New insights into physiology and pathophysiology by resistance-volume recordings.

This work deals with the assessment of airway resistance in the course of a single breath. The study showed the presence of an early increase in the resistance at the beginning of expiration, which intensifies during expiration and ends up with a sharp decline during expiring the last remaining volume of ca 350 ml. The dynamic changes in airway resistance over a breath depend on the disharmonic interplay between diaphragm function and bronchial wall tonus. Thus, airway resistance is not constant during breathing, as could be misleadingly judged from the total resistance averaged over a breath. The study underscores the importance of recording the resistance-volume curves alongside the standard flow-volume curves to be able to discern the peculiarities of airway resistance changes during a single breath. Knowing changes in the instantaneous airway resistance characteristic for a given lung pathology could appreciably improve the diagnostic and therapeutic powers.

Lung function--clinical importance, problems, and new results.

This review tackles the usefulness of spirometry, a more than century old method of assessing pulmonary lung function. Variables measured with a spirometer, such as forced expiratory volume in 1 s, have long been the mainstays of the diagnosis and treatment of lung disorders. But there are problems with the reliability of spirometric measurements. The method depends on the cooperation of the investigated subject, which introduces a confounding subjective element and all too often results in test failure, and the results are evaluated against the predicted values that are based on a set of fixed factors, some of which, such as body height, are not in a straight proportion to the intrathoracic gas volume. Substantial spread of results arises, which makes a reliable assessment of lung function difficult. New methods, such as the resistance-volume curve, provide better information on airway behavior in different conditions. These new methods, which basically evolved from spirometry, show that the old idea of lung function analysis is still viable and may remain helpful for diagnosis and treatment of respiratory pathological states.

[Stability of lung function parameters: spirometry, body plethysmography and mouth occlusion pressure (p0.1)]. / Zur Stabilität lungenfunktionsanalytischer Parameter: Spirometrie, Bodyplethysmographie und Mundverschlussdruck (P0.1).

Spirometric, bodyplethysmographic and mouth occlusion results of 9 healthy probands were measured 9 - 11 times over a total of 28 - 39 days. Interindividual predicted values based on large studies show SDs of +/- 20 %, which is not acceptable for the judgement of individual values. Individual values are much less scattered (SD +/- 10 %). Each test person showed a differing individual range of 75 - 140 %. Functional basic facts can be derived from the different levels of individual values. Early changes in the individual range are of special interest. For the evaluation of individual results the earliest possible basic values are of importance.

[Stress test blood gas analysis in chronic obstructive lung diseases]. / Die Belastungs-Blutgasanalyse bei chronisch obstruktiven Lungenerkrankungen.

This study was conducted to investigate the clinical value of blood gas analysis during exercise in patients with COPD and healthy controls using the new criteria of the Deutsche Gesellschaft für Pneumologie (DGP) for performance and interpretation of blood gas analysis during exercise. A total of 64 patients with COPD (age: 63.7 +/- 10.1 years) and 35 healthy controls (age: 35.0 +/- 14.3 years) exercised on a bicycle ergometer to their submaximal capacity under steady state conditions (patients: 44.4 +/- 24.6 watt vs. 102.4 +/- 32.1 watt; p < 0.01). A pathological response for PaO2 occurred in 3 of 35 controls (8.6%) and 14 of 64 patients (21.9%; p < 0.01). A decrease in PaO2 yielded a sensitivity of 28% and a specificity of 92% in respect of patients with emphysema. Significant associations of lung function parameters at rest and blood gases under exercise were found by linear regression analysis (airway resistance (Rt): beta = -0.48; p < 0.001) and PaCO2 (FEV1: beta = -0.27; p < 0.05). This study demonstrates that in patients with COPD parameters of lung function and blood gas analysis at rest are already good predictors of gas exchange under exercise conditions. In individual cases, however, prediction may not be possible. This underlines the importance of the exercise test to investigate gas exchange under diagnostic (i.e. dyspnoea, medical opinion) and therapeutic aspects (i.e. therapy control). For COPD patients, the rule of the DGP yielded a poor sensitivity, but an excellent specificity in the diagnosis of emphysema, which yields confirmation of the diagnosis only in conjunction with, and complementary to, other methods.

[Clinical investigation of the action of tramazoline inpatients with chronic obstructive bronchitis. The importance of mucosal swelling]. / Klinische Untersuchungen zur Wirkung von Tramazolin bei Patienten mit chronisch obstruktiver Bronchitis. Ein Beitrag zur Bedeutung der Schleimhaustschwellung.

