BJA/RCoA Project Grant

King's College, London

Title
Investigation into blood biomarkers for chemotherapy-induced peripheral neuropathy

Amount
£69,938

Scientific Abstract
Up to 70% of patients undergoing standard chemotherapy treatment will develop chemotherapy-induced peripheral neuropathy (CIPN) as a dose-limiting side-effect, which markedly impacts on quality of life and patient survival. There is no treatment to prevent CIPN and only one drug can inhibit CIPN once established. Prevention of CIPN would be greatly aided if we could identify those patients susceptible to CIPN and understand causal mechanisms of CIPN. This project will address both these aims. Preclinical studies using rat models of CIPN have shown increased mitochondrial DNA and mitochondrial dysfunction in blood and tissues. Such studies generated our central hypothesis that CIPN arises due to mitochondrial dysfunction which increases production of mitochondria to counteract this dysfunction. Based on our hypothesis, this project will assay mitochondrial parameters in blood samples from patients to identify potential blood biomarkers and causal mechanisms for CIPN. Parameters will be measured in blood samples before chemotherapy, after the first cycle, and at neuropathy onset, to investigate their potential as blood biomarkers and advance mechanistic understanding of CIPN.

St Bartholomew's Hospital, London

Title
The prognostic value of pupillometry in patients with return of spontaneous circulation after out-of-hospital cardiac arrest

Amount
£23,350

Scientific Abstract
Improving patient outcomes from out of hospital cardiac arrest (OHCA) is a key priority for the NHS. Withdrawal of life-sustaining treatment by medical staff because of failure to regain consciousness is the cause of death in around two thirds of survivors of OHCA. These data, coupled with expanding use of mechanical circulatory support to support patients in cardiogenic shock or even refractory cardiac arrest, support the study of proposed predictors of neurological outcomes that will inform clinical decision making.

We aim to conduct a single centre, prospective, observational study to assess the pupillary light reflex (PLR) using a hand-held infrared quantitative device in patients with neurological impairment who have presented to the Barts Heart Attack Centre following OHCA. PLR may reflect midbrain injury and herald the inability to awaken from coma.

We will assess the relationship between pupillometry data and neurological outcome at hospital discharge as assessed by the modified Rankin Scale and Cerebral Performance Category. The study will account for confounding variables and statistical censoring if life supporting therapies are withdrawn by the relevant clinical team, who will be blinded to pupillometry data.

Royal Free Hospital, London

Title
The relationship between oxidative stress, mitochondrial function and postoperative outcomes in high risk patients undergoing major surgery

Amount
£93,878

Scientific Abstract
Many patients who undergo surgery suffer postoperative complications. These are diverse in nature, and may cause problems at the surgical site, such as infection or impaired wound healing, or in remote organs, resulting in pneumonia, kidney injury or delirium. Complications lead to prolonged hospital stay, shortened lifespan and reduced quality of life; and may sometimes spiral into critical illness, multi-organ failure and even death. Elucidating mechanisms underlying pathological responses to the challenge of major surgery may be the key to preventing these complications.

Complications may be related to surgery-induced oxidative stress, and its downstream effects on mitochondrial function and energy availability. Mitochondria are both a key target and source of reactive oxygen species, and mitochondrial dysfunction has been linked to worse outcomes in critical illness. We intend to measure mitochondrial function and biomarkers of oxidative stress prior to and following elective major surgery. We will compare these measures in patients who develop complications and those who do not. We will investigate whether these measures correlate with current measures of preoperative fitness, determined by cardiopulmonary exercise testing. We aim to shed light on cellular mechanisms underlying the development of complications following major surgery, and to identify targets for their prevention and treatment.

Royal Infirmary of Edinburgh

Title
The impact of liberal versus restrictive transfusion strategy on cardiac injury in patients undergoing surgery for fractured neck of femur: a feasibility study

Amount
£99,774

Scientific Abstract

Background
Evidence for perioperative transfusion in fractured neck of femur (NOF) lacks wider applicability and is contradictory to published guidance, particularly in those with cardiovascular disease (CVD).

Objectives
Feasibility study of liberal versus restrictive transfusion in patients with fractured NOF and CVD.

Setting
Large teaching hospital.

Design
Prospective feasibility study of two transfusion strategies. Eligible patients will be enrolled into an observational study to establish the incidence of myocardial injury based on measurement of highly sensitive troponin (HST) (Stage 1). Patients in whom haemoglobin (Hb) value is ≤9 g.dL-1 during inpatient admission will be randomised to a restrictive (≤7g.dl-1) or liberal transfusion (≤9 g.dL-1) strategy for the remainder of hospital stay (Stage 2).

Main outcome measures
Feasibility: Enrolment rate, protocol compliance, difference in Hb concentration and transfusion rates between groups. Clinical outcomes: myocardial injury using HST;
major adverse cardiac events using standard definitions.
Other outcomes: postoperative complications, duration of hospitalisation, mortality and quality of life.

Expected outcome
To achieve the following aims: the prevalence of anaemia, myocardial injury and the feasibility of a transfusion trigger study in patients with fractured NOF. Data will inform the design of a larger multicentre randomised trial of perioperative transfusion in this group.

