Methanol and Ethylene Glycol Toxicity: Clinical Guidelines

List of Abbreviations

BE – base excess

EAPCCT – European Association of Poisons Centres and Clinical Toxicologists

LD – lethal dose

pH — indicator reflecting the concentration of hydrogen ions in a solution (blood, urine, etc.)

BP – blood pressure

ADH – alcohol dehydrogenase

ALT – alanine aminotransferase

ALDH – aldehyde dehydrogenase

AST – aspartate aminotransferase

ATP – adenosine triphosphate

aPTT – activated partial thromboplastin time

BAS — biologically active substances

HIV – human immunodeficiency virus

ANS – autonomic nervous system

WHO – World Health Organization

WEC — water-electrolyte balance

HPLC-MS – high-performance liquid chromatography with mass spectrometric detection

GGT – gamma-glutamyl transpeptidase

GGT — gamma-glutamyl transferase

HD – hemodialysis

HDF – hemodiafiltration

GLC – gas-liquid chromatography

GC-MS – gas chromatography-mass spectrometry

DNA – deoxyribonucleic acid

TV – tidal volume

GI – gastrointestinal tract

NLG – nasogastric gastric lavage

TBI – traumatic brain injury

CHD – coronary heart disease

IMV – invasive mechanical ventilation

EIA – enzyme immunoassay

IA — immunochromatographic assay

ABDS – acid-base balance status

CK – creatine kinase

LDH – lactate dehydrogenase

MAO – monoamine oxidase

ICD-10 – International Statistical Classification of Diseases and Related Health Problems 10th Revision

INR – international normalized ratio

MRI – magnetic resonance imaging

NA – noradrenaline

CVA – cerebrovascular accident

ARF – acute renal failure

AKI – acute kidney injury

ARDS – acute respiratory distress syndrome

ICU – intensive care unit

ACVI – acute cardiovascular insufficiency

BV – blood volume

PE – plasmapheresis

FPIA — fluorescence polarization immunoassay

PCR – polymerase chain reaction

RCT – randomized controlled trial

RNA – ribonucleic acid

SV – stroke volume

SCT – spiral computed tomography

THE – toxic-hypoxic encephalopathy

LCE – level of confidence of evidence

US – ultrasound examination

GRS – grade of recommendation strength

FBS — fiberoptic bronchoscopy

FD – forced diuresis

CVP – central venous pressure

CNS – central nervous system

RR – respiratory rate

TBI – traumatic brain injury

HR – heart rate

ALP – alkaline phosphatase

ECG – electrocardiography

EFGDS – esophagogastroduodenoscopy

EchoEG – echoencephalography

EEG – electroencephalography

Terms and Definitions

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.

Toxicogenic stage of poisoning – the period of the acute chemical disease starting from the moment the toxic substance enters the body at 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 effects on target organs.

Somatogenic stage of poisoning – the period of the acute chemical disease starting after the elimination or destruction of the toxic substance from the body as a trace lesion of the structure and functions of various organs and systems, typically manifested by various somatic and neuropsychiatric complications [1, 21].

Detoxification – the process of neutralization and elimination of an exogenously introduced 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 routes through the kidneys, intestines, liver, lungs, and skin. During natural detoxification, metabolites more toxic than the original 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 [19, 21].

Methanol (also known as methyl alcohol, wood alcohol) – an organic chemical and the simplest aliphatic alcohol with the formula CH3OH (a methyl group linked to a hydroxyl group, often abbreviated as MeOH). It is a light, volatile, colorless, and flammable liquid with a characteristic alcoholic odor similar to that of ethanol (drinking alcohol) [National Institute for Occupational Safety and Health (August 22, 2008). "Emergency Response Safety and Health Database: Methanol"]. Methanol was named wood alcohol because it was once produced primarily by the destructive distillation of wood. Today, methanol is produced mainly on an industrial scale by the hydrogenation of carbon monoxide [49].

Ethylene glycol (1,2-dihydroxyethane[5], 1,2-dioxyethane, ethane-1,2-diol), HO-CH2-CH2-OH – an oxygen-containing organic compound, a dihydric alcohol, and a representative of polyols (polyhydric alcohols). In purified form, it is a transparent, colorless liquid with a slightly oily consistency. It is odorless and has a sweetish taste. The substance is toxic, explosive, and fire-hazardous [57].

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Methanol and/or ethylene glycol poisoning is a disease developing as a result of the external (exogenous) exposure of the body to methanol and/or ethylene glycol, which causes physiological impairments and poses an extremely high hazard to health and life [28].

These clinical guidelines provide data on acute poisonings with methanol and ethylene glycol, including: T51.1 – methanol; T51.3 – ethylene glycol. Because the clinical presentation, diagnostic algorithms, and treatment technologies are virtually identical, it is most rational to include them in a single set of guidelines. In addition, the circumstances leading to poisoning with methanol and glycols are often similar.

It should be noted that in clinical practice, given that methanol, ethylene glycol, and ethylene glycol ethers are consumed in the vast majority of cases for the purpose of alcohol intoxication, these substances are traditionally and erroneously classified as alcohol substitutes, which is often reflected in the formulation of the diagnosis. However, the International Classification of Diseases, 10th Revision (ICD-10) does not provide subcategories for "alcohol substitute poisoning" or "counterfeit vodka poisoning" for understandable reasons. The ICD-10 poisoning section includes specific chemical substances, including alcohols, and the term "alcohol substitutes" is currently unacceptable.

It should also be noted that these types of poisonings occupy a special place among occupational hazards of a chemical nature, among which one should distinguish, on the one hand, the contamination of working area air with vapors, and on the other hand, the direct contact of workers with toxic technical liquids, organic solvents, and other aggressive and toxic chemical compounds. The most frequent cause of acute poisonings is toxic technical liquids containing alcohols and chlorinated hydrocarbons. Acute poisonings with methanol and ethylene glycol can occur in emergency situations and as a result of ingestion for the purpose of alcohol intoxication. Poisonings with these substances can be extremely severe and frequently lead to fatal outcomes [15, 27]. It should be noted that methanol and ethylene glycol are relatively of low toxicity, and all adverse effects are associated with the high toxicity of their metabolites [57].

Methanol and ethylene glycol poisonings are characterized by severe medical, social, and economic consequences (expensive treatment, prolonged disability, high rates of disability, and high mortality).

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

Methyl alcohol (methanol, carbinol, wood alcohol, CH₃OH) was first discovered in 1661 in the products of dry wood distillation. Poisonings with methanol can occur from accidental ingestion for intoxication, as well as from inhaling its vapors or skin contact. Individual human sensitivity to methanol varies. The lethal dose upon ingestion ranges from 50 to 500 mL (averaging 100 mL) [28].

1.2.1. Toxicokinetics and biotransformation of methanol

Methanol enters the human body via inhalation, oral, and transdermal routes, as evidenced by cases of occupational poisoning [34].

Poisoning predominantly occurs via ingestion of methanol. Upon entering through the gastrointestinal tract, methanol is rapidly absorbed; at doses of 71-84 mg/kg, its level reaches 4.7-7.6 mg/100 mL within 3 hours. Following inhalation exposure for 3-4 hours, methanol is detected at a concentration of 1-3 mg/100 mL. In healthy volunteers after an 8-hour inhalation of 50-300 mg/m³, maximum urinary excretion was completed within 12 hours. Lung retention averaged 58%. Upon percutaneous absorption, maximum adsorption is observed within 35 minutes, then gradually decreases. Methanol is excreted via exhaled breath up to 5-70%, and in the urine unchanged and as a glucuronide in 1-10% of cases. Formic acid, as a metabolite of methanol, is excreted in the urine in amounts of 5-9% of the administered dose [5, 15].

