Estimates of actual and potential lives saved in the United States from the use of COVID-19 convalescent plasma.

In the Spring of 2020, the United States of America (USA) deployed COVID-19 convalescent plasma (CCP) to treat hospitalized patients. Over 500,000 patients were treated with CCP during the first year of the pandemic. In this study, we estimated the number of actual inpatient lives saved by CCP treatment in the United States of America based on CCP weekly use, weekly national mortality data, and CCP mortality reduction data from meta-analyses of randomized controlled trials and real-world data. We also estimate the potential number of lives saved if CCP had been deployed for 100% of hospitalized patients or used in 15 to 75% of outpatients. Depending on the assumptions modeled in stratified analyses, we estimated that CCP saved between 16,476 and 66,296 lives. The CCP ideal use might have saved as many as 234,869 lives and prevented 1,136,133 hospitalizations. CCP deployment was a successful strategy for ameliorating the impact of the COVID-19 pandemic in the USA. This experience has important implications for convalescent plasma use in future infectious disease emergencies.

Central α2-adrenergic mechanisms regulate human sympathetic neuronal discharge strategies.

The present study investigated the impact of central α2-adrenergic mechanisms on sympathetic action potential (AP) discharge, recruitment and latency strategies. We used the microneurographic technique to record muscle sympathetic nerve activity and a continuous wavelet transform to investigate postganglionic sympathetic AP firing during a baseline condition and an infusion of a α2-adrenergic receptor agonist, dexmedetomidine (10 min loading infusion of 0.225 µg kg-1; maintenance infusion of 0.1-0.5 µg kg h-1) in eight healthy individuals (28 ± 7 years, five females). Dexmedetomidine reduced mean pressure (92 ± 7 to 80 ± 8 mmHg, P < 0.001) but did not alter heart rate (61 ± 13 to 60 ± 14 bpm; P = 0.748). Dexmedetomidine reduced sympathetic AP discharge (126 ± 73 to 27 ± 24 AP 100 beats-1, P = 0.003) most strongly for medium-sized APs (normalized cluster 2: 21 ± 10 to 5 ± 5 AP 100 beats-1; P < 0.001). Dexmedetomidine progressively de-recruited sympathetic APs beginning with the largest AP clusters (12 ± 3 to 7 ± 2 clusters, P = 0.002). Despite de-recruiting large AP clusters with shorter latencies, dexmedetomidine reduced AP latency across remaining clusters (1.18 ± 0.12 to 1.13 ± 0.13 s, P = 0.002). A subset of six participants performed a Valsalva manoeuvre (20 s, 40 mmHg) during baseline and the dexmedetomidine infusion. Compared to baseline, AP discharge (Δ 361 ± 292 to Δ 113 ± 155 AP 100 beats-1, P = 0.011) and AP cluster recruitment elicited by the Valsalva manoeuvre were lower during dexmedetomidine (Δ 2 ± 1 to Δ 0 ± 2 AP clusters, P = 0.041). The reduction in sympathetic AP latency elicited by the Valsalva manoeuvre was not affected by dexmedetomidine (Δ -0.09 ± 0.07 to Δ -0.07 ± 0.14 s, P = 0.606). Dexmedetomidine reduced baroreflex gain, most strongly for medium-sized APs (normalized cluster 2: -6.0 ± 5 to -1.6 ± 2 % mmHg-1; P = 0.008). These data suggest that α2-adrenergic mechanisms within the central nervous system modulate sympathetic postganglionic neuronal discharge, recruitment and latency strategies in humans. KEY POINTS: Sympathetic postganglionic neuronal subpopulations innervating the human circulation exhibit complex patterns of discharge, recruitment and latency. However, the central neural mechanisms governing sympathetic postganglionic discharge remain unclear. This microneurographic study investigated the impact of a dexmedetomidine infusion (α2-adrenergic receptor agonist) on muscle sympathetic postganglionic action potential (AP) discharge, recruitment and latency patterns. Dexmedetomidine infusion inhibited the recruitment of large and fast conducting sympathetic APs and attenuated the discharge of medium sized sympathetic APs that fired during resting conditions and the Valsalva manoeuvre. Dexmedetomidine infusion elicited shorter sympathetic AP latencies during resting conditions but did not affect the reductions in latency that occurred during the Valsalva manoeuvre. These data suggest that α2-adrenergic mechanisms within the central nervous system modulate sympathetic postganglionic neuronal discharge, recruitment and latency strategies in humans.

