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.

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.

Gelatinase activities in the airways of premature infants and development of bronchopulmonary dysplasia.

Matrix-degrading metalloproteinases may play a role in the pathophysiology of bronchopulmonary dysplasia (BDP). We, therefore, evaluated correlations between gelatinase activities [metalloproteinase (MMP)-2 and MMP-9] or tissue inhibitor of metalloproteinase (TIMP)-1 levels present in the airways during the initial phase of hyaline membrane disease and the onset of BPD. Tracheal aspirates were obtained within 6 h of birth (day 0) from 64 intubated neonates with a gestational age < or =30 wk. Forty-five neonates were resampled on day 3 or 5. Total MMP-2 level measured by zymography fell with time, whereas total MMP-9 level and TIMP-1 levels, assayed by ELISA, increased; the MMP-9 increase correlated with the increase in airway inflammatory cell numbers. Among the parameters measured on day 0, 3, or 5, lower total MMP-2 level, lower birth weight, and higher fraction of inspired oxygen on day 0 were significantly and independently associated with the development of BPD. In conclusion, MMP-9 level and TIMP-1 levels increased after birth but are not linked to BPD outcome. In contrast, low MMP-2 level at birth is strongly associated with the development of BPD.

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.

Effects of birthweight and oxygen supplementation on lung function in late childhood in children of very low birth weight.

Impaired respiratory function has been found frequently in ex-premature children, but it is unclear which specific factors influence this impairment the most. The aim of this study was to determine the importance of the contributions of birth weight, gestational age, neonatal respiratory disease, and its treatment on subsequent childhood lung function at age 11 years in a cohort of children of very low birth weight (VLBW; 2,000 g) of similar age. VLBW children were shorter and lighter than controls (P < 0.0001) at 11 years of age, and had reduced expiratory flows (P < 0.00001) and forced vital capacities (P < 0.001). The residual volume to total lung capacity ratio (RV/TLC ratio) was increased (P < 0.00001), while total lung capacity (TLC) remained unchanged. Those with bronchopulmonary dysplasia (BPD) had the lowest mean expiratory flows. Males had lower expiratory flows than females. On univariate analysis, gestational age by itself accounted for 8.8% of the explained variance in FEV(1) at 11 years of age, but birth weight accounted for 16% on its own; both together accounted for a further 0.2% (16.2%), suggesting that the latter was the dominant factor. On multivariate analysis, the contribution of birth weight and gestational age was small, and the best predictors at 11 years of age, which together explained 43.4% of the total variance in FEV(1), were log days of supplemental oxygen (9.6%) and a reported history of asthma (10.8%). For FEF(25-75), these predictors explained 7.2% and 13.4%, respectively, of the total explained variance of 40.6%. The relation between neonatal oxygen supplementation and childhood FEV(1) was such that up to 20 days of supplemental oxygen had little effect on subsequent FEV(1) at 11 years of age, but each additional week of supplemental oxygen after that time was associated with a progressive reduction in FEV(1) of 3%. These data confirm the significant role of supplemental oxygen in the neonatal period and a history of asthma on the subsequent reduction of expiratory flows in VLBW children. Birth weight was a more important prenatal factor than gestational age, but both were of lesser predictive significance than either supplemental oxygen or a reported history of asthma.

Cardiopulmonary exercise performance in prematurely born children.

Prematurely born children have reduced peak VO2 compared with their peers, inferentially attributed to ventilatory limitation. The primary purpose of this study was to compare exercise ventilation and cardiac output in a sample of childhood survivors of lung disease of prematurity with those of a control group to elucidate reasons for lower peak VO2. A secondary aim was to describe and compare the ventilatory response to incremental exercise. Thirty-two children, aged 8-9 y, were recalled for lung function and progressive exercise tests. Fifteen of them also performed submaximal exercise with measurement of cardiac output (indirect [CO2] Fick) and physiologic dead space. Results were compared with those of term-born, age- and sex-matched, control children. Pulmonary function tests showed mild airflow limitation. Peak VO2 was lower in prematurely born children compared with control children, and was correlated with lean body mass. Their heart rate-VO2 relationship and stroke volume were similar to that of term-born control children. Children with a history of bronchopulmonary dysplasia and hyaline membrane disease as infants exhibited greater exercise hyperpnea than did healthy control children, because of higher breathing frequency, and maintained lower end-tidal PCO2 during submaximal exercise. Physiologic dead space normalized for body weight was similar in preterm and term-born children. Lower peak VO2 in this population is not caused by cardiopulmonary factors, but is best predicted by lean body mass. Ventilation did not limit exercise performance, although it appears that breathing during exercise is regulated differently in prematurely born children than in term-born children.

