子癲前症之麻醉及相關研究

Anesthesia in Preeclampsia and Related Researches

陳李魁(Li-Kuei Chen)

指導教授 ： 孫維仁 ； 謝豐舟

國立臺灣大學/醫學院/臨床醫學研究所/博士(2007年)

https://doi.org/10.6342/NTU.2007.02685

摘要

本論文的宗旨為子癲前症產婦麻醉相關之臨床與基礎相關研究。雖然大多數產科病人為年輕的健康人，但是婦產科手術麻醉仍然屬於高風險麻醉，原因在於懷孕婦女所發生的生理變化使得麻醉風險提高，根據美國1985到1990年的統計，每一百萬次生產就有1.7個產婦因麻醉致死，大部分發生在剖腹產尤其是緊急剖腹產。事實上剖腹生產麻醉是一般手術麻醉風險的兩倍。產科麻醉的範圍包括剖腹生產麻醉與其手術後之止痛、協助高危險妊娠產婦之處理、自然生產時之無痛分娩。剖腹生產麻醉可以選擇全身麻醉或半身麻醉，除了特定狀況發生，如母親或胎兒突發的健康狀況不佳（如突發胎兒窘迫症、產婦大量出血等），須在最短時間內將胎兒產出時，或在醫療評估後（評估內容與無痛分娩一樣）有不適宜做半身麻醉者，才採用全身麻醉。一般而言，如果無上述特殊問題時，都是採用半身區域性麻醉。半身麻醉又可分為硬脊膜外及硬脊膜內麻醉。以技術而言，硬脊膜外麻醉技術比硬脊膜內困難，且需要等待較長時間才會產生麻醉作用；但因為硬脊膜外麻醉、止痛技術有以下的特點：（一）硬脊膜外麻醉對於母體血壓影響較硬脊膜內少，因此對胎兒的影響相對減少。（二）置放一加藥導管，因此可隨時加藥配合手術或自然生產待產時間。（三）用於術後止痛，使產婦儘可能免除開刀後疼痛的問題，更因早期下床可促進血液循環，使傷口儘早癒合。所以硬脊膜外麻醉、止痛技術無論在剖腹生產麻醉或硬脊膜外減痛分娩時都被廣泛接受、使用；只是減痛分娩施行硬脊膜外持續注射局部麻醉藥物，所使用的藥物或藥物濃度與剖腹生產硬脊膜外麻醉時不同。本論文的第一部分是有關高危險妊娠產婦中常見的子癲前症探討，第二部分主要是希望探討硬脊膜外止痛（減痛分娩）對一般健康產婦或子癲前症產婦的子宮或胎兒血流量的影響。第三部分主要是研究施行硬脊膜外麻醉、止痛技術，因意外穿刺硬脊膜所引起特殊頭痛的相關議題。
論文中的第一部分為針對台灣產婦子癲前症可能的致病機轉，進行基因多形性的關連性研究。題目為：「血管內皮細胞一氧化氮合成酵素的基因多形性對於臺灣族群產婦子癲前症的形成可能具有保護的作用」。產婦子癲前症無論在任何種族身上，一直是高危險妊娠產婦中常見也是非常棘手的懷孕併發症，長久以來其致病的真正機轉或可能原因也是許多研究學者想要破解的『謎團』。血管內皮細胞一氧化氮合成酵素的基因多形性，與西方國家族群心血管疾病的相關性，或是與日本族群產婦嚴重子癲前症形成的關連性，在過去都已被報告或證實；然而卻欠缺臺灣族群中血管內皮細胞一氧化氮合成酵素基因多形性與產婦子癲前症是否相關的資料。第一部分的研究，主要針對92位患有子癲前症的台灣產婦（實驗組）與256位正常健康台灣產婦（對照組），進行子癲前症與血管內皮細胞一氧化氮合成酵素基因兩種常見多形性間的關連性研究。根據以前的報告，血管內皮細胞一氧化氮合成酵素基因型態兩種常見多形性分別是：位於血管內皮細胞一氧化氮合成酵素基因第七編碼序列位置的Glu298Asp多形性與位於血管內皮細胞一氧化氮合成酵素基因第四內含子位置的27對重複出現鹼基配對多形性；無論是血管內皮細胞一氧化氮合成酵素基因第七編碼序列上的T對偶基因或是第四內含子上的血管內皮細胞一氧化氮合成酵素4a對偶基因，出現在患有子癲前症的台灣產婦的頻率，在統計上都顯著的低於出現在正常健康台灣產婦。血管內皮細胞一氧化氮合成酵素基因型態的分佈，無論是血管內皮細胞一氧化氮合成酵素基因第七編碼序列上的 Glu298Glu、Glu298Asp及Asp298Asp或是血管內皮細胞一氧化氮合成酵素基因第四內含子上的bb及ab基因型態，在兩組病患上出現的頻率都具有統計上顯著的差異。這是第一個實驗設計針對臺灣族群產婦，同時分析兩種常見的血管內皮細胞一氧化氮合成酵素基因多形性與子癲前症間的關連性研究。本部分研究的結論是，與西方國家族群的研究發現類似，血管內皮細胞一氧化氮合成酵素基因的兩種常見的基因多形性，對於臺灣族群產婦子癲前症的形成應該具有保護的作用，此推論與針對日本族群中，產婦嚴重子癲前症之形成與血管內皮細胞一氧化氮合成酵素基因多形性間的關連性研究結果並不相同。
論文中的第二部分為針對自然生產待產孕婦接受硬脊膜外減痛分娩時，探討在不同時段使用硬脊膜外持續注射局部麻醉藥物，對於子宮動脈都卜勒超音波血流速度測量的影響。題目為：「在自然生產的不同時段使用持續性硬脊膜外止痛對於子宮動脈都卜勒超音波血流速度測量的影響」。硬脊膜外持續注射局部麻醉藥物是近年來最常被使用、接受，也是被公認相對安全的減痛分娩方法。過去大多認為硬脊膜外注射的局部麻醉藥物應該不會進入產婦體內血液循環，因此雖然硬脊膜外注射局部麻醉藥物往往持續5-6個小時以上，仍相信該方法對胎兒應該是非常安全的。過去硬脊膜外減痛分娩對胎兒出生結果的報告，也多只探討硬脊膜外減痛分娩對胎兒心跳變化的影響，或是分析對胎兒出生後的阿普加分數及血液中酸鹼度的變化；而過去的報告也都幾乎一致認為，硬脊膜外減痛分娩對胎兒的出生結果無明顯的負面影響。只是硬脊膜外注射局部麻醉藥物（0.25-0.5% bupivacaine）對於子宮動脈與臍血流都卜勒超音波血流量的短暫影響已經被報告過，但是自然生產減痛分娩時，使用硬脊膜外持續注射低劑量局部麻醉藥物（0.05-0.1% bupivacaine）對於子宮動脈與臍血流都卜勒超音波血流量的影響從未被報告過。因此我們設計本實驗來探討硬脊膜外持續注射低劑量局部麻醉藥物（0.075% bupivacaine）對子宮動脈都卜勒超音波血流量的影響。本實驗包含20位產婦於自然生產減痛分娩時接受硬脊膜外持續注射0.075% bupivacaine。我們使用4-MHz持續波的都卜勒探頭（Multigon 500A）帶有200Hz thump filter來測量子宮動脈的血流速度。在自然生產減痛分娩過程中的五個不同時間點（硬脊膜外導管放置前、硬脊膜外持續注射0.075% bupivacaine後1小時、2小時、4小時及停止硬脊膜外持續注射0.075% bupivacaine後4小時），於子宮舒張或收縮時，我們分別記錄當時的子宮動脈的血流速度。我們的資料顯示在硬脊膜外持續注射0.075% bupivacaine後1小時、2小時及4小時後，子宮動脈血管阻力的血流速度參數明顯地比硬脊膜外導管放置前升高；但這些參數於停止硬脊膜外持續注射0.075% bupivacaine後4小時，又下降到硬脊膜外導管放置前的基線。本部分研究的結論是自然生產減痛分娩時接受硬脊膜外持續注射0.075% bupivacaine明顯地升高子宮動脈血管的阻力，因此可能會降低子宮動脈的血流量。
