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D F McAuley

Publications and source records attributed to D F McAuley.

16 recordsLinked to original sources
PubMed2006

In vitro and in vivo effects of salbutamol on neutrophil function in acute lung injury.

BACKGROUND: Intravenous salbutamol (albuterol) reduces lung water in patients with the acute respiratory distress syndrome (ARDS). Experimental data show that it also reduces pulmonary neutrophil accumulation or activation and inflammation in ARDS. AIM: To investigate the effects of salbutamol on neutrophil function. METHODS: The in vitro effects of salbutamol on neutrophil function were determined. Blood and bronchoalveolar lavage (BAL) fluid were collected from 35 patients with acute lung injury (ALI)/ARDS, 14 patients at risk from ARDS and 7 ventilated controls at baseline and after 4 days' treatment with placebo or salbutamol (ALI/ARDS group). Alveolar-capillary permeability was measured in vivo by thermodilution (PiCCO). Neutrophil activation, adhesion molecule expression and inflammatory cytokines were measured. RESULTS: In vitro, physiological concentrations of salbutamol had no effect on neutrophil chemotaxis, viability or apoptosis. Patients with ALI/ARDS showed increased neutrophil activation and adhesion molecule expression compared with at risk-patients and ventilated controls. There were associations between alveolar-capillary permeability and BAL myeloperoxidase (r = 0.4, p = 0.038) and BAL interleukin 8 (r = 0.38, p = 0.033). In patients with ALI/ARDS, salbutamol increased numbers of circulating neutrophils but had no effect on alveolar neutrophils. CONCLUSION: At the onset of ALI/ARDS, there is increased neutrophil recruitment and activation. Physiological concentrations of salbutamol did not alter neutrophil chemotaxis, viability or apoptosis in vitro. In vivo, salbutamol increased circulating neutrophils, but had no effect on alveolar neutrophils or on neutrophil activation. These data suggest that the beneficial effects of salbutamol in reducing lung water are unrelated to modulation of neutrophil-dependent inflammatory pathways.

Albuterol↗
PubMed2005

Randomised controlled cross-over comparison of continuous positive airway pressure through the Hamilton Galileo ventilator with a Dräger CF 800 device.

In this controlled, randomised cross-over trial on 26 intensive care patients, we compared the effects on haemodynamic and respiratory profiles of continuous positive airway pressure delivered through the Hamilton Galileo ventilator or a Drager CF 800 device. We also compared the nursing time saved using the two approaches when weaning patients from mechanical ventilation. We did not find significant differences in haemodynamics, respiratory rate, physiological dead space, oxygen saturation and carbon dioxide production between the continuous positive airway pressure generated by the Galileo and Drager machines. However, there was a 10-fold reduction in nursing time using the Galileo ventilator compared with the Drager generator. We conclude that continuous positive airway pressure delivered through the Galileo ventilator is as efficient as a Drager device but consumes less nursing time.

Adult↗
PubMed2005

Regulation of vascular endothelial growth factor bioactivity in patients with acute lung injury.

