Cardiac output is not a significant source of low frequency mean arterial pressure variability.

Spontaneous mean arterial pressure (MAP) variability may be mainly due to fluctuations in cardiac output (CO) and total peripheral resistance (TPR). While high frequency (HF ∼ 0.25 Hz) oscillations in MAP are ultimately driven by respiration, the source of low frequency (LF ∼ 0.1 Hz) fluctuations has not been fully elucidated. It is known that CO buffers these oscillations, but there is no evidence on its potential role in also generating them. The main goal was to determine whether CO is a source of LF variability in MAP. Six dogs were chronically instrumented to obtain beat-to-beat measurements of CO and MAP while the dogs were fully awake and at rest. A causal dynamic model was identified to relate the fluctuations in CO to MAP. The model was then used to predict the MAP fluctuations from the CO fluctuations. The CO fluctuations were able to predict about 70% of the MAP oscillations in the HF band but showed no predictive value in the LF band. Hence, respiration induces CO fluctuations in the HF band that, in turn, cause MAP oscillations, while TPR fluctuations appear to be the dominant mediator of LF fluctuations of MAP. CO is not a significant source of these oscillations, and it may only be responsible for dampening them, likely through the baroreflex.

Continuous and minimally invasive cardiac output monitoring by long time interval analysis of a radial arterial pressure waveform: assessment using a large, public intensive care unit patient database.

BACKGROUND: A potential practical approach for continuous and minimally invasive cardiac output (CO) monitoring in intensive care unit (ICU) patients is to mathematically analyse an arterial pressure (AP) waveform using an existing radial artery line ('pulse contour analysis'). We recently proposed a technique to estimate the relative CO change by unique long time interval analysis (LTIA) of an AP waveform. We aimed to test this technique in an ICU patient population and compare its accuracy relative to other techniques. METHODS: We studied a public, electronic ICU patient database. We extracted 1482 pairs of radial AP waveforms and thermodilution CO measurements (via single bolus injections) from 169 patients. We applied the LTIA and previous pulse contour analysis techniques to the AP waveforms. We assessed the calibrated CO estimates against the thermodilution measurements. RESULTS: The overall root-mean-squared-error of the LTIA technique was 18.8%. This total level of accuracy was not better than the previous techniques. However, the average magnitude of the thermodilution changes was only 12.3% (9.9 sd). When the magnitude of the thermodilution change exceeded 30%, 50%, and 70%, the median squared-error differences between the LTIA technique and the most accurate previous technique were -45 (-322:69 quartiles) (P=0.005), -128 (-704:23) (P=0.006), and -862 (-2871:306)%(2) (P=0.055), respectively. The LTIA technique was therefore superior in detecting clinically important CO changes. CONCLUSIONS: The LTIA technique attained an overall accuracy that may be considered clinically acceptable after taking into account the known thermodilution error and became progressively more accurate than previous techniques with increasing CO changes.

Monitoring non-invasive cardiac output and stroke volume during experimental human hypovolaemia and resuscitation.

BACKGROUND: Multiple methods for non-invasive measurement of cardiac output (CO) and stroke volume (SV) exist. Their comparative capabilities are not clearly established. METHODS: Healthy human subjects (n=21) underwent central hypovolaemia through progressive lower body negative pressure (LBNP) until the onset of presyncope, followed by termination of LBNP, to simulate complete resuscitation. Measurement methods were electrical bioimpedance (EBI) of the thorax and three measurements of CO and SV derived from the arterial blood pressure (ABP) waveform: the Modelflow (MF) method, the long-time interval (LTI) method, and pulse pressure (PP). We computed areas under receiver-operating characteristic curves (ROC AUCs) for the investigational metrics, to determine how well they discriminated between every combination of LBNP levels. RESULTS: LTI and EBI yielded similar reductions in SV during progressive hypovolaemia and resuscitation (correlation coefficient 0.83) with ROC AUCs for distinguishing major LBNP (-60 mm Hg) vs resuscitation (0 mm Hg) of 0.98 and 0.99, respectively. MF yielded very similar reductions and ROC AUCs during progressive hypovolaemia, but after resuscitation, MF-CO did not return to baseline, yielding lower ROC AUCs (ΔROC AUC range, -0.18 to -0.26, P < 0.01). PP declined during hypovolaemia but tended to be an inferior indicator of specific LBNP levels, and PP did not recover during resuscitation, yielding lower ROC curves (P < 0.01). CONCLUSIONS: LTI, EBI, and MF were able to track progressive hypovolaemia. PP decreased during hypovolaemia but its magnitude of reduction underestimated reductions in SV. PP and MF were inferior for the identification of resuscitation.

