今日の臨床サポート

呼吸窮迫症候群(小児科)

著者: 大井田憲泰 東京都立墨東病院 新生児科

監修: 渡辺博 帝京大学老人保健センター

著者校正/監修レビュー済:2021/06/02
患者向け説明資料

概要・推奨   

  1. 妊娠34週までの妊婦で、1週間以内に早産が予想される場合には、出生前ステロイド投与が勧められる(推奨度1)
  1. 出生前ステロイドの複数クールの投与については、児の長期予後に影響を与えることが懸念され、現時点では1クール投与が推奨される(推奨度2)
  1. 呼吸窮迫症候群では人工肺サーファクタント投与が重症度と死亡率を減少させる(推奨度1)
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
大井田憲泰 : 特に申告事項無し[2021年]
監修:渡辺博 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 定期レビューを行い、サーファクタントの投与方法について加筆修正を行った。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 新生児の呼吸窮迫症候群(Respiratory Distress Syndrome、RDS)は、肺胞虚脱を防ぐ肺サーファクタントが欠乏するために起こる呼吸障害である[1][2][3]
  1. RDSは早産児(特に在胎32週未満)で出生した場合の呼吸障害で最も多く認められる疾患であり、週数が早いほどその頻度は高くなる(わが国の周産期母子医療センターネットワークのデータベースでは、在胎23~25週:約75%、26~27週:約70%、28~29週:約60%、30~31週:約40%である。母体への出生前ステロイド使用の有無で頻度は大きく変わる)[1][4]
  1. RDSは適切な治療が行われなければ死に至る場合もあり、新生児集中治療施設(Neonatal Intensive Care Unit、NICU)に入院し適切な呼吸・循環管理が必要である。
  1. 予防は早産にならないことであるが、早産が避けられない場合には母体への出生前ステロイド投与が有効である[5][6][7][8]
  1. RDSの診断は、臨床症状と胸部X線所見から行う。
 
RDSのX線分類(Bomsel,1970)

肺サーファクタント不足の程度により、胸部X線所見が分けられる。サーファクタント不足が強いほど含気が減少し肺野の透過性が低下する。

出典

img1:  [Radiologic study of hyaline membrane disease: 110 cases].
 
 J Radiol Electrol Med Nucl. 1970 May;51(・・・
 
RDS胸部X線

在胎25週の児。 出生直後に挿管したあとの胸部X線写真。心肺境界不明瞭、含気不良ですりガラス陰影を認める(BomselⅢ度)。このあとサーファクタント投与を行った。

出典

img1:  大森意索先生ご提供
 
 
 
RDS胸部X線

在胎31週の児。出生後呼吸障害に対しCPAPを行ったが、酸素化不良、陥没呼吸増悪のため気管内挿管を行ったのちの胸部X線写真(BomselⅡ度)。含気不良で気管支透亮像を認める。

出典

img1:  大森意索先生ご提供
 
 
 
  1. 臨床症状は多呼吸、陥没呼吸、呻吟および酸素化不良のためのチアノーゼであるが、これらの症状はRDSに特異的なものではない。
  1. RDSと診断された場合には酸素投与や呼吸補助を行うとともに、重症の場合には早期に人工サーファクタントを投与する[9][10][11][12][13][14]
 
人工サーファクタント投与前後の胸部X線

a:サーファクタント投与前
b:サーファクタント投与後

出典

 
  1. 人工サーファクタント治療が開始されて以降RDSに伴う死亡は減少したが、RDS軽快後も早産児に対する長期間の入院管理を必要とする。
問診・診察のポイント  
  1. 切迫早産で早産児が出生することが予測される妊婦の場合には、RDS を含め早産児に対する対応が可能なNICUの整った施設に母体搬送する必要がある。

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最新のエビデンスに基づいた二次文献データベース「今日の臨床サポート」。
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文献 

著者: David G Sweet, Virgilio Carnielli, Gorm Greisen, Mikko Hallman, Eren Ozek, Richard Plavka, Ola D Saugstad, Umberto Simeoni, Christian P Speer, Henry L Halliday, European Association of Perinatal Medicine
雑誌名: Neonatology. 2010 Jun;97(4):402-17. doi: 10.1159/000297773. Epub 2010 Jun 10.
Abstract/Text Despite recent advances in the perinatal management of neonatal respiratory distress syndrome (RDS), controversies still exist. We report the updated recommendations of a European panel of expert neonatologists who had developed consensus guidelines after critical examination of the most up-to-date evidence in 2007. These updated guidelines are based upon published evidence up to the end of 2009. Strong evidence exists for the role of a single course of antenatal steroids in RDS prevention, but the potential benefit and long-term safety of repeated courses are unclear. Many practices involved in preterm neonatal stabilisation at birth are not evidence-based, including oxygen administration and positive pressure lung inflation, and they may at times be harmful. Surfactant replacement therapy is crucial in the management of RDS, but the best preparation, optimal dose and timing of administration at different gestations is not always clear. Respiratory support in the form of mechanical ventilation may also be lifesaving, but can cause lung injury, and protocols should be directed at avoiding mechanical ventilation where possible by using nasal continuous positive airways pressure or nasal ventilation. For babies with RDS to have best outcomes, it is essential that they have optimal supportive care, including maintenance of a normal body temperature, proper fluid management, good nutritional support, management of the ductus arteriosus and support of the circulation to maintain adequate tissue perfusion.

Copyright 2010 S. Karger AG, Basel.
PMID 20551710  Neonatology. 2010 Jun;97(4):402-17. doi: 10.1159/000297・・・
著者: William A Engle, American Academy of Pediatrics Committee on Fetus and Newborn
雑誌名: Pediatrics. 2008 Feb;121(2):419-32. doi: 10.1542/peds.2007-3283.
Abstract/Text Respiratory failure secondary to surfactant deficiency is a major cause of morbidity and mortality in preterm infants. Surfactant therapy substantially reduces mortality and respiratory morbidity for this population. Secondary surfactant deficiency also contributes to acute respiratory morbidity in late-preterm and term neonates with meconium aspiration syndrome, pneumonia/sepsis, and perhaps pulmonary hemorrhage; surfactant replacement may be beneficial for these infants. This statement summarizes indications, administration, formulations, and outcomes for surfactant-replacement therapy. The impact of antenatal steroids and continuous positive airway pressure on outcomes and surfactant use in preterm infants is reviewed. Because respiratory insufficiency may be a component of multiorgan dysfunction, preterm and term infants receiving surfactant-replacement therapy should be managed in facilities with technical and clinical expertise to administer surfactant and provide multisystem support.

PMID 18245434  Pediatrics. 2008 Feb;121(2):419-32. doi: 10.1542/peds.2・・・
著者: D Roberts, S Dalziel
雑誌名: Cochrane Database Syst Rev. 2006 Jul 19;(3):CD004454. doi: 10.1002/14651858.CD004454.pub2. Epub 2006 Jul 19.
Abstract/Text BACKGROUND: Respiratory distress syndrome (RDS) is a serious complication of preterm birth and the primary cause of early neonatal mortality and disability.
OBJECTIVES: To assess the effects on fetal and neonatal morbidity and mortality, on maternal mortality and morbidity, and on the child in later life of administering corticosteroids to the mother before anticipated preterm birth.
SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group Trials Register (30 October 2005).
SELECTION CRITERIA: Randomised controlled comparisons of antenatal corticosteroid administration (betamethasone, dexamethasone, or hydrocortisone) with placebo or with no treatment given to women with a singleton or multiple pregnancy, expected to deliver preterm as a result of either spontaneous preterm labour, preterm prelabour rupture of the membranes or elective preterm delivery.
DATA COLLECTION AND ANALYSIS: Two review authors assessed trial quality and extracted data independently.
MAIN RESULTS: Twenty-one studies (3885 women and 4269 infants) are included. Treatment with antenatal corticosteroids does not increase risk to the mother of death, chorioamnionitis or puerperal sepsis. Treatment with antenatal corticosteroids is associated with an overall reduction in neonatal death (relative risk (RR) 0.69, 95% confidence interval (CI) 0.58 to 0.81, 18 studies, 3956 infants), RDS (RR 0.66, 95% CI 0.59 to 0.73, 21 studies, 4038 infants), cerebroventricular haemorrhage (RR 0.54, 95% CI 0.43 to 0.69, 13 studies, 2872 infants), necrotising enterocolitis (RR 0.46, 95% CI 0.29 to 0.74, eight studies, 1675 infants), respiratory support, intensive care admissions (RR 0.80, 95% CI 0.65 to 0.99, two studies, 277 infants) and systemic infections in the first 48 hours of life (RR 0.56, 95% CI 0.38 to 0.85, five studies, 1319 infants). Antenatal corticosteroid use is effective in women with premature rupture of membranes and pregnancy related hypertension syndromes.
AUTHORS' CONCLUSIONS: The evidence from this new review supports the continued use of a single course of antenatal corticosteroids to accelerate fetal lung maturation in women at risk of preterm birth. A single course of antenatal corticosteroids should be considered routine for preterm delivery with few exceptions. Further information is required concerning optimal dose to delivery interval, optimal corticosteroid to use, effects in multiple pregnancies, and to confirm the long-term effects into adulthood.

PMID 16856047  Cochrane Database Syst Rev. 2006 Jul 19;(3):CD004454. d・・・
著者: Caroline A Crowther, Christopher Jd McKinlay, Philippa Middleton, Jane E Harding
雑誌名: Cochrane Database Syst Rev. 2011 Jun 15;(6):CD003935. doi: 10.1002/14651858.CD003935.pub3. Epub 2011 Jun 15.
Abstract/Text BACKGROUND: It has been unclear whether repeat dose(s) of prenatal corticosteroids are beneficial.
OBJECTIVES: To assess the effectiveness and safety of repeat dose(s) of prenatal corticosteroids.
SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 March 2011), searched reference lists of retrieved studies and contacted authors for further data.
SELECTION CRITERIA: Randomised controlled trials of women who had already received a single course of corticosteroids seven or more days previously and considered still at risk of preterm birth.
DATA COLLECTION AND ANALYSIS: We assessed trial quality and extracted data independently.
MAIN RESULTS: We included 10 trials (more than 4730 women and 5650 babies) with low to moderate risk of bias. Treatment of women who remain at risk of preterm birth seven or more days after an initial course of prenatal corticosteroids with repeat dose(s), compared with no repeat corticosteroid treatment, reduced the risk of their infants experiencing the primary outcomes respiratory distress syndrome (risk ratio (RR) 0.83, 95% confidence interval (CI) 0.75 to 0.91, eight trials, 3206 infants, numbers needed to treat (NNT) 17, 95% CI 11 to 32) and serious infant outcome (RR 0.84, 95% CI 0.75 to 0.94, seven trials, 5094 infants, NNT 30, 95% CI 19 to 79).Treatment with repeat dose(s) of corticosteroid was associated with a reduction in mean birthweight (mean difference (MD) -75.79 g, 95% CI -117.63 to -33.96, nine trials, 5626 infants). However, outcomes that adjusted birthweight for gestational age (birthweight Z scores, birthweight multiples of the median and small-for-gestational age) did not differ between treatment groups.At early childhood follow-up no statistically significant differences were seen for infants exposed to repeat prenatal corticosteroids compared with unexposed infants for the primary outcomes (total deaths; survival free of any disability or major disability; disability; or serious outcome) or in the secondary outcome growth assessments.
AUTHORS' CONCLUSIONS: The short-term benefits for babies of less respiratory distress and fewer serious health problems in the first few weeks after birth support the use of repeat dose(s) of prenatal corticosteroids for women still at risk of preterm birth seven days or more after an initial course. These benefits were associated with a small reduction in size at birth. The current available evidence reassuringly shows no significant harm in early childhood, although no benefit.Further research is needed on the long-term benefits and risks for the woman and baby. Individual patient data meta-analysis may clarify how to maximise benefit and minimise harm.    

