Blood pressure measurement has been and continues to be one of the most important measurements in clinical practice and yet, it remains one of the most inaccurately performed. The use of oscillometric blood pressure measurement monitors has become common in hospitals, clinics and even homes. Typically, these monitors assume that the heartbeat rate remains stable, which is contrary to what happens in atrial fibrillation. In this thesis, a new method that provides a more precise estimate of Mean Arterial Pressure (MAP) is proposed using anon-invasive oscillometric blood pressure monitor. The proposed method is based on calculating a ratio of peak amplitude to trough amplitude for every pulse, then identifying where the ratio first reaches a value of 2. The performance of the proposed method is assessed by comparing the accuracy and variability of the readings against reference monitors -first in healthy subjects, then in atrial fibrillation patients. In healthy subjects and in atrial fibrillation patients, the proposed method achieved a performance accuracy that is well within the ANSI/AAMI SP10 protocol requirements of the reference monitors. The presence of atrial fibrillation diminished the performance of the reference monitor by increasing the variability of the reference readings. The proposed algorithm, on the other hand, performed better by achieving substantially lower variability in the readings than the reference device.

L-serine, a non-essential amino acid, plays a role in the biosynthesis of the amino acids, proteins, purine and pyrimidine nucleotides. It is important for the proper functioning of the nervous system. It has been considered in the treatment of patients with schizophrenia, depression, chronic fatigue syndrome and psychomotor retardation, and of the seizures encountered in patients with rare inborn errors of L-serine biosynthesis. However, there are no reports in the literature of the direct cardiovascular effects of L-serine. Using normotensive Sprague-Dawley rats, Sprague-Dawley rats rendered hypertensive by chronic treatment with the nitric oxide (NO) synthase inhibitior NG nitro L-arginine methyl ester (L-NAME) and spontaneously hypertensive rats (SHR), the present study examined the in vitro and in vivo effects of L-serine. In vitro studies focused on L-serine induced changes in phenylephrine constricted third order branches of rat mesenteric arterioles while the in vivo studies examined the effects of intravenous infusion of L-serine on mean arterial pressure (MAP) and heart rate (HR) in intact anaesthetized rats. L-serine (10 to 200 µmol/L) evoked concentration-dependent vasodilatation in phenylephrine constricted endothelium-intact, but not in endothelium-denuded, rat mesenteric arterioles. The vasodilator responses to L-serine were absent in the combined presence of apamin, a calcium activated small conductance potassium (SKCa) channel inhibitor, and TRAM-34, a calcium activated intermediate conductance potassium (IKCa) channel inhibitor, or ouabain, a sodium pump inhibitor and barium (Ba2+), an inward rectifying potassium (Kir) channel inhibitor, or when the vessels were depolarized by potassium chloride. The maximal vasodilatation response (Emax) to L-serine was higher in vessels from L-NAME treated rats (40%) than from control rats (20%). In anesthetized rats, L-serine evoked a rapid, reversible, dose-dependent fall in MAP (without a significant change in HR), which was more pronounced in L-NAME treated rats (> 60 mmHg) than in normotensive control rats (25 mmHg). The fall in MAP was inhibited (p<0.01) by apamin plus charybdotoxin pretreatment. Charybdotoxin was used in place of Tram-34 in in vivo studies since Tram-34 is not soluble in water or saline. In age matched Sprague-Dawley, Wistar-Kyoto (WKY) and SHR strains, D-serine had the same effects on MAP and HR as L-serine; however, L-serine evoked a greater maximal fall in MAP in all strains, and the effect was more pronounced in hypertensive rats. In contrast, the infusion of glycine, a metabolite of L-serine led to a dose-dependent fall in MAP in normotensive rats but a dose-dependent increase in MAP in both SHR and L-NAME treated hypertensive WKY rats. Both the depressor and pressor responses to glycine were abolished by pretreatment with the N-methyl D-aspartate receptor antagonist, MK-801. Regional hemodynamic studies performed using the fluorescent tagged microsphere distribution technique revealed that the fall in MAP and profound decrease in total peripheral resistance (TPR) evoked by acute L-serine infusion is due to increased blood flow in the splanchnic region and more particularly in the small intestinal vascular beds. This effect is blocked by the combined treatment with the KCa channel inhibitors, apamin plus charybdotoxin. Although resting MAP and TPR are higher, and cardiac output (CO) is lower both in SHR and in WKY rats rendered hypertensive by L-NAME treatment compared to normotensive WKY rats, L-serine infusion leads to a rapid fall in TPR and MAP, and an increase in CO in all models. This effect was more profound in the hypertensive rats. These findings suggest that L-serine could be helpful in overcoming splanchnic organ failure observed in patients with cardiopulmonary bypass. In addition, L-serine, either alone or in combination with other antihypertensive medications, could be considered in the management of endothelial dysfunctional states with reduced NO bioavailability such as hypertension and diabetes.

