今日の臨床サポート

輸血後の肺合併症

著者: 岡崎仁 東京大学医学部附属病院輸血部

監修: 長瀬隆英 東京大学 内科学専攻器官病態内科学講座

著者校正/監修レビュー済:2019/05/09
患者向け説明資料

概要・推奨   

  1. 輸血によるアナフィラキシーの治療は、通常のアナフィラキシーの治療と同様である。アドレナリンが初期治療に用いられてはいるが、アドレナリンと偽薬/無治療/他のアドレナリン作動薬とのランダム化比較試験の報告がないために新たにこれを推奨するという結論には至っていないが、初期治療としてアドレナリンの筋注はおそらく推奨される(推奨度2)。
  1. 輸血によるアナフィラキシーの治療薬は、通常のアナフィラキシーの治療と同様である。ステロイドのアナフィラキシーに対する緊急治療薬としての有効性に関するエビデンスは乏しく、投与に関しては推奨も否定もしないが、アナフィラキシーを起こした患者に喘息や遷延または遅発型薬物アレルギーの既往のある場合に投与はおそらく推奨される(推奨度3)。
  1. 抗ヒスタミン薬のアナフィラキシー治療における有用性については、エビデンスに乏しく推奨されない。ただし、随伴する蕁麻疹、掻痒感、鼻炎症状などの局所的症状には効果があるとされているが、気道狭窄などには効果は期待できない(推奨度3)。
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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:
岡崎仁 : 講演料(日本赤十字社)[2021年]
監修:長瀬隆英 : 講演料(アストラゼネカ),研究費・助成金など(中外製薬)[2021年]

改訂のポイント:
  1. 定期レビューを行い、準拠ガイドラインを追加した。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 輸血のアレルギー性副作用(アナフィラキシー)の部分症状としての喉頭浮腫、喘息様気管支攣縮も呼吸困難を来す重篤な肺合併症であり、胸部X線写真上は異常を示さないことが多い。重篤なアナフィラキシーに至る頻度は1:20,000~47,000といわれており、米国FDAの統計でも死亡例も年間1~2例である。原因不明の場合が多いが、原因の特定されたものとしては患者の蛋白欠損(ハプトグロビン、IgAなど)がある。
  1. 輸血による肺合併症のなかで、最も注目を集めているのは輸血関連急性肺障害(TRALI)であり、輸血中もしくは輸血後6時間以内(多くは2時間以内)に急性肺障害/急性呼吸窮迫症候群(ALI/ARDS)を起こす。人工呼吸管理を要するような重篤な呼吸不全を呈することが多いが、予後は一般のALI/ARDSよりもよいといわれている。頻度は患者の原疾患の重篤度などにより違いがある可能性があるが、1:1,300~1:5,000程度といわれている。米国FDAには輸血関連の原因による、毎年15例程度の死亡例の報告がある。重症患者における頻度はこれよりも高いといわれており、1つの前方視的研究では輸血バッグあたり1.1%、輸血された患者あたり8%、1つの後方視的研究では輸血バッグあたり0.9%、輸血された患者あたり5.1%となっている。
  1. 実際には輸血による容量負荷のための心原性肺水腫ではあるが、頻度が多いため肺合併症として認識されてしまう輸血関連循環過負荷(transfusion associated circulatory overload:TACO)と最近呼ばれるようになった病態が存在する。特に幼児、高齢者において多くみられる。
病歴・診察のポイント  
  1. アレルギー性の副作用の場合は皮膚の症状などがでることが多いのでその確認を行う。TACO(心不全)の場合は起座呼吸、頚静脈怒張、頻脈、血圧上昇、心音でのS3(+)、下肢の浮腫などの症状に注意。心エコーでのIVC径の確認。

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文献 

著者: Steven Kleinman, Tim Caulfield, Penny Chan, Robertson Davenport, Janice McFarland, Susan McPhedran, Maureen Meade, Douglas Morrison, Thomas Pinsent, Pierre Robillard, Peter Slinger
雑誌名: Transfusion. 2004 Dec;44(12):1774-89. doi: 10.1111/j.0041-1132.2004.04347.x.
Abstract/Text
PMID 15584994  Transfusion. 2004 Dec;44(12):1774-89. doi: 10.1111/j.00・・・
著者: G R Bernard, A Artigas, K L Brigham, J Carlet, K Falke, L Hudson, M Lamy, J R Legall, A Morris, R Spragg
雑誌名: Am J Respir Crit Care Med. 1994 Mar;149(3 Pt 1):818-24. doi: 10.1164/ajrccm.149.3.7509706.
Abstract/Text The acute respiratory distress syndrome (ARDS), a process of nonhydrostatic pulmonary edema and hypoxemia associated with a variety of etiologies, carries a high morbidity, mortality (10 to 90%), and financial cost. The reported annual incidence in the United States is 150,000 cases, but this figure has been challenged, and it may be different in Europe. Part of the reason for these uncertainties are the heterogeneity of diseases underlying ARDS and the lack of uniform definitions for ARDS. Thus, those who wish to know the true incidence and outcome of this clinical syndrome are stymied. The American-European Consensus Committee on ARDS was formed to focus on these issues and on the pathophysiologic mechanisms of the process. It was felt that international coordination between North America and Europe in clinical studies of ARDS was becoming increasingly important in order to address the recent plethora of potential therapeutic agents for the prevention and treatment of ARDS.

