Breath Acetone Research Articles

Sensing Technologies for Detection of Acetone in Human Breath for Diabetes Diagnosis and Monitoring.

The review describes the technologies used in the field of breath analysis to diagnose and monitor diabetes mellitus. Currently the diagnosis and monitoring of blood glucose and ketone bodies that are used in clinical studies involve the use of blood tests. This method entails pricking fingers for a drop of blood and placing a drop on a sensitive area of a strip which is pre-inserted into an electronic reading instrument. Furthermore, it is painful, invasive and expensive, and can be unsafe if proper handling is not undertaken. Human breath analysis offers a non-invasive and rapid method for detecting various volatile organic compounds thatare indicators for different diseases. In patients with diabetes mellitus, the body produces excess amounts of ketones such as acetoacetate, beta-hydroxybutyrate and acetone. Acetone is exhaled during respiration. The production of acetone is a result of the body metabolising fats instead of glucose to produce energy. There are various techniques that are used to analyse exhaled breath including Gas Chromatography Mass Spectrometry (GC–MS), Proton Transfer Reaction Mass Spectrometry (PTR–MS), Selected Ion Flow Tube-Mass Spectrometry (SIFT–MS), laser photoacoustic spectrometry and so on. All these techniques are not portable, therefore this review places emphasis on how nanotechnology, through semiconductor sensing nanomaterials, has the potential to help individuals living with diabetes mellitus monitor their disease with cheap and portable devices.

Water-Resistant Polymeric Acid Membrane Catalyst for Acetone Detection in the Exhaled Breath of Diabetics.

Endogenous volatile organic compounds (VOCs) such as acetone in exhaled human breath are associated with metabolic conditions in the bloodstream. Development of compact, rapid detectors of exhaled breath chemical composition in clinical settings is challenging due to the small sample size that can be collected during a single exhalation as well as spectroscopic interference by the abundance of water. In this paper, we show that the activity of a catalytic polymer membrane (Nafion 117) toward the heterogeneous condensation reaction of immobilized resorcinol reagent with gas-phase acetone can be preserved even at 100% ambient relative humidity through the incorporation of organic acids such as vanillic or tiglic. The reaction produces a colored flavan product that permits highly selective and sensitive correlation to acetone concentration in exhaled breath. Such behavior suggests solvent displacement, analogous to homogeneous liquid-phase systems. However, unlike classic acid-base equilibria, the extent of optode water resistance is shown to increase with the pKa of the imbibed organic acid while peak signal intensity of the imbibed acid undergoes a bathochromic shift to longer wavelengths. These observations are consistent with competition between organic acid deprotonation by water in a mixed solvent system on the one hand and immobilization on the other. Finally, we demonstrate how when applied to the direct chemical analysis of acetone in exhaled human breath, the approach yields excellent correlation to blood glucose in diabetics.

Feasibility of skin acetone analysis in patients with cardiovascular diseases.

Breath acetone is reported to be a noninvasive biomarker for heart failure. However, the measurement of this metabolite requires expertize and is not standardized yet. Acetone is also released from the skin; thus, measuring acetone as a skin gas may be easier than breath analysis. We analyzed skin acetone collected from 41 hospitalized patients with cardiovascular diseases. Passive samplers were used to measure skin acetone emission. Passive sampler was softly fixed on the surface of forearm skin for 10 hour at night. Skin acetone emission ranged from 0.00 to 2.70 ng/cm2/h, and was significantly correlated with blood ketone bodies (r = 0.377, p = 0.017). This is the first study to analyze skin gas in patients with cardiovascular diseases. Skin acetone emission was found to reflect blood ketone bodies. It is feasible to measure skin acetone emission for reflecting blood ketone bodies in patients with cardiovascular diseases.

