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1.  Plasma catecholamines in the acute phase of the response to myocardial infarction. 
Plasma catecholamine (adrenaline, noradrenaline and dopamine) concentrations have been measured in 48 patients within 6 hours of the onset of symptoms of an acute myocardial infarction. The concentrations of all three catecholamines were elevated, and there were positive correlations between plasma noradrenaline concentrations and the severity of infarct as assessed by the coronary prognostic index and serum LDH levels. Plasma glucose, free fatty acid, lactate and cortisol levels were elevated while insulin levels were reduced. The site of infarction did not influence the pattern of hormonal and metabolic responses although heart rate was significantly lower in the inferior than in the anterior infarct group. Seven patients went into ventricular fibrillation shortly (less than 1.8 h) after blood sampling. Plasma catecholamine concentrations were markedly elevated in these patients with levels similar to those previously reported after cardiac arrest.
PMCID: PMC1285314  PMID: 3524599
2.  Stimulation of alveolar epithelial fluid clearance in human lungs by exogenous epinephrine 
Critical care medicine  2006;34(3):676-681.
Because several experimental studies have demonstrated that cyclic adenosine monophosphate generation following β-adrenoceptor activation can markedly stimulate alveolar fluid clearance, we determined whether the endogenous levels of catecholamines that occur in the pulmonary edema fluid and plasma of patients with acute lung injury are high enough to stimulate alveolar fluid clearance in the human lung.
Observational clinical study.
Academic university hospital and laboratory.
Twenty-one patients with acute pulmonary edema plus ex vivo human lungs.
Measurements of catecholamine levels in patient samples and controlled laboratory studies of the effects of these catecholamine levels on the rates of alveolar fluid clearance in ex vivo human lungs.
Measurements and Main Results
The concentrations of both epinephrine and norepinephrine in the pulmonary edema fluid and plasma were ~10-9 M (range of 1-8 × 10-9 M) in hydrostatic pulmonary edema (n = 6) and acute lung injury patients (n = 15). We therefore tested whether 10-9 M epinephrine or norepinephrine stimulated alveolar fluid clearance in isolated human lungs and found that these epinephrine or norepinephrine concentrations did not stimulate alveolar fluid clearance. However, higher concentrations of epinephrine (10-7 M), but not norepinephrine (10-7 M), significantly stimulated alveolar fluid clearance by 84% above control. Glibenclamide (10-5 M) and CFTRinh-172 (10-5 M), cystic fibrosis transmembrane conductance regulator inhibitors, completely inhibited the epinephrine-induced stimulation of alveolar fluid clearance.
These results indicate that endogenous catecholamine concentrations in pulmonary edema fluid are probably not sufficient to stimulate alveolar fluid clearance. In contrast, administration of exogenous catecholamines into the distal airspaces can stimulate alveolar fluid clearance in the human lung, an effect that is mediated in part by cystic fibrosis transmembrane conductance regulator. Therefore, exogenous cyclic adenosine monophosphate-dependent stimulation will probably be required to accelerate the resolution of alveolar edema in the lungs of patients with pulmonary edema.
PMCID: PMC2765117  PMID: 16505652
pulmonary edema; alveolar epithelium; catecholamine; norepinephrine; cystic fibrosis transmembrane conductance regulator; glibenclamide
3.  Plasma catecholamines during exercise-induced bronchoconstriction in bronchial asthma. 
Thorax  1980;35(11):823-827.
Plasma levels of adrenaline and noradrenaline during and after submaximal exercise in patients with bronchial asthma were investigated. Three groups were studied comprising 10 patients with exercise-induced bronchoconstriction (EIB), 10 asthmatic patients without EIB and four normal control subjects. Plasma catecholamines were measured at rest, at the end of exercise, and five and 15 minutes after exercise. Changes in airway resistance were assessed by measuring peak expiratory flow rate. Significant differences in catecholamine levels between reacting and non-reacting patients were found. In 10 patients developing EIB adrenaline and noradrenaline levels had risen significantly by the end of exercise and remained elevated up to the fifth minute of recovery. The rise in catecholamine levels in non-reacting asthmatics was insignificant. In control subjects noradrenaline had increased significantly by the end of exercise.
PMCID: PMC471391  PMID: 7221977
4.  Plasma catecholamine levels and cardiac rhythm before and after cardiac catheterisation. 
British Heart Journal  1977;39(12):1307-1311.
