pulmo grand rounds

1. R. Phillip Dellinger, MD
Professor of Medicine
Robert Wood Johnson Medical School/UMDNJ
Director Critical Care Medicine
Cooper University Hospital
Camden, New Jersey
Septic Shock: Current
Management and New
Therapeutic Frontiers

2. Personal Financial Disclosures
• None relevant to presentation today

3. Background - Basic Definitions
• Sepsis = known or suspected infection plus
systemic manifestations of infection (SIRS
and others)
• Severe Sepsis = Sepsis + either
– Acute organ dysfunction thought to be due to
sepsis
– Acute tissue hypoperfusion thought to be due to
sepsis
• Hypotension
• Elevated lactate
• Oliguria
• (Altered mental status)

4. Background - Basic Definitions
• Severe Sepsis Organ Dysfunctions
– Acute lung injury
– Acute kidney injury
– Coagulopathy
• Thrombocytopenia
• Increased INR
– Liver Dysfunction
– (Cardiovascular)
• Septic Shock
– Vasopressors +/- organ dysfunction

5. Surviving Sepsis Campaign (SSC)
guidelines for management of severe
sepsis and septic shock
Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T,
Cohen J, Gea-Banacloche J, Keh D, Marshall JC, Parker
MM, Ramsay G, Zimmerman JL, Vincent JL, Levy MM
and the SSC Management Guidelines Committee
Crit Care Med 2004;32:858-873
Intensive Care Med 2004;30:536-555

6. Surviving Sepsis Campaign: International guidelines for
management of severe sepsis and septic shock: 2008
Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM,
Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale
R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ,
Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson
BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL.
Crit Care Med 2008; 36:296-327
Intensive Care Med 2008;30:536-555

7. Sponsoring Organizations
2008 Guidelines
•American Association of Critical
Care Nurses
•American College of Chest
Physicians
•American College of Emergency
Physicians
•Canadian Critical Care Society
•European Respiratory Society
•European Society of Clinical
Microbiology and Infectious
Diseases
•European Society of Intensive Care
Medicine
•Indian Society of Critical Care
Medicine
• International Sepsis Forum
• Japanese Society of Intensive
Care Medicine
• Japanese Association of Acute
Medicine
• Society of Hospital Medicine
• Society of Critical Care Medicine
• Surgical Infection Society
• World Federation of Critical Care
Nurses
• World Federation of Societies of
Intensive and Critical Care
Medicine

8. SSC Update 2010/2011

9. Current Surviving Sepsis Campaign Guideline Sponsors
(2010/11 Update)
• 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
• 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
• German Sepsis Society
• 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 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

10. Evidence Based Medicine
Grading System

13. Grades of Recommendation,
Assessment, Development
and Evaluation (GRADE)

14. Grading Quality
of Evidence
• A- high quality
– Randomized controlled trial (RCT)
• B- intermediate
– Downgraded RCT or upgraded observational
• C- low
– Observational or cohort
• D- very low
– Case series or expert opinion
• Upgrade capability

15. Grading Strength of Recommendation
• 1- strong recommendation – Do it
– We recommend
• 2- weak recommendation – Probably do it
– We suggest
• Determinants of strength
– Quality of evidence
– Relative importance of outcomes
– Risks and costs
– Absolute magnitude and precision of effect

16. Kumar A, et al. Crit Care Med 2006; 34:1589-1596

17. Antibiotic Therapy
 We recommend beginning intravenous
antibiotics within first hour of recognition
of severe sepsis
1B

18. • Broad antibiotic coverage initially
• Narrow coverage after return of cultures
• Source control as soon as possible and within
6 hours

21. Initial Resuscitation

22. Resuscitation of Sepsis Induced
Tissue Hypoperfusion
• Recommend MAP 65 mm Hg
• Recommend urine output .5 ml/kg/hr
Grade 1C

23. Fluid Therapy
• Recommend fluid resuscitation may
consist of natural or artificial colloids or
crystalloids.
Grade 1B

24. The SAFE Study Investigators, N Engl J Med 2004;350:2247
Probability of Survival

25. The SAFE Study Investigators, N Engl J Med 2004;350:2247
Relative Risk of Death from Any Cause
among All the Patients and among the
Patients in the Six Predefined Subgroups of Survival

26. Sepsis Induced Hypotension
• Fluid challenge
– Minimum of 20 ml/kg crystalloid or colloid
equivalent

27. Sepsis Induced Tissue
Hypoperfusion
 Requirement for Vasopressors after
initial fluid challenge
Lactate ≥ 4 mg/dL

28. Figure B, page 948, reproduced with permission from Dellinger RP. Cardiovascular
management of septic shock. Crit Care Med 2003;31:946-955.

