High altitudes and partial pressure of arterial oxygen in patients with chronic obstructive pulmonary disease - A systematic review and meta-analysis.

IMPORTANCE: Prior study in healthy subjects has shown a reduction of partial pressure of arterial oxygen (PaO2) by -1.60 kPa/kilometre of altitude gain. However, the association of altitude-related change in PaO2 and altitude-related adverse health effects (ARAHE) in patients with chronic obstructive pulmonary disease (COPD) remain unknown. OBJECTIVE: To provide an effect size estimate for the decline in PaO2 with each kilometre of altitude gain and to identify ARAHE in relation to altitude in patients with COPD. www.crd.york.ac.uk/prospero: CRD42020217938. DATA SOURCES: A systematic search of PubMed and Embase was performed from inception to May 30, 2023. STUDY SELECTION: Peer-reviewed and prospective studies in patients with COPD staying at altitudes >1500 m providing arterial blood gases within the first 3 days at the target altitude. DATA EXTRACTION AND SYNTHESIS: Aggregate data (AD) on study characteristics were extracted, and individual patient data (IPD) were requested. Estimates were pooled using random-effects meta-analysis. MAIN OUTCOME AND MEASURES: Relative risk estimates and 95 % confidence intervals for the association between PaO2 and altitude in patients with COPD. RESULTS: Thirteen studies were included in the AD analysis, of which 6 studies (222 patients, 45.2 % female) provided IPD, thus were included in the quantitative analysis. The estimated effect size of PaO2 was -0.84 kPa [95 %CI, -0.92 to -0.76] per 1000 m of altitude gain (I2=65.0 %, P < 0.001). In multivariable regression analysis, COPD severity, baseline PaO2, age and time spent at altitude were predictors for PaO2 at altitude. Overall, 37.8 % of COPD patients experienced an ARAHE, whereas older age, female sex, COPD severity, baseline PaO2, and target altitude were predictors for the occurrence of ARAHE (area under ROC curve: 0.9275, P < 0.001). CONCLUSIONS AND RELEVANCE: This meta-analysis, providing altitude-related decrease in PaO2 and risk of ARAHE in patients with COPD ascending to altitudes >1500 m, revealed a lower altitude-related decrease in PaO2 in COPD patients compared with healthy. However, these findings might improve patient care and facilitate decisions about initiating preventive measures against hypoxaemia and ARAHE in patients with COPD planning an altitude sojourn or intercontinental flight, i.e. supplemental oxygen or acetazolamide.

Cerebral homeostasis and orthostatic responses in residents of the highest city in the world.

Permanent residence at high-altitude and chronic mountain sickness (CMS) may alter the cerebrovascular homeostasis and orthostatic responses. Healthy male participants living at sea-level (LL; n = 15), 3800 m (HL3800m; n = 13) and 5100 m (HL5100m; n = 17), respectively, and CMS highlanders living at 5100 m (n = 31) were recruited. Middle cerebral artery mean blood flow velocity (MCAv), cerebral oxygen delivery (CDO2), mean blood pressure (MAP), heart rate variability and spontaneuous cardiac baroreflex sensitivity (cBRS) were assessed while sitting, initial 30 s and after 3 min of standing. Cerebral autoregulation index (ARI) was estimated (ΔMCAv%baseline)/ΔMAP%baseline) in response to the orthostatic challenge. Altitude and CMS were associated with hypoxemia and elevated hemoglobin concentration. While sitting, MCAv and LFpower negatively correlated with altitude but were not affected by CMS. CDO2 remained preserved. BRS was comparable across all altitudes, but lower with CMS. Within initial 30 s of standing, altitude and CMS correlated with a lesser ΔMAP while ARI remained unaffected. After 3 min standing, MCAv, CDO2 and cBRS remained preserved across altitudes. The LF/HF ratio increased in HL5100m compared to LL and HL3800m from sitting to standing. In contrary, CMS showed blunted autonomic nervous activation in responses to standing. Despite altitude- and CMS-associated hypoxemia, erythrocytosis and impaired blood pressure regulation (CMS only), cerebral homeostasis remained overall preserved.

