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The Division of Lung Diseases of the National Heart, Lung, and Blood Institute (NHLBI) recently held a workshop to identify gaps in our understanding and treatment of childhood lung diseases and to define strategies to enhance translational research in this field. Leading experts with diverse experience in both laboratory and patient-oriented research reviewed selected areas of pediatric lung diseases, including perinatal programming and epigenetic influences; mechanisms of lung injury, repair, and regeneration; pulmonary vascular disease; sleep and control of breathing; and the application of novel translational methods to enhance personalized medicine. This report summarizes the proceedings of this workshop and provides recommendations for emphasis on targeted areas for future investigation. The priority areas identified for research in pediatric pulmonary diseases included: (1) epigenetic and environmental influences on lung development that program pediatric lung diseases; (2) injury, regeneration, and repair in the developing lung; (3) pulmonary vascular disease in children; (4) development and adaptation of ventilatory responses to postnatal life; (5) nonatopic wheezing: aberrant large airway development or injury?; (6) strategies to improve assessment, diagnosis, and treatment of pediatric respiratory diseases; and (7) predictive and personalized medicine for children.

This paper focuses on the main problems that authors of rejected papers have had in their submissions to Pediatric Pulmonology over the past 5 years or so. It is intended as a teaching tool for residents, fellows, allied health personnel, practicing physicians and even some academic physicians who need a refresher on what goes wrong and how they may avoid rejection of their labor. The approach is somewhat lighthearted but nevertheless the message is quite serious.

This paper is an attempt to convey in a lucid way how to go about writing a scientific article for publication in an appropriate journal. Topics covered are: a) reasons to write a paper b) types of papers c) asking a question and formulating an hypothesis d) the complex series of steps necessary before you begin your study e) additional considerations once your study is complete f) the process of writing the paper and g) writing skills. In the concluding remarks I comment on the possibility of rejection of your submission which should not be taken personally. If this does occur it should not deter you from contributing to medical science.

Spinal braces such as the Soft Boston Orthosis (SBO) help stabilize scoliosis and improve sitting, positioning, and head control in individuals with cerebral palsy. However, their impact on pulmonary mechanics in this population has not been studied. We examined the effect of a Soft Boston Orthosis on the pulmonary mechanics and gas exchange in 12 children and young adults (5-23 years of age) with severe cerebral palsy. Pulmonary resistance, compliance, tidal volume, minute ventilation, work of breathing, oxygen saturation, and end-tidal CO2 tension were measured with the subjects seated both with and without the orthosis and in the supine position without the orthosis. There were no significant differences in the measured parameters when comparing subjects with and without their orthoses in the sitting or in the supine position. As would be expected in individuals with severe cerebral palsy, pulmonary resistance was increased (7.33 cm H2O/L/s) and compliance was decreased (0.12 L/cm H2O) compared to reported normal values. Work of breathing was greatest in the sitting position without the orthosis (1.2 dynes/cm), suggesting that the improved positioning achieved with the orthosis may decrease the work of breathing. We conclude that the application of a Soft Boston Orthosis does not impact negatively on pulmonary mechanics and gas exchange in young people with severe cerebral palsy.

We developed a new method for repetitive recording of medullary neurons in fetal sheep in situ. The technique involves chronically fixing the fetal head to the flank of the ewe by way of a Teflon plate that has a removable window. This window allows direct access of a recording electrode to the floor of the fourth ventricle of the fetus. In four of six fetuses, repetitive recordings lasting 3-4 h were possible for up to 6 days. By operating on younger fetuses and with care, this time span could be extended. This novel method should be useful in the future for extracellular and intracellular recordings of neurons in the developing fetus without disturbing the fetal state and for the study of putative neurotransmitters during development with iontophoretic techniques.

In a multicenter, double-blind, placebo-controlled rescue trial conducted at 13 Canadian hospitals, two 5 ml/kg doses of a synthetic surfactant or air placebo were administered to 344 infants with birth weights of 750 to 1249 gm who had established respiratory distress syndrome and an arterial/alveolar oxygen tension ratio less than 0.22. The first dose was given between 2 and 24 hours of age, and the second dose was given 12 hours later to the infants remaining on mechanical ventilation. Infants were stratified at study entry by birth weight and gender. The trial was terminated short of the targeted sample size because significant reductions in mortality were observed in another rescue trial completed in the United States in the same weight class of infants. Despite premature termination of the trial, the rate of survival without bronchopulmonary dysplasia was increased (61% vs 52%; p = 0.046) in infants treated with surfactant. In addition, there was a significant reduction in the incidence of overall pulmonary air leak (46% vs 32%; p = 0.009), pneumothorax (27% vs 17%; p = 0.023), and pulmonary interstitial emphysema (40% vs 28%; p = 0.018) in infants treated with synthetic surfactant. There was no difference in the incidence of bronchopulmonary dysplasia, apnea, or pulmonary hemorrhage. Significant improvements in alveolar-arterial oxygen tension gradient, arterial/alveolar oxygen tension ratio, and oxygen and ventilator requirements through day 7 were present. These findings indicate that rescue therapy with synthetic surfactant can improve outcome for premature infants weighing 750 to 1249 gm with respiratory distress syndrome.

We evaluated the effectiveness of the Home Care Program of Children's Hospital of Winnipeg for ventilator-dependent children by retrospectively examining morbidity and mortality from February 1, 1979, to July 31, 1992. For the 22 study subjects, the cause of chronic respiratory failure was neurologic disorders for 14 (64%) (group A) and pulmonary disorders for eight (36%) (group B). There were no significant differences between groups A and B in the average number of hospital days, readmission rate, or length of stay per admission. Eleven patients have remained ventilator-dependent at home, four no longer require mechanical ventilation, and seven died. Factors such as diagnosis, type of family, home location, age at initiation of mechanical ventilation, and initial duration of hospital stay did not influence morbidity or mortality in either group. Within the overall mortality rate of 32% is a higher rate among patients whose disorders initially carried a poor prognosis. Ventilator-dependent children can be successfully managed at home, with few nonelective hospital readmissions, through a well-organized home care program.

The effect of large doses of salbutamol (S) and ipratropium bromide (IB) were tested in a double-blind, randomized, crossover study. Nine patients with cystic fibrosis (CF), aged 12.8 +/- 2 years (mean +/- SE), were studied for 8 h on 2 separate days. Pulmonary function tests (PFTs) included spirometry (FEV1), lung volumes (FRC), and airway resistance (Raw) measured by body plethysmography. Heart rate (HR) and oxygen saturation (SaO2) were measured before each test. On 1 day patients received S 200 micrograms, S 400 micrograms, and IB 80 micrograms, by inhalation at 45-min interval (sequence A). On the other day, the sequence was IB 80 micrograms, S 200 micrograms, and S 400 micrograms (sequence B). The PFTs were obtained at baseline, 45 min after each inhalation, and 4 and 8 h after baseline measurements. Baseline PFTs (mean +/- SE) were not significantly different on the 2 study days (FEV1, 1.48 +/- 0.1 vs 1.42 +/- 0.1 L; FRC, 2.77 +/- 0.6 vs 2.87 +/- 0.6 L; Raw, 4.04 +/- 0.2 vs 4.00 +/- 0.3 cm H2O/L/s). The FEV1 and Raw improved from baseline after each inhalation, and at 4 and 8 h during both days (p0.05). Forty-five minutes after S 200 micrograms, plus S 400 micrograms, FEV1, FRC, and Raw were not significantly different compared with the values 45 min after IB 80 micrograms, plus S 200 micrograms (1.67 +/- 0.1 vs 1.63 +/- 0.1 L; 2.81 +/- 0.6 vs 2.65 +/- 0.5 L; and 2.98 +/- 0.2 vs 2.66 +/- 0.1 cm H2O/L/s, respectively). The PFTs were not significantly different after maximal doses of IB (80 micrograms) compared with S (600 micrograms). The HR and SaO2 were not significantly different from baseline throughout the study period. These results indicate that both single and sequential therapy have a similar acute bronchodilator effect provided that large doses are used. We speculate that adrenergic and muscarinic pathways are equally important in airflow obstruction in patients with CF.

