AAGBI/Anaesthesia & BJA/RCoA Small Project Grant
Pilot study of xenon neuroprotection in a mouse model of subarachnoid haemorrhage
Dr Robert Dickinson
Background: Subarachnoid haemorrhage (SAH) is a form of stroke caused by rupture of a blood vessel in the brain. SAH may occur spontaneously as a result of rupture of an aneurysm (a bulge in a blood vessel), or may be a consequence of a head injury. SAH is associated with a high level of death and longterm disability. As many as 40% to 60% of patients suffering SAH will die within the first 48 hours. Of those that survive SAH only 35%-55% are likely to achieve a level of independent living and 75% will suffer long-term deficits in memory, cognition or language. It is estimated that the cost to the UK economy of SAH is £510 million per year. The long-term damage caused by SAH is thought to stem from the Early Brain Injury that occurs in the first 72 hours after SAH.
Xenon is an anaesthetic gas that shows great potential as a treatment for brain injury, because it very rapidly gets to the brain, is non-toxic and is not metabolised. Xenon has already been shown to be neuroprotective (to
protect brain cells) in animal models of another form of stroke (ischemic stroke). We have exciting new data in mice showing that xenon significantly protects the brain against traumatic brain injury. We are seeking funding to
evaluate xenon neuroprotection in an mouse model of SAH. If xenon is sufficiently effective in an animal model the next stage will be a clinical trial to determine its efficacy in SAH patients. The ultimate goal of this work is the use of xenon in a clinical setting to improve long-term outcome following SAH.
Objective/Hypothesis: This proposal will determine whether xenon may be an effective treatment for SAH using an animal model, and will test 4 hypotheses. 1. That xenon treatment improves functional neurological outcome after SAH. 2. That xenon attenuates early brain injury after SAH, as assessed by brain histology and odema.
3. That xenon acts in a concentration dependent manner to improve outcome after SAH.
4. That there is a therapeutic time window after SAH, within which xenon remains effective, that realistically reflects when a SAH patient could receive treatment (1 - 3hrs).
Study Design: We will use a recognised mouse model of SAH to test our hypotheses. The model involves rupture of a cerebral blood vessel by insertion of a nylon filament. Mice will be randomly assigned to different treatment groups (with and without xenon). Neurological outcome will be measured in the using of a 10 point acute neurological outcome score that measures motor ability, balance, alertness and general behaviour. We will also assess outcome histologicaly by looking at cell death in brain-slices from the mice and by measuring brain water content (cerebral odema). The outcomes will be determined by an experimenter who does not know which treatment group the animal comes from.
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.
Dr Benjamin Holst
When foreign organisms such as bacteria or fungi invade part of the body, the immune system responds with a number of defensive measures. Chemical messengers are released that recruit white blood cells to the site of the infection, and blood vessels become leaky to permit the white cells to migrate into the infected tissue. Once they encounter foreign organisms, the white cells respond by engulfing and digesting them, and releasing chemicals
that kill them. This process, which is known as inflammation, involves a certain amount of 'collateral damage' to the infected tissue, but this is preferable to allowing the infection to progress unchecked, and is part of the normal working of the immune system. However, in some cases of severe infection, the inflammation is not confined to the infected tissue but is propagated out into healthy tissues, causing inflammation and injury to vital organs that are not infected. This is known as the Systemic Inflammatory Response Syndrome (SIRS), which is a characteristic of the syndrome of sepsis (sometimes known as septicaemia). Sepsis is the commonest cause of death on intensive care units, and kills more people each year than
heart attacks.
The reasons why an infection may progress to sepsis are not fully understood, but almost certainly involve the chemical messengers that trigger inflammation. These chemical messengers are known as cytokines, and it is thought that the excessive production and release of these inflammatory cytokines is responsible for the exaggerated inflammatory response in cases of sepsis. For this reason much attention has been given to the mechanisms that control the release of cytokines, with a view to finding a treatment that may dampen down the excessive inflammatory response but still allow the infection to be cleared. Our previous research has examined the interaction between two components of the immune system which, when acting together, result in a much greater release of inflammatory cytokines than the sum of the two components acting alone. We have identified a particular protein that seems to control this interaction and have some evidence that suggests it may be possible to block the communication between the two parts of the immune system that results in an excessive cytokine release while preserving the ability of each of the two components to respond independently.
