Thiamine as a Metabolic Resuscitator After Cardiac Arrest

Phase 2

Terminated

Conditions: Cardiac Arrest

Interventions: Other: Placebo
Drug: Thiamine 500 mg IV

Registration Number: NCT03450707

Lead Sponsor: Michael Donnino

Brief Summary: This is a randomized, double-blind, placebo controlled study to investigate the effect of intravenous thiamine (vitamin B1) on lactate, cellular oxygen consumption, global oxygen consumption and biomarkers of neurologic injury after out-of-hospital cardiac arrest (OHCA). .

Detailed Description: This is a randomized, double-blind, placebo controlled study to investigate the effect of intravenous thiamine (vitamin B1) on lactate, cellular oxygen consumption, global oxygen consumption and biomarkers of neurologic injury after out-of-hospital cardiac arrest (OHCA). Patients who have sustained return of spontaneous circulation (ROSC) after OHCA and have a lactate of 3 or greater will be eligible for the study. Enrolled patients will be randomized to intravenous thiamine 500mg twice daily for 5 doses or matching placebo (100cc normal saline). Blood will be drawn at several time points and patients will be connected to a noninvasive monitor for continuous measurement of global oxygen consumption. The primary endpoint is change in lactate level. Secondary endpoints include change in pyruvate dehydrogenase activity, change in cellular and global oxygen consumption, change in NSE and S100 (biomarkers of neurologic injury) and CPC-E score (a score that assesses neurologic and functional impairment) at hospital discharge, 30 and 90 days.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 93

Inclusion Criteria

Adult patient (age ≥ 18 years)
Cardiac arrest occurring with sustained (> 20 minutes) return of spontaneous circulation (ROSC)
Within 4.5 hours of cardiac arrest event
Lactate >/=3

Exclusion Criteria

Clinical indication for thiamine administration (alcoholism, known or highly suspected deficiency) or treatment with thiamine beyond the amount found in a standard multivitamin within the last 10 days
Traumatic etiology of arrest
Comfort measures only or anticipated withdrawal of support within 24 hours
Protected populations (pregnant women, prisoners)
Known allergy to thiamine

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Patients randomized to placebo will receive 100mL normal saline intravenously every 12 hours for 5 doses. All other aspects of the protocol will be the same as in the experimental arm. Patients will be connected to a noninvasive monitor for measurement of global oxygen consumption (VO2) for at least 48 hours or until extubated, whichever comes first. Blood will be drawn at 0,6,12,24,72 and 168 hours for measurement of lactate, thiamine level, pyruvate dehydrogenase, NSE, S100 and other markers of organ injury. CPC-E score will be assessed prior to hospital discharge and at 30 and 90 days to evaluate differences in neurologic and functional impairment.
Thiamine	Thiamine 500 mg IV	Patients randomized to the thiamine arm will receive thiamine 500mg in 100mL of normal saline intravenously every 12 hours for 5 doses. Patients will be connected to a noninvasive monitor for measurement of global oxygen consumption (VO2) for at least 48 hours or until extubated, whichever comes first. Blood will be drawn at 0,6,12,24,72 and 168 hours for measurement of lactate, thiamine level, pyruvate dehydrogenase, NSE, S100 and other markers of organ injury. CPC-E score will be assessed prior to hospital discharge and at 30 and 90 days to evaluate differences in neurologic and functional impairment.

Primary Outcome Measures

Name	Time	Method
Lactate	24 hours	Blood Lactate Over Time

Secondary Outcome Measures

Name	Time	Method
Lactate	72 hours	Absolute Blood Level of Lactate
Pyruvate Dehydrogenase (PDH) Specific Activity	72 hours	Absolute PDH specific activity value
Pyruvate Dehydrogenase (PDH) Activity	72 hours	Absolute PDH Activity Value
Pyruvate Dehydrogenase (PDH) Quantity	72 hours	Absolute PDH Quantity. Please note that the measurement of Absolute PDH Quantity is done using a relative quantity assay, and that PDH is an enzyme and not a stable protein; therefore the units of measure cannot be provided in "mg" and are instead listed in "mini OD unit/min/mg protein".
Mortality	will be assessed at hospital discharge and up to 30 and 90 days.	Mortality in the study assessed at three timepoints.
Favorable Cerebral Performance Category (CPC)	will be assessed up to 30 and 90 days	Count/Proportion of Patients Scoring a Favorable CPC, defined as a score of 1 or 2. Cerebral performance category scores range from 1-5. Lower scores mean better outcomes.
Sequential Organ Failure Assessment (SOFA) Score	over 72 hours	SOFA score over time. SOFA score: Sequential Organ Failure Assessment Score, ranges from 0-24, higher scores mean worse outcomes.
Acute Renal Failure	First 7 days following Arrest	Determined using the Kidney Disease Improving Global Outcomes (KDIGO) criteria for Stage 3 acute kidney injury/kidney failure.
Cellular Oxygen Consumption	0 hours and 24 hours.	Absolute Cellular Oxygen Consumption Rate: We use two measures to capture Oxygen Consumption Rate; the basal respiration and the maximal respiration.
Creatinine	72 hours	Creatinine over Time
Biomarkers of Neurologic Injury	various time points over 7 days	S100 and NSE levels at various time points
Global Oxygen Consumption	48 hours	Global Oxygen Consumption over Time