Convalescent Plasma Antibody Levels and the Risk of Death from Covid-19.

BACKGROUND: Convalescent plasma has been widely used to treat coronavirus disease 2019 (Covid-19) under the presumption that such plasma contains potentially therapeutic antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that can be passively transferred to the plasma recipient. Whether convalescent plasma with high antibody levels rather than low antibody levels is associated with a lower risk of death is unknown. METHODS: In a retrospective study based on a U.S. national registry, we determined the anti-SARS-CoV-2 IgG antibody levels in convalescent plasma used to treat hospitalized adults with Covid-19. The primary outcome was death within 30 days after plasma transfusion. Patients who were enrolled through July 4, 2020, and for whom data on anti-SARS-CoV-2 antibody levels in plasma transfusions and on 30-day mortality were available were included in the analysis. RESULTS: Of the 3082 patients included in this analysis, death within 30 days after plasma transfusion occurred in 115 of 515 patients (22.3%) in the high-titer group, 549 of 2006 patients (27.4%) in the medium-titer group, and 166 of 561 patients (29.6%) in the low-titer group. The association of anti-SARS-CoV-2 antibody levels with the risk of death from Covid-19 was moderated by mechanical ventilation status. A lower risk of death within 30 days in the high-titer group than in the low-titer group was observed among patients who had not received mechanical ventilation before transfusion (relative risk, 0.66; 95% confidence interval [CI], 0.48 to 0.91), and no effect on the risk of death was observed among patients who had received mechanical ventilation (relative risk, 1.02; 95% CI, 0.78 to 1.32). CONCLUSIONS: Among patients hospitalized with Covid-19 who were not receiving mechanical ventilation, transfusion of plasma with higher anti-SARS-CoV-2 IgG antibody levels was associated with a lower risk of death than transfusion of plasma with lower antibody levels. (Funded by the Department of Health and Human Services and others; ClinicalTrials.gov number, NCT04338360.).

Human sympathetic neuronal discharge and recruitment patterns regulate neuropeptide Y bioavailability.

What is the purpose of sympathetic neuronal action potential (AP) discharge and recruitment patterns for human vascular regulation? This study tested the hypothesis that sympathetic neuronal discharge and recruitment patterns regulate neuropeptide Y (NPY) bioavailability. We used microneurography to record muscle sympathetic nerve activity (MSNA) and a continuous wavelet transform to detect sympathetic APs during a baseline condition and intravenous dexmedetomidine infusion (α2-adrenergic agonist, 10 min loading infusion of 0.225 µg kg-1; maintenance infusion of 0.1-0.5 µg kg h-1) in six healthy individuals (5 females, 27 ± 6 years). Arterial blood samples provided NPY (enzyme-linked immunosorbent assay) and norepinephrine (Liquid Chromatography Tandem Mass Spectrometry) levels during baseline and the dexmedetomidine maintenance infusion. Linear mixed model regressions assessed the relationships between AP discharge, recruitment, and neurotransmitter levels. Across baseline and the dexmedetomidine condition, NPY levels were positively related to mean arterial pressure (ß = 1.63 [0.34], P = 0.002), total AP clusters (ß = 0.90 [0.22], P = 0.005), and AP frequency (ß = 0.11 [0.03], P = 0.003). Norepinephrine levels were not related to mean arterial pressure (ß = 0.03 [0.02], P = 0.133) but were positively related to total AP clusters (ß = 19.50 [7.07], P = 0.030) and AP frequency (ß = 2.66 [0.81], P = 0.014). These data suggest that sympathetic neuronal discharge and recruitment patterns regulate NPY and norepinephrine bioavailability in healthy adults. As such, sympathetic neuronal firing strategies are important for human vascular regulation.

Comparing the compensatory reserve metric obtained from invasive arterial measurements and photoplethysmographic volume-clamp during simulated hemorrhage.

