Naloxone reverses neonatal depression caused by fetal asphyxia.

Pregnant near-term rabbits were given an intravenous dose of saline or the opiate antagonist naloxone and then asphyxiated. The fetuses were delivered by cesarean section and evaluated for respiration, color, muscle tone, response to stimulation, and general activity at 1, 3, 5, 10, 15, and 30 minutes of age. The naloxone-treated pups had significantly better scores during the first 15 minutes after birth than the saline-treated pups. Naloxone did not adversely affect the scores of nonasphyxiated pups. These data suggest that endogenous opiates worsen the neonatal depression caused by intrauterine asphyxia and that this effect can be reversed by naloxone.

Correlations of mechanical stability, morphology, pulmonary surfactant, and phospholipid content in the developing lamb lung.

Pressure-volume characteristics and surface tension measurements of the lamb of 120 to 130 days gestational age were typical of the mature lung in the upper lobes and the immature lung in the lower lobes. By term both upper and lower lobes had findings characteristic of the mature animal. Phospholipid concentration per milligram DNA and per cent saturated fatty acids on pulmonary phosphatidyl choline were relatively constant from 60 to 120 days gestational age; thereafter there was a significant increase in both measurements. These changes usually coincided with an increase in osmiophilic inclusion bodies in the large alveolar cell.A concentration of disaturated phosphatidyl choline per milligram DNA in excess of 0.170 mg per mg was associated with a minimal surface tension below 13 dynes per cm (p < 0.001). Newborn animal lungs contained over 3 times this critical concentration, whereas adult lungs contained 1.5 times this value. The excess disaturated phosphatidyl choline per milligram DNA may represent a reservoir of pulmonary surfactant.

Human pancreatic growth hormone releasing factor (hpGRF-1-40) stimulates GH release in the ovine fetus.

The effects of growth hormone-releasing factor, hpGRF (1-40), on plasma GH levels were studied in chronically catheterized ovine fetuses between 71 to 134 days of gestation. The basal ovine (o) GH levels in the fetus ranged between 41 - 144 ng/ml, while values in the ewe were often less than 6 ng/ml. hpGRF (1-40), 5 micrograms/kg infused into a fetal vein, markedly stimulated GH release in all nine fetuses. The maximum increase above pretreatment levels (net increases) ranged from 65 ng/ml to 498 ng/ml, with a mean net increase of 229 ng/ml. The responses of oGH in fetuses at younger gestational age appeared to be greater than in older fetuses. Mean plasma oPRL did not change after hpGRF infusion. These results indicate that somatotrophs in fetal sheep in mid- and late gestation have receptors for GRF, and GH secretion may be modulated by GRF at this stage of gestation.

Prolonged effects of maternal alcohol ingestion on the neonatal electroencephalogram.

Newborn infants of mothers who drink heavily (greater than 2 oz alcohol per day) during pregnancy have been shown to have hypersynchrony of the EEG. The possibility that hypersynchrony is related to acute alcohol withdrawal was tested. Eleven preterm infants of mothers who drank heavily ("alcoholic") were studied at a postnatal age of 4 to 6 weeks using power spectral analysis of EEG signals. This group was compared with a control group with similar racial and socioeconomic status. In addition, a group of ten "healthy" preterm infants was compared with a carefully matched control group. Total power of the EEG during quiet, indeterminate and rapid eye movement (REM) sleep was 162%, 183%, and 188%, respectively, in the infants whose mothers were alcoholic when compared with their control infants or with the healthy preterm infants and their control infants. It is concluded that ingestion of alcohol during pregnancy may result in potentially serious prolonged effects on brain function of the offspring, even in the absence of dysmorphology.

Bronchopulmonary dysplasia and lung rupture in hyaline membrane disease: influence of continuous distending pressure.

Review of 158 patients with hyaline membrane disease was undertaken. The introduction of artificial ventilation with a positive end-expiratory pressure (IPPB and PEEP) has doubled the prevalence of pneumothorax, pneumomediastinum and interstitial emphysema from 20.7% to 39.7%). Continuous negative distending pressure during spontaneous ventilation (CNP) was associated with a prevalence of lung rupture similar to that occurring spontaneously (4.8%). No patient treated with CNP alone developed bronchopulmonary dysplasia. Patients treated with IPPB with PEEP had a marked decreased prevalence of bronchopulmonary dysplasia (17.2%) when compared to patients treated with IPPB alone (36.2%), probably related to the enhanced overdistension of relatively normal areas of the lung may be related to the increased prevalence of lung rupture seen during IPPB with PEEP.

Hypercapnia alters sleep state pattern.