Indoor air quality (IAQ) evaluation of a Novel Tobacco Vapor (NTV) product

The impact of using a Novel Tobacco Vapor (NTV) product on indoor air quality (IAQ) was simulated using an environmentally-controlled chamber. Three environmental simulations were examined; two non-smoking areas (conference room and dining room) and one ventilated smoking area (smoking lounge). IAQ was evaluated by (i) measuring constituents in the mainstream NTV product emissions, (ii) and by determining classical environmental tobacco smoke (ETS) and representative air quality markers. Analysis of the mainstream emissions revealed that vapor from the NTV product is chemically simpler than cigarette smoke. ETS markers (RSP, UVPM, FPM, solanesol, nicotine, 3-ethenylpyridine), volatile organic compound (toluene), carbon monoxide, propylene glycol, glycerol, and triacetin were below the limit of detection or the limit of quantification in both the non-smoking and smoking environments after using the NTV product. The concentrations of ammonia, carbonyls (formaldehyde, acetaldehyde, and acetone), and total volatile organic compounds were the same levels found in the chamber without NTV use. There was no significant increase in the levels of formaldehyde, acetone or ammonia in exhaled breath following NTV use. In summary, under the simulations tested, the NTV product had no measurable effect on the IAQ, in either non-smoking or smoking areas.

Determination of volatile organic compounds in exhaled breath of heart failure patients by needle trap micro-extraction coupled with gas chromatography-tandem mass spectrometry

The analytical performances of needle trap micro-extraction (NTME) coupled with gas chromatography-tandem mass spectrometry were evaluated by analyzing a mixture of twenty-two representative breath volatile organic compounds (VOCs) belonging to different chemical classes (i.e. hydrocarbons, ketones, aldehydes, aromatics and sulfurs). NTME is an emerging technique that guarantees detection limits in the pptv range by pre-concentrating low volumes of sample, and it is particularly suitable for breath analysis. For most VOCs, detection limits between 20 and 500 pptv were obtained by pre-concentrating 25 ml of a humidified standard gas mixture at a flow rate of 15 ml min−1. For all compounds, inter- and intra-day precisions were always below 15%, confirming the reliability of the method. The procedure was successfully applied to the analysis of exhaled breath samples collected from forty heart failure (HF) patients during their stay in the University Hospital of Pisa. The majority of patients (about 80%) showed a significant decrease of breath acetone levels (a factor of 3 or higher) at discharge compared to admission (acute phase) in correspondence to the improved clinical conditions during hospitalization, thus making this compound eligible as a biomarker of HF exacerbation.

Pentane and other volatile organic compounds, including carboxylic acids, in the exhaled breath of patients with Crohn’s disease and ulcerative colitis

A study has been carried out on the volatile organic compounds (VOCs) in the exhaled breath of patients suffering from inflammatory bowel disease (IBD), comprising 136 with Crohn’s disease (CD) and 51 with ulcerative colitis (UC), together with a cohort of 14 healthy persons as controls. Breath samples were collected by requesting the patients to inflate Nalophan bags, which were then quantitatively analysed using selected ion flow tube mass spectrometry (SIFT-MS). Initially, the focus was on n-pentane that had previously been quantified in single exhalations on-line to SIFT-MS for smaller cohorts of IBD patients. It was seen that the median concentration of pentane was elevated in the bag breath samples of the IBD patients compared to those of the healthy controls, in accordance with the previous study. However, the absolute median pentane concentrations in the bag samples were about a factor of two lower than those in the directly analysed single exhalations—a good illustration of the dilution of VOCs in the samples of breath collected into bags. Accounting for this dilution effect, the concentrations of the common breath VOCs, ethanol, propanol, acetone and isoprene, were largely as expected for healthy controls. The concentrations of the much less frequently measured hydrogen sulphide, acetic acid, propanoic acid and butanoic acid were seen to be more widely spread in the exhaled breath of the IBD patients compared to those for the healthy controls. The relative concentrations of pentane and these other VOCs weakly correlate with simple clinical activity indices. It is speculated that, potentially, hydrogen sulphide and these carboxylic acids could be exhaled breath biomarkers of intestinal bacterial overgrowth, which could assist therapeutic intervention and thus alleviate the symptoms of IBD.

Biochemical Gas Sensors (Biosniffers) Using Forward and Reverse Reactions of Secondary Alcohol Dehydrogenase for Breath Isopropanol and Acetone as Potential Volatile Biomarkers of Diabetes Mellitus.

