Upright posture increases oxyhemoglobin saturation in Peruvian highlanders.

At high altitude, hypoxia amplifies oxyhemoglobin saturation (SPO2) swings with changes in respiratory mechanics. Our objective was to examine the effects of posture on SPO2 and determine predictors of postural SPO2 changes in highlanders. 50 native highlanders from Puno, Peru (3825 m) assumed supine and upright-seated postures, in rotating sequence, while undergoing continuous pulse-oximetry. We compared mean SpO2 in each posture with a paired t-test. We examined associations of BMI, age, sex and spirometry with postural SpO2 changes with mixed-effects linear regression. In highlanders, SpO2 was 84% in the supine posture and was 1.0% ± 1.1 (p < 0.0001) greater in the upright-seated posture. Greater postural changes in SpO2 were associated with older age (p = 0.01 for interaction) but not with sex, BMI, FVC or FEV1. In highlanders, SpO2 is higher in the upright-seated compared to supine posture, especially with older age. Because we generally sleep flat, posture may contribute significantly to highlanders' hypoxemic burden during sleep. Postural intervention during sleep may mitigate nocturnal hypoxemia.

A Novel Non-invasive Approach for Measuring Upper Airway Collapsibility in Mice.

Introduction: Invasive procedures were previously developed for measuring pharyngeal collapsibility in rodents during expiration, when declining neuromuscular activity makes the airway unstable. We developed a non-invasive approach for streamlining collapsibility measurements by characterizing responses in physiologic markers of dynamic expiratory airflow obstruction to negative nasal pressure challenges. Methods: Anesthetized mice were instrumented to monitor upper airway pressure-flow relationships with head-out plethysmography while nasal pressure was ramped down from ~ +5 to -20 cm H2O over several breaths. Inspiratory and expiratory flow, volume, and timing characteristics were assessed breath-wise. Pcrit was estimated at transitions in expiratory amplitude and timing parameters, and compared to gold standard PCRIT measurements when nasal and tracheal pressures diverged during expiration. Predictions equations were constructed in a development data set (n = 8) and applied prospectively to a validation data set (n = 16) to estimate gold standard PCRIT. Results: The development data demonstrated that abrupt reversals in expiratory duration and tidal volume during nasal pressure ramps predicted gold standard PCRIT measurements. After applying regression equations from the development to a validation dataset, we found that a combination of expiratory amplitude and timing parameters proved to be robust predictors of gold standard PCRIT with minimal bias and narrow confidence intervals. Conclusions: Markers of expiratory airflow obstruction can be used to model upper airway collapsibility, and can provide sensitive measures of changes in airway collapsibility in rodents. This approach streamlines repeated non-invasive PCRIT measurements, and facilitates studies examining the impact of genetic, environmental, and pharmacologic factors on upper airway control.

Cardiometabolic correlates of sleep disordered breathing in Andean highlanders.

Associations between sleep disordered breathing (SDB) and cardiometabolic outcomes have not been examined in highlanders.We performed nocturnal polygraphy in Peruvian highlanders (3825 m). Multivariable linear regression models examined associations between SDB metrics and haemoglobin, glucose tolerance (haemoglobin A1c (HbA1c)), fasting glucose, homeostatic model-based assessments of insulin resistance and ß-cell function (HOMA-IR and HOMA-ß, respectively), blood pressure, and lipids, while adjusting for age, sex, body mass index (BMI) and wake oxygenation.Participants (n=187; 91 men) were (median (interquartile range)) 52 (45-62) years old, and had a BMI of 27.0 (24.3-29.5) kg·m-2 and 87% (85-88%) oxyhaemoglobin (arterial oxygen) saturation during wakefulness. In fully adjusted models, worsening nocturnal hypoxaemia was associated with haemoglobin elevations in men (p=0.03), independent of wake oxygenation and apnoea-hypopnoea index (AHI), whereas worsening wake oxygenation was associated with haemoglobin elevations in older women (p=0.02). In contrast, AHI was independently associated with HbA1c elevations (p<0.05). In single-variable models, nocturnal hypoxaemia was associated with higher HbA1c, HOMA-IR and HOMA-ß (p<0.001, p=0.02 and p=0.04, respectively), whereas AHI was associated with HOMA-IR, systolic blood pressure and triglyceride elevations (p=0.02, p=0.01 and p<0.01, respectively). These associations were not significant in fully adjusted models.In highlanders, nocturnal hypoxaemia and sleep apnoea were associated with distinct cardiometabolic outcomes, conferring differential risk for excessive erythrocytosis and glucose intolerance, respectively.

