How to overcome surfactant dysfunction in meconium aspiration syndrome?

Surfactant dysfunction in meconium aspiration syndrome (MAS) is caused by meconium components, by plasma proteins leaking through the injured alveolocapillary membrane and by substances originated in meconium-induced inflammation. Surfactant inactivation in MAS may be diminished by several ways. Firstly, aspirated meconium should be removed from the lungs to decrease concentrations of meconium inhibitors coming into the contact with surfactant in the alveolar compartment. Once the endogenous surfactant becomes inactivated, components of surfactant should be substituted by exogenous surfactant at a sufficient dose, and surfactant administration should be repeated, if oxygenation remains compromised. To delay the inactivation by inhibitors, exogenous surfactants may be enriched with surfactant proteins, phospholipids, or other substances such as polymers. Finally, to diminish an adverse action of products of meconium-induced inflammation on both endogenous and exogenously delivered surfactant, anti-inflammatory drugs may be administered. A combined therapeutic approach may result in better outcome in patients with MAS and in lower costs of treatment.     

In vitro effect of meconium on the physical surface properties and morphology of exogenous pulmonary surfactant.

The pathophysiology of meconium aspiration syndrome(MAS) is related to mechanical obstruction of the airways and to chemical pneumonitis. Meconium is also suggested to cause functional deterioration of pulmonary surfactant. Recent studies have reported that meconium inhibits the physical surface properties of pulmonary surfactant, and that administration of exogenous surfactant may provide therapeutic benefits in animal models or infants with respiratory distress due to MAS. To assess the effects of meconium on physical surface properties, especially the changes on the air-liquid interface and hypophase of pulmonary surfactant in vitro, we studied the following findings; a) the surface spreading rate(SSR) and the surface adsorption rate(SAR), b) the viscosity, c) the electron microscopic changes, on a series of mixtures with various concentrations of lyophilized human meconium and Surfactant-TA(SurfactenTM). The human meconium has significantly increased the surface tension of SSR and the viscosity of pulmonary surfactant, but had decreased the surface pressure of SAR of surfactant, and changed the electron microscopic findings of surfactant. We have concluded that these findings support the concept that meconium-induced surfactant dysfunction may play a role in the pathophysiology of MAS.     

87例胎粪吸入综合征临床病理分析

目的　探讨胎粪吸入综合征 (MAS)的防治措施及产前监护。方法　对本文 87例MAS临床与病理资料进行回顾性分析 ,其中足月儿 6 0例 ,过期儿 3例 ,早产儿 2 4例。结果　 4 9例MAS新生儿死亡中产前有胎心音异常改变 4 8例 ,死胎2 6例 ,死产 12例。主要病理改变为胎粪吸入性肺炎 ,肺气肿以及各脏器出血。结论　MAS发生因素与妊娠期合并症 ,胎儿宫内排粪及分娩早期缺氧密切相关。     

Meconium aspiration syndrome treatment - new approaches using old drugs

Presently, modern medicine does not offer any disease-modifying treatment for meconium aspiration syndrome (MAS). Several medications with already established safety profiles when employed for similar or other conditions could be useful for MAS treatment. N-Acetylcysteine and DNAse have the capability to reduce viscosity and thickness of meconium by breaking disulfide bonds and slicing DNA, respectively. N-Acetylcysteine, antiprotease drugs, or low pH buffer solutions may have the capability to neutralize meconium's digestive enzymes responsible for lung damage in patients with MAS. All these compounds have great potential to reduce meconium's pathogenic properties which in turn could alleviate MAS severity.     

