Influence of secular trends and sample size on reference equations for lung function tests.

The aim of our study was to determine the contribution of secular trends and sample size to lung function reference equations, and establish the number of local subjects required to validate published reference values. 30 spirometry datasets collected between 1978 and 2009 provided data on healthy, white subjects: 19,291 males and 23,741 females aged 2.5-95 yrs. The best fit for forced expiratory volume in 1 s (FEV(1)), forced vital capacity (FVC) and FEV(1)/FVC as functions of age, height and sex were derived from the entire dataset using GAMLSS. Mean z-scores were calculated for individual datasets to determine inter-centre differences. This was repeated by subdividing one large dataset (3,683 males and 4,759 females) into 36 smaller subsets (comprising 18-227 individuals) to preclude differences due to population/technique. No secular trends were observed and differences between datasets comprising >1,000 subjects were small (maximum difference in FEV(1) and FVC from overall mean: 0.30- -0.22 z-scores). Subdividing one large dataset into smaller subsets reproduced the above sample size-related differences and revealed that at least 150 males and 150 females would be necessary to validate reference values to avoid spurious differences due to sampling error. Use of local controls to validate reference equations will rarely be practical due to the numbers required. Reference equations derived from large or collated datasets are recommended.

Impaired lung compliance and DL,CO but no restrictive ventilatory defect in sarcoidosis.

Sarcoidosis is a systemic granulomatous disease with predominant manifestation in the lungs, often presenting as interstitial lung disease. Pulmonary function abnormalities in sarcoidosis include restriction of lung volumes, reduction in diffusing capacity of the lung for carbon monoxide (D(L,CO)), reduced static lung compliance (C(L,s)) and airway obstruction. The aim of the present study was to assess various lung function indices, including C(L,s) and D(L,CO), as markers of functional abnormality in sarcoidosis patients. Results from 830 consecutive patients referred for lung function tests with a diagnosis of sarcoidosis (223 in stage I, 486 in stage II and 121 in stage III) were retreospectively analysed. The mean ± sd age of the patients was 40 ± 11 yrs; 18% were active smokers and 24% were former smokers. Normal total lung capacity was found in 772 (93%) patients. Of these cases, 24.5% had a low C(L,s) and 21.5% had a low D(L,CO). At least one abnormality was observed in 39.3% of these patients, whereas, in restrictive patients, this figure was 88%. Airway obstruction was present in 11.7% of cases. Lung volumes usually remain within the normal range and measurement of either C(L,s) or D(L,CO) often reveal impaired lung function in sarcoidosis patients, even when their lung volumes are still in the normal range; these two measurements provide complementary information.

Changes in the FEV1/FVC ratio during childhood and adolescence: an intercontinental study.

In children, the ratio of forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) is reportedly constant or falls linearly with age, whereas the ratio of residual volume (RV) to total lung capacity (TLC) remains constant. This seems counter-intuitive given the changes in airway properties, body proportions, thoracic shape and respiratory muscle function that occur during growth. The age dependence of lung volumes, FEV1/FVC and RV/TLC were studied in children worldwide. Spirometric data were available for 22,412 healthy youths (51.4% male) aged 4-20 yrs from 15 centres, and RV and TLC data for 2,253 youths (56.7% male) from four centres; three sets included sitting height (SH). Data were fitted as a function of age, height and SH. In childhood, FVC outgrows TLC and FEV1, leading to falls in FEV1/FVC and RV/TLC; these trends are reversed in adolescence. Taking into account SH materially reduces differences in pulmonary function within and between ethnic groups. The highest FEV1/FVC ratios occur in those shortest for their age. When interpreting lung function test results, the changing pattern in FEV1/FVC and RV/TLC should be considered. Prediction equations for children and adolescents should take into account sex, height, age, ethnic group, and, ideally, also SH.

