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To the Editors: In 1986, the American Thoracic Society (ATS) first suggested a fixed ratio of forced expiratory volume in one second (FEV1) to forced vital capacity (FVC)

To understand potential benefits of exercise in the cystic fibrosis (CF) population, there needs to be accurate methods to quantify it. The Habitual Activity Estimation Scale (HAES) questionnaire has been shown to be a feasible tool to measure physical activity however the reliability and validity have yet to be determined in the CF population.Fourteen (seven male, seven female) patients aged 16.2 +/- 4.2 years with CF participated in this study. Participants were clinically stable at the time of the study and participating in their habitual physical activity. To assess reliability, patients completed the HAES and a validated 3-day activity diary, and wore an ActiGraph Accelerometer for two consecutive weeks. Validity was assessed by comparing the activity results of each of the three instruments over a single week time period.ICC estimates of reliability for the HAES, diary, and accelerometer were 0.72 (P0.0001), 0.76 (P0.0001), 0.63 (P0.0001), respectively. Validity analysis indicated that there were significant relationships between the participants' activity results as estimated by the HAES, diary and accelerometer. Further, significant relationships were detected between activity measures when broken into morning, afternoon, or evening periods, and between measures from weekday or weekend days. There were also significant relationships among the three instruments when recording different activity levels (somewhat inactive, somewhat active, and very active).The findings of this study suggest that the HAES questionnaire is a reliable and valid instrument that can be used to assess activities of varying intensity in patients with CF.

A model of targeted drug delivery to the lung uses magnetized droplets and a magnetic field.

Udgivelsesdato: 2007-Mar

The purpose of this study was to compare three valved holding chambers (VHC) with facemasks attached. One VHC (AeroChamber Max[TM] with medium mask) was made with materials that dissipate surface electrostatic charge, and the others (OptiChamber Advantage and ProChamber[TM] with pediatric facemask) were made from non-conducting materials. The OptiChamber Advantage and ProChamber VHCs were each washed with an ionic detergent and drip dried before testing to minimize surface electrostatic charge. The AeroChamber Max VHCs were tested "out of the package" and also after wash, rinse, and drying. An infant face model incorporating an electrostatic filter in the oral cavity was connected to a breath simulator using a standard waveform for a small child. The fit of each VHC with facemask was demonstrated by agreement of inspiratory flow measurements between a pneumotachograph connected to the system with those set on the simulator. An HFA-fluticasone propionate metered dose inhaler (MDI; 125 microg/dose) was inserted into the VHC, two actuations were delivered, and the filters were subsequently assayed using high-pressure liquid chromatography (HPLC). Testing and sample assay order was randomized, and HPLC assays were undertaken blinded. Drug delivery efficiency expressed as a percentage of the total dose of fluticasone propionate (250 microg) for the AeroChamber Max VHC "out-of-the-package" was 22.0(0.7)% (mean [99% CI]) and 21.2(1.5)% when pre-washed/rinsed. Results for the pre-washed ProChamber and OptiChamber Advantage VHCs were 10.2(0.55)% and 8.8(1.9)%, respectively. The more efficient delivery of medication via VHCs made from electrostatic charge dissipative materials should be considered when choosing doses for small children.

The impact of "gentle ventilation" (GV) strategies on morbidity and mortality of patients with congenital diaphragmatic hernia (CDH) in our institution has not been determined. This study reviews the primary and secondary outcomes of our patients with CDH treated with the GV approach.We performed a retrospective chart review of respiratory, neurologic, nutritional, and musculoskeletal morbidities in patients with CDH treated at a single institution between 1985 and 1989 with conventional ventilation (CV) compared with those treated from 1996 to 2000 with GV.There were 77 CV-treated and 66 GV-treated patients with CDH, with 51% survival in the CV cohort compared with 80% in the GV group (chi(2), P.05). At 3-year follow-up, we found no statistically significant differences in the frequency of respiratory (38% of CV patients, 50% of GV patients), neurologic (29% of CV patients, 34% of GV patients), or musculoskeletal morbidity (46% of CV vs 29% of GV-treated patients). There was a difference in nutritional morbidity as indicated by the increased frequency of gastrostomy tube use in the GV-treated patients (34%) compared with the CV patients (8%; chi2, P.05).The implementation of GV techniques has significantly decreased mortality in infants with CDH. This has been associated with a documented increase in nutritional morbidity among survivors.

Our objective was to study exercise capacity and cardiorespiratory response to exertion in survivors of congenital diaphragmatic hernia (CDH). This was a cross-sectional cohort study of 23 CDH survivors, aged 10-16 years, and 23 gender- and age-matched controls. Exercise testing was performed on a cycle ergometer, with cardiac output measurements made using exponential CO2 rebreathing. Pretest cardiorespiratory assessment was done by echocardiography and pulmonary function testing. Statistical analysis was performed using Student's t-test, regression analysis, and longitudinal model computing with spatial covariance structure. No echocardiographic evidence for pulmonary hypertension was found at rest (right ventricular systolic pressures, 27 +/- 6 mmHg). Mean pulmonary artery diameter on the side of the CDH was significantly smaller than contralaterally, but was within normal range (z-score, 0 +/- 1.1 vs. 1.2 +/- 1.6, P < 0.01). Exercise capacity was mildly reduced in CDH compared to controls and predictive data (maximum workload, 77% +/- 12% vs. 91% +/- 16% of predicted, P < 0.01). Cardiorespiratory response to exertion was not significantly different between groups. In conclusion, most adolescent CDH survivors have nearly normal exercise capacity and cardiorespiratory response to exertion. This study may prove useful in comparisons with future cohorts comprising more severely affected individuals now surviving due to improved neonatal care.

