Alcohol Withdrawal

Alcohol Withdrawal / Delirium tremens
Delirium tremens:
The criteria for withdrawal delirium are delirium (a rapid-onset fluctuating disturbance of attention and cognition, sometimes with hallucinations) plus alcohol withdrawal.
Clinical features:
Most common signs and symptoms of alcohol withdrawal are tremors, autonomic hyperreactivity ( fever, tachycardia, sweating, tachypnea, elevated blood pressure) , GI upset, nausea, anxiety, irritability, disorientation, psychomotor agitation, hallucinations and seizures.
Most common signs and symptoms of delirium tremens are decreased attention, disturbances in visuo-spatial ability, disturbances in memory and orientation, absence of any other neurocognitive disorders. Profound global confusion is the hallmark of delirium tremens.
Timing of symptoms:
Because of the short action of ethanol (beverage alcohol), withdrawal symptoms usually begin within 6-8 hours after blood alcohol levels decrease, peak at about 72 hours, and are markedly reduced by days 5-7 of abstinence. The rate of drop in alcohol level is more important in inducing withdrawal symptoms than the absolute alcohol level.
Withdrawal delirium usually begins about 48-72 hours after last drink and can last up to 2 weeks, but typically 1-5 days. A graph depicting the time course of alcohol withdrawal symptoms is shown below.
Alcohol is a CNS depressant, influencing the inhibitory GABA receptors. Ordinarily, the excitatory (glutamate) and inhibitory (GABA) neurotransmitters are in a state of homeostasis. In the long-term, alcohol causes a decrease in the number of GABA receptors (down regulation). This results in the requirement of increasingly larger doses of ethanol to achieve the same euphoric effect, a phenomenon known as tolerance. Alcohol also acts as an N-methyl-D-aspartate (NMDA) receptor antagonist, thereby reducing the CNS excitatory tone. Chronic use of alcohol leads to an increase in the number of NMDA receptors (up regulation) and production of more glutamate to maintain CNS homeostasis.
With the sudden cessation of alcohol in the chronic user, the alcohol mediated CNS inhibition is reduced and the glutamate mediated CNS excitation is left unopposed, resulting in a net CNS excitation. This CNS excitation results in the clinical symptoms of alcohol withdrawal in the form of autonomic over activity such as tachycardia, tremors, sweating and neuropsychiatric complications such as delirium and seizures
Thus, alcohol withdrawal is due to inadequate inhibitory GABA activity combined with excessive excitatory glutamate activity.  
Phenobarbital and diazepam both bind to the GABA receptor in different locations.  Benzodiazepines increase the frequency of GABA-receptor channel opening, whereas phenobarbital increases the duration of channel opening.  Therefore, these drugs may act synergistically.  
In addition to affecting the GABA receptor, phenobarbital also inhibits glutamate receptors.  By simultaneously enhancing GABA activity and inhibiting glutamate activity, phenobarbital perfectly reverses the pathophysiology of alcohol withdrawal.  This could help explain why some patients fail to respond to benzodiazepines but subsequently respond well to phenobarbital. 
CIWA protocol: It is a tool used commonly in the US that helps clinicians assess and treat potential alcohol withdrawal. The CIWA scale has well-documented reliability, reproducibility and validity, based on comparison to rating by expert clinicians. It was developed in 1981, modified in 1989 but hasn’t been challenged since then. J Clin Psychopharmacol. 1981 Nov;1(6):382-89
Symptom triggered therapy has been shown to have better outcomes than fixed benzodiazepine scheduling in managing alcohol withdrawal. Arch Intern Med. 2002 May 27; 162(10):1117-21. The CIWA score is a widely cited method of using symptom triggered therapy.
The Clinical Institute Withdrawal Assessment measures 10 items that are associated with withdrawal:
  • Nausea / vomiting
  • Anxiety
  • Paroxysmal sweats
  • Tactile disturbances (itching, bugs crawling on skin, etc)
  • Visual disturbances
  • Tremors
  • Agitation
  • Orientation
  • Auditory disturbances
  • Headache
All items are measured on a scale of 0-7 with the exception of orientation, which uses a scale of 0-4. All subscores are tallied to arrive at the final score. 
