ABSTRACT

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 Vanguard Study 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 oral midodrine versus placebo on the duration of IV vasopressor-dependent shock in the intensive care unit (ICU) on the first 20% of planned sample size for the LIBERATE trial. The study was performed in 9 Alberta and Ontario medical centres between September 16, 2022 and September 30, 2024. 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 174 patients fulfilled eligibility criteria and were enrolled in the trial. The mean age was 61.5 (SD 15.3) and 68 (40.2%) were female. The mean Acute Physiology and Health Evaluation (APACHEII) score at ICU admission was 23.5 (SD 7.3) and the mean Sequential Organ Failure Assessment (SOFA) score at time of study enrollment was 10.2 (SD 2.9). Sepsis was the most common cause of shock in both groups. Average recruitment was 1.6 participants (range 0.4 to 3.0) per study site per month, protocol adherence was 83.9%, retention rate was 97.1%, and there were no reports of unblinding of treatment allocation by the study sites. 2 adverse events were reported and resolved with no sequelae.

Conclusion The LIBERATE Vanguard trial is feasible and safe, supporting a larger trial to investigate the utility of midodrine in critically ill patients with IV vasopressor dependent shock.

Competing Interest Statement

The authors have declared no competing interest.

Clinical Trial

NCT05058612

Clinical Protocols

https://www.ualberta.ca/en/critical-care/research/liberate/index.html

Funding Statement

This study was funded by the University of Alberta Kaye Competition.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethics committee/IRB of the University of Alberta gave ethical approval for this work.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data Availability

Data produced in the present study are available upon reasonable request to the authors. However, group clinical outcome data remain blinded to the authors as this study is the vanguard phase of the LIBERATE trial.

List of AbbreviationsIVintravenousRCTrandomized control trialLOSlength of staySDMsubstitute decision makerIPinvestigational productAPACHEAcute Physiology and Chronic Health EvaluationSOFASequential Organ Failure Assessment