a b s t r a c t

Introduction: Alcohol use is widespread, and withdrawal symptoms are common after decreased Alcohol intake. Severe alcohol withdrawal may manifest with Delirium tremens, and new therapies may assist in management of this life-threatening condition.

Objective: To provide an evidence-based review of the emergency medicine management of alcohol withdrawal and delirium tremens.

Discussion: The underlying pathophysiology of alcohol withdrawal syndrome (AWS) is central nervous system hyperexcitation. Stages of withdrawal include initial withdrawal symptoms, hallucinations, seizures, and deliri- um tremens. Management focuses on early diagnosis, resuscitation, and providing medications with gamma- aminobutyric acid (GABA) receptor activity. Benzodiazepines with symptom-triggered therapy have been the predominant medication class utilized and should remain the first treatment option with rapid escalation of dos- ing. Treatment resistant withdrawal warrants the use of phenobarbital or propofol, both demonstrating efficacy in management. Propofol can be used as an Induction agent to decrease the effects of withdrawal. Dexmedetomidine does not address the underlying pathophysiology but may reduce the need for intubation. Ke- tamine requires further study. Overall, benzodiazepines remain the cornerstone of treatment. Outpatient man- agement of patients with minimal symptoms is possible.

Conclusions: alcohol withdrawal syndrome can result in significant morbidity and mortality. Physicians must rapidly diagnose these conditions while evaluating for other diseases. Benzodiazepines are the predominant medication class utilized, with adjunctive treatments including propofol or phenobarbital in patients with with- drawal resistant to benzodiazepines. Dexmedetomidine and ketamine require further study.

Introduction

Alcohol use is widespread throughout developed countries, with over 8 million people in the U.S. dependent on alcohol [1]. Approximately 20% of men and 10% of women will suffer an alcohol-use disorder, and ap- proximately half will experience withdrawal symptoms following de- creased alcohol consumption [2,3]. Extreme complications, including seizures and delirium tremens, may occur in 3-5% [3]. The objective of this review is to summarize the current literature concerning emergency medicine management of alcohol withdrawal and delirium tremens (DT).

Pathophysiology

Alcohol is a central nervous system depressant through po- tentiation of gamma-aminobutyric acid (GABA) receptors, enhancing

* Corresponding author at: 3841 Roger Brooke Dr., San Antonio, TX 78234, United States.

E-mail addresses: [email protected] (D. Long), [email protected] (B. Long), [email protected] (A. Koyfman).

central inhibitory tone [1,4]. Chronic ethanol use leads to down-regula- tion and conformational changes of the GABA receptor. Additionally, in chronic alcoholics, N-methyl-D-aspartate (NMDA) receptors undergo conformational changes and up-regulation [1,5-7]. After discontinua- tion of alcohol consumption, patients lose the GABA inhibitory effect with potentiation of NMDA excitatory effects, leading to CNS hyperstim- ulation [6,8].

Stages of withdrawal

The diagnosis of alcohol withdrawal is defined by the Diagnostic and Statistical Manual of Mental disorders (DSM-5), displayed in Table 1 [3]. Acute reduction in serum alcohol concentration leads to symptoms that begin within 6-8 h, peak at 72 h, and diminish by days 5 to 7 of absti- nence [1,7]. Broad withdrawal signs and symptoms include insomnia, anxiety, nausea/vomiting, tremulousness, headache, diaphoresis, palpi- tations, increased body temperature, tachycardia, and hypertension [1, 3]. Patients taking Beta blockers or alpha-2 agonists may display blunted vital signs [5,8]. If the patient’s withdrawal does not progress, these withdrawal symptoms may resolve within 24 to 48 h, but more

http://dx.doi.org/10.1016/j.ajem.2017.02.002 0735-6757/

Table 1

Diagnostic criteria of alcohol withdrawal [3].

Diagnostic and statistical manual of mental disorders (DSM-5) criteria for alcohol withdrawal

Cessation or reduction in alcohol use that has been heavy and prolonged.

Two (or more) of the following, developing within several hours to a few days after criterion A.

