REBEL Cast Ep88: The MIDAS Trial – Midodrine vs Placebo for Pressor Discontinuation

Background: ICU discharge is often delayed due to intravenous vasopressor requirements to maintain clinically indicated blood pressure goals. In some patients without impairment of tissue oxygenation, the use of oral agents could facilitate weaning from IV vasopressors and lead to earlier ICU discharge. Midodrine is an oral alpha1 adrenergic agonist that may facilitate liberation from IV vasopressors. Evidence for this is mostly observational without randomized clinical trials (See PulmCrit).

REBEL  Cast Episode 88 –  The MIDAS Trial – Midodrine vs Placebo for Pressor Discontinuation

Paper: 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. PMID: 32885276

Clinical Question: Does the administration of midodrine shorten duration of IV vasopressor requirements compared to placebo?

What They Did:

• Multicenter, randomized, double-blind, placebo-controlled trial
• 3 hospitals in the US and Australia
• Patients enrolled from Oct 2012 to June 2019
• Randomized in 1:1 fashion to:
  • Midodrine 20mg PO q8hr
  • Placebo PO q8hr (matched in appearance)
• Study drugs administered until any of the following occurred:
  • ICU discharge
  • Worsening hypotension requiring high-dose vasopressors (>100mcg/min phenylephrine, >8 mcg/min norepinephrine, or >60mcg/min metaraminol)
  • Epinephrine requirement
  • Signs or symptoms of organ failure or hypoperfusion
  • Adverse events related to midodrine (i.e. allergic reaction)
  • Death
• If BP goal was met for at least 24hrs without IV vasopressors, the study drug could be discontinued at the discretion of the clinical team following a standardized weaning protocol
  • If patient’s BP was stable, the daily dose was then titrated down every 1 – 2days using a stepwise weaning approach
  • 10mg PO q8hr
  • 5mg PO q8hr
  • Discontinue

Outcomes:

• Primary: Vasopressor discontinuation (Length of time, measured in hours, from study drug initiation until discontinuation of IV vasopressors for ≤24hrs)
• Secondary:
  • Time to ICU discharge readiness
  • ICU and hospital LOS
  • ICU readmission rate
  • Adverse event rates
    • Hypertension (SBP >160mmHg or an increase by ≥20% from prespecified goal set by the primary team)
    • Bradycardia (HR <40BPM or a decrease by ≥20% from the pre-specified goal)
    • Hemodynamically significant tachyarrhythmias (Drop in SBP >20mmHg)
    • New onset organ failure (Inadequate tissue oxygenation)
    • Liver or renal failure

Inclusion:

• Adult patients aged ≥18 years
• Admitted to ICU or high dependency unit
• No evidence of inadequate tissue oxygenation
• Hypotension
• Adequately resuscitated
• Reversible cause of hypotension treated
• Requiring single-agent IV vasopressor for ≥24hrs
  • <100mcg/min phenylephrine
  • <8mcg/min norepinephrine
  • <60mcg/min metaraminol
• Patients receiving vasopressor doses higher than the specified infusion rates or more than one vasopressor during the 24hr preceding randomization were still eligible as long as the criterion of single-agent IV vasopressor requirement was below the specified cut-off values above

Exclusion:

• Inadequate tissue oxygenation (based on clinical judgment)
• Hypovolemic shock
• Hypotension due to adrenal insufficiency
• Liver failure
• Chronic renal failure (Cr >2mg/dL)
• Severe organic heart disease (LVEF <30%)
• Acute urinary retention
• Pheochromocytoma
• Thyrotoxicosis
• Bradycardia (HR <50BPM)
• Pregnancy
• Received midodrine prior to enrollment
• Known allergy to midodrine
• Enrolled in another trial
• Unable to receive medications enterally

Results:

• 530 patients assessed
  • 213 met eligibility criteria
  • 136 patients randomized
  • 132 patients included in analysis (modified intention-to-treat)
  • ≈65% of patients were post-op
  • Due to the long recruitment period, the authors stratified the primary analysis by study center and year of enrollment and found no differences in time to vasopressor discontinuation
  • To address possibility of delayed or impaired gastrointestinal absorption of study drug due to opioid analgesics, assessed opioid doses administered during the 1^st 24hrs after study drug initiation and found no difference between groups
• Median Time to Vasopressor Discontinuation (Primary Outcome):
  • Midodrine: 23.5hr (Range 10 to 54)
  • Placebo: 22.5hr (Range 10.4 to 40)
  • Difference 1hr; 95% CI – 10.4 to 12.3hr; p = 0.62
• In 31pts (23.5%) who received epidural analgesia, time to vasopressor discontinuation was significantly shorter with midodrine vs placebo
  • Difference of -18.4hr; 95% CI -33.5 to -3.3hr
  • IRR 0.53; 95% CI 0.28 to 0.99; p = 0.045
• No differences in time to ICU discharge readiness (5hr vs 5hr), ICU LOS (6d vs 6d), hospital LOS (11d vs 14d), or ICU readmission rates (1pt vs 3pts)
• Bradycardia occurred more often after midodrine administration:
  • Midodrine: 5pts (7.6%)
  • Placebo: 0pts (0%)
  • P = 0.02

Strengths:

