Latest Sepsis Guidelines

1. SURVIVING SEPSIS CAMPAIGN

2. OUTLINE
• Introduction
• Definitions
– SIRS
– Sepsis
– Severe sepsis
– Septic shock
• Pathophysiology
• Protocols for treatment
• SURVIVING SEPSIS CAMPAIGN

3. INTRODUCTION
• Major cause of morbidity and mortality
worldwide.
• Leading cause of death in noncoronary ICU.
• 11th leading cause of death overall.
• Mortality
– Sepsis: 30% - 50%
– Septic Shock: 50% - 60%
• For every hour delay in the administration of
treatment, there is an associated 6% rise in
mortality.

4. SIRS
• Widespread inflammatory response to a
variety of severe clinical insults.
• Clinically recognized by the presence of 2 or
more of the following:
– Temperature >38C or < 36C
– Heart Rate >90
– Respiratory Rate > 20 or PaCO2 <32
– WBC > 12,000, < 4000 or > 10% immature forms

5. Stages In the Development of SIRS
(Bone, 1996)
• Stage 1. In response to injury / infection, the local
environment produces cytokines.
• Stage 2. Small amounts of cytokines are released
into the circulation:
• Recruitment of inflammatory cells.
• Acute Phase Response.
• Normally kept in check by endogenous anti-inflammatory
mediators (IL-10, PGE2, Antibodies, Cytokine receptor
antagonists).

6. Stages In the Development of SIRS
• Stage 3. Failure to control inflammatory
cascade:
• Loss of capillary integrity.
• Stimulation of Nitric Oxide Production.
• Maldistribution of microvascular blood flow.
• Organ injury and dysfunction.

7. SEPSIS
• SIRS criteria + evidence of infection, or:
– White cells in normally sterile body fluid
– Perforated viscus
– Radiographic evidence of pneumonia
– Syndrome associated with a high risk of infection

8. SEVERE SEPSIS
• Sepsis criteria + evidence of organ dysfunction or tissue
hypoperfusion, including:
– CV: Systolic BP < 90 mmHg, MAP < 70 mm Hg for at least 1 hour
despite volume resuscitation, or the use of vasopressors.
– Renal: Urine output < 0.5 ml/kg body weight/hr for 1 hour
despite volume resuscitation
– Pulmonary: PaO2/FiO2 < 250 in absence of pneumonia as
infection source or < 200 in presence of pneumonia as infection
source.
– Hematologic: Platelet count < 1L or decreased by 50% in 3 days
– Metabolic: pH < 7.3 and plasma lactate > upper normal
– INR > 1.5, S. Bil > 2 mg/dl, S. Creat >2 mg/dl

9. SEPTIC SHOCK
• Septic Shock
– Hypotension secondary to Sepsis that is resistant
to adequate fluid administration.

10. PATHOPHYSIOLOGY

11. Pathophysiology of Sepsis-Induced
Organ Injury
• Multiple Organ Dysfunction (MODS) and Multiple
Organ Failure (MOF) result from diffuse cell injury /
death resulting in compromised organ function.
• Mechanisms of cell injury / death:
• Cellular Necrosis (ischemic injury).
• Apoptosis.
• Leukocyte-mediated tissue injury.
• Cytopathic Hypoxia

12. Pathophysiology of Sepsis-Induced
Ischemic Organ Injury
• Cytokine production leads to massive production of
endogenous vasodilators.
• Structural changes in the endothelium result in
extravasation of intravascular fluid into interstitium and
subsequent tissue edema.
• Plugging of select microvascular beds with neutrophils,
fibrin aggregates, and microthrombi impair microvascular
perfusion.
• Organ-specific vasoconstriction.

13. Pathogenesis of Vasodilation in Sepsis
• Loss of Sympathetic Responsiveness:
• Down-regulation of adrenergic receptor number and
sensitivity, possible altered signal transduction.
• Vasodilatory Inflammatory Mediators.
• Endotoxin has direct vasodilatory effects.
• Increased Nitric Oxide Production.

