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Kathleen M. Vollman RN, MSN, CCNS, FCCM Clinical Nurse Specialist/Educator/Consultant ADVANCING NURSING Northville, Michigan

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Presentation on theme: "Kathleen M. Vollman RN, MSN, CCNS, FCCM Clinical Nurse Specialist/Educator/Consultant ADVANCING NURSING Northville, Michigan"— Presentation transcript:

1 Kathleen M. Vollman RN, MSN, CCNS, FCCM Clinical Nurse Specialist/Educator/Consultant ADVANCING NURSING Northville, Michigan Nurse’s role In Comprehensive Sepsis Management © Vollman 2009

2 Overview Significance of the Problem Defining the continuum Brief overview of Pathophysiologic derangements Prevention Early Recognition & Resuscitation

3 * Based on data for septicemia †Reflects hospital-wide cases of severe sepsis as defined by infection in the presence of organ dysfunction 1 Sands KE, et al. JAMA 1997;278: National Vital Statistics Reports Angus DC, et al. Crit Care Med 2001;29: Severe Sepsis: A Significant Healthcare Challenge Major cause of morbidity and mortality worldwide –Leading cause of death in noncoronary ICU (US) 1 –10th leading cause of death overall (US) 2 * More than 750,000 cases of severe sepsis in the US annually 3 In the US, more than 500 patients die of severe sepsis daily 3†

4 Severe Sepsis Is Common 1 in 10 patients admitted to the ICU has severe sepsis.* 2.26% of total hospital discharges nationally Incidence is expected to increase by nearly 17% by All analyses were performed using the 2000 MEDPAR Hospital Discharge Database. The information presented represents national averages, and similar analyses performed at an individual institution may provide different results. 1. Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome and associated costs of care. Crit Care Med. 2001;29(7): Data of file, Eli Lilly and Company: XIG b.

5 Severe Sepsis Is Common AIDS 1 Colon Cancer 2 Breast Cancer 2 CHF 3 Severe Sepsis 4 Cases/100,000 Incidence 1. National Center for Health Statistics, American Cancer Society, American Heart Association Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome and associated costs of care. Crit Care Med. 2001;29(7):  Severe sepsis is more common than AIDS, colon cancer, and breast cancer combined.

6 Begin Proven Care Strategies Early appropriate antibiotic use EGDT: Early Goal-Directed Therapy Low-tidal volume ventilation/ARDS/ALI Xigris if not contraindicated Tight glycemic control Low-dose steroid administration for refractory septic shock particularly in patients with relative adrenal insufficiency Implementation Through Proven Change Strategies

7 IHI/VHA Change Strategy Care Bundles –Grouping of care elements for particular symptoms, procedures or treatments –Strong science, good methodology, poor process –Bundle characteristics Solid evidence Relatively easy & inexpensive Individual components defined well Process not defined well

8 How Does Severe Sepsis Compare to Your Current Care Priorities? Quality Projects US Incidence # of DeathsMortality Rate AMI 1 895,000171,00019% Stroke 1 700,000157,80023% Pneumonia 2 1,300,00061,8004.8% Severe Sepsis 3 751,000215,00029% Why do you think that severe sepsis has not received the same focus as these other common disease states? 1. American Heart Association. Heart Disease and Stroke Statistics 2006 Update. 2. National Center for Health Statistics. Available at: Accessed February 4, Angus DC, et al. Crit Care Med 2001;29(7):

9 Organizational Consensus that Severe Sepsis Must be Managed Early and Aggressively Early Screening with Tools and Triggers Implementation of the Sepsis Bundle Measuring Success 4-Tier Process for Severe Sepsis Program Implementation

10 *All analyses were performed using the 2004 through 2006 MEDPAR Hospital Discharge Databases. Cost and charge data are reported in year-appropriate US Dollars. † Severe sepsis patients were identified by looking for combinations of ICD-9-CM codes indicating infection and new onset of acute organ failure following SCCM/ACCP guidelines as described in Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome and associated costs of care. Crit Care Med. 2001;29 (7): ‡ Average total hospital costs for patients treated in the ICU Severe Sepsis Report National-All Hospital, Medicare Reporting-3670 Copyright © 2007, Eli Lilly and Company. All rights reserved Top Ten Severe Sepsis Diagnosis-Related Groups *† (53.5% of all cases with severe sepsis fell within 10 DRGs) Severe Sepsis Cases (average) All Others (average) Mortality27%7% Ventilator Use30%2% Hospital Length of Stay11.1 days7.2 days ICU Length of Stay6.5 days4.2 days Cost per Case ‡ $22,000$12,000 Payment-to-Cost Ratio-24%8% (costs exceeds payment)

11 Organization Support  Executive management at hospital actively supports the program  Managing severe sepsis is aligned with hospital ‘s current year goals  Willingness to align resources with program  Understanding that this is a 2-3+ year program to make this the standard of practice for this patient population  Existing culture that supports change Successfully implemented other major change programs—eg: vent bundle, tight glucose control, CR-BSI  Established team in place with ICU physician and nurse champion, ED physician and nurse champion that are respected by staff

12 Building a Severe Sepsis Tool Kit: Project Team Charter Severe Sepsis is Common and Deadly : Problem Statement : Team Members ED, ICU, Patient Care Unit Representatives, Administration, Medical Staff, Nursing, Pharmacy, Performance Improvement, Case Management, Laboratory Business Case In comparison to other ICU patients, severe sepsis patients have a higher mortality rate, increased LOS, and an increased need for a ventilator Benefits Potential to improve outcomes Goals Reduce severe sepsis mortality (make the goal specific and measurable) Scope Severe sepsis patients in the ED, ICU, and patient care units Milestones Implementation of tiers 1, 2, 3, and 4

13 The Team is KEY!! Can Be Major Barrier If Not Functioning Well Must have nurse and physician champions from ED and ICU (need at least one physician at all meetings) Must be linked in the organization’s quality or operational structure Must meet at least 2 times per month Team members must be well educated on the evidence and armed with tools and knowledge to change behavior at the bedside MUST have bedside nurses on team— provide reality check and best knowledge of barriers

14 Severe Sepsis: Defining a Disease Continuum SIRS with a presumed or confirmed infectious process Sepsis SIRS Infection or Trauma Severe Sepsis Sepsis with  1 sign of organ dysfunction, hypoperfusion or hypotension. Examples: Cardiovascular (refractory hypotension) Renal Respiratory Hepatic Hematologic CNS Unexplained metabolic acidosis Adult Criteria A clinical response arising from a nonspecific insult, including ≥ 2 of the following: Temperature:> 38°C or < 36°C Heart Rate: > 90 beats/min Respiration:> 20/min WBC count:> 12,000/mm 3, or < 4,000/mm 3, or > 10% immature neutrophils SIRS = Systemic Inflammatory Response Syndrome Bone et al. Chest.1992;101: Shock

15 Severe Sepsis: Defining a Disease Continuum Sepsis SIRS Infection or Trauma Severe Sepsis Adult Criteria A clinical response arising from a nonspecific insult, including ≥ 2 of the following: Temperature:> 38°C or < 36°C Heart Rate: > 90 beats/min Respiration:> 20/min WBC count:> 12,000/mm 3, or < 4,000/mm 3, or > 10% immature neutrophils SIRS = Systemic Inflammatory Response Syndrome Bone et al. Chest.1992;101:

16 Signs & Symptoms of Sepsis   Platelets  Bands  Skin perfusion  Urine output Skin mottling Poor capillary refill Hyperglycemia Purpura/petechia 31 Chills Alteration in LOC Tachypnea Unexplained metabolic acidosis  Heart rate Altered blood pressure Levy M, et al. Crit Care Med 2003;31:

