Barbiturate poisoning (T42.3): clinical guidelines

List of Abbreviations

Terms and Definitions

Barbiturates (lat. barbiturate) are a group of medicinal products derived from barbituric acid that have a depressant effect on the central nervous system. Depending on the dose, their effect can range from a mild sedative state to surgical anesthesia [28, 30, 43].

Previously, barbiturates were widely prescribed as sedatives and hypnotics. Currently, their scope of application is significantly limited because, firstly, they have a narrow therapeutic index, which can lead to overdose and toxic effects, and secondly, prolonged use of barbiturates can lead to tolerance and drug dependence [28, 35, 43]. In clinical practice today, barbituric acid derivatives (barbiturates) are used as antiepileptic drugs for focal seizures, as well as for drug-induced epileptic seizures [5, 27].

Detoxification is the process of neutralizing and removing an exogenous toxic substance from the body. Detoxification, as a natural process of protecting the body against a toxicant, includes various mechanisms aimed at converting the poison into non-toxic compounds (metabolites), carried out predominantly in the liver, and eliminating the poison or its metabolites through various pathways—via the kidneys, intestines, liver, lungs, and skin. During natural detoxification, metabolites more toxic than the toxicant entering the body may be formed (lethal synthesis); furthermore, passing through metabolism in the liver and excretion via the kidneys, the toxicant and its toxic metabolites can lead to damage to these organs and the development of acute renal or hepatic failure [9, 12].

Accelerated detoxification – in order to more intensively remove the toxicant from the body, various methods of accelerated detoxification are used, such as forced diuresis (drug-induced diuresis enhancement), gastrointestinal tract cleansing (gastric lavage, administration of laxatives, enterosorbents, intestinal lavage), extracorporeal blood purification methods (hemodialysis and its modifications, hemoperfusion, peritoneal dialysis, plasmapheresis, etc.) [9].

Disease – a disturbance of bodily function, working capacity, and the ability to adapt to changing environmental 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 vital activity caused by toxic substances penetrating the body from the outside or formed 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 perhaps to a greater extent endogenous toxicosis [9].

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

Poisoning is a disease developing as a result of external (exogenous) exposure of a human or animal organism to chemical compounds in quantities that cause disruptions of physiological functions and pose a danger to life [10, 11].

Barbiturate poisoning is a comatose state that develops acutely as a result of ingesting a toxic dose of barbituric acid derivatives [12].

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

Somatogenic stage of poisoning is the period of the course of an acute chemical illness, beginning after the elimination from the body or destruction of the toxic substance in the form of residual damage to the structure and functions of various organs and systems of the body [12], manifesting, as a rule, with various somatic and psychoneurological complications such as pneumonia, acute renal or hepatic failure, toxic polyneuropathy, anemia, psychoorganic syndrome, etc. In this stage of poisoning, specific (antidote) therapy is not required, and detoxification can be aimed solely at treating endotoxicosis.

Condition – changes in the body arising in connection with the action of pathogenic and/or physiological factors and requiring medical care.

Toxicogenic stage of poisoning is the period of the course of an acute chemical illness, starting from the moment the toxic substance enters the body in a concentration capable of causing a specific effect and lasting until its elimination. It is characterized by the specificity of 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 ingested poison and its concentration in the blood. The main therapeutic task in this period is to shorten its duration as early as possible by using various methods of accelerated detoxification, antidote therapy, and symptomatic therapy [9, 12].

Rhabdomyolysis is a syndrome representing the extreme degree of myopathy and characterized by the destruction of muscle tissue cells, a sharp increase in the levels of creatine kinase and myoglobin, myoglobinuria, and the development of acute renal failure [11, 37].

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Barbituric acid derivative (barbiturate) poisoning is a disease developing as a result of the external (exogenous) exposure of the body to barbituric acid derivatives (barbiturates), causing disruptions of physiological functions and posing a danger to health and life [12].

Barbituric acid derivatives (barbiturates) are a group of medicinal products that exert a depressant effect on the central nervous system. The toxic effect is determined by the dose taken and manifests as consciousness disorders in the form of CNS depression ranging from nubilation to atonic coma [12].

The main representatives of barbituric acid derivatives of greatest toxicological significance are amobarbital, barbital, heptobarbital, phenobarbital, cyclobarbital, and diallylbarbituric acid [12].

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

Barbituric acid derivatives (barbiturates) comprise an extensive group of chemical compounds obtained by the interaction of malonic acid and urea, numbering over 2,500 different substances that vary in their structure and pharmacological action. In medical practice, barbituric acid derivatives are used as sedative-hypnotics, antiepileptic drugs, and anesthetics. Combination drugs containing barbiturates are widespread. Depending on the nature of the radical, barbiturates have a shorter or longer duration of action, ranging from 15–20 minutes to 1–2 days. Depending on the duration of action, the following groups of barbiturates are distinguished: 1. Long-acting (8–12 hours) – phenobarbital (luminal), barbital (veronal), barbital sodium (medinal); 2. Intermediate-acting (6–8 hours) – amobarbital (barbamyl), pentobarbital sodium (nembutal); 3. Short-acting (4–6 hours) – hexobarbital, thiopental sodium. In addition, barbiturates are contained in a number of combination drugs, for example, Valocordin, Corvalol, Dipasalin, Bromital, etc. [12, 14].

All barbituric acid derivatives are CNS depressants [12].

The selectivity of the action of barbiturates on the CNS can be divided into two main categories: 1. enhancement of the synaptic activity of inhibitory neurotransmitters; 2. blockade of the synaptic action of excitatory neurotransmitters. GABA receptors are the sole proven site of action for barbiturate-induced anesthesia. By binding to GABA receptors, barbiturates enhance and mimic the action of GABA, increasing chloride flux through the ion channel, which leads to hyperpolarization of the cell membrane and an increase in the excitation threshold of the postsynaptic neuron [53].

At higher concentrations, barbiturates directly activate chloride channels without binding GABA, acting as agonists. The GABA-mimetic effect at somewhat higher concentrations may be responsible for so-called barbiturate anesthesia [57].

