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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 Medicine. 2020. 46(10):1884-1893.
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Clinical Question

In adult, critically ill patients requiring low-dose vasopressors, does the addition of oral midodrine decrease the time to removal of vasopressor support.

Bottom Line

Midodrine did not hasten liberation from vasopressor support

Major Points

A small proportion of patients who survive their critical illness have persistent vasopressor-dependant hypotension. This ongoing vasoplegia if a barrier to ICU discharge. Midodrine is an oral, alpha1-adrenergiec agonist with indication for orthostatic hypotension. It has been utilized off-label in critical care to attempt to liberate vasopressor-dependant patients. This trial was enrolled adult, critically ill patients from three centres in two high-income countries dependent on vasopressors to maintain blood pressure goals. The authors randomized patients to receive either midodrine 20mg orally every 8 hours (n=66) or matched placebo (n=66). With a primary outcome of time to vasopressor discontinuation, the midodrine intervention led to 23.5 hours as compared to the placebo group stopping vasopressors at 22.5 hours (P = 0.62). For their secondary outcomes, there was no statistical difference for time to ICU discharge readiness, ICU and hospital length of stay. There was no difference in ICU readmission or most adverse events except there was more bradycardia in the midodrine group (P = 0.02).

Following this trial, there was also pilot trial that utilized midodrine 10mg orally every 8 hours versus placebo and it did not demonstrate an physiologic or clinical effect on the outcome.[1]


As of May 2023, no guidelines have been published that reflect the results of this trial.


  • Multicenter, double-blind, parallel-group, randomized, controlled trial
  • N=132
    • Midodrine (n=66)
    • Placebo (n=66)
  • Setting: three tertiary referral hospitals in USA and Australia
  • Enrollment: October 2012 to June 2019
  • Analysis: modified Intention-to-Treat
  • Primary Outcome: Time to discontinuation of intravenous vasopressors


Inclusion Criteria

  • ≥ 18 years old
  • admitted to ICU
  • requires single agent vasopressor support for ≥ 24 hours
    • <100 mcg/min phenylephrine
    • <8 mcg/min norepinephrine, or
    • <60 mcg/min metaraminol

Exclusion Criteria

  • receiving more than 1 vasopressor
  • clinical evidence of inadequate tissue oxygenation (based on clinical judgment)
  • hypovolaemic shock or hypotension due to adrenal insufficiency
  • liver failure
  • chronic renal failure (serum creatinine >2 mg/dL or 153 mcmol/L)
  • severe organic heart disease (left ventricular ejection fraction <30%)
  • acute urinary retention
  • pheochromocytoma
  • thyrotoxicosis
  • bradycardia (heart rate <50 beats/min)

Baseline Characteristics

Midodrine Group displayed

  • Demographics: 45.5% female, mean age 70 years
  • Reason for ICU admission: 68.2% surgical, 19.7% sepsis, 12.1% medical
  • Anthropomorphics: mean 78.6 kg, mean 169 cm, mean boy mass index 27.9 kg/m^2, baseline mean arterial pressure 75.9 mmHg
  • Mean SOFA scores: 4 Day 1, 3 Day 2, 3 Day 3, 3 Day 4, 3 Day 5
  • Vasopressor: total duration 76.6 hours, time before study drug administration 35.5 hours
  • Vasopressor dose at enrolment: norepinephrine 0.06 mcg/kg/min, phenylephrine 0.61 mcg/kg/min, metarmaminol 0.6 mcg/kg/min


  • midodrine 20mg orally 20 mg every 8 hours
  • Matched placebo

Study drug stopped at ICU discharge, blood pressure goal not requiring vasopressor support for 24 hours or:

  • worsening hypotension requiring increase vasopressor dose
  • epinephrine requirement
  • signs / symptoms of organ failure or hypoperfusion
  • adverse events related to midodrine (serious allergic reaction)
  • death


Comparisons are midodrine vs. placebo group.

Primary Outcomes

Time to vasopressor discontinuation
23.5 hours vs. 22.5 hours (difference 1, 95% CI -10.4 to 12.3) P = 0.6

Secondary Outcomes

Time to ICU discharge
5 days vs. 5 days (difference 0, 95% CI -1 to 1) P = 0.64
ICU length of stay
6 days vs. 6 days (difference 0, 95% CI -0.5 to 0.5) P = 0.46
Hospital length of stay
11 days vs. 14 Fays (difference -3, 95% CI -6.3 vs. 0.3) P = 0.45

Subgroup Analysis

Epidural analgesia, time to vasopressor discontinuation (for interaction P = 0.030)
Epidural 14.8 hours vs. 33.1 hours (difference -18.4, 95% CI -33.5 to -3.3) P = 0.045
No epidural 31.7 hours vs. 22 (difference 9.7, 95% CI -6.3 to 25.7) P = 0.103
ICU admission indication, time to vasopressor discontinuation
Surgical 22.2 hours vs. 23.8 hours (difference -1.6, 95% CI -13.1 to 9.9)
Sepsis 40 hours vs. 24 hours (difference 16, 95% -65.7 to 97.7)
Medical 24.1 hours vs. 15 (difference 9.1, 95% -18.1 to 36.2)

Adverse Events

ICU readmission rate
1.5% vs. 4.5% (difference -3, 95% CI -8.9 to 2.8) P = 0.62
At least one adverse event
30.3% vs. 25.8% (P = 0.56)
10.6% vs. 4.6% (P = 0.19)
Atrial fibrillation
4.6% vs. 1.5% (P = 0.31)
7.6% vs. 0 (P = 0.02)


  • Inclusion vasopressor dosing was not weight adjusted so per kg exposure would be vastly different based on patient size
  • baseline characteristics between groups was not balanced: MAP and age was higher in midodrine group, weight and body mass index higher in placebo group
  • Fluid balance higher in midodrine group
  • small sample size, potentially underpowered to find the statistical difference
  • largest proportion were surgical ICU admissions, effect could be different in other shock states
  • external validity may be affected for pediatric patients and in low-income countries
  • other organ supports were not reported so unclear of the affect of the intervention on the overall patient
  • selection bias may have occurred with a long recruitment phase and the majority of patients coming from one site


  • An unrestricted philanthropic donations from Jeffrey and Judy Buzen

Further Reading