To the Editor:
We read with interest the randomized clinical trial reported by Moskowitz and colleagues on intravenous thiamine versus placebo for renal protection in septic shock (1). The authors found no statistically significant effect regarding their primary endpoint of serum creatinine concentration over 72 hours. There were also no statistically significant differences in secondary outcomes, although a trend toward benefit in the intervention group and reduction in ICU-free days was found. With our group’s interest in the role of intravenous thiamine, its pharmacokinetics (PKs) and pharmacodynamics (PDs) in critical illness, and a potential role in delirium, we would like to raise the following points.
First, although the authors describe a limitation in the dosing of intravenous thiamine in septic shock, the PKs of intravenous thiamine in septic shock may also play a role (2). Intravenous thiamine is a hydrophilic drug, eliminated by the kidneys, which typically correlates with a low apparent volume of distribution. PKs of hydrophilic drugs are altered greatly in septic shock, primarily because of the increased volume of distribution of the central compartment due to a number of factors, including crystalloid resuscitation and a hyperdynamic circulation (3). This means that the concentration of hydrophilic drug (in this case, intravenous thiamine) in the central compartment—blood or plasma—is diluted, requiring a greater dosing to obtain adequate concentrations. Dose optimization and understanding of drug PKs and their influence on PDs in critical illness may be needed to ensure maximum effect. We wonder if the authors had considered the altered PKs in their dose decision for intravenous thiamine.
Second, we would be interested whether a validated delirium screening tool was used in this trial. The high prevalences of delirium in both arms may also be attributed to sepsis being a major confounder of delirium detection (4). In line with this, we wonder whether higher dosages of intravenous thiamine have resulted in detectable differences in the incidence of delirium, given the recommended intravenous doses of 500 mg or more three times per day for a thiamine-depleted brain in Wernicke’s encephalopathy.
Finally, we concur with Fujii and Sevransky in their editorial that the “gold” measurement for thiamine is indeed whole blood (5). Thiamine diphosphate, as the bioactive form of thiamine, is present in negligible amounts in plasma, whereas whole-blood thiamine makes up 80% of total circulating thiamine and is therefore a good derivative of whole-body stores of thiamine (6). Did the authors consider measuring whole-blood thiamine levels, which could have led to different conclusions of the trial? What would be their thoughts regarding the inclusion of the PK/PD parameters of intravenous thiamine, as well as whole-blood thiamine levels, in future studies of thiamine in critically ill patients?
Footnotes
Supported by National Institute of Health and Social Care Research Predoctoral Clinical and Practitioner Academic Fellowship Programme Development Grants NIHR302686 (M.A.M.); Research Leaders Programme, University Hospital Southampton, National Health Service Foundation Trust (C.A.M.); National Institute of Health and Care Research Wessex Applied Research Collaboration (C.A.M.); National Institute for Health Research Southampton Biomedical Research Centre (C.A.M.); an honorarium for work as Editor-in-Chief of Critical Illness (www.medicinescomplete.com) and publisher (Pharmaceutical Press); and a payment from Sedana Medical Limited for an educational event.
Author Contributions: M.A.M. prepared an early draft. All authors then reviewed and edited it to devise the final letter to the editor.
Originally Published in Press as DOI: 10.1164/rccm.202309-1641LE on November 16, 2023
Author disclosures are available with the text of this letter at www.atsjournals.org.
References
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