Papers by Jochen Schubert
The European respiratory journal, Jan 20, 2012
Noninvasive breath analysis may provide valuable information for cancer recognition if disease-sp... more Noninvasive breath analysis may provide valuable information for cancer recognition if disease-specific volatile biomarkers could be identified. In order to compare nondiseased and diseased tissue in vivo, this study took advantage of the special circumstances of one-lung ventilation (OLV) during lung-surgery. 15 cancer patients undergoing lung resection with OLV were enrolled. From each patient, alveolar breath samples were taken separately from healthy and diseased lungs before and after tumour resection. Volatile substances were pre-concentrated by means of solid-phase microextraction, and were separated, identified and quantified by means of gas chromatography-mass spectrometry. Different classes of volatile substances could be identified according to their concentration profiles. Due to prolonged fasting and activation of lipolysis, concentrations of endogenous acetone significantly increased during surgery. Exogenous substances, such as benzene or cyclohexanone, showed typical washout exhalation kinetics. Exhaled concentrations of potentially tumour associated substances, such as butane or pentane, were different for nondiseased and diseased lungs and decreased significantly after surgery. Separate analysis of volatile substances exhaled from healthy and diseased lungs in the same patient, together with thorough consideration of substance origins and exhalation kinetics offers unique opportunities of biomarker recognition and evaluation.
International Journal of Cancer, 2009
There is experimental evidence that volatile substances in human breath can reflect presence of n... more There is experimental evidence that volatile substances in human breath can reflect presence of neoplasma. Volatile aldehydes were determined in exhaled breath of 12 lung cancer patients, 12 smokers and 12 healthy volunteers. Alveolar breath samples were collected under control of expired CO 2. Reactive aldehydes were transformed into stable oximes by means of on-fiber-derivatization (SPME-OFD). Aldehyde concentrations in the ppt and ppb level were determined by means of gas chromatography-mass spectrometry (GC-MS). Exhaled concentrations were corrected for inspired values. Exhaled C 1-C 10 aldehydes could be detected in all healthy volunteers, smokers and lung cancer patients. Concentrations ranged from 7 pmol/ l (161 pptV) for butanal to 71 nmol/l (1,582 ppbV) for formaldehyde. Highest inspired concentrations were found for formaldehyde and acetaldehyde (0-55 nmol/l and 0-13 nmol/l, respectively). Acetaldehyde, propanal, butanal, heptanal and decanal concentrations showed no significant differences for cancer patients, smokers and healthy volunteers. Exhaled pentanal, hexanal, octanal and nonanal concentrations were significantly higher in lung cancer patients than in smokers and healthy controls (p pentanal 5 0.001; p hexanal 5 0.006; p octanal 5 0.014; p nonanal 5 0.025). Sensitivity and specificity of this method were comparable to the diagnostic certitude of conventional serum markers and CT imaging. Lung cancer patients could be identified by means of exhaled pentanal, hexanal, octanal and nonanal concentrations. Exhaled aldehydes reflect aspects of oxidative stress and tumor-specific tissue composition and metabolism. Noninvasive recognition of lung malignancies may be realized if analytical skills, biochemical knowledge and medical expertise are combined into a joint effort. Material and Methods Study design This study represents an observational investigation without any intervention. Ten volatile aliphatic aldehydes were
Volatile Biomarkers for Human Health
20. Workshop des Arbeitskreises ‚Respiratorisches System‘ der Deutschen Veterinärmedizinischen Gesellschaft (DVG) in Kooperation mit der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin (DPG), 2017
Journal of Breath Research, 2018
Proton transfer reaction time-of-flight mass spectrometry (PTR-ToF-MS) represents an attractive t... more Proton transfer reaction time-of-flight mass spectrometry (PTR-ToF-MS) represents an attractive tool for the real-time analysis of VOC profiles in human breath. Quantification of breath VOCs by means of direct MS may be affected by the matrix, as human breath not only contains several hundred VOCs at the ppbV-pptV level, but is water saturated and contains percentage levels of CO2. Investigation of breath biomarkers in clinical studies requires quantitative and comparable results. We therefore systematically assessed the effect of humidity, CO2 and O2 on the results of PTR-MS analysis. We investigated more than 20 VOCs, including aldehydes, ketones, aromatic compounds and hydrocarbons with different sample humidity, CO2 and O2 content. The influence of data processing (e.g. normalization to the H3O+ ion count) was also addressed. An increase of the H3O+ count of about 20% was observed when the humidity in the sample was increased to breath levels. Large differences regarding the measured VOC intensities were found between the dry and humid samples. Data normalization to the H3O+ or water-clusters could not fully compensate for the humidity-dependent effects. However, as the determination of most VOCs linearly depends on the humidity over the whole investigated range, factor-based correction seems possible. The effects of CO2 were more pronounced in the dry samples than in the humid samples but only had a minor influence on the results. The same was true for the influence of O2. For the reliable quantification of VOCs in clinical studies and for the standardization of VOC research, well-adapted calibration standards are required for PTR-MS analysis.
