Electrical stimulation of the whole hypoglossal nerve in patients with obstructive sleep apnea.

PURPOSE: Electrical stimulation of the whole hypoglossal nerve (HGp-ES) has been demonstrated to enlarge the pharynx and improve pharyngeal stability and patency to airflow in all animals studied, but not in humans. The present study was undertaken to better understand the effect of HGp-ES on the human pharynx. METHODS: Eight patients with obstructive sleep apnea who had implanted stimulators with electrodes positioned proximally on the main truck of the hypoglossus were studied under propofol sedation. Pharyngoscopy and air flow measurements at multiple levels of continuous positive airway pressure (CPAP) were performed before and during Hgp-ES. RESULTS: HGp-ES that activates both tongue protrusors and retractors narrowed the pharyngeal lumen at the site of collapse (velopharynx in all subjects) from 1.38 ± 0.79 to 0.75 ± 0.44 cm2, p < 0.05 (measured at mid-range of CPAP levels) and lowered airflow (from 8.88 ± 2.08 to 6.69 ± 3.51 l/min, p < 0.05). Changes in critical pressure (Pcrit) and velopharyngeal compliance were not significant, but oropharyngeal compliance decreased (from 0.43 ± 0.18 to 0.32 ± 0.13 cm2/cmH2O, p < 0.05). No correlation was found between the pattern of change in luminal shape (determined as the ratio of a-p vs. lateral diameter when lowering CPAP) or changes in cross-sectional area and airflow during Hgp-ES. CONCLUSIONS: Our findings indicate that human retractors dominate when stimulated together with the protrusors during HGp-ES. While co-activation of retractors may be beneficial, it should be limited. We speculate that exercises that augment protrusor force may improve the response to hypoglossal stimulation. The exclusion of patients with concentric pharyngeal obstruction should be re-evaluated.

Differential effects of respiratory and electrical stimulation-induced dilator muscle contraction on mechanical properties of the pharynx in the pig.

Respiratory stimulation (RS) during sleep often fails to discontinue flow limitation, whereas electrical stimulation (ES) of the hypoglossus (HG) nerve frequently prevents obstruction. The present work compares the effects of RS and HG-ES on pharyngeal mechanics and the relative contribution of tongue muscles and thoracic forces to pharyngeal patency. We determined the pressure-area relationship of the collapsible segment of the pharynx in anesthetized pigs under the following three conditions: baseline (BL), RS induced by partial obstruction of the tracheostomy tube, and HG-ES. Parameters were obtained also after transection of the neck muscles and the trachea (NMT) and after additional bilateral HG transection (HGT). In addition, we measured the force produced by in situ isolated geniohyoid (GH) during RS and HG-ES. Intense RS was recognized by large negative intrathoracic pressures and triggered high phasic genioglossus and GH EMG activity. GH contraction produced during maximal RS less than a quarter of the force obtained during HG-ES. The major finding of the study was that RS and ES differed in the mechanism by which they stabilized the pharynx: RS lowered the pressure-area slope, i.e., reduced pharyngeal compliance (14.1 ± 2.9 to 9.2 ± 1.9 mm(2)/cmH2O, P < 0.01). HG-ES shifted the slope toward lower pressures, i.e., lowered the calculated extraluminal pressure (17.4 ± 5.8 to 9.2 ± 7.4 cmH2O, P < 0.01). Changes during RS and HG-ES were not affected by NMT, but the effect of RS decreased significantly after HGT. In conclusion, HG-ES and RS affect the pharyngeal site of collapse differently. Tongue muscle contraction contributes to pharyngeal stiffening during RS.

The effect of leptin replacement on sleep-disordered breathing in the leptin-deficient ob/ob mouse.

Obese leptin-deficient (ob/ob) mice demonstrate defects in upper airway structural and neuromuscular control. We hypothesized that these defects predispose to upper airway obstruction during sleep, and improve with leptin administration. High-fidelity polysomnographic recordings were conducted to characterize sleep and breathing patterns in conscious, unrestrained ob/ob mice (23 wk, 67.2 ± 4.1 g, n = 13). In a parallel-arm crossover study, we compared responses to subcutaneous leptin (1 µg/h) vs. vehicle on respiratory parameters during NREM and REM sleep. Upper airway obstruction was defined by the presence of inspiratory airflow limitation (IFL), as characterized by an early inspiratory plateau in airflow at a maximum level (V̇Imax) with increasing effort. The severity of upper airway obstruction (V̇Imax) was assessed along with minute ventilation (V̇E), tidal volume (VT), respiratory rate (RR), inspiratory duty cycle, and mean inspiratory flow at each time point. IFL occurred more frequently in REM sleep (37.6 ± 0.2% vs. 1.1 ± 0.0% in NREM sleep, P < 0.001), and leptin did not alter its frequency. V̇Imax (3.7 ± 1.1 vs. 2.7 ± 0.8 ml/s, P < 0.001) and V̇E increased (55.4 ± 22.0 vs. 39.8 ± 16.4 ml/min, P < 0.001) with leptin vs. vehicle administration. The increase in V̇E was due to a significant increase in VT (0.20 ± 0.06 vs. 0.16 ± 0.05 ml, P < 0.01) rather than RR. Increases in V̇E were attributable to increases in mean inspiratory flow (2.5 ± 0.8 vs. 1.8 ± 0.6 ml/s, P < 0.001) rather than inspiratory duty cycle. Similar increases in V̇E and its components were observed in non-flow-limited breaths during NREM and REM sleep. These responses suggest that leptin stabilized pharyngeal patency and increased drive to both the upper airway and diaphragm during sleep.

Novel whole body plethysmography system for the continuous characterization of sleep and breathing in a mouse.

Sleep is associated with marked alterations in ventilatory control that lead to perturbations in respiratory timing, breathing pattern, ventilation, pharyngeal collapsibility, and sleep-related breathing disorders (SRBD). Mouse models offer powerful insight into the pathogenesis of SRBD; however, methods for obtaining the full complement of continuous, high-fidelity respiratory, electroencephalographic (EEG), and electromyographic (EMG) signals in unrestrained mice during sleep and wake have not been developed. We adapted whole body plethysmography to record EEG, EMG, and respiratory signals continuously in unrestrained, unanesthetized mice. Whole body plethysmography tidal volume and airflow signals and a novel noninvasive surrogate for respiratory effort (respiratory movement signal) were validated against simultaneously measured gold standard signals. Compared with the gold standard, we validated 1) tidal volume (correlation, R(2) = 0.87, P < 0.001; and agreement within 1%, P < 0.001); 2) inspiratory airflow (correlation, R(2) = 0.92, P < 0.001; agreement within 4%, P < 0.001); 3) expiratory airflow (correlation, R(2) = 0.83, P < 0.001); and 4) respiratory movement signal (correlation, R(2) = 0.79-0.84, P < 0.001). The expiratory airflow signal, however, demonstrated a decrease in amplitude compared with the gold standard. Integrating respiratory and EEG/EMG signals, we fully characterized sleep and breathing patterns in conscious, unrestrained mice and demonstrated inspiratory flow limitation in a New Zealand Obese mouse. Our approach will facilitate studies of SRBD mechanisms in inbred mouse strains and offer a powerful platform to investigate the effects of environmental and pharmacological exposures on breathing disturbances during sleep and wakefulness.

Pitot-tube flowmeter for quantification of airflow during sleep.