14. Infection
Inflammatory
Mediators
Endothelial
Dysfunction
Vasodilation
Hypotension Vasoconstriction Edema
Maldistribution of Microvascular Blood Flow
Organ Dysfunction
Microvascular Plugging
Ischemia
Cell Death

15. MANAGEMENT

16. PIRO staging for sepsis
• Aims to describe the sepsis considering the
relationship amongst premorbid factors,
infection insult & host response and how it
impacts on development of organ dysfuction
& prognosis of septic patients

18. SEPSIS SIX
• The Sepsis Six is the name given to a bundle of medical
therapies designed to reduce the mortality of patients
with sepsis.
• The Sepsis Six consists of three diagnostic and three
therapeutic steps – all to be delivered within one hour
of the initial diagnosis of sepsis.
– Deliver high-flow oxygen.
– Take blood cultures.
– Administer empiric intravenous antibiotics.
– Measure serum lactate and send full blood count.
– Start intravenous fluid resuscitation.
– Commence accurate urine output measurement.
Daniels et al. The sepsis six and the severe sepsis resuscitation bundle: a prospective observational cohort study. Emerg Med J
(2011) vol. 28 (6) pp. 507-12

20. • The Surviving Sepsis Campaign (SSC) - global
initiative to bring together professional
organizations in reducing mortality from
sepsis.
• The Surviving Sepsis Campaign and the
Institute for Healthcare Improvement teamed
up to achieve a 25 percent reduction in sepsis
mortality by 2009.

21. History of the guideline
• 2004
– The initial SSC guidelines incorporated the evidence
available through the end of 2003
• 2008
– Publication analyzed evidence available through the
end of 2007
• 2012
– The most current iteration is based on updated
literature search incorporated into the evolving
manuscript through fall 2012

22. Selection and Organization of
Committee Members
• Appointed by the Society of Critical Care
Medicine and European Society of Intensive
Care Medicine
• Sepsis expertise
• Four clinicians with experience in the GRADE
process application (referred as GRADE group
or Evidence-Based Medicine [EBM] group)

23. GRADING
• Grading of Recommendations Assessment,
Development and Evaluation (GRADE) system
• Quality of evidence
– High (grade A)
– Moderate (grade B)
– Low (grade C)
– Very low (grade D)
• Classification of recommendations
– Strong (grade 1)
– Weak (grade 2)

24. GRADING
• Strength of recommendation and quality of
evidence assessed using GRADE criteria,
presented in brackets after each guideline. For
added clarity:
• Indicates a strong recommendation or “we
recommend.”
o Indicates a weak recommendation or “we
suggest.”
UG means the evidence is ungraded

25. MANAGEMENT OF SEVERE SEPSIS
• Initial Resuscitation and Infection Issues
• Hemodynamic Support and Adjunctive
Therapy
• Supportive Therapy of Severe Sepsis

26. Initial Resuscitation and Infection
Issues
WORLD SEPSIS DAY – 13 SEPTEMBER

28. Initial Resuscitation and Infection
Issues
• A. Initial Resuscitation
• B. Screening for Sepsis and Performance
Improvement
• C. Diagnosis
• D. Antimicrobial Therapy
• E. Source Control
• F. Infection Prevention

29. A. Initial Resuscitation
• Resuscitation of patients with sepsis- induced
tissue hypoperfusion
– defined as hypotension persisting after initial fluid
challenge or blood lactate concentration ≥ 4 mmol/L
• 1.EGDT (first 6 hrs of resuscitation)
– a) Central venous pressure (CVP) 8–12 mm Hg
– b) Mean arterial pressure (MAP) ≥ 65 mm Hg
– c) Urine output ≥ 0.5 mL/kg/hr
– d) Scvo2 or Svo2 70% or 65%, respectively- 1C
2. If Elevated Lactate- target resuscitation to
normalize lactate – 2C

30. How to Resuscitate
• Resuscitate with IVF to reduce lactate
• Resuscitate early ( if <6h- mortality by 16%)
• If Hypotension + Lactate – mortality 16%
• if ScvO2 <70% / SvO2 <65% despite adequate
intravascular volume repletion with persisting
tissue hypoperfusion-
Dobutamine @ max 20 μg/kg/min
OR
PRBC- to achieve Hct >= 30%

31. How to Resuscitate
• Target CVP 12-25mm Hg – if known Ventricular
compliance
• Don’t Use CVP guided IVF if known PAH
SEVERE SEPSIS INCIDENCE MORTALITY
Hypotension + Lactate
>4mmol/l
16% 46
Hypotension Only 49% 36%
Only Lactate >4mmol/l 5.4% 30%

32. B. Screening for Sepsis and
Performance Improvement
• Routine screening of seriously ill patients for
severe sepsis to
– increase the early identification of sepsis (1C)
– allow implementation of early sepsis therapy
• Performance improvement efforts to improve
patient outcomes and decrease sepsis-related
mortality.