L-serine, a non-essential amino acid, plays a role in the biosynthesis of the amino acids, proteins, purine and pyrimidine nucleotides. It is important for the proper functioning of the nervous system. It has been considered in the treatment of patients with schizophrenia, depression, chronic fatigue syndrome and psychomotor retardation, and of the seizures encountered in patients with rare inborn errors of L-serine biosynthesis. However, there are no reports in the literature of the direct cardiovascular effects of L-serine. Using normotensive Sprague-Dawley rats, Sprague-Dawley rats rendered hypertensive by chronic treatment with the nitric oxide (NO) synthase inhibitior NG nitro L-arginine methyl ester (L-NAME) and spontaneously hypertensive rats (SHR), the present study examined the in vitro and in vivo effects of L-serine. In vitro studies focused on L-serine induced changes in phenylephrine constricted third order branches of rat mesenteric arterioles while the in vivo studies examined the effects of intravenous infusion of L-serine on mean arterial pressure (MAP) and heart rate (HR) in intact anaesthetized rats. L-serine (10 to 200 µmol/L) evoked concentration-dependent vasodilatation in phenylephrine constricted endothelium-intact, but not in endothelium-denuded, rat mesenteric arterioles. The vasodilator responses to L-serine were absent in the combined presence of apamin, a calcium activated small conductance potassium (SKCa) channel inhibitor, and TRAM-34, a calcium activated intermediate conductance potassium (IKCa) channel inhibitor, or ouabain, a sodium pump inhibitor and barium (Ba2+), an inward rectifying potassium (Kir) channel inhibitor, or when the vessels were depolarized by potassium chloride. The maximal vasodilatation response (Emax) to L-serine was higher in vessels from L-NAME treated rats (40%) than from control rats (20%). In anesthetized rats, L-serine evoked a rapid, reversible, dose-dependent fall in MAP (without a significant change in HR), which was more pronounced in L-NAME treated rats (> 60 mmHg) than in normotensive control rats (25 mmHg). The fall in MAP was inhibited (p<0.01) by apamin plus charybdotoxin pretreatment. Charybdotoxin was used in place of Tram-34 in in vivo studies since Tram-34 is not soluble in water or saline. In age matched Sprague-Dawley, Wistar-Kyoto (WKY) and SHR strains, D-serine had the same effects on MAP and HR as L-serine; however, L-serine evoked a greater maximal fall in MAP in all strains, and the effect was more pronounced in hypertensive rats. In contrast, the infusion of glycine, a metabolite of L-serine led to a dose-dependent fall in MAP in normotensive rats but a dose-dependent increase in MAP in both SHR and L-NAME treated hypertensive WKY rats. Both the depressor and pressor responses to glycine were abolished by pretreatment with the N-methyl D-aspartate receptor antagonist, MK-801. Regional hemodynamic studies performed using the fluorescent tagged microsphere distribution technique revealed that the fall in MAP and profound decrease in total peripheral resistance (TPR) evoked by acute L-serine infusion is due to increased blood flow in the splanchnic region and more particularly in the small intestinal vascular beds. This effect is blocked by the combined treatment with the KCa channel inhibitors, apamin plus charybdotoxin. Although resting MAP and TPR are higher, and cardiac output (CO) is lower both in SHR and in WKY rats rendered hypertensive by L-NAME treatment compared to normotensive WKY rats, L-serine infusion leads to a rapid fall in TPR and MAP, and an increase in CO in all models. This effect was more profound in the hypertensive rats. These findings suggest that L-serine could be helpful in overcoming splanchnic organ failure observed in patients with cardiopulmonary bypass. In addition, L-serine, either alone or in combination with other antihypertensive medications, could be considered in the management of endothelial dysfunctional states with reduced NO bioavailability such as hypertension and diabetes.