PURPOSE: The compensatory reserve metric (CRM) is a novel tool to predict cardiovascular decompensation during hemorrhage. The CRM is traditionally computed using waveforms obtained from photoplethysmographic volume-clamp (PPGVC), yet invasive arterial pressures may be uniquely available. We aimed to examine the level of agreement of CRM values computed from invasive arterial-derived waveforms and values computed from PPGVC-derived waveforms. METHODS: Sixty-nine participants underwent graded lower body negative pressure to simulate hemorrhage. Waveform measurements from a brachial arterial catheter and PPGVC finger-cuff were collected. A PPGVC brachial waveform was reconstructed from the PPGVC finger waveform. Thereafter, CRM values were computed using a deep one-dimensional convolutional neural network for each of the following source waveforms; (1) invasive arterial, (2) PPGVC brachial, and (3) PPGVC finger. Bland-Altman analyses were used to determine the level of agreement between invasive arterial CRM values and PPGVC CRM values, with results presented as the Mean Bias [95% Limits of Agreement]. RESULTS: The mean bias between invasive arterial- and PPGVC brachial CRM values at rest, an applied pressure of -45mmHg, and at tolerance was 6% [-17%, 29%], 1% [-28%, 30%], and 0% [-25%, 25%], respectively. Additionally, the mean bias between invasive arterial- and PPGVC finger CRM values at rest, applied pressure of -45mmHg, and tolerance was 2% [-22%, 26%], 8% [-19%, 35%], and 5% [-15%, 25%], respectively. CONCLUSION: There is generally good agreement between CRM values obtained from invasive arterial waveforms and values obtained from PPGVC waveforms. Invasive arterial waveforms may serve as an alternative for computation of the CRM.

Attenuated cardiac autonomic function in humans with high-affinity hemoglobin and compensatory polycythemia.

During hypoxic exposure, humans with high-affinity hemoglobin (and compensatory polycythemia) have blunted increases in heart rate compared with healthy humans with typical oxyhemoglobin dissociation curves. This response may be associated with altered autonomic control of heart rate. Our hypothesis-generating study aimed to investigate cardiac baroreflex sensitivity and heart rate variability among nine humans with high-affinity hemoglobin [6 females, O2 partial pressure at 50% [Formula: see text] (P50) = 16 ± 1 mmHg] compared with 12 humans with typical affinity hemoglobin (6 F, P50 = 26 ± 1 mmHg). Participants breathed normal room air for a 10-min baseline, followed by 20 min of isocapnic hypoxic exposure, designed to lower the arterial partial pressure O2 ([Formula: see text]) to ∼50 mmHg. Beat-by-beat heart rate and arterial blood pressure were recorded. Data were averaged in 5-min periods throughout the hypoxia exposure, beginning with the last 5 min of baseline in normoxia. Spontaneous cardiac baroreflex sensitivity and heart rate variability were determined using the sequence method and the time and frequency domain analyses, respectively. Cardiac baroreflex sensitivity was lower in humans with high-affinity hemoglobin than controls at baseline and during isocapnic hypoxic exposure (normoxia: 7 ± 4 vs. 16 ± 10 ms/mmHg, hypoxia minutes 15-20: 4 ± 3 vs. 14 ± 11 ms/mmHg; group effect: P = 0.02, high-affinity hemoglobin vs. control, respectively). Heart rate variability calculated in both the time (standard deviation of the N-N interval) and frequency (low frequency) domains was lower in humans with high-affinity hemoglobin than in controls (all P < 0.05). Our data suggest that humans with high-affinity hemoglobin may have attenuated cardiac autonomic function.

Effects of dietary nitrate supplementation on peak power output: Influence of supplementation strategy and population.

Increasing evidence indicates that dietary nitrate supplementation has the potential to increase muscular power output during skeletal muscle contractions. However, there is still a paucity of data characterizing the impact of different nitrate dosing regimens on nitric oxide bioavailability and its potential ergogenic effects across various population groups. This review discusses the potential influence of different dietary nitrate supplementation strategies on nitric oxide bioavailability and muscular peak power output in healthy adults, athletes, older adults and some clinical populations. Effect sizes were calculated for peak power output and absolute and/or relative nitrate doses were considered where applicable. There was no relationship between the effect sizes of peak power output change following nitrate supplementation and when nitrate dosage when considered in absolute or relative terms. Areas for further research are also recommended including a focus on nitrate dosing regimens that optimize nitric oxide bioavailability for enhancing peak power at times of increased muscular work in a variety of healthy and disease populations.

