Whats HOT and Whats not in sepsis

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Whats HOT and Whats not in sepsis?

• Tim Walsh
• Edinburgh Royal Infirmary
• Scotland

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A Case

• 62 year old man
• 3 days of increasing breathlessness
• Productive cough
• Smoker
• Fever
• No recent travel
• Office worker
• No pets

• Hypoxic (SpO2 84)
• RR 45/min
• Hypotensive BP 70/30
• Tachycardic 130/min
• Pyrexial T 38.5 C
• Cold peripheries
• CXR LML/LUL consolidation

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A Case

• Hb 10.5g/dL WCC 20 platelets 70
• Urea 15 mmol/L Creatinine 230 umol/L
• LFTs normal
• Coagulation screen normal
• ECG normal
• Blood gas
• PaO2 7 kPa (60 O2) PaCO2 3.2 kPa H 65 nmol/L
  lactate 4.8 mmol/L

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Sepsis

• Documented or suspected infection with one or
  more of
• Fever
• Hypothermia
• Tachypnoea (or low PaCO2)
• Heart rate gt90/minute
• Leucocytosis or leucopenia
• Normal WBCs with gt10 immature forms

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Severe Sepsis

• Sepsis associated with Organ dysfunction
• Hypoxaemia
• Oliguria or raised creatinine
• Coagulopathy
• Thrombocytopenia
• Elevated bilirubin
• Elevated blood lactate
• Arterial hypotension

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Septic shock

• Acute circulatory failure unexplained by other
  causes
• Persistent arterial hypotension unresponsive to
  fluids

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The GRADE system(Grades of Recommendation,
Assessment, Development, and Evaluation)

• Quality of Evidence
• Methodology
• A. RCT
• B. Downgraded RCT/upgraded observational study
• C. Well-done observational study
• D. Case series or expert opinion

• Factors decreasing strength of evidence
• Poor quality trials
• Inconsistent results
• Indirect evidence
• Imprecise results
• High likelihood reporting bias
• Factors increasing strength of evidence
• Large treatment effects especially if direct
  evidence
• Dose response effects

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The GRADE systemSome factors determining a
strong versus weak recommendationStrong
1 Weak 2

• The quality of the available evidence
• The importance of the outcomes to patients and
  clinicians
• The baseline risk of the outcome
• Magnitude of benefits
• Size and numbers of potential adverse effects
• Precision of the estimates of the effects
• Costs

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What is the priority?

• Begin fluid resuscitation immediately
• Warning signals hypotension and lactate (gt4
  mmol/L)
• Grade 1C

• Resuscitation goals
• MAP gt65 mmHg
• CVP 8-12 mmHg (higher if ventilated or impaired
  cardiac function
• Grade 1C

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ABCs

• Fluids
• Crystalloid or colloid (ratio 3-4 to 1 volume)
• Response to boluses
• Little to support albumin
• Recent concern regarding starches

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Case

• More history
• Underwent elective uneventful aortic aneurysm
  repair 1month ago.
• Discharged 3 weeks ago
• Received prophylactic antibiotics for procedure

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What is the priority?

• Identify source
• What samples to take?
• Cultures from relevant sites
• Two or blood cultures (at least one percutaneous)
• From vascular access devices in place gt48 hours
  (esp CVP lines)
• Dont delay antibiotics unnecessarily
• Grade 1C

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Antibiotics

• Begin antibiotics within an hour of recognition
• Appropriate cover
• Adequate penetration to suspected/proven site
• Grade 1B

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Harbarth S et al. Am J Med 2003
115529-535 Analysis of data from the lenercept
(antiTNF p55 fusion protein antibody RCT)
1342 patients enrolled with severe sepsis or
early septic shock
904 microbiologically confirmed infecting
organism (52 bloodstream)
If patient did not receive at least one
antimicrobial to which isolated organism
susceptible within 24 hours from diagnosis severe
sepsis considered inappropriate
211 inappropriate initial therapy What was the
outcome (28 days mortality) for appropriate
versus inappropriate groups?
Lenercept 24 vs 40 P 0.001 Placebo 25 vs 38
P 0.01 Overall 24 vs 39 P lt 0.001
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MacArthur RD et al. Clin Infect Dis 2004
38284-288 Analysis of data from the MONARCS
trial (antiTNF (afelimomab antibody RCT)
2634 patients enrolled with sepsis syndrome
Independent blinded committee classified patients
by primary site of infection, causative organism,
and adequacy of empiric antibiotic therapy
Broad definition of adequate empiric therapy
based on in vitro susceptibility and/or
initiation between 24 hours before to 72 hours
after enrolment (also considered no organism as
adequate)
Adequate empiric therapy Inadequate empiric
therapy Mortality 33 43 P lt
0.001 Difference present across virtually all
sub groups of organisms Greater difference shock
versus no shock
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Which antibiotic

• Our patient
• Ceftriaxone/ or Meropenem/
• Clarithromycin Vancomycin
• ?

