今日の臨床サポート

動脈管依存性先天性心疾患(小児科)

著者: 渋谷和彦 東京都立府中療育センター

監修: 五十嵐隆 国立成育医療研究センター

著者校正/監修レビュー済:2021/06/09
参考ガイドライン:
  1. 日本小児循環器学会:胎児心エコー検査ガイドライン 第2版 (2021年発刊)
  1. アメリカ心臓協会(AHA):Diagnosis and Treatment of Fetal Cardiac Disease: A Scientific Statement From the American Heart Association (2014年発刊)
  1. 日本小児循環器学会:小児心不全薬物治療ガイドライン 平成27年改訂版 (2015年発刊)
患者向け説明資料

概要・推奨   

  1. 本疾患は、胎児心エコー検査により出生前診断して周産期管理をすることが推奨される[1][2]推奨度JG)。
  1. 本疾患は、出生後早期にプロスタグランジンの点滴を開始することが推奨される[1][2]推奨度JG)。
  1. 妊娠中期・後期におけるNSAIDs母体投与は、胎児の動脈管収縮させる危険があり避けることが推奨される[1](推奨度G
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:
渋谷和彦 : 特に申告事項無し[2021年]
監修:五十嵐隆 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 胎児心エコー検査による出生前診断が本疾患の予後を改善させる可能性を明記した。
  1. 2021年2月に国内で発刊された胎児心エコー検査ガイドライン第2版に基づいている。
  1. 2014年4月に国外で発刊されたAHAのScientific Statementに基づいている。

まとめ

疾患情報(疫学・病態)  
  1. 動脈管依存性先天性心疾患は、胎児心エコー検査にて出生前診断が可能である。
  1. 循環を維持させるために動脈管が必要な先天性心疾患の総称である。
  1. 新生児(あるいは乳児)の生命予後を左右する重要な疾患である。
  1. 動脈管依存性肺循環、動脈管依存性体循環、肺体循環混合、重篤な肺高血圧に分類される。
  1. 発症時期や症状も様々で出生後の診断は必ずしも容易ではない。
  1. 出生後に動脈管が狭小化または閉鎖してから、哺乳不良、尿量低下、チアノーゼ、ショックなどが顕在化する。
  1. 第一に行うべき治療はプロスタグランジンの点滴である。効果が得られない場合は、ステント留置または手術を考慮する。
問診・診察のポイント  
  1. 原因不明で状態が悪い新生児(あるいは乳児)を診たら、発症時期や症状にかかわらず必ず鑑別診断に挙げる。

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文献 

著者: Mary T Donofrio, Anita J Moon-Grady, Lisa K Hornberger, Joshua A Copel, Mark S Sklansky, Alfred Abuhamad, Bettina F Cuneo, James C Huhta, Richard A Jonas, Anita Krishnan, Stephanie Lacey, Wesley Lee, Erik C Michelfelder, Gwen R Rempel, Norman H Silverman, Thomas L Spray, Janette F Strasburger, Wayne Tworetzky, Jack Rychik, American Heart Association Adults With Congenital Heart Disease Joint Committee of the Council on Cardiovascular Disease in the Young and Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and Council on Cardiovascular and Stroke Nursing
雑誌名: Circulation. 2014 May 27;129(21):2183-242. doi: 10.1161/01.cir.0000437597.44550.5d. Epub 2014 Apr 24.
Abstract/Text BACKGROUND: The goal of this statement is to review available literature and to put forth a scientific statement on the current practice of fetal cardiac medicine, including the diagnosis and management of fetal cardiovascular disease.
METHODS AND RESULTS: A writing group appointed by the American Heart Association reviewed the available literature pertaining to topics relevant to fetal cardiac medicine, including the diagnosis of congenital heart disease and arrhythmias, assessment of cardiac function and the cardiovascular system, and available treatment options. The American College of Cardiology/American Heart Association classification of recommendations and level of evidence for practice guidelines were applied to the current practice of fetal cardiac medicine. Recommendations relating to the specifics of fetal diagnosis, including the timing of referral for study, indications for referral, and experience suggested for performance and interpretation of studies, are presented. The components of a fetal echocardiogram are described in detail, including descriptions of the assessment of cardiac anatomy, cardiac function, and rhythm. Complementary modalities for fetal cardiac assessment are reviewed, including the use of advanced ultrasound techniques, fetal magnetic resonance imaging, and fetal magnetocardiography and electrocardiography for rhythm assessment. Models for parental counseling and a discussion of parental stress and depression assessments are reviewed. Available fetal therapies, including medical management for arrhythmias or heart failure and closed or open intervention for diseases affecting the cardiovascular system such as twin-twin transfusion syndrome, lung masses, and vascular tumors, are highlighted. Catheter-based intervention strategies to prevent the progression of disease in utero are also discussed. Recommendations for delivery planning strategies for fetuses with congenital heart disease including models based on classification of disease severity and delivery room treatment will be highlighted. Outcome assessment is reviewed to show the benefit of prenatal diagnosis and management as they affect outcome for babies with congenital heart disease.
CONCLUSIONS: Fetal cardiac medicine has evolved considerably over the past 2 decades, predominantly in response to advances in imaging technology and innovations in therapies. The diagnosis of cardiac disease in the fetus is mostly made with ultrasound; however, new technologies, including 3- and 4-dimensional echocardiography, magnetic resonance imaging, and fetal electrocardiography and magnetocardiography, are available. Medical and interventional treatments for select diseases and strategies for delivery room care enable stabilization of high-risk fetuses and contribute to improved outcomes. This statement highlights what is currently known and recommended on the basis of evidence and experience in the rapidly advancing and highly specialized field of fetal cardiac care.