Barbiturates also inhibit the synaptic transmission of excitatory neurotransmitters such as glutamate and acetylcholine. The ability of barbiturates to block excitation transmission in the CNS is specific to synaptic ion channels. However, thiopental may exert GABA-independent effects by acting on the glutamatergic NMDA system [41].

Barbiturates are weak acids when dissolved, with a negative logarithm of the dissociation constant ($pK_a$) of 7.2–8.0 under physiological conditions. They are well absorbed when taken orally (bioavailability 90–100%). Resorption occurs in the stomach and small intestine via passive diffusion, a process significantly accelerated by alcohol intake. For example, peak plasma concentration is reached in 4–8 hours for barbital, and 12–18 hours for phenobarbital. However, poisoning is frequently accompanied by depression of gastrointestinal motility, which can cause barbiturates to be retained in the body for up to several days [12]. It is also worth noting that the depression of gastrointestinal motility in short-acting barbiturate poisoning contributes to an increase in endogenous ammonia in the blood and brain, depletes the Krebs cycle intermediate pool, and alters acetylcholinesterase activity [26]. Barbiturates are distributed to all body tissues and biological fluids; however, their concentration may vary depending on lipophilicity, protein binding, molecule ionization, and tissue blood flow intensity. Their varying duration of action is due to differing degrees of plasma protein binding, rates of biotransformation in the body, and excretion. The free fraction of barbiturates determines the physiological activity of the substance. For instance, hypoproteinemia, acidosis, and hypothermia lead to an increase in the free fraction of barbiturates and enhance toxic effects. The lower the binding of barbiturates to blood proteins, the more they are excreted in the urine. Barbiturates also induce the hepatic cytochrome P450 enzyme system [29], producing inactive metabolites that are excreted in the urine both unchanged and as metabolites (glucuronic acid conjugates), wherein alkaline urine pH values increase the excretion of the unchanged substance (without affecting the half-life) [12, 51, 52].

Barbiturates, much like CNS depressants, have a potent effect on cerebral metabolism. Dose-dependent depression of cerebral oxygen consumption (CMRO₂) causes progressive EEG depression, decreases the adenosine triphosphate consumption rate, and protects against incomplete cerebral ischemia [47].

The effect of barbiturates on cerebral metabolism peaks at 50% depression of brain function, at which the decrease in oxygen levels is defined as a reduction in cerebral oxygen consumption, releasing all metabolic energy to maintain cellular integration. With the decrease in cerebral oxygen consumption, there is a parallel reduction in cerebral perfusion, which is expressed as a decrease in cerebral blood flow and intracranial pressure (ICP). As cerebral oxygen consumption is restricted, cerebrovascular resistance increases and cerebral blood flow decreases [36].

Comatose states caused by the toxic effect of barbiturates on the CNS are characterized by a specific staging. These sequentially develop into lethargy and deep soporose sleep (Stage 1 – mild poisoning), superficial coma with increased or decreased tendon reflexes and altered pupillary light reflexes (Stage 2 – moderate poisoning). Finally, deep coma with areflexia and lack of response to painful stimuli (Stage 3 – severe poisoning), which proceeds most severely, with respiratory and circulatory disorders. Marked dynamics of neurological symptoms and the absence of persistent focal symptoms help differentiate these comatose states from coma caused by acute cerebrovascular accidents (stroke) or traumatic brain injury [12, 34].

The depressant effect of barbiturates on the cardiovascular system is the result of central and peripheral (direct vascular and cardiac) effects [50, 56].

The primary cardiovascular effect of barbiturate induction is peripheral vasodilation due to the depressive effect on the cardiovascular center and non-specific histamine release, leading to a decrease in venous return [3, 40].

Another effect is a decrease in myocardial contractility associated with reduced calcium availability for myofibrils. Mechanisms of decreased cardiac output include: (1) direct negative inotropic action, (2) decreased ventricular filling due to increased capacitance, and (3) transient reduction in sympathetic nervous system activity [44, 54].

Thiopental administration should be avoided in hypovolemic patients due to a significant decrease in cardiac output (69%) and a marked drop in blood pressure [24]. In decompensated patients, barbiturate induction may cause pronounced hemodynamic depression [39].

The main clinical symptoms of acute barbiturate poisoning concerning the cardiovascular system are tachycardia and hypotension. The most typical electrocardiographic changes are sinus tachycardia, prolongation of the electrical systole, ST-segment depression below the isoelectric line, and a negative T wave. These changes reflect dystrophic myocardial disorders and are observed during the development of a deep comatose state [12].

Thus, the toxic effect of barbiturates on the cardiovascular system can be defined as the result of a sharp decrease in venous and arterial pressure; reduced cardiac output; decreased circulating blood volume; and tissue hypoxia.

Along with this, hemodynamic disorders cause metabolic disturbances, increased heat dissipation, and, consequently, a drop in body temperature.

Barbiturates cause dose-dependent central respiratory depression. Transient apnea also frequently develops after barbiturate administration for induction during anesthesia. Evidence of central depression is the correlation between EEG suppression and minute ventilation. As the sedative effect increases, minute ventilation decreases [42].

Contraindications to the intravenous use of barbiturates include: (1) airway obstruction or breathing disorders, as thiopental may worsen respiratory depression; (2) severe cardiovascular failure or shock may preclude their use; (3) status asthmaticus is a condition where airway control and ventilation can be worsened by thiopental administration; (4) an acute porphyria attack may be triggered following thiopental administration; (5) without proper equipment (venous access) and respiratory apparatus (mechanical ventilation devices), thiopental must not be used [55].

In acute poisonings, central forms of respiratory disorders manifest as hypoventilation caused by the direct depressant effect of barbiturates on the respiratory center and medulla oblongata, which is manifested by a decrease in respiratory rate and tidal volume. The aspiration-obstructive form of respiratory disorders is caused by mechanical asphyxia due to bronchorrhea and hypersalivation, tongue drop, laryngospasm, and gastric content aspiration. Bronchobstructive events may develop due to enhanced vagal tone.

The most severe respiratory disorders are observed with a combination of central and obstructive respiratory disturbances. Following the resolution of acute external respiration disorders, the main cause of respiratory failure becomes inflammatory processes in the lungs—pneumonia and tracheobronchitis [3, 12].

