Benzodiazepine Poisoning: Clinical Guidelines

List of Abbreviations

Terms and Definitions

Benzodiazepines are agonists of specific benzodiazepine sites of GABA receptors coupled with chloride channels [55]. According to the Anatomical Therapeutic Chemical (ATC) classification system, benzodiazepine drugs belong to anxiolytics (antianxiety agents), hypnotics and sedatives, and antiepileptic drugs.

Intoxication is a disruption of vital activity caused by toxic substances penetrating the body from the outside or formed within it due to impaired various biochemical processes and excretory organ functions, leading to the development of endotoxemia. Intoxication is a broader pathological process that includes not only and not so much exogenous, but possibly to a greater extent endogenous toxemia [16, 18].

Poisoning is a disease developing as a result of external (exogenous) exposure of the human or animal body to chemical compounds in amounts that cause disorders of physiological functions and pose a threat to life [16, 18].

Toxicogenic stage of poisoning is the period of acute chemical illness course starting from the moment the toxic substance enters the body at a concentration capable of causing a specific effect and lasting until its elimination. It is characterized by the specificity of clinical manifestations reflecting the chemical and toxicological properties of the toxic substance and its effect 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 goal in this period is to shorten its duration as early as possible using various methods of enhanced elimination, antidote, and symptomatic therapy [18, 21].

Somatogenic stage of poisoning is the period of acute chemical illness course starting after the elimination or destruction of the toxic substance from the body as a trace lesion of the structure and functions of various organs and systems of the body [18], manifesting, as a rule, with various somatic and neuropsychiatric complications such as pneumonia, acute renal or hepatic failure, toxic polyneuropathy, anemia, psycho-organic syndrome, etc. In this stage of poisoning, specific (antidote) therapy is not required, and detoxification can be aimed solely at treating endotoxemia [23].

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Benzodiazepine poisoning (ICD-10 code T42.4) refers to a health disorder caused by the ingestion of one or more representatives of this group in a dosage exceeding the therapeutic dose.

Benzodiazepines exert anxiolytic, hypnotic, sedative, and antiepileptic effects.

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

The range of benzodiazepine applications is extensive. These include neurotic and neurosis-like disorders accompanied by fear, anxiety, panic; insomnia; epilepsy; spastic conditions [1].

Of more than 20 known benzodiazepine derivatives, only some are approved for the treatment of anxiety disorders (alprazolam, clonazepam, diazepam, and lorazepam); and for panic disorders (alprazolam).

Depending on their duration of action, benzodiazepines are subdivided into 3 groups:

1) short-acting (T_1/2 1-12 hours) – midazolam;

2) intermediate-acting (T_1/2 12-40 hours) – nitrazepam, lorazepam, alprazolam, bromdihydrochlorphenylbenzodiazepine, oxazepam;

3) long-acting (T_1/2 40-250 hours) – diazepam, chlordiazepoxide, clonazepam.

Clonazepam is used as an anticonvulsant [26, 46].

The mechanism of anxiolytic action is associated with the activation of GABAergic inhibition in the central nervous system (limbic system, hypothalamus, thalamus, hippocampus, ascending activating nonspecific system – reticular formation).

Benzodiazepines act both on GABA receptors in the central nervous system and on certain types of peripheral benzodiazepine receptors, which, despite their name, are located in various tissues. The exact role of these receptors has not been established, but it is believed that benzodiazepines can affect basic cellular functions (regulation of the respiratory chain, cell growth and differentiation). Peripheral benzodiazepine receptors are likely involved in the pathogenesis of hepatic encephalopathy, anxiety disorders, and immune disorders [50, 60].

Another unique property of benzodiazepines is their relative safety even when taken in large doses. Fatal poisonings with benzodiazepines are extremely rare; death mostly occurs with the simultaneous intake of benzodiazepines and alcohol or other tranquilizers and hypnotics.

