Sepsis 2013: Hot off the Press Kaplow,

Introduction > 750,000 cases/year > Americans die daily Overall mortality rate 28-50% Estimated cost of $5-10B/year 2

SIRS SepsisSevere Septic MODS Sepsis Shock Sepsis: A Clinical Continuum 3

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Diagnostic Criteria for Sepsis Physical Findings Fever (> 38.3 ｰ C) Hypothermia (core < 36° C) Heart rate > 90/min Tachypnea Altered mental status Significant edema or positive fluid balance (> 20 mL/kg over 24 hr) Hemodynamic variables Hypotension (SBP 40 mm Hg Lab Findings Hyperglycemia (glucose > 140 mg/dL) in the absence of diabetes Leukocytosis (WBC count > 12,000) Leukopenia (WBC count < 4000) Normal WBC count with > 10% bands Elevated CRP Elevated procalcitonin level 6

Diagnostic Criteria for Sepsis (cont’d) Organ Dysfunction Variables Hypoxemia (PaO 2 /FiO 2 < 300) Acute oliguria (urine output < 0.5 mL/kg/hr for at least 2 hrs despite adequate fluid resuscitation) Creatinine increase > 0.5 mg/dL Coagulation abnormalities (INR > 1.5 or aPTT > 60 s) Ileus (absent bowel sounds) Thrombocytopenia (PLT < 100,000) Total bilirubin > 4 mg/dL) Tissue Perfusion Variables Hyperlactatemia (> 1 mmol/L) Decreased capillary refill or mottling 7

Diagnostic Criteria for Severe Sepsis Sepsis-induced hypotension Lactate above ULN Urine output < 0.5 mL/kg/hr for more than 2 hrs despite adequate fluid resuscitation Acute lung injury with: –PaO 2 /FiO 2 < 250 without pneumonia –PaO 2 /FiO 2 < 200 with pneumonia Creatinine > 2.0 mg/dL Bilirubin > 2 mg/dL Platelet count < 100,000 μL Coagulopathy (INR > 1.5) 8

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CNSAcute change in MS (confusion, agitation, lethargy) or GCS < 15 (previously normal or decreased by 1) PulmonaryUnexplained hypoxemia with suspected sepsis (P/F < 200), bilateral infiltrates with PAOP < 18 RenalOliguria, inc. serum creatinine from normal with urine Na < 40 mmol/L, rise in serum creatinine by 2 mg/dL in presence of preexisting renal insufficiency HepatobiliaryInc. LFTs to 2x normal, serum bilirubin > 2 mg/dL GIParalytic ileus, GI bleeding CoagulationConfirmatory test for DIC (FDP > 1.4 or D-dimers > 2, thrombocytopenia or fall in platelets by 25%, inc. PT, PTT, clinical evidence of bleeding 10

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Cytokines Mediators of inflammation Critical parts of the immune system Increased levels during shock TNF and IL-1: widespread effects released early in systemic inflammatory response 13

Systems and Mediators Affected In Septic Shock Complement SystemCoagulation Cascade Fibrinolytic SystemCatecholamines Cachetin (TNF)Histamine IL-1Circulating MDF PAFMacrophage LeukotrienesO 2 free radicals ProstaglandinsInflammatory proteins Thromboxane A 2 14

Vascular Endothelium Regulates: Blood vessel tone Vascular permeability Coagulation WBC and platelet activity Phagocytosis of bacteria 15

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Signs and Symptoms of Sepsis General Fever Chills Fatigue Malaise Rigors Warm, pink peripheries 19

Signs and Symptoms of Sepsis CNS Confusion Anxiety Disorientation Apprehension Agitation Obtunded or comatose 20

Signs and Symptoms of Sepsis Cardiovascular Tachycardia Increased pulse pressure Hypotension Cardiac output normal or increased Normal capillary refill 21

Signs and Symptoms of Sepsis Pulmonary Hyperventilation Respiratory alkalosis SOB Tachypnea 22

Signs and Symptoms of Sepsis GI/GU Nausea and vomiting Decreased albumin Jaundice Oliguria 23

