1. Sepsis- overview and
management 2016
DR SUBHANKAR CHATTERJEE

2. Mortality
Sepsis:
30% - 50%
Septic Shock:
50% - 60%
Why we are spending time on sepsis?

3. Why we are spending time on sepsis?
0
50000
100000
150000
200000
250000
AIDS Breast
Cancer
AMI SEPSIS
Mortality
0
50
100
150
200
250
300
AIDS Breast
Cancer
1st MI sepsis
Incidence
Cases/100,000
Deaths/Year

4. The third International Consensus 2016
Definition for Sepsis ( Sepsis 3)
SEPSIS IS A
 LIFE THREATENING
 ORGAN DYSFUNCTION
 CAUSED BY A DYSREGULATED HOST
RESPONSE
 TO INFECTION

5. Epidemiology
Martin, G. S., Mannino, D. M., Eaton, S., & Moss, M. (2003). The
epidemiology of sepsis in the United States from 1979 through 2000.
New England Journal of Medicine, 348(16), 1546–1554.
Harrison, D. A., Welch, C. A., & Eddleston, J. M. (2006). The
epidemiology of severe sepsis in England, Wales and
Northern Ireland, 1996 to 2004: secondary analysis of a high
quality clinical database, the ICNARC Case Mix Programme
Database. Critical Care, 10(2), R42.
Brun-Buisson, C., Meshaka, P., Pinton, P., Vallet, B., EPISEPSIS
Study Group. (2004). EPISEPSIS: a reappraisal of the epidemiology
and outcome of severe sepsis in French intensive care units.
Intensive Care Medicine, 30(4), 580–588.
[1993 - 2001]...a 17%
reduction in mortality.
[1993-2001]...a
75% increase in... severe
sepsis...
Incidence
of Sepsis
Mortality
of Sepsis

6. Why the burden of sepsis increasing?
 Increased geriatric population
 Increasing number of immunocompromised host
 Increasing drug resistant organism
 Increasing metabolic disorder

7.  either
Bacteraemia (or viraemia/fungaemia/protozoan)
is the presence of bacteria within the bloodstream
Septic focus (abscess / cavity / tissue mass)
Infection

8. Sepsis is not merely an infection
 THE CULPRIT HERE IS OVER REACTION OF OUR
DEFENCE MECHANISM – NOT THE INVADER ALONE.

10. Dysregulated host response leads to..

11. Immune system Vs. mortality

12. How to suspect sepsis?

13. Suspect sepsis…

14. Altered mental status
Edema or increased fluid balance
Hyperglycemia (absent diabetes)
Hypoglyemia
Increased CRP or procalcitonin
Hypotension
Increased SvO2
CI > 3.5 L/min/m2
Arterial hypoxemia (PaO2/FiO2 < 300)
Acute oliguria (> 2 hours)
Increased serum Cr (> 0.5 mg/dL)
Coagulopathy (INR > 1.5)
Ileus (absent bowel sounds)
Thrombocytopenia (< 100,000/uL)
Hyperbilirubinemia (> 40 mg/dL or 70 mmol/L)
Hyperlactatemia (> 1 mmol/L)
Decreased capillary refill or mottling
Levy MM, et al. Crit Care Med. 2003.
How to recognize organ dysfunction?

15. Change in international guideline
Sepsis 2
 Sepsis = SIRS + Infection
 Infection sepsis severe
sepsis septic shock MODS
Sepsis 3
 Sepsis= infection + >2 SOFA score
from baseline
 NO Severe sepsis

16. SIRS to SOFA

17. Organ failure in sepsis
Vincent, J.-L., Sakr, Y., Sprung, C. L., Ranieri, V. M., Reinhart, K., Gerlach, H., Moreno, R., et al. (2006). Sepsis in European intensive care units: results of the SOAP study. Critical Care Medicine, 34(2), 344–353.
P/F
Platelets
Bili
BP
GCS
Cr/UOP

18. SOFA SCORE VARIABLES

19. Sequential Organ Failure Assessment (SOFA)
► Previously known as Sepsis-related Organ Failure Assessment because it was
initially developed in 1994 to describe the degree of organ dysfunction associated with
sepsis in a mixed, medical-surgical ICU patients.
► Nowadays, it has since been validated to describe the degree of organ dysfunction in
various ICU patient groups with organ dysfunctions not due to sepsis.
► The SOFA score involves six organ systems (respiratory, cardiovascular, renal, hepatic,
central nervous, coagulation), and the function of each is scored from 0 (normal
function) to 4 (most abnormal), giving a possible score of 0 to 24.