Swelling of the bronchial mucosa is discussed as part of the increased airways on patients with obstructive bronchitis (OB). The excellent effect of alpha-receptor-stimulants like tramazoline for the deblockage of the nasal mucosa has been previously established experimentally as well as clinically. On 19 patients with OB tramazoline (CAS 74195-73-6) aerosol (Rhinospray) (0.14 (n = 9) resp. 0.19 (n = 10 mg) was administered into the bronchial system. There were no effects seen on airways resistance nor on the intrathoracic gas volume. The important improvement on patients with OB and nasal blockage at the same time seen after tramazoline aerosol given into the nose is caused only by the effect on the nasal mucosa.

Lung function testing: the dilemma of predicted values in relation to the individual variability.

Quantitated lung function parameters are usually interpreted in relation to so-called "normal ranges' obtained from healthy study groups. The aim of this paper is the critical review of formulas and the evaluation of intraindividual variation in modern lung function testing. To which extent is the total variation of lung function parameters in cross-sectional studies (usually serving as basis for the normal range) attributed to the intraindividual variation between repeated measurements? This question raises a further question: are lung function values in the normal range really normal? To assess spirometric and body plethysmographic parameters 26 healthy subjects from three medical centers underwent 30-72 measurements over a period of 2 months for the determination of variations due to (1) intraindividual variation over time and (2) interindividual variation. For each subject, predicted values of different lung function parameters published by Quanjer et al. [Eur Respir J 1993; 6:5-40.1], of intrathoracic gas volume by Ulmer et al. [Die Lungenfunktion; Stuttgart, Thieme, 1991] and of total airway resistance by Ruehle and Matthys [Pneumologie 1976;153:223] were applied. When converted into percent predicted and adjusted for differences in medical centers, the intraindividual standard deviation was estimated to be about half of the interindividual standard deviation. We conclude that the normal range of lung function parameters derived from the standard deviation within populations is too wide for the assessment of individual values. Interpretation of individual lung function measurements should primarily be based on the "individual normal range' derived from former lung function measurements of the individual and only secondly on the "predicted value'.

Effects on the lung function of exposure to carbon black dusts. Results of a study carried out on 677 members of staff of the DEGUSSA factory in Kalscheuren/Germany.

Spirometry, full-bodyplethysmography, and inhalation challenge tests are the most frequently used methods for lung function testing. In all, 677 examinations were performed among exposed employees at the Degussa carbon black plant in Kalscheuren/Germany using the above mentioned methods, in order to detect whether there is a measurable impact of carbon black fine dust on pulmonary function, or a higher prevalence of obstructive air-way diseases among the study candidates, and whether fine dust exposure is related to the prevalence of bronchial hyperresposiveness. Within the smokers' group carbon black dust exposure reveals a (minimal) impact upon the lung function of the study subjects. However, the impact of fine dust exposure within that group is less significant than the influence of smoking on pulmonary function. Nevertheless, smokers are displaying significant more frequently signs of obstructive airway diseases compared with nonsmokers. In the smokers' group we found 7.3% of study subjects with signs of obstructive airway diseases compared with 3.9% in the group of nonsmokers. No significant impact of fine dust exposure on lung function could be detected within former- and nonsmokers. The overall percentage of 5.1% is not higher than that of subjects with bronchial hyperresponsiveness in other comparable studies.

[Responder and non-responder in the bronchodilator test?]. / Responder und Non-Responder im Bronchodilatationstest?

In 15 patients with chronic airflow obstruction 0.2 mg salbutamol was administered to determine reversibility within 15 minutes ("test effect"). Subsequently, maximum 24-hour effects of three beta 2-agonists (fenoterol 0.2 mg, salbutamol 0.2 mg, salmeterol 0.05 mg, each by MDI) were determined in random order ("best effect"). Airways obstruction was measured by FEV1, MEF50, MEF25, airway resistance Raw and thoracic gas volume TGV. "Best effects" were compared with "test effects". As a whole test effects were significantly smaller than best effects, often not reaching a 15% change, normally achieved during the 24-hour observation. Significant correlations existed between FEV1 and the corresponding values of Raw, MEF50 and MEF25, although there were considerable individual differences between test results. The reduction of TGV after a beta 2-agonist was significantly related to TGV-baseline values. We conclude in line with other authors that tests of acute reversibility of airways obstruction cannot reliably differentiate between "responders" and "non-responders" and that such tests may mislead if used for the differentiation of asthma and COPD.

[Effect duration and treatment effectiveness of salmeterol, fenoterol and salbutamol in severe forms of respiratory tract obstruction]. / Wirkdauer und Wirkstärke von Salmeterol, Fenoterol und Salbutamol bei schweren Formen obstruktiver Atemwegserkrankungen.