Methanol that is not eliminated via exhaled breath and urine in unchanged form is metabolized and distributed among organs and tissues, with the highest amounts accumulating in the liver and kidneys, and lesser amounts in muscles, fat, and the brain [5].

It has been established that a portion of the methanol that enters the body is secreted several days later by the mucous membrane into the gastric lumen and then reabsorbed. The greatest accumulation and metabolism of methanol occur in the liver. The oxidation of methanol takes place under the action of alcohol dehydrogenase (ADH), the hepatic microsomal system, and the catalase-peroxidase system [5].

It is known that a portion of the absorbed methanol is excreted unchanged in exhaled breath (1%) and urine (5%). Another portion is slowly metabolized. Furthermore, it has been established that absorbed methanol and its metabolic products are also secreted by the gastric mucosa into the gastric lumen for several days following poisoning and are subsequently reabsorbed in the intestine. Methanol metabolism occurs primarily in the liver, which possesses the highest oxidative capacity toward alcohols (up to 95%). The main products of methyl alcohol oxidation are formaldehyde and formic acid. Their action on the body is predominantly responsible for the toxicity of methanol.

During the first stage of methyl alcohol biotransformation, which occurs mainly via the alcohol dehydrogenase (ADH) system, an extremely toxic product—formaldehyde—is formed. Subsequently, some formaldehyde binds to proteins, but the major part is converted into formic acid under the influence of aldehyde dehydrogenase (ALDH). It should be noted that the oxidation of formaldehyde to formic acid proceeds very rapidly, whereas the acid metabolizes quite slowly.

The toxicity of formaldehyde via the inhalation route is due to its adsorption in the upper respiratory tract; about 70–80% is oxidized to formate ion and CO₂ and eliminated via exhaled air [15, 60].

Upon entering the bloodstream, it rapidly concentrates in tissues. The distribution among organs and tissues is uneven. The maximum level is detected in tissues with high cell division rates: hematopoietic organs, lymphoid tissue, intestinal mucosa, as well as in organs with a high rate of protein synthesis—the salivary glands and pancreas. Following oral administration, the highest amount of formaldehyde is found in the bone marrow after 12 hours [34].

It has been proven that with a blood plasma formaldehyde concentration of 1.07 ± 0.25 mg/L, 1.7 ± 0.87 mg/kg is detected in the liver [53].

Formaldehyde readily interacts with proteins, amines, amides, nucleoproteins, and nucleic acids.

Formaldehyde is a poison with a generalized toxic effect on the body. Like methanol, it damages the nervous system, respiratory tract, liver, kidneys, and organs of vision, exhibits a strong irritating effect on the mucous membranes of the respiratory tract and eyes, as well as sensitizing, carcinogenic, teratogenic, embryotoxic, and mutagenic effects [6].

In addition, methanol is a potent protoplasmic poison that disrupts oxidative phosphorylation in the cytochrome oxidase system, causing a deficiency of adenosine triphosphate (ATP), especially in the brain and retina, promotes demyelination and subsequent optic atrophy, and due to the blocking effect of methanol and formic acid on cellular respiratory enzymes, contributes to the development of metabolic acidosis [3, 33].

Intentional ingestion of formaldehyde leads to atrophy, hemorrhage, and necrosis of the gastric mucosa, hepatomegaly, and the development of jaundice [54].

Formaldehyde and methanol contribute to the development of degenerative liver damage: they cause endothelial cell proliferation and desquamation of endothelial cells, proliferation of stellate reticuloendotheliocytes, granular dystrophy, decrease glycogen content, and disrupt the distribution of acidic mucopolysaccharides [34].

Clinically, it manifests as signs of liver damage with elevated nonspecific liver function tests [3]. The development of fatal acute renal failure within 24 hours in humans is described by several authors following intentional ingestion of formaldehyde [54].

Formaldehyde has an irritant effect on the upper respiratory tract [64].

Hematotoxicity of formaldehyde is noted [64].

The effect of methanol and formaldehyde on immune mechanisms has been proven [6].

A certain role in the development of the toxic effect of methyl alcohol is played by the fact that folic acid—one of the cofactors of alcohol-oxidizing enzyme systems—plays a special role in methanol metabolism. Further metabolism of methanol to its final oxidation products (CO₂ and H₂O) is completed in the citric acid (Krebs) cycle [7, 21, 43].

1.2.2. Mechanism of the toxic action of methanol

Methanol and its metabolites are considered potent neurovascular and protoplasmic poisons that disrupt oxidative phosphorylation, thereby causing ATP deficiency, particularly in brain tissues and the retina. All this leads to a disruption of local metabolism of biologically active substances (BAS) and ultimately causes demyelination and subsequent optic atrophy. As a result of the accumulation of organic acids in the body (lactic, glucuronic, etc.), metabolic acidosis develops, which is exacerbated by the disruption of oxidative processes in the body due to the blocking effect of methanol and formic acid on cellular respiratory enzymes. At the same time, metabolic acidosis itself also blocks cellular respiration.

The disruption of oxidative processes is facilitated by vitamin deficiencies accompanying the intoxication, primarily vitamin C (ascorbic acid) and vitamin B₁ (thiamine chloride).

Ethylene glycol is a dihydric alcohol (CH₂OH-CH₂OH) included in many industrial fluids, including antifreezes used to cool internal combustion engines, as well as brake, shock absorber, and various hydraulic fluids.

In most cases, ethylene glycol (antifreeze) poisoning occurs when it is ingested for the purpose of intoxication [2].

Inhalation poisonings with ethylene glycol do not occur (due to the low volatility of the poison).

There is a wide variation in individual human sensitivity to ethylene glycol. Lethal doses range from 50 to 500 ml (average 100 ml) [40].

1.2.3. Toxicokinetics and biotransformation of ethylene glycol

Ethylene glycol is rapidly absorbed in the stomach and intestines (on average within 1 hour), enters the bloodstream, and reaches maximum concentration in the first 6 hours, while its circulation duration is 48 hours. It is excreted unchanged by the kidneys in 20–30%. Ethylene glycol undergoes quite intensive metabolism in the body, carried out predominantly in the liver by ADH. The activity of enzyme systems metabolizing alcohols has a very significant impact on the realization of the toxic properties of ethylene glycol. At the first stage of biotransformation, ethylene glycol is metabolized by ADH to glycolaldehyde.

The biotransformation products of ethylene glycol—aldehydes (glycolaldehyde, glyoxylic aldehyde) and acids (glycolic, glyoxylic, oxalic)—are much more toxic than ethylene glycol. The metabolism of ethylene glycol is an example of a toxification reaction resulting in the formation of more toxic products than the parent compounds; about 70–80% is oxidized in the liver under the action of ADH to form glycolaldehyde and organic acids (glycolic, glyoxylic, and oxalic) [16]. Subsequently, under the influence of ALDH or aldehyde oxidase, glycolaldehyde is converted into glycolic acid, which, in turn, is oxidized to glyoxylic acid with the participation of lactate dehydrogenase or hydroxy acid oxidase. A certain portion of glycolaldehyde is metabolized to glyoxal, whose transformation into glyoxylate can occur via both enzymatic (using ALDH) and non-enzymatic pathways. According to modern concepts, it is specifically glycolic and especially glyoxylic acids that are the most toxic products of ethylene glycol metabolism. These metabolites cause the development of the main toxic effects of ethylene glycol. The accumulation of organic acids, especially glycolic acid, leads to severe metabolic acidosis, which affects many cellular functions. Ethylene glycol transformation products suppress oxidative phosphorylation, cellular respiration, protein synthesis, deoxyribonucleic acid (DNA) replication, and ribonucleic acid (RNA) formation [46, 57, 65]. In turn, the metabolism of glyoxylic acid in the body proceeds through several pathways: transformation into oxalic acid under the influence of lactate dehydrogenase or aldehyde oxidase; formation of formic acid with subsequent oxidation to carbonic acid and decomposition of the latter into water and carbon dioxide; transformation into glycine via transamination with the participation of vitamin B₆ and further, upon interaction with benzoic acid, conversion into hippuric acid; conjugation to form oxalomalate, formyl-S-CoA, α-hydroxy-3-ketoadipate, and α-hydroxy-3-ketoglutarate [7].

