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Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of Chicago Medical Center Chicago, Illinois GRADE Methodology Expert Contributing Author, “Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2012”

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Page 1: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Mark E. Nunnally, MD, FCCM

Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of Chicago Medical CenterChicago, Illinois

GRADE Methodology ExpertContributing Author, “Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2012”

Page 2: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Making GRADE work: a how-to for guidelines authors

Mark E. Nunnally, MD, FCCMAssociate Professor

Department of Anesthesia & Critical CareThe University of Chicago

Page 3: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Course objectives I

• Translate evidence into graded recommendations.

• Identify the features that reduce or increase the quality of evidence.

Page 4: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Course objectives II

• Appraise clinical data to determine quality of evidence.

• Integrate quality of evidence for an intervention with costs, the balance between desirable and undesirable effects and values to determine the strength of a recommendation.

Page 5: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Contents

• GRADE- why?• Transparency and Certainty• The Guidelines process: a methodologist’s

perspective• GRADE- components• Summary

Page 6: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Conflict of interest.

I am a GRADE advisor for the Surviving Sepsis Campaign

Page 7: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Conflict of interest.

I am also only a consultant. YOU are the experts.

Page 8: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

WHY GRADE?

Page 9: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Many guidelines, little standardizationSome inform…Some restrict…All claim to be evidence-based…

…how can we be certain a guideline is supported by the evidence?

…how can we be certain its recommendations will hold over time?

…how relevant is the recommendation to the things that matter to me?

Page 10: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Should we rate evidence?

• ‘Quality’ is a diluted term• Quality is a continuum• Decisions are always somewhat arbitrary• ‘Experts’ and clinicians don’t always share the

same view– This is one reason evidence and

recommendations should be separate.

Page 11: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Should we rate evidence?

• You need some reference• Simplicity• Transparency• Vividness

Page 12: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Grading of Recommendations Assessment, Development and

Evaluation

• www.gradeworkinggroup.org• International consensus document • Template for systematic reviews,

recommendations

http://www.gradeworkinggroup.org/
Page 13: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of
Page 14: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

TRANSPARENCY AND CERTAINTY

Page 15: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

QOE- Philosophical Bent

• We are going to make recommendations that we (or others) will subsequently change.– GRADE lets us:

• try to define how likely that is• communicate our certainty in any effect• translate findings to clinical realities, by accounting for

the costs, tradeoffs and effort behind following a recommendation

Page 16: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Example- Glycemic Control

• 2001: Van den Berghe publishes sentinel article: NEJM 2001, 345

• 2003-2008: Guidelines, protocols, quality metrics proposed

• 2009: NICE SUGAR• 2009-present: Re-write or retire

Page 17: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Be Explicit

• What are the data?• What are their limitations?• How easy is it to do something?• How confident are you in recommending?

Page 18: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

The guidelines process: a methodologist’s perspective

Page 19: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Getting from evidence to guidelines

Evidence Hierarchy• Experience• Reports• Observational Studies• RCTs• Meta-analyses

Guidelines Hierarchy• Clinical biases• Experience-based

tendencies• Cost analyses• Decision analyses• Formal Guidelines

Not all guidelines are created equal

Page 20: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

recommendation

Outcome1

Outcome2

Outcome3

Outcome4

Formulate question

Rateimportanceof outcomes

Critical

Important

Critical

Not important

Evidence Profile (GRADEpro)

Pooled estimate of effect for each outcome

Rate overall quality of evidence across outcomes

high low

1. risk of bias2. inconsistency3. indirectness4. imprecision5. publication bias

1. large effect2. dose-response3. antagonistic bias

Quality of evidence for each outcomeSelect

outcomes

High Moderate Low Very low

Formulate recommendationsFor or against an actionStrong or weak (strength)

Strong or weak:Quality of evidenceBalance benefits/downsidesValues and preferencesResource use (cost)

Wording “We recommend…” | “Clinicians should…” “We suggest…” | “Clinicians might…”

Systematic Review(outcomes across studies)

action

PICOrate down

RCT observational

rate

up

12

start

High | Moderate | Low | Very low

unambiguous clear implications for action transparent (values & preferences statement)

systematic review of evidence

Page 21: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Question

Evidence

Judge

PICO

Summarize

QOESOR

Page 22: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

THE QUESTION

Page 23: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

PICO

• Population – Ventilated patients, APACHE scores

• Intervention– Medicine, therapy, education, systems intervention

• Comparison– High(how high) versus low (how low) tidal volume

• Outcome– FBI: mortality (at what follow-up), LOS, VAP

Page 24: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Rating outcomes

• 7-9: critical [death, disability or both]• 4-6: important [skin breakdown, sepsis]• 1-3: limited [ileus, ICU stay]