33. B. Screening for Sepsis and
Performance Improvement*
• The SSC guidelines and bundles as the basis of
a sepsis performance improvement program
• A bundle is a selected set of elements of care
derived from evidence based practice
guidelines
– effect on outcomes beyond implementing the
individual elements alone.

35. SEVERE SEPSIS
SEPTIC SHOCK
2016- not mandatory if
early recognition of
sepsis & timely Abx
given

36. How to Screen
• Use Sepsis screening tools
• Many tools eg. St. Joseph Mercy, Sepsis Surv
Campaign etc
• Any can be used as per hospital
requirements/equipment

38. C. Diagnosis
• Cultures before antibiotic therapy
– Without causing significant delay
• At least 2 blood cultures (both aerobic and anaerobic)
– percutaneous
– drawn through each lumen of each vascular access device
(if >48 hrs)
• Imaging studies in attempts to confirm a potential
source of infection
– Balancing risks & benefits

39. C. Diagnosis
o Other Cultures if indicated- Urine, CSF, sputum etc
o Vol of blood sample > 10ml
o Adjunct Methods- PCR, Mass Spectroscopy,
Microarrays
o Procalcitonin & CRP – can’t differentiate b/w Sepsis
& other Inflammatory States (Not Recommended)
o 1,3 β-d-glucan assay (2B), mannan and anti-mannan
antibody assays
– If invasive candidiasis suspected

40. D. Antimicrobial Therapy
• Goal - Administration of effective i/v antibiotics
within the first hour of recognition of septic shock
(grade 1B) and severe sepsis (grade 1C).
• ? Premixed Abx Solutions
• Abx Bolus vs Infusions
• Initial empiric anti-infective therapy
– one or more drugs
– activity against all likely pathogens (bacterial and/or fungal
or viral) presumed to be the source of sepsis (grade 1B)

41. D. Antimicrobial Therapy
• Reassessed daily for potential de-escalation
(grade 1B)
– prevent the development of resistance
– to reduce toxicity
– to reduce costs
o Combination empiric therapy (>=2 classes of
Abx)-
o neutropenic patients with severe sepsis (grade 2B)
o difficult-to-treat, multidrug-resistant bacterial
pathogens such as Acinetobacter and
Pseudomonas spp.

42. D. Antimicrobial Therapy
o Extended spectrum beta-lactam + AGS/FQs for
P. aeruginosa bacteremia
o Beta-lactam and macrolide for bacteremic
Streptococcus pneumoniae infections
o Not for more than 3–5 days
o De-escalation to the most appropriate single
therapy as per susceptibility

43. D. Antimicrobial Therapy
o Duration of therapy 7–10 days
o Longer courses
o slow clinical response
o undrainable foci of infection
o bacteremia with S. aureus
o some fungal and viral infections
o immunologic deficiencies, including neutropenia
(grade 2C).

44. D. Antimicrobial Therapy
o Antiviral therapy – suspected to be viral origin
(grade 2C).
• Should not be used in severe inflammatory
states determined to be of non-infectious
cause (UG)

45. How to Give Antibiotics
• Choice- based on
– History
– Previous Abx usage
– Clinical Features
– Community pathogenic susceptibility
– Renal/ Hepatic function
• M/C Organisms- G+ > G- > Mixed

46. E. Source Control
• Specific anatomical diagnosis of infection
requiring emergent source control- Imaging
• Intervention for source control within the first
12 hr of diagnosis.
• Source control with least physiological insult
in severe sepsis.