[For or against the early use of nasal continuous positive pressure and exogenous surfactant in hyaline membrane disease. Physiopathologic arguments]. / Pour ou contre une utilisation précoce de la pression positive continue nasale et du surfactant exogène au cours de la maladie des membranes hyalines. Arguments physiopathologiques.

The use of nasal CPAP in the treatment of respiratory distress syndrome in very premature newborns follows pathophysiological basis. The authors emphasize the usefulness of nasal CPAP and surfactant in the treatment of respiratory distress syndrome. The aim of this strategy is to reduce alveolar atelectasis, thus reducing the incidence and the severity of respiratory distress syndrome, together with a possible reduction of the incidence of bronchopulmonary dysplasia.

Lung function outcome in children of premature birth.

Since the 1960s there has been a continual improvement in the survival of premature infants of birthweight less than 1500 g. This has resulted in an increase in the prevalence of bronchopulmonary dysplasia (BPD), or its milder form, chronic lung disease (CLD) of prematurity. In children with BPD; the initial air trapping improves in the first 3-4 years of life, but small airway obstruction is often slow to improve, suggesting dysanaptic lung growth. Despite this, the majority of older children and adolescents with BPD/CLD do not have significant respiratory symptoms. Children born prematurely with or without hyaline membrane disease may also have a reduction in expiratory flows during childhood, albeit less severe. The clinical significance of this in the longer term is unclear. Although significant associations between decrements in expiratory flows, neonatal oxygen therapy and assisted ventilation have been demonstrated. Airway function has also been reported to be largely unrelated with perinatal events but strongly associated with birthweight. The latter suggests that intra-uterine factors such as under-nutrition may be more important than hitherto recognized. Because of a lack of longitudinal studies, it is unclear how lung function will track during adolescence and adult life. Bronchial hyper-responsiveness is significantly increased in children with BPD and to a lesser extent in those born prematurely with or without hyaline membrane disease. It is unclear whether this is due to a genetic predisposition, neonatal lung injury or anatomically smaller airways. Given the morbidity and fiscal cost of a premature birth, effective strategies to reduce the premature birth rate are needed.

Continuous tracheal gas insufflation enables a volume reduction strategy in hyaline membrane disease: technical aspects and clinical results.

OBJECTIVE: Instrumental dead space wash-out can be used to improve carbon dioxide clearance. The aim of this study was to define, using a bench test, an optimal protocol for long-term use, and to assess the efficacy of this technique in neonates. DESIGN: A bench test with an artificial lung model, and an observational prospective study. Dead space wash-out was performed by continuous tracheal gas insufflation (CTGI), via six capillaries molded in the wall of a specially designed endotracheal tube, in 30 preterm neonates with hyaline membrane disease. SETTING: Neonatal intensive care unit of a regional hospital. RESULTS: The bench test study showed that a CTGI flow of 0.5 l/ min had the optimal efficacy-to-side-effect ratio, resulting in a maximal or submaximal efficacy (93 to 100%) without a marked increase in tracheal and CTGI circuit pressures. In the 30 newborns, 15 min of CTGI induced a significant fall in arterial carbon dioxide tension (PaCO2), from 45 +/- 7 to 35 +/- 5 mmHg (p = 0.0001), and in 14 patients allowed a reduction in the gradient between Peack inspirating pressure and positive end-expiratory pressure from 20.8 +/- 4.6 to 14.4 +/- 3.7 cmH2O (p < 0.0001) while keeping the transcutaneous partial pressure of carbon dioxide constant. As predicted by the bench test, the decrease in PaCO2 induced by CTGI correlated well with PaCO2 values before CTGI (r = 0.58, p < 0.002) and with instrumental dead space-to-tidal volume ratio (r = 0.54, p < 0.005). CONCLUSION: CTGI may be a useful adjunct to conventional ventilation in preterm neonates with respiratory disease, enabling an increase in CO2 clearance or a reduction in ventilatory pressure.

A new method to analyze lung compliance when pressure-volume relationship is nonlinear.

