TOXIC EFFECT OF OTHER POISONOUS SUBSTANCES EATEN AS MUSHROOMS (PSYCHODYSLEPTIC [HALLUCINOGENIC] MUSHROOMS EXCLUDED): clinical guidelines

List of Abbreviations

Terms and Definitions

Detoxification is the process of neutralizing and eliminating an exogenous toxic substance from the body. Detoxification, as a natural defense process of the body against a toxicant, includes various mechanisms aimed at converting the poison into non-toxic compounds (metabolites), carried out predominantly in the liver, and eliminating the poison or its metabolites via various pathways through the kidneys, intestines, liver, lungs, and skin. During natural detoxification, metabolites more toxic than the ingested toxicant may form (lethal synthesis); furthermore, undergoing metabolism in the liver and excretion through the kidneys, the toxicant and its toxic metabolites can lead to damage to these organs and the development of acute renal or hepatic failure.

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.

Plant poisons are toxic substances contained in plants.

Somatogenic stage of poisoning is a period in the course of acute chemical illness beginning after the elimination or destruction of the toxic substance from the body as a residual lesion of the structure and functions of various organs and systems, typically manifested by various somatic and neuropsychiatric complications such as pneumonia, acute renal failure, hepatic failure, toxic polyneuropathy, anemia, and psycho-organic syndrome. In this stage of poisoning, specific (antidote) therapy is not required, and detoxification may be aimed solely at treating endotoxicosis.

Toxicogenic stage of poisoning is a period in the course of acute chemical illness beginning from the moment the toxic substance enters the body in a concentration capable of causing a specific effect and lasting until its elimination. It is characterized by specific clinical manifestations reflecting the chemical and toxicological properties of the toxic substance and its effect on target organs. The severity of this disease period directly depends on the dose of ingested poison and its concentration in the blood. The main therapeutic goal in this period is to shorten its duration as early as possible using various methods of accelerated detoxification, antidote, and symptomatic therapy.

Poisonous plants are plants that produce and accumulate toxic substances causing poisoning in humans and animals.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Toxic effects of substances contained in mushrooms (according to ICD-10 formulation) refer to health disorders caused by the ingestion of one or more mushrooms, defined as the toxic effect of substances contained in mushrooms (synonym — acute poisoning).

The toxic effect of other toxic substances contained in ingested mushrooms, according to the ICD classification (T62.0), is classified as adverse effects resulting from contact with toxic substances contained in ingested foodstuffs, specifically mushrooms (wild-growing). This refers to toxic substances produced by the mushroom itself, such as amatoxin, muscarine, orellanine, coprine, and others [1, 2].

Mushrooms are living organisms whose cells contain a nucleus, combining features of both plants and animals. They constitute one of the largest and most diverse groups of living organisms, forming an integral part of all aquatic and terrestrial ecosystems. According to modern estimates, there are between 100,000 and 250,000, and by some estimates up to 1.5 million, species of mushrooms on Earth. Many species of mushrooms are actively used by humans for food, household, and medical purposes. Edible mushroom dishes are traditionally included in the national cuisines of many nations worldwide. Industrial cultivation of edible mushrooms is developed in many countries. In animals and humans, mushrooms cause skin diseases (dermatomycoses) and sometimes internal organ infections (deep mycoses). The consumption of wild mushrooms can lead to acute poisoning and undesirable disease outcomes [3, 4, 5, 6, 7, 8].

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

Poisonings continue to be a significant cause of morbidity and mortality [9]. The primary reason for the toxic effects of substances contained in mushrooms is poor mushroom species identification skills. Poisonings caused by insufficient knowledge of the mushroom picker account for about 95% of cases. Typically, a toxic product visually resembling an edible mushroom variety is consumed. Less frequently, symptoms of poisoning occur in people who confuse the cep (porcini) with the bitter bolete or Satan's bolete. Mushroom poisoning can also develop for other reasons.

Errors in culinary processing. Some mushroom species (such as the rufous milk cap or European white milk cap) contain acrid milky juice that irritates the tissues of the digestive tract. To eliminate this, mushrooms are soaked. When insufficiently processed fruiting bodies are eaten, signs of acute gastroenteritis typically occur.

Presence of extraneous toxicants. Fruiting bodies growing near chemical plants whose operations involve heavy metals can accumulate poisonous substances. Slightly less hazardous are plants gathered along roadsides, but they too can provoke symptoms of acute poisoning.

Concurrent alcohol consumption. Certain species (such as the common ink cap, Coprinus) taken simultaneously with alcohol lead to a disulfiram-like effect. Ethanol metabolism is interrupted at the acetaldehyde stage. The victim experiences symptoms: vomiting, flushing of the skin in the neck and face area, tachycardia, and bronchospasm.

Due to the wide variety of poisonous mushrooms and, accordingly, the clinical symptoms of acute poisoning, it is customary in scientific literature and clinical practice to view the pathogenesis of poisoning from the standpoint of syndromes characterizing the main mechanism of toxic action and the pathogenesis of acute poisoning by a particular type of mushroom, indicating the main representatives causing the manifestation of the syndrome [8, 9, 10, 11].

1.2.1. Pathogenesis of phalloidin syndrome

It develops in poisoning with mushrooms of various groups:

1) highly toxic mushrooms: Death cap (Amanita phalloides), destroying angel (Amanita virosa), spring amanita (Amanita verna), two-spored amanita (Amanita bisporigera);

2) toxic mushrooms: Lepiota helveola, Lepiota brunneoincarnata, Lepiota subincarnata, Lepiota cristata, Galerina marginata, Galerina autumnalis, and Conocybe filaris.

The most toxic mushroom is the Death cap (Amanita phalloides).

The death cap (Amanita phalloides) is often mistaken for edible mushrooms based on its appearance (such as the green russula, field mushroom, and parasol mushroom). Its distinguishing structural features are: a) a pale green, pale yellow, or white cap with pale gills that have a greenish tint; b) a scaly stalk with a wide ring; c) a bulbous structure at the base of the stalk.

The toxic substances responsible for acute poisoning are amatoxins (amanitins, amanin) and phallotoxins. Amatoxins disrupt cellular protein synthesis, leading to cell death. The most vulnerable cells are those with high rates of protein synthesis: hepatocytes, enterocytes, nephrocytes, and lymphocytes. Intestinal mucosal cells are the first to be affected. According to experimental data, phallotoxins disrupt hepatocyte membranes and inhibit oxidative phosphorylation in mitochondria. Phallotoxins are largely degraded by gastrointestinal enzymes and, due to their low intestinal absorption, have virtually no toxic effect. Severe poisoning develops when consuming 1 g of mushrooms per 1 kg of body weight.

Amatoxins are thermostable, insoluble in water, and not destroyed by drying. To date, at least 5 amatoxin subtypes are known, among which the alpha- and beta-amanitin subtypes exhibit the most significant toxicity.

In addition to the death cap, amatoxins have been found in other species of the genus Amanita (bisporigera, hygroscopia, ocreata, suballiacea, tenuifolia, verna, and virosa). There are publications evaluating the toxic properties of Amanita proxima, which is characterized by kidney damage that occurs earlier than in poisoning by Cortinarius orellanus and typically resolves completely within ten days [12].

Clinical manifestations of death cap poisoning are caused by the combined action of cyclopeptide phallotoxins and amatoxins. Phalloidin causes symptoms of acute gastroenteritis 6–12 hours after initial ingestion. Its toxic action on gastrointestinal (GI) cells is limited because it is inactivated by digestive enzymes upon entering the intestinal lumen. Cyclic octapeptides, namely amanitins (primarily α-amanitin), are responsible for clinical manifestations of liver and kidney damage, followed by encephalopathy. Tissues with a high rate of protein synthesis are primarily involved in the toxic process, particularly the liver, kidneys, and pancreas.

Amatoxin is eliminated from the body via urine and intestinal contents within 2–5 days after ingestion. The lethal dose is less than 0.1 mg/kg.

A compounding factor in the pathogenesis is the resistance of death cap toxins to culinary processing and mushroom drying.

A major role in the pathogenesis of poisoning by amanitin- and phalloidin-containing mushrooms is played by the damage they cause to the intestinal wall, resulting in widespread necrotic changes, nutritional impairment followed by the death of saprophytic flora, and colonization by pathogenic flora.

The damaged intestinal wall loses its barrier function, creating an additional source of bacterial toxemia in the circulatory bed and contributing to further liver cell damage.

The severity of the toxic process in the liver during amanitin poisoning is attributed to their toxicokinetics. According to several authors, about 60% of the α-amanitin absorbed in the intestine, after 'first-pass' intracellular cycling in hepatocytes, is excreted with bile into the intestinal lumen and reabsorbed through the intestinal wall into the liver via the portal vein system. As a result, the liver is exposed to high concentrations of amanitoxin via the portal circulation and due to prolonged enterohepatic circulation. Evidence suggests that hepatocytes are damaged prior to hepatic sinusoids. In these cases, fatty degeneration of the hepatic parenchyma occurs via a centrilobular necrosis model with hemorrhage.

Amanitins, at high concentrations and with prolonged exposure, can stimulate the production of reactive oxygen species and the development of oxidative stress, which may enhance their hepatotoxic effect.

Renal dysfunction in the early stages of poisoning may be due to water-electrolyte and hemodynamic disorders; however, there are also reports of a direct toxic effect of α-amanitin on the proximal tubules.

It is generally accepted that changes in myocardial and pancreatic cells are secondary, resulting from homeostasis disorders, blood rheology alterations, and progressive endogenous intoxication.

