Mental and behavioral disorders due to psychoactive substance use. Withdrawal state (withdrawal syndrome) with delirium: clinical guidelines

List of Abbreviations

WS – withdrawal state

WD – withdrawal syndrome

AP – alcohol psychoses

ICD-10 – International Classification of Diseases

ALT – alanine aminotransferase

AST – aspartate aminotransferase

GGT – gamma-glutamyl transferase

ECG – electrocardiographic examination

ESR – erythrocyte sedimentation rate

CT – computed tomography

MRI – magnetic resonance imaging

TBI – traumatic brain injury

BP – blood pressure

HR – heart rate

PS – psychoactive substance, which, when ingested or introduced into the human body, affects mental processes, for example, cognitive or affective spheres.

GABA – gamma-aminobutyric acid

GHB – gamma-hydroxybutyric acid

IMV – invasive mechanical ventilation

NMDA – N-methyl-D-aspartate

CIWA-Ar (Clinical Institute Withdrawal Assessment-Alcohol, revised scale) – Clinical Institute Withdrawal Assessment for Alcohol scale

RASS (Richmond Agitation-Sedation Scale) – Richmond Agitation-Sedation Scale

ABCDE – assessment algorithm for deteriorating or critically ill patients: The mnemonic ABCDE stands for: (A) Airway assessment and management, (B) Breathing assessment and management, (C) Circulation assessment and management, (D) Disability (neurological status and consciousness) assessment, (E) Exposure and comprehensive examination

DSM-V (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) – Diagnostic and Statistical Manual of Mental Disorders, 5th edition, of the American Psychiatric Association

Terms and Definitions

Abstinent state (withdrawal state (WS)) – a group of symptoms of varying combinations and severity occurring upon complete cessation of a psychoactive substance or reduction of its dose after repeated, usually prolonged and/or high-dose use of the substance. The onset and course of the withdrawal state are time-limited and correspond to the type of psychoactive substance and the dose immediately preceding abstinence.

Delirium – an exogenous mental disorder characterized by clouded consciousness. It is characterized by true, predominantly visual hallucinations and illusions, and, as a consequence, secondary delusions; affective disturbances, sleep disorders, behavioral disturbances, and disorientation in place and time with preserved orientation to self.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Abstinent state (withdrawal state WS) with delirium – a transient, usually short-term, potentially life-threatening acute psychotic state accompanied by impaired consciousness, hallucinations, and concurrent somatic and neurological disorders. It typically occurs as a result of complete or partial cessation of psychoactive substance use (primarily alcohol and certain other psychoactive substances) in individuals dependent on it who have used the substance for a long time. It may occur upon emerging from a severe bout (binge).

In the vast majority of cases, delirium as a complication of withdrawal state occurs upon alcohol withdrawal, which is why clinical practice guidelines focus mainly on this pathology.

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

The pathogenesis of delirium involves hyperactivity of excitatory and inhibition of inhibitory neurotransmitter systems in the central nervous system. The inhibitory effect of alcohol on the brain is primarily achieved via the neurotransmitter gamma-aminobutyric acid (GABA). Three distinct types of GABA receptors are known (ionotropic GABA_A and GABA_C, and metabotropic GABA_B), with GABA_A being the most significant. Stimulation of the ligand-gated ion channel of the GABA_A receptor causes membrane hyperpolarization by enhancing the influx of chloride ions, which leads to an overall slowdown of neurotransmission, exerting anxiolytic, sedative, and anticonvulsant effects. Similar effects are produced by several GABA_A receptor-active pharmacological agents, including benzodiazepine derivatives, barbiturates and their derivatives, and propofol**. Alcohol intake causes increased release of the neurotransmitter GABA and increases the sensitivity of the GABA_A receptor, leading to an overall increase in inhibitory neurotransmission. In addition to direct stimulation of GABA_А receptors, alcohol also leads to physiological changes in excitatory neurotransmission. Alcohol competitively inhibits the binding of glycine to N-methyl-D-aspartate (NMDA) receptors in the brain, thereby preventing the action of the primary excitatory neurotransmitter glutamate on NMDA receptors.

With chronic alcohol consumption, the human brain functionally adapts, which ultimately leads to the phenomenon of tolerance. To compensate for the persistent inhibition of glycine binding to NMDA receptors, there is a gradual increase in NMDA receptor expression and a compensatory downregulation of GABA_A receptors. This compensation leads to tolerance and the resulting need for higher blood alcohol levels to achieve the same effect. If the presence of alcohol is constant, the balance between excitatory and inhibitory actions is maintained [1-4].

Elimination of alcohol from the body causes dysregulation of glutamate neurotransmission and suppression of GABA activity, leading to alcohol withdrawal state, and in severe cases, to withdrawal state with delirium [5, 6].

Impaired cholinergic transmission in the brain may be one of the causes of delirium, especially in the elderly. Another neurotransmitter playing a role in the development of alcohol withdrawal syndrome and alcohol delirium is dopamine. As a result of chronic alcohol consumption followed by its withdrawal, there is an increase in dopamine levels in the CNS, which causes hyperexcitation and hallucinations [7].

Another predisposing factor in the development of delirium is electrolyte imbalance, particularly the redistribution of electrolytes between cells and the extracellular fluid, local circulatory disorders, and increased vascular permeability to toxic substances.

It is also necessary to point out the role of thiamine (vitamin B1) in the development of psychotic disorders; it acts as a cofactor for several key enzymes of the Krebs cycle and the pentose phosphate pathway, including α-ketoglutarate dehydrogenase, pyruvate dehydrogenase, and transketolase [8].

Since thiamine-dependent enzymes play a major role in meeting the energy demands of the brain, their deficiency can initiate tissue damage as a result of metabolism inhibition in brain areas with high metabolic requirements [9]. With insufficient intake, stored thiamine is depleted in approximately 1 month [10, 11]. Thiamine deficiency is one of the main causes of Wernicke-Korsakoff syndrome and Marchiafava-Bignami disease, which manifest with delirium symptoms [12].

It should be noted that numerous repeated episodes of alcohol withdrawal (AW) lead to a lowering of the seizure threshold and the development of seizure paroxysms, which are a frequent predictor of delirium tremens [13].

In most cases, the onset of delirium tremens is preceded by provoking factors: older age, trauma (especially traumatic brain injury), surgical interventions, comorbid somatic diseases, infectious diseases, and intoxications with other substances and medications [2, 3].

1.3 Epidemiology of the Disease or Condition

The incidence of alcohol-induced psychoses (AIP) correlates most clearly with the level of alcohol consumption. It is believed that the higher the consumption, the higher the morbidity rates. Mortality in alcohol withdrawal delirium can reach 8% [14]. According to official statistics in the Russian Federation, the number of patients with AIP registered by addiction treatment facilities in 2019 was 30.83 per 100,000 population [15]. Over recent years, there has been a downward trend in the overall incidence of AIP; in 2015–2016 alone, it decreased from 45.5 to 40.6 per 100,000 population, which accounts for a 10.8% reduction [15]. In 2020, AIP incidence was 26.9 per 100,000 population, and in 2021 it was 24.9 per 100,000 population [16, 17].

Wernicke's encephalopathy is in most cases undiagnosed during routine examination. In 75–80% of adult patients who abused alcohol and had HIV infection at the AIDS stage, Wernicke's encephalopathy is diagnosed only at autopsy [18, 19].

1.4 Features of Coding the Disease or Condition

F10.4 Mental and behavioural disorders due to use of alcohol. Withdrawal state with delirium

F11.4 Mental and behavioural disorders due to use of opioids. Withdrawal state with delirium

F13.4 Mental and behavioural disorders due to use of sedatives or hypnotics. Withdrawal state with delirium

F19.4 Mental and behavioural disorders due to multiple drug use and use of other psychoactive substances. Withdrawal state with delirium)^[1]

When using code F1x.4 (withdrawal state with delirium), the following rules apply: the presence of an alcohol withdrawal state as defined in F1x.3 and the presence of delirium as defined in F05.

The diagnosis of withdrawal state with delirium can be specified by the fifth character depending on the form (type of course) of delirium.

F1x.40 – Withdrawal state with delirium ("classical delirium")

F1x.41 – Withdrawal state with delirium with convulsions

F1x.42 – Withdrawal state with muttering delirium

F1x.43 – Withdrawal state with "professional" delirium

F1x.44 – Withdrawal state with delirium without hallucinations (lucid delirium)

F1x.46 – Withdrawal state with abortive delirium

F1x.48 – Withdrawal state with other delirium

F1x.49 – Withdrawal state with unspecified delirium

The category Withdrawal state with delirium (F1x.4) includes:

Wernicke's encephalopathy (F10.4x)

Marchiafava-Bignami disease (F10.4x)

Other acute alcoholic encephalopathies (F10.4x)

^[1]"International Statistical Classification of Diseases and Related Health Problems (10th Revision) (ICD-10) (Version 2.27 dated 02.09.2024)"

1.5 Classification of the disease or condition

In clinical practice, various clinical variants of alcohol withdrawal delirium are distinguished. According to researchers, in some cases hypnagogic and abortive deliriums are not separate variants, but merely stages in the dynamics of psychosis [20], just as the forms of alcohol delirium ("classical", atypical, and severe delirium) are successive pathogenetic variants in the development of a single psychopathological syndrome [21].

1. Reduced forms of alcohol withdrawal delirium:

• hypnagogic delirium (not classified as a separate nosological entity in ICD-10; it is advisable to code such states as F10.46);

• hypnagogic delirium of fantastic content (hypnagogic oneirism) (not classified as a separate nosological entity in ICD-10; it is advisable to code such states as F10.46);

• delirium without delirium (lucid delirium, tremor syndrome) (F10.44);

• abortive delirium (F10.46).

2. Typical, or classical, delirium tremens (F10.40).

3. Mixed forms of alcohol withdrawal delirium (systematized delirium and delirium with prominent verbal hallucinations—these forms are not distinguished in ICD-10; it is advisable to code them as F10.48).

4. Severe deliriums:

• professional delirium (delirium with occupational delusions) (F10.43);

• muttering delirium (F10.42).

5. Atypical deliriums: (such clinical forms are not distinguished in ICD-10 as clearly defined syndromes; in this case, it is justified to classify such states as withdrawal state with other delirium (F10.48)):

• delirium with fantastic content (fantastic delirium, alcoholic oneroid state, oneiroid delirium);

• delirium with oneiric disorders (alcoholic oneirism);

• delirium with psychic automatisms [22].

Currently, foreign scientific literature and DSM-5 distinguish three subtypes of delirium: hyperactive, hypoactive, and mixed. The determining criterion in this case is psychomotor agitation:

• Hyperactive – psychomotor agitation, which may be accompanied by mood lability, fear, aggression, and a lack of productive contact with medical staff;

• Hypoactive – the level of psychomotor activity is reduced, and may be accompanied by sluggishness and somnolence approaching stupor;

• Mixed – a normal level of psychomotor activity even in the presence of disturbances in attention and orientation to the environment. It also includes cases of rapid fluctuations in activity levels [23, 24].

1.6 Clinical presentation of the disease or condition

The clinical picture of "classical" delirium is described using alcohol withdrawal state with delirium as an example [2, 3, 22, 25].

The onset of delirium tremens without concomitant somatic or neurological pathology is usually observed 48–72 hours after cessation of alcohol consumption (alcohol withdrawal delirium may start abruptly as early as 8 hours after a sharp reduction/cessation of alcohol intake, especially in patients with a history of alcohol-induced psychoses and/or complications such as alcohol withdrawal with seizures). Prodromal symptoms of alcohol withdrawal delirium include complaints of poor sleep with frequent awakenings in a state of anxiety, marked tremor, fear, anxiety, and sweating.

The clinical picture of "classical" delirium exhibits distinct stages.

Initial manifestations include: rapid shifts of opposite affects, akathisia, disorientation or incomplete orientation to place and time with preserved orientation to person, psychic hyperesthesia, illusions, and episodes of auditory hallucinations in the form of acoasms and phonemes. Symptoms intensify by evening; insomnia, pareidolia, hypnagogic hallucinations of varying intensity, total insomnia, true visual hallucinations, and tactile hallucinations are observed.

As the delirium deepens, stupor is observed, and hallucinations are added: auditory, olfactory, thermal, tactile, and somatic sensations. Attention becomes highly distractible.

Recovery from delirium can be critical (following deep, prolonged sleep) or lytic (fragmentary manifestations of the psychotic episode persist, along with marked emotional lability and distractibility of attention).

Deliriums are conventionally classified according to the depth of impaired consciousness, concomitant psychopathological disorders, the severity of somatoneurological disorders, and their combinations.

Clinical differences between reduced and severe forms of delirium are presented in Tables 1–2.

Table 1. Special forms of delirium: reduced

Table 2. Special forms of delirium: severe types

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis of the disease/condition: diagnostic rules for establishing the diagnosis of «Withdrawal state (WS) with delirium» (F1x.4) – the presence of a withdrawal state as defined in F1x.3 and the presence of delirium as defined in F05 are required.

1. Diagnostic criteria for WS (F1x.3) according to ICD-10:

a) There must be clear evidence of recent cessation of or reduction in substance use following prolonged and/or high-dose use of the substance;

b) The symptoms and signs are consistent with the known characteristics of the withdrawal state of the specific substance or substances;

c) The symptoms and signs are not attributable to a medical disorder not related to substance use and are not better accounted for by another mental or behavioral disorder.

