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Biomedical subjects

Andrew Bush

Publications and source records attributed to Andrew Bush.

At least 73 records · Page 4Linked to original sources
PubMed2004

Insulin-like growth factor 1 improves the relationship between systemic oxygen consumption and delivery in piglets after cardiopulmonary bypass.

OBJECTIVE: We sought to assess the effects of insulin-like growth factor 1 on the balance between systemic oxygen consumption and oxygen delivery after cardiopulmonary bypass in piglets. METHODS: Twelve piglets weighing 4.5 to 8.3 kg undergoing hypothermic (28 degrees C) cardiopulmonary bypass for 70 to 120 minutes with 40 minutes of aortic crossclamping were studied before and during the first 6 hours after cardiopulmonary bypass. Oxygen consumption was continuously measured by an indirect calorimeter, Deltatrac II MBM-200 Metabolic Monitor (Datex Division Instrumentarium, Helsinki, Finland). Oxygen delivery and cardiac output were calculated from oxygen consumption and the arterial and mixed venous oxygen contents sampled before and every 30 minutes after cardiopulmonary bypass. Oxygen extraction ratio was derived by the ratio of oxygen consumption to oxygen delivery. Arterial blood lactate was measured before and every 30 minutes after cardiopulmonary bypass. Six animals were randomly assigned to receive an intravenous infusion of insulinlike growth factor 1 at 1.2 mg/h from 1 to 6 hours after cardiopulmonary bypass; the remaining 6 served as a control group. RESULTS: Relative to the control group, intravenous infusion of insulin-like growth factor 1 significantly reduced oxygen consumption (P =.02) and increased cardiac output (P =.016) and oxygen delivery (P =.049) during the first 6 hours after surgery with hypothermic cardiopulmonary bypass. As a result, oxygen extraction was significantly decreased (P =.012). CONCLUSIONS: Intravenous infusion of insulin-like growth factor 1 improved oxygen transport by reducing oxygen consumption as well as increasing cardiac output and oxygen delivery during the first 6 hours after cardiopulmonary bypass in piglets. This may have important clinical implications for the care of critically ill children after surgery with cardiopulmonary bypass.

Age Factors↗
PubMed2004

Phenotype-specific treatment of difficult asthma in children.

Most children with asthma can be treated successfully with low-to-moderate doses of inhaled corticosteroid and long-acting beta-2 agonist. Those that fail to respond are a heterogeneous group. We propose that the nature and type of any steroid-resistant inflammation, the extent of any persistent airflow limitation and the extent of bronchial hyper-reactivity should be determined separately to allow a rational treatment approach to these children, rather than the haphazard advice of many current guidelines. Reasons for persistent difficult asthma include persistent eosinophilic inflammation, non-eosinophilic inflammation, airway reactivity without residual inflammation and persistent airflow limitation. We propose a protocol that uses non-invasive and invasive (bronchoscopic) methods to document the response to systemic steroids (depot triamcinolone). The aim of the protocol is to determine an individualised treatment plan; for example, cyclosporin for persistent eosinophilic inflammation, azithromycin for persistent neutrophilic inflammation and continuous subcutaneous terbutaline if there is airway reactivity without residual inflammation. Multi-centre studies are required to test the utility of this approach.

Asthma↗
PubMed2004

Phenotype specific treatment of asthma in childhood.

