Drive-by Epidemiology Up to one-third of adult inpatients have problems related to alcohol 20% of the total national expenditure for

or hospital care is related to alcohol abuse.4,5 Alcoholism is the leading cause of morbidity and mortality in the United States. One study determined that 40% of all patients presenting to the ED in the evening had been drinking and had blood alcohol concentrations (BAC) greater than 80 mg/dL.6 Alcohol abuse and the risk of alcohol withdrawal syndrome are under-recognized by physicians. This is illustrated in a study of 100 acute orthopedic admissions that found that only 37% of patients had an adequate drinking record correctly identifying alcohol problems.1 o In the population that was identified as problem drinkers, action was taken in only 36% of cases, usually after withdrawal symptoms appeared. o Otherwise, no action was taken, even when it was recognized that the admission was the direct consequence of drinking. 1. Hamilton MR, Menkes DB. How alert are hospital doctors to alcohol misuse among
acute orthopedic patients? N Z Med J 1992;105:167-169.

Complications of AWS -range in severity from hangover and insomnia, tremor and tachycardia, to life-threatening delirium tremens. Their common mechanism is rebound of the altered metabolic and neurohormonal physiology of ethanol exposure when ethanol is abruptly withdrawn or reduced. Effects on the Heart and Cardiovascular System: Alcoholism is often associated with the abuse of tobacco as well as cocaine, which cause coronary artery disease and hypertension. Both adrenaline and noradrenaline secretion are increased during withdrawal from alcohol in dependent subjects, resulting in the tachycardia and hypertension seen in withdrawal states. Acute myocardial ischemia may ensue.21 Alcoholic Ketoacidosis: Alcoholic ketoacidosis (AKA) is defined as a wide anion gap metabolic acidosis, with ketonemia occurring in the dehydrated, fasting, chronic alcoholic who is undergoing

withdrawal from ethanol and in whom other causes of metabolic acidosis have been ruled out.22 (See Table 3.) It is rapidly reversible and has a low mortality when recognized.

Tolerance and Withdrawal from Alcohol and Other Sedatives

Time course Longer acting sedatives and mixed alcohol-sedative Change in time course Delayed onset of symptoms Phenobarbital conversion method The time course and symptomatology for sedative-hypnotic and mixed alcohol-sedative withdrawal can be variable. Time of onset of symptoms depends on the half-life of the drug ranging from 3-6 hours post cessation of a short-acting drug to over 100 hours for a long acting substance. In addition to half-life, duration of the symptoms is a function of dose and duration of use, and the presence of concurrent medical conditions. Symptoms include those of AWS but can be more varied and can include sensory disturbances and tinnitus. The presentation of mixed alcohol-sedative and sedative-sedative presentations can be confusing and difficult to manage, with delayed onset and masking of symptoms. Treatment of such intra-class mixed drug withdrawals is done by estimating and combining the phenobarbital equivalents of the various sedatives.

Predictors of Alcohol Withdrawal Severity

Prior history of severe withdrawal symptoms High blood alcohol w/o sx of intoxication Symptoms of AWS in presence of high BAC Concurrent use Sedative Hypnotics Coexisting medical problems Concurrent sedative/hypnotic use has been discussed as have coexisting medical problems as an independent risk factor. Prior history of severe withdrawal makes severe, complicated withdrawal more likely this time. This is the kindling hypothesis and is an argument for the aggressive treatment of alcohol withdrawal syndrome in hopes of preventing the neurological changes that presumably underlie this phenomenon. A patient with a high BAC without symptoms and signs of intoxication, or worse, with signs and symptoms of withdrawal, is clinically demonstrating high tolerance and a more severe withdrawal syndrome is expected.

Alcohol Withdrawal Syndrome

Tremor, anxiety, agitation, HTN, tachycardia, diaphoresis, hyperpyrexia, insomnia, hallucination, seizure Sensorium usually clear Treat AWS to prevent seizures , DT's, and kindling

AWS may appear within hours of the patients last drink, and reach peak intensity at 24-36 hours. Early symptoms include gastrointestinal problems, anxiety, tremor, diaphoresis, tachycardia, hypertension, and insomnia. Alcohol withdrawal seizures usually occur within the first 48 hours. Alcohol withdrawal accompanied by delirium, the DTs, can begin around 48 to 72 hours post cessation.

Alcohol related seizures

Gran mal in 10-15% (Guthrie, 1989) Usually in first 48 hours but may be seen up to 10 days May be multiple, rarely status, may require diazepam 10 mg slow IVP 1st episode or atypical seizure: evaluate for other causes Ongoing pharmacotherapy not indicated for w/d seizures Alcohol related seizures can be very upsetting for family and staff. They are generally self limited. However, providers of ambulatory assessment and detoxification services need to have the staff an equipment necessary to start an intravenous line and administer diazepam parenterally if necessary to stabilize the patient for admission.

