AAGBI/Anaesthesia Research Grants

Background
Every year, efforts are made to resuscitate about 30,000 people when their hearts stop outside of the hospital environment ('out-of-hospital cardiac arrest'). Early damage to the brain due to 'oxygen starvation' (seemingly paradoxically) gets worse when blood flow is restored. Of the 6,350 survivors admitted to intensive care units, 46% die from brain damage, and half of those who survive suffer long-term brain damage. Apart from avoiding a high temperature, nothing has been found which can protect the brain or improve outcome.

'Ketones' are chemicals naturally produced in the body from fat during starvation. They act as an energy source, but also as regulators of metabolism, and appear to protect cells from damage when oxygen supplies are scarce, or when blood flow is restored. Until recently, there was no safe way of giving ketones to people. Now a company 'spun-out' from Oxford University has solved the problem, and their ketone supplement has been safely taken by large numbers of athletes to improve their metabolic efficiency, and thus physical performance. We want to see whether it will also protect the brain after out-of-hospital cardiac arrest.

Aims
Whilst we know the drink can be taken safely by healthy people, we need to confirm that this is also true when people are very sick. Experts at the UCL School of Pharmacy have assured us that the chemical nature of the ketones should not affect any other drugs the patients receive. However it might be, for instance, that the ketone is not well-absorbed in sick patients.

Methods
We will study 10 cardiac arrest patients, and will give them the ketone drink via a feeding tube (which is routinely passed into the stomach in such cases). We will start as soon as the patient arrives in hospital, and continue giving for 48 hours at the dose previously used in healthy people. The patients will be in a coma due to their cardiac arrest and will be recruited based on clinical presentation. A discussion will be held with a consultee (e.g. next-of-kin) as soon as practicable, and patients' individual consent will be sought as and when they regain capacity. We shall check that the drink is absorbed, and measure the ketone levels in the blood. We will also measure important aspects of blood chemistry (including pH and blood sugar) and collect data on brain (electrical recordings called 'EEG' and 'SSEP') and heart function (ultrasound scans or 'echocardiographs') - both of which we hope might improve - in order to demonstrate that this is possible if it is to be included in a subsequent large trial. The study will be scrutinised by world experts in the field, who have also helped design the study.

Implications
If this pilot study is a success, we will apply to a major grant body to fund an appropriately-powered randomised controlled trial to determine whether ketones improve neurological outcome and survival in these patients. Results will also allow us to plan similar studies in heart attack, stroke and traumatic brain injury.

Introduction
Patients admitted to intensive care units (ICU) receive the most up to date medical treatments available. These treatments allow patients to survive conditions that would otherwise be terminal. Whilst ICU care is technologically far advanced to that on general wards, it is a busy, restless environment. Good evidence exists which demonstrates that nocturnal exposure to light is bad for patients. We know that inappropriate light exposure alters the natural day-night cycle in patients, which can cause patients to become confused and disorientated. This disruption can also affect the way critically ill patients respond to infection and inflammation. This in turn can have a negative impact on length of ICU stay, morbidity and mortality.

There is currently no good data looking at how much nocturnal light patients are exposed to, when they are exposed to it, and which patients are affected most. There is also no medical guidance on limits to nocturnal light exposure. This project will quantify how much nocturnal light ICU patients are being exposed to. It will also assess who, when and why patients are exposed to this light in order to make suggestions on how to minimise exposure, and thus improve patient outcome.

The project
Lux (a measure of light intensity) will be measured at 5 second intervals overnight for 10 hours. This will allow accurate measurement of light, and short, but significant spikes in Lux can be measured. Other data collected include how unwell the patient is, and how unwell those around them are. This is to identify if being more sick exposes patients to more Lux, and also if being positioned next to a patient who is very unwell exposes patients to higher Lux. We are also analysing whether position in the ICU (general ward vs side room) has an impact on Lux exposure. We plan to collect over 100 nights worth of data, making this the largest study of its kind worldwide.

When the project is complete we aim to make recommendations in order to decrease nocturnal lux exposure and therefore improve patient outcomes.

Funding requirements
Funding is being sought in order to purchase accurate, calibrated lightmeters in order to measure the nocturnal Lux in 5 Intensive Care units in the South of England. This is an Anaesthetic trainee led project, in conjunction with the Wessex trainee research network SPARC (South Coast Perioperative Audit and Research Collaborative). A pilot study has been completed in a single ICU (self-funded by trainees), which has proven the process provides good data. Moving forward more accurate, adequately calibrated lightmeters on multiple sites are required in order to carry scientific credibility.

