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Foster, Katharine, James D. Anholm, Gary Foster, Suman Thapamagar, and Prajan Subedi. Effects of naltrexone on sleep quality and periodic breathing at high altitude. High Alt Med Biol. 00:000-000, 2024. Objective: This study examined the effects of naltrexone on breathing and sleep at high altitude. Mu-opioid receptor (MOR) agonists have a depressive effect on respiration. Naltrexone is known to block the MOR. We hypothesized that MOR blockade with naltrexone would result in higher nocturnal oxygen saturations, fewer apneas, and improved sleep at high altitude. Methods: This double-blind, placebo-controlled, crossover study included nine healthy volunteers (four females, five males) aged 27.9 (4.6) (mean [standard deviation]) years. Two overnight trips spaced at least 2 weeks apart took participants from Loma Linda, CA (355 m) to the Barcroft Laboratory, CA (3,810 m) for each arm. Participants ingested either 50 mg naltrexone or matching placebo at bedtime. Sleep metrics were recorded using an ambulatory physiological sleep monitor (APSM). Subjective data were measured with the Groningen Sleep Quality Scale, Stanford Sleepiness Scale, and the 2018 Lake Louise Score (LLS) for acute mountain sickness (AMS). Results: Mean overnight SpO2 was lower after taking naltrexone, 81% (6) versus 83% (4) (mean difference 1.9% [2.1, 95% confidence interval or CI = 0.1-3.6, p = 0.040]). The lowest overnight SpO2 (nadir) was lower on naltrexone 70% (6) versus 74% (4) (dif. 4.6% [4.3], CI = 1.0-8.2, p = 0.020). Total sleep time and total apnea-hypopnea index were unchanged. Subjective sleep quality was significantly worse on naltrexone measured via the Groningen Sleep Quality Scale (p = 0.033) and Stanford Sleepiness Scale (p = 0.038). AMS measured via LLS was significantly worse while taking naltrexone (p = 0.025). Conclusion: Contrary to our hypothesis, this study demonstrated a significant decrease in nocturnal oxygen saturation, worse sleep quality, and AMS scores. Further characterization of the MOR's effects on sleep and AMS is needed to evaluate potential exacerbating mechanisms for AMS and poor sleep quality at altitude.
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Periodic breathing during sleep at high altitude is almost universal among sojourners. Here, in the context of acclimatization and adaptation, we provide a contemporary review on periodic breathing at high altitude, and explore whether this is an adaptive or maladaptive process. The mechanism(s), prevalence and role of periodic breathing in acclimatized lowlanders at high altitude are contrasted with the available data from adapted indigenous populations (e.g. Andean and Tibetan highlanders). It is concluded that (1) periodic breathing persists with acclimatization in lowlanders and the severity is proportional to sleeping altitude; (2) periodic breathing does not seem to coalesce with poor sleep quality such that, with acclimatization, there appears to be a lengthening of cycle length and minimal impact on the average sleeping oxygen saturation; and (3) high altitude adapted highlanders appear to demonstrate a blunting of periodic breathing, compared to lowlanders, comprising a feature that withstands the negative influences of chronic mountain sickness. These observations indicate that periodic breathing persists with high altitude acclimatization with no obvious negative consequences; however, periodic breathing is attenuated with high altitude adaptation and therefore potentially reflects an adaptive trait to this environment.
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Background: Dyspnea is frequently a debilitating symptom of chronic obstructive pulmonary disease (COPD). Cannabinoid receptor agonists have the potential to alter dyspnea in these patients. Objective: Our objective was to determine if dronabinol, a pure cannabinoid, improves dyspnea and exercise tolerance in COPD. Methods: In this double-blind randomized, crossover pilot study, COPD patients received up to 20mg of oral dronabinol or placebo daily for 6 weeks with an intervening washout period. Dyspnea and fatigue were assessed using the Borg scale at rest and after an incremental shuttle walk. Functional status, mood, and depression were measured using the St George's Respiratory Questionnaire (SGRQ), the Pulmonary Functional Status and Dyspnea Questionnaire (PFSDQ), and the Geriatric Depression Scale (GDS). Results: A total of 11 participants (with mean forced expiratory volume in 1 second 50.8 ± 24.8%) completed the study with no improvement in dyspnea at rest or postexercise taking dronabinol versus placebo (Borg scale 0.27, 95% confidence interval [CI] -0.59 to 1.14 versus 0.23 points, 95% CI -0.71 to 1.07 at rest and 0.82, 95% CI -0.59 to 2.22 versus 0.36 points, 95% CI 0.13 to 2.78 post exercise; p=0.94 and p=0.69 respectively). Dronabinol compared with placebo showed no significant change in PFSDQ dyspnea scores (0.64, 95% CI -3.92 to 5.20 versus 5.0, 95% CI -6.29 to 16.29; p=0.43) or shuttle walk distances (20.7m, 95% CI -21.5 to 62.8 versus 13.7m, 95% CI -24.8 to 52.2; p=0.69). There were no significant differences in fatigue at rest and postexercise, SGRQ scores, or GDS scores. Conclusion: In this pilot study, dronabinol did not significantly improve dyspnea or exercise capacity compared with placebo.