17 Severe Sepsis: Defining a Disease Continuum SIRS with a presumed or confirmed infectious process Sepsis SIRS Infection or Trauma Severe Sepsis SIRS = Systemic Inflammatory Response Syndrome Bone et al. Chest.1992;101:

18 Severe Sepsis: Defining a Disease Continuum SepsisSIRS Infection or Trauma Severe Sepsis. Examples: Cardiovascular (refractory hypotension) Renal Respiratory Hepatic Hematologic CNS Unexplained metabolic acidosis SIRS = Systemic Inflammatory Response Syndrome Bone et al. Chest.1992;101: Shock Sepsis with  1 sign of organ dysfunction, hypoperfusion or hypotension

19 Identifying Acute Organ Dysfunction as a Marker of Severe Sepsis Tachycardia SBP<90mmHg MAP < 70mmHg (despite fluid) Need for Vasopressors Unexplained metabolic acidosis Lactate > 1.5 times upper normal PaO 2 /FiO 2  200 if lung only dysfunction/site of infection PaO 2 /FiO 2  250 with other organ dysfunction/lung not site of infection UO <0.5 ml/kg per hr (despite fluid) Platelets <80,000/mm 3 Decline in platelet count of 50% over 3 days Respiratory Metabolic Cardiovascular Renal Hematologic

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21 21 Deterioration of Cardiovascular Function on Day 1 was Associated with Increased Mortality in Placebo Patients * 28-day mortality for standard therapy patients enrolled in PROWESS and a Phase II study of an investigational anti-sepsis drug. † Vasopressor requirement at study entry through day 1. Based on the Sequential Organ Failure Assessment (SOFA) score, low dose was defined as dopamine 6-15 µg/kg/min, epinephrine  0.1 µg/kg/min, or norepinephrine  0.1 µg/kg/min. High dose was defined as dopamine > 15 µg/kg/min, epinephrine > 0.1 µg/kg/min, or norepinephrine >0.1 µg/kg/min. Levy, M., Macias, W., Vincent, J., et al. Early changes in organ function predict eventual survival in severe sepsis. Crit Care Med. 2005; 33:1-8. Change in Vasopressor Dose on Day 1* † No VasopressorNo Vasopressor to Low Dose No Vasopressor to High Dose CV SOFA Increased by  1 % Mortality n=294n=41n=36n=46 P<

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23 PaO 2 /FiO 2 Ratio User friendly tool Crude assessment of the severity of lung injury May be used in the assessment of Acute Respiratory Dysfunction due to Severe Sepsis Also used in the definition of Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS) PaO 2 = 70 torr FiO 2 = 60% or.60 P/F Ratio = 70/.60 Answer: 117

24 24 Respiratory Dysfunction (Mortality by Change in SOFA Score) in Placebo Patients N=355N=398N=94 Levy, M., Macias, W., Vincent, J., et al. Early changes in organ function predict eventual survival in severe sepsis. Crit Care Med. 2005; 33:1-8. Severe sepsis mortality predictors (Baseline to Day 1) Population-based outcomes observed in severe sepsis patients p=0.0004

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26 26 Renal Dysfunction (Mortality by Change in Serum Creatinine) in Placebo Patients †Renal SOFA Score = 2 equivalent to creatinine range mg/dL. ‡APACHE (Acute Physiology And Chronic Health Evaluation). For more information on using the APACHE II scoring system, please see Levy, M., Macias, W., Vincent, J., et al. Early changes in organ function predict eventual survival in severe sepsis. Crit Care Med. 2005; 33:1-8. Data on file, Eli Lilly and Company: XIG a. CMH Trend Test P< % 35% 61% 1.2 TO 1.9 mg/dL TO < 1.2 mg/dL 1.2 TO 1.9 mg/dL TO 1.2 TO 1.9 mg/dL TO > 1.9 mg/dL Severe sepsis mortality predictors (Baseline to Day 1) Population-based outcomes observed in severe sepsis patients In PROWESS, patients with chronic kidney failure on dialysis were excluded. The following was observed in patients with acute kidney dysfunction at baseline (renal SOFA = 2)†‡ N=129N=109N=38

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32 Homeostasis Homeostasis Is Unbalanced in Severe Sepsis Carvalho AC, Freeman NJ. J Crit Illness 1994;9: Kidokoro A, et al. Shock 1996;5: Vervloet MG, et al. Semin Thromb Hemost 1998;24: COAGULATIONINFLAMMATION FIBRINOLYSIS

33 S EVERE S EPSIS P ATHOPHYSIOLOGY Microvascular dysfunction  Inflammation  Coagulation  Fibrinolysis Hypoperfusion/hypoxia Microvascular thrombosis Endothelial dysfunction Organ dysfunction Global tissue hypoxia Direct tissue damage  

34 Inflammation, Coagulation and Impaired Fibrinolysis In Severe Sepsis Adapted from Bernard GR, et al. N Engl J Med. 2001;344: Endothelium Neutrophil Monocyte IL-6 IL-1 TNF-  IL-6 Inflammatory Response to Infection Thrombotic Response to Infection Fibrinolytic Response to Infection PAI-1 Suppressed fibrinolysis Factor VIIIa Tissue Factor COAGULATION CASCADE Factor Va THROMBIN Fibrin Fibrin clot Tissue Factor

35 The Role Of Endogenous Activated Protein C In Severe Sepsis Adapted from Bernard GR, et al. N Engl J Med. 2001;344: Endothelium Neutrophil Monocyte IL-6 Activated Protein C Inactivation Activated Protein C PAI-1 Suppressed fibrinolysis Activated Protein C Reduction of Rolling Inhibition Activated Protein C Factor VIIIa Tissue Factor Factor Va THROMBIN Fibrin Fibrin clot Tissue Factor Organisms Inflammatory Response to Infection Thrombotic Response to Infection Fibrinolytic Response to Infection COAGULATION CASCADE

36 Pathophysiologic Characteristics in Severe Sepsis Maldistribution of blood flow Imbalance of oxygen supply & demand Metabolic alterations & activation of the stress response © Vollman 2001

37 Maldistribution of Blood Flow Mechanical obstruction –Micro-emboli –Increased blood viscosity –Compression Systemic & local mediator & ion influence –Constriction vs. dilation Loss of regulatory activities/endothelial cell injury –Reactive hyperemia –Anticoagulation © Vollman 2001

38 Imbalance of Oxygen Supply & Demand SUPPLY DEMAND © Vollman 2001

39 OXYGEN SUPPLY/DEMAND DYNAMICS ScvO2 CVP, CO, CI, SV, SVI

40 O 2 Supply/Demand Compensatory Mechanisms  Improve pulmonary gas exchange  Increase oxygen delivery  Alter the distribution of blood flow

41 O 2 Supply Debt

42 Metabolic Alterations & The Stress Response Initiation of the Stress Response Sympathetic Nervous System Activation Hypothalamus Activation

43 Metabolic Alterations & The Stress Response SNS Activation Gut hypothesis  BMR Inhibition of insulin secretion Inhibition of glucose uptake by the tissues Hypothalamus Activation Adrenal cortex stimulation Changes in carbohydrate, protein & fat metabolism resulting in  glucose concentration

44 Except on few occasions, the patient appears to die from the body's response to infection rather than from it." Sir William Osler – 1904 The Evolution of Modern Medicine

45 The Nurse’s Role Prevention of infection Early recognition of patients with signs of sepsis Early initiation of evidence-based practice therapies appropriate for your area of practice (antibiotics, fluids/blood, and vasopressors) Swift disposition to care areas where the rest of the bundle can be started

46 Prevention of Infection Ventilator-associated pneumonia Hospital acquired pneumonia Bloodstream infection related to an invasive catheter Are you currently working on strategies to prevent infections?

