Theoretical Analysis of the Relative Impact of Obesity on Hemodynamic Stability During Acute Hemorrhagic Shock

Background: Evidence suggests that morbid obesity may be an independent risk factor for adverse outcomes in patients with traumatic injuries. Objectives: In this study, a theoretic analysis using a derivation of the Guyton model of cardiovascular physiology examines the expected impact of obesity on hemodynamic changes in Mean Arterial Pressure (MAP) and Cardiac Output (CO) during Hemorrhagic Shock (HS). Patients and Methods: Computer simulation studies were used to predict the relative impact of increasing Body Mass Index (BMI) on global hemodynamic parameters during HS. The analytic procedure involved recreating physiologic conditions associated with changing BMI for a virtual subject in an In Silico environment. The model was validated for the known effect of a BMI of 30 on iliofemoral venous pressures. Then, the relative effect of changing BMI on the outcome of target cardiovascular parameters was examined during simulated acute loss of blood volume in class II hemorrhage. The percent changes in these parameters were compared between the virtual nonobese and obese subjects. Model parameter values are derived from known population distributions, producing simulation outputs that can be used in a deductive systems analysis assessment rather than traditional frequentist statistical methodologies. Results: In hemorrhage simulation, moderate increases in BMI were found to produce greater decreases in MAP and CO compared to the normal subject. During HS, the virtual obese subject had 42% and 44% greater falls in CO and MAP, respectively, compared to the nonobese subject. Systems analysis of the model revealed that an increase in resistance to venous return due to changes in intra-abdominal pressure resulting from obesity was the critical mechanism responsible for the differences. Conclusions: This study suggests that obese patients in HS may have a higher risk of hemodynamic instability compared to their nonobese counterparts primarily due to obesity-induced increases in intra-abdominal pressure resulting in reduced venous return

Pharmacometric modelling of haemodynamics in humans

Current pharmacokinetic-pharmacodynamic models describing changes to the haemodynamic system often do not include necessary feedback mechanisms. These models often provide an adequate empirical description of data but may fail to adequately extrapolate to additional scenarios. This study aimed to develop a minimal model to describe the short-term changes of haemodynamics that can be used as the basis for future model development. The model was used to describe the haemodynamic effects of sodium nitroprusside (SNP) in adolescents undergoing surgery. A minimal haemodynamic model was developed to describe the influence of drugs on blood pressure components. The model structure was defined based on known mechanisms and previously published models. The model parameters were calibrated to describe (without estimation) the heamodynamics of two antihypertensive drugs with data extracted from the literature. Structural identifiability analysis was done using various combinations of the observed variables. The model was applied to clinical data from patients receiving SNP infusion. The model was extended to accommodate the postulated mechanism of action of SNP in the literature. The proposed model structure included mean arterial pressure (MAP), heart rate (HR), and stroke volume and was composed of four states described by differential equations. The model evaluation showed flexibility in describing haemodyanmics at different target perturbations. Overlay plots of model predictions and literature data showed a good description without data fitting. The structural identifiability analysis revealed all model parameters and initial conditions were identifiable only when HR, MAP, and cardiac output were measured together. In addition, model evaluation using SNP data suggested its mechanistic plausibility and the flexibility to describe various response patterns elicited by SNP A minimal model of the haemodynamic system was developed and evaluated. The model accounted for short-term haemodynamic feedback processes. We propose that this model can be used as the basis for future pharmacometric analyses of drugs acting on the haemodynamic system