The formation of oxalic acid during the metabolism of ethylene glycol leads to the deposition of calcium oxalate crystals in the meninges, blood vessel walls, lungs, and myocardium, resulting in secondary hypocalcemia [46, 57].

1.2.4. Mechanism of the toxic action of ethylene glycol

Ethylene glycol is considered a protoplasmic and vascular poison causing damage to the nervous system, parenchymal organs (especially the kidneys and liver), and the gastrointestinal tract.

Periods are distinguished in the development of ethylene glycol intoxication. Initially, the main manifestations of intoxication are due to the action of ethylene glycol as an intact molecule. Ethylene glycol easily penetrates the central nervous system, sorbs on cell membranes, and exerts a narcotic effect, which is characteristic of alcohols (the period of the non-specific narcotic effect of the poison on the central nervous system [CNS]). In this phase, ethylene glycol acts as a neurovascular poison, damaging primarily the cerebral vessels.

The second period consists of morphological destructive changes in internal organs (renal and hepatorenal phase). This period is associated with the metabolism products of ethylene glycol (glycolic, glyoxylic, and oxalic acids).

All the specified substances, except ethylene glycol itself, are capable of inhibiting mitochondrial electron transport, uncoupling oxidation and phosphorylation, and suppressing protein synthesis. The suppression of tissue respiration by biotransformation products is further exacerbated by the metabolic acidosis that develops due to the accumulation of under-oxidized products.

Glyoxylic acid is a potent agent that uncouples oxidation and phosphorylation. At the same time, a number of authors, while not denying the extremely high toxicity of glyoxylate, believe that in ethylene glycol poisoning, the main carrier of toxicity is glycolic acid, which accumulates in the body in concentrations exceeding the level of glyoxylate by 1300–1400 times.

Oxalic acid also plays a certain role in the development of the toxic effect, although it is a minor metabolite of ethylene glycol (from 0.5 to 10% of all biotransformation products).

Oxalic acid in blood plasma precipitates calcium ions in the form of water-insoluble calcium oxalate salt (oxalates). A decrease in calcium content in the blood and tissue fluid can lead to weakened cardiac contractions, hypotension, motor disorders, and even the development of seizures (tetany syndrome).

In the second period, toxic nephropathy manifests early. The basis of toxic nephropathy in ethylene glycol intoxication is hydropic degeneration of the tubular epithelium, leading to the development of glycol excretory nephrosis. In mild intoxications, this process is reversible; in more severe cases, bilateral renal cortical necrosis develops. Toxic nephropathy is also aggravated by a mechanical factor—the tubules and renal pelves become blocked with oxalates, which act both locally and reflexively, leading to impaired renal blood flow and filtration processes in the kidneys. Similar processes in severe ethylene glycol poisonings can also lead to the development of toxic hepatopathy [7, 12, 21].

1.3 Epidemiology of the Disease or Condition

According to the state report «On the State of Sanitary and Epidemiological Welfare of the Population in the Russian Federation in 2021», 470,358 cases of acute poisoning by alcohol-containing products were registered in the Russian Federation between 2012 and 2021, 124,813 of which were fatal (26.5%). The incidence rate of acute poisoning by alcohol-containing products in 2021 was 21.19 cases per 100,000 population.

The main alcohol-containing substances that caused acute poisonings for the period from 2012 to 2021 include: ethanol (77.4%), unspecified alcohol (16.7%), other alcohols (3.3%), methanol (2.2%), 2-propanol (0.3%), and fusel oil (0.1%). Fatal poisonings during the specified period were caused by: ethanol (85.6%), methanol (6.9%), unspecified alcohol (5.4%), other alcohols (1.3%), 2-propanol (0.7%), and fusel oil (0.2%) [26].

Given the general stable trend of alcohol abuse in Russia, the population's propensity to use various falsified alcoholic beverages for intoxication purposes (in addition to ethyl alcohol-based products) containing various alcohols and solvents as impurities, as well as the more toxic methyl alcohol, there is a constant potential probability of mass or group poisonings by various alcohols and solvents, as well as other highly toxic substances that are part of alcohol-containing liquids not intended for internal consumption. Examples include recent cases of mass methanol poisoning that occurred in the Moscow and Kemerovo Oblasts and Krasnoyarsk Krai as a result of consuming cheap drinks purchased via the Internet, such as Bacardi rum, whiskey, Kizlyar cognac, etc. They were accompanied by a significant number of fatalities; for example, in Krasnoyarsk Krai, out of 48 poisoned individuals, 14 died, and in Kemerovo Oblast, out of 30, 13 died. In recent years, cases of accidental ingestion of a few sips of counterfeit windshield washer fluid containing methanol, the illegal sale of which is widespread in the winter, have become relevant. At the same time, the packaging indicates that the liquid does not contain methyl alcohol. In December 2016, a high-profile case of mass methanol poisoning was noted in Irkutsk Oblast as a result of consuming the «Boyaryshnik» bath concentrate. In the case of mass methyl alcohol poisoning in the city of Irkutsk, 77 deaths were registered; this is the total number of individuals whose death occurred at home, as well as those who received medical care and died in medical institutions. According to the autopsy department of the State Budgetary Healthcare Institution «Irkutsk Regional Bureau of Forensic Medical Examination», the proportion of deaths from acute methyl alcohol poisoning in 2016 was 2.01% of all deaths from various causes, and 34.53% of all deaths resulting from acute poisonings of chemical etiology in 2016 [8].

Ethylene glycol, which has an aromatic odor and a sweetish taste, can also cause poisoning, including mass poisoning. An internationally famous case was the mass poisoning with diethylene glycol, which was mistakenly included in children's paracetamol syrup in Haiti in 1996. At that time, children were affected, and 88 of them died from renal failure [18, 21].

Using Saint Petersburg as an example, according to the reports of the Toxicology Center of Saint Petersburg (Form No. 64), patients with this pathology accounted for 10 admissions with acute methanol poisoning (of whom 3 patients died) and 1 patient with acute glycol poisoning in 2019; 11 patients with acute methanol poisoning (3 died) and 1 patient with ethylene glycol poisoning in 2020; in 2021, out of 15 admissions with acute methanol poisoning, 12 patients died, and out of 2 patients, 1 patient died from glycol poisoning. In 2022, out of 10 admissions with acute methanol poisoning, 7 patients died, and out of 2 patients with acute glycol poisoning, 1 patient died.

It should be noted that almost all admitted patients with acute methanol or ethylene glycol poisonings were in critical condition with severe impairments of vital organs in the form of acute respiratory and acute cardiovascular failure [29, 30, 31, 32].

1.4 Features of Coding the Disease or Condition

The diagnosis is coded using the International Classification of Diseases, 10th Revision. The ICD-10 version adapted for Russia uses 7 characters, which allow for the formalization of the diagnosis of the disorder detected in the patient.

T51.1 – Toxic effect of methanol.

T52.3 – Toxic effect of glycols.

1.5 Classification of the disease or condition

1.5.1. Acute methanol poisoning

In acute methanol poisoning, the severity is classified into mild (general disorder syndrome, toxic gastritis), moderate (ophthalmic), and severe (generalized) forms [39]. In mild poisoning, during the period of pronounced clinical manifestations, the following are observed: dizziness, headache, abdominal pain, nausea, vomiting, and visual disturbances (blurred vision, dark spots before the eyes, flashing floaters) [39]. Objective examination reveals moderate pupillary dilation and sluggish photoreaction [28]. The fundus oculi retains a normal appearance [13]. The duration of disorders most often does not exceed 3–5 days. In some cases, patients develop prolonged narcotic sleep, after which only mild malaise is noted [11]. This degree of poisoning usually ends in recovery with complete restoration of vision [11, 13, 39]. Moderate poisoning is characterized by progressively worsening severe visual impairment, up to complete blindness with optic nerve atrophy. Cases have been described where patients who consumed methanol woke up blind the next day, but by days 3–4, vision was restored to normal. However, in such cases, vision improvement is not always lasting, and repeated vision deterioration and blindness are possible over the subsequent days. Examination of the fundus reveals hyperemia and blurred margins of the optic disc, dilated veins, and hemorrhages [28, 39]. In severe poisoning, the latent period is short or absent, and clinical symptoms rapidly appear: nausea, vomiting, weakness, pain in the epigastrium, lower back, and calf muscles, mydriasis, and rapid visual impairment. The patient loses consciousness, respiration is rapidly impaired, cyanosis increases, and cardiovascular failure progresses up to exotoxic shock. In individual cases, the development of marked agitation and clonic seizures is possible [13, 28]. With an unfavorable course, on days 1–2, death occurs due to central respiratory and circulatory disorders [28, 59]. With a favorable course, visual impairments persist due to irreversible optic nerve atrophy. Subsequently, continued asthenization is possible, often combined with signs of organic brain damage. Complications frequently join: pneumonia, myocardial dystrophy, and manifestations of moderately severe hepatic and renal failure [13, 28].

Thus, according to the severity of poisoning, mild, moderate (ophthalmic in methanol poisoning), and severe (generalized) forms are distinguished.

1.5.2. Acute ethylene glycol poisoning

According to the severity, acute ethylene glycol poisoning is divided into mild, moderate, and severe degrees.

In mild ethylene glycol poisoning, a state of mild intoxication and a latent period lasting 8–12 hours or more are noted. Subsequently, the clinical picture is limited to general symptoms of intoxication: headache, nausea, vomiting, moderate abdominal pain, thirst, and general weakness. Pronounced disorders of renal function do not occur. Short-term toxic nephropathy is possible, characterized by mild changes in the urine.

In moderate poisonings, intoxication is more pronounced, and the latent period is shorter (6–8 hours). There are more distinct symptoms of toxic damage to the brain and internal organs. Subsequently, toxic nephropathy develops, with short-term oliguria, possibly with a slight increase in blood residual nitrogen, but without clinically pronounced signs of uremia.

In severe poisonings, the latent period is shortened to 1–5 hours. Signs of intoxication are observed during this time. Later, sleep, sopor, and coma ("brain" phase) set in. If death does not occur (days 1–2), the intoxication transitions to the next—renal phase. Severe toxic nephropathy, acute renal failure, and uremia develop. Sometimes the "brain" phase is poorly expressed or absent, and from the end of the first day after poisoning, the disease manifests as progressive severe acute renal failure [7, 41, 55].

1.6 Clinical presentation of the disease or condition

The rapid development of symptoms and complications makes acute methanol and ethylene glycol poisoning one of the most severe diseases of chemical etiology. Signs of acute poisoning occur immediately after ingestion; the severity of clinical manifestations and poisoning depends on the dose (concentration) of the ingested substance, its exposure time, age, and concomitant pathology.

1.6.1 Clinical presentation of acute methanol poisoning

Methyl alcohol poisonings are characterized by a biphasic development of the pathological process. Thus, at the first stage, the leading effect is the narcotic effect associated with the action of the parent substance, which can lead to toxic coma with respiratory and cardiac arrest. However, compared to other alcohols, methanol causes less pronounced central nervous system depression, even despite its high concentrations in biological fluids. At the second stage, changes in parenchymal organs and intermediary metabolism, caused by methanol toxification products, prevail [28].

The clinical course of methanol poisoning includes 4 periods: initial, latent (period of apparent well-being), period of pronounced clinical manifestations, and period of sequelae [28]. Immediately after methanol ingestion, a state similar to alcohol intoxication develops, whose distinguishing feature is that it is less pronounced than after ingestion of equivalent doses of ethanol. If intoxication is caused by methanol alone, it generally does not reach the narcotic phase. Already in this period, patients may note malaise, general weakness, dizziness, headache, and nausea. The state of intoxication may be replaced by heavy sleep, the duration of which is directly proportional to the dose of the poison. The initial period, based on the narcotic effect of methanol on the central nervous system, resembles ordinary alcohol intoxication [14]. Characteristically, the degree of intoxication is usually less than what would be expected from ingesting equivalent doses of ethyl alcohol. The duration of this period can range from 1–2 to 12 hours or more [35]. Following intoxication, a latent period ensues, proceeding without pronounced clinical manifestations. Its duration is individual and varies from 6 to 44 hours [28, 35]. The period of pronounced clinical manifestations begins with the appearance of symptoms of toxic gastritis (nausea, vomiting, epigastric pain, abdominal wall muscle tension). A characteristic manifestation of intoxication during this period is the appearance and gradual increase of toxic ophthalmopathy phenomena: flashing floaters before the eyes, double vision, blurred vision, sluggish or absent reaction to light, and in severe cases, the development of blindness. Against this background, in severe intoxications, acute cardiovascular and respiratory failure rapidly progresses. At later stages, phenomena of toxic hepatopathy, nephropathy, and myocardial dystrophy come to the forefront in the clinical picture of intoxication. Symptoms of general intoxication develop: malaise, headache, dizziness, and muscle weakness. Symptoms of toxic encephalopathy appear and increase, accompanied by psychomotor agitation, stupor, and confusion, up to a comatose state. Among metabolic disorders, decompensated metabolic acidosis is predominant. At later stages, complications involving the liver, kidneys, and heart appear [28, 35, 66].

1.6.2. Clinical presentation of acute ethylene glycol poisoning

The clinical course exhibits the following periods:

I – initial or intoxication period, with agitation and euphoria;

II – latent period or period of apparent well-being, lasting from 1 to 12 hours, sometimes longer;

III – period of pronounced manifestations of intoxication:

a) phase of predominantly cerebral disorders;

b) phase of kidney and liver damage (hepatorenal phase).

IV – recovery period.

Clinical manifestations of ethylene glycol poisoning are characterized by the development of three stages: the first is central nervous system depression (narcotic phase), the second is toxic damage to the heart and lungs, and the third is toxic damage to the kidneys and liver [4, 17, 46, 48, 57].

The clinical picture of acute ethylene glycol poisonings features the following syndromes: toxic encephalopathy, gastrointestinal syndrome, acute cardiovascular failure syndrome (primary toxicogenic collapse, exotoxic shock, secondary somatogenic collapse, hemodynamic disorders against the background of acute renal failure), acute renal failure syndrome, and acute liver failure syndrome.

The initial period resembles alcohol intoxication, the degree of which depends on the dose of the ingested poison. During this period, the administration of antidotes and methods for the accelerated removal of the poison from the body are most beneficial.

