BJA/RCoA Project Grant

The successful applicants for the BJA & RCoA Project Grant were:

Principle Applicant
Dr Gareth Ackland
William Harvey Research Institute, QMUL

Title
Preventing postoperative infections through exercise induced mitophagy.

Amount
£90,327

Scientific Abstract

Established, or acquired, bioenergetic dysfunction in lymphocytes promotes postoperative infectious complications and delays hospital discharge. Aerobic exercise training may improve postoperative outcomes, although the underlying mechanisms remain unclear. Exercise increases mitophagy, an essential process for elimination of damaged mitochondria and reducing bioenergetic dysfunction/apoptosis. I hypothesize that aerobic exercise induces mitophagy in lymphocytes- in addition to cardiovascular/muscle tissue-, thereby enhancing bioenergetic function and reducing perioperative infections. I will test this hypothesis using two complementary models.

First, metabolic, autophagic and effector function in lymphocytes from patients with low and normal exercise capacity (assessed by cardiopulmonary exercise testing) will be measured. Second, a translational model will be explored where the impact of major surgery on mice genetically deficient in mitophagic machinery will be explored. These experiments will establish the molecular basis for improving immune health prior to major surgery through exercise, laying the groundwork for future targeted clinical trials.


Principal Applicant
Dr Iain Moppett
University of Nottingham

Title
Biomarkers of postoperative delirium

Amount
£87,087

Scientific Abstract

Background
Delirium is common (c.30% of patients) in older people undergoing surgery. It is distressing to the individuals and their carers and may be associated with poorer outcomes - both cognitive (earlier onset of dementia) and mortality. There is no effective treatment other than treating associated conditions such as infection and pain. The causes of delirium are unclear but may involve genetic predisposition (ApoE and dopaminergic pathways); pre-existing microvascular cerebral disease; ageing-associated changes in functional neural connectivity; and inflammation associated with injury and surgery. We propose an observational cohort study of the association between biomarkers and the occurrence of postoperative delirium.

Method
Cohort of 100 older (>70 years) patients undergoing elective or trauma-orthopaedic surgery. Primary outcome delirium in the first 3 days following surgery (5 days for trauma). All patients will undergo Affymetrix chip genotyping and assessment of early (blood) inflammatory marker response. Pre-op fMRI for cohort of elective patients (n=30) - default mode network connectivity; markers of subclinical microvascular disease. CSF inflammatory response in cohort of trauma patients (n = 25) obtained at spinal anaesthesia.

Expected outcomes
Association between biomarkers and delirium. Hypothesis-generation of mechanistic interactions. Capacity building for a new collaboration in peri‐operative cognition.


Principal Applicant
Dr Michael O'Dwyer
The Royal London Hospital

Title
Sepsis induced histone modifications: epigenetic regulation of the host response in post-septic immune suppression

Amount
£83,745

Scientific Abstract

In-hospital mortality from severe sepsis exceeds 40%. Furthermore, patients surviving the acute illness experience double the mortality risk of a matched non-septic cohort over the subsequent three years. Recurrent infectious complications in conjunction with cellular surrogates of immune suppression are characteristic of the acute and chronic phases of this illness. Interestingly, animal models demonstrate that infectious insults induce epigenetic changes that chronically alter the function of key immune-related genes. This project will explore the hypothesis that, in humans, severe infections induce host epigenetic changes that mediate both immediate and persistent immune suppression, thereby compromising a patient's ability to overcome the primary infection and also increasing the risk of acquiring later additional infections. Currently (September 2015), 65 patients with blood culture positive sepsis have been recruited and samples have been acquired both acutely and, in survivors, 1 year following hospital discharge. Recruitment is ongoing. Epigenetic mechanisms causing acute and chronic immune suppression will be explored with an emphasis on sepsis-induced host histone modifications. An improved understanding of the mechanisms that underlie the immune compromise complicating sepsis is an essential first step in developing novel interventions that may reduce both the early and late mortality and morbidity in these patients.