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.

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.

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.

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.

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.

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.

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.

Abnormalities in autonomic function in obese boys at-risk for insulin resistance and obstructive sleep apnea.

STUDY OBJECTIVES: Current evidence in adults suggests that, independent of obesity, obstructive sleep apnea (OSA) can lead to autonomic dysfunction and impaired glucose metabolism, but these relationships are less clear in children. The purpose of this study was to investigate the associations among OSA, glucose metabolism, and daytime autonomic function in obese pediatric subjects. METHODS: Twenty-three obese boys participated in: overnight polysomnography; a frequently sampled intravenous glucose tolerance test; and recordings of spontaneous cardiorespiratory data in both the supine (baseline) and standing (sympathetic stimulus) postures. RESULTS: Baseline systolic blood pressure and reactivity of low-frequency heart rate variability to postural stress correlated with insulin resistance, increased fasting glucose, and reduced beta-cell function, but not OSA severity. Baroreflex sensitivity reactivity was reduced with sleep fragmentation, but only for subjects with low insulin sensitivity and/or low first-phase insulin response to glucose. CONCLUSIONS: These findings suggest that vascular sympathetic activity impairment is more strongly affected by metabolic dysfunction than by OSA severity, while blunted vagal autonomic function associated with sleep fragmentation in OSA is enhanced when metabolic dysfunction is also present.

Real-time multislice MRI during continuous positive airway pressure reveals upper airway response to pressure change.

PURPOSE: To determine if a real-time magnetic resonance imaging (RT-MRI) method during continuous positive airway pressure (CPAP) can be used to measure neuromuscular reflex and/or passive collapsibility of the upper airway in individual obstructive sleep apnea (OSA) subjects. MATERIALS AND METHODS: We conducted experiments on four adolescents with OSA and three healthy controls, during natural sleep and during wakefulness. Data were acquired on a clinical 3T scanner using simultaneous multislice (SMS) RT-MRI during CPAP. CPAP pressure level was alternated between therapeutic and subtherapeutic levels. Segmented airway area changes in response to rapid CPAP pressure drop and restoration were used to estimate 1) upper airway loop gain (UALG), and 2) anatomical risk factors, including fluctuation of airway area (FAA). RESULTS: FAA significantly differed between OSA patients (2-4× larger) and healthy controls (Student's t-test, P < 0.05). UALG and FAA measurements indicate that neuromuscular reflex and passive collapsibility varied among the OSA patients, suggesting the presence of different OSA phenotypes. Measurements had high intrasubject reproducibility (intraclass correlation coefficient r > 0.7). CONCLUSION: SMS RT-MRI during CPAP can reproducibly identify physiological traits and anatomical risk factors that are valuable in the assessment of OSA. This technique can potentially locate the most collapsible airway sites. Both UALG and FAA possess large variation among OSA patients. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2017;46:1400-1408.

Individuals with sickle cell disease have a significantly greater vasoconstriction response to thermal pain than controls and have significant vasoconstriction in response to anticipation of pain.

The painful vaso-occlusive crises (VOC) that characterize sickle cell disease (SCD) progress over hours from the asymptomatic steady-state. SCD patients report that VOC can be triggered by stress, cold exposure, and, pain itself. We anticipated that pain could cause neural-mediated vasoconstriction, decreasing regional blood flow and promoting entrapment of sickle cells in the microvasculature. Therefore, we measured microvascular blood flow in the fingers of both hands using plethysmography and laser-Doppler flowmetry while applying a series of painful thermal stimuli on the right forearm in 23 SCD patients and 25 controls. Heat pain applied to one arm caused bilateral decrease in microvascular perfusion. The vasoconstriction response started before administration of the thermal pain stimulus in all subjects, suggesting that pain anticipation also causes significant vasoconstriction. The time delay between thermal pain application and global vasoconstriction ranged from 5 to 15.5 seconds and increased with age (P < .01). Although subjective measures, pain threshold and pain tolerance were not different between SCD subjects and controls, but the vaso-reactivity index characterizing the microvascular blood flow response to painful stimuli was significantly higher in SCD patients (P = .0028). This global vasoconstriction increases microvascular transit time, and may promote entrapment of sickle cells in the microvasculature, making vaso-occlusion more likely. The rapidity of the global vasoconstriction response indicates a neural origin that may play a part in the transition from steady-state to VOC, and may also contribute to the variability in VOC frequency observed in SCD patients.

Evaluation of upper airway collapsibility using real-time MRI.

PURPOSE: To develop and demonstrate a real-time MRI method for assessing upper airway collapsibility in sleep apnea. MATERIALS AND METHODS: Data were acquired on a clinical 3 Tesla scanner using a radial CAIPIRIHNA sequence with modified golden angle view ordering and reconstructed using parallel imaging and compressed sensing with temporal finite difference sparsity constraint. Segmented airway areas together with synchronized facemask pressure were used to calculate airway compliance and projected closing pressure, Pclose , at four axial locations along the upper airway. This technique was demonstrated in five adolescent obstructive sleep apnea (OSA) patients, three adult OSA patients and four healthy volunteers. Heart rate, oxygen saturation, facemask pressure, and abdominal/chest movements were monitored in real-time during the experiments to determine sleep/wakefulness. RESULTS: Student's t-tests showed that both compliance and Pclose were significantly different between healthy controls and OSA patients (P < 0.001). The results also suggested that a narrower airway site does not always correspond to higher collapsibility. CONCLUSION: With the proposed methods, both compliance and Pclose can be calculated and used to quantify airway collapsibility in OSA with an awake scan of 30 min total scan room time. J. Magn. Reson. Imaging 2016;44:158-167.

Evaluation of an independent linear model for acoustic noise on a conventional MRI scanner and implications for acoustic noise reduction.

