Midodrine for the early liberation from vasopressor support in the ICU (LIBERATE): A Vanguard Randomized Clinical Trial

Midodrine for the early liberation from vasopressor support in the ICU (LIBERATE): A Vanguard Randomized Clinical Trial | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Midodrine for the early liberation from vasopressor support in the ICU (LIBERATE): A Vanguard Randomized Clinical Trial Dawn Opgenorth , Fadi Hammal , Deborah J. Cook , D’Arcy Duquette , Stephanie Sibley , Jennifer Tsang , Janek Senaratne , Kirsten Fiest , Vincent Lau , Fernando G Zampieri , Sean M Bagshaw , Oleksa G Rewa doi: https://doi.org/10.1101/2025.07.31.25332174 Dawn Opgenorth 1 Department of Critical Care Medicine, Faculty of Medicine and Dentistry, University of Alberta, and Alberta Health Services , Edmonton AB, Canada Find this author on Google Scholar Find this author on PubMed Search for this author on this site Fadi Hammal 1 Department of Critical Care Medicine, Faculty of Medicine and Dentistry, University of Alberta, and Alberta Health Services , Edmonton AB, Canada Find this author on Google Scholar Find this author on PubMed Search for this author on this site Deborah J. Cook 2 Department of Medicine, McMaster University, McMaster Health Sciences Center , Hamilton, ON, Canada Find this author on Google Scholar Find this author on PubMed Search for this author on this site D’Arcy Duquette 3 Critical Care Program Improvement and Integration Network, Alberta Health Services , Alberta, Canada Find this author on Google Scholar Find this author on PubMed Search for this author on this site Stephanie Sibley 4 Department of Critical Care Medicine, Queens University , Kingston, ON, Canada Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jennifer Tsang 5 Niagara Health Knowledge Institute , Niagara Health, St Catharines, ON, Canada Find this author on Google Scholar Find this author on PubMed Search for this author on this site Janek Senaratne 1 Department of Critical Care Medicine, Faculty of Medicine and Dentistry, University of Alberta, and Alberta Health Services , Edmonton AB, Canada Find this author on Google Scholar Find this author on PubMed Search for this author on this site Kirsten Fiest 6 Cumming School of Medicine, University of Calgary , Calgary, AB, Canada Find this author on Google Scholar Find this author on PubMed Search for this author on this site Vincent Lau 1 Department of Critical Care Medicine, Faculty of Medicine and Dentistry, University of Alberta, and Alberta Health Services , Edmonton AB, Canada Find this author on Google Scholar Find this author on PubMed Search for this author on this site Fernando G Zampieri 1 Department of Critical Care Medicine, Faculty of Medicine and Dentistry, University of Alberta, and Alberta Health Services , Edmonton AB, Canada Find this author on Google Scholar Find this author on PubMed Search for this author on this site Sean M Bagshaw 1 Department of Critical Care Medicine, Faculty of Medicine and Dentistry, University of Alberta, and Alberta Health Services , Edmonton AB, Canada Find this author on Google Scholar Find this author on PubMed Search for this author on this site Oleksa G Rewa 1 Department of Critical Care Medicine, Faculty of Medicine and Dentistry, University of Alberta, and Alberta Health Services , Edmonton AB, Canada Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: rewa{at}ualberta.ca Abstract Full Text Info/History Metrics Supplementary material Data/Code Preview PDF 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. Trial Registration Registered September 28, 2021. https://clinicaltrials.gov/study/NCT05058612 Background Intravenous (IV) vasopressors are the standard of care for critically ill patients who develop shock.[ 1 – 5 ] This is necessary in 15-40% of critically ill patients.[ 1 ] However, vasopressors for hemodynamic support can be associated with risk of tissue necrosis, vascular injury, cardiac dysrhythmias, and bowel ischemia.[ 6 ] Oral vasopressors do not carry these risks.[ 7 ] Current clinical practice guidelines do not include a statement on the use of oral vasopressor therapy, and only provide support for the use of IV vasopressors for hemodynamic management of critically ill patients in shock.