Model-Based Closed-Loop Glucose Control in Critical Illness

Stress hyperglycemia is a common complication in critically ill patients and is associated with increased mortality and morbidity. Tight glucose control (TGC) has shown promise in reducing mean glucose levels in critically ill patients and may mitigate the harmful repercussions of stress hyperglycemia. Despite the promise of TGC, care must be taken to avoid hypoglycemia, which has been implicated in the failure of some previous clinical attempts at TGC using intensive insulin therapies. In fact, a single hypoglycemic event has been shown to result in worsened patient outcomes. The nature of tight glucose regulation lends itself to automatic monitoring and control, thereby reducing the burden on clinical staff. A blood glucose target range of 110-130 mg/dL has been identified in the High-Density Intensive Care (HIDENIC) database at the University of Pittsburgh Medical Center (UPMC). A control framework comprised of a zone model predictive controller (zMPC) with moving horizon estimation (MHE) is proposed to maintain euglycemia in critically ill patients. Using continuous glucose monitoring (CGM) the proposed control scheme calculates optimized insulin and glucose infusion to maintain blood glucose concentrations within the target zone. Results from an observational study employing continuous glucose monitors at UPMC are used to reconstruct blood glucose from noisy CGM data, identify a model of CGM error in critically ill patients, and develop an in silico virtual patient cohort. The virtual patient cohort recapitulates expected physiologic trends with respect to insulin sensitivity and glycemic variability. Furthermore, a mechanism is introduced utilizing proportional-integral-derivative (PID) to modulate basal pancreatic insulin secretion rates in virtual patients. The result is virtual patients who behave realistically in simulated oral glucose tolerance tests and insulin tolerance tests and match clinically observed responses. Finally, in silico trials are used to simulate clinical conditions and test the developed control system under realistic conditions. Under normal conditions the control system is able to tightly control glucose concentrations within the target zone while avoiding hypoglycemia. To safely counteract the effect of faulty CGMs a system to detect sensor error and request CGM recalibration is introduced. Simulated in silico tests of this system results in accurate detection of excessive error leading to higher quality control and hypoglycemia reduction

REGULATION OF BLOOD GLUCOSE IN TYPE I DIABETIC PATIENTS

Ph.DDOCTOR OF PHILOSOPH

Efficacy and pharmacokinetics of intravenous paracetamol in the critically ill patient

Introduction: Paracetamol (PCM) is a drug with analgesic and antipyretic properties. Despite its frequent use, little is known about its efficacy and pharmacokinetics (PK) when intravenously administered in the critically ill patient. A previous study suggests that therapeutic concentrations are not always reached [1]. The primary aim of this open-label, multiple-dose study was to evaluate intravenous PCM therapy in critically ill, secondary aim was to study the PK of intravenous PCM. Methods: Ventilated patients needing PCM treatment according to our ICU protocol (1 g PCM intravenously four times daily) were eligible for inclusion. Excluded were those with severe liver failure and those treated with PCM on the time of admission to the ICU. Blood samples were collected at 0, 30, 60, 180 and 300 minutes after the first and, if possible, the fifth and 21st doses. A computerized model was used to estimate population PK. Results: Nineteen patients were included of which 13 were male, with a mean APACHE IV score of 94.8. No antipyretic effect could be measured in any of the patients. PK parameters have been calculated for all patients after the first PCM dose. The half-life was 2.2 hours, the volume of distribution was 1.03 l/kg, and the clearance was 0.33 l/kg/hour. Data from 15 patients could be analysed after the fifth dose and from five patients after the 21st dose. The PK of intravenous PCM in our population show a biphasic profile (Figure 1). One hour after the dose, the mean serum concentration level was below the therapeutic level. In 18 out of 19 patients serum concentration dropped below 5 mg/ml before the next dose, resulting in a lack of build-up of a suitable therapeutic level of PCM after multiple dosages. Conclusions: The recommended dose of 1 g intravenous PCM four times daily is not sufficient to achieve a therapeutic effect in critically ill patients. This can be explained by the low serum levels reached. These results warrant the development of an adequate dosing scheme for intravenous PCM followed by a large clinical trial studying the effects and safety of this regimen in critically ill patients

The conditioning of medical gases with hot water humidifiers

During invasive mechanical ventilation due to the dryness of medical gases is necessary to provide an adequate level of conditioning. The hot water humidifiers (HWH) heat the water, thus allowing the water vapor to heat and humidify the medical gases. In the common HWH there is a contact between the medical gases and the sterile water, thus increasing the risk of patient’s colonization and infection. Recently to avoid the condensation in the inspiratory limb of the ventilator circuit, new heated ventilator circuits have been developed. In this in vitro study we evaluated the efficiency (absolute/relative humidity) of three HWH: (1) a common HWH without a heated ventilator circuit (MR 730, Fisher&Paykel, New Zeland), (2) the same HWH with a heated ventilator circuit (Mallinckrodt Dar, Italy) and (3) a new HWH (DAR HC 2000, Mallinkckrodt Dar, Italy) with a heated ventilator circuit in which the water vapor reaches the medical gases through a gorotex membrane, avoiding any direct contact between the water and gases. At a temperature of 35°C and 37°C the HWH and heated tube were evaluated. The absolute humidity (AH) and relative humidity (RH) were measured by a psychometric method. The minute ventilation, tidal volume respiratory rate and oxygen fraction were: 5.8 ± 0.1 l/min, 740 ± 258 ml, 7.5 ± 2.6 bpm and 100%, respectively. Ventilator P2 Use of a bougie during percutaneous tracheostom

Proceeding for Recent Trends in Biomedical Sciences-2018 (RTBS-2018)