Abrupt cessation of benzodiazepines after long-term treatment can cause withdrawal syndrome, which is characterized by consciousness disorders (delirium), anxiety, fear, autonomic instability, perceptual disturbances, paresthesia, headache, diarrhea, tremor, and epileptic seizures. Withdrawal syndrome peaks by days 3-4 and gradually resolves over 3-4 weeks. It is particularly severe after discontinuing short-acting benzodiazepines. To avoid these phenomena, benzodiazepine discontinuation must be carried out by gradually reducing doses and increasing intervals between administrations [18, 53].

It is necessary to note the penetration of benzodiazepines across the placenta and into breast milk. In the first trimester of pregnancy, benzodiazepines can cause teratogenic effects (cleft lip and palate in newborns), and in the third trimester, fetotoxic effects (arrhythmias, hypothermia, muscular hypotonia, central nervous system depression, in particular respiratory depression lasting several days and capable of leading to respiratory and subsequently metabolic acidosis).

Newborns born to mothers who took benzodiazepines for a long time often exhibit withdrawal syndrome: hyperexcitability, tremor, hyperreflexia, muscle hypertonus. These phenomena can persist for 2-6 weeks, and phenobarbital at 5-10 mg/kg per day is sometimes prescribed for relief [10, 20].

The "GABA receptor-Cl^--channel" complex contains an allosteric benzodiazepine receptor site ("benzodiazepine receptor"). The binding of benzodiazepines causes an increased frequency of chloride channel opening within the GABA_A receptor complex, and an increase in the inward Cl^- current leads to hyperpolarization of cell membranes and inhibition of neuronal activity [18, 60]. Enhanced GABA neurotransmission leads to a sedative effect, skeletal muscle relaxation, anxiolysis, and anticonvulsant effects. Stimulation of central nervous system GABA receptors can cause a decrease in myocardial contractility and vasodilation. These changes can affect tissue perfusion.

The binding site for benzodiazepines is determined by the α and γ subunits of the receptor complex. Several isoforms of the α subunit have been identified with their localization in various parts of the brain. Receptors containing the α₁ subunit are conventionally called BZ₁₍ω₁₎ benzodiazepine receptors (responsible for sedative and amnestic effects); BZ_{2 (}ω₂₎ receptors (but not ω₃), including the α₂, α₃, or α₅ subunits, mediate the anxiolytic action.

Another mechanism also exists, for example, the reuptake inhibition of adenosine and potentiation of its inhibitory effect on neurons.

The anticonvulsant effect of benzodiazepines is associated with the suppression of epileptogenic activity, which is explained by the enhancement of inhibitory GABAergic processes in the central nervous system.

The exact mechanism of the muscle-relaxant action of benzodiazepines has not been established; an important role is noted for the inhibition of spinal polysynaptic reflexes and the disruption of their supraspinal regulation (central muscle-relaxant action).

Depending on the dose, benzodiazepines produce various effects: in small doses, they exert a sedative effect; with increasing doses, a hypnotic effect; they potentiate the central nervous system depressant effects of general anesthetics, opioid analgesics, and alcohol; in high doses, they can cause anterograde amnesia [12, 19, 61].

The onset of action of benzodiazepines is determined by their ability to cross the blood-brain barrier. A relatively lipophilic benzodiazepine (e.g., diazepam) usually has a more rapid onset of action than a relatively water-soluble benzodiazepine (e.g., lorazepam). The effects of benzodiazepines may be enhanced if ethanol is present as a concomitant substance.

Peak blood concentrations of most substances occur within 1–3 hours. Following a single dose, lipophilic agents have a shorter duration of action (less central nervous system effect) than water-soluble agents because they rapidly redistribute from the central nervous system to peripheral sites (e.g., adipose tissue); thus, lorazepam has a longer central nervous system duration of action than diazepam. However, the latter is metabolized to active intermediate products with an increased half-life, which prolongs its therapeutic effects.

Benzodiazepines are metabolized predominantly in the liver via oxidation and/or conjugation. Most benzodiazepines are broken down into pharmacologically active metabolites that may have a longer half-life than the parent compounds.

