in the form of the toxemic theory of traumatic shock, proposed by P. Delbet (1918) and E. Quenu (1918). Much evidence in favor of this theory was presented in the works of the famous American pathophysiologist W. B. Cannon (1923). The theory of toxemia was based on the fact of the toxicity of hydrolysates of crushed muscles and the ability of the blood of animals or patients with traumatic shock to retain toxic properties when administered to a healthy animal.

The search for a toxic factor, which was intensively carried out in those years, did not lead to anything, if we do not count the works of H. Dale (1920), who discovered histamine-like substances in the blood of shock victims and became the founder of the histamine theory of shock. His data on hyperhistamineemia in shock were confirmed later, but the monopathogenetic approach to explaining intoxication in traumatic shock was not confirmed. The fact is that in recent years a large number of compounds formed in the body during trauma have been discovered, which claim to be toxins and are pathogenetic factors of intoxication in traumatic shock. A picture of the origin of toxemia and the intoxication accompanying it began to emerge, which is associated, on the one hand, with a multitude of toxic compounds formed during trauma, and on the other, is caused by endotoxins of bacterial origin.

The overwhelming majority of endogenous factors are associated with protein catabolism, which increases significantly in shock-producing trauma and averages 5.4 g/kg-day with a norm of 3.1. Muscle protein breakdown is especially pronounced, increasing 2-fold in men and 1.5-fold in women, since muscle hydrolysates are particularly toxic. The threat of poisoning is posed by protein breakdown products in all fractions, from high-molecular to final products: carbon dioxide and ammonia.

In terms of protein breakdown, any denatured protein in the body that has lost its tertiary structure is identified by the body as foreign and is the target of attack by phagocytes. Many of these proteins, which appear as a result of tissue injury or ischemia, become antigens, i.e. bodies that are subject to removal, and are capable, due to their redundancy, of blocking the reticuloendothelial system (RES) and leading to detoxification deficiency with all the consequences that follow. The most serious of these is a decrease in the body's resistance to infection.

A particularly large number of toxins are found in the medium-molecular fraction of polypeptides formed as a result of protein breakdown. In 1966, A. M. Lefer and C. R. Baxter independently described the myocardial depressant factor (MDF), formed during shock in the ischemic pancreas and representing a polypeptide with a molecular weight of about 600 daltons. In this same fraction, toxins were found that cause depression of the RES, which turned out to be ring-shaped peptides with a molecular weight of about 700 daltons.

A higher molecular weight (1000-3000 daltons) was determined for a polypeptide that forms in the blood during shock and causes lung damage (we are talking about the so-called adult respiratory distress syndrome - ARDS).

In 1986, American researchers A. N. Ozkan and co-authors reported the discovery of a glycopeptidase with immunosuppressive activity in the blood plasma of polytraumatized and burn patients.

It is interesting that in some cases toxic properties are acquired by substances that perform physiological functions under normal conditions. An example is endorphins, which belong to the group of endogenous opiates, which, when produced in excess, can act as agents that suppress respiration and cause depression of cardiac activity. Especially many of these substances are found among low-molecular products of protein metabolism. Such substances can be called facultative toxins, in contrast to obligate toxins, which always have toxic properties.

Protein toxins

Toxins	Who has been diagnosed with	Types of shock	Origin	Molecular weight (daltons)
MDF Lefer	Human, cat, dog, monkey, guinea pig	Hemorrhagic, endotoxin, cardiogenic, burn	Pancreas	600
Williams	Dog	Superior mesospermous artery occlusion	Intestine
PTLF Nagler	Human, rat	Hemorrhagic, cardiogenic	Leukocytes	10,000
Goldfarb	Dog	Hemorrhagic, splanchnic ischemia	Pancreas, splanchnic zone	250-10,000
Haglund	Cat, rat	Splanchnic ischemia	Intestine	500-10,000
Mс Conn	Human	Septic	-	1000

Examples of facultative toxins in shock include histamine, which is formed from the amino acid histidine, and serotonin, which is a derivative of another amino acid, tryptophan. Some researchers also classify catecholamines, which are formed from the amino acid phenylalanine, as facultative toxins.