[ 8 ] An effective oral vasopressor could plausibly shorten the duration of IV vasopressors, reduce the risk of adverse effects, and allow earlier transition of patients from the intensive care unit (ICU). Midodrine hydrochloride is a commonly used alpha-agonist oral vasopressor, and has been traditionally used to reduce symptoms of orthostatic and intra-dialytic hypotension in non-critically ill patients.[ 9 – 12 ] Midodrine has good oral bioavailability (i.e., 93%), and a half-life of 3 hours, allowing less frequent dosing and auto-off titration when stopping the medication. A systematic review by our study team identified 17 studies evaluating the role of midodrine in 2,567 critically ill patients.[ 13 ] In pooled analysis from 6 RCTs published in complete form (i.e., 374 patients), we found that midodrine may decrease ICU length of stay (LOS) by 1.01 days when compared with placebo, with a low certainty of evidence. Findings of this systematic review provided strong rationale for a more robust and rigorous evidence base to understand the role for midodrine in critically ill patients receiving IV vasopressors.[ 14 – 19 ] The LIBERATE Vanguard study is a pilot multi-centre, concealed-allocation, parallel-group, blinded randomized controlled trial (RCT) that tests the hypothesis that use of adjunctive midodrine will decrease ICU LOS in ICU patients with IV vasopressor–dependent shock. Previously, we conducted a pilot single-centre RCT to refine the study protocol demonstrate the feasibility and safety of the trial design.[ 20 ] As a next step we have conducted a multi-centre pilot RCT to assess the feasibility of timely recruitment and protocol adherence in the implementation of the protocol in a multi-centre setting to include both academic and community sites. The results of the LIBERATE Vanguard study will inform the LIBERATE trial. Methods Study Design We conducted a pilot multi-centre, concealed-allocation, parallel-group, blinded randomized controlled trial (RCT) in 9 Canadian mixed medical surgical ICUs, in which patients were allocated to a placebo or midodrine in a 1:1 ratio. We included the first 20% of patients from the sample size of the planned LIBERATE RCT. This study was registered with clinicaltrials.gov on September 28, 2021 ( NCT05058612 ). Ethics and consent for participation This study was approved by the University of Alberta Research Ethics Board (ARISE) on November 26, 2021 (Pro00112293) and the Queen’s University Health Sciences and Affiliated Teaching Hospitals Research Ethics Board on September 1, 2023 (CTO Project ID: 4459). Informed consent was provided by either the patient or their surrogate decision maker (SDM). If the patient lacked capacity and an SDM could not be identified or contacted at the time of study eligibility, a deferred consent model was utilized (also known as consent to continue), and written consent was obtained from the patient once they regained capacity. Study setting The trial was conducted at 3 academic and 6 community hospitals in Alberta and Ontario. The Research Office in the Department of Critical Care Medicine at the University of Alberta was the Coordinating Centre and responsible for protocol development, data capture, preparation and dispensing of the study investigational product (IP) and the overall coordination and maintenance of study operations. The study was monitored by the Clinical Trials Office (CTO) at the University of Alberta ( https://www.ualberta.ca/en/health-sciences/research/university-of-alberta-clinical-trials/clinical-trials-office.html ) Inclusion criteria Adult patients aged ≥18 years, admitted to ICU and receiving a continuous infusion of IV vasopressor support, defined by a minimum of any one of norepinephrine ≥0.05 mcg/kg/min, epinephrine ≥0.05 mcg/kg/min, vasopressin ≥0.04LU/min, or phenylephrine ≥0.1mcg/kg/min; along with evidence of a decreasing vasopressor dose, defined as the dose at the time of screening being less than peak dose in the preceding 24 hours were screened for eligibility. Exclusion criteria Those whose were over 24 hours from peak vasopressor dose, had a contraindication to enteral medications or had a known allergy to midodrine, had