Surfactant Metabolism Dysfunction and Childhood Interstitial Lung Disease (chILD).

Surfactant deficiency and the resultant respiratory distress syndrome (RDS) seen in preterm infants is a major cause of respiratory morbidity in this population. Until recently, the contribution of surfactant to respiratory morbidity in infancy was limited to the neonatal period. It is now recognised that inborn errors of surfactant metabolism leading to surfactant dysfunction account for around 10% of childhood interstitial lung disease (chILD). These abnormalities can be detected by blood sampling for mutation analysis, thereby avoiding the need for lung biopsy in some children with chILD.

Plasminogen activator inhibitor-1 in acute hyperoxic mouse lung injury.

Hyperoxia-induced lung disease is associated with prominent intraalveolar fibrin deposition. Fibrin turnover is tightly regulated by the concerted action of proteases and antiproteases, and inhibition of plasmin-mediated proteolysis could account for fibrin accumulation in lung alveoli. We show here that lungs of mice exposed to hyperoxia overproduce plasminogen activator inhibitor-1 (PAI-1), and that PAI-1 upregulation impairs fibrinolytic activity in the alveolar compartment. To explore whether increased PAI-1 production is a causal or only a correlative event for impaired intraalveolar fibrinolysis and the development of hyaline membrane disease, we studied mice genetically deficient in PAI-1. We found that these mice fail to develop intraalveolar fibrin deposits in response to hyperoxia and that they are more resistant to the lethal effects of hyperoxic stress. These observations provide clear and novel evidence for the pathogenic contribution of PAI-1 in the development of hyaline membrane disease. They identify PAI-1 as a major deleterious mediator of hyperoxic lung injury.

[Dynamic change in respiratory mechanic dynamics and its clinical significance during mechanical ventilation in hyaline membrane disease of children].

OBJECTIVE: To explore the characteristics of changes in respiratory mechanic dynamics and clinical significance in hyaline membrane disease (HMD) under mechanical ventilation. METHODS: One hundred and twenty-six newborns with HMD undergoing mechanical ventilation were divided into two groups: complication group with 43 cases and no-complication group with 83 cases. The blood gases and indices of respiratory mechanic dynamics were monitored 2, 24, 48 and 72 hours after the first ventilation and before the first weaning from ventilation. RESULTS: Pulmonary compliance [(0.55+/-0.10) ml.cm H(2)O(-1).kg(-1), (0.43+/-0.10) ml.cm H(2)O(-1).kg(-1)] and minute volume [MV, (0.65+/-0.10) L/min, (0.62+/-0.30) L/min] were elevated compared with that after ventilation for 2-72 hours, however the oxygenation index [OI, (10.2+/-1.9)mm Hg vs. (13.6+/-4.3) mm Hg] significantly lower. The compliance and MV in no-complication group were higher than that in complication group 24 and 48 hours after ventilation. There were no differences in the airway resistance and lung inflation index between two groups. The pulmonary compliance was negatively correlated with OI (r=-0.208, P<0.01) and corrected with MV (r=0.218, P<0.01). In no-complication group, all cases ventilation was weaned successfully at once in all the patients,and their mean compliance and MV were (0.55+/-0.10) ml.cm H(2)O(-1).kg(-1) and (0.65+/-0.20) L/min respectively. However, in complication group, weaning failed 38 patients, their mean compliance and MV were (1.03+/-0.30) ml.cm H(2)O(-1).kg(-1) and (0. 33+/-0.30) L/min respectively. CONCLUSION: Respiratory mechanic dynamics monitoring is beneficial in evaluating the severity of hyaline membrane disease and complications, guiding mechanical ventilation management and weaning.

Pregnancy and diabetes. Team approach.

Each year, 10,000 babies are born to diabetic women. Gestational diabetes occurs in 2% of all pregnant women, resulting in 60,000 to 90,000 cases of gestational diabetes yearly. Prior to 1922 and the discovery of insulin, fetal mortality for the pregnant diabetic was almost 100%. Today, total fetal mortality for the pregnant and gestational diabetic is approaching that of the nondiabetic. This has been achieved by extremely tight control of blood glucose levels throughout pregnancy, with blood glucose levels averaging under 100 mg/dL/day and glycosylated hemoglobin levels in the normal range throughout pregnancy. An increased number of malformations in fetuses of pregnant diabetic women is still a problem. However, animal and human studies indicate that a normal level of glycosylated hemoglobin at conception may significantly reduce these malformations.

