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CE Article: Withdrawal and the Chronic Alcohol User
A 62-year-old male presents at Sunnyside Nursing Home’s subacute rehabilitation center supine in bed, agitated, with an altered mental status. The staff reports he suffered a stroke while asleep at home three days prior. He’d awakened with left-sided weakness and a facial droop and called 9-1-1. The exact time of onset of symptoms could not be identified, so he was not a candidate for tPA therapy. A CT scan was positive for ischemic stroke, and he was discharged 24 hours later to the Sunnyside Nursing Home for rehabilitation.
The staff says when he arrived 48 hours ago, he was conscious, fully alert and oriented, and able to interact normally with staff. Since then he’s become increasingly agitated and earlier this morning developed an altered mental status.
Your exam reveals the patient to be alert but altered and unable to answer questions appropriately, and he appears to be hallucinating. He is noticeably diaphoretic and vomits during the exam. His vital signs are a heart rate of 104/min., respiratory rate of 22/min. with good tidal volume, blood pressure of 152/100 mmHg, and a room air SpO2 of 96%. He has left-sided weakness and a facial droop, which the staff reports is no worse than when he arrived. You note on his chart that prior to his stroke he had a history of hypertension treated with amlodipine (Norvasc).
Definitions
Prior to 2013 the American Psychiatric Association described two distinct disorders of alcohol in its Diagnostic and Statistical Manual of Mental Disorders (fourth edition, aka DSM–IV). Alcohol abuse and alcohol dependence were classified separately, with specific criteria for the diagnosis of each. In May 2013 the APA issued the fifth edition of the DSM (DSM–5), which integrated the two DSM-IV disorders into the single alcohol use disorder (AUD). AUD is stratified into mild, moderate and severe classifications (Table 1). Any person meeting any two of the 11 criteria listed in Table 1 would receive a diagnosis of AUD. The severity of an AUD is based on the number of criteria met.1
The term alcoholism is often used to describe more severe manifestations of AUD.2 The Joint Committee of the National Council on Alcoholism and Drug Dependence and the American Society of Addiction Medicine defines alcoholism as a primary, chronic disease with genetic, psychosocial and environmental factors influencing its development and manifestations. The disease is often progressive and fatal.3 That the term disease is used in the definition is not trivial, and is an important concept for healthcare providers at any level to appreciate.
Addiction, including alcohol addiction, is thought to be the result of the interaction of our genes with the environment, the duration of a drug exposure, and an individual’s balance between personal risk and the socioeconomic protective factors present in their home, school and community.4 Over the past two decades, our understanding of addiction has evolved. Current understanding encourages us to recognize all addiction, alcohol included, as a chronic medical problem no different than cancer, asthma, diabetes or seizure disorder. As such, addiction to alcohol and chronic alcoholism constitute disease. This perception change regarding addiction is apparent in new policies regarding the reimbursement of medical services for substance abuse, including chronic alcoholism. Under the Affordable Care Act, the coverage insurers must offer persons with a substance use disorder will be comparable to the coverage provided for other chronic illnesses such as hypertension, diabetes and asthma. It lists substance abuse disorders as one of the 10 elements of essential health benefits.5
The National Institute on Alcohol Abuse and Alcoholism (NIAAA) has published recommendations on how much drinking is too much. For healthy men under 65, the limit of low-risk drinking is defined as no more than four drinks in a day (and not within a two-hour period) or 14 in a week. Healthy women of all ages and healthy men older than 65 are advised to drink no more than three drinks in a day (and not within a two-hour period) and no more than seven in a week.
Gender and age differences in volume of distribution and concentrations of alcohol dehydrogenase in the liver and gastrointestinal tract account for the differences in recommendations. The NIAAA defines binge drinking (which should be avoided) as a pattern of alcohol consumption that results in a blood alcohol level over the legal limit of 0.08 g/dL, which for the average male is the result of more than four drinks in two hours (three drinks for the average female).6
Pathophysiology of Alcohol Use Disorder and Withdrawal
Alcohol is a central nervous system depressant, stimulating gamma-aminobutyric acid (GABA) receptors and as an antagonist at N-methyl-D-aspartate (NMDA) receptors. It also interacts with other neurotransmitter systems in the brain, such as the endogenous opioid, serotonin and dopamine systems, but its interactions with NMDA and GABA receptors have the most profound effects.
GABA is the chief inhibitory neurotransmitter in the brain, and binding sites specific for ethanol are located on the GABA receptor complex. GABA plays an active and important role in regulating neuronal excitability in the brain, and in humans it is also responsible for the regulation of muscle tone. Ethanol acts as an indirect GABA agonist. With chronic ethanol use, the human brain becomes increasingly insensitive to GABA, so that more ethanol is required to maintain a consistent inhibitory tone and prevent neuronal excitability.
