Computational simulation of patients with respiratory disease - what is it good for? Declan Bates Professor of Bioengineering Co-Director WISB /

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1 Computational simulation of patients with respiratory disease - what is it good for? Declan Bates Professor of Bioengineering Co-Director WISB / SynBio CDT / ICSM School of Engineering University of Warwick

2 Optimising paediatric / neonatal critical care Talk Overview Introduction to Systems Medicine Simulators as systems engineering tools for therapeutic optimisation Protective ventilation in acute respiratory distress syndrome (ARDS) Treating pulmonary hypertension in chronic obstructive pulmonary disease (COPD)

3 Introduction to Systems Medicine Systems Medicine: Fuses disciplines underlying medicine (biology, physiology, pathology, pharmacology, epidemiology and therapeutics) with computer science, mathematics, and engineering Exploits the development of computational models that map the (mal)functioning of the human body, its processes and interactions across multiple levels of structural and functional organisation - from molecular reactions, to cell-cell interactions in tissues, to the physiology of organs and organ systems

4 Introduction to Systems Medicine Key drivers: Data avalanches (at all scales) Dramatic increases in computational power (and reductions in cost) Patient demand for more personalised treatment strategies Faltering industrial drug development pipeline too slow, too expensive, not enough new targets, too many failed clinical trials Reduction, refinement & replacement of animal models Attention of regulatory agencies

5 USING THIS CONTENT... II PUBLISHER... II TABLE OF CONTENT... III PREAMBLE... V THE NEED FOR A NEW CONCEPT IN MEDICINE... V ABBREVIATIONS... 2 WHY IS Strong SYSTEMS MEDICINE interest NEEDED?... from funding agencies: 3 A PARADIGM SHIFT TOWARD IMPLEMENTING SYSTEMS MEDICINE... 5 BACKGROUND... 6 A NEW PARADIGM IN HEALTHCARE... 6 WHY THIS ROADMAP?... 7 THE AIMS OF THE ROADMAP ARE TO:... 7 TO DEFINE OR NOT DEFINE?... 7 DEFINITION OF SYSTEMS MEDICINE... 7 STATE OF THE ART... 8 THE CHALLENGE OF DISEASE COMPLEXITY... 8 RELEVANCE OF SYSTEMS MEDICINE TO CLINICIANS... 9 HARNESSING COMPUTATIONAL, STATISTICAL AND MATHEMATICAL TOOLS TO ANALYSE AND INTERPRET BIOMEDICAL DATA... 9 RECOMMENDATION IMPLEMENTATION STRATEGY FOR SYSTEMS MEDICINE THE TEN KEY AREAS FOR A SUCCESSFUL IMPLEMENTATION OF SYSTEMS MEDICINE IMPROVING THE DESIGN OF CLINICAL TRIALS METHODOLOGY AND TECHNOLOGY DEVELOPMENT INCLUDING MODELLING DATA GENERATION TECHNOLOGICAL INFRASTRUCTURE PATIENT STRATIFICATION FOR A MORE PERSONALIZED MEDICINE WORKING WITH INDUSTRY ETHICAL AND REGULATORY ISSUES MULTIDISCIPLINARY TRAINING STAKEHOLDER ENGAGEMENT: COMMUNITY BUILDING, NETWORKING AND DISSEMINATING THE SYSTEMS MEDICINE CONCEPT INTEGRATION OF NATIONAL EFFORTS IN SYSTEMS MEDICINE AND WITHIN THE EU CORE PRIORITY ACTIONS Introduction to Systems Medicine THE CAS

6 Introduction to Systems Medicine Strong interest from industry: Virtual patients allow novel treatment strategies to be investigated across different types of patients in a safe, cost-effective and reproducible in silico environment Entelos: asthma, obesity, Type 1 and Type 2 diabetes, rheumatoid arthritis, cholesterol metabolism, cardiovascular, skin sensitization, etc. Bio-Simulation Market to exceed $2B by 2020 US FDA starting to explore use of simulators for certification

7 Simulators as systems engineering tools for therapeutic optimisation The problem: Treatment strategies for critical lung disease essentially based on mechanical ventilation to restore physiological flows and tissue oxygenation Despite numerous studies: Mortality rate of ICU patients has not changed significantly over the past 30 years Still at about 35% Little progress in shortening the period of time spent on the ventilator

8 Simulators as systems engineering tools for therapeutic optimisation The problem: Very difficult to conduct clinical research on critically ill patients many practical / ethical issues Animal models not fit for purpose Limited understanding of the human/machine interface Difficult to look inside the lung Clinical trials massively expensive and difficult

