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

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.

Hemodynamic Effects of an Increased Midodrine Dosing Frequency.

In practice, midodrine has been used to reduce IV vasopressor requirements and decrease ICU length of stay. However, recent publications have failed to show clinical success when midodrine was administered every 8 hours. One possible reason for the lack of clinical efficacy at this dosing interval may be the pharmacokinetic properties of midodrine that support a more frequent dosing interval. Here, we report our institutional experience with midodrine at a dosing frequency of every 6 hours. DESIGN: Single, quaternary academic medical center, retrospective, descriptive study. SETTING: Floor and ICU patients admitted to Mayo Clinic, Rochester, from May 7, 2018, to September 30, 2020. PATIENTS: Adult patients with an order for midodrine with a dosing frequency of "every 6 hours" or "four times daily" were eligible for inclusion. INTERVENTIONS: No intervention performed. All data were abstracted retrospectively from the electronic medical record. MEASUREMENTS AND MAIN RESULTS: Forty-four unique patients were identified that met inclusion criteria. Patients were an average of 65 years and 63.6% were male. The individual doses of midodrine ranged from 5 to 20 mg. Twenty-three patients (52.3%) were receiving IV vasopressors at the time midodrine was ordered every 6 hours. Vasopressor requirements decreased from an average of 0.10 norepinephrine equivalents 24 hours prior to the every 6-hour order to 0.05 norepinephrine equivalents 24 hours after an order for midodrine every 6 hour was placed. CONCLUSIONS: Increasing the dosing frequency of midodrine to every 6 hours may optimize its pharmacokinetic profile without compromising safety. This midodrine dosing frequency should be prospectively evaluated as a primary strategy for accelerated IV vasopressor wean.