Maximizing information from space data resources: a case for expanding integration across research disciplines.

Regulatory systems are affected in space by exposure to weightlessness, high-energy radiation or other spaceflight-induced changes. The impact of spaceflight occurs across multiple scales and systems. Exploring such interactions and interdependencies via an integrative approach provides new opportunities for elucidating these complex responses. This paper argues the case for increased emphasis on integration, systematically archiving, and the coordination of past, present and future space and ground-based analogue experiments. We also discuss possible mechanisms for such integration across disciplines and missions. This article then introduces several discipline-specific reviews that show how such integration can be implemented. Areas explored include: adaptation of the central nervous system to space; cerebral autoregulation and weightlessness; modelling of the cardiovascular system in space exploration; human metabolic response to spaceflight; and exercise, artificial gravity, and physiologic countermeasures for spaceflight. In summary, spaceflight physiology research needs a conceptual framework that extends problem solving beyond disciplinary barriers. Administrative commitment and a high degree of cooperation among investigators are needed to further such a process. Well-designed interdisciplinary research can expand opportunities for broad interpretation of results across multiple physiological systems, which may have applications on Earth.

Teaching fluid shifts during orthostasis using a classic paper by Foux et al.

Hypovolemic and orthostatic challenge can be simulated in humans by the application of lower body negative pressure (LBNP), because this perturbation leads to peripheral blood pooling and, consequently, central hypovolemia. The classic paper by Foux and colleagues clearly shows the effects of orthostasis simulated by LBNP on fluid shifts and homeostatic mechanisms. The carefully carried out experiments reported in this paper show the interplay between different physiological control systems to ensure blood pressure regulation, failure of which could lead to critical decreases in cerebral blood flow and syncope. Here, a teaching seminar for graduate students is described that is designed in the context of this paper and aimed at allowing students to learn how Foux and colleagues have advanced this field by addressing important aspects of blood regulation. This seminar is also designed to put their research into perspective by including important components of LBNP testing and protocols developed in subsequent research in the field. Learning about comprehensive protocols and carefully controlled studies can reduce confounding variables and allow for an optimal analysis and elucidation of the physiological responses that are being investigated. Finally, in collaboration with researchers in mathematical modeling, in the future, we will incorporate the concepts of applicable mathematical models into our curriculum.

Time delay in physiological systems: analyzing and modeling its impact.

This article examines the functional and clinical impact of time delays that arise in human physiological systems, especially control systems. An overview of the mathematical and physiological contexts for considering time delays will be illustrated, from the system level to cell level, by examining models that incorporate time delays. This examination will highlight how such delays in combination with other system structures and parameters influence system dynamics. Model analysis that reveals the influence of delays can also reveal related physiological effects which may have medical consequences and clinical applications.

Modeling of hyaluronan clearance with application to estimation of lymph flow.

One of the important factors in blood pressure regulation is the maintenance of the level of blood volume, which depends on several factors including the rate of lymph flow. Lymph flow can be measured directly using cannulation of lymphatic vessels, which is not clinically feasible, or indirectly by the tracer appearance rate, which is the rate at which macromolecules appear into the blood from the peritoneal cavity. However, indirect lymph flow measurements do not always provide consistent results. Through its contribution to osmotic pressure and resistance to flow, the macromolecule hyaluronan takes part in the regulation of tissue hydration and the maintenance of water and protein homeostasis. It arrives in blood plasma through lymph flow. Lymphatic hyaluronic acid (HA, hyaluronan) concentration is several times higher than that in plasma, suggesting that the lymphatic route may account for the majority of HA found in plasma. Furthermore, circulating levels of HA reflect the dynamic state between delivery to-and removal from-the bloodstream. To develop an accurate estimation of the fluid volume distribution and dynamics, the rate of lymph flow needs to be taken into account and hyaluronan could be used as a marker in estimating this flow. To examine the HA distribution and system fluid dynamics, a six-compartment model, which could reflect both the steady-state relationships and qualitative characteristics of the dynamics, was developed. This was then applied to estimate fluid shifts from the interstitial space via the lymphatic system to the plasma during different physiological stresses (orthostatic stress and the stress of ultrafiltration during dialysis). Sensitivity analysis shows that during ultrafiltration, lymph flow is a key parameter influencing the total HA level, thus suggesting that the model may find applications in addressing the problem of estimating lymph flow. Since the fluid balance between interstitium and plasma is maintained by lymph flow and microvasculature filtration, our novel method of flow estimation may provide an important tool for understanding fluid dynamics during perturbations of the cardiovascular system. Since the fluid balance between interstitium and plasma is maintained by lymph flow and microvasculature filtration, our novel method of flow estimation may provide an important tool for understanding fluid dynamics during perturbations of the cardiovascular system.

