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The Treatment of Sepsis: Early Goal Directed Therapy and Beyond Anthony J. Hericks, D.O. South Dakota ACP Scientific Meeting September 13 th, 2013.

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Presentation on theme: "The Treatment of Sepsis: Early Goal Directed Therapy and Beyond Anthony J. Hericks, D.O. South Dakota ACP Scientific Meeting September 13 th, 2013."— Presentation transcript:

1 The Treatment of Sepsis: Early Goal Directed Therapy and Beyond Anthony J. Hericks, D.O. South Dakota ACP Scientific Meeting September 13 th, 2013

2 A clinician, armed with the sepsis bundles, attacks the three heads of severe sepsis: hypotension, hypoperfusion and organ dysfunction. Crit Care Med 2004; 320(Suppl):S595-S597

3 Surviving Sepsis Campaign Sponsoring Organizations American Association of Critical-Care Nurses American College of Chest Physicians American College of Emergency Physicians Australian and New Zealand Intensive Care Society Asia Pacific Association of Critical Care Medicine American Thoracic Society Brazilian Society of Critical Care(AIMB) Canadian Critical Care Society Emirates Intensive Care Society European Respiratory Society European Society of Clinical Microbiology and Infectious Diseases European Society of Intensive Care Medicine European Society of Pediatric and Neonatal Intensive Care Infectious Diseases Society of America Indian Society of Critical Care Medicine Japanese Association for Acute Medicine Japanese Society of Intensive Care Medicine Latin American Sepsis Institute Pan Arab Critical Care Medicine Society Pediatric Acute Lung Injury and Sepsis Investigators Society for Academic Emergency Medicine Society of Critical Care Medicine Society of Hospital Medicine Surgical Infection Society World Federation of Critical Care Nurses World Federation of Societies of Intensive and Critical Care Medicine German Sepsis Society

4 Surviving Sepsis Campaign (SSC) Guidelines for Management of Severe Sepsis and Septic Shock Dellinger RP, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004, 32: Dellinger RP, et al. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008 Crit Care Med 2008, 36: Levy MM, et al. Surviving Sepsis Campaign: Results of an international guidelines performance improvement program targeting severe sepsis. Crit Care Med 2010, 38: Dellinger RP, et al. Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: Crit Care Med 2013, 41(2): Angus DC, et al. Severe Sepsis and Septic Shock. NEJM 2013; 369(9):

5 Surviving Sepsis Campaign Conclusions Strong agreement among a large cohort of international experts Many level 1 recommendations Significant number of recommendations with relatively weak recommendations Evidence-based recommendations are the foundation of improved outcomes Dellinger RP, CCM 2013

6 Grading of Recommendations (Grading of Recommendations Assessment, Develop and Evaluation – GRADE)

7

8 A 82 year old white female present to the emergency department with complaints of dysuria, frequency and urgency. Her temperature is F, HR 92, RR 21 and BP 122/86. What should she be classified as? 1. Systemic Inflammatory Response Syndrome 2. Sepsis 3. Severe Sepsis 4. Septic Shock 5. Multi-Organ Dysfunction/Failure Syndrome

9 A 82 year old white female present to the emergency department with complaints of dysuria, frequency and urgency. Her temperature is F, HR 92, RR 21 and BP 122/86. What should she be classified as? 1. Systemic Inflammatory Response Syndrome 2. Sepsis 3. Severe Sepsis 4. Septic Shock 5. Multi-Organ Dysfunction/Failure Syndrome

10 Identification of Sepsis: Definitions Systemic Inflammatory Response (SIRS) Sepsis Severe Sepsis Septic Shock Multi-Organ Failure Syndrome (MOFS) Death

11 SIRS Heart Rate > 90 Respiratory Rate > 20 WBC > 12K or 12K or < 4K Temp > 38 C (100.4 F) or 38 C (100.4 F) or < 36 C (96.8 F)  Any two of the above  Very nonspecific

12 Sepsis SIRS + signs of a suspected or known infection –WBC’s in normally sterile fluid –Infiltrate on chest x-ray –Bacteria in normally sterile fluid

