Brazilian Psychiatric Association Consensus for the Management of Acute Intoxication: general management and specific interventions for drugs of abuse

Abstract Objectives To present the Brazilian Psychiatric Association’s Consensus on the Management of Acute Intoxication. Methods A group of experts selected by the Brazilian Psychiatric Association searched for articles on the MEDLINE (by PubMed) and Cochrane databases, limited to human studies and acute intoxication. Working groups reviewed these materials for appropriateness to the topic and the quality of the work. A survey was conducted using the Delphi method to produce a table of agreed recommendations presented at the end of the systematic review. Three survey rounds were held to reach consensus. Results Support for intoxication should start with Initial Management: Resuscitation/Life Support/Differential Diagnosis. For this, the group proposed the following sequence of assessments: A (airway), B (breathing), C (circulation), D.1 (disability), D.2 (differential diagnosis), D.3 (decontamination), D.4 (drug antidotes), E (enhanced elimination). The group of experts then presented specific interventions for the main drugs of abuse. Conclusions Management of intoxication with drugs of abuse is complex and requires systematic protocols. The group suggests adoption of the A-B-C-D-E technique first, with constant investigation. Then, specific conduct and support until remission of intoxication. The literature is still scarce in evidence on the subject. Therefore, this consensus was necessary. We believe that at present this document can help psychiatric, general, and emergency physicians deal with emergency psychiatric episodes due to acute intoxication. This work could stimulate future studies on the topic.


Introduction
Acute intoxication is a clinically significant transient condition that develops during, or shortly after, consumption of a drug and is characterized by disturbances in consciousness, cognition, perception, affect, behavior, and/or coordination. 1,2These changes are caused by known pharmacological effects of substances in the brain and their intensity is closely related to the amount consumed.They are time-limited and abate as the drug is cleared from the body. 1,2esenting features may vary for each substance and can evolve into several complications, from physical damage (toxic hepatitis, seizures, cardiac arrhythmias) to cardiorespiratory arrest, agitation with aggression, car accidents, and suicidal behavior. 1,2oisoning is probably one of the leading causes of admission to emergency departments (EDs) and intensive care units.The frequency of death ranges from 0.05% (United States) to 4% (South Africa). 3 Data from the World Health Organization (WHO) report mortality rates from unintentional poisoning ranging from 0.001 to 5.45 per 100,000 inhabitants worldwide. 4Poisoning is also the preferred method of suicide, suicide attempt, and self-harm. 5In England, poisoning accounts for 5-10% of ED workload. 6 Brazil, between 2010 and 2014, 376,506 suspected cases of poisoning were registered on the Notifiable Diseases Information System (Sistema de Informação de Agravos de Notificação [SINAN]), although the true magnitude is not yet fully known.Notification of Exogenous Intoxications became mandatory as of 2011, when exogenous intoxication (EI) was added to the list of compulsory notification diseases.7 Another study analyzed compulsory notifications for EI in Brazil between 2007 and 2017 using SINAN data.Of 833,282 cases of EI, 54.25% were women and 54.47% were between 15 and 39 years old.The injuries were recorded mainly in the urban area (86.3%) of the Southeast Region (47.65%). 8 2018, an estimated 269 million (range: 166-373 million) people had used a drug at least once in the previous year, equivalent to 5.4% (range: 3.3-7.5%) of the global population aged 15-64. 2 Assuming no change in the global prevalence of drug use, considering solely the projected increase in the global population would result in the global number of people who use drugs rising by an estimated 11 percent, to 299 million people by 2030.
The health consequences of drug use can include a range of negative outcomes such as drug use disorders, mental health disorders, human immunodeficiency virus (HIV) infection, hepatitis-related liver cancer and cirrhosis, overdose, and premature death. 9spite being a frequent situation in emergencies, EI is still a cause of great difficulties for physicians. 10,11e literature is extensive, but provides little evidence.
Lack of training and stigma related to mental illness are factors that further hinder the care of these patients. 12Therefore, documents that standardize care of such cases could help health professionals act more effectively and help with planning of public prevention policies.
This work aims to standardize information on management of patients in acute intoxication from drugs of abuse and present it for physicians, especially psychiatrists.

