CO2 Breath Test Research Articles

The [13 C]octanoic acid breath test for gastric emptying quantification: A focus on nutrition and modeling.

Gastric emptying (GE) is the process of food being processed by the stomach and delivered to the small intestine where nutrients such as lipids are absorbed into the blood circulation. The combination of an easy and inexpensive method to measure GE such as the CO2 breath test using the stable isotope [13C]octanoic acid with semi‐mechanistic modeling could foster a wider application in nutritional studies to further understand the metabolic response to food. Here, we discuss the use of the [13C]octanoic acid breath test to label the solid phase of a meal, and the factors that influence GE to support mechanistic studies. Furthermore, we give an overview of existing mathematical models for the interpretation of the breath test data and how much nutritional studies could benefit from a physiological based pharmacokinetic model approach.

Development of Analytical Methods and Nutritional Studies Using Synthetic Fatty Acids and Triacylglycerols.

The metabolism of fatty acids or triacylglycerol (TAG) is affected by their molecular structures. Several methods to separate and quantify TAG isomers in natural fats and oils were developed. For instance, an analytical method of TAG molecular species using a gas chromatograph-flame ionization detector and the analytical method to separate and quantify TAG positional isomers and enantiomers using a high performance liquid chromatograph-mass spectrometer were established. Furthermore, using these analytical methods, the relationship between molecular structure and metabolism of fatty acid and TAG were investigated. Using the CO2 breath test in ddY mice revealed that saturated fatty acids such as palmitic acid bound to the sn-2 (β) position of TAG were highly catabolized in the presence of calcium, whereas saturated fatty acids bound to the sn-1, 3 (α) position of TAG were not well catabolized. Recently, the distribution of dietary fatty acids in the body were visualized by combining a stable isotope labeling technique with imaging mass spectrometry, which revealed that the administered arachidonic and docosahexaenoic acid accumulated as phospholipid in the mouse brain. The methods developed can assess food quality and create new functional foods.

13CO2 breath tests, a tool to assess intestinal and liver function in the ICU?

CO2 breath tests, based on nondispersive infrared (NDIR) measurement technology, offer the chance for a noninvasive online quantitation of physiological processes. With recent extensions of the NDIR measurement technology breath tests could be used in an ICU setting without any restriction. Since online tools to assess feed intolerance with gastric emptying and to quantify gradual changes in liver function are still missing, this review explores the potential of breath tests to fill this gap. Gastric emptying may be correctly quantified; however, the corresponding tests fail to capture aberrations in nutrient absorption, which appear to be linked to hyperglycemia and insulin resistance and may contribute to feed intolerance. The progression or ameloriation of liver injury could be assessed with breath tests, which cannot, however, distinguish between functional and macrocirculatory or microcirculatory disorders. Breath tests for liver function and gastric emptying taken alone may fail in their ability to specifically quantify the clinical disorders. However, invasive test extensions could help to characterize their validity and thus to identify additional, noninvasive measurements to assure and expand this domain.

Effects of inspiratory pause on CO2 elimination and arterial Pco2 in acute lung injury

A high respiratory rate associated with the use of small tidal volumes, recommended for acute lung injury (ALI), shortens time for gas diffusion in the alveoli. This may decrease CO(2) elimination. We hypothesized that a postinspiratory pause could enhance CO(2) elimination and reduce Pa(CO(2)) by reducing dead space in ALI. In 15 mechanically ventilated patients with ALI and hypercapnia, a 20% postinspiratory pause (Tp20) was applied during a period of 30 min between two ventilation periods without postinspiratory pause (Tp0). Other parameters were kept unchanged. The single breath test for CO(2) was recorded every 5 min to measure tidal CO(2) elimination (VtCO(2)), airway dead space (V(Daw)), and slope of the alveolar plateau. Pa(O(2)), Pa(CO(2)), and physiological and alveolar dead space (V(Dphys), V(Dalv)) were determined at the end of each 30-min period. The postinspiratory pause, 0.7 +/- 0.2 s, induced on average <0.5 cmH(2)O of intrinsic positive end-expiratory pressure (PEEP). During Tp20, VtCO(2) increased immediately by 28 +/- 10% (14 +/- 5 ml per breath compared with 11 +/- 4 for Tp0) and then decreased without reaching the initial value within 30 min. The addition of a postinspiratory pause significantly decreased V(Daw) by 14% and V(Dphys) by 11% with no change in V(Dalv). During Tp20, the slope of the alveolar plateau initially fell to 65 +/- 10% of baseline value and continued to decrease. Tp20 induced a 10 +/- 3% decrease in Pa(CO(2)) at 30 min (from 55 +/- 10 to 49 +/- 9 mmHg, P < 0.001) with no significant variation in Pa(O(2)). Postinspiratory pause has a significant influence on CO(2) elimination when small tidal volumes are used during mechanical ventilation for ALI.

