BJA/RCoA Project Grant
Imaging NMDA (N-methyl-D-aspartate) receptor activation following head injury using positron emission tomography
Dr Jonathan Coles
Traumatic brain injury (TBI) is a major cause of death and disability despite advances in specialist supportive treatment, leading to great personal suffering to victims and relatives, and huge costs to society. While TBI results in bruises (contusions), bleeding (haemorrhage) and disruption of connections (diffuse axonal injury) within the brain at the time of injury, the extent of such lesions can increase over days to months due to various pathological processes. These include the release of a range of chemical mediators, one of which is glutamate an excitatory mediator within the brain. Glutamate increases excitatory transmission through activation of the NMDA (N-â€methyl-â€D-â€aspartate) receptor and experimental studies have shown that excess NMDA activation is harmful and can result in epilepsy and nerve cell death, and is associated with poor recovery. In patients brain glutamate levels can be measured within specialist neurosciences intensive care units (ICU) by means of a standard monitoring technique called microdialysis. This technique uses a probe placed within the brain and provides a continuous measure of brain metabolism and various mediators, and studies have demonstrated high glutamate levels in patients who do not survive. However, clinical studies using drugs that have tried to block the effects of glutamate in the brain have not shown benefit. This may be due to poor understanding of the spatial and temporal profile of NMDA activation within the brain of patients rather than experimental models. This is particularly relevant around areas with obvious injury since microdialysis can only sample brain tissue within the immediate vicinity of the probe tip and not from across the whole brain. Further research is needed to address these concerns and help target potential therapies to the right patients at the right time.
The aim of the study is to delineate the pattern of glutamate - NMDA receptor activation within the brain following TBI and its impact on the evolution of structural injury, epilepsy and functional recovery. This will be done using a whole brain imaging technique called positron emission tomography (PET) and a novel tracer (18F-â€GE-â€179) that binds to activated NMDA receptors. PET imaging within 48 hours, day 5 - 14 and at 6 - 18 months post injury in 18 TBI patients will be compared with continuous focal microdialysis glutamate levels and standard monitoring of the adequacy of brain metabolism on the ICU. Patients will undergo serial high-â€resolution magnetic resonance (MR) imaging to map the burden of injury and its development from ictus to recovery. Ten healthy controls will undergo similar imaging and patient outcome assessments will identify the incidence of post-â€traumatic epilepsy, functional recovery and quality of life.
While the data provided by this study will be provisional it will provide information concerning an important facet of this complex injury process in patients that may help improve how we deliver current treatment and lead to novel therapeutic approaches. We will use this information to refine our PET imaging technique, and to inform the design and conduct of future clinical trials that aim to improve patient outcome following head injury.
Transcriptome changes induced by shift working and the effect of administered melatonin
Professor Helen Galley & Professor Nigel Webster
Background
Melatonin is produced by the brain and controls sleeping patterns. Levels peak at around 4 am and when night shift workers attempt to sleep in the daytime when melatonin levels are low, a 'mismatch' between melatonin levels and timing of sleep occurs. It takes several days to adapt.
The genome is made up of DNA, which contains instructions to build and maintain cells. For these instructions to be carried out, DNA is changed or 'transcribed' into molecules of RNA; this is similar to DNA but has a different sugar molecule in its structure and is a single strand instead of the double strands seen in DNA. A 'transcriptome' is a collection of RNA transcripts. There are various kinds of RNA - messenger RNA is needed for making proteins. Other types of RNA do not code for proteins but can also affect cells and regulate other genes.
The transcriptome can vary with external environmental conditions and changes in this can tell us a lot about gene activity. Recent studies have shown that when there is a mismatch between melatonin secretion and sleep patterns, there are changes in the transcriptome in the blood of health subjects. Night shift working has been associated with adverse health effects, which might be related to transcriptome changes.
Poorer performance and alertness has been reported in night shift workers and this continues until the timing of the melatonin secretion has changed to match sleeping patterns. Administration of melatonin has been used previously in 'jet lag' - which is a similar situation to that of night shift workers. However it is unknown whether taking a dose of melatonin affects transcriptome changes or if it helps sleeping patterns and work performance to recover quicker. Melatonin has an excellent safety profile and may be a novel treatment to improve sleep patterns, improve performance and possibly correct the adverse health effects of night shift working.
Aim
We will determine the effects of giving doses of melatonin compared with a placebo (dummy drug) in medical staff working night shifts. We will assess whether melatonin given before sleep time is able to: 1. Improve sleep 2. Improve alertness assessed using a computer based reaction test 3. Affect transcriptome changes.