In patients with obstructive sleep apnea episodes due to decreased smooth muscle tone of the upper respiratory tract, benzodiazepines can increase the severity of apnea and exacerbate alveolar hypoxemia, pulmonary hypertension, and changes in ventricular filling. Therefore, the presence of obstructive sleep apnea in patients is considered a contraindication to the use of benzodiazepines. Caution is also necessary regarding children who constantly snore during sleep, since existing partial airway obstruction (causing snoring) may progress to obstruction with apnea under the influence of benzodiazepines [10, 21, 42].

High doses of benzodiazepines used to control seizures can cause a drop in blood pressure through various mechanisms. For example, midazolam acts by decreasing peripheral vascular resistance, whereas diazepam acts by decreasing left ventricular contractile force and cardiac output. This negative inotropic effect of diazepam is due to its effect on increasing interstitial adenosine concentration, which increases coronary blood flow and causes bradycardia [18, 44, 62].

1.3 Epidemiology of the Disease or Condition

Data from reports of the Acute Poisoning Treatment Center of St. Petersburg (Form No. 64) for 2021–2023, as well as materials obtained for the preparation of these guidelines from Acute Poisoning Centers of the Russian Federation, show that acute benzodiazepine poisoning accounts for about 4% of the structure of acute poisonings, typically for suicidal purposes or self-treatment [14, 35, 36, 37].

Using St. Petersburg as an example, according to toxicology center reports from the I.I. Dzhanelidze St. Petersburg Research Institute of Emergency Medicine (Form No. 64), patients with this pathology accounted for 90 admissions (of whom 4 patients died) in 2021; 81 patients with acute poisoning by benzodiazepine derivatives (2 deaths) in 2022; in 2023, out of 31 admissions for acute poisoning by 1,4-benzodiazepine derivatives, there were no deaths [35, 36, 37].

1.4 Features of Coding the Disease or Condition

Poisoning by benzodiazepines is coded as T42.4 in ICD-10.

Benzodiazepines include alprazolam, diazepam, lorazepam, midazolam, nitrazepam, oxazepam, bromdihydrochlorphenylbenzodiazepine, and chlordiazepoxide [26].

1.5 Classification of the disease or condition

Depending on the clinical presentation, acute benzodiazepine poisonings are classified by the severity of the disease, which is determined using the Poisoning Severity Score proposed by the members of the European Association of Poisons Centres and Clinical Toxicologists (Appendix G2).

1.6 Clinical presentation of the disease or condition

When benzodiazepines enter the body in a toxic dose, their psychotropic and neurotoxic effects manifest, caused by central nervous system depression.

The clinical presentation of poisoning partly depends on the drug taken. Thus, nitrazepam causes intoxication similar to alcohol intoxication, with lethargy, drowsiness, and muscle relaxation. Bromdihydrochlorphenylbenzodiazepine is characterized by disinhibition and unmotivated motor activity, while diazepam causes euphoria. Upon a single intake of 4–5 tablets, diazepam causes euphoria characterized by elevated mood, restlessness, and an urge to "go somewhere, do something." Perception of the surroundings becomes less clear, shifting attention is impaired, and reaction speed decreases. Some patients note a sensation of flying or weightlessness. Patients exhibit impaired coordination and gait. They are animated, talkative, and have dysarthric speech. The skin is pale, pupils are dilated, and muscle tone (especially in the lower extremities) is decreased. A state of physical weakness and sluggishness gradually develops.

Patients with benzodiazepine poisoning present with slurred speech, ataxia, and impaired motor coordination. Doses of benzodiazepines significantly exceeding therapeutic levels can cause psychomotor agitation, sometimes accompanied by illusions and hallucinations. The intake of substantial doses of benzodiazepines leads to a soporous state progressing to coma, life-threatening impairments of external respiration, and cardiovascular dysfunction. Areflexia and mydriasis are noted. Hypoventilation leads to respiratory acidosis, which exacerbates cardiovascular disorders [18].

2. Diagnostics, medical indications and contraindications for diagnostic methods

The diagnosis of acute benzodiazepine poisoning should be based on the following criteria: evidence of recent benzodiazepine use in toxic doses (history); presence of symptoms and signs of poisoning (clinical presentation); and detection of benzodiazepine derivatives in biological fluids via chemical-toxicological analysis (laboratory confirmation of the diagnosis).