© 2014 American Heart Association, Inc.
PMID 24763516  Circulation. 2014 May 27;129(21):2183-242. doi: 10.1161・・・
著者: Mark S Sklansky, Darren P Berman, Jay D Pruetz, Ruey-Kang R Chang
雑誌名: J Ultrasound Med. 2009 Jul;28(7):889-99.
Abstract/Text OBJECTIVE: The purpose of this study was to determine the relative importance of the 4-chamber view (4CV) compared with the outflow tract views (OFTVs) in prenatal screening for major congenital heart disease (CHD).
METHODS: We prospectively evaluated 200 consecutive infants undergoing cardiac surgery at our institution for major CHD. By reviewing the infants' medical records and conducting bedside interviews with their parents or guardians, we evaluated detection rates both prenatally and postnatally (before and after discharge to home), and we noted any prenatally identifiable risk factors for CHD. For each infant, we determined whether the 4CV or OFTVs would be expected to have been normal or abnormal on routine midgestation screening fetal sonography.
RESULTS: A prenatal diagnosis of CHD was made in 65 infants (33%): 30 of 124 low-risk pregnancies (24%) and 35 of 76 high-risk pregnancies (46%). An abnormal screening midgestation 4CV would have been expected in up to 63% of the infants, whereas abnormal midgestation OFTVs would have been expected in up to 91% of the infants. Thus, the potential sensitivity for detecting major CHD was higher with the OFTVs than with the 4CV (91% versus 63%; P < .001). Moreover, the OFTVs were more sensitive than the 4CV for detecting ductal-dependent forms of CHD. Diagnosis after discharge to home occurred in 39 of 135 postnatal diagnoses (29%), including many cases of isolated outflow tract abnormalities requiring early invasive intervention.
CONCLUSIONS: Cases of major neonatal CHD with OFTV abnormalities predominate over cases with 4CV abnormalities, particularly among those forms of CHD requiring early invasive intervention.

PMID 19546331  J Ultrasound Med. 2009 Jul;28(7):889-99.
著者: Senka Dinarević, Hajrija Maksić, Majda Haznadar
雑誌名: Bosn J Basic Med Sci. 2005 Feb;5(1):14-8.
Abstract/Text Ductal dependent congenital heart diseases represent 14-20% of all congenital heart diseases. A primary goal of the treatment of these diseases is to retain ductus open until the final cardiosurgical treatment. Prostaglandins are presently the only medicaments, which have a capability to keep ductus open. By means of a retrospective study in a period from January, 2000 until December, 2002 at the Paediatric clinic of the Clinical centre of the University in Sarajevo, 14 patients (treated with prostaglandins) diagnosed with ductal dependent congenital heart diseases were analyzed. In our sample, there are 9/14 male patients (64.3%), 11/14 (78.6%) were full-term newborns, while 10/14 (71.4%) were eutrophic at birth. An average saturation increase, after the prostaglandin therapy, measured in blood from the capillaries is 29, and measured transcutanlly is 32 units. Duration of prostaglandin therapy in our study was on average 17.2 days. The most common cause of death was insufficientia cardiorespiratoria (4 out of 11), but sepsis/infection (3 out of 11) and insufficientia renalis were also common. 78.6% (11 out of 14) patients died partly because of the complexity of these diseases, but also because a cardiosurgical treatment is delayed. A goal of this study is evaluation of saturation with oxygen before and after the prostaglandin therapy.

PMID 15771597  Bosn J Basic Med Sci. 2005 Feb;5(1):14-8.
著者: T R Hoke, P K Donohue, P K Bawa, R D Mitchell, A Pathak, P C Rowe, B J Byrne
雑誌名: Pediatr Cardiol. 2002 Jul-Aug;23(4):403-9. doi: 10.1007/s00246-002-1482-8.
Abstract/Text The aim of this study was to assess the utility of arm and leg oxygen saturation as a candidate screening test for the early detection of ductal-dependent left heart obstructive disease. We measured arm and leg oxygen saturation in 2876 newborns admitted to well baby nurseries and 32 newborns with congenital heart disease. Fifty-seven newborns in the well baby nurseries (0.02%) had an abnormal test (leg saturation less than 92% in room air or 7% lower saturation in the leg than in the arm). Four of the 57 had critical congenital heart disease, including 1 with coarctation of the aorta. Of the 32 newborns with congenital heart disease, 11/13 (85%) with left heart obstructive disease had abnormal oxygen saturation tests, as did 15/19 (79%) with other forms of congenital heart disease. Pulse oximetry deserves further study as a screening test for critical congenital heart disease.

PMID 12170356  Pediatr Cardiol. 2002 Jul-Aug;23(4):403-9. doi: 10.1007・・・
著者: F Viñals, J Tapia, A Giuliano
雑誌名: Ultrasound Obstet Gynecol. 2002 Mar;19(3):246-9. doi: 10.1046/j.1469-0705.2002.00651.x.
Abstract/Text OBJECTIVE: To improve the detection of ductal dependence in fetuses with severe anomalies of the outflow tracts by observing, with directional power Doppler, reverse flow through the aortic arch or ductus arteriosus in a transverse view of the upper mediastinum.
METHODS: A slight cranial move of the ultrasound beam from the three-vessel view allows the transverse view of the aortic arch and ductus arteriosus to be visualized simultaneously. This view is orthogonal to the fetal body axis and parallel to the plane of the four-chamber view. In normal fetuses, directional power Doppler interrogation at this level identifies forward flow in both oblique vessels.
RESULTS: We examined 43 fetuses with cardiac defects. In five of the cases, there was reversed flow in the aortic arch or ductus arteriosus in addition to severe anomalies of the outflow tracts, including four with hypoplastic left ventricle and one with pulmonary atresia.
CONCLUSIONS: Prenatal detection of reversed flow in the aortic arch or ductus arteriosus is associated with complex congenital heart disease with major diminution of forward flow to the corresponding great vessels.

