Michael C. K. Khoo

An integrative model of respiratory and cardiovascular control in sleep-disordered breathing

While many physiological control models exist in the literature, none thus far has focused on characterizing the interactions among the respiratory, cardiovascular and sleep-wake regulation systems that occur in sleep-disordered breathing. The model introduced in this study integrates the autonomic control of the cardiovascular system, chemoreflex and state-related control of respiration, including respiratory and upper airway mechanics, along with a model of circadian and sleep-wake regulation. The integrative model provides realistic predictions of the physiological responses under a variety of conditions including: the sleep-wake cycle, hypoxia-induced periodic breathing, Cheyne-Stokes respiration in chronic heart failure, and obstructive sleep apnoea (OSA). It can be used to investigate the effects of a variety of interventions, such as isocapnic and hypercapnic and/or hypoxic gas administration, the Valsalva and Mueller maneuvers, and the application of continuous positive airway pressure on OSA subjects. By being able to delineate the influences of the various interacting physiological mechanisms, the model is useful in providing a more lucid understanding of the complex dynamics that characterize state-cardiorespiratory control in the different forms of sleep-disordered breathing.

Assessment of closed-loop ventilatory stability in obstructive sleep apnea

Previous studies on ventilatory control in obstructive sleep apnea (OSA) have generally indicated depressed chemosensitivity, implying greater stability of the chemical control of breathing in these subjects. However, these results were based on tests involving steady-state or quasi-steady measurements obtained in wakefulness. We have developed a method for assessing the dynamic stability characteristics of chemoreflex control in OSA patients during sleep. While continuous positive airway pressure was applied to stabilize the upper airways, acoustically stimulated arousals were used to perturb the respiratory system during sleep. The fluctuations in esophageal pressure that ensued were analyzed, using a closed-loop minimal model, to estimate the chemoreflex loop impulse response (CLIR). Tests using simulated data confirmed the validity of our estimation algorithm. Application of the method to arousal responses measured in six OSA and five normal subjects revealed no statistically significant differences in gain margins and loop gain magnitudes between the two groups. However, the CLIR in the OSA subjects exhibited faster and more oscillatory dynamics. This result implies that, in addition to unstable upper airway mechanics, an underdamped chemoreflex control system may be another important factor that promotes the occurrence of periodic obstructive apneas during sleep.

Estimation of peripheral chemoreflex gain from spontaneous sigh responses

A method is proposed for quantifying the responsiveness of the peripheral chemoreflex loop to CO2 by utilizing the natural fluctuations in ventilation and endtidal PCO2 which occur subsequent to the appearance of spontaneous sighs. The advantage of this method lies in its simplicity and noninvasiveness: the need for administering inhaled mixtures with high CO2 content is eliminated. Using autoregressive moving-average (ARMA) analysis, we demonstrate that post-sigh responses can be adequately described by a simple chemoreflex model that contains first order dynamics and a pure time delay. The effective gain of this model is shown to reflect peripheral chemosensitivity closely when the estimation procedure is applied to ‘data’ obtained from computer simulations of the respiratory control system. Although central chemosensitivity affects the absolute values of effective gain, the slope of the linear correlation between effective and peripheral gains remains unchanged. Application of the procedure to spontaneously breathing anesthetized dogs shows that, in every case, effective gain increased with the induction of hypoxia, which is known to enhance peripheral chemosensitivity.

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 (SG, 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.

Sickle cell disease: Selected aspects of pathophysiology

Sickle cell disease (SCD), a genetically-determined pathology due to an amino acid substitution (i.e., valine for glutamic acid) on the beta-chain of hemoglobin, is characterized by abnormal blood rheology and periods of painful vascular occlusive crises. Sickle cell trait (SCT) is a typically benign variant in which only one beta chain is affected by the mutation. Although both SCD and SCT have been the subject of numerous studies, information related to neurological function and transfusion therapy is still incomplete: an overview of these areas is presented. An initial section provides pertinent background information on the pathology and clinical significance of these diseases. The roles of three factors in the clinical manifestations of the diseases are then discussed: hypoxia, autonomic nervous system regulation and blood rheology. The possibility of a causal relationship between these three factors and sudden death is also examined. It is concluded that further studies in these specific areas are warranted. It is anticipated that the outcome of such research is likely to provide valuable insights into the pathophysiology of SCD and SCT and will lead to improved clinical management and enhanced quality of life.

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 system–mediated sigh–vasoconstrictor response in patients with sickle cell that could increase red cell retention in the microvasculature, promoting vasoocclusion.