Plasma catecholamine concentrations were estimated in a group of 17 fasting patients immediately before and 3 days after cardiac catheterisation. At both times electrocardiograms were recorded and blood pressures, heart rates, and respiration rates measured. Control catecholamine values were established in a group of 10 male and 10 female volunteers, bled at the same time of day under the same conditions of nutrition and posture. Levels of adrenaline and noradrenaline were increased substantially before catheterisation; 3 days later, the values were comparable to those of the control group, though still marginally higher. The increments in catecholamine levels were independent of sex and of the presence or otherwise of persistent supraventricular arrhythmias. In spite of the considerably raised catecholamine levels, electrocardiographic patterns remained unchanged, as did the other physiological values. The absence of any relation between enhanced catecholamine secretion and physiological effects is considered to be the result either of enhanced parasympathetic activity or of adaptation to a prolonged period of stress.
PMCID: PMC483414  PMID: 603731
5.  Role of the Sympathetic Nervous System in Regulating Renin and Aldosterone Production in Man * 
Journal of Clinical Investigation  1967;46(4):599-605.
Several lines of evidence have been developed indicating that the sympathetic nervous system may play a role in mediating the renal and adrenocortical secretory responses to upright posture and sodium deprivation. Despite concurrent increases in arterial blood pressure, the plasma renin activity of normal subjects increased both in response to the infusion of catecholamines (norepinephrine: epinephrine, 10:1) and in response to stimulation of the sympathetic nervous system by cold. Aldosterone excretion was also increased by catecholamine infusion. In normal subjects the stimuli of upright posture and of sodium depletion both resulted in increases in urinary catecholamines, plasma renin activity, and urinary aldosterone. A patient with severe autonomic insufficiency did not experience normal elevations of urinary catecholamines, plasma renin activity, or urinary aldosterone in response to upright posture or sodium deprivation, despite a substantial fall in arterial blood pressure. When orthostatic hypotension was prevented by infusion of catecholamines, however, increases in plasma renin activity and in aldosterone excretion were observed.
We suggest that both upright posture and sodium depletion lead to decreases in effective plasma volume and increases in sympathetic nervous system activity. This increase in sympathetic activity is then responsible for an increase in renal afferent arteriolar constriction, leading to an increase in renin secretion and, ultimately, an increase in aldosterone secretion.
PMCID: PMC442043  PMID: 6021207
6.  Neurogenic hypertension associated with an excessively high excretion rate of catecholamine metabolites. 
British Heart Journal  1987;57(5):487-489.
A 60 year old hypertensive patient suffered several cerebral infarctions. A phaeochromocytoma was suspected because the excretion rates of vanillylmandelic acid and its methoxy derivatives were raised and the patient had hypertensive crises. No tumour was found, however, by 131mI-iodobenzylguanidine scintigraphy and computed tomography of the abdomen. Moreover, the enhanced orthostatic plasma catecholamine response suggested that the high excretion rates of catecholamine metabolites were more likely to be caused by the syndrome of raised catecholamines after cerebrovascular accidents than a phaeochromocytoma. A phaeochromocytoma should not be diagnosed within several months of cerebral infarction without first excluding the possibility of a hyperadrenergic state induced by cerebral infarction.
PMCID: PMC1277206  PMID: 3593621
7.  Plasma cyclic nucleotide levels in exercise-induced asthma. 
Thorax  1981;36(11):823-827.
It is known that sympatho-adrenal control of airways is increased in asthma since beta blockade can cause severe bronchoconstriction in asthmatic individuals. It has not been established whether an altered catecholamine response to exercise plays any part in the production of the common symptom of exercise-induced asthma (EIA). We have investigated this indirectly by measuring arterial plasma cyclic nucleotide levels in 10 subjects with EIA and five normal subjects. Cyclic AMP, which in this context reflects beta stimulation, rose significantly by 25.4% in the normal subjects during exercise, while there was no significant change during or after exercise (less than 5%) in the asthmatic subjects. Cyclic GMP rose significantly after exercise in the asthmatic subjects. Six normal subjects repeated the protocol before and after inhalation of salbutamol aerosol, 1600 microgram daily for 18 days. This did not reduce the cAMP response to exercise, and we conclude that the diminished cAMP response of the asthmatic subjects was not caused by their medication. The results may indicate either impaired catecholamine production or endogenous beta receptor hyporesponsiveness in some asthmatic subjects and this may contribute to the development of EIA.