PMID 7509706  Am J Respir Crit Care Med. 1994 Mar;149(3 Pt 1):818-24.・・・
著者: Rutger A Middelburg, Daniëlle van Stein, Ernest Briët, Johanna G van der Bom
雑誌名: Transfusion. 2008 Oct;48(10):2167-76. doi: 10.1111/j.1537-2995.2008.01810.x. Epub 2008 Jun 28.
Abstract/Text BACKGROUND: The majority of cases of transfusion-related acute lung injury (TRALI) are thought to be caused by the presence of leukocyte antibodies in the blood of the donor. We performed a systematic search of the literature to quantify the contribution of donor antibodies to the occurrence of TRALI.
STUDY DESIGN AND METHODS: We conducted a systematic search of the PubMed and EMBASE databases. Retrieved articles were judged by three authors independently. Reference lists of all articles were subsequently screened for relevant references. All articles in English, German, French, and Dutch, published at any time before December 2007, were eligible for inclusion.
RESULTS: Of 77 articles on leukocyte antibodies in donors involved in a case of TRALI, 14 articles contained sufficient data. These 14 articles reported leukocyte antibodies in 24 of 51 donors (47%) associated with 24 of 28 TRALI cases (86%). Of 15 articles that reported the prevalence of leukocyte antibodies in the general donor population, 2 articles reported a prevalence of 17 percent in (452) randomly selected donors. The odds ratio for developing TRALI was 15 (95% confidence interval [CI], 5.1-45) for patients who received a transfusion from a donor who tested positive for the presence of leukocyte antibodies, compared to donors who tested negative. Leukocyte antibodies contributed to 80 percent (95% CI, 51%-92%) of all TRALI cases.
CONCLUSION: Leukocyte antibodies were more prevalent in donors involved in TRALI cases than among randomly selected donors. These findings suggest that donor antibodies contribute to four-fifths of all TRALI cases.

PMID 18564387  Transfusion. 2008 Oct;48(10):2167-76. doi: 10.1111/j.15・・・
著者: Steven H Kleinman, Darrell J Triulzi, Edward L Murphy, Patricia M Carey, Jerome L Gottschall, John D Roback, Danielle Carrick, Sunitha Mathew, David J Wright, Ritchard Cable, Paul Ness, Ognjen Gajic, Rolf D Hubmayr, Mark R Looney, Ram M Kakaiya, National Heart, Lung, and Blood Institute Retrovirus Epidemiology Donor Study-II
雑誌名: Transfusion. 2011 Oct;51(10):2078-91. doi: 10.1111/j.1537-2995.2011.03120.x. Epub 2011 Mar 29.
Abstract/Text BACKGROUND: We used a multicenter retrospective cohort study design to evaluate whether human leukocyte antigen (HLA) antibody donor screening would reduce the risk of transfusion-related acute lung injury (TRALI) or possible TRALI.
STUDY DESIGN AND METHODS: In the Leukocyte Antibody Prevalence Study-II (LAPS-II), we evaluated pulmonary outcomes in recipients of 2596 plasma-rich blood components (transfusable plasma and plateletpheresis) sent to participating hospitals; half of the components were collected from anti-HLA-positive donors (study arm) and half from anti-HLA-negative donors (control arm) matched by sex, parity, and blood center. A staged medical record review process was used. Final recipient diagnosis was based on case review by a blinded expert panel of pulmonary or critical care physicians.
RESULTS: TRALI incidence was 0.59% (seven cases) in study arm recipients versus 0.16% (two cases) in control arm recipients for an odds ratio (OR) of 3.6 (95% confidence interval [CI], 0.7-17.4; p = 0.10). For possible TRALI cases (nine study arm, eight control arm), the OR was 1.2 (95% CI, 0.4-3.0; p = 0.81), and for TRALI and possible TRALI aggregated together, it was 1.7 (95% CI, 0.7-3.7; p = 0.24). Transfusion-associated circulatory overload incidence was identical in the two arms (1.17 and 1.22%, respectively; OR, 1.0; p = 1.0).
CONCLUSIONS: TRALI incidence in recipients of anti-HLA-positive components was relatively low for a lookback study (1 in 170) and was higher than in the control arm, but did not reach significance. Based on this trend, the data are consistent with the likelihood that TRALI risk is decreased by selecting high-volume plasma components for transfusion from donors at low risk of having HLA antibodies.

