Sepsis: Evidence Based Controversies Rachel Hinerman, MD FCCP

Definitions Sepsis = suspected or proven infection and some of the following: General Variables Inflammatory Variables Hemodynamic Variables Organ Dysfunction Variables Tissue Perfusion Variables SIRS- A clinical response arising from a nonspecific insult, including 2 of the following:

Sepsis Variables General Inflammatory Fever Hypothermia Tachycardia Altered Mental Status Edema Hyperglycemia Leukocytosis Leukopenia Normal WBC with > 10 % immature forms C-reactive protein > 2 SD Procalcitonin > 2 SD

Sepsis Variables Hemodynamic Organ Dysfunction Tissue Perfusion SBP <90 MAP < 70 SBP decrease > 40 Tissue Perfusion Lactate > 1 Mottling Decreased Capillary Refill P/F < 300 UO < .5 ml/kg for 2 hours despite volume resuscitation Cr increase > .5 INR > 1.5 Ileus Plt < 100 K Bili > 4

Severe Sepsis Definition Sepsis induced organ dysfunction, hypoperfusion, or hypotension Hypotension Elevated Lactic Acid Oliguria ALI with P/F < 250 without pneumonia ALI with P/F < 200 with pneumonia Cr > 2 Bili > 2 Plt < 100K INR > 1.5

Septic Shock Sepsis-induced hypotension that persists despite adequate fluid resuscitation *All definitions cited from “Surviving Sepsis Campaign” published in Critical Care Medicine Feb 2013

Dellinger, RP. et al. Crit Care Med 2004;32 Spectrum Of Severity Infection Sepsis Severe Sepsis Septic Shock Sepsis associated with any of the single organ dysfunctions is defined as severe sepsis, Although not shown here, severe sepsis with two or more organs out is MODS. Severe sepsis with hypotension refractory to resuscitation is septic shock. Dellinger, RP. et al. Crit Care Med 2004;32

Scope of The Problem

A National Health Concern? Myocardial Infarction Incidence 900,000 Deaths 225,000 Mortality 25% Cerebrovascular Accident Incidence 700,000 Deaths 163,5000 Mortality 23% Trauma Incidence 2,900,000 Deaths 42,643 Mortality 1.5% Severe Sepsis Incidence 751,000 Deaths 215,000 Mortality 40-60% Angus, DC. et al Crit Care Med 2000;29 National Highway Traffic Safety Commission, 2003 AHA- Heart Disease and Stroke Statistics, 2005 update

Relative Mortality Deaths/Year More people die in one year in North America from severe sepsis than from breast cancer, lung cancer, and colon cancer combined More than 751,000 cases of severe sepsis in US annually. Increasing 1.5 % per annum, 1 mil/yr 2020 projection Angus DC et al. Crit Care Med 2001; 29. American Cancer Society Karon et al. Am J Public Health 2001; 91. American Heart Assoc., 2001

Determinants of Mortality Source control is most vital factor Adequate resuscitation or re-established perfusion in 6 hours Appropriate antibiotic therapy within 1 hr of hypotension

Improving Outcomes

Interventions Early Goal Directed Therapy (EGDT) Anti-microbials Steroids Glucose Control Lung Protective Ventilation

Absolute Risk Reduction % EGDT- ARR 15.1%; NNT 7 Bernard et al. NEJM 2001; 344. Van den Berghe et al. NEJM 2001; 345. Rivers et al. NEJM 2001; 345 Annane et al. JAMA 2002; 288. ARDS-Net Investigators, NEJM; 2000

Rivers E et al. N Engl J Med 2001; 345:1368–1377 EGDT Resuscitation Begin at onset of hypotension or lactate >4 Do not delay while awaiting ICU admission Initial bolus is 30 ml/kg crystalloid Or mixed venous greater than or equ to 65%; Dobut infusion to max 20microgr/kg/minute. Early goal-directed resuscitation has been shown to The consensus panel judged use of central venous and mixed venous oxygen saturation targets to be equivalent. Either intermittent or continuous measurements of oxygen saturation were judged to be acceptable. Studies of patients with shock indicate that mixed venous oxygen saturation runs 5–7% lower than central venous oxygen saturation (Scvo2) Reinhart K, Kuhn HJ, Hartog C, et al: Continuous central venous and pulmonary artery oxygen saturation monitoring in the critically ill. Intensive Care Med 2004; 30:1572–1578 Rivers E et al. N Engl J Med 2001; 345:1368–1377