To test the efficacy of a combined alpha- and beta-receptor agonist in acute bronchiolitis, we compared inhaled racemic epinephrine with salbutamol in a double-blind, crossover, randomized protocol. Twenty-four infants, 4.6 +/- 0.5 (mean +/- SEM) months of age, with their first episode of bronchiolitis were tested. After sedation with chloral hydrate, a clinical score and pulmonary mechanics measurements using simultaneous signals of airflow volume and transpulmonary pressure were recorded. After baseline measurements, infants received either nebulized salbutamol, 0.03 ml/kg, or racemic epinephrine, 0.1 ml/kg. Thirty minutes later, there was a significant decrease in clinical score after treatment with racemic epinephrine compared with the baseline score (p0.001); this difference was not present after salbutamol inhalation (p = 0.42). Only 13 patients had a decrease in clinical score after salbutamol therapy, in comparison with 20 infants treated with racemic epinephrine (p0.01). Both drug decreased respiratory rate, but the decrease was greater after the use of racemic epinephrine (p0.001). There was a significant decrease in inspiratory, expiratory, and total pulmonary resistance after treatment with racemic epinephrine compared with baseline values (p0.01) but no significant change after salbutamol inhalation. There was no significant correlation between the clinical score and pulmonary mechanics either at baseline or after drug treatment. We conclude that racemic epinephrine is superior to salbutamol in the treatment of infants with their first episode of acute bronchiolitis.

We developed a new method to monitor fetal medullary respiratory neurons utilizing a two-stage approach. At 129–133 days of gestation, sheep were anesthetized, and a window was placed over the area of the fourth ventricle. After a recovery period of 3–5 days, the fetus was exteriorized into a saline bath under maternal spinal anesthesia, and the head was connected rigidly to a stereotaxic frame. Microelectrodes were inserted into the area of the nucleus tractus solitarius during rapid-eye-movement sleep, and extracellular recordings of 223 respiratory neurons were analyzed: 76% were inspiratory, 9% expiratory, and 15% phase spanning, as classified by visual and computer correlation to diaphragmatic activity. More detailed analysis of 100 neurons was done to assess the respiratory component (eta 2) by use of a modification of the method developed by Orem and Dick (J. Neurophysiol, 50: 1098–1107, 1983). With use of cohorts of 25 breaths, fetal respiratory neurons were found to frequently change their phase relationship to diaphragmatic activity. The eta 2 statistic of fetal respiratory neurons was not a stable characteristic but changed over time. This could be a reflection of an immature central respiratory system before birth or the lack of major sensory inputs.

A proportion of patients with cystic fibrosis (CF) suffer from increased airway hyperreactivity but their response to bronchodilators is variable. Adrenergic agents may produce an increase, no change or a decrease in forced expiratory volume in 1 second (FEV1). We hypothesized that the variable response might be related to poor aerosol distribution caused by the presence of secretions. Therefore, in 11 children with CF and airway hyperreactivity the influence of pretreatment with either 0.9% saline, salbutamol, or ipratropium bromide on the methacholine challenge test was evaluated in a double-blind, randomized, cross-over study. FEV1 (mean +/- S.E.) did not change following pretreatment with saline, salbutamol, or ipratropium (1.64 +/- 0.22, 1.63 +/- 0.16 and 1.67 +/- 0.19, respectively). All patients demonstrated airway hyperreactivity with a PC20 below 8 mg/mL (geometric mean, 0.41 mg/mL) after saline pretreatment. Salbutamol inhalation significantly increased the PC20 to 1.24 mg/mL (P less than 0.01), but ipratropium bromide was found to be even more effective than salbutamol (PC20 = 7.37 mg/mL) (P less than 0.0001). We conclude that the variable response to bronchodilator is not secondary to impaired aerosol distribution since ipratropium bromide effectively blocked the response to methacholine. The improvement in PC20 without a change in baseline FEV1 following salbutamol suggests that the adrenergic agent altered the contractile mechanism of smooth muscle.

