Jacqueline Renée Pichler Hefti

Nocturnal periodic breathing during acclimatization at very high altitude at Mount Muztagh Ata (7,546 m)

RATIONALE Quantitative data on ventilation during acclimatization at very high altitude are scant. Therefore, we monitored nocturnal ventilation and oxygen saturation in mountaineers ascending Mt. Muztagh Ata (7,546 m). OBJECTIVES To investigate whether periodic breathing persists during prolonged stay at very high altitude. METHODS A total of 34 mountaineers (median age, 46 yr; 7 women) climbed from 3,750 m within 19-20 days to the summit at 7,546 m. During ascent, repeated nocturnal recordings of calibrated respiratory inductive plethysmography, pulse oximetry, and scores of acute mountain sickness were obtained. MEASUREMENTS AND MAIN RESULTS Nocturnal oxygen saturation decreased, whereas minute ventilation and the number of periodic breathing cycles increased with increasing altitude. At the highest camp (6,850 m), median nocturnal oxygen saturation, minute ventilation, and the number of periodic breathing cycles were 64%, 11.3 L/min, and 132.3 cycles/h. Repeated recordings within 5-8 days at 4,497 m and 5,533 m, respectively, revealed increased oxygen saturation, but no decrease in periodic breathing. The number of periodic breathing cycles was positively correlated with days of acclimatization, even when controlled for altitude, oxygen saturation, and other potential confounders, whereas symptoms of acute mountain sickness had no independent effect on periodic breathing. CONCLUSIONS Our field study provides novel data on nocturnal oxygen saturation, breathing patterns, and ventilation at very high altitude. It demonstrates that periodic breathing increases during acclimatization over 2 weeks at altitudes greater than 3,730 m, despite improved oxygen saturation consistent with a progressive increase in loop gain of the respiratory control system. Clinical trial registered with www.clinicaltrials.gov (NCT00514826).

Adaptive servo-ventilation as treatment of persistent central sleep apnea in post-acute ischemic stroke patients

BACKGROUND Adaptive servo-ventilation (ASV) is a well-established treatment of central sleep apnea (CSA) related to congestive heart failure (CHF). Few studies have evaluated the effectiveness and adherence in patients with CSA of other etiologies, and even less is known about treatment of CSA in patients of post ischemic stroke. METHODS A single-centre retrospective analysis of ASV treatment for CSA in post-acute ischemic stroke patients without concomitant CHF was performed. Demographics, clinical data, sleep studies, ventilator settings, and adherence data were evaluated. RESULTS Out of 154 patients on ASV, 15 patients had CSA related to ischemic stroke and were started on ASV a median of 11 months after the acute cerebrovascular event. Thirteen out of the 15 patients were initially treated with continuous positive airway pressure (11/15) and bilevel positive airway pressure (2/15) therapy with unsatisfactory control of CSA. ASV significantly improved AHI (46.7 ± 24.3 vs 8.5 ± 12/h, P = 0.001) and reduced ESS (8.7 ± 5.7 vs 5.6 ± 2.5, P = 0.08) with a mean nightly use of ASV of 5.4 ± 2.4 h at 3 months after the initiation of treatment. Results were maintained at 6 months. CONCLUSION ASV was well tolerated and clinically effective in this group of patients with persistent CSA after ischemic stroke.

Oxidative Stress in Hypobaric Hypoxia and Influence on Vessel-Tone Modifying Mediators