Page 25: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

THE EVIDENCE

Page 26: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Collect evidence

• Be thorough– Use explicit search strategies– Decide on published v unpublished data

• Consider gray literature in some cases– Proceedings papers– Abstracts– Clinicaltrials.gov

– ALWAYS consider comparator

Page 27: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Assembling Evidence is HardData have to be summarized to inform

Page 28: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

GRADE pragmatic approach

• Get a good meta-analysis (MA)• If no MA, identify main studies• If possible, do your own MA• If no MA, describe main studies/results

– Be explicit (inclusion/exclusion, flaws)• Keep the link between recommendation and

evidence

Page 29: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Meta Analysis-the Good and the Bad

Page 30: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Don’t GRADE everything

• No plausible alternative– Surveying for infection, resuscitating shock,

practicing quality improvement

• Recommend to consider– As opposed to not considering?

• Statements lacking specificity– Intervention, Comparison, relevant Outcomes

(good and bad)

Page 31: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

JUDGING

Page 32: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Judge Evidence and Recommendation

• Unique to GRADE• Related, but distinct• Recommendation must take clinical realities

into account– Costs– Burdens– Benefits/risks– Values

Page 33: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Recommendations

• Strength

• Direction

Have 2 Components:

Page 34: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

GRADE COMPONENTS

Page 35: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Entering the GRADE meat-grinder

• RCT- High quality• Observational study- Low quality• Expert report- Very Low quality

Page 36: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Grade Down

Page 37: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Grade Down

Page 38: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Study Limitations/Risk of Bias

• Bias definition: 1. Unequal distribution of risk factors (confounders) across study groups. 2. Factors that systematically change study effects to result in a directional change in the signal.

Page 39: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Risk of Bias

• GRADE treats bias by individual outcomes– Pain scores- strong effect if unblinded– Mortality- effect of blinding less clear– Loss to follow-up for different outcome windows

• With multiple studies and different risks of bias, quality should be judged by the relative contribution of studies to the confidence in the effect.

Page 40: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Risk of Bias

• Blinding– Patient, clinician, data assessor

• Concealment of allocation• Intention-to-treat principle

– Absence negates the balance from randomization

Page 41: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Risk of Bias

• Stopping Early for Benefit, especially if trials have < 500 events– Brassler D, et al. JAMA, 2010;303(12):1180-7

• Selective outcome reporting– Only positive outcomes, composite results only, or

lack of pre-specified outcomes

• Loss to follow-up– Significance relates to # of events

Page 42: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Risk of bias- Observational Studies

• Prognosis can differ• Groups can have multiple differences:

– Time– Place– Population– Co-morbidityThis is why observational studies typically enter as

“Low” quality of evidence

Page 43: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Grade Down

Page 44: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Inconsistency

• Definition: 1. Heterogeneity. 2. Lack of similarity of point estimates or confidence intervals. 3. Variable findings unexplained by a priori hypotheses. 4. Subgroup effects that cannot be sufficiently explained.

Page 45: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Inconsistency

• Generally, effects are looked at in relative terms, rather than absolute– Subgroups may have different baseline rates, but

similar relative effects

Page 46: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Inconsistency

• Inconsistency can come from study diversity:– Populations– Interventions – Outcomes– Study methods

• Credible inconsistency may lead to split recommendations

Page 47: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Basic assessments of inconsistency

• Point estimates vary widely• Little or no CI overlap

• Test of heterogeneity shows a low p value– 𝛘2

• I2 is large:(P ≤ 0.10 may be sufficient)

Page 48: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of
Page 49: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of
Page 50: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of
Page 51: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of
Page 52: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Context

• It is only significant inconsistency if the variability would influence a clinical decision– If point estimates and CIs favor treatment over

costs/burdens/side effects, no need to downgrade

Page 53: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Inconsistency

• Example: • Low-dose steroids in sepsis:

– 6 studies, 3 high baseline mortality, 3 low, with difference in effect:

• Patel GP. Am J Respir Crit Care Med 2012;185:133-139

Page 54: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Grade Down

Page 55: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Indirectness

• Definition: 1. Evidence does not directly compare to the clinical question of interest. 2. Differing patients, interventions, comparisons or outcomes in available studies necessitate extrapolation of evidence to question being addressed.