新型鼻塞持续气道正压治疗新生儿低氧血症疗效分析

目的回顾性的研究新型鼻塞持续气道正压(nCPAP)治疗新生儿严重低氧血症的疗效及安全性。方法以常规给氧无效的83例严重低氧血症患儿为研究对象,其中足月儿32例,早产儿51例。呼吸暂停33例,肺炎并呼吸衰竭(呼衰)21例,肺透明膜病19例,胎粪吸入综合征6例,新生儿湿肺4例。给予使用新型nCPAP治疗,观察治疗效果、并发症发生情况。结果给予nCPAP治疗后绝大多数患儿缺氧状态得到改善。治愈67例,16例效果不好转为气管插管行其他模式机械通气治疗。腹胀8例,心功能不全5例,鼻前庭皮肤部压迫伤2例,无一例发生气漏、慢性肺疾病和早产儿视网膜病。结论新型nCPAP治疗新生儿严重低氧血症操作方便,疗效满意,可以很好的控制温度和吸入氧的浓度,避免了因吸入纯氧、高浓度氧引起的视网膜病、慢性肺疾病等氧中毒性损伤。减少了气管插管的机会,降低了呼吸机相关性肺炎的发生率,相对比较安全。     

Meconium aspiration syndrome induces complement-associated systemic inflammatory response in newborn piglets

The pathophysiology of meconium aspiration syndrome (MAS) is complex. We recently showed that meconium is a potent activator of complement. In the present study, we investigated whether the complement activation occurring in experimental MAS is associated with a systemic inflammatory response as judged by granulocyte activation and cytokine and chemokine release. MAS was induced by the instillation of meconium into the lungs of newborn piglets (n = 8). Control animals (n = 5) received saline under otherwise identical conditions. Haemodynamic and lung dynamic data were recorded. Complement activation, revealed by the terminal sC5b-9 complex (TCC), and cytokines [interleukin (IL)-6 and IL-8] were measured in plasma samples by enzyme immunoassays. The expression of CD18, CD11b and oxidative burst in granulocytes was measured in whole blood by flow cytometry. Plasma TCC increased rapidly in the MAS animals in contrast with controls (P < 0.0005). The TCC concentration correlated closely with oxygenation index (r = 0.48, P < 0.0005) and ventilation index (r = 0.57, P < 0.0005) and inversely with lung compliance (r = -0.63, P < 0.0005). IL-6 and IL-8 increased in MAS animals compared with the controls (P = 0.002 and P < 0.001, respectively). Granulocyte oxidative burst declined significantly in the MAS animals compared with the controls (P < 0.02). TCC correlated significantly with IL-6 (r = 0.64, P < 0.0005) and IL-8 (r = 0.32; P = 0.03) and inversely with oxidative burst (r = -0.37; P = 0.02). A systemic inflammatory response associated with complement activation is seen in experimental MAS. This reaction may contribute to the pathogenesis of MAS.     

糖皮质激素治疗胎粪吸入综合征疗效和安全性的Meta分析

目的评价糖皮质激素治疗胎粪吸入综合征（MAS）的疗效及安全性。方法检索PubMed、MEDLINE、EMBASE、EBSCOhost、Cochrane图书馆、Cochrane临床对照试验库（CENTRAL）、Ovid、中国生物医学文献数据库、万方数据库和维普中文科技期刊数据库,检索时间均从建库至2010年12月,并辅以手工检索,获得糖皮质激素治疗MAS的RCT文献。依据随机方法、分配隐藏、盲法、结果数据的完整性、选择性报告研究结果和其他偏倚来源进行文献偏倚评价。采用RevMan5.0.23软件进行Meta分析,根据异质性结果选择相应的效应模式分析;无法进行Meta分析时采用描述性分析。结果共检索到1012篇文献,符合纳入标准的5篇RCT文献（n=295）进入Meta分析。文献偏倚评价结果显示,存在低度和高度偏倚风险的文献各1篇,3篇文献存在中度偏倚风险。Meta分析结果显示,糖皮质激素能显著缩短住院时间（MD=-5.42,95%CI：-7.38～-3.45,P〈0.0001）,减少败血症发生率（OR=0.33,95%CI：0.12～0.78,P=0.01）。亚组分析结果显示,布地奈德混悬液雾化吸入可显著缩短住院时间（MD=-6.11,95%CI：-8.88～-3.34,P〈0.0001）、呼吸窘迫持续时间（SMD=-1.56,95%CI：-2.12～-1.00,P〈0.00001）和氧疗时间（SMD=-1.22,95%CI：-1.96～-0.48,P=0.001）,减少败血症发生率（OR=0.25,95%CI：0.07～0.95,P=0.04）。②糖皮质激素组住院期间病死率、胸部X线片恢复正常的时间与对照组差异均无统计学意义。③糖皮质激素组持续性肺动脉高压、鹅口疮及其他浅表部位真菌感染、脑膜炎、高血糖、高血压、慢性肺疾病和生长发育延迟发生率与对照组差异均无统计学意义。结论出生后48h内雾化吸入布地奈德混悬液可显著缩短MAS患儿住院时间、呼吸窘迫及氧疗时间。糖皮质激素治疗不能改善MAS患儿最终结局,亦不会增加糖皮质激素相关感染的发生。鉴于纳入的RCT文献较少,研究间异质性较大,故结论应谨慎对待。     