received midodrine in the last 7 days prior to screening, were expected to die or have withdrawal of life-sustaining therapies in the next 24 hours or were pregnant, were excluded from participation. Study intervention All participants received standardized vital and physiological monitoring while they received the study intervention. Monitoring included continuous heart rate, 3-lead electrocardiogram (ECG), pulse oximetry and intravascular blood pressure monitoring. Vital signs and physiological parameters including but not limited to respiratory rate, non-invasive blood pressure monitoring, Glasgow Coma Scale, and urine output were monitored hourly – or more frequently – as needed. Patients randomized to the experimental treatment received midodrine 10 mg administered enterally, every 8 hours from time of study inclusion to 24 hours after IV vasopressor termination. This dose was chosen as it was the most commonly used dose of midodrine used in previous studies and the highest dose as per the product monograph.[ 21 ] Due to its prolonged half-life when compared to norepinephrine, midodrine does not require a tapering of dose. Patients randomized to the control arm received a placebo administered enterally every 8 hours from time of study inclusion to 24 hours after IV vasopressor termination. The study investigational product (IP) was prepared by a compounding pharmacy in Edmonton, Alberta ( https://www.strathconapharmacy.com/strathcona-compounding-ltd-.html ) and underwent dosage testing at an accredited laboratory ( https://www.keystonelabs.ca/ ) prior to dispensation. The IP was prepared, labelled and dispensed by an unblinded research pharmacy and administered by the blinded bedside nurse. If the patient had an oral/nasal feeding tube, the contents was removed from the study capsule, mixed with water and administered through the feeding tube. Sites without a dedicated research pharmacy received pre-dispensed, blinded study drug containers prepared by the Edmonton compounding pharmacy, labeled with randomization codes and assigned sequentially upon patient enrollment. Randomization, blinding and allocation concealment Patients were randomized in a 1:1 ratio to midodrine or placebo using permuted blocks of undisclosed and variable size. Randomization was stratified by site. Intensivists, research personnel, patients, the ICU treating team, members of the executive and steering committees and data analysts were blinded to the treatment allocations. The midodrine and placebo IP were indistinguishable, in identical capsule form. Only the research pharmacy team responsible for conducting the treatment allocation and preparation of the IP were unblinded to prepare study drug. Primary feasibility outcomes The primary feasibility outcomes were, 1) recruitment rates, with a target average of >= 1 patient per site per month; 2) screening and enrollment characteristics; 3) protocol adherence for administered study medication, with a target protocol adherence of >= 80%; 4) retention rate, with a target of having >= 90% of recruited participants completing study outcomes, 5) data completeness, with a target of >=95% of all data being collected as intended; and 6) adverse event, with a target of monitoring and reporting on all adverse events. Secondary clinical outcomes The secondary clinical outcome measures included: ICU mortality, ICU and hospital length of stay, duration of IV vasopressor support, 90-day all-cause mortality, ICU readmission, and re-initiation of IV vasopressors. Data collection Data was collected from the patient clinical record and entered into an electronic case report form (CRF) (REDCap, Vanderbilt [ https://project-redcap.org/ ]). Study sites were provided an identical paper CRF as a data collection tool, however study coordinators could opt to enter data directly into the electronic CRF and only electronic CRF data was reviewed by the study monitor. Variables collected included demographics, baseline characteristics, daily ICU treatments (mechanical ventilation, renal replacement therapy, vasopressors, corticosteroids, intravenous fluids, fluid balance, blood products and sedatives) until ICU discharge, death or day 30, whichever came first. Follow up