This study describes two biosniffers to determine breath acetone and isopropanol (IPA) levels and applies them for breath measurement in healthy subjects and diabetic patients. Secondary alcohol dehydrogenase (S-ADH) can reduce acetone and oxidize nicotinamide adenine dinucleotide (NADH to NAD+) in a weak acid environment. NADH can be excited by 340 nm excitation lights and subsequently emit 490 nm fluorescence. Therefore, acetone can be measured by the decrease in NADH fluorescence intensity. S-ADH can also oxidize IPA and reduce NAD+ to NADH when it is in an alkaline environment. Thus, IPA can be detected by the increase of fluorescence. The developed biosniffers show rapid response, high sensitivity and high selectivity. The breath acetone and IPA analysis in healthy subjects shows that the mean values were 750.0 ± 434.4 ppb and 15.4 ± 11.3 ppb. Both acetone and IPA did not show a statistical difference among different genders and ages. The breath acetone analysis for diabetic patients shows a mean value of 1207.7 ± 689.5 ppb, which was higher than that of healthy subjects (p < 1 × 10-6). In particularly, type-1 diabetic (T1D) patients exhaled a much higher concentration of acetone than type-2 diabetic (T2D) patients (p < 0.01). The breath IPA also had a higher concentration in diabetic patients (23.1 ± 20.1 ppb, p < 0.01), but only T2D patients presented a statistical difference (23.9 ± 21.3 ppb, p < 0.01). These findings are worthwhile in the study of breath biomarkers for diabetes mellitus diagnosis. Additionally, the developed biosniffers provide a new technique for volatolomics research.

On the Metabolism of Exogenous Ketones in Humans.

Background and aims: Currently there is considerable interest in ketone metabolism owing to recently reported benefits of ketosis for human health. Traditionally, ketosis has been achieved by following a high-fat, low-carbohydrate “ketogenic” diet, but adherence to such diets can be difficult. An alternative way to increase blood D-β-hydroxybutyrate (D-βHB) concentrations is ketone drinks, but the metabolic effects of exogenous ketones are relatively unknown. Here, healthy human volunteers took part in three randomized metabolic studies of drinks containing a ketone ester (KE); (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, or ketone salts (KS); sodium plus potassium βHB.Methods and Results: In the first study, 15 participants consumed KE or KS drinks that delivered ~12 or ~24 g of βHB. Both drinks elevated blood D-βHB concentrations (D-βHB Cmax: KE 2.8 mM, KS 1.0 mM, P < 0.001), which returned to baseline within 3–4 h. KS drinks were found to contain 50% of the L-βHB isoform, which remained elevated in blood for over 8 h, but was not detectable after 24 h. Urinary excretion of both D-βHB and L-βHB was <1.5% of the total βHB ingested and was in proportion to the blood AUC. D-βHB, but not L-βHB, was slowly converted to breath acetone. The KE drink decreased blood pH by 0.10 and the KS drink increased urinary pH from 5.7 to 8.5. In the second study, the effect of a meal before a KE drink on blood D-βHB concentrations was determined in 16 participants. Food lowered blood D-βHB Cmax by 33% (Fed 2.2 mM, Fasted 3.3 mM, P < 0.001), but did not alter acetoacetate or breath acetone concentrations. All ketone drinks lowered blood glucose, free fatty acid and triglyceride concentrations, and had similar effects on blood electrolytes, which remained normal. In the final study, participants were given KE over 9 h as three drinks (n = 12) or a continuous nasogastric infusion (n = 4) to maintain blood D-βHB concentrations greater than 1 mM. Both drinks and infusions gave identical D-βHB AUC of 1.3–1.4 moles.min.Conclusion: We conclude that exogenous ketone drinks are a practical, efficacious way to achieve ketosis.

A Fuel Cell Based Sensing Platform for Selective Detection of Acetone in Hyperglycemic Patients

Elevated level of acetone in breath or sweat is an indication of type-I diabetes, which can turn into ‘ketoacidosis’- a serious hyperglycemic condition. Continuous monitoring is a challenge among the conventional sensing methods. Though real-time detection of acetone from different biofluids is promising, signal interference from other biomarkers remains an issue. A minor fluctuation of the signals in micro-Ampere range causes substantial overlapping in linear/polynomial calibration fittings. To address the above in non-invasive detection, principal component analysis (PCA) was demonstrated which generated specific pattern for the different concentration points of acetone in the subspace. It improves the overlapping of the signals in between of two or different concentration points of the data sets and eliminate dimensionality and redundancy of data variables. An algorithm following PCA was incorporated into the microcontroller (nRF51822) for the functionality of wearable device in a selective manner in the physiological range (0.5ppm to 4ppm) of acetone.

