Search

We are interested in determining whether premature birth alters expression of counterregulatory cytokines which modulate lung inflammation. Production of proinflammatory cytokines tumor necrosis factor alpha. IL-1 beta, and IL-8 is regulated in part by the antiinflammatory cytokine IL-10. For preterm newborns with hyaline membrane disease, deficiencies in the ability of lung macrophages to express antiinflammatory cytokines may predispose to chronic lung inflammation. We compared the expression of pro- and antiinflammatory cytokines at the mRNA and protein level in the lungs of preterm and term newborns with acute respiratory failure from hyaline membrane disease or meconium aspiration syndrome. Four sequential bronchoalveolar lavage (BAL) samples were obtained during the first 96 h of life from all patients. All patients rapidly developed an influx of neutrophils and macrophages. Over time, cell populations in both groups became relatively enriched with macrophages. The expression of proinflammatory cytokine mRNA and/or protein was present in all samples from both patient groups. In contrast, IL-10 mRNA was undetectable in most of the cell samples from preterm infants and present in the majority of cell samples from term infants. IL-10 concentrations were undetectable in lavage fluid from preterm infants with higher levels in a few of the BAL samples from term infants. These studies demonstrate that 1) IL-10 mRNA and protein expression by lung inflammatory cells is related to gestational age and 2) during the first 96 h of life neutrophil cell counts and IL-8 expression decrease in BAL from term infants, but remain unchanged in BAL samples from preterm infants.

To describe the physiologic effects of surfactant treatment on gas exchange in human premature infants with hyaline membrane disease, functional residual capacity (FRC), tidal volume (VT), the alveolar portion of tidal volume (VA), alveolar ventilation (VA), nitrogen clearance index, effective breath fraction calculated as VA/VT, compliance of the respiratory system, and arterial oxygen and carbon dioxide tensions were measured in 17 patients before and 0.5, 2, and 6 h after the administration of a single dose of either a synthetic surfactant (SS), Exosurf (n = 10), or a bovine surfactant (BS), Survanta (n = 7). By 2 h, treatment with either BS or SS was followed by an increase in the arterial/alveolar ratio of Po2 (a/A) and in FRC (p < 0.01 for both a/A and FRC). The a/A and FRC improved sooner (p < 0.001) and to a greater extent (p < 0.01) after BS than after SS. Compliance of the respiratory system and VT were decreased after either BS or SS at 0.5 h (p < 0.01) and remained decreased after SS at 2 h (p < 0.01). There was no significant change in VA or VA after either BS or SS. Because FRC and a/A increased without an accompanying increase in VA, VA, or compliance of the respiratory system, we believe that the immediate increase in FRC in this study was caused by stabilization of gas exchange units already being ventilated in addition to recruitment of new units. Nitrogen clearance index decreased and effective breath fraction increased after treatment, indicating an improved efficiency in gas mixing also thought to result from stabilization and maintenance of patency of distal airways by surfactant.

IL-8, a chemokine with striking neutrophil-activating properties, is important in the pathogenesis of various disorders of the adult lung. Little is known about its production and possible role in fetal and neonatal lung disorders. We therefore examined IL-8 expression by immunohistochemistry in lung tissue from neonates with hyaline membrane disease, from fetuses with amniotic infection, and from a fetal control group with noninflammatory diseases. In the majority of cases with hyaline membrane disease, intense IL-8 immunoreaction was seen in fetal and neonatal neutrophils and in almost half of these cases, in epithelial cells of the terminal airways as well as in the connective tissue cell compartment. In contrast, in the amniotic infection group, strong IL-8 immunostaining was almost exclusively seen in maternal aspirated neutrophils. Little or no IL-8 signal was seen in the control cases in all cell types examined. Also, no IL-8 production by fetal lung cells was detected in fetuses

Congenital diaphragmatic hernia, a highly lethal condition, displays at term the pulmonary biochemical and morphologic immaturity characteristic of premature delivery. We hypothesized that antenatal glucocorticoid, now the standard treatment to prevent hyaline membrane disease in premature human beings, might correct the parameters of the pulmonary biochemical and morphologic immaturity in severe congenital diaphragmatic hernia. A total of 112 fetal rats with or without nitrofcn-induced congenital diaphragmatic hernias from 34 pregnancies were treated antenatally with either saline or dexamethasone. Antenatal dexamethasone increased the lung disaturated phosphatidylcholine content, reduced the lung glycogen concentration, reduced the saccular septal thickness, and increased the mean saccular size and volume fraction of saccules in the lungs of rats with large congenital diaphragmatic hernia in comparison with similar rats not so treated. All differences were statistically significant. Antenatal glucocorticoid therapy was efficacious in treating rats with nitrofen-induced congenital diaphragmatic hernia. This encouraging finding warrants further investigation in a large animal model with surgically created congenital diaphragmatic hernia.

