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標題: | Fontan單一心室手術之預後分析:危險因子、生物指標及開窗手術的關聯性 Outcomes After Fontan-Type Operation: Risk Factors, Impact of Biomarkers and Association with Fenestration |
其他標題: | Outcomes After Fontan-Type Operation: Risk Factors, Impact of Biomarkers and Association with Fenestration |
作者: | 林杏佳 Hsin-Chia Lin |
指導教授: | 吳美環邱舜南 Mei-Hwan WuShuenn-Nan Chiu |
關鍵字: | Fontan手術,先天性心臟病,異位症,肺高壓,N端前腦利鈉肽, Fontan operation,Congenital heart disease,Heterotaxy syndrome,Pulmonary hypertension,N-terminal pro-brain natriuretic peptide, |
出版年 : | 2022 |
學位: | 博士 |
摘要: | 背景: 單一心室複雜性先天性心臟病是先天性心臟病中罕見的一個類別,無法利用手術建立雙心室循環。異位症是其中的一個特別族群,其定義為胸腹器官左右位置異常。因為異位症的解剖構造更為複雜,手術修補困難程度更高。Fontan類手術是單一心室複雜性先天性心臟病達到長期存活的標準手術,手術中,唯一有功能的心室留給體循環使用。因為沒有有功能/肺動脈下的右心室,體靜脈完全被動地回流至肺部。因此有必要在整個通道保持低的肺動脈壓力和肺血管阻力。如果Fontan循環的血液動力學狀況不良,即稱為Fontan衰竭。造成Fontan衰竭最重要的原因是Fontan壓力升高及肺血管阻力指數升高。即使是些微的肺血管阻力指數升高,心輸出量就會明顯降低。循環目前手術前後和長期的死亡率仍然不低,因此有需要建立一個包含肺動脈壓和肺動脈阻力指數在內,更完整的手術前篩選原則。現今對Fontan衰竭最主要的治療藥物是肺血管舒張劑,可以降低Fontan/肺動脈壓力及肺血管阻力指數。但是,此種治療對死亡率沒有明顯統計差異。此外,分析生物指標可能有額外幫助。在肺動脈高壓的病理機轉中,血管內皮指標(循環內皮細胞、血管內皮前驅細胞)、胞外基質指標(基質金屬蛋白酶1和2)和微小RNA都有參與原發性肺動脈高壓及Eisenmenger症候群的病理機轉。但是否可以在Fontan手術中應用這些肺血管重塑的生物因子,目前仍然未知。 目標: (1)我們回溯性分析台大兒童醫院的Fontan病人群體,以得知手術前後和術後長期的危險因子和存活率。 (2)我們利用術前的生物指標納入預測模型,以判別進行手術的危險程度。 方法:對於手術前後和長期預後,我們回溯分析所有過去30年來單一心室複雜性先天性心臟病的病患病歷資料。此外,我們前瞻性對於所有準備進行Fontan手術而入院進行心導管術前評估的病患分析肺動脈高壓相關的生物指標。主要試驗終點指標為死亡、Fontan循環拆除手術和心臟移植。次要試驗終點指標為需要住院治療心衰竭。 結果: (1)對於Fontan手術前後的預後方面:總共納入154位病患,男女各為92及62人,平均進行Fontan手術的年齡是5.1 ± 2.2歲。有11位(7.1%)病患發生手術前後死亡。2008年後的無事件存活率比較早期更好(分別為95.7%及78.4%,P = 0.003)。在我們的病人群體中,右心室同位症(47位)佔全部異位症(51位)的大多數(92.1%)。手術前後無事件存活率為91.6%。於單一變項分析中,異位症病患的手術前後死亡率為15.7%,高於其他非異位症的複雜性先天性心臟病病患的4.9%(P = 0.032)。兩組病患加護病房住院時間過久及持續胸水引流時間過長的比率沒有統計顯著意義。多變項回歸分析發現和不良預後相關的術前危險因子有手術時間在2007年之前和較高的肺動脈壓。在經過術前肺動脈壓和手術年份調整之後,異位症不再是重要的預後不良因子。使用接受者操作特徵曲線決定術前肺動脈壓力及術後中心靜脈壓的最佳切點分別為14 mmHg(敏感度0.600,特異度0.787)及16 mmHg(敏感度0.800,特異度0.769)。 (2)對於長期預後,我們納入110位病患(62位男性及48位女性),平均接受Fontan手術的年齡為4.1(3.4,5.8)歲。其中91位病患有術前血清log10 N端前腦利鈉肽的數據。使用單一變項Cox迴歸分析發現,對於死亡、Fontan循環拆解手術和心臟移植,心室收縮功能不良、肺動脈壓力大於或等於15 mmHg、肺血管阻力指數以及log10 N端前腦利鈉肽數值和不良預後有關。然而在多變項Cox迴歸分析發現log10 N端前腦利鈉肽數值(風險比:24.08,95%信賴區間:3.83-151.24,P = 0.001)是唯一顯著可以預測所有主要次要終點指標的因子。接受者操作特徵曲線,N端前腦利鈉肽可用以預測主要預後指標的最佳切點是280 pg/mL (log10 N端前腦利鈉肽2.45),其敏感度為0.75而特異度為0.71。根據使用肺動脈壓、肺血管阻力指數及N端前腦利鈉肽可以建立一個評分系統,其危險分級與Fontan手術的預後相關。在術前N端前腦利鈉肽高於或等於280 pg/mL與低於280 pg/mL的病人次族群相比,有較高的術前肺血管阻力指數(1.59 [0.47,2.47] 相比於0.66 [0.31,1.37],P = 0.007)、較低的術後脈衝式血液氧氣濃度(88.3 ± 8.8相比於91.5 ± 5.8,P = 0.037)以及較高的術後Fontan壓力(15.5 ± 4.1 vs. 13.5 ± 3.3, P = 0.012)。使用Cox迴歸分析術前N端前腦利鈉肽高於或等於280 pg/mL也和較差的無事件存活率(風險比:6.30 [1.27-31.27],P = 0.024)相關。對於需住院的心衰竭,多變項迴歸分析中,唯獨有log10 N端前腦利鈉肽和不良預後相關。 結論: (1)目前Fontan手術前後的的預後近年來已經大幅進步。異位症病人手術前後的預後較差,可能和本身較差的血液動力學因子相關,經過血液動力學因子的調整過後,異位症本身並非可以預測手術前後死亡的因子。術前的肺動脈壓力和術後的中心靜脈壓是預測Fontan術後預後的最重要指標,異位症則不相關。 (2)較高的N端前腦利鈉肽與不良預後有關。使用術前的肺動脈壓力、肺血管阻力指標及N端前腦利鈉肽建立分數模型可以對於中期預後進行危險分級,選擇真正適合進行Fontan手術的病人。 未來計畫: 我們計畫分析其他肺動脈高壓的生物指標於Fontan手術的效用,以作為可替代診斷性心導管的非侵入性指標。病患於術前入院接受心導管檢查時納入收案,收集血液檢體計算其中的CEC和EPC數量。主要試驗終點為死亡、Fontan循環拆除手術及心臟移植。次要試驗終點為因為心衰竭而住院。此外也分析CEC和EPC數量和血液動力學數值的關聯性。 