PMID 11896944  Ultrasound Obstet Gynecol. 2002 Mar;19(3):246-9. doi: 1・・・
著者: G Satomi, S Yasukochi, T Shimizu, K Takigiku, T Ishii
雑誌名: Pediatr Int. 1999 Dec;41(6):728-32.
Abstract/Text BACKGROUND: As prenatal diagnosis of congenital heart disease has gained in popularity, the questions of whether prenatal diagnosis of congenital heart disease is beneficial for the patient and whether fetal echocardiography has improved the prognosis of congenital heart disease are arising.
METHODS: We compared four patients with prenatally diagnosed hypoplastic left heart syndrome (HLHS) with 10 patients of non-prenatally diagnosed HLHS from the view points of (i) age at transfer to our Children's Hospital; (ii) whether the oxygen was inhaled during perinatal period; (iii) whether prostaglandin E1 was administered in the period of waiting before operation; (iv) whether the patient had ductal shock; (v) timing of operation; and (vi) surgical outcome.
RESULTS: The timing of the transfer to our Children's Hospital was earlier in prenatally diagnosed group than in non-diagnosed group. Oxygen was not given to any of the patients in prenatally diagnosed group. In contrast, oxygen inhalation was given in two of 10 patients in the non-prenatally diagnosed group. Prostaglandin E1 was administrated in three of four patients in the prenatally diagnosed group and seven of 10 patients in the non-prenatally diagnosed group. In terms of ductal shock, none of the patients in prenatally diagnosed group had ductal shock. However, four of 10 patients had ductal shock in the non-prenatally diagnosed group. The median age at Norwood operation was 7 days in the prenatally diagnosed group; however, it was 19 days in non-prenatally diagnosed group. Surgical outcomes showed no significant changes between the two groups.
CONCLUSIONS: Prenatal diagnosis of HLHS was surely beneficial for preventing ductal shock and for keeping the patients' preoperative condition good.

PMID 10618902  Pediatr Int. 1999 Dec;41(6):728-32.
著者: D Bonnet, A Coltri, G Butera, L Fermont, J Le Bidois, J Kachaner, D Sidi
雑誌名: Circulation. 1999 Feb 23;99(7):916-8.
Abstract/Text BACKGROUND: Transposition of the great arteries (TGA) is a life-threatening malformation in neonates, but it is amenable to complete repair. Prenatal detection, diagnosis, and early management may modify neonatal mortality and mortality.
METHODS AND RESULTS: Preoperative and postoperative morbidity and mortality were compared in 68 neonates with prenatal diagnosis and in 250 neonates with a postnatal diagnosis of TGA over a period of 10 years. The delay between birth and admission was 2+/-2.8 hours in the prenatal group and 73+/-210 hours in the neonatal group (P<0.01). Clinical condition at arrival, including metabolic acidosis and multiorgan failure, was worse in the neonatal group (P<0.01). Once in the pediatric cardiology unit, the management was identical in the 2 groups (atrioseptostomy, PGE1 infusion, operation date). Preoperative mortality was 15 of 250 (6%; 95% CI, 3% to 9%) in the neonatal group and 0 of 68 in the prenatal group (P<0.05). Postoperative morbidity was not different (25 of 235 versus 6 of 68), but hospital stay was longer in the neonatal group (30+/-17 versus 24+/-11 days, P<0.01). In addition, postoperative mortality was significantly higher in the neonatal group (20 of 235 versus 0 of 68, P<0.01); however, the known risk factors for operative mortality were identical in the 2 groups.
CONCLUSIONS: Prenatal diagnosis reduces mortality and morbidity in TGA. Prenatal detection of this cardiac defect must be increased to improve early neonatal management. In utero transfer of fetuses with prenatal diagnosis of TGA in an appropriate unit is mandatory.

PMID 10027815  Circulation. 1999 Feb 23;99(7):916-8.
著者: W Tworetzky, D B McElhinney, V M Reddy, M M Brook, F L Hanley, N H Silverman
雑誌名: Circulation. 2001 Mar 6;103(9):1269-73.
Abstract/Text BACKGROUND: Hypoplastic left heart syndrome (HLHS) is frequently diagnosed prenatally, but this has not been shown to improve surgical outcome.
METHODS AND RESULTS: We reviewed patients with HLHS between July 1992 and March 1999 to determine the influence of prenatal diagnosis on preoperative clinical status, outcomes of stage 1 surgery, and parental decisions regarding care. Of 88 patients, 33 were diagnosed prenatally and 55 after birth. Of 33 prenatally diagnosed patients, 22 were live-born, and pregnancy was terminated in 11. Of 22 prenatally diagnosed patients who were live-born, 14 underwent surgery, and parents elected to forego treatment in 8. Of 55 patients diagnosed postnatally, 38 underwent surgery, and 17 did not because of parental decisions or clinical considerations. Prenatally diagnosed patients were less likely to undergo surgery than patients diagnosed after birth (P:=0.008). Among live-born infants, there was a similar rate of nonintervention. Among patients who underwent surgery, survival was 75% (39/52). All patients who had a prenatal diagnosis and underwent surgery survived, whereas only 25 of 38 postnatally diagnosed patients survived (P:=0.009). Patients diagnosed prenatally had a lower incidence of preoperative acidosis (P:=0.02), tricuspid regurgitation (P:=0.001), and ventricular dysfunction (P:=0.004). They were also less likely to need preoperative inotropic medications or bicarbonate (P:=0.005). Preoperative factors correlating with early mortality included postnatal diagnosis (P:=0.009), more severe acidosis (P:=0.03), need for bicarbonate or inotropes (P:=0.008 and 0.04), and ventricular dysfunction (P:=0.05).
CONCLUSIONS: Prenatal diagnosis of HLHS was associated with improved preoperative clinical status and with improved survival after first-stage palliation in comparison with patients diagnosed after birth.