Page 56: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Indirectness

• Examples: – Animal studies: downgrade 1 or 2 levels, in

general, but consider the relevance of the data (toxicity v therapeutic benefit)

– If drug A>B and B>C, is A>C?– Low-fat diet: US versus French population

• Setting, co-”interventions,” genetics

– Surrogate outcomes: Blood pressure control versus cardiovascular events

Page 57: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Indirectness

• Example: – H2RA and PPI: C. Difficile infection: observational

study not direct to critically ill patients, but with interesting effect: Very Low QOE

• Leonard J et al. Am J Gastroenterol 2007;102: 2047

Page 58: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Grade Down

Page 59: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Imprecision

• Definition: 1. High impact of random error on evidence quality. 2. Wide range of results to be expected from repetitive study. 3. Wide range in which the truth likely lies.

Page 60: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Imprecision

• Driven by # of events and by degree of effect• 95% confidence intervals may encompass

harm and benefit– Taken in the context of the recommendation

• More important: 95% CIs embrace absolute values that reduce our confidence in a recommendation

Page 61: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Use absolute effects

Page 62: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of
Page 63: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of
Page 64: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of
Page 65: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Toxicity

Page 66: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Imprecision

• Example: – NE v Vasopressin: Mortality CI wide, spanned RR =

1.• for ventricular arrhythmias, RR 0.47 (0.38, 0.58), but 21

events FRAGILE

– H2RA and pneumonia: unable to exclude harm– Negative factors may require tighter CIs:

• Side effects/toxicity• Burdens/costs

Page 67: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Grade Down

Page 68: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Publication Bias

• Definition: 1. Studies with statistically significant results more likely to be counted than negative studies. 2. Smaller, high-effect studies disproportionately impact published literature. 3. Published commercially-funded studies are more likely to be positive.

Page 69: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Publication Bias

• Publication: + Studies > – Studies (RR 1.78)– Hopewell S, The Cochrane Database of Systematic

Reviews, 2007.

• – Studies: delayed, obscure publication• + studies: duplicate publication• Small studies, industry sponsor ⇒

↑publication bias

Page 70: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Publication Bias

• How to detect? It’s more difficult than one might think.– Look for:

• Small trials• Conflicts in authors/study sponsors• Duplications• Abstracts, grey literature with negative findings• Unpublished data

– Ideally, we would trend MAs over time

Page 71: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Publication BiasPooled Estimate

Page 72: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Publication BiasSelective PublicationGreater Study LimitationsMore Restrictive/Responsive Population

Page 73: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Publication Bias

Page 74: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Publication Bias-Testing

• Tests of asymmetry• Imputing missing information• Repeated MA over time

Page 75: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Publication Bias-Addressing the Problem

• Thorough research– Gray Literature– FDA submissions– Abstracts, proceedings– Author Contact

• Clinicaltrials.gov– N.B: only for RCTs, not observational studies

Page 76: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Grade Up

Page 77: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Grade Up

Page 78: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Grade Up

Page 79: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Grade Up

Page 80: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Moving Up- Examples

• Very strong, consistent association; no plausible confounders, up 2 grades– insulin in diabetic ketoacidosis– antibiotics in septic shock

• Strong, consistent association with no plausible confounders up 1 grade

Page 81: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of
Page 82: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

How to get GRADEpro on your computer?

• Cochrane IMS website• cc-ims.net/revman/gradepro/download• http://www.cc-ims.net/revman/gradepro/dow

nload• Google ‘gradepro’

http://www.cc-ims.net/revman/gradepro/download
http://www.cc-ims.net/revman/gradepro/download
http://www.cc-ims.net/revman/gradepro/download
Page 83: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of
Page 84: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

GRADE output: Summary of Findings

Page 85: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

GRADE output: Evidence Profile

Quality assessmentSummary of findings

Importance

No of patients Effect

QualityNo of studies Design Limitations Inconsistency Indirectness Imprecision

Other considerations

longer term (7 day) low dose (up to 300 mg/day of hydrocortisone)

glucocorticosteroids

controlRelative(95% CI)

Absolute

Mortality, 28 days

12 randomised trials

no serious limitations

serious1 no serious indirectness

no serious imprecision

none236/629 (37.5%)

264/599 (44.1%)

RR 0.84 (0.72 to 0.97)

71 fewer per 1000 (from 13 fewer to 123

fewer)

MODERATE

CRITICAL2

GI bleeding

3 randomised trials

no serious limitations

no serious inconsistency3

no serious indirectness

serious4 none

65/827 (7.9%) 56/767 (7.3%)RR 1.12 (0.81 to

1.53)