Diagnostics of pulmonary embolism with emphasis on ventilation/perfusion scintigraphy and dead-space analysis

Ventilation/perfusion scintigraphy, a first hand method for diagnosis of pulmonary embolism, PE, is challenged by tomography of the pulmonary arteries, CT. An additional method is based upon dead space analysis. Tomographic ventilation/perfusion scintigraphy, V/PSPECT is superior to planar technique. Important is interpretation criteria based upon pattern recognition and clinical information. With optimal strategy, the rate of non-diagnostic findings is only about 1%. The sensitivity of CT is too low to exclude subsegmental PE,. The radiation dose is for CT is several times higher than for V/PSPECT. Quantification of PE, only offered by V/PSPECT has impact on therapy and is vital for follow up. Limited availability of V/PSPECT makes CT an essential element in a strategy for diagnosis of PE. The single breath test for CO2 offers an alternative when imaging techniques are not available or when radiation is a particular problem in early pregnancy.

Pigs are not a reliable experimental model in the study of the haemodynamic and respiratory effects of CO2 pneumoperitoneum.

Haemodynamic and respiratory effects of a CO2 pneumoperitoneum (intra-abdominal pressure = 12 mmHg) associated to a head-up position(15 degrees ) were studied in 20 pigs using a Swan-Ganz catheter and the Single Breath Test for CO2. The pneumoperitoneum induced a moderate rise in mean arterial pressure (+17%) (P<0.001) without any variation in heart rate, cardiac output and systemic vascular resistances. The following respiratory effects were observed: an increase in PaCO2 (+20%) (P<0.001), PE'CO2 (+31%) (P<0.001), expired volume of CO2 (+28%) (P<0.001), arterial to end-tidal CO2 gradient (+80%) (P<0.001) and alveolar dead space (+40%) (P<0.001) occured. Alveolar ventilation remained stable. Finally and contrary to healthy human patient, intraperitoneal CO2 insufflation in pig induced slight haemodynamic changes and major respiratory modifications. Thus, our data do not support the conclusion that the pig is a reliable experimental model for studying the pathophysiology of CO2 pneumoperitoneum-induced changes in haemodynamic and respiratory parameters, in human patients.

Simple Sampling Method and Routine Gas Chromatography-Mass Spectrometry Analysis in 13C Breath Tests

The 13C-labeled CO2 breath tests are convenient methods for various uses. They can be used to measure gastric emptying rate of solids (1), detect fat malabsorption (2), and evaluate pancreatic lipase activity (3), exocrine pancreatic insufficiency (4), glucose adsorption and utilization (5), liver function control (6), and lactase deficiency (7) with appropriate 13C isotope-labeled compounds. In recent years, the 13C-urea breath test has been used to detect Helicobacter pylori (8). With an appropriate analytical background and the facilities required for the detection or quantification of labeled CO2, the 13CO2 breath test could be widely applied for diagnostic purposes in the medical practice. Although several infrared or mass spectrometric methods (9) are available, the transport of large volumes of gaseous samples to analytical centers as well as storage before measurement involves great problems. Therefore, we have developed a simple method that allows storage of these samples in minimal liquid volume. By this technique, the liberation of isotope-labeled CO2-containing gas occurs immediately before measurements. Because most medical centers are not equipped with expensive and complex isotope-ratio mass spectrometers but generally have a routine low-mass-resolution gas chromatography-mass spectrometry (GC-MS) apparatus, we have also used a simple detection method for 13CO2 by standard GC-MS techniques. Analysis requires only a few minutes, and the method is suitable for selection of 13CO2-containing samples. In our test experiments, we used an air …

Changes in airway dead space in response to methacholine provocation in normal subjects.