St James's University Hospital, Leeds

Title
Multidisciplinary working across perioperative medicine and primary care: a health informatics feasibility study

Amount
£45,480

Scientific Abstract

The proposed project represents a collaboration across anaesthesia, surgery, primary care, and health informatics. The objective of this study is to demonstrate the feasibility of adding to preoperative assessment information taken from the primary care electronic patient record to predict medium to long term outcome and complications following major vascular and colorectal surgery. We will use a large anonymised database of primary care records (ResearchOne) for this work. We will identify the codes in the database that identify risk factors for perioperative complications. Similarly we will identify codes describing specific operations and codes for postoperative complications of interest, ranging from specific illnesses such as chest infection through to malaise, disability and post-hospital syndrome. We will use these data to generate statistical models to predict long-term outcome following surgery. We will implement the statistical models as software in a current live electronic patient record system (SystemOne) and we will test the functionality of the software. This initial work will demonstrate the feasibility of using primary care records to inform and support perioperative decision-making care and provide data to support further studies of the predictive value and impact on outcome of the predictive models that we develop.

St James's University Hospital, Leeds

Title
Functional analysis of putative pathogenic genetic variants associated with Malignant Hyperthermia susceptibility

Amount
£21,164

Scientific Abstract

Research into patients with susceptibility to Malignant Hyperthermia (MH) has revealed that there are a number of families to which no known causative variant has been attributed. Currently, there are 34 known causative mutations in RYR1 (encoding Ryanodine receptor type 1, RyR1) and two known causative variants in CACNA1S (encoding Cav1.1). Genetic screening has been performed in individuals where a known cause has been ruled out. This has revealed some very interesting rare variants, but without functional assessment we cannot determine whether they actually cause MH. We have a recently discovered 6 rare variants in RyR1 in multiple MH families that require further in vitro functional testing to determine whether they are causative. Furthermore, there is a subgroup of MH patients that have no potentially pathogenic variants in either RYR1 or CACNA1S but have interesting rare non-synonymous variants in other functionally related proteins. An example of this is skeletal muscle isoform of calsequestrin (CASQ1), an endoluminal Sarcoplasmic Reticulum protein that has been previously suggested to cause MH through animal models. We propose performing functional studies using fluorescence techniques to assess whether these novel RyR1 and calsequestrin variants are causative in the pathogenesis of MH.

Leicester Royal Infirmary

Title
Opioids and Anaesthesia (equipment purchase)

Amount
£24,805

Scientific Abstract

The study of opioids has undergone a significant paradigm shift in recent years. Previously, novel opioids were investigated using the canonical signaling pathway (G-protein activation, cyclic AMP reduction and ion channel interaction). However, it is now appreciated that activation of the noncanonical signaling pathways (G-protein-receptor kinases and arrestin recruitment) offers the potential to identify opioids with reduced side-effects. Coupled with the novel understanding that opioid peptides affect inflammatory mediators, unique methods to investigate opioids are required. This application is for a luminometer with BRET (Biofluorescence Resonance Energy Transfer) capabilities. The equipment will be used in several major areas within our group: (1) the testing of novel opioids to determine biased agonism (G-protein versus Arrestin recruitment), which may have long-term benefits for opioid dependence and tolerance; (2) The use of ELISA to determine the effects of opioid peptides on cytokine release from inflammatory cells; (3) the establishment of high throughput non-radioactive binding and cyclic AMP assays. Use of this equipment will be critical in both supporting existing activity and generating preliminary data for substantial new grant applications. The application for a luminometer should be seen as a long-term investment in the future research at Leicester for both academic and NHS colleagues.

UCL Institute of Child Health, London

Title
Impact of surgery and anaesthesia on brain structure and connectivity: age and sex-dependent changes in a rodent model

Amount
£98,598

Scientific Abstract

Background
Surgery, anaesthesia and pain in early postnatal life have long‐term consequences that intensify and prolong pain responses in later life. Mechanisms include neuroimmune interactions in the spinal cord but age and sex‐dependent effects in the brain require evaluation.

Aims
1. What is the long‐term impact of neonatal incision and/or anaesthesia on brain structure and plasticity?
2. How does adult incision affect the brain and what is the impact of prior neonatal surgery and/or anaesthesia?
3. How does microglial inhibition modify the long‐term behavioural and structural impact of surgical incision?

Methodology
Using hindpaw incision in mice we will quantify behavioural responses and use high resolution fixed-brain Magnetic Resonance Imaging and Diffusion Tensor Imaging to reveal changes in volume across the brain. Subsequent quantitative immunohistochemical techniques will define the cellular basis underlying these changes.

Expected outcomes
Results will describe the structural phenotype of the brain, the anatomical and cellular changes following surgical incision, and how they are influenced by early life surgery/anaesthesia and neuroimmune mechanisms.

Implications
These findings have invaluable translational potential for identifying effects of surgery and anaesthesia on the developing brain and understanding risk of persistent post‐surgical pain, with potential to identify novel therapeutic targets appropriate to both sexes.

University of Aberdeen

Title
Metabolomic analysis after exogenous melatonin administration

Amount
£51,237

Scientific Abstract
Exogenously administered melatonin has antioxidant and anti-inflammatory properties and and is able to protect mitochondria from oxidative stress. It is being investigated as a potential therapy in patients with sepsis and has been advocated as a 'wonder drug' for a range of different conditions. It appears non-toxic yet little is known either of its final fate after exogenous administration nor its effects on cellular metabolism. This proposed study will investigate such effects in detail.

We have recently completed a Phase I trial of melatonin administration in healthy subjects and the proposed project will use existing serum and urine samples from this trial to investigate the 'metabolome' (physiological metabolic pathways) and the 'metabonome' (pathways specifically related to melatonin metabolism) after four different doses of exogenous melatonin administration. The data obtained will be related to our existing physiological and biochemical data. Identification of both the human metabolome (metabolic effects of melatonin) and the metabonome metabolic fate of melatonin) will contribute to the understanding of the global cellular effects of giving exogenous melatonin. The study is a bench-to-bedside-to-bench approach which will further detail the effects of giving exogenous melatonin to patients, making use of existing samples and data.