The gold-standard pneumotachograph is not routinely used to quantify airflow during overnight polysomnography due to the size, weight, bulkiness and discomfort of the equipment that must be worn. To overcome these deficiencies that have precluded the use of a pneumotachograph in routine sleep studies, our group developed a lightweight, low dead space 'pitot flowmeter' (based on pitot-tube principle) for use during sleep. We aimed to examine the characteristics and validate the flowmeter for quantifying airflow and detecting hypopneas during polysomnography by performing a head-to-head comparison with a pneumotachograph. Four experimental paradigms were utilized to determine the technical performance characteristics and the clinical usefulness of the pitot flowmeter in a head-to-head comparison with a pneumotachograph. In each study (1-4), the pitot flowmeter was connected in series with a pneumotachograph under either static flow (flow generator inline or on a face model) or dynamic flow (subject breathing via a polyester face model or on a nasal mask) conditions. The technical characteristics of the pitot flowmeter showed that, (1) the airflow resistance ranged from 0.065 ± 0.002 to 0.279 ± 0.004 cm H(2)O L(-1) s(-1) over the airflow rates of 10 to 50 L min(-1). (2) On the polyester face model there was a linear relationship between airflow as measured by the pitot flowmeter output voltage and the calibrated pneumotachograph signal a (ß(1) = 1.08 V L(-1) s(-1); ß(0) = 2.45 V). The clinically relevant performance characteristics (hypopnea detection) showed that (3) when the pitot flowmeter was connected via a mask to the human face model, both the sensitivity and specificity for detecting a 50% decrease in peak-to-peak airflow amplitude was 99.2%. When tested in sleeping human subjects, (4) the pitot flowmeter signal displayed 94.5% sensitivity and 91.5% specificity for the detection of 50% peak-to-peak reductions in pneumotachograph-measured airflow. Our data validate the pitot flowmeter for quantification of airflow and detecting breathing reduction during polysomnographic sleep studies. We speculate that quantifying airflow during sleep can differentiate phenotypic traits related to sleep disordered breathing.

Developing quantitative physiological phenotypes of sleep apnea for epidemiological studies.

Existing physiological databases have not been sufficiently detailed to provide relevant and important information for characterizing the pathophysiology of obstructive sleep apnea. Critical collapsing pressure (P(CRIT)) is a standard method for determining upper airway patency during sleep, however is labor intensive and prohibits large-scale studies. Based on previously published data indicating R(US) does not significantly vary between groups, our aim was to develop an approach to estimate the P(CRIT) from airflow at atmospheric pressure (V(atm)). In a dataset of 126 subjects, where P(CRIT) and R(US) were measured using standard techniques. We then determined the minimum sample size required to estimate the R(US) mean and variance by utilizing a bootstrap procedure (30 times for n=3 to 126). We first estimated the minimum number of subjects needed for obtaining a group for a two-tailed (z=1.96) standard error for R(US) in the population. Then in 75 individuals, quantitative estimates of airflow were obtained at atmospheric pressure. Using the estimated R(US) and atmospheric, we determined an estimated P(CRIT) (ЄP(CRIT)). Bland-Altman plots were generated to determine the agreement between the measured P(CRIT) and ЄP(CRIT). For the entire population the mean ± SEM R(US) was 23 ± 1 cmH(2)O/L/s (± 95% CI: 21, 25). ~40 subjects represent the minimum sample required to estimate the population variance within ± 2 SEM. In the subsample with atmospheric flow measurements, a linear regression model (ЄP(CRIT) [cmH(2)O] = V(@PN) [L/s]x-23[cmH(2)O/L/s]), ЄP(CRIT) ranged from 0 to -9.6 cmH(2)O. In the Bland-Altman analysis there was no mean difference between the measured P(CRIT) and ЄP(CRIT) (-0.01 cmH(2)O; p=0.8) with upper and lower limits of agreement at ± 2.3 cmH(2)O. The variance of upstream resistance approaches a constant value in groups with approximately 40 subjects. Utilizing a fixed up-stream resistance to estimate P(CRIT) from the airflow at atmospheric pressure agrees with the measured values. These data suggest that measurements of quantitative airflow during standard polysomnography can be used to determine upper airway properties in large cohorts.

Inspiratory duty cycle responses to flow limitation predict nocturnal hypoventilation.

