Clinical diagnosis with the stable isotope 13C in CO2 breath tests: methodology and fundamental considerations

The methodology for measuring in vivo oxidation of substrates labeled with the nonradioactive carbon isotope 13C has been developed with isotope ratio mass spectrometry. The use of 13C offers the possibility of utilizing CO2 breath tests in infants, children, pregnant women, and all subjects in whom 14CO2 breath tests cannot be used. The excretion of 140 nmol/kg-hr of 13CO2 produced from the oxidation of the labeled substrate could be detected with 95% confidence during a total CO2 excretion of 9 mM/kg-hr. The precision of CO2 breath tests using 13C is limited by the natural fluctuations of the ratio of 13C/12C in expired CO2, which occur with a standard deviation of 0.72%, or approximately 7 parts 13CO2 per 10(6) parts expired CO2. Larger excursions in the ratio were observed if the subjects ate shortly before or during the breath test. Clinically significant diagnostic tests can reasonably be expected to require the excretion of 2 to 20 times as much labeled CO2, or 0.28 to 1.4 micronM/kg-hr.     

Tidal expired airflow patterns in adults with airway obstruction

Earlier studies have shown that time and flow indices derived from tidal expiratory flow patterns can be used to distinguish the severity of airway obstruction. This study was designed to address two aspects of tidal expiratory flow patterns: 1) how do expiratory flow patterns differ between subjects with normal and obstructed airways; and 2) can a sensitive index of airway obstruction be derived from these pattern differences? Tidal expiratory flow patterns from 66 adult subjects with varying degrees of airway obstructive disease with a forced expiratory volume in one second (FEV1) of 20-121% predicted were examined. In each subject, the expired flow pattern from each consecutive breath was scaled and then averaged together to create a single expired pattern. A detailed examination of the scaled flow patterns in 12 subjects (six with normal airways and six with airway obstruction) showed that the shape of the post-peak expiratory flow portion was different in the subjects with airway obstruction. A slope index, S, was derived from the scaled patterns and found to be sensitive to the severity of airway obstruction, correlating with FEV1 (% pred) with r2=0.74 (p<0.05, n=57). The S index also correlated (r2=0.36, p<0.05, n=47) with the functional residual capacity (FRC) (% pred) which was >100% in subjects with severe airway obstruction and lung overinflation. In subjects with normal airways, three further airflow patterns could be distinguished, which were different from the patterns seen in subjects with the severest airway obstruction. Scaled flow patterns from tidal expiration collected from uncoached subjects, can be used to derive an index of airway obstruction.     

13C-urea breath test for diagnosis of experimental Helicobacter pylori infection in barrier born pigs

Previous studies with Helicobacter pylori infected barrier born pigs indicate that the infection has a patchy distribution, resulting in false negative culture results on endoscopic biopsy specimens. This study aimed to adapt the 13C-urea breath test as used in humans to diagnose H pylori infection in barrier born pigs. The breath test was also performed after bismuth as a single treatment and after triple therapy (bismuth, ampicillin, metronidazole). In control pigs the median excess of 13CO2 in expired air was 2.2 (range 0-12 n = 22) ppm. The infected pigs (n = 4) showed consistently high values (median 23 range 14-43) when examined on four occasions (n = 16) four to 10 weeks after inoculation. Biopsy specimens for culture had lower sensitivity than the breath test. No reduction in excess 13CO2 was seen after three days' single bismuth treatment, but after two weeks' triple therapy the breath test results had returned to normal. This suppression was temporary only, however, as the breath test was positive again four weeks after stopping treatment. In conclusion, the 13C-urea breath test is a simple and reliable test for determining H pylori infection and monitoring treatment effects in barrier born pigs. Because the test can be performed in awake pigs anaesthesia and gastroscopy are unnecessary.     

