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

Treatment with vasopressors is one of the most common reasons for admission to an intensive care unit (ICU) [1]. Persistent hypotension in otherwise resuscitated patients can be a delay to discharging patients from the ICU. The addition of oral midodrine may be a solution to reduce the duration of time the patient remains on IV vasopressors and ICU length of stay (LOS).

Midodrine, an oral alpha-1 adrenergic agonist, has approval by the United States Federal Drug Administration (FDA) for the treatmentof symptomatic orthostatic hypotension [2]. Midodrine is a prodrug that is metabolized to form desglymidodrine, with peak blood levels of midodrine reached within 30 min and the active metabolite peaking about 1 to 2 h after administration [3]. It has a relatively safe side effect profile with minimal central nervous system side effects, and good oral bioavailability [4].

Midodrine has previously been evaluated in a series of prospective trials for orthostatic hypotension. Jankovic et al. found a dose of 10 mg three times daily (TDS) increased standing systolic blood pressure by 22 mmHg versus placebo [5]. Wright et al. conducted a dose response study and found that midodrine (10 mg and 20 mg) increased standing blood pressure compared with placebo [3].

Midodrine has also been studied in the setting of dialysis-induced hypotension, and administration of 2.5-10 mg prior to dialysis improved the symptoms of intradialytic hypotension and increased post-dialysis systolic blood pressure [6].

In the critical care environment, the authors have obtained an Investigational New Drug (IND) approval from the United States FDA (IND 113,330; date of receipt: September 12, 2011) to study its effects in patients who require low dose IV vasopressors following resuscitation. We then conducted an observational study on the use of oral midodrine to hasten weaning of IV vasopressors in a cohort of surgical ICU patients [7]. In this prospective observational study, 20 patients who met surgical ICU discharge criteria except for persistent requirement for IV vasopressors (phenylephrine <150 mcg/min or noradrenaline <8 mcg/min) received oral midodrine (modal dose 20 mg, range 5–20 mg) TDS. Requirements for IV vasopressors were assessed following each of the first four doses of midodrine. The rates of decline of vasopressor requirement in the 12 h preceding midodrine, and from initiation of midodrine until 4 h post the fourth dose were calculated. 6 of 20 study patients were able to be weaned from vasopressors following the first dose of midodrine, increasing to 14 of 20 following the fourth dose. The rate of decline in vasopressor requirements increased from 0.62 mcg/min per hour to 2.20 mcg/min per hour (p = 0.012), meaning less IV vasopressor was required. Mean arterial pressure (MAP), heart rate (HR), and total body fluid balance were not significantly different pre and post midodrine administration, suggesting that changes in hemodynamic status or fluid resuscitation were not responsible for the change in the rate of decline in vasopressor requirements.

Cardenas et al. reported on the use of midodrine to wean requirement of IV vasopressors in a medical ICU population [8]. During a six month period, 50 patients who met discharge criteria except for the use of low to moderate dose of a single IV vasopressor were administered oral midodrine (average initial and maximal doses 30.5 mg and 66.6 mg per day). Midodrine was continued on the ward and reduced as tolerated by the admitting team. No adverse effects were observed. In this study, 27 (54%) of the patients were discharged from the hospital on midodrine (average dose 17.8 mg per day). Another recent retrospective study from a medical ICU included 275 patients over one year, with a diagnosis of septic shock and required at least 24 h of IV vasopressors, who were stable or on reducing doses of IV vasopressors. The authors compared patients on IV vasopressors only to those who received IV vasopressors plus adjunctive midodrine (with a starting dose of 10 mg TDS) and showed a reduction in the mean IV vasopressor duration (2.9 days versus 3.8 days, p < 0.001) and reduced ICU length of stay (7.5 versus 9.4 days, p = 0.017) in the IV vasopressor plus midodrine group [9].