- Autonomic hyperactivity, increased hand tremor, insomnia, nausea or vomiting, transient visual/auditory/tactile hallucinations or illusions, psycho- motor agitation, anxiety, Generalized tonic-clonic seizures

Table 3

Development of DT [17-19]

Factors associated with DT development

• History of previous DT
  • Recent withdrawal seizures, specifically if left untreated
  • Clinical Institute Withdrawal Assessment of Alcohol Scale, revised (CIWA-

Ar) >= 15

• • History of sustained drinking
  • Patients with SBP N 150 mm Hg, or patients with HR N 100 beats/min
  • Last alcohol intake N 2 days
  • Age N 30 years
  • Recent misuse of other depressants such as benzodiazepines
  • Concurrent medical illness such as pneumonia or active ischemia

commonly 5-7 days [9]. Alcohol withdrawal syndromes (AWS) are demonstrated in Table 2. Severe withdrawal with seizures or delirium tremens occurs in approximately 5% of patients [5,8].

Delirium tremens occurs in 3-5% of patients who are hospitalized for alcohol withdrawal [7,13,14]. DT usually begins 3 days after the appear- ance of withdrawal symptoms and lasts for 1 to 8 days, though symp- toms may appear as quickly as 8 h from the last drink [7,8,15,16]. The mortality of hospitalized patients with DT is currently estimated to be 1-4%; however, prior to the era of benzodiazepine use and intensive care, mortality reached 35% [7,8,14-16]. DT can be predicted by several factors, demonstrated in Table 3. If seizures remain untreated, up to one third of patients progress to DT. Other common factors include history of prior DT and Clinical Institute Withdrawal Assessment of Alcohol Scale, revised (CIWA-Ar) score >= 15 [17-19].

Discussion

Patients with alcohol withdrawal require immediate evaluation for life-threatening DT, as well as other conditions that may mimic with- drawal. The first aspect of management is resuscitation and stabiliza- tion, while evaluating for life-threatening conditions. Alcohol withdrawal is a clinical diagnosis, as well as a diagnosis of exclusion.

Table 2

Alcohol withdrawal syndromes (AWS).

Once other conditions have been considered and the emergency provid- er has diagnosed withdrawal, management of symptoms is required. A pitfall to avoid in the management of AWS is attributing complications from AWS to another condition and administering the incorrect treat- ment. For example, in alcoholic hallucinosis, the management is benzo- diazepines, with limited data showing that antipsychotics are detrimental in acute AWS [8,22]. For withdrawal seizures, there is no role for outpatient antiepileptic medications such as phenytoin, and benzodiazepines are the treatment of choice [8,23].

Additionally, it is important to consider the reason for cessation of al- cohol ingestion. While patients may admit ceasing alcohol consumption for multiple reasons, it is important to consider acute illnesses. alcoholic patients may develop diseases such as pneumonia, pancreatitis, hepati- tis, alcoholic gastritis, sepsis, acute coronary syndrome, meningitis/en- cephalitis, and many other pathologic processes leading to alcohol withdrawal. Other conditions such as trauma, infection, metabolic de- rangement, drug overdose, gastrointestinal bleeding, and hepatic failure may coexist with withdrawal. A concise and focused history and physi- cal examination are necessary to evaluate for other co-existing disease processes. Any suspicion of another disease process requires immediate treatment and stabilization [24,25]. For example, patients with fever, al- tered mental status, and signs of alcohol withdrawal should be assessed for other conditions. In particular, meningitis and encephalitis may present in a similar manner, with lumbar puncture and neuroimaging

warranted for further evaluation, while the patient receives antimicro-

Syndrome Timeline Characteristics

bials. Intracerebral hemorrhage may also cause similar symptoms,

Initial

Withdrawal Symptoms [1,3]

Alcohol hallucinations [10,11]

Withdrawal seizures [6,8,12]

Begins 6-8 h after last drink - Includes tachycardia,

hypertension, increased body temperature, tremulousness, anxiety, nausea/vomiting, headache, diaphoresis, and palpitations

12-24 h after last drink - 7-8% of patients with AWS

• Tactile hallucinations common, visual less likely
• Auditory hallucinations possible (sometimes per- secutory)
• May present with tremors and other withdrawal symptoms, though some do not
• Normal sensorium

12-48 h after last drink - Generalized tonic-clonic,

though often isolated, short in duration, short post-ictal period

• 1/3 of patients with with- drawal seizures will prog- ress to delirium tremens

with noncontrast head computed tomography required for diag- nosis. If these investigations are not conducted in a rapid manner, pa- tients may experience severe morbidity and mortality. An electrocardiogram (ECG) is warranted to assess for signs of acute ische- mia and evidence of QT interval prolongation. In practice, an ethanol level is often obtained in these patients. A patient experiencing with- drawal symptoms with an elevated ethanol level will worsen with con- tinued metabolism of ethanol, thus requiring immediate management.