20. Sequential Organ Failure Assessment (SOFA)
► Mortality rate increases as number of organs with dysfunction increases.
► Unlike other scores, the worst value on each day is recorded.
► A key difference is in the cardiovascular component; instead of the composite
variable, the SOFA score uses a treatment-related variable (dose of vasopressor
agents).

21. Sequential Organ Failure Assessment (SOFA)
► Maximal (highest total) SOFA score: is the sum of highest scores per individual
during the entire ICU stay. A score of >15 predicted mortality of 90%.
► Mean SOFA score (ΔSOFA): is the average of all total SOFA scores in the entire ICU
stay. ΔSOFA for 1st 10 days is significantly higher in non-survivors.
► Delta SOFA score: maximum SOFA – admission SOFA
Crit Care Med 1998;26:1793-1800

22. Sequential Organ Failure Assessment

23. qSOFA for Non ICU patients with
Infection –
early recognition of severity

24. SEPTIC SHOCK
 Septic shock is a subset of sepsis in which
profound circulatory, cellular and
metabolic abnormalities are associated
with a greater risk of mortality than sepsis
alone

25. CLINICAL CRITERIA FOR SEPTIC
SHOCK 2016
 DESPITE ADEQUATE FLUID RESUSCITATION
 VASOPRESSOR NEEDED TO MAINTAIN MAP >_65mm Of
Hg AND
 LACTATE >2 MMOL/LIT

26. Basal lactate production
Muscle Brain RBC WBC Platelets
Renal
medulla
Gut
mucosa
Skin
0.13 mmol/
kg/hr
0.14 mmol/
kg/hr
0.18 mmol/
kg/hr
0.11 mmol/kg/hr
0.11 mmol/
kg/hr
Total = 1290 mmol / 24 hours for 70 kg

27. Hyperlactataemia (> 2mmol/L)

28. How is lactate produced?
If pyruvate production > oxidation in CAC then lactate formation increases
PDH

29.  Hypoxia blocks oxidative phosphorylation
 prevents NADH re-oxidation to NAD
 increases the NADH/NAD ratio
 increases the lactate/pyruvate ratio
 Normal ratio around 10:1
Cardiogenic shock
L/P ratio 40:1
Consistent with hypoxia
Resuscitated septic shock
L/P ratio 14:1
Not consistent with hypoxia

30. When lactate hypoperfusion
Cardiogenic shock
Hemorrhagic shock
Septic shock if
Catecholamine resistant + depressed Cardiac Index
Unresuscitated (see Rivers)

31. Prognostic value
 Source doesn’t matter
 High lactate still a marker of severe
physiological stress
and risk of death
 High lactate often not hypoxia
related but represents metabolic
changes of severe stress

33. Management of SEPSIS
 FLUIDS
 ANTIBIOTICS
 SOURCE IDENTIFICATION AND CONTROL
 VASOACTIVE DRUGS TO MAINTAIN MAP
 EARLY ORGAN SUPPORT
 LUNG PROTECTIVE VENTILATION
 AND MANY MORE…
 BUT THE MOST IMPORTANT IS A SYSTEMATIC APPROACH

34. System-based Approaches to sepsis
Rivers, E., Nguyen, B., Havstad, S., Ressler, J., Muzzin, A., Knoblich, B., Peterson, E., et al. (2001). Early goal-directed therapy in the treatment of severe sepsis and septic shock. New England Journal of Medicine, 345(19), 1368–1377.

35. System-based Approaches to sepsis
Early-Goal Directed Therapy
INCLUSION = SEPSIS AND [BP < 90 after fluid OR Lactate > 4]
CVP 8-12 Fluids CVP 8-12
MAP > 65 Vasopressors MAP > 65
Transfusions
Dobutamine
ScvO2 > 70%
49% mortality 33% mortality
Rivers, E., Nguyen, B., Havstad, S., Ressler, J., Muzzin, A., Knoblich, B., Peterson, E., et al. (2001). Early goal-directed therapy in the treatment of severe sepsis and septic shock. New England Journal of Medicine, 345(19), 1368–1377.
Control Intervention EGDT

36. System-based Approaches to sepsis
Rivers, E., Nguyen, B., Havstad, S., Ressler, J., Muzzin, A., Knoblich, B., Peterson, E., et al. (2001). Early goal-directed therapy in the treatment of severe sepsis and septic shock. New England Journal of Medicine, 345(19), 1368–1377.
Used to promote:
1. CVP > 8 as an initial target
2. Use of Svo2 monitoring and use of blood/dobutamine

37. A Multidisciplinary Community Hospital Program for Early and Rapid
Resuscitation of Shock in Non-trauma Patients
Sebat, F., Johnson, D., Musthafa, A. A., Watnik, M., Moore, S., Henry, K., & Saari, M. (2005). A multidisciplinary community hospital program for early and rapid resuscitation of shock in
nontrauma patients. Chest, 127(5), 1729–1743.