PMID 11238272  Circulation. 2001 Mar 6;103(9):1269-73.
著者: O Franklin, M Burch, N Manning, K Sleeman, S Gould, N Archer
雑誌名: Heart. 2002 Jan;87(1):67-9.
Abstract/Text OBJECTIVE: To investigate whether antenatal diagnosis of coarctation of the aorta results in reduced mortality and improved preoperative haemodynamic stability compared with postnatal diagnosis.
DESIGN: Retrospective review of all cases of coarctation of the aorta presenting to a tertiary fetal and neonatal cardiology service from January 1994 to December 1998.
METHODS: Prenatal, postnatal, and necropsy records were reviewed to determine survival in the two groups. Markers of preoperative illness severity were recorded, including presence of femoral pulse, collapse, left ventricular function, ductal patency on echocardiography, coagulation status, duration of intensive care unit and total hospital stay, heart rate, respiratory rate, plasma creatinine, plasma potassium, and right upper limb blood pressure. A univarate and multivariate analysis was conducted on all variables and a cumulative score was created and subjected to logistic regression analysis.
RESULTS: Both collapse and death were more common in the postnatally diagnosed group (p < 0.05). Femoral pulses were more likely to be palpable and there was echocardiographic evidence of duct patency in the antenatally diagnosed infants (p < 0.001 and p < 0.05, respectively). An increased respiratory rate was associated with postnatal presentation (p < 0.05). Infants with haemodynamic instability preoperatively were more likely to have been diagnosed postnatally (p < 0.01).
CONCLUSIONS: Antenatal diagnosis of coarctation of the aorta is associated with improved survival and preoperative clinical condition.

PMID 11751670  Heart. 2002 Jan;87(1):67-9.
著者: P M Verheijen, L A Lisowski, P Stoutenbeek, J F Hitchcock, J I Brenner, J A Copel, C S Kleinman, E J Meijboom, G B Bennink
雑誌名: J Thorac Cardiovasc Surg. 2001 Apr;121(4):798-803. doi: 10.1067/mtc.2001.112825.
Abstract/Text OBJECTIVES: Congenital heart disease is the leading cause of death in the first year after birth. Prenatal diagnosis of the disease can optimize the preoperative condition of the patient and may help in the prevention of acidosis. In this retrospective study we compared the occurrence of metabolic acidosis in patients with and without prenatal diagnosis of a congenital heart disease.
METHODS: Data of 408 patients who needed an operation for congenital heart disease within 31 days of life were analyzed retrospectively. Arterial blood gases at fixed time intervals and worst blood gas of 81 patients with and 327 patients without a prenatal diagnosis were compared, categorizing the patients on ductus dependency, anticipated univentricular or biventricular repair, and left-sided, right-sided, or no heart obstruction.
RESULTS: In the overall group significant differences in lowest pH, lowest base excess, and highest lactate level were found, with metabolic acidosis more common among the patients with a postnatal diagnosis. In the group of patients with ductus-dependent congenital heart disease, the difference between patients receiving a prenatal and those receiving a postnatal diagnosis was more significant than in the group with non-ductus-dependent lesions. Analyzing patients with right-sided, left-sided, and no obstruction separately, significant differences were found in the group with left-sided heart obstruction for lowest pH and base excess and in the group with right-sided heart obstruction for lowest base excess.
CONCLUSIONS: Prenatal diagnosis of congenital heart disease minimizes metabolic acidosis in patients with congenital heart disease and may be associated with improved long-term outcome and prevention of cerebral damage among this fragile group of patients, although no significant effect on direct surgical outcome was encountered.

PMID 11279423  J Thorac Cardiovasc Surg. 2001 Apr;121(4):798-803. doi:・・・
著者: Varsha Thakur, Nathalie Dutil, Steven M Schwartz, Edgar Jaeggi
雑誌名: Cardiol Young. 2018 Apr;28(4):548-553. doi: 10.1017/S1047951117002682. Epub 2018 Feb 7.
Abstract/Text OBJECTIVE: The objective of this study was to compare the preoperative management and outcome of neonates with duct-dependent critical CHD with fetal versus postnatal diagnosis.
METHODS: Patients referred with CHD to our centre from January 1, 2009 to December 31, 2010 were enrolled prospectively. Live births with a critical form of CHD, a gestational age ⩾36 weeks and a weight ⩾2 kg at birth, and the intention-to-treat were included in this sub-study. Excluded were neonates with lethal non-cardiac and/or genetic anomalies.
RESULTS: In total, 129, 63 fetal and 66 postnatal, cases met the study inclusion criteria. All had received appropriate antenatal care, including a routine fetal anatomy scan. Both cohorts were comparable in weight, gestational age, and APGAR scores at birth. Unlike the postnatal cases, there were no deaths (0/63 versus 5/66; p=0.06) and no cardiac arrests (0/63 versus 9/63; p=0.003) before surgery or catheter intervention in those cases with a prenatal diagnosis of critical CHD. Moreover, newborns with fetal diagnoses were admitted earlier (median 0 (range 0-3) versus 2 (0-25) days; p<0.001) and were less likely to require preoperative ventilation (19/63 versus 31/61, p=0.03) and vasoactive medication (4/63 versus 15/61, p=0.006) than the postnatal cases.
CONCLUSIONS: Prenatal diagnosis of critical CHD in this study was associated with significantly shorter time intervals from birth to neonatal admission and the absence of life-threatening or fatal preoperative cardiac events. Increased efforts should be made to improve rates of prenatal diagnosis.