Methods
The group's initial objective was to develop a guideline and score studies according to the 2011 Oxford evidence levels.However, after a detailed search, not enough articles were found with sufficient evidence to accomplish this task.As an alternative, a Consensus document was developed.Procedures focused on discussion and integration of findings from peer-reviewed published research on the topic.
Working groups then reviewed these materials for their appropriateness to the topic and study quality.A survey using the Delphi method was then conducted to construct a table of agreed recommendations at the end of the systematic review.

The panel of experts
A group of experts selected by the Brazilian Psychiatric Association, based on publications or clinical experience in psychiatric emergencies, medical emergencies, or substance abuse disorders.

Eligibility criteria
Inclusion criteria for the literature research included papers published (or in press) on adults (18 years old), from 2010 to 2020.Editorials, narrative reviews, small naturalistic studies, case reports, animal or in vitro studies, and letters to the editor were excluded.
However, other manuscripts that did not meet the inclusion criteria were assessed when needed, including association guidelines, government documents, and articles published outside the search period.

Search strategy
Searches for articles were run on the MEDLINE (by PubMed), SciELO, and Cochrane databases, limited to human studies and acute intoxication.Keywords used were poisoning OR emergencies OR drug abuse OR detoxification OR acute intoxication AND management (Figure 1).

Selection process
First, two panel members, LB and AGP, searched for abstracts and selected the most relevant.Second, LB, AGP, CPM, and RAF analyzed full manuscripts to select the most important and those of the highest quality.

Data collection
This process was conducted by LB, AGP, CPM, and RAF.

Data items
LB, AGP, CPM, and RAF wrote an outline of the manuscript.Items included for discussion were selected by another panel of experts in the first phase of the Delphi process.

Delphi method
We conducted a survey using the Delphi method to construct a table of agreed recommendations at the end of the systematic review. 13

Endorsed items
Items rated by the panel of experts as "essential" or "important" were included in the recommendations.

Re-rated items
Items rated as "essential" or "important" by 65-79% of panel experts were included in the next survey for re-rating after considering feedback from firstround results.Panel members could decide whether they wanted to maintain or change their earlier rating on these relatively controversial items.Items were rerated only once; if they still did not achieve the criterion for endorsement, they were rejected.

Rejected items
Items that were not included by at least 65% of panelists in the first round were rejected and excluded.
The first survey included 102 items.The second survey included 57 items.The briefer third survey consisted of eight items that needed re-rating.Fifty-two were endorsed and formed the final manuscript in the item results.

Results and discussion
Initial management: Resuscitation/Life support/

Differential diagnosis
All situations of acute intoxication must be taken extremely seriously.Screening and hospitalization will be necessary when intentional self-poisonings or recreation ingestion occur.[17] The patient physical examination verifies the main signs and symptoms related to each intoxication condition, which, when grouped, can characterize a certain toxic syndrome. 11,15itial assessment of the patient must go through specific steps, 16,17 as outlined in Figure 2.

A. Airway
The airway must be kept patent through positioning, suction, or insertion of an artificial nasal or oropharyngeal airway.If there are signs of coma or depressed airway reflexes, perform endotracheal intubation or insert an extra-glottic device (supraglottic or retroglottic). 17

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Clinically assess the quality and depth of respiration and assist, if necessary, with a bag valve-mask device or mechanical ventilator. 17terial blood PO 2 analysis may reveal hypoxemia, which may be caused by respiratory

Specific interventions
Alcohol -Avoid sedatives.Haloperidol if there is agitation.Thiamine, evaluate hydration and glycemic levels.
Control of cardiovascular side effects.
Hallucinogens -Support and antipsychotics if necessary.
Opioids -Avoid benzodiazepines.Use naloxone.which antihypertensive to use, if necessary, considering the mechanism of action and which adrenergic receptors will be blocked. 17