PMCID: PMC471822  PMID: 6277033
8.  Circulating catecholamines in acute asthma. 
Plasma catecholamine concentrations were measured in 15 patients (six male) aged 14-63 years attending the casualty department with acute severe asthma (peak expiratory flow 27% (SEM 3%) of predicted). Nine patients were admitted and six were not. The plasma noradrenaline concentration, reflecting sympathetic nervous discharge, was two to three times normal in all patients and was significantly higher in those who required admission compared with those discharged home (mean 7.7 (SEM 0.6) v 4.7 (0.5) nmol/l (1.3 (SEM 0.1) v 0.8 (0.08) ng/ml); p less than 0.001). Plasma adrenaline concentration, however, was not increased in any patient. This surprising failure of the plasma adrenaline concentration to increase during the stress of an acute attack of asthma was unexplained and contrasts with the pronounced rise in plasma adrenaline and noradrenaline concentrations in acute myocardial infarction, heart failure, and septicaemia. The failure of plasma adrenaline concentration to increase in acute asthma is unlikely to be explained by adrenal exhaustion, but it may be another example of impaired adrenaline secretion in asthma.
PMCID: PMC1417554  PMID: 3917781
9.  Nocturnal asthma and urinary adrenaline and noradrenaline excretion 
Thorax  1977;32(6):677-683.
Soutar, C. A., Carruthers, M., and Pickering, C. A. C. (1977).Thorax, 32, 677-683. Nocturnal asthma and urinary adrenaline and noradrenaline excretion. Urinary adrenaline and noradrenaline excretion, heart rate, and peak expiratory flow rate have been measured every two hours for 24 hours in seven asthmatic patients suffering from nocturnal or early morning exacerbations of dyspnoea. The excretions of these catecholamines were normal or slightly raised, this being consistent with a normal response to asthma or the conditions of the test.
The expected physiological fall in catecholamine excretion occurred at night. In every patient the peak expiratory flow rate fell to its lowest values during the period of lowest catecholamine excretion, and the mean two-hourly peak expiratory flow rate for all seven patients was significantly related to the sum of the mean adrenaline and noradrenaline excretion in each preceding two-hour period (p<0·05).
Individually, in three patients the relationship between peak expiratory flow rate and adrenaline and noradrenaline excretion during the evening and night was so close as to be consistent with the hypothesis that changes in sympathetic tone mediated the changes in asthma. In a further three patients the relationship was present but less clear, and in one the changes in peak flow rate and catecholamine excretion were dissociated.
Studies of mean heart rate and sinus arrhythmia gap suggested that an increase in vagal tone at night might have mediated the early morning asthma in the patient in whom changes in catecholamine excretion were dissociated from change in peak flow rate.
These findings would be consistent with the view that the physiological reduction in sympathetic tone at night mediates the nocturnal and early morning exacerbation of dyspnoea in some asthmatics, although other mechanisms such as alterations in vagal tone must be important in others. Confirmation of a causal relationship requires further study.
PMCID: PMC470812  PMID: 601729
10.  Response of Leucocyte Adenyl Cyclase to Isoprenaline and Effect of Alpha-blocking Drugs in Extrinsic Bronchial Asthma 
British Medical Journal  1974;1(5898):90-93.
The finding by several workers that biochemical responses to catecholamines are diminished in asthmatic patients during periods of active asthma as compared to normal subjects has led to the recognition of the beta-adrenergic blockade phenomenon, a common accompaniment of extrinsic bronchial asthma. Using an intact cell method to measure leucocyte adenyl cyclase activity, we have been able to show that there is a noticeably reduced responsiveness of this enzyme system (which is now identified with beta-receptor function) to isoprenaline in the leucocytes of patients suffering from acute bronchial asthma, but that asthmatic patients in remission could not be distinguished from normal persons in this respect. Evidently the defective beta-receptor function may be associated with overactivity of the alpha-receptors in acute bronchial asthma, since the responsiveness to isoprenaline stimulation could be restored towards normal by concomitant treatment of the leucocytes of these patients with alpha-receptor blocking drugs such as phentolamine or thymoxamine. Ouabain, though somewhat less potent, also enhanced responsiveness to isoprenaline stimulation. The relation of these results to the clinical observation of adrenaline resistance in active asthma suggests that alpha-receptor blocking drugs may be of value in restoring the sensitivity of beta-receptors to sympathomimetic amines.
PMCID: PMC1632910  PMID: 4149122
11.  Sry delivery to the adrenal medulla increases blood pressure and adrenal medullary tyrosine hydroxylase of normotensive WKY rats 
Our laboratory has shown that a locus on the SHR Y chromosome increases blood pressure (BP) in the SHR rat and in WKY rats that had the SHR Y chromosome locus crossed into their genome (SHR/y rat). A potential candidate for this Y chromosome hypertension locus is Sry, a gene that encodes a transcription factor that is responsible for testes development and the Sry protein may affect other target genes.
The following study examined if exogenous Sry would elevate adrenal Th, adrenal catecholamines, plasma catecholamines and blood pressure. We delivered 10 μg of either the expression construct, Sry1/pcDNA 3.1, or control vector into the adrenal medulla of WKY rats by electroporation. Blood pressure was measured by the tail cuff technique and Th and catecholamines by HPLC with electrochemical detection.