Duration and intensity of bronchodilator action of 0.2 mg Fenoterol, 0.2 mg Salbutamol, and 0.05 mg Salmeterol were investigated in 15 subjects with COPD over a period of 12 hours. Airway resistance and FEV1 were measured and subjective side effects noted. Salbutamol MDI was used as rescue medication. Airway resistance and FEV1 demonstrated significant bronchodilation with all bronchodilator drugs after 15 min and maximum bronchodilation between 1 and 2 hrs. After 3 to 5 hrs. bronchodilator effects of fenoterol and salbutamol are lost by at least 50%, whereas this effect is only seen after 8 to 9.5 hrs. with salmeterol. There were considerable individual differences of the efficacy of all three drugs. However, salmeterol was equally efficaceous, compared to fenoterol and salbutamol, but its duration was at least twice as long. Consequently, rescue medication was used in only about 50% of the cases. Side effects of all substances were comparable. From these data it may be concluded that the efficacy of beta2-adrenergic agonists is comparable, irrespective of the duration of action of a single administration, if repeated administrations are used with short acting substances. In addition, this study confirmed that in individual patients a) the response to beta2-adrenergic agonists is variable and b) that different lung function parameters such as airway resistance and FEV1 may give different results.

[Dependence of airway resistance and intrathoracic gas volume on airflow and respiratory frequency in health adults]. / Abhängigkeit des Strömungswiderstandes und des intrathorakalen Gasvolumens von der Strömung und der Atemfrequenz bei gesunden Erwachsenen.

With a routine body plethysmograph with computerized calculation of airway resistance (Rt) and intrathoracic gas volume (IGV) on 11 healthy volunteers the correlations between Rt, IGV, breathing frequency (15-120) and flow (1.4-4.2 l/s) were examined. Rt increases significantly with increasing flow. In the range of clinical examinations with increasing frequency in the range between 15 and 30/min the flow increases only for a small amount. The increase of airway resistance in this range is very small. At an increase of the flow from 1 to 2 l/s an increase of Rt of 20% can be expected. An increase of the flow for 300% (1.25-5.0 l/s) is followed by an increase of Rt for 60%. IGV values are not influenced by these different frequencies and flows.

Methacholine-induced histamine liberation during airway challenge tests in Ascaris skin-sensitive sheep.

The interaction of vagal neuronal and pharmacological mediator mechanisms on the airway-constrictory responses obtained from challenges with aerosolized methacholine (MCH) before and after bilateral vagotomy and in combination with electrical stimulation of the peripheral ends of the cut vagal nerves was investigated in anesthetized Ascaris allergen skin-sensitive sheep. Inhalation of aerosols of 2 and 5% MCH for 2 min in a control group of 10 sheep resulted in airway muscle constriction indicated by an increase in dynamic elastance (Edyn) (+70 and +256% of the basic value) or inspiratory airway resistance (RI) (+45 and +155%) and was associated with a significant rise in plasma histamine concentration (HiPl) from 0.2 +/- 0.2 to 0.9 +/- 1.1 and 1.5 +/- 1.2 ng/ml, respectively. Respiratory and cardiovascular responses to MCH were reproducible after 90 min of recovery. A second group of another 6 intact sheep showed similar alterations of respiratory mechanical parameters and HiPl after MCH challenges. After bilateral vagotomy, Edyn and RI increased after 2 and 5% MCH inhalation only by 15-30% of the control responses with intact vagi. The diminished airway constriction was associated with similar changes in HiP1 as observed with intact vagi. Inspite of severe cardiovascular responses, the most effective electrical stimulation of the peripheral ends of the vagal nerves resulted in an increase in Edyn or RI by only 40-50% of the basic value. In a tracheal segment beneath the cuff of the endotracheal tube isometric pressure effectively increased by almost 500% of the basic value. Vagus nerve stimulation was found without detectable changes in HiPl. Stimulation of the central ends of the vagal nerves did not induce airway constriction or alterations in HiPl. The combination of electrical vagus nerve stimulation and MCH inhalation resulted in a more than additive increase in Edyn and RI, but the airway responses did not reach the same level of obstruction after challenge with 5% MCH as observed with intact vagi. Electrical stimulation of the efferent vagi failed to stimulate spontaneous vagal nerve activity at higher levels of airway muscle responses. The results demonstrate that vagal neuronal mechanisms interact with local mediator liberation in acute airway obstruction. Airway challenge tests using cholinergic substances liberate histamine from inflammatory cells in the lungs of Ascaris skin-sensitive sheep.

Pharmacokinetics and pharmacodynamics of beta 2-agonists (in the light of fenoterol).

As an example of beta 2-agonists fenoterol was used in this study on 27 patients with chronic obstructive airways diseases (COAD). After refraining from any kind of bronchodilator during 12 h the patients were given the drug in a crossover design in three groups. Using aerosol inhalation, intravenous route and nasal instillation we measured the response of airway resistance, intrathoracic gas volume and fenoterol plasma concentrations. The plethysmographic measurement of airways resistance (Rt) and intrathoracic gas volume showed comparable results of bronchodilation (at different dosages) for each of the routes. Even the onset of action was nearly the same with all the different routes. The amount of bronchodilatation was in the range of 59% of the initial Rt values. The duration of bronchodilatation was much longer after metered dose inhalers (MDI) inhalation ( > 4 h) than after intravenous routes. The duration after nasal administration was in between. The infusion maintains its effect only as long as the infusion is given. The bronchodilation response induced by fenoterol reaches the same values with different routes of administration and depends on the amount of decrease of airway obstruction. The highest plasma concentrations were reached with the intravenous boluses. Immediately after injection the concentration decreased rapidly. The maximum plasma concentrations after MDI were around 20% of that after the intravenous route for the same bronchodilatation. The heart rate is a function of the plasma concentration. At low concentrations such as after aerosol inhalation of 200 micrograms the influence on the heart rate is not significant. After aerosol inhalation the effect at the receptor can be calculated to be > 7 times stronger than seen from any plasma concentration after intravenous administration. It is assumed that there are structures near the beta 2-bronchodilator receptor which are responsible for the long-lasting effect that is observed only after aerosol inhalation. These depot structures cannot be reached from the plasma in concentrations needed under in vivo conditions. Loss of these structures shortens the duration of the bronchodilator effect. In respect to effect/side effect relationship, more frequent administration of smaller doses may be the best method for administering beta 2-agonists as aerosols in patients with COAD. For many patients with severe forms of this disease, individual optimal dosage with MDI has to be defined following repeated measurements of the airway obstruction so as to achieve the best possible bronchodilatation.

[Diagnostic value of right thoracic ECG recording in detection of pulmonary hypertension in chronic obstructive respiratory disease]. / Diagnostischer Wert rechtsthorakaler EKG-Ableitungen in der Erkennung der pulmonalen Hypertonie bei der chronisch obstruktiven Atemwegserkrankung.

There are many electrocardiographic criteria of pulmonary hypertension and cor pulmonale. These criteria are generally highly specific but not sensitive. Therefore many patients with pulmonary hypertension remain undetected. The aim of this study was to delineate a sensitive as well as a specific ECG parameter for noninvasive prediction of pulmonary hypertension under special consideration of the right thoracic leads. 75 patients were included in this study, 62 male and 13 female, mean age 62.7 +/- 9.5 years. All presented with chronic obstructive lung disease known since 12.1 +/- 9.7 years. The underlying disease had been confirmed clinically and by body plethysmography. Laboratory and lung function data showed a high air way resistance with a mean value of 6.8 +/- 3.3 cm H2O/l/s and a high intrathoracic gas volume of 149.1% of the expected value. The severity of hypoxemia was variable but generally moderate with a PaO2 of 65.3 +/- 11.6 mm Hg on average. All patients applied aerosols with ipratropiumbromid, fenoterol and glucocorticoids. 92% additionally received aminophylline and 87.0% oral glucocorticoids. Diuretics and glycosides were prescribed in 50.0% and 34.8% respectively. The four right thoracic ECG leads Vr3 to Vr6 were recorded in addition to the common twelve leads I to III, a VR, aVL, aVF and V1 to V6. A modified Sokolow-Lyon-Index (SIm) as a sum of amplitudes of R in lead Vr3 and S in lead V6 and the combination of SIm with PaO2 (SIm-PaO2, n = 44) according to the formula SIm + 0.02 (100--PaO2%) were established. Additionally a right heart catherization by Swan-Ganz technique was performed. The mean values of hemodynamic data demonstrated a constellation of precapillary pulmonary hypertension with high PAPm and pulmonary resistance and low pulmonary capillary wedge pressure (26.4 +/- 12.9 mm Hg, 396.0 +/- 294.0 dyn.s./cm5 and 8.7 +/- 4.2 mm Hg, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

[Nonspecific inhalative provocation in the sheep as an asthma model--correlation of respiratory and cardiovascular effects]. / Unspezifische inhalative Provokation am Schaf als ein Asthmamodell--Korrelation respiratorischer und kardiovaskulärer Wirkungen.

Respiratory responses after inhalative challenge tests using methacholine (MCH) are intensively investigated and described in the literature. There is however a considerable lack of knowledge about the correlation of bronchoconstrictory responses to cardiovascular changes like pulmonary arterial pressure or blood gas tensions after unspecific challenges with methacholine or with specific allergens. Ten yearling sheep inhaled MCH-aerosols in increasing concentrations of 0.5, 1.0, 2.0, 5.0 and 10% for one minute respectively in 15 minutes intervals. Airway resistance (RI), dynamic elastance (Edyn) were measured along with systemic and pulmonary artery pressure. Transcutaneously measured oxygen partial pressure (PtcO2) was recorded and correlated to arterial blood gas samples. Mean threshold concentrations of MCH for changes in RI and Edyn were found at 0.9% and for PC100 of 2.2% MCH. Bronchoconstriction was detected with a latency of 30-40 s. Maximum responses occurred after 2-5 min (p < 0.0005) after onset of the challenge. Within 15 minutes, baseline values were almost reached. While mean inspiratory air-flow remained almost unaltered, increased airway resistance and work of breathing was compensated by an increased transpulmonary pressure. A decrease in tidal volume and a rise in respiratory frequency left ventilation almost unaltered. MCH-challenge results in insignificant changes in systemic arterial pressure, while pulmonary arterial pressure increased by more than 50% of the basic value. Arterial PO2 decreased by more than 20 mmHg and was closely correlated to transcutaneously measured O2-pressure (e = 0.93). However, PaCO2 did not increase significantly. (ABSTRACT TRUNCATED AT 250 WORDS)

[Bronchial hyperreactivity and obstructive respiratory tract diseases. A 2.8 year follow-up study]. / Bronchiale Hyperreagibilität und obstruktive Atemwegserkrankungen. Eine Verlaufsuntersuchung über 2,8 Jahre.

BACKGROUND: Nonspecific bronchial hyperreactivity (BHR) is under discussion as a possible risk factor for the development of chronic obstructive pulmonary disease. METHOD: Within the framework of a prospective study, we investigated the course of the disease in 50 inpatients with BHR, and the clinical symptoms of airways disease (coughing, dyspnea and expectoration) with no manifest airways obstruction at rest (Rt < 3.5 cm H2O/l/s) on admission to the hospital. The unspecific inhalative provocation challenge was carried out with metacholine. The presence of BHR was assumed when the resting respiratory resistance (Rt) of < 3.5 cm H2O/l/s increased to more than 6 cm H2O/l/s. On admission to hospital, all the patients were treated with inhalative bronchodilators and glucocorticosteroids. RESULTS: After an average period of 2.8 years, BHR was no longer measurable in only 7 of the patients (14%), while 28 patients (56%) continued to have a BHR with clinical symptomatology presenting. In 15 patients (30%), manifest airways obstruction at rest, with an average Rt of 6.4 cm H2O/l/s developed. In patients with an uncharacteristic cough, dyspnea and unremarkable lung function parameters at rest, a provocation test should be done to identify BHR. A prognosis can, however, not be established on the basis of a single demonstration of BHR, but only after observation over a longer period.

[Whole body plethysmography for determining intrathoracic gas volume]. / Ganzkörperplethysmographische Messung des intrathorakalen Gasvolumens.

For early diagnosis of lung diseases the plethysmographic measurement of IGV is important. The influences of gases in the abdomen as the influences of pressure swings between mouth and alveolar space were several times investigated and did not show clinical relevance. The position of the mouthpiece in relation to the measured person should be taken carefully into consideration. We compared for the measurement of the occlusion-angel, which allows the calculation of the IGV, the panting- with the breathing going-on method. On 42 persons there were no significant differences between the results (o different laboratories: painting--breathing going-on = 2.8 resp. -0.6%). We prepare the breathing going-on method because it seems better that the person does not change his breathing level what could happen during the otherwise necessary instruction of the person.

[Lung function and normal values]. / Lungenfunktion und die Normwerte.

Interindividual derived predicted values of lung function are not suitable for detection of early changes of lung function. Intraindividual values show variability, which should be considered. Many of the very common obstructive lung diseases start with small variations of the individual values of lung function, long time before clinical manifestation takes place. Followup of the most useful measurements (FEV1, MEF 50%, Rt und IGV%) show reliable early changes, important for preventive therapeutic intervention. Strong variability of the individual values argue for hyperreagibility of the airways, even as a risk factor for manifestation of obstructive airway diseases.