2015 IEEE 15th International Conference on Bioinformatics and Bioengineering (BIBE), 2015
Heart Failure (HF) is a rapidly increasing cardiovascular chronic disease that affects millions o... more Heart Failure (HF) is a rapidly increasing cardiovascular chronic disease that affects millions of people globally. Lack of proper management of HF patients increases the risk of frailty and other undesirable effects and contributes to loss of independence. The engagement of the HF patient and all actors related to his/her disease management is critical for empowering the patients in achieving sustainable behaviour change, regarding their adherence and compliance. To address this, the concept and the architecture of a mobile cooperative platform are described. The design and development is based on a multi-stakeholder patient centered mHealth ecosystem for HF patients that will facilitate the collaboration of multidisciplinary actors. I. INTRODUCTION eart Failure (HF) is a debilitating and long-term condition which affects 26 million people globally, The work of the authors was supported by the HEARTEN project that has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 643694.
Journal of breath research, Jan 9, 2017
Analysis of exhaled VOCs can provide information on physiology, metabolic processes, oxidative st... more Analysis of exhaled VOCs can provide information on physiology, metabolic processes, oxidative stress and lung diseases. In critically ill patients, VOC analysis may be used to gain complimentary information beyond global clinical parameters. This seems especially attractive in mechanically ventilated patients frequently suffering from impairment of gas exchange. This study was intended to assess (a) the effects of recruitment maneuvers onto VOC profiles, (b) the correlations between electrical impedance tomography (EIT) data and VOC profiles and (c) the effects of recruitment onto distribution of ventilation. Eleven mechanically ventilated patients were investigated during lung recruitment after cardiac surgery. Continuous breath gas analysis by means of PTR-ToF-MS, EIT and blood gas analyses were performed simultaneously. More than 300 mass traces could be detected and monitored continuously by means of PTR-ToF-MS in every patient. Exhaled VOC concentrations varied with recruitmen...
Journal of Cardiothoracic Surgery, Sep 18, 2007
Background: Volatile breath biomarkers provide a non-invasive window to observe physiological and... more Background: Volatile breath biomarkers provide a non-invasive window to observe physiological and pathological processes in the body. This study was intended to assess the impact of heart surgery with extracorporeal circulation (ECC) onto breath biomarker profiles. Special attention was attributed to oxidative or metabolic stress during surgery and extracorporeal circulation, which can cause organ damage and poor outcome. Methods: 24 patients undergoing cardiac surgery with extracorporeal circulation were enrolled into this observational study. Alveolar breath samples (10 mL) were taken after induction of anesthesia, after sternotomy, 5 min after end of ECC, and 30, 60, 90, 120 and 150 min after end of surgery. Alveolar gas samples were withdrawn from the circuit under visual control of expired CO 2. Inspiratory samples were taken near the ventilator inlet. Volatile substances in breath were preconcentrated by means of solid phase micro extraction, separated by gas chromatography, detected and identified by mass spectrometry. Results: Mean exhaled concentrations of acetone, pentane and isoprene determined in this study were in accordance with results from the literature. Exhaled substance concentrations showed considerable inter-individual variation, and inspired pentane concentrations sometimes had the same order of magnitude than expired values. This is the reason why, concentrations were normalized by the values measured 120 min after surgery. Exhaled acetone concentrations increased slightly after sternotomy and markedly after end of ECC. Exhaled acetone concentrations exhibited positive correlation to serum Creactive protein concentrations and to serum troponine-T concentrations. Exhaled pentane concentrations increased markedly after sternotomy and dropped below initial values after ECC. Breath pentane concentrations showed correlations with serum creatinine (CK) levels. Patients with an elevated CK-MB (myocardial&brain)/CK ratio had also high concentrations of pentane in exhaled air. Exhaled isoprene concentrations raised significantly after sternotomy and decreased to initial levels at 30 min after end of ECC. Exhaled isoprene concentrations showed a correlation with cardiac output. Conclusion: Oxidative and metabolic stress during cardiac surgery could be assessed continuously and non-invasively by means of breath analysis. Correlations between breath acetone profiles and clinical conditions underline the potential of breath biomarker monitoring for diagnostics and timely initiation of life saving therapy.
