Search

Common methods for evaluating history of traumatic brain injury (TBI) include self-report, electronic medical record review (EMR), and structured interviews such as the Head Trauma Events Characteristics (HTEC). Each has strengths and weaknesses, but little is known regarding how TBI diagnostic rates or the associated symptom profile differ among them. This study examined 200 Veterans recruited within the VA Portland Health Care System, each evaluated for TBI using self-report, EMR, and HTEC. Participants also completed validated questionnaires assessing chronic symptom severity in broad health-related domains (pain, sleep, quality of life, post-concussive symptoms). The HTEC was more sensitive (80% of participants in our cohort) than either self-report or EMR alone (40%). As expected from the high sensitivity, participants screening positive for TBI through the HTEC included many people with mild or no post-concussive symptoms. Participants were grouped according to degree of concordance across these diagnostic methods: no TBI, n = 43; or TBI-positive in any one method (TBI-1dx, n = 53), positive in any two (TBI-2dx, n = 45), or positive in all three (TBI-3dx, n = 59). The symptom profile of the TBI-1dx group was indistinguishable from the no TBI group. The TBI-3dx group had the most severe symptom profile. Our results show that understanding the exact methods used to ascertain TBI is essential when interpreting results from other studies, given that results and conclusions may differ dramatically depending on the method. This issue will become even more critical when interpreting data merged from multiple sources within newer, centralized repositories (e.g., Federal Interagency Traumatic Brain Injury Research [FITBIR]).

Blood flow through intrapulmonary arteriovenous anastomoses (QIPAVA) occurs in healthy humans at rest and during exercise when breathing hypoxic gas mixtures at sea level and may be a source of right-to-left shunt. However, at high altitudes, QIPAVA is reduced compared with sea level, as detected using transthoracic saline contrast echocardiography (TTSCE). It remains unknown whether the reduction in QIPAVA (i.e., lower bubble scores) at high altitude is due to a reduction in bubble stability resulting from the lower barometric pressure (PB) or represents an actual reduction in QIPAVA. To this end, QIPAVA, pulmonary artery systolic pressure (PASP), cardiac output (QT), and the alveolar-to-arterial oxygen difference (AaDO2) were assessed at rest and during exercise (70–190 W) in the field (5,260 m) and in the laboratory (1,668 m) during four conditions: normobaric normoxia (NN; [Formula: see text] = 121 mmHg, PB = 625 mmHg; n = 8), normobaric hypoxia (NH; [Formula: see text] = 76 mmHg, PB = 625 mmHg; n = 7), hypobaric normoxia (HN; [Formula: see text] = 121 mmHg, PB = 410 mmHg; n = 8), and hypobaric hypoxia (HH; [Formula: see text] = 75 mmHg, PB = 410 mmHg; n = 7). We hypothesized QIPAVA would be reduced during exercise in isooxic hypobaria compared with normobaria and that the AaDO2 would be reduced in isooxic hypobaria compared with normobaria. Bubble scores were greater in normobaric conditions, but the AaDO2 was similar in both isooxic hypobaria and normobaria. Total pulmonary resistance (PASP/QT) was elevated in HN and HH. Using mathematical modeling, we found no effect of hypobaria on bubble dissolution time within the pulmonary transit times under consideration ( NEW & NOTEWORTHY Blood flow through intrapulmonary arteriovenous anastomoses, detected by transthoracic saline contrast echocardiography, was reduced during exercise in acute hypobaria compared with normobaria, independent of oxygen tension, whereas pulmonary gas exchange efficiency was unaffected. Modeling the effect(s) of reduced air density on contrast bubble lifetime did not result in a significantly reduced contrast stability. Interestingly, total pulmonary resistance was increased by hypobaria, independent of oxygen tension, suggesting that pulmonary blood flow may be changed by hypobaria.

Blood flow through intrapulmonary arteriovenous anastomoses (Q̇IPAVA) increases in healthy humans breathing hypoxic gas and is potentially dependent on body position. Previous work in subjects breathing room air has shown an effect of body position when Q̇IPAVA is detected with transthoracic saline contrast echocardiography (TTSCE). However, the potential effect of body position on Q̇IPAVA has not been investigated when subjects are breathing hypoxic gas or with a technique capable of quantifying Q̇IPAVA. Thus the purpose of this study was to quantify the effect of body position on Q̇IPAVA when breathing normoxic and hypoxic gas at rest. We studied Q̇IPAVA with TTSCE and quantified Q̇IPAVA with filtered technetium-99m-labeled macroaggregates of albumin (99mTc-MAA) in seven healthy men breathing normoxic and hypoxic (12% O2) gas at rest while supine and upright. On the basis of previous work using TTSCE, we hypothesized that the quantified Q̇IPAVA would be greatest with hypoxia in the supine position. We found that Q̇IPAVA quantified with 99mTc-MAA significantly increased while subjects breathed hypoxic gas in both supine and upright body positions (ΔQ̇IPAVA = 0.7 ± 0.4 vs. 2.5 ± 1.1% of cardiac output, respectively). Q̇IPAVA detected with TTSCE increased from normoxia in supine hypoxia but not in upright hypoxia (median hypoxia bubble score of 2 vs. 0, respectively). Surprisingly, Q̇IPAVA magnitude was greatest in upright hypoxia, when Q̇IPAVA was undetectable with TTSCE. These findings suggest that the relationship between TTSCE and 99mTc-MAA is more complex than previously appreciated, perhaps because of the different physical properties of bubbles and MAA in solution. NEW & NOTEWORTHY Using saline contrast bubbles and radiolabeled macroaggregrates (MAA), we detected and quantified, respectively, hypoxia-induced blood flow through intrapulmonary arteriovenous anastomoses (Q̇IPAVA) in supine and upright body positions in healthy men. Upright hypoxia resulted in the largest magnitude of Q̇IPAVA quantified with MAA but the lowest Q̇IPAVA detected with saline contrast bubbles. These surprising results suggest that the differences in physical properties between saline contrast bubbles and MAA in blood may affect their behavior in vivo.