© 2011 American Association of Blood Banks.
PMID 21446938  Transfusion. 2011 Oct;51(10):2078-91. doi: 10.1111/j.15・・・
著者: Shiho Hashimoto, Fumiaki Nakajima, Hiromi Kamada, Kumiko Kawamura, Masahiro Satake, Kenji Tadokoro, Hitoshi Okazaki
雑誌名: Transfusion. 2010 Dec;50(12):2582-91. doi: 10.1111/j.1537-2995.2010.02779.x.
Abstract/Text BACKGROUND: Antibodies against the human leukocyte antigen (HLA) in donors' blood are implicated in the development of transfusion-related acute lung injury (TRALI). Screening of female donors for HLA antibodies has been introduced to prevent TRALI; however, the relationship of HLA antibody strength in the transfused components to the development of TRALI has not been evaluated in detail.
STUDY DESIGN AND METHODS: Donors involved in 1038 cases of nonhemolytic transfusion reactions (NHTRs) including 283 cases of TRALI were screened for HLA antibodies by the fluorescence beads method. HLA antibody specificity and strength were analyzed in detail. The usefulness of enzyme-linked immunosorbent assay (ELISA) for screening HLA antibodies was also evaluated.
RESULT: Among 21 cases of TRALI, four cases of possible TRALI, and five cases of other NHTRs, the sum of mean fluorescence intensity (MFI) of donors' HLA antibodies to patients' cognate antigen(s) was determined in 18, four, and three cases, respectively. The sum of MFI in TRALI cases was significantly higher than that in other NHTR cases (p<0.05). When HLA antibody-positive samples were reevaluated by ELISA, the ELISA optical density ratio was significantly higher in donors' samples associated with TRALI than in those associated with other NHTRs (p<0.01)
CONCLUSIONS: A correlation between the HLA antibody strength and development of TRALI was indicated. The antibody strength measured by ELISA could be used as the basis for the screening of HLA antibodies in place of the fluorescence beads method. This study provided clues to the establishment of a cutoff value for HLA antibody screening in an evidence-based manner for the prevention of TRALI.

© 2010 American Association of Blood Banks.
PMID 20667042  Transfusion. 2010 Dec;50(12):2582-91. doi: 10.1111/j.15・・・
著者: Lan Zhou, Donald Giacherio, Laura Cooling, Robertson D Davenport
雑誌名: Transfusion. 2005 Jul;45(7):1056-63. doi: 10.1111/j.1537-2995.2005.04326.x.
Abstract/Text BACKGROUND: Transfusion-associated circulatory overload (TACO) occurs when the transfusion rate or volume exceeds the capacity of a compromised cardiovascular system. Characteristic symptoms and signs associated with TACO are neither sensitive nor specific. B-natriuretic peptide (BNP) is a 32-amino-acid polypeptide secreted from the cardiac ventricles in response to ventricular volume expansion and pressure overload. This study was performed to explore the usage of BNP in the differential diagnosis of TACO.
STUDY DESIGN AND METHODS: Pre- and posttransfusion BNP levels were determined in 21 patients with suspected TACO and 19 control patients. The BNP was considered significant if the posttransfusion-to-pretransfusion ratio was at least 1.5 and the posttransfusion BNP level was at least 100 pg per mL.
RESULTS: The BNP test has a sensitivity and specificity of 81 and 89 percent, respectively, in diagnosis of TACO. It has a positive predictive value of 89 percent, a negative predictive value of 81 percent, and an accuracy of 87 percent. In logistic regression analysis, BNP was found to have significant predictive power independent of other clinical variables in models predicting which patients had TACO.
CONCLUSIONS: Our study suggests that in patients who present symptoms suggestive of TACO, BNP can be a useful adjunct marker in confirming volume overload as the cause of acute dyspnea and symptoms related to cardiovascular compromise.

PMID 15987348  Transfusion. 2005 Jul;45(7):1056-63. doi: 10.1111/j.153・・・
著者: Aaron A R Tobian, Lori J Sokoll, Daniel J Tisch, Paul M Ness, Hua Shan
雑誌名: Transfusion. 2008 Jun;48(6):1143-50. doi: 10.1111/j.1537-2995.2008.01656.x. Epub 2008 Feb 22.
Abstract/Text BACKGROUND: Transfusion-associated circulatory overload (TACO) can be difficult to diagnose and distinguish from transfusion-related acute lung injury (TRALI), but is a relatively common complication that occurs when increases in blood volume overwhelm the cardiovascular system. Brain natriuretic peptide (BNP) has been shown to be a functional marker for TACO. N-terminal pro-brain natriuretic peptide (NT-proBNP) is another marker that could be more helpful than BNP since it has a longer half-life in circulation and is also much more stable in laboratory samples. In this study, whether NT-proBNP is a useful diagnostic marker for TACO was evaluated.
STUDY DESIGN AND METHODS: Forty patients were enrolled into a case-control study (16 patients with TACO and 24 control patients) and had pre- and posttransfusion NT-proBNP concentrations evaluated from submitted type-and-screen blood samples.
RESULTS: The sensitivity of elevated posttransfusion NT-proBNP to diagnose TACO was 93.8 percent, the specificity was 83.8 percent, and the accuracy was 87.5 percent. Elevated posttransfusion NT-proBNP is the only independent variable for the diagnosis of TACO based on multivariate logistic regression.
CONCLUSION: NT-proBNP is both a sensitive and a specific marker for TACO and can be helpful in confirming transfusion associated fluid overload. This study also demonstrates that many patients who experience TACO may already be in a state of excess volume. Clinicians should be aware that many asymptomatic patients have excess fluid and transfusion may cause these patients to become symptomatic.

