High-dose midodrine is not effective for treatment of persistent hypotension in the intensive care unit

Abstract

We are thankful to Riker and Gagnon for their comment [1] on our recently published MIDAS trial [2]. Many intensivists would like to use midodrine to facilitate discharge from the intensive care unit (ICU) in scenarios where patients are expected to require low dose intravenous vasopressors for a few days. Midodrine is a long-acting drug with a half-life of the active metabolite of 3–4 h in patients with normal renal and hepatic function—the drug can therefore not be easily titrated in the ICU. We administered midodrine at a high dose of 20 mg every 8 h—the maximum recommended daily dose is 30 mg—and demonstrated a lack of effectiveness in treating refractory hypotension in the ICU [2]. In filing studies for orthostatic hypotension, up to 20 mg of midodrine were administered [3]. The lowest effective dose was found to be 10 mg; doses greater than 10 mg increased standing systolic blood pressure by 30–40 mmHg after 1 h. This increase was sustained for 2 h after a single dose of 10 mg of midodrine and up to 4 h after 20 mg. In the ICU setting, however, the mechanism of hypotension is normally not related to orthostasis, and its magnitude is typically more severe. In addition, bioavailability is variable due to frequent gastrointestinal dysfunction in critically ill patients [4]. Based on these considerations, we used the high dose of 20 mg three times per day. This dose reflected clinician behavior at the institution where the MIDAS trial was initiated and was also the most frequently used dose in our observational study conducted at the same institution, which was cited by Riker and Gagnon as an indicator of the effectiveness of midodrine [5]. The MIDAS trial was the first prospective, randomized, placebo controlled trial evaluating the effectiveness of midodrine in the ICU. Thus, we provide the highest level of evidence currently available to conclude that midodrine—even at high doses—is not effective for the treatment of persistent hypotension in the surgical ICU. Given the absence of effectiveness of high-dose midodrine, we are skeptical towards a need for dose titration—we rather suggest avoiding midodrine in surgical ICU patients. Based on our exploratory analyses, we speculate that midodrine’s absence of effectiveness in critically ill patients may be explained by impaired gastrointestinal function. In the MIDAS trial, midodrine was effective in the subgroup of patients who received epidural analgesia, a strategy known to improve postoperative recovery of gastrointestinal function [6].