Raising milk energy content retards gastric emptying of lactose in lactose-intolerant humans with little effect on lactose digestion

Lactose digestion improves when the energy content of a meal is raised, perhaps due to delayed gastric emptying; however, this has not been demonstrated directly. It is not known whether lactose-intolerant subjects should consume full-fat or high energy milk instead of half-skimmed milk. In this study, breath 13CO2 and hydrogen (H2) measurements were combined to assess simultaneously the effect of increasing milk energy content on gastric emptying, digestion, and tolerance of lactose. On two separate days, 11 adult lactose maldigesters ingested, in the fasting state, a single dose of 710 kJ half-skimmed milk or 1970 kJ high energy milk. Both contained 18 g lactose and were supplemented with 100 mg 13C-glycine for breath 13CO2 measurement. For 6 h after milk ingestion, samples of expired breath were collected, and subjects scored their symptoms on a four-grade questionnaire. Gastric emptying was measured from excretion of breath 13CO2. The mean gastric emptying half-time was significantly longer after ingestion of high energy milk than after half-skimmed milk (84 +/- 4 vs. 64 +/- 4 min, P = 0.004). The mean area under the breath H2 excretion curve measured for 6 h was 330 +/- 61 microL/L after subjects consumed high energy milk vs. 470 +/- 82 microL/L after they consumed half-skimmed milk (P = 0.07). Mean symptom scores did not differ after ingestion of the two milks, but only two subjects experienced disturbing symptoms after high energy milk ingestion compared with five subjects after ingestion of half-skimmed milk (P = 0.56). Although ingestion of high energy milk delayed the gastric emptying of lactose for significantly longer than the ingestion of half-skimmed milk (P < 0.01), it did not lead to significant improvement in symptoms and reflected only a trend toward improved lactose digestion (P = 0.07), as measured by the area under the breath H2 excretion curve. These results indicate that it is not beneficial for most lactose-intolerant subjects to replace consumption of half-skimmed milk by milk with a higher energy content.     

Alveolar gas exchange during simulated breath-hold diving to 20 m

Alveolar gas exchange, as affected by changes in pulmonary blood flow, was studied in five subjects performing breath holds lasting 75 s at the surface and during compression to 20 m in a hyperbaric chamber. After reaching the maximal depth, VO2 started to increase, compared to control, reaching a maximum of 346 +/- 66 (SE) ml (STPD).min-1.m2 (body surface area) at 50 s, i.e., early in the ascent; it exceeded the 50-s surface breath-hold value by 214 +/- 9 ml.min-1.m2. During descent, CO2 was absorbed from the alveoli into the blood, initially at 140 +/- 24 ml.min-1.m2; during ascent CO2 was transferred back into the lungs. These changes reflected compression and expansion of lung air. The increase in VO2 during the dives, which are not steady states, may be explained by an increasing cardiac output at depth. An augmented cardiac output had earlier been observed under identical conditions and explained by a drop in transthoracic pressure, enhancing venous return. Upon surfacing, the PAO2 was about 20 mmHg lower than after surface breath holds, reflecting the effects of changes in cardiac output.     

