Bronchopulmonary dysplasia (chronic lung disease of infancy): an update for the pediatrician.

This paper is a review of the changes that have occurred over the past 35 years in the clinical and radiologic presentation of bronchopulmonary dysplasia (BPD), now more commonly referred to as chronic lung disease of infancy (CLD). Curent thoughts on etiology are only briefly discussed. The major focus is the management of the patient with CLD by the primary care physician once the patient has been discharged from hospital. Oxygen, diuretic, bronchodilator, antiinflammatory and nutritional therapies are discussed in detail. Finally, current information on long-term prognosis and recommendations for the prevention of RSV and influenza infections are reviewed.

Effect of a Soft Boston Orthosis on pulmonary mechanics in severe cerebral palsy.

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.

Recurrent thoracic duplication cyst with associated mediastinal gas.

Mediastinal cysts are not uncommon in the pediatric age group. Presentation varies from an abnormality found on routine chest radiograph to severe respiratory distress and even respiratory failure. Presentation depends on the age of the patient, the location of the lesion, the extent and the size of the mass, and what structures are involved. The case of a six-year-old boy who presented with recurrence of a mediastinal mass associated with gas two years after surgical removal of an infected esophageal duplication cyst is described. No connection between the cyst and the esophagus to explain the presence of gas was documented. This appears to be the first reported case of esophageal duplication cyst associated with mediastinal gas.

Pleural infection in children.

The physiology of pleural liquid formation and stages of pleural effusion are reviewed in this article in our recent experience, only 50% of pleural effusions in hospitalized patients were parapneumonic and only about 7% of these patients could be classified as having an empyema. These findings are in contrast to children 20 to 30 years ago in whom over 40% of parapneumonic effusions were empyemas. Diagnostic approaches are also controversial. The accuracy, sensitivity and specificity of various biochemical tests of pleural fluid have not been assessed in children. It seems reasonable to avoid thoracentesis if the clinician is certain of etiology of the pleural effusion from the history, physical examination, and supporting laboratory data. Treatment is also controversial. Indeed, most patients recover without tube thoracostomy. In our series, only 27% of patients were treated with tube drainage. It is suggested that drainage is necessary to relieve respiratory difficulty or pleuritic pain when effusions are relatively large. The need to drain all empyemas is also a controversial issue both in the child and adult. Clearly, what is needed is a carefully designed multicentered prospective study of pleural effusion in children.

Effect of sinus denervation and vagotomy on c-fos expression in the nucleus tractus solitarius after exposure to CO2.

Exposure to hypercapnia and electrical stimulation of the carotid sinus nerve (CSN) has been shown to induce c-fos expression in several brain stem regions including the nucleus tractus solitarius (NTS). To test whether the labeled neurons were activated directly by hypercapnia or secondarily via the carotid bodies (sinus nerve), adult rats were exposed to either air or 14-16% CO2 for 1 h. Experiments were done on eight groups: (1) exposure to air, (2) exposure to CO2, (3) chronic CSN denervation/CO2, (4) chronic unilateral CSN denervation/CO2, (5) chronic sham CSN denervation/CO2, (6) anesthetized/CO2, (7) anesthetized and acute vagotomy/CO2, and (8) premedicated with morphine, 10 mg s.c., 20 min before exposure to CO2. After exposure to CO2 or air the rats were anesthetized, perfused with 4% paraformaldehyde and the brains processed for immunohistochemical staining for c-fos protein using the PAP (i.e. peroxidase anti-peroxidase) technique. Labeled neurons in the area of the NTS in every second 50- "mu"m section were counted and their position plotted using a microscope and camera lucida attachment. Rats exposed to CO2 had a significantly greater number of labeled neurons in the NTS than those exposed to air. Other interventions, such as CSN denervation, surgery, anesthesia, vagotomy or injection of morphine did not significantly affect the level of c-fos expression in rats exposed to hypercapnia, indicative of central stimulation rather than secondary peripheral input. These responsive neurons may be part of a widespread central chemoreceptive complex.

Technique for repetitive recording from fetal respiratory neurons.

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.

Pleural fluid in hospitalized pediatric patients.