13 Diagnostic Criteria for Sepsis

14 Severe Sepsis Sepsis + sepsis-induced tissue hypoperfusion or organ dysfunction

15 Sepsis Induced Hypotension SBP < 90 mmHg OR MAP < 70 mmHg OR SBP > 40 mmHg 40 mmHg < 2 SD below the nml for age

16 Septic Shock Severe Sepsis or sepsis-induced hypoperfusion persistent despite: –Adequate/initial fluid challenge/resuscitation –Lactate > 4 mmol –Addition of pressors  Sepsis-induced hypoperfusion = infection- induced hypotension, elevated lactate or oliguria

17 MOFS Altered organ function, involving two or more organs, in an acutely ill patient requiring medical intervention to achieve homeostasis

18 Death The permanent the cessation of all vital functions in an individual who has sustained either (1) irreversible cessation of circulatory and respiratory functions, or (2) irreversible cessation of all functions of the entire brain, including the brain stem Severe Sepsis/Septic Shock mortality = ~30-46%

19 Consideration for Limitation of Support “We recommend that the goals of care and prognosis be discussed with patients and families and these be incorporated into the patients treatment along with end-of-life care planning and utilizing palliative care principles.” –Re-address goals as earlier as feasible, but no later than 72 hours of admit Grade 1B Grade 2C

20 Incidence of Severe Sepsis Estimated to be: – 2% of all patients admitted to the hospital –10% of all patients in the ICU –< 750,000 cases per year and rising –Mortality rate of 20-30% NEJM 369(9):

21 Pathophysiology of Sepsis

22 Based on Dr. Rivers article re: Early Goal Directed Therapy, what is the ultimate goal in the first 6 hours? 1. CVP of 8-12 unventilated/12-15 ventilated 2. MAP >65 3. Cardiac Output > 8 LPM 4. Hemoglobin > 10 gm/dL 5. ScvO2 > 70%

23 Based on Dr. Rivers article re: Early Goal Directed Therapy, what is the ultimate goal in the first 6 hours? 1. CVP of 8-12 unventilated/12-15 ventilated 2. MAP >65 3. Cardiac Output > 8 LPM 4. Hemoglobin > 10 gm/dL 5. ScvO2 > 70%

24 Initial Resuscitation: Goals of Early Goal Directed Therapy CVP 8-12 cmH 2 O –12-15 cmH 2 O on the ventilator MAP > 65 mmHg –May need to be higher in patients with HTN UOP > 0.5 mL/Kg /hour ScvO 2 > 70% –SvO 2 > 65% Goal: Normalize lactate  Goal in the first 6 hours after diagnosis  16-17% decrease in mortality Rivers E. N Engl J Med 2001; 345: Grade 1C Grade 2C

25 Central Venous Pressure Crystalloid or Colloid? Volume?Goal?

26 Crystalloid or Colloid SAFE Study –Crystalloid (NS) = Colloid (4% Albumin) Less volume, more PRBC’s, higher CVP and Albumin –No difference in mortality (p = 0.87) Trend for increased risk of death in Trauma (0.06) Trend for decreased risk of death in Severe Sepsis (0.09) Finfer S. N Engl J Med 2004; 350:2247–2256Grade 1B

27 SSC Recommendations CrystalloidsAlbumin –If substantial fluid is required Grade 1B Grade 2C

28 Hydroxyethyl Starch (HES) Increased risk of acute kidney injury and death in sepsis –Variable findings depending on studies Schortgen G. Lancet 2001; 357: Sakr Y. Br J Anaesth 2007; 98: Brunkhorst FM. N Engl J Med 2008; 358: Perner A. N Engl J Med 2012; 367: Risk and no benefit, HES should not be used!!! Grade 1B

29 Fluid Volume 30 mL/Kg crystalloid –A portion may be an albumin equivalent –More rapid administration or larger amounts may be needed Continue fluid administration as long as there appears to be hemodynamic improvement Grade 1C Grade UG

30 Volume Responsiveness CVP > 8 cmH 2 O –> 12 cmH 2 O on the vent Swan-Ganz Catheter –PCWP –Cardiac output Non-invasive Monitors –PiCCO Catheter –FloTrac –Pulse Pressure Variation IVC via Echo MAP and Heart Rate Grade 1D Grade 1C

31 CVP Spontaneous Breathing > 8 cmH 2 O Ventilatory Breathing > 12 cmH 2 O  Primarily based on expert opinion –Dellinger RP. Crit Care Med 2004; 32:858–873 –Rivers E. N Engl J Med 2001; 345:1368–1377 –Practice parameters for hemodynamic support of sepsis in adult patients with sepsis. Crit Care Med 1999; 27:639–660

