Chronic lung disease in infants--long-term pulmonary sequelae.
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Biomedical subjects
Publications and source records attributed to A L Coates.
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There is limited information concerning the exercise performance of long-term survivors of bronchopulmonary dysplasia (BPD), and much of what is available pertains to those with relatively mild disease. The present study was undertaken to describe exercise responses in patients with a history of severe BPD, defined as those patients with a clinical and radiographic diagnosis of BPD who required supplemental oxygen at least until they were 44 wk postconceptual age and who were discharged home on oxygen. Fifteen children with a history of severe BPD were matched for gestational age with 15 children who had previously had respiratory distress syndrome but who did not develop BPD (Prem). These Prem control children were subsequently compared with 13 healthy control children born at term (Control) who were of similar postnatal age. Participants underwent pulmonary function testing, progressive exercise testing on a cycle ergometer, and a steady-state exercise test with cardiac output determined by CO2-rebreathing. Despite the patients with BPD having a lower FEV1 than those in the Prem group, who had lower values than the Control group (BPD, 64 +/- 21%; Prem, 85 +/- 11%; Control, 95 +/- 8%), the exercise capacity did not differ between the BPD and the Prem and between the Prem and the Control groups (BPD, 84 +/- 15%; Prem, 81 +/- 17%; Control, 91 +/- 12%). However, the BPD patients used a greater percentage of their ventilatory reserve (VEmax/40 FEV1: BPD, 93 +/- 20%; Prem, 67 +/- 12%; Control, 59 +/- 13%). Of the four patients with BPD who had significant oxygen desaturation with exercise, three had the lowest values for FEV1. Cardiac output was appropriate for oxygen consumption in most patients.
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.
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The two most common albuterol preparations used for nebulization are: (1) Ventolin (albuterol) respirator solution (Glaxo Canada Inc; Montreal, Canada) of which 2.5 mg (0.5 mL) is diluted with 2 mL of normal saline solution, and (2) the preservative-free, prediluted Ventolin (albuterol) Nebules PF (Glaxo) (2.5 mg/2.5 mL). The two preparations were compared using both a Hudson 1720 "T" up-draft Neb-U-Mist jet nebulizer and a Hudson 1730 "T" up-draft Neb-U-Mist II jet nebulizer (Hudson; Temecula, Calif), which were driven by a compressor (Pulmo-Aide; Devilbiss; Somerset, Pa) and by dry compressed air at 6 and 8 L/min. Particle size distribution was measured with a particle sizer (Malvern 2600; Malvern Instruments; Malvern, UK) and drug output for the nebulizer was calculated from the differences in predrug and postdrug volume and concentration. Drug availability was defined as the amount of drug carried in particles less than 5 microns in diameter. Drug availability was greater with the albuterol respiratory solution, due to the surface activity of the preservative benzalkonium chloride, for both nebulizers but particularly for the 1720. Differences in drug availability between nebulizers exceeded fourfold depending on the preparation, the nebulizer, and the nebulizing flow. These differences could not have been predicted from the manufacturer's specifications. The results suggest that prediction of drug availability must be based on measurements with the specific preparation and the specific nebulizer used.
The use of inhaled antibiotics in the treatment of cystic fibrosis has become widespread despite controversy in the literature as to the appropriate dosing regimen and its effectiveness. This study compared two tobramycin (T) preparations (one with and one without the addition of albuterol) using two different jet nebulizers in order to determine if drug output would be affected. Using calibrated flows from a dry compressed gas source of 6 and 8 L/min as well as a specific compressor (Pulmo-Aide), the Hudson 1720 nebulizer was compared with the newer disposable Hudson 1730. The albuterol preparation used in this study was the Ventolin (albuterol) Respirator Solution (VRS). The nebulizers were charged with (1) 2 mL T (80 mg/2 mL) with 0.5 mL VRS (5 mg/mL) and normal saline solution to make the total nebulizer charge of 3 or 4 mL, or (2) 2 mL T and either 1 or 2 mL normal saline solution. A laser diffraction analyzer (Malvern 2600) was used to determine the aerosol particle size distribution. From the distribution, the respirable fraction, which is the fraction of aerosol that could enter and remain in the lungs, was calculated. For all solutions and each particular flow, the Hudson 1730 had a larger respirable fraction of T. The addition of VRS lowered the surface tension of the solution in the nebulizer and resulted in a greater output of T. This effect was most apparent for the 3-mL volume fills of the Hudson 1720. The greatest differences were between the 3-mL nebulizer charges of T using the Hudson 1720 driven by a flow of 6 L/min, which produced 8 mg of T in the respirable fraction, compared with 35 mg produced by the Hudson 1730 driven by a flow of 8 L/min. These results suggest that different nebulizers, different nebulizer solutions, and different techniques of nebulization may result in very different amounts of T aerosol output in the respirable fraction.
