Midodrine in the Intensive Care Unit (ICU)

Midodrine (brand name Proamatine), is an alpha-1 adrenergic agonist that is orally administered. It is used in both in the outpatient setting as well as inpatient setting to restore vascular tone and increase blood pressure. One of the benefits of this medication in the Intensive Care Unit (ICU) is that we can administer it to our patients in order wean off catecholamine drips faster. It is considered a catecholamine-spring agent. More on that below.

Some of what I will be discussing in this post is off-label. Ultimately, it is challenging to define recommendations and dosing strategies as you will notice after looking through the available data. Many times, we provide it to our patients and watch what happens. Our utilization of this medication is increasing and therefore our knowledge base has to increase as well.

If you want to learn more about vasopressors, click here.

Cite this post as: Eddy J. Gutierrez, “Midodrine in the Intensive Care Unit (ICU)”, eddyjoemd blog, February 20, 2022. Available at: https://eddyjoemd.com/midodrine/

Midodrine Uses/Indications:

FDA Approved Use

Midodrine is FDA approved for the treatment of symptomatic orthostatic hypotension. This approval happened in 1996 for historical context.

Off-label uses:

This has, of course, been prescribed for patients who are on hemodialysis. This helps to prevent the hypotension associated with ultrafiltration. In addition, it is also provided to patients with hepatorenal syndrome, to prevent vasovagal syncope, and those who receive carotid artery stents. My experience in the NeuroICU during fellowship saw many s/p carotid artery intervention patients on peripheral phenylephrine for several hours. Perhaps that could have been prevented with midodrine. Another noted off-label indication I found in the literature includes advanced cardiac failure after a stunned myocardium. I struggle with this one as its mechanism would increase afterload, therefore worsening cardiac output.

Uses in the ICU

Starting patients on midodrine can potentially help avoid inserting a central line. I know that there’s now data to support the utilization of peripheral vasopressors, but this caveat won’t hurt. Avoiding central line insertions keeps the CLASBIs away and everything else that comes with any venous cannulation including patient morbidity.

Another benefit is that it could potentially decrease length of stay in the ICU. Think about it, if we’re able to wean off the vasopressors earlier, the shorter we can make the length of stay. The caveat, of course, is that our hospital medicine colleague will have to be careful in weaning midodrine off. From my experience they do a great job at it.

Pharmacy Stuff:

Midodrine is rapidly absorbed after oral intake with a high bioavailability of 93%. It is an inactive prodrug which undergoes enzymatic hydrolysis in the liver to for its active metabolite, desglymidodrine. This peaks 1-2 hours after ingestion. This metabolite is expelled by the kidneys by active secretion where 80% of it goes. Careful with renal failure patients, of course. The half life of midodrine is approximately 25 minutes. The half life of desglymidodrine is 3-4 hours.

This all means that the increase we want in the blood pressure can be sustained for 3-4 hours. Hence the dosing regimen of three times a day we typically use.

Midodrine Mechanism of Action:

Desglymidodrine stimulates the alpha-1 adrenergic receptors of the arteriolar and venous capacitance vessels causing vasoconstriction. It increases peripheral vascular resistance and augments the venous return.

In our critically ill patients, this may all be different. We need to remember that absorption parameters such as edema of the gastrointestinal tract when we overdo the volume resuscitation (a post to help us avoid doing that) or simple intestinal vasoconstriction. This is a question we just do not know the exact answer to at this time.

Midodrine Dosage:

FDA approved dose: 10mg three times a day (for orthostatic hypotension)

Doses used in ICU studies showing efficacy: 5 – 40mg three times a day.
(Side note: the Whitson study mentioned using 40mg TID)

From a dosage form perspective, midodrine comes in 2.5, 5, and 10mg tablet form.

Midodrine Side/Adverse Effects:

  • compensatory reflex bradycardia ≤ 50 (15% in Rizvi study)
  • compensatory reflex bradycardia ≤ 40 (9% in Rizvi study)
  • ADDENDUM: The MIDAS trial found 7.6% of patients suffered bradycardia
  • piloerection
  • urinary retention
  • dysuria
  • chills
  • shivering
  • paresthesia
  • pruritus
  • supine hypertension
  • ischemic bowel (0.18% in Rizvi study, reasoning explained in their paper)

Efficacy studies

Let me be completely honest that the data is not the most robust when it comes to efficacy and safety profile of this medication. Nonetheless, it is useful to reduce the duration of IV vasopressors and ICU length of stay. Needless to say, these articles are fraught with limitations based on their study designs. That does not mean that they’re not useful.

