Key pointsr The contribution of blood flow through intrapulmonary arteriovenous anastomoses (IPAVAs) to pulmonary gas exchange efficiency remains unknown and controversial.r Intravenous infusion of adrenaline (epinephrine) increases blood flow through IPAVAs detected by the transpulmonary passage of saline contrast and breathing 40% O 2 minimizes potential contributions from ventilation-to-perfusion inequality and diffusion limitation. r Pulmonary gas exchange efficiency was impaired to the same degree, and the transpulmonary passage of saline contrast was not different, in humans at rest during the intravenous infusion of adrenaline before and after atropine when breathing room air and 40% O 2 .r Cardiac output increased to the same degree during intravenous infusion of adrenaline before and after atropine, but pulmonary artery systolic pressure only increased significantly before atropine.r These data demonstrate that blood flow through IPAVAs contributes to pulmonary gas exchange efficiency and that blood flow through IPAVAs is predominantly mediated by increases in cardiac output rather than increases in pulmonary artery systolic pressure.Abstract 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 /Q T ) that impairs pulmonary gas exchange efficiency (i.e. increases the alveolar-to-arterial P O 2 difference (A-aDO 2 )) remains controversial and unknown. We hypothesized that blood flow through IPAVAs does provide a source ofQ VA /Q T . To test this, blood flow through IPAVAs was increased in healthy humans at rest breathing room air and 40% O 2 : (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-aDO 2 increased by 6 ± 2 mmHg during 320 ADR and by 5 ± 2 mmHg during ATR + 80 ADR, and the change in calculatedQ VA /Q T was +2% in both conditions. When breathing 40% O 2 , which minimizes contributions from diffusion limitation and alveolar ventilation-to-perfusion inequality, the A-aDO 2 increased by 12 ± 7 mmHg during 320 ADR, and by 9 ± 6 mmHg during ATR + 80 ADR, and the change in calculatedQ VA /Q T was +2% in both conditions. During 320 ADR cardiac output (Q T ) and pulmonary artery systolic pressure (PASP) were significantly increased; however, during ATR + 80 ADR onlyQ T 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 inQ T rather than PASP. Abbreviations A-aDO 2 , alveolar-to-arterial difference in P O2 ; ADR, adrenaline (epinephrine); ATR, atropine; C aO2 , arterial oxygen content; C vO...

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.

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 (Q IPAVA ) 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 (F IO 2 = 1.0). Additionally,Q IPAVA 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 ofQ IPAVA 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 quantifyQ IPAVA and identify the consequences ofQ IPAVA on physiological and pathophysiological processes. Nevertheless, based on currently published data, our proposed working model is thatQ IPAVA 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. AbbreviationsA − aD O2 , alveolar-to-arterial partial pressure of O 2 difference; C aO2 , arterial O 2 content; F IO2 , fraction of inspired oxygen; HHT, hereditary haemorrhagic telangiectasia; HPV, hypoxic pulmonary vasoconstriction; IPAVA, intrapulmonary arteriovenous anastomoses; MAA, macroaggregates of albumin; MIGET, multiple inert gas elimination technique; Pv O2 , mixed venous partial pressure of O 2 ; P aO2 , arterial partial pressure of O 2 ; PASP, pulmonary artery systolic pressure; PAVM, pulmonary arteriovenous malformation; PFO, patent foramen ovale; S aO2 , arterial O 2 saturation; S pO2 , peripheral estimate of arterial O 2 saturation; 99m Tc-MAA, technetium-99m-labelled MAA; TIA, transient ischaemic attack; TTSCE, transthoracic saline contrast echocardiography;Q T , cardiac output;Q IPAVA , blood flow through IPAVA;Q S /Q T , shunt fraction;V O2 , O 2 consumption, ventilation to perfusion ratio (V/Q ).Andrew Lovering, PhD, is an integrative physiologist who has investigated a wide range of respiratory system questions from understanding how medullary respiratory neurons reconfigure their activity during hypoxia-induced periodic breathing in sleeping cats to understanding the roles of intracardiac and intrapulmonary shunt on the regulation of pulmonary gas exchange efficiency in humans exercising above 5000 m; he thinks that the patent foramen ov...