[High-frequency oscillatory lung ventilation in complex therapy for congenital pneumonia and hyaline membrane disease in newborns].

Fifty-eight neonatal infants with hyaline membrane disease (HMD) and congenital pneumonia were examined in the critical status. In 32 of them, high-frequency oscillatory lung ventilation (HFOLV) was employed. The use of HFOLV was found to reduce the length of stay in neonates on toxic oxygen concentrations by more than 2 times and to accelerate the normalization of ventilation-perfusion relationships by more than 3 times. A study of the basic parameters of central and regional hemodynamics showed that HFOLV failed to affect the patients' hemodynamic status. The efficiency of correction of severe respiratory disorders in neonatal infants with HMD was ascertained to increase with the combined use of the Russian surfactant and HFOLV. A formula was developed to calculate the starting amplitude of oscillations when HFOLV was employed. The maximum allowable values of mean airway pressure at which HFOLV could be discontinued were determined, which prevented the regimens from toughening when HFOLV was changed to the routine artificial ventilation. The use of HFOLV was established to reduce the risk of severe cerebral structural and vascular lesions and mortality rates.

Uso convencional de surfactante en recién nacidos con enfermedad de membrana hialina / Conventional use of surfactant in newborns with hyaline membrane disease

La enfermedad de membrana hialina se debe a la deficiencia de surfactante en los pulmones de los recién nacidos especialmente los menores de 37 semanas de gestación. El manejo materno con corticoides prenatales en este grupo, disminuye la morbimortalidad asociada a esta patología neonatal. Se analiza desde el punto de la evidencia actualmente existente la administración de surfactante a estos prematuros y se revisa el tipo de surfactante a administrar, cuando es el mejor momento para administrarlo, la dosis y la forma de administrarlo.

Hyaline membrane disease is due to surfactant deficiency in the lungs of newborns, especially those younger than 37 weeks gestation. Maternal management with prenatal corticosteroids in this group reduces the morbidity and mortality associated with this neonatal pathology. The administration of surfactant to these preterm infants is analyzed from the point of the currently existing evidence and the type of surfactant to be administered is reviewed, when is the best time to administer it, the dose and the form of administration.

Skin surface carbon dioxide tension in sick infants.

Skin surface PCO2 (PSCO2) was measured at 44 C in 17 sick infants using a Radiometer surface PCO2 electrode. Values obtained for PSCO2 were compared with simultaneous values for arterial PCO2 (PaCO2). PSCO2 was found to be linerarly related to PaCO2 by a regression line with a slope 1.37. PaCO2 could be predicted from PSCO2 to within 6 torr in all instances. The relationship was not affected by the patient's gestational age, postnatal age, weight, or blood pressure. This electrode is a valuable clinical tool in the management of sick infants.

Airway resistance in infants after various treatments for hyaline membrane disease: special emphasis on prolonged high levels of inspired oxygen.

Thoracic gas volume, airway resistance (Raw), and dynamic lung compliance (CL) were measured in 48 infants surviving after hyaline membrane disease. Some infants were found to have a small reduction in CL after recovery from the acute phase of the illness but no other abnormalities were detected, irrespective of the type of treatment received. When studied again between the ages of 4 and 10 months, CL had returned to normal, but all infants who had been treated with intermittent positive pressure ventilation (IPPV) during the neonatal period were found to have developed a raised Raw. In contrast, all nonventilated infants, including those who had received up to five days of oxygen therapy in concentrations above 80%, had normal lung function. We conclude that IPPV, and not the increased inspired oxygen concentration, damaged the airways and interfered with their growth.

Early and late surfactant treatments in baboon model of hyaline membrane disease.

