Novel methodology to perform sulfur hexafluoride (SF6)-based multiple-breath wash-in and washout in infants using current commercially available equipment.

Multiple-breath inert gas washout (MBW) is ideally suited for early detection and monitoring of serious lung disease, such as cystic fibrosis, in infants and young children. Validated commercial options for the MBW technique are limited, and suitability of nitrogen (N2)-based MBW is of concern given the detrimental effect of exposure to pure O2 on infant breathing pattern. We propose novel methodology using commercially available N2 MBW equipment to facilitate 4% sulfur hexafluoride (SF6) multiple-breath inert gas wash-in and washout suitable for the infant age range. CO2, O2, and sidestream molar mass sensor signals were used to accurately calculate SF6 concentrations. An improved dynamic method for synchronization of gas and respiratory flow was developed to take into account variations in sidestream sample flow during MBW measurement. In vitro validation of triplicate functional residual capacity (FRC) assessments was undertaken under dry ambient conditions using lung models ranging from 90 to 267 ml, with tidal volumes of 28-79 ml, and respiratory rates 20-60 per minute. The relative mean (SD, 95% confidence interval) error of triplicate FRC determinations by washout was -0.26 (1.84, -3.86 to +3.35)% and by wash-in was 0.57 (2.66, -4.66 to +5.79)%. The standard deviations [mean (SD)] of percentage error among FRC triplicates were 1.40 (1.14) and 1.38 (1.32) for washout and wash-in, respectively. The novel methodology presented achieved FRC accuracy as outlined by current MBW consensus recommendations (95% of measurements within 5% accuracy). Further clinical evaluation is required, but this new technique, using existing commercially available equipment, has exciting potential for research and clinical use.

Asthma phenotypes and lung function up to 16 years of age-the BAMSE cohort.

BACKGROUND: Asthma is a disease affecting many locations throughout the airway. Most studies have used spirometry as the primary assessment of airway obstruction, a method that may be less sensitive in regard to peripheral airway obstruction. The aim of this study was to elucidate the associations between asthma phenotypes based on age of onset and duration of symptoms, and (i) spirometry and (ii) small airway involvement measured by impulse oscillometry (IOS) in adolescence. METHODS: Children and adolescents taking part in BAMSE, a prospective birth cohort study, performed spirometry at 8 and 16 years and IOS at 16 years of age. Based on data collected in questionnaires, children were categorized into the following groups: 'never asthma', 'early transient asthma', 'early persistent asthma', and 'late onset asthma'. RESULTS: Compared with the never asthma group, all asthma groups were associated with lower FEV1 at 16 years of age (early transient-119 ml, 95% confidence interval -204 to -34; early persistent-410 ml, 95%CI -533; -287; and late onset-148 ml, 95%CI -237; -58). Between 8 and 16 years, significantly less increase in FEV1 was observed in the early persistent and late onset groups. The small airway index 'R5-20 ' was significantly associated with active asthma at 16 years, but not transient asthma. CONCLUSIONS: All asthma phenotypes studied were negatively associated with FEV1 in adolescence. IOS measurements indicated that active asthma could be associated with small airway impairments. These results provide new insights into the physiology underlying wheezing phenotypes based on age of onset and duration of disease.

Slow and fast lung compartments in cystic fibrosis measured by nitrogen multiple-breath washout.

Imaging studies describe significant ventilation defects across a wide range of cystic fibrosis (CF) related lung disease severity. These are unfortunately poorly reflected by phase III slope analysis-derived Scond and Sacin from multiple-breath washout (MBW). Methodology extending previous two-lung compartment model-based analysis is presented describing size and function of fast- and slow-ventilating lung compartments from nitrogen (N2) MBW and correlation to obstructive lung disease severity. In 37 CF subjects (forced expiratory volume in 1 s [FEV1] mean [SD] 84.8 [19.9] % predicted; abnormal lung clearance index [LCI] in 36/37, range 7.28-18.9) and 74 matched healthy controls, volume and specific ventilation of both fast and slowly ventilated lung compartments were derived from N2-based MBW with commercial equipment. In healthy controls lung emptying was characterized by a large compartment constituting 75.6 (8.4)% of functional residual capacity (FRC) with a specific ventilation (regional alveolar tidal volume/regional lung volume) of 13.9 (3.7)% and a small compartment with high specific ventilation (48.4 [15.7]%). In CF the slowly ventilated lung compartment constituted 51.9(9.1)% of FRC, with low specific ventilation of 5.3 (2.4)%. Specific ventilation of the slowly ventilated lung compartment showed stronger correlation with LCI (r2 = 0.70, P < 0.001) vs. Sacin (r2 = 0.44, P < 0.001) or Scond (no significant correlation). Overventilation of the fast lung compartment was no longer seen in severe CF lung disease. Magnitude and function of under- and overventilated lung volumes can be derived from routine N2 MBW in CF. Reported values agree with previous modelling-derived estimates of impaired ventilation and offer improved correlation to disease severity, compared with SnIII analysis.

