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Three Part Question

In [patients with alcohol related thiamine deficiency]
Is [oral thiamine better than parenteral thiamine]
As [Prophylaxis against development of Wernicke’s Encephalopathy]?

Clinical Scenario

32 years old chronic alcoholic patient was brought in the Emergency department with symptoms of withdrawal from alcohol, as he did not drank for last few days, in an attempt to stop drinking without taking medical advice. Patient been shivering, sweating, had some epigastric pains, stomach cramps, nausea & sickness. After getting intravenous access, taking routine blood sample and giving him Librium (chlordiazepoxide), he got stabilized; you wonder whether oral thiamine and multivitamin supplements are better compared to intravenous thiamine and multivitamins, in order to avoid development of Wernicke – Korsakoff Syndrome?

Search Strategy

Ovid MEDLINE(R) <1950 to March Week 5 2010>

The Cochrane Library; Cochrane Database of Systematic Reviews (Cochrane Reviews), Cochrane Central Register of Controlled Trials (Clinical Trials) 1950 – 2010
Mesh words
Thiamine deficiency

wernicke's encephalopathy.mp. or exp Wernicke Encephalopathy/ OR vitamin B1.mp. or exp Thiamine/ OR exp Thiamine Deficiency/ or exp Thiamine/ or exp Vitamin B Complex/ or oral thiamine.mp. or exp Wernicke Encephalopathy/
AND
exp Alcohol Withdrawal Seizures/ or exp Psychoses, Alcoholic/ or exp Alcohol Withdrawal Delirium/ or alcohol withdrawal.mp.

limits to (english language and humans and yr="1950 -Current")

Search Outcome

MEDLINE: 98 papers found, of which 2 were relevant.

10 Cochrane reviews, out of which 1 were relevant

50 clinical trials, none relevant

2 further articles found in references of other articles.

Total 5 articles were critically appraised.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Ed Day et al 2008 UK	(Cochrane Review) Randomized controlled trials (RCTs) in which treatment with thiamine or thiamine-containing products was administered and compared with alternative interventions for people with or at risk of developing, Wernicke-Korsakoff Syndrome (WKS) secondary to alcohol abuse. (The specialist Register of Cochrane dementia and Cognitive Improvement Group (CDCIG) was searched upto December 2005. The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS were searched separately from December 2005 to January 2008). 2-studies identified but only one contained sufficient data for quantitative analysis.	Level 1a : Systematic review and meta-analysis	Learning and memory	Ambrose 2001, 200 mg/day thiamine (i.m.) vs 5mg/day. MD – 17.90 95% CI – 35.4 to -0.40 P = 0.04	One study had sufficient data for qualitative analysis; the other study (Nichols et al unpublished) had insufficient data for full analysis. Even in study which is analysed (Ambrose 2001) 25% dropped out and focus on group without the classical triad of symptoms of WKS. Delayed alteration test, used as main outcome in Ambrose 2001 but there is no report how this was done. Assessment of further outcomes has not been described in this study as well. Nichols et al (unpublished) results undermined by small number of participants and limited reporting of data. Also it describes the group with history of chronic alcohol abuse and evidence of neuropsychological memory impairment but did not describe the presence or absence of other symptoms of WKS.
			Global Confusional state, nystagmus, ataxia, gaze palsies.	Ambrose 2001, did not report the effect of thiamine treatment on these outcomes.
			Deaths	Ambrose 2001, No deaths reported.
			Adverse effects	Ambrose 2001, No adverse effects recorded
				Nichols et al (unpublished) used Buschke CLTR and delayed Recall when compared with baseline in groups treated with thiamine 5 g/day orally showed significant improvements. Participants in placebo group failed to show improvement in any measures.
Thomson A.D. et al 2002 UK	Recommendations from Royal College of Physicians for management of patients in the Accident and Emergency (A&E) who may possibly have or are at risk of developing, Wernicke’s Encephalopathy (WE). There is no simple blood test to determine patients at risk of WE.	Guidelines	Patients with evidence of chronic alcohol misuse and any of following: Acute confusion, Decreased conscious level, Ataxia, Ophthalmoplegia Memory disturbance, Hypothermia with hypotension	Intravenous (i.v.) vitamin B complex (Pebrinex) 2 pairs of vials should be given over 30 minutes in A&E.
				If patient is admitted, consider 2 pairs of vials 3 times daily for 2 days, (if any improvement), followed by one pair daily for 5 days (i.v. or i.m.)
			All hypoglycaemic patients with chronic alcohol ingestion must be given i.v.Pebrinax immediately because of precipitating WE
Cook C.C. 2000 UK	Author compares the oral and Parenteral vitamins supplements for prophylaxis and effective treatment of Wernicke’s Encephalopathy	Level 5: Journal article (Expert opinion based on physiology, bench research)	Recommendation based upon published literature; Prophylaxis of WE.	1. Prophylactic treatment should be offered to all inpatients undergoing alcohol withdrawal.	Literature review of same subject an year before this article & recommendations for prophylactic & treatment of WE
				2. Recommended prophylaxis against development of WE, one pair of i.m. high potency parenteral B-complex vitamins once daily for 3-5 days (Bligh and Madden, 1983).
Hope et al 1999 UK	Questionnaires sent in January 1997 to 1598 UK physicians involved in chronic alcohol misusers. Questionnaires designed to elicit current practice, involvement, and opinions about management of chronic alcohol misusers.	Questionnaire Survey	Vitamin B1 (Thiamine) important in treatment of chronic alcohol abusers	88% Psychiatrists vs 54% A&E specialists	The response rate was low (25%), which hardly represents the full spectrum of population of interest. High level of non-response by A&E specialists which is leading to bias results. Study was unable to establish the practice regarding the dosage levels given in treatment.
			Route of administration for Vitamin B	Oral vs Parenteral
			In chronic alcohol misusers	Psychiatrists 66% vs 9% (20% preferred both oral & parenteral routes) A&E 14% vs 35% (10% preferred both)
			In patients at risk to develop WE.	Psychiatrists 7% vs 76% (4% preferred both routes) A&E 2% vs 53% (0% preferred both)
			Restricting the use of parenteral vitamin B because of allergy or anaphylaxis	Psychiatrists 70% vs A&E 18%
			Parenteral vitamin B complex in chronic alcoholic patients presenting with -Confusion	Psychiatrists 19% vs A&E 4%
			 -Ataxia	Psychiatrists 19% vs A&E 6%
			 -Ophthalmoplegia	Psychiatrists 22% vs A&E 9%
Cook CC et al 1998 UK	This review evaluates the research literature, B vitamins in the aetiology and treatment of neuropsychiatric syndromes associated with alcohol misuse, with particular emphasis on Wernicke’s Encephalopathy; and makes recommendations for clinical management of such patients.	Level 2a: Systematic review of literature	Prevalence of Wernicke’s Encephalopathy (WE) in alcoholics (post-mortem	Torvik et al., (1982) 12.5%	No qualitative analysis only literature review done. Review included neuropsychiatric conditions associated with alcohol misuse; not focussed on WE or WKS.
			Incidence of WE and /or Cerebellar atrophy	Torvik et al., (1982); Victor et al., (1989) Appx. 35%.
			Parenteral vs Oral B vitamin supplementation	Thomson et al., (1970); Greenwood et al.,(1985b); Thomson (1990); In malnourished alcoholics the oral absorption of thiamine is reduced (30% compared to healthy individuals ie. Maximum 1.5mg of thiamine can be absorbed from a single dose of 10mg or more. Chataway and Hardman, (1995); described development of WE in alcoholics on oral high dose vitamin B supplements. Baines et al., (1988); oral 50mg thiamine vs i.m. 250 mg thiamine daily for 5 days, The levels of thiamine were more elevated in group which received thiamine i.m. Baker and Frank, (1976); Thomson et al (1983); showed that in contrast to parenterally administration, oral administration neither elevate thiamine activity in cerebrospinal fluid nor restored transketolase activity, in alcoholics with thiamine deficiency.
			Prophylaxis of WE in alcoholics	Majumdar, (1980); Prophylactic regime of one pair of high potency vitamin B complex once daily for 5 days in at risk alcoholics undergoing detoxification; was clinically effective in preventing the development of WE.