Study Design
Each person will be studied twice during one series of night shifts they will make melatonin and the other they will take a placebo. The order in which they take melatonin or placebo will be decided randomly. They will complete questionnaires about their normal sleeping habits, their sleeping patterns during the night shift and how sleepy they feel. Subjects will do computer reaction tests and we will measure transcriptome changes in the blood. Subjects will also wear a wristband monitor during sleep periods to obtain data on sleeping patterns and restlessness.
The study will tell us whether melatonin might help people undertaking night shifts adapt more quickly to a new sleeping pattern and whether taking melatonin affects the transcriptome changes which have been previously described, which may improve adverse health outcomes.
Pilot study of the Diagnosis and Impact of Frailty in Patients Undergoing Elective Colorectal Surgery
Dr Simon Howell
The past decades have seen a significant increase in life expectancy in the UK. This is a triumph for healthcare and for society as a whole but brings with it major challenges. As people age they often become frail. In medical terms frailty describes the gradual decline in the function of the organ systems of the body such that they have limited reserve to deal with shocks such as they imposed by major surgery. Frail people are up to nine times more likely to suffer major complications following such surgery. They are slow to recover from major operations with up to 50% having incomplete recovery at six months after surgery. There is evidence in non-surgical groups that interventions such as supervised exercise programs and improve diet may slow decline and perhaps partially reverse some deficits. Similarly, there is emerging evidence that the same interventions delivered before surgery may improve function reserve in all surgical patients. It would be rational to consider a program whereby frail elderly patients presenting for elective major surgery are offered interventions such as supervised exercise and nutritional supplementation before surgery to reduce perioperative risk and this is continued through postoperative recovery and beyond to show the progress of frailty. Such a program has significant challenges for the integration of primary and secondary care but should be possible and our group are planning a study for such a programme. This grant application is for pilot work to inform the design of this large scale study. A number of different tools are currently used for the diagnosis of frailty. Some are relatively straightforward and essentially consist of rating the patient on a simple scale. Others require an extensive interview and examination together with some tests. It is not clear that these tools yield identical answers. We will compare three commonly used tools and an electronic frailty index in a group of patients being assessed for colorectal surgery to determine which is best for clinical and research use. Only limited data are available comparing the recovery of frail and non-frail patients following major surgery. We will compare the recovery of quality of life of frail and non-frail colorectal patients following surgery. There is evidence that some frail patients may choose to turn down other lifesaving treatments such as dialysis. There are also some data to suggest that patients may overestimate their ability to recover following surgery while surgeons may focus on the age of the patient rather than their degree of fitness. We will conduct focus group studies to establish the expectations of frail and non-frail patients, carers, and clinical staff for recovery after colorectal surgery. We will hold a consensus conference to establish appropriate outcome measures for studies of interventions in frail patients facing elective surgery. We will establish a patient and public involvement group for this research and we will develop and submit a funding application for a large study.
Hip Fracture Intervention Study for Prevention of Hypotension (HIP-HOP) Trial
Dr Iain Moppett
Evaluating the quality of care given by anaesthetists to hip fracture patients has traditionally relied on important outcomes such as death and length of hospital stay. However, these are measured weeks after anaesthesia, and are affected by many other factors. More recently, research has focused on specific outcomes that are more directly linked time-wise to anaesthesia, and which might delay recovery after surgery or hinder patients returning to the same level of function that they had before the fracture.
Low blood pressure (hypotension) around the time of surgery is one such outcome. National audit data has shown that episodes of hypotension are very common (~90%) in hip fracture patients and, when severe (~30%), are associated with increased death rates, possibly related to decreased blood flow to the brain (causing delirium), heart (causing heart rhythm and pumping abnormalities), lungs (causing postoperative pulmonary complications) and kidneys (causing kidney injury) after surgery. Alternatively, those patients whose blood pressure falls more, may be those with greater co-existing illness and frailty and therefore more likely to have a poor outcome, regardless of intervention.
The aim of this study is to see whether reducing the amount of hypotension (number, severity and duration of episodes) during anaesthesia for hip fracture surgery decreases the frequency of delirium, heart abnormalities and kidney failure within five days after the operation. Once we have received all appropriate regulatory approvals, we will randomly allocate eligible participants into one of two groups. A control group will receive standard care. The intervention group will have their blood pressure will be monitored and treated more rigorously according to a predetermined protocol, which describes acceptable blood pressure limits and treatment options involving intravenous fluids and drugs to increase blood pressure.
We will include all patients over the age of 70 with a single broken hip who are able to consent to participation, requiring any type of hip fracture surgery except total hip joint replacement, under general or spinal anaesthesia with a pain-relieving nerve block. Validated assessment tools will be used to determine whether or not one or more of the clinical outcomes we are interested in have occurred in the five days after surgery.
Initially, we are seeking to fund the pilot phase of this study, so that we can further refine the number of participants required in total and resolve any problems with our intended methods; data from pilot participants will be included in the full study.
