Hannah C. Tighe

Differences in Ventilatory Inefficiency Between Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension

BACKGROUND Measures of ventilatory efficiency during cardiopulmonary exercise testing (CPX) are increasingly being used as prognostic markers in heart failure and pulmonary hypertension (PH). Little is known about whether these measures can be applied to all forms of PH, in particular chronic thromboembolic pulmonary hypertension (CTEPH), wherein thrombotic vascular occlusion has an impact on gas exchange. METHODS One hundred twenty-seven patients, 50 with CTEPH and 77 with pulmonary arterial hypertension (PAH), underwent incremental CPX. RESULTS Physiologic ventilatory dead space fraction (Vd/Vtphys) measured at peak exercise with arterial blood gas analysis was higher in CTEPH than PAH (52.9% vs 41.8%, P < .001). The V(E)/V(CO(2)) slope was higher in patients with CTEPH than in patients with PAH (50.7 L/min/L/min vs 44.4 L/min/L/min, P = .024) and was mirrored by similar changes in the ventilatory equivalent for CO(2) at anaerobic threshold (Eqco(2)_AT) (47.7 L/min/L/min vs 42.0 L/min/L/min, P = .008). In a multivariate linear regression analysis, disease subtype was found to be an independent predictor of Vd/Vtphys (P < .001), V(E)/V(CO(2)) slope (P = .003), and Eqco(2)_AT (P < .001). These three measures could distinguish between World Health Organization functional classes I/II and III/IV in PAH but not CTEPH. CONCLUSION Significant differences in gas exchange exist between CTEPH and PAH, due to differences in Vd/Vtphys likely as a result of vascular occlusion due to thromboembolic disease. This dissociates measures of ventilatory efficiency from disease severity and also contributes to our understanding of the differences in exercise limitation and breathlessness in PAH and CTEPH. Common prognostic end points from CPX cannot be applied to all forms of PH.

Embolisation of pulmonary arteriovenous malformations: no consistent effect on pulmonary artery pressure

Increasing evidence supports the use of embolisation to treat pulmonary arteriovenous malformations (AVMs). Most pulmonary AVM patients have hereditary haemorrhagic telangiectasia (HHT), a condition that may be associated with pulmonary hypertension. The current authors tested whether pulmonary AVM embolisation increases pulmonary artery pressure (Ppa) in patients without baseline severe pulmonary hypertension. Ppa was measured at the time of pulmonary AVM embolisation in 143 individuals, 131 (92%) of whom had underlying HHT. Angiography/embolisation was not performed in four individuals with severe pulmonary hypertension, whose systemic arterial oxygen saturation exceeded levels usually associated with dyspnoea in pulmonary AVM patients. In 143 patients undergoing pulmonary AVM embolisation, Ppa was significantly correlated with age, with the most significant increase occurring in the upper quartile (aged >58 yrs). In 43 patients with repeated measurements, there was no significant increase in Ppa as a result of embolisation. In half, embolisation led to a fall in Ppa. The maximum rise in mean Ppa was 8 mmHg: balloon test occlusion was performed in one of these individuals, and did not predict the subsequent rise in Ppa following definitive embolisation of the pulmonary AVMs. In the present series of patients, which excluded those with severe pulmonary hypertension, pulmonary artery pressure was not increased significantly by pulmonary arteriovenous malformation embolisation.