In the animals receiving Sry there were significant increases after 3 weeks in resting plasma NE (57%) and adrenal Th content (49%) compared to vector controls. BP was 30 mmHg higher in Sry injected animals (160 mmHg, p < .05) compared to vector controls (130 mmHg) after 2–3 weeks. Histological analysis showed that the electroporation procedure did not produce morphological damage.
These results provide continued support that Sry is a candidate gene for hypertension. Also, these results are consistent with a role for Sry in increasing BP by directly or indirectly activating sympathetic nervous system activity.
PMCID: PMC1810322  PMID: 17324261
12.  Diagnostic value of detailed metabolic pathway investigations in two cases of phaeochromocytoma with minimal increase in total catecholamine output 
Journal of Clinical Pathology  1966;19(5):482-486.
Two patients with phaeochromocytoma having atypical biochemical features are described. Total catecholamine excretion was normal in one and only slightly raised in the other; both had a diagnostic rise in output of metadrenaline and 4-hydroxy-3-methoxymandelic acid whilst 4-hydroxy-3-methoxyphenylglycol excretion was increased in one of them. During hypertensive attacks adrenaline excretion became greater than that of noradrenaline. The diagnostic usefulness of separate adrenaline and noradrenaline estimations in addition to catecholamine metabolite assay is discussed. A lack of relationship between tumour catecholamine content and urinary catecholamine output is emphasized.
PMCID: PMC473355  PMID: 5919361
13.  Social stress and asthma: The role of corticosteroid insensitivity 
Psychosocial stress alters susceptibility to infectious and systemic illnesses and may enhance airway inflammation in asthma by modulating immune cell function through neural and hormonal pathways. Stress activates the hypothalamic-pituitary-adrenal (HPA) axis. Release of endogenous glucocorticoids, as a consequence, may play a prominent role in altering the airway immune homeostasis. Despite substantial corticosteroid and catecholamine plasma levels, chronic psychosocial stress evokes asthma exacerbations.
Animal studies suggest that social stress induces corticosteroid insensitivity that in part may be due to impaired glucocorticoid receptor (GR) expression and/or function. Such mechanisms likely promote and amplify airway inflammation in response to infections, allergen or irritant exposure. This review discusses evidence of an altered corticosteroid responsive state as a consequence of chronic psychosocial stress. Elucidation of the mechanisms of stress-induced impairment of glucocorticoid responsiveness and immune homeostasis may identify novel therapeutic targets that could improve asthma management.
PMCID: PMC2839059  PMID: 20153032
Airway inflammation; psychosocial stress; corticosteroids; innate immune system
14.  Pheochromocytoma mimicking an acute myocardial infarction 
Netherlands Heart Journal  2007;15(7-8):248-251.
We report a 42-year-old female who presented with retrosternal pain, dyspnoea and nausea. Electrocardiography suggested a recent anterior myocardial infarction. However, emergency coronary angiography showed normal blood flow through all the coronary arteries. Paroxysmal hypertension raised the suspicion of a pheochromocytoma. Indeed, abdominal ultrasonography and computed tomography revealed a mass in the left adrenal gland. Elevated levels of plasma and urine catecholamines supported the diagnosis of pheochromocytoma. Left adrenalectomy was performed without complications and pathological examination revealed a 5.5 cm pheochromocytoma. After surgery, all antihypertensive medication was discontinued and the blood pressure returned to normal within several days. Currently, the patient is asymptomatic, has normal catecholamine levels and the electrocardiographic signs of ischaemia have resolved entirely. This case illustrates that a rare clinical entity such as pheochromocytoma should be considered in the differential diagnosis of acute coronary syndrome. (Neth Heart J 2007;15:248-51.17923879)
PMCID: PMC1995109  PMID: 17923879
pheochromocytoma; myocardial infarction; Q wave
15.  Guillain-Barré Syndrome as a Cause of Reversible Cardiomyopathy 
Texas Heart Institute Journal  2006;33(1):57-59.
Although autonomic dysfunction is a common manifestation of Guillain-Barré syndrome, cardiovascular involvement in this setting has rarely been reported in the literature. We describe a case of reversible left ventricular systolic dysfunction in a 60-year-old man with Guillain-Barré syndrome. Our patient had no history or signs of cardiac dysfunction on initial presentation. During the clinical manifestation of his autonomic dysfunction, he developed electrocardiographic changes accompanied by mildly elevated cardiac enzymes and severe left ventricular systolic dysfunction and segmental wall motion abnormality, which coincided with elevated urinary catecholamine and vanilmandelic acid levels. These abnormalities, and his symptoms, resolved rapidly once the acute episode was over. We believe the reversible left ventricular dysfunction was due to the toxic effect of increased catecholamines and to the transiently damaged sympathetic nerve endings in the myocardium, presumably a consequence of Guillain-Barré syndrome. We recommend that echocardiography be performed in patients with clinical signs of autonomic dysfunction, especially if they are associated with abnormal electrocardiographic findings, cardiac enzyme elevation, or hemodynamic instability, so that appropriate medical therapy can be instituted in a timely manner.