PMID 29409551  Cardiol Young. 2018 Apr;28(4):548-553. doi: 10.1017/S10・・・
著者: Keita Yamauchi, Shoji Yasunaga, Hiromu Kawasaki, Yuji Kurosaki
雑誌名: Biol Pharm Bull. 2003 Feb;26(2):210-5.
Abstract/Text The usefulness of kinetic analysis of pharmacological response data was discussed in investigating the ductus arteriosus dilating effect (DADE) of lipo-PGE1 (a lipid emulsion preparation of prostaglandin E1 for injection) preparations. Lipo-PGE1 was administered intravenously via the umbilical vein by a bolus injection or an infusion in newborn rats 60 min after the delivery. The DADE data were expressed as the inner diameter ratio between the ductus arteriosus and the main pulmonary artery, and were analyzed by a pharmacological response kinetic (PRK) model consisting of an Emax model and a simple pharmacokinetic model as the pharmacodynamic- and the pharmacokinetic-component, respectively. The latter component includes the release process of free-PGE1 from the lipid phase of lipo-PGE1, followed by distribution to the effect compartment. The Emax value was estimated by the maximal DADE observed 10 min after the bolus administration of each dose, and the value was fixed in the PRK analysis. The regression curves given by simultaneous non-linear least squares regression analysis were satisfactorily fitted to the observed DADE data at all doses. Prediction of the DADE of lipo-PGE1 in an infusion study was satisfactorily done using the estimated parameters in the i.v.-study. These findings indicate that PRK modeling based on the intensities of the observed pharmacological response-time data is a meaningful tool in some targeting-type drugs, for which pharmacokinetic analysis itself is meaningless or acquisition of pharmacokinetic data is technically impossible, in predicting the time courses of the drug's pharmacological response in different dosage regimens.

PMID 12576682  Biol Pharm Bull. 2003 Feb;26(2):210-5.
著者: N Takeda, S Hiraishi, H Misawa, Y Agata, Y Horiguchi, N Fujino, H Hirota, S Kawamura, N Ogawa
雑誌名: Pediatr Int. 2000 Apr;42(2):134-8.
Abstract/Text BACKGROUND: Lipo-prostaglandin (PG)E1 is effective at lower doses and has fewer side effects than PGE1-cyclodextrin (CD). Previous studies, however, have suggested that some patients show refractoriness to lipo-PGE1 in the course of treatment. The present paper examines: (i) whether such cases can be predicted by examining the ductal morphology before and 24 h after the start of lipo-PGE1 infusion; and (ii) whether PGE1-CD dilates the ductus arteriosus in patients with refractoriness to lipo-PGE1.
METHODS: The ductal morphology was evaluated with two echo indices, such as minimal and minimal plus maximal intraluminal diameters of the ductus. Two-dimensional echocardiography was performed in 24 patients with ductus-dependent congenital heart disease. The two echo indices were measured before and 24 h after lipo-PGE1 infusion and also at least twice per week until surgery.
RESULTS: In 19 of 24 patients, ductal patency was maintained until surgical treatment (group A). The remaining five patients (21%) showed ductal closure during the course of the lipo-PGE1 therapy (group B). There were no significant differences between the two groups, in either the maximal or minimal diameters, which were examined before and 24 h after treatment. In the five patients of group B, lipo-PGE1 was replaced with a relatively high dosage of PGE1-CD (50-100 ng/kg per min), resulting in good ductal patency until surgery.
CONCLUSIONS: Patients with refractoriness to lipo-PGE1 therapy could not be predicted from initial intraluminal diameters of the ductus using echocardiography. Therefore, serial echocardiographic examinations are important to detect early findings of ductal closure. In addition, PGE1-CD is still useful as back-up therapy in such patients.

PMID 10804727  Pediatr Int. 2000 Apr;42(2):134-8.
著者: Y Chino, T Minagawa, Y Kohno, K Fukushima, K Momma
雑誌名: Jpn J Pharmacol. 1999 Sep;81(1):107-14.
Abstract/Text Prostaglandin E1 incorporated in lipid microspheres (lipo PGE1) was administered to the umbilical vein of neonatal rats. Morphological measurement and quantitative autoradioluminography assessed the relationship between the vasodilating effect and tissue accumulation of lipo PGE1 in the ductus arteriosus. In the morphological measurement under microscopy, the inner diameter ratio of the ductus arteriosus to the main pulmonary artery after infusion of 3H-labeled lipo PGE1 (3H-lipo PGE1) continued to remain significantly higher than that of free 3H-PGE1. Autoradioluminography of the frozen frontal section of neonates after intravenous infusion of 3H-lipo PGE1 for 2 h revealed that the ductus levels of radioactivity were higher than those of free 3H-PGE1 in saline solution, although the blood levels were almost equal. Localization of lipo PGE1 labeled with a lipophilic fluorescent probe, 1,1'-dioctadecyl-3,3,3',3-tetramethyl-indocarbocyanine perchlorate (diI), in the endothelial cells of the ductus arteriosus was confirmed by confocal laser scanning microscopy. These findings suggest that the incorporation of lipid microspheres by the endothelial cells is one of the mechanisms that enables lipo PGE1 to accumulate to higher levels in the ductus tissue and to act more efficiently than free PGE1 in neonatal rats.