Background: Carbon dioxide (CO 2 ) retention during exercise is uncommon in mild to moderate lung disease in cystic fibrosis (CF). The ability to deal with increased CO 2 is dependent on the degree of airflow limitation and inherent CO 2 sensitivity. CO 2 retention (CO 2 R) can be defined as a rise in P ET CO 2 tension of ⩾5 mm Hg with exercise together with a failure to reduce P ET CO 2 tension after peak work by at least 3 mm Hg by the termination of exercise. Aim: To ascertain if carbon dioxide retention during exercise is associated with more rapid decline in lung function. Methods: Annual spirometric and exercise data from 58 children aged 11–15 years, with moderate CF lung disease between 1996 and 2002 were analysed. Results: The mean FEV 1 at baseline for the two groups was similar; the CO 2 R group (n = 15) was 62% and the non-CO 2 retention group (CO 2 NR) was 64% (n = 43). The decline in FEV 1 after 12 months was −3.2% (SD 1.1) in the CO 2 R group and −2.3% (SD 0.9) in the CO 2 NR group. The decline after 24 months was −6.3% (SD 1.3) and −1.8% (SD 1.1) respectively. After 36 months, the decline in FEV 1 was −5.3% (SD 1.2) and −2.6% (SD 1.1) respectively. The overall decline in lung function was 14.8% (SD 2.1) in the CO 2 R group and 6.7% (SD 1.8) in the CO 2 NR group. Using the primary outcome measure as a decline in FEV 1 of >9%, final multivariate analysis showed that the relative risks for this model were (95% CIs in parentheses): ΔP ET CO 2 11.61 (3.41 to 24.12), peak V˙O 2 1.23 (1.10 to 1.43), and initial FEV 1 1.14 (1.02 to 1.28). Conclusion: Results show that the inability to defend carbon dioxide during exercise is associated with a more rapid decline in lung function.

Objective The purpose of this study was to determine the fetal response to submaximal maternal exercise at 22 to 26 weeks in pregnancies with abnormal uterine artery Doppler. Study design This was a prospective comparison of singleton pregnancies with uteroplacental vascular insufficiency (UPVI) (mean uterine pulsatility index [PI] values >1.45 [n = 12]) and those with normal uterine artery Doppler (n = 23). Maternal and fetal cardiovascular responses to 5 minutes of steady state cycling at 10% and at 15% of predicted work rate maximum were studied. Results Umbilical artery Doppler deteriorated after exercise in patients with UPVI (pre PI 1.4 [0.35-2.14], post PI 1.64 [0.45-2.18]). Three (25%) had transient absent-end diastolic flow (AEDF) in umbilical artery, 2 of which developed early-onset intrauterine growth restriction (IUGR) with AEDF. Fetal cardiac output studies remained stable during the examinations. Conclusion Submaximal steady state exercise had a transient deleterious effect in a subset of women with uteroplacental vascular insufficiency destined to develop early-onset IUGR.

SERIES “ATS/ERS TASK FORCE: STANDARDISATION OF LUNG FUNCTION TESTING” Edited by V. Brusasco, R. Crapo and G. Viegi Number 5 in this Series This section is written to provide guidance in interpreting pulmonary function tests (PFTs) to medical directors of hospital-based laboratories that perform PFTs, and physicians who are responsible for interpreting the results of PFTs most commonly ordered for clinical purposes. Specifically, this section addresses the interpretation of spirometry, bronchodilator response, carbon monoxide diffusing capacity ( D L,CO) and lung volumes. The sources of variation in lung function testing and technical aspects of spirometry, lung volume measurements and D L,CO measurement have been considered in other documents published in this series of Task Force reports 1–4 and in the American Thoracic Society (ATS) interpretative strategies document 5. An interpretation begins with a review and comment on test quality. Tests that are less than optimal may still contain useful information, but interpreters should identify the problems and the direction and magnitude of the potential errors. Omitting the quality review and relying only on numerical results for clinical decision making is a common mistake, which is more easily made by those who are dependent upon computer interpretations. Once quality has been assured, the next steps involve a series of comparisons 6 that include comparisons of test results with reference values based on healthy subjects 5, comparisons with known disease or abnormal physiological patterns ( i.e. obstruction and restriction), and comparisons with self, a rather formal term for evaluating change in an individual patient. A final step in the lung function report is to answer the clinical question that prompted the test. Poor choices made during these preparatory steps increase the risk of misclassification, i.e. a falsely negative or falsely positive interpretation for a lung function abnormality or a change …

[⇓][1] SERIES “ATS/ERS TASK FORCE: STANDARDISATION OF LUNG FUNCTION TESTING” Edited by V. Brusasco, R. Crapo and G. Viegi Number 3 in this Series [1]: #F7

In neonatal lung disease, chemical and physical noxious stimuli, microbial aggression, host defence, and an ill-timed exposure to the extrauterine environment all act together in compromising the i

To evaluate the feasibility of measuring habitual physical activity (HPA) in children with cystic fibrosis (CF) and to assess the relation between HPA and the rate of decline in FEV1 over a period of 2 years.At regular clinic visits, 109 patients (7 to 17 years; 56 girls) performed pulmonary function testing and completed the Habitual Activity Estimation Scale (HAES). Patients were divided into quartiles, based on activity levels derived from the HAES.Girls in the two lowest activity quartiles had a more rapid rate of decline FEV1 (-3.40% and -3.05% predicted, respectively) than girls in the two highest activity quartiles (-0.93% and +1.17% predicted, respectively) (P = .02). In boys, the rate of decline of FEV1 was similar in all activity quartiles (-1.95% predicted). Patients reported significantly more activity in summer compared with spring, winter, and fall (P.0001), and boys reported greater activity than girls (6.5 +/- 2.9 vs 5.4 +/- 2.5 h/d, P.05).The annual rate of change of FEV1 was related to activity quartile in girls but not in boys. This research suggests that an inactive lifestyle may partially explain the poorer survival of female patients with CF. The HAES is a feasible tool for routine follow-up of HPA in our CF clinic.

