1. Surviving Sepsis CLS Alaska April 6, 2011 Session 8
John J. Ancy, MA, RRT
Senior Clinical Consultant
Instrumentation Laboratory

2. Surviving Sepsis Sepsis, as many deaths as from MI
How to improve survival?
Rapid accurate diagnosis and treatment (lab tests are critical)
Appropriate antimicrobial therapy
Compliance with Sepsis Bundles

3. Surviving Sepsis Campaign
Worldwide, started in 2001
11medical organizations in 2004
Currently, 18 organizations
Goal – reduce mortality by 25%

4. Surviving Sepsis Guidelines
First guidelines – 2001
Updated – 2004, 2006 & 2007
Current guidelines – 2008
Graded recommendations
Strength of recommendations 1-2
Evidence A-D
1A – 2D
Surviving Sepsis Campaign. Crit Care Med 2008; 36: & 36:

5. Sepsis Uncontrolled inflammatory response, secondary to infection.
30 to 40% associated with bacteremia

6. Sepsis & Friends Definitions
SIRS
Sepsis
Severe Sepsis
Septic Shock
MOF (MODS)
ALI/ARDS

7. SIRS Systemic Inflammatory Response Syndrome
Systemic inflammatory state without proven source of infection

8. Sepsis Infection + systemic manifestations of infection Sepsis =
Some manifestations:
Fever or hypothermia
Elevated HR
Tachypnea
Arterial hypotension
Hypoxemia
Hyperlactatetemia

9. Sepsis Inflammatory Variables Leukocytosis WBC > 12000
Leukopenia WBC < 4000
Normal WBC with > 10% immature
Plasma C-reactive proteins >2 SD above norm
Plasma Procalcitonin > 2SD above norm

10. Early Lab Clues Glucose > 120mg/dL
Creatinine increase > 2.0 mg/dL
INR > 1.5 or aPTT > 60 sec
Thrombocytopenia <
Hyperbilirubinemia > 2 mg/dL
Lactate > 1mM/L ? (>2.0)
Balk, RA, Dis Mon Apr (4):

11. Severe Sepsis
Sepsis with acute, sepsis-induced organ dysfunction and/or tissue hypoperfusion

12. Septic Shock
Sepsis + sepsis-induced hypotension, despite adequate fluid resuscitation

13. MOF/MODS
Multiple Organ Failure or Multiple Organ Dysfunction Syndrome

14. ALI/ARDS ALI ARDS Acute Respiratory Distress Syndrome
Acute Lung Inflammation
ARDS
Acute Respiratory Distress Syndrome
SEPSIS is the most common cause of ARDS

15. ALI/ARDS Acute Lung Inflammation CXR Bilateral diffuse infiltrates
No clinical evidence of ▲left atrial pressure or ▼PCWP<18mm Hg
P/F ratio (PaO2/FiO2)
PaO2 100mmHg/ FiO2 0.5 = 200

16. ALI/ARDS Lung inflammation CXR Bilateral diffuse infiltrates
Acute Respiratory Distress Syndrome
(Sepsis most common cause)
Lung inflammation
CXR Bilateral diffuse infiltrates
No clinical evidence of ▲left atrial pressure or ▼PCWP<18mm Hg
P/F ratio <200 (PaO2/FiO2)
PaO2 100mmHg/ FiO2 0.6 = 166

17. SIRS Mortality Mortality goes up with organ failure
7% SIRS+2 failed organs
10% SIRS+3
17% SIRS+4
Rangel-Frausto, M., Pettet, D., Costigan, M., et. al. The natural history of the systemic inflammatory response syndrome (SIRS). JAMA 273: , 1995

18. Sepsis Mortality Millions affected worldwide
At minimum, 25% mortality (51% in some studies)

19. Epidemiology
“Severe sepsis is a common, expensive and frequently fatal condition, with as many deaths as those from acute myocardial infarction”
Martin, GS; Mannino, DM; Eaton, S; Moss, M. The Epidemiology of Sepsis in the United States from 1979 through N Engl J Med. 2003;348:

20. 20

21. Epidemiology 2004 Severe Sepsis 750,000 (US)
US cost $16.7 B
$22,100 per case
Mortality 25% to 51%
210,000 annual deaths (US)

22. Epidemiology Incidence increasing Morbidity/mortality decreasing
More common in winter months
Sepsis survivors have increased morbidity/mortality for 5 years
Curr Pharm Des. 2008; 14 (19):

