A Superior Cocktail

A SUPERIOR COCKTAIL

Chief Complaint:

Seizures

HPI:

26-year-old male presents to the emergency department by EMS after he reportedly had 2 witnessed seizures by friends, who then called EMS. Described as tonic-clonic. EMS notes that he was postictal on arrival. Patient notes that he has not had seizures before in the past. He reports that he typically drinks a pint of rum a day and it has been about a day since he had any alcohol. No prior seizures related to alcohol or withdrawal per his report. He denies any pain or recollection of hitting his head or fevers.

Past Medical History

- Deaf
- Heart murmur
- Meningitis (as an infant)

Surgical History

- Cochlear implants
- Balloon Valvuloplasty

Social History

- Alcohol use: Alcohol use (750 mL daily)
- Drug use: Denies recreational drugs
- Smoking status: Never smoker

Pertinent Exam Findings:

General Appearance: Patient is awake, alert and in no acute distress
Eyes: Pupils equal at 3mm, eye movements normal
ENT, Mouth: Mucous membranes are dry
Respiratory: Lungs are clear to auscultation patient is in no respiratory distress, not using any accessory muscles, and speaking in full sentences.
Cardiovascular: Tachycardic rate and irregularly irregular rhythm
Gastrointestinal: Abdomen is soft, nontender
Musculoskeletal: Extremities with full range of motion
Skin: Warm, dry, no rashes
Neurologic: Awake, alert, oriented x 3. Motor grossly intact. Speech is normal and patient is able to ambulate at their baseline, upper extremities are tremulous

Labs:

CBC: There is no acute leukocytosis or unstable anemia, but a thrombocytopenia of 103 noted consistent with alcohol abuse
BMP: There is no acute renal dysfunction or significant electrolyte abnormality
Troponin negative
EKG: Atrial fibrillation with rapid ventricular response, no STEMI or significant interval
TSH: unremarkable
LFT: AST 175, ALT 133 consistent with transaminitis from alcohol abuse
Chest X-ray: No acute process

ED Course:

26-year-old male presents to the emergency department status post new onset seizure related to alcohol cessation as well as A. fib RVR also likely related. CHA2DS2-VASc score 0. Could consider aspirin but held while in the emergency department. Patient treated with IV normal saline, phenobarbital, diltiazem, and an oral GI cocktail. Symptoms resolved and rate control was obtained.

Hospital Course:

Alcohol withdrawal was treated with CIWA protocol. Paroxysmal atrial fibrillation was likely secondary to alcohol withdrawal and initially treated with diltiazem in ED, but spontaneously converted to normal sinus rhythm while on the floor. A transesophageal echocardiogram was normal, and patient was educated to abstain from alcohol. Patient was discharged on hospital day 2 without antiepileptic medications.

DISCUSSION:

Background:

The 2017 National Survey on Drug Use and Health estimated that in individuals ages 12 and older, 14.5 million people in the US (5%) had an alcohol use disorder. Further, approximately half of patients with alcohol use disorder report they experience withdrawal symptoms. Alcohol withdrawal results from a state of overactivity in the central nervous system following the abrupt cessation of chronic ethanol ingestion.

Ethanol affects multiple neurotransmitters, receptors, and transporters in the brain. Withdrawal specifically arises from ethanol’s ability to depress the central nervous system via two mechanisms: enhancing inhibitory tone and inhibiting excitatory tone. Inhibitory tone in the brain is maintained primarily by GABA. Via binding to GABA receptors, ethanol enhances the effect of GABA in the brain. With chronic use, the brain will down-regulate GABA receptors such that a chronic consumer of alcohol is able to maintain normal arousal levels when consuming alcohol at levels that would cause severe CNS depression in non-chronic consumers. Excitatory tone in the brain is maintained primarily by NMDA. In an inverse mechanism to GABA, the brain will upregulate NMDA when alcohol is chronically present to maintain appropriate levels of arousal. The product of chronic alcohol ingestion is a central nervous system with low levels of endogenous inhibitors and high levels of endogenous activators. When alcohol is suddenly removed, homeostasis is lost – low levels of GABA and high levels of NMDA result in an excitatory state. Given the severity and prevalence of alcohol withdrawal in the United States, every emergency physician should know how to characterize and manage this disease.

Diagnosis:

Alcohol withdrawal presents in a varied manner and can be predicted based on time since last drink: 6-12 hours: Minor withdrawal symptoms: insomnia, tremulousness, mild anxiety, gastrointestinal upset, headache, diaphoresis, palpitations, anorexia 6-48 hours: Seizures 12-24 hours: Alcoholic hallucinosis (visual, auditory, or tactile hallucinations) 48-72 Hours: Alcohol withdrawal delirium (delirium tremens): hallucinations (predominantly visual), disorientation, tachycardia, hypertension, low-grade fever, agitation, diaphoresis.

