Midodrine for the Early Liberation of Vasopressor Support in the ICU (LIBERATE Multi-Site)

Study Overview
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Brief Summary
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Vasopressors are medications that are given intravenously to increase the blood pressure of patients with illnesses that cause dangerous blood pressure drops. When a doctor prescribes a vasopressor, they ask that the dose be adjusted to achieve a specific blood pressure. This kind of medical support with intravenous (IV) vasopressors are usual treatments in intensive care unit (ICU) settings. Oral vasopressors, such as midodrine, have been historically used to maintain blood pressure in non-critically ill patients. In this study, the investigators will be using midodrine to reduce the need for IV vasopressors as blood pressure improves during the stay in the ICU. The LIBERATE multi-site study will continue the work of the pilot study to evaluate the role of midodrine for patients with low blood pressure in the ICU.

Detailed Description
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Purpose: Resuscitation and hemodynamic support with intravenous (IV) vasopressors is a prime indication of treatment in intensive care unit (ICU) settings. Hemodynamic support is typically provided with intravenous (IV) vasopressors. However, these have been shown to have significant negative effects including increased central venous catheter line associated infections, venous thromboembolic disease, impaired mobility and gastrointestinal injury and ischemia. Oral vasopressors, such as midodrine, have been historically used for hemodynamic support in non-critically ill patients, but their study in patients as IV pressor sparing therapy has been limited. Hypothesis: to evaluate the expanded role of midodrine for any vasoplegic patients in the ICU. Justification: In 2018, there were 1,613 admissions to the adult general systems ICU (GSICU) at the University of Alberta Hospital (UAH). Patients were sick, with a mean Acute Physiology and Chronic Health Evaluation II (APACHE) score of 21.3, with 36.4% requiring vasopressors on admission, accounting for 1942 patient-days (data from eCritical TRACER database). In the environment strained healthcare resources and limited ICU capacity, the ability to safely wean patients from IV vasopressors with transition to oral hemodynamic supporting agents would greatly improve how patients navigate through the healthcare system. This in turn will improve patient-centered case. Primary Objective: To compare the effect of enteral midodrine vs. placebo in critically ill patients with vasoplegia receiving continuous IV vasopressor therapy on ICU length of stay. Secondary Objectives: To compare the effect of enteral midodrine vs. placebo on: Total and post-hospital length of stay, Duration of IV vasopressor support, 90-day all-cause mortality, Rates of ICU re-admission, Rate of re-initiation of IV vasopressors. Tertiary Objectives: To determine the health economic effects of the usage of midodrine vs placebo on: ICU costs, Hospital costs, Total healthcare costs, Cost-effectiveness. Safety Endpoints: Adverse drug reactions, Serious adverse drug reactions, Suspected unexpected serious adverse reactions. Research Method/Procedures: The LIBERATE Trial is a multi center, concealed-allocation parallel-group blinded randomized controlled trial. Patients will be randomly assigned to midodrine (enteral, 10mg every 8h) or placebo (microcrystalline cellulose) for the duration of their IV vasopressor therapy and 24h following the discontinuation of their IV vasopressor therapy. The recruitment target is 350 patients (i.e., 175 patients per arm) with full follow-up.

Official Title
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Midodrine for the Early Liberation From Vasopressor Support in the ICU - The LIBERATE Multi-Site Study

Conditions
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Vasoplegia

Intervention / Treatment
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* Drug: Midodrine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 18 years Ongoing vasopressor support Decreasing vasopressor dose(s) Exclusion Criteria: Greater than 24 hours from peak vasopressor dose Contraindication to enteral medications Previously received midodrine in last 7 days Expected death or anticipated withdrawal of life-sustaining therapies in next 24 hours Pregnancy Known allergy to midodrine

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Midodrine<br>Midodrine 10 mg PO/NG q8h | Drug: Midodrine<br>* 10 mg PO/NG q8h<br>|
| Placebo Comparator: Placebo<br>Microcrystalline cellulose PO/NG q8h | Drug: Placebo<br>* Microcrystalline cellulose PO/NG 18h<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ICU length of stay | The total duration of patient stay in ICU | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total and post-ICU length of stay | The total duration of patient stay in hospital and the duration of hospital stay after ICU discharge | 1 year | 
| Duration of vasopressor support | Duration of intravenous vasopressor support | 1 year | 
| Mortality | All cause mortality within 90 days of study recruitment | up to 90 days | 
| ICU readmission | Rate of ICU re-admissions during the index hospitalization | 1 year | 
| Re-initiation of vasopressors | Rate of re-initiation of intravenous vasopressors during ICU stay | 1 year | 
| ICU costs | Total cost of ICU stay | 1 year | 
| Hospital costs | Total cost of hospital stay | 1 year | 
| Total health care costs | Total healthcare costs | 1 year | 
| Cost effectiveness | Incremental costs and effectiveness based on daily ICU costs | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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critical care medicine, intensive care, shock, midodrine