47 PREVENTING THE INVASION © Vollman 2001 Oral care Oral care Line care Line care Handwashing Handwashing HOB HOB

48 EARLY MANAGEMENT Early Recognition ICU/Additional Evidence Based Therapies Early Antibiotics Prompt/Aggressive Resuscitation

49 Organizational Consensus that Severe Sepsis Must be Managed Early and Aggressively Screens and triggers developed to ID Severe Sepsis patients in the ED, ICU, and on patient care units 2nd-Tier Implementation of Early Screening Tools and Triggers

50 Early Recognition: A Screening Process TIME IS TISSUE!! –If you identify patients early then you can intervene and prevent further tissue damage To screen effectively, it must be part of the nurses’ daily routine Must define a process for what to do with the results of the screen If you don’t screen you will miss patients that could have benefited from the interventions

51 Make it Process Dependent Weave into fabric of current practice Assess for daily Identify strategies for initiation of therapy response once patient is identified

52 Location/ Trigger Type Standard Procedure Manual Alert Message Computerized Alert Message Emergency Department Triage: Criteria-Based Early Response Concurrent coder or case manager Upon pharmacy entry of vasopressor/ antibiotic Lactate drawn as a screen Order sheets antibiotic/ vasopressor Upon withdrawal of med from Automated Dispensing Cabinet Change in lactate Change in lab values (lactate) Upon scanning of medication at bedside “Triggers” for Identifying Severe Sepsis

53 Location/ Trigger Type Standard Procedure Manual Alert Message Computerized Alert Message ICU Upon admission From concurrent coder or case manager Upon pharmacy entry of vasopressor/ antibiotic By nurse at shift change Nurse MAR review (for antibiotic/ vasopressor) In note field on computerized MAR Change in lactate During MD, RN, RPh, rounds Change in lab values (lactate) In note field of vasopressor computerized label Criteria-Based Early Response Place on all ICU charts (daily) Upon withdrawal of med from Automated Dispensing Cabinet Upon scanning of medication at bedside

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56 “Triggers” for Identifying Severe Sepsis Location/ Trigger Type Standard Procedure Manual Alert Message Computerized Alert Message Patient Care Units Upon admission From concurrent coder or case manager Upon pharmacy entry of antibiotic During MD, RN, RPh, rounds Nurse MAR review for antibiotic In note field on computerized MAR Criteria-Based Early Response teams Change in patient hemodynamics In note field of vasopressor computerized label Need to mobilize MET Upon withdrawal of med from Automated Dispensing Cabinet Change in lab values (e.g., elevated WBC, decreased platelet count) Upon scanning of medication at bedside

57 Reaching Outside the ICU: Early Recognition Models Shock Program Medical Emergency Response Team (MET) Critical Care Nurse Consultant Service

58 Screening: Barriers/Strategies  Barriers  Time for nurses to do it (perception vs reality)  Screening is not sensitive only for severe sepsis  Positive screen is not a diagnosis of severe sepsis  Strategies  Must assign responsibility and hold them accountable--  Perform audits to measure compliance and identify problems  Round on unit and ask nurses how it is going and discuss issues

59 Screening: Barriers/Strategies Lesson Learned: Bedside nurse must do screening Lesson Learned: Bedside nurse must do screening Education/Simulation/Education Education/Simulation/Education - Every 6 months - Build into orientation - Must be part of their documentation structure - Practice-Practice-Practice The END RESULT—anytime patient has 2 or more SIRS—will think that this patient might have sepsis and can screen at that time

60 EARLY MANAGEMENT Early Recognition ICU/Additional Evidence Based Therapies Early Antibiotics Prompt/Aggressive Resuscitation

61 Organizational Consensus that Severe Sepsis Must be Managed Early and Aggressively Early Screening with Tools and Triggers Implementation of the Sepsis Bundle with protocol & order sets 3rd-Tier Implementation of Evidence-Based Sepsis Bundles

62 The Severe Sepsis Bundles: Surviving Sepsis Campaign/IHI Bleeding is the most common adverse effect associated with Xigris therapy. See Important Safety Information in this presentation. Management Bundle (To be accomplished as soon as possible and scored over first 24 hours): Low-dose steroids administered for septic shock in accordance with a standardized ICU policy. (Given to patients who respond poorly to fluids or vasopressors) (2C) Drotrecogin alfa (activated) administered in accordance with a standardized ICU policy. (Given to patients with sepsis induced organ dysfunction at high risk of death (2B) Glucose control maintained to < 150 mg/dL (8.3 mmol/L). (2C) Tidal volume 6 ml/kg (1B) Inspiratory plateau pressures < 30 cmH 2 O for mechanically ventilated patients. (1C) Resuscitation Bundle (To be accomplished as soon as possible and scored over first 6 hours): Serum lactate measured. Blood cultures obtained prior to antibiotics administered. (1C) Perform imaging studies promptly to fine source (1C) From the time of presentation, broad- spectrum antibiotics within 3 hours for ED admissions and 1 hour for non-ED ICU admissions. (1D/1B) For hypotension and/or lactate > 4 mmol/L: Deliver an initial minimum of 20 mL/kg of crystalloid (or colloid equivalent) (1C) Apply vasopressors for hypotension not responding to initial fluid resuscitation to maintain MAP > 65 mmHg. For persistent hypotension despite initial fluid resuscitation (septic shock) and/or lactate > 4 mmol/L: 1C Achieve CVP > 8 mmHg & MAP > 65 mmHg & UO >0.5mL/kg/hr Achieve ScvO 2 of > 70% or SvO 2 > 65%. if ScvO 2 not > 70% blood or dobutamine (2C) Adapted from the revised guidelines: CCM 2008;36:

63 SURVIVING SEPSIS GUIDELINES 2008 The GRADE system is based on a sequential assessment of the quality of evidence, followed by assessment of the balance between benefits versus risks, burden, and cost and, based on the above, development and grading of a management recommendations. Keeping the rating of quality of evidence and strength of recommendation explicitly separate constitutes a crucial and defining feature of the GRADE approach. This system classifies quality of evidence as high (Grade A), moderate (Grade B), low (Grade C), or very low (Grade D). The GRADE system classifies recommendations as strong (Grade 1) or weak (Grade 2). The grade of strong or weak is considered of greater clinical importance than a difference in letter level of quality of evidence. 1. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: Crit Care Med. 2008;36:

64 Strength of the Science: Part 1 of Grading System A.Supported by at least two level I investigations B.Supported by one level I investigation C.Supported by level II investigations only D.Supported by at least one level III investigation E.Supported by level IV or V evidence Grading of Recommendations: Dellinger RP, et al. Crit Care Med. 2008;36: Recommendations are published in groups by category and not by hierarchy

65 New Grading System Quality of the evidence process = no change Recommendation process = new

66 Which components of the bundle do you believe will encounter the most resistance?

67 “Early Goal Directed Therapy” PROMPT AGGRESSIVE RESUSCITATION

68 Sepsis Resuscitation Bundle (To be accomplished as soon as possible over first 6 hours): 1. Serum lactate measured. 2. Blood cultures obtained prior to antibiotic administration. 3. From the time of presentation, broad-spectrum antibiotics administered within 3 hours for ED admissions and 1 hour for non-ED ICU admissions. 4. In the event of hypotension and/or lactate > 4 mmol/L (36 mg/dl): a) Deliver an initial minimum of 20 ml/kg of crystalloid (or colloid equivalent*). b) Apply vasopressors for hypotension not responding to initial fluid resuscitation to maintain mean arterial pressure (MAP) > 65 mm Hg. 5. In the event of persistent hypotension despite fluid resuscitation (septic shock) and/or lactate > 4 mmol/L (36 mg/dl): a) Achieve central venous pressure (CVP) of > 8 mm Hg. b) Achieve central venous oxygen saturation (ScvO2) of > 70%.**