Organised by Department of Medical Laboratory Sciences, Lovely Professional University PunjabSmt. Shanti Devi Mittal Auditorium, Lovely Professional University Punjabon 16th March 2018 (Friday

Advanced multiparametric optimization and control studies for anaesthesia

Anaesthesia is a reversible pharmacological state of the patient where hypnosis, analgesia and muscle relaxation are guaranteed and maintained throughout the surgery. Analgesics block the sensation of pain; hypnotics produce unconsciousness, while muscle relaxants prevent unwanted movement of muscle tone. Controlling the depth of anaesthesia is a very challenging task, as one has to deal with nonlinearity, inter- and intra-patient variability, multivariable characteristics, variable time delays, dynamics dependent on the hypnotic agent, model analysis variability, agent and stability issues. The modelling and automatic control of anaesthesia is believed to (i) benefit the safety of the patient undergoing surgery as side-effects may be reduced by optimizing the drug infusion rates, and (ii) support anaesthetists during critical situations by automating the drug delivery systems. In this work we have developed several advanced explicit/multi-parametric model predictive (mp-MPC) control strategies for the control of depth of anaesthesia. State estimation techniques are developed and used simultaneously with mp-MPC strategies to estimate the state of each individual patient, in an attempt to overcome the challenges of inter- and intra- patient variability, and deal with possible unmeasurable noisy outputs. Strategies to deal with the nonlinearity have been also developed including local linearization, exact linearization as well as a piece-wise linearization of the Hill curve leading to a hybrid formulation of the patient model and thereby the development of multiparametric hybrid model predictive control methodology. To deal with the inter- and intra- patient variability, as well as the noise on the process output, several robust techniques and a multiparametric moving horizon estimation technique have been design and implemented. All the studies described in the thesis are performed on clinical data for a set of 12 patients who underwent general anaesthesia.Open Acces

Implantable medical devices for drug and cell release

This work is focused on the research on how to leverage 3D printing technology in the field of cell transplantation. More specifically, the study of an artificial organ for hormone replacement therapies thanks to the close collaboration between the Methodist Hospital Research Institute, Houston, Texas and Politecnico di Torino, Turin, Italy. Cell transplantation offers an attractive therapeutic approach for many endocrine deficiencies. Transplanted endocrine cells or engineered cells encapsulated in the here presented 3D printed device, can act as biological sensors detecting changes in hormonal levels and secrete molecules in response to maintain homeostasis. The major advantage of this technology is that patients affected by endocrine disorder could potentially avoid the need of frequent hormone injections, such as insulin or testosterone, resulting in an improved quality of life and lower chronic side effects associated to external hormone supplementations. This implant was extensively tested both in vitro and in vivo condition, providing remarkable results that lead to several publications. The cell encapsulation system was fabricated via 3D printing technology adopting an FDA approved polymeric material. The structure, composed by an array of micro and macro channels, was specifically designed in order to allow vasculature formation within the device and for housing cells while avoiding cell clustering. Over the course of the Ph.D., the technology was designed, fabricated and tested for the encapsulation of several cell lines and for small and large animal models. According to the in vivo results, we demonstrated that our 3D printed device exemplifies a clinically translatable strategy for preserving viability and function of transplanted cells. Currently, is ongoing an experiment in Non-Human Primates (data not shown), last pre- clinical study before the possibility to move to the clinical development in humans. The pre-vascularization approach to achieve an ideal intra-device milieu prior to transplantation, transcutaneous cell loading and refilling capabilities, as well as the potential for rapid device retrievability, addresses current challenges in transplantation. This technology may offer exciting potential for clinical adoption in relevant medical areas of diabetes, hypogonadism, hypothyroidism, cancer, and neurological diseases among others

Separator fluid volume requirements in multi-infusion settings

INTRODUCTION. Intravenous (IV) therapy is a widely used method for the administration of medication in hospitals worldwide. ICU and surgical patients in particular often require multiple IV catheters due to incompatibility of certain drugs and the high complexity of medical therapy. This increases discomfort by painful invasive procedures, the risk of infections and costs of medication and disposable considerably. When different drugs are administered through the same lumen, it is common ICU practice to flush with a neutral fluid between the administration of two incompatible drugs in order to optimally use infusion lumens. An important constraint for delivering multiple incompatible drugs is the volume of separator fluid that is sufficient to safely separate them. OBJECTIVES. In this pilot study we investigated whether the choice of separator fluid, solvent, or administration rate affects the separator volume required in a typical ICU infusion setting. METHODS. A standard ICU IV line (2m, 2ml, 1mm internal diameter) was filled with methylene blue (40 mg/l) solution and flushed using an infusion pump with separator fluid. Independent variables were solvent for methylene blue (NaCl 0.9% vs. glucose 5%), separator fluid (NaCl 0.9% vs. glucose 5%), and administration rate (50, 100, or 200 ml/h). Samples were collected using a fraction collector until <2% of the original drug concentration remained and were analyzed using spectrophotometry. RESULTS. We did not find a significant effect of administration rate on separator fluid volume. However, NaCl/G5% (solvent/separator fluid) required significantly less separator fluid than NaCl/NaCl (3.6 ± 0.1 ml vs. 3.9 ± 0.1 ml, p <0.05). Also, G5%/G5% required significantly less separator fluid than NaCl/NaCl (3.6 ± 0.1 ml vs. 3.9 ± 0.1 ml, p <0.05). The significant decrease in required flushing volume might be due to differences in the viscosity of the solutions. However, mean differences were small and were most likely caused by human interactions with the fluid collection setup. The average required flushing volume is 3.7 ml. CONCLUSIONS. The choice of separator fluid, solvent or administration rate had no impact on the required flushing volume in the experiment. Future research should take IV line length, diameter, volume and also drug solution volumes into account in order to provide a full account of variables affecting the required separator fluid volume