Study Objectives To describe the crude prevalence of rapid eye movement (REM) sleep behavior disorder (RBD) following traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) in Veterans, given potential relationships between TBI, PTSD, RBD, and neurodegeneration. Methods Veterans (n = 394; 94% male; 54.4 ± 15.5 years of age) were prospectively/cross-sectionally recruited from the VA Portland Health Care System and completed in-lab video-polysomnography and questionnaires. TBI and PTSD were assessed via diagnostic screening and medical record review. Subjects were categorized into four groups after assessment of REM sleep without atonia (RSWA) and self-reported dream enactment: (1) “Normal,” neither RSWA nor dream enactment, (2) “Other Parasomnia,” dream enactment without RSWA, (3) “RSWA,” isolated-RSWA without dream enactment, and (4) “RBD,” RSWA with dream enactment. Crude prevalence, prevalence odds ratio, and prevalence rate for parasomnias across subjects with TBI and/or PTSD were assessed. Results Overall prevalence rates were 31%, 7%, and 9% for Other Parasomnia, RSWA, and RBD, respectively. The prevalence rate of RBD increased to 15% in PTSD subjects [age adjusted POR: 2.81 (1.17–4.66)] and to 21% in TBI + PTSD subjects [age adjusted POR: 3.43 (1.20–9.35)]. No subjects met all diagnostic criteria for trauma-associated sleep disorder (TASD), and no overt dream enactment was captured on video. Conclusions The prevalence of RBD and related parasomnias is significantly higher in Veterans compared with the general population and is associated with PTSD and TBI + PTSD. Considering the association between idiopathic-RBD and synucleinopathy, it remains unclear whether RBD (and potentially TASD) associated with PTSD or TBI + PTSD similarly increases risk for long-term neurologic sequelae.

Novel approaches are needed to accurately classify and monitor sleep patterns in older adults, particularly those with cognitive impairment and non-normative sleep. Traditional methods ignore underlying sleep architecture in these patient populations, and other modern approaches tend to focus on healthy, normative patient populations. In this paper, we developed a model using a long-short-term memory neural network (LSTM) and trained it on a sample of older, non-normative patients. The 22 nights of data collected were trained on gold-standard polysomnography (PSG) as ground truth and were compared against the clinical standard threshold-based method for sleep detection. The LSTM more than doubled the traditional method's ability to detect clinically-relevant wakefulness during sleep (37.7% vs. 15%) without significantly sacrificing accuracy (67.7% vs. 75%) or precision (90.7% vs. 94%) of sleep classification.

Introduction Sleep disturbances are common in elderly patients and may contribute to disease progression in certain populations (e.g., Alzheimer’s Disease). Light therapy is a simple and cost-effective intervention to improve sleep. Primary barriers to light therapy are 1) poor acceptability to use of devices and 2) inflexibility of current devices to deliver beyond a fixed spectrum and throughout the entirety of the day. However, dynamic, tunable lighting integrated into the native home lighting system can maximize short-wavelength light in the morning and minimize short-wavelength light in the evening, thus entraining circadian rhythms and treating sleep disturbances, and overcome these limitations. We determined the feasibility of implementing a whole-home tunable lighting system as a potential sleep intervention. Methods Tunable LED lights were installed throughout the homes of healthy older adults already enrolled in an existing study with embedded home assessment platforms (ORCATECH study; n=4 subjects in n=3 homes). In ORCATECH, continuous data on room location, activity, sleep, and general health parameters are collected at minute-to-minute resolution over months to years of participation. This single arm longitudinal design collected participants’ light usage in addition to ORCATECH outcome measures. Primary outcomes for this pilot study included the feasibility and patient acceptability. Exploratory outcomes were sleep metrics (sleep time, latency, efficiency), mobility (room transitions and actigraphy), and overall health indices (weekly body weight, self-report general health questionnaires) both pre- and post-intervention. Results Two subjects terminated the study citing technical difficulties with the lights and a preference for brighter illumination. Of the remaining 2 participants, sleep metrics were explored over a 12-month period spanning pre- and post-installation of lights. Nightly duration in bed was compared with minute-to-minute room entry data and actigraphy with high inter-measure reliability. Conclusion These data support that tunable whole-home lighting systems are reasonably acceptable and feasibly implemented using an automated platform for continuous data collection. Quantification of sleep over long periods of time is robust and reliable in the home environment of elderly subjects. These results will inform implementation of future large-scale lighting intervention studies in patients at risk for developing Alzheimer’s Disease. Support (if any) Hartford Gerontological Center Interprofessional Award, Pacific Northwest National Laboratory, OHSU ORCATECH

Introduction A bidirectional relationship exists between sleep disruption and neuropathology in Alzheimer’s disease (AD). The sleep electroencephalogram (EEG) is a highly stereotyped, direct neurophysiological window into brain function; prior studies have identified abnormalities in EEG slow waves in early AD. EEG coherence across channels during sleep, a normally highly coherent brain state, could be an indicator of network coordination across brain regions. Accordingly, altered slow wave coherence during sleep may be an early indicator of cognitive decline. Methods EEG was collected during an attended overnight polysomnogram (PSG) from a community-based cohort of older subjects (n=44, average age = 71), approximately 25% of whom met criteria for mild cognitive impairment or early AD. Files were exported to EDF and a slow wave peak detector was implemented in MATLAB to count the number of slow wave oscillations, with automated artifact rejection, across 6 EEG leads standard for PSG (C3, C4, F3, F4, O1, and O2). Slow wave coherence was inferred when slow waves occurred in temporal synchrony across channels within 100 ms. Results Subjects with cognitive impairment showed significantly reduced total sleep time and time spent in rapid eye movement (REM) sleep compared to age-matched controls. EEG slow wave coherence was reliably quantified during wake, non-REM stages N1, N2, N3, and REM vigilance states as well as during transition periods between sleep stages. Using this algorithm, specific signatures of slow wave propagation during sleep were identified, including increased variability in slow wave activity and coherence, that appeared more prominent in subjects with impaired cognition. Conclusion EEG slow wave coherence during sleep and wake states can be calculated by applying automated algorithms to PSG data, and may be associated with cognitive impairment. Support (if any) NIH R01 AG059507