The authors analyze the results of 5 years in thefield of respiratory neonatal assistance from 2005till 2009. 337 newborns were analyzed retrospectively whom200 boys and 137 girls Out born represents 35,6 %of hospitalizations (120/337). The immature infants represent 68,2 % of studiedcases (230 cases) among which 80 extremelyimmature infants, The indications of assisted ventilation arerepresented by the Hyaline membrane diseasein 92 cases (37,3 %) the perinatal asphyxia in 50cases (14,8 %), the alveolitis in 75 cases (22,3 %), in 15 cases (4,5 %), persistent pulmonary high bloodpressure in 33 cases (9,8 %) and vital distress in 72cases (21,3 %). The techniques of artificial respiration wereprincipally conventional in 198 cases (58,8 %), notconventional in 139 cases (41,2 %) among which133 newborn babies benefited of NCPAP (39,5 %)and 6 (1,8 %) of an artificial breathing by vibrationwith high frequency. The exogenous surfactant was used in 95 cases(28,2 %), indication was principally the illness ofhyalines membranes in 85 cases (25,2 %) anddestruction of the secondary endogenous surfactantin a contagious alveolite or a meco The monoxideof inhaled nitrogen was used at 30 sick. The SE association and NOi was 17 times used infront of presence of resistant hypoxemie. The total mortality rate is is 35,3 %. The ratemortality of the premature is 28,2 % (65/230). Themajor after-effects are (25 cases) cerebral paralysiswith a detachment of 5 years.

945 Gastric Aspirate Shake Test for Predicting of Surfactant Therapy in Premature Neonates with Hyaline Membrane Disease

Purpose of study– Transient hyperammonemia of the newborn can lead to an overwhelming and potentially fatal illness. The etiology of this condition is obscure although hypoxia, immature urea cycle and inadequate hepatic blood flow have all been implicated. We hypothesized that preterm infants with hypoxia would have elevated ammonia levels after birth that normalize within 3–4 weeks. The study aim was to measure serial plasma ammonia levels in preterm infants with hyaline membrane disease (HMD) or perinatal asphyxia to elucidate the role of hypoxia in the pathogenesis of hyperammonemia.

Background: Sequestration and the persistence of neutrophils in the lungs of infants with hyaline membrane disease (HMD) have been associated with pulmonary injury and the subsequent development of chronic lung disease (CLD). While activation of the transcription factor, NF-kappa B, in these cells could upregulate the expression of various mediators that enhance the pulmonary inflammatory process, apoptosis of neutrophils may promote the resolution of lung inflammation. We aimed to determine the proportion of tracheal aspirate samples from infants with HMD that had neutrophils showing evidence of NF-kappa B activation and/or apoptosis.

Ventilation by HFO or CMV in premature neonates of less than 30 weeks' gestational age with hyaline membrane disease: functional outcome at one year

A Population-Based Study of the Epidemiology of Hyaline Membrane Disease and Maternal Birthweight Effects

Surfactant (S) replacement therapy for hyaline membrane disease (HMD) has been implicated in increased shunting across the patent ductus arteriosus(PDA) secondary to drop in PAP. However this is controversial based on limited human studies. Also effects of synthetic versus natural surfactants on PAP is unkown

Introduction. Dysregulated metalloproteinase activities in airways may contribute to the pathogenesis of bronchopulmonary dysplasia. We therefore evaluated gelatinase activities present in airways at initial phase of hyaline membrane disease (HMD).

Dexamethasone (Dex) is an effective drug in the treatment of bronchopulmonary dysplasia (BPD) and there is some evidence that early Dex may be better at reducing inflammation and minimizing lung damage. However Dex is a potent drug with potential serious side effects. We wished to identify which babies develop severe BPD and would therefore be potential candidates for early Dex. We retrospectively studied all babies 30%.

We analyzed the data from the ICST to assess the effectiveness of prophylactic surfactant for treatment of hyaline membrane disease compared to any other treatment in patients with birthweights of 501-1250 gms and gestational age

It is not clear why some premature babies who develop a GMH have an associated severe (S) IVH while others have only a GMH or minor (M) IVH. We reviewed the courses of 103 babies who developed a GMH within 7 postnatal days who were born with a gestational age (GA) of 23-32 wks from 1990-1995. Important differences between babies having only a GMH and those with an associated IVH included the following: Table There were no differences in gender distribution or the incidence of hyaline membrane disease requiring surfactant, prenatal steroids, or complications of prematurity. Clearly babies with an associated IVH were smaller, younger, and sicker. We then compared babies who had a GMH and M-IVH with those who had a GMH and S-IVH. Table

EVALUATION OF VT REDUCTION WITH CONTINUOUS TRACHEAL GAS INSUFFLATION (CTGI) IN HYALINE MEMBRANE DISEASE (HMD). • 1485

EFFECT OF LUNG RECRUITMENT STRATEGIES ON GAS EXCHANGE AND LUNG INFLAMMATION IN SEVERE EXPERIMENTAL HYALINE MEMBRANE DISEASE. ♦ 1529

Does Inhaled Nitric Oxide (No) Modify Lung Function and Oxidative Stress Parameters in Experimental Hyaline Membrane Disease (Hmd)? 231

DOES INHALED NITRIC OXIDE MODIFY LUNG DIFFUSING CAPACITY AND MECHANICS IN EXPERIMENTAL HYALINE MEMBRANE DISEASE (HMD)? 2073

TGFβ BIOACTIVITY AND ITS RELATIONSHIP WITH INFLAMMATION IN THE LUNGS OF PRETERM NEWBORNS WITH HYALINE MEMBRANE DISEASE. † 2009

