Síndrome de aspiración meconial: revisión de la fisiopatología y estrategias de manejo / Meconium aspiration syndrome: review of the pathophysiology and management strategies

El síndrome de aspiración meconial, es una condición clínica caracterizada por insuficiencia respiratoria que ocurre en neonatos nacidos a través de líquido amniótico teñido de meconio, y que puede presentarse como una enfermedad grave con riesgo vital. Su incidencia ha disminuido gracias a mejores prácticas obstétricas y atención perinatal y se ha observado una mejoría en la sobrevida, gracias a mejores prácticas en la UCI neonatal. Sin embargo, el abordaje más adecuado sigue siendo un tema de debate, dado que hasta el momento se basa sólo en medidas de soporte, sin que existan medidas que actúen sobre los mecanismos de daño. Por otro lado, la morbilidad a largo plazo entre los sobrevivientes sigue siendo una preocupación importante. Esta revisión ofrece una visión general actualizada de la epidemiología, la fisiopatología, el diagnóstico, el manejo terapéutico, la prevención y el pronóstico de los pacientes que presentan este cuadro.

Meconium aspiration syndrome is a clinical condition characterized by respiratory failure that occurs in neonates born through meconium-stained amniotic fluid and can present as a serious life-threatening disease. Its incidence has decreased thanks to better obstetric practices and perinatal care, and an improvement in survival has been observed, thanks to better practices in the neonatal ICU. However, the most appropriate approach is still a matter of debate, given that so far it is based only on support measures, without any measures that act on the damage mechanisms. On the other hand, long-term morbidity among survivors remains a major concern. This review offers an updated overview of the epidemiology, pathophysiology, diagnosis, therapeutic management, prevention, and prognosis of patients with this condition.

Heart rate during the first 24 hours in term-born infants.

OBJECTIVE: Heart rate (HR) is an important clinical parameter in newborn infants, but normal ranges are poorly defined. Our aim was to establish normal reference ranges and individual variations in HR as obtained by auscultation in healthy term-born infants during the first 24 hours of life. DESIGN: Observational study. SETTING: Single hospital in Norway. METHODS: HR was assessed by auscultation for 30 s at 2, 4, 8, 16 and 24 hours of age. Auscultation was validated against ECG recordings. SUBJECTS: Healthy term-born infants who were asleep or awake in a quiet resting state. MAIN OUTCOME MEASURES: Construction of percentile curves for resting HR. RESULTS: The study included 953 infants. The 50th percentile was 126 beats per minute (bpm) at age 2 hours and thereafter 120-122 bpm. The respective 2nd and 98th percentiles were 102 (thereafter 96-100) bpm and 162 (thereafter 150-156) bpm. The mean HR was 5.6 bpm higher when awake than asleep, 4.9 bpm higher when on the mother's chest than in the cot, 1.6 bpm higher in girls than in boys, and increased by 0.5 bpm per 0.1°C increase in rectal temperature. Mode of delivery, meconium staining, birth weight and maternal smoking during pregnancy were of no significance. For each infant, HR varied considerably during the first 24 hours (intraclass correlation 0.21 (95% CI 0.18 to 0.24), coefficient of variation 9.2%). CONCLUSIONS: The HR percentiles allow for a scientifically based use of HR when assessing newborn infants born at term.

Extra-Corporeal Membrane Oxygenation for Neonatal Respiratory Support.

To review our experience with Extra-Corporeal Membrane Oxygenation (ECMO) for respiratory support in neonates. From 1989 to 2018 2114 patients underwent respiratory ECMO support, with 764 (36%) neonates. Veno-Venous (V-V) cannulation was used in 428 (56%) neonates and Veno-Arterial (V-A) in 336 (44%). Historically V-V ECMO was our preferred modality, but due to lack of suitable cannula in the last 7 years V-A was used in 209/228 (92%) neonates. Mean and inter-quartile range of ECMO duration was 117 hours (inter-quartile range 90 to 164 hours). Overall 724 (95%) neonates survived to ECMO decannulation, with 640 (84%) hospital discharge. Survival varied with underlying diagnosis: meconium aspiration 98% (354/362), persistent pulmonary hypertension 80% (120/151), congenital diaphragmatic hernia 66% (82/124), sepsis 59% (35/59), pneumonia 86% (6/7), other 71% (43/61). Survival was 86% with V-V and 80% with V-A cannulation, better than ELSO Registry with 77% V-V and 63% V-A. Major complications: cerebral infarction/hemorrhage in 4.7% (31.1% survival to discharge), renal replacement therapy in 17.6% (58.1% survival to discharge), new infection in 2.9%, with negative impact on survival (30%). Following a circuit design modification and subsequent reduction in heparin requirement, intracerebral hemorrhage decreased to 9/299 (3.0%) radiologically proven cerebral infarction/hemorrhage. We concluded (1) outcomes from neonatal ECMO in our large case series were excellent, with better survival and lower complication rate than reported in ELSO registry. (2) These results highlight the benefits of ECMO service in high volume units. (3) The similar survival rate seen in neonates with V-A and V-V cannulation differs from the ELSO register; this may reflect the change in cannulation enforced by lack of suitable V-V cannula and all neonates undergoing V-A cannulation.