2.1 Complaints and Anamnesis

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

Comment: Patients may complain of dizziness, drowsiness, ataxia, disorientation, blurred vision, lethargy, and anxiety. In some cases, paradoxical reactions are possible (psychomotor agitation, fear, aggressive outbursts, suicidal thoughts, nightmares, delirium, psychosis, transient complete amnesia). This is particularly pronounced in elderly patients and individuals with alcoholism due to reduced GABA levels [12, 32, 44].

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

Comment: the emergency medical team has more opportunities: 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 the ambulance. When taking the history, it is necessary to identify the nature of the toxic agent, dose, exposure time, 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 poisoning, and determine treatment tactics.

The most frequent causes of acute benzodiazepine poisoning are suicide or intentional exceeding of the therapeutic dose in the absence of the desired effect. When taking an anamnesis in patients with suspected benzodiazepine poisoning, special attention must be paid to the psychiatric history [1, 40].

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

Practically none of the above can be ascertained, especially when accompanying relatives or acquaintances of the victim are absent, and the patient themselves cannot or will not provide the necessary information about themselves. In such cases, the diagnosis is made based on the leading clinical syndrome.

A characteristic feature of poisonings by psychotropic substances is the absence of subjective complaints from the patient in the majority of cases—medical assistance is usually sought by relatives or acquaintances who have noticed impairments in the patient's consciousness, behavior, or appearance [18, 32, 44].

2.2 Physical Examination

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

Comments: the diagnosis of benzodiazepine poisoning is based on anamnestic data and, mainly, on characteristic symptoms: depression of consciousness, respiration, and cardiovascular system disorders. The main clinical manifestation is the development of toxic or toxic-hypoxic encephalopathy, clinically manifesting, as a rule, in the development of deficit disorders of consciousness. This is one of the factors making diagnostic search difficult, which is carried out according to the diagnostic algorithm for comatose states [12, 19].

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

Comments: appearance of the skin—no specific coloration; in case of respiratory failure, cyanosis of the lips, face, and acrocyanosis are noted; 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 sores" resulting from positional trauma caused by the pressure of one's own body weight, the so-called positional pressure on individual soft tissue areas, leading to the appearance of skin hyperemia areas that are often regarded as bruises, hematomas, burns, phlebitis, allergic edema, etc., and are usually detected at early periods (1-3 days) [10, 18, 47].

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

Comments: to assess the neuropsychological status—the state of consciousness (clear, obtundation, sopor, coma, psychomotor agitation, hallucinations). If coma is present, assess its depth using the Glasgow Coma Scale (Appendix G1), the presence or absence of reflexes, pupil width, their reaction to light, the presence (absence) of anisocoria, and the state of 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 noted: asthenic confusion of consciousness, psycho-organic and asthenic symptom complexes, as well as withdrawal, epileptic, and delirious syndromes, and toxic substance withdrawal syndrome [7, 11, 12, 18].

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

Comments: to assess the state of respiration—adequacy, rate, depth, uniform participation of all parts of the chest in the act of 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 any patient [9, 38, 41, 58].

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

Comment: in addition to the occurrence of central disorders of respiratory regulation and respiratory muscle functions, aspiration-obstructive disorders associated with mechanical asphyxia may occur, and pathological processes in the lungs—atelectasis and pneumonia—are also a cause of hypoxia. In the pathogenesis of pneumonia, which serves as one of the frequent causes of death of patients in the somatogenic stage, two main factors are important: a prolonged comatose state complicated by aspiration-obstructive disorders. These disorders do not have diagnostic significance, but only allow assessing the severity of poisoning and predicting the outcome [10, 18, 32].

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

Comments: toxic damage to the cardiovascular system manifests in circulatory disorders (cardiac arrhythmias, primary toxicogenic collapse, exotoxic shock) and is caused by damage to the mechanisms regulating blood circulation and the cardiovascular system (e.g., due to the progression of hypoxic damage). The most severe form of cardiovascular complications is the development of exotoxic shock, requiring immediate implementation of a complex of resuscitation measures [18, 50, 62].