Background Surfactant-replacement therapy is now recognized as a life-saving and safe intervention in small premature infants, but there is little evidence concerning its risks and benefits in larger premature infants. Methods We conducted a placebo-controlled, blinded trial in 1237 infants with respiratory distress who were enrolled at 23 hospitals in the United States and 13 hospitals in Canada. At entry all the infants weighed at least 1250 g, were receiving mechanical ventilation, and had a ratio of arterial to alveolar oxygen tension below 0.22. The initial dose of either the synthetic surfactant (Exosurf, 5 ml per kilogram of body weight) or air (the placebo) was administered less than 24 hours after birth, with a second dose given 12 hours later. A total of 614 infants were assigned to receive surfactant, and 623 to receive placebo. Results Fewer infants in the surfactant group than in the placebo group died before 28 days of age or survived at 28 days with bronchopulmonary dysplasia (7 percent vs. 12 percent, P = 0.002). In the first 28 days of life, there were fewer deaths due to respiratory distress syndrome in the surfactant group (1 percent vs. 3 percent, P = 0.043), lower overall neonatal mortality (4 percent vs. 7 percent, P = 0.04), and a lower incidence of bronchopulmonary dysplasia (3 percent vs. 6 percent, P = 0.008). There was also a significantly lower incidence of pulmonary air leaks, intraventricular hemorrhage, patent ductus arteriosus, seizures, hypotension, and pulmonary hypertension in the surfactant group. The infants treated with surfactant were weaned from oxygen and mechanical ventilation significantly sooner than those given placebo, and they less often required high-frequency ventilation or extracorporeal membrane oxygenation. The primary side effect observed more frequently among the infants who received surfactant treatment was pulmonary hemorrhage (six infants vs. one infant, P = 0.055). Conclusions In infants weighing at least 1250 g at birth who have respiratory distress syndrome, treatment with two doses of synthetic surfactant improves survival and reduces perinatal morbidity.

The effect of theophylline (T) was studied in 12 children with cystic fibrosis (CF) (seven males and five females) aged 7 to 17 yr (mean, 11.8 +/- 2.8). T or placebo (P) was taken for 10 days in a double-blind, crossover controlled trial. During Nights 9 and 10 of each study period, the subjects slept in a sleep laboratory, where complete polysomnographs were recorded. Patients were subdivided according to T blood levels above or below 10 micrograms/ml: five children had a mean serum T of 11.7 +/- 1.6 micrograms/ml (Group 1), and seven patients had serum T levels of 6.7 +/- 1.5 micrograms/ml (Group 2). There was no difference in pulmonary function between the two periods, but Group 2 had significantly better baseline lung function (p less than 0.01). During sleep while on T, Group 1 had a higher mean SaO2 (93.1 +/- 0.3% T versus 90.7 +/- 0.3% P; p less than 0.0001), less time with a decrease greater than 5% in SaO2 from baseline (43.7 +/- 7.9 min T versus 85.8 +/- 7.9 min P; p less than 0.01), and a lower heart rate (HR), (77.9 +/- 5.1 bpm T versus 86.1 +/- 4.2 bpm P; p less than 0.01). Group 2 did not show differences in these parameters. T significantly disrupted sleep as measured by sleep efficiency and total wake time independently of serum level (p less than 0.01). There was no significant effect of T on the incidence of apnea, hypopnea, or body movements during sleep.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of theophylline and cromolyn sodium on sleep was studied in 10 children with asthma who were 10 to 17 years of age (mean 13.5 +/- 2.4 years). Theophylline or cromolyn sodium was taken for 14 days in a double-blind, crossover, placebo-controlled trial. Theophylline blood levels before sleep were 10.2 +/- 4 micrograms/ml during the theophylline period. There was no difference in pulmonary function between the two periods. Theophylline did not disrupt sleep as measured by sleep latency, total sleep time, sleep efficiency, movement time, microarousals, and arousals. Apneic episodes (greater than or equal to 10 seconds) were of central origin and less frequent during the theophylline period (p less than 0.05). Arterial oxygen desaturation (greater than 5% decrease from baseline saturation when awake) was less frequent during the theophylline treatment (p less than 0.05). We conclude that theophylline treatment of the children's asthma did not disrupt sleep and appeared to have a protective effect in regard to apnea, hypopnea, and arterial oxygen saturation.