BACKGROUND: Reduced bioactive vascular endothelial growth factor (VEGF) has been demonstrated in several inflammatory lung conditions including the acute respiratory distress syndrome (ARDS). sVEGFR-1, a soluble form of VEGF-1 receptor, is a potent natural inhibitor of VEGF. We hypothesised that sVEGFR-1 plays an important role in the regulation of the bioactivity of VEGF within the lung in patients with ARDS. METHODS: Forty one patients with ARDS, 12 at risk of developing ARDS, and 16 normal controls were studied. Bioactive VEGF, total VEGF, and sVEGFR-1 were measured by ELISA in plasma and bronchoalveolar lavage (BAL) fluid. Reverse transcriptase polymerase chain reaction for sVEGFR-1 was performed on BAL cells. RESULTS: sVEGFR-1 was detectable in the BAL fluid of 48% (20/41) of patients with early ARDS (1.4-54.8 ng/ml epithelial lining fluid (ELF)) compared with 8% (1/12) at risk patients (p = 0.017) and none of the normal controls (p = 0.002). By day 4 sVEGFR-1 was detectable in only 2/18 ARDS patients (p = 0.008). Patients with detectable sVEGFR-1 had lower ELF median (IQR) levels of bioactive VEGF than those without detectable sVEGFR-1 (1415.2 (474.9-3192) pg/ml v 4761 (1349-7596.6) pg/ml, median difference 3346 pg/ml (95% CI 305.1 to 14711.9), p = 0.016), but there was no difference in total VEGF levels. BAL cells expressed mRNA for sVEGFR-1 and produced sVEGFR-1 protein which increased following incubation with tumour necrosis factor alpha. CONCLUSION: This study shows for the first time the presence of sVEGFR-1 in the BAL fluid of patients with ARDS. This may explain the presence of reduced bioactive VEGF in patients early in the course of ARDS.

Adolescent↗
PubMed2002

What is the optimal duration of ventilation in the prone position in acute lung injury and acute respiratory distress syndrome?

OBJECTIVE: To evaluate the effects of prone ventilation on respiratory parameters and extravascular lung water (EVLW) in patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in order to characterise the optimal duration of ventilation in the prone position. DESIGN: Prospective, observational study. SETTING: Nine-bed general intensive care unit. PATIENTS: Eleven patients with refractory hypoxaemia due to ALI/ARDS were prospectively investigated during 12 consecutive episodes of prone ventilation. INTERVENTIONS: Ventilation in the prone position for 18 h. MEASUREMENTS AND MAIN RESULTS: Measurements were obtained supine and after 1, 2, 6, 12 and 18 h in the prone position and 1 h after returning supine. There was a progressive improvement in PaO(2)/fraction of inspired oxygen (FIO(2)) ratio which reached significance after 12 h [121 (81-151) to 258 (187-329) torr; p<0.05]. EVLW index increased transiently at 1 h [14.2 (7.6-20.8) to 15.1 (9.0-20.2); p=0.05] and thereafter declined progressively and was significantly decreased at 18 h [12.1 (7.2-17.0); p=0.043]. The shunt fraction showed an early fall [0.41 (0.40-0.42) to 0.31 (0.30-0.32) at 1 h; p<0.001] preceding a subsequent progressive fall [0.22 (0.21-0.23) at 18 h; p<0.001]. CONCLUSIONS: Over the 18 h period studied there was progressive improvement in gas exchange, pulmonary shunt and EVLW. Although it is not possible to exclude that improvement over this period was unrelated to prone positioning, these findings suggests that ventilation in the prone position for more prolonged periods may be required for optimal improvement and warrants further study.

Adolescent↗
PubMed2001

The effect on endothelial function of vitamin C during methionine induced hyperhomocysteinaemia.

BACKGROUND: Manipulation of total homocysteine concentration with oral methionine is associated with impairment of endothelial-dependent vasodilation. This may be caused by increased oxidative stress. Vitamin C is an aqueous phase antioxidant vitamin and free radical scavenger. We hypothesised that if the impairment of endothelial function related to experimental hyperhomocysteinaemia was free radically mediated then co-administration of vitamin C should prevent this. METHODS: Ten healthy adults took part in this crossover study. Endothelial function was determined by measuring forearm blood flow (FBF) in response to intra-arterial infusion of acetylcholine (endothelial-dependent) and sodium nitroprusside (endothelial-independent). Subjects received methionine (100 mg/Kg) plus placebo tablets, methionine plus vitamin C (2 g orally) or placebo drink plus placebo tablets. Study drugs were administered at 9 am on each study date, a minimum of two weeks passed between each study. Homocysteine (tHcy) concentration was determined at baseline and after 4 hours. Endothelial function was determined at 4 hours. Responses to the vasoactive substances are expressed as the area under the curve of change in FBF from baseline. Data are mean plus 95% Confidence Intervals. RESULTS: Following oral methionine tHcy concentration increased significantly versus placebo. At this time endothelial-dependent responses were significantly reduced compared to placebo (31.2 units [22.1-40.3] vs. 46.4 units [42.0-50.8], p < 0.05 vs. Placebo). Endothelial-independent responses were unchanged. Co-administration of vitamin C did not alter the increase in homocysteine or prevent the impairment of endothelial-dependent responses (31.4 [19.5-43.3] vs. 46.4 units [42.0-50.8], p < 0.05 vs. Placebo) CONCLUSIONS: This study demonstrates that methionine increased tHcy with impairment of the endothelial-dependent vasomotor responses. Administration of vitamin C did not prevent this impairment and our results do not support the hypothesis that the endothelial impairment is mediated by adverse oxidative stress.

