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Non-anemic iron deficiency predicts prolonged hospitalisation following surgical aortic valve replacement: a single-centre retrospective study.
BACKGROUND: Iron deficiency has deleterious effects in patients with cardiopulmonary disease, independent of anemia. Low ferritin has been associated with increased mortality in patients undergoing cardiac surgery, but modern indices of iron deficiency need to be explored in this population. METHODS: We conducted a retrospective single-centre observational study of 250 adults in a UK academic tertiary hospital undergoing median sternotomy for non-emergent isolated aortic valve replacement. We characterised preoperative iron status using measurement of both plasma ferritin and soluble transferrin receptor (sTfR), and examined associations with clinical outcomes. RESULTS: Measurement of plasma sTfR gave a prevalence of iron deficiency of 22%. Patients with non-anemic iron deficiency had clinically significant prolongation of total hospital stay (mean increase 2.2 days; 95% CI: 0.5-3.9; P = 0.011) and stay within the cardiac intensive care unit (mean increase 1.3 days; 95% CI: 0.1-2.5; P = 0.039). There were no deaths. Defining iron deficiency as a plasma ferritin
Regulation of human metabolism by hypoxia-inducible factor.
The hypoxia-inducible factor (HIF) family of transcription factors directs a coordinated cellular response to hypoxia that includes the transcriptional regulation of a number of metabolic enzymes. Chuvash polycythemia (CP) is an autosomal recessive human disorder in which the regulatory degradation of HIF is impaired, resulting in elevated levels of HIF at normal oxygen tensions. Apart from the polycythemia, CP patients have marked abnormalities of cardiopulmonary function. No studies of integrated metabolic function have been reported. Here we describe the response of these patients to a series of metabolic stresses: exercise of a large muscle mass on a cycle ergometer, exercise of a small muscle mass (calf muscle) which allowed noninvasive in vivo assessments of muscle metabolism using (31)P magnetic resonance spectroscopy, and a standard meal tolerance test. During exercise, CP patients had early and marked phosphocreatine depletion and acidosis in skeletal muscle, greater accumulation of lactate in blood, and reduced maximum exercise capacities. Muscle biopsy specimens from CP patients showed elevated levels of transcript for pyruvate dehydrogenase kinase, phosphofructokinase, and muscle pyruvate kinase. In cell culture, a range of experimental manipulations have been used to study the effects of HIF on cellular metabolism. However, these approaches provide no potential to investigate integrated responses at the level of the whole organism. Although CP is relatively subtle disorder, our study now reveals a striking regulatory role for HIF on metabolism during exercise in humans. These findings have significant implications for the development of therapeutic approaches targeting the HIF pathway.
The mechanics and control of ventilation
The lungs are responsible for oxygenating the blood and removing carbon dioxide from the body. They are also responsible for a very substantial burden of disease in the UK and worldwide population, and for the cancellation or complication of many surgical procedures. This brief article reviews the basic mechanics of the respiratory system, and highlights some of the important and interesting aspects of the regulation of ventilation, focussing on the role of the peripheral and central chemoreceptors. A sound knowledge of this basic respiratory physiology and pathophysiology is a prerequisite for effective preoperative assessment and good perioperative care. © 2011 Elsevier Ltd. All rights reserved.
Regulation of hepcidin expression at high altitude.
Enhanced erythropoietic drive and iron deficiency both influence iron homeostasis through the suppression of the iron regulatory hormone hepcidin. Hypoxia also suppresses hepcidin through a mechanism that is unknown. We measured iron indices and plasma hepcidin levels in healthy volunteers during a 7-day sojourn to high altitude (4340 m above sea level), with and without prior intravenous iron loading. Without prior iron loading, a rapid reduction in plasma hepcidin was observed that was almost complete by the second day at altitude. This occurred before any index of iron availability had changed. Prior iron loading delayed the decrease in hepcidin until after the transferrin saturation, but not the ferritin concentration, had normalized. We conclude that hepcidin suppression by the hypoxia of high altitude is not driven by a reduction in iron stores.
The increase in pulmonary arterial pressure caused by hypoxia depends on iron status.