Mild hypercapnia in the adult animal does not affect sleep pattern but more severe hypercapnia in the fetus increases the duration of REM sleep. Adult male rats were exposed daily for 2-3 h sessions at random to 6, 7, and 8% CO2 or room air. Breathing CO2 caused a 60% increase in sleep onset latency, a 28% decrease in sleep duration, but no change in percent time spent in REM. However, the duration of REM sleep episodes increased by 30%. Thus, in both fetal and adult animals severe hypercapnia appears to have a similar effect on sleep pattern.

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.

Adenovirus bronchiolitis in Manitoba: epidemiologic, clinical, and radiologic features.

We reviewed our experience with 41 children hospitalized from 1974 to 1978 for adenovirus (ADV) bronchiolitis. Thirty-two patients (78 percent) were native Indians between four and 12 months old. In 18 of the 41 patients (43.9 percent) acute complications developed. The five fatal cases (12.2 percent) were confined to native children. The initial chest roentgenograms showed lobar consolidation in 35 patients (85.4 percent). Atelectasis developed in five (12.2 percent) during hospitalization. Sixteen of 25 patients (64 percent) with adequate radiologic follow-up examination had subsequent pneumonias or showed residual chronic changes. The reasons for the predilection of ADV bronchiolitis in native Indian children and the precise effect on subsequent airway function in survivors are unknown and require further study. We emphasize the importance of ADV as a cause of bronchiolitis in native Indian children. Furthermore, this report focuses attention on the contribution of this disease to the spectrum of chronic pulmonary disorders in the pediatric group.

Fetal breathing and development of control of breathing.

Technical advances during the last several decades have greatly facilitated research into fetal physiology and behavior, specifically fetal breathing (FB). Breathing movements have been demonstrated in the fetuses of every mammalian species investigated and appear to be part of normal fetal development. In this review we focus on the methods of measuring FB and on some of the problems associated with these measurements and their interpretation. We also review fetal behavior, the role of the peripheral and central chemoreceptors in spontaneous FB, the fetal respiratory response to hypercapnia and hypoxia, and the transition to continuous breathing at birth. It is clear that in many ways the control of breathing movements in utero differs from that after birth. In particular, inhibitory influences are much more prominent before than after birth. Possibly this is due to the unique fetal situation, in which conservation of energy may be more important than any advantage breathing activity imparts to the fetus.

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.

Maturation of spontaneous fetal diaphragmatic activity and fetal response to hypercapnia and hypoxemia.

The electromyogram (EMG) of the diaphragm, lateral rectus, and nuchal and hindlimb muscles were studied during spontaneous activity and during hypercapnia or hypoxemia in eight fetal sheep from 0.5 to 0.8 gestation (73-128 days). At the earliest gestational age, diaphragmatic EMG activity was mainly tonic and associated with tonic activity of somatic muscles. The stimulus for the diaphragmatic activity originated centrally. Brief periods of a rapid-eye-movement (REM) state characterized by phasic lateral rectus and diaphragmatic activity and absence of nuchal activity were recognized. Furthermore, from 0.5 to 0.7 gestation onward, activity of all muscles increased. Thereafter increased specificity of activity in relation to the apparent REM and non-rapid-eye-movement (NREM) state occurred. With maturation, phasic diaphragmatic activity increased at the expense of tonic activity. The most striking effect of maturation on apnea was a greater proportion of apnea lasting greater than 1 min, but the total duration of apnea as a percent of a total recording remained unchanged. The quantitative response to hypercapnia during maturation was independent of the pattern of spontaneous diaphragmatic activity. Hypercapnia at 0.5 gestation changed the pattern of diaphragmatic EMG activity from mainly tonic to phasic. Thus the central chemoreceptors and appropriate neuronal pathways are present and functional as early as 0.5 gestation. Hypercapnia at 0.5 gestation caused a shift in diaphragmatic EMG power to lower frequencies similar to that found during control conditions in the older fetus. This might suggest that during maturation there is increased recruitment of phrenic motoneurons. Hypoxemia abolished tonic somatic activity at 0.5 gestation and decreased phasic diaphragmatic activity at more advanced gestational ages. Therefore the central inhibitory mechanisms of hypoxemia are developed by 0.5 gestation.

Stimulation of fetal breathing activity by beta-adrenergic mechanisms.