was performed 90 days after discharge to record death or persistent organ dysfunction (defined as dependency on mechanical ventilation, renal replacement therapy or ongoing IV vasopressor use) ( https://www.ualberta.ca/en/critical-care/media-library/documents/liberate-crf-v8.0_may_18_2023_clean.pdf ). Statistical analysis Analyses of the primary outcome was descriptive. Secondary outcomes involved summary measures obtained by aggregating the endpoints. No comparisons were conducted between groups as this vanguard study was conducted to address trial objectives as outlined earlier; allocation primarily to assess recruitment rates and protocol adherence, retention rates, data completeness and safety. Results are reported herein as proportions and means with standard deviations, as appropriate. Management To ensure protocol adherence and data quality, site initiation visits were held for research personnel at each site. In addition, the Coordinating Centre provided additional one on one training on request. A manual of procedures, training slides and website containing study documents ( https://www.ualberta.ca/en/critical-care/research/liberate/index.html ) were available to each research site. A newsletter containing frequently asked questions was published quarterly. This trial is Health Canada regulated. The Clinical Trials Office at the University of Alberta developed a detailed monitoring plan and conducted ongoing study monitoring of all study sites. Safety and adverse events Reportable adverse events (AEs) were those considered to be related to study treatment or in the principal investigator’s clinical judgement were not recognised events consistent with the participants underlying critical illness and/or chronic diseases and expected clinical course. The reporting of adverse events followed the 5 recommendations for rational reporting of serious adverse events in investigator-initiated critical care trials of drugs in common use.[ 22 ] The adverse events to be reported included: clinically significant bradycardia (as per the judgement of the treating team); acute coronary syndrome (unstable angina, non-STEMI or STEMI); allergic event(s) (paresthesia, piloerection, dysuria, pruritis, chills, pain or rash); hypertension (sustained systolic measurement over 180mm Hg; bowel ischemia (clinically significant as per the judgement of the treating team); limb ischemia (clinically significant as per the judgement of the treating team); stroke (radiographical diagnosis); or other event considered to be related to study treatment or in the PI’s clinical judgement is not recognised as consistent with the subjects underlying critical illness and/or chronic disease and expected clinical course. Results Patient characteristics Patients had a mean age of 61.5 (SD 15.3) and 68 (40.2%) were female. (Table 1) The mean Acute Physiology and Health Evaluation (APACHEII) score 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). The mean Clinical Frailty Scale score was 4.0 (SD 1.6). Etiology of shock included: sepsis (61.5%, n=104), hypovolemia (13.0%, n=22), anaphylaxis (1.2%, n=2), cardiogenic (9.5%, n=16), neurogenic (6.5%, n=11), other cause (7.1%, n=12) and unknown (1.2%, n=2). The most frequently reported comorbid conditions at baseline included: diabetes mellitus (29.3%, n=51), respiratory insufficiency (18.4%, n=32), immune suppression (16.7%, n=29), coronary artery disease (13.8%, n=24) and congestive heart failure (11.5%, n=20). Aside from IV vasopressors, ventilation was the most common reported intervention (87.9%, n=153), followed by sedation (60.9%, n=106), corticosteroids (33.3%, n=58), blood products (10.9%, n=19), and renal replacement therapy (5.2%, n=9). (Table 2) IV vasopressor and inotropic treatment included norepinephrine (99.4%, n=167), vasopressin (40.5%, n=68), epinephrine (3.0%, n=5), dobutamine (2.4%, n=4), and phenylephrine (2.4%, n=4) with approximately half the patients receiving one vasopressor (58.9%, n=99); others were receiving two or more vasopressors (41.0%, n=69) at time of study enrollment. Primary Outcomes Recruitment rate The primary feasibility outcomes are outlined in Table 3. A total of 174 patients were enrolled over a 25-month period with