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Acute alcohol intoxication

  • Luisa Vonghia
    Affiliations
    Institute of Internal Medicine, Catholic University of Rome, Italy
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  • Lorenzo Leggio
    Affiliations
    Institute of Internal Medicine, Catholic University of Rome, Italy
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  • Anna Ferrulli
    Affiliations
    Institute of Internal Medicine, Catholic University of Rome, Italy
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  • Marco Bertini
    Affiliations
    Medical Department, Baldacci Laboratories, Pisa, Italy
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  • Giovanni Gasbarrini
    Affiliations
    Institute of Internal Medicine, Catholic University of Rome, Italy
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  • Giovanni Addolorato
    Correspondence
    Corresponding author. Institute of Internal Medicine, Catholic University of Rome, L. go A. Gemelli 8, I-00168 Rome, Italy. Tel.: +39 06 30154334; fax: +39 06 35502775.
    Affiliations
    Institute of Internal Medicine, Catholic University of Rome, Italy
    Search for articles by this author
  • Alcoholism Treatment Study Group
    Author Footnotes
    1 Alcoholism Treatment Study Group: L. Abenavoli M.D., C. D'Angelo M.D., S. Cardone M.D., A. Mirijello M.D, V. Leso M.D., S. Piano M.D., A. Nesci M.D.; Institute of Internal Medicine, Catholic University of Rome; Italy. E. Capristo M.D., N. Malandrino M.D.; Metabolic Unit, Institute of Internal Medicine, Catholic University of Rome; Italy. F. Caputo M.D., S. Francini M.D., M. Stoppo, T. Vignoli M.D., M. Bernardi M.D.; “G. Fontana” Centre for the Study and Multidisciplinary Treatment of Alcohol Addiction, Institute of Internal Medicine, Cardioangiology and Epatology, University of Bologna; Italy.
  • Author Footnotes
    1 Alcoholism Treatment Study Group: L. Abenavoli M.D., C. D'Angelo M.D., S. Cardone M.D., A. Mirijello M.D, V. Leso M.D., S. Piano M.D., A. Nesci M.D.; Institute of Internal Medicine, Catholic University of Rome; Italy. E. Capristo M.D., N. Malandrino M.D.; Metabolic Unit, Institute of Internal Medicine, Catholic University of Rome; Italy. F. Caputo M.D., S. Francini M.D., M. Stoppo, T. Vignoli M.D., M. Bernardi M.D.; “G. Fontana” Centre for the Study and Multidisciplinary Treatment of Alcohol Addiction, Institute of Internal Medicine, Cardioangiology and Epatology, University of Bologna; Italy.
Published:March 31, 2008DOI:https://doi.org/10.1016/j.ejim.2007.06.033

      Abstract

      Acute alcohol intoxication is a clinically harmful condition that usually follows the ingestion of a large amount of alcohol. Clinical manifestations are heterogeneous and involve different organs and apparatuses, with behavioral, cardiac, gastrointestinal, pulmonary, neurological, and metabolic effects. The management of an intoxicated patient occurs mainly in the emergency department and is aimed at stabilizing the clinical condition of the patient, depending on his/her clinical presentation. One specific drug that is useful in the treatment of acute alcohol intoxication is metadoxine, which is able to accelerate ethanol excretion. In patients presenting an acute alcohol intoxication, alcohol-related disorders should be detected so that the patient can be directed to an alcohol treatment unit, where a personalized, specific treatment can be established.