PMID 18298592  Transfusion. 2008 Jun;48(6):1143-50. doi: 10.1111/j.153・・・
著者: Guangxi Li, Craig E Daniels, Marija Kojicic, Tami Krpata, Greg A Wilson, Jeffrey L Winters, S Breanndan Moore, Ognjen Gajic
雑誌名: Transfusion. 2009 Jan;49(1):13-20. doi: 10.1111/j.1537-2995.2008.01941.x. Epub 2008 Oct 14.
Abstract/Text BACKGROUND: The diagnostic workup of transfusion-related acute lung injury (TRALI) requires an exclusion of transfusion-associated circulatory overload (TACO). Brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic (NT-pro-BNP) accurately diagnosed TACO in preliminary studies that did not include patients with TRALI.
STUDY DESIGN AND METHODS: In this prospective cohort study, two critical care experts blinded to serum levels of BNP and NT-pro-BNP determined the diagnosis of TRALI, TACO, and possible TRALI based on the consensus conference definitions. The accuracy of BNP and NT-pro-BNP was assessed based on the area under the receiver operating curve (AUC).
RESULTS: Of 115 patients who developed acute pulmonary edema after transfusion, 34 were identified with TRALI, 31 with possible TRALI, and 50 with TACO. Median BNP was 375 pg per mL (interquartile range [IQR], 123 to 781 pg/mL) in TRALI, 446 pg per mL (IQR, 128 to 743 pg/mL) in possible TRALI, and 559 pg per mL (IQR, 288 to 1348 pg/mL) in TACO patients (p = 0.038). The NT-pro-BNP levels among patients with TRALI, possible TRALI, and TACO differed significantly with a median value of 1559 pg per mL (IQR, 629 to 5114 pg/mL), 2349 pg/mL (IQR, 919 to 4610 pg/mL), and 5197 pg/mL (IQR, 1695 to 15,714 pg/mL; p = 0.004), respectively. The accuracy of BNP and NT-pro-BNP to diagnose TACO was moderate with an AUC of 0.63 (95% confidence interval [CI], 0.51-0.74) and 0.70 (95% CI, 0.59 to 0.80).
CONCLUSIONS: Natriuretic peptides are of limited diagnostic value in a differential diagnosis of pulmonary edema after transfusion in the critically ill patients.

PMID 18954397  Transfusion. 2009 Jan;49(1):13-20. doi: 10.1111/j.1537-・・・
著者: A Sheikh, Y A Shehata, S G A Brown, F E R Simons
雑誌名: Allergy. 2009 Feb;64(2):204-12. doi: 10.1111/j.1398-9995.2008.01926.x.
Abstract/Text BACKGROUND: Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death. Adrenaline is recommended as the initial treatment of choice for anaphylaxis.
OBJECTIVES: To assess the benefits and harms of adrenaline in the treatment of anaphylaxis.
METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, Issue 1), MEDLINE (1966 to March 2007), EMBASE (1966 to March 2007), CINAHL (1982 to March 2007), BIOSIS (to March 2007), ISI Web of Knowledge (to March 2007) and LILACS (to March 2007). We also searched websites listing ongoing trials: http://www.clinicaltrials.gov/, http://www.controlledtrials.com and http://www.actr.org.au/ and contacted pharmaceutical companies and international experts in anaphylaxis in an attempt to locate unpublished material. Randomized and quasi-randomized controlled trials comparing adrenaline with no intervention, placebo or other adrenergic agonists were eligible for inclusion. Two authors independently assessed articles for inclusion.
RESULTS: We found no studies that satisfied the inclusion criteria.
CONCLUSIONS: On the basis of this review, we are unable to make any new recommendations on the use of adrenaline for the treatment of anaphylaxis. In the absence of appropriate trials, we recommend, albeit on the basis of less than optimal evidence, that adrenaline administration by intramuscular injection should still be regarded as first-line treatment for the management of anaphylaxis.