47. E. Source Control
• Intravascular access suspected to be source of
severe sepsis or septic shock – remove
promptly after other vascular access has been
established (UG).
• Surgical intervention done when minimally
invasive approaches are inadequate / when
diagnostic uncertainty persists despite
imaging

48. F. Infection Prevention
o Selective Oral decontamination(SOD)- 2%
gentamicin, 2% colstin, and 2% vancomycin paste
has been shown to reduce VAP
o Oral CHG be used (2B)
o Selective digestive decontamination (SDD)-
o oral cavity paste + GI tract solution, and IV antibiotics
x 4 days.
o Eliminates harmful bacteria & allows native flora to
thrive. – CONTOVERSIAL

49. HAEMODYNAMIC SUPPORT &
ADJUNCTIVE THERAPY

50. HAEMODYNAMIC SUPPORT &
ADJUNCTIVE THERAPY
• FLUID THERAPY
• VASOPRESSORS
• INOTROPIC SUPPORT
• CORTICOSTEROIDS

51. FLUID THERAPY
• Crystalloids*
• Against the use of hydroxyethyl starches
o Albumin for fluid resuscitation when patients
require substantial amounts of crystalloids
• Initial fluid challenge in patients with sepsis-
induced tissue hypoperfusion & suspected of
hypovolemia @ 30 mL/kg of crystalloids
(minimum)*

52. VASOPRESSORS
• Target a mean arterial pressure (MAP) of 65 mm Hg
• Norepinephrine* as the first choice vasopressor
o Epinephrine added when an additional agent is needed
to maintain adequate B.P.
• Vasopressin 0.03 U/min added to NE for raising MAP or
decreasing NE dosage (UG)
• Low dose vasopressin not recommended as the single
initial vasopressor for sepsis-induced hypotension (UG)
• Vasopressin doses > 0.03-0.04 U/min reserved for
salvage therapy (UG)

53. VASOPRESSORS
• Dopamine as an alternative vasopressor agent to
NE only in highly selected patients
– with low risk of tachyarrhythmias
– absolute or relative bradycardia
• Phenylephrine not recommended except when
– NE associated with serious arrhythmias
– cardiac output high and BP persistently low
– as salvage therapy when combined
inotrope/vasopressor drugs and low dose vasopressin
have failed to achieve MAP

54. VASOPRESSORS
• Low dose dopamine should not be used for
renal protection

55. INOTROPIC THERAPY
• Trial of dobutamine infusion up to 20
mcg/kg/min be administered or added to
vasopressor (if in use) (grade 1C)
– myocardial dysfunction suggested by elevated
cardiac filling pressures and low cardiac output
– ongoing signs of hypoperfusion, despite achieving
adequate intravascular volume and adequate
MAP.

56. CORTICOSTEROID
o Not indicated if adequate fluid resuscitation
and vasopressor therapy able to restore
hemodynamic stability
o In case not achievable, iv hydrocortisone at a
dose of 200 mg per day
• Corticosteroids not be administered for
treatment of sepsis in the absence of shock

57. CORTICOSTEROID
o Not using the ACTH stimulation test to identify
adults with septic shock who should receive
hydrocortisone (grade 2B).
o In treated patients hydrocortisone tapered
when vasopressors are no longer required
o Low-dose hydrocortisone to be given as
continuous infusion rather than repetitive
bolus injections

58. OTHER SUPPORTIVE THERAPY

59. OTHER SUPPORTIVE THERAPY
• Blood products administration
• Immunoglobulins*
• Selenium*
• Mechanical ventilation of sepsis induced ARDS
• rhAPC*
• Sedation, anaelgesia & neuromuscular blockade
• Glucose control
• Renal replacement therapy
• Bicarbonate therapy
• DVT prophylaxis
• Stress ulcer prophylaxis
• Nutrition*
• Setting goals of care

60. BLOOD PRODUCT ADMINISTRATION
• PRBC transfusion only when Hb <7.0 g/dl
– Target Hb of 7.0 –9.0 g/dl
• EPO not be used as specific treatment of
anemia associated with severe sepsis
o FFP not be used to correct laboratory clotting
abnormalities in the absence of bleeding or
planned invasive procedures
• Not using antithrombin for the treatment of
severe sepsis and septic shock

61. BLOOD PRODUCT ADMINISTRATION
o Platelet transfusion
– <10,000/mm3 in the absence of apparent
bleeding*
– < 20,000/mm3 if the patient has a significant risk
of bleeding
– Higher platelet counts (≥50,000/mm3) advised for
active bleeding, surgery, or invasive procedures

