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Anticoagulation by ancrod for carbon dioxide removal by extracorporeal membrane lung in the dog.
Ten dogs were subjected to defibrinogenation with an intravenous perfusion of ancrod (1 unit/kg) (Arvin, Knoll AG, Ludwigshafen, Federal Republic of Germany) over a 2 1/2 hour period. Six of them were subjected to extracorporeal elimination of carbon dioxide with a polypropylene membrane lung by means of veno-venous bypass. The remaining four dogs did not undergo extracorporeal circulation and served as control subjects. In both groups, ancrod administration itself resulted in a marked drop in alpha 2-antiplasmin (33% and 67%, respectively, of the baseline values) and in slight but significant decreases in factor II and plasminogen activities of 25% and 20%, respectively (p less than 0.05), in the group subjected to carbon dioxide removal. There were no significant changes in platelet number or factor V and antithrombin III activities. During the 6-hour bypass period, platelet count and antithrombin III and factor II and V levels decreased significantly. No bleeding was observed. Histologic examination of lung biopsy tissue showed no pathologic features. Analysis of the membrane of the artificial lungs revealed no fibrin deposits. In the control group, except for a drop in alpha 2-antiplasmin levels (54%), no significant changes in hemostatic parameters occurred during the corresponding 6 hours. We conclude that, despite the drop in coagulation factors and in alpha 2-antiplasmin activity during bypass, ancrod can be considered as a valuable alternative anticoagulant for extracorporeal carbon dioxide removal.
Time course of hypoxic pulmonary vasoconstriction: a rabbit model of regional hypoxia.
There is disagreement in the literature about the time required for hypoxic constriction of pulmonary vessels to reach its full intensity. Some studies suggest that only minutes are required, others that several hours are needed. We examined the time course over 6 h of changes in pulmonary shunt (as a fraction of cardiac output) following induction of unilateral hypoxia by collapse or liquid filling of the left lung in 47 anesthetized rabbits. The time course was examined at four degrees of lung inflation: during collapse and at airway pressures of 0.3 kPa, 0.6 kPa, and 0.9 kPa. The respective volumes (mean +/- SD) of the liquid-filled lung were estimated to be 6.4 +/- 1.0, 12.8 +/- 2.5, and 15.8 +/- 1.6 ml/kg body weight (BW). During sustained hypoxia (the period from 150 to 360 min after inducing hypoxia), shunt declined at a slow linear rate of 2.37 x 10(-4)/min, which was independent of lung inflation (p = 0.65 analysis of variance [ANOVA]) and significantly different from zero (p < 0.001). The stability of cardiac output in this animal model, as measured sequentially by thermodilution, was confirmed in a further 20 animals. The experiments provide evidence for a slow intensification of blood-flow diversion at a rate that does not depend upon the degree of lung inflation. Whether this change is a feature of hypoxic constriction itself, or some modulation of it, remains unclear.
Effect of potassium on ventilation in the rhesus monkey.
Increasing the concentration of arterial plasma K+ to 6-8 mM increased ventilation in two sedated analgesic-treated rhesus monkeys who had their end-tidal CO2 held constant during euoxia (arterial oxygen pressure, Pa,O2, ca 100 Torr) and hypoxia (Pa,O2, ca 40 Torr). During euoxia and hypoxia, hyperkalaemia increased ventilation up to 40 and 250%, respectively. This effect was reduced in euoxia and virtually abolished in hypoxia following an abrupt switch to 100% oxygen. Thus the ventilatory response of this primate to hyperkalaemia is at least as sensitive as that of the cat and if hypoxia is added the two stimuli generate a powerful drive to breathing.
Physiological profile during venovenous perfusion in dogs using a polypropylene membrane lung with secondary flows.
Venovenous perfusion has been conducted in 12 healthy dogs to examine carbon dioxide (CO2) transfer and haemocompatibility over 9 h during total extracorporeal CO2 removal using a microporous polypropylene membrane lung with secondary flows in the blood channel. The anaesthetized animals were maintained normocapnic by including CO2 in the inspired gases. The CO2 removal was achieved using 0.631 m2 of active membrane, at a pulsatile Reynolds number of 50, and a CO2 extraction from blood of 17.8 ml (STP) dl-1. Gas exchange remained constant during the perfusions. Several aspects of our results suggest that the haemocompatibility of a system of the kind used here is at least as favourable as that of a steady flow device using a continuous silicone rubber membrane of equivalent gas transfer capability.
Extracorporeal oxygen and CO2 transfer of a polypropylene dimpled membrane lung with variable secondary flows: partial bypass in the dog.
In vivo gas transfer performance, during veno-venous bypass, is presented for one form of the Oxford membrane lung in which vortex mixing is induced in blood flow across a dimpled polypropylene membrane. Good agreement has been found with in vitro data presented in an earlier paper. Two experiments were extended to attain total extracorporeal CO2 removal with apnoeic diffusion oxygenation to motionless lungs. Measurements of arterial oxygen partial pressure during apnoea suggest that the time-constant for equilibration of alveolar nitrogen partial pressure with that on the gas side of the membrane lung is of the order of 100 min.
