This study details the creation of two Simulat1on models for a cardiac surgery specialty in a Midlands hospital The models were designed to help the specialty meet waiting time targets set out by the Government in their NHS Plan. The first model is a spreadsheet data Simulation that gives a general prediction of patients waiting for surgery by time band for up to a year in the future based on previous data. The study uses the qualitative analysis of Interviews and documents to generate the second model The first part of this model is a qualitative causal loop diagram of the cardiac surgery system A quantitative 'Stock & Flow' model is drawn from this qualitative model which gives detailed predict1ons of waiting lists and times and other system variables for the cardiac surgery specialty The system dynamics model is validated it can estimate the maximum number of new outpatient attendances the system can support whilst keeping inpatient waiting times below three months for various configurations of theatre time and Cardiac lntensive Care Unit (CICU) beds The study concludes that CICU beds are a bigger constraint on inpatient waiting times in the cardiac surgery specialty at the hospital than theatre time. Measures to improve waiting times and shorten lists should therefore concentrate on improving patient flow through the CICU, for example more beds in the unit would enable more patients to be treated The model can also demonstrate the use of the theory of constraints in managing waiting lists, which is the method used by the NHS Modernisation Agency in their guidance on wait1ng list management.

Laser assisted vascular anastomosis has been reported to have potential advantages over sutured anastomosis, such as reduced operating time, reduced foreign body reactions and lower potential for vessel constriction. The anastomosis of graft material during coronary bypass surgery is one possible use of laser anastomosis. Although laser anastomosis has achieved some success, a major limitation of the approach has been the lack of knowledge regarding the optimal laser exposure necessary to produce a consistent weld. The first section of this thesis describes an investigation into the interaction of light within vascular tissue. Utilising the conventional kubelka-Munk treatment of reflectance and transmission measurements, values of the absorption and scattering coefficients were obtained. Additionally, spatially resolved reflection measurements, (typically used for determining the optical properties of highly scattering homogenious samples such as silica and aluminium oxide), were performed on sections of porcine aorta to determine absorption, scattering and anisotropy coefficients. The suitability of a series of chromophores to ·enhance the absorption of laser radiation at the site of anastomosis have been assessed from the aspect of spectral profile, temperature generating ability, and determination of the fluorescence quantum yield. The second section introduces the use of the Argon ion laser for tissue bonding. A range of in vitro experiments are detailed involving the repair of longitudinal arteriotomies and end-to-end anastomoses in porcine splenic arteries. These vessels have a similar wall thickness and diameter to human coronary arteries, furthermore, they have fewer side branches. An Argon laser was used with and without a range of chromophores and various protein additives. The use of a suitably absorbing chromophore and a reinforcing protein coagulant significantly increased the strength of blood vessel repair. Histological examination of the anastomotic sites, and the results of bursting pressure tests on end-toend anastomoses are detailed. The final section involved the development of chromophores whose absorption characteristics could be altered by irradiation . Steady state irradiation of various compositions of dye/reducing agent has allowed detennination of the quantum yields of photobleaching. Used in conjunction with a results of bursting pressure experiments, where the optimum irradiating conditions for successful bonding were detennined, a system has been created whereby over-irradiation of blood vessels during anastomosis can be eradicated. The assessment of this system is presented. Histological examination and bursting pressure tests performed on end-to-end anastomoses of porcine splenic arteries are detailed. Nanosecond laser flash photolysis studies have been used to investigate the process of dye photobleaching. These studies have shown that the process of photofading is somewhat complicated, however, a mechanism involving the triplet excited state of the Eosin Y dimer has been proposed.