Upper airway obstruction (UAO) can elicit neuromuscular responses that mitigate and/or compensate for the obstruction. It was hypothesised that flow-limited breathing elicits specific timing responses that can preserve ventilation due to increases in inspiratory duty cycle rather than respiratory rate. By altering nasal pressure during non-rapid eye movement (non-REM) sleep, similar degrees of UAO were induced in healthy males and females (n = 10 each). Inspiratory duty cycle, respiratory rate and minute ventilation were determined for each degree of UAO during non-REM sleep and compared with the baseline nonflow-limited condition. A dose-dependent increase in the inspiratory duty cycle and respiratory rate was observed in response to increasing severity of UAO. Increases in the inspiratory duty cycle, but not respiratory rate, helped to acutely maintain ventilation. Heterogeneity in these responses was associated with variable degrees of ventilatory compensation, allowing for the segregation of individuals at risk for hypoventilation during periods of inspiratory airflow limitation. Upper airway obstruction constitutes a unique load on the respiratory system. The inspiratory duty cycle, but not the respiratory rate, determine the individual's ability to compensate for inspiratory airflow limitation during sleep, and may represent a quantitative phenotype for obstructive sleep apnoea susceptibility.

Effect of genioglossus contraction on pharyngeal lumen and airflow in sleep apnoea patients.

The purpose of the present study was to quantify the mechanical effect of genioglossus stimulation on flow mechanics and pharyngeal cross-sectional area in patients with obstructive sleep apnoea, and to identify variables that determine the magnitude of the respiratory effect of tongue protrusion. The pressure/flow and pressure/cross-sectional area relationships of the velo- and oropharynx were assessed in spontaneously breathing propofol-anaesthetised subjects before and during genioglossus stimulation. Genioglossus contraction decreased the critical pressure significantly from 1.2+/-3.3 to -0.7+/-3.8 cmH(2)O, with individual decreases ranging -0.6-5.9 cmH(2)O. Pharyngeal compliance was not affected by genioglossus contraction. The pharyngeal response to genioglossus stimulation was related to the magnitude of advancement of the posterior side of the tongue, but not to the severity of sleep apnoea, critical pressure, compliance or the shape and other characteristics of the velopharynx. Genioglossus contraction enlarges both the velo- and the oropharynx and lowers the critical pressure without affecting pharyngeal stiffness. The response to genioglossus stimulation depends upon the magnitude of tongue protrusion achieved rather than on inherent characteristics of the patient and their airway.

A pilot study of quantitative assessment of mandible advancement using pressure-flow relationship during midazolam sedation.

It has been proposed that a titration of the mandibular positioner would be a promising method for predicting the outcome of nasal continuous positive airway pressure (CPAP) therapy. This study was carried out to test the hypothesis that mandible advancement could be evaluated by analysis of inspiratory flow limitation using a titration procedure. To explore its effect, we examined upper airway pressure-flow relationships using a titrated mandible positioner during midazolam sedation. Non-flow limited inspiration occurred when the mandible was advanced 7.1 +/- 1.2 mm from centric occlusion position. In the centric occlusion position (0 mm advancement), Pcrit was -1.9 +/- 2.9 cmH2O and Rua was 23.3 +/- 4.5 cmH2O L(-1) s(-1). In the eMAP position, Pcrit was -7.3 +/- 1.9 cmH2O and Rua was 27.8 +/- 3.3 cmH2O L(-1) s(-1). Essentially no CPAP was required to overcome flow limitation in eMAP position, whereas 3.7 +/- 2.2 cmH2O CPAP was required in centric occlusion position. We conclude that assessing inspiratory flow limitation using a titrated mandible positioner was effective for estimating individual-matched mandible positions.

Effect of mandibular position on upper airway collapsibility and resistance.

