MODELLING AND CONTROL IN BIOMEDICAL SYSTEMS 2006


By DAVID DAGAN FENG OLIVIER DUBOIS JANAN ZAYTOON EWART CARSON

Elsevier

Copyright © 2006 IFAC
All right reserved.

ISBN: 978-0-08-047949-1

Contents

Author Index......................................................................................561


Chapter One

DYNAMIC MODELING IN DIABETES: FROM WHOLE BODY TO GENES

Claudio Cobelli

Department of Information Engineering, University of Padova, Italy

Abstract: Diabetes is one of the major chronic diseases such that, together with its complications it can account for more than 10% of national healthcare expenditure. Mathematical modeling can enhance understanding of this disease in quantitative terms and is becoming an increasingly important aid in diagnosis, prognosis and in the planning of therapy. Mathematical modeling in relation to carbohydrate metabolism and diabetes has a long history stretching back some 45 years. Initially modeling has focused on the dynamics of glucose and insulin and their interactions, principally at the whole body and organ levels. However, over recent years the scope of mathematical modeling in relation to diabetes has seen dramatic expansion such that it is now being applied across the spectrum from populations of patients (public health) to the molecular level. This paper will explore recent developments of mathematical modeling in our laboratory across this ever increasing spectrum. Ingredients will include models to assess, at whole body, the efficacy of homeostatic control and system fluxes and, at organ level, unit processes in skeletal muscle, a key target tissue. To do so both whole body as well as regional tracer experiments, these last employing Positron Emission Tomography, will be discussed not only to understand the physiology but also the pathophysiology of glucose metabolism, like obesity and diabetes. Microarray technology offers an important tool to understand how genes change expression and interact as a consequence of externallinternal stimuli. Dynamic stimulus/response experiments can provide time series expression data from which regulatory networks can be obtained by reverse engineering, and this is illustrated for insulin stimulation of muscle rat cells. Recent technological advances in diabetes include more reliable subcutaneous glucose sensors: interpretation and clinical use of continuous glucose monitoring time series data can be powered by dynamic modeling, in particular we show how critical hypoglycemic events can be predicted ahead in time. Finally, the importance of dynamic modeling in an important diabetes health care problem is discussed by showing its use in conjunction with gait analysis for preventing diabetic foot complications. Copyright © 2006 IFAC

LIDCO – FROM THE LABORATORY TO PROTOCOLIZED GOAL DIRECTED THERAPY

Terry O'Brien

CEO LiDCO Group PIC Research Fellow Dept. of Applied Physiology St Thomas' Hospital, London

Abstract: A new generation of cardiovascular monitors, fueled by data from non or minimally invasive sensors, employing algorithms that model the cardiovascular system combined with user interfaces that facilitate decision support and protocolization of care are entering a new era where the costs and risks of applying the technology are going to be far outweighed by the clinical, human and financial returns. Copyright © 2006 IFAC

Keywords: Cardiovascular modelling, monitoring, critical care, visualization, protocol, oxygen delivery.

1. INTRODUCTION

LiDCO Group Plc is based in London and was founded in the early 1990's by Dr Terry O'Brien and Dr David Band in collaboration with the United Dental and Medical Schools of St Thomas' and Guys Hospitals (now King's College, London.) Since that time, the Group has developed inventions within the cardiovascular monitoring field. LiDCO's products have been extensively validated and demonstrated to reduce the hospital stay of high risk surgery patients by twelve days - saving £4,800 per patient treated. Extrapolated to the whole of the UK this would equate to a saving of £500 million per annum for the National Health Service.

LiDCO applies a multi-disciplinary combination of physiological expertise, sensor and computing technology to monitor and display the relationship between linked physiological variables. The transformation of raw physiological data into useable information and then specific treatment protocols that can improve clinical outcome has been a key objective throughout the development of the Company's products. LiDCO's principal products are a sensorlin vivo diagnostic product (the LiDCO System) and a continuous waveform analysis algorithm (the PulseCO System) housed in a platform monitoring product (the LiDCOplus Hemodynamic Monitor), which when used together provide a range of data concerning the performance of a patient's heart, blood volume and systemic oxygen delivery.

Our financing strategy was two stage, firstly to partner with our host Medical School for the start-up and pre product registration / product development phase. The funding of salaries, intellectual property development and all of the running costs were paid for though raising funds - seed capital from founders, followed by early corporate marketing license fees payments and private individuals. In this phase in total the Company raised £9.25 million. LiDCO Group became a PICin July 2001 when it floated on the Alternative Investment Market (AIM, London) raising £1 5 million. Subsequent to the Aim listing we raised an additional £5 million - these funds were used for sales expansion purposes. In summary, to bring the technology to the international market has cost £29 million and taken more than ten years.