We reviewed 105 charts of children who were hospitalized in a major teaching hospital between 1987 and 1993 with a diagnosis of pleural effusion established by radiographic study of the chest. There were 75 males and 30 females; mean age was 7.2 years (range 1 day-18 years). Pleural fluid was secondary to trauma, renal disease, or malignancy in 31.5% of patients. Parapneumonic effusions were found in the majority of patients, 64/105 (61%). However, in only 38 of the 64 patients (59%) was an organism isolated from any source. The most common bacterial organism cultured was Haemophilus influenzae (11 patients), followed by Staphylococcus aureus (seven patients). In five of 38 patients, a viral etiology was diagnosed. Pleural fluid was examined in only 35 patients (34%) and a pathogen found in only five (three bacterial, one Candida, one respiratory syncytial virus). It was possible to classify only 17 cases as exudate (fluid/blood protein ratio > or = 0.5) and six cases as transudate (fluid/blood protein < 0.5). Of 64 patients with suspected pleural fluid secondary to infection, 25 (39%) underwent thoracentesis and only 17 (27%) required tube drainage. This study demonstrates a wide spectrum of etiologies for pleural fluid in children, as well as the reduced use of thoracentesis or chest tube drainage in suspected infection. We speculate that this is probably because of the extensive empiric use of broad-spectrum antibiotics. The biochemical criteria established for adults for distinguishing pleural fluid exudates and transudates need to be studied in children.

Effects of two rescue doses of synthetic surfactant in 344 infants with respiratory distress syndrome weighing 750 to 1249 grams: a double-blind, placebo-controlled multicenter Canadian trial. Canadian Exosurf Neonatal Study Group.

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.

Morbidity and mortality patterns of ventilator-dependent children in a home care program.

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.

Effect of medullary lesions, vagotomy and carotid sinus denervation on fetal breathing.

Chronically prepared fetal sheep were subjected to bilateral surface lesions of the Area "S" on the ventrolateral medulla and/or to peripheral chemoreceptor denervation by section of the vagus, sinus or both nerves. Sino-aortic denervation or Area "S" lesions reduced the incidence of fetal breathing (FB) for several days. Area "S" lesions also disrupted the pattern of FB; diaphragmatic EMG activity initially was mostly tonic and then of very high frequency, up to 7 Hz. Incidence and pattern of FB generally recovered by 7 days, but mean Ti was reduced in Area "S" lesioned fetuses (0.14 +/- 0.01 sec) compared to nonlesioned fetuses (0.19 +/- 0.01 sec) (P < 0.0001). Respiratory sensitivity to CO2 was variable but not different between control, denervated, and Area "S" lesioned groups. Eight of eight fetuses with Area "S" lesions were unable to initiate breathing at birth, but three sham operated fetuses were born normally. These data suggest that the classical peripheral and central chemoreceptors have a negligible influence on the control of FB, and that breathing activity in the fetus is mediated by a different mechanism than during postnatal life.

The effect of high doses of inhaled salbutamol and ipratropium bromide in patients with stable cystic fibrosis.

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 (p < 0.05). 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.

Fetal respiratory neuronal activity during REM and NREM sleep.

Chronically prepared near-term fetal lambs (129-133 days gestation) were exteriorized into a saline bath under maternal spinal anesthesia, and each head was rigidly connected to a stereotaxic frame. Multibarrel glass electrodes were inserted into the region of the nucleus tractus solitarius (NTS) during fetal breathing (FB) in rapid-eye-movement (REM) sleep. Of a total of 223 neurons, it was possible to record only 6 neurons for which firing amplitude did not change during the transition from REM to non-REM (NREM) sleep. The burst frequency, number of spikes per breath, and association with diaphragmatic activity were variable, with phasic activity preceding FB or disappearing and reappearing during FB. During the transition from REM to NREM sleep, phasic neuronal activity ceased, became tonic, and finally ceased altogether. L-Glutamate increased the number of spikes per breath and caused previous phasic activity to reappear but in NREM sleep produced only tonic activity. We conclude that during REM sleep the fetal respiratory neurons in the region of the NTS are to a large degree influenced by nonrespiratory REM sleep factors and that quiescence of respiratory neurons during NREM sleep is due to the lack of phasic input rather than to direct inhibition. Inhibition of FB during NREM sleep must occur upstream of the NTS neuron.

Influence of prolonged adenosine receptor blockade on fetal sleep and breathing patterns.

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% (p < 0.02) and wakefulness from 1.3 +/- 1.4% to 8.1 +/- 7.1% (p < 0.01). 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 (p < 0.002) and from 76.4 +/- 10.2% to 87.6 +/- 10.3% of REM sleep (p < 0.02). Diaphragmatic EMG/min increased from 6.9 +/- 4.0 to 17.3 +/- 13 arbitrary units (p < 0.02). 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 (p < 0.001) 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.

Effect of racemic epinephrine and salbutamol on clinical score and pulmonary mechanics in infants with bronchiolitis.

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 (p < 0.001); 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 (p < 0.01). Both drug decreased respiratory rate, but the decrease was greater after the use of racemic epinephrine (p < 0.001). There was a significant decrease in inspiratory, expiratory, and total pulmonary resistance after treatment with racemic epinephrine compared with baseline values (p < 0.01) 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.

Analysis of respiratory neuronal activity in fetal sheep.

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.