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ONLINE SUPPLEMENT I. Question clarifying living situation prior to and after severe sepsis hospitalization. II. Eligibility criteria for ACCESS trial III. Eligibility criteria for PROWESS-SHOCK trial IV. Clinical characteristics of patients enrolled in ACCESS and PROWESS-SHOCK trial cohorts 1 I. Question clarifying living situation prior to and after severe sepsis hospitalization. Subject living situation prior to hospitalization (check one box): 1. Home without help (subject is fully functional) 2. Home with help from a family member 3. Home with paid help 4. Nursing home or extended care nursing facility 5. Rehabilitation facility or chronic ventilator facility 6. Other, specify Only subjects who resided at home without help (option #1) before severe sepsis hospitalization were included in this analysis. II. Eligibility criteria for ACCESS trial Inclusion criteria Evidence of infection, 3 SIRS criteria, and 1 major organ dysfunction. SIRS Criteria Tachycardia (heart rate >90 beats/min) Tachypnea (respiratory rate >20/min while breathing spontaneously, or PaCO2 <32 mm Hg [4.3 kPa], or use of mechanical ventilation) Leukocytosis (>12 x 103/μL) or leukopenia (<4 x 103/μL) or >10% immature forms Organ Dysfunction Criteria Shock: Acute-onset systolic blood pressure <90 mm Hg or mean arterial pressure <65 mm Hg in the absence of other causes of hypotension. The decrease in blood pressure did not respond adequately to at least 1 hour of a fluid challenge (of 500 mL of a crystalloid solution or 200 mL of a colloid solution) and required the use of vasopressors (excluding dopamine <5 μg/kg/min) to maintain mean arterial pressure >65 mm Hg. Respiratory failure: For subjects without pneumonia or other pre-existing lung disease: acute lung injury (PaO2/FiO2 <300), diffuse bilateral pulmonary infiltrates, need for endotracheal intubation with positive pressure ventilation, and absence of elevated left atrial pressure‒related pulmonary edema all within a 24-hour interval). For subjects with pneumonia without shock: evidence of acute respiratory distress syndrome required a PaO2/FiO2 <200. Thrombocytopenia: Acute-onset platelet count <100 x 109/L or reduction by >50% from prior known levels, without another attributable cause of thrombocytopenia. Acute kidney injury: Urine output of <0.5 mL/kg ideal body weight/hour for >2 hours despite adequate fluid challenge (500 mL of a crystalloid solution or 200 mL of a colloid solution over 30 minutes); patients with preexisting chronic kidney disease were excluded from using this definition of kidney injury. Acute lactic acidosis: Unexplained metabolic acidosis pH <7.30, or a base deficit >5.0 mmol/L, in association with a plasma lactate level >2.2 mmol/L (>19.8 mg/dL). 2 Key exclusion criteria Expected survival <2 months or chronic vegetative state Pregnant or lactating Concurrent immunosuppressive therapy Patients receiving a mean dose of >0.5 mg/kg prednisone (to a maximum of 30 mg/d) or equivalent dose of another agent in the 7 days before screening were excluded. Hydrocortisone at doses >300 mg/d for treatment of septic shock was acceptable. Third-degree burns (within the previous 7 days) covering >20% of body surface area APACHE score <21 or >37 within 24 hours of enrollment HIV+ with CD4 count <5 x 107/L Cancer with current chemotherapy or radiotherapy CPR within the previous 4 weeks Significant hepatic impairment, portal hypertension, or esophageal varices Severe heart failure Hemofiltration or hemodiafiltration for the indication of sepsis, use of endotoxinremoval devices, such as polymixin B columns, administration of IV polymixins, or plasma exchange for the indication of sepsis Weight >150 kg III. Eligibility criteria for PROWESS-SHOCK Inclusion criteria to obtain informed consent 18 years old Must have an infection requiring intravenous antimicrobial therapy Must meet at least 2 of the 4 systemic inflammatory response syndrome (SIRS) criteria. Must have septic shock, defined as: o The