PMID 10580378  Jpn J Pharmacol. 1999 Sep;81(1):107-14.
著者: E D Silove, J Y Coe, M F Shiu, J D Brunt, A J Page, S P Singh, M D Mitchell
雑誌名: Circulation. 1981 Mar;63(3):682-8.
Abstract/Text Prostaglandin E2 (PGE2) was administered orally, in doses of 12-65 microgram/kg at intervals of 1-4 hours, to 12 neonates in whom the pulmonary circulation depended on patency of the ductus arteriosus. After an oral dose, both oxygen saturation (SaO2) and plasma PGE2 concentration increased consistently within 15-30 minutes, reaching values comparable to those during i.v. infusions. Treatment continued for 5 days to 4 months. In eight infants, PGE2 withdrawal resulted in a decrease of SaO2, from a mean of 75 +/- 7% to 57 +/- 10% (+/- SD). The ductus remained responsive for long periods--in four infants, for over 3 months. Consequently, surgery could be delayed until the infants and their pulmonary arteries had grown. Side effects during oral therapy were similar to those during i.v. infusion but were less severe in this series. The effectiveness and simplicity of oral PGE2 administration have advantages over i.v. administration, especially for long-term treatment.

PMID 7460252  Circulation. 1981 Mar;63(3):682-8.
著者: K A Hallidie-Smith
雑誌名: Arch Dis Child. 1984 Nov;59(11):1020-6.
Abstract/Text Fifty two sick neonates with major duct dependent cardiac defects were given short term intravenous infusions of prostaglandin E1 (alprostadil) in doses varying between 0.005 and 0.1 micrograms/kg/minute. The object of the study was to try to achieve an effective but safe regiment that could be instituted as soon as such a diagnosis was suspected. Effective clinical improvement was achieved at each dosage but the incidence of side effects seemed to be dose related, and no serious side effects were noted at a dosage of 0.005 to 0.01 micrograms/kg/minute. It is recommended that a low dosage regimen be started before transfer to a paediatric cardiac centre.

PMID 6542338  Arch Dis Child. 1984 Nov;59(11):1020-6.
著者: E D Silove, D G Roberts, J V de Giovanni
雑誌名: Arch Dis Child. 1985 Nov;60(11):1025-30.
Abstract/Text Prostaglandin E2 was given orally to 59 infants with ductus dependent congenital heart disease, and intravenous infusions were substituted for varying periods in 27 of them. An additional three neonates received intravenous treatment alone. Mean oral maintenance dose was 27 micrograms/kg per hour and the mean intravenous dose was 0.005 micrograms/kg per minute. Mean duration of treatment was 49 days (range 16 hours to 272 days). Oral treatment was almost always effective and was especially suitable for long term use. Low dose intravenous treatment was readily substituted when indicated. Complications were usually 'minor'. Growth of the infants and of their pulmonary arteries facilitated later surgical management.

PMID 3865636  Arch Dis Child. 1985 Nov;60(11):1025-30.
著者: Mariel A Fernández, Enrique Gebara
雑誌名: Arch Argent Pediatr. 2011 Apr;109(2):154-9. doi: 10.1590/S0325-00752011000200011.
Abstract/Text Prostaglandin E1 (PGE1) infusion is usually administered for short periods to maintain patency of ductus arteriosus in infants with cyanotic heart disease. Prolonged therapy may be necessary while patients are awaiting surgical treatment. Several side effects occur at the onset of the treatment, most of them reversible once the treatment is discontinued. Cortical hyperostosis is a frequent complication of prolonged PGE1 infusion. Objective is to determine the incidence and severity of cortical hyperostosis in newborn requiring prolonged prostaglandin E1 infusion. 61 newborn babies were admitted in the Neonatal Intensive Care Unit at Bazterrica Clinic, Buenos Aires City, from January 2006 to May 2010. Five newborn received prolonged PGE1 therapy defined as a longer-than-one-week treatment. Four of them had radiologic evidence of cortical hyperostosis and elevated serum alkaline phosphatase. Accurate and rapid diagnosis of this condition is critical to reduce unnecessary laboratory tests and to avoid cardiac surgery cancelling.

PMID 21465075  Arch Argent Pediatr. 2011 Apr;109(2):154-9. doi: 10.159・・・
著者: H H Kramer, M Sommer, S Rammos, O Krogmann
雑誌名: Eur J Pediatr. 1995 Sep;154(9):700-7.
Abstract/Text UNLABELLED: This study reports our experience with low-dose prostaglandin E1 (PGE1) treatment of 91 newborns with ductus dependent congenital heart disease (CHD). PGE1 efficacy, side-effects as well as the cardiovascular and respiratory profile of the patients were analysed. PGE1 doses > 0.02 microgram/kg per minute were used for only 5.3% of the total 23,656 h of treatment. The mean systolic blood pressures did not differ from the normal mean for patients with cyanotic CHD, while the diastolic values were lowered. Respiratory support was required only during 13.7% of the total treatment time. Apnoeas occurred in 21 (38%) of the 55 spontaneously breathing infants, who all had a cyanotic CHD. The incidence of apnoeas was lower during treatment with doses < 0.01 microgram/kg per minute.
CONCLUSION: PGE1 can be successfully administered in lower doses than previously recommended. Especially high initial doses can be avoided and low maintenance doses allow long-term treatment without serious complications.

