RATIONALE FOR THE USE OF SYSTEMATIC THIAMINE AT PHARMOCOLOGICAL DOSE
IN MALNOURISHED CHILDREN REQUIRING HOSPITAL ADMISSION
L.
Hiffler1
2,
, D. Martinez Garcia
N.
3
Salse ,
N.
2
Lafferty ,
M.C .
4
Bottineau ,
B.
MSF Ped Days 2016
E-poster 1416
Ethical Review Board: not required.
5
Rakotoambinina
1,
Pediatric Advisor, MSF OCBA, Dakar Unit, Senegal and 2, Pediatric Advisor, Medical Department of MSF OCBA, Barcelona, Spain. [email protected] ;
3, Nutrition advisor, Medical Department MSF OCBA; 4, Leader of MSF Paediatric Working group, Geneva, MSF OCG; 5 Unit of Nutrition Physiology, Antananarivo University, Antananarivo, Madagascar
BACKGROUND and AIMS:
Complicated severe acute malnutrition (SAM) remains a major
challenge in MSF programmes and carries significant mortality. As the
body has a very limited, diet-dependent store of thiamine (vitamin B1),
deficiency is common in malnourished children. Thiamine has many
functions, and is an essential component of key metabolic pathways
involving glucose, nucleic acids and branched-chain amino acids. It is
also involved in the production of neurotransmitters, myelin and
nucleic acids. Aside from classic beriberi, thiamine deficiency (TD) is
implicated in a large spectrum of clinical and sub-clinical conditions
and may have an impact on the prognosis of critically ill children with
SAM, however the diagnosis is frequently overlooked.
METHOD:
Literature review of current knowledge including thiamine function in
humans and clinical presentation of TD in the context of SAM
(PubMed, Google Scholar).
Fig 1: Thiamine-B1 functions (Hiffler et al 2016; Frontiers in Nutrition)
RESULTS:
Thiamine has dual coenzymatic and non-coenzymatic functions. It is
involved in the production of acetyl-CoA and succinyl-CoA, as a
cofactor of pyruvate dehydrogenase and alpha-ketoglutarate
dehydrogenase complexes respectively, thus is essential for the proper
functioning of the Krebs cycle (Fig 1). Consequently, TD is associated
with lactic acidosis and reduced ATP production through disruption of
the Krebs cycle, and could be considered an acquired mitochondrial
disease.
Common risk factors for TD are SAM, monotonous diet, diarrhoea and
malabsorption, while acute precipitating factors include refeedinginduced cellular hyper-utilisation of thiamine, hypermetabolic states
associated with critical illness, and resuscitation with dextrose-based
fluids, all of which increase cellular thiamine demand (Table 1).
Table 1: TD prevalence in SAM and in critically ill children
Ghana
Jamaica
Brazil
USA
43% in SAM
children
40% in SAM
children
N=28
N= 25
N= 202
N= 22
Neumann
1979
Hailemariam
1985
Lima
2011
Rosner
2015
28% upon admission
24% in diabetic ketoacidosis
in PICU
(35% after 8h of insulin therapy)
Recent evidence suggests that thiamine administration in TD patients
with septic shock significantly increases survival (Graph 1).
Graph 1: Kaplan Meier survival curves for the thiamine and placebo
groups among patients with TD (Donnino et al 2016; Crit Care Med)
Hiffler L, Rakotoambinina B, Lafferty N, Martinez Garcia D: Thiamine Deficiency in Tropical Pediatrics: New insights into a Neglected but Vital Metabolic Challenge. Front. Nutr., 14 June 2016 : http://dx.doi.org/10.3389/fnut.2016.00016
Donnino M : Randomized, Double-Blind, Placebo-Controlled Trial of Thiamine as a Metabolic Resuscitator in Septic Shock: A Pilot Study. Crit Care Med. 2016 Feb;44(2):360-7.