      Keywords

      1. Introduction

      Ethanol (CH3CH2OH) is a water-soluble compound that rapidly crosses cell membranes, resulting in ready equilibration between intra- and extra-cellular concentrations [
      • Marco C.A.
      • Kelen G.D.
      Acute intoxication.
      ]. Its absorption occurs mainly in the proximal intestinal tract, namely, in the stomach (70%) and in the duodenum (25%), while only a small percentage occurs in the remaining intestinal tracts [
      • Marco C.A.
      • Kelen G.D.
      Acute intoxication.
      ]. Gastric alcohol dehydrogenase (ADH) is responsible for 10% of alcohol metabolism (so called “first pass metabolism”) and has important gender-related differences [
      • Frezza
      • Di Padova C.
      • Pozzato G.
      • Terepin M.
      • Barona E.
      • Lieber C.S.
      High blood alcohol levels in women: role of decreased gastric alcohol dehydrogenase activity and first pass metabolism.
      ]. The remaining 90% of ingested ethanol is metabolized in acetaldehyde along three liver enzymatic pathways in different percentages: (1) liver ADH (90%), (2) microsomal ethanol oxidizing system (MEOS; 8–10%), and (3) catalase (0–2%) [
      • Lieber C.S.
      Hepatic metabolic and toxic effects of ethanol: 1991 uptake.
      ].
      Alcohol is a substance that is widely used, mostly in western countries. It also represents the oldest and the most diffuse substance of abuse. In the United States, 20–40% of the subjects admitted to hospitals have alcohol-related problems [
      • Lieber C.S.
      Medical disorders of alcoholics.
      ] and, in elderly people, alcohol-related disorders are as common a reason for hospitalization as myocardial infarctions [
      • Adams W.L.
      • Yuan Z.
      • Barboriak J.J.
      • Rimm A.A.
      Alcohol-related hospitalizations of elderly people.
      ].
      In Italy, some four million individuals are reported to have alcohol-related disorders; of them, approximately one million satisfy the Diagnostic and Statistical Manual of Mental Disorders IV edition criteria [
      ] for alcohol dependence [
      • Addolorato G.
      • Armuzzi A.
      • Gasbarrini G.
      Alcoholism Treatment Study Group
      Pharmacological approaches to the management of alcohol addiction.
      ]. The social cost of alcohol-related disorders – including alcohol-related mortality, morbidity, loss of productivity, absenteeism, and hospitalization – is estimated to be around 5–6% of the gross national product (GNP) of Italy [
      ]. Similarly, in the rest of Europe, the full economic cost of alcohol abuse is calculated to be around 2–5% of the GNP (corresponding to €26–66 billion in the year 2003) [
      ].
      Of the many alcohol-related disorders present in subjects referred to emergency care departments, acute alcohol intoxication is the most frequent [
      • te Wildt B.T.
      • Andreis C.
      • Auffahrt I.
      • Tettenborn C.
      • Kropp S.
      • Ohlmeier M.
      Alcohol related conditions represent a major psychiatric problem in emergency departments.
      ]. This condition is present not only in adults but also in adolescents. Among the teenaged population evaluated in a recent Australian study, 29% of the subjects reported drinking to the point of intoxication [
      ]. It is a matter of great concern that data from the United States suggest that children of an increasingly younger age are using alcohol and that up to 32% of adolescents have difficulties with alcohol intoxication/self-poisoning or dependence [
      • Gilvarry E.
      Substance abuse in young people.
      ]. In the European School Survey Project on Alcohol and Other Drugs, 7% of all males between 15 and 16 years of age and 2% of all females interviewed reported ten or more episodes of drunkenness in the previous year. Moreover, the percentage of subjects reporting three or more episodes of alcohol intoxication in the previous month increased from 3% in 1999 to 7% in 2003 [
      European School Survey Project on Alcohol and Other Drugs.
      ].
      The aim of the present paper is to focus attention on the main clinical aspects of acute alcohol intoxication and its pharmacological management, taking into account that this disorder is common, potentially life-threatening, and linked to other harmful conditions, such as trauma and chronic alcohol use disorders.

      2. Acute alcohol intoxication

      2.1 Clinical features

      Acute alcohol intoxication is a clinically harmful condition that usually follows the ingestion of a large amount of alcohol. In the pediatric population, it may the result of the ingestion of household products that contain alcohol, such as colognes, mouthwash, after shave, hair tonics, medication, and solvents.
      The Diagnostic and Statistical Manual of Mental Disorders IV edition criteria [
      ] for acute alcohol intoxication include: (a) recent alcohol ingestion; (b) clinically significant maladaptive behavioral or psychological changes developing during or shortly after alcohol ingestion and including inappropriate sexual or aggressive behavior, unstable mood, impaired judgment, and impaired social or occupational functioning; and (c) one or more of the following signs that develop during or shortly after alcohol use: (i) slurred speech; (ii) lack of coordination; (iii) unsteady gait; (iv) nystagmus; (v) impairment of attention or memory; (vi) stupor or coma; and (vii) symptoms that are not due to a general medical condition and that cannot be accounted for by another mental disorder.
      Several factors can influence the extent of acute alcohol intoxication; besides the amount of alcohol ingested, individual body weight and tolerance to alcohol, the percentage of alcohol in the beverage, and the period of alcohol ingestion seem to be particularly important [

      Yost DA. Acute care for alcohol intoxication. Be prepared to consider clinical dilemmas. Postgrad Med 2002; 112: 14–6, 21–2, 25–6.

      ].
      Symptoms are usually related to blood alcohol concentration (BAC; Table 1). At a BAC higher than 300 mg/dl (65.1 mmol/l), there is an increased risk of respiratory depression and arrest. Death attributable to acute alcohol intoxication generally occurs at a BAC higher than 500 mg/dl (108.5 mmol/l), although the lethal dose of alcohol can be variable [
      • Wallgren H.
      Actions of alcohol.
      ]. Specifically, death has been observed at lower BACs in “non-tolerant” subjects (300 mg/dl; 65.1 mmol/l) [
      • Wallgren H.
      Actions of alcohol.
      ] and recovery has been reported at higher levels (>1200 mg/dl; 260.4 mmol/l) [

      Gordis E. Alcohol and trauma. In: National Institute on Alcohol Abuse and Alcoholism. Alcohol alert, no 3. Aviable at: http://pubs.niaaa.nih.gov/publications/aa03.htm. Accessed January 1989.