69 Early Goal Directed Therapy Early Goal-Directed Therapy (EGDT) Continuous ScvO2 monitoring & tx with fluids, blood, inotropes &/or vasoactives to maintain:  ScvO2 >70%, SaO2 > 93%, Hct > 30%, CI/VO2  CVP > 8-12  MAP > 65  UO >.5ml/kg/hr Standard Therapy CVP > 8-12 MAP > 65 UO >.5ml/kg/hr Rivers et. al. N Engl J Med. 2001;345;19: Methodology: 263 severe sepsis patients

70 49.2% 33.3% Standard Therapy n=133 EGDT n=130 P = 0.01* *Key difference was in sudden CV collapse, not MODS 28-day Mortality Rivers E. N Engl J Med 2001;345: Early Goal-Directed Therapy Results NNT = 7-8

71 Evidence of Early Goal Directed Therapy First 6 hours of EGDT: –1500cc more fluid –64% received blood products vs. 18.5% –13.7% received inotropes vs. 0.8% –No difference in vasopressor use or mechanical ventilation Rivers et. al. N Engl J Med. 2001;345;19:

72  Protocolized resuscitation should begin as soon as sepsis induced tissue hypoperfusion is recognized or  Elevated Serum lactate identifies tissue hypoperfusion in patients at risk who are not hypotensive  Initial fluid challenges be started at > 1000 mL/kg or mL of colloid over 30 minutes (1C) Rivers E. N Engl J Med 2001;345: Initial Resuscitation (1C) Dellinger, et. al. Crit Care Med 2008, 36:

73 Early Goal-Directed Therapy: SSC Recommendations Goals of therapy within first 6 hours are: (1C) Central Venous Pressure  mmHg Mean arterial pressure  65 mmHg Urine output  0.5 mL/kg/hr ScvO 2  70%; if not achieved with fluid resuscitation during first 6 hours (2C) - Transfuse PRBC to hematocrit >27% and/or - Administer dobutamine (max 20 mcg/kg/min) to goal Dellinger RP, et al. Crit Care Med. 2008;36:

74 Potential Emergency Department Challenges Screening in Triage Drawing lactic acid level with less than one hour turn around time When and who will place the central line? Physician skill level ? Monitoring CVPs and ScvO2-nurses skill level and available resources? When to transfer to ICU? ED-ICU handoff If long ED LOS---does the ED implement both resuscitation and management bundles

75 EGDT: Revisited  Outcomes Survey: 12 programs  1,298 patients with severe sepsis and septic shock  Treated with EGDT and/or the sepsis bundles  Pre implementation mortality: %  Post implementation mortality: % Otero RM. et al Chest; 2006:130: % Reduction in Mortality, NNT 5

76 EGDT: Revisited  Cost Effectiveness of EGDT/Guideline Based Care (ED, ICU or RRT initiated)  23.4% reduction in hospital cost (incorporated additional training, personnel and equipment) Huang et al Crit Care Med 2003:7(suppl S116)  Henry Ford Hospital:  4 day Hospital LOS (32.6% reduction)  Reduction in hospital charges from $135,199 to $82,233 (39.2% reduction) Trzeciak S et al, Chest 2006:129: Otero RM. et al Chest; 2006:130:

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78 Before1104After1175 Peer Review Publications Favors EGDT Favors No EGDT

79 3311 Before 3223 After Abstracts and Publications

80 1 of every 6 Patients Abstracts and Publications 4125 Before 3328 After

81 Vasopressors Recommend that MAP be maintain > 65 mmhg (1C) Ideally adequate fluid resuscitation should be achieved before vasopressors and inotropes are used, but use early in septic shock may need to occur. When it does the goal should be to try and wean with continuing fluid resuscitation. Norepinephrine or dopamine as first choice. (1C) Epinephrine, phenylephrine or vasopression should not be used as the initial vasopressor. (2C) Vasopresion may be added to norepinephrine at 0.03 units/min. Suggest that epinephrine be the first chosen alternative. (2B) Low dose dopamine not be used for renal perfusion. (1A) Dellinger RP, et al. Crit Care Med. 2008;36:

82 Vasopressin vs Norepinephrine Infusion in Septic Shock VASST Study Design: Multicenter, randomized, double- blinded Population: 778 patients with septic shock and were receiving a minimum of 5mcq/min of norephinephrine (or equivalent) for 6 hours (excluded pts with underlying heart disease) Methods: Received either low dose vasopressin ( U per minutes) or norepinephrine in addition to open-label vasopressors End point: 28 day mortality Russell et al NEJM, 2008; Vol. 58, No 9

83 VASST Study Results No significant difference in 28 day or 90 day mortality between the two groups –Among patients who had less severe septic shock(on norepinephrine between 5-15 mcq/min) there was a trend toward improved mortality with vasopressin (hypothesis generating) No significant difference in rates of organ dsyfunction between the two groups No significant difference in overall rates of serious adverse events between the two groups –Trend toward higher rate of cardiac arrest in norepinephrine group –Trend toward higher rate of digital ischemia in the vasopressin group Russell et al NEJM, 2008; Vol. 58, No 9

84 Additional Findings Vasopressin infusion allowed a rapid decrease in the total norepinephrine dose while maintaining mean arterial pressure Overall rates of serious adverse events were approximately 10% each in the vasopressin and norepinephrine groups. The MAP at baseline was 72-73mmHg— essentially making this a study of the effects of low dose vasopressin as a “catecholamine- sparing drug” not an evaluation of vasopressin in patients with catecholamine- unresponsive refractory shock Russell et al NEJM, 2008; Vol. 58, No 9

85 EARLY MANAGEMENT Early Recognition ICU/Additional Evidence Based Therapies Early Antibiotics Prompt/Aggressive Resuscitation

86 Start intravenous antibiotic therapy within the first hour of recognition of severe sepsis after obtaining appropriate cultures (1D) for Septic shock (1B) Board spectrum: include one or more agents active against likely bacterial/fungal pathogens, & with good penetration into presumed source (1B) Reassess regimen daily to optimize efficacy, prevent resistance, avoid toxicity & minimize costs. (1C) Kreger BE. Am J Med 1980;68: Ibrahim EH. Chest 2000;118: Ibrahim EH. Chest 2000;118: Hatala R. Ann Intern Med 1996; Antibiotic Therapy Dellinger, et. al. Crit Care Med 2008, 36:

87 Mortality as a Function of Adequacy of Empiric Antimicrobial Therapy Hospital Mortality (%) All causesInfection-related P<0.001 Inadequate Therapy Adequate Therapy P<0.001 Kollef MH, et al. Chest 1999;115:

88 Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock *Effective antimicrobial administration within the 1 st hour of documented hypotension was associated with increased survival in patients with septic shock. *Each hour of delay over the next 6 hours was associated with an average decrease in survival of 7.6% (range %) CCM 2006 Vol. 34 No.6

89 Antibiotic Challenges Appropriate selection – determined based upon consensus guidelines and pathogen sensitivity at your institution Timing issues  How? Delivery time challenges of antibiotics  Possible solutions

90 Case Study Disclaimer: –This is intended for education purposes –Judgment of physician/clinician should always be the deciding factor –The following case represents individual experience that are specific to these patients and may not reflect the typical course of recovery

91 Clinical Scenario 2 : Early Identification and Intervention 88 year old, 51.6kg,white, female presented to ED at 1345 from ECF History: CAD, COPD, dementia, Alzheimer disease, depression, SVT Chief Complaint: rib pain, chest congestion and SOB Awake, alert and oriented, slight combative (history of combative behavior)

