Protocolized Care for Early Septic Shock

Septic shock is a condition of acute organ dysfunction due to severe infection, with a
mortality of up to 50%. Current efforts to improve care are limited by little practical
evidence regarding the interventions in and timing of sepsis therapies. ProCESS is a
prospective, randomized, three-arm parallel-group trial of alternative resuscitation
strategies for early septic shock. The study objective is to improve the management of
septic shock by exploring the clinical, biological, and economic aspects of alternative
resuscitation strategies. This will be done by comparing two alternative resuscitation
strategies to usual care in subjects with septic shock.

Comparisons:

1. Early Goal Directed Therapy (EGDT) - The subjects' blood pressure and blood oxygen
levels will be monitored via the insertion of a central venous catheter (CVC). The
study team will use this information to give fluid, blood and heart medications in a
structured fashion. The central venous catheter to be used in this plan is FDA approved
and routinely used in hospitals.

2. Protocolized Standard Care (PSC) - The subjects' blood pressure and blood oxygen levels
will be monitored with standard equipment (without the CVC). The study team will use
this information to prescribe fluid and heart medications in a structured fashion.
CVCs will only be used when standard IVs cannot give the proper amount of fluids and
medicines. Blood transfusions will be given according to currently recommended
guidelines.

3. Usual Care (UC) - Subjects will be treated according to their attending physician's
standard treatment plan and without any influence from the study team.

The primary hypotheses to be tested sequentially are that: protocolized resuscitation (EGDT
and PSC) results in lower hospital mortality than usual care and Early Goal Directed Therapy
results in lower hospital mortality than Protocolized Standard Care. These hypotheses will
be tested on all enrolled subjects.

The study is powered to find an absolute mortality reduction (ARR) of ~6-7%. Based on the
control arm mortality rate, we originally estimated a sample size of 1950. During the trial,
the ProCESS Coordinating Center monitored the overall mortality rate, and appreciated that
it was markedly lower than originally projected. Therefore, following a series of new
calculations, in February 2013, the trial was re-sized to 1350 patients (450 patients per
arm). The new size preserves the same power to find the same ARR. The resizing was fully
blinded and approved by the NIH.

Inclusion criteria:

- At least 18 years of age

- Suspected infection

- Two or more systemic inflammatory response syndrome (SIRS) criteria

- Temperature /= 38˚C

- Heart rate >/= 90 beats per minute

- Mechanical ventilation for acute respiratory process or respiratory rate >/= 20
breaths per minute or PaC02 < 32 mmHg

- WBC >/= 12,000/mm³ OR 10% bands

- Refractory hypotension (a systolic blood pressure < 90 mm Hg despite an IV fluid
challenge of at least 1,000 mLs over a 30 minute period) or evidence of hypoperfusion
(a blood lactate concentration >/= 4 mmol/L)

Exclusion criteria:

- Known pregnancy

- Primary diagnosis of acute cerebral vascular event, acute coronary syndrome, acute
pulmonary edema, status asthmaticus, major cardiac arrhythmia, active
gastrointestinal hemorrhage, seizure, drug overdose, burn or trauma

- Requirement for immediate surgery

- ANC < 500/mm³

- CD4 < 50/mm³

- Do-not-resuscitate status

- Advanced directives restricting implementation of the protocol

- Contraindication to central venous catheterization

- Contradiction to blood transfusion (e.g., Jehovah's Witness)

- Treating physician deems aggressive care unsuitable

- Participation in another interventional study

- Transferred from another in-hospital setting