Standard treatment

Management for any patient with suspected alcohol withdrawal is Initial resuscitation and rehydration. Classic treatment of mild, moder- ate, and severe alcohol withdrawal is to administer GABA agonists [7, 8,15,20]. Benzodiazepines act as central GABA_A agonists, increasing the frequency of GABA-receptor channel opening. Benzodiazepines treat the Psychomotor agitation experienced by withdrawing alcoholics in addition to preventing progression to more serious withdrawal symptoms [7,8]. While benzodiazepines are one treatment option, there is debate regarding which benzodiazepine is most efficacious.

Several benzodiazepines available for treatment include diazepam,

Delirium tremens [5]

Begins 3 days after the appearance of withdrawal symptoms and lasts for 1 to 8 days

• Rapid-onset, fluctuating disturbance of attention and cognition plus alcohol withdrawal symptoms
• Diagnosis requires auto- nomic instability

lorazepam, midazolam, oxazepam, and chlordiazepoxide. Table 4 com- pares these agents in the treatment of AWS. For acute symptom control, many clinicians prefer intravenous (IV) diazepam or lorazepam, though Oral medications are acceptable for non-severe symptoms [5-9]. Diaze- pam has a faster onset of action compared to lorazepam, which may

Table 4

Benzodiazepines for AWS [5,6,8].

Drug Time to

onset

Diazepam	1-5 min IV	Yes	43 +- 13	10-20 mg IV
Lorazepam	5-20 min IV	No	14 +- 5	10-20 mg PO 2-4 mg IV
				2-4 mg PO
Midazolam	2-5 min IM/	Yes	2 +- 1	2-4 mg IM/IV
Oxazepam	IV 2-3 h PO	No	8 +- 2	15-30 mg PO every
Chlordiazepoxide	2-3 h PO	Yes	10 +- 3	8h 50-100 mg PO

Active metabolites?

Half-life (hrs)

Initial dose

peak onset of action. An initial infusion of 10 mg/kg IV over 30 min will reach predictable, therapeutic levels (15-40 ug/ml) [37-40].

Literature does support phenobarbital monotherapy in withdrawal and DT, though this is not commonly done due to the extensive use and efficacy of benzodiazepines. Kramp in 1978 compared oral barbital and diazepam, finding barbiturate to be superior, though numerous flaws were present in methodology [33]. In 1991 Ives evaluated pheno- barbital 15 mg/kg IV followed by a fixed protocol-based taper [37]. A 2010 study found equivalence between IV diazepam and oral phenobar- bital [16]. The subgroup of diazepam patients who failed treatment responded to phenobarbital [16]. Hendey in 2011 found similar results between IV lorazepam and IV phenobarbital [38].A study in 2013 eval- uated phenobarbital at 10 mg/kg IV with lorazepam based protocol ver- sus lorazepam based protocol alone, with a primary outcome of level of

allow for easier titration and avoidance of dose stacking [7,8,21]. This faster onset of action is due to increased blood brain barrier penetration. Diazepam also has active metabolites, nordiazepam (otherwise known as desmethyldiazepam) and oxazepam, with nordiazepam predomi- nantly extending the duration of sedating effects. Lorazepam does not have active metabolites, thus faster clearance. In the presence of ad- vanced cirrhosis or hepatitis (moderate elevations of AST/ALT (b 300 IU/ml), AST:ALT ratio N 2, elevated Serum bilirubin, elevated GGT, moderate leukocytosis (neutrophils), and elevated INR), the dura- tion of lorazepam and diazepam is extended due to hepatic metabolism. Oxazepam may be a better option in this setting due to the shorter half- life and absence of liver metabolites [6,8,26]. However, oxazepam is only available by mouth. Renal disease can cause significant prolonga- tion of diazepam action, as the active metabolite of diazepam undergoes predominantly renal clearance [7,8].