Effects of dietary nitrate supplementation on muscular power output: Influence of supplementation strategy and population.

Increasing evidence indicates that dietary nitrate supplementation has the potential to increase muscular power output during skeletal muscle contractions. However, there is still a paucity of data characterizing the impact of different nitrate dosing regimens on nitric oxide bioavailability its potential ergogenic effects across various population groups. This narrative review discusses the potential influence of different dietary nitrate supplementation strategies on nitric oxide bioavailability and muscular power output in healthy adults, athletes, older adults and some clinical populations. Areas for further research are also recommended including a focus individualized nitrate dosing regimens to optimize nitric oxide bioavailability and to promote muscular power enhancements in different populations.

The oxygen transport cascade and exercise: Lessons from comparative physiology.

Studies of animal physiology not only provide valuable knowledge for the species in question, but also offer insights into human physiology. This thought is best highlighted by the 'Krogh Principle', which states "for many problems there is an animal on which it can be most conveniently studied". This graphical review focuses on three distinct stages of the oxygen transport cascade in which human exercise physiology knowledge has been enhanced by studies carried out in animal models. We begin by exploring ventilation, and the detrimental effects of cold, dry air on the airways in two sets of elite athletes, the cross-country skier and the racing sled dog. We then discuss the transport of oxygen via hemoglobin in humans and deer mice with relatively shifted oxygen dissociation curves. Finally, we consider the technical difficulties of measuring respiratory muscle blood flow in exercising humans and how an equine model can provide an understanding of the distribution of blood flow during exercise. These cases illustrate the complementary nature of physiological studies across species.

Muscle oxygenation during normoxic and hypoxic cycling exercise in humans with high-affinity haemoglobin.

NEW FINDINGS: What is the central question of this study? Do humans with high-affinity haemoglobin (HAH) demonstrate attenuated skeletal muscle deoxygenation during normoxic and hypoxic exercise? What is the main finding and its importance? Examination of near-infrared spectroscopy-derived muscle oxygenation profiles suggests that fractional oxygen extraction is blunted during hypoxic exercise in humans with HAH compared with control subjects. However, muscle tissue oxygen saturation levels were higher in humans with HAH during exercise in normoxia compared with control subjects. These alterations in fractional oxygen extraction in humans with HAH might influence blood flow regulation and exercise capacity during hypoxia. ABSTRACT: Recently, researchers in our laboratory have shown that humans with genetic mutations resulting in high-affinity haemoglobin (HAH) demonstrate better maintained aerobic capacity and peak power output during hypoxic exercise versus normoxic exercise in comparison to humans with normal-affinity haemoglobin. However, the influence of HAH on tissue oxygenation within exercising muscle during normoxia and hypoxia is unknown. Therefore, we examined near-infrared spectroscopy-derived oxygenation profiles of the vastus lateralis during graded cycling exercise in normoxia and hypoxia among humans with HAH (n = 5) and control subjects with normal-affinity haemoglobin (n = 12). The HAH group elicited a blunted increase of deoxygenated haemoglobin + myoglobin during hypoxic exercise compared with the control group (P = 0.03), suggesting reduced fractional oxygen extraction in the HAH group. In addition, the HAH group maintained a higher level of muscle tissue oxygen saturation during normoxic exercise (HAH, 75 ± 4% vs. controls, 65 ± 3%, P = 0.049) and there were no differences between groups in muscle tissue oxygen saturation during hypoxic exercise (HAH, 68 ± 3% vs. controls, 68 ± 2%, P = 0.943). Overall, our results suggest that humans with HAH might demonstrate divergent patterns of fractional oxygen extraction during hypoxic exercise and elevated muscle tissue oxygenation during normoxic exercise compared with control subjects.

AI-Enabled Advanced Development for Assessing Low Circulating Blood Volume for Emergency Medical Care: Comparison of Compensatory Reserve Machine-Learning Algorithms.