In the clinical symptoms of acute barbiturate poisoning, a specific place is occupied by trophic disorders in the form of bullous dermatitis and necrotic dermatomyositis, proceeding like rapidly developing pressure ulcers. In the most severe cases, the development of prolonged crush syndrome or positional compression syndrome [9, 12] or systemic rhabdomyolysis is observed, typically proceeding with acute kidney injury syndrome [9, 37]. Clinical cases of Stevens-Johnson syndrome following barbiturate intake have been described in the literature [45, 46].

1.3 Epidemiology of the Disease or Condition

Currently, the scope of barbiturate use has significantly narrowed, which has led to a decrease in the prevalence of barbiturate dependence. The risk group for developing barbiturate dependence includes individuals who need to take barbituric acid-based medications for medical indications.

A distinctive feature of barbiturate dependence is a wide variation in the time frame from the first drug intake to the onset of addiction (from several years when used for medical indications to several weeks or months with uncontrolled intake).

Regarding acute barbiturate poisonings, taking Saint Petersburg as an example, according to reports from the Saint Petersburg Toxicology Center (Form No. 64), patients with this pathology accounted for 5.2%, 2.4%, and 1.7% of all admissions to the toxicology department in 2017–2019, respectively. In-hospital mortality relative to overall mortality in acute poisonings averaged 13.2%, 8.1%, and 4.8% for barbiturate poisoning during 2017–2019, respectively [8, 19, 20, 21].

1.4 Features of Coding the Disease or Condition

Poisoning by antiepileptic, sedative-hypnotic and antiparkinsonism drugs (T42):

T42.3 – Poisoning by barbiturates.

1.5 Classification of the disease or condition

There are 4 clinical stages of intoxication:

Stage 1 – "somnolence": characterized by drowsiness, apathy, decreased response to external stimuli, although contact with the patient can be established.

Stage 2 – "superficial coma": loss of consciousness is noted. Patients may respond to painful stimuli with a weak motor reaction and transient pupil dilation. Swallowing is impaired, the cough reflex is weakened, and respiratory disorders develop due to tongue drop.

Stage 3 – "deep coma": characterized by the absence of all reflexes; signs of life-threatening impairment of vital body functions are observed.

The forefront is taken by respiratory disorders ranging from shallow, arrhythmic breathing to complete paralysis associated with central nervous system depression.

In stage 4 – the "post-comatose state" – consciousness is gradually restored. During the first 24 hours after awakening, most patients exhibit asthenovegetative syndrome.

Toxic effects of barbituric acid derivatives.

Classified by severity:

• mild – not accompanied by loss of consciousness,

• moderate – with impaired consciousness resembling a soporose state or toxic encephalopathy, but without complications,

• severe – characterized by complete loss of consciousness (coma), which may be accompanied by various complications [12].

1.6 Clinical presentation of the disease or condition

The rapid development of symptoms and complications makes acute poisoning by barbituric acid derivatives one of the most severe diseases of chemical etiology. Signs of acute poisoning appear immediately after substance ingestion; the severity of clinical manifestations and poisoning severity depend on the dose (concentration) of the ingested substance, its exposure time, age, and comorbid pathology [10, 12].

Clinical manifestations of acute poisonings by barbituric acid derivatives are uniform and consist of a combination of symptoms of CNS depression (obtundation, sopor, coma), respiratory depression (bradypnea, suppression of the cough reflex, asphyxia), gastrointestinal tract dysfunction (decreased peristalsis), and renal impairment (urinary retention). The most informative signs of this poisoning are the development of toxic-hypoxic encephalopathy, accompanied by respiratory depression in the most severe cases. Criteria for assessing the severity of poisoning should include the level of consciousness depression, respiratory depression, and cardiovascular system disorders [10, 12, 48].

Complications should be considered taking into account the toxicogenic and somatogenic stages of poisoning. The most dangerous are rapidly developing complications in the toxicogenic stage, such as respiratory depression, especially following intravenous administration of a toxic dose of the drug or asphyxia due to aspiration of gastric contents. Characteristic complications of the somatogenic stage include: pneumonia, toxic-hypoxic encephalopathy, and myorenal syndrome associated with positional trauma during prolonged bed rest of the patient [12, 49].

2. Diagnostics, medical indications and contraindications for diagnostic methods

• evidence of recent use of barbituric acid derivatives (barbiturates) in toxic doses;

• presence of symptoms and signs of poisoning consistent with the known action of barbituric acid derivatives (barbiturates), manifested by the development of varying degrees of consciousness impairment, sufficiently pronounced to lead to clinically significant disorders of consciousness and life support systems (respiratory, cardiovascular) hazardous to the patient's health and life;

• the existing symptoms or signs cannot be explained by a disease unrelated to the use of barbituric acid derivatives (barbiturates), nor by another mental or behavioral disorder [17, 18, 31, 32].

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

2.1 Complaints and Anamnesis

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

• All patients with acute poisoning by barbituric acid derivatives are recommended to receive emergency medical care outside a medical organization by an ambulance team, including either an examination by an emergency physician (specialist physician) during the provision of emergency medical care, or an examination by an emergency paramedic (mid-level medical specialist) during the provision of emergency medical care [8, 21].

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

Comment. The emergency physician or emergency paramedic performs a detailed medical history collection in patients with suspected use of barbituric acid derivatives. Diagnosis of poisonings must be carried out based on the toxicological situation (discovery of containers, packaging from consumed liquids, etc.), toxicological history aimed at identifying information about the use of other chemical substances, ethanol, dependence on certain substances, as well as the clinical picture of poisoning. The ambulance team has a greater opportunity directly at the scene to assess the circumstances of the poisoning and the initial clinical manifestations, and to obtain necessary information not only from the victim, but also from people around them, including those who called for an ambulance.

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

When taking the medical history (if feasible), attention should be paid to which specific drug from the barbituric acid derivatives group the patient took, where it was acquired, for what purpose the substance was taken (intoxication, self-treatment, suicide attempt), the time elapsed since ingestion, and whether ethanol was consumed [8, 21].

