published_or_final_version / Medicine / Master / Master of Medical Sciences

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Purpose: Exercise testing modalities to assess the effects of a given intervention should prove to be reliable and reproducible. This study reports on test-retest reproducibility of the 3-min shuttle walking and step testing exercise protocols to assess exertional dyspnea and exercise physiology in COPD patients. / Methods: Stable COPD patients (N=43; 65 +/- 6.5 years; FEV1 = 49 +/- 16% pred.) equipped with a portable Jaeger Oxycon MobileRTM metabolic system repeated the walking or stepping tests on two occasions separated by 7 to 14 days. At each visit, participants performed, in a randomized order, four externally paced 3-min bouts of shuttle walking at speeds of 1.5, 2.5, 4.0 and 6.0 km·h-1 or of stepping at a constant rate of 18, 22, 26 and 32 steps·min-1, respectively. Each exercise bout was separated by a 10-min rest period. Ventilation, heart rate, gas exchange parameters and Borg dyspnea score were obtained for each bout during the last 30-seconds of exercise. / Results: The majority of patients completed stepping or walking at the slowest cadence but only 33% completed walking at 6.0 km·h -1 and 40% completed stepping at 32 steps·min-1. Test-retest Pearson correlation coefficients for ventilation, heart rate, gas exchange parameters and dyspnea scores over the four exercise bouts, all exceeded 0.80 with the highest coefficient found for ventilation (r≥.95). Intra-class correlation coefficients were similar to Pearson. Bland & Altman representation showed that a similar proportion of dyspnea data points (92 vs. 96%) lied within 2 SD of the mean difference between test-retest values for dyspnea Borg scores during walking and stepping. / Conclusion: Results show very good reproducibility for both 3-min shuttle walking and stepping exercise protocols in patients with COPD. / This study was supported by an unrestricted grant from Boehringer-Ingelheim/Pfizer.

Rationale. There is a need for the development of a field test to evaluate exertional dyspnea in the primary care setting. This study examined the applicability of a 3-minute constant rate step test in patients with COPD. / Methods. This test involved 4 stepping rates (18, 22, 26, 32 steps.min-1) equivalent to approximately 4.5, 5.3, 6.0, and 7.2 MET with the ultimate goal that in its final development, the assessment will be made a single stepping rate based on disease severity. Stable COPD patients (N = 43; 65 +/- 6.5 years; FEV1 = 49 +/- 16% pred.; SpO2 (%) rest: 95 +/- 2) were equipped with a portable Jaeger Oxycon MobileRTM metabolic system and followed an audio signal for stepping up and down a single 20 cm step for 3 minutes. Borg dyspnea scores were obtained at the end each stepping bout. A 10-min rest was given between each stepping bout. / Results. Of the 43 patients, 80% completed stages 1 and 2, 74 and 37% stages 3 and 4 while no patient of MRC class 4 or 5 (N = 8) completed stage 1. Breathing frequency (breaths.min-1) spanned from 26.5 +/- 4.1 to 39.0 +/- 6.4 but VT (L) remained unchanged (1.4 +/- 0.3 vs. 1.5 +/- 0.4) from stage 1 to 4 while Borg scores were 3 +/- 1, 4 +/- 1, 5 +/- 2, 6 +/- 3 respectively and SpO2 (%) were 92 +/- 5, 91 +/- 4, 91 +/- 4 and 90 +/- 4. / Conclusions. Preliminary findings indicate that a 3-minute constant rate step test may present a feasible alternative to laboratory testing to assess exertional dyspnea in moderately severe COPD. In this population, a stepping rate of 26 steps.min-1 could be sustained by the majority of patients while producing a level of dyspnea potentially amenable to therapy. / This study was supported by an unrestricted grant from Boehringer-Ingelheim/Pfizer.

Ipratropium bromide is a short-acting, non-selective, muscarinic antagonist frequently prescribed for the treatment of Chronic Obstructive Pulmonary Disease (COPD) and as an emergency adjunct therapy for acute asthma. Within the past decade, there has been an accumulating wealth of clinical evidence which indicates that anti-muscarinic drugs, such as ipratropium, are responsible for an increased risk of stroke or, an adverse cardiovascular outcome (including increasing the risk and severity of myocardial infarction (MI)). MI remains the highest risk factor of death for COPD patients due to the systemic co-morbidities associated with COPD, which includes ischaemic heart disease (IHD). Despite the knowledge that approximately 22% of COPD patients also suffer from underlying IHD, the cardiovascular safety of muscarinic antagonists, such as ipratropium, has not been tested in a non-clinical setting of IHD or MI. In order to address this, the current project was designed to investigate, for the first time, the effects of ipratropium on the myocardium in a non-clinical setting. It was identified that under normoxic conditions, ipratropium did not have a significant effect on cardiac myocyte viability or infarction, from 3 month Sprague Dawley rats. In addition to this, following simulated ischaemia, ipratropium also did not appear to exacerbate myocardial injury. However, when ipratropium was administered in the context of simulated ischaemia followed by reperfusion, there was a significant exacerbation in myocardial injury which was characterised by increases in infarction, apoptosis, necrosis and a loss of resilience of oxidative stress. In order to characterise the mechanism by which ipratropium exerts the observed cardio-toxic effects, it was investigated whether acetylcholine (ACh) or cyclosporin A (CsA) were capable of attenuating the ipratropium induced cardiotoxicity. Both agents showed significant limitation of injury when co-administered with ipratropium indicating that ipratropium exerts its cardio-toxic effect through a mechanism which links muscarinic signalling to the mitochondrial permeability transition pore (mPTP). This supports previously published work where the protective signalling of ACh has been shown to promote the phosphorylation of pro-survival kinases, such as Akt and Erk1/2 and that this provides inhibition of the mPTP. Western blotting was employed to identify whether there was an involvement of the pro-survival kinases Akt and Erk1/2, as well as the stress induced kinase JNK. Ipratropium significantly increased levels of phospho-Akt and phospho-Erk1/2. However, JNK levels appeared to be insignificantly altered in comparison with the control groups. Both ACh and CsA were capable of limiting these increases. Further to this, an aged study was carried out, which showed that, within the aged myocardium, ipratropium is capable of eliciting further injury in comparison with the 3 month age groups. The effect of ipratropium on tolerance of oxidative stress was not significant, but, also, ACh and CsA were shown as unable to protect. Significant levels of JNK were also observed in the aged animals in comparison with the 3 month groups. In combination, the results presented here demonstrate, for the first time, that ipratropium is capable of exacerbating ischaemia/reperfusion injury in in vitro models of myocardial ischaemia/reperfusion. In addition, ACh and CsA are capable of limiting this injury, implying a role for pro-survival kinases and the mPTP in ipratropium induced myocardial injury. In the aged study, ipratropium still exacerbated injury, however, ACh and CsA appeared unable to protect, therefore promoting previous work that cellular signalling is altered in the senescent myocardium. In conclusion, further studies must be carried out in order to fully characterise the cardio-vascular safety profile of ipratropium.

No description available.

No description available.

Thesis (PhD)--Stellenbosch University, 2015. / ENGLISH ABSTRACT: Tuberculosis (TB) in children is a common infectious disease in the world affecting approximately 550 000 children annually and contributing to approximately 10-15% of the TB caseload. The estimate is that 75% of the children who have TB live in the 22 countries that have the highest burden of TB disease. In these 22 countries, the technology required to make the diagnosis and manage complicated cases is limited. The epidemiological data required to estimate the proportion of children with severe disease requiring intervention at a global level are lacking. Airway involvement is commonly seen in children with primary TB, but only in a small group of children the compression is severe, needing intervention. The incidence of children with airway obstruction requiring intervention due to primary TB in the chemotherapeutic era is not known. The incidence of complicated lymph node disease in two recent reports varied from 8-38% in children younger than 15 years of age. Flexible bronchoscopy (FB) is an invasive procedure performed under general anesthetic is used to assess the airways of children. Few studies have been published on the use of FB in the diagnosis of paediatric TB and most have concentrated on the use of bronchoscopy as an intervention for obtaining samples to diagnose pulmonary TB (PTB). All previous studies only examined broncho-alveolar lavage (BAL) for Ziehl Neelsen (ZN) positive organisms and mycobacterial culture. All the published studies are from developed countries with a very low incidence of PTB in children. It has been postulated that HIV positive children with TB are more likely to have airway obstruction, but this hypothesis has not been studied. The same is true for children infected with drug-resistant strains of tuberculosis. Similarly, there have been few reports on the correlation between the findings at bronchoscopy and those found on chest computer tomography (CT). The aim of this research project was to systematically determine airways involvement in childhood pulmonary TB and assess the role paediatric bronchoscopy plays in the diagnosis, sample collection and the management of severe airway obstruction. The first part of the thesis describes the bronchoscopic assessment of airway obstruction due to pulmonary TB in children, specifically concentrating on the areas of the airway involved and the severity of the obstruction. We investigated which factors determine the severity of airway obstruction and this included age, sex, HIV status and drug sensitivities. We have shown that there was no difference in airway obstruction in HIV positive children and in children with drug resistance TB. More severe airway obstruction was seen in the younger child. The second question that was analysed is the value of flexible bronchoscopy in collecting samples for TB culture and drug sensitivity testing. It has previously been reported that BAL culture was inferior to gastric lavage in isolating the bacilli. We set out to evaluate which factors determine if a child will be culture-positive on BAL. Most childhood pulmonary TB is postulated to have a low yield of ZN positive cases. We found a higher yield from BAL as was previously reported, and the yield was increased if segmental or lobar pneumonia was present on the chest radiography. We developed novel interventions of finding the organism and increasing the yield from BAL. About 80% of children with PTB have enlarged subcarinal lymph nodes. We performed a trans-bronchial needle aspiration (TBNA) biopsy of these lymph nodes for culture. This technique enables us to differentiate the cause of enlarged mediastinal lymph nodes. This is especially important in children who are HIV positive, as they are prone to have other causes of enlarged lymph nodes. We successfully performed TBNA, even in very young infants, which resulted in a diagnostic yield of 55%. The use of Xpert has been described on other tissue, but not on BAL. We wanted to test if the use of Xpert on BAL is feasible in children, and determine if it will increase the diagnostic yield by using BAL samples. The third aspect of this research was to compare flexible bronchoscopy findings with those of chest CT scan finding. Firstly, the aim was to describe the CT scan findings of mediastinal glands and lungs in children with significant airway obstruction due to PTB. The second aim was to investigate how these two investigations of airway obstruction compared, with particular emphasis on their advantages and disadvantages. The areas of airway obstruction as well as the severity of the obstruction as determined by CT scan were very similar to the findings with bronchoscopy. The final part under this aspect of the study was to analyze airway shape using a computer model to asses if this could predict TB. This was done by extracting components of the airway surface mesh and branch radius and orientation features. This method showed the potential of computer-assisted detection of TB and other airway pathology by using airway shape deformation analysis. The fourth aspect investigated was to determine which children with severe airway obstruction would benefit from a surgical intervention. Surgical enucleation is done via a lateral thoracotomy in children with severe airway obstruction. We investigated which factors determine the need for surgical enucleation, the optimal timing of this intervention, and – if surgical enucleation was done as an emergency intervention – which factors would predict for this. The combination of trachea, left main bronchus and bronchus intermedius involvement was the best predictor for children requiring surgical enucleation. Involvement of the smaller airway divisions did not play a significant role. Children needing enucleation were younger and had more severe airway obstruction. The fifth aspect of this thesis was to measure the outcome following surgical enucleation. Measurements used included clinical measurements, radiological measurements and bronchoscopy. The response in children treated surgically were compared to those treated medically by estimating airway size with flexible bronchoscopy. Both groups showed significant improvement with the magnitude of improvement greater in those surgically treated. We have demonstrated in this thesis that the site and severity of severe airway obstruction can be assessed by either bronchoscopy or chest CT scan. Approximately one third of children with severe airway compression due to TB lymph nodes can be successfully treated surgically with a low morbidity and mortality. / AFRIKAANSE OPSOMMING: Tuberkulose (TB) by kinders is wêreldwyd ’n algemene siekte wat jaarliks ongeveer 550 000 kinders raak en sowat 10-15% van die algehele TB-siektelas uitmaak. Na raming kom 75% van alle kinders met TB van die 22 lande met die hoogste TB-siektelas. Hierdie 22 lande beskik oor beperkte tegnologie om die siekte te diagnoseer en ingewikkelde gevalle te bestuur. Die vereiste epidemiologiese data om te raam watter persentasie kinders wêreldwyd ernstig siek is en intervensie vereis, ontbreek ook. Lugwegaantasting word algemeen by kinders met primêre TB aangetref. Tog is die kompressie by slegs ’n klein groepie kinders so erg dat dit intervensie vereis. Die voorkoms van kinders in die chemoterapeutiese era met primêre-TB-verwante obstruksie van die lugweë wat intervensie vereis, is onbekend. In twee onlangse verslae het die voorkoms van gekompliseerde limfkliersiekte by kinders jonger as 15 jaar van 8% tot 38% gewissel. Buigbare brongoskopie is ’n indringende prosedure wat onder algemene verdowing uitgevoer word om kinders se lugweë te ondersoek. ’n Paar studies is reeds gepubliseer oor die gebruik van buigbare brongoskopie om pediatriese TB te diagnoseer. Die meeste daarvan het gekonsentreer op die gebruik van brongoskopie as intervensie vir die insameling van monsters om pulmonêre TB (PTB) te diagnoseer. Alle vorige studies het uitsluitlik ondersoek ingestel na brongo-alveolêre spoeling (BAS) vir die opsporing van Ziehl Neelsen- (ZN-)positiewe materiaal en vir kweking. Geen ander diagnostiese tegnieke is tot dusver ondersoek nie, wat die waarde daarvan vir populasies met ’n hoë siektelas beperk. Boonop is alle gepubliseerde studies in ontwikkelde lande met ’n baie lae voorkoms van PTB by kinders onderneem. Daar word aangevoer dat MIV-positiewe kinders met TB meer waarskynlik aan obstruksie van die lugweë sal ly, hoewel hierdie hipotese nog nie bestudeer is nie. Dieselfde geld vir kinders wat aan middelweerstandige vorme van TB ly. Daar is ook weinig verslae oor die verband tussen die bevindinge van brongoskopie en dié van rekenaartomografie (RT) van die borskas. Die doel van hierdie navorsing was om stelselmatig vas te stel hoe pulmonêre TB by kinders die lugweë aantas, en watter rol pediatriese brongoskopie in diagnose, monsterinsameling en die hantering van ernstige obstruksie van die lugweë speel. Die eerste deel van die tesis beskryf die brongoskopiese voorkoms van PTB-verwante obstruksie van die lugweë, met bepaalde klem op die aangetaste dele van die lugweg en die erns van die obstruksie. Daar is ondersoek ingestel na watter faktore die erns van die obstruksie bepaal, onder meer ouderdom, geslag, MIV-status en middelsensitiwiteit. Die resultate toon geen verskil in obstruksie by MIV-positiewe kinders en kinders met middelweerstandige TB nie, hoewel ernstiger obstruksie van die lugweë by die jonger kind opgemerk is. Die tweede kwessie wat ontleed is, is die waarde van buigbare brongoskopie in die verkryging van monsters vir TB-kweking en toetse vir middelsensitiwiteit. Daar is voorheen aangemeld dat BAS-kweking minder doeltreffend is as gastriese spoeling om die basille te isoleer. Hierdie studie was daarop toegespits om te beoordeel watter faktore bepaal of ’n kind kwekingspositief met BAS sal wees. Die meeste PTB by kinders toon na bewering ’n lae opbrengs van ZN-positiewe gevalle. Tog het BAS in hierdie studie ’n hoër opbrengs gehad as wat voorheen aangemeld is, welke opbrengs hoër was met die aanwesigheid van segmentale of lobêre pneumonie op die borskasradiogram. Innoverende intervensies is ontwikkel om die organisme op te spoor en die opbrengs met BAS te verhoog. Sowat 80% van kinders met PTB het vergrote subkarinale limfkliere. ’n Transbrongiale naaldaspirasie- (TBNA-)biopsie is gevolglik vir die doeleinde van kweking op hierdie kliere uitgevoer. Hierdie tegniek het die navorser in staat gestel om tussen die verskillende oorsake vir vergrote mediastinale limfkliere te onderskei. Dít is veral belangrik by MIVpositiewe kinders, wat geneig is om ander oorsake vir vergrote limfkliere te toon. Die TBNA-biopsies is selfs by baie jong babas suksesvol uitgevoer, wat tot ’n diagnostiese opbrengs van 55% gelei het. Die gebruik van Xpert op ander weefsel as BAS is al voorheen beskryf. Die navorser wou dus vasstel of die gebruik van Xpert by BAS haalbaar is by kinders, en of dit die diagnostiese opbrengs deur die gebruik van BAS-monsters sal verhoog. Die derde aspek van hierdie navorsing was om die bevindinge van buigbare brongoskopie met dié van RT-skanderings van die borskas te vergelyk. Die doel was eerstens om die bevindinge van die RT-skanderings van mediastinale kliere en longe by kinders met beduidende PTB-verwante lugweg-obstruksie te beskryf. Tweedens wou die navorser vasstel wat die verskille tussen hierdie twee ondersoeke van lugweg-obstruksie is, met bepaalde klem op die voordele en nadele daarvan. Die RT-skandering en die bevindinge van brongoskopie lewer betreklik soortgelyke resultate op wat die aangetaste gedeeltes van die lugweg sowel as die erns van sodanige obstruksie betref. Die laaste doel onder hierdie studieaspek was om die vorm van die lugweg met behulp van ’n rekenaarmodel te ontleed om te bepaal of dit TB kan voorspel. Dít is gedoen deur komponente van die die erns van die obstruksie. Daar is ondersoek ingestel na watter faktore die erns van die obstruksie bepaal, onder meer ouderdom, geslag, MIV-status en middelsensitiwiteit. Die resultate toon geen verskil in obstruksie by MIV-positiewe kinders en kinders met middelweerstandige TB nie, hoewel ernstiger obstruksie van die lugweë by die jonger kind opgemerk is. Die tweede kwessie wat ontleed is, is die waarde van buigbare brongoskopie in die verkryging van monsters vir TB-kweking en toetse vir middelsensitiwiteit. Daar is voorheen aangemeld dat BAS-kweking minder doeltreffend is as gastriese spoeling om die basille te isoleer. Hierdie studie was daarop toegespits om te beoordeel watter faktore bepaal of ’n kind kwekingspositief met BAS sal wees. Die meeste PTB by kinders toon na bewering ’n lae opbrengs van ZN-positiewe gevalle. Tog het BAS in hierdie studie ’n hoër opbrengs gehad as wat voorheen aangemeld is, welke opbrengs hoër was met die aanwesigheid van segmentale of lobêre pneumonie op die borskasradiogram. Innoverende intervensies is ontwikkel om die organisme op te spoor en die opbrengs met BAS te verhoog. Sowat 80% van kinders met PTB het vergrote subkarinale limfkliere. ’n Transbrongiale naaldaspirasie- (TBNA-)biopsie is