PMID 19178399  Allergy. 2009 Feb;64(2):204-12. doi: 10.1111/j.1398-999・・・
著者: Terry L Vanden Hoek, Laurie J Morrison, Michael Shuster, Michael Donnino, Elizabeth Sinz, Eric J Lavonas, Farida M Jeejeebhoy, Andrea Gabrielli
雑誌名: Circulation. 2010 Nov 2;122(18 Suppl 3):S829-61. doi: 10.1161/CIRCULATIONAHA.110.971069.
Abstract/Text
PMID 20956228  Circulation. 2010 Nov 2;122(18 Suppl 3):S829-61. doi: 1・・・
著者: Jasmeet Soar, Gavin D Perkins, Gamal Abbas, Annette Alfonzo, Alessandro Barelli, Joost J L M Bierens, Hermann Brugger, Charles D Deakin, Joel Dunning, Marios Georgiou, Anthony J Handley, David J Lockey, Peter Paal, Claudio Sandroni, Karl-Christian Thies, David A Zideman, Jerry P Nolan
雑誌名: Resuscitation. 2010 Oct;81(10):1400-33. doi: 10.1016/j.resuscitation.2010.08.015.
Abstract/Text
PMID 20956045  Resuscitation. 2010 Oct;81(10):1400-33. doi: 10.1016/j.・・・
著者: K J L Choo, E Simons, Aziz Sheikh
雑誌名: Allergy. 2010 Oct;65(10):1205-11. doi: 10.1111/j.1398-9995.2010.02424.x. Epub 2010 Jun 18.
Abstract/Text BACKGROUND: Anaphylaxis is a serious hypersensitivity reaction that is rapid in onset and may result in death. A number of guidelines recommend glucocorticoids for the treatment of people experiencing anaphylaxis.
OBJECTIVES: We sought to assess the benefits and harms of glucocorticoid treatment during episodes of anaphylaxis.
METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, Issue 3), MEDLINE (Ovid) (1966 to September 2009), EMBASE (Ovid) (1988 to September 2009), CINAHL (EBSCOhost) (to September 2009) and The Science Citation Index Expanded (SCI-EXPANDED) (1945 to September 2009). We also searched the UK National Research Register and websites listing ongoing trials and contacted international experts in anaphylaxis in an attempt to locate unpublished material. We sought to include randomized and quasi-randomized controlled trials comparing glucocorticoids with any control (either placebo, adrenaline (epinephrine), an antihistamine, or any combination of these). Two authors independently assessed articles for inclusion.
RESULTS: None of the 2496 reports identified satisfied the inclusion criteria.
CONCLUSIONS: We conclude that there is no evidence from high-quality studies for the use of steroids in the emergency management of anaphylaxis. Therefore, we can neither support nor refute the use of these drugs for this purpose.

PMID 20584003  Allergy. 2010 Oct;65(10):1205-11. doi: 10.1111/j.1398-9・・・
著者: A Sheikh, V Ten Broek, S G A Brown, F E R Simons
雑誌名: Allergy. 2007 Aug;62(8):830-7. doi: 10.1111/j.1398-9995.2007.01435.x.
Abstract/Text BACKGROUND: Anaphylaxis is an acute systemic allergic reaction, which can be life-threatening. H(1)-antihistamines are commonly used as an adjuvant therapy in the treatment of anaphylaxis. We sought to assess the benefits and harm of H(1)-antihistamines in the treatment of anaphylaxis.
METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library); MEDLINE (1966 to June 2006); EMBASE (1966 to June 2006); CINAHL (1982 to June 2006) and ISI Web of Science (1945 to July 2006). We also contacted pharmaceutical companies and international experts in anaphylaxis in an attempt to locate unpublished material. Randomized and quasi-randomized-controlled trials comparing H(1)-antihistamines with placebo or no intervention were eligible for inclusion. Two authors independently assessed articles for inclusion.
RESULTS: We found no studies that satisfied the inclusion criteria.
CONCLUSIONS: Based on this review, we are unable to make any recommendations for clinical practice. Randomized-controlled trials are needed, although these are likely to prove challenging to design and execute.

PMID 17620060  Allergy. 2007 Aug;62(8):830-7. doi: 10.1111/j.1398-9995・・・
著者: Ritesh Agarwal, Alok Nath, Ashutosh N Aggarwal, Dheeraj Gupta
雑誌名: Respirology. 2007 Jul;12(4):585-90. doi: 10.1111/j.1440-1843.2007.01060.x.
Abstract/Text BACKGROUND AND OBJECTIVES: Glucocorticoids have been shown to improve survival when used in patients with septic shock. The aim of this study was to analyse the role of glucocorticoids in decreasing mortality in acute respiratory distress syndrome (ARDS) both in the acute and the fibroproliferative phases.
METHODS: We searched the MEDLINE database for relevant studies published between 1980 and 2006, and included studies if the study design was a randomized controlled trial or observational study (comparing historical controls). The study population included patients with ARDS treated with glucocorticoids. We calculated the odds ratio and 95% confidence intervals (CI) for the outcome of mortality.
RESULTS: Six trials met the inclusion criteria; three investigated the role of steroids in early stage disease (n = 300) and three investigated the role of steroids in late stage disease (n = 235). The odds of glucocorticoids decreasing mortality in patients with early ARDS were 0.57 (95% CI: 0.25-1.32) with a number needed to treat of 10 for benefit (818 harm to 5 benefit) whereas the odds of glucocorticoids decreasing mortality in patients with late ARDS was 0.58 (95% CI: 0.22-1.53) with a number needed to treat of 15 for harm (6 harm to 21 benefit). However, there was significant heterogeneity.
CONCLUSIONS: Current evidence does not support a role for corticosteroids in the management of ARDS in either the early or late stages of the disease. More research is required to establish the role of steroids in specific subgroups of patients with severe sepsis and early ARDS who have relative adrenal insufficiency and patients with late ARDS 7-14 days after the onset of disease.