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

Comments: in cases of barbiturate poisoning, the principles of toxicological history-taking are not always applicable. This applies to ascertaining such information as: the type or name of the toxic substance taken by the victim; the time of ingestion (poison exposure in the body), which allows with a certain degree of accuracy to assume which phase of poisoning (toxicogenic or somatogenic) the patient is in; the dose of the ingested toxic substance, which determines the likelihood of development and severity of the poisoning; the route of administration of the toxic substance into the body; and clarification of circumstances accompanying the development of poisoning (accidental or intentional).

A specific feature of barbiturate poisoning is the absence in most cases of subjective complaints from the patient – medical assistance is usually sought by relatives or acquaintances who noticed disturbances in their consciousness, behavior, or appearance. Patient complaints in acute poisoning depend on the type, dose, and duration of action (exposure) of barbituric acid derivatives (barbiturates) and are determined either by their primary pharmacological or side effects. Also, patient complaints may be due to the development of complications. It should be noted that in most cases of acute poisoning by barbituric acid derivatives (barbiturates), complaints are generally absent due to the difficulty or impossibility of contacting the patient [17, 18, 31, 32].

Diagnosis of poisoning by barbituric acid derivatives (barbiturates) is based on medical history data and, mainly, on characteristic symptoms: depression of consciousness, respiration, and cardiovascular system disorders. In addition, when barbituric acid derivatives (barbiturates) are administered intravenously (e.g., sodium thiopental**), there are injection marks along the subcutaneous veins of the extremities. It should be noted that poisonings by barbituric acid derivatives do not have diagnostically specific and sharply defined clinical manifestations. The main clinical manifestation is the development of toxic or toxic-hypoxic encephalopathy, which clinically manifests, as a rule, in the development of deficit disorders of consciousness. This is one of the factors complicating the diagnostic search, which is carried out according to the diagnostic algorithm for comatose states [1, 12, 17, 18].

2.2 Physical Examination

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

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

Comments: appearance of the skin: no specific discoloration; in case of respiratory failure, cyanosis of the lips, face, and acrocyanosis are observed; the skin is cold; in deep coma, increased moisture may be noted. It is necessary to identify the presence/absence of rashes, local changes, the so-called "pressure ulcers" resulting from positional trauma due to pressure from the patient's own body weight, known as positional pressure on individual soft tissue areas, leading to areas of skin hyperemia that are often regarded as bruises, hematomas, burns, phlebitis, allergic edema, etc., and are usually detected early on (1–3 days) [12, 17, 18, 37].

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

Comments: assess neuropsychological status: state of consciousness (clear, obtundation, stupor, coma, psychomotor agitation, hallucinations). In the presence of a coma, assess its depth using the Glasgow Coma Scale, the presence or absence of reflexes, pupil width, their reaction to light, the presence (absence) of anisocoria, and muscle tone. When anisocoria or pathological reflexes are detected, pay attention to their constancy ("pupillary play"). In the somatogenic stage, negative psychopathological symptoms may be observed: asthenic confusion, psychoorganic and asthenic symptom complexes, as well as withdrawal, epileptic, and delirious syndromes, and substance withdrawal syndrome [12, 18, 31].

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

Comments: assess the state of breathing: adequacy, rate, depth, symmetry of chest excursion during breathing, and auscultatory findings. Respiratory failure may occur due to alveolar hypoventilation, possible aspiration pneumonitis, or non-cardiogenic pulmonary edema. Pulse oximetry must be performed in every patient [12, 18, 31].

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

Comment: in addition to central disorders of respiratory regulation and respiratory muscle function, aspiration-obstructive disorders associated with mechanical asphyxia may occur, and pathological processes in the lungs—atelectasis and pneumonia—are also causes of hypoxia. In the pathogenesis of pneumonia, which is one of the frequent causes of death in the somatogenic stage, two main factors are important: a prolonged comatose state complicated by aspiration-obstructive disorders. These disorders have no diagnostic value, but merely allow for assessing the severity of poisoning and predicting the outcome [12, 18, 31].

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

Comments: toxic damage to the cardiovascular system manifests as circulatory disorders (cardiac arrhythmias, primary toxicogenic collapse, exotoxic shock) and is caused by impairments in the regulatory mechanisms of circulation and the cardiovascular system (e.g., due to the progression of hypoxic damage). The most severe form of cardiovascular complication is the development of exotoxic shock, which requires immediate resuscitation measures [12, 22, 31].

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 some cases, in patients with acute poisoning accompanied by a comatose state, the odor emanating from the patient is important as it can help identify the psychoactive substance causing intoxication [12]. The clinical presentation of acute poisoning with barbituric acid derivatives (barbiturates) can vary greatly both among different subjects and within the same subject depending on multiple factors. Thus, it may depend on the dose taken, the administration pattern (the time over which the total amount was ingested), individual characteristics of the subject (age, ethnicity, gender, mental and physical condition), characteristics of the toxic substance, and ambient temperature. Finally, the degree of tolerance to barbituric acid derivatives (barbiturates) in dependent individuals is of great importance. Also, when diagnosing acute poisoning with barbituric acid derivatives, it must be taken into account that its symptoms do not always reflect the primary action of the substance; for example, individuals abusing barbiturates may develop symptoms of psychomotor agitation [12, 24].

Furthermore, clinical diagnosis should be carried out taking into account the stage of poisoning—toxicogenic and somatogenic. The leading features are, first of all, signs of toxic damage to the central nervous system, in particular—obtundation, stupor, and coma [12].

During the toxicogenic stage, in mild forms of poisoning, or in patients with high tolerance to barbiturates (e.g., due to a long history of substance use), as well as due to mixed poisonings, for example, in combination with psychostimulants, productive psychopathological disorders may be observed [12, 31].