Increased pulmonary artery pressure is a well-known phenomenon of hypoxia and is seen in patients with chronic pulmonary diseases, and also in mountaineers on high altitude expedition. Different mediators are known to regulate pulmonary artery vessel tone. However, exact mechanisms are not fully understood and a multimodal process consisting of a whole panel of mediators is supposed to cause pulmonary artery vasoconstriction. We hypothesized that increased hypoxemia is associated with an increase in vasoconstrictive mediators and decrease of vasodilatators leading to a vasoconstrictive net effect. Furthermore, we suggested oxidative stress being partly involved in changement of these parameters. Oxygen saturation (Sao2) and clinical parameters were assessed in 34 volunteers before and during a Swiss research expedition to Mount Muztagh Ata (7549 m) in Western China. Blood samples were taken at four different sites up to an altitude of 6865 m. A mass spectrometry-based targeted metabolomic platform was used to detect multiple parameters, and revealed functional impairment of enzymes that require oxidation-sensitive cofactors. Specifically, the tetrahydrobiopterin (BH4)-dependent enzyme nitric oxide synthase (NOS) showed significantly lower activities (citrulline-to-arginine ratio decreased from baseline median 0.21 to 0.14 at 6265 m), indicating lower NO availability resulting in less vasodilatative activity. Correspondingly, an increase in systemic oxidative stress was found with a significant increase of the percentage of methionine sulfoxide from a median 6% under normoxic condition to a median level of 30% (p<0.001) in camp 1 at 5533 m. Furthermore, significant increase in vasoconstrictive mediators (e.g., tryptophan, serotonin, and peroxidation-sensitive lipids) were found. During ascent up to 6865 m, significant altitude-dependent changes in multiple vessel-tone modifying mediators with excess in vasoconstrictive metabolites could be demonstrated. These changes, as well as highly significant increase in systemic oxidative stress, may be predictive for increase in acute mountain sickness score and changes in Sao2.

Morphological Brain Changes after Climbing to Extreme Altitudes—A Prospective Cohort Study

Background Findings of cerebral cortical atrophy, white matter lesions and microhemorrhages have been reported in high-altitude climbers. The aim of this study was to evaluate structural cerebral changes in a large cohort of climbers after an ascent to extreme altitudes and to correlate these findings with the severity of hypoxia and neurological signs during the climb. Methods Magnetic resonance imaging (MRI) studies were performed in 38 mountaineers before and after participating in a high altitude (7126m) climbing expedition. The imaging studies were assessed for occurrence of new WM hyperintensities and microhemorrhages. Changes of partial volume estimates of cerebrospinal fluid, grey matter, and white matter were evaluated by voxel-based morphometry. Arterial oxygen saturation and acute mountain sickness scores were recorded daily during the climb. Results On post-expedition imaging no new white matter hyperintensities were observed. Compared to baseline testing, we observed a significant cerebrospinal fluid fraction increase (0.34% [95% CI 0.10–0.58], p = 0.006) and a white matter fraction reduction (-0.18% [95% CI -0.32–-0.04], p = 0.012), whereas the grey matter fraction remained stable (0.16% [95% CI -0.46–0.13], p = 0.278). Post-expedition imaging revealed new microhemorrhages in 3 of 15 climbers reaching an altitude of over 7000m. Affected climbers had significantly lower oxygen saturation values but not higher acute mountain sickness scores than climbers without microhemorrhages. Conclusions A single sojourn to extreme altitudes is not associated with development of focal white matter hyperintensities and grey matter atrophy but leads to a decrease in brain white matter fraction. Microhemorrhages indicative of substantial blood-brain barrier disruption occur in a significant number of climbers attaining extreme altitudes.

Hypoxia-induced changes in plasma microRNAs correlate with pulmonary artery pressure at high altitude

In vitro and animal studies revealed micro-RNAs (miRs) to be involved in modulation of hypoxia-induced pulmonary hypertension (HPH). However, knowledge of circulating miRs in humans in the context of HPH is very limited. Since symptoms of HPH are nonspecific and noninvasive diagnostic parameters do not exist, a disease-specific and hypoxemia-independent biomarker indicating HPH would be of clinical value. To examine whether plasma miR levels correlate with hypoxia-induced increase in pulmonary artery pressures, plasma miRs were assessed in a model of hypoxia-related pulmonary hypertension in humans exposed to extreme altitude. Forty healthy volunteers were repetitively examined during a high-altitude expedition up to an altitude of 7,050 m. Plasma levels of miR-17, -21, and -190 were measured by real-time quantitative PCR and correlated with systolic pulmonary artery pressure (SPAP), which was assessed by echocardiography. A significant altitude-dependent increase in circulating miR expression was found (all P values < 0.0001). Compared with baseline at 500 m, miR-17 changed by 4.72 ± 0.57-fold, miR-21 changed by 1.91 ± 0.33-fold, and miR-190 changed by 3.61 ± 0.54-fold at 7,050 m (means ± SD). Even after adjusting for hypoxemia, miR-17 and miR-190 were found to be independently correlated with increased SPAP. Progressive hypobaric hypoxia significantly affects levels of circulating miR-17, -21, and -190. Independently from the extent of hypoxemia, miR-17 and -190 significantly correlate with increased SPAP. These novel findings provide evidence for an epigenetic modulation of hypoxia-induced increase in pulmonary artery pressures by miR-17 and -190 and suggest the potential value of these miRs as biomarkers for HPH.