PMID 8582419  Eur J Pediatr. 1995 Sep;154(9):700-7.
著者: Vladimiro L Vida, Simone Speggiorin, Nicola Maschietto, Massimo A Padalino, Chiara Tessari, Roberta Biffanti, Alessia Cerutti, Ornella Milanesi, Giovanni Stellin
雑誌名: Ann Thorac Surg. 2010 Aug;90(2):605-9. doi: 10.1016/j.athoracsur.2010.04.007.
Abstract/Text BACKGROUND: Stenting of the patent ductus arteriosus (PDA) has been recently introduced to palliate patients with duct-dependent pulmonary circulations. We evaluated the surgical outcome of patients who had a previous PDA stent, focusing on their pulmonary arteries status.
METHODS: This study included 15 patients (11 boys, 4 girls) who underwent cardiac operations after PDA stenting between August 2004 and April 2009. Outcomes included hospital mortality, morbidity, and need for reintervention or operation on the PDA and on the pulmonary artery branches.
RESULTS: Thirteen patients underwent elective cardiac operations at a median of 11 months (range, 0.3 months to 3.7 years) from PDA stenting. Two patients underwent emergency operations due to stent migration during percutaneous positioning. Six patients (46%) required a preoperative interventional cardiology procedure, including PDA stent dilatation in 5 and multiple left pulmonary artery dilatations in 1. During elective surgical repair, PDA stents were completely retrieved in 3 patients (23%) and partially removed in 10 (77%) due to the fusion of the stent to the vascular wall. Seven patients (53.8%) required surgical pulmonary artery plasty. One in-hospital death (6%) occurred after an emergency operation. Median follow-up was 16.7 months (range, 1 month to 2.5 years). Two late deaths (14%) occurred at 4 and 9 months. Four patients required additional interventional procedures on the left pulmonary artery after surgical repair.
CONCLUSIONS: Operations after PDA stenting are safe and low-risk. The presence of PDA stents requires additional surgical maneuvers on pulmonary arteries in near half of the patients, and postoperative interventions can be required.

Copyright 2010 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.
PMID 20667358  Ann Thorac Surg. 2010 Aug;90(2):605-9. doi: 10.1016/j.a・・・
著者: Ender Odemis, Sertac Haydin, Alper Guzeltas, Isa Ozyilmaz, Meki Bilici, Ihsan Bakir
雑誌名: Eur J Cardiothorac Surg. 2012 Jul;42(1):57-60. doi: 10.1093/ejcts/ezr258. Epub 2012 Jan 26.
Abstract/Text OBJECTIVES: Implantation of stents into the ductus arteriosus is an alternative treatment to palliative or corrective cardiac surgery in newborns with duct-dependent pulmonary circulation, although the use of this technique for congenital heart disease is limited.
METHODS: Between April 2010 and June 2011, 13 patients underwent patent ductus arteriosus stenting after full assessment by echocardiogram and angiogram, two of patients had pulmonary atresia (PA) and ventricular septal defect (VSD), six patients had PA with intact ventricular septum (IVS), four patients had critical pulmonary stenosis with IVS and one single ventricle physiology with PA and four patients had radiofrequency-assisted perforation of the pulmonary valve at the same time. All procedures were retrograde through the femoral artery, except one, which was by the femoral vein approach.
RESULTS: The mean age and weight during intervention were 10.5±5.7 days and 3.1±0.4 kg, respectively. The mean of procedure and scopy time, time of stay in intensive care, total out-of-hospital and total follow-up time were 138.88±67.11 min; 40.32±25.86 min; 4.88±6.07 days; 11.00±6.89 days and 86.40±73.21 days, respectively. The mean of the radiation amount was 1054.27±1106.91 cGy/cm2. The mean of saturation before and after intervention were 64.44±5.83; 81.88±6.95%, respectively. Procedure-related deaths were observed in two patients. The causes of death were pulmonary haemorrhage (n=1) and retroperitoneal haemorrhage (n=1). Two patients also died after discharge before surgery due to sepsis (n=1) and aspiration pneumonia (n=1). Eight of 13 patients achieved stent patency during 6 months of follow up and re-stenosis developed in one patient (1/8; 12.5%) who had undergone a Glenn operation at 4.5 months of age.
CONCLUSIONS: Ductal stenting is a practicable, effective, safer and less invasive method compared palliative or corrective surgery. Patients with ductal stenting have growth of the pulmonary artery which provides additional time for surgical repair. Our data suggested that ductal stenting should be considered as a first treatment step in newborns with duct-depended pulmonary circulation. However, long-term palliation without stent re-stenosismight still be a concern especially in patients with hypoplastic pulmonary arteries.

PMID 22290915  Eur J Cardiothorac Surg. 2012 Jul;42(1):57-60. doi: 10.・・・
著者: Jeremy M Ringewald, Gary Stapleton, Elsa J Suh
雑誌名: Cardiol Young. 2011 Dec;21 Suppl 2:47-52. doi: 10.1017/S1047951111001570.
Abstract/Text The hybrid approach to the treatment of patients with hypoplastic left heart syndrome most commonly includes transcatheter placement of a stent in the arterial duct and surgical placement of bands on the branch pulmonary arteries via median sternotomy. This manuscript will review the concept of hybrid palliation and discuss topics related to several time intervals: peri-procedural, post-procedural, interstage, and comprehensive stage 2.