PMID 21678343  Cochrane Database Syst Rev. 2011 Jun 15;(6):CD003935. d・・・
著者: Elisa Bevilacqua, Roberto Brunelli, Maurizio M Anceschi
雑誌名: J Matern Fetal Neonatal Med. 2010 Apr;23(4):244-60. doi: 10.1080/14767050903165222.
Abstract/Text BACKGROUND: Preterm birth causes infant morbidity and mortality. A single course of antenatal corticosteroids (ACS) should be considered routine for preterm delivery. Benefits of therapy before 34 weeks' gestation have been established for infants born between 24 h and 7 days after treatment. It is still unclear whether multiple courses (MC) of ACS should be performed in women at risk of preterm delivery 7 days or more after initial treatment.
OBJECTIVES: To determine the risks and benefits of MC of ACS.
METHODS: Search and selection for human randomized controlled trials were conducted in PubMed and The Cochrane Central Register of Controlled Trials. Statistical analysis was performed using the Review Manager 4.3 software.
MAIN RESULTS: MC of ACS were associated with a statistically decrease in the occurrence of respiratory distress syndrome, patent ductus arteriosus, use of surfactant, ventilation support, and any maternal side effects. This treatment was also associated with a significant reduction in birth weight and head circumference.
CONCLUSIONS: MC of ACS in women at risk of preterm birth do not offer significant benefits concerning the composite neonatal morbidity. Data on long-term safety are still insufficient. Further evaluations, most by follow-up studies, are required to study the long-term effects.

PMID 19670040  J Matern Fetal Neonatal Med. 2010 Apr;23(4):244-60. doi・・・
著者: E A Liechty, E Donovan, D Purohit, J Gilhooly, B Feldman, A Noguchi, S E Denson, S S Sehgal, I Gross, D Stevens
雑誌名: Pediatrics. 1991 Jul;88(1):19-28.
Abstract/Text To determine if outcomes of low birth weight neonates with respiratory distress syndrome can be improved by the administration of multiple doses of bovine surfactant, we conducted two identical multicenter, controlled trials, and the results were combined for analysis. Seven hundred and ninety-eight neonates weighing 600 to 1750 g at birth who had developed respiratory distress syndrome within 6 hours of birth were assigned randomly to receive either 100 mg of phospholipid/kg of Survanta, a modified bovine surfactant (n = 402), or a sham dosing procedure (n = 396). Neonates whose respiratory distress persisted could be given up to three more doses, with all doses to be given in the first 48 hours after birth. Dosing was performed by investigators not involved in the clinical care of the neonates; nursery staff were kept blinded as to the treatment assignment. Fewer Survanta-treated neonates died of any cause (18.4% vs 27.3%, P = .002), died of respiratory distress syndrome (9.0% vs 20.3%, P less than .001), and either died or developed bronchopulmonary dysplasia due to respiratory distress syndrome (51.2% vs 64.6%, P less than .001). Neonates who received Survanta also had greater improvement in their oxygenation and ventilatory status from baseline to 72 hours than did control neonates. Survanta-treated neonates were at lowered risk for developing pulmonary interstitial emphysema (18.6% vs 39.3%, P less than .001) and other pulmonary air leaks (11.5% vs 25.9%, P less than .001). We conclude that multiple doses of Survanta given after diagnosis of respiratory distress syndrome reduce mortality and morbidity.

PMID 2057268  Pediatrics. 1991 Jul;88(1):19-28.
著者: J D Horbar, E C Wright, L Onstad
雑誌名: Pediatrics. 1993 Aug;92(2):191-6.
Abstract/Text OBJECTIVE: To determine whether the introduction of surfactant therapy was associated with decreased mortality for high-risk preterm neonates weighing 601 to 1300 g at birth.
DESIGN: Before-after observational study.
SETTING: Eight tertiary care neonatal intensive care units participating in the National Institute of Child Health and Human Development Neonatal Research Network.
PATIENTS: The outcomes for neonates with birth weight 601 to 1300 g admitted in the 2 years before surfactants became available (n = 2780) were compared with those of neonates admitted in the year beginning 2 months after surfactants became available (n = 1413).
MAIN OUTCOME MEASURES: The primary outcome measure was in-hospital mortality; secondary outcome measures included durations of assisted ventilation, length of hospitalization, and neonatal morbidity.
RESULTS: Forty percent of neonates in the postsurfactant group received surfactant (range 28% to 69% at the centers). Mortality decreased from 27.8% before to 19.9% after surfactant therapy was introduced (Mantel-Haenszel chi 2 = 31.4, P = .001). The adjusted odds ratio for mortality after surfactants became available was 0.73 (95% confidence interval 0.55 to 0.95). The duration of assisted ventilation and length of hospitalization increased after surfactants were introduced (P = .0001 for both outcomes).
CONCLUSION: Mortality for neonates weighing 601 to 1300 g decreased after surfactant therapy was introduced, suggesting that the efficacy of surfactants demonstrated in randomized controlled trials will translate into effectiveness in routine clinical care.

PMID 7710456  Pediatrics. 1993 Aug;92(2):191-6.
著者: R F Soll
雑誌名: Cochrane Database Syst Rev. 2000;(2):CD000511. doi: 10.1002/14651858.CD000511.
Abstract/Text BACKGROUND: This section is under preparation and will be included in the next issue.
OBJECTIVES: To assess the effect of prophylactic intratracheal administration of natural surfactant extract in preterm newborns at risk for developing respiratory distress syndrome (RDS).
SEARCH STRATEGY: Searches were made of the Oxford Database of Perinatal Trials, Medline (MeSH terms: pulmonary surfactant; limits: age groups; newborn infants), previous reviews including cross references, abstracts, conference and symposia proceedings, expert informants and journal hand searching in the English language.
SELECTION CRITERIA: Randomized controlled trials which compared the effect of prophylactic natural surfactant administration (surfactant obtained from human or bovine sources, either modified with additional phospholipids or not) administered to high risk preterm newborns at or shortly after birth in order to prevent respiratory distress syndrome, other complications of prematurity, and mortality.
DATA COLLECTION AND ANALYSIS: Data regarding clinical outcomes including incidence of pneumothorax, pulmonary interstitial emphysema, patent ductus arteriosus, necrotizing enterocolitis, intraventricular hemorrhage (any grade and severe intraventricular hemorrhage), bronchopulmonary dysplasia, mortality, bronchopulmonary dysplasia or death, and retinopathy of prematurity were excerpted from the reports of the clinical trials by the reviewer. Data analysis was done in accordance with the standards of the Cochrane Neonatal Review Group.
MAIN RESULTS: All of the included studies note an initial improvement in respiratory status and a decrease in the risk of respiratory distress syndrome in infants who receive prophylactic natural surfactant extract. The meta-analysis supports a decrease in the risk of pneumothorax (typical relative risk 0.35, 95% CI 0.26, 0.49; typical risk difference -0.15, 95% CI -0.20, -0.11), a decrease in the risk pulmonary interstitial emphysema (typical relative risk 0.46, 95% CI 0.35, 0.60; typical risk difference -0.19, 95% CI -0.25, -0.13), a decrease in the risk of neonatal mortality (typical relative risk 0. 60, 95% CI 0.44, 0.83; typical risk difference -0.07, 95% CI -0.12, -0.03), and a decrease in the risk of bronchopulmonary dysplasia or death (typical relative risk 0.84, 95% CI 0.75, 0.93; typical risk difference -0.10, 95% CI -0.16, -0.04. No differences are reported in the risk of intraventricular hemorrhage, patent ductus arteriosus, necrotizing enterocolitis or retinopathy of prematurity. Few data are available on long-term followup of treated infants.
REVIEWER'S CONCLUSIONS: Prophylactic intratracheal administration of natural surfactant extract to infants judged to be at risk of developing respiratory distress syndrome (intubated infants <30 weeks gestation) has been demonstrated to improve clinical outcome. Infants who receive prophylactic natural surfactant extract have a decreased risk of pneumothorax, a decreased risk of pulmonary interstitial emphysema, a decreased risk of mortality, and a decreased risk of bronchopulmonary dysplasia or death.

PMID 10796380  Cochrane Database Syst Rev. 2000;(2):CD000511. doi: 10.・・・
著者: J K H Sinn, M C Ward, D J Henderson-Smart
雑誌名: J Paediatr Child Health. 2002 Dec;38(6):597-600.
Abstract/Text 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.

PMID 12410874  J Paediatr Child Health. 2002 Dec;38(6):597-600.
著者: C C Yost, R F Soll
雑誌名: Cochrane Database Syst Rev. 2000;(2):CD001456. doi: 10.1002/14651858.CD001456.
Abstract/Text BACKGROUND: This section is under preparation and will be included in the next issue.
OBJECTIVES: To compare the effects of early vs. delayed selective surfactant therapy for newborns intubated for respiratory distress within the first two hours of life. Planned subgroup analyses include separate comparisons for studies utilizing natural surfactant extract and synthetic surfactant.
SEARCH STRATEGY: Searches were made of the Oxford Database of Perinatal Trials, Medline (MeSH terms: pulmonary surfactant; text word: early; limits: age, newborn: publication type, clinical trial), PubMed, abstracts, conference and symposia proceedings, expert informants, and journal hand searching in the English language.
SELECTION CRITERIA: Only randomized controlled clinical trials comparing early selective surfactant administration (surfactant administration via the endotracheal tube in infants intubated for respiratory distress, not specifically for surfactant dosage) within the first 2 hours of life versus delayed selective surfactant administration to infants with established respiratory distress syndrome were considered for review.
DATA COLLECTION AND ANALYSIS: Data regarding clinical outcomes including the incidence of pneumothorax, patent ductus arteriosus, pulmonary interstitial emphysema, pulmonary hemorrhage, necrotizing enterocolitis, retinopathy of prematurity, intraventricular hemorrhage (any and severe IVH), bronchopulmonary dysplasia, chronic lung disease, neonatal mortality, mortality prior to hospital discharge, bronchopulmonary dysplasia or death, and chronic lung disease or death were excerpted from the reports of the clinical trials by the reviewers. Data regarding the average number of surfactant doses per infant were also analyzed. Further analysis of data with regard to surfactant type was performed. Data analysis was performed in accordance with the standards of the Cochrane Neonatal Review Group.
MAIN RESULTS: Four randomized controlled trials met selection criteria. Two of the trials utilized synthetic surfactant (Exosurf Neonatal) and two utilized a natural surfactant extract. The meta-analyses demonstrated significant reductions in risk of pneumothorax (Typical RR 0.70, 95%CI 0.59, 0.82; Typical RD -0.05, 95%CI -0.08, -0.03), and pulmonary interstitial emphysema (Typical RR 0.63, 95%CI 0.43, 0.93; Typical RD -0.06, 95%CI -0.10, -0.01) in infants randomized to early selective surfactant administration. Infants randomized to early selective surfactant administration also demonstrated a decreased risk of neonatal mortality (Typical RR 0.87, 95%CI 0.77, 0.99; Typical RD -0.03, 95%CI -0.06, -0.00), chronic lung disease (Typical RR 0.70, 95%CI 0. 55, 0.88; Typical RD -0.03, 95%CI -0.05, -0.01), and chronic lung disease or death at 36 weeks (Typical RR 0.84, 95%CI 0.75, 0.93; Typical RD -0.06, 95%CI -0.09, -0.03). A trend toward risk reduction for bronchopulmonary dysplasia or death at 28 days was also evident (Typical RR 0.94, 95%CI 0.88, 1.00; Typical RD -0.04, 95%CI -0.07, -0.00). No differences in other complications of RDS or prematurity were noted.
REVIEWER'S CONCLUSIONS: Early selective surfactant administration given to infants with RDS requiring assisted ventilation leads to a decreased risk of acute pulmonary injury (decreased risk of pneumothorax and pulmonary interstitial emphysema) and a decreased risk of neonatal mortality and chronic lung disease compared to delaying treatment of such infants until they develop established RDS.

PMID 10796266  Cochrane Database Syst Rev. 2000;(2):CD001456. doi: 10.・・・
著者: R F Soll, C J Morley
雑誌名: Cochrane Database Syst Rev. 2001;(2):CD000510. doi: 10.1002/14651858.CD000510.
Abstract/Text BACKGROUND: Clinical trials have proven that surfactant therapy is effective in improving the immediate need for respiratory support and the clinical outcome of premature newborns (Soll 1992, Jobe 1993). Trials have studied a wide variety of surfactant preparations used either to prevent (prophylactic or delivery room administration) or treat (selective or rescue administration) respiratory distress syndrome. Using either treatment strategy, significant reductions in the incidence of pneumothorax, as well as significant improvement in survival, have been noted. It is unclear if there is an advantage to choosing either the prophylactic or selective approach to treatment
OBJECTIVES: To compare the effect of prophylactic surfactant administration to surfactant treatment of established respiratory distress syndrome in premature infants.
SEARCH STRATEGY: Searches were made of the Oxford Database of Perinatal Trials, Medline (MeSH terms: pulmonary surfactant; limits: age groups, newborn infants; publication type, clinical trials), previous reviews including cross-references, abstracts, conference and symposia proceedings, expert informants, and journal handsearching in the English language.
SELECTION CRITERIA: Randomized controlled trials that compared the effects of prophylactic surfactant administration to surfactant treatment of established respiratory distress syndrome in premature infants were included in the analysis.
DATA COLLECTION AND ANALYSIS: Data regarding clinical outcomes including the incidence of pneumothorax, pulmonary interstitial emphysema, patent ductus arteriosus, necrotizing enterocolitis, intraventricular hemorrhage (any grade and severe intraventricular hemorrhage), bronchopulmonary dysplasia, mortality, bronchopulmonary dysplasia or death, and retinopathy of prematurity were excerpted from the reports of the clinical trials by the reviewers. Data analysis was done in accordance with the standards of the Cochrane Neonatal Review Group.
MAIN RESULTS: Eight studies were identified that met inclusion criteria. The majority of included studies noted an initial improvement in the respiratory status and a decrease in the incidence of respiratory distress syndrome in infants who received prophylactic surfactant. The meta-analysis supports a decrease in the incidence of pneumothorax, a decrease in the incidence of pulmonary interstitial emphysema, a decrease in the incidence of mortality and a decrease in the incidence of bronchopulmonary dysplasia or death associated with prophylactic administration of surfactant. No significant untoward effects of prophylactic surfactant administration are noted. In a secondary analysis of infants less than 30 weeks gestation, the meta-analysis suggests a significant decrease in the risk of neonatal mortality and the risk of mortality or bronchopulmonary dysplasia.
REVIEWER'S CONCLUSIONS: Prophylactic surfactant administration to infants judged to be at risk of developing respiratory distress syndrome (infants less than 30-32 weeks gestation), compared to selective use of surfactant in infants with established RDS, has been demonstrated to improve clinical outcome. Infants who receive prophylactic surfactant have a decreased risk of pneumothorax, a decreased risk of pulmonary interstitial emphysema and a decreased risk of mortality. However, it remains unclear exactly which criteria should be used to judge "at risk" infants who would require prophylactic surfactant administration.

PMID 11405966  Cochrane Database Syst Rev. 2001;(2):CD000510. doi: 10.・・・
著者: Caroline A Crowther, Ross R Haslam, Janet E Hiller, Lex W Doyle, Jeffrey S Robinson, Australasian Collaborative Trial of Repeat Doses of Steroids (ACTORDS) Study Group
雑誌名: Lancet. 2006 Jun 10;367(9526):1913-9. doi: 10.1016/S0140-6736(06)68846-6.
Abstract/Text BACKGROUND: The efficacy and safety of repeat doses of prenatal corticosteroids remains uncertain. Our aim was to establish whether repeat prenatal corticosteroids given to women at risk of preterm birth can reduce neonatal morbidity without harm.
METHODS: In this hospital-based study, 982 women who remained at risk of preterm birth at less than 32 weeks' gestation, 7 or more days after receiving a first course of prenatal corticosteroids, were randomly assigned to receive a repeat intramuscular dose of either 11.4 mg betamethasone (as Celestone Chronodose), or saline placebo. This was repeated every week the woman remained undelivered, at less than 32 weeks' gestation, and at risk of preterm birth. Primary outcomes were occurrence and severity of neonatal respiratory distress syndrome, use and duration of oxygen and mechanical ventilation, and weight, length, and head circumference at birth and hospital discharge. Statistical analyses were on an intention to treat basis. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN48656428.
FINDINGS: Fewer babies exposed to repeat corticosteroids had respiratory distress syndrome (33%vs 41%; relative risk 0.82, 95% CI 0.71-0.95, p=0.01) and fewer had severe lung disease (12%vs 20%; relative risk 0.60, 95% CI 0.46-0.79, p=0.0003) than those in the placebo group. In keeping with these benefits, babies exposed to repeat corticosteroids needed less oxygen therapy (p=0.03), and shorter duration of mechanical ventilation (p=0.01). Mean weight, length, and head circumference at birth and hospital discharge did not differ between treatment groups. Z-scores for weight (p=0.04) and head circumference (p=0.03) at birth were lower in the babies who received repeat corticosteroids although at the time of hospital discharge Z-scores did not differ between treatment groups (p=0.29 for weight, p=0.48 for head circumference).
INTERPRETATION: Exposure to repeat doses of antenatal corticosteroids reduces neonatal morbidity. Pending long-term outcome results, the short-term benefits for the babies in our study support the use of repeat doses of corticosteroids in women who remain at risk of very preterm birth 7 or more days after an initial course.

PMID 16765760  Lancet. 2006 Jun 10;367(9526):1913-9. doi: 10.1016/S014・・・
著者: S Chida, T Fujiwara
雑誌名: Eur J Pediatr. 1993 Feb;152(2):148-51.
Abstract/Text With the advent of surfactant replacement therapy, there is an increasing need for a rapid test of predicting the development of respiratory distress syndrome (RDS). We evaluated the clinical usefulness of the stable microbubble (SM) test in predicting the development of RDS by comparison with other tests in amniotic fluid samples obtained within 12 h before delivery from 40 pregnancies between 23-35 weeks of gestation. These tests included the lecithin/sphingomyelin (L/S) ratio, disaturated phosphatidylcholine/sphingomyelin (DSPC/S) ratio, concentrations of lecithin, DSPC, and surfactant-associated proteins A and B, C (SP-A, SP-B,C). The cut-off value of each test for predicting RDS was determined at a point of maximum diagnostic accuracy. The overall diagnostic accuracy of the SM test was similar to that of other tests. However, both the SM test and the SP-B,C concentration had positive predictive values of 100%. We conclude that the rapid (< 10 min) and reliable information obtained by this test should encourage its use in defining a population of neonates with surfactant deficiency in a multicentre trial of prophylactic surfactant therapy.

PMID 8444224  Eur J Pediatr. 1993 Feb;152(2):148-51.
著者: S Chida, T Fujiwara, M Konishi, H Takahashi, M Sasaki
雑誌名: Eur J Pediatr. 1993 Feb;152(2):152-6.
Abstract/Text We determined prospectively if the stable microbubble (SM) test on gastric aspirate obtained at birth was as useful as that on amniotic fluid in predicting respiratory distress syndrome (RDS). One hundred and five paired samples of amniotic fluid obtained at delivery from 105 consecutive women with gestation of 35 weeks or less and gastric aspirates from their neonates obtained within 30 min of birth were studied. The SM test with the predefined cut-off value of less than 5 bubbles/mm2 for amniotic fluid and less than 10 bubbles/mm2 for gastric aspirate signified the risk of RDS with the positive predictive value of 100% and 96% and with the negative predictive value of 91% and 84%, respectively. We conclude that the SM test on both amniotic fluid and gastric aspirate obtained at birth is a rapid (< 10 min), simple and reliable procedure for predicting neonates who will develop RDS. It may be used as a bedside test to define a population of neonates with surfactant deficiency in clinical trials of prophylactic surfactant therapy.

PMID 8444225  Eur J Pediatr. 1993 Feb;152(2):152-6.
著者: SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network, Neil N Finer, Waldemar A Carlo, Michele C Walsh, Wade Rich, Marie G Gantz, Abbot R Laptook, Bradley A Yoder, Roger G Faix, Abhik Das, W Kenneth Poole, Edward F Donovan, Nancy S Newman, Namasivayam Ambalavanan, Ivan D Frantz, Susie Buchter, Pablo J Sánchez, Kathleen A Kennedy, Nirupama Laroia, Brenda B Poindexter, C Michael Cotten, Krisa P Van Meurs, Shahnaz Duara, Vivek Narendran, Beena G Sood, T Michael O'Shea, Edward F Bell, Vineet Bhandari, Kristi L Watterberg, Rosemary D Higgins
雑誌名: N Engl J Med. 2010 May 27;362(21):1970-9. doi: 10.1056/NEJMoa0911783. Epub 2010 May 16.
Abstract/Text BACKGROUND: There are limited data to inform the choice between early treatment with continuous positive airway pressure (CPAP) and early surfactant treatment as the initial support for extremely-low-birth-weight infants.
METHODS: We performed a randomized, multicenter trial, with a 2-by-2 factorial design, involving infants who were born between 24 weeks 0 days and 27 weeks 6 days of gestation. Infants were randomly assigned to intubation and surfactant treatment (within 1 hour after birth) or to CPAP treatment initiated in the delivery room, with subsequent use of a protocol-driven limited ventilation strategy. Infants were also randomly assigned to one of two target ranges of oxygen saturation. The primary outcome was death or bronchopulmonary dysplasia as defined by the requirement for supplemental oxygen at 36 weeks (with an attempt at withdrawal of supplemental oxygen in neonates who were receiving less than 30% oxygen).
RESULTS: A total of 1316 infants were enrolled in the study. The rates of the primary outcome did not differ significantly between the CPAP group and the surfactant group (47.8% and 51.0%, respectively; relative risk with CPAP, 0.95; 95% confidence interval [CI], 0.85 to 1.05) after adjustment for gestational age, center, and familial clustering. The results were similar when bronchopulmonary dysplasia was defined according to the need for any supplemental oxygen at 36 weeks (rates of primary outcome, 48.7% and 54.1%, respectively; relative risk with CPAP, 0.91; 95% CI, 0.83 to 1.01). Infants who received CPAP treatment, as compared with infants who received surfactant treatment, less frequently required intubation or postnatal corticosteroids for bronchopulmonary dysplasia (P<0.001), required fewer days of mechanical ventilation (P=0.03), and were more likely to be alive and free from the need for mechanical ventilation by day 7 (P=0.01). The rates of other adverse neonatal outcomes did not differ significantly between the two groups.
CONCLUSIONS: The results of this study support consideration of CPAP as an alternative to intubation and surfactant in preterm infants. (ClinicalTrials.gov number, NCT00233324.)