The clinical syndrome associated with alcohol withdrawal may include autonomic hyperactivity, insomnia, nausea, vomiting, anxiety, and psychomotor agitation. History may reveal sudden decrease in otherwise chronic alcohol use.

Alcoholic hallucinosis and delirium tremens are occasionally grouped together as severe alcohol withdrawal syndrome. Distinguishing their presence is clinically important. In alcoholic hallucinosis, hallucinations can be visual, auditory, or tactile and are distressing to the patient who is acutely aware they are hallucinating. Additionally, vital signs are typically normal. Patients with delirium tremens have altered sensorium with possible tachycardia, hypertension, hyperthermia, and hyperventilation resulting in respiratory alkalosis.

One common tool used to evaluate suspected alcohol withdrawal is CIWA-Ar. This scoring algorithm provides guidance for determining severity of alcohol withdrawal. Scores <8 typically do not require medication while scores ≥20 frequently require medication and possible admission to ICU. A more useful tool used when titrating phenobarbital for withdrawal treatment is the Richmond Agitation-Sedation Score (RASS). RAAS uses a single number score from -5 to +4 to denote the spectrum from sedation to agitation. A score of 0 is “alert and calm”; scores >0 indicate increasing degree of agitation while scores <0 indicate increasing degree of sedation. Advantages of RASS in the emergency room setting include ease of scoring, allowing for clear communication of patient assessment between providers. RASS scores are related to simple definitions of easily observable behaviors, thus RASS can be administered in 30-60 seconds without need for addition of subscores or use of equipment-based interventions. In phenobarbital administration for the alcohol withdrawal, the RASS goal is a score of 0 to minus 1. A simple decision can be made to administer phenobarbital for score >0 or not administer for score < -1. Clinical judgment should be used in conjunction with scores.

Management in ED:

Management of acute alcohol withdrawal begins with suppressing the overactive central nervous system. ruling out alternative diagnoses and then providing supportive care including intravenous fluids, nutritional supplementation, and frequent clinical reassessment.

Benzodiazepines, such as diazepam, lorazepam, and chlordiazepoxide are the most used medications for the management of psychomotor agitation associated with alcohol withdrawal. Benzodiazepines bind to and stimulate GABA-A receptors which increases the frequency of chloride channel activation leading to postsynaptic hyperpolarization and a decreased ability to initiate action potentials. The neuroinhibitory effect of benzodiazepines leads to relative sedation which counteracts the excitatory psychomotor agitation brought on by alcohol withdrawal.

Phenobarbital has a similar mechanism of action as benzodiazepines in that it also causes GABA-A chloride channel activation, but it differs in that it prolongs the duration of channel opening rather than increasing the frequency of opening. Many guidelines recommend the use of phenobarbital as an adjunct therapy in cases of alcohol withdrawal refractory to benzodiazepines, but the use of phenobarbital as monotherapy for the treatment of alcohol withdrawal is becoming more accepted in emergency medicine. There are several advantages to using phenobarbital monotherapy as opposed to benzodiazepines to manage alcohol withdrawal, most notably that phenobarbital has more predictable pharmacokinetics and pharmacodynamics, a wider therapeutic level, and a longer half-life than benzodiazepines.

Phenobarbital has been extensively studied due to its role in epilepsy management, and it has been shown to have a wide therapeutic window of 15-40 mcg/mL with clear boundaries for mild and severe toxicity at 50 mcg/mL and 65 mcg/mL respectively. Additionally, pharmacokinetic studies indicate that the dosage of phenobarbital has a linear relationship with the therapeutic level of the drug. This means that weight-based dosing of phenobarbital results in predictable drug levels allowing for the patient to reach a therapeutic concentration safely and efficiently. A loading dose of 10 mg/kg of phenobarbital is equivalent to a blood concentration of 15 mcg/mL at the start of the therapeutic window, which is less than four times the level required to reach severe toxicity. Patients can therefore receive this loading dose of phenobarbital and then be safely titrated up without risking oversedation and intubation.

The effectiveness of phenobarbital monotherapy in the management of alcohol withdrawal has been the subject of several recent studies. These studies have shown that phenobarbital monotherapy is well tolerated and quite effective in the management of alcohol withdrawal patients. One study comparing the efficacy of phenobarbital versus benzodiazepines for alcohol withdrawal showed no significant difference in the rate of return ED visits between the two cohorts within 48 hours of discharge. Additionally, rates of ICU admission and hypotension were similar for both treatment regimens when used as monotherapy, but increased significantly when used in combination. Another study showed that alcohol withdrawal patients who received phenobarbital either as monotherapy or in combination with lorazepam were less likely to return to the ED within three days of the index encounter than were patients receiving just lorazepam. Furthermore, patients in alcohol withdrawal who received phenobarbital monotherapy in either the ED or ICU had significant decreases in average length of hospital stay compared to those receiving benzodiazepines. While there is still much research being conducted regarding the ideal pharmacotherapy for alcohol withdrawal management, the use of phenobarbital monotherapy has shown to be both effective and well tolerated in this patient population while also being simple and straightforward for ED staff to administer.

