crystalloid liberal or vasopressors early resuscitation in sepsis

Conditions: Septic Shock

Summary: multicenter, prospective, phase 3 randomized non-blinded interventional trial of fluid treatment strategies in the first 24 hours for patients with sepsis-induced hypotension. the aim of the study is to determine the impact of a restrictive fluids strategy (vasopressors first followed by rescue fluids) as compared to a liberal fluid strategy (fluids first followed by rescue vasopressors) on 90-day in-hospital mortality in patients with sepsis-induced hypotension.

primary hypothesis: restrictive (vs liberal) fluid treatment strategy during the first 24 hours of resuscitation for sepsis-induced hypotension will reduce 90-day in-hospital mortality. 1. we will emphasize early screening and protocol initiation, and enroll a maximum of 2320 patients with suspected sepsis-induced hypotension. * all patients will receive at least 1 liter of fluids prior to meeting study inclusion criteria (and no more than 3 liters prior to randomization). * patients will be enrolled within 4 hours of meeting study inclusion criteria * any type of isotonic crystalloid (normal saline, ringers lactate, or a balanced solution such as plasmalyte) is permitted. 2. restrictive fluids (early vasopressors) group * norepinephrine will be used as preferred vasopressor and titrated to achieve mean arterial pressure (map) between 65 mmhg and 75 mmhg * "rescue fluids" may be administered as 500ml boluses if predefined rescue criteria are met 3. liberal fluids (fluids first) * 2 liter infusion upon enrollment (may forego second liter if map/sbp and heart rate are normalized and clinical assessment if patient is fluid replete after the first liter). * administer 500ml fluid boluses for fluid triggers until 5 liters administered or development of clinical signs of acute volume overload develop * "rescue vasopressors" may be administered after 5 liters of fluid, for development of acute volume overload, or if other predefined rescue criteria are met

Eligibility criteria:
inclusion criteria: * age ≥ 18 years * a suspected or confirmed infection (broadly defined by administration or planned administration of antibiotics) * sepsis-induced hypotension defined as systolic blood pressure \< 100 mmhg or map \< 65 mmhg after a minimum of at least 1 liter of fluid (\*fluids inclusive of pre-hospital fluids; blood pressure must be below any known or reported pre-morbid baseline). exclusion criteria: * more than 4 hours elapsed since meeting inclusion criteria or 24 hours elapsed since admission to the hospital * patient already received 3 liters of intravenous fluid (includes prehospital volumes) * unable to obtain informed consent * known pregnancy * hypotension suspected to be due to non-sepsis cause (e.g. hemorrhagic shock) * blood pressure is at known or reported baseline level * severe volume depletion from an acute condition other than sepsis. in the judgment of the treating physician, the patient has an acute condition other than sepsis causing (or indicative) of \*severe volume depletion; examples include: diabetic ketoacidosis, high volume vomiting or diarrhea, hyperosmolar hyperglycemic state, and nonexertional hyperthermia (heat stroke); severe is defined by the need for substantial intravenous fluid administration as part of routine clinical care * pulmonary edema or clinical signs of new fluid overload (e.g. bilateral crackles, new oxygen requirement, new peripheral edema, fluid overload on chest x-ray) * treating physician unwilling to give additional fluids as directed by the liberal protocol * treating physician unwilling to use vasopressors as directed by the restrictive protocol. * current or imminent decision to withhold most/all life-sustaining treatment; this does not exclude those patients committed to full support except cardiopulmonary resuscitation * immediate surgical intervention planned such that study procedures could not be followed * prior enrollment in this study

Keywords: fluid management sepsis-induced hypotension vasopressors