Midodrine for the early liberation from vasopressor support in the ICU (LIBERATE): A feasibility study

doi:10.21203/rs.3.rs-3843817/v1

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Research Article

Midodrine for the early liberation from vasopressor support in the ICU (LIBERATE): A feasibility study

https://doi.org/10.21203/rs.3.rs-3843817/v1

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Background: Malnutrition is the most common nutritional disorder in developing countries and it remains one of the most common causes of morbidity and mortality among children worldwide. Childhood malnutrition is a multi-dimensional problem. An increase in household income is not sufficient to reduce childhood malnutrition if children are deprived of food security, education, access to water, sanitation and health services. However, due to regional variations in prevalence of acute malnutrition, it is important to explore the risk factors specific to the region, for designing and implementing public health interventions.

Objective: To assess the prevalence and risk factors of malnutrition among children under five years

Methods: A descriptive study enrolled 100 children under five years in Helat Hassan Health Centre, Wad-Medani, Gezira State during the period from November 2020 - March 2021. Data regarding children and families characteristics, nutritional history, health and medical history and anthropometric measurements were collected. Malnutrition was defined according to WHO guideline as -3SD of age specific BMI

Results: Among 100 children, 59(59%) males and 41(41%) females, their mean age was 33±18 months. The frequency of malnutrition was 10% (n=10) and underweighting was 18% (n=18). Child's related risk factors associated with malnutrition were; children order above 4th (P. value= 0.000) and number of under 5 children in family above 3 children (P. value= 0.00). Family's related risk factors associated with malnutrition were; younger mother blow 30 years (P. value= 0.001), non-mother (relative) caregivers (P. value= 0.000), illiterate mothers (P. value= 0.046), employed mothers (P. value= 0.000), relative as income responsible (P. value= 0.009), lack of medical insurance (P. value= 0.047), lack of in-home source of water (P. value= 0.003), and low income blow 6,000 SDG (P. value= 0.000). Nutritional related risk factors associated with malnutrition were; lack of exclusive breastfeeding (P. value= 0.000), less than three meals per day (P. value= 0.021), lack of vegetables and fruits in daily nutrition (P. value= 0.006) and lack of milk and dietary products in daily nutrition (P. value= 0.000). Health related risk factors associated with malnutrition were; illness as cause of health care center visit (P. value= 0.018), anemia (P. value= 0.002), admission to hospital in last 2 months (P. value= 0.005), fever, cough, runny rose or chest infection in last 2 weeks (P. value= 0.032), chronic diarrhea (20.7%; P. value= 0.018) and history of malnutrition (P. value= 0.001).

Conclusion: The frequency of malnutrition is not neglectable in Helat Hassan Health Centre at Wad-Medani. Malnutrition was found to be multi-factorial and associated with child, family, nutritional and health related factors. Effective, efficient and equitable program and intervention should be designed to reduce child malnutrition

Intensive Care Unit

Critical Care

Shock

Vasopressors

Midodrine

Resuscitation and hemodynamic support with intravenous (IV) vasopressors is one of the primary indications for admission and treatment in intensive care units (ICU) (2). Patients in need of hemodynamic support require IV vasopressors, however, use of these drugs is associated with important negative patient effects including tissue necrosis, tissue thrombosis, cardiac dysrhythmias and dysfunction, bowel ischemia, as well as need of central venous catheters (3). The presence of central venous catheters required for the infusion of IV vasopressors can lead to adverse events such as increased risk of central line-associated bloodstream infections, venous thrombosis, impaired mobilization, and can prolong ICU length of stay (LOS) (4–7). Oral vasopressors have been historically used for hemodynamic support in non-critically ill patients, but their study in critically ill patients as IV vasopressor sparing therapy has been limited (8–10). One such oral vasopressor is midodrine hydrochloride, which is an alpha agonist that has previously been used to attenuate symptoms of orthostatic and intra-dialytic hypotension (11, 12).