• 1^st randomized, double-blind, placebo-controlled trial on this topic
• Multicenter design and broad eligibility criteria included a wide spectrum of critically ill patients which increases generalizability of results
• Clinical teams, study personnel, and participants were masked to the treatment allocation
• Used a modified intention-to-treat analysis to include all randomized patients who received at least one dose of study medication
• No data missing for the analysis of the primary endpoint
• Baseline characteristics of APACHE II scores, indication for ICU admission, and vasopressor doses were similar between groups

Limitations:

• Adverse events were collected daily from medical records, which most likely underreports these events if they were not put into the chart
• Convenience sample: Over 6 ½ years only 530 patients from 3 centers were assessed for eligibility. 34 patients were not approached and 37 declined to participate.
• Small number of patients leads to very wide CI
• Non-patient centered outcome
• Selection bias: long exclusion list and exclusion of patients already receiving midodrine
• Lack of pre-specified subgroup analyses which doesn’t allow for drawing conclusions on patients receiving epidural analgesia
• No low-income countries included in the trial

Discussion:

• A sample size of 50 patients per group was needed to detect a difference of 6hrs in time to vasopressor discontinuation between groups. The expected effect size was based on observational data
• The significant effect modification of midodrine vs placebo in patients using epidural analgesia:
  • Post-hoc analysis and exploratory. Study not powered for this outcome and hypothesis generating only
  • Epidural analgesia results in neural vasoplegia, resulting from dilation of both resistance and capacitance of vessels compared to sepsis, which is multifactorial

Author Conclusion: “Midodrine did not accelerate liberation from intravenous vasopressors and was not effective for the treatment of hypotension in critically ill patients.”

Clinical Take Home Point: Midodrine did not reduce time to discontinuation of IV vasopressors in critically ill patients with persistent hypotension.  The lack of effectiveness combined with higher rate of bradycardia does not support the routine use of midodrine to accelerate liberation from IV vasopressors in the ICU.

Expert Peer Review by Frank Lodeserto, MD (Twitter: @FrankLodeserto)

Pediatric & Adult Intensivist
Geisinger Medical Center

Well the MIDAS trial certainly didn’t help Midodrine turn into the golden drug of the ICU, but before we dismiss it’s use, let me give you my 2 cents. My first issue with the trial is the patient population that Midodrine was used on. The majority of these patient were post-operative patients without hypovolemic shock, which one may possible assume had temporary vasodilatory effects from anesthetics which usually wear off in about 24 hours. This may have led to the results showing that Midodrine showed no difference vs placebo on weaning off vasopressor support. The other question is what does 8mcg/min of norepinephrine or 100 mcg/min of phenylephrine really mean as we don’t know the weight of these patients. As a Pediatric & Adult Intensivist, 8mcg/min is very different in a 100 kg individual (low dose) than a 40kg individual (moderate dose)?

These issues aside, I want to make sure I am very clear that I would never use Midodrine in a patient early in their resuscitation period. For example, if you are treating a patient with sepsis or septic shock, and you have given broad spectrum antibiotics and/or obtained adequate source control, gave the correct amount of fluids and the patient remains hypotensive, then don’t hesitate to start vasopressors. The use of Midodrine should not be used early to prevent an ICU transfer or admission, as this is unsafe and not the correct role for this drug. This may lead to unsafe practice and the wrong therapy for your patient.

So, where do I use it? Well, now we are truly entering an evidence free zone here, and I can’t say I have the data to back me, but none-the-less I will give you my non-evidence-based opinion. I use Midodrine once I know my patient has improved and there is no evidence of end organ hypoperfusion, however they are still stuck on a very low dose amount of norepinpherine (< 0.05 mcg/kg/min +/- 0.02 ). My patient is doing well, usually extubated, maybe even be tolerating a diet, but every time we shut off their vasopressors they have a low MAP with usually wide pulse pressure indicating persistent vasoplegia. Now here is the big caveat, despite this low MAP and vasoplegia, my patient is “doing well”, and I am only using vasopressors to make the numbers (MAP) on the monitor pretty (ie MAP 65 mm Hg). This patient has proven that they are tolerating this low MAP just fine and they can tolerate a low MAP in the ICU because they have proven to me and the nursing staff that they are fine with this low MAP ( ex 50 mm Hg). However, it’s going to be a hard sell to convince my Hospitalist colleagues to accept my patient to the general wards with a MAP ~ 50 mm Hg without an RRT being called immediately. So, I will start them on Midodrine in hopes that it temporarily boasts their numbers (MAP) with the goal of eventually discontinuing midodrine before they are discharged.

My thought process is my patient has dramatically improved despite persistent vasoplegia and low MAP without evidence of end organ dysfunction, no longer needs ICU level care and can safely transfer without harm. So, with these caveats there is still a role for this drug, but it’s not a robust group that meets this criterion, but still has a role. Despite this trial, I will continue to use Midodrine in that select population that I have described. It has a role although limited but can be golden if the right patient is appropriately selected.

References:

1. 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. PMID: 32885276

For More Thoughts on This Topic Checkout:

• PulmCrit: Oral Vasopressor to Accelerate Liberation from the ICU
• The Bottom Line: MIDAS

Post Peer Reviewed By: Anand Swaminathan, MD (Twitter: @EMSwami)