論文中的第三部分為探討台灣婦女使用硬脊膜外注射血液補釘法，可以有效治療硬脊膜穿刺引起頭痛時所需要的適當血液量；題目為：「研究治療台灣婦女使用硬脊膜外注射血液補釘法有效治療硬脊膜穿刺引起頭痛所需要的適當血液量」。硬脊膜外注射血液補釘法是臨床上最常被用來治療因硬脊膜穿刺引起頭痛的有效方法之一，但對於最適量且有效的血液注射量仍有爭議而無定論。因此我們設計本實驗來比較經由硬脊膜外導管注射7.5mL血液或15mL血液，對治療硬脊膜穿刺頭痛的臨床效果。針對33位接受剖腹生產硬脊膜外麻醉或自然生產硬脊膜外減痛時，因意外硬脊膜穿刺引起嚴重頭痛的台灣孕婦，被隨機的分為兩組。硬脊膜外注射血液被用來治療硬脊膜穿刺引起的嚴重頭痛。第一組病患（17名）在採半坐姿下經由硬脊膜外導管注射7.5mL血液，第二組病患（16名）接受7.5mL血液注射。兩組所有的病患在接受硬脊膜外注射血液治療後的第一、二十四小時及三天後，分別使用四分的疼痛評估表（無疼痛、輕微、中度或重度疼痛）來紀錄其因硬脊膜穿刺引起頭痛的程度。在所有的時間點（硬脊膜外注射血液治療後的第一、二十四小時及三天後)，兩組病患因硬脊膜穿刺引起的頭痛程度並沒有統計學上顯著的差別。第一組病患中有兩名在接受硬脊膜外注射血液治療時引發脊椎神經根的刺激性疼痛，而第二組病患中有九名抱怨相同的症狀於接受硬脊膜外注射血液治療時，具有統計學上明顯的差異（p < 0.05)。在整個硬脊膜外注射血液治療過程中，並沒有病患產生其他明顯的併發症。 本部分研究的結論是，在採半坐姿下經由硬脊膜外導管注射7.5mL自體血液對於因硬脊膜穿刺引起頭痛的臨床治療效果與注射15mL血液相當，但卻大大降低因硬脊膜外注射血液所引發脊椎神經根刺激性疼痛的比率。
產科麻醉中最棘手的難題就是高危險妊娠產婦的止痛、麻醉，其中以產婦子癲前症是臨床上最常遇見的懷孕併發症之一。過去曾有不少報告，針對不同種族進行研究血管內皮細胞一氧化氮合成酵素基因多形性與產婦子癲前症形成間的關聯性，其結論不盡相同也引發不少爭議；然而至今仍然缺乏針對臺灣族群研究報告的資料。此外硬脊膜外減痛分娩是近年來最常被使用、接受的方法，只是臨床上硬脊膜外注射局部麻醉藥物往往需持續5-6個小時以上，其可能對產婦子宮或胎兒血流的影響卻未曾被探討研究過。硬脊膜外注射血液補釘法是臨床上最常被用來治療因硬脊膜穿刺引起頭痛的有效方法，過去對於最適量且有效的血液注射量，大多是參考國外的研究報告，但卻發現硬脊膜外注射較高血液量時，往往會導致注射血液引發的神經疼痛；然而針對台灣婦女接受硬脊膜外注射血液補釘法時，所需最適量且有效的血液注射量也未曾被探討研究過。本論文就是針對上述三個部分的問題，提出適當的假設，進行研究、實驗與分析，並獲得合理的推論與結論。