Previous studies have evaluated the use of midodrine for hemodynamic support in the ICU (13–24). The earliest of these involved retrospective exploratory cohort studies with inconsistent midodrine administration protocols, heterogeneous and poorly defined patient populations, small sample sizes, and variable study outcomes (13–15). Subsequently, several small randomized controlled trials (RCTs) have evaluated the role of midodrine in critically ill patients. Our study team recently completed a systematic review and meta-analysis to examine the role of midodrine in critically ill patients (25). This review identified 6 recent RCTs evaluating the role of midodrine in various critically ill populations (16, 18–21). However, while identifying midodrine may reduce ICU LOS, duration of IV vasopressor support, and may even decrease hospital mortality, these studies were all underpowered, imprecise, and contained significant risks of bias (25). While potentially important, these findings are based on low certainty of evidence. Additionally, the timing of midodrine administration was inconsistent (i.e., early vs. late), further limiting the ability to evaluate the data in aggregate. The notion that the use of an oral agent such as midodrine may be used as patients are beginning to recover from their critical illness remains unexplored. Larger trials are needed to determine the role of midodrine in this setting.

The LIBERATE study (NCT05058612) will be the largest study to date, will be adequately powered for a minimal clinically important outcome (MCID), and will follow a rigorous trial methodology to determine whether midodrine should be used routinely in critically ill patients requiring IV vasopressor therapy as they begin to recover from their critical illness. Accordingly, we conducted this pilot RCT to determine the feasibility of conducting an adequately powered clinical trial to evaluate the efficacy of the implementation of midodrine for early liberation of IV vasopressor support in an ICU setting.

This pilot RCT was registered at clinicaltrials.gov (NCT04489589) and a No Objection Letter was obtained from Health Canada in April 2020 (Supplementary File 1). The study is reported according to the CONSORT statement for pilot studies (Supplementary File 2).

Study Design

The LIBERATE Trial was a single centre, parallel-group, blinded pilot RCT. Patients were randomly assigned to midodrine (oral, 10mg every 8h) or a placebo (identical administration) for the duration of their IV vasopressor therapy, and for 24h following the discontinuation of their IV vasopressor therapy. Patients were followed from recruitment to hospital discharge and then again at 90-days post-discharge.

Ethics

This trial was approved by the local Research Ethics Board (REB) in August 2020 (Pro00096716). Informed consent was obtained from the patient or surrogate decision maker (SDM) prior to being enrolled in the study. A deferred consent model was utilized if the patient lacked capacity and an SDM could not be identified. In these cases, written informed consent was obtained from the patient once they regained capacity.

Setting

This pilot RCT was centrally coordinated by the Department of Critical Care Medicine (DCCM) Research Department at the University of Alberta Hospital. The DCCM Research Department, University of Alberta, was responsible for programming and maintaining the randomization system and REDCap electronic data capture system. The Research Pharmacy at the University of Alberta Hospital was responsible for preparing and dispensing study medication. The study was performed at the General Systems ICU at the University of Alberta Hospital. The study was monitored by the Clinical Trials Office (CTO) of the University of Alberta.

Recruitment

Potentially eligible patients were referred to the research team by intensivists and other ICU staff following admission. When eligible, the research team approached the patient to obtain consent from them or their SDM, or when appropriate, enrolled and obtained consent under a deferred consent model as per local REB recommendations. Patients were then randomized to the midodrine group or the control group, and began treatment immediately per trial allocation. The aim was to recruit a cohort of 20 patients. We believed that this was the minimal amount required to determine our primary feasibility outcomes.

Eligibility

Inclusion criteria

Patients aged 18 years or older admitted to the ICU receiving ongoing vasopressor support (e.g., norepinephrine ≥ 0.05mcg/kg/min, epinephrine ≥ 0.05mcg/kg/min, vasopressin ≥ 0.04u/min or phenylephrine ≥ 0.1mcg/kg/min) with decreasing vasopressor dose(s) (e.g., current dose less than peak dose(s)) were eligible for participation.

Exclusion criteria

Exclusion criteria included being greater than 24 hours from peak vasopressor dose, having contraindications to oral medications, previous midodrine in-take in the last 7 days, expected death or withdrawal of life-sustaining therapies, pregnancy, or known allergy to midodrine.

Randomization and Intervention

Randomization was done by a pharmacist at the research site. Eligible patients were randomized in a 1:1 ratio in variable blocks to midodrine or placebo. We used permuted blocks of undisclosed and variable size. There was no stratification for this pilot study.

Intensivists, research personnel, ICU personnel, participants, members of the Executive and Steering Committees, and the data analysts were blinded to the treatment allocations. Only the pharmacist at the Research Pharmacy who prepared the study drug (e.g., midodrine or placebo) was not blinded. The complete blinding of study medication was achieved by using capsules of crushed midodrine and placebo that were identical in nature.