Measurements of bronchial hyper-responsiveness rely on sensitive techniques for measurement of bronchoconstriction, ideally based on tidal breathing. A potentially useful technique is measurement of airway dead space (VDaw), which reflects the volume of the conducting airways. The aim of this study was to evaluate measurements of VDaw with the single breath test for CO2 (SBT-CO2), compared to spirometric measurements, as a method of measuring bronchial response to methacholine challenge. Nineteen healthy adults were studied. Dosimetric methacholine challenge tests were performed on two study days. Forced expirations or the SBT-CO2 were used to assess the response. There were dose-dependent reductions in the spirometric measurements, with a 10 +/- 10% reduction from the baseline value of forced expiratory volume at the highest dose of methacholine. There was a dose-dependent reduction from the baseline value of VDaw by 19 +/- 9% at the highest dose. There was also a dose-dependent increase in the slope of the alveolar plateau of the SBT-CO2. This study provides support for measurement of VDaw as a means of evaluating bronchial responsiveness after methacholine challenge. In a group of healthy adults, this method shows a greater response but with similar dispersion as measurement of forced expiratory volume after methacholine challenge.

Stable Isotopes Labeling of Drugs in Pediatric Clinical Pharmacology

Stable isotope labeling (SIL) still has not been used very much in pediatric and perinatal clinical pharmacology. However, this method has numerous advantages. It allows one to determine the concentration of drugs with great sensitivity, thereby allowing quantification in small amounts of biologic samples. It also allows quantification with great specificity, eliminating interference by drug metabolites found in some radioactive tracer methods. SIL is safe because stable isotopes are not radioactive. The only possible toxicity that may be related to an isotope effect is a slowing of biochemical reactions because of the greater mass of the stable isotope. Because of the great difference between deuterium and hydrogen, a significant isotope effect occurs only with deuterium. However, toxicity related to the isotope effect of deuterium can only be produced by very high levels of deuteration (>15% of body water), far higher than the amount of deuterium in a typical tracer dose of drug.1 SIL also allows noninvasive in vivo studies such as the co2 breath test (CBT). All of these advantages explain the great potential interest in SIL in pediatric pharmacology. The costs of stable isotopes and limited facilities available for sample analysis are undoubtedly the greatest limitations to their increased use. SIL is useful in different types of studies,2 such as studies on the fate of drugs (drug metabolic pathways and pharmacokinetics), determination of compliance, and assessment of therapeutic and unwanted effects of drugs. The use of SIL of drugs in positron emission tomography investigations is not addressed in this article. ### Definition In the periodic table, the elements are ranked according to their atomic number, ie, the number of protons contained in the nucleus. All elements located at the same place in the table are isotopes of the same family, for example, the family of carbon. All members …

Diagnosis of pulmonary embolism by measurement of alveolar dead space.

Pulmonary embolism (PE) gives rise to alveolar dead space, which can be measured with a single breath test for CO2 (SBT-CO2). The characteristics of the SBT-CO2 are different in PE and other common conditions giving rise to alveolar dead space, notably airways disease. An analysis of alveolar dead space focusing on the late part of the breath (fDlate) has been suggested as a method for diagnosis of PE. Our aim was to evaluate this technique by comparison with lung scintigraphy. We randomly selected patients with clinical suspicion of PE. SBT-CO2 and lung scintigraphy were performed on the same day. The scintigraphies were reviewed and classified as high, intermediate and low probability of PE. Out of 223 patients able to be evaluated, there were 20 of the high, 29 of the intermediate and 174 of the low probability category. There were large differences between the means of fDlate in the high and the intermediate and in the high and the low categories. We obtained a sensitivity of 85% and a specificity of 93% for diagnosis of PE, based on high and low probability categories. If a patient with previous PE, but no scintigraphic evidence of current PE, is excluded the sensitivity increases to 90%. This study provides further support for the measurement of fDlate by the SBT-CO2 as a diagnostic test in patients with suspicion of PE. The test should be especially useful in small hospitals without access to pulmonary scintigraphy or pulmonary angiography.

Measuring energy costs of leisure activity in adolescents using a CO2 breath test.

To determine whether a 13C-bicarbonate, isotope dilution technique could be used to estimate relative changes in energy expenditure of leisure activities of short duration, we studied eight adolescents who performed the following activities: watching television (120 min); playing a stringed instrument (60 min plus 60 min of sitting); and walking plus rest during two approximately isocaloric sessions (slow walk at 40% of peak VO2 for 43 min plus 77 min of sitting; fast walk at 73% of peak VO2 for 22 min plus 98 min of sitting). The rate of appearance of CO2 (RaCO2) was determined from the ratio of the oral dose of 13C-bicarbonate and the isotopic enrichment of breath CO2. The net rates of excretion of CO2 (VCO2) and oxygen consumption were measured. VCO2 and RaCO2, were correlated (r = 0.93; P < 0.05). To adjust for the systematic difference in CO2 production between methods, determinations were expressed as a fraction of that during television viewing. For RaCO2, the ratios for instrument playing, walking at 40% peak VCO2, and walking at 73% peak VO2 were respectively 133 +/- 20%, 186 +/- 38%, and 206 +/- 34%; for VCO2, the respective ratios were 129 +/- 19, 210 +/- 50, and 232 +/- 39 (P > 0.05 for methods and interaction, two-way ANOVA). RaCO2 may be a useful method for detecting relative differences in energy expenditure associated with leisure activities of brief duration.