At the Anual SLAIP Meeting in 1988 we presented the method of procedure and biochemical features of a Nat obtained by bronchioalveolar lavage of bovine lungs. This product is how being elaborated by an Argentinan laboratory. Between 8-1-90 and 7-31-91, 40 premature infants (Pret) less than 37 weeks gestational age, diagnosed a HMD and in mechanical ventilation, were treated by tracheal insulation with Nat (90mg/kg) in the first hours of life. Additional doses were given up to 48 hs., based on clinical requirements. The treated group had a birth weight of =1268gr (r=630-2470) and a gestational age of =29.1 weeks (r=23-36). The first dose was administered at =4.7hs. (r=0.5-24). Before it the FiO2 was =0.81 (SD=0.2), the PaO2 =59mmhg (SD=15) and the mean airway pressure (Paw) =9.2cm H2O (SD=3.8). Ten minutes afterwards the PaO2 was =145mmHg (SD=51)(p 1000gr. Seven patients (17.5%) had air leaks (4 pneumothorax and 4 interstitial emphysema). Three Pret developed bronchopulmonary dysplasia. Nat may be helpful in the treatment of the HMD in Pret.

Studies with animal surfactant preparations have shown dramatic improvements in oxygenation without concomitant changes in dynamic compliance. The present study deals with the effects of a purely synthetic surfactant (E) upon arterial blood gases (ABG) and compliance (Crs)/resistance (Rrs), determined by the recently introduced single breath occlusion technique. Six premature babies with HMD, enrolled in the European OSIRIS trial were studied. Crs/Rrs and ABG were determined 30 min. before and after E administration and repeated at 24 h intervals. Results: Pre- and post values (means) are given for the 1st and 2nd dose. Measurements 3 and 4 are follow-ups. *p

Prophylactic treatment with ovine surfactant was evaluated in preterm lambs at risk for development of hyaline membrane disease. Eight mechanically ventilated newborn lambs were treated before delivery and 10 served as controls (gestational age 129–131 d). Lung mechanics, functional residual capacity, alveolar ventilation, efficiency of ventilation, and distribution of ventilation were tested using pressure, flow, and nitrogen elimination (nitrogen washout during 100% oxygen breathing) measurements in the endotracheal tube. The surfactant-treated animals showed significantly improved gas mixing efficiency in the lung with improved alveolar ventilation. Single exponential washout pattern dominated in both groups. Adequate functional residual capacity was established earlier after birth in the treated lambs than in the control animals. Lung mechanics in the treated group showed significant improvement in dynamic lung compliance. Surfactant treatment also improved gas exchange and reduced respirator pressure requirement. We speculate that the main functional effect of surfactant treatment in preterm lambs at risk to develop hyaline membrane disease is to maintain the patency of the peripheral airways in the lung, which improves diffusive gas mixing, alveolar ventilation, and gas exchange. The techniques used in this study should also be useful to evaluate lung function in preterm human infants after specific adaptation of the equipment size.

In the presence of Tricuspid Regurgication (TR), Doppler ultrasound can accurately determine systolic pulmonary artery pressure (PAP) by application of the Bernoulli equation to the maximal TR jet velocity. 152 serial ultrasound scans were performed from birth to extubation on 20 neonates ventilated for HMD (27-39 weeks, 945-3020g). Maximal TR jet velocity was measured using continuous wave Doppler. Systemic blood pressure (BP) was measured directly by intraarterial catheter or by Doppler sphygmomanometry. PAP was expressed as a percentage of systemic BP (PAP/BP%). Results were compared with values obtained from 17 healthy preterm neonates examined serially from birth to 72 hours.

Ventilation for HMD can lead to BPD resulting in long lasting functional lung impairment. Whether this also occurs when BPD does not develop, is not known. Therefore, we tested lung function in 18 children (median age 7 7/12 years) who had been ventilated for HMD without BPD, in 20 non-ventilated siblings (9 10/12) and in 20 controls matched for gestational age, birth weight, and sex (6 2/12).

The possible acute deleterious effects of maternal glucocorticoid administration on the fetal nervous system and the pathologic significance of sudanophilic lipids in glial cells were studied in the premature pigtail monkey (macaca mulatta). At 72, 48, and 24 h before delivery at 135 +/- 1 d gestation, dams were treated with either 4 mg dexamethasone or saline. After delivery, respiratory function of each fetus was determined and supported. The animals were sacrificed at 3 h of age. Brain weights were similar in the two groups. Dark, shrunken, pyknotic neurons were present in the hippocampus of three treated and two control animals. Lipid-containing glial cells were present in all animals. Neither appeared to be related to steroid treatment or to the degree of respiratory distress. We conclude that short-term glucocorticoid therapy in doses analogous to those used in humans for the prevention of hyaline membrane disease does not result in acute neuronal damage. Sudanophilic lipid accumulation in glial cells is not always abnormal and must be distinguished from glial fatty metamorphosis.