The experimental arm was midodrine 10mg administered orally q8h from time of study inclusion to 24 hours post IV vasopressor support termination. Participants in the control arm were given placebo orally q8h from time of study inclusion to 24 hours post IV vasopressor support termination. (Supplementary File 3).

Data Collection and Participant Follow-up

Data was gathered April 2021 to July 2022. Outcome data was also collected at 90 days. All study outcomes were documented on the electronic CRFs (i.e., REDCap). Time Points: 1. Baseline data: patient demographics, etiology for hypotension, severity of illness, pre-existing comorbidities, clinical frailty scale 2. Daily data until ICU discharge or 30 days after randomization (whichever came first), protocol adherence, co-interventions (administration of mechanical ventilation, kidney replacement therapy (KRT), vasopressors, corticosteroids, blood products), total daily urine output and net daily fluid balance. 3. 90-day data: death or persistent organ dysfunction (defined as dependency on mechanical ventilation, KRT, or ongoing IV vasopressor use).

Primary outcome

The primary outcomes assessed were whether recruitment for LIBERATE was achievable and feasible. This was assessed through rate of patient recruitment (e.g., number of patients recruited per month, with feasibility defined as greater or equal to 1 patient per month) (1), adherence to study protocol (e.g., proportion of patients participated in the study with full adherence to study protocol, with feasibility determined as greater or equal to 90%) (1), and patient safety (e.g., number of study adverse events recorded, with feasibility determined as no study adverse events).

Secondary outcomes

Secondary outcomes of interest included comparing the effect of oral midodrine vs. placebo on: ICU length of stay, duration of IV vasopressor support, 90-day all-cause mortality, rate of re-initiation of IV vasopressors, rates of ICU re-admission, and adverse events. Co-interventions (i.e., ventilatory support, KRT, steroid use, blood product administration and fluid balance) were also captured.

Data Analysis

Analyses of the primary outcome was descriptive. Secondary outcomes involved summary measures obtained by aggregating the endpoints using Excel 2016. No comparisons were conducted between groups as this was a pilot study being conducted primarily to ensure study feasibility and protocol refinement. Results were reported as proportions and means with standard deviations, as appropriate.

Safety and Adverse Events

During the intervention and while in ICU, all participants received standardized vital and physiological monitoring. This monitoring included continuous heart rate, 3-lead electrocardiogram (ECG), pulse oximetry, and intravascular blood pressure monitoring. Additional vitals and physiological parameters, including but not limited to respiratory rate, non-invasive blood pressure monitoring, Glasgow Coma Scale (GCS), and urine output, were monitored hourly - or more frequently - as needed. A urine or serum pregnancy test for females of childbearing potential was done to exclude pregnant women, as per the clinical team.

We identified 130 patients who were potentially eligible for this study. Of these, 20 (15.4%) were enrolled in the trial. Two patients were enrolled by informed consent, seventeen were enrolled via deferred consent and 1 patient subsequently withdrew from participation. Of the 20 patients who underwent randomization, 11 (55%) were randomly assigned to the midodrine group and 9 (45%) assigned to the placebo group (Fig. 1). All patients who agreed to participate in the study completed follow up at 90 days.

Patient Demographics

Baseline characteristics of the enrolled patients can be seen in Table 1. Participants mean age was 57.8 (SD 9.0) and 56.8 (SD 17.3) for the midodrine and placebo groups, respectively. Sepsis was the most common cause of shock in both the midodrine group (n = 8, 72.7%) and the control group (n = 4, 50.0%), with the second most common cause being hypovolemia (n = 2, 18.2%; n = 2, 25.0%, respectively). One (n = 1, 9%) patient was admitted for anaphylactic shock (midodrine), one (n = 1, 12.5%) for cardiogenic shock (control), and one (n = 1, 12.5%) patient was admitted for shock of an unknown etiology (control).

