Toxic effects of halogenated aliphatic and aromatic hydrocarbons: clinical guidelines

List of Abbreviations

ALT – alanine aminotransferase

AST – aspartate aminotransferase

GGT — gamma-glutamyl transferase

GLC – gas-liquid chromatography

HHC — halogenated hydrocarbons

GI – gastrointestinal tract

IMV – invasive mechanical ventilation

ABDS – acid-base balance status

LDH – lactate dehydrogenase

MRI – magnetic resonance imaging

ARF – acute renal failure

PCBs — polychlorinated biphenyls

LCE – level of confidence of evidence

US – ultrasound examination

GRS – grade of recommendation strength

FBS — fiberoptic bronchoscopy

CHCs — chlorinated hydrocarbons

CVP – central venous pressure

CNS – central nervous system

ALP – alkaline phosphatase

ECG – electrocardiography

ETS — exotoxic shock

EchoEG — brain echoencephalography

EEG – electroencephalography

SCT – spiral computed tomography

Terms and Definitions

Halogenated hydrocarbons (HHCs) are derivatives of aliphatic and aromatic hydrocarbons in which one or more hydrogen atoms are replaced by halogen atoms (fluorine, chlorine, bromine).

Aliphatic hydrocarbons are acyclic hydrocarbons of linear or branched structure, containing only single bonds and forming a homologous series with the general formula CₙH₂ₙ₊₂ (alkanes or paraffins) or a single double bond between carbon atoms, forming a homologous series with the general formula CₙH₂ₙ (alkenes or ethylene hydrocarbons).

Aromatic hydrocarbons are cyclic hydrocarbons containing an aromatic system — benzene and its homologues (methylbenzene or toluene, dimethylbenzene or xylene, etc.) or its derivatives with unsaturated side chains (styrene or vinylbenzyl, etc.).

Poisoning is a disease developing as a result of external (exogenous) exposure of a human or animal body to chemical compounds in quantities that cause disorders of physiological functions and pose a threat to life.

Sniffing is a type of substance abuse characterized by achieving euphoric intoxication (bemusement) by inhaling vapors of volatile substances.

Acute kidney injury is a pathological condition developing as a result of a direct acute effect of renal and (or) extrarenal damaging factors, lasting up to seven days and characterized by the rapid (hours to days) development of signs of kidney damage or dysfunction of varying severity.

Freons (chlorofluorocarbons) is the chemical name for a group of halogen-containing derivatives of saturated hydrocarbons (mainly methane and ethane) used as refrigerants, propellants, blowing agents, and solvents, in which hydrogen atoms are most often replaced by fluorine, chlorine, bromine, or (less frequently) iodine.

Lethal synthesis is the process of formation of highly toxic compounds from non-toxic or low-toxicity substances during biotransformation, leading to intoxication of the body.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Chlorinated hydrocarbons under normal conditions are colorless liquids with a characteristic odor. Chlorinated hydrocarbon vapors are heavier than air and can accumulate in enclosed and poorly ventilated areas, increasing the risk of inhalation poisoning. Acute poisoning occurs when they enter the body via inhalation, through the skin, and via the gastrointestinal tract. So-called acute inhalation poisonings are likely. The toxic effect manifests as disorders of internal organs with a predominance of hepato-, nephro-, and neurotoxicity. The local effect of chlorinated hydrocarbons is associated with the development of acute dermatitis (eczema and ulcer-necrotic processes). The hepatotoxicity of chlorinated hydrocarbons manifests as cytotoxic (necrosis, steatosis, fibrosis, carcinogenesis) and cholestatic (impaired bile secretion) disorders. Kidney damage in chlorinated hydrocarbon poisoning is predominantly secondary [3, 13, 27].

Chlorofluorocarbons are organic compounds consisting exclusively of carbon, chlorine, and fluorine atoms (CFCl). A distinction is made between lower — low-boiling organic compounds based on methane, ethane, and propane series, as well as higher chlorofluorocarbons, which are high-molecular-weight compounds. Many chlorofluorocarbons are widely used as refrigerants, propellants (in aerosol applications), and solvents. They are used as refrigerants, propellants, blowing agents, and solvents. In addition to fluorine and chlorine atoms, chlorofluorocarbons may contain bromine atoms. They decompose when heated in a mixture with air to form hydrogen halides and phosgenes. They usually have a low level of toxicity [15, 69]. In high doses, they damage the cardiovascular and nervous systems, cause vascular spasms and microcirculatory blood disorders. They damage the liver, and consequently the kidneys due to the development of poisoning. They destroy lung membranes, especially in the presence of organic solvent and carbon tetrachloride impurities — emphysema and scarring develop. Fatalities can be caused by a combination of direct toxicity and hypoxemic asphyxia due to the saturation of the atmosphere with freon in the confined environment where the intoxication occurred [69]. Accidental oral ingestion results in necrosis and multiple stomach perforations [62].

Methyl bromide is an extremely hazardous convulsant-paralytic toxicant and an emergency hazardous chemical. The main routes of entry of the substance into the human body are the respiratory system and skin, since it is most commonly used in gaseous form. Extremely toxic to humans, but moderately toxic to experimental animals (rats, mice, and dogs) [33]. It has an irritating effect on the skin and mucous membranes and is capable of being absorbed through them. In this case, its toxic effect may be enhanced. It possesses high neurotoxicity.

Vinyl chloride is a neurotropic poison affecting brain stem structures [65]. It causes damage to the central nervous system, peripheral nerves, systemic damage to connective tissue and blood vessels, and reproductive function. It has an immunotoxic effect. With chronic exposure, it causes carcinogenic, teratogenic, and mutagenic effects. It exerts a predominantly inhalation effect on humans, while its hazardous concentration in the air (10 ppm) is below the limit of human olfactory detection (300 ppm) [66]. Prolonged exposure to higher concentrations of vinyl chloride can cause death due to central nervous system paralysis and respiratory arrest. It is heavier than air and can cause asphyxiation in poorly ventilated or confined spaces. A deep narcotic state can develop very rapidly, sometimes within a few minutes, up to a fatal outcome. Even short-term inhalation of vinyl chloride can cause sudden loss of consciousness. Chronic exposure to vinyl chloride leads to manifestations such as pneumoconiosis, hepatic angiosarcoma, acroosteolysis, Raynaud's disease, whereas acute exposure to high levels is very rare and manifests as toxic encephalopathy, metabolic acidosis, and possible seizures [67].

Biphenyl chlorides are a group of organic compounds including all chlorine-substituted diphenyl derivatives, representing a complex mixture of 209 isomers or congeners that differ significantly in their structure and mechanisms of action. Despite the cessation of polychlorinated biphenyl (PCB) production, the risk of acute PCB poisoning still persists today during the disposal of PCBs and plastic waste [37]. Workers are at risk of PCB exposure during the repair of electrical cables, transformers, and capacitors, transportation of hazardous waste and/or treatment of disposal sites, processing of used transformer oil, and others [1].

