Integrating Machine Learning with Biomedical Signal Processing and Systems Analysis: An Applications-based Course.

The growing importance of data analytics in biomedicine is increasingly becoming recognized in biomedical engineering curricula through the introduction of machine learning classes that generally run in parallel to, but separately from, more traditional engineering courses, such as signal and systems analysis. We propose a new approach that systematically integrates signal processing and systems analysis with key techniques in machine learning. In the proposed course, the student obtains hands-on experience in applying algorithms that can be applied to practical problems of physiological signal conditioning, analysis and interpretation. This is achieved by exposing the student to a sequence of 4 applications-based modules that represent different biomedical engineering problems: human activity recognition from wearable devices, epileptic seizure detection, quantification of dynamic respiratory-cardiac coupling in humans under different conditions, and detection of sleep apnea episodes from heart rate variability data. Within each module, the student gains the experience of working with the data in question "from the ground up". We also introduce a general plan for assessment of student learning, and discuss the expected outcomes and limitations of this integrative approach to teaching.Clinical Relevance- The proposed course is targeted at biomedical engineering students at the senior undergraduate or first-year graduate level who are interested in learning how to analyze physiological signals. The course would also be suitable for clinician-scientists who have prior training in statistics with some exposure to engineering mathematics.

McDAPS: A multi-channel physiological signals display and analysis system for clinical researchers.

We introduce McDAPS, an interactive software for assessing autonomic imbalance from non-invasive multi-channel physiological recordings. McDAPS provides a graphical user interface for data visualization, beat-to-beat processing and interactive analyses. The software extracts beat-to-beat RR interval systolic blood pressure, diastolic blood pressure, the pulse amplitude of photoplethysmogram and the pulse-to-pulse interval. The analysis modules include stationary and time-varying power spectral analyses, moving-correlation analysis and univariate analyses. Analyses can also be performed in batch mode if multiple datasets have to be processed in the same way. The program exports results in standard CSV format. McDAPS runs in MATLAB, and is supported on MS Windows and MAC OS systems. The MATLAB source code is available at https://github.com/thuptimd/McDAPS.git.

Functional near-infrared spectroscopy-based prefrontal cortex oxygenation during working memory tasks in sickle cell disease.

Significance: Sickle cell disease (SCD), characterized by painful vaso-occlusive crises, is associated with cognitive decline. However, objective quantification of cognitive decline in SCD remains a challenge, and the associated hemodynamics are unknown. Aim: To address this, we utilized functional near-infrared spectroscopy (fNIRS) to measure prefrontal cortex (PFC) oxygenation responses to N-back working memory tasks in SCD patients and compared them with healthy controls. Approach: We quantified the PFC oxygenation rate as an index of cognitive activity in each group and compared them. In half of the participants, a Stroop test was administered before they started N-back to elevate their baseline stress level. Results: In SCD compared to healthy controls, we found that (1) under a high baseline stress level, there were significantly greater oxygenation responses during the 2-back task, further elevated with histories of stroke; (2) there was a marginally slower N-back response time, and it was even slower with a history of stroke; and (3) the task accuracy was not different. Conclusions: Additional requirements for processing time, PFC resources, and PFC oxygenation in SCD patients offer an important basis for understanding their cognitive decline and highlight the potential of fNIRS for evaluating cognitive functions.

A 30-Minute Spontaneous Breathing Trial Misses Many Children Who Go On to Fail a 120-Minute Spontaneous Breathing Trial.

