Otitis media: treatment with intranasal aerosolized surfactant

OBJECTIVES/HYPOTHESIS: The objective was to determine the effect of intranasal surfactant alone and with other medications administered by metered dose inhaler aerosol on the function of the eustachian tube and on the resolution of experimentally induced otitis media with effusion (OME) and acute otitis media (AOM). STUDY DESIGN: Randomized, experimental, controlled animal studies. METHODS: Previously unreported (experiment 4) as well as published (experiments 1-3) data were detailed so that the reader could understand the continuum of information leading to the conclusions. In experiment 1, after a live-animal technique of measuring eustachian tube passive opening pressure was developed and validated, eustachian tube passive opening pressure was determined in 61 adult gerbils and 34 mice at baseline and 5 and 10 minutes after delivery of aerosolized intranasal metered dose inhaler surfactant. In experiments 2 and 3 (Klebsiella pneumoniae), lipopolysaccharide-induced OME was developed in gerbils. Thirty-five animals were randomly assigned to control, placebo, surfactant, surfactant with betamethasone, and surfactant with phenylephrine groups. Seventy animals were randomly assigned to control, placebo once daily (QD) and twice daily (BID), surfactant QD and BID, surfactant with betamethasone QD and BID, and surfactant with phenylephrine QD and BID groups. Intranasal aerosolized MDI medications were administered from postinfection day 2 until the effusion resolved. Otomicroscopy and tympanometry were performed on alternate days for 30 days. In experiment 4, AOM was developed in 39 chinchillas via transbullar injection of nontypeable Haemophilus influenzae on day 1. Thirteen animals each received placebo BID or surfactant BID, beginning on day 1. Thirteen animals received surfactant BID beginning on day 3. All administrations were continued for 10 days. Examinations were performed on seven occasions until day 27. Appropriate statistical measurements were employed, including one- and two-way ANOVA, strength-of-association measure (omega) calculation, chi, and Newman-Keuls post hoc multiple comparison tests. Significance was set as P value of less than.05. RESULTS: In experiment 1, a significant reduction in passive opening pressure was seen in both 5- and 10-minute postsurfactant measurements. Propellant alone was not effective. In experiments 2 and 3, OME resolved after an average period of 16 to 16.5 days in control, placebo QD and BID, and surfactant with phenylephrine QD groups. A significant decrease in OME days was seen in the surfactant QD (10.57 d) and BID (8.57 d), and surfactant with betamethasone QD (8.57 d) and BID (6.3 d) groups. A significant increase was seen in the phenylephrine BID group (18.67 d). In experiment 4, tympanometry was normal or near-normal in 62% and 48% of treated ears and in only 24% of placebo ears on day 12. Sixty-seven percent of placebo ears were culture positive at day 27, compared with 10% and 16% in surfactant groups 1 and 2. Seventy-five percent of untreated animals developed severe labyrinthitis, compared with 15% in groups 1 and 2. On day 27, 58% of placebo group middle ears had fluid, whereas 61% and 62% of ears in groups 1 and 2, respectively, were dry. These findings were significant. CONCLUSION: Intranasal application of aerosolized metered dose inhaler surfactant alone or with steroid reduced eustachian tube passive opening pressure in normal animals and duration of effusion in animals with experimental OME. Intranasal surfactant reduced the severity and duration of middle ear infection in AOM in this animal model.     

Surfactant does not improve survival rate in preterm infants with congenital diaphragmatic hernia

Background

Use of exogenous surfactant in congenital diaphragmatic hernia (CDH) patients is routine in many centers. The authors sought to determine the impact of surfactant use in the premature infant with CDH.

Methods

Data on liveborn infants with CDH from participating institutions were collected prospectively. Surfactant use and timing and outcome data were analyzed retrospectively. The authors evaluated the prenatal diagnosis patients as well. The outcome variable was survival to discharge. Odds ratios with confidence intervals were calculated.

Results

Five hundred ten infants less than 37 weeks’ gestation were entered in the CDH registry. Infants with severe anomalies (n = 80) were excluded. Information on surfactant use was available for 424 patients. Infants receiving surfactant (n = 209) had a greater odds of death than infants not receiving surfactant (n = 215, odds ratio, 2.17, 95% CI: 1.5 to 3.2; P < .01). In prenatally diagnosed infants with immediate distress, there was a trend toward worse survival rates among those receiving surfactant at 1 hour (52 patients) versus those that did not (93 patients; odds ratio, 1.93, 95% CI: 0.96 to 3.9; P < .07).

Conclusions

Surfactant, as currently used, is associated with a lower survival rate in preterm infants with CDH. The use of surfactant replacement in premature infants with CDH can be recommended only within the context of a randomized clinical trial.     