Evolution of volume sensitivity during hemodialysis and ultrafiltration.

OBJECTIVE: This study aimed at assessing the evolution of cardiovascular characteristics during hemodialysis and ultrafiltration by a perturbation accurately defined in its magnitude and directly relevant to the problem of volume adjustment in stable hemodialysis patients. METHODS: Excess fluid volume was removed by constant ultrafiltration-rate as prescribed. Hemodynamic variables were continuously measured throughout treatments using non-invasive finger plethysmography. In addition to ongoing volume reduction by ultrafiltration (long-term perturbation), well-defined magnitudes of intravascular volume were transiently and reversibly sequestered (short-term perturbation) into the extracorporeal circulation at hourly intervals. Sensitivities of hemodynamic variables and of the baroreflex to the acute change in intravascular volume (volume sensitivities) were analyzed. RESULTS: Eight stable patients were assessed during two subsequent treatments. Treatments were accompanied by a decrease in cardiac output (p<0.05) and stroke volume (p<0.01), and by an increase in peripheral resistance (p<0.05) and diastolic pressure (p<0.05). Mean arterial pressure remained unchanged for the whole group but correlated with the change in total peripheral resistance in individual treatments (p<0.01). The average volume sensitivity of mean arterial pressure was 11.9±9.9 mmHg/L and increased (p<0.01) during treatments, while the average volume sensitivity of heart rate remained unchanged at -7.9±8.58 1/(min L). The corresponding volume sensitivity of the baroreflex was -0.81±1.5 1/(min mmHg) and remained unchanged for the whole group, but the change correlated with the change in mean arterial pressure in individual treatments (p<0.05). INTERPRETATION: The changes in arterial pressures during hemodialysis appear to relate to an unbalanced response of barocontrol mechanisms characterized by a compromised chronotropy and vascular over-reactivity.

Modeling cardio-respiratory system response to inhaled CO2 in patients with congestive heart failure.

In this paper we examine a cardiovascular-respiratory model of mid-level complexity designed to predict the dynamics of end-tidal carbon dioxide (CO(2)) and cerebral blood flow velocity in response to a CO(2) challenge. Respiratory problems often emerge as heart function diminishes in congestive heart failure patients. To assess system function, various tests can be performed including inhalation of a higher than normal CO(2) level. CO(2) is a key quantity firstly because any perturbation in system CO(2) quickly influences ventilation (oxygen perturbations need to be more severe). Secondly, the CO(2) response gain has been associated with respiratory system control instability. Thirdly, CO(2) in a short time impacts the degree of cerebral vascular constriction, allowing for the assessment of cerebral vasculature function. The presented model can be used to study key system characteristics including cerebral vessel CO(2) reactivity and ventilatory feedback factors influencing ventilatory stability in patients with congestive heart failure. Accurate modeling of the dynamics of system response to CO(2) challenge, in conjunction with robust parameter identification of key system parameters, can help in assessing patient system status.

Modeling the cardiovascular-respiratory control system: data, model analysis, and parameter estimation.

Several key areas in modeling the cardiovascular and respiratory control systems are reviewed and examples are given which reflect the research state of the art in these areas. Attention is given to the interrelated issues of data collection, experimental design, and model application including model development and analysis. Examples are given of current clinical problems which can be examined via modeling, and important issues related to model adaptation to the clinical setting.