NMDA receptors in the brain are activated when bound to glutamate, one of the more prominent excitatory amino acids. Ethanol inhibits glutamate-inducted central nervous system excitation and results in lethargy. Adaptation to ethanol occurs when the brain increases sensitivity to glutamate in an attempt to maintain a normal state of arousal.
As the chronic alcoholic continues to expose his or her body (and in turn its GABA and NMDA receptors) to ethanol, those receptors begin to upregulate, or increase in number. This upregulation is the basis of tolerance: When the body has a greater number of receptors, a greater amount of stimulation (or suppression) is required to cause the end effect. GABA is inhibitory, so once the chronic alcoholic has a much greater number of GABA receptors and stops drinking, many of the receptors are not stimulated, and the overall neurologic suppression effect cannot be achieved. As a result, the patient becomes hyperactive, agitated and hallucinogenic.
The NMDA is excitatory and leads to catecholamine release in the body. The chronic alcoholic has been suppressing these NMDA receptors, leading to the sedative effects of alcohol. Over time the body upregulates the NMDA receptors, which leads to the person needing a larger amount of alcohol to suppress the now-larger number of receptors and achieve the sedative intoxicated state. If that heavy drinker abruptly stops drinking, they have a larger-than-normal number of NMDA receptors that are all uninhibited. The result is diffuse stimulation of catecholamines throughout the body, leading to CNS hyperactivity, agitation, tachycardia and diaphoresis.
Chronic alcoholism results in a myriad of physiologic changes and comorbidities that complicate its clinical picture.
Ethanol Withdrawal
It is well known but not completely understood why some persons suffer more severe withdrawal symptoms than others. Genetic predisposition to withdrawal and the amount and duration of ethanol ingestion are thought to play roles.7,8 A classic 1955 study demonstrated that individuals who drink alcohol continuously for longer periods of time and who develop high, sustained levels of blood ethanol are more likely to suffer severe withdrawal after abrupt reduction or cessation than are those who drink for shorter periods of time. Ethanol withdrawal does not usually occur in persons who drink in an intermittent manner that does not lead to the sustained high blood levels of ethanol needed to develop tolerance and withdrawal.8
It is worth noting that total cessation of ethanol ingestion is not required for withdrawal symptoms to occur. Rather, withdrawal can occur any time after blood ethanol levels start to fall, not just when blood ethanol is absent. Consequently, the chronic alcoholic can start to have symptoms of withdrawal at blood alcohol levels that would render other individuals profoundly intoxicated.
For example, an occasional drinker might drink heavily, develop a blood alcohol content (BAC) of 0.15 g/dL, and not only be above the legal limit to drive in most states (typically around 0.08 g/dL) but also experience lethargy and difficulty sitting upright without assistance. A BAC of 0.25–0.3 g/dL will render this occasional drinker comatose. Most important, the occasional drinker of alcohol will not experience withdrawal symptoms when they stop drinking alcohol and their BAC returns to the normal baseline of 0.0 g/dL. A chronic alcoholic may live at a BAC of 0.35 g/dL, a level that would render unhabituated persons comatose, and his stopping drinking for even a short time may result in withdrawal symptoms at a BAC of 0.15 g/dL.
Minor ethanol withdrawal can occur as early as six hours after the fall of blood ethanol levels and usually peaks within 24–36 hours if the withdrawal is not going to progress.9,10 The signs and symptoms of minor withdrawal include anxiety, gastrointestinal distress, anorexia, nausea, insomnia, vivid dreams, tremors, headache, diaphoresis, tachycardia and palpitations. These findings are all consistent with increased autonomic activity and catecholamine release.
Major ethanol withdrawal occurs after about 24 hours and usually peaks at about 50 hours but can take up to five days to resolve after the decline or termination of drinking.9 It is characterized by the greater and prolonged signs and symptoms of minor ethanol withdrawal as well as hypertension, fever, hallucinations, decreased seizure threshold and delirium.
Delirium and Seizures
Delirium tremens (DT) is a life-threatening manifestation of ethanol withdrawal characterized by tremors, hallucinations (most often visual), confusion and agitation, tachycardia, tachypnea, hypertension and diaphoresis. It is worth noting that a patient can have hallucinations without DT and its characteristic alterations of vital signs. The symptoms of DT typically appear 48–96 hours after the fall of blood ethanol levels and can persist for 1–7 days.