Iron and carbon codoped WO3 with hierarchical walnut-like microstructure for highly sensitive and selective acetone sensor

Current metal-oxide-based sensing materials are confronted with several challenges, especially in sensitivity, selectivity and stability, for their application in the breath acetone analysis. Herein, hierarchical walnut-like Fe-C-codoped WO3 microspheres were synthesized and characterized by X-ray diffraction (XRD), Raman spectra, X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The amount of Fe doping was optimized based on detecting the acetone responses dependent on the operating temperature. The sensor based on the optimal Fe-C-codoped WO3 (FW3) exhibited high response to acetone and very low responses to NH3, CO, toluene, methanol, ethanol and NO. The results indicate that the optimized material possesses high sensitivity and good selectivity toward acetone vapor. Besides, the FW3 sensor presented superior anti-interferential ability to various mixed-gas systems. More importantly, the responses of the sensor exhibited no obvious fluctuation over 12 weeks, implying good long-term stability of the synthesized material. We suggest that the phase, morphology and the increased number of oxygen vacancies induced by Fe doping are the underlying reason for the improved gas sensing performance of the Fe-C-codoped WO3 microspheres.

Breath Level Acetone Discrimination Through Temperature Modulation of a Hierarchical ZnO Gas Sensor

A hierarchical ZnO nanostructure gas sensor was fabricated to evaluate the concentration of acetone in exhaled human breath. Such information can be used for the diagnosis of diabetes since acetone levels in exhaled breath in excess of 1.8ppm are typically associated with diabetes sufferers. When exposed to acetone, the fabricated sensor exhibits a unique U-shaped response curve as a function of temperature. It was discovered that its acetone sensing behavior changes from oxidizing to reducing as the temperature increases. The sensor's characteristic response was shown to be associated to the carbonyl group present in the acetone molecule. The fabricated hierarchical ZnO nanostructure sensor is able to detect acetone concentration levels as low as 1ppm even at room temperature, making it suitable for noninvasive diabetes diagnosis.

Noninvasive Body Fat Burn Monitoring from Exhaled Acetone with Si-doped WO3-sensing Nanoparticles.

Obesity is a global health threat on the rise, and its prevalence continues to grow. Yet suitable biomedical sensors to monitor body fat burn rates in situ, to guide physical activity or dietary interventions toward efficient weight loss, are missing. Here, we introduce a compact and inexpensive breath acetone sensor based on Si-doped WO3 nanoparticles that can accurately follow body fat burn rates in real time. We tested this sensor on 20 volunteers during exercise and rest and measured their individual breath acetone concentrations in good agreement with benchtop proton transfer reaction time-of-flight mass spectrometry (PTR-TOF-MS). During exercise, this sensor reveals clearly the onset and progression of increasing breath acetone levels that indicate intensified body fat metabolism, as validated by parallel venous blood β-hydroxybutyrate (BOHB) measurements. Most importantly, we found that the body fat metabolism was especially pronounced for most volunteers during fasting for 3 h after exercise, with strong variation between subjects, and this was displayed correctly by the sensor in real-time. As a result, this simple breath acetone sensor enables easily applicable and hand-held body fat burn monitoring for personalized and immediate feedback on workout effectiveness that can guide dieting as well.

A Fuel Cell Sensing Platform for Selective Detection of Acetone in Hyperglycemic Patients