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Pentoxifylline is a nonselective phosphodiesterase inhibitor used for the treatment of peripheral artery disease. Pentoxifylline acts through cyclic adenosine monophosphate, thereby enhancing red blood cell deformability, causing vasodilation and decreasing inflammation, and potentially stimulating ventilation. We conducted a double-blind, placebo-controlled, crossover, counter-balanced study to test the hypothesis that pentoxifylline could lower blood viscosity, enhance cerebral blood flow, and decrease pulmonary artery pressure in lowlanders following 11-14 days at 3,800 m. Participants (6 males/10 females; age, 27 ± 4 yr old) received either a placebo or 400 mg of pentoxifylline orally the night before and again 2 h before testing. We assessed arterial blood gases, venous hemorheology (blood viscosity, red blood cell deformability, and aggregation), and inflammation (TNF-α) in room air (end-tidal oxygen partial pressure, â¼52 mmHg). Global cerebral blood flow (gCBF), ventilation, and pulmonary artery systolic pressure (PASP) were measured in room air and again after 8-10 min of isocapnic hypoxia (end-tidal oxygen partial pressure, 40 mmHg). Pentoxifylline did not alter arterial blood gases, TNF-α, or hemorheology compared with placebo. Pentoxifylline did not affect gCBF or ventilation during room air or isocapnic hypoxia compared with placebo. However, in females, PASP was reduced with pentoxifylline during room air (placebo, 19 ± 3; pentoxifylline, 16 ± 3 mmHg; P = 0.021) and isocapnic hypoxia (placebo, 22 ± 5; pentoxifylline, 20 ± 4 mmHg; P = 0.029), but not in males. Acute pentoxifylline administration in lowlanders at 3,800 m had no impact on arterial blood gases, hemorheology, inflammation, gCBF, or ventilation. Unexpectedly, however, pentoxifylline reduced PASP in female participants, indicating a potential effect of sex on the pulmonary vascular responses to pentoxifylline.NEW & NOTEWORTHY We conducted a double-blind, placebo-controlled study on the rheological, cardiorespiratory and cerebrovascular effects of acute pentoxifylline in healthy lowlanders after 11-14 days at 3,800 m. Although red blood cell deformability was reduced and blood viscosity increased compared with low altitude, acute pentoxifylline administration had no impact on arterial blood gases, hemorheology, inflammation, cerebral blood flow, or ventilation. Pentoxifylline decreased pulmonary artery systolic pressure in female, but not male, participants.
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Pentoxifilina , Masculino , Humanos , Femenino , Adulto Joven , Adulto , Pentoxifilina/farmacología , Pentoxifilina/uso terapéutico , Hemorreología , Factor de Necrosis Tumoral alfa , Hipoxia , Oxígeno , Aclimatación/fisiología , Inflamación/complicaciones , Gases , Circulación Cerebrovascular , AltitudRESUMEN
Cerebral blood flow (CBF) increases during hypoxia to counteract the reduction in arterial oxygen content. The onset of tissue hypoxemia coincides with the stabilization of hypoxia-inducible factor (HIF) and transcription of downstream HIF-mediated processes. It has yet to be determined, whether HIF down- or upregulation can modulate hypoxic vasodilation of the cerebral vasculature. Therefore, we examined whether: 1) CBF would increase with iron depletion (via chelation) and decrease with repletion (via iron infusion) at high-altitude, and 2) explore whether genotypic advantages of highlanders extend to HIF-mediated regulation of CBF. In a double-blinded and block-randomized design, CBF was assessed in 82 healthy participants (38 lowlanders, 20 Sherpas and 24 Andeans), before and after the infusion of either: iron(III)-hydroxide sucrose, desferrioxamine or saline. Across both lowlanders and highlanders, baseline iron levels contributed to the variability in cerebral hypoxic reactivity at high altitude (R2 = 0.174, P < 0.001). At 5,050 m, CBF in lowlanders and Sherpa were unaltered by desferrioxamine or iron. At 4,300 m, iron infusion led to 4 ± 10% reduction in CBF (main effect of time p = 0.043) in lowlanders and Andeans. Iron status may provide a novel, albeit subtle, influence on CBF that is potentially dependent on the severity and length-of-stay at high altitude.