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 a number of cases, in patients with acute poisonings accompanied by the development of a comatose state, the odor emanating from the patient is of importance, as it can help identify the psychoactive substance that caused the intoxication [18]. The clinical presentation of acute benzodiazepine poisoning can vary greatly both between different subjects and within the same subject depending on a multitude of factors. Thus, it may depend on the dose of the substance taken, the dynamics of administration (the time during which its total amount was taken), the individual characteristics of the subject (age, ethnicity, gender, mental and physical condition), the characteristics of the toxic substance, and ambient temperature. Finally, the degree of tolerance to benzodiazepines in dependent individuals is of great importance. Also, when diagnosing acute benzodiazepine poisoning, it must be taken into account that its symptoms do not always reflect the primary action of the substance; for example, individuals abusing benzodiazepines may develop symptoms of psychomotor agitation [18].

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

2.3 Laboratory Diagnostics

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

Comments: the choice of diagnostic method depends primarily on the circumstances in which the test is performed (primary health care in an outpatient clinic or 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 use of benzodiazepines or other psychotropic drugs, 2. identifying a specific substance or substances in the patient's biological fluids. In the first case, a qualitative IA test is sufficient. When using IA, it should be borne in mind that a negative result always indicates the absence of the target toxic substance in the sample, while a positive result, due to a possible false positive (cross-reactivity), may lead to a diagnostic error, thus requiring verification by a more accurate GC-MS method [3, 18, 27, 30].

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: GC-MS is a confirmatory method for the qualitative and quantitative determination of psychoactive substances in biological fluids. It also allows for untargeted analysis, i.e., simultaneous determination of a large number of various psychoactive substances. HPLC-MS is less accessible due to its high cost, but has a significant advantage in that it allows the detection of psychoactive substances 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 benzodiazepine poisoning is frequently accompanied by water-electrolyte balance and acid-base disorders. These manifest as major disturbances, most commonly decompensated mixed respiratory and metabolic acidosis, as well as hyperkalemia.

2.4 Instrumental Diagnostics

Performing these diagnostic procedures is essential for the early detection of existing complications in moderate and severe benzodiazepine poisonings, which can significantly affect 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 cardiac conditions (especially since the social history of such patients upon hospital admission is virtually unknown); an ECG must be mandatory for individuals with a history (or suspicion) of cardiotoxic drug use [1, 18, 54].

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

Comments: Monitoring of vital functions should preferably be performed using hardware methods (via an intensive care monitor). In the absence of a monitor, vital signs must be checked periodically by hand. The frequency of repeated measurements is determined by the attending physician depending on the severity of the patient's condition [8, 20, 48].

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.

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.

2.5 Other Procedures

Since acute benzodiazepine poisonings are accompanied by impaired consciousness and characterized by high variability of clinical manifestations, high probability of life-threatening conditions and complications, differential diagnosis is frequently required.

• traumatic brain injury, acute cerebrovascular accident;

• hypoglycemic coma;

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

• hepatic and uremic coma, comas in endocrinological diseases, severe encephalopathies in water-electrolyte and metabolic disorders, and other endogenous intoxications in various somatic conditions [9, 18, 31, 32, 38].

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.

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 management of benzodiazepine poisoning

Mild acute benzodiazepine poisonings may manifest as behavioral disorders, which may require psychopharmacotherapy and further dynamic monitoring. Moderate and severe acute benzodiazepine poisonings require emergency medical care. The severity of acute benzodiazepine poisonings does not always correlate with the concentration of benzodiazepines in the patient's blood. The possibility of immediate quantitative determination of benzodiazepine concentrations in body fluids is not always technically feasible; therefore, when choosing treatment tactics, the physician is often forced to adhere to a symptomatic approach. For clinical diagnosis, assessing the degree of the patient's agitation or sedation is extremely important. A very convenient diagnostic tool for this is the clinical scale for assessing the level of consciousness — the Glasgow Coma Scale (Appendix G1) [1, 10, 18, 27].

