Sepsis Purvin Shah, DO, MS, FCCP, MBA 5/15/2014 15th Annual CV & Medicine Symposium Outline 1. Introduction 2. Definitions 3. Epidemiology 4. Pathophysiology 5. Evaluation & Management 6. Prognosis 7. Conclusion Introduction Why do we care so much about sepsis? • Sepsis and its advanced forms (severe sepsis and septic shock): • • • • Are major healthcare problems Affect millions of people around the world each year Kill 1 in 4 patients (and often more) Are increasing in incidence • Just like MI and Stroke, the outcome of patients with sepsis is highly dependent on the speed and appropriateness of therapy in the initial hours after sepsis develops. Introduction • As a non-ICU physician, how do YOU play a role in caring for patients with sepsis? • Surviving Sepsis Campaign (SSC) Guidelines: “…the committee believes that the greatest outcome improvement can be made through education and process change for those caring for severe sepsis patients in the non-ICU setting and across the spectrum of acute care.” Critical Care Medicine, Feb. 2013, Vol. 41, No. 2, pp 577-637 Surviving Sepsis Campaign (SSC) Guidelines • 2004 – Initial SSC guidelines were published in 2004 and incorporated evidence available through the end of 2003 • 2008 – Updated SSC guidelines in 2008 based on evidence available through the end of 2007 • 2012 – Revised SSC guidelines based on literature through Fall 2012 • Quality of evidence = high (A) to very low (D) • Strength of recommendations = strong (1) or weak (2) Definitions • Spectrum of severity of illness: Sepsis/SIRS  Severe Sepsis  Septic ShockMODS • 1991 – initially defined by ACCP and SCCM • 2001 – reconsidered by ACCP, SCCM, ATS, ESICM, SIS (Surg. Inf. Soc.) • 2012 – SCCM and ESICM (European Society of Inten. Care Medicine) Definitions • Infection – presence of bacteria in a normally sterile tissue • Bacteremia – presence of bacteria in blood • Sepsis – complicates severe infection  • SIRS – complicates a non-infectious insult  • Severe Sepsis – hypoperfusion or organ dysfunction • Septic Shock – sepsis-induced hypotension despite fluids • MODS – Multiple Organ Dysfunction Syndrome Definitions • Sepsis • Problem with regulating the body’s inflammatory response to an infection • Characterized by the cardinal signs of inflammation in tissues remote from the infection: • Vasodilation • Leukocyte accumulation • Increased microvascular permeability • SIRS – Systemic Inflammatory Response Syndrome • Identical to Sepsis BUT complicates a non-infectious insult: • Pancreatitis, Surgery, Burns, Autoimmune D/O, Trauma, Thromboembolism, etc. • Massive and uncontrolled release of pro-inflammatory mediators leads to widespread tissue injury and possibly MODS (high mortality) Definitions • Diagnostic Criteria for Sepsis = probable or documented infection PLUS some systemic manifestations of infection: • General: • • • • Temp. >38.3 C or <36 C HR > 90/min. or >2 std. dev. above normal value for age Resp. Rate > 20/min. Altered mental status • Inflammatory variables: • WBC > 20K or < 4K • Normal WBC with >10% immature forms (e.g. Bands) • Plasma Procalcitonin more than 2 std. dev. above normal value Definitions • Diagnostic Criteria for Sepsis (continued): • Hemodynamic variables: • • • • SBP < 90 mmHg MAP < 70 mmHg SBP decrease > 40 mmHg, or SBP < 2 std. dev. Below normal for age • Organ Dysfunction variables: • • • • Hypoxemia (PaO2 / FiO2 < 300) Oliguria (urine output < 0.5 mL/kg/hr for >2 hrs. despite fluids) Platelets < 100K Plasma total bilirubin > 4 mg/dL Definitions • Diagnostic Criteria for Severe Sepsis = sepsis-induced tissue hypoperfusion (low BP, high lactate or oliguria) or organ dysfunction (any of the following thought to be due to the infection): • • • • • • • • Sepsis-induced hypotension Lactate > ULN (upper limits of normal) U.O. < 0.5 mL/kg/hr. for >2 hrs. despite adequate fluid resuscitation Acute lung injury (PaO2/FiO2<250) w/o pneumonia as infection source Acute lung injury (PaO2/FiO2<200) with pneumonia as infection source Creatinine > 2 mg/dL Platelet count < 100 K Coagulopathy: INR > 1.5 Definitions • Septic Shock: sepsis-induced hypotension that persists despite adequate fluid resuscitation (30 mL/kg of crystalloids – some of this may be albumin) • MODS: progressive organ dysfunction • The severe end of the illness spectrum • Primary