gevolglik vir die doeleinde van kweking op hierdie kliere uitgevoer. Hierdie tegniek het die navorser in staat gestel om tussen die verskillende oorsake vir vergrote mediastinale limfkliere te onderskei. Dít is veral belangrik by MIVpositiewe kinders, wat geneig is om ander oorsake vir vergrote limfkliere te toon. Die TBNA-biopsies is selfs by baie jong babas suksesvol uitgevoer, wat tot ’n diagnostiese opbrengs van 55% gelei het. Die gebruik van Xpert op ander weefsel as BAS is al voorheen beskryf. Die navorser wou dus vasstel of die gebruik van Xpert by BAS haalbaar is by kinders, en of dit die diagnostiese opbrengs deur die gebruik van BAS-monsters sal verhoog. Die derde aspek van hierdie navorsing was om die bevindinge van buigbare brongoskopie met dié van RT-skanderings van die borskas te vergelyk. Die doel was eerstens om die bevindinge van die RT-skanderings van mediastinale kliere en longe by kinders met beduidende PTB-verwante lugweg-obstruksie te beskryf. Tweedens wou die navorser vasstel wat die verskille tussen hierdie twee ondersoeke van lugweg-obstruksie is, met bepaalde klem op die voordele en nadele daarvan. Die RT-skandering en die bevindinge van brongoskopie lewer betreklik soortgelyke resultate op wat die aangetaste gedeeltes van die lugweg sowel as die erns van sodanige obstruksie betref. Die laaste doel onder hierdie studieaspek was om die vorm van die lugweg met behulp van ’n rekenaarmodel te ontleed om te bepaal of dit TB kan voorspel. Dít is gedoen deur komponente van die lugwegoppervlaknetwerk en vertakkingsradius- en oriëntasiekenmerke te onttrek. Hierdie metode het daarop gedui dat rekenaargesteunde opsporing van TB en ander lugwegpatologie deur middel van ’n ontleding van lugwegvervorming wél potensiaal toon. Die vierde aspek was om te bepaal watter kinders met ernstige obstruksie van die lugweë by intervensie sal baat vind. By sulke kinders word chirurgiese enukleëring deur ’n laterale torakotomie uitgevoer. Die studie het ondersoek ingestel na watter faktore die behoefte aan chirurgiese enukleëring bepaal, wat die optimale tyd vir sodanige intervensie sou wees, en – indien chirurgiese enukleëring as noodintervensie uitgevoer word – watter faktore so ’n noodintervensie sou vereis. Die kombinasie van aantasting van die tragea, linkerhoofbrongus en brongus intermedius was die beste voorspeller van kinders wat chirurgiese enukleëring benodig. Aantasting van die kleiner lugwegverdelings het nie ’n beduidende rol gespeel nie. Kinders wat enukleëring vereis, was jonger en het aan ernstiger obstruksie van die lugweë gely. Die vyfde aspek van hierdie tesis was om die uitkoms na afloop van chirurgiese enukleëring te meet. Kliniese metings, radiologiese metings en brongoskopie is hiervoor gebruik. Die reaksie by kinders wat chirurgies behandel is, is vergelyk met diegene wat medies behandel is deur lugweggrootte met behulp van buigbare brongoskopie te raam. Albei groepe het beduidende verbetering getoon. In die studie het ons getoon dat die ligging en die erns van ernstige lugwegobstruksie kan geassesseer word deur óf brongoskopie of rekenaartomografie van die borskas. Ongeveer een derde van kinders met 'n ernstige lugweg-obstruksie weens TB limfkliersiekte kan suksesvol chirurgies met 'n lae morbiditeit en mortaliteit behandel word.

No description available.

A nursing concern for patients with chronic obstructive airway disease (COAD) is to assist the patient/family in improving adaptation strategies and self-care abilities. Identification of emotional and behavioral characteristics impacting on symptoms and life quality may predict individuals at risk for greater utilization of health care resources. The purpose of this descriptive study was to apply Traver's Prediction Formula for Emergent Use to a more general COAD population to determine if the formula would accurately predict those subjects who have high versus low emergent use of institutional health care resources. Fifty subjects with a range of COAD severity were studied. Subjects completed instruments which measured symptoms and life quality: the Bronchitis-Emphysema Symptom Checklist and the Sickness-Impact Profile. Findings demonstrated Traver's Formula predicted low emergent subjects with 76 percent accuracy, high emergent subjects with 53 percent accuracy and predicted the overall emergent status of subjects with 67 percent accuracy.