2. Diagnostic criteria for delirium (F05 according to ICD-10). For a definitive diagnosis of delirium, mild or severe symptoms from each of the following groups must be present:

a) altered consciousness and attention (from stupor to coma; reduced ability to direct, focus, sustain, and shift attention);

b) global cognitive impairment (perceptual disturbances, illusions, and hallucinations, predominantly visual; impairments of abstract thinking and comprehension with or without transient delusions, but usually with some degree of incoherence; impairment of immediate recall and recent memory with relative preservation of remote memory; disorientation in time and place, and in more severe cases, in place and personal identity);

c) psychomotor disturbances (hypo- or hyperactivity and unpredictability of transition from one state to another; slowed time perception; increased or decreased speech output; startle reactions);

d) sleep-wake cycle disturbances (insomnia or inversion of the sleep-wake cycle: daytime drowsiness, worsening of symptoms at night; restless dreams or nightmares that may persist as hallucinations upon awakening);

e) emotional disturbances, such as depression, anxiety, or fears. Irritability, euphoria, apathy, or perplexity and confusion.

3. The disturbances develop over a short period of time (usually hours to days), represent a change from the baseline level of attention and orientation, and tend to fluctuate over the course of the day. The disturbances are not caused by another pre-existing, established, or evolving neurocognitive disorder and do not occur in the context of a severely depressed level of consciousness, such as coma.

Case history, physical examination, or laboratory findings indicate that the disturbances are a direct physiological consequence of alcohol withdrawal syndrome or can be explained by multiple causes, including the withdrawal of alcohol or another psychoactive substance. Seizures may occur prior to the onset of delirium.

2.1 Complaints and Anamnesis

Comment: Complaints presented by patients with alcohol withdrawal with delirium are described in section 1.6. «Clinical presentation».

Taking a history from a patient with WS with delirium is difficult due to the specifics of their condition; the reliability of information obtained from a patient in a psychotic state during the diagnostic search is low. Therefore, anamnestic data obtained from relatives or accompanying persons, as well as from the electronic medical information system, are of primary importance for diagnosis. For the diagnosis of acute alcohol encephalopathies, in addition to the addiction history, it is important to ascertain the presence of social isolation, nutritional deficiencies, including those caused by gastrointestinal diseases [12, 26, 27].

Comments: The classic triad of Wernicke's encephalopathy occurs in 10% of cases. To establish the diagnosis in a patient abusing alcohol, the presence of 2 of the following features is required:

malnutrition (undernutrition and/or vomiting, gastrointestinal diseases);

ocular symptoms (bilateral and asymmetrical oculomotor disorders, ophthalmoparesis, strabismus, external ophthalmoplegia, decreased light reflexes, horizontal and rotatory nystagmus);

cerebellar dysfunction (pronounced cerebellar ataxia up to astasia-abasia);

mental status changes or memory impairment (psychiatric disorders – global disorientation and indifference; alcohol delirium, alcohol withdrawal symptoms, or their variants are detected in 20%).

Causes of Wernicke's encephalopathy: alcohol abuse, thyrotoxicosis, hemodialysis, severe malnutrition due to gastric cancer and pyloric obstruction, anorexia, HIV infection [27, 28]. If Wernicke's encephalopathy is not diagnosed or is inadequately treated, it transforms into Korsakoff's syndrome in survivors [28].

Comments: This clinical picture is observed in patients with alcohol dependence syndrome due to progressive demyelination and necrosis of the corpus callosum. It is usually associated with other manifestations of chronic alcohol abuse, such as Wernicke's encephalopathy, central pontine myelinolysis, Morel's laminar sclerosis, and is also considered a thiamine-deficient state [31, 32]. Marchiafava-Bignami encephalopathy is believed to co-occur with Wernicke-Korsakoff syndrome in 15-20% of cases [22]. Its antemortem diagnosis is based mainly on the results of a neurological examination and neuroimaging data, primarily brain MRI [33]. The cause of death is cardiovascular and respiratory failure associated with necrosis of structures belonging to the limbic system [32, 33].

Comments: Symptoms are most commonly represented by delirium, clinically similar to alcohol withdrawal delirium, which is relatively rarely diagnosed correctly. The clinical presentation of delirium resulting from sedative and hypnotic withdrawal features greater severity of anxiety, tension, and aggression, with a higher proportion of auditory hallucinations. Vivid, fantastic visual hallucinations are rare. The duration of such psychoses ranges from 2–3 days to 2 weeks.

Following the discontinuation of sodium oxybate** or gamma-butyrolactone, delirium may develop approximately 24 hours after cessation of substance use. The clinical picture is similar to that of alcohol withdrawal delirium. Treatment may reveal resistance to benzodiazepine derivatives, which is associated with certain pharmacological differences between benzodiazepines and general anesthetic agents [34–37].

Benzodiazepine withdrawal syndrome complicated by delirium is more frequently observed in general somatic healthcare settings and typically occurs in cases of polysubstance use (alcohol and benzodiazepines, or benzodiazepines and other psychoactive substances), as well as in elderly patients receiving low doses of benzodiazepines in the postoperative period [37].

Comments: The potential development of delirium is often attributed to adulterants present in the heroin used (List of narcotic drugs, psychotropic substances, and their precursors whose turnover is prohibited in the Russian Federation in accordance with the legislation of the Russian Federation and international treaties of the Russian Federation (List I)). Furthermore, the onset of delirium is noted during rapid detoxification using buprenorphine** or naltrexone** in patients dependent on methadone (List of narcotic drugs, psychotropic substances, and their precursors whose turnover is prohibited in the Russian Federation in accordance with the legislation of the Russian Federation and international treaties of the Russian Federation (List I)) [38].

2.2 Physical Examination

Comments: It is advisable to consider that predictors of delirium development include hyperthermia, hypotension, advanced age, pulmonary diseases, and cardiovascular diseases [3, 25, 45].

Comments: The ABCDE approach must be used for the assessment and management of critically ill patients:

A – Airway: Assessment of airway patency and establishment of a patent airway if necessary

B – Breathing: Assessment of respiratory status, including pulse oximetry and oxygen therapy when indicated

C – Circulation: Assessment of circulatory status

D – Disability: Assessment of neurological status, including blood glucose levels and other potential causes of altered mental status

E – Exposure: Correction of abnormalities identified at step D, evaluation of other organ systems, laboratory tests, and physical examination

The core principles and approaches of ABCDE are universal for all patients and are applied in cases of suspected or evident critical illness or trauma. Continuous and simultaneous assessment and treatment are essential, with immediate correction of life-threatening signs. Life-saving treatment does not require a definitive diagnosis. Reassessment must be performed at any sign of clinical deterioration [40].