They can enter the body through the skin, lungs, and gastrointestinal tract. In industrial settings, they enter mainly through the skin. Once in the blood, PCBs rapidly accumulate in the liver and muscles and redistribute into adipose tissue. It exhibits irritant and general toxic effects via all routes of entry into the body. A specific feature of the toxic effect of PCBs is the development of chloracne — a nodular-pustular skin disease, independent of the route of entry into the body and observed after prolonged exposure. The clinical picture of acute and subacute forms of dermatoses caused by PCB exposure is most commonly noted in combination with naphthalenes, and in mild cases is characterized by skin swelling and redness, itching that intensifies when staying outdoors on sunny days [22, 61].

The classification of HHC poisoning is carried out according to the severity grade in acute oral, inhalation, and (or) percutaneous poisoning.

Acute toxic effect of halogenated hydrocarbons refers to rapidly developing life-threatening structural and functional specific and non-specific disorders of the body following a single or short-term inhalation, percutaneous, or oral exposure to a toxic dose of halogenated hydrocarbons, caused by pulmono-, neuro-, cardio-, hepato-, nephrotoxic, general toxic, and locally caustic effects, requiring emergency medical care.

Dichloroethane is a colorless, volatile liquid with a sweetish odor, readily soluble in alcohol and ether, and poorly soluble in water. Dichloroethane belongs to the second hazard class. The fatal dose of dichloroethane for adults varies depending on individual sensitivity and is about 20 ml per person (of pure substance). The average lethal concentration of dichloroethane vapors in the air is about 1.5–2.5 g/m³ [7, 8].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Halogenated hydrocarbons are a class of highly reactive chemical compounds capable of causing acute and chronic poisonings via various routes of entry. Halogenated hydrocarbon intoxication can occur due to:

• emergencies at hazardous chemical facilities that use halogenated hydrocarbons as starting and intermediate components of organic synthesis, including terrorist attacks, resulting in chemical contamination zones;

• violations of safety regulations when handling these substances in industrial and domestic settings;

• intentional use of halogenated hydrocarbons to achieve euphoria or commit suicide;

• terrorist acts involving these substances;

• accidents at facilities using halogenated hydrocarbons in total flooding fire suppression systems, as well as the activation of such systems [7, 8, 39, 42, 46].

The risk of halogenated hydrocarbon poisoning is increased in individuals occupationally exposed to these toxicants (inhalation and percutaneous poisonings); children (accidental domestic oral poisonings); adolescents or young adults (inhalation of halogenated hydrocarbon vapors for recreational intoxication/huffing) [45, 53].

According to hygienic standards GN 2.2.5.3532-18 "Maximum Permissible Concentrations of Harmful Substances in the Working Zone Air" [9], the proportion of halogenated hydrocarbons among the 2,495 harmful substances in the working zone air requiring strict hygienic control is about 7% (166 items). Of these, 67 items represent extremely hazardous and highly hazardous compounds. Table 1 presents various subgroups of halogenated hydrocarbons in the working zone air along with their hazard classes.

Table 1 ‑ Hazard classes and structure of harmful halogenated hydrocarbons in the working zone air

Group and mass poisonings with halogenated hydrocarbons (bromomethane, dichloroethane, carbon tetrachloride, vinyl chloride, chlorobenzene, etc.) have been described during agricultural work, mitigation of accidents at hazardous chemical facilities, cleaning of industrial tanks, firefighting, waste leakage, capacitor bank explosions, etc. [44].

Currently, a rapid spread of "huffing" (inhalation of volatile substance vapors) – a type of substance abuse characterized by achieving a euphoric effect – is registered in many regions of the country [54]. In the USA, young people commonly use para-dichlorobenzene to achieve euphoria; it is used domestically as an air freshener, deodorant, and in so-called "mothballs" containing para-dichlorobenzene instead of naphthalene. The toxicity of this aromatic chlorine derivative is caused by neurological disorders, the development of toxic leukoencephalopathy, and ichthyosiform erythroderma [4]. The high lipophilicity of the toxicants and acute cerebral hypoxia play an important role in the development of toxic leukoencephalopathy. The prognosis in toxic leukoencephalitis is highly variable and depends on many factors, including the degree and duration of exposure to the toxic substance, the patient's age, the condition of the liver and kidneys responsible for the elimination of toxic compounds, as well as comorbid conditions and neurological status [26].

Pathogenetic processes caused by halogenated hydrocarbons are related to their physicochemical properties, chemical structure, and metabolic pathway. For example, two isomers of dichloroethane are known with different chlorine positions on the ethane carbon atom: 1,1-dichloroethane ($CH_3CHCl_2$) and 1,2-dichloroethane ($ClCH_2CH_2Cl$). Such minor changes in the geometric structure of dichloroethane determine significant differences in its toxicity and reactivity. The toxic effect of 1,1-dichloroethane is less pronounced than that of 1,2-dichloroethane, which is due to differences in their biotransformation processes. The biotransformation products of 1,2-dichloroethane are monochloroacetic and oxalic acids, whereas the metabolism of 1,1-dichloroethane proceeds through the formation of acetic acid, the toxicity of which is significantly lower compared to monochloroacetic acid, which possesses cytotoxic activity. Alimentary intake of 20–30 ml of 1,2-dichloroethane causes extremely severe intoxication leading to death, whereas an equivalent dose of 1,1-dichloroethane leads to moderate intoxication [5].

Among aliphatic halogenated hydrocarbons, chlorine, bromine, and fluorine derivatives follow in descending order of toxicity; for aromatic ones, bromine, chlorine, and fluorine derivatives. Mixed forms have low toxicity but may contain highly toxic impurities [15].

Halogenated hydrocarbons are absorbed into the blood, and within 6 hours, about 70% of the toxicant is distributed into the tissues. Simultaneous ingestion of chlorinated hydrocarbons with fats and alcohol accelerates their resorption [3].

In acute poisoning with chlorinated volatile hydrocarbons (chlorine derivatives of methane, ethane, ethylene), central nervous system depression is primarily noted. The effect of these substances on the central nervous system is similar to that of other inhalational anesthetics on ion channels, leading to changes in synaptic transmission. This effect also affects the ion channels of peripheral organs, primarily the heart. The general anesthetic effect is based on the physicochemical interaction of volatile hydrocarbons with hydrophobic regions of proteins and lipids in cell membranes. The activity of inhalational anesthetics is proportional to their lipophilicity [11, 17]. Among halogenated hydrocarbons, the most rapid development of the anesthetic effect is noted with 1,1,1-trichloroethane and carbon tetrachloride.