Introduction Asymptomatic gastro-oesophageal reflux and aspiration may be associated with allograft dysfunction post lung transplant. Early anti-reflux surgery has been advocated in selected patients and may improve long-term survival. Little has been published on this topic and the current evidence supporting this is flawed. The understanding of the pathophysiology of aspiration in lung transplant recipients is currently limited. This study reports a prospective analysis of reflux/aspiration immediately post-transplantation to date and its subsequent management. Methods Lung transplant recipients were recruited over 12 months. At one and six months post-transplantation, patients completed a reflux symptom index (RSI) questionnaire for symptoms of extra-oesophageal reflux and underwent objective assessment for reflux (manometry & pH/impedance). Testing was performed with subjects on maintenance proton pump inhibitor. Bronchoalveolar lavage fluid was assessed for pepsin, bile salts, interleukin-8 and neutrophils. Laparoscopic fundoplication was performed on selected patients. Subsequent laboratory based work was performed to determine the composition of gastric juice and to assess the effects of aspiration on primary bronchial epithelial cells and HT29-MTX goblet cells. Results 18 patients with a median age of 46 years (range 22-59) were studied. Manometry was abnormal in 8/18 (44%) patients. Seventeen patients completed 24 hour pHimpedance measurements. 12 of 17 (71 %) had evidence of GORD on pH-impedance monitoring. 3 of 12 (25%) of patients had exclusively weakly-acid reflux. A statistically significant correlation existed between proximal reflux events and neutrophilia at one month (n=13)(Spearman correlation r=0.52, p=0.03). Pepsin was detected in BALF signifying aspiration. Bile salts were rarely detected using 3 separate assays [sensitivity 0.1 /lmolll]. The prevalence of reflux increased over the first six months post-transplant despite a reduction in immunosuppression and normal lung function. Nine patients have subsequently undergone fundoplication for severe Xlil or symptomatic reflux. No major complications occurred. This was associated with improved quality of life and decreased symptoms. Laboratory work gave useful background information on pepsin and bile salts. Mean levels in gastric juice were 380llg/ml (range 0-3892) for pepsin and 50llmolll (range 0-8000) for bile salts. Microaspiration may lead to primary bronchial epithelial cell damage and death. Conclusion Reflux/aspiration is prevalent early post-operatively. Pepsin but rarely bile salts were detected in the lavage fluid suggesting pepsin to be a more common biomarker of aspiration. This study suggests that the causes for reflux are not all related to adverse thoracic changes and immunosuppression as surprisingly. despite a lack of a significant increase in immunosuppression levels, reflux indices increased over the first six months. Laboratory based work provides background information on the use of biomarkers and suggests aspiration could lead to cell death. Fundoplication is safe in selected patients and improved quality of life and GORD symptoms. Further studies are required to assess the effects on lung function and survival.

No description available.

Removal of fracture fixation devices due to symptomatic or asymptomatic reasons is a costly procedure which is further increased when complications are encountered. One of the main difficulties faced by a surgeon is a timely and successful removal of the device due to excessive bone overgrowth. Due to the increased time required for removal of the bone from the device, complications such as increased surgery time, excessive blood loss, debris contamination and implant breakage are often encountered. Practically all internal fixation systems such as locking compression plate constructs, and intramedullary nails, are fabricated for clinics with a micro-rough surface. However, it is well known, that surface micro-topography can be a major factor in determining the type, and extent of tissue integration. Despite the knowledge that surface microtopography can be a major determinant of osseointegration, this avenue has only been investigated for applications requiring accelerated bony integration and has not previously been explored as a potential resolution to issues involving device removal. Thus, we hypothesise that reducing the surface micro-topography of clinically available materials will reduce the incidence of excessive bony over-growth, and consequently will ease implant removal. To investigate this hypothesis, we first characterised, using atomic force microscopy, scanning electron microscopy, contact angle, and white light profilometry, changes in the surface micro-topography of the clinically available materials commercially pure titanium (cpTi), titanium-6%aluminum-7%niobium (TAN), and titanium-15%molybdenum (Til5Mo) in their standard micro-rough form, as well as in their experimental electropolished, and paste polished form. Stainless steel (Ss) was included as the orthopaedic grade 'smooth9 surface control. Additionally, we employed X-ray photoelectron spectroscopy to examine the changes, if any, in the chemical composition of the surfaces. Overall, it was shown that both electropolishing and paste polishing techniques were successful at reducing the micro-roughness of the respective materials, as well as producing a smoothened surface morphologically. As all surfaces were anodised subsequent to polishing, alterations in the surface chemical composition were not evident. Initial in vitro analysis, which involved culturing rat calvarial cells on the various surfaces, showed that surface polishing did not significantly influence cell growth compared to standard micro-rough counterparts. Furthermore, viability on these surfaces was not found to be significantly different from standard micro-rough samples, indicating that overall, surface polishing does not affect the cytocompatibility of cpTi, TAN or Til5Mo. However, paste polished TAN was found to be the exception. Specifically, viability was significantly reduced on this surface compared to standard micro-rough TAN. While cell growth was not significantly affected on paste polished TAN, it was observed that initial cell attachment for this surface was lower compared to standard micro-rough TAN. Fluorescent labelling of the cytoskeletal components actin, tubulin and vinculin revealed that cell morphology was differentially influenced by the various surface morphologies. Generally, polished surfaces advocated a more well spread, elongated phenotype compared to the cuboidal phenotype noted for cells cultured on micro-rough surfaces. Paste polished TAN and standard micro-rough TAN samples also showed some degree of cytoskeletal disruption attributable to the inherent presence of beta-phase particles on their surface. Subsequent analysis of genotype, using real time PCR technology, revealed that for cpTi, TAN and Til5Mo samples, surface polishing essentially provokes its influence in different manners at initial stages of differentiation and consequently then similarly at the later stages of terminal differentiation, and that the magnitude of this effect is material dependent.. Subsequently, we applied surface polishing technology to two clinically relevant internal fixation systems, namely locking compression plates (LCP) and screws, and intramedullary nails (IM), to assess if surface polishing holds potential for reducing implant removal related morbidity. In our LCP model electropolished, paste polished and standard TAN cortical screws were evaluated in combination with electropolished, paste polished and standard cpTi plates, respectively, with stainless steel screws and plates included as a control system. Samples were implanted in a bilateral non-fracture sheep tibia model for 6, 12 and 18 months. At each timepoint, removal torque and percentage of bone contact were quantified for each screw type. Results indicate that both polishing techniques significantly reduce the torque removal required for cortical screws, compared to standard micro-rough cortical screws. Histomorphometric analyses indicated that polished constructs showed a trend for reduced bone contact, however, this was only found to be significantly different for paste polished screws. In our second in vivo model, IM nails fabricated from standard micro-rough TAN and paste polished TAN were implanted in a bilateral, non-fracture sheep model for 12 months. Control animals were implanted with Ss IM nails and standard micro-rough TAN IM nails in the contralateral tibia.