For those using phenobarbital as monotherapy for the treatment of alcohol withdrawal, starting with a loading dose of 10 mg/kg is often recommended, then titrating up with 130 mg every 15 minutes in conjunction with clinical reevaluation. It is essential to track the cumulative dose of phenobarbital with a general stop point at 20 mg/kg. Consider ICU admission based on clinical condition. It is likely that any patient who has received 20 mg/kg or more of phenobarbital will require ICU level care. If phenobarbital has not effectively controlled withdrawal symptoms at this point, ICU admission and alternative treatments such as dexmedetomidine, ketamine, or propofol should be considered. It is possible to continue phenobarbital up to a maximum of 30 mg/kg, but any additional phenobarbital usage beyond that point risks toxicity. Use of either benzodiazepines or phenobarbital is recommended as a monotherapy rather than in conjunction to treat alcohol withdrawal due to an increased risk of over sedation and respiratory depression.

One of the benefits of phenobarbital is its long half-life, which allows for a natural slow, self-tapering of the drug from its therapeutic level as it is metabolized. This provides longer term coverage for patients after discharge which lessens the risk of breakthrough or rebound withdrawal symptoms while simultaneously decreasing the requirement for prescribed benzodiazepine therapy. There is a risk that if a patient resides in an area with multiple emergency medicine systems that use phenobarbital for alcohol withdrawal management, then they may arrive at the ED with already elevated phenobarbital levels due to its longer half-life. Conveniently, phenobarbital levels can be easily checked to reduce the risk of oversedation or to evaluate the patient should they display symptoms of phenobarbital toxicity.

There are three major contraindications to phenobarbital monotherapy. HIV patients on antiretrovirals, acute intermittent porphyria, and those with advanced cirrhosis and hepatic encephalopathy. Phenobarbital is known to interact with and reduce the serum concentration of antiretroviral medications and can also exacerbate acute intermittent porphyria. For patients with severe cirrhosis with hepatic encephalopathy, phenobarbital use increases the risk of severe prolonged coma and should therefore be avoided in favor of alternative treatment options. Caution should also be exercised in using phenobarbital in patients who have already received other potential respiratory depressants such as benzodiazepines, or in patients for which the diagnosis of alcohol withdrawal is uncertain. In these cases, consider a trial of a small dose of benzodiazepines and then reassess the patient before considering phenobarbital.

Prognosis:

Ultimately, alcohol withdrawal syndrome is a challenging but frequently encountered condition in emergency medicine. The long-term prognosis for alcohol withdrawal is still difficult to predict for each individual due to the high rates of relapse and resumed alcohol consumption, but in the setting of acute alcohol withdrawal, the prognosis generally depends on the severity of alcohol withdrawal syndrome with length of hospital stay and length of time in the ICU serving as key indicators for increased morbidity and mortality.

Approximately half of all adults with alcohol use disorder will suffer from alcohol withdrawal symptoms during their lifetime. One recent study showed that 14.3% of adults with reported unhealthy alcohol use suffered from withdrawal symptoms within the last year, most notably vomiting, insomnia, and psychomotor agitation. More severe symptoms including withdrawal seizures and delirium tremens occur less frequently but can lead to significant mortality and morbidity. Hospitalized patients treated for alcohol withdrawal developed delirium tremens in 24 to 33% of cases, and the mortality rate associated with severe alcohol withdrawal can reach 37% if untreated.

Early recognition of alcohol withdrawal improves the patient’s prognosis as it allows for the onboarding of medications such as benzodiazepines or phenobarbital that counter the sympathetic activation brought on by abrupt alcohol cessation. Additionally, early identification of alcohol withdrawal enables providers to better diagnose and manage associated illnesses such as pneumonia, pancreatitis, and hepatitis which complicate withdrawal management and increase the risk of death. If alcohol withdrawal is recognized and treated quickly and efficiently, the mortality rate of severe alcohol withdrawal including delirium tremens is less than 5%.