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Blood stream infection Leibovici L et al. J
Intern Med 1998 244379
3415 hospital patients

• Most important
• paediatrics
• intraadominal infections
• skin/soft tissues

Appropriate 2158 20 died
Inappropriate 1255 34 died
P 0.0001
Ibrahim EH et al. Chest 2000 118 146
492 ICU patients
Appropriate 345 28 died
Inappropriate 147 62 died
P lt 0.001 RR 2.18
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Blood stream infection Leibovici L et al. J
Intern Med 1998 244379
3415 hospital patients

• Most important
• paediatrics
• intraadominal infections
• skin/soft tissues

Appropriate 2158 20 died
Inappropriate 1255 34 died
P 0.0001
Ibrahim EH et al. Chest 2000 118 146
492 ICU patients
Appropriate 345 28 died
Inappropriate 147 62 died
P lt 0.001 RR 2.18
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Case

• 1500 mLs Gelofusine given
• Blood cultures and sputum sent
• Meropenem/vancomycin given
• Required ventilation
• Still MAP 55 mmHg
• CVP inserted (reading 12 mmHg)
• A-line inserted

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What next?
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Early goal-directed therapy in the treatment of
severe sepsis and septic shockRivers E et al.
NEJM 2001 345 1368
266 patients presenting to ER with severe sepsis
or septic shock
or
133 standard therapy 6 hours
130 goal-directed therapy for 6 hours using
algorithm
Admitted to ICU (staff blinded)
Primary outcome mortality
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Goal directed algorithm
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Goal directed algorithm
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Central venous saturation a simple surrogate for
oxygen supply/demand imbalance
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• Mortality ()
• Control Treatment p NNT
• Hospital 46.5 30.5 0.009 7
• 60 days 56.9 44.3 0.03 8
• Rivers E et al, N Engl J Med 2001 34513681377

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What should you do?

• MAP gt65mmHg (Grade 1C)
• Norepinephrine initial vasopressor (or dopamine)
  (Grade 1C)
• Second line agents if non-responsive
• Consider adrenaline or vasopressin (Grade 2B)
• If an inotrope is needed because cardiac output
  is inadequate use dobutamine (grade 1C)

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The case

• Admitted to ICU
• Stabilised on noradrenaline, mechanical
  ventilation, fluids and antibiotics
• Worsening renal function

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Anything else?

• Standard ICU bundles
• Follow standard ICU protocols, eg blood
  transfusion, glucose control, ventilation
  management
• Steroids
• Human activated protein C

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Steroids

• High dose steroids are of no benefit (Grade 1A)
• Physiological dose steroids (maximum 300mg per
  24 hours)
• Decrease time in shock
• Increase new infections
• May increase ICU neuropathy
• Controversial effects on mortality
• Consider hydrocortisone for patients with shock
  not responding to fluids and vasopressors alone
  (Grade 2C)

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hrAPC

• Controversial
• Mortality benefit restricted to patients at
  highest risk of death (multiple organ failures,
  especially septic shock)
• Increase risk of serious bleeding by about 2
• Higher risk in surgical patients
• Use in patients with sepsis and multiple organ
  failure, high perceived risk of death, and low
  risk of bleeding (Grade 2B)

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Post hoc analyses Ely et al. Crit Care Med 2003
31 12-19 Sub-group analyses
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Site
Early sepsis
Late sepsis
Lungs
Hypoxic
Hypoxic
Anaemic
Anaemic
Blood
Distributive or convective
Distributive or convective
Tissues
Cytopathic
Cytopathic
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Site
Early sepsis
Late sepsis
Lungs
Hypoxic
Hypoxic
Anaemic
Anaemic
Blood
Distributive or convective
Distributive or convective
Tissues
Cytopathic
Cytopathic
Reversible shock
Irreversible shock
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Golden rules

• Recognise severe sepsis early

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TIME IS TISSUE
TISSUE IS LIVES
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Relation between organ failures and mortality

• Number of organ failures Mortality ()
• 1 11
• 2 25
• 3 51
• 4 61
• 5 68
• 6 90

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Golden rules
TIME IS TISSUE

• Recognise severe sepsis early

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TIME IS TISSUE