2.3 Laboratory Diagnostics

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

Comments. Qualitative determination of barbiturates is carried out by immunoassay (IA) and gas chromatography-mass spectrometry (GC-MS) [13, 15, 33], while quantitative evaluation is performed by spectrophotometry [12]. The choice of laboratory diagnostic method depends primarily on the circumstances in which the test is performed (primary health care in an outpatient clinic or the emergency department of a non-specialized hospital, specialized inpatient medical care), as well as on the objective of the study: 1. determining the fact of barbiturate or other psychotropic substance use, 2. identifying a specific substance or substances in the patient's biological media. In the first case, a qualitative immunoassay is sufficient. When using immunoassay, it should be kept in mind that a negative result always indicates the absence of the target toxic substance in the sample, while a positive result, due to potential false positives (cross-reactivity), may lead to a diagnostic error, thus requiring verification by a more precise GC-MS method [12]. Additional chemical and toxicological diagnostics are recommended when a combination of poisoning with barbituric acid derivatives (barbiturates) and psychoactive substances (ethanol, psychotropic drugs), other alcohols, chlorinated and aromatic hydrocarbons is suspected. Research methods will depend on the identified toxicant [12].

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

Comments: test methods will depend on the identified toxicant [12].

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

Comments: GC-MS is an accurate method for the qualitative and quantitative determination of surface-active substances (surfactants/toxicants) in biological environments. It also allows for untargeted analysis, i.e., simultaneously identifying a large number of various toxicants. The HPLC-MS method is less accessible due to its high cost, but it has a significant advantage in that it can detect toxicants that degrade upon heating.

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: severe acute poisoning with barbituric acid derivatives (barbiturates) is frequently complicated by water-electrolyte balance (WEB) and acid-base balance (ABB) disorders. These present as severe abnormalities, most commonly decompensated mixed respiratory and metabolic acidosis, as well as hyperkalemia.

Laboratory diagnostics (minimum analysis including potassium, sodium, blood gas panel, pH, BE) is required to confirm or rule out these abnormalities [4, 16].

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

Comment: for differential diagnosis and severity assessment of poisoning caused by barbituric acid derivatives (barbiturates) and other toxicants inducing altered mental status, it is recommended to determine blood glucose and ABB levels to assess homeostatic status and indirectly identify poisonings associated with prolonged exposure, which are characterized by the development of decompensated mixed respiratory and metabolic acidosis.

The frequency of these tests depends on the severity of the poisoning and the duration of the patient's hospital stay [4, 12, 16, 31, 32, 58, 59].

2.4 Instrumental Diagnostics

Performing these diagnostic procedures does not specify the diagnosis of acute poisoning by barbituric acid derivatives (barbiturates). Nevertheless, they are essential for the early diagnosis of existing complications in moderate and severe poisonings with barbituric acid derivatives (barbiturates), the identification of which can significantly impact the outcome of acute poisoning.

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

Comments: An ECG is performed to rule out or confirm cardiomyopathy and chronic heart disease (especially since the social and medical history of such patients is virtually unknown upon hospital admission).

Level of Proof (LoP) – 5, Level of Recommendation (LoR) – C.

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

Comments: Monitoring of vital functions should preferably be performed instrumentally (using an ICU monitor). If a monitor is unavailable, vital signs are monitored manually at regular intervals.

The frequency of repeated measurements is determined by the attending physician based on the severity of the patient's condition [4, 12, 22, 32].

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

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

• It is strongly recommended that all patients with acute barbiturate poisoning who are delivered from the street or public places, or who have signs of traumatic injuries, undergo skull radiography in one or more projections or brain computed tomography to confirm or rule out traumatic, neurological, or other pathology capable of causing impaired consciousness [1, 17, 18, 32, 60, 64].

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

• It is strongly recommended that all patients with acute barbiturate poisoning and suspected gastric content aspiration undergo diagnostic and therapeutic fiberoptic bronchoscopy (FOB) to detect or rule out gastric content aspiration [3, 18, 31, 32].

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

• It is strongly recommended that all patients with severe and extremely severe acute barbiturate poisoning admitted to the intensive care unit undergo continuous monitoring of cardiac activity, respiration, and body temperature to assess the dynamics of disease severity and evaluate the efficacy of intensive care [4, 22, 33, 60, 64].

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

2.5 Other Procedures

Since acute poisonings by barbituric acid derivatives (barbiturates) are accompanied by impaired consciousness and are characterized by high variability of clinical manifestations, as well as a high probability of life-threatening conditions and complications, differential diagnosis is frequently required.

1. traumatic brain injury, acute cerebrovascular accident;

2. hypoglycemic coma;

3. infectious disease (meningitis, encephalitis, etc.);

4. hepatic and uremic coma, coma associated with endocrine disorders, severe encephalopathies due to water-electrolyte and metabolic imbalances, and other endogenous intoxications in various somatic conditions [3, 17, 18, 60].

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.

• neurosurgeon,

• neurologist,

• infectious disease physician,

• surgeon,

• general practitioner,

• psychiatrist [3, 17, 18, 32, 58, 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.

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. General approaches to the treatment of acute poisoning by barbituric acid derivatives (barbiturates)

Mild acute poisoning by barbituric acid derivatives may manifest as behavioral disorders that may require psychopharmacotherapy and dynamic monitoring. Moderate and severe acute poisoning by barbiturates requires emergency medical care. The severity of acute poisoning by barbituric acid derivatives (barbiturates) does not always correlate with the concentration of barbiturates in the patient's blood. The possibility of immediate quantitative determination of barbiturate concentration in body fluids is not always technically feasible, so when choosing treatment tactics, the physician is often forced to adhere to a symptomatic approach. Assessment of the patient's degree of agitation or sedation is extremely important for clinical diagnosis.

A very convenient diagnostic tool for this is the clinical sedation scale, the Glasgow-Pittsburgh Coma Scale (Appendix G1) [17].

3.2. Provision of emergency medical care outside a medical organization for acute poisoning by barbituric acid derivatives (barbiturates)

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

Comments: treatment should be initiated in all patients by restoring adequate pulmonary ventilation depending on the type of respiratory disorder.

In cases of aspiration and obturation respiratory disorders, it is necessary to perform toilet of the oral cavity, aspiration of upper respiratory tract contents, ensure patency of the upper respiratory tracts, including using airways, laryngeal tube, combitube, laryngeal mask, endotracheal intubation by direct laryngoscopy; in the event of acute respiratory failure, initiate mechanical ventilation (MV) using various types of mechanical ventilators and manual resuscitator kits. In case of hemodynamic disorders, as well as for detoxification therapy, intravenous infusion of solutions affecting water-electrolyte balance and dextrose** solutions is indicated. Therefore, ensuring venous access is important when providing emergency medical care [4, 8, 21].