92 Case Study 2: Early Identification and Intervention Initial VS: –Temp: F –RR: 31 –HR: 109, atrial fib with occasional SVT –B/P: 79/51 –2L of O2, O2 sat of 96% Positive Screen for severe sepsis: –SIRS: HR >90; RR> 20; Temp > 38 –Organ dysfunction: SBP<90mmHg Early Treatment –IV started –Received 500cc NS bolus over 30 minutes –Labs drawn

93 Advanced Treatment Guidelines Department of Emergency Services PURPOSE: To provide prompt, consistent nursing interventions for the patient with SIRS or sepsis prior to physician evaluation, to enable rapid diagnosis and slow the progression of illness. IMPLEMENTATION: The nursing staff may implement these interventions for patients who present with all three of the following criteria. The nurse should take into consideration the patient’s baseline vital signs when evaluating as a potential candidate. Also, these interventions should not conflict with the patient/family goals. (i.e. DNR, comfort care) 1.Clinical suspicion of systemic infection 2.At least two of the following: »Hyperthermia :Temperature greater than 38 °C (100.4 °F) »Hypothermia: Temperature less than < 36 °C (96.8 °F) »Tachycardia Pulse > 90 bpm »Tachypnea RR > SBP < 90 –Patients who meet all three criteria will be placed in a room immediately after consultation with charge nurse and/or attending.

94 Advanced Treatment Guidelines Department of Emergency Services TREATMENT 1.Notify Physician 2.Place Intermittent Infusion Device (large bore catheter) in 2 sites 3.Place on cardiac monitor 4.Continuous pulse oximetry 5.Vital signs every 15 minutes 6.Administer oxygen at 2 L/min per nasal cannula if O2 sat <92% 7.Draw and hold blood cultures x 2, Type & screen 8.Draw tube for serum lactate and place on ice. 9.Collect CCMS urine sample in the non-menstruating patient. Send for Urinalysis and urine culture. 10.Portable CXR 11.Intravenous hydration: Administer 500ml bolus of normal saline over 15 minutes.

95 Case Study 2: Early Identification and Intervention Labs: –WBC: 11.5 –Hgb: 15.8 –Hct: 47.4 –BUN: 28 Creatinine:1.6 –Glucose:158 –BNP:78 (moderate CHF); troponin:0.03 –Lactic acid: 4.6 –U/A: positive for bacteria –ScvO2: 49.1% –Blood cultures X 2 drawn

96 Case Study 2: Early Identification and Intervention CXR: RLL consolidation Additional Interventions: –Broad spectrum antibiotics given within 3 hours of presentation –Lactic acid >4mmol/L so CVP inserted –Fluid resuscitation continued –Foley inserted Received total of 3 Liters of NS during 3 hour ED stay ED diagnosis: Severe sepsis, Pneumonia, UTI, CHF Transferred to MICU

97 Case Study 2 : Early Identification and Intervention--MICU Additional Interventions: Day 1 –Continued fluid resuscitation—7 L –Low dose vasopressor –Low dose steroids –Remained on 2 L nasal canula –Not eligible for Xigris (renal failure resolved and vasopressor weaned off within 12hours after ICU admission) Labs: –ScvO2: 72.8 (after resuscitation) – Lactic acid: 4 hours after ICU admission: hours after ICU admission: 3.0 Bleeding is most common adverse effect associated with Xigris therapy, please see important safety information in this presentation

98 Case Study 2: Early Identification and Intervention Day 2: –Vasopressor weaned off –Lasix to assist with fluid mobilization –Lactic acid: 3.0 Day 3: –Lactic acid: 1.2 –O2 sat 93% on room air –Central line discontinued Transferred to intermediate care on Day 3 Discharged from hospital on day 7

99 EARLY MANAGEMENT Early Recognition ICU/Additional Evidence Based Therapies Early Antibiotics Prompt/Aggressive Resuscitation

100 Management Bundle Components

101 Recombinant human Activated Protein C [Drotrecogin alfa (activated)] is recommended in patients at a high risk of death ( APACHE II score  25, or Sepsis-induced multiple organ failure) if there are no contraindications. Within 30 days of surgery with the above indications (2C) Drotrecogin alfa (activated) is not indicated in adult patients with severe sepsis and lower risk of death. (1A) Relative contraindications/warnings should be consider Recombinant human Activated Protein C (2B) Dellinger, et. al. Crit Care Med 2008, 36:

102 *as defined by APACHE II  25 †relative risk reduction at 28 days Data on file, Eli Lilly and Company. PROWESS 28-Day Mortality – High Risk of Death Patients* PlaceboDrotrecogin alfa (activated) Absolute Risk Reduction = 13% Mortality Rate Drotrecogin Alfa (Activated) In Severe Sepsis: PROWESS Results  29% reduction in relative risk of death with Xigris † See important safety information in this presentation.

103 Survival Benefit Consistent across High-risk Severe Sepsis Patients The 95% relative risk confidence interval for each subgroup included the point estimate for the overall PROWESS population (0.80). The point estimate of relative risk of death in each subgroup is indicated by a solid circle, and the 95% confidence interval is indicated by the horizontal lines. Note the consistency between the overall trial result and the subgroup analyses. *APACHE (Acute Physiology And Chronic Health Evaluation). For more information on using the APACHE II scoring system, please see †Nonprospectively defined population 1. Barie P, et al. Am J Surg. 2004; 188: Dhainaut JF MD, PhD, et al. For the PROWESS Study Group. Intensive Care Med. 2003;29(6): Laterre P-F et al. Crit Care Med. 2005;33(5): Data on file, Eli Lilly and Company. 6. Dhainaut JF, Yan SB, Joyce DE, et al. J Thromb Haemost 2004; 2: Xigris ® (drotrecogin alfa [activated]) benefits consistent See Important Safety Information in this presentation Relative Risk of Death (95% CI) FAVORS XIGRISFAVORS PLACEBOTOTALRELATIVE RISKXIGRISPLACEBO (CONFIDENCE INTERVAL) APACHE II* ≥ ( ) ORGAN DYSFUNCTION ≥ ( ) CAP WITH APACHE II ≥ ( ) CAP S. PNEUMONIAE920.40( ) WITH APACHE II ≥ 25 4 INTRA-ABDOMINAL SURGERY ( ) WITH APACHE II ≥ 25 1 OVERT DIC ( ) DAY MORTALITY 6

104 Fine-Tuning Xigris Therapy in Adult High-Risk Severe Sepsis Patients Right Patient, Right Drug, Right Time New: Clinical trials to help advance care of adult patients with severe sepsis at high risk of death: Contact LILLY-RX for more information. RESPOND Targeted Enrollment = 500 Enrollment started in Nov Phase 2 trial investigating a biomarker (Protein C) to help guide Xigris therapy in adult patients with severe sepsis at high risk of death. NEW Placebo Controlled Trial in Adult High-Risk Severe Sepsis Help clinicians better identify patients who are most likely to benefit from Xigris, as well as to further clarify the benefit/risk profile of the drug. Please see Important Safety Information in this presentation and accompanying full Prescribing Information. Bleeding is the most common adverse effect associated with Xigris therapy.

105 Concerns about risk of bleeding Restrictive order set Inconsistent screening process Cost issues What are the Challenges to Appropriate Screening and Administration of Xigris ® (drotrecogin alfa [activated])?

106 Safety Profile  Low incidence of serious bleeding events*  Rate of serious bleeding events during infusion in high-risk patients:  PROWESS: 2.2% (9 of 414) in drotrecogin alfa (activated) patients vs 0.7% (3 of 403) in standard therapy patients  Rate of ICH in high-risk patients during infusion:  PROWESS: 0.2% (1 of 414) in drotrecogin alfa (activated) patients  Associated with severe thrombocytopenia (platelet count < 30,000/mm 3 ) †  Not associated with other adverse events *Serious bleeding events were defined as any intracranial hemorrhage, any life-threatening bleeding, any bleeding event requiring the administration of ≥3 units of packed red blood cells per day for 2 consecutive days, or any bleeding event assessed as a serious adverse event. †At the time of enrollment in the PROWESS study, the patient had a platelet count above 30,000/mm 3. The patient’s platelet count fell to less than 30,000/mm 3 after drotrecogin alfa (activated) therapy was initiated. Data on file, Eli Lilly and Company See important safety information and full prescribing information in this presentation.

