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C R I S M AC R I S M A
Surviving Sepsis: where the
guidelines went wrong
Jeremy M. Kahn, MD MS
Associate Professor of Critical Care Medicine
Director, Program on Critical Care Health Policy
University of Pittsburgh
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C R I S M AC R I S M A
Disclosures
• Grant funding from NIH/HRSA
• Consulting fees from the US
Department of Veterans Affairs
• In-kind research support from Cerner
• No other industry relationships
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C R I S M AC R I S M A
Additional notes:
• I won’t be discussing bundles
• I won’t be making any Rob Ford jokes
• I think the guidelines are pretty great
• Had I known RPD and JLV would be up
here, I wouldn’t have agreed to this
talk
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C R I S M AC R I S M A
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C R I S M AC R I S M A
Outline
• Rationale for guidelines
• Review of GRADE
• Some examples and suggestions
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C R I S M AC R I S M A
Why do we have guidelines?
• Evidence is complex and voluminous
• Interpreting the evidence is inherently
subjective
Eddy Health Affairs 2007
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C R I S M AC R I S M A
Guidelines exist to serve both
steps in this process
• Rate the quality of the evidence
• Make a practice
recommendation based on
– The quality of the evidence
–Preferences and values
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C R I S M AC R I S M A
Grading of Recommendations Assessment,
Development and Evaluation (GRADE)
Strength Benefit
Separates evidence
from recs
Flexibility to incorporate values and
preferences, not just evidence
Systematic Specific road-map leads to more
consistent recommendations
Transparent Even if we disagree with the conclusions,
we can see how the conclusion was
reached
Guyatt JCE 2011
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C R I S M AC R I S M A
Strength of evidenceStudy Design Quality of Evidence Lower if Higher if
Randomized trial High (A) Risk of bias: Large effect:
-1 Serious +1 Large
-2 Very serious +2 Very large
Moderate (B) Inconsistency Dose response
-1 Serious +1 Evidence of a gradient
-2 Very serious
All plausible confounding
Indirectness + 1 Would reduce a
Observational study Low (C) -1 Serious demonstrated effected or
-2 Very serious
+1 Would suggest a
Imprecision spurious effect when
-1 Serious results show no effect
Very low (D) -2 Very serious
Publication bias
-1 Likely
-2 Very likely
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C R I S M AC R I S M A
Strength of recommendation
Factors
Quality of evidence
Balance between desirable and undesirable effects
Importance of the outcome
Costs (resources allocation)
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C R I S M AC R I S M A
Result of a GRADE evaluation
• Strength of recommendation
– Strong (1-“We recommend”)
– Weak (2- “We suggest”)
• Quality of evidence
– High (A)
– Moderate (B)
– Low (C)
– Very low (D)
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C R I S M AC R I S M A
Dellinger CCM 2012
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C R I S M AC R I S M A
Two potential missteps
• Fluid management in ARDS
• Stress ulcer prophylaxis in
mechanical ventilation
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C R I S M AC R I S M A
Fluid management in ARDS
• “We recommend a conservative fluid
strategy for patients with established
sepsis-induced ARDS who do not have
evidence of tissue perfusion (1C)”
– Strong recommendation based on low
quality evidence
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C R I S M AC R I S M A
• Directness: only 25% had sepsis
• Patient-centeredness:
– No impact on mortality
– 2.5 additional VFDs
• Relative burden
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C R I S M AC R I S M A
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C R I S M AC R I S M A
Impaired Not impaired P value Adjusted OR
PaO2 86 71 0.021.51
(1.01 – 2.26)
Conservative
fluid strategy32% 66% 0.004
3.35
(1.16 – 9.70)
Mikkelsen AJRCCM 2012
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C R I S M AC R I S M A
Stress ulcer prophylaxis
• “We recommend that stress ulcer
prophylaxis be given to patients with
severe septic shock who have
bleeding risk factors (1B)”
– Strong recommendation based on high
quality evidence
– PPIs > H2 blockers (2C)
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C R I S M AC R I S M A
Evidence
• Cited studies:
– do not compare prophylaxis to no
prophylaxis
– do not post-date 1986
• Meta-analyses do not report patient-
centered endpoints
• Potential harm
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C R I S M AC R I S M A
• No effect on mortality
• Higher mortality in patients who are
enterally fed and received H2
blockers
Marik Crit Care Med 2010
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C R I S M AC R I S M A
Herzig JAMA 2009; Howell Archives 2010
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C R I S M AC R I S M A
Strong recommendations
• Just do it
• If giving the choice, nearly all patients
would want the therapy
• Rarely base on low quality evidence
Is that the case here?
Guyatt BMJ 2008
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C R I S M AC R I S M A
GRADE to the rescue
• Guideline committee:
– Considered GI bleeding to be morbid and
worthy of prevention
– Did not find evidence of harm convincing
• Subjective but transparent
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C R I S M AC R I S M A
Just 2 examples, but…
• Of 83 adult recommendations, 13
(16%) are strong recs based on low
quality evidence
1A/B
1C/D2 A/B
2 C/D
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C R I S M AC R I S M A
Unintended consequences
• Stress ulcer prophylaxis as a quality
measure (just do it!)
• Decreases trustworthiness of the rest of
the guideline
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C R I S M AC R I S M A
Conclusions
• The Surviving Sepsis Guidelines are an
impressive undertaking that are likely
to improve sepsis care
• Guideline developers both smart and
handsome
• But
– Too many recommendations
– Too many 1 C/D recommendations
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C R I S M AC R I S M A
www.ccm.pitt.edu/crisma