Alteration of bile acid metabolism by cimetidine in healthy humans

BACKGROUND: To clarify an effect of cimetidine on bile acid metabolism, we evaluated whether an increased deconjugation of bile acids would occur in healthy humans who have received cimetidine. We examined: 1) whether healthy volunteers taking cimetidine would have positive bile acid breath tests because of bacterial overgrowth in the jejunum; 2) whether the isolated bacteria would exhibit deconjugation ability; and 3) whether a change in gastric pH was related to the bacterial overgrowth. METHODS: We evaluated 73 healthy Japanese volunteers; 53 of them received cimetidine and 20 did not. Deconjugation of bile acids was detected as 14CO2 specific activity of expired air measured by a bile acid breath test giving 5 muCi of oral glycine-1-(14)C labeled glycocholate. Aspiration of jejunal fluids was performed by a double lumen tube with a rubber cover on the tip, and deconjugation ability of bacteria was evaluated using thin layer chromotography. RESULTS: Samples of expired breath from the 53 healthy volunteers showed a significant increase in 14CO2 specific activity after the administration of cimetidine rather than before the administration of cimetidine. Bacterial over-growth was found in the jejunal fluid after the administration of cimetidine. The administration of tetracycline to 27 subjects significantly reduced the 14CO2 specific activity. The following species were identified in the jejunal fluid samples obtained from the subjects: enterococcus, Lactobacillus bifidus, Bacteroides vulgatus, B uniformis, Eubacterium lentum, E parvum, and Escherichia coli. Except for E coli, all of the bacterial species identified deconjugated bile acids. We observed a significant relationship between 14CO2's specific activity and gastric pH before and after administration of cimetidine, respectively. CONCLUSIONS: Healthy volunteers who received cimetidine showed an increased deconjugation of bile acid caused by overgrowth of bacteria in the jejunum, which can deconjugate bile acids. The bacterial overgrowth is probably associated with a shift to neutral pH in the gastric juice caused by cimetidine.     

关于露天矿工作帮坡角的研究与优化

为了正确选择和运用露天矿合理的工作帮坡角，确保露天矿开采全过程处于良好状态，并提高露天矿开采的综合经济效益，通过对露天矿山缓帮开采方式和陡帮开采方式的对比及其开采全过程的分析比较，阐述合理选择工作帮坡角的必要性及其重大价值和意义。优化工作帮坡角的合理性体现在：基建剥离工程量小；剥采比较稳定均衡以利生产稳定，并具有较好的效益；计算年采剥总量峰值较低，且可推迟出现，以利降低矿山基建剥离量和前期生产剥采比，减少基建投资；稳定生产的时间长。露天矿工作帮坡角应精心选择，并根据开采实际和市场情况，在不脱离合理工作帮坡角基本准则的基础上进行灵活的调整。     

Lithium dilution cardiac output measurement: a comparison with thermodilution

OBJECTIVE: To compare the results of cardiac output measurements obtained by lithium dilution and thermodilution. DESIGN: Case series, observational study. SETTING: High-dependency postoperative unit and intensive care unit of a teaching hospital. PATIENTS: Forty patients were studied. Thirty-four patients had undergoing heart surgery requiring cardiopulmonary bypass within the previous 2 days; the diagnoses in the other patients were myocardial infarct (n = 2), septicemia (n = 2), adult respiratory distress syndrome, and pericardectomy. INTERVENTIONS: Cardiac output was measured five times in each patient, using lithium dilution (single measurement) and bolus thermodilution (series of three to six measurements according to standard clinical practice, taking the average of the closest three). In a subgroup of 14 patients, cardiac output was also measured using "continuous thermodilution." MEASUREMENTS AND MAIN RESULTS: Comparing lithium dilution with bolus thermodilution, the mean of the differences (lithium dilution-thermodilution) was -0.25 +/- 0.46 [SD] L/min. Linear regression analysis gave y = 0.31 + 0.89x (r2 = .94) for lithium dilution vs. thermodilution. CONCLUSIONS: The overall agreement between the two methods was good. The variability of the thermodilution measurements was greater than that of the lithium dilution measurements. The lithium dilution method is at least as accurate as bolus thermodilution and, since pulmonary artery catheterization is not needed, it has the advantages of being safe and quick to perform.     

Cardiac output determination by simple one-step rebreathing technique

We have developed a rebreathing technique for measuring cardiac output in resting or exercising subjects. The data needed are the subject's CO2 dissociation curve, the initial volume and CO2 fraction of the rebreathing bag, and a record of CO2 at the mouth during the maneuver. From these one can obtain all the values required to solve the Fick equation. The combined error due to inaccuracy in reading the tracings and to the simplifying assumptions was found to be small (mean = 0.5%, SD ;.5%). Cardiac output values determined with this technique in normal subjects were on the average 2% higher than those obtained simultaneously with an acetylene rebreathing method (n = 49, SD = 11%). Among the advantages of the technique are that it requires analysis of a single gas, takes less than thirty seconds per determination, allows one to obtain repeated measurements at rapid intervals, is not affected by the ability of lung tissue to store CO2, and eliminates many of the assumptions usually made in non-invasive measurements of cardiac output.     

