Effects of antenatal glucocorticoids on circulatory adaptation at birth in the ovine fetus.

OBJECTIVE: Adaptation to extra-uterine life requires dramatic increase in pulmonary blood flow. Mechanisms that induce pulmonary vasodilatation at birth are incompletely understood but include alveolar ventilation, increase in PaO2, and production of vasoactive mediators. We hypothesized that antenatal glucocorticoids (GC) increase pulmonary vasodilatation to birth-related stimuli. STUDY DESIGN: To test this hypothesis, we studied the pulmonary hemodynamic response at birth to mechanical ventilation with low (<10%) and then with high (100%) FiO2 in chronically prepared late-gestation fetal lambs treated or not by antenatal maternal steroids. RESULTS: Basal mean aortic and pulmonary artery pressure (PAP), left pulmonary blood flow, pulmonary vascular resistance (PVR), and blood gas were similar between control and dexamethasone-treated animals (GC group). During mechanical ventilation with low FiO2, mean PVR decreased by 40% in the control group (from 0.44 +/- 0.01 to 0.25 +/- 0.01 mm Hg/ml/min) and by 60% in the GC group (from 0.44 +/- 0.02 to 0.19 +/- 0.02 mm Hg/ml/min) (p < 0.01). When subsequently ventilated with 100% O2, there was no difference in PVR decrease between groups (0.15 +/- 0.02 mm Hg/ml/min in the GC group vs. 0.14 +/- 0.01 mm Hg/ml/min in the control group). CONCLUSION: Antenatal GC enhance pulmonary vasodilatation induced by alveolar ventilation at birth but do not alter the pulmonary vascular response to O2. We speculate that antenatal steroids exposure improve adaptation at birth through acceleration of both parenchymal and vascular lung maturation.

Pulmonary vasodilator effects of norepinephrine during the development of chronic pulmonary hypertension in neonatal lambs.

BACKGROUND: This experimental study was performed to determine the effects of norepinephrine on: (i) the pulmonary vascular tone during the development of pulmonary hypertension (PH) in the fetus and (ii) the circulatory adaptation at birth after chronic intrauterine PH. METHODS: Chronically instrumented fetal lambs were randomized into two groups: (i) a group with PH obtained by antenatal partial ligation of the ductus arteriosus (DA) (n=9) and (ii) a control group without DA ligation (n=6). Pulmonary vascular responses to norepinephrine (1.5 microg min(-1)) were measured in utero 7 days after surgery. At day 8 post-surgery, after delivery, animals were ventilated for 3 h with oxygen 100%. The group with PH was randomly assigned to receive norepinephrine or saline. RESULTS: Mean pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) were higher in the PH group (P<0.01). Norepinephrine-induced decrease in PVR was more pronounced in the PH group than in the control group (63 vs 35%, respectively; P<0.01). In the PH group, the decrease in PVR during mechanical ventilation was greater in the animals receiving norepinephrine than in the animal receiving saline (from 1.05 (0.12) to 0.1 (0.02) vs from 1.04 (0.1) to 0.2 (0.04) mm Hg ml(-1) min(-1), respectively; P<0.01). After 3 h of ventilation, mean PVR in the PH lambs treated by norepinephrine was similar to those measured in the control lambs. Aortic pressure was higher in the group treated with norepinephrine. CONCLUSION: The data suggest that norepinephrine may improve post-natal pulmonary adaptation in the newborn with persistent PH both by increasing systemic vascular pressure and by increasing pulmonary blood flow.

Effects of catecholamines on the pulmonary circulation in the ovine fetus.

High levels of circulating catecholamines are found in the fetus, and fetal stress and birth induce a marked surge in catecholamine secretion. Little is known about the role of catecholamines on the fetal pulmonary circulation. To determine the effects of catecholamines on the pulmonary vascular tone, we tested the hemodynamic response to norepinephrine and dopamine infusion in chronically prepared late-gestation fetal lambs. We found that norepinephrine infusion (0.5 microg. kg(-1). min(-1)) increased pulmonary artery pressure (PAP) by 10 +/- 1% (P < 0.01), left pulmonary artery blood flow by 73 +/- 14% (P < 0.01), and decreased pulmonary vascular resistance (PVR) by 33 +/- 6% (P < 0.01). The pulmonary vasodilator effect of norepinephrine was abolished after nitric oxide synthase inhibition. Dopamine infusion at 5 microg. kg(-1). min(-1) did not significantly change PVR. Conversely, dopamine infusion at 10 microg. kg(-1). min(-1) increased PAP (P < 0.01) and progressively increased PVR by 30 +/- 14% (P < 0.01). These results indicate that catecholamines may modulate basal pulmonary vascular tone in the ovine fetus. We speculate that catecholamines may play a significant role in the maintenance of the fetal pulmonary circulation and in mediating changes in the transitional pulmonary circulation.