Hypoxia is a major cause of pulmonary hypertension. Gene expression activated by the transcription factor hypoxia-inducible factor (HIF) is central to this process. The oxygen-sensing iron-dependent dioxygenase enzymes that regulate HIF are highly sensitive to varying iron availability. It is unknown whether iron similarly influences the pulmonary vasculature. This human physiology study aimed to determine whether varying iron availability affects pulmonary arterial pressure and the pulmonary vascular response to hypoxia, as predicted biochemically by the role of HIF. In a controlled crossover study, 16 healthy iron-replete volunteers undertook two separate protocols. The 'Iron Protocol' studied the effects of an intravenous infusion of iron on the pulmonary vascular response to 8 h of sustained hypoxia. The 'Desferrioxamine Protocol' examined the effects of an 8 h intravenous infusion of the iron chelator desferrioxamine on the pulmonary circulation. Primary outcome measures were pulmonary artery systolic pressure (PASP) and the PASP response to acute hypoxia (DeltaPASP), assessed by Doppler echocardiography. In the Iron Protocol, infusion of iron abolished or greatly reduced both the elevation in baseline PASP (P < 0.001) and the enhanced sensitivity of the pulmonary vasculature to acute hypoxia (P = 0.002) that are induced by exposure to sustained hypoxia. In the Desferrioxamine Protocol, desferrioxamine significantly elevated both PASP (P < 0.001) and DeltaPASP (P = 0.01). We conclude that iron availability modifies pulmonary arterial pressure and pulmonary vascular responses to hypoxia. Further research should investigate the potential for therapeutic manipulation of iron status in the management of hypoxic pulmonary hypertensive disease.
Effects of iron supplementation and depletion on hypoxic pulmonary hypertension: two randomized controlled trials.
CONTEXT: Hypoxia is a major cause of pulmonary hypertension in respiratory disease and at high altitude. Recent work has established that the effect of hypoxia on pulmonary arterial pressure may depend on iron status, possibly acting through the transcription factor hypoxia-inducible factor, but the pathophysiological and clinical importance of this interaction is unknown. OBJECTIVE: To determine whether increasing or decreasing iron availability modifies altitude-induced hypoxic pulmonary hypertension. DESIGN, SETTING, AND PARTICIPANTS: Two randomized, double-blind, placebo-controlled protocols conducted in October-November 2008. In the first protocol, 22 healthy sea-level resident men (aged 19-60 years) were studied over 1 week of hypoxia at Cerro de Pasco, Peru (altitude 4340 m). In the second protocol, 11 high-altitude resident men (aged 30-59 years) diagnosed with chronic mountain sickness were studied over 1 month of hypoxia at Cerro de Pasco, Peru. INTERVENTION: In the first protocol, participants received intravenous infusions of Fe(III)-hydroxide sucrose (200 mg) or placebo on the third day of hypoxia. In the second protocol, patients underwent staged isovolemic venesection of 2 L of blood. Two weeks later, patients received intravenous infusions of Fe(III)-hydroxide sucrose (400 mg) or placebo, which were subsequently crossed over. MAIN OUTCOME MEASURE: Effect of varying iron availability on pulmonary artery systolic pressure (PASP) assessed by Doppler echocardiography. RESULTS: In the sea-level resident protocol, approximately 40% of the pulmonary hypertensive response to hypoxia was reversed by infusion of iron, which reduced PASP by 6 mm Hg (95% confidence interval [CI], 4-8 mm Hg), from 37 mm Hg (95% CI, 34-40 mm Hg) to 31 mm Hg (95% CI, 29-33 mm Hg; P = .01). In the chronic mountain sickness protocol, progressive iron deficiency induced by venesection was associated with an approximately 25% increase in PASP of 9 mm Hg (95% CI, 4-14 mm Hg), from 37 mm Hg (95% CI, 30-44 mm Hg) to 46 mm Hg (95% CI, 40-52 mm Hg; P = .003). During the subsequent crossover period, no acute effect of iron replacement on PASP was detected. CONCLUSION: Hypoxic pulmonary hypertension may be attenuated by iron supplementation and exacerbated by iron depletion. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00952302.
Lack of involvement of the autonomic nervous system in early ventilatory and pulmonary vascular acclimatization to hypoxia in humans.