107 Drotrecogin Alfa (Activated) Has a Favorable Risk/Benefit Profile 8 times more likely to save an additional life than observe an additional serious bleeding event * *Based on a 13% 28-day survival benefit and a serious bleeding rate during infusion attributable to Xigris of 1.5% (13% ÷ 1.5% = 8.7) in patients with an APACHE II score > 25. Data on file, Eli Lilly and Company.

108 CONTRAINDICATIONS –Active internal bleeding –Recent (within 3 months) hemorrhagic stroke –Recent (within 2 months) intracranial or intraspinal surgery, or severe head trauma –Trauma with an increased risk of life-threatening bleeding –Presence of an epidural catheter –Intracranial neoplasm or mass lesion or evidence of cerebral herniation See full Prescribing Information available at this presentation. Important Safety Information Drotrecogin alfa (activated) increases the risk of bleeding. Drotrecogin alfa (activated) is contraindicated in patients with the following clinical situations in which bleeding could be associated with a high risk of death or significant morbidity. Drotrecogin alfa (activated) is contraindicated in patients with known hypersensitivity to drotrecogin alfa (activated) or any component of this product.

109 WARNINGS Bleeding Bleeding is the most common serious adverse effect associated with drotrecogin alfa (activated) therapy. Each patient being considered for therapy with drotrecogin alfa (activated) should be carefully evaluated and anticipated benefits weighed against potential risks associated with therapy Certain conditions, many of which led to exclusion from the Phase 3 trial, are likely to increase the risk of bleeding with drotrecogin alfa (activated) therapy. For individuals with one or more of the following conditions, the increased risk of bleeding should be carefully considered when deciding whether to use drotrecogin alfa (activated) therapy: –Concurrent therapeutic dosing of heparin to treat an active thrombotic or embolic event –Platelet count < 30,000 x 10 6 /L, even if the platelet count is increased after transfusions –Prothrombin time-INR > 3.0 –Recent (within 6 weeks) gastrointestinal bleeding –Recent administration (within 3 days) of thrombolytic therapy –Recent administration (within 7 days) of oral anticoagulants or glycoprotein IIb/IIIa inhibitors –Recent administration (within 7 days) of aspirin > 650 mg per day or other platelet inhibitors –Recent (within 3 months) ischemic stroke –Intracranial arteriovenous malformation or aneurysm –Known bleeding diathesis –Chronic severe hepatic disease –Any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location See full Prescribing Information available at this presentation. Important Safety Information

110 Additional Management Bundle Components

111 Low Tidal Volume Ventilation: SSC Recommendations Target tidal volumes to < 6 mL/kg (predicted body weight) in patients with ALI/ARDS (1B) Initial upper limit goal for plateau pressures in a passively inflated patient be < 30 cm H 2 O (1C) Hypercapnia can be tolerated in patients with ALI/ARDS if required to minimize plateau pressures and tidal volumes (1C) Recommend that positive end expiratory pressure be set as to avoid extensive lung collapse at end- expiration (1C) Suggest prone positioning in ARDS patients requiring potentially injurious levels of FiO2 or plateau pressures in facilities that have experience with the practice (2C) Dellinger RP, et al. Crit Care Med. 2008;36;

112 ARDS Network ALI/ARDS Ventilator Study Methodology: –Inclusion criteria: p/f ratio < 300, bilateral infiltrates, no cardiac cause, receiving mechanical ventilation –Outcomes: mortality/VFD –841 patients randomized –12 ml/kg TV group – Plat < 50 cm H 2 O –6 ml/kg TV group - Plat < 30 cm H 2 O ARDS Network, N Engl J Med 2000;342:

113 ARDS Network ALI/ARDS Ventilator Study Results :  PEEP: no difference in average amount used  Mortality: 31% ( 6 ml/kg TV) vs. 40% (12 ml/kg TV) p=0.007  VFD: vs (p=0.007)  Greater organ failure free days in protective group  Reduction in IL-6 levels by day 3  Difficulty with agitation/high rates in the 6 ml/kg group ARDS Network, N Engl J Med 2000;342:

114 Additional Mechanical Ventilation Recommendations Unless contraindicated, maintain HOB elevated to limit aspiration and prevent VAP (1B). Elevation should be 30 to 45 degrees (2C) Non-invasive mask ventilation only be considered in that minority of mild to moderate hypoxemic respiratory failure patients who are able to protect their airway & are hemodynamically stable. A low threshold for intubation should be maintain (2B) Dellinger RP, et al. Crit Care Med. 2008;36;

115 Additional Mechanical Ventilation Recommendations Weaning protocol in place where patients undergo SBT if the satisfy criteria (1A) Recommend against the routine use of PA catheters (1A) Recommend a conservative fluid strategy for patients with established ALI/ARDS who do not have evidence of tissue hypoperfusion (1C) Dellinger RP, et al. Crit Care Med. 2008;36;

116 Intravenous corticosteroids should only be given to adult septic shock patients after it has been confirmed that their blood pressure is poorly responsive to fluid resuscitation and vasopressor therapy Suggest that the ACTH stimulation test should NOT BE used to identify the subset of adult with septic shock who should receive hydrocortisone. (2B) We suggest that patients with septic shock should not receive dexamethasone if hydrocortisone is available. (2B) –Administer intravenous hydrocortisone <300 mg daily (1A) –Fludrocortisone is optional if hydrocortisone is used (2C) Dellinger RP, et al. Crit Care Med. 2008;36: Corticosteroids In Septic Shock: SSC Recommendations (2C)

117 Hydrocortisone Therapy for Patients with Septic Shock Design: Multicenter, randomized, double- blind, placebo-controlled trial Population: 499 patients with septic shock— BP<90 systolic despite adequate fluid replacement or vasopressors for at least one hour (onset of shock within previous 72 hrs) Method: 2 groups: one group received 50mg hydrocortisone every 6 hrs for 5 days, then tapered; other group received a placebo. End Point: 28 day mortality Sprung, NEJM,2008; Vol 358 No 2

118 Hydrocortisone Therapy for Patients with Septic Shock--Results No significant difference between 2 study groups in rate of death at 28 days (no matter if responded or not to corticotropin) Duration of time to reversal of shock was significantly shorter among all pts receiving hydrocortisone (3.3 days vs 5.8 days; p<0.001) Pts in this study who has a SBP of< 90mmHg at 1 day after fluid and vasopressor resuscitation had mortality of 56% if received placebo and mortality of 44.9 if received hydrocortisone (difference of 11.4%)—similar to Annane et al results. In hydrocortisone group there was an increased incidence of superinfections, including new episodes of septic shock Sprung, NEJM,2008; Vol 358 No 2

119 Initial stabilization of patients with severe sepsis and hyperglycemia who are admitted to the ICU receive IV insulin therapy to reduce blood glucose levels. (1B) Use of a validated protocol and target glucose levels to < 150 mg/dL range. (2C) All patients receiving IV insulin should receive a glucose calorie source and blood glucose values should be initially assesses every 1-2 hrs, then q 4 hours after stabilization. (1C) Low glucose levels obtained by Point of Care testing should be interpreted with caution (1B) Dellinger RP, et al. Crit Care Med. 2008;36: Glucose Control: SSC Recommendations