It has been proposed that advancement of the mandible is a useful method for decreasing upper airway collapsibility. We carried out this study to test the hypothesis that mandibular advancement induces changes in upper airway patency during midazolam sedation. To explore its effect, we examined upper airway pressure-flow relationships in each of 4 conditions of mouth position in normal, healthy subjects (n = 9). In the neutral position, Pcrit (i.e., critical closing pressure, an index of upper airway collapsibility) was -4.2 cm H(2)O, and upstream resistance (Rua) was 21.2 cm H(2)O/L/sec. In the centric occlusal position, Pcrit was -7.1 cm H(2)O, and Rua was 16.6 cm H(2)O/L/sec. In the incisor position, Pcrit was significantly reduced to -10.7 cm H(2)O, and Rua was significantly reduced to 14.0 cm H(2)O/L/sec. Mandibular advancement significantly decreased Pcrit to -13.3 cm H(2)O, but did not significantly influence Rua (22.1 cm H(2)O/L/sec). We conclude that the mandibular incisors' position improved airway patency and decreased resistance during midazolam sedation.

Mouth-opening increases upper-airway collapsibility without changing resistance during midazolam sedation.

Sedative doses of anesthetic agents affect upper-airway function. Oral-maxillofacial surgery is frequently performed on sedated patients whose mouths must be as open as possible if the procedures are to be accomplished successfully. We examined upper-airway pressure-flow relationships in closed mouths, mouths opened moderately, and mouths opened maximally to test the hypothesis that mouth-opening compromises upper-airway patency during midazolam sedation. From these relationships, upper-airway critical pressure (Pcrit) and upstream resistance (Rua) were derived. Maximal mouth-opening increased Pcrit to -3.6 +/- 2.9 cm H2O compared with -8.7 +/- 2.8 (p = 0.002) for closed mouths and -7.2 +/- 4.1 (p = 0.038) for mouths opened moderately. In contrast, Rua was similar in all three conditions (18.4 +/- 6.6 vs. 17.7 +/- 7.6 vs. 21.5 +/- 11.6 cm H2O/L/sec). Moreover, maximum mouth-opening produced an inspiratory airflow limitation at atmosphere that was eliminated when nasal pressure was adjusted to 4.3 +/- 2.7 cm H2O. We conclude that maximal mouth-opening increases upper-airway collapsibility, which contributes to upper-airway obstruction at atmosphere during midazolam sedation.

Elimination of central sleep apnoea by mitral valvuloplasty: the role of feedback delay in periodic breathing.

Central sleep apnoea is a form of periodic breathing which resembles Cheyne-Stokes respiration but occurs only during sleep. One mechanism in the pathogenesis is a delay in chemical feedback from the lungs to the medullary respiratory centre. We explored the relationship between circulatory feedback delay in a patient with central sleep apnoea and Cheyne-Stokes respiration before and after mitral valve repair. Preoperatively the patient had severe central sleep apnoea and an increased circulation time. Following mitral valvuloplasty the circulation time was decreased with resolution of central sleep apnoea. This case demonstrates the role of feedback delay in central sleep apnoea and suggests that similar haemodynamic mechanisms may lead to central sleep apnoea and Cheyne-Stokes respiration.

Women have a greater ventilatory responses to upper airway obstruction than men.

We examined whether gender specific differences exist in defending inspiratory tidal volumes in the face of upper airway obstruction. In normal weight- and aged-matched men (n=9) and women (n=9), we induced upper airway obstruction with inspiratory flow limitation during NREM sleep by exposing individuals to sub-atmospheric nasal pressure. The mean inspiratory airflow was used to define three distinct levels of upper airway obstruction, based on a mean inspiratory airflow of 175-225 ml/s, 125-175 ml/s and 75-125 ml/s. While duty cycle responses were similar between genders, women had a greater response in T(TOT) at all flow limited conditions. (p<0.05). However, the greater response in T(TOT) led to a more pronounced decline in tidal volume in women compared to men (p<0.05), particularly during the mild and moderate upper airway obstruction. Our data demonstrate that the respiratory rate determines the tidal volume during periods of upper airway obstruction and indicate that individuals with a higher respiratory rate are at risk to develop hypoventilation in face of upper airway obstruction. Because women have a more brisk response in the respiratory rate than men, this may explain the difference in the expression of sleep disordered breathing between genders.