Comments: The CIWA-Ar scale is used to assess the severity of alcohol withdrawal syndrome and select treatment tactics only when the patient is communicative; for example, its use is not feasible in a patient with alcohol withdrawal delirium undergoing mechanical ventilation [42]. The use of CIWA-Ar can serve as a useful guide for benzodiazepine dosing during withdrawal delirium, such as in patients undergoing gamma-hydroxybutyrate (GHB) withdrawal [41]

Comment: In patients with delirium, RASS scores typically range from +4 to -3 [43]. A RASS score of -4 or -5 warrants a re-evaluation of the delirium diagnosis, as these scores correspond to a state of coma or deep sedation. Assessing attention is crucial for diagnosing delirium. Impaired attention is one of the core features of delirium, manifested in two ways: difficulty directing attention and inability to sustain it [44].

It must be taken into account that RASS results depend on the patient's hearing and visual acuity; therefore, the RASS scale is not suitable for patients with severe hearing and visual impairments.

2.3 Laboratory Diagnostics

- general clinical biochemical blood test (total bilirubin, gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total protein, urea, creatinine, glucose);

- assessment of acid-base balance and blood gases (whole venous blood);

- blood electrolyte panel (chloride, potassium, and sodium levels);

- complete blood count (differential leukocyte count, erythrocyte sedimentation rate (ESR));

- urinalysis (physicochemical properties, protein, glucose, bilirubin, urobilinogen, ketone bodies, hemoglobin, nitrites and other salts, cellular elements, casts).

GCR CLEL 5Grade of Recommendations C (Level of Evidence 5)

Comments:

Patients frequently exhibit significant fluid-electrolyte imbalances and acid-base disturbances, which serve as important predictors of delirium during withdrawal. Sodium, potassium, and platelet levels are of major significance in predicting condition severity [45, 46, 47–50].

2.4 Instrumental Diagnostics

Comments: Although numerous reports highlight the risks of acute coronary syndrome during alcohol withdrawal, clinical evidence supporting this association remains limited [39]. Nevertheless, tachyarrhythmias are frequently observed in patients experiencing severe alcohol withdrawal syndrome. Furthermore, the majority of patients exhibit a prolonged QT interval and arrhythmias, necessitating rigorous cardiac monitoring [51].

Electrocardiography (including interpretation, description, and analysis of ECG data) must be performed no later than 24 hours after hospital admission.

2.4.1. Instrumental Diagnostic Examinations

Comments: Alcohol can affect the oropharyngeal flora, promoting colonization by resistant Gram-negative microorganisms; alcohol consumption reduces cough and gag reflexes, predisposing patients to the aspiration of both microorganisms and vomitus [52].

The risk of pneumonia among individuals who consume large amounts of alcohol ("heavy drinking") is 83% higher compared to those who do not exceed the alcohol doses recommended by the WHO [53].

Comments: Brain MRI is a valuable diagnostic tool in diagnosing acute Wernicke's encephalopathy, most commonly revealing symmetrical high signal intensity on T2 FLAIR images in the periventricular regions of the thalamus and the third ventricle [54, 102].

Comments: Besides alcohol withdrawal, causes of seizures may include trauma (hematoma, contusion), use of other psychotropic substances, space-occupying lesions, and infectious processes. Therefore, despite the obvious relationship between alcohol intake and seizure paroxysm, a brain CT scan with and without intravenous contrast is indicated for a first-time seizure [55].

2.5 Other Procedures

No

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

The treatment of delirium should be based on the following principles:

Mental status monitoring.

Rational pharmacotherapy and a comprehensive approach to treatment; elimination of factors provoking delirium (supportive and protective regimen)

Correction of acute respiratory failure (if present);

Maintenance of hemodynamics (if disorders are present);

Correction of water-electrolyte balance and metabolic disorders (if present);

3.1. Organization of Care

Comments: Initial and, if necessary, follow-up visits (examinations, consultations) by a general practitioner, neurologist, and other specialists are indicated for patients with alcohol withdrawal delirium. In a general somatic hospital ward, an initial and follow-up visit (examination, consultation) by a psychiatrist is mandatory if alcohol withdrawal delirium is suspected.

Comment: Considering that medical treatment can exacerbate delirium, lead to coma, and cause side effects—especially regarding the cardiovascular system—it is advisable to use physical restraints. The necessity of physical fixation measures must be justified and recorded in the patient's medical documentation (containing the rationale, start and discontinuation times of this measure, and a description of subsequent changes in the patient's condition).

To prevent nosocomial pneumonia, the following are necessary: elevating the head of the bed by 15-30 degrees, frequent repositioning of the patient, breathing exercises, and percussion chest massage in the event of hypoactive delirium [60].

3.2. Pharmacological and non-pharmacological therapy, diet therapy, pain management, medical indications and contraindications for treatment methods

The main goal of treating patients with alcohol withdrawal delirium is to minimize the risk of complications and eliminate psychotic symptoms. To achieve this goal, it is necessary to apply the principles of rational pharmacotherapy and a comprehensive treatment approach, taking into account the regular association of delirium and its complications with concomitant somatic pathology, decompensation of chronic somatic diseases, and an obligate connection with neurological disorders. Correction of somatic and neurological disorders and elimination of factors contributing to the development or worsening of delirium constitute the main therapeutic strategy that increases treatment efficacy.

Comments: To relieve psychomotor agitation and achieve an adequate level of sedation (sleep from which the patient is easily awakened), benzodiazepine derivatives are used, most commonly: diazepam**, bromdihydrochlorphenylbenzodiazepine**, administered parenterally (IM, IV), or chlordiazepoxide administered orally.

Benzodiazepine derivative therapy must be prescribed no later than 2 hours from the moment of hospital admission.

Lorazepam** can be used in patients with liver disease, decompensated lung disease, or elderly individuals where there is a risk of excessive sedation and respiratory depression with diazepam** administration (lorazepam** is not available in injectable form in the Russian Federation).

Benzodiazepine derivatives are administered until adequate sedation is achieved. If psychomotor agitation persists for an hour after administration, the dose is repeated until the patient remains calm for ≥1 hour.

Refractory alcohol withdrawal delirium (resistant to benzodiazepine derivatives) is defined as requiring >40 mg of diazepam** per hour.

There are three regimens for prescribing benzodiazepine derivatives: fixed-dose, symptom-triggered, and loading-dose regimens.

The symptom-triggered regimen is the most appropriate, as in this case the patient receives medications only in the presence of corresponding symptoms and taking into account their severity, which helps avoid risks associated with excessive sedation in hypokinetic or mixed variants of alcohol withdrawal delirium. Utilizing this approach requires regular patient assessment using the CIWA-Ar scale, or the RASS scale if productive contact with the patient is absent. In patients with pronounced psychotic symptoms receiving intravenous benzodiazepines, assessment should be performed every 10-15 minutes. After acute symptoms resolve, assessments should be performed every hour. For stable patients with mild symptoms receiving oral benzodiazepines, assessments can be performed at 4-6 hour intervals.

Comment: The rate of dose reduction varies for each patient and must be individualized, taking into account age and comorbidities.