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

Comments: GTL should be performed starting from the emergency pre-hospital stage as early as possible after toxicant ingestion, as well as in the event of coma and if a large dose of the toxicant is suspected to have been ingested.

Gastrointestinal decontamination via GTL is unlikely to be effective because barbiturates are rapidly absorbed and most patients do not seek care until clinical signs of poisoning appear. In cases of acute severe barbiturate poisoning and deep coma, endotracheal intubation should be performed prior to GTL to prevent aspiration of gastric contents.

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

Comment: Activated charcoal effectively adsorbs barbiturates. [1, 9, 11, 18].

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: in superficial coma – aspiration of upper respiratory tract contents is performed using an airway; in deep coma – endotracheal intubation is performed; in central-type respiratory failure, mechanical ventilation must be performed after preliminary endotracheal intubation [17, 18]; in mixed forms of disorders, aspiration and obturation respiratory disorders are eliminated first, and then mechanical ventilation is connected [17, 18, 60].

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.

3.3. Treatment at the stage of specialized medical care for acute poisoning by barbituric acid derivatives (barbiturates)

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

Comments: it is necessary to ensure restoration and maintenance of airway patency (sanation of the upper respiratory tract (URT), tracheobronchial tree (TBT), insertion of airways, endotracheal intubation, etc.); provision of adequate gas exchange (various respiratory support options); correction of intracranial hypertension (if indicated); maintenance of central and peripheral hemodynamics (blood substitutes and plasma protein fractions, and intravenous irrigation solutions, solutions affecting water-electrolyte balance; in case of circulatory failure – adrenergic and dopaminergic agents, except for cardiac glycosides). The main goal of respiratory support in ventilatory ARF is to replace lost or sharply weakened spontaneous breathing due to dysfunction of the respiratory center and/or disorders of respiratory muscle activity (paralysis, paresis). Dysfunction of the respiratory center in acute poisoning by barbituric acid derivatives (barbiturates) leads to suppression or weakening of the sensitivity of central chemoreceptors, which causes hypoventilation accompanied by life-threatening hypercapnia and hypoxemia.

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

Comments: in patients with acute poisoning by barbituric acid derivatives (barbiturates) who develop acute respiratory failure requiring mechanical ventilation (in the absence of lung injury), CMV (VC) or PCV (PC) should be used as initial (starting) ventilation modes according to the following algorithm (against the background of sedation and/or muscle relaxation):

1. During CMV, set the tidal volume (Vt) equal to 6–8 ml/kg of predicted body weight (in PC mode – peak inspiratory pressure 18–20 cm H₂O); F = 8–12 breath/min; I/E ratio = 1:2; inspiratory flow rate 20–25 l/min (constant or sinusoidal flow waveform), PEEP = 3–5 cm H₂O, FiO₃ = 0.6.

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

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

4. If hyperventilation needs to be established, change the number of machine respiratory cycles to achieve mild hyperventilation (PaCO₂ = 32–35 mm Hg) or moderate hyperventilation (PaCO₂ = 25–30 mm Hg).

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

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

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

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

Taking into account the above algorithm, the most frequently used respiratory support parameters in ventilatory acute respiratory failure (ARF) are presented in Table 1.

Table 1 – Most frequently used parameters of respiratory support in ventilatory acute respiratory failure

In patients with acute barbiturate poisoning complicated by acute respiratory failure, the following main criteria should be used to decide on weaning from respiratory support: "normalization" of neurological status; the patient's ability to initiate spontaneous breathing. During the weaning process, it is necessary to constantly maintain adequate oxygenation (PaO₂ = 85–100 mm Hg, SaO₂ = 96–98% at FiO₂ < 0.4), PaCO₂ within 35–40 mm Hg, and continuously monitor the patient's level of consciousness. After complete discontinuation of machine breath cycles, the ventilator is switched to CPAP mode with a positive pressure level of 3–4 cm H₂O.

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

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

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

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

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

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

In a stable condition (no increase in respiratory failure symptoms and/or neurological deficit), the patient can be extubated and completely switched to spontaneous breathing with humidified oxygen delivery (FiO₂ = 0.3–0.35) for 3–14 hours [25].

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 should be individualized. The volume and composition of the infusion program depend on age, patient condition, concomitant pathology, and complications. Infusion therapy should be carried out under strict volemic control to avoid hyperhydration [1, 10, 45].

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

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

Comment. Indications for prescription include infusion detoxification therapy in acute poisoning and forced diuresis. Adults are administered IV by drip at a rate of 1–4.5 mL/min (up to 90 drops/min). The average daily dose is 10 mL/kg. The course of therapy is up to 11 days. Patients older than 1 year are administered IV by drip at a rate of 6–10 mL/kg/day at a rate of 3–4 mL/min. The course of therapy is up to 11 days. Contraindications include hyperkalemia, hypernatremia, acute kidney injury, and allergic reaction to the drug [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.

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: to correct metabolic acidosis, it is recommended to use 3-5% sodium bicarbonate** solution [4, 16, 18, 22, 38]. Early elimination of acid-base balance disorders is of great importance in the course of acute barbiturate poisoning, since prolonged metabolic acidosis, which naturally develops in barbiturate poisoning, is capable of exerting a pronounced adverse effect on various body systems by itself [16, 22].

Level of Proof (LoP) – 5, Level of Recommendation (LoR) – C.

Comment. Indications for prescription are infusion detoxification therapy in acute poisoning, and alkaline forced diuresis. Adults are administered IV by drip at a rate of 1–4.5 mL/min (up to 90 drops/min). The average daily dose is 10 mL/kg. The course of therapy is up to 11 days. Patients older than 1 year are administered IV by drip at a rate of 6–10 mL/kg/day at a rate of 3–4 mL/min. The course of therapy is up to 11 days.