The activity within the autonomic nervous system may be altered following sustained exposure to hypoxia, and it is possible that this increase in activity underlies the early acclimatization of both ventilation and the pulmonary vasculature to hypoxia. To test this hypothesis, seven individuals were infused with the ganglionic blocker trimetaphan before and after an 8 h exposure to hypoxia. The short half-life of trimetaphan should ensure that the initial infusion does not affect acclimatization to the 8 h hypoxia exposure, and the use of a ganglion blocking agent should inhibit activity within all branches of the autonomic nervous system. During the infusions of trimetaphan, measurements of ventilation and echocardiographic assessments of pulmonary vascular tone (DeltaPmax) were made during euoxia and during a short period of isocapnic hypoxia. Subjects were also studied on two control days, when a saline infusion was substituted for trimetaphan. Trimetaphan had no effect on either euoxic ventilation or the sensitivity of ventilation to acute hypoxia. Trimetaphan significantly reduced DeltaPmax in euoxia (P<0.05), but had no significant effect on the sensitivity of DeltaPmax to acute hypoxia once changes in cardiac output had been controlled for. The 8 h period of hypoxia elevated euoxic ventilation (P<0.001) and DeltaPmax (P<0.001) and increased their sensitivities to acute hypoxia (P<0.001 for both), indicating that significant acclimatization had occurred. Trimetaphan had no effect on the acclimatization response of any of these variables. We conclude that altered autonomic activity following 8 h of hypoxia does not underlie the acclimatization observed in ventilation or pulmonary vascular tone.
An assessment of central-peripheral ventilatory chemoreflex interaction using acid and bicarbonate infusions in humans.
1. The object of this study was to investigate the effect of central chemoreceptor stimulation on the ventilatory responses to peripheral chemoreceptor stimulation. 2. The level of central chemoreceptor stimulation was varied by performing experiments at two different levels of end-tidal CO2 pressure (PCO2). Variations in peripheral chemoreceptor stimulus were achieved by varying arterial pH (at constant end-tidal PCO2) and by varying end-tidal O2 pressure (PO2). 3. Two protocols were each performed on six human subjects. In one protocol ventilatory measurements were made during eucapnia, when the arterial pH was lowered from 7.4 to 7.3. The variation in pH was achieved by the progressive infusion of acid (0.1 M HCl). In the other protocol ventilatory measurements were made during hypercapnia, when the arterial pH was increased from 7.3 to 7.4. The variation in pH was achieved by the progressive infusion of 1.26% NaHCO3. In each protocol ventilatory responses were measured during euoxia (end-tidal PO2, 100 Torr), hypoxia (end-tidal PO2, 50 Torr) and hyperoxia (end-tidal PO2, 300 Torr), with end-tidal PCO2 held constant. 4. The increase in ventilatory sensitivity to arterial pH induced by hypoxia (50 Torr) was not significantly different between protocols (acid protocol, -104 +/- 31 l min-1 (pH unit)-1 vs. bicarbonate protocol, -60 +/- 44 l min-1 (pH unit)-1; mean +/- S.E.M.; not significant (n.s.)). The ventilatory sensitivity to hypoxia at an arterial pH of 7.35 was not significantly different between protocols (acid protocol, 14.7 +/- 3.3 l min-1 vs. bicarbonate protocol, 15.6 +/- 2.4 l min-1; mean +/- S.E.M.; n.s.). The results provide no evidence to suggest that peripheral chemoreflex ventilatory responses are modulated by central chemoreceptor stimulation.
Time course of the human pulmonary vascular response to 8 hours of isocapnic hypoxia
To examine the hypothesis that the human pulmonary vascular response to hypoxia has a component with a slow time course, we measured pulmonary vascular resistance (PVR) in six healthy adult males during 8 h of isocapnic hypoxia. A balloon-tipped pulmonary artery catheter with thermistor was introduced via a forearm vein and used to derive PVR. The subjects were seated in a chamber in which the oxygen and carbon dioxide concentrations were adjusted to maintain an end-tidal PO2 of 50 Torr and an end-tidal PCO2 equal to the subject's normal prehypoxic value. PVR was measured before and at 0.5-h intervals during 8 h of hypoxia, the following 3 h of isocapnic euoxia (end-tidal PO2 100 Torr), and a subsequent 1-h reexposure to hypoxia. PVR rose from 1.23 ± 0.26 (SE) Torr · min · l-1 under euoxia [time (t) = 0] to 1.77 ± 0.21 Torr · min · l-1 at t = 0.5 h, reached a maximum at 2 h (2.91 ± 0.33 Torr · min · l-1), and remained fairly constant between 2 and 8 h. Restoration of euoxia at 8 h led to a reduction in PVR with a slow component. Reexposure to hypoxia at 11 h resulted in a greater increase in PVR than at 1 h. Systemic vascular resistance had a similar slow component to its response, falling from 18.6 ± 1.3 Torr · min · l-1 at t = 0 to 17.3 ± 1.4 Torr · min · l-1 at t = 0.5 h, 14.4 ± 0.6 Torr · min · l-1 at t = 4 h, and 13.8 ± 0.8 Torr · min · l-1 at t = 8 h. The human pulmonary and systemic vascular responses to hypoxia extend over at least several hours.
Effects of modest iron loading on iron indices in healthy individuals.