The ability of an individual to withstand elevated head-to-toe gravitoinertial (+Gz) forces is determined by the capacity of their body to maintain sufficient head-level arterial pressure. Recent studies have shown a relationship between resting blood-vessel stiffness and an individual’s +Gz-tolerance, although the mechanisms behind this relationship are unclear. The aim of this project is to determine whether or not +Gz-tolerance is affected by a change inresting vasomotor tone. To evaluate this relationship, seven participants were asked to complete a +Gz-tolerance protocol using a human-use centrifugeon two different occasions. On both visits, gradual onset rate (0.1 G.s−1)and rapid onset rate (3.5 G.s−1) tests were done to evaluate the participants+Gz-tolerance. On one of the two visits, prior to the +Gz-tolerance testing,participants performed a 20-min cycle intervention to induce postexercisehypotension, with the aim of temporarily reducing participants’ resting bloodpressure and vasomotor tone. The cycling intervention was successful atinducing postexercise hypotension, as mean arterial pressure was significantlylower on the cycling visit (P&lt;0.05). +Gz-tolerance was significantly lower(P&lt;0.05) on the cycling visit compared with the non-cycling visit for both theGOR and ROR tests (absolute difference of 0.5 G and 0.25 G, respectively).The effect of the type of test on +Gz-tolerance was not influenced by the effectof the cycling intervention (P&gt;0.05). Being the most documented mechanismlinked to postexercise hypotension, sustained vasodilation was assumed tohave occurred. This would have increased distensibility of the affected vessels,explaining the decrease in +Gz-tolerance. The decrease in +Gz-tolerance wassimilar for both tests, indicating that the baroreflex was not affected by thecycling intervention. Assuming that vasodilation occurred, this study showedthat a decrease in resting vasomotor tone decreased +Gz-tolerance, indicatingthe importance of this variable in the relationship between resting blood-vesselstiffness and an individual’s +Gz-tolerance.

No description available.