PMID 17587427  Respirology. 2007 Jul;12(4):585-90. doi: 10.1111/j.1440・・・
著者: John Victor Peter, Preeta John, Petra L Graham, John L Moran, Ige Abraham George, Andrew Bersten
雑誌名: BMJ. 2008 May 3;336(7651):1006-9. doi: 10.1136/bmj.39537.939039.BE. Epub 2008 Apr 23.
Abstract/Text OBJECTIVE: To systematically review the efficacy of steroids in the prevention of acute respiratory distress syndrome (ARDS) in critically ill adults, and treatment for established ARDS.
DATA SOURCES: Search of randomised controlled trials (1966-April 2007) of PubMed, Cochrane central register of controlled trials, Cochrane database of systematic reviews, American College of Physicians Journal Club, health technology assessment database, and database of abstracts of reviews of effects.
DATA EXTRACTION: Two investigators independently assessed trials for inclusion and extracted data into standardised forms; differences were resolved by consensus.
DATA SYNTHESIS: Steroid efficacy was assessed through a Bayesian hierarchical model for comparing the odds of developing ARDS and mortality (both expressed as odds ratio with 95% credible interval) and duration of ventilator free days, assessed as mean difference. Bayesian outcome probabilities were calculated as the probability that the odds ratio would be > or =1 or the probability that the mean difference would be > or =0. Nine randomised trials using variable dose and duration of steroids were identified. Preventive steroids (four studies) were associated with a trend to increase both the odds of patients developing ARDS (odds ratio 1.55, 95% credible interval 0.58 to 4.05; P(odds ratio > or =1)=86.6%), and the risk of mortality in those who subsequently developed ARDS (three studies, odds ratio 1.52, 95% credible interval 0.30 to 5.94; P(odds ratio > or =1)=72.8%). Steroid administration after onset of ARDS (five studies) was associated with a trend towards reduction in mortality (odds ratio 0.62, 95% credible interval 0.23 to 1.26; P(odds ratio > or =1)=6.8%). Steroid therapy increased the number of ventilator free days compared with controls (three studies, mean difference 4.05 days, 95% credible interval 0.22 to 8.71; P(mean difference > or =0)=97.9%). Steroids were not associated with increase in risk of infection.
CONCLUSIONS: A definitive role of corticosteroids in the treatment of ARDS in adults is not established. A possibility of reduced mortality and increased ventilator free days with steroids started after the onset of ARDS was suggested. Preventive steroids possibly increase the incidence of ARDS in critically ill adults.

PMID 18434379  BMJ. 2008 May 3;336(7651):1006-9. doi: 10.1136/bmj.3953・・・
著者: G Umberto Meduri, Emmel Golden, Amado X Freire, Edwin Taylor, Muhammad Zaman, Stephanie J Carson, Mary Gibson, Reba Umberger
雑誌名: Chest. 2007 Apr;131(4):954-63. doi: 10.1378/chest.06-2100.
Abstract/Text OBJECTIVE: To determine the effects of low-dose prolonged methylprednisolone infusion on lung function in patients with early severe ARDS.
DESIGN: Randomized, double-blind, placebo-controlled trial.
SETTING: ICUs of five hospitals in Memphis.
PARTICIPANTS: Ninety-one patients with severe early ARDS (INTERVENTIONS: Patients were randomized (2:1 fashion) to methylprednisolone infusion (1 mg/kg/d) vs placebo. The duration of treatment was up to 28 days. Infection surveillance and avoidance of paralysis were integral components of the protocol.
MAIN OUTCOME MEASURE: The predefined primary end point was a 1-point reduction in lung injury score (LIS) or successful extubation by day 7.
RESULTS: In intention-to-treat analysis, the response of the two groups (63 treated and 28 control) clearly diverged by day 7, with twice the proportion of treated patients achieving a 1-point reduction in LIS (69.8% vs 35.7%; p = 0.002) and breathing without assistance (53.9% vs 25.0%; p = 0.01). Treated patients had significant reduction in C-reactive protein levels, and by day 7 had lower LIS and multiple organ dysfunction syndrome scores. Treatment was associated with a reduction in the duration of mechanical ventilation (p = 0.002), ICU stay (p = 0.007), and ICU mortality (20.6% vs 42.9%; p = 0.03). Treated patients had a lower rate of infections (p = 0.0002), and infection surveillance identified 56% of nosocomial infections in patients without fever.
CONCLUSIONS: Methylprednisolone-induced down-regulation of systemic inflammation was associated with significant improvement in pulmonary and extrapulmonary organ dysfunction and reduction in duration of mechanical ventilation and ICU length of stay.

