Abstract Body: Introduction: Prophylactic antibiotics can reduce infections after acute brain injury; Ceftriaxone (CTX) also modulates glutamate (GLUT) transporter function, which may reduce excitotoxicity and improve neurological outcomes. No study has described blood GLUT concentration in humans after out-of-hospital cardiac arrest (OHCA).
Research Question: Is plasma GLUT associated with neurological outcome after OHCA?
Goals/Aim: Assay plasma GLUT in a cohort of OHCA survivors randomized to CTX or placebo (PLAC) in the PROTECT trial (NCT04999592).
Methods/Approach: Plasma GLUT concentrations were analyzed with the Promega bioluminescent assay from samples prospectively collected before study drug (baseline) and post-randomization days 1 and 3. Neurological risk was stratified blinded to outcome using the Pittsburgh Cardiac Arrest Category (PCAC) severity score iPhone app and the Vista EEG suppression ratio 6 hours after ROSC (SR6). Plasma GLUT was compared between PLAC and CTX groups and between CPC categories (1-2 = good outcome, 3-5 = poor) with the Mann-Whitney test. Stratification was compared with Area under Receiver Operator Characteristic (AUROC) curves.
Results: PROTECT enrolled 52 subjects. Post-hoc stratification identified greater baseline neurological risk for subjects randomized to PLAC by SR6 (88 [63-96] vs 30 [3-84] CTX, p=0.008) but not by PCAC (4 [4-4] PLAC vs 4 [3-4] CTX, p=0.075). Poor neurological outcome was observed in 22/26 (85%) PLAC vs 13/26 (50%, p=0.018) CTX patients. The AUROC to predict poor neurological outcome was 0.93 (0.87-0.99) for SR6 vs 0.73 (0.57-0.89) for PCAC. Plasma GLUT was greater for the PLAC cohort at baseline (118.4 [87-180] vs 88.5 [69-103] µM, p=0.009) and on day 1 (102 [69-119] PLAC vs 70 [50-87] µM CTX, p=0.017). Change in GLUT from baseline to day 1 (p=0.68) or baseline to Day 3 (p=0.20) was similar in CTX and PLAC groups. Baseline (p=0.46), Day 1 (p=0.49), and Day 3 (p=0.99) plasma GLUT were similar among outcome groups.
Conclusions: Subjects randomized to CTX had better neurological outcomes after OHCA, mainly related to lower baseline risk. Higher risk in the PLAC group was associated with higher baseline glutamate prior to study drug administration. Plasma GLUT did not differ between patients with good or poor outcome. More research is needed to assess glutamate dynamics beyond plasma levels after OHCA and to investigate the association between improved neurological outcomes and CTX.