3.2. Provision of ambulance care outside a medical organization for benzodiazepine poisoning

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

Comments: treatment for all patients should begin with the restoration of adequate pulmonary ventilation depending on the type of respiratory disorder. In cases of aspiration-obstructive respiratory disorders, it is necessary to perform oral cavity toilet, aspiration of upper respiratory tract contents, and ensure upper respiratory tract patency, including using airways, laryngeal tubes, combitubes, laryngeal masks, and 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. For hemodynamic disorders, as well as for detoxification therapy, intravenous infusion of solutions affecting the water-electrolyte balance and dextrose** solutions is indicated. Therefore, ensuring venous access is important when providing ambulance care [8, 18, 58].

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

Comments: GLT should be performed starting from the ambulance stage as early as possible after toxicant ingestion, as well as in cases of coma development and suspected ingestion of a large dose of the toxicant. In deep depression of consciousness, endotracheal intubation and, if necessary, initiation of mechanical ventilation are indicated prior to gastric lavage. It is also necessary to take measures to stabilize hemodynamics and stop convulsive syndrome. Currently, the size of gastric lavage tubes (sterile, single-use gastric tubes) ranges from F22 (diameter 7.3 mm) to F34 (diameter 11.3 mm). During tube insertion, the patient is either in a sitting position or lying on the left side with the chin pressed against the chest. The correct insertion of the tube is determined by introducing air with a Janet syringe (noises in the stomach should be audible upon auscultation). 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 gastric lavage via a tube is:

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

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

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

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

• in adults – up to 10 l.

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.

3.3. Specialized medical care stage management in benzodiazepine poisoning

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

Comments: The main goal of respiratory support in ventilatory ARF is the replacement of lost or severely weakened spontaneous breathing due to impaired respiratory center function and/or respiratory muscle dysfunction (paralysis, paresis). Impairment of respiratory center function in acute poisoning with benzodiazepine derivatives leads to suppression or attenuation of central chemoreceptor sensitivity, causing 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 benzodiazepine poisoning 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 (under 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 sufficient (PaO₂ ≥ 80 mm Hg, SaO₂ > 95%), then the oxygen concentration in the inspiratory gas mixture is reduced to the minimum level at which SaO₃ = 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 benzodiazepine poisoning complicated by acute respiratory failure, the following main criteria should be used to decide on the withdrawal of respiratory support: "normalization" of neurological status; the patient's ability to initiate spontaneous breathing. During the withdrawal of respiratory support, it is necessary to continuously maintain adequate oxygenation (PaO₂ = 85–100 mmHg, SaO₂ = 96–98% at FiO₂ <0.4), PaCO₂ = within 35–40 mmHg), and continuously monitor the patient's level of consciousness. After complete withdrawal of mechanical breath cycles, the ventilator is switched to CPAP mode with a positive pressure level of 3–4 cm H₂O.

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

1) The lower 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.

If the condition is stable (no increase in respiratory failure symptoms and/or neurological deficit), the patient can be extubated and completely transferred to spontaneous breathing with humidified oxygen delivery (FiO₂ = 0.3–0.35) for 3–4 hours [8, 18, 38, 41, 51, 56].

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 individual. The volume and composition of the infusion program depend on age, patient condition, presence of comorbid conditions, and complications. Benzodiazepine poisoning carries a high risk of acute kidney injury, so infusion therapy must be performed under strict volume status monitoring to avoid hypervolemia [18, 48, 52].

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

Level of Reliability of Evidence – 5, Level of Recommendation Validity – C for children.

Level of Reliability of Evidence – 3, Level of Recommendation Validity – B for adults.

Comment: in acute benzodiazepine poisoning accompanied by water-electrolyte balance disorders, infusion detoxification therapy and forced diuresis are indicated. Meglumine sodium succinate** is contraindicated in children under 1 year of age, in case of allergy to meglumine sodium succinate** or any other components of the drug, in conditions following traumatic brain injury accompanied by cerebral edema, in acute renal failure, chronic kidney disease, and during pregnancy or breastfeeding [10, 13, 20].

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: for the correction of metabolic acidosis, the use of 3-5% sodium bicarbonate solution** is recommended. Early elimination of acid-base balance disorders is of great importance during acute benzodiazepine poisoning, since a prolonged state of metabolic acidosis, which naturally develops in benzodiazepine poisoning, can by itself have a pronounced adverse effect on various body systems [31, 34].