      ,
      • Johnson R.A.
      • Noll E.C.
      • Rodney W.M.
      Survival after a serum ethanol concentration of 1½%.
      ]. However, in alcohol-dependent patients who develop tolerance to alcohol as a result of repeated exposure to ethanol, these effects may become reduced [
      • Chandler L.J.
      • Harris R.A.
      • Crews F.T.
      Ethanol tolerance and synaptic plasticity.
      ]. This phenomenon seems to be related to compensatory changes in excitatory N-methyl-d-aspartate (NMDA) and inhibitory gamma-aminobutyric acid (GABA) [
      • Chandler L.J.
      • Harris R.A.
      • Crews F.T.
      Ethanol tolerance and synaptic plasticity.
      ].
      Table 1Main clinical symptoms in acute alcohol intoxication according to blood alcohol concentration (BAC)
      SymptomsBAC
      Impairment in some tasks requiring skillBAC<50 mg/dl (10.9 mmol/l)
      Increase in talkativeness
      Relaxation
      Altered perception of the environmentBAC>100 mg/dl (21.7 mmol/l)
      Ataxia
      Hyper-reflexia
      Impaired judgment
      Lack of coordination
      Mood, personality, and behavioral changes, nystagmus
      Prolonged reaction time
      Slurred speech
      AmnesiaBAC>200 mg/dl (43.4 mmol/l)
      Diplopia
      Dysarthria
      Hypothermia
      Nausea
      Vomiting
      Respiratory depressionBAC >400 mg/dl (86.8 mmol/l)
      Coma
      Death
      The clinical findings usually present in alcohol-intoxicated subjects are due to the effect of acute ingestion of alcohol on different organs and apparatuses. Acute alcohol intoxication is able to cause several metabolic alterations, including hypoglycemia, lactic acidosis, hypokalemia, hypomagnesemia, hypoalbuminemia, hypocalcemia, and hypophosphatemia [
      • Marco C.A.
      • Kelen G.D.
      Acute intoxication.
      ]. Acute alcohol intoxication-related cardiovascular effects include tachycardia, peripheral vasodilation, and volume depletion; these features can contribute to the induction of hypothermia and hypotension [
      • Marco C.A.
      • Kelen G.D.
      Acute intoxication.
      ]. Another possible cardiovascular effect is “holiday heart syndrome”, characterized by atrial or ventricular tachyarrhythmias and new-onset atrial fibrillation after acute alcohol ingestion [
      • Ettinger P.O.
      • Wu C.F.
      • De La Cruz Jr, C.
      • Weisse A.B.
      • Ahmed S.S.
      • Regan T.J.
      Arrhythmias and the “Holiday Heart”: alcohol-associated cardiac rhythm disorders.
      ,
      • Lowenstein S.R.
      • Gabow P.A.
      • Cramer J.
      • Oliva P.B.
      • Ratner K.
      The role of alcohol in new-onset atrial fibrillation.
      ]. The main life-threatening respiratory consequence of acute alcohol intoxication is respiratory depression. Other respiratory effects include decreased airway sensitivity to foreign bodies, decreased ciliary clearance and aspiration, and increased risk of bacterial infection with consequent bronchitis and pneumonia [
      • Happel K.I.
      • Odden A.R.
      • Zhang P.
      • Shellito J.E.
      • Bagby G.J.
      • Nelson S.
      Acute alcohol intoxication suppresses the interleukin 23 response to Klebsiella pneumoniae infection.
      ]. Gastrointestinal effects include nausea, vomiting, diarrhea, abdominal pain secondary to gastritis, peptic ulcer, and pancreatitis [
      • Hanck C.
      • Whitcomb D.C.
      Alcoholic pancreatitis.
      ,
      • Addolorato G.
      • Montalto M.
      • Capristo E.
      • et al.
      Influence of alcohol on gastrointestinal motilty: lactulose breath hydrogen testing on orocecal transit time in chronic alcoholics, social drinkers and teetotaler subjects.
      ]. Prolonged vomiting can lead to hyponatremia [
      • Caputo F.
      • Marchi B.
      • Coralli B.
      • et al.
      Symtomatic hypotonic hyponatremia in an alcoholic polydipsic patient: a favourable clinical outcome after sodium correction.
      ]. Acute alcohol intoxication can cause a dysfunction of esophageal, gastric, and duodenal motility [
      • Burbige E.J.
      • Lewis Jr, D.R.
      • Halsted C.H.
      Alcohol and the gastrointestinal tract.
      ] and an increase in duodenal type III (propulsive) waves in the ileum [
      • Pirola R.C.
      • Davis A.E.
      Effects of intravenous alcohol on motility of the duodenum and the sphincter of Oddi.
      ]; this increased transit of intestinal contents may contribute to diarrhea [
      • Addolorato G.
      • Montalto M.
      • Capristo E.
      • et al.
      Influence of alcohol on gastrointestinal motilty: lactulose breath hydrogen testing on orocecal transit time in chronic alcoholics, social drinkers and teetotaler subjects.
      ]. Acute alcohol intoxication can induce acute alcoholic hepatitis [
      • Agarwal K.
      • Kontorinis N.
      • Kontorinis N.
      • Dieterich D.T.
      • Dieterich D.T.
      Alcoholic hepatitis.
      ], usually in subjects with chronic alcohol abuse and/or in patients affected by alcoholic cirrhosis. Most often the diagnosis is suggested by a history of excessive alcohol abuse in patients with features of hepatic decompensation [
      • Agarwal K.
      • Kontorinis N.
      • Kontorinis N.
      • Dieterich D.T.
      • Dieterich D.T.
      Alcoholic hepatitis.
      ,
      • Ceccanti M.
      • Attili A.
      • Balducci G.
      • et al.
      Acute alcoholic hepatitis.
      ,
      • Mora J.M.
      • Olmedo R.
      • Curiel E.
      • Munoz J.
      • Herrera M.
      • Seller G.
      MARS (molecular absorbent recirculating system) as hepatic extracorporeal care in serious acute liver failure of alcoholic etiology.
      ,
      • Boirie Y.
      • Thiefin G.
      • Diebold M.D.
      • Leutenegger M.
      Significant increase of serum CA 19-9 antigen level in acute alcoholic hepatitis.
      ,
      • Asnis D.S.
      • Mollura J.L.
      Acute febrile alcoholic hepatitis treated with corticosteroids.
      ].
      Symptoms usually include nausea, vomiting, and abdominal pain. Less frequently, fever, shivering, and jaundice can occur. Zieve syndrome has also occasionally been reported; this consists of hemolytic anemia, jaundice, and hypertriglyceridemia [
      • Piccini J.
      • Haldar S.
      • Jefferson B.
      Cases from the Osler Medical Service at Johns Hopkins University. Zieve syndrome.
      ,
      • Addolorato G.
      • Gasbarrini G.
      • Pompili M.
      • et al.
      Abuso e dipendenza da alcol: principali aspetti internistici.
      ]. Finally, acute alcohol intoxication can be found in patients affected by such psychiatric disorders as affective disorders and antisocial personality [
      • Rund D.A.
      • Summers W.K.
      • Levin M.
      Alcohol use and psychiatric illness in emergency patients.
      ]; suicide or suicidal gestures are also highly associated with alcohol intoxication [
      • Marco C.A.
      • Kelen G.D.
      Acute intoxication.
      ].
      An increased risk of injury has been found in individuals with alcohol intoxication [
      • Maier R.V.
      Ethanol abuse and the trauma patient.
      ]. An Australian study showed that conditions deriving from acute alcohol intoxication, such as trauma and violence, were responsible for 46% of potential life years lost, twice that from chronic alcohol-related conditions [
      • Chikritzhs T.N.
      • Jonas H.A.
      • Stockwell T.R.
      • Heale P.F.
      • Dietze P.M.
      Mortality and life-years lost due to alcohol: a comparison of acute and chronic causes.
      ]. Although all groups of drinkers are at risk of alcohol-related injury, those who usually drink little, but on occasion drink heavily, are at the highest risk, probably because of a low alcohol tolerance [
      • Gmel G.
      • Bissery A.
      • Gammeter R.
      • et al.
      Alcohol-attributable injuries in admissions to a Swiss emergency room—an analysis of the link between volume of drinking, drinking patterns, and preattendance drinking.
      ]. Moreover, alcohol can worsen the clinical course of the injury, increasing the frequency of intubation, the duration of hospitalization, and the risk of mortality [
      • Maier R.V.
      Ethanol abuse and the trauma patient.
      ,
      • Choudhry M.A.
      • Chaudry I.H.
      Alcohol intoxication and post-burn complications.
      ]. A correlation has been reported between the severity of injury and alcohol misuse in adults [
      • Berkelman R.L.
      • Herndon J.L.
      • Callaway J.L.
      • et al.
      Fatal injuries and alcohol.
      ,
      • Marx J.
      Alcohol and trauma.
      ], while in children this correlation is controversial [
      • Meropol S.B.
      • Mascati R.M.
      • Lillis K.A.
      • Ballow S.
      • Janicke D.M.
      Alcohol-related injuries among adolescents in the emergency department.
      ,
      • Weinberg L.
      • Wyatt J.P.
      Children presenting to hospital with acute alcohol intoxication.
      ].
      Finally, recent findings support a strong connection between binge drinking and violent crimes such as homicide (28–86%), assault (24–37%), robbery (7–72%), and sexual offenses (13–60%) [
      • Brewer R.D.
      • Swahn M.H.
      Binge drinking and violence.
      ].