The liver is an essential site for the production of many blood clotting proteins and liver disease is often associated with abnormalities of blood coagulation tests. It has previously been thought that the rise in specific clotting tests seen in more advanced liver disease indicates an increased risk of bleeding. In recent years, new research into coagulation indicates that despite abnormal laboratory tests, many patients with liver disease actually have a relatively normal ability to clot their blood, or even a predisposition to develop clots.

Today, it is more likely that patients undergoing liver transplantation (LT) will not require a blood transfusion. This is in part due to the way coagulation is monitored intraoperatively bedside viscoelastic tests (VET), designed to measure how blood is clotting globally, rather than using standard laboratory based tests. VETs enable rapid identification and correction of any clotting abnormalities during LT that might predispose to bleeding. VETs have shown that despite conventional tests indicating poor blood clotting, many patients actually have normal clotting in LT, and in some cases accelerated clotting. This has changed the way patients are managed in the operating theatre, with many avoiding unnecessary blood transfusion to correct abnormalities seen in conventional coagulation tests.

VET samples required expert processing to ensure reliable results; this meant they had little use outside of theatres. On the intensive care unit, management of postoperative bleeding in LT patients relies on conventional tests, which poorly differentiate between patients with poor, normal or excessive coagulation.

The majority of patients will have conventional coagulation tests that indicate poor blood clotting for the first few days after LT. This can lead to transfusion of blood products to correct abnormalities in these tests, even though the patient is not actually at an increased bleeding risk, or lead to a delay in thrombosis prevention with anticoagulants, because of the perceived risk of bleeding. Blood transfusion is not risk-free and can lead to a number of adverse effects for the patients.

It is certain that there are many complex changes in coagulation that occur in the early days following a LT, but surprisingly little work has been done in this area. VETs enable a more detailed and comprehensive overview of real time clot formation, and potentially provide more information than conventional coagulation tests about the underlying bleeding or thrombotic risk in a given individual.

Our proposed observational study will monitor postoperative coagulation using both VET and additional specific haematological clotting assays. We will compare the coagulation picture suggested by these tests to conventional coagulation and determine which method is a more accurate representation of the true coagulation status. We intended to establish if VET are a more accurate way of monitoring the coagulation status in patients following LT. If this is the case, it could substantially change the way we manage our patients postoperatively, and lead to improved liver graft and patient outcomes.

Introduction
Lung complications after major surgery are the most common causes of serious problems during early and mid-term recovery. Because surgery is so common, this affects a huge number of people each year, especially those who are older, frailer or who have other illnesses. Robotic surgery has been introduced and is increasing in popularity. However this frequently requires the extreme positioning of the patient, commonly with very marked head down tilt. This means that when the abdomen is filled with carbon dioxide to allow the surgeons to see what they are doing, the diaphragm is forced headwards and the lungs are squashed in a pattern not seen when the patient is horizontal. Mechanical ventilation is routinely needed to make breathing possible. Unfortunately, some less dependent areas of lung will become overinflated and others will collapse. This causes over expansion of some parts and forced opening and closing of others and total collapse in some places. All damage the lung and make postoperative breathing problems likely. We do not know how much of a problem this is, nor do we know whether certain current approaches make it more likely. Therefore a study to assess what is going on anaesthetically, including ventilation pressures and techniques as well as aspects of the surgery may help us describe the problem and develop plans for reducing complications that happen during and after surgery, which can be as severe as needing reventilation and return to intensive care, which can be life threatening.

Method
As part of a worldwide study we plan to take a one month snapshot of robotic surgery, recruiting above 100 patients in the UK. Worldwide it is anticipated that more than 700 patients will be recruited. Data will be gathered to see what complications occur and what factors, including the way we ventilate patients, these are most commonly associated with. Patients will be recruited ahead of their surgery and followed up in detail for a minimum of 5 days after surgery. No additional tests will be required from these patients, but we will analyse the results of tests gathered as part of their normal care.

Results and impact on future care
This study will help us assess the greatest contributory factors to lung complications in this group. This is very important because although robotic surgery is still at an early stage, its use is likely to grow greatly over the coming years and at present its risks and complications, especially in terms of how people breathe after surgery is not fully appreciated or understood. Now is the time to learn about this and to develop safer techniques, including those related to the mechanical ventilation of these patients and the support given to their breathing after surgery and also to determine the best place for their care and monitoring after surgery.