Journal of Breath Research, Feb 27, 2013
Patients with end-stage renal disease (ESRD) are at risk for a numerous complications. This study... more Patients with end-stage renal disease (ESRD) are at risk for a numerous complications. This study was intended to evaluate breath analysis for monitoring and therapy initiation under haemodialysis (HD). Exhaled alveolar air from 30 ESRD patients during 4 h thrice-weekly HD was analysed by means of HS-SPME-GC-MS. Venous blood samples were taken for determination of conventional serum parameters. Exhaled concentrations of isoprene (10-589 ppbV) were dropped at initiation of HD and increased at the end of HD. Isoprene concentration changes were similar to changes of serum LDH activities. Variation of exhaled acetone concentrations (59 to 8509 ppbV) was significantly lower in diabetic patients when compared to non-diabetics. Exhaled pentane (0.3 to 12 ppbV) increased at onset of HD and returned to baseline levels afterwards. Benzene concentrations showed typical washout characteristics. Ethanol and DMS concentrations remained constant during HD. Breath analysis can be used to recognize oxidative stress, metabolic conditions and haemolysis during HD. Hence, non-invasive breath testing could be used to monitor ESRD patients under HD and prevent them from being affected by well-known detrimental side effects of renal replacement therapy.
Background: Isoprene (C5H8) is a clinically important breath metabolite. Although, hundreds of st... more Background: Isoprene (C5H8) is a clinically important breath metabolite. Although, hundreds of studies have reported differential expressions in isoprene exhalation as breath biomarker for diverse diseases, the substance couldn’t enter to clinical practice as diagnostic marker. Moreover, many experimental/basic observations upon breath isoprene remained unrelated to the corresponding pathophysiological effects on its putative metabolic origin (i.e. mevalonate pathway). Here, we investigated the fundamental reason that hindered the rational interpretation and translation of this marker from basic to clinical science.Methods: Via high-resolution mass-spectrometry based breathomics in 1026 human subjects, we discovered adults with significant deficiency (order of magnitude lower than the normal) and complete absence of breath isoprene. We prospectively applied real-time breathomics, quantitative gene expression analysis of the mevalonate pathway enzymes, lipid-profiling and hemodynamic...
Journal of Breath Research, 2018
Volatile organic compound (VOC) profiles emitted in trace concentrations from bacteria or cells h... more Volatile organic compound (VOC) profiles emitted in trace concentrations from bacteria or cells has gained increasing importance over the decades. Analysis of VOCs in the headspace does not interfere with in vitro systems and, therefore, offers new options for non-invasive monitoring of cultures. Currently there is not any available standardized in vitro sampling system which considers effects of dilution and contamination onto ppbV to pptV VOC concentrations during. In this study a new in vitro system for online and offline headspace measurement of biological cultures was designed. The system was built from inert materials, equipped with universal sampling ports and easily adjustable volume options. Standard VOC mixtures in the system were analyzed by means of proton-transfer-reaction time-of-flight mass spectrometry and needle-trap-microextraction coupled with gas chromatography/mass spectrometry with a variance of 5%-14% and 10%-15%, respectively. In a proof of concept setup volatile emissions over cell cultures and pure media were assessed. The newly developed system enabled reliable and reproducible headspace analyses of in vitro cultures. As parallel application of different analytical methods is possible and confounding factors could be minimized, this set-up represents an important step towards standardization of headspace analysis over biological cultures.
Scientific Reports, 2018
Influenza is one of the most common causes of virus diseases worldwide. Virus detection requires ... more Influenza is one of the most common causes of virus diseases worldwide. Virus detection requires determination of Influenza RNA in the upper respiratory tract. Efficient screening is not possible in this way. Analysis of volatile organic compounds (VOCs) in breath holds promise for non-invasive and fast monitoring of disease progression. Breath VOC profiles of 14 (3 controls and 11 infected animals) swine were repeatedly analyzed during a complete infection cycle of Influenza A under high safety conditions. Breath VOCs were pre-concentrated by means of needle trap micro-extraction and analysed by gas chromatography mass spectrometry before infection, during virus presence in the nasal cavity, and after recovery. Six VOCs could be related to disease progression: acetaldehyde, propanal, n-propyl acetate, methyl methacrylate, styrene and 1,1-dipropoxypropane. As early as on day four after inoculation, when animals were tested positive for Influenza A, differentiation between control an...