23. Epidemiology GI Genitourinary Primary bloodstream
Gram+ most common organisms
Majority of infectious sources
Pulmonary GI
Genitourinary
Primary bloodstream

24. Risk Factors Over 65 YOA Male Bacteremia Weakened immune system
AIDS, cancer, diabetes or chronic disease
Pneumonia
Hospitalization
Severe traumatic injuries
Invasive medical devices
Genetic susceptibility
Lower socioeconomic status

25. Micro-organisms
Bacterial
Fungal
Viral
Protozoan

26. Community Acquired Microorganisms
Lung
Abdomen
Skin/Soft Tissue
Urinary Tract
CNS
Streptococcus
pneumonia
Hemophilus
influ.
Legionella sp
Chlamydia pneumonia
Escherichia coli
Bacteroides fragilisn
Streptococcus pyogenes
Staph. aureus
Clostridium sp.
Polymicrobial
Aerobic gr neg
Pseudomonas aeruginosa
Staph. sp.
Klebsiella sp.
Enterobacter sp.
Proteus sp.
Neiserria meningitidis
Listeria monocytogen

27. Nosocomial Pathogens Lung Abdomen Skin/Soft Tissue Urinary Tract CNS
Aerobic
gram negative bacilli
Aerobic gram neg bac
Anaerobes
Candida sp.
Staph. Aureus
Aerobic gram negative bacilli
Enterococcus sp.
Pseudomonas aeruginosa
Escherichia
coli
Klebsiella sp.
Staph. sp

28. Sepsis Pathophysiology
Heterogenous
No single mediator/system/pathway/pathogen
Derangements involving several organ systems
Hyperinflammatory response (commonly), suppressed inflammatory response or
mixed response

29. Sepsis Pathophysiology
Life threatening changes in coagulation
Neutrophils mixed response
Apoptosis of lymphocytes/other cells

30. Inflammatory Response
Eliminate invading microorganisms without damaging tissues or cells

31. Aberrant Inflammatory Mediator Production
“Inflammatory response an important component of sepsis as it drives physiologic responses that result in organ dysfunction.”
Remick, DG; Am J Pathol May; 170(5);

32. Hyperinflammatory Response
Numerous and plentiful proinflammatory molecules released in sepsis
Tumor Necrosing Factor (TNF), interleukins, cytokines and many others elevated
Endotoxin elevated = increased inflammatory response
Blunt inflammation and save lives?
rhAPC-recombinant human activated protein C (Dotrecogen)

33. Blunted Inflammatory Response
Studies show that some patients have inhibited proinflammatory response and unabated anti-inflammatory response.
Failure to control bacteria infection and succumb as a result of immunosuppression rather than immunostimulation.

34. Mixed Inflammatory Response
Some studies indicate pathophysiologic contributions from proinflammatory and anti-inflammatory mediators

35. Normal Hemostasis
Allows blood to remain liquid and flowing and clots to control bleeding

36. Dysregulated Coagulation
Coagulation cascade alteration
Sepsis patients often have DIC
platelet consumption
prolonged clotting time
microcirculatory clotting
profuse bleeding

37. Dysregulated Coagulation
Virchow’s Triad
Altered coagulation
Endothelial cell injury-inflammatory agents
Abnormal blood flow
Poor tissue perfusion in vital organs
Inappropriate O2 delivery/useage
Cytopathic hypoxia
Lactic acid production

38. Cellular Dysfunction
Many cellular aspects are dysfunctional in sepsis (neutrophils)
Excessive activation
Neutrophils generating excessive inflammatory product damaging nearby cells
Depressed function
Neutrophil failure to phagocytize

39. Neutrophil activity
Neutrophilic function key component of immune response:
Neutropenia = infectious complications
Overactive neutrophilic activity = hyperinflammatory response
In sepsis and other serious illness neutrophil response is very complex and heterogenous. Some patients have excessive response, others blunted activity. Either case results in less effective immune response.