關鍵字

子癲前症 ； 基因多形性 ； 血管內皮細胞一氧化氮合成酵素 ； 硬脊膜外減痛分娩 ； 子宮動脈血流量 ； 硬脊膜穿刺引起頭痛 ； 硬脊膜外注射血液補釘法

並列摘要

The main objective of this thesis is focus on the clinical and basic research of obstetric anesthesia & analgesia. Although the majority of obstetric patients are young and healthy women, risk of obstetric anesthesia is still much higher than the other field of anesthesia, due to the unpredictable physiological change of those pregnant women. According the statistics from 1985 to 1990 in US, every 1,000,000 parturient women happened to produce 1.7mortality, attributed to the risk and complications of obstetric anesthesia, particularly for urgent Caesarean section. In fact, the risk of obstetric anesthesia is almost 2 times higher than anesthesia for general operation. The scope of obstetric anesthesia includes anesthesia for cesarean section, including post operative pain conrol0, the anesthetic management of high risk pregnancy and painless labor during natural spontaneous delivery. Either general or regional anesthesia could be applied for cesarean delivery anesthesia, but for general practice, regional anesthesia should be superior to general, due to the safety consideration for mother and fetus. Clinically under some special conditions or dangerous situations for parturient or fetus (like the spontaneous fetal distress or unexpected massive bleeding of pregnant women in labor), general anesthesia should be conducted immediately, in order to deliver the fetus as soon as possible. Both spinal and epidural anesthesia are categorized as the regional anesthesia. Technically, epidural anesthesia is more difficult, complicated and risky than spinal anesthesia, and epidural anesthesia always needs longer time for the onset of drug effect. Due to the following characteristics: (1) Less influence on the blood pressure of parturient, with less negative impact on the fetus. (2) Anesthetic or analgesic drug for operaton or for painless could be injected through the epidural catheter at any time. (3) More analgesic effect and convenient, epidural analgesia for post operative pain control is better for early ambulation and for wound healing, epidural anesthesia or analgesia for painlees labor and obstetric anesthesia (including post operative pain relief) could be accepted and used widely in clinical practice. Except the different drug or different dose injected through epidural catheter, the thechnique of epidural anesthesia for obstetric anesthesia or painless lobor might be similar. In the first part of this thesis, preeclampsia (one of the common disease of high risk pregnancy) is the target for study. In the second and third part of this thesis, the issues of epidural for obstetric anesthesia or painless lobor could be the focus for research.

Part I
The first part of the study tries to elucidate the pathogenesis of preeclampsia, through the evaluation on the association study between Taiwanese pregnant women with preeclampsia and the genetic polymorphism of endothelial nitric oxide synthase.
Li-Kuei Chen, Chi-Hsiang Huang, Heui-Ming Yeh, Chien-Nan Lee, Ming-Kwang Shyu, Fon-Jou Hsieh, Ling-Ping Lai , Wei-Zen Sun. Polymorphisms in the Endothelial Nitric Oxide Synthase Gene May Be Protective Against Preeclampsia in a Taiwanese Population. Reproductive Sciences 2007; 14: (2): 175-181.
Preeclampsia (PE) is a common disease of human pregnancy with an unidentified genetic component. Past reports have demonstrated that endothelial nitric oxide synthase (eNOS) gene is associated with vascular diseases in western countries population and severe PE in the Japanese population. The association data between PE and eNOS gene is lacking in the Taiwanese population. Therefore, we examined the association between PE and two common polymorphisms of maternal eNOS gene in a Taiwanese population.We included 92 women with PE (systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg, on at least two occasions 6 hours apart, and proteinuria > 0.3 g/L or a dipstick proteinuria reading of 2+) and 256 healthy control pregnant who were genotyped for the Glu298Asp polymorphism in exon7 and the number of 27 base-pair repeats in intron 4 of the eNOS gene. The frequency of the variant T allele was significantly lower in PE group than in control group (9.24% vs 18.16%, p<0.05) and the frequency of eNOS4a (small allele with 4 repeats of 27 bp) was also significantly lower in PE group than in control group (4.9% vs 9.8%, p<0.05). The genotype distribution of Glu298Glu, Glu298Asp and Asp298Asp in eNOS exon 7 revealed statistically significant differences between control and PE groups (71.1% vs 84.8%, 21.5% vs 12.0% and 7.4% vs 3.2% respectively, p<0.05). The genotype distribution of bb type and ab type in eNOS intron 4 was also significantly different between control and PE groups (80.5% vs 90.2% and 19.5% vs 9.8%, p<0.05). This is the first study to evaluate the association between two polymorphisms in maternal eNOS gene with PE simultaneously in a Taiwanese population. Similar to the findings in other western countries population, but in contrast to the result in other Japanese populations, polymorphisms in the eNOS gene may be protective against PE in a Taiwanese population.