patient must have received intravenous fluid resuscitation of > 30 mL/kg administered within the time period spanning the 4 hours before and 4 hours after initiation of vasopressor therapy. o The patient must have a continuous requirement for at least one of the vasopressors listed below at the dose shown below for at least four hours: Norepinephrine > 5 mcg/min Dopamine > 10 mcg/kg/min Phenylephrine > 25 mcg/min Epinephrine > 5 mcg/min Vasopressin > 0.03 units/min The patient must meet at least 1 of the following criteria consistent with hypoperfusion during the 36 hours prior to study entry: Metabolic acidosis: base deficit > 5.0 mmol/L or venous bicarbonate < 18 mmol/L or lactate > 2.5 mMol/L. Urine output < 0.5 mL/kg/h for 1 hour or a 50% increase in creatinine from a known baseline level. Acute hepatic dysfunction: AST or ALT >500 IU/dL or bilirubin >2 g/dL. Inclusion criterion to proceed to randomization Patients must remain vasopressor dependent throughout the pretreatment period and through the time of randomization with the goal of maintaining a systolic blood pressure of approximately 90 mm Hg or higher or a mean arterial pressure of 65 mm Hg 3 or higher with reasonable attempts made to wean the patient from vasopressor support, if applicable. (Note: dopamine at doses < 5 mcg/kg/min does not fulfill the criteria for vasopressor dependency.) Key exclusion criteria <18 years old Sepsis Induced Organ Dysfunction > 36 Hours Single Organ Dysfunction and Recent Surgery (within last 30 days) Post-op < 12 hours, Evidence of Bleeding, or Planned Surgery Platelet Count < 30x 109/L INR > 5.0 Active Internal Bleeding or Increased Risk for Bleeding Receiving or Concurrent Need for Bleeding Risk Medications Not Expected to Survive 28 Days due to Pre-existing Condition Moribund & Death is Perceived to be Imminent Not Committed to Aggressive Management Received Drotrecogin alpha activated within last 30 days Pregnant or Lactating & the Milk is to be Ingested by the Newborn Fail to Give Written Informed Consent Participating in Competing Study of Investigational Drug or Device IV. Clinical characteristics of patients enrolled in ACCESS and PROWESS-SHOCK trial cohorts. Clinical characteristics of patients enrolled in ACCESS trial The mean age was 63.2 years and 454 (39.7%) were women (Table 1). Five hundred and eighty six (51.3%), 340 (29.7%), and 80 (7.0%), 73 (6.4%), 64 (5.6%) were from Europe, North America, Asia, South America, and rest of the world, respectively. Three hundred and forty seven (30.3%), 254 (14.0%), 235 (13.4%), 161 (8.9%), 142 (7.8%), and 58 (3.2%) had diabetes, pulmonary disease, cancer, kidney disease, ischemic heart disease, and heart failure, respectively. Eight hundred and twenty seven patients (72.4%) had at least one or more chronic disease. The lung was the most common primary site of infection in 571 patients (44.1%). A microbiologic etiology was determined in 762 (66.6%) patients, and among these, a bacterial source was identified in 753 (98.8%) patients. At enrollment, the illness severity was high. For 4 example, 1,269 (64%) had an APACHE II score of 25 or higher and 397 (34.7%), 273 (23.9%), and 111 (9.7%) had dysfunction in 2, 3, and 4 or more organ systems, respectively. Additionally, 551 (48.2%) had shock and 116 (10.1%) had acute respiratory distress syndrome (ARDS). The median duration of mechanical ventilation and vasopressor use and the intensive care unit and hospital stay were 7, 3, 11, and 21 days, respectively. Clinical characteristics of patients enrolled in PROWESS-SHOCK trial The demographic characteristics, chronic disease burden, and illness severity of patients analyzed from the PROWESS-SHOCK trial were similar to those analyzed from the ACCESS trial (Table 1). The illness severity at enrollment was also high and 547 (47.9%) patients had an APACHE II score of 25 or greater. The median duration of mechanical ventilation, vasopressor usage, and length of intensive care unit and hospital stay were 6, 5.8, 11, and 22 days, respectively. 5