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Mal de Altura , Altitud , Humanos , Aclimatación/fisiología , Deferoxamina , Compuestos Férricos , Hipoxia , Circulación CerebrovascularRESUMEN
NEW FINDINGS: What is the central question of this study? How does hypoxic pulmonary vasoconstriction and the response to supplemental oxygen change over time at high altitude? What is the main finding and its importance? Lowlanders and partially de-acclimatized Sherpa both demonstrated pulmonary vascular responsiveness to supplemental oxygen that was maintained for 12 days' exposure to progressively increasing altitude. An additional 2 weeks' acclimatization at 5050 m altitude rendered the pulmonary vasculature minimally responsive to oxygen similar to the fully acclimatized non-ascent Sherpa. Additional hypoxic exposure at that time point did not augment hypoxic pulmonary vasoconstriction. ABSTRACT: Prolonged alveolar hypoxia leads to pulmonary vascular remodelling. We examined the time course at altitude, over which hypoxic pulmonary vasoconstriction goes from being acutely reversible to potentially irreversible. Study subjects were lowlanders (n = 20) and two Sherpa groups. All Sherpa were born and raised at altitude. One group (ascent Sherpa, n = 11) left altitude and after de-acclimatization in Kathmandu for â¼7 days re-ascended with the lowlanders over 8-10 days to 5050 m. The second Sherpa group (non-ascent Sherpa, n = 12) remained continuously at altitude. Pulmonary artery systolic pressure (PASP) and pulmonary vascular resistance (PVR) were measured while breathing ambient air and following supplemental oxygen. During ascent PASP and PVR increased in lowlanders and ascent Sherpa; however, with supplemental oxygen, lowlanders had significantly greater decrease in PASP (P = 0.02) and PVR (P = 0.02). After â¼14 days at 5050 m, PASP decreased with supplemental oxygen (mean decrease: 3.9 mmHg, 95% CI 2.1-5.7 mmHg, P < 0.001); however, PVR was unchanged (P = 0.49). In conclusion, PASP and PVR increased with gradual ascent to altitude and decreased via oxygen supplementation in both lowlanders and ascent Sherpa. Following â¼14 days at 5050 m altitude, there was no change in PVR to hypoxia or O2 supplementation in lowlanders or either Sherpa group. These data show that both duration of exposure and residential altitude influence the pulmonary vascular responses to hypoxia.
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Mal de Altura , Altitud , Humanos , Hipoxia , Aclimatación/fisiología , OxígenoRESUMEN
Excessive decrease in the flow of the late expiratory portion of a flow volume loop (FVL) or "flattening", reflects small airway dysfunction. The assessment of the flattening is currently determined by visual inspection by the pulmonary function test (PFT) interpreters and is highly variable. In this study, we developed an objective measure to quantify the flattening. We downloaded 172 PFT reports in PDF format from the electronic medical records and digitized and extracted the expiratory portion of the FVL. We located point A (the point of the peak expiratory flow), point B (the point corresponding to 75% of the expiratory vital capacity), and point C (the end of the expiratory portion of the FVL intersecting with the x-axis). We did a linear fitting to the A-B segment and the B-C segment. We calculated: 1) the AB-BC angle (â ABC), 2) BC-x-axis angle (â BCX), and 3) the log ratio of the BC slope over the vertical distance between point A and x-axis [log (BC/A-x)]. We asked an expert pulmonologist to assess the FVLs and separated the 172 PFTs into the flattening and the non-flattening groups. We defined the cutoff value as the mean minus one standard deviation using data from the non-flattening group. â ABC had the best concordance rate of 80.2% with a cutoff value of 149.7°. We then asked eight pulmonologists to evaluate the flattening with and without â ABC in another 168 PFTs. The Fleiss' kappa was 0.320 (lower and upper confidence intervals [CIs]: 0.293 and 0.348 respectively) without â ABC and increased to 0.522 (lower and upper CIs: 0.494 and 0.550) with â ABC. There were 147 CT scans performed within 6 months of the 172 PFTs. Twenty-six of 55 PFTs (47.3%) with â ABC <149.7° had CT scans showing small airway disease patterns while 44 of 92 PFTs (47.8%) with â ABC ≥149.7° had no CT evidence of small airway disease. We concluded that â ABC improved the inter-rater agreement on the presence of the late expiratory flattening in FVL. It could be a useful addition to the assessment of small airway disease in the PFT interpretation algorithm and reporting.
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Steele, Andrew R., Philip N. Ainslie, Rachel Stone, Kaitlyn Tymko, Courtney Tymko, Connor A. Howe, David MacLeod, James D. Anholm, Christopher Gasho, and Michael M. Tymko. Global REACH 2018: characterizing acid-base balance over 21 days at 4,300 m in lowlanders. High Alt Med Biol. 23:185-191, 2022. Introduction: High altitude exposure results in hyperventilatory-induced respiratory alkalosis, followed by metabolic compensation to return arterial blood pH (pHa) toward sea level values. However, previous work has limited sample sizes, short-term exposure, and pharmacological confounders (e.g., acetazolamide). The purpose of this investigation was to characterize acid-base balance after rapid ascent to high altitude (i.e., 4,300 m) in lowlanders. We hypothesized that despite rapid bicarbonate ([HCO3-]) excretion during early acclimatization, partial respiratory alkalosis would still be apparent as reflected in elevations in pHa compared with sea level after 21 days of acclimatization to 4,300 m. Methods: In 16 (3 female) healthy volunteers not taking any medications, radial artery blood samples were collected and analyzed at sea level (150 m; Lima, Peru), and on days 1, 3, 7, 14, and 21 after rapid automobile (â¼8 hours) ascent to high altitude (4,300 m; Cerro de Pasco, Peru). Results and Discussion: Although reductions in [HCO3-] occurred by day 3 (p < 0.01), they remained stable thereafter and were insufficient to fully normalize pHa back to sea level values over the subsequent 21 days (p < 0.01). These data indicate that only partial compensation for respiratory alkalosis persists throughout 21 days at 4,300 m.
