barcelona . spain - European Association for the Study of the Liver

BARCELONA . SPAIN
94 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE 95
APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESS TM 2012
MECHANISMS OF AWS
The pathophysiology of AWS is related to the effects of alcohol upon neurotransmitters in the central
nervous system. Prolonged alcohol exposure leads to a down-regulation of gamma-aminiobutyric acid
type-A (GABAA) receptors and an up-regulation of N-methyl-D-aspartate (NMDA), which leads to the
development of tolerance. During withdrawal there is reduced GABAergic transmission, enhanced NMDA,
glutaminergic and adrenergic transmission and dysregulation of dopaminergic transmission. Repeated
detoxification may lead to a ‘kindling’ effect with increased neuronal responsivity and increased severity
of AWS and risk of seizures. The mainstay of treatment of AWS remains benzodiazepine therapy. These
drugs enhance GABA activity and counteract adrenergic hyperactivity. The use of benzodiazepines also
seems to reduce the kindling effect of repeated withdrawal.
DRUG THERAPY FOR AWS
On meta-analysis however the evidence suggests that benzodiazepines are only better than placebo in
preventing alcohol withdrawal seizures. However the quality of the published trials is sub-optimal and
clinical experience indicates that benzodiazepines have a more generalized beneficial effect in AWS.
For most patients with AWS it is recommended that long-acting benzodiazepines such as diazepam or
chlordiazepoxide are used. These agents allow a smoother course of withdrawal. Diazepam is also more
lipophilic allowing rapid central nervous system distribution, however this feature also leads to re-distribution
to peripheral fat in a less predictable fashion. Both diazepam and chlordiazepoxide require oxidation in the
liver to produce active metabolites which themselves have long half-lives. This complex metabolism is
impaired in liver disease with reduced hepatic oxidative capacity. Unpredictable metabolism and erratic
drug accumulation can lead to enhanced sedation in patients with significant liver dysfunction.
For this reason lorazepam is preferred in liver disease patients. This shorter acting benzodiazepine
undergoes hepatic glucuronidation which is reasonably well preserved in the damaged liver. It is metabolized
to an inactive product. In studies lorazepam has been shown to be equally effective to chlordiazepoxide
in the management of AWS and is regarded by some s the drug of choice for the management of alcoholrelated
seizures. In severe cases of AWS neuroleptic agents such as haloperidol can be used, ideally in
conjunction with benzodiazepines. Chlorpromazine is best avoided as it lowers the seizure threshold. In
patients with severe AWS it is necessary that there is adequate nursing supervision to monitor response to
treatment and to ensure that patients do not become over-sedated and put at risk of aspiration pneumonia
amongst other possible complications. In extreme cases patients may require full general anaesthesia in
an intensive care setting to manage their symptoms.
METHOD OF DRUG ADMINISTRATION
The method of administration of benzodiazepines in AWS is controversial. Many units adhere to fixed dose
treatment (FDT) regimens with set initial doses of treatment and subsequent reductions over a fixed period
of time. However symptom-triggered treatment (STT) has been shown to reduce the duration and amount
of benzodiazepine therapy given for AWS. The most commonly used STT instrument is the Clinical Institute
of Withdrawal Assessment for Alcohol (CIWA-Ar). However the majority of studies investigating STT and
comparing it with FDT have been set in specific alcohol detoxification units. There are few studies assessing
CIWA-Ar in general hospital settings, and those that have frequently exclude patients with complex medical
co-morbidity such as significant liver disease. Whilst an effective tool when used appropriately, the CIWA-Ar
is cumbersome and is difficult to administer at the appropriate time intervals in a general ward setting. One
study auditing the use of a CIWA-Ar based STT in clinical practice found that it was initiated inappropriately
in 52% of cases. On multivariate analysis the presence of liver disease was the only significant factor
associated with inappropriate treatment.
(Modified) Alcohol Withdrawal Score (GMAWS) which is less time consuming and easier to administer
in a general ward setting (data awaiting publication). However there are exceptions to this approach. In
particular patients with evidence of significant liver disease are managed specifically by STT (GMAWS)
with lorazepam.
ALTERNATIVES TO BENZODIAZEPINE THERAPY
Carbemazepine prescribed in a reducing FDT fashion has been shown to be effective in managing AWS in
some studies, however on meta-analysis the benefit is questionable and there is no evidence of superiority
over benzodiazepines. Gamma-hydroxybutyrate (GHB) may be more effective than placebo in managing
AWS but again does not appear to offer any advantage over benzodiazepines. Baclofen is another drug
with potential in the management of AWS and the lack of sedating side-effects make this drug especially
appealing in patients with ALD. A greater evidence base is required before these drugs can be recommended
in the routine management of AWS.
DIFFERENTIAL DIAGNOSIS
Confusion, disorientation and agitation have a broad differential diagnosis amongst heavy drinking patients
with liver disease. Care must be taken to differentiate between acute alcohol intoxication, intoxication
from other substances, hepatic encephalopathy, Wernicke’s encephalopathy as well as AWS. A good
clinical history (if obtainable) plus blood alcohol concentration and urine toxicology assessment will help to
differentiate some of these presentations. Clinical signs such as asterixis or opthalmoplegia/nystagmus will
also point to an alternative diagnosis. Clearly the prescription of benzodiazepines to patients with hepatic
encephalopathy may be detrimental and so close observation of patients with liver disease treated for
AWS is essential. Treatment of Wernicke’s encephalopathy with intravenous thiamine and correction of
hypomagnesaemia is generally safe and should be considered in all patients presenting in this fashion.
Figure 1: The FAST Screening Tool
1. MEN: How often do you have EIGHT or more drinks on one occasion
WOMEN: How often do you have SIX or more drinks on one occasion
Never
0 Less than monthly 1 Monthly 2 Weekly 3 Daily or almost daily 4
2. How often during the last year have you been unable to remember what happened the night
Before because you had been drinking
Never
0 Less than monthly 1 Monthly 2 Weekly 3 Daily or almost daily 4
3. How often during the last year have you failed to what was normally expected of you because of drinking
Never
0 Less than monthly 1 Monthly 2 Weekly 3 Daily or almost daily 4
4. In the last year has a relative or friend, or a doctor or other health worker been concerned
about your drinking or suggested you cut down
No
0 Yes, on one occasion 2 Yes, on more than one occasion 4
FAST≥3 indicates hazardous drinking behavior.
In the light of this we stratified the majority of AWS patients into those a standard risk of severe withdrawal
and those at high risk of severe withdrawal. Standard risk patients receive STT, whilst high risk patients
receive FDT plus STT. Risk is assessed by the presence of high initial symptom score, high FAST score,
history of alcohol related seizures and/or severe AWS in the past. Instead of CIWA-Ar we use the Glasgow