BJA/RCoA Project Grants

Background
People suffering from certain severe illnesses may have an elevated 'lactate' level when their blood is tested. Lactate is a molecule produced by the body when not enough oxygen is available for its organs and tissues. In the past it was thought that lactate was a waste product; more recently it's been suggested that lactate may have an important role to play in the body in certain circumstances.

Patients suffering from severe infections which the body cannot properly control (sepsis), who have sustained severe injuries (major trauma), or who are suffering from a crisis of diabetes with very high blood sugar (diabetes ketoacidosis) may all develop raised lactate levels. High lactate levels - hyperlactaemia - are strongly predictive of worse illness, and of death, when someone is ill.

However, some people with hyperlactaemia do not suffer poor health. Marathon runners will have very raised lactate levels, and generally tolerate this. We don't yet fully understand what lactate does, or why it is associated with harm in only some cases.

Aims
To understand the meaning of hyperlactaemia in different types of disease

Methodology
We will start the research by examining historical medical records to find out how raised lactate levels affect patients' pathways through our hospital.

Following this, patients presented to the emergency department at the Queen Elizabeth Hospital Birmingham will be invited to take part in a research project. In total, 48 patients will be recruited:
- 16 patients in diabetic ketoacidosis (half of whom will have raised lactate)
- 16 patients with sepsis (half of whom will have raised lactate)
- 16 patients with major trauma (half of whom will have raised lactate)

Each patient who is potentially eligible will be spoken to about the trial by the author of this proposal. They will be given a written information sheet setting out the aims, objectives and plan. Should they agree to take part, an extra blood sample will be taken immediately, and a further one in 24 hours. All blood will be collected and processed by the author. Patients will be prospectively enrolled until each subgroup is filled.

Blood samples will be analysed using a technique called metabolomics, which uses a mass spectrometer device to identify the quantity of thousands of individual molecules within the blood sample. This will be correlated with data from their medical records.

Expected outcomes
We expect to detect differences in the blood samples of patients suffering from sepsis, DKA or trauma, despite their lactate levels; however we also expect to find some similarities. We hope to build a testable hypothesis to lead into our next research project.

Implications
Our work will help improve our understanding of lactate. Amongst patients with raised lactate levels, if we can find out who is most at risk of harm, we could possibly tailor their treatment towards them as an individual, and monitor its effectiveness via metabolomics. It will be the basis for future research, and for a PhD project for the author of this proposal.

Increasing numbers of people who are survivors of strokes and heart attacks are being offered surgery. We know that having a previous stroke or heart attack is associated with an increased risk of worse outcomes after surgery - these outcomes include death, having a stroke or heart attack soon after surgery, staying in hospital longer than normal and having to be readmitted to hospital after discharge home. What we don't know is how these risks are affected by time (that is, the length of time between having a stroke or heart attack and having an operation), by the type of surgery, or by the type of stroke or heart attack. If we had better understanding about this, we would be able to have more informed discussions between surgeons, anaesthetists and patients about the most appropriate plans. For example, if there is a high risk in the first few months, then delaying surgery might be in the patient's interest. On the other hand, if there is a time after which risks do not decrease any more then there is probably little point in delaying surgery. Improved understanding might also allow researchers to design clinical trials of drugs or other therapies to reduce the risks following surgery in those people who have had strokes or heart attacks.

We plan to study information from three very large databases that are collected routinely about patients in England and Wales. The Hospital Episode Statistics (HES) dataset is a very comprehensive database of all admissions to hospital with information about operations, current and previous diagnoses. The Sentinel Stroke National Audit Programme (SSNAP) records information about people who have stroke and the Myocardial Infarction National Audit Programme (MINAP) records information about people who have heart attacks. We will be looking at people who have had surgery between 2007 and 2017 and linking this to information about previous strokes or heart attacks. There is a rigorous process to be followed to ensure that this information is only analysed in accordance with current legal and ethical guidance and that all data are kept secure.

At the end of the study we hope to be able to provide better information to patients, doctors and other healthcare professionals, and researchers about the risks around the time of surgery for people who have had strokes or heart attacks previously. We hope to be able to provide accurate information that is specific to the type of surgery they are having.

Patients with traumatic injury to the brain are believed to be at an increased risk of blood clots forming in the legs and pelvis. The risks of blood clot formation can be reduced by administration of blood thinning drugs to inhibit the clot forming process. However clinical staff worry that this thinning of the blood could lead to bleeding in and around the brain, causing further injury to the brain. The use of blood thinning drugs therefore tends to be delayed for many days compared to normal care. This therefore increases the risk that blood clots can form.

The consequences of these clots can be serious. They can move into the lungs, causing an immediate and dramatic threat to life. More subtly, it has been suggested they may also be associated with greater requirements for life supporting care, and poorer outcomes. Furthermore, this patient group is also at increased risk of respiratory infection, and we propose that this could be related to the presence of clots.

Unfortunately, the existing research literature is incomplete. Not only is the best time to start blood thinning treatment unknown but the risks of blood clot formation in brain trauma patients has not been conclusively proven. This later point means that studies to answer the question of timing cannot be justified and will not get funded.

This study aims to address the question of risk associated with blood clots in patients with brain trauma. To identify clots we will screen patients using a non-invasive ultrasound scan of the leg veins. This will be repeated on alternate days over the first 10 days following brain trauma. This time window has been selected because by ten days post injury most patients will be receiving blood thinning treatment. We aim to record evidence of harm that could be associated with the presence of blood clots. We will collect information on the incidence of injury to the lungs, including infection, the number of days of needing to be ventilated on a breathing machine, the number of days required in intensive care, the total number of days required in hospital and measure the quality of the patient's recovery, using established scales. These different outcomes will be compared between those patients who develop blood clots in the legs and those that do not.

It is unlikely that this study will have enough patients to answer the question of whether blood clots in brain trauma patients are associated with harm, outright. Rather it is intended to act as a preliminary study to check we can do the necessary work effectively. The information collected will allow the size of a definitive study, containing the necessary number of patients, to be designed and funding sought.

If, ultimately, an association between leg clots and harm is proven, we would anticipate planning a study to investigate if earlier administration of blood thinning medication, than is current practice, could reduce harms associated with clot formation and improve outcomes following brain trauma.

Lung transplantation is the optimal treatment for patients with end-stage lung disease and provides the best clinical results and optimal quality of life. Despite the demonstrated advantages of transplantation, the full potential of these benefits cannot be obtained due to the severe shortage of donated lungs. Efforts are underway to expand the potential donor pool, including the use of sub-optimal lung donors. However, lungs from these donors are often damaged by injury and stress responses prior to the surgery. These would explain the apparent synergy noted clinically between the effects of primary lung graft dysfunction and acute rejection episodes, leading to increasing deterioration and failure of the graft over time. Understanding of the pathophysiology and the cell biology of lung grafts injury are essential for the search of the targets as the new therapeutic platform. Novel therapeutic approaches designed to protect the lung during the preserving stage, i.e. before transplant surgery, are urgently required.