The duration of the latent period also depends on the dose of the poison. The more severe the poisoning, the shorter the latent period. During this period, the poisoned individual may feel healthy, and sleep frequently ensues.

Following the latent period, the main symptoms of intoxication develop. On days 1–2, they are primarily caused by brain damage. Patients experience general weakness, dizziness, unsteady gait, headache, impaired motor coordination, nausea, frequent vomiting, severe pain in the abdomen and lumbar region, which often leads to such patients frequently undergoing surgery with suspected acute surgical abdominal pathology. Subsequently, depression, somnolent stupor, loss of consciousness, cardiac and respiratory disorders, and involuntary urination and defecation occur. The patient's face is hyperemic and bloated; breathing is irregular, sometimes deep and noisy (Kussmaul breathing); the pulse is initially frequent, then slow, of satisfactory or weak volume. Blood pressure drops. In some comatose patients, nuchal rigidity, pathological Babinski reflexes, and a sharp decrease in abdominal and cremasteric reflexes are observed. In severe poisonings, an elevated hematocrit (hemoconcentration) is frequently noted.

If the patient survives, their condition improves briefly and then deteriorates again between days 2 and 5 due to the transition into the hepatorenal phase with impaired renal and hepatic function. Headache, general weakness, loss of appetite, nausea, vomiting, abdominal and lumbar pain reappear or worsen; blood pressure rises. The liver enlarges. Diuresis decreases down to anuria. Urine has a low specific gravity, contains protein, and the sediment contains hyaline and granular casts, erythrocytes, and oxalates. Acute kidney injury and azotemic uremia develop. Patient death occurs mainly on days 5–15.

However, the stages and symptoms in a specific patient may not have a clear demarcation and may overlap. Central nervous system depression develops within 30 minutes to 12 hours from the moment of ethylene glycol ingestion. Ethylene glycol easily penetrates the central nervous system, sorbs onto cell membranes, and exerts a narcotic effect. Within the first 30 minutes, a state similar to alcohol intoxication occurs: euphoria, agitation, ataxia, dysarthria; then symptoms of general intoxication develop: headache, weakness, dizziness, as well as nausea, vomiting, epigastric pain, and intestinal cramping associated with the direct irritant effect of ethylene glycol. In this stage, ethylene glycol acts as a neurovascular poison, primarily damaging the cerebral blood vessels. After 4–12 hours, as ethylene glycol metabolites form and metabolic acidosis progresses, CNS depression may manifest as seizures, cerebral edema, and coma. In the second stage, clinical manifestations are caused by the biotransformation products of ethylene glycol, with cardiorespiratory poisoning symptoms typically appearing 12–24 hours after ethylene glycol ingestion. Tachypnea, tachycardia, and Kussmaul breathing are compensatory in nature due to the developed severe metabolic acidosis and hypoxia. The development of pulmonary edema, acute respiratory distress syndrome, pneumonitis, heart failure, and shock is characteristic. Severe metabolic acidosis and electrolyte imbalance lead to arrhythmias, up to cardiac arrest. Most fatalities occur in the second phase. Autopsy of patients reveals pulmonary edema with hemorrhagic exudate, bronchopneumonia (possibly aspirational), calcium oxalate deposits in the lung parenchyma, myocardium, blood vessel walls, and meninges [25]. The third stage develops 24–72 hours after the oral ingestion of ethylene glycol and is characterized by kidney and liver damage. Ethylene glycol metabolites sharply increase the osmotic pressure of the intracellular fluid in hepatocytes and renal epithelial cells, which is accompanied by the development of hydropic (ballooning) degeneration.

Thus, acute hepatorenal failure develops, the morphological basis of which is ballooning degeneration of hepatocytes in the center of the hepatic lobules and renal tubular epithelium, culminating in colliquative necrosis [17, 26]. Symptoms developing in patients include pain in the lumbar region and abdomen, a positive Pasternatsky sign, and acute kidney injury (AKI). Calcium oxalate microcrystal deposits lead to cranial nerve damage, which develops on days 6–18, manifests as facial muscle paralysis, hearing loss, and vision loss; cases of dysarthria and dysphagia have also been described [46, 57]. Complete functional recovery may occur within a year. Some researchers suggest considering cranial nerve damage as the fourth stage of ethylene glycol poisoning, while others regard cranial nerve dysfunction as evidence of chronic ethylene glycol intoxication [57]. Ethylene glycol poisoning is accompanied by significant changes in bone marrow hematopoiesis [40]. Laboratory tests show hypocalcemia, crystalluria, high anion gap metabolic acidosis caused by the formation of glycolic acid [46, 47, 57]. Calcium oxalate crystals may appear in the urine as early as the first phase, but their absence does not rule out ethylene glycol poisoning. The "gold standard" for diagnosis is the determination of glycols (ethylene glycol) and their ethers in blood and urine using gas chromatography [4, 47, 57].

Recovery is slow. Following the polyuric stage, which develops after anuria, renal function recovers after several months. A so-called recovery with defects is also possible, where a varying degree of renal and hepatic impairment persists.

2. Diagnostics, medical indications and contraindications for diagnostic methods

The diagnosis of methanol and ethylene glycol poisoning is based on anamnestic data and, primarily, on characteristic symptoms: the presence of gastrointestinal syndrome, visual impairment, respiratory disorders, and impaired consciousness, as well as chemical and toxicological testing data [1, 28, 36].

2.1 Complaints and Anamnesis

The diagnosis of acute poisoning is carried out comprehensively, taking into account the leading syndromes and symptoms observed in the patient.

• All patients with acute poisoning by toxicizable alcohols require emergency medical care outside a medical organization by an ambulance team, including either an examination by an emergency physician (specialist physician) during the provision of emergency medical care, or an examination by an emergency paramedic (mid-level medical specialist) during the provision of emergency medical care. These medical workers perform a detailed medical history collection from patients suspected of consuming toxicizable alcohols. Poisoning diagnosis must be carried out based on the toxicological situation (discovery of containers, packaging from the consumed liquid, etc.), toxicological history aimed at identifying information about the consumption of other chemicals, ethanol, dependence on certain substances, as well as the clinical picture of the poisoning [25, 28].

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

Comment. The emergency ambulance team has a greater opportunity to directly familiarize themselves at the scene with the circumstances of the poisoning and the initial clinical manifestations, and to obtain necessary information not only from the victim, but also from people around them, including those who called the ambulance.

When taking the medical history, it is necessary to identify the nature of the toxic agent, dose, exposure, route of entry into the body, and the cause of the poisoning. All this, combined with the patient's complaints and physical examination data, will help establish an accurate or presumptive diagnosis, anticipate the expected clinical picture and severity of the poisoning, and determine treatment tactics.

When taking the medical history (if feasible), attention should be paid to what alcohol-containing liquid the patient ingested (windshield washer fluid, antifreeze, etc.), where the alcohol products were purchased, for what purpose the substance was taken (intoxication, suicide attempt), the time elapsed since ingestion, and whether ethanol was ingested.

If the patient complains of visual disturbances after ingesting an alcohol-containing liquid, potential methanol poisoning should be suspected (however, visual disturbances also occur in other conditions accompanied by the development of decompensated metabolic acidosis).

During the period of pronounced clinical manifestations, the collection of complaints and medical history is generally difficult due to the severity of the condition (depressed consciousness) [25, 28].

• Upon admission to the hospital, all patients with acute poisoning by toxicizable alcohols require an initial consultation (examination) by a toxicologist and/or an initial consultation (examination) by an anesthesiologist-resuscitator [1, 45, 50].

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

Comment. In cases of methanol and ethylene glycol poisoning, the general principles of taking a toxicological history are far from always applicable. This applies to determining such information as: the type or name of the toxic substance ingested by the victim; the time of ingestion of the toxic substance (the duration of the poison's exposure in the body), which makes it possible to assume with a certain degree of accuracy which phase of poisoning (toxicogenic or somatogenic) the patient is in; the dose of the toxic substance ingested, which determines the likelihood and severity of the poisoning; the route of administration of the toxic substance into the body; and clarifying the circumstances accompanying the development of the poisoning (accidental or intentional).

A specific feature of methanol and ethylene glycol poisonings is the absence of subjective complaints from the patient in the majority of cases—medical assistance is typically sought by relatives or acquaintances who have noticed impairments in the patient's consciousness, behavior, or appearance.

2.2 Physical Examination

• Examination of the patient's external appearance [1, 45, 28];

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

• Assessment of neurological status [1, 45, 28];

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

• Assessment of psychoneurological status: level of consciousness (clear, obtundation, stupor, coma). In the event of a coma, assess its depth using the Glasgow Coma Scale (Appendix G1), the presence or absence of reflexes, pupil width and light reaction, presence (absence) of anisocoria, and muscle tone [1, 42, 45];

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

• Assessment of the respiratory system. Specifically, the rate, depth, and symmetry of chest movement during breathing, and evaluation of lung auscultation findings [21, 45, 28];

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

• The development of decompensated metabolic acidosis is characterized by rapid, deep, and "noisy" breathing (Kussmaul breathing) [1, 28];

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

• Assessment of the cardiovascular system: pulse examination, auscultation in heart pathology, heart rate measurement, cardiac rhythm assessment, and blood pressure measurement [21, 28];

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

• To identify or rule out traumatic injuries, it is recommended to check for the presence or absence of injuries, particularly in the facial, cranial, abdominal, and lumbar regions, to confirm or exclude traumatic pathology [1, 28].

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

2.3 Laboratory Diagnostics

When providing medical care in inpatient settings:

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

Comments: The choice of method for determining ethanol, methanol, and ethylene glycol levels in blood and urine depends primarily on the availability of hardware in the chemical-toxicological/clinical diagnostic laboratory:

1. gas chromatograph with a flame ionization detector [23, 24, 38];

2. gas chromatograph with a thermal conductivity detector [22];

3. gas chromatograph with a mass spectrometric detector [38].

Information obtained from chemical-toxicological testing (along with history, clinical presentation, and laboratory and instrumental test results) will determine the strategy for antidote therapy and extracorporeal detoxification.

Assessment of blood ethanol levels will determine the indications for antidote therapy. If necessary, tests are repeated dynamically to identify the need to continue or discontinue antidote and extracorporeal therapy [7, 36, 37].

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

Comments: The test is performed for differential diagnosis against poisoning by other alcohols, and is also a requirement of Order No. 203n of the Ministry of Health of the Russian Federation dated May 10, 2017, "On Approval of Criteria for Assessing the Quality of Medical Care" [36, 39].

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

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: Patients with severe acute poisoning by toxic alcohols frequently develop water-electrolyte balance (WEB) and acid-base balance (ABB) disorders. These manifest as severe disturbances, most commonly presenting as decompensated mixed respiratory and metabolic acidosis, as well as hyperkalemia.

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: individuals who abuse toxic alcohols belong to a high-risk group for infection. Serological testing is performed:

• Determination of hepatitis B virus surface antigen (HBsAg) in blood;

• Determination of hepatitis B virus e antigen (HBeAg) in blood;

• Determination of hepatitis B virus core antibody (HB-core Ag) in blood;

• Qualitative determination of antibodies to hepatitis B virus surface antigen (anti-HBs) in blood;

• Qualitative and quantitative determination of hepatitis B virus DNA in blood by PCR;

• Determination of total class M and G antibodies (anti-HCV IgM and anti-HCV IgG) to hepatitis C virus in blood;

• Determination of hepatitis C virus Core antigen in blood;

• Qualitative determination of hepatitis C virus RNA in blood by PCR;

• Testing for class M and G antibodies (IgM, IgG) to human immunodeficiency virus HIV-1/2 and antigen p24 (Human immunodeficiency virus HIV 1,2/+Ag p24) in blood;

• Qualitative determination of human immunodeficiency virus RNA by PCR.

2.4 Instrumental Diagnostics

Instrumental diagnostic methods are an integral part of the diagnostic process and are implemented to monitor the patient's condition.

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

Comments: Diagnosis of rhythm disorders and detection of signs of myocardial ischemia and injury [28, 36].

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: Radiological imaging studies allow for differential diagnosis in patients with altered mental status in order to identify brain lesions of another etiology (traumatic brain injury (TBI), acute cerebrovascular accident (ACVA)), as well as brain lesions associated with the toxic process in the setting of metabolic acidosis (cerebral edema).

In the absence of technical capability to perform SCT, in accordance with Order of the Russian Ministry of Health No. 203n dated May 10, 2017, "On Approval of Criteria for Assessing the Quality of Medical Care", it is recommended to perform two-view skull radiography [27, 36].

2.5 Other Procedures

Differential diagnosis should be performed with other conditions accompanied by impaired consciousness: TBI, ACVA, poisoning with ethanol and other alcohols, poisoning with drugs of abuse and psychodysleptics (hallucinogens), poisoning with other psycholeptics and psychoanaleptics, carbohydrate metabolism disorders (diabetic ketoacidosis), and infectious and inflammatory diseases of the central nervous system.

When providing medical care in inpatient settings:

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.

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

3.1. Provision of emergency medical care outside a medical facility

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

Comments: Treatment for all patients should begin with the restoration of adequate pulmonary ventilation depending on the type of respiratory disorder:

In cases of aspiration-obstructive respiratory disorders, it is necessary to perform oral cavity toilet, aspiration of upper airway contents, and secure upper airway patency, including the use of airways, laryngeal tubes, combitubes, laryngeal masks, and endotracheal intubation via direct laryngoscopy. If acute respiratory failure develops, initiate mechanical ventilation using various types of mechanical ventilators and manual resuscitation bags. In cases of hemodynamic disorders, as well as for detoxification therapy, intravenous infusion of solutions affecting water-electrolyte balance and dextrose solutions is indicated. Therefore, establishing venous access is critical during the provision of emergency medical care [25, 28, 41].

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

Comments: Gastric lavage should be performed starting from the emergency medical care stage as early as possible after toxicant ingestion, as well as in the event of coma and when a large dose of toxicant is suspected.

Given that alcohols are rapidly absorbed from the gastrointestinal tract (GIT), the efficacy of this procedure after several hours is questionable.

GI decontamination via gastric lavage is unlikely to be effective since methanol and ethylene glycol are rapidly and completely absorbed, and the majority of patients do not seek medical attention until clinical signs of poisoning appear.

Performing gastric lavage is a requirement of Order of the Russian Ministry of Health No. 203n dated May 10, 2017, "On Approval of Criteria for Assessing the Quality of Medical Care" [21, 25, 28, 36, 41].

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

Comment: Activated charcoal practically does not adsorb or has very poor adsorption capacity for alcohols, particularly methanol, and is therefore not used [21, 28, 50].

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

3.2. Provision of specialized medical care

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

Comment: The antidote for methanol and ethylene glycol poisoning is #ethanol**.

Indications for use:

• confirmed blood toxicant level above 0.2 g/L;

• metabolic acidosis with an increased anion gap, even if the poison level is below 0.2 g/L;

• presence of clinical manifestations and anamnesis indicating the ingestion of methanol or ethylene glycol.

Administration of #ethanol** should be continued until the levels of methanol and ethylene glycol drop below 0.1 g/L, formic acid derivatives drop below 0.012 g/L (for methanol), glycolic acid concentration (for ethylene glycol) drops below 0.015 g/L, metabolic acidosis and CNS symptoms resolve, and the normal anion gap is restored.

During antidote therapy, the blood concentration of #ethanol** must be maintained at 1–2 g/L. If blood ethanol monitoring is impossible, its administration in patients with methanol poisoning should be continued for at least 3–5 days, provided that hemodialysis is not performed.

In cases where hemodialysis is performed, #ethanol** therapy is usually limited to the first 24 hours.

It should be noted that the only pharmaceutical dosage form of #ethanol** available is 70% ethyl alcohol for external use.

The high affinity of #ethanol** for ADH, as well as its relatively low intrinsic toxicity, justifies its use in poisonings with toxifying alcohols, the toxicity of which is primarily determined by their biotransformation products.

It is believed that the affinity of ADH for ethanol is significantly higher than for other alcohols. This ensures the preferential metabolism of #ethanol** and inhibits the biotransformation of methanol and ethylene glycol. Since the interaction of toxicants and ethyl alcohol with ADH is competitive, it is very important to maintain a constant presence of #ethanol** in biological fluids at a level of at least 1 g/L.

#Ethanol** can be administered orally or intravenously in the form of 5%, 10%, 20%, 40% and 5%, 10% solutions, respectively. Oral administration (or via a nasogastric tube) is technically simpler and safer.

Due to the fact that #ethanol** is eliminated more intensively during hemodialysis than other alcohols (except methyl alcohol), its administration doses must be increased.

Table 1 – Simplified dosing regimen for #ethanol** (adults) [45]

Due to the high individual variability in #ethanol** metabolism, its serum concentration should be monitored every 1–2 hours, whenever possible.

The administration of #ethanol** should be performed when providing medical care in an inpatient setting. Initiating #ethanol** administration at the pre-hospital stage of emergency medical care is impractical, as it is impossible to accurately diagnose methanol, ethylene glycol, or ether poisoning and, accordingly, determine the indications for administering this antidote.

There are insufficient data in the literature regarding the use of #ethanol** in pediatric practice due to rare cases of poisoning in children. There are isolated reports of parenteral #ethanol** administration with a positive effect in 3-year-old children at a dosage of 0.3 g/kg/hour [1, 7, 10, 16, 18, 21, 25, 28, 41, 45].

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

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

Comment: The approach to infusion therapy must be individualized. The volume and composition of the infusion program depend on age, patient condition, presence of comorbidities, and complications. In methanol poisoning, and especially in ethylene glycol poisoning, there is a high risk of acute kidney injury; therefore, infusion therapy must be carried out under strict vollemic control to avoid hyperhydration [1, 10, 45].

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

Comment: Indications for administration include infusion detoxification therapy in acute poisoning and forced diuresis. Adults are prescribed a 1.5% solution of 400 ml 2 times a day as part of infusion therapy (children 200 ml). The treatment is administered in courses of 3–6–10 days. Contraindications are: hyperkalemia, hypernatremia, acute kidney injury, allergic reaction to the drug [1].

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

Comments: Most clinical toxicologists recommend aggressive treatment of metabolic acidosis via sodium bicarbonate** administration, despite the lack of prospective studies.

In the acute period of poisoning, primary attention should be paid to its elimination, since acidosis poses the main threat to the patient's life. During the first 24 hours of intoxication, up to 1.5–3.0 liters of acid-base balance-correcting solutions can be administered. The degree of visual impairment also largely depends on how quickly and to what extent acidosis is corrected. [21, 28, 41, 45, 50].

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

Comments: Forced diuresis is a generally accepted accelerated detoxification method.

The use of forced diuresis is determined by the fact that virtually all alcohols and their metabolites are predominantly excreted from the body in the urine. Acidic biotransformation products of alcohols are excreted more intensively when urine pH is increased; therefore, combining forced diuresis with alkalinization is recommended.

However, infusion therapy should be performed with caution, considering the risk of acute kidney injury. [18, 28].

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

Comments: The basis for using dialysis methods is the high dialyzability of both parent compounds and their metabolites. Essentially, hemodialysis is the primary method of emergency detoxification in these poisonings.

Hemodialysis provides a methanol and ethylene glycol clearance ranging from 80 to 150 ml/min (at a blood flow through the dialyzer of 200 ml/min), and when the perfusion rate is increased to 500 ml/min, it rises to 200–250 ml/min.

In poisonings with toxicifying alcohols, early hemodialysis within the first 6–12 hours is indicated.

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

LCE – 5 GLE – C.

Comment. Extracorporeal detoxification methods are indicated if any of the following conditions are present:

• history of ingestion of a dose capable of causing severe poisoning (when chemical-toxicological analysis is unavailable);

• coma;

• seizures;

• onset of visual impairment;

• blood pH ≤ 7.15;

• persistent metabolic acidosis despite adequate intensive care and antidotes;

• anion gap above 24 mmol/l, calculated from serum concentrations [Na⁺] - [Cl^-] - [HCO₃^-];

• serum toxicant concentration above 0.5 g/l;

• presence of renal dysfunction.

Extracorporeal detoxification methods may be discontinued when the methanol concentration is < 0.1 g/l, metabolic acidosis is corrected, and clinical improvement is observed [1, 14, 18, 20, 21, 28, 41, 44, 45, 50, 63].

LCE – 5 GLE – C.

Comments: The use of #folic acid** in methanol poisoning is based on the theory that endogenous formate metabolism is folate-dependent; thus, metabolizing enzymes become saturated.

A positive effect of folate supplementation has been demonstrated experimentally (in animals), but clinical studies have failed to confirm improved treatment outcomes.

To accelerate the utilization of single-carbon metabolites of methanol, #folic acid** is administered to adults at 50 mg every 4 hours, and to children at 1 mg/kg during the first 24 hours [10, 45].

In ethylene glycol poisoning, to accelerate the conversion of glyoxylate to glycine, #pyridoxine** is used in adults at a dosage of 50 mg intravenously every 6 hours until acidosis resolves (there are no data on the use of #pyridoxine** in children with ethylene glycol poisoning); #thiamine** (adults intramuscularly once at 100 mg/day, children intramuscularly once at 50 mg/day) [1, 10, 28, 45].

LCE – 5 GLE – C.

Comment: for hypocalcemia, calcium chloride** is prescribed for adults at 10% – 10 ml (for children 0.3 mg/kg) or #calcium gluconate** for adults at 10% – 20 ml (for children 0.2–0.3 mg/kg) intravenously slowly. The frequency of administration is determined based on the patient's condition and plasma calcium level [1, 41, 45].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

In uncomplicated poisoning, rehabilitation is not required.

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

5. Prevention and Dispensary Observation

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

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

6. Organization of Medical Care

6.1. Indications for hospitalization

All patients with acute methanol and ethylene glycol poisoning should ideally be hospitalized in a specialized acute poison control center. In the absence of an acute poison control center, patients with severe poisoning and complications, especially with impaired vital functions, should be hospitalized in an intensive care unit or an emergency department intensive care unit equipped for hemodialysis, followed by transfer to an acute poison control center or, once stabilized, to a specialized department.

The duration of hospitalization is determined by the severity of the poisoning. Treatment of patients is carried out in the acute poisoning unit in mild cases and averages up to 5 days; in moderate and severe poisonings, the patient is admitted to the intensive care unit until detoxification measures are completed and their condition stabilizes. The length of stay in the intensive care unit for severe uncomplicated cases is 3-5 days; for cases complicated by pneumonia, renal-hepatic insufficiency, or toxic-hypoxic encephalopathy, it is up to 10 days or more, followed by rehabilitation in the acute poisoning unit for up to 14 days or more.

