1. Sepsis and Septic Shock
Therapy in 2012
Dr Masood ur Rahman. FCCP.
Senior Consultant Intensive care
Deputy Chairman Department of Critical Care
Medicine, Tawam Hospital
Al Ain, United Arab Emirates.

2. Objectives
• Incidence
• End point of resuscitation
– CVP and ScVo2? Or ?
• Update on role of
– Early Goal directed therapy
– Antibiotics
– Glycemic control
– Steroid
– Activated protien c

3. Severe Sepsis: Comparison With
Other Major Diseases
Incidence of Severe Sepsis Mortality of Severe Sepsis
300 250,000
250 200,000
Cases/100,000
Deaths/Year
200
150,000
150
100,000
100
50,000
50
0
0
AIDS* Colon Breast CHF† Severe AIDS* Breast AMI† Severe
Cancer Sepsis‡ Cancer Sepsis‡
†NationalCenter for Health Statistics, 2001. American Cancer Society, 2001. *American Heart
Association. 2000. ‡Angus DC et al. Crit Care Med 2001

7. Severe Sepsis: Comparison With
Other Major Diseases
Incidence of Severe Sepsis Mortality of Severe Sepsis
300 250,000
250 200,000
Cases/100,000
Deaths/Year
200
150,000
150
100,000
100
50,000
50
0
0
AIDS* Colon Breast CHF† Severe AIDS* Breast AMI† Severe
Cancer Sepsis‡ Cancer Sepsis‡
†NationalCenter for Health Statistics, 2001. American Cancer Society, 2001. *American Heart
Association. 2000. ‡Angus DC et al. Crit Care Med 2001

8. Severe Sepsis:
A Growing Healthcare Challenge
Today Future
1,800,000 600,000
Severe Sepsis Cases
Total US Population/1,000
1,600,000 US Population
500,000
1,400,000
>750,000
Sepsis Cases 1,200,000 400,000
cases of severe 1,000,000
sepsis/year 800,000
300,000
in the US* 600,000 200,000
400,000
100,000
200,000
2001 2025 2050
Year
*Angus DC. Crit Care Med 2001;29:1303-10

9. Goals of Treatment
• ABCDE
• Airway
• control work of Breathing
• optimize Circulation
• assure adequate oxygen Delivery
• achieve End points of resuscitation

10. SIRS- It All Starts Out So Innocent
• Clinical Response to nonspecific insult
• Temperature > 380 C or < 360 C
• Heart Rate > 90 per minute
• Respirations > 20 per minute
• WBC > 12,000 or < 4,000 or > 10% bands
• PaCO2 < 32
Members of the American College of Chest Physicians/Society of Crit Care
Med Consensus Conference Committee: American College of Chest
Physicians/Society of Crit Care Med Consensus Conference: Definitions for
sepsis and organ failure and guidelines for the use of innovative therapies in
sepsis. Crit Care Med 1992; 20: 864–874

11. Definition
• Sepsis- 2 or more SIRS criteria with infection
• Severe Sepsis- Sepsis with evidence of organ
dysfunction
• Septic Shock- Sepsis with refractory hypotension
• Multiple Organ Dysfunction Syndrome (MODS)

12. Down a Slippery Slope

13. How to prevent this?

16. EGDT
• 263 patients randomized to goal directed or
standard therapy
• In hospital mortality for EGDT patients
30.5% versus 46.5% for standard therapy
• Longer length of stay and consumption of
resources for standard therapy patients
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 345. 1368-1377.2001;

17. The Importance of Early Goal-Directed
Therapy for Sepsis Induced Hypoperfusion
NNT to prevent 1 event (death) = 6-8
60 Standard therapy
EGDT
50
Mortality (%)
40
30
20
10
0
In-hospital 28-day 60-day
mortality mortality mortality
(all patients)
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