BACKGROUND: The optimal length of spontaneous breathing trials (SBTs) in children is unknown. RESEARCH QUESTIONS: What are the most common reasons for SBT failure in children, and when do they occur? Can clinical parameters at the 30-min mark of a 120-min SBT predict outcome? STUDY DESIGN AND METHODS: We performed a secondary analysis of a clinical trial in pediatric ARDS, in which 2-h SBTs are conducted daily. SBT failure is based on objective criteria, including esophageal manometry for effort of breathing, categorized as passage, early failure (≤ 30 min), or late failure (30-120 min). Spirometry was used to calculate respiratory rate (RR), tidal volume (Vt), and rapid shallow breathing index (RSBI), in addition to pulse oximetry and capnography. Predictive models evaluated parameters at 30 min against SBT outcome, using receiver operating characteristic plots and area under the curve. RESULTS: We included 100 children and 305 SBTs, with 42% of SBTs being successful, 32% failing within 30 min, and 25% failing between 30 and 120 min. Of the patients passing SBTs at 30 min, 40% went on to fail by 120 min. High respiratory effort (esophageal manometry) was present in > 80% of failed SBTs. At the 30-min mark, there were no clear thresholds for RR, Vt, RSBI, Fio2, oxygen saturation, or capnography that could reliably predict SBT outcome. Multivariable modeling identified RR (P < .001) and RSBI > 7 (P = .034) at 30 min, pre-SBT inspiratory pressure level (P = .009), and pre-SBT retractions (P = .042) as predictors for SBT failure, but this model performed poorly in an independent validation set with the receiver operating characteristic plot crossing the reference line (area under the curve, 0.67). INTERPRETATION: A 30-min SBT may be too short in children recovering from pediatric ARDS because many go on to fail between 30 and 120 min. Reassuring values of Vt, RR, and gas exchange at 30 min do not reliably predict SBT passage at 2 h, likely because they do not capture the effort of breathing. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT03266016; URL: www. CLINICALTRIALS: gov.

Treatment of Cheyne-Stokes Respiration in Heart Failure with Adaptive Servo-Ventilation: An Integrative Model.

The SERVE-HF (Treatment of Predominant Central Sleep Apnea by Adaptive Servo Ventilation in Patients with Heart Failure) multicenter trial found a small but significant increase in all-cause and cardiovascular mortality in patients assigned to adaptive servo-ventilation (ASV) versus guideline-based medical treatment. To better understand the physiological underpinnings of this clinical outcome, we employ an integrative computer model to simulate congestive heart failure with Cheyne-Stokes respiration (CHF-CSR) in subjects with a broad spectrum of underlying pathogenetic mechanisms, as well as to determine the in silico changes in cardiopulmonary and autonomic physiology resulting from ASV. Our simulation results demonstrate that while the elimination of CSR through ASV can partially restore cardiorespiratory and autonomic physiology toward normality in the vast majority of CHF phenotypes, the degree of restoration can be highly variable, depending on the combination of CHF mechanisms in play. The group with the lowest left ventricular ejection fraction (LVEF) appears to be most vulnerable to the potentially adverse effects of ASV, but the level of pulmonary capillary wedge pressure (PCWP) plays an important role in determining the nature of these effects.

Vasoconstriction Response to Mental Stress in Sickle Cell Disease: The Role of the Cardiac and Vascular Baroreflexes.

Recent studies have shown that individuals with sickle cell disease (SCD) exhibit greater vasoconstriction responses to physical autonomic stressors, such as heat pain and cold pain than normal individuals, but this is not the case for mental stress (MTS). We sought to determine whether this anomalous finding for MTS is related to inter-group differences in baseline cardiac and vascular autonomic function. Fifteen subjects with SCD and 15 healthy volunteers participated in three MTS tasks: N-back, Stroop, and pain anticipation (PA). R-R interval (RRI), arterial blood pressure and finger photoplethysmogram (PPG) were continuously monitored before and during these MTS tasks. The magnitude of vasoconstriction was quantified using change in PPG amplitude (PPGa) from the baseline period. To represent basal autonomic function, we assessed both cardiac and vascular arms of the baroreflex during the baseline period. Cardiac baroreflex sensitivity (BRSc) was estimated by applying both the "sequence" and "spectral" techniques to beat-to-beat measurements of systolic blood pressure and RRIs. The vascular baroreflex sensitivity (BRSv) was quantified using the same approaches, modified for application to beat-to-beat diastolic blood pressure and PPGa measurements. Baseline BRSc was not different between SCD and non-SCD subjects, was not correlated with BRSv, and was not associated with the vasoconstriction responses to MTS tasks. BRSv in both groups was correlated with mean PPGa, and since both baseline PPGa and BRSv were lower in SCD, these results suggested that the SCD subjects were in a basal state of higher sympathetically mediated vascular tone. In both groups, baseline BRSv was positively correlated with the vasoconstriction responses to N-back, Stroop, and PA. After adjusting for differences in BRSv within and between groups, we found no difference in the vasoconstriction responses to all three mental tasks between SCD and non-SCD subjects. The implications of these findings are significant in subjects with SCD since vasoconstriction reduces microvascular flow and prolongs capillary transit time, increasing the likelihood for vaso-occlusive crisis (VOC) to be triggered by exposure to stressful events.