Lung clearance index is a sensitive, repeatable and practical measure of airways disease in adults with cystic fibrosis.

BACKGROUND: Lung clearance index (LCI) is a sensitive marker of early lung disease in children but has not been assessed in adults. Measurement is hindered by the complexity of the equipment required. The aims of this study were to assess performance of a novel gas analyser (Innocor) and to use it as a clinical tool for the measurement of LCI in cystic fibrosis (CF). METHODS: LCI was measured in 48 healthy adults, 12 healthy school-age children and 33 adults with CF by performing an inert gas washout from 0.2% sulfur hexafluoride (SF6). SF6 signal:noise ratio and 10-90% rise time of Innocor were compared with a mass spectrometer used in similar studies in children. RESULTS: Compared with the mass spectrometer, Innocor had a superior signal:noise ratio but a slower rise time (150 ms vs 60 ms) which may limit its use in very young children. Mean (SD) LCI in healthy adults was significantly different from that in patients with CF: 6.7 (0.4) vs 13.1 (3.8), p<0.001. Ten of the patients with CF had forced expiratory volume in 1 s > or = 80% predicted but only one had a normal LCI. LCI repeats were reproducible in all three groups of subjects (mean intra-visit coefficient of variation ranged from 3.6% to 5.4%). CONCLUSIONS: Innocor can be adapted to measure LCI and affords a simpler alternative to a mass spectrometer. LCI is raised in adults with CF with normal spirometry, and may prove to be a more sensitive marker of the effects of treatment in this group.

Multiple-breath inert gas washout and spirometry versus structural lung disease in cystic fibrosis.

BACKGROUND: A sensitive and valid non-invasive marker of early cystic fibrosis (CF) lung disease is sought. The lung clearance index (LCI) from multiple-breath washout (MBW) is known to detect abnormal lung function more readily than spirometry in children and teenagers with CF, but its relationship to structural lung abnormalities is unknown. A study was undertaken to determine the agreements between LCI and spirometry, respectively, with structural lung disease as measured by high-resolution computed tomography (HRCT) in children and teenagers with CF. METHODS: A retrospective study was performed in 44 consecutive patients with CF aged 5-19 years (mean 12 years). At an annual check-up inspiratory and expiratory HRCT scans, LCI and spirometric parameters (forced expiratory volume in 1 s (FEV1) and maximal expiratory flow when 75% of forced vital capacity was expired (FEF75)) were recorded. Abnormal structure was defined as a composite HRCT score of >5%, the presence of bronchiectasis or air trapping >30%. Abnormal lung function was defined as LCI above the predicted mean +1.96 residual standard deviations (RSD), or FEV1 or FEF75 below the predicted mean -1.96 RSD. Sensitivity/specificity assessments and correlation analyses were done. RESULTS: The sensitivity to detect abnormal lung structure was 85-94% for LCI, 19-26% for FEV1 and 62-75% for FEF75. Specificity was 43-65% for LCI, 89-100% for FEV1 and 75-88% for FEF75. LCI correlated better with HRCT scores (Rs +0.85) than FEV1 (-0.62) or FEF75 (-0.66). CONCLUSIONS: LCI is a more sensitive indicator than FEV1 or FEF75 for detecting structural lung disease in CF, and a normal LCI almost excludes HRCT abnormalities. The finding of an abnormal LCI in some patients with normal HRCT scans suggests that LCI may be even more sensitive than HRCT scanning for detecting lung involvement in CF.

Poor asthma control in children: evidence from epidemiological surveys and implications for clinical practice.

