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

Abstract

BackgroundPatients 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.MethodsThe 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.DiscussionMidodrine 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 RegistrationThis study has been registered at clinicaltrials.gov on 02/09/2012 (NCT01531959).

Catecholamine Vasopressor Support Sparing Strategies in Vasodilatory Shock

“…Published reports evaluating midodrine as a catecholamine‐sparing agent are limited to four studies (Table ). Currently, no prospective randomized clinical trials have evaluated midodrine as a catecholamine‐sparing agent in adults with septic shock, although such trials are ongoing . The first published evaluation of midodrine's catecholamine‐sparing effects was a prospective observational study that observed a precipitous decline in the vasopressor infusion rate during the first 4 doses of midodrine in surgical ICU patients .…”

“…Currently, no prospective randomized clinical trials have evaluated midodrine as a catecholamine-sparing agent in adults with septic shock, although such trials are ongoing. 68 The first published evaluation of midodrine's catecholamine-sparing effects was a prospective observational study that observed a precipitous decline in the vasopressor infusion rate during the first 4 doses of midodrine in surgical ICU patients. 69 Two subsequent retrospective studies evaluated patients treated with adjunctive midodrine to facilitate vasopressor liberation compared with patients treated with vasopressors alone.…”

Potential risks in using midodrine for persistent hypotension after cardiac surgery: a comparative cohort study

“…Of note, Rizvi et al [ 23 ] have presented a mixed case series of 1119 patients who received midodrine during a 5 years period, showing a steady increase in the popularity of this practice in the ICU despite the absence of solid evidence in its favor, leading to heterogeneous and worrisome prescription patterns after ICU discharge [ 24 ]. A multicentric randomized controlled trial is underway to better assess the efficacy and safety of using midodrine in the ICU [ 28 ].…”

“…Still, its characteristics make midodrine an attractive agent for ICU patients presenting prolonged hypotension attributed to vasodilation who are otherwise stable, and this particular use has been increasingly described in the last few years [ 23 , 24 ]. Results from small cohort studies suggest that weaning of intravenous vasopressors is accelerated with midodrine administration, without significant side effect [ 25 – 28 ], although a recent meta-analysis has not confirmed such results [ 29 ]. Most patients in these cohorts presented with hypotension from sepsis and none had undergone cardiac surgery with CPB.…”

The Role of Midodrine for Hypotension Outside of the Intensive Care Unit

“…29 Currently, the Midodrine as Adjunctive Support for Treatment of Refractory Hypotension in the Intensive Care Unit: (the MIDAS trial), a multicenter, randomized, placebo-controlled trial is underway to better understand the role of midodrine in expediting IV vasopressor weaning. 31 One hundred twenty medical ICU patients who require low-dose vasopressor but who are otherwise stable for ICU discharge will be randomized to midodrine 20 mg or placebo 3-times daily in addition to usual care. The primary outcome is time from drug administration to discontinuation of IV vasopressor.…”