We describe the development of pediatric pulmonology in North America, from its rudimentary beginning in the early part of the 20th century. Milestones in the history of lung diseases affecting children, such as tuberculosis, cystic fibrosis, asthma, and neonatal lung disease, are discussed. Finally, maturation into a subspecialty recognized by the American Board of Pediatrics is described.

El tiempo inspiratorio previo a la realización de una maniobra espiratoria forzada máxima (FEM) es una variable que no ha sido completamente estudiada en Fibrosis Quística (FQ). El objetivo de este estudio fue evaluar la hipótesis que niños con FQ tendrían mayores volúmenes y flujos espiratorios forzados al disminuir la duración del tiempo inspiratorio. Se estudiaron 16 niños con FQ, en etapa estable, sin haber presentado una exacerbación respiratoria en los últimos dos meses, (10 hombres), de edad 11,9 ± 0,7 años (promedio ± ES), con un FEV1 de 62,8 ± 6,4% predicho. Las pruebas de función pulmonar consistieron en la medición de volúmenes pulmonares estáticos y resistencia de la vía aérea, seguido de evaluación dinámica de la función pulmonar. Esta última medición fue precedida de 3 maniobras inspiratorias diferentes en forma aleatoria [inspiración y detención de 0 segundos (M0), 2 segundos (M2) o 5 segundos (M5)]. El grupo se dividió en pacientes con hiperinsuflación pulmonar detectada por VR/CPT > 30%, (n = 9) y sin hiperinsuflación pulmonar RV/CPT < 30% (n = 7). Los resultados demostraron que, en los pacientes con hiperinsuflación, VEF1 y CVF fueron 8,9 ± 3,4% (p < 0,02) y 9,3 ± 2,1% (p < 0,001) mayores respectivamente, después de M0 en comparación a después de M2 y 2,4 ± 2,8% (p = ns), y 2,8 ± 3,2% (p = ns) menor respectivamente después de M5 en relación a después de M2 (M0 vs M5: p < 0,01 para ambos, VEF1 y CVF). En resumen, en pacientes portadores de Fibrosis Quística e hiperinsuflación, VEF1 y CVF son significativamente mayores luego de realizar una espiración sin detención de inspiración comparado a una detención de inspiración de 2 ó 5 segundos. Sugerimos que los mecanismos de relajación de la musculatura lisa del árbol bronquial pueden ser los responsables de este hallazgo. The time course of the inspiration preceding the maximal forced expiratory maneuver (MFEM) has not been studied in cystic fibrosis (CF). We tested the hypothesis that CF children would have significantly higher forced expiratory volumes (FVC) and flows with decreasing duration of the inspiratory breathhold. We studied 16 stable CF patients (10 males) with no pulmonary exacerbation 2 months prior to the study, aged 11.9 ± 0.7 years (mean ± SEM) with a FEV1 of 62.8 ± 6.4% predicted. Pulmonary function tests included static lung volume and airway resistance measurements, followed by dynamic lung function measurements. The latter were preceded by 3 different inspiratory maneuvers in a random order [breathhold of 0 (M0), 2 (M2) or 5 seconds (M5)]. Patients were divided by the presence of lung hyperinflation (RV/TLC > 30%), with 9 children with hyperinflation and 7 no-hyperinflated patients. We found that, in the hyperinflated CF patients (RV/TLC > 30%), FEV1 and FVC were 8.9 ± 3.4% (p < 0.02) and 9.3 ± 2.1% (p < 0,001) higher respectively after M0 than after M2 and 2.4 ± 2.8% (p = ns) and 2.8 ± 3.2% (p = ns) lower respectively after M5 than after M2 (M0 vs M5: p < 0.01 for both FEV1 and FVC). In summary, in hyperinflated CF children, FEV1 and FVC are significantly higher after no inspiratory breathhold compared to a breathhold of 2 or 5 sec and we speculate that stress relaxation may account for this phenomenon. We suggest that standardization of the inspiratory maneuver is important in lung function studies in CF patients.