Identifying elevated risk for future pain crises in sickle-cell disease using photoplethysmogram patterns measured during sleep: A machine learning approach.

Transient increases in peripheral vasoconstriction frequently occur in obstructive sleep apnea and periodic leg movement disorder, both of which are common in sickle cell disease (SCD). These events reduce microvascular blood flow and increase the likelihood of triggering painful vaso-occlusive crises (VOC) that are the hallmark of SCD. We recently reported a significant association between the magnitude of vasoconstriction, inferred from the finger photoplethysmogram (PPG) during sleep, and the frequency of future VOC in 212 children with SCD. In this study, we present an improved predictive model of VOC frequency by employing a two-level stacking machine learning (ML) model that incorporates detailed features extracted from the PPG signals in the same database. The first level contains seven different base ML algorithms predicting each subject's pain category based on the input PPG characteristics and other clinical information, while the second level is a meta model which uses the inputs to the first-level model along with the outputs of the base models to produce the final prediction. Model performance in predicting future VOC was significantly higher than in predicting VOC prior to each sleep study (F1-score of 0.43 vs 0.35, p-value < 0.0001), consistent with our hypothesis of a causal relationship between vasoconstriction and future pain incidence, rather than past pain leading to greater propensity for vasoconstriction. The model also performed much better than our previous conventional statistical model (F1=0.33), as well as all other algorithms that used only the base-models for predicting VOC without the second tier meta model. The modest F1 score of the present predictive model was due in part to the relatively small database with substantial imbalance (176:36) between low-pain and high-pain subjects, as well as other factors not captured by the sleep data alone. This report represents the first attempt ever to use noninvasive finger PPG measurements during sleep and a ML-based approach to predict increased propensity for VOC crises in SCD. The promising results suggest the future possibility of embedding an improved version of this model in a low-cost wearable system to assist clinicians in managing long-term therapy for SCD patients.

Nocturnal peripheral vasoconstriction predicts the frequency of severe acute pain episodes in children with sickle cell disease.

The basic model of SCD physiology states that vaso-occlusion occurs when hemoglobin S-containing red blood cells (RBC) undergo sickling before they escape the capillary into a larger vessel. We have shown that mental stress, pain and cold, and events reported by patients to trigger SCD vaso-occlusive crisis (VOC), cause rapid and significant decrease in blood flow, reducing the likelihood that RBC could transit the microvasculature before sickling occurs. However, the critical link between decrease in microvascular blood flow and the incidence of future sickle VOC has never been established experimentally in humans. Using data from centrally adjudicated, overnight polysomnograms (PSG), previously collected in a prospective multi-center cohort sleep study, we analyzed the beat-to-beat amplitudes of vasoconstriction reported by the fingertip photoplethysmogram in 212 children and adolescents with SCD and developed an algorithm that detects vasoconstriction events and quantifies the magnitude (Mvasoc ), duration, and frequency of vasoconstriction that reflect the individual's inherent peripheral vasoreactivity. The propensity to vasoconstrict, quantified by median Mvasoc , predicted the incidence rate of post-PSG severe acute vaso-occlusive pain events (P = .006) after accounting for age and hemoglobin. Indices of sleep-disordered breathing contributed to median Mvasoc but did not predict future pain rate. Median Mvasoc was not associated with vaso-occlusive pain events that occurred prior to each PSG. These results show that SCD individuals with high inherent propensity to vasoconstrict have more frequent severe acute pain events. Our empirical findings are consistent with the fundamental SCD hypothesis that decreased microvascular flow promotes microvascular occlusion.

Tricuspid regurgitant jet velocity and myocardial tissue Doppler parameters predict mortality in a cohort of patients with sickle cell disease spanning from pediatric to adult age groups - revisiting this controversial concept after 16 years of additional evidence.