an average overall recruitment rate of 7.0 (range 1-20) patients per month and a per site recruitment rate of 1.6 (range 0.4-3.0) patients per month. Screening and enrollment characteristics Screening statistics were reported from 5 of the 9 sites (n=85, 50%); the other 4 sites did not collect screening statistics. For those sites reporting, 705 patients were screened and 620 were excluded. The 3 most common causes for non-enrollment were: a contraindication to enteral medication (n=199, 31.4%); over 24 hours from peak vasopressor dose (n=141, 22.2%); and expected death or withdrawal of treatment (n=98, 15.4%) (Figure 1). Overall, consent was obtained from 34 patients (19.5%), while an SDM provided consent for 62 (35.6%) of the patients and 78 (45.8%) of patients were enrolled under the deferred consent model. Protocol adherence, retention and data completeness Protocol adherence was 83.9% with study medication dose missed/dispensing errors being the most common deviation (14.9%, 26 occurrences) followed by randomized but did not meet inclusion/exclusion criteria (1.1%, 2 occurrences). There were no reports of unblinding of treatment allocation by the study sites. The retention rate was 97.1% with 3 patients withdrawing consent once they regained capacity and 2 patients who died before they could be approached for a regained capacity consent and for who the local REB did not provide waiver of consent. Data completeness was high with an average completion rate of 96%. Adverse events Two reportable adverse events were documented. One patient experienced hypertension (defined as sustained systolic measurement over 180mm Hg) and one patient’s heartrate decreased to 41 beats per minute (clinically significant bradycardia as per the judgement of the treating team). Both events were assessed as moderate in severity, probable for a causal relationship between the study treatment and adverse event, and in both cases, the study treatment was permanently discontinued. Both patients recovered from the adverse event with no sequelae. There were no serious adverse events reported. Secondary outcomes The secondary clinical outcomes are outlined in Table 4, reported in aggregate. The mean length of IV vasopressor support was 43.2 (SD 43.0 hours) and IV vasopressors were reinitiated over 24 hours after cessation in 18.9% (n=32) of patients. Mean ICU and hospital lengths of stay were 11.8 days (SD: 15.6) and 24.7 days (SD: 26.0) respectively. ICU death occurred in 14.8% (n=25) of patients and hospital death in 24.3% (n=41). 1 patient (0.6%) was readmitted to ICU within 48 hours of discharge. Death at 90 days was 33.1% (n=56). 2 patients (1.8%) of patients required ongoing supportive therapies at 90 days and this included, 2 (0.9%) patient receiving renal replacement therapy. Trial oversight A Management Committee comprised of the Principal Investigator and Project Manager acted as the Coordinating Centre and oversaw the study set up and day-to-day activities. The Management Committee met weekly to manage development and execution of the study and ensure appropriate adherence to the study protocol, and was responsible for reporting to and updating the Steering Committee and the Data Safety Management Committee of all study proceedings. The Steering Committee is a multidisciplinary body consisting of research clinicians, a patient-partner, an epidemiologist and a health economics expert. The Steering Committee meets quarterly and provides input on all matters related to the research and protocol agenda and is also responsible for local endorsement of the program of work. The Data Safety Monitoring Committee (DSMC) is an independent body that safeguards the interests of study participants by assessing the safety of study procedures and provides recommendations about continuing or stopping the study based on safety considerations. Every 6 months the DSMC assessed data quality; monitored protocol compliance and participant recruitment, accrual and retention; reviewed adverse event and serious adverse event data; and assessed any external data that may impact the safety of the participants or the ethics of the study. The LIBERATE trial is a Canadian Critical Care Trials (CCCTG) endorsed research program. The CCCTG is a pan-Canadian partnership of multi-disciplinary, interprofessional researchers dedicated to the pursuit of excellence and advancement of critical care research in Canada.