Table 1

Baseline characteristics
Characteristic	Midodrine	Placebo*	Total (n=19)
Age, years	n=11	n=8	n=19
Mean (SD)	57.8 (9.0)	56.8 (17.3)	57.4 (12.8)
Sex (%)	n=11	n=8	n=19
Female	6 (54.5)	1 (12.5)	7 (36.8)
Male	5 (45.5)	7 (87.5)	12 (63.1)
Weight (kg)	n=11	n=8	n=19
Median	65 (61.0-92.9)	80.8 (73.1-115.6)	75.0 (64.2-101.6)
APACHEII	n=11	n=8	n=19
Mean (SD)	24.3 (6.3)	19.5 (11.0)	22.3 (8.6)
CFS	n=10	N=5	N=15
Mean (SD)	3.4 (1.5)	3.8 (2.8)	3.5 (1.9)
Etiology of Shock (%)	n=11	n=8	n=19
Sepsis	8 (72.7)	4 (50.0)	12 (63.1)
Hypovolemia	2 (18.2)	2 (25.0)	4 (21.0)
Anaphylactic	1 (9.0)	-	1 (5.3)
Cardiogenic	-	1 (12.5)	1 (5.3)
Unknown	-	1 (12.5)	1 (5.3)
Comorbid conditions (%)	n=11	n=8	n=19
Chronic dialysis	-	-	-
Congestive heart failure	1 (9.0)	-	1 (5.3)
Respiratory insufficiency	1 (9.0)	-	1 (5.3)
Chronic liver failure	-	2 (25.0)	2 (10.5)
Diabetes mellitus	3 (27.3)	1 (12.5)	4 (21.0)
Acute liver failure	-	-	-
Immune suppression	1 (9.0)	1 (12.5)	2 (10.5)
Leukemia/lymphoma	-	-	-
Metastatic cancer	-	-	-
Coronary artery disease	1 (9.0)	1 (12.5)	2 (10.5)

*one patient assigned to placebo arm withdrew from study. No study data is available.

Primary Outcome

Our primary outcomes are presented in Table 2. We recorded a recruitment rate of 1.2 participants/month. From the point of initiation to trial completion there were two deviations from study protocol reported (90% adherence), though there were no logistical errors or problems noted with the protocol itself. One, a dispensing error and the other, premature discontinuation of study medication due to an early transfer out of the ICU. Neither deviation necessitated a change to the study protocol or procedures. Allocation remained concealed through the study period, risk of bias remained limited, and there were no safety events reported in the treatment arm.

Table 2

Primary Outcomes
Assessment of Feasibility	Value	Comments
Rate of Patient Recruitment (monthly)	1.2	20 subjects recruited over 16 month period
Protocol Adherence	90%	1. Dispensing error 2. Premature discontinuation of study medication due to early transfer from ICU
Adverse Events	0	No adverse events reported at cause to study medication or otherwise
*Loss of Allocation Concealment	0	Allocation remained concealed through the study period
*Unblinding of Participants and Outcome	0	Blinding maintained through the study period
*Incomplete Outcomes	0	All proposed outcomes were recorded and reported
*Supplementary indices of feasibility not formally specified in methods

Secondary Outcomes

Clinical outcomes of the enrolled patients can be seen in Table 3. Those who received midodrine had a shorter ICU LOS in days (9.6; SD 8.7 vs 10.4; SD 14.5) when compared to placebo. Paradoxically, patients in the midodrine group were on IV vasopressors for longer hours (82.1; SD 84.9) vs 71.9; SD 84.5) when compared to their control group counterparts. Re-initiation on IV vasopressor occurred in four patients (n = 4; 36.4%) in the midodrine group and two (n = 2; 25.0%) in placebo. For both groups, no adverse events at cause to the study medications or otherwise were reported. As well, none of the patients enrolled in the study required readmission to the ICU less than 48 hours following discharge.

Table 3

Clinical Outcomes
Outcome	Midodrine	Placebo*	Total
	n = 11	n = 8	n = 19
Total duration vasopressor support (hrs)
Mean (SD)	82.1 (84.9)	71.9 (84.5)	77.8 (82.5)
Vasopressors initiated over 24 hours after cessation (%)	4 (36.4)	2 (25.0)	6 (31.6)
Death in ICU	1 (9.1)	3 (37.5)	4 (21.0)
ICU length of stay (days)	n = 10	n = 5	n = 15
Mean (SD)	9.6 (8.7)	10.4 (14.5)	9.9 (10.4)
ICU readmission less than 48 hours after ICU discharge	0	0	0
Death in hospital	2 (18.2)	3 (37.5)	5 (26.3)
Hospital length of stay (days)	n = 9	n = 5	n = 15
Mean (SD)	28.3 (20.8)	21.2 (12.4)	25.7 (18.0)
Discharge location (%)
Home	6 (66.7)	4 (80.0)	10 (71.4)
Another hospital	2 (22.2)	1 (20.0)	3 (21.4)
Long-term care facility	1 (11.1)	-	1 (7.1)
*one patient assigned to placebo arm withdrew from study. No study data is available.

