Is the Juice Worth the Squeeze? Using Midodrine

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Lauren Igneri
Lauren Igneri
Critical care pharmacist and proud Rutgers University graduate. Enjoys rock climbing, cycling, travel, and lively discussions on the finer points of pharmacokinetics and critical care over a beer with friends.

The Pre-brief

  • Patients admitted to the ICU may require vasoactive medications to maintain normotension or other specific BP goals. Some patients may develop a persistent vasopressor dependency to meet BP goals despite any evidence of organ hypoperfusion.
  • The need for IV vasopressor therapy may result in prolonged ICU and hospital lengths of stay, or become a barrier to hospital discharge, so there is interest in utilizing oral agents to facilitate vasopressor weaning.
  • Midodrine is an oral α1-adrenergic agonist approved for orthostatic hypotension at doses ranging from 2.5 to 10 mg three times daily.
  • Midodrine increases vascular tone and BP by activating α1-adrenergic receptors of the arteriolar and venous vasculature.
  • It has increasingly been used off-label at higher doses to wean patients off vasopressors.

Midodrine as a vasopressor weaning agent

Until recently, only small prospective, observational studies or larger retrospective studies evaluated the use of midodrine in weaning vasopressor agents in the ICU. The MIDAS trial was the first prospective, multicenter, randomized controlled trial on this subject published in 2020. Table 1 summarizes key findings of select studies evaluating midodrine for vasopressor weaning.

While numerous studies demonstrated a benefit with the use of midodrine to wean vasopressors, the largest prospective, randomized MIDAS trial was unable to confirm this benefit. MIDAS enrolled 132 patients with hypotension requiring low-dose, single-agent IV vasopressors for ≥24 hours and randomized them to either midodrine 20 mg oral every 8 hours vs. placebo. Study drugs were administered for a median duration of 42.4 (IQR, 23.5-71.3) hours in the midodrine group and 47.5 (IQR, 34.1-72.4) hours in the placebo group. The median time to discontinuation of IV vasopressors was not different, with 23.5 (IQR, 10-54) hours in the midodrine group and 22.5 (IQR, 10.4-40) hours in the placebo group, p=0.62. There was no significant difference in time to ICU discharge readiness, ICU LOS, or hospital LOS. A post-hoc analysis in the subgroup of patients receiving epidural analgesia (n=31) showed that midodrine significantly reduced the time to IV vasopressor discontinuation, -18.4 hours (95% CI -33.5 to -3.3 hours). Overall, adverse effects were similar between groups with the exception of increased bradycardia associated with the use of midodrine.

A recently published meta-analysis including three studies in a shock population confirmed that the midodrine juice may not be worth the squeeze: Midodrine use compared to no midodrine use did not affect ICU LOS (mean difference 1.38 days [95% CI: -3.48 to 6.23, I2=93%]), hospital LOS (mean difference 4.37 days [95% CI: -3.45 to 12.19, I2=93%]), mortality (odds ratio 0.74, [95% CI: 0.44-1.27, I2=65%]), or IV vasopressor duration (mean difference 7.28 days, [95% CI: 0.86 to 15.41, I2=97%]). Furthermore, another study showed that 67% of patients were continued on midodrine at ICU discharge and 34% at hospital discharge, with 50% of patients having antihypertensive therapy initiated while on midodrine therapy. This underscores the importance of establishing a tapering and discontinuation plan for any new start midodrine in the ICU setting.

The Debrief

  • Historically, observational and retrospective studies demonstrated a benefit with the initiation of midodrine to wean IV vasopressor therapy.
  • Recent literature including the prospective, randomized controlled MIDAS study and a large meta-analysis did not find that the addition of midodrine resulted in significant differences in time to IV vasopressor discontinuation, ICU LOS, hospital LOS, or mortality.
  • Midodrine initiated for vasopressor weaning is commonly inadvertently continued at ICU or hospital discharge. In many cases, antihypertensive therapy is initiated to combat BP elevations from midodrine.
  • If midodrine is used for vasopressor weaning, it is important to have plans in place for tapering and discontinuation at transitions of care.

References

  1. Santer P, Anstey MH, Patrocinio MD, 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 randomized clinical trial. Intensive Care Med. 2020; 46:1884-1893.
  2. Midodrine hydrochloride tablet [package insert]. Lexington, MA: Shire US Inc, January 2017.
  3. Levine AR, Meyer MJ, Bittner EA, et al. Oral midodrine treatment accelerates the liberation of intensive care unit patients from intravenous vasopressor infusions. J Crit Care. 2013; 28:756-62.
  4. Whitson MR, Mo E, Nabi T, et al. Feasibility, utility, and safety of midodrine during recovery phase from septic shock. Chest. 2016; 149:1380-3.
  5. Poveromo LB, Michalets EL, Sutherland SE. Midodrine for the weaning of vasopressor infusions. J Clin Pharm Ther. 2016; 41:260-5.
  6. Rizvi MS, Trivedi V, Nasim F, et al. Trends in use of midodrine in the ICU: a single-center retrospective case series. Crit Care Med. 2018;46:e628-33.
  7. Hammond DA, Smith MN, Peksa GD, et al. Midodrine as an adjuvant to intravenous vasopressor agents in adults with resolving shock: systematic review and meta-analysis. J Intensive Care Med. 2020; 35(11):1209-1215.
  8. Rizvi MS, Nei AM, Gajic O, et al. Continuation of newly initiated midodrine therapy after intensive care and hospital discharge: a single-center retrospective study. Crit Care Med. 2019; 47(8):e648-53.
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