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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.
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 time course of inspiration has been shown to have a significant influence on the subsequent maximal expiratory flows and timed forced expiratory volumes in healthy adults and those with COPD. The purpose of this study was to evaluate the effect of two different inspiratory maneuvers on the spirogram in 15 patients with cystic fibrosis, aged 13 to 35 years, who had mild to moderate airway obstruction. Patients performed a forced expiratory maneuver either after a rapid inspiration without an end-inspiratory pause or after a slow inspiration with a 4-s end-inspiratory pause. Flow-time and volume-time curves were measured by a pneumotachograph. The mean values of FVC, FEV1, and peak expiratory flow were significantly larger by 11%, 13%, and 26%, respectively, after the rapid inspiration without an end-inspiratory pause compared to the slow inspiration with the end-inspiratory pause. This discrepancy probably reflects differences in effective elastic recoil pressure between the two maneuvers. Although the nature of this phenomenon is not fully understood, our results show that for spirometry in patients with cystic fibrosis, the preceding inspiratory maneuver influences the results. An important corollary is that this inspiratory maneuver should be standardized.
Previous studies suggest that women with asthma are at increased risk of preterm birth. Moreover, drugs (especially beta-agonists) used to treat asthma are also used to treat preterm labor. The authors carried out a case-control study of 555 women from three hospital centers with idiopathic preterm labor (< 37 weeks), including two overlapping (i.e., non-mutually exclusive) subsamples: cases with early idiopathic preterm labor (< 34 weeks) and cases with idiopathic recurrent preterm labor (< 37 weeks plus a previous history of preterm delivery or second-trimester miscarriage). Controls were matched to cases according to race and smoking history prior to and during pregnancy. All subjects responded in person to questions about atopic, respiratory, obstetric, and sociodemographic histories. Subjects in the early and recurrent preterm labor subsamples were also asked to undergo spirometric testing with methacholine challenge 6-12 weeks after delivery. Cases were significantly more likely to report histories of asthma symptoms and physician-diagnosed asthma (matched odds ratios of 2-3) than controls, particularly those cases with recurrent preterm labor. No significant associations were observed, however, with methacholine responsiveness. These results could not be explained by residual confounding by smoking or other variables, nor by selective recall of asthma symptoms and histories by cases. Women with asthma are at increased risk of idiopathic preterm labor. The fact that no such association was seen with methacholine responsiveness suggests that nonatopic, noncholinergic mechanisms may link bronchial and uterine smooth muscle lability.
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.
The single breath test for the measurement of respiratory system resistance and compliance in newborns consists of an end inspiratory occlusion which is subsequently released, allowing expiration to proceed through a pneumotachograph (PNT). The measured flow is then integrated to give volume. The simplicity of the test is one of the major reasons for its popularity. However, some investigators have cautioned against the use of an occlusion distal to the PNT because pressurization of the PNT may introduce artifacts in the flow measurement. Despite this caution, many commercial systems use a pressurized PNT. This study investigated the errors that would result from pressurization of the PNT by providing a step function of flow to two infant PNTs, a Fleisch #0 and a Hans Rudolph 4500, in the unpressurized and pressurized state. In each case there was an initial rapid rise of the flow signal, followed by some overshoot and oscillations that rapidly died out. The overshoot and oscillations for the Hans Rudolph PNT were greater when pressurized whereas pressurization had little effect on the Fleisch PNT. Unpressurized, the two were similar. In either case, the artifact introduced by pressurization of the PNT died out so quickly that it would have little effect on any measurement in an infant.
Although tracheoesophageal fistula and esophageal atresia (TEF-EA) are surgically correctable, late respiratory complications have been reported. We administered a respiratory and gastrointestinal symptom questionnaire and performed standard pulmonary function tests (PF T's) and methacholine challenge testing on an unselected group of 25 subjects with TEF-EA who underwent surgery at our institution between 1963 and 1985. Results were compared to predicted normals, as well as 10 sibling controls. While the mean values of lung function test results for the TEF-EA group were within the normal range, they were significantly different from their siblings. Thirteen of the 25 TEF-EA group (52%), but none (0%) of the controls, had abnormal pulmonary function. This was classified as restrictive in 9 (36%), obstructive in 3 (12%), and mixed in 1. In addition, airway hyperreactivity [defined as a positive methacholine challenge (PC20 < or = 8 mg/mL)], was found in 6 of 18 TEF-EA subjects and 4 of the 9 controls who were evaluated. Comparison of TEF-EA subjects with normal and abnormal PFTs showed no difference in the incidence of tracheomalacia, esophageal strictures or dilatation, recurrent pneumonias, or gastroesophageal reflux. The respiratory symptom score in the subjects and controls was similar, and did not correlate with abnormal pulmonary function. The cause of the pulmonary function abnormalities remains unexplained.