Biotransformation of halogenated hydrocarbons in acute poisoning is a toxification reaction ("lethal synthesis"). The metabolites of the first phase of biotransformation are mainly free radicals, chlorinated alcohols and aldehydes, epoxides, and halogen ions. Free radicals are capable of initiating lipid peroxidation processes, interacting with macromolecules, and leading to the formation of secondary and tertiary radicals [3, 7, 8].

Toxicokinetics and metabolism of chlorofluorocarbons have been insufficiently studied. The absorption of these compounds after inhalation is indicated by elevated urinary fluorine levels in experimental animals. Studies on volunteers investigating the absorption and elimination of chlorodifluoromethane (freon 22) upon inhalation exposure revealed the presence of the unchanged substance in blood, exhaled air, and urine. In terms of toxicokinetics, freons are similar to inert gases. At low concentrations, they exhibit anesthetic effects; upon inhalation of high concentrations, they can exert toxic effects on the cardiovascular and respiratory systems. As the number of chlorine atoms in the compound increases, their toxicity also increases. Freons derived from ethane are more toxic than those derived from methane. The toxic effect occurs rapidly, and elimination from the body is slow. Toxicity also significantly depends on the degree of purification of freons from impurities. Upon contact with the skin or eyes, liquid freons can cause rapid cooling, leading to frostbite [21].

Pathogenetic mechanisms and the selectivity of the toxic action of individual halogenated hydrocarbons may have significant differences, but at a sufficient level of exposure, all of them exert a polytropic effect on the body: an anesthetic effect on the central nervous system, an irritating effect on the mucous membranes of the eyes and upper respiratory tract, and damage to the liver, kidneys, heart, and other organs and systems.

1.3 Epidemiology of the Disease or Condition

Over the past decade, there has been a pronounced trend toward a decrease in hospitalization and mortality rates resulting from the toxic effects of halogenated hydrocarbons; however, the risks remain high, and cases of acute halogenated hydrocarbon poisoning, including fatal ones, are registered annually. Thus, acute poisonings of humans with 1,2-dichloroethane, despite a significant decrease in their share in the overall structure of poisonings, continue to be an urgent problem of modern clinical toxicology due to the severe clinical course and high mortality rate [14, 34].

Halogenated hydrocarbons (HHs) are components of a number of medicinal, alkylating, and disinfecting agents, refrigerants, detergents and cleaning products, installation materials, sealants, liquid nails, various adhesives, paints and varnishes, solvents, and waterproofing materials (fluorocarbons and mixed HHs, trichloromethane, vinyl chloride, chloroprene, dichloroethane, etc.). Their widespread use in everyday life increases the risk of acute poisoning not only in adults, but also in the pediatric population [10, 12].

Between 2016 and 2020, the Information and Consultative Toxicology Department of the Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical-Biological Agency of Russia (Lopukhin Center) registered 58 requests from Moscow for consultative support regarding the diagnosis and management of HH poisoning. Eight cases involved occupational exposure (including mass exposure to Moment glue in 31 workers); 9 were intentional poisonings (8 cases of "sniffing" and 1 suicide attempt); 41 cases were domestic poisonings (including 10 pediatric patients). Twenty-five cases were associated with Moment glue, 17 cases with freons, 4 cases with BF glue, 3 cases with waterproofing mastic, 2 cases with perchloroethylene, and 1 case each with carbon tetrachloride, chloroethane, chloroform, chloroethylene, chlorobenzene, dichlorobenzene, unspecified chlorinated hydrocarbon, and liquid nails [43].

According to the industry statistical reports of 26 toxicological centers (departments) in the Russian Federation, 119 patients were hospitalized with acute HH poisoning in 2023. Of these, 3 patients were poisoned with dichloroethane, 2 with carbon tetrachloride, 3 with dichloromethane, as well as freons, glue, and other compounds not specified in the reports. Three fatalities were recorded: two cases of dichloroethane poisoning and one case of carbon tetrachloride poisoning [25].

According to the Center for Acute Poisonings at the Dzhanelidze Research Institute of Emergency Medicine (Saint Petersburg), 13 patients diagnosed with toxic effect of halogen derivatives of aliphatic and aromatic hydrocarbons (T53) were hospitalized between 2013 and 2023. These were predominantly poisonings with carbon tetrachloride and chlorofluorocarbons [41].

1.4 Features of Coding the Disease or Condition

Diagnosis coding is carried out in accordance with the International Classification of Diseases, 10th Revision (ICD-10).

In ICD-10, the toxic effect of halogen derivatives of aliphatic and aromatic hydrocarbons has the code T53, which includes 9 specific diagnostic subcategories.

T53 Toxic effect of halogen derivatives of aliphatic and aromatic hydrocarbons

1.5 Classification of the disease or condition

In clinical practice, the relative selective toxicity of HHs can serve as a reference point for verifying the diagnosis and predicting the course of the disease.

Depending on the nature, direction, and severity of the toxic effect, one can conventionally distinguish hydrocarbons with predominantly narcotic, irritant, hepatotoxic, or nephrotoxic action. Mixed halogen derivatives of hydrocarbons are less toxic than chlorine or bromine derivatives and are generally low-toxicity substances with a predominantly narcotic type of action.

Based on the identified differences in selective toxicity, HHs are divided into four main groups:

• with pronounced narcotic, hepatotoxic, and nephrotoxic action (most aliphatic and aromatic chlorinated hydrocarbons, methyl bromide, benzotrifluoride, trifluorochloroethylene);

• with pronounced narcotic effect and mildly pronounced hepatotoxic and nephrotoxic action (most bromine, fluorine, and mixed halogen derivatives of hydrocarbons);

• with irritant action on the mucous membranes of the eyes, upper respiratory tract, and lungs (tetrafluoroethylene);

• with damaging action on mucous membranes, skin, and parenchymal organs (hexafluoropropylene) [7].

• The classification of HH poisonings can be based on their chemical structure or the type of substituted halogen (chlorine, fluorine, chlorine-bromine-iodine derivatives, as well as mixed derivatives), which largely determines the toxicity of the compound (Table 2) [48].

Table 2 — Toxicity indicators for individual groups of HHs according to the Federal Register of Potentially Hazardous Chemical and Biological Substances

Irritating effect on the skin and mucous membranes is especially pronounced in brominated HWD (methyl bromide, propyl bromide, butyl bromide, hexyl bromide, decyl bromide); among chlorinated HWD—in methyl chloride, tetrachloropentane, chlorotoluene; among fluorinated HWD—in hexafluoropropylene. Mixed halogenated hydrocarbon derivatives (freons, trifluorochloroethylene, chloran) do not have a pronounced irritating effect [7].

The narcotic effect of various substances varies: some have a pronounced narcotic effect (trichloromethane, carbon tetrachloride, di- and tetrachloroethane, di-, tri- and tetrachloropropane, chlorobenzene, benzyl chloride, propyl bromide, benzotrifluoride), while others (methyl chloride, trichloroethane, dichloroethylene, tetrachloropentane, most bromo-, fluoro- and mixed hydrocarbon derivatives) have a mild narcotic effect.