32 Pulmonary Capillary Wedge Pressure PCWP < 12 mmHg predicts a fluid bolus with increase cardiac output with a PPV of only 54% However the “Gold Standard” for “volume responsiveness” may be a increase in cardiac output of > 15% after a fluid challenge Osman D. Crit Care Med 2007; 35:64–68

33 Non-invasive Monitoring

34 PPV CVP PCWP PPV

35 Echocardiography

36 Does volume overload contribute to morbidity and mortality? 1. True 2. False

37 Does volume overload contribute to morbidity and mortality? 1. True 2. False

38 Avoid Volume Overload Tolerated as long as volume responsive –Fluid challenges usually required for the initial hours Finfer S. N Engl J Med 2004; 350:2247–2256 Decrease the rate when no longer volume responsive Grade 1D

39 Volume Overload, Cont’d Independent predictor of mortality –Boyd JH. Crit Care Med 2011; 39(2): –Vincent JL. Crit Care Med 2006; 34:344–353 –Uchino S. Crit Care Med 2006; 10:R174 Prolonged mechanical ventilation –Upadya A. Intensive Care Med 2005; 31:1643–1647 ARDS –Humphrey H. Chest 1990; 97:1176–1180 –Simmons RS. Am Rev Respir Dis 1987; 135:924–929 –Mitchell JP. Am Rev Respir Dis 1992; 145:990–998 –Wiedemann HP. N Engl J Med 2006; 354:2564–2575 Sepsis –Alsous F. Chest 2000; 117:1749–1754 –Rivers E. N Engl J Med 2001; 345:1368–1377 Abdominal compartment syndrome –Malbrain ML. Crit Care Med 2005; 33:315–322 –McNelis J. Arch Surg 2002;137:133–136 Cerebral edema and herniation –Uchino S. Crit Care 2006; 10:R174

40 MAP Grade 1C

41 What is the pressor of choice for a patient in septic shock? 1. Dopamine 2. Norepinephrine (Levophed) 3. Vasopressin 4. Phenylephrine (Neosynephrine) 5. All the above

42 What is the pressor of choice for a patient in septic shock? 1. Dopamine 2. Norepinephrine (Levophed) 3. Vasopressin 4. Phenylephrine (Neosynephrine) 5. All the above

43 Vasopressors NorepinephrineDopamineVasopressinEpinephrinePhenylephrine

44 Norepinephrine vs Dopamine No significant difference in mortality (p = 0.10) –Trend for less death in the ICU (p = 0.07) –No difference at hospital discharge or 1 yr Increased rate of adverse events with Dopamine –Arrhythmias (p = < 0.001) Atrial Fibrillation Ventricular Tachycardia Ventricular Fibrillation –Skin Ischemia (trend; p = 0.09) DeBacker D. N Engl J Med 2010; 362:

45 Norepinephrine vs Dopamine, Cont’d Norepinephrine should be the first line vasopressor Dopamine is an alternative to Norepinephrine –Only in highly selected patients with low risk of: Tachyarrhythmias Absolute or relative bradycardia Grade 1B Grade 2C

46 Vasopressin Adding Vasopressin to Norepinephrine showed no mortality benefit compared to Norepinephrine alone (p = 0.26) –Did lower Norepinephrine requirements –May have other potential physiologic benefits  Should not be used as a single agent Russel JA. N Engl J Med 2008; 358: Grade UG

47 Epinephrine First line in pts poorly responsive to Norepinephrine and Dopamine –No evidence of worse outcomes Increased risk of: –Tachycardia –Elevated lactate –Decreased splanchnic circulation Add to or instead of Norepinephrine Grade 2B

48 Phenylephrine Not recommended!!! –Except: Norepinephrine induced arrhythmias Cardiac output is high Persistently low BP Salvage therapy Decreases cardiac output Grade 1C

49 Hemodynamic Equations DaO 2 = CO x Hgb x SaO 2 –Oxygen delivery VO 2 = CO x Hgb x (SaO 2 - SvO 2 ) –Oxygen consumption O 2 ER= VO 2 /DaO 2 –Oxygen extraction ratio ~ 0.2 to 0.3  VO 2 > DaO 2 OR DaO 2 DaO 2 OR DaO 2 < VO 2 = Dysoxia –Dysoxia = lactic acidosis = organ failure = death