Classification of acute respiratory disorders of all newborns in a tertiary care center

OBJECTIVE: To assess the usefulness of current diagnostic criteria in the understanding of neonatal respiratory distress in a tertiary care hospital. METHODS: We prospectively studied 2824 consecutive deliveries to determine the frequency of respiratory disorders of all types. We used definitions based on standard texts, with borderline cases being classified as having the disease in question. RESULTS: Somewhat less than half of all symptomatic infants met textbook criteria for a respiratory diagnosis. Of this subset, the most common diagnosis was respiratory distress syndrome (RDS), followed by transient tachypnea of newborn (TTN), meconium aspiration syndrome (MAS), pneumonia and others. The 323 infants who fit no standard diagnosis all had self-limited conditions similar to TTN. Most (52%) were well in less than 12 hours. Those still symptomatic after 12 hours differed from the definition of TTN by having a clear chest film (38%) and/or by requiring mechanical ventilation (10%). A slight revision of the traditional diagnostic criteria allowed classification of all these cases. CONCLUSION: More than 50% of newborns with acute respiratory symptoms do not fit textbook definitions, even broad definitions which include borderline cases. The concept of TTN should be expanded to include cases with a normal chest film. In addition, we suggest adding the category "transient respiratory insufficiency of the newbom" (TRIN) for babies ventilated briefly but not demonstrably surfactant deficient or infected. This category probably includes infants with many contributing etiologies.     

Morphometric analysis of the lung vasculature after extracorporeal membrane oxygenation treatment for pulmonary hypertension in newborns

Persistent pulmonary hypertension in the newborn (PPHN) is characterised by increased medial and adventitial thickness in the lung vasculature. This study describes morphometry of lung vasculature after extracorporeal membrane oxygenation (ECMO) in newborns with PPHN, due to meconium aspiration syndrome, sepsis or idiopathic persistent pulmonary hypertension of the newborn (i-PPHN). Three groups were studied: newborns with PPHN treated with ECMO (n=9), newborns with PPHN not treated with ECMO (n=12) and age-matched controls without PPHN (n=11). In pulmonary arteries with an external diameter of less than 150 m, arterial media, adventitia and total wall thickness, expressed as a percentage of the external diameter, and their cross-sectional areas were calculated. Newborns with PPHN, compared with controls, demonstrated increased percentage of media thickness, adventitia thickness and total wall thickness, and increased medial, adventitial and total wall cross-sectional area. Newborns treated with ECMO, compared with those not treated so, showed a decreased percentage of media thickness and medial cross-sectional area in arteries with an external diameter less than 75 m, and decreased percentage of media thickness and decreased medial, adventitial and total wall cross-sectional area in arteries with an external diameter of 75–150 m. ECMO for persistent PPHN, due to meconium aspiration syndrome, sepsis or i-PPHN, reduces the abnormal morphometry of small pulmonary arteries. The underlying mechanisms contributing to this improved morphometry are yet unknown.     