The foramen ovale, which is part of the normal fetal cardiopulmonary circulation, fails to close after birth in ∼35% of the population and represents a potential source of right-to-left shunt. Despite the prevalence of patent foramen ovale (PFO) in the general population, cardiopulmonary, exercise, thermoregulatory, and altitude physiologists may have underestimated the potential effect of this shunted blood flow on normal physiological processes in otherwise healthy humans. Because this shunted blood bypasses the respiratory system, it would not participate in either gas exchange or respiratory system cooling and may have impacts on other physiological processes that remain undetermined. The consequences of this shunted blood flow in PFO-positive (PFO+) subjects can potentially have a significant, and negative, impact on the alveolar-to-arterial oxygen difference (AaDO2), ventilatory acclimatization to high altitude and respiratory system cooling with PFO+ subjects having a wider AaDO2 at rest, during exercise after acclimatization, blunted ventilatory acclimatization, and a higher core body temperature (∼0.4°C) at rest and during exercise. There is also an association of PFO with high-altitude pulmonary edema and acute mountain sickness. These effects on physiological processes are likely dependent on both the presence and size of the PFO, with small PFOs not likely to have significant/measureable effects. The PFO can be an important determinant of normal physiological processes and should be considered a potential confounder to the interpretation of former and future data, particularly in small data sets where a significant number of PFO+ subjects could be present and significantly impact the measured outcomes.

What is the central question of this study? Do individuals with chronic obstructive pulmonary disease have blood flow through intrapulmonary arteriovenous anastomoses at rest or during exercise? What is the main finding and its importance? Individuals with chronic obstructive pulmonary disease have a greater prevalence of blood flow through intrapulmonary arteriovenous anastomoses at rest than age-matched control subjects. Given that the intrapulmonary arteriovenous anastomoses are large enough to permit venous emboli to pass into the arterial circulation, patients with chronic obstructive pulmonary disease and an elevated risk of thrombus formation may be at risk of intrapulmonary arteriovenous anastomosis-facilitated embolic injury (e.g. stroke or transient ischaemic attack). The pulmonary capillaries prevent stroke by filtering venous emboli from the circulation. Intrapulmonary arteriovenous anastomoses are large-diameter (≥50 μm) vascular connections in the lung that may compromise the integrity of the pulmonary capillary filter and have recently been linked to cryptogenic stroke and transient ischaemic attack. Prothrombotic populations, such as individuals with chronic obstructive pulmonary disease (COPD), may be at increased risk of stroke and transient ischaemic attack facilitated by intrapulmonary arteriovenous anastomoses, but the prevalence and degree of blood flow through intrapulmonary arteriovenous anastomoses in this population has not been fully examined and compared with age-matched healthy control subjects. We used saline contrast echocardiography to assess blood flow through intrapulmonary arteriovenous anastomoses at rest (n = 29 COPD and 19 control subjects) and during exercise (n = 10 COPD and 10 control subjects) in subjects with COPD and age-matched healthy control subjects. Blood flow through intrapulmonary arteriovenous anastomoses was detected in 23% of subjects with COPD at rest and was significantly higher compared with age-matched healthy control subjects. Blood flow through intrapulmonary arteriovenous anastomoses at rest was reduced or eliminated in subjects with COPD after breathing hyperoxic gas. Sixty per cent of subjects with COPD who did not have blood flow through the intrapulmonary arteriovenous anastomoses at rest had blood flow through them during exercise. The combination of blood flow through intrapulmonary arteriovenous anastomoses and potential for thrombus formation in individuals with COPD may permit venous emboli to pass into the arterial circulation and cause stroke and transient ischaemic attack. Breathing supplemental oxygen may reduce this risk in COPD. The link between blood flow through intrapulmonary arteriovenous anastomoses, stroke and transient ischaemic attack is worthy of future investigation in COPD and other populations.

International audience

Key points The mechanism(s) that regulate hypoxia-induced blood flow through intrapulmonary arteriovenous anastomoses (QIPAVA ) are currently unknown. Our previous work has demonstrated that the mechanism of hypoxia-induced QIPAVA is not simply increased cardiac output, pulmonary artery systolic pressure or sympathetic nervous system activity and, instead, it may be a result of hypoxaemia directly. To determine whether it is reduced arterial PO2 (PaO2) or O2 content (CaO2) that causes hypoxia-induced QIPAVA , individuals were instructed to breathe room air and three levels of hypoxic gas at rest before (control) and after CaO2 was reduced by 10% by lowering the haemoglobin concentration (isovolaemic haemodilution; Low [Hb]). QIPAVA , assessed by transthoracic saline contrast echocardiography, significantly increased as PaO2 decreased and, despite reduced CaO2 (via isovolaemic haemodilution), was similar at iso-PaO2. These data suggest that, with alveolar hypoxia, low PaO2 causes the hypoxia-induced increase in QIPAVA , although where and how this is detected remains unknown. Abstract Alveolar hypoxia causes increased blood flow through intrapulmonary arteriovenous anastomoses (QIPAVA ) in healthy humans at rest. However, it is unknown whether the stimulus regulating hypoxia-induced QIPAVA is decreased arterial PO2 (PaO2) or O2 content (CaO2). CaO2 is known to regulate blood flow in the systemic circulation and it is suggested that IPAVA may be regulated similar to the systemic vasculature. Thus, we hypothesized that reduced CaO2 would be the stimulus for hypoxia-induced QIPAVA . Blood volume (BV) was measured using the optimized carbon monoxide rebreathing method in 10 individuals. Less than 5 days later, subjects breathed room air, as well as 18%, 14% and 12.5% O2 , for 30 min each, in a randomized order, before (CON) and after isovolaemic haemodilution (10% of BV withdrawn and replaced with an equal volume of 5% human serum albumin-saline mixture) to reduce [Hb] (Low [Hb]). PaO2 was measured at the end of each condition and QIPAVA was assessed using transthoracic saline contrast echocardiography. [Hb] was reduced from 14.2 ± 0.8 to 12.8 ± 0.7 g dl(-1) (10 ± 2% reduction) from CON to Low [Hb] conditions. PaO2 was no different between CON and Low [Hb], although CaO2 was 10.4%, 9.2% and 9.8% lower at 18%, 14% and 12.5% O2 , respectively. QIPAVA significantly increased as PaO2 decreased and, despite reduced CaO2, was similar at iso-PaO2. These data suggest that, with alveolar hypoxia, low PaO2 causes the hypoxia-induced increase in QIPAVA . Whether the low PO2 is detected at the carotid body, airway and/or the vasculature remains unknown.