62. IMMUNOGLOBULINS*
SELENIUM*

63. MECHANICAL VENTILATION OF SEPSIS
INDUCED ARDS
• Target tidal volume of 6 mL/kg predicted body
weight in patients with sepsis-induced ARDS
• Positive end-expiratory pressure (PEEP) be
applied to avoid alveolar collapse at end
expiration
• Mechanically ventilated sepsis patients be
maintained with the head end elevation of 30-45
o
– limit aspiration risk
– prevent the development of VAP

64. MECHANICAL VENTILATION OF SEPSIS
INDUCED ARDS
• Weaning protocol to be in place
• Spontaneous breathing trials regularly to evaluate the
ability to discontinue mechanical ventilation if
– arousable
– hemodynamically stable (without vasopressor agents)
– no new potentially serious conditions
– low ventilatory and end-expiratory pressure requirements
– low Fio2 requirements which can be met safely delivered
with a face mask or nasal cannula.
• If the spontaneous breathing trial is successful,
consideration should be given for extubation

65. MECHANICAL VENTILATION OF SEPSIS
INDUCED ARDS
• Beta 2-agonists not be used for sepsis-induced
ARDS, in absence of bronchospasm
• Pulmonary artery catheter not to be used
routinely for patients with sepsis-induced
ARDS
• Conservative fluid strategy for patients with
established sepsis-induced ARDS without
evidence of tissue hypoperfusion

66. rhAPC (drotecogin alpha)*
• PROWESS trial (2001)
– Included in 2004 SSC
• Downgraded to suggestion in 2008 SSC
• PROWESS SHOCK trial (2011)
– No benefit
– Drug withdrawn from market
– No recommendation in SSC 2012

67. SEDATION, ANAELGESIA &
NEUROMUSCULAR BLOCKADE
• Continuous or intermittent sedation be
minimized in mechanically ventilated sepsis
patients
– Morphine vs morphine + propofol/midazolam
• NMBAs avoided if possible in the septic patient
without ARDS
– risk of prolonged neuromuscular blockade following
discontinuation.
– If required, either intermittent bolus or continuous
infusion with monitoring of the depth of blockade

68. GLUCOSE CONTROL
• Protocolised approach
– Insulin when two consecutive blood glucose > 180
mg/dL
– upper target blood glucose ≤180 mg/dL rather
than ≤ 110 mg/dL*
• Blood glucose values every 1–2 hrs until
glucose values and insulin infusion rates stable
and then every 4 hrs thereafter

69. RENAL REPLACEMENT THERAPY
o Continuous renal replacement therapies and
intermittent hemodialysis equivalent in
patients with severe sepsis and acute renal
failure (grade 2B).
o Continuous therapies to facilitate management
of fluid balance in hemodynamically unstable
septic patients (grade 2D).

70. BICARBONATE THERAPY
o NaHCO3 therapy not useful for the purpose of
improving hemodynamics or reducing
vasopressor requirements in patients with
hypoperfusion-induced lactic acidemia.

71. DVT PROPHYLAXIS
• VTE prophylaxis required using daily
subcutaneous LMWH*
• If creatinine clearance <30 mL/min, use
dalteparin or UFH
o Combination of pharmacologic therapy and
intermittent pneumatic compression devices
whenever possible
o C/I for heparin – use mechanical prophylaxis.
Start pharmacological Rx when risk decreases.

72. STRESS ULCER PROPHYLAXIS
• Stress ulcer prophylaxis using H2 blocker or
proton pump inhibitor in patients with GI
bleeding risk factors
– Coagulopathy
– Mechanical ventilation for at least 48 hrs
– Hypotension
o PPIs > H2RA*
o Patients without risk factors do not receive
prophylaxis

73. NUTRITION*
o Oral or enteral feeding, as tolerated, rather than
complete fasting or only i/v glucose within the first 48
hours after diagnosis of severe sepsis/septic shock
o Low dose feeding > full caloric feeding in the first week
(upto 500 Calories/day, advancing as tolerated)
o Use i/v glucose + enteral nutrition rather than TPN
alone or parenteral nutrition + enteral feeding in the
first 7 days
• Nutrition without specific immunomodulating
supplementation

74. SETTING GOALS OF CARE
• Discuss goals of care and prognosis with
patients and families
• Goals of care to be incorporated into
treatment and end-of-life care planning

75. CONCLUSION
• Optimum treatment of severe sepsis and
septic shock is a dynamic and ever evolving
process.
• SSC provides guidelines for evolving protocols
at institution.

76. THANK YOU