Effects of intravenous phosphodiesterase inhibitors and corticosteroids on severe meconium aspiration syndrome.

BACKGROUND: Meconium aspiration syndrome (MAS) is a major cause of severe respiratory failure in near- and full-term neonates. Alleviating inflammation is key to successfully treating severe MAS. Phosphodiesterase (PDE) inhibitors are known to play a role in airway smooth muscle relaxation and alveolar inflammation inhibition. This study aimed to investigate the effects of various intravenous (IV) PDE inhibitors and corticosteroids on MAS. METHODS: MAS was induced in newborn piglets by instilling human meconium in them. The piglets were randomly divided into five groups (n = 5 in each group): (1) control (sham treatment); (2) dexamethasone (Dex) (IV 0.6 mg/kg of dexamethasone); (3) aminophylline (Ami) (IV 6 mg/kg of aminophylline, followed by continuous infusion of 0.5 mg/kg/h of aminophylline; (4) milrinone (Mil) (IV 50 µg/kg of milrinone, followed by continuous infusion of 0.75 µg/kg/h of milrinone); and (5) rolipram (Rol) (IV 0.8 mg/kg of rolipram). The duration of the experimental period was 4 hours. RESULTS: Compared to the control group, all the four treatment groups revealed better oxygenation 3 hours and more after the start of treatment. The Rol group had a significantly elevated heart beat (p < 0.05) and relatively lower blood pressure compared to the other groups during the first 2 hours of the experiment. The Dex group had significantly lower interleukin (IL)-1ß levels in the lung tissue compared to the other groups (p < 0.05) and significantly lower IL-6 levels compared to the Ami and Mil groups (p < 0.05). Lung histology showed slightly less inflammation and atelectasis in the Dex group compared to the other groups, but lung injury scores showed no significant between-group differences. CONCLUSION: Using IV corticosteroids or any type of PDE inhibitors has some beneficial effects in improving oxygenation in MAS. PDE inhibitors are not superior to IV corticosteroids; in fact, adverse cardiovascular effects occur with the phosphodiesterase type 4 (PDE4) inhibitor. Further investigations are required before using IV corticosteroids and PDE inhibitors in future clinical application.

Recombinant Human Superoxide Dismutase and N-Acetylcysteine Addition to Exogenous Surfactant in the Treatment of Meconium Aspiration Syndrome.

This study aimed to evaluate the molecular background of N-acetylcysteine (NAC) and recombinant human superoxide dismutase (rhSOD) antioxidant action when combined with exogenous surfactant in the treatment of meconium aspiration syndrome (MAS), considering redox signalling a principal part of cell response to meconium. Young New Zealand rabbits were instilled with meconium suspension (Mec) and treated by surfactant alone (Surf) or surfactant in combination with i.v. NAC (Surf + NAC) or i.t. rhSOD (Surf + SOD), and oxygen-ventilated for 5 h. Dynamic lung-thorax compliance, mean airway pressure, PaO2/FiO2 and ventilation efficiency index were evaluated every hour; post mortem, inflammatory and oxidative markers (advanced oxidation protein products, total antioxidant capacity, hydroxynonenal (HNE), p38 mitogen activated protein kinase, caspase 3, thromboxane, endothelin-1 and secretory phospholipase A2) were assessed in pulmonary tissue homogenates. rhSOD addition to surfactant improved significantly, but transiently, gas exchange and reduced levels of inflammatory and oxidative molecules with higher impact; Surf + NAC had stronger effect only on HNE formation, and duration of treatment efficacy in respiratory parameters. In both antioxidants, it seems that targeting reactive oxygen species may be strong supporting factor in surfactant treatment of MAS due to redox sensitivity of many intracellular pathways triggered by meconium.