Central nervous system (CNS) disorders, such as agitation, hallucinations, euphoria, and altered consciousness, lack definitive confirmation of a direct toxic effect of cyclopeptides on neurons.

The development of asthenia and vascular collapse in poisoning by amanitin-containing mushrooms is explained both by the direct toxic effect of amanitins on the vascular endothelium and by secondary changes in the adrenal cortex due to endogenous intoxication [6, 8].

1.2.2. Pathogenesis of gyromitrin syndrome

Gyromitra: Gyromitra esculenta, Gyromitra gigas, Gyromitra infula, Morchella esculenta, Morchella conica. The toxic substance gyromitrin (N-methyl-N-formylacetaldehyde hydrazone) undergoes hydrolysis in the body to form the cytotoxic compound N-methylhydrazine, which can inhibit DNA and RNA synthesis, with ethylene-gyromitrin being the most toxic.

In liver cells, hydrazines form unstable diazo compounds that serve as a source of free radical generation, cytolysis, and necrosis in liver tissue. In the clinical presentation of Gyromitra poisoning, in addition to liver and kidney damage caused by organic acids present in the mushrooms (such as fumaric acid), hemolysis and, consequently, hemoglobinuric nephrosis develop. These acids are destroyed by boiling and prolonged drying (at least 3 weeks) in the presence of atmospheric oxygen. When mushrooms are soaked, the acids partially dissolve while retaining their toxic properties, whereas prolonged boiling and drying can reduce the concentration of toxic substances to a safe level.

Gyromitric acid, previously considered responsible for hemolysis, is now recognized as a laboratory artifact. Among Gyromitra species, Gyromitra esculenta is the most toxic [8].

Monomethylhydrazine (MMH) is formed in the human body as a result of the hydrolysis of gyromitrin. This substance is the primary active mycotoxin found in mushrooms of the genus Gyromitra, especially the false morel (Gyromitra esculenta), and is responsible for neurological disorders (seizures). High gastric acidity promotes greater formation of monomethylhydrazine during gyromitrin hydrolysis. About 35% of ingested gyromitrin is converted into monomethylhydrazine (the human LD50 is approximately 1.6–4.8 mg/kg for children and 4.8–8 mg/kg for adults) [103].

Caution should be exercised regarding the cup fungus Disciotis venosa (syn. Discina venosa), a cup fungus belonging to the morel family, as literature sources contain reports of gyromitrin poisoning associated with it.

1.2.3. Pathogenesis of paxillus syndrome

Poisonings occur upon the consumption of mushrooms of the family Paxillaceae, specifically Paxillus involutus and Paxillus atromentosus. The toxin has not been definitively identified (structurally similar to hydrazine). It is thermolabile and crosses the intestinal barrier. The resulting immuno-allergic reaction damages erythrocytes, causing hemolysis. The substance is cumulative. Sensitization is required for acute poisoning to develop, although some poisoning cases do not develop in certain patients. According to some authors, sensitization is a predisposing factor [8]. The mushroom toxin damages the membranes of hepatocytes, nephrocytes, and enterocytes, leading to multi-organ failure with a fatal outcome.

1.2.4. Pathogenesis of orellanine syndrome

Acute poisonings occur upon the consumption of mushrooms of the family Cortinariaceae, genus Cortinarius, containing the toxic substance orellanine as well as cortinarius A and cortinarius B. The target organ is the kidneys (cellular membrane damage, inhibition of protein synthesis, disruption of RNA and DNA structure). Pronounced renal tissue damage is caused by the reabsorption of orellanine in the proximal renal tubules [13]. Cortinarius orellanus and Cortinarius rubellus are classified as deadly poisonous mushrooms [14, 15, 16, 17].

1.2.5. Pathogenesis of proximan syndrome

This develops upon the consumption of Amanita proxima, in which the toxin remains unidentified. The toxic substance in the mushroom leads to a fatal outcome upon entering the body [8, 10].

1.2.6. Pathogenesis of coprine syndrome

Acute poisoning develops with the combined consumption of mushrooms of the genus Coprinus (family Coprinaceae; Coprinopsis atramentaria, Coprinus comatus) and alcohol.

When consuming mushrooms of the inky cap family (Coprinaceae)—such as the mica cap, common ink cap, domestic ink cap, fairy inkcap, and pleated inkcap, classified as category IV edible mushrooms—poisoning generally does not occur if they are harvested at a “young age” and cooked immediately. The syndrome may also occur after ingesting the lurid bolete (Boletus luridus) and the club-footed clitocybe (Clitocybe clavipes).

The pathogenesis of mushroom toxin toxicity is modeled on the mechanism of action of the inky cap (Coprinus atramentarius), which contains the toxic compound coprine. Upon ingestion, the substance is hydrolyzed, and the resulting L-aminocyclopropanol inhibits the enzyme aldehyde dehydrogenase; this impairs the metabolism (oxidation) of ethanol and other alcohols, promoting the accumulation of acetaldehyde and autonomic nervous system dysfunction. Following mushroom ingestion and delayed alcohol intake, even on day 4, an autonomic reaction and other clinical manifestations of the syndrome may develop.

1.2.7. Pathogenesis of resinoid syndrome

Gastrointestinal syndrome occurs after ingestion of mushrooms containing resin-like substances, aldehydes, and ketones. These toxicants exert an irritant effect on the gastrointestinal mucosa, causing acute toxic gastroenteritis (mild poisoning). The substances also have a systemic resorptive effect, which leads to severe poisoning—hypovolemia, electrolyte disturbances, and toxic hepatitis.

1.2.8. Pathogenesis of muscarine syndrome

The syndrome is caused by the ingestion of mushrooms with a high content of muscarine and its isomers: Clitocybe species—such as the fool's funnel (Clitocybe rivulosa/cerussata); and Inocybe species—such as the deadly fibrecap (Inocybe patouillardii), earth ball fibrecap, split fibrecap, and fibrous fibrecap. Toxic substances include the alkaloid muscarine (2-methyl-3-hydroxy-5-trimethylammonium) and its isomers: epimuscarine, allomuscarine, epiallomuscarine, muscazone, and muscimol, which act on cholinoceptive structures to exert an M-cholinomimetic effect. Its action on the synaptic membranes of acetylcholine-sensitive receptors of the parasympathetic and sympathetic (certain divisions) nervous system increases their permeability; this leads to ion transport across the cell membrane, membrane depolarization, and generation of an action potential, resulting in prolonged polarization of muscarine-sensitive receptors. The substance's action on the anterior branches of parasympathetic ganglia produces a peripheral parasympathetic effect.

Muscarine and its isomers are thermostable, water-soluble, and exhibit low lipophilicity, which prevents their accumulation in CNS tissue. The antagonist of muscarine is atropine**.

1.3 Epidemiology of the Disease or Condition

In the Russian Federation, poisonings by the following poisonous and conditionally poisonous mushrooms are most frequently registered: false morel (Gyromitra esculenta), Satan's bolete (Boletus satanas), sulfur tuft (Hypholoma fasciculare), species of the genus Inocybe (Inocybe fastigiata, napipes), of the genus Tricholoma (Tricholoma georgii), of the genus Clitocybe (Clitocybe dealbata), and of the genus Amanita: death cap (Amanita phalloides), destroying angel (Amanita virosa), and panther cap (Amanita pantherina). The cause of the most severe poisonings is the accidental ingestion of mushrooms of the Amanitaceae family of the genus Amanita, in particular the death cap (Amanita phalloides) with a mortality rate of up to 50%. The urgency of creating clinical protocols (federal guidelines) for the diagnosis and treatment of victims of poisonous mushroom poisoning is due to the prevalence of this type of chemical disease. Acute poisonings by wild-growing mushrooms are typical for regions where this product is traditionally consumed. They regularly occur in the territory of the Russian Federation, as well as in many countries: USA, Canada, Colombia, Poland, Bulgaria, Hungary, Sweden, Norway, Serbia, Turkey, Uzbekistan, Chile, Thailand. These poisonings are seasonal. Up to 83.38% of mushroom poisoning cases are registered in Russia from the last decade of July to the end of October, which corresponds to the mushroom growing season. The range of poisonings covers the Central Chernozem, Volga, Volga-Vyatka regions and, less frequently, the Central regions. At the same time, poisonings are often mass-scale, which is most typical for the Voronezh, Rostov, and Volgograd regions, and they have also been noted in Krasnodar Krai. Thus, in 1999, 1,054 cases of poisoning due to the consumption of conditionally edible and poisonous mushrooms were registered in the territory of the Russian Federation, including 202 children under the age of 14. 202 people died from poisoning, including 18 children. In Lipetsk Oblast, 135 cases of mushroom poisoning were registered in 2000, of which 3 were fatal; in 2001, 116 and 13, respectively. In Lipetsk Oblast, 73 cases of poisoning were registered in 2016 (2 fatal – mortality rate was 2.7%), and 78 cases of poisoning were registered in 2017 (3 fatal – mortality rate was 3.8%). The largest number of victims – 1,239 (ranging from 65 to 350) people, resulting from mushroom poisoning that occurred in Russia in 1996–2002, was noted in Voronezh Oblast. The mortality rate for this region ranged from 10.6% in 2003 to 16.6% in 1997. The main cause of poisonings was the accidental ingestion of poisonous mushrooms, including 63% of cases belonging to the genus Amanita (Amanita phalloides). In 95% of cases, poisonings by wild mushrooms occur as a result of incorrect identification of edible and poisonous species during "amateur" mushroom picking. This is due both to the public's lack of awareness of the properties of mushrooms and to the lack of sufficient knowledge about their appearance. The second cause of mushroom poisoning is errors in the culinary processing of such mushrooms as Russula, Lactarius torminosus (woolly milk cap), slippery jack, Lactarius necator (black milk cap), and others; in particular, for consumption, some varieties of white milk caps must be soaked to remove milky juice, which can irritate the gastrointestinal tract. Thus, during the mass poisoning in Voronezh Oblast, in 17% of cases the cause of poisoning was a violation of the rules for culinary processing of mushrooms. In 20% of cases, an intestinal infection was present. According to the American Association of Poison Control Centers and Clinical Toxicologists (AAPCC), 5,902 mushroom poisonings were registered in 2009, with the mushroom species remaining unidentified in 77% of cases. Mushrooms containing cyclopeptides (amanitotoxin) were identified in 35 cases, among which 3 (9%) ended fatally in children under the age of 6 [6, 8, 10, 2121].

