Evidence and MedicineEvidence and Medicine

Bradford HillBradford HillStrength of associationStrength of associationConsistency of associationConsistency of associationSpecificitySpecificityTemporalityTemporalityBiologic gradientBiologic gradientPlausibilityPlausibilityCoherence Coherence ExperimentationExperimentationAnalogyAnalogy

Evidence and MedicineObjectives:Objectives:

Judicious skepticismJudicious skepticismDirected investigationDirected investigationResist the urge to do somethingResist the urge to do something

OutcomesDeathDeathDiseaseDiseaseDisabilityDisabilityDespair/ DysphoriaDespair/ DysphoriaDebtDebt

21

5

101

1 2

8

7

8

12

4

3

1

1

2

8

7

2

1

1

12

8

1

5

15

6

Not

Men

tione

d

Rou

tine

Expe

rimen

tal

Rar

e/N

ever

Spec

ific

MMMM

MM

Textbook/ReviewRecommendations

Odds Ratio (Log Scale)

0.5 1.0 2.0

Favours Treatment Favours Control

RCTs Pts

1 23

2 65

3 149

4 316 7 1793

10 254411 265115 331117 392922 5452

P<.01

23 5767

27 612530 634633 657143 21 05954 22 051

67 47 53165 47 185

70 48 154

P<.001

P<.00001

CumulativeYear

1960

1965

1970

1980

1985

1990

Thrombolytic Therapy

Prophylactic Lidocaine in MIProphylactic Lidocaine in MI

1970 2 304

1974 9 1451

1976 11 1686

1978 12 1986

1985 14 8412

1988 15 8745

9 1 1

8 0 2

5 0 2

8 0 3

14 4 6

4 2 1

1989 - 1st meta-analysis published

RecommendationsYes No Not mentioned

Favors treatment Favors placeboOutcome = death

Relative risk (CI)0.5 1 1.5 2 Cumulative

Year # RCTs Subjects

Calcium Channel Blocker Post-MICalcium Channel Blocker Post-MI

0.5 1 1.5 2

1988 - 1st meta-analysis published

1984 4 486

1985 7 587

1986 11 5857

1987 12 5879

1988 16 6420

2 3 8

2 3 6

2 2 6

7 10 7

0 5 2

Relative risk (CI)

Outcome = death

CumulativeYear # RCTs Subjects

RecommendationsYes No Not mentioned

Favors treatment Favors placebo

Growth HormoneGrowth Hormone• strong physiological rationalestrong physiological rationale

– high dose GH reverses -ve nitrogen balance in high dose GH reverses -ve nitrogen balance in severe burns, trauma, sepsis, other critically illsevere burns, trauma, sepsis, other critically ill

– preserves muscle glutamine, preserves muscle glutamine, hand-grip strength, hand-grip strength, improves cough, increases MIPSimproves cough, increases MIPS

• randomized trial resultsrandomized trial results– two RCTs, one Finland, one other Europetwo RCTs, one Finland, one other Europe– heterogeneous ICU pts, expected stay 10 daysheterogeneous ICU pts, expected stay 10 days– Finland: 20% mortality control, 39% GH, p < 0.001Finland: 20% mortality control, 39% GH, p < 0.001– Europe: 18% mortality control, 44% GH, p < 0.001Europe: 18% mortality control, 44% GH, p < 0.001

Failures of physiological Failures of physiological rationalerationale

• cardiology examplescardiology examples

• chronic heart failure chronic heart failure – milrinone, amrinone, ibopamine, epoprostonolmilrinone, amrinone, ibopamine, epoprostonol– beta-blockers in heart failurebeta-blockers in heart failure

• rhythm disturbancesrhythm disturbances– encainide and flecainide and other Class I encainide and flecainide and other Class I

agentsagents

Physiology failure in ICUPhysiology failure in ICU• penetrating chest traumapenetrating chest trauma

– early volume replacement early volume replacement • increased mortalityincreased mortality

• nitric oxide nitric oxide – impressive improved oxygenationimpressive improved oxygenation– pooled results RR: 1.12 (0.90-1.40) pooled results RR: 1.12 (0.90-1.40)

• prone positioning prone positioning – impressive improved oxygenationimpressive improved oxygenation– three negative RCTsthree negative RCTs

Beta blockers airflow Beta blockers airflow obstructionobstruction

• do you give beta blockers?do you give beta blockers?– COPD?COPD?– asthma?asthma?

• systematic review 17 blinded x-over trials systematic review 17 blinded x-over trials cardioselective bb in 226 COPD ptscardioselective bb in 226 COPD pts– no difference in FEV1 (short or long-term) or no difference in FEV1 (short or long-term) or

symptoms (short or long)symptoms (short or long)

• systematic review 29 blinded RCTs, 381 mild to systematic review 29 blinded RCTs, 381 mild to moderate asthmatics moderate asthmatics – 8% drop in FEV1 in short term8% drop in FEV1 in short term– no drop in FEV1 in longer studies, no change in no drop in FEV1 in longer studies, no change in

symptoms, inhaler usesymptoms, inhaler use

Critical Care ExamplesHistoric practiceHistoric practiceThe logicThe logicThe resultsThe resultsYour practiceYour practice

Critical Care ExamplesThe PAC trialThe PAC trialIntensive InsulinIntensive InsulinSaline vs AlbuminSaline vs AlbuminLess Intensive InsulinLess Intensive InsulinRenal ReplacementRenal ReplacementTransfusion TriggersTransfusion Triggers

Hierarchy of EvidenceHierarchy of EvidenceMeta-analysis of RCTsMeta-analysis of RCTssystematic review of RCTssystematic review of RCTs

Individual RCTIndividual RCTObservational studiesObservational studies

patient-important outcomespatient-important outcomes

Basic researchBasic researchtest tube, animal, human physiologytest tube, animal, human physiology

Clinical experienceClinical experience

Model of evidence based Model of evidence based clinical decisionsclinical decisions

clinical circumstancesclinical circumstances

patient preferencepatient preference research research evidenceevidence

Clinical expertise