Diagnosis of acute respiratory distress syndrome (DARTS) by bedside exhaled breath octane measurements in invasively ventilated patients: protocol of a multicentre observational cohort study

Abstract

Background: Acute respiratory distress syndrome (ARDS) is currently diagnosed by the Berlin Definition. Diagnosis is subjective and often late. Untargeted metabolomics analysis of exhaled breath with gas chromatography and mass spectrometry (GC-MS) showed that the breath concentration of octane has a high diagnostic accuracy for ARDS. To facilitate rapid bedside measurement of this biomarker, a point-of-care (POC) breath test was developed. A prototype already showed good reproducibility and repeatability for the detection of octane. In this study we aim to measure octane in exhaled breath of invasively ventilated intensive care unit (ICU) patients and validate the diagnostic accuracy of the breath test for the early diagnosis of ARDS.

Methods: This is a multicentre observational cohort study in patients admitted to the ICU receiving invasive ventilation for at least 24 hours. At least 500 patients in two academic hospitals in The Netherlands will be included. ARDS patients will be compared to patients without ARDS. ARDS diagnosis will be based on the Berlin Definition. Two diagnostic assessments will be performed during the first 72 hours of invasive ventilation, including breath sampling, arterial blood gas analysis and lung ultrasound (LUS). In patients fulfilling the criteria for ARDS, three additional breath samples will be taken to assess resolution. The primary endpoint is the diagnostic accuracy for ARDS, defined by the area under the receiver operating characteristics curve (AUROCC) of octane concentration in exhaled breath. Secondary endpoints are the association between exhaled breath octane and ARDS adjusted for confounders, and the added diagnostic accuracy of the breath test on top of the Lung Injury Prediction Score (LIPS).

Discussion: This is the first study that validates a metabolic biomarker of ARDS in an adequate sample size. The major novelty is the use of a POC breath test that has been specifically developed for the purpose of diagnosing ARDS. Strengths are; assessment in the early phase, in patients at risk for ARDS, longitudinal sampling and an expert panel to reliably diagnose ARDS. This study will provide a decisive answer on the question if exhaled breath metabolomics can be used to diagnose ARDS.

Trial registration: The trial is registered at trialregister.nl (ID: NL8226) with the tag "DARTS".

Keywords: Acute respiratory distress syndrome (ARDS); biomarker; diagnosis; exhaled breath; intensive care; metabolomics.

Figure 1

Overview of study procedures. Timeline with assessment 1 and 2 on day 1 and day 2. The researcher assesses if the patient fulfils the ARDS criteria at any time during the first 2 days. If the researcher diagnoses the patient with ARDS, the patient will undergo assessment 3 to 5, as indicated with the arrow “yes”, otherwise the patient will directly proceed to the follow up. In the box below the collected data per assessment is described. ARDS, acute respiratory distress syndrome; ABG, arterial blood gas; CXR, chest radiography; LUS, lung ultrasound.

Figure 2

Classification of ARDS in three different settings; by the clinician, researcher and by an expert panel. The diagnosis of ARDS by the researcher is used to decide if additional measurements as shown in Figure 1 will be performed. The diagnosis of ARDS by the expert panel will be used as the reference value. ARDS, acute respiratory distress syndrome.

Figure 3

Breath sampling with a BGS through a side stream connection, distal from the HME filter. VOCs are collected on the sorbent tube. BGS, breath gas sampler; HME, heat-moisture exchange; VOCs, volatile organic compounds; PTFE, polytetrafluoroethylene.