Assessment of whole body L-leucine oxidation by noninvasive L-[1-13C]leucine breath tests: a reappraisal in patients with maple syrup urine disease, obligate heterozygotes, and healthy subjects

Suitability of a recently proposed noninvasive L-[13C]leucine breath test for assessment of whole body leucine oxidation in maple syrup urine disease (MSUD) was examined. Oral L-[1-13C]leucine loads (38 micromol/kg body weight) were performed in overnight fasted MSUD patients (n = 6, classical form), obligate heterozygote parents (n = 6), and control subjects (n = 10). Three-hour 13CO2 exhalation kinetics were evaluated using curve fitting procedures. Venous blood was obtained in most cases and analyzed for 13C-labeled plasma metabolites. In control subjects, maximal 13CO2 exhalation was reached at tmax = 55 +/- 18 min. Cumulative 13CO2 output at 3 h amounted to 4.7 +/- 0.7 micromol x (kg body weight)(-1). Estimated total 3CO2 exhalation was 7.2 +/- 1.4 micromol x (kg body weight)(-1) (19.0 +/- 3.6% of the dose). Half of this amount was expired at t1/2 = 130 +/- 18 min. The data show a considerable degree of intersubject variability. Intraindividual variability was comparable, however, when checked in two volunteers. In obligate heterozygotes, 13CO2 kinetics were similar to controls (tmax = 35 +/- 8 min, t1/2 = 95 +/- 16 min). Total 13CO2 output [5.7 +/- 1.4 micromol x (kg body weight)(-1)] tended to be in the lower control range. None of the MSUD patients under study exhibited a significant increase in 13CO2 output after load. Maximal increase of label in plasma 4-methyl-2-oxopentanoate, the physiologic precursor of 13CO2, was 16.1 +/- 3.5 MPE in control subjects. In MSUD, label dilution was increased and correlated with the patients' leucine/4-methyl-2-oxopentanoate plasma levels. Considering the generally high variability of 13CO2 output and the unstable substrate pools in MSUD, we discuss the limitations of whole body leucine oxidation measurements by noninvasive approaches.     

The biology of restenosis

To determine whether changes mixed-venous PCO2 or PO2 affect cardiac output independent of changes in arterial blood gases, we used extracorporeal gas exchange to increase mixed-venous PCO2 or decrease mixed-venous PO2 in adult sheep. Sheep were anesthetized, mechanically ventilated, and connected to a veno-venous extracorporeal circuit. The circuit included a gas exchanger which was used to increase mixed-venous PCO2 or decrease mixed-venous PO2; the native lungs were ventilated to maintain arterial PCO2 and PO2 at control levels. When mixed-venous PCO2 was increased by 32% above control levels for a period of 60 min, cardiac output increased significantly to 28% above control levels. Cervical vagotomy abolished this response. In contrast, decreasing mixed-venous PO2 by 29% did not increase cardiac output. These results demonstrate that increasing mixed-venous PCO2 can increase cardiac output independent of changes in arterial blood gases and that intact vagus nerves are necessary for this response to occur.     