The final low-molecular products of protein breakdown - carbon dioxide and ammonia - have significant toxic properties. This primarily concerns ammonia, which even in relatively low concentrations causes a disorder of brain function and can lead to coma. However, despite the increased formation of carbon dioxide and ammonia in the body during shock, hypercarbia and ammoniacemia apparently do not have much significance in the development of intoxication due to the presence of powerful systems for neutralizing these substances.

Factors of intoxication also include peroxide compounds formed in significant quantities during shock-induced trauma. Usually, oxidation-reduction reactions in the body consist of fast-flowing stages, during which unstable but very reactive radicals are formed, such as superoxide, hydrogen peroxide and OH” radical, which have a pronounced damaging effect on tissues and thus lead to protein breakdown. During shock, the rapidity of oxidation-reduction reactions decreases and during its stages, accumulation and release of these peroxide radicals occurs. Another source of their formation can be neutrophils, which release peroxides as a microbicidal agent as a result of increased activity. The peculiarity of the action of peroxide radicals is that they are able to organize a chain reaction, the participants of which are lipid peroxides formed as a result of interaction with peroxide radicals, after which they become a factor in tissue damage.

Activation of the described processes observed in shockogenic trauma is apparently one of the serious factors of intoxication in shock. That this is so is evidenced, in particular, by the data of Japanese researchers who compared the effect of intra-arterial administration of linoleic acid and its peroxides at a dose of 100 mg/kg in animal experiments. In observations with the introduction of peroxides, this led to a 50% decrease in the cardiac index 5 minutes after injection. In addition, the total peripheral resistance (TPR) increased, and the pH and excess base of the blood decreased noticeably. In dogs with the introduction of linoleic acid, the changes in the same parameters were insignificant.

Another source of endogenous intoxication should be mentioned, which was first noted in the mid-1970s by R. M. Hardaway (1980). This is intravascular hemolysis, and the toxic agent is not free hemoglobin moving from the erythrocyte into the plasma, but the erythrocyte stroma, which, according to R. M. Hardaway, causes intoxication due to proteolytic enzymes localized on its structural elements. M. J. Schneidkraut, D. J. Loegering (1978), who studied this issue, found that the erythrocyte stroma is very quickly removed from circulation by the liver, and this, in turn, leads to depression of the RES and phagocytic function in hemorrhagic shock.

At a later stage after the injury, a significant component of intoxication is poisoning of the body with bacterial toxins. Both exogenous and endogenous sources are possible. In the late 1950s, J. Fine (1964) was the first to suggest that intestinal flora, under conditions of a sharp weakening of the RES function during shock, can cause a large amount of bacterial toxins to enter the circulation. This fact was later confirmed by immunochemical studies, which revealed that with various types of shock, the concentration of lipopolysaccharides, which are a group antigen of intestinal bacteria, significantly increases in the blood of the portal vein. Some authors believe that endotoxins are phosphopolysaccharides by nature.

Thus, the ingredients of intoxication in shock are numerous and diverse, but the overwhelming majority of them are of an antigenic nature. This applies to bacteria, bacterial toxins and polypeptides that are formed as a result of protein catabolism. Apparently, other substances with a lower molecular weight, being haptens, can also act as an antigen by combining with a protein molecule. In the literature devoted to the problems of traumatic shock, there is information about the excessive formation of auto- and heteroantigens in severe mechanical trauma.

In conditions of antigen overload and functional blockade of the RES in severe trauma, the frequency of inflammatory complications increases proportionally to the severity of the trauma and shock. The frequency of occurrence and severity of the course of inflammatory complications correlates with the degree of impairment of the functional activity of various populations of blood leukocytes as a result of the impact of mechanical trauma on the body. The main reason is obviously associated with the action of various biologically active substances in the acute period of trauma and metabolic disorders, as well as the influence of toxic metabolites.