Hypercapnic duty cycle is an intermediate physiological phenotype linked to mouse chromosome 5.

We hypothesized that upper airway obstruction (UAO) leads to a compensatory increase in the duty cycle [ratio of inspiratory time to respiratory cycle length (Ti/Tt)], which is determined by genetic factors. We examined the compensatory Ti/Tt responses to 1). UAO and hypercapnia among normal individuals and 2). hypercapnia in different inbred strains, C3H/HeJ (C3) and C57BL/6J (B6), and their first- and second-generation (F2) offspring. 3). We then used the compensatory Ti/Tt response in the F2 to determine genetic linkage to the mouse genome. First, normal individuals exhibited a similar increase in the Ti/Tt during periods of hypercapnia (0.11 +/- 0.07) and UAO (0.09 +/- 0.06) compared with unobstructed breathing (P < 0.01). Second, the F2 offspring of C3 and B6 progenitors showed an average Ti/Tt response to 3% CO2 (0.42 +/- 0.005%) that was significantly (P < 0.01) greater than that of the two progenitors. Third, with a peak log of the odds ratio score of 4.4, Ti/Tt responses of F2 offspring are genetically linked to an interval between 58 and 64 centimorgans (cM) on mouse chromosome 5. One gene in the interval, Dagk4 at 57 cM, is polymorphic for C3 and B6 mice. Two other genes, Adrbk2 at 60 cM and Nos1 at 65 cM, have biological plausibility in mechanisms of upper airway patency and chemosensitivity, respectively. In summary, Ti/Tt may serve as an intermediate physiological phenotype for compensatory neuromuscular response mechanisms for maintaining ventilation in the face of UAO and hypoventilation and to help target specific candidate genes that may play a role in the expression of sleep-disordered breathing.

Upper airway collapsibility: measurement techniques and therapeutic implications.

Several techniques are currently available that aim to characterize upper airway function/mechanics during wakefulness or sleep. Based on the concept of a Starling resistor, we propose a standardized protocol to measure the critical pressure (Pcrit) (an indicator of upper airway collapsibility) during sleep. The effect of therapeutic interventions such as weight loss, positional changes or uvulopalatopharyngoplasty on Pcrit is illustrated by data from the literature. We propose that measurement of Pcrit become implemented in the diagnostic work-up of selected patients with sleep-related breathing disorder to help making a correct therapeutic decision.

Therapeutic electrical stimulation of the hypoglossal nerve in obstructive sleep apnea.

BACKGROUND: Hypoglossal nerve stimulation has been demonstrated to relieve upper airway obstruction acutely, but its effect on obstructive sleep apnea is not known. OBJECTIVE: To determine the response in obstructive sleep apnea to electrical stimulation of the hypoglossal nerve. METHODS: Eight patients with obstructive sleep apnea were implanted with a device that stimulated the hypoglossal nerve unilaterally during inspiration. Sleep and breathing patterns were examined at baseline before implantation and after implantation at 1, 3, and 6 months and last follow-up. RESULTS: Unilateral hypoglossal nerve stimulation decreased the severity of obstructive sleep apnea throughout the entire study period. Specifically, stimulation significantly reduced the mean apnea-hypopnea indices in non-rapid eye movement (mean +/- SD episodes per hour, 52.0 +/- 20.4 for baseline nights and 22.6 +/- 12.1 for stimulation nights; P<.001) and rapid eye movement (48.2 +/- 30.5 and 16.6 +/- 17.1, respectively; P<.001) sleep and reduced the severity of oxyhemoglobin desaturations. With improvement in sleep apnea, a trend toward deeper stages of non-rapid eye movement sleep was observed. Moreover, all patients tolerated long-term stimulation at night and did not experience any adverse effects from stimulation. Even after completing the study protocol, the 3 patients who remained free from stimulator malfunction continued to use this device as primary treatment. CONCLUSION: The findings demonstrate the feasibility and therapeutic potential for hypoglossal nerve stimulation in obstructive sleep apnea.