The clinical presentation of HWD poisoning includes four periods: latent period, period of cerebral disorders, period of hepatorenal failure, and recovery period. In inhalation poisoning, the latent period is practically absent [8].

1.6 Clinical presentation of the disease or condition

HWDs can mainly enter the body through the upper respiratory tract, intact skin, and more rarely through the gastrointestinal tract (in case of accidental or intentional ingestion). The clinical manifestations of acute oral, inhalation, and percutaneous HWD poisoning are similar, but develop more slowly following inhalation and percutaneous routes, and may remain undiagnosed for a long time [45].

In case of a favorable outcome, recovery is generally slow, and long-term consequences and complications (neurological disorders, asthenovegetative syndrome, hepatitis, nephropathy, dermatitis, etc.) are frequently noted [7].

Skin, mucous membranes of the eyes and respiratory tract

When HWDs get on the skin, itching, burning, and redness of the affected area occur. Increased sweating and contact dermatitis with the development of blisters, erythema, and vesicles are possible, which may progress to 2nd and 3rd degree burns. On the mucous membranes of the eye, signs of conjunctivitis occur, and at high concentrations—corneal necrosis; on the mucous membranes of the respiratory tract—catarrhal inflammation causing acute laryngitis, pharyngotracheitis, bronchitis, bronchiolitis, and in severe cases, pulmonary edema. Skin lesions caused by HWDs manifest as itching, burning, and hyperemia, burns, frostbite. Allergic vasculitis, Lyell's syndrome, contact dermatitis, and vesicles that can progress to 2nd and 3rd degree burns, and necrosis are possible. Ichthyosiform eruptions caused by exposure to paradichlorobenzene have been described [8].

Early clinical manifestations of burns and frostbite often do not reflect the actual depth of the injury and may deceptively appear benign or be misdiagnosed as an allergic reaction [57]. The latent period for the manifestation of a chemical burn lasts several hours. In the reported case of a chemical burn following a jet of bromomethane spraying from a canister onto the legs of a worker wearing chemical-protective overalls and footwear, the first clinical signs (slight edema, tingling in the legs) were noted after 8 hours. Subsequently, over the course of several hours, pain syndrome developed, with the burn spreading up to 1% of the total body surface area (left leg) and gradually progressing to 13% (legs, left buttock, and posterior thigh) [68]. The threat of percutaneous HWD injury (chloroform, methyl bromide, methyl iodide, etc.) is often underestimated, and the victim remaining in contaminated clothing can lead to deep chemical burns and severe poisoning [20, 64]. The irritant effect may be accompanied by a reflex action (laryngospasm, asphyxia, syncope, etc.), which can lead to sudden death, for example, upon exposure to methyl bromide or methyl chloride, etc. [31].

Central nervous system

The exact mechanism of central nervous system (CNS) depression is unclear. Currently, there is no convincing evidence of hydrocarbons binding to specific cellular receptors. During hydrocarbon aspiration, hypoxia caused by lung injury may exacerbate CNS depression.

A typical CNS response to the toxic effects of HWDs is an intoxication-like state and excitation accompanied by depressed consciousness. Headache, nausea, ataxia, limb tremor, and slurred speech are noted. Severe poisoning involves visual disturbances, convulsions, paralysis, delirium, euphoria, and apathy.

Prolonged or massive short-term exposure (occupational or in substance abuse) to certain HWDs, especially volatile lipophilic compounds, can lead to toxic leukoencephalopathy, clinically manifesting as significant CNS depression (ataxia, spasticity, dysarthria, confusion, vision loss, peripheral neuropathy, stupor, coma) resulting in prolonged hospitalization and disability [26, 51].

Autonomic Nervous System

Exposure to certain halogenated hydrocarbon derivatives can cause autonomic nervous system disorders: carbon tetrachloride—toxic polyneuropathy; trichloroethylene—trigeminal neuralgia caused by its metabolites or impurities present in it; biphenyls—axonal polyneuropathy, etc. [61].

Cardiovascular system

The cardiotoxic effect of HWDs is due to an emerging increase in myocardial sensitivity to catecholamines, which can lead to sudden death from ventricular fibrillation. It is suggested that a triggering role in the development of arrhythmia is played by extrasystoles arising from the action of endogenous catecholamines against the background of ventricular repolarization changes, the presence of which is indicated by QTc interval prolongation [45]. Following the inhalation of a computer-duster aerosol based on difluoroethane for euphoric effects, a young patient exhibited elevated troponin levels (17 ng/mL [normal 0–0.5 ng/mL]) and a non-ST-elevation non-transmural myocardial infarction [50].

Gastrointestinal tract

Upon oral ingestion of HWDs, an early sign of poisoning is acute gastroenteritis syndrome with nausea, sialorrhea, repeated vomiting with bile, a feeling of constriction in the esophagus and intestines, tenderness and enlargement of the liver, vomiting, cramping abdominal pain, and diarrhea. In severe poisoning, hematemesis occurs. The risk of lung injury increases. Washings have a characteristic odor of organochlorine compounds.

A serious but rarely reported complication of inhaling fluorinated hydrocarbons is severe frostbite (chemical burn) of the mucous membrane of the upper gastrointestinal tract—the oropharynx and esophagus [47, 59]. Cases of first- and second-degree frostbite of the oral mucosa, tongue, and larynx, with involvement of the vocal cords, trachea, bronchi, and esophagus requiring surgical treatment, have been described following fluorinated hydrocarbon inhalation [58].

Liver

The strongest hepatotoxic effect is exerted by chlorinated hydrocarbons, especially carbon tetrachloride. In most cases, the effect of halogenated hydrocarbon derivatives is due to the formation of a chemically active intermediate metabolite with cytotoxic action in phase I of hepatic metabolism [27]. The toxic effect of hepatotropic chloro- and bromo-derivatives of hydrocarbons (carbon tetrachloride, dichloroethylene, tetrachloroethane, vinyl chloride, bromomethane, etc.) is marked by the development of a nonspecific cytolytic syndrome—impaired permeability of cell membranes and their organelles, and the release of intracellular enzymes into blood plasma. The cytolytic process may affect a small number of hepatocytes or be more widespread [3].

Clinical signs of toxic hepatopathy typically develop on days 2–3 and manifest as hepatomegaly and tenderness on palpation, hepatic colic of varying intensity, and jaundice of the sclera and skin. Hemorrhagic syndrome frequently develops, presenting with subconjunctival hemorrhages, epistaxis, and gastrointestinal bleeding.