Lung-function reference values play a vital role in the management of respiratory disorders. There are many proposed reference equations for pediatric spirometry. Recently, spirometric reference equations were proposed, using data from people aged 8-80 years living in the US compiled by the third National Health and Nutrition Examination Survey. Our objective was to compare the predictive value of wider age-range reference equations to established pediatric reference equations for the pediatric population. Spirometry, height, and weight were obtained from 70 normal children aged 6-18 years. The difference between measured and predicted values as suggested by different reference equations was compared. Predicted values from general equations significantly differed from those generated from pediatric equations and from measured values in this population. The difference between measured and predicted values from the wider age-range equations varied between 7-16% for forced expired volume in 1 sec (FEV1) and forced vital capacity (FVC). The difference between measured and predicted values for the pediatric equations varied between 1-4%. Although wider age-range equations provide continuity through age ranges, their predictive accuracy may be low in the pediatric age group, especially for the youngest, smallest children. Extrapolating reference equations beyond the age range of subjects used to generate then is not recommended. (C) 2004 Wiley-Liss, Inc.

Since cross-infection occurs between cystic fibrosis (CF) siblings, we hypothesized that subsequent siblings may acquire respiratory pathogens at an earlier age and have a more severe course of pulmonary disease. We studied a retrospective cohort of 31 sibling pairs from the CF database at the Hospital for Sick Children. Kaplan-Meier curves and modified log-rank tests were used to test sibling differences in age of acquisition of Pseudomonas aeruginosa (PA), Staphylococcus aureus (SA), or any positive culture. Differences in disease severity outcomes were explored. Older siblings were more likely to have both SA and any CF pathogen first isolated from respiratory culture at an older age than younger siblings (P = 0.0050 and P = 0.0008, respectively, by modified log-rank tests). However, more of the older siblings were positive on first culture at time of diagnosis, introducing an age-of-diagnosis bias. Hospitalization rates, courses of oral antibiotics, FEV1 % predicted, and weight and height measurements were not better in the older children. No differences in clinical parameters were found between older and younger siblings. The apparent finding of younger age at first isolation of pathogens from respiratory cultures in younger siblings is likely because many older siblings were already infected with these organisms at time of diagnosis. Pediatr Pulmonol. 2004; 37:407–412. © 2004 Wiely-Liss, Inc.

Objective: To examine the efficacy of oral dexamethasone in acute bronchiolitis. Study design: A double-blind randomized, placebo-controlled trial involving 70 children

The objective of this study was to evaluate relative efficiency in vitro of four reusable breath-enhanced nebulizers (Pari LC Star, Medic-Aid Ventstream, Devilbiss PermaNeb, Salter Ultramist), and to integrate the in vitro performance data of the nebulizers with the respiratory patterns of four cystic fibrosis (CF) patients to compare efficiency in vivo of each device for each individual patient. Six nebulizers of each type were used to nebulize a solution of 2.5 mg (0.5 mL) albuterol with 3.5 mL of 0.9% saline. Total albuterol output and the rate of albuterol output of each device were measured until end-nebulization and for 4 min, respectively, using entrained flows from 0 to 20 L/min through the inspiratory valve of the device. Particle size distributions and the respirable fraction (RF) were evaluated by laser diffraction technique. Regression analysis of the change in rate of output and change in RF values with inspiratory flows was done to characterize each nebulizer's performance over the complete range of interest. Actual breath tracings of four CF patients were integrated with the equations specific to the in vitro performance of each nebulizer and in vivo nebulizer efficiency was calculated. The change in efficiency in vitro from 0 to 20 L/min flow, respectively, was highest for the Star (44-57%) and lowest for the Ultramist (13-15%). The mean predicted efficiency in vivo for the Star was threefold that of the Ultramist. Although all four nebulizers are breath-enhanced in design, clearly there are measurable differences in the performance and efficiency of each type. The Pari LC Star nebulizer has proven to be the nebulizer of choice among the devices tested.

Importance Routine use of pulse oximetry has been associated with changes in bronchiolitis management and may have lowered the hospitalization threshold for patients with bronchiolitis. Objective To examine if infants with bronchiolitis whose displayed oximetry measurements have been artificially elevated 3 percentage points above true values experience hospitalization rates at least 15% lower compared with infants with true values displayed. Design, Setting, and Participants Randomized, double-blind, parallel-group trial conducted from 2008 to 2013 in a tertiary-care pediatric emergency department in Toronto, Ontario, Canada. Participants were 213 otherwise healthy infants aged 4 weeks to 12 months with mild to moderate bronchiolitis and true oxygen saturations of 88% or higher. Interventions Pulse oximetry measurements with true saturation values displayed or with altered saturation values displayed that have been increased 3 percentage points above true values. Main Outcomes and Measures The primary outcome was hospitalization within 72 hours, defined as inpatient admission within this interval or active hospital care for greater than 6 hours. Secondary outcomes included the use of supplemental oxygen in the emergency department, level of physician agreement with discharge from the emergency department, length of emergency department stay, and unscheduled visits for bronchiolitis within 72 hours. Results Forty-four of 108 patients (41%) in the true oximetry group and 26 of 105 (25%) in the altered oximetry group were hospitalized within 72 hours (difference, 16% [95% CI for the difference, 3.6% to 28.4%]; P = .005). Using the emergency department physician as a random effect, the primary treatment effect remained significant (adjusted odds ratio, 4.0 [95% CI, 1.6 to 10.5]; P = .009). None of the secondary outcomes were significantly different between the groups. There were 23 of 108 (21.3%) subsequent unscheduled medical visits for bronchiolitis in the true oximetry group and 15 of 105 (14.3%) in the altered oximetry group (difference, 7% [95% CI, −0.3% to 0.2%]; P = .18). Conclusions and Relevance Among infants presenting to an emergency department with mild to moderate bronchiolitis, those with an artificially elevated pulse oximetry reading were less likely to be hospitalized within 72 hours or to receive active hospital care for more than 6 hours than those with unaltered oximetry readings. This suggests that oxygen saturation should not be the only factor in the decision to admit, and its use may need to be reevaluated. Trial Registration clinicaltrials.gov Identifier:NCT00673946