There are also a case report and two case series of the use of midodrine to wean from or prevent the need for IV vasopressors. O’Donnell reported on the use of midodrine 10 mg TDS to wean a patient from noradrenaline infusion post C7 to T6 laminectomy for spinal cord compression secondary to a leukemic deposit [10]. Sharma reported the use of oral midodrine 10 mg TDS to wean IV dopamine infusions in three patients with hypotension secondary to myocardial stunning post percutaneous coronary intervention [11]. Sharma also reported on the use of oral midodrine for hypotension post carotid artery stenting. Four patients with persistent hypotension post carotid artery stenting were successfully treated with midodrine 10 mg TDS, avoiding the requirement for ICU admission (the preceding 11 cases required IV dopamine infusions in ICU) [12].

The primary objective of this trial is to determine whether addition of midodrine to standard care reduces the time to discontinuation of IV vasopressor use. We will also study whether hospital and ICU LOS are decreased, as well as rates of ICU or high dependency unit (HDU) readmission, and rates of adverse events related to the use of midodrine (such as bradycardia and other hemodynamically significant arrhythmias).

This article presents the protocol and data analysis plan for the MIDAS trial; an international, multicenter, randomized, double-blind, placebo-controlled clinical trial evaluating the addition of midodrine to IV vasopressor treatment in otherwise stable ICU patients.

Midodrine, an oral alpha-1 adrenergic agonist, was approved for the treatment of symptomatic orthostatic hypotension under the United States FDA’s accelerated approval regulations in 1996 [2]. In August 2010, the FDA proposed to withdraw approval because of the lack of post-approval studies that confirm the clinical benefit of the drug [14]. It was the first time the agency had issued such a notice. Subsequent to support for its use from patients, doctors and professional organizations, the FDA reversed its decision to withdraw approval [15], but this decision was met with mixed response [16, 17].

Over recent years, there has been increasing interest in using midodrine to help patients wean off or avoid IV vasopressors [6, 10‐12]. The drug has a reasonable safety profile, its main side effects being pilomotor reaction, urinary retention, and supine hypertension. The use of an oral vasopressor such as midodrine in addition to IV vasopressors in otherwise resuscitated and stable ICU patients has several reasons for attractiveness. Firstly, it helps to avoid some of the potential complications of administering IV vasopressors, such as risks of central line insertion and catheter-related bloodstream infections. Secondly, they may help to shorten the duration of IV vasopressor treatment, and hence reduce ICU length of stay and ICU-acquired complications. This has significant cost implications for the patient and hospital.

We communicated directly with the United States FDA and obtained IND approval to study the use of midodrine in the ICU setting. In our pilot observational study [7], we detected that midodrine treatment was associated with an increase in the magnitude of decline of the IV vasopressor rate. This pilot study offered promising data, but was limited in its small sample size (20 patients) and lack of a control group. We designed the MIDAS trial as a pragmatic clinical trial to study its use in routine patient care conditions. We have designed the inclusion and exclusion criteria so they can be applied to a broad clinical setting across a wide range of patients. We hope to improve the generalizability of our results by carrying out the study in a multicentric design.

One limitation of this study is the fixed drug dosing. This was selected to simplify the protocol and it was shown to be safe during the pilot study. However, an individualized dose titrated according to renal or hepatic function may allow midodrine to be used in a wider range of patients. A second limitation is we do not have a standardized protocol with regards to blood pressure targets for initiation, escalation, or weaning of IV vasopressors. The different blood pressure goals set by the primary care team may confound the individual duration of vasopressor treatment. A third limitation is that we are not studying the use of this drug on the ward environment, which is another useful indication of midodrine in preventing ICU admission.

This manuscript provides a description of our study protocol and analysis plans for the MIDAS international, multicenter, randomized placebo- controlled clinical trial. This trial is an opportunity to improve the efficiency of our ICU beds and healthcare costs by facilitating early and safe cessation of intravenous vasopressors in ICU patients.