1.4 Features of Coding the Disease or Condition

Coding of the diagnosis is performed according to the International Classification of Diseases, 10th Revision (ICD-10):

T62.0 Toxic effect of other noxious substances eaten as food: Ingested mushrooms.

1.5 Classification of the disease or condition

For clinical and diagnostic purposes (to establish a preliminary diagnosis and determine management tactics), the toxic effects of poisonous mushrooms are divided into two groups: poisonings with a short and a long latent period [7, 8, 11].

Poisonings with a short incubation period are characteristic of mushrooms of: Clitocybe species (Tricholomataceae family), Inocybe species (Cortinariaceae family), Entoloma species (Entolomataceae family), and certain Amanita species (Amanitaceae family) (fly agaric and panther cap) [21].

Poisonings with a long incubation period are characteristic of the ingestion of mushrooms of: the Amanita genus—death cap (Amanitaceae family); Gyromitra species—false morel, snow false morel, hooded false morel (Discinaceae family); the Morchella genus—true morel; and Cortinarius species—fool's webcap, deadly webcap (Cortinariaceae family).

Classification by severity of the toxic effect of poisons contained in ingested mushrooms [7, 8, 21, 109].

Mild severity – occurs in 12.8% of patients; the duration of acute toxic gastroenteritis is 2–3 days with diarrheal stools up to 3–4 times per day. Patients develop hepatopathy stage I, characterized by the absence of overt clinical signs of liver damage: the severity of the patient's condition is determined by the extent of gastroenteritis and fluid-electrolyte imbalances. Hepatic dysfunction is identified via laboratory and instrumental diagnostic methods. Biochemical tests reveal signs of moderate cytolysis—transaminase elevation up to 1300–1500 nmol/L; bilirubin up to 22 µmol/L or higher. Some patients exhibit symptoms of biliary dyskinesia.

Moderate severity – marked acute toxic gastroenteritis lasting up to 4 days, with diarrheal stools up to 4–6 times per day, leading to dehydration. Circulating blood volume is decreased by 10–20%, accompanied by a drop in blood pressure to 90/60 mmHg and tachycardia up to 100 bpm. Metabolic acidosis is observed. Liver damage presents with clinical signs of hepatopathy stage II (according to E.A. Luzhnikov's classification): development of central nervous system dysfunction—disorientation (loss of orientation ability) combined with hepatomegaly, jaundice, scleral icterus, and cutaneous jaundice at bilirubin levels above 50 µmol/L. Concurrently, signs of increased bleeding tendency appear. Duplex ultrasound reveals reduced hepatic blood flow in the portal zone. Laboratory findings: bilirubin level from 71 to 120 µmol/L, transaminases elevated 2–4-fold, total protein reduced to 56–59 g/L, fibrinogen to 1.8 g/L, prothrombin index 59–68%. Acute kidney injury develops, with moderate qualitative and quantitative urinalysis changes. Serum urea is 9–12 mmol/L, creatinine 0.19–0.21 mmol/L.

Severe degree – accompanied by toxic shock, diarrheal stools up to 10 times per day or uncounted. Acute toxic gastroenteritis lasts up to 6–7 days. Circulating blood volume decreases by 20–35%, accompanied by dehydration and electrolyte disorders. Metabolic acidosis is difficult to correct, even with hemodiafiltration. Hepatic encephalopathy (hepatargia) develops against a background of hepatomegaly, with bilirubin rising to 170–220 µmol/L by days 5–8 and cytosolic enzymes increasing 5–7-fold. Impairment of hepatic protein-synthetic function—hypoproteinemia (from day one), total protein reduced to 40 g/L. Hepatic dysfunction is accompanied by hemorrhages and gastrointestinal bleeding. A decrease in fibrinogen and prothrombin index to 46–50% is noted. Hepatic coma is associated with the accumulation of breakdown products, impaired protein metabolism, and disruption of neurotransmitter processes in the CNS.

Extremely severe – characterized by a severe course of gastroenteritis with copious cholera-like stools too numerous to count, occurring hourly and often containing blood. Marked hypovolemia, electrolyte disturbances, and toxic shock are noted from day one. Fulminant hepatic failure develops, in which, in addition to metabolic acidosis (BE – -18 mmol/L), diffuse hepatic dystrophy occurs, although hyperbilirubinemia may not reach high levels (200 µmol/L) due to Kupffer cell death and cessation of bilirubin synthesis.

In 2019, White J., Weinstein S.A., and De Haro L. [22] developed a classification with inclusion criteria encompassing: fungal identity, clinical profile, epidemiology, and poisoning features compared to previously documented syndromes. The authors propose six main groups based on key clinical features essential for differentiating mushroom poisoning syndromes. Some clinical features, particularly gastrointestinal symptoms, are shared across many mushroom poisoning syndromes.

Group 1 – Cytotoxic mushroom poisoning. Syndromes with specific major internal organ pathology: (Subgroup 1.1; Primary hepatotoxicity); 1A – Primary hepatotoxicity (amatoxins); (Subgroup 1.2; Primary nephrotoxicity); 1B – Early primary nephrotoxicity (aminohexadienoic acid; AHDA); 1C – Delayed primary nephrotoxicity (orellanines).

Group 2 – Neurotoxic mushroom poisonings. Syndromes with primary neurotoxicity: 2A – Hallucinogenic mushrooms (psilocybins and related toxins); 2B – Mushrooms with autonomic toxicity (muscarines); 2C – Mushrooms with CNS toxicity (ibotenic acid/muscimol); 2D – Morel neurological syndrome (Morchella spp.).

Group 3 – Myotoxic mushroom poisoning. Syndromes with rhabdomyolysis as the primary feature: 3A – Rapid onset (Russula spp.); 3B – Delayed onset (Tricholoma spp.).

Group 4 – Metabolic, endocrine, and associated toxicity of mushroom poisoning. Syndromes with diverse clinical manifestations affecting metabolic and/or endocrine processes: 4A, GABA-blocking mushroom poisoning (gyromitrins); 4B – disulfiram-like (Coprinus); 4C – polypore mushroom poisoning (polyporic acid); 4D – trichothecene mushroom poisoning (Podostroma spp.); 4E – hypoglycemic mushroom poisoning (Trogia venenata); 4F – hyperprocalcitonemia mushroom poisoning (Boletus satanas); 4G, pancytopenic mushroom poisoning (Ganoderma neojaponicum).

Group 5 – Gastrointestinal irritant mushroom poisoning. This group includes a wide variety of mushrooms that cause gastrointestinal effects without other clinically significant effects.

Group 6 – Miscellaneous adverse reactions to mushrooms. Syndromes not included in the first 5 groups: 6A, shiitake mushroom dermatitis; 6B – erythromelalgic mushrooms (Clitocybe acromelalga); 6C – Paxillus syndrome (Paxillus involutus); 6D, encephalopathy syndrome (Pleurocybella porrigens) [22].

1.6 Clinical presentation of the disease or condition

The toxic effect of mushroom toxins on internal organs is caused by: a direct damaging effect; an indirect effect mediated through a cycle of metabolic transformations in the human body. For clinical and diagnostic purposes, mushroom poisonings are subdivided into two groups: poisonings with a short and a long latent period. Poisonings with a short incubation period are caused by mushrooms of the following genera: Clitocybe, Psilocybe, Inocybe, and certain representatives of the genus Amanita (Amanita muscaria and Amanita pantherina). Poisonings with a long incubation period are caused by the consumption of Amanita phalloides, Gyromitra esculenta, Gyromitra gigas, Morchella esculenta, and Cortinarius.

Clinical manifestations of acute mushroom poisonings are polymorphous and accompanied by impaired functions of the gastrointestinal tract, central and peripheral nervous system, liver and kidneys, water-electrolyte and acid-base balance, blood gases, and cardiovascular system functions. Coagulopathy and endotoxicosis are observed [7, 8]. The severity of acute poisoning in a patient is assessed using the Poisoning Severity Score, presented in Appendix G 3.

1.6.1. Gastrointestinal tract injury

One of the first clinical manifestations of the toxic effect of mushroom poisons is presented by symptoms of acute toxic gastroenteritis (ATG), resulting from the action of toxins on enterocytes, which always accompanies the disease and develops after a latent period, the duration of which depends on the mushroom species. The longest latent period (from 6 to 12 hours or more) is characteristic of mushroom poisoning causing gyromitrid and phalloidin syndromes (Amanita phalloides). Spastic abdominal pain, indomitable vomiting, and profuse watery diarrhea with cholera-like rice-water stools tinged with blood are characteristic. The severity of gastroenteritis determines the clinical picture of hypovolemia and dyselectrolytemia, the symptoms of which include: thirst, weakness, asthenia, decreased blood pressure, tachycardia, and clonic contractions of individual muscle groups. Laboratory findings show metabolic acidosis, hemoconcentration, and electrolyte disturbances. The extent of intestinal damage may determine the severity of liver and kidney damage.

