Midodrine Use in Septic Shock

A growing body of literature comprising largely retrospective data seems to support the safety and efficacy of midodrine in the intensive care unit for decreasing IV vasopressor use. The investigators hypothesize that administration of midodrine in the early phase of septic shock in patients with adequate enteral access will result in a significant decrease in time to IV vasopressor liberation (increase in vasopressor-free days), secondarily resulting in decreased central venous catheter dwell times and intensive care unit length of stay.

• Midodrine Hydrochloride (Drug): Midodrine Hydrochloride, enteral, 10 or 20 mg
• placebo (Other): investigational pharmacy formulated placebo comparator

Primary outcomes

• Days Free of Vasopressors (Days) [90 days from enrollment]: days without vasopressor adjusted with mortality

Secondary outcomes

• Central Venous Catheter Free Days [90 days from enrollment]
• Intensive Care Unit Length of Stay (ICU LOS; Days) [90 days from enrollment]
• Hospital Length of Stay (Hospital LOS; Days) [90 days from enrollment]
• 30-day Mortality [30 days from enrollment]
• 90-day Mortality [90 days from enrollment]
• In-hospital Mortality [From randomization until date of death if occurred prior to discharge from sentinel hospitalization, assessed up to 52 weeks]: Mortality during sentinel admission
• Intensive Care Unit Mortality [From randomization until date of death if occurred prior to discharge from the sentinel intensive care unit admission, assessed up to 52 weeks]: Mortality during intensive care unit stay during sentinel admission
• Need to Re-initiate IV Vasopressors 2 or More Hours After Discontinuation [From randomization until date of discharge from the sentinel intensive care unit admission, assessed up to 52 weeks]

Sex: All, ages: 18 Years to 89 Years, accepts healthy volunteers

Inclusion Criteria:

* Patients aged ≥18-89 years old
* Admitted to UVA medical ICU with diagnosis of septic shock.
* Patients requiring at least 5 mcg/min norepinephrine infusion (or equivalent) for blood pressure support for at least 3 hours
* Patients with enteral access established within 12 hours of admission (either able to swallow, or feeding tube in place)

Exclusion Criteria:

* Pregnant females; (due to the potential adverse effects to an unborn child); patients with childbearing potential will have results of pregnancy test checked (which is routinely performed on admission); should the patient have child-bearing potential and the pregnancy status is not checked as part of routine care, such patients will be excluded from the study (i.e. pregnancy testing will not be performed for research purposes)
* Patients < 18 years
* Prisoners
* Patients already taking midodrine
* Patients with cirrhosis of the liver as defined by either biopsy, imaging findings of cirrhosis AND thrombocytopenia or patients otherwise undergoing liver transplant evaluation
* Patients with Increased intraocular pressure and glaucoma
* Patients with allergy to midodrine
* Non-English speaking patients, due to the narrow time-frame for study enrollment and execution of study protocol, employing interpreters is deemed to be a significant burden on the investigators with potential to hamper study enrollment. Non-english speaking patients are not deemed to be adversely affected by exclusion from study as there is no clear a priori reason why study results would not also apply to non-English speakers.
* Patients without enteral access within 12 hours of initiation of IV vasopressors
* Patients where the attending physician does not clinically intend to target a mean arterial pressure of > 65 mmHg
* Patients with pheochromocytoma or thyrotoxicosis
* Patients with active bowel ischemia

Participant flow

Outcome results

• Days Free of Vasopressors (Days) (Primary), Mean, days: Placebo 24.3 (24 to 25); Midodrine Hydrochloride 10 mg TID 7.5 (0 to 27); Midodrine Hydrochloride 20 mg TID 25.6 (24 to 27)
• Central Venous Catheter Free Days (Secondary), Mean, days: Placebo 15.3 (0 to 23); Midodrine Hydrochloride 10 mg TID 7.25 (0 to 28); Midodrine Hydrochloride 20 mg TID 25 (23 to 28)
• Intensive Care Unit Length of Stay (ICU LOS; Days) (Secondary), Mean, days: Placebo 6 (5 to 7); Midodrine Hydrochloride 10 mg TID 10 (1 to 23); Midodrine Hydrochloride 20 mg TID 7.6 (5 to 10)
• Hospital Length of Stay (Hospital LOS; Days) (Secondary), Mean, days: Placebo 11.3 (8 to 17); Midodrine Hydrochloride 10 mg TID 11 (1 to 23); Midodrine Hydrochloride 20 mg TID 15.7 (10 to 26)
• 30-day Mortality (Secondary), Count of participants, Participants: Placebo 2; Midodrine Hydrochloride 10 mg TID 1; Midodrine Hydrochloride 20 mg TID 0
• 90-day Mortality (Secondary), Count of participants, Participants: Placebo 2; Midodrine Hydrochloride 10 mg TID 1; Midodrine Hydrochloride 20 mg TID 0
• In-hospital Mortality (Secondary), Count of participants, Participants: Placebo 1; Midodrine Hydrochloride 10 mg TID 1; Midodrine Hydrochloride 20 mg TID 0
• Intensive Care Unit Mortality (Secondary), Count of participants, Participants: Placebo 1; Midodrine Hydrochloride 10 mg TID 1; Midodrine Hydrochloride 20 mg TID 0
• Need to Re-initiate IV Vasopressors 2 or More Hours After Discontinuation (Secondary), Number, participants: Placebo 2; Midodrine Hydrochloride 10 mg TID 0; Midodrine Hydrochloride 20 mg TID 0

Adverse events

Time frame: Adverse event data were collected for 30 days. All-Cause Mortality was assessed from randomization until date of discharge from the sentinel intensive care unit admission, up to 52 weeks.

• Study Protocol and Statistical Analysis Plan (PDF, 2018-11-27)
• Informed Consent Form (PDF, 2018-07-31)

• Alexandra Kadl, MD, Principal investigator, University of Virginia