120 NICE Study 6104 Critically Ill Patients within 24 hrs of admission to ICU randomized Data evaluated on 3010 pts in intensive control group (target mg/dL) & 3012 pts to conventional group (target < 180 mg/dL) Similar characteristics at baseline Results: Conventional group has significantly lower number of deaths Severe hypoglycemia (blood glucose < 40mg per dL greater in intensive control group (6.8% vs..5% (p<0.001 NICE-SUGAR Investigators, N Engl J Med;2009: % vs. 24.9% (p =0.02)

121 Procedure or Population Breakdown NICE-SUGAR Investigators, N Engl J Med;2009:

122 What to Do Now? Continue to Optimize Management of Glucose to Prevent Hyperglycemic & Hypoglycemic Events…range target to < 180 mg/dL, stop infusion at 140 mg/dL Do NOT Return to Sliding Scale Inzucchi SE, Siegel MD. N Engl J Med;2009;360(13):

123 Additional Management Bundle Components Barriers TGC: Lack of tested nomogram What target range to pick? Evaluating success Increase nursing time Not enough monitors Low TV ventilation Lack of knowledge of research by physicians, RT and nursing No defined policy Lack of accountability Identifying patients who have ALI or ARDS?

124 Sepsis Evidence Implementation Making it a Reality Sepsis Bundle

125 Sepsis Bundles Screen for Severe Sepsis YesNo Management Sepsis Bundle (24 hour) Maintain serum glucose levels on average < 150 mg/dl. (8.3 mmol/L )Maintain serum glucose levels on average < 150 mg/dl. (8.3 mmol/L ) Drotrecogin alfa (activated) administered in accordance with hospital guidelinesDrotrecogin alfa (activated) administered in accordance with hospital guidelines Steroids given for septic shock requiring continued use of vasopressors for equal to or greater than 6 hoursSteroids given for septic shock requiring continued use of vasopressors for equal to or greater than 6 hours Adoption of a lung protective strategy (tidal volumes < 6ml/kg) with plateau pressures of 30 cm H2O for mechanically ventilated patientsAdoption of a lung protective strategy (tidal volumes < 6ml/kg) with plateau pressures of 30 cm H2O for mechanically ventilated patients Resuscitation Sepsis Bundle (6-Hour) Obtain Cultures before antibiotic administrationObtain Cultures before antibiotic administration Lactate LevelLactate Level In the event of hypotension (SBP 4 mmol/L, begin initial fluid resuscitation with ml of crystalloid (or colloid equivalent) per estimated kg of body weightIn the event of hypotension (SBP 4 mmol/L, begin initial fluid resuscitation with ml of crystalloid (or colloid equivalent) per estimated kg of body weight Vasopressors employed for hypotension ((MAP) Less than 65 mm Hg) during and after initial fluid resuscitationVasopressors employed for hypotension ((MAP) Less than 65 mm Hg) during and after initial fluid resuscitation Board spectrum antibiotics administered Within 3 hours of presentationBoard spectrum antibiotics administered Within 3 hours of presentation In the event of septic shock or lactate > 4 mmol/L, CVP and ScvO2 or SVO2 measured.In the event of septic shock or lactate > 4 mmol/L, CVP and ScvO2 or SVO2 measured. In the event of septic shock or lactate > 4 mmol/L, CVP maintained 8-12 mmhgIn the event of septic shock or lactate > 4 mmol/L, CVP maintained 8-12 mmhg Inotropes (and/or PRBC’s if hematocrit = 8 mmhgInotropes (and/or PRBC’s if hematocrit = 8 mmhg Standard care If on Antibiotic, then Monitor Q24H FL Monitor Per shift ICU

126 Develop Protocols & Order Sets to Implement Resuscitation in Medical-Surgical Area Draw blood –Lactate Level –Obtain blood cultures before administration of antibiotic In the event of hypotension (SBP 4 mmol/L, begin initial fluid resuscitation with ml of crystalloid (or colloid equivalent) per estimated kg of body weight Vasopressors employed for hypotension ((MAP) Less than 65 mm Hg) during and after initial fluid resuscitation Broad spectrum antibiotics administered within three hours of presentation

127 Within 6 hrs (Transport to the ICU is Key) In the event of septic shock or lactate > 4 mmol/L, CVP and ScvO2 or SVO2 measured. (line inserted) In the event of septic shock or lactate > 4 mmol/L, CVP maintained 8-12 mmhg Inotropes (and/or PRBC’s if hematocrit = 8 mmhg

128  Adoption of a lung protective strategy (tidal volumes < 6ml/kg) with plateau pressures of 30 cm H2O for mechanically ventilated patients with ALI/ARDS  Drotrecogin alfa (activated) administered in accordance with hospital guidelines  Maintain serum glucose levels on average < 150 mg/dl. (8.3 mmol/L)  Consider steroids given for septic shock requiring continued use of vasopressors and fluid resuscitation and remains unstable Develop Protocols & Order Sets to Implement Management 24-Hour Severe Sepsis Bundles

129 Organizational Consensus that Severe Sepsis Must be Managed Early and Aggressively Early Screening with Tools and Triggers Implementation of the Sepsis Bundle Measuring Success Fourth Tier: Measuring Process and Outcomes Changes

130 Sepsis Measurement tool found at &

131 Data Collection Outcome –Mortality (ICU and Hosp) –Hosp LOS –Cost per case (total and direct) Process –SSC database –Data elements that measure implementation of resuscitation and management bundle

132 Role of Data Outcome data –Share with staff and administration to keep momentum going –Helps convince/move skeptics Process data –Celebrate small successes –Helps identify where opportunities for improvement still exist

133 Implementation Hospital resources often focused on planning phase and then back off after implementation. The implementation phase is the most critical Frequent rounds recommended on unit by project champion to support staff and answer questions. Defined resources for bedside nurse-IE: –Project champion has pager to be available 24/7 initially –Clinical nurse champions identified on each ICU unit and ED to be resources to bedside staff (these staff should be a member of the sepsis team/committee from the beginning)

134 Severe Sepsis Bundle Implementation Results Loma Linda, California England Germany St. Louis, Missouri

135 Surviving Sepsis Campaign 252 hospitals in 18 countries Data from January 2005-March 2008 Observational; time series Baseline is first quarter data was collected Use of standardized screening tool Excluded site if less than 20 patients or less than 3 months of results M Levy, presented at SCCM 02/2009 Nashville

136 Surviving Sepsis Campaign Results Final Sample Size: 15,022 patients from 166 sites (95% of total) –North America: 58% –Europe: 31% –South America: 10% M Levy, presented at SCCM 02/2009 Nashville

137 Surviving Sepsis Campaign Results Entry PointSubjectsMortality (hosp) ED52%27.6 ICU12.8%41.3 Ward34.8%46.8 Hospital mortality went from 37% to 30% 7% ARR; 19% RRR; p< M Levy, presented at SCCM 02/2009 Nashville

138 Surviving Sepsis Campaign Bundle Compliance BundleBaseline2 year Resuscitation10.9 %31.3 % Management18 %36 % Risk Adjusted Hospital Mortality decreased by 5.4% 20 % improvement in compliance with bundles M Levy, presented at SCCM 02/2009 Nashville

139 A Prospective Multi-Center Collaborative Study Before and After Implementation of an Early Sepsis Initiative The Multi-Center Severe Sepsis & Septic Shock Collaborative Group Presented by Emanuel Rivers at the World Federation of Critical care Medicine, Florence Italy 08/09

140 Methods  Pre-implementation analysis occurred from with post-implementation observation from  11 centers ranging from community (N=6) to academic tertiary care (N=5) settings were included in the study.  In this intention-to-treat evaluation, all patients including DNR were examined. Presented by Emanuel Rivers at the World Federation of Critical care Medicine, Florence Italy 08/09

