Early detection of critical illnesses using exhaled aldehydes: a non-invasive breath analysis approach

Abstract

Early recognition of critical illness is crucial for timely intervention and improved prognosis. However, conventional diagnostic methods are often invasive and time-consuming, limiting their utility for rapid screening in critical care. Breath analysis has recently emerged as a promising approach in metabolomics due to its non-invasive, repeatable, and rapid-response characteristics. Volatile organic compounds (VOCs), as byproducts of cellular metabolism, dynamically reflect metabolic status, oxidative stress, and pathophysiological changes, offering broad potential for disease monitoring. Prior studies have linked VOC profiles to conditions such as ventilator-associated pneumonia and cognitive impairment [1, 2], but their application in critical illness remains exploratory. Chen et al. demonstrated that aldehyde metabolism is dysregulated in early and progressive stages of critical illness, resulting in toxic aldehyde accumulation, cellular injury, and organ dysfunction, and suggested that monitoring aldehyde fluctuations could guide treatment decisions [3]. Lipid peroxidation products are established markers of oxidative stress and potential non-invasive biomarkers across diseases. Based on the theory of aldehyde dysregulation, we hypothesize that exhaled aldehyde detection may facilitate early identification of critically ill patients.

From January 2024 to January 2025, we conducted a prospective observational study at Qilu Hospital of Shandong University, enrolling 787 adults (230 ICU patients and 557 healthy controls) and collecting exhaled breath samples. The study was approved by the Ethics Committee of Qilu Hospital of Shandong University (approval number KYLL-202401-047) and adhered to the Declaration of Helsinki. Baseline characteristics are summarized in Table 1. We used photoelectron-induced chemical ionization time-of-flight mass spectrometry (CITOF-MS) to analyze VOCs in exhaled breath; this method requires no preprocessing or enrichment, offers high sensitivity and precision, and acquires each spectrum within one second [4]. Ten aldehyde VOCs were preselected for quantitative analysis and group comparison.

Table 1 Demographic characteristics of participants

Full size table

Critically ill patients exhibited significantly elevated exhaled aldehyde levels compared to healthy controls (Fig. 1). The heatmap (Fig. 1A) shows uniformly low, tightly clustered aldehyde expression in controls versus marked heterogeneity in patients, indicating metabolic dysregulation. Analysis of ten aldehydes confirmed this pattern (Fig. 1B). Multivariate analyses (PCA, PLS-DA; Fig. 1C–D) demonstrated clear group separation, highlighting the discriminatory capacity of aldehyde profiles. LASSO regression with stability testing identified four key biomarkers—propionaldehyde, acrolein, pentanal, and benzaldehyde—significantly upregulated in critical illness. An XGBoost model based on these markers achieved excellent performance, with an AUC of 0.968 and PR-AUC of 0.963 in nested cross-validation (Fig. 2), suggesting reliable classification of critical illness using breath metabolite profiles.

Fig. 1

Heatmap and Distribution Differences of Aldehyde Expression Profiles. (A) The heatmap shows the expression differences of aldehyde molecules between the case and control groups; (B) Comparison of the expression of 10 representative aldehyde molecules: the case group (red) shows high and dispersed expression, while the control group (green) clusters in the low expression region; (C) PCA results illustrate the spatial distribution of metabolites between the critically ill group and the control group; (D) PLS-DA discriminant analysis shows clear separation between the two groups

Full size image

Fig. 2

Diagnostic Model Performance Evaluation. (A) Receiver operating characteristic (ROC) curve; (B) Precision-recall area under the curve (PR-AUC)

Full size image

Our findings suggest that exhaled aldehydes may serve as real-time biomarkers for critical illness. We reason that, in critical illness, disruptions in homeostasis, oxidative stress, and metabolic dysfunction promote lipid peroxidation and increase aldehyde generation. As markers of oxidative stress and cellular injury, these aldehydes can be detected in exhaled breath, offering insights for early diagnosis [5]. The non-invasive nature of breath testing enables safe repeat assessments, making it suitable for screening, early triage, and dynamic monitoring in emergency and intensive care settings.

We acknowledge limitations in our study. Demographic differences between control and patient groups (e.g., age, sex, comorbidity profiles) may confound metabolite levels. Moreover, because we sampled breath after onset of critical illness, our findings reflect diagnostic rather than predictive utility. We plan to validate breath aldehyde testing in the emergency department at initial presentation to predict ICU admission, organ dysfunction, or mortality risk, which would enhance clinical relevance. We will address methodological refinements in future studies.

In conclusion, our study provides preliminary evidence that exhaled aldehydes may serve as screening biomarkers for critical illness, underscoring their potential clinical utility as a non-invasive, rapid diagnostic modality. We recommend that future studies validate these biomarkers in larger, multicenter cohorts, evaluating predictive performance and dynamic monitoring in early disease stages. Integration with portable breath-analysis devices for real-time bedside assessment could establish breath aldehyde profiling as a convenient, scalable early warning tool in emergency and critical care.

The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request.

VOCs:

Volatile Organic Compounds

CITOF-MS:

Chemical Ionization Time-of-Flight Mass Spectrometry

ICU:

Intensive Care Unit

LASSO:

Least Absolute Shrinkage and Selection Operator

PCA:

Principal Component Analysis

PLS-DA:

Partial Least Squares Discriminant Analysis

1. Filipiak W, Włodarski R, Żuchowska K, Tracewska A, Winiarek M, Daszkiewicz D, et al. Analysis of bacterial metabolites in breath gas of critically ill patients for diagnosis of Ventilator-Associated Pneumonia-A proof of concept study. Biomolecules. 2024;14(12):1480. https://doi.org/10.3390/biom14121480.