18. EGDT is Liberal?
• Average of 5 Liters of crystalloid in 6 hours
• After 72 hours no difference between standard and EGDT group
• Timing is the key
• Less intubation in EGDT group after 6 hours
• Dialysis patients less intubation in EGDT
Otero, RM, Nguyen, B, Huang, DT, et al (2006) Early goal-directed therapy in severe
sepsis and septic shock revisited. Chest 130,1579-1595
Wiedemann, HP, Wheeler, AP, Bernard, GR, et al Comparison of two fluid-management
strategies in acute lung injury. N Engl J Med 2006;354,2564-2575
Jones A, et al, The effect of a quantitative resuscitation strategy on mortality in patients
with sepsis: A meta-analysis. Critical Care Medicine: October 2008 - Volume 36 - Issue
10 - pp 2734-2739
Boyd J, et al, Fluid resuscitation in septic shock: A positive fluid balance and elevated
central venous pressure are associated with increased mortality. Critical Care Medicine:
February 2011 - Volume 39 - Issue 2 - pp 259-265

19. Guidelines 2008

20. Guidelines 2008

21. • There is poor relationship between CVP and
blood volume as well as the inability of
CVP/ΔCVP to predict the hemodynamic
response to a fluid challenge. CVP should not
be used to make clinical decisions regarding
fluid management.

22. Conclusion:
Applying an early quantitative resuscitation strategy to patients with sepsis imparts
a significant reduction in mortality

23. Retrospective review of use of IV fluid used during
first 4 days.
VASST ( vasopressin in shock trial).
? Positive fluid balance and CVP are associated with
mortality.

24. Cox survival curves, adjusted for
Age,
(APACHE) II score.
severity of shock (dose of norepinephrine),

26. • limitation of study • Conclusion
– A more positive fluid balance
– Retrospective both early in resuscitation and
– Type of IV fluid not cumulatively over 4 days is
associated with an increased risk
documented of mortality in septic shock.
– Unable to determine if – Central venous pressure may be
CVP and fluid balance used to gauge fluid balance <12
hrs into septic shock but
are independetly effect becomes an unreliable marker
the out come. of fluid balance thereafter.

27. How to decide end point of resucitation?
• Static hemodynamic measure
– CVP , PAOP
• Dynamic hemodynamic measure
– Respiratory changes in the radial artery pulse pressure( pulse pressure variation),
– Aortic blood flow peak velocity,
– Brachial artery blood flow velocity
– Stroke volume variation
• Mixed venous saturation (SvO2)
• Central venous saturation (ScvO2)
• Lactic acidosis

28. Which is better measure dynamic
versus static?
• Increasing evidence that dynamic measures are
more accurate predictors of fluid responsiveness
than static measures, as long as the patients are
in sinus rhythm and controlled ventilated with a
sufficient tidal volume
Intensive Care Med. 2003;29(3):476.
Am J Respir Crit Care Med. 2000;162(1):134.
Intensive Care Med. 2005;31(9):1195

29. Get a Leg Up!
• Passive leg raise (PLR) increased
radial arterial pulse pressure.
• Pulse pressure = Systolic BP-
Diastolic BP.
• PP= 9% correlates with fluid
response.
• Change with PLR correlated with
an increase in stroke volume.
• PLR changes correlated with
stroke volume changes when
same patients received a fluid
bolus.
, Crit Care Med 2010; 38:819–825.

30. How accurate are they?

31. PPV better than CVP
Crit Care Med 2009 Vol. 37, No. 9

32. Got Ultrasound ?
 IVC diameter changes with volume
 IVC diameter will decrease during inspiration
Diameter will increase with expiration
 Caval Index = 100 x (IVC expiration-IVC
inspiration)/IVC expiration.
 caval index is greater than 50% it suggests low
central venous pressure (CVP less than 8 mmHg)
and high probability of fluid responsiveness
 Limitations need to be considered
Blehar DJ, et al, Identification of congestive heart failure via
respiratory variation of inferior vena cava diameter, Am J Emerg Med -
01-JAN-2009; 27(1): 71-5
Nagdev, et al, Emergency Department Bedside Ultrasonographic
Measurement of the Caval Index for Noninvasive Determination of
Low Central Venous Pressure, Volume 55, Issue 3 March 2010, 290-
295

33. Got Alternative Technology ?
The placement of four dual disposable sensors on the neck and
chest are used to transmit and detect electrical and impedance
changes in the thorax, which are used to measure and calculate
hemodynamic parameters
 Impedance cardiography
Napoli A, Machan J, et al, The Use of Impedance Cardiography in Predicting Mortality in Emergency Department Patients
With Severe Sepsis and Septic Shock, Academic Emergency Medicine 2010; 17:452–455

34. Esophageal Doppler-Minimally Invasive
Option
• Deltex CardioQ
• Placement of flexible orogastric
or nasogastric probe
• Doppler technology
• Measures blood flow velocity in
descending aorta
• Able to derive values for
cardiac output, preload and
contractility

35. New guideline 2012?
• Dynamic measures such as delta pulse
pressure or stroke volume variation to
determine the adequacy of fluid resuscitation,
rather than such static measures as central
venous pressure.
Annual meeting of the Society for
Academic Emergency Medicine (SAEM)
2012

36. ScVO2 Revisited
• Lactate vs ScVO2

37. Venous Oxygen Saturation
• Measure of global oxygen extraction
• Central versus mixed
• Compromised by cirrhosis or shunt

38. ScVo2
• Svo2 ≥has significant impact on mortality than
rest of the components of resuscitation
bundle.
CCM 2010
• Failure to achieve ScVo2≥ 70 within first 6
hours is associated with significantly high
mortality( 14%).
Pope et al:Annal of emergency medicine
2010

39. Lactate?
Serum lactate identifies hypoperfusion
Shapiro N, et al, Serum Lactate as a Predictor of Mortality in Emergency Department Patients with
Infection, Annals of Emergency Medicine, Volume 45, Issue 5 (May 2005), 524-528

40. Got Lactate ?
• Recent prospective study reveals utility of lactate
clearance
• Potential use as resuscitation endpoint
Nguyen HB, et al, Early lactate clearance is associated with improved outcome in severe
sepsis and septic shock Critical Care Medicine - Volume 32, Issue 8 (August 2004)
Arnold R, et al, Multicenter Study Of Early Lactate Clearance as a Determinant Of Survival in
Patients With Presumed Sepsis, SHOCK Vol. 32, No. 1, pp. 35-39, 2009
Jones A, et al, Lactate Clearance Versus Central Venous Oxygenation as Endpoints of Early
Sepsis Therapy: A Randomized Clinical Trial. (49), Critical Care Medicine. 37(12), December
2009
Adams BD, Bonzani TA, Hunter CJ. The anion gap does not accurately screen for lactic
acidosis in emergency department patients. Emerg Med J 2006;23:179–8

42. Colloids
• Option in addition to crystalloids
• Albumin is SAFE
• Subset analysis suggests mortality decrease
• Possible anti-inflammatory component
The SAFE Study Investigators. A comparison of albumin and saline for fluid resuscitation in the intensive
care unit. N Engl J Med 2004;350:2247-2256.
Brunkhorst F , et al, Intensive Insulin Therapy and Pentastarch Resuscitation in Severe Sepsis, NEJM
2008;358:125-139.
Kirschenbaum L, Effect Of Resuscitative Fluids On Cell Activation In Septic Shock (439), Critical Care
Medicine. 37(12):A1-A542, December 2009
Mullen M, Use of Concentrated Albumin in the Emergency Department May Improve Morbidity in Severe
Sepsis and Septic Shock (482), Critical Care Medicine. 37(12):A1-A542, December 2009
Delaney A, et al, The role of albumin as a resuscitation fluid for patients with sepsis: a systematic
review and meta-analysis, Crit Care Med. 2011 Feb;39(2):386-91

43. The role of albumin as a resuscitation fluid for patients with sepsis: A
systematic review and meta-analysis*
Conclusion
use of albumin-containingsolutions for the resuscitation of patients with sepsis was associated with lower mortality compared
with other fluid resuscitation regimens. Until the results of ongoing randomized controlled trials are known, clinicians should
consider the use of albumin-containing solutions for the resuscitation of patient swith sepsis.
Delaney A, et al,, Crit Care Med. 2011 Feb;39(2):386-9 1

44. Better than crystalloids in septic
patient ?

45. New Twist on Pressors
• Epinephrine and norepinephrine plus
dobutamine compared in 330 patients
• No difference in mortality at 28 days
• No statistical difference in adverse effects
Annane D, Norepinephrine plus dobutamine versus
epinephrine alone for management of septic shock: a
randomized trial . The Lancet , Volume 370 , Issue
9588, Pages 676 - 684 D, 2007