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144 In-Hospital Mortality: M SS/SS C vs. SSC PRE %POST %ARR %RRR % M SS/SS C st QLast Q SSC Presented by Emanuel Rivers at the World Federation of Critical care Medicine, Florence Italy 08/09

145 Mortality by Lactate & SBP Subsets PRE-POST- Lactate > 4 Only SBP < 90 Only Lactate > 4 & SBP < Presented by Emanuel Rivers at the World Federation of Critical care Medicine, Florence Italy 08/09

146 Bundle Implementation: Decreased Mortality 2 year prospective study in academic tertiary care facility, with majority of care delivered in the ED 330 patient enrolled Measured 5 quality indicators related to management of Severe sepsis & septic shock population. CVP/ScvO2 by 2 hrs, antibiotics by 4 hours, EGDT completed at 6 hours, appropriate steroids, lactate clearance Nguyen et al CCM, 2007 Vol 35, No. 4, Methodology

147 Bundle Implementation: Decreased Mortality In hospital mortality in patients who completed the bundle was significantly lower then those who did not complete the bundle (20.8 vs 39.5; p<0.01) 14% of patients that completed the bundle received rhAPC. Completing EGDT in 6 hours was the only quality indicator with a significant odds ratio for decreased mortality using multivariate regression analysis After 2 years, achieved 51% compliance with all five indicators Nguyen et al CCM, 2007 Vol 35, No. 4, Results:

148 Bundle Component Compliance and Impact on Mortality Nguyen et al CCM, 2007 Vol 35, No. 4

149 Prospective External Validation of Effectiveness of EGDT Prospective interventional study conducted over 2 years Compared 79 patients in pre-intervention year and 77 patients in post intervention year Intervention group received significantly more fluid (2L), less vasopressors Mortality 18% vs. 27% Jones AE, et al. Chest, 2007;132:

150 Source: Gao F, Melody T, Daniels D, et al. The impact of compliance with 6-hour and 24-hour sepsis bundle on hospital mortality in patients with severe sepsis: A prospective observational study. Crit Care Med. 2005;9(6):R764-R770. Is a two-fold mortality improvement a possibility in your institution? Sepsis Bundles: Significant Impact on Hospital Outcomes Two acute National Health Service Trust Teaching Hospitals in England performed a prospective observational study with 101 adult patients with severe sepsis or septic shock Outcomes measures –Rate of compliance with 6-hour and 24-hour bundles adapted from 2004 SSC guidelines –Hospitality mortality between compliant and noncompliant groups Compliance with Bundles 6-hour bundle 52% 24-hour bundle 30% Bundle Mortality Noncompliant 49% (p=.001) Compliant 23% (p=.001)  More than two-fold increase in hospital mortality associated with noncompliant group  Assessed compliance as “all or none” for the bundle elements

151 Compliance with 6hr Bundle Gao F, et al. Critical Care, 2005;9:R % 74% 84% 70%

152 6hr Bundle & Hosp Mortality Gao F, et al. Critical Care, 2005;9:R N=12/52 N=24/49 RR=2.12 ( ) NNT = % 49% Mortality P=0.01

153 Compliance with 24hr Bundle Gao F, et al. Critical Care, 2005;9:R % 43% 85% 30%

154 24hr Bundle & Hosp Mortality Gao F, et al. Critical Care, 2005;9:R N=6/21 N=24/48 RR=1.75( ) NNT = % 50% Mortality P=0.16

155 Severe Sepsis Protocol in Use Germany Retrospective cohort study in 10 bed mixed ICU in Germany 60 patients (30 consecutive receiving SOP severe sepsis management compared to historical controls) Measured: Primary endpoint 28 day mortality Measured: Secondary endpoints; ABG’s, lactate, glucose, creat, WBC, Plat, time to dx & 7am on day 2 & 4 SOFA scores Results: In SOP group: ↑ use of dobutamine, glucose control, steroids & rhAPC Mortality: Control vs SOP (53% vs. 27% p <.05) Independent predictors of survival: lactate on admission, age, gender, blood glucose < 150 mg/dl, adm of rhAPC & steroids Kortgen A et al. Crit Care Med, 2006:34:

156 Standardized Order Set-Sepsis Bundles St. Louis, Missouri Before-after study design with prospective consecutive data collection of 120 patients 1,200 bed academic medical center Primary endpoint: 28 day mortality Other measures: hospital LOS, IV fluid intact for shock, appropriate antibiotic Results: after group: received more IV fluids in ED (p=0.002); more likely to receive >20ml/kg of fluid prior to vasopressors; had lower risk of mortality (48.3% vs 30%, p=0.04); lower hospital LOS (12.1 vs 8.9 days, p=0.038) Independent predictors of survival: increased pt age and not receiving >20 ml/kg of IV fluid prior to vasopressors Micek, Scott et al., Critical Care Medicine, 2006; 34:

157 Standardized Order Set-Sepsis Bundles Decreases Cost St. Louis, Missouri Before-after study design with prospective consecutive data collection of 120 patients to determine financial impact of sepsis protocol 1,200 bed academic medical center Primary endpoint: Overall Hospital costs Secondary endpoint: Hospital LOS Results: after group: Hospital costs $16,103 vs. $21,985, p =.008; LOS 5 days less in the protocol group (p=.023) Use of protocol independently associated with less per patient cost. Shorr AF, et al. Critical Care Medicine, 2007; 35:

158 Case Study Disclaimer: –This is intended for education purposes –Judgment of physician/clinician should always be the deciding factor –The following case represents individual experience that are specific to these patients and may not reflect the typical course of recovery

159 Case Study 3: Early Identification and Intervention 63 year old white female directly admitted to a med-surg floor from a free standing urgent care at 2130 Hx: NIDDM, COPD, HTN Chief complaint: pain right lower sternal border times 2 days, worse with deep breath, SOB. CXR: right pleural effusion Orthostatic hypotension, renal insufficiency (creatinine 3.4—previously 1.2)

160 Case Study 3: Early Identification And Intervention Initial VS: stable BP, HR-102, RR-WNL On 2L nasal cannula, IV at 150/hr Labs: WBC-7.5, plat 197, D-dimer: 273 Resp distress at 0600 next am Transferred to MICU Possible PE—heparin gtt started Broad spectrum antibiotics started

161 Case Study 3: Early Identification And Intervention ICU course: –2000: BP: 79/34, HR: 123, WBC: 3.3 – Dx of severe sepsis at 2000 –2 liter fluid bolus –Intubated and ventilated –Lactic acid 0.9 –Levophed started, heparin gtt d/c’d –CVP inserted

162 Case Study 3: Early Identification And Intervention ICU course-continued: – Xigris started at 0600 (still on vasopressors, vent, creat-3.9) – 1000: Stopped Xigris for CT guided pleural aspirtation – 1200: CT- 2 loculated cavities in right lung; Cardio thoracic surgery consulted – OR at 1700 for drainage of empyema Right mini-thorocotomy, empyema drainage, decortication and bronchoscopy. CT (2) inserted

163 Case Study 3: Early Identification And Intervention Post-op – Temp-97, HR: 84, BP-139/69 on levophed and vasopressin and bicarb gtt. – Xigris restarted Post-op Day 1 – Levophed off at 0400 – Bicarb gtt off at 0400 – Vasopressin gtt off at 1000 – Vent FiO2 decreased to 0800 Full course of Xigris Off vent/extubated in 6 days (hx of COPD) Transfer out of ICU- post-op day 11 Discharge home- post-op day 25

164 The Nurses Role Early recognition of patients with signs of sepsis Early initiation of evidence based practice therapies appropriate for your area of practice (antibiotics, fluids/blood & pressors) Swift disposition to care areas where the rest of the bundle can be started.


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