Wiggins, Chad C

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 mm 2 , 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.

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. AbstractThe 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 () was ∼7% higher. Those with HAH had an attenuated decline in maximal oxygen uptake () (4 ± 5% vs. 12 ± %, p < 0.001) in hypoxia and the change in between trials was related to the change in (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.

Arterial oxygen tension and oxyhemoglobin saturation ([Formula: see text]) decrease in parallel during hypoxia. Distinguishing between changes in oxygen tension and oxygen content as the relevant physiological stimulus for cardiorespiratory alterations remains challenging. To overcome this, we recruited nine individuals with hemoglobinopathy manifesting as high-affinity hemoglobin [HAH; partial pressure at 50% [Formula: see text] (P50) = 16 ± 0.4 mmHg] causing greater [Formula: see text] at a given oxygen partial pressure compared with control subjects ( n = 12, P50 = 26 ± 0.4 mmHg). We assessed ventilatory and cardiovascular responses to acute isocapnic hypoxia, iso-oxic hypercapnia, and 20 min of isocapnic hypoxia (arterial Po2 = 50 mmHg). Blood gas alterations were achieved with dynamic end-tidal forcing. When expressed as a function of the logarithm of oxygen partial pressure, ventilatory sensitivity to hypoxia was not different between groups. However, there was a significant difference when expressed as a function of [Formula: see text]. Conversely, the rise in heart rate was blunted in HAH subjects when expressed as a function of partial pressure but similar when expressed as a function of [Formula: see text]. Ventilatory sensitivity to hypercapnia was not different between groups. During sustained isocapnic hypoxia, the rise in minute ventilation was similar between groups; however, heart rate was significantly greater in the controls during 3 to 9 min of exposure. Our results support the notion that oxygen tension, not content, alters cellular Po2in the chemosensors and drives the hypoxic ventilatory response. Our study suggests that in addition to oxygen partial pressure, oxygen content may also influence the heart rate response to hypoxia.NEW & NOTEWORTHY We dissociated the effects of oxygen content and pressure of cardiorespiratory regulation studying individuals with high-affinity hemoglobin (HAH). During hypoxia, the ventilatory response, expressed as a function of oxygen tension, was similar between HAH variants and controls; however, the rise in heart rate was blunted in the variants. Our work supports the notion that the hypoxic ventilatory response is regulated by oxygen tension, whereas cardiovascular regulation may be influenced by arterial oxygen content and tension.

Airway luminal area is the major determinant of resistance to airflow in the tracheobronchial tree. Women may have smaller central conducting airways than men; however, previous evidence is confounded by an indirect assessment of airway geometry and by subjects with prior smoking history. The purpose of this study was to examine the effect of sex on airway size in healthy nonsmokers. Using low-dose high-resolution computed tomography, we retrospectively assessed airway luminal area in healthy men ( n = 51) and women ( n = 73) of varying ages (19–86 yr). Subjects with a positive smoking history, cardiopulmonary disease, or a body mass index > 40 kg/m2 were excluded. Luminal areas of the trachea, right and left main bronchus, bronchus intermediate, left and right upper lobes, and the left lower lobe were analyzed at three discrete points. The luminal areas of the conducting airways were ~26%–35% smaller in women. The trachea had the largest differences in luminal area between men and women (298 ± 47 vs. 195 ± 28 mm2 or 35% smaller for men and women, respectively), whereas the left lower lobe had the smallest differences (57 ± 15 vs. 42 ± 9 mm2 or 26% smaller for men and women, respectively). When a subset of subjects was matched for height, the sex differences in airway luminal area persisted, with women being ~20%–30% smaller. With all subjects, there were modest relationships between height and airway luminal area ( r = 0.73–0.53, P < 0.05). Although there was considerable overlap between sexes, the luminal areas of the large conducting airways were smaller in healthy women than in men. NEW & NOTEWORTHY Previous evidence for sex differences in airway size has been confounded by indirect measures and/or cohorts with significant smoking histories or pathologies. We found that central airways in healthy women were significantly smaller (~26%–35%) than men. The significant sex-difference in airway size was attenuated (20%–30% smaller) but preserved in a subset of subjects matched for height. Over a range of ages, healthy women have smaller central airways than men.