Adults with a history of very preterm birth (<32 wk gestational age; PRET) have reduced lung function and significantly lower lung diffusion capacity for carbon monoxide (DLCO) relative to individuals born at term (CONT). Low DLCO may predispose PRET to diffusion limitation during exercise, particularly while breathing hypoxic gas because of a reduced O2 driving gradient and pulmonary capillary transit time. We hypothesized that PRET would have significantly worse pulmonary gas exchange efficiency [i.e., increased alveolar-to-arterial Po2 difference (AaDO2)] during exercise breathing room air or hypoxic gas (FiO2 = 0.12) compared with CONT. To test this hypothesis, we compared the AaDO2 in PRET (n = 13) with a clinically mild reduction in DLCO (72 ± 7% of predicted) and CONT (n = 14) with normal DLCO (105 ± 10% of predicted) pre- and during exercise breathing room air and hypoxic gas. Measurements of temperature-corrected arterial blood gases, and direct measure of O2 saturation (SaO2), were made prior to and during exercise at 25, 50, and 75% of peak oxygen consumption (V̇o2peak) while breathing room air and hypoxic gas. In addition to DLCO, pulmonary function and exercise capacity were significantly less in PRET. Despite PRET having low DLCO, no differences were observed in the AaDO2 or SaO2 pre- or during exercise breathing room air or hypoxic gas compared with CONT. Although our findings were unexpected, we conclude that reduced pulmonary function and low DLCO resulting from very preterm birth does not cause a measureable reduction in pulmonary gas exchange efficiency.

Edited by: Ken O'Halloran New Findings r What is the central question of this study?Adult survivors of preterm birth without (PRE) and with bronchopulmonary dysplasia (BPD) have airflow obstruction at rest and significant mechanical ventilatory constraints during exercise compared with those born at full term (CON). Do PRE/BPD have smaller airways, indexed via the dysanapsis ratio, than CON? r What is the main finding and its importance?The dysanapsis ratio was significantly smaller in BPD and PRE compared with CON, with BPD having the smallest dysanapsis ratio. These data suggest that airflow obstruction in PRE and BPD might be because of smaller airways than CON.Adult survivors of very preterm birth (ࣘ32 weeks gestational age) without (PRE) and with bronchopulmonary dysplasia (BPD) have obstructive lung disease as evidenced by reduced expiratory airflow at rest and have significant mechanical ventilatory constraints during exercise. Airflow obstruction, in any conditions, could be attributable to several factors, including small airways. PRE and/or BPD could have smaller airways than their counterparts born at full term (CON) owing to a greater degree of dysanaptic airway development during the pre-and/or postnatal period. Thus, the purpose of the present study was to compare the dysanapsis ratio (DR), as an index of airway size, between PRE, BPD and CON. To do so, we calculated DR in PRE (n = 21), BPD (n = 14) and CON (n = 34) individuals and examined flow-volume loops at rest and during submaximal exercise. The DR, using multiple estimates of static recoil pressure, was significantly smaller in PRE and BPD (0.16 ± 0.05 and 0.10 ± 0.03 a.u.) compared with CON (0.22 ± 0.04 a.u.; both P < 0.001) and smallest in BPD (P < 0.001). The DR was significantly correlated with peak expiratory airflow at rest (r = 0.42; P < 0.001) and the extent of expiratory flow limitation during exercise (r = 0.60; P < 0.001). Our findings suggest that PRE/BPD might have anatomically smaller airways than CON, which might help to explain their lower expiratory airflow rate at rest and during exercise and further our understanding of the consequences of preterm birth and neonatal O 2 therapy.

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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.

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