2010 Massachusetts Medical Society
PMID 20472939  N Engl J Med. 2010 May 27;362(21):1970-9. doi: 10.1056/・・・
著者: J J Ho, P Subramaniam, D J Henderson-Smart, P G Davis
雑誌名: Cochrane Database Syst Rev. 2002;(2):CD002271. doi: 10.1002/14651858.CD002271.
Abstract/Text BACKGROUND: Respiratory distress syndrome (RDS) is the single most important cause of morbidity and mortality in preterm infants (Greenough 1998, Bancalari 1992). Intermittent positive pressure ventilation (IPPV) with surfactant is the standard treatment for the condition. The major difficulty with IPPV is that it is invasive, resulting in airway and lung injury and contributing to the development of chronic lung disease.
OBJECTIVES: In spontaneously breathing preterm infants with RDS, to determine if continuous distending pressure (CDP) reduces the need for IPPV and associated morbidity without adverse effects.
SEARCH STRATEGY: The standard search strategy of the Neonatal Review group was used. This included searches of the Oxford Database of Perinatal Trials, Cochrane Controlled Trials Register (The Cochrane Library, Issue 1, 2002), MEDLINE (1966-January 2002), and EMBASE (1980-January 2002), previous reviews including cross references, abstracts, conference and symposia proceedings, expert informants, journal hand searching mainly in the English language.
SELECTION CRITERIA: All trials using random or quasi-random allocation of preterm infants with RDS were eligible. Interventions were continuous distending pressure including continuous positive airway pressure (CPAP) by mask, nasal prong, nasopharyngeal tube, or endotracheal tube, or continuous negative pressure (CNP) via a chamber enclosing the thorax and lower body, compared with standard care.
DATA COLLECTION AND ANALYSIS: Standard methods of the Cochrane Collaboration and its Neonatal Review Group were used, including independent assessment of trial quality and extraction of data by each author.
MAIN RESULTS: CDP is associated with a lower rate of failed treatment (death or use of assisted ventilation) [summary RR 0.70 (0.55, 0.88), RD -0.22 (-0.35, -0.09), NNT 5 (3, 11)], overall mortality [summary RR 0.52 (0.32, 0.87), RD -0.15 (-0.26, -0.04), NNT 7 (4, 25)], and mortality in infants with birthweights above 1500 g [summary RR 0.24 (0.07, 0.84), RD -0.281 (-0.483, -0.078), NNT 4 (2, 13)]. The use of CDP is associated with an increased rate of pneumothorax [summary RR 2.36 (1.25, 5.54), RD 0.14 (0.04, 0.23), NNH 7 (4, 24)].
REVIEWER'S CONCLUSIONS: In preterm infants with RDS the application of CDP either as CPAP or CNP is associated with benefits in terms of reduced respiratory failure and reduced mortality. CDP is associated with an increased rate of pneumothorax. The applicability of these results to current practice is difficult to assess, given the intensive care setting of the 1970s when four out of five of these trials were done. Where resources are limited, such as in developing countries, CPAP for RDS may have a clinical role. Further research is required to determine the best mode of administration and its role in modern intensive care settings

PMID 12076445  Cochrane Database Syst Rev. 2002;(2):CD002271. doi: 10.・・・
著者: T P Stevens, M Blennow, R F Soll
雑誌名: Cochrane Database Syst Rev. 2002;(2):CD003063. doi: 10.1002/14651858.CD003063.
Abstract/Text BACKGROUND: Both early and prophylactic surfactant replacement therapy compared with later selective surfactant administration reduces mortality and pulmonary complications in ventilated infants with respiratory distress syndrome (RDS). Continuous distending pressure (CDP) has also been shown to improve clinical outcomes in preterm infants with RDS.
OBJECTIVES: To compare two treatment strategies in preterm infants with, or at risk for, RDS: early surfactant administration with brief mechanical ventilation (less than 1 hour) followed by extubation, vs later, selective surfactant administration, continued mechanical ventilation and extubation from low respiratory support. Two populations of infants receiving early surfactant were considered: spontaneously breathing infants with signs of RDS (surfactant administration during evolution of RDS prior to requiring intubation for respiratory failure) and infants at high risk for RDS (prophylactic surfactant administration within 15 minutes after birth).
SEARCH STRATEGY: Searches were made of the Oxford Database of Perinatal trials, MEDLINE (1966-December 2001), CINAHL (1982-December 2001), EMBASE (1980-December 2001), Cochrane Controlled Trials Register (The Cochrane Library, Issue 1, 2002), Pediatric Research (1990-2001), abstracts, expert informants and hand searching. No language restrictions were applied.
SELECTION CRITERIA: Randomized or quasi-randomized controlled clinical trials comparing early surfactant administration with planned brief mechanical ventilation (less than one hour) followed by extubation, vs selective surfactant administration, continued mechanical ventilation and extubation from low respiratory support.
DATA COLLECTION AND ANALYSIS: Data were sought regarding effects on incidence of mechanical ventilation (ventilation continued or initiated beyond one hour after surfactant administration), incidence of bronchopulmonary dysplasia (BPD, need for oxygen at 28 days of age), incidence of chronic lung disease (CLD, need for oxygen at 36 weeks' post-conceptional age), mortality (neonatal mortality < 28 days and mortality prior to hospital discharge), duration of mechanical ventilation, duration of hospitalization, time in oxygen, duration of respiratory support (including CPAP and nasal cannula), number of patients receiving surfactant, number of surfactant doses administered per patient, incidence of air leak syndromes (pulmonary interstitial emphysema, pneumothorax), incidence of pulmonary hemorrhage, and other complications of prematurity. Data analyses were performed in accordance with the standards of the Cochrane Neonatal Review Group.
MAIN RESULTS: Only one randomized controlled clinical trial met selection criteria and was included in this review (Verder 1994). In this study of infants with signs of RDS, intubation and early surfactant therapy followed by extubation to nasal CPAP (NCPAP) compared with later, selective surfactant administration was associated with a lower incidence of mechanical ventilation (ventilation continuing for one hour or more after surfactant administration in the early surfactant group or initiated for respiratory insufficiency or apnea in either group [RR 0.51, 95% CI 0.32, 0.76]). A larger proportion of infants in the early surfactant group received surfactant than in the selective surfactant group [RR 1.74, 95% CI 1.30, 2.33]. The number of surfactant doses per patient was significantly greater among patients randomized to the early surfactant group [MD 0.51, 95% CI 0.32, 0.70]. Trends towards a decreased incidence of mortality, and a higher rate of patent ductus arteriosus requiring treatment were seen in the early surfactant group. There was no evidence of effect on median time in oxygen, duration of mechanical ventilation, or incidence of BPD (oxygen at 28 days).
REVIEWER'S CONCLUSIONS: Early surfactant replacement therapy with extubation to NCPAP compared with later, selective surfactant replacement and continued mechanical ventilation with extubation from low ventilator support is associated with a reduced need for mechanical ventilation and increased utilization of exogenous surfactant therapy. These conclusions are based on findings from one small randomized clinical trial. Additional randomized trials are needed and are underway.

PMID 12076469  Cochrane Database Syst Rev. 2002;(2):CD003063. doi: 10.・・・
著者: Roger Soll, Eren Ozek
雑誌名: Cochrane Database Syst Rev. 2009 Jan 21;(1):CD000141. doi: 10.1002/14651858.CD000141.pub2. Epub 2009 Jan 21.
Abstract/Text BACKGROUND: Randomized controlled trials have demonstrated the efficacy of surfactant therapy in the treatment of infants at risk for or having respiratory distress syndrome (RDS). Due to surfactant inactivation, multiple doses of surfactant may lead to improved outcome.
OBJECTIVES: To determine the effect of multiple doses of exogenous surfactant compared to single doses of exogenous surfactant on mortality and complications of prematurity in premature infants at risk for or having respiratory distress syndrome.
SEARCH STRATEGY: For the initial search in 1999, searches were made of the Oxford Database of Perinatal Trials, Medline (MeSH terms: pulmonary surfactant; limits: age groups, newborn infant; publication type, clinical trials), previous reviews including cross references, abstracts, conference and symposia proceedings, expert informants, and journal hand searching in the English language.In June 2008, the searches were updated including Medline, Cinhal and Embase using similar terms as the original search.
SELECTION CRITERIA: Randomized controlled trials comparing a policy of multiple doses of surfactant to a policy of single doses of surfactant extract in premature infants at risk for or having respiratory distress syndrome were considered for this review.
DATA COLLECTION AND ANALYSIS: Data on clinical outcomes including pneumothorax, patent ductus arteriosus, necrotizing enterocolitis, intraventricular hemorrhage (all intraventricular hemorrhage and severe intraventricular hemorrhage), bronchopulmonary dysplasia, retinopathy of prematurity, and mortality were excerpted by the both reviewers (R. Soll; E. Ozek). For this update additional data were sought on pulmonary hemorrhage, periventricular leukomalacia, neurodevelopmental follow-up, rehospitalization for pulmonary reasons,and reactive airway disease. Data were analyzed according to the standards of the Cochrane Neonatal Review Group.
MAIN RESULTS: Three trials were identified that met study criteria. Two studies were randomized controlled trials of multiple vs. single dose animal derived surfactant extract in infants with established respiratory distress syndrome. Meta-analysis of these trials suggests a reduction in the risk of pneumothorax (typical relative risk 0.51, 95% CI 0.30, 0.88; typical risk difference-0.09, 95% CI -0.15, -0.02) and a trend towards a reduction in the risk of mortality (typical relative risk 0.63, 95% CI 0.39, 1.02; typical risk difference -0.07, 95% CI -0.14, 00.00).One study of multiple vs. single dose synthetic surfactant in infants at high risk of respiratory distress syndrome was identified. This study reported a decrease in NEC (relative risk 0.20, 95% CI 0.08, 0.51; risk difference-0.05, 95% CI -0.07, -0.02) and mortality (relative risk 0.56, 95% CI 0.39, 0.81; risk difference-0.07, 95% CI -0.12, -0.03)No data on long-term neurological or pulmonary outcome were reported.No complications associated with multiple dose treatment were reported in the identified trials.
AUTHORS' CONCLUSIONS: In infants with established respiratory distress, a policy of multiple doses of animal derived surfactant extract resulted in greater improvements regarding oxygenation and ventilatory requirements, a decreased risk of pneumothorax and a trend toward improved survival.In infants at high risk of respiratory distress, a policy of multiple doses of synthetic surfactant resulted in greater improvements regarding oxygenation and ventilatory requirements, a decreased risk of NEC and decreased mortality.The ability to give multiple doses of surfactant to infants with ongoing respiratory insufficiency leads to improved clinical outcome and appears to be the most effective treatment policy.

