Integrated cardiopulmonary modelling for the investigation of the management of disturbed tissue perfusion
Lead Research Organisation:
University of Nottingham
Department Name: School of Clinical Sciences
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.
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.
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.