Neural correlates of β-lactam exposure in intensive care unit patients: an observational, prospective cohort study

Abstract

Background: BetaLactam induced neurotoxicity in critical care patients can compromise clinical outcomes. Despite the growing use of therapeutic drug monitoring (TDM) for betalactams, clear toxicity thresholds remain undefined, leaving clinicians uncertain about dosing adjustments when adverse effects occur. Identifying a relevant and easily detectable neurophysiological biomarker for beta-lactam exposure would improve monitoring and prevent serious complications. Methods: In a prospective multicenter, non-interventional study, we analysed electroencephalographic (EEG) signals of 56 patients hospitalized in intensive care units (ICUs) receiving continuous infusions of five betalactams (meropenem, piperacillin/tazobactam, cefepime, cefotaxime, or ceftazidime). We applied a time frequency decomposition on these EEG data to investigate quantitatively the power of neural dynamics across frequencies ranging from 1 to 45 Hz. We used a multivariate pattern decoding method to correlate the betalactam exposure and Sepsis related Organ Failure Assessment (SOFA) scores with the neural activity. Results: betalactam exposure correlated with increased beta to low gamma neural dynamics (20 to 40 Hz) (p < 0.001, FDR corrected), independent of other clinical factors or medications. Beta neural activity was most pronounced in central electrodes (C3 : r = 0.20, p < 0.01; C4 : r = 0.26, p < 0.01) and the right frontal electrode (Fp2 : r = 0.12, p = 0.02). Lower theta to alpha activity (3.5 to 5 Hz and 12 to 18 Hz) was associated with higher SOFA scores (p < 0.001, FDR corrected). No significant correlations were observed between other drugs (opioids, antiseizure medications, psychotropics) and beta or theta to alpha dynamics. Conclusions: These results suggest that beta neural dynamics represent a potential biomarker for betalactam exposure in ICU patients. They highlight the potential of quantitative EEG and advanced multivariate decoding methods to identify subtle neurophysiological features that are otherwise difficult to detect. Trial registration: ClinicalTrials.gov IDNCT03339869. Registered 14 September 2017.