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Equilibrio Ácido-Base , Alcalosis Respiratoria , Aclimatación , Altitud , Bicarbonatos , Femenino , HumanosRESUMEN
High-altitude exposure results in a hyperventilatory-induced respiratory alkalosis followed by renal compensation (bicarbonaturia) to return arterial blood pH (pHa) toward sea-level values. However, acid-base balance has not been comprehensively examined in both lowlanders and indigenous populations-where the latter are thought to be fully adapted to high altitude. The purpose of this investigation was to compare acid-base balance between acclimatizing lowlanders and Andean and Sherpa highlanders at various altitudes (â¼3,800, â¼4,300, and â¼5,000 m). We compiled data collected across five independent high-altitude expeditions and report the following novel findings: 1) at 3,800 m, Andeans (n = 7) had elevated pHa compared with Sherpas (n = 12; P < 0.01), but not to lowlanders (n = 16; 9 days acclimatized; P = 0.09); 2) at 4,300 m, lowlanders (n = 16; 21 days acclimatized) had elevated pHa compared with Andeans (n = 32) and Sherpas (n = 11; both P < 0.01), and Andeans had elevated pHa compared with Sherpas (P = 0.01); and 3) at 5,000 m, lowlanders (n = 16; 14 days acclimatized) had higher pHa compared with both Andeans (n = 66) and Sherpas (n = 18; P < 0.01, and P = 0.03, respectively), and Andean and Sherpa highlanders had similar blood pHa (P = 0.65). These novel data characterize acid-base balance acclimatization and adaptation to various altitudes in lowlanders and indigenous highlanders.NEW & NOTEWORTHY Lowlander, Andean, and Sherpa arterial blood data were combined across five independent high-altitude expeditions in the United States, Nepal, and Peru to assess acid-base status at â¼3,800, â¼4,300, and â¼5,000 m. The main finding was that Andean and Sherpa highlander populations have more acidic arterial blood, due to elevated arterial carbon dioxide and similar arterial bicarbonate compared with acclimatizing lowlanders at altitudes ≥4,300 m.
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Mal de Altura , Expediciones , Aclimatación , Equilibrio Ácido-Base , Altitud , HumanosRESUMEN
BACKGROUND: Increasing iron bioavailability attenuates hypoxic pulmonary vasoconstriction in both lowlanders and Sherpas at high altitude. In contrast, the pulmonary vasculature of Andean individuals with chronic mountain sickness (CMS) is resistant to iron administration. Although pulmonary vascular remodeling and hypertension are characteristic features of CMS, the effect of iron administration in healthy Andean individuals, to our knowledge, has not been investigated. If the interplay between iron status and pulmonary vascular tone in healthy Andean individuals remains intact, this could provide valuable clinical insight into the role of iron regulation at high altitude. RESEARCH QUESTION: Is the pulmonary vasculature in healthy Andean individuals responsive to iron infusion? STUDY DESIGN AND METHODS: In a double-blinded, block-randomized design, 24 healthy high-altitude Andean individuals and 22 partially acclimatized lowlanders at 4,300 m (Cerro de Pasco, Peru) received an IV infusion of either 200 mg of iron (III)-hydroxide sucrose or saline. Markers of iron status were collected at baseline and 4 h after infusion. Echocardiography was performed in participants during room air breathing (partial pressure of inspired oxygen [Pio2] of approximately 96 mm Hg) and during exaggerated hypoxia (Pio2 of approximately 73 mm Hg) at baseline and at 2 and 4 h after the infusion. RESULTS: Iron infusion reduced pulmonary artery systolic pressure (PASP) by approximately 2.5 mm Hg in room air (main effect, P < .001) and by approximately 7 mm Hg during exaggerated hypoxia (main effect, P < .001) in both lowlanders and healthy Andean highlanders. There was no change in PASP after the infusion of saline. Iron metrics were comparable between groups, except for serum ferritin, which was 1.8-fold higher at baseline in the Andean individuals than in the lowlanders (95% CI, 74-121 ng/mL vs 37-70 ng/mL, respectively; P = .003). INTERPRETATION: The pulmonary vasculature of healthy Andean individuals and lowlanders remains sensitive to iron infusion, and this response seems to differ from the pathologic characteristics of CMS.
