Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis

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) Group

- Additional 2 liter intravenous fluid bolus upon enrollment

- 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

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