The pulmonary vasculature in meconium aspiration

Some studies have suggested that pulmonary hypertension in the newborn with meconium aspiration can be attributed to a primary prenatal increase in pulmonary arterial musculature; but this concept has been controversial. To examine this question, we reviewed 62 infants autopsied at The Johns Hopkins Hospital, 24 of whom demonstrated meconium aspiration, 20 with meconium staining but no aspiration, and 18 with abruptio placentae without meconium aspiration or staining. Clinical and pathologic features were evaluated and cross-sectional arterial medial area was determined at the junction of the conducting and respiratory airways in nondistended lungs. No significant difference in arterial medial area was found between infants with meconium aspiration and those with meconium staining only or abruptio placentae. In addition, circumferentially muscularized intraacinar arteries were present in all infants with meconium aspiration and abruptio placentae, and all but one infant with meconium staining alone. Comparison of lungs with and without arterial injection and fixation in distention showed that injection does not uniformly distend vessels and that formalin distention may remove or mask meconium. The study suggests that meconium aspiration and its complications, not primary structural arterial changes, account for pulmonary hypertension in infants with meconium aspiration.     

ECMO for meconium aspiration syndrome: support for relaxed entry criteria

We compared the morbidity of patients with meconium aspiration syndrome (MAS) with that in patients with all other respiratory conditions treated with extracorporeal membrane oxygenation (ECMO) (no MAS). If ECMO for MAS was associated with a lower complication rate, then relaxed ECMO entry criteria could be considered. A retrospective review was performed of all patients in the national extracorporeal life support (ELSO) registry from 1989 to 2004. Complications were divided into mechanical, hematologic, neurologic, renal, pulmonary, cardiovascular, infectious, and metabolic categories. MAS and no-MAS patients were divided into veno-venous (VV) or veno-arterial (VA) ECMO categories, based on mode of ECMO used, and number of complications per patient in each category was determined. Statistical significance was determined by Chi-square test. A total of 1587 patients (700 MAS, 887 no MAS) on VV ECMO and 2723 (572 MAS, 2151 no MAS) on VA ECMO were identified with a total of 2415 complications in MAS and 9550 in no-MAS patients. Overall, MAS patients had a significantly lower number of complications per patient in each category versus no-MAS patients. These results indicate that regardless of type of ECMO, there are fewer complications on ECMO in MAS versus no-MAS patients. These data support the consideration of relaxed ECMO entry criteria for MAS.     

硝基酪氨酸和诱导型一氧化氮合酶在大鼠胎粪吸入性肺损伤中表达的研究

目的：观察大鼠胎粪诱导肺损伤时肺组织硝基化酪氨酸和诱导型一氧化氮合酶（iNOS）表达的改变，探讨两者在此种损伤中的作用。 方法： 16只雄性SD大鼠，随机分为对照组和胎粪组，分别由气管插管注入生理盐水或20%胎粪生理盐水混悬液1 mL/kg。24 h后取材，观察支气管肺泡灌洗液（BALF）细胞计数，比色法检测肺组织匀浆髓过氧化物酶（MPO）活性、一氧化氮（NO）含量，Western blot法测定硝基酪氨酸和iNOS蛋白表达改变。 结果： 胎粪组BALF细胞计数、肺组织MPO活性、NO含量分别为(4.04±1.01)×109cells/L、(1.49±0.22)U/g wet lung tissue、(12.77±5.00)mmol/g protein，对照组BALF细胞计数、肺组织MPO活性、NO含量分别为(0.53±0.19)×109cells/L、(0.62±0.16)U/g wet lung tissue、(4.89±1.32)mmol/g protein，两组比较差异显著（均P<0.01）；Western blot结果显示胎粪组肺组织硝基酪氨酸和iNOS蛋白表达明显强于对照组，分别为0.46±0.19和1.49±0.60，与对照组（0.15±0.04和0.09±0.04）比较, 差异显著（均P<0.01）。 结论： 胎粪可诱导iNOS表达增强并产生过量的硝基酪氨酸，两者可能在胎粪性肺损伤发病机制中发挥重要作用。     

