於不同年齡施行矯正手術之法洛氏四重症長期心肺功能之比較

Comparative Long-term Cardiopulmonary Outcomes of Tetralogy of Fallot Repaired at Different Ages

楊明浚(Ming-Chun Yang)

指導教授 ： 吳美環

國立臺灣大學/醫學院/臨床醫學研究所/碩士(2014年)

https://doi.org/10.6342/NTU.2014.01789

摘要

研究背景
法洛式四重症是最常見的發紺性先天性心臟病，其矯正手術的最佳時機仍是臨床醫師爭辯的焦點，嬰兒期早期(三個月內)及嬰兒期晚期(六到十二個月大)進行矯正手術都有專家各自支持。
這些病人在矯正手術前、手術後各自有不同的問題；矯正手術前，患者長期血氧飽合度低下、因肺動脈狹窄之故右心室壓力過度負荷，心肌功能逐漸退化。矯正手術當中，cardiopulmonary bypass及術中心臟肌肉麻痺對心肌亦可能造成傷害。矯正手術後，雖然血氧正常，但常常無法避免肺動脈瓣膜閉鎖不全的問題，導致右心室容積過度負荷，所以即使在矯正手術後，右心室功能仍可能持續惡化。
因此，此類患者不管在術前或術後，右心室處於功能衰退與心室心律不整威脅之中。開刀年齡雖然不同，術前、術後右心室持續衰退卻是不變的原則。較晚接受手術的病人，雖然長期發紺、右心室壓力負荷過度，但相對其術後右心室容積過度負荷的時間反而較短，究竟手術年齡的早晚與病人長期心肺功能有否負相關、何時為手術之最佳時機，正是我們想知道的答案。
法洛氏四重症術後患者因受其心臟矯正手術後可能殘留有肺動脈狹窄、肺動脈瓣膜閉鎖不全、心室中膈缺損、心肌功能異常、心律不整等現象，進而限制其運動之參與。目前，此疾病大多在嬰幼兒時期或兒童期的早期即進行手術矯正。過去國內外的相關研究，從未特別針對晚期矯正的病人探討其心肺功能變化，以及矯正後的長期預後。
本研究擬將「矯正手術年齡」的時間軸放大，探討「矯正年紀」與長期預後，如嚴重心室心律不整、心室功能、心肺運動能力之相關性。嘗試回答最佳開刀時機應在嬰兒期早期或嬰兒期晚期。

研究方法
每位患者皆接受靜態心電圖評估QRS duration；利用24小時心電圖監測平時時否有嚴重心室心律不整之發生；心臟超音波評估矯正後是否仍有肺動脈狹窄、肺動脈瓣膜閉鎖不全、心室中膈缺損、心肌功能異常等現象；並利用心臟磁振造影技術，量化左右心室收縮期及舒張期分別之大小，及量化肺動脈瓣膜逆流程度。每位病人接受腳踏車心肺運動功能測試並取得相關心肺功能指標，包含每分鐘最高耗氧量(peak oxygen consumption)、每分鐘換氣量(minute ventilation, VE)與二氧化碳生成量(CO2 production, VCO2)之比值(VE/VCO2)、Oxygen Uptake Efficiency Plateau (OUEP)。
本研究完成 158 位法洛氏四重症開刀患者之分析，利用迴歸分析探究運動時心肺功能與矯正年齡是否相關，並探究靜態時心室功能是否能預測運動時心肺功能指標；本研究同時亦將病患依矯正年齡分成5歲前矯正、5到10歲間矯正、10歲矯正三組，利用ANOVA test分析不同矯正年齡在運動時，心肺功能指標是否會有不同。

研究結果
158個法洛氏四重症病人之中，平均手術年齡是7.75 ± 9.05 (0.08 – 49.19)歲，接受追蹤檢查時平均年齡為29.48 ± 12.23 (6.97 – 56.99)歲，其中92位病人於5歲前開刀，31位病人開刀年紀介於5到10歲，35位病人10歲以後才矯正手術。
24小時心電圖發現有24位(15.2%)患者有Lown grade 3、4、5的嚴重心室心律不整，執行腳踏車運動心肺功能測驗時，14位(8.7%)患者出現嚴重心室心律不整，利用logistic regression分析發現，嚴重心室心律不整與矯正手術年齡無關；反之，與追蹤時年齡(p=0.036)、右心室出口狹窄壓力差大於40mmHg (p=0.005)、肺動脈逆流分率(p=0.033)、右心室舒張末期容積(RVEDV index, p<0.001)、右心室收縮末期容積(RVESV index, p<0.001)、右心室質量(RV mass index, p=0.008)有很強的相關性。
運動時心跳速率反應(chronotropic response to exercise) 中，高達56.0%的病人運動時心率無法相對應地正常增加 (chronotropic incompetence)，追蹤時年齡(p=0.006)、右心室舒張末期容積(RVEDV index, p=0.005)、右心室收縮末期容積(RVESV index, p=0.016)、右心室肌肉質量(RV mass index, p=0.040)為chronotropic incompetence之危險預測因子。矯正手術年齡與運動時心率反應(chronotropic competence)無顯著相關。
磁振造影於病人靜止狀態下進行，檢查結果中，各項參數並不因矯正手術年齡不同，而有不同之結果，包含左心室及右心室容積大小、左心室及右心室收縮分率、肺動脈瓣逆流分率，顯示手術進行的早或晚，並不影響後來的靜態心室功能。
然而，在運動狀態下的心肺功能，確實受到矯正手術進行的年齡影響。所有患者的平均peak oxygen consumption (Peak VO2)為預測值之68%，平均OUEP為預測值之90%，平均VE/VCO2 slope為27。「手術年齡」 (p=0.034) 、 「肺動脈瓣逆流分率」(p=0.036) 與Peak VO2呈線性負相關；「手術年齡」(p=0.002) 、「肺動脈瓣逆流分率」(p=0.003) 與OUEP也是呈線性負相關。