We tested the hypothesis that high frequency oscillatory ventilation (HFOV) would result in decreased pulmonary barotrauma in infants with hyaline membrane disease by comparing HFOV at 10 Hz to conventional positive pressure ventilation with continual distending airway pressure (PPV/PEEP) in premature baboons with hyaline membrane disease. Nineteen baboon fetuses were randomized to one of two treatment groups, delivered at 140 ± 2 days, and, after stabilization and instrumentation of PPV/PEEP, placed in their respective ventilator group. Animals on conventional ventilation were managed by adjustment of tidal volume and frequency (to 1 Hz) to keep PaCO2 below 55 and by adjustment of the mean airway pressure. One of the “HFOV” group died of cardiovascular complications before going on HFOV and was eliminated from data analysis. The remaining HFOV baboons survived the 11-day experimental period without evidence of airleak. Six of the 11 prematures treated with PPV/PEEP developed pulmonary interstitial emphysema and/or pneumothorax and five of the animals died within 48 h. The intergroup differences in airleak were significant (p < 0.05). Mean airway pressure (measured at the proximal airway) was higher initially with HFOV but then was lowered more rapidly than in the PPV/PEEP animals. The arterial to alveolar oxygen ratio rose and the FIO2 could be lowered more rapidly with HFOV than with conventional ventilation. These differences reached significance by 20 h. After 60 h there were no significant differences between HFOV and the PPV/PEEP survivors. HFOV resulted in more uniform saccular expansion, higher arterial to alveolar oxygen ratio, less oxygen exposure, and decreased acute barotrauma when compared to PPV/PEEP. Although initially mean airway pressure was in the HFOV animals this was not associated with measurable baroinjury. These data support the efficacy of HFOV in the treatment of prematures with hyaline membrane disease.

The present experiments were undertaken to study the effect of exogenous corticosteroids on carbonic anhydrase (CA) activity in fetal erythrocytes. Rabbit fetuses from 24 days of gestation to term (31 days) were injected intraperitoneally with either 0.2 ml of 0.9% saline or 2.5 mg hydrocortisone succinate. Nonoperated, noninjected animals served as controls. Carbonic anhydrase activity measured at 24 hr after injection was increased in the saline-injected group at all ages studies when compared with the noninjected fetuses. A marked increase (2- to 7-fold) in enzyme activity was demonstrated after steroid injection at 24 but not 48 hr after treatment. An increase in CA activity was also demonstrated after incubating fetal erythrocytes for 2, 4, and 8 hr in the presence of hydrocortisone succinate. It is suggested that low CA activity in infants with hyaline membrane disease (HMD) may reflect lack of enhancement by steroid.

In a group of infants with hyaline membrane disease, the level of optimal constant positive airway pressure (CPAP) was assessed by raising CPAP in small steps from an initial low value, and after each change measuring the arterial alveolar difference for CO2 (aADCO2) and transmission of airway pressure to the esophagus. Below optimal CPAP there was a progressive increase in mixed alveolar partial pressure of CO2 (PACO2) and no change in arterial partial pressure of CO2 (PaCO2), so that aADCO2 declined and reached a lowest value at optimal CPAP. Correspondingly, transmission of airway pressure increased progressively and reached a highest value at optimal CPAP. Between 1 step below and optimal CPAP, PACO2 rose from 30.9 to 34.0 torr, and aADCO2 declined from 16.6 to 12.7 torr. Between optimal and 1 step above optimal CPAP, PaCO2 increased from 46.7 to 51.0 torr, PACO2 rose slightly, and aADCO2 increased from 12.7 to 15.6 torr. Thus, the aADCO2 was an excellent index of optimal CPAP. In five patients with measurements of PaO2 at constant fractional inspired oxygen, calculated values for arterial oxygen saturation changed from 80.8 to 91.5 to 92.2%, and calculated values for venous admixture changed from 0.61 to 0.48 to 0.46 as CPAP was raised from 1 step below through optimal to 1 step above optimal CPAP. The results are interpreted to mean a progressive improvement in perfusion of well ventilated lung units as CPAP increased to optimal levels, but a significant reduction of both ventilation and perfusion above optimal CPAP.(ABSTRACT TRUNCATED AT 250 WORDS)

Summary: Delivery of M. nemestrina at 80% of normal gestation provides a population of neonates at high risk for hyaline membrane disease (HMD). The diagnosis of HMD was made by the presence of reticulogranular densities and air bronchograms on chest radiographs. Patchy atelectasis was seen in the lungs of animals assigned by clinical and radiographic criteria to the HMD group and not in the normal lungs of animals matched for gestational and postnatal age. Total phospholipid and phosphatidylcholine in whole lung, airway lavage fluid, and surface-active materials were lower in animals with HMD. Amniotic fluid L/S ratios were lower in the group that developed HMD. Pressure-volume measurements indicated decreased distensibility and unstable terminal air spaces in the HMD group. Alveolar-arterial oxygen pressure differences were greater in animals with HMD. There were no differences between HMD and normal groups in body weight, lung weight, percent dry lung weight, gestational age, and postnatal age at death. This primate species, subjected to premature delivery, is a suitable animal model of HMD in human neonates.