29. Which two adrenergic agents are most appropriate to
maintain acceptable blood pressure in a patient with
septic shock?
A. Dopamine or epinephrine
B. Epinephrine or vasopressin
C. Vasopressin or norepinephrine
D. Norepinephrine or dopamine

30. Which two adrenergic agents are most appropriate to
maintain acceptable blood pressure in a patient with
septic shock?
A. Dopamine or epinephrine
B. Epinephrine or vasopressin
C. Vasopressin or norepinephrine
D. Norepinephrine or dopamine

31. During Septic Shock
10 Days Post Shock
Diastole Systole
Diastole Systole
Images used with permission from Joseph E. Parrillo, MD

32. Effects of Dopamine, Norepinephrine,
and Epinephrine on the Splanchnic
Circulation in Septic Shock
Figure 2, page 1665, reproduced with permission from De Backer D, Creteur J, Silva E, Vincent JL. Effects of
dopamine, norepinephrine, and epinephrine on the splanchnic circulation in septic shock: Which is best?
Crit Care Med 2003; 31:1659-1667

33. Norepinephrine vs. Dopamine

34. De Backer D, et al. N Engl J Med 2010, 362;9:779-789
28-day Survival

35. De Backer D, et al. N Engl J Med 2010, 362;9:779-789
Predefined subgroup analysis by type
of shock

36. Phenylephrine
• Pure vasoconstrictor in general should be
avoided
– Decreases cardiac output
• Rare exceptions
– Cardiac output measured and high and difficulty
with maintaining MAP with other vasopressor
agents
– Profound tachycardia or severe ventricular
arrhythmias with norepinephrine

37. Initial Resuscitation of Persistent
Hypotension or Lactate >4
Recommend
Insertion central venous catheter
Recommended goals :
• Central venous pressure: 8–12 mm Hg
• Higher with altered ventricular compliance or
increased intrathoracic pressure
• ScvO2 saturation (SVC)  70%
Grade 1C

38. The Early Bird Gets the Worm

39. The Importance of Early Goal-Directed
Therapy for Sepsis Induced Hypoperfusion
Adapted from Table 3, page 1374, with permission from Rivers E, Nguyen B, Havstad S, et al. Early goal-
directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345:1368-1377
In-hospital
mortality
(all
patients)
0
10
20
30
40
50
60 Standard therapy
EGDT
28-day
mortality
60-day
mortality
NNT to prevent 1 event (death) = 6-8
Mortality
(%)

40. Trials of Late Hemodynamic Optimization
with Control Group Mortality > 20%
Kern and Shoemaker Crit Care Med 2002
After onset of organ failure
Alia et al. 1999
Yu et al. 1998
Yu et al. 1998
Gattinoni et al. 1995
Hayes et al. 1994
Yu et al. 1993
OVERALL RESULT
Favors
Optimization
Favors
Control
0.0
-0.4 0.4

41. Role of Collaboration
ICU
ED

42. Jones AE, Shapiro NI, Trzeciak S, et al. Lactate
clearance vs central venous oxygen saturation as
goals of early sepsis therapy: a randomized
clinical trial. JAMA. 2010;303(8):739-46.

43. Copyright restrictions may apply.
Jones, A. E. et al. JAMA 2010;303:739-746.
Hospital Mortality
and Length of Stay

44. Vasopressin
• Continue to recommend against using high
doses of vasopressin (unless salvage
therapy)
• Vasopressin .03 units per min plus NE
equivalent to norepinephrine alone
– VASST trial

46. Figure 2A, page 867, reproduced with permission from Annane D, Sébille V, Charpentier C, et al. Effect of
treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock.
JAMA 2002; 288:862-871
Steroid Therapy

47. CORTICUS: Results
• No benefit in intent to treat
– Mortality
– Shock reversal
• Earlier reversal of shock with steroids in
those that had shock reversal

48. FRENCH TRIAL CORTICUS
Overall Severity of Illness ++++ ++
Duration of Shock
< 8 hrs < 72 hrs
Degree of Hypotension ++++ ++
Potential for Selection Bias Unlikely Yes

49. Steroids
Suggest intravenous hydrocortisone be
given only to adult septic shock patients
after blood pressure is identified to be
poorly responsive to fluid resuscitation and
vasopressor therapy
Grade 2C

