Encephalopathy in mechanically ventilated adult patients in the intensive care unit: the role of β-Lactam overdosing

Delirium is common in ICU and the neurotoxicity induced by antibiotics could be at least in part responsible for it. This study explored the association between β-Lactam overdosing and persistent coma or delirium in patients under mechanical ventilation. All adult patients admitted in ICU receiving continuous sedation were included. β-Lactam's concentrations were collected during sedation, and up to 48 h after end of continuous sedation. Antibiotic dosings were performed 24 h after initiation or after changing the dose or every 48 h. Overdosing was defined as β-Lactam concentrations above the target for the most resistant pathogen empirically considered, therefore 8 times its clinical breakpoint (BP) according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST). The primary outcome was encephalopathy, defined as either delirium or persistent coma during the 48 h following sedation removal. 224 mechanically ventilated patients were prospectively included, and 190 patients assessed for primary outcome. 58% of patients presented an encephalopathy (30/111 persistent coma and 81/111 delirium), and had longer ventilation duration, more extubation failure, longer ICU length of stay, and higher mortality. β-Lactam overdosing rate was similar in patients with or without encephalopathy. Factors associated with encephalopathy were age, sedation duration and SOFA score. A subgroup analysis suggested an association of encephalopathy with overdosing when defined as per published neurotoxic thresholds. β-Lactam's overdosing was not associated with occurrence of encephalopathy. These data highlight the complexity of delayed awakening and may suggest to broadening the identification of neurotoxic thresholds of individual antibiotics in further studies.