MODS – organ dysfunction occurs early and directly from the insult (e.g. renal failure due to rhabdomyolysis) • Secondary MODS – organ failure is NOT due to the insult itself but rather is a consequence of host response (e.g. ARDS in patients with pancreatitis) • Includes: PaO2/FiO2 ratio, Platelet count, Bilirubin, Creatinine, Low BP, GCS Epidemiology • Incidence: More than 1,665,000 cases diagnosed in the U.S. annually. • An analysis reported increased rates from 13 to 78 cases per 100,000 between 1998 and 2009. • Greatest in African-American males, during winter and patients > 65 yrs of age. Epidemiology • Pathogens: Gram-positive bacteria more than Gram-negative. Also, fungal sepsis has increased over the past decade. • Disease Severity: Increase in disease severity is noted – e.g., severe sepsis increased from 26% to 44% over a 10-year period. Most common organ dysfunctions: ARDS, AKI, DIC. • Mortality: High mortality rate (12 to 50%). Increases stepwise: SIRS = 7%, Sepsis = 16%, Severe Sepsis = 20%, Septic Shock = 46% Mortality remains elevated at one-year among survivors of sepsis. Risk Factors for Sepsis • Bacteremia (study of 270 blood cultures: 95% of positive blood cultures were associated with sepsis, severe sepsis, or septic shock) • Advanced age (>65 yrs) – age is an independent predictor of mortality • Immunosuppression – neoplasm, renal failure, hepatic failure, AIDS, asplenism or immunosuppressant medications • Diabetes • Community-acquired pneumonia (CAP): severe sepsis develops in 48% of patients with CAP Pathophysiology • Normal Response to Infection: - Host immune cells (esp. macrophages) recognize and bind to microbial components - Activates an inflammatory response (release of proinflammatory cytokines TNF / IL-1, chemokines, NO, etc.) - Polymorphonuclear leukocytes (PMN) become activated, migrate to injury site, release mediators causing inflammation (edema, erythema, warmth) and tissue repair & healing. Pathophysiology • Transition to Sepsis: - the normal inflammatory response becomes uncontrolled and generalized because a large quantity of proinflammatory cytokines are released - Complement cascade gets activated - Bacterial cell wall components and bacterial products may enhance progression to sepsis Pathophysiology • Systemic effects: - widespread cellular injury derangements in metabolic auto-regulation imbalances in coagulation and fibrinolytic systems mitochondrial dysfunction delayed apoptosis of activated macrophages and neutrophils Pathophysiology • Organ-specific effects: - Hypotension (from diffuse vasodilation), myocardial depression Pulmonary edema, V/Q mismatch, hypoxemia Translocation of bacteria and endotoxin in the GI tract Liver dysfunction Acute renal failure Encephalopathy Evaluation & Management • Early Management: First, stabilize airway & breathing – supplemental O2, monitor pulse ox, may need to intubate and place on mechanical ventilation. Check PCXR and ABG. Then, assess & restore perfusion – if low BP, then insert A-line catheter for accurate BP. EXAM: HR>90/min, obtundation / restless, oliguria / anuria, cool vasoconstricted skin. LABS: lactate > 4mmol/L Insert central venous catheter for infusion of meds & fluids / blood draws / measuring CVP and central venous O2 sat. (ScvO2). Evaluation & Management • Goals of initial resuscitation: (SSC Guidelines) within 1st 6 hours based on an EGDT trial of 263 patients (and a meta-analysis) with targeting of specific goals resulted in lower mortality (31% vs. 47%): - ScvO2 > 70% - CVP = 8-12 mmHg - MAP > 65 mmHg - U.O. > 0.5 mL/kg/hour Rivers E et al. “Early Goal-Directed Therapy in the treatment of severe sepsis and septic shock”; NEJM 2001; 345: 1368-1377 Evaluation & Management • Lactate clearance – targeting a lactate clearance of >10% (versus targeting ScvO2 > 70%) gives same mortality benefit, hospital LOS, ventilator-free days, or incidence of multi-organ failure. • Recommend targeting normalization of lactate level if initially elevated. • Other targets (besides ScvO2, CVP, MAP, U.O.) – radial pulse pressure, aortic blood flow peak velocity, brachial artery blood flow velocity, passive leg raising, etc. can be used to guide fluid resuscitation. Evaluation & Management • Screening – recommend routine screening for Sepsis in potentially infected seriously ill patients (so