ICU interventions are presented in Table 4. Invasive ventilation was the most common intervention recorded in both the midodrine group (n = 8, 72.7%) and the control group (n = 6, 75%). Of all patients enrolled in the trial, six patients did not receive any form of ventilation (midodrine: n = 4, 36.4%; control: n = 2, 25%). KRT was the least common intervention between both groups (n = 3, 15.8%). Hydrocortisone was the most commonly administered corticosteroid within the total cohort; the steroid was infused intravenously to four patients in the midodrine group (n = 4, 36.4%) and three in the control group (n = 3, 37.5%). Concerning blood products, five patients (n = 5, 45.4%) in the midodrine group received pRBC and one (n = 1, 9.1%) received albumin. Comparatively, three patients in the control group received pRBC (n = 3, 37.5%) and no patients received albumin. The reported mean fluid balances were 408.4 mL (SD = 5709.9) and 7752.5 mL (SD = 6088.7) in the midodrine and control groups, respectively.

Table 4

ICU Interventions
Intervention	Midodrine	Placebo*	Total
	n = 11	n = 8	n = 19
Ventilation (%)
Invasive	8 (72.7)	6 (75.0)	14 (73.7)
Non-invasive	2 (18.2)	1 (12.5)	3 (15.8)
High flow	2 (18.2)	1 (12.5)	3 (15.8)
Nasal cannula	3 (27.3)	2 (25.0)	5 (26.3)
none	4 (36.4)	2 (25.0)	6 (31.6)
RRT (%)
CRRT	1 (9.1)	1 (12.5)	2 (10.5)
IHD	-	1 (12.5)	1 (5.3)
Corticosteroids (%)
Hydrocortisone (IV)	4 (36.4)	3 (37.5)	7 (36.8)
Dexamethasone (IV)	2 (18.2)	-	2 (10.5)
Prednisone	2 (18.2)	1 (12.5)	3 (15.8)
Blood products (%)
PRBC	5 (45.4)	3 (37.5)	8 (42.1)
Albumin	1 (9.1)	-	1 (5.3)
FFP	-	-	-
Platelets	-	-	-
cryoprecipitate	-	-	-
Fluid balance (ml)
Mean (SD)	408.4 (5709.9)	7752.5 (6088.7)	3500.6 (6812.4)
*one patient assigned to placebo arm withdrew from study. No study data is available.

In this pilot study, we sought to determine the feasibility of conducting an RCT for the evaluation of midodrine as an adjunctive medication for the weaning of IV vasopressors in the ICU. We found that the study is feasible; recruitment of 1.2 participants per month is achievable, no safety events were reported, and there were no critical deviations from the study protocol. Regarding the clinical outcomes of interest, there was a signal indicating that midodrine may decrease ICU LOS, though counter intuitively we also recognized a longer duration of IV vasopressor administration in the midodrine group. There exists many possible reasons for this, including, but not limited to, the difference in mean fluid balance between both groups, as well as logistical factors. For instance, the decision for ICU discharge is often determined early in the day. Though intriguing, neither of the clinical outcomes were powered for significance, nor were they the focus of this trial.

To date, research evaluating midodrine as an adjunctive vasopressor weaning agent in the ICU has largely been in the form of retrospective, observational studies (13–15, 17, 23, 24). These studies, however, have been limited in terms of their ability to inform clinical practice given the inherent bias attributed to retrospective studies (26). More recently, several small RCTs have been conducted assessing the role of midodrine in the ICU. The largest of these, the MIDAS trial, found there was no difference in IV vasopressor duration or ICU LOS when comparing midodrine to placebo (16). However, the relevance of these findings is arguably limited as patient recruitment took place over 7 years, potentially contributing to selection bias considering the changes one might expect in clinical practice over such a timeframe. As well, despite being the largest RCT of its kind, the study potentially lacks wider generalizability as recruitment was only undertaken at 3 centres and thus possibly a more narrow patient demographic. Furthermore, subsequent RCTs have produced results indicating the oral alpha agonist may influence clinical outcomes for those admitted with vasopressor dependent shock, evidently adding to the uncertainty regarding the utility of midodrine in a critical care setting (19–22). Despite the differences in clinical outcomes, an aspect common to all RCTs evaluating midodrine to date is their clinical utility. Given the relatively small sample sizes and long recruitment periods of past RCTs, the significance of the associated findings is hindered, thus limiting their relevance to clinical practice.