Sickle cell disease (SCD) is a monogenic hemoglobinopathy associated with significant morbidity and mortality. Cardiopulmonary, vascular and sudden death are the reasons for the majority of young adult mortality in SCD. To better understand the clinical importance of multi-level vascular dysfunction, in 2009 we assessed cardiac function including tricuspid regurgitant jet velocity (TRV), tissue velocity in systole(S') and diastole (E'), inflammatory, rheologic and hemolytic biomarkers as predictors of mortality in patients with SCD. With up to 9 years of follow up, we determined survival in 95 children, adolescents and adults with SCD. Thirty-eight patients (40%) were less than 21 years old at initial evaluation. Survival and Cox proportional-hazards analysis were performed. There was 19% mortality in our cohort, with median age at death of 35 years. In the pediatric subset, there was 11% mortality during the follow up period. The causes of death included cardiovascular and pulmonary complications in addition to other end-organ failure. On Cox proportional-hazards analysis, our model predicts that a 0.1 m/s increase in TRV increases risk of mortality 3%, 1 cm/s increase in S' results in a 91% increase, and 1 cm/s decrease in E' results in a 43% increase in mortality. While excluding cardiac parameters, higher plasma free hemoglobin was significantly associated with risk of mortality (p=.049). In conclusion, elevated TRV and altered markers of cardiac systolic and diastolic function predict mortality in a cohort of adolescents and young adult patients with SCD. These predictors should be considered when counseling cardiovascular risk and therapeutic optimization at transition to adult providers.

Loss of alpha-globin genes in human subjects is associated with improved nitric oxide-mediated vascular perfusion.

Alpha thalassemia is a hemoglobinopathy due to decreased production of the α-globin protein from loss of up to four α-globin genes, with one or two missing in the trait phenotype. Individuals with sickle cell disease who co-inherit the loss of one or two α-globin genes have been known to have reduced risk of morbid outcomes, but the underlying mechanism is unknown. While α-globin gene deletions affect sickle red cell deformability, the α-globin genes and protein are also present in the endothelial wall of human arterioles and participate in nitric oxide scavenging during vasoconstriction. Decreased production of α-globin due to α-thalassemia trait may thereby limit nitric oxide scavenging and promote vasodilation. To evaluate this potential mechanism, we performed flow-mediated dilation and microvascular post-occlusive reactive hyperemia in 27 human subjects (15 missing one or two α-globin genes and 12 healthy controls). Flow-mediated dilation was significantly higher in subjects with α-trait after controlling for age (P = .0357), but microvascular perfusion was not different between groups. As none of the subjects had anemia or hemolysis, the improvement in vascular function could be attributed to the difference in α-globin gene status. This may explain the beneficial effect of α-globin gene loss in sickle cell disease and suggests that α-globin gene status may play a role in other vascular diseases.

Effects of Ventilation-Perfusion Mismatch on Severity of Obstructive Sleep Apnea: A Modeling Study.

Plant gain quantifies the extent and rapidity with which arterial blood gases change following hypopneic or hyperpneic events. High plant gain, acting in concert with a highly collapsible upper airway and low arousal threshold, may contribute significantly towards increasing the severity of obstructive sleep apnea (OSA), even when controller gain is low. Elevated plant gain may be a manifestation of abnormal gas exchange resulting from ventilation-perfusion mismatch in the lungs. Using a mathematical model, we explore in this paper how ventilation-perfusion mismatch can affect plant gain, as well as the severity of OSA.

High Breath-by-Breath Variability Is Associated With Extubation Failure in Children.