The objectives of this study is to compile current knowledge about asthma control in children in relation to goals proposed in international guidelines, to elucidate the factors associated with insufficient asthma control and to address the implications for clinical practice. Review of recent worldwide large population epidemiological surveys and clinical asthma studies of more than 20,000 children are the methods used in this study. The studies report high frequencies of sleep disturbances, emergency visits, school absence and limitations of physical activity due to asthma. Only a small percentage of children with asthma reach the goals of good asthma control set out by Global Initiative for Asthma (GINA). There is evidence of underuse of inhaled corticosteroids even in children with moderate or severe persistent asthma and over-reliance on short-acting beta(2)-agonist rescue medication. Both parents and physicians generally overestimate asthma control and have low expectations about the level of achievable control. Many children with asthma are not being managed in accordance with guideline recommendations, and asthma management practices vary widely between countries. Asthma control falls short of guideline recommendations in large proportions of children with asthma worldwide. Simple methods for assessing asthma control in clinical practice are needed. Treatment goals based on raised expectations should be established in partnership with the asthmatic child and the parents. Effective anti-inflammatory treatment should be used more frequently, and patients should be reviewed regularly.

Evaluation of ventilation maldistribution as an early indicator of lung disease in children with cystic fibrosis.

Many children with cystic fibrosis (CF), receiving modern, aggressive CF care, have normal spirometry results. This study aimed to see if homogeneity of ventilation distribution is impaired early in the course of CF lung disease, and if ventilation inhomogeneity is a more frequent finding than abnormal spirometry in children benefiting from modern CF care. The study compared spirometry findings to two indices of ventilation inhomogeneity (mixing ratio (MR) and lung clearance index (LCI)) from multiple-breath inert gas washout in 43 children with CF, aged 3-18 yrs, and 28 healthy children. In total, 10/43 CF subjects (23%) had reduced forced expiratory volume in one second (FEV1) and 14/34 (41%) showed abnormal maximum expiratory flow at 25% of forced vital capacity (MEF25). In contrast, MR was abnormal in 31/43 (72%) and LCI in 27/43 (63%). MR was abnormal in 22/33 CF subjects with normal FEV1, versus 0/28 controls (p<0.001), and abnormal MR was found in 10/20 CF subjects with normal MEF25, versus 0/22 controls (p<0.001). Nine of the 10 CF subjects with reduced FEV1 and 12/14 with abnormal MEF25 showed abnormal MR. Inert gas washout discloses airway dysfunction in the majority of children with cystic fibrosis with normal lung function judged by spirometry. These findings suggest that multiple-breath inert gas washout is of greater value than spirometry in detecting early cystic fibrosis lung disease.

Peripheral airway involvement in asthma assessed by single-breath SF6 and He washout.

The aim of the study was to assess how deep into the acinar region the airway response to cold dry-air hyperventilation challenge (CACh) reaches in subjects with asthma of different severity. Peripheral airway function was measured using a single-breath sulphur hexafluoride (SF6) and helium (He) washout test and overall airway function by forced expiratory volume in one second (FEV1) at rest, after CACh and beta2-therapy in 55 adults with a history of asthma. The normalised phase-III slopes (SnIII) for SF6 and He were used to assess peripheral airway obstruction and the (SF6-He) SnIII difference to indicate where obstruction occurred. While a greater He versus SF6 slope increase indicates a response close to the acinar entrance, the reverse indicates a response deeper into the acinar airspaces. Twelve subjects had a major fall in FEV1 (> or = 20%) after CACh, 16 a minor fall (10-19%), and 27 did not react. Resting He and SF6 SnIII were significantly greater in major responders with respect to minor and nonresponders, while resting FEV1 did not differ between the three groups. The major responders showed marked increases of He and SF6 SnIII after CACh, with greater increase for He resulting in a negative (SF6-He) SnIII difference. To conclude, airways close to the acinar entrance participate in the overall airway response to cold-air challenge in asthmatic adults with marked airway hyperresponsiveness to cold, dry air.

Asthma severity, allergy and lung function during young middle life in subjects with asthma in childhood.

The further course of asthma severity lung function, bronchial hyperresponsiveness (BHR) to cold air challenge (CACh), clinical allergies and allergic sensitization in young middle adulthood was studied in a cohort of 55 subjects with childhood asthma. All subjects (27 females) have attended all five previous and the current follow-up visit, undertaken at a mean age of 35 years. Twelve subjects (22%) reported no current asthma, 28 (51%) mild/intermittent, and 15 (27%) moderate/severe asthma. Asthma severity changed little in the individual subjects over the last 5-year period. Females continued to have higher asthma severity scores than the males, but the previously noted lower resting and post-bronchodilator % predicted FEV1 in females was not confirmed now. Pathological BHR to CACh tended to be more common among the males. Forty-four subjects were still allergic to animal danders and 35 to pollens. Sensitization rates (skin prick test or RAST) were similar to those recorded 5 years earlier and there was no clear evidence of tolerance developing. Five subjects have never shown evidence of allergy or sensitization. The extent of sensitization to animal danders showed statistically significant relationships to asthma severity and BHR to CACh. Social development and professional careers continued to be good.

Effects of hypergravity and anti-G suit pressure on intraregional ventilation distribution during VC breaths.

The effects of increased gravity in the head-to-foot direction (+G(z)) and pressurization of an anti-G suit (AGS) on total and intraregional intra-acinar ventilation inhomogeneity were explored in 10 healthy male subjects. They performed vital capacity (VC) single-breath washin/washouts of SF(6) and He in +1, +2, or +3 G(z) in a human centrifuge, with an AGS pressurized to 0, 6, or 12 kPa. The phase III slopes for SF(6) and He over 25-75% of the expired VC were used as markers of total ventilation inhomogeneity, and the (SF(6) -- He) slopes were used as indicators of intraregional intra-acinar inhomogeneity. SF(6) and He phase III slopes increased proportionally with increasing gravity, but the (SF(6) -- He) slopes remained unchanged. AGS pressurization did not change SF(6) or He slopes significantly but resulted in increased (SF(6) -- He) slope differences at 12 kPa. In conclusion, hypergravity increases overall but not intraregional intra-acinar inhomogeneity during VC breaths. AGS pressurization provokes increased intraregional intra-acinar ventilation inhomogeneity, presumably reflecting the consequences of basilar pulmonary vessel engorgement in combination with compression of the basilar lung regions.

[Children with asthma followed up for 21 years. Reduced severity, but patients seldom grow out of asthma by adulthood]. / Barn med astma följdes under 21 år. Besvären minskar, men astman växer sällan bort i vuxen ålder.

The course of asthma severity, clinical allergies, allergic sensitization, lung function, changes in living conditions and social outcome were studied prospectively in 55 asthmatic children for 21 years, from a mean age of 9 to 30 years. Asthma severity improved, but only 16 percent were in remission at the final follow-up. After adolescence, clinical improvement continued among males but not among females. Lung function showed a similar gender difference with respect to clinical course. Generally, clinical allergies and sensitization to pollens and animal danders persisted in adulthood. In adulthood, asthma severity and degree of bronchial hyperresponsiveness correlated with the extent of sensitization to furred animals.

Asthma from childhood to adulthood: asthma severity, allergies, sensitization, living conditions, gender influence and social consequences.

The course of asthma severity, clinical allergies, allergic sensitization, changes in living conditions and social outcome were studied prospectively over five follow-up visits from the mean age of 9 to 30 years in a cohort of 28 boys and 27 girls, selected randomly among asthmatic children attending a paediatric outpatient unit. Asthma severity improved from childhood to adulthood, judged by symptom and medication scores and by the number of hospital admissions, but only nine subjects (16%) had been free from symptoms and medication over the last year of follow-up. After adolescence, asthma continued to improve among the males but not among the females. This difference could not be explained by gender differences in the course of clinical allergies or sensitization (skin-prick-tests and RAST) to common inhaled allergens, or by differences in environmental or social conditions. Sensitization to relevant perennial inhaled allergens correlated with asthma severity during adulthood. In general, clinical allergies and sensitization to inhaled allergens adopted during childhood persisted into adulthood. Approximately 10% of the subjects never adopted a clinical allergy or a positive allergy test. The social outcome was good.

Asthma from childhood to adulthood: course and outcome of lung function.

Lung function (FEV1 before and after bronchodilatation) was studied prospectively over five visits in 55 asthmatic children (28 boys) from childhood to adulthood (age 30). At the last follow-up recordings were made at rest, after cold air challenge (CACh), and after bronchodilatation. Results were related to clinical asthma scoring and to sensitization to furred animals, as described in a companion paper. Lung function outcome was shown to be influenced by initial FEV1 (% predicted) and gender, but not by initial asthma severity or sensitization. FEV1 (% predicted) was higher in females than in males over the first two follow-ups, but the reverse was found over the subsequent visits. It deteriorated from childhood to adulthood in the females but improved in the males. In adulthood the females (for height 170 cm) had a steeper normalized annual fall in post-bronchodilator FEV1 than the males (55 +/- 38 vs. 25 +/- 36 ml; P = 0.006). The degree of bronchial hyperresponsiveness was associated significantly with asthma severity and the extent of sensitization to furred animals, but not with gender. The results indicate a better lung function outcome for asthmatic boys than for girls, confirming trends seen in clinical asthma severity. In adulthood the extent of sensitization to relevant perennial inhaled allergens significantly influences airway responsiveness and asthma severity, but not lung function.

Ventilation inhomogeneity assessed by nitrogen washout and ventilation-perfusion mismatch by capnography in stable and induced airway obstruction.

Few studies have been published on gas distribution in the lung during acute and stable airway obstruction in children. Multiple breath nitrogen (N(2)) washout is an established method for assessing ventilation inhomogeneity, while the tidal breathing capnogram may be used as an indicator of ventilation-perfusion (V(')(A)/Q) mismatch. We hypothesized that significant V(')(A)/Q mismatch is not seen in stable airway obstruction unless obstruction is severe, and that stable and induced airway obstruction of similar severity would result in different degrees of V(')(A)/Q mismatch. To test this hypothesis, we performed spirometry measurements of forced expiratory volume in 1 sec (FEV(1)), multiple breath N(2) washout, and tidal breathing capnography in 11 young patients (9-30 years) with cystic fibrosis, 37 asthmatic patients (8-18 years), and 34 healthy subjects (7-20 years). Lung function was measured at rest, after airway obstruction induced by cold dry air hyperventilation or methacholine challenge, and after beta(2)-agonist treatment. V(')(A)/Q mismatch was assessed from the slopes of the phases II and III of the capnogram. We observed a normal capnogram during stable obstruction of moderate severity despite significant ventilation inhomogeneity. In patients with severe stable obstruction and in those with induced airway obstruction significant ventilation inhomogeneity and pathological capnograms were seen. Induced airway obstruction, resulted in a more pathological capnogram than stable obstruction of similar severity. beta(2)-agonist treatment reduced ventilation inhomogeneity, but did not improve the capnogram. Our findings are compatible with the presence of an efficient pulmonary blood flow regulatory mechanism that adequately compensates for chronic ventilation inhomogeneity of moderate severity, but not for severe or sudden airway obstruction.

A method for measuring the CO2 dead space volume in facial visors and respiratory protective devices in human subjects.

The external CO2 dead space volume (Vd) in facial visors and respiratory protective devices is difficult, but important, to measure in human subjects. The lack of proper methods for its assessment has hampered the development of standards and the improvement of visor and device design. We have improved and evaluated a method for measuring Vd and the mean inspired fraction of CO2 (FI,CO2) in human subjects wearing facial visors or respiratory protective devices. The method is based on indirect measurements of inspiratory volumes using a calibrated respiratory inductive plethysmograph (RIP), and measurements of FCO2 with a mass spectrometer. The accuracy of the RIP method was assessed in eight subjects and its repeatability was studied during nasal and oral breathing, at rest and after bicycle ergometer work. We related the Vd,RIP results to two known external VdS (with the effective Vd equal to the geometric volume; 15 ml and 320 ml), through which the subjects breathed, using RIP and a pneumotachometer (PTM) simultaneously (Vd,RIP and Vd,PTM). The repeatability of Vd and mean FI,CO2 results was determined from duplicate recordings during the wearing of a welding visor. Initial RIP calibration was accepted if the inspiratory tidal volume error was < or = 10%. This resulted in an acceptable Vd,RIP error (< or = 20%; Vd = 320 ml) in six eight subjects. The validation technique allowed us to separate the Vd,RIP error into a volumetric error and an error related to CO2 measurement. Poor RIP volumetric accuracy over the initial portion of inspiration was detrimental to Vd accuracy. Using the welding visor, Vd and mean FI,CO2 were less at rest than after work and less during nasal breathing than during oral breathing. The intra-individual variability of Vd and mean FI,CO2 were lower during nasal breathing than during oral breathing. To summarize, the improved RIP based method can accurately (< or = 20% error) assess Vd and mean FI,CO2 in facial visors and respiratory protective devices in standardized work situations. A meticulous RIP calibration procedure and repeated validations of RIP volume and CO2 measurement accuracy must, however, be applied.

Breathing pattern variability during bronchial histamine and methacholine challenges in asthmatics.

Breathing pattern variability was determined in 10 asthmatic adolescents during repeated bronchial histamine and methacholine challenges (HiCh/MeCh). The purpose was to provide information on ventilatory control in asthmatics by comparing the variability of the various breathing pattern parameters at rest and during induced bronchial obstruction. Changes in variability during bronchial obstruction might be explained by either anxiety effects causing increased variability or by the minimization of the work of breathing causing decreased variability. Ventilation was monitored by respiratory inductive plethysmography in order to minimize the effects on the spontaneous pattern of breathing. Breath-to-breath and day-to-day variability were determined concerning respiratory frequency (fR), inspiratory tidal volume (VTI), inspiratory ventilation (V'I), inspiratory time to total cycle time ratio (TI/TTOT), mean inspiratory flow (VTI/TI, an index of ventilatory drive), rib cage fraction of VTI (VRC/VTI), and maximum compartmental amplitude to VTI ratio (MCA/VTI; an index of rib cage and abdominal phasing). No difference in any parameter was found regarding breath-to-breath coefficient of variation (CV = SD/mean) between recordings at baseline, after saline inhalation and after threshold dose of the provocative agents, i.e. > 20% fall in FEV1. Variability was less for MCA/VTI and VRC/VTI (mean CV 1.3 and 7.7%, respectively) than for TI/TTOT, fR, VTI/TI, VTI, and V'I (14.2, 15.8, 20.9, 22.2 and 21.1%, respectively) (P < 0.01). Likewise, the day-to-day variability did not differ in any parameter between recordings at baseline, after saline inhalation and after threshold dose. The variability was less for MCA/VTI (0.7%) than for TI/TTOT, VRC/VTI, V'I, VTI/TI, fR and VTI (7.1, 12.1, 12.8, 14.2, 13.0 and 15.4%) (P < 0.05). Furthermore, TI/TTOT was less variable than VTI (P < 0.05). Thus, the ventilatory pattern was quite reproducible on a day-to-day basis, despite considerable breath-to-breath variability. Ventilatory drive and tidal volumes were more variable than the rib cage and abdominal phasing, the respiratory timing and the rib cage fraction of tidal volume. The lack of difference in variability between rest and induced bronchial obstruction indicates that other factors than anxiety or minimization of the work of breathing are important for the control of respiration in asthmatics during bronchial challenge.

Hyperventilation during bronchial challenges in asthmatics: reproducibility and assessment of contributing factors.

Among asthmatics, the ventilatory response is heterogeneous during bronchial challenge. This study aimed to investigate the reproducibility of the response and to assess possible causes for hyperventilation. Repeated bronchial histamine and methacholine challenges (HiCh/MeCh) were performed in 10 asthmatic adolescents. Ventilation was monitored by respiratory inductive plethysmography (RIP), in order to minimally affect the spontaneous breathing pattern. FEV1 and the volume of trapped gas (measured as the volume of air mobilized by five maximal breaths after a multiple breath nitrogen washout to 2% N2), were used to assess mainly central and peripheral airways obstruction, respectively. When FEV1 had decreased by at least 20%, mean inspiratory flow (VTI/TI) increased by 21% and minute ventilation (V'I) by 21% and 23% during HiCh and MeCh, respectively (both P < 0.05). No correlation was found between the magnitude of the ventilatory response and either: the degree of FEV1 decline, the increase in gas trapping, SaO2 decline or the increase in dyspnoea score. Histamine challenge after beta 2-agonist pre-treatment was associated with increased ventilatory drive in one patient despite the absence of bronchial obstruction, indicating that histamine might directly stimulate afferent airway nerves which cause hyperventilation. The intra-individual variability of the ventilatory response (increase in V'I and VTI/TI) was more than 100% of the mean ventilatory response, while the variability of the bronchomotor response was about 25% of the mean bronchomotor response. Thus, during induced bronchial obstruction in asthmatics, the occurrence of hyperventilation and its intensity are not related to either the degree of central or peripheral airways obstruction, or to the degree of dyspnoea. The reproducibility of the ventilatory response is poor. The ventilatory response appears to be the result of a complex interaction between several afferent stimuli and central ventilatory control.