The application of artificial intelligence (AI) has provided new capabilities to develop advanced medical monitoring sensors for detection of clinical conditions of low circulating blood volume such as hemorrhage. The purpose of this study was to compare for the first time the discriminative ability of two machine learning (ML) algorithms based on real-time feature analysis of arterial waveforms obtained from a non-invasive continuous blood pressure system (Finometer®) signal to predict the onset of decompensated shock: the compensatory reserve index (CRI) and the compensatory reserve metric (CRM). One hundred ninety-one healthy volunteers underwent progressive simulated hemorrhage using lower body negative pressure (LBNP). The least squares means and standard deviations for each measure were assessed by LBNP level and stratified by tolerance status (high vs. low tolerance to central hypovolemia). Generalized Linear Mixed Models were used to perform repeated measures logistic regression analysis by regressing the onset of decompensated shock on CRI and CRM. Sensitivity and specificity were assessed by calculation of receiver-operating characteristic (ROC) area under the curve (AUC) for CRI and CRM. Values for CRI and CRM were not distinguishable across levels of LBNP independent of LBNP tolerance classification, with CRM ROC AUC (0.9268) being statistically similar (p = 0.134) to CRI ROC AUC (0.9164). Both CRI and CRM ML algorithms displayed discriminative ability to predict decompensated shock to include individual subjects with varying levels of tolerance to central hypovolemia. Arterial waveform feature analysis provides a highly sensitive and specific monitoring approach for the detection of ongoing hemorrhage, particularly for those patients at greatest risk for early onset of decompensated shock and requirement for implementation of life-saving interventions.

Access to and safety of COVID-19 convalescent plasma in the United States Expanded Access Program: A national registry study.

BACKGROUND: The United States (US) Expanded Access Program (EAP) to coronavirus disease 2019 (COVID-19) convalescent plasma was initiated in response to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. While randomized clinical trials were in various stages of development and enrollment, there was an urgent need for widespread access to potential therapeutic agents. The objective of this study is to report on the demographic, geographical, and chronological characteristics of patients in the EAP, and key safety metrics following transfusion of COVID-19 convalescent plasma. METHODS AND FINDINGS: Mayo Clinic served as the central institutional review board for all participating facilities, and any US physician could participate as a local physician-principal investigator. Eligible patients were hospitalized, were aged 18 years or older, and had-or were at risk of progression to-severe or life-threatening COVID-19; eligible patients were enrolled through the EAP central website. Blood collection facilities rapidly implemented programs to collect convalescent plasma for hospitalized patients with COVID-19. Demographic and clinical characteristics of all enrolled patients in the EAP were summarized. Temporal patterns in access to COVID-19 convalescent plasma were investigated by comparing daily and weekly changes in EAP enrollment in response to changes in infection rate at the state level. Geographical analyses on access to convalescent plasma included assessing EAP enrollment in all national hospital referral regions, as well as assessing enrollment in metropolitan areas and less populated areas that did not have access to COVID-19 clinical trials. From April 3 to August 23, 2020, 105,717 hospitalized patients with severe or life-threatening COVID-19 were enrolled in the EAP. The majority of patients were 60 years of age or older (57.8%), were male (58.4%), and had overweight or obesity (83.8%). There was substantial inclusion of minorities and underserved populations: 46.4% of patients were of a race other than white, and 37.2% of patients were of Hispanic ethnicity. Chronologically and geographically, increases in the number of both enrollments and transfusions in the EAP closely followed confirmed infections across all 50 states. Nearly all national hospital referral regions enrolled and transfused patients in the EAP, including both in metropolitan and in less populated areas. The incidence of serious adverse events was objectively low (<1%), and the overall crude 30-day mortality rate was 25.2% (95% CI, 25.0% to 25.5%). This registry study was limited by the observational and pragmatic study design that did not include a control or comparator group; thus, the data should not be used to infer definitive treatment effects. CONCLUSIONS: These results suggest that the EAP provided widespread access to COVID-19 convalescent plasma in all 50 states, including for underserved racial and ethnic minority populations. The study design of the EAP may serve as a model for future efforts when broad access to a treatment is needed in response to an emerging infectious disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT#: NCT04338360.

Use of convalescent plasma in COVID-19 patients with immunosuppression.