Because the issue of optimal time for artificial surfactant therapy for hyaline membrane disease has not been established, the effects of treatment with a reconstituted bovine surfactant (surfactant TA) were compared at two time periods in a hyaline membrane disease model in a premature baboon. The baboons were delivered by cesarean section at 75% of gestation (139.5 +/- 1.5 days, mean +/- SD). One group was treated with surfactant TA within ten minutes after birth (ultraearly), another group was treated at two hours of age (late) and a third (comparison group) did not receive the surfactant. Both treatment groups had significantly higher compliance and ratio of arterial to alveolar Po2 ratio and lower mean airway pressure and oxygen requirement (Fio2) than the comparison group. At autopsy, the largest residual volume and hysteresis in pulmonary pressure-volume curves were noted in the ultraearly group, intermediate values were found in the late group, and least values were found in the comparison group. These data indicate that early surfactant therapy for hyaline membrane disease results in greater improvement in lung mechanics than delaying treatment, even for two hours. Delivery room treatment with surfactant of infants at risk for hyaline membrane disease is perhaps better than therapy for established hyaline membrane disease.

Reduced incidence of hyaline membrane disease in extremely premature infants following delay of delivery in mother with preterm labor: use of ritodrine and betamethasone.

Data from two groups of infants (24 to 28 weeks' gestational age) excluded from a controlled trial of the use of calf lung surfactant extract for the prevention of hyaline membrane disease are reported. The two groups were excluded from the trial because the mothers had received betamethasone for greater than 24 hours prior to delivery or because, on admission to the hospital, labor was too far advanced for proper informed consent to enter the trial. Attempts were made to delay delivery of threatened premature labor by the use of ritodrine in all mothers without evidence of infection, heavy vaginal bleeding, or severe preeclampsia and to induce surfactant production by maternal injection of betamethasone. A prospective scoring system and respiratory support variables were used to compare the groups. Infants born to mothers who successfully completed this regimen had a 28% incidence of hyaline membrane disease v a 68% incidence in infants in whose mothers it was unsuccessful due to inability to stop advanced labor (P = .001). Inspired oxygen, mean airway pressure, and ventilator rate were lower and the ventilator efficiency index was higher in the treated group during the first 48 hours of life. An aggressive approach to postpone premature delivery and to induce surfactant production by using tocolysis and a regimen of glucocorticoids reduces the incidence of hyaline membrane disease in very premature infants, 24 to 28 weeks' gestation.

Clinical significance of monitoring anterior fontanel pressure in sick neonates and infants.

The intracranial pressure was monitored via the anterior fontanel, using a noninvasive technique, in 78 acutely ill, 39 normal term, and 6 normal preterm infants. In normal term and preterm infants the anterior fontanel pressure (AFP) was 10.2 +/- 0.4 and 9.5 +/- 0.8 cm H2O, respectively. Infants with hyaline membrane disease had elevated pressure (13.3 +/- 0.6 cm H2O), which was higher than that of normal preterm infants. Following an episode of intracranial hemorrhage in four infants, the AFP increased to 26.2 +/- 2.5 cm H2O. Elevated pressure was noted in infants with meconium aspiration syndrome (24.1 +/- 1.8 cm H2O); the pressure decreased during the phase of recovery (15.6 +/- 3.5 cm H2O). Elevated pressure was noted in infants with meningitis and hydrocephalus. Repeated measurements helped to diagnose shunt obstruction in an infant with hydrocephalus.

Pulmonary mechanics in preterm neonates with respiratory failure treated with high-frequency oscillatory ventilation compared with conventional mechanical ventilation.

Pulmonary mechanics were measured in 43 preterm neonates (mean +/- SD values of birth weight 1.2 +/- 0.3 kg, gestational age 30 +/- 2 weeks) with respiratory failure who were concurrently randomly assigned to receive conventional mechanical ventilation (n = 22) or high-frequency ventilation (n = 21). The incidence of bronchopulmonary dysplasia was comparable in the two groups (high-frequency ventilation 57%, conventional ventilation 50%). Pulmonary functions were determined at 0.5, 1.0, 2.0, and 4.0 weeks postnatal ages. Data were collected while subjects were in a nonsedated state during spontaneous breathing. These sequential data show similar patterns of change in pulmonary mechanics during high-frequency ventilation and conventional mechanical ventilation irrespective of gestational age, birth weight stratification, or bronchopulmonary dysplasia. There was no significant difference in the pulmonary functions with either mode of ventilation during the acute phase (less than or equal to 4 weeks) of respiratory disease. When evaluated by the clinical diagnosis of bronchopulmonary dysplasia, the pulmonary data suggested a less severe dysfunction in the high-frequency oscillatory ventilation-treated bronchopulmonary dysplasia group compared with the conventional mechanical ventilation-treated group. These results indicate that high-frequency oscillatory ventilation in preterm neonates does not reduce the risk of acute lung injury; however, the magnitude of the pulmonary dysfunction in the first 2 weeks of life merits a reevaluation.

