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Randomized, Double-Blind, Placebo-Controlled Trial of Thiamine as a Metabolic Resuscitator in Septic Shock: A Pilot Study.

ABSTRACT: To determine if intravenous thiamine would reduce lactate in patients with septic shock.Randomized, double-blind, placebo-controlled trial.Two US hospitals.Adult patients with septic shock and elevated (> 3 mmol/L) lactate between 2010 and 2014.Thiamine 200 mg or matching placebo twice daily for 7 days or until hospital discharge.The primary outcome was lactate levels 24 hours after the first study dose. Of 715 patients meeting the inclusion criteria, 88 patients were enrolled and received study drug. There was no difference in the primary outcome of lactate levels at 24 hours after study start between the thiamine and placebo groups (median: 2.5 mmol/L [1.5, 3.4] vs. 2.6 mmol/L [1.6, 5.1], p = 0.40). There was no difference in secondary outcomes including time to shock reversal, severity of illness and mortality. 35% of the patients were thiamine deficient at baseline. In this predefined subgroup, those in the thiamine treatment group had statistically significantly lower lactate levels at 24 hours (median 2.1 mmol/L [1.4, 2.5] vs. 3.1 [1.9, 8.3], p = 0.03). There was a statistically significant decrease in mortality over time in those receiving thiamine in this subgroup (p = 0.047).Administration of thiamine did not improve lactate levels or other outcomes in the overall group of patients with septic shock and elevated lactate. In those with baseline thiamine deficiency, patients in the thiamine group had significantly lower lactate levels at 24 hours and a possible decrease in mortality over time.

SUBMITTER: Donnino MW

PROVIDER: S-EPMC4754670 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Randomized, Double-Blind, Placebo-Controlled Trial of Thiamine as a Metabolic Resuscitator in Septic Shock: A Pilot Study.

Donnino Michael W MW Andersen Lars W LW Chase Maureen M Berg Katherine M KM Tidswell Mark M Giberson Tyler T Wolfe Richard R Moskowitz Ari A Smithline Howard H Ngo Long L Cocchi Michael N MN

Critical care medicine 20160201 2

<h4>Objective</h4>To determine if intravenous thiamine would reduce lactate in patients with septic shock.<h4>Design</h4>Randomized, double-blind, placebo-controlled trial.<h4>Setting</h4>Two US hospitals.<h4>Patients</h4>Adult patients with septic shock and elevated (> 3 mmol/L) lactate between 2010 and 2014.<h4>Interventions</h4>Thiamine 200 mg or matching placebo twice daily for 7 days or until hospital discharge.<h4>Measurements and main results</h4>The primary outcome was lactate levels 24 ...[more]

PMID: 26771781

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Project description:We previously found decreased levels of Coenzyme Q10 (CoQ10) in patients with septic shock. The objective of the current study was to assess whether the provision of exogenous ubiquinol (the reduced form of CoQ10) could increase plasma CoQ10 levels and improve mitochondrial function.We performed a randomized, double-blind, pilot trial at a single, tertiary care hospital. Adults (age ?18 years) with severe sepsis or septic shock between November 2012 and January 2014 were included. Patients received 200 mg enteral ubiquinol or placebo twice a day for up to seven days. Blood draws were obtained at baseline (0 h), 12, 24, 48, and 72 h. The primary outcome of the study was change in plasma CoQ10 parameters (total CoQ10 levels, CoQ10 levels relative to cholesterol levels, and levels of oxidized and reduced CoQ10). Secondary outcomes included assessment of: 1) vascular endothelial biomarkers, 2) inflammatory biomarkers, 3) biomarkers related to mitochondrial injury including cytochrome c levels, and 4) clinical outcomes. CoQ10 levels and biomarkers were compared between groups using repeated measures models.We enrolled 38 patients: 19 in the CoQ10 group and 19 in the placebo group. The mean patient age was 62?±?16 years and 47% were female. Baseline characteristics and CoQ10 levels were similar for both groups. There was a significant increase in total CoQ10 levels, CoQ10 levels relative to cholesterol levels, and levels of oxidized and reduced CoQ10 in the ubiquinol group compared to the placebo group. We found no difference between the two groups in any of the secondary outcomes.In this pilot trial we showed that plasma CoQ10 levels could be increased in patients with severe sepsis or septic shock, with the administration of oral ubiquinol. Further research is needed to address whether ubiquinol administration can result in improved clinical outcomes in this patient population.Clinicaltrials.gov identifier NCT01948063. Registered on 18 February 2013.

Project description:BackgroundProfound lymphopenia is an independent predictor of adverse clinical outcomes in sepsis. Interleukin-7 (IL-7) is essential for lymphocyte proliferation and survival. A previous phase II study showed that CYT107, a glycosylated recombinant human IL-7, administered intramuscularly reversed sepsis-induced lymphopenia and improved lymphocyte function. Thepresent study evaluated intravenous administration of CYT107. This prospective, double-blinded, placebo-controlled trial was designed to enroll 40 sepsis patients, randomized 3:1 to CYT107 (10 µg/kg) or placebo, for up to 90 days.ResultsTwenty-one patients were enrolled (fifteen CYT107 group, six placebo group) at eight French and two US sites. The study was halted early because three of fifteen patients receiving intravenous CYT107 developed fever and respiratory distress approximately 5-8 h after drug administration. Intravenous administration of CYT107 resulted in a two-threefold increase in absolute lymphocyte counts (including in both CD4+ and CD8+ T cells (all p < 0.05)) compared to placebo. This increase was similar to that seen with intramuscular administration of CYT107, was maintained throughout follow-up, reversed severe lymphopenia and was associated with increase in organ support free days (OSFD). However, intravenous CYT107 produced an approximately 100-fold increase in CYT107 blood concentration compared with intramuscular CYT107. No cytokine storm and no formation of antibodies to CYT107 were observed.ConclusionIntravenous CYT107 reversed sepsis-induced lymphopenia. However, compared to intramuscular CYT107 administration, it was associated with transient respiratory distress without long-term sequelae. Because of equivalent positive laboratory and clinical responses, more favorable pharmacokinetics, and better patient tolerability, intramuscular administration of CYT107 is preferable.Trial registrationClinicaltrials.gov, NCT03821038. Registered 29 January 2019, https://clinicaltrials.gov/ct2/show/NCT03821038?term=NCT03821038&draw=2&rank=1 .

Dataset Information

Randomized, Double-Blind, Placebo-Controlled Trial of Thiamine as a Metabolic Resuscitator in Septic Shock: A Pilot Study.

Publications

Randomized, Double-Blind, Placebo-Controlled Trial of Thiamine as a Metabolic Resuscitator in Septic Shock: A Pilot Study.

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