D.2. Differential diagnosis
The "5 Ws" strategy is used in the clinical interview of the patient and/or their companions for initial assessment of an intoxicated patient.The "5 Ws" refer to data related to the patient (Who?) -obtain the patient's history of diseases, medications in use, previous suicide attempts, occupation, access to substances, drug use, and pregnancy; to the substance used (What?) -find out which substance was used and the quantity; to time of occurrence (When?) -check the time of exposure and for how long the substance was used, in cases of repeated exposures; to place of occurrence (Where?)where the exposure occurred and if bottles, packages, syringes, or pill packs were found close to the patient, check which medicines the patient has access to; and to the reason for the exposure (Why?) -identify the circumstance of the exposure, since it is extremely important to know whether it was a suicide attempt, homicide, accident, recurrent episodes of drug abuse, or others. 11,15Basic support should be provided for all patients as described below.However, ongoing management will depend on the type of substance used, and so it is essential to identify it.Four measures can be used to find out what substances are involved: 1) Questioning the patient and their companions; 2) Finding substances or documents in their clothes; 3) Indirectly, by the signs or symptoms of identification; or 4) through toxicology tests. 11,15

D.3. Decontamination
In case of contact with eyes, irrigate with saline solution. 17In case of skin contamination, remove clothes and wash with plenty of soap and water. 22egarding the gastrointestinal tract, a variety of methods may be considered, such as emesis (no role in the hospital setting) and administration of ipecac at the site of ingestion or in the ED, but should be avoided. 22stric lavage should not be performed routinely, and in situations where gastric lavage might seem proper, consider treatment with activated charcoal and always observe for supportive care. 23Activated charcoal, used for prompt adsorption of drugs or toxins in the stomach and intestine, is contraindicated in patients with an altered state of consciousness and in intoxication by ethanol/glycols, alkalis/corrosives, metals including lithium, iron compounds, potassium, fluoride, cyanide, hydrocarbons, and mineral acids such as boric acid. 16,17,24Whole bowel irrigation, is not routinely indicated, but can be considered for cases of potentially toxic ingestion of sustained-release or enteric substances such as coated drugs, drugs not absorbed by activated charcoal (e.g., lithium, potassium, and iron) and for the removal of illicit drugs in "packers" or "stuffers" from the body. 25

D.4. Drug antidotes, see specific guidelines.
Aiming to help in diagnosis and treatment, the possibility of assaying serum drug levels can also be useful for choosing antidotes, if there are any.