[ 23 ] Discussion The Vanguard LIBERATE study established the feasibility of conducting the LIBERATE trial across multiple centers in multiple jurisdictions in a variety of different settings. We determined a mean recruitment rate of 1.6 patients/month/site (range 0.4-6), a screening and enrollment procedure that achieved recruitment targets, adequate protocol adherence (83.9%), high study retention (96.5%) and completeness of data (96%) and only 2 reportable adverse events. Further, we demonstrated that the LIBERATE Vanguard study was feasible at both academic and community sites, having established a mechanism to provide IP in a blinded manner to sites without a dedicated research pharmacy. IV vasopressor therapy for dependant shock is one of the most common forms of physiological support delivered in ICUs.[ 24 ] This occurs across all centers. Further, ICU capacity strain is not limited to a specific type of ICU, and the potential use of midodrine to decrease ICU length of stay is applicable to all ICUs. Having established feasibility at both academic and community sites, the LIBERATE study will ensure to engage with community sites in order to provide equitable access to clinical research and build research capacity in the ICU research community. This is a key goal of the CCCTG through the Canadian Community ICU Research Network.[ 25 – 27 ] To that end, the study protocol was developed according to the Pragmatic-Explanatory Continuum Indicator Summary (PRECIS-2) framework for pragmatic trials.[ 28 ] This pragmatic protocol, which evaluates an inexpensive, readily available therapy, was designed to maximize acceptability at non-traditional research sites, such as community hospitals. One item that emerged was the inconsistencies of sites to collect enrollment data and other complexities and variabilities in recruitment dynamics across different ICUs. This is consistent with findings from previous critical care RCTs.[ 29 ] This variability highlights the need to protocolize the recording of recruitment dynamics and enrollment data for the LIBERATE trial. The LIBERATE Vanguard study is the largest RCT evaluating the use of midodrine in critically ill patients to date. Further, it is the RCT with the highest number of participating sites. The MIDAS study by Santer et al., is next largest. However, this study evaluated 132 patients across 3 centers and required 7 years to recruit this sample size. Additionally, with an extensive list of exclusion criteria that may not truly represent critically ill patients requiring IV vasopressor, may have led to a possible selection bias. It also focused on a non-patient centered outcome (i.e., time to IV vasopressor discontinuation) and did not include a subgroup analysis. Finally, in our recent systematic review, our time sequential analysis revealed a minimal sample size of 1124 patients to determine the effects of midodrine on ICU LOS. While the LIBERATE Vanguard study will add to the published literature, we will not yet achieve the minimal sample size necessary determined by our systematic review. However, the LIBERATE Vanguard study has established feasibility for the LIBERATE study which aims to recruit 870 participants across 25 centers which will definitely determine the utility of adjunctive midodrine therapy for critically ill patients with IV vasopressor dependent shock. Limitations of this study include heterogeneity of recruitment rates between study sites (range 0.3-3.0), although a sufficient number of patients were enrolled overall to meet our recruitment objectives. Reasons provided by low enrolling sites were mainly due to internal resource issues (i.e., inadequate number of research staff, high turn over rate of research staff). The range of recruitments rates will inform our study center to assist sites in achieving adequate recruitment into the LIBERATE study. We have also identified barriers and facilitators for recruitment, and will communicate these with sites. Other important limitations were protocol deviations due