Differential Diagnoses:

- Serotonin Syndrome
- Hepatic Encephalopathy
- Uremia
- Hypoglycemia
- Diabetic Ketoacidosis
- Ingestion of toxic chemicals
- Meningitis
- Thyrotoxicosis
- Epilepsy
- Sedative, hypnotic, or anxiolytic withdrawal

Clinical Pearls:

- Alcohol Withdrawal results from the abrupt cessation of chronic alcohol use with a subsequent increase in overactivity of the CNS.
- Common symptoms of alcohol withdrawal include nausea, insomnia, anxiety, tremulousness, psychomotor agitation, hallucinations.
- CIWA scores can be used to grade the severity of alcohol withdrawal.
- Alcoholic hallucinosis and delirium tremens are severe forms of alcohol withdrawal that should be appreciated and treated for promptly.
- Management of alcohol withdrawal involves ruling out other possible causes and then providing supportive care such as IV fluids and nutritional supplementation.
- Commonly used medications for treating alcohol withdrawal include benzodiazepines and phenobarbital.
- Recent studies have highlighted the effectiveness of phenobarbital in the treatment of alcohol withdrawal with decreased hospital stay and fewer readmission rates when compared to benzodiazepines.
- Patients who have received 10 mg/kg or 20mg/kg of phenobarbital should be considered for admission to the floor or ICU respectively.

References:

Methaneethorn J, Leelakanok N. Pharmacokinetic variability of phenobarbital: a systematic review of population pharmacokinetic analysis. Eur J Clin Pharmacol. 2021;77(3):291-309.
Tangmose K, Nielsen MK, Allerup P, Ulrichsen J. Linear correlation between phenobarbital dose and concentration in alcohol withdrawal patients. Dan Med Bull. 2010;57(8):A4141.
Olkkola KT, Ahonen J. Midazolam and other benzodiazepines. Handb Exp Pharmacol. 2008(182):335-360.
Bayard M, McIntyre J, Hill KR, Woodside J Jr. Alcohol withdrawal syndrome. Am Fam Physician. 2004;69(6):1443-1450.
Hikasa S, Sawada A, Seino H, et al. A potential drug interaction between phenobarbital and dolutegravir: A case report. J Infect Chemother. 2018;24(6):476-478.
Vidaurre J, Gedela S, Yarosz S. Antiepileptic Drugs and Liver Disease. Pediatr Neurol. 2017;77:23-36.
Staidle A, Geier C. Phenobarbital and/or benzodiazepines for recurrent alcohol withdrawal: A self-controlled, retrospective cohort study. Am J Emerg Med. 2022;54:263-266.
Lebin JA, Mudan A, Murphy CEt, Wang RC, Smollin CG. Return Encounters in Emergency Department Patients Treated with Phenobarbital Versus Benzodiazepines for Alcohol Withdrawal. J Med Toxicol. 2022;18(1):4-10.
Hawa F, Gilbert L, Gilbert B, et al. Phenobarbital Versus Lorazepam for Management of Alcohol Withdrawal Syndrome: A Retrospective Cohort Study. Cureus. 2021;13(2):e13282.
Substance Abuse and Mental Health Services Administration. (2018). Key substance use and mental health indicators in the United States: Results from the 2017 National Survey on Drug Use and Health (HHS Publication No. SMA 18-5068, NSDUH Series H-53). Rockville, MD: Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration. Retrieved from https://www.samhsa.gov/data/
Olsen, R.W., Liang, J. Role of GABAA receptors in alcohol use disorders suggested by chronic intermittent ethanol (CIE) rodent model. Mol Brain 10, 45 (2017). https://doi.org/10.1186/s13041-017-0325-8
Banerjee N. Neurotransmitters in alcoholism: A review of neurobiological and genetic studies. Indian J Hum Genet. 2014;20(1):20-31. doi:10.4103/0971-6866.132750
Sullivan JT, Sykora K, Schneiderman J, Naranjo CA, Sellers EM. Assessment of alcohol withdrawal: the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar). Br J Addict. 1989;84(11):1353-1357. doi:10.1111/j.1360-0443.1989.tb00737.x
Goodson CM, Clark BJ, Douglas IS. Predictors of severe alcohol withdrawal syndrome: a systematic review and meta-analysis. Alcohol Clin Exp Res 2014; 38:2664.
Livne O, Feinn R, Knox J, et al. Alcohol withdrawal in past-year drinkers with unhealthy alcohol use: Prevalence, characteristics, and correlates in a national epidemiologic survey. Alcohol Clin Exp Res. 2022;46(3):422-433.
Smith JT, Sage M, Szeto H, et al. Outcomes After Implementation of a Benzodiazepine-Sparing Alcohol Withdrawal Order Set in an Integrated Health Care System. JAMA Netw Open. 2022;5(2):e220158.
Sessler CN, Gosnell MS, Grap MJ, Brophy GM, O’Neal PV, Keane KA, Tesoro EP, Elswick RK. The Richmond Agitation–Sedation Scale: validity and reliability in adult intensive care unit patients. American journal of respiratory and critical care medicine. 2002 Nov 15;166(10):1338-44.

Authors

Jack Spartz, MSIV

Peter Haskins, MSIV

Josh Wahba, MSIV

Kirsten Hughes, MSIII

Mark O’Brien, MSIII