OBJECTIVES: Extubation failure is multifactorial, and most tools to assess extubation readiness only evaluate snapshots of patient physiology. Understanding variability in respiratory variables may provide additional information to inform extubation readiness assessments. DESIGN: Secondary analysis of prospectively collected physiologic data of children just prior to extubation during a spontaneous breathing trial. Physiologic data were cleaned to provide 40 consecutive breaths and calculate variability terms, coefficient of variation and autocorrelation, in commonly used respiratory variables (i.e., tidal volume, minute ventilation, and respiratory rate). Other clinical variables included diagnostic and demographic data, median values of respiratory variables during spontaneous breathing trials, and the change in airway pressure during an occlusion maneuver to measure respiratory muscle strength (maximal change in airway pressure generated during airway occlusion [PiMax]). Multivariable models evaluated independent associations with reintubation and prolonged use of noninvasive respiratory support after extubation. SETTING: Acute care, children's hospital. PATIENTS: Children were included from the pediatric and cardiothoracic ICUs who were greater than 37 weeks gestational age up to and including 18 years who were intubated greater than or equal to 12 hours with planned extubation. We excluded children who had a contraindication to an esophageal catheter or respiratory inductance plethysmography bands. INTERVENTIONS: Noninterventional study. MEASUREMENTS AND MAIN RESULTS: A total of 371 children were included, 32 of them were reintubated. Many variability terms were associated with reintubation, including coefficient of variation and autocorrelation of the respiratory rate. After controlling for confounding variables such as age and neurologic diagnosis, both coefficient of variation of respiratory rate(p < 0.001) and low PiMax (p = 0.002) retained an independent association with reintubation. Children with either low PiMax or high coefficient of variation of respiratory rate had a nearly three-fold higher risk of extubation failure, and when these children developed postextubation upper airway obstruction, reintubation rates were greater than 30%. CONCLUSIONS: High respiratory variability during spontaneous breathing trials is independently associated with extubation failure in children, with very high rates of extubation failure when these children develop postextubation upper airway obstruction.

Progressive vasoconstriction with sequential thermal stimulation indicates vascular dysautonomia in sickle cell disease.

Persons with sickle cell disease (SCD) exhibit subjective hypersensitivity to cold and heat perception in experimental settings, and triggers such as cold exposure are known to precipitate vaso-occlusive crises by still unclear mechanisms. Decreased microvascular blood flow (MBF) increases the likelihood of vaso-occlusion by increasing entrapment of sickled red blood cells in the microvasculature. Because those with SCD have dysautonomia, we anticipated that thermal exposure would induce autonomic hypersensitivity of their microvasculature with an increased propensity toward vasoconstriction. We exposed 17 patients with SCD and 16 control participants to a sequence of predetermined threshold temperatures for cold and heat detection and cold and heat pain via a thermode placed on the right hand. MBF was measured on the contralateral hand by photoplethysmography, and cardiac autonomic balance was assessed by determining heart rate variability. Thermal stimuli at both detection and pain thresholds caused a significant decrease in MBF in the contralateral hand within seconds of stimulus application, with patients with SCD showing significantly stronger vasoconstriction (P = .019). Furthermore, patients with SCD showed a greater progressive decrease in blood flow than did the controls, with poor recovery between episodes of thermal stimulation (P = .042). They had faster vasoconstriction than the controls (P = .033), especially with cold detection stimulus. Individuals with higher anxiety also experienced more rapid vasoconstriction (P = .007). Augmented vasoconstriction responses and progressive decreases in perfusion with repeated thermal stimulation in SCD are indicative of autonomic hypersensitivity in the microvasculature. These effects are likely to increase red cell entrapment in response to clinical triggers such as cold or stress, which have been associated with vaso-occlusive crises in SCD.

Autonomically-mediated decrease in microvascular blood flow due to mental stress and pain in sickle cell disease: A target for neuromodulatory interventions.

Pain and vaso-occlusive crises (VOC) are hallmark complications of sickle cell disease (SCD) and result in significant physical and psychosocial impairment. The variability in SCD pain frequency and triggers for the transition from steady state to VOC are not well understood. This paper summarizes the harmful physiological effects of pain and emotional stressors on autonomically-mediated vascular function in individuals with SCD and the effects of a cognitive, neuromodulatory intervention (i.e. hypnosis) on microvascular blood flow. We reviewed recent studies from the authors' vascular physiology laboratory that assessed microvascular responses to laboratory stressors in individuals with SCD. Results indicate that participants with SCD exhibit marked neurally mediated vascular reactivity in response to pain, pain-related fear, and mental stress. Further, pilot study results show that engagement in hypnosis may attenuate harmful microvascular responses to pain. The collective results demonstrate that autonomically-mediated vascular responses to pain and mental stress represent an important SCD intervention target. This ongoing work provides physiological justification for the inclusion of cognitive, neuromodulatory and complementary treatments in SCD disease management and may inform the development of targeted, integrative interventions that prevent the enhancement of autonomic vascular dysfunction in SCD.

