The aim of this study was to investigate the balance of pro- and anti-inflammatory cytokines in patients undergoing cardiac and hip fracture surgery in relation to the development of postoperative acute kidney injury (AKI). 400 patients undergoing elective cardiac surgery and 237 patients undergoing emergency hip fracture surgery were recruited. For each patient blood and urine samples were analysed preoperatively and postoperatively to determine how cytokine balance alters in those patients who develop postoperative AKI. In both patients groups, the balance of pro- and anti-inflammatory cytokines in the blood was maintained, regardless of whether or not the patient developed postoperative AKI. This demonstrates that the underlying process responsible for AKI in these patients was not located within the systemic circulation. In the cardiac surgery patients who developed postoperative AKI, it was found that there was a local imbalance of pro- and anti-inflammatory cytokines in the urine, indicating that the pathological cause of AKI is located within the kidney. What was observed was an inadequate anti-inflammatory response to the pro-inflammatory insult of surgery, thus, leaving the kidney vulnerable to the pro- inflammatory onslaught and, subsequently renal injury. A different picture was seen in the hip fracture patients, where elevated pro- and anti-inflammatory mediators were observed preoperatively due to the trauma that occurred in sustaining the hip fracture. This showed an important finding that the hip fracture patients had been undergone cytokine preconditioning as a result of trauma, prior to surgery. In this group the cytokines behaved quite differently to the cardiac surgery group. In the absence of preconditioning, postoperative AKI is associated with an inadequate anti- inflammatory cytokine response to the pro-inflammatory rise associated with surgery. However, when preconditioning is present, the cytokine levels must be analysed more carefully with the clinical context in mind.

Myocardial ischaemia reperfusion injury is common in clinical prac.tice. Myocardial infarction is a good example, in which prolonged coronary artery occlusion by a thrombus may be followed by reperfusion either spontaneously or by medical intervention with thrombolytic drugs or acute angioplasty. The heart may also undergo ischaemia-reperfusion during operations that require temporary interruption of myocardial blood supply s~ch as, coronary artery bypass grafting and heart transplantation. Carbon monoxide, one of the products of haem degradation by the enzyme haem oxygenase, has been shown to protect the myocardium against reperfusion injury and confer other desirable effects despite the bad historical reputation it always had (the silent killer and waste product). Special molecules (COtRMs) capable of carrying carbon monoxide and releasing it in physiological solution have been developed to facilitate further investigation of the role of this gas in biosystems under physiological and pathological conditions and to provide the basis for potential therapeutic agent in the future. The aims of this study are to examine: 1) the effects of CO-RMs on hearts perfused under normal physiologic conditions; 2) the mechanism of the positive inotropic effect induced by some CORMs; 3) to test CO positive inotropic action in failing rat hearts; 4) to study the ability of CO-RMs these molecules to protect against ischaemia-reperfusion injury in models resembling myocardial infarction and heart cold preservation. Results demonstrated for the first time that CO-RM possess positive inotropic effects, and that protection was afforded by the drug against myocardial IIR.

This thesis examines the use of adhesives in the fabrication of microvascular anastomoses. Chapter 1 broadly examines the development, application and current practice of Microvascular Surgery. A historical review of vascular repair leads into a discusion of early and contemporary replantation and free tissue transfer operations. Chapter 2 focuses on the technical aspects of microvascular anastomosis. A review of the many techniques used is folowed by a description of the microvascular healing process. Chapter 3 reviews the use of surgical adhesives. The characteristics of an ideal surgical adhesive are set out. Previous work with surgical adhesives is discussed, and the composition, mode of action, application and fate of fibrinogen adhesive is described in detail. Chapter 4 describes a preliminary study in which a new adhesive microvascular anastomosis was developed. Using 6 rats and 12 rabbits an adhesive end-in-end technique was found to be easy to carry out and appeared to produce satisfactory vascular patency. A rabbit groin flap model was developed to test the new technique in a controlled manner. Chapter 5 describes an experimental study to test the new technique in 50 rabbits using 100 consecutive flaps. Each animal acted as its own control: one flap had a sutured anastomosis and one flap an adhesive anastomosis. Despite numerous technical differences between adhesive and sutured anastomoses, flap survival and patency rates were not significantly different, although adhesive anastomoses were faster and less difficult. The healing of the two types of anastomoses was compared and contrasted using histological sections and scanning electron microscopy. Chapter 6 examines the relevance of the adhesive technique to the contemporary Microvascular Surgeon, suggests other possible uses for fibrinogen adhesive in Microvascular Surgery, and speculates a little on future developments in this area of reconstructive surgery.

