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Midodrine — why don't you just work better?

Matthew Anstey, Shahzad Shaefi, Bradley Wibrow

Crit Care Resusc 2022; 24 (4): 296-7

  • Author Details
  • Competing Interests

    All authors declare that they do not have any potential conflict of interest in relation to this manuscript.

  • References
    1. Cardenas-Garcia JL, Withson M, Healy L, et al. Safety of oral midodrine as a method of weaning from intravenous vasoactive medication in the medical intensive care unit. Chest 2014; 146: 224A
    2. Santer P, Anstey MH, Patrocínio 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 randomised clinical trial. Intensive Care Med 2020; 46: 1884-93
    3. Costa-Pinto R, Yong ZT, Yanase F, et al. 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: 166-71
    4. Wood AJ, Rauniyar R, Jacques A, et al. Oral midodrine does not expedite liberation from protracted vasopressor infusions: a case-control study. Anaesth Intensive Care 2022; doi: 10.1177/0310057X221105297 [Epub ahead of print]
    5. Tremblay JA, Laramée P, Lamarche Y, et al. Potential risks in using midodrine for persistent hypotension after cardiac surgery: a comparative cohort study. Ann Intensive Care 2020; 10: 121
    6. Jans Ø, Mehlsen J, Kjærsgaard-Andersen P, et al. Oral midodrine hydrochloride for prevention of orthostatic hypotension during early mobilization after hip arthroplasty: a randomized, double-blind, placebo-controlled trial. Anesthesiology 2015; 123: 1292-300
    7. Smits M, Lin S, Rahme J, et al. Blood pressure and early mobilization after total hip and knee replacements: a pilot study on the impact of midodrine hydrochloride. JB JS Open Access 2019; 4: e0048
    8. FIGUEROA JJ, BASFORD JR, LOW PA. Preventing and treating orthostatic hypotension: as easy as A, B, C. Cleve Clin J Med 2010; 77: 298-306
    9. Lamontagne F, Richards-Belle A, Thomas K, et al. Effect of reduced exposure to vasopressors on 90-day mortality in older critically ill patients with vasodilatory hypotension: a randomized clinical trial. JAMA 2020; 323: 938-49
    10. Tanioku T, Yoshida A, Aratani Y, et al. Validation of noninvasive continuous arterial pressure measurement by ClearSight System during induction of anesthesia for cardiovascular surgery. BMC Anesthesiol 2020; 20: 176
Successful identification and characterisation of a titratable and safe oral agent that consistently increases blood pressure carries a great deal of appeal and the promise of negating physician and patient frustration and morbidity in a significant tranche of intensive care unit (ICU) patients. Universally, ICUs often house patients with mild hypotension rate limiting them from going to the ward, be that in the postoperative period, during recovery from critical illness, or in patients with decompensation of a chronic condition where augmented blood pressure for a period may be beneficial. These groups of patients are not traditionally “shocked” and perhaps do not require the full gamut of intensive management that we are used to providing to critically ill patients but are unable to be cared for on the ward. An oral vasopressor could provide this treatment and conceivably relieve some of the capacity constraints that units are facing.

Midodrine is being increasingly used as the oral vasopressor of choice, based largely on its allied use in the outpatient setting for orthostatic hypotension. Apart from mild side effects, it appears safe. 1 The question remains inconveniently unanswered, which is whether it actually works. Several smaller trials in intensive care participants have interrogated the hypothesis. The randomised controlled MIDAS trial, 2 providing high dose 20 mg three times a day, did not show any reduction in duration of intravenous vasopressors, but demonstrated potential efficacy and benefit in a subgroup of patients with epidural-related hypotension. This was replicated in a pilot randomised controlled trial that used a 10 mg dose. 3 A case–control study comparing patients “stuck” on low dose vasopressors, who had received midodrine off label by their treating clinicians did not show any difference between midodrine and placebo. 4 Furthermore, a retrospective cohort study looking at post-cardiac surgery hypotension suggested that midodrine may have been associated with harm. 5 Trials based on the ward environment with the aim of allowing mobilisation without hypotension have also had limited success to date. A randomised control trial of midodrine 5 mg versus placebo before mobilisation in postoperative hip arthroplasty patients failed to reduce orthostatic hypotension with mobilisation, whereas a pilot change of practice study did find 10 mg to have a significant systolic blood pressure response. 6, 7

Faced with these results, there are several possible avenues to explore. One may argue that the dosing regimens have not been optimal and that a 4–6 hourly dosing regimen may be more efficacious. A responsive dosing protocol (where the dose provided is dependent on the patient’s blood pressure) is another strategy. An alternative argument is that patient selection has been the issue, since many of the patients in the trials have had heterogenous causes of hypotension, and a more targeted approach may be of benefit (such as the epidural-related hypotension group).

Alternatively, we could stop investigating midodrine and look for other agents. Dopamine has gone out of fashion, but many hospitals still allow it to be infused on the ward, it is relatively safe, and can be an effective way of boosting blood pressure. Oral agents such as droxidopa or pyridostigmine are alternate targets that are often combined with midodrine when treating refractory orthostatic hypotension. 8

A final suggestion may be that, in patients without evidence of tissue hypoperfusion, asymptomatic hypotension carries no consequences. The 65 trial suggested that a mean arterial pressure of 60 mmHg was not harmful in older patients with vasodilatory hypotension. 9 This may be the hardest path for us to follow, as doing nothing is a challenge for clinicians. Perhaps in the future, non-invasive monitoring devices will reduce in cost and could provide better monitoring of patients on the ward, allowing us to relax or individualise haemodynamic targets. 10 Or it may be these same monitoring advances will allow us to have more confidence in permitting extension of typically critical care treatments beyond the borders of intensive care.

So where can we go from here? There remains a need for greater understanding of the types of patients and their pathophysiology that will potentially glean a benefit from midodrine or indeed other oral hypertensive choices. The mechanisms of persistent hypotension would seem to differ considerably between different aetiologies, and predictive enrichment with mechanistic underpinning could move this question forward. Furthermore, we do not have good data on the prevalence of patients who could benefit from an oral vasopressor to examine the benefits of reduced or avoided ICU length of stay, and central venous or arterial catheterisation. Without a good understanding of the scope, the pathobiology, and a better handle of interventional efficacy, this question will continue to meander with somewhat disappointing inertia. Ideally, investigative utilisation of enrichment strategies, mechanistic studies shedding more physiological understanding, and an exploration of other potential dosing regimens and agents may be needed to move this important area forward.