Comparison of different dosing strategies of intratracheally instilled budesonide on meconium injured piglet lungs.

BACKGROUND: Severe inflammation plays a vital role in the pathogenesis of meconium aspiration syndrome (MAS). Intratracheal (IT) instillation of corticosteroids may be beneficial for MAS in optimizing local effect and reducing systemic adverse effects, but the optimum dosing course remains open to question. METHODS: Thirty meconium-injured newborn piglets were enrolled into six study groups. The first four groups consisted of the IT instillation of 0.25/0.5 mg/kg using either one (IT-B251/IT-B501) or two (IT-B252/IT-B502) doses of budesonide, while the other two groups were the intravenous (IV) dexamethasone (0.5 mg/kg) (IV-Dex) group and the control group (Ctrl). Vital signs and cardiopulmonary functions were monitored throughout the experiments. Pulmonary histology was examined after completing the experiments. RESULTS: Both the IV-Dex and IT-B501 groups got significant improvement in oxygenation (P < 0.05). Lung compliance became worse after one dose of 0.25 mg/kg of IT budesonide. Pulmonary histology revealed that there were significantly lower lung injury scores for all treatment groups compared to control group, especially at the non-dependent sites of both the IT-B501 and IT-B502 groups. There was no significant difference between double- and single-dose groups, no matter whether 0.25 or 0.5 mg/kg of budesonide was used. CONCLUSIONS: IT instillation of one dose of 0.5 mg/kg budesonide is beneficial in treating meconium-injured piglet lungs during the first 8 h of injury, but a second dose at an interval of 4 h does not have a superior beneficial effect compared to one dose.

Effects on Lung Function of Small-Volume Conventional Ventilation and High-Frequency Oscillatory Ventilation in a Model of Meconium Aspiration Syndrome.

For treatment of severe neonatal meconium aspiration syndrome (MAS), lung-protective mechanical ventilation is essential. This study compared short-term effects of small-volume conventional mechanical ventilation and high-frequency oscillatory ventilation on lung function in experimentally-induced MAS. In conventionally-ventilated rabbits, MAS was induced by intratracheal instillation of meconium suspension (4 ml/kg, 25 mg/ml). Then, animals were ventilated conventionally with small-volume (f-50/min; VT-6 ml/kg) or with high frequency ventilation (f-10/s) for 4 h, with the evaluation of blood gases, ventilatory pressures, and pulmonary shunts. After sacrifice, left lung was saline-lavaged and cells in bronchoalveolar lavage fluid (BALF) were determined. Right lung was used for the estimation of lung edema formation (wet/dry weight ratio). Thiobarbituric acid-reactive substances (TBARS), oxidative damage markers, were detected in lung tissue and plasma. Meconium instillation worsened gas exchange, and induced inflammation and lung edema. Within 4 h of ventilation, high frequency ventilation improved arterial pH and CO2 elimination compared with conventional ventilation. However, no other significant differences in oxygenation, ventilatory pressures, shunts, BALF cell counts, TBARS concentrations, or edema formation were observed between the two kinds of ventilation. We conclude that high frequency ventilation has only a slight advantage over small-volume conventional ventilation in the model of meconium aspiration syndrome in that it improves CO2 elimination.

Cardiovascular effects of N-acetylcysteine in meconium-induced acute lung injury.

Anti-inflammatory drugs are increasingly used for treatment of neonatal meconium aspiration syndrome (MAS), but their adverse effects are poorly known. Therefore, the aim of this study was to evaluate the effects of the antioxidant N-acetylcysteine on cardiovascular parameters in an animal model of MAS. Oxygen-ventilated rabbits were intratracheally instilled 4 mL/kg of meconium suspension (25 mg/mL) or saline. Thirty minutes later, meconium-instilled animals were given N-acetylcysteine (10 mg/kg, i.v.) or the same volume of saline. Changes in cardiovascular parameters (blood pressure, heart rate, and heart rate variability) were recorded over a 5-min course of solution administration, over 5 min after its end, and then hourly for 5 h. Oxidation markers (thiobarbituric acid-reactive substances (TBARS) and total antioxidant status) and aldosterone, as a non-specific marker of cardiovascular injury, were determined in plasma. Meconium instillation did not evoke any significant cardiovascular changes, but induced oxidative stress and elevated plasma aldosterone. N-acetylcysteine significantly reduced the mentioned markers of injury. However, its administration was associated with short-term increases in blood pressure and in several parameters of heart rate variability. Considering these effects of N-acetylcysteine, its intravenous administration in newborns with MAS should be carefully monitored.