Clinical and Experimental Pharmacology, 2017
The generation of methaemoglobin is a rare but potential life-threatening side effect in the use ... more The generation of methaemoglobin is a rare but potential life-threatening side effect in the use of the local anaesthetic prilocaine. It is currently only possible to ensure the diagnosis by means of blood tests. Rapid noninvasive diagnosis is desirable, especially for risk patients. Using a pig model, we induced methaemoglobinemia via application of dimethyl aminophenol and prilocaine (setup I) or natrium nitrite and prilocaine (setup II). Continuous real time breath gas monitoring was performed by proton transfer reaction-time-of-flight-mass spectrometry (PTR-TOF-MS) for non-invasive determination of volatile organic compounds (VOCs). O-Toluidine, the main metabolite of prilocaine, could be detected in alveolar breath gas by means of PTR-TOF-MS and was confirmed by NTME-GC-MS (needle trap micro-extraction gas chromatography-mass spectrometry). The administration of prilocaine intravenously was clearly reflected with a time lag of a few min by the detection of O-Toluidine in the respiratory gas. If reliable correlations between prilocaine and methaemoglobin concentrations in blood and O-Toluidine levels in breath can be established, detection of prilocaine induced methaemoglobinemia and prevention of prilocaine poisoning with potentially life threatening hypoxia might be possible by means of non-invasive O-Toluidine analysis in breath.
Journal of breath research, 2015
Bulky and hyphenated laboratory-based analytical instrumentation such as gas chromatography/mass ... more Bulky and hyphenated laboratory-based analytical instrumentation such as gas chromatography/mass spectrometry is still required to trace breath biomarkers in the low ppbV level. Innovative sensor-based technologies could provide on-site and point-of-care (POC) detection of volatile biomarkers such as breath aldehydes related to oxidative stress and cancer.An electrochemical sensor system was developed for direct detection of the total abundance of aldehydes in exhaled breath in the ppbV level and for simultaneous determination of the airway inflammation markers carbon monoxide (CO) and nitric oxide (NO). The sensor system was tested in vitro with gaseous standard mixtures and in vivo in spontaneously breathing patients and under mechanical ventilation in an animal model.The sensor system provided in vitro and in vivo detection of trace levels of aldehydes, CO and NO. Inertness of the tubing system was important for reliable results. Sensitivity of the aldehyde sensor increased with ...
Metabolites
Regional anaesthesia is well established as a standard method in clinical practice. Currently, th... more Regional anaesthesia is well established as a standard method in clinical practice. Currently, the local anaesthetics of amino-amide types such as prilocaine are frequently used. Despite routine use, complications due to overdose or accidental intravenous injection can arise. A non-invasive method that can indicate such complications early would be desirable. Breath gas analysis offers great potential for the non-invasive monitoring of drugs and their volatile metabolites. The physicochemical properties of o-toluidine, the main metabolite of prilocaine, allow its detection in breath gas. Within this study, we investigated whether o-toluidine can be monitored in exhaled breath during regional anaesthesia in an animal model, if correlations between o-toluidine and prilocaine blood levels exist and if accidental intravenous injections are detectable by o-toluidine breath monitoring. Continuous o-toluidine monitoring was possible during regional anaesthesia of the cervical plexus and du...
Scientific Reports, 2018
Natural menstrual cycle and/or oral contraception diversely affect women metabolites. Longitudina... more Natural menstrual cycle and/or oral contraception diversely affect women metabolites. Longitudinal metabolic profiling under constant experimental conditions is thereby realistic to understand such effects. Thus, we investigated volatile organic compounds (VOCs) exhalation throughout menstrual cycles in 24 young and healthy women with- and without oral contraception. Exhaled VOCs were identified and quantified in trace concentrations via high-resolution real-time mass-spectrometry, starting from a menstruation and then repeated follow-up with six intervals including the next bleeding. Repeated measurements within biologically comparable groups were employed under optimized measurement setup. We observed pronounced and substance specific changes in exhaled VOC concentrations throughout all cycles with low intra-individual variations. Certain blood-borne volatiles changed significantly during follicular and luteal phases. Most prominent changes in endogenous VOCs were observed at the ...