The outcome of toxic hepatopathy can be hepatic failure. In carbon tetrachloride poisoning, moderate hepatopathy develops in 20% of cases and severe hepatopathy in 80%. According to blood biochemistry data, in severe liver damage, the activity of intracellular enzymes increases significantly as early as the first 24 hours: FMPA, LDH₅, LDH₄; on days 2–3, SDH, GLD, MDH_3-4, and non-specific enzymes. A gradual decrease in their activity begins from days 5–6, and they normalize by the end of the fourth week post-exposure. Blood bilirubin is elevated, predominantly the direct fraction. According to radionuclide studies, impairments in the uptake and excretory functions of the liver are observed as early as the first 24 hours. In moderate hepatopathy, all parameters normalize by days 30–40 post-exposure, whereas in severe hepatopathy, only after 1.5–2 years in 36% of patients [40].

Liver damage manifested by elevated aminotransferase activity and hepatomegaly, or without it, is usually reversible, except in cases of severe poisoning. Acute liver injury presents with a pronounced clinical picture including weakness, fever, loss of appetite, nausea, vomiting, right upper quadrant tenderness upon percussion, hemostasis disorders, jaundice, encephalopathy, and toxic coma. Sometimes in veno-occlusive disease, portal hypertension and ascites, as well as hepatopulmonary syndrome, develop rapidly and lead to death.

Clinical manifestations of hepatopulmonary syndrome are non-specific and include dyspnea, ortodoxia, clubbing of the fingers, cyanosis, and spider angiomas [7].

Kidneys

Toxic nephropathy is one of the most common pathological syndromes in acute hydrocarbon (HC) poisonings. Chlorinated hydrocarbons (chloroform, carbon tetrachloride, dichloroethane) and the aromatic hydrocarbon bromobenzene exert a direct damaging effect on the renal epithelium, causing degenerative changes in the epithelium of the convoluted tubules and Bowman's capsule with the development of diffuse cholemic nephrosis. At the same time, signs of necrotizing nephrosis are typically absent. The pathogenesis of nephrosis has not been fully elucidated. Degenerative changes in the renal parenchyma and glomeruli lead to oligoanuria, causing the deposition of lipoid and protein particles, the development of proteinuria, and metabolic disorders. In the pathogenesis of toxic renal injury from acute carbon tetrachloride poisoning, the nephrotoxic effect of certain amino acids (leucine, tyrosine) which are normally deaminated in the liver but excreted by the kidneys in large amounts during massive parenchymal damage, may play a significant role. Large losses of albumins in the urine alter the ratio of protein fractions in blood plasma (globulins outnumber albumins), leading to a decrease in the colloid-osmotic pressure of the serum and the development of edema. Passing from the blood into the urine, some of the proteins coagulate and form hyaline casts. The edema fluid contains little protein. In mild forms of nephrosis, symptoms are mild. Proteinuria is usually insignificant, and a small number of degenerated renal epithelial cells are found in the urine [2].

In severe cases, the urine composition changes significantly. Proteinuria corresponds to the degree of edema and reaches 3–5%. Degenerated renal epithelium, hyaline, epithelial, and granular casts appear in the urinary sediment (under acidic urine reaction). Specific gravity is increased. Due to massive protein losses in the body, dry skin, muscle atrophy, gastrointestinal disorders, edema, and sometimes ascites occur. Blood formed elements in the urine, which are not detected in nephrosis, may be identified due to vascular damage or renal epithelial necrosis. In severe poisonings, functional impairment of renal blood flow and glomerular filtration against the background of acute liver injury can lead to hepatorenal syndrome.

As a result of combined liver and kidney damage, the mutually compensating influence of organ functions is lost, which introduces significant changes into the clinical manifestations of these poisonings and causes severe alterations in the brain and lungs with the development of psychoneurotic disorders and external respiration impairments. These manifest as the "wet lung" syndrome representing various stages of increasing interstitial pulmonary edema. These pulmonary changes usually disappear completely upon restoration of diuresis and reduction of hyperhydration, but they can lead to pneumonia, the differential diagnosis of which is extremely difficult. In addition, acute renal failure can lead to impaired erythropoiesis and the development of iron deficiency anemia [2]. With a favorable outcome of severe HC poisonings, renal function recovery is observed 3–6 weeks post-exposure; blood creatinine levels and minute diuresis normalize, while glomerular filtration, the creatinine concentration index, and tubular water reabsorption remain reduced and recover over several months.

Blood and hemostatic system

Blood coagulation disorders in carbon tetrachloride poisoning manifest in the first 24 hours by an increase in blood fibrinogen levels and fibrinolytic activity. Total coagulation time, according to thromboelastography, decreases. In severe hepatopathy, distinct signs of hypocoagulation are detected (decreased plasma tolerance to heparin, decreased fibrinogen content, increased fibrinolytic activity, increased recalcification time). In oral administration of paradichlorobenzene, cases of hemolysis and methemoglobinemia against the background of severe oxidative stress [63] and aplastic anemia [55, 63] have been described.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnostic criteria:

Diagnostic criteria for HC poisoning are based on medical history, clinical presentation, and chemical-toxicological testing. During inpatient care, clinical diagnosis based on history and clinical presentation of intoxication is supplemented by chemical-toxicological, clinical-biochemical, and instrumental examination methods.

2.1 Complaints and Anamnesis

Diagnosis of acute poisoning is performed comprehensively, taking into account the leading syndromes and symptoms observed in the victim.

LE – 5, GOR – C

LE – 5, GOR – C

Comment. Diagnosis of acute poisoning is comprehensive, taking into account the leading syndromes and symptoms observed in the casualty. Alimentary intake of HCs leads to irritation of the gastrointestinal mucosa, nausea, vomiting, and diarrhea. Inhalation exposure is accompanied by damage to the respiratory system, manifested by cough, shortness of breath, cyanosis, and rales in the lungs (asymptomatic forms of poisoning can occur). Complications such as pneumatocele, pneumothorax, pleural effusion, and pneumonia are possible. Fever and leukocytosis are frequently observed in the first 24 hours. Neurological symptoms include anxiety, stupor, drowsiness, and coma.

When consciousness is preserved, complaints are characteristic of narcotic and irritant substances: weakness, dizziness, headache, epigastric pain, nausea, vomiting.

The medical history should aim to ascertain the following data: type of toxic substance (the specific substance), dose, time of toxicant ingestion, and route of entry into the body. In addition, it is advisable to ascertain certain life history data: past illnesses, injuries, bad habits. Most often, the medical history can only be gathered after the patient's consciousness is restored, since HC poisonings frequently cause a comatose state. Casualties are typically delivered by emergency medical teams from public places or the street upon calls from accidental passersby; however, even in such cases, a conscious patient is far from always able to remember and provide the necessary anamnestic information [8, 18, 22, 27, 28, 45].