Avaliação da ativação do sistema nervoso vegetativo pelo nitroprussiato de sódio

Ao longo dos anos, intrincados modelos matemáticos foram desenvolvidos e aperfeiçoados, para descrever a dinâmica dos vários sistemas do organismo humano. Estes modelos matemáticos conjugados com complexos algoritmos e protocolos de atuação médica, serviram de base para desenvolver e aprimorar sistemas de administração automática de fármacos. Estes sistemas têm como objetivo tornar mais eficiente e segura a prestação de cuidados de saúde, diminuindo simultaneamente a carga de trabalho dos profissionais. O presente trabalho visa compreender quais os indicadores ou testes que permitem a avaliação do estado de ativação do sistema nervoso autónomo humano. Adicionalmente, pretende-se compreender como interage o Nitroprussiato de Sódio com esses indicadores. Este estudo será incorporado num sistema de administração automática de Nitroprussiato de Sódio, para controlo da tensão arterial, como forma de melhorar a precisão e segurança do algoritmo de controlo. Para alcançar os objetivos deste trabalho foi realizada uma pesquisa e revisão da literatura médica disponível em bases de dados eletrónicas.Over the years, intricate mathematical models have been developed and refined to describe the dynamics of the various systems of the human body. These mathematical models combined with complex algorithms and protocols of medical action, served as a basis to develop and enhance automated drug delivery systems. These systems are developed in order to create a more efficient and secure provision of health care while reducing the workload of professionals. The objective of this study is to understand which indicators or tests allow the assessment of the state of activation of the human autonomic nervous system. Additionally, we intend to understand how the state of activation of the human autonomic nervous system interacts with sodium nitroprusside. This study will be incorporated in an automatic sodium nitroprusside administration system blood pressure control with the objective of improving the accuracy and reliability of the control algorithm. A survey and review of the available medical literature was performed in electronic databases

Body Fluid Metabolism in the Rat: A Computer Simulation

Toates and Oatley (1970) presented a computer simulation of rat body fluid dynamics. Whilst their two- compartment (intracellular and extracellular) model was a significant contribution, it does not adequately represent cardiovascular, renal or hormonal aspects of water metabolism. Two models are presented. The simpler model ('small rat') was designed to meet educational criteria, whilst the more complex model ('large rat') is more research-oriented. Both supercede existing models, but the large rat is the more detailed representation. Both are three-compartment models- intracellular, interstitial and vascular. The cardiovascular system is well represented; this has permitted the realistic simulation of many renal, neuronal and endocrine systems important to water homeostasis. Many other related systems are also described, such as the gastro-intestinal tract, energy balance, insensible water loss and electrolyte metabolism in each of the body compartments. The inclusion of such systems has permitted analyses of the 'volemic' (extracellular) drinking stimuli, and their interactions with other stimuli. The concept of redundancy in drinking stimuli is examined, and a new theory presented that permits its inclusion in current drinking models. The functional significance of central osmoreceptor siting is discussed, in the light of simulations of fluid absorption dynamics following drinking. Simulations of drinking responses following deprivation are studied. The results indicate an explanation for 'voluntary dehydration', in which water-deprived rats do not restore fluid balance to pre-deprivation levels when subsequently offered water. The inclusion of 'peripheral' drinking stimuli in the 'small rat' has enabled an analysis of such phenomena as sham drinking. The nature of the intracellular stimulus to thirst is examined, and a new energy-based theory is presented, which promises to resolve many apparent paradoxes. Finally, potential improvements and future developments are discussed

Modeling and estimation for non-invasive monitoring of intracranial pressure and cerebrovascular autoregulation

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2011.Cataloged from PDF version of thesis.Includes bibliographical references (p. 187-202).Brain tissue is highly vulnerable to unbalanced oxygen demand and supply. A few seconds of oxygen deficit may trigger neurological symptoms, and sustained oxygen deprivation over a few minutes may result in severe and often irreversible brain damage. The rapid dynamics coupled with the potential for severe injury necessitate continuous cerebrovascular monitoring in the populations at greatest risk for developing or exacerbating brain injury. Intracranial pressure (ICP), which is the pressure of the cerebrospinal fluid, is a vitally important variable to monitor in a wide spectrum of medical conditions involving the brain, such as traumatic brain injury, stroke, hydrocephalus, or brain tumors. However, clinical measurement of ICP is highly invasive, as it requires neurosurgical penetration of the skull and placement of a pressure sensor in the brain tissue or ventricular spaces. Measurement of ICP is thus currently limited to only those patient populations in which the benefits of obtaining the measurement outweigh the significant attendant risks, thus excluding a large pool of patients who could potentially benefit from ICP monitoring. The primary goal of our work is to address the non-invasive monitoring of ICP. A secondary aim of this work is to develop methods for the assessment of cerebrovascular autoregulation, which is the innate ability of the vasculature to maintain cerebral blood flow in the face of changes in cerebral perfusion pressure. Cerebrovascular autoregulation is often impaired in patients with brain trauma or stroke, and also in pre-term neonates, as their cerebrovascular system is not fully matured. We develop methods for non-invasive, continuous, calibration-free and patientspecific ICP monitoring. Specifically, we present a model-based approach to providing real-time estimates of ICP and cerebrovascular resistance and compliance, for each cardiac cycle, from non- or minimally-invasive time-synchronized measurements of arterial blood pressure and cerebral blood flow velocity in a major cerebral artery. In the first step, our approach exploits certain features of cerebrovascular physiology, along with model reduction ideas, to deduce a simple mathematical model of the cerebrovascular system. In the second step, we develop algorithms to compute robust estimates of model parameters by processing the measured waveforms through the constraints provided by the models dynamic equation. For validation, our non-invasive estimates of ICP were compared against invasive measurements from 45 comatose brain-injury patients, with a total of 35 hours of data (over 150,000 beats), providing more than 3,500 independent ICP estimates. Our estimates track measured ICP closely over a range of dynamic variations. Pooling all independent estimates resulted in a mean estimation error (bias) of less than 2 mmHg and a standard deviation of error of about 8 mmHg. We also suggest how variations in estimated cerebrovascular resistance and compliance in response to variations in cerebral perfusion pressure may be used to provide novel approaches for assessment of cerebrovascular autoregulation.by Faisal M. Kashif.Ph.D