40. Lymphocyte Apoptosis Very pronounced in sepsis
Observed in virtually all lymphoid organs
Spleen
Thymus
Gastric tissues
Reduces immune response effectiveness

41. Septic Apopotosis Affects many cells/tissues Dendritic cells
Macrophages
Monocytes
Mucosal epithelial cells
Endothelial cells
Others

42. Altered Metabolism Diabetes of stress (Sepsis) Insulin resistance
Hyperglycemia

43. Elevated Glucose Decreased function of polymorphonuclear neutrophils
Decreased bactericidal activity
Endothelial cell disruption

44. Glycemic Control Reduces infection/faster resolution
Improves renal function
Reduces muscle wasting
Reduces severity and incidence of anemia
Protects endothelial cells
Improved morbidity and mortality

45. Sepsis Pathophysiology
Infection triggers hyperinflammatory response or (blunted response = sepsis) Coagulation dysregulation Lymphocyte & neutorophil dysfunction Microcirculatory and perfusion failure Tissue oxygenation disruption Stress diabetes

46. Sepsis Pathophysiology
Tissue and organ failure Pulmonary and peripheral edema Cardiac output is often elevated BP difficult to maintain- extreme vasodilation Maldistribution in microcirculatory beds Higher morbidity/mortality in those with pre-existing cardiovascular disease

47. Surviving Sepsis 2008 Graded Recommendations 1.Treatment
Emergency Resuscitation (6 Hours)
Management ( Within 24 Hours)
2. Supportive Care

48. GRADE
Grade Recommendation Assessment Development Evaluation

49. GRADE Surviving Sepsis Recommendations
Numerical
1= treatment outweighs harm/burden/costs
2= treatment carries risk/burden/costs
Letter
A = well documented
B = moderate
C = low
D = very low

50. 2008 GRADE Recommendations
40 level 1
21 level 2
7 1A recommendations
DVT prophylaxis
Stress ulcer prophylaxis
Ventilator weaning protocol
Avoid routine PACs in ALI/ARDS

51. 2008 GRADE Recommendations
16 1B
Sedation weaning protocol for vent patients
Either crystal or colloid for fluid resuscitation
Blood glucose < 150 mg/dL
17 1C
Blood cultures before antibiotic therapy
Imaging confirmation for infection source
Broad spectrum antibiotics within 1hr of sepsis confirmation

52. Treatment Initial Resuscitaion Diagnosis Antibiotic Therapy
Source Control
Fluid Therapy

53. Treatment
F. Vasopressors G. Inotropic Therapy H. Corticosteroids I. Recombinant Human Activated Protein C J. Blood Product Administration

54. Supportive Care Mechanical Ventilation
Sedation, Analgesia, & Neuromuscular Blockade
Glucose Control
Renal Replacement
Bicarbonate Therapy
DVT Prophylaxis
Stress Ulcer Prophylaxis

55. Initial Resuscitation (1C)
Sepsis induced shock
Persistent hypotension with fluid admin
Lactate > 4.0 mM/L
Tx Goals
CVP 8-12mm Hg (higher if on ventilator)
MAP > 65mm Hg
Urine output > 0.5 ml/kg/hr
O2 Sat CV > 70% or Mixed Venous > 65%

56. Initial Resucitation If venous saturation is not achieved (2C)
Consider more fluid
Transfuse packed RBCs to Hct > 30% and/or dobutamine infusion
Rationale: increase O2 delivery and CO

57. Diagnosis
Cultures before antimicrobial therapy if cultures do not delay antibiotics (1C)
Obtain 2 or more Blood Cultures
Obtain 1 BC percutaneously
Obtain BC from each vascular device in place > 48hr
Culture other sites as clinically indicated (preferably quantitative)

58. Diagnosis
Rationale: Obtaining BCs peripherally and via access important If same organism, likely sepsis agent If access device organism is + 2hrs before peripheral culture, device is probable source

59. Antibiotic Therapy Antibiotic therapy within 1Hr of recognition
Septic shock (1B)
Severe sepsis without shock (1D)
Obtain appropriate cultures prior to initiating therapy, but should not prevent antimicrobial therapy (1D)
Consider premixed antibiotics, bolus admin. for some agents

60. Antibiotic Therapy
Initial empirical therapy to include one or more drugs that have activity against likely pathogens (bacterial/fungal) and penetrate into presumed source (1B)
Choices are very complex, considerations:
Hx, drug intolerances, underlying disease, susceptibility patterns of pathogens, neutropenia, etc.