2.2 Physical Examination

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comment. The initial assessment of the patient's general condition must be comprehensive and include a physical examination to assess the severity of poisoning and determine the presence and severity of existing or imminent life-threatening disorders of vital functions (respiration, circulation, etc.) that could negatively impact the patient's life, as well as obtaining as accurate an anamnesis and history of comorbid conditions as possible [8, 29, 38, 49].

During the general examination, attention is paid to signs of head, trunk, and limb trauma, tongue biting, burns, skin damage, signs of a general disease (color, turgor, and temperature of the skin, nutritional status, rashes on the skin and mucous membranes, edema, etc.), odors from clothing, skin, or mouth, injection traces, etc. [7, 22, 38].

Appearance of the skin: no specific discoloration; in case of respiratory failure or shock, cyanosis of the lips and face, acrocyanosis, and coldness are observed. It is necessary to identify the presence (absence) of rashes, chemical burns, local changes, the so-called "pressure sores" due to positional trauma leading to areas of skin hyperemia, which are often regarded as bruises, hematomas, burns, phlebitis, allergic edema, etc., and are usually detected at early stages (1–3 days) [23, 24].

During the neurological examination, special attention should be paid to the following symptom groups: body position (head, limbs in flexion or extension, presence of convulsions, fibrillary twitches in various muscle groups, hyperkinesia, motor agitation); verbal contact and its characteristics, orientation in time and space, presence of delirium, hallucinations; compliance with instructions and assessment of motor responses; state of reflexes; eye-opening in response to sound or pain; position and movements of the eyeballs; state of the pupils and their reaction to light; corneal reflexes [24, 26, 51, 65].

2.3 Laboratory Diagnostics

Laboratory and instrumental studies in halogenated hydrocarbon poisoning should be based on data regarding the toxicant, its route of entry into the body, and the most accurate possible estimation of the dose.

Comment. The study for the presence and level of ethyl alcohol in blood and urine is performed for the differential diagnosis of intoxication versus other central nervous system disorders. Blood and urine tests for ethyl alcohol are performed using gas-liquid chromatography, which provides high accuracy (sensitivity of 0.005 g/L of ethanol) and specificity [18, 38, 45, 47].

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comment. Measuring the concentrations of individual hydrocarbons in the blood is either unfeasible or takes too much time to be of practical use in treatment. Diagnosis of carbon tetrachloride poisoning is carried out by gas-liquid chromatography.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comment. The frequency of these tests will depend on the severity of the poisoning and the duration of the patient's stay in the hospital. The assessment of the respiratory system, heart, liver, kidneys, central nervous system, and blood parameters is based on the clinical picture [8, 18, 30, 78].

2.4 Instrumental Diagnostics

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comment. Immediate X-ray examination is indicated in cases of severe poisoning. A chest X-ray (A06.09.007.001) performed no later than 2 hours after hospital admission has high prognostic value. Electrocardiography (A05.10.006) is performed if there are signs of cardiomyopathy or chronic heart failure.

Additional instrumental diagnostic methods are recommended to be performed once to detect trauma, comorbid pathology, or potential complications (ultrasound (echography) of the brain, computed tomography (CT) and magnetic resonance imaging (MRI) of the brain, ultrasound of the abdominal organs, kidneys, pancreas, bronchoscopy) [18, 19, 23, 50].

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comment. Continuous monitoring of vital functions is mandatory, especially for patients treated in the intensive care unit [7, 28, 45].

2.5 Other Procedures

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comment. Differential diagnosis of depressed consciousness should be performed with traumatic brain injury, acute cerebrovascular accident; hypoglycemic coma; infectious diseases (meningitis, encephalitis, etc.); hepatic and uremic coma; coma in endocrinological diseases; severe encephalopathies in water-electrolyte and metabolic disorders [29, 38, 45, 47].

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comment. In a hospital setting, in the absence of positive dynamics, a more in-depth study is recommended, including chemical and toxicological testing, in order to rule out the combined intake of any psychotropic substances or other somatic or infectious diseases. The frequency and multiplicity of diagnostic examinations of the patient depend on the severity of poisoning. For mild poisoning, the frequency of prescribing biochemical and chemical and toxicological tests is 2-3 times during the treatment period as indicated; for moderate and severe poisoning, from 3 or more examinations depending on the dynamics of parameters, the patient's condition, and the presence of complications [8, 21, 23, 38].

The presence of severe injuries, persistent focal neurological symptoms, prolonged coma, and the absence of positive dynamics with ongoing treatment indicate a traumatic brain injury and serve as the basis for an in-depth examination using radiography of the entire skull in one or more projections (A06.03.005), Echo-EG, electroencephalography (A05.23.001), and lumbar puncture (A11.23.001) [8, 23, 29, 51].

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1. Provision of emergency medical care outside a medical facility

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comment. Starting from the pre-hospital stage, the main measures should be aimed at maintaining adequate pulmonary ventilation, restoring and maintaining patent airways, and preventing aspiration-obstructive complications.

Treatment should be initiated in all patients by restoring adequate pulmonary ventilation depending on the forms of respiratory impairment.

In cases of aspiration-obstructive respiratory disorders, it is necessary to perform oral cavity toilet, aspiration of upper respiratory tract contents, ensure upper respiratory tract patency, including using reusableoro-pharyngeal airways, reusable reinforced laryngeal tubes, reusable reinforced laryngeal masks, endotracheal intubation by direct laryngoscopy, and medical tracheoesophageal tubes in various design options [8, 23, 45, 49].

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comment. When chemical agents get on the skin, their removal is one of the priority steps, especially when dealing with highly toxic compounds. Simply washing them off with water is difficult in most cases, but quickly washing the skin with soap and water may be sufficient [7, 23].

3.2. Provision of specialized medical care

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comment. Gastric lavage is performed to remove unabsorbed toxicant. Impaired consciousness and seizure syndrome of any genesis are indications for tube gastric lavage [7, 23].

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comment. Restoration of adequate pulmonary ventilation is carried out depending on the forms of respiratory disorders. In cases of aspiration-obstructive respiratory disorders, oral cavity toilet is recommended. In superficial coma, aspiration of upper respiratory tract contents using an airway is performed. In deep coma, endotracheal intubation is performed. In central-type respiratory disorders, artificial pulmonary ventilation is necessary after prior endotracheal intubation. In mixed-type disorders, aspiration-obstructive respiratory disorders are eliminated first, and then artificial pulmonary ventilation is performed [8, 29, 64].

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comment. A (1.5%) solution of meglumine sodium succinate** is used at an average daily dose for adults of 10 ml/kg, and for children from 1 year of life – 6-10 ml/kg per day for up to 11 days [8, 16].

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comment. Correction of water-electrolyte balance is carried out using volume replacers and perfusion solutions under the control of pulse (pulse monitoring method, A02.12.001.001), peripheral arterial blood pressure (A02.12.002), and central venous pressure (A02.12.003, with central venous catheterization), hematocrit (A12.05.117), total blood hemoglobin level (A09.05.003), blood sodium (A09.05.030) and potassium (A09.05.031) levels, as well as diuresis. The volume of fluid administered for this purpose averages about 2.0-3.0 L (under fluid balance control) with a colloidal to crystalloid solution ratio of 1:3 [18, 28, 29].