50 Venous Oxygen Saturation Physiology Adapted from:

51 ScvO 2 /SvO 2 Goal > 70%/65% respectively –Normal or shunt physiology < 70%/65% respectively –Transfuse to a Hgb > 10 OR –Start Dobutamine No specific cardiac output/index Grade 1C ScvO 2 = subclavian vein SvO 2 = pulmonary artery

52 Ionotropic Therapy Dobutamine: –Max dose 20 mcg/Kg/min Titrate to NO pre-defined CO –Used in states with: Elevated cardiac filling pressures Low cardiac output ScvO 2 < 70% OR SvO 2 < 65% Grade 1B Grade 1C

53 RBC Transfusion Therapy Only if the Hgb < 10 with EGDT Only if the Hgb < 7.0 g/dL in other ICU patients –Target 7 to 9 g/dL –Consider earlier for myocardial ischemia/ischemic coronary disease, severe hypoxemia, acute hemorrhage, cyanotic heart disease or lactic acidosis No EPO Grade 1B Napolitano LM. Crit Care Med 2009; 37(12): Grade 1B

54 FFP Transfusion Therapy No FFP to reverse coagulopathy in the absence of bleeding or invasive procedures No high-dose Antithrombin –Studies had revealed that a subgroup with severe sepsis and high risk of death = better survival Grade 2D Grade 1B

55 Platelet Transfusion Therapy < 10,000 – prophylactically in absence of bleeding < 20,000 - significant risk of bleeding > 50,000 – active bleeding, surgery or invasive procedures Grade 2D

56 Other Investigation Therapy Immunoglobulins –No use Selenium –Antioxidant –No use Grade 2B Grade 2C

57 Diagnostic Testing Lactate level –Within 3 hours Cultures –Prior to antibiotic administration Do not delay resuscitation for antibiotic administration > 50% of cases of severe sepsis and septic shock will be culture negative –Minimum 2 blood cultures One peripheral and one from each vascular access device Imaging –If not too unstable Grade 1C Grade 1D

58 Diagnostic Testing, Cont’d Serologies: –Strep pneumo and Legionella Urine Ag –Mycoplasma IgM –1,3 B-D-glucan –Mannan and anti-mannan Ab’s Procalcitonin –Use low levels to assist with Abx D/C Grade 2B Grade 2C

59 Antibiotic Therapy IV route within the 1 st hour –Septic Shock –Severe Sepsis One or more drugs with activity against the likely pathogens –Double cover if MDR pathogens –Combo therapy for neutropenic fever –Beta-lactam and macrolide for Strep pneumonia Grade 1B Grade 1C Grade 1B Grade 2B

60 ABX, Cont’d Reassess routinely De-escalate after >3-5 days Duration of treatment ~7-10 days Stop therapy if the syndrome is not infectious Grade 1B Grade 2B Grade 2C Grade 1D

61 Source Control Seek, diagnose or exclude potential anatomical infections and treat expectantly –Within the first 12 hrs Delay definitive treatment of peripancreatic necrosis until demarcation of tissue has occurred Attempt percutaneous over surgical intervention if possible Remove vascular access suspected after other access has been placed Grade 1C Grade 2B Grade UG

62 Corticosteroids Hydrocortisone –200 mg/day –Only with persistent hypotension/poorly responsive to vasopressor therapy –Consider a continuous infusion –Do not do an ACTH stimulation test No Dexamethasone Fludrocortisone if other steroid than HCT Wean steroids when off pressors Grade 2B Grade 2C Grade 2B Grade 2C Grade 2D

63 Corticosteroids, Cont’d Annane D. JAMA 2002; 288:862–871 –Cosyntropin Stim Test delta < 9 = non-responders –10% decrease in mortality if treated with steroids –17% decrease in pressor requirements Sprung CL. N Engl J Med 2008; 358: –No significant difference in mortality –Shock was reversed more quickly –More episodes of superinfection, including new sepsis and septic shock but not statistically significant

64 CIRCI ( Critical Illness Related Corticosteroid Insufficiency) Marik PE. Crit Care Med 2008 Vol. 36 (6):

65 CIRCI, Cont’d

66 Recombinant Human Activated Protein C (Xigris) Withdrawn from the market 2011 –No benefit

67 Mechanical Ventilation Target tidal volume = 6 mL/Kg Plateau pressure goal < 30 cmH 2 O Allow permissive hypercapnia Use PEEP to decrease FiO 2 –Higher PEEP vs lower Recruitment maneuvers Grade 1A Grade 1C Grade 1B Grade 2C