      2.2 Diagnosis

      Although it is often difficult, history-taking is needed in order to collect important information, including the quantity of alcohol and the type of beverage consumed, the time course of the symptoms, the circumstances, and eventual injuries. Physical examination must include an analysis of vital signs as well as nutritional status [
      • Addolorato G.
      Chronic alcohol abuse and nutritional status: recent acquisitions.
      ,
      • Addolorato G.
      • Capristo E.
      • Greco A.V.
      • Stefanini G.F.
      • Gasbarrini G.
      Influence of chronic alcohol abuse on body weight and energy metabolism: is ethanol consumption in excess a risk factor for obesity or malnutrition?.
      ,
      • Addolorato G.
      • Capristo E.
      • Leggio L.
      • et al.
      Relationship between ghrelin levels, alcohol craving, and nutritional status in current alcoholic patients.
      ], hydration, and alcoholism-related signs (capillary prominence, spider naevi, talengiectasias, palmar erythema, and muscular atrophy) [
      • Addolorato G.
      • Gasbarrini G.
      • Pompili M.
      • et al.
      Abuso e dipendenza da alcol: principali aspetti internistici.
      ]. Moreover, it should include cardiac and chest examination, abdominal examination, and neurological examination. Physical examination must be repeated often in order to follow up acute alcohol intoxication-related alterations. With regard to laboratory analysis, the determination of BAC is most important [
      • Sillanaukee P.
      Laboratory markers of alcohol abuse.
      ]. However, this examination has some limitations since it does not necessarily correlate with clinical presentation and does not predict clinical severity or outcome [
      • Marco C.A.
      • Kelen G.D.
      Acute intoxication.
      ]. Alcohol levels can also be determined by breath analysis [
      • James J.J.
      • Dargon D.
      • Day R.G.
      Serum vs breath alcohol levels and accidental injury: analysis among US Army personnel in an emergency room setting.
      ] or with a saliva dipstick, although these methods are less reliable [
      • Schwartz R.H.
      • O'Donnell R.M.
      • Thorne M.M.
      • Getson P.R.
      • Hicks J.M.
      Evaluation of colorimetric dipstick test to detect alcohol in saliva: a pilot study.
      ]. In addition, levels of free ethanol and ethanol conjugates can be measured in urine [
      • Yu M.C.
      • Tang B.K.
      • Ross R.K.
      A urinary marker of alcohol intake.
      ]. The determination of serum osmolality usually shows a hyperosmolality with an “osmolal gap” [
      • Marco C.A.
      • Kelen G.D.
      Acute intoxication.
      ]. Specifically, serum osmolality rises about 22 mOsm/l for every 100 mg/100 ml increment in BAC [
      • Marco C.A.
      • Kelen G.D.
      Acute intoxication.
      ]. Serum osmolality can be important, particularly when a BAC is not available. Taking into account the more frequent clinical alterations, it is also important to determine levels of sodium, potassium, chloride, bicarbonate, urea nitrogen, glucose, calcium, magnesium, amylase, liver parameters, toxicological screen, arterial blood gas, and blood or urine ketones. Chest radiography and electrocardiography must be performed. Moreover, computed tomography (CT) of the brain should be included when neurological symptoms are present and/or a head trauma is suspected [