New Findings What is the central question of this study? Several rat models are commonly used to study the physiology of ageing (e.g. Fischer 344 and Brown Norway rats are recommended by the USA National Institute of Ageing). Diaphragm muscle sarcopenia (ageing-related muscle weakness and atrophy) remains incompletely described in these rat models. What is the main finding and its importance? Diaphragm muscle sarcopenia is present in both the Fischer 344 and Brown Norway rat strains, but appears more pronounced in Fischer 344 rats. The risk for respiratory diseases increases in adults >65 years of age, which may be attributable in part to ageing-related weakening and atrophy (i.e. sarcopenia) of the diaphragm muscle (DIAm). The mechanisms underlying DIAm sarcopenia remain unknown. Based on existing evidence, we hypothesized that sarcopenia is most evident in type IIx and/or IIb DIAm fibres, i.e. more fatigable motor units. Currently, the USA National Institute on Aging supports Fischer 344 (F344) and Brown Norway (BN) rat strains for ageing-related research, yet DIAm sarcopenia has not been evaluated comprehensively in either strain. Thus, the present study examined DIAm sarcopenia in older adult F344 (24 months old, 50% survival) and BN rats (32 months old, 50% survival), compared with young adult (6-month-old) F344 and BN rats. Measurements of contractility, contractile protein concentration, fibre type distribution and fibre cross-sectional area were obtained from midcostal DIAm strips. Maximal specific force was reduced by ∼24 and ∼13% in older F344 and BN rats, respectively. Additionally, although the cross-sectional area of type I and IIa DIAm fibres was unchanged in both F344 and BN rats, the cross-sectional area of type IIx and/or IIb DIAm fibres was reduced by ∼20 and ∼15% in F344 and BN rats, respectively. Thus, although there was ageing-related DIAm weakness and atrophy, selective to type IIx and/or IIb DIAm fibres, in both F344 and BN rats, the sarcopenic phenotype was more pronounced in F344 rats.

Many military service members and veterans who have been exposed to high-intensity blast waves experience traumatic brain injury (TBI), resulting in chronic auditory deficits despite normal hearing sensitivity. The current study sought to examine the neurological cause of this chronic dysfunction by testing the hypothesis that blast exposure leads to impaired filtering of sensory information at brainstem and early cortical levels. Groups of blast-exposed and non-blast-exposed participants completed self-report measures of auditory and neurobehavioral status, auditory perceptual tasks involving degraded and competing speech stimuli, and physiological measures of sensory gating, including pre-pulse inhibition and habituation of the acoustic startle reflex and electrophysiological assessment of a paired-click sensory gating paradigm. Blast-exposed participants showed significantly reduced habituation to acoustic startle stimuli and impaired filtering of redundant sensory information at the level the auditory cortex. Multiple linear regression analyses revealed that poorer sensory gating at the cortical level was primarily influenced by a diagnosis of TBI, whereas reduced habituation was primarily influenced by a diagnosis of post-traumatic stress disorder. A statistical model was created including cortical sensory gating and habituation to acoustic startle, which strongly predicted performance on a degraded speech task. These results support the hypothesis that blast exposure impairs central auditory processing via impairment of neural mechanisms underlying habituation and sensory gating.

STUDY OBJECTIVES: Veterans are at an increased risk for traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD), both of which are associated with sleep disturbances and increased pain. Furthermore, sleep disturbances and pain are reciprocally related such that each can exacerbate the other. Although both TBI and PTSD are independently linked to sleep disturbances and pain, it remains unclear whether Veterans with comorbid TBI+PTSD show worse sleep disturbances and pain compared to those with only TBI or PTSD. We hypothesized that sleep and pain would be worse in Veterans with comorbid TBI+PTSD compared to Veterans with only TBI or PTSD. METHODS: Veterans (n = 639) from the VA Portland Health Care System completed overnight polysomnography and self-report questionnaires. Primary outcome variables were self-reported sleep disturbances and current pain intensity. Participants were categorized into four trauma-exposure groups: (1) neither: without TBI or PTSD (n = 383); (2) TBI: only TBI (n = 67); (3) PTSD: only PTSD (n = 126); and (4) TBI+PTSD: TBI and PTSD (n = 63). RESULTS: The PTSD and TBI+PTSD groups reported worse sleep compared to the TBI and neither groups. The TBI+PTSD group reported the greatest pain intensity compared to the other groups. CONCLUSIONS: These data suggest sleep and pain are worst in Veterans with TBI and PTSD, and that sleep is similarly impaired in Veterans with PTSD despite not having as much pain. Thus, although this is a complex relationship, these data suggest PTSD may be driving sleep disturbances, and the added effect of TBI in the comorbid group may be driving pain in this population. CITATION: Balba NM, Elliott JE, Weymann KB, Opel RA, Duke JW, Oken BS, Morasco BJ, Heinricher MM, Lim MM. Increased sleep disturbances and pain in Veterans with comorbid traumatic brain injury and posttraumatic stress disorder. J Clin Sleep Med. 2018;14(11):1865–1878.

Sleep disturbances following traumatic brain injury (TBI) in Veterans are very common and often persist as chronic sequelae. In addition, sensory sensitivity, ie, discomfort upon exposure to light and noise, is common after TBI. However, the relationship between sleep disturbances and sensory sensitivity in Veterans following TBI has not yet been examined, yet both are established early markers of neurodegeneration.Veterans (n = 95) in the chronic phase of recovery from TBI at the VA Portland Health Care System completed an overnight polysomnography and provided self-report data on sensory (eg, light and noise) sensitivity, and sleep disturbances. Participants were categorized into four sensory sensitivity groups: (1) "neither," neither light nor noise sensitivity (n = 36); (2) "light," only light sensitivity (n = 12); (3) "noise," only noise sensitivity (n = 24); and (4) "both," light and noise sensitivity (n = 23).Veterans with TBI reported sleep disturbances that were significantly correlated with the severity of their sensory sensitivity and associated with posttraumatic stress disorder (PTSD). Multiple linear regression revealed insomnia severity to be the strongest predictor of the relationship between sleep disturbances and sensory sensitivity. Furthermore, sensory sensitivity was associated with a higher mean heart rate during sleep, even after controlling for PTSD status.These data are the first to report the prevalence and association between sensory sensitivity and sleep disturbances in Veterans with TBI. These data also suggest that the underlying mechanism of the sleep-sensory relationship could be due in part to comorbid PTSD and autonomic nervous system hyperarousal.

