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.

Evidence of both foetal inflammation and hypoxia-ischaemia is associated with meconium aspiration syndrome.

Foetal hypoxia-ischaemia is a key trigger of meconium aspiration syndrome (MAS). However, many neonates develop MAS without evidence of hypoxia-ischaemia, suggesting the presence of covert but important risk variables. We evaluated the association of MAS with clinical variables, placental histopathologic findings, and inflammatory biomarkers at birth. Of 1336 symptomatic and asymptomatic term singleton neonates with meconium-stained amniotic fluid, 88 neonates (6.6%) developed MAS. Univariate analysis showed that MAS development was associated with low 1- and 5-min Apgar scores, low cord blood pH, funisitis, higher α1-acid glycoprotein levels, and higher haptoglobin levels (all p < 0.001 except for p = 0.001 for haptoglobin). Associations of MAS with caesarean delivery (p = 0.004), premature rupture of the membranes (p = 0.006), chorioamnionitis (p = 0.007), and higher C-reactive protein levels (p = 0.008) were lost when adjusted for multiple comparisons. The final multivariate model to explain MAS development comprised lower cord blood pH (odds ratio [OR] 0.58; 95% confidence interval [CI] 0.47-0.73; p < 0.001), funisitis (OR 2.45; 95% Cl 1.41-4.26; p = 0.002), and higher α1-acid glycoprotein levels (OR 1.02; 95% Cl 1.01-1.03; p = 0.001). Our data from a large cohort of neonates suggested that intrauterine inflammation is one of the key independent variables of MAS development, together with foetal hypoxia-ischaemia.

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.

Pathophysiological effects of intravenous phosphodiesterase type 4 inhibitor in addition to surfactant lavage in meconium-injured newborn piglet lungs.

BACKGROUND: Nonsteroidal anti-inflammatory drugs, such as selective phosphodiesterase type 4 (PDE4) inhibitors have potential anti-inflammatory and respiratory smooth muscle relaxation effects. This study aimed to investigate the pathophysiological effects of an intravenous PDE4 inhibitor (rolipram) and surfactant lavage (SL) in a newborn piglet model of meconium aspiration syndrome (MAS). METHODS: MAS was induced in 25 newborn piglets, which were randomly divided into control and four SL treatment groups administered with different doses of intravenous rolipram (0, 0.1, 0.5, and 1 mg/kg). Cardiopulmonary variables were monitored and recorded. The experimental time was 4 hours. Serial blood was drawn for blood gas and biomarker analyses. Lung tissue was examined for histological analysis. RESULTS: All SL-treated groups revealed improved oxygenation during the 4-hour experiments and had significantly lower peak inspiratory pressure levels than the control group at the end of experiments. All SL plus rolipram-treated groups exhibited significantly higher lung compliance than the control group. However, the animals receiving high-dose (0.5 and 1.0 mg/kg) rolipram demonstrated significantly elevated heart rates. Lung histology of the nondependent sites revealed significantly lower lung injury scores in all SL-treated groups compared with that in the control group, but there were no differences among the rolipram-treated groups. CONCLUSIONS: In addition to SL, intravenous PDE4 inhibitors may further improve lung compliance in treating MAS; however, it is necessary to consider cardiovascular adverse effects, primarily tachycardia. Further investigations are required before the clinical application of intravenous PDE4 inhibitor as an anti-inflammatory agent to treat severe MAS.

Surfactant Injury in the Early Phase of Severe Meconium Aspiration Syndrome.

No in vivo data are available regarding the effect of meconium on human surfactant in the early stages of severe meconium aspiration syndrome (MAS). In the present study, we sought to characterize the changes in surfactant composition, function, and structure during the early phase of meconium injury. We designed a translational prospective cohort study of nonbronchoscopic BAL of neonates with severe MAS (n = 14) or no lung disease (n = 18). Surfactant lipids were analyzed by liquid chromatography-high-resolution mass spectrometry. Secretory phospholipase A2 subtypes IB, V, and X and SP-A (surfactant protein A) were assayed by ELISA. SP-B and SP-C were analyzed by Western blotting under both nonreducing and reducing conditions. Surfactant function was assessed by adsorption test and captive bubble surfactometry, and lung aeration was evaluated by semiquantitative lung ultrasound. Surfactant nanostructure was studied using cryo-EM and atomic force microscopy. Several changes in phospholipid subclasses were detected during MAS. Lysophosphatidylcholine species released by phospholipase A2 hydrolysis were increased. SP-B and SP-C were significantly increased together with some shorter immature forms of SP-B. Surfactant function was impaired and correlated with poor lung aeration. Surfactant nanostructure was significantly damaged in terms of vesicle size, tridimensional complexity, and compactness. Various alterations of surfactant phospholipids and proteins were detected in the early phase of severe meconium aspiration and were due to hydrolysis and inflammation and a defensive response. This impairs both surfactant structure and function, finally resulting in reduced lung aeration. These findings support the development of new surfactant protection and antiinflammatory strategies for severe MAS.

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.

Delivery room emergencies: Respiratory emergencies in the DR.