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

Comment. The drug is administered exclusively intravenously by drip as part of infusion therapy, diluted in 100–200 mL of 5–10% dextrose solution or 0.9% sodium chloride** solution. It is prescribed in a volume of 10 mL per injection 2 times/day every 8–12 hours for 5 days. In a comatose state ‑ in a volume of 20 mL per injection [1, 6, 7, 19].

• To enhance natural detoxification, it is recommended, especially in oral poisonings: gastric lavage via tube [9, 10, 11, 17, 18]; bowel cleansing [9, 12].

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

In uncomplicated poisoning, rehabilitation is not required.

Patients with depression or other mental disorder causing poisoning with barbituric acid derivatives (barbiturates) require rehabilitation in a psychiatric hospital or psycho-neurological dispensary. Further treatment and monitoring of patients are carried out in accordance with clinical guidelines for the disease that caused acute barbiturate poisoning [63, 65].

5. Prevention and Dispensary Observation

In acute poisoning with barbituric acid derivatives (barbiturates), tertiary (modifying) prevention is of the utmost importance; it is primarily medical, individualized, and aimed at preventing re-intoxication and reducing harmful consequences for the mental and somatic spheres of a patient who has suffered severe acute poisoning.

To determine the form of prevention and dispensary monitoring, it is necessary to ascertain whether the patient's acute poisoning was a single incident or occurred as part of a substance use disorder [12, 24]. If substance use with harmful consequences is identified in a patient during a clinical examination, the patient should be offered preventive monitoring at a narcological dispensary for 1 year; if psychoactive substance dependence syndrome is identified, dispensary monitoring for 3 years [65].

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

6. Organization of Medical Care

6.1. Indications for hospitalization in acute poisoning with barbituric acid derivatives (barbiturates)

All victims of acute poisoning with barbituric acid derivatives should be hospitalized, preferably in a specialized acute poison control center. In mild acute poisoning, hospitalization in an acute poison center or on toxicological beds of a hospital is advisable. In the absence of an acute poison center, patients with severe poisoning and complications, especially with vital function disorders, should be hospitalized in an intensive care unit or an intensive care ward of an emergency hospital department where hemodialysis or hemoperfusion can be performed, followed by transfer to an acute poison center or, once the condition stabilizes, to a specialized department.

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

Criteria for discharge from the hospital include restoration of consciousness, normalization of spontaneous breathing and hemodynamics, and normalization of homeostasis parameters.

6.2. Indications for discharge from the hospital of a patient with acute poisoning with barbituric acid derivatives (barbiturates)

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

7. Additional Information

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 — from 3 to 5 bed-days;

3. severe degree without complications — from 7 to 14 bed-days;

4. severe degree (with complications: pneumonia, acute kidney injury (AKI), acute hepatorenal failure) — from 14 to 24 bed-days.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Lodyagin, Alexey Nikolaevich – MD, PhD, Associate Professor, Chief Freelance Toxicologist of the Northwestern Federal District, Head of the Department of Clinical Toxicology, St. Petersburg I.I. Dzhanelidze Research Institute of Emergency Care.

2. Bair V. Batsyrenov – D.Sc. in Medicine, Associate Professor, Chief Researcher at the Department of Clinical Toxicology, Saint Petersburg Research Institute of Emergency Medicine named after I.I. Dzhanelidze.

3. Sinenchenko, Andrey Georgievich – PhD in Medicine, Head of the Department of Emergency Psychiatry, Addiction Medicine and Psychorehabilitation, St. Petersburg I.I. Dzhanelidze Research Institute of Emergency Care.

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

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

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

7. Makhnovsky Andrey Ivanovich – Candidate of Medical Sciences, Deputy Chief Physician for Emergency Medical Care, SB "St. Petersburg Research Institute of Emergency Care named after I.I. Janelidze", St. Petersburg.

8. Teplov Vadim Mikhailovich – Doctor of Medical Sciences, Associate Professor, Head of the Inpatient Emergency Department, Professor at the Department of Emergency Medical Care and Injury Surgery, FSBEI HE "Pavlov First Saint Petersburg State Medical University".

9. Reinyuk Vladimir Leonidovich – Doctor of Medical Sciences, Associate Professor, Acting Director of the FSBSI "Scientific and Clinical Center of Toxicology named after Academician S.N. Golikov of the FMBA of Russia".

10. Semyon V. Kuznetsov – Ph.D. in Medicine, Associate Professor, Leading Researcher at the Scientific and Clinical Center of Toxicology named after Academician S.N. Golikov of the Federal Medical-Biological Agency (FMBA of Russia), Senior Researcher at the Department of Clinical Toxicology, Saint Petersburg Research Institute of Emergency Medicine named after I.I. Dzhanelidze.

11. Demidova Ekaterina Olegovna – Junior Researcher, FSBSI "Scientific and Clinical Center of Toxicology named after Academician S.N. Golikov of the FMBA of Russia".

12. Loladze Alexandre Tarielovich – Anesthesiologist-Resuscitator of the Intensive Care Unit No. 11 (toxicology), Junior Researcher at the Department of Clinical Toxicology, SB "St. Petersburg Research Institute of Emergency Care named after I.I. Janelidze".

There is no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of these clinical guidelines:

1. general practitioner (family physician);

2. psychiatrist-narcologist.

3. emergency and critical care physician;

4. forensic medical expert;

5. functional diagnostics physician;

6. anesthesiologist-intensivist;

7. gastroenterologist;

8. allergist-immunologist;

9. infectious disease physician;

10. cardiologist;

11. laboratory diagnostic physician;

12. neurologist;

13. neurosurgeon;

14. otorhinolaryngologist;

15. district general practitioner;

16. internist;

17. toxicologist;

18. transfusiologist;

19. surgeon;

20. endoscopist;

Methodology for Developing Clinical Guidelines

Working group members independently performed a systematic search and selection of publications. The search was conducted in the PubMed search engine (http://www.ncbi.nlm.nih.gov/pubmed/), the Cochrane Library (http://www.cochranelibrary.com/), the eLIBRARY.ru scientific electronic library (http://elibrary.ru/defaultx.asp), as well as in clinical trial registries: https://clinicaltrials.gov/ and https://www.clinicaltrialsregister.eu/ctr search/search. A total of 220 publications were found, of which 116 publications were selected. Based on the selected publications, thesis-recommendations were formulated, which were evaluated using the scales for assessing the levels of evidence certainty and diagnostic methods, scales for assessing levels of evidence certainty (level of evidence certainty) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, rehabilitation interventions), and scales for assessing the grades of recommendation strength (grade of recommendation strength) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, rehabilitation interventions). (Table 3, Table 4, Table 5) Subsequently, each thesis-recommendation was thoroughly discussed at the general meeting of the working group, and a consensus was reached in all cases of disagreement.