In this work, a three-electrode fuel cell sensor is integrated with a miniaturized potentiostat (LMP91000) and a microcontroller (nRF51822) for selective detection of acetone. Elevated level of acetone in breath or sweat is an indication of systemic ketosis, hyperglycemia or type-I diabetes [1]. Rise of ketone concentrations leads to an increase in acid levels in the blood, called ‘Ketoacidosis’. Ketoacidosis is a serious hyperglycemic condition in patients with type-I diabetes. Among the conventional sensing methods (e.g. breathalyzer for lung ketone analysis, chemical strips, laboratory blood test and urine test), continuous monitoring is a challenge [2]. Also, though real time detection of acetone from different biofluids is promising, interference from other biomarkers remains an issue [3]. To address the above in non-invasive detection, we have developed a statistical model and algorithm which enable separation of signals and eliminate interference from other associated biomarkers. In the developed sensing platform, our fabricated sensor comprises an electrolyte membrane, nafion and monel mesh, as electrodes. Catalytic oxidation of acetone occurs on the working electrode in presence of moisture while oxygen is reduced on the counter electrode. Applying a constant potential across the working and reference electrodes, current is measured between the working and counter electrodes. With the change of concentrations of acetone, the current varies linearly. From this study, it is observed that the sensor is capable to detect as low as 1 ppm of acetone with the sensitivity of 60 nA ppm-1 cm-2. The developed platform has been based on the pre-calibrated data to interpret precise measurement of acetone. Reference: Matzeu, G.; Florea, L.; Diamond, D. 2015. Advances in wearable chemical sensor design for monitoring biological fluids, Sensors and Actuators B, 211:403–418.Tricoli, A.; Nasiri, N.; De, S. 2017. Wearable and Miniaturized Sensor Technologies for Personalized and Preventive Medicine, Advanced Functional Materials, 27(15): 1-19.Jalal, A. H.; Umasankar, Y.; Gonzalez, P. J.; Alfonso, A.; Bhansali, S. 2017. Multimodal technique to eliminate humidity interference for specific detection of ethanol, Biosensors and Bioelectronics, 87(15): 522–530.

Highly Selective Volatile Organic Compounds Breath Analysis Using a Broadly-Tunable Vertical-External-Cavity Surface-Emitting Laser.

A broadly tunable mid-infrared vertical-external-cavity surface-emitting laser (VECSEL) is employed in a direct absorption laser spectroscopic setup to measure breath acetone. The large wavelength coverage of more than 30 cm-1 at 3.38 μm allows, in addition to acetone, the simultaneous measurement of isoprene, ethanol, methanol, methane, and water. Despite the severe spectral interferences from water and alcohols, an unambiguous determination of acetone is demonstrated with a precision of 13 ppbv that is achieved after 5 min averaging at typical breath mean acetone levels in synthetic gas samples mimicking human breath.

Amplifying the Signal of Metal Oxide Gas Sensors for Low Concentration Gas Detection

Nowadays, detection of trace concentration gases is still challenging for portable sensors, especially for the low-cost and easily operated metal-oxide-semiconductor (MOX) gas sensors. In this paper, a widely applicable amplification circuit is designed and fabricated to evidently enhance the signal of the MOX sensors by adding a field effect transistor (FET) into the conventional circuits. By optimizing the FET parameters and the loading resistance, this amplification circuit enables the commercial Figaro TGS2602 toluene sensors response effectively to the highest permissive limit (0.26 ppm) of toluene in indoor air of cars, with the detection limit of ~0.1 ppm. Furthermore, this circuit can also make the commercial Hanwei MP502 acetone sensors and MQ3 ethanol sensors response to the 1-2-ppm acetone in breath of diabetes and 2-ppm ethanol for fast and effectively drinker driver screening. The mechanism is investigated to be the gate voltage induced resistance change of the FET, with the highest theoretically estimated and experimentally measured magnification factor of 5-6. This FET amplifier can effectively enable the ppm level commercial MOX sensors response to sub-ppm level gases, promising for MOX gas sensor integration and also for other kind of resistive sensors.

1-Butyl-3-Methylimidazolium Tetrafluoroborate Film as a Highly Selective Sensing Material for Non-Invasive Detection of Acetone Using a Quartz Crystal Microbalance.

Breath acetone serves as a biomarker for diabetes. This article reports 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim][BF4]), a type of room temperature ionic liquid (RTIL), as a selective sensing material for acetone. The RTIL sensing layer was coated on a quartz crystal microbalance (QCM) for detection. The sensing mechanism is based on a decrease in viscosity and density of the [bmim][BF4] film due to the solubilization of acetone leading to a positive frequency shift in the QCM. Acetone was detected with a linear range from 7.05 to 750 ppmv. Sensitivity and limit of detection were found to be 3.49 Hz/ppmv and 5.0 ppmv, respectively. The [bmim][BF4]-modified QCM sensor demonstrated anti-interference ability to commonly found volatile organic compounds in breath, e.g., isoprene, 1,2-pentadiene, d-limonene, and dl-limonene. This technology is useful for applications in non-invasive early diabetic diagnosis.

