How the Knowledge Proceeds in Intensive Care: the ARDS Example 2016, Antalya Luciano Gattinoni, MD, FRCP Georg-August-Universität Göttingen Germany INDUCTION: From particular (application) to general (law/theory) DEDUCTION: From general (law/theory) to particular (application) Usually in science i.e. series of premises or assumptions RCT, a kind of experiments Wrong or incomplete? Extracorporeal support Zapol W. JAMA 1979:242:2193-6 1) The respiratory support must provide normal PO 2 and PCO 2. 2) High FiO 2 is harmful for the lung. Providing normal blood gases by artificial lungs at reduced FiO 2 of the ventilator improves survival. 1
Correct interpretation: are wrong: Normal gases not mandatory FiO 2 not the devil Zapol W. JAMA 1979:242:2193-6 However Actual interpretation: ECMO is useless ECMO disappeared for 30 years Wrong or incomplete? PEEP trials NHLBI ARDS Clinical Trials Network; LOVS; ExPress 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. 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. The National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. N Engl J Med 2004;351:327-336. 2
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 Comment The premises are wrong, new theory has to be formulated (recruitability/severity/tv-reduction?) JAMA. 2008;299(6):637-645. doi:10.1001/jama.299.6.637 Figure Legend: Patients were censored at hospital discharge and at death in the 2 analyses, respectively. Date of download: 5/25/2015 Copyright 2015 American Medical Association. All rights reserved. Wrong or incomplete? Prone Position /1 (Trials by Gattinoni and Guerin 2004) Better oxygenation leads to better survival. six-hour prone position improves survival. Kaplan Meier Estimates of Survival at Six Months. 2001 2004 Gattinoni et al. Guérin et al. Patients (n) Study period (years) 304 1996-1999 802 1998-2002 Enrolment rate (pts/ month/unit) Trial ended early 0.28 Yes (slow enrolment) 0.24 No Gattinoni L et al. N Engl J Med 2001;345:568-573. 3
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. Patients (n) Study period (years) Enrolment rate (pts/ month/unit) Trial ended early 2006 2009 Mancebo et al. 142 1998-2002 0.24 Yes (slow enrolment) Taccone et al. 344 2004-2008 0.26 No Kaplan-Meier survival curves at 6 months of the EUPAPS population 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 One PowerPoint slide of each figure may be downloaded and used for educational not promotional purposes by an author for slide presentations only. The ATS citation line must appear in at least 10-point type on all figures in all presentations. Pharmaceutical and Medical Education companies must request permission to download and use slides, and authors and/or publishing companies using the slides for new article creations for books or journals must apply for permission. For permission requests, please contact the Publisher at dgern@thoracic.org or 212-315-6441. Minerva Anestesiol. 2010 Jun;76(6):448-54 Kaplan-Meier survival curves at 6 months of the EUPAPS population 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. Minerva Anestesiol. 2010 Jun;76(6):448-54 4
Guerin C. et al. N Engl J Med. 2013 Jun 6;368(23):2159-68 Gattinoni L. et al. Minerva Anestesiol. 2010 Jun;76(6):448-54 Comment Gas exchange unrelated with survival Stress and strain maldistribution must be relevant premises only in severe ARDS 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. Low Tidal Volume Ventilation (6 ml/kg IBW) Comment proved within the specified limits Tidal Volume 7 vs 8 ml/kg ideal body weight? Driving Airway pressure? ARDSnet. N Engl J Med. 2000 May 4;342(18):1301-8. 5
Wrong or incomplete? Early goal-directed therapy Rivers, ProCess, ARISE, ProMISe Oxygen imbalance leads to MOF In sepsis oxygen imbalance is common SvO 2 is marker of oxygen imbalance Early correction of oxygen imbalance (SvO 2 target) improves survival by decreasing MOF Probability of survival 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 45 90 135 180 Days after randomization Patients at risk (N of events) Cardiac index group (156 events) Oxygen-saturation group (164 events) Control group (157 events) 253 (133) 102 (8) 90 (4) 86 (3) 83 257 (133) 106 (16) 89 (4) 85 (1) 84 252 (129) 108 (13) 94 (4) 90 (3) 87 Gattinoni L et al. N Engl J Med 333;1025-32, 1995 Early goal direct therapy S v O 2 70% In hospital 28 days 60 days Baseline S v O 2 Control therapy n 133 Control 49.2 Treated 48.6 Mortality Treatment n 130 46.5% 30.5% 49.2% 56.9% 33.3% 44.3% P 0.009 0.01 0.03 Rivers et al. N Engl J Med 2001; 345:1368-77 P = 0.82 by the logrank test for the between-group difference N Engl J Med. 2014 May 1;370(18):1683-93 N Engl J Med. 2014 Oct 16;371(16):1496-506. 6
Comment s were performed in patients without oxygen imbalance cannot be proved or disproved Whatever conclusion on SvO 2 arbitrary Makes sense? ARDS is an inflammatory syndrome. Simvastatin has anti-inflammatory effect. (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 Makes sense? Surviving Sepsis Campaign recommends 65 mmhg pressure. (deduction) Lower or greater pressure may be good (Poor Descartes!) RCT (experiment) What do you expect? 7
Traditional (and intuitive)target Mean Arterial Pressure distribution at ICU entry (751 patients) Mean Arterial Pressure 60<MAP<70 mmhg Trials? Cardiac surgery or ongoing N patients 160 140 120 100 80 60 40 20 0 MORTALITY 65% 49% 44% 39% P <.0001 20 30 40 50 60 70 80 90 100 110 120 130 140 150 MAP (mmhg) 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. N Engl J Med. 2014 Apr 24;370(17):1583-93. Beautiful example of eternal validity Clinical trials on severe sepsis/septic shock (NEJM, 2014) Study ALBIOS SEPSISPAM TRISS ProCESS ARISE Europe Europe Europe Australia/New Geography USA (Italy) (France) (Scandinavia) Zealand (90%) Patients (N) 1810 776 998 1341 1591 Death 90 days (%) Mechanical ventilation (%) Severity Score 42.2% 43.0% 44.0% 32.0% 18.7% 79.8% 76.5% 69.0% 14% 15.2% SAPS II 48 SAPS II 56.1-57.2 SAPS II 51-52 APACHE II 20-21 APACHE II 15-16 Gattinoni et al. Intensive Care Med. 2015 Mar;41(3):551-2. Conclusions in ARDS derive (or at least should) from physiology. Physiology generates theory must be tested with appropriate experiments You ll see with ECMO 8