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

Comment. The indication for prescribing in adults and children over 1 year of age is the use of the drug as an antihypoxic and detoxifying agent in acute endogenous and exogenous intoxications of various etiologies. Adults are administered intravenously 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. Children from 1 year of age are administered intravenously by drip at the rate of 6-10 ml/kg/day at a rate of 3-4 ml/min. The course of therapy is 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 5-10% dextrose** solution or 0.9% sodium chloride** solution 100-200 ml. It is prescribed in a volume of 10 ml per administration 2 times/day every 8-12 hours for 5 days. In a comatose state – in a volume of 20 ml per administration 2 times/day every 8-12 hours for 5 days [13, 26].

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 method of choice for extracorporeal blood purification in benzodiazepine poisoning is plasmapheresis or hemosorption. Indications for extracorporeal blood purification:

• ingestion of a dose 50 times exceeding the therapeutic dose (more than 0.5 g) + corresponding clinical presentation of severe poisoning (depression of consciousness to the level of coma (less than 8 points), myorelaxation, tachycardia, arterial hypotension;

• clinical presentation of severe poisoning + presence of the toxin in the blood/urine;

• concentration of the drug in the blood of more than 20 mcg/ml (2 mg%).

Extracorporeal blood detoxification is performed with full-scale treatment and the absence of improvement in the clinical manifestations of poisoning within 6 hours from the moment of starting treatment in a hospital. Prior to its initiation, it is necessary to exclude: the overriding effect of alcohol and psychotropic drugs not removable by extracorporeal detoxification methods; consciousness disorders of non-exotoxic genesis; acute neurological and neurosurgical pathology. Extracorporeal blood detoxification is performed after: repeated tube gastric lavage, enterosorption, bowel cleansing, adequate infusion therapy; recording of an electrocardiogram, general (clinical) blood count, general therapeutic biochemical blood test, coagulogram (exploratory study of the hemostasis system), determination of main blood groups by the AB0 system, determination of the D antigen of the Rhesus system (Rh factor). In case of increasing symptoms of poisoning and worsening of the patient's condition against the background of ongoing full-scale treatment, extracorporeal blood detoxification is performed before the expiration of 6 hours from the start of hospital treatment.

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

4. Medical Rehabilitation and Sanatorium-Resort Treatment

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

5. Prevention and Dispensary Observation

In acute benzodiazepine poisoning, tertiary (modification) prevention is of paramount importance; it is primarily medical and individual, aimed at preventing repeated intoxications and reducing harmful consequences for the mental and somatic health of the patient who has suffered severe acute poisoning.

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

6. Organization of Medical Care

6.1. Indications for hospitalization

All casualties with acute benzodiazepine poisoning should ideally be hospitalized in a specialized acute poisoning center. In mild cases of acute poisoning, hospitalization in an acute poisoning department or in a hospital with an intensive care unit (ward, block) is appropriate. In the absence of an acute poisoning center, patients with severe poisoning and complications, especially with vital function disorders, should be hospitalized in an intensive care unit or an emergency department intensive care ward equipped for hemodialysis or hemoperfusion, followed by transfer to an acute poisoning center or, once stabilized, to a specialized department.

The duration of hospitalization is determined by the severity of the poisoning. Treatment of patients is carried out in the acute poisoning department—in mild cases, on average up to 2 days; in moderate and severe poisonings, the patient is hospitalized in the intensive care unit until detoxification measures are completed and the patient's condition stabilizes. The duration of stay in the intensive care unit in severe uncomplicated cases is 3–5 days; in 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 department 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 patient discharge from the hospital

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.

Indications for discharge:

• a patient can be discharged after 4 hours of observation if there are no signs or symptoms of benzodiazepine poisoning;

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 degree without complications — days 7–14;

4. severe degree (with complications: pneumonia, acute kidney injury, acute hepatorenal syndrome) — duration of treatment from 14 to 24 bed-days.

7. Additional Information

Characteristics in children: rarely can lead to paradoxical agitation and restlessness.

