The LIBERATE Internal Randomized Controlled Pilot Trial: Adjunctive midodrine therapy for early liberation from vasopressor support in critically ill patients

Background Intravenous (IV) vasopressors are the mainstay of hemodynamic physiological support for critically ill patients. However, the role of oral vasopressors in the management of IV vasopressor-dependent shock remains unclear. The LIBERATE body of work aims to examine the role of midodrine as an IV vasopressor sparing agent for critically ill patients with IV vasopressor dependent shock. The objective of the LIBERATE internal randomized controlled trial was to evaluate the implementation of the LIBERATE protocol in a multi-centre randomized control trial setting. Methods We conducted a pilot multi-centre, concealed-allocation, parallel-group, blinded randomized controlled trial (RCT) evaluating the effect of midodrine 10mg q8h versus placebo on the duration of IV vasopressor-dependent shock in the intensive care unit (ICU) on the first 200 of planned sample size for the LIBERATE trial. The study was performed in 9 Alberta and Ontario medical centres between September 16, 2022 and January 22, 2025. We included patients aged 18 years or older admitted to the ICU receiving ongoing IV vasopressor support. Patients were randomly assigned 1:1 to enteral midodrine or an identical placebo and received the study treatment until 24 hours after discontinuation of their IV vasopressor therapy. The primary endpoints were study feasibility and included: recruitment rate (monthly enrollment per study site), screening and enrollment characteristics, protocol adherence, retention rate, data completeness, and safety (adverse event reporting), Secondary endpoints focused on aggregate patient-centered outcomes. Results There were 200 patients who fulfilled eligibility criteria and were enrolled in the trial. The mean age was 61.7 (SD 15.0), and 80 (40.1%) were female. The mean Acute Physiology and Health Evaluation (APACHE II) score at ICU admission was 23.7 (SD 7.6) and the mean Sequential Organ Failure Assessment (SOFA) score at the time of study enrollment was 10.1 (SD 2.9). Sepsis was the most common cause of shock in both groups. Average recruitment was 1.4 participants (range 0.3 to 3.0) per study site per month, protocol adherence was 84.5%, retention rate was 97.0%, and there were no reports of unblinding of treatment allocation by the study sites. Two adverse events were reported and resolved with no sequelae. Conclusion The LIBERATE internal randomized controlled trial is feasible and safe, supporting a larger trial to investigate the utility of midodrine in critically ill patients with IV vasopressor-dependent shock.