Pulmonary function and exercise capacity in survivors of congenital diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) is associated with pulmonary hypoplasia and pulmonary hypertension. The objective of this study was to assess pulmonary function and exercise capacity and its early determinants in children and adolescents born with high-risk CDH (CDH-associated respiratory distress within the first 24 h) and to explore the relationship of these findings with CDH severity. Of 159 patients born with high-risk CDH, 84 survived. Of the 69 eligible patients, 53 children (mean+/-SD age 11.9+/-3.5 yrs) underwent spirometry, lung volume measurements and maximal cardiopulmonary exercise testing (CPET). Results of the pulmonary function tests were compared with those from a healthy control group matched for sex, age and height. CDH survivors had a significantly lower forced expiratory volume in 1 s (FEV(1)), forced vital capacity (FVC), FEV(1)/FVC, maximum mid-expiratory flow and peak expiratory flow when compared with healthy controls. The residual volume/total lung capacity ratio was significantly higher. Linear regression analysis showed that gastro-oesophageal reflux disease was an independent determinant of reduced FEV(1) and FVC. CPET results were normal in those tested. High-risk CDH survivors have mild to moderate pulmonary function abnormalities when compared with a healthy matched control group, which may be related to gastro-oesophageal reflux disease in early life. Exercise capacity and gas exchange parameters were normal in those tested, indicating that the majority of patients do not have physical impairment.

Using the lower limit of normal for the FEV1/FVC ratio reduces the misclassification of airway obstruction.

AIM: The prevalence of airway obstruction varies widely with the definition used. OBJECTIVES: To study differences in the prevalence of airway obstruction when applying four international guidelines to three population samples using four regression equations. METHODS: We collected predicted values for forced expiratory volume in 1 s/forced vital capacity (FEV(1)/FVC) and its lower limit of normal (LLN) from the literature. FEV(1)/FVC from 40 646 adults (including 13 136 asymptomatic never smokers) aged 17-90+years were available from American, English and Dutch population based surveys. The prevalence of airway obstruction was determined by the LLN for FEV(1)/FVC, and by using the Global Initiative for Chronic Obstructive Lung Disease (GOLD), American Thoracic Society/European Respiratory Society (ATS/ERS) or British Thoracic Society (BTS) guidelines, initially in the healthy subgroup and then in the entire population. RESULTS: The LLN for FEV(1)/FVC varied between prediction equations (57 available for men and 55 for women), and demonstrated marked negative age dependency. Median age at which the LLN fell below 0.70 in healthy subjects was 42 and 48 years in men and women, respectively. When applying the reference equations (Health Survey for England 1995-1996, National Health and Nutrition Examination Survey (NHANES) III, European Community for Coal and Steel (ECCS)/ERS and a Dutch population study) to the selected population samples, the prevalence of airway obstruction in healthy never smokers aged over 60 years varied for each guideline: 17-45% of men and 7-26% of women for GOLD; 0-18% of men and 0-16% of women for ATS/ERS; and 0-9% of men and 0-11% of women for BTS. GOLD guidelines caused false positive rates of up to 60% when applied to entire populations. CONCLUSIONS: Airway obstruction should be defined by FEV(1)/FVC and FEV(1) being below the LLN using appropriate reference equations.

[Comments on screening spirometry for detection of COPD]. / Kanttekeningen bij screenend longfunctieonderzoek voor detectie van COPD.

World COPD day is an annual event intended to increase awareness of chronic obstructive pulmonary disease. During this day, in November 2006, free spirometry testing was offered to the public in approximately 100 places including hospitals, pharmacies, offices of GPs and tents on main squares throughout the Netherlands. The objective of this action is laudable. However, screening for COPD is generally considered ineffective. Furthermore, the application of a fixed ratio of forced expiratory volume in one second (FEV1) to forced vital capacity (FVC) (FEV1/FVC < 0.70) as recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) to detect airflow limitation, required for a diagnosis of COPD, may lead to underdiagnosis of COPD in the young and to overdiagnosis in the elderly. In addition, spirometry was generally performed without bronchodilation, thus further increasing the likelihood of a false-positive diagnosis ofCOPD. Smoking cessation is important in halting the progression of COPD. Therefore, identifying smokers at risk for developing COPD seems a logical reason for screening or case finding for COPD. However, it has not been clearly demonstrated that early detection of COPD may contribute to improved smoking cessation rates. Also, smokers with normal spirometry may be led to believe that smoking has no adverse effects on their health. Therefore, a different strategy should be adopted to increase awareness of COPD on the next World COPD day.

Long-term effect of inhaled corticosteroids on growth rate in adolescents with asthma.