The onset of ATG after a short latent period is typical for mushrooms of the genera Clitocybe and Inocybe (15 minutes–2 hours), causing resinoid syndrome: Entoloma sinuatum, Tricholoma, Omphalotus olearius, Boletus satanas, Tylopilus felleus, and Agaricus xanthodermus (30 minutes–3 hours). After the resolution of ATG, a period of "false well-being" begins, lasting about 2–4 days. In severe forms of poisoning, this period is shortened to 8–12 hours.

1.6.2. Liver injury

Liver damage depends on the absorbed mushroom toxin and its dose. At the beginning of the disease, despite the patient's apparent well-being, a biochemical blood test shows an increase in transaminases, a trend toward hypoproteinemia and hyperbilirubinemia, and a prolonged prothrombin time. The first laboratory signs of cytolysis can occur on days 1–2. The activity of AST, followed by ALT and a day later the enzyme lactate dehydrogenase (LDH), increases sequentially. An increase in LDH above 1500 IU is prognostically unfavorable. AST, ALT, and LDH are markers of cytolysis and hepatocellular necrosis, which accompany jaundice (skin discoloration occurs at bilirubin levels above 60 µmol/L), increased bleeding tendencies, and encephalopathy. Poisoning is characterized by an initial increase in unconjugated bilirubin, followed by an increase in the conjugated fraction. After a short period of hyperglycemia, there is a trend toward persistent hypoglycemia.

The increase in cytolysis and bilirubinemia is combined with the onset of: weakness, "hepatic" fetor, epigastric tenderness on palpation, hepatomegaly, sleep and appetite disorders, symptoms of CNS dysfunction, and impaired mental functions. At the final stage of the disease, signs of severe acute liver failure progress, accompanied by symptoms of hepatic encephalopathy, azotemia, hepatic coma, respiratory failure, hyper- or hypothermia, and acute kidney injury (proteinuria, microhematuria, decreased urine output (mL/kg/h), and creatinine clearance down to 50 mL/min) [7, 8, 23].

Coagulopathy (DIC syndrome) occurs as a result of specific damage to the main coagulation factors—hepatic blood-clotting factors (II, V, VII, and X) decrease, which is accompanied by: gum bleeding, petechial skin hemorrhages and hemorrhages in the mucous membranes, "coffee-ground" emesis, bloody diarrhea, dark tarry stools, epistaxis, uterine bleeding, and hematuria.

1.6.3. Kidney injury

The predominance of acute kidney injury (prerenal, renal) occurs under the toxic action of mushroom poisons causing orellanine syndrome: Cortinarius orellanus, Cortinarius rubellus (acute kidney injury). A characteristic feature is a long incubation period – from 3 to 17 days (up to 20 days) after the consumption of 40–60 g of fresh mushrooms (containing 10–15 mg of orellanine). Clinical signs of kidney damage begin with lumbar pain, nausea, vomiting, and hyperthermia. Subsequently, patients report thirst, joint pain, myalgia, paresthesia. The overwhelming majority of patients develop tubulointerstitial nephritis, manifested by oligoanuria, proteinuria, peripheral edema (anasarca is observed). In 15–25% of cases, acute kidney injury is noted, ending in 20–30% with a transition to chronic renal failure. The toxic agent, orellanine, can be present in the victim's blood up to the 10th day. Liver damage is very moderate and limited to mild-to-moderate hepatopathy.

The toxic substance in various mushroom species has a specific biological action. The chemical structure of the poison determines the tropism for the body's organs and systems, defined as "selective toxicity," which is clinically manifested by the development of disease syndromes, sometimes combined with each other [7, 10, 11].

1.6.4. Syndromes arising from the toxic action of mushroom poisons

Phalloidin Syndrome

The syndrome is accompanied by a latent period of up to 6–36 hours. Period of acute toxic gastroenteritis – symptoms of gastrointestinal tract damage. Acid-base and water-electrolyte disturbances – hyponatremia, hypokalemia, hypochloremia, metabolic acidosis. Further, the clinical manifestations of acute toxic gastroenteritis diminish – period of false well-being (1–2 days) and then clinical manifestations of pronounced liver and kidney dysfunction appear.

The syndrome following the consumption of Lepiota helveola (from the toxic mushroom group) is accompanied by pronounced liver and kidney dysfunction.

Gyromitrin Syndrome

The syndrome is accompanied by a latent period of up to 3–25 hours. Period of acute toxic gastroenteritis – symptoms of gastrointestinal tract damage. Clinical manifestations of pronounced liver dysfunction appear – grade I–III hepatopathy. Kidney damage proceeds with or without grade I nephropathy. The severity of the course and organ damage depend on the dose of the toxic substance received. Hemolysis and hemoglobinuric nephrosis may occur .

Paxillus Syndrome

The syndrome is accompanied by a latent period of up to 1–6 hours. Spastic pain and acute toxic gastroenteritis occur. Grade I–II hepatopathy and nephropathy. Acute hemolysis. With delayed care – grade III hepatopathy and nephropathy, DIC syndrome.

Orellanine Syndrome

The course of the syndrome is largely determined by the patient's individual sensitivity and premorbid condition. The latent period ranges from 36 hours to 10–17 days [14]. The initial symptoms are hyperthermia, weakness, and pain in the lumbar and abdominal regions. Symptoms of gastrointestinal tract involvement and neurological disorders (headache, tinnitus, lethargy) occur, along with acute kidney injury and serositis. Central nervous system dysfunction progresses, manifesting as tremor, paresthesia, and coma. On the 10th day, orellanine was detected in the patient's blood at a concentration of 6.12 mg/L [14]. The recovery stage lasts for several months and may progress to chronic kidney disease [8]. Considering the above, poisoning by Cortinarius orellanus and Cortinarius speciosissimus, unlike poisonings by other mushroom toxins, is characterized by a prolonged latent period, the development of acute kidney injury, and minimal liver tissue damage.

Proximan syndrome

The incubation period lasts from 8 to 48 hours. Initial clinical manifestations are accompanied by acute toxic gastroenteritis, followed by the development of acute kidney injury and grade II hepatopathy, which has a "background" course and is generally favorable.

Coprine syndrome

As noted in the pathogenesis, this syndrome develops as a result of acetaldehyde accumulation. When the common ink cap (Coprinus atramentarius) is ingested simultaneously with alcohol, the incubation period lasts 20–30 minutes. An extended duration of up to 2–3 days may occur if alcohol is consumed with a delay after eating the mushrooms.

Leading clinical manifestations: central nervous system disorders – headache, dizziness, tinnitus, followed by psychomotor agitation, seizure, and unproductive forms of impaired consciousness; cardiovascular system disorders – sinus tachycardia, hypotension; autonomic disorders – skin hyperemia, hyperhidrosis, nausea, vomiting, and loose stools. The presence of coronary artery disease, atherosclerosis, or bronchial asthma in the patient implies an increased risk of myocardial and cerebral ischemia, as well as an unfavorable disease outcome.

Resinoid syndrome

The syndrome is accompanied by acute toxic gastroenteritis, which can be mild, without dysfunction of other organs, or severe, when gastrointestinal disturbances are accompanied by hypovolemia, electrolyte imbalances, acid-base disorders, kidney injury, and toxic hepatitis.

Mild form of the toxic process is observed after the ingestion of:

1. Common earthball (Scleroderma aurantium).

2. Yellow-staining mushroom (Agaricus xanthodermus, syn. Psalliota xanthoderma).

3. Bitter bolete (Tylopilus felleus, syn. Boletus felleus).

4. Pale coral fungus (Ramaria pallida).

5. Fringed bell (Hebeloma crustuliniforme).

6. Yellow milkcap (Lactarius helvus).

7. Grey milkcap (Lactarius vietus).

8. The emetic russula (Russula emetica).

9. Peppery bolete (Suillus piperatus, syn. Boletus piperatus).

10. Lactarius zonarius (Lactarius zonarius).

11. Lactarius blennius (Lactarius blennius).

12. Clavaria aurea (Clavaria aurea, syn. Ramaria aurea).

13. False chanterelle (Hygrophoropsis aurantiaca).

14. Grey-pink milkcap (Lactarius helvus).

15. Wheel parachutist (Marasmius rotula).

16. Clavaria formosa (Clavaria formosa, syn. Ramaria formosa).

The latent period ranges from 15 minutes to 3 hours, after which nausea, vomiting, and loose stools occur, sometimes leading to prolonged diarrhea resulting in hypovolemia, electrolyte imbalances, acid-base disorders, prerenal kidney injury, and toxic hepatitis. Enterogenic intoxication occurs as a result of increased intestinal barrier permeability to opportunistic intestinal microflora.

Severe form of the toxic process is observed after the ingestion of:

Highly toxic mushrooms:

1. Livid pinkgill (Entoloma sinuatum), syn. Rhodophyllus lividus.

2. Tiger knight (Tricholoma pardinum).

3. Pointed knight (Tricholoma virgatum).

4. Sulfur tuft (Hypholoma fasciculare).

5. Smith's amanita (Amanita smithiana).

Toxic mushrooms:

1. Sulfur knight (Tricholoma sulphureum).

2. Satan's bolete (Boletus satanas).

3. Woolly milkcap (Lactarius torminosus).

4. Entoloma nidosorum (Entoloma nidosorus).

5. Entoloma lividoalbus (Entoloma lividoalbus).

6. Entoloma vernum (Entoloma vernus).

Upon ingestion of highly toxic mushrooms, clinical manifestations appear after a latent period of 1–9 hours and are accompanied by: acute toxic gastroenteritis with persistent, intractable vomiting and spastic abdominal pain; profuse, foul-smelling enteritis; hypovolemia, electrolyte imbalances, and acid-base disorders; prerenal kidney injury and toxic hepatitis.