PURPOSE: To evaluate an independent linear model for gradient acoustic noise on a conventional MRI scanner, and to explore implications for acoustic noise reduction in routine imaging. METHODS: Acoustic noise generated from each physical gradient axis was modeled as the prescribed gradient waveform passed through a linear time-invariant system. Homogeneity and superposition properties were experimentally determined. We also developed a new method to correct relative time shifts between the measured impulse responses for different physical gradient axes. Model accuracy was determined by comparing predicted and measured sound using normalized energy difference. Transfer functions were also measured in subjects with different body habitus and at multiple microphone locations. RESULTS: Both superposition and homogeneity held for each physical gradient axis with errors less than 3%. When all gradients were on simultaneous sound prediction, error was reduced from 32% to 4% after time-shift correction. Transfer functions also showed high sensitivity to body habitus and microphone location. CONCLUSION: The independent linear model predicts MRI acoustic noise with less than 4% error. Acoustic transfer functions are highly sensitive to body habitus and position within the bore, making it challenging to produce a general approach to acoustic noise reduction based on avoiding system resonance peaks.

Real-time 3D magnetic resonance imaging of the pharyngeal airway in sleep apnea.

PURPOSE: To investigate the feasibility of real-time 3D magnetic resonance imaging (MRI) with simultaneous recording of physiological signals for identifying sites of airway obstruction during natural sleep in pediatric patients with sleep-disordered breathing. METHODS: Experiments were performed using a three-dimensional Fourier transformation (3DFT) gradient echo sequence with prospective undersampling based on golden-angle radial spokes, and L1-norm regularized iterative self-consistent parallel imaging (L1-SPIRiT) reconstruction. This technique was demonstrated in three healthy adult volunteers and five pediatric patients with sleep-disordered breathing. External airway occlusion was used to induce partial collapse of the upper airway on inspiration and test the effectiveness of the proposed imaging method. Apneic events were identified using information available from synchronized recording of mask pressure and respiratory effort. RESULTS: Acceptable image quality was obtained in seven of eight subjects. Temporary airway collapse induced via inspiratory loading was successfully imaged in all three volunteers, with average airway volume reductions of 63.3%, 52.5%, and 33.7%. Central apneic events and associated airway narrowing/closure were identified in two pediatric patients. During central apneic events, airway obstruction was observed in the retropalatal region in one pediatric patient. CONCLUSION: Real-time 3D MRI of the pharyngeal airway with synchronized recording of physiological signals is feasible and may provide valuable information about the sites and nature of airway narrowing/collapse during natural sleep.

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.

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.

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.

Sleep fragmentation and intermittent hypoxemia are associated with decreased insulin sensitivity in obese adolescent Latino males.

BACKGROUND: Although sleep-related breathing disorder (SRBD) has been linked to insulin resistance in adults, this has not been as well established in children. We hypothesized that the severity of SRBD in adolescents was associated with metabolic impairment. METHODS: Polysomnography was performed on obese, Latino males referred for snoring. The frequently sampled intravenous glucose tolerance test was used to assess glucose homeostasis. Total-body dual-energy X-ray absorptiometry was used to quantify adiposity. RESULTS: A total of 22 males (mean age ± SD: 13.4 ± 2.1 y, BMI z-score 2.4 ± 0.3, obstructive apnea hypopnea index 4.1 ± 3.2) were studied. After correcting for age and adiposity in multiple-regression models, Log frequency of desaturation (defined as ≥3% drop in oxygen saturation from baseline) negatively correlated with insulin sensitivity. Sleep efficiency was positively correlated with glucose effectiveness (S(G), the capacity of glucose to mediate its own disposal). The Log total arousal index was positively correlated with Log homeostasis model assessment-estimated insulin resistance. CONCLUSION: Sleep fragmentation and intermittent hypoxemia are associated with metabolic impairment in obese adolescent Latino males independent of age and adiposity. We speculate that SRBD potentiates the risk for development of metabolic syndrome and type 2 diabetes in the obese adolescent population.

Peripheral vasoconstriction and abnormal parasympathetic response to sighs and transient hypoxia in sickle cell disease.

RATIONALE: Sickle cell disease is an inherited blood disorder characterized by vasoocclusive crises. Although hypoxia and pulmonary disease are known risk factors for these crises, the mechanisms that initiate vasoocclusive events are not well known. OBJECTIVES: To study the relationship between transient hypoxia, respiration, and microvascular blood flow in patients with sickle cell. METHODS: We established a protocol that mimics nighttime hypoxic episodes and measured microvascular blood flow to determine if transient hypoxia causes a decrease in microvascular blood flow. Significant desaturations were induced safely by five breaths of 100% nitrogen. MEASUREMENTS AND MAIN RESULTS: Desaturation did not induce change in microvascular perfusion; however, it induced substantial transient parasympathetic activity withdrawal in patients with sickle cell disease, but not controls subjects. Marked periodic drops in peripheral microvascular perfusion, unrelated to hypoxia, were triggered by sighs in 11 of 11 patients with sickle cell and 8 of 11 control subjects. Although the sigh frequency was the same in both groups, the probability of a sigh inducing a perfusion drop was 78% in patients with sickle cell and 17% in control subjects (P < 0.001). Evidence for sigh-induced sympathetic nervous system dominance was seen in patients with sickle cell (P < 0.05), but was not significant in control subjects. CONCLUSIONS: These data demonstrate significant disruption of autonomic nervous system balance, with marked parasympathetic withdrawal in response to transient hypoxia. They draw attention to an enhanced autonomic nervous system­mediated sigh­vasoconstrictor response in patients with sickle cell that could increase red cell retention in the microvasculature, promoting vasoocclusion.