Comments: Barbiturates and their derivatives are used only when maximum therapeutic doses of benzodiazepines fail to control severe psychomotor agitation and there is a history of seizures. Phenobarbital** may also be prescribed for phenobarbital withdrawal with delirium and as an adjunctive agent for the treatment of gamma-hydroxybutyric acid (GHB) withdrawal with delirium [73].

In this case, phenobarbital** has an advantage over benzodiazepine derivatives, even though benzodiazepine derivatives have a safer application profile. The main disadvantage of using drugs from the "barbiturates and their derivatives" group is their narrow "therapeutic window" and the potential for respiratory depression.

Comments: Haloperidol** is considered a fairly safe and effective antipsychotic agent for the treatment of delirium. Haloperidol** is a dopamine blocker with mild anticholinergic and minimal cardiovascular side effects, as well as a lack of active metabolites. It is considered a second-line drug of choice in the treatment of delirium.

Haloperidol** can be administered orally, intramuscularly, or intravenously at a dose of 1–2 mg every 2–4 hours depending on age, weight, and symptom severity. If an adequate response is absent, the dosage can be doubled from the initial dose every 15–30 minutes until the patient is calm; thereafter, if the patient's symptoms are controlled, 25% of the last dose is administered every 6 hours, up to a maximum of 10 mg/day. For elderly patients, the dose is 0.25–0.5 mg every 4 hours as needed, with a maximum daily dose of 5 mg (1 ml of solution).

Comments: Haloperidol** has arrhythmogenic properties that exacerbate ischemia and other perfusion-related disorders.

In patients with a history of seizures and traumatic brain injury, haloperidol** increases the risk of extrapyramidal side effects.

Since the use of butyrophenone derivatives may be associated with QT interval prolongation, it is advisable to perform an ECG prior to their administration, paying special attention to the duration of the QT interval. The duration of the QT interval depends on the heart rate and the patient's gender. Therefore, instead of the absolute value, the corrected QT interval (QTc) is used, which is calculated using Bazett's formula: QTc = K × √RR, where RR is the distance between adjacent R waves on the ECG in seconds; K = 0.37 for men and K = 0.40 for women. QT interval prolongation is diagnosed if the duration of QTc exceeds 0.44 s [77].

QT interval prolongation to greater than 0.45 s or by more than 25% compared to previous ECGs may serve as a basis for a cardiology consultation, a dose reduction, or discontinuation of the drug. In this case, serum magnesium and potassium levels must also be monitored [45, 78].

Haloperidol** may cause hyponatremia, hypo- and hyperglycemia, which requires additional monitoring of blood sodium and glucose levels.

Comments: Although some antipsychotic agents demonstrate certain efficacy in relieving symptoms of delirium, they are significantly less effective than benzodiazepine derivatives in preventing seizures, which often complicate the clinical picture of delirium. In hypoactive delirium (mussitant, professional), antipsychotic agents must not be used, as patients have a decreased level of arousal, and their administration may further depress the level of consciousness.

Comment: The use of phenothiazine antipsychotics may be associated with sedative, anticholinergic, and anti-alpha-adrenergic effects that complicate the course of delirium.

Comments: Thiamine should always be administered before the administration of dextrose** [28, 81, 85, 104]. Patients with alcohol dependence frequently experience thiamine deficiency; in patients with alcohol withdrawal syndrome with delirium, this deficiency is even more pronounced. It is associated with Wernicke-Korsakoff syndrome and Korsakoff's amnestic syndrome. The use of #thiamine** carries a low risk of side effects and can prevent the development of the aforementioned conditions. It must be taken into account that patients at risk for thiamine deficiency may require high doses administered 2–4 times a day to achieve clinically significant results, as its half-life is less than 2 hours [10, 104]. The usual prophylactic dose of #thiamine** required for most patients with delirium tremens is up to 500 mg per day parenterally 3 times a day (for 3–5 days), followed by a transition to oral administration [85]. Caution must be exercised when parenterally administering high doses of #thiamine** due to its ability to induce mast cell degranulation and non-specific anaphylactic reactions.

Therapy with #thiamine** must be performed no later than 2 hours from the time of hospital admission.

The prescription of higher doses and the intravenous route of administration, which are not provided for in the instructions for use of #thiamine**, must be carried out on the basis of a decision by a medical commission, accompanied by the appropriate execution of a protocol and the entry of the decision into the patient's medical documentation [102].

Comments: #Thiamine** should be prescribed before any carbohydrate intake and preferably intravenously rather than intramuscularly, given that the required dose of thiamine constitutes a rather painful volume for intramuscular injection. It is advisable to prescribe a #thiamine** infusion at a dose of 500 mg (diluted in 100 ml of normal saline**) three times a day for 3–5 days, followed by a transition to intramuscular injection or oral administration [28, 85, 102, 104]. Taking into account modern knowledge about the synergistic effect of #folic acid** (1 mg/day), B vitamins such as #pyridoxine** (B6) (50–100 mg 1–2 times/day), and #cyanocobalamin** (B12) (500 mcg/day)) [81, 102, 104, 105], it is important to consider their potential role in the treatment of encephalopathies.

An inadequate response to thiamine** may be related to magnesium deficiency [102, 103].

Comment: Dexmedetomidine is a selective alpha-2 adrenergic receptor agonist with a broad spectrum of pharmacological properties. Intravenous administration is used exclusively in an intensive care unit setting as an infusion using a syringe pump [83].

Propofol** acts on receptors different from benzodiazepine derivatives and is effective when tolerance to the latter has developed. The use of the drug is advisable in patients requiring mechanical ventilation support. Propofol** is associated with fewer instances of bradycardia but more frequent instances of hypotension compared to dexmedetomidine, thus requiring hemodynamic monitoring [87].

The dosage and administration rate should be selected individually to achieve the desired effect, taking into account factors such as the patient's underlying medical conditions, age, and previously administered drugs, in accordance with the guidelines for patient sedation in anesthesiology and intensive care units [83]. The infusion rate should be adjusted according to the required depth of the sedative effect. An administration rate within 0.3-0.4 mg/kg/h should ensure a satisfactory sedative effect [84, 85].

Comments: Hypomagnesemia is almost universally present in chronic alcohol abuse due to inadequate intake, malabsorption, and excessive renal excretion of magnesium. The most important clinical features of hypomagnesemia are neuromuscular excitability, central nervous system hyperexcitability, and cardiac arrhythmias. Seizures (usually generalized tonic-clonic) can occur in adults with severe hypomagnesemia. HIV-seropositive patients with hypomagnesemia are particularly prone to epileptic seizures. Administration of magnesium sulfate** during substance withdrawal syndrome reduces the severity of clinical symptoms and normalizes plasma lactate concentrations when combined with thiamine** [89]. Dexmedetomidine infusion combined with magnesium sulfate** has proven effective in the treatment of patients with delirium tremens [87].

Comment: Respiratory support in this patient population has the same indications as in somatic diseases not accompanied by psychosis [92]. Oxygen therapy must be prescribed if oxygen saturation drops below 94% (measured by pulse oximetry). If symptoms of acute respiratory failure develop, diagnostic and therapeutic approaches set out in the clinical guidelines relevant to this condition should be used [94, 95, 96].