BACKGROUND: Growth in stature in asthmatic adolescents may be delayed compared to normals as a result of treatment with inhaled corticosteroids (CS) or because of a delay in puberty. However, growth rates in asthmatic children have never been studied when treatment with CS was randomized and when growth was compared with that of matched healthy control subjects. OBJECTIVE: To assess the long-term effect of CS treatment on growth rates in asthmatic adolescents. METHODS: Participants were 40 asthmatic teenagers (mean age 12.8 years) who received randomized treatment with 0.2 mg of albuterol (salbutamol) with either placebo three times a day (BA + PL) or 0.2 mg of budesonide three times a day (BA + CS) for a median period of 22 months in a double-blind controlled study. Growth rates were compared with those of 80 control subjects who were matched for sex, age, height, and duration of follow-up. RESULTS: Growth rates in male patients, but not in female patients, were significantly less than in control subjects (P < .05), a finding consistent with a delay of puberty due to asthma. The mean difference (95% confidence interval) in growth rates between patients treated with BA+PL and their controls was -0.70 (-1.62, 0.22) cm/y; that between patients treated with BA + CS and their controls was -0.44 (-1.25, 0.37) cm/y. The observed mean (SEM) case-control difference between treatment groups was +0.27 (0.58) cm/y in favor of BA + CS. CONCLUSION: Growth retardation observed in adolescents with asthma may be due to a delay in puberty but not to the prescription of 0.6 mg of budesonide daily.

Pulmonary function and postoperative complications after wedge and flap reconstructions of the main bronchus.

Between 1980 and 1989, 8 wedge and 17 flap main bronchoplasties were done in 24 patients (4 carcinoid tumors, 4 benign lesions, 17 carcinomas). Bronchial anastomotic stenoses, pulmonary function, and survival were evaluated. Preoperative ventilation/perfusion scans with preoperative and postoperative spirometry were done in all patients except two who underwent a wedge bronchoplasty. Postoperative bronchoscopy was done in all patients. Follow-up was complete for the patients with carcinoma (N = 17). In the wedge group bronchial anastomotic stenoses occurred in three (38%) of eight patients. All three patients had serious postoperative complications (persistent atelectasis in one, prolonged ventilatory support in two); one patient died and the other two had impaired postoperative pulmonary function. Complete function recovery occurred in only three (38%) of eight patients who underwent wedge bronchoplasty. In the flap group, bronchostenosis occurred in 3 (18%) of 17 patients. The associated complications (mucus retention, minor atelectasis, partial lobar torsion) were mild. Complete pulmonary function recovery occurred in 13 (76%) of 17 patients who had flap bronchoplasty. Actuarial survival, for the patients with carcinoma, was 88%, 47%, and 41% after 1, 3, and 5 years, respectively. The local recurrence rate was 25% (4/16). In our series, flap main bronchoplasties were effective for the resection of bronchial tumors with local involvement of the adjacent main bronchus. Wedge main bronchoplasties, however, were associated with substantial postoperative complications.

Water-sealed spirometer for measurements in newborns and infants.

Details are given of two spirometers for use in neonates and infants < 12 mo old. The minimum volumes are 520 and 670 ml, respectively. The maximum volume changes that can be recorded are 250 and 450 ml, respectively. The minimal detectable volume changes are 0.4 and 0.6 ml, respectively. Rebreathing of dead space gas is prevented by a fan producing a flow of 6.2 and 10.2 l/min, respectively; 100% gas mixing after injecting a gas bolus in the two spirometers is achieved in 5.7 and 6.6 s, respectively. Resistance to airflow is 0.2 kPa.l-1.s (2 cmH2O.l-1.s) at 150 ml/s in both spirometers. The frequency response of both instruments is flat to 6 cycles/s. The instruments can be easily cleaned and are suitable for bedside measurements.

Strength of the Breuer-Hering inflation reflex in term and preterm infants.

The effect of the presence of the respiratory distress syndrome (RDS) or related factors (static compliance of the respiratory system and transcutaneous blood gases) and gestational age on the strength of the Breuer-Hering inflation reflex (BHIR) was studied in three groups of infants. Twenty-six ventilated preterm infants with and without RDS were studied 6 h after birth (group 1). In 24 preterm infants, we followed the development of reflex strength during the first year of life (group 2). Twenty-one healthy nonintubated term infants were studied within the first week of life (group 3). The BHIR was initiated by end-inspiratory occlusions, and the strength was characterized by the ratio of expiratory time after and without preceding airway occlusion. The static compliance of the respiratory system in ventilated infants was assessed by the multiple-occlusion technique. In group 1, reflex strength declined with increasing gestational age; in the presence of RDS or low respiratory compliance, the decline was less. Transcutaneous blood gases did not affect reflex strength. At term age, reflex strength was similar in spontaneously breathing preterm (group 2) and term infants (group 3). The BHIR decreased in strength during the first year after preterm birth. We conclude that 1) the strength of the BHIR decreases with increasing gestational and postnatal ages and 2) RDS, due to changes in respiratory system mechanics, causes an increase in reflex strength.