50. Recombinant Human
Activated Protein C (rhAPC)
• Suggest use in patients with clinical
assessment of high risk of death due to
sepsis induced organ dysfunction typically
with APACHE II 25 or greater or multiple organ
failure
• No absolute contraindications
• Weigh relative contraindications
Grade 2B

51. PROWESS SHOCK

52. As to Guidelines Publications
• “Knowledge is Good”

53. “Knowledge is Good”

55. Guidelines Are Not Enough
• Protocols
• Performance Improvement Programs

56. Severe Sepsis Resuscitation Bundle
Implement the 6-hour bundle. Available at: http://ssc.sccm.org/6hr_bundles.
Complete tasks within 6 hours of identifying severe sepsis.
1. Measure serum lactate.
2. Obtain blood cultures prior to antibiotic administration.
3. Administer broad-spectrum antibiotic within 3 hours of ED admission
and within 1 hour of non-ED admission.
4. In the event of hypotension and/or serum lactate > 4 mmol/L:
a. Deliver an initial minimum of 20 mL/kg of crystalloid or equivalent.
b. Begin vasopressors for hypotension not responding to initial fluid
resuscitation to maintain MAP > 65 mm Hg.
5. In the event of persistent hypotension despite fluid resuscitation (septic
shock) and/or lactate > 4 mmol/L:
a. Achieve a central venous pressure (CVP) of > 8 mm Hg
b. Achieve a central venous oxygen saturation (ScvO2) > 70% or mixed
venous oxygen saturation (ScvO2) > 65%

58. SSC Interactive Database

59. Surviving Sepsis Campaign:
Phase III
• A global, multi-center, 2-year trial
–Multiple hospital networks
–166 sites
–15,022 patients
• Primary outcome
–The impact of a model for changing
bedside management of sepsis
• Secondary outcome
–Mortality

61. Findings
• Primary outcome of SSC: behavior change
– 20% increase in bundle compliance over 24
months
• Secondary outcome - Mortality
-- 7.0% ARR, 19% RRR
-- 5.4% ARR after severity adjustment

62. Septic Shock Research at Cooper

63. Intrathoracic Pressure Regulation (ITPR) in Porcine
Peritonitis Septic Shock

64. 0.0
1.0
2.0
3.0
4.0
5.0
Stroke
Volume
(mL)
ITPR ON ITPR OFF
Peak Changes in Stroke Volume
p<0.001
n=28
n=28

65. Peak Changes in Mean Arterial Pressure
0
5
10
15
20
25
30
1 2
ITPR ON ITPR OFF
Mean
Arterial
Pressure
(mmHg)
p<0.001
n=28
n=28

66. : ITPR application and duration

67. FE202158
•Vasopressin A1 receptor agonist

68. Septic sheep – Traber et al.

69. V1a Receptor Agonist in a Rat Model of PAF-
Induced Hypotension & Vascular Leak
Syndrome
Resuscitation Period (min)
0 15 30 45 60 75 90 105 120 135 150 165 180
Survival
(%)
0
20
40
60
80
100
VEHICLE-VEHICLE (n=3)
PAF-VEHICLE (n=14)
PAF-AVP (n=9)
PAF-FE 202158 (n=10)

70. The EUPHRATES Trial
Evaluating the Use of
Polymyxin B Hemoperfusion
in a Randomized controlled trial of
Adults Treated for Endotoxemia and
Septic shock

71. Endotoxemia
Sources of Endotoxin
Endotoxin translocation
from GI Tract
 Every human has 25-30 grams
of Endotoxin in their GI tract
 Less than 0.001 grams of Endotoxin
is enough to kill a person
Endotoxin shed from local
bacterial infection

72. Opal SM, et al. Infect Dis, 1999
Sepsis and Endotoxin

73. Intervention
DIRECT HEMOPERFUSION WITH ADSORBENT COLUMN
USING POLYMYXIN B IMMOBILIZED FIBER
ANTICOAGULANT
FEMORAL or IJ VEIN
FEMORAL or IJ VEIN
BLOOD TUBE
P
BLOOD PUMP
Perfusion rate 80-120 ml/min
Duration: 2 hours
73

75. EUPHAS: 10 centres, Italy, randomized, unblinded
Groups were equal at baseline

76. Endotoxin Activity Assay
EAA™
Spectral Diagnostics Inc. 76
The only FDA cleared test for detection of Endotoxin

77. THANK YOU