Randomized Control TrialsA multicenter randomized clinical trial of pharmacological vitamin B1 administration to critically ill patients who develop hypophosphatemia during enteral nutrition (The THIAMINE 4 HYPOPHOSPHATEMIA trial)
Introduction
Enteral nutrition is provided to the majority of patients who are admitted to the Intensive Care Unit (ICU) [1]. Patients who receive enteral nutrition frequently develop low serum phosphate concentrations [[2], [3], [4], [5]], and clinical manifestations of hypophosphatemia may be life-threatening [6,7].
Vitamin B1 (thiamine) is essential for producing energy from glucose via the generation of pyruvate and conversion to acetyl coenzyme A for entry into the citric acid (Krebs) cycle [7,8]. Accordingly, thiamine is essential to metabolise carbohydrate. Whilst thiamine deficiency is reported as prevalent in the critically ill [[9], [10], [11], [12], [13]], there is no current point of care measurement for plasma thiamine concentrations [14].
Thiamine exists in multiple forms through the addition of one or more phosphate groups: including thiamine, thiamine monophosphate, thiamine diphosphate and thiamine triphosphate [15]. Thiamine diphosphate is the principal active coenzyme form required for entry to the citric acid cycle. It is therefore plausible that hypophosphatemia may exacerbate adverse effects associated with thiamine deficiency, and hypophosphatemia may be a useful biomarker to identify those at risk of thiamine deficiency [14,15].
When commencing a diet with a proportion of carbohydrate, consistent with standard enteral nutrition formula used in the ICU [16], relative thiamine deficiency can be followed by changes in intermediate metabolism that produce an increase in lactate [17]. Not only is blood lactate a robust biomarker of impaired glucose metabolism [18,19] but increasing concentrations are strongly associated with inferior clinical outcomes, including increased mortality [[19], [20], [21]].
In summary, thiamine is an essential cofactor for glucose utilization, and there is biological plausibility that phosphate deficiency may identify a cohort at greater risk of thiamine deficiency, and that these deficiencies are synergistic. Accordingly, this trial aimed to test the null hypothesis that in critically ill enterally-fed patients who develop hypophosphatemia, the administration of pharmacological doses of intravenous (IV) thiamine, when compared to standard care, would have no effect on blood lactate concentrations.
Section snippets
Trial design
This was an investigator-initiated, multi-center, open-label, parallel-group, randomized clinical trial to compare pharmacological administration of thiamine (200 mg IV twice daily for a maximum of seven days) to usual care (physician prescribed enteral feed) in critically ill enterally fed patients with hypophosphatemia to determine the effect on blood lactate.
The protocol was approved by the Human Research Ethics Committee of Melbourne Health, Australia (2018.283). Written informed consent
Study participants
Between March 2019 and December 2020, 380 patients from five ICUs met all inclusion criteria with 90 patients meeting no exclusion criterion and randomized (Fig. 1).
The study participants were well balanced in terms of baseline characteristics, pre-randomization treatments and biochemistry (Table 1 and Table S1, Supplementary Material). The majority of participants did not have risk factors on clinical history that would have identified a high risk of refeeding syndrome (Table 1).
Study treatment
At least 1
Discussion
The major observation from this trial is that the administration of IV thiamine to critically ill patients who developed hypophosphatemia during enteral nutrition administration did not result in detectable differences in blood lactate or any measured biochemical or clinical outcome.
Severe metabolic disturbances occur in patients with refeeding syndrome. Indeed, severe hypophosphatemia in patients with risk factors is considered the pathognomonic feature of the syndrome [28,29]. In patients
Source of funding
The trial was supported by a Royal Melbourne Hospital Grant in Aid. AMD was supported by a NHMRC Career Development Fellowship.
Author contributions
A.M.D was responsible for trial conceptualization, methodology, obtaining resources, funding, conducting the trial, analysis and drafting the manuscript; A.J was responsible for trial conceptualization, methodology, conducting the trial, analysis and critical revision of the manuscript; B.T and A.C were responsible for conducting the trial, project administration and critical revision of the manuscript; M.E.F was responsible for trial conceptualization, methodology, funding, data resources,
Conflict of interest
The authors have disclosed there are no potential conflicts of interest.
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