Study objectives In previous work, dietary branched-chain amino acid (BCAA) supplementation, precursors to de novo glutamate and γ-aminobutyric acid (GABA) synthesis, restored impaired sleep-wake regulation and orexin neuronal activity following traumatic brain injury (TBI) in mice. TBI was speculated to reduce orexin neuronal activity through decreased regional excitatory (glutamate) and/or increased inhibitory (GABA) input. Therefore, we hypothesized that TBI would decrease synaptic glutamate and/or increase synaptic GABA in nerve terminals contacting orexin neurons, and BCAA supplementation would restore TBI-induced changes in synaptic glutamate and/or GABA. Methods Brain tissue was processed for orexin pre-embed diaminobenzidine labeling and glutamate or GABA postembed immunogold labeling. The density of glutamate and GABA immunogold within presynaptic nerve terminals contacting orexin-positive lateral hypothalamic neurons was quantified using electron microscopy in three groups of mice (n = 8 per group): Sham/noninjured controls, TBI without BCAA supplementation, and TBI with BCAA supplementation (given for 5 days, 48 hr post-TBI). Glutamate and GABA were also quantified within the cortical penumbral region (layer VIb) adjacent to the TBI lesion. Results In the hypothalamus and cortex, TBI decreased relative glutamate density in presynaptic terminals making axodendritic contacts. However, BCAA supplementation only restored relative glutamate density within presynaptic terminals contacting orexin-positive hypothalamic neurons. BCAA supplementation did not change relative glutamate density in presynaptic terminals making axosomatic contacts, or relative GABA density in presynaptic terminals making axosomatic or axodendritic contacts, within either the hypothalamus or cortex. Conclusions These results suggest TBI compromises orexin neuron function via decreased glutamate density and highlight BCAA supplementation as a potential therapy to restore glutamate density to orexin neurons.

A patent foramen ovale (PFO), present in ∼40% of the general population, is a potential source of right-to-left shunt that can impair pulmonary gas exchange efficiency [i.e., increase the alveolar-to-arterial Po2 difference (A-aDO2)]. Prior studies investigating human acclimatization to high-altitude with A-aDO2 as a key parameter have not investigated differences between subjects with (PFO+) or without a PFO (PFO−). We hypothesized that in PFO+ subjects A-aDO2 would not improve (i.e., decrease) after acclimatization to high altitude compared with PFO− subjects. Twenty-one (11 PFO+) healthy sea-level residents were studied at rest and during cycle ergometer exercise at the highest iso-workload achieved at sea level (SL), after acute transport to 5,260 m (ALT1), and again at 5,260 m after 16 days of high-altitude acclimatization (ALT16). In contrast to PFO− subjects, PFO+ subjects had 1) no improvement in A-aDO2 at rest and during exercise at ALT16 compared with ALT1, 2) no significant increase in resting alveolar ventilation, or alveolar Po2, at ALT16 compared with ALT1, and consequently had 3) an increased arterial Pco2 and decreased arterial Po2 and arterial O2 saturation at rest at ALT16. Furthermore, PFO+ subjects had an increased incidence of acute mountain sickness (AMS) at ALT1 concomitant with significantly lower peripheral O2 saturation (SpO2). These data suggest that PFO+ subjects have increased susceptibility to AMS when not taking prophylactic treatments, that right-to-left shunt through a PFO impairs pulmonary gas exchange efficiency even after acclimatization to high altitude, and that PFO+ subjects have blunted ventilatory acclimatization after 16 days at altitude compared with PFO− subjects.

Intrapulmonary arteriovenous anastomoses (IPAVA) are large diameter (>50 μm) vascular conduits, present in >95% of healthy humans. Because IPAVA are large diameter pathways that allow blood flow to bypass the pulmonary capillary network, blood flow through IPAVA (QIPAVA) can permit the transpulmonary passage of particles larger than pulmonary capillaries. IPAVA have been known to exist for over 50 years, but their physiological and clinical significance are still being established; although, currently suggested roles for QIPAVA include allowing emboli to reach the systemic circulation and providing a source of shunt. Studying QIPAVA is an important area of research and as the suggested roles become better established, detecting and quantifying QIPAVA may become significantly more important in the clinic. Several techniques that can be used to quantify and/or detect QIPAVA in animals, ex vivo human/animal lungs, and intact healthy humans; microspheres, radiolabeled macroaggregated albumin particles, and saline contrast echocardiography, are reviewed with limitations and advantages to each. The current body of literature using these techniques to study QIPAVA in animals, ex vivo lungs, and healthy humans has established conditions when QIPAVA is present, such as during exercise or with arterial hypoxemia and conditions when QIPAVA is absent, such as at rest or during exercise breathing 100% O2 . Many of these physiological studies have direct application to patient populations and we discuss each of these findings in the context of their potential to influence the clinical utility, and interpretation, of the results from these techniques highlighted in this review.

Intrapulmonary arteriovenous anastomoses (IPAVA) have been known to exist in human lungs for over 60 years. The majority of the work in this area has largely focused on characterizing the conditions in which IPAVA blood flow (QIPAVA) is either increased, e.g. during exercise, acute normobaric hypoxia, and the intravenous infusion of catecholamines, or absent/decreased, e.g. at rest and in all conditions with alveolar hyperoxia (FIO2 = 1.0). Additionally, QIPAVA is present in utero and shortly after birth, but is reduced in older (>50 years) adults during exercise and with alveolar hypoxia, suggesting potential developmental origins and an effect of age. The physiological and pathophysiological roles of QIPAVA are only beginning to be understood and therefore these data remain controversial. Although evidence is accumulating in support of important roles in both health and disease, including associations with pulmonary arterial pressure, and adverse neurological sequelae, there is much work that remains to be done to fully understand the physiological and pathophysiological roles of IPAVA. The development of novel approaches to studying these pathways that can overcome the limitations of the currently employed techniques will greatly help to better quantify QIPAVA and identify the consequences of QIPAVA on physiological and pathophysiological processes. Nevertheless, based on currently published data, our proposed working model is that QIPAVA occurs due to passive recruitment under conditions of exercise and supine body posture, but can be further modified by active redistribution of pulmonary blood flow under hypoxic and hyperoxic conditions.