Currently there are no guidelines indicating utility of oral therapies when managing patients in need of hemodynamic support in the ICU (27). The standard of care is limited to three main arms: IV vasopressors, fluid therapy, and time. The success of IV vasopressors in the setting of shock is difficult to refute, as a mainstay the standard of care has saved countless lives. That considered, time is arguably more valuable of a commodity than any, and finding an adjunctive therapy capable of freeing up more of this commodity could serve to help far more than only those in need of hemodynamic support. Finding an effective oral adjuvant for the weaning of IV vasopressors could serve to aid in more than only the earlier liberation of patients admitted to the ICU for shock, a crucial by-product of this effect would be the freeing of ICU beds and other associated resources. Such resources could be allocated to patients in need of critical care that may otherwise be unable to be admitted into the ICUs. Earlier exposure to acute interventions in the ICU due to increased patient turnover can influence patient outcomes (28). Similarly, research has shown that those in hospital in need of intensive care but declined admittance due to triage are at an increased risk of death (29). Determining the clinical utility of midodrine may serve to inform future guidelines of treating shock, one of the most common indications for ICU admission, and thus allow for a higher standard of care for those in need of critical care.

Several key strengths associated with this pilot RCT include the rigorous methodology and strict midodrine dosing protocol, as evidenced by our success in following the study protocol without serious alteration or complication. Additionally, we were able to achieve our primary outcomes by ensuring feasibility of participant recruitment, achieving a recruitment rate of greater than 1 participant per month.

While having these strengths, several weaknesses do exist. First, this was a small pilot study of only 20 patients conducted at a single center. However, with this recruited sample size, we were able to demonstrate study feasibility, protocol adherence, and safety. Further, the size of this study is consistent with other studies evaluating midodrine in critically ill patients (18, 19). Second, due to the small sample size, we were not able to definitively report nor compare patient-centered outcomes. However, this was not the intention of this pilot study, and we will focus on these outcomes in the subsequent multicentered RCT. Finally, there is some suggestion that a higher dose of midodrine may be used (30). However, the product monograph states that our dosing is the highest suggested by the manufacturer and is the most commonly used dosing regime in studies evaluating the role of midodrine in critically ill patients (Supplementary File 4).

This pilot RCT of critically ill patients with vasopressor dependent shock demonstrates the feasibility and safety of implementing a protocol using midodrine as an adjunctive agent in the management of these patients. The experiences learnt from this pilot will guide the design and implementation of a large-scale RCT that will determine the role of midodrine as an IV vasopressor sparing agent used to decrease ICU length of stay.

CTO

Clinical trials office

DCCM

Department of Critical Care Medicine

ECG

Electrocardiogram

eCRF

Electronic case report form

GCS

Glasgow come scale

ICU

Intensive care unit

KRT

Kidney replacement therapy

LOS

Length of stay

MCID

Minimal clinically important difference

REB

Research ethics board

RCT

Randomized controlled trial

SDM

Substitute decision maker

Intravenous

IVF

Intravenous fluid

Ethics Approval and Consent to Participate

Consent for Publication

Not applicable

Competing Interests

The authors declare that they have no competing interests

Funding

University of Alberta Hospital Foundation

Authors’ Contributions

SK contributed to development and drafting of the manuscript, FH, DLO, KF, CK, VL, EM, JS, JS, WS, FZ, DD, LG and NG contributed to study protocol development and critical revision of the manuscript, SB and OR conceived the study, developed the protocol and contributed to the development and drafting of the manuscript. All authors read and approved the final manuscript.

Acknowledgments

This study was made possible by funding from the University of Alberta Hospital Foundation.

Availability of Data and Materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

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Midodrine for the early liberation from vasopressor support in the ICU (LIBERATE): A feasibility study

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Abstract

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BACKGROUND

METHODS

Study Design

Ethics

Setting

Recruitment

Eligibility

Randomization and Intervention

Data Collection and Participant Follow-up

Data Analysis

Safety and Adverse Events

RESULTS

Patient Demographics

Primary Outcome

Secondary Outcomes

DISCUSSION

CONCLUSIONS

Abbreviations

Declarations

Competing Interests

Funding

Authors’ Contributions

Acknowledgments

Availability of Data and Materials

References

Supplementary Files

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Version 1