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Mal de Altura , Expediciones , Altitud , Humanos , Hipoxia , Hierro , VasoconstricciónRESUMEN
Hemoconcentration can influence hypoxic pulmonary vasoconstriction (HPV) via increased frictional force and vasoactive signaling from erythrocytes, but whether the balance of these mechanism is modified by the duration of hypoxia remains to be determined. We performed three sequential studies: 1) at sea level, in normoxia and isocapnic hypoxia with and without isovolumic hemodilution (n = 10, aged 29 ± 7 yr); 2) at altitude (6 ± 2 days acclimatization at 5,050 m), before and during hypervolumic hemodilution (n = 11, aged 27 ± 5 yr) with room air and additional hypoxia [fraction of inspired oxygen ([Formula: see text])= 0.15]; and 3) at altitude (4,340 m) in Andean high-altitude natives with excessive erythrocytosis (EE; n = 6, aged 39 ± 17 yr), before and during isovolumic hemodilution with room air and hyperoxia (end-tidal Po2 = 100 mmHg). At sea level, hemodilution mildly increased pulmonary artery systolic pressure (PASP; +1.6 ± 1.5 mmHg, P = 0.01) and pulmonary vascular resistance (PVR; +0.7 ± 0.8 wu, P = 0.04). In contrast, after acclimation to 5,050 m, hemodilution did not significantly alter PASP (22.7 ± 5.2 vs. 24.5 ± 5.2 mmHg, P = 0.14) or PVR (2.2 ± 0.9 vs. 2.3 ± 1.2 wu, P = 0.77), although both remained sensitive to additional acute hypoxia. In Andeans with EE at 4,340 m, hemodilution lowered PVR in room air (2.9 ± 0.9 vs. 2.3 ± 0.8 wu, P = 0.03), but PASP remained unchanged (31.3 ± 6.7 vs. 30.9 ± 6.9 mmHg, P = 0.80) due to an increase in cardiac output. Collectively, our series of studies reveal that HPV is modified by the duration of exposure and the prevailing hematocrit level. In application, these findings emphasize the importance of accounting for hematocrit and duration of exposure when interpreting the pulmonary vascular responses to hypoxemia.NEW & NOTEWORTHY Red blood cell concentration influences the pulmonary vasculature via direct frictional force and vasoactive signaling, but whether the magnitude of the response is modified with duration of exposure is not known. By assessing the pulmonary vascular response to hemodilution in acute normobaric and prolonged hypobaric hypoxia in lowlanders and lifelong hypobaric hypoxemia in Andean natives, we demonstrated that a reduction in red cell concentration augments the vasoconstrictive effects of hypoxia in lowlanders. In high-altitude natives, hemodilution lowered pulmonary vascular resistance, but a compensatory increase in cardiac output following hemodilution rendered PASP unchanged.
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Aclimatación , Altitud , Presión Arterial , Eritrocitos/metabolismo , Hemodilución , Hipoxia/sangre , Policitemia/sangre , Arteria Pulmonar/fisiopatología , Vasoconstricción , Adulto , Viscosidad Sanguínea , Gasto Cardíaco , Frecuencia Cardíaca , Hematócrito , Humanos , Hipoxia/diagnóstico , Hipoxia/fisiopatología , Masculino , Persona de Mediana Edad , Policitemia/diagnóstico , Policitemia/fisiopatología , Factores de Tiempo , Resistencia Vascular , Adulto JovenRESUMEN
KEY POINTS: Humans suffering from polycythaemia undergo multiple circulatory adaptations including changes in blood rheology and structural and functional vascular adaptations to maintain normal blood pressure and vascular shear stresses, despite high blood viscosity. During exercise, several circulatory adaptations are observed, especially involving adrenergic and non-adrenergic mechanisms within non-active and active skeletal muscle to maintain exercise capacity, which is not observed in animal models. Despite profound circulatory stress, i.e. polycythaemia, several adaptations can occur to maintain exercise capacity, therefore making early identification of the disease difficult without overt symptomology. Pharmacological treatment of the background heightened sympathetic activity may impair the adaptive sympathetic response needed to match local oxygen delivery to active skeletal muscle oxygen demand and therefore inadvertently impair exercise capacity. ABSTRACT: Excessive haematocrit and blood viscosity can increase blood pressure, cardiac work and reduce aerobic capacity. However, past clinical investigations have demonstrated that certain human high-altitude populations suffering from excessive erythrocytosis, Andeans with chronic mountain sickness, appear to have phenotypically adapted to life with polycythaemia, as their exercise capacity is comparable to healthy Andeans and even with sea-level inhabitants residing at high altitude. By studying this unique population, which has adapted through natural selection, this study aimed to describe how humans can adapt to life with polycythaemia. Experimental studies included Andeans with (n = 19) and without (n = 17) chronic mountain sickness, documenting exercise capacity and characterizing the transport of oxygen through blood rheology, including haemoglobin mass, blood and plasma volume and blood viscosity, cardiac output, blood pressure and changes in total and local vascular resistances through pharmacological dissection of α-adrenergic signalling pathways within non-active and active skeletal muscle. At rest, Andeans with chronic mountain sickness had a substantial plasma volume contraction, which alongside a higher red blood cell volume, caused an increase in blood viscosity yet similar total blood volume. Moreover, both morphological and functional alterations in the periphery normalized vascular shear stress and blood pressure despite high sympathetic nerve activity. During exercise, blood pressure, cardiac work and global oxygen delivery increased similar to healthy Andeans but were sustained by modifications in both non-active and active skeletal muscle vascular function. These findings highlight widespread physiological adaptations that can occur in response to polycythaemia, which allow the maintenance of exercise capacity.