EGDT Initial Resuscitation targets CVP 8-12 (12-15 if mechanically ventilated) Mean arterial pressure ≥65 Urine output ≥ 0.5 ml/kg/hour Central venous oxygen saturation ≥ 65% If venous oxygen target still not achieved: trial of fluid or transfuse PRBCs to HCT ≥30% and/or start dobutamine infusion

Rivers, NEJM 2001; 345:1368

Rivers, E et al. N Engl J Med 2001; 345 EGDT Outcomes Rivers, E et al. N Engl J Med 2001; 345

EGDT Cost 23% reduction in hospital cost Most cost effective if patient volume > 16 cases/year Mean reduction of 4 days per hospital admission Cost per life saved of approximately $32,336 Reduction in hospital charges from $135,000 to $82,000 Cost-Effectiveness of EGDT- SHLD DEMONSTARTE FISCAL JUSTIFICATION. The potential benefits that can be realized through a program such as EGDT should demonstrate fiscal justification. An examination118 of EGDT included factors such as additional training, personnel, possible physical plant changes, and equipment necessary to screen patients, and concluded that EGDT is a cost-effective intervention. Huang et al118 in a formal cost-effectiveness analysis found that EGDT can provide up to a 23.4% reduction in hospital costs related to the treatment of patients with severe sepsis and septic shock. EGDT was found to be most cost-effective if the volume of patients exceed 16 patients per year. The cost-effectiveness was demonstrated in all models of care including whether the care was provided primarily by the ED, rapid response team, or the ICU. For HFH in particular, there was a mean reduction of 4 days per hospital admission (a 32.6% reduction in hospital length of stay) for survivors and a 13.9% reduction in PAC use (both p < 0.03). Similar findings have been noted by other investigators. Shapiro et al83 have reported a cost per life saved of $32,336, and Trzeciak et al82 found a reduction in median hospital facility charges from $135,199 to $82,233 (reduction, 39.2%; p = 0.14) and in PAC use from 43.8 to 9.1% (p = 0.01). Trzeciak, S, Dellinger, RP, Abate, NL, et al Translating research to clinical practice: a 1-year experience with implementing early goal-directed therapy for septic shock in the emergency department. Chest 2006;129,225-232[CrossRef][Medline] Shapiro, NI, Howell, MD, Talmor, D, et al Implementation and outcomes of the Multiple Urgent Sepsis Therapies (MUST) protocol. Crit Care Med 2006;34,1025-1032 Huang, DT, Angus, DC, Dremsizov, TT, et al Cost-effectiveness of early goal-directed therapy in the treatment of severe sepsis and septic shock [abstract]. Crit Care 2003;7(suppl),S116 Treciak S et al. Chest 2006;129:225-232 Huang DT, et al Crit Care 2003;7:S116 Shapiro N, et al. Crit Care Med 2006;34:1025-1032

What to Use? SAFE study: 28 day outcomes RCT n=6997, 4% albumin or normal saline Albumin group, 726 deaths - Saline group, 729 deaths New organ failure was similar in the two groups No difference: ICU or hospital LOS, mechanical ventilation days, or days of renal-replacement therapy Guideline: colloid or crystalloid may be used Background It remains uncertain whether the choice of resuscitation fluid for patients in intensive care units (ICUs) affects survival. We conducted a multicenter, randomized, double-blind trial to compare the effect of fluid resuscitation with albumin or saline on mortality in a heterogeneous population of patients in the ICU. Methods We randomly assigned patients who had been admitted to the ICU to receive either 4 percent albumin or normal saline for intravascular-fluid resuscitation during the next 28 days. The primary outcome measure was death from any cause during the 28-day period after randomization. Results Of the 6997 patients who underwent randomization, 3497 were assigned to receive albumin and 3500 to receive saline; the two groups had similar baseline characteristics. There were 726 deaths in the albumin group, as compared with 729 deaths in the saline group (relative risk of death, 0.99; 95 percent confidence interval, 0.91 to 1.09; P=0.87). The proportion of patients with new single-organ and multiple-organ failure was similar in the two groups (P=0.85). There were no significant differences between the groups in the mean (±SD) numbers of days spent in the ICU (6.5±6.6 in the albumin group and 6.2±6.2 in the saline group, P=0.44), days spent in the hospital (15.3±9.6 and 15.6±9.6, respectively; P=0.30), days of mechanical ventilation (4.5±6.1 and 4.3±5.7, respectively; P=0.74), or days of renal-replacement therapy (0.5±2.3 and 0.4±2.0, respectively; P=0.41). Conclusions In patients in the ICU, use of either 4 percent albumin or normal saline for fluid resuscitation results in similar outcomes at 28 days. 65. Finfer S, Bellomo R, Boyce N, et al: A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004; 350:2247–2256 68. Schierhout G, Roberts I: Fluid resuscitation with colloid or crystalloid solutions in critically ill patients: A systematic review of randomized trials. BMJ 1998; 316:961–964 Although administration of hydroxyethyl starch may increase the risk of acute renal failure in patients with sepsis, variable findings preclude definitive recommendations 69. Schortgen F, Lacherade JC, Bruneel F, et al: Effects of hydroxyethyl starch and gelatin on renal function in severe sepsis: A multicentre randomized study. Lancet 2001; 357:911–916 Schierhout G et al. BMJ 1998; 316:961–964 Finfer S et al. N Engl J Med 2004; 350:2247–2256