to errors in medication dispensing, administration and storage, and that screening logs were not maintained at all study sites. Potential strategies would include, 1) offering additional one on one training sessions for new or existing research staff, and 2) discussing strategies or providing additional tools (i.e., IP discontinuation reminder cards) to mitigate medication errors. In addition, increasing the uptake of screening logs could be achieved by being more prescriptive in the expectations of the study sites or by providing additional financial compensation if a resource issue is identified. Conclusions The utility of midodrine in critically ill patients with IV vasopressor shock is uncertain. The LIBERATE Vanguard study is a vital first step to fulfilling this critical knowledge gap and informing practice. 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. DECLARATIONS Competing interests We confirm there are no conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. All authors are involved in the LIBERATE study in some capacity. Consent for publication We confirm that this manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all. We confirm we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication with respect to intellectual property. In doing so we confirm that we have followed the regulation of our institutions concerning intellectual property. Ethics approval and consent to participate We further confirm any aspect of the work covered in this manuscript that has involved human patients has been conducted with the ethical approval of all relevant bodies and that such approvals are acknowledged within the manuscript. We understand that the Corresponding Author is the sole contact for the Editorial process (including Editorial Manager and direct communications with the office). He is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs. We confirm that we have provided a current, correct email address which is accessible by the Corresponding Author. Availability of data and materials not applicable. Funding Funding is provided by the University of Alberta Hospital Foundation Kaye Fund Role of Funders The funder had no role in development of the study protocol, drafting of the manuscript or decision to submit the work for publication. Contributors DO contributed to study protocol development and drafting of the manuscript, FH, DJC, DD, SS, JT, JS, VL and FZ contributed to study protocol development and critical revision of the manuscript, SMB and OGR conceived the study, developed the protocol and contributed to development and drafting of the manuscript. All of the authors approved the final version to be published. LIBERATE vanguard trial clinical collaborators ⍰ Dr. Janek Senaratne, Anushka Jayasekara, Bernadette Fernando, Isabel Kwek, Larissa Fedor-Turchenek, Grey Nuns Community Hospital, Edmonton, AB ⍰ Dr. Maureen Meade, Lori Hand, Hamilton Health Sciences, Hamilton General Hospital, Hamilton, ON ⍰ Dr. Erika Macintyre, Daniel Ofosu, Misericordia Community Hospital, Edmonton, AB ⍰ Dr. Sangeeta Mehta, Sumesh Shah, Mount Sinai Hospital, Toronto, ON ⍰ Dr. Jocelyn Slemko, Sargun Sokhi, Sturgeon Community Hospital, Edmonton, AB ⍰ Dr. Deborah Cook, France Clarke, St Joseph’s Healthcare, Hamilton, ON ⍰ Dr. Jennifer Tsang, Anna Kim, Emily Baker, Lisa Patterson, Niagara Health, St Catharines, St Catharines, ON ⍰ Dr Victor Dong, Ish Bains, Rockyview General Hospital, Calgary, AB ⍰ Dr. Stephanie Sibley, Miranda Hunt, Tracy Boyd, Kingston Health Sciences Centre, Kingston, ON ⍰ Dr. Oleksa Rewa, Caylin Chadwick, Nadia Baig, Lily Guan, University of Alberta Hospital, Edmonton, AB Acknowledgements SB is supported by a Canada Research Chair in Critical Care Outcomes and Systems Evaluation. DJC is supported by a Canada Research Chair in Knowledge Translation in Critical Care. Footnotes dawno{at}ualberta.ca hammal{at}ualberta.ca debcook{at}mcmaster.ca dvcjduquette{at}shaw.ca Stephanie.Sibley{at}kingstonhsc.ca jennifer.tsang{at}mail.utoronto.ca janeks{at}ualberta.ca kmfiest{at}ucalgary.ca vince.lau{at}ualberta.ca fzampieri{at}ualberta.ca bagshaw{at}ualberta.ca List of Abbreviations IV intravenous RCT randomized control trial LOS length of stay SDM substitute decision maker IP investigational product APACHE Acute Physiology and Chronic Health Evaluation SOFA Sequential Organ Failure Assessment References 1. ↵ Blanch , L. , et al. , Triage decisions for ICU admission: Report from the Task Force of the World Federation of Societies of Intensive and Critical Care Medicine . J Crit Care , 2016 . 