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

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.

Keywords: Antibiotic; Cefepime; Encephalopathy; Piperacillin/tazobactam.

Figure 1. Study Protocol:

Study flow diagram of derivation and validation cohorts of ICU patients receiving beta-lactams. Final derivation cohort after applying exclusion criteria was 1323 patients, 34 of whom had neurotoxicity. The final validation cohort included 767 patients, with true neurotoxicity identified in 16 patients.

Figure 2. Incidence of Neurotoxicity:

Cumulative incidence of neurotoxicity in derivation cohort patients (n = 34). The highest incidence of neurotoxicity was found in patients on cefepime and toxicity occurred at a median of two days into beta-lactam therapy.