Ischaemic Strokes in Patients with Pulmonary Arteriovenous Malformations and Hereditary Hemorrhagic Telangiectasia: Associations with Iron Deficiency and Platelets

Background Pulmonary first pass filtration of particles marginally exceeding ∼7 µm (the size of a red blood cell) is used routinely in diagnostics, and allows cellular aggregates forming or entering the circulation in the preceding cardiac cycle to lodge safely in pulmonary capillaries/arterioles. Pulmonary arteriovenous malformations compromise capillary bed filtration, and are commonly associated with ischaemic stroke. Cohorts with CT-scan evident malformations associated with the highest contrast echocardiographic shunt grades are known to be at higher stroke risk. Our goal was to identify within this broad grouping, which patients were at higher risk of stroke. Methodology 497 consecutive patients with CT-proven pulmonary arteriovenous malformations due to hereditary haemorrhagic telangiectasia were studied. Relationships with radiologically-confirmed clinical ischaemic stroke were examined using logistic regression, receiver operating characteristic analyses, and platelet studies. Principal Findings Sixty-one individuals (12.3%) had acute, non-iatrogenic ischaemic clinical strokes at a median age of 52 (IQR 41–63) years. In crude and age-adjusted logistic regression, stroke risk was associated not with venous thromboemboli or conventional neurovascular risk factors, but with low serum iron (adjusted odds ratio 0.96 [95% confidence intervals 0.92, 1.00]), and more weakly with low oxygen saturations reflecting a larger right-to-left shunt (adjusted OR 0.96 [0.92, 1.01]). For the same pulmonary arteriovenous malformations, the stroke risk would approximately double with serum iron 6 µmol/L compared to mid-normal range (7–27 µmol/L). Platelet studies confirmed overlooked data that iron deficiency is associated with exuberant platelet aggregation to serotonin (5HT), correcting following iron treatment. By MANOVA, adjusting for participant and 5HT, iron or ferritin explained 14% of the variance in log-transformed aggregation-rate (p = 0.039/p = 0.021). Significance These data suggest that patients with compromised pulmonary capillary filtration due to pulmonary arteriovenous malformations are at increased risk of ischaemic stroke if they are iron deficient, and that mechanisms are likely to include enhanced aggregation of circulating platelets.

Arterial Oxygen Content Is Precisely Maintained by Graded Erythrocytotic Responses in Settings of High/Normal Serum Iron Levels, and Predicts Exercise Capacity: An Observational Study of Hypoxaemic Patients with Pulmonary Arteriovenous Malformations

Background Oxygen, haemoglobin and cardiac output are integrated components of oxygen transport: each gram of haemoglobin transports 1.34 mls of oxygen in the blood. Low arterial partial pressure of oxygen (PaO2), and haemoglobin saturation (SaO2), are the indices used in clinical assessments, and usually result from low inspired oxygen concentrations, or alveolar/airways disease. Our objective was to examine low blood oxygen/haemoglobin relationships in chronically compensated states without concurrent hypoxic pulmonary vasoreactivity. Methodology 165 consecutive unselected patients with pulmonary arteriovenous malformations were studied, in 98 cases, pre/post embolisation treatment. 159 (96%) had hereditary haemorrhagic telangiectasia. Arterial oxygen content was calculated by SaO2 x haemoglobin x 1.34/100. Principal Findings There was wide variation in SaO2 on air (78.5–99, median 95)% but due to secondary erythrocytosis and resultant polycythaemia, SaO2 explained only 0.1% of the variance in arterial oxygen content per unit blood volume. Secondary erythrocytosis was achievable with low iron stores, but only if serum iron was high-normal: Low serum iron levels were associated with reduced haemoglobin per erythrocyte, and overall arterial oxygen content was lower in iron deficient patients (median 16.0 [IQR 14.9, 17.4]mls/dL compared to 18.8 [IQR 17.4, 20.1]mls/dL, p<0.0001). Exercise tolerance appeared unrelated to SaO2 but was significantly worse in patients with lower oxygen content (p<0.0001). A pre-defined athletic group had higher Hb:SaO2 and serum iron:ferritin ratios than non-athletes with normal exercise capacity. PAVM embolisation increased SaO2, but arterial oxygen content was precisely restored by a subsequent fall in haemoglobin: 86 (87.8%) patients reported no change in exercise tolerance at post-embolisation follow-up. Significance Haemoglobin and oxygen measurements in isolation do not indicate the more physiologically relevant oxygen content per unit blood volume. This can be maintained for SaO2 ≥78.5%, and resets to the same arterial oxygen content after correction of hypoxaemia. Serum iron concentrations, not ferritin, seem to predict more successful polycythaemic responses.