68 ARDS ARMA Trial –The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000;342: Alveoli Trial –Brower RG. N Engl J Med 2004;351:327-36

69

70

71 Mechanical Ventilation, Cont’d Consider prone positioning –P:F ration <100 HOB elevated –Goal > NIPPV considered in mild ALI/ARDS –Low threshold for intubation Grade 1B Grade 2B Grade 2C

72 Mechanical Ventilation, Cont’d Weaning protocols Selective Oral/Digestive Decontamination –Oral chlorhexidine gluconate –Decreases VAP Avoid pulmonary artery catheters Conservative fluid management (FACTT) –Wiedemann et al. N Engl J Med 2006; 354: Grade 1A Grade 1C Grade 2B

73 Beta-Agonists No recommended for routine use –Nebulized (Ok if concern for bronchospasm) Trend for less vent days Slightly faster heart rates at day #2 Trend for increased mortality –Intravenous (Salbutamol) Increased mortality Grade 1B

74 Sedation, Analgesia and NMB Use Sedation protocol –Minimize intermittent and continuous treatments Use Sedation scales Avoid NMB –Without ARDS –With ARDS (Sepsis-induced and P:F <150) < 48 hours Grade 1B Grade 1C Grade 2C

75 Glucose Control Use intravenous insulin to control blood sugars –If 2 consecutive BS’s > 180 Goal < 180 –? Target range mg/dL  Avoid hypoglycemia Grade 1B Grade ? 1A Grade 2C

76 Renal Replacement Therapy CRRT and Intermittent HD are equivalents CRRT should be used if hemodynamically unstable Grade 2B Grade 2D

77 Bicarbonate Therapy Avoid NaHCO 3 in patients with a pH > 7.15 and lactic acidemia for the purpose of improving hemodynamics or to reduce vasopressor requirements Grade 2B

78 Thromboembolism Prophylaxis LMWH daily vs Low dose UFH BID LMWH daily vs Low dose UFH TID Dalteparin if creat clearance < 30 mL/min –LMWH or UFH Mechanical prophylaxis if contraindications to heparin products Combo therapy in patients who are high risk –Severe sepsis, history of DVT, or orthopedic surgery Grade 1B Grade 2C Grade 1A Grade 2CGrade 1A

79 Stress Ulcer Prophylaxis If risk of bleeding –H2 blocker –Proton Pump Inhibitor –PPI over H2 No risk of bleeding = no PPI Grade 1B Grade 2C Grade 2B

80 Nutrition Oral or enteral nutrition in the 1 st 48 hrs vs complete fasting or just glucose Avoid full caloric feeding for the 1 st full week –Low dose feeding up to 500 Kcal/day and advance as tolerated (60-70%) IV glucose and EN vs TPN alone or TPN and EN in the 1 st week No specific immunomodulating form Grade 2C Grade 2B Grade 2C

81 Surviving Sepsis Bundles

82 Bundles Point/Counterpoint Editorials –Are the best patient outcomes achieved when ICU bundles are rigorously adhered to? Pros: Dr. Delinger –Not perfect/have flaws, but are based on the best available evidence. Cons: Dr. Marik –Not completely “evidence based” and “cook book” medicine can harm the patient. CHEST 2013; 144(2):

83 Is there byass/conflict of interest when it comes to the Surviving Sepsis Campaign Guidelines and Early Goal Directed Therapy? 1. Yes 2. No

84 Is there byass/conflict of interest when it comes to the Surviving Sepsis Campaign Guidelines and Early Goal Directed Therapy? 1. Yes 2. No

85 Benefits of the Surviving Sepsis Campaign Surviving Sepsis Campaign Improvement Program –Resuscitation Bundle - First 6 hours Compliance increase linearly from 10.9% to 31.3% over two years ( p = ) –Management Bundle - First 24 hours Compliance increase linearly from 18.4% to 36.1% over two years ( p = 0.008) –Unadjusted odds ratio for hospital mortality decreased from 37% to 30.8% over two years (p = 0.001)

86 THE END ?? QUESTIONS ??


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