The appearance of phosphatidylglycerol in the tracheal wash of infants with hyaline membrane disease (HMD) has been reported to be associated with clinical signs of recovery. We analyzed lung tissue and bronchoalveolar lavage surfactant in an animal model of HMD to determine whether phosphatidylglycerol or some other component is necessary for recovery. The amount and composition of phospholipid (PL) was determined in the premature Macaca nemestrina monkey (140 days' gestation) during an acute stage of HMD, and in two stages of recovery. These changes were compared to observations made in healthy premature controls (140 days), gestational age-matched fetuses (140 days), and fetuses of 150 days' gestation (term=168 days). The amount of PL and its surfactant composition in lung homogenates of the right lower lobe and in lavage of the excised left lung was determined. Compared to 140-day fetuses, the healthy controls had a several-fold increase in lavage PL and disaturated phosphatidylcholine (DSPC) during the first few days of life (p

Extract: Twenty infants with a clinical and radiologic diagnosis of hyaline membrane disease were studied serially by measurement of functional residual capacity (FRC) and arterial and alveolar gradients for O2, CO2, and N2. Nitrogen washouts were determined as well in nine infants. The FRC, alveolar-arterial O2 gradients (AaDo2) in 100% O2, and true shunt (Qs/Qt), which are different ways of quantitating atelectasis and shunt in hyaline membrane disease, were shown to be statistically related. The FRC was below 1.0 ml/cm in all infants when sick and returned to the usual range for gestational age, generally around 15 days. Extensive cardiopulmonary shunting was recorded both at the height of illness and for a considerable time during recovery. However, during recovery, not all of the venous admixture was due to shunt. As maldistribution of ventilation was excluded, the possibility of a diffusion barrier was raised. Alveoli with a high VA/Q were identified by large arterial-alveolar CO2 gradients (aADCO2) both during illness and recovery. This indicates that maldistribution of pulmonary blood flow is an important physiologic abnormality in hyaline membrane disease. Speculation: The FRC was shown to correlate inversely with AaDo2 and Qs/Qt ratios. As a low FRC is the only true unique characteristic of hyaline membrane disease, it is suggested that in the future the disease be defined in terms of the lung volume as well as in terms of the usual clinical and biochemical parameters which appear in other forms of respiratory distress in neonates. Constant positive airway pressure is an attempt to approach treatment from this point of view.

Pulmonary Plasminogen-Activator Activity in Hyaline Membrane Disease: A Reevaluation on Human, Bovine, and Rabbit Fibrin Substrates

Summary: The number and distribution of bombesin immunoreactive pulmonary neuroendocrine cells (PNEC) in fetuses and infants up to 6 months of age was determined on postmortem lung specimens. Individual cells and clusters of cells (neuroepithelial bodies) were found in airways of all sizes, although greater than 95% of the positive cells were located in bronchioles, terminal bronchioles, and respiratory bronchioles. These infants were separated into two groups. In control infants, who died primarily from noncardiopulmonary causes, bombsin immunoreactive neuroendocrine cells were identified throughout the latter half of gestation. As gestation advanced, progressively more positive bronchioles/cm2 of lung tissue and cells/bronchiole were identified. In these control infants, the number of positive bronchioles/cm2 and cells/bronchiole were at the highest level at or near the time of delivery and then gradually declined throughout the first 6 months of life. In contrast, infants who died of acute hyaline membrane disease (1–7 days of life) or bronchiopulmonary dysplasia (2 wk to 6 months of life) demonstrated marked differences in the number of identifiable bombesin immunoreactive neuroendocrine cells when compared to control infants. In early hyaline membrane disease, the number of positive bronchioles/cm2 and cells/bronchiole was markedly decreased. During the transition to chronic bronchopulmonary dysplasia, there appeared to be a marked increase in the number of bombesin immunoreactive cells. The peak number of cells occurred at 2–3 months of life, when substantially more bombesin-immunoreactive cells could be identified in children with bronchopulmonary dysplasia than control infants of similar age. Speculation: This study demonstrates that a specific pulmonary cell type containing bioactive molecules undergoes marked changes during acute and chronic neonatal lung disease. Anatomic and physiologic evidence suggests that these cells may be in an ideal position to exert control on pulmonary vessel and airway tone either at the local level or throughout the entire lung through vascular and neural connections. These data do not prove that alterations in this cell population are the cause of changes noted in airway and in vascular resistance in infants with lung disease. They do identify, however, a new area of potential investigation in these disease states.

Pulmonary superoxide dismutase (SOD) acitivity was determined for various groups of human fetuses, infants, and adults. Enzyme activity was found to increase with age from a low of 17 +/- 1 units/mg DNA in fetal lung to 49 +/- 6 units/mg DNA in infant lung and finally to 110.2 +/- 14.8 units/mg DNA in adult lung (P less than 0.05). No difference in lung SOD activity was demonstrated between normal infants and those with idiopathic respiratory distress/hyaline membrane disease (IRDS/HMD). No significant differences in SOD activity were found among all the samples of infant blood. Adult blood samples, however, contained significantly greater SOD activity both in terms of heme concentration and volume of whole blood (P less than 0.05). SOD activity in lung tissue from both rats and rabbits were also found to increase with age from a low value in fetal animals to a maximum activity in adults (P less than 0.05). Exposure of New Zealand White rabbits, prematurely delivered by caesarian section, to 80% oxygen for 24 hr resulted in a 42% increase in lung SOD activity. Similarly, 7-day-old Sprague-Dawley rats exposed to 85% oxygen for 24 hr showed a 43% increase in pulmonary SOD activity. No increase in pulmonary SOD was observed when adult rats were exposed to 85% oxygen for 24 hr. The effect of hyperoxia on SOD activity in excised lung was investigated. Rat lung, incubated in either heparinized whole blood or in plasma and exposed to 100% oxygen, showed a 30% increase in SOD activity after 2 hr. This capacity of lung tissue to respond to hyperoxia in vitro with increased SOD activity was age dependent. The maximum increase in SOD activity was seen with lungs from 10-12-day-old rats. The oxygen-stimulated increase in lung SOD activity disappeared at about 19-20 days of age.

