Alcohol Withdrawal Syndrome : a Review

1 Clinical Emergency Hospital of Bucharest, Bucharest, Romania 2 „Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania 3 „Prof. Dr. D. Hociota” Institute of Phonoaudiology and Functional ENT Surgery, Bucharest, Romania 4 „St. Pantelimon” Emergency Hospital, Bucharest, Romania 5 Clinic of Urology, Central Military Hospital, Bucharest, Romania 6 Academy of Romanian Scientists, Bucharest, Romania Corresponding author: Iustin Moroi, Clinical Emergency Hospital of Bucharest, 8th Calea Floreasca, Bucharest, Romania. E-mail: moroi.iustin@yahoo.com Abstract


INTRODUCTION
Alcoholism is a common condition and frequently clinicians are forced to confront its complications in general hospital settings.Within each country, there is an excellent correlation between the level of alcohol consumption and the prevalence of alcohol-related harm.In fact, the consumption in Europe is 10.9 liters of pure alcohol per person per year 1 .Th ere are an estimated 3 million alcohol-dependent people in Romania alone, with episodes of withdrawal severe enough to require pharmacologic treatment 1 .
Studies have shown that patients with sudden cessation of chronic and sustained alcohol intake develop a more severe alcohol withdrawal syndrome (AWS) than the casual drinkers, who do not have constant high blood concentrations of alcohol necessary to develop tolerance.It is still unclear why some people develop more severe withdrawal syndromes than others, but genetics may play a role.

PATHOPHYSIOLOGY
Alcohol is a central nervous system (CNS) inhibitor, concurrently enhancing the inhibitory tone (through gamma-aminobutyric acid activity) and inhibiting the excitatory tone (through the modulation of excitatory amino acids activity).Chronic intake of alcohol leads to a homeostasis kept in place by its constant presence, with sudden cessation often resulting in over-activity of the CNS.
Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the CNS and its receptor complex has highly specifi c binding sites for ethanol.Chronic and sustained alcohol usage induces insensitivity to GABA in such a way that more inhibitor is required to maintain a decreased CNS excitability.CNS adapts by down-regulating the GABA receptors, thus increasing the requirement of larger quantities of ethanol for achieving the same euphoric eff ect.
Glutamate is one of the major excitatory aminoacids.Its binding to NMDA (N-methyl-D-aspartate) receptor causes neuronal excitation.Because ethanol inhibits glutamate-induced excitation, CNS adapts by up-regulating NMDA receptors and increase the production of glutamate, in an attempt to maintain a normal state of awakening.
Because of its eff ects of inhibiting the excitatory state of the CNS and enhancing the inhibitory eff ect of GABA, sudden cessation of alcohol in the chronic user often leaves CNS glutamate excitation unopposed, expressed in mild autonomic over-activity, such as tachycardia, sweating or more severe symptoms such as delirium tremens and withdrawal seizures 2 .

PAWSS SCORE (Prediction of Alcohol Withdrawal Severity Score)
A tool for predicting the risk for alcohol withdrawal is the PAWSS Score (Table 1).Th is instrument is intended as a screening tool.Th e maximum number of points is 10.A greater number of points shows a higher risk for developing AWS.A value below 4 shows a low risk for developing AWS, while a value above sets a moderate risk.

COMPLICATIONS OF ALCOHOL WITHDRAWAL
A diagnosis of AWS is made when:  a clear evidence of recent cessation/reduction of alcohol intake after heavy and prolonged use is confi rmed;  the patients' symptoms are not accounted for by another medical or behavioral disorder.Diagnosis requires the history of the amount and frequency of alcohol intake, the temporal relation between reduction of intake and the onset of symptoms that may resemble a withdrawal state.AWS can occur as early as 6 hours after alcohol cessation, peaks after 2-3 days and can persist up to 7 days after alcohol cessation.If the onset of withdrawal-like symptoms is after more than 14 days of complete cessation of alcohol, the diagnosis of AWS becomes unsustainable.Symptoms range from minor to severe 4  including nutritional supplementation and frequent clinical reassessment, is of crucial importance.
An instrument to objectively measure the severity of alcohol withdrawal is the CIWA-Ar scale (Clinical Institute Withdrawal Assessment -Alcohol Revised).It is not useful in diff erentiating between DT and delirium caused by other medical illnesses 8 .Th e scale includes 10 common signs and symptoms of alcohol withdrawal, with notable exceptions of pulse rate and blood pressure.Scores of 0-9 indicate absent to minimal withdrawal, 10-19 indicate mild to moderate withdrawal (increased autonomic arousal) and scores greater than 20 or more indicate severe withdrawal, with a high risk of developing DT.Th e score can be used to monitor the severity of withdrawal and in titrating pharmacotherapy.
Observations should be carried out every 2 hours and consist of:  Measuring blood pressure. Measuring pulse. Measuring respiratory rate [if below 10 breaths per minute -call emergency team]. Applying CIWA-Ar scale.Th e descriptions of each withdrawal syndrome is rated and then added for a fi nal score.
CIWA-Ar maximum score is 67.In the fi rst 24 hours, the score should be re-evaluated every 2 hours; if the score is between 0 to 9 or the patient is asleep, no treatment is needed, if it is above 8, pharmacologic treatment is needed.

