AAGBI/Anaesthesia Departmental Project Grant
Characterising T-reg subgroup phenotypes in human sepsis
Dr Andrew Conway Morris
Patients with severe infections (sepsis) usually show signs of severe inflammation throughout the body, with high temperature and elevated levels of bacteria-killing white blood cells. Damage to organs such as the lungs and kidneys is common, and is probably in part the result of excessive immune system activation. However, paradoxically, these patients are at high risk of secondary infections (i.e. infections which are not present at the time of admission) some of which are multi-resistant bacteria such as MRSA. Analysis of immune cell function in sepsis often shows decreased or defective function, but the mechanisms which underlie this surprising defect in immunity are incompletely understood.
Recent work from our group and others has identified a population of immunosuppressive white blood cells, known as regulatory T-cells (Tregs), which are increased in patients with sepsis and other severe illnesses. However human Tregs are increasingly recognized as a more heterogeneous population than previously thought, with sub-types which can have either pro- or anti-inflammatory effects. To date there has been no characterization of these subtypes in patients with sepsis, nor has it been confirmed that these subtypes respond in the same way in sepsis as they do in healthy humans. Furthermore the way these cells interact with other immune cells in sepsis is uncertain. Our group has shown that higher levels of Tregs, together with abnormalities in other white blood cell function (called monocytes and neutrophils) are associated with a greater chance of developing a secondary infection in the ICU. It is unclear whether this relationship is indeed simply additive or whether it results from the interaction between these cells. As Tregs are known to have a role in controlling the immune system, their activity could be pivotal.
This study intends to describe the Treg cells found in human patients with sepsis. We will measure the proportions of each subtype as well as analyzing functional responses to stimulation in the laboratory. Further experiments will be undertaken to examine the suppressive effects of these sub-types on non-regulatory 'effector' T cells, which is an accepted way of assessing Treg cell function. We will also explore the effects of Tregs on the function of other important immune cells, such as monocytes and neutrophils. This will allow us to assess whether interactions between the cells in patients may be important.
We will take a blood sample from patients with sepsis in the intensive care unit, and separate blood cells into Tregs, monocytes and neutrophils using standard separation techniques available in our lab. The Treg cell subsets will be identified and separated by labelling cell surface molecules with fluorescent makers. After participating patients provide a blood sample they will be followed to determine what happens during their subsequent ICU stay. This will also allow us to see whether the levels or types of Treg cells found in patients is associated with their chance of recovery, which our pilot data suggest may be the case.
The impact of statins on perioperative mortality in noncardiac surgery in a United Kingdom database
Dr Robert Sanders
Every year surgery is conducted in millions of patients on chronic cardiovascular medication yet we know relatively little about their potential benefits and harms. Statins, drugs used to lower cholesterol in the community, have been suggested to reduce death from surgery however definitive evidence is lacking and hence further studies are needed to (i) support the accumulating data suggesting benefit and (ii) provide feasibility analyses for future randomized controlled trials (the closest study to "definitive") in the United Kingdom to address this knowledge gap. While statins are used very commonly in the United Kingdom either for primary prevention (to reduce the risk of a primary vascular event e.g. a heart attack) or secondary prevention (to improve outcomes following a vascular event) they are not ubiquitously prescribed. For example only 40% of patients undergoing abdominal aortic aneurysm (AAA) repair have been reported to be on a statin. Further United Kingdom data are required to investigate the numbers of patients on statins and the potential benefits of statins in high (AAA), intermediate (total hip or knee replacement) or low (hysterectomy)
risk surgery. This will provide feasibility data for future randomized controlled trials. We will address this by analysis of (i) all patients undergoing this surgery and also (ii) those requiring secondary prevention due to a previous vascular event, as these patients are higher risk and therefore may particularly benefit from statin therapy. More data are also required on the safety of other chronic cardiovascular medication such as beta blockers, angiotensin converting enzyme inhibitors and other cardiovascular medication. The effect of beta blockers remains controversial because the largest trial showed an increase in perioperative mortality however given previous data and their mechanism of effect, it is plausible they may improve outcomes in our study. Angiotensin converting enzyme inhibitors have been associated with a higher incidence of low blood pressure during surgery hence further data are required to indicate whether this may exert significant effects on patient health. We will include these drugs in our analysis to give further data on their safety. The aims of our study are to (i) investigate the impact of statins and other chronic cardiovascular medication on perioperative mortality from high, low and intermediate risk non-cardiac surgery and (ii) show the prevalence of drug use in the United Kingdom as feasibility data for randomized controlled trials. In order to understand which populations of patients may benefit from a randomized controlled trial and the feasibility of the approach, we will analyze data from the general population and those requiring secondary prevention (a higher risk group) undergoing high, intermediate and low risk surgery. We hypothesize that patients requiring secondary prevention therapy may particularly benefit from perioperative statin therapy as they are a higher risk population of patients.