結論
由本研究得知，心臟節律問題，包含嚴重心室心律不整、運動時心跳速率反應，並不與矯正手術年齡相關。由磁振造影或心臟超音波於靜止狀態下測得的心室功能，亦與矯正手術年齡無關。然而，手術愈晚進行，運動心肺功能中的「每分鐘最高耗氧量」、「Oxygen Uptake Efficiency Plateau」將會愈差。肺動脈瓣逆流嚴重度亦與病人的長期運動心肺功能成負相關。
本研究將時間軸放大，試圖回答何時是矯正手術的最佳時機，發現隨著「矯正年齡的增加」、「肺動脈瓣逆流嚴重度」分別與病人的長期運動心肺功能顯著相關。因此，問題的答案可分兩個層次探討:
一、若嬰兒期早期矯正手術「無法」克服術後嚴重肺動脈瓣逆流的問題，寧可將手術時間延至嬰兒期晚期六至十二個月大時手術，雖然術前暴露於右心室壓力負荷及低血氧的時間較長，但只延遲六個月，相對於造成術後嚴重肺動脈瓣閉鎖不全，這六個月的時間對長期心肺功能的負面影響並不大(每晚一歲矯正，每分鐘最高耗氧量減少預測值的0.293%，OUEP減少預測值的0.377%)。
二、若嬰兒期早期矯正手術「可以」克服術後嚴重肺動脈瓣逆流的問題，如病童肺動脈環夠大、適合做non-transannular patch，則應以嬰兒期早期完全矯正為原則。

關鍵字

法洛氏四重症 ； 心肺功能

並列摘要

Background
Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease all over the world. There is still a debate about the optimal timing of total correction. Some experts recommend total repair before 3 months-old. Others suggest repair at the age between 6 months-old to 12 months-old.
Before total repair of TOF, patients experience long term hypoxemia and PS related right ventricular (RV) pressure overload, so that myocardial function deteriorates gradually. At the time of surgical repair, cardiopulmonary bypass and intraoperative cardioplegia are another factors leading to possible myocardial injury. After total repair, patients usually have pulmonary valvular insufficiency, which will cause RV volume overload.
Either before or after surgical repair, TOF patients always face the threat of RV dysfunction and ventricular arrhythmia. Even though patients receive total repair at older age, and have longer period of hypoxemia befor erpair, they experience shorter period of RV volume overload. That’s why we would like to know the association between surgical age and longterm cardiopulmonary function.
TOF patients may have exercise restriction and subnormal cardiopulmonary function at long term follow-up because of post-op residual PS, pulmonary regurgitation (PR), VSD, myocardial dysfunction and ventricular arrhythmia. With the advances in surgical techniques and postoperative care, total correction is now mostly performed in infancy or early childhood. Based on our previous study and clinical experience, ventricular dysfunction also seems to be a threat for patients who had their cardiac defects repaired relatively late. However, there is no published data regarding cardiopulmonary function and clinical outcomes in those repaired in adolescence or adulthood.
The purpose of this study is to investigate influence of surgical age on longterm outcome, such as high grade ventricular arrhythmia, ventricular function/size, and cardiopulmonary exercise capacity in TOF patients. We try to answer the question “ when is the optimal timing for total repar.”