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Symptoms bodily intoxication

Intoxication during shock-induced trauma is characterized by a variety of clinical signs, many of which are not specific. Some researchers include such indicators as hypotension, rapid pulse, and increased respiratory rate.

However, based on clinical experience, it is possible to identify signs that are more closely related to intoxication. Among these signs, encephalopathy, thermoregulation disorders, oliguria and dyspeptic disorders have the greatest clinical significance.

Typically, in victims with traumatic shock, intoxication develops against the background of other signs characteristic of shockogenic trauma, which can increase its manifestations and severity. Such signs include hypotension, tachycardia, tachypnea, etc.

Encephalopathy is a reversible disorder of the central nervous system (CNS) that occurs as a result of the effect of toxins circulating in the blood on brain tissue. Among a large number of metabolites, ammonia, one of the end products of protein catabolism, plays an important role in the development of encephalopathy. It has been experimentally established that intravenous administration of a small amount of ammonia leads to the rapid development of cerebral coma. This mechanism is most likely in traumatic shock, since the latter is always accompanied by increased protein breakdown and a decrease in detoxification potential. A number of other metabolites formed in increased quantities during traumatic shock are related to the development of encephalopathy. G. Morrison et al. (1985) reported that they studied a fraction of organic acids, the concentration of which increases significantly in uremic encephalopathy. Clinically, it manifests itself as adynamia, pronounced drowsiness, apathy, lethargy, and indifference of patients to the environment. The increase in these phenomena is associated with loss of orientation in the environment, and a significant decrease in memory. A severe degree of intoxication encephalopathy may be accompanied by delirium, which, as a rule, develops in victims who have abused alcohol. In this case, clinically, intoxication manifests itself in sharp motor and speech agitation and complete disorientation.

Usually, the degree of encephalopathy is assessed after communication with the patient. Mild, moderate and severe degrees of encephalopathy are distinguished. For its objective assessment, judging by the experience of clinical observations in the departments of the I. I. Dzhanelidze Research Institute of Emergency Care, the Glasgow Coma Scale, which was developed in 1974 by G. Teasdale, can be used. Its use makes it possible to parametrically assess the severity of encephalopathy. The advantage of the scale is its regular reproducibility even when it is calculated by mid-level medical personnel.

In case of intoxication in patients with shock-producing trauma, a decrease in the diuresis rate is observed, the critical level of which is 40 ml per minute. A decrease to a lower level indicates oliguria. In cases of severe intoxication, complete cessation of urine excretion occurs and uremic encephalopathy joins the phenomena of toxic encephalopathy.

Glasgow Coma Scale

Speech response	Score	Motor response	Score	Opening the eyes	Score
Oriented The patient knows who he is, where he is, why he is here	5	Executing commands	6	Spontaneous Opens eyes when awakened, not always consciously	4
		Meaningful pain response	5
Vague Conversation The patient answers questions in a conversational manner, but the responses show varying degrees of disorientation	4			Opens eyes to voice (not necessarily on command, but just to voice)	3
		Pulling away from pain, mindless	4
		Flexion to pain can vary as fast or slow, the latter being characteristic of a decorticated response	3	Opening or closing eyes more intensely in response to pain	2
Inappropriate speech Increased articulation, speech includes only exclamations and expressions combined with abrupt phrases and curses, cannot maintain a conversation	3
				No	1
		Extension to pain decerebrate rigidity	2
		No	1
		Incoherent speech Defined as groans and moans	2
No	1

Dyspeptic disorders as manifestations of intoxication are much less common. Clinical manifestations of dyspeptic disorders include nausea, vomiting, and diarrhea. Nausea and vomiting, caused by endogenous and bacterial toxins circulating in the blood, are more common than others. Based on this mechanism, vomiting during intoxication is classified as hematogenous-toxic. It is typical that dyspeptic disorders during intoxication do not bring relief to the patient and occur in the form of relapses.