A respiratory system model: parameter estimation and sensitivity analysis.

In this paper we compare several approaches to identifying certain key respiratory control parameters relying on data normally available from non-invasive measurements. We consider a simple model of the respiratory control system and describe issues related to numerical estimates of key parameters involved in respiratory function such as central and peripheral control gains, transport delay, and lung compartment volumes. The combination of model-specific structure and limited data availability influences the parameter estimation process. Methods for studying how to improve the parameter estimation process are examined including classical and generalized sensitivity analysis, and eigenvalue grouping. These methods are applied and compared in the context of clinically available data. These methods are also compared in conjunction with specialized tests such as the minimally invasive single-breath CO2 test that can improve the estimation, and the enforced fixed breathing test, which opens the control loop in the system. The analysis shows that it is impossible to estimate central and peripheral gain simultaneously without usage of ventilation measurement and a controlled perturbation of the respiratory system, such as the CO2 test. The numerical results are certainly model dependent, but the illustrated methods, the nature of the comparisons, and protocols will carry over to other models and data configurations.

Aspects of control of the cardiovascular-respiratory system during orthostatic stress induced by lower body negative pressure.

This paper considers a model developed to study the cardiovascular control system response to orthostatic stress as induced by two variations of lower body negative pressure (LBNP) experiments. This modeling approach has been previously applied to study control responses to transition from rest to aerobic exercise, to transition to non-REM sleep and to orthostatic stress as produced by the head up tilt (HUT) experiment. LBNP induces a blood volume shift because negative pressure changes the volume loading characteristics of the compartment which is subject to the negative pressure. This volume shift induces a fall in blood pressure which must be counteracted by a complicated control response involving a variety of mechanisms of the cardiovascular control system. There are a number of medical issues connected to these questions such as orthostatic intolerance in the elderly resulting in dizziness or fainting during the transition from sitting to standing. The model presented here is used to study the interaction of changes in systemic resistance, unstressed venous volume, venous compliance, heart rate, and contractility in the control of orthostatic stress. The overall short term response depends on a combination of these physiological reactions which may vary from individual to individual. There remain open questions about which factors have greater importance. The model simulations are compared to experimental data collected for LBNP exerted from the hips to feet and from ribs to feet.

A cardiovascular-respiratory control system model including state delay with application to congestive heart failure in humans.

This paper considers a model of the human cardiovascular-respiratory control system with one and two transport delays in the state equations describing the respiratory system. The effectiveness of the control of the ventilation rate is influenced by such transport delays because blood gases must be transported a physical distance from the lungs to the sensory sites where these gases are measured. The short term cardiovascular control system does not involve such transport delays although delays do arise in other contexts such as the baroreflex loop (see [46]) for example. This baroreflex delay is not considered here. The interaction between heart rate, blood pressure, cardiac output, and blood vessel resistance is quite complex and given the limited knowledge available of this interaction, we will model the cardiovascular control mechanism via an optimal control derived from control theory. This control will be stabilizing and is a reasonable approach based on mathematical considerations as well as being further motivated by the observation that many physiologists cite optimization as a potential influence in the evolution of biological systems (see, e.g., Kenner [29] or Swan [62]). In this paper we adapt a model, previously considered (Timischl [63] and Timischl et al. [64]), to include the effects of one and two transport delays. We will first implement an optimal control for the combined cardiovascular-respiratory model with one state space delay. We will then consider the effects of a second delay in the state space by modeling the respiratory control via an empirical formula with delay while the the complex relationships in the cardiovascular control will still be modeled by optimal control. This second transport delay associated with the sensory system of the respiratory control plays an important role in respiratory stability. As an application of this model we will consider congestive heart failure where this transport delay is larger than normal and the transition from the quiet awake state to stage 4 (NREM) sleep. The model can be used to study the interaction between cardiovascular and respiratory function in various situations as well as to consider the influence of optimal function in physiological control system performance.