N-acetylcysteine alleviates the meconium-induced acute lung injury.

Meconium aspiration in newborns causes lung inflammation and injury, which may lead to meconium aspiration syndrome (MAS). In this study, the effect of the antioxidant N-acetylcysteine on respiratory and inflammatory parameters were studied in a model of MAS. Oxygen-ventilated rabbits were intratracheally given 4 mL/kg of meconium (25 mg/mL) or saline. Thirty minutes later, meconium-instilled animals were administered N-acetylcysteine (10 mg/kg; i.v.), or were left without treatment. The animals were oxygen-ventilated for additional 5 h. Ventilatory pressures, oxygenation, right-to-left pulmonary shunts, and leukocyte count were measured. At the end of experiment, trachea and lung were excised. The left lung was saline-lavaged and a total and differential count of cells in bronchoalveolar lavage fluid (BAL) was determined. Right lung tissue strips were used for detection of lung edema (expressed as wet/dry weight ratio) and peroxidation (expressed by thiobarbituric acid-reactive substances, TBARS). In lung and tracheal strips, airway reactivity to acetylcholine was measured. In addition, TBARS and total antioxidant status were determined in the plasma. Meconium instillation induced polymorphonuclear-derived inflammation and oxidative stress. N-acetylcysteine improved oxygenation, reduced lung edema, decreased polymorphonuclears in BAL fluid, and diminished peroxidation and meconium-induced airway hyperreactivity compared with untreated animals. In conclusion, N-acetylcysteine effectively improved lung functions in an animal model of MAS.

Anti-inflammatory treatment in dysfunction of pulmonary surfactant in meconium-induced acute lung injury.

Inflammation, oxidation, lung edema, and other factors participate in surfactant dysfunction in meconium aspiration syndrome (MAS). Therefore, we hypothesized that anti-inflammatory treatment may reverse surfactant dysfunction in the MAS model. Oxygen-ventilated rabbits were given meconium intratracheally (25 mg/ml, 4 ml/kg; Mec) or saline (Sal). Thirty minutes later, meconium-instilled animals were treated by glucocorticoids budesonide (0.25 mg/kg, i.t.) and dexamethasone (0.5 mg/kg, i.v.), or phosphodiesterase inhibitors aminophylline (2 mg/kg, i.v.) and olprinone (0.2 mg/kg, i.v.), or the antioxidant N-acetylcysteine (10 mg/kg, i.v.). Healthy, non-ventilated animals served as controls (Con). At the end of experiments, left lung was lavaged and a differential leukocyte count in sediment was estimated. The supernatant of lavage fluid was adjusted to a concentration of 0.5 mg phospholipids/ml. Surfactant quality was evaluated by capillary surfactometer and expressed by initial pressure and the time of capillary patency. The right lung was used to determine lung edema by wet/dry (W/D) weight ratio. Total antioxidant status (TAS) in blood plasma was evaluated. W/D ratio increased and capillary patency time shortened significantly, whereas the initial pressure increased and TAS decreased insignificantly in Sal vs. Con groups. Meconium instillation potentiated edema formation and neutrophil influx into the lungs, reduced capillary patency and TAS, and decreased the surfactant quality compared with both Sal and Con groups (p > 0.05). Each of the anti-inflammatory agents reduced lung edema and neutrophil influx into the lung and partly reversed surfactant dysfunction in the MAS model, with a superior effect observed after glucocorticoids and the antioxidant N-acetylcysteine.