Further study is needed to determine if this interaction (which we have studied in isolated human cells and laboratory animals) actually contributes to the disease process in humans with sepsis. If this proves to be the case, it will be necessary to identify exactly which cellular processes are critical in controlling the interaction in order to attempt to develop a treatment that may block it. Accordingly we propose to recruit a group of 60 people with
sepsis and assess the degree to which their blood cells are influenced by this interaction between the two components of the immune system; if there appears to be a relationship between this and the severity of their illness, this would suggest that it may be an important factor in the disease process. At the same time, we intend to study the interaction in more detail with a view to identifying specific proteins controlling it that may be amenable to medical treatment. Our application is for funds to purchase experimental reagents that will enable us to do this.
Protective Ventilation During General Anaesthesia for Open Abdominal Surgery: a Randomized Controlled Trial. (PROVHILO). UK arm
Dr Gary Mills
Background: This study looks at the problems that occur in the lungs and elsewhere in the body during and after surgery inside the abdomen.
What is known: Previous research has suggested that when patients need to be on mechanical ventilators (as they do for this type of surgery) that blow air in and out of the lungs because they are either anaesthetized or needing this because they are too ill to breathe for themselves then the lungs suffer. This can also impact on other parts of the body. Although this ventilation is essential, the lungs are subjected to unusual pressures and stretch, which can damage them. One way that may reduce this problem is to leave some pressure in the lungs at the end of each breath (PEEP) so the lungs do not collapse down. As a result the air passages stay open rather than closing up and they are not then subjected to forces that inflame them by pulling them open during each breath. Short periods of extra pressure can also be applied to the lung to reopen closed up airways called "lung recruitment" (RM). It may be that these ways of ventilating the lung decrease lung problems after surgery and could save lives, reduce suffering and mean that patients are fitter faster after surgery, with the potential for going home earlier. However, the benefits that can be gained using these techniques for patients undergoing operations that last hours rather than the days or weeks of ventilation we see in intensive care patients are not clear cut. As a result most anaesthetists in a survey conducted in France did not routinely use these techniques. Our aim is to determine whether these techniques are helpful for patients who are undergoing abdominal surgery and whether they should be
routinely adopted.
What will we do?: We will randomly allocate patients either to receive protective ventilation (PEEP and RM) or to receive conventional ventilation with very little pressure remaining in the lung at the end of each breath. Across Europe 900 patients will be recruited. We aim to recruit at least 100 patients in the UK, initially in three centres. We will record how well they are before and on the first five days after surgery and on the day before they go home. It may be that patients receiving protective ventilation have fewer problems in and outside the lungs during this period. Therefore we will follow up their physiology, including heart rate, blood pressure, oxygen requirements and other routinely measured indicators over this time. It may even be that patients get better faster and could be ready to go home earlier.
Conclusion: We hope that we can establish whether the benefits of protective ventilation outweigh any adverse effects. If this proves to be the case, this could quickly be applied all over Europe at very little cost because the ability to use these techniques is already built in to most modern anaesthetic machines. This is why this is such an important study.
Measurement of spontaneous low frequency oscillations of cerebral haemodynamics in the human brain with functional magnetic resonance imaging
Dr Kyle Pattinson
Subarachnoid haemorrhage is a type of stroke in which blood leaks onto the surface of the brain from a weakness in the walls of an artery. About a third of patients suffer secondary strokes a few days later that leads to significant disability or death.
The aim of this research is to develop brain scanning techniques that will help us to identify why secondary strokes occur after subarachnoid haemorrhage. Subarachnoid haemorrhage is associated with changes in the way blood flows in the brain, and improving the measurement of these changes is likely to help us understand and treat the disease better. Additionally these techniques could also be applied to understanding other types of stroke.