Mental stress causes vasoconstriction in subjects with sickle cell disease and in normal controls.

Vaso-occlusive crisis (VOC) is a hallmark of sickle cell disease (SCD) and occurs when deoxygenated sickled red blood cells occlude the microvasculature. Any stimulus, such as mental stress, which decreases microvascular blood flow will increase the likelihood of red cell entrapment resulting in local vaso-occlusion and progression to VOC. Neurally mediated vasoconstriction might be the physiological link between crisis triggers and vaso-occlusion. In this study, we determined the effect of mental stress on microvascular blood flow and autonomic nervous system reactivity. Sickle cell patients and controls performed mentally stressful tasks, including a memory task, conflict test and pain anticipation test. Blood flow was measured using photoplethysmography, autonomic reactivity was derived from electrocardiography and perceived stress was measured by the State-Trait Anxiety Inventory questionnaire. Stress tasks induced a significant decrease in microvascular blood flow, parasympathetic withdrawal and sympathetic activation in all subjects. Of the various tests, pain anticipation caused the highest degree of vasoconstriction. The magnitude of vasoconstriction, sympathetic activation and perceived stress was greater during the Stroop conflict test than during the N-back memory test, indicating the relationship between magnitude of experimental stress and degree of regional vasoconstriction. Baseline anxiety had a significant effect on the vasoconstrictive response in sickle cell subjects but not in controls. In conclusion, mental stress caused vasoconstriction and autonomic nervous system reactivity in all subjects. Although the pattern of responses was not significantly different between the two groups, the consequences of vasoconstriction can be quite significant in SCD because of the resultant entrapment of sickle cells in the microvasculature. This suggests that mental stress can precipitate a VOC in SCD by causing neural-mediated vasoconstriction.

Vaso-Occlusion in Sickle Cell Disease: Is Autonomic Dysregulation of the Microvasculature the Trigger?

Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by polymerization of hemoglobin S upon deoxygenation that results in the formation of rigid sickled-shaped red blood cells that can occlude the microvasculature, which leads to sudden onsets of pain. The severity of vaso-occlusive crises (VOC) is quite variable among patients, which is not fully explained by their genetic and biological profiles. The mechanism that initiates the transition from steady state to VOC remains unknown, as is the role of clinically reported triggers such as stress, cold and pain. The rate of hemoglobin S polymerization after deoxygenation is an important determinant of vaso-occlusion. Similarly, the microvascular blood flow rate plays a critical role as fast-moving red blood cells are better able to escape the microvasculature before polymerization of deoxy-hemoglobin S causes the red cells to become rigid and lodge in small vessels. The role of the autonomic nervous system (ANS) activity in VOC initiation and propagation has been underestimated considering that the ANS is the major regulator of microvascular blood flow and that most triggers of VOC can alter the autonomic balance. Here, we will briefly review the evidence supporting the presence of ANS dysfunction in SCD, its implications in the onset of VOC, and how differences in autonomic vasoreactivity might potentially contribute to variability in VOC severity.

Phenotype of ventilatory control in children with moderate to severe persistent asthma and obstructive sleep apnea.

STUDY OBJECTIVES: To examine the role of ventilatory control in asthmatic children with obstructive sleep apnea (OSA) and the relationships between measures of ventilatory control, OSA severity, and pulmonary function. METHODS: Five- to 18-year-old children with persistent asthma and nightly snoring were enrolled in the study. Children had physical examination, pulmonary function test, and polysomnography. Loop and controller gains were derived from 5 min segments which included a sigh during nonrapid eye movement sleep by applying a mathematical model that quantifies ventilatory control from the ensuing responses to the sighs. Plant gain was derived from 5 min segments of spontaneous breathing (i.e. without sighs). Nonparametric statistical tests were used for group comparisons. Cluster analysis was performed using Bayesian profile regression. RESULTS: One hundred thirty-four children were included in the study, 77 with and 57 without OSA. Plant gain was higher in children with OSA than in those without OSA (p = 0.002). A negative correlation was observed between plant gain and forced expiratory volume in 1 second (p = 0.048) and the ratio of f forced expiratory volume to forced vital capacity (p = 0.02). Plant gain correlated positively with severity of OSA. Cluster analysis demonstrated that children with more severe OSA and abnormal lung function had higher plant gain and a lower controller gain compared with the rest of the population. CONCLUSIONS: Children with OSA and persistent asthma with abnormal lung function have phenotypic characteristics which consist of diminished capacity of the lungs to maintain blood gas homeostasis reflected by an increase in plant gain and decreased chemoreceptor sensitivity.