Changes in dynamic lung compliance during inspiration and expiration cannot be modeled accurately with conventional algorithms. We developed a simple method to analyze pressure-volume (P/V) relationships under condition of nonlinearity (APVNL) and tested it in a lung model with known resistance and nonlinear P/V relationship. In addition, pulmonary mechanics in 22 infants, 11 of them with nonlinear P/V relationships, were analyzed with the new method. The findings were compared with those obtained by a recently introduced algorithm, multiple linear regression analysis (MLR) of the equation of motion. The APVNL method described the changing compliance (C) of the lung model accurately, whereas the MLR method underestimated C especially in the first half of the breath. In infants the MLR method gave highly variable, often nonphysiological C values in the beginning of a breath. In contrast, the coefficient of variability of measurements obtained by the APVNL method was significantly smaller (p < 0.02), and the indices of model-fit showed better agreement between calculated and observed pressure than for the MLR method (p < 0.02). We conclude that the APVNL method accurately describes nonlinear P/V relationships present during spontaneous breathing or mechanical ventilation. The method may be helpful in identifying and preventing pulmonary overdistention.

Lung function and airway responsiveness in children and adolescents after hyaline membrane disease: a matched cohort study.

Some investigators consider prematurity to be responsible for the lung function abnormalities found in prematurely born children and adolescents who had neonatal respiratory diseases. This study attempts to measure the effect of neonatal respiratory disease on lung function during school age and adolescence, by controlling the confounding effect due to prematurity. Lung volumes, airway resistance and specific airway conductance measured by plethysmography, maximum expiratory flow-volume curves, pulmonary diffusion of carbon monoxide, and the airway responsiveness to a challenge with methacholine, were determined in a cohort of children aged 8-14 yrs, who had suffered from hyaline membrane disease but who did not develop bronchopulmonary dysplasia. The values obtained were compared with those of children without hyaline membrane disease, not ventilated for other causes, and matched for gestational age, sex and age. Thirty six pairs of children were enrolled, of which 26 participated in the methacholine test. Compared to their paired controls, children with hyaline membrane disease had a significantly lower forced expiratory volume in one second (FEV1), forced mid-expiratory flow (FEF25-75), and maximal expiratory flow when 75, 50 and 25% of the forced vital capacity remained in the lung (MEF75, MEF50 and MEF25, respectively), and a significantly higher airway resistance (Raw). The effect was less in children born more prematurely, who showed less difference in FEF25-75, MEF75 and MEF25. The duration of treatment with steroids in the neonatal period was associated with a reduction in the differences in FEV1, MEF25 and Raw. Independent of prematurity, hyaline membrane disease and its treatment is associated with alterations in long-term lung function, even in children who do not develop bronchopulmonary dysplasia. The effect can be less in more premature children, and neonatal steroids can have a long-term preventive effect.

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.

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.

Síndrome de dificultad respiratoria / Respiratory distress syndrome

Con el objeto de uniformar su denominación y facilitar la interpretación de las publicaciones sobre ellas en el país, se sugieren criterios para la caracterización de algunas afecciones respiratorias de los recién nacidos. Se propone hablar de enfermedad de membrana hialina (o síndrome de dificultad respiratoria del prematuro por déficit de surfactante) en casos de prematurez y déficit de surfactante; requerimientos precoces (antes de transcurridas 6 horas desde el nacimiento) de O2, progresivamente mayores y de duración igual o mayor a tres días; opacidad difusa, broncograma aéreo y disminución de volumen pulmonar en las radiografías de tórax. El pulmón inmaduro se caracteriza por prematurez (menos de 28 semanas de edad gestacional), insuficiencia respiratoria causada principalmente por inmadurez morfológica del pulmón, requerimientos de O2 en general bajos (no obstante requieran ventilación mecánica), no progresivos y de duración igual o mayor a 7 días, con alteraciones pulmonares mínimas inespecíficas, con volumen pulmonar conservado en las radiografías de tórax. El pulmón húmedo o taquipnea transitoria es un trastorno en que los antecedentes no son requisitos determinantes para hacer el diagnóstico y sus manifestaciones clínicas son taquipnea; aumento de los requerimientos de O2, generalmente no progresivos y de corta duración igual o menor a 5 días; infiltrado intersticial, cisuras visibles y aumento del volumen pulmonar en las radiografias de tórax

Morphine increases synchronous ventilation in preterm infants.