Comments: Correction of water-electrolyte disorders can trigger demyelinating brain lesions (osmotic demyelination syndrome, central pontine and extrapontine myelinolysis). Osmotic demyelination syndrome has been recognized over recent decades as a complication of rapid hyponatremia correction. In recent years, it has also been proven that the pathogenesis of osmotic demyelination syndrome may be more complex, involving the inability of brain cells to respond to rapid changes in the osmolarity of the interstitial (extracellular) brain compartment, leading to axonal damage in characteristic areas detectable by brain magnetic resonance imaging.

Patients with hyponatremia are difficult to manage. On the one hand, hyponatremia itself provokes brain edema and increases intracranial pressure, potentially leading to subsequent neurological sequelae or death; on the other hand, overcorrection of hyponatremia can lead to the development of demyelinating brain lesions with severe disability or death.

Hyponatremia is defined as a serum sodium level of less than 135 mEq/L and is considered severe when the serum level is below 125 mEq/L.

The risk of brain edema and neurological manifestations is minimized if the decrease in serum sodium level occurs slowly and gradually (≥48 hours), even in the case of a marked absolute decrease in serum sodium. Conversely, in the case of a rapid drop in serum sodium (acute hyponatremia), brain edema with neurological symptoms may occur.

Acute hyponatremia (developing in less than 48 hours) usually occurs in a hospital setting, mainly after excessive fluid administration, and can be the cause of central pontine myelinolysis, the general symptoms of which include weakness, quadriplegia, pseudobulbar palsy, behavioral changes, psychoses, and cognitive impairments resembling schizophrenia and severe alcohol withdrawal syndrome [99].

Patients with asymptomatic hyponatremia do not require rapid correction, and treatment should be more conservative. Serum sodium and potassium must be monitored. If necessary, the correction of electrolyte disturbances should be halted. Rapid correction of sodium into the hypernatremic range, especially in the presence of hepatic encephalopathy, is a factor contributing to demyelination. Other risk factors for myelinolysis include hypokalemia and malnutrition.

Acute and severe electrolyte imbalance can also manifest as seizures, which may be the sole symptom. Seizures are more frequently observed in patients with sodium concentration disorders (especially hyponatremia), hypocalcemia, and hypomagnesemia. In this case, prompt identification and correction of the underlying electrolyte disturbances to prevent osmotic brain injury is required rather than antiepileptic treatment [97, 98].

Hypernatremia is defined as a plasma sodium concentration >145 mEq/L. The degree of central nervous system impairment in hypernatremia is mainly related to how rapidly the serum sodium level increases—acutely or gradually (chronically). Severe neurological symptoms of hypernatremia are usually the result of a rapid (i.e., within hours) increase in plasma sodium concentration to >158-160 mEq/L.

Comments: Balanced crystalloid solutions, which are close to blood plasma in electrolyte composition and osmolality, form the basis of modern infusion therapy [96]. Small volumes of infusion media are used as a solvent for drugs and essential electrolytes.

Comments: Signs of malnutrition include underweight (less than 80% of ideal body weight), alcohol or substance dependence, lack of regular food intake over the past 5 days, nutrient malabsorption, increased nutrient losses, etc. More physiological enteral nutrition (natural feeding, prescription of traditional therapeutic nutrition) should be preferred to prevent certain adverse gastrointestinal effects that occur in the absence of dietary chyme in the gut, provided there are no contraindications to enteral nutrition. When indicated, parenteral nutrition must be used (ATC group – B05BA – Solutions for parenteral nutrition) [99, 100].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Rehabilitation of patients during the treatment of delirium tremens or delirium within the framework of withdrawal syndrome from other psychoactive substances is not performed, but should be provided after the resolution of delirium, provided there are no symptoms corresponding to the diagnostic criteria for "Amnestic syndrome" (F1x.6) or "Residual and late-onset psychotic disorders" (F1x.7).^[2]

^[2] Clinical guidelines for the medical rehabilitation of patients with addictive disorders (ICD-10 F10-F19) (Approved by the professional association of addiction psychiatrists "National Association of Addiction Doctors")

5. Prevention and Dispensary Observation

The main measures for the prevention of withdrawal state (WS) with delirium include reducing the availability and consumption of psychoactive substances (PAS), particularly alcohol, hypnotics, and sedatives. It is necessary to conduct informational campaigns targeted at the public to promote a healthy lifestyle, as well as provide training and organizational-methodological support for physicians of various specialties for the early detection and rational treatment of WS with a risk of developing delirium.

Dispenser observation (follow-up) is carried out in accordance with Order No. 1034n^[3] and Order No. 573n^[4]

^[3] Order of the Russian Ministry of Health No. 1034n dated December 30, 2015, "On Approval of the Procedure for Providing Medical Care in the Profile 'Psychiatry-Narcology' and the Procedure for Dispenser Observation of Persons with Mental Disorders and (or) Behavioral Disorders Associated with the Use of Psychoactive Substances" (Registered with the Ministry of Justice of Russia on March 22, 2016, No. 41495)

^[4] Order of the Ministry of Health of the Russian Federation No. 573n dated July 30, 2019, "On Amendments to Appendices No. 1 and 2 of the Order of the Ministry of Health of the Russian Federation No. 1034n dated December 30, 2015, 'On Approval of the Procedure for Providing Medical Care in the Profile 'Psychiatry-Narcology' and the Procedure for Dispenser Observation of Persons with Mental Disorders and (or) Behavioral Disorders Associated with the Use of Psychoactive Substances'"

6. Organization of Medical Care

It is necessary to perform an initial admission (examination, consultation) of a patient with suspected WS with delirium by a psychiatrist-narcologist and/or an anesthesiologist-intensivist and/or a psychiatrist no later than 1 hour from the moment of admission to the hospital in order to establish a diagnosis and determine treatment tactics.

Treatment of WS with delirium must be carried out in a hospital setting (anesthesiology-resuscitation department, intensive care unit, or emergency narcology department), especially in cases of ineffective ongoing therapy with unremitting psychomotor agitation, high risk of complications from delirium, or comorbid conditions, to ensure round-the-clock observation and monitoring of vital functions. This is due to the fact that WS with delirium is associated with increased mortality, prolonged hospital stay, and subsequent long-term neuropsychiatric deficits.

Hospitalization/transfer of patients is required: to an intensive care unit or intensive care wards (units) of general somatic hospitals or narcological dispensaries/narcological hospitals; to emergency narcology departments of narcological dispensaries/narcological hospitals.

If a withdrawal state with delirium develops in a general somatic hospital department, arrange for a transfer to an intensive care unit or ward, with mandatory consultation by a psychiatrist-narcologist or psychiatrist (including a physician from a mobile narcological or psychiatric emergency team).

