Ph.H. Quanjer

Standardization of the measurement of transfer factor (diffusing capacity)

### 1.1 What is being measured The lung is the organ of external respiration for the exchange of oxygen and carbon dioxide between the blood and the surrounding air. The stages in the process of gas transfer include: 1. Ventilation of the airways and some air spaces by bulk flow of gas; 2. Mixing and diffusion of gases in the alveolar ducts, air sacs and alveoli; 3. Transfer of gases across the gaseous to liquid interface of the alveolar membrane; 4. Mixing and diffusion in the lung parenchyma and alveolar capillary plasma; 5. Chemical reaction with constituents of blood; 6. Circulation of blood between the pulmonary and systemic vascular beds. The capacity of the lung to exchange gas is determined by the structural and functional dimensions of these processes. The structural dimensions include the lung volume, the path length for diffusion in the gas phase, the thickness and area of the alveolar capillary membrane including any effects of airway closure, and the volume of blood in capillaries supplying alveoli which are ventilated. The principal functional dimensions are the absolute levels of ventilation and perfusion and the uniformity of their distribution with respect to both each other and the diffusion characteristics of the membrane. Other functional dimensions are the quantity of haemoglobin in the alveolar capillaries, the composition of the alveolar gas, the gas tensions in blood entering the alveolar capillaries, the rates of chemical reaction with haemoglobin and of dissociation of the compound so formed, the transit time of blood through that part of the pulmonary vascular bed which exchanges gas with the alveoli and the slope of the relevant haemoglobin dissociation curve. The latter is a function of the temperature of the lung and the prevailing levels of oxygen, carbon dioxide, hydrogen ions and 2,3-diphosphoglycerate; many of these variables are dependent on the level of …

References values for forced spirometry

The European Coal and Steel Community (ECSC) prediction equations exemplify a significant effort carried out approximately 15 yrs ago to provide uniform standards for lung function testing, but this set of equations has not been properly validated as yet. The present study evaluates the ECSC reference values and four other sets of prediction equations, using spirometric data collected in 12,900 nonasthmatic subjects (43% lifetime nonsmokers and 36% active smokers) aged 20-44 yrs from the European Community Respiratory Health Survey (ECRHS). Standardized spirometric measurements were obtained using a common protocol in 34 centres in 14 countries. For each prediction equation, the prediction deviations (i.e. observed minus predicted value) for forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) were examined for the whole study population and for each centre. For the age range included, the errors about the ECSC equations showed the most prominent underestimation of both predicted FVC (+355 and +360 mL on average in males and females, respectively) and predicted FEV1 (+211 and +200 mL, respectively) among the five studies examined. As expected, FVC and FEV1 in active smokers from the ECRHS were significantly lower than in lifetime nonsmokers (each p<0.01). We conclude that the present European recommendations on lung function reference values should be reconsidered, but further data for nonsymptomatic subjects above the age of 44 yrs are needed.

Inhaled corticosteroids and growth of airway function in asthmatic children

Airway inflammation and remodelling play an important role in the pathophysiology of asthma. Remodelling may affect childhood lung function, and this process may be reversed by anti-inflammatory treatment. The current study assessed longitudinally whether asthma affects growth of airway function relative to airspaces, and if so whether this is redressed by inhaled corticosteroids (ICS). Every 4 months for up to 3 yrs, lung function was assessed in 54 asthmatic children (initial age 7–16 yrs), who inhaled 0.2 mg salbutamol t.i.d. and 0.2 mg budesonide t.i.d. (β2‐agonist (BA)+ICS), or placebo (PL) t.i.d. (BA+PL) in a randomised, double-blind design. Measurements were carried out before and after maximal bronchodilation. Airway growth was assessed from the change of forced expiratory volume in one second and of maximal expiratory flows (at 60% and 40% of total lung capacity (TLC) remaining in the lung) relative to TLC, as measures of more central, intermediate and more peripheral airways. Growth patterns were compared with the longitudinal findings in 376 healthy children. Airway patency after maximal bronchodilation in patients on BA+PL remained reduced compared to healthy subjects, whereas in patients on BA+ICS a marked improvement was observed to subnormal. No differences between patients and controls could be demonstrated for growth patterns of central and intermediate airway function. Compliance with BA+ICS was 75% of the prescribed dose, resulting in significant, sustained improvement of symptoms and postbronchodilator calibre of central and intermediate airways to subnormal within 2 months, but postbronchodilator small airway patency remained reduced, though improved compared to patients on BA+PL. Anti-inflammatory treatment of asthmatic children is associated with normal functional development of central and intermediate airways. The persistently reduced postbronchodilator patency of peripheral airways may reflect remodelling, or insufficient anti-inflammatory treatment.