EGDT (and we mean EARLY) Retrospective analysis of 212 patients Diagnosis: septic shock and ALI within 72 hours Adequate initial fluid resuscitation (AIFR) group Administration of an initial fluid bolus of ≥ 20 mL/kg prior to and achievement of a central venous pressure of ≥ 8 mm Hg within 6 h after the onset of therapy with a vasopressor Conservative late fluid management (CLFM) Even-to-negative fluid balance measured on at least 2 consecutive days during the first 7 days after septic shock onset Murphy C V et al. Chest 2009;136:102-109 Adequate initial fluid resuscitation (AIFR) group was defined as the. Conservative late fluid management (CLFM) was defined as even-to-negative fluid balance measured on at least 2 consecutive days during the first 7 days after septic shock onset. The study cohort was made up of 212 patients with ALI complicating septic shock. Hospital mortality was statistically lowest for those achieving both AIFR and CLFM and higher for those achieving only CLFM, those achieving only AIFR, and those achieving neither (17 of 93 patients [18.3%] vs. 13 of 31 patients [41.9%] vs. 30 of 53 patients [56.6%] vs. 27 of 35 [77.1%], respectively; p < 0.001). Murphy C V et al. Chest 2009;136:102-109

Mean daily fluid balance days 1 through 7 NONSURVIVORS SURVIVORS Mean (± SE) cumulative daily fluid balance for days 1 through 7 following the onset of septic shock. Nonsurvivors are depicted by squares, and survivors by circles. * = p < 0.05. Murphy C V et al. Chest 2009;136:102-109

Hospital mortality for AIFR, CLFM, both, or neither 77% 57% 42% 18% Hospital mortality according to whether or not patients achieved AIFR, CLFM, both, or neither. Results: The study cohort was made up of 212 patients with ALI complicating septic shock. Hospital mortality was statistically lowest for those achieving both AIFR and CLFM and higher for those achieving only CLFM, those achieving only AIFR, and those achieving neither (17 of 93 patients [18.3%] vs. 13 of 31 patients [41.9%] vs. 30 of 53 patients [56.6%] vs. 27 of 35 [77.1%], respectively; p < 0.001). Hospital mortality: AIFR and CLFM- 18% Only CLFM- 42% AIFR only- 57% Achieving neither- 77% Murphy CV et al. Chest 2009; 136:102-109

Rivers, E et al. N Engl J Med 2001; 345 EGDT & Intubation Comparing the PaO2/fraction of inspired oxygen (FIO2) ratios between the EGDT and standard-care groups. Despite more volume resuscitation in the EGDT group during initial 6 h, there was no net difference in PaO2/FIO2 ratio (p = 0.34) No difference: P/F ratio at 6h; EGDT with higher P/F at 72h No difference in intubation rates at 6 hours 7-72 hour intubation rate: EGDT 2% vs. standard 16.8% Rivers, E et al. N Engl J Med 2001; 345 Otero R, et al. Chest 2006;130:1579-1595

