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

Abstract

BackgroundDelirium is a potentially severe form of acute encephalopathy. Minocycline has neuroprotective effects in animal models of neurological diseases; however, data from human studies remain scarce. Research QuestionDoes the neuroprotective effect of minocycline prevent delirium occurrence in critical ill patients? Study design and MethodsThis study was a randomized, placebo-controlled, double-blind trial conducted in four Intensive Care Units (ICUs). Patients aged 18 years or older were eligible and randomized to receive minocycline (100 mg twice a day) 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 different inflammatory (interleukin-1β, interleukin-6, interleukin-10, and C-reactive protein) and brain-related biomarkers (brain-derived neurotrophic factor and S-100B) were used as exploratory outcomes. ResultsA total of 160 patients were randomized, but one patients on the placebo group died before treatment, thus 159 patients were analyzed (minocycline, n=84; placebo, n=75). After the COVID-19 pandemic it was decided to early stop patient inclusion. There was a small but significant decrease in delirium incidence (17 (20%) patients in the minocycline arm compared to 26 (35%) patients in the placebo arm, P=0.043). No other delirium-related outcomes were modified by minocycline treatment. Unexpectedly, there was a significant decrease in hospital mortality (39% vs. 23%, P=0.029). Among all analyzed biomarkers, only plasma levels of C-reactive protein decreased significantly after minocycline treatment (F=0.75, P=0.78 within time; F=4.09, P=0.045 group⋅time). InterpretationOur findings in this rather small study signals 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 RegistrationNCT04219735