How the knowledge proceeds

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How the Knowledge Proceeds in Intensive Care:

the ARDS Example 2016, Antalya

Luciano Gattinoni, MD, FRCP Georg-August-Universität Göttingen

Germany

DEDUCTION: From general (law/theory) to

particular (application)

INDUCTION: From particular (application) to

general (law/theory)

Usually in science Inductive reasoning

Theory

Hypothesis

Experiment

Prove - Disprove

i.e. series of premises or assumptions

RCT, a kind of experiments

Inductive reasoning

Theory

Hypothesis

Experiment

Prove - Disprove

Makes sense?

•  Right •  Wrong or incomplete?


Inductive reasoning

Theory

Hypothesis

Experiment

Prove - Disprove

Makes sense?

•  Right

•  Wrong or incomplete?


Extracorporeal support Zapol W. JAMA 1979:242:2193-6

1) The respiratory support must provide normal PO2 and PCO2. 2) High FiO2 is harmful for the lung.

Deductive hypothesis Providing normal blood gases by artificial lungs at reduced FiO2 of the ventilator improves survival.

Premises

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Zapol W. JAMA 1979:242:2193-6

Correct interpretation:

Premises are wrong: •  Normal gases not mandatory •  FiO2 not the devil

However…

Actual interpretation:

ECMO is useless

ECMO disappeared for 30 years

Inductive reasoning

Theory

Hypothesis

Experiment

Prove - Disprove

Makes sense?

•  Right



PEEP trials NHLBI ARDS Clinical Trials Network; LOVS; ExPress

1) Some level of PEEP is always necessary for oxygenation 2) The adverse effects of higher PEEP (overdistension) are inferior to its beneficial effects (prevention of damages induced by intra-tidal collapse).

Using higher PEEP improves survival. Deductive hypothesis

Premises

The National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. N Engl J Med 2004;351:327-336.

Probabilities of Survival and of Discharge Home While Breathing without Assistance, from the Day of Randomization (Day 0) to Day 60 among Patients with Acute Lung Injury and ARDS, According to

Whether Patients Received Lower or Higher Levels of PEEP.

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Date of download: 5/25/2015 Copyright © 2015 American Medical Association. All rights reserved.

From: Ventilation Strategy Using Low Tidal Volumes, Recruitment Maneuvers, and High Positive End-Expiratory Pressure for Acute Lung Injury and Acute Respiratory Distress Syndrome: A Randomized Controlled Trial

JAMA. 2008;299(6):637-645. doi:10.1001/jama.299.6.637

Patients were censored at hospital discharge and at death in the 2 analyses, respectively.Figure Legend:

The premises are wrong, new theory has to be formulated (recruitability/severity/TV-reduction?)

Comment

Inductive reasoning

Theory

Hypothesis

Experiment

Prove - Disprove

Makes sense?

•  Right •  Wrong or

incomplete?


Prone Position /1 (Trials by Gattinoni and Guerin 2004)

Better oxygenation leads to better survival.

six-hour prone position improves survival. Deductive hypothesis

Premises

Patients (n)

Study period (years)

Enrolment rate (pts/month/unit)

Trial ended early

Gattinoni et al. 304

1996-1999

0.28

Yes (slow enrolment)

Guérin et al. 802

1998-2002

0.24

No

2001 2004

Gattinoni L et al. N Engl J Med 2001;345:568-573.

Kaplan–Meier Estimates of Survival at Six Months.

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Prone Position /2 Trials by Mancebo and Taccone

Prone position in ARDS increases lung homogeneity decreasing the uneven distribution of stress and strain thus decreasing the lung damage.

long term prone position decreases mortality by decreasing stress and strain maldistribution in all ARDS patients.

Deductive hypothesis

Premises

Mancebo et al. 142

1998-2002

0.24

Yes (slow enrolment)

Taccone et al. 344

2004-2008

0.26

No

2006 2009

Patients (n)

Study period (years)

Enrolment rate (pts/month/unit)

Trial ended early

Figure 5. Kaplan-Meier estimates of intensive care unit survival for the supine and the prone groups (up to 60 d).

Am J Respir Crit Care Med, http://www.atsjournals.org/doi/abs/10.1164/rccm.200503-353OC Published in: Jordi Mancebo; Rafael Fernández; Lluis Blanch; Gemma Rialp; Federico Gordo; Miquel Ferrer; Fernando Rodríguez; Pau Garro; Pilar Ricart; Immaculada Vallverdú; Ignasi Gich; José Castaño; Pilar Saura; Guillermo Domínguez; Alfons Bonet; Richard K. Albert; Am J Respir Crit Care Med 2006, 173, 1233-1239. DOI: 10.1164/rccm.200503-353OC © 2006 The American Thoracic Society

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Kaplan-Meier survival curves at 6 months of the EUPAPS population

Minerva Anestesiol. 2010 Jun;76(6):448-54

Kaplan-Meier survival curves at 6 months of the EUPAPS population

Minerva Anestesiol. 2010 Jun;76(6):448-54

Prone Position /3 Trial by Guerin 2013

Prone position in ARDS decreases the uneven distribution of stress and strain thus decreasing the lung damage, only in severe ARDS patients (moro inhomogeneous).