Respiratory modulation of peripheral vasoconstriction: a modeling perspective.

Although respiratory sinus arrhythmia and blood pressure variability have been investigated extensively, there have been far fewer studies of the respiratory modulation of peripheral blood flow in humans. Existing studies have been based primarily on noninvasive measurements using digit photoplethysmography and laser-Doppler flowmetry. The cumulative knowledge derived from these studies suggests that respiration can contribute to fluctuations in peripheral blood flow and volume through a combination of mechanical, hemodynamic, and neural mechanisms. However, the most convincing evidence suggests that the sympathetic nervous system plays the predominant role under normal, resting conditions. This mini-review provides a consolidation and interpretation of the key findings reported in this topical area. Given the need to extract dynamic information from noninvasive measurements under largely "closed-loop" conditions, we propose that the application of analytical tools based on systems theory and mathematical modeling can be of great utility in future studies. In particular, we present an example of how the transfer relation linking respiration to peripheral vascular conductance can be derived using measurements recorded during spontaneous breathing, spontaneous sighs, and ventilator-induced sighs.

Sickle Cell Disease Subjects Have a Distinct Abnormal Autonomic Phenotype Characterized by Peripheral Vasoconstriction With Blunted Cardiac Response to Head-Up Tilt.

In sickle cell disease (SCD), prolonged capillary transit times, resulting from reduced peripheral blood flow, increase the likelihood of rigid red cells entrapment in the microvasculature, predisposing to vaso-occlusive crisis. Since changes in peripheral flow are mediated by the autonomic nervous system (ANS), we tested the hypothesis that the cardiac and peripheral vascular responses to head-up tilt (HUT) are abnormal in SCD. Heart rate, respiration, non-invasive continuous blood pressure and finger photoplethysmogram (PPG) were monitored before, during, and after HUT in SCD, anemic controls and healthy subjects. Percent increase in heart rate from baseline was used to quantify cardiac ANS response, while percent decrease in PPG amplitude represented degree of peripheral vasoconstriction. After employing cluster analysis to determine threshold levels, the HUT responses were classified into four phenotypes: (CP) increased heart rate and peripheral vasoconstriction; (C) increased heart rate only; (P) peripheral vasoconstriction only; and (ST) subthreshold cardiac and peripheral vascular responses. Multinomial logistic regression (MLR) was used to relate these phenotypic responses to various parameters representing blood properties and baseline cardiovascular activity. The most common phenotypic response, CP, was found in 82% of non-SCD subjects, including those with chronic anemia. In contrast, 70% of SCD subjects responded abnormally to HUT: C-phenotype = 22%, P-phenotype = 37%, or ST-phenotype = 11%. MLR revealed that the HUT phenotypes were significantly associated with baseline cardiac parasympathetic activity, baseline peripheral vascular variability, hemoglobin level and SCD diagnosis. Low parasympathetic activity at baseline dramatically increased the probability of belonging to the P-phenotype in SCD subjects, even after adjusting for hemoglobin level, suggesting a characteristic autonomic dysfunction that is independent of anemia. Further analysis using a mathematical model of heart rate variability revealed that the low parasympathetic activity in P-phenotype SCD subjects was due to impaired respiratory-cardiac coupling rather than reduced cardiac baroreflex sensitivity. By having strong peripheral vasoconstriction without compensatory cardiac responses, P-phenotype subjects may be at increased risk for vaso-occlusive crisis. The classification of autonomic phenotypes based on HUT response may have potential use for guiding therapeutic interventions to alleviate the risk of adverse outcomes in SCD.