Serial assessment of ductus arteriosus hemodynamics in hyaline membrane disease.

OBJECTIVES: To assess the efficacy of Doppler echocardiography (DE) in the quantification of patent ductus arteriosus (PDA) shunt volume and to correlate PDA shunt volume with clinical outcome in infants with hyaline membrane disease. METHODS: Ninety-eight DE studies were performed in 30 preterm ventilated infants with hyaline membrane disease within the first 24 hours of age and then at 48-hour intervals to a maximum of three studies while ventilated with a final study after extubation. Right and left ventricular outputs (QRV and QLV, respectively) and PDA flow were calculated using cross-sectional area and flow velocity integrals. Left atrial-to-aortic root diameter measurements were also taken. Clinical outcomes were correlated with the shunt fraction (QLV/QRV). RESULTS: QLV/QRV demonstrated a linear relationship with the left atrial-to-aortic root diameter ratio (n = 92; r = .79). In the absence of a PDA (n = 33 studies), QRV versus QLV demonstrated a linear relationship (r = .88). In the presence of a PDA (n = 64 studies) the mean QLV (334 +/- 133 ml/kg per minute) was significantly greater than the mean QRV (237 +/- 84 ml/kg per minute). There was a linear relationship between QLV-QRV (PDA shunt volume) and PDA flow (n = 60; r = .84). In studies with exclusive left-to-right shunting at the PDA (n = 48), the mean QLV-QRV (112 +/- 83 ml/kg per minute) was significantly higher than in those with bidirectional shunting (n = 16; mean QLV-QRV = 50 +/- 27 ml/kg per minute). Two infants with severe intraventricular hemorrhage (IVH grade 3) and two infants with periventricular leukomalacia (PVL) had significantly higher QLV/QRV (2.09 +/- 0.36 and 1.67 +/- 0.02 respectively) than those with no IVH (n = 6; QLV/QRV = 1.31 +/- 0.18) or those with IVH grades 1 and 2 (n = 8; QLV/QRV = 1.48 +/- 0.27). There was no difference in QLV/QRV in infants with or without bronchopulmonary dysplasia and retinopathy of prematurity. Necrotizing enterocolitis did not develop in any of the 30 infants. CONCLUSION: PDA shunt volume can be quantified by DE. Larger studies are needed to correlate clinical outcome with QLV/QRV.

Relation between arterial blood pressure and blood volume and effect of infused albumin in sick preterm infants.

The relation between directly measured arterial blood pressure and blood volume was studied in 61 sick preterm infants. Mean blood volume (derived from plasma volume [T1824 ten-minute albumin space] and hematocrit value) of 26 hypotensive infants (89.1 +/- 17.26 ml/kg) was not significantly different from that of 35 normotensive, but otherwise comparable, infants (91.4 +/- 14.57 ml/kg). There was no relation between arterial mean blood pressure and blood volume. Twenty-one infants with arterial mean blood pressure less than 30 mm Hg were given 1.0 g/kg of 10% salt-poor albumin. Significant increases in blood pressure occurred but were small in magnitude; more than one half of infants had arterial mean blood pressures persistently less than 30 mm Hg. Arterial/alveolar PO2 ratio decreased significantly with albumin infusion in six infants with hyaline membrane disease not receiving continuous distending-airway pressure, suggesting an association between infused albumin and impaired oxygen exchange.

Hyaline membrane disease treated with early nasal end-expiratory pressure: one year's experience.

This report describes one year's experience treating hyaline membrane disease (HMD) with nasal end-expiratory pressure (NEEP). During the 12 months from July 1, 1973 through June 30, 1974, 119 children with HMD were admitted to the Intensive Care Unit of St. Paul Children's Hospital. Sixty-nine infants were treated early in the course of their disease with NEEP. The survival, incidence of complications, and the number of endotracheal intubations are reported and compared to our experience during a similar time period prior to the use of NEEP (1971-1972). Since the advent of the early application of modest amounts of end-expiratory pressure by nasopharyngeal tube, there has been an increase in the survival of all admissions with HMD, but the increase was statistically significant (P less than .01) only in those weighing 1,501 to 2,000 gm. There was a significant decrease (P less than .025) in the total number of children with HMD requiring endotracheal intubation. There was no change in the incidence of pneumothoraces or bronchopulmonary dysplasia. NEEP is a simple and effective technique for creating continuous airway distending pressure. Its effectiveness and ready availability make the routine endotracheal intubation of infants requiring only continuous airway distending pressure no longer justifiable.

Furosemide in hyaline membrane disease.

In a randomized clinical trial designed to evaluate the effect of diuresis on infants with hyaline membrane disease, seven infants were treated with furosemide (2 mg/kg intravenously) and five received 5% dextrose water in 0.225% sodium chloride (control group). Arterial blood gas analyses performed before and during the six hours after treatment showed no significant difference between control and treated infants. Urine output and urine sodium and calcium loss were significantly increased (P less than .05) in the infants receiving furosemide. The diuresis seemed to have no effect on left atrial size determined echocardiographically, whereas measurements of dynamic skinfold thickness suggested mobilization of subcutaneous water. One infant became seriously dehydrated and hypotensive secondary to a massive diuresis. We concluded that furosemide had a potent diuretic effect in infants with hyaline membrane disease but does not improve cardiorespiratory function acutely. This may be because of failure to mobilize pulmonary interstitial fluid in the time period tested. It may also be possible that the presence of pulmonary interstitial fluid does not play an important role in the impairment of gas exchange in the acute stage of hyaline membrane disease.

Increased systemic vascular resistance in neonates with pulmonary hypertension.

The time necessary for aortic diastolic pressure to decrease to 50 percent of an initially selected value after dissipation of the dicrotic notch (T 1/2) was determined in newborn infants with and without pulmonary hypertension. The mean T 1/2 was 671 +/- 167 msec in seven infants with clinical evidence of pulmonary hypertension and documented right to left ductus arteriosus shunting; 849 +/- 243 msec in nine infants with clinical evidence of pulmonary hypertension but no documented right to left ductus arteriosus shunting; and 457 +/- 66 msec in eight infants with hyaline membrane disease and no clinical evidence of pulmonary hypertension or a patent ductus arteriosus. The mean T 1/2 values in the former two groups were significantly different from that in the group with no pulmonary hypertension (P less than 0.01). An evaluation of factors affecting T 1/2 leads to the conclusion that the patients with pulmonary hypertension had increased systemic vascular resistance as well. This finding has important diagnostic, etiologic and therapeutic implications.

Sleep architecture and continuity measures of neonates with chronic lung disease.

Electroencephalographic (EEG) sleep studies of 25 preterm neonates with chronic lung disease (CLD) corrected to a fullterm postconceptional age were compared with recordings from two groups of neonates without CLD: a fullterm appropriate for gestational age group (9 patients) and a preterm group studied at a corrected term postconceptional age (15 patients). Electrographic/polygraphic studies were obtained using 21-channel EEG recordings. Scores were tabulated based on minute-by-minute visual analyses of sleep state, number and duration of arousals, body movements and rapid eye movements (REM). A significant reduction in the percentage of active sleep was noted in the CLD group compared to both control groups (31.15% vs. 47.01% and 52.9%, respectively). The mean percentage of indeterminate sleep was significantly increased in the study group as compared to both control groups (31.23% vs. 15.18% and 11.5%). In addition, significant differences were noted between the CLD group and the healthy preterm control group with respect to the number (0.29/minute vs. 0.13/minute) and duration (4.8 seconds vs. 2.94 seconds) of arousals as well as the total number of body movements (1.57/minute vs. 0.74/minute). These data suggest that neurophysiological organization of the immature brain, as reflected in neonatal sleep architecture and continuity measures, is adversely affected in neonates with CLD. EEG sleep architecture and continuity measures may be helpful in predicting the longitudinal outcome of infants with CLD as this group is at risk for adverse neurodevelopmental outcome.