The causes of morbidity and mortality among infants born at term

Previous studies have reported on the pathologic spectrum of perinatal mortality; however, in our opinion, the problems pertaining to the term newborn have not been emphasized sufficiently. We reviewed the autopsies of all term infants up to 2 months of age in a ten-year period (July 1975 to July 1985). These 342 patients comprised 20% of all pediatric autopsies. The patients were grouped according to cause of death in the following categories: congenital anomalies (59%); infection (10%); perinatal injury, including meconium aspiration (9%); maternal-placental problems (11%); and miscellaneous (5%). In 4% of the cases, mainly stillbirths, the cause of death was unclear. Of the congenital anomalies, the cardiovascular system was most affected (57%). Hyaline membrane disease and intraventricular hemorrhage, usually frequent in series involving many preterm patients, were seldom seen. This study emphasizes the different pathologic spectrum of mortality between premature and term newborns.     

深圳地区羊水过少226例临床分析

目的探讨羊水过少与妊娠并发症的关系及其分娩方式的选择与围生儿预后关系。方法收集我院2005年6月至2006年5月住院分娩的羊水过少孕妇226例,随机抽取我院同期分娩的羊水量正常孕妇220例为对照组,两组病例就妊娠并发症、分娩方式及围生儿情况进行比较。结果羊水过少组中过期妊娠、妊娠期高血压疾病、胎儿生长受限（FGR）及胎儿畸形的发生率均高于对照组（P〈0.01）。羊水过少组羊水粪染、胎儿窘迫、胎粪吸入综合征（MAS）的发生率明显高于对照组（P〈0.05,P〈0.01）。羊水过少伴妊娠并发症组羊水粪染、胎儿窘迫、新生儿窒息的发生率明显高于无并发症组,（P〈0.01,P〈0.05）,剖宫产率明显增加（P〈0.01）,而胎粪吸入综合征（MAS）与围生儿死亡率无显著差异（P〉0.05）。单纯羊水过少者围生儿结局与对照组无显著差异（P〉0.05）。结论羊水过少与妊娠并发症密切相关,羊水过少伴有妊娠并发症者围生儿结局不良,应放宽手术指征,单纯羊水过少者可以阴道试产。     

Scleroderma Lung Disease

Pulmonary involvement is second in frequency only to esophageal involvement as a visceral complication of systemic sclerosis (SSc) and has surpassed renal involvement as the most common cause of death. Interstitial lung disease and pulmonary vascular disease, particularly pulmonary arterial hypertension, are the most commonly encountered types of lung involvement. Chronic aspiration, airway disease, neuromuscular weakness, extrinsic pulmonary restrictive pathology, pleural effusions, pneumothorax, and lung cancer cause clinically significant disease and occur commonly enough to be routinely considered in the assessment of the SSc patient with respiratory symptoms. Affected patients have a significantly worse prognosis than patients with SSc who are free of pulmonary involvement.     

Limonene and its ozone-initiated reaction products attenuate allergic lung inflammation in mice

Inhalation of indoor air pollutants may cause airway irritation and inflammation and is suspected to worsen allergic reactions. Inflammation may be due to mucosal damage, upper (sensory) and lower (pulmonary) airway irritation due to activation of the trigeminal and vagal nerves, respectively, and to neurogenic inflammation. The terpene, d-limonene, is used as a fragrance in numerous consumer products. When limonene reacts with the pulmonary irritant ozone, a complex mixture of gas and particle phase products is formed, which causes sensory irritation. This study investigated whether limonene, ozone or the reaction mixture can exacerbate allergic lung inflammation and whether airway irritation is enhanced in allergic BALB/cJ mice. Naïve and allergic (ovalbumin sensitized) mice were exposed via inhalation for three consecutive days to clean air, ozone, limonene or an ozone–limonene reaction mixture. Sensory and pulmonary irritation was investigated in addition to ovalbumin-specific antibodies, inflammatory cells, total protein and surfactant protein D in bronchoalveolar lavage fluid and hemeoxygenase-1 and cytokines in lung tissue. Overall, airway allergy was not exacerbated by any of the exposures. In contrast, it was found that limonene and the ozone–limonene reaction mixture reduced allergic inflammation possibly due to antioxidant properties. Ozone induced sensory irritation in both naïve and allergic mice. However, allergic but not naïve mice were protected from pulmonary irritation induced by ozone. This study showed that irritation responses might be modulated by airway allergy. However, aggravation of allergic symptoms was observed by neither exposure to ozone nor exposure to ozone-initiated limonene reaction products. In contrast, anti-inflammatory properties of the tested limonene-containing pollutants might attenuate airway allergy.     

