Lu Gaohua

Abstract: Background: The physiological fact that a stable level of brain glucose is more important than that of blood glucose suggests that the ultimate goal of the glucose-insulin-glucagon (GIG) regulatory system may be homeostasis of glucose concentration in the brain rather than in the circulation. Methods: In order to demonstrate the relationship between brain glucose homeostasis and blood hyperglycemia in diabetes, a brain-oriented mathematical model was developed by considering the brain as the controlled object while the remaining body as the actuator. After approximating the body compartmentally, the concentration dynamics of glucose, as well as those of insulin and glucagon, are described in each compartment. The brain-endocrine crosstalk, which regulates blood glucose level for brain glucose homeostasis together with the peripheral interactions among glucose, insulin and glucagon, is modeled as a proportional feedback control of brain glucose. Correlated to the brain, long-term effects of psychological stress and effects of blood-brain-barrier (BBB) adaptation to dysglycemia on the generation of hyperglycemia are also taken into account in the model. Results: It is shown that simulation profiles obtained from the model are qualitatively or partially quantitatively consistent with clinical data, concerning the GIG regulatory system responses to bolus glucose, stepwise and continuous glucose infusion. Simulations also revealed that both stress and BBB adaptation contribute to the generation of hyperglycemia. Conclusions: Simulations of the model of a healthy person under long-term severe stress demonstrated that feedback control of brain glucose concentration results in elevation of blood glucose level. In this paper, we try to suggest that hyperglycemia in diabetes may be a normal outcome of brain glucose homeostasis.

Abstract: Brain hypothermia treatment (BHT) requires proper mechanical ventilation and therapeutic cooling. The cooling strategy for BHT has been mainly discussed in the literature while little information is available on the respiratory management. We first developed a mathematical model that integrates the respiratory and biothermal dynamics to discuss the simultaneous managements of mechanical ventilation and therapeutic cooling. The effect of temperature on the linear approximations of hemoglobin-oxygen dissociation, together with temperature dependency of metabolism, is introduced during modeling to combine the respiratory system with the biothermal system. By comparing its transient behavior with published data, the model is verified qualitatively and then quantitatively. Second, model-based simulation of the current respiratory management in BHT suggests reduction of minute ventilation in reference to cooled brain temperature to stabilize the states of blood and brain oxygenation. Lastly, the relationship between cooling temperature and minute ventilation is approximated by a linear first-order transfer function of static gain 0.61min(-1) degrees C(-1) and time constant 8.9 h, which is used to develop a feedforward control to tune the mechanical ventilator in concert with temperature regulation of the cooling blanket. Discussion of the model encourages further studies that provide direct evidence from clinical experiments.

Abstract: BACKGROUND: Although propofol is commonly used for general anaesthesia of normothermic patients in clinical practice, little information is available in the literature regarding the use of propofol anaesthesia for intracranial decompression using brain hypothermia treatment. A novel propofol anaesthesia scheme is proposed that should promote such clinical application and improve understanding of the principles of using propofol anaesthesia for hypothermic intracranial decompression. METHODS: Theoretical analysis was carried out using a previously-developed integrative model of the thermoregulatory, hemodynamic and pharmacokinetic subsystems. Propofol kinetics is described using a framework similar to that of this model and combined with the thermoregulation subsystem through the pharmacodynamic relationship between the blood propofol concentration and the thermoregulatory threshold. A propofol anaesthesia scheme for hypothermic intracranial decompression was simulated using the integrative model. RESULTS: Compared to the empirical anaesthesia scheme, the proposed anaesthesia scheme can reduce the required propofol dosage by more than 18%. CONCLUSION: The integrative model of the thermoregulatory, hemodynamic and pharmacokinetic subsystems is effective in analyzing the use of propofol anaesthesia for hypothermic intracranial decompression. This propofol infusion scheme appears to be more appropriate for clinical application than the empirical one.