      Yost DA. Acute care for alcohol intoxication. Be prepared to consider clinical dilemmas. Postgrad Med 2002; 112: 14–6, 21–2, 25–6.

      ].
      Multiple factors can confuse the diagnostic picture and affect the choice of therapy. Therefore, patients should be evaluated by expert clinicians, bearing in mind that a diagnosis of intoxication may lead some clinicians not to search for additional severe diseases. For this reason, after breath alcohol measures or BAC determination, additional investigations should be considered, depending on the clinical features of the patient, to evaluate potentially harmful alcohol-related and non-alcohol-related diseases. Special attention should be paid to mental status changes of the patient. Alcohol-induced psychopathologic conditions in patients with alcohol intoxication can range from lethargic depression to violent delirium. For patients with a history of previous intoxication episodes, mental status changes tend to be similar with each bout of binge drinking. Mental status changes that are markedly uncharacteristic of a patient's previous intoxication pattern are often a warning sign that more aggressive assessment is needed for head injuries, cerebral hemorrhage, electrolyte abnormalities, and consumption of illicit drugs together with alcoholic beverages [

      Yost DA. Acute care for alcohol intoxication. Be prepared to consider clinical dilemmas. Postgrad Med 2002; 112: 14–6, 21–2, 25–6.

      ]. Moreover, the temptation to minimize issues in pleasantly intoxicated patients or to rapidly discharge unruly ones must be avoided [

      Yost DA. Acute care for alcohol intoxication. Be prepared to consider clinical dilemmas. Postgrad Med 2002; 112: 14–6, 21–2, 25–6.

      ].
      Several different conditions can mimic the clinical features of acute alcohol intoxication and should, therefore, be excluded (Table 2). These conditions include: other substance-related intoxication, metabolic alterations, neurological causes (including seizure and trauma), infectious diseases, hypotension, hypo- or hyperthermia, hypo- or hyperthyroidism, dehydration, hypoxia, and respiratory depression [
      • Marco C.A.
      • Kelen G.D.
      Acute intoxication.
      ,

      Yost DA. Acute care for alcohol intoxication. Be prepared to consider clinical dilemmas. Postgrad Med 2002; 112: 14–6, 21–2, 25–6.

      ].
      Table 2Main clinical conditions that can mimic an acute alcohol intoxication and that should be considered as possible differential diagnosis
      Main clinical conditionsDetailed clinical conditions
      Other substance-related intoxicationAlcohol other than ethanol
       Methanol
       Isopropyl alcohol
      Drugs of abuse:
       Cocaine
       Opiates
       Tetrahydrocannabinoil
      Barbiturates
      Benzodiazepine
      Tricyclic antidepressants
      Disulfiram
      Carbon monoxide
      Metabolic causesHepatic encephalopathy
      Hypoglycemia
      Electrolyte abnormalities:
       Hyper-/hypo natremia
       Hyper-/hypo calcemia
      Alcoholic ketoacidosis
      Diabetic ketoacidosis
      Non-ketotic hyperosmolar coma
      Uremia
      Hypertensive encephalopathy
      Infectious diseaseSepsis
      Meningitis
      Encephalitis
      Neurological causesAlcohol withdrawal syndrome
      Wernike–Korsakoff syndrome
      Cerebrovascular accidents
      Seizure disorders
      TraumaIntracranial bleeding
       Subdural hematoma
       Concussion syndromes
      Respiratory causesHypoxia
      Respiratory depression
      OtherHypotension
      Hyper-/hypothermia
      Hyper-/hypothyroidism
      Dehydration