In the absence of effective countermeasures, human convalescent plasma has been widely used to treat severe acute respiratory syndrome coronavirus 2, the causative agent of novel coronavirus disease 19 (COVID-19), including among patients with innate or acquired immunosuppression. However, the association between COVID-19-associated mortality in patients with immunosuppression and therapeutic use of convalescent plasma is unknown. We review 75 reports, including one large matched-control registry study of 143 COVID-19 patients with hematological malignancies, and 51 case reports and 23 case series representing 238 COVID-19 patients with immunosuppression. We review clinical features and treatment protocols of COVID-19 patients with immunosuppression after treatment with human convalescent plasma. We also discuss the time course and clinical features of recovery. The available data from case reports and case series provide evidence suggesting a mortality benefit and rapid clinical improvement in patients with several forms of immunosuppression following COVID-19 convalescent plasma transfusion. The utility of convalescent plasma or other forms of antibody therapy in immune-deficient and immune-suppressed patients with COVID-19 warrants further investigation.

Heat Versus Altitude Training for Endurance Performance at Sea Level.

Environmental stressors, such as heat or altitude, elicit dissimilar physiological adaptations to endurance training programs. Whether these differences (i.e., increased hemoglobin mass vs plasma volume) differentially influence performance is debated. We review data in support of our novel hypothesis, which proposes altitude as the preferred environmental training stimulus for elite endurance athletes preparing to compete in temperate, sea-level climates (5°C-18°C).

Experiments of nature and within species comparative physiology.

This graphical review highlights a focused application of a key principle ('Krogh Principle') identified by Nobel-prize winning physiologist Professor August Krogh (1874-1949) that states "for many problems there is an animal on which it can be most conveniently studied". We apply the Krogh Principle to human physiology by proposing that "for many problems there is a unique group of humans on which it can be most conveniently studied". As such, we present 5 unique human case studies. Case 1 discusses whether signals from exercising muscles cause blood pressure to rise using a patient with a spinal cord lesion. Case 2 investigates the role of the sympathetic nervous system in the blood pressure response to exercise using patients who have undergone sympathectomy for hypertension. Case 3 asks whether increases in blood lactate are necessary for the non-linear increase in breathing with heavy exercise using patients with McArdle's disease. Case 4 applies fundamental scaling principles from comparative physiology to elite athletes to investigate the role of body size on maximal aerobic capacity. Finally, Case 5 describes our recent work that investigates whether a left shift in the oxygen hemoglobin dissociation curve can facilitate hypoxic exercise using patients with left-shifted hemoglobinopathies. In summary, we have expanded the inter-species message of the August Krogh Principle and highlighted the need to search for odd examples and experiments of nature. In this context, observations from unusual humans are a source of insights into physiology, which may be translated into therapeutic approaches for disease.

Convalescent Plasma for Infectious Diseases: Historical Framework and Use in COVID-19.

Convalescent plasma has emerged as a promising therapeutic agent for patients with coronavirus disease 2019 (COVID-19), has received emergency use authorization, and is being widely used during the COVID-19 pandemic. Passive antibody therapy via plasma or serum has been successfully used to treat infectious diseases for more than a century. Passive antibody administration is based on the presumption that convalescent plasma or serum contains therapeutic antibodies that can be passively transferred to the plasma recipient. There are numerous examples in which convalescent plasma has been used successfully as post-exposure prophylaxis and treatment of infectious diseases, including previous coronavirus outbreaks. In the context of the COVID-19 pandemic, convalescent plasma was demonstrated to be safe and potentially effective among patients infected with COVID-19. This review provides an overview of the historical uses of convalescent plasma therapy, summarizes current evidence for convalescent plasma use for COVID-19, and highlights future antibody therapies.

Influence of high affinity haemoglobin on the response to normoxic and hypoxic exercise.

