AAGBI/Anaesthesia & BJA/RCoA Small Project Grant
Dr Robert Dickinson
Lecturer, Department of Anaesthetics, Imperial College, London
Pilot study of xenon neuroprotection in a mouse model of subarachnoid haemorrhage
Subarachnoid haemorrhage (SAH) may arise spontaneously from an aneurysm or as a sequel to traumatic brain injury (TBI). In the UK 5000 patients each year suffer an aneurismal subarachnoid haemorrhage, accounting for approximately 5% of all strokes. SAH is associated with a very high mortality and morbitity. As SAH can occur at any age, the costs of long-term morbidity are substantial. It is estimated that the cost to the UK
economy of SAH is £510 million per year. The long-term damage and neurological deficits caused by SAH are thought to stem from the Early Brain Injury that occurs in the first 72 hours after SAH. The inert gas xenon is an anaesthetic that is neuroprotective in models of ischemic stroke and we now have exciting preliminary data showing that xenon is neuroprotective in an animal model of TBI (that includes subdural haemorrhage). This project will evaluate xenon neuroprotection in a mouse model of SAH. The mouse model
allows assessment functional neurological outcome, together with histological analysis of cellular damage and quantification of brain oedema following injury. If we show xenon is neuroprotective in an animal model, this would provide support for a first-in-man clinical trial to determine its efficacy in SAH patients. It would be entirely feasible to use xenon clinically, as diagnosis of SAH involves early CT scanning where the patient is required to be sedated. Xenon could be used for sedation or anaesthesia during diagnostic CT scanning and/or later coiling of the aneurism.
Please see the NIAA's position statement on the use of animals in medical research.
Dr Benjamin Holst
Lecturer, Cardiff University School of Medicine
Lipopolysaccharide-induced hypersensitivity to complement component C5a: investigation of its contribution to the pathophysiology of sepsis and identification of the signal transduction intermediates that regulate it
Severe sepsis and septic shock are the commonest cause of death in intensive care units. The systemic inflammatory response to infection is caused by massive release of proinflammatory cytokines, and is strongly implicated in the pathophysiology of sepsis. However, therapies aimed at inhibiting cytokine release have been disappointing. Toll-like receptors (TLRs) and the Complement system are two components of the innate immune system that contribute to this response. TLR ligands such as lipopolysaccharide (LPS), and complement activation products such as C5a, are potent stimuli to the release of inflammatory mediators; it is also known that they interact synergistically to further enhance inflammatory responses. Our previous investigation has shown that TLR activation can enhance the cytokine response of leucocytes to C5a, and that the capacity of TLR ligands to induce hypersensitivity to C5a varies greatly between individuals. We hypothesise that this variability predicts the susceptibility of an individual to an excessive inflammatory response to a given infective insult. We propose to investigate the relationship between TLR-induced hypersensitivity to C5a and disease severity in patients with sepsis, and to identify the signalling intermediates that regulate it. This may provide a basis for identifying a sub-population of patients that might benefit from an immunomodulatory therapy.
Dr Gary Mills
Anaesthesia and Intensive Care Consultant, Sheffield Teaching Hospitals NHS Foundation Trust
Protective Ventilation During General Anesthesia for Open Abdominal Surgery: a Randomized Controlled Trial. (PROVHILO). UK arm
Postoperative respiratory failure, particularly after abdominal surgery is a major source of suffering and mortality in patients. Although lung protective ventilation including positive end expiratory pressure and recruitment manoeuvres have evidence to show effectiveness in intensive care patients, the situation with their intraoperative use is not clear and as a result they are often not employed.
To determine whether an intraoperative lung-protective mechanical ventilation strategy protects against post-operative pulmonary and extra-pulmonary complications, and shortens length of hospital stay using a randomized controlled trial.
We plan to recruit 100+ patients as the UK contribution to the European PROVHILO study in 3 centres. The Primary endpoint will be: postoperative pulmonary complications; secondary endpoints: intra-operative complications, need for ICU admission or readmission, hospital-free days at day 90, post-operative non-pulmonary organ function; post-operative wound healing; systemic markers of distal organ injury.
We will randomly allocate patients to receive protective ventilation (12 cmH2O PEEP) and recruitment manoeuvres (35 cmH2O pressure application after intubation, disconnection and before extubation) or to receive conventional ventilation (PEEP 2cm H2O or less). Both groups will have a tidal volume of 8ml/kg. The UK data will be pooled with the European data.
Dr Kyle Pattinson
Honorary Consultant Anaesthetist, Oxford Radcliffe Hospital NHS Trust
Measurement of spontaneous low frequency oscillations of cerebral haemodynamics in the human brain with functional magnetic resonance imaging
Low frequency oscillations (LFOs) in cerebrovascular tone occur spontaneously in the human brain. Alterations to LFOs are seen in conditions of cerebral compromise. We aim to develop a functional magnetic resonance imaging (FMRI) technique to measure LFOs in the cerebral vasculature. The aim is to develop a non-invasive and localized early biomarker of brain injury that could be used as a surrogate measure of treatment response in critically ill patients and might highlight patients at risk of further deterioration.
In a cohort of 15 healthy volunteers we plan to record LFOs with a standard FMRI sequence combined with near infrared spectroscopy (NIRS), and a novel fast acquisition FMRI sequence. These combined techniques will allow us to fully characterise LFOs so that in the future they can be detected with standard FMRI alone. Cerebral blood flow will be experimentally manipulated to determine whether changes in LFOs can be reliably detected.
The techniques developed in this study will be incorporated into an ongoing FMRI study of subarachnoid haemorrhage but will also have applications throughout neuroanaesthesia and critical care.
First year progress report from Dr K Pattinson (18 KB)
Dr Mark Rockett
Consultant in Pain Medicine and Anaesthesia, Derriford Hospital, Plymouth
The impact of Patient Controlled Analgesia (PCA) use in the Emergency Department on the prevalence of chronic pain at six months following trauma and abdominal pain
Following severe acute pain, some individuals will develop chronic pain (lasting over three months), particularly if acute pain has been poorly controlled. Chronic pain has a significant negative impact on patients' quality of life and results in high healthcare and benefit costs. Little is known about the occurrence of chronic pain following admission to the Emergency Department (ED) with severe acute pain. Currently, patients presenting to the ED in severe pain, may be recruited to the PASTIES trial and randomised to Patient Controlled Analgesia or standard care. For the proposed study, PASTIES participants will be sent questionnaires six months after recruitment, measuring the prevalence, severity and impact of chronic pain using standardised validated tools (the Brief Pain Inventory, Hospital Anxiety and Depression Scale and EQ5D quality of life measures). The proportion of participants with chronic pain will be compared between groups (PCA vs. standard care, abdominal pain vs. trauma). The effect of gender, age and overall pain score during the first 12 hours of care on the risk of chronic pain will also be studied. The findings will provide much needed long term data on pain outcomes following injury and inform pain management strategies in EDs throughout the NHS.