Integrated cardiopulmonary modelling for the investigation of the management of disturbed tissue perfusion

Lead Research Organisation: University of Nottingham
Department Name: School of Medicine

Abstract

The management of low cardiac output states (where inadequate blood flows to the organs, causing organ damage) is poorly researched. These ?shock? states are a common feature of critical illness, and consume a large part of the healthcare budget.

Previous attempts to investigate shock states have had conflicting results because of the complexity of human and animal models, and the difficulty of measuring outcomes of interest. This issue could be investigated in great detail and depth using computer simulation of multiple organs, and this is the basis of our proposed project. Findings from this research will be directly applicable to critically ill patients, and have the potential to save many lives and reduce healthcare expenditure.

Step 1: We will design and develop ground-breaking computer simulations of heart, blood vessels and tissue. We will combine these with our existing, published lung simulation. The resulting, multiple organ simulation will include great detail of the structure and function of these organ systems and will allow very detailed interrogation of microscopic areas to determine the interaction between organ systems and treatment strategies in critically ill patients.

Step 2: We will apply ground-breaking validation (testing) techniques to test and improve the accuracy and usefulness of the new multi-organ models; these will include techniques from space and flight-control engineering and techniques designed in our labs for ?smart? validation against individual patient monitoring data and previous clinical studies.

Step 3: Using the multi-organ models we will investigate the disturbed physiology of shock states and potential treatment strategies. Initially, we will address poorly understood aspects of the disorder of normal function, and the potential to affect tissue blood flow and oxygenation (e.g. how does lung-protective life-support affect organ oxygenation during shock?).

Step 4: Using the knowledge generated in the previous phase, we will construct simple algorithms for the management of various types of shock state and test these in a large population of simulated subjects, assessing the ability of the algorithms to improve outcome from shock.

Outcomes: Successful completion of the project will yield novel multi-organ models that may be re-used in investigating critical illness, greater understanding of shock states and potential treatment pathways, and, finally, treatments that may be used in patient care to optimise methods of treating critically ill patients with shock states.

Technical Summary

We will design and develop novel computational simulation models of the human cardiac and vascular (large and small vessel) physiological systems and integrate these with our published, validated pulmonary model. The resulting integrated multi-organ models will include conducting airways, branching bronchioles and compliant, structurally-interdependent alveolar spaces. Pulmonary arterial flow will be affected by alveolar contents and structural deformation. Blood will be modelled as a non-Newtonian fluid containing cell-constrained haemoglobin with interdependence of carbon dioxide, oxygen and plasma pH. Arterial flow will terminate in the tissue vascular model, comprising a branching three-dimensional vessel-bed containing variable depths of cells. Tissue perfusion distribution will be affected by endogenous mediators and drugs. The heart will comprise four chambers with intrinsic, stretch- and perfusion-affected myocardial contractility and configurable valvular outlets. The heart will be contained within an inelastic pericardium, within a mediastinum, within a musculoskeletal thorax, flanked by the lungs. The thorax will be externally compressible (to allow simulation of cardiac massage). Gravitational effects will allow modelling of the effects of positioning (e.g. prone). Each compartment of the models will communicate with and affect neighbouring compartments; flow between compartments (of gas/blood/extracellular fluid) will be governed by inter-compartmental resistance and the volume and compliance curve of each compartment. Flows between compartments will be calculated arithmetically for micro-epochs ( 1 ms) and a new dynamic state calculated by moving compartmental contents as determined by calculated flows.

We will apply novel ?smart? validation techniques to test the veracity and fitness-for-purpose of the integrated models; these will include robustness analysis techniques, prospective validation against single-patient data streams and replication of previously published clinical research.

Using these integrated multi-organ models we will investigate the disturbed physiology of low cardiac output states and generate novel therapeutic strategies. Such ?shock states? are poorly understood and are a common feature of critical illness, which consumes a large part of the healthcare budget. Initially, we will address poorly understood aspects of shock states, addressing in particular mechanisms of affecting tissue perfusion, oxygenation and carbon dioxide clearance (e.g. How does manipulation of blood viscosity affect cellular oxygenation during shock? How does permissive hypercapnia affect cellular oxygenation and pH during shock?). Using the knowledge generated in this phase, we will construct simple algorithms for the management of various types of shock state and test these in a large population of in-silico subjects, assessing the capacity of the algorithms to improve organ outcome in shocked patients.

Publications

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Das A (2015) Development of an integrated model of cardiovascular and pulmonary physiology for the evaluation of mechanical ventilation strategies. in Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference

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Das A (2013) Optimization of mechanical ventilator settings for pulmonary disease states. in IEEE transactions on bio-medical engineering

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Saffaran S (2017) Development and validation of a computational simulator for pediatric acute respiratory distress syndrome patients. in Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference

 
Description Healthcare Impact Partnerships
Amount £866 (GBP)
Funding ID EP/P023444/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 06/2017 
End 05/2020
 
Title High-fidelity, multi-organ simulation of human cardiopulmonary pathophysiology 
Description A novel and highly-integrated, high-fidelity suite of models or human pathology and physiology. To-date, we have very detailed, validated models of the pulmonary, cardiac and vascular systems. Cardiopulmonary interaction is fully realised, and novel outputs are already arising from this. We have less detailed models of renal, cerebrovascular and haematological systems, which will be developed over coming months and years. 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2015 
Provided To Others? Yes  
Impact - High impact publications have been produced. These have influenced policies and guidelines in medicine. - Large pharma companies (e.g. Bayer) have contracted our group to use our simulation to investigate new medicinal products. - Large manufacturers of mechanical ventilators (e.g. Medtronic, Draeger) have expressed an interest in collaborating to progress understanding of methods of ventilating critically ill patients' lungs. 
URL http://www.icsm.info/
 
Description Modelling research group 
Organisation University of Exeter
Department Centre for Systems, Dynamics and Control
Country United Kingdom 
Sector Academic/University 
PI Contribution My team (Nottingham) provides medical and physiological expertise, along with design of models.
Collaborator Contribution Declan Bates' team (Exeter) provides engineering and computational expertise, particular in validation & verification of models.
Impact Several research manuscripts, employed post-doctoral staff and successful grant applications.
Start Year 2006
 
Description Modelling research group 
Organisation University of Warwick
Department School of Engineering
Country United Kingdom 
Sector Academic/University 
PI Contribution My team (Nottingham) provides medical and physiological expertise, along with design of models.
Collaborator Contribution Declan Bates' team (Exeter) provides engineering and computational expertise, particular in validation & verification of models.
Impact Several research manuscripts, employed post-doctoral staff and successful grant applications.
Start Year 2006
 
Title Integrated, high-fidelity cardiovascular simulation. 
Description A detailed model of the intact human cardiovascular system. This was integrated into our existing simulation suite (comprising detailed pulmonary models). 
Type Of Technology Software 
Year Produced 2014 
Impact The integration of cardiovascular and pulmonary models has taken high-fidelity, multi-organ simulation to a new level. Multiple high-impact publications will follow.