Ventilatory effects of laparoscopic cholecystectomy.

During laparoscopic cholecystectomy the arterial-end-tidal CO2 gradient (Fa-ETCO2) has been variously shown to be unchanged, increased, decreased or even negative. The goal of this study was to evaluate Fa-ETCO2, and to determine the proper contribution of VECO2 and VA in regard to the increase of FETCO2. Ventilatory patterns were studied in 15 ASA 1-2 patients (mean age +/- SD: 48.5 +/- 15.0) undergoing laparoscopic cholecystectomy, with intraperitoneal CO2 insufflation limited to 12 mmHg, 15 degrees head-up position, during general anaesthesia and controlled ventilation. The following were studied before, during and after the pneumoperitoneum: FaCO2, FETCO2, nasopharyngeal temperature; dead space ventilation, and expired volumes using the Single Breath Test for CO2. VA was calculated as the alveolar fraction of expired VT multipled by the respiratory frequency. During pneumoperitoneum it is shown that: 1) Fa-ETCO2 either decreases and becomes even negative (n = 8) (P < 0.01), or stays unchanged (n = 7), but never elevates; 2) VECO2 increases (peak value: +22.6%) (P < 0.01); 3) VA is unchanged, and 4) dead space ventilation, determined in 7 patients, remains unchanged. We conclude that only exogenous CO2 loading, and not VA, can explain such increase in FETCO2 and FaCO2, in cases of limited CO2 insufflating pressure in ASA 1-2 patients.

Comments on the methods used to determine the energy values of carbohydrates: Dietary fibre, sugar alcohols and other bulking agents

Methods to evaluate the availability of food energy from difficult to digest carbohydrates are described. Emphasis is given to problems of interpreting results from energy determinations and to the accuracy and precision of the methods used. Consideration is given to determination of the heats of combustion of food components; determination of the metabolisable energy of diets and both apparent and partial metabolisable energy values of dietary components; and derivation and determination of net energy values of carbohydrates including methods to assess the availability of carbohydrates using enzymatic models, the ileostomy model, intubation, the labelled CO2 breath test, the hydrogen (H2) breath test, and isotopic tracer methods. The use and misuse of animals and indirect calorimetry in humans are also considered. Energy evaluation methods are classified into those which make direct determinations and those which determine indices for which established factors are needed for conversion into energy values. The direct methods appear less precise and potentially less accurate than methods that measure indices and use factors. In the latter, the precision (standard error of the determination) of several procedures is about 1 kJ/g (0.25 kcal/g) but in none is the accuracy established to be better than 2.5 kJ/g (0.6 kcal/g). Such precision is sufficient to allow inter-laboratory, inter-method and intersubstrate studies to be made. Discrimination between difficult to digest carbohydrates in food labelling could easily be justified at the 2 kJ/g (0.5 kcal/g) level provided that inter-substrate trials were undertaken, but, without such trials, discrimination greater than 3.5 kJ/g (1 kcal/g) would not seem warranted. The most precise and accurate approach to obtain energy values in humans appears to be one that couples the determination of apparent metabolisability with the determination of availability via the small intestine.

Maturation of caffeine N-demethylation in infancy: a study using the 13CO2 breath test.

Four premature neonates and eight infants 1-19 months old received caffeine for apnea. The usual morning oral dose was substituted by 1,3,7 13C-trimethylxanthine (13C-tri CAF) as the citrate salt. Five breath samples were collected the day before (day 1) and the day of 13C-tri CAF administration (day 2). Plasma (after each breath collection) and urine were collected on day 2. 13C-CO2 exhalation was determined by isotope ratio mass spectrometry. Caffeine and its metabolites were measured using high-pressure liquid chromatography. Assessment of the labeled CO2 in the breath revealed no detectable 13C-tri CAF N-demethylation activity in infants before 45 wk postconceptional age. However, demethylation (as urinary metabolites) has been detected before that age. Two-, 4-, and 6-h cumulative excretion of 13C-tri CAF as 13C-CO2 increased with postnatal age and correlated with caffeine plasma clearance (r = 0.840, p less than 0.01). These results were consistent with those obtained for urinary metabolites. In one infant (19 months old) the cumulative excretion of 13C-CO2 while crying was 65% of the value observed during quiet breathing. The measurement of caffeine demethylation using the caffeine CO2 breath test is feasible in infants and is a safe and noninvasive method to determine age related changes in P4501-dependent N-demethylase activity.