PMID 19160177  Cochrane Database Syst Rev. 2009 Jan 21;(1):CD000141. d・・・
著者: P G Davis, D J Henderson-Smart
雑誌名: Cochrane Database Syst Rev. 2003;(2):CD000143. doi: 10.1002/14651858.CD000143.
Abstract/Text BACKGROUND: Preterm infants being extubated following a period of intermittent positive pressure ventilation via an endotracheal tube are at risk of developing respiratory failure as a result of apnea, respiratory acidosis and hypoxia. Nasal continuous positive airway pressure appears to stabilise the upper airway, improve lung function and reduce apnea and may therefore have a role in facilitating extubation in this population.
OBJECTIVES: In preterm infants having their endotracheal tube removed following a period of intermittent positive pressure ventilation (IPPV), does management with nasal continuous positive airways pressure (NCPAP) lead to an increased proportion remaining free of additional ventilatory support, compared to extubation directly to headbox oxygen?
SEARCH STRATEGY: Searches were made of the Oxford Database of Perinatal Trials, MEDLINE up to November 2002, Cochrane Controlled Trials Register (The Cochrane Library, Issue 4, 2002), previous reviews including cross references, abstracts of conferences and symposia proceedings, expert informants and journal handsearching mainly in the English language.
SELECTION CRITERIA: All trials utilising random or quasi-random patient allocation, in which NCPAP (delivered by any method) was compared with headbox oxygen for post-extubation care were included. Methodological quality was assessed independently by the two authors.
DATA COLLECTION AND ANALYSIS: Data were extracted independently by the two authors. Prespecified subgroup analysis to determine the impact of different levels of NCPAP, differences in duration of IPPV and use of aminophylline were also performed using the same package. Data were analysed using relative risk (RR), risk difference (RD) and number needed to treat (NNT).
MAIN RESULTS: Nasal CPAP, when applied to preterm infants being extubated following IPPV, reduces the incidence of adverse clinical events (apnea, respiratory acidosis and increased oxygen requirements) indicating the need for additional ventilatory support [RR 0.62 (0.49, 0.77), RD -0.17 (-0.24,-0.10), NNT 6 (4,10)].
REVIEWER'S CONCLUSIONS:
IMPLICATIONS FOR PRACTICE: nasal CPAP is effective in preventing failure of extubation in preterm infants following a period of endotracheal intubation and IPPV. Implication for research: further definition of the gestational age and weight groups in whom these results apply is required. Optimal levels of NCPAP as well as methods of administration remain to be determined.

PMID 12804388  Cochrane Database Syst Rev. 2003;(2):CD000143. doi: 10.・・・
著者: T P Stevens, E W Harrington, M Blennow, R F Soll
雑誌名: Cochrane Database Syst Rev. 2007 Oct 17;(4):CD003063. doi: 10.1002/14651858.CD003063.pub3. Epub 2007 Oct 17.
Abstract/Text BACKGROUND: Both prophylactic and early surfactant replacement therapy reduce mortality and pulmonary complications in ventilated infants with respiratory distress syndrome (RDS) compared with later selective surfactant administration. However, continued post-surfactant intubation and ventilation are risk factors for bronchopulmonary dysplasia (BPD). The purpose of this review was to compare outcomes between two strategies of surfactant administration in infants with RDS; prophylactic or early surfactant administration followed by prompt extubation, compared with later, selective use of surfactant followed by continued mechanical ventilation.
OBJECTIVES: To compare two treatment strategies in preterm infants with or at risk for RDS: early surfactant administration with brief mechanical ventilation (less than one hour) followed by extubation vs. later selective surfactant administration, continued mechanical ventilation, and extubation from low respiratory support. Two populations of infants receiving early surfactant were considered: spontaneously breathing infants with signs of RDS (who receive surfactant administration during evolution of RDS prior to requiring intubation for respiratory failure) and infants at high risk for RDS (who receive prophylactic surfactant administration within 15 minutes after birth).
SEARCH STRATEGY: Searches were made of the Oxford Database of Perinatal Trials, MEDLINE (1966 - December 2006), CINAHL (1982 to December Week 2, 2006), EMBASE (1980 - December 2006), Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2006), Pediatric Research (1990 - 2006), abstracts, expert informants and hand searching. No language restrictions were applied.
SELECTION CRITERIA: Randomized or quasi-randomized controlled clinical trials comparing early surfactant administration with planned brief mechanical ventilation (less than one hour) followed by extubation vs. selective surfactant administration continued mechanical ventilation, and extubation from low respiratory support.
DATA COLLECTION AND ANALYSIS: Data were sought regarding effects on the incidence of mechanical ventilation (ventilation continued or initiated beyond one hour after surfactant administration), incidence of bronchopulmonary dysplasia (BPD), chronic lung disease (CLD), mortality, duration of mechanical ventilation, duration of hospitalization, duration of oxygen therapy, duration of respiratory support (including CPAP and nasal cannula), number of patients receiving surfactant, number of surfactant doses administered per patient, incidence of air leak syndromes (pulmonary interstitial emphysema, pneumothorax), patent ductus arteriosus requiring treatment, pulmonary hemorrhage, and other complications of prematurity. Stratified analysis was performed according to inspired oxygen threshold for early intubation and surfactant administration in the treatment group: inspired oxygen within lower (FiO2< 0.45) or higher (FiO2 > 0.45) range at study entry. Treatment effect was expressed as relative risk (RR) and risk difference (RD) for categorical variables, and weighted mean difference (WMD) for continuous variables.
MAIN RESULTS: Six randomized controlled clinical trials met selection criteria and were included in this review. In these studies of infants with signs and symptoms of RDS, intubation and early surfactant therapy followed by extubation to nasal CPAP (NCPAP) compared with later selective surfactant administration was associated with a lower incidence of mechanical ventilation [typical RR 0.67, 95% CI 0.57, 0.79], air leak syndromes [typical RR 0.52, 95% CI 0.28, 0.96] and BPD [typical RR 0.51, 95% CI 0.26, 0.99]. A larger proportion of infants in the early surfactant group received surfactant than in the selective surfactant group [typical RR 1.62, 95% CI 1.41, 1.86]. The number of surfactant doses per patient was significantly greater among patients randomized to the early surfactant group [WMD 0.57 doses per patient, 95% CI 0.44, 0.69]. In stratified analysis by FIO2 at study entry, a lower threshold for treatment (FIO2< 0.45) resulted in lower incidence of airleak [typical RR 0.46 and 95% CI 0.23, 0.93] and BPD [typical RR 0.43, 95% CI 0.20, 0.92]. A higher treatment threshold (FIO2 > 0.45) at study entry was associated with a higher incidence of patent ductus arteriosus requiring treatment [typical RR 2.15, 95% CI 1.09, 4.13].
AUTHORS' CONCLUSIONS: Early surfactant replacement therapy with extubation to NCPAP compared with later selective surfactant replacement and continued mechanical ventilation with extubation from low ventilator support is associated with less need mechanical ventilation, lower incidence of BPD and fewer air leak syndromes. A lower treatment threshold (FIO2< 0.45) confers greater advantage in reducing the incidences of airleak syndromes and BPD; moreover a higher treatment threshold (FIO2 at study > 0.45) was associated with increased risk of PDA. These data suggest that treatment with surfactant by transient intubation using a low treatment threshold (FIO2< 0.45) is preferable to later, selective surfactant therapy by transient intubation using a higher threshold for study entry (FIO2 > 0.45) or at the time of respiratory failure and initiation of mechanical ventilation.

PMID 17943779  Cochrane Database Syst Rev. 2007 Oct 17;(4):CD003063. d・・・
著者: R F Soll
雑誌名: Cochrane Database Syst Rev. 2000;(2):CD001079. doi: 10.1002/14651858.CD001079.
Abstract/Text BACKGROUND: This section is under preparation and will be included in the next issue.
OBJECTIVES: To assess the effect of prophylactic administration of synthetic surfactant in preterm newborns at risk for developing respiratory distress syndrome (RDS).
SEARCH STRATEGY: Searches were made of the Oxford Database of Perinatal Trials, Medline (MeSH terms: pulmonary surfactant; limits: age groups, newborn infants; publication type, clinical trial), previous reviews including cross-references, abstracts, conference and symposia proceedings, expert informants, and journal hand searching in the English language.
SELECTION CRITERIA: Randomized, controlled trials which compared the effect of prophylactic synthetic surfactant administered to high risk preterm newborns at or shortly after birth in order to prevent respiratory distress syndrome and other complications of prematurity.
DATA COLLECTION AND ANALYSIS: Data regarding clinical outcomes including the incidence of pneumothorax, pulmonary interstitial emphysema, patent ductus arteriosus, necrotizing enterocolitis, intraventricular hemorrhage (any grade and severe intraventricular hemorrhage), bronchopulmonary dysplasia, mortality, bronchopulmonary dysplasia or death, retinopathy of prematurity (any retinopathy, and retinopathy stages 3-4) mortality to one year of age, and cerebral palsy was excerpted from the report of the clinical trials by the reviewer. Data were analyzed according to the standards of the Cochrane Neonatal Review Group.
MAIN RESULTS: Studies of prophylactic administration of synthetic surfactant note a variable improvement in the respiratory status and a decrease in respiratory distress syndrome in infants who receive prophylactic synthetic surfactant. The meta-analysis supports a decrease in the risk of pneumothorax (typical relative risk 0.67, 95% CI 0.50, 0.90; typical risk difference -0.05, 95% CI -0.09, -0. 02), a decrease in the risk of pulmonary interstitial emphysema (typical relative risk 0.68, 95% CI 0.50, 0.93; typical risk difference -0.06, 95% CI -0.11, -0.01), and a decrease in risk of neonatal mortality (typical relative risk 0.70, 95% CI 0.58, 0.85; typical risk difference -0.07, 95% CI -0.11, -0.03). No differences were seen in the risk of intraventricular hemorrhage, necrotizing enterocolitis, bronchopulmonary dysplasia, retinopathy of prematurity and cerebral palsy. The meta-analysis supports an increase in the risk of patent ductus arteriosus associated with prophylactic synthetic surfactant administration (typical relative risk 1.11, 95% CI 1.00, 1.22; typical risk difference 0.05, 95% CI 0. 00,0.10), and an increase in the risk of pulmonary hemorrhage (typical relative risk 3.28, 95% CI 1.50, 7.16; typical risk difference 0.03, 95% CI 0.01, 0.05).
REVIEWER'S CONCLUSIONS: Prophylactic intratracheal administration of synthetic surfactant to infants judged to be at risk of developing respiratory distress syndrome has been demonstrated to improve clinical outcome. Infants who receive prophylactic synthetic surfactant have a decreased risk of pneumothorax, a decreased risk of pulmonary interstitial emphysema, and a decreased risk of neonatal mortality. Infants who receive prophylactic synthetic surfactant have an increased risk of developing patent ductus arteriosus and pulmonary hemorrhage.