treatment can be started early) • Diagnosis – 2 sets of blood cultures BEFORE Abx Tx is started (as long as there is no significant delay >45 min. in starting Abx). • • • • • • - blood cultures (peripheral and through each vascular access device) - sputum cultures - urine cultures - wound cultures - rapid influenza antigen testing (during the flu season) - appropriate imaging studies (to identify abscess for I&D, etc.) Evaluation & Management • Antibiotics – administer effective IV Abx within the 1st hour of recognizing septic shock and severe sepsis. • Each hour delay is associated with increase in mortality • Initial empiric Abx Tx should have activity against all likely pathogens (bacterial, viral, fungal) and penetrate in adequate concentrations into the tissues that are thought to be infected. • • • • Hospitalized patients – Gram-positives are most common, then Gram-negatives Neutropenic patients – wide range of potential pathogens, esp. Gram-negatives Avoid recently used anti-infective agents Add fluconazole or an echinocandin if candidemia is a concern • (e.g., neutropenia, immunosuppressed, prior broad-spectrum abx tx, etc.) Evaluation & Management • Antibiotics – • Studies have shown combination therapy produces better clinical outcomes in severely ill, septic patients with a high risk of death. • Duration = 7-10 days based on clinical judgment • Longer if: • • • • slow clinical response undrainable focus of infection bacteremia with S. aureus some fungal and viral infections • Re-assess patients daily for de-escalation of abx tx once pathogen is known. • Start anti-viral tx early if a viral infection is suspected (e.g., influenza). Evaluation & Management • Source Control – • Look for specific anatomical diagnosis of infection and intervene w/in 12 hrs. • Necrotizing soft tissue infection  debridement • Abscess  drainage • peritonitis, cholangitis, intestinal infarction  surgical intervention • Use the intervention with the least physiologic insult • e.g. percutaneous rather than surgical drainage of an abscess • Remove any potentially infected intravascular access devices Evaluation & Management • IV Fluids – rapid, large volumes are indicated (e.g., 5 liters in 6 hours) unless CHF is present. Repeat IV fluid boluses until: - BP is acceptable - tissue perfusion is acceptable - CHF develops - perfusion fails to improve with IV fluids • Crystalloids – initial fluid of choice (e.g., NS, LR) = 30 mL/kg bolus • Albumin (more costly) – should be used if amount of crystalloids will be too much. • DO NOT USE hydroxyethyl starch (Hespan) b/c of increased mortality (51% vs. 43%). SAFE trial, 6S trial, VISEP trial Evaluation & Management • Vasopressors – used in patients that remain hypotensive despite adequate fluid resuscitation (or that develop pulmonary edema from IV fluids). • • • • • Target – MAP > 65 mmHg Norepinephrine is preferred 1st choice (more potent, more effective for BP) Epinephrine – 2nd choice Vasopressin – can also be added at low-dose Dopamine – only for highly selected pts (low risk of arrhythmias, low EF) • Do NOT use low-dose dopamine for renal protection  does not work. • Phenylephrine – use if norepinephrine causes arrhythmias, high CO with low BP or add as combination therapy to other vasopressor/inotrope drugs Evaluation & Management • Inotropic Therapy – • Dobutamine – • Upto 20 mcg/kg/min added to vasopressors • Use if: • Persistent Hypoperfusion • ScvO2 remains < 70% (despite adequate intravascular volume and adequate MAP) • Myocardial Dysfunction (low CO) is present • Recommend against using it to increase cardiac index to a predetermined supranormal levels – no benefit shown with this strategy Evaluation & Management • Corticosteroids – • Use only if BP is still low despite adequate fluid resuscitation and vasopressor therapy • Dose of 200 mg / day in divided doses (e.g., 100 mg Hydrocortisone Q12 hrs) • Do not use the ACTH stimulation test to identity pts to give steroids • Random cortisol levels have not been demonstrated to be useful. • Taper steroids when pt is off vasopressors • No recommendation for optimal duration • No difference in outcome was noted in 3 vs. 7 days of treatment • Do not use as “preventive” therapy if shock is not present Evaluation & Management • Packed Red Blood Cell (PRBC) Transfusions – • Give PRBCs when Hb < 