Comparison of cardiac output monitoring methods for detecting central hypovolemia due to lower body negative pressure.

Reduction in mean arterial pressure (MAP) is a late indictor of progressive circulatory pathology. Non-invasive monitoring methods that are superior indicators of circulatory compromise would be clinically valuable. With IRB approval, 21 healthy volunteers were subjected to progressive lower body negative pressure (LBNP) until the onset of presyncopal symptoms. We evaluated the usefulness of four investigational methods of arterial blood pressure waveform analysis during progressive hypovolemia: mean arterial pressure (MAP); the ModelFlow cardiac output algorithm (MF); the long time interval method (LTI); and the product of pulse pressure and heart rate (PP*HR). Electrical bioimpedance measurement of cardiac output (EBI) provided a reference. When results were analyzed, we found significant differences between the methods. MF, LTI, and EBI all corresponded with LBNP severity, while MAP and PP*HR did not. In terms of discriminating between (a) decompression to -45 mmHg; versus (b) recovery five minutes after LBNP cessation, there was a significant difference between MF and LTI: the receiver operating characteristic area-under-the-curve (ROC AUC) for MF was 0.57 and for LTI was 0.76. In terms of discriminating between (a) the 11 subjects who tolerated the protocol (i.e., tolerated higher levels of LBNP); versus (b) the 10 non-tolerant subjects, there was also a significant difference between MF and LTI: the ROC AUC for MF was 0.40 and for LTI was 0.66. There were no significant differences between MF nor EBI, however. In conclusion, LTI is notable as the only method which (a) correlated with decompression: (b) distinguished between decompression to -45 mmHg versus recovery; and (c) distinguished between those subjects who adequately compensated for central hypovolemia (tolerant) and those who did not have such robust physiologic compensation (non-tolerant).

Identification of the arterial and cardiopulmonary total peripheral resistance baroreflex gain values from spontaneous hemodynamic variability.

We have previously proposed a potentially noninvasive technique for determining the closed-loop gain values of the arterial and cardiopulmonary total peripheral resistance (TPR) baroreflex systems by mathematical analysis of beat-tobeat fluctuations in arterial blood pressure, cardiac output, and stroke volume. In this paper, we describe an evaluation of the technique with respect to spontaneous hemodynamic variability measured from seven conscious dogs before and after chronic arterial baroreceptor denervation. We report that the technique correctly predicted the expected changes in the TPR baroreflex gain values induced by the baroreceptor denervation.

Non-invasive monitoring of left ventricular contractility and ventilatory mechanics.

The maximum left ventricular elastance (Emaxiv) is a valuable index of ventricular contractility. However, conventional methods for its measurements are too invasive for routine use. We propose a non-invasive technique for tracking changes in Emaxivby mathematically determining the dynamic coupling between beat-to-beat fluctuations in instantaneous lung volume and arterial blood pressure measured during random-interval breathing. The mathematical technique also provides an estimate of the dominant time constant of the ventilatory system (), which is equal to the product of the airway resistance and lung compliance. We then describe a theoretical evaluation of the technique with respect to realistic beat-to-beat variability generated by a cardiovascular simulator. Our results show that the technique is able to detect actual changes in the Emaxivand values of the simulator. With successful experimental testing, the technique may ultimately be employed to help guide therapy in heart failure patients.

