Title: Bringing a fast intra-arterial oxygen sensor to readiness for commercialisation and future patient trials.
Funder: Department of Health and Social Care

Abstract: Elsewhere in Case for Support - Part 2;Research Plan" the project has been divided into its component steps and associated milestones. In this section below, we describe the scientific background and justification of the project. The Clinical Pathophysiology Mechanical ventilation is the mainstay of treatment of patients with acute severe respiratory failure. Unfortunately however, mechanical ventilation itself, and in combination with a severe systemmic inflammatory response, conspire to injure the lung yet further [1]. Mortality in these patients is high. The mechanisms by which mechanical ventilation can cause cause lung injury are beginning ot be understood. Whilst excessive inflation pressure and volume and their associated stresses are implicated, more so is the repetitive recruitment and de-decruitment of lung units, so called 'cyclical atelectasis' (CA) [2] which may fuel the systemic inflammatory resonse [3]. This leaves a clinical dilemma: whilst mechanical ventilation is vital for survival, it also contributes to mortality, so there is a quest to find the least harmful modes of ventilation on an individual patient basis. We know from rapid sequence CT scanning that atelectasis is recruitable within the timeframe of a single breath [4], and that by application of the correct ammount of positive end expiratory pressure (PEEP), CA is reduced. The problem is knowing what is the correct ammount of PEEP for an individual patient [5], and that continual (or even one-off) CT scanning is not a practical option for ITU patients. Attempts have been made to find a practical means of determining when CA is occuring and of titrating optimal PEEP with minimal shear stress, but none has been successful. None of the traditional bedside respiratory measurements which we use can predict the degree of recruitable atelectasis which is visible on CT[6]. Clinicians need a biomarker of CA and a technology to detect it [7]. Our sensor has been developed with this main aim. The Sensor and the Technology The principle underlying our sensor is the quenching of fluorescence by oxygen. This is well established, and the relationship between quenching and PO2 is given by the Stern-Volmer equation. In practical terms, a fluorophore is excited by a given wavelength of light and fluorescence is emmitted at a lower energy. The lifetime of each quantal emission is influenced by the local PO2, such that at high ambient PO2 values, the lifetime of photon emission is short, and so the light intenstity is low (and vice versa). There are a number of novelties in our sensor. First, we use a non-toxic fluorophore mounted on an inert medical grade polymer fibre. The fibre itself (its core, cladding, its taper, its stepped refractive indices) is uniquely designed to suit its purpose. The nature of the matrix in which the fluorophore is embedded is such that diffusivity is maximised yet oxygen content is minimised (these properties are not natural bedfellows). Consequently we have the world's fasted oxygen sensor, with some embodiments having response times faster than we can easily measure. Sensors which sit in blood are problematic because of clot formation. As a result of our EPSRC development work, our prototype sensor is entirely clot resistent (for at least 24h). Measurement in blood is also problematic because the haemoglobin itself will variably absorb and scatter some of the light, so introducing errors in the registered PO2. We have been working on a system which measures the fluorescence decay lifetime directly, and so we are not reliant on measuring light intensity. As such the system is uninfluenced by the optical properties of the medium. Our aim under this project is to develop this system into a clinician friendly unit. "

Lay abstract: It is well established that in the diseased lung, particularly in sick patients undergoing mechanical ventilation in Intensive Care Units, some of the lung's tiny air sacs may collapse completely in expiration and pop open again in the subsequent inspiration. This process (cyclical atelactasis, (CA)) causes the oxygen concentration in the arterial blood (PaO2) to oscillate breath-by-breath; rising on inspiration as the air sacs pop open and oxygen is transeferred to the blood, and falling in expiration as they collapse again thereby halting the transfer of oxygen to blood. No conventional sensors exist to measure these rapid changes in PaO2. We intend to further develop a brand new sensor, using new technology, to measure these fast blood oxygen oscillations. It is also established that this repetitive 'collapse-re-open' cycle in ventilated patients can cause lung damage, known as Ventilator Induced Lung Injury (VILI). There is an international quest to understand the mechanisms underlying VILI, and to moderate its effects. Key to this will be a means of detecting when it is occuring, yet there is currently no routine way of doing this. Previous work has shown that the presence of PaO2 oscillations in arterial blood is a a biomarker of CA, and can direct the clinician to adjust the ventilator settings and thus minimise the process and mitigate its injurious effects. A clinical need therefore exists for a rapid-response sensor to detect these PaO2 oscillations in real time, however, traditional sensors are far too slow to be used for this purpose. A novel fast response oxygen sensor developed during our previous NIHR grant must now be further developed to the point where it can be evaluated for future development as a medical device, and that is the reason for this NIHR application.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: RESPIRATORY