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Forms

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Crush syndrome

The prevalence of toxicosis in the acute period is clinically manifested in the development of the so-called crush syndrome, which was described by N. N. Yelansky (1950) as traumatic toxicosis. This syndrome usually accompanies crushing of soft tissues and is characterized by the rapid development of disorders of consciousness (encephalopathy), a decrease in diuresis up to anuria and a gradual decrease in blood pressure. Diagnosis, as a rule, does not cause any particular difficulties. Moreover, the type and localization of the crushed wound can quite accurately predict the development of the syndrome and its outcome. In particular, crushing of the thigh or its rupture at any level leads to the development of fatal intoxication if amputation is not performed. Crushing of the upper and middle third of the shin or the upper third of the shoulder is always accompanied by severe toxicosis, which can still be dealt with under the condition of intensive treatment. Crushing of more distal segments of the limbs is usually not so dangerous.

Laboratory data in patients with crush syndrome are quite characteristic. According to our data, the greatest changes are characteristic of the SM and LII levels (0.5 ± 0.05 and 9.1 ± 1.3, respectively). These indicators reliably distinguish patients with crush syndrome from other victims with traumatic shock, who had reliably different SM and LII levels (0.3 ± 0.01 and 6.1 ± 0.4). 14.5.2.

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Sepsis

Patients who have survived the acute period of traumatic disease and the early toxicosis that accompanies it may then again find themselves in a serious condition due to the development of sepsis, which is characterized by the addition of intoxication of bacterial origin. In most observations, it is difficult to find a clear time boundary between early toxicosis and sepsis, which in patients with trauma usually constantly pass into each other, creating a mixed symptom complex in the pathogenetic sense.

In the clinical picture of sepsis, encephalopathy remains pronounced, which, according to R. O. Hasselgreen, I. E. Fischer (1986), is a reversible dysfunction of the central nervous system. Its typical manifestations consist of agitation, disorientation, which then turn into stupor and coma. Two theories of the origin of encephalopathy are considered: toxic and metabolic. In the body, during sepsis, myriads of toxins are formed, which can have a direct effect on the central nervous system.

Another theory is more specific and is based on the fact that during sepsis, aromatic amino acids are increased in production, which are precursors of such neurotransmitters as norepinephrine, serotonin, and dopamine. Derivatives of aromatic amino acids displace neurotransmitters from synapses, which leads to disorganization of the central nervous system and the development of encephalopathy.

Other signs of sepsis - hectic fever, exhaustion with the development of anemia, multiple organ failure are typical and are usually accompanied by characteristic changes in laboratory data in the form of hypoproteinemia, high levels of urea and creatinine, elevated levels of SM and LII.

A typical laboratory sign of sepsis is a positive blood culture. Doctors who conducted a survey of six trauma centers around the world found that this sign is considered the most consistent criterion for sepsis. The diagnosis of sepsis in the post-shock period, based on the above indicators, is very important, primarily because this complication of trauma is accompanied by a high mortality rate - 40-60%.

Toxic shock syndrome (TSS)

Toxic shock syndrome was first described in 1978 as a severe and usually fatal infectious complication caused by a special toxin produced by staphylococcus. It occurs in gynecological diseases, burns, postoperative complications, etc. TSS manifests clinically as delirium, significant hyperthermia reaching 41-42 °C, accompanied by headache, abdominal pain. Characteristic are diffuse erythema of the trunk and arms and a typical tongue in the form of the so-called "white strawberry".

In the terminal phase, oliguria and anuria develop, and sometimes disseminated intravascular coagulation syndrome with hemorrhages into internal organs joins in. The most dangerous and typical is hemorrhage into the brain. The toxin that causes these phenomena is found in staphylococcal filtrates in approximately 90% of cases and is called the toxic shock syndrome toxin. Toxin damage occurs only in those people who are unable to produce the corresponding antibodies. Such unresponsiveness occurs in approximately 5% of healthy people; apparently, only people with a weak immune response to staphylococcus get sick. As the process progresses, anuria appears and a lethal outcome quickly occurs.