Study of Breath Acetone in a Rat Mode of 126 Rats with Type 1 Diabetes

We investigate correlations of breath acetone with blood glucose (BG) and blood beta-hydroxybutyrate (BHB) in a rat model of 126 streptozotocin-induced Type 1 diabetic (T1D) and 32 healthy rats, and evaluate the role of breath acetone analysis as a non-invasive alternative in diabetes screening and management. We conducted breath acetone analysis using a T1D rat model under various conditions, including fasting and insulin-treated. Breath acetone concentrations were measured using a cavity ringdown breath acetone analyzer, LaserBreath-001. The results showed that the breath acetone, BG, and BHB in the T1D rat group were significantly different from those in the healthy group (P<0.05). Significant positive relationships between breath acetone and blood BHB existed in both T1D and healthy groups, as well as in a group of T1D rats under fasting condition and insulin treatment. When the BG concentrations were grouped as follows: 16.5-24.4, 24.5-27.7, and 27.8-41.7 mmol/L, a moderate negative correlation between breath acetone and BG was observed in the T1D group. Furthermore, the accuracy of diabetes screening using breath acetone was analyzed using the receiver operating characteristic (ROC) analysis method and results showed that the accuracy is low when the area under ROC curve (AUC) is <0.6425.

Continuous Monitoring of Breath Acetone, Blood Glucose and Blood Ketone in 20 Type 1 Diabetic Outpatients Over 30 Days

Although breath acetone (BA) has been identified as a breath biomarker for some abnormal metabolic status, such as diabetic ketoacidosis, diabetes under insulin treatments, on a ketogenic diet, heart congestion failure, and post intense exercises, many intra-individual biological parameters also influence the breath acetone concentration. Therefore, it would be insightful to study longitudinal variations of breath acetone concentration in given individuals that have no baseline effect resulting from individual physiological heterogeneity. We carried out a daily-based continuous monitoring of BA, blood glucose (BG), and blood ketone (BK) in 20 type 1 diabetic (T1D) outpatients and 5 healthy volunteers over a period of 30 days. 600 breath samples from the T1D outpatients and the healthy subjects were collected and tested. BA was measured using a cavity ringdown BA analyzer. Simultaneous BG and BK levels were also measured using a standard BG/ketone meter. Our findings include: (1) The T1D subjects have elevated mean BA concentrations as compared to the controls. (2) There exists a positive correlation (R=0.57, P<0.05) between the individual mean BA concentration and the individual mean BK in the 20 T1D outpatients. (3) Some adverse or abnormal physiological conditions such as diabetic ketoacidosis, low body mass index or a special daily activity (e.g., exercises) can be identified via an abnormal BA concentration. This study suggests that continuous monitoring BA is useful in monitoring some abnormal physiological status such as T1D outpatients with very high BG or ketone bodies.

Non-invasive prediction of diabetes through breath analysis: a literature review

Diabetes is a chronic disorder that can only be managed, not cured. Successful management of this disease requires monitoring blood glucose levels at regular intervals. Hence the need for a non-invasive technique is of utmost importance in today's world. Recent studies show that acetone gas in exhaled breath has a high correlation with the glucose levels in breath. Therefore, by analysing the breath samples and calculating the levels of acetone present in them it is possible to monitor diabetes. This paper reviews various approaches used to detect the presence of acetone in breath samples. Also the different sensors technologies used in calculating the acetone in breath are also reviewed in this paper.

Non-invasive prediction of diabetes through breath analysis: a literature review

Diabetes is a chronic disorder that can only be managed, not cured. Successful management of this disease requires monitoring blood glucose levels at regular intervals. Hence the need for a non-invasive technique is of utmost importance in today's world. Recent studies show that acetone gas in exhaled breath has a high correlation with the glucose levels in breath. Therefore, by analysing the breath samples and calculating the levels of acetone present in them it is possible to monitor diabetes. This paper reviews various approaches used to detect the presence of acetone in breath samples. Also the different sensors technologies used in calculating the acetone in breath are also reviewed in this paper.