Factores epidemiológicos y Apgar bajo al nacer / Epidemiological factors and low-Apgar at birth

INTRODUCCIÓN: El período más crucial de la vida humana corresponde a las primeras 24 h que siguen al nacimiento. En este período, la morbilidad y la mortalidad son elevadas, por lo que es necesario prevenir y conocer los factores de riesgo que puedan interferir en su normal desarrollo, evaluándose al nacer la puntuación de Apgar. OBJETIVOS: Identificar la posible asociación causal entre el índice de Apgar bajo y algunos factores epidemiológicos. Estimar a través del riesgo atribuible, aquellos factores que al actuar sobre ellos se lograría un mayor impacto en la población expuesta. MÉTODOS: Se realizó un estudio analítico observacional tipo caso control, relacionado con algunos factores epidemiológicos que inciden en la ocurrencia de Apgar bajo al nacer, en el Hospital Materno Provincial Docente Mariana Grajales Coello de Santiago de Cuba, desde el 1ro de enero de 2006 hasta el 31 de diciembre de 2007 . RESULTADOS: La edad materna y la edad gestacional al parto, el meconio en el líquido amniótico, las anomalías del cordón umbilical, el parto distócico y la restricción del crecimiento intrauterino están relacionados con el índice de Apgar bajo al nacer en esta institución. CONCLUSIONES: La depresión al nacer se asoció causalmente con las anomalías del cordón umbilical y el líquido amniótico meconial, teniendo asociación significativa la desnutrición fetal intrauterina, la edad gestacional al parto < 37 sem y ³ 42 sem y la presentación fetal distócica. Se comprobó que al actuar en el diagnóstico temprano y de certeza de un CIUR se lograría un mejor y mayor impacto en la población expuesta

INTRODUCTION: The more crucial moment in human life is that corresponding with the first 24 hr post-partum. During this period, morbidity and mortality are high, this it is necessary to prevent and to know risk factors that may to interfere in its normal development, assessing at birth the Apgar score. OBJECTIVES: To identify the possible causal association between the low Apgar score and some epidemiological factors. To estimate according to the attributing risk factors that acting on them it will be a great impact in exposed population. METHODS: An observational and analytical type case-control study was conducted related to some epidemiological factors having an impact on a low Apgar score at birth in the Mariana Grajales Mother Teaching Provincial Hospital of Santiago de Cuba from January 1, 2006 to December 31, 2007. RESULTS: Age mother and gestational age at labor, presence of meconium in amniotic fluid, umbilical cord abnormalities, dystocic labor and the intrauterine growth retard are related to a low Apgar score at birth in this institution. CONCLUSIONS: Depression at birth was associated in a causal way with umbilical cord abnormalities and the presence of meconium in amniotic fluid and a significant association with intrauterine fetal malnutrition, the gestational age at labor < 37 of weeks and ³ 42 weeks and dystocic fetal presentation. It was demonstrated that the retarded intrauterine growth (RIUG) acting in the early and certainty diagnosis it will be possible to achieve a better and major impact in exposed population

Role of distinct phospholipases A2 and their modulators in meconium aspiration syndrome in human neonates.

PURPOSE: Meconium aspiration syndrome (MAS) is a life-threatening neonatal lung injury, whose pathophysiology has been mainly studied in animal models. In such models, pancreatic secretory phospholipase A2 (sPLA2-IB) and proinflammatory cytokines present in meconium challenge the lungs, catabolising surfactant and harming the alveoli. Locally produced phospholipases might perpetuate the injury and influence clinical pictures and therapeutic approaches. Our aim is to verify whether pulmonary phospholipase A2 (sPLA2-IIA) is involved in the damage and to determine if phospholipases and their modulators are associated with MAS clinical pictures. METHODS: We studied distinct phospholipases A2 and their modulators in broncho-alveolar lavage (BAL) fluids and in meconium of five MAS neonates and in five control neonates ventilated for extrapulmonary reasons. RESULTS: MAS patients have higher amounts of pulmonary phospholipase (sPLA2-IIA; P = 0.016) and Clara cell secretory protein (CCSP; P = 0.032). The local production of such proteins by the lung is confirmed by their very low levels in meconium. sPLA2-IIA contributes to the higher total enzyme activity in MAS patients, as compared to controls (P = 0.008). Cytosolic phospholipase was not detected in meconium or alveolar fluid. sPLA2 activity and sPLA2-IIA concentrations are correlated with the TNFα and with the release of CCSP. sPLA2 total activity, sPLA2-IIA and TNFα concentrations in BAL fluids correlate with the oxygenation impairment and haemorrhagic lung oedema. CONCLUSIONS: Pulmonary sPLA2 is locally produced and contributes to the total sPLA2 activity during MAS. CCSP is also produced in trying to lower the inflammation. Both sPLA2 activity and sPLA2-IIA are significantly correlated with oxygenation impairment and haemorrhagic lung oedema.