The majority of newborns transition to extra uterine life without support. However, respiratory emergencies in the delivery room are a common occurrence. Whilst some situations are predictable e.g. the anticipated birth of an extremely preterm infant, others are less so. In this chapter we address the most frequent scenarios that result in delivery room respiratory emergencies and discuss the latest recommendations for their management. We outline the need for a trained resuscitation team and appropriate equipment to provide respiratory support at every birth. We address the basic care that all infants should receive, the detailed application of non-invasive ventilation and the use of advanced airway techniques. We discuss the unique challenges presented by extreme prematurity including umbilical cord management, use of supplemental oxygen, initial modes of respiratory support and surfactant delivery. We will explore optimal techniques in the management of infants with lung hypoplasia, pneumothorax and meconium aspiration.

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.

Management of Meconium-Stained Newborns in the Delivery Room.

The approach to the management of meconium-stained newborns in the delivery room has been changing for over 40 years. The goal is to prevent meconium aspiration syndrome (MAS) and complications related to MAS. For decades, airway obstruction was believed to be a major component of MAS and, consequently, suction maneuvers to remove meconium from the airways were recommended to decrease the frequency and severity of MAS. Initial recommendations were based on observational studies. However, the incidence of MAS and mortality related to MAS has declined since the 1970s, mostly because of a decrease in the number of postterm deliveries. Recently updated guidelines by the American Heart Association and the Neonatal Resuscitation Program have reflected the strength of evidence supporting tracheal intubation and suctioning for nonvigorous, meconium-stained newborns. This article examines practice change since the 1970s in the delivery room management of meconium-stained newborns and evaluates evidence behind the changes.

Controlled hypothermia may improve surfactant function in asphyxiated neonates with or without meconium aspiration syndrome.

BACKGROUND: Whole-body hypothermia (WBH) is used to improve neurological outcomes in perinatal asphyxia. Recent studies suggested a beneficial effect of hypothermia for some types of acute respiratory failure. However, no data are available about the biophysical function of human surfactant during WBH. We investigated whether WBH improves surfactant biophysical properties in asphyxiated neonates with or without meconium aspiration syndrome (MAS). METHODS: Non-bronchoscopic bronchoalveolar lavage (BAL) has been collected from 10 asphyxiated neonates (2 with MAS, 8 with no lung disease (NLD)) at different time-points (pre-WBH, 24h, 48h, 72h of WBH and post-WBH). Surfactant was extracted and tested by captive bubble surfactometry (CBS) in triplicate, at 37°C and 33.5°C, through initial adsorption and dynamic compression-expansion cycling. Phosphatidylcholine and cholesterol were assayed using enzymatic methods. Clinical data were recorded in real-time. RESULTS: Minimum surface tension under dynamic testing was significantly improved as assessed at 33.5°C compared with its behavior at 37°C in NLD neonates: the difference was evident after at least 72h of WBH and remained significant at 6h after rewarming (72h: p = 0.009; rewarming: p = 0.040). Similar results were obtained in MAS patients whose surfactant activity improved already at 48h of hypothermia. Total cholesterol showed a trend to increase at the first 24-48h of hypothermia in NLD patients. Conversely, hypothermia seemed to reduce the excess of exogenous cholesterol in MAS surfactant. CONCLUSIONS: Surfactant biophysical properties may improve after 48-72h of WBH in asphyxiated neonates and the improvement is maintained shortly after rewarming. Due to study limitations, further studies are warranted to better clarify the effects of hypothermia on surfactant activity.

Experimental models of acute lung injury in the newborns.

Acute lung injury in the preterm newborns can originate from prematurity of the lung and insufficient synthesis of pulmonary surfactant. This situation is known as respiratory distress syndrome (RDS). In the term neonates, the respiratory insufficiency is related to a secondary inactivation of the pulmonary surfactant, for instance, by action of endotoxins in bacterial pneumonia or by effects of aspirated meconium. The use of experimental models of the mentioned situations provides new information on the pathophysiology of these disorders and offers unique possibility to test novel therapeutic approaches in the conditions which are very similar to the clinical syndromes. Herewith we review the advantages and limitations of the use of experimental models of RDS and meconium aspiration syndrome (MAS) and their value for clinics.

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.

Meconium "aspiration" (or respiratory distress associated with meconium-stained amniotic fluid?).

The designation meconium aspiration syndrome (MAS) reflects a spectrum of disorders in infants born with meconium-stained amniotic fluid, ranging from mild tachypnea to severe respiratory distress and significant mortality. The frequency of MAS is highest among infants with post-term gestation, thick meconium, and birth asphyxia. Pulmonary hypertension is an important component in severe cases. Prenatal hypopharyngeal suctioning and postnatal endotracheal intubation and suctioning of vigorous infants are not effective. Intubation and suctioning of non-breathing infants is controversial and needs more investigation. Oxygen, mechanical ventilation, and inhaled nitric oxide are the mainstays of treatment. Surfactant is often used in infants with severe parenchymal involvement. High-frequency ventilation and extracorporeal membrane oxygenation are usually considered rescue therapies.

In-depth performance analysis of an EEG based neonatal seizure detection algorithm.