Patients with DT have increased metabolism and oxygen requirements. In addition, hyperventilation can result in the development of a respiratory alkalosis and subsequent reduction in cerebral perfusion secondary to cerebral vasoconstriction. Patients in DT (and therefore severe ethanol withdrawal) can develop hypovolemia and electrolyte abnormalities as a result of the fever, tachypnea, hyperthermia and vomiting characteristic of the state. This can lead to cardiac dysrhythmias, cardiac failure and seizures. The mortality associated with DT is about 5%, and advanced age, hyperthermia and preexisting liver or respiratory disease increase its risk.10
Alcohol withdrawal seizures are tonic-clonic seizures that can occur as early as six hours after the fall of blood ethanol levels. About 90% of withdrawal-related seizures occur within 48 hours after the fall of blood ethanol levels. Withdrawal seizures are usually singular or occur as a series of brief periods of seizure activity over a short time. If you witness recurrent seizures or prolonged seizure activity (status epilepticus), consider other etiologies for the seizure; the chronic alcohol abuser is at increased risk for trauma, hypoglycemia and sepsis. Table 2 lists the differential considerations for patients with suspected ethanol-related symptoms.
Withdrawal Management
The goals of prehospital management of the patient with ethanol withdrawal revolve around:
• Ensuring an open and protected airway and protecting against aspiration;
• Ensuring adequate ventilation;
• Replacing volume depletion;
• Preventing and/or stopping seizure activity;
• Ruling out and/or treating hypoglycemia; and
• Reducing patient agitation and discomfort.
Create as much of a quiet, protective space as possible for the patient suffering mild withdrawal. This can be difficult in the prehospital environment, but little efforts (e.g., turning down the lights in the patient compartment, reducing speed and bumps during transport, not using lights and sirens unnecessarily) can contribute to a more optimal environment. Patients suffering nausea can be administered an antiemetic such as ondansetron (Zofran) or prochlorperazine (Compazine) to control it and prevent vomiting.
To protect both the patient and caregivers, restraints may be necessary for patients in withdrawal with profound agitation or DT. Physical restraints must be padded, preferably applied to the extremities, and not restrict breathing. If physical restraints are utilized, consider the concomitant use of sedation. A patient resisting against physical restraints can cause themselves physical injury, raise their metabolism and body temperature, and possibly produce rhabdomyolysis. Benzodiazepines such as diazepam (Valium), lorazepam (Ativan) and midazolam (Versed) and IV antipsychotics such as haloperidol (Haldol) are sedatives commonly used in the prehospital environment for this purpose.
All patients in DT require sedation with benzodiazepines, and the total amount of IV benzodiazepines that can be administered to control the symptoms of withdrawal is not insignificant. As was discussed earlier, chronic alcohol abuse desensitizes patients to GABA stimulation, which is the primary mechanism for benzodiazepines. Since the chronic alcoholic has a larger-than-normal number of GABA receptors, they will require a larger-than-normal amount of benzodiazepine to adequately stimulate the receptors to reach the goal of sedation.
The Clinical Institute Withdrawal Assessment (CIWA) recommendations for administration of midazolam for severe alcohol withdrawal say a patient unable to take oral medications can receive 2–5 mg every five minutes x3, then 4–10 mg IV x3 until improvement, up to a total of 50 mg of midazolam. Most EMS systems do not have paramedic units stocking 50 mg of midazolam, nor do many prehospital protocols allow for the administration of that much. Consult online medical direction for guidance when presented with a patient in severe ethanol withdrawal.
Many clinicians use the CIWA protocol to help assess the degree of withdrawal and amount of medication therefore needed (Table 3). While prehospital care providers will most likely not use this tool to direct total doses, it is useful to consider your clinical exam findings against the CIWA criteria to determine the degree of withdrawal in your patient.
Chronic alcoholics, because of the derangements of liver function characteristic of the disease, are at increased risk of developing hypoglycemia. Any patient with an altered mental status, especially the chronic alcoholic suffering from withdrawal, should have their blood glucose level determined and dextrose administered if they are found to be hypoglycemic. Patients with AMS or a decreased level of consciousness should have IV access established and dextrose administered via that route. Patients in withdrawal who are alert and oriented, have an intact gag reflex and can follow directions may be administered oral glucose. However, the risk of aspiration should be evaluated, and IV dextrose administered if any risk of aspiration or vomiting exists. Chronic alcoholics are at high risk for aspiration and the development of pneumonia due to their inability to adequately protect their airway when they are heavily intoxicated and also because of the immunosuppression characteristic of alcoholism.