For patients with severe AWS, repeated escalating doses of IV diaze- pam (10, 20, 40 mg) or lorazepam (4, 8, 16 mg) are recommended [5,8, 15]. An escalating dose of diazepam can be given every 5-10 min as re- quired due to its rapid peak onset of action, while an escalating dose of lorazepam can be given every 15-20 min as required [5-9,22-25]. Both agents are efficacious in treating withdrawal. Provider choice of agent will likely depend on comfort with the medication and institution. Im- portantly, there is no maximum dose of benzodiazepines. Diazepam in doses of 500 mg IV initially and 2000 mg IV over 48 h have previously been provided [5,6,8].

Adjunctive treatment options and controversies

A small subgroup of patients may have benzodiazepine-resistant al- cohol withdrawal and DT. This has not been clearly defined in the liter- ature, but may be present if diazepam 50 mg or lorazepam 10 mg within the first hour, or if doses N 200 mg diazepam or 40 mg lorazepam within the three hours of treatment, fail to control symptoms [8,27]. Early ag- gressive treatment of these patients is warranted, including rapid esca- lation of doses of benzodiazepines [28,29]. If benzodiazepines are not effective, other treatment options are available, including phenobarbi- tal, propofol, ketamine, and dexmedetomidine [8,29-36]. Patients with refractory withdrawal and DT may require intubation for further evalu- ation and symptom control.

Phenobarbital

Benzodiazepines and phenobarbital are both efficacious in AWS management. However, while benzodiazepines increase the frequency of receptor opening, phenobarbital has dual activity through an increase in the duration of GABA-receptor opening and inhibition of glutamate receptor activity [8,16,30,33,36,38]. These two actions oppose alcohol withdrawal effects. Phenobarbital has an onset of action of approxi- mately 5 min, peaks at 20-30 min, and possesses a half-life of approxi- mately 3-4 days. Phenobarbital dosing can be accomplished several ways: infusion of 10-15 mg/kg IV or in 65, 130, or 260 mg IV boluses [16,30,37-40]. Phenobarbital is not readily titratable due to the delayed

admission [30]. The phenobarbital plus lorazepam group demonstrated decreased ICU admission rates by 17%, with no difference in adverse outcomes [30]. However, there are several limitations to this study. All patients received lorazepam infusion, and admission to ICU was based on the sole emergency medicine provider. No standardized protocol for admission was used, and inter-rater reliability of assessment was not measured. Providers used the Alcohol Withdrawal Clinical Assess- ment (AWCA) score, a simplified version of CIWA-Ar not validated for use [30]. This study requires further validation.

Despite the evidence suggesting safety of phenobarbital monothera- py, few providers utilize the benefits of this medication due to unfamil- iarity with the medication and institutional guidelines [16,33,37,38]. Combination therapy with benzodiazepines, particularly in the setting of benzodiazepine resistant withdrawal or DT, is efficacious and sup- ported in the literature [29,30,36,37-40]. If the patient in severe with- drawal is resistant to repeated doses of benzodiazepines IV, phenobarbital is recommended if available. Of note, phenobarbital may have significant effects on hemodynamic status, resulting in hypo- tension and respiratory depression, which increase when used with benzodiazepines. Phenobarbital does have lower therapeutic index compared to benzodiazepines. Patients receiving phenobarbital may re- quire intubation.

Propofol

Propofol potentiates GABA receptor activity and can also inhibit NMDA receptors, thus acting at several receptors to decrease withdraw- al effects [8,31,32,39-41]. Literature has evaluated several aspects of propofol for withdrawal and DT. Case series and trials have supported the use of propofol in refractory DT and withdrawal, particularly in pa- tients requiring intubation [39-46]. One study by Sohraby et al. evaluat- ed the time to symptom resolution in ventilated patients receiving propofol infusion versus benzodiazepine [44]. No difference was found in the primary outcome of days to symptom resolution, and length of stay was similar between groups [44]. Lorentzen in 2014 evaluated the viability of propofol infusion for withdrawal in 15 patients [45]. These patients all had received 1500 mg of benzodiazepines, 2000 mg of chlordiazepoxide, or 1200 mg of phenobarbital before propofol was initiated. Propofol was efficacious in 12 of 15 patients, with 3 needing further treatment [45]. If the patient reaches the point of requiring intu- bation due to treatment resistant DT, intubation should be completed with propofol induction [5-9,40-46]. Propofol induction and intubation will require further critical management in the ICU [44-47]. Current lit- erature supports the viability of propofol for patients with DT resistant to benzodiazepines. If using propofol, intubation is strongly recom- mended [41-46].