Blood flow in the brain is rarely constant, even in healthy people. It fluctuates due to rhythmic widening and narrowing of the arteries in the brain. We are particularly interested in the low frequency fluctuations (LFOs) in diameter that occur about once every ten seconds in blood vessels in the brain. LFOs change in conditions of brain damage, and therefore may be a potential marker of potential or actual brain damage.
We intend to use a brain scanning technique called functional magnetic resonance imaging (FMRI). FMRI measures blood flow in the brain, is completely safe, does not require injections or X-rays, and gives images of the whole brain. Normally FMRI only collects images at a rate that is too slow (about every three seconds) to separate LFOs from other sources of blood flow fluctuation (mostly breathing and heart beats). With this research we aim to optimise the techniques in order to measure LFOs independently.
We will therefore combine standard FMRI with a fast new FMRI sequence that collects multiple images every second. We will also use a technique called near infrared spectroscopy that measures LFOs by shining infrared light onto the surface of the brain from a sensor placed on the forehead. By combining the results of the standard FMRI, fast FMRI and infrared spectroscopy in health volunteers, we will be able to find out which parts of the standard FMRI signal relate to the LFOs, enabling us to focus on them when we scan patients.
This study will be performed in a group of 15 healthy adult volunteers who will be scanned on two occasions. On one occasion they will breathe room air, and on another occasion they will breathe air enriched with a small amount of carbon dioxide, which alters blood flow and LFOs in the brain. The differences in LFOs will be examined using powerful computer programmes specially designed by our laboratory to analyse FMRI.
Once we have a better understanding of how to manage LFOs and how they may change, we will apply this to brain scans that we are currently collecting in patients with subarachnoid haemorrhage. The results could allows us to better identify patients at risk of deterioration and monitor response to treatments.
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
Dr Mark Rockett
Background:
Following injury or illness many people experience severe short term (acute) pain. Usually, pain improves with time and most people would expect to be pain-free after 3 months. Unfortunately, some people develop long lasting (chronic) pain despite the resolution of their original problem. This may happen after surgery or injury and is far more common than was previously thought. For example, 1 in 8 people develop long term pain following hernia repair and over half following amputation. Known risk factors for chronic pain (CP) after surgery include: younger age, depression or severe acute pain.
CP is usually not severe but in 5% it results in significant disability. Severe CP often means people cannot work, suffer anxiety and depression and frequently attend for healthcare (five times more healthcare use than individuals without chronic pain). As CP is a common problem with significant negative impact on the individual and society as a whole, it is important to try and predict and prevent it. Treatment of established CP is expensive and
difficult.
Surprisingly little is known about the long-term outcomes of short term pain in patients attending the Emergency Department (ED). Pain management in the ED is often difficult - we are carrying out a study to assess the impact of different pain management techniques on short-term pain (the PAin SoluTIons in the Emergency department Setting - PASTIES - study). Participants in the PASTIES study have severe pain from trauma or an abdominal illness when they arrive in the ED and are treated with either intravenous morphine given by a nurse (standard care) or are given a device to allow them to control their own morphine delivery (patient controlled analgesia device - PCA).
Aims: The aim of the study for which we are now applying for funding is to answer the question: "Does PCA use reduce the risk of chronic pain at 6 months following enrolment in the PASTIES trial?" The study may also provide the answer to a number of other questions about long term pain. We will also discover how common long term pain is after trauma and abdominal pain and whether age, sex or severity of short term pain are important factors in the progression from acute to chronic pain. The study also aims to determine how severe long term pain is and what impact it has on the lives of those affected.
Methods: PASTIES participants will be sent questionnaires six months after recruitment, measuring the severity and impact of chronic pain using well-established 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.
Importance of study: The findings will provide long term data on pain outcomes following injury and may inform pain management strategies in the ED.
