Cerebral Abscess Associated With Odontogenic Bacteremias, Hypoxemia, and Iron Loading in Immunocompetent Patients With Right-to-Left Shunting Through Pulmonary Arteriovenous Malformations.

Background: Cerebral abscess is a recognized complication of pulmonary arteriovenous malformations (PAVMs) that allow systemic venous blood to bypass the pulmonary capillary bed through anatomic right-to-left shunts. Broader implications and mechanisms remain poorly explored. Methods: Between June 2005 and December 2016, at a single institution, 445 consecutive adult patients with computed tomography-confirmed PAVMs (including 403 [90.5%] with hereditary hemorrhagic telangiectasia) were recruited to a prospective series. Multivariate logistic regression was performed and detailed periabscess histories were evaluated to identify potential associations with cerebral abscess. Rates were compared to an earlier nonoverlapping series. Results: Thirty-seven of the 445 (8.3%) patients experienced a cerebral abscess at a median age of 50 years (range, 19-76 years). The rate adjusted for ascertainment bias was 27 of 435 (6.2%). Twenty-nine of 37 (78.4%) patients with abscess had no PAVM diagnosis prior to their abscess, a rate unchanged from earlier UK series. Twenty-one of 37 (56.7%) suffered residual neurological deficits (most commonly memory/cognition impairment), hemiparesis, and visual defects. Isolation of periodontal microbes, and precipitating dental and other interventional events, emphasized potential sources of endovascular inoculations. In multivariate logistic regression, cerebral abscess was associated with low oxygen saturation (indicating greater right-to-left shunting); higher transferrin iron saturation index; intravenous iron use for anemia (adjusted odds ratio, 5.4 [95% confidence interval, 1.4-21.1]); male sex; and venous thromboemboli. There were no relationships with anatomic attributes of PAVMs, or red cell indices often increased due to secondary polycythemia. Conclusions: Greater appreciation of the risk of cerebral abscess in undiagnosed PAVMs is required. Lower oxygen saturation and intravenous iron may be modifiable risk factors.

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

RATIONALE: PaO2 and SaO2 are commonly measured in respiratory practice, but arterial oxygen content (CaO2) refers to the volume of oxygen delivered to the tissues per unit blood volume. CaO2 is calculated from SaO2 and the hemoglobin concentration in blood, recognizing that each gram of hemoglobin can transport approximately 1.34 ml of oxygen when fully saturated. OBJECTIVES: To prospectively evaluate serial changes in CaO2 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 SaO2 (breathing room air, by pulse oximetry), hemoglobin, red cell and iron indices were measured, and CaO2 calculated as SaO2 × hemoglobin × 1.34 ml/g. Serial measurements were evaluated in 100 cases spanning up to 32.1 (median, 10.5) years. RESULTS: Presentation CaO2 ranged from 7.6 to 27.5 (median, 17.6) ml/dl. CaO2 did not change appreciably across the SaO2 quartiles. In contrast, hemoglobin ranged from 5.9 to 21.8 g/dl (median, 14.1 g/dl), with a linear increase in CaO2 across hemoglobin quartiles. After PAVM embolization and an immediate increase in SaO2, hemoglobin fell and CaO2 was unchanged 1.6-12 (median, 4) months later. When hemoglobin fell because of iron deficiency, there was no change in SaO2. Similarly, when hemoglobin rose after iron treatment, there was no change in SaO2, and the expected CaO2 increment was observed. These relationships were not evident during pregnancy when hemoglobin fell, and PAVMs usually deteriorated: in pregnancy SaO2 commonly increased, and serial CaO2 values (incorporating hemodilution/anemia) more accurately reflected deteriorating PAVM status. An apparent fall in CaO2 with age in females was attributable to the development of iron deficiency. There was an unexplained increase in CaO2 with age in follow-up of males after embolization. CONCLUSIONS: Hemoglobin/CaO2 should be further incorporated into oxygenation considerations. More attention should be given to modest changes in hemoglobin that substantially modify CaO2.

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.

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.