Background: Single-ventricular complex congenital heart disease (SV-CHD) is a rare type of congenital heart disease (CHD), which is unable to achieve biventricular repair. Heterotaxy syndrome is a special disease group in SV-CHD. It is defined as having abnormality of the thoraco-abdominal organs in the left-right axis. The more complex anatomical structure results in the more difficulty for repair or palliation. Fontan-type operation is the standard surgical procedure for achieving long-term survival in SV-CHD. The only one functional ventricle is reserved as the systemic ventricle. Without the pumping of the functional/subpulmonary right ventricle, the driving force of systemic venous return to the lungs is totally passive. Therefore, low pulmonary artery pressure and pulmonary vascular resistance are required. Fontan failure developed if the hemodynamic condition of Fontan circulation goes wrong. The most important causes that lead to Fontan failure are elevated Fontan pressure and pulmonary vascular resistance index (PVRI). Even a slight increase in PVRI may lead to markedly decreased cardiac output. Since the perioperative and late mortality/morbidity is still not low, a more comprehensive patient selection criterion for preoperative risk factors, including pulmonary artery pressure (PAP) and PVRI measurement, and analyses of biomarkers may be beneficial. The mainstay of treatment for Fontan failure is using pulmonary vasodilators to decrease the Fontan /pulmonary artery pressure and PVRI; however, there is no significant change in mortality. For the pathogenesis of pulmonary hypertension (PAH), endothelial markers (circulating endothelial cell [CEC] and endothelial progenitor cell [EPC]), extracellular matrix markers (matrix metalloproteinase [MMP]-1 and 2), and microRNA (miRNA) are involved in the pathogenesis of idiopathic PAH and Eisenmenger syndrome. However, the role of pulmonary vascular remodeling and the application of these biomarkers on Fontan operation are still unknown. Objectives: (1) We analyze the cohort of Fontan patients in National Taiwan University Children’s Hospital retrospectively to understand the risk factors and survival of perioperative and long-term outcomes. (2) We construct a risk-scoring model including only preoperative risk factors for risk stratification. Methods: Retrospectively, medical records of all patients with SV-CHD in the past 30 years were analyzed for perioperative and long term outcome. The primary outcomes were death, Fontan takedown, and cardiac transplantation. The secondary outcomes were heart failure requiring hospitalization. Results: (1) Perioperative outcomes of Fontan operation: A total of 154 patients, with a male to female ratio of 92:62, were enrolled, and the mean age at Fontan operation was 5.1 ± 2.2 years. Perioperative mortality occurred in 11 (7.1%) patients. Event-free survival after 2008 was better than that before 2007 (95.7% vs. 78.4%, respectively, P = 0.003). In our cohort, RAI (47 of 51 patients, 92.1%) comprised the majority of HS. Overall perioperative event-free survival was 91.6%. In univariable analysis, perioperative mortality was 15.7% in the patients with HS compared with 4.9% in the patients with other complex CHDs (P = 0.032). In multivariable regression analysis, preoperative risk factors including operation year before 2007 and high PAP were associated with worse outcomes. Heterotaxy syndrome was not a predictor of worse