Time for change in ICU: the role of circadian clocks in critical illness

The intensive care environment is challenging, with disruption to the normal sleep/wake, day/night, and fed/fasted physiological states. It remains unclear what adverse consequences flow from these disruptive influences, but such an environment will disrupt the body clock, or circadian clock.

The body clock coordinates many processes in people including regulating immunity to infection. Therefore, it is important to determine how the ICU environment affects the clock, and what the consequences are for lung defence against infection.

In my first aim I will study patients awaiting heart transplant, who are obliged to remain in ICU for a prolonged period, but typically lack a history of previous disease processes, and injuries often seen in ICU patients. This is important, as I want to find out how the ICU environment works, without having to consider a diverse mix of other disease processes. I will measure the body clock in circulating cells, and will also document circadian control of the circulating immune system cells.

In my second aim I will use a pre-clinical model of the ICU environment, namely light disruption. I will challenge mice with constant light, or light-dark cycles shorter than 24 hours to disrupt the body clock. I will then challenge the mice with a common respiratory pathogen, pneumococcus. I will measure the development, and resolution of infection, and see if light challenge exerts an adverse effect, and how this is achieved. I will go on to target the circadian clock in component cells of the immune system, and repeat the infection challenge to identify which cells are responsible for conveying the clock signal to combat infection.

In my third aim I will take a different approach to study how infection or inflammation in the lung, a common event in ICU due to immobility, and assisted breathing machines, can affect the lung clock. Emerging evidence in other systems suggest that inflammation may abolish clock control of some pathways in cells, but importantly confers clock control to others. Therefore I will challenge mice with pneumococcus, and measure the resulting impact on the body clock operating in the infected lung itself, but also in other organs not directed infected. I have access to novel technology permitting measurement of circadian oscillations in live animals over time, and also in isolated lung tissue. Longitudinal tracking is a powerful approach to resolve circadian oscillation, and also allows clock effects to be measured during the elaboration, and resolution phases of infection. I will also use this model to identify patterns of gene expression that lose or acquire a circadian signature in healthy, or infected lung.

Taken together, I propose a comprehensive analysis of circadian biology in the lung in the context of ICU. I will acquire human samples in aim 1 to which I can return to test hypotheses that emerge from the pre-clinical animal model work. The programme will yield new insights into appropriate care models for ICU, which will inform subsequent clinical trials.

Approximately 90,000 patients per year are admitted into UK intensive care units (ICUs). Disruption to the circadian clock is often observed in these patients however both the aetiology and consequences for recovery are poorly characterised.

Aim1: Does environmental disruption on ICU cause circadian disruption?
Blood samples will be taken from patients who receive a BiVAD (biventricular assist device) soon after admission to ICU and when they are convalescing either at home or on ICU. These will be used to identify whether the ICU environment or physiological disruption affect circadian oscillations. Secondary analysis will analyse circadian control of the circulating immune cell repertoire, and serum mediators of immunity, including pro-inflammatory cytokines.

Aim2: Whether environmental disruption (constant light exposure) alters outcomes after pneumonia
To investigate the effect of the ICU environment, a model of constant light will be used. Pneumococcal infection will be done under constant light or light:dark conditions. By measuring inflammatory cell infiltrates and pulmonary inflammation I will be able to demonstrate whether constant light increases the inflammatory response and whether it disrupts circadian oscillations. Further environmental challenges may include forced desynchrony protocols, to disrupt circadian oscillations, and targeted deletion of the key clock gene BMAL1 in myeloid, or macrophage cells.

Aim 3: Analysis of lung and peripheral blood circadian oscillations in pneumonia
Pulmonary inflammation and infection are common in ICU. Inflammation may affect the pulmonary circadian clock with consequences for recovery. I will investigate how pulmonary infection impacts the pulmonary clock using both in-vivo and in-vitro approaches.

The research questions posed within this proposal are of significant interest to ACADEMIC GROUPINGS in Biological and Biomedical Sciences. The academic community will benefit from elucidation of novel mechanisms causing circadian disturbance on ICU. Critical Care creates a virtual laboratory for human studies; it is vital that we capitalise on this not only to benefit critical care patients, but also to provide novel mechanistic insights into how basic human physiology works. The findings from this study can also be rapidly translated into CLINICAL TRIALS. I would expect the early clinical trials to be interventional studies using technology that is currently available to us e.g. eye mask, ear plugs, filter on lights in ICU. These studies can be conducted relatively rapidly and would pave the way for pharmacological interventions currently being developed.

HEALTH CARE PROFESSIONALS will benefit from this research as it will uncover why environment is important at night in critical care. Simple interventions such as eliminating unnecessary nighttime intervention, reducing music and conversation during the night as well as optimisation of care bundles; this can be quickly achieved if the right science is produced showing the critical care environment affects this patient population.

The sickest HOSPITAL PATIENTS will ultimately benefit from this research as we believe it will unlock a modifiable risk factor which can shorten length of stay, as well as reducing the morbidity and mortality from nosocomial infection on ICU. This will have a significant ECONOMIC benefit to the NHS; the cost of an ICU bed is £1000 - £1800 per day. Considering the current financial climate, where the NHS is being asked to save money and cancel operations due to a lack of critical care beds, this study is exceptionally timely.

In addition to environmental changes, there are opportunities for INDUSTRY to swiftly capitalise on this research. For instance, there are easy hi-tech solutions to some of the causes of night time disturbance, such as remote/ silent alarms for patient monitors, and altering the light wavelength on ICU. Manchester University may capitalise on the research findings as they have established pathways to help commercialise cutting edge research.

Although there is no direct pharmaceutical company involvement in our research, confirmation of the link between circadian disruption and worse outcome from pulmonary infection will impact PHARMACEUTICAL COMPANIES who choose to invest in drugs that can re-entrain the clock, or prevent clock disruption. My supervisors already have a track record of collaborations with a number of pharmaceutical companies; I will capitalise on this during my fellowship.

The GENERAL PUBLIC will also be interested in this research; with newspapers recently reporting the increased incidence of cancer in shift workers, and sleep deprivation in those using tablets to read at night the public is developing an increasing awareness of the importance of circadian rhythms. . My supervisors have already engaged with several newspapers and also helped to design the recent BBC's Day of the Body Clock public engagement exercise.

Myself as the FELLOW will benefit from this research; my passion isto become a clinician scientist. I will work in the largest European circadian laboratory under the guidance of world-leading researchers, ensuring that I maximise my chances of producing high quality publication(s), whilst receiving mentorship for my future career.