Study objective: To compare the effect of the prone position (PP) vs supine position (SP) on oxygenation in children with acute respiratory failure (ARF). Design: Prospective, randomized controlled trial. Setting: A 36-bed pediatric critical-care unit in a tertiary-care, university-based children’s hospital. Patients: Ten children (mean [SD] age, 5 6 3.6 years) with ARF with a baseline oxygenation index (OI) of 22 6 8.5. Interventions: Following a period of stabilization in the SP, baseline data were collected and patients were randomized to one of two groups in a two-crossover study design: group 1, supine/prone sequence; group 2, prone/supine sequence. Each position was maintained for 12 h. Lung mechanics and acute response to inhaled nitric oxide were examined in each position. Measurements and main results: OI was significantly better in the PP compared to the SP over the 12-h period (analysis of variance, p 5 0.0016). When patients were prone, a significant improvement in OI was detected (7.9 6 5.3; p 5 0.002); this improvement occurred early (withi n2hi n 9 of 10 patients) and was sustained over the 12-h study period. Static respiratory system compliance and resistance were not significantly affected by the position change. Inhaled nitric oxide had no effect on oxygenation in either position. Urine output increased while prone, resulting in a significantly improved fluid balance (1 6.6 6 15.2 mL/kg/12 h in PP vs 1 18.9 6 13.6 mL/kg/12 h in SP; p 5 0.041). No serious adverse effects were detected in the PP. Conclusion: In children with ARF, oxygenation is significantly superior in the PP than in the SP. This improvement occurs early, remains sustained for a 12-h period, and is independent of changes in lung mechanics. (CHEST 2001; 119:211‐218)

Study objectives: To develop practical ways ofnebulizing colistin by determining the rate of drug output, total drugoutput, and particle-size distribution of two commercially availablejet nebulizers, the disposable Hudson 1730 Updraft II (Hudson Respiratory Care; Temecula, CA) and the reusable Pari LC Starbreath-enhanced nebulizer (Pari Respiratory Equipment; Midlothian, VA). Methods: The nebulizers contained colistin, 75 mg, in 4 m, L of isotonic solution. Particle-size distribution was measuredby helium-neon laser diffraction, allowing calculation of therespirable fraction (RF), the mass of aerosol comprised of droplets Results: The mean (95% confidenceinterval [CI]) total rate of output of the Updraft II was 2.6 mg/min(2.0, 3.1; n = 4) with 1.3 mg/min (1.0, 1.5) mg/min within the RF. The rate of output of the LC Star increased in a quadratic relationshipto the inspiratory flow, delivering 1.8 mg/min (0.7, 2.0; n = 4) with1.4 mg/min (1.3, 1.6) within the RF, and 6.2 mg/min (5.6, 6.8) with 5.3mg/min (4.8, 5.7) within the RF, at 0 L/min and 20 L/min inspiratoryflows, respectively. Efficiency, as the rate of expected pulmonarydeposition divided by rate of total output, was then calculated. The LCStar estimated 56% (51, 61) efficiency, with pulmonary delivery of29% (26, 32) of the charge of the nebulizer, compared to the Updraft II at 22% (22, 23) efficiency and expected pulmonary deposition of10% (10, 10) of the dose. Conclusions: Colistin canbe successfully nebulized with both nebulizers tested. This studyprovides an estimate of in vivo efficiency and expectedpulmonary deposition that may be used in futuretrials.

In order for an individual FVC maneuver to be considered acceptable according to the 1994 American Thoracic Society (ATS) standards it must meet end of test (EOT) criteria of a minimum expiration time of 6 s with minimal volume change (0.03 L) over 1 s. We have found that while these criteria are often not met in children, most of the tests do meet the ATS criteria for reproducibility with repeated efforts. We, therefore, sought to develop new EOT criteria that would be more appropriate for children and in keeping with the findings for reproducibility. Using an exponential curve fitting of the volume time tracing, we determined a theoretical curve that closely approximated the actual curve (mean difference between actual and derived FEV1 0.01 +/- 0.04 L). The theoretical FVC (FVCFULL) at the point where the curve reached its asymptote was then determined using the fitted curve. Since this point could be difficult to reach for some patients, 95% of FVCFULL (FVC95) was proposed as the new EOT in children. Data from 382 patients were reviewed. Their ages ranged from 5 to 18 yr and their FEV1s from 21 to 120% of predicted. Only 19% of the patients met current ATS EOT requirements despite the fact that 91% met the reproducibility criteria for both FEV1 and FVC. However, 90% of them reached their FVC95. When this was broken down by age, 37% of those < or = 7 yr failed to reach FVC95 whereas only 4% of the older children failed to do so. It is proposed that patients be coached to obtain maximal effort and that the curves be individually fitted to an exponential equation to determine whether the patient has achieved EOT as defined by FVC95.