The pulmonary vasculitides are one component of a variety of systemic disorders in which there is vascular inflammation. This inflammation may lead to a progressive destruction of the pulmonary circulation, granuloma formation, tissue necrosis and end-organ failure. The vasculitides are uncommon conditions and they involve the lung with variable frequency (Table 1). The true incidence of the systemic vasculitides in children is not known but is probably around 2–5 cases per million population per annum. Only a small proportion of these cases proceed to pulmonary involvement that is clinically significant. However, there is a paucity of lung biopsy examination in most cases so that the incidence of pulmonary involvement may be higher than we think it is on purely clinical grounds. The clinical presentation of vasculitis depends on the size of vessel involved. If medium or large size vessels are affected this will result in infarction, necrosis and end-organ dysfunction. When smaller vessels such as arterioles, capillaries or venules are affected there is leakage of blood into the tissues. In the lung this causes diffuse alveolar hemorrhage. Wegener’s Granulomatosis (WG), first described in l935, involves small and medium size vessels where, in addition to vascular inflammation and tissue necrosis, there is an adjacent granulomatous process. These are areas of central necrosis surrounded by acute and chronic inflammatory cells, histiocytes and giant cells. The lung is involved in the majority of cases and focal segmental glomerulonephritis involving small vessels often causes substantial renal impairment. Often the first manifestation of the disease is in the upper airway including the nose (septal perforation, saddle nose deformity) and in the sinuses (pansinusitis). Diffuse

In this issue of the Journal, Wainwright et al.1 provide data from a clinical trial in which 194 infants hospitalized with bronchiolitis were treated with inhaled epinephrine or placebo. In this age of commercial support for clinical trials, funding is available only when commercial sponsors stand to make a profit from the manufacture of a drug. Thus, Wainwright et al. are to be congratulated for having tackled an important question using a multicenter, randomized, blinded clinical trial that does not involve a new drug. The authors' findings overturn the popular notion that treatment of bronchiolitis with inhaled epinephrine, as compared . . .

Elevated plasma atrial natriuretic peptide (ANP) levels have been shown to blunt pulmonary hemodynamic responses to chronic hypoxia, but whether elevated circulating ANP levels negatively feedback on cardiac expression of the ANP gene is unknown. Using a recently developed strain of transgenic mouse (TTR-ANF) that expresses a transthyretin promoter-ANP fusion gene in the liver, we studied the effect of chronically elevated plasma ANP levels on cardiac hypertrophic and pulmonary hemodynamic responses and expression of the endogenous cardiac ANP gene during chronic hypoxia. Plasma ANP levels were 10-fold higher in TTR-ANF mice than in their non-transgenic littermates. After 3 wk of hypobaric hypoxia (0.5 atm), right ventricular hypertrophy and pulmonary hypertension had developed in both groups of mice, but TTR-ANF mice had lower right ventricle-to-left ventricle plus septum weight ratios (0.39 +/- 0.01 vs. 0.45 +/- 0.02), right ventricular systolic pressures (25 +/- 2 vs. 29 +/- 2 mmHg), and lung dry weight-to-body weight ratios (0.48 +/- 0.03 vs. 0.57 +/- 0.01 mg/g) and less muscularization of peripheral pulmonary vessels (8.3 +/- 1.4 vs. 17.4 +/- 2.5%) than nontransgenic controls. Right atrial and ventricular steady-state ANP mRNA levels were the same in both groups of mice under normoxic and hypoxic conditions despite much higher plasma ANP levels and less pulmonary hypertension in TTR-ANF mice. We conclude that chronically elevated plasma ANP levels attenuate the development of hypoxic pulmonary hypertension in mice but do not suppress cardiac expression of the endogenous ANP gene under normoxic conditions nor blunt the upregulation of right ventricular ANP expression during chronic hypoxia.