      2.3 Treatment

      The management of an intoxicated patient occurs mainly in the emergency department and is aimed at stabilizing the clinical condition of the patient, depending on his/her clinical presentation (Table 3). Airway assessment and observation of the development of respiratory function should be done. Prevention of aspiration is also mandatory; therefore, placement of the patient in a lateral position may be helpful. Intravenous access should be obtained and an intravenous fluid solution should be administered in order to hydrate the patient as well as to correct electrolyte imbalances and hypoglycemia. In current clinical practice, a protocol intravenous solution containing dextrose, magnesium, folate, thiamine, and multivitamins is used (e.g., a premixed intravenous solution of 1 l of 5% dextrose and 0.45% sodium chloride, 2 g of magnesium sulfate, 1 mg of folate, and 100 mg of thiamine) [
      • Marco C.A.
      • Kelen G.D.
      Acute intoxication.
      ]. Anti-emetic drugs may be useful in patients with nausea and/or vomiting. Prolonged vomiting can lead to hyponatremia; this should not be corrected too rapidly since it can induce a central pontine myelinolysis [
      • Caputo F.
      • Marchi B.
      • Coralli B.
      • et al.
      Symtomatic hypotonic hyponatremia in an alcoholic polydipsic patient: a favourable clinical outcome after sodium correction.
      ].
      Table 3Management of acute alcohol intoxication
      Patient stabilizationAirway assessment
      Observation of respiratory function
      Prevention of aspiration
      Mechanical ventilation, if necessary
      Intravenous access
      Intravenous solution administration correction of hypoglycemia and electrolyte imbalances (dextrose+magnesium+folate+thiamine+multivitamins)
      Anti-emetic drugs
      Patient sedation (if necessary)Droperidol
      Haloperidol
      Physical restraints (not advised)
      Acceleration of ethanol eliminationMetadoxine (300–900 mg i.v.)
      In agitated and violent patients, sedative substances may be used, including droperidol or haloperidol; however, one must bear in mind the possibility of a pharmacological interaction between the sedative drugs and the alcohol that could lead to respiratory depression and hypotension. The use of physical restraints to prevent patients from escaping and/or physical trauma should be avoided, given the ethical concerns about their use; they should be considered only in extreme conditions. In some cases, mechanical ventilation and intensive care must be provided [

      Yost DA. Acute care for alcohol intoxication. Be prepared to consider clinical dilemmas. Postgrad Med 2002; 112: 14–6, 21–2, 25–6.

