15 Years Of Clinical Trials In ARDS: What Progress Have We Made?

Transcription

1 15 Years Of Clinical Trials In ARDS: What Progress Have We Made? Niall D. Ferguson, MD, FRCPC, MSc Head of Critical Care Medicine University Health Network & Mount Sinai Hospital Senior Scientist, Toronto General Research Institute Associate Professor, Depts of Medicine & Physiology, Institute of Health Policy, Management and Evaluation Interdepartmental Division of Critical Care Medicine University of Toronto

2 1952: Copenhagen Polio Epidemic First month 31 patients with respiratory paralysis 27 patients died (87%)

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4 Bjørn Ibsen The tank respirator (negativepressure) did not provide adequate ventilation An elevated CO 2 was indicative of CO 2 retention, and not, as the epidemiologists thought, of metabolic alkalosis Early application of positivepressure ventilation

5 Hand ventilator used in the Copenhagen polio epidemic of 1952 by hundreds of ventilators

6 Mortality July 1952 March 1953 Months

7 AUGUST 26 TH 1952 Birth of mechanical ventilation and intensive care unit

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10 Advances in Mechanical Ventilators Improvements in technical aspects of ventilators Flow delivery Exhalation valves Microprocessor-controlled ventilators Improved monitors and monitoring Better triggering, cycling Better flow delivery systems New modes of ventilation IMV, HFV, PC-IRV, PSV, APRV, PAV, NAVA,..

11 Iatrogenic Consequences of Ventilation: First, do no harm!

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15 Observational Mortality Rate since 1994 = 40-45%

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17 RCTs: Absolutely Necessary

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21 Survival Curve

22 Why Randomise? ALLOCATION CONCEALMENT Minimise allocation bias, selection bias Balances known and unknown prognostic (confounding) factors, including time Facilitates statistical hypothesis testing, maximize statistical power

23 Alternatives to RCTs We should just carefully analyse observational data but of course we need to avoid complicated statistics.

24 Problematic RCTs Dumb idea Wrong patients Incorrect protocolization of therapy

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26 Poor Quality RCTs Inadequate concealment Unbalanced cointerventions Loss to follow-up Lack of intention-to-treat analysis Lack of blinding Bad luck Table 1 not balanced Stopped early

27 P-values are necessary but insufficient the reader must estimate the prior probability that the research hypothesis is true

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30 Interpreting RCT Results I already knew that I don t believe it

31 ARDS Network High Stretch V T : 11.8 P PLAT : RR: 18 V MIN : 13 PEEP: 8 Low Stretch V T : 6.2 ml/kg P PLAT : 25 cm H 2 O RR: 29 V MIN : 13 L/min PEEP: 9 cm H 2 O Mortality 40% Mortality 31% N Engl J Med :1301-8

32 FACCT

33 28-day Mortality: 24% - Nimbex 33% - Placebo p=0.05

34 28-day mortality: 34% Salbutamol 23% Placebo RR 1.47 ( )

35 What They Found ICU Mortality: RR 0.85 ( )

36 28-day Mortality: 16% vs. 33%; p<0.001

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38 How has practice changed? Has the evidence been a factor?

39 Mechanical ventilation practice has changed significantly from 1998 to 2004

40 Patients in 103 Repeat ICUs patients in 103 Repeat ICUs Literature Review Practice-change Hypotheses

41 Hypotheses: ARDS Decreased tidal volumes in ALI/ARDS A minimal increase in PEEP No significant increase in PC mode use No significant increase in prone ventilation

42 20 Tidal volume (ml/kg ABW) P < ± ± 1.8 (8.8 ml/kg PBW) ARDS

43 PEEP (cm of water) ± ± p=0.02 ARDS

44 3 rd International Study of Mechanical Ventilation ( 2010) Countries 37 ICUs 520 Patients 8.152

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46 Tidal Volume (ml/kg ABW) in ARDS Means & %age

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48 Where do we go from here?

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50 clinicaltrials.gov current ARDS studies

51 Reliable and Valid Definitions are ESSENTIAL to Conduct and Interpret Clinical Research

52 Berlin Definition of ARDS

53 Distribution of patients across categories of ARDS ARDS 22% % 27% Mortality Mild 50% 32% Mortality Moderate 45% Mortality Severe

54 AECC Limitations Berlin Modifications No definition of acute ALI/ARDS confusion Inconsistency of PaO 2 /F I O 2 ratio Effect of PEEP Effect of F I O 2 CXR has poor reliability PAWP & ARDS can coexist Risk factors not included No Acute definition onset defined of acute ALI/ARDS eliminated confusion 3 mutually exclusive grades of Inconsistency ARDS of PaO 2 /F I O 2 ratio Inconsistency of PaO 2 /F I O 2 ratio Effect of PEEP Minumum PEEP required F I O 2 effect reduced with Severe Effect of F I O 2 CXR clarified + examples PAWP removed CXR has poor reliability PAWP & ARDS can coexist Risk factors included Risk factors not included

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56 The importance of recognising ARDS

57 From Ware & Matthay NEJM 2000

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59 Importance of Specificity in RCTs Specific Test Non-Specific Test Other Diseases

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61 Enriching a Trial Population Goligher EC et al. Am J Respir Crit Care Med; 2015 In Press A. Conventional enrolment design épeep ARDS pa ents Randomize êpeep B. Conventional restricted (severity-based) enrolment design épeep ARDS pa ents Exclude less severely ill pa ents based on baseline P/F Randomize êpeep C. Novel restricted (response-based) enrolment design #1 épeep Responders Randomize Eligible pa ents Response assessment êpeep Non-responders Exclude

62 Study population randomized Original Trial ARDS P/F < 150 ARDS with positive O 2 response* Control group mortality 40% 49% 40% Treatment group mortality Hypothesized effect size Number required to be randomized (α = 0.05 and β = 0.2) Proportion of patients with P/F < threshold for inclusion Frequency of positive response to PEEP Total number of ARDS patients required to be evaluated 36% 43% 32% 4% 6% 8% n/a 56% n/a n/a n/a 54%** Goligher EC et al. Am J Respir Crit Care Med; 2015 In Press

63 ARMA & ALVEOLI Trials Latent Class Modeling 63

64 The Future of ARDS Trials?

65 New Monitoring Devices Electrical Impedance Tomography Extravascular Lung Water measurement Specific Elastance measurement PET Scanning Lung Ultrasound

66 New Therapeutic Devices New modes of ventilation NAVA PAV BiLevel / APRV ASV ECMO ECCO2R

67 Novel Applications ARDS Prevention PEEP Settings and Titration Transpulmonary pressure Staircase recruitment Noninvasive ventilation Neurmuscular blockers Spontaneous breathing in ARDS

68 New Therapeutics & Diagnostics Steroids Mesenchymal stem cells Specific anti-inflammatories Anti Tissue Factor Ab Biomarkers srage VEGF strem Ang2

69 Challenge Translational Medicine There is a translational block leading to a disconnect between basic science success and negative clinical trials

70 Opportunity Translational Medicine We need to make periodic revisions to our syndromic definitions Gradually incorporating more basic science into them Maintain the genotype-phenotype link We need a large detailed observational study of acute respiratory failure to further inform ARDS definitions We need to work collaboratively together on large international RCTs based on sound physiology

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72 Every science begins as philosophy and ends as art Will Durant

73 October Sheraton Centre Hotel, Toronto