PMID 10796410  Cochrane Database Syst Rev. 2000;(2):CD001079. doi: 10.・・・
著者: L Gortner, R R Wauer, H Hammer, G J Stock, F Heitmann, H L Reiter, P G Kühl, J C Möller, H J Friedrich, I Reiss, R Hentschel, G Jorch, G Hieronimi, E Kuhls
雑誌名: Pediatrics. 1998 Nov;102(5):1153-60. doi: 10.1542/peds.102.5.1153.
Abstract/Text OBJECTIVE: To investigate whether early (<1 hour after birth) surfactant administration would be superior to late treatment (2-6 hours after birth) in preterm infants.
STUDY DESIGN: Randomized controlled multicenter clinical trial.
PATIENTS AND METHODS: Prenatal randomization of all infants of 27 to 32 weeks' gestational age stratified by center after parental informed consent. Early treatment: 100 mg/kg body weight bovine surfactant (SF-RI1, Alveofact; Dr K. Thomae, Biberach, Germany) to infants requiring intubation after birth. Late treatment: identical dosage to infants requiring intubation up to 6 hours of age with the fraction of inspired oxygen >0.4 at 2 to 6 hours after birth. Primary endpoint: the time on mechanical ventilation. Main secondary endpoints: mortality, bronchopulmonary dysplasia, intraventricular hemorrhage >/=grade III, and periventricular leukomalacia. Sample size calculation: at least 280 infants to prove superiority of either approach (alpha = 0.05; beta = 0.90).
RESULTS: Enrollment of 317 infants, 154 randomized to early surfactant treatment, 163 to late surfactant treatment. Study infants (all following data intent-to-treat groups: early versus late surfactant) were similar with respect to: gestational age, 29.5 +/- 1.6 weeks versus 29.7 +/- 1.6 weeks; birth weight, 1227 +/- 367 g versus 1269 +/- 334 g; and the rate of prenatal corticosteroids, 79.9% versus 72.8%. Duration of mechanical ventilation: 3 days (0-8) versus 2 days (0-6) (median, interquartile); further outcome variables: death or bronchopulmonary dysplasia (day 28) 25.9% versus 23.9%, mortality 3.2% versus 1.8%, intraventricular hemorrhage >/=grade III 6.5% versus 3.7%, and periventricular leukomalacia 5.2% versus 5.5% not differing statistically.
CONCLUSION: In preterm infants with a high rate of prenatal glucocorticoids, early surfactant administration was not found to be superior to late treatment in terms of relevant outcome variables.

PMID 9794948  Pediatrics. 1998 Nov;102(5):1153-60. doi: 10.1542/peds.・・・
著者: Roger Soll, Eren Ozek
雑誌名: Cochrane Database Syst Rev. 2010 Jan 20;(1):CD001079. doi: 10.1002/14651858.CD001079.pub2. Epub 2010 Jan 20.
Abstract/Text BACKGROUND: Respiratory distress syndrome (RDS) is caused by a deficiency or dysfunction of pulmonary surfactant. A variety of surfactant products including protein free synthetic surfactant have been developed and tested in the prevention and treatment of RDS.
OBJECTIVES: To assess the effect of prophylactic administration of protein free synthetic surfactant (SS) on mortality, chronic lung disease and other morbidities associated with prematurity in preterm newborns at risk for developing RDS. Subgroup analysis were planned according to the degree of prematurity, surfactant product and dosage schedule.
SEARCH STRATEGY: Searches were made of the The Cochrane Library, MEDLINE, OVID, EMBASE, CINAHL from 1966 to 2009. In addition, previous reviews including cross references and abstracts from the Society for Pediatric Research were searched. No language restrictions were applied.
SELECTION CRITERIA: Randomized and quasi-randomized controlled trials that compared the effect of protein free SS administered to high risk preterm newborns at or shortly after birth in order to prevent RDS, mortality and complications of prematurity.
DATA COLLECTION AND ANALYSIS: Data regarding clinical outcomes was excerpted from the clinical trials by the reviewers. Data were analyzed according to the standards of the Cochrane Neonatal Review Group.
MAIN RESULTS: Studies of prophylactic administration of protein free SS note a variable improvement in the respiratory status and a decrease in respiratory distress syndrome in infants who receive prophylactic protein free SS. The meta-analysis supports a decrease in the risk of pneumothorax (typical relative risk 0.67, 95% CI 0.50, 0.90), pulmonary interstitial emphysema (typical relative risk 0.68, 95% CI 0.50, 0.93), and neonatal mortality (typical relative risk 0.70, 95% CI 0.58, 0.85). No differences were seen in the risk of intraventricular hemorrhage, necrotizing enterocolitis, bronchopulmonary dysplasia, retinopathy of prematurity and cerebral palsy. The meta-analysis supports an increase in the risk of patent ductus arteriosus associated with prophylactic SS administration (typical relative risk 1.11, 95% CI 1.00, 1.22), and an increase in the risk of pulmonary hemorrhage (typical relative risk 3.28, 95% CI 1.50, 7.16).
AUTHORS' CONCLUSIONS: Prophylactic intratracheal administration of protein free synthetic surfactant to infants at risk of developing respiratory distress syndrome has been demonstrated to improve clinical outcome. Infants who receive prophylactic protein free SS have a decreased risk of pneumothorax, a decreased risk of pulmonary interstitial emphysema, and a decreased risk of neonatal mortality. Infants who receive prophylactic protein free SS have an increased risk of developing patent ductus arteriosus and pulmonary hemorrhage.

PMID 20091513  Cochrane Database Syst Rev. 2010 Jan 20;(1):CD001079. d・・・
著者: Lisa M Askie, Roberta A Ballard, Gary R Cutter, Carlo Dani, Diana Elbourne, David Field, Jean-Michel Hascoet, Anna Maria Hibbs, John P Kinsella, Jean-Christophe Mercier, Wade Rich, Michael D Schreiber, Pimol Srisuparp Wongsiridej, Nim V Subhedar, Krisa P Van Meurs, Merryn Voysey, Keith Barrington, Richard A Ehrenkranz, Neil N Finer, Meta-analysis of Preterm Patients on Inhaled Nitric Oxide Collaboration
雑誌名: Pediatrics. 2011 Oct;128(4):729-39. doi: 10.1542/peds.2010-2725. Epub 2011 Sep 19.
Abstract/Text BACKGROUND: Inhaled nitric oxide (iNO) is an effective therapy for pulmonary hypertension and hypoxic respiratory failure in term infants. Fourteen randomized controlled trials (n = 3430 infants) have been conducted on preterm infants at risk for chronic lung disease (CLD). The study results seem contradictory.
DESIGN/METHODS: Individual-patient data meta-analysis included randomized controlled trials of preterm infants (<37 weeks' gestation). Outcomes were adjusted for trial differences and correlation between siblings.
RESULTS: Data from 3298 infants in 12 trials (96%) were analyzed. There was no statistically significant effect of iNO on death or CLD (59% vs 61%: relative risk [RR]: 0.96 [95% confidence interval (CI): 0.92-1.01]; P = .11) or severe neurologic events on imaging (25% vs 23%: RR: 1.12 [95% CI: 0.98-1.28]; P = .09). There were no statistically significant differences in iNO effect according to any of the patient-level characteristics tested. In trials that used a starting iNO dose of >5 vs ≤ 5 ppm there was evidence of improved outcome (interaction P = .02); however, these differences were not observed at other levels of exposure to iNO. This result was driven primarily by 1 trial, which also differed according to overall dose, duration, timing, and indication for treatment; a significant reduction in death or CLD (RR: 0.85 [95% CI: 0.74-0.98]) was found.
CONCLUSIONS: Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended. The use of a higher starting dose might be associated with improved outcome, but because there were differences in the designs of these trials, it requires further examination.

PMID 21930540  Pediatrics. 2011 Oct;128(4):729-39. doi: 10.1542/peds.2・・・
著者: K J Barrington, N N Finer
雑誌名: Cochrane Database Syst Rev. 2007 Jul 18;(3):CD000509. doi: 10.1002/14651858.CD000509.pub3. Epub 2007 Jul 18.
Abstract/Text BACKGROUND: Inhaled nitric oxide (iNO) has been proven to be effective in term infants with hypoxic respiratory failure. The pathophysiology of respiratory failure, and the potential risks, differ substantially in preterm infants. Therefore, analysis of the efficacy and toxicities of iNO in infants born before 35 weeks is necessary.
OBJECTIVES: To determine the effect of treatment with iNO on the rates of death, bronchopulmonary dysplasia (BPD), intraventricular haemorrhage (IVH), or neurodevelopmental disability in preterm newborn infants (< 35 weeks gestation) with respiratory disease.
SEARCH STRATEGY: Standard methods of the Cochrane Neonatal Review Group were used. MEDLINE, EMBASE, Healthstar and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library) were searched, using the following keywords: nitric oxide, clinical trial, and newborn covering the years from 1985 to 2006. In addition, the abstracts of the Pediatric Academic Societies were also searched.
SELECTION CRITERIA: Randomised and quasi-randomised studies in preterm infants with respiratory disease that compared the effects of administration of iNO gas compared to control, with or without placebo are included in this review.
DATA COLLECTION AND ANALYSIS: Data regarding clinical outcomes including death, BPD (defined as oxygen dependence at 36 weeks postmenstrual age), IVH, periventricular leukomalacia (PVL), long term neurodevelopmental outcome and short term effects on oxygenation were excerpted from the trial reports by the investigators. Standard methods of the Cochrane Neonatal Review Group were used. Two investigators extracted, assessed and coded separately all data for each study. Any disagreement was resolved by discussion.
MAIN RESULTS: Eleven randomised controlled trials of inhaled nitric oxide therapy in preterm infants were found. The trials have been grouped post hoc into three categories depending on the entry criteria; entry in the first three days of life based on oxygenation criteria (Kinsella 1999; Hascoet 2004; INNOVO 2005; Van Meurs 2004; Mercier 1999; Dani 2006), routine use in intubated preterm babies (Schreiber 2003; Kinsella 2006) and later enrolment based on an increased risk of BPD (Subhedar 1997; Ballard 2006). The usefulness of the overall analyses was considered limited by the differing characteristics of the studies, and only subgroup analyses were performed. Trials of early rescue treatment of infants based on oxygenation criteria demonstrated no significant effect of iNO on mortality or BPD. The subgroup of studies with routine use of iNO in intubated preterm infants demonstrated a marginally significant reduction in the combined outcome of death or BPD [typical RR 0.91 (95% CI 0.84, 0.99); typical RD -0.06 (95% CI -0.12, -0.01)]. Later treatment with iNO based on the risk of BPD demonstrated no significant benefit for this outcome in our analysis. Studies of early rescue treatment with iNO demonstrated a trend toward increased risk of severe IVH, whereas the subgroup of studies with routine use in intubated preterm infants seems to show a reduction in the risk of having either a severe IVH or PVL [typical RR 0.70 (95% CI 0.53, 0.91); typical RD -0.07 (95% CI -0.12, -0.02)]. Later iNO treatment of infants at risk of BPD is given after the major risk period for IVH, and does not appear to lead to progression of old lesions. Two studies (Schreiber 2003; INNOVO 2005) presented data on long term neurodevelopmental outcome. The early routine treatment study (Schreiber 2003) showed an improved outcome at two years corrected age, while the rescue treatment study (INNOVO 2005) showed no effect of iNO.
AUTHORS' CONCLUSIONS: iNO as rescue therapy for the very ill ventilated preterm infant does not appear to be effective and may increase the risk of severe IVH. Later use of iNO to prevent BPD also does not appear to be effective. Early routine use of iNO in mildly sick preterm infants may decrease serious brain injury and may improve survival without BPD. Further studies are needed to confirm these findings, to define groups most likely to benefit, and to describe long term outcomes.