A new look at the pathogenesis of the meconium aspiration syndrome: a role for fetal pancreatic proteolytic enzymes in epithelial cell detachment.

We hypothesized that fetal pancreatic digestive enzymes play a role in the lung damage after meconium aspiration. We studied the effect of meconium on the A549 alveolar epithelial cell line. The exposure of the cells to 0.5 to 5% meconium resulted in significant disruption of connections between A549 cells and caused dose-dependent cell detachment, without signs of cell death. A protease inhibitor cocktail prevented the A549 cell detachment induced by meconium. After the exposure to 2.5% meconium, a protective effect was quantified by measuring light absorbance by gentian violet stain of still attached cells. The protease inhibitor cocktail and chymostatin showed significant protective effects, increasing the number of attached cells by 135 and 123%, respectively (p < 0.05). Other individual protease inhibitors tested in the detachment assay (AEBSF, leupeptin, E-64, aprotinin, benzamidine, phosphamidon, and aminohexanoic acid) did not offer statistically significant protection. These results afford a new perspective on the pathophysiology of meconium aspiration syndrome (MAS). We speculate that disruption of intercellular connections and cell detachment from the basement membrane are key events in the pathology associated with MAS. The observed protective effects of protease inhibitors suggest that they may be useful in the treatment and/or prophylaxis of MAS.

In vitro assessment of proportional assist ventilation.

OBJECTIVE: During proportional assist ventilation (PAV) the timing and frequency of inflations are controlled by the patient and the patient's work of breathing may be relieved by elastic and/or resistive unloading. It is important and the authors' objective to determine whether ventilators delivering PAV function well in situations mimicking neonatal respiratory conditions. DESIGN: In vitro laboratory study. SETTING: Tertiary neonatal ICU. INTERVENTIONS: Dynamic lung models were developed which mimicked respiratory distress syndrome, bronchopulmonary dysplasia and meconium aspiration syndrome to assess the performance of the Stephanie neonatal ventilator. MAIN OUTCOME MEASURES: The effects of elastic and resistive unloading on inflation pressures and airway pressure wave forms and whether increasing unloading was matched by an 'inspiratory' load reduction. RESULTS: During unloading, delivered pressures were between 1 and 4 cm H(2)O above those expected. Oscillations appeared in the airway pressure wave form when the elastic unloading was greater than 0.5 cm H(2)O/ml with a low resistance model and 1.5 cm H(2)O/ml with a high resistance model and when the resistive unloading was greater than 100 cm H(2)O/l/s. There was a time lag in the delivery of airway pressure of at least 60 ms, but increasing unloading was matched by an inspiratory load reduction. CONCLUSIONS: During PAV, unloading does reduce inspiratory load, but there are wave form abnormalities and a time lag in delivery of the inflation pressure. The impact of these problems needs careful evaluation in the clinical setting.

Angiotensin II in apoptotic lung injury: potential role in meconium aspiration syndrome.

Meconium aspiration injures a number of cell types in the lung, most notably airway and alveolar epithelial lining cells. Recent data show that at least some of the cell death induced by meconium occurs by apoptosis, and therefore has the potential for pharmacologic inhibition through the use of apoptosis blockers or other strategies. Related work in adult animal models of lung injury has shown that apoptosis of lung epithelial cells induces a local (that is, entirely lung tissue specific) renin-angiotensin system (RAS(L)). Furthermore, this inducible RAS(L) is required for the apoptotic response and affects other adjacent cell types through the release of angiotensin II and related peptides. This manuscript reviews the published data supporting this viewpoint as well as more recent works that suggest the involvement of a RAS(L) in the perinatal lung damage associated with meconium aspiration syndrome (MAS). The implications of these findings regarding their potential for the clinical management of MAS are also discussed.

Albumin lavage does not improve the outcome of meconium aspiration syndrome.

OBJECTIVE: Meconium aspiration syndrome is still a serious condition with high mortality and morbidity. No specific treatment is yet available, although surfactant is known to reduce the need for extracorporeal membrane oxygenation and surfactant lavage has shown promising results in animal studies. Our group has previously shown reduced oxygenation index in an experimental model of meconium aspiration syndrome in newborn pigs when mixing albumin with meconium before endotracheal instillation. Lung compliance increased when albumin was instilled after meconium as a rescue. The aim of this study was to combine the effect of albumin and lavage. METHODS: Sixteen newborn pigs (six in the meconium-albumin group, six in the meconium group, and four control animals) were anesthetized and tracheotomized. Meconium 4 mL/kg was instilled endotracheally. After five minutes, albumin 15 mL/kg was instilled in the meconium-albumin group followed by endotracheal suctioning. The observation time was six hours. Respiratory and hemodynamic parameters were measured. The terminal complement complex and proinflammatory cytokines were analyzed in plasma. RESULTS: Oxygenation index, ventilatory index, and the terminal complement complex (sC5b-9) increased significantly in both groups, but significantly more in the meconium-albumin group. Compliance decreased, but significantly more in the meconium-albumin group. The terminal sC5b-9 complex increased in both groups, but significantly more in the meconium-albumin group. Tumor necrosis factor-alpha, interleukin (IL)- 1beta, and IL-6 increased significantly in both groups. CONCLUSION: Albumin-lavage did not improve the outcome of experimental meconium aspiration syndrome.

CC10 reduces inflammation in meconium aspiration syndrome in newborn piglets.

Complications from meconium aspiration syndrome (MAS) remain significant despite a variety of therapeutic interventions. Clara cell protein (CC10) is a novel anti-inflammatory agent that can also inhibit phospholipase A2 (PLA2) (an important component of meconium). The present study examined whether administration of recombinant human CC10 (rhCC10) would reduce inflammation and improve lung function in a piglet model of MAS. Following meconium instillation, piglets exhibited significant physiologic dysfunction that improved significantly after surfactant administration. Analysis of tracheal aspirates revealed significant increases in both tumor necrosis factor (TNF) alpha and interleukin (IL)-8 after meconium instillation. rhCC10-treated animals had significantly lower TNF-alpha levels at 24 h (561 +/- 321 versus 1357 +/- 675 pg/mL, p < 0.05) compared with saline controls. There were no differences between rhCC10-treated and untreated groups with respect to other measured physiologic variables or inflammatory markers, including secretory PLA2 activity. Histologic analyses revealed marked inflammatory infiltrates and thickened alveolar walls, but no significant differences among rhCC10 and control animals. Newborn piglets with MAS have significant physiologic dysfunction, marked inflammatory changes and histologic abnormalities, which was partially counteracted by a single dose of exogenous surfactant and rhCC10.

Inhaled nitric oxide treatment inhibits neuronal injury after meconium aspiration in piglets.

BACKGROUND: Meconium aspiration-induced hypertensive lung injury is frequently associated with neuronal damage. Inhaled nitric oxide (iNO) is widely used in the treatment of pulmonary hypertension, but its effects on the brain are poorly known. AIMS: The aim of this study was to determine the effects of iNO treatment on the neuronal tissue after meconium aspiration. STUDY DESIGN: 71 anesthetized, catheterized and ventilated newborn piglets were studied for 6 h. Thirty-five piglets were instilled with a bolus of human meconium intratracheally and 36 piglets with saline instillation served as controls. Nineteen meconium piglets and 17 control piglets were continuously treated with 20 ppm of iNO, started at 30 min after the insult. The extent of neuronal injury was analysed histologically, and the levels of brain tissue lipid peroxidation products, reduced glutathione (GSH), myeloperoxidase activity and oxidized DNA were analysed as indicators of oxidative stress. RESULTS: iNO treatment diminished the pulmonary hypertensive response caused by meconium aspiration, but did not change systemic or carotid hemodynamics. NO administration was associated with reduced neuronal injury and diminished amount of oxidized DNA in the hippocampus of the meconium piglets. Further, iNO treatment was associated with decreased level of GSH in the cortex, but no change in lipid peroxidation production or myeloperoxidase activity was detected in any of the studied brain areas. CONCLUSIONS: Our results suggest that iNO treatment may inhibit DNA oxidation and neuronal injury in the hippocampus, associated with newborn meconium aspiration.