Upon hospitalization of a patient in a psychiatric hospital with a clinical presentation of withdrawal state with delirium, involuntary hospitalization must be arranged in accordance with the grounds of Article 29 of the Law of the Russian Federation No. 3185-1 dated July 2, 1992 (as amended on July 4, 2023), "On Psychiatric Care and Guarantees of Citizens' Rights Granted in Its Provision."

Hospitalization of a patient with the clinical presentation of withdrawal state with delirium to emergency narcology departments, intensive care units (wards) of a narcological dispensary, and other somatic medical organizations is carried out without the patient's consent based on a medical council decision, taking into account the patient's condition—which prevents them from expressing their will—and the necessity of medical intervention for emergency indications to eliminate a threat to the patient's life in accordance with Article 20, Paragraph 10 of Federal Law No. 323-FZ dated November 21, 2011, "On the Fundamentals of Health Protection of Citizens in the Russian Federation."

After the cessation of withdrawal state with delirium (elimination of the symptoms of WS with delirium specified in ICD-10 diagnostic criteria (F1x.4, F05) is achieved), it is necessary to:

1) motivate the patient for further treatment in the narcological department of a medical organization;

2) if medical indications exist, refer the patient to structural subdivisions of medical organizations for the treatment of alcohol-associated diseases;

3) upon completion of the therapy course, recommend consulting a local psychiatrist-narcologist at the place of residence;

4) in the event of amnesic syndrome or residual and delayed mental disorders, the patient is transferred to the narcological or psychiatric department of a medical organization for the treatment of these disorders.

7. Additional Information

The severity of a patient's condition with delirium largely depends on comorbid somatic pathology. Delirium acts as a trigger mechanism for the decompensation of any pre-existing chronic diseases. Most frequently, delirium is accompanied by and can cause the patient's death due to the following conditions: pneumonia, alcoholic cardiomyopathy, acute pancreatitis, liver failure, liver cirrhosis, acute renal failure, cerebral edema, acid-base balance disorders, vitamin metabolism disorders, rhabdomyolysis. In this regard, tertiary medical prevention acquires special significance [101].

Criteria for Evaluating the Quality of Medical Care

Quality criteria for specialized medical care for adults with withdrawal state (abstinent syndrome) with delirium (ICD-10 codes: F10.4; F11.4, F13.4; F19.4)

References

Appendix A1. Working Group Composition

Working Group

Co-Chairs:

Klimenko, Tatyana Valentinovna, MD, Prof.

Krupitsky, Evgeny Mikhailovich, MD, Prof.

Secretary:

Gubanov, Georgy Alexandrovich

Working Group Members:

Agibalova, Tatyana Vasilyevna, MD

Buzik Oleg Zhanovich, Doctor of Medical Sciences

Vinnikova, Maria Alekseevna, MD

Mikhailov Mikhail Albertovich, D.Sc. in Medicine

Arkus, Maxim Leonidovich, PhD

Buzik Oleg Zhanovich, Doctor of Medical Sciences

Korchagina, Galina Alexandrovna, MD, Prof.

Ilyuk Ruslan Dmitrievich, D.Sc. in Medicine

Lobacheva Anna Stanislavovna, Ph.D. in Medicine

Rybakova Ksenia Valeryevna, D.Sc. in Medicine

Shevtsova Yulia Bronyusovna, Candidate of Medical Sciences

Poplevchenkov Konstantin Nikolaevich, Ph.D. in Medicine

Nenastyeva Anna Yuryevna, PhD

Authors:

Tetenova Elena Yuryevna – Candidate of Medical Sciences, Leading Researcher, Moscow Scientific and Practical Centre on Addictology of the Moscow Healthcare Department, Russian Society of Psychiatrists

Nadezhdin Alexey Valentinovich – Candidate of Medical Sciences, Leading Researcher, Moscow Scientific and Practical Centre on Addictology of the Moscow Healthcare Department, Russian Society of Psychiatrists

Utkin Sergey Ionovich – Candidate of Medical Sciences, Leading Researcher, Moscow Scientific and Practical Centre on Addictology of the Moscow Healthcare Department, member of the FAR and the Russian Society of Psychiatrists

Andrusenko Anatoly Anatolyevich – Candidate of Medical Sciences, Associate Professor at the Department of Psychiatry, Addictology and Medical Psychology, Privolzhsky Research Medical University (Perm State Medical University named after Academician E.V. Wagner of the Ministry of Health of Russia), Deputy Chief Medical Officer for Medical Affairs, Regional Clinical Psychiatric Hospital, Russian Society of Psychiatrists

Shurygin Vadim Vladimirovich – Psychiatrist-Narcologist, Psychiatrist, City Clinical Hospital named after V.P. Demikhov of the Moscow Healthcare Department, Russian Society of Psychiatrists

Bulygina Irina Evgenyevna – Candidate of Medical Sciences, Chief Psychiatrist-Narcologist of the Ministry of Health of the Chuvash Republic, Russian Society of Psychiatrists

Zharikov Dmitry Konstantinovich, Anesthesiologist-Intensivist, Moscow Scientific and Practical Centre on Addictology of the Moscow Healthcare Department, member of the FAR

Kolgashkin Alexey Yuryevich – Senior Researcher, Moscow Scientific and Practical Centre on Addictology of the Moscow Healthcare Department, Russian Society of Psychiatrists

Gorbachev Vladimir Ilyich – Doctor of Medical Sciences, Professor, Head of the Department of Anesthesiology and Reanimatology, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of Russia, Presidium member of the FAR, Irkutsk.

Gritsan Alexey Ivanovich – Doctor of Medical Sciences, Professor, Head of the Department of Anesthesiology and Reanimatology, Institute of Postgraduate Education, Krasnoyarsk State Medical University named after Prof. V.F. Voino-Yasenetsky of the Ministry of Health of Russia, Director of the Krasnoyarsk Regional Center for Medical Education, Vice-President of the FAR, Krasnoyarsk, member of the FAR

Zabolotskikh Igor Borisovich – Doctor of Medical Sciences, Professor, Head of the Department of Anesthesiology, Reanimatology and Transfusiology, Faculty of Advanced Training and Professional Retraining, Kuban State Medical University of the Ministry of Health of Russia, Chief Researcher, Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology of the Ministry of Science and Higher Education of Russia, Head of the Anesthesiology and Intensive Care Service, Regional Clinical Hospital No. 2 of the Ministry of Health of Krasnodar Krai, First Vice-President of the FAR, Krasnodar

Ershov Vadim Ivanovich – Doctor of Medical Sciences, Professor, Head of the Department of Anesthesiology and Reanimatology, Orenburg State Medical University of the Ministry of Health of Russia, Orenburg, member of the FAR

Kuzovlev Artem Nikolaevich – Doctor of Medical Sciences, Deputy Director – Head of the V.A. Negovsky Research Institute of General Reanimatology, Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Head of the Department of Anesthesiology and Reanimatology, Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, member of the FAR

Muronov Alexey Evgenyevich – Candidate of Medical Sciences, Associate Professor at the Department of Anesthesiology, Reanimatology and Transfusiology, Faculty of Advanced Training and Professional Retraining, Kuban State Medical University of the Ministry of Health of Russia, member of the FAR

Conflict of interest

All members of the Working Group and authors have declared no financial support or conflicts of interest that need to be disclosed.