2. LIDCO'S TECHNOLOGY

Monitoring of the key cardiovascular parameters - blood pressure, cardiac output (blood flow in litres 1 minute) and oxygen delivery (total oxygen in mls 1 minute/ body surface area) - can provide a practical, early warning of cardiovascular change and adverse events in surgery and critical care patients. Improved care in this high-risk group should reduce the incidence of adverse events in hospitals and thereby reduce costs. The current market leader for the measurement of cardiac output and oxygen delivery is the highly invasive, thermodilution pulmonary artery catheter (PAC). Thermodilution derived cardiac output is the measurement of blood flow using a cold injection of an isotonic solution into the right atrium of the heart and the measurement via a thermister of the subsequent temperature change in the pulmonary artery. In addition to the risks of this technique, there are problems with the interpretation of this complex data set in the hospital acute care setting. Thus, despite being available for more than 30 years, the therapeutic value of the PAC has yet to be established and its use has been restricted to a small number of patients who could benefit from these measurements.

The LiDCO™ plus is a cardiovascular monitor, providing continuous, reliable and accurate assessment of the hemodynamic status of critical care and surgery patients. This is achieved by running two proprietary algorithms: a continuous arterial waveform analysis system (PulseCO™) coupled to a single point lithium indicator dilution calibration system (LiDCO™). The design objective of the LiDCO™ plus Monitor was to develop a novel platform monitor that would provide an easily interpretable user interface displaying real time: blood pressure, pre load (fluid management), cardiac output/oxygen delivery and after load (peripheral resistance) parameters. The technical innovation of the LiDCO technology is both in the method of using lithium as an intra vascular marker substance to accurately measure cardiac output and the design and clinical application of the lithium ion-selective electrode. The lithium method is at least as accurate a measurement of cardiac output as the older and more invasive PAC approach, but with the advantages of being simple and quick to set-up by a nurse or doctor, with no complications associated with its use. The LiDCOplus Monitor user interfaces are designed to simplify the setting and achievement of individualized target cardiovascular parameters in the acute care setting. The user, often a nurse, should be helped by interaction with the monitor interface to achieve the target by the appropriate administration of fluids and inotropic drugs and then with decision support to maintain the patient to the required target.

3. GOAL-DIRECTED THERAPY (GDT) AND IMPROVING OUTCOMES

Goal-directed therapy is a general term used to describe the use of pre-set cardiac output and oxygen delivery levels to guide intravenous fluid and inotropic drug therapy. GDT has not yet been introduced into routine practice. The principal reason for this is the limited availability of intensive care unit (ICU) facilities and staff coupled to safety concerns regarding the use of the invasive PAC to measure cardiac output. Clearly, LiDCO's minimally invasive technology could be used to implement GDT by nursing staff in risk patients after major general surgery. Therefore, a study was undertaken to assess the effect of post-operative GDT on complication rates and duration of hospital stay in high-risk general surgical patients (Pearse et al., 2005). This was a randomised controlled study conducted in the adult ICIJ at St George's Hospital, London. Patients were assigned to GDT (62 patients) or control group (60 patients) by computer-generated random sequence. Patients in the control group were administered intravenous colloid solution to achieve a sustained increase in central venous pressure (CVP) of at least 2 mmHg for 20 minutes. GDT patients received intravenous colloid solution to achieve a sustained rise in stroke volume (amount of blood in each heart beat; cardiac output = stroke volume x heart rate) of at least 10% for 20 minutes. The GDT group also received an inotrope (dopexamine) if the targeted oxygen delivery index (DO2I is oxygen delivery per square meter of body surface area) did not reach 600 ml min-1 m-2 with intravenous fluid alone.

The GDT group achieved significantly greater levels of oxygen delivery in the first 8 hours after surgery. Fewer patients developed complications in the GDT group (27 patients (44%) versus 41 patients (68%). The total number of complications per patient was also lower in the GDT group (0.7 per patient (SD 0.9) versus 1.5 per patient (SD 1.5); p = 0.002). The reduction in the number of post-operative complications in the GDT group was associated with a reduction in mean duration of hospital stay by 12 days (17.5 days versus 29.5 days, 41% reduction (95% confidence intervals 0 to 81); p = 0.001).

4. CONCLUSIONS

This is the first study to investigate the effects of post-operative GDT in high-risk patients undergoing major general surgery. The effect of the GDT protocol was to reduce the number of patients developing complications and shorten the hospital stay in comparison with a protocol designed to reflect standard care. LiDCO's technology uniquely provides real-time measurement of the absolute level of oxygen delivery, minimally invasively, without the need for insertion of an invasive catheter into a major artery or the heart. Using this technology to apply a nurse led GDT protocol to high-risk surgery patients reduced total hospital stay by an average of 12 days saving £4,800 per patient treated. Implementation of a similar strategy in other hospitals across the IJK National Health System could result in estimated savings of £500 million annually. This GDT protocol has now become a standard of care at this hospital and is targeted to save the hospital £2 million pounds per year in bed days. The next generation of more cardiovascular monitors, coupled to treatment protocols, can dramatically reduce complications and hospital stay in risk surgery patients.

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