9 A computational simulator that includes representations of multiple, interacting organ systems (cardiac, vascular, pulmonary, etc) Simulators as systems engineering tools for therapeutic optimisation Multiple, independent, viscoelastic, gasexchanging alveolar compartments Interdependent blood-gas solubilities Pulsatile blood flow generated by a multichamber heart Heterogeneous distributions of

10 Verification & Validation: Statistical clinical approaches + formal engineering methods Essential to convince clinicians and regulatory authorities Simulators as systems engineering tools for therapeutic optimisation

11 Optimising settings ventilator Optimal settings are different for different disease states Protective ventilation in acute respiratory distress syndrome (ARDS) Lower risk of lung injury Sweet Spot Combinatorial complexity of the problem defeats clinical intuition Better gas exchange A. Das, P.P. Menon, J. Hardman and D.G. Bates, Optimization of Ventilation Settings for Pulmonary Disease States, IEEE Transactions on Biomedical Engineering, A. Das, O. Cole, M. Chikhani, W. Wang, J.G. Hardman and D.G. Bates, "Evaluation of lung recruitment maneuvers in Acute Respiratory Distress Syndrome using computer simulation", Critical Care, M. Chikhani, A. Das, M. Haque, W. Wang, D.G. Bates, and J.G. Hardman, "High PEEP in ARDS: evaluating the

12 Protective ventilation in acute respiratory distress syndrome (ARDS) Optimising ventilator settings: PEEP: pressure in the lungs at the end of expiration ΔP: plateau

13 Optimising ventilator settings: Protective ventilation in acute respiratory distress syndrome (ARDS) PEEP: pressure in the lungs at the end of expiration ΔP: plateau

14 Optimising ventilator settings: Protective ventilation in acute respiratory distress syndrome (ARDS) A B C D E F G H I J K L A. Das, L. Camporota, J.G. Hardman and D.G. Bates, "What links ventilator driving pressure with survival in the acute respiratory distress syndrome?", under review, Critical Care Medicine, 2018.

15 Optimising ventilator settings: Protective ventilation in acute respiratory distress syndrome (ARDS) A B C D E F G H I J K L M N O P Q R S T U A. Das, L. Camporota, J.G. Hardman and D.G. Bates, "What links ventilator driving pressure with survival in the acute respiratory distress syndrome?", under review, Critical Care Medicine, 2018.

16 COPD: Treating pulmonary hypertension in chronic obstructive pulmonary disease (COPD) A leading cause of mortality and disability Predicted to be the 3rd greatest cause of death worldwide by 2020 Causes: smoking (mainly), long-term exposure to lung irritants such as industrial dust and chemical fumes, preterm birth, inherited factors A progressive disease, associated with increasing frequency and severity of exacerbations

17 Treating pulmonary hypertension in chronic obstructive pulmonary disease (COPD) What we want to match: Measured outputs + V/Q curves Healthy lung Ventilation and Perfusion must be matched at the alveolar capillary level ideal V/Q ratio is 1

18 Deadspac Treating pulmonary hypertension in chronic obstructive pulmonary disease (COPD) What we want to match: Measured outputs + V/Q curves Shunt Diseased lung Disease increases number of alveoli with low and high V/Q ratios (shunt and dead space, respectively)

19 Treating pulmonary hypertension in chronic obstructive pulmonary disease (COPD) Automated matching to patient V/Q curves: compartments 50 compartments 100 Need sufficient model complexity to represent individual patients W. Wang, A. Das, T. Ali, O. Cole, M. Chikhani, M. Haque, J.G. Hardman and D.G. Bates, "Can computer simulators accurately represent the pathophysiology of individual COPD patients?", Intensive Care Medicine

20 Treating pulmonary hypertension in chronic obstructive pulmonary disease (COPD) The problem: Pulmonary Hypertension (PH) One of the most serious complications of COPD A progressive and debilitating condition associated with a sustained increase in: mean pulmonary artery pressure (mpap) pulmonary vascular resistance (PVR) Joint work with:

21 Treating pulmonary hypertension in chronic obstructive pulmonary disease (COPD) The problem: Various drugs with different modes of action investigated as potential PH-specific therapies in clinical studies Generally aim for a dilation or relaxation of the pulmonary arterial vessels, thus reducing the arterial pressure Sildenafil PDE 5 inhibitor Riociguat - soluble guanylate synthase (sgc) stimulator

22 Treating pulmonary hypertension in chronic obstructive pulmonary disease (COPD) In recent clinical trials: Systemic (oral) administration of Riociguat resulted in: Improved 6-minute walk distance Significant reductions in mpap and PVR But Deterioration of V/Q matching and oxygenation Why?