38. A Multidisciplinary Community Hospital Program for Early and Rapid
Resuscitation of Shock in Non-trauma Patients
Sebat, F., Johnson, D., Musthafa, A. A., Watnik, M., Moore, S., Henry, K., & Saari, M. (2005). A multidisciplinary community hospital program for early and rapid resuscitation of shock in
nontrauma patients. Chest, 127(5), 1729–1743.

39. Early Goal-Directed Therapy in the Treatment of Severe
Sepsis and Septic Shock
Control EGDT
Relative Risk
(95% Confidence
Interval)
P
In-Hospital 46.5 30.5
0.58
(0.38-0.87)
0.009
28-day Mortality 49.2 33.3
0.58
(0.39 – 0.87)
0.01
60-day Mortality 56.9 44.3
0.67
(0.46-0.96)
0.03
Rivers E. N Engl J Med. 2001;345: 1368-1377.
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40. Surviving Sepsis Campaign
Suggests bundled initiative for hospitals to reduce sepsis related
mortality.
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Resuscitation Bundle Management Bundle
Compliant
Non-Compliant

41. TO BE COMPLETED WITHIN 3
HOURS OF TIME OF
PRESENTATION*:1. Measure lactate level
2. Obtain blood cultures prior to administration of antibiotics
3. Administer broad spectrum antibiotics
4. Administer 30ml/kg crystalloid for hypotension or lactate ≥4mmol/L
* “Time of presentation” is defined as the time of triage in the emergency
department or, if presenting from another care venue, from the earliest
chart annotation consistent with all elements of severe sepsis or septic
shock ascertained through chart review.

42. TO BE COMPLETED WITHIN 6
HOURS OF TIME OF
PRESENTATION:5. Apply vasopressors (for hypotension that does not
respond to initial fluid resuscitation) to maintain a mean
arterial pressure (MAP) ≥65mmHg
6. In the event of persistent hypotension after initial fluid
administration (MAP < 65 mm Hg) or if initial lactate was
≥4 mmol/L, re-assess volume status and tissue perfusion
and document findings according to Table 1
7. Re-measure lactate if initial lactate elevated

43. DOCUMENT REASSESSMENT OF
VOLUME STATUS AND TISSUE
PERFUSION WITH
 EITHER • Repeat focused exam (after initial fluid resuscitation) by
licensed independent practitioner including vital signs, cardiopulmonary,
capillary refill, pulse, and skin findings.
 OR TWO OF THE FOLLOWING:
 • Measure CVP
 • Measure ScvO2
 • Bedside cardiovascular ultrasound
 • Dynamic assessment of fluid responsiveness with passive leg raise or
fluid challenge
 Of note, Central Line no harm no gain. Needed for vasoactive drug
therapy.
 Bedside sonologic assessment of Volume status is prioritized.

45. fluid in septic shock, How much ?

46. IVF recommendation
 Initial fluid challenge ≥ 1000 mL of crystalloids or minimum
of 30 mL/kg of crystalloids in the 1st 4-6 hours
 (Strong recommendation; Grade 1C).
 Crystalloids is the initial fluid for resuscitation
 (Strong recommendation; Grade 1A).
 Adding albumin to the initial fluid resuscitation
 (Weak recommendation; Grade 2B).
 Against hydroxyethyl starches (hetastarches) with MW >200
dalton
 (Strong recommendation; Grade 1B).

47. Timing of Antibiotic Administration

48. Septic Shock: Timing of Antibiotics
Kumar Crit Care Med 2006
0.0
.20
.40
.60
.80
1.00
% Survival
% Total receiving antibiotics
Percent
Time, hrs
14 ICUs; n = 2,731
Only 50% of patients in Septic Shock
received antibiotics w/in 6 hrs.