Diagnostics bodily intoxication

To determine the severity of intoxication in shock-producing trauma, various laboratory analysis methods are used. Many of them are widely known, others are used less often. However, from the numerous arsenal of methods, it is still difficult to single out one that would be specific for intoxication. Below are the laboratory diagnostic methods that are the most informative in determining intoxication in victims with traumatic shock.

Leukocyte intoxication index (LII)

Proposed in 1941 by J. J. Kalf-Kalif and calculated as follows:

LII = (4Mi + ZY2P + S) • (Pl +1) / (L + Mo) • (E +1)

Where Mi are myelocytes, Yu are young, P are band neutrophils, S are segmented neutrophils, Pl are plasma cells, L are lymphocytes, Mo are monocytes; E are eosinophils. The number of these cells is taken as a percentage.

The meaning of the indicator is to take into account the cellular reaction to the toxin. The normal value of the LII indicator is 1.0; in case of intoxication in victims with shockogenic trauma it increases by 3-10 times.

The level of medium molecules (MM) is determined colorimetrically according to N. I. Gabrielyan et al. (1985). Take 1 ml of blood serum, treat with 10% trichloroacetic acid and centrifuge at 3000 rpm. Then take 0.5 ml over the sedimentary liquid and 4.5 ml of distilled water and measure on a spectrophotometer. The MM indicator is informative in assessing the degree of intoxication and is considered its marker. The normal value of the MM level is 0.200-0.240 relative units. With a moderate degree of intoxication, the MM level = 0.250-0.500 relative units, with severe intoxication - over 0.500 relative units.

Determination of creatinine in blood serum. Of the existing methods for determining creatinine in blood serum, the method of FV Pilsen, V. Boris is currently most often used. The principle of the method is that in an alkaline medium, picric acid interacts with creatinine to form an orange-red color, the intensity of which is measured photometrically. The determination is made after deproteinization.

Creatinine (µmol/L) = 177 A/B

Where A is the optical density of the sample, B is the optical density of the standard solution. Normally, the level of creatinine in the blood serum is on average 110.5 ±2.9 μmol/l.

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Determination of blood filtration pressure (BFP)

The principle of the method proposed by R. L. Swank (1961) consists of measuring the maximum level of blood pressure that ensures a constant volumetric rate of blood passage through a calibrated membrane. The method as modified by N. K. Razumova (1990) consists of the following: 2 ml of blood with heparin (at the rate of 0.02 ml of heparin per 1 ml of blood) are mixed and the filtration pressure in the physiological solution and in the blood is determined using a device with a roller pump. The FDC is calculated as the difference in the filtration pressures of the blood and the solution in mm Hg. The normal FDC value for donor heparinized human blood is on average 24.6 mm Hg.

The number of floating particles in blood plasma is determined (according to the method of N. K. Razumova, 1990) as follows: 1 ml of blood is collected in a defatted test tube containing 0.02 ml of heparin and centrifuged at 1500 rpm for three minutes, then the resulting plasma is centrifuged at 1500 rpm for three minutes. For analysis, 160 μl of plasma is taken and diluted in a ratio of 1:125 with physiological solution. The resulting suspension is analyzed on a celloscope. The number of particles in 1 μl is calculated using the formula:

1.75 • A,

Where A is the celloscope index. Normally, the number of particles in 1 µl of plasma is 90-1000, in victims with traumatic shock - 1500-1600.

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Degree of blood hemolysis

Severe trauma is accompanied by the destruction of red blood cells, the stroma of which is the source of intoxication. For analysis, blood is taken with any anticoagulant. Centrifuge for 10 minutes at 1500-2000 rpm. Plasma is separated and centrifuged at 8000 rpm. In a test tube, measure out 4.0 ml of acetate buffer; 2.0 ml of hydrogen peroxide; 2.0 ml of benzidine solution and 0.04 ml of test plasma. The mixture is prepared immediately before the analysis. It is mixed and left to stand for 3 minutes. Then photometry is carried out in a 1 cm cuvette against the compensation solution with a red light filter. Measure 4-5 times and record the maximum readings. Compensation solution: acetate buffer - 6.0 ml; hydrogen peroxide - 3.0 ml; benzidine solution - 3.0 ml; physiological solution - 0.06 ml.