Signs and Symptoms of Sepsis Hematologic WBC increased or decreased Increased INR, aPTT DIC Decreased platelets 24

Signs and Symptoms of Sepsis Metabolic Increased base deficit Increased lactate Increased glucose 25

Surviving Sepsis Campaign Bundles To be completed within 3 hours: Measure lactate level Obtain blood cultures prior to administration of antibiotics Administer broad spectrum antibiotics Administer 30 ml/kg crystalloid for hypotension or lactate ≥4mmol/L *Targets are CVP of ≥8 mm Hg; ScvO 2 of ≥70%, and normalization of lactate. ​ To be completed within 6 hours: Apply vasopressors (for hypotension that does not respond to initial fluid resuscitation) to maintain a MAP ≥65 mm Hg In the event of persistent hypotension despite volume resuscitation or initial lactate ≥4 mmol/L (36 mg/dL): --Measure CVP* and central venous oxygen saturation (ScvO 2 )* Remeasure lactate if initial lactate was elevated* 26

Management of Septic Shock ABCs, antimicrobials Volume resuscitation Vasopressor therapy Inotropic support ? Steroids ? Bicarbonate therapy Blood products Glucose control Supportive therapies Ventilator support Sedation, analgesia, and neuromuscular blockade 27

Recommendations: Initial Resuscitation and Infection Issues: Initial Resuscitation 1. Resuscitation of patients with sepsis-induced tissue hypoperfusion (defined as hypotension persisting after initial fluid challenge or blood lactate ≥ 4 mmol/L). Goals during the first 6 hours of resuscitation: a) Central venous pressure 8–12 mm Hg b) MAP ≥ 65 mm Hg c) U/O ≥ 0.5 mL/kg/hr d) Central venous (superior vena cava) or mixed venous oxygen saturation 70% or 65%, respectively 2. In patients with elevated lactate levels targeting resuscitation to normalize lactate 28

Recommendations: Initial Resuscitation and Infection Issues: Antimicrobial Therapy 1. Administration of effective intravenous antimicrobials within the first hour of recognition of septic shock and severe sepsis. 2a. Initial empiric anti-infective therapy of one or more drugs that have activity against all likely pathogens and that penetrate tissues presumed to be the source of sepsis. 2b. Antimicrobial regimen should be reassessed daily for potential de-escalation. 29

Recommendations: Initial Resuscitation and Infection Issues: Antimicrobial Therapy (cont’d) 3. Use of low procalcitonin levels or biomarkers to assist in the discontinuation of empiric antibiotics in patients who initially appeared septic, but have no evidence of infection. 4a. Combination empirical therapy for neutropenic patients with severe sepsis and those with difficult-to-treat, MDR bacteria such as Acinetobacter and Pseudomonas. 4b. Empiric combination therapy should not be administered for more than 3–5 days. De-escalation to the most appropriate single therapy should be performed as soon as the susceptibility profile is known. 30

Recommendations: Initial Resuscitation and Infection Issues: Antimicrobial Therapy (cont’d) 5. Duration of therapy typically 7–10 days; longer courses may be appropriate in patients who have a slow clinical response, undrainable foci of infection, S. aureus; some fungal and viral infections or immunologic deficiencies, including neutropenia. 6. Antiviral therapy initiated as early as possible in patients with severe sepsis or septic shock of viral origin. 7. Antimicrobial agents should not be used in patients with severe inflammatory states determined to be of noninfectious cause. 31

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Volume Resuscitation Crystalloids for initial choice No hydroxyethyl starches Albumin in severe sepsis and septic shock if substantial amounts of crystalloids are required. Titrate to clinical endpoints  urine output  lactic acid  decreased HR  increased B/P  improved mental status 34

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Vasopressor Therapy Norepinephrine (NE) Epinephrine (added or substitute for NE) Vasopressin 0.03 units/min (may be added to supplement or decrease NE). Higher doses should be reserved for salvage therapy. Low dose vasopressin not recommended as a single agent. Dopamine (only in highly selected patients) No renal dopamine. Phenylephrine (not recommended except in serious arrhythmias, high CO and persistent hypotension, or salvage therapy). (Titrate to MAP 65 mm Hg. All patients on pressors should have an arterial catheter placed ASAP.) 36

