Oral Midodrine Administration During the First 24 Hours of Sepsis to Reduce the Need of Vasoactive Agents: Placebo-Controlled Feasibility Clinical Trial

Abstract

Objectives: Our preliminary data and observational studies suggested an increasing “off label” use of oral midodrine as a vasopressor sparing agent in various groups of critically ill patients, including those with sepsis. We designed this clinical trial to evaluate the feasibility of use of midodrine hydrochloride in early sepsis to reduce the duration for IV vasopressors and decrease ICU and hospital length of stay. Design: Pilot, two-center, placebo-controlled, double blinded randomized clinical trial. Setting: Medical ICUs at Mayo Clinic Rochester and Cleveland Clinic Abu Dhabi were the study sites. Patients and Methods: Adult patients (≥ 18 yr old) were included within 24 hours of meeting the Sepsis-3 definition if the mean arterial pressure remained less than 70 mm Hg despite receiving timely antibiotics and initial IV fluid bolus of 30 cc/kg. Intervention: Three doses of 10 mg midodrine versus placebo were administered. Measurements and Main Results: Total 32 patients were randomized into midodrine ( n = 17) and placebo groups ( n = 15). There were no major differences in baseline variables between the groups except for higher baseline creatinine in the midodrine group (2.0 ± 0.9 mg/dL) versus placebo group (1.4 ± 0.6 mg /dL), p = 0.03. The median duration of IV vasopressor requirement was 14.5 ± 8.1 hours in midodrine group versus 18.8 ± 7.1 hours in the placebo group, p value equals to 0.19. Patients in the midodrine group needed 729 ± 963 norepinephrine equivalent compared with 983 ± 1,569 norepinephrine equivalent in the placebo group, p value equals to 0.59. ICU length of stay was 2.29 days (interquartile range, 1.65–3.9 d) in the midodrine group, compared with 2.45 days (interquartile range, 1.6–3.2 d) in the placebo group, p value equals to 0.36. No serious adverse events were observed in either group. Conclusions: Phase II clinical trial powered for clinical outcomes (duration of vasopressor use, need for central venous catheter, and ICU and hospital length of stay) is justified.

Septic shock definitions and associated outcomes in blood culture positive critically ill patients

“…This study showed that bacteremic patients who meet both the new Sepsis-3 and old Sepsis-1 (combined group of both new Sepsis-3 and Sepsis-1) definitions have a higher severity of illness and higher hospital mortality compared to those who meet only the old Sepsis-1 definition. This becomes very important with treatable medical conditions like bacteremia and sepsis in which early therapy and diagnostic testing with multidisciplinary team involvement make a significant impact on patient outcome (10)(11)(12).…”

Characteristics and Predictors of Patients with Sepsis who are Candidates for Minimally Invasive Approach Outside of Intensive Care Unit

“…Midodrine has been shown to reduce the duration and cumulative dose of vasopressors and improve lactic acid clearance in patients with sepsis when used during early hours ( 12 , 25 ). It is possible that midodrine could be used in certain MIS group patients precluding the need for vasopressor support.…”

Oral midodrine does not expedite liberation from protracted vasopressor infusions: A case-control study

“…This case-control study sought to understand whether the oral vasopressor midodrine expedited weaning of IV vasopressors in patients who had already received prolonged courses of these medications, often at low doses. This aim is in contrast to the randomised controlled MIDAS trial 7 and other randomised studies, 12 which evaluated the early use of oral midodrine to accelerate liberation from IV vasopressors. This is a controversial and important issue, as expedited weaning from IV vasopressors may accelerate ICU discharge and reduce complications related to their use.…”

“…This finding is in keeping with the primary outcome of MIDAS, the only appropriatelypowered, randomised study of this question, 7 as well as several other studies and meta-analyses which showed no effect of midodrine on similar outcomes. [12][13][14][15] Earlier retrospective or observational studies demonstrated that midodrine accelerated either liberation from vasopressors or discharge from the ICU. 1,6,16 These differences are likely due to heterogeneous study populations, retrospective or observational designs and differing dose regimens.…”