Variations in alveolar partial pressure for carbon dioxide and oxygen have additive not synergistic acute effects on human pulmonary vasoconstriction.
The human pulmonary vasculature constricts in response to hypercapnia and hypoxia, with important consequences for homeostasis and adaptation. One function of these responses is to direct blood flow away from poorly-ventilated regions of the lung. In humans it is not known whether the stimuli of hypercapnia and hypoxia constrict the pulmonary blood vessels independently of each other or whether they act synergistically, such that the combination of hypercapnia and hypoxia is more effective than the sum of the responses to each stimulus on its own. We independently controlled the alveolar partial pressures of carbon dioxide (Paco 2) and oxygen (Pao 2) to examine their possible interaction on human pulmonary vasoconstriction. Nine volunteers each experienced sixteen possible combinations of four levels of Paco 2 (+6, +1, -4 and -9 mmHg, relative to baseline) with four levels of Pao 2 (175, 100, 75 and 50 mmHg). During each of these sixteen protocols Doppler echocardiography was used to evaluate cardiac output and systolic tricuspid pressure gradient, an index of pulmonary vasoconstriction. The degree of constriction varied linearly with both Paco 2 and the calculated haemoglobin oxygen desaturation (1-So2). Mixed effects modelling delivered coefficients defining the interdependence of cardiac output, systolic tricuspid pressure gradient, ventilation, Paco 2 and So2. No interaction was observed in the effects on pulmonary vasoconstriction of carbon dioxide and oxygen (p>0.64). Direct effects of the alveolar gases on systolic tricuspid pressure gradient greatly exceeded indirect effects arising from concurrent changes in cardiac output.
Iron bioavailability and cardiopulmonary function during ascent to very high altitude.
Intravenous iron supplementation at sea level is associated with enhanced stroke volume and higher SpO2 on ascent to very high altitude (5100 m). These effects appear to result from reduced pulmonary vascular resistance and improved right heart function. https://bit.ly/2VQX5fR
Differential responses to breath-holding, voluntary deep breathing and hypercapnia in left and right dorsal anterior cingulate.
NEW FINDINGS: What is the central question of this study? What is the role of dorsal anterior cingulate cortex (ACC) in respiration control in humans? What is the main finding and its importance? Direct evidence is provided for a role of the ACC in respiratory control in humans. The neurophysiological responses in dorsal ACC to different breathing tasks varied and were different between left and right ACC. ABSTRACT: The role of subcortical structures and cerebral cortex in the maintenance of respiratory homeostasis in humans remains poorly understood. Emerging evidence suggests an important role of the anterior cingulate cortex (ACC) in respiratory control. In this study, local field potentials (LFPs) from dorsal ACC were recorded in humans through implanted deep brain electrodes during several breathing activities, including voluntary activities of breath-holding and deep breathing, and involuntary activities of inspiration of varying concentrations of carbon dioxide (1%, 3%, 5% and 7%). We found that the breath-holding task induced significant unilateral left-sided ACC changes in LFP power, including an increased activity in lower frequency bands (3-5 Hz) and decreased activity in higher frequency bands (12-26 Hz). The respiratory task involving reflex increase in ventilation due to hypercapnia (raised inspired CO2 ) was associated with bilateral changes in activity of the ACC (again with increased activity in lower frequency bands and reduced activity in higher frequency bands). The voluntary breathing task with associated hypocapnia (deep breathing) induced bilateral changes in activity within low frequency bands. Furthermore, probabilistic diffusion tractography analysis showed left-sided connection of the ACC with the insula and frontal operculum, and bilateral connections within subsections of the cingulate gyrus and the thalamus. This electrophysiological analysis provides direct evidence for a role of the ACC in respiratory control in humans.
Intravenous iron delivers a sustained (8-week) lowering of pulmonary artery pressure during exercise in healthy older humans.
In older individuals, pulmonary artery pressure rises markedly during exercise, probably due in part to increased pulmonary vascular resistance and in part to an increase in left-heart filling pressure. Older individuals also show more marked pulmonary vascular response to hypoxia at rest. Treatment with intravenous iron reduces the rise in pulmonary artery pressure observed during hypoxia. Here, we test the hypothesis that intravenous iron administration may also attenuate the rise in pulmonary artery pressure with exercise in older individuals. In a randomized double-blind placebo-controlled physiology study in 32 healthy participants aged 50-80 years, we explored the hypothesis that iron administration would deliver a fall in systolic pulmonary artery pressure (SPAP) during moderate cycling exercise (20 min duration; increase in heart rate of 30 min-1 ) and a change in maximal cycling exercise capacity ( V˙O2max ). Participants were studied before, and at 3 h to 8 weeks after, infusion. SPAP was measured using Doppler echocardiography. Iron administration resulted in marked changes in indices of iron homeostasis over 8 weeks, but no significant change in hemoglobin concentration or inflammatory markers. Resting SPAP was also unchanged, but SPAP during exercise was lower by ~3 mmHg in those receiving iron (P
Abnormal whole-body energy metabolism in iron-deficient humans despite preserved skeletal muscle oxidative phosphorylation.