Table 3 – Scale for assessing levels of evidence certainty (level of evidence certainty (LEC)) for diagnostic methods (diagnostic interventions)

Table 4 – Scale for assessing levels of evidence certainty (level of evidence certainty (LEC)) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, rehabilitation interventions)

Table 5 – Scale for assessing grades of recommendation strength (grade of recommendation strength (GRS)) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, rehabilitation interventions)

Procedure for updating clinical guidelines.

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

Appendix A3. Reference Materials

1. Order of the Russian Ministry of Health No. 289 dated October 5, 1998, "On Analytical Diagnostics of Narcotic Drugs, Psychotropic and Other Toxic Substances in the Human Body."

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

3. Order of the Russian Ministry of Health No. 925n dated November 30, 2012, "On Approval of the Procedure for Providing Medical Care for Acute Chemical Poisoning."

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

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

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

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

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

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

Appendix B. Physician Action Algorithms

Treatment of acute barbiturate poisonings includes the following stages.

Detoxification:

• forced diuresis and dialysis-filtration methods are ineffective;

• gastric tube lavage, repeated lavages for 1-2 days;

• administration of carbon enterosorbent (1-2 g/kg);

• intestinal lavage, bowel irrigation;

• surgical methods of detoxification;

  indications:

• moderate or severe poisonings;

• poisonings accompanied by the development of a primary cardiotoxic effect (arrhythmias, electrocardiographic precursors of ventricular rhythm disturbances);

• impaired hepatic detoxification function and renal excretory function.

  contraindications:

• decompensated exotoxic shock;

• method of choice is hemosorption.

In severe poisonings, a repeated hemosorption session is performed after 2-3 hours; blood stabilization in the extracorporeal circuit is ensured by metered heparinization (heparin – 100-200 IU/kg per hour) or intravenous administration of a 4% sodium citrate solution at a rate of 5% of the hemoperfusion rate;

preparation for hemosorption:

• restoration of BCC;

• resuscitation from shock;

challenges of sorption detoxification:

• insufficiently high efficacy;

• hemostatic disorders, potential for bleeding after the procedure.

Intensive care:

- correction of respiratory disorders;

- correction of hypovolemia – infusion therapy;

- prevention and non-specific treatment of manifestations of the primary cardiotoxic effect:

• administration of non-specific membranoprotectors – sodium dimercaptopropanesulfonate up to 2 g/day intravenously, 5% ascorbic acid – 0.5-1.0 g/day intravenously, vitamin E – 300 mg/day intramuscularly;

• metabolic therapy – reamberin, inosine, potassium chloride, thiamine, pyridoxine, cyanocobalamin;

• plasma alkalinization to pH 7.5 – intravenous administration of sodium bicarbonate;

- cessation of rhythm and conduction disturbances:

• antiarrhythmic drugs of groups IA, IC, III, IV, atropine, isoproterenol, and low doses of dopamine are contraindicated;

• - termination of supraventricular reciprocal tachycardias – overdrive transesophageal pacing, 4% sodium bicarbonate solution, use β-blockers with caution (propranolol no more than 0.2 mg/kg IV drip under blood pressure and heart rate monitoring);

• termination of ventricular tachycardias – pacing, use lidocaine with caution at 1 mg/kg IV push (reduces myocardial contractility);

• termination of blocks – 4% sodium bicarbonate solution, for third-degree AV block – transvenous pacing;

• for severe bradycardia associated with SA node depression or arrest – replacement transesophageal or transvenous pacing;

- treatment of exotoxic shock:

• cardiac glycosides, isoproterenol, and low doses of dopamine are contraindicated;

• inotropic myocardial support – high doses of dopamine or dobutamine (7.5-10.0 mcg/kg per minute);

• norepinephrine;

• correction of hypovolemia;

• correction of rhythm and conduction disorders.

Common errors in providing emergency care:

• irrational use of drugs (e.g., procainamide for paroxysmal tachycardia, atropine for bradycardia);

• erroneous interpretation of atrial tachycardias with wide complexes due to aberrant conduction as ventricular rhythm disorders.

Table 6 – Mild Poisoning

Table 7 – Moderate and Severe Uncomplicated Poisoning

Table 8 – Severe poisoning with complications (pneumonia, toxic-hypoxic encephalopathy, positional injury, toxic nephro-hepatopathy, acute renal failure, multiorgan failure, sepsis, apallic syndrome)

Appendix C. Patient Information

Information for a patient admitted in a state of toxic coma is provided after the restoration of consciousness and must contain details regarding complications that occurred in the toxicogenic stage of poisoning, as well as the planned treatment during the rehabilitation process (if such is necessary for the given patient).

In cases of mild and moderate acute poisoning with barbituric acid derivatives (barbiturates), the patient is informed about the health hazards of these toxic substances, potential complications, long-term consequences of the poisoning, planned examinations (chemical-toxicological, clinical-biochemical, instrumental), and treatment (detoxification methods, pathogenetic and specific therapy). The patient (or their legal representatives) signs an informed voluntary consent for the proposed scope of examination and treatment.

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

Appendix G1. Glasgow Coma Scale

Table specifications:

Russian name: Glasgow Coma Scale

Original name: Glasgow Coma Scale

Source: https://www.glasgowcomascale.org

Type: Rating scale

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

Contents:

Key:

15 points – clear consciousness

10–14 points – moderate and deep obtundation

8–10 points – stupor

6–7 points – moderate coma

4–5 points – terminal coma

3 points – brain death

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

Appendix G2. Poisoning Severity Scale

Table specifications:

Russian name: Poisoning Severity Scale

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.

[3, 7, 13, 41, 43].