Orthodeoxia and postural orthostatic tachycardia in patients with pulmonary arteriovenous malformations: a prospective 8-year series

Postural changes in 258 patients with pulmonary arteriovenous malformations (PAVMs) reviewed between 2005 and 2013 were evaluated prospectively using validated pulse oximetry methods. Of the 257 completing the test, 75 (29%) demonstrated orthodeoxia with an oxygen saturation fall of at least 2% on standing. None described platypnoea (dyspnoea on standing). The heart rate was consistently higher in the erect posture: 74 (29%) had a postural orthostatic tachycardia of ≥20 min−1, and in 25 (10%) this exceeded 30 min−1. Orthostatic tachycardia was more pronounced in PAVM patients than controls without orthodeoxia (age-adjusted coefficient 5.5 (95% CIs 2.6, 8.4) min−1, p<0.001). For PAVM patients, the age-adjusted pulse rise was 0.79 min−1 greater for every 1% greater drop in oxygen saturation on standing (p<0.001). In contrast to the postural orthostatic tachycardia syndrome, in this population, there was a trend for more pronounced orthostatic tachycardia to be associated with better exercise tolerance.

Cardiopulmonary Exercise Testing Demonstrates Maintenance of Exercise Capacity in Patients With Hypoxemia and Pulmonary Arteriovenous Malformations

BACKGROUND Patients with pulmonary arteriovenous malformations (PAVMs) are unusual because hypoxemia results from right-to-left shunting and not airway or alveolar disease. Their surprisingly well-preserved exercise capacity is not generally appreciated. METHODS To examine why exercise tolerance is preserved, cardiopulmonary exercise tests were performed while breathing room air in 21 patients with radiologically proven PAVMs, including five restudied 3 to 12 months after embolization when their PAVMs had regressed. Where physiologic matching was demonstrable, comparisons were made with 12 healthy control subjects. RESULTS The majority of patients achieved their predicted work rate despite a resting arterial oxygen saturation (SaO₂) of 80% to 96%. Peak work rate and oxygen consumption (VO₂) were no lower in patients with more hypoxemia. Despite higher SaO₂ following embolization (median, 96% and 90%; P = .009), patients achieved similar work rates and similar peak VO₂. Strikingly, treated patients reset to virtually identical peak oxygen pulses (ie, VO₂ per heart beat) and in many cases to the same point on the peak oxygen pulse/work rate plot. The 21 patients had increased minute ventilation (VE) for given increases in CO₂ production (VE/VCO₂ slope), but perceived dyspnea was no greater than in the 12 control subjects or in the same patients before compared to after embolization comparison. Overall, work rate and peak VO₂ were associated not with oxygenation parameters but with VE/VCO₂ slope, BMI, and anaerobic threshold. CONCLUSIONS Patients with hypoxemia and PAVMs can maintain normal oxygen delivery/VO₂ during peak exercise. Following improvement of SaO₂ by embolization, patients appeared to reset compensatory mechanisms and, as a result, achieved similar peak VO₂ per heart beat and peak work rates.

Cerebral abscess associated with odontogenic bacteremias, hypoxemia, and iron loading in immunocompetent patients with right-to-left shunting through pulmonary arteriovenous malformations.

Summary In a UK series, 37 of 445 (8.3%) patients with pulmonary arteriovenous malformations (PAVMs) experienced a cerebral abscess, often pre-PAVM diagnosis as first presentation. Odontogenic organisms, dental interventions, lower oxygen saturation, iron loading, and intravenous iron use were associated with abscess risk.

