Clinical trial NCT03554668: Systemic Inflammatory Response: Thiamine and Magnesium Status (Sir TaM Study)
Official title: The Relation Between Acute Changes in the Systemic Inflammatory Response, Thiamine and Magnesium Concentrations and Transketolase Activity After Elective Knee Arthroplasty.
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Inflammation
Magnesium Deficiency
Iron-deficiency
Thiamine Deficiency
Lead sponsor: Glasgow Royal Infirmary
Sponsor class: OTHER
Collaborators: name: NHS Greater Glasgow and Clyde
First posted: 2018-06-13
Enrollment: 47
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients undergoing elective TKR

Brief summary: We wish to determine to what extent magnesium, thiamine and transketolase activity are affected by the Systemic Inflammatory Response (SIR). The knee arthroplasty model affords the ideal study design, as surgery generates an inflammatory response.

Blood samples are drawn preoperatively and for up to four days post operatively, and again at three months post-operation.

Detailed description: Thiamine and magnesium play a critical role in glucose metabolism and deficiency results in the accumulation of anaerobic metabolites including lactate (1-3).

Thiamine requires magnesium to be converted to its active form, thiamine pyrophosphate (TPP) (4). TPP also requires magnesium to achieve activation of TPP dependent enzymes during metabolism of glucose (5, 6). The 'gold standard' for the measurement of thiamine status is the measurement of Erythrocyte Transketolase Activity (ETKA)(4, 7-9), and this enzyme's activity is dependent on the presence both thiamine pyrophosphate and magnesium (8, 10). ETKA may therefore represent a 'functional marker' of magnesium status (7, 9, 11, 12).

Studies indicate that low plasma thiamine and magnesium are associated with a range of disease processes, many of which are inflammatory (13-17). Other lipid-soluble vitamins and minerals are known to decrease during the systemic inflammatory response (18, 19), however this relationship is not proven for magnesium. The systemic inflammatory response may therefore confound the interpretation of plasma thiamine and magnesium in the context of sepsis, surgery or autoimmune disease. Elective knee arthroplasty, provokes an inflammatory response and therefore provides an excellent controlled model for understanding the body's response to a systemic insult (19).

Obesity is reported to be associated with magnesium deficiency (17, 20). Intracellular magnesium plays a key role in regulating insulin action, insulin-mediated-glucose-uptake and vascular tone (21-23). Several epidemiologic studies have shown that adults and children consuming a western type diet are consuming 30 - 50% of the RDA for magnesium (24, 25). This deficiency appears to be predominantly subclinical and therefore not routinely investigated.

Obesity is also associated with thiamine and magnesium depletion (17, 20, 26, 27). Magnesium deficiency is also associated with a CRP rise (28-30). Thiamine status is proven to affect lactate concentrations in the blood (2, 3). Lactate accumulation is known to precede the onset of insulin resistance and be characteristically found in patients with obesity related diabetes (31-37).

It is therefore possible that an underlying quiescent magnesium and / or thiamine deficiency may mediate insulin resistance. Thiamine, and its more lipid soluble derivative, benfothiamine, have already shown some promise in the treatment of diabetic complications. The therapeutic potential is intriguing, however the relation between acute changes in the systemic inflammatory response and thiamine and magnesium concentrations, require clarification. Failure to prove the reliability of the thiamine and magnesium measurements in the context of the systemic inflammatory response may lead to patients receiving treatment for a measured deficiency of red cell thiamine and serum magnesium concentrations, which is unreliable. If the therapeutic potential of combined treatment with thiamine and magnesium for the optimization of ETKA function is to be realized (8), it is essential that the erythrocyte and plasma values used to determine thiamine status are definitively established in the context of the systemic inflammatory response. The knee arthroplasty model affords the ideal study design for this as there is a strong association between obesity and knee osteoarthritis (38, 39).

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38. Guenther D, Schmidl S, Klatte TO, Widhalm HK, Omar M, Krettek C, et al. Overweight and obesity in hip and knee arthroplasty: Evaluation of 6078 cases. World J Orthop. 2015;6(1):137-44.
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Eligibility criteria: Inclusion Criteria:

* undergoing elective total knee replacement

Exclusion Criteria:

* taking multivitamin

Primary outcomes:
measure: serum magnesium
timeFrame: three months
measure: thiamine
timeFrame: three months
measure: erythrocyte transketolase activity
timeFrame: three months
Secondary outcomes:
Other outcomes:
measure: Iron receptor status
timeFrame: three months
Locations:
city: Glasgow
country: United Kingdom
facility: Glasgow Royal Infirmary
Study officials:
References:
citation: Altura BM, Shah NC, Shah GJ, Zhang A, Li W, Zheng T, Perez-Albela JL, Altura BT. Short-term Mg deficiency upregulates protein kinase C isoforms in cardiovascular tissues and cells; relation to NF-kB, cytokines, ceramide salvage sphingolipid pathway and PKC-zeta: hypothesis and review. Int J Clin Exp Med. 2014 Jan 15;7(1):1-21. eCollection 2014.
citation: Wolf E, Utech M, Stehle P, Busing M, Stoffel-Wagner B, Ellinger S. Preoperative micronutrient status in morbidly obese patients before undergoing bariatric surgery: results of a cross-sectional study. Surg Obes Relat Dis. 2015 Sep-Oct;11(5):1157-63. doi: 10.1016/j.soard.2015.03.018. Epub 2015 Apr 2.
citation: Dibaba DT, Xun P, He K. Dietary magnesium intake is inversely associated with serum C-reactive protein levels: meta-analysis and systematic review. Eur J Clin Nutr. 2015 Mar;69(3):409. doi: 10.1038/ejcn.2014.275. Epub 2015 Jan 7. No abstract available.
citation: Crawford SO, Hoogeveen RC, Brancati FL, Astor BC, Ballantyne CM, Schmidt MI, Young JH. Association of blood lactate with type 2 diabetes: the Atherosclerosis Risk in Communities Carotid MRI Study. Int J Epidemiol. 2010 Dec;39(6):1647-55. doi: 10.1093/ije/dyq126. Epub 2010 Aug 25.
citation: Salih S, Sutton P. Obesity, knee osteoarthritis and knee arthroplasty: a review. BMC Sports Sci Med Rehabil. 2013 Dec 4;5(1):25. doi: 10.1186/2052-1847-5-25.
citation: Maguire D, Catchpole A, Sheerins O, Talwar D, Burns A, Blyth M, Shaw A, Jones B, Drury C, Harten J, Smith I, McMillan DC. The relation between acute changes in the systemic inflammatory response and circulating thiamine and magnesium concentrations after elective knee arthroplasty. Sci Rep. 2021 May 28;11(1):11271. doi: 10.1038/s41598-021-90591-y.