It has been suggested that during tidal breathing, the time to maximal expiratory flow, as a proportion of total expiratory time (Tme/TE), can be used as an index of airways obstruction. However, the relationship of Tme/TE to lung mechanics in infants is unclear. We examined this relationship in 42 premature infants (21 intubated and 21 not intubated) by comparing direct measures of pulmonary mechanics (lung resistance, dynamic lung compliance, and lung impedance) with Tme/TE measured over the same sample of tidal breathing. Tme/TE was positively correlated with lung compliance, expressed as a percent of the predicted value, in both intubated (r = 0.69, p < 0.005) and nonintubated (r = 0.64, p < 0.02) infants. There was no significant association between Tme/TE and lung resistance, expressed as a percent of the predicted value, in intubated (r = 0.32) and nonintubated (r = 0.23) infants. Tme/TE also showed, in nonintubated infants, a positive association with lung impedance, expressed as a percent of the predicted value, on the basis of the predictive values for compliance and resistance at the infant's unique respiratory rate, but this was significant only because of the influence of compliance on Tme/TE. These findings suggest that, in infants, the relationship between pulmonary mechanics and Tme/TE is complex, with Tme/TE being influenced by the elastic rather than the flow-resistive properties of the lungs.

The noninvasive measurement of cardiac output (Q) by the Indirect Fick CO2-rebreathing technique requires mixed venous P CO2 (P CO2) to be determined by the rebreathing maneuver, and Pa CO2 to be estimated from end-tidal P CO2 (PET CO2). Previous work has suggested that although P CO2 can be determined, Pa CO2 cannot be accurately estimated in patients with significant airflow limitation. Nineteen patients with cystic fibrosis who had severe airflow limitation (%FEV1, 29.3 +/- 7.12 SD) were studied during steady-state exercise at 50% of their measured maximal work capacity. Estimated Pa CO2 was slightly lower than Pa CO2 measured from blood samples obtained from an indwelling arterial catheter (measured: 45.2 +/- 4.92; estimate: 42.7 +/- 5.68 mm Hg). To calculate arterial blood content, the values derived from Pa CO2, pH, hemoglobin (Hb), and O2 saturation were compared with those derived from PET CO2 and O2 saturation, where (1) pH was assumed to be 7.40 and Hb was measured, and (2) pH was assumed to be 7.40 and Hb was assumed to be 15 g/dl (measured mean pH, 7.34; Hb, 14.4 g/dl). No difference in arterial CO2 content was seen between the three methods (measured: 47.53 +/- 5.17; estimate 1: 49.57 +/- 6.58; estimate 2: 49.12 +/- 6.61 ml/100 ml). As pH and Hb can also affect mixed venous CO2 content, the effect on Q was also assessed. Both estimates fit closely with measured Q (r2=0.77 and 0.76), with intercepts not different from zero and slopes not different from 1, and coefficients of variation of 13.5 and 14.6%. When viewed with regard to the confidence intervals for Q as a function of O2 consumption, Q was altered to a minor extent. We conclude that the use of PET CO2 to estimate Pa CO2 can give reasonable values for Q determined noninvasively in patients with severe airflow limitation.

Commercially available automated pulmonary monitors are used increasingly in neonatal intensive care units. However, detailed information regarding the static and dynamic accuracy of these monitors is rarely available. Collaboration between scientists, clinicians, and manufacturers is essential to establish improved technical standards and protocols for testing of equipment and for the development of more reliable neonatal pulmonary monitors. The aim of this study was to develop a protocol for the in vitro assessment of commercial infant pulmonary function equipment which could be applied within the laboratory to provide rapid feedback to the manufacturer. A recently released neonatal pulmonary monitor, the Bicore CP100 (software version 3.3), was selected for the development of this protocol. The deadspace and resistance of the measuring device were determined. The flow and airway pressure measuring systems were evaluated alone and connected to a tracheal tube for both static accuracy and frequency response. The pressure— volume relationship of the esophageal balloon was determined and its static accuracy and frequency response were assessed. The algorithms for on-line calculations were checked and their correct application confirmed by examination of an ASCII data print out. Finally, the pulmonary monitor was tested during intermittent positive pressure ventilation of a neonatal lung model of known compliance and resistance. © 1995 Wiley-Liss, Inc.

The American Thoracic Society (ATS) recommendations to establish reproducibility of the forced expiratory volume in one second (FEV1) are that the value come from "at least 3 acceptable forced expiratory curves" where "the largest forced vital capacity maneuver (FVC) and the second largest FVC should not vary by more than 5%." It has been suggested that there is a "negative effort dependence" of the FEV1 and, alternatively, that the magnitude of the FVC influences the FEV1. We examined the relationship between FEV1 and a direct measurement of effort, or work, defined as the area under the alveolar pressure-volume curve in 1 s. Thirteen normal individuals and 17 patients with cystic fibrosis or asthma were instructed to make a series of maximal efforts, as in routine testing. Comparing the maneuver that resulted in the greatest work to that with the lowest work, all with FVCs within 5% of one another, there was no correlation between change in work and change in FEV1 (delta FEV1). There was a significant relationship between delta FEV1 and changes in FVC (r = 0.49, p0.01). The delta FEV1 did not correlate with the degree of hyperinflation (the FRC) or degree of airflow limitation (the initial FEV1). The magnitude of changes in FEV1 was small and almost always within acceptable limits for reproducibility. Because a larger FVC is due either to an increased inspiration, which could affect the FEV1, or to an increased expiratory reserve volume, which occurs only after the first second, these results emphasize the importance of a maximal inspiration at the start of the test.