Association of cardiac autonomic function measures with severity of sleep-disordered breathing in a community-based sample

The goal of this study was to test the hypothesis that spectral indices of heart rate variability, such as high‐frequency power (HFP), low‐to‐high frequency power (LHR), and their respiration‐adjusted counterparts (HFPra, LHRra) are correlated with severity of sleep‐disordered breathing (SDB), as quantified by the respiratory disturbance index (RDI). A total of 436 subjects, non‐smoking, normotensive, and free of cardiovascular disease and diabetes were selected from the Sleep Heart Health Study (SHHS). Of these, 288 records with sufficiently high quality electrocardiogram signals were selected for further analysis [males/females: 221/67; age: 46.1 to 74.9 years; body mass index (BMI): 21.5 to 46.4 kg m−2; 0.3 < RDI < 85.0−1]. From each polysomnogram, the respiration channels (thoracic and abdominal) and R‐R interval (RRI) derived from the electrocardiogram were subjected to spectral analysis and autoregressive moving average modeling in consecutive 5‐min segments. After adjusting for age and BMI, mean RRI was found to be negatively correlated with RDI in men in all sleep‐wake states (all P < 0.001). HFP and HFPra were negatively correlated with RDI in men only during wakefulness (all P < 0.01). In women, LHR and LHRra were not correlated with RDI during wakefulness, but were positively correlated during non‐rapid eye movement Stage 1 and 2 sleep (all P < 0.01). These findings suggest that the indices of cardiac autonomic control are correlated with SDB severity, but gender and state affect the nature of these correlations. In both genders, however, vagal modulation of heart rate increases while sympathetic modulation decreases from wakefulness to sleep.

A Nonlinear Model of Cardiac Autonomic Control in Obstructive Sleep Apnea Syndrome

Using the Volterra–Wiener approach, we employed a minimal model to quantitatively characterize the linear and nonlinear effects of respiration (RCC) and arterial blood pressure (ABR) on heart rate variability (HRV) in normal controls and subjects with moderate-to-severe obstructive sleep apnea syndrome (OSAS). Respiration, R–R interval (RRI), blood pressure (BP) and other polysomnographic variables were recorded in eight normal controls and nine OSAS subjects in wakefulness, Stage 2 and rapid eye-movement sleep. To increase respiratory and cardiovascular variability, a preprogrammed ventilator delivered randomly timed inspiratory pressures that were superimposed on a baseline continuous positive airway pressure. Except for lower resting RRI in OSAS subjects, summary statistical measures of RRI and BP and their variabilities were similar in controls and OSAS. In contrast, RCC and ABR gains were significantly lower in OSAS. Nonlinear ABR gain and the interaction between respiration and blood pressure in modulating RRI were substantially reduced in OSAS. ABR gain increased during sleep in controls but remained unchanged in OSAS. These findings suggest that normotensive OSAS subjects have impaired daytime parasympathetic and sympathetic function. Nonlinear minimal modeling of HRV provides a useful, insightful, and comprehensive approach for the detection and assessment of abnormal autonomic function in OSAS.

Estimation of chemoreflex loop gain using pseudorandom binary CO/sub 2/ stimulation

The authors have developed a method for deriving estimates of the chemoreflex control loop gain (LG) from the ventilatory response to inhaled CO/sub 2/, modulated between 0% and 5% in the form of a pseudorandom binary sequence. The corresponding changes in alveolar (and thus, arterial) CO/sub 2/ result from two components: (1) the direct effect of breath-to-breath changes in inhaled CO/sub 2/ and (2) the chemoreflex-mediated changes in ventilation. LG between 0.01 and 0.03 Hz, the frequency range pertinent to periodic breathing, was estimated by computationally delineating the first component from the overall ventilatory response. The method was tested against simulated and experimental data. In both cases, the authors found strong correlations between their predictions and LG magnitude estimates derived by other methods. However, LG phase estimates mere considerably more variable when compared to model predictions based on small-signal analysis. The authors propose that their method, which uses data from a single test procedure lasting <10 min, may be more useful than traditional tests of chemoresponsiveness for the quantitative assessment of respiratory control stability during changes in sleep-wake state.

Optimal ventilatory patterns in periodic breathing

The goal of this study was to determine whether periodic breathing (PB), which is highly prevalent during sleep at high altitudes, imposes physiological penalties on the respiratory system in the absence of any accompanying disease. Using a computer model of respiratory gas exchange, we compared the effects of a variety of PB patterns on the chemical and mechanical costs of breathing to those resulting from regular tidal breathing. Although PB produced considerable fluctuation in arterial blood gas tensions, for the same cycle-averaged ventilation, higher arterial oxygen saturation and lower arterial carbon dioxide levels were achieved. This result can be explained by the fact that the combination of large breaths and apnea in PB leads to a substantial reduction in dead space ventilation. At the same time, the savings in mechanical cost achieved by the respiratory muscles during apnea partially offset the increase during the breathing phase. Consequently, the “pressure cost,” a criterion based on mean inspiratory pressure, was elevated only slightly, although the average work rate of breathing increased significantly. We found that, at extreme altitudes, PB patterns with clusters of 2 to 4 large breaths that alternate with apnea produce the highest arterial oxygenation levels and lowest pressure costs. The common occurrence of PB patterns with closely similar features has been reported in sleeping healthy sojourners at extreme altitudes. Taken together, these findings suggest that PB favors a reduction in the oxygen demands of the respiratory muscles and therefore may not be as detrimental as it is generally believed to be.