Blood glucose, Intensive Care Unit, Control system, Safety
Critically ill patients, admitted to the Intensive Care Unit (ICU) are in an imminent life-threatening condition. Critical illness typically leads to increased blood glucose concentrations: the so-called stress hyperglycaemia. While stress hyperglycaemia has traditionally been regarded as an adaptive, beneficial response, it has also been clear from observational studies that hyperglycaemia, as well as hypoglycaemia, are associated with increased risk of death in critically ill patients. Three randomized controlled trials (surgical, medical and paediatric ICU) show that tight glycaemic control (TGC) actively contributes to improved patient outcome (lower mortality, lower complications, lower costs). Large multi-centre follow-up trials could not confirm this survival benefit or even resulted in an increased mortality due to underestimation of methodological aspects of TGC. Conclusion: TGC is an effective but complex intervention
The European Union and the USA are large markets of intensive care use. The annual patient number in each region can be summarized as follows: * Europe: 3,000,000 * US: 6,000,000. Critical illness has an enormous socio-economic burden. Cost-effectiveness analyses demonstrate a clear economic benefit of TGC. TGC both increased hospital survival and lowered critical illness-associated morbidity (prolonged ventilation and ICU dependency, acute kidney injury, polyneuropathy and infections). Those complications lead to prolonged hospitalisation and require expensive treatments such as dialysis and antibiotics. Given the relatively small cost of achieving TGC (approximately € 150 per patient) health economic analyses have demonstrated that TGC is cost saving. In comparison with the patients in the conventional group, TGC cut the costs of ICU stay by € 2638 per patient in our surgical ICU study.
The LOGIC-Insulin software that will be clinically validated in this project will be a ‘breakthrough’ innovation because of the following reasons: • The LOGIC-Insulin algorithm has been designed in the clinical research group that has developed the concept of TGC and that has more than 10 years experience in TGC. • Secondly, from this vast clinical experience we developed an adaptive patient model on which the LOGIC-Insulin algorithm is based (which is not simple feedback regulation). • Thirdly, through discussions with the regulatory authorities we plan a stepwise approach in the clinical validation of LOGIC-Insulin. • Finally, the planned single-centre and multi-centre study will be randomised and sufficiently statistically powered to clinically relevant outcome measures. This strive for high scientific standards has been uniformly absent in the observational studies of most algorithms.
The cost-effectiveness of TGC is very high, given the low intrinsic cost of the treatment combined with increased hospital survival and lowered critical illness-associated morbidity. Because of the difficulties in its implementation, a large number of patients cannot benefit from this effective, preventative strategy. The LOGIC-Insulin software will be firstly clincially validated in two randomized clinical trials: a single-centre study and a multi-centre ("confirmation") study. A central aspect in the preparation of the multi-centre study will be to obtain the approval of the study design by the European competent authorities. Ultimately, CE-mark filing will be initiated for distribution of medical devices in the EU.
During the design of the LOGIC-Insulin software, the algorithm and the graphical user interface were tested in controlled pilot observations in close collaboration with the nurses of our ICU. This is an iterative process where the LOGIC-Insulin is continuously updated and improved. General blood glucose control was found to be acceptable and dangerous hypoglycaemic events could be avoided. However, commercial valorisation for the LOGIC-Insulin algorithm is barely impossible as stand alone software. The market, i.e. the hospitals and their medical and nursing staff, are warrent for a reliable, continuous blood glucose sensor embarking on TGC; but a continuous sensor will not be available in the upcoming years. Interest from the industry has further weakened because of the large clinical studies required by competent authorities (average costs per patient is 6000 USD) and the current controversy (association between TGC and increased mortality in multi-centre study).
The submitted project represents the late stage, clinical validation of the LOGIC-Insulin algorithm in a single-centre and multi-centre randomised clinical trial. Between both RCTs, the mathematics of the algorithm will be optimised to accommodate use in less controlled conditions. The ultimate goal of the project is to reach approval by the European regulatory agencies, the conditio sine qua non for applying the LOGIC-Insulin algorithm in broad clinical practice. In general the following milestones will be set: 1. Clinical validation of the LOGIC-Insulin software in a single-centre study 2. Clinical validation of the LOGIC-Insulin software in a multi-centre study 3. CE-mark filing, required for distribution and sale of medical devices in the EU.