PMID 17426195  Chest. 2007 Apr;131(4):954-63. doi: 10.1378/chest.06-21・・・
著者: Bernhardt G Zeiher, Antonio Artigas, Jean-Louis Vincent, Alexei Dmitrienko, Kimberley Jackson, B Taylor Thompson, Gordon Bernard, STRIVE Study Group
雑誌名: Crit Care Med. 2004 Aug;32(8):1695-702.
Abstract/Text OBJECTIVE: Neutrophil elastase is believed to be an important mediator of acute lung injury. Sivelestat (ONO-5046, Elaspol) is a small molecular weight inhibitor of neutrophil elastase. The primary objectives of this study were to determine whether sivelestat would reduce 28-day all-cause mortality or increase the number of ventilator-free days (days alive and free from mechanical ventilation from day 1 to day 28) compared with placebo in mechanically ventilated patients with acute lung injury.
DESIGN: Multiple-center, double-blind, placebo-controlled trial administering a continuous infusion of sivelestat at a dose of 0.16 mg.kg(-1)hr(-1).
SETTING: One hundred and five institutions in the United States, Canada, Belgium, Spain, Australia, and New Zealand.
PATIENTS: A total of 492 mechanically ventilated patients with acute lung injury.
INTERVENTIONS: Patients were randomized in a 1:1 fashion to sivelestat or placebo. Study drug was administered as a continuous infusion for the duration of mechanical ventilation plus 24 hrs for a maximum of 14 days. All patients were managed using low tidal volume mechanical ventilation.
MEASUREMENTS AND MAIN RESULTS: The study was stopped prematurely at the recommendation of an external Data and Safety Monitoring Board, which noted a negative trend in long-term mortality rate. Final analysis revealed no effect of sivelestat on the primary end points of ventilator-free days (day 1-day 28) or 28-day all-cause mortality. There were 64 deaths in each treatment group within the 28-day study period, and the mean number of ventilator-free days was 11.4 and 11.9 in the sivelestat and placebo treatment groups, respectively (p =.536). There was no evidence of effect on measures of pulmonary function, including Pao2/Fio2, static lung compliance, and time to meeting weaning criteria. There was no difference in adverse events or serious adverse events between treatment groups. A comparison of the Kaplan-Meier 180-day survival curves showed no difference between treatment groups (p =.102), but there was an increase in 180-day all-cause mortality in the sivelestat treatment group compared with the placebo group (p =.006).
CONCLUSIONS: Intravenous sivelestat had no effect on 28-day all-cause mortality or ventilator-free days in a heterogeneous acute lung injury patient population managed with low tidal volume mechanical ventilation.

PMID 15286546  Crit Care Med. 2004 Aug;32(8):1695-702.
著者: Kentaro Iwata, Asako Doi, Goh Ohji, Hideaki Oka, Yuichiro Oba, Kohei Takimoto, Wataru Igarashi, David H Gremillion, Toshihiko Shimada
雑誌名: Intern Med. 2010;49(22):2423-32. Epub 2010 Nov 15.
Abstract/Text INTRODUCTION: Sivelestat is neutrophil elastase inhibitor, which is widely used in Japan for the treatment of acute lung injury. However, the clinical efficacy of the medication has not been convincingly demonstrated.
METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials on sivelestat for the treatment of acute lung injury and acute respiratory distress syndrome. Studies were identified using MEDLINE, EMBASE, Cochrane library, conference proceedings, and references of included studies. Authors were contacted if necessary. ICHUSHI, the Japanese database for medical literature and conference proceedings was also used for the search, since many studies on sivelestat were published in Japanese language and not registered in major databases such as MEDLINE. The primary outcome was mortality within 28-30 days after randomization. Relative risks were pooled with the random effect model.
RESULTS: 8 trials were included in the analysis. There was no difference in mortality within 28-30 days after randomization (relative risk 0.95, 95% confidence interval 0.72 to 1.26). Subgroup analysis conducted only on studies conducted in Japan showed the same result (0.59, 0.28 to 1.28). There was no difference in mechanical ventilation days (standardized mean difference -0.43, -1.12 to 0.27), but sivelestat was associated with a better short term PaO(2)/FiO(2) ratio (0.30, 0.05 to 0.56). Heterogeneity was not significant for the main analysis and funnel plot did not suggest publication bias.
CONCLUSION: Sivelestat was not associated with decreased mortality, even when including studies published in Japanese language.