OBJECTIVE: To assess the etiologic role of maternal short stature, low pre-pregnancy body mass index (BMI), and low rate of gestational weight gain in idiopathic preterm labor. METHODS: We carried out a three-center case-control study of 555 women with idiopathic onset of preterm labor (before 37 completed weeks), including two overlapping (ie, nonmutually exclusive) subsamples: cases with early preterm labor (before 34 completed weeks) and cases with recurrent preterm labor (before 37 completed weeks plus a history of prior preterm delivery or second-trimester miscarriage). Controls were matched to cases by race and smoking history. All subjects responded in person to questions about height, pre-pregnancy weight, gestational weight gain, and obstetric and sociodemographic histories. RESULTS: Maternal height, pre-pregnancy weight, and gestational weight gain demonstrated excellent test-retest reliability, with intra-class correlation coefficients of 0.97, 0.99, and 0.91, respectively. Based on matched analyses, women with a height of 157.5 cm or less had an increased risk of idiopathic preterm labor (odds ratio [OR] 1.85, 95% confidence interval [CI] 1.25-2.74), as did those with a pre-pregnancy BMI less than 19.8 kg/m2 (OR 1.63, 95% CI 1.09-2.44) or a gestational weight gain rate less than 0.27 kg/week (OR 1.74, 95% CI 1.16-2.62). Conditional logistic regression models containing all three anthropometric variables and controlling for parity, marital status, language, age, and education yielded virtually identical point estimates and CIs. CONCLUSION: Maternal short stature, low pre-pregnancy BMI, and low rate of gestational weight gain may lead to shortened gestation by increasing the risk of idiopathic preterm labor.
Cardiac output (CO) during exercise can be determined noninvasively by using the indirect Fick CO2-rebreathing technique. CO2 measurements for this technique are usually performed with an infrared analyzer (IA) or mass spectrometer (MS). However, IA CO2 measurements are susceptible to underreading in the face of high O2 concentrations because of collision broadening. We compared an IA (Ametek model CD-3A) with a MS (Marquette model MGA-1100) to see the effect this would have on mixed venous PCO2 (PVCO2) and CO measurements. After calibration with room air and a gas mixture of 5% CO2-12% O2-83% N2, both devices were tested with three different gas mixtures of CO2 in O2. For each gas mixture, IA gave lower CO2 values than did the MS (4.1% CO2: IA, 3.85 +/- 0.01% and MS, 4.13 +/- 0.01%; 9.2% CO2: IA, 8.44 +/- 0.07% and MS, 9.19 +/- 0.01%; 13.8% CO2: IA, 12.57 +/- 0.15% and MS, 13.82 +/- 0.01%). Warming and humidifying the gases did not alter the results. The IA gave lower values than did the MS for eight other medical gases in lower concentrations of O2 (40-50%). Equilibrium and exponential rebreathing procedures were performed. Values determined by the IA were > 10% higher than those determined by the MS for both rebreathing methods. We conclude that all IAs must be checked for collision broadening if they are to be used in environments where the concentration of O2 is > 21%. If collision broadening is present, then either a special high O2-CO2 calibration curve must be constructed, or the IA should not be used for both arterial PCO2 and PVCO2 estimates because it may produce erroneously low PVCO2 values, with resultant overestimation of CO.
When using Boyle's Law for thoracic gas volume (Vtg) measurement, it is generally assumed that the alveolar pressure (Palv) does not differ from barometric pressure (Pbar) at the start of rarefaction and compression and that the product of the change in volume and pressure (delta P x delta V) is negligibly small. In a gentle panting maneuver in which the difference between Palv and Pbar is small, errors introduced by these assumptions are likely to be small; however, this is not the case when Vtg is measured using a single vigorous inspiratory effort. Discrepancies in the Vtg between the "complex" version of Boyle's Law, which does not ignore delta P x delta V and accounts for large swings in Palv, and the "simplified" version, during both a panting maneuver and a single inspiratory effort were calculated for normal control subjects and patients with cystic fibrosis or asthma. Defining the Vtg from the complete version as "correct," the errors introduced by the simplified version ranged from -3 to +3% for the panting maneuver whereas they ranged from 2 to 9% for the inspiratory maneuver. Using the simplified equation, the Vtg for the inspiratory maneuver was 0.135 +/- 0.237 L greater (p < 0.02) than for the panting maneuver. This discrepancy disappeared when the complete equation was used. While the errors introduced by the use of the simplified version of Boyle's Law are small, they are systematic and unnecessary.