The term "asthma syndrome" encompasses a range of disorders, all characterised clinically by combinations of cough, wheeze and breathlessness. In older children, evidence of variable airway obstruction is manifest by change in peak flow over time or with treatment, reduction in peak flow on exercise, and a positive methacholine challenge. The underlying pathology includes combinations of bronchial hyperreactivity (BHR), airway inflammation and alterations in underlying baseline airway calibre or compliance. This is not merely of academic importance, but is fundamental to organizing appropriate treatment. In children with symptoms with viral colds and also between colds, and in particular if they are atopic, the underlying abnormality is likely to be T-cell driven, eosinophil-mediated airway inflammation. There is compelling evidence that early treatment with inhaled corticosteroids is essential if airway remodelling is to be avoided and optimum long-term lung function is to be achieved. The pathophysiology of wheezing with viral colds in the non-atopic infant is completely different; such infants have evidence of abnormal lung function soon after birth and before their first episode of viral wheeze, and no evidence of either bronchial hyperreactivity or airflow inflammation. Response to inhaled steroids is very poor. For most infants with wheeze, it is currently not possible to predict whether they will go on to the picture of established asthma. Post-bronchiolitic asthma syndrome also does not respond to inhaled steroids, because prolonged symptoms are likely due to abnormal pre-morbid airway function, albeit worsened by atopy. Phenotype-specific treatment is also important in older children who have severer asthma and do not respond to high dose inhaled steroids. We have delineated a group with marked BHR but no evidence of inflammation who respond to subcutaneous terbutaline, and a second group with steroid resistant inflammation who may do better with cyclosporin. A phenotype-specific treatment approach may also help to delineate which add on therapy (long-acting beta agonist, leukotriene receptor antagonist, theophylline) is best for children with moderate asthma not controlled by moderate dose (400 mcg/day) inhaled corticosteroids. Asthma is not one disease but many, and attention to delineating clinical phenotypes, rather than being obsessed with guidelines based on large heterogeneous groups, may allow rational individual treatment.

Adult↗
PubMed2004

Breath condensate pH in children with cystic fibrosis and asthma: a new noninvasive marker of airway inflammation?

STUDY OBJECTIVES: The noninvasive assessment and monitoring of airway inflammation could be important in respiratory disease. The pH of exhaled breath condensate (EBC) is a promising marker. Although pH has been measured in the EBC of adults with inflammatory airway diseases, no study has measured this in children. DESIGN: This study aimed to assess whether there is a change in pH in the EBC of children with cystic fibrosis (CF) and asthma, and to try to determine whether pH could be used as a marker of airway inflammation. Furthermore, the relationships among EBC pH, severity of disease, and oxidative stress were studied. PATIENTS AND METHODS: We studied 20 children with CF (mean [+/- SEM] age, 7 +/- 3 years), 20 children with asthma (mean age, 7 +/- 2 years), and 15 age-matched healthy children (mean age, 7 +/- 2 years). The pH of EBC was measured using a pH meter. MEASUREMENTS AND RESULTS: Lower pH values were observed in the EBC of children with CF and asthma compared to control subjects (mean pH, 7.23 +/- 0.03 and 7.42 +/- 0.01 vs 7.85 +/- 0.02, respectively). Furthermore, relationships among EBC pH, severity of asthma, and the presence of an infective exacerbation of CF was found. There was a negative correlation between exhaled pH and exhaled leukotriene B(4) concentrations (r = -0.5; p < 0.005). CONCLUSION: We conclude that the measurement of EBC pH may be useful in the evaluation of airway inflammation in children with asthma and CF.

Asthma↗
PubMed2003

Free secretory component from cystic fibrosis sputa displays the cystic fibrosis glycosylation phenotype.

Secretory IgA contributes to humoral defense mechanisms against pathogens targeting mucosal surfaces, and secretory component (SC) fulfills multiple roles in this defense. The aims of this study were to quantify total SC and to analyze the form of free SC in sputa from normal subjects, subjects with asthma, and subjects with cystic fibrosis (CF). Significantly higher levels of SC were detected in CF compared with both other groups. Gel filtration chromatography revealed that SC in CF was relatively degraded. Free SC normally binds interleukin (IL)-8 and inhibits its function. However, in CF sputa, IL-8 binding to intact SC was reduced. Analysis of the total carbohydrate content of free SC signified overglycosylation in CF compared with normal subjects and subjects with asthma. Monosaccharide composition analysis of free SC from CF subjects revealed overfucosylation and undersialylation, in agreement with the reported CF glycosylation phenotype. SC binding to IL-8 did not interfere with the binding of IL-8 to heparin, indicating distinct binding sites on IL-8 for negative regulation of function by SC and heparin. We suggest that defective structure and function of SC contribute to the characteristic sustained inflammatory response in the CF airways.

Adult↗
PubMed2003

Early thickening of the reticular basement membrane in children with difficult asthma.

