BJA/RCoA Project Grant
Preventing postoperative infections through exercise induced mitophagy
Dr Gareth Ackland
Postoperative infections, including wound infections, prolong patients stay in hospital and increase their longer term risk of death. Specialized cells in the immune system are particularly important to fight off postoperative infections. These cells- called lymphocytes- require specialized energy supplies to function normally. In many patients- up to 20% - energy production in lymphocytes is either impaired before surgery or becomes dysfunctional after surgery. This causes lymphocytes to die or function poorly, and increases the risk of infectious complications.
Exercise is known to promote both immune health but too much exercise also can make immune cells malfunction. Exercise may improve recovery after surgery, although the reasons remain unclear. In some patients, exercise is detrimental. In athletes, too much exercise causes failure to fight off common viruses and infections. This suggests that the good effects of exercise are finely balanced, but exercise can prepare the immune system to function more efficiently.
Lymphocytes - just like other cells in the body - need specialized parts of the cell called mitochondria to produce energy. As part of the process of producing energy, mitochondria release toxic side-products that can damage the mitochondria themselves. Damaged mitochondria cause injury within the cell by releasing lots of noxious substances which reduce energy supply and increase the risk of cell death. Mitophagy is an essential process to get rid of these damaged mitochondria and improve the health of the cell. Interestingly, exercise increases the process of mitophagy in the heart and muscles, but we don't know whether this also happens in lymphocytes. Preliminary work for this proposal suggests that this may be the case. This raises the strong possibility that exercise can improve energy production and efficiency in lymphocytes, and prepare them better to function during and after surgery.
Experiments will establish the molecular reasons by which immune health can be improved prior to major surgery. This will pave the way for the crucial next step: establishing the use of safe, commonly used drugs and/or exercise to improve immune function in patients by making energy production in lymphocytes more efficient through mitophagy. This proposal has been reviewed by PCPIE, Royal College of Anaesthetists.
Biomarkers of postoperative delirium
Dr Iain Moppett
Background
Delirium (sometimes known as acute confusional state) is common after surgery. It affects around 1 in 3 older people after surgery to a varying degree and it is often distressing for the individuals concerned, their families and for the staff caring for them. Although the immediate effects of delirium usually recover there are some studies that link delirium with worsening brain function (memory and attention) and possibly a more rapid onset of dementia in some people, though the evidence for this is not completely clear. People who have an episode of delirium may also be more likely to die. It is not known whether the delirium is causing these problems of whether some people are simply at risk of both delirium and other complications. There are many factors which make people more likely to experience delirium: older age, infections and injuries (particularly hip fractures) are well described risk factors. There is currently no known method to effectively treat delirium once it has occurred other than treating the underlying cause. We do not really know what causes delirium. The evidence that we have suggests that it is a combination of genes (especially those linked with Alzheimer's disease and those involved in brain signalling); the body's response to injury and surgery (the 'inflammatory response'); and age-related changes in the brain such as insufficient blood supply (but not bad enough to cause a stroke) and changes in the way some parts of the brain connect to other parts. With the increasing numbers of older people having surgery, having an improved understanding of how and why delirium occurs is becoming more important.
Methods
We hope to undertake an observational study to try to tease out some of these issues. This will involve recruiting healthy older people coming for elective surgery and people who have need surgery to fix fractures. We will not be changing their care in any way and all parts of the study will only take place with the written permission of the participants. The outcome we are looking for is how many people develop delirium in the first few days following surgery. All participants will have a blood test to look for any differences in their genes. Separate groups will also have different investigations including brain scans (MRI), blood tests just after their operation and tests on the fluid surrounding the spinal cord (collected when they have a spinal anaesthetic).
Expected outcomes
We hope to be able to describe some of the factors which are associated with the development of delirium after surgery. These results should help to understand better what actually causes delirium and in the future may help in the development of ways to prevent or treat it.
In addition, the PhD programme will provide training to an early career scientist in techniques that will be useful for a future career supporting peri-operative care research.
Sepsis induced histone modifications: epigenetic regulation of the host response in post-septic immune suppression
Dr Michael O'Dwyer
Background
More than one third of patients who contract an infection severe enough to require treatment in an Intensive Care Unit (ICU) die in hospital. More people die each year from infections than die following heart attacks yet the scale of this problem is frequently underestimated. It is also often not appreciated that those patients discharged home following ICU treatment for a severe infection and notionally 'cured' have a mortality rate far in excess of the general population for many years after the event. Indeed, more than a quarter of patients discharged from hospital are readmitted within a month. The most frequent cause of recurrent illness is further infections.
The majority of people, when exposed to bacteria capable of causing an infection, develop a relatively mild illness during which their immune system successfully fights off and clears the infection. In some patients however, the immune system reacts inappropriately when faced with an infection and this can lead to a more severe illness. Thereafter these patient's immune systems may be permanently damaged and function ineffectually, leading to an increased vulnerability to recurrent infections and an increased risk of death for many years after the event.
In separate laboratory research it has been shown that bacteria have the ability to directly alter the structure of specific genes, crucial for normal immune function, in the DNA of the patient they infect. This spacial reconfiguration causes these immune genes to be 'hidden' within the patient's cell such that they may not function efficiently. Such a repackaging, perhaps combined with other changes in the way gene activity is controlled, could deactivate a patient's immune system making it far more difficult to eliminate the infection. It is thought that bacteria evolved these mechanisms in order to evade the body's immune defences. Proving that this occurs in patients, and not just in a laboratory setting, could lead to novel treatments to help fight infections and their long-term consequences.
Hypothesis
Severe infections cause an immune defect in patients by altering the way in which specific genes in a patient's DNA are 'packaged' and regulated. This phenomenon becomes permanent, causing a long-term susceptibility to develop further infections and an increased risk of death.
Methods
Patients with severe infections being treated both in the ICU and on the general wards at Barts Health NHS Trust are currently being recruited to this study. Blood samples are collected whilst in hospital and again 12 months following hospital discharge at an outpatients visit. These samples will be analysed in order to investigate the patient's immune system, how this is related to DNA structure and packaging and how the presence of bacteria may affect these.
Summary
Severe infections are frequently fatal and survivors often experience impaired long term well-being and longevity. This project will explore the mechanisms underlying the aberrant immune function that contributes to these poor outcomes as the essential first step in developing novel treatments that may prevent the large number of potentially avoidable deaths associated with severe infections