6.2. Indications for patient discharge from the hospital

Treatment in the intensive care unit is continued until vital functions are stabilized and detoxification measures are completed, followed by rehabilitation in an acute poison control center or department, or other specialized departments.

7. Additional Information

It is crucial to monitor the behavior of patients presenting with mental disorders such as toxic encephalopathy or delirium tremens. Although predicting the exact frequency of these services in advance is difficult, data from toxicology center reports indicate that these disorders occur regularly.

Criteria for Evaluating the Quality of Medical Care

Criteria for assessing the quality of inpatient medical care

References

Appendix A1. Working Group Composition

1. Balabanova Olga Leonidovna – Candidate of Medical Sciences, Senior Researcher at the Department of Clinical Toxicology, Dzhanelidze St. Petersburg Research Institute of Emergency Medicine.

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

3. Oleg A. Kuznetsov – Candidate of Medical Sciences, Researcher at the Department of Clinical Toxicology, Saint Petersburg Research Institute of Emergency Medicine named after I.I. Джанелидзе.

4. Semyon V. Kuznetsov – Candidate of Medical Sciences, Associate Professor, Senior Researcher at the Department of Clinical Toxicology, Saint Petersburg Research Institute of Emergency Medicine named after I.I. Dzhanelidze; Leading Researcher at the Scientific and Clinical Center for Toxicology named after S.N. Golikov of the FMBA of Russia.

5. Aleksey N. Lodyagin – Doctor of Medical Sciences, Chief Freelance Specialist Toxicologist of the Northwestern Federal District, Chief Freelance Specialist Toxicologist of the St. Petersburg Health Committee, Head of the Department of Clinical Toxicology, Saint Petersburg Research Institute of Emergency Medicine named after I.I. Dzhanelidze.

6. 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.

There is 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. clinical laboratory diagnostics physician;

7. neurologist;

8. neurosurgeon;

9. general practitioner (family physician);

10. otorhinolaryngologist;

11. ophthalmologist;

12. emergency physician;

13. forensic medical expert;

14. internist;

15. district general practitioner;

16. toxicologist;

17. transfusiologist;

18. functional diagnostics physician;

19. surgeon;

20. endoscopist;

21. psychiatrist-narcologist;

22. radiologist;

23. emergency medical technician (paramedic).

Methodology for developing clinical guidelines:

Information resources used to develop the clinical guidelines:

• electronic databases (MEDLINE, "POISON" computerized information and poisons toxicological system, version 3.1, INCHEM IPCS WHO);

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

• thematic monographs, textbooks, guidelines published between 1999 and 2019.

Methods used to assess the quality and validity of clinical guidelines:

Based on the selected publications, recommendation statements were formulated and evaluated using scales for assessing levels of evidence (LoE) for diagnostic methods (diagnostic interventions), levels of evidence for prevention, treatment, and rehabilitation methods (preventive, therapeutic, rehabilitation interventions), and grades of recommendation (GoR) for prevention, diagnostics, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, rehabilitation interventions). (Table 2, Table 3, Table 4) Subsequently, each recommendation statement was thoroughly discussed at the general meeting of the working group, and consensus was reached in all cases of disagreement.

Table 2 – Scale for assessing levels of evidence (LoE) for diagnostic methods (diagnostic interventions)

Table 3 – Scale for assessing levels of evidence (LoE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, rehabilitation interventions)

Table 4 – Scale for assessing grades of recommendation (GoR) for prevention, diagnostics, 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. Toxic effect of substances of predominantly non-medical use (T51-T65) / World Health Organization // International Statistical Classification of Diseases and Related Health Problems. Tenth Revision. Volume 1 (Part 2) – M.: Meditsina, 1995. – P. 337-344. (In Russ.)

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

3. Order of the Russian Ministry of Health No. 925n dated November 15, 2012, "On approval of the procedure for providing medical care for acute chemical poisoning." (In Russ.)

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

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

6. Order of the Russian Ministry of Health No. 804n dated October 13, 2017, as amended on September 24, 2020, with amendments dated October 26, 2022, "On approval of the nomenclature of medical services." (In Russ.)

7. Federal Law No. 489-FZ dated December 25, 2018, as amended on June 11, 2021, "On amendments to Article 40 of the Federal Law 'On Compulsory Medical Insurance in the Russian Federation' and the Federal Law 'The Fundamentals of Protecting Citizens' Health in the Russian Federation' regarding clinical guidelines." (In Russ.)

8. Order of the Russian Ministry of Health No. 103n dated February 28, 2019, as amended on June 26, 2020, "On approval of the procedure and deadlines for the development of clinical guidelines, their revision, the standard form of clinical guidelines and requirements for their structure, composition, and the scientific validity of the information included in clinical guidelines." (In Russ.)

9. Order of the Russian Ministry of Health No. 1165n dated October 28, 2020, "On approval of requirements for equipping first-aid kits, bags, and sets with medicines and medical devices for the provision of emergency medical care." (In Russ.)

Appendix B. Physician Action Algorithms

A patient with suspected acute methanol and ethylene glycol poisoning:

1. Taking an anamnesis to identify the nature of the toxic agent: type, name, purpose, dose, exposure, route of entry into the body, and cause of poisoning.

2. Presence of various consciousness disorders (productive, deficit).

Provision of emergency medical care outside a medical organization:

1. In cases of aspiration-obstructive respiratory disorders, it is necessary to perform oral cavity toilet, aspiration of upper respiratory tract contents, and ensure upper respiratory tract patency.

2. In the event of acute respiratory failure, initiate artificial lung ventilation using mechanical ventilators.

   In case of hemodynamic disorders, as well as for detoxification therapy, it is necessary to ensure venous access and intravenous infusion of solutions affecting water-electrolyte balance, dextrose solutions, and saline solutions.

3. Medical evacuation of the patient to a hospital specializing in the treatment of acute poisoning, or if impossible, to a hospital with hemodialysis capabilities.

Provision of medical care in inpatient settings:

1. Assessment of the condition and decision-making regarding the need for hospitalization in the ICU or the emergency department's resuscitation and intensive care unit.

2. Tracheal intubation, initiation of mechanical ventilation upon the development of a comatose state and/or presence of respiratory failure (if not performed at the prehospital stage).

3. Syndromic therapy aimed at restoring and maintaining vital functions.

4. Correction of acid-base balance (sodium bicarbonate infusion).

5. Antidote therapy (ethanol).

6. Detoxification hemodialysis.

7. Forced diuresis.

Appendix C. Patient Information

Information for patients admitted in a coma is provided after the recovery of consciousness; it must include information about complications that occurred in the toxicogenic stage of poisoning and planned treatment during the rehabilitation process (if necessary for the given patient).

In acute mild to moderate alcohol poisonings, the patient is informed about the health hazards of these toxic substances, potential complications, long-term consequences of poisoning, planned examinations (chemical-toxicological, clinical-biochemical, instrumental), and treatment (detoxification methods, pathogenetic and specific therapy). The patient (or their legal representatives) signs an informed voluntary consent to 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

Indication: For the quantitative assessment of the severity of a comatose state and neuropsychiatric disorders related to consciousness disturbances of any etiology.

Contents:

Key:

15 points – clear consciousness

10–14 points – moderate and deep obtundation

8–10 points – stupor

6–7 points – moderate coma

4–5 points – terminal coma

3 points – brain death

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

Appendix G2. Poisoning Severity Score

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

Indication: 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.