Remodeling of the airway wall occurs in adults with asthma, and reticular basement membrane (RBM) thickening is pathognomonic of the asthma process. To investigate whether RBM thickening is present in children with difficult asthma and comparable to that seen in adults with asthma, we used light microscopy to measure RBM thickness in plastic-embedded endobronchial biopsy sections from 19 children with difficult asthma who were prescribed 1,600 microg/day or more of inhaled steroids (age range, 6-16 years), 10 children without asthma (7-16 years), and three adult groups: 8 healthy control subjects (21-42 years), 10 mild steroid-naive subjects with asthma (18-41 years), and 6 adults (3 steroid naive and 3 on inhaled steroids) intubated after a life-threatening attack of asthma (20-64 years). RBM thickness in the children with asthma was similar to that in adults with either mild or life-threatening asthma (median 8.2 [range 5.4-11.1] versus 8.1 [5.8-10.0] and 7.2 [2.8-10.0] microm, respectively) and greater than either adult or pediatric control subjects (8.2 [5.4-11.1] versus 4.4 [3.2-6.3] microm, p < 0.01, and 4.9 [3.7-8.3] microm, p < 0.01). We conclude that RBM thickening is already present in children with difficult asthma and to a similar extent to that seen in adults with asthma. In addition, we find no association with age, symptom duration, lung function, or concurrent eosinophilic airway inflammation.

Adolescent↗
PubMed2003

Safety and use of sputum induction in children with cystic fibrosis.

We assessed the safety and use of induced sputum (IS) in children with cystic fibrosis (CF). Forty-eight children (19 males) with CF, mean age 12.6 (range, 7.3-17.0) years and median forced expired volume in 1 sec (FEV(1)) 48% (range, 14-77%) predicted were recruited. Patients spontaneously expectorated sputum and then performed sputum induction by inhalation of nebulized 7% hypertonic saline. Samples were sent for bacteriological culture, and for measurement of the following inflammatory mediators: interleukin-8, myeloperoxidase, eosinophil cationic protein, and neutrophil elastase activity. FEV(1) was performed before and after inhalation of hypertonic saline. There was no increase in mediator levels in IS compared to expectorated sputum (ES) samples. Only 3 patients demonstrated significant bronchoconstriction following inhalation of hypertonic saline, by the method used. From the ES samples, Pseudomonas aeruginosa was isolated in 13 patients, Staphylococcus aureus in 7 patients, Stenotrophomonas maltophilia in 1 patient, and both Pseudomonas aeruginosa and Staphylococcus aureus in 5 patients. All these organisms were found in the IS samples. However, in 2 patients whose ES grew no organisms, one patient's IS grew Pseudomonas aeruginosa, and the other patient's IS grew Staphylococcus aureus. In our study, sputum induction was safe, with no proinflammatory effect.

Adolescent↗
PubMed2003

Bronchoscopy in paediatric intensive care.

Bronchoscopy is a highly versatile technique in the context of intensive care and has many potentially valuable indications. Safety is of paramount importance and the risks in critically unstable patients are correspondingly greater than in more stable children. The main contraindication to bronchoscopy is if it will provide no useful information. The procedure is obviously more risky in children with severe hypoxia, uncontrolled bleeding diathesis, cardiac failure or severe pulmonary hypertension. Monitoring should include at least oxygen saturation, blood pressure (ideally by continuous, invasive monitoring) and preferably capnography. Indications for bronchoscopy in paediatric intensive care include endobronchial toilet, sometimes instilling recombinant human DNAase even in children who do not have cystic fibrosis; checking tube patency and position; assisting in a difficult intubation or tube change; achieving the selective intubation of a main bronchus; the diagnosis and management of ventilator-associated pneumonia or the ventilated, immunocompromised host; the assessment of lobar collapse or focal hyperinflation; airway stent assessment; assessment of stridor on extubation and the diagnosis of any associated disease. New iatrogenic complications are also likely to be discovered. The procedure is very safe if performed by experienced operators with back-up from doctors skilled in airway management and the monitoring of sick children.

Bronchoscopes↗
PubMed2003

Growth factors in cystic fibrosis - when more is not enough.