   Article CAS PubMed PubMed Central Google Scholar

2. Jiao B, Zhang S, Bei Y, Bu G, Yuan L, Zhu Y, et al. A detection model for cognitive dysfunction based on volatile organic compounds from a large Chinese community cohort. Alzheimer’s Dement. 2023;19(11):4852–62. https://doi.org/10.1002/alz.13053.

   Article Google Scholar

3. Chinese Society Of Emergency Medicine. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2023;36(1):6–15. https://doi.org/10.3760/cma.j.cn121430-20231201-01026. 2024. Chest Pain Branch Of China International Exchange And Promotive Association For Medical And Health Care, Multidisciplinary Joint Committee On Cardiopulmonary Resuscitation And Extracorporeal Life Support Of Shandong Medical Association, & Workgroup Of The Chinese Experts Consensus On Aldehyde Metabolism Disorder Guided The Early Management Of Emergency And Critical Care Medicine

4. Liu R, Guo Y, Li M, Li J, Yang D, Hou K. Development and application of a chemical ionization focusing integrated ionization source TOFMS for online detection of OVOCs in the atmosphere. Molecules. 2023;28(18):6600. https://doi.org/10.3390/molecules28186600.

   Article CAS PubMed PubMed Central Google Scholar

5. Floss MA, Fink T, Maurer F, Volk T, Kreuer S, Müller-Wirtz LM. Exhaled aldehydes as biomarkers for lung diseases: A narrative review. Molecules. 2022;27(16):5258. https://doi.org/10.3390/molecules27165258.

   Article CAS PubMed PubMed Central Google Scholar

Download references

All the authors of this manuscript would like to express their gratitude to the emergency department and emergency intensive care unit.

This work was supported by the Key R&D Program of Shandong Province (2024CXPT089).

Author notes

1. Shuangying Tian, Longxin Li and Yingzhe Guo contributed equally to this work.

Authors and Affiliations

1. Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China

   Shuangying Tian, Xiuting Yang, Jianhua Gu, Hui Lin, Yanzhen Wang, Yuan Bian, Feng Xu & Yuguo Chen

2. Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Chest Pain Center, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China

   Shuangying Tian, Xiuting Yang, Jianhua Gu, Hui Lin, Yanzhen Wang, Yuan Bian, Feng Xu & Yuguo Chen

3. Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital of Shandong University, Jinan, China

   Shuangying Tian, Xiuting Yang, Jianhua Gu, Hui Lin, Yanzhen Wang, Yuan Bian, Feng Xu & Yuguo Chen

4. The Key Laboratory of Cardiovascular Remodeling and Function Research, The State andShandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan, China

   Shuangying Tian, Xiuting Yang, Jianhua Gu, Hui Lin, Yanzhen Wang, Yuan Bian, Feng Xu & Yuguo Chen

5. School of Nursing and Rehabilitation, Shandong University, Jinan, China

   Longxin Li

6. Environment Research Institute, Shandong University, Qingdao, 266237, China

   Yingzhe Guo & Keyong Hou

Authors

1. Shuangying TianView author publications

   Search author on:PubMed Google Scholar

2. Longxin LiView author publications

   Search author on:PubMed Google Scholar

3. Yingzhe GuoView author publications

   Search author on:PubMed Google Scholar

4. Xiuting YangView author publications

   Search author on:PubMed Google Scholar

5. Jianhua GuView author publications

   Search author on:PubMed Google Scholar

6. Hui LinView author publications

   Search author on:PubMed Google Scholar

7. Yanzhen WangView author publications

   Search author on:PubMed Google Scholar

8. Yuan BianView author publications

   Search author on:PubMed Google Scholar

9. Keyong HouView author publications

   Search author on:PubMed Google Scholar

10. Feng XuView author publications

    Search author on:PubMed Google Scholar

11. Yuguo ChenView author publications

    Search author on:PubMed Google Scholar

Contributions

Shuangying Tian, Longxin Li and Yingzhe Guo contributed equally to this work, collected the data and interpreted the results. Yingzhe Guo, chemical analyze of the exhaled breath. Jianhua Gu analyzed the data. Hui Lin and Yanzhen Wang collected the samples. Yuanbian, Keyong Hou, Feng Xu and Yuguo Chen are the researcher, interpreted the results, and revised the final version of the paper and development of the study concept. All authors have read and agreed to the published version of the manuscript.

Corresponding authors

Correspondence to Yuan Bian, Keyong Hou, Feng Xu or Yuguo Chen.

Competing interests

The authors declare no competing interests.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Reprints and permissions

Cite this article

Tian, S., Li, L., Guo, Y. et al. Early detection of critical illnesses using exhaled aldehydes: a non-invasive breath analysis approach. Crit Care 29, 416 (2025). https://doi.org/10.1186/s13054-025-05529-x

Download citation

• Received: 08 June 2025

• Accepted: 24 June 2025

• Published: 01 October 2025

• DOI: https://doi.org/10.1186/s13054-025-05529-x

Share this article

Anyone you share the following link with will be able to read this content:

Get shareable link

Sorry, a shareable link is not currently available for this article.

Copy shareable link to clipboard

Provided by the Springer Nature SharedIt content-sharing initiative