Cross-Sectional Comparison of Sleep-Disordered Breathing in Native Peruvian Highlanders and Lowlanders.

Pham, Luu V., Christopher Meinzen, Rafael S. Arias, Noah G. Schwartz, Adi Rattner, Catherine H. Miele, Philip L. Smith, Hartmut Schneider, J. Jaime Miranda, Robert H. Gilman, Vsevolod Y. Polotsky, William Checkley, and Alan R. Schwartz. Cross-sectional comparison of sleep-disordered breathing in native Peruvian highlanders and lowlanders. High Alt Med Biol. 18:11-19, 2017. BACKGROUND: Altitude can accentuate sleep disordered breathing (SDB), which has been linked to cardiovascular and metabolic diseases. SDB in highlanders has not been characterized in large controlled studies. The purpose of this study was to compare SDB prevalence and severity in highlanders and lowlanders. METHODS: 170 age-, body-mass-index- (BMI), and sex-matched pairs (age 58.2 ± 12.4 years, BMI 27.2 ± 3.5 kg/m2, and 86 men and 84 women) of the CRONICAS Cohort Study were recruited at a sea-level (Lima) and a high-altitude (Puno, 3825 m) setting in Peru. Participants underwent simultaneous nocturnal polygraphy and actigraphy to characterize breathing patterns, movement arousals, and sleep/wake state. We compared SDB prevalence, type, and severity between highlanders and lowlanders as measured by apnea-hypopnea index (AHI) and pulse oximetry (SPO2) during sleep. RESULTS: Sleep apnea prevalence was greater in highlanders than in lowlanders (77% vs. 54%, p < 0.001). Compared with lowlanders, highlanders had twofold elevations in AHI due to increases in central rather than obstructive apneas. In highlanders compared with lowlanders, SPO2 was lower during wakefulness and decreased further during sleep (p < 0.001). Hypoxemia during wakefulness predicted sleep apnea in highlanders, and it appears to mediate the effects of altitude on sleep apnea prevalence. Surprisingly, hypoxemia was also quite prevalent in lowlanders, and it was also associated with increased odds of sleep apnea. CONCLUSIONS: High altitude and hypoxemia at both high and low altitude were associated with increased SDB prevalence and severity. Our findings suggest that a large proportion of highlanders remain at risk for SDB sequelae.

The Efficacy of Low-Level Continuous Positive Airway Pressure for the Treatment of Snoring.

STUDY OBJECTIVES: To assess effects of low-level continuous positive airway pressure (CPAP) on snoring in habitual snorers without obstructive sleep apnea (OSA). METHODS: A multicenter prospective in-laboratory reversal crossover intervention trial was conducted between September 2013 and August 2014. Habitual snorers were included if they snored (inspiratory sound pressure level ≥ 40 dBA) for ≥ 30% all sleep breaths on a baseline sleep study (Night 1), and if significant OSA and daytime somnolence were absent. Included participants then underwent a CPAP titration study at 2, 4, or 6 cm H2O (Night 2) to examine snoring responses to step-increases in nasal pressure, a treatment night at optimal pressure (Night 3), followed by baseline night (Night 4). At each pressure, snoring intensity was measured on each breath. Snoring frequency was quantified as a percentage of sleep breaths at thresholds of 40, 45, 50, and 55 dBA. Sleep architecture and OSA severity were characterized using standard measurements. RESULTS: On baseline sleep studies, participants demonstrated snoring at ≥ 40 dBA on 53 ± 3% and ≥ 45 dBA on 35 ± 4% of breaths. Snoring frequency decreased progressively as nasal pressure increased from 0 to 4 cm H2O at each threshold, and plateaued thereafter. CPAP decreased snoring frequency by 67% and 85% at 40 and 45 dBA, respectively. Intervention did not alter sleep architecture and sleep apnea decreased minimally. CONCLUSIONS: Low-level CPAP below the range required to treat OSA diminished nocturnal snoring, and produced uniform reduction in nightly noise production below the World Health Organization's limit of 45 dBA. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT01949584.