Ketamine

Ketamine is a NMDA antagonist, which may have a role in alcohol withdrawal, as alcohol use results in upregulation of NMDA receptors [8,35]. One study conducted in 2015 evaluated patients receiving an in- fusion of 0.20 mg/kg/h of ketamine IV [35]. No change in sedation or al- cohol withdrawal scores was found, but ketamine reduced the amount

of benzodiazepines received, from 40 mg to 13.3 mg [35]. Unlike dexmedetomidine, discussed next, ketamine does target the underlying pathophysiology in withdrawal states by depressing the CNS hyperexcitation state experienced by patients with AWS. Ketamine is readily available in the ED, and emergency physicians are familiar with its use. With appropriate dosing, Respiratory effects are limited [8,35]. Further study utilizing ketamine in AWS and DT is needed. Phe- nobarbital and propofol have more literature support than ketamine in benzodiazepine-resistant withdrawal, but ketamine is an option as an adjunctive medication.

Dexmedetomidine

A great deal of controversy surrounds the use of dexmedetomidine in alcohol withdrawal and DT. Dexmedetomidine is a centrally acting alpha-2-agonist that reduces sympathetic output, while providing ti- tratable sedation without affecting airway reflexes [8,34,47-52]. Of note, this agent is only recommended as an adjunct to benzodiazepines and phenobarbital or propofol. Several case series evaluated this medi- cation, followed by the first randomized trial in 2014 [47]. This trial studied lorazepam alone, versus lorazepam plus dexmedetomidine at

0.4 mcg/kg/h or 1.2 mcg/kg/h. Primary outcome included total benzodi- azepine dosing in 24 h. Lorazepam dosing was reduced in the dexmedetomidine group from 56 mg to 8 mg based on CIWA-Ar or Riker scale scores. However, the patients included in this study were randomized after 24 h of initial treatment, and eleven of 24 patients were already intubated. The primary outcome of reduction in benzodi- azepine use is unfortunately not a patient-centered outcome [47]. The second randomized trial in 2015 used a similar primary outcome of total benzodiazepine use in 24 h, with similar design [48]. Patients were divided into two groups, one receiving benzodiazepines with dexmedetomidine dosed at 0.2-1.4 mcg/kg/h titrated to RASS -2 to 0 versus diazepam dosed at 10 mg boluses IV based on symptoms, with median patient enrollment 24 h after hospital admission. A 20 mg de- crease in benzodiazepine dosing was found in the dexmedetomidine group. Bradycardia is a common event with dexmedetomidine, and in this study occurred in close to one third of patients in the dexmedetomidine group [48]. This known side effect of dexmedetomidine may or may not be beneficial to patients. A retro- spective controlled cohort study in 2016 found similar results with de- crease in total benzodiazepine use [49]. Frazee et al. found a reduction in heart rate, as well as a 20 mg decrease in benzodiazepine use in pa- tients given dexmedetomidine [50].

Dexmedetomidine may reduce the need for intubation and hospital length of stay, as demonstrated in a 2015 retrospective study [51]. This study evaluated dexmedetomidine and propofol and/or lorazepam. Two patients in the dexmedetomidine group required intubation, ver- sus 10 in the comparison group. ICU length of stay was also decreased [51]. Crispo et al. found no difference in rates of intubation or seizure in- cidence when dexmedetomidine was compared to benzodiazepine treatment, though increased incidence of bradycardia and hypotension was found [52]. Despite the increasing popularity of dexmedetomidine, this medication does not address the underlying pathophysiology of al- cohol withdrawal, as it lacks GABA activity. If used alone, it may increase the risk of further progressing AWS and seizures due to lack of GABA ac- tivity. Dexmedetomidine may prove useful as an adjunct to attenuate symptoms, but it does not replace benzodiazepines [52]. Providers should begin with benzodiazepines, followed by dexmedetomidine for symptom attenuation.