PMCID: PMC1413614  PMID: 16572872
Autonomic nervous system diseases/complications; cardiomyopathy/etiology; catecholamines/adverse effects; demyelinating diseases/complications; Guillain-Barre syndrome/complications; hypertension/etiology; tachycardia/etiology; vanilmandelic acid/urine; ventricular dysfunction; left/etiology
16.  Increased biogenic catecholamine and metabolite levels in two patients with malignant catatonia 
The pathophysiology of malignant catatonia, a rare life-threatening psychiatric syndrome, has not yet been elucidated. This paper reports on two patients with malignant catatonia who showed elevated urinary or plasma catecholamine levels. Patient 1 had high catecholamine and metabolite levels in a 24-hour urine sample, and patient 2 had elevated plasma catecholamine levels. These findings indicate the presence of peripheral sympathetic nervous system hyperactivity in malignant catatonia. Symptoms of autonomic dysfunction, including tachycardia, labile blood pressure, and diaphoresis, are typical features of malignant catatonia and may be related to the increased levels of biogenic amines in these cases. Although the findings in the present study cannot entirely explain the pathophysiology of malignant catatonia, they do indicate that hyperactivity of the sympathetic nervous system may be involved in the pathology of this condition.
PMCID: PMC3747023  PMID: 23976859
malignant catatonia; catecholamine levels; neuroleptic malignant syndrome
17.  Effect of Heparin on Serum Free-fatty-acids, Plasma Catecholamines, and the Incidence of Arrhythmias following Acute Myocardial Infarction 
British Medical Journal  1970;3(5725):735-737.
The effect of intravenous heparin in a therapeutic dosage on cardiac arrhythmias in patients with indubitable acute myocardial infarction was investigated. The value of serum free-fatty-acids (F.F.A.s) and plasma catecholamines in the prediction of patients vulnerable to serious arrhythmias was also studied.
Heparin produced a significant rise in F.F.A., maximal within 10 minutes of injection, but did not increase the incidence of cardiac arrhythmias.
No relationship was found between the incidence of arrhythmias and the initial levels of F.F.A. or adrenaline. No correlation was obtained between F.F.A. and plasma catecholamine levels. Heparin did not have a consistent effect on plasma catecholamines. Initial control plasma noradrenaline concentrations, however, were found to be significantly correlated with the incidence of subsequent arrhythmias. It is suggested that the level of plasma noradrenaline may be a valuable predictive guide to those patients likely to develop significant arrhythmias after acute myocardial infarction.
PMCID: PMC1701629  PMID: 5472756
18.  Epithelial Cell Proliferation Contributes to Airway Remodeling in Severe Asthma 
Rationale: Despite long-term therapy with corticosteroids, patients with severe asthma develop irreversible airway obstruction.
Objectives: To evaluate if there are structural and functional differences in the airway epithelium in severe asthma associated with airway remodeling.
Methods: In bronchial biopsies from 21 normal subjects, 11 subjects with chronic bronchitis, 9 subjects with mild asthma, and 31 subjects with severe asthma, we evaluated epithelial cell morphology: epithelial thickness, lamina reticularis (LR) thickness, and epithelial desquamation. Levels of retinoblastoma protein (Rb), Ki67, and Bcl-2 were measured, reflecting cellular proliferation and death. Terminal deoxynucleotidyl-mediated dUTP nick end labeling (TUNEL) was used to study cellular apoptosis.
Measurements and Main Results: Airway epithelial and LR thickness was greater in subjects with severe asthma compared with those with mild asthma, normal subjects, and diseased control subjects (p = 0.009 and 0.033, respectively). There was no significant difference in epithelial desquamation between groups. Active, hypophosphorylated Rb expression was decreased (p = 0.002) and Ki67 was increased (p < 0.01) in the epithelium of subjects with severe asthma as compared with normal subjects, indicating increased cellular proliferation. Bcl-2 expression was decreased (p < 0.001), indicating decreased cell death suppression. There was a greater level of apoptotic activity in the airway biopsy in subjects with severe asthma as compared with the normal subjects using the TUNEL assay (p = 0.002), suggesting increased cell death.