Alcohol
Alcohol is a substance commonly used all over the world, mainly in Western countries.It also constitutes the oldest and most widespread substance of abuse. 28hanol is a biphasic psychoactive substance, a CNS depressant whose effects of intoxication can vary according to the dose, type of drink ingested, speed of ingestion, genetic factors, and consumption pattern (degree of tolerance of the user). 10,11The manifestations of intoxication are heterogeneous, affecting neurological, cardiac, gastrointestinal, pulmonary, and metabolic functions.Among the many alcohol-related problems referred to emergency units, acute intoxication is the most common, mainly in adults and adolescents. 10,11gns and symptoms.Ethyl breath, conjunctival hyperemia, altered speech, altered motor coordination, impaired attention, altered ability to discern, altered affect (euphoria, joy, sadness, irritation), behavior change, ability to cooperate, and presence of nystagmus 1,28-30 can be seen.
An alcoholic drink is considered to have 14 g of alcohol.[30] Use is considered compulsive or binge drinking when, in a period of 2 h, there is the consumption of four or more drinks in the case of women and five or more drinks in the case of men.People over 60 years old should avoid drinking more than one dose per day or seven doses per week, with no difference between genders.triggering mood and psychotic episodes, death. 10,11,28ble 2 shows the severity of alcohol levels.
Management of alcohol intoxication.The treatment of acute ethanol intoxication begins with immediate interruption of alcohol consumption and protection of the airways in all cases, considering that the main clinical complication is respiratory depression.
Aspiration prevention is mandatory and positioning the patient laterally can be useful. 28Hydration and intravenous glucose should only be administered if the patient has dehydration or hypoglycemia. 10,11ministration of thiamine is recommended for all patients with alcohol-related disorders, considering that it is difficult to detect hidden thiamine deficiency and Wernicke's encephalopathy, which constitutes an increased risk. 28,33 cases of mild to moderate intoxication, checking of vital signs is indicated and if there is evidence of dehydration, intravenous fluid administration.The patient must be kept under observation, whether in hospital or an outpatient setting, to detect signs of alcohol withdrawal.Psychomotor agitation and aggressiveness are common in patients with severe intoxication and, in these situations, use of intramuscular injectable haloperidol in monotherapy is indicated, but after verbal de-escalation. 15,28,34It is important to avoid benzodiazepines and antihistamines, 23 with the risk of interaction effects with alcohol.In extreme cases of agitation, when the patient is a risk to himself or others, mechanical restraint may be necessary.Antiemetic medications can be useful in case of nausea and/or vomiting. 28[37] Cocaine and other stimulants Cocaine, benzoylmethylecgonine is an alkaloid extracted from the leaves of Erythroxylon coca. 38,39caine increases the activity of monoamine neurotransmitters in the central and peripheral nervous system by blocking reuptake pumps (transporters) of dopamine, norepinephrine, and serotonin. 38,39eurological complications are seizures, hemorrhage, intracranial infarction, altered mental status, and spinal cord infarction. 10,11,39,40Other common complications we should be alert for include severe hypertension, acute renal failure, hyperthermia, pneumothorax, and deep vein thrombosis. 10,11,39,40nagement protecting the airways and maintaining oxygenation and ventilation, in addition to obtaining venous access. 38,40r patients with moderate psychomotor agitation who are collaborative, have no warning signs indicating immediate risk, and have no significant changes to vital signs, benzodiazepines are recommended, such as diazepam orally at a dose of 5-10 mg, which can be repeated according to the patient's progress.
In patients with intense psychomotor agitation and/or aggressiveness, the recommendation is to use benzodiazepine intravenously (diazepam) or intramuscularly (midazolam).The option most available in Brazil is diazepam 0.2-0.3mg/kg/dose, by slow infusion, without dilution.In cases lacking intravenous access, the choice is midazolam 0.2-0.7 mg/kg administered intramuscularly.In some cases of severe agitation, to protect the patient, mechanical restraint may be necessary for the shortest time. 38,40aloperidol can also be used in cases of intense psychomotor agitation and paranoid delusions, but special attention should be paid to its cardiovascular effects, the decrease in the seizure threshold, and a possible increase in heart temperature.This medication should be avoided in people who have seizures, hyperthermia, severe hypertension, or cardiac arrhythmias; in these cases, use of benzodiazepines should be prioritized. 11,15,17Phenothiazine antipsychotics such as chlorpromazine should be avoided due to the significant reduction in the seizure threshold and the potential to trigger cardiac arrhythmias.Use of betablockers should be avoided in patients who have used cocaine in the past 24 h, due to its potential to trigger a reduction in blood flow and increase severe coronary events. 10,11,34e challenge for the physician in the ED is to identify patients at risk who would benefit from a specific intervention.All patients with acute coronary syndrome, especially young men, without risk factors other than smoking, should be asked about cocaine usage. 38 However, labetalol is a non-selective β-blocker with only modest α-blocking properties. 38Thrombolysis should only be given when a thrombus has been shown on angiography or if pharmacological treatment has failed and angiography is not possible.Administration of naloxone and flumazenil should be avoided since they may lead to severe complications. 38 severe and resistant cases, there may be a need for patient intubation for better clinical stabilization and protection of the airway, in which case benzodiazepines or propofol should be prioritized.Use of succinylcholine in intubation is contraindicated in these cases.

Hallucinogens
This group includes serotonin 2A receptor (5-HT2AR) agonists (lysergic acid diethylamide, psilocybin, and N,Ndimethyltryptamine); mixed serotonin and dopamine reuptake inhibitors and releasers (3,4-methylenedioxymethamphetamine); N-methyl-D-aspartate antagonists (ketamine and dextromethorphan); kappa opioid receptor agonist salvinorin A; and anticholinergics. 41,42igns and symptoms.Drug-induced conditions associated with perceptual changes are generally accompanied by physiological abnormalities.With hallucinogens, sympathomimetic effects are common, occur shortly after ingestion, and usually precede the hallucinogenic effects. 42,43Delirium or psychosis, however, is also observed with other drugs that show similar effects, such as phencyclidine (PCP), amphetamines, cocaine, and anticholinergics. 42Patients with amphetamine intoxication typically present with elaborate and paranoid delusions, as well as visual disturbances.Agitation or extreme agitation along with marked hyperthermia should suggest possible exposure to drugs such as cocaine or PCP.(THCV), and many others, have also been elucidated. 45day, over 100 phytocannabinoids have been discovered, with THC and CBD being the two most studied cannabinoids. 45These phytocannabinoids can interact with the brain's endogenous cannabinoid system (ECS) to elicit a range of neurobehavioral outcomes, including perturbation to the normal structure and function of the brain.The ECS consists of two main cannabinoid receptors (CB1 and CB2 receptors), endogenous cannabinoids (termed endocannabinoids, with two of the most well-studied being anandamide

Complications
[AEA] and 2-AG [2-arachidonoylglycerol]) that act as natural ligands at the cannabinoid receptors, and enzymes that participate in their synthesis, uptake, or metabolism (e.g., fatty acid amide hydrolase 6][47] Within the CNS, their relative densities vary across brain regions.Early autoradiography studies in rodents and humans showed a high concentration of CB1 receptors in the cerebellum, hippocampus, and basal ganglia. 45,47They are also densely expressed across the cortex, particularly in the frontal, cingulate, and temporal cortices. 45Meanwhile, CB2 receptors are predominantly found in immune cells across the body. 45,46 Signs and symptoms.Changes in mood (predominance of euphoria).The classic syndrome of opioid toxicity includes apnea, stupor, and miosis.
However, not all these findings are always present. 52The essential symptom of opioid intoxication is respiratory depression.In non-tolerant individuals, therapeutic doses of opioids cause a noticeable decline in all phases of respiratory activity, which is progressive depending on the dose. 52In cases of overdose, the decline in respiratory rate is the most noticeable and can progress to apnea. 52 Complications.Coma, respiratory depression, 52 pulmonary edema, lung injury, hypothermia, seizures, rhabdomyolysis, myoglobinuric renal failure, and compartment syndrome (caused by immobility). 52anagement of opioid intoxication.First, provide support as mentioned previously (A-B-C-D-E), especially respiratory support. 52The opioid overdose antidote, naloxone, is a competitive mu opioid-receptor antagonist that reverses all indicators of intoxication.
Adults should receive a starting dose of 0.1 to 2 mg of naloxone; if no response occurs, the dose should be raised every 2 minutes according to the schedule, up to a maximum of 15 mg. 43,44Orotracheal intubation is an alternative to naloxone administration.Activated charcoal for gastrointestinal decontamination should be reserved for individuals who present within 1 h after ingestion. 43Examine the axillae, perineum, scrotum, and oropharynx; any transdermal patches found should be removed, and the skin should be cleaned with soap and cool water. 52

Multiple drug intoxication
Management of acute multidrug intoxication is a challenge.First, all conduct should focus on support (A-B-C-D).As for specific procedures, they must only be performed in case of serious effects (of any of the substances) that could put the patient's life at risk (e.g., severe tachyarrhythmia or severe hypertensive crisis due to severe cocaine intoxication associated with acute alcohol intoxication).In the case cited as an example, use of benzodiazepines, vasodilators, and antiarrhythmics should be considered and monitoring should be redoubled.