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comment. To correct metabolic acidosis, alkalizing solutions (sodium bicarbonate**) are used under the control of acid-base status and blood gases (B03.016.011) [18, 28, 29].

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comment. To normalize energy metabolism, succinic acid preparations – meglumine sodium succinate** and others – are used as antihypoxic and detoxifying agents. A (1.5%) solution of meglumine sodium succinate** is used at an average daily dose for adults of 10 ml/kg, and for children from 1 year of life – 6-10 ml/kg per day for up to 11 days [16, 71].

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

5. Prevention and Dispensary Observation

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

6. Organization of Medical Care

6.1. Indications for hospitalization

In chemical-agent poisoning, it is advisable to hospitalize patients in a specialized acute poisoning treatment center. In the absence of an acute poisoning treatment center, patients with severe intoxication and complications, especially with impaired vital functions, should be hospitalized in an intensive care unit or critical care unit, with subsequent transfer to a therapeutic department once their condition stabilizes.

6.2. Indications for patient discharge from the hospital

Treatment in the intensive care unit is carried out until the stabilization of impaired vital functions and the completion of detoxification measures, followed by rehabilitation measures in the acute poisoning treatment center, therapeutic, and pediatric departments.

The duration of hospitalization is determined by the severity of the poisoning.

Average duration of inpatient treatment:

• mild severity – 1–2 bed-days;

• moderate severity – 3–5 bed-days;

• severe degree without complications – 7–14 bed-days;

• severe degree (with complications: pneumonia, acute renal failure, acute hepatorenal failure) – 14–24 bed-days.

7. Additional Information

Factors influencing the disease outcome:

1. Inhalational and percutaneous toxic exposures to halogenated hydrocarbons typically lead to a slower development of clinical manifestations of poisoning compared to ingestion and, accordingly, a longer latent period of intoxication, which contributes to late seeking of medical care by victims and largely determines the disease outcome. Alcohol consumption contributes to a more severe course of inhalational poisonings.

2. Symptoms of pronounced irritating action of most chlorine and bromine derivatives of aliphatic hydrocarbons (feeling of scratching in the throat, rhinitis, breathing difficulty, catarrhal inflammation of the respiratory tract mucous membranes, pain along the airways, possible hyperthermia up to 38–39 °C, edema of the oral and pharyngeal mucous membranes) in the first days of poisoning do not always allow for a timely and correct diagnosis and determination of the tactics and place of treatment.

3. Most halogenated hydrocarbons are classified as combustible, highly flammable, and fire- and explosion-hazardous substances. Thermal decomposition of low-toxicity halogenated hydrocarbons can produce highly toxic substances with pulmonotoxic action (halogens, hydrogen halides, phosgene, perfluoroisobutylene, etc.). Individuals delivered from a fire zone (especially during the combustion of materials containing halogenated hydrocarbons) or an explosion in a confined space must be considered as potentially poisoned by highly toxic substances.

Criteria for Evaluating the Quality of Medical Care

Criteria for assessing the quality of inpatient medical care

References

Appendix A1. Working Group Composition

1. Yatsinyuk Boris Borisovich – Chief Toxicologist of the Department of Health of the Khanty-Mansi Autonomous Okrug - Ugra, Candidate of Medical Sciences, Associate Professor, Anesthesiologist-Reanimatologist of the intensive care units at the Khanty-Mansiysk Clinical Psychoneurological Hospital.

2. Lodyagin Alexey Nikolayevich – Doctor of Medical Sciences, Chief Freelance Specialist Toxicologist of the Northwestern Federal District, Head of the Department of Clinical Toxicology, Dzhanelidze St. Petersburg Research Institute of Emergency Medicine.

3. Batotsyrenov Bair Vasilyevich – Doctor of Medical Sciences, Chief Researcher at the Department of Clinical Toxicology, Dzhanelidze St. Petersburg Research Institute of Emergency Medicine.

4. Shikalova Irina Anatolyevna – Candidate of Medical Sciences, Researcher at the Department of Clinical Toxicology, St. Petersburg Research Institute of Emergency Care named after I.I. Janelidze.

5. Narziculov Rustam Abdukhalimovich – Doctor of Medical Sciences, Researcher at the Department of Clinical Toxicology, St. Petersburg Research Institute of Emergency Care named after I.I. Janelidze.

6. Kuznetsov Oleg Anatolyevich – Candidate of Medical Sciences, Researcher at the Department of Clinical Toxicology, Dzhanelidze St. Petersburg Research Institute of Emergency Medicine.

7. Alyanov Alexander Leonidovich – Candidate of Medical Sciences, Associate Professor, Head of the Department of General Surgery and Anesthesiology at the Medical Institute, Orel State University named after I.S. Turgenev.

8. Gavrikov Pavel Pavlovich – Forensic Medical Expert, Khanty-Mansiysk Interdistrict Department of the Bureau of Forensic Medical Examination of the Khanty-Mansi Autonomous Okrug - Ugra.

9. Zhidkov Vyacheslav Alexandrovich – Head of the Intensive Care Units at the Khanty-Mansiysk Clinical Psychoneurological Hospital.

10. Kosarev Alexey Nikolaevich – Candidate of Medical Sciences, Anesthesiologist-Resuscitator at the Intensive Care Units, Khanty-Mansiysk Clinical Psychoneurological Hospital (Budgetary Institution of Khanty-Mansi Autonomous Okrug – Ugra).

11. Barats Ekaterina Alekseevna – Anesthesiologist-Resuscitator at the Intensive Care Units, Khanty-Mansiysk Clinical Psychoneurological Hospital (Budgetary Institution of Khanty-Mansi Autonomous Okrug – Ugra).

12. Tolkach Pavel Gennadievich – Doctor of Medical Sciences, First-Category Toxicologist, Deputy Head of the Department of Military Toxicology and Medical Defense, Military Medical Academy.

13. Shilov Yuri Vladimirovich – Candidate of Medical Sciences, Associate Professor at the Department of Military Toxicology and Medical Defense, Military Medical Academy.

14. Smirnov Anton Nikolaevich – Adjunct at the Department of Military Field Therapy, Military Medical Academy, First-Category General Practitioner.

Conflict of interest.

All members of the Working Group have confirmed that they have no financial support or conflicts of interest to disclose.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of these clinical guidelines:

1. anesthesiologist-intensivist;

2. gastroenterologist;

3. infectious disease physician;

4. immunologist;

5. cardiologist;

6. clinical laboratory diagnostics physician;

7. neurologist;

8. neurosurgeon;

9. general practitioner (family physician);

10. otorhinolaryngologist;

11. ophthalmologist;

12. emergency physician;

13. forensic medical expert;

14. internist;

15. district general practitioner;

16. toxicologist;

17. transfusiologist;

18. functional diagnostics physician;

19. surgeon;

20. endoscopist;

21. psychiatrist-narcologist;

22. radiologist;

23. emergency medical technician (paramedic).