Several methods exist to study intrapulmonary arteriovenous anastomoses (IPAVA) in humans. Transthoracic saline contrast echocardiography (TTSCE), i.e., bubble scores, is minimally-invasive, but cannot be used to quantify the magnitude of blood flow through IPAVA (QIPAVA). Radiolabeled macroaggregates of albumin (99mTc-MAA) have been used to quantify QIPAVA in humans, but this requires injection of radioactive particles. Previous work has shown agreement between 99mTc-MAA and TTSCE, but this has not been tested simultaneously in the same group of subjects. Thus, the purpose of this study was to determine if there was a relationship between QIPAVA quantified with 99mTc-MAA and bubble scores obtained with TTSCE. To test this, we used 99mTc-MAA and TTSCE to quantify and detect QIPAVA at rest and during exercise in humans. QIPAVA significantly increased from rest to exercise using 99mTc-MAA and TTSCE and there was a moderately-strong, but significant relationship between methods. Our data suggest that high bubble scores generally correspond with large QIPAVA quantified with 99mTc-MAA during exercise.

Adults born very to extremely preterm, with or without bronchopulmonary dysplasia (BPD), have obstructive lung disease, but it is unknown whether this results in respiratory limitations, such as mechanical constraints to Vt expansion during exercise leading to intolerable dyspnea and reduced exercise tolerance, as it does in patients with chronic obstructive pulmonary disease.To test the hypothesis that adult survivors of preterm birth (≤32 wk gestational age) with (n = 20) and without BPD (n = 15) with reduced exercise capacity demonstrate clinically important respiratory limitations at near-maximal exercise compared with full-term control subjects (n = 20).Detailed ventilatory and sensory measurements were made before and during exercise on all patients in the three study groups.During exercise at 90% of peak [Formula: see text]o2 ([Formula: see text]o2peak), inspiratory reserve volume decreased to ∼0.5 L in all groups, but this occurred at significantly lower absolute workloads and [Formula: see text]e in ex-preterm subjects with and without BPD compared with full-term control subjects. Severe dyspnea was present and similar at comparable [Formula: see text]e between all groups, but leg discomfort at comparable workloads was greater in ex-preterm subjects with and without BPD compared with control subjects. At 50 to 90% of [Formula: see text]o2peak, exercise-induced expiratory flow limitation was significantly greater in ex-preterm subjects with BPD compared with ex-preterm subjects without BPD and control subjects. The degree of expiratory flow limitation in ex-preterm subjects with and without BPD was significantly related to neonatal O2 therapy duration.Severe dyspnea and leg discomfort associated with critical constraints on Vt expansion may lead to reduced exercise tolerance in adults born very or extremely preterm, whether or not their birth was complicated by BPD and despite differences in expiratory flow limitation. In this regard, adults born very or extremely preterm have respiratory limitations to exercise similar to patients with chronic obstructive pulmonary disease.

New Findings What is the central question of this study? Compared with exercise while breathing room air, blood flow through intrapulmonary arteriovenous anastomoses during exercise while breathing 100% O2 is prevented/reduced, presumably due to vasoconstriction of these vessels. We sought to investigate the effect of sildenafil, nifedipine and acetazolamide, which are known modulators of pulmonary vascular tone, on the hyperoxia-induced reduction in blood flow through intrapulmonary arteriovenous anastomoses during exercise. What is the main finding and its importance? We show that,independently, sildenafil, nifedipine and acetazolamide do not prevent the hyperoxia-induced reduction in blood flow through intrapulmonary arteriovenous anastomoses during exercise. These data provide the first insight into the regulation of intrapulmonary arteriovenous anastomoses during exercise while breathing 100% O2. Blood flow through intrapulmonary arteriovenous anastomoses (IPAVAs) is known to increase in healthy humans during exercise while breathing room air, but is prevented or significantly reduced during exercise while breathing 100% O2, potentially due to vasoconstriction of IPAVAs. Thus, pharmacological interventions that target known pathways regulating the cardiopulmonary circulation may be able to prevent the hyperoxia-induced reduction in IPAVA blood flow (Q IPAVA ) during exercise. In nine healthy human subjects, we investigated the effects of sildenafil (100 mg p.o.), nifedipine (20 mg p.o.) and acetazolamide (250 mg p.o. three times a day for 3 days) on Q IPAVA at rest and during cycle ergometer exercise at 50, 100, 150, 200 and 250 W, while breathing room air (normoxia) and 100% O2 (hyperoxia). Transthoracic saline contrast echocardiography and a 0–5 bubble scoring system were used to detect and assess Q IPAVA qualitatively; ultrasound was used to assess the blood flow velocity oftricuspid regurgitation and the left ventricular outflow tract blood flow to calculate pulmonary artery systolic pressure (PASP) and cardiac output, respectively. Without drugs, bubble scores increased significantly to ≥2 at 150 W in normoxia and to ≤2 at 200 W in hyperoxia. Only nifedipine consistently increased cardiac output at rest and during low-intensity exercise in normoxia and hyperoxia. However, there was no detectable effect of any drug on Q IPAVA ; specifically, bubble scores were the same during exercise in either normoxia or hyperoxia. Accordingly, the reduction in Q IPAVA during exercise while breathing 100% O2 is likely not to be due to the independent pharmacological mechanisms of action associated with sildenafil, nifedipine or acetazolamide.

Blood flow through intrapulmonary arteriovenous anastomoses (IPAVAs) has been demonstrated to increase in healthy humans during a variety of conditions; however, whether or not this blood flow represents a source of venous admixture (Q VA /QT) that impairs pulmonary gas exchange efficiency (i.e. increases the alveolar-to-arterial PO2 difference (A-aDO2)) remains controversial and unknown. We hypothesized that blood flow through IPAVAs does provide a source of Q VA /QT. To test this, blood flow through IPAVAs was increased in healthy humans at rest breathing room air and 40% O2: (1) during intravenous adrenaline (epinephrine) infusion at 320 ng kg(-1) min(-1) (320 ADR), and (2) with vagal blockade (2 mg atropine), before and during intravenous adrenaline infusion at 80 ng kg(-1) min(-1) (ATR + 80 ADR). When breathing room air the A-aDO2 increased by 6 ± 2 mmHg during 320 ADR and by 5 ± 2 mmHg during ATR + 80 ADR, and the change in calculated Q VA /QT was +2% in both conditions. When breathing 40% O2, which minimizes contributions from diffusion limitation and alveolar ventilation-to-perfusion inequality, the A-aDO2 increased by 12 ± 7 mmHg during 320 ADR, and by 9 ± 6 mmHg during ATR + 80 ADR, and the change in calculated Q VA /QT was +2% in both conditions. During 320 ADR cardiac output (QT) and pulmonary artery systolic pressure (PASP) were significantly increased; however, during ATR + 80 ADR only QT was significantly increased, yet blood flow through IPAVAs as detected with saline contrast echocardiography was not different between conditions. Accordingly, we suggest that blood flow through IPAVAs provides a source of intrapulmonary shunt, and is mediated primarily by increases in QT rather than PASP.