Characteristics in the elderly: benzodiazepine use increases the risk of delirium, falls, fractures, and cognitive impairment.

Indications for referral to subspecialists: psychiatric consultation if intentional overdose is suspected.

Outpatient management: patients who have developed tolerance may experience withdrawal syndrome after discontinuing benzodiazepines: autonomic instability, tremor, paresthesia, seizures.

Important: intravenous formulations of certain benzodiazepines (e.g., lorazepam) may contain a propylene glycol diluent, which can lead to an increased osmolal gap and high anion gap metabolic acidosis.

Criteria for Evaluating the Quality of Medical Care

Table 2 – Criteria for assessing the quality of medical care

References

Appendix A1. Working Group Composition

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

2. Narziculov Rustam Abdukhalimovich – Doctor of Medical Sciences, Senior Researcher at the Department of Clinical Toxicology, Dzhanelidze St. Petersburg Research Institute of Emergency Medicine.

3. Batotsyrenova, Khandazhap Vladimirovna – Candidate of Medical Sciences, Researcher at the Department of Clinical Toxicology, Saint Petersburg Research Institute of Emergency Medicine.

4. 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.

5. Shikalova, Irina Anatolyevna – PhD in Medicine, Senior Researcher at the Department of Clinical Toxicology, St. Petersburg I.I. Dzhanelidze Research Institute of Emergency Care.

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

7. Kuznetsov, Semyon Valerievich – Candidate of Medical Sciences, Senior Researcher at the Department of Clinical Toxicology, Saint Petersburg Research Institute of Emergency Medicine.

8. 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.

9. Antonova, Anna Mikhailovna – Candidate of Medical Sciences, Staff Member at the Department of Clinical Toxicology, Saint Petersburg Research Institute of Emergency Medicine.

10. Makhnovsky, Andrey Ivanovich – Candidate of Medical Sciences, Deputy Chief Physician for Emergency Medical Care, Saint Petersburg Research Institute of Emergency Medicine, St. Petersburg.

11. 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, Academician I.P. Pavlov First Saint Petersburg State Medical University.

    There is no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of these clinical guidelines:

1. anesthesiologist-intensivist;

2. gastroenterologist;

3. infectious disease physician;

4. immunologist;

5. cardiologist;

6. laboratory diagnostic physician;

7. neurologist;

8. neurosurgeon;

9. general practitioner (family physician);

10. otorhinolaryngologist;

11. pediatrician;

12. emergency and critical care physician;

13. forensic medical expert;

14. internist;

15. district general practitioner;

16. toxicologist;

17. transfusiologist;

18. functional diagnostics physician;

19. surgeon;

20. endoscopist;

21. psychiatrist-narcologist.

Methodology for Developing Clinical Guidelines

Working group members independently performed a systematic search and selection of publications. The search was conducted in the PubMed database (http://www.ncbi.nlm.nih.gov/pubmed/), the Cochrane Library (http://www.cochranelibrary.com/), the eLIBRARY.ru scientific electronic library (http://elibrary.ru/defaultx.asp), as well as clinical trial registries: https://clinicaltrials.gov/ and https://www.clinicaltrials.gov/ search/search. A total of 210 publications were retrieved, of which 124 were selected. Based on the selected publications, thesis-recommendations were formulated and evaluated using scales for assessing the levels of evidence and diagnostic methods, levels of evidence for prevention, treatment, and rehabilitation methods (interventions), and grades of recommendation for prevention, diagnostic, treatment, and rehabilitation methods (interventions). (Table 3, Table 4, Table 5) Subsequently, each thesis-recommendation was thoroughly discussed at a general meeting of the working group, and consensus was reached in all cases of disagreement.

Table 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. 298 dated October 5, 1998, "On Analytical Diagnostics of Narcotic Drugs, Psychotropic Substances, and Other Toxic Substances in the Human Body".

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

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

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

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

8. Order of the Russian Ministry of Health No. 919n 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 Drugs for Medical Use and the Minimum Assortment of Drugs Required for Medical Care"

Appendix B. Physician Action Algorithms

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 mild and moderate acute benzodiazepine poisoning, the patient is informed about the health risks associated with 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.