Acetylcholine↗
PubMed2001

The effects of oral methionine and homocysteine on endothelial function.

BACKGROUND: Raised homocysteine is a risk factor for vascular disease. Homocysteine is formed from methionine, and dietary manipulation of homocysteine in primates and humans with oral methionine is associated with endothelial dysfunction. A cause-effect relation has not been clearly established. AIM: To study the effect of oral methionine and then oral homocysteine on endothelial function. METHODS: 22 healthy adults were recruited for two randomised crossover studies, each containing 11 subjects. Endothelial function was determined by measuring forearm blood flow in response to intra-arterial infusion of acetylcholine (endothelium dependent) and sodium nitroprusside (endothelium independent). Subjects received methionine or placebo (study 1), or homocysteine or placebo (study 2). Methionine and homocysteine were determined at baseline and t = 4 hours. Endothelial function was determined at four hours. The responses to the vasoactive substances are expressed as the area under the curve of change in forearm blood flow from baseline. RESULTS: Study 1: plasma methionine and homocysteine concentrations increased significantly versus placebo. The increases were associated with a reduction of endothelium dependent responses (mean (95% confidence interval), arbitrary units), from 48.8 (95% CI 36.4 to 61.2) to 29.9 (95% CI 18.0 to 41.1), p < 0.04; endothelium independent responses were unchanged. Study 2: homocysteine concentration increased significantly while methionine remained unchanged. Endothelium dependent responses were reduced from 34.6 (95% CI 20.6 to 48.6) to 22.8 (95% CI 12.0 to 33.6), p < 0.03. CONCLUSIONS: Homocysteine and not methionine is responsible for the changes in endothelial function. This supports the hypothesis that homocysteine promotes atherosclerosis by inducing endothelial dysfunction.

Administration, Oral↗
PubMed2001

Hyperhomocysteinaemia in young adults is not associated with impaired endothelial function.

A mild to moderate elevation of the total homocysteine concentration (tHcy) is now recognized as a risk factor for vascular disease. It is also associated with endothelial dysfunction in middle-aged and elderly individuals without overt atherosclerotic vascular disease. This is important, as endothelial dysfunction is a well recognized early and potentially reversible marker of the atherosclerotic process. We investigated whether mild hyperhomocysteinaemia was associated with endothelial dysfunction in otherwise healthy young males. We compared endothelial function, by measuring forearm blood flow, in 17 males with mild hyperhomocysteinaemia (defined as tHcy >10 micromol/l) and 14 controls with low tHcy (defined as <5 micromol/l). Forearm blood flow was measured in response to the intra-arterial infusion of acetylcholine (endothelial-dependent response) or sodium nitroprusside (endothelial-independent response). Responses to the vasoactive substances were expressed as the area under the curve of the change in forearm blood flow from baseline. Data are given as mean (95% confidence interval). The two groups were well matched for age, body mass index, pulse rate and blood pressure. tHcy was significantly different between the groups [12.3 (10.4-14.2) micromol/l compared with 4.9 (4.6-5.1) micromol/l; P<0.001]. Concentrations of vitamin B(12) and folate were significantly higher in the control group. There was no difference in basal forearm blood flow between the group with mild hyperhomocysteinaemia and the controls, and both the endothelial-dependent [37.5 (26.2-38.8) and 35.3 (26.1-44.4) arbitrary units respectively] and -independent [26.1 (22.2-29.9) and 25.9 (21.0-30.8) units respectively] responses were not significantly different between the groups. Thus the present study demonstrates that, in healthy adults, mild elevation of tHcy was not associated with impaired endothelial-dependent vasodilation. These data suggest an age effect with regard to homocysteine and endothelial dysfunction. The development of vascular disease in individuals with hyperhomocysteinaemia may only result with higher concentrations or after prolonged exposure.