outcome after adjusting for preoperative PAP and operation era. We used the receiver operating characteristic curve to determine the cut-off points of 14 mmHg for preoperative PAP (sensitivity: 0.600, specificity: 0.787) and of 16 mmHg for postoperative CVP (sensitivity: 0.800, specificity: 0.769), with the best sensitivity and specificity. (2) For mid- to long-term outcomes, we enrolled 110 patients (62 men and 48 women). Their mean age at the time of the Fontan operation was 4.1 (3.4, 5.8) years. Preoperative NT-proBNP data were available for 91 patients. For death, Fontan takedown, and heart transplantation, in univariable Cox regression analysis, abnormal ventricular contractility, PAP ≥15 mmHg, PVRI, and log10NT-proBNP were associated with poor outcomes; whereas in multivariable analysis, only log10NT-proBNP (HR: 24.08, 95% CI: 3.83-151.24, P = 0.001) was associated with poor outcomes. According to receiver operating characteristic (ROC) curve, the best cut point of NT-proBNP value for predicting primary outcomes was 280 pg/mL (log10NT-proBNP 2.45), with the sensitivity 0.75 and specificity 0.71. A scoring system including factors of PAP, PVRI, and NT-proBNP was established, and the risk stratification is associated with outcomes after the Fontan operation. High preoperative PVRI (1.59 [0.47, 2.47] vs. 0.66 [0.31, 1.37], P = 0.007), low postoperative SpO2 (88.3 ± 8.8 vs. 91.5 ± 5.8, P = 0.037), and high postoperative Fontan pressure (15.5 ± 4.1 vs. 13.5 ± 3.3, P = 0.012) were observed in the subgroup NT-proBNP ≥ 280 pg/mL. NT-proBNP ≥ 280 pg/mL was also associated with poor event-free survival (HR 6.30 [1.27-31.27], P = 0.024) in Cox regression analysis. For heart failure requiring hospitalization and postoperative tachyarrhythmias, only log10NT-proBNP was associated with poor outcomes in multivariable analysis. Conclusion: (1) Surgical outcomes of Fontan operation in the current era are excellent. Patients of heterotaxy syndrome have higher perioperative mortality, which may relate to poor hemodynamic factors. Preoperative PAP and postoperative CVP are the most essential predictors of the outcomes of Fontan operation, whereas heterotaxy syndrome is not. (2) High preoperative NT-proBNP was associated with poor outcomes after the Fontan operation. A scoring system using preoperative PAP, PVRI, and NT-proBNP levels may stratify mid-term risks and can be used to select good candidates for the Fontan operation. Future Plans: We plan to analyze biomarkers of PAH in patients undergoing Fontan operation in order to search for a non-invasive tool for preoperative evaluation. Patients are prospectively enrolled at the time of admission for preoperative cardiac catheterization. Blood samples are collected for circulating endothelial cells (CEC) and epithelial progenitor cells (EPC) counts. The primary endpoints are death, Fontan takedown, and heart transplantation. The secondary endpoint is heart failure requiring hospitalization. Associations of CEC and EPC counts and hemodynamic values are also checked. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/79225 |
DOI: | 10.6342/NTU202204248 |
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顯示於系所單位: | 臨床醫學研究所 |
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