Pulmonary function during the first year of life in healthy infants born prematurely

Premature birth is associated with increased respiratory morbidity. We investigated cross-sectionally, in 69 healthy infants who had never had cardiorespiratory problems, whether premature birth is associated with diminished pulmonary function. The study comprised 26 healthy infants born prematurely (PT), median gestational age 32 (26-36) weeks, and 43 healthy controls born full-term (FT), median gestational age 40 (37-42) weeks. Static respiratory system compliance (Crs) was assessed by weighted spirometry, combined with the measurement of the functional residual capacity by closed circuit helium dilution (FRCHe) and with assessment of ventilation distribution from the mixing index (MI). Repeatability of these indices was also assessed. Premature and full-term infants had the same length-corrected FRCHe; their Crs was different, but the difference disappeared when gestational age was taken into account. Mixing index was unrelated to body size and was not different between full-term and premature infants. Crown-heel length and lung volume were not different for any postconceptional age. However, infants born prematurely were smaller and had smaller lung volume at any postnatal age compared to those born at term. Repeatability of the indices was fair. These findings suggest that gestational age < 37 weeks is associated with normal respiratory system mechanics for body size, and normal distribution of ventilation in healthy infants who never had cardiorespiratory problems.

Central respiratory CO2 sensitivity at extreme hypocapnia.

In 7 cats anaesthetized with chloralose-urethane the ponto-medullary region was artificially perfused with blood having PaCO2 values (central PaCO2) in the range of 0.3-4.5 kPa. The ventilatory response to changes in central PaCO2 was measured at constant hypercapnic and hypoxic conditions in the systemic circulation. Ventilation decreased upon lowering the central PaCO2 down to values of 0.5 kPa. There was no threshold for the effect of the central PaCO2 on ventilation. The CO2 sensitivity was undiminished at extreme hypocapnia compared to eucapnia. Under extreme central hypocapnic conditions the breathing pattern became irregular. It is concluded that there is still central CO2 sensitivity related to ventilation at extreme hypocapnia. Our findings suggest that central chemosensitive structures have a neural threshold below a PaCO2 of 0.5 kPa.

Influence of the CSF bicarbonate concentration on the ventilatory response to CO2 in relation to the location of the central chemoreceptors

In anaesthetized cats, in which the cerebrospinal fluid bicarbonate concentration was varied by a ventriculocisternal perfusion technique, the ventilatory response to CO2 during hyperoxia could be satisfactorily described by VE = S(PCSFCO2 -B). Both the slope S and the intercept B were positively and linearly related to the CSF bicarbonate concentration. Assuming that the PCSFCO2 is equal to the PCO2 in extracellular fluid, it can be shown that VE is a linear, but not a unique function of the [H+] at the site of the chemoreceptors; the slope of this relation varies with the bicarbonate concentration at that site, possibly due to chemical complex formation between HCO-3 and Ca2+ or Mg2+. Changes in the B-value were related to the location of the central chemoreceptors with the models of Pappenheimer and Berndt aand their coworkers. It was found that changes in the CSF bicarbonate concentration are reflected for 60 per cent at the site of the central chemoreceptors, and that this was independent of the cerebral perfusion. Using Berndts model a distance between CSF and central chemoreceptors of approximately 100 micron was found; this calculated distance is relatively insensitive to relationship (logarithmic or not) between ventilation and H+ concentration and to changes in cerebral perfusion, owing to the approximate nature of the diffusion model.

In vivo measurement of carbon dioxide tension with a miniature electrode.

A commercially available catheter type electrode with whichPCO2 can be continuously measured in vivo and in vitro gave progressively less accurate results the longer the measuring period was extended. This proved to be due to temperature effects and a change in sensitivity with time. A correction procedure for these effects was developed which was based on two observations. 1. The relationship between temperature and the logarithm of the sensitivity of the electrodeamplifier combination was linear and virtually identical for 9 electrodes: 8% change in sensitivity for a deviation of 1° C from the temperature during calibration. 2. The change in sensitivity due to drift of the electrode output is approximately a logarithmic function of time: 1 h after calibration all electrodes exhibited a decreased sensitivity, varying between 0.3 and 16.7%. The drift effect can be dealt with by repeated calibrations, preferably at 11/2 h intervals.The adequacy of the correction procedure was assessed in in vivo measurements in cats and dogs. The meanPCO2 difference between the in vivo measurement, corrected for temperature and drift, and samples analyzed with a conventional electrode, was 0.005 kPa (0.04 mm Hg) with a standard deviation of 0.187 kPa (1.39 mm Hg).