Acetylcholine↗
PubMed2000

Cystic fibrosis: basic science.

Advances in the elucidation of cystic fibrosis transmembrane regulator (CFTR) function have resulted in a greater understanding of the relationship between the CF gene defect and clinical disease. The clinical phenotype is influenced by the class of mutation and possibly by other modifier genes. CFTR regulates the volume and composition of airways surface liquid, primarily by controlling chloride ion transport. However, CFTR also regulates other membrane channels and transports other molecules which may be important in mucocilary clearance and innate defence mechanisms. CFTR may also modulate the inflammatory response in respiratory epithelial cells and other inflammatory cells through a range of mechanisms. It is apparent that CFTR dysfunction results in a range of effects which may contribute to the clinical phenotype. These may contribute to the development of clinical disease at different stages of the natural history of cystic fibrosis. A greater understanding of the basic defect and its implications is likely to result in novel therapeutic approaches.

Bacterial Infections↗
PubMed2000

Vasoconstriction to endothelin-1 is blunted in non-insulin-dependent diabetes: a dose-response study.

The haemodynamic hypothesis for the pathogenesis of diabetic microangiopathy argues that an initial increase in microvascular blood flow leads to microvascular sclerosis and disturbed autoregulation. Endothelin-1 (ET-1) is an endothelium-derived vasoconstrictor peptide that contributes to basal vascular tone. Impairment of the vasoconstrictor response to ET-1 could result in hyperperfusion and subsequent microvascular damage. The purpose of this study was to determine whether vascular responses to ET-1 are impaired in patients with non-insulin-dependent diabetes mellitus (type 2 diabetes). Ten patients with type 2 diabetes and nine control subjects underwent brachial artery cannulation. Forearm blood flow was measured using strain-gauge venous occlusion plethysmography. ET-1 in three doses of 5, 10, and 20 pmol/min and 0.9% saline placebo was infused in a balanced double-blind randomised manner. Vascular smooth muscle function also was assessed using sodium nitroprusside. Control subjects showed vasoconstriction to ET-1 of 5 (p < 0.05), 10 (p < 0.05), and 20 pmol/min (p < 0.01). In the diabetic group, there was no significant response to ET-1 at 5 pmol/min (p > 0.05); however, significant vasoconstriction developed at 10 and 20 pmol/min (p < 0.01). There was a significant difference in response to ET-1 at 5 pmol/min between the diabetic and control groups (p < 0.05). Responses to sodium nitroprusside were similar in both groups (p > 0.05). Patients with type 2 diabetes have a blunted vasoconstrictor response to ET-1 despite preserved vascular smooth muscle function.

Adult↗
PubMed2000

Vasoconstriction to endogenous endothelin-1 is impaired in patients with type II diabetes mellitus.