肺泡表面活性物质在金黄地鼠实验性慢性阻塞性肺病中的防治作用

目的探讨肺泡表面活性物质(PS)对慢性阻塞性肺病(COPD)的防治作用.方法通过给金黄地鼠吸入烟雾或气道内注入弹性蛋白酶两种方法,经1～3个月建立COPD动物模型,并应用外源性PS进行防治.对动物肺组织行光镜、电镜观察及显微微机图像分析进行形态定量.免疫组织化学法观察肺泡Ⅱ型上皮细胞表面活性物质蛋白A(SP-A)的表达情况.结果吸烟3个月及气道内注入弹性蛋白酶1和3个月,动物有明显的慢性支气管炎和肺气肿的病理变化.应用PS防治1个月,肺组织病变无明显改善;防治3个月后,肺组织损伤明显减轻,肺泡Ⅱ型上皮细胞的数量明显多于模型组,SP-A的表达比模型组增加(P＜0.01).结论经3个月的外源性PS干预,可减轻吸烟及弹性蛋白酶对肺组织的损伤,保护肺泡Ⅱ型上皮细胞的结构和分泌PS的功能,从而可有效减轻COPD的肺部病变.     

Developmental outcome of preterm infants after surfactant therapy: systematic review of randomized controlled trials

OBJECTIVES: To review neuro-developmental outcome at 1 and 2 years of age following randomized controlled trials (RCT) of neonatal surfactant therapy. METHODS: A systematic review of the MEDLINE, Embase and Cochrane Controlled Trial Register databases, searching for RCT of surfactant replacement therapy with follow-up outcomes, was carried out. The main outcome measures were severe and mild disability at 1 and 2 years plus composite adverse outcome of death and/or severe disability. RESULTS: A meta-analysis using odds ratios was carried out on 13 RCT. There were a total of 2218 treated and 2090 control infants who underwent follow up at 1 year of age. There were 303 treated and 292 control infants with follow up at between 18 months and 2 years of age. Surfactant therapy was associated with a lower rate of mild disability at 1 year (OR 0.79; 95% CI 0.66-0.95). There was a reduction in the combined adverse outcome (death or severe disability rate) at 1 year (OR 0.8; 95% CI 0.72-0.89). Neither the 1 year nor the 2 year follow-up examination showed a statistical difference in the severe disability rate between the control and treated group. CONCLUSION: Surfactant therapy increases survival without an increase in subsequent morbidity at 1 and 2 years of age.     

Aerosolized surfactant and dextran for experimental acute respiratory distress syndrome caused by acidified milk in rats

BACKGROUND: Inhibition of pulmonary surfactant by plasma-derived proteins is an important pathogenetic factor of acute respiratory distress syndrome (ARDS). Inhalation of aerosolized surfactant may be suitable for early treatment of ARDS. However, requirement of a high dose is a drawback. Because dextran reverses surfactant inhibition, we examined whether dextran improves the therapeutic effects of aerosolized surfactant in rats with experimental ARDS. METHODS: Acidified milk (pH 1.8, 1.5 ml kg(-1)) was injected into the trachea of the rats ventilated with pure oxygen using 2.45 kPa peak inspiratory pressure and 0.74 kPa positive end-expiratory pressure. When PaO2 decreased to <13 kPa, the rats were assigned to four groups: control group (n = 8), receiving no material; D-only group (n = 6), receiving aerosolized dextran for 45 min; S-only group (n = 8), receiving aerosolized modified natural surfactant (MNS) for 30 min; and S-plus-D group (n = 9), receiving aerosolized MNS for 30 min followed by aerosolized dextran for 15 min. RESULTS: In the control group and D-only groups, the mean PaO2 remained at <10 kPa for 180 min. In the S-only and S-plus-D groups, the PaO2 increased to 50 kPa (P < 0.01 vs. untreated). The PaO2 of the surfactant-only group gradually decreased to <17 kPa at 180 min, whereas the PaO2 of the S-plus-D group was maintained at >38 kPa for 180 min (P < 0.01 vs. S-only group). CONCLUSION: Inhalation of aerosolized dextran potentiates the effects of aerosolized surfactant by prolonging the therapeutic response.     

Patent ductus arteriosus and cystic periventricular leucomalacia in preterm infants

AIM: To test the association between early disturbances in hemodynamics induced by left-to-right shunting through the duct and cystic periventricular leucomalacia. PATIENTS: Forty-six preterm infants (27-32 wk) admitted to the neonatal intensive care unit with risk criteria. METHODS: Patent ductus arteriosus was evaluated on days 1 and 4, and was significant (sPDA) in cases of absent or reversed end diastolic flow in the subductal aorta. Resistance index was measured in the anterior cerebral artery and in the subductal aorta. MAIN OUTCOME: Diagnosis of cystic periventricular leucomalacia between day 10 and day 50. RESULTS: The 12 infants who developed cystic periventricular leucomalacia were compared with those who did not. On day 1, sPDA was more frequent (64% vs 26%; p = 0.03) in the cystic periventricular leucomalacia group, left ventricular output was higher (median = 341 vs 279 ml kg-1.min-1; p = 0.005), and rescue surfactant was more frequently used (83% vs 47%; p = 0.03). This latter association was confirmed by multivariate analysis. Resistance index in the anterior cerebral artery was increased in cases of significant patent ductus arteriosus (p < 0.01) and was correlated with resistance index in the subductal aorta. CONCLUSION: On day 1 in this selected population, sPDA has an effect on blood flow velocity waveform in cerebral arteries and is associated with an increase in the emergence of cystic periventricular leucomalacia. This association could be casual rather than causal.     