Sleep apnea in school-age children living at high altitude.

INTRODUCTION: Among adults, sleep apnea is more common in highlanders than in lowlanders. We evaluated the sleep apnea prevalence in children living at high altitude compared to age-matched low-altitude controls. METHODS: Healthy children, 7-14 y of age, living at 2500-3800m in the Tien Shan mountains, Kyrgyzstan, were prospectively studied in a health post at 3250m. Healthy controls of similar age living at 700-800m were studied in a University Hospital at 760m in Bishkek. Assessments included respiratory sleep studies scored according to pediatric standards, clinical examination, medical history, and the pediatric sleep questionnaire (PSQ, range 0 to 1 with increasing symptoms). RESULTS: In children living at high altitude (n = 37, 17 girls, median [quartiles] age 10.8y [9.6;13.0]), sleep studies revealed: mean nocturnal pulse oximetry 90% (89;91), oxygen desaturation index (ODI, >3% dips in pulse oximetry) 4.3/h (2.5;6.7), apnea/hypopnea index (AHI) total 1.7/h (1.0;3.6), central 1.6/h (1.0;3.3), PSQ 0.27 (0.18;0.45). In low-altitude controls (n=41, 17 girls, age 11.6y [9.5;13.0], between-groups comparison of age P=0.69) sleep studies revealed: pulse oximetry 97% (96;97), ODI 0.7/h (0.2;1.2), AHI total 0.4/h (0.1;1.0), central 0.3/h (0.1;0.7), PSQ 0.18 (0.14;0.31); P<0.05, all corresponding between-group comparisons. CONCLUSIONS: In school-age children living at high altitude, nocturnal oxygen saturation was lower, and the total and central AHI were higher compared to children living at low altitude. The greater score of sleep symptoms in children residing at high altitude suggests a potential clinical relevance of the nocturnal hypoxemia and subtle sleep-related breathing disturbances.

Effect of 5 weeks of oral acetazolamide on patients with pulmonary vascular disease: A randomized, double-blind, cross-over trial.

BACKGROUND: The carbonic anhydrase inhibitor acetazolamide stimulates ventilation through metabolic acidosis mediated by renal bicarbonate excretion. In animal models, acetazolamide attenuates acute hypoxia-induced pulmonary hypertension (PH), but its efficacy in treating patients with PH due to pulmonary vascular disease (PVD) is unknown. METHODS: 28 PVD patients (15 pulmonary arterial hypertension, 13 distal chronic thromboembolic PH), 13 women, mean±SD age 61.6±15.0 years stable on PVD medications, were randomised in a double-blind crossover protocol to 5 weeks acetazolamide (250mg b.i.d) or placebo separated by a ≥2 week washout period. Primary endpoint was the change in 6-minute walk distance (6MWD) at 5 weeks. Additional endpoints included safety, tolerability, WHO functional class, quality of life, arterial blood gases, and hemodynamics (by echocardiography). RESULTS: Acetazolamide had no effect on 6MWD compared to placebo (treatment effect: mean change [95%CI] -18 [-40 to 4]m, p=0.102) but increased arterial blood oxygenation through hyperventilation induced by metabolic acidosis. Other measures including pulmonary hemodynamics were unchanged. No severe adverse effects occurred, side effects that occurred significantly more frequently with acetazolamide vs. placebo were change in taste (22/0%), paraesthesia (37/4%) and mild dyspnea (26/4%). CONCLUSIONS: In patients with PVD, acetazolamide did not change 6MWD compared to placebo despite improved blood oxygenation. Some patients reported a tolerable increase in dyspnoea during acetazolamide treatment, related to hyperventilation, induced by the mild drug-induced metabolic acidosis. Our findings do not support the use of acetazolamide to improve exercise in patients with PVD at this dosing. GOV IDENTIFIER: NCT02755298.