Impairment of plasma fibrinolysis in young survivors of myocardial infarction with silent ischaemia

OBJECTIVE: To determine the effect of mild dehydration (5%) on expired breath H2 concentrations in dogs. ANIMALS: 10 healthy, colony-source dogs. PROCEDURE: Expired breath samples were collected at baseline, and every 90 minutes for 18 hours after ingestion of a test meal (commercial dog food and kibbled wheat) in fully hydrated dogs and in the same dogs when they had lost 5% of their body weight after food and water deprivation. The areas under the breath H2 concentration versus time curves (AUC) for the dehydrated and nondehydrated states were compared, using a two-stage, balanced, crossover, repeated measures technique. The number of breath samples considered to be contaminated by flatus were compared by use of a one-sided sign test. RESULTS: Expired breath H2 concentration of dogs during the dehydration test period was significantly (P < 0.02) greater than that during the nondehydration test period. In addition, flatulence was significantly (P < 0.033) more frequent in dogs during the dehydration period. CONCLUSIONS: Dehydrated dogs have greater expired breath H2 concentration and produce more flatus after ingestion of a carbohydrate-containing meal. Considered together, these findings suggest that dehydration results in an increase in the net amount of H2 produced in the gastrointestinal tract. CLINICAL RELEVANCE: Care should be taken to assess the hydration status, and to correct hydration deficits of dogs prior to breath H2 testing.     

The effects of changes in ventilation and cardiac output on expired nitric oxide

The measurement of nitric oxide (NO) in expired gas is being increasingly reported in disease states such as sepsis, heart failure, and asthma. However, the effects of changes in ventilatory and cardiac parameters on expired NO are not known. Therefore, we assessed the effects of changes in minute ventilation (VE), ventilatory pattern, and cardiac output on expired gas NO levels in five anesthetized, intubated pigs. The animals were mechanically ventilated at three settings for each of respiratory rate (12 to 14, 16 to 18, and 22 to 24/min) and tidal volume (10, 15, and 20 mL/kg) applied in random sequence, yielding nine ventilatory patterns and a range of VE (3.7+/-0.1 to 13.2+/-0.8 L/min). When VE was increased, expired NO concentration declined slightly (r=-0.40, p<0.01), but the rate of excretion of NO in expired gas increased significantly (r=0.60, p<0.01). In contrast, when cardiac output was increased progressively from 3.6+/-0.1 to 4.7+/-0.3 and 5.8+/-0.4 L/min (p<0.01) by volume loading during constant eucapneic ventilation, there was no change in expired NO. Changes in VE over a physiologic range significantly affect the measurement of NO in expired gas, whereas short-term changes in cardiac output do not. To facilitate comparison between studies, we suggest that the measurement of expired NO should be reported in conjunction with data on VE.     

Mass spectrometry: application in the exercise sciences

This paper outlines a computerized system for monitoring physiological functions during exercise, using a mass spectrometer for analyzing the concentration of the mixed expired air. Examples are provided illustrating the operation of this system in both research and clinical situations. The most remarkable aspect of the system is its versatility, coupled with its accuracy. While the applications reviewed in this paper are rather narrow, work has been initiated using the mass spectrometer to measure residual lung volumes by the oxygen dilution technique, cardiac output by the CO2 rebreathing technique, and total body density by the helium dilution technique. The application of the mass spectrometer into other areas most certainty will occur in the near future.     

Adaptive buffering of breath-by-breath variations of end-tidal CO2 of humans

We have designed and implemented a computer-controlled system that uses an adaptive control algorithm (generalized minimum variance) to buffer the breath-by-breath variations of the end-tidal CO2 fraction (FETCO2) that occur spontaneously or are exaggerated in certain experimental protocols (e.g., induced hypoxia, any type of induced variations in the ventilatory pattern). Near the end of each breath, FETCO2 of the following breath is predicted and the inspired CO2 fraction (FICO2) of the upcoming breath is adjusted to minimize the difference between the predicted and desired FETCO2 of the next breath. The one-breath-ahead prediction of FETCO2 is based on an adaptive autoregressive with exogenous inputs (ARX) model: FETCO2 of a given breath is related to FICO2, FETCO2 of the previous breath, and inspiratory ventilation. Adequacy of the prediction is demonstrated using data from experiments in which FICO2 was varied pseudorandomly in wakefulness and sleep. The algorithm for optimally buffering changes in FETCO2 is based on the coefficients of the ARX model. We have determined experimentally the frequency of FETCO2 variations that can be buffered adequately by our controller, testing both spontaneous variations in FETCO2 and variations induced by hypoxia in young awake human subjects. The controller is most effective in buffering variations of FETCO2 in the frequency range of <0.1 cycle/breath. Some potential applications are discussed.     