Scores of less than 8 indicate mild withdrawal. Scores of 8-15 indicate moderate withdrawal (marked autonomic arousal); and scores of 15 or more indicate severe withdrawal. Typically, a score of less than 8-10 doesn’t need any treatment. Once it is exceeded, graduated doses of benzodiazepine or phenobarbital are given and vital signs + CIWA scores are repeated regularly. The protocol is discontinued once the patient has three determinations that are under the threshold.
A simple tool to calculate CIWA score can be found here.
CIWA limitations:
Because accurate application of CIWA scores requires taking a detailed medical history, it is dependent on patient’s ability to answer questions and follow commands. It should not be used when a substantial language barrier exists, or when patients cannot provide a reliable history because of delirium, dementia, psychosis, etc.  
An important limitation of the CIWA is its heavily subjective nature. Only, 3 of 10 components (tremor, paroxysmal sweats, and agitation) can be rated by observation alone. The other 7 components require at least some discussion with the patient. If two people were to assess the same patient, both of them could come up with different scores, especially if patient is not a good historian. CIWA might not always be a reliable tool in the management of alcohol withdrawal. Can Fam Physician. 2017 Sep; 63(9): 691–695.
A lot of times, patients are misdiagnosed to have alcohol withdrawal symptoms without giving a consideration for any alternative diagnoses. In one of the studies at Mayo clinic, less than 50% of the patients who met the CIWA criteria has true alcohol withdrawal. Mayo Clin Proc. 2008 Mar;83(3):274-9
The CIWA score also does not address any vital signs abnormalities, use of adjuvant medications and underlying medical conditions (renal failure, liver failure, respiratory failure, cardiac disease, age, etc.)
In the ICU, RASS score should be used in conjunction with the CIWA score for all patients receiving sedation for alcohol withdrawal in the ICU. 
CIWA vs SAS (Sedation-Agitation scale):
A symptom-triggered benzodiazepine protocol utilizing SAS in critically ill patients is associated with a reduction in the duration of alcohol withdrawal treatment, benzodiazepine exposure, need for mechanical ventilation, and ICU and hospital LOS compared with a CIWA based protocol using fixed benzodiazepine dosing. Ann Pharmacother. 2017 Feb;51(2):101-110
  1. Chlordiazepoxide (Librium): Initial dosing is 50-100mg oral. Longer duration of action (and active metabolites) may decrease rate of breakthrough symptoms and have an added auto tapering effect. Half-life is up to 48 hours.
  2. Lorazepam (Ativan): Initial dosing is 2-4mg IV. Slower in onset and may lead to iatrogenic over-sedation if titrated too rapidly. Preferred over diazepam in the presence of COPD, hepatic dysfunction (INR >1.6) and/or renal dysfunction and/or age >65 years. Lorazepam infusions carry risk of propylene glycol toxicity with metabolic acidosis and renal failure. Half-life is around 12 hours.
  3. Diazepam (Valium): Initial dosing is 5-10mg IV. Diazepam has a very rapid onset and therefore is preferred for rapid titration in severe cases. It is also very long acting with a half-life up to 48 hours.
In general, long-acting benzodiazepines with active metabolites (eg, diazepam or chlordiazepoxide) are preferred because they seem to result in a smoother course with less chance of recurrent withdrawal or seizures.  Short acting agents (Ativan) are preferred in patients with advanced cirrhosis or acute alcoholic hepatitis. The shorter half-life and the absence of active metabolites with lorazepam may prevent prolonged effects if over sedation occurs.
Its recommended avoiding more than 166 mg/day lorazepam (7 mg/hour infusion) or 832 mg/day diazepam.  Adjunctive phenobarbital reduces the requirement for benzodiazepine, rendering propylene glycol intoxication less likely. 