Validity of ECSC prediction equations for spirometric indices in Dutch conscripts

A study was performed to determine whether prediction equations issued by the European Community for Steel and Coal (ECSC) and the European Respiratory Society (ERS) fit spirometric data in young adult males. The study comprised 246 randomly selected Dutch conscripts, who participated in the study on the basis of informed consent. A questionnaire was used to assess respiratory symptoms and smoking habits. Maximal expiratory flow-volume curves were obtained with a rolling seal spirometer, and summary statistics selected according to ECSC/ERS recommendations. In addition, standing height and body weight were obtained. We analysed the data of 100 conscripts of European descent, with no history of respiratory symptoms. They were all life-long nonsmokers. Their mean (SD) age was 18 (0.12) yrs (range 17.9-19.0 yrs), with a mean (SD) standing height of 1.84 (0.06) m (range 1.68-2.00 m). The data for forced vital capacity (FVC), forced expiratory volume in one second (FEV1) and maximal mid-expiratory flow (MMEF) agreed well with ECSC predictions; 95% confidence intervals (95% CI) of differences between measured and predicted values were -0.174 to 0.044 l, -0.012 to 0.174 l.s-1 and -0.114 to 0.302 l.s-1, respectively. Peak expiratory flow was systematically larger than predicted, as was FEV1 % FVC (95% CI 0.74 to 1.31 l.s-1 and 2.50 to 5.24%, respectively), due to the intercept being inappropriate. The residual standard deviation in the conscripts was somewhat less than in the ECSC/ERS predictions equations, except for peak expiratory flow (PEF).(ABSTRACT TRUNCATED AT 250 WORDS)

Respiratory illness in families of preterm infants with chronic lung disease

AIMS--To examine the relation, based on two types of questionnaires, between (1) chronic lung disease of the newborn (CLDN) and lower respiratory illness (LRI) in siblings, and between (2) CLDN and asthma, chronic obstruction pulmonary disease (COPD), or allergy in parents and grandparents. METHODS--Data from 209 children born before 32 weeks of gestation were randomly taken from the records of three neonatal units. Taking into account age and gender, the excess of LRI was calculated for each family compared with the average of all families. Subsequently whether CLDN was associated with an excess of LRI in the family was tested. RESULTS--Thirty one (14.8%) children were diagnosed as having CLDN. The family probability index for LRI did not differ between children with or without CLDN. The prevalence of COPD, asthma, and allergy in parents of children with CLDN was similar to that of children without CLDN. The prevalence of LRI was 18.1% in study children, 29.6% in children with CLDN, and 16.9% in children without CLDN (P < 0.01). These prevalences were higher compared with that of a group of term siblings (9.3%) (P = 0.05). CONCLUSIONS--These findings suggest that CLDN in preterm children is not related to a genetic or familial predisposition towards asthma, COPD, or allergy.

Thermal dilution measurement of cardiac output in dogs using an analog computer.

SummaryThermal dilution cardiac output determinations in dogs were compared to simultaneously performedFick oxygen measurements. The purpose of this study was to validate in dog experiments a method for thermal dilution measurement which employs a double-thermistor catheter combined with an automatic computer as described byOlsson et al. Dilution and injectate temperature are entered directly into the calculation. The method does not employ logarithmic extrapolation, integration of the dilution signal being terminated when a preset cut-off level is reached. Errors due to recirculation, thermal capacitance of the right heart and heat exchange with the catheters dead space require the use of an empirically derived correction factor, which in dogs was found to be significantly different from the factor used for human thermal dilution curves. With the appropriate cut-off level and correction factor a good agreement was found between the results of the thermal dilution and theFick method. The regression equation for 47 experiments was found to be COtd=0.95 COFick+0.08; the correlation coefficient was 0.94.ZusammenfassungMinutenvolumenbestimmungen beim Hund aufgrund der Thermodilutionstechnik wurden mit gleichzeitig durchgeführten Messungen nach demFickschen Prinzip verglichen. Der Zweck der Studie war, im Hundeversuch eine Thermodilutionsmethode zu bewerten, in der ein Doppelthermistor-Katheter verwendet wird, verbunden mit einem automatischen Computer, wie vonOlsson et al. beschrieben. Verdünnung und Temperatur der injizierten Flüssigkeit wurden direkt in die Berechnung einbezogen. Die Methode verwendet keine logarithmische Extrapolierung; die Integration des Signals wird beendet, wenn eine vorgegebene Grenzkonzentration erreicht wird. Fehler durch Rezirkulation, durch die Wärmekapazität des rechten Herzens und Wärmeaustausch mit dem Totraum des Katheters machen einen empirisch abgeleiteten Korrekturfaktor erforderlich. Es zeigte sich, daß dieser Faktor bei Hunden sich deutlich von dem Faktor unterschied, der für Thermodilutionskurven beim Menschen gebraucht wird. Wurden passende Werte für Grenzkonzentration und Korrekturfaktor gewählt, so ergab sich eine gute Übereinstimmung zwischen den Ergebnissen des Kälteverdünnungsverfahrens und derFickschen Methode. Aus 47 Experimenten wurde folgende Regressionsgleichung errechnet: COtd=0.95COFick+0.08; der Korrelationskoeffizient war 0,94.