Effects of Obesity and Leptin Deficiency on Morphine Pharmacokinetics in a Mouse Model.

BACKGROUND: Obesity causes multiorgan dysfunction, specifically metabolic abnormalities in the liver. Obese patients are opioid-sensitive and have high rates of respiratory complications after surgery. Obesity also has been shown to cause resistance to leptin, an adipose-derived hormone that is key in regulating hunger, metabolism, and respiratory stimulation. We hypothesized that obesity and leptin deficiency impair opioid pharmacokinetics (PK) independently of one another. METHODS: Morphine PK were characterized in C57BL/6J wild-type (WT), diet-induced obese (DIO), and leptin-deficient (ob/ob) mice, and in ob/ob mice given leptin-replacement (LR) therapy. WT mice received several dosing regimens of morphine. Obese mice (30 g) received one 80 mg/kg bolus of morphine. Blood was collected at fixed times after morphine injection for quantification of plasma morphine and morphine 3-glucuronide (M3G) levels. PK parameters used to evaluate morphine metabolism included area-under the curve (AUC150), maximal morphine concentration (CMAX), and M3G-to-morphine ratio, and drug elimination was determined by clearance (Cl/F), volume of distribution, and half-life (T1/2). PK parameters were compared between mouse groups by the use of 1-way analysis of variance, with P values less than .05 considered significant. RESULTS: DIO compared with WT mice had significantly decreased morphine metabolism with lower M3G-to-morphine ratio (mean difference [MD]: -4.9; 95% confidence interval [CI]: -8.8 to -0.9) as well as a decreased Cl/F (MD: -4.0; 95% CI: -8.9 to -0.03) Ob/ob compared with WT mice had a large increase in morphine exposure with a greater AUC150 (MD: 980.4; 95% CI: 630.1-1330.6), CMAX (MD: 6.8; 95% CI: 2.7-10.9), and longer T1/2 (MD: 23.1; 95% CI: 10.5-35.6), as well as a decreased Cl/F (MD: -7.0; 95% CI: -11.6 to -2.7). Several PK parameters were significantly greater in ob/ob compared with DIO mice, including AUC150 (MD: 636.4; 95% CI: 207.4-1065.4), CMAX (MD: 5.3; 95% CI: 3.2-10.3), and T1/2 (MD: 18.3; 95% CI: 2.8-33.7). When leptin was replaced in ob/ob mice, PK parameters began to approach DIO and WT levels. LR compared with ob/ob mice had significant decreases in AUC150 (MD: -779.9; 95% CI: -1229.8 to -330), CMAX (MD: -6.1; 95% CI: -11.4 to -0.9), and T1/2 (MD: -19; 95% CI: -35.1 to -2.8). Metabolism increased with LR, with LR mice having a greater M3G-to-morphine ratio compared with DIO (MD: 5.3; 95% CI: 0.3-10.4). CONCLUSIONS: Systemic effects associated with obesity decrease morphine metabolism and excretion. A previous study from our laboratory demonstrated that obesity and leptin deficiency decrease the sensitivity of central respiratory control centers to carbon dioxide. Obesity and leptin deficiency substantially decreased morphine metabolism and clearance, and replacing leptin attenuated the PK changes associated with leptin deficiency, suggesting leptin has a direct role in morphine metabolism.