Conclusions: In subjects with severe asthma, as compared with subjects with mild asthma, normal subjects, and diseased control subjects, we found novel evidence of increased cellular proliferation in the airway contributing to a thickened epithelium and LR. These changes may contribute to the progressive decline in lung function and airway remodeling in patients with severe asthma.
PMCID: PMC1994213  PMID: 17463414
epithelium; desquamation; airflow obstruction
19.  Neurohumoral, immunoinflammatory and cardiovascular profile of patients with severe tetanus: a prospective study 
Autonomic disturbances in tetanus are traditionally associated with adrenergic variations and/or cardiac dysfunction, based on case report data. The objective of this study was to measure catecholamines, (TNF)-α and troponin T relative to and left ventricular ejection fraction (LVEF) in patients with severe tetanus.
This prospective study was carried out at two general Intensive Care Units and included 21 patients consecutively admitted with severe tetanus. Catecholamines (dopamine, norepinephrine, epinephrine and total catecholamines), tumor necrosis factor (TNF)-α and LVEF were assessed during the first week of autonomic instability and following tetanus recovery. Troponin T was measured during autonomic instability only.
Mean age of patients was 46 ± 17 years, median Acute Physiology and Chronic Health Evaluation II (APACHE II) score was 8 (range 1–23). All patients had both blood pressure and heart rate instability. Two patients were recuperated from cardiac arrest. Intensive Care Unit mortality was 14% (3 cases). No increase in total catecholamines or in TNF-α levels was observed during autonomic instability or in the recovery period. Six patients had troponin T >0.01 ng/ml and six had >0.1 ng/ml. Mean LVEF was similar during autonomic instability and after tetanus recovery, 67 ± 7% and 65 ± 7%, respectively. Troponin T levels correlated with pressoric instability during autonomic instability.
Our study demonstrated that in patients with severe tetanus no significant increased levels of catecholamines or TNF-α or evidence of cardiac systolic dysfunction was observed either during autonomic instability or in the recovery period. Elevated values of troponin T detected during autonomic instability were not associated with left ventricular dysfunction. Our data do not support the hypothesis that autonomic disturbances in tetanus are associated with adrenergic variations or cardiac dysfunction.
PMCID: PMC1434771  PMID: 16503969
20.  The clinical significance of exhaled nitric oxide in asthma 
Asthma is an inflammatory disease of the airways, for which many therapeutic options are available. Guidelines for the management of asthma suggest a stepwise approach to pharmacotherapy based on assessment of asthma severity and control. However, the assessment of asthma control presently relies on surrogate measures, such as the frequency of symptoms or the frequency of use of short-acting beta2-adrenergic agonists. There is no simple, noninvasive technique for the assessment of severity of actual airway inflammation in asthma. The collection and analysis of nitric oxide (NO) levels in exhaled breath has recently become feasible in humans. Based on increased exhaled NO (eNO) levels in patients with asthma, eNO analysis has been proposed as a novel, noninvasive approach to the assessment and monitoring of airway inflammation, and as a basis for adjustments in asthma therapy. In the present paper, the relationship of elevated eNO levels in asthma with inflammatory, physiological and clinical markers of asthma in adults was reviewed. Use of eNO is a promising tool for diagnosing asthma, for monitoring asthma control and for guiding optimal anti-inflammatory asthma therapy. However, because of many unresolved questions, eNO cannot be recommended at present for routine clinical management of adults with asthma.
PMCID: PMC2677842  PMID: 18354750
Airways inflammation; Asthma; Exhaled nitric oxide
21.  Evaluation and Validation of a Method for Determining Platelet Catecholamine in Patients with Obstructive Sleep Apnea and Arterial Hypertension 
PLoS ONE  2014;9(6):e98407.
Measurements of plasma and urinary catecholamine are susceptible to confounding factors that influence the results, complicating the interpretation of sympathetic nervous system (SNS) activity in the Obstructive sleep apnea (OSA) and arterial hypertension (HYP) conditions.
In this study, we validated a test for platelet catecholamine and compared the catecholamine levels (adrenaline and noradrenaline) in urine, plasma and platelets in patients with OSA and HYP compared with controls.
In the validation, 30 healthy, nonsmoking volunteers who were not currently undergoing treatment or medication were selected as the control group. One hundred fifty-four individuals (114 OSA, 40 non-OSA) were consecutively selected from the outpatient clinic of the Sleep Institute and underwent clinical, polysomnographic and laboratory evaluation, including the urinary, plasma and platelet levels of adrenaline (AD) and noradrenaline (NA). Patients were then allocated to groups according to the presence of OSA and/or hypertension.