23 Treating pulmonary hypertension in chronic obstructive pulmonary disease (COPD) Hypoxic vasoconstriction Natural physiological response that reduces blood flow to hypoxic (unoxygenated) regions of the lung Systemic (oral) administration of of Riociguat inhibits hypoxic vasoconstriction by increasing blood flow throughout the whole

24 Treating pulmonary hypertension in chronic obstructive pulmonary disease (COPD) Hypoxic vasoconstriction Natural physiological response that reduces blood flow to hypoxic (unoxygenated) regions of the lung Systemic (oral) administration of of Riociguat inhibits hypoxic vasoconstriction by increasing blood flow throughout the whole PaO2 reduced by 13% PaCO2 increased by 4% Deadspace Shunt

25 Treating pulmonary hypertension in chronic obstructive pulmonary disease (COPD) What if the drug was administered via inhalation? Here Now the drug should only be deposited in those regions of the lung that are oxygenated Could achieve same level of PVR reduction without worsening oxygenation? Not Here

26 Treating pulmonary hypertension in chronic obstructive pulmonary disease (COPD) Model matching: PVR reduction due to drug:

27 Treating pulmonary hypertension in chronic obstructive pulmonary disease (COPD) Assuming the same PVR reduction, we modelled systemic drug application and administration via dry powder inhalation (DPI) DPI is associated with a deep breath and hence a transitory reduction in airway resistance:

28 Even better under exercise Treating pulmonary hypertension in chronic obstructive pulmonary disease (COPD) Results PaO2 (mmhg) PaO2 (mmhg) PaO2 (mmhg) Patient 1 Patient 2 Patient 3 Systemic Application PaCO2 (mmhg) PaCO2 (mmhg) Inhalation with Deep Breath at Rest Inhalation with Deep Breath under Exercise PaCO2 (mmhg) W. Wang, A. Das, W. Schmitt, J.G. Hardman, G. Weimann and D.G. Bates, "An inhaled sgc modulator can lower G +20.2% H PH in COPD patients without deteriorating oxygenation", 50 in press, CPT: Pharmacometrics -11.2% & Systems 120 Hg) A C E +5.1% +0.8% +2.4% Exercise -29.4% -24.3% -18.6% +1.6% +1.5% +1.7% mhg) B D -3.3% -2.0% -2.5% Exercise Inhalation with Normal Breath F +9.9% +8.8% +9.0% Deterioration in oxygenation after systematic application matches that seen in clinical trials +0.1% +0.0% -0.7% No deterioration in oxygenation when drug administered via DPI

29 Optimising paediatric / neonatal critical care Two new collaborations with paediatric intensive care clinicians: Simulator adapted to paediatric physiology: S. Saffaran, A. Das, J.G. Hardman, N. Yehya, and D.G. Bates, "Development and Validation of a Computational Simulator for Pediatric ARDS Patients", in proceedings of the 39th Annual International Conference of the IEEE Engineering in Medicine and Biology Society, JeJu Island, S. Korea, 2017.

30 present the distribution of patients driving pressures and mechanical power. Tables: Optimising paediatric / neonatal critical care Table 1. Patient characteristics and mechanical ventilator settings for each individual patient, and as mean and standard deviations (SD) across the cohort. Patient Age Weight FiO 2 RR V T PEEP PF OI PaO 2 P E CO 2 PaCO 2 PIP mpaw (y) (kg) (bpm) (ml/kg) (cmh 2O) (mmhg) (cmh 2O) # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # Mean SD

31 Optimising paediatric / neonatal critical care Lowering tidal volumes during mechanical ventilation decreases mortality in adult ARDS patients No randomized trials to determine appropriate tidal volumes in paediatric ARDS Available observational studies are inconclusive Average reductions in tidal volume of 21% could be safely achieved in

32 Acknowledgements Synthetic Biology: Jack Bowyer, Nuno Paulino, Mathias Foo, Alex Darlington, Iulia Gherman Wilson Wong (Boston) Victoria Hsiao (Caltech / Aymeris) Katherine Denby (York) Systems Medicine: Anup Das, Sina Saffaran, Wenfei Wang Jonathan Hardman, Don Sharkey (Nottingham), Nadir Yehya (CHOPS) Luigi Camporota (KCL) Walter Schmitt (Bayer)