Hemoglobin Is a Vital Determinant of Arterial Oxygen Content in Hypoxemic Patients with Pulmonary Arteriovenous Malformations

Rationale: Symbol and Symbol are commonly measured in respiratory practice, but arterial oxygen content (Symbol) refers to the volume of oxygen delivered to the tissues per unit blood volume. Symbol is calculated from Symbol and the hemoglobin concentration in blood, recognizing that each gram of hemoglobin can transport approximately 1.34 ml of oxygen when fully saturated. Symbol. No caption available. Symbol. No caption available. Objectives: To prospectively evaluate serial changes in Symbol in humans, incorporating and excluding dynamic changes to oxygenation and hemoglobin parameters that may occur during life. Methods: A cohort of 497 consecutive patients at risk of both hypoxemia and anemia were recruited. The patients had radiologically proven pulmonary arteriovenous malformations (PAVMs), which result in hypoxemia due to right‐to‐left shunting, and concurrent hereditary hemorrhagic telangiectasia, which placed them at risk of iron deficiency anemia due to recurrent hemorrhagic iron losses. Presentation Symbol (breathing room air, by pulse oximetry), hemoglobin, red cell and iron indices were measured, and Symbol calculated as Symbol × hemoglobin × 1.34 ml/g. Serial measurements were evaluated in 100 cases spanning up to 32.1 (median, 10.5) years. Results: Presentation Symbol ranged from 7.6 to 27.5 (median, 17.6) ml/dl. Symbol did not change appreciably across the Symbol quartiles. In contrast, hemoglobin ranged from 5.9 to 21.8 g/dl (median, 14.1 g/dl), with a linear increase in Symbol across hemoglobin quartiles. After PAVM embolization and an immediate increase in Symbol, hemoglobin fell and Symbol was unchanged 1.6‐12 (median, 4) months later. When hemoglobin fell because of iron deficiency, there was no change in Symbol. Similarly, when hemoglobin rose after iron treatment, there was no change in Symbol, and the expected Symbol increment was observed. These relationships were not evident during pregnancy when hemoglobin fell, and PAVMs usually deteriorated: in pregnancy Symbol commonly increased, and serial Symbol values (incorporating hemodilution/anemia) more accurately reflected deteriorating PAVM status. An apparent fall in Symbol with age in females was attributable to the development of iron deficiency. There was an unexplained increase in Symbol with age in follow‐up of males after embolization. Conclusions: Hemoglobin/Symbol should be further incorporated into oxygenation considerations. More attention should be given to modest changes in hemoglobin that substantially modify Symbol.

P38 Which patients with pulmonary arteriovenous malformations are dyspnoeic? Retrospective analysis of a single centre 2005–2010 cohort

Introduction/objectives Pulmonary arteriovenous malformations (PAVMs) are aberrant connections between pulmonary arteries and veins, creating a right-to-left shunt. Hypoxaemia is common,1 but dyspnoea is usually not the presenting complaint.2 We hypothesised this may be relevant to dyspnoea mechanisms in the general population. Methods With ethical approval, new patients presenting with CT-proven PAVMs between June 2005 and July 2010 were studied retrospectively. Based on self-reported exercise tolerance at presentation, and blinded to physiological measurements, two investigators assigned patients to the MRC dyspnoea scale, grading dyspnoea on strenuous exertion only (normal, Grade 1); on incline/stairs (2); and on the level (3–5 according to severity). Individuals undertaking regular/intense sport were reclassified as Grade ‘0’. Four separate SpO2 measurements, after standing for 7, 8, 9 and 10 min, were used for statistical calculations using GraphPad software. Interim analyses were performed on the first 88 patients. Results In the absence of severe pulmonary hypertension or emphysema, only 18% of patients were dyspnoeic (Abstract P38 Table 1). To determine which factors might influence dyspnoea, single variables were examined. There was considerable overlap in the SpO2 values between the three groups of Grade ‘0’, 1 and 2, and no relationship between dyspnoea grade and SpO2 demonstrated by Spearmans rank correlation coefficient (r=0.09; p=0.39). The patients however, ranged in age from 17 to 87 years, and older patients were more dyspnoeic (Spearman r=0.33; p=0.0016). Multiple regression analyses were therefore performed to determine whether there was a relationship between SpO2 and dyspnoea that was masked by differences in age. These suggested SpO2 may make an independent contribution to dyspnoea (p=0.064), although age was still more strongly associated (p=0.0044). However, these factors alone did not account for most of the population variation in dyspnoea grade (overall model: r2=11.37%, p=0.0073).Abstract P38 Table 1 Population stratification by dyspnoea grade: *Quartile distribution (Q1, Q2, Q3) where Q2 represents the median value MRC grade Number of cases SpO2 (%) range SpO2 (%) quartiles* Corrected* number (%) “0” 19 78.5–99 90.7, 94.5, 96.2 19 (22) 1 51 83.5–98 93.6, 95.5, 96.5 51 (60) 2 15 80.8–98 85.6, 90.5, 93.1 15 (18) 3 2 89–92.5 89.1, 89.2, 90.8 0 4 1 95–95 95.0, 95.0, 95.0 0 5 0 – – 0* Excludes patients with severe pulmonary hypertension (n =2), or severe emphysema (n = 1). Summary These data imply that it is unusual for PAVMs alone to account for moderate to severe dyspnoea, and that there is less of an influence of SpO2 than expected. Further study is warranted.