Observational and Prospective Studies

Levine, et al. performed a prospective, observational study in the surgical ICU at Massachusetts General Hospital. The team looked at 20 patients who were on phenylephrine. An important piece of information, the mean phenylephrine equivalent dose they were on at initiation of midodrine was 41.0±33.4mcg/min. Not exactly jet fuel. 70% of patients were weaned off of vasopressors within the first 24 hours. There was an acceleration of weaning from IV vasopressors (p=0.012). The curious occurrence was that the mean arterial pressure values did not differ before and during the midodrine administration (p=0.66).

Whitson, et al. performed a single-center, observational study in the medical ICU. The team looked at 275 patients, 140 with IV vasopressors and 135 with IV vasopressors with midodrine. They had some promising results where midodrine plus IV vasopressors caused a shortening of the duration of IV vasopressors (2.9d vs 3.8d, p<0.001), a decease in the reinstitution of IV vasopressors (5.2% vs. 15%, p=0.007), a smaller increase in serum creatinine (0.5 vs 0.8mg/dL, p=0.048), and a shorter mean length of stay in the ICU (7.5d vs. 9.4d, p=0.017). There was no difference in hospital length of stay, ICU nor hospital mortality. This makes sense.

Rizvi et al. conducted a retrospective, single-center case series from the Mayo Clinc, Rochester from 2011-2016. In total, they looked at 1119 patients who were initiated on midodrine in the ICU. It was curious to me to see that the surgery ICU used more than the medical ICU, 56% and 42% respectively. The team found that using midodrine did help decrease the number of patients on vasopressors after 24 hours (p<0.001). If the patients remained on vasopressors, their dose was lower (p=0.002). Lastly, if the patients were not on vasopressors, their mean blood pressure after 24 hours was improved. The data regarding bradycardia comes from this study.

Systematic Reviews and Meta-analyses

Hammond, et al. published a systematic review and meta-analysis in 2019 evaluating the clinical effects of midodrine on IV vasopressors in patients recovering from shock. You know how I had mentioned that there was a lack of good data? Well, they were only able to include three studies in the meta-analysis. This led to them finding that there was no statistically significant decrease in ICU length of stay. Meta-analyses will only become more robust when the studies listed below are complete. The authors state that the ideal starting dose may be 20mg three times a day. I personally start at either 5-10mg three times a day.

How to wean Midodrine:

Honestly we have no standardized manner to look at this. No one has studied it to my knowledge. At the moment, it becomes a trial and error process.

Midodrine Cost:

Per Rizvi, et al., the cost is less than $50 per day. They compare it to the cost of an ICU bed being $3000-4000 per day. This treatment could potentially save a few bucks and hopefully lead to pay raises for our staff.

UpToDate states the following average wholesale prices per tablet (6/15/20):
2.5mg: $1.03-1.69
5mg: $1.04-4.49
10mg: $4.84-9.72

Midodrine Research Pipeline

There are several active trials on clinicaltrials.gov looking at midodrine in sepsis.

NCT03129542 with the official title of “Oral Midodrine Hydrochloride in Early Sepsis: Randomized, Double Blind and Placebo-Controlled Feasibility Study”. It will be looking at midodrine 10mg PO TID versus placebo. Key words in the title include “feasibility study”. They do not specify when it will be complete.

NCT03706053 with the official title of “Midodrine Use for Hypotension Requiring IV Vasopressor Therapy in Early Septic Shock” will be a triple-blind randomized trial. They will have three arms: midodrine 10mg TID, 20mg TID, and placebo. May 2020 was the date of completion. Impatiently waiting….

NCT01531959 the MIDAS trial. Due out soon. Official title of “Midodrine for the Treatment of Refractory Hypotension in Patients Otherwise Ready for Discharge From the ICU”. This study will use 20mg TID vs. placebo. I have updated this post on 9/5/2020 with this study. See below.

