Midodrine as adjunctive support for treatment of refractory hypotension in the intensive care unit: a multicenter, randomized, placebo controlled trial (the MIDAS trial)

Matthew H Anstey, Bradley Wibrow, Tharusan Thevathasan, Brigit Roberts, Khushi Chhangani, Pauline Yeung Ng, Alexander Levine, Alan DiBiasio, Todd Sarge, Matthias Eikermann, Matthew H Anstey, Bradley Wibrow, Tharusan Thevathasan, Brigit Roberts, Khushi Chhangani, Pauline Yeung Ng, Alexander Levine, Alan DiBiasio, Todd Sarge, Matthias Eikermann

Abstract

Background: Patients admitted to intensive care units (ICU) are often treated with intravenous (IV) vasopressors. Persistent hypotension and dependence on IV vasopressors in otherwise resuscitated patients lead to delay in discharge from ICU. Midodrine is an oral alpha-1 adrenergic agonist approved for treatment of symptomatic orthostatic hypotension. This trial aims to evaluate whether oral administration of midodrine is an effective adjunct to standard therapy to reduce the duration of IV vasopressor treatment, and allow earlier discharge from ICU and hospital.

Methods: The MIDAS trial is an international, multicenter, randomized, double-blind, placebo-controlled clinical trial being conducted in the USA and Australia. We are targeting 120 patients. Adult patients admitted to the ICU who are resuscitated and otherwise stable on low dose IV vasopressors for at least 24 h will be considered for recruitment. Participants will be randomized to receive midodrine (20 mg) or placebo three times a day, in addition to standard care. The primary outcome is time (hours) from initiation of midodrine or placebo to discontinuation of IV vasopressors. Secondary outcomes include time (hours) from ICU admission to discharge readiness, ICU length of stay (LOS) (days), hospital LOS (days), rates of ICU readmission, and rates of adverse events related to midodrine administration.

Discussion: Midodrine is approved by the Food and Drug Administration (FDA) for the treatment of symptomatic orthostatic hypotension. In August 2010, FDA proposed to withdraw approval of midodrine because of lack of studies that verify the clinical benefit of the drug. We obtained Investigational New Drug (IND 113,330) approval to study its effects in critically ill patients who require IV vasopressors but are otherwise ready for discharge from the ICU. A pilot observational study in a cohort of surgical ICU patients showed that the rate of decline in vasopressor requirements increased after initiation of midodrine treatment. We hypothesize that midodrine administration is effective to wean IV vasopressors and shorten ICU and hospital LOS. This trial may have significant implications on lowering costs of hospital care and obtaining FDA approval for new indications for midodrine.

Trial registration: This study has been registered at clinicaltrials.gov on 02/09/2012 (NCT01531959).

Keywords: Alpha adrenergic agonist; High dependency unit; Hypotension; Intensive care unit; Midodrine; Vasopressor.

Figures

Fig. 1
Fig. 1
Outline of study design
Fig. 2
Fig. 2
Flowchart of study procedures

References

    1. Thongprayoon C, Cheungpasitporn W, Harrison AM, Carrera P, Srivali N, Kittamongkolchai W, Erdogan A, Kashani KB. Temporal trends in the utilization of vasopressors in intensive care units: an epidemiologic study. BMC Pharmacol Toxicol. 2016;17(1):19. doi: 10.1186/s40360-016-0063-z.
    1. Midodrine Information []. Accessed 1 Mar 2017.
    1. Wright RA, Kaufmann HC, Perera R, Opfer-Gehrking TL, McElligott MA, Sheng KN, Low PA. A double-blind, dose–response study of midodrine in neurogenic orthostatic hypotension. Neurology. 1998;51(1):120–124. doi: 10.1212/WNL.51.1.120.
    1. Low PA, Gilden JL, Freeman R, Sheng KN, McElligott MA. Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension. A randomized, double-blind multicenter study. Midodrine study group. JAMA. 1997;277(13):1046–1051. doi: 10.1001/jama.1997.03540370036033.
    1. Jankovic J, Gilden JL, Hiner BC, Kaufmann H, Brown DC, Coghlan CH, Rubin M, Fouad-Tarazi FM. Neurogenic orthostatic hypotension: a double-blind, placebo-controlled study with midodrine. Am J Med. 1993;95(1):38–48. doi: 10.1016/0002-9343(93)90230-M.
    1. Prakash S, Garg AX, Heidenheim AP, House AA. Midodrine appears to be safe and effective for dialysis-induced hypotension: a systematic review. Nephrol Dial Transplant. 2004;19(10):2553–2558. doi: 10.1093/ndt/gfh420.
    1. 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;28(5):756–762. doi: 10.1016/j.jcrc.2013.05.021.
    1. Cardenas-Garcia JL, Withson M, Healy L, Koenig S, Narasimhan M, Mayo P. Safety of oral midodrine as a method of weaning from intravenous vasoactive medication in the medical intensive care unit. Chest. 2014;146(4):224A. doi: 10.1378/chest.1990326.
    1. 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;149(6):1380–1383. doi: 10.1016/j.chest.2016.02.657.
    1. O'Donnell B, Synnott A. Midodrine, an alternative to intravenous vasopressor therapy after spinal surgery. Eur J Anaesthesiol. 2002;19(11):841–842. doi: 10.1017/S0265021502251352.
    1. Sharma S, Bhambi B. Successful treatment of hypotension associated with stunned myocardium with oral midodrine therapy. J Cardiovasc Pharmacol Ther. 2005;10(1):77–79. doi: 10.1177/107424840501000109.
    1. Sharma S, Lardizabal JA, Bhambi B. Oral midodrine is effective for the treatment of hypotension associated with carotid artery stenting. J Cardiovasc Pharmacol Ther. 2008;13(2):94–97. doi: 10.1177/1074248408317709.
    1. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42(2):377–381. doi: 10.1016/j.jbi.2008.08.010.
    1. FDA Proposes Withdrawal of Low Blood Pressure Drug: Companies failed to provide evidence of clinical benefit of midodrine hydrochloride []. Accessed 1 Mar 2017.
    1. Midodrine update []. Accessed 1 Mar 2017.
    1. Dhruva SS, Redberg RF. Accelerated approval and possible withdrawal of midodrine. JAMA. 2010;304(19):2172–2173. doi: 10.1001/jama.2010.1695.
    1. Holtzman NA, Starfield B. Withdrawing FDA approval of midodrine after marketing. JAMA. 2011;305(8):781–782. doi: 10.1001/jama.2011.161.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi