Thesis (Ph. D.)--University of Alabama at Birmingham, 2007. / Title from first page of PDF file (viewed Feb. 15, 2008). Includes bibliographical references.

No description available.

Submitted in partial fulfilment of the requirements for the Degree of Masters in Technology: Clinical Technology, Durban University of Technology, 2009. / Currently, off-pump coronary artery bypass surgery (OPCAB) is a selectively employed technique for myocardial revascularization used in the majority of heart units worldwide. This strategy obviates the documented deleterious effects of cardiopulmonary bypass. However the occurrence of neurological sequelae associated with OPCAB ranges from minor cognitive dysfunction to major stroke. Haemodynamic instability throughout the positioning, stabilization and interruption of coronary blood flow are regarded as important factors that affect the performance of off-pump surgery. Fluctuations during the perioperative period, in particular manipulation of the heart could result in temporary brain hypoperfusion and neurological sequelae. To predict those patients that are predisposed to cerebral complications, investigators have used neurological monitoring, in particular Near-infra red spectroscopy (NIRS) during cardiac surgery. Aims and Objectives of the study This prospective, observational study was carried out to assess the correlation between cerebral oxygen saturation and central venous saturation during OPCAB surgery. Central venous saturation is an important variable used to assess global tissue perfusion and could therefore be advocated as a surrogate measure of cerebral oxygen saturation. In addition variables such as mean arterial (MAP) pressure, heart rate (HR), patient oxygen saturation (SpO2), partial pressure of carbon dioxide (PcvCO2), haematocrit (Hct) and lactate were also measured to determine if they were independent predictors of cerebral desaturation. This study is one of the first done in the South African population group. iv Methodology Twenty patients undergoing OPCAB surgery from the Cardiothoracic unit at Inkosi Albert Luthuli Central Hospital, Durban, South Africa were recruited in the trial. Cerebral somasensors were placed on the patients forehead to measure left and right cerebral saturations. These sensors were linked by cables to the cerebral monitor (NIRS), INVOS model 5100C. Eight time periods throughout the surgical procedure whereby patients would be haemodynamically unstable were identified. These time periods included, post induction and pre sternotomy, pre and post placement of swabs beneath the heart, pre and post placement of the stabilizer device (Octopus), pre and post snaring of the LAD (left anterior branch of the coronary arteries), pre anastomosis and during anastomosis of the coronary arteries, second sample during anastomosis and post anastomosis, pre and post removal of swabs from beneath the heart, pre and post transfer of the patient to the ICU bed. These time periods constituted the sampling period pre and post manoeuvres. Eight paired measurements, i.e., MAP, PaCO2, HR, Hct, lactate, SpO2, central venous saturation (ScvO2) and cerebral oxygen saturation (rSo2) per patient were taken during these time periods. Recording of cerebral saturations and blood samples from the central venous line were taken during these eight time periods in order to determine the correlation between central venous and cerebral oxygen saturations. Results Strong positive correlations between central venous saturation and cerebral saturation presented in majority of the sampling time periods throughout the study (post induction and pre sternotomy, post placement of swabs beneath the heart, post snaring of the LAD (left anterior branch of the coronary arteries, pre anastomosis and during anastomosis of the coronary arteries, second sample during v anastomosis, pre and post transfer of the patient to the ICU bed). The positive correlation indicates that central venous saturation can be used as a surrogate measure of cerebral oxygen saturation during OPCAB surgery. Conclusion The absence or poor correlation of MAP, HR, PcvCO2, heamatocrit, lactate, and patient saturation to cerebral saturation in this study suggests that insertion of a central venous line (CVP) during OPCAB should be a fundamental clinical requirement.

Submitted in partial fulfilment of the requirements for the Degree of Doctor of Technology: Clinical technology, Durban University of Technology, 2011. / Surgical revascularization of the coronary arteries is a cornerstone of cardiothoracic surgery. The enduring nature of coronary artery bypass grafting (CABG) bespeaks of its history and proven efficacy. However, cerebral deoxygenation during on-pump coronary artery bypass graft surgery may be associated with adverse neurological sequelae. Advanced age and the incidence of preoperative co-morbidity in patients presenting for coronary artery bypass graft surgery increases the potential for stroke and other adverse perioperative outcomes (Murkin, Adams, Quantz, Bainbridge and Novick, 2007). It is hypothesized, that by using the brain as an index organ, interventions to improve cerebral oxygenation would have systemic benefits for cardiac surgical patients. In an attempt to predict those patients that are predisposed to cerebral complications, investigators have used neurological monitoring ie, Near infrared spectroscopy (NIRS) to enhance detection of hypoxic conditions associated with neurological injury (Hoffman, 2006). Serum S100B protein has been used as a biochemical marker of brain injury during cardiac surgery. Elevated levels serve as a potential marker of brain cell damage and adverse neurological outcomes (Einav, Itshayek, Kark, Ovadia, Weiniger and Shoshan, 2008). Aims and Objectives of the study This prospective, quantitative, interventional study was carried out to maintain cerebral tissue oxygen saturation during cardiopulmonary bypass above 75% of the baseline level by implementation of a proposed interventional protocol. The analysis of S100B which is a marker of neurological injury and optimization of regional cerebral oxygen saturation would allow for the formulation of an algorithm which could be implemented during on-pump coronary artery bypass graft surgery as a preventive clinical measure further reducing the risk of neurological injury. Central venous lines (CVP) are inserted routinely during cardiac surgery. Central venous oxygen saturation is a global marker of tissue oxygenation. A secondary aim of the study was to determine if a correlation existed between central venous and cerebral tissue oxygen saturations. If a positive correlation existed then central venous oxygen saturation could be used as a surrogate measure of cerebral tissue oxygen saturation during on-pump coronary artery bypass graft surgery. This study is one of the first done in the South African population group. Methods Forty (40) patients undergoing on-pump coronary artery bypass graft surgery were recruited at Inkosi Albert Luthuli Central Hospital. Patients were randomized into a control group (n=20) and interventional group (n=20) using a sealed envelope system. The envelope contained designation to either group. Envelopes were randomly chosen. Intraoperative regional cerebral oxygen saturation (rSO2 ) monitoring with active display and treatment intervention protocol was administered for the interventional group. In the control group regional cerebral oxygen saturation monitoring was not visible to the perfusionist operating the heart lung machine during cardiopulmonary bypass (blinded). Recording of regional cerebral saturation was conducted by an independent person (another perfusionist) who was not involved in the management of the case so as to ensure that no interventions were carried out on the control group. Arterial blood samples for the measurement of serum S100B were taken pre and postoperatively. An enzyme immunoassay (ELISA) was used for the quantitative and comparative measurement of human S100B concentrations for both groups. Central venous oxygen saturation was monitored from the CVP using the Edwards Vigileo monitor. Cerebral monitoring constituted the use of Near infrared spectroscopy monitoring using the Invos 5100c, Somonetics Corp, Troy MI monitor. Adhesive optode pads were be placed over each fronto- temporal area for cerebral oxygen measurement. During cardiopulmonary bypass, eight time period measurements of mean arterial pressure (MAP), heart rate, temperature, activated clotting time (ACT), patient oxygen saturation (SpO2), partial pressure of carbon dioxide (pCO2), haematocrit, lactate, pH, haemoglobin (Hb), base excess (BE), potassium (K+), sodium (Na+), glucose, calcium (Ca2+), central venous oxygen saturation (ScvO2), cerebral tissue oxygen saturation (rSO2), fraction inspired oxygen (FiO2 ), sweep rate, pump flow rate (cardiac index), and percentage isoflurane per patient were taken. The time periods when data was recorded included: 5 minutes after onset of cardiopulmonary bypass, aortic cross clamping, after cardioplegic arrest, during distal anastomosis, during proximal anastomosis, during rewarming, after aortic cross clamp release and before termination of cardiopulmonary bypass. Baseline measurements were also taken. Clinical data recorded for both groups included: the number of grafts performed, cardiopulmonary bypass time, cross clamp time, red blood cells administered (packed cells), amount of adrenalin infused and total cerebral desaturation time. A prioritized intraoperative management protocol to maintain rSO2 values above 75% of the baseline threshold during cardiopulmonary bypass was followed. Cerebral desaturation was defined as a decrease in saturation values below 70% of baseline for more than one minute. Interventions commenced within 15 seconds of decrease below 75% of baseline value. Results The results of the study show that there was a highly significant difference in the change in S100B concentrations pre and post surgery between the interventional and control groups. The intervention vii group showed a smaller increase in S100B concentration of 37.3 picograms per millilitre (pg/ml) while the control group showed a larger increase of 139.3 pg/ml. Therefore, the control group showed a significantly higher increase in S100B concentration over time than the intervention group (p < 0.001). Maximizing pump flow rates was the most common intervention used (45 times) followed by maintaining partial pressure of carbon dioxide to approximately 40 mmHg (28 times), increasing mean arterial pressure by administration of adrenalin (11 times) and administration of red blood cells to increase haematocrit (11 times). There was a highly statistically significant treatment effect within the intervention group for each of the above interventions compared with no intervention. The above mentioned interventions significantly affected right and left cerebral oxygen saturations. However, administration of red blood cells was not found to significantly increase right (p = 0.165) and left (p = 0.169) cerebral oxygen saturation within the intervention group. The study highlighted a significant difference between the intervention and control groups in terms of cerebral desaturation time (p <0.001). The mean desaturation time for the control group was 63.85 minutes as compared to 24.7 minutes in the interventional group. Cerebral desaturation occurred predominantly during aortic cross clamping, distal anastomosis of coronary arteries and aortic cross clamp release. Predictors of cerebral oxygen desaturation included, partial pressure of carbon dioxide (pCO2), temperature, pump flow rate (LMP), mean arterial pressure (MAP), haematocrit, heart rate (HR) and patient oxygen saturation (SpO2). Central venous oxygen saturation was not significantly related to right (p = 0.244) or left (p = 0.613) cerebral oxygen saturations. Therefore central venous oxygen saturation cannot be used as a surrogate measure of cerebral tissue oxygen saturation during on-pump coronary artery bypass graft surgery. viii Conclusion These findings demonstrate the positive effect of optimizing cerebral oxygen saturation using an interventional protocol on markers of neurological injury (S100B). Optimization of pump flow rate, partial pressure of carbon dioxide and mean arterial pressure would result in increased cerebral oxygen saturation levels and a reduction in neurological injury. Therefore, an algorithm incorporating these interventions can be formulated. Monitoring specifically for brain oxygen saturation together with an effective treatment protocol to deal with cerebral desaturation during on-pump CABG must be advocated.

Thesis (MCur)--Stellenbosch University, 2015. / ENGLISH ABSTRACT: A heart attack is a medical emergency and a life threatening disease. Patients with chest pain and a possible diagnosis of myocardial infarction require a detailed assessment and prompt medical management. The aim of the study was to determine the in-hospital delay in administrating thrombolytic therapy to patients with acute myocardial infarction (AMI) A mixed method with convergent parallel design was applied to the study. The population consisted of N=63 case notes of adult patients diagnosed with acute myocardial infarction and who had received thrombolytic therapy. The other population included (n=8) registered professional nurses working in the coronary care unit (CCU) of a tertiary hospital in the Western Cape. A record review was done using a data extraction form and semi-structured interview guide was used for data collection purposes. Reliability and validity was tested by the use of a nurse expert and a statistician. The nurse expert evaluated the data extraction form to ensure that all variables are included. A pilot study was done to test the data extraction form for errors. Ethical approval was obtained from the Health Research Ethics Committee of Stellenbosch University and permission to conduct the study was obtained from the management where the study was conducted. Informed consent was obtained from the participants. Data analysis was done by the researcher and a qualified statistician. Data was presented in the form of tables, histograms and frequencies. Analysis for the qualitative data was done by the researcher and the following themes were identified: cardiovascular nursing care, roles and responsibilities of nurses, scope of practice, perceptions of nurses on DNT and factors influencing DNT. Themes were presented in a form of a table and thereafter discussed extensively. Results: A total of 63 case notes of patients diagnosed with AMI were identified. The case notes were identified from the register kept in the CCU of the tertiary hospital. The case notes were of patients diagnosed with AMI and received thrombolytic therapy between the period of January 2009 to January 2014. A list of identified case notes was sent to Medical Records department for the retrieval of files. Once the files were retrieved, notes were obtained and used for data collection and analysis purposes (record review). Eleven (11) case notes could not be recovered, ten other case notes had incomplete data, two patients were thrombolysed at remote hospitals and one had a negative value after analysis. A total of 24 patients were excluded from the study. Only 39 patients were eligible for the study. The median door-to-needle time (DNT) of 30 minutes with a range between five to eighty five minutes was achieved. A door-to-needle time of 30 minutes or less was achieved in 23 (59.0%) of the patients; 56.25% of the patients arrived by ambulance and 43.75% used private transport. Of all the patients diagnosed, 24.5% had a pre-hospital ECG; more than 50% (n=30, 76.9%) of the population were smokers and 53.8% of the population had a risk factor of hypertension. The predominant infarct was inferior (61.5%), followed by anterior (38.5%). More than 70% of the patients were assessed by a junior registrar and only (23.1%) by the senior. Furthermore, (n=10, 25.6%) of the population was assessed by the junior registered professional nurse (RPN) and (n=29, 74.4%) by the senior RPN. Population had a median length in hospital of four days. Three patients died due to complications. The researcher read through all the transcriptions to achieve an overview of the interview. The aim was for the researcher to become immersed with the data. From the data, the researcher created codes and themes qualitatively and counted the number of times they occurred. Similar themes were grouped together and subthemes that emerged from the main themes were identified. The main themes identified were: cardiovascular nursing care, roles and responsibilities, scope of practice, perceptions of nurses on door-to-needle time (DNT) and factors influencing DNT. Conclusions: The majority of patients (74.4%) were assessed by a senior registered professional nurse (RPN) on presentation, yet (n=16) of the patients were not thrombolysed within 30 minutes. Patient, doctor, personnel, hospital and ECG factors influenced door-toneedle time in this study. Few nurses working in the CCU showed insight into DNT. The majority of the nurses reported that they have never seen a delay in DNT yet not all patients achieved a DNT of 30 minutes or less. No significant relationship was found between DNT and factors associated with DNT. There was no significant relationship between door-toneedle time and length of hospital stay p=0.40. Recommendations were made to improve patient care and management. / AFRIKAANSE OPSOMMING: ’n Hartaanval is ’n mediese noodgeval en ’n lewensgevaarlike siekte. Pasiënte met borspyn en ’n moontlike diagnose van miokardiale infarksie benodig ’n gedetailleerde assessering en vinnige mediese bestuur. Die doel van die studie was om die in-hospitaal vertraging in pasiënte met akute miokardiale infarksie (AMI) wat trombolitiese terapie benodig, te bepaal. ’n Gemengde metode is gebruik in die studie. Die populasie het bestaan uit N=63 gevalnotas van volwasse pasiënte wat gediagnoseer is met akute miokardiale infarksie en wat trombolitiese terapie ontvang het. Die ander populasie het bestaan uit (n=8) geregistreerde, professionele verpleegkundiges wat in die koronêre sorgeenheid van ’n tersiêre hospital in die Wes-Kaap werk. ’n Data-ontginningsvorm en semi-gestruktureerde onderhoude is gebruik vir data insamelingsdoeleindes. Betroubaarheid en geldigheid is getoets deur ’n verpleegkundige deskundige en statistikus. Die verpleegkundige deskundige het die dataontginningsvorm geëvalueer om te verseker dat alle veranderlikes ingesluit is. ’n Loodsstudie is onderneem om die data-ontginningsvorm vir foute te toets. Etiese toestemming is verkry van die Gesondheidsnavorsing-etiekkomitee van Stellenbosch Universiteit en toestemming om die studie uit te voer is van die bestuuur van die instansie waar die navorsing uitgevoer is, verkry. Ingeligte toestemming is van die deelnemers verkry. Data-analise is gedoen deur die navorser en ’n gekwalifiseerde statistikus. Data is aangebied in die vorm van tabelle, histogramme en frekwensies. Resultate: ’n Totaal van 63 gevalnotas van pasiënte gediagnoseer met AMI is geïdentifiseer. Elf (11) gevalnotas kon nie verkry word nie en tien ander gevalnotas het onvolledige inligting bevat, twee pasiënte is getrombolitiseer by afgeleë hospitale en een het ’n negatiewe waarde na analise gehad. ’n Totaal van 24 pasiënte is uitgesluit uit die studie. Slegs 39 pasiënte was in aanmerking vir die studie. Die median deur-tot-naald (DTN) tyd van 30 minute is bereik wat strek tussen vyf tot vyf-en-tagtig minute. ’n DTN tyd van 30 minute of minder is bereik in 23 (59.0%) van die pasiënte, 56.25% van die pasiënte het per ambulans aangekom en 43.75% het privaatvervoer gebruik. Van al die pasiënte gediagnoseer het 24.5% ’n prehospitaal EKG gehad, meer as 50% (n=30, 76.9%) van die populasie was rokers en 53.8% van die populasie het ’n risikofaktor vir hipertensie gehad. Die oorhersende infark was minderwaardig (61.5%), gevolg deur anterior (38.5%). Meer as 70% van die pasiënte is deur ’n junior registratrateur geassesser en slegs 23.1% deur die senior registrateur. Verder is 25.6% (n=10) van die populasie deur die junior professionele geregistreerde verpleegkundige geassesseer, en 74.4% (n=29) deur die senior geregistreerde verpleegkundige. Die populasie het ’n median lengte van verblyf van vier dae in die hospitaal gehad. Drie pasiënte is dood as gevolg van komplikasies. Konklusie: Die meerderheid van pasiënte (74.4%) is geassesseer deur ’n senior geregistreerde professionele verpleegkundige tydens aanbieding, alhoewel (n=16) pasiënte nie binne die eerste 30 minute getrombolitiseer nie. Pasiënt, dokter, personeel, hospitaal EKG was faktore wat deur-tot-naald tyd in die studie beïnvloed het. Min verpleegkundiges wat in die koronêre versorginseenheid gewerk het, het insig in DTN getoon. Die meerderheid van die verpleegkundiges het gerapporteer dat hulle nog nooit ’n vertraging in DTN gesien hiet nie, tog het nie alle pasiënte DTN in 30 minute of minder behaal nie. Geen beduidende verhouding is tussen deur-tot-naald tyd en lengte van verblyf in die hospital gevind nie (p=40). Aanbevelings is gemaak om pasiënt-behandeling en –bestuur te verbeter.

published_or_final_version / abstract / Medicine / Master / Master of Philosophy

published_or_final_version / Physiology / Doctoral / Doctor of Philosophy

This exploratory study used Diagnostic Content Validity (DCV) and the Clinical Diagnostic Validation (CDV) models proposed by Fehring (1986) to clinically identify and validate the defining characteristics for Alteration in Tissue Perfusion: Cardiac. The literature based Kelly Cardiac Assessment Tool (KCAT) was designed as the data collection tool. The diagnostic content validity of the KCAT was 0.70. Twenty subjects, 18 years old and older were selected from a population who were admitted as inpatients in a southwestern university affiliated hospital. Data were collected through patient interviews, independent nurse assessment, and review of laboratory data. Using the steps described in Fehring's CDV model (1986) one major defining characteristic and 13 minor defining characteristics were clinically validated. The tool CDV score was 0.62. The nursing diagnosis Alteration in Tissue Perfusion: Cardiac was clinically validated and one major and 13 minor defining characteristics were identified.

Myocardial infarction activates the renin-angiotensin system, consequently upregulating aldosterone production that may stimulate pathological cardiac fibrosis via mineralocorticoid receptor (MR) activation. Results presented in this thesis were derived from an in vitro experimental model using cultures of human cardiac fibroblasts to study the effect of aldosterone on elastin production. They first confirmed that treatment with 1-50 nM of aldosterone leads to a significant increase in collagen type I production via MR activation. Most importantly, we discovered that treatment with 1-50 nM of aldosterone also increases elastin mRNA levels, tropoelastin synthesis, and elastic fiber deposition. Strikingly, pretreatment with MR antagonist spironolactone did not eliminate aldosterone-induced increases in elastin production. Interestingly, while cultures treated with elevated aldosterone concentrations (100 nM and 1 µM) showed a further increase (~3.5-fold) in collagen and (~3-fold) in elastin mRNA levels, they demonstrated subsequent increases only in the net deposition of collagen but not elastin. In fact, cultures treated with elevated aldosterone concentrations displayed a striking decrease in the net deposition of insoluble elastin, which could be reversed with spironolactone or with MMP inhibitors doxycycline or GM6001. Most importantly, we discovered that the pro-elastogenic effect of aldosterone involves a rapid increase in tyrosine phosphorylation of the insulin-like growth factor-I receptor (IGF-IR) and that the IGF-IR kinase inhibitor AG1024 or an anti-IGF-IR neutralizing antibody inhibits both IGF-I- and aldosterone-induced elastogenesis (Bunda et al., Am J Pathol. 171:809-819, 2007). Furthermore, we showed that the PI3 kinase signaling pathway propagates the elastogenic signal following IGF-IR activation and that activation of c-Src is an important prerequisite for aldosterone-dependent facilitation of the IGF-IR/PI3 kinase signaling. Results of explorative microarray analysis of 1 hour aldosterone-treated cultures revealed that aldosterone treatment upregulated expression of a heterotrimeric G protein, Gα13, that activates the PI3 kinase signaling pathway. We additionally demonstrated that aldosterone treatment transiently increases the interaction between Gα13 and c-Src and that siRNA-dependent elimination of Gα13 inhibited the pro-elastogenic effect of aldosterone. In summary, aldosterone, which stimulates collagen production in cardiac fibroblasts through the MR-dependent pathway, also increases elastogenesis via a parallel MR-independent pathway involving the activation of Gα13, c-Src, and IGF-IR/PI3 kinase signaling.