Upon ingestion of toxic mushrooms, clinical manifestations appear after a latent period of 2–4 hours and are accompanied by: acute toxic gastroenteritis with vomiting; hypovolemia, electrolyte imbalances, and acid-base disorders; prerenal kidney injury and toxic hepatitis.

Sudorine syndrome (muscarinic)

The incubation period ranges from 15 minutes to 2 hours.

The course of the syndrome is caused by the influence of toxic substances that produce a muscarine-like syndrome, manifesting as:

• acute toxic gastroenteritis (initial clinical manifestations) characterized by increased tone (myogenic tone) and peristalsis;

• hypersecretion – hyperhidrosis, hypersalivation, rhinorrhea, and epiphora;

• cardiovascular dysfunction – bradycardia, vasodilation, hypotension;

• respiratory dysfunction – bronchorrhea, bronchospasm;

• central nervous system dysfunction, determined by the fact that muscarine does not cross the blood-brain barrier, and patient consciousness remains intact; emotional disorders arise in response to the aforementioned organ and system dysfunctions, manifesting as impaired understanding, awareness, and expression of natural emotions, including their depth, intensity, and lability;

• mental function disorders – dysphoria, anxiety, aggressiveness, delirium (clinical presentation resembles psychodysleptic syndrome);

• other symptoms – miosis, inability of convergence, pollakiuria, sensation of cold (chills occurring at normal body temperature), paresthesias, muscle tremors;

• duration of clinical symptoms up to 5 hours.

Psychomimetic syndromes

1. Psychotonic (myco-atropine) syndrome

The incubation period ranges from 15 minutes to 4 hours. Clinical manifestations of the disease present as an anticholinergic syndrome: disorientation in time, space, identity, and events; hallucinations (visual, auditory); seizures, dry skin and mucous membranes, mydriasis, tachycardia, and decreased intestinal peristalsis. The variability of these symptoms and their severity depend on the type of toxin and its concentration in the mushrooms.

In addition to the above, clinical manifestations of acute poisoning by Amanita pantherina include dysphoria giving way to fear and delirium, ataxia, and potential signs of lower motor neuron involvement manifesting as areflexia, atonia, fasciculations, alongside upper motor neuron signs – muscle hypertonia, hyperreflexia of deep reflexes and areflexia (hyporeflexia) of cutaneous reflexes, pathological synkinesias (involuntary associated movements occurring alongside voluntary ones; all symptoms are variable). In severe cases of poisoning, gastrointestinal disturbances occur. The multidirectional, dose-dependent, and transient effects of the substance complex vary within ranges significant for the clinical course: tachycardia-bradycardia; dry mucous membranes vs. increased salivation; dry skin vs. hyperhidrosis; mydriasis vs. miosis; hypertension vs. collapse; atonia vs. seizures.

When ingesting toadstools that cause clinical manifestations of the psychotonic (myco-atropine) syndrome – Amanita muscaria, A. pantherina, A. gemmata, A. regalis – unlike narcotic drugs, there is no euphoria, and the leading clinical sign is depressed mood and a sense of fear [8]. Upon ingestion of Amanita muscaria and A. pantherina, depression, ataxia, hyperkinesia, hallucinations, and hysteroid behavior occur within 30–180 minutes [24]. In severe poisoning by Amanita muscaria,

2. Psychodysleptic syndromes

Psilocybin syndrome manifests as synesthetic hallucinations in response to the effects of psychoactive chemical substances.

Steril-pyrone syndrome develops on the basis of visual hallucinations. The mechanism of action of meconic acid on the human body is poorly understood; nevertheless, its effects on the central nervous system are specifically attributed to this chemical substance [8].

Indolamine syndrome develops on the basis of auditory hallucinations arising from the effect of indolamine derivatives on serotonergic receptors of the brain [8].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnosis must be based on the following diagnostic criteria:

• clear evidence of mushroom ingestion;

• presence of symptoms and signs of toxic effects corresponding to syndromes dangerous to the life and health of patients;

• existing symptoms or signs cannot be explained by a disease unrelated to mushroom ingestion, or by other conditions.

2.1 Complaints and Anamnesis

Complaints in acute poisoning depend on the type of mushroom and the dose of the ingested substance, and are determined by symptoms and syndromes, the period of poisoning, and the failure of bodily organ and system functions. Furthermore, patient complaints may be caused by the development of complications during the toxicogenic and somatogenic periods of acute poisoning. During the latent period and the period of apparent well-being, clinical manifestations may be absent or minimal. During the period of pronounced clinical manifestations of the disease, complaints may be absent due to severe functional impairments, primarily of the central nervous system, as contact with the patient is limited.

Level of Evidence (LE) – 5, Grade of Recommendation (GR) – C.

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

Comments: In cases of mushroom poisoning, general principles of toxicological history-taking are not always applicable. This concerns ascertaining such information as: the species or name of the mushroom consumed by the victim; the time of their ingestion (toxin exposure time in the body), which makes it possible to determine the stage of poisoning with a certain degree of accuracy; and the circumstances accompanying the development of poisoning (accidental or intentional poisoning). Virtually none of the above can be ascertained when relatives are absent and the patient is unable to report the necessary information due to their condition. In such cases, the diagnosis is established based on the clinical syndrome. It is also necessary to clarify the fact of mushroom ingestion by several persons in order to diagnose "group" mushroom poisoning.

The patient's complaints in acute mushroom poisoning depend on the type of mushrooms, dose, and exposure time. At the onset of the disease, complaints are associated with toxic gastroenteritis (nausea, vomiting, dyspeptic disorders); during the latent period, complaints may be absent. During the period of pronounced clinical manifestations, the patient's complaints are associated with the progression of hepatic failure, dyselectrolytemia, and central nervous system damage [3, 6, 7, 8].

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

Comments: Diagnosis of the toxic effects of mushrooms is based on anamnestic data and, primarily, on characteristic symptoms: acute toxic gastroenteritis, hypovolemia, dyselectrolytemia, acute kidney injury, hepatopathy, metabolic acidosis, and central nervous system dysfunction. In addition, pieces of mushrooms may be found in the washings (vomitus) during gastric lavage. In poisonings with certain types of mushrooms, there is a sequential series of periods (latent, acute toxic gastroenteritis, apparent well-being, and pronounced clinical manifestations) in the development of syndromes. Clinical diagnosis must also be performed taking into account the stage of poisoning – toxicogenic and somatogenic [3, 7].

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

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.

Comments. Changes in the skin may indicate liver damage. The specific skin coloration – a yellowish hue – depends on the stage of poisoning. Impairment of protein-synthetic function contributes to the formation of edema. Attention should be paid to petechial rash and intradermal hemorrhages, the formation of which results from toxic liver damage – hemorrhagic syndrome, coagulopathy (impaired clearance of activated clotting factors) [3, 7, 8].

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

Comments. It is necessary to assess central nervous system functions – the state of consciousness (clear, obtundation, stupor, coma); convulsive seizures; psychomotor agitation, sensory distortions, hallucinations of various sensory spheres. When establishing coma, its depth must be assessed using the Glasgow Coma Scale (Appendix G1). Assess the presence or absence of reflexes (motor, autonomic) and muscle tone.

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

Comments. Respiratory system disorders may be of central origin (resulting from toxic encephalopathy or hepatoencephalopathy) or peripheral origin (resulting from aspiration syndrome, pneumonia).

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.

Comments. Attention should be paid to the presence or absence of a hepatic odor from the patient; signs of toxic gastroenteritis, hypovolemia, hepatopathy. Abdominal palpation may reveal tenderness and abdominal distension. Stool changes should be evaluated – profuse watery, choleriforming "rice-water" stool with streaks of blood. Physical findings must be compared with the duration of the latent period typical for mushrooms of the genera Clitocybe, Inocybe (15 minutes–2 hours), causing resinoid syndrome: Entoloma sinuatum, Tricholoma spp., Omphalotus olearius, Rubroboletus satanas, Leccinum/Bile bolete, Agaricus xanthodermus (30 minutes–3 hours). After the end of acute toxic gastroenteritis, the period of "apparent well-being" begins, lasting about 2–4 days. In severe forms of poisoning, this period shortens to 8–12 hours.

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.

Comments: during differential diagnosis, it is necessary to take into account the history of mushroom consumption, the duration of the latent period, and the subsequent onset of initial symptoms accompanied by abdominal pain, vomiting, and cholera-like stools mixed with blood, which gives grounds to suspect mushroom poisoning. It is recommended during differential diagnosis to take into account that the pathological process arising from mushroom poisoning is not characterized by fever, unlike the above-mentioned diseases accompanied by inflammation [3, 7, 8].

2.3 Laboratory Diagnostics

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

Comments: Currently, there are no approved methods for testing chemical substances contained in mushrooms.

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.

Comments: in acute mushroom poisoning (Gyromitra esculenta, G. gigas, G. infula; Morchella esculenta and M. conica) resulting in gyromitrin syndrome, hemolysis develops, leading to hemoglobinuric nephrosis [6].

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 Evidence (LoE) – 5, Grade of Recommendation (GoR) – C.