49. G. Fluid Therapy of Severe Sepsis
H. Vasopressors
I. Inotropic Therapy
J. Corticosteroids
2. Hemodynamic Support and Adjunctive Therapy

50. Adrenergic Agents
Isoproterenol
Dobutamine
Dopamine
Epinephrine
Norepinephrine
Phenylephrine
Beta
Alpha

51. Which Inotropes to use?
 Norepinephrine as the first choice
 ( Grade 1B)
 Adding or substituting epinephrine when an additional drug is
needed
 (Strong recommendation; Grade 1B).
 Vasopressin 0.03 units/min may be added
 (Weak recommendation; Grade 2A)
 Dopamine only in highly selected patients at very low risk of
arrhythmias or low heart rate
 (Weak recommendation; Grade 2C).
 Dobutamine infusion be started or added with low cardiac output)
or ongoing signs of hypoperfusion, even after adequate
intravascular volume
 (Strong recommendation; Grade 1C)

52. Inotropic Therapy
• We recommend that a trial of dobutamine infusion up to 20 μg/kg/min be administered or
added to vasopressor (if in use) in the presence of:
• myocardial dysfunction as suggested by elevated cardiac filling pressures and low
cardiac output, or
• ongoing signs of hypoperfusion, despite achieving adequate intravascular volume
and adequate mean arterial pressure. (Grade 1C)
• We recommend against the use of a strategy to increase cardiac index to predetermined
supranormal levels. (Grade 1B)
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53. Diagnosis of Infection
 Appropriate cultures before antimicrobial therapy as soon as possible (<45
minutes) (Grade 1C).
 At least two sets of blood cultures (both aerobic and anaerobic bottles)
before antimicrobial therapy, with at least one drawn percutaneously and one
drawn through each vascular access device, unless the device was recently
(<48 hours) inserted. Blood cultures can be drawn at the same time if from a
different anatomic site (Grade 1C).
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54. Diagnosis
 Cultures of other sites (preferably quantitative where
appropriate), such as urine, cerebrospinal fluid, wounds,
respiratory secretions, or other body fluids that may be the
source of infection, should also be obtained before antimicrobial
therapy if doing so does not cause significant delay in antibiotic
administration (Grade 1C).
 We suggest the use of the 1,3 β-D-glucan assay (Grade 2B),
mannan and anti-mannan antibody assays (Grade 2C) when
invasive candidiasis is in the differential diagnosis of infection.
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55. Diagnosis
 Imaging studies be performed promptly in attempts to
confirm a potential source of obscure infection. and
aggressive monitoring if the decision is made to transport
for a CT-guided needle aspiration) .
 Bedside studies, such as ultrasound, may avoid patient
transport (Ungraded).
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56. Antimicrobial Therapy
 The administration of effective intravenous antimicrobials as soon
as possible , but never beyond the first hour of recognition of
SEPSIS
 Initial empiric anti-infective therapy include one or more drugs that
have activity against all likely pathogens (bacterial and/or fungal or
viral) and that penetrate in adequate concentrations into the tissues
presumed to be the source of sepsis (Grade 1B).
 The antimicrobial regimen should be reassessed daily for potential
de-escalation to prevent the development of resistance, to reduce
toxicity, and to reduce costs (Grade 1B).
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57. Antibiotics
• Abx within 1 hr hypotension: 79.9% survival
• Survival decreased 7.6% with each hour of delay
• Mortality increased by 2nd hour post hypotension
• Time to initiation of Antibiotics was the single strongest predictor of
outcome

58. Antimicrobial Therapy …
 use of low procalcitonin levels or similar biomarkers to assist the
clinician in the discontinuation of empiric antibiotics in patients who
appeared septic, but have no subsequent evidence of infection
 Empiric therapy should attempt to provide antimicrobial activity against
the most likely pathogens based upon each patient’s presenting illness
and local patterns of infection.
 We suggest combination empiric therapy for neutropenic patients with
severe sepsis (Grade 2B) and for patients with difficult-to-treat,
multidrug-resistant bacterial pathogens such as Acinetobacter and
Pseudomonas spp.

59. Antimicrobial Therapy …
 Duration of therapy typically be 7 to 10 days if clinically indicated;
 longer courses may be appropriate in patients
 who have a slow clinical response,
 Undrainable foci of infection,
 Bacteremia with Staphylococcus aureus,
 some fungal and viral Infections, or
 Immunologic deficiencies, including neutropenia

60. Source Control
 When source control in a severely septic patient is required,
the effective intervention associated with the least
physiologic insult should be used (eg, percutaneous rather
than surgical drainage of an abscess) (Ungraded).
 If intravascular access devices are a possible source of
severe sepsis or septic shock, they should be removed
promptly after other vascular access has been established
(Ungraded).