Vasopressors Mean arterial pressure (MAP) maintained ≥ 65 First choice: norepinephrine or epinephrine Vasopressin 0.03 units/min may be added Rationale -there is no high qual evidence to rec one catechol over another. -norepi is more potent than da and may be more effect at revers hypotens in pts c sept shk -Da more tachy and arrythmogenic -86. Regnier B, Rapin M, Gory G, et al: Hemodynamic effects of dopamine in septic shock. Intensive Care Med 1977; 3:47–53 -place art catheter ASAP grade 1D- using a cuff is inaccurate and AC allows cont analysis and immed response

Vasopressin VASST Trial Hypothesis: VP will increase survival compared to NE at 28d 779 patients in septic shock requiring vasopressors for ≥6 hours Randomization to vasopressin or norepinephrine No difference in 28-day survival (35.4% v 39.3%, P =.27). When groups were stratified by severity of hypotension Low-dose NE improved survival with VP 26% v 35%, P .05 Result persisted at 90 days: mortality of 36% vs. 46 %, P =.04 The VASST study’s primary hypothesis is that low dose Vasopressin infusion compared to Norepinephrine infusion will increase 28-day survival in human septic shock. Patients are eligible to participate in the study if they have septic shock, at least one other sepsis related organ failure and are on vasopressor infusion(s) for ≥ 6 hours (≥5mcg/kg/min) or for ≥3 hours if in severe septic shock (≥15mcg/kg/min of vasopressor requirements). Patients who participate are randomized to receive either Norepinephrine or Vasopressin. Norepinephrine is started at 1.3ug/min and is titrated up to 15ug/min in 40 min. Vasopressin is started at 0.0026 units/min and is titrated up to 0.03 units/min in 40min.The Vasopressin in Septic Shock Trial ---When we set the sample size for VASST, we estimated that the mortality from septic shock would be 60%. However, the mortality in the control group in VASST was 39.3%, so the power was less than originally planned. (VASST) was recently completed.[10] VASST analyzed 779 patients in septic shock requiring vasopressors for at least 6 hours and having at least 1 additional dysfunctional organ system present for less than 24 hours, who were randomized to receive AVP or norepinephrine (NE). Overall there was no difference in 28-day survival between groups (35.4% vs. 39.3%, P =.27). However, the groups were stratified according to severity of hypotension (requiring > 15 mcg/min or < 15 mcg/min of NE at enrollment), and the patients taking lower-dose NE had improved survival with AVP (26.5% vs. 35.7%, P =.05). This result persisted at 90 days, when mortality was 35.8% vs. 46.1%, P =.04). There were no differences in MAP, although the addition of AVP to NE predictably resulted in a reduction in NE dose. Digital ischemia was somewhat more common in the AVP group (P =.06), while cardiac arrest was slightly more common in the NE group (P =.11). Russell J et al. NEJM2008;358,9.

Inotropes Dobutamine infusion for suspected myocardial dysfunction suggested by elevated cardiac filling pressures and low cardiac output Recommend against a strategy to increase cardiac index to supranormal levels -Dobut first chce for pts c low measured or suspected cardiac output c adequate filling pressure and adequ MAP. -2 lg prospect trials failed to benefit in opts c sever sepsis- inc ox deliv to supranormal targets Gattinoni L, et al. New Engl J Med 1995; 333:1025-32 Hayes MA, et al. New Engl J Med 1994; 330:1717-22

Interventions Anti-microbials Early Goal Directed Therapy (EGDT) Steroids Glucose Control

Garnacho-Montero J et al. CCM2007;25:1888-1895 Antimicrobials Begin therapy within the first hour of recognizing severe sepsis or septic shock Broad spectrum: one or more agents against likely bacterial or fungal pathogens Consider combination therapy for potentially resistant gram negative pathogens Consider combination therapy in neutropenic patients Narrow coverage when culture data available In the presence of septic shock, each hour delay in achieving administration of effective antibiotics is associated with a measurable increase in mortality Kumar A, Roberts D, Wood KE, et al: Duration of hypotension prior to initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006; 34:1589–1596. Because patients with severe sepsis or septic shock have little margin for error in the choice of therapy, the initial selection of antimicrobial therapy should be broad enough to cover all likely pathogens. There is ample evidence that failure to initiate appropriate therapy (i.e., therapy with activity against the pathogen that is subsequently identified as the causative agent) correlates with increased morbidity and mortality (45–48). McCabe WR, Jackson GG: Gram negative bacteremia. Arch Intern Med 1962; 110:92–100 [Context Link] -Although no study or meta-analysis has convincingly demonstrated that combination therapy produces a superior clinical outcome for individual pathogens in a particular patient group, combination therapies do produce in vitro synergy against pathogens in some models (although such synergy is difficult to define and predict). In some clinical scenarios, such as the two preceding, combination therapies are biologically plausible and are likely clinically useful even if evidence has not demonstrated improved clinical outcome (53–56). Combination therapy for suspected known Pseudomonas pending sensitivities increases the likelihood that at least one drug is effective against that strain and positively affects outcome (57). Garnacho-Montero J, Sa-Borges M, Sole-Violan J, et al: Optimal management therapy for Pseudomonas aeruginosa ventilator-associated pneumonia: An observational, multicenter study comparing monotherapy with combination antibiotic therapy. Crit Care Med 2007; 25:1888–1895 Garnacho-Montero J et al. CCM2007;25:1888-1895

