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

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.

We will design and develop novel computational models of the human cardiac and vascular systems and integrate these with our published, validated pulmonary models. The resulting multi-organ modelling will be multiscalar and will have great scope and depth of detail (e.g. a branching three-dimensional vessel-bed containing variable depths of cells, tissue perfusion distribution affected by endogenous mediators and drugs, heart comprising four chambers with stretch- and perfusion-affected myocardial contractility and valvular outlets, heart contained within a pericardium/mediastinum/thorax complex that will be externally compressible to allow simulation of cardiac massage). Each compartment will affect neighbouring compartments and flow 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 potential 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 such states (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 test algorithms for the management of various shock states in large populations of in-silico subjects.

The management of low cardiac output states is inadequately researched and the risk factors for end-organ damage are poorly understood. Such "shock states" are a common feature of critical illness, which consumes a large part of the healthcare budget.

There is significant interaction between cardiac, pulmonary and vascular function, such that treatments intended to improve function in one part of the system may be detrimental to others. Clinicians inevitably have to adopt compromise approaches based on theory and experience. No measurement techniques exist that can quantify within-organ, real-time perfusion and cellular oxygenation; this limits the potential of clinical or animal-model research, which may only provide surrogate outcomes with limited relevance to human pathology. In human studies, the techniques and outcomes have varied considerably, making comparisons difficult; even apparently similar studies have come to opposing conclusions. All of the above issues have hampered the development of coherent protocols that allow optimal clinical management of shock states. There is increasing interest in protocol-guided management of at-risk patients but the pathophysiology that causes between-patient differences is still poorly understood.

The huge potential for the application of systems approaches and computational modelling in healthcare has been limited by the lack of rigorous model validation procedures, and by the difficulty in applying physiological models to heterogeneous patient populations; our proposal has the potential to directly address both these issues and expand the applicability of systems biology approaches to real clinical situations. The substantial advances offered by the proposal are in main two areas: (i) the advancement of techniques for the development and validation of computational models in healthcare research, and (ii) advances in the systems level understanding and clinical management of low cardiac output (shock) states.

- Validated, high-fidelity, organ-level models are under-used in medical research; they offer insights into real-world clinical scenarios and provide a powerful, credible and cost-effective methodology to investigate different therapeutic strategies. In the proposed research we expect to make significant advances in this area, and to demonstrate the impact of (i) modelling of uncertain parameters representing variations across patient populations (simulating heterogeneous population outcomes, rather than the simplistic idealised patient), (ii) use of novel, rigorous and scalable model validation techniques. The development and application of novel methods for validating pathophysiological simulation models could enable significant breakthroughs in medical modelling. Compared to the state-of-the-art in systems engineering, current approaches to validation of medical/physiological models not fit-for-purpose; we believe that through "smart validation" we can radically reduce the human validation studies required to make computational methodology findings applicable to clinical practice.

- Advances in the delivery of clinical care: An increased understanding of the management of shock states has the potential to radically improve critical care and acute/emergency medicine. Millions of lives worldwide could be saved and massive expenditure in critical care could be saved. Currently, there is significant clinical controversy about optimal management of patients with impaired cardiac output, particularly in the surgical, emergency and critical care setting. The proposed research will provide a much more in-depth understanding of the disordered physiology of shock states and offer understandings key to creating novel therapeutic approaches to manage these patients. In particular, the development and testing of management strategies for shock states in in-silico subjects is likely to offer a fast-track advance in managing these patients.