MANAGEMENT OF ACUTE ALCOHOL WITHDRAWAL SYNDROME
Prior to treatment, patients should be investigated clinically and paraclinically, regarding the degree of possible liver alterations or other comorbidities [9][10][11][12][13][14] 2).If withdrawal does not progress, the symptoms resolve within 24 to 48 hours and can be managed in ambulatory settings.
Moderate to severe withdrawal usually begins 48-72 h after the last drink and can last up to 14 days.Syndromes specifi c for non-minor withdrawal are alcoholic hallucinosis, alcohol withdrawal seizure and delirium tremens.Severe alcohol withdrawal is often associated with fl uid and electrolyte status abnormalities.Due to diaphoresis, hyperthermia and decreased oral intake, many patients are hypovolemic.Hypomagnesemia may predispose to seizures and dysrhythmias 5 .
Alcoholic hallucinosis -visual/tactile/auditory hallucinations that appear in a well-oriented patient with stable vitals.In most cases lasts between 24 h and 6 days 6 .
Alcohol withdrawal seizure -usually generalized tonico-clonic seizures.May begin within 6-48 h after last drink.It presents a high risk of progression towards delirium tremens.
Delirium tremens (DT) -is a specifi c type of delirium in patients suff ering from alcohol withdrawal, consisting in altered sensorium with disorientation, perceptual abnormalities (illusions and hallucinations) and psychomotor agitation with altered sleep wake-cycle.It begins after 48-72 h after the last drink and may last up to 14 days.Studies show a mortality between 5 and 10 percent, hence early recognition is important.Death usually occurs due to arrhythmia or associated comorbid illness such as pneumonia 7 .

CLINICAL INSTITUTE WITHDRAWAL ASSESSMENT FOR ALCOHOL SCALE, REVISED (CIWA-AR)
After the clinical diagnosis of alcohol withdrawal syndrome has been established, the management is directed at alleviating symptoms and identifying and correcting metabolic derangements.Supportive care,  valent clinical endpoints while requiring lower total doses of sedatives and shorter periods of hospitalization 18 .
Symptom-monitored loading regimen: In the presence of acute medical illness or a past history of severe withdrawals, a single loading dose of 20 mg diazepam should preferably be given immediately.Further doses of diazepam should be given orally every 2 h until CI-WA-Ar scores are less than ten.Th is strategy combines the principles of symptom-triggered treatment strategy while also taking into account the past history of severe withdrawals 17 .

MANAGEMENT OF MINOR ALCOHOL WITHDRAWAL SYNDROME
Minor cases of withdrawal may not need pharmacologic treatment in most cases, and often the supportive care in a calm and quiet environment over a 36 h period is enough 16 .An acute medical illness or a history of severe episodes of alcohol withdrawal justify the use of a single dose of 20 mg of diazepam and further monitoring 19 .In the absence of these risk factors, out-patient treatment is possible.Pharmacotherapy is started if the patient presents signs of CNS hyperexcitability, like increased systolic blood pressure (above 150 mmHg), increased diastolic blood pressure (above 90 mmHg), tachycardia (above 100/min), fever (body temperature above 37.7 Celsius degrees), agitation or insomnia 4 .