Our purpose was to report the prevalence of healthy, young, asymptomatic humans who demonstrate left heart contrast at rest, breathing room air. We evaluated 176 subjects (18-41 years old) using transthoracic saline contrast echocardiography. Left heart contrast appearing ≤3 cardiac cycles, consistent with a patent foramen ovale (PFO), was detected in 67 (38%) subjects. Left heart contrast appearing >3 cardiac cycles, consistent with the transpulmonary passage of contrast, was detected in 49 (28%) subjects. Of these 49 subjects, 31 were re-evaluated after breathing 100% O2 for 10-15min and 6 (19%) continued to demonstrate the transpulmonary passage of contrast. Additionally, 18 of these 49 subjects were re-evaluated in the upright position and 1 (5%) continued to demonstrate the transpulmonary passage of contrast. These data suggest that ~30% of healthy, young, asymptomatic subjects demonstrate the transpulmonary passage of contrast at rest which is reduced by breathing 100% O2 and assuming an upright body position.

The mechanism or mechanisms that cause intrapulmonary arteriovenous anastomoses (IPAVA) to either open during exercise in subjects breathing room air and at rest when breathing hypoxic gas mixtures, or to close during exercise while breathing 100% oxygen, remain unknown. During conditions when IPAVA are open, plasma epinephrine (EPI) and dopamine (DA) concentrations both increase, potentially representing a common mechanism. The purpose of this study was to determine whether EPI or DA infusions open IPAVA in resting subjects breathing room air and, subsequently, 100% oxygen. We hypothesized that these catecholamine infusions would open IPAVA. We performed saline-contrast echocardiography in nine subjects without a patent foramen ovale before and during serial EPI and DA infusions while breathing room air and then while breathing 100% oxygen. Bubble scores (0–5) were assigned based on the number and spatial distribution of bubbles in the left ventricle. Pulmonary artery systolic pressure (PASP) was estimated using Doppler ultrasound, while cardiac output (QC) was measured using echocardiography. Bubble scores were significantly greater during EPI infusions of 80–320 ng·kg−1·min−1 compared with baseline when subjects breathed room air; however, bubble scores did not increase when they breathed 100% oxygen. At comparable QC and PASP, intravenous DA (16 μg·kg−1·min−1) and EPI (40 ng·kg−1·min−1) resulted in identical bubble scores. Subsequent studies revealed that β-blockade did not prevent hypoxia-induced opening of IPAVA. We suggest that increases in QC or PASP (or both) secondary to EPI or DA infusions open IPAVA in normoxia. The closing mechanism associated with breathing 100% oxygen is independent from the opening mechanisms.

Concern has been raised that altering the fraction of inspired O2 (FiO2) 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 FiO2. The present study determined whether the gaseous component used for saline contrast echocardiography affects the detection of exercise-induced intrapulmonary arteriovenous shunt under varying FiO2. Twelve healthy human subjects (6 men, 6 women) performed three 11-min bouts of cycle ergometer exercise at 60% peak O2 consumption (V̇o2peak) in normoxia, hypoxia (FiO2 = 0.14), and hyperoxia (FiO2 = 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 FiO2 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 FiO2. These results suggest that in vivo gas bubbles are less susceptible to changes in the ambient external environment than previously suspected.

Sources of venous admixture (QVA/QT) that impair pulmonary gas exchange efficiency, defined by an increased alveolar-arterial PO2 difference (AaDO2), are ventilation-perfusion inequality (VA/Q), diffusion limitation, and shunt. Blood flow through intrapulmonary arteriovenous anastomoses (QIPAVA) increases QVA/QT and the AaDO2. However, it is unclear whether increased cardiac output (QT) or pulmonary artery systolic pressure (PASP) cause the increase in QIPAVA. We hypothesized that an increase in QT alone would increase QIPAVA resulting in an increased AaDO2 at rest breathing room air and 40% O2 to prevent contributions from diffusion and VA/Q. Epinephrine, i.v. at 320 ng/kg/min (EPI), and low dose epinephrine (80 ng/kg/min) combined with 2 mg of atropine (EPI+ATR) were used in healthy human subjects (n=5) to increase QT. When breathing either room air or 40% O2, EPI and EPI+ATR increased QT, (measured by acetylene uptake) from 7.8±1.0 to 13.3±3.4 L/min. Only EPI significantly increased PASP (to 54±14 mmHg...

Advances in perinatal care in the post surfactant era have increased survivability of infants born extremely preterm (