PMID 17636641  Cochrane Database Syst Rev. 2007 Jul 18;(3):CD000509. d・・・
著者: John P Kinsella, Gary R Cutter, William F Walsh, Dale R Gerstmann, Carl L Bose, Claudia Hart, Kris C Sekar, Richard L Auten, Vinod K Bhutani, Jeffrey S Gerdes, Thomas N George, W Michael Southgate, Heather Carriedo, Robert J Couser, Mark C Mammel, David C Hall, Mariann Pappagallo, Smeeta Sardesai, John D Strain, Monika Baier, Steven H Abman
雑誌名: N Engl J Med. 2006 Jul 27;355(4):354-64. doi: 10.1056/NEJMoa060442.
Abstract/Text BACKGROUND: The safety and efficacy of early, low-dose, prolonged therapy with inhaled nitric oxide in premature newborns with respiratory failure are uncertain.
METHODS: We performed a multicenter, randomized trial involving 793 newborns who were 34 weeks of gestational age or less and had respiratory failure requiring mechanical ventilation. Newborns were randomly assigned to receive either inhaled nitric oxide (5 ppm) or placebo gas for 21 days or until extubation, with stratification according to birth weight (500 to 749 g, 750 to 999 g, or 1000 to 1250 g). The primary efficacy outcome was a composite of death or bronchopulmonary dysplasia at 36 weeks of postmenstrual age. Secondary safety outcomes included severe intracranial hemorrhage, periventricular leukomalacia, and ventriculomegaly.
RESULTS: Overall, there was no significant difference in the incidence of death or bronchopulmonary dysplasia between patients receiving inhaled nitric oxide and those receiving placebo (71.6 percent vs. 75.3 percent, P=0.24). However, for infants with a birth weight between 1000 and 1250 g, as compared with placebo, inhaled nitric oxide therapy reduced the incidence of bronchopulmonary dysplasia (29.8 percent vs. 59.6 percent); for the cohort overall, such treatment reduced the combined end point of intracranial hemorrhage, periventricular leukomalacia, or ventriculomegaly (17.5 percent vs. 23.9 percent, P=0.03) and of periventricular leukomalacia alone (5.2 percent vs. 9.0 percent, P=0.048). Inhaled nitric oxide therapy did not increase the incidence of pulmonary hemorrhage or other adverse events.
CONCLUSIONS: Among premature newborns with respiratory failure, low-dose inhaled nitric oxide did not reduce the overall incidence of bronchopulmonary dysplasia, except among infants with a birth weight of at least 1000 g, but it did reduce the overall risk of brain injury. (ClinicalTrials.gov number, NCT00006401 [ClinicalTrials.gov].).

Copyright 2006 Massachusetts Medical Society.
PMID 16870914  N Engl J Med. 2006 Jul 27;355(4):354-64. doi: 10.1056/N・・・
著者: Roberta A Ballard, William E Truog, Avital Cnaan, Richard J Martin, Philip L Ballard, Jeffrey D Merrill, Michele C Walsh, David J Durand, Dennis E Mayock, Eric C Eichenwald, Donald R Null, Mark L Hudak, Asha R Puri, Sergio G Golombek, Sherry E Courtney, Dan L Stewart, Stephen E Welty, Roderic H Phibbs, Anna Maria Hibbs, Xianqun Luan, Sandra R Wadlinger, Jeanette M Asselin, Christine E Coburn, NO CLD Study Group
雑誌名: N Engl J Med. 2006 Jul 27;355(4):343-53. doi: 10.1056/NEJMoa061088.
Abstract/Text BACKGROUND: Bronchopulmonary dysplasia in premature infants is associated with prolonged hospitalization, as well as abnormal pulmonary and neurodevelopmental outcome. In animal models, inhaled nitric oxide improves both gas exchange and lung structural development, but the use of this therapy in infants at risk for bronchopulmonary dysplasia is controversial.
METHODS: We conducted a randomized, stratified, double-blind, placebo-controlled trial of inhaled nitric oxide at 21 centers involving infants with a birth weight of 1250 g or less who required ventilatory support between 7 and 21 days of age. Treated infants received decreasing concentrations of nitric oxide, beginning at 20 ppm, for a minimum of 24 days. The primary outcome was survival without bronchopulmonary dysplasia at 36 weeks of postmenstrual age.
RESULTS: Among 294 infants receiving nitric oxide and 288 receiving placebo birth weight (766 g and 759 g, respectively), gestational age (26 weeks in both groups), and other characteristics were similar. The rate of survival without bronchopulmonary dysplasia at 36 weeks of postmenstrual age was 43.9 percent in the group receiving nitric oxide and 36.8 percent in the placebo group (P=0.042). The infants who received inhaled nitric oxide were discharged sooner (P=0.04) and received supplemental oxygen therapy for a shorter time (P=0.006). There were no short-term safety concerns.
CONCLUSIONS: Inhaled nitric oxide therapy improves the pulmonary outcome for premature infants who are at risk for bronchopulmonary dysplasia when it is started between 7 and 21 days of age and has no apparent short-term adverse effects. (ClinicalTrials.gov number, NCT00000548 [ClinicalTrials.gov] .).

Copyright 2006 Massachusetts Medical Society.
PMID 16870913  N Engl J Med. 2006 Jul 27;355(4):343-53. doi: 10.1056/N・・・
著者: Neil N Finer, Waldemar A Carlo, Shahnaz Duara, Avroy A Fanaroff, Edward F Donovan, Linda L Wright, Sarah Kandefer, W Kenneth Poole, National Institute of Child Health and Human Development Neonatal Research Network
雑誌名: Pediatrics. 2004 Sep;114(3):651-7. doi: 10.1542/peds.2004-0394.
Abstract/Text OBJECTIVE: Although earlier studies have suggested that early continuous airway positive pressure (CPAP) may be beneficial in reducing ventilator dependence and subsequent chronic lung disease in the extremely low birth weight (ELBW) infant, the time of initiation of CPAP has varied, and there are no prospective studies of infants who have received CPAP or positive end-expiratory pressure (PEEP) from initial resuscitation in the delivery room (DR). Current practice for the ELBW infant includes early intubation and the administration of prophylactic surfactant, often in the DR. The feasibility of initiating CPAP in the DR and continuing this therapy without intubation for surfactant has never been determined prospectively in a population of ELBW infants. This study was designed to determine the feasibility of randomizing ELBW infants of <28 weeks' gestation to CPAP/PEEP or no CPAP/PEEP during resuscitation immediately after delivery, avoiding routine DR intubation for surfactant administration, initiating CPAP on neonatal intensive care unit (NICU) admission, and assessing compliance with subsequent intubation criteria.
METHODS: Infants who were of <28 weeks' gestation, who were born in 5 National Institute of Child Health and Human Development Neonatal Research Network NICUs from July 2002 to January 2003, and for whom a decision had been made to provide full treatment after birth were randomized to receive either CPAP/PEEP or not using a neonatal T-piece resuscitator (NeoPuff). Infants would not be intubated for the sole purpose of surfactant administration in the DR. After admission to the NICU, all nonintubated infants were placed on CPAP and were to be intubated for surfactant administration only after meeting specific criteria: a fraction of inspired oxygen of >0.3 with an oxygen saturation by pulse oximeter of <90% and/or an arterial oxygen pressure of <45 mm Hg, an arterial partial pressure of carbon dioxide of >55 mm Hg, or apnea requiring bag and mask ventilation.
RESULTS: A total of 104 infants were enrolled over a 6-month period: 55 CPAP and 49 control infants. No infant was intubated in the DR for the exclusive purpose of surfactant administration. Forty-seven infants were intubated for resuscitation in the DR: 27 of 55 CPAP infants and 20 of 49 control infants. Only 4 of the 43 infants who had a birth weight of <700 g and 3 of the 37 infants of <25 weeks' gestation were resuscitated successfully without positive pressure ventilation, and no difference was observed between the treatment groups. All infants of 23 weeks' gestation required intubation in the DR, irrespective of treatment group, whereas only 3 (14%) of 21 infants of 27 weeks' required such intubation. For infants who were not intubated in the DR, 36 infants (16 CPAP infants and 20 control infants) were subsequently intubated in the NICU by day 7, in accordance with the protocol. Overall, 80% of studied infants required intubation within the first 7 days of life. The care provided for 52 (95%) of 55 CPAP infants and 43 (88%) of the 49 control infants was in compliance with the study protocol, with an overall compliance of 91%.
CONCLUSIONS: This study demonstrated that infants could be randomized successfully to a DR intervention of CPAP/PEEP compared with no CPAP/PEEP, with intubation provided only for resuscitation indications, and subsequent intubation for prespecified criteria. Forty-five percent (47 of 104) of infants <28 weeks' gestation required intubation for resuscitation in the DR. CPAP/PEEP in the DR did not affect the need for intubation at birth or during the subsequent week. Overall, 20% of infants did not need intubation by 7 days of life. This experience should be helpful in facilitating the design of subsequent prospective studies of ventilatory support in ELBW infants.

PMID 15342835  Pediatrics. 2004 Sep;114(3):651-7. doi: 10.1542/peds.20・・・
著者: Hany Aly, Joshua D Milner, Kantilal Patel, Ayman A E El-Mohandes
雑誌名: Pediatrics. 2004 Sep;114(3):697-702. doi: 10.1542/peds.2003-0572-L.
Abstract/Text OBJECTIVE: Early use of nasal continuous positive airway pressure (ENCPAP) in extremely low birth weight (ELBW) infants continues to be a source of debate. Centers are applying this management strategy with varying success. Our center has implemented this strategy of care over the past 4 years, and the objective of this study was to evaluate the impact of experience over time with the use of ENCPAP on outcomes of ELBW infants.
METHODS: All ELBW infants who were born at our hospital since the institution of the ENCPAP practice (n = 101) were analyzed retrospectively. Patients were divided into 3 terciles according to their birth date. A baseline group of ELBW infants who were born in the 2 years preceding the institution of the ENCPAP practice (group 0; n = 45) were used for comparison. Trends in practices and outcomes over time were analyzed using the 2-sided Cochran-Armitage linear trend test. Statistical significance for these trends were then analyzed again using a multivariate regression model controlling for significant variables. Bivariate analyses comparing individual groups were also conducted.
RESULTS: There were no significant trends in mortality rate among the baseline group and the 3 terciles since the institution of the ENCPAP practice (26.7% vs 26.5% vs 11.8% vs 18.2%). ENCPAP management increased in the surviving infants over time (14% vs 19.2% vs 65.52% vs 70.4%), whereas the use of surfactant decreased (51.5% vs 48% vs 13.3% vs 33.3%) and the incidence of bronchopulmonary dysplasia (BPD) decreased (33.3% vs 46.2% vs 25.9% vs 11.1%). The average ventilator days per infant decreased, the rate of sepsis decreased, and the average daily weight gain increased. There were no significant trends in the incidence of intraventricular hemorrhage or necrotizing enterocolitis (NEC). When comparing the cohorts of survivors in the 3 terciles since the institution of ENCPAP system, ELBW infants who were started on ENCPAP but intubated within 1 week (CPAP failure) decreased over time (38.5% vs 13.8% vs 7.4%). There were other trends that did not reach significance, such as increased incidence of necrotizing enterocolitis (NEC). In a multivariate analysis controlling for gestational age, birth weight, and sepsis, the incidence of BPD was significantly lower over time (regression coefficient = -1.002 +/- 0.375).
CONCLUSIONS: The frequency of use of ENCPAP in ELBW infants and its success improved in our unit over time. The major positive association in this population was a reduction in BPD rates and an increase in average weight gain. Relation of ENCPAP and NEC should be evaluated further.