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Mal de Altura , Policitemia , Aclimatación , Altitud , Animales , Humanos , FenotipoRESUMEN
INTRODUCTION: Chronic obstructive pulmonary disease (COPD) patients have poor sleep quality, longer time to sleep onset and frequent nocturnal awakenings. Poor sleep quality in COPD is associated with poor quality of life (QoL), increased exacerbations and increased mortality. Pulmonary rehabilitation (PR) improves functional status and QoL in COPD but effects on sleep are unclear. PR improves subjective sleep quality but there is paucity of objective actigraphy data. We hypothesized that actigraphy would demonstrate subjective and objective improvement in sleep following PR. Paired comparisons (t-test or Wilcoxon-signed-rank test) were performed before and after PR data on all variables. METHODS: This retrospective study of COPD patients undergoing PR utilized actigraphy watch recordings before and after 8-weeks of PR to assess changes in sleep variables including total time in bed (TBT), total sleep time (TST), sleep onset latency (SOL), sleep efficiency (SE), wakefulness after sleep onset (WASO) and total nocturnal awakenings. A change in Pittsburg Sleep Quality Index (PSQI) was a secondary outcome. PSQI was performed before and after PR. RESULTS: Sixty-nine patients were included in the final analysis. Most participants were male (97%), non-obese (median BMI 27.5, IQR 24.3 to 32.4 kg/m2) with an average age of 69 ± 8 years and 71% had severe COPD (GOLD stage 3 or 4). Prevalence of poor sleep quality (PSQI ≥5) was 86%. Paired comparisons did not show improvement in actigraphic sleep parameters following 8-weeks PR despite improvements in 6-min-walk distance (6MWD, mean improvement 54 m, 95% CI 34 m to 74 m, p<0.0001) and St. George's Respiratory Questionnaire scores (SGRQ, mean improvement 7.7 points, 95% CI 5.2 to 10.2, p<0.0001). Stratified analysis of all sleep variables by severity of COPD, BMI, mood, mental status, 6-MWD and SGRQ did not show significant improvement after PR. In Veterans with poor sleep quality (PSQI ≥ 5), PR improved subjective sleep quality (PSQI, mean difference 0.79, 95% CI 0.07 to 1.40, p = 0.03). CONCLUSIONS: Pulmonary rehabilitation improved subjective sleep quality in Veterans who had poor sleep quality at the beginning of the PR but did not improve objective sleep parameters by actigraphy. Our findings highlight the complex interactions among COPD, sleep and exercise.
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Terapia por Ejercicio/métodos , Enfermedad Pulmonar Obstructiva Crónica/rehabilitación , Calidad de Vida , Automanejo/educación , Trastornos del Inicio y del Mantenimiento del Sueño/diagnóstico , Actigrafía/estadística & datos numéricos , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Educación del Paciente como Asunto , Estudios Prospectivos , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/psicología , Estudios Retrospectivos , Trastornos del Inicio y del Mantenimiento del Sueño/etiología , Trastornos del Inicio y del Mantenimiento del Sueño/psicología , Resultado del TratamientoRESUMEN
KEY POINTS: Iron acts as a cofactor in the stabilization of the hypoxic-inducible factor family, and plays an influential role in the modulation of hypoxic pulmonary vasoconstriction. It is uncertain whether iron regulation is altered in lowlanders during either (1) ascent to high altitude, or (2) following partial acclimatization, when compared to high-altitude adapted Sherpa. During ascent to 5050 m, the rise in pulmonary artery systolic pressure (PASP) was blunted in Sherpa, compared to lowlanders; however, upon arrival to 5050 m, PASP levels were comparable in both groups, but the reduction in iron bioavailability was more prevalent in lowlanders compared to Sherpa. Following partial acclimatization to 5050 m, there were differential influences of iron status manipulation (via iron infusion or chelation) at rest and during exercise between lowlanders and Sherpa on the pulmonary vasculature. ABSTRACT: To examine the adaptational role of iron bioavailability on the pulmonary vascular responses to acute and chronic hypobaric hypoxia, the haematological and cardiopulmonary profile of lowlanders and Sherpa were determined during: (1) a 9-day ascent to 5050 m (20 lowlanders; 12 Sherpa), and (2) following partial acclimatization (11 ± 4 days) to 5050 m (18 lowlanders; 20 Sherpa), where both groups received an i.v. infusion of either iron (iron (iii)-hydroxide sucrose) or an iron chelator (desferrioxamine). During ascent, there were reductions in iron status in both lowlanders and Sherpa; however, Sherpa appeared to demonstrate a more efficient capacity to mobilize stored iron, compared to lowlanders, when expressed as a Δhepcidin per unit change in either body iron or the soluble transferrin receptor index, between 3400-5050 m (P = 0.016 and P = 0.029, respectively). The rise in pulmonary artery systolic pressure (PASP) was blunted in Sherpa, compared to lowlanders during ascent; however, PASP was comparable in both groups upon arrival to 5050 m. Following partial acclimatization, despite Sherpa demonstrating a blunted hypoxic ventilatory response and greater resting hypoxaemia, they had similar hypoxic pulmonary vasoconstriction when compared to lowlanders at rest. Iron-infusion attenuated PASP in both groups at rest (P = 0.005), while chelation did not exaggerate PASP in either group at rest or during exaggerated hypoxaemia ( PIO2 = 67 mmHg). During exercise at 25% peak wattage, PASP was only consistently elevated in Sherpa, which persisted following both iron infusion or chelation. These findings provide new evidence on the complex interplay of iron regulation on pulmonary vascular regulation during acclimatization and adaptation to high altitude.