Effects of dietary protein on theophylline pharmacokinetics and caffeine and aminopyrine breath tests.

The effects of low- and high-protein diets on theophylline kinetics and the time course of changes in 13C-labeled caffeine and aminopyrine CO2 breath tests were examined in six young men. With a low-protein diet, mean theophylline clearance fell 21% (P less than 0.04) and the t1/2 rose from 8.0 to 10.6 hours (P less than 0.02). With a high-protein diet, mean theophylline clearance rose 26% (P less than 0.004) and the t1/2 shortened to 7.4 hours (P less than 0.03). Theophylline volume of distribution and protein binding did not change. Renal clearance of theophylline was lowered during the low-protein diet. Theophylline clearance correlated with caffeine breath test values during the low- (r = 0.73) and high- (r = 0.70) protein diets. Theophylline clearance correlated less well with the aminopyrine breath test values during the low- (r = 0.47) and high- (r = 0.55) protein diets. Thus dietary protein significantly influenced theophylline clearance, but the caffeine and aminopyrine breath tests showed a differential response to this important environmental factor.

The caffeine CO2 breath test: dose response and route of N-demethylation in smokers and nonsmokers.

The optimal conditions for performing the caffeine CO2 breath test (CBT) were investigated in smokers and nonsmokers. Caffeine labeled with 13C or 14C in all three (1, 3, and 7) methyl groups or specifically in the 1-, 3-, or 7-methyl groups were orally administered to healthy adults and the expiration of labeled CO2 was measured for 8 or 24 hr. The absolute rate of labeled CO2 excretion from trilabeled caffeine was proportional to the dose up to 3 mg/kg in all subjects. In smokers, the rate of labeled CO2 excretion averaged twice that in nonsmokers at all doses. A correlation was observed between the 2-hr cumulative CO2 excretion from trilabeled caffeine and the apparent oral metabolic clearance rate (MCR) of caffeine (R = 0.90). Monolabeled CBTs in smokers and nonsmokers demonstrated that 80% +/- 4% of labeled CO2 expired in the breath during the first 2 hr of a trilabeled CBT was derived from the 3 position; at 6 to 8 hr equal amounts were derived from the 3 and 7 positions. Little N-demethylation was observed from the 1 position at any time during the 8-hr test. The results indicate that the 2-hr cumulative excretion of labeled CO2 could be used to accurately predict the metabolic clearance rate of caffeine is the best CBT parameter for detecting the effect of smoking on caffeine N-demethylation. The data suggest that the primary routes of caffeine metabolism are 3-N-demethylation and ring hydroxylation and confirm that caffeine metabolites are N-demethylated primarily in the 3 and 7 positions.

Comparison of Different Methods of Expressing Results of the Aminopyrine Breath Test

Different methods of expressing the results of the aminopyrine CO2 breath test (ABT) were compared to determine the method that would be most sensitive for evaluating liver function. The patient population included health controls (n = 22); patients with mild (4), moderate (9), and severe (7) alcoholic liver disease; and patients with chronic persistent hepatitis (7), chronic active hepatitis (18), chronic active hepatitis with bridging (18), and chronic active hepatitis with cirrhosis (17). The ABT was performed with 2 micro Ci [14C]aminopyrine or 2 mg per kg [13C]aminopyrine, and the results were expressed as the instantaneous labeled CO2 excretion rates at 30, 60, 90, and 120 min after the dose, the maximum excretion rate, and the 120-min cumulative excretion. The 30-min parameter had the highest sensitivity toward moderate alcoholic hepatitis, severe alcoholic hepatitis, chronic active hepatitis with bridging, and chronic active hepatitis with cirrhosis (96%); however, when the ABT was repeated in six normal controls with 225 ml of orange juice, the 30-min rate was significantly reduced (7.8 +/- 1.3 vs. 5.6 +/- 1.2% dose per hr), and the rate of false-positive test results was increased (0 of 6 vs. 2 of 6) indicating that gastric delay influenced the 30-min parameter. The 60-min excretion rate, maximum rate, and 120-min cumulative excretion were the next most sensitive expressions of the ABT, and were not altered by the small gastric load. Of these three expressions, the 60-min parameter was the most convenient because it required fewer samples and a shorter test period.