Other medications

Medications under study for alcohol withdrawal management in- clude ethanol, beta-blockers, anticonvulsants, alpha-2-agonists, anti- psychotics, and baclofen [8]. Ethanol is not recommended due to difficulty with titration, inferiority to benzodiazepines, and adverse events [53]. Beta blockers can reduce minor withdrawal symptoms but cannot treat seizures or DT. Patients taking beta blockers for

baseline conditions (cardiovascular disease) should be given their spe- cific beta blocker. Otherwise, beta blockers should not be used for treat- ment of severe withdrawal. Anticonvulsants are not required for treatment and have no role in patients with isolated withdrawal sei- zures [8,54]. Most seizures are self-limited. Evidence is lacking for carba- mazepine use in withdrawal. Antipsychotics including phenothiazines and butyrophenones lower the seizure threshold in withdrawal [8,55]. They should not be routinely used for withdrawal, though they may be beneficial in patients with known or suspected thought disorders (schizophrenia) [55]. Alpha-2-agonists including clonidine have been advocated, as they may reduce symptoms. However, they do not pre- vent seizures or DT and do not target the primary mechanism of with- drawal. Baclofen is a selective GABA-B receptor agonist for management of spasticity, but it is not recommended for withdrawal therapy [56,57].

Treatment target

targeted therapy is required for management of the patient with AWS. Treatment goals can utilize several components. Saitz et al. in 1994 validated symptom-triggered therapy [58]. This study was a ran- domized double-blind controlled trial comparing patients receiving chlordiazepoxide for AWS with either a fixed schedule or symptom- triggered therapy, finding patients in the symptom-triggered therapy group require less medication (median 100 vs. 425 mg) and a shorter treatment period (median 9 vs. 68 h) [58].

Several scales are available for symptom assessment and withdrawal severity. One of the most commonly utilized systems is the Clinical Insti- tute Withdrawal Assessment for Alcohol scale, revised (CIWA-Ar). Of note, alcohol withdrawal is a clinical diagnosis, and this scale is used for assessing the Severity of symptoms. This scale is scored based on pa- tient symptoms: nausea/vomiting, tremors, paroxysmal sweating, anx- iety, agitation, tactile disturbances, auditory disturbances, Visual disturbances, headache/head fullness, and orientation/clouding of sen- sorium [58-61]. The maximum score of the CIWA-Ar scale is 67. Mild withdrawal is defined by a score of 15 or less, moderate is 16-20, and severe withdrawal is a score N 20. For CIWA-Ar monitoring, evaluations as frequent as every 10-15 min will be needed in initial stages of man- agement. Once symptoms are under control, hourly reassessment with CIWA-Ar is effective [58-61].

If the patient is in severe withdrawal, including patients requiring endotracheal intubation, the CIWA-Ar scale cannot be assessed effec- tively [5-9,58-61]. optimal management in severe withdrawal can be measured with ICU sedation scales, such as the Richmond Agitation Se- dation Score (RASS) or the Riker Sedation Analgesia score. A RASS score of 0 to - 2 or Riker score of 3-4 is equivalent to a patient in a calm, arousable state [6-9]. As discussed, the use of benzodiazepines in rapidly escalating doses has been shown to reduce seizures, DT, and the need for mechanical ventilation in patients with severe AWS [6,8,28,29]. Uti- lization of the CIWA-Ar scale can be more labor-intensive than RASS, and for initial stabilization, scores based on RASS or Riker are less com- plicated in the ED.

The clinician at the bedside must monitor the patient’s status with treatment, as well as assess for other causes of patient decompensation and coexisting conditions, as discussed previously. For example, assum- ing all tachycardia is due to a withdrawal state may result in misdiagno- sis. Tachycardia may be due to hypovolemia, sepsis, heart failure, thyrotoxicosis, and many other etiologies. Failing to consider this can lead to increased morbidity and mortality. If tachycardia does not im- prove with treatment, other conditions should be considered.