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Sacral nerve stimulation (SNS) was introduced for urge urinary incontinence in 1981. It resulted in a significant improvement in 80% of patients. In the 1990s it was recognised that the treatment had a beneficial effect on bowel function, particularly faecal incontinence. This led to prospective trials to assess its role in this condition's treatment and more recently in the treatment of constipation. SNS has, so far, been assessed in specialist centres for the treatment of faecal incontinence in patients with an intact external. anal sphincter. The aetiology of incontinence has varied in the reported series. This thesis demonstrates that SNS for faecal incontinence may be undertaken on a national scale, in units with a specialist interest, without compromise of the outcome. Specific aetiologies of faecal incontinence including partial spinal injury and full thickness rectal prolapse or following anterior resection for rectal cancer are assessed separately. The results indicate that SNS has a role to playin each of these groups. Supplied by The British Library - 'The world's knowledge' The work leading to this thesis includes new indications. These include patients with obstetric-related external anal sphincter defects, which would otherwise have been treated by overlapping sphincter repair. All patients tested in this group proceeded to pennanent SNS with improvement in faecal incontinent episodes from a median (range) of 5.5 (4.5-21.5) to 2 (0-5.5) episodes per week (p=0.017) at a median (range) follow up of 4.5 (1-12) months. In this group of females of childbearing age sexual activity is investigated by a retrospective sex life questionnaire analysis. Quality of sexual activity is improved in nearly 80% of patients with a statistically greater improvement in younger patients. It had been noted in patients treated with SNS for UrInary incontinence that constipation was improved. Subsequent pilot studies in the UK and Italy have led to a pan-European trial of the use of SNS in patients with slow and normal transit constipation. The thesis presents work undertaken at S1. Mark's Hospital that will be included in the European trial. Results suggest that SNS may be beneficial in both types of constipation. The proportion of patients with constipation proceeding to pennanent implant was 57% as opposed to approximately 85% for incontinence. In those proceeding to permanent implant, bowel opening over a three week period improved from a median (range) of 7 (1-23) at baseline to 21 (4-102) (p=0.003). Significant improvements in abdominal symptoms were associated with an improvement in quality of life. The results suggest that SNS could become an exciting new treatment option for patients in this difficult clinical group. Supplied by The British Library - 'The world's knowledge' Solitary rectal ulcer syndrome (SRUS) is a discrete clinical condition associated with an evacuation disorder and specific histopathological features. The condition is difficult to treat. Biofeedback is often the first line therapy. This research shows that rectal mucosal blood flow in these patients is reduced compared to controls (mean (sd) 163(27) versus 186 (14) flux units (FU) (p<0.01)). The findings are similar to those found in patients with normal transit constipation. It also demonstrates that successful biofeedback results in a significant improvement in rectal mucosal blood flow in patients who feel subjectively better after biofeedback from 165 (30) FU to 190 (40) FU (p=0.001). Knowing SNS increases rectal mucosal blood flow and leads to improvement in patients with constipation, three patients with SRUS were trialed with SNS. No patient proceeded to permanent implantation, although all felt some benefit. The results of physiology testing carried out during the studies into SNS have allowed theorisation concerning the mechanism of action of SNS. This is likely to be multifactorial with effects on the sphincter complex, bowel motility, rectal sensitivity and cerebral cortex all having a role.

Cognitive impairment is a common consequence of cardiac surgery using cardiopulmonary bypass and embolisation of particulate and gaseous debris is believed to be the most important cause. Using a new generation of transcranial Doppler (TCD) ultrasonography the aim was to quantify gaseous and solid cerebral microemboli during different cardiac surgical procedures and to relate this to cerebral abnormalities identified using magnetic resonance imaging techniques. A substantial reduction in microembolic load was demonstrated with avoidance of cardiopulmonary bypass (CPB). The majority of microemboli detected during cardiac surgical procedure~ were gaseous and use of CPB was associated with a significantly higher proportion of solid microemboli - regarded as potentially more harmful. Reduction or elimination of aortic m~ipulation resulted in a significant reduction in intraoperative cerebral microembolisation with the potential for reduction of postoperative cerebral injury. Microemboli are not' only restricted to the intraoperative period and could be detected postoperatively following aortic valve replacement. Use ofa mechanical prosthesis is associated with significant increases in solid and gaseous microemboli. Functional magnetic resonance imaging (FMRI) performed serially in patients pre- and postoperatively demonstrated a significant overall reduction in taskassociated activation in the postoperative period. However, increased activation in certain regions of interest suggested a compensatory mechanism or adaptive change that may contribute to functional recovery after cerebral injury from microemboli. Then comparing off-pump and on-pump surgery, there was a significant reduction in prefrontal cerebral activation in patients undergoing on-pump surgery but preservation of cerebral activity following off-pump surgery. These changes in activation correlate with intraoperative microembolic load and were persistent at longer-term follow-up. Magnetic resonance spectroscopy of the frontal white matter showed no significant reductions in N-acetyl aspartate (NAA) levels - a marker of neuronal integrity. This was reassuring indicating that neuroaxonal damage is an unlikely explanation of the functional cerebral changes observed with FMRI. Careful assessment and further understanding of the pathophysiology of postoperative neurological injury would allow the development of targeted neuroprotective strategies aiming to reduce the rate and severity of this important complication

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