Purchena en la Historia Noticias históricas sobre la comarca.

►

Test of working memory (delayed alternation task):

There was a significant difference between dosage groups in the number of trials taken to reach the alternation task criterion, p=0.047, with 50 mg thiamine treatment group needing the fewest trials (38) to reach the criterion and the 20mg treatment group needing the most (56).

Although the 50mg treatment group appeared to require fewer trials, post-hoc comparisons made between the 50mg group and the other treatment groups were non-significant (5 versus 50 mg p=0.166; 20 versus 50mg p=0.043; 100 versus 50mg p=0.090; 200 versus 50mg p=0.561; critical alpha for all

comparisons 0.013)

A comparison between the 200mg treatment group and the mean of the other dosage groups was significant, p=0.031

68

►

The initial study by Wood et al.66 _{reported on change in clinical characteristics}

admission and follow-up after treatment with thiamine hydrochloride. See

Table 2-17 and Table 2-18 below.

Level 3

Table 2-17.

On admission and discharge (N=32)

Outcome On admission At discharge RR (95% CI) P value Ophthalmoplegia 30/32 (94%) 2/32 (13%) 15.00 (3.91, 57.57) <0.001 Nystagmus 29/32 (91%) 26/32 (81%) 1.12 (0.91, 1.36) 0.29 Long-term memory deficit 28/31 (90%) 18/31 (58%) 1.56 (1.13, 2.14) <0.01 Short-term memory deficit 30/30 (100%) 24/29 (83%) 1.20 (1.01, 1.44) <0.05

94 Peripheral neuropathy: Muscle weakness 16/31 (51%) 6/30 (20%) 2.58 (1.17, 5.70) <0.05 Reflex impairment 30/32 (94%) 27/30 (90%) 1.04 (0.90, 1.21) 0.59 Sensory impairment 22/31 (71%) 17/30 (57%) 1.25 (0.85, 1.84) 0.25 Table 2-18.

At discharge and at last visit (N=27)

Outcome At

discharge

At last visit RR (95% CI) P value

Ophthalmoplegia 4/22 (15%) 2/27 (15%) 2.45 (0.49, 12.17) 0.27 Nystagmus 22/27 (82%) 21/27 (78%) 1.05 (0.80, 1.37) 0.74 Long-term memory deficit 14/26 (54%) 21/26 (81%) 0.67 (0.45, 1.00) 0.05 Short-term memory deficit 17/24 (71%) 24/26 (92%) 0.77 (0.58, 1.01) 0.06 Peripheral neuropathy: Muscle weakness 5/25 (20%) 3/24 (13%) 1.60 (0.43, 5.97) 0.48 Reflex impairment 23/25 (92%) 21/25 (92%) 1.10 (0.89, 1.35) 0.39 Sensory impairment 12/25 (48%) 10/25 (40%) 1.20 (0.64, 2.25) 0.57 Korsakoff’s psychosis 14/27 (52%) 16/26 (52%) 0.84 (0.52, 1.35) 0.48

A significant reduction was seen in: Ophthalmoplegia

Long-term memory deficit Short-term memory deficit Muscle weakness66_.

Level 3

►Mortality

At long term follow up (5 lost) 2/27 (7%) patients died and three others could not be located.66_.

95 The second publication from the same cohort of patients reported further details on ophthalmoplegia, nystagmus, global confusion state and global severity of Wernicke’s encephalopathy, see below 67_.

Level 3

►Ophthalmoplegia

The participants of improvement was affected by the severity of liver disease, p<0.001 and by the severity of fatty liver, p<0.001

Participants with no fatty liver had the fastest improvement in ophthalmoplegia to treatment, but all participants reached the same level by the end of 14 days. 67

Level 3

►Nystagmus

Scores for individual tests of nystagmus all showed improvement, p<0.01 At discharge only six participants were completely free of nystagmus67_.

Level 3

►Global confusion state (see Table 2-20 below)

The state of consciousness rapidly improved within hours of thiamine treatment, p<0.001 and continued to improve slowly, p<0.02

The severity of disorientation in time improved over time, p<0.001, but improvement slowed by 7 days, p<0.05, and thereafter, p<0.01.