OBJECTIVE: To examine the short-term cardiorespiratory effects of intravenous morphine infusion in ventilated preterm infants. METHODOLOGY: A randomized double-blind placebo-controlled trial in a neonatal intensive care unit. Twenty-six preterm infants (29-36 weeks gestation) with hyaline membrane disease requiring ventilatory assistance on the first day after birth were included in the study. A loading dose of morphine 100 micrograms/kg over 30 min followed by a continuous intravenous infusion at 10 micrograms/kg per hour was given. Primary measures were heart rate, blood pressure, respiratory rate and interaction of spontaneous respiration with mechanical ventilation. Secondary measures were durations of oxygen therapy, ventilator therapy and hospitalization as well as incidence of bronchopulmonary dysplasia, periventricular haemorrhage and pneumothorax. RESULTS: Morphine-treated infants spent a significantly greater percentage of total ventilated time breathing in synchrony with their ventilators (median [IQ] = 72[58-87] vs 31[17-51]%; P = 0.0008). Heart rate and respiratory rate, but not blood pressure, were reduced in morphine-treated infants. Duration of oxygen therapy was reduced (median [IQ] = 4.5[3-7] vs 8[4.75-12.5] days; P = 0.046). CONCLUSIONS: Intravenous morphine infusion increases synchronicity of spontaneous and ventilator-delivered breaths in preterm infants. Morphine reduces heart rate and respiratory rate without reducing blood pressure, and may help to reduce duration of oxygen therapy in preterm infants with hyaline membrane disease.

Inhaled nitric oxide improves gas exchange and lowers pulmonary vascular resistance in severe experimental hyaline membrane disease.

To determine the effects of inhaled nitric oxide (NO) on pulmonary hemodynamics and gas exchange in experimental hyaline membrane disease (HMD), we studied 16 premature lambs (0.78 term) in two separate protocols. All animals were treated with exogenous surfactant before mechanical ventilation. In protocol 1, we measured the acute response to brief treatment with inhaled NO (20 ppm, 20 min) after 2 h of mechanical ventilation with fraction of inspired oxygen of 1.00 (n = 5). After 2 h, brief NO treatment lowered pulmonary vascular resistance from 0.26 +/- 0.05 to 0.16 +/- 0.03 mm Hg.(mL/min)-1 (p < 0.01) and improved gas exchange (arterial PO2, 44 +/- 9 mm Hg baseline to 168 +/- 45 mm Hg NO, p < 0.01; arterial PCO2 45 +/- 5 mm Hg baseline to 35 +/- 4 mm Hg NO, p < 0.05). In protocol 2, to determine whether early and continuous treatment with inhaled NO could sustain improvement in gas exchange and pulmonary hemodynamics in severe HMD, we compared the physiologic effects of ventilation with high inspired oxygen concentrations for 3 h with NO (20 ppm, n = 6) and without NO (controls, n = 5). After 3 h, the NO treatment group had sustained reduction in pulmonary vascular resistance (0.10 +/- 0.01 mm Hg.(mL/min)-1 NO versus 0.25 +/- 0.04 mm Hg.(mL/min)-1 control, p < 0.05), increased left pulmonary artery blood flow (204 +/- 24 mL/min NO versus 109 +/- 15 mL/min control, p < 0.05), and increased arterial PO2 (114 +/- 27 mm Hg NO versus 36 +/- 11 mm Hg control, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Variación de los fosfolípidos, colesterol y triglicéridos en el suero con el uso de surfactante en neonatos con enfermedad de membrana hialina / Variations in phospholipids, cholesterol and triglycerids with exogen surfactant application in neonates with hialine membrane disease

El objetivo de este estudio prospectivo fue analizar las variaciones séricas de los lípidos y su repercusión al aplicar surfactante endotraqueal. Se formaron dos grupos, el A de neonatos a los cuales se les puso surfactante natural de extracto de pulmón de bovino y el grupo B al cual se les puso solución fisiológica. Los criterios de inclusión para ambos grupos fueron: ser menores de 37 semanas, diagnóstico de enfermedad de membrana hialina, necesidad de ventilación mecánica. A los dos grupos se les determinó fosfolípidos, colesterol y triglicéridos séricos antes (basales) y 24 horas después de aplicado el surfactante y la solución fisiológica (controles). Al conformar el grupo A vs el B los resultados obtenidos fueron: no encontramos diferencia estadística en cuanto a peso (1340 ñ 341 vs 1320 ñ 377) y edad gestacional (34 ñ 2.3 vs 34.6 ñ 1.8), tampoco en sexo, vía de nacimiento, Apgar y trofismo. Al comparar los valores controles de ambos grupos encontramos un aumento en el grupo A para fosfolípidos y colesterol (P<0.01). Al confrontar los valores basales vs controles encontramos aumento en el grupo A para fosfolípidos y colesterol (P<0.001), en el grupo B hubo una disminución en el colesterol (P<0.05). Concluimos que el uso de surfactante natural de extracto de pulmón de bovino, produce un aumento de los fosfolípidos y colesterol en sangre, sin repercusión hemodinámica