I detta projekt har tiden för hur länge en patient befinner sig i hypotension samt hypotensionsdosen beräknats. Tiden i hypotension har beräknats med hjälp av episoder i över en minut och hypotensionsdosen har kalkylerats som integralen mellan hypotensionsgränsen 65 mmHg och den estimerade medelartärtryckskurvan (MAP-kurvan). Flera metoder användes, såsom klassificering av extrempunkter i rådata och kurvanpassning genom interpolation, vilket gav varierande och olika goda resultat. Detta framförallt beroende på hur datan behandlades med olika filter, till exempel så kallat “smoothing”-filter samt medianfilter. / In this project the time of how long a person is in hypotension and the hypotension exposure have been calculated. The time was calculated using episodes longer than one minute and the hypotension exposure has been calculated as the integral between the hypotension limit 65 mmHg and the estimated mean arterial pressure curve (MAP-curve). Several methods were used, such as classification of extreme values in raw data and curve fitting through interpolation, which gave diverse results and of varied accuracy. This primarily because of which filter that was used, for example smoothing and median filters.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / As serpentes do gÃnero Crotalus estÃo representadas no Brasil por apenas uma espÃcie, a Crotalus durissus, o envenenamento pela sub-espÃcie Crotalus durissus cascavella conduz à alteraÃÃo sistÃmica, sendo responsÃvel pela causa preliminar de morte apÃs o acidente ofÃdico. Este trabalho teve como objetivo avaliar os efeitos farmacolÃgicos do veneno da serpente Crotalus durissus cascavella â Ce (Cdcasca). Neste trabalho estudou-se as aÃÃes do Cdcasca no sistema vascular, avaliando os parÃmetros fisiolÃgicos da pressÃo arterial e analisando as alteraÃÃes histolÃgicas no coraÃÃo, pulmÃo, rim, cÃrebro e fÃgado retirados apÃs os experimentos de pressÃo arterial. A atividade citotÃxica do Cdcasca foi avaliada em quatro linhas humanas de cÃlulas tumorais: leucemia, tumor de mama, tumor de cÃlon e tumor do sistema nervoso. Realizou-se uma investigaÃÃo do provÃvel mecanismo de aÃÃo do Cdcasca utilizando-se as metodologias de viabilidade celular por exclusÃo de Azul de Tripan, inibiÃÃo na sÃntese de DNA, atividade antiproliferativa de cÃlulas mononucleares (Alamar Blue). A integridade da membrana celular, fragmentaÃÃo do DNA e a alteraÃÃo do potencial transmembrÃnico mitocondrial foram analisados por citometria de fluxo. Investigou-se a aÃÃo do PeptÃdeo NatriurÃtico (NPcasca) isolado do veneno da Cdcasca nos sistemas de pressÃo arterial, anel de aorta e perfusÃo renal. ApÃs a perfusÃo renal, os rins foram submetidos à anÃlise histolÃgica e ao estudo da biologia molecular. Todos os parÃmetros estudados foram analisados pelo ANOVA e Student t-test, com p<0,05. Observou-se que o Cdcasca no sistema vascular causou uma diminuiÃÃo significativa nas freqÃÃncias cardÃaca e respiratÃria, bem como na pressÃo arterial mÃdia, havendo um aumento na produÃÃo de Ãxido nÃtrico no sangue dos animais tratados. Realizou-se o bloqueio farmacolÃgico com L-Name e os efeitos nas freqÃÃncias cardÃaca e respiratÃria e na pressÃo arterial mÃdia foram abolidos. O veneno bruto Cdcasca nÃo apresentou efeitos no leito vascular arteriolar mesentÃrico. O veneno bruto da Cdcasca foi fortemente citotÃxico na linhagem tumoral de leucemia, onde ocorreu uma diminuiÃÃo na viabilidade celular, bem como um aumento na fragmentaÃÃo do DNA. O NPcasca diminuiu as freqÃÃncias cardÃaca e respiratÃria e pressÃo arterial mÃdia. Ocorreu um aumento na produÃÃo de nitrito no sangue dos animais tratados. Nos experimentos de anel de aorta onde utilizou-se o NPcasca, observou-se um relaxamento dependente de endotÃlio. O NPcasca promoveu aumento significativo na pressÃo de e na resistÃncia vascular renal. O fluxo urinÃrio e o ritmo de filtraÃÃo glomerular tambÃm aumentaram significativamente. As alteraÃÃes histolÃgicas dos rins perfundidos foram discretas, comparando-as com as alteraÃÃes observadas com o veneno total. Nos experimentos com rim isolado nÃo houve alteraÃÃo de expressÃo gÃnica de mediadores inflamatÃrios. AtravÃs destes resultados concluÃmos que algum componente do veneno Cdcasca seja responsÃvel pelo efeito hipotensor e citotoxicidade em cÃlulas tumorais. O NPcasca apresentou um efeito hipotensor e aumentou a diurese e natriurese. NÃo houve alteraÃÃo de expressÃo gÃnica de mediadores inflamatÃrios no tecido renal / The snakes from the genus Crotalus in Brazil are represented by only one specie, Crotalus durissus. The poisoning by a sub-specie Crotalus durissus cascavella leads to systemic alterations, and is responsible for preliminary cause of death after the ophidic accident. This study aimed to evaluate the pharmacological effects of the snake venom Crotalus durissus cascavella - Ce (Cdcasca). This work looked at the actions of Cdcasca on the vascular system, assessing the physiological