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Altitud , Vasoconstricción , Aclimatación , Humanos , Hipoxia , HierroRESUMEN
NEW FINDINGS: What is the central question of this study? Herein, a methodological overview of our research team's (Global REACH) latest high altitude research expedition to Peru is provided. What is the main finding and its importance? The experimental objectives, expedition organization, measurements and key cohort data are discussed. The select data presented in this manuscript demonstrate the haematological differences between lowlanders and Andeans with and without excessive erythrocytosis. The data also demonstrate that exercise capacity was similar between study groups at high altitude. The forthcoming findings from our research expedition will contribute to our understanding of lowlander and indigenous highlander high altitude adaptation. ABSTRACT: In 2016, the international research team Global Research Expedition on Altitude Related Chronic Health (Global REACH) was established and executed a high altitude research expedition to Nepal. The team consists of â¼45 students, principal investigators and physicians with the common objective of conducting experiments focused on high altitude adaptation in lowlanders and in highlanders with lifelong exposure to high altitude. In 2018, Global REACH travelled to Peru, where we performed a series of experiments in the Andean highlanders. The experimental objectives, organization and characteristics, and key cohort data from Global REACH's latest research expedition are outlined herein. Fifteen major studies are described that aimed to elucidate the physiological differences in high altitude acclimatization between lowlanders (n = 30) and Andean-born highlanders with (n = 22) and without (n = 45) excessive erythrocytosis. After baseline testing in Kelowna, BC, Canada (344 m), Global REACH travelled to Lima, Peru (â¼80 m) and then ascended by automobile to Cerro de Pasco, Peru (â¼4300 m), where experiments were conducted over 25 days. The core studies focused on elucidating the mechanism(s) governing cerebral and peripheral vascular function, cardiopulmonary regulation, exercise performance and autonomic control. Despite encountering serious logistical challenges, each of the proposed studies was completed at both sea level and high altitude, amounting to â¼780 study sessions and >3000 h of experimental testing. Participant demographics and data relating to acid-base balance and exercise capacity are presented. The collective findings will contribute to our understanding of how lowlanders and Andean highlanders have adapted under high altitude stress.
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Adaptación Fisiológica/fisiología , Mal de Altura/fisiopatología , Corazón/fisiopatología , Hipoxia/fisiopatología , Adulto , Altitud , Enfermedad Crónica , Estudios de Cohortes , Expediciones , Humanos , Masculino , PerúRESUMEN
Background: Body position alters aspects of pulmonary function in health and disease. Although studies have assessed positional effects on the heart and lungs, little is known about positional changes in gas exchange parameters at high altitude. We hypothesized that following ascent, supine positioning would cause lower oxygen saturation than sitting, partially due to decreased ventilation and increased partial pressure of end-tidal carbon dioxide (Petco2). Materials and Methods: Twenty-eight healthy subjects were studied at sea level and following gradual ascent to 5150 m. After 10 minutes of sitting rest, subjects were studied for 5 minutes each in the sitting, supine, and prone positions with the order randomly assigned. Pulse oximeter oxygen saturation (SpO2), minute ventilation (VE), end-tidal O2 (Peto2) and Petco2, oxygen consumption, and CO2 production were continuously measured. Alveolar ventilation (VA) was calculated from the measured parameters. Results: At high altitude, VE was not affected by body position (12.96 ± 3.09 and 11.54 ± 3.45 L/min in the sitting and supine positions, respectively, p = 0.255). Petco2 increased from sitting to supine (22.8 ± 3.1 to 23.5 ± 3.3 mm Hg, p < 0.005), but VE and Petco2 were not different between the supine and prone positions. Calculated VA was not significantly affected by body position at either sea level or high altitude. SpO2 decreased from 81.3% ± 4.4% sitting to 78.8% ± 6.0% supine (p = 0.025), with a mean positional SpO2 difference of 2.5% ± 4.9% (95% confidence interval 0.6%-4.4%). SpO2 was not different between the supine and prone positions. Twenty-two of 28 subjects had lower SpO2 supine compared with sitting. Conclusions: These results extend earlier low-altitude studies and demonstrate the importance of postural regulation in different environments. As 79% of subjects had lower SpO2 while supine than sitting, control of body position is necessary for SpO2 comparisons at altitude to be meaningful.