The normal content of free hemoglobin is 18.5 mg%; in victims with shock-producing trauma and intoxication, its content increases to 39.0 mg%.

Determination of peroxide compounds (diene conjugates, malondialdehyde - MDA). Due to their damaging effect on tissues, peroxide compounds formed during shockogenic trauma are a serious source of intoxication. To determine them, 1.0 ml of bidistilled water and 1.5 ml of cooled 10% trichloroacetic acid are added to 0.5 ml of plasma. The samples are mixed and centrifuged for 10 min at 6000 rpm. 2.0 ml of supernatant are collected in test tubes with ground sections and the pH of each test and blank sample is adjusted to two with a 5% NaOH solution. The blank sample contains 1.0 ml of water and 1.0 ml of trichloroacetic acid. 

Ex tempore, prepare a 0.6% solution of 2-thiobarbituric acid in bidistilled water and add 1.0 ml of this solution to all samples. The test tubes are closed with ground stoppers and placed in a boiling water bath for 10 min. After cooling, the samples are immediately photometered on a spectrophotometer (532 nm, 1 cm cuvette, against the control). The calculation is made using the formula

C = E • 3 • 1.5 / e • 0.5 = E • 57.7 nmol/ml,

Where C is the concentration of MDA, normally the concentration of MDA is 13.06 nmol/ml, in shock - 22.7 nmol/ml; E is the sample extinction; e is the molar extinction coefficient of the trimethine complex; 3 is the sample volume; 1.5 is the dilution of the supernatant; 0.5 is the amount of serum (plasma) taken for analysis, ml.

Determination of the intoxication index (II). The possibility of integrally assessing the severity of intoxication based on several indicators of protein catabolism was almost never used, primarily because it remained unclear how to determine the contribution of each of the indicators to determining the severity of toxicosis. Doctors attempted to rank the supposed signs of intoxication depending on the actual consequences of the injury and its complications. Having designated the life expectancy in days of patients with severe intoxication by the index (-T), and the length of their stay in the hospital by the index (+T), it turned out to be possible to establish correlations between the indicators claiming to be criteria for the severity of intoxication in order to determine their contribution to the development of intoxication and its outcome.

Treatment bodily intoxication

The analysis of the correlation matrix, performed during the development of the prognostic model, showed that of all the intoxication indicators, this indicator has the maximum correlation with the outcome; the highest values of II were observed in deceased patients. The convenience of its use is that it can be a universal sign in determining indications for extracorporeal detoxification methods. The most effective detoxification measure is the removal of crushed tissues. If the upper or lower limbs are crushed, then we are talking about primary surgical treatment of the wound with maximum excision of destroyed tissues or even amputation, which is performed on an emergency basis. If it is impossible to excise crushed tissues, a set of local detoxification measures is performed, including surgical treatment of wounds and the use of sorbents. In case of suppurating wounds, which are often the primary source of intoxication, detoxification therapy also begins with local action on the lesion - secondary surgical treatment. The peculiarity of this treatment is that the wounds, as in the primary surgical treatment, are not sutured after its implementation and are widely drained. If necessary, flow drainage is used with the use of various types of bactericidal solutions. The most effective is the use of a 1% aqueous solution of dioxidine with the addition of broad-spectrum antibiotics. In case of insufficient evacuation of the contents from the wound, drainage with active aspiration is used.

In recent years, locally applied sorbents have been widely used. Activated carbon is applied to the wound as a powder, which is removed after a few hours and the procedure is repeated again.

More promising is the local use of membrane devices that provide a controlled process of introducing antiseptics, analgesics into the wound and removing toxins.