Delirium Tremens
Acute, reversible, organic psychosis; significant morbidity and mortality Usually begins approx. 72 hours; may last 2 - 6 days and sometimes longer Severe AWS symptoms with clouded sensorium Hallucinations w/o insight produce panic and severe agitation Mortality increases with delayed Dx, inadequate Rx, and concurrent medical conditions. Delirium Tremens. Delirium tremens (DT) is a severe, life-threatening complication of alcohol withdrawal. It is characterized by increasingly pronounced disorientation, agitation, and autonomic stimulation, with hypertension, tachycardia, hyperthermia, and profound diaphoresis. Mortality rates of up to 20% have been noted in the past but have improved gradually with the development of intensive care units, more aggressive investigation of traumatic and infectious complications, better fluid replacement, rapid cooling of critical hyperthermia, and the advent of benzodiazepines.23, 30-32 Onset typically occurs approximately 48 hours after cessation of drinking. The mild tremor and lucid hallucinations of early withdrawal give way to delirium and agitation. The patient begins to pull at imaginary objects or at his or her clothing and sheets. Lifethreatening hyperthermia, which results from increased motor activity and is exacerbated by volume depletion may develop, with temperatures reaching 104F or greater. Dehydration is a critical factor in the appearance of DT and may be severe. Of the 39 fatalities described by Tavel et al, dehydration was a factor in all cases in which volume status was noted.31

Mechanisms of fluid depletion: include profuse diaphoresis, increased pulmonary losses related to fever and tachypnea, nausea, vomiting, diarrhea, and decreased oral intake secondary to increasing confusion. A recent study found elevated alpha-atrial natriuretic peptide in every patient who went on to develop DT.33 This suggests an even greater need for aggressive fluid and electrolyte replacement in DT.

DO NOT assume that alcohol withdrawal accounts for the entire clinical picture of a patient who presents with these symptoms. The following illnesses must be considered, particularly those which can also produce any or all of the symptoms of DT: alcohol intoxication, other toxins, hypoglycemia, sepsis, severe dehydration, CNS infection, hepatic insufficiency, cerebral injury and/or hemorrhage, and seizure (post-ictal).

Alcohol-Related Seizure. Seizures related to alcohol are a common cause of adult convulsions presenting to the ED. The term alcohol withdrawal seizures was originally described by Victor and Brausch in adult patients who were confirmed alcoholics of many years duration.28 They reported these seizures as occurring in approximately 10% of people withdrawing from alcohol. They found them to be generalized tonic-clonic (95%), often multiple (60%), and usually occurring 7-48 hours after cessation of drinking (90%). Most were noted to have normal EEGs (90%). They reported the time interval from first to last seizure was less than six hours in 85% of patients. Recently, Ng et al reported that alcohol itself may induce seizures.36 The fact that patients seize who have high blood alcohol levels, and that many patients with seizures related to alcohol do not exhibit other signs or symptoms of withdrawal, support this possibility. Alcohol itself may also exacerbate other existing conditions, such as epilepsy.37-39 Because of the multifactorial origin of seizures in the setting of acute and chronic alcoholism, the term alcohol-related seizure (ARS) is frequently used instead of alcohol withdrawal seizure.44 Lorazepam is conjugated to form an inactive glucuronide that is excreted in the urine. Therefore, its elimination half-life is not substantially prolonged in patients with liver dysfunction such as cirrhosis.64,39 The combination of minimal accumulation in the plasma after multidose therapy, metabolism that is unaffected by concurrent drug therapy (i.e., cimetidine, disulfiram, ethanol), disease states such as cirrhosis, its lower abuse potential compared to other benzodiazepines, and the fact that its metabolism is not altered in the elderly, make it an ideal drug for the population of patients with ARS.53,65-68
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Repeated episodes of alcohol withdrawal may lead to an increase in the severity of subsequent episodes and a lower seizure threshold through a process known as kindling.45-47 Individuals who have had five or more alcohol detoxifications have a greater risk of withdrawal seizures.48
[[48. Lechtenberg R, Worner TM. Relative kindling effect of detoxification and nondetoxification admissions in alcoholics. Alcohol Alcohol 1991;26:221-225.]]

Managing a case of delirium tremens is a frightening experience. The patient generally exhibits all of the symptoms of AWS but often in extreme form, and unlike AWS, the sensorium is clouded and the patient is often frankly delirious. When death occurs, reportedly in 1 5% of cases, it is usually due to cardiovascular collapse secondary to the hyperadrenergic state. We will cover treatment of the DTs in a later slide, but prevention of such a critical condition is obviously the way to go and the only way known to prevent the DTs is to adequately treat the AWS.

Treatment of AWS Fixed Dose Regimen

Librium 50 / 25 / 10mg PO Q4hr W/A Ativan 2 / 1.5 / 1mg PO Q4hr W/A Three days meds, one day observation, hold for sedation Ativan 1-2 mg PO or IM prn Symptoms of AWS Ancillary medications
The goal is to minimize adverse outcomes such as discomfort, seizures, delirium and death while avoiding complications of withdrawal medication such as oversedation.