Selective quantification of cardiac sympathetic and parasympathetic nervous function from non-invasive measurements.

Power spectral analysis of spontaneous heart rate (HR) variability is a popular and convenient technique for quantifying cardiac autonomic nervous function. While this technique can provide an effective index of parasympathetic nervous function, it cannot provide a pure index of A -sympathetic nervous function. We have developed a non-invasive technique for selectively quantifying cardiac sympathetic and parasympathetic nervous function by employing a multi-signal approach in conjunction with prior physiologic knowledge. We have tested the technique in 14 human subjects under pharmacological autonomic blockade, and our results show that the technique can substantially outperform traditional HR power spectral indices in terms of predicting the known drug effects.

Cardiac output monitoring in intensive care patients by radial artery pressure waveform analysis.

We have developed a novel technique for monitoring cardiac output (CO) changes by mathematically analyzing a single peripheral arterial blood pressure (ABP) waveform. In contrast to all previous techniques, our technique analyzes the ABP waveform over time scales greater than a cardiac cycle in which complex wave reflections are attenuated. We have previously validated the technique in swine instrumented with aortic flow probes. We present here an initial evaluation of the technique in 16 patient records of the MIMIC (Multi-parameter Intelligent Monitoring for Intensive Care) database, consisting of 122 simultaneous pairs of radial ABP waveforms and thermodilution CO. We report an overall error in the technique of 18.1% with respect to the error-prone clinical thermodilution measurements. This study promotes thorough future testing of the technique in humans.

Quantifying cardiac parasympathetic and sympathetic function based on a weighted-principal component regression method.

A quantitative evaluation of autonomic cardiovascular control is important in understanding basic pathophysiological mechanisms or for patient monitoring, treatment design and follow-up. Noninvasive techniques for this purpose have been the focus of many research endeavors. We previously proposed a method to extract pure parasympathetic and pure sympathetic indices based on the impulse response between instantaneous lung volume and heart rate. Identification of this impulse response involves a dual-input, single-output system in which one input interacts with the output in closed-loop. To identify this relatively complicated system, we propose here a new system identification technique based on a weighted-principal component regression method. Asymptotically, this technique implements model selection in the frequency domain. Therefore, in contrast to the conventional methods, it allows the data to play a significant role in determining candidate models. Moreover, the estimated model parameters reflect a trade-off between bias and variance to reach a relatively small mean squared prediction error. We employ experimental data to demonstrate that this technique is superior to a more traditional technique in terms of measuring cardiac autonomic indices.

Effects of prolonged bed rest on the total peripheral resistance baroreflex.

Orthostatic intolerance following prolonged exposure to microgravity continues to be a primary concern of the human space program. Reduced autonomic tone has been demonstrated to contribute to this phenomenon, and the heart rate baroreflex, in particular, has been repeatedly shown to be impaired. However, only the works of Yelle et al. have attempted to address the role of the total peripheral resistance (TPR) baroreflex, a potentially more significant contributor to blood pressure regulation. We applied a previously developed method for estimating the static gains of both the arterial and cardiopulmonary TPR baroreflexes to data obtained before and after 16-day bed rest. Reductions in the estimated static gains of the arterial (statistically significant) and cardiopulmonary TPR baroreflexes were found after bed rest. This study supports the works of Yelle et al, which imply that the TPR baroreflex is reduced after spaceflight.

A computational model-based validation of Guyton's analysis of cardiac output and venous return curves.

Guyton developed a popular approach for understanding the factors responsible for cardiac output (CO) regulation in which 1) the heart-lung unit and systemic circulation are independently characterized via CO and venous return (VR) curves, and 2) average CO and right atrial pressure (RAP) of the intact circulation are predicted by graphically intersecting the curves. However, this approach is virtually impossible to verify experimentally. We theoretically evaluated the approach with respect to a nonlinear, computational model of the pulsatile heart and circulation. We developed two sets of open circulation models to generate CO and VR curves, differing by the manner in which average RAP was varied. One set applied constant RAPs, while the other set applied pulsatile RAPs. Accurate prediction of intact, average CO and RAP was achieved only by intersecting the CO and VR curves generated with pulsatile RAPs because of the pulsatility and nonlinearity (e.g., systemic venous collapse) of the intact model. The CO and VR curves generated with pulsatile RAPs were also practically independent. This theoretical study therefore supports the validity of Guyton's graphical analysis.