7.0 g/dL • If no MI, ischemic CAD, severe hypoxemia or acute hemorrhage • Optimal Hb level is not known but Hb b/t 7-9 vs. 10-12 g/dL was NOT associated with increased mortality in critically ill pts. • Do not use erythropoietin as a tx of anemia in severe sepsis • No specific info. is available regarding its use in septic pts. • Fresh Frozen Plasma (FFP) – • Do not use to correct clotting abnormalities unless bleeding is present or invasive procedures are planned Evaluation & Management • Platelets – • Sepsis is thought to be associated with • Limitation of platelet production • Increased platelet consumption • Transfuse when: • Plts < 10K if no bleeding is present • Plts < 20K if pt has a significant risk of bleeding • Higher platelet levels (> 50K) are advised if: • Active bleeding • Surgery • Invasive procedures Evaluation & Management • Recombinant Activated Protein C (rhAPC, Xigris) – • Approved in 2001 after PROWESS trial showed a significant reduction in mortality (24.7% vs. 30.8% with placebo) • Shown to be ineffective in later studies (e.g., PROWESS SHOCK trial in 2011) so the drug was withdrawn from the market by Eli Lilly. Evaluation & Management • Glucose Control – • Recommend a protocolized approach to be used when 2 consecutive blood glucose levels are > 180 mg/dL. • Target blood glucose level < 180 mg/dL. • Monitor blood glucose levels every 1-2 hours. • Other – • DVT / PUD Px, Enteral feedings, vent. support Surviving Sepsis Campaign Bundles • Within 3 hours: • Measure lactate level (to assess perfusion) • Obtain blood cultures before giving antibiotics • Administer broad-spectrum antibiotics • Administer 30 mL/kg crystalloid if: • Hypotension • Lactate > 4 mmol/L Surviving Sepsis Campaign Bundles • Within 6 hours: • Start vasopressors if hypotension persists despite initial fluid resuscitation • Maintain MAP > 65 mmHg • If hypotension persists despite volume resuscitation OR initial lactate > 4 mmol/L, then: • Measure CVP (central venous pressure) – target CVP > 8 mmHg • Measure ScvO2 – target ScvO2 > 70% • Remeasure lactate if initial lactate was elevated • Target lactate – normal value (< 2.2 mmol/L) ProCESS Trial • Protocolized Care for Early Septic Shock – 31 hospitals in the U.S. • 1341 patients in 3 groups: protocol-based EGDT (439 pts), protocol-based standard therapy (446 pts), or usual care (456 pts) • Results: 60-day mortality rates were similar (21.0%, 18.2%, 18.9%). No significant differences in 90-day or 1-year mortality. • SSC Response: usual care mortality (18.9%) is already low (b/c of overall improvement in our care of these sick pts – 70% of hospitals use a “sepsis protocol”) vs. 46.5% in 2001 EGDT trial. Also, this study does not address pts with severe sepsis without septic shock – aggressive mgt of these pts has likely lowered mortality rates. “A Randomized Trial of Protocol-Based Care for Early Septic Shock”. NEJM May 1, 2014, Vol. 370, No.18, pp. 1683-1693 Other Recent Trials • High vs. Low Blood-Pressure Target in Patients with Septic Shock (NEJM 4/24/14, vol. 370, no. 17, pp. 1583-1593) – 776 pts • No significant difference in mortality (28-day or 90-day) with MAP of 65-70 mmHg vs. 80-85 mmHg • Albumin Replacement in Patients with Severe Sepsis or Septic Shock (NEJM 4/10/14, vol. 370, no. 15, pp. 1412-1421) – 1818 pts • Use of Albumin in addition to crystalloids did not improve survival at 28 and 90 days. Prognostic Factors • Host Response – Leukopenia or Failure to develop a fever = poor prognosis • Co-Morbidities – new-onset a. fib., age > 40 yrs, AIDS, liver disease, cancer, EtOH abuse, immunosuppression = poor prognosis • Site of infection – UTI = lowest mortality rate BUT GI or pulmonary source = higher mortality • Type of infection – nosocomial infection = higher mortality (compared to community-acquired pathogens) • Abx Tx – Appropriate Abx Tx = lower mortality. BUT, prior Abx Tx = higher mortality • Failure to restore perfusion early = higher mortality Conclusion • Sepsis – • • • • Is a major healthcare problem with an increasing incidence and a high mortality rate affecting millions of people around the world every year. • Its outcome depends on the speed and appropriateness of therapy early after recognizing its presence. • There are evidence-based guidelines published to guide its management with updates every 4 years.