OBJECTIVE: To describe a novel neurophysiology based performance analysis of automated seizure detection algorithms for neonatal EEG to characterize features of detected and non-detected seizures and causes of false detections to identify areas for algorithmic improvement. METHODS: EEGs of 20 term neonates were recorded (10 seizure, 10 non-seizure). Seizures were annotated by an expert and characterized using a novel set of 10 criteria. ANSeR seizure detection algorithm (SDA) seizure annotations were compared to the expert to derive detected and non-detected seizures at three SDA sensitivity thresholds. Differences in seizure characteristics between groups were compared using univariate and multivariate analysis. False detections were characterized. RESULTS: The expert detected 421 seizures. The SDA at thresholds 0.4, 0.5, 0.6 detected 60%, 54% and 45% of seizures. At all thresholds, multivariate analyses demonstrated that the odds of detecting seizure increased with 4 criteria: seizure amplitude, duration, rhythmicity and number of EEG channels involved at seizure peak. Major causes of false detections included respiration and sweat artefacts or a highly rhythmic background, often during intermediate sleep. CONCLUSION: This rigorous analysis allows estimation of how key seizure features are exploited by SDAs. SIGNIFICANCE: This study resulted in a beta version of ANSeR with significantly improved performance.

High-Frequency Jet Ventilation against Small-Volume Conventional Mechanical Ventilation in the Rabbit Models of Neonatal Acute Lung Injury.

Patients with acute lung injury are ventilated by conventional mechanical ventilation (CMV) rather than high-frequency jet ventilation (HFJV). This study estimated the potential usefulness of HFJV in acute lung injury. The issue was addressed by comparing the effects on lung function of CMV and HFJV in two rabbit models of neonatal acute lung injury: repetitive saline lung lavage (LAV) and meconium aspiration syndrome (MAS) induced by intratracheal meconium instillation. The animals were then ventilated with either HFJV or CMV for 4 h. Ventilatory pressures, blood gases, and indexes of gas exchange were assessed. Lung edema formation was expressed as wet-dry lung weight ratio. Both LAV and MAS significantly decreased lung compliance, increased airway resistance, and caused severe hypoxemia, hypercarbia, and acidosis. Although CMV was superior to HFJV at 1 h of ventilation, there were no clinically relevant differences in lung function or edema formation between CMV and LAV in both models of respiratory insufficiency at 4 h of ventilation. We conclude that, HFJV may be used for ventilation in acute non-homogenous lung injury.

Neonatal resuscitation adhering to oxygen saturation guidelines in asphyxiated lambs with meconium aspiration.

BACKGROUND: The Neonatal Resuscitation Program (NRP) recommends upper and lower limits of preductal saturations (SpO2) extrapolated from studies in infants resuscitated in room air. These limits have not been validated in asphyxia and lung disease. METHODS: Seven control term lambs delivered by cesarean section were ventilated with 21% O2. Thirty lambs with asphyxia with meconium aspiration were randomly assigned to resuscitation with 21% O2 (n = 6), 100% O2 (n = 6), or initiation with 21% O2 followed by variable FIO2 to maintain NRP target SpO2 ranges (n = 18). Hemodynamic and ventilation parameters were recorded for 15 min. RESULTS: Control lambs maintained preductal SpO2 near the lower limit of NRP target range. Asphyxiated lambs had low SpO2 (38 ± 2%), low arterial pH (6.99 ± 0.01), and high PaCO2 (96 ± 7 mm Hg) at birth. Resuscitation with 21% O2 resulted in SpO2 values below the target range with low pulmonary blood flow (Qp) compared to variable FIO2 group. The increase in PaO2 and Qp with variable FIO2 resuscitation was similar to control lambs. CONCLUSION: Maintaining SpO2 as recommended by NRP by actively adjusting inspired O2 leads to effective oxygenation and higher Qp in asphyxiated lambs with lung disease. Our findings support the current NRP SpO2 guidelines for O2 supplementation during resuscitation of an asphyxiated neonate.

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.

Meconium aspiration syndrome: possible pathophysiological mechanisms and future potential therapies.

Does meconium cause meconium aspiration syndrome (MAS) or is meconium discharge only a marker of fetal hypoxia? This dispute has lasted for centuries, but since the 1960s, detrimental effects of meconium itself on the lungs have been demonstrated in animal experiments. In clinical MAS, persistent pulmonary hypertension of the newborn is the leading cause of death in MAS. Regarding the complex chemical composition of meconium, it is difficult to identify a single agent responsible for the pathophysiology. However, considering that meconium is stored in the intestines, partly unexposed to the immune system, aspirated meconium could be recognized as 'danger', representing damaged self. The common denominator in the pathophysiology could therefore be activation of innate immunity. Thus, a bulk of evidence implies that meconium is a potent activator of inflammatory mediators, including cytokines, complement, prostaglandins and reactive oxygen species. We hypothesize that the two main recognition systems of innate immunity, the Toll-like receptors and the complement system, recognize meconium as 'danger', which leads not only to lung dysfunction but also to a systemic inflammatory response. This might have therapeutic implications in the future.