Iron deficiency impairs skeletal muscle metabolism. The underlying mechanisms are incompletely characterised, but animal and human experiments suggest the involvement of signalling pathways co-dependent upon oxygen and iron availability, including the pathway associated with hypoxia-inducible factor (HIF). We performed a prospective, case-control, clinical physiology study to explore the effects of iron deficiency on human metabolism, using exercise as a stressor. Thirteen iron-deficient (ID) individuals and thirteen iron-replete (IR) control participants each underwent 31P-magnetic resonance spectroscopy of exercising calf muscle to investigate differences in oxidative phosphorylation, followed by whole-body cardiopulmonary exercise testing. Thereafter, individuals were given an intravenous (IV) infusion, randomised to either iron or saline, and the assessments repeated ~ 1 week later. Neither baseline iron status nor IV iron significantly influenced high-energy phosphate metabolism. During submaximal cardiopulmonary exercise, the rate of decline in blood lactate concentration was diminished in the ID group (P = 0.005). Intravenous iron corrected this abnormality. Furthermore, IV iron increased lactate threshold during maximal cardiopulmonary exercise by ~ 10%, regardless of baseline iron status. These findings demonstrate abnormal whole-body energy metabolism in iron-deficient but otherwise healthy humans. Iron deficiency promotes a more glycolytic phenotype without having a detectable effect on mitochondrial bioenergetics.
Cardiopulmonary phenotype associated with human PHD2 mutation.
Oxygen-dependent regulation of the erythropoietin gene is mediated by the hypoxia-inducible factor (HIF) family of transcription factors. When oxygen is plentiful, HIF undergoes hydroxylation by a family of oxygen-dependent prolyl hydroxylase domain (PHD) proteins, promoting its association with the von Hippel-Lindau (VHL) ubiquitin E3 ligase and subsequent proteosomal degradation. When oxygen is scarce, the PHD enzymes are inactivated, leading to HIF accumulation and upregulation not only of erythropoietin expression, but also the expression of hundreds of other genes, including those coordinating cardiovascular and ventilatory adaptation to hypoxia. Nevertheless, despite the identification of over 50 mutations in the PHD-HIF-VHL pathway in patients with previously unexplained congenital erythrocytosis, there are very few reports of associated cardiopulmonary abnormalities. We now report exaggerated pulmonary vascular and ventilatory responses to acute hypoxia in a 35-year-old man with erythrocytosis secondary to heterozygous mutation in PHD2, the most abundant of the PHD isoforms. We compare this phenotype with that reported in patients with the archetypal disorder of cellular oxygen sensing, Chuvash polycythemia, and discuss the possible clinical implications of our findings, particularly in the light of the emerging role for small molecule PHD inhibitors in clinical practice.
Human hypoxic pulmonary vasoconstriction is unaltered by 8 h of preceding isocapnic hyperoxia.
Exposure to sustained hypoxia of 8 h duration increases the sensitivity of the pulmonary vasculature to acute hypoxia, but it is not known whether exposure to sustained hyperoxia affects human pulmonary vascular control. We hypothesized that exposure to 8 h of hyperoxia would diminish the hypoxic pulmonary vasoconstriction (HPV) that occurs in response to a brief exposure to hypoxia. Eleven healthy volunteers were studied in a crossover protocol with randomization of order. Each volunteer was exposed to acute isocapnic hypoxia (end-tidal PO2 = 50 mmHg for 10 min) before and after 8 h of hyperoxia (end-tidal PO2 = 420 mmHg) or euoxia (end-tidal PO2 = 100 mmHg). After at least 3 days, each volunteer returned and was exposed to the other condition. Systolic pulmonary artery pressure (an index of HPV) and cardiac output were measured, using Doppler echocardiography. Eight hours of hyperoxia had no effect on HPV or the response of cardiac output to acute hypoxia.
Intravenous iron supplementation may protect against acute mountain sickness: a randomized, double-blinded, placebo-controlled trial.
Acute mountain sickness (AMS) is a common and disabling condition that occurs in healthy individuals ascending to high altitude. Based on the ability of iron to influence cellular oxygen sensing pathways, we hypothesized that iron supplementation would protect against AMS. To examine this hypothesis, 24 healthy sea-level residents were randomized to receive either intravenous iron(III)-hydroxide sucrose (200 mg) or saline placebo, before ascending rapidly to Cerro de Pasco, Peru (4340 m). The Lake Louise scoring system was used to assess incidence and severity of AMS at sea level and on the first full day at altitude. No significant difference in absolute AMS score was detected between the two groups either at baseline or at high altitude. However, the mean increase in AMS score was 65% smaller in the iron group than in the saline group (p<0.05), and the change in AMS score correlated negatively with the change in ferritin (R=-0.43; p<0.05). Hematocrit and arterial oxygen saturation were unaffected by iron. In conclusion, this preliminary randomized, double-blinded, placebo-controlled trial suggests that intravenous iron supplementation may protect against the symptoms of AMS in healthy volunteers.