Part II
The second part of the study tries to invesigate the effects of continuous epidural local anesthetic (0.075% bupivacaine) on the Doppler velocimetry of uterine arterie at five different periods during painless labor.
Li-Kuei Chen, Chen-Jung Lin, Chi-Hsiang Huang, Mao-Hsien Wang, Pei-Lin Lin, Chien-Nan Lee, Wei-Zen Sun. The Effects of Continuous Epidural Analgesia on Doppler Velocimetry of Uterine Arteries during Different Periods of Labour Analgesia. Br J Anaesth. 2006; 96(2):226-30.
The effects of epidural anaesthesia with 0.25-0.5% bupivacaine on the Doppler velocimetry of umbilical and uterine arteries for caesarean section pregnant women had been reported, but the effects of continuous epidural with lower dose bupivacaine (0.05-0.1%) infusion for labour analgesia on the Doppler velocimetry of uterine arteries have never been reported. In this study, we evaluated the effects of continuous epidural 0.075% bupivacaine on the Doppler velocimetry of uterine arteries. Twenty pregnant women for labour analgesia received continuous epidural 0.075% bupivacaine infusion. We used a 4-MHz continuous-wave Doppler probe (Multigon 500A) with a 200-Hz thump filter to detect uterine blood flow velocity. We recorded the velocimetry data of uterine blood flow (during uterine relaxation and contraction) in five periods: pre-epidural insertion, 1 hr, 2 hr and 4 hr post-epidural infusion and after foetus delivered to evaluate the effects of continuous epidural bupivacaine infusion for labour analgesia on the uterine blood flow. Our data showed that when uterus was under relaxation or contraction condition, the mean velocimetric indices (S/D ratio, PI and RI) of uterine artery were significantly increased post-epidural infusion (1h, 2h and 4 hr) when compared with the pre-epidural level, but almost returned to baseline post-delivery. This study demonstrates that continuous epidural analgesia for labour analgesia with 0.075% bupivacaine increases the resistance of uterine artery and therefore possibly reduces the uterine blood flow. Further studies are required to elucidate whether the decrease of uterine blood flow during epidural labour analgesia with 0.075% bupivacaine will result in a significant clinical impact on the fetus or the mother.

Part III
The third part of the study tries to evaluate the optimal and effective blood volume in conducting epidural blood patch for Taiwanes pregnant women with post-dural puncture headache (PDPH).
Li-Kuei Chen, Wei-Horng Jean, Chi-Hsiang Huang, Cheng-Wei Lu, Chen-Jung Lin, Wei-Zen Sun, Mao-Hsien Wang. The Effective Epidural Blood Patch Volume to Treat Post Dural Puncture Headache for Taiwanese Women. J Formos Med Assoc, 2007; 106(2): 134-140.

Epidural blood patch (EDBP) is the most commonly used method to treat post-dural puncture headache (PDPