Short-term effects of physiotherapy on ventilation inhomogeneity in cystic fibrosis patients with a wide range of lung disease severity.

BACKGROUND: Lung clearance index (LCI) is increasingly used as a study endpoint for therapeutic interventions in cystic fibrosis (CF) patients. We set out to assess the effect of chest physiotherapy on ventilation inhomogeneity in clinically stable patients with CF lung disease of varying severity. METHODS: In 29 CF patients (7.3-43.7 years) N2MBW (nitrogen multiple breath washout), plethysmography, and spirometry measurements were conducted, followed by 30 min of supervised PEP mask chest physiotherapy and repeated measurements 30 min after therapy. RESULTS: We observed a mean change in LCI after physiotherapy from 15.00 to 14.80 (range, -4.84 to 3.37; p=0.578). In seven patients, LCI decreased, and in ten patients, LCI increased by ≥1. For the whole group, statistically significant improvements were seen in Reff, FEV1, FVC, and MEF50. CONCLUSIONS: By opening up previously poorly ventilated lung regions, physiotherapy may either increase or decrease ventilation inhomogeneity; the short-term effect of physiotherapy on LCI appears to be unpredictable.

Predicting coronary heart disease after kidney transplantation: Patient Outcomes in Renal Transplantation (PORT) Study.

Traditional risk factors do not adequately explain coronary heart disease (CHD) risk after kidney transplantation. We used a large, multicenter database to compare traditional and nontraditional CHD risk factors, and to develop risk-prediction equations for kidney transplant patients in standard clinical practice. We retrospectively assessed risk factors for CHD (acute myocardial infarction, coronary artery revascularization or sudden death) in 23,575 adult kidney transplant patients from 14 transplant centers worldwide. The CHD cumulative incidence was 3.1%, 5.2% and 7.6%, at 1, 3 and 5 years posttransplant, respectively. In separate Cox proportional hazards analyses of CHD in the first posttransplant year (predicted at time of transplant), and predicted within 3 years after a clinic visit occurring in posttransplant years 1-5, important risk factors included pretransplant diabetes, new onset posttransplant diabetes, prior pre- and posttransplant cardiovascular disease events, estimated glomerular filtration rate, delayed graft function, acute rejection, age, sex, race and duration of pretransplant end-stage kidney disease. The risk-prediction equations performed well, with the time-dependent c-statistic greater than 0.75. Traditional risk factors (e.g. hypertension, dyslipidemia and cigarette smoking) added little additional predictive value. Thus, transplant-related risk factors, particularly those linked to graft function, explain much of the variation in CHD after kidney transplantation.

Racial disparity trends for graft failure in the US pediatric kidney transplant population, 1980-2004.

Graft survival among adult African American kidney transplant patients remains low compared to whites, but little information is available for children and adolescents. We examined trends in graft failure among US incident primary kidney transplant patients aged <19 years (n = 13 692), 1980-2004. Trends in 1-year and 2- to 5-year graft failure (for patients whose grafts survived the first year) were analyzed in 5-year intervals. One-year graft failure declined 70% for white and 77% for African American patients over the 25-year period, and 1-year graft failure rates improved at a slightly higher rate for African American compared to white patients (p = 0.02). In contrast, the graft failure rates for years 2-5 declined 53% for white and only 41% for African American patients over the 25 years (p = 0.29). In fully adjusted Cox proportional hazards analysis, the rate of graft failure among African Americans was approximately 2-fold higher than for white patients over the entire study period. Graft survival has improved slightly more for African American than white pediatric patients over the past 25 years. However, graft survival for African American pediatric patients remains poor compared with white patients.

Effect of comorbidity adjustment on CMS criteria for kidney transplant center performance.

The Centers for Medicare & Medicaid Services (CMS) uses kidney transplant outcomes, unadjusted for standard comorbidity, to identify centers with sufficiently higher than expected rates of graft failure or patient death (underperforming centers) that they may be denied Medicare participation. To examine whether comorbidity adjustment would affect this determination, we identified centers that would have failed to meet 1-year graft survival criteria, 1992-2005, with and without adjustment using the Elixhauser Comorbidity Index. Adjustment was performed for each U.S. center for 24 consecutive (overlapping) 30-month intervals, including 102 176 adult deceased-donor and living-donor kidney transplant patients with Medicare as primary payer 6 months pretransplant. For each interval, we determined percent positive agreement (PPA) (number of centers underperforming both before and after adjustment, divided by number underperforming either before or after adjustment). Overall PPA was 80.8%, with no evidence of a trend over time. Among deceased-donor recipients, 10 of 31 comorbid conditions were predictors of graft failure in at least half of the intervals, as were six conditions among living-donor recipients. Lack of comorbidity adjustment may disadvantage centers willing to accept higher risk patients. Risk of jeopardizing Medicare funding may give centers incentive to deny transplantation to higher risk patients.

Effects of nedocromil and salbutamol on airway reactivity in children with asthma.

Nedocromil and salbutamol are effective drugs in preventing exercise-induced asthma (EIA). The aim of this study was to compare the protective effects of both drugs and a combination of both drugs against cold dry air-induced bronchoconstriction, using cold dry air challenges (CACh) as a surrogate for exercise. Twenty-five atopic children (mean age 13.7, range 8-18 yrs) with EIA participated in the study. Lung function tests were performed before medication, 30 min after medication and just before CACh, and 3 and 15 min after the challenge on four consecutive days. CACh consisted of a 4-min isocapnic hyperpnoea of -10 degrees C, absolutely dry air. Treatment consisted of nedocromil (two puffs of 2 mg) plus placebo, salbutamol (two puffs of 100 microg) plus placebo, the combination of both drugs, and placebo alone, in a random order. Both active drugs were significantly more protective than placebo and the combination showed an additive effect. Mean maximum postchallenge decrease in forced expiratory volume in one second after placebo was 27+/-8.1%, 12+/-9.5% after nedocromil, 8+/-10.4% after salbutamol, and 4.5+/-6.71% after the combination of both drugs, respectively. These results suggest that both drugs protect against exercise-induced asthma. Although not as effective as salbutamol and combined medication, nedocromil can give sufficient protection for many patients.

Laser acupuncture in children and adolescents with exercise induced asthma.

BACKGROUND: Laser acupuncture, a painless technique, is a widely used alternative treatment method for childhood asthma, although its efficacy has not been proved in controlled clinical studies. METHODS: A double blind, placebo controlled, crossover study was performed to investigate the possible protective effect of a single laser acupuncture treatment on cold dry air hyperventilation induced bronchoconstriction in 44 children and adolescents of mean age 11.9 years (range 7.5-16.7) with exercise induced asthma. Laser acupuncture was performed on real and placebo points in random order on two consecutive days. Lung function was measured before laser acupuncture, immediately after laser acupuncture (just before cold dry air challenge (CACh)), and 3 and 15 minutes after CACh. CACh consisted of a 4 minute isocapnic hyperventilation of -10 degrees C absolute dry air. RESULTS: Comparison of real acupuncture with placebo acupuncture showed no significant differences in the mean maximum CACh induced decrease in forced expiratory volume in 1 second (27.2 (18.2)% v 23.8 (16.2)%) and maximal expiratory flow at 25% remaining vital capacity (51.6 (20.8)% v 44.4 (22.3)%). CONCLUSIONS: A single laser acupuncture treatment offers no protection against exercise induced bronchoconstriction in paediatric and adolescent patients.

Assessment of bronchodilator responsiveness in infants with bronchiolitis. A comparison of the tidal and the raised volume rapid thoracoabdominal compression technique.

Whether bronchodilators should be used for the treatment of infants with bronchiolitis is subject to debate, partly because of the low sensitivity of the methods for assessing lung function changes in infants. In the present study, we compared the recently introduced raised volume (RVRTC) with the conventional end-tidal rapid thoracoabdominal compression (ETRTC) technique in infants with acute viral bronchiolitis. In 17 infants lung function was assessed by both methods, at baseline values and after salbutamol inhalation. Forced expiratory volumes (FEV(0.5), FEV(0.75), FEV(1.0)) were used for the quantification of RVRTC measurement, and maximal expiratory flow at functional residual capacity (Vmax (FRC)) for ETRTC measurements. A significant individual change was defined by a mean postbronchodilator value that differed from baseline value by more than twice the within-subject coefficient of variation (CV). Group mean intrasubject CVs ranged from 4.7% to 5.3% for FEV parameters; it was 14.0% for Vmax (FRC). For the group, post-bronchodilator measurements did not differ significantly from baseline measurements. For the majority of infants, however, the within-subject comparison of responses revealed substantial differences between both techniques; while no infant demonstrated a significant increase in Vmax (FRC), eight (47%) infants responded with significantly improved timed volumes. The RVRTC technique provides the investigator with a more sensitive diagnostic tool for documenting the effectiveness of therapeutic interventions on an individual basis. Furthermore, the findings of the present study provide a rationale for the application of bronchodilators in a subgroup of infants with acute bronchiolitis.

Reproducibility of forced expiratory flow and volume measurements in infants with bronchiolitis.

The end-tidal rapid thoracoabdominal compression (ETRTC) technique is an established method for lung function testing in infancy. Previous work in healthy infants, however, has shown that measurements with the newly developed raised volume rapid thoracoabdominal compression (RVRTC) technique are more reproducible than those with the ETRTC technique. So far, reproducibility of the two techniques has not been compared in infants with acute airway disease. Twenty-three infants with acute viral bronchiolitis underwent lung function assessment with both the ETRTC and the RVRTC technique. A series of 8-10 measurements with each technique was done in randomized order. Forced expired volumes at 0.5, 0.75, and 1 sec after chest compression (FEV(0.5), FEV(0.75), and FEV(1.0)) were measured with the RVRTC technique; maximum expiratory flow at functional residual capacity (V'(maxFRC)) was measured with the ETRTC technique. Group mean intrasubject coefficients of variation (CV) were 4.84% for FEV(0.5), 5.01% for FEV(0.75), 5.43% for FEV(1. 0), and 13.79% for V'(maxFRC), respectively. Differences between FEV parameters were statistically insignificant, whereas the difference between each FEV parameter and V'(maxFRC) was highly significant (P < 0.001). In infants with acute viral bronchiolitis, RVRTC measurements have significantly less intraindividual variability than flow rates assessed with the conventional ETRTC technique. This finding provides the basis for assessing disease course and effects of therapeutic interventions on an individual basis.

Serum eosinophil cationic protein and bronchial responsiveness in pediatric and adolescent asthma patients.

BACKGROUND: Serum eosinophil cationic protein (ECP) has been promoted as a marker of inflammatory activity in bronchial asthma. Bronchial responsiveness, measured either by inhaling pharmacologically active substances such as histamine or methacholine, or by applying physical stimuli such as the hyperventilation of cold dry air, is also considered to be an indirect marker of bronchial inflammation. OBJECTIVES: In this study, we investigated the possible relationship between serum ECP and bronchial responsiveness to both cold dry air and histamine in presently symptom- and medication-free pediatric and adolescent asthma patients. SUBJECTS: Thirty-six children and adolescents with atopic asthma were studied. METHODS: On 2 consecutive days, bronchial responsiveness was assessed nonpharmacologically by cold dry air and pharmacologically by histamine in random order. Blood samples for determination of ECP were collected before each challenge. RESULTS: Serum ECP levels correlated with neither cold dry air-induced changes in FEV1 nor the provocation concentrations of histamine causing a 20% fall in FEV1. Subjects with bronchial hyperresponsiveness to cold dry air and histamine had somewhat higher levels of serum ECP than subjects with normal responses, but these differences were insignificant. CONCLUSIONS: Our results indicate a lack of relationship both between serum ECP and bronchial responsiveness to cold dry air and between serum ECP and bronchial responsiveness to histamine.

Effect of sleep stages on measurements of passive respiratory mechanics in infants with bronchiolitis.

The measurement of passive respiratory mechanics by the single-breath occlusion technique is one of the more frequently used tests of infant lung function. Measurements are routinely done under chloral hydrate sedation, and a possible influence of sleep stages on these measurements has not been evaluated so far. We combined the assessment of passive respiratory mechanics with sleep stage monitoring in 44 infants and toddlers with mild to moderately severe bronchiolitis. In 31 infants, only nonrapid eye movement (NREM) sleep was recorded. In 13 patients who showed both NREM and rapid eye movement (REM) sleep, compliance of the respiratory system was significantly lower during REM than NREM sleep (73.2 +/- 19.7 vs. 81.2 +/- 21.3 mL/kPa, P = 0.0007), while resistance remained essentially unchanged. This finding was explained by an unchanged airway opening pressure in combination with a significantly decreased extrapolated volume. As tidal volume did not change from NREM to REM, this indicates reduced dynamic elevation of lung volume during REM sleep and thus supports previous observations of decreased lung volume in this sleep stage. From a practical perspective, these findings argue for the monitoring of sleep stage during measurements of passive respiratory mechanics, thereby increasing the complexity of these measurements significantly.

Effect of specific immunotherapy with house dust mite extract on the bronchial responsiveness of paediatric asthma patients.

BACKGROUND AND OBJECTIVE: Allergic asthma is common in children, and house dust mite (HDM) is an important source of perennial allergens. Bronchial hyperresponsiveness is a functional hallmark of asthma. Specific immunotherapy (SIT) with HDM extracts were shown to decrease symptoms, but its effect on bronchial responsiveness, as measured by non-pharmacological challenges, has not been evaluated. METHODS: Twenty-six paediatric asthma patients allergic to HDM participated in this study. Fourteen patients received SIT with a HDM extract (Alavac, Bencard) for 2 years, and 12 served as controls. Bronchial responsiveness was assessed non-pharmacologically by cold dry air challenge (CACh) before and 3, 6, 12 and 24 months after SIT, and 12 months after termination of SIT. RESULTS: After 24 months, the SIT group showed a statistically significant reduction of the mean CACh-induced changes of both forced expiratory volume in one second (-21.8+/-2.7% vs. -13.7+/-2.4%; P = 0.03) and maximal expiratory flow at 25% remaining vital capacity (-48.9+/-4.9% vs. -27.9+/-6.2%; P = 0.01). In contrast, no significant changes of bronchial responsiveness were observed in the control group. In the SIT group more patients lost their bronchial hyperresponsiveness than in the control group (6/14 vs. 1/12; P<0.05). One year after terminating SIT, the treatment group showed a tendency towards returning bronchial hyperresponsiveness. CONCLUSION: These results demonstrate that during 2 years of SIT there was a reduction of bronchial hyperresponsiveness in HDM-allergic paediatric asthma patients.

Atopy, lung function and bronchial responsiveness in symptom-free paediatric asthma patients.

In adolescence, some paediatric asthma patients will become symptom-free and require no further treatment. There is little information on the atopic status, lung function and bronchial responsiveness of these patients. Symptom-free asthma patients (n=118) aged 7.7-19.2 yrs, were evaluated 1 year after termination of therapy. Bronchial asthma had previously been diagnosed on the basis of recurrent wheezing episodes. Atopic status was assessed by skin-prick testing. Baseline lung function was measured by spirometry, flow-volume curve and plethysmography. Bronchial responsiveness was assessed nonpharmacologically by cold dry air challenge. Eighty one patients had at least one positive skin test result, and the remaining 37 were defined as nonatopic. In atopic subjects, the prevalence of bronchial hyperresponsiveness was significantly higher than in nonatopic patients (41 out of 81 versus 7 out of 37; p=0.001). Atopic subjects showed a significantly lower maximal expiratory flow at 25% remaining vital capacity (p<0.05) and a higher residual volume (p<0.05) than nonatopic subjects. Nonatopic subjects were significantly younger than atopic patients (p<0.01). These symptom- and medication-free paediatric and adolescent asthma patients could, thus, be divided into two groups: 1) atopic subjects with a tendency towards bronchial hyperresponsiveness; and 2) nonatopic subjects with better lung function and normal bronchial responsiveness In view of the increased understanding of the epidemiology of early childhood wheezing, these findings support the concept of different pathogenic mechanisms underlying wheezing episodes in early childhood.

Comparing methods for assessing bronchial responsiveness in children: single step cold air challenge, multiple step cold air challenge, and histamine provocation.

Cold air challenge (CACh) can be applied by either a single step (SSCACh) or a multiple step (MSCACh) protocol. The interrelationship of the responses of the different protocols has not yet been studied. Furthermore, there is contradictory information on the correlation of cold air challenge responses to the outcome of pharmacological provocations. A single and a multiple step cold air challenge and a histamine provocation were performed in random order on three consecutive days on 28 children and adolescents with bronchial asthma, who were currently symptom- and medication-free. Single step cold air challenge consisted of a 4 min isocapnic hyperventilation of dry, -10 degrees C air; the subjects's response was quantified by the induced change in forced expiratory volume in one second (FEV1). Multiple step cold air challenge consisted of a series of 3 min, cold dry air hyperventilation steps from 20 to 80% of maximal voluntary ventilation (MVV); response was expressed as the provocative dose causing a 10% fall in FEV1 (PD10). Histamine provocation consisted of a series of 2 min inhalations of stepwise increasing histamine concentrations from 0.03 to 8.0 mg.mL-1; response was expressed as the provocative concentration of histamine causing a 20% fall in FEV1 (PC20). Change in FEV1 (delta FEV1) (SSCACh) correlated closely with PD10 (MSCACh); scatter around the regression line was minimal. With one exception, both types of CACh identified the same subjects as hyper- and normoresponsive. delta FEV1 (SSCACh) correlated significantly to PC20 (histamine), but scatter around the regression line was substantial. The correlation of PD10 (MSCACh) to PC20 (histamine) failed to reach statistical significance. These results indicate that the stimulus applied and the bronchoconstrictor mechanism activated, and not the challenge protocol, determine the outcome of a cold air challenge. In clinical practice, a brief single step cold air challenge can substitute for a more time-consuming multiple step cold air challenge. As nonpharmacological challenges seem to measure a different type of bronchial responsiveness, neither a single step nor a multiple step cold air challenge can substitute for a pharmacological provocation.

A comparison of a single-step cold-dry air challenge and a routine histamine provocation for the assessment of bronchial responsiveness in children and adolescents.

BACKGROUND: It has remained unclear whether bronchial responsiveness as measured by a single-step cold-dry air challenge (CACh) correlates closely to the responsiveness that is assessed by a routine pharmacologic challenge. METHODS: On 2 consecutive days, we performed a CACh and a histamine challenge in 128 symptom- and medication-free pediatric and adolescent asthma patients. The CACh consisted of 4 min of isocapnic hyperventilation of -10 degrees C, absolutely dry air; responsiveness was expressed by the induced change in FEV1 (delta FEV1). The histamine challenge consisted of sequential inhalations of incremental increases in concentrations of histamine; responsiveness was expressed by the concentration which caused a 20% fall of FEV1 (PC20). RESULTS: Five children did not bronchoconstrict sufficiently in the histamine challenge for measuring a PC20 and were excluded from analysis. In the remaining 123, delta FEV1 (CACh) ranged from +5 to -73%, PC20 (histamine) from 0.05 to 7.2 mg/mL. There was a statistically significant correlation between delta FEV1 and PC20 (r = 0.54, p < 0.001), but also a considerable scatter of individual data points around the regression line. Fifty-two subjects were hyperresponsive by CACh and 114 by histamine criteria. CONCLUSIONS: There is a relatively weak correlation between the results of these two challenges; thus, one cannot be substituted one for the other. Histamine appears as more sensitive in detecting airway hyperresponsiveness than CACh. The poor correlation between the responses to these two challenges can be explained by differences between the challenge protocols, or, alternatively, by differences between applied stimuli and activated mechanisms.

Lung volume measurements in wheezy infants: comparison of plethysmography and gas dilution.

The accuracy both of plethysmographic measurements of thoracic gas volume (TGV) and determinations of functional residual capacity (FRC) by gas dilution techniques in infants with obstructive lung disease is subject to continued dispute. We studied 25 wheezy infants and compared TGV derived from end-expiratory airway occlusions (TGVEE), corrected TGV after end-inspiratory airway occlusions (TGVEI), and FRC determined by nitrogen wash-out (FRCN2). Group mean TGVEE and TGVEI differed significantly (25.8 +/- 8.4 versus 24.6 +/- 7.1 ml.kg-1). TGVEE and FRCN2 did not differ significantly. TGVEE and TGVEI, as well as TGVEE and FRCN2, and TGVEI and FRCN2 data, respectively, showed lack of agreement. Based on 95% confidence intervals, calculated from TGVEE data, 14 of the 25 infants showed a significantly higher TGVEI than TGVEE; only one patient had a significantly lower TGVEI. Compared to FRCN1 data, TGVEE and TGVEI measurements yielded lower values in at least one third of our patients. The present study illustrates, that there is no gold standard for the measurement of lung volume in infants with airway obstruction.

[Measuring lung volume in the infant--problems with the nitrogen washout method]. / Die Messung des Lungenvolumens beim Säugling--Probleme mit der Stickstoffauswaschmethode.

The open-circuit nitrogen washout technique, as developed by Gerhardt et al., seems to be ideally suited for assessing functional residual capacity (FRC) in infants. By performing this measurement in over 250 infants throughout the last three years, we gathered considerable practical experience of our own, but also encountered several methodological problems, which, so far, have received only little attention by the relevant literature, or have remained unresolved altogether. Our data illustrate the importance of reproducing the infant's own breathing rate and tidal volume when calibrating the system. The choice of the O2-background-flow should be based on the individual peak tidal inspiratory flow, as derived from the tidal flow-volume loop. The importance of maintaining this O2-background-flow unchanged between calibration and measurement is also demonstrated. The question, at which N2-concentration the measurement should be terminated, has remained unresolved. Diffusion of N2 from blood and tissue into the alveolar space is responsible for considerable noise. Our own measurements resulted in widely differing FRC-values for different N2-target-concentrations; these differences seem to increase with more severe bronchial obstruction. Finally, there remains the question, how long the minimal interval between two subsequent measurements should be. In conclusion, these unresolved questions have to be answered in relevant prospective studies, before recommending this technique for routine clinical application.