Experiments were done on chronically prepared fetal lambs, 125-135 days gestation, to test the effects of various catecholamines on fetal breathing (FB) as well as the influence of isoproterenol on the fetal respiratory response to hypoxemia. Bolus injections of epinephrine, norepinephrine, and isoproterenol (5-20 micrograms) were administered via the lingual artery or femoral or jugular vein during periods of FB activity or apnea. The effects of epinephrine and norepinephrine on FB were variable and not statistically significant. Isoproterenol produced a significant increase in FB, frequency of breathing, and mean inspiratory effort, when infused during rapid-eye-movement (REM) sleep but it failed to induce FB during non-rapid-eye-movement (NREM) sleep. The positive response during REM sleep was absent following pretreatment with 3-5 mg propranolol and after bilateral section of the sinus nerves. The effect of hypoxia on FB was tested before and during constant infusion of isoproterenol (1 microgram/min iv). A reduction of the fetal arterial PO2 by 3-10 Torr produced the characteristic depression of FB in either situation. These results indicate that the fetal carotid body chemoreceptors can reflexly stimulate FB under certain circumstances but that their effectiveness is limited by more powerful inhibitory mechanisms such as those operative during NREM sleep and hypoxemia.

Effects of hypercapnia and hypoxemia on fetal breathing after decortication.

The effects of hypercapnia and hypoxemia on breathing movements were studied in 12 chronically decorticated fetal sheep, 127-140 days gestation. The fetal state of consciousness was defined in terms of activity of the lateral rectus and nuchal muscles. Arterial blood pressure was monitored. Fetal breathing was determined by integrated diaphragmatic electromyogram (EMG) and analyzed in terms of inspiratory time (TI), expiratory time (TE), electrical equivalent of tidal volume (EVT), breath interval (TT), duty cycle (TI/TT), mean inspiratory flow equivalent (EVT/TI), and instantaneous ventilation equivalent (EVT/TT). Fetal breathing occurred only during episodes of rapid-eye movements, and the response to hypercapnia consisted of an increase in EVT, TI, EVE, and EVT/TI and a decrease in the coefficient of variation of all measured parameters. Induction of hypoxia during episodes of spontaneous fetal breathing produced a decrease in the rate of breathing and an increase in EVT and TI with no change in the variability of all parameters studied. Since similar responses to hypercapnia and hypoxemia are seen in the intact fetus, we conclude that the cerebral cortex has no obvious effect on the chemical control of fetal breathing.

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.

Maturation of steady-state CO2 sensitivity in vagotomized anesthetized lambs.

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.

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.

Efficacy of salbutamol and ipratropium bromide in decreasing bronchial hyperreactivity in children with cystic fibrosis.

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.

Normal lung growth following antenatal dexamethasone treatment for respiratory distress syndrome.

Antenatal steroid therapy reduces the incidence of respiratory distress syndrome (RDS) in premature infants. However, animal studies showed a decrease in lung cell number and lower lung weights in fetal rabbits exposed to hydrocortisone. This prompted us to measure flows and lung volumes (by spirometry and helium-dilution method) in children greater than 6 years who were part of a study by the Collaborative Group on Antenatal Steroid Therapy. The effect of antenatal steroids on subsequent pulmonary function had not previously been studied. Of the 158 children originally enrolled before birth, a total of 8 dexamethasone (DEX)- and 11 placebo-treated children were still local residents and fulfilled the criteria of the study (gestational age, 28-34 weeks; DEX/placebo treatment 1-7 days before delivery). Mean heights and weights were normal with no significant differences between the groups. Pulmonary function tests showed no differences in lung volumes or expiratory flows between the children whose mothers had received antenatal DEX and those who had received placebo. These results indicate no adverse effect of antenatal DEX on subsequent lung volumes and expiratory flows in childhood.

Endogenous opiates and response to exercise in asthmatic children and adolescents.

Whether endorphins secreted during stressful exercise may play a role in the physiologic response of asthmatics was investigated. Thirteen asthmatic subjects were studied: seven (mean age 16 years +/- 2.8 SEM) had perennial asthma and exercise-induced bronchospasm (EIB), and six (mean age 18 years +/- 2) had mild seasonal asthma without EIB. Each subject performed two matched progressive exercise challenges on consecutive days. Baseline lung function was measured before each challenge and was measured again after exercise at regular intervals for 30 minutes. One minute before exercise each subject received intravenously either i.v. naloxone (0.04 mg/kg), an opiate receptor blocker, or saline, in a double-blind crossover fashion. Heart rate, oxygen consumption, minute ventilation, tidal volume, and arterial oxygen saturation were recorded throughout the tests. During the two challenges these parameters were not significantly different for all 13 patients. The mean percentage reduction in FEV1 after exercise for the seven subjects with EIB was slightly but not significantly less with naloxone (25% +/- 7 SEM) than with placebo (32% +/- 7) during the first 10 minutes after exercise. Naloxone had no obvious effect on EIB or the other parameters measured in association with strenuous exercise in asthmatic patients.

Relationship between response to inhaled salbutamol and methacholine bronchial provocation in children with suspected asthma.

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.