Level of Reliability of Evidence (LRE) – 4, Level of Recommendation Validity (LRV) – C.

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

2.4 Instrumental Diagnostics

Performing these diagnostic tests does not clarify the specific diagnosis of the toxic effects of poisons contained in the ingested mushrooms. Nevertheless, they are necessary for the early diagnosis of complications in mild, moderate, and severe cases. These conditions may indicate changes in various organs and systems that require verification and assessment, thereby expanding supportive care options.

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.

Comments: electrocardiography (ECG) makes it possible to assess the likelihood of the toxicant's effect on the myocardium, cardiomyopathy, chronic heart disease, electrolyte disturbances, and cardiac rhythm and conduction disorders.

Vital sign monitoring should preferably be performed by hardware methods using an intensive care cardiac monitor. In the absence of a monitor, periodic monitoring of vital signs is performed manually. The frequency of repeated measurements is determined by the attending physician depending on the severity of the patient's condition [7, 45, 57].

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.

2.5 Other Procedures

Additional diagnostic methods are prescribed by specialists based on the specific clinical situation and indications. Because the toxic effects of poisons contained in ingested mushrooms are accompanied by various disorders in the body's organs and systems, exhibit variable clinical manifestations, and cause diverse complications, differential diagnosis is frequently necessary.

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.

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

3.1. Toxin elimination measures

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

Comments. In case of depressed consciousness, endotracheal intubation and, if necessary, initiation of mechanical ventilation are indicated prior to gastric lavage. It is also necessary to take measures to stabilize hemodynamics and stop convulsions. The size of rubber gastric feeding tubes in adults and adolescents is F36-45, and in children F22-28. During tube insertion, the patient should be either in a sitting position or lying on the left side with the chin pressed against the chest. Correct insertion is verified by injecting air with a Janet syringe (stomach sounds should be audible upon auscultation). The single water dose for a child is 10 ml/kg, but not more than 250 ml. The single water dose for an adult is 250 ml. The recommended total volume of water for tube gastric lavage is:

• in children under one year old – up to 1 l.

• in children aged 2-5 years – up to 3 l.

• in children aged 6-10 years – up to 4 l.

• in children older than 10 years – up to 5 l.

• for adults – up to 10 L

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

Comments: Gastrointestinal sorption is based on the ability of intestinal adsorbents to bind protein-based toxic substances, including amatoxins and phallotoxins, as well as medium- and large-molecular-weight oligopeptides.

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.

Comments. Forced diuresis includes three stages: preliminary water loading, diuretic administration, and electrolyte replenishment. At the first stage, hypovolemia is compensated by administering solutions that affect the water-electrolyte balance, plasma expanders, blood plasma preparations, and irrigation solutions under the control of pulse examination, heart rate measurement, blood pressure measurement on peripheral arteries, central venous pressure measurement, hematocrit evaluation, blood sodium level testing, blood chloride level testing, blood potassium level testing, and urine volume determination. At the second stage, furosemide** is prescribed. Then, solutions affecting the water-electrolyte balance are administered at a rate equal to the diuresis rate. The infusion dose (volume) is determined based on the body's loss of fluid, sodium ions, and chloride ions [2, 7, 45, 125].

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

Comments: during forced diuresis, it is necessary to test blood sodium and blood potassium levels. In children, the daily dose should not exceed 2–3 mmol/kg of body weight or 40 mmol/m² of body surface area.

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

Comments: Indications for extracorporeal detoxification methods [59]: 1) there is evidence of mushroom ingestion with a corresponding anamnesis and clinical-laboratory picture of severe poisoning (for death cap – gastrointestinal syndrome, impaired consciousness in the form of delirium or stupor, elevated transaminase levels) within the first two days after poison ingestion. 2) presence of the toxicant in blood/urine + clinical picture of severe poisoning. 3) toxic concentration of poison in the blood. Most commonly, hemisorption, plasmapheresis, or plasma exchange (PE) are used. Hemodialysis (HD) as an elimination method is rarely used because cyclopeptides have a high molecular weight and do not pass through the dialysis membrane. Isolated plasmapheresis leads to the loss of serum protein, so it is supplemented by the administration of fresh frozen plasma (FFP) and human albumin**. The administration of FFP is of great importance in impaired liver function since it is a source of blood coagulation factors. Plasmasorption (PS) allows the removal of unwanted exo- and endogenous toxicants from the body. To remove amanitins from the body, hemisorption is indicated within the first 36 hours of poisoning. Plasmapheresis, plasma exchange, and plasmasorption are performed to remove protein-bound toxic metabolites from the body. In psychomimetic syndromes, dialysis-filtration detoxification methods are mandatory in case of recurrent medically refractory seizure attacks and a level of impaired consciousness corresponding to coma [1, 2].

3.2. Antidote and pathogenetic therapy

Antidote therapy in mushroom poisoning can only be discussed with respect to muscarine and gyromitrin syndromes. In other types of poisoning, this term is conditional, as the drugs considered in this context do not meet the requirements for antidotes.

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

Comments: Manifestations of muscarine syndrome: acute toxic gastroenteritis with increased tone and peristalsis of the gastrointestinal tract; hypersecretion – hyperhidrosis, hypersalivation, rhinorrhea, and epiphora; cardiovascular system disorders – bradycardia; respiratory system disorders – bronchorrhea, bronchospasm; miosis. If necessary, #Atropine** is re-administered until poisoning symptoms disappear.

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

Comments: monomethylhydrazine (MMH) is formed as a result of the hydrolysis of gyromitrin (mycotoxin of fungi of the genus Gyromitra), which determines the development of neurological disorders (seizure attack). #Pyridoxine**, by interacting with MMH, helps counteract the inhibition by MMH of the pyridoxine-dependent stage of GABA neurotransmitter synthesis. Thus, GABA synthesis can continue, and symptoms subside [1].

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

Comments: #Benzylpenicillin** (included in the WHO list as an antidote) is capable of binding free amatoxins, displacing alpha-amanitin from its bond with albumin, thereby preventing its penetration into hepatocytes and preventing the binding of alpha-amanitin to RNA polymerase.

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

Comments: #Acetylcysteine** is used in the treatment of acute liver necrosis of various etiologies. According to several authors, the antidote effects of acetylcysteine are due to its antioxidant properties. #Acetylcysteine** is a donor of sulfhydryl groups, the level of which decreases when glutathione stores are depleted upon the entry of a hepatotoxic toxicant into the patient's body. The following administration regimens for #Acetylcysteine** have been proposed: 1) the intravenous loading dose is 150 mg/kg in 200 ml of 5% dextrose** IV over 60 min, followed by a maintenance dose of 50 mg/kg in 500 ml of 5% dextrose** over 4 hours, then 100 mg/kg in 1000 ml of 5% dextrose** over 16 hours (regimen for adults). In young children, intravenous administration of #acetylcysteine** at the specified doses is performed under the control of water-electrolyte balance. 2) The oral loading dose is 140 mg/kg. Then 17 doses of 70 mg/kg every 4 hours. All doses are taken independently by the patient or administered via a tube. If treatment is initiated 16–24 hours after toxicant exposure, oral administration according to the 72-hour regimen is more effective. In liver failure, #acetylcysteine** is administered intravenously at a dose of 150 mg/kg in 5% dextrose** over 24 hours, and the infusion is continued until consciousness is restored (disappearance of clinical manifestations of hepatic encephalopathy), INR drops below 2.0, or until liver transplantation.  When administering the drug intravenously, one must remember the threat of dangerous complications, in particular, anaphylactoid shock [1, 2, 41, 56].

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

Comments: The substances contained in Spotted thistle fruit extract prevent the penetration of α-amanitin into liver cells by interacting with free radicals in the liver, converting them into less toxic compounds and interrupting lipid peroxidation processes. In damaged hepatocytes, it stimulates the synthesis of structural and functional proteins and phospholipids (via specific stimulation of RNA polymerase, stabilizes cell membranes, prevents the loss of cellular components (transaminases), and accelerates liver cell regeneration. A positive effect on the course of hepatopathy is exerted by the combined administration of the drug #Benzylpenicillin** (at the previously indicated doses) and #Spotted thistle fruit extract 10-20 mg/kg/day [1, 2, 122].

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

Comments: Thioctic acid** has an antioxidant effect. The drug should not be used in children under 18 years of age.

3.3. Infusion therapy, rehydration

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

Comment: Infusion therapy is performed under the control of pulse examination, heart rate measurement, blood pressure measurement on peripheral arteries, central venous pressure measurement, hematocrit evaluation, blood sodium level testing, blood chloride level testing, blood potassium level testing, and urine volume determination.

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

Comments: The infusion dose or the volume of the administered drug – sodium bicarbonate is determined depending on the level of hemolysis and acidosis. To reduce the deposition of hemoglobin derivatives, the urine pH reaction must be maintained above 6.0 [90].

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

Comment: Poisoning accompanied by vomiting and diarrhea can lead to severe water-electrolyte balance and acid-base balance disorders.

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

Comments: the indication for administration is the need for infusion detoxification and antihypoxic therapy in acute poisoning (can be used as an infusion medium during forced diuresis). Adults are prescribed intravenous administration at a rate of 1-4.5 ml/min (up to 90 drops/min). The average daily dose is 10 ml/kg. Used in children from 1 year of age at a rate of 6-10 ml/kg/day at a speed of 3-4 ml/min. The duration of use is up to 11 days [88, 91].

3.4. Management of gastrointestinal disorders

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

Comments: The drug has age restrictions in accordance with the instructions depending on the dosage form.