Endothelin-1 has potent vasoconstrictor and vasopressor actions contributing to basal vascular tone and maintenance of blood pressure acting predominantly through endothelin-A receptors. Endothelin antagonists may be of value in the treatment of hypertension and heart failure. However, the role of endothelin-1 in the regulation of vascular tone and the potential benefits of endothelin antagonists in non-insulin-dependent diabetes mellitus (Type II diabetes) are less clear. Vasoconstriction to exogenous endothelin-1 is impaired in Type II diabetes. The purpose of this study was to determine whether vasoconstriction to endogenous endothelin-1 acting through the endothelin-A receptor is impaired in Type II diabetes. In ten patients with Type II diabetes and nine controls the endothelin-A receptor antagonist BQ123 was infused intra-arterially at 100 nmol/min for 60 min followed by normal saline for 30 min. Forearm blood flow was measured using venous occlusion plethysmography. Control subjects showed gradual onset of vasodilation in response to BQ123 (P < 0.001). Diabetic subjects, however, showed no significant response (P > 0.05). There was a significant difference between the diabetic and control groups (P < 0.05). Blockade of the endothelin-A receptor is associated with impaired vasodilation in Type II diabetes indicating vasoconstriction to endogenous endothelin-1 mediated by the endothelin-A receptor is impaired.

Adult↗
PubMed1999

Effect of methionine supplementation on endothelial function, plasma homocysteine, and lipid peroxidation.

BACKGROUND: Acetaminophen (paracetamol) poisoning is a major source of morbidity and mortality. It has been proposed that methionine be incorporated into acetaminophen tablets routinely as a protective mechanism. Methionine has been shown to be effective in the treatment of acetaminophen toxicity and a combination preparation of acetaminophen and methionine may prevent toxicity. However, there has been some concern that chronic methionine supplementation may be associated with vascular disease. The aim of the study was to investigate if methionine supplementation causes changes in endothelial function, plasma homocysteine, or lipid peroxidation which may be associated with atherosclerosis. METHODS: Sixteen healthy volunteers were studied. Forearm blood flow in response to local intra-arterial infusion of acetylcholine to assess endothelium-dependent vasodilatation and sodium nitroprusside to assess endothelium-independent vasodilatation was measured by venous occlusion plethysmography. Plasma homocysteine and lipid peroxidation, measured as thiobarbituric acid reactive substances, were measured using high-performance liquid chromatography. Forearm vascular responses, plasma homocysteine concentrations, and thiobarbituric acid reactive substances were measured at baseline and following methionine supplementation. RESULTS: There was no significant difference in endothelial-dependent vascular responses after acute (methionine 250 mg orally, p > 0.05), 1 month of low-dose (methionine 250 mg daily, p > 0.05), or 1 week of high-dose (methionine 100 mg/kg daily, p > 0.05) methionine administration. There was no significant difference in plasma homocysteine concentrations after acute (p > 0.05) or 1 month of low-dose (p > 0.05) methionine administration. However, 1 week of high-dose methionine (100 mg/kg) administration daily significantly increased homocysteine concentrations (p < 0.0015). Thiobarbituric acid reactive substances were unchanged during the period of study (p > 0.05). CONCLUSIONS: Methionine supplementation does not impair endothelial-dependent vascular responses in healthy volunteers. Although high-dose methionine administration causes elevation of plasma homocysteine concentrations, doses similar to those used in combination preparations with acetaminophen do not affect plasma homocysteine concentrations.

Acetylcholine↗
PubMedDate not supplied

No evidence of endothelial dysfunction in patients with Alzheimer's disease.

In view of accumulating evidence of vascular pathology in Alzheimer's disease (AD), we tested the hypothesis that AD patients have impaired endothelial function. This was assessed using the technique of strain-gauge venous occlusion plethysmography, which measures forearm blood flow (FBF). Intra-arterial (brachial) infusion of acetylcholine (ACh) and sodium nitroprusside (SNP) was used to assess local endothelial dependent and independent responses, respectively. There was no difference in the basal FBF of patients and controls. ACh and SNP caused dose-related increases in FBF from baseline, but no difference was recorded between the AD and control group. This study provides no evidence of endothelial dysfunction in the systemic circulation of patients with AD.

Acetylcholine↗