PMID 22152528  Cardiol Young. 2011 Dec;21 Suppl 2:47-52. doi: 10.1017/・・・
著者: James R Bentham, Ngoni K Zava, Wendy J Harrison, Arjamand Shauq, Atul Kalantre, Graham Derrick, Robin H Chen, Rami Dhillon, Demetris Taliotis, Sok-Leng Kang, David Crossland, Akintayo Adesokan, Anthony Hermuzi, Vikram Kudumula, Sanfui Yong, Patrick Noonan, Nicholas Hayes, Oliver Stumper, John D R Thomson
雑誌名: Circulation. 2018 Feb 6;137(6):581-588. doi: 10.1161/CIRCULATIONAHA.117.028972. Epub 2017 Oct 30.
Abstract/Text BACKGROUND: Infants born with cardiac abnormalities causing dependence on the arterial duct for pulmonary blood flow are often palliated with a shunt usually between the subclavian artery and either pulmonary artery. A so-called modified Blalock-Taussig shunt allows progress through early life to an age and weight at which repair or further more stable palliation can be safely achieved. Modified Blalock-Taussig shunts continue to present concern for postprocedural instability and early mortality such that other alternatives continue to be explored. Duct stenting (DS) is emerging as one such alternative with potential for greater early stability and improved survival.
METHODS: The purpose of this study was to compare postprocedural outcomes and survival to next-stage palliative or reparative surgery between patients undergoing a modified Blalock-Taussig shunt or a DS in infants with duct-dependent pulmonary blood flow. All patients undergoing cardiac surgery and congenital interventions in the United Kingdom are prospectively recruited to an externally validated national outcome audit. From this audit, participating UK centers identified infants <30 days of age undergoing either a Blalock-Taussig shunt or a DS for cardiac conditions with duct-dependent pulmonary blood flow between January 2012 and December 31, 2015. One hundred seventy-one patients underwent a modified Blalock-Taussig shunt, and in 83 patients, DS was attempted. Primary and secondary outcomes of survival and need for extracorporeal support were analyzed with multivariable logistic regression. Longer-term mortality before repair and reintervention were analyzed with Cox proportional hazards regression. All multivariable analyses accommodated a propensity score to balance patient characteristics between the groups.
RESULTS: There was an early (to discharge) survival advantage for infants before next-stage surgery in the DS group (odds ratio, 4.24; 95% confidence interval, 1.37-13.14; P=0.012). There was also a difference in the need for postprocedural extracorporeal support in favor of the DS group (odds ratio, 0.22; 95% confidence interval, 0.05-1.05; P=0.058). Longer-term survival outcomes showed a reduced risk of death before repair in the DS group (hazard ratio, 0.25; 95% confidence interval, 0.07-0.85; P=0.026) but a slightly increased risk of reintervention (hazard ratio, 1.50; 95% confidence interval, 0.85-2.64; P=0.165).
CONCLUSIONS: DS is emerging as a preferred alternative to a surgical shunt for neonatal palliation with evidence for greater postprocedural stability and improved patient survival to destination surgical treatment.

© 2017 American Heart Association, Inc.
PMID 29084734  Circulation. 2018 Feb 6;137(6):581-588. doi: 10.1161/CI・・・
著者: Lindsay R Freud, Louise E Wilkins-Haug, Rebecca S Beroukhim, Terra LaFranchi, Colin K Phoon, Julie S Glickstein, Kristopher M Cumbermack, Majd Makhoul, Shaine A Morris, Heather Y Sun, Queralt Ferrer, Simone R Pedra, Wayne Tworetzky
雑誌名: Am J Cardiol. 2021 Feb 15;141:106-112. doi: 10.1016/j.amjcard.2020.11.013. Epub 2020 Nov 18.
Abstract/Text Ebstein anomaly (EA) and tricuspid valve dysplasia (TVD) are rare congenital malformations associated with nearly 50% mortality when diagnosed in utero. The diseases often produce severe tricuspid regurgitation (TR) in the fetus and in some cases, pulmonary regurgitation (PR) and circular shunting ensue. Since the ductus arteriosus (DA) plays a critical role in the circular shunt and may be constricted by transplacental nonsteroidal anti-inflammatory drugs (NSAIDs), we sought to assess the effect of NSAIDs on fetuses with EA/TVD. We reviewed mothers of singleton fetuses with EA/TVD and PR, indicative of circular shunting, who were offered NSAIDs at multiple centers from 2010 to 2018. Initial dosing consisted of indomethacin, followed by ibuprofen in most cases. Twenty-one patients at 10 centers were offered therapy at a median gestational age (GA) of 30.0 weeks (range: 20.9 to 34.9). Most (15/21 = 71%) mothers received NSAIDs, and 12 of 15 (80%) achieved DA constriction after a median of 2.0 days (1.0 to 6.0). All fetuses with DA constriction had improved PR; 92% had improved Doppler patterns. Median GA at pregnancy outcome (live-birth or fetal demise) was 36.1 weeks (30.7 to 39.0) in fetuses with DA constriction versus 33 weeks (23.3 to 37.3) in fetuses who did not receive NSAIDs or achieve DA constriction (p = 0.040). Eleven of 12 patients (92%) with DA constriction survived to live-birth, whereas 4 of 9 patients (44%) who did not receive NSAIDs or achieve DA constriction survived (p = 0.046). In conclusion, our findings demonstrate the proof of concept that NSAIDs mitigate circular shunt physiology by DA constriction and improve PR among fetuses with severe EA/TVD. Although the early results are encouraging, further investigation is necessary to determine safety and efficacy.

Copyright © 2020 Elsevier Inc. All rights reserved.
PMID 33217351  Am J Cardiol. 2021 Feb 15;141:106-112. doi: 10.1016/j.a・・・

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