61. Corticosteroids
 Only when Blood Pessure is not maintained with adquate flid
resuscitation and vasoacive
 Intravenous hydrocortisone alone at a dose of 200 mg per
day. Continuous Infusion preferred over bolus doses.
 Taper steroid when vasopressors are no longer required
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62. Blood product Administration
 Transfuse PRBC only when Hb%v<7.0 g/dL to target a hemoglobin
concentration of 7.0 to 9.0 g/dL in adults (Grade 1B).
 Exceptions are myocardial ischemia, severe hypoxemia, acute
hemorrhage, or ischemic coronary artery disease.
 NO Erythropoetin in sepsis
 No FFP to correct lab abnormality in absence of Bleeding or planned
invasive procedure.
 Platelet transfusion –
 <10,000 in absence of bleeding
 <20000 if bleeding risk high
 <50,000 if planned procedure, active bleeding or surgery

63. Glucose Control
• We recommend protocolized approach to blood glucose
management, commencing insulin dosing when two
consecutive blood glucose levels are >180 mg/dL.
• This protocolized approach should target upper blood
glucose <180 mg/dL rather than <110 mg/dL (Grade 1A).
• Treatment should avoid hyperglycemia (>180 mg/dL),
hypoglycemia, and wide swings in glucose levels
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64. Glucose control…
 Glucometer measured capillary blood be interpreted with
caution, as such measurements may not accurately
estimate arterial blood or plasma glucose values
 Capillary point-of-care testing found to be inaccurate with
frequent false glucose elevations over range of glucose
levels, but especially in hypoglycemic and hyperglycemic
glucose ranges and in hypotensive patients or patients
receiving catecholamines..

65. Bicarbonate Therapy
• No to sodium bicarbonate therapy for the purpose of
improving hemodynamics or reducing vasopressor
requirements in patients with hypoperfusion-induced lactic
acidemia with pH ≥7.15 (Grade 2B), in absence of Renal
acidosis.
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66. Nutrition
• We suggest administering oral or enteral feedings, as
tolerated, rather than complete fasting or provision of only
intravenous glucose within the first 48 hours after a
diagnosis of severe sepsis/septic shock (Grade 2C).
• We suggest avoiding mandatory full caloric feeding in the
first week, but rather suggest low-dose feeding (e.g., up to
500 kcal per day), advancing only as tolerated
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Marik and Zaloga. Crit Care Med. 2001;29:2264–2270
Heyland et al. JPEN J Parenter Enteral Nutr. 2003;27:355-373
Doig et al. Intensive Care Med. 2009;35:2018–2027

67. • Enteral nurtrition combined with IV Glucose supplementation
is preferred than Total parenteral Nutrition
• No evidence for the use of Arginine, Glutamine and Omega 3
fatty acid therapy during acute illness with sepsis
Nutrition…

68. Renal Replacement Therapy
• Continuous renal replacement therapies and intermittent
hemodialysis are equivalent in patients with sepsis and
acute renal failure because they achieve similar short-term
survival rates (Grade 2B).
• We suggest the use of continuous therapies to facilitate
management of fluid balance in hemodynamically unstable
septic patients (Grade 2D).
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69. Prophylaxis for VTE
 We recommend that patients with severe sepsis receive daily pharmacoprophylaxis
against VTE (Grade 1B).
 We recommend that septic patients who have a contraindication to heparin not
receive pharmacoprophylaxis (Grade 1B).
 Rather, we suggest they receive mechanical prophylactic treatment, such as
graduated compression stockings or intermittent compression devices, unless
contraindicated (Grade 2C).
 When the risk decreases, we suggest starting pharmacoprophylaxis (Grade 2C).
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70. Stress Ulcer Prophylaxis
• We recommend that stress ulcer prophylaxis using H2
blocker or proton pump inhibitor be given to patients with
sepsis/septic shock who have bleeding risk factors (Grade
1B).
• We suggest that patients without risk factors should not
receive prophylaxis (Grade 2B).
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71. Setting Goals of Care
 We recommend that goals of care and prognosis be
discussed with patients and families (Grade 1B).
 Goals of care be incorporated into treatment and end-of-life
care planning, utilizing palliative care principles where
appropriate
 Goals of care be addressed as early as feasible, but no later
than within 72 hours of ICU admission
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72. Take Home message

73. Take home message…
 Identify sepsis early
 More and faster fluid
 Send cultures early
 Antibiotic Fast <1 hr, consider early antifungals, use
biomarkers to deescalate or stop
 Earlier Inotropes, Use norepineprine
 Chase Lactic acid clearance
 Sonologic volume assessment is better than CVP
 Wet first, dry later
 Higher PEEP

74. THE END