36 : p. 301 – 305 . OpenUrl PubMed 2. Jentzer , J.C. , et al. , Pharmacotherapy update on the use of vasopressors and inotropes in the intensive care unit . 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OpenUrl PubMed Web of Science 13. ↵ Kilcommons , S.J. , et al. , Adjunctive Midodrine Therapy for Vasopressor-Dependent Shock in the ICU: A Systematic Review and Meta-Analysis . Crit Care Med , 2025 . 53 ( 2 ): p. e384 – e399 . OpenUrl PubMed 14. ↵ Davoudi-Monfared , E. , et al. , The effect of midodrine on lactate clearance in patients with septic shock: a pilot study . J Comp Eff Res , 2021 . 10 ( 8 ): p. 673 – 683 . OpenUrl PubMed 15. Lal , A. , et al. , Oral Midodrine Administration During the First 24 Hours of Sepsis to Reduce the Need of Vasoactive Agents: Placebo-Controlled Feasibility Clinical Trial . Crit Care Explor , 2021 . 3 ( 5 ): p. e0382 . OpenUrl CrossRef 16. Adly , D.H.E. , et al. , Midodrine improves clinical and economic outcomes in patients with septic shock: a randomized controlled clinical trial . Ir J Med Sci , 2022 . 191 ( 6 ): p. 2785 – 2795 . OpenUrl CrossRef PubMed 17. Ahmed Ali , A.T. , et al. , Effect of Oral Vasopressors Used for Liberation from Intravenous Vasopressors in Intensive Care Unit Patients Recovering from Spinal Shock: A Randomized Controlled Trial . Crit Care Res Pract , 2022 . 2022 : p. 6448504 . OpenUrl PubMed 18. Costa-Pinto , R. , et al. , A pilot, feasibility, randomised controlled trial of midodrine as adjunctive vasopressor for low-dose vasopressor-dependent hypotension in intensive care patients: The MAVERIC study . J Crit Care , 2022 . 67 : p. 166 – 171 . OpenUrl PubMed 19. ↵ Santer , P. , et al. , Effect of midodrine versus placebo on time to vasopressor discontinuation in patients with persistent hypotension in the intensive care unit (MIDAS): an international randomised clinical trial . Intensive Care Med , 2020 . 46 ( 10 ): p. 1884 – 1893 . OpenUrl CrossRef PubMed 20. ↵ Kilcommons , S.J. , et al. , Midodrine for the early liberation from vasopressor support in the ICU (LIBERATE): a feasibility study . Pilot Feasibility Stud , 2024 . 10 ( 1 ): p. 147 . OpenUrl PubMed 21. ↵ Inc., M.P ., MARUMIDODRINE (midodrine hydrochloride) tablets product monograph . 2020 , June 16. 22. ↵ Cook , D. , et al. , Serious adverse events in academic critical care research . CMAJ , 2008 . 178 ( 9 ): p. 1181 – 4 . OpenUrl FREE Full Text 23. ↵ (n.d.)., C.C.C.T.G. Canadian Critical Care Trials Group. Available from: https://www.ccctg.ca . 24. ↵ Thongprayoon , C. , et al. , Temporal trends in the utilization of vasopressors in intensive care units: an epidemiologic study . BMC Pharmacol Toxicol , 2016 . 17 ( 1 ): p. 19 . OpenUrl PubMed 25. ↵ Gehrke , P. , et al. , Factors influencing community intensive care unit research participation: a qualitative descriptive study . Can J Anaesth , 2024 . 71 ( 12 ): p. 1755 – 1768 . OpenUrl 26. Quigley , N. , et al. , Modelling the potential increase in eligible participants in clinical trials with inclusion of community intensive care unit patients in Alberta, Canada: a decision tree analysis . Can J Anaesth , 2024 . 71 ( 3 ): p. 390 – 399 . OpenUrl 27. ↵ Tsang , J.L.Y. , et al. , Academic and Community ICUs Participating in a Critical Care Randomized Trial: A Comparison of Patient Characteristics and Trial Metrics . Crit Care Explor , 2022 . 4 ( 11 ): p. e0794 . OpenUrl PubMed 28. ↵ Loudon , K. , et al. , The PRECIS-2 tool: designing trials that are fit for purpose . BMJ , 2015 . 350 : p. h2147 . OpenUrl FREE Full Text 29. ↵ Takaoka , A. , et al. , Enrolment patterns in a randomized controlled trial of probiotics in critically ill patients: a retrospective analysis of the PROSPECT trial . Trials , 2024 . 25 ( 1 ): p. 851 . OpenUrl PubMed View the discussion thread. Back to top Previous Next Posted August 01, 2025. 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