Comment(s)

Wernicke’s Encephalopathy (WE), first described by Carl Wernicke in 1881, is characterised by clouding of consciousness (acute confusion/delirium), ocular signs (nystagmus, ophthalmoplegia) and ataxia of gait, occurring in various combinations, due to deficiency of vitamin B1, thiamine (also known as aneurin). The guidelines and recommendations published in 2002 by Royal College of Physicians for management of patients at risk of developing Wernicke’s Encephalopathy in Accident & Emergency (A&E) department offers assistance to physicians in appropriate management of this common clinical problem. The only available intravenous treatment in UK, which includes thiamine (B1) is Pabrinex. All patients presumed to have Wernicke’s Encephalopathy or at risk of developing Wernicke’s Encephalopathy should receive two pairs of vials of Pabrinex in 100 ml of crystalloid i.v. over 30 minutes initially in A&E. If the patient is admitted than two pairs of vials three times daily for 2 days i.v. to be followed (if any improvement), one pair per day for 5 days (i.v. or i.m.). Effective treatment and prophylaxis may only be achieved by use of parenteral vitamin supplements, since oral supplements are not absorbed in significant amounts. In chronic alcohol misusers malnutrition can reduce intestinal thiamine absorption and alcohol itself decrease the absorption as well. Although there are rare anaphylactic reactions associated with the use of parenteral thiamine preparations, the risks and consequences of inadequate prophylaxis and treatment, in appropriately targeted groups of patients, are far greater. It is therefore proposed that all in-patient alcohol withdrawal should be covered by prophylactic use of parenteral thiamine, that there should be a low threshold for making a presumptive diagnosis of Wernicke’s Encephalopathy. If inadequately treated with thiamine leads to irreversible structural changes producing loss of short term memory and impaired ability to acquire new information.

Clinical Bottom Line

Parenteral vitamin supplementation provides a safe and effective form of prophylaxis and treatment against Wernicke’s Encephalopathy.

References

1. Ed Day et al Thiamine for Wernicke-Korsakoff Syndrome in people at risk from alcohol abuse The Cochrane Library, The Cochrane Collaboration 2008; issue 4
2. Thomson A.D. et al THE ROYAL COLLEGE OF PHYSICIANS REPORT ON ALCOHOL: GUIDELINES FOR MANAGING WERNICKE’S ENCEPHALOPATHY IN THE ACCIDENT AND EMERGENCY DEPARTMENT Alcohol & Alcoholism 2002; Volume 37, Issue 6, pages 513 – 521
3. Cook C.C. Prevention and Treatment of Wernicke – Korsakoff Syndrome Alcohol & Alcoholism 2000; Volume 35, Issue 1, pages 19 – 20.
4. Hope L. C. et al A Survey of the Current Clinical Practice of Psychiatrists and Accident and Emergency Specialists in the United Kingdom concerning vitamin supplementation for chronic alcohol misusers Alcohol & Alcoholism 1999; Volume 34, Issue 6, pages 862 – 867
5. Cook CC et al B Vitamin Deficiency and Neuropsychiatric syndrome in Alcohol Misuse Alcohol & Alcoholism 1998; Volume 33, Issue 4, pages 317 – 336.