KEY POINTS: Theoretical models suggest there is no benefit of high affinity haemoglobin to preserve maximal oxygen uptake in acute hypoxia but the comparative biology literature has many examples of species that are evolutionarily adapted to hypoxia and have high affinity haemoglobin. We studied humans with high affinity haemoglobin and compensatory polycythaemia. These subjects performed maximal exercise tests in normoxia and hypoxia to determine how their altered haemoglobin affinity impacts hypoxic exercise tolerance. The high affinity haemoglobin participants demonstrated an attenuated decline in maximal aerobic capacity in acute hypoxia. Those with high affinity haemoglobin had no worsening of pulmonary gas exchange during hypoxic exercise but had greater lactate and lower pH than controls for all exercise bouts. High affinity haemoglobin and compensatory polycythaemia mitigated the decline in exercise performance in acute hypoxia through a higher arterial oxygen content and an unchanged pulmonary gas exchange. ABSTRACT: The longstanding dogma is that humans exhibit an acute reduction in haemoglobin (Hb) binding affinity for oxygen that facilitates adaptation to moderate hypoxia. However, many animals have adapted to high altitude through enhanced Hb binding affinity for oxygen. The objective of the study was to determine whether high affinity haemoglobin (HAH) affects maximal and submaximal exercise capacity. To accomplish this, we recruited individuals (n = 11, n = 8 females) with HAH (P50  = 16 ± 1 mmHg), had them perform normoxic and acute hypoxic (15% inspired oxygen) maximal exercise tests, and then compared their results to matched controls (P50  = 26 ± 1, n = 14, n = 8 females). Cardiorespiratory and arterial blood gases were collected throughout both exercise tests. Despite no difference in end-exercise arterial oxygen tension in hypoxia (59 ± 6 vs. 59 ± 9 mmHg for controls and HAH, respectively), the HAH subjects' oxyhaemoglobin saturation ( Sa,O2 ) was ∼7% higher. Those with HAH had an attenuated decline in maximal oxygen uptake ( V̇O2max ) (4 ± 5% vs. 12 ± %, p < 0.001) in hypoxia and the change in V̇O2max between trials was related to the change in SaO2 (r = -0.75, p < 0.0001). Compared to normoxia, the controls' alveolar-to-arterial oxygen gradient significantly increased during hypoxic exercise, whereas pulmonary gas exchange in HAH subjects was unchanged between the two exercise trials. However, arterial lactate was significantly higher and arterial pH significantly lower in the HAH subjects for both exercise trials. We conclude that HAH attenuates the decline in maximal aerobic capacity and preserves pulmonary gas exchange during acute hypoxic exercise. Our data support the comparative biology literature indicating that HAH is a positive adaptation to acute hypoxia.

Sex differences in paediatric airway anatomy.

NEW FINDINGS: What is the central question of this study? Are sex difference in the central airways present in healthy paediatric patients? What is the main finding and its importance? In patients ≤12 years we found no sex differences in central airway luminal area. After 14 years, the males had significantly larger central airway luminal areas than the females. The sex differences were minimized, but preserved when correcting for height. Luminal area is the main determinant of airway resistance and our finding could help explain sex differences in pulmonary system limitations to exercise in paediatric patients. ABSTRACT: Cross-sectional airway area is the main determinant of resistance to airflow in the respiratory system. In paediatric patients (<18 years), previous evidence for sex differences in cross-sectional airway area was limited to patients with history of pulmonary disease or cadaveric studies with small numbers of subjects. These studies either only report tracheal data and do not include a range of ages or correct for height. Therefore, we sought to assess sex differences in airway luminal area utilizing paediatric patients of varying ages and no history of respiratory disease. Using three-dimensional reconstructions from high-resolution computed tomography scans, we retrospectively assessed the cross-sectional airway area in healthy paediatric females (n = 97) and males (n = 128) over a range of ages (1-17 years). The areas of the trachea, left main bronchus, left upper lobe, left lower lobe, right main bronchus, intermediate bronchus and right upper lobe were measured at three discrete points by a blinded investigator. No differences between the sexes were noted in the cross-sectional areas of the youngest (ages 1-12 years) patients (P > 0.05). However, in patients ≥14 years the cross-sectional areas were larger in the males compared to females in most airway sites. For instance, the cross-sectional size of the trachea was 25% (218 ± 44 vs. 163 ± 24 mm2 , P < 0.01) larger in males vs. females among ages 13-17 years. When accounting for height, these sex differences in airway areas were attenuated, but persisted. Our results indicate that sex differences in paediatric airway cross-sectional area manifest after age ≥14 years and are independent of height.