46. Vasopressin versus norepinephrine?
• Results of a multi-center trial of
septic shock patients receiving
0.03 units/min of vasopressin
versus norepinephrine
• 776 patients
• No difference in mortality
• Trend toward improved outcome
with vasopressin in less severe
shock
• Higher doses may be future
intervention
Russell JA, Walley KR, Singer J, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J
Med 2008;358:877-887.
Luckner G , Comparison of two dose regimens of arginine vasopressin in advanced vasodilatory shock. Crit Care Med OCT-
2007; 35(10): 2280-5

47. Low dose vasopressin plus steroid better
than Norepinephrine plus steroids
• Post hoc analysis of patients in
VAAST
• Review of patients with
norepinephrine (293) and
steroids and vasopressin (295)
and steroids
• 28 day mortality difference
44.7% versus 35.9% (p=0.03)
• ? Increased responsiveness to
catecholamines
• ? Increased vasopressin levels
• ? Decreased inflammation
Russell J, et al, Interaction of vasopressin infusion, corticosteroid treatment, and
mortality of septic shock, Crit Care Med 2009 Vol. 37, 811-8

48. Blood?!!
• Hebert did not address severe sepsis/tissue hypoxia
• 79% EGDT patients did show improvement in ScVO2
• Need to consider infection issues/ALI/age of PRBC’s
• Vincent-Observational study (n=1040) did not show
increased mortality with transfusion
• Napolitano- Transfusion needs on individual basis
Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements
in critical care: Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J
Med 1999; 340:409–417T
Friedlander M, et al, The relationship of packed cell transfusion to red blood cell deformability in systemic inflammatory
response syndrome patients, SHOCK 1998 Feb;9(2):84-8.
Vincent JL, Sakr Y, et al, Are blood transfusions associated with greater mortality rates? Results of the Sepsis
Occurrence in Acutely Ill Patients study. Anesthesiology. 2008 Jan;108(1):31-9.
Napolitano L, et al, Clinical Practice Guideline: Red Blood Cell Transfusion in Adult Trauma and Critical Care, Crit Care
Med 2009, Vol 37 (12), 3124-3157

49. Early Antibiotics:
• Kumar (2009)- 5000 patient study
• 20 % patients received inappropriate antibiotics
• Increased mortality by factor of 5
• Combination therapy needs to be considered
• Rise of Extended Spectrum Beta Lactam (ESBL) Gram Negative
infection
Kumar A, et al, Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival
in human septic shock. Chest 2009 Nov;136(5):1237-48.
Kumar A, Early combination antibiotic therapy yields improved survival compared with monotherapy in
septic shock: A propensity-matched analysis. Critical Care Medicine: September 2010 - Volume 38 -
Issue 9 - pp 1773-1785
Quinn JP, Clinical significance of extended-spectrum beta-lactamases. European Journal of Clinical
Microbiology & Infectious Diseases, Volume 13, Supplement 1 1994 , S39-S42

50. Early Antibiotics
(Even in the ED)
• ED based retrospective study
• 231 patients
• Time to appropriate antibiotics mortality factor
• Less than 1hour - 19% mortality
• Greater than 1 hour - 33.2 % mortality
Gaieski D, et al, Impact of time to antibiotics on survival in patients with severe sepsis or septic shock
in whom early goal-directed therapy was initiated in the emergency department, Crit Care Med 2010;
38:1045–1053.

52. Got Glucose ?
• Glycemic control impacts critical illness
• Maintenance of blood glucose between 80-110 mg/dl
• Absolute reduction in ICU mortality
• Reduction of in-hospital mortality by 34%
• Reduction in morbidity as well
• Mixed support in follow-up studies
Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in
critically ill patients. N Engl J Med 2001;345:1359-1367
Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in
the medical ICU. N Engl J Med 2006;354:449-461.
Krinsley JS, Effect of an intensive glucose management protocol on the
mortality of critically ill adult patients. Mayo Clin Proc. 2004 Aug;79(8):992-
1000
Carr J, Sellke F, et al, Implementing Tight Glucose Control After Coronary
Artery Bypass Surgery Ann. Thorac. Surg., Sep 2005; 80: 902 - 909.