61. Antibiotic Therapy Empirical continued: Severe sepsis or septic shock
Avoid recently used antibiotics
MRSA considerations
Antifungal therapy (fluconazole, ampho B, echinocandin should be tailored to local pattern of Candida and prior admin. of azoles
Severe sepsis or septic shock
Broad-spectrum therapy

62. Antibiotic Therapy Further recommendations
Duration 7-10 days, longer for slow response, undrainable foci, immunologic deficiencies
Stop therapy promptly if proven noninfectious
CAUTION: > 50% of blood cultures in severe sepsis or septic shock will be negative for bacteria or fungi

63. Antibiotic Therapy Serum antimicrobial monitoring daily (1C)
Rationale:
Septic shock/sepsis may inhibit renal and/or hepatic function
Abnormal volume distribution due to aggressive fluid therapy
Goal: adequate distribution without toxicity
Goal: Narrow spectrum and to reduce duration to minimize super-infection, but balance with effective duration

64. Vasopressors
Norepinephrine or dopamine firstline vasopressors All patients requiring vasopressors should be monitored with indwelling arterial pressure catheter (1D) Monitor adequacy of perfusion with lactate levels (maintain below 4 mM/L )and urine output

65. Vasopressors
Use vasopressors to maintain mean arterial pressure > 65mm Hg (1C)
Higher MAP for patient with previously controlled hypertension
Lower MAP adequate for young previously normotensive patient

66. Inotropic Therapy
Dobutamine infusion for myocardial dysfunction as indicated by elevated cardiac filling pressures and low CO (1C)
Septic patients often require vasopressor and inotropic therapy
Mechanically ventilated patients with sepsis are particularly at risk for cardiac decompensation.

67. Dotrecogen (Xigris®) recombinant human activated protein C rhAPC
FDA approved (some controversy)
Anti-inflammatory activity and improved hemostasis

68. Dotrecogen (Xigris®) recombinant human activated protein C rhAPC
Consider rhAPC in adults with sepsis induced organ dysfunction or high risk of death (APACHE II > 25) 2B (2C postoperative)
Septic patients with low risk ( APACHE < 20 should not receive rhAPC )1A

69. Blood Product Administration
RBC transfusion (target Hb 7-9 g/dL) once hypoperfusion, severe hypoxemia, lactic acidosis are resolved (1B)
No difference in mortality compared to
Hb 10-12g/dL

70. Blood Product Administration
Fresh frozen plasma should not be used to correct laboratory clotting abnormalities (increased PT,INR, PTT) in the absence of bleeding (2D)

71. Blood Product Administration
Antithrombin administration should not be used in treatment of severe sepsis and septic shock (1B)
Studies show mixed mortality and morbidity results

72. Supportive Therapy Mechanical Ventilation
Sedation, Analgesia, & Neuromuscular Blockade
Glucose Control
Renal Replacement
Bicarbonate Therapy
DVT Prophylaxis
Stress Ulcer Prophylaxis

73. Mechanical Ventilation
Lung protective ventilation septic ALI/ARDs patients
Tidal volume of 6ml/kg for (1B)
Plateau Pressure < 30 cm H2O (1C)
Permissive hypercapnia to minimize tidal volume and plateau pressure (1C)
PEEP to avoid extensive lung collapse (1C)
HOB elevated to help prevent VAPs (1B)

74. Sedation, Analgesia & NMBA
Sedation and analgesia protocols (1B)
Avoid neuromuscular blocking agents if possible (1B)

75. Glucose Control
Administer iv insulin for hyperglycemia in severe sepsis (1B)
Use glycemic control protocol to maintain glucose < 150 mg/dL (2C)
Patients receiving iv insulin and glucose calorie source have glucose level monitored Q2 (1C)
Low glucose levels monitored at POC should be interpreted with caution (1B)

76. Bicarbonate Therapy
Bicarb therapy should not be used for purpose of improving hemodynamics or reducing vasopressor requirements in patients with hypoperfusion-induced lactic acidemia with pH > 7.15 (1B)
Bicarb admin shown to increase Na, lactate, pCO2 decreased iCa, and fluid overload

77. Labs Cultures Antibiotic levels CBC Coagulation Chemistries
Blood Gases
Renal function & liver function tests
Lactate

78. Lactate
Lactate is a key indicator of tissue oxygenation. Successful treatment of sepsis requires restoration and maintenance of tissue perfusion and oxygenation.

