Exercise capacity reflects airflow limitation rather than hypoxaemia in patients with pulmonary arteriovenous malformations

Background: Pulmonary arteriovenous malformations (PAVMs) generate a right-to-left shunt. Impaired gas exchange results in hypoxemia and impaired CO2 clearance. Most patients compensate effectively but a proportion are dyspneic, and these are rarely the most hypoxaemic. Aim: To test degrees of concurrent pathology influencing exercise capacity. Design: Replicate, sequential single centre, prospective studies. Methods: Cardiopulmonary exercise tests (CPET) were performed in 26 patients with PAVMs, including individuals with and without known airflow obstruction. To replicate, relationships were tested prospectively in an independent cohort where self-reported exercise capacity evaluated by the Veterans Specific Activity Questionnaire (VSAQ) was used to calculate metabolic equivalents at peak exercise (METS N = 71). Additional measurements included oxygen saturation (SpO2), forced expiratory volume in 1 second (FEV1), vital capacity (VC), exhaled nitric oxide (FeNO), haemoglobin and iron indices. Results: By CPET, the peak work-rate was only minimally associated with low SpO2 or low arterial oxygen content (CaO2=1.34 x SpO2 x haemoglobin), but was reduced in patients with low FEV1 or VC. Supranormal work-rates were seen in patients with severe right-to-left shunting and SpO2 80% predicted. VSAQ-calculated METS also demonstrated little relationship with SpO2, and in crude and CaO2-adjusted regression, were lower in patients with lower FEV1 or VC. Bronchodilation increased airflow even where spirometry was in the normal range: exhaled nitric oxide measurements were normal in 80% of cases, and unrelated to any PAVM-specific variable. Conclusions: Exercise capacity is reduced by relatively mild airflow limitation (obstructive or restrictive) in the setting of PAVMs

The effects of prolonged hypoxia on respiration in man

This thesis is concerned with the effects of prolonged hypoxia on ventilatory control in humans. Chapter 1 reviews some of the relevant studies in animals and humans relating to this thesis. Chapter 2 describes the experimental apparatus and technique employed in dynamic endtidal forcing using a computer-controlled gas-mixing system. It also details some of the basic analytical procedures used. Chapter 3 describes the construction of a chamber for the long-term control of end-tidal gases. Preliminary testing showed this technique to be successful. Chapter 4 documents the ventilatory response to 8 hours of isocapnic and poikilocapnic hypoxia. Ventilation rose dramatically during isocapnic hypoxia, but not during poikilocapnic exposure. The next chapter investigated the mechanisms responsible for these changes. Chapter 5 assessed the changes in the ventilatory response to acute changes in hypoxia during the isocapnic and poikilocapnic hypoxic exposures of Chapter 4. Hypoxic sensitivity and hypoxia-independent ventilation increased during both hypoxic exposures and the changes were not significantly different between protocols. It was, therefore, proposed that hypoxia per se was responsible for the changes in ventilation during isocapnic hypoxia. Hypoxic sensitivity was thought to rise as a result of increased carotid body function. However, the mechanism responsible for the rise in hypoxia-independent ventilation was not clear. Chapter 6 repeated the experiments of Chapters 4 and 5, but over a 48-hour period of hypoxic exposure and over the 48 hours of deacclimatization subsequent to the exposure. In addition, measurements of the eupnoeic ventilation and hypercapnic response were made. Ventilation continued to rise in the isocapnic exposure after 8 hours and also showed a gradual, but smaller, increase during the poikilocapnic exposure. Eupnoeic ventilation rose during both exposures and fell during deacclimatization towards the pre-exposure levels. These changes were similar in both protocols. The changes in hypoxic sensitivity and hypoxia-independent ventilation suggested that hypoxia was the major factor in determining the changes in respiratory control during prolonged hypoxia, in both poikilocapnia and isocapnia. Hypoxia was proposed to be the principal factor in the early stages of altitude acclimatization, and not the associated acid-base changes. Chapter 7 describes the attempt to find a protocol to measure the hypoxic response (ventilation vs. Po2). This initial attempt was not successful, but, with modifications, the basic form of this protocol may provide a suitable test of the hypoxic response. Chapter 8 presents a brief summary of the findings of this thesis and suggestions for future work.</p

Triage assessment of cardiorespiratory risk status based on measurement of the anaerobic threshold, and estimation by activity limitation in patients with pulmonary arteriovenous malformations and hereditary haemorrhagic telangiectasia

BACKGROUND: Rapid triaging, as in the current COVID-19 pandemic, focuses on age and pre-existing medical conditions. In contrast, preoperative assessments use cardiopulmonary exercise testing (CPET) to categorise patients to higher and lower risk independent of diagnostic labels. Since CPET is not feasible in population-based settings, our aims included evaluation of a triage/screening tool for cardiorespiratory risk. METHODS: CPET-derived anaerobic thresholds were evaluated retrospectively in 26 patients with pulmonary arteriovenous malformations (AVMs) who represent a challenging group to risk-categorise. Pulmonary AVM-induced hypoxaemia secondary to intrapulmonary right-to-left shunts, anaemia from underlying hereditary haemorrhagic telangiectasia and metabolic equivalents derived from the 13-point Veterans Specific Activity Questionnaire (VSAQ) were evaluated as part of routine clinical care. Pre-planned analyses evaluated associations and modelling of the anaerobic threshold and patient-specific variables. RESULTS: In the 26 patients (aged 21-77, median 57 years), anaerobic threshold ranged from 7.6-24.5 (median 12.35) ml.min-1kg-1 and placed more than half of the patients (15, 57.7%) in the >11 ml.min-1kg-1 category suggested as lower-risk for intra-abdominal surgeries. Neither age nor baseline SpO2 predicted anaerobic threshold, or lower/higher risk categories, either alone or in multivariate analyses, despite baseline oxygen saturation (SpO2) ranging from 79 to 99 (median 92)%, haemoglobin from 108 to 183 (median 156)g.L-1. However, lower haemoglobin, and particularly, arterial oxygen content and oxygen pulse were associated with increased cardiorespiratory risk: Modelling a haemoglobin increase of 25g.L-1 placed a further 7/26 (26.9%) patients in a lower risk category. For patients completing the VSAQ, derived metabolic equivalents were strongly associated with anaerobic threshold enabling risk evaluations through a simple questionnaire. CONCLUSIONS: Baseline exercise tolerance may override age and diagnostic labels in triage settings. These data support approaches to risk reduction by aerobic conditioning and attention to anaemia. The VSAQ is suggested as a rapid screening tool for cardiorespiratory risk assessment to implement during triage/screening

Supplementation of iron in pulmonary hypertension: Rationale and design of a phase II clinical trial in idiopathic pulmonary arterial hypertension

Our aim is to assess the safety and potential clinical benefit of intravenous iron (Ferinject) infusion in iron deficient patients with idiopathic pulmonary arterial hypertension (IPAH). Iron deficiency in the absence of anemia (1) is common in patients with IPAH; (2) is associated with inappropriately raised levels of hepcidin, the key regulator of iron homeostasis; and (3) correlates with disease severity and worse clinical outcomes. Oral iron absorption may be impeded by reduced absorption due to elevated hepcidin levels. The safety and benefits of parenteral iron replacement in IPAH are unknown. Supplementation of Iron in Pulmonary Hypertension (SIPHON) is a Phase II, multicenter, double-blind, randomized, placebo-controlled, crossover clinical trial of iron in IPAH. At least 60 patients will be randomized to intravenous ferric carboxymaltose (Ferinject) or saline placebo with a crossover point after 12 weeks of treatment. The primary outcome will be the change in resting pulmonary vascular resistance from baseline at 12 weeks, measured by cardiac catheterization. Secondary measures include resting and exercise hemodynamics and exercise performance from serial bicycle incremental and endurance cardiopulmonary exercise tests. Other secondary measurements include serum iron indices, 6-Minute Walk Distance, WHO functional class, quality of life score, N-terminal pro-brain natriuretic peptide (NT-proBNP), and cardiac anatomy and function from cardiac magnetic resonance. We propose that intravenous iron replacement will improve hemodynamics and clinical outcomes in IPAH. If the data supports a potentially useful therapeutic effect and suggest this drug is safe, the study will be used to power a Phase III study to address efficacy