A forward model-based validation of cardiovascular system identification.

We present a theoretical evaluation of a cardiovascular system identification method that we previously developed for the analysis of beat-to-beat fluctuations in noninvasively measured heart rate, arterial blood pressure, and instantaneous lung volume. The method provides a dynamical characterization of the important autonomic and mechanical mechanisms responsible for coupling the fluctuations (inverse modeling). To carry out the evaluation, we developed a computational model of the cardiovascular system capable of generating realistic beat-to-beat variability (forward modeling). We applied the method to data generated from the forward model and compared the resulting estimated dynamics with the actual dynamics of the forward model, which were either precisely known or easily determined. We found that the estimated dynamics corresponded to the actual dynamics and that this correspondence was robust to forward model uncertainty. We also demonstrated the sensitivity of the method in detecting small changes in parameters characterizing autonomic function in the forward model. These results provide confidence in the performance of the cardiovascular system identification method when applied to experimental data.

Midodrine prevents orthostatic intolerance associated with simulated spaceflight.

Many astronauts after being weightless in space become hypotensive and presyncopal when they assume an upright position. This phenomenon, known as orthostatic intolerance, may interfere with astronaut function during reentry and after spaceflight and may limit the ability of an astronaut to exit a landed spacecraft unaided during an emergency. Orthostatic intolerance is more pronounced after long-term spaceflight and is a major concern with respect to the extended flights expected aboard the International Space Station and for interplanetary exploration class missions, such as a human mission to Mars. Fully effective countermeasures to this problem have not yet been developed. To test the hypothesis that alpha-adrenergic stimulation might provide an effective countermeasure, we conducted a 16-day head-down-tilt bed-rest study (an analog of weightlessness) using normal human volunteers and administered the alpha(1)-agonist drug midodrine at the end of the bed-rest period. Midodrine was found to significantly ameliorate excessive decreases in blood pressure and presyncope during a provocative tilt test. We conclude that midodrine may be an effective countermeasure for the prevention of orthostatic intolerance following spaceflight.

Introduction of computational models to PhysioNet.

PhysioNet is a national research resource that provides experimental data sets and open-source software for their analysis. Computational modeling can complement studies of these experimental data sets so as to facilitate the advancement of physiologic research. Thus, in order to introduce computational models to PhysioNet, we have developed and posted a cardiovascular model designed for research that generates reasonable human pulsatile hemodynamic waveforms, cardiac output and venous return curves, and beat-to-beat variability. Some of the key features of the software include: 1) compatibility with PhysioNet's open-source data analysis software; 2) online viewing and parameter updating as the data are being calculated; 3) off-line viewing after completion of the simulation; 4) pre-compiled Linux binaries; 5) open-source code that may be compiled on other platforms; and 6) an extensive user's manual and software guide.

Do nonlinearities play a significant role in short term, beat-to-beat variability?

Numerous studies of short-term beat-to-beat variability in cardiovascular signals have not resolved the debate about the completeness of linear analysis techniques. This aim of this paper is to evaluate further the role of nonlinearities in short-term, beat-to-beat variability. We compared linear autoregressive moving average (ARMA) and nonlinear neural network (NN) models for predicting instantaneous heart rate (HR) and mean arterial blood pressure (BP) from past HR and BP. To evaluate these models, we used HR and BP time series from the MIMIC database. Experimental results indicate that NN-based nonlinearities do not play a significant role and suggest that ARMA linear analysis techniques provide adequate characterization of the system dynamics responsible for generating short-term, beat-to-beat variability.

A noninvasive method for total peripheral resistance baroreflex identification.