79. Lactate Normal concentration 0.5 – 2.2 mM/L
Normal production 15 – 20 mM/kg day
Increases with increased production and/or decreased utilization or clearance (liver failure)

80. Lactate Production & Metabolism
Lactate normally produced by RBCs (no mitochondria)
During anaerobic metabolism in most tissues (sepsis, cardiac arrest)
Kidneys and liver can convert lactate to glucose (gluconeogenesis)

81. Lactate Production & Metabolism
Liver lactate metabolism inhibited as lactate increases (as in sepsis)
Uptake of lactate by liver inhibited by acidosis, hypoperfusion and hypoxia

82. Lactic Acidosis Decreased tissue perfusion and/or oxygenation Type A
Hypoperfusion (decreased CO, hypovolemia, excessive vasoconstriction)
Reduced O2 content (hypoxemia, anemia, dyshemoglobinemia)

83. Lactic Acidosis
Type B
B1 common disorders (liver failure, renal failure, diabetes, cancer, cholera, malaria)
B2 drugs and toxins (ethanol, methanol, ethylene glycol, cocaine, zidovudine, acetaminophen, salicylates, catecholamines, niacin and many more)
B3 other (seizures, strenuous exercise, status asthmaticus)

84. Lactate Precautions Not specific for perfusion/tissue oxygenation
Arterial or mixed venous samples reflect total body lactate
Peripheral samples reflect lactate level in limb (influenced by tourniquet, local circulation, etc.)

85. Lactate Precautions
Lactate may transiently increase with improvement in circulation
Rapid TAT needed (whole blood)
Serial sampling very helpful
Interpret relative to clinical condition

86. Interpretation of Blood Lactate Results
< 2.0 mmol/L: Normal adult at rest
mmol/L: Moderately elevated
> 4.0 mmol/L: Seriously elevated
Smith, et al used blood lactate levels to discriminate between intensive care patients with low and high risks of morbidity and mortality (Intensive Care Med 2001; 27: 74). They found that patients in intensive care with blood lactate greater than 1.5 mmol/L had a mortality of 61%. They suggest that any lactate above 1.5 mmol/L should be considered abnormal.
As noted in earlier slide, a blood lactate of 4 mmol/L or above must be interpreted with the patient’s history. If the elevation is because the patient has just undergone surgery, this lactate is not necessarily serious. If the lactate is increasing despite full medical intervention (cardiac, pulmonary, fluid, antibiotic, etc, support), a lactate above 4 mmol/L represents a very serious situation.

87. Lactate and Mortality
Prolonged elevation of lactate and metabolic acidosis are predictive of higher mortality
Lactate greater than 8 mM/L for 2hrs = 90% mortality *
*Weil, WM, Affifi, AA. Experimental and Clinical Studies on Lactate and Pyruvate as Indicators of the Severity of Shock. Circulation, 41: , 1970.

88. Lactate and Mortality
Lactate of > 5mM and pH < 7.35 have mortality of 75% at 6 months

89. Lactate and Sepsis
Sepsis induced shock diagnosis includes
Lactate > 4.0 mM/L
Monitor adequacy of perfusion with lactate levels (maintain below 4.0 mM/L )and urine output
Effective monitor of tissue oxygenation
(lactate < 4.0 mM/L)
Serial lactate highly recommended

90. Sepsis Survival Improvement
Early and appropriate fluid and blood administration improves outcome
Early antibiotic administration with appropriate ongoing management improves outcome (survival decreases by 7.6% for every hour antibiotic therapy is delayed)*
*Kumar A, Roberts D, Wood DO, et al.; Crit Care Med 2006;34:

91. Sepsis Survival Improvement
Goal of 25% mortality decrease thought to be attainable ( to )
Surviving Sepsis Recommendations are critical to improved outcome
Recommendations continue to evolve

92. Mortality Reduction-2010
Compliance with resuscitation and management bundles
2 year study
165 Sites
15022 subjects
Surviving Sepsis Campaign: Results of an international guideline based performance improvement program targeting severe sepsis.
Crit Care Med 2010 Vol. 38 No. 2

93. Mortality Reduction-2010 Guideline Compliance after 2 years
Resuscitation bundle
increased from 10.9% to 31.3%
Management bundle
increased from 18.4% to 36.1%

94. Mortality Reduction-2010 2 year reduction
Decreased from 37.0% to 30.8%

95. Summary Sepsis is complex with many causes
Early and accurate diagnosis are essential
Lab tests need quick TAT
Adherence to resuscitation and management bundles reduces mortality (2010 study) Goal of 25% mortality decrease thought to be attainable ( to )
Surviving Sepsis Guidelines continue to evolve