Check out this post on my Podcast and YouTube channel!

MIDAS Trial (Updated 09/05/20)

On 9/3/2020 we were provided the results of the long awaited MIDAS trial. I can’t say I was expecting the results of this study to be the flop that they were. I personally have been using midodrine in my practice for several years. Like everything, it works on some patients and doesn’t on others. I have seen patients become normotensive on midodrine, and they when I attempt to wean it off, they’re hypotensive again. What the authors were looking for in this study was to see if midodrine shortens the duration of time patients need IV vasopressors. As mentioned above, the authors wanted some concrete data as opposed to the observational/anecdotal practices such as mine. Good for them.

How did they conduct the study?

The authors did a really good job here. It is a multi center (USA and Australia), randomized, double-blind, placebo controlled trial. It took them from 2012 to 2019 to conduct this study! Great job in sticking to it. They used a vasopressor in this trial named metaraminol which I have never heard of to be quite frank. Time to do some reading on that. I digress. The patients needed to be lingering for more than 24 hours on a single vasopressor below a certain dose. Cool.

Patients were randomized in a 1:1 fashion to get either 20mg of midodrine every 8 hours or placebo. They were able to enroll a total of 132 patients. Must have been hard to enroll patients to be able to collect that many over a little more than 6 years in all these centers. When you look at the characteristics of study participants, you’ll see that 19.7% of the patients in each group are there because of sepsis. This is different than the way I use it in my practice which is most commonly in sepsis. The majority of the patients in this study are surgical patients.

What did they find when providing Midodrine?

The primary outcome was median time to discontinuation of IV vasopressors. No difference here, my friends (p=0.62). 23.5 hours in the midodrine arm and 22.5 in the control arm.

There was also no difference in the time to discharge readiness from ICU, median length of stay, hospital length of stay, nor ICU readmission rate.

With regards to adverse effects, bradycardia was noted in 7.6% of patients.

What to do with the results of the MIDAS trial?

Some people will look at the data and say “we need to throw midodrine in the trash, it simply does not work”. This is not how I feel. First, this is quite the heterogenous patient population. Most of the patients were surgical rather than sepsis. The following is my opinion and absolutely not medical advice. It’s my rationale. Second, midodrine is extremely inexpensive compared to an ICU bed. Therapeutics such as this do not necessarily work on absolutely everyone. It is plausible to try it on your patient and assess for a response. If no response, peel it off. If there’s a response, continue forward. This is the beauty but also frustration of medicine. It’s an inexact science. We need to continue trying to do our best.

MAVERICK Study (Updated 02/20/22)

Costa-Pinto et al. published the MAVERICK study late 2021 looking at adjunctive midodrine in patients on vasopressors. It was a small study of just 62 patients. After all, they did specify that it is a pilot, feasibility, randomized controlled trial. To note, this study was open label. That means everyone, doctors, patients, staff, knew whether patients were getting the midodrine or not.

When it was all said and done, patients got off of vasopressors faster in the midodrine group but this was not statistically significant. They also spent fewer hours in the ICU, but again, not statistically significant. It also did not change how long patients stayed at the hospital. It is important to note that 40.6% of the patients in the midodrine group has sepsis and 40.6% were post-operative patients. This really limits how one could apply these data to certain subgroups. Not to mention the previously mentioned fact that this was a pilot study.

Midodrine in the CVICU (Updated 09/15/20)

The MIDAS trial showed us that midodrine may not be great in post-surgical patients, but what about the patients who are status-post cardiopulmonary bypass (CPB) for valves or CABG’s? The simplified mechanism by which this should work is that some patients who undergo CPB undergo a vasodilatory process that looks like a transient septic shock. This cited article found that this occurs between 5-25% of the time.

Since this is a vasodilatory process, using a vasoconstrictor such as midodrine should help, right? That’s what the authors sought to find. They wanted to investigate if it had an effect on the length of vasopressor duration as well as length of stay. The dose they used here was 10mg.

Unfortunately, in this well conducted retrospective cohort study with a contemporary propensity score matched control group found no benefit to providing patients in the CVICU with midodrine for their hypotension. One needs to take in consideration the limitations tangled together of this type of study. That being said, the patients actually did worse when receiving midodrine. We’re in the business of not causing harm.

