Acute poisoning with non-opioid analgesics, antipyretics, and antirheumatic drugs: clinical guidelines

List of Abbreviations

Terms and Definitions

Detoxification is the process of neutralizing and removing 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 primarily in the liver—and eliminating the poison or its metabolites through various pathways: kidneys, intestines, liver, lungs, and skin. During natural detoxification, metabolites that are more toxic than the original toxicant entering the body may form (lethal synthesis); furthermore, while undergoing metabolism in the liver and excretion through the kidneys, the toxicant and its toxic metabolites can cause damage to these organs and lead to acute renal or hepatic failure.

Accelerated detoxification—to more intensively eliminate the toxicant from the body, various methods of accelerated detoxification are used, such as forced diuresis (pharmacological enhancement of urine output), cleansing of the gastrointestinal tract (gastric lavage, laxatives, intestinal sorbents, intestinal lavage), and extracorporeal renal replacement therapies (hemodialysis and its modifications, hemosorption, peritoneal dialysis, plasmapheresis, etc.).

Disease – a disorder of bodily function, working capacity, and the ability to adapt to changing environmental and internal conditions arising from the impact of pathogenic factors, accompanied by alterations in the body's protective-compensatory and protective-adaptive reactions and mechanisms.

Instrumental diagnostics – diagnostics using various devices, apparatuses, and instruments to examine a patient.

Intoxication is a disruption of normal vital functions caused by toxic substances penetrating the body from the outside or generated within it due to impaired biochemical processes and excretory organ functions, leading to the development of endotoxicosis. Intoxication is a broader pathological process that includes not only and not so much exogenous, but possibly to a greater extent endogenous toxicosis.

Laboratory diagnostics – a set of methods aimed at analyzing test material using various specialized equipment.

Non-steroidal anti-inflammatory and antirheumatic drugs (NSAIDs) are a group of chemically diverse medicinal products sharing common pharmacological effects, possessing analgesic, antipyretic, and anti-inflammatory properties [1].

Selective non-steroidal anti-inflammatory and antirheumatic drugs are a group of chemically heterogeneous medicinal products possessing anti-inflammatory, antipyretic, and analgesic properties, whose mechanism of action is primarily related to COX-2 inhibition.

Non-selective non-steroidal anti-inflammatory and antirheumatic drugs are a group of chemically heterogeneous medicinal products possessing anti-inflammatory, antipyretic, and analgesic properties, whose mechanism of action is related to the inhibition of both COX-1 and COX-2 [2].

Poisoning is a medical condition resulting from the external (exogenous) exposure of a human or animal body to chemical compounds in amounts that cause physiological dysfunction and pose a threat to life [3].

Syndrome is a set of symptoms sharing a common etiology and pathogenesis.

Somatogenic stage of poisoning is the period of acute chemical illness beginning after the elimination from the body or destruction of the toxic substance, manifesting as residual structural and functional damage to various organs and systems [4], typically expressed as various somatic and neuropsychiatric complications such as pneumonia, acute renal failure, hepatic failure, toxic polyneuropathy, anemia, psycho-organic syndrome, etc. During this stage of poisoning, specific (antidote) therapy is not required, and detoxification may be directed solely at treating endotoxicosis.

Condition is an alteration of the organism arising from the impact of pathogenic and/or physiological factors that requires medical care.

Toxicogenic stage of poisoning is the period of acute chemical illness beginning at the moment the toxic substance enters the body at a concentration capable of causing a specific effect [4] and lasting until its elimination. It is characterized by specific clinical manifestations reflecting the chemical and toxicological properties of the toxic substance and its impact on target organs. The severity of this disease period is directly dependent on the dose of the ingested poison and its concentration in the blood. The primary therapeutic objective in this period is to shorten its duration as early as possible using various methods of accelerated detoxification, antidote therapy, and symptomatic therapy.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Non-steroidal anti-inflammatory and antirheumatic drugs (NSAIDs) are medications with analgesic, antipyretic, and anti-inflammatory properties [5, 6].

Poisoning by non-opioid analgesic, antipyretic, and antirheumatic drugs (T39) (according to ICD-10 terminology) refers to a health disorder caused by the ingestion of one or more agents from this group and classified as acute poisoning [5, 6].

Non-steroidal anti-inflammatory and antirheumatic drugs (NSAIDs) represent a group of medications widely used worldwide, with the majority available over-the-counter. Consequently, there is a risk of poisoning from overdose or regular intake, which may occur with mild or absent symptoms. Special cases include the use of drugs from this group for non-medical purposes [7].

Considering the higher toxicity and specific clinical manifestations and complications, these guidelines do not cover the toxic effects (poisoning) of paracetamol** and opioids, which are addressed in separate clinical guidelines.

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

1.2.1. Etiology

Poisoning remains a major cause of morbidity and mortality. Approximately 60 million prescriptions for NSAIDs are written worldwide each year, and 30 million people worldwide take them regularly [8].

The widespread distribution and use of this group of medicinal agents as prophylactic, analgesic, and anti-inflammatory treatments for a multitude of pathological conditions, the availability of liquid dosage forms containing high concentrations of the drugs, the emergence of packages containing a large number of tablets, as well as the over-the-counter dispensing of these drugs and their easy accessibility to the public, account for a significant number of intentional and accidental poisonings worldwide, including those resulting from medication errors. The most common poisonings among this group of drugs involve paracetamol**, salicylic acid, and its derivatives. The primary causes of medication poisoning in adults are suicidal acts, whereas in children it is accidental ingestion [9].

1.2.2. Pathogenesis

Manifestations of acute poisoning are caused by COX inhibition. NSAIDs prevent the production of prostaglandins and thromboxanes mediated by COX. In general, all NSAIDs inhibit both COX-1 and COX-2 isoforms, but most adverse reactions are associated with COX-1 inhibition [1].

NSAID-associated nephrotoxicity is linked to the blockade of prostaglandin E₂ and prostacyclin synthesis in the kidneys, leading to pronounced vasoconstriction, decreased renal blood flow, glomerular filtration, and diuresis. Fluid and electrolyte balance disorders include water retention, hypernatremia, hyperkalemia, and edema. NSAIDs also exert a direct effect on the renal parenchyma, causing acute papillary necrosis (ibuprofen** and naproxen) and acute interstitial nephritis (phenylbutazone, indomethacin, metamizole sodium, ibuprofen**).

As a rule, poorly metabolized NSAIDs that inhibit cyclooxygenase-2 are absorbed and distributed in individual components of the nephron's blood-tissue barrier in accordance with their physicochemical properties, and then either undergo gradual disposal, exerting toxic damage to the structural elements of the kidneys, or are "stored", heavily clogging the glomerular filter. Some drugs, conversely, are rapidly metabolized and lead to the formation of nephrotoxic intermediate products—metabolites that accumulate in large quantities in the renal tissue, destroying its structural components. The cumulative effects of prolonged or repeated exposure of drugs to the renal tissue generally distort the disposal processes and the compensatory capabilities of the organ, thereby also leading to gross structural deformations of the nephron [10].

NSAID-associated gastrotoxicity. The main cause of gastric mucosa damage is a decrease in PG synthesis, which leads to a reduction in energy production and microcirculation disorders. Gastric mucosal damage includes the local toxic effect of high doses of NSAIDs. Dissociation of drugs in parietal cells leads to the formation of protons responsible for the suppression of mitochondrial functions. Protons promote the release of lysosomal enzymes leading to cell autolysis. Suppression of PG formation by blocking COX leads to a decrease in the formation of protective mucopolysaccharides and a decrease in the reparative capacity of the mucosa [11].

New selective NSAIDs inhibit COX-2. Celecoxib has low toxicity towards the digestive organs. However, unlike COX-1 inhibitors, COX-2 inhibitors do not reduce platelet aggregation and therefore increase the risk of myocardial infarction and stroke [12].

NSAID-associated hepatotoxicity. The main target of NSAIDs at the subcellular level is the mitochondria. During the metabolism of NSAIDs by cytochrome P450, NSAID derivatives are formed (e.g., 5-hydroxydiclofenac and n,5-dihydroxydiclofenac), which are capable of affecting electron transport processes in the respiratory chain on mitochondrial cristae, leading to impaired oxidative phosphorylation, ATP synthesis, and energy deficiency in the cell. It is also possible that native NSAIDs possess a toxic effect on mitochondria as well. Impairment of oxidative phosphorylation processes in mitochondria and microsomal oxidation of certain NSAIDs (e.g., naproxen) lead to the activation of free radical oxidation, lipid peroxidation of membranes, NADP, and thiol groups of proteins. The result of these processes ultimately is membrane disorganization, hepatocyte death, and sinotopic cell structures (bile duct cells). It is possible that during disorganization, the cytolemma acquires antigenic properties, which leads to the induction of an autoimmune response and morphologically manifests as periportal edema and mononuclear infiltration [13].

NSAID-associated neurotoxicity is characteristic of indomethacin, as well as acetylsalicylic acid**, used as an antipyretic in children (Reye's syndrome).

1.2.3. Classification of NSAIDs

Official international classification – Anatomical Therapeutic Chemical (ATC) classification system:

1. M Musculoskeletal system;

2. M01 Anti-inflammatory and antirheumatic products;

3. M01A Anti-inflammatory and antirheumatic products, non-steroids;

4. M01AB Acetic acid derivatives and related substances.

NSAIDs are also classified:

• by the duration of the half-life (T_1/2);

• by the selectivity of inhibition of isoforms of the main enzyme cyclooxygenase;

• by chemical structure.

NSAIDs with a short half-life (T_1/2 less than 6 hours) include acetylsalicylic acid**, diclofenac**, ibuprofen**, indomethacin, ketoprofen**.

Long half-lives (more than 6 hours) are characteristic of piroxicam, naproxen, celecoxib, meloxicam, tenoxicam, etoricoxib.

Selective COX-2 inhibitors include etodolac, celecoxib.

The pharmacological properties of various NSAIDs are related to their molecular structure, which can be divided into five classes [14].

I. Carboxylic acids.

1. Salicylic acid derivatives: acetylsalicylic acid**.

2. Anthranilic acid derivatives (fenamates): etofenamate.

3. Arylalkanoic acid derivatives (carbo- and heterocyclic compounds): indomethacin, ketorolac**, etodolac, amtolmetin guacyl.

4. Propionic acid derivatives: ibuprofen**, naproxen, ketoprofen**, flurbiprofen.

5. Phenylacetic acid derivatives: diclofenac**.

II. Enolic acids.

1. Pyrazolone derivatives: metamizole sodium, phenylbutazone.

2. Oxicam derivatives: piroxicam, lornoxicam, meloxicam, tenoxicam.

III. Sulfonamide derivatives: nimesulide, celecoxib, etoricoxib, parecoxib, polmacoxib.

IV. Unclassified NSAIDs: benzydamine.

V. Para-aminophenol derivatives (aniline derivatives): paracetamol**. These drugs belong to other analgesics and antipyretics, rather than NSAIDs.

Most of the drugs used today belong to non-selective COX inhibitors.

Drugs exhibiting preferential action on COX-2 include nimesulide, nabumetone, and meloxicam.

I. Irreversible non-selective COX inhibitors (salicylates).

II. Reversible selective COX inhibitors.

1. pyrazolidines – pyrazolone derivatives (metamizole sodium, phenylbutazone);

2. indoleacetic acid derivatives (indometacin);

3. propionates (ibuprofen**, naproxen, ketoprofen**);

4. oxicams (piroxicam, meloxicam);

5. indazole derivatives (benzydamine);

6. others.

III. Selective COX-2 inhibitors (coxibs) – celecoxib, etoricoxib, parecoxib, polmacoxib, rofecoxib.

IV. Preferential COX-2 inhibitors (sulfonanilides).

Drugs included in the T39 group are generally available as injection and tablet formulations; therefore, acute oral poisonings with NSAIDs taken most frequently with suicidal intent are the most common in clinical practice [1, 4, 5].

Table 1 – Classification according to the potency of the main pharmacological properties of NSAIDs [15]

1.2.4. Pharmacokinetic characteristics of NSAIDs

Most NSAIDs are weak organic acids, are well absorbed from the gastrointestinal tract, and have small volumes of distribution. The drugs bind to albumins by 90–99%, so in hypoproteinemia, toxicity and the likelihood of adverse effects increase. Upon oral administration, absorption of most NSAIDs occurs rapidly and almost completely, resulting in bioavailability exceeding 80%. Peak serum concentration is reached within 2 hours (within 3–4 hours when taking high doses). The volume of distribution is 0.1–0.2 L/kg. NSAIDs undergo active hepatic metabolism and are excreted unchanged in urine in minor amounts (less than 10%, indometacin – 10–20%) [1]. Half-lives vary widely (from 1 to 50 hours) and may increase in liver diseases. The main kinetic parameters are presented in Table 2.

Table 2 – Kinetic parameters of major NSAIDs and non-narcotic analgesics [16, 17]

Note: * – volume of distribution largely depends on concentration, ** – for metabolites – 7-7.5 L/kg

1.2.5. Mechanism of Action of NSAIDs

The action of NSAIDs is primarily aimed at eliminating inflammatory reactions mediated by vascular responses, biochemical and enzymatic disorders, and damage to cellular and subcellular membranes. The mechanisms of action of NSAIDs are very multifaceted, including: limiting the synthesis of acidic mucopolysaccharides, inhibiting free radical reactions, uncoupling glycolysis and oxidative phosphorylation, suppressing the formation of kinins, and reducing the activity of enzymes involved in synthesis of mediators. The action is mainly directed at suppressing pathological processes in the inflammation focus, but when high doses are taken, the activity of the drugs can reach a systemic level.

One of the most significant mechanisms of the therapeutic action of NSAIDs is the inhibition of cyclooxygenase enzymes (COX) activity and the synthesis of prostaglandins (PG) from arachidonic acids. This precisely explains many systemic reactions of the drugs. The main human PGs, E and F, are synthesized from linoleic acid. The local reaction of PG E leads to the dilation of small vessels and an increase in their permeability. At the systemic level, the activity of PG E leads to a decrease in gastrointestinal secretion and tone, blood pressure, the activity of antidiuretic hormone (ADH), and a lowering of the pain sensitivity threshold. PGs lead to an increased sensitivity of hypothalamic thermoregulation centers to the action of endogenous pyrogens. Class F PGs cause vasodilation and a decrease in blood pressure, an increase in GI tone, and a decrease in insulin release. In the focus of inflammation, PG F leads to the constriction of arterioles, venules, stasis, increased vascular permeability, and pain. Thromboxane A2 (TXA A2) causes platelet aggregation and vasoconstriction, while prostacyclin (PG I2), which is found in the endothelium, is an inhibitor of platelet aggregation and causes vasodilation.

NSAIDs limit the function of PGs themselves, as well as their ability to potentiate the activity of mediators and biologically active substances. Knowing the systemic action of PGs, one can predict the therapeutic, toxic, and undesirable effects of NSAIDs by inverse logic.

The effect of NSAIDs on PGs of various tissues, as well as on enzyme subtypes involved in PG synthesis, explains the heterogeneity of drug actions. Pronounced non-selective COX inhibition can lead to an alternative pathway for arachidonic acid utilization and leukotriene synthesis, which explains the development of aspirin-induced asthma. Cyclooxygenases are represented by at least two forms. COX-1 is a systemic enzyme, found in many tissues and controls the production of prostaglandins that regulate the integrity of the gastrointestinal mucosa, platelet function, and renal blood flow. Another isoenzyme, COX-2, is excreted by macrophages, synovial cells, fibroblasts, endothelial cells, and chondrocytes in the focus of inflammation. A distinct characteristic of COX-2 is that its expression is suppressed by endogenous glucocorticoids [18]. The ratio of NSAID activity in inhibiting isoenzymes (COX-1/COX-2) allows us to judge their potential toxicity. The possibility of the existence of a third isomer, COX-3, is not ruled out; it does not take part directly in the focus of inflammation, but its activity is directed at the synthesis of PG subtypes responsible for systemic reactions of pain and fever.

1.2.6. Main Pharmacological Effects of NSAIDs

The anti-inflammatory action is the most valuable property of the drugs, carried out mainly by suppressing the exudative and proliferative phases of inflammation [19-22].

The analgesic action in the focus of inflammation is closely related to the anti-inflammatory effect of the drugs and is realized by reducing exudation and limiting the action of inflammatory mediators on nerve endings.

The antipyretic effect is also provided by a decrease in PG concentration in the central nervous system, realized through vasodilation and increased sweating.

The desensitizing effect when taking NSAIDs develops within 2-6 months.

The disaggregatory effect is used for the prevention of thrombotic complications. Low doses of acetylsalicylic acid** are most often used for this purpose. The use of other NSAIDs also reduces the risk of thrombosis; a combination of acetylsalicylic acid** with other NSAIDs is not ruled out. It should be noted that isolated intake of selective and specific COX-2 inhibitors, on the contrary, increases the risk of thrombosis. This is due to the fact that drugs of these groups do not inhibit thromboxane synthesis, but at the same time limit the production of the disaggregant and vasodilator prostacyclin.

1.2.7. Adverse Effects of NSAIDs

1. Side effects (SEs), which are inherent in almost all NSAIDs, are associated with GI tract damage and most often limit their intake. In the mildest variant, SEs manifest as dyspeptic disorders. With oral administration, the possibility of GI side effects is higher, but the risk also exists with parenteral and rectal routes of administration, since the inhibition of PG synthesis at the systemic level leads to increased production of hydrochloric acid and pepsin, which causes the ulcerogenic effect. Peptic erosions and ulcers develop more often, which can become a source of bleeding. An important clinical feature of such erosions and ulcers is the possibility of their asymptomatic course up to the development of perforation and major bleeding, which is explained by the analgesic action of NSAIDs. Upon drug withdrawal, erosions and ulcerations heal rapidly. In the case of nimesulide, aceclofenac, and meloxicam, the frequency of dyspepsia and asymptomatic ulcers is lower than with non-selective NSAIDs. The risk of gastrointestinal bleeding when using aceclofenac, meloxicam, and nimesulide may be lower than when using other non-selective NSAIDs. Factors predisposing to gastrointestinal bleeding from the wall of the stomach, small and large intestines include: age over 60 years, peptic ulcer disease, smoking, alcohol abuse, high doses and long duration of drug use, intake of systemic corticosteroids, antithrombotic agents, ACE inhibitors, and taking more than one NSAID [16].

2. Arterial hypertension associated with fluid retention; decreased efficacy of loop diuretics.

3. Increased bleeding tendency. In addition to gastrointestinal bleeding, uterine and epistaxis (nasal bleeding) are most often provoked.

4. Increased activity of liver transaminases.

5. Hypoglycemia; its possibility must be considered when co-administering drugs for the treatment of diabetes mellitus.

6. With prolonged use of NSAIDs, the risk of hematological complications increases, such as leukopenia, agranulocytosis, and thrombocytopenia. The development of agranulocytosis is particularly dangerous, with mortality reaching 10-30% [16].

Atypical reactions occurring only in certain patients include:

1. Hemolysis in glucose-6-phosphate dehydrogenase enzyme deficiency in erythrocytes. Such functional insufficiency is more often observed in children.

2. Immediate and delayed type allergic reactions.

3. Rhinitis and bronchospasm are more often observed when taking acetylsalicylic acid**.

4. Widal's syndrome ("aspirin triad"); its development is the result of the preferential synthesis of leukotrienes and thromboxane A₂ – potent bronchoconstrictors – from arachidonic acid [16].

With extremely prolonged use of the drugs, analgesic nephropathy and hepatotoxicity may develop. Bone marrow suppression with the development of neutropenia and thrombocytopenia is more characteristic of pyrazolones.

1.2.8. Drug Interactions of NSAIDs

Co-administration of NSAIDs with other drugs can affect not only their efficacy, but also toxicity. Pyrazolones inhibit the hepatic metabolism of many drugs. Phenylbutazone increases the plasma concentration of phenytoin**, valproic acid**, sulfonylurea derivatives, and vitamin K antagonists. Their interaction with drugs can lead to an enhancement and prolongation of the hypoglycemic effect, an increase in the anticoagulant effect, and an increase in the blood concentration and toxicity of phenytoin**. NSAIDs impair the renal tubular excretion of digoxin**, aminoglycosides, and certain other drugs, leading to an increase in their concentration and toxicity. NSAIDs, especially pyrazolones and indomethacin, reduce the efficacy of loop diuretics. In addition, their use in combination with aldosterone antagonists and other potassium-sparing agents, and with anticholinesterase agents, can lead to hyperkalemia and renal dysfunction; Paracetamol** enhances the hepatotoxicity of aliphatic, piperazine, and piperidine phenothiazine derivatives, anti-tuberculosis drugs, and other compounds that exert an adverse effect on the liver.

The combination of all NSAIDs, and especially acetylsalicylic acid**, with antithrombotic agents leads to an increased risk of gastrointestinal bleeding. The interaction of NSAIDs with aminoquinolines (hydroxychloroquine**, chloroquine) can lead to the development of seizures. NSAIDs reduce the antihypertensive effect when taken concomitantly with antihypertensive agents. NSAIDs increase the risk of the toxic effect of lithium [1].

1.3 Epidemiology of the Disease or Condition

Nonsteroidal anti-inflammatory and antirheumatic drugs (NSAIDs) are widely used not only in medical practice, but also for self-medication, and are present in almost any home first-aid kit. Therefore, these drugs are often the cause of accidental and intentional poisoning.

According to the Saint Petersburg Center for Acute Poisoning of the Dzhanelidze Research Institute of Emergency Medicine, drugs from the NSAID group and other analgesics and antipyretics are detected in 86–159 cases in the biological fluids of admitted patients with drug poisoning for the period from 2020 to 2023. Sometimes the drugs are part of a mixture of medications taken by patients for suicidal purposes, often proceeding without clinical manifestations or characterized by a mild course. Nevertheless, sufficiently severe and even fatal cases of NSAID poisoning have been described in the literature. In our practice, we have also encountered severe courses of diseases caused mainly by 2 drugs: acetylsalicylic acid** and paracetamol**. The latter does not belong to NSAIDs, and therefore, considering its higher toxicity and the specifics of clinical manifestations and complications, these guidelines do not examine the toxic effect (poisoning) of paracetamol**, which has been singled out into separate clinical guidelines. According to the Center for Acute Poisoning of the Sklifosovsky Research Institute of Emergency Medicine, in recent years there has been a trend towards an increase in the number of acute poisonings by non-opioid analgesic, antipyretic, and antirheumatic drugs (T39 according to ICD-10): in 2020 – 170 cases, in 2021 – 233, in 2022 – 254 cases, in 2023 – 242 cases. This is likely due to the expansion of the list of over-the-counter pharmacy drugs.

1.4 Features of Coding the Disease or Condition

Diagnosis coding is carried out using the International Classification of Diseases, 10th Revision (ICD-10). In the version of ICD-10 adapted for Russia, 7 characters are used, which make it possible to formalize the diagnosis of the disorder detected in the patient.

Toxic effect of non-opioid analgesic, antipyretic, and antirheumatic drugs (T39):

T39.0 – Poisoning by salicylates;

T39.1 – Poisoning by 4-aminophenol derivatives;

T39.2 – Poisoning by pyrazolone derivatives;

T39.3 – Poisoning by other nonsteroidal anti-inflammatory drugs;

T39.4 – Poisoning by antirheumatic agents;

T39.8 – Poisoning by other non-narcotic analgesic and antipyretic drugs, not elsewhere classified;

T39.9 – Poisoning by non-narcotic analgesic, antipyretic, and antirheumatic drugs, unspecified.

1.5 Classification of the disease or condition

Certain types of acute poisonings caused by NSAIDs are classified depending on the substance that caused the acute poisoning. In addition, the severity of the poisoning course is taken into account. The severity of poisoning is assessed clinically and based on instrumental and laboratory study data.

1.6 Clinical presentation of the disease or condition

NSAID poisonings share common features. However, differences in their structure, as well as the unequal sensitivity of differently localized cyclooxygenases to the drugs, introduce specific features into the clinical picture. At high doses, COX-2 inhibitors lose their selectivity of action, so the symptoms of poisoning are the same as in overdose of non-selective NSAIDs [1].

1.6.1. Central Nervous System Disorders

Toxic encephalopathy, varying degrees of central nervous system depression, up to the development of coma. The severity of central nervous system depression directly depends on the dose of the ingested poison and correlates with the severity of poisoning. CNS damage in NSAID poisoning manifests in the early stages of intoxication; in mild and moderate cases, weakness, drowsiness, and lethargy are observed. Comatose states are described in poisoning with high doses of acetylsalicylic acid**, ibuprofen**, piroxicam, and other drugs. Seizures are typical in fenamate poisoning and likely in severe salicylate** poisonings. Seizures were registered in poisoning with ibuprofen**, phenylbutazone, diclofenac**, indomethacin.

1.6.2. Respiratory System Disorders

Bronchospasm due to activation of the leukooxygenase pathway is more typical for salicylate poisoning, more often observed in children. NSAIDs can induce the development of eosinophilic pneumonia with cough, shortness of breath, fever, and less commonly, lymphadenopathy and pleural effusion. Cases of pulmonary edema have been described. At the same time, an increased number of eosinophils and ESR are determined in the blood. The course of pneumonitis is benign.

1.6.3. Cardiovascular System Disorders

Cardiovascular system damage and the development of exotoxic shock are extremely rare in severe courses of poisoning accompanied by acid-base balance (ABB) and water-electrolyte balance (WEB) disorders. Direct cardiotoxicity has been described for pyrazolones. Pronounced hypotension was registered in severe ibuprofen** poisoning [23].

Acid-base balance and water-electrolyte balance disorders.

Fluid retention, hypernatremia, and arterial hypertension are possible, but more characteristic as adverse effects. In acute poisonings with an aggressive course of toxic gastritis accompanied by vomiting, dehydration and the development of hypochloremic alkalosis may be observed. This is more likely for young children. Acidosis is more common in salicylate and phenylbutazone poisoning.

1.6.4. Hematopoietic System Disorders

Toxic coagulopathy: hemostasis disorders are associated with impaired platelet function and possible hypoprothrombinemia due to impaired synthesis of vitamin K-dependent blood clotting factors. Hemolysis may occur in NSAID poisoning; its probability increases in the case of glucose-6-phosphate dehydrogenase enzyme deficiency, which is why it is frequently encountered in children.

1.6.5. Gastrointestinal Disorders

Toxic gastroenteritis or toxic gastritis due to systemic and local action is the most frequent sign of intoxication. It must be taken into account that there is no correlation between the severity of gastroenteritis and the severity of the disease. Gastrointestinal bleeding in acute poisonings is rare and caused by the development of coagulopathy.

1.6.6. Toxic Hepatopathy

Pronounced hepatotoxicity is inherent in paracetamol. In some cases, asymptomatic activation of liver transaminases may be observed. Cases of asymptomatic elevation of amylase activity have been described. The nature of the lesion is predominantly hepatocellular, although cases of cholestatic (ibuprofen**) and mixed (naproxen) damage have been reported. Typical symptoms include fever, malaise, jaundice, and pruritus. Hepatocellular injury manifests with a marked increase in serum aminotransferases, fatigue, and jaundice, whereas cholestatic injury manifests with jaundice and pruritus with a marked increase in alkaline phosphatase and bilirubin levels.

1.6.7. Nephrotoxicity

When taking NSAIDs, it is more likely in elderly patients with pre-existing renal pathology. Kidney damage is facilitated by dehydration. Acute kidney injury (AKI) has been described in poisoning with ibuprofen**, diclofenac**, piroxicam, and other drugs, but the dysfunction is usually short-lived.

1.6.8. Altered Carbohydrate Metabolism

Hypoglycemia should be expected more frequently. However, impaired glucose utilization and increased insulinase activity may occur, leading to hyperglycemia.

1.6.9. Salicylate Poisoning

There are two groups of salicylic acid esters: by the phenolic (acetylsalicylic acid**) and carboxylic (including methyl salicylate and phenyl salicylate (registered in the Russian Federation only as part of fixed combinations)) groups [1].

Salicylic acid** in 1-2-3-5-10% concentrations is used to treat skin diseases.

Acetylsalicylic acid** is currently a widely used analgesic and a widely prescribed antiplatelet therapy for patients with cardiovascular and cerebrovascular diseases, and thus salicylate poisoning remains an important clinical problem [24]. In addition to acetylsalicylic acid**, there are also combined forms containing acetylsalicylic acid** in combination with paracetamol**, caffeine**, ascorbic acid**, and other drugs.

Acetylsalicylic acid** is well absorbed from the stomach and upper intestine, has a low acidity constant (pK = 3.5); the volume of distribution is 0.15-0.3 L/kg of body weight, sharply increasing with concentration growth. Acetylsalicylic acid** is hydrolyzed in plasma to salicylic acid, which is metabolized in the liver to form salicyluric and salicylglucuronic acids. At therapeutic concentrations, the drug obeys first-order kinetics laws; at toxic doses, due to the saturation of conjugation, salicylic acid elimination occurs via zero-order kinetics with salicylate accumulation. It is eliminated by the kidneys predominantly as metabolites. T_1/2 of the therapeutic dose is 2-4 hours.

A single dose of acetylsalicylic acid** of 150–300 mg/kg of body weight causes moderate toxic manifestations, while a dose of 300–500 mg/kg causes severe toxicity. A dose of 100 mg/kg/day taken for two or more days leads to symptoms of chronic intoxication.

Acetylsalicylic acid** is a potent inhibitor of COX-1 and COX-2, with COX-2 being more sensitive to the drug than COX-1. Acute acetylsalicylic acid** poisoning leads to the following pathological processes:

• irritation of the gastrointestinal tract, with potential erosion and bleeding;

• the volume of distribution increases with higher concentrations, facilitating the penetration of the drug into cells and tissues, as well as the central nervous system; the appearance of central nervous system symptoms indicates the ingestion of a significant dose;

• development of metabolic acidosis resulting from elevated salicylic acid concentrations and impaired oxidative phosphorylation, leading to the accumulation of lactic and pyruvic acids; furthermore, acetylsalicylic acid** stimulates lipid metabolism with the accumulation of ketone bodies; metabolic acidosis, in turn, facilitates the penetration of the drug into tissues;

• respiratory alkalosis resulting from stimulation of the respiratory center as a consequence of increased carbon dioxide due to excessive oxygen consumption caused by uncoupling of oxidative phosphorylation; a direct toxic effect on the respiratory center cannot be ruled out; in the early stages of poisoning, the patient may even exhibit an elevated blood pH, leading to a loss of bicarbonate, potassium, sodium, and water; in turn, depletion of the bicarbonate buffer system makes the body vulnerable to the development of metabolic acidosis, for which all conditions are present; therefore, metabolic acidosis is the leading acid-base disturbance; in extremely severe cases of intoxication, depression of the respiratory center develops; in pediatric poisoning, the phase of respiratory alkalosis may be absent due to more rapid distribution;

• hyperthermia and central hearing impairment;

• fluid loss (vomiting, hyperthermia, tachypnea, increased diuresis in the early stages of intoxication);

• tendency toward bleeding due to impaired platelet aggregation and synthesis of blood coagulation factors II, VII, IX, and X; clinically, bleeding manifests relatively late—on days 4–7 after poison ingestion.

The clinical presentation of poisoning is characterized by early gastroenteritis with a potential hemorrhagic component. Early vomiting facilitates drug elimination, but given its rapid absorption, it does not provide a significant therapeutic effect. Early manifestations also include hyperthermia and hearing impairment. The patient may complain of tinnitus, hearing loss up to temporary deafness. Acetylsalicylic acid** uncouples oxidative phosphorylation, leading to increased oxygen consumption and glucose utilization, which causes increased heat production. This is accompanied by fever, hyperhidrosis, tachypnea, tachycardia, and hypoglycemia. Vomiting can be pronounced and lead to water-electrolyte balance disorders.

Severe poisonings are accompanied by anxiety, agitation, seizures, coma, hyperthermia, hypoglycemia (or sometimes hyperglycemia), as well as pulmonary edema.

Impaired consciousness is generally mild—weakness, drowsiness. In severe cases (a dose exceeding 300 mg/kg of body weight), against the background of the described clinical picture, central nervous system disorders progress; agitation is replaced by lethargy, then stupor and coma. A dangerous manifestation of intoxication can be seizures. Pronounced hyperthermia may lead to skeletal muscle necrosis. In children, central nervous system disorders are more pronounced. Stimulation of the respiratory center leads to tachypnea and transient respiratory alkalosis. However, the primary background of metabolic disorders is high anion gap metabolic acidosis, the severity of which depends on the degree of intoxication. Inhibition of the Krebs cycle is accompanied by the development of lactic acidosis. In adults with acute salicylate poisoning, both types of acid-base disturbances develop: respiratory and metabolic. In children, acidosis develops more rapidly [1]. The prognosis is determined by the level of consciousness, acidosis, and the development of seizure activity.

Fluid loss with the development of hypovolemia and shock is more characteristic of poisoning in children. Hypoglycemia and a significantly higher rate of drug elimination are also more frequently observed in children. Death may occur as a result of central nervous system disorders, heart failure, or pulmonary edema.

In acute salicylate poisonings, cases of rhabdomyolysis due to hyperthermia, hepatic impairment, and renal failure have been described.

Even with a favorable course of intoxication, one must keep in mind the potential development of coagulopathy and bleeding.

Chronic intoxication is characterized by the so-called "pseudoseptic syndrome":

• hyperthermia;

• leukocytosis with a left shift;

• hypotension;

• PSS;

• respiratory system dysfunction;

• coagulopathy.

• tinnitus, nausea, vomiting

Chronic poisoning is more commonly characterized by non-specific symptoms—lethargy, hallucinations, agitation, stupor, confusion, metabolic acidosis, and dehydration. In chronic intoxication, death is more frequently caused by pulmonary or cerebral edema and occurs at lower salicylate levels in the body than in acute poisoning. The slow onset and milder clinical picture in chronic salicylate poisonings are the reasons for delayed diagnosis.

1.6.10. Fenamate Poisoning (Anthranilic Acid Derivatives)

Drugs belonging to this group include:

• etofenamate.

Poisonings with drugs of this group are characterized by gastroenteritis, generally moderate in severity, and central nervous system damage manifesting as convulsive syndrome. Short-term recurrent seizure episodes develop 1.5–2 hours after drug ingestion and relapse over 12–24 hours. Toxic doses of the drug range from 60–100 mg/kg of body weight, but seizures are also possible at significantly lower doses—three to five times the single therapeutic dose. In severe cases, coma and brainstem disorders develop.

1.6.11. Poisoning by Acetic Acid Derivatives and Related Compounds

The main drug of this group is indometacin.

The maximum blood concentration is reached 2 hours after oral administration of standard formulations and 3–4 hours after extended-release formulations, $\text{pK}_a$ 4.5. The half-life is 4–5 hours for the non-extended-release formulation. The toxic dose is 30–50 mg/kg of body weight. Features of intoxication include pronounced gastroenteritis, central nervous system effects—ataxia, dizziness, as well as an impact on renal excretory function, sharply reducing the efficacy of loop diuretics, which should be considered when treating poisonings.

Ketorolac** is a heterocyclic compound, a derivative of pyrrolizinecarboxylic acid. It possesses potent analgesic efficacy, surpassing many other NSAIDs and comparable to opioid analgesics. It is used to relieve pain of various localizations. In ketorolac** poisoning, gastrotoxicity and nephrotoxicity are less pronounced than in indometacin intoxication; however, depression of consciousness down to stupor develops more frequently.

Isolated cases of poisoning with other drugs in this group have been described, which include etodolac (acetic acid derivatives and related compounds) and amtolmetin guacil. Toxic and lethal doses have not been established.

Diclofenac**

Diclofenac** is well absorbed in the gastrointestinal tract. Bioavailability is 50–60%, due to the "first-pass" effect. The maximum blood concentration is observed 0.5–2 hours after oral administration and 10–30 minutes after intramuscular injection. The half-life is 1.5–2 hours. Diclofenac** in the form of potassium salt differs from the sodium salt by rapid resorption, predominantly in the stomach; it is used for rapid pain relief.

The toxic dose of diclofenac** is 100 mg/kg of body weight. Poisonings are extremely rare, accompanied by confusion and hypotension. Hyperkalemia is likely with intoxication by the potassium salt. Hemolysis is possible in children.

Phenylbutazone exhibits high anti-inflammatory activity. Phenylbutazone—maximum blood concentration develops 2 hours after oral administration, and the half-life is approximately 50–60 hours.

1.6.12. Propionic Acid Derivative Poisoning

A large group of drugs, the main representatives and progenitors of which are ibuprofen** and naproxen.

Ibuprofen**

Ibuprofen** is rapidly absorbed in the gastrointestinal tract. Upon oral administration, the maximum blood concentration is observed 1–2 hours after ingestion. It undergoes biotransformation in the liver and is excreted from the body mainly as metabolites. The half-life is 2–4 hours.

The toxic dose of the drug is 200–400 mg/kg of body weight. As a rule, intoxications have a benign course, accompanied by gastroenteritis, lethargy, sluggishness, and hepatopathy. It is necessary to monitor free hemoglobin in young children, in whom hemolysis may develop. Despite a wide therapeutic index, severe ibuprofen** poisonings have been described, which may be associated with its widespread use. Intoxication manifests as gastroenteritis and rapid, within 2 hours, CNS damage up to the development of coma. Children may experience seizures. There is a tendency toward hypotension and bradycardia; metabolic disturbances manifest as acidosis and hyperkalemia. Cases of acute kidney injury (AKI) have been described. Treatment is symptomatic, and there are no antidotes.

Other representatives of this group include naproxen, its sodium salt, flurbiprofen, and ketoprofen**. The clinical presentation of overdose and poisoning is similar to that of ibuprofen**.

1.6.13. Pyrazolone Toxicology

Currently, clinically significant acute NSAID poisonings are extremely rare. Metamizole sodium has weak anti-inflammatory activity, but pronounced analgesic and antipyretic effects. Metamizole sodium is a component of many combination drug formulations. Metamizole sodium is rapidly and almost completely absorbed. Peak blood concentration occurs in 1–2 hours. The half-life is 2.5 hours. Metamizole sodium is often one of the components in mixed-drug poisonings. Mild poisonings are characterized by dyspeptic symptoms, moderate lethargy, and toxic hepatopathy. A feature of the action of drugs in this group is possible fluid retention associated with the effect on antidiuretic hormone (ADH) activity, which may cause arterial hypertension in adults. Pyrazolones can reduce the efficacy of loop diuretics. This must be remembered when prescribing infusion therapy. Particular attention should be paid to this when treating patients with congestive heart failure. High toxic doses can lead to severe intoxication with central nervous system depression down to a coma. In high doses, especially against the background of a burdened medical history, pyrazolones exhibit cardiotoxicity, leading to conduction abnormalities and decreased myocardial contractility. Hemolytic anemia is potentially probable. The development of granulocytopenia up to agranulocytosis is practically never encountered in acute poisonings. Urine in pyrazolone poisoning is colored red of varying intensity. The toxic dose for metamizole sodium is 100–200 mg/kg of body weight. Cases of severe intoxication with phenylbutazone at a dose of 200 mg/kg of body weight have been described, with the development of seizures, coma, and acute respiratory failure. Cases of AKI have been observed as complications.

1.6.14. Coxib Poisoning

There is no specific antidote therapy for pyrazolone poisoning. Support of vital body functions, correction of acidosis (which develops in severe variants of the course), and management of water-electrolyte balance under the control of urine output are necessary.

Representatives of this group—celecoxib and nimesulide—are new-generation NSAIDs, selective COX-2 inhibitors. Consequently, the drugs do not affect renal blood flow, possess minimal gastrotoxicity, and do not reduce platelet aggregation because they do not disrupt thromboxane synthesis.

Celecoxib. The drug is not an acid. It is well absorbed in the gastrointestinal tract; peak blood concentration occurs in 3 hours, and food intake slows down the rate of resorption. It is metabolized in the liver, with a half-life ($T_{1/2}$) of 7–10 hours, which may increase in liver diseases.

Nimesulide. It is rapidly and completely absorbed in the gastrointestinal tract; the maximum blood concentration is observed 1.5–3 hours after administration, and protein binding is 99%. The volume of distribution of the drug is 0.2–0.4 L/kg. It is excreted in negligible amounts unchanged, undergoes hydroxylation, and is excreted predominantly (70%) as metabolites via the kidneys, and only 30% via the intestines. In nimesulide poisoning, central effects such as lethargy and somnolence are observed quite frequently. A cardiotoxic effect—slowing of cardiac conduction—has also been noted.

Benzydamine is well absorbed in the gastrointestinal tract and is also readily resorbed through the skin and mucous membranes. It is used mainly for topical application. When administered orally, it is excreted by the kidneys and intestines as metabolites. Adverse effects are the same as with other NSAIDs; overdoses lead to central disorders in the form of perceptual disturbances and visual hallucinations.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnosis must be based on the following diagnostic criteria:

• evidence of the intake of NSAID medications;

• presence of symptoms and signs of NSAID poisoning that are dangerous to the life and health of patients.

2.1 Complaints and Anamnesis

In severe forms of acute NSAID poisoning, complaints may be practically absent due to pronounced functional disorders, primarily of the central nervous system, as contact with the patient is limited. CNS symptoms in NSAID poisoning may include cognitive impairment, hallucinations, and seizures [25, 26].

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

Comments: in cases of NSAID poisoning, general principles of toxicological history-taking cannot always be applied. This concerns ascertaining such information as: the type of toxic substance (name of the medicinal product) taken by the victim, the dose, the time of intake of the toxicant (exposure time of the poison in the body)—which allows one to determine with a certain degree of accuracy which stage of poisoning (toxicogenic or somatogenic) the patient is in—and the circumstances accompanying the development of the poisoning (accidental or intentional). Virtually all of the above cannot be ascertained in severe forms of NSAID poisoning, in which pronounced functional disorders (primarily of the CNS) are observed, in cases where relatives or acquaintances of the victim are absent or do not know this information, and the patient themselves is unable due to their condition to provide the necessary information, or is unwilling to provide it. In such cases, the diagnosis is made based on the clinical picture. In the vast majority of cases, the first symptoms of NSAID poisoning are nonspecific (nausea, vomiting, somnolence, etc.), which is why taking a toxicological history is a crucial point. The earliest and most characteristic symptom in salicylate poisoning, apart from nausea and vomiting, is tinnitus. In this regard, it is essential to ask the patient whether there are any hearing changes, as the patient may not associate this with taking the medication [28].

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.

2.2 Physical Examination

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

Comments. In NSAID poisoning, specific skin coloration is absent upon examination of the skin; in cases of respiratory failure or shock, cyanosis of the lips, face, and acrocyanosis, as well as cold extremities, are observed, and diaphoresis may occur in deep coma. It is necessary to identify the presence or absence of a rash, local changes, and pressure ulcers resulting from positional trauma due to the weight of one's own body—so-called positional pressure on specific areas of soft tissue—leading to areas of skin hyperemia that are frequently regarded as bruises, hematomas, burns, phlebitis, allergic edema, etc., and are usually detected in the early stages (1–3 days). Attention should be paid to the presence or absence of injuries, especially in the area of the face, head, abdomen, and lower back. It is necessary to assess the neuropsychiatric status: state of consciousness (clear, lethargy, sopor, coma, psychomotor agitation, hallucinations). In the presence of coma, assess its depth, the presence or absence of reflexes, pupil size, their reaction to light, the presence (absence) of anisocoria, and muscle tone. When anisocoria or pathological reflexes are detected, pay attention to their consistency ("pupillary play"), since in superficial alcoholic coma, anisocoria and pathological reflexes may appear and rapidly disappear. It is necessary to pay attention to the color of vomitus, as signs of gastrointestinal bleeding may be present [20, 21, 29]. General thermometry is necessary because hyperthermia and hyperhidrosis may be recorded in salicylate poisoning due to the uncoupling of mitochondrial oxidative phosphorylation. However, the absence of hyperthermia does not rule out acute salicylate poisoning. It is also important to assess signs of hypovolemia (decreased skin turgor, cold extremities) in salicylate poisoning [1].

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

Comments. To detect impaired respiratory function, it is necessary to assess the rate, depth, and symmetry of involvement of all chest compartments in the breathing act, evaluate the pulmonary auscultatory findings, and assess clinical data corresponding to respiratory failure. To evaluate the cardiovascular system, pulse examination, auscultation for cardiac and pericardial pathology, heart rate measurement, and blood pressure measurement on peripheral arteries are performed. Signs of hypovolemia, electrolyte imbalances, and acid-base disorders are identified, along with signs of hepatopathy, acute kidney injury, coagulopathy, and altered gastrointestinal function [21].

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. Salicylate poisoning must be differentiated from diabetic ketoacidosis, which presents with nausea, vomiting, depressed consciousness, signs of hypovolemia, hyperglycemia, metabolic acidosis, and ketonuria. In salicylate poisoning, hypoglycemia or mild hyperglycemia is more likely. In sepsis, pneumonia, and systemic inflammatory response syndrome, hyperthermia, metabolic acidosis, tachypnea, hypoglycemia, signs of hypovolemia, leukocytosis, and blood coagulation disorders are observed. Differential diagnosis must be performed with diseases causing metabolic acidosis [1, 30, 31, 32, 33].

2.3 Laboratory Diagnostics

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

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

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

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

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

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

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

Comments: in moderate-to-severe salicylate poisoning, water-electrolyte balance (WEB) and acid-base balance (ABB) disorders frequently develop. In most cases, they manifest as mixed respiratory alkalosis and metabolic acidosis, as well as electrolyte imbalances [41, 42].

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

Comments. In salicylate poisoning, marked water-electrolyte balance alterations may occur as a result of fluid loss from repeated vomiting, hyperhidrosis, hyperthermia, and tachypnea [44].

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: perform a serological test for differential diagnosis of the pathological process (toxic hepatopathy and liver disease of viral etiology):

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

- Determination of hepatitis B virus (Hepatitis B virus) HBeAg in blood;

- Determination of hepatitis C virus core antigen in blood;

- Determination of antibodies to hepatitis B virus surface antigen (anti-HBs) in blood, qualitative assay;

- Determination of hepatitis B virus (Hepatitis B virus) DNA in blood by PCR, qualitative and quantitative;

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

- Determination of hepatitis C virus core antigen in blood;

- Determination of hepatitis C virus (Hepatitis C virus) RNA in blood by PCR, qualitative assay;

- Assay for antibodies of classes M and G (IgM, IgG) to human immunodeficiency virus HIV-1/2 and antigen p24 (Human immunodeficiency virus HIV 1,2/+Agp24) in blood;

- Determination of human immunodeficiency virus RNA by PCR, qualitative assay [45, 46, 47].

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

Comments: to prepare for a blood transfusion in a patient with coagulopathy and bleeding [38].

2.4 Instrumental Diagnostics

Performing these diagnostic tests does not clarify the diagnosis of NSAID poisoning. However, they are necessary for the early diagnosis of complications in moderate and severe cases. These conditions may indicate changes in various organs and systems that require verification and assessment, and they help expand 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 probability of cardiomyopathy, chronic heart disease, electrolyte disturbances, and cardiac rhythm and conduction disorders.

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

Comments: vital sign monitoring should preferably be performed using hardware methods with the MARG 10-01 "Mikrolyuks" computerized anesthesiology-resuscitation monitor for hemodynamic monitoring (TU 9441-001-21486834-2002). In the absence of a monitor, periodic vital sign control is performed manually. The frequency of repeat measurements is determined by the attending physician depending on the severity of the patient's condition. Instrumental diagnostic methods are an integral part of the diagnostic process and are carried out in settings where dynamic monitoring of the patient's condition is possible. The inability to perform hardware monitoring in a severely ill patient requires considering medical evacuation to a medical organization where this is possible [20, 21, 43].

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

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

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

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

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

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

Comments: additional instrumental diagnostic methods are performed when acute NSAID poisoning is combined with trauma or other comorbidities in order to detect trauma, concomitant pathology, or potential complications (ultrasound examination (echoscopy) of the brain, brain computed tomography (CT) and magnetic resonance imaging (MRI), comprehensive abdominal ultrasound, ultrasound of the kidneys, pancreas, and EGD).

2.5 Other Procedures

Additional diagnostic methods are prescribed by specialists based on the clinical situation and indications. Since NSAID poisoning is accompanied by various disorders in body organs and systems, has variable clinical manifestations, and leads to various complications, differential diagnosis is frequently required.

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.

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

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

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

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

Comment: indications for prescription include infusion detoxification therapy in acute poisoning. Adults are prescribed as part of infusion therapy 1.5% solution 400 ml twice a day (children 200 ml). Course treatment: 3-6-10 days [48].

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: method of administration of #activated charcoal: 1 tablet 250 mg; a suspension of tablets is used – 25-40 g diluted in 50-100 ml of water in the form of a "slurry". After a single administration of the indicated dose, 20-40 g is administered at intervals of 2-4 hours for 12 hours [4]. After gastric lavage in children under 2 years old, the dose is 0.5-1 g; up to 3 years old – up to 10 g; 3-7 years old – 10-15 g; 7-10 years old – 20-25 g; older than 10 years old – 30-40 g as a single dose [37]. In children over three years old, the drug is prescribed on average at the rate of 0.05 g/kg of body weight. The maximum single dose is up to 0.2 g/kg of body weight [1, 4, 8]. It can be used at the end of tube gastric lavage in a dose of 50-60 g (0.5-1.0 g per kg of body weight) [54]. Solution for intravenous and intramuscular administration of the medicinal product A03FA01 Metoclopramide** is used in adults at 10-20 mg with a frequency of administration of the indicated dose up to 3 times a day (maximum daily dose 60 mg); in children over 6 years old up to 5 mg 1-3 times a day [98]

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

Comments: depending on clinical necessity, the route of administration of the medicinal product and its dose (dosage regimen) can be chosen – adults and adolescents over 14 years of age are prescribed the drug orally at 10–15 mg 3-4 times a day, intramuscularly or intravenously at 10 mg 3–4 times a day. The maximum daily dose is 500 mg/kg. For children under 14 years of age, a single dose is 0.1 mg of #metoclopramide** per 1 kg of body weight, the highest daily dose is 0.5 mg per 1 kg. In case of altered renal function, the dose of the drug is selected according to the filtration rate. With a creatinine clearance up to 10 ml/min, the dose is 10 mg once a day; from 11 to 60 ml/min – 10 mg once a day and 5 mg once a day [55].

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: this recommendation is achieved via parenteral administration of an antiepileptic drug (benzodiazepine derivatives – Diazepam**) intravenously, intramuscularly: adults – 10 mg. It is prescribed to children after the 5th week of life intravenously slowly at 0.1-0.3 mg/kg of body weight up to a maximum dose of 5 mg. If necessary, the injection is repeated after 2-4 hours depending on the clinical situation. Children 5 years of age and older receive 1 mg IV slowly every 2-5 min up to a maximum dose of 10 mg. If necessary, treatment can be repeated in 2-4 hours [57].

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

Comments: the choice of the direction of medical evacuation will optimize the treatment tactics in providing care, providing timely and effective assistance to casualties [20, 21].

3.2. Treatment at the Specialized Medical Care Stage

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 medical technique is based on oral or tube administration of intestinal adsorbents into the stomach or intestine. The size of tubes in adults and adolescents is F36-40, in children – F22-28. During tube insertion, the patient is either in a sitting position or lying on the left side with the chin pressed to the chest. The correctness of tube insertion is determined by injecting air with a Janet syringe (auscultation should reveal sounds in the stomach). A single dose of water for a child is 10 ml/kg, but not more than 250 ml. A single dose of water for an adult is 250 ml. The recommended total volume of water for tube gastric lavage [48]:

• 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.

• in adults – up to 10 l.

The administered dose of sorbent is #Activated charcoal (1 tablet 250 mg; a tablet suspension is used) 20–30–50 g, diluted in 50–100 ml of water. After gastric lavage, the dose for children under 2 years is 0.5–1 g; up to 3 years, up to 10 g; 3–7 years, 10–15 g; 7–10 years, 20–25 g; over 10 years, 30–40 g as a single dose [37]. For children older than 3 years, the drug is prescribed on average at 0.05 g/kg of body weight (0.15 g/kg of body weight/day). The maximum single dose is up to 0.2 g/kg of body weight [21]. The method is effective in poisoning with various NSAIDs, including acetylsalicylic acid** [48, 64, 92].

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

Comments. Intestinal lavage is a method of clearing toxic substances from the intestine by washing it using tubing and solution administration. To perform the lavage, a double-channel silicone intestinal tube for decompression and enteral administration is inserted through the nose into the stomach. Administration principles: the solution, warmed to 40 °C, is administered at a rate of 100 ml/min. After 10–20 min, washout water with intestinal contents drains through the aspiration channel. After 0.5–1.5 h, rectal contents appear from the rectal drainage tube, while diuresis simultaneously increases. Bowel cleansing requires the administration of 50 ml of saline solution per 1 kg of the patient's body weight (total 4.5–5 L) [64].

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

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

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

Comment. The approach to infusion therapy must be individualized. The volume and composition of the infusion program depend on age, the patient's condition, comorbid pathology, and the presence of complications. In salicylate poisoning, there is a high risk of volemic disorders; infusion therapy must be carried out under strict volume status monitoring [20, 21, 43, 64, 65].

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 poisonings (it can be used as an infusion medium during forced diuresis). Adults are administered intravenously at a rate of 1–4.5 ml/min (up to 90 drops/min). The average daily dose in adults is 10 ml/kg, in children from 1 year of age, 6–10 ml/kg/day, with an administration rate of 3–4 ml/min. Duration of use is up to 11 days [66, 67].

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

Comments. In salicylate poisoning, acidosis should be corrected as quickly as possible because it promotes the penetration of salicylic acid derivatives (N02BA Salicylic acid and its derivatives) into CNS tissues. When pH is below 7.2, the dose of sodium bicarbonate** is 1–2 mEq/kg of body weight, administered over 1–2 hours. When pH is above 7.25, sodium bicarbonate** is administered at a slower rate. Urine alkalinization drastically increases the renal elimination of salicylic acid derivatives (N02BA Salicylic acid and its derivatives) by restricting their passive tubular reabsorption. Electrolyte losses, primarily potassium, must be kept in mind and replenished. Correction of hypokalemia is necessary to achieve urine alkalinization [68-70].

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

Comments. Hemodialysis is effective in salicylate poisoning. Indications for this treatment method include: altered level of consciousness, psychomotor agitation, seizures, acidosis (blood pH < 7.2), cerebral edema, pulmonary edema, clinical deterioration despite ongoing therapy, presence of acute kidney injury or chronic kidney disease, and high blood concentrations of salicylic acid derivatives (N02BA Salicylic acid and its derivatives) in acute chemical poisoning. Sodium bicarbonate** infusion must be stopped during dialysis. Since quantitative determination of salicylic acid derivatives (N02BA Salicylic acid and its derivatives) in the blood is practically unavailable in our country, the decision to initiate hemodialysis must be guided by the anamnestic data and severity of the clinical presentation. Depression of consciousness to stupor-coma, seizures, respiratory disorders, severe acidosis, and hyperthermia are alarming signs of intoxication. When performing extracorporeal therapy, it must be kept in mind that patients are dehydrated. Fluid replacement is carried out under the control of diuresis (filtration parameters must be assessed). Acidosis should be corrected as quickly as possible because it promotes the penetration of salicylic acid derivatives (N02BA Salicylic acid and its derivatives) into CNS tissues. When pH is below 7.2, the dose of sodium bicarbonate** is 1–2 mEq/kg of body weight, administered over 1–2 hours. When pH is above 7.25, sodium bicarbonate is administered at a slower rate. Hemodialysis performed to eliminate the toxin will also help correct acidosis [71]. The use of hemodialysis in NSAID poisoning, excluding salicylic acid derivatives (N02BA Salicylic acid and its derivatives), is ineffective [21, 39].

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

Comments: depending on clinical necessity, the route of administration and dosage regimen of the medicinal product may be selected—for adults and adolescents over 14 years of age, the drug is prescribed orally at 10–15 mg 3–4 times daily, intramuscularly or intravenously at 10 mg 3–4 times daily. The maximum daily dose is 500 mg/kg. For children under 14 years of age, the single dose is 0.1 mg of #metoclopramide per 1 kg of body weight, and the maximum daily dose is 0.5 mg per 1 kg. In case of impaired renal function, the dose of the drug is adjusted according to the filtration rate. At a creatinine clearance up to 10 mL/min, the dose is 10 mg once daily; from 11 to 60 mL/min—10 mg once daily and 5 mg once daily [55].

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

Comments: depending on clinical necessity, the route of administration of the medicinal product is chosen individually. For adults, an intravenous dose of 40 mg daily is recommended. The infusion solution of the drug is administered as an intravenous drip over 20–30 minutes. Use in children under 18 years of age is contraindicated [72].

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 main goal of respiratory support in ventilatory acute respiratory failure is the substitution of lost or sharply weakened spontaneous breathing due to impaired function of the respiratory center and/or respiratory muscle dysfunction (paralysis, paresis). Impairment of the respiratory center function in the setting of cerebral edema and other pathological conditions leads to the depression or weakening of the sensitivity of central chemoreceptors, causing hypoventilation accompanied by hypercapnia and hypoxemia.

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 indication for administration is the need for infusion detoxification and antihypoxic therapy in acute poisoning (it can be used as an infusion medium during forced diuresis). Adults are administered intravenously at a rate of 1-4.5 mL/min (up to 90 drops/min). The average daily dose is 10 mL/kg. It is used in children aged 1 year and older at a dose of 6–10 mL/kg/day at a rate of 3-4 mL/min. The duration of use is up to 11 days [67, 73].

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. In salicylate poisoning, acidosis must be eliminated as quickly as possible, as it facilitates the penetration of salicylic acid derivatives (N02BA Salicylic acid and its derivatives) into central nervous system tissues. At a pH below 7.2, the dose of #sodium bicarbonate** is 1-2 mEq per kg of body weight, administered over 1-2 hours. At a pH above 7.25, the drug is administered at a lower rate [36, 43, 65]. Urine alkalinization promotes a sharp increase in the renal elimination of salicylic acid derivatives (N02BA Salicylic acid and its derivatives) by restricting their passive tubular reabsorption. Electrolyte losses, primarily potassium, must be kept in mind and replenished. Correction of hypokalemia is necessary for urine alkalinization [68-70].

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. Adults are administered intravenously at a rate of 1-4.5 mL/min (up to 90 drops/min). The average daily dose is 10 mL/kg. It is used in children aged 1 year and older at a rate of 6-10 mL/kg/day at 3-4 mL/min. The duration of use is up to 11 days [67, 73].

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

Comments: Dosage depends on age, body weight, and the patient's condition. The 5% solution is administered intravenously by drip at a maximum rate of 500 mL/h (150 drops/min), the 10% solution at up to 60 drops/min (3 mL/kg/h); the 20% solution at up to 30–40 drops/min (150 mL/h); the 40% solution at up to 30 drops/min (1.5 mL/kg/h). Under normal metabolic conditions, the maximum administration rate for adults is 0.25-0.5 g/kg/h for a 5% dextrose solution**; when metabolic rate decreases, the administration rate is reduced to 0.125-0.25 g/kg/h. For parenteral nutrition in children, along with fats and amino acids, 6 g of dextrose**/kg/day is administered on the first day, and up to 15 g/kg/day thereafter. When calculating the dextrose** dose for 5% and 10% solutions, the allowable fluid intake volume must be taken into account: 100-165 mL/kg/day for children weighing 2-10 kg, and 45-100 mL/kg/day for children weighing 10-40 kg. The administration rate must not exceed 0.75 g/kg/h. For more complete utilization of dextrose** administered in high doses, soluble insulin [human genetically engineered]** is prescribed concurrently at 1 IU of "A10AB Short-acting insulins and analogues for injection" per 3-5 g of dextrose**. In patients with diabetes mellitus, dextrose** is administered under blood and urine glucose monitoring [21, 43, 75].

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

Comments: Depending on the severity of hypokalemia, #Potassium chloride** is administered to children intravenously as a 4% solution at 1 mL/kg in Dextrose** solution [37]. The maximum daily dose is 0.4 mmol/kg/hour. The physiological requirement for #potassium chloride is 2-3 mmol/kg/day [43].

Comments: Monitoring of magnesium and its correction are necessary in salicylate poisoning.

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

Comments: Patients with salicylate poisoning may exhibit severe hypovolemia. In severe poisoning in adults, in the absence of cerebral edema and pulmonary edema, a large volume of infusion therapy may be required to restore circulating blood volume [76]. The risk of pulmonary and/or cerebral edema during infusion therapy should be kept in mind, and continuous laboratory monitoring is required [76].

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: Heparin group medications are administered subcutaneously for prophylactic purposes at 5000 IU/day, 4–5 times a day. The site for subcutaneous injections is the anterolateral abdominal wall, alternating injection sites (to prevent hematoma formation). The initial dose of the medicinal product B01AB01 #Heparin sodium** administered for therapeutic purposes (depending on clinical data and the use of extracorporeal detoxification methods) ranges from 5000–10000 IU administered intravenously. The maintenance dose is determined based on the route of administration. In children, the initial dose of the medicinal product (depending on clinical data) is 75–100 IU/kg IV bolus over 10 minutes. Maintenance dose: children aged 1 to 3 months, 25–30 IU/kg/hour (800 IU/kg/day); children older than 1 year, 18–20 IU/kg/hour intravenous drip [21, 43].

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

Comments: Information on the treatment of pneumonia is presented in the relevant clinical guidelines [77].

There are no antidotes for NSAID poisoning.

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: Depending on the course of clinical manifestations in patients, it is necessary to consider parenteral administration of: hypnotics and sedatives: Dexmedetomidine, Midazolam**; general anesthetics: Propofol**, Sodium oxybate**; anxiolytics: Diazepam** [57, 65, 81, 84, 85, 97].

To relieve psychomotor agitation and delirium in adult patients, Diazepam** is administered:

IV at an initial dose of 0.1–0.2 mg/kg (0.02–0.04 ml/kg). Injections are repeated every 8 hours until acute symptoms disappear.

IM 2.5–10 mg (0.5–2 ml). If necessary, administered repeatedly after 3–4 hours.

In patients under 18 years of age, Diazepam** is administered to relieve convulsive states:

neonates older than 30 days and children under 5 years – IV slowly at 0.1–0.3 mg/kg body weight up to a maximum dose of 5 mg; if necessary, injections are repeated after 2–4 hours (depending on clinical symptoms).

children aged 5 to 18 years – IV slowly at 1 mg every 2–5 min up to a maximum dose of 10 mg; if necessary, treatment can be repeated in 2–4 hours.

For long-term sedation in intensive care for patients of all ages, IV administration of Midazolam** is possible:

Adults – an initial dose of 0.03–0.3 mg/kg is administered IV fractionally. Maintenance dose – 0.03–0.2 mg/kg/h.

Neonates and children under 6 months – continuous IV infusion starting at 0.03 mg/kg/h (gestational age less than 32 weeks) or 0.06 mg/kg/h (from 32 weeks up to 6 months).

Children over 6 months – administered IV slowly at an initial dose of 0.05–0.2 mg/kg [57, 65, 81, 97];

Dexmedetomidine** is used as a sedative agent (medical sleep) in adult patients and children over 12 years of age (contraindicated in children under 12 years; contraindicated in children under 18 years for procedural sedation) admitted to an anesthesiology, resuscitation and intensive care unit, whose required depth of sedation does not exceed arousal in response to verbal stimulation (corresponding to a range of 0 to -3 on the Richmond Agitation-Sedation Scale (RASS). During mechanical ventilation and sedation, the initial infusion rate of the drug is 0.7 mcg/kg/h, with subsequent dose adjustment within the range of 0.2 to 1.4 mcg/kg/h to achieve the desired level of sedation; the maximum dose of the drug should not exceed 1.4 mcg/kg/h [82, 83].

Propofol** (10 mg/ml) is a general anesthetic agent used intravenously in patients in anesthesiology, resuscitation and intensive care units.

Adults: For the induction of general anesthesia, it is administered slowly at a dose of approximately 40 mg every 10 seconds until signs of anesthesia appear. For adult patients under 55 years of age, the average dose of the drug is 1.5–2.5 mg/kg (the required effect may be achieved at a lower dose – 20–50 mg/min). For sedation (in patients over 16 years of age receiving mechanical ventilation in the ICU), the dose of the drug is selected individually and depends on the required degree of sedation, usually being 0.3–4.0 mg/kg/h; the infusion rate should not exceed 4.0 mg/kg/h.

Children: Propofol** is not recommended for use under 1 month of age. For the induction of general anesthesia in children aged 1 month to 3 years, the dose is 2.5–4 mg/kg, and over 8 years – 2.5 mg/kg.

Providing a sedative effect during intensive care is recommended via continuous infusion. The infusion rate should be adjusted taking into account the required depth of the sedative effect. A dose ranging from 0.3 to 4.0 mg/kg/h should ensure the achievement of a satisfactory sedative effect [84, 85]; To maintain general anesthesia, the infusion rate is within 9–15 mg/kg/h.

Sodium oxybate** is used as an antishock agent for sedative and hypnotic purposes at a dose of 50–100 mg/kg [21].

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

Comments: The drug is administered only parenterally in 100–200 ml of 5% or 10% dextrose solution or 0.9% sodium chloride solution. Administration rate is 3–4 ml/min. Administered to adults: in acute poisoning, 10–20 ml intravenous drip after dilution in 5% or 10% dextrose** solution; in toxic and hypoxic encephalopathy, in a volume of 10 ml per administration twice a day with an interval of 8–12 hours (treatment course of 5 days in adults and children); in a comatose state – in a volume of 20 ml per administration diluted in 200 ml of dextrose** solution. Administered to children of all ages at a rate of 2 ml/kg, at a speed of 1 to 4 ml/h after dilution in 5% or 10% dextrose** solution[34, 86, 87].

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

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

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

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

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

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Rehabilitation focuses on restoring somatovegetative and mental functions impaired as a result of intoxication. In uncomplicated poisoning, rehabilitation is not required.

• If mental function disorders occur during the somatogenic stage of poisoning, rehabilitation is recommended in a psychiatric inpatient facility or psychoneurological dispensary (following an initial examination/consultation by a psychiatrist or a pediatric psychiatrist, and a conclusion regarding the necessity of inpatient or outpatient treatment) [91].

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.

5. Prevention and Dispensary Observation

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

6. Organization of Medical Care

Medical care for patients with acute NSAID poisoning is provided in accordance with Order of the Russian Ministry of Health No. 925n dated November 15, 2012, "On Approval of the Procedure for Providing Medical Care to Patients with Acute Chemical Poisoning."

All victims with NSAID poisoning should preferably be hospitalized in a specialized acute poisoning center. In the absence of an acute poisoning center, patients with severe poisoning and complications, especially with vital function impairment, should be hospitalized in an intensive care unit or an intensive care ward of an emergency hospital department equipped for hemodialysis, with subsequent transfer to an acute poisoning center or, upon stabilization, to a specialized department.

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

According to this order, medical care for patients with acute poisoning is provided in the following forms:

• primary health care;

• emergency medical care, including specialized emergency medical care;

• specialized medical care.

Medical care is provided under the following conditions:

• outside a medical organization (at the location of the ambulance team dispatch call, as well as in a vehicle during medical evacuation);

• outpatiently (under conditions not providing for round-the-clock medical monitoring and treatment), including at home upon calling a healthcare professional;

• inpatient (in settings providing round-the-clock medical observation and treatment).

Medical care is provided in the following forms:

• emergency – for acute chemical poisoning presenting a life threat to the patient;

• urgent – for acute chemical poisoning without overt signs of a life threat to the patient.

Primary health care includes: primary pre-medical health care; primary medical (physician-led) health care; primary specialized health care. Primary pre-medical health care is provided by mid-level medical personnel. Primary medical health care is provided by a general practitioner, district general practitioner, or family physician. Primary specialized health care is provided by medical specialists.

Ambulance, including specialized ambulance, medical care is provided by paramedic dispatch teams and physician-led dispatch teams. Ambulance, including specialized ambulance, care is provided in emergency and urgent forms outside a medical organization as well as in inpatient settings of a medical organization. When providing ambulance care, medical evacuation is carried out when necessary, which includes air-medical and standard medical evacuation.

Specialized, including high-tech, medical care includes diagnosis, treatment of acute chemical poisoning, other diseases and conditions requiring special methods and complex medical technologies, measures aimed at preventing complications caused by acute chemical poisoning, as well as medical rehabilitation.