Limitations
The Delphi method enabled production of a document based on the opinions of a group of experts.
It was not possible to quantify the quality of evidence using the Oxford method, GRADE, or the Amstar instrument.However, the process allowed us to provide standards for decision-making on a topic on which there is little evidence in the literature and allowed us to bring together diverse types of knowledge in a document.
The Delphi technique was used to minimize the chances of error and bias.

Conclusion
The approach to acute poisoning is complex and requires systematic protocols.We suggest adoption of the A-B-C-D-E technique first, with constant investigation.Then, specific conduct and support until remission of intoxication.The literature is still scarce in evidence on the subject.Therefore, this consensus was necessary.We believe that at present this document can help psychiatric, general, and emergency physicians deal with emergency psychiatric episodes due to acute intoxication.This work could stimulate future studies on the topic.

Figure 1 -
Figure 1 -The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 flow diagram.

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Some intoxications can cause hypertension.The most common substances in this case are amphetamines and synthetic stimulants, anticholinergics, cocaine, performanceenhancing products (e.g., caffeine, phenylephrine, ephedrine, or yohimbine), monoamine oxidase (MAO) inhibitors, and other drugs.It is important to consider

Figure 2 -
Figure 2 -Flow diagram for the management of acute intoxication.

D. 1 .
Disability•Seizures are always generalized and usually respond to benzodiazepines with barbiturates as second line.Phenytoin is ineffective.
of intoxication by cocaine and other stimulants.The treatment for cocaine intoxication must consist of vital and symptomatic support according to the patient's symptoms.Antidotes are not yet known.Screening tests for psychoactive substances are also rarely available in emergency units in Brazil.In addition to careful physical examination, if possible, a detailed history taking is recommended and it is also important to obtain more information about the condition from family members, friends, the removal team who brought the patient to the hospital, or the police authority who accompanied the patient.The first action is to diagnose and treat any eventual organic changes that could put the patient's life at risk.Special attention should be given to the cardiovascular and neurological systems due to specific fatal impairments.In case of mild cocaine intoxication, in which the patient does not have any warning signs such as chest pain, severe hypertension, major increase in heart rate, or signs of neurological impairment, one should only observe progress, keeping the patient in a safe place, with regular evaluation, and without environmental stimuli.In patients with severe intoxication, the initial priority involves clinical support of the patient, mainly First-line treatment of a patient with cocainerelated chest pain compatible with myocardial ischemia and ST-segment elevation consists of administration of oxygen and sublingual nitroglycerin or verapamil.If there is no response, immediate coronary angiography should be performed.Both nitroglycerin and verapamil have been shown to reverse cocaine-induced hypertension, coronary arterial vasoconstriction, and tachycardia. 38Beta-blockers (especially non-selective β-blockers) are relatively contraindicated in cocaineassociated acute coronary syndrome.Beta-receptor blockade causes unopposed α-receptor stimulation, which may lead to aggravation of coronary arterial vasoconstriction and systemic hypertension.Some authors recommend labetalol, a joint α-and β-blocker. 16

Table 2 -
20rum alcohol levels and clinical repercussion20 52ose that mediate nociception are in the anterior and ventrolateral thalamus, amygdala, and dorsal root ganglia.52Modulation of respiratory responses to hypercarbia and hypoxemia occurs in the brainstem with contributions from dopaminergic neurons, and control of pupillary constriction occurs by receptors in the Edinger-Westphal nucleus of the oculomotor nerve.52 49n more severe cases, panic attacks, paranoia, and psychosis can occur.49Psychotic smptoms may occur, but are not necessary for a diagnosis of intoxication, however, insight must be preserved, and psychosis must not be severe or