PMID 15342841  Pediatrics. 2004 Sep;114(3):697-702. doi: 10.1542/peds.・・・
著者: Filip Cools, Lisa M Askie, Martin Offringa, Jeanette M Asselin, Sandra A Calvert, Sherry E Courtney, Carlo Dani, David J Durand, Dale R Gerstmann, David J Henderson-Smart, Neil Marlow, Janet L Peacock, J Jane Pillow, Roger F Soll, Ulrich H Thome, Patrick Truffert, Michael D Schreiber, Patrick Van Reempts, Valentina Vendettuoli, Giovanni Vento, PreVILIG collaboration
雑誌名: Lancet. 2010 Jun 12;375(9731):2082-91. doi: 10.1016/S0140-6736(10)60278-4.
Abstract/Text BACKGROUND: Population and study design heterogeneity has confounded previous meta-analyses, leading to uncertainty about effectiveness and safety of elective high-frequency oscillatory ventilation (HFOV) in preterm infants. We assessed effectiveness of elective HFOV versus conventional ventilation in this group.
METHODS: We did a systematic review and meta-analysis of individual patients' data from 3229 participants in ten randomised controlled trials, with the primary outcomes of death or bronchopulmonary dysplasia at 36 weeks' postmenstrual age, death or severe adverse neurological event, or any of these outcomes.
FINDINGS: For infants ventilated with HFOV, the relative risk of death or bronchopulmonary dysplasia at 36 weeks' postmenstrual age was 0.95 (95% CI 0.88-1.03), of death or severe adverse neurological event 1.00 (0.88-1.13), or any of these outcomes 0.98 (0.91-1.05). No subgroup of infants (eg, gestational age, birthweight for gestation, initial lung disease severity, or exposure to antenatal corticosteroids) benefited more or less from HFOV. Ventilator type or ventilation strategy did not change the overall treatment effect.
INTERPRETATION: HFOV seems equally effective to conventional ventilation in preterm infants. Our results do not support selection of preterm infants for HFOV on the basis of gestational age, birthweight for gestation, initial lung disease severity, or exposure to antenatal corticosteroids.
FUNDING: Nestlé Belgium, Belgian Red Cross, and Dräger International.

PMID 20552718  Lancet. 2010 Jun 12;375(9731):2082-91. doi: 10.1016/S01・・・
著者: David J Henderson-Smart, Antonio G De Paoli, Reese H Clark, Tushar Bhuta
雑誌名: Cochrane Database Syst Rev. 2009 Jul 8;(3):CD002974. doi: 10.1002/14651858.CD002974.pub2. Epub 2009 Jul 8.
Abstract/Text BACKGROUND: Pulmonary disease is a major cause of mortality and morbidity in term and near term infants. Conventional ventilation (CV) has been used for many years but may lead to lung injury, require the subsequent use of more invasive treatment such as extracorporeal membrane oxygenation (ECMO), or result in death. There are some observational studies indicating that high frequency oscillatory ventilation (HFOV) may be more effective in these infants as compared to CV.
OBJECTIVES: To determine the effect of HFOV as compared with CV on mortality and morbidity in infants born at 35 weeks gestational age or more with severe respiratory failure requiring mechanical ventilation.
SEARCH STRATEGY: Standard search methods of the Cochrane Neonatal Review group were used. These included searches in January 2009 of The Cochrane Library, MEDLINE, EMBASE, previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants, and journal hand searching by the Cochrane Collaboration.
SELECTION CRITERIA: Randomized or quasi-randomized trials comparing HFOV and CV in term or near term infants with intractable respiratory failure were included in this review.
DATA COLLECTION AND ANALYSIS: The standard methods of the Cochrane Neonatal Review Group were used. The investigators separately extracted, assessed and coded all data for each study. Any disagreement was resolved by discussion. Data were synthesized using risk ratio [RR with (95% confidence intervals, CI)] and mean difference (with standard deviation, SD).
MAIN RESULTS: Two trials met the inclusion criteria. One trial involving the "elective" use of HFOV randomized 118 infants at the start of CV. The other trial of "rescue" HFOV randomized 81 infants with later respiratory failure on CV. Neither trial showed evidence of a reduction in mortality at 28 days or in failed therapy on the assigned mode of ventilation requiring cross-over to the other mode. Neither study reported significant differences in the risk of pulmonary air leak, chronic lung disease (28 days or more in oxygen) or intracranial injury. In the study of elective HFOV, there was no difference noted in days on a ventilator or days in hospital. In the one rescue study, there was no difference in the risk of needing extracorporeal membrane oxygenation.
AUTHORS' CONCLUSIONS: There are no data from randomized controlled trials supporting the use of rescue HFOV in term or near term infants with severe pulmonary dysfunction. The area is complicated by diverse pathology in such infants and by the occurrence of other interventions (surfactant, inhaled nitric oxide, inotropes). Randomized controlled trials are needed to establish the role of elective or rescue HFOV in near term and term infants with pulmonary dysfunction before widespread use of this mode of ventilation in such infants.

PMID 19588337  Cochrane Database Syst Rev. 2009 Jul 8;(3):CD002974. do・・・
著者: Filip Cools, David J Henderson-Smart, Martin Offringa, Lisa M Askie
雑誌名: Cochrane Database Syst Rev. 2009 Jul 8;(3):CD000104. doi: 10.1002/14651858.CD000104.pub3. Epub 2009 Jul 8.
Abstract/Text BACKGROUND: Respiratory failure due to lung immaturity is a major cause of mortality in preterm infants. Although the use of intermittent positive pressure ventilation (IPPV) in neonates with respiratory failure saves lives, its use is associated with lung injury and chronic lung disease (CLD). A newer form of ventilation called high frequency oscillatory ventilation (HFOV) has been shown to result in less lung injury in experimental studies.
OBJECTIVES: The objective of this review is to determine the effect of the elective use of high frequency oscillatory ventilation (HFOV) as compared to conventional ventilation (CV) on the incidence of chronic lung disease, mortality and other complications associated with prematurity and assisted ventilation in preterm infants who are mechanically ventilated for respiratory distress syndrome (RDS).
SEARCH STRATEGY: Searches were made of the Oxford Database of Perinatal Trials, MEDLINE, EMBASE, previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants, journal hand searching by the Cochrane Collaboration, mainly in the English language. The search was updated in January 2009.
SELECTION CRITERIA: Randomised controlled trials comparing HFOV and CV in preterm or low birth weight infants with pulmonary dysfunction, mainly due to RDS, who required assisted ventilation. Randomisation and commencement of treatment needed to be as soon as possible after the start of CV and usually in the first 12 hours of life.
DATA COLLECTION AND ANALYSIS: The methodological quality of each trial was independently reviewed by the various authors. The standard effect measures are relative risk (RR) and risk difference (RD). From 1/RD the number needed to treat (NNT) to produce one outcome were calculated. For all measures of effect, 95% confidence intervals were used. In subgroup analyses the 99% CIs are also given for summary RRs in the text. Meta-analysis was performed using a fixed effects model. Where heterogeneity was over 50%, the random effects RR is also given.
MAIN RESULTS: Seventeen eligible studies of 3,652 infants were included. Meta-analysis comparing HFOV with CV revealed no evidence of effect on mortality at 28 - 30 days of age or at approximately term equivalent age. These results were consistent across studies and in subgroup analyses. The effect of HFOV on CLD in survivors at term equivalent gestational age was inconsistent across studies and the reduction was of borderline significance overall. The effect was similar in trials with a high lung volume strategy for HFOV targeting at very low FiO(2) and trials with a high lung volume strategy with somewhat higher or unspecified target FiO(2). Subgroups of trials showed a significant reduction in CLD with HFOV when no surfactant was used, when piston oscillators were used for HFOV, when lung protective strategies for CV were not used, when randomisation occurred at two to six hours of age, and when inspiratory:expiratory ratio of 1:2 was used for HFOV. In the meta-analysis of all trials, pulmonary air leaks occurred more frequently in the HFOV group.In some studies, short-term neurological morbidity with HFOV was found, but this effect was not statistically significant overall. The subgroup of two trials not using a high volume strategy with HFOV found increased rates of Grade 3 or 4 intraventricular haemorrhage and of periventricular leukomalacia. An adverse effect of HFOV on long-term neurodevelopment was found in one large trial but not in the five other trials that reported this outcome. The rate of retinopathy of prematurity is reduced overall in the HFOV group.
AUTHORS' CONCLUSIONS: There is no clear evidence that elective HFOV offers important advantages over CV when used as the initial ventilation strategy to treat preterm infants with acute pulmonary dysfunction. There may be a small reduction in the rate of CLD with HFOV use, but the evidence is weakened by the inconsistency of this effect across trials and the overall borderline significance. Future trials on elective HFOV should target those infants who are at most risk of CLD (extremely preterm infants), compare different strategies for generating HFOV and CV, and report important long-term neurodevelopmental outcomes.

PMID 19588317  Cochrane Database Syst Rev. 2009 Jul 8;(3):CD000104. do・・・
著者: V H Joshi, T Bhuta
雑誌名: Cochrane Database Syst Rev. 2006 Jan 25;(1):CD000437. doi: 10.1002/14651858.CD000437.pub2. Epub 2006 Jan 25.
Abstract/Text BACKGROUND: Chronic pulmonary disease is a major cause of mortality and morbidity in very low birth weight infants despite increased use of antenatal steroids and surfactant therapy. Ventilator injury and oxygen toxicity are thought to be important factors in the pathogenesis of chronic pulmonary disease. There is evidence in animal studies and adult human studies that high frequency jet ventilation may reduce the severity of lung injury associated with mechanical ventilation.
OBJECTIVES: In preterm infants with severe pulmonary dysfunction, does the use of high frequency jet ventilation (HFJV) compared to conventional ventilation (CV) reduce mortality and morbidity without an increase in adverse effects?
SEARCH STRATEGY: We searched MEDLINE (1966 - August 2005), Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2005), and EMBASE (1988 - August 2005). Information was also obtained from experts in the field and cross references were checked.
SELECTION CRITERIA: Randomized and quasi-randomized controlled trials of rescue high frequency jet ventilation versus conventional ventilation in preterm infants born at less than 35 weeks of gestation or with a birth weight less than 2000 grams with respiratory distress were included in the systematic review.
DATA COLLECTION AND ANALYSIS: The standard methods of the Cochrane Neonatal Review Group were used, including independent trial assessment and data extraction. Data were analysed using relative risk (RR) and risk difference (RD).
MAIN RESULTS: Two randomized trials were identified. One trial (Engle 1997) was excluded as the study was restricted to term and near-term infants. The included trial (Keszler 1991) randomized 166 preterm infants and reported data on 144 infants. Cross-over to the alternate treatment was permitted if the initial treatment failed. There was no statistically significant difference in the overall mortality (including survival after cross-over) between the two groups [RR 1.07, (95% CI 0.67, 1.72)]. The survival by original assignment was identical. In a secondary analysis, the study demonstrated rescue treatment with HFJV, up until the time of cross-over, was associated with lower mortality, [RR 0.66 (95% CI 0.45,0.97)]. No significant differences were found in the incidence of CLD in survivors at 28 days of age, IVH, new air leaks, airway obstruction and necrotizing tracheobronchitis.
AUTHORS' CONCLUSIONS: There was no significant difference in the overall mortality between rescue high frequency jet ventilation and conventional groups. In a secondary analysis, rescue treatment with HFJV, up until the time of cross-over, was associated with lower mortality. There was no significant increase in adverse effects like intraventricular hemorrhage, new air leaks, airway obstruction and necrotizing tracheobronchitis with rescue high frequency jet ventilation. The included study was done before the introduction of surfactant and widespread use of antenatal steroids. The number of infants included was small and there were high numbers of post randomization exclusions. Due to the crossover design and small numbers of infants in the included study, there is insufficient information to assess the effectiveness of rescue HFJV in preterm infants. Studies that target the most at-risk population and have appropriate power to assess some of the important outcomes are needed. These trials would also need to incorporate long term pulmonary and neurodevelopmental outcomes.

PMID 16437423  Cochrane Database Syst Rev. 2006 Jan 25;(1):CD000437. d・・・

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