P172 Pre-operative insights from cardiopulmonary exercise testing in patients with pulmonary arteriovenous malformations

Introduction and Objectives Patients with pulmonary arteriovenous malformations (PAVMs) are difficult to assess for anaesthetic risks. Generally, they display well-preserved exercise tolerance, yet may have very low oxygen saturation due to their anatomical intrapulmonary right-to-left shunts. During pre-operative assessments in the general population, anaerobic threshold and peak VO2, measured by cardiopulmonary exercise testing (CPET), are increasingly recommended to identify high-risk patients, and appropriately plan post-operative management. For example, “high-risk” for major abdominal surgery has been suggested as an anaerobic threshold <11 ml min-1 kg-1 and peak VO2 <20 ml min-1 kg-1. Methods In order to evaluate “pre-operative” risk categories for PAVM patients, anaerobic threshold and peak VO2, measured by ethically approved research cardiopulmonary exercise tests, were evaluated. Results 26 PAVM patients underwent research CPET evaluations between April 2011-May 2017. Their median age was 57 years (interquartile range (IQR): 42–66). 16 (61.5%) were male. The median oxygen saturation (SaO2) was 92% (IQR: 88–95) and median haemoglobin 15.6 g/dl (IQR: 14.2–16.6). Overall, the PAVM group achieved a median 92% of the predicted maximum work (IQR: 67–106), anaerobic threshold ranged from 7.6–24.5 ml min-1 kg-1 (median: 12.35; IQR: 9.5–17.35), and peak VO2 ranged from 11.2–45.5 ml min-1 kg-1 (median: 19.8; IQR: 16.7–28.4). Anaerobic threshold placed 11/26 (42.3%) in the suggested high-risk category for major abdominal surgery. In this group, the anaerobic threshold ranged from 7.6–10.8 ml min-1 kg-1. Similarly, peak VO2 placed 14/26 (53.8%) in a high-risk category. Their peak VO2 ranged from 11.2–16.5 ml min-1 kg-1. There was full concordance between the categories determined by the 2 measurements. Notably, 6 patients were retested 3–31 months after embolization treatment resulting in increased SaO2. However, there was no increase in anaerobic threshold or peak VO2, and the 3 patients from this group initially in a higher risk category remained. Conclusion Anaerobic threshold and peak VO2 suggest high proportions of PAVM patients are in a high-risk pre-operative risk category. The data suggest an important role for anaesthetic assessments. Noting that 1 in 2600 people are estimated to have PAVMs, further study is recommended to develop appropriate clinical guidance, and allocate resources to optimise care.