The measurement of resistive and elastic components of the respiratory system in neonates has been used to define disease severity and the response to therapy. The lung resistance (RL) and dynamic lung compliance (CLdyn) partition the impediment to gas flow into two components, each of which may be altered independently. The concept of lung impedance (ZLdyn) is the combined effect of the elastic and resistive loads presented to the respiratory muscles, which determines the gas flow that will result from the pressures generated by the respiratory muscles. In a first order system where RL and CLdyn are single values (independent of volume or respiratory rate), ZLdyn is the vector sum of the reactive [1/2 pi fb x CLdyn)] and resistive (RL) components at the infant's breathing rate (fb), if the transpulmonary pressure (Ptp) generated by the respiratory muscles during spontaneous respiration can be modeled mathematically by a sinusoidal function. Furthermore, the phase angle (theta) between the impedance and the resistive component will represent the relative magnitude of the resistive and reactive components. The validity of this model can be establishing by comparing the calculated theta to the observed temporal difference (measured theta) between the Ptp and flow derived from the polygraph tracing. This hypothesis was tested in 10 spontaneously breathing neonates with lung disease of differing etiology and severity. No significant difference was found between the measured and calculated theta values (mean difference, 1.2 +/- 3.9 degrees).(ABSTRACT TRUNCATED AT 250 WORDS)

In all rapidly changing systems, an appropriate response time of all sensing devices is essential for the accurate conversion of a physiological parameters to a proportional electrical signal. The frequency response of equipment is the ability to accurately reflect both the magnitude and temporal relationship of dynamic events over a defined frequency range. The phase lag expresses the temporal delay between the physical event being measured and the output signal. The attenuation expresses diminution of the amplitude ratio of the output signal in relation to the input signal over a range of frequencies. We have developed a method that specifically addresses the measurement of frequency response and attenuation of pneumotachographs and low pressure transducers. The system consists of a 81 liter rectangular box separated in the middle by a 30.5 cm acoustic loudspeaker, the cone sealed by latex, and driven by a signal generator coupled to a low frequency amplifier. This system can produce an undistorted sinusoidal signal between 0 and 20 Hz, and the peak flow through the pneumotachograph is only minimally affected by changes in frequency. Rapid analysis is possible using an oscilloscope to produce Lissajou loops. There is no measurable attenuation between the electrical signal and the pressure generated over frequencies from 1 to 20 Hz. The system is accurate at low frequencies and can generate appropriate signals over the frequency range of interest for respiratory applications, and it can be inexpensively constructed.

The use of spirometry in the assessment of children with asthma is taking on new importance with the realization that considerable airway obstruction may exist in the absence of clinically detectable abnormalities. There has been controversy over the value and relative sensitivity of various spirometry indices. This study evaluated the forced expiratory flow between 25% and 75% of vital capacity (FEF25-75), forced expired volume in 1 second (FEV1), and the ratio between the FEV1 and the forced vital capacity (FVC) in 100 asthmatic children aged 6-17 years, 29 of whom were wheezing at the time of the evaluation. All children with clinical wheezing had a FEV25-75 < 2 standard deviations (SD) below the mean (-2 SD), whereas 8 had a normal FEV1. The majority of the wheezing children had abnormalities of all 3 indices, whether expressed as < or = -2 SD or, in the case of the FEV1/FVC, arbitrarily taken as < 80%. Sixty-seven children of the entire study group had at least 1 abnormal spirometric index, but 38 of these had no clinical abnormalities. Twelve children had a reduced FEF25-75 as the only abnormality. These results suggest that FEF25-75 is a sensitive index of airway obstruction.

Pulmonary function tests in adults with sickle cell disease have shown a restrictive pattern that has been attributed to the sequelae of acute chest syndrome (ACS). We compared pulmonary function test results in 37 children with sickle cell anemia (20 with SS hemoglobin (HbSS), 14 with SC hemoglobin, and 3 with S beta hemoglobin) with those in 22 control subjects matched for sex, race, and height and compared pulmonary function in patients with and without a history of ACS. Of the 10 patients with a history of ACS, all but one had HbSS. Pulmonary function tests measured forced vital capacity (FVC), the diffusion capacity of carbon monoxide, and the plethysmographic determination of lung volumes. The FVC and forced expiratory volume in 1 second (FEV1), expressed as the percentage of the predicted value, were significantly less for those with HbSS with or without a history of ACS than for control subjects (p0.05), but the FEV1/FVC ratio, an index of airway obstruction, was normal in all groups. Total lung capacity was also significantly lower in patients with HbSS with or without a history of ACS than in control subjects (p0.05), but the ratio of residual volume to total lung capacity, another index of airway obstruction, was normal. We conclude that children with sickle cell disease, particularly those with HbSS, may have abnormally small lungs that function normally relative to their size; clustering of ACS episodes is not specifically associated with the observed abnormality.

A reduction of lung recoil pressure could aggravate any airflow limitation that might be present in patients with cystic fibrosis (CF) or asthma. In a group of 22 children and young adults (8 with cystic fibrosis, 8 with asymptomatic asthma, and 6 healthy controls) aged 8-24 years, lung recoil pressure (Pst) at 100%, 90%, and 60% of TLC and static lung compliance (Cst) were measured using an esophageal balloon. The indices of airflow limitation, including maximal expiratory flow at 25% VC (Vmax25), forced expiratory volume in 1 second (FEV1), and specific airway conductance (sGaw), were also measured. In all patients, Vmax25 was reduced, the airway obstruction being more pronounced in patients with CF. Pst was reduced in CF and asthma, again more in the patients with CF. Cst was normal in both groups because the pressure volume curve was shifted up and to the left. There were significant correlations between Pst at 60%, 90%, and 100% of TLC and both Vmax25 and FEV1 (P < 0.01). sGaw correlated with Pst90 and Pst60 (r = 0.47 and 0.53, respectively; P < 0.05 for both). No correlation was found between Cst and Pst at any lung volume. No correlations were observed between Cst and Vmax25, FEV1, or sGaw. These results suggest that loss of elastic lung recoil pressure is a factor in airflow limitation of children and young adults with CF or asthma.