A logistic regression model, controlled for age and BMI, showed that urinary AD and urinary NA were risk factors in the OSA+HYP group and the HYP group; however, the model showed higher levels of platelet NA for OSA without HYP. After 1 year of CPAP (continuous upper airway pressure) treatment, patients (n = 9) presented lower levels of urinary NA (p = 0.04) and platelet NA (p = 0.05).
Urinary NA and AD levels were significantly associated with the condition of hypertension with and without OSA, whereas platelet NA with OSA without comorbidity. These findings suggest that platelet catecholamine levels might reflect nocturnal sympathetic activation in OSA patients without hypertension.
PMCID: PMC4049580  PMID: 24911183
22.  Albuterol enantiomer levels, lung function and QTc interval in patients with acute severe asthma and COPD in the emergency department 
This observational study was designed to investigate plasma levels of albuterol enantiomers among patients with acute severe asthma or COPD presenting to the emergency department, and the relationship with extra-pulmonary cardiac effects (QTc interval) and lung function. Recent reviews have raised concerns about the safety of using large doses of β2-agonists, especially in patients with underlying cardiovascular comorbidity. It has been demonstrated that significant extrapulmonary effects can be observed in subjects given nebulised (R/S)-albuterol at a dose of as little as 6.5 mg.
Blood samples were collected and plasma/serum levels of (R)- and (S)-albuterol enantiomers were determined by LC-MS and LC-MS/MS assay. Extra-pulmonary effects measured at presentation included ECG measurements, serum potassium level and blood sugar level, which were collected from the hospital medical records.
High plasma levels of both enantiomers were observed in some individuals, with median (range) concentrations of 8.2 (0.6-24.8) and 20.6 (0.5-57.3) ng/mL for (R)- and (S)- albuterol respectively among acute asthma subjects, and 2.1 (0.0-16.7) to 4.1 (0.0-36.1) ng/mL for (R)- and (S)- albuterol respectively among COPD subjects. Levels were not associated with an improvement in lung function or adverse cardiac effects (prolonged QTc interval).
High plasma concentrations of albuterol were observed in both asthma and COPD patients presenting to the emergency department. Extra-pulmonary cardiac adverse effects (prolonged QTC interval) were not associated with the plasma level of (R)- or (S)-albuterol when administered by inhaler in the emergency department setting. Long-term effect(s) of continuous high circulating albuterol enantiomer concentrations remain unknown, and further investigations are required.
PMCID: PMC3135507  PMID: 21676212
23.  Hyperventilation and asymptomatic chronic asthma 
Thorax  2000;55(12):1016-1022.
BACKGROUND—We have consistently argued that mild asthma is an important underlying aetiological factor in patients with severe symptomatic hyperventilation. While hyperventilation has been demonstrated in acute asthma, there have been few studies in mild chronic asthma, and mechanisms are uncertain.
METHODS—Twenty three currently asymptomatic chronically asthmatic patients (occasional use of bronchodilators, normal lung function, hyperresponsive to methacholine) were studied and 17 matched normal subjects acted as controls. Ventilation, pattern of breathing, arterial carbon dioxide and oxygen tensions (PaCO2, PaO2), end tidal PCO2 (PETCO2), standard lung function, airway responsiveness to methacholine, airway inflammation assessed by eosinophils in induced sputum, and psychiatric morbidity (Spielberger STAI-Y and Beck Depression Inventory) were measured.
RESULTS—Despite the absence of current asthmatic symptoms, no clinical evidence of hyperventilation, and normal lung function in the patients with asthma, PaCO2 and PETCO2 were significantly (p<0.01) lower in the patients than in the control group (mean (SD) PaCO2 4.96 (0.43) kPa for patients versus 5.27 (0.38) kPa for controls (mean difference 0.31 kPa, 95% confidence interval (CI) 0.06 to 0.56, p<0.02)). PETCO2 was very similar to PaCO2 in both groups (mean (SD) PETCO2 4.89 (0.47) kPa for the patients and 5.28 (0.40) for the controls (mean difference 0.39 kPa, 95% CI 0.12 to 0.66,p<0.01)). There was no significant difference in ventilation or respiratory pattern between the two groups. The reduced PaCO2 in the asthmatic patients correlated significantly with the concentration of methacholine provoking a fall in FEV1 of more than 20% (PC20) (r = 0.56, p<0.01) but not with any aspect of lung function, eosinophil count, or anxiety/depression.
CONCLUSION—Mild asymptomatic asthma is not associated with clinically significant hyperventilation but is associated with a significant reduction in both arterial and end tidal PCO2 which relates to airway hyperresponsiveness rather than to the degree of airway obstruction or mucosal inflammation. Anxiety and depression appear not to be implicated.