Chronically prepared fetal sheep were subjected to 48 h infusions of theophylline, an adenosine antagonist, enprofylline, a xanthine without adenosine antagonism, or saline. Theophylline increased mean (+/- SD) incidence of REM sleep from 49.3 +/- 8.3% to 57.3 +/- 6.7% (p0.02) and wakefulness from 1.3 +/- 1.4% to 8.1 +/- 7.1% (p0.01). On the first day of theophylline infusion incidence of fetal breathing (FB) increased from 37.9 +/- 8.1% to 53.7 +/- 11.6% of total time (p0.002) and from 76.4 +/- 10.2% to 87.6 +/- 10.3% of REM sleep (p0.02). Diaphragmatic EMG/min increased from 6.9 +/- 4.0 to 17.3 +/- 13 arbitrary units (p0.02). By the second day of infusion, FB had returned to baseline value. Enprofylline and saline had no effect. 125 micrograms phenyl isopropyl adenosine (PIA) i.v. caused fetal apnea that was reduced from 143 +/- 45.5 min on the control day to 39.8 +/- 34.7 min (p0.001) during theophylline infusion. Enprofylline and saline had no effect, suggesting that the observed theophylline effect was due to its adenosine antagonism rather than to non-specific xanthine action. We conclude that endogenous adenosine suppresses FB, but since theophylline did not alter the basic relationship between FB and REM sleep it is not primarily responsible for apnea during NREM sleep.

We tested the hypothesis that children with CF who have a significant response to bronchodilator (BD) would respond positively to standard methacholine (Mch) challenge. Our objective was to correlate the response to BD with the concentration that produced a 20% fall (PC20) in forced expiratory volume in 1 second (FEV1). We studied 22 patients (12 males), aged 10.5 +/- 0.7 years (mean +/- SE), with a Shwachman-Kulczycki score 82 +/- 2.6 and baseline FEV1 of 80 +/- 4.5% predicted. Baseline expiratory flows, static lung volumes, and airway resistance were measured before and 30 min after inhaled salbutamol. On a separate day, within 2 weeks, a Mch challenge was given, with doubling concentrations from 0.03 to 8.0 mg/mL. A positive challenge was defined as a PC20 less than or equal to 2.0 mg/mL, and a positive response to BD as a greater than 6% of FEV1 increase. Mch challenge yielded 17 responders (R) with a PC20 of 0.5 +/- 0.1 mg/mL, and 5 nonresponders (NR) with a PC20 of 8.8 +/- 2.9 mg/mL. Baseline FEV1 was 77 +/- 5.3% predicted in R compared to 89 +/- 6.3% in NR (P = less than 0.001). History of springtime rhinitis was positive in 9/17 R and 2/5 NR. No significant correlation was found between baseline FEV1 and PC20, or between change in FEV1 post-BD and PC20. A greater than 6% increase in FEV1 was seen in 14/17 R (83% sensitivity) and in none of the 5 NR (100% specificity). In R, 8/17 patients had baseline FEV1 less than 80% predicted, compared to 1/5 in NR.(ABSTRACT TRUNCATED AT 250 WORDS)