Medical care for patients with acute chemical poisoning is provided:

• in acute poisoning centers (departments);

• in medical organizations having an intensive care unit (ward, block);

If a medical organization lacks an acute poisoning center (department) but has an intensive care unit (ward, block), medical care for patients with severe acute chemical poisoning is provided in the intensive care unit (ward, block), while for patients with moderate acute chemical poisoning and those transferred from the intensive care unit (ward, block), it is provided in the therapeutic departments of the medical organization.

If the medical organizations providing care lack specialized toxicological units, round-the-clock informational and consultative support is provided by the information and consultation toxicological center (department) via telephone.

Medical care for patients under the age of 15 with acute chemical poisoning is provided in an acute poisoning center (department) or in an intensive care unit (ward, block) featuring an acute poisoning ward operating within a pediatric medical organization, or on specially allocated pediatric beds in the acute poisoning center (department) of an adult medical organization.

If medical care requires the mandatory use of extracorporeal detoxification methods (hemodialysis, hemoperfusion, etc.) as decided by a medical board involving a toxicologist from the acute poisoning center (department) and in the absence of medical contraindications for transportation, patients with acute chemical poisoning are transferred to the acute poisoning center (department) of a medical organization.

In the event of complications requiring specialized treatment (post-hypoxic encephalopathy resulting in a vegetative state, exacerbation of a mental illness, etc.), patients are subject to transfer to the appropriate department of the medical organization according to the disease (complication) profile.

Indications for hospitalization

All victims with NSAID poisoning should preferably be hospitalized in a specialized acute poisoning center. In the absence of an acute poisoning center, patients with severe poisoning and complications, especially with vital function impairment, should be hospitalized in an intensive care unit or an intensive care ward of an emergency hospital department equipped for hemodialysis, with subsequent transfer to an acute poisoning center or, upon stabilization, to a specialized department.

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

Indications for Hospital Discharge

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.

Average duration of inpatient treatment:

1. mild severity – 1 to 2 bed-days;

2. moderate severity – 3–5 bed-days;

3. severe without complications – 7–14 days;

4. severe (with complications: pneumonia, acute kidney injury, acute hepato-renal failure) – duration of treatment from 14 to 24 bed-days.

7. Additional Information

Factors influencing the course and outcome of the disease.

1. Advanced and senile age of the patient;

2. Presence of chronic cardiovascular, hepatic, or renal diseases, as well as metabolic disorders.

Criteria for Evaluating the Quality of Medical Care

Table 3 – Quality of medical care evaluation criteria [28]

References

Appendix A1. Working Group Composition

1. Lodyagin Alexey Nikolaevich – Doctor of Medical Sciences, Associate Professor, Head of the Department of Clinical Toxicology, Saint Petersburg Research Institute of Emergency Medicine named after I.I. Dzhanelidze, Co-Chairman of the Interregional Charitable Public Organization "Association of Clinical Toxicologists", Chief freelance specialist toxicologist of the Healthcare Committee of Saint Petersburg, Chief freelance specialist toxicologist of the Northwestern Federal District.

2. Batotsyrenov Bair Vasilievich – Doctor of Medical Sciences, Associate Professor, Chief Researcher of the Department of Clinical Toxicology, Saint Petersburg Research Institute of Emergency Medicine named after I.I. Dzhanelidze, Member of the Interregional Charitable Public Organization "Association of Clinical Toxicologists".

3. Simonova Anastasia Yuryevna – Candidate of Medical Sciences, Leading Researcher at the Department of Acute Poisonings and Somatopsychiatric Disorders, Toxicologist of the highest qualification category at the Admission Department for Patients with Acute Poisonings and Somatopsychiatric Disorders, Research Institute of Emergency Medicine named after N.V. Sklifosovsky of the Moscow Healthcare Department, Chief freelance toxicologist of the Moscow Healthcare Department.

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

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

6. Narsiculov Rustam Abduhalimovich – Doctor of Medical Sciences, Researcher at the Department of Clinical Toxicology, Saint Petersburg Research Institute of Emergency Medicine named after I.I. Dzhanelidze.

7. Medvedev Anton Alexandrovich – Physician of the Chemical-Toxicological Laboratory of the Department of Clinical Toxicology, Saint Petersburg Research Institute of Emergency Medicine named after I.I. Dzhanelidze.

8. Antonova Anna Mikhailovna – Candidate of Medical Sciences, Staff Member of the Department of Clinical Toxicology, Saint Petersburg Research Institute of Emergency Medicine named after I.I. Dzhanelidze.

Conflict of interest

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

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience:

1. Medical professionals providing primary pre-medical, medical, and specialized health care: secondary medical education personnel, emergency and urgent medical care physicians, general practitioners, family physicians;

2. Medical professionals providing specialized inpatient medical care: toxicologists, anesthesiologists-intensivists;

3. Medical professionals providing inpatient medical care in non-specialized treatment units of medical organizations: general practitioners, pediatricians;

4. Psychiatrists-narcologists.

5. Forensic medical experts

In these clinical guidelines, all information is presented taking into account its validity (level of evidence) depending on the quantity and quality of studies on the given topic.

Scales for assessing levels of evidence (LE) for diagnostic, preventive, treatment, and rehabilitation methods (diagnostic, preventive, therapeutic, rehabilitation interventions) and the scale for assessing grades of recommendation (GR) for preventive, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, rehabilitation interventions)

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

Table 3 – Scale for assessing levels of evidence (LE) for methods of prevention, treatment, and medical rehabilitation, including those based on natural therapeutic factors (preventive, therapeutic, rehabilitation interventions)

Table 4 – Scale for assessing grades of recommendation (GR) for methods of prevention, diagnosis, treatment, and medical rehabilitation, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, rehabilitation interventions)

Appendix A3. Reference Materials

• Toxic effects of substances of chiefly nonmedicinal origin (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.;

• Order of the Ministry of Health of the Russian Federation No. 925n dated November 30, 2012 "On approval of the procedure for providing medical care for acute chemical poisoning";

• Order of the Ministry of Health and Social Development of the Russian Federation 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."

• CR400. Chronic pain syndrome (CPS) in adult patients in need of palliative medical care (http://cr.rosminzdrav.ru/#!/schema/708)

• CR337. Pain syndrome (PS) in children in need of palliative medical care (http://cr.rosminzdrav.ru/#!/schema/886)

Appendix B. Physician Action Algorithms

Diagnosis of uncomplicated NSAID poisoning

A. Clinical examination:

• assessment of the severity of the condition;

• assessment of the level of consciousness (using the Glasgow Coma Scale, points);

• pupillary status (diameter, reaction to light, presence of anisocoria);

• presence or absence of nuchal rigidity;

• muscle tone status;

• status of reflexes (hypo- or hyperreflexia, presence of pathological reflexes);

• condition of the skin and visible mucous membranes, presence of visible injuries;

• hemodynamic status (heart rate, pulse examination, blood pressure);

• status of external respiration functions (respiratory rate, effectiveness of spontaneous breathing, rhythm, presence of pathological breathing patterns, percussion and auscultation of the chest organs, pulse oximetry);

• state of the digestive system (visual and auscultatory examination of the abdomen, shape, symmetry, tension of the abdominal wall, presence of reaction to palpation, assessment of peristalsis);

• state of the urogenital system (color and amount of urine, presence of the costovertebral angle tenderness sign, vaginal discharge).

B. Laboratory tests

• complete blood count (CBC) with differential;

• general general-clinical blood chemistry test;

• general (clinical) urinalysis;

• study of acid-base balance and blood gases;

• study of the blood coagulation system, including determining the blood fibrinogen level, international normalized ratio (INR), and prothrombin (thromboplastin) time in blood or plasma.

C. Instrumental tests:

• electrocardiography recording;

• radiography of the entire skull in one or more projections, or computed tomography of the brain, or computed tomography of the brain with intravenous contrast;

• targeted radiography of the chest organs or computed tomography of the chest cavity.

Diagnosis of complicated poisoning with an unspecified NSAID accompanied by impaired consciousness:

I. Central nervous system complication:

D. Clinical examination (additionally to A as indicated):

• neurologist consultation;

• neurosurgeon consultation;

• psychiatrist consultation;

• infectious disease specialist consultation.

E. Laboratory tests (additionally to B as indicated):

• lumbar puncture;

• Microscopic examination of cerebrospinal fluid, cell count in a counting chamber (determination of pleocytosis).

F. Instrumental tests (additionally to V as indicated):

• brain CT;

• brain MRI;

• electroencephalography.

II. Respiratory system complication

D. Clinical examination (additionally to A as indicated):

• general practitioner consultation.

E. Laboratory tests (additionally to B as indicated):

• Microbiological (cultural) examination of sputum for aerobic and facultatively anaerobic microorganisms and determination of microbial sensitivity to antimicrobial chemotherapeutic agents.

• F. Instrumental tests (additionally to V as indicated):

• lung CT;

• Bronchoscopy (diagnosis [e.g., in case of gastric content aspiration], sanitation of the tracheobronchial tree).

III. Cardiovascular system complication:

D. Clinical examination (additionally to A as indicated):

• general practitioner consultation;

• cardiologist consultation.

E. Laboratory tests (additionally to B as indicated):

• general general-clinical blood chemistry test (myocardial damage markers).

F. Instrumental tests (additionally to V as indicated):

• Echocardiography.

IV. Urinary system complication:

D. Clinical examination (additionally to A as indicated):

• general practitioner consultation.

E. Laboratory tests (additionally to B as indicated):

• general general-clinical blood chemistry test (determination of blood creatine kinase activity, blood myoglobin level study, blood aspartate aminotransferase activity determination, blood urea level study, blood creatinine level study).

F. Instrumental tests (additionally to V as indicated):

• Ultrasound of the kidneys and urinary tract.

V. Digestive system complications

F. Instrumental tests (additionally to V as indicated):

• EGD (fistulae, tracheostomy tube perforations, bleeding).

Appendix C. Patient Information

Information for a patient admitted in a coma is provided after the recovery of consciousness and must include details on complications that occurred during the toxigenic stage of poisoning, as well as the planned rehabilitation treatment (if necessary for the specific patient).

In mild and moderate poisoning, 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, hepatoprotective therapy). The patient (or their legal representative) 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 G1. 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

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.