Summary: ACTH stimulation tests were performed in 15 premature infants in a serial fashion at the ages of 5-10 days and 27-31 days. Six of the 15 had subsequent ACTH stimulation tests at 6-8 weeks and/or 12-13 weeks. The pre- and post-ACTH serum cortisol and dehydroepiandrosterone sulfate (DHAS) levels were determined by radioimmunoassay. The mean basal levels of cortisol, 55 ng/ml, and DHAS, 4108 ng/ml, were significantly higher (P< 0.05 and P < 0.025, respectively) at 5-10 days than those of 24 ng/ml and 1858 ng/ml, respectively, at 27-31 days. The mean net change (Δ) of cortisol after ACTH at 5-10 days, 95 ng/ml, increased significantly to 148 ng/ml at 27-31 days. However, ΔDHAS did not differ significantly between the two periods (1514 ng/ml vs. 972 ng/ml). Therefore, ΔDHAS/Δcortisol was lower (P < 0.05) at 27-31 days than at 5-10 days. No further significant changes were observed after 4 weeks of age in the levels of the two steroids. There was little correlation of basal levels between cortisol and DHAS, nor between Δcortisol and ΔDHAS at any age period we studied. There were four infants whose mothers had prenatal steroid treatment for the prevention of hyaline membrane disease and their values were not different from the other infants. Speculation: Increased responsiveness of cortisol to ACTH at 1 month of age may suggest that there is increasing 3β-hydroxysteroid dehydrogenase in the neonatal adrenal gland in this period. The well maintained DHAS responsiveness to ACTH until 3 months of age, however, implies that there is a persistence of fetal corticosteroidogenic pathways through the first months of life.

Summary: We studied transmission of a constant mean airway pressure through the lungs to the pleural space in nine mechanically-ventilated neonates with low-compliance lung disease. Infants were studied for 3.1 ± 1.6 hr during a period of clinical improvement, but at a time when lung compliance was still markedly reduced. Two of our infants were studied during recovery from fluid overload, while seven infants with hyaline membrane disease were studied at a stage of disease during which maximal diuresis has been found to occur. During the study period, mean esophageal pressure decreased in all infants from 5.6 ± 1.3 to 4.2 ± 1.8 cm H2O (P < 0.001) while total compliance increased slightly. Speculation: Edema of the pulmonary interstitium may contribute to airway-closure and gas-trapping. We propose that a loss of fluid from the interstitium during early recovery from low-compliance lung disease may lead to less gas-trapping and a fall in mean esophageal (pleural) pressure.

Summary: The fatty acid chains of lecithin, phosphatidyl ethanolamine (PE), and phosphatidyl dimethylethanolamine (PDME) in human neonatal alveolar washes were analyzed. Both α- and β-palmitic acid increased with gestational age on all phospholipids analyzed. No evidence for high concentrations of myristic acid was found on any phospholipid. Babies who were stillborn or who had died of hyaline membrane disease (HMD) had lower proportions of β-lecithin palmitic acid when compared with babies who breathed normally before death. In the HMD group these levels were significantly lower. Speculation: The fatty acid chains of the phospholipids in lung surfactant probably influence the degree of surface activity of the phospho

A model based on the course of 31 infants with uncomplicated hyaline membrane disease is described. Based on data collected over the first 12 hr of life, it predicts the course of an infant for the next 60 hr, and estimates the outcome in terms of length of oxygen requirement and assisted ventilation. For the construction of the model, right-to-left intra- and extra-pulmonary shunting, expressed as venous admixture, was considered as the principal mechanism of hypoxemia in hyaline membrane disease and mean applied proximal airway pressure was used to quantify management. The model provides an objective estimate of severity early in the course of the disease, uses variables routinely available in an intensive care unit, and its use would strengthen the interpretation of clinical studies in which the comparability of experimental and control groups is critical.

Summary: Full-term newborns (FTN) plasminogen was evaluated by different techniques (affinity chromatography, immunologic technique, casein method, and chromogenic substrate). The functional activity of the FTN plasminogen was about 50% of that of the adult. This suggests the possible existence of a functional anomaly of plasminogen in FTN. FTN plasminogen aminoacids were studied, and, besides small qualitative anomalies, a decrease in amino acid residues per mole of protein and a different N-terminal amino acid were detected. Speculation: The existence of a functional anomaly in full-term newborns plasminogen has been suggested. The possible role of this anomaly in the pathogenesis of the hemorraghic diseases of the neonate and in hyaline membrane disease is not known, thus, the identification of this anomaly could contribute to a better understanding of these diseases.