Surfactant phosphatidylcholine metabolism in neonates with meconium aspiration syndrome.

OBJECTIVE: Because meconium directly inhibits surfactant function, we sought to determine the effect of meconium on endogenous surfactant synthesis and clearance. STUDY DESIGN: We studied surfactant phosphatidylcholine kinetics with the use of stable isotopes in 11 newborn infants with meconium aspiration syndrome (MAS) who required extracorporeal membrane oxygenation (ECMO). For comparison we studied 6 neonates with persistent pulmonary hypertension (PPHN) on ECMO and 10 term neonates ventilated for non-pulmonary indications and not on ECMO. All patients received a 24-hour [U- 13C]glucose infusion as precursor for the palmitic acid in surfactant phosphatidylcholine. RESULTS: In the meconium group, the maximal 13C-incorporation in phosphatidylcholine (PC) was half of that in controls (0.09 +/- 0.01 vs 0.18 +/- 0.03 atom percent excess [APE], P = .027). There was a trend toward lower surfactant synthesis in the MAS group (3.3 +/- 0.7%/day) and PPHN group (2.6 +/- 0.3%/day) compared with controls 8.0 +/- 2.4%/day, P = .058). Significantly lower PC concentrations in tracheal aspirates were found in the MAS group (4.4 +/- 2.6 mg/mL) and PPHN group (3.6 +/- 2.0 mg/mL) compared with controls (12.8 +/- 2.6 mg/mL, P = .01). Endogenously synthesized surfactant had a similar half-life in all groups, ranging from 63 to 98 hours. CONCLUSION: We conclude that surfactant synthesis is disturbed and that surfactant PC concentrations are low in infants with MAS on ECMO.

Novas opções terapêuticas na síndrome de aspiração de mecônio / New therapeutic options in meconium aspiration syndrome

OBJETIVOS: revisar a literatura sobre a síndrome de aspiração de mecônio (SAM), enfocando aspectos clínicos, fisiopatológicos e abordagem terapêutica, com destaque ao uso do surfactante e lavado broncoalveolar. MÉTODOS: revisão baseada em artigos publicados na MEDLINE, SCIELO e resumos de congressos internacionais de 1988 a 2004, incluindo ensaios randomizados ou quasi-randomizados, estudos caso-controle e metanálises. RESULTADOS: devido à comprovação da inibição do surfactante na SAM, houve modificações em sua abordagem terapêutica. O manejo atual consiste na aspiração das vias aéreas na sala de parto, seguida de suporte ventilatório necessário para manter a oxigenação arterial adequada, e tratamento das complicações. Tendo em vista a obstrução mecânica do mecônio e seu efeito inibitório sobre o surfactante, a reposição e lavado broncoalveolar com surfactante estão sendo estudados atualmente. CONCLUSÕES: estudos em animais e em recém-nascidos apresentam resultados controversos quanto aos benefícios do uso de surfactante e lavado broncoalveolar na SAM. Torna-se importante a realização de mais estudos para avaliar novas estratégias ventilatórias e se existem vantagens no uso do surfactante e lavado broncoalveolar com surfactante na SAM.

OBJECTIVES: to review the literature on meconium aspiration syndrome (MAS) focusing on clinical aspects, pathophysiology, and treatment with emphasis on surfactant and bronchoalveolar lavage. METHODS: review including articles from MEDLINE, SCIELO and abstracts published in the national and international literature, from 1988 to 2004 using the keywords meconium aspiration syndrome, surfactant and bronchoalveolar lavage. Randomized and quasi-randomized trials, case control studies, meta-analyses and recently published reviews were selected. Other articles were included for their valuable contribution to the subject. RESULTS: the discovery of new pathophysiological mechanisms ensued new therapeutic options availability. MAS management is initiated with airway aspiration in the delivery room, followed by the ventilatory management required to maintain optimal arterial oxygenation, as well as complications treatment. Considering evidences showing that meconium mechanical airway obstruction and its inhibitory effect on the surfactant system, the use of surfactant replacement and bronchoalveolar lavage with surfactant suspension are under study. CONCLUSIONS: experimental studies and studies focused on newborn using different surfactant suspensions have demonstrated controversial results. Therefore, it is very important to identify new ventilatory strategies and evaluate whether there are advantages in using surfactant and bronchoalveolar lavage with surfactant suspension in MAS.