No description available.

Kidney transplantation remains the best modality for renal replacement therapy, the key problem being lack of suitable organs for transplantation. Thus renewed interest in non-heart-beating-donor (NHBD) organs is on the increase to bridge this gap. NHBD organs are subjected to ischaemia-reperfusion (I/R) injury; the underlying pathophysiology, a complex inter-related sequence leading to short and long term renal allograft dysfunction. The aim of the study was to validate normothermic resuscitation perfusion (NP) as a preservation model followed by investigating the use of erythropoietin (EPO) and carbon-monoxide (CO). Porcine kidneys were perfused with normothermic-autologus blood on an isolated-organ perfusion system (IOPS), design based on cardio-pulmonary bypass technology. Renal haemodynamics and functions were then measured during 3hr reperfusion. NP restored renal blood flow and improved renal function, as assessed by % serum creatinine fall, area under curve (AUC) of serum creatinine. EPO when added to NP did not seem to add any major benefit other than marginally improve oxygen consumption. Carbon monoxide delivered as carbon monoxide-releasing molecule-3 (CORM-3) was able to improve urine output, renal blood flow, reduce intrarenal resistance as well as improve renal function reflected by significant improvement in AUC of creatinine clearance. Normothermic resuscitation preservation not only reversed some of the deleterious effects of I/R injury, it also plays an important role as a versatile delivery system to assess various manipulatory agents that have potential in ameliorating I/R injury. This study provides further evidence that CO may be protective in renal perfusion injury and supports the use of low-dose CO releasing molecules as a method of CO delivery. Thus CORM-3 has the potential application in the field of NHBD kidney transplantation, which continues to be an expanding source of transplant kidneys. While EPO did not add any major benefits when used as a manipulating agent, may have its shortfall when applied to a NHBD kidney programme.

Introduction: The shortage of donors necessitates the use of organs from donation after cardiac death (DCD) donors. These organs demonstrate a high rate of delayed graft function (DGF) and primary non-function (PNF) when compared to those from non-DCD donors. DGF and PNF are associated with shorter graft survival times. Reperfusion injury (RI) is important in the aetiology of DGF and PNF. The roles of leukocytes and nitric oxide (NO) are pivotal in the generation of RI. The aim of this study was to assess the effect on RI of modulating leukocyte and NO levels at the time of reperfusion. Methods: This study utilised a porcine extra-corporeal normothermic perfusion model of RI. Kidneys were perfused with whole (WB) or leukocyte depleted blood (LDB) alone, or with an inducible nitric oxide (iNOS) inhibitor or NO donor. This model allows the collection of haemodynamic and functional data, as well as plasma and urine for biochemical analysis. Results: Kidneys reperfused with LDB demonstrated improved blood flow and function compared to those reperfused with WB. Initial blood flow and function in the iNOS supplemented groups was worse than in the WB/LDB perfused groups, but improved in the NO donor groups. Late blood flow plateaued in the NO donor groups but improved in the iNOS supplemented WB group. LDB and iNOS supplementation together gave poor blood flow and function throughout reperfusion. Conclusion: Depletion of leukocytes abrogates the no-reflow phenomenon and reduces the oxidative stress caused by white cell infiltration, thereby improving blood flow and function. The effects of nitric oxide and its inhibition on the endothelium, glomerulus and renal tubule during initial reperfusion are dependent upon the phase of reperfusion. Early benefits to blood flow by NO supplementation are offset by the generation of NO free radicals later after reperfusion.

