Title: Breath Analysis in Intensive Care: Proof of Concept for Non-Invasive Diagnosis of Ventilator Associated Pneumonia
Funder: Department of Health and Social Care

Abstract: We will develop our method for sample collection, analysis and interpretation of volatile organic compounds (VOCs) in order to deliver proof of concept for a rapid diagnostic for ventilator associated pneumonia (VAP) that is ready for translation into subsequent clinical validity and efficacy technology assessment. The project will run in four phases over 36 months to address the four objectives stated above: 1. Sampler development. We will refine and investigate our breath sampling approach for ventilated patients that was used to determine feasibility. The current sampling method is relatively labour- and skill- intensive, and most importantly is semi-invasive, requiring aspiration of gas samples from a sterile catheter inserted through the lung suction port down the oral tracheal tube into the deep airways inside the chest. Ideally sampling would occur external to the patient. We will develop and test new approaches for sampling at two new sites: (i) adjacent to the external end of the oral tracheal tube and (ii) at the ventilator intake interface with the connector circuit. For this proof of concept, these approaches will be used simultaneously with our original feasibility sampling approach for comparison. It is vital that breath sample VOC quality is maintained, the main concern being that gas mixing will dilute the sample, which may require optimisation of specific components such as tubing, filters and flow rates. In addition, ventilator gases are routinely humidified during patient care and may influence breath sample VOC quality. We will investigate these effects systematically and determine optimal humidification approaches that promote VOC signal quality while maintaining a minimally-invasive sample. We will iterate sample collection ex-vivo using entrained exemplar VOCs within a complete mechanical ventilator, connector circuit and tracheal tubes, humidification and interfaced to a dummy lung, before testing in ventilated patients. Milestone (month 11): produce two revised non-invasive prototypes for sampling ventilated breath gas and determine preferred non-invasive sampling approach compared to our semi-invasive sampling system used for feasibility. 2. Sample analysis platform development. We have demonstrated that our mass spectrometry method detects discriminatory breath volatile patterns. Changes in sampling method may necessitate iterative changes in this system, to maintain sensitivity and selectivity for both volatile patterns and the identification of individual volatiles. Deliverables (month 13): comparative data for the existing and two novel prototypes demonstrating reproducibility and sensitivity for representative volatiles (including both overall patterns of volatiles and individually identified compounds); selection of the optimal prototype for testing in the proof of concept study. 3. Data analysis. We will investigate changes in the volatile signals acquired in the study below (both for overall patterns and for individually identified compounds) between patients with and without VAP, with input both from bioinformatics and medical statistics. Deliverable (month 34): comparative proof of concept VOC breath data from a well characterised cohort of patients with and without VAP. Deliverable (month 35): finalise definitive approach for future clinical trial of technology 4. Proof of concept (POC) study: The non-invasive optimised system (determined in 1 and 2 above) will be tested in an 18-month proof of concept study where the ability of the breath VOC profile, and/or individual volatile compounds, to exclude (rule-out) patients with VAP, will be compared with international clinical standard diagnosis, based on laboratory culture for identification of infecting microorganisms. We will recruit 100 patients with suspected VAP within intensive care units in our NIHR local research network, of which 35% will subsequently be shown to have VAP following microbiological investigation. Milestone (month 31): Complete data collection for 18-month POC study.

Lay abstract: Intensive Care Units (ICUs) treat and monitor critically ill or unstable patients who may be unable to breathe on their own and whose organs may not function adequately. Medical equipment supports organ function until the patient recovers. Mechanical ventilators ( life support machines ) support breathing. While this technology is effective, it can lead to life-threatening lung infection (pneumonia) as a complication. Pneumonia is treated quickly and effectively with antibiotic drugs. However, because patients on ventilators are already ill, it is not possible to diagnose pneumonia quickly and accurately. Therefore many mechanically ventilated patients will also receive antibiotic treatments just in case so that antibiotics will be used unnecessarily. A consequence of antibiotic overuse is that infecting bugs (microorganisms) become resistant so that it will be difficult to treat life-threatening pneumonia in the future. We need to develop new technologies to help decide quickly who has developed pneumonia during mechanical ventilation. Recently, we have discovered that it is feasible to capture and measure breath chemicals of patients who are mechanically ventilated. The chemical profiles appear to distinguish patients acquiring dangerous lung microorganisms. This exciting finding implies that we could use these chemical patterns to determine quickly who is likely to require antibiotics and who does not. To progress this idea, we plan to develop a simple non-invasive breath capture system that will be part of normal connections between a mechanical ventilator and patient. We will refine our design using a ventilator and artificial mechanical lung. We will then adopt the system to capture breath in ICU ventilated patients and, using analysis already developed in our laboratories, we will seek proof that these chemicals can distinguish between the presence and absence of pneumonia. At project completion we will be able to decide whether our innovation is ready for clinical testing across NHS ICUs.

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