M.Sear et al: Thiamine, Riboflavin, and Pyridoxine deficiencies in population of critically ill children; J Pediatr 1992; 121: 533-8
Rosner EA, Strezlecki KD, Clark JA, Lieh-Lai M. Low thiamine levels in children with type 1 diabetes and diabetic ketoacidosis: a pilot study. Pediatr Crit Care Med. 2015 Feb;16(2):114-8
Lima LF, Leite HP, Taddei JA. Low blood thiamine concentrations in children upon admission to the intensive care unit: risk factors and prognostic significance. Am J Clin Nutr. 2011;93(1):57-61
Rao SN, Chandak GR. Cardiac beriberi: often a missed diagnosis. J Trop Pediatr. 2010;56(4):284-5
Barennes H, Sengkhamyong K, René JP, Phimmasane M. Beriberi (thiamine deficiency) and high infant mortality in northern Laos. PLoS Negl Trop Dis. 2015; 9(3):e0003581
In this randomised controlled trial by Donnino et al (2016), 35% of
patients had TD on admission, while thiamine treatment in TD patients
with septic shock was associated with a lower mortality: 13% vs 46%.
The thiamine content of therapeutic F75 alone is markedly lower than
the 2mg/kg recommended for the prevention of refeeding syndrome
(Table 2), as well as the treatment doses used in critical illness.
Table 2: Thiamine content of therapeutic milk and estimated thiamine needs in
children during the acute phase of refeeding in SAM
Body
Weight
(kg)
Approximate amount of F75 in mL (and equivalent
of thiamine content -ref. F75 MSF 2014-) given in 8
meals / day in acute stabilization phase according
to refeeding protocols (WHO 2013)
South African and Australian
guidelines for prevention of
refeeding syndrome (2 mg/kg
of thiamine) ref. below
5 Kg
8 x 85 ml/d (~ 0.75 mg of thiamine)
10 mg of thiamine
7 Kg
8 x 120 ml/d (~ 1 mg of thiamine)
14 mg of thiamine
10 kg
8 x 170 ml/d (~ 1.5 mg of thiamine)
20 mg of thiamine
15 Kg
8 x 250 ml/d (~ 2.2mg of thiamine)
30 mg of thiamine
Legend: F-75 is the therapeutic milk used during early refeeding (75 Kcal/100 ml). As an example,
a 7 kg child with complicated SAM would be given 8 meals of 120 ml of F-75 on admission. The
dose recommended in the above guidelines (third column) would give approximately 14 times
more thiamine than the amount found in F75 alone.
CONCLUSION:
Complicated SAM is often associated with acute conditions such as
severe malaria, pneumonia and septic shock. Pre-existing low or
borderline thiamine stores in SAM are rapidly consumed in these
hypermetabolic states, exacerbated by refeeding. We recommend
systematic thiamine for all complicated SAM patients at the
pharmacological dose of 25 mg (1/2 tablet) PO, preceded by a loading
dose of 100 mg (1 ml) by slow IV infusion for the first 48 hours in severe
acute conditions.
Hailemariam B, Landman JP, Jackson AA. thiamine status in normal and malnourished children in Jamaica. Br J Nutr. 1985;53(3):477-83
World Health Organisation. Guideline: Updates on the Management of Severe Acute Malnutrition in Infants and Children. Geneva: WHO (2013).
F75 MSF Product Specification Sheet, ref MSF-QA-NFOS-PPS4-rev04, 28/01/2014. )
Refeeding Syndrome: Guidelines; Cape Town Metropole Paediatric Interest Group; March 2009. Retrieved from http://www.adsa.org.za/Portals/14/Documents/Clinical20Guidelines20Refeeding20Syndrome20Paeds20Section20Only20.pdf
Refeeding Syndrome: Prevention and Management - SCH Practice Guideline. Sydney Children’s Hospital Guidelines. Australia. June 2013. Retrieved from: http://www.schn.health.nsw.gov.au/_policies/pdf/ 2013-7036.pdf
Duke T: New WHO guidelines on emergency triage assessment and treatment (ETAT 2016):. The lancet - Vol 387 February 20, 2016
Giacalone M, Martinelli R, Abramo A, Rubino A, Pavoni V, Iacconi P, et al. Rapid reversal of severe lactic acidosis after thiamine administration in critically ill adults: a report of 3 cases. Nutr Clin Pract (2015) 30(1):104–10.
doi:10.1177/0884533614561790 .