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Incidence and Predictive Factors Associated with Beta-Lactam Neurotoxicity in the Critically Ill: A Retrospective Cohort Study

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Abstract

Background

Beta-lactam neurotoxicity is a relatively uncommon yet clinically significant adverse effect in critically ill patients. This study sought to define the incidence of neurotoxicity, derive a prediction model for beta-lactam neurotoxicity, and then validate the model in an independent cohort of critically ill adults.

Methods

This retrospective cohort study evaluated critically ill patients treated with ≥ 48 h of cefepime, piperacillin/tazobactam, or meropenem. Two separate cohorts were created: a derivation cohort and a validation cohort. Patients were screened for beta-lactam neurotoxicity by using search terms and diagnosis codes, followed by clinical adjudication using a standardized adverse event scoring tool. Multivariable regression models and least absolute shrinkage and selection operator were used to identify surrogates for neurotoxicity and develop a multivariable prediction model.

Results

The overall incidence of beta-lactam neurotoxicity was 2.6% (n/N = 34/1323) in the derivation cohort and 2.1% in the validation cohort (n/N = 16/767). The final multivariable neurotoxicity assessment tool included weight, Charlson comorbidity score, age, and estimated creatinine clearance as predictors of neurotoxicity. Incidence of neurotoxicity reached 4% in those with a body mass index more than 30 kg/m2. Use of the candidate variables in the neurotoxicity assessment tool suggested that a score more than 35 would identify a patient at high risk for neurotoxicity with 75% sensitivity and 54% specificity.

Conclusions

In this single center cohort of critically ill patients, beta-lactam neurotoxicity was demonstrated less frequently than previously reported. We identified obesity as a novel risk factor for the development of neurotoxicity. The prediction model needs to be further refined before it can be used in clinical practice as a tool to avoid drug-related harm.

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Funding

This study was supported in part by the Mayo Clinic Department of Pharmacy, the National Institutes of Health National Center for Advancing Translational Sciences under Award Number UL1 TR002377, and the National Institute of Allergy and Infectious Diseases under Award Number K23AI143882 (PI; EFB). The aforementioned funding sources had no role in study development, data accrual, statistical analysis, or interpretation of study findings do not represent the official views of the National Institutes of Health.

Author information

Authors and Affiliations

  1. Department of Pharmacy, Mayo Clinic, 200 1st St SW, Rochester, MN, 55902, USA

    Natalie A. Haddad, Diana J. Schreier, Sarah B. Leung & Erin F. Barreto

  2. Division of Neurology, Mayo Clinic, Rochester, MN, USA

    Jennifer E. Fugate, Sara E. Hocker & Alejandro A. Rabinstein

  3. Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA

    Ognjen Gajic

  4. Department of Pharmacy, Spectrum Health, Grand Rapids, MI, USA

    Calvin J. Ice

  5. Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN, USA

    Kristin C. Mara

  6. Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA

    Andrew D. Rule

  7. Division of Epidemiology, Mayo Clinic, Rochester, MN, USA

    Andrew D. Rule

Authors
  1. Natalie A. Haddad
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  2. Diana J. Schreier
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  3. Jennifer E. Fugate
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  4. Ognjen Gajic
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  5. Sara E. Hocker
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  6. Calvin J. Ice
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  7. Sarah B. Leung
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  8. Kristin C. Mara
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  9. Alejandro A. Rabinstein
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  10. Andrew D. Rule
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  11. Erin F. Barreto
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Contributions

NH had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the analysis. She helped to design the study, gather data on included patients with assistance from the members of the Mayo Clinic Anesthesia Clinical Research Unit team cited in the Acknowledgments, and draft the article. CI and SL assisted with study design. EB and DS assisted with study design, data collection, and contributed heavily to article drafting. KM helped to design the study and to review the statistical analysis. AAR, JF, SH, NH, and EB assisted with clinical adjudication of possible neurotoxicity cases. ADR and OG contributed to article editing and analysis. All authors reviewed the data, participated in discussions related to interpretation, and read and approved the final manuscript.

Corresponding author

Correspondence to Erin F. Barreto.

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Ethical approval/informed consent

This study was approved by the Mayo Clinic Investigational Review Board (number 14-007857), and all ethical guidelines have been adhered to.

Conflicts of interest

All authors report no conflicts of interest or financial relationships to disclose.

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Haddad, N.A., Schreier, D.J., Fugate, J.E. et al. Incidence and Predictive Factors Associated with Beta-Lactam Neurotoxicity in the Critically Ill: A Retrospective Cohort Study. Neurocrit Care 37, 73–80 (2022). https://doi.org/10.1007/s12028-022-01442-1

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  • DOI: https://doi.org/10.1007/s12028-022-01442-1

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