The maturation of the respiratory sensitivity to CO2 was studied in three groups of anesthetized (ketamine, acepromazine) lambs 2–3, 14–16, and 21–22 days old. The lambs were tracheostomized, vagotomized, paralyzed, and ventilated with 100% O2. Phrenic nerve activity served as the measure of respiration. The lambs were hyperventilated to apneic threshold, and end-tidal PCO2 was raised in 0.5% steps for 5–7 min each to a maximum 7–8% and then decreased in similar steps to apneic threshold. The sinus nerves were cut, and the CO2 test procedure was repeated. Phrenic activity during the last 2 min of every step change was analyzed. The CO2 sensitivity before and after sinus nerve section was determined as change in percent minute phrenic output per Torr change in arterial PCO2 from apneic threshold. Mean apneic thresholds (arterial PCO2) were not significantly different among the groups: 34.8 +/- 2.08, 32.7 +/- 2.08, and 34.7 +/- 2.25 (SE) Torr for 2- to 3-, 14- to 16-, and 21- to 22-day-old lambs, respectively. After sinus denervation, apneic thresholds were raised in all groups [39.9 +/- 2.08, 40.9 +/- 2.08, and 45.3 +/- 2.25 (SE) Torr, respectively] but were not different from each other. CO2 response slopes did not change with age before or after sinus nerve section. We conclude that carotid bodies contribute to the CO2 response during hyperoxia by affecting the apneic threshold but do not affect the steady-state CO2 sensitivity and the central chemoreceptors are functionally mature shortly after birth.

Patients with cystic fibrosis had a better acute bronchodilator response to albuterol and ipratropium bromide than to either drug alone. Further studies of long-term efficacy and safety seem justified.

Fifty children (27 females, 23 males) ages 6-15 years who were referred for evaluation of suspected asthma had baseline FEV1 and FEF25-75 of greater than or equal to 80% and FEF50 greater than or equal to 70% of predicted values. All had these tests repeated on the same day, after inhaling salbutamol. On a subsequent day PC-20 (methacholine) was determined as an index of bronchial hyperreactivity (BH). Fourteen age-matched healthy children (6 females, 8 males) were studied in a similar manner. There was no significant relationship between the PC20 and the change in FEF25-75 or FEF50 following salbutamol. There was a negative correlation between the initial FEV1 (% predicted) and the percent change in FEV1 following salbutamol (P less than 0.01). An increase in FEV1 of greater than 6% occurred in 7/12 (58.3%) patients with PC20 less than or equal to 0.25 mg/mL (Group I); in 7/24 (29.2%) patients with PC20 = 0.26-2.0 mg/mL (Group II); in only 1/14 (7.1%) patients with PC20 greater than 2.1 mg/mL (Group III) and in none of those asymptomatic (control) children with PC20 greater than 8.0 mg/mL (Group IV). All subjects who had a change in FEV1 greater than 6% after salbutamol had a PC20 less than 8 mg/mL and this test detected the majority of patients with severe BH. However, although the sensitivity of the test was 100%, the predictive value was only 36%. We conclude that in the presence of a normal baseline FEV1 a change of greater than 6% following salbutamol inhalation is indicative of bronchial hyperreactivity.

Aim. To develop a method for stimulating sweating that is rapid, painless, and avoids the risk of heat stress.Background. Since the discovery that there is a high concentration of sodium and chloride in the sweat of patients with cystic fibrosis of the pancreas in 1953, the sweat test has been performed by placing the patient's body in a plastic bag with or without hot water bottles to stimulate sweating. This method is unsatisfactory because of complications such as hyperpyrexia and heat stroke. Direct injection of a cholinergic agent intradermally is painful and therefore not practical.Methods. A rheostat with a milliampere meter was constructed at a cost of ∼$7 that allowed the iontophoresis of pilocarpine into the skin using negative and positive (2-cm diameter) electrocardiography electrodes. The positive electrode was placed on the flexor surface of the arm over a filter paper soaked in 0.2 mL of 0.2% pilocarpine nitrate. Current (0.2 mA) was applied for 5 minutes and then sweat was collected onto a preweighed filter paper for 30 minutes. Sweat chloride was determined by a polarographic method. Sweat tests were performed on 25 patients with cystic fibrosis (CF), 17 asymptomatic relatives and 27 control patients. Patients with CF had sweat chloride concentration >80 mEq/L; relatives, 32.5 mEq/L (highest 57 mEq/L); and control subjects, 21.1 mEq/L (highest 60 mEq/L).Conclusions. The iontophoresis of pilocarpine into the skin is a rapid, painless, safe, and reliable method for stimulating sweating and facilitating the determination of sweat chloride concentration.