An understanding of human responses to hypoxia is important for the health of millions of people worldwide who visit, live, or work in the hypoxic environment encountered at high altitudes. In spite of dozens of studies over the last 100 years, the basic mechanisms controlling acclimatization to hypoxia remain largely unknown. The AltitudeOmics project aimed to bridge this gap. Our goals were 1) to describe a phenotype for successful acclimatization and assess its retention and 2) use these findings as a foundation for companion mechanistic studies. Our approach was to characterize acclimatization by measuring changes in arterial oxygenation and hemoglobin concentration [Hb], acute mountain sickness (AMS), cognitive function, and exercise performance in 21 subjects as they acclimatized to 5260 m over 16 days. We then focused on the retention of acclimatization by having subjects reascend to 5260 m after either 7 (n = 14) or 21 (n = 7) days at 1525 m. At 16 days at 5260 m we observed: 1) increases in arterial oxygenation and [Hb] (compared to acute hypoxia: PaO2 rose 9±4 mmHg to 45±4 while PaCO2 dropped a further 6±3 mmHg to 21±3, and [Hb] rose 1.8±0.7 g/dL to 16±2 g/dL; 2) no AMS; 3) improved cognitive function; and 4) improved exercise performance by 8±8% (all changes p<0.01). Upon reascent, we observed retention of arterial oxygenation but not [Hb], protection from AMS, retention of exercise performance, less retention of cognitive function; and noted that some of these effects lasted for 21 days. Taken together, these findings reveal new information about retention of acclimatization, and can be used as a physiological foundation to explore the molecular mechanisms of acclimatization and its retention.

Intrapulmonary arteriovenous (IPAV) shunting has been shown to occur at rest in some subjects breathing a hypoxic gas mixture [fraction of inspired oxygen (FI(O(2))) = 0.12] for brief periods of time. In the present study we set out to determine if IPAV shunting could be induced at rest in all subjects exposed to hypoxia for 30 min. Twelve subjects (6 women) breathed four levels of hypoxia (FI(O(2)) = 0.16, 0.14, 0.12, and 0.10) for 30 min each in either an ascending or descending order with a 15-min normoxic break between bouts. Saline contrast echocardiography was used to detect IPAV shunt and a shunt score (0-5) was assigned based on contrast in the left ventricle with a shunt score ≥ 2 considered significant. Pulmonary artery systolic pressure (PASP) was determined using Doppler ultrasound. The total number of subjects demonstrating shunt scores ≥ 2 for FI(O(2)) = 0.16, 0.14, 0.12, and 0.10 was 1/12, 7/12, 9/12, and 12/12, respectively. Shunt scores were variable between subjects but significantly greater than normoxia for FI(O(2)) = 0.12 and 0.10. Shunt scores correlated with peripheral measurements of arterial oxygen saturation (SpO(2)) (r(w) = -0.67) and PASP (r(w) = 0.44), despite an increased shunt score but no increase in PASP while breathing an FI(O(2)) = 0.12. It is unknown how hypoxia induces the opening of IPAV shunts, but these vessels may be controlled via similar mechanisms as systemic vessels that vasodilate in response to hypoxia. Despite intersubject variability our results indicate significant IPAV shunting occurs at rest in all subjects breathing an FI(O(2)) = 0.10 for 30 min.

Sleep-wake disturbances following traumatic brain injury (TBI) are increasingly recognized as a serious consequence following injury and as a barrier to recovery. Injury-induced sleep-wake disturbances can persist for years, often impairing quality of life. Recently, there has been a nearly exponential increase in the number of primary research articles published on the pathophysiology and mechanisms underlying sleep-wake disturbances after TBI, both in animal models and in humans, including in the pediatric population. In this review, we summarize over 200 articles on the topic, most of which were identified objectively using reproducible online search terms in PubMed. Although these studies differ in terms of methodology and detailed outcomes; overall, recent research describes a common phenotype of excessive daytime sleepiness, nighttime sleep fragmentation, insomnia, and electroencephalography spectral changes after TBI. Given the heterogeneity of the human disease phenotype, rigorous translation of animal models to the human condition is critical to our understanding of the mechanisms and of the temporal course of sleep-wake disturbances after injury. Arguably, this is most effectively accomplished when animal and human studies are performed by the same or collaborating research programs. Given the number of symptoms associated with TBI that are intimately related to, or directly stem from sleep dysfunction, sleep-wake disorders represent an important area in which mechanistic-based therapies may substantially impact recovery after TBI.

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Concern has been raised that altering the fraction of inspired O₂ (Fi(O₂)) could accelerate or decelerate microbubble dissolution time within the pulmonary vasculature and thereby invalidate the ability of saline contrast echocardiography to detect intrapulmonary arteriovenous shunt in subjects breathing either a low or a high Fi(O₂). The present study determined whether the gaseous component used for saline contrast echocardiography affects the detection of exercise-induced intrapulmonary arteriovenous shunt under varying Fi(O₂). Twelve healthy human subjects (6 men, 6 women) performed three 11-min bouts of cycle ergometer exercise at 60% peak O₂ consumption (Vo(2peak)) in normoxia, hypoxia (Fi(O₂) = 0.14), and hyperoxia (Fi(O₂) = 1.0). Five different gases were used to create saline contrast microbubbles by two separate methods and were injected intravenously in the following order at 2-min intervals: room air, 100% N₂, 100% O₂, 100% CO₂, and 100% He. Breathing hyperoxia prevented exercise-induced intrapulmonary arteriovenous shunt, whereas breathing hypoxia and normoxia resulted in a significant level of exercise-induced intrapulmonary arteriovenous shunt. During exercise, for any Fi(O₂) there was no significant difference in bubble score when the different microbubble gas compositions made with either method were used. The present results support our previous work using saline contrast echocardiography and validate the use of room air as an acceptable gaseous component for use with saline contrast echocardiography to detect intrapulmonary arteriovenous shunt during exercise or at rest with subjects breathing any Fi(O₂). These results suggest that in vivo gas bubbles are less susceptible to changes in the ambient external environment than previously suspected.