Desaturation in patients with sickle cell anemia (SCA) can lead to intravascular sickling and vascular occlusion. The increased metabolic demands of exercise tend to increase oxygen extraction, giving rise to a fall in saturation in the capillary bed that may predispose to sickling. This could be minimized with an increase in cardiac output. The aims of this study were to assess the role of increased stroke volume (SV) in augmenting cardiac output (Q) and to estimate the role of enlarged arteriovenous O2 content difference in maintaining O2 transport in children with SCA. A group of 30 children with SCA (Hb 65 to 133 g/L) and 16 healthy controls of the same racial group and of similar height and weight performed incremental and steady-state exercise at 50% Wmax. Cardiac output (Q) was measured by the indirect (CO2) Fick method during steady state. The slope of delta HR/delta VO2 during incremental exercise was higher in SCA subjects compared with controls (4.01 +/- 1.73 versus 2.80 +/- 0.61 bpm per ml/min/kg VO2, p = 0.001). Q for VO2 was abnormally high in patients, particularly older ones with lower Hb levels. HR (% predicted) was higher in patients than in controls (106 +/- 11 versus 92 +/- 8% predicted, p less than 0.0001), as was SV (113 +/- 16 versus 98 +/- 14% predicted, p = 0.002). Multiple linear regression of Q % predicted and SV % predicted on Hb and age showed a positive correlation with age and a negative correlation with Hb (r = 0.84 for Q and r = 0.76 for SV).(ABSTRACT TRUNCATED AT 250 WORDS)

Adults with sickle cell anemia (SCA) have restrictive lung impairment, increased alveolar dead space, and hypoxemia. These factors, together with increased anaerobic metabolism, are thought to cause exercise hyperventilation. To assess the role of each of these in children, 34 patients with SCA and 16 control subjects performed pulmonary function and exercise tests. Twenty-eight patients with SCA had spirometric values and lung volumes, and all but two patients with SCA had arterial saturation greater than 91% during exercise. Despite a low VO2max (30.07 +/- 6.55 ml/min/kg), the ventilatory anaerobic threshold (VAT) in the patients occurred at a similar %VO2max as in the control subjects (69 +/- 9% versus 63 +/- 12%). The slope of the delta VE/delta VCO2 relationship for sub-VAT work was steeper in the patients (29.4 +/- 6.5 versus 24.7 +/- 5.2, p = 0.01), and the ventilatory equivalent for CO2 (VE/VCO2) in steady-state exercise was greater in the patients than in the control subjects (33.2 +/- 3.5 versus 30.8 +/- 3.5, p = 0.03). End-tidal PCO2 did not differ (38.3 +/- 3.0 versus 39.2 +/- 3.1), indicating equivalent alveolar ventilation. The patients had a higher dead space:tidal volume ratio (VD/VT) than did the control subjects (0.204 +/- 0.033 versus 0.173 +/- 0.024, p = 0.0005). The PaCO2 was significantly lower in those with lower Hb, but there was no difference in pH. In conclusion, children with SCA have an increased exercise ventilatory response caused in part by increased physiologic dead space, and in part by their low Hb. The greater dead space may be the result of sickle cells impairing capillary perfusion to ventilated alveoli.

In 377 children, the commercially available Siregnost FD-5 was used to measure respiratory system resistance (Rrs) by forced oscillation at 10 Hz. The children were between 3 and 18 years of age and, by a detailed questionnaire and conventional pulmonary function testing in 335, they were shown to be representative of the normal pediatric population. There was a linear relationship between Rrs and height (Rrs = 13.9-0.064 x ht (cm), r = -0.87). Children less than 6 years of age had no trouble with using the forced oscillation technique. The smoking of tobacco in the house, the presence of carpets in the child's bedroom, or an atopic family history, alone or in combination, had no influence on Rrs or on any spirometric measure. Forced oscillation is useful in children too young to be able to cooperate with conventional pulmonary function testing.

Previous pulmonary function studies in subjects with thalassemia major (TM) who were on regular transfusion programs have demonstrated results ranging from small airway obstruction to a restrictive pattern. Ten subjects with TM were studied pre- and postdiuresis, and again 24 hr after transfusion, in order to evaluate the role of possible fluid overload in altering pulmonary function. Subjects underwent spirometry and had lung volume and flow volume curves (MEFVC) measured in a volume displacement plethysmograph while breathing air and a mixture of 80% helium and 20% oxygen (HeO2). Six patients had pulmonary mechanics measured with esophageal balloons in place. Baseline function was normal and no change occurred following diuresis. Following transfusion, the volume of isoflow (VisoV) decreased, but other parameters did not change. Subsequent analysis revealed 5 subjects with an initial VisoV greater than 20 (% FVC) but, paradoxically, less evidence of flow limitation in the small airways than those with a VisoV less than 20 (% FVC). Posttransfusion, in those subjects with an initially high VisoV, the Vmax25(air) tended to fall without a change of MEFVC in HeO2, resulting in a decreased VisoV. This was interpreted as evidence of subtle abnormalities in the small airways caused by volume expansion, raising doubts about the value of the VisoV as a measure of small airway disease. As a group, our subjects did not demonstrate any abnormalities in baseline function. Some subjects had mild flow limitation in small airway while other developed comparable levels of flow limitation following the volume expansion associated with transfusion.

