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Thiamine as an adjunctive therapy in cardiac surgery: a randomized, double-blind, placebo-controlled, phase II trial.

ABSTRACT: Thiamine is a vitamin that is essential for adequate aerobic metabolism. The objective of this study was to determine if thiamine administration prior to coronary artery bypass grafting would decrease post-operative lactate levels as a measure of increased aerobic metabolism.We performed a randomized, double-blind, placebo-controlled trial of patients undergoing coronary artery bypass grafting. Patients were randomized to receive either intravenous thiamine (200 mg) or placebo both immediately before and again after the surgery. Our primary endpoint was post-operative lactate levels. Additional endpoints included pyruvate dehydrogenase activity, global and cellular oxygen consumption, post-operative complications, and hospital and intensive care unit length of stay.Sixty-four patients were included. Thiamine levels were significantly higher in the thiamine group as compared to the placebo group immediately after surgery (1200 [683, 1200] nmol/L vs. 9 [8, 13] nmol/L, p < 0.001). There was no difference between the groups in the primary endpoint of lactate levels immediately after the surgery (2.0 [1.5, 2.6] mmol/L vs. 2.0 [1.7, 2.4], p = 0.75). Relative pyruvate dehydrogenase activity was lower immediately after the surgery in the thiamine group as compared to the placebo group (15% [11, 37] vs. 28% [15, 84], p = 0.02). Patients receiving thiamine had higher post-operative global oxygen consumption 1 hour after the surgery (difference: 0.37 mL/min/kg [95% CI: 0.03, 0.71], p = 0.03) as well as cellular oxygen consumption. We found no differences in clinical outcomes.There were no differences in post-operative lactate levels or clinical outcomes between patients receiving thiamine or placebo. Post-operative oxygen consumption was significantly increased among patients receiving thiamine.clinicaltrials.gov NCT02322892, December 14, 2014.

SUBMITTER: Andersen LW

PROVIDER: S-EPMC4820988 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Thiamine as an adjunctive therapy in cardiac surgery: a randomized, double-blind, placebo-controlled, phase II trial.

Andersen Lars W LW Holmberg Mathias J MJ Berg Katherine M KM Chase Maureen M Cocchi Michael N MN Sulmonte Christopher C Balkema Julia J MacDonald Mary M Montissol Sophia S Senthilnathan Venkatachalam V Liu David D Khabbaz Kamal K Lerner Adam A Novack Victor V Liu Xiaowen X Donnino Michael W MW

Critical care (London, England) 20160314

<h4>Background</h4>Thiamine is a vitamin that is essential for adequate aerobic metabolism. The objective of this study was to determine if thiamine administration prior to coronary artery bypass grafting would decrease post-operative lactate levels as a measure of increased aerobic metabolism.<h4>Methods</h4>We performed a randomized, double-blind, placebo-controlled trial of patients undergoing coronary artery bypass grafting. Patients were randomized to receive either intravenous thiamine (20 ...[more]

PMID: 27044557

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Project description:BACKGROUND:Identifying new antifungals for cryptococcal meningitis is a priority given the inadequacy of current therapy. Sertraline has previously shown in vitro and in vivo activity against cryptococcus. We aimed to assess the efficacy and cost-effectiveness of adjunctive sertraline in adults with HIV-associated cryptococcal meningitis compared with placebo. METHODS:In this double-blind, randomised, placebo-controlled trial, we recruited HIV-positive adults with cryptococcal meningitis from two hospitals in Uganda. Participants were randomly assigned (1:1) to receive standard therapy with 7-14 days of intravenous amphotericin B (0·7-1·0 mg/kg per day) and oral fluconazole (starting at 800 mg/day) with either adjunctive sertraline or placebo. Sertraline was administered orally or via nasogastric tube at a dose of 400 mg/day for 2 weeks, followed by 200 mg/day for 12 weeks, then tapered off over 3 weeks. The primary endpoint was 18-week survival, analysed by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT01802385. FINDINGS:Between March 9, 2015, and May 29, 2017, we screened 842 patients with suspected meningitis and enrolled 460 of a planned 550 participants, at which point the trial was stopped for futility. Three patients in the sertraline group and three patients in the placebo group were lost to follow-up and therefore discontinued before study end. At 18 weeks, 120 (52%) of 229 patients in the sertraline group and 106 (46%) of 231 patients in the placebo group had died (hazard ratio 1·21, 95% CI 0·93-1·57; p=0·15). The fungal clearance rate from cerebrospinal fluid was similar between groups (0·43 -log10 CFU/mL per day [95% CI 0·37-0·50] in the sertraline group vs 0·47 -log10 CFU/mL per day [0·40-0·54] in the placebo group; p=0·59), as was occurrence of grade 4 or 5 adverse events (72 [31%] of 229 vs 75 [32%] of 231; p=0·98), most of which were associated with amphotericin B toxicity. INTERPRETATION:Sertraline did not reduce mortality and should not be used to treat patients with HIV-associated cryptococcal meningitis. The reasons for sertraline inactivity appear to be multifactorial and might be associated with insufficient duration of therapeutic sertraline concentrations. FUNDING:National Institutes of Health and Medical Research Council, Wellcome Trust.

