Inclusion criteria:

Patients diagnosed with sepsis within 24 hours of meeting all of the following criteria will be eligible to participate in the study:

* Sepsis-3 criteria: acute hospital admission for suspected infection with new or worsening organ dysfunction measured by the increase in Sequential Organ failure Assessment (SOFA) score of 2 points or more.
* IV vasopressor use or persistent hypotension (MAP \< 65 mm Hg) after initial fluid resuscitation in the ED or ICU (30 mL/kg unless deemed excessive by the treating clinician).

Exclusion criteria:

* High-dose vasopressors (norepinephrine equivalent \> 0.3 µg/kg/min).
* Inadequately controlled source of infection.
* Cardiogenic or obstructive (massive pulmonary embolism) shock.
* Clinical suspicion or confirmed diagnosis of bowel obstruction, bowel ischemia, or ileus.
* Contraindication to enteral intake (ileus, vomiting, gastrointestinal bleeding, endoscopic procedures etc.).
* Recent myocardial infarction (within the past 3 months).
* Recent treatment for peripheral vascular disease (within the past 3 months).
* Current use of monoamine oxidase inhibitors.
* Recent stroke (within the past 3 months).
* Prior use of midodrine as a home medication.
* Known allergy to midodrine.
* Comfort care measures.
* Pregnancy.
* Fludrocortisone acetate as a current home medication.
* Bradycardia (heart rate \< 50 beats/min).
* Untreated pheochromocytoma.
* Untreated thyrotoxicosis.
* Open-angle glaucoma.
* Treating emergency or critical care physician unwilling to enroll patient in trial.
* Inability to give consent for participation and no representative or surrogate available to consent.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 9/4/2024. Questions regarding updates should be directed to the study team contact.