Pulmonary immaturity, oxygen exposure that elicits cellular damage by free radicals, and barotrauma induced by mechanical ventilation are implicated in the pathogenesis of bronchopulmonary dysplasia. In the adult counterpart of adult respiratory distress syndrome, diffuse alveolar damage characterizes a histopathological sequence of lung findings that can occur during the disease course. Although adult respiratory distress syndrome has many etiologies, elevated oxygen exposure is known to be a contributor to the ensuing lung injury. In bronchopulmonary dysplasia, oxygen exposure is thought to be a primary agent of injury. The evolution of the histopathological findings in the premature baboon model of hyaline membrane disease/bronchopulmonary dysplasia was investigated in this study and compared to that in oxygen-treated adult baboons with adult respiratory distress syndrome. Findings from lung specimens of 121 prematurely delivered baboons at 0, 0.5, 1, 2, 3-6, 7-11+ days after delivery document that the premature lung has a delayed and more blunted exudative response when compared to that of human and baboon adults. Saccular edema, not hyaline membranes, is the dominant histopathological finding in the exudative phase of diffuse alveolar damage and occurs later (7-11 days) in infant lungs when compared to comparably treated adult lungs in which maximal exudative changes are seen at 3-6 days. The reparative response in the premature baboon is characterized by saccular wall thickening and fibrosis, with less intramural organization of exudate in saccular/alveolar spaces when compared to adults. The airway changes in the premature are more severe than those seen in adult disease. These findings indicate that diffuse alveolar damage does occur in the immature lung albeit with differing characteristics when contrasted to comparably injured adults.(ABSTRACT TRUNCATED AT 250 WORDS)

Previous studies have shown large inhomogeneities in the distributions of ventilation and perfusion of newborn infants with hyaline membrane disease. The purpose of this study was to show that measurements of lung mechanics also show evidence of lung inhomogeneities and that a multiple compartment analysis of mechanics gives a more accurate representation of passive exhalation flow and volume than single valued mechanics. We studied 10 sedated preterm lambs (130 d gestation) weighing 2.2 +/- 0.3 kg at 4 h postnatal age. Passive exhalation lung mechanics of the respiratory system were measured by obstructing gas flow near end inhalation then, after pressures within the lung reached equilibrium, allowing the animals to exhale to the atmosphere. Airway pressure and flow signals were monitored by a computer then analyzed using single and multiple compartment analyses. Single compartment analysis of time constant (tau) in s, respiratory system resistance (R) in cm H2O/L/s and quasistatic compliance (C) in mL/cm H2O yielded tau = 0.16 +/- 0.07, R = 92 +/- 17, and C = 1.8 +/- 1.1 (mean +/- SD). Multiple compartment analysis yielded "fast compartment" tau 1 = 0.10 +/- 0.04, R1 = 90 +/- 28, and C1 = 1.1 +/- 0.5 and "slow compartment" tau 2 = 0.25 +/- 0.12, R2 = 503 +/- 288, and C2 = 0.7 +/- 0.6. All of the animals studied exhibited nonlinearity in their flow-volume plots. Calculated flow-volume plots were much more accurately portrayed by the two-compartment analysis than by single valued mechanics. Multiple compartment analysis of lung mechanics may provide useful insight into the pathophysiology of the preterm lab with hyaline membrane disease.

The effect of early treatment of patent ductus arteriosus (PDA) on the acute course of hyaline membrane disease was tested in a primate model, after intratracheal administration of 100 mg/kg exogenous bovine surfactant phospholipids at mean ages between 2.3-2.4 h. Twentytwo premature baboons were divided into four groups: seven animals were controls (group A); five were treated with surfactant but PDA was not intervened (group B); in five surfactant treatment was followed by three doses of 0.2 mg/kg intravenous indomethacin beginning at a mean age of 5.5 h (group C); and in five surfactant treatment was followed by a surgical ligation of PDA between 5-5.5 h of age. After surfactant instillation in groups B, C, and D, a prompt and sustained improvement was noted in a/APO2, mean airway pressure, ventilator efficiency index and pulmonary compliance. However, no consistent differences were found in the respiratory variables within the surfactant treated groups during the 72-h experiment: the respiratory course in the animals treated for PDA (groups C and D) was generally similar to the animals in which PDA was not treated (group B). In animals treated with surfactant and indomethacin (group C) the mean aortic blood pressure was maintained more optimally as compared to the other three groups. These findings suggest that although a significant early ductal shunting does occur after exogenous surfactant therapy in this animal model, the expected pulmonary deterioration does not occur, and an early abrupt interruption of PDA does not seem to provide additional advantage to the immediate course of hyaline membrane disease.

Disturbances in ventilation-perfusion relationships (VA/Q) and functional residual capacity (FRC) are the most important abnormalities of physiology in distressed neonates. These parameters were measured serially from birth to recovery in 14 infants with hyaline membrane disease. VA/Q relationships were studied by determining alveolar arterial gradients for oxygen, carbon dioxide and nitrogen. FRC was determined by a helium rebreathing method. AaDo2 was measured after 100% oxygen breathing, and where possible during air breathing. Venous admixture and shunts were calcultaed using standard formulae and assumptions. Three infants had nitrogen washout determinations during the recovery period. Arterial samples were obtained from the temporal or right radial artery. The data allows the following conclusion: (1) In most infants FRC decreased between the first and second day (2) Underperfusion (VA/Q > 1) increased progressively in the first 2 days (3) Venoarterial shunting varied little in the first 2 days (4) Most infants reach a normal FRC by 15 days (5) During recovery the absence of nitrogen gradient, normal nitrogen washout, and the presence of a large venous admixture with a small shunt suggests that diffusion limitation is a major problem.