Methods
Every patient receives 12-lead EKG to obtain QRS duration; 24-hour Holter monitor to evaluate severe ventricular arrhythmia at rest; echocardiography to assess pulmonary stenosis, pulmonary regurgitation (PR), residual ventricular septal defect and myocardial dysfunction; Cardiac magnetic resonance to quantify biventricular size and PR fraction; Cycle ergometer cardiopulmonary exercise test to obtain cardiopulmonary exercise capacity parameters, including peak oxygen consumption, ratio of minute ventilation and CO2 production (VE/VCO2), Oxygen Uptake Efficiency Plateau (OUEP).
In this study, 158 TOF patients will be evaluated. Regression analysis was applied to analyze the association between repair age and exercise cardiopulmonary parameters. Regression analysis was also used to realize the association between resting myocardial function and exercise cardiopulmonary function.
We also divided patients into 3 subgroups according to their surgical age (< 5 year-old, 5 to 10 year-old, > 10 year-old). ANOVA was applied to compare the differences in cardiopulmonary exercise parameters between these three subgroups.

Results
The mean age of surgery among the 158 TOF patients was 7.75 ± 9.05 (0.08 – 49.19) years old, and the mean age of follow-up was 29.48 ± 12.23 (6.97 – 56.99) years old. Nity-two patients underwent surgical correction before 5 years old, 31 patients between the age of 5 and 10, and 32 patients after 10 years old.
Twenty-four (15.2%) patients developed Lown grade 3, 4, 5 ventricular arrhythmia on 24-hour Holter tracing. Fourteen (8.7%) experienced Lown grade 3, 4, 5 ventricular arrhythmia while doing cycle ergometer exercise test. By using logistic regression analysis, high grade ventricular arrhythmia was not related to surgical age. However, high grade ventricular arrhythmia was strongly related to age at follow-up (p=0.036), right ventricular outlet tract obstruction (p=0.005), PR fraction (p=0.033), right ventricle end-diastolic volume index (p<0.001), right ventricle end-systolic volume (p<0.001), right ventricle mass index (p=0.008).
Inadequate acceleration of heart rate during exercise (chronotropic incompetence) occurred in 56% of patients. Chronotropic incompetence was related to age at follow-up (p=0.006), right ventricular end-diastolic volume index (p=0.005), right ventricular end-systolic volume index (p=0.016), right ventricle mass index (p=0.040). Surgical age was not a predictor of chronotropic incompetence.
Cardiac magnetic resonance (CMR) was performed at resting state. All the parameters measured on resting CMR, including left ventricular volume, right ventricular volume, biventricular ejection raction and pulmonary regurgitation fraction, were not related to surgical age.
However, we found exercise cardiopulmonary function was related to surgical age. Among the 158 TOF patients, mean peak oxygen consumption was 68% of predicted value. Mean OUEP was 90% of predicted value. Mean VE/VCO2 slope was 27. Surgical age (p=0.034) and PR fraction (p=0.036) were inversely related peak oxygen consumption with a linear relationship. Surgical age (p=0.002) and PR fraction (p=0.003) were also inversely related to OUEP.

Conclusion
Based on our study, cardiac rhythm disorder, including high grade ventricular arrhythmia and chronotropic incompetence, was not related to surgical age. Resting ventricular function, which was inspected with CMR and echocardiography, was not related to surgical age, either. However, peak oxygen consumption and Oxygen Uptake Efficiency Plateau were inversely related to surgical age. Severity of PR was also a significant parameter that inversely related to longterm exercise cardiopulmonary outcome.
This study tried to find out when is the optimal timing for total correction. We found age at total repair was as important as PR severity. To answer the question “when will be the best timing of total correction”, we should take both PR and surgical age into consideration.
1.If significant post-op PR is not avoidable, we would rather postpone total repair to 6 to 12 months old. Although they have longer period of hypoxemia, the effects on longterm cardiopulmonary function are only mild. (Based on our study, postponing surgery for every 1 year leads to decrement of peak oxygen consumption 0.293%, and decrement of OUEP 0.377%.)
2.If significant PR can be avoid, early total correction is recommended in order to achieve better long-term exercise function.

並列關鍵字

Tetralogy of Fallot ； Cardiopulmonary Outcomes

參考文獻

Apitz C SL, Latus H, Kerst G, Baden W, Hofbeck M.: Impaired contractility reserve in response to dobutamine stress -preclinical indicator for right ventricular dysfunction in asymptomatic patients with pulmonary regurgitation. Circ 2008;118:S962-963.

Apitz C, Webb GD, Redington AN: Tetralogy of fallot. Lancet 2009;374:1462-1471.

Babu-Narayan SV KP, Li W, Moon JC, Goktekin O, Davlouros PA, Khan M, Ho SY, Pennell DJ, Gatzoulis MA. : Ventricular fibrosis suggested by cardiovascular magnetic resonance in adults with repaired tetralogy of fallot and its relationship to adverse markers of clinical outcome. . Circ 2006;113:405-413.

Borow KM GL, Castaneda AR, Keane JF.: Left ventricular function after repair of tetralogy of fallot and its relationship to age at surgery. . Circ 1980;61:1150-1158.

Bouzas B KP, Gatzoulis MA. : Pulmonary regurgitation: Not a benign lesion. Eur Heart J 2005;26:433-439.