Table 1 Study inclusion and exclusion criteria

• Adults patients ≥ 18 years old with persistent vasodilatory shock despite moderate-dose vasopressor therapy, defined as those who require norepinephrine or other vasopressor therapy with total norepinephrine equivalent dose (NED) at ≥ 0.1 mcg/kg/min for at least 30 min to maintain a MAP between 65 and 70 mm Hg [4, 33, 34]

• Central venous and arterial catheters present and expected to remain in place for ≥ 72 h

• Patients must have received ≥ 20 mL/kg of crystalloid over the previous 24-h period, as clinically appropriate, and no longer be fluid responsive as per local protocol^a. Patients for whom the treating physicians feel that 20 mL/kg of crystalloid may be clinically inappropriate may qualify for the study if the reason for withholding further IV fluids is documented

• Patient or legal authorized representative is willing and able to provide written informed consent and comply with all protocol requirements

• Approval from the attending physician supervising care of the patient and the clinical pharmacist conducting the study

• Age < 18 years

• Acute occlusive coronary syndrome requiring intervention and/or cardiogenic shock

• Known or suspected abdominal aortic aneurysm or aortic dissection

• Acute stroke

• Acute mesenteric ischemia or history of mesenteric ischemia

• Known Raynaud’s phenomenon, systemic sclerosis, or vasospastic disease

• Requirement for venoarterial ECMO

• Liver failure with a MELD score [35] of ≥ 30

• Burns covering > 20% of total body surface area

• History of asthma or COPD with active acute bronchospasm or (if not mechanically ventilated) with an acute exacerbation of their asthma/COPD requiring the use of inhaled bronchodilators

• Requirement for > 500 mg daily of hydrocortisone or equivalent glucocorticoid medication as a standing dose

• Absolute neutrophil count < 1000/mm³

• Hemorrhagic shock OR active bleeding AND an anticipated need (within 48 h of initiation of the study) for transfusion of > 4 units of packed red blood cells

• Active bleeding AND hemoglobin < 7 g/dL or any other condition that would contraindicate serial blood sampling

• Untreated venous thromboembolism (VTE) or inability to tolerate pharmacologic VTE prophylaxis

• Known allergy to mannitol

• Expected survival < 24 h, SOFA score [36] ≥ 16, or death deemed to be imminent or inevitable during the admission

• Comfort measures status (limitations such as DNR or DNI status permitted if the patient is otherwise pursuing life-prolonging therapies)

• Pregnancy (all women ≤ 50 years-old require negative serum quantitative beta-hCG to enroll)

• Prisoner status

• Current participation in another interventional clinical trial