The importance of platelets emerged from a local research programme, which aimed to reduce the stroke risk associated with carotid endarterectomy (CEA). It had been demonstrated that intra-operative heparinisation induced a transient reversal of aspirin inhibition; platelets were able to aggregate in response to arachidonic acid (AA). It was hypothesized that intra-operative anticoagulation with intravenous low molecular weight heparin (LMWH) instead of unfractionated heparin (UFH) might be associated with a reduction in pleiotropic platelet effects, and that this would result in a reduction of post-CEA embolization, a surrogate marker for stroke risk. A randomized controlled trial recruited 183 patients; 91 randomized to receive standard intra-operative anticoagulation with 5000IU UFH, and; 92 who received 2500IU LMWH intravenously. Studies conducted in sub-populations aimed to investigate the platelet aggregatory responses to AA and adenosine diphosphate (ADP) and the platelet pathways that were active (plasma and serum were assayed for the stable products of platelet metabolism; thromboxane (TXB2) from the cyclo-oxygenase-1 (COX-1) pathway and 12- hydroxyeicosatretraenoic acid (12-HETE) from the 12-lipoxygenase (12-LOX) pathway). To determine how heparin might interact with the platelet, lipase activity, the presence of heparin antibodies and anti-factorXa (FXa) activity were studied. Increases in platelet aggregation to AA and ADP were observed 3 minutes after heparinisation. In response to AA, these increases were similar for both UFH and LMWH, but patients who received UFH demonstrated significantly greater aggregation in response to ADP. Whilst there was no increase in the production of TXB2, there was a significant increase in the generation of 12-HETE. The increase in platelet response was associated with anti-FXa activity, but not with lipase or heparin antibody activity. The intra-operative substitution of LMWH for UFH was associated with a significant reduction in the risk of patients experiencing high-rate embolization post-operatively, and there is an argument for the re-evaluation of anticoagulation during CEA.

Objectives: Chronic total coronary artery occlusion (CTO) remains a significant challenge for percutaneous coronary intervention. Using a novel endovascular porcine model of coronary occlusion we investigated a strategy of promoting antegrade collateral vessels without crossing the occlusion. The prolyl-4-hydroxylase inhibitor, dimethyl oxalyl glycine (DMOG) was used to up-regulate a pro-angiogenic transcription factor, hypoxia inducible factor-1α. Method: DMOG was loaded onto a polymer-coated coronary stent. We developed a novel, entirely endovascular, method of inducing a coronary occlusion. Copper-coated stents were delivered percutaneously to produce CTO lesions in 20 Yorkshire white pigs. DMOG stents were implanted at day 28 and angiographic and physiological data collected on distal coronary and collateral flow. At day 56 the animals were sacrificed and histological analysis performed. Results: A complete total coronary occlusion was present in all animals at day 28 following implantation of a copper stent. At 56 days there was a greater percentage increase in angiographic collateral area in the DMOG group compared with the control (polymer-only stent) group (84.5±34.5% versus 16.5±5.9%, p=0.057). There was no difference between the groups in a surrogate measure of collateral flow at day 56. Histology revealed a significant increase in collateral vessels around the site of occlusion in the DMOG group compared with controls (29.9±2.6 versus 18.4±3.1, p=0.01). Conclusions: DMOG increased the number of collateral vessels at the site of vessel occlusion but not in the distal vessel. The angiogenic effect of DMOG appeared to be restricted to ischaemic tissue. Implantation of a copper stent provides a reliable entirely endovascular method of producing a CTO, with marked antegrade collateral formation present at 28 days. Proximal placement of stents delivering angiogenic compounds such as DMOG may provide a clinical management option in resistant CTO lesion.