Two years' follow-up of newborn infants after extracorporeal membrane oxygenation (ECMO).

OBJECTIVE: Extracorporeal membrane oxygenation (ECMO) is a technique of extracorporeal oxygenation used in newborn infants with refractory hypoxemia after failure of maximal conventional medical management, when mortality risk is higher than 80%. We retrospectively reviewed all the neonates treated by ECMO between October 1991 and September 1997 in our newborn intensive care unit. METHODS: Fifty-seven patients were treated with ECMO for severe respiratory failure: congenital diaphragmatic hernia (CDH) (n=23), neonatal sepsis (NS) (n=14), meconium aspiration syndrome (MAS) (n=12), and others (n=8). Mean gestational age and birth weight were 38+/-2 weeks and 3200+/-500 g, respectively. Oxygenation index was 61+/-8. Both venovenous (n=28) or venoarterial ECMO (n=29) were used. The mean time at ECMO initiation was 47 h (range 8 h-2 months). The mean duration was 134+/-68 h. In each case of VA ECMO, carotid reconstruction was performed. Survival at 2 years was 40/57 (70%) (CDH 12/23 (52%), NS 11/14 (79%), MAS 12/12 (100%), others 5/8). Follow-up at 2 years was available in 36 survivors. RESULTS: Neurodevelopmental outcome was not related to the initial diagnosis: normal neurologic development (n=30), cerebral palsy (n=5), and neurologic developmental delay (n=1). Two patients remained oxygen dependant at 2 years, and four required surgical treatment for severe gastroesophageal reflux. Respiratory and digestive sequelae were more frequent in the CDH group (P<0.01). Patency and flow of the repaired carotid artery was assessed in 20 infants at 1 year of age using Doppler ultrasonography: normal (n=10), <50% stenosis (n=9), and >50% stenosis (n=1). CONCLUSION: ECMO increased survival of newborn infants with refractory hypoxemia. However, higher a survival rate and lower morbidity were found in non-CDH infants than in congenital diaphragmatic hernia.

Effects of inhaled nitric oxide on gas exchange and acute lung injury in premature lambs with moderate hyaline membrane disease.

OBJECTIVE: The purpose of this study was to examine whether inhaled nitric oxide (iNO) may change lung injury in moderate hyaline membrane disease (HMD). METHODS: Fifteen moderately premature lambs (128 days gestation, term=147 days) were randomly assigned to treatment with 20 ppm inhaled NO (n=7) from the onset of ventilation or control (n=8). Except for inhaled NO, treatments were intentionally similar to those applied in clinical situations. After porcine surfactant administration (Curosurf, 100 mg/kg), mechanical ventilator settings were modified during the course of the study to maintain PaCO(2) between 40 and 50 mmHg and post-ductal SpO(2) between 90 and 95%. The main studied parameters were gas exchanges parameters, respiratory mechanics (static compliance and functional residual capacity) and pulmonary vascular permeability and/or filtration rate indices. RESULTS: We found that 20 ppm of inhaled NO for 5 h significantly reduce ventilatory and oxygen requirements, but only during the first hour of mechanical ventilation. No increase in extravascular lung water content (5.41+/-0.96 vs. 5.46+/-1.09 ml/g bloodless dry lung in the control group and in the NO group, respectively) and no impairment of the respiratory mechanics could be found in the NO-treated group. However, inhaled NO increased the albumin lung leak index in this model (6.09+/-1.51 in the NO-treated group vs. 4.08+/-1.93 in the control group; P<0.05). CONCLUSIONS: Our results do not therefore support a detrimental effect of short-term exposure to low doses of NO inhalation in moderate HMD. However, it may induce an increase in lung vascular protein leakage. The pathophysiological consequences of this finding remain to be elucidated.

[Congenital hernia of the diaphragm. A retrospective study of 123 cases recorded in the Neonatal Medicine Department, URHC in Lille between 1985 and 1996]. / Les hernies congénitales des coupoles diaphragmatiques. Etude rétrospective de 123 observations recueillies dans le service de médecine néonatale du CHRU de Lille entre 1985 et 1996.

BACKGROUND: During the last ten years, new therapeutic strategies have been used in order to improve the management of congenital diaphragmatic hernia (CDH). CDH is associated with pulmonary hypoplasia, abnormal pulmonary vascular reactivity and pulmonary immaturity. Between 1985 and 1990, mechanical hyperventilation and early surgery were provided systematically. Since 1991, the management of CDH in our institution has involved a preoperative stabilization with exogenous surfactant replacement, gentle ventilation, high-frequency oscillation, nitric oxide or extracorporeal membrane oxygenation. PURPOSE: To analyse the impact of the new therapeutic strategy on the survival and outcome of newborns with CDH. METHODS: Retrospective review of all infants with CDH admitted to our institution from 1985 through 1996. Mortality and morbidity were compared between period I (1985-1990) and period II (1991-1996). RESULTS: Between 1985 and 1996, 123 neonates were admitted to our Neonatal Department. Nine of them had another severe congenital malformation and were excluded from the study. Survival was 23% (12/52) in period I and 56% (35/62) in period II (p < 0.001). In period II, complications were more frequent among survivors in whom an extracorporeal membrane oxygenation was required (13 infants): bronchopulmonary dysplasia 77% (10/13), gastroesophageal reflux 61% (8/13), and hypotrophy 61% (8/13). CONCLUSION: These data demonstrate a significant improvement in survival in CDH since the implementation of new therapeutic modalities. Nevertheless, a significant morbidity exists among the infants who survive a severe respiratory failure.

Comparison of four methods for measuring elevation of FRC in mechanically ventilated infants.

The aim of the study was to compare measurements of the elevation of functional residual capacity (FRC) above the relaxation volume obtained in 34 mechanically ventilated infants (median weight 2.6 kg, range 1.2-9) from four different methods: (1) direct measurement of the complete exhalation volume after brief disconnection from the ventilator, (2) calculated measurement from total positive end-expiratory pressure (PEEP) measured by end-expiratory occlusion of the breathing circuit, (3) extrapolated evaluation from the mathematical model of Brody, (4) extrapolated evaluation from the passive expiration method. We considered the direct measurement (1) as the "gold standard". Measurements obtained by total PEEP (2) and by the Brody's mathematical model (3) provided similar results than the direct measurement. Conversely, graphical extrapolation from the passive expiration method (4) underestimated the elevation of FRC. In conclusion, we suggest using the mathematical extrapolation from the Brody's model to evaluate the elevation of FRC in mechanically ventilated infants: this method is non-invasive, does not require disruption of gas flow, can be easily performed with all the neonatal ventilators, and allows continuous breath-by-breath measurements.

[Exhale nitric oxide (NO) and respiratory function measured with body plethysmography in children]. / Monoxyde d'azote (NO) exhalé et fonction ventilatoire mesurée par pléthysmographie corporelle chez l'enfant.

BACKGROUND: Exhaled nitric oxide (NO) may be a marker of airway inflammation. Previous studies in adults have shown that the level of NO in exhaled air is influenced by several factors (breath holding, exercise, etc), or by several disease (asthma, congestive heart failure, diseases of the upper respiratory tract, cystic fibrosis, etc). However, few studies have been performed in children less than 3 years of age. The aim of this study was to determine endogenous NO levels in children with various diseases during lung volume measurements. PATIENTS AND METHODS: Fifty-two children aged 18.3 +/- 9.5 months were studied. The population was divided in two groups, according to the underlying disease: a group of 39 children with cystic fibrosis (n = 7), bronchopulmonary dysplasia (n = 17), asthma (n = 7) or recurrent respiratory tract infections (n = 8) and a second group of 13 children without respiratory disease. Lung function was measured by whole body plethysmography and several respiratory parameters were calculated (functional residual capacity [FRC], compliance and resistances of the respiratory system, trapped volume). NO production was measured on a chemiluminescence analyzer from mixed exhaled air collected into a bag, over a period of 5 minutes. RESULTS: NO production was related to disease: exhaled NO levels were three times higher in bronchopulmonary dysplasia and cystic fibrosis, compared to NO levels in children without respiratory disease. They were higher in asthma. They were not altered in recurrent respiratory tract infections. No correlation was found between respiratory parameters and NO production. However, exhaled NO levels were correlated to trapped volume, which defined dynamic part of pulmonary hyperinflation. CONCLUSION: Levels of endogenous NO in infants were similar to those measured in adults with and without inflammatory respiratory disease. Lung distention influenced exhaled NO production.

Inhaled nitric oxide neither alters oxidative stress parameters nor induces lung inflammation in premature lambs with moderate hyaline membrane disease.

The purpose of this investigation was to examine whether inhaled nitric oxide (NO) may alter oxidative stress parameters and induce lung inflammation in moderate hyaline membrane disease (HMD). Eighteen moderately premature lambs (130 days gestation, term = 147 days) were randomly assigned to treatment with 20 ppm inhaled NO (n = 8) from the onset of ventilation or used as control (n = 10). Except inhaled NO, treatments were intentionally similar to those applied in clinical situations. The main studied parameters were oxidative stress index measurements on lung parenchyma and in circulating blood, lung parenchyma microscopic examination and bronchoalveolar lavage cell count. We found that 20 ppm of inhaled NO for 5 h did not change significantly either malondialdehyde and total antioxidant status levels in circulating blood, or malondialdehyde, reduced glutathione, glutathione peroxidase and glutathione reductase in lung parenchyma. Amino-imino-propene bond generation, which are lipoperoxidation markers, was similar in both groups. Furthermore, no significant changes in the number of inflammatory cells in lung lavage products and in lung parenchyma microscopic examination could be found. Therefore, these data do not support the hypothesis that short-term NO inhalation increases oxidative stress and lung inflammation in an experimental model of moderate HMD.

Inhaled nitric oxide for a severe respiratory syncytial virus infection in an infant with bronchopulmonary dysplasia.

OBJECTIVE: To report the first case of ARDS in children treated with nitric oxide (NO) inhalation. METHODS: A 13-months infant presented with BPD and severe hypoxemia related to RSV infection and ARDS. Inhaled NO was delivered in the ventilatory circuit of a continuous flow ventilator (Babylog 8000, Dräger) in a concentration of 20-80 ppm for 7 days. NO and NO2 were continuously monitored (Polyton Draeger). Respiratory mechanics were evaluated by using the method of passive inflation by the ventilator. RESULTS: NO inhalation improved oxygenation (tcSaO2) and reduced respiratory system resistance without affecting arterial pressure. NO2 level remained below 5 ppm, and methaemoglobin level below 1%. The child survived without neurologic sequela. CONCLUSIONS: Two mechanisms to explain oxygenation improvement can be suggested: selective improvement in perfusion of ventilated regions and bronchodilation.

Latent pulmonary involvement in Crohn's disease: biological, functional, bronchoalveolar lavage and scintigraphic studies.

We have investigated the following pulmonary related parameters in 22 patients with Crohn's disease who were free of clinical pulmonary symptoms and had normal chest roentgenograms and in 25 controls: serum angiotensin converting enzyme, pulmonary function tests, bronchoalveolar lavage (lymphocyte count and subpopulations, macrophage viability and superoxide anion release by macrophages) and pulmonary scannings. Serum angiotensin converting enzyme was lower in Crohn's disease (14.1 +/- 5.1) than in controls (25.2 +/- 4.7) (p less than 0.001). Twelve of 22 Crohn's disease (54%) had a bronchoalveolar lavage lymphocytosis (greater than 18% alveolar lymphocytes). Bronchoalveolar lavage lymphocytes subpopulations were quite variable. Twelve of 17 Crohn's disease (71%) had an increase spontaneous and/or stimulated superoxide anion production by alveolar macrophages. Six of 12 Crohn's disease (50%) had an increase physiologic dead space in the upper part of their lung against one of 11 controls (9%). These data suggest that most patients with Crohn's disease have a latent pulmonary involvement.

Immediate postnatal decontamination as a means of obtaining axenic animals and human infants.

A technique not involving surgery is described for obtaining axenic (germ-free) newborn animals and human infants by decontamination immediately after birth. Three steps are involved: cleansing ther perineal region of the mother with an iodinated bactericidal solution, washing the newborn with the same solution, and after the newborn has been placed in a sterile isolater, administering a single oral dose of an antibiotic mixture previously determined to be active against the fecal and vaginal flora of the mother. All of the newborn obtained by means of this technique, including 13 piglets, 2 lambs, and 4 human infants, were found to be axenic throughout their stay in the isolators. Four piglets obtained by the same technique, but without adminstration of antibiotic mixture, were found not to be anenic. This technique, as compared with methods of surgical delivery of axenic young, embodies a number of advantages. It is harmless to the mother and to the newborn, it is relatively inexpensive, and it obviates the risk of prematurity involved in elective surgical delivery before term.