BJA/RCoA Project Grant
Pilot study of the extent and distribution of microglial activation in young and elderly rats undergoing cardiopulmonary bypass, as detected by Positron Emission Tomography, using the tracer 11C-PK11195, and immunochemistry staining techniques
Professor Anthony Absalom
Elderly patients undergoing cardiac surgery commonly experience post-operative cognitive decline. Many researchers believe that POCD is the result of damage caused by inflammation that arises from the use of a heart-lung bypass machine, causing the blood to come into contact with artificial materials and sometimes with air. This theory is now being questioned, since recent studies have shown similar incidences of POCD after newer techniques, in which heart surgery is performed without bypass. Until now, studies have mostly used blood tests to identify inflammation in the body and brain, but the significance of these tests has also been questioned. At our hospital, a technique has been developed that is capable of detecting cells that change shape and activity when the brain is inflamed. We would like to use these scans to improve our understanding of POCD. As they have not been used before in patients after surgery, we first need to be sure that this scan will actually detect any inflammation that may arise from the bypass machine, and so the purpose of this study is to provide proof of concept evidence in rats before we move on to study humans.
The influence of obesity on the pathobiology of acute lung injury
Dr Michael Wilson
Acute lung injury (ALI) is a major reason people require intensive care treatment. It is a potentially fatal condition that develops as a result of some 'insult' to the lung, including influenza/pneumonia and a host of others. If a patient develops severe ALI they have about a 50% chance of survival. Major factors deciding survival include how the patient's immune system reacts to the initial insult, and how quickly the lung repairs itself. Currently no drug treatments exist for ALI, partly because our understanding of the disease is incomplete. To further our understanding, we intend to look at the influence of obesity. Unexpectedly, there is growing evidence to suggest that being obese might be beneficial in ALI (obese patients with ALI have better survival than non-obese ones). To investigate this, we intend to carry out animal experiments looking at different forms of ALI in lean and obese mice (made obese by eating a high fat diet). We will investigate whether obesity has some beneficial effect related to an altered immune response, and whether the lungs are more able to repair themselves. We believe that such studies of animals with differing susceptibility to ALI could eventually help design new therapies.
Investigation of the effects of dopexamine on leucocyte-endothelial interaction, microvascular flow and tissue inflammatory pathways and the underlying mechanisms in a rodent model of laparotomy and endotoxaemia
Dr Rupert Pearse
The microcirculation consists of small blood vessels including arterioles, capillaries, and venules. Major functions of the microcirculation include increasing the surface area for exchange of oxygen, metabolic substrate and waste products between the body tissues and the blood stream. The microcirculation also plays a central role in mediating the inflammatory response to tissue damage caused by major surgery. These effects are linked to failure of vital organs and death. Adrenergic agents (such as adrenaline and dopexamine) are administered in high doses in over half of all critically ill patients. However, the diverse and potent effects of these drugs are poorly understood. Adrenergic agents may have important effects on immune function within the microcirculation which could either be beneficial or harmful. We are interested in the synthetic adrenergic drug dopexamine, which may improve survival after certain types of surgery. Dopexamine may have many important effects on the microcirculation and may possess a novel mechanism of action. We therefore propose to investigate these potential effects of dopexamine in order to improve our understanding of this class of drug.
Novel strategies to ameliorate pain associated with avulsion injury
Dr Peter Shortland
Avulsion (tearing of spinal nerve roots) produces a discrete spinal cord injury resulting in bladder and bowel dysfunction, limb paralysis and muscle atrophy, sensory impairment and chronic pain. The mechanisms underlying these changes are poorly understood and the pain is refractory to drug treatment. We hypothesise that the pain may be caused by ischaemia which subsequently leads to cell death and that this can be prevented or reversed by drugs that protect cells from dying and promote new blood vessel formation. Initially experiments will examine blood flow and oxygen levels in the damaged spinal cord segment and compare it to the normal situation using fibre optic probes. The blood flow patterns will be compared to quantitative assessment of cell number and pain related behaviour 2 weeks post-injury. Subsequently, clinically relevant drugs already in use for other conditions that have neuroprotective and blood vessel growth promoting properties will be administered and their effects on pain behavioural, cell survival and blood vessel growth and oxygen levels. It is anticipated that the drugs will promote cell survival, improved oxygen supply and reduce pain levels and will offer a new way of treating the chronic pain associated with avulsion injury.
Does intra-operative goal directed fluid therapy reduce clinically important post-operative complications in patients undergoing elective non-vascular major abdominal surgery associated with extensive tissue trauma?
Dr Gary Minto
During major surgery patients need to be given extra intravenous fluid so as to improve the blood supply to the healing areas and to the body organs. It is important to give neither too little, which risks an inadequate blood supply, nor too much, which may "waterlog" the patient. Either of these situations can lead to increased complications such as infection or breakdown at the operation site and prolong the time it takes to recover. Specialised monitoring gives us more precise information about fluid status, however it is not clear whether this extra information is necessary for a lot of operations. We think it may be worthwhile when patients are having particularly big operations, or when they are particularly unfit. Maybe getting the fluid balance just right opens up the small vessels, capillaries that take the blood the last bit of the journey to supply the organs. We wish to test this in a trial in which patients will have their fluid treatment guided by either the usual monitors or the specialised monitoring, and we will use a video camera to see whether the capillaries open up well. Afterwards we will check the rate of complications and recovery time.
