Midodrine use in critically ill patients: a narrative review

Costa-Pinto R, Jones DA, Udy AA, Warrillow SJ, Bellomo R. Midodrine use in critically ill patients: a narrative review. Crit Care Resusc. 2022;24(4):298-308. doi:10.51893/2022.4.R. Available from: https://www.sciencedirect.com/science/article/pii/S1441277223000364

Summary of "Midodrine Use in Critically Ill Patients: A Narrative Review"

Abstract

• Overview: Midodrine, a peripherally acting oral α-agonist, is increasingly used in ICU settings despite conflicting evidence about its effectiveness. Initially approved for orthostatic hypotension, its off-label use has expanded to critical care, particularly as an adjunctive therapy for weaning patients off intravenous vasopressors. However, questions about its efficacy, ideal dosing, patient selection, and timing remain unresolved.

Introduction

• Background: Midodrine has gained interest for reducing ICU admission and length of stay by minimizing the need for intravenous vasopressors. Despite growing usage, evidence on its effectiveness is mixed, with concerns about optimal dosing, timing, and patient selection.
• Objective: To provide a comprehensive overview of midodrine's use in critically ill patients, exploring its pharmacological properties, trends, evidence supporting its use, and directions for future research.

Historical Context

• Development: Midodrine was first developed in the 1960s and found clinical utility in treating various conditions, including orthostatic hypotension and urinary incontinence. Its safety and efficacy were established in the 1990s through larger clinical trials, leading to FDA approval in 1996 for orthostatic hypotension.
• Emerging Uses: Beyond its initial indications, midodrine has been explored for managing hypotension during hemodialysis, hepatorenal syndrome, and more recently, in ICU settings for vasopressor weaning.

Pharmacology of Midodrine

• Mechanism of Action: Midodrine's active metabolite, desglymidodrine, selectively stimulates α1-receptors, increasing peripheral vascular resistance and venous tone. It has a short half-life and poor blood-brain barrier penetration, resulting in minimal central nervous system effects.
• Adverse Effects: Common side effects include piloerection, gastrointestinal issues, bradycardia, and urinary retention. Severe cases have reported takotsubo cardiomyopathy and cerebral hemorrhage.

Use in Critical Care Settings

• ICU Applications: Midodrine is mainly used as an adjunct to wean patients off intravenous vasopressors or as a primary oral vasopressor. Early studies showed promise in reducing ICU stay and vasopressor duration, but recent randomized controlled trials (RCTs) have questioned its effectiveness.
• Clinical Evidence: Initial retrospective studies supported midodrine’s use, but larger and more recent RCTs, such as the MIDAS and MAVERIC studies, did not demonstrate significant benefits in reducing intravenous vasopressor duration or ICU length of stay.

Discussion

• Challenges in Efficacy: The inconsistency in results may be due to various factors, including the multifactorial nature of hypotension in critically ill patients and potential downregulation of adrenergic receptors. The fixed dosing protocols in RCTs may also not reflect real-world clinical practice, where titration to target mean arterial pressure is common.
• Future Research Directions: Prospective studies should explore early initiation of midodrine, patient populations with specific types of vasoplegia, and adaptive dosing protocols. Additionally, understanding the long-term impacts of midodrine use after ICU discharge is crucial.

Conclusions

• Summary: While midodrine has potential as an oral vasopressor in ICU settings, its role remains uncertain due to mixed evidence from clinical trials. Future research should focus on refining patient selection, dosing strategies, and understanding the drug’s long-term effects on critically ill patients.

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Discussion Questions

1. How can future clinical trials be designed to better assess the efficacy of midodrine as an adjunctive therapy for vasopressor weaning in the ICU?
2. What are the potential risks of discharging ICU patients on midodrine, and how can these risks be mitigated?
3. How might adaptive dosing protocols for midodrine improve its effectiveness and safety in critically ill patients?

Javier Amador-Casta?eda, BHS, RRT, FCCM

Interprofessional Critical Care Network (ICCN)

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