parameters of blood pressure and analyzing the histological changes in the heart, kidney, lung, brain and liver removed after the trials of blood pressure. The cytotoxic activity of Cdcasca was examined in four lines of human tumor cells: leukemia, breast tumor, colon tumor and nervous system tumor. There was an investigation of the likely mechanism of action of Cdcasca using the methods of viability cell by the exclusion of Trypan Blue, inhibition in the synthesis of ADN, antiproliferative activity of mononuclear cells (Alamar Blue). The integrity of the cell membrane, the ADN fragmentation and alteration of the mitochondrial transmembranic potential were analyzed by flow cytometry. It was Investigated the action of a Natriuretic Peptide (NPcasca) isolated from the venom of Cdcasca on a blood pressure system, on aortic rings assay and renal perfusion. After renal perfusion, the kidneys were subjected to histological analysis and study of its molecular biology. All parameters studied were analyzed by ANOVA and Student t-test, p <0.05. It was observed that the Cdcasca on the vascular system caused a significant decrease in heart and respiratory rates, and in the mean arterial pressure, with an increase in the production of nitric oxide in the blood of treated animals. There was made a pharmacological blockade with L-Name and the effects on heart and respiratory rates and mean arterial pressure were abolished. The total venom Cdcasca did not produced effects on the arteriolar mesenteric vascular bed. The whole venom Cdcasca was strongly cytotoxic on tumor line for leukemia, where there was a decrease in cell viability, as well as an increase in fragmentation of ADN. The NPcasca produced a decreased in heart and respiratory rates, and in the mean arterial pressure, with an increase in the production of nitric oxide in the blood of treated animals. In the experiments using NPcasca on aortic rings, there was a vasorelaxation dependent on endothelium. The NPcasca promoted a significant increase in perfusion pressure, and in renal vascular resistance. The urinary flow and the glomerular filtration rate also increased significantly. The perfused kidneys histological alterations were discrete, compared to the changes observed by the total venom Cdcasca. In experiments with isolated kidneys there was no change in gene expression of inflammatory mediators. Through these results we conclude that any component of poison Cdcasca is responsible for lowering effect and cytotoxicity in tumor cells. The NPcasca presented a hypotensive effects and increased the diuresis and natriurese. There was no change in gene expression of inflammatory mediators in kidney tissue

Objectives: Adequate organ perfusion, as well as appropriate blood pressure levels at the time of unclamping, is crucial for early and long-term graft function and outcome in simultaneous pancreas–kidney transplantation (SPKT). However, the optimal intraoperative mean arterial pressure (MAP) level has not well been defined. Methods: From a prospectively collected database, the medical data of 105 patients undergoing SPKT at our center were retrospectively analyzed. A receiver operating characteristic (ROC) analysis was preliminarily performed for optimal cut-off value for MAP at reperfusion, to predict early pancreatic graft function. Due to these results, we divided the patients according to their MAP values at reperfusion into <91 mmHg (n = 47 patients) and >91 mmHg (n = 58 patients) groups. Clinicopathological characteristics and outcomes, as well as early graft function and long-term survival, were retrospectively analyzed. Results: Donor and recipient characteristics were comparable between both groups. Rates of postoperative complications were significantly higher in the <91 mmHg group than those in the >91 mmHg group (vascular thrombosis of the pancreas: 7 (14%) versus 2 (3%); p = 0.03; pancreatitis/intraabdominal abscess: 10 (21%) versus 4 (7%); p = 0.03; renal delayed graft function (DGF): 11 (23%) versus 5 (9%); p = 0.03; postreperfusion urine output: 106 ± 50 mL versus 195 ± 45 mL; p = 0.04). There were no significant differences in intraoperative volume repletion, central venous pressure (CVP), use of vasoactive inotropic agents, and the metabolic outcome. Five-year pancreas graft survival was significantly higher in the >91 mmHg group (>91 mmHg: 82% versus <91 mmHg: 61%; p < 0.01). No significant differences were observed in patient and kidney graft survival at 5 years between both groups. Multivariate Cox regression analysis affirmed MAP < 91 mmHg as an independent prognostic predictor for renal DGF (HR 3.49, 1.1–10.8, p = 0.03) and pancreas allograft failure (HR 2.26, 1.0–4.8, p = 0.01). Conclusions: A MAP > 91 mmHg at the time point of reperfusion was associated with a reduced rate of postoperative complications, enhancing and recovering long-term graft function and outcome and thus increasing long-term survival in SPKT recipients.