A model of sleep-disordered breathing in the C57BL/6J mouse.

To investigate the pathophysiological sequelae of sleep-disordered breathing (SDB), we have developed a mouse model in which hypoxia was induced during periods of sleep and was removed in response to arousal or wakefulness. An on-line sleep-wake detection system, based on the frequency and amplitude of electroencephalograph and electromyograph recordings, served to trigger intermittent hypoxia during periods of sleep. In adult male C57BL/6J mice (n = 5), the sleep-wake detection system accurately assessed wakefulness (97.2 +/- 1.1%), non-rapid eye movement (NREM) sleep (96.0 +/- 0.9%) and rapid eye movement (REM) sleep (85.6 +/- 5.0%). After 5 consecutive days of SDB, 554 +/- 29 (SE) hypoxic events were recorded over a 24-h period at a rate of 63.6 +/- 2.6 events/h of sleep and with a duration of 28.2 +/- 0.7 s. The mean nadir of fraction of inspired O(2) (FI(O(2))) on day 5 was 13.2 +/- 0.1%, and 137.1 +/- 13.2 of the events had a nadir FI(O(2)) <10% O(2). Arterial blood gases confirmed that hypoxia of this magnitude lead to a significant degree of hypoxemia. Furthermore, 5 days of SDB were associated with decreases in both NREM and REM sleep during the light phase compared with the 24-h postintervention period. We conclude that our murine model of SDB mimics the rate and magnitude of sleep-induced hypoxia, sleep fragmentation, and reduction in total sleep time found in patients with moderate to severe SDB in the clinical setting.

Female gender exacerbates respiratory depression in leptin-deficient obesity.

Obese females are less predisposed to sleep-disordered breathing and have higher serum leptin levels than males of comparable body weight. Because leptin is a powerful respiratory stimulant, especially during sleep, we hypothesized that the elevated leptin level is necessary to maintain normal ventilatory control in obese females. We examined ventilatory control during sleep and wakefulness in male and female leptin-deficient obese C57BL/6J-Lep(ob) mice, wild-type C57BL/6J mice with dietary-induced obesity and high serum leptin levels, and normal weight wild-type C57BL/6J mice. Both male and female C57BL/6J-Lep(ob) mice had depressed hypercapnic ventilatory response (HCVR) in comparison with wild-type animals. In comparison with male C57BL/6J-Lep(ob) mice, female C57BL/6J-Lep(ob) mice had reduced HCVR and respiratory drive (a ratio of tidal volume to inspiratory time) both during non-rapid eye movement (NREM) sleep and wakefulness. In contrast, the HCVR did not differ between sexes in wild-type mice during NREM sleep and wakefulness, but was lower in females during REM sleep. Thus, leptin deficiency in female obesity is even more detrimental to hypercapnic ventilatory control during wakefulness and NREM sleep than in obese, leptin-deficient males.

Long-term monitoring of respiration with a mediastinal pressure sensor in dogs.

The ability of an implanted mediastinal pressure sensor to produce a stable respiratory signal that could be used to trigger stimulation of upper airway muscles was examined. In 6 dogs, a pressure sensor was secured to the manubrium (4 by wires and 2 by transmanubrial placement). In 6 other dogs, the pressure sensor was placed in the upper anterior mediastinum. The animals were monitored for a minimum of 8 weeks (2 transmanubrial sensors for 12 months). Sensors that were able to maintain a midline position, high in the mediastinum, had the best signals. A caudal sensor position or abutment against an intrathoracic structure caused signal inversion (unusable signals). Transmanubrial placement resulted in a stable signal for 1 year. We conclude that long-term monitoring of respiration with a mediastinal pressure sensor can be successfully performed in dogs, providing an adequate signal for nerve-muscle stimulation. Separation from cardiovascular structures improves signal quality.