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Altitud , Dióxido de Carbono , Humanos , Oximetría , Oxígeno , Intercambio Gaseoso PulmonarRESUMEN
KEY POINTS: In an anaesthetised animal model, independent stimulation of baroreceptors in the pulmonary artery elicits reflex sympathoexcitation. In humans, pulmonary arterial pressure is positively related to basal muscle sympathetic nerve activity (MSNA) under conditions where elevated pulmonary pressure is evident (e.g. high altitude); however, a causal link is not established. Using a novel experimental approach, we demonstrate that reducing pulmonary arterial pressure lowers basal MSNA in healthy humans. This response is distinct from the negative feedback reflex mediated by aortic and carotid sinus baroreceptors when systemic arterial pressure is lowered. Afferent input from pulmonary arterial baroreceptors may contribute to sympathetic neural activation in healthy lowland natives exposed to high altitude. ABSTRACT: In animal models, distension of baroreceptors located in the pulmonary artery induces a reflex increase in sympathetic outflow; however, this has not been examined in humans. Therefore, we investigated whether reductions in pulmonary arterial pressure influenced sympathetic outflow and baroreflex control of muscle sympathetic nerve activity (MSNA). Healthy lowlanders (n = 13; 5 females) were studied 4-8 days following arrival at high altitude (4383 m; Cerro de Pasco, Peru), a setting that increases both pulmonary arterial pressure and sympathetic outflow. MSNA (microneurography) and blood pressure (BP; photoplethysmography) were measured continuously during ambient air breathing (Amb) and a 6 min inhalation of the vasodilator nitric oxide (iNO; 40 ppm in 21% O2 ), to selectively lower pulmonary arterial pressure. A modified Oxford test was performed under both conditions. Pulmonary artery systolic pressure (PASP) was determined using Doppler echocardiography. iNO reduced PASP (24 ± 3 vs. 32 ± 5 mmHg; P < 0.001) compared to Amb, with a similar reduction in MSNA total activity (1369 ± 576 to 994 ± 474 a.u min-1 ; P = 0.01). iNO also reduced the MSNA operating point (burst incidence; 39 ± 16 to 33 ± 17 bursts·100 Hb-1 ; P = 0.01) and diastolic operating pressure (82 ± 8 to 80 ± 8 mmHg; P < 0.001) compared to Amb, without changing heart rate (P = 0.6) or vascular-sympathetic baroreflex gain (P = 0.85). In conclusion, unloading of pulmonary arterial baroreceptors reduced basal sympathetic outflow to the skeletal muscle vasculature and reset vascular-sympathetic baroreflex control of MSNA downward and leftward in healthy humans at high altitude. These data suggest the existence of a lesser-known reflex input involved in sympathetic activation in humans.
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Hipertensión Pulmonar , Presorreceptores , Barorreflejo , Presión Sanguínea , Femenino , Frecuencia Cardíaca , Humanos , Músculo Esquelético , Arteria Pulmonar , Sistema Nervioso SimpáticoRESUMEN
Although there is evidence supporting the benefit of regular exercise, and recommendations about exercise and physical activity, the process of individually prescribing exercise following exercise testing is more difficult. Guidelines like % heart rate (HR) reserve (HRR) require an anchoring maximal test and do not always provide a homogenous training experience. When prescribing HR on the basis of % HRR, rating of perceived exertion or Talk Test, cardiovascular/perceptual drift during sustained exercise makes prescription of the actual workload difficult. To overcome this issue, we have demonstrated a strategy for "translating" exercise test responses to steady state exercise training on the basis of % HRR or the Talk Test that appeared adequate for individuals ranging from cardiac patients to athletes. However, these methods depended on the nature of the exercise test details. In this viewpoint, we combine these data with workload expressed as Metabolic Equivalent Task (METs). We demonstrate that there is a regular stepdown between the METs during training to achieve the same degree of homeostatic disturbance during testing. The relationship was linear, was highly-correlated (r = 0.89), and averaged 71.8% (Training METs/Test METs). We conclude that it appears possible to generate a generalized approach to correctly translate exercise test responses to exercise training.
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BACKGROUND: Left ventricular (LV) twist mechanics are augmented with both acute and chronic hypoxemia. Although the underlying mechanisms remain unknown, sympathetic activation and a direct effect of hypoxemia on the myocardium have been proposed, the latter of which may produce subendocardial dysfunction that is masked by larger subepicardial torque. This study therefore sought to (1) determine the individual and combined influences of ß1-AR (ß1-adrenergic receptor) stimulation and peripheral O2 saturation (Spo2) on LV twist in acute and chronic hypoxia and (2) elucidate whether endocardial versus epicardial mechanics respond differently to hypoxia. METHODS: Twelve males (27±4 years) were tested near sea level in acute hypoxia (Spo2=82±4%) and following 3 to 6 days at 5050 m (high altitude; Spo2=83±3%). In both settings, participants received infusions of ß1-AR blocker esmolol and volume-matched saline (double-blind, randomized). LV mechanics were assessed with 2-dimensional speckle-tracking echocardiography, and region-specific analysis to compare subendocardial and subepicardial mechanics. RESULTS: At sea level, compared with baseline (14.8±3.0°) LV twist was reduced with esmolol (11.2±3.3°; P=0.007) and augmented during hypoxia (19.6±4.9°; P<0.001), whereas esmolol+hypoxia augmented twist compared with esmolol alone (16.5±3.3°; P<0.001). At 5050 m, LV twist was increased compared with sea level (19.5±5.4°; P=0.004), and reduced with esmolol (13.0±3.8°; P<0.001) and Spo2 normalization (12.8±3.4°; P<0.001). Moreover, esmolol+normalized Spo2 lowered twist further than esmolol alone (10.5±3.1°; P=0.036). There was no mechanics-derived evidence of endocardial dysfunction with hypoxia at sea level or high altitude. CONCLUSIONS: These findings suggest LV twist is augmented in hypoxia via ß1-AR-dependent and ß1-AR-independent mechanisms (eg, α1-AR stimulation), but does not appear to reflect endocardial dysfunction.