In the airways of patients with cystic fibrosis, repeated cycles of infection and inflammation are responsible for bronchial wall thickening, a major determinant of loss of FEV(1) and progressive damage to the small and large airways. Proteolytic degradation of elastin, collagen and fibronectin fibrils in the tissue matrix leads to the loss of normal tissue architecture and the development of bronchiectasis, the most commonly observed morphological change on high-resolution computed tomography examination. We have reviewed the evidence for increased expression of growth factors (TGF, HGF, FGF, EGF, VEGF) and activation of tissue repair processes in cystic fibrosis. Significantly higher concentrations of the growth factors compared with normal do not appear to prevent or reverse structural remodelling in the airways. The reasons why this process appears to be ineffective are discussed and we speculate on alternative strategies that might have a significant impact on the observed structural changes.

Cystic Fibrosis↗
PubMed2003

A cost-effectiveness analysis of rhDNase in children with cystic fibrosis.

OBJECTIVES: This study compared the relative cost-effectiveness of daily recombinant human deoxyribonuclease (rhDNase), with alternate day rhDNase and hypertonic saline (HS) for treating children with cystic fibrosis (CF). METHODS: A randomized controlled trial with a crossover design allocated 40 CF children consecutively to 12 weeks of daily rhDNase, alternate day rhDNase, or HS. The primary outcome measure was forced expiratory volume in 1 second (FEV1), a measure of lung function. All health resource use was prospectively documented for each patient and multiplied by unit costs to give a total health service cost for each 12-week treatment period. The nonparametric bootstrap method was used to present cost-effectiveness acceptability curves and net benefit statistics for each treatment comparison, for various hypothetical levels of the decision maker's ceiling ratio. RESULTS: Compared with HS, there was a 14% improvement in FEV1 for daily rhDNase (95% Cl, 5% to 23%), and a 12% improvement (95% Cl, 2% to 22%) for alternate day rhDNase. For a ceiling ratio of 200 pounds sterling per 1% gain in FEV1, the mean net benefits of daily and alternate day rhDNase compared with HS were 1,158 pounds sterling (95% Cl, -621pounds sterling to 2,842) and 1,188 pounds sterling (95% Cl, -847 to 3,343), respectively; the mean net benefit of daily compared with alternate day rhDNase was -30 pounds sterling (95% Cl, -2,091 pounds sterling to 1,576). CONCLUSIONS: If decision makers are prepared to pay 200 pounds sterling for a 1% gain in FEV1 over a 12-week period, then on average either rhDNase strategy is cost-effective.

Child↗
PubMed2003

Macrolides as biological response modifiers in cystic fibrosis and bronchiectasis.

For 50 years, macrolide antibiotics have been used to treat community acquired pneumonia and atypical infections such as Chlamydia pneumonia and Mycoplasma. In the late 1960s it was noted that when the 14-member ring macrolide antibiotic troleandomycin was given to asthma patients who required large doses of systemic corticosteroids, they could often reduce their steroid dose or even stop steroids completely without exacerbation of their asthma. Because of this experience, Prof. S. Kodoh and colleagues first used erythromycin as an immunomodulatory agent to treat diffuse panbronchiolitis (DPB). DPB is a cystic fibrosis (CF)-like condition seen predominantly in young, nonsmoking adults in Japan and Korea. The introduction of erythromycin profoundly improved survival, and in many of these very ill patients the illness disappeared. Since then, research has focused attention on many non-antibacterial, disease modifying effects of this class of compounds. These include downregulation of proinflammatory cytokines via an effect on nuclear transcription factors, reduction in adhesion molecule expression, suppression of inducible nitric oxide synthase (iNOS), reduced neutrophil chemotaxis and degranulation, inhibition of neutrophil elastase, cytoprotection against bioactive phospholipids, improvement in the rheological properties of mucus, reduction in bronchial hyperreactivity, and, perhaps, modulation of neutrophil death by apoptosis pathways, and in the end, airway remodeling. Additionally, they have unconventional effects on microorganisms, including inhibiting Pseudomonas aeruginosa twitching motility and thus biofilm formation. There are small case series and three large randomized controlled trials that have established unequivocal evidence of benefit in CF. There is less evidence for an immunomodulatory effect in bronchiectasis. Future work is likely to focus on the development of macrolides with disease-specific modes of action.

Journal Article↗