PMCID: PMC1745650  PMID: 11083886
24.  Croup 
Clinical Evidence  2009;2009:0321.
Croup is characterised by the abrupt onset, most commonly at night, of a barking cough, inspiratory stridor, hoarseness, and respiratory distress due to upper airway obstruction. It leads to signs of upper airway obstruction, and must be differentiated from acute epiglottitis, bacterial tracheitis, or an inhaled foreign body. Croup affects about 3% of children a year, usually between the ages of 6 months and 3 years, and 75% of infections are caused by parainfluenza virus. Symptoms usually resolve within 48 hours, but severe infection can, rarely, lead to pneumonia, and to respiratory failure and arrest.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments in children with: mild croup; moderate to severe croup; and impending respiratory failure because of severe croup? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2008 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 43 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antibiotics, corticosteroids, dexamethasone (intramuscular, oral, single-dose oral, route of administration), heliox, humidification, intermittent positive pressure breathing, L-adrenaline, nebulised adrenaline (epinephrine), nebulised budesonide, nebulised short-acting beta2 agonists, oral decongestants, oral prednisolone, oxygen, and sedatives.
Key Points
Croup leads to signs of upper airway obstruction, and must be differentiated from acute epiglottitis, bacterial tracheitis, or an inhaled foreign body. Croup affects about 3% of children a year, usually between the ages of 6 months and 3 years, and 75% of infections are caused by parainfluenza virus.Symptoms usually resolve within 48 hours, but severe infection can, rarely, lead to respiratory failure and arrest.
A single oral dose of dexamethasone improves symptoms in children with mild croup, compared with placebo. Although humidification and oral decongestants are often used in children with mild to moderate croup, there is no evidence to support their use in clinical practice.There is consensus that antibiotics do not improve symptoms in croup of any severity, as croup is usually viral in origin.
In children with moderate to severe croup, intramuscular or oral dexamethasone, nebulised adrenaline (epinephrine), and nebulised budesonide reduce symptoms compared with placebo. Oxygen is standard treatment in children with respiratory distress. Oral dexamethasone is as effective as nebulised budesonide at reducing symptoms, and is less distressing for the child.A dexamethasone dose of 0.15 mg/kg may be as effective as a dose of 0.6 mg/kg. Adding nebulised budesonide to oral dexamethasone does not seem to improve efficacy compared with either drug alone.Nebulised adrenaline (epinephrine) has a short-term effect on symptoms of croup, but we don't know whether adding intermittent positive-pressure breathing to nebulised adrenaline further improves symptoms.We don't know whether heliox (helium–oxygen mixture), humidification, short-acting nebulised beta2 agonists, or oral decongestants are beneficial in children with moderate to severe croup, or with impending respiratory failure.
In children with impending respiratory failure caused by severe croup, nebulised adrenaline (epinephrine) is considered likely to be beneficial. Oxygen is standard treatment. Nasogastric prednisolone reduces the need for, or duration of, intubation, but sedatives and antibiotics are unlikely to be beneficial.
PMCID: PMC2907784  PMID: 19445760
25.  Enhanced Dense Core Granule Function and Adrenal Hypersecretion in a Mouse Model of Rett Syndrome 
Rett Syndrome (RTT) is a progressive developmental disorder resulting from loss of function mutations in the gene encoding MeCP2 (methyl-CpG-binding protein 2), a transcription regulatory protein. The RTT phenotype is complex and includes severe cardiorespiratory abnormalities, dysautonomia and behavioral symptoms of elevated stress. These findings have been attributed to an apparent hyperactivity of the sympathetic nervous system due to defects in brainstem development; however, the possibility that the peripheral sympathoadrenal axis itself is abnormal has not been explored. The present study demonstrates that the adrenal medulla and sympathetic ganglia of Mecp2 null mice exhibit markedly reduced catecholamine content compared to wildtype controls. Despite this, null animals exhibit significantly higher plasma epinephrine levels, suggesting enhanced secretory granule function in adrenal chromaffin cells. Indeed, we find that Mecp2 null chromaffin cells exhibit a cell autonomous hypersecretory phenotype characterized by significant increases in the speed and size of individual secretory granule fusion events in response to electrical stimulation. These findings appear to indicate accelerated formation and enhanced dilation of the secretory granule fusion pore, resulting in elevated catecholamine release. Our data therefore highlight abnormal catecholamine function in the sympathoadrenal axis as a potential source of autonomic dysfunction in RTT. These findings may help to explain the apparent “overactivity” of the sympathetic nervous system reported in RTT patients.
PMCID: PMC2758854  PMID: 19674087
exocytosis; chromaffin; sympathetic; neurosecretion; neuroendocrine

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