Prophylactic Minocycline for Delirium in Critically Ill Patients: A Randomized Controlled Trial

Abstract

Background: Delirium is a potentially severe form of acute encephalopathy. Minocycline has neuroprotective effects in animal models of neurologic diseases; however, data from human studies remain scarce.

Research question: Does the neuroprotective effect of minocycline prevent delirium occurrence in critically ill patients?

Study design and methods: This study was a randomized, placebo-controlled, double-anonymized trial conducted in four ICUs. Patients aged 18 years or older were eligible and randomized to receive minocycline (100 mg, twice daily) or placebo. The primary outcome was delirium incidence within 28 days or before ICU discharge. Secondary outcomes included days in delirium during ICU stay, delirium/coma-free days, length of mechanical ventilation, ICU length of stay, ICU mortality, and hospital mortality. The kinetics of various inflammatory (IL-1β, IL-6, IL-10, and C-reactive protein) and brain-related biomarkers (brain-derived neurotrophic factor and S100B) were used as exploratory outcomes.

Results: A total of 160 patients were randomized, but one patient in the placebo group died before treatment; thus the data from 159 patients were analyzed (minocycline, n = 84; placebo, n = 75). After the COVID-19 pandemic it was decided to stop patient inclusion early. There was a small but significant decrease in delirium incidence: 17 patients (20%) in the minocycline arm compared with 26 patients (35%) in the placebo arm (P = .043). No other delirium-related outcomes were modified by minocycline treatment. Unexpectedly, there was a significant decrease in hospital mortality (39% vs. 23%; P = .029). Among all analyzed biomarkers, only plasma levels of C-reactive protein decreased significantly after minocycline treatment (F = 0.75, P = .78, within time; F = 4.09, P = .045, group × time).

Interpretation: Our findings in this rather small study signal a possible positive effect of minocycline on delirium incidence. Further studies are needed to confirm the benefits of this drug as a preventive measure in critically ill patients.

Clinical trial registration: ClinicalTrials.gov; No.: NCT04219735; URL: www.

Clinicaltrials: gov.

Keywords: brain dysfunction; delirium; inflammation; microglia; minocycline.