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Inotropic Therapy Optimization of filling pressures Tachyarrhythmias – undesirable s/e Usually need in conjunction with vasopressor Not used to increase CI to supra-normal levels  Dobutamine trial up to 20 mcg/kg/min if myocardial dysfunction is suspected by elevated PAOP 40

Corticosteroid Therapy Do not use for sepsis– only septic shock. Do not use if fluids and vasopressors keep MAP > 65. If MAP not maintained, administer hydrocortisone 200 mg/day Do not use ACTH stimulation test. Don’t forget to taper. 41

Bicarbonate Therapy Not routinely indicated Doesn’t improve effectiveness of vasoactive agents Doesn’t correct hemodynamics or decrease pressor requirements despite correction of acidemia No longer given empirically. May be used for pH <

Blood Product Administration Target hemoglobin 7-9 g/dL in adults. May be administered once hypoperfusion resolved, or May be administered immediately if: Myocardial ischemia Severe hypoxemia Acute hemorrhage Ischemic CAD Do not use erythropoietin. 43

Glucose Control Use arterial or serum blood sugar measurement; capillary blood may not be accurate. Treat after two consecutive blood glucose levels > 180 mg/dL. Maintain blood glucose mg/dL. Monitor every 1-2 hours until stable; then every 4 hours. 44

Do Not Use Immunoglobulins Selenium rhAPC 45

Supportive Therapies Renal replacement therapies VTE prophylaxis Sepsis: LMWH Septic shock: LMWH + intermittent pneumatic compression Stress ulcer prophylaxis (H 2 blocker or PPI for patients with severe sepsis factors who have bleeding risk factors 46

Supportive Therapies (cont’d) Nutrition (oral or enteral as tolerated within the first 48 hours). TPN + enteral for first 7 days for severe sepsis or septic shock. Enteral up to 500 cal/day; advance only as tolerated. 47

Ventilator Support Target tidal volume 6 mL/kg in patients with sepsis- induced ARDS. PEEP to avoid alveolar collapse (higher levels in patients with sepsis-induced moderate or severe ARDS.) Recruitment maneuvers in severe refractory hypoxemia. 48

Sedation, Analgesia, and Neuromuscular Blockade 1. Sedation be minimized in ventilated sepsis patients, targeting specific titration endpoints. 2. NMBAs be avoided if possible in the septic patient without ARDS due to the risk of prolonged blockade after d/c’d. If NMBAs must be maintained, TOF monitoring should be used. 3. A short course of NMBA < 48 hours for patients with early sepsis-induced ARDS and a PaO 2 /FiO 2 <

For more information: Dellinger RP, Levy MM, Rhodes A, et al: Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: Crit Care Med 2013; 41:

Nursing Implications Identify patient at risk Identify patient who may be developing sepsis Recognition of subtle changes in condition Proactive treatment Emergent resuscitation 51

Nursing’s role in identifying and helping in the treatment of sepsis is more important than ever before. 52

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Nursing Implications Methods to minimize host stress response Prevent infection Avoid further tissue damage Control hyper/hypothermia Manage pain/anxiety/delirium 54

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Infection Prevention Oral CHG for oropharnygeal decontamination. Selective digestive decontamination to prevent VAEs. 62

Nursing Implications Source control Preserve organ function Prevent complications of nutritional support  prevent obstruction  manage diarrhea  prevent ileus 63

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Prognosis: Factors to Consider Patient’s underlying health status Development of organ failure Prevention of complications Infecting organism Shock and low arterial pH during first days 65

Rangel-Frausto, et al., JAMA 273:

Complications of Sepsis and SIRS CNS Dysfunction (19%) ARDS (2-8%) Liver Failure (12%) Acute Renal Failure (9-23%) DIC (8-19%) 67

68 Patients admitted with septic shock to ED Reduction in mortality: 70% vs. 52% 5-day reduction in hospital LOS Reduction in costs: $16,103 vs. $21,985 Schorr AF, Micek ST, Jackson WL, Kollef MH – CCM 2007;35: Implications of SSC Implementation

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