We developed a noninvasive method for estimating the static gains of the arterial and cardiopulmonary total peripheral resistance (TPR) baroreflexes. The method involves a system identification analysis of beat-to-beat fluctuations in arterial blood pressure (ABP), cardiac output (CO), and stroke volume (SV) in order to identify two transfer functions relating CO fluctuations to ABP fluctuations and SV fluctuations to ABP fluctuations. The static gains of each of the TPR baroreflexes may then be computed from the static gains of the two identified transfer functions. In order to evaluate the method, we constructed a computer model of the human cardiovascular system. We applied the method to data generated from the computer model and found close agreement between the estimated and actual static gains of the model TPR baroreflexes. We also applied the method to experimental human data and obtained encouraging results. These results motivate the experimental validation of the method.

System identification of closed-loop cardiovascular control mechanisms: diabetic autonomic neuropathy.

We applied cardiovascular system identification (CSI) to characterize closed-loop cardiovascular regulation in patients with diabetic autonomic neuropathy (DAN). The CSI method quantitatively analyzes beat-to-beat fluctuations in noninvasively measured heart rate, arterial blood pressure (ABP), and instantaneous lung volume (ILV) to characterize four physiological coupling mechanisms, two of which are autonomically mediated (the heart rate baroreflex and the coupling of respiration, measured in terms of ILV, to heart rate) and two of which are mechanically mediated (the coupling of ventricular contraction to the generation of the ABP wavelet and the coupling of respiration to ABP). We studied 37 control and 60 diabetic subjects who were classified as having minimal, moderate, or severe DAN on the basis of standard autonomic tests. The autonomically mediated couplings progressively decreased with increasing severity of DAN, whereas the mechanically mediated couplings were essentially unchanged. CSI identified differences between the minimal DAN and control groups, which were indistinguishable based on the standard autonomic tests. CSI may provide a powerful tool for assessing DAN.

Multifunctional cytokine expression by human coronary endothelium and regulation by monokines and glucocorticoids.

Human endothelium is capable of expressing a variety of molecules, including cytokines and growth factors, critical to inflammation. This aspect of coronary endothelium has not been studied in detail. In this study, we report, for the first time, expression of multifunctional cytokines by human coronary artery endothelial cells (HCAEC) and their regulation by inflammatory cytokines and glucocorticoids. We also compared expression of cytokine transcripts in two additional cell lines derived from pulmonary artery (HPAEC) and umbilical vein (HUVEC) endothelium. HCAEC expressed transcripts for interleukin 5 (IL-5), IL-6, IL-8, and monocyte chemotactic protein-1 (MCP-1) constitutively. Induction of IL-1alpha, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), and MCP-1 was seen following treatment with TNFalpha. We found no expression of IL-1RA, IL-2, IL-4, IL-13, TNF-alpha, or IFN-gamma in HCAEC. IL-1beta and TNF-alpha synergistically induced IL-6 and GM-CSF and additively induced IL-8 and MCP-1 production, while IL-2, IL-10, IFN-alpha, and IFN-gamma had little or no additional effects. Interestingly, no IL-1alpha or IL-5 protein product was found even after maximal stimulation of HCAEC. No significant differences were seen in the profile of cytokine genes expressed by HCAEC, HPAEC, or HUVEC. Glucocorticoids inhibited IL-8 production from all three cell lines. This study demonstrates that human coronary endothelial cells are capable of expressing a wide variety of multifunctional cytokines which may be of relevance to vascular inflammation.

Pulmonary blastomycosis with acute respiratory failure as predominant clinical feature.

Two previously healthy young adults came to our community hospital with rapidly progressive respiratory failure. Investigation confirmed Blastomyces as the responsible etiologic agent. Despite adequate antifungal chemotherapy and intensive supportive care, both patients died, one within 24 hours and the other after 14 days. Overwhelming infection with Blastomyces dermatitidis can cause acute respiratory failure, possibly the adult respiratory distress syndrome, even in immunocompetent hosts.