PMID 21088343  Intern Med. 2010;49(22):2423-32. Epub 2010 Nov 15.
著者:
雑誌名: N Engl J Med. 2000 May 4;342(18):1301-8. doi: 10.1056/NEJM200005043421801.
Abstract/Text BACKGROUND: Traditional approaches to mechanical ventilation use tidal volumes of 10 to 15 ml per kilogram of body weight and may cause stretch-induced lung injury in patients with acute lung injury and the acute respiratory distress syndrome. We therefore conducted a trial to determine whether ventilation with lower tidal volumes would improve the clinical outcomes in these patients.
METHODS: Patients with acute lung injury and the acute respiratory distress syndrome were enrolled in a multicenter, randomized trial. The trial compared traditional ventilation treatment, which involved an initial tidal volume of 12 ml per kilogram of predicted body weight and an airway pressure measured after a 0.5-second pause at the end of inspiration (plateau pressure) of 50 cm of water or less, with ventilation with a lower tidal volume, which involved an initial tidal volume of 6 ml per kilogram of predicted body weight and a plateau pressure of 30 cm of water or less. The primary outcomes were death before a patient was discharged home and was breathing without assistance and the number of days without ventilator use from day 1 to day 28.
RESULTS: The trial was stopped after the enrollment of 861 patients because mortality was lower in the group treated with lower tidal volumes than in the group treated with traditional tidal volumes (31.0 percent vs. 39.8 percent, P=0.007), and the number of days without ventilator use during the first 28 days after randomization was greater in this group (mean [+/-SD], 12+/-11 vs. 10+/-11; P=0.007). The mean tidal volumes on days 1 to 3 were 6.2+/-0.8 and 11.8+/-0.8 ml per kilogram of predicted body weight (P<0.001), respectively, and the mean plateau pressures were 25+/-6 and 33+/-8 cm of water (P<0.001), respectively.
CONCLUSIONS: In patients with acute lung injury and the acute respiratory distress syndrome, mechanical ventilation with a lower tidal volume than is traditionally used results in decreased mortality and increases the number of days without ventilator use.

PMID 10793162  N Engl J Med. 2000 May 4;342(18):1301-8. doi: 10.1056/N・・・
著者: Peter Q Eichacker, Eric P Gerstenberger, Steven M Banks, Xizhong Cui, Charles Natanson
雑誌名: Am J Respir Crit Care Med. 2002 Dec 1;166(11):1510-4. doi: 10.1164/rccm.200208-956OC. Epub 2002 Aug 28.
Abstract/Text
PMID 12406836  Am J Respir Crit Care Med. 2002 Dec 1;166(11):1510-4. d・・・
著者: National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Arthur P Wheeler, Gordon R Bernard, B Taylor Thompson, David Schoenfeld, Herbert P Wiedemann, Ben deBoisblanc, Alfred F Connors, R Duncan Hite, Andrea L Harabin
雑誌名: N Engl J Med. 2006 May 25;354(21):2213-24. doi: 10.1056/NEJMoa061895. Epub 2006 May 21.
Abstract/Text BACKGROUND: The balance between the benefits and the risks of pulmonary-artery catheters (PACs) has not been established.
METHODS: We evaluated the relationship of benefits and risks of PACs in 1000 patients with established acute lung injury in a randomized trial comparing hemodynamic management guided by a PAC with hemodynamic management guided by a central venous catheter (CVC) using an explicit management protocol. Mortality during the first 60 days before discharge home was the primary outcome.
RESULTS: The groups had similar baseline characteristics. The rates of death during the first 60 days before discharge home were similar in the PAC and CVC groups (27.4 percent and 26.3 percent, respectively; P=0.69; absolute difference, 1.1 percent; 95 percent confidence interval, -4.4 to 6.6 percent), as were the mean (+/-SE) numbers of both ventilator-free days (13.2+/-0.5 and 13.5+/-0.5; P=0.58) and days not spent in the intensive care unit (12.0+/-0.4 and 12.5+/-0.5; P=0.40) to day 28. PAC-guided therapy did not improve these measures for patients in shock at the time of enrollment. There were no significant differences between groups in lung or kidney function, rates of hypotension, ventilator settings, or use of dialysis or vasopressors. Approximately 90 percent of protocol instructions were followed in both groups, with a 1 percent rate of crossover from CVC- to PAC-guided therapy. Fluid balance was similar in the two groups, as was the proportion of instructions given for fluid and diuretics. Dobutamine use was uncommon. The PAC group had approximately twice as many catheter-related complications (predominantly arrhythmias).
CONCLUSIONS: PAC-guided therapy did not improve survival or organ function but was associated with more complications than CVC-guided therapy. These results, when considered with those of previous studies, suggest that the PAC should not be routinely used for the management of acute lung injury. (ClinicalTrials.gov number, NCT00281268.).

Copyright 2006 Massachusetts Medical Society.
PMID 16714768  N Engl J Med. 2006 May 25;354(21):2213-24. doi: 10.1056・・・

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