Growth of airways and air spaces in teenagers is related to sex but not to symptoms.

To determine growth patterns of the lung and airways in adolescents, we analyzed maximal expiratory flow-volume curves, closing capacity, and residual volume. They were obtained every 6 mo for up to 7 yr in 430 boys and 125 girls (11-19 yr), of whom 143 boys and 36 girls were classified as symptomatic; symptoms were most often minor and limited to childhood. Development of flows vs. volumes was used to investigate growth of the airways relative to lung size. A model of isotropic growth of the airways and air spaces (J. Appl. Physiol. 65: 822-828, 1988) was modified for increasing elastic recoil pressure with growth. Growth of airways relative to volume occurred faster in teenage boys than in teenage girls and was compatible with isotropic growth in 92% of asymptomatic boys and in 44% of asymptomatic girls: dysanaptic growth in teenage girls seems to be a normal phenomenon and not a unique characteristic of symptomatic subjects. Subjects with respiratory symptoms in childhood and/or adolescence have lower flows for a given lung size and airway closure at a greater lung volume when they enter adulthood. However, no difference in patterns of lung growth was observed in association with the presence of respiratory symptoms.

Respiratory system compliance assessed by the multiple occlusion and weighted spirometer method in non-intubated healthy newborns.

In 28 healthy newborn infants (median age 3.5 days), we compared the weighted spirometer (WS) with the multiple occlusion (MO) method for measuring respiratory system compliance (Crs). The MO method was unsuccessful in 8 infants. On average the two methods gave comparable results for compliance (Crs,ws = 40.4 +/- 13.8 and Crs,MO = 45.2 +/- 10.4 mL.kPa-1) in the remaining 20 infants; however, within-individual differences were often considerable, so that the methods did not give interchangeable results. Individual pressure-volume curves almost always intercepted the volume axis below the functional residual capacity with the MO technique, compatible with dynamic elevation of end-expiratory lung volume (EEL) due to inspiratory muscle activity during expiration. A (small) negative volume intercept occurred in less than 50% of curves with the WS method; in these cases it probably reflects alinearity of the compliance curve, an alteration in laryngeal braking or in respiratory muscle control of EEL, or all of these. Both methods provide valuable means for the non-invasive determination of respiratory system compliance in newborn infants, the differences in Crs being small and of minimal physiological significance; however, for individual follow-up they should not be used interchangeably.

Spirometric reference values for white European children and adolescents: Polgar revisited.

We analyzed six spirometric data sets collected in the Netherlands, Austria, the United Kingdom, Spain, and Italy. The objectives were to establish whether (1) it was possible to describe spirometric indices from childhood to adulthood, taking into account the adolescent growth spurt, and (2) there are systematic differences in ventilatory function between children and adolescents in different parts of Western Europe. The study comprised 2,269 girls and 3,592 boys, aged 6-21 years. The range in standing height was 110-185 in girls, 110-205 in boys. The model applicable to all data sets was ln FVC or ln FEV1 = a + (b + c x A) x H, where H = standing height and A = age; this model prevents the phase shift between the adolescent growth spurt in length and lung volume from leading to an age-dependent bias in predicted values. There was surprising agreement between most of the data sets; systematic differences are probably due to technical factors arising from ATPS-BTPS corrections and from defining the end of breath with pneumotachometer systems. Taking those into account, prediction equations for FVC, FEV1, and FEV1%FVC were developed with "lower limits of normal" which should be applicable to children and adolescents of European descent. It is proposed that the approach of analyzing available data sets should also be applied to other ventilatory indices, data collected in adults and elderly subjects, or in other ethnic groups, and that an international data base be set up to that end.

Biochemical lung maturity, static respiratory compliance, and pulmonary gas transfer in intubated preterm infants with and without respiratory distress syndrome.

We investigated the relationship between tests of biochemical lung maturity [lecithin/sphingomyelin ratio (L/S ratio)], static compliance of the respiratory system (Crs), and estimates of pulmonary gas transfer [venous admixture and arterial/alveolar (a/A) ratio] in a group of intubated preterm infants with and without respiratory distress syndrome (RDS). Thirty infants were studied once (n = 26) or twice (n = 4). The L/S ratio was obtained by means of high-performance thin-layer chromatography and determination of the phosphorus content. Crs was obtained by the multiple occlusion technique. Transcutaneous blood gases and the percentage of oxygen in the inspired gas were recorded and estimates of pulmonary gas transfer were calculated using algorithms. L/S ratio and Crs correlated well (r = 0.73), indicating a higher compliance in biochemically more mature lungs. Both the a/A ratio and venous admixture correlated significantly with the L/S ratio and Crs (P < 0.001). Crs, L/S ratio, and a/A ratio decreased with increasing severity of radiological RDS, and the percentage venous admixture increased (P < 0.001). Sequential measurements in four infants during the acute phase and after RDS resolved indicated that clinical improvement coincided with improvements in biochemical lung maturity, Crs, and estimates of pulmonary gas transfer.

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.

Lung function and perfusion after bronchial and pulmonary arterial sleeve resection.

Between January 1985 and December 1991, six patients underwent arterial and bronchial sleeve resections of the left upper lobe. Preoperative and postoperative spirometry, preoperative split pulmonary radionuclide ventilation/perfusion (V/Q) scans and postoperative bronchoscopy were obtained in four patients. Postoperative serial digital vascular images (DVI) of the pulmonary artery were obtained in three patients and one patient had a postoperative V/Q scan. For each patient the preoperative and postoperative forced expiratory volume in is (FEV1) were determined to assess the postoperative ventilatory recovery. At bronchoscopy all patients had a patent bronchial anastomosis. At postoperative DVI, in three patients, vascularization of the residual left lung was delayed and less intense compared with the non-operated right lung. Postoperative V/Q scan, in one patient, showed reduced ventilation and perfusion of the residual lung. Preoperative and postoperative FEV1 of the four patients were 2688/1998 ml, 2154/1752 ml, 2618/2100 ml and 2277/2015 ml. Operative mortality was zero. One patient had a postoperative atelectasis of the left lower lobe. In our series, ventilation and vascularization of the reimplanted and revascularized left lower lobe were reduced. But, in our opinion, the preserved residual lung parenchyma was still a relevant advantage.

Determination of diffusing capacity by modeling the dynamics of C18O uptake in newborns.

Dynamic modeling of lung C18O diffusion is used to measure the C18O transfer factor (TLCO) of 14 newborns aged 1-4 mo. The model equation is based on the alveolar fractions of C18O and on changing alveolar ventilation induced by the rebreathing conditions. The model does not involve the volume of the rebreathing bag which is usually needed when applying rebreathing technique and which is a source of error. The equation is discretized and solved for recorded data obtained with equipment adapted to use in newborns. A least-square parameter calculation technique is applied to estimate TLCO. Results show a strong relationship between this index and the biometrical ones and confirm those found in the literature featuring that the measurement duration can be considerably shortened.

Validity of the forced rebreathing method in the measurement of residual volume in patients with airflow limitation.

The validity of the forced rebreathing method (FRM) in the measurement of residual volume (RVn) was assessed in two groups (28 and 12) of patients with significant airflow limitation. The mean FEV1% FVC% were 48.28%, SD = 8.91% and 54.3%, SD = 0.23% respectively. Patients performed at least 30 forced rebreathings into a bag and bottle system at about 28 breaths per minute. RVn per breath was regressed on breath and gas dilution was considered complete at the breath number where the regression line deviated from the nitrogen washout curve. Residual volume computed four breaths after the breath number where the regression line deviated from the curve were compared with results derived from helium dilution (RVHe), mouth (RVmo) and oesophageal (RVOeS) pressure changes in the body plethysmograph. The mean RVn was similar to RVHe (P > 0.98) and correlated well with RVHe (r = 0.908, P < 0.001). RVn and RVHe were significantly smaller than RVmo and RVoes (P < 0.001). The difference between RVn and RVmo was smaller than the difference with RVoes. RVmo was larger than RVoes (P < 0.001) and correlated well with RVoes (r = 0.939, P < 0.001). It is concluded that the FRM can be used with reasonable accuracy to measure residual volume in patients with airflow limitation, and has advantages over the plethysmographic and conventional helium dilution methods.