Antimicrobials Study objective: to determine the impact of initial antimicrobial therapy on survival in patients with septic shock Data: 5,715 cases between 1996 and 2005 Community-acquired = 55%; nosocomial origin = 45% Appropriate empiric antimicrobial therapy = 80% Overall rate of survival to hospital discharge = 43% The survival rates: Appropriate initial therapy 52% Inappropriate initial therapy 10% Objective: Our goal was to determine the impact of the initiation of inappropriate antimicrobial therapy on survival to hospital discharge of patients with septic shock. Conclusions: Inappropriate initial antimicrobial therapy for septic shock occurs in about 20% of patients and is associated with a fivefold reduction in survival. Efforts to increase the frequency of the appropriateness of initial antimicrobial therapy must be central to efforts to reduce the mortality of patients with septic shock. The decrease in survival with inappropriate initial therapy ranged from 2.3-fold for pneumococcal infection to 17.6-fold with primary bacteremia. Kumar A et al. Chest 2009;136:1237-1248

Diagnosis Obtain cultures before starting antimicrobial therapy Obtain two or more blood cultures (BC) One or more BC should be percutaneous One BC from each vascular access devise in for > 48 hrs Urine and sputum cultures Other cultures as dictated by initial exam and imaging Prompt imaging studies in search of source -BC negative in > 50% of cases- so base antibiot changes on clinical judgement -Obt cxs prior to antibiotics provided this does not delay antimicr administration Imaging studies prompt if safe to do so… Rapid steriliz of blood cxs can occur within a few hrs of antibiotic administration Vasc access device- BC through EACH LUMEN- if the same org is recovered from both the VAD and peripheral- the likelihood of the right dx is enhanced In addition, if the vasc access devise cx is positive much earlier than the periph cx (und 2 hours) the data support that the VAD is the source of infection Blot F, Schmidt E, Nitenberg G, et al: Earlier positivity of central venous versus peripheral blood cultures is highly predictive of catheter-related sepsis. J Clin Microbiol 1998; 36:105–109 -Diagnostic studies may identify a source of infection that requires removal of a foreign body or drainage to maximize the likelihood of a satisfactory response to therapy. However, even in the most organized and well-staffed healthcare facilities, transport of patients can be dangerous, as can placing patients in outside-unit imaging devices that are difficult to access and monitor. Balancing risk and benefit is therefore mandatory in those settings. -recomm quantit cxs of blood, respiratory secretions (or semiquant)

Interventions Steroids Early Goal Directed Therapy (EGDT) Anti-microbials Steroids Glucose Control

Dellinger RP, et al Crit Care Med 2008;36:296-327 2012 Steroid Guidelines The ACTH stimulation test should not be used to identify the subset of adults with septic shock who should receive hydrocortisone. Do not use corticosteroids in the treatment of sepsis in the absence of shock. Corticosteroid therapy may be weaned when vasopressors are no longer required. Recommended: hydrocortisone 50 mg iv q 6 hours No ACTH- bc of CORTICUS trial. Also most cortisol assays measure total and free cortisol, while free is likely the pertinent measurement. The corticol assays may over or underestimate the the actual cortisol level since the relationship between free and total cortisol depends on serum protein concentration. Dex can lead to profound and prolonged supression of the adrenal axis and along with no ACTH test, no need for dex. Dellinger RP, et al Crit Care Med 2008;36:296-327

Interventions Glucose Control Early Goal Directed Therapy (EGDT) Anti-microbials Steroids Glucose Control