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

In their letter (Frise & Dorrington, 2015), Drs Frise and Dorrington have provided a number of critiques on our recent study, entitled ‘Increased cardiac output, not pulmonary artery systolic pressure, increases intrapulmonary shunt in healthy humans breathing room air and 40% O2’ (Elliott et al. 2014). Specifically, they have concerns, ‘that the title and content of [our] manuscript raise two fundamental issues related to fluid mechanics.’ First, it was most appropriate to specify ‘pulmonary artery systolic pressure’ (PASP) in the title because Doppler ultrasound was used to determine pulmonary pressure and we did not want readers to think that we had measured anything but PASP. This technique measures the velocity of retrograde blood flow across the tricuspid valve during systole, and thus the peak blood pressure developed in the pulmonary artery during systole can be calculated using the modified Bernoulli equation. The potential that ‘systolic [pulmonary] pressure’ per se, is the period of the cardiac cycle responsible for increasing intrapulmonary arteriovenous anastomoses (IPAVAs) blood flow () is neither implied from the title, nor discussed in our manuscript. Second, Drs Frise and Dorrington state: ‘cardiac output cannot directly increase an intrapulmonary shunt, since the latter is simply a flow of blood down some tubes.’ In our opinion, this is an oversimplification that ignores the many physiological intricacies of the regulation of pulmonary blood flow. For example, pulmonary blood flow is dependent upon a myriad of factors, including, but not limited to, gravity, architecture of the pulmonary vascular tree, oxygen tension, and may even be determined by precapillary sphincters associated with supernumerary vessels that are still poorly understood. Clearly pressure at the beginning of the tube needs to be greater than the pressure at the end of the tube to facilitate orthograde blood flow. However, in one of our experimental conditions, that combined atropine (ATR) and intravenous (i.v.) adrenaline (ADR) at 80 ng kg−1 min−1 (ATR + 80 ADR), PASP was not statistically increased, and therefore we could not state that there was an increase in pulmonary pressure; had we done so, we would have been lying and likely to be challenged by the reviewers, and rightly so, for over-interpreting or misinterpreting our data. Additionally, when cardiac output () increases, as occurs during low intensity exercise, there is recruitment of under- and/or non-perfused pulmonary blood vessels, which may include IPAVAs. In this way, increases in may be able to recruit IPAVAs without significant increases in pulmonary pressure and subsequently result in a shunt, if blood flow through these pathways does not participate in gas exchange. Several other studies, referenced in our manuscript, demonstrate an increase in right-to-left shunt secondary to increases in . Third, Drs Frise and Dorrington state: ‘It would seem desirable to avoid the use of vasoactive drugs, which might directly alter IPAVA tone independent of an effect on cardiac output.’ Central to this concern is the assumption that ATR and ADR specifically affect the vascular tone of IPAVAs, and do not alter the tone of the rest of the pulmonary vasculature. For example, the observation of increased without significant increases in PASP could be explained independent of any change in the vascular tone of IPAVAs if either ATR caused pulmonary vasodilatation of the conventional pulmonary circulation (not IPAVAs), or the lower dose of ADR provided less of a vasoconstrictor influence on the rest of the conventional pulmonary circulation – possibilities that we detailed in our manuscript. Our data neither imply, nor do we claim, that there was a ‘constant drop in pressure across the tubes [IPAVAs]’ during ATR + 80 ADR. We also addressed this issue by providing references to work where other authors concluded that, ‘…the increase in shunt from pharmacologically increased is probably not due to vasoconstrictor or vasodilator activity of these drugs as the increase in shunt is observed when is increased via mechanical means as well.’ A final statement from Drs Frise and Dorrington was that the complexity of our study ‘…makes it difficult to draw any conclusions about mechanisms determining flow through IPAVA…’ and quoted us as follows: ‘considering the unique experimental conditions used in the present study, it is difficult to extrapolate these findings to their potential physiological relevance.’ The entire quote from our work was: ‘Considering the unique experimental conditions used in the present study, it is difficult to extrapolate these findings to their potential physiological relevance during other conditions known to increase blood flow through IPAVAs, such as exercise.’ Again, we acknowledged the complexities of the regulation of pulmonary blood flow while being careful not to misinterpret or over-interpret our data. We recognize the complexities of quantifying pressure, flow and in humans. As such, we specifically commented in our paper that: ‘Nevertheless, future work in this area will be helpful in clarifying the roles of pressure and flow under other experimental conditions such as hypoxia and exercise.’ This statement very clearly acknowledges that our findings might not be applicable to other conditions. In summary, our manuscript measured PASP and and provides evidence that: (1) is associated with an impairment in pulmonary gas exchange efficiency, i.e. an increase in the alveolar-to-arterial difference (A-aDO2), and calculated volume of venous admixture during unique and tightly controlled experimental conditions that reduce/eliminate the potential contribution of alveolar ventilation-to-perfusion inequality and diffusion limitation to the A-aDO2, and (2) primarily depends on increases in , as it occurred independent of significant increases in PASP. These data provide the impetus to investigate the relative importance of and mean pulmonary arterial pressure or pulmonary vascular resistance with respect to , and we are actively working on this. For more information on this exciting area of physiology, and a description of the various physiological conditions in which is, and is not, detected, we refer the reader to very recent reviews (Duke et al. 2014; Lovering et al. 2015) of the relevant literature to date on this topic.

Embolic insults account for a significant number of neurologic sequelae following many routine surgical procedures. Clearly, these post-intervention embolic events are a serious public health issue as they are potentially life altering. However, the pathway these emboli utilize to bypass the pulmonary microcirculatory sieve in patients without an intracardiac shunt such as an atrial septal defect or patent foramen ovale, remains unclear. In the absence of intracardiac routes and large diameter pulmonary arteriovenous malformations, inducible large diameter intrapulmonary arteriovenous anastomoses in otherwise healthy adult humans may prove to be the best explanation. Our group and others have demonstrated that inducible large diameter intrapulmonary arteriovenous anastomoses are closed at rest but can open during hyperdynamic conditions such as exercise in more than 90% of healthy humans. Furthermore, the patency of these intrapulmonary anastomoses can be modulated through the fraction of inspired oxygen and by body positioning. Of particular clinical interest, there appears to be a strong association between arterial hypoxemia and neurologic insults, suggesting a breach in the filtering ability of the pulmonary microvasculature under these conditions. In this review, we present evidence demonstrating the existence of inducible intrapulmonary arteriovenous anastomoses in healthy humans that are modulated by exercise, oxygen tension and body positioning. Additionally, we identify several clinical conditions associated with both arterial hypoxemia and an increased risk for embolic insults. Finally, we suggest some precautionary measures that should be taken during interventions to keep intrapulmonary arteriovenous anastomoses closed in order to prevent or reduce the incidence of paradoxical embolism.

Intrapulmonary arteriovenous (IPAV) shunting has been shown to occur at rest in some subjects breathing a hypoxic gas mixture [fraction of inspired oxygen (FiO2) = 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 (FiO2 = 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 FiO2 = 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 FiO2 = 0.12 and 0.10. Shunt scores correlated with peripheral measurements of arterial oxygen saturation (SpO2) ( r w = −0.67) and PASP ( r w = 0.44), despite an increased shunt score but no increase in PASP while breathing an FiO2 = 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 FiO2 = 0.10 for 30 min.