53. Not So Nice, Sugar….
• Intensive versus Conventional Glucose Control in
Critically Ill Patients, NEJM, March 26, 2009
• 6104 randomized patients
• Intensive (80-108) versus conventional (less than 180)
• Increase 90 day mortality 27.5% versus 24.9% with tight
control
• Expect a possible wider range (?140-180)
Nice-Sugar Investigators, Intensive versus Conventional Glucose Control
in Critically Ill Patients, N Engl J Med 2009;360:1283-97

54. Still important……
• Retrospective cohort 259,040 patients
• Review risk adjusted mortality in this cohort
• Hyperglycemia does affect mortality
• Risk varies with admission diagnosis
• Adjusted mortality lowest with glucose 111 to
145 mg/dL
Falciglia M, et al, Hyperglycemia-related Mortality in Critically Ill patients Varies with Admission
Diagnosis, Critical Care Medicine. 37(12):3001-3009, December 2009

55. CORTICUS
• CORTICUS- Randomized, controlled study
hydrocortisone vs placebo in septic shock.
• 500 patients multi-center, multinational study
• No difference in the overall 28-day mortality rate
• Cosyntropin responsiveness made no difference
• Tapered steroids
• Cosyntropin test called into question
• Shock resolution faster with steroids
Sprung CL, Annane D, et al, Hydrocortisone therapy for patients with septic shock. N Engl J Med.
2008 Jan 10;358(2):111-24

56. Update
• Most recent literature-comprehensive meta-analysis
Review of 17 studies
• Overall steroids do not affect 28 day mortality
• 12 studies of low dose prolonged steroids did
suggest improved outcome
• Recommended for vasopressor refractory shock
Annane D, et al, Corticosteroids in the Treatment of Severe Sepsis and Septic Shock in AdultsA Systematic
Review, JAMA. 2009;301(22):2362-2375.

57. Activated protien C?
• Activated Protein C- Anti-inflammatory, anti-thrombotic,
profibrinolytic properties
• 28 day mortality study/1690 randomized patients
• Mortality decrease and relative risk reduction statistically
significant
• Mortality decrease from 30.8% to 24.7%
• First agent in 20 years to modify course of severe sepsis
• Increased bleeding risk (3.5% vs 2.0%)
• Exclusion criteria extensive
Bernard GR, Vincent J-L, Laterre P-F, et al.
Efficacy and safety of recombinant human
activated protein C for severe sepsis. N Engl J
Med 2001;344:699-709

61. Low Tidal Volume Mechanical Ventilation
• Multicenter, randomized trial of over 800 patients
• Comparison of 12 ml/kg versus 6ml/kg tidal volume
• Lower volumes to keep plateau pressure 30 mm H2O
or less
• More recent smaller trial 6 ml/kg vs 10 ml/ kg
• Less inflammatory markers
• Less incidence of ALI/ Stopped early
The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as
compared with traditional tidal volumes for acute lung injury and the acute respiratory distress
syndrome. N Engl J Med 2000;342:1301-1308
Determann R, Ventilation with lower tidal volumes as compared to conventional tidal volumes
for patients without acute lung injury - a preventive randomized controlled trial, Critical
Care 2010, 14:R1 (7 January 2010)

62. Putting It All Together
• Early goal directed therapy still valid/ Likely to change
• Early aggressive antibiotics remain key/ Resistance emerging
• Glycemic control still has benefit
• Consider adrenal insufficiency in fluid resuscitated shock
• Low tidal volume remains the best practice
• Exciting new therapies/ monitoring on horizon
• Activated protien C is History

63. What Should We Do

65. Impact of order sets

66. What are We Doing At Tawam
• Implementing sepsis clinical pathway.
• Sepsis care set

67. Establishing Measure
• SEPSIS RESUCITATION BUNDLE
– Serum Lactate measured
– Blood culture obtained before antibiotics
administered.
– Timing of antibiotics
– CVP goal
– Central venous saturation

68. • SEPSIS MANAGEMENT BUNDLE
– Glycemic control
– Plateau pressure
– Low dose steroids administered

69. THANK YOU