9 more per 1000 (from 14

fewer to 39 more)

MODERATE

IMPORTANT

Superinfections

45 randomised trials

no serious limitations

no serious inconsistency6

no serious indirectness

no serious imprecision7

none184/983 (18.7%)

170/934 (18.2%)

RR 1.01 (0.82 to 1.25)

2 more per 1000 (from 33

fewer to 46 more)

HIGH

IMPORTANT

1 Meta-regression examining the effect of severity of illness (baseline mortality) on efficacy suggested an effect - p value 0.04 using fixed effect and 0.06 using random effect model. JAMA 2009; 302:1643-1645.2 Reported for all trials3 I2=04 RR up to 1.535 need to check6 I2=8%

Question: Should longer term (7 day) low dose (up to 300 mg/day of hydrocortisone) glucocorticosteroids be used in severe sepsis and septic shock?Settings: ICUBibliography: Annane 2009

Page 86: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Final QOE

• High: A , ++++, ↑↑↑↑• Medium: B, +++-, ↑↑↑ • Low: C, ++--, ↑↑• Very Low: D, +---, ↑

Page 87: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Alternate QOE interpretation

• High- Further research very unlikely to change confidence

• Moderate- likely to have an important impact• Low- very likely to impact• Very Low- uncertain

Page 88: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Separate QOE and Strength of Recommendation

• Evidence: high or low quality?• likelihood estimates are true and adequate

• Recommendation: weak or strong?• confidence that following recommendation will cause

more good than harm

GRADE’s defining feature

Page 89: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Factors- STRONG vs WEAK

Page 90: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Factors- STRONG vs WEAK

Page 91: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Factors- STRONG vs WEAK

Page 92: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Factors- STRONG vs WEAK

Page 93: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Factors- STRONG vs WEAK

Page 94: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

STRONG to stakeholders

• Patient: most people would want it• Clinician: most should receive, uniform

behavior• Policymaker: adopt as policy, use as quality

indicator

Page 95: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

WEAK to stakeholders

• Patient: many people would not want it• Clinician: help patient make a balanced

decision– decision aid might be needed

• Policymaker: debate

Page 96: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Final Strength of Recommendations

Page 97: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

recommendation

Outcome1

Outcome2

Outcome3

Outcome4

Formulate question

Rateimportanceof outcomes

Critical

Important

Critical

Not important

Evidence Profile (GRADEpro)

Pooled estimate of effect for each outcome

Rate overall quality of evidence across outcomes

high low

1. risk of bias2. inconsistency3. indirectness4. imprecision5. publication bias

1. large effect2. dose-response3. antagonistic bias

Quality of evidence for each outcomeSelect

outcomes

High Moderate Low Very low

Formulate recommendationsFor or against an actionStrong or weak (strength)

Strong or weak:Quality of evidenceBalance benefits/downsidesValues and preferencesResource use (cost)

Wording “We recommend…” | “Clinicians should…” “We suggest…” | “Clinicians might…”

Systematic Review(outcomes across studies)

action

PICOrate down

RCT observational

rate

up

12

start

High | Moderate | Low | Very low

unambiguous clear implications for action transparent (values & preferences statement)

systematic review of evidence

Page 98: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Useful Resources

• BMJ: GRADE series– GRADE Introduction:

• BMJ 2008;336;924-926

– Overview of Quality of Evidence:• BMJ 2008;336;995-998

– Translating Evidence to Recommendations:• BMJ 2008;336;1049-1051

– How to handle disagreements in guidelines panels: BMJ 2008;337:a744

Page 99: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Useful Resources II

• Journal of Clinical Epidemiology– GRADE Guidelines Series: 1-9. 2011– April, 2011 (64(4)): 1-4

• Intro, framing the question and outcomes, rating quality of evidence, risk of bias

– December, 2011 (64(12)): 5-9• Publication bias, imprecision, inconsistency,

indirectness, rating up

Page 100: Mark E. Nunnally, MD, FCCM Co-Director, Critical Care Fellowship and Associate Professor in the Department of Anesthesia and Critical Care University of

Useful Resources II

• Journal of Clinical Epidemiology– GRADE Guidelines Series: 1-9. 2011– April, 2011 (64(4)): 1-4

• Intro, framing the question and outcomes, rating quality of evidence, risk of bias

– December, 2011 (64(12)): 5-9• Publication bias, imprecision, inconsistency,

indirectness, rating up


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