Visuomotor performance at high altitude in COPD patients. Randomized placebo-controlled trial of acetazolamide.

Introduction: We evaluated whether exposure to high altitude impairs visuomotor learning in lowlanders with chronic obstructive pulmonary disease (COPD) and whether this can be prevented by acetazolamide treatment. Methods: 45 patients with COPD, living <800 m, FEV1 ≥40 to <80%predicted, were randomized to acetazolamide (375 mg/d) or placebo, administered 24h before and during a 2-day stay in a clinic at 3100 m. Visuomotor performance was evaluated with a validated, computer-assisted test (Motor-Task-Manager) at 760 m above sea level (baseline, before starting the study drug), within 4h after arrival at 3100 m and in the morning after one night at 3100 m. Main outcome was the directional error (DE) of cursor movements controlled by the participant via mouse on a computer screen during a target tracking task. Effects of high altitude and acetazolamide on DE during an adaptation phase, immediate recall and post-sleep recall were evaluated by regression analyses. www.ClinicalTrials.gov NCT03165890. Results: In 22 patients receiving placebo, DE at 3100 m increased during adaptation by mean 2.5°, 95%CI 2.2° to 2.7° (p < 0.001), during immediate recall by 5.3°, 4.6° to 6.1° (p < 0.001), and post-sleep recall by 5.8°, 5.0 to 6.7° (p < 0.001), vs. corresponding values at 760 m. In 23 participants receiving acetazolamide, corresponding DE were reduced by -0.3° (-0.6° to 0.1°, p = 0.120), -2.7° (-3.7° to -1.6°, p < 0.001) and -3.1° (-4.3° to -2.0°, p < 0.001), compared to placebo at 3100 m. Conclusion: Lowlanders with COPD travelling to 3100 m experienced altitude-induced impairments in immediate and post-sleep recall of a visuomotor task. Preventive acetazolamide treatment mitigated these undesirable effects.

Markers of cardiovascular risk and their reversibility with acute oxygen therapy in Kyrgyz highlanders with high altitude pulmonary hypertension.

BACKGROUND: High altitude pulmonary hypertension (HAPH), a chronic altitude related illness, is associated with hypoxemia, dyspnea and reduced exercise performance. We evaluated ECG and pulse wave-derived markers of cardiovascular risk in highlanders with HAPH (HAPH+) in comparison to healthy highlanders (HH) and lowlanders (LL) and the effects of hyperoxia. METHODS: We studied 34 HAPH+ and 54 HH at Aksay (3250m), and 34 LL at Bishkek (760m), Kyrgyzstan. Mean pulmonary artery pressure by echocardiography was mean±SD 34±3, 22±5, 16±4mmHg, respectively (p<0.05 all comparisons). During quiet rest, breathing room air or oxygen in randomized order, we measured heart-rate adjusted QT interval (QTc), an ECG-derived marker of increased cardiovascular mortality, and arterial stiffness index (SI), a marker of cardiovascular disease derived from pulse oximetry plethysmograms. RESULTS: Pulse oximetry in HAPH+, HH and LL was, mean±SD, 88±4, 92±2 and 95±2%, respectively (p<0.05 vs HAPH+, both comparisons). QTc in HAPH+, HH and LL was 422±24, 405±27, 400±28ms (p<0.05 HAPH+ vs. others); corresponding SI was 10.5±1.9, 8.4±2.6, 8.5±2.0m/s, heart rate was 75±8, 68±8, 70±10 bpm (p<0.05, corresponding comparisons HAPH+ vs. others). In regression analysis, HAPH+ was an independent predictor of increased QTc and SI when controlled for several confounders. Oxygen breathing increased SI in HH but not in HAPH+, and reduced QTc in all groups. CONCLUSIONS: Our data suggest that HAPH+ but not HH may be at increased risk of cardiovascular mortality and morbidity compared to LL. The lack of a further increase of the elevated SI during hyperoxia in HAPH+ may indicate dysfunctional control of vascular tone and/or remodelling.