Using our perinatal data bank, clinical and pathological data on 104 sigleton infants who died with germinal layer haemorrhage and intraventricular haemorrhage /IVH/ at Hammersmith were analyzed in comparison with data from babies dying of other conditions, and with the background population. Of 31 cases of IVH without hyaline membrane disease /HMD/ only four infants were born at a gestation of 30 weeks or more, whereas in 73 cases of IVH with HMD 49 were born at over 30 weeks gestation. At all gestations infants who died with HMD + IVH had received more intense alkali therapy than those who died with HMD alone, although there was no difference in acid-base status or PaO2 measurements. Administration of alkali /THAM and bicarbonate/ in excess of 8 mEq/Kg body weight over any 12 hour period was significantly associated with the development of IVH. In babies of 30 weeks gestation or less the association between IVH and alkali therapy was significant whereas the association with HMD was not. It is suggested that the expansion of blood volume caused by administration of hypertonic solutions for treatment of HMD may be a significant factor in the causation of IVH.

Nineteen infants with hyaline membrane disease (HMD) were studied to determine if the time of initiation of continuous negative pressure(CNP) affected the course of the disease. All infants had an initial PaO2 between 50-100mmHg on 0.7FiO2. They were then randomly assigned to one of two groups: the early-onset group (n=9, mean B.W. 1626 Grams) started on CNP while the PaO2 was between 50-100mmHg on 0.7FiO2; the late-onset group (n=10, mean B.W. 1866 Grams) started on CNP after the PaO2 fell below 50mmHg on 0.7FiO2. Results are as follows: The early-onset group responded better to CNP in terms of the initial increase in PaO2 (ΔPaO2), required a shorter period of oxygen therapy, and needed a shorter period of ventilatory assistance which consisted only of CNP. Three of the late-onset group required mechanical ventilation and four had either pneumomediastinum, pneumothorax, patent ductus arteriosus requiring ligation, or right diaphragmatic paralysis. There were no complications in the early-onset group. This study indicates that it is desirable to begin CNP as soon as possible in infants witli HMD.

We evaluated prolonged use of total parenteral nutrition (TPN) and the effects of perinatal factors in infants who developed neonatal cholestasis (CH). Only infants 2 weeks, had no GI disease and received TPN ⩾14 days were studied; 40 infants met these criteria. 19 infants developed CH (direct bilirubin > = 1.5 mg/dl >1 week) and 21 did not. Infants who developed CH received TPN longer than those without CH (P

It is known that infants of diabetic mothers(IDM) have a higher incidence of hyaline membrane disease(HMD). To determine the effect of continuous glucose infusion on PC and DSPC in lung tissue in vivo, a rabbit model was used. On 26th day of gestation, femoral vein was catheterized in a pregnant rabbit and D25 0.45% saline(group 1)or 0.9% saline(group 2)was infused over 46 to 48 hours. Sham operated pregnant rabbits underwent exposure of femoral vein and attempted catheterization(group 3). C-hysterectomy was performed on 28th day of gestation. Necks of the fetal rabbits were tied at delivery to prevent air breathing. Lungs were removed and analysed for PC and DSPC. Serum insulin and glucose were determined on fetal and doe's blood. Data on 6 rabbits in group 1, 4 rabbits in group 2 and 5 rabbits in group 3 are available. The serum insulin level in does in group 1 was higher compared to other two groups after 24 hours of infusion. The serum glucose in does after 24 hours in group 1 was higher than other two groups. As a % of total phospholipid(TPL), PC and DSPC were not different in all three groups.

We describe 7 infants (6 males, 1 female) seen over the last 3 yrs. initially diagnosed with bronchopulmonary dysplasia (BPD) or chronic lung disease and subsequently found to have tracheobronchomalacia (TBM). None had congenital anatomical abnormalities such as tracheoesophageal fistula or vascular rings. 5 were premature babies who had been ventilated for hyaline membrane disease, 2 presented with viral infections. All 7 had required intermittent ventilation, with 5/7 ventilated for most of their lives (9 mo.- 38 mo.). The diagnosis was suspected in all 7 because they had either cyanotic spells (“BPD” or “blue” spells) requiring manual ventilation, or wheezing unresponsive to usual therapy (bronchodilators, steroids). The diagnosis was confirmed by either bronchoscopy or fluoroscopy showing>75% collapse of the central airways during expiration or Valsalva. The mean time from onset of symptoms to diagnosis was 3-20 mos. Some associated factors include Pseudomonas sp. or Staphylococcus aureus tracheitis in 6/7, gastroesophageal reflux in 3/7, patent ductus in 4/7, and pneumothoraces in 4/7. Management was facilitated by finding optimal positive end-expiratory pressure (PEEP) during fluoroscopy. 6/7 require PEEP of at least 10-15cmH2O pressure for at least 3 mos., and 5/7 are still ventilated. All patients responded clinically with decreased cyanotic spells and improved ventilation. Bronchodilators, diuretics and sedation were all used with varying success. Tracheostomy without PEEP was not helpful. Thus TBM is a treatable, diffuse process which requires long term therapy, the incidence of TBM may be higher than suspected, and the therapy of choice is long term optimal distending PEEP.