Vitamin and electrolyte treatment

Nutritional support is an important adjunctive treatment in alcohol withdrawal. Thiamine is often deficient in these patients, increasing the risk of Wernicke’s encephalopathy [7,8,62,63]. Thiamine is a vital

component of carbohydrate metabolism, and deficiency leads to de- creased glucose utilization. Thiamine is a major cofactor in glucose me- tabolism, as several enzymes in the Krebs cycle that catalyze the oxidation of pyruvate, branched chain amino acids, and alpha- ketoglutarate require thiamine. The classic findings of altered mental status, ophthalmoplegia, and difficulty with ambulation is concerning for Wernicke’s encephalopathy. However, this full triad is present in one third of cases, requiring a high degree of suspicion [64]. The diagno- sis of Wernicke’s encephalopathy is missed in up to 80% of patients, with a mortality of 20% [65,66]. Any concern for Wernicke’s encephalopathy, for example patients unable to ambulate appropriately, requires thia- mine 500 mg IV or intramuscular every 8 h for three days and in- patient admission [67,68]. Thiamine by mouth is not well absorbed in alcoholic patients, and IV and IM routes offer higher levels of medica- tion, increasing bioavailability. Prophylaxis entails 100 mg IV [67,68]. folate supplementation is recommended due to nutritional deficiencies with 1 mg IV, as folate is depleted within days of last intake, leading to megaloblastic anemia [69]. Low dietary folate intake can cause anemia within 5 weeks in chronic alcoholics [70]. Hypokalemia is frequently en- countered, and repletion is necessary [71]. Magnesium and phosphate supplementation intravenously is not required on a routine basis [71]. If discovered on laboratory testing, supplementation may be beneficial, but more literature is required. B12 supplementation is not recom- mended on a regular basis [70]. In patients with withdrawal, thiamine and folate supplementation can be beneficial, and potassium repletion is recommended if the patient is hypokalemic [8].

Treatment summary

The treatment of alcohol withdrawal focuses on addressing the un- derlying pathophysiology of withdrawal, which will both alleviate the

patient’s symptoms and prevent progression to DT. Patients with AWS are in a state of CNS hyperstimulation due to loss of GABA inhibitory ef- fect, and thus the primary treatment is providing GABA agonism with benzodiazepines. Intravenous diazepam or lorazepam should be given at a starting dose of 10 mg or 4 mg as depicted in Fig. 1 with rapid esca- lation of dosing. Symptom-triggered administration of benzodiazepines is utilized, in which the frequency of therapy depends on the patient’s CIWA-Ar score. For patients in severe withdrawal, we recommend using an ICU sedation scale (either the Richmond Agitation sedation score or Riker Sedation Analgesia score) for initial stabilization in the ED. If Large doses of benzodiazepines are administered and the patient is still agitated and hyperdynamic, phenobarbital or propofol therapy is warranted. Phenobarbital can be given as an infusion of 10- 15 mg/kg IV or in 65, 130, or 260 mg IV boluses. Propofol also potenti- ates GABA receptors and is particularly useful as an induction agent in patients requiring intubation for withdrawal. If phenobarbital is not available or is inadequate in controlling withdrawal, we recommend utilizing propofol as an induction agent followed by propofol IV infu- sion. Patients receiving phenobarbital or propofol will likely require in- tubation. This algorithm for AWS management is provided in Fig. 1.

Other agents in the management of AWS include ketamine and

dexmedetomidine. Given the limited data on the use of these agents in AWS, these medications should only be used as adjuncts in treat- ment-resistant AWS and DT. An adjunctive treatment is nutritional sup- port. It is important to consider replenishing thiamine, folate, and potassium in every patient with AWS.

Disposition

Disposition of the AWS patient depends on accurate identification of the patient’s degree of withdrawal. Patients who have a mild CIWA-Ar

Fig. 1. Management of severe alcohol withdrawal syndrome.

Table 5

Disposition for AWS [6,36,72].