Cerebral oxygenation in highlanders with and without high-altitude pulmonary hypertension.

NEW FINDINGS: What is the central question of this study? Cerebral hypoxia impairs cognitive function and exercise performance and may result in brain damage. Residents at high altitude, in particular those with high-altitude pulmonary hypertension, are prone to hypoxaemia due to the exposure to reduced barometric pressure and impaired pulmonary gas exchange. Whether highlanders have a reduced cerebral oxygenation has not been studied. What is the main finding and its importance? We found that despite a reduced arterial oxygen saturation, healthy highlanders and even those with pulmonary hypertension have a similar cerebral oxygenation to healthy lowlanders, suggesting that compensatory mechanisms protect long-term residents at high altitude from cerebral hypoxia. Abstract High-altitude pulmonary hypertension (HAPH), a chronic altitude-related illness, causes hypoxaemia and impaired exercise performance. We evaluated the hypothesis that haemodynamic limitation and hypoxaemia in patients with HAPH are associated with impaired cerebral tissue oxygenation (CTO) compared with healthy highlanders (HH) and lowlanders (LL). We studied 36 highlanders with HAPH and 54 HH at an altitude of 3250 m, and 34 LL at 760 m. Mean(±SD) pulmonary artery pressures were 34(±3), 22(±5) and 16(±4) mmHg, respectively (P < 0.05, all comparisons). The CTO was monitored by near-infrared spectroscopy along with pulse oximetry (peripheral arterial oxygen saturation, SpO2) during quiet breathing of room air (RA) and oxygen for 20 min each, and during hyperventilation with RA and oxygen, respectively. In HAPH, HH and LL breathing RA, SpO2 was 88(±4), 92(±2) and 95(±2)%, respectively (P < 0.001, all comparisons), and CTO was similar in the three groups, at 68(±3), 68(±4) and 69(±4)%, respectively (n.s., all comparisons). Breathing oxygen increased SpO2 and CTO significantly more in HAPH than in HH and LL. Hyperventilation (RA) did not reduce CTO in HAPH but did in HH and LL; hyperventilation (oxygen) increased CTO in HAPH only. Highlanders with and without HAPH studied at 3250 m had a similar CTO to healthy lowlanders at 760 m even though highlanders were hypoxaemic. The physiological response to hyperoxia and hypocapnia assessed by cerebral near-infrared spectroscopy suggests that healthy highlanders and even highlanders with HAPH effectively maintain an adequate CTO. This adaptation may be of particular relevance because adequate cerebral oxygenation is essential for vital brain functions.

Oxigenación cerebral en habitantes de gran altura con y sin hipertensión pulmonar de altura / Cerebral oxygenation in high altitude inhabitants with and without high altitude pulmonary hypertension

La Hipertensión pulmonar de gran altura (HAPH),una enfermedad crónica relacionada con laaltura, que causa hipoxemia y un deterioro enel rendimiento del ejercicio. Se ha evaluadola hipótesis que, la limitación hemodinámicae hipoxemia en pacientes con (HAPH), estánasociados con un deterioro en la oxigenación deltejido cerebral (CTO), comparados con habitantes...

Pancreatic stromal tumor of nerve sheath origin treated by pancreatoduodenectomy.

A pancreatic sarcoma of nerve sheath origin is reported in a 28-year-old female patient, who presented with melaena. Preoperative imaging showed an 8.5 cm diameter mass in the head of pancreas. There was bleeding from the papilla of Vater at endoscopy and a highly vascular lesion on arteriography. The patient was submitted to proximal pancreatoduodenectomy and remains symptom-free at 1 year follow-up.