Methodology for developing clinical guidelines:

Information resources used to develop the clinical guidelines:

• electronic databases (MEDLINE, KIPTS "POISON", version 3.1, INCHEM IPCS WHO, PubMed, Google Scholar);

• consolidated clinical experience of leading specialized centers for the treatment of acute chemical poisonings, clinical toxicologists of St. Petersburg, Moscow, and Yekaterinburg;

• thematic monographs, textbooks, and guidelines published between 1999–2024.

Based on the selected publications, recommendation statements were formulated and evaluated using scales for assessing the levels of evidence for diagnostic methods, levels of evidence (LE) for preventive, therapeutic, and rehabilitation methods (preventive, therapeutic, rehabilitation interventions), and grades of recommendation (GR) for preventive, diagnostic, therapeutic, and rehabilitation methods (preventive, diagnostic, therapeutic, rehabilitation interventions). (Table 3, Table 4, Table 5). Subsequently, each recommendation statement was thoroughly discussed at a general meeting of the working group, and consensus was reached in all cases of disagreement.

Table 3 – Scale for assessing the levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 4 – Scale for assessing the levels of evidence (LE) for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitation interventions)

Table 5 – Scale for assessing the grades of recommendation (GR) for prevention, diagnosis, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitation interventions)

Procedure for updating clinical guidelines.

The clinical guidelines update mechanism provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions (comments) to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

1. Toxic effect of substances of predominantly non-medical use (T51-T65) / World Health Organization // International Statistical Classification of Diseases and Related Health Problems. Tenth Revision. Volume 1 (Part 2). – Moscow: Meditsina, 1995. – P. 337-344. (In Russ.)

2. Order of the Ministry of Health and Social Development of the Russian Federation No. 40 dated January 27, 2006, "On the organization of chemical-toxicological studies in the analytical diagnosis of alcohol, narcotic drugs, psychotropic, and other toxic substances in the human body." (In Russ.)

3. Order of the Ministry of Health of the Russian Federation No. 925n dated November 15, 2012, "On approval of the Procedure for providing medical care to patients with acute chemical poisonings." (In Russ.)

4. Order of the Ministry of Health of the Russian Federation No. 388n dated June 20, 2013, "On approval of the Procedure for providing emergency, including specialized emergency, medical care." (In Russ.)

5. Order of the Ministry of Health of the Russian Federation No. 203n dated May 10, 2017, "On approval of criteria for assessing the quality of medical care." (In Russ.)

6. Order of the Russian Ministry of Health No. 804n dated October 13, 2017, "On Approval of the Nomenclature of Medical Services".

7. Federal Law No. 489-FZ dated December 25, 2018 (as amended on June 11, 2021) "On Amendments to Article 40 of the Federal Law 'On Compulsory Medical Insurance in the Russian Federation' and the Federal Law 'On the Fundamentals of Protecting the Health of Citizens in the Russian Federation' Regarding Clinical Guidelines".

8. Order of the Russian Ministry of Health No. 103n dated February 28, 2019, "On Approval of the Procedure and Deadlines for the Development and Revision of Clinical Guidelines, Their Standard Template, and Requirements for Their Structure, Composition, and Scientific Validity of Information Included in Clinical Guidelines".

9. Order of the Russian Ministry of Health No. 1165n dated October 28, 2020, "On Approval of Requirements for the Equipment of First Aid Kits and Packs with Medications and Medical Devices".

10. Military Field Therapy: National Guidelines / ed. by E. V. Kryukov. – 2nd ed., rev. and supp. – Moscow: GEOTAR-Media, 2024. – 736 p.: ill. – (Series "National Guidelines").

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Information for a patient admitted with impaired consciousness (obtundation, stupor, coma; impaired mental functions – delirium, hallucinations, and other forms of impairment) is provided after the recovery of consciousness and mental functions, and must contain information on complications that occurred in the toxicogenic stage of poisoning, and planned treatment during the rehabilitation process (if required for the given patient).

In cases of mild-to-moderate toxic effects of poisons contained in ingested mushrooms, the patient is informed about the health hazards of these toxic substances, potential complications, and long-term consequences of poisoning,

planned examination (chemical-toxicological, clinical-biochemical,

instrumental), and treatment (detoxification methods, pathogenetic, and specific therapy). The patient (or their legal representatives) signs an informed voluntary consent for the proposed scope of examination and treatment.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. Glasgow Coma Scale [8]

Table specifications:

Russian name: Glasgow Coma Scale

Original name: Glasgow Coma Scale

Source: https://www.glasgowcomascale.org

Type: Rating scale

Purpose: For the quantitative assessment of the severity of coma and neuropsychiatric disorders related to impaired consciousness of any etiology.

Contents:

Key:

15 points – clear consciousness

10–14 points – moderate and deep obtundation

8–10 points – stupor

6–7 points – moderate coma

4–5 points – terminal coma

3 points – brain death

Explanation: A patient's condition according to the Glasgow Coma Scale is assessed based on three parameters, each scored in points. The points are summed up. The sum of the three responses ranges from 3 (deep coma) to 15 points (conscious patient).

Appendix G2. Poisoning Severity Score [72]

Russian title

European Association of Poisons Centres and Clinical Toxicologists

Original title: The European Association of Clinical Poison Centres and Clinical Toxicologists Poisoning severity score.

Source (official developer website, validated publication): Persson H.E., Sjöberg G.K., Haines J.A., Pronczuk de Garbino J. Poisoning severity score. Grading of acute poisoning. // Assessment of coma and impaired consciousness. A practical scale. // J. Clin. Toxicol. – 1998. – Vol. 36, №3. – P. :205-213. doi: 10.3109/15563659809028940.

• rating scale

• index

• questionnaire

Purpose: For the quantitative assessment of acute poisoning severity.

Contents:

Key:

1 – asymptomatic, mild: symptoms are mild, rapidly and spontaneously resolving;

2 – moderate – pronounced or persistent symptoms;

3 – severe – severe or life-threatening symptoms;

4 – clinical death.

Explanation: The patient's condition, according to the Poisoning Severity Scale, is assessed by the degree of organ and system damage. The occurrence of a specific symptom is checked against a scale that lists vital systems: cardiovascular, respiratory, nervous, circulatory, and gastrointestinal tract, as well as organs involved in the elimination of the toxic agent: liver and kidneys; the muscular system, local toxic effects on the body, and metabolic disorders associated with the toxicant are also evaluated. The severity grade is determined by the dominant symptom.