High blood pressure, also called hypertension is one of the most common worldwide diseases afflicting humans and is a major risk factor for stroke, myocardial infarction, vascular disease, and chronic kidney disease. If blood pressure is controlled and oscillations in the hemodynamic variables are reduced, patients experience fewer complications after surgery. In clinical practice, this is usually achieved using manual drug delivery. Given that different patients have different sensitivity and reaction time to drugs, determining manually the right drug infusion rates may be difficult. This is a problem where automatic drug delivery can provide a solution, especially if it is designed to adapt to variations in the patient’s conditions. This research work presents an investigation into the development of abnormal blood pressure (hypertension) controllers for postoperative patients. Control of the drugs infusion rates is used to simultaneously regulate the hemodynamic variables such as the Mean Arterial Pressure (MAP) and the Cardiac Output (CO) at the desired level. The implementation of optimal control system is very essential to improve the quality of patient care and also to reduce the workload of healthcare staff and costs. Many researchers have conducted studies earlier on modelling and/or control of abnormal blood pressure for postoperative patients. However, there are still many concerns about smooth transition of blood pressure without any side effect. The blood pressure is classified in two categories: high blood pressure (Hypertension) and low blood pressure (Hypotension). The hypertension often occurred after cardiac surgery, and the hypotension occurred during cardiac surgery. To achieve the optimal control solution for these abnormal blood pressures, many methods are proposed, one of the common methods is infusing the drug related to blood pressure to maintain it at the desired level. There are several kinds of vasodilating drugs such as Sodium Nitroprusside (SNP), Dopamine (DPM), Nitro-glycerine (NTG), and so on, which can be used to treat postoperative patients, also used for hypertensive emergencies to keep the blood pressure at safety level. A comparative performance of two types of algorithms has been presented in chapter four. These include the Internal Model Control (IMC), and Proportional-Integral-Derivative (PID) controller. The resulting controllers are implemented, tested and verified for three sensitivity patient response. SNP is used for all three patients’ situation in order to reduce the pressure smoothly and maintain it at the desire level. A Genetic Algorithms (GAs) optimization technique has been implemented to optimise the controllers’ parameters. A set of experiments are presented to demonstrate the merits and capabilities of the control algorithms. The simulation results in chapter four have demonstrated that the performance criteria are satisfied with the IMC, and PID controllers. On the other hand, the settling time for the PID control of all three patients’ response is shorter than the settling time with IMC controller. Using multiple interacting drugs to control both the MAP and CO of patients with different sensitivity to drugs is a challenging task. A Multivariable Model Reference Adaptive Control (MMRAC) algorithm is developed using a two-input, two-output patient model. Because of the difference in patient’s sensitivity to the drug, and in order to cover the wide ranges of patients, Model Reference Adaptive Control (MRAC) has been implemented to obtain the optimal infusion rates of DPM and SNP. This is developed in chapters five and six. Computer simulations were carried out to investigate the performance of this controller. The results show that the proposed adaptive scheme is robust with respect to disturbances and variations in model parameters, the simulation results have demonstrated that this algorithm cannot cover the wide range of patient’s sensitivity to drugs, due to that shortcoming, a PID controller using a Neural Network that tunes the controller parameters was designed and implemented. The parameters of the PID controller were optimised offline using Matlab genetic algorithm. The proposed Neuro-PID controller has been tested and validated to demonstrate its merits and capabilities compared to the existing approaches to cover wide range of patients.

High blood pressure, also called hypertension is one of the most common worldwide diseases afflicting humans and is a major risk factor for stroke, myocardial infarction, vascular disease, and chronic kidney disease. If blood pressure is controlled and oscillations in the hemodynamic variables are reduced, patients experience fewer complications after surgery. In clinical practice, this is usually achieved using manual drug delivery. Given that different patients have different sensitivity and reaction time to drugs, determining manually the right drug infusion rates may be difficult. This is a problem where automatic drug delivery can provide a solution, especially if it is designed to adapt to variations in the patient’s conditions. This research work presents an investigation into the development of abnormal blood pressure (hypertension) controllers for postoperative patients. Control of the drugs infusion rates is used to simultaneously regulate the hemodynamic variables such as the Mean Arterial Pressure (MAP) and the Cardiac Output (CO) at the desired level. The implementation of optimal control system is very essential to improve the quality of patient care and also to reduce the workload of healthcare staff and costs. Many researchers have conducted studies earlier on modelling and/or control of abnormal blood pressure for postoperative patients. However, there are still many concerns about smooth transition of blood pressure without any side effect. The blood pressure is classified in two categories: high blood pressure (Hypertension) and low blood pressure (Hypotension). The hypertension often occurred after cardiac surgery, and the hypotension occurred during cardiac surgery. To achieve the optimal control solution for these abnormal blood pressures, many methods are proposed, one of the common methods is infusing the drug related to blood pressure to maintain it at the desired level. There are several kinds of vasodilating drugs such as Sodium Nitroprusside (SNP), Dopamine (DPM), Nitro-glycerine (NTG), and so on, which can be used to treat postoperative patients, also used for hypertensive emergencies to keep the blood pressure at safety level. A comparative performance of two types of algorithms has been presented in chapter four. These include the Internal Model Control (IMC), and Proportional-Integral-Derivative (PID) controller. The resulting controllers are implemented, tested and verified for three sensitivity patient response. SNP is used for all three patients’ situation in order to reduce the pressure smoothly and maintain it at the desire level. A Genetic Algorithms (GAs) optimization technique has been implemented to optimise the controllers’ parameters. A set of experiments are presented to demonstrate the merits and capabilities of the control algorithms. The simulation results in chapter four have demonstrated that the performance criteria are satisfied with the IMC, and PID controllers. On the other hand, the settling time for the PID control of all three patients’ response is shorter than the settling time with IMC controller. Using multiple interacting drugs to control both the MAP and CO of patients with different sensitivity to drugs is a challenging task. A Multivariable Model Reference Adaptive Control (MMRAC) algorithm is developed using a two-input, two-output patient model. Because of the difference in patient’s sensitivity to the drug, and in order to cover the wide ranges of patients, Model Reference Adaptive Control (MRAC) has been implemented to obtain the optimal infusion rates of DPM and SNP. This is developed in chapters five and six. Computer simulations were carried out to investigate the performance of this controller. The results show that the proposed adaptive scheme is robust with respect to disturbances and variations in model parameters, the simulation results have demonstrated that this algorithm cannot cover the wide range of patient’s sensitivity to drugs, due to that shortcoming, a PID controller using a Neural Network that tunes the controller parameters was designed and implemented. The parameters of the PID controller were optimised offline using Matlab genetic algorithm. The proposed Neuro-PID controller has been tested and validated to demonstrate its merits and capabilities compared to the existing approaches to cover wide range of patients. / Libyan Ministry of Higher Education scholarship