Midodrine administration during critical illness: fixed-dose or titrate to response?
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CORRESPONDENCE
Midodrine administration during critical illness: fixed‑dose or titrate to response? Richard R. Riker1* and David J. Gagnon2 © 2020 Springer-Verlag GmbH Germany, part of Springer Nature
Dear Editor, We read with interest the multicenter, randomized, double-blind, placebo-controlled trial conducted by Santer and colleagues examining midodrine administration to expedite weaning of intravenous vasopressor medications [1]. In a heterogeneous cohort of 132 critically ill patients enrolled in three centers over 81 months, the investigators concluded midodrine administration (20 mg every 8 h) was ineffective at hastening time to discontinuation of single intravenous vasopressor medication compared to placebo (23.5 vs. 22.5 h; p = 0.62), and caused significantly more bradycardia (7.6% vs. 0%; p = 0.02). We thank them for conducting this trial, but have several concerns that may raise alternate conclusions. We are aware of six published reports of midodrine administration to expedite weaning of intravenous vasopressors (Table 1). When midodrine was titrated to clinical response, all four research teams concluded midodrine was effective [2–5]. Three of these four studies were retrospective however, limiting the strength of their conclusions. Two studies employed a fixed-dose strategy (including Santer et al.), and both concluded midodrine was ineffective [1, 6]; one of these was retrospective. Wright et al. performed a placebo-controlled, midodrine dose–response crossover trial in patients with orthostatic hypotension, finding a linear relation between midodrine dose and mean systolic blood pressure [7] with drug titration. It is likely Santer’s fixed-dose design limited the therapeutic benefit of midodrine, much like
*Correspondence: [email protected] 1 Neuroscience Institute and Department of Critical Care Services, Maine Medical Center, Professor of Medicine, Tufts University School of Medicine, 22 Bramhall Street, Portland, ME 04102, USA Full author information is available at the end of the article
using norepinephrine at a single dose (rather than titrating to effect) would. In addition, 15% of patients stopped midodrine before vasopressors were discontinued, and the duration of midodrine therapy at 42 h was short compared to the dose titration trials (Table 1). It is unclear if midodrine titration and continued use throughout vasopressor titration would have changed their results, but these issues should be considered. Although Santer identified bradycardia in 5 patients (7.6%) randomized to midodrine, no clinical impact of this bradycardia, need for intervention, or related discontinuation of the medication were reported. Others have reported asymptomatic bradycardia in 0.7–15% of patients treated with midodrine [3, 5], raising the issue whether Santer’s bradycardia was clinically significant or not. We thank Santer et al. for their report, but wonder if their conclusions would be better framed as “midodrine at a fixed-dose among patients receiving single vasopressor therapy was not effec
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