There is little data comparing benzodiazepines to barbiturates.  A strategy of escalating doses of benzodiazepines and phenobarbital administration reduces the need for mechanical ventilation in delirium tremens. Crit Care Med. 2007 Mar;35(3):724-30. , J Trauma Acute Care Surg. 2014 Dec;77(6):938-43 
Phenobarbital is an effective alternative treatment to benzodiazepines in the treatment of severe alcohol withdrawal. J Investig Med High Impact Case Rep. 2017 Nov 3;5(4):2324709617742166
Phenobarbital monotherapy is extremely simple, as it amounts to a dose-titration using a single medication.  Phenobarbital has a half-life of about three days, so successive doses will accumulate in an additive fashion.  The main requirement for using phenobarbital is patience, because it may take some time to reach an effective level.  However, this time investment is worth it, because once a therapeutic level is reached, little additional therapy may be needed (the phenobarbital will gradually auto-titrate off, providing therapy for days).  
Intravenous phenobarbital takes effect over 20-30 minutes, and therefore can be given every thirty minutes without causing dose-stacking. Subsequently, it has an enormous half-life of about 4 days.  This long half-life is helpful because it allows the drug to auto-taper, decreasing risk of rebound symptoms. Also, a subset of patients with severe withdrawal will fail to respond to benzodiazepines, yet will subsequently respond to phenobarbital. 
The clinical effect of phenobarbital alone is more predictable. Phenobarbital administration elicits very predictable serum level of drug. In the absence of confounding factors (e.g., benzodiazepines, other neurologic problems), the safe level of phenobarbital is well established.  For most patients who are initially presenting with alcohol withdrawal, 10 mg/kg of phenobarbital may be given.  This dose will produce a serum level of phenobarbital around 15-25 ug/ml, which by itself isn't nearly enough to cause respiratory suppression. 
Plasma therapeutic range for phenobarbital  is 15-40 ug/ml. Mild signs of toxicity are usually noted such as ataxia and nystagmus at levels > 50 ug/ml, and stupor or coma at levels >65 ug/ml. There was a linear correlation between phenobarbital dose and concentration in alcohol withdrawal patients. 
Treatment algorithm for phenobarbital:  

Ref: Taken from

Dexmedetomidine (Precedex):
An α2 -adrenergic agonist that is used to produce a state in which the patient is sedated but arousable, with decreased sympathetic tone. Rapid bolus can precipitate hypotension and bradycardia.
Dexmedetomidine's ability to provide titratable sedation without affecting airway reflexes could make it useful.  However, dexmedetomidine doesn't address the underlying neurobiology of alcohol withdrawal, leading to a potential danger of masking symptoms without truly treating the disease.  
Propofol: In patients who do not respond to the above therapies, profol has been used with some success. However, Propofol may not treat the underlying withdrawal syndrome.
Other medications:
Beta-Blockers, clonidine, carbamazepine (up to 800mg per day), and antipsychotics may be used as adjunctive therapy but are not recommended as monotherapy. JAMA. 1997 Jul 9;278(2):144-51.
  • Thiamine deficiency: Chronic thiamine deficiency can cause biochemical changes in the brain and Wernicke’s encephalopathy – and if Wernicke's goes untreated, it can cause the structural lesions and permanent brain damage of Korsakoff syndrome (also known as wet brain – a permanent condition of memory loss/amnesia).
  • Why alcoholics needs thiamine supplementation: Healthy adults need between 1-2 mg of thiamine from dietary sources on an average daily basis and the body stores between 30 to 50 mg of thiamine in the liver to act as a buffer for temporary shortfalls of this essential vitamin. Over time, heavy drinkers may deplete thiamine in the liver as they fail to take adequate thiamine from dietary sources. Chronic alcoholism also impair the gut ability to absorb thiamine properly. Alcohol damage reduces the liver's thiamine holding capacity (and this is a progressive reduction – as damage worsens, thiamine capacity declines). Liver damage also reduces the liver’s ability to activate thiamine to thiamine pyrophosphate, which is an enzyme co-factor. Heavy alcohol use also impairs cells ability to use the thiamine that is absorbed.  

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