Changes in mitochondrial enzymatic activities of monocytes during prolonged hypobaric hypoxia and influence of antioxidants: A randomized controlled study

Abstract Objectives Exposure to high altitudes is associated with oxidative cellular damage due to the increased level of reactive oxygen and nitrogen species and altered activity of antioxidant systems. Subjects were submitted to prolonged hypoxia, to evaluate changes in mitochondrial enzyme activities of monocytes and their attenuation by supplementation with antioxidants. Methods Twelve subjects were randomly assigned to receive antioxidant supplements or placebo prior to and during an expedition to Pik Lenin (7145 m). Monocytes were isolated from blood samples to determine the activity of mitochondrial enzymes cytochrome c oxidase and citrate synthase at 490 m (baseline) and at the altitudes of 3550 m, 4590 m, and 5530 m. Results An increase in citrate synthase activity at all altitudes levels was observed. Hypoxia induced an increase in the activity of cytochrome c oxidase only at 4590 m. Neither citrate synthase activity nor cytochrome c oxidase activity differed between the subjects receiving antioxidant supplements and those receiving placebo. Conclusions Hypoxia leads to an increase in citrate synthase activity of monocyte mitochondria as a marker of mitochondrial mass, which is not modified by antioxidant supplementation. The increase in mitochondrial mass may represent a compensatory mechanism to preserve oxidative phosphorylation of monocytes at high altitudes.

A 58-Year-Old Man With Position-Dependent Nocturnal Dyspnea

CASE PRESENTATION A 58-year-old man with idiopathic pulmonary fibrosis, who had received a right-sided single-lung transplant 2 years earlier, was referred to the sleep clinic for the assessment of nocturnal position-dependent episodes of dyspnea and frequent arousals when lying on his right side. There was no subjective worsening of daytime respiratory symptoms, but he complained of fatigue and unrefreshing sleep. His Epworth Sleepiness Scale score was 12/24. After lung transplantation he had a favorable course while receiving immunosuppression with prednisolone, everolimus, and mycophenolate mofetil. In addition, he had received diagnoses of stable coronary artery disease and moderate chronic kidney failure.

When “High” Is not Very High: High Altitude Pulmonary Edema as First Manifestation of Sarcoidosis-Related Pulmonary Hypertension

High altitude pulmonary edema (HAPE) is a life-threatening complication of high altitude stay, which may occur above altitudes of 2500 m. This is a case report of a healthy 41-year-old man, presenting with recurrent HAPE at moderate altitude. Medical work-up revealed an idiopathic pulmonary artery hypertension (PAH), and specific vasoactive treatment was started. Despite treatment with an endothelin receptor antagonist, the patient deteriorated clinically. Subsequent medical reevaluation showed a significant progress of mediastinal lymphadenopathy. Due to the histological proof of sarcoidosis, the initial diagnosis of PAH had to be changed to sarcoidosis-related pulmonary hypertension. Initiation of immunosuppressive therapy with corticosteroids led to significant and clinically relevant decrease in pulmonary artery pressure, even allowing episodes of asymptomatic re-exposure to moderate altitude. This case describes HAPE as first manifestation of a sarcoidosis-related pulmonary hypertension with a very unusual and early presentation of the underlying disease in an apparently healthy mountaineer.