Project description:Adjunctive dexamethasone reduces mortality from tuberculous meningitis (TBM) but not disability, which is associated with brain infarction. We hypothesised that aspirin prevents TBM-related brain infarction through its anti-thrombotic, anti-inflammatory, and pro-resolution properties. We conducted a randomised controlled trial in HIV-uninfected adults with TBM of daily aspirin 81 mg or 1000 mg, or placebo, added to the first 60 days of anti-tuberculosis drugs and dexamethasone (NCT02237365). The primary safety endpoint was gastro-intestinal or cerebral bleeding by 60 days; the primary efficacy endpoint was new brain infarction confirmed by magnetic resonance imaging or death by 60 days. Secondary endpoints included 8-month survival and neuro-disability; the number of grade 3 and 4 and serious adverse events; and cerebrospinal fluid (CSF) inflammatory lipid mediator profiles. 41 participants were randomised to placebo, 39 to aspirin 81 mg/day, and 40 to aspirin 1000 mg/day between October 2014 and May 2016. TBM was proven microbiologically in 92/120 (76.7%) and baseline brain imaging revealed ?1 infarct in 40/114 (35.1%) participants. The primary safety outcome occurred in 5/36 (13.9%) given placebo, and in 8/35 (22.9%) and 8/40 (20.0%) given 81 mg and 1000 mg aspirin, respectively (p=0.59). The primary efficacy outcome occurred in 11/38 (28.9%) given placebo, 8/36 (22.2%) given aspirin 81 mg, and 6/38 (15.8%) given 1000 mg aspirin (p=0.40). Planned subgroup analysis showed a significant interaction between aspirin treatment effect and diagnostic category (Pheterogeneity = 0.01) and suggested a potential reduction in new infarcts and deaths by day 60 in the aspirin treated participants with microbiologically confirmed TBM (11/32 (34.4%) events in placebo vs. 4/27 (14.8%) in aspirin 81 mg vs. 3/28 (10.7%) in aspirin 1000 mg; p=0.06). CSF analysis demonstrated aspirin dose-dependent inhibition of thromboxane A2 and upregulation of pro-resolving CSF protectins. The addition of aspirin to dexamethasone may improve outcomes from TBM and warrants investigation in a large phase 3 trial.

Project description:BackgroundStaphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection.MethodsIn this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants.FindingsBetween Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005).InterpretationAdjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia.FundingUK National Institute for Health Research Health Technology Assessment.

Project description:Lower oxygen consumption is associated with worse survival in septic shock and in other forms of critical illness. No treatment that increases oxygen extraction, a key determinant of oxygen consumption, has been found. Thiamine is required for aerobic metabolism, and deficiency is common in the critically ill.ObjectivesWe evaluated the effect of thiamine on oxygen consumption in patients requiring mechanical ventilation for an acute illness.DesignPhase II, randomized, double-blind, and placebo-controlled trial.Setting and participantsICUs in a tertiary care hospital in the United States. Patients admitted to the ICU and requiring mechanical ventilation were screened for enrollment.InterventionsAfter enrollment, baseline measurement of oxygen consumption and baseline laboratories including lactate, central venous oxygen saturation, and pyruvate dehydrogenase, a single dose of 200 mg IV thiamine or placebo was administered. Oxygen consumption was then monitored for 6 additional hours and repeat laboratories were drawn at the end of the protocol.Main outcomes and measuresThe primary outcome was the change in oxygen consumption. Analysis was done using linear regression with a first-order autoregressive variance-covariance structure to account for repeated measures within subjects. Secondary outcomes included change in lactate, central venous oxygen saturation, and pyruvate dehydrogenase quantity and activity.ResultsSixty-seven patients were enrolled. After excluding 11 patients due to inadequate quantity or quality of oxygen consumption data, 56 patients were included. There was no difference in change in oxygen consumption in the 6 hours after study drug. Results for secondary outcomes were similarly negative. In the prespecified subgroup of 18 thiamine deficient patients, there was a difference in the two oxygen consumption curves (p = 0.006), although no difference in median oxygen consumption or area under the curve.Conclusions and relevanceA single dose of IV thiamine did not alter oxygen consumption in patients requiring mechanical ventilation for acute illness.

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Thiamine as an adjunctive therapy in cardiac surgery: a randomized, double-blind, placebo-controlled, phase II trial.

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Thiamine as an adjunctive therapy in cardiac surgery: a randomized, double-blind, placebo-controlled, phase II trial.

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