Evaluation of [14C]aminopyrine breath test, peripheral clearance of [99mTc]EHIDA, and serum bile acid levels in liver function and disease

The purpose of this study is to evaluate the diagnostic value of the following tests in the assessment of patients with chronic liver disease (CLD) and cholestatic syndrome (CS): (1) aminopyrine breath test, measuring 14CO2 excretion in the expired air, (2) peripheral clearance of [99mTc]EHIDA, and (3) postprandial levels of glycocholic acid (GCA) and glycochenodeoxycholic acid (GCDCA). The results indicate that: (1) 14CO2 2-hr excretion rate is a specific and sensitive marker of liver function, with good correlation with postprandial bile acid levels, [99mTc]EHIDA retention, and the conventional tests of serum albumin and prothrombin time. (2) Peripheral clearance and retention of [99mTc]EHIDA increased in both groups of CLD and CS vs controls, but it does not discriminate between the two. (3) Postprandial bile acids were elevated in CLD, particularly those of GCDCA, whereas GCA levels were significantly elevated in CS compared with CLD. This may be due to increased synthesis and entry into the blood. (4) The combination of [14C]aminopyrine breath test and postprandial levels of GCDCA enhance the diagnostic value, specificity, and sensitivity in the assessment of patients with CLD.     

Carbon dioxide spirogram (but not capnogram) detects leaking inspiratory valve in a circle circuit

Expiratory valve incompetence in the circle circuit is diagnosed by using capnography (PCO2 versus time) when significant CO2 is present throughout inspiration. However, inspiratory valve incompetence will allow CO2-containing expirate to reverse flow into the inspiratory limb. CO2 rebreathing occurs early during the next inspiration, generating a short extension of the alveolar plateau and decreased inspiratory downslope of the capnogram, which may be indistinguishable from normal. We hypothesized that CO2 spirography (PCO2 versus volume) would correctly measure inspired CO2 volume (VCO2) during inspiratory valve leak. Accordingly, a metabolic chamber (alcohol combustion) was connected to a lung simulator, which was mechanically ventilated through a standard anesthesia circle circuit. By multiplying and integrating airway flow and PCO2, overall, expired, and inspired VCO2 (VCO2,br = VCO2,E - VCO2,I) were measured. When the inspiratory valve was compromised (by placing a wire between the valve seat and diaphragm), VCO2,I increased from 2.7 +/- 1.7 to 5.7 +/- 0.2 mL (P < 0.05), as measured by using CO2 spirography. In contrast, the capnogram demonstrated only an imperceptible lengthening of the alveolar plateau and did not measure VCO2,I. To maintain effective alveolar ventilation and CO2 elimination, increased VCO2,I requires a larger tidal volume, which could result in pulmonary barotrauma, decreased cardiac output, and increased intracranial pressure. Implications: Circle circuit inspiratory valve leak will allow CO2-containing expirate to reverse flow into the inspiratory limb, with subsequent rebreathing during the next inspiration. This CO2 rebreathing causes imperceptible lengthening of the alveolar plateau of the capnogram and is detected only by using the CO2 spirogram (PCO2 versus volume).     