By discharge, most participants were still disorientated in time and 18 patients still did not know the day of the week67_.

Level 3 Table 2-19.

Global severity of acute Wernicke’s Admission Discharge

Class 4: ophthalmoplegia, ataxia +/- confusion 3/32 0/32 Class 3: ophthalmoplegia, nystagmus, ataxia +/-

confusion

27/32 4/32 (a)

Class 2: nystagmus, ataxia +/- confusion 2/32 (b) 22/32

Class 1: nystagmus, +/- confusion 0/32 0/32

Class 0: complete absence of these features 0/32 6/32 (a)- Residual ophthamoplegia only

(b)- One case was subsequently found to have received thiamine just prior to assessment.

Limitations:

The study did not report the dose of thiamine given. It is also possible that the dose of thiamine that they gave was too small and/or the treatment period too short.

96

►

1

The response of Erythrocyte thiamine diphosphate (TDP) level

2

One study reported on the response of erythrocyte TDP level when giving oral compared to i.m. (parental) preparations of thiamine 70_{. See Table} 3

2-20 below for results. 4

Level 1+

5

Table 2-20. (Normal reference range for TDP level 165-286 nmol/l)

6

The response of erythrocyte thiamine diphosphate (TDP) level

None (n=9) Oral (n=8) Parenteral

(n=8)

RR (95% CI) P value

Mean (± S.D.) Erythrocyte TDP (nmol/l)

Day 0 (pre-treatment) 218 (± 29) 218 (± 27) 207 (± 47) Oral versus none: 0.00 (-26.63, 26.63)

Oral versus none: 1.00 Parenteral versus none:

-11.00 (-48.68, 26.68)

Parenteral versus none: 0.57

Day 1

(post 250mg thiamine orally or parenterally)

209 (± 39) 265 (± 51) 328 (± 117) Oral versus none: 56.00 (12.43, 99.57)

Oral versus none: 0.01 Parenteral versus none:

119.00 (61.12, 176.88)

Parenteral versus none: <0.001

Day 7

(post 5 × 250mg thiamine as above)

220 (± 56) 308 (± 64) 298 (± 75) Oral versus none: 88.00 (30.51, 145.49)

Oral versus none: 0.003 Parenteral versus none:

78.00 (14.44, 141.56)

Parenteral versus none: 0.02

Change in mean after 250mg thiamin, or control

-9 +47 +121 - -

Change in mean after 5 × 250mg thiamine or control

97 Limitations:

There is some debate over the most accurate measure of tissue thiamine level, with previous studies reporting erythrocyte enzyme transketolase (ETKA) rather than TDP. This may affect the final results.

This study excluded patients with vitamin deficiencies, which may be an important group of patients in which thiamine is used. Also there was no explanation of what defined a patient as vitamin deficient..

Short-term follow up of only 7 days may have not been a sufficient time to see results.

►

One study reported on the response of ETK to treatment with intravenous and oral thiamine compared with placebo 69_.

intravenous thiamine (n=26) versus placebo (n=23) at day 2:

o Mean ± SD: 68.7*± 14.0 versus 68.4 ± 13.8; MD 0.30 (-7.50, 8.10), p=0.94

intravenous thiamine (n=26) versus placebo (n=23) at day 5:

o Mean ± SD: 75.5**±12.9 versus 75.8**± 15.2; MD -0.30 (-8.25, 7.65), p=0.94

Oral thiamine (n=24) versus placebo (n=23) at day 2:

o Mean ± SD: 70.0* ±12.5 versus 68.4 ± 13.8; MD 1.60 (-5.94, 9.14), p=0.68

Oral thiamine (n=24) versus placebo (n=23) at day 5:

o Mean ± SD: 76.8**± 11.4 versus 75.8**± 15.2; MD 1.00 (-6.71, 8.71), p=0.8069

Level 2+

Note: the significant differences (within each group) from the previous mean are indicated at the 95% (*) and 99.9% (**) confidence levels.