Long term prone position works it only in severe ARDS patents. Deductive hypothesis

Premises

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Gattinoni L. et al. Minerva Anestesiol. 2010 Jun;76(6):448-54

Guerin C. et al. N Engl J Med. 2013 Jun 6;368(23):2159-68

•  Gas exchange unrelated with survival •  Stress and strain maldistribution must be

relevant •  Right premises only in severe ARDS

Comment

Inductive reasoning

Theory

Hypothesis

Experiment

Prove - Disprove

Makes sense?



High versus low tidal volume ventilation (ARDSnet. N Engl J Med. 2000 May 4;342(18):1301-8.)

1) Twelve mL/kg ideal body weight, causes unphysiological strain in a size-reduced ARDS lung. 2) This strain increases lung inflammation and inflammatory cytokine may reach distal organs.

Halving the tidal volume considered harmful (and accepting hypercapnia) decreases mortality attributable to high tidal volume mechanical ventilation.


Premises

ARDSnet. N Engl J Med. 2000 May 4;342(18):1301-8.

Low Tidal Volume Ventilation (6 mL/kg IBW)

•  Tidal Volume 7 vs 8 mL/kg ideal body weight?

•  Driving Airway pressure?

Comment

•  Theory proved within the specified limits

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Inductive reasoning

Theory

Hypothesis

Experiment

Prove - Disprove

Makes sense?


•  Right


Early goal-directed therapy Rivers, ProCess, ARISE, ProMISe

•  Oxygen imbalance leads to MOF •  In sepsis oxygen imbalance is common •  SvO2 is marker of oxygen imbalance

Early correction of oxygen imbalance (SvO2 target) improves survival by decreasing MOF


Premises

Pro

babi

lity

of s

urvi

val

Days after randomization 0 45 90 135 180

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Patients at risk (N° of events)

257 (133) 106 (16) 89 (4) 85 (1) 84

Oxygen-saturation group (164 events)

252 (129) 108 (13) 94 (4) 90 (3) 87

Control group (157 events)

253 (133) 102 (8) 90 (4) 86 (3) 83

Cardiac index group (156 events)

Gattinoni L et al. N Engl J Med 333;1025-32, 1995

Early goal direct therapy SvO2 70%

Baseline SvO2 Control 49.2 Treated 48.6

In hospital

28 days

60 days

Control therapy n° 133

Treatment n° 130

P

Mortality

46.5% 30.5%

49.2%

56.9%

33.3%

44.3%

0.009

0.01

0.03

Rivers et al. N Engl J Med 2001; 345:1368-77

N Engl J Med. 2014 May 1;370(18):1683-93

P = 0.82 by the log-rank test for the between-group difference

N Engl J Med. 2014 Oct 16;371(16):1496-506.

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Comment

•  Experiments were performed in patients without oxygen imbalance

•  Theory cannot be proved or disproved

•  Whatever conclusion on SvO2 arbitrary

Inductive reasoning

Theory

Hypothesis

Experiment

Prove - Disprove

Makes sense? •  Right •  Wrong or incomplete?


Theory ARDS is an inflammatory syndrome.

Simvastatin has anti-inflammatory effect.

Hypothesis (deduction) Treatment with enteral simvastatin improves

ARDS outcome.

RCT (experiment) Simvastatin therapy did

not improve clinical outcomes in patients with ARDS.

Ki/lung inhomogeneity interaction and gas/tissue composition

MILD

MODERATE

SEVERE

Inductive reasoning

Theory

Hypothesis

Experiment

Prove - Disprove

Makes sense? •  Right •  Wrong or incomplete?


Theory Surviving Sepsis Campaign recommends 65

mmHg pressure.

Hypothesis (deduction) Lower or greater pressure may be good

(Poor Descartes!)

RCT (experiment) What do you expect?

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Traditional (and intuitive)Target

Mean Arterial Pressure 60<MAP<70 mmHg

Trials? Cardiac surgery or ongoing

Mean Arterial Pressure distribution at ICU entry (751 patients)

MAP (mmHg)20 30 40 50 60 70 80 90 100 110 120 130 140 150

N p

atie

nts

0

20

40

60

80

100

120

140

160MORTALITY 65% 49% 44% 39%

P <.0001

N Engl J Med. 2014 Apr 24;370(17):1583-93.

MAP 80 to 85 mm Hg

MAP 65 to 70 mm Hg

RCTs, deductive method, may work only if the theories, assumptions and premises

are strong.

This rarely happens in ICU.

Study ALBIOS SEPSISPAM TRISS ProCESS ARISE

Geography Europe (Italy)

Europe (France)

Europe (Scandinavia) USA

Australia/New Zealand (90%)

Patients (N) 1810 776 998 1341 1591

Death 90 days (%)

42.2% 43.0% 44.0% 32.0% 18.7%

Mechanical ventilation

(%) 79.8% 76.5% 69.0% 14% 15.2%

Severity Score SAPS II ≈

48 SAPS II ≈ 56.1-57.2

SAPS II ≈ 51-52

APACHE II ≈ 20-21

APACHE II ≈ 15-16

Beautiful example of eternal validity Clinical trials on severe sepsis/septic shock (NEJM, 2014)

Gattinoni et al. Intensive Care Med. 2015 Mar;41(3):551-2.

Conclusions

•  Inductive reasoning in ARDS derive (or at least should) from physiology.

•  Physiology generates theory •  Theory must be tested with

appropriate experiments

You’ll see with ECMO…

How the knowledge proceeds

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