Abstract

Background Β-Lactam-induced neurotoxicity in critical care patients can compromise clinical outcomes. Despite the growing use of therapeutic drug monitoring (TDM) for β-lactams, clear toxicity thresholds remain undefined, leaving clinicians uncertain about dosing adjustments when adverse effects occur. Identifying a relevant and easily detectable neurophysiological biomarker for β-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 β-lactams (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 β-lactam exposure and Sepsis-related Organ Failure Assessment (SOFA) scores with the neural activity.

Results β-lactam exposure correlated with increased β-low γ neural dynamics (20–40 Hz) (p < 0.001, FDR corrected), independent of other clinical factors or medications. Β 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 θ-α activity (3.5-5 Hz and 12-18 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 β or θ-α dynamics.

Conclusions These results suggest that β neural dynamics represent a potential biomarker for β-lactam 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.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This work was supported by the Fondation pour la Recherche Medicale (FRM) (SPF202209015740) (AZ). This study was sponsored by the Assistance Publique Hopitaux de Marseille (DRC) and funded by a grant from Appel d'Offres de Recherche Clinique (AORC) to R.G.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study received approval from the ethics committee Comite de Protection des Personnes Sud-Est I (Ref 2017-A01446 47).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data Availability

Numerical data supporting this study will be available on GitHub upon publication.

List of abbreviationsEEGElectroencephalographyqEEGquantitative ElectroencephalographySOFASepsis-related Organ Failure AssessmentICUIntensive Care UnitTDMTherapeutic Drug MonitoringMICMinimum Inhibitory ConcentrationGABAGamma Aminobutyric AcidIPSPInhibitory Postsynaptic PotentialNMDAN-methyl-D-aspartateGLT1Glutamate transporter 1