      ].
      One specific drug that is useful in the treatment of acute alcohol intoxication is metadoxine (pyridoxol l-2-pyrrolidone-5-carboxilate), which is the ion pair between pyrrolidone carboxilate and pyridoxine. Pyrrolidone carboxylate is involved in amino acid metabolism through the glutathione pathway [
      • Meister A.
      • Anderson M.E.
      Glutathione.
      ]. It facilitates de novo ATP synthesis [
      • Shull K.H.
      • Kisilevsky R.
      Effects of l-2-pyrrolidone-5-carboxylate on hepatic adenosine triphosphate levels in the ethionine-treated rat.
      ] and prevents ATP decrease in both the brain and liver of rats acutely intoxicated with ethanol [
      • Felicioli R.
      • Saracchi I.
      • Flagiello A.M.
      • Bartoli C.
      Effects of pyridoxine–pyrrolidon–carboxylate on hepatic and cerebral ATP levels in ethanol treated rats.
      ]. Pyridoxine increases the metabolic degradation rate of ethanol, thereby reducing the damage to cell functions caused by acetaldehyde, the first metabolite in the ethanol elimination process [
      • Wordsworth V.P.
      Intravenous detoxication of drunkness.
      ]. Metadoxine appears to be able to accelerate ethanol metabolism in both rats and humans [
      • Addolorato G.
      • Ancona C.
      • Capristo E.
      • Gasbarrini G.
      Metadoxine in the treatment of acute and chronic alcoholism: a review.
      ] due to several mechanisms including an increase in acetaldehyde dehydrogenase activity [
      • Pares X.
      • Moreno A.
      • Peralba J.M.
      • Font M.
      • Bruseghini L.
      • Esteras A.
      Action of metadoxine on isolated human and rat alcohol and aldehyde dehydrogenases. Effect on enzymes in chronic ethanol-fed rats.
      ], ethanol and acetaldehyde plasma clearance, and urinary elimination of ketones [
      • Calabrese V.
      • Calderone A.
      • Ragusa N.
      • Rizza V.
      Effects of metadoxina on cellular status of glutathione and of enzymatic defence system following acute ethanol intoxication in rats.
      ]. In animals, metadoxine inhibits the increase in fatty acid esters in the liver of ethanol-treated rats, restoring the ratio between saturated and unsaturated fatty substances [
      • Calabrese V.
      • Ragusa N.
      • Rizza V.
      Effects of pyrrolidone carboxylate (PCA) and pyridoxine on liver metabolism during ethanol intake in rats.
      ]. Moreover, metadoxine is able to prevent glutathione depletion, lipid peroxidation damage, collagen deposition, and TNF alpha secretions induced by alcohol and acetaldehyde in hepatocytes and hepatic stellate cells [
      • Gutierrez-Ruiz M.C.
      • Bucio L.
      • Correa A.
      • et al.
      Metadoxine prevents damage produced by ethanol and acetaldehyde in hepatocyte and hepatic stellate cells in culture.
      ].
      Recently, the first double-blind, controlled clinical trial with metadoxine compared to placebo was performed by our group in patients with acute alcohol intoxication [
      • Shpilenia L.S.
      • Muzychenko A.P.
      • Gasbarrini G.
      • Addolorato G.
      Metadoxine in acute alcohol intoxication: a double-blind, randomized, placebo-controlled study.
      ]. A single intravenous injection of metadoxine (900 mg i.v.) significantly decreased the half-life of ethanol in the blood and showed a faster rate of ethanol elimination. The accelerated elimination of ethanol from the blood led to a faster onset of recovery from intoxication (defined as a decrease of at least one category of intoxication according to alcohol levels) in metadoxine-treated patients with respect to the placebo (control) group. The median time to onset of recovery was 2.34 h with placebo and 0.95 h with a single dose of metadoxine (900 mg i.v.). Accordingly, parameters of toxic behavioral symptomatology, such as agitation and mental function impairment scores, decreased significantly faster in metadoxine-treated patients than in controls. Moreover, the proportion of completely symptom-free patients was significantly higher in the metadoxine-treated group than in the control group.
      In line with this observation, previous animal data showed the antagonization of locomotor-stimulatory effect of ethanol by metadoxine [
      • Garau B.
      • Fadda F.
      • Melis F.
      • Gelso E.
      • Gessa G.L.
      Metadoxine (pyrrolidone carboxylate of pyridoxine) antagonizes the locomotor-stimulatory effect of ethanol in mice.
      ]. Another double-blind, controlled clinical trial compared metadoxine to a conventional treatment (parenteral solutions, multi-vitamin preparations, BDZ, or neuroleptics, as appropriate) for acute alcohol intoxication in an emergency unit [
      • Diaz Martinez M.C.
      • Diaz Martinez A.
      • Villamil Salcedo V.
      • et al.
      Efficacy of metadoxine in the management of acute alcohol intoxication.
      ]. The patients received a single dose of metadoxine (300 mg i.v.); a second equal dose was administered after 1 h (only if necessary) and patients were re-examined at 2 h. Significantly greater improvement was found on a clinical scale based on somatic and psychological symptoms, as well as significantly lower BACs, in the metadoxine-treated patients compared to the control group [
      • Diaz Martinez M.C.
      • Diaz Martinez A.
      • Villamil Salcedo V.
      • et al.
      Efficacy of metadoxine in the management of acute alcohol intoxication.
      ]. We conclude that metadoxine is a useful drug in clinical practice since it is effective in reducing BAC within a short time and in accelerating clinical and metabolic recovery from intoxication. Moreover, it appears to be manageable and safe [
      • Addolorato G.
      • Ancona C.
      • Capristo E.
      • Gasbarrini G.
      Metadoxine in the treatment of acute and chronic alcoholism: a review.
      ,
      • Shpilenia L.S.
      • Muzychenko A.P.
      • Gasbarrini G.
      • Addolorato G.
      Metadoxine in acute alcohol intoxication: a double-blind, randomized, placebo-controlled study.
      ,
      • Corsini G.
      • Gelso E.
      • Giuliano G.
      Effects of metadoxine on main biohumoral changes induced by chronic alcoholism.
      ,
      • Caballeria J.
      • Pares A.
      • Bru C.
      • et al.
      Metadoxine accelerates fatty liver recovery in alcoholic patients: result of a randomized double-blind, placebo-control trial.
      ,
      • Lheureux P.
      • Penalozza A.
      • Gris M.
      Pyridoxine in clinical toxicology: a review.
      ]. Finally, it should be stressed that metadoxine is able to improve steatosis and liver function tests [
      • Caballeria J.
      • Pares A.
      • Bru C.
      • et al.
      Metadoxine accelerates fatty liver recovery in alcoholic patients: result of a randomized double-blind, placebo-control trial.
      ], an effect that is due to metadoxine's ability to maintain intracellular redox homeostasis [
      • Scanlan M.J.
      • Raj B.K.
      • Calvo B.
      • et al.
      Molecular cloning of fibroblast activation protein alpha, a member of the serine protease family selectively expressed in stromal fibroblasts of epithelial cancers.
      ].

      3. Acute alcohol intoxication or chronic alcohol abuse?

      All patients admitted to an emergency department for acute alcohol intoxication should be examined for chronic alcohol abuse and/or dependence [
      ]. At an initial screening, both the daily consumption and the weekly frequency of drinking should be recorded, and one or more tests, such as the AUDIT or AUDIT-C [
      • Reinert D.F.
      • Allen J.P.
      The alcohol use disorders identification test (AUDIT): a review of recent research.
      ,
      • Dawson D.A.
      • Grant B.F.
      • Stinson F.S.
      • Zhou Y.
      Effectiveness of the derived alcohol use disorders identification test (AUDIT-C) in screening for alcohol use disorders and risk drinking in the U.S. general population.
      ] and/or the CAGE [
      • Ewing J.A.
      Detecting alcoholism. The CAGE questionnaire.
      ], should be administered. A positive result on either of these tests indicates the probable presence of an alcohol-related disorder and calls for further evaluation using the DSM-IV criteria for alcohol abuse or alcohol dependence [
      ]. Patients who abuse or who are dependent on alcohol may experience an alcohol withdrawal syndrome following detoxification. Such a syndrome, in its severe form, may be life-threatening and present with delirium tremens and seizures [

      Fiellin DA, O'Connor PG, Holmboe ES, Horzwitz RI. Risk of delirium tremens in patients with alcohol withdrawal syndrome. Subst Abuse 23: 83–94.