Appendix A2. Methodology for Developing Clinical Guidelines

These Guidelines have been developed taking into account the Clinical Guidelines for the Diagnosis and Treatment of Mental and Behavioral Disorders Due to Psychoactive Substance Use (ICD-10 F10-F19) approved by the Association of Narcologists of Russia in 2014, based on the analysis of existing domestic clinical practice, modern foreign guidelines for the treatment of withdrawal syndrome (abstinence syndrome) with delirium, large-scale studies conducted on various aspects of the diagnosis and treatment of delirium, and the experience of domestic research.

Target audience of these clinical guidelines:

1. psychiatrist-narcologist

2. psychiatrist

3. anesthesiologist-resuscitologist

The development of the clinical guidelines utilized rating scales to assess the level of evidence certainty and recommendation strength for diagnostic interventions and recommendation statements regarding therapeutic, rehabilitative, and preventive interventions (Tables 1-4).

Table 1. Scale for grading levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 2. Scale for assessing levels of evidence certainty (LEC) for methods of prevention, treatment, and medical rehabilitation, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions)

Table 3. Scale for assessing grades of recommendation (GR) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, rehabilitation interventions)

Procedure for updating clinical guidelines

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

Appendix A3. Reference Materials

1. Order of the Ministry of Health of Russia No. 1034n dated December 30, 2015, "On Approval of the Procedure for Providing Medical Care in the Profile 'Psychiatry-Narcology' and the Procedure for Dispensary Observation of Persons with Mental Disorders and (or) Behavioral Disorders Associated with Psychoactive Substance Use"

2. Clinical guidelines for the medical rehabilitation of patients with addiction profiles (ICD-10 F10-F19) (Approved by the professional community of narcologists "Association of Narcologists of Russia")

3. Order of the Ministry of Health of the Russian Federation No. 103n dated February 28, 2019, "On approval of the procedure and timelines for the development of clinical guidelines, their revision, the standard form of clinical guidelines, and requirements for their structure, composition, and scientific validity of the information included in clinical guidelines"

4. 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 'On the Fundamentals of Protecting the Health of Citizens in the Russian Federation' regarding Clinical Guidelines."

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

6. Procedure for the Provision of Medical Care to the Adult Population in the Profile "Anesthesiology and Intensive Care", approved by Order of the Ministry of Health of the Russian Federation No. 919n of November 15, 2012.

7. 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."

8. Professional Standard "Anesthesiologist-Resuscitator" (Order No. 554 of August 27, 2018, of the Ministry of Labor and Social Protection of the Russian Federation)

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Alcohol withdrawal delirium (delirium tremens, alcoholic psychosis) is an acutely developing disorder following severe and prolonged binges, heavy alcohol use, and alcohol surrogates against the background of poor nutrition and pronounced somatic pathology (cardiovascular diseases, pneumonia, pancreatitis, liver damage, head injuries, etc.). This is a very serious condition that can result in death or the development of severe central nervous system damage, leading to mental disability. Following delirium, long-term medical follow-up, appropriate treatment, and complete abstinence from alcohol are required.

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

Appendix G1. Clinical Institute Withdrawal Assessment-Alcohol, revised scale (CIWA-Ar)

Russian title: Clinical Institute Withdrawal Assessment for Alcohol scale

Original title: Clinical Institute Withdrawal Assessment-Alcohol, revised scale (CIWA-Ar)

Source (official developer website, publication with

validation): Sullivan J.T., Sykora K., Schneiderman J., Naranjo C.A., Sellers E.M. Assessment of Alcohol Withdrawal: the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar) British Journal of Addiction 1989; 84: 1353-1357

http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.489.341&rep=rep1&type=pdf

Type (underline):

- rating scale

- index

- questionnaire

- other (specify):

Purpose: The scale is intended for monitoring and optimizing therapy in patients with alcohol withdrawal syndrome. The tool evaluates 10 parameters: sweating, anxiety, tremor, auditory disturbances, visual disturbances, agitation, nausea, tactile disturbances, headache, and orientation/sensorium. Each parameter grades the severity of symptoms. The tool demonstrates high validity and reliability.

Content (template):

Key (interpretation):

Notes: The CIWA-Ar scale can only be applied if the patient is responsive and contact is possible.

Alcohol withdrawal delirium can be anticipated if the CIWA-Ar score is ≥15 combined with systolic BP >150 mmHg or HR >100 bpm, recent seizures, history of delirium or seizures, advanced age, recent sedative-hypnotic drug abuse, or concurrent respiratory, cardiovascular, or gastrointestinal diseases.

Appendix G2. Richmond Agitation-Sedation Scale (RASS Scale)

Russian title: Richmond Agitation-Sedation Scale (RASS)

Original title: Richmond Agitation-Sedation Scale (RASS)

Source (official developer website, validation publication): Sessler C.N., Gosnell M.S., Grap M.J., Brophy G.M., O’Neal P.V., Keane K.A., Tesoro E.P., Elswick R.K. The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med. 2002; 166 (10): 1338–1344.

Type (underline):

- assessment scale

- index

- questionnaire

- other (specify):

Purpose: The scale is used to describe the degree of patient psychomotor agitation or the depth of sedation. The scale allows assessment of sedative therapy and improves communication among medical staff. It is easy to use and assesses the level of sedation or agitation in 30–60 seconds using three consecutive steps: observation, response to auditory stimulation, and response to physical stimulation.

Content (template):

Key (interpretation):

RASS Assessment Procedure

1. Patient observation

• If the patient is alert, calm, and attentive? – 0 points.

• Does the patient exhibit behavioral signs characterized by anxiety or agitation – score from +1 to +4 points using the criteria listed above in the description.

2. If the patient is somnolent, ask them in a loud voice, calling them by name, to open their eyes and look at you. Repeat this several times if necessary. Ask the patient to maintain eye contact.

• If the patient makes eye contact and sustains it for more than 10 seconds — score -1.

• If the patient makes eye contact, but it is not sustained for 10 seconds — score -2.

• If the patient makes any movement in response to voice, except for eye contact — score -3.

3. If patient does not respond to voice, physically stimulate patient by shaking shoulder and/or rubbing sternum.

• If the patient responds with any movement to physical stimulation — score -4.

• If the patient does not respond to voice or physical stimulation — score -5.

Notes: RASS depends on the patient's hearing and vision and is not suitable for patients with severe impairments. The scale is most commonly used during mechanical ventilation to avoid inadequate or excessive sedative drug effects.