The microscopic appearance of a sodium-potassium exchange resin in histologic sections

The histologic appearance of Kayexalate, an ion-exchange resin, in bronchioles and alveolar spaces is described. Aspiration of this material occurred as a terminal event in an infant who suffered neonatal asphyxia and meconium aspiration. A solution of Kayexalate prepared for comparison appears to be identical to that found in the lung sections.     

Rothia dentocariosa septicemia without endocarditis in a neonatal infant with meconium aspiration syndrome

Rothia dentocariosa, a gram-positive coccoid- to rod-shaped bacterium with irregular morphology, is a rare cause of bacteremia in patients without endocarditis. We report the first case of R. dentocariosa septicemia without endocarditis, which occurred in a neonatal infant with meconium aspiration syndrome.     

Sequential changes of surfactant phosphatidylcholine in hyaline-membrane disease of the newborn

Although reduced levels of lung surfactant are known to predispose to hyaline-membrane disease, the role of biochemical changes in surfactant composition has not been defined. We found that surfactant isolated from pharyngeal and tracheal aspirates of newborns with hyaline-membrane disease had a distinctly different phosphatidylcholine fatty acid composition from surfactant of control infants. Surfactant phosphatidylcholine from newborns with hyaline-membrane disease had a lower percentage of palmitic acid and higher percentages of the 18-carbon and 20-carbon fatty acids, irrespective of gestational age. Evaluation of serial aspirates for 18 days revealed that in hyaline-membrane disease the surfactant phosphatidylcholine fatty acids followed a predictable pattern of change, gradually becoming similar to those of the control group. Evaluation of surfactant from tracheal and pharyngeal aspirates effectively monitors the biochemical maturation of the surfactant system in hyaline-membrane disease.     

Adenosine triphosphate treatment for meconium aspiration-induced pulmonary hypertension in pigs

To investigate the pulmonary haemodynamic effects of meconium aspiration and subsequent adenosine triphosphate (ATP) treatment, 12 anaesthetized and ventilated pigs (wt 24-28 kg) received either ATP or an equal volume of saline into the right heart in doses of 0.02 to 0.80 lmol kg^-1 min^?1 after intratracheal administration of 2 mL kg^?1 of human meconium. Meconium instillation induced significant increases in pulmonary vascular pressures and total and postarterial resistances calculated from pulmonary artery occlusion studies, but did not affect the systemic haemodynamics, except for a fall in heart rate and increase in central venous pressure. Infusion of ATP at the lowest doses (0.02 and 0.08 µmol kg^?1 min^?1) selectively decreased the pulmonary arterial pressure and vascular resistance and at 0.32 and 0.80 µmol kg^?1 min^?1 reduced both the pulmonary and systemic resistances. In the lung circulation the increasing doses of ATP reduced preferably the arterial, but also the postarterial resistance. Withdrawal of ATP infusion led to a significant rebound effect especially in the postarterial segment of the lung circulation. Meconium aspiration thus induces an acute, predominantly postarterial obstruction in the lung circulation and infusion of ATP at low doses selectively dilates the pulmonary vascular bed and may help to preclude elevation of capillary pressures in meconium aspiration-induced pulmonary hypertension.