Malnutrition and hyperinflation may both lead to respiratory muscle weakness. To assess separately the effects of chronic hyperinflation and malnutrition on respiratory muscle strength (RMS), 22 subjects with cystic fibrosis (CF) with both hyperinflation and malnutrition were compared to 10 asthmatic patients, a group with hyperinflation without malnutrition, 9 subjects with anorexia nervosa (AN), a group with malnutrition without lung disease, and 14(6 males and 8 females) control subjects with neither compromise. Nutritional status was assessed by body mass percentile (BMP) and percentage ideal weight (PIWT). RMS was diminished in the AN and CF groups (PImax 90 +/- 27, 88 +/- 31 versus 124 +/- 40 cm H2O, p less than 0.05; PEmax 87 +/- 12, 93 +/- 39 versus 121 +/- 32 cm H2O, p less than 0.05), but no difference was found when the AN group was compared with only the female controls. The decrease in PImax in the CF group was primarily due to the mechanical disadvantage placed on the diaphragm by their marked hyperinflation, a mean RV/TLC ratio of 50 +/- 23%. As older CF subjects had previously been shown to have decreased RMS when malnourished, a CF subgroup in the same age range as the controls was evaluated. RMS in this group did not differ from controls despite the presence of malnutrition and hyperinflation. RMS is mildly influenced by nutritional status as assessed by BMP and PIWT but not to any degree of clinical significance.

Children with croup are often treated with humidity even though this is not scientifically based, consumes time, and can be harmful. Although humidity using the traditional blow-by technique is similar to room air and no water droplets reach the nasopharynx, particles sized for laryngeal deposition (5-10 microm) could be beneficial.To determine whether a significant difference in the clinical Westley croup score exists in children with moderate to severe croup who were admitted to the emergency department and who received either 100% humidity or 40% humidity via nebulizer or blow-by humidity.A randomized, single-blind, controlled trial conducted between 2001 and 2004 in a tertiary care pediatric emergency department.A convenience sample of 140 previously healthy children 3 months to 10 years of age with Westley croup score of more than 1 or 2 or higher (scoring system range, 0-17); 21 families refused participation.Thirty-minute administration of humidity using traditional blow-by technique (commonly used placebo, n = 48), controlled delivery of 40% humidity (optimally delivered placebo, n = 46), or 100% humidity (n = 46) with water particles of mass median diameter 6.21 microm.A priori defined change in the Westley croup score from baseline to 30 and 60 minutes in the 3 groups.Groups were comparable before treatment. At 30 minutes the difference in the improvement in the croup score between the blow-by and low-humidity groups was 0.03 (95% confidence interval [CI], -0.72 to 0.66), between low- and high-humidity groups, 0.16 (95% CI, -0.86 to 0.53), and between blow-by and high-humidity groups, 0.19 (95% CI, -0.87 to 0.49). Results were similar at 60 minutes. Differences between groups in pulse and respiratory rates and oxygen saturation changes were insignificant, as were proportions of excellent responders; proportions with croup score of 0 at study conclusion; and proportions receiving dexamethasone, epinephrine, or requiring additional medical care or hospitalization.One hundred percent humidity with particles specifically sized to deposit in the larynx failed to result in greater improvement than 40% humidity or humidity by blow-by technique. This study does not support the use of humidity for moderate croup for patients treated in the emergency department.ClinicalTrials.gov Identifier: NCT00230841.

Inspired and expired lung volumes measured by spirometry have been used clinically for over one hundred years and have proved useful in the detection, characterization, and quantification of the severity of lung disease. Measurements of absolute lung volumes, residual volume (RV), functional residual capacity (FRC), and total lung capacity (TLC) have been used clinically for fewer years, are technically more challenging, and the results are more controversial regarding their clinical usefulness. In contrast with the relative simplicity of spirometric volumes, because the measurements of absolute lung volumes include the "inaccessible" space of residual volume, a variety of techniques have been developed to make these measurements. These include gas dilution (as used in the helium or argon dilution technique), gas washout (as used in the nitrogen washout measurements), body plethysmography using a variety of specific methodologies, and radiographic imaging using standard posterior-anterior and lateral chest radiographs and computerized tomography. As part of the ongoing efforts of the American Thoracic Society (ATS) to develop recommendations and standards regarding clinical testing, a workshop was convened and charged with developing recommendations for measuring absolute lung volumes in humans. In order to provide the diversity of expertise necessary to meet these challenges, and with the goal of developing recommendations that could be endorsed by the European Respiratory Society (ERS) as well as the ATS, many of those invited to participate in the workshop were from Europe. It was recognized that these measurements often presented different challenges in infants and children; however, we also concluded that, in the workshop, it would be useful to integrate those with experience in making these measurements in both adult and pediatric environments, not only with the goal of developing more universally applicable recommendations and "standards", but also because we believed that exchanges of information about the measurements unique to either adult or paediatric population might be helpful for better defining optimal techniques and clinical limitations for both groups of subjects. Optimal predictive normal values for lung volumes may be as important as optimal measurement techniques. For this reason we also included a review of normal predictive values. It was recognized that the clinical usefulness of measurements of absolute lung volumes is an important issue (especially in these days of limited resources for medical care), so reviews and developed conclusions regarding the pathophysiology of lung volumes and the clinical applications and usefulness of these measurements were solicited. The scope of the resulting review was considerable. If all of the background information and recommendations developed by consensus were compressed into a single document of length suitable for publication as a

Development of safe and effective vectors remains a major challenge for lung gene therapy. We developed a helper-dependent adenoviral vector for cystic fibrosis (CF) lung gene therapy, using epithelium-specific control elements to drive expression of the CF transmembrane conductance regulator (Cftr) gene. The vector expressed properly localized CFTR in human CF bronchial epithelial cells cultured at an air-liquid interface. Following a single intranasal dose, the vector expressed human CFTR specifically in the airway epithelium of mice, for up to 3 months. Acute inflammation was minimal to moderate. CFTR protein was also detected in the airway epithelium of 2 month-old mice that received one vector dose postnatally. Delivery of the vector to rabbit lung, in an aerosol containing surfactant, yielded strong gene expression (lacZ reporter) specifically in the airway epithelium, including trachea, bronchi, and bronchioles.