Title: A unique non-invasive device to measure cardiopulmonary function; - from Invention to Evaluation.
Funder: Department of Health and Social Care

Abstract: Our research has led to the invention of a prototype device to make useful clinical measurements non-invasively in a range of patient groups. The technique is a refinement of many years of development from theoretical modelling through animal studies and ultimately to pilot studies in human volunteers and patients. This work has been funded by the EPSRC to this point. The principle is that by using a rapid electropneumatic feedback system we create an oscillatory signal in the inspired air. This signal is not in the form of pressure or flow, but rather an invisible signal in the form of a sinusoidally varying concentration of a tracer gas in low dose. There are no special manoeuvres required of the patient (or the clinician, in the case of ventilated patients), and breathing is entirely unrestricted. This oscillatory input signal is moderated by the lung and the pulmonary blood flow, such that the output (exhaled) signal is diminished in amplitude and shifted in phase, since the lung and pulmonary blood flow behave like a complex array of first order filters [1]. If the lung were a single homogeneous unit, it would be straightforward to characterise its volume, dead-space and blood flow by measuring the relationship between the inspired and expired sinewaves for any given single frequency [2]. If however, the lung were a complex and unknown array of units with different ventilations and perfusions, it would not be possible to determine any single lumped property such as volume or blood flow using a single interrogating frequency. This is analogous to the electrical concept that whilst it is possible to determine the time-constant of a simple RC or LC circuit by considering its reactance at any single frequency, it would not be possible to do so for a complex circuit containing a distribution of RC units, in which case the apparent time constant would appear to be frequency dependent [2]. Inhomogeneity of ventilatory time constants (tau) and of ventilation/perfusion ratios (V/Q) in the lung are a sensitive marker of pulmonary dysfunction [3,4]. Abnormalities in these properties are evident in disease states before any other routinely used diagnostic test, and certainly in all tests used clinically or at the bedside. With our device, by evaluating how the expired sinusoidal signal responds to a variety of interrogating frequencies, we can characterise the lung in terms of its inhomogeneity, as well as more familiar properties such as lung volumes and pulmonary blood flow. Our EPSRC-funded work has delivered a working prototype. The inspiratory signal is generated by a rapid feedback controller which injects a tracer gas (nitrous oxide in low dose i.e. mean 4%) into the airstream at a rate proportional to the inspiratory flow rate in real time. This clamps the inspired concentration of the tracer at a constant value for that breath. Over subsequent breaths, the inspired concentration is forced to vary sinusoidally at a set frequency (or at a frequency which itself is frequency modulated). Using rapid mainstream gas and flow sensors we monitor the inspired and expired signals. We have developed algorithms which compensate for some inadequacies of the injector system, to enhance the sensor responses and determine mass fluxes. We have developed a number of different analytical techniques to determine the degree of heterogeneity in 'tau' and V/Q distributions, ranging from simple pragmatic techniques, to more complex characterisations using Bayesian inference. We are now in a position to test the device in a larger patient cohort, to refine the hardware and analysis as necessary and to move towards device regulation and commercial development.

Lay abstract: Patients suffering from lung disease require lung function tests to assess the disease severity and to monitor the benefit of therapy. These tests (not yet available at general practices) are commonly performed in specialised laboratories, and require the effort of the child/adult. As well as being cumbersome to perform, these tests are also surprisingly insensitive to underlying disease processes. Patients generally have to have quite established disease before many of these standard tests register an abnormality. Patients in Intensive Care Units (ICUs) cannot be moved to these specialised laboratories. Unfortunately therefore, those patients who would benefit most from heart and lung function tests are the most difficult to be assessed by conventional means. For sick patients undergoing mechanical ventilation in ICUs, there is at present no way to determine how much inflating pressure to apply to the lungs. Too little results in under-aeration, and too much causes lung trauma. A great need therefore exists for a new system to measure lung function parameters, (most notably, lung volume and non-uniformity of the lung) noninvasively. Our technique makes this possible, thanks to recent advancements in optical gas sensors and flow control technologies. By applying small perturbations in nitrous oxide concentration in the inhaled breath, and measuring the responses, we can measure heart/lung function directly and in real time. A computer model of the lung is used to convert sensor data to robust estimations of lung volume, the efficiency (or inefficiency) of ventilation, and lung blood flow. This approach eliminates the need for patients effort, and also does not interfere with his/her breathing pattern. As no similar technology currently exists, our measurement technique and device will have a large impact on UK and global health care, especially in the ICU, the operating theatre, and potentially in outpatient clinics.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: RESPIRATORY