MANAGEMENT OF MODERATE TO SEVERE ALCOHOL WITHDRAWAL SYNDROME
Cases without seizures or DT are best managed using a symptom-monitored loading regimen (treating with benzodiazepines only if CIWA-Ar score is above 9) or with a fi xed-dose regimen, where adequate personnel for calculating CIWA-Ar score is not available 20 .
In cases with seizures or DT, a rapid loading regimen is preferred, with frequent boluses of intravenous diazepam, until the patient is calm and sedated, regardless of the CIWA-Ar score [21][22][23][24] .Seizure prophylaxis with 2 mg IV lorazepam is recommended for patients with past history of withdrawal seizure.Lorazepam is more eff ective than diazepam in preventing seizure recurrence, due to its poor lipid solubility, which does not let brain levels fall rapidly.In such patients, it may still be required do give diazepam doses of at least 20 mg -venously, due to impaired gastrointestinal absorption often met in chronic alcohol users.During the early phases of withdrawal, patients are given nothing by mouth, to decrease the risk of aspiration.
Th e main treatment of AWS is detoxifi cation and consists in gradually tampering the dependence.
Studies are strongly in favor of using benzodiazepines for treating acute AWS, because they undoubtedly reduce the risk of seizures and DT15.Diazepam, lorazepam and chlordiazepoxide are most commonly used.Benzodiazepines enhance the eff ect of the gammaaminobutyric acid at the GABA receptor, resulting in sedative, hypnotic and anxiolytic eff ects.Chlordiazepoxide and diazepam are the agents of choice, but in the presence of co-morbidities, oxazepam and lorazepam are recommended, due to their shorter half-life, that prevents prolonged eff ects if over-sedation occurs.Patients with impaired hepatic function (advanced cirrhosis or acute alcoholic hepatitis) are best treated with lorazepam or oxazepam.Th e equivalency of benzodiazepine doses (approximate) are as following: diazepam 10 mg = chlordiazepoxide 25 mg = lorazepam 1 mg 16 .
Anticonvulsants have not been proven to be better than benzodiazepines, but may be considered in mild withdrawal states, because of lower sedation and lower chances of abuse potential.

TREATMENT REGIMENS USED IN ALCOHOL WITHDRAWAL STATES
Th e fi xed-dose regimen consists in giving benzodiazepines (dose based upon the severity of the withdrawal and time since the last drink) at fi xed intervals.Because frequent reassessment of the clinical status of the patient is not needed, this regimen is best suited for minimally symptomatic patients in out-patient settings 16 .
Th e loading dose regimen consists in treating the patient with 20 mg of diazepam per os every 2 h, but before each administration, the clinical condition and the withdrawal severity using CIWA-Ar score must be checked.Th is regimen has been shown to reduce the total dose of administered benzodiazepines and the duration of withdrawal symptoms 17 .
Symptom-triggered treatment (STT) requires close monitoring of symptoms and treating the in-patient with drugs only when CIWA-Ar ratings are 8 or more.Frequent re-evaluation of the clinical status is needed.It is useful in patients who have never had complicated withdrawals.Multiple randomized and observational studies support this regimen because it achieves equi-Wernicke's encephalopathy is reversible in the early stages, if a rapid restoration of B vitamins (in particular thiamine -B1) in CNS is initiated.
All patients undergoing alcohol withdrawal should be treated prophylactically for WE with thiamine 100 mg IV ampoule, three times a day.Every ampoule should be diluted in 50 ml to 100 ml sodium chloride 0.9% and infused over 30 minutes.Absorption of oral thiamine is limited and not suffi cient to treat WE.

CONCLUSIONS
Chronic alcohol consumption poses many risks on the health status.AWS is associated with risks of complications and should be carefully managed in the clinical practice, by non-pharmacologic measures and pharmacological treatment.
Compliance with ethics requirements: Th e authors declare no confl ict of interest regarding this article.Th e authors declare that all the procedures and experiments of this study respect the ethical standards in the Helsinki Declaration of 1975, as revised in 2008 (5), as well as the national law.Informed consent was obtained from all the patients included in the study.60 mg in a symptom-monitored regimen 25 .In patients with seizures, a neurological workup is needed to detect alternative causes [26][27][28] .DT is best treated with the use of IV diazepam administered at frequent intervals, with close monitoring.Treatment begins with an initial dose of 10 mg of diazepam.Further doses of 10 mg are given at approximately 15 minutes interval [29][30] .Once the goal of light somnolence is achieved, the patient can be shifted to a symptom-triggered regimen 23,31 .
Th e undiluted emulsion is administered at a rate of 1 ml (5 mg) per minute.For patients with liver failure, IV lorazepam is the drug of choice.Th e goal of sedation is a calm, but alert state.In the elderly, only half the benzodiazepine dose is recommended.
For patients who are diffi cult to assess using the CI-WA-Ar score, a fi xed schedule reducing regimen is recommended.Th is includes patients who are confused, don't speak the native tongue or are unable to communicate eff ectively.
Inappropriately managed WE is a major contributory cause of death in patients suff ering from alcohol withdrawal syndrome and results in permanent brain damage in a great number of survivors.Because the classic triad of signs, consisting in acute confusion, ataxia and ophthalmoplegia, is only seen in 10% percent of patients, it cannot be used as a basis of diagnosis.

Table 2 .
Minor alcohol withdrawal signs and symptoms