Discharge with detoxification referral

Inpatient detoxification or medical unit

• CIWA-Ar Score b 8
• Patient not currently intoxicated (alcohol or other drugs)
• No history of complicated AWS (seizures, halluci- nosis, DT)
• No significant medical or Psychiatric comorbidities
• Patient ability to comply with outpatient visits and therapy
• No underlying medical or surgical condition re- quiring ICU-level care
• Normalization or near-normalization of vitals within ED
• Clear sensorium
• Responsive to 10-20 mg diazepam
• Tolerates 2-4 h between benzodiazepine doses
• Presence of medical or psychiatric condition re- quiring inpatient admission

with symptom-triggered therapy have been the predominant medica- tion class utilized. Intravenous diazepam or lorazepam should be given at a starting dose of 10 mg or 4 mg, respectively, with rapid esca- lation of dosing utilizing symptom-triggered administration. Literature supports the use of phenobarbital if the patient is still hyperdynamic after receiving benzodiazepine therapy. Propofol can be used if pheno- barbital is not available or inadequate to control withdrawal. Ketamine and dexmedetomidine require further study. Many patients with AWS require thiamine and folate supplementation. Overall, benzodiazepines remain the cornerstone of treatment.

Conflicts of interest

None.

Intensive Care Unit - Cardiac disease (heart failure, arrhythmia, angina,

myocardial ischemia, recent myocardial infarction)

• • Hemodynamic instability
  • Severe electrolyte abnormalities (hypokalemia, hypophosphatemia, hypomagnesemia, hypocalce- mia)
  • Respiratory insufficiency (hypoxemia, hypercapnia, severe hypocapnia, pneumonia, asthma, COPD)
  • Potential serious infections (wounds, pneumonia)
  • Signs of gastrointestinal pathology (pancreatitis, GI bleeding, hepatic insufficiency, suspected peritoni- tis)
  • Persistent hyperthermia (T N 39C [103F])
  • Evidence of rhabdomyolysis
  • Renal insufficiency or increased fluid requirements
  • History of prior alcohol withdrawal complications (eg, DT, seizure)
  • Need for frequent or high doses of sedatives of an intravenous infusion to control symptoms
  • Withdrawal despite an elevated ethanol concentration

score and are not currently intoxicated may be considered for discharge. On the other end of the spectrum, patients with severe AWS or medical comorbidities will need ICU admission [5,6,8,24,58-61]. Table 5 outlines aspects to consider in the disposition of patients with AWS.

Role of adjunctive treatments for discharged patients

outpatient treatment for detoxification can be difficult. Patients often experience significant craving due to complex pathways involved in dopaminergic and opioid center dysregulation [24,36,73,74]. Patients may experience obsession and intrusive thoughts through serotonin de- ficiency. Benzodiazepines do not treat this aspect of detoxification effi- ciently. Thus, many patients cannot detoxify on their own. Outpatient detoxification requires several aspects including a CIWA-Ar score b 15, no symptoms of delirium tremens or seizures, ability to take oral med- ications, presence of a family member or close contact who is able to stay with the patient, no unstable medical condition, no psychosis or suicidality, and ability to commit to daily medical visits [36,73-75]. In order to be discharged, patients must have adequate follow up. Medica- tions available include oral benzodiazepines, chlordiazepoxide, and an- ticonvulsants. Outpatient therapy is outside the scope of this review.

Conclusions

Due to the widespread prevalence of alcohol use, disorders involving alcohol withdrawal are common. Alcohol withdrawal syndrome may result in morbidity and mortality, thus requiring early recognition and management. Stages of withdrawal include withdrawal symptoms, hal- lucinations, seizures, and delirium tremens. Treatment of AWS focuses on providing medications with GABA receptor activity. Benzodiazepines

Acknowledgements

This manuscript did not utilize any grants, and it has not been pre- sented in abstract form. This clinical review has not been published, it is not under consideration for publication elsewhere, its publication is approved by all authors and tacitly or explicitly by the responsible au- thorities where the work was carried out, and that, if accepted, it will not be published elsewhere in the same form, in English or in any other language, including electronically without the written consent of the copyright-holder. This review does not represent the views or opinions of the U.S. Army, U.S. Air Force, Department of Defense, or the SAUSHEC Emergency Medicine Department.

DL, BL, and AK conceived the topic idea, completed the literature re- view, and drafted the manuscript. BL and AK assisted with editing and further refining the manuscript. References were confirmed by DL, BL, and AK.

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