Glucocorticoids can reduce infarct size when given immediately after myocardial infarction (MI) but are detrimental when administration is continued into the post-infarct healing phase. A number of experimental studies have shown that reduction of infarct expansion by enhancing blood supply to the infarct border reduces remodelling and improves heart function post-MI. Previous experiments from this laboratory have shown that mice unable to locally regenerate corticosterone due to deficiency in 11β-hydroxysteroid dehydrogenase type 1 (11HSD1) have an enhanced angiogenic response during myocardial infarct healing that is associated with improved cardiac function. We hypothesized that the enhanced angiogenic response in 11HSD1 knock out (-/-) mice would be preceded by augmented inflammation. Moreover this would be associated with improved cardiac function. This thesis aimed firstly to establish that murine cardiac phenotype was not influenced by 11HSD1 deficiency. 11HSD1-/- and C57Bl6 control mice had comparable cardiac structure and function. 11HSD1 expression was localised to fibroblasts and vascular smooth muscle cells in the myocardium. The second aim of this thesis was to characterise the healing response after MI in 11HSD1-/- mice compared to C57Bl6 mice. Neutrophil infiltration peaked 2 days after MI and was significantly enhanced in the 11HSD1-/- mice relative to C57Bl6 mice, despite comparable infarct size in both groups. This was followed by increased macrophage accumulation in the infarct border. Furthermore, in the 11HSD1-/- mice a greater proportion of macrophages were of the alternatively activated phenotype. Left ventricular expression of pro-angiogenic IL-8, but not VEGF, was increased. Cellular proliferation and vessel density at 7 days were greater in 11HSD1-/- compared to C57Bl6 hearts. This was associated with improved cardiac function 7 days post-MI. The third aim of this thesis was to determine whether the enhancement in vessel density and cardiac function was maintained beyond the initial wound healing phase. 11HSD1-/- mice retained the increased vessel density compared to C57Bl6 mice and these vessels were smooth muscle coated suggesting vessel maturation. This was associated with sustained improvement in cardiac function and modification of the scar characteristics. The final aim of this thesis was to establish whether the effect of the knock out could be recapitulated by administration of a small molecule inhibitor of 11HSD1 after MI. Oral administration of the 11HSD1 inhibitor had no effect on inflammation, angiogenesis and heart function as determined at 7 days post-MI relative to vehicle treated animals. In conclusion, the data confirm the enhancement in vessel density and cardiac function in 11HSD1-/- mice and demonstrate that this was preceded by enhanced inflammation. This was not due to an underlying cardiac phenotype or modification of the infarct size. Increased infiltration of alternatively activated macrophages may have been the source of pro-angiogenic factor, IL-8, which was also increased at the time of angiogenesis. Importantly the enhanced vessel density was retained 4 weeks after MI, these vessels were mature suggesting longevity and the improvement in cardiac function was retained. While pharmacological inhibition did not recapitulate the effect of the knock out this may have been due to route of administration. The data provides compelling evidence that further development and use of small molecule inhibitors of 11HSD1 may be of benefit post-MI.