Intravenous iron administration is typically indicated in individuals who have iron deficiency refractory to oral iron. However, in certain chronic disease states such as heart failure, it may be beneficial to administer intravenous iron to individuals who are not strictly iron deficient. The purpose of this study was to define a dose-response relationship between clinical indices of iron status and modest loading with intravenous iron in healthy, iron-replete participants. This was a double-blind, controlled study involving 18 male participants. Participants were block-randomized 2:1 to the iron and saline (control) groups. Participants in the iron group received 3.75 mg/kg body wt up to a maximum of 250 mg of intravenous iron, once a month for 6 mo, provided that their ferritin remained measured <300 µg/l within the week before a dose was due and their transferrin saturation remained <45%. Otherwise they received a saline infusion, as did the control participants. Iron indices were measured monthly during the study. The pulmonary vascular response to sustained hypoxia and total hemoglobin mass were measured before, at 3 mo (hemoglobin mass only), and at 6 mo as variables that may be affected by iron loading. Serum ferritin was robustly elevated by intravenous iron by 0.21 µg·l-1·mg-1 of iron delivered (95% confidence interval: 0.15-0.26 µg·l-1·mg-1), but the effects on all other iron indices did not reach statistical significance. The pulmonary vascular response to sustained hypoxia was significantly suppressed by iron loading at 6 mo, but the hemoglobin mass was unaffected. We conclude that the robust effect on ferritin provides a quantitative measure for the degree of iron loading in iron-replete individuals.NEW & NOTEWORTHY There has been an increasing interest in administering intravenous iron to patients to alter their iron status. Here, we explore various indices of iron loading and show that in healthy volunteers serum ferritin provides a robust indicator of the amount of iron loaded, with a value of 21 µg/l increase in ferritin per 100 mg of iron loaded.
Sir George Johnson FRCP (1818-96), high blood pressure and the continuing altercation about its origins.
NEW FINDINGS: What is the topic of this review? The review takes a historical approach to examining where in the body it might be possible to identify the most common cause, or causes, of long-term hypertension. It gathers evidence from histology, human and animal physiology, and computational modelling. The burden of decades of controversy is noted. What advances does it highlight? The review highlights the distinctive pathology of the afferent renal circulation and what its consequences are for the widespread view that essential hypertension is caused by elevated peripheral vascular resistance. ABSTRACT: The widely promulgated notion that long-term elevation in mean arterial blood pressure (MAP) can be caused by raised peripheral vascular resistance remains a subject of vigorous debate. According to the 1967 mathematical model of Guyton and Coleman, such a causal relationship is impossible, kidney function being the determining factor. We explore this altercation starting with Sir George Johnson's 19th-century renal vascular histological observations in patients with Bright's disease. We note the striking physiological measurements in hypertensives by Gómez and Bolomey in the 1950s, moving on to the mathematical modelling of the circulation from the 1960s up to the ∼100-parameter computer models of the present day. Confusion has been generated by the fact that peripheral resistance is raised in hypertension in close proportion to MAP whilst cardiac output often stays normal, an apparent autoregulation, the mechanism of which is poorly understood. All models allowing for the circulation to be an open system show that isolated changes in peripheral resistance cannot lead to long-term hypertension, but models fail so frequently to account for results from experiments such as salt loading that their credibility with regard to this key finding is compromised. Laboratory animal models of adrenergic renal actions resonate with a contemporary emphasis on the sympathetic nerve supply to the kidney as contributing to the characteristically markedly elevated renal afferent resistance that appears to be the most common cause of hypertension. Remarkably, there remains no account of the way in which the fixed structural changes in vessels observed by Johnson relate to this sympathetic overactivity, which can itself be modified by drugs in the medium term. In this account, we seek to locate the crime scene and identify a smoking gun.
Lessons of the month 1: Learning from Harvey; improving blood-taking by pointing the needle in the right direction.
The taking of blood for diagnostic purposes is a frequent cause of difficulty for physicians. In patients with intact visible or palpable large veins, such as those often seen in the antecubital fossa, a needle or cannula entering from any direction will usually be rewarded with any quantity of blood. In smaller veins in less convenient locations, such as in the hand, the direction of the needle becomes much more important. Failure to take blood is very commonly because of failure to appreciate the direction of flow of venous blood up the arm, and the ubiquitous presence of valves in the veins, both aspects of the circulation clearly described by William Harvey nearly 4 centuries ago. This paper encourages more frequent success with phlebotomy by remembering Harvey's work and pointing the needle in the right direction; this is not always towards the heart.