Response of ETK activity to vitamin supplementation in patients originally deficient

intravenous thiamine (n=16) versus placebo (n=15) at day 2:

o Mean ± SD: 59.5* ± 7.8 versus 60.6 ± 9.9; MD -1.10 (-7.40, 5.20), p=0.73

intravenous thiamine (n=16) versus placebo (n=15) at day 5:

o Mean ± SD: 66.8**± 6.1 versus 67.9** ± 12.1 ; MD -1.10 (-7.91, 5.71), p=0.75

Oral thiamine (n=16) versus placebo (n=15) at day 2:

o Mean ± SD: 64.4* ± 8.5 versus 60.6 ± 9.9 ; MD 3.80 (-2.72, 10.32), p=0.25

Oral thiamine (n=16) versus placebo (n=15) at day 5:

o Mean ± SD: 71.8** ± 8.2 versus 67.9** ± 12.1 ; MD 3.90 (-3.42, 11.22), p=0.3069

98 Note: the significant differences (within each group) from the previous mean are indicated at the 95% (*) and 99.9% (**) confidence levels.

Limitations:

The measure ETK may not be the most accurate measure of tissue thiamine levels.

The doses of oral and parenteral thiamine given were not equal, and may not have been given at an adequate dose.

Both groups were given i.v. thiamine at the start, which may have affected the final results.

Short term follow up of only five days may not have been sufficient.

2.7.4 H

No relevant economic analysis was identified assessing the cost-effectiveness of vitamin supplementation for the treatment/prevention of Wernicke’s encephalopathy. Costs and resource use information associated with the use of vitamin

supplementation for the treatment/prevention of Wernicke’s encephalopathy were presented to the GDG.

2.7.5 H

Vitamin-supplementation options used for the treatment/prevention of Wernicke’s encephalopathy have a low-drug cost (especially oral preparations). Pabrinex is the only treatment given parenterally for rapid correction of acute vitamin depletion and is more costly than oral preparations (few pence for high dose of oral preparations versus £1.96 for Pabrinex intravenous preparation [10 ml in 2 ampoules] and for Pabrinex intramuscular preparation [7 ml in 2 ampoules]72,73_{). Parenteral treatment is} normally given to patients when hospitalized for a co-morbidity and therefore use of Pabrinex does not affect the length of hospital stay in its current use. Nevertheless, additional staff time is associated with giving parenteral preparations.

The use of parenteral thiamine (Pabrinex) is associated with a potentially serious allergic adverse reaction that may rarely occur during, or shortly after administration. Since the January 1989 UK Committee on Safety of Medicines warning, 0.5 to 1 million pairs of ampoules of each preparation of Parentrovite were sold annually in the UK. There were four reports of an anaphylactoid reaction for every 1 million pairs of intravenous ampoules and one report per five million intramuscular ampoules sold74_. This reaction may incur extra treatment costs in addition to morbidity. However, allergic reactions from the use of parenteral thiamine are extremely rare and the extra cost associated to it is likely to be marginal. The BNF72 _{recommends that the potential} serious allergic adverse reaction should not preclude the use of parenteral thiamine in patients where this route of administration is required. This is crucial in patients at risk of Wernicke-Korsakoff syndrome where treatment with thiamine is essential considering the serious long-term implications of developing this syndrome and the high cost related to it (supported accommodation for example). In light of the above,

99 the treatment/prevention of Wernicke’s encephalopathy with vitamin-

supplementation is likely to be highly cost-effective.

2.7.6 E

The GDG noted that the absence of RCTs on this subject would mean any

recommendations would need to be by consensus. Due to this lack of RCTs and the potentially catastrophic long term effects of acute thiamine deficiency some of the evidence that was presented was based on clinical studies of thiamine absorption and metabolism.

The GDG first considered evidence on prevention of Wernicke’s encephalopathy with thiamine prophylaxis. It then considered treatment where there was a presumptive or actual diagnosis.