Journal of Breath Research, 2017
Respiratory parameters such as flow or rate have complex effects onto exhalation of volatile subs... more Respiratory parameters such as flow or rate have complex effects onto exhalation of volatile substances and can hamper clinical interpretation of breath biomarkers. We investigated effects of progressively applied upper-airway resistances onto exhalation of volatile organic compounds (VOCs) in healthy humans. We performed real-time mass-spectrometric determination of breath volatiles in 50 subjects with parallel non-invasive hemodynamic monitoring, breath-resolved spirometry and capnometry during controlled tidal breathing (12 breaths/min). Airway resistance was increased by changing mouthpiece diameters from 2.5cm to 1.0cm and to 0.5cm. At smallest diameter, oxygen uptake increased (35%↑). Cardiac output decreased (6%↓) but end-tidal PCO<sub>2</sub> (8%↑) and exhalation of blood-borne isoprene (19%↑) increased. Carbon dioxide production remained constant. Furan, hydrogen sulphide mirrored isoprene. Despite lowered minute- ventilation (4%↓) acetone concentrations decreased (3%↓). Exogenous acetonitrile, propionic acid, isopropanol, limonene mimicked acetone. VOC concentration changes could be modelled through substance volatility. Airway resistance induced changes in hemodynamics and ventilation can affect VOC exhalation and thereby interfere with breath biomarker interpretation. Effects of collateral ventilation, intra-alveolar pressure gradients and respiratory mechanics had to be considered to explain exhalation kinetics of CO<sub>2</sub> and VOCs. Conventional breath sampling via smaller mouthpiece diameters (≤1.0cm; e.g. via straw in Tedlar bags or canisters etc.) will immediately affect VOC exhalation and thereby mislead analysis of obtained results. Endogenous isoprene may probe respiratory muscle work load under obstructive conditions. Breath-gas analysis might enhance our understanding of diagnosis and management of obstructive lung diseases, in the future.
Scientific Reports, 2016
Breath volatile organic compound (VOC) analysis can open a non-invasive window onto pathological ... more Breath volatile organic compound (VOC) analysis can open a non-invasive window onto pathological and metabolic processes in the body. Decades of clinical breath-gas analysis have revealed that changes in exhaled VOC concentrations are important rather than disease specific biomarkers. As physiological parameters, such as respiratory rate or cardiac output, have profound effects on exhaled VOCs, here we investigated VOC exhalation under respiratory manoeuvres. Breath VOCs were monitored by means of real-time mass-spectrometry during conventional FEV manoeuvres in 50 healthy humans. Simultaneously, we measured respiratory and hemodynamic parameters noninvasively. Tidal volume and minute ventilation increased by 292 and 171% during the manoeuvre. FEV manoeuvre induced substance specific changes in VOC concentrations. pET-CO 2 and alveolar isoprene increased by 6 and 21% during maximum exhalation. Then they decreased by 18 and 37% at forced expiration mirroring cardiac output. Acetone concentrations rose by 4.5% despite increasing minute ventilation. Bloodborne furan and dimethyl-sulphide mimicked isoprene profile. Exogenous acetonitrile, sulphides, and most aliphatic and aromatic VOCs changed minimally. Reliable breath tests must avoid forced breathing. As isoprene exhalations mirrored FEV performances, endogenous VOCs might assure quality of lung function tests. Analysis of exhaled VOC concentrations can provide additional information on physiology of respiration and gas exchange. Breath analysis is an evolving interdisciplinary science that involves physiology and medicine with analytical chemistry and engineering. It holds promise towards noninvasive clinical diagnosis as well as therapeutic and physiological monitoring 1-10. In early years, researchers were mainly focused on the discovery of trace (~ppbV to ~pptV ranges) gases in human breath as unique biomarkers for diseases. Despite the identification of more than 300 volatile organic compounds (VOCs) in exhaled breath during the last decade, not a single substance could be established as disease specific biomarker for clinical use. This was not only a consequence of inadequate fundamental knowledge on the origin, distribution and exhalation kinetics of individual markers but also due to insufficient understanding of complex physiological effects on breath VOC concentrations. Pulmonary ventilation and perfusion are physiological determinants, which influence the alveolar gas exchange and thereby, VOC exhalation. Simple changes in physiology may have sudden and profound effects on breath VOC concentrations, which often override the actual pathophysiological effects. Recent studies have clearly demonstrated that hemodynamic changes induced by different breathing patterns or postures have immediate substance specific effects on VOC exhalation 11,12. In addition, confounders such as environmental, dietary or oral/nasal cavity exposure and clinical contaminations are equally important as pathophysiological conditions or biological pathways 11-13. Recent development and application of advanced real-time mass-spectrometric (MS) techniques such as selected ion flow-tube (SIFT)-MS, proton transfer reaction (PTR)-Quadrupol-MS and PTR-Time of flight (ToF)-MS along with online end-tidal/alveolar sampling have substantially reduced several confounding variables
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Papers by Jochen Schubert