Human SP-A and a pharmacy-grade porcine lung surfactant extract can be reconstituted into tubular myelin--a comparative structural study of alveolar surfactants using cryo-transmission electron microscopy

Cryo-transmission electron microscopy (cryo-TEM) is a rather artefact-free method, well suited to study the alveolar surfactant system. A pharmacy grade porcine lung surfactant extract (HL-10) was mixed with human SP-A and Ringer's solution (for calcium ions), and it was shown by cryo-TEM that the tubular myelin (TM) type of structure was reconstituted. These aggregates were associated to liposomal aggregates, and resulted in macroscopic phase-separation. This phase showed a weak birefringence in the polarising microscope, which is characteristic for a liquid-crystalline type of structure. TM from rabbit lung lavage was also examined, and showed the same periodic arrangement of bilayers as alveolar surface layer from freshly cut rabbit lungs deposited directly on the cryo-TEM grids. The distance between the bilayers of TM was 40-50 nm, and an electron dense material, assumed to be SP-A, was sometimes seen to occur periodically along the bilayers, oriented perpendicularly to the tubuli. The results are consistent with the surface-phase model of the alveolar lining.     

急性肺损伤幼鼠肺泡Ⅱ型上皮细胞和SP-A变化相关性的研究

目的：该实验旨在研究急性肺损伤（ALI）时肺泡Ⅱ型上皮细胞（AEC-Ⅱ）超微结构变化和肺组织表面活性蛋白SP-A含量的变化关系，从而探讨ALI的发病机制。方法：48只Sprague-Dawley幼鼠被随机分为正常对照组和ALI组。 腹腔注射脂多糖（LPS，4 mg/kg）建立ALI模型，正常对照组注射等量生理盐水。 LPS注射后24，48，72 h每亚组各处死8只大鼠。 取左肺下肺组织待透射电镜检查。 用Western blot方法测定肺组织SP-A的相对含量。结果：ALI 24 h时，AEC-Ⅱ微绒毛消失。24 h及48 h时板层小体（lamellar body, Lb）数量增加，体积增大，密度减低，排空明显增强，呈指环状绕核排列，细胞增生活跃，代谢旺盛。48 h时Lb呈巨大空泡样变性。肺组织SP-A含量明显高于对照组（24 h时ALI组为6.52±0.62，对照组为5.02±0.35， P< 0.01；48 h时ALI组为6.65±0.62，对照组为5.01±0.36，P< 0.01）。72 h时Lb破溃，数目明显减少，细胞核形态不规则，部分核边界不清，肺组织SP-A含量下降(ALI组为3.87±0.50，对照组为5.22±0.36，P<0.01)。结论： LPS致幼鼠ALI时AEC-Ⅱ和肺组织SP-A的变化为时间依赖性，随AEC-Ⅱ损伤程度的加重肺组织SP-A由代偿转为失代偿，可能是发生ARDS的重要机制之一。     

高氧致慢性肺疾病早产鼠肺组织水通道蛋白-5及表面活性蛋白-A、B基因表达的意义

目的 探讨慢性肺疾病(CLD)早产鼠肺上皮细胞特异性标志物表面活性蛋白A、B(SP-A、SP-B)通道蛋白-5(AQP5)基因表达规律及其意义.方法 将80只早产鼠随机分为模型和对照组(每组40只),采用高体积分数氧诱导慢性肺疾病模型,于实验后1、3、7、14、21 d应用反转录聚合酶链式反应(RT-PCR)检测其肺组织SP-A、SP-B及AQP5 mRNA表达.结果 生后初期2组SP-A、SP-B及AQP5均无统计学差异(Pa＞0.05),7 d实验组SP-A及SP-B明显高于对照组(Pa＜0.05),14 d时显著高于对照组(Pa＜0.01),21 d时仍明显高于对照组(Pa＜0.05);同时间点与对照组比较,AQP5均维持在较低水平(Pa＜0.05).结论 高体积分数氧诱导早产鼠的Ⅱ型肺泡上皮细胞(AEC-Ⅱ)向Ⅰ型肺泡上皮细胞(AEC-Ⅰ)分化障碍可能是CLD肺上皮修复异常的重要机制.