      ]. If these conditions appear, correct drug treatment is mandatory [
      • Mayo-Smith M.F.
      Pharmacological management of alcohol withdrawal. A meta-analysis and evidence-based practice guideline. American Society of Addiction Medicine Working Group on Pharmacological Management of Alcohol Withdrawal.
      ,
      • Mayo-Smith M.F.
      • Beecher L.H.
      • Fisher T.L.
      • et al.
      Management of alcohol withdrawal delirium. An evidence-based practice guideline.
      ,
      • Addolorato G.
      • Leggio L.
      • Abenavoli L.
      • et al.
      Baclofen in the treatment of alcohol withdrawal syndrome: a comparative study vs diazepam.
      ]. Therefore, once a patient has become stabilized and both the acute alcohol intoxication symptoms and the related clinical complications have been treated, the patient should be monitored for 72 h following a BAC of 0 mg/dl (0 mmol/l). Alcohol administration, a practice that is still frequently adopted by some emergency departments, should be avoided [
      • Saitz R.
      Unhealthy alcohol use.
      ,
      • Sattar S.P.
      • Qadri S.F.
      • Warsi M.K.
      • et al.
      Use of alcoholic beverages in VA medical centers.
      ] since medical and surgical treatments for alcoholic diseases and their complications have limited success when drinking continues [
      • Yates W.R.
      • Labrecque D.R.
      • Pfab D.
      The reliability of alcoholism history in patients with alcohol-related cirrhosis.
      ]. Moreover, ethanol can reinforce the craving for alcohol, limiting the possibility of relapse prevention [
      • Addolorato G.
      • Leggio L.
      • Abenavoli L.
      • Gasbarrini G.
      Alcoholism Treatment Study Group
      Neurobiochemical and clinical aspects of craving in alcohol addiction: a review.
      ]. Finally, when a diagnosis of alcohol abuse or dependence can be established, the patient should be referred to an alcohol treatment unit so that he or she can start a multimodal treatment including a psychological and/or pharmacological approach [
      • Addolorato G.
      • Leggio L.
      • Abenavoli L.
      • Gasbarrini G.
      Alcoholism Treatment Study Group
      Neurobiochemical and clinical aspects of craving in alcohol addiction: a review.
      ,
      • Addolorato G.
      • Abenavoli L.
      • Leggio L.
      • Gasbarrini G.
      How many carving? Pharmacological aspects of craving treatment in alcohol addiction: a review.
      ].
      If the AUDIT and/or CAGE are negative, the risk of an emerging alcohol-related disorder could be considered low. In this case, a brief intervention or a one-on-one counseling session can be provided [
      • Fleming M.F.
      • Mundt M.P.
      • French M.T.
      • Manwell L.B.
      • Stauffacher E.A.
      • Barry K.L.
      Brief physician advice for problem drinkers: long-term efficacy and benefit–cost analysis.
      ,

      National Institute on Alcohol Abuse and Alcoholism. Alcohol alert, no 66. Aviable at: http://pubs.niaaa.nih.gov/publications/AA66/AA66.htm. Accessed July 2005.

      ] in order to moderate alcohol consumption and to eliminate harmful drinking practices [

      National Institute on Alcohol Abuse and Alcoholism. Alcohol alert, no 66. Aviable at: http://pubs.niaaa.nih.gov/publications/AA66/AA66.htm. Accessed July 2005.

      ]. Brief intervention usually includes personalized feedback and counseling based on the patient's risk of harmful drinking and may also include motivational interviewing [

      Moyer A, Finney JW. Brief intervention for alcohol problems: factos that facilitate implementation. Alcohol Research and Health 2004/2005; 28: 44–50.

      ,
      • Miller W.R.
      • Rollnick S.
      Motivational interviewing: preparing people for change.
      ]. Such interventions can be useful in reducing the costs of, and burden on, health services [
      • Pirmohamed M.
      • Brown C.
      • Owens L.
      • et al.
      The burden of alcohol misuse on an inner-city general hospital.
      ].

      4. Conclusions

      Acute alcohol intoxication is a clinically harmful condition that usually follows the ingestion of a large amount of alcohol. It can manifest itself clinically in various ways and have behavioral, cardiac, gastrointestinal, pulmonary, neurological, and metabolic effects. The management of acute alcohol intoxication is aimed primarily at stabilizing the patient's clinical condition, hastening the elimination of alcohol, and defining and treating all of the abovementioned clinical alterations. Metadoxine is an effective and useful drug [
      • Addolorato G.
      • Ancona C.
      • Capristo E.
      • Gasbarrini G.
      Metadoxine in the treatment of acute and chronic alcoholism: a review.
      ]. For patients with an acute alcohol intoxication, alcohol-related disorders should be detected and the patient referred to an alcohol treatment unit for a specific, personalized treatment.

      5. Learning points

      • Acute alcohol intoxication is a clinically harmful condition that usually follows the ingestion of a large amount of alcohol.
      • Clinical manifestations involve different organs and apparatuses. Behavioral, cardiac, gastrointestinal, pulmonary, neurological, and metabolic manifestations can occur.
      • The management of an intoxicated patient occurs mainly in the emergency department and is aimed at stabilizing the clinical condition of the patient, depending on his/her clinical presentation.
      • Metadoxine is an effective pharmacological treatment for patients affected by acute alcohol intoxication.

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