Here is the main point of what they found: “midodrine use was associated with significantly less days free from ICU and higher mortality”. These findings caught me by surprise and the same can be said for the authors. They are recommending a prospective randomized controlled trial to verify this but we need to keep this in mind and be very careful using midodrine in this patient population moving forward. Hat tip to the authors.

Citations:

FDA Data on Midodrine

Sharma S, Bhambi B. Successful treatment of hypotension associated with stunned myocardium with oral midodrine therapy. J Cardiovasc Pharmacol Ther. 2005 Mar;10(1):77-9. doi: 10.1177/107424840501000109. PMID: 15821841.
Link to Abstract

Levine AR, Meyer MJ, Bittner EA, Berg S, Kalman R, Stanislaus AB, Ryan C, Ball SA, Eikermann M. Oral midodrine treatment accelerates the liberation of intensive care unit patients from intravenous vasopressor infusions. J Crit Care. 2013 Oct;28(5):756-62. doi: 10.1016/j.jcrc.2013.05.021. Epub 2013 Jul 8. PMID: 23845791.
Link to Abstract

Whitson MR, Mo E, Nabi T, Healy L, Koenig S, Narasimhan M, Mayo PH. Feasibility, Utility, and Safety of Midodrine During Recovery Phase From Septic Shock. Chest. 2016 Jun;149(6):1380-3. doi: 10.1016/j.chest.2016.02.657. Epub 2016 Mar 4. PMID: 26953217.
Link to Abstract

Rizvi MS, Trivedi V, Nasim F, Lin E, Kashyap R, Andrijasevic N, Gajic O. Trends in Use of Midodrine in the ICU: A Single-Center Retrospective Case Series. Crit Care Med. 2018 Jul;46(7):e628-e633. doi: 10.1097/CCM.0000000000003121. PMID: 29613861.
Link to Abstract

Hammond DA, Smith MN, Peksa GD, Trivedi AP, Balk RA, Menich BE. Midodrine as an Adjuvant to Intravenous Vasopressor Agents in Adults With Resolving Shock: Systematic Review and Meta-Analysis. J Intensive Care Med. 2020 Nov;35(11):1209-1215. doi: 10.1177/0885066619843279. Epub 2019 Apr 28. PMID: 31030630.
Link to Abstract

Tchen S, Sullivan JB. Clinical utility of midodrine and methylene blue as catecholamine-sparing agents in intensive care unit patients with shock. J Crit Care. 2020 Jun;57:148-156. doi: 10.1016/j.jcrc.2020.02.011. Epub 2020 Feb 19. PMID: 32145658.
Link to Abstract

Most recent literature citations

Santer P, Anstey MH, Patrocínio MD, Wibrow B, Teja B, Shay D, Shaefi S, Parsons CS, Houle TT, Eikermann M; MIDAS Study Group. 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 Oct;46(10):1884-1893. doi: 10.1007/s00134-020-06216-x. Epub 2020 Sep 3. PMID: 32885276; PMCID: PMC8273663.
Link to Abstract
Link to FULL FREE PDF

Costa-Pinto R, Yong ZT, Yanase F, Young C, Brown A, Udy A, Young PJ, Eastwood G, Bellomo R. A pilot, feasibility, randomised controlled trial of midodrine as adjunctive vasopressor for low-dose vasopressor-dependent hypotension in intensive care patients: The MAVERIC study. J Crit Care. 2022 Feb;67:166-171. doi: 10.1016/j.jcrc.2021.11.004. Epub 2021 Nov 18. PMID: 34801917.
Link to Article (NOT FREE)

Tremblay JA, Laramée P, Lamarche Y, Denault A, Beaubien-Souligny W, Frenette AJ, Kontar L, Serri K, Charbonney E. Potential risks in using midodrine for persistent hypotension after cardiac surgery: a comparative cohort study. Ann Intensive Care. 2020 Sep 14;10(1):121. doi: 10.1186/s13613-020-00737-w. PMID: 32926256; PMCID: PMC7490305.
Link to Article
Link to FULL FREE PDF

My buddy Dr. Rishi Kumar also posted on midodrine HERE.

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