Intraoperative end-tidal carbon dioxide values and derived calculations correlated with outcome: prognosis and capnography

OBJECTIVE: To determine how much information concerning resuscitation and outcome is provided by the end-tidal CO2 and derived variables obtained during surgery. DESIGN: Retrospective chart review. SETTING: Emergency hospital operating room. PATIENTS: One hundred critically ill or injured patients requiring major surgery and having a mortality rate of 41%. INTERVENTIONS: Standard intraoperative monitoring, including continuous capnography, plus arterial blood gas analyses every 1 to 1.5 hrs during surgery. MEASUREMENTS AND MAIN RESULTS: There was only a fair correlation between the PaCO2 and end-tidal CO2 (r2 = .14). The mortality rates in these patients were highest in those patients who had the lowest end-tidal CO2 values, the highest arterial to end-tidal CO2 differences, and the highest estimated alveolar deadspace fraction. A persistent end-tidal CO2 of < or = 28 torr (< or = 3.8 kPa) was associated with a mortality rate of 55% (vs. 17% in those patients with a higher end-tidal CO2). The mortality rate was also increased in patients with a persistent arterial to end-tidal CO2 difference of > or = 8 torr (> or = 1.1 kPa) (58% vs. 23%). CONCLUSIONS: End-tidal CO2 and derived values should be monitored closely in critically ill or injured patients. Efforts should be made--by increasing cardiac output and core temperature and by adjusting ventilation as needed--to maintain the end-tidal CO2 at > or = 29 torr (> or = 3.9 kPa) and the arterial to end-tidal CO2 difference at < or = 7 torr (< or = 1.0 kPa).     

A multicenter evaluation of a new continuous cardiac output pulmonary artery catheter system

OBJECTIVE: To validate a new system of continuous cardiac output monitoring. DESIGN: Multicenter, prospective, nonrandomized clinical study. SETTING: Four university hospitals. PATIENTS: Forty-seven adult intensive care unit patients. INTERVENTIONS: Pulmonary artery catheterization. MEASUREMENTS AND MAIN RESULTS: Continuous and bolus cardiac output measurements were obtained over 72 hrs. The 327 continuous cardiac output measurements compared favorably with bolus cardiac output measurements (bias = 0.12 L/min, precision = +/-0.84). The continuous cardiac measurement was not adversely affected by temperatures of <37 degrees C or >38 degrees C, high (>7.5 L/min) or low (<4.5 L/min) cardiac output values, or duration (72 hrs) of the study. CONCLUSIONS: This continuous cardiac output system provides a reliable estimate of cardiac output for clinical use if applied in conditions similar to this study. The combination of a continuous measure of cardiac output with other continuous physiologic monitoring (arterial and mixed venous oxygen saturation, oxygen consumption, etc.) may provide important information that no single parameter could achieve.     

Single-exhalation profiles of NO and CO2 in humans: effect of dynamically changing flow rate

Endogenous production of nitric oxide (NO) in the human lungs has many important pathophysiological roles and can be detected in the exhaled breath. An understanding of the factors that dictate the shape of the NO exhalation profile is fundamental to our understanding of normal and diseased lung function. We collected single-exhalation profiles of NO and CO2 from normal human subjects after inhalation of ambient air (approximately 15 parts/billion) and examined the effect of a 15-s breath hold and exhalation flow rate (VE) on the following features of the NO profile: 1) series dead space, 2) average concentration in phase III with respect to time and volume, 3) normalized slope of phase III with respect to time and volume, and 4) elimination rate at end exhalation. The dead space is approximately 50% smaller for NO than for CO2 and is substantially reduced after a breath hold. The concentration of exhaled NO is inversely related to VE, but the average NO concentration with respect to time has a stronger inverse relationship than that with respect to volume. The normalized slope of phase III NO with respect to time and that with respect to volume are negative at a constant VE but can be made to change signs if the flow rate continuously decreases during the exhalation. In addition, NO elimination at end exhalation vs. VE produces a nonzero intercept and slope that are subject dependent and can be used to quantitate the relative contribution of the airways and the alveoli to exhaled NO. We conclude that exhaled NO has an airway and an alveolar source.