Patients with clinical evidence of volume depletion and dehydration should be administered an isotonic electrolyte solution such as normal saline, and IV thiamine can be given to the chronic alcoholic to prevent or treat Wernicke’s encephalopathy. In the emergency department, these patients are commonly administered a multivitamin, glucose and folate-containing solution to correct the deficiencies in glucose, potassium, magnesium and phosphate typical in the chronic alcoholic. This solution, because of the multivitamins, has a bright yellow appearance and is commonly referred to as a “banana bag.” However, this treatment has not been well studied, and it is unknown if it actually meets the vitamin, glucose and electrolyte demands of the patient with ethanol withdrawal.10
Case Wrap-up
The patient is placed on oxygen via nasal cannula at 4 lpm, which brings his SpO2 up to 100%. He is placed on the cardiac monitor, which shows a sinus tachycardia. IV access is obtained with an 18-gauge angiocath in the right antecubital area. The patient receives 2 mg of Ativan for his agitation and 4 mg of ondansetron for his nausea. He gets another 2 mg of Ativan IV 10 minutes later when he’s noted to still be agitated. He remains agitated but otherwise has an uneventful transport to the emergency department.
At the ED the patient continues to be agitated and is restrained in soft four-point restraints. While being restrained he suffers a brief seizure and is given additional Ativan. Although the seizure activity is halted, the patient continues to be tremulous and tachycardic. He is placed on an Ativan drip and admitted to the ICU. Over the next four days the Ativan drip is down-titrated, and the patient is ultimately transitioned to PO benzodiazepines. After five days he is discharged to a rehab facility.
References
1. National Institute on Alcohol Abuse and Alcoholism. Alcohol Use Disorder: A Comparison Between DSM-IV and DSM-5, https://pubs.niaaa.nih.gov/publications/dsmfactsheet/dsmfact.htm.
2. Gold MS, Aronson MD. Alcohol use disorder: epidemiology, pathogenesis, clinical manifestations, adverse consequences, and diagnosis. UpToDate, www.uptodate.com/contents/alcohol-use-disorder-epidemiology-pathogenesis-clinical-manifestations-adverse-consequences-and-diagnosis.
3. Morse RM, Flavin DK. The definition of alcoholism. The Joint Committee of the National Council on Alcoholism and Drug Dependence and the American Society of Addiction Medicine to study the definition and criteria for the diagnosis of alcoholism. JAMA, 1992 Aug 26; 268(8): 1,012–4.
4. Bernstein E, Bernstein JA, Fernandez W, D’Onofrio G. Chapter 289: Alcohol and Other Drugs of Abuse. In: Tintinalli JE, et al., Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 7th ed. New York: McGraw-Hill, 2011.
5. Office of National Drug Control Policy. Substance Abuse and the Affordable Care Act, www.whitehouse.gov/ondcp/healthcare.
6. U.S. Department of Health & Human Services, National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism. Helping Patients Who Drink Too Much: A Clinician’s Guide, https://pubs.niaaa.nih.gov/publications/Practitioner/CliniciansGuide2005/guide.pdf.
7. Saitz R, O’Malley SS. Pharmacotherapies for alcohol abuse. Withdrawal and treatment. Med Clin North Am, 1997 Jul; 81(4): 881–907.
8. Isbell H, Frasher HF, Wilker A, Belleville RE, Eisenman AJ. An experimental study of the etiology of rum fits and delirium tremens. Q J Stud Alcohol, 1955 Mar; 16(1): 1–33.
9. Finnell JT. Chapter 185: Alcohol-related Disease. In: Marx J, Hockberger R, Walls R, Rosen’s Emergency Medicine, 8th ed. Mosby, 2013.
10. Hoffman RS, Weinhouse GL. Management of moderate and severe alcohol withdrawal syndromes. UpToDate, www.uptodate.com/contents/management-of-moderate-and-severe-alcohol-withdrawal-syndromes.
11. Charness ME. So YT. Wernicke’s encephalopathy. UpToDate, www.uptodate.com/contents/wernickes-encephalopathy.
12. Harper CG, Giles M, Finlay-Jones R. Clinical signs in the Wernicke-Korsakoff complex: a retrospective analysis of 131 cases diagnosed at necropsy. J Neurol Neurosurg Psychiatry, 1986 Apr; 49(4): 341–5.
13. Victor M, Brausch C. The role of abstinence in the genesis of alcoholic epilepsy. Epilepsia, 1967 Mar; 8(1): 1–20.
Scott R. Snyder, BS, NREMT-P, is a faculty member at the Public Safety Training Center in the Emergency Care Program at Santa Rosa Junior College, CA. E-mail scottrsnyder@me.com.
Sean M. Kivlehan, MD, MPH, NREMT-P, is an emergency medicine resident at the University of California, San Francisco. E-mail sean.kivlehan@gmail.com.
Kevin T. Collopy, BA, FP-C, CCEMT-P, NREMT-P, WEMT, is performance improvement coordinator for Airlink/Vitalink in Wilmington, NC, and a lead instructor for Wilderness Medical Associates. E-mail kcollopy@colgatealumni.org.