Abstract: Brain hypothermia treatment is used as a neuroprotectant to decompress the elevated intracranial pressure (ICP) in acute neuropatients. However, a quantitative relationship between decompression and brain hypothermia is still unclear, this makes medical treatment difficult and ineffective. The objective of this paper is to develop a general mathematical model integrating hemodynamics and biothermal dynamics to enable a quantitative prediction of transient responses of elevated ICP to ambient cooling temperature. The model consists of a lumped-parameter compartmental representation of the body, and is based on two mechanisms of temperature dependence encountered in hypothermia, i.e. the van't Hoff's effect of metabolism and the Arrhenius' effect of capillary filtration. Model parameters are taken from the literature. The model is verified by comparing the simulation results to population-averaged data and clinical evidence of brain hypothermia treatment. It is possible to assign special model inputs to mimic clinical maneuvers, and to adjust model parameters to simulate pathophysiological states of intracranial hypertension. Characteristics of elevated ICP are quantitatively estimated by using linear approximation of step response with respect to ambient cooling temperature. Gain of about 4.9 mmHg degrees C(-1), dead time of about 1.0 h and a time constant of about 9.8h are estimated for the hypothermic decompression. Based on the estimated characteristics, a feedback control of elevated ICP is introduced in a simulated intracranial hypertension of vasogenic brain edema. Simulation results suggest the possibility of an automatic control of the elevated ICP in brain hypothermia treatment.

Abstract: Brain hypothermia treatment (BHT) is an intensive care characterized by simultaneous managements of various vital signs, such as intracranial temperature (ICT) and pressure (ICP), of the severe neuropatient. Medical treatments including therapeutic ambient cooling and diuresis are separately carried out based on the experience of the medical staff involved in the clinical management of various pathophysiological processes, such as thermodynamics, hemodynamics and pharmacokinetics. However, no special attention has been paid to the interactions among these subsystems in therapeutic hypothermia because of the lack of theoretical knowledge. Therefore, quantitative analyses using an integrated model of various physiological processes and their interactions are of pressing need. In the present paper, we propose a general compartmental model to describe the pathophysiological processes of the three aforementioned dynamics, on account of the dynamical analogy of temperature, pressure and concentration. The model is verified by the agreement of model-based simulation results with clinical evidence. Based on responses of the integrated model to various stimuli, a transfer function matrix is identified to linearly approximate the characteristic interrelationships between medical treatments (ambient cooling and diuresis) and the vital signs (ICT and ICP). Then a controller that decouples ambient cooling and diuresis is proposed for efficient management of ICT and ICP, enhancement of hypothermic decompression and reduction of diuretic dosage. Decoupling control simulation indicates that ICT and ICP of the integrated model, representing a patient under BHT, can be simultaneously regulated by a single PID controller for ambient cooling and another for diuresis. The proposed decoupler effectively establishes hypothermic decompression, reduces the dosage of diuretic and improves ICP management. Theoretical analyses of the integrated model and decoupling control of ICT and ICP provide insights into the intensive care of various pathophysiological processes in patients undergoing BHT.

Abstract: A new automatic air-cooling system is proposed using a cooling incubator to replace the manual water-cooling blanket which has traditionally been used to lower brain tissue temperature (BTT) in brain hypothermia treatment (BHT). This study concerns its feasibility through a simulation. First, a biothermal model is proposed for the adult incubating system based on the geometric structure and parameters of patients. Its dynamics were carefully examined by two simulation experiments testing its step response and feedback control. Then a model reference adaptive control algorithm was introduced for the automatic regulation of BTT, where the newly developed adult incubating biothermal model, represented by a state equation, was replaced for the hypothermic patient with a cooling blanket, thus introducing a first-order lag system given as its basic characteristic model. Finally, the proposed cooling incubator was controlled by the adaptive control mechanism, which gives a follow-up of BTT to a given reference temperature course, even if a possible environmental change in the therapeutic cooling system exists, including the individual differences of patients and any chronic conditional change. The automatic cooling incubating system based on the air-cooling method was confirmed to be superior to the water-cooling one. Thus, this work supports the possible development of an air-cooling adult incubating system for the automatic regulation of BTT in an intensive care unit (ICU) application.

Abstract: An automatic thermal control system is proposed for the treatment of cerebral injury and inflammation. The system is based on the reference model adaptive control method. It works adaptively according to the difference between individuals, and chronic change of the patient’s physiological state, and changes in the environmental conditions. Using the human thermal system of the Stolwijk-Hardy model, the brain temperature is dynamically related to the ambient temperature of the head, trunk, and extremities and their metabolic heat production. The dynamic characteristics of brain temperature under various physical conditions, as examined by simulation experiments, provide improved understanding of clinical brain cooling treatment, which simultaneously give good evidence for the validity of the model. The brain temperature is adaptively controlled in accordance with the appropriate physiological state suggested by various clinical experiences. This kind of adaptive control system is useful for the practical implementation of automatic hypothermia control in seriously injured or inflamed brain.

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