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.

Comments: Contraindications for the use of Chloramphenicol** are hepatic and/or renal failure, pregnancy, breastfeeding, and age under 3 years with a body weight of less than 20 kg.

3.5. Correction of liver and kidney dysfunction

Mushroom poisoning causing phalloidin syndrome is often complicated by liver damage with impairment of its main functions – detoxification and synthetic, which clinically manifests as hepatic encephalopathy, coagulopathy, and hypoproteinemia.

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.

Comments: Amino acid imbalance in liver failure plays a crucial role in the development of hepatic encephalopathy, which requires careful consideration when prescribing drugs containing amino acids. It is considered necessary to maintain a sufficient level of branched-chain amino acids (valine, leucine, and isoleucine) and arginine, while limiting the level of aromatic amino acids and methionine. For this reason, methionine is contraindicated in severe liver failure and hepatic encephalopathy [46].

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

Comments: The maximum daily dose for children is 10 mg.

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.

Comments: indications for liver transplantation in patients with toxic effects of *Amanita phalloides* poisons are: lack of positive effect from intensive care within 48–72 hours; negative dynamics of the patient's condition and laboratory parameters—coagulopathy with a prothrombin index below 20%, bleeding time increased over 100 seconds, hypofibrinogenemia; severe hyperbilirubinemia, hyperfermentemia; hyperammonemia; metabolic acidosis, hypoglycemia, hypophosphatemia. The effectiveness of the surgery increases if it is performed before the development of multiple organ failure and cerebral edema [6]. More than half of patients with toxic effects of amatoxin are candidates for liver transplantation [21, 23].

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.

3.6. Maintenance (restoration) of vital functions

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

Comments. In cases of aspiration-obstructive respiratory disorders, it is necessary to ensure upper airway patency using a combitube, laryngeal mask, or laryngeal tube, perform oral suction and remove mucus from the upper airways. If acute respiratory failure develops, initiate mechanical ventilation (MV) using various types of mechanical ventilators and manual ventilation bags. To stabilize hemodynamics, securing venous access and intravenous infusion and vasopressor therapy are indicated.

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

Comments. When acute respiratory failure develops during mechanical ventilation (in the absence of lung injury), use CMV (VC) or PCV (PC) as initial (starting) ventilation modes according to the following algorithm (against the background of sedation and/or muscle relaxation):

1. During CMV, set the tidal volume (Vt) equal to 6–8 ml/kg of predicted body weight (in PC mode – peak inspiratory pressure 18–20 cm H2O); F = 8–12 breath/min; I/E ratio = 1:2; inspiratory flow rate 20–25 l/min (constant or sinusoidal flow waveform), PEEP = 3–5 cm H2O, FiO2 = 0.6.

2. If, against the background of the parameters specified in clause 1, chest excursion is satisfactory, respiratory sounds are audible and transmitted bilaterally upon lung auscultation, and oxygenation is adequate (PaO2 ≥ 80 mm Hg, SaO2 > 95%), then the oxygen concentration in the inspiratory gas mixture is reduced to the minimum level at which SaO2 = 96–98%.

3. If chest movements are limited and respiratory sounds are poorly transmitted, Vt is stepwise increased by 30–50 ml (or PiP by 2–3 cm H2O) until a "normal" level of chest excursion and transmission of respiratory sounds bilaterally upon lung auscultation are achieved. After that, FiO2 is reduced as specified in clause 2.

4. If it is necessary to induce hyperventilation, change the number of machine breathing cycles until mild hyperventilation (PaCO2 = 32–35 mm Hg) or moderate hyperventilation (PaCO2 = 25–30 mm Hg) is achieved.

5. When increasing the I/E ratio to 1:1, it is necessary to increase the inspiratory flow rate until the I/E is reduced to at least 1:1.5.

6. Perform "optimization" of Vt using Vt/Paw curve analysis.

7. Evaluate the Flow/Vt loop and the Flow/Time curve. If the Flow/Vt loop is not closed and/or the expiratory part of the Flow/Time curve does not reach the baseline by the beginning of the next breath, reduce the inspiratory time (it may simultaneously be necessary to increase the inspiratory flow rate) until a fully closed Flow/Vt loop is obtained and the expiratory flow reaches the baseline of the Flow/Time curve by the end of exhalation.

8. If necessary, change the oxygen concentration in the inspiratory gas mixture (to maintain adequate oxygenation) and set an automatic "sigh" (usually 3 times per hour, 1.5 × Vt).

Taking into account the above algorithm, the most commonly used respiratory support parameters in ventilatory acute respiratory failure (ARF) are presented in Table 4.

Table 4 – Most commonly used respiratory support parameters in ventilatory acute respiratory failure

To decide on withdrawing respiratory support, use the following main criteria: «normalization» of neurological status; the patient's ability to initiate spontaneous breathing. During the withdrawal of respiratory support, it is necessary to constantly maintain adequate oxygenation (PaO₂ = 85–100 mmHg, SaO₂ = 96–98% at FiO₂ <0.4), PaCO₂ within 35–40 mmHg, and continuously monitor the patient's level of consciousness. After complete withdrawal of mechanical breath cycles, the ventilator is switched to CPAP mode with a positive pressure level of 3–4 cm H₂O.

Particular difficulties at this stage of respiratory support may arise in the following two cases: 1) the duration of mechanical ventilation was 8 days or more; 2) the patient has apallic syndrome (vegetative coma). In such situations, the most optimal option for adapting patients to spontaneous breathing is the use of the BiPAP + MMV protocol according to the following method:

1) The lower level of positive pressure (EPAP) is set within 3–4 cm H2O, and the upper level (IPAP) at 6–8 cm H2O.

2) The target level of mandatory minute ventilation (MMV) is determined based on 150–200 ml/kg/min of ideal body weight.

3) The IPAP level is gradually decreased (by 1 cm H2O every 4–5 hours) down to the EPAP value.

4) Switch the ventilator to CPAP mode with a positive pressure level of 2–4 cm H2O. If necessary, the MMV mode can be continued.

On average, the duration of the BiPAP + MMV protocol is 18–24 hours.

In a stable condition (no progression of respiratory failure symptoms and/or neurological deficit), the patient can be extubated and fully switched to spontaneous breathing with humidified oxygen delivery (FiO2 = 0.3–0.35) for 3–4 hours

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

3.7. Other Treatments

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.

Comments: the drug is administered intravenously as an infusion in 100–200 ml of a 5 or 10% dextrose** solution or a 0.9% sodium chloride** solution. Administration rate is 3–4 ml/min. Adults are administered: in acute poisoning, a volume of 10 ml twice a day with an interval of 8–12 hours. In a comatose state—used in a volume of 20 ml per administration diluted in 200 ml of Dextrose** solution. Treatment course is up to 5 days [2, 3, 29, 54, 61, 97].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

In uncomplicated acute poisoning, rehabilitation is not required.

• If mental function disorders occur in the somatogenic stage of poisoning, rehabilitation is recommended in a psychiatric hospital or psychoneurological dispensary (following an initial appointment (examination, consultation) by a psychiatrist or initial appointment (examination, consultation) by a pediatric psychiatrist and a conclusion on the need for inpatient or outpatient treatment) [102].

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.

5. Prevention and Dispensary Observation

• In the toxic action of poisons contained in ingested mushrooms, accompanied by the development of psychodysleptic syndrome, tertiary (modification) prevention is of paramount importance; it is primarily medical and individual in nature, aimed at preventing recurrent intoxications and reducing harmful mental and somatic consequences in patients who have suffered acute severe poisoning. If a patient is found during clinical examination to have used narcotic and (or) psychotropic substances with harmful consequences, the patient should be offered preventive follow-up at a narcological dispensary for 1 year; if a narcotic substance dependence syndrome is identified, dispensary follow-up for 3 years is indicated. In case of substance dependence, follow-up at a narcological dispensary and timely, regular anti-relapse treatment are recommended [7, 8].

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.

6. Organization of Medical Care

6.1. Indications for hospitalization

All injured patients with the toxic action of poisons contained in ingested mushrooms should be hospitalized in a specialized acute poisoning center (or in the relevant departments of a medical organization if such a center is absent). In the absence of an acute poisoning center, patients with severe poisoning and complications, especially with impaired vital functions, should be hospitalized in an intensive care unit or in the intensive care unit of an emergency inpatient department. Emergency admission to the intensive care unit is indicated in the following conditions:

• - severe toxic action of poisons contained in ingested mushrooms, complicated by life-threatening comorbid somatoneurological pathology;

• - severe toxic action of poisons contained in ingested mushrooms, complicated by a seizure;

• - severe toxic action of poisons contained in ingested mushrooms, complicated by cerebral edema/swelling, respiratory disorders, acid-base and water-electrolyte balance disorders, cardio- and hemodynamic disturbances, acute kidney injury, and stage II-III hepatopathy.

Emergency transfer of patients to the anesthesiology and intensive care unit of a toxicological center or to a general intensive care unit is indicated under the following conditions: toxic action of poisons contained in ingested mushrooms with a level of consciousness depression on the Glasgow Coma Scale < 9 points (Appendix G1).

Emergency transfer of patients to the anesthesiology and intensive care unit of a toxicological center or to a general intensive care unit (if the toxicology department lacks an ICU) is performed if the patient develops respiratory failure, cardiovascular failure, acid-base and water-electrolyte balance disorders, acute kidney injury, or liver failure secondary to the toxic action of poisons contained in ingested mushrooms.

Treatment in the intensive care unit is carried out until vital function impairments stabilize and detoxification measures are completed, followed by rehabilitation measures in the acute poison treatment center, therapeutic, and pediatric departments.