We have already reviewed initial patient assessment which should concentrate on identifying medical and psychiatric comorbidities, substance abuse and treatment history, and estimation of withdrawal severity. Alcohol related complications (pancreatitis, liver disease, gastritis, etc) should be sought out and treated. Appropriate labs include electrolytes, CBC, LFTs, Mg++, Ca++, phosphate, and urine tox. Pregnancy testing, and screening for the hepatitis, TB, and HIV should be strongly considered. CXR and EKG should be obtained as warranted by the patients age and past medical history. Pharmacological management is straightforward. Benzodiazepines such as diazepam (Valium), lorazepam (Ativan), and chlordiazepoxide (Librium) effectively relieve signs and symptoms of withdrawal and prevent seizures and DTs. Benzodiazepines are the mainstay of therapy due to their rapid absorption and cross-tolerance with alcohol. They have been shown in randomized trials to treat the symptoms of withdrawal and reduce the frequency of seizures and delirium tremens.50-57 The benzodiazepines have anticonvulsant activity, minimal respiratory and cardiac depression, and can be administered parenterally.

Chlordiazepoxide is the most commonly used benzodiazepine for AWS in the US (Saitz et al, 1994). Shorter-acting agents such as lorazepam may have less risk of excess sedation and are sometimes choosen in the elderly and those with major hepatic or pulmonary disease. It is prudent to withhold benzodiazepine treatment until the BAC falls to less than 0.15 unless indicated for treatment of withdrawal symptoms in the presence of a high BAC. Benzodiazepines are generally administered orally are not well absorbed IM. Lorazepam is the exception and is absorbed muscularly. It is also important to note that when diazepam and lorazepam are used intravenously the duration of action is much reduced (about 30 minutes for diazepam and 2 hours for lorazepam). Thiamine should always be given, 100 to 200 mg / day, PO or IM. Other medications may be useful for associated symptoms, for example, anti-emetics, analgesics, and anti-diarrhea meds. Severe AWS is a true medical emergency requiring rapid intervention. All aspects of treatment listed in Table 6 must be addressed. Physical restraints must be applied to prevent injury pending adequate sedation, which must be accomplished quickly in order to allow an adequate assessment of underlying conditions. In addition to sedation, rehydration is extremely important because dehydration is a significant contributing factor to mortality in AWS. Proper fluid management also protects the restrained, hyperthermic, agitated patient from possible acute tubular necrosis (ATN) due to rhabdomyolysis. Light and noise exacerbate the agitation and delirium of AWS, and the patient should be placed in a quiet room with subdued lighting under constant, direct observation. Significant control of symptoms should be obtained in the ED, and aggressive therapy must continue during and after the transition to an inpatient unit.

There are three main alcohol detoxification strategies, the fixed dose or structured regimen, the symptom-driven regimen, and the loading dose method. There are pros and cons to each approach. The fixed dose regimen is medically and administratively easy. Every patient has the same orders for standing benzodiazepine plus prn doses if needed. One convenient thing about fixed-dose detoxification is that everyone knows when the treatment will end. It requires little special staff training and skill maintenance. But since every patient is treated for the same number of days with similar doses of medication, some patients are being over-treated receiving more medication for more days than necessary.

Treatment of AWS Symptom-driven Regimen

Use CIWA scale serially

Medicate or observe based on w/d score Pro's: less meds, shorter LOS Con's: requires training, discharge flexibility
Symptom-triggered therapy using a structured and validated instrument such as the CIWA permits individualization of sedative dosage.

Generally, the CIWA-Ar is administered and if it is greater than 8-10, a 25-100mg dose of chlordiazepoxide is administered and the test is repeated in one hour. If the CIWA is < 8-10 four hours apart, the detox is considered complete. Saitz, Mayo-Smith, and Roberts, 1994, have shown that this regimen reduces the amount of medication used and the duration of treatment without increasing adverse outcomes.

Treatment of Delirium Tremens

Fluid and electrolyte management Pharmacotherapy - hourly Librium 100 mg PO, or valium 10mg IV, till asleep Consider addition of anti-psychotics (after administration of benzodiazepines or phenobarbital or may precipitate seizure!) Physical restraint may be necessary
Treatment of the patient with DTs is challenging. Older studies showed a mortality rate of 30% but this has been decreased to less than 1% with modern care. The underlying principles of treatment are adequate sedation and meticulous attention to supportive medical at care. Management of fluids and electrolytes is critical in this hyperdynamic state. A search for other medical problems is essential as DTs are often encountered in patients with co-existing medical conditions. A high index of suspicion for infection is appropriate as the withdrawal symptoms can mask presenting signs of infection.

The goal is to sedate the patient to the point of light sleep preventing the patient from harming self or others and making possible the provision of medical care. Intravenous diazepam is often necessary. Respiratory depression is a complication and respiratory support must be quickly available. One benefit of using diazepam is that the peak effect is seen with 5 minutes of IV administration. Once established, the delirium will last for at least several hours, and may very well last days, and can be very difficult to break. Neuroleptic agents such as haloperidol can be used, but only after adequate benzodiazepine has been given or they can precipitate seizures.