Glucose Controversy Leuven protocol: 80-110 Cardiac-surgical ICU Reduced ICU LOS Less organ dysfunction Hypoglycemia 6.2% Decreased Mortality 3.4% ARR all patients 9.4% ARR LOS >5 days Leuven protocol: 80-110 Medical ICU Reduced ICU LOS Less ventilator days Less acute renal injury Hypoglycemia 18% Mortality difference Overall: no difference LOS > 3 days: ↓ mortality Study 1- We would say "No, not quite." The original study recruited only surgery patients from a single center where all subjects received intravenous glucose and parenteral nutrition, starting immediately postoperatively, a practice that is not the norm. Study2- dec icu and hospital los. Los > 3 days, hospit mortality 52% v 43% c tight control. 36% with los < 3 days, and there was no way to predict los., 3 fold higher rate of hypoglycemia. Van den Berghe G, et al. NEJM 2006; 354:449-461 Van den Berghe G, et al. NEJM 2001;345:1359-1367

The NICE-SUGAR Study Investigators NEJM 2008; Volume 360:1283-1297 RCT open-label comparing intensive BS 80-110 vs.. conventional BS <180 6,104 ICU heterogeneous patients Primary end point: 90-day mortality Secondary end points: Hypoglycemia Infection Need for organ support Intensive care unit and hospital length of stay Methods Within 24 hours after admission to an intensive care unit (ICU), adults who were expected to require treatment in the ICU on 3 or more consecutive days were randomly assigned to undergo either intensive glucose control, with a target blood glucose range of 81 to 108 mg per decilite, or conventional glucose control with a target of 180 mg or less per deciliter. We defined the primary end point as death from any cause within 90 days after randomization. Results Of the 6104 patients who underwent randomization, 3054 were assigned to undergo intensive control and 3050 to undergo conventional control; data with regard to the primary outcome at day 90 were available for 3010 and 3012 patients, respectively. The two groups had similar characteristics at baseline. A total of 829 patients (27.5%) in the intensive-control group and 751 (24.9%) in the conventional-control group died (odds ratio for intensive control, 1.14; 95% confidence interval, 1.02 to 1.28; P=0.02). The treatment effect did not differ significantly between operative (surgical) patients and nonoperative (medical) patients (odds ratio for death in the intensive-control group, 1.31 and 1.07, respectively; P=0.10). Severe hypoglycemia (blood glucose level, 40 mg per deciliter [2.2 mmol per liter]) was reported in 206 of 3016 patients (6.8%) in the intensive-control group and 15 of 3014 (0.5%) in the conventional-control group (P<0.001). There was no significant difference between the two treatment groups in the median number of days in the ICU (P=0.84) or hospital (P=0.86) or the median number of days of mechanical ventilation (P=0.56) or renal-replacement therapy (P=0.39). Conclusions In this large, international, randomized trial, we found that intensive glucose control increased mortality among adults in the ICU: a blood glucose target of 180 mg or less per deciliter resulted in lower mortality than did a target of 81 to 108 mg per deciliter. The NICE-SUGAR Study Investigators NEJM 2008; Volume 360:1283-1297

2012 Glucose Control Guidelines Patients with severe sepsis and hyperglycemia in the ICU should receive intravenous insulin. Use validated protocol for insulin dose adjustment with a target glucose <180. All patients on intravenous insulin receive a glucose calorie source. Dellinger RP, et al Crit Care Med 2008;36:296-327

Resuscitation “Bundles” Severe Sepsis 3 Hour Bundle Recognition Fluid Resuscitation Antimicrobial Therapy Oxygen Delivery Severe Sepsis 6 Hour Bundle Low-dose Steroids Glucose Control Lung Protective Ventilation

Gao F, et al. Critical Care 2006; 9:R764-770 Outcomes Prospective observational study: 101 patients Rate of compliance with 6 and 24 hour bundles Impact of compliance on hospital mortality 52% Compliance with the 6 hour bundle Mortality 23% compliant vs. 49% non-compliant 30% compliance with the 24 hour bundle Mortality 21% compliant vs. 50% non-compliant Gao F, et al. Critical Care 2006; 9:R764-770

NYS Sepsis Initiative Hospitals shall have in place evidence-based protocols for the early recognition and treatment of severe sepsis and septic shock. Hospitals shall have a process for screening all adult and pediatric patients for sepsis, severe sepsis, and septic shock in the ED and hospital. Quality measures will be collected and reported.