The duration of hospitalization is determined by the severity of the poisoning. Treatment of patients is carried out in the acute poisoning department (specialized department) in mild cases and lasts on average up to 5 days; in moderate and severe poisonings, the patient is hospitalized in the intensive care unit until detoxification measures are completed and the patient's condition stabilizes. The length of stay in the intensive care unit in severe uncomplicated cases is 3-5 days; in cases complicated by pneumonia, renal-hepatic failure, or toxic-hypoxic encephalopathy, it is up to 10 days or more, followed by rehabilitation in the acute poisoning department for up to 14 days or more. Other treatment periods are established depending on the course of the toxicogenic and somatogenic stages of acute poisoning.

The attending physician providing medical care determines the medical indications or contraindications for extracorporeal detoxification methods. The decision is documented in the inpatient medical record by a medical board involving a clinical toxicologist [146].

6.2. Indications for patient discharge from the hospital

Following the restoration of consciousness and vital functions in patients with the toxic action of poisons contained in ingested mushrooms without complications and dependence syndrome (when the poison contained in ingested mushrooms was used by the patient to induce a psychodysleptic syndrome or euphoric effect), treatment is concluded (recovery refers strictly to the poisoning/toxic effect).

Following the restoration of consciousness and vital functions in patients with the toxic action of poisons contained in ingested mushrooms with dependence syndrome (when psychodysleptic syndrome is present and mushroom consumption was aimed at achieving a euphoric effect), the patient is advised to consult a psychiatrist-narcologist.

7. Additional Information

The duration of hospitalization is determined by the severity of the toxic action of poisons contained in ingested mushrooms.

Average duration of inpatient treatment:

1. mild severity – from 3 to 7 bed-days;

2. moderate severity – 10–14 bed-days;

3. severe degree without complications – 21-28 days;

4. severe degree (with complications: cerebral edema/swelling, pneumonia, acute kidney injury, stage III hepatopathy) – treatment duration from 30 to 60 bed-days. Depending on clinical data, complications, and the patient's condition, the treatment duration may vary.

Criteria for Evaluating the Quality of Medical Care

Table 1 – Criteria for assessing the quality of medical care [28]

References

Appendix A1. Working Group Composition

1. Boris B. Yatsinyuk – Chief Toxicologist of the Department of Health of the Khanty-Mansi Autonomous Okrug – Yugra, Candidate of Medical Sciences, Associate Professor, Anesthesiologist-Intensivist at the ICU wards of the budgetary institution of KhMAO-Yugra "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. Anastasia Yu. Simonova – Head of the Department of Clinical Toxicology, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Candidate of Medical Sciences, Associate Professor; Chief Toxicologist of the Moscow Healthcare Department.

5. Olga L. Balabanova – Candidate of Medical Sciences, Researcher at the Department of Clinical Toxicology, Saint Petersburg Research Institute of Emergency Medicine named after I.I. Janelidze.

6. 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.

7. 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.

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

9. 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.

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

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

12. 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).

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

No conflict of interest.

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. laboratory diagnostic physician;

7. neurologist;

8. neurosurgeon;

9. general practitioner (family physician);

10. otorhinolaryngologist;

11. emergency and critical care physician;

12. forensic medical expert;

13. internist;

14. district general practitioner;

15. toxicologist;

16. transfusiologist;

17. functional diagnostics physician;

18. surgeon;

19. endoscopist;

20. psychiatrist-narcologist.

Methodology for Developing Clinical Guidelines

Working group members independently performed a systematic search and selection of publications. The search was conducted in the PubMed search engine (http://www.ncbi.nlm.nih.gov/pubmed/), the Cochrane Library (http://www.cochranelibrary.com/), the eLIBRARY.ru scientific electronic library (http://elibrary.ru/defaultx.asp), as well as clinical trial registries: https://clinicaltrials.gov/ and https://www.clinicaltrialsregister.eu/ctrsearch/search. A total of 220 publications were found, of which 101 were selected. Based on the selected publications, thesis-recommendations were formulated and evaluated using the levels of evidence (LE) for diagnostic methods/interventions, levels of evidence (LE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, rehabilitation interventions), and grades of recommendation (GR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, rehabilitation interventions) (Table 2, Table 3, Table 4). Subsequently, each thesis-recommendation was thoroughly discussed at a general meeting of the working group, and consensus was reached in all cases of disagreement.

Table 1 – Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 2 – Scale for assessing levels of evidence (LE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, rehabilitation interventions)

Table 3 – Scale for assessing grades of recommendation (GR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, 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 data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or 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. Federal Law of the Russian Federation No. 323-FZ dated November 21, 2011, "on the Fundamentals of Protecting the Health of Citizens in the Russian Federation".

2. 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.)

3. Order of the Ministry of Health and Social Development of Russia No. 40 dated January 27, 2006, "On the Organization of Chemical and Toxicological Studies for the Analytical Diagnostics of Alcohol, Narcotic Drugs, Psychotropic and Other Toxic Substances in the Human Body".

4. 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.)

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

6. Federal Law No. 489-FZ of December 25, 2018, "On Amendments to Article 40 of the Federal Law 'On Compulsory Medical Insurance in the Russian Federation' and the Federal Law 'The Fundamentals of Healthcare Protection in the Russian Federation' Regarding Clinical Practice Guidelines."

7. 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".

8. Order of the Russian Ministry of Health No. 919n of November 15, 2012, "On Approval of the Procedure for Providing Medical Care to Adult Patients Profiled in 'Anesthesiology and Reanimatology'."

9. Order of the Government of the Russian Federation No. 2406-r of October 12, 2019, "On Approval of the List of Vital and Essential Drugs, as Well as Lists of Medicinal Products for Medical Use and the Minimum Assortment of Medicinal Products Required for Medical Care."

10. Order of the Russian Ministry of Health No. 491n of September 25, 2023, "On Approval of the Procedure for Conducting Forensic Medical Examinations."

11. Order of the Russian Ministry of Health No. 1129n of October 20, 2020, "On Approval of the Rules for Conducting Mandatory Medical Examinations to Detect Human Immunodeficiency Virus (HIV Infection)."

12. Order of the Russian Ministry of Health No. 381n of July 25, 2023, "On Approval of the Standard of Medical Care for Adults with Chronic Viral Hepatitis C (Diagnosis, Treatment, and Dispensary Monitoring)."

13. Resolution of the Chief State Sanitary Doctor of the Russian Federation No. 4 of January 28, 2021 (as amended on May 25, 2022) On Approval of Sanitary Rules and Norms SanPiN 3.3686-21 Sanitary and Epidemiological Requirements for the Prevention of Infectious Diseases (together with SanPiN 3.3686-21 Sanitary Rules and Norms...) (Registered with the Ministry of Justice of Russia on February 15, 2021, No. 62500).

14. Order of the Ministry of Health and Social Development of Russia No. 17n of January 18, 2012, "On Approval of the Procedure for Providing Medical Care to Adult Patients Profiled in 'Nephrology'."

15. Order of the Russian Ministry of Health No. 922n of November 15, 2012, "On Approval of the Procedure for Providing Medical Care to Adult Patients Profiled in 'Surgery'."

16. Order ofeva Ministry of Health and Social Development of Russia No. 69n of January 31, 2012 (as amended on February 21, 2020) "On Approval of the Procedure for Providing Medical Care to Adult Patients with Infectious Diseases."

17. Order of the Ministry of Health and Social Development of Russia No. 521n of May 5, 2012 (as amended on February 21, 2020) "On Approval of the Procedure for Providing Medical Care to Children with Infectious Diseases."

18. Order of the Russian Ministry of Health No. 923n of November 15, 2012, "On Approval of the Procedure for Providing Medical Care to Adult Patients Profiled in 'Internal Medicine'."

19. Order of the Russian Ministry of Health No. 491n of September 25, 2023, "On Approval of the Procedure for Conducting Forensic Medical Examinations."

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

21. Order of the Russian Ministry of Health No. 1170n of October 28, 2020, On Approval of the Procedure for Providing Medical Care Profiled in 'Transfusiology'.

22. Instructions LP-№(005229)-(RG-RU) dated 04/18/2024 for the medical use of the medicinal product Metoclopramide (5 mg/mL) solution for intravenous and intramuscular administration.

23. Instructions LP-№(004978)-(RG-RU) for the medical use of the medicinal product Atropine.

24. Instructions LP-006703 for the medical use of the medicinal product Diazepam.

25. Instructions LS-002567-121021 for the medical use of the medicinal product Valproic Acid. Solution for intravenous administration 100 mg/mL.

26. Instructions LP-№(005448)-(RG-RU) for the use of the medicinal product Omeprazole.

27. Instructions №LP-003720 for the use of the medicinal product Midazolam.

28. Instructions LP-№(001790)-(RG-RU) for the medical use of the medicinal product Phenobarbital.

29. Methodological guidelines. Sedation of patients in anesthesiology, resuscitation, and intensive care units 2023. All-Russian Public Organization "Federation of Anesthesiologists and Reanimatologists". Approved by the Presidium of the All-Russian Public Organization "Federation of Anesthesiologists and Reanimatologists" on June 21, 2023.

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 mild and 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

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

Appendix G2 POISONING SEVERITY SCORE (PSS)

Table specifications:

Russian title: Poisoning severity score

Original title: Poisoning severity score

Source: https://www.who.int/publications/m/item/poisoning-severity-score

Type: Rating scale

Purpose: for quantitative assessment of the severity of acute poisonings.

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.