Investigating the renal and vascular mechanisms of salt-induced hypertension in C57BL6/J mice

Dietary salt intake has a detrimental relationship with blood pressure (BP); the more salt consumed per day, the higher the incidence of hypertension and its cardiorenal consequences within a population. However, the underlying mechanisms responsible remain controversial. Research supports roles for both the kidneys and the vasculature in salt-induced hypertension. Here, I investigated the effect of a high salt diet (HSD) on BP, renal function and the vascular responses to vasoconstrictors and vasodilators in adult male C57BL6/JCrl mice. In my experiments, mice were fed either a HSD (3% sodium) or a standard salt (0.25% sodium) diet (SSD). BP was measured in conscious, freely moving animals by radiotelemetry. After measurements on the SSD, mice were fed the HSD and BP increased by ~5mmHg after 3-4 days and remained elevated for up to 3 weeks. Plasma aldosterone concentration was suppressed after 1 week HSD. Assessment of the acute pressure natriuresis (PN) response under anaesthesia illustrated increased urinary sodium excretion at any given BP and messenger RNA (mRNA) levels of some key renal sodium transporters were appropriately decreased by the HSD. Isolated renal arteries displayed increased sensitivity to the vasoconstrictor phenylephrine after 1 week of high salt. In mesenteric arteries, no functional changes were observed to the HSD, supported by no changes in endothelial NO synthase mRNA levels compared to the SSD. Urinary catecholamine concentration was used as an index of sympathetic nerve system (SNS) activity. Adrenaline excretion increased significantly on the HSD, indicating SNS involvement. To test this, the ganglionic blocker hexamethonium was administered via intraperitoneal injection and the resulting transient dip in BP was modestly increased and persisted after 3 weeks of the HSD. In conclusion, I observed a sustained salt-induced increase in BP in C57BL6/JCrl mice. Appropriate adaptation of aldosterone production and the acute PN response to salt challenge was seen. Increased excretion of adrenaline, elevated contractility of renal arteries and a greater effect on SBP with hexamethonium suggests over-activity of the SNS is an important factor in salt-induced hypertension in C57BL6/JCrl mice

L’insuffisance rénale aiguë congestive en chirurgie cardiaque

Background: Every year, more than 2 million people undergo cardiac surgery including 15 000 Canadians (1). Acute kidney injury remain a frequent complication in this setting which can affect up to 39% of patients (2). This complication is associated with a significant increase in the risk of short-term and long-term mortality after cardiac surgery (1). Multiple mechanisms can lead to acute kidney injury in the peri-operative period which complexify prevention and treatment. Among them, multiple clinical factors can result in an increase in venous pressure leading to a state of systemic congestion deleterious to kidney function in addition to other organs. The detection of congestion at the bedside of patients after cardiac surgery could be used to identify patients at risk of developing congestive complications such as congestive acute kidney injury as well as opening possibilities for prevention and treatment. Doppler ultrasound is a non-invasive technology enabling the assessment of blood flow velocity within the venous system. A reduction of systemic venous compliance lead to the appearance of alterations in portal vein flow and intra-renal venous flow. The objectives of the work presented in this thesis were the following: To determine the prevalence and predictive factor associated with the appearance of venous flow alterations during the intra-operative and post-operative period, to determine if their detection is associated with acute kidney injury in the post-operative period and to determine the clinical significance of their detection in the immediate post-operative period. Main results: This thesis is comprised of 3 cohort studies including a total of 1497 ultrasound asessments in 362 patients. Alterations in venous Doppler signals were observed in a subtantial proportion of patients during the per-operative period, from 10.8% to 24.3% depending on the time of assessment and the site assessed. We observed significant correlations between venous Doppler alterations and other clinical markers of congestion including central venous pressure, NT-pro-BNP and fluid balance. Furthermore, we observed that portal flow pulsatility and abnormal patterns of intrarenal venous flow were correlated. Using repeated assessments in a cohort of 145 patients, we observed that portal flow pulsatility and severe alterations in intrarenal venous flow were associated with the subsequent development of acute kidney injury in the post-operative period. A re-analysis of this data suggested that a grading system combining mutliple Doppler assesments at intensive care admission after cardiac surgery including heaptic veins, the portal vein and intrarenal veins may be able to identify patients at risk of developping acute kidney injury with high specificity. Conclusions: In the context of cardiac surgery, Doppler ultrasound can be used to identify alterations in peripheral venous Doppler signals suggestive of a congestion phenomenon and may be able to anticipate complications related to venous congestion such as acute kidney injury.Contexte : Chaque année, plus de 2 millions de personnes subissent une chirurgie cardiaque, dont 15 000 Canadiens (1). L’insuffisance rénale aiguë demeure une complication fréquente chez les patients subissant une chirurgie cardiaque atteignant une incidence jusqu’à 39 % dans la période postopératoire (2). Cette complication est associée à une augmentation du risque de mortalité à court et long termes. Plusieurs mécanismes peuvent engendrer l’insuffisance rénale aiguë dans la période peropératoire, ce qui complexifie la prévention et le traitement. Parmi ceux-ci, divers facteurs peuvent engendrer une augmentation des pressions veineuses menant à un état de congestion systémique qui affecte la fonction des reins ainsi que celle des autres organes vitaux. La détection de la congestion au chevet des patients durant la période intraopératoire et postopératoire pourrait permettre d’identifier les individus à risque de développer des complications de nature congestive telles que l’insuffisance rénale aiguë ainsi que de mettre en place des stratégies de prévention et de traitement. L’échographie Doppler est une technologie non invasive qui permet d’évaluer la vélocité du sang dans le réseau veineux. La diminution de la compliance veineuse entraine l’apparition d’altérations du flot veineux de la veine porte et des veines intrarénales. Les objectifs des travaux présentés dans cette thèse étaient les suivants : déterminer la prévalence ainsi que les facteurs prédicteurs de l’apparition de ces altérations durant la période peropératoire; déterminer si la détection de ces altérations est en mesure de prédire l’apparition d’insuffisance rénale aiguë dans la période postopératoire; et déterminer quelle est la signification clinique de l’apparition de ces signes dans la période postopératoire immédiate. Résultats principaux : Les travaux contenus dans cette thèse comportent trois études de cohorte comprenant 1497 examens échographiques chez 362 patients. La présence d’altération du flot veineux a été observée chez une proportion substantielle des patients durant la période post-opératoire, allant de 10.8% à 24.3% selon le site intérrogé et le moment où l’examen est effectué. Nous avons observé des associations entre les altérations du flot veineux et les autres marqueurs de congestion incluant la pression veineuse centrale, la mesure du NT-pro-BNP et la balance liquidienne. De plus, nous avons observé que la pulsatilité du flot portal est corrélée aux altérations du signal Doppler dans les veines intrarénales. Grâce à des examens répétées effectuées dans une cohorte de 145 patients, nous avons observé que la pulsatilité du flot portal et la présence d’un profil compatible avec une anomalie sévère du flot intrarénal veineux étaient associées indépendamment avec la survenue subséquente d’insuffisance rénale aiguë durant la période postopératoire. Une réanalyse de ces données nous a permis de constater qu’un système de gradation combinant la présence des altérations du flot veineux à plusieurs sites, incluant les veines hépatiques, la veine porte et les veines intrarénales, au moment de l’admission aux soins intensifs permet d’indentifier les patients qui développeront une insuffisance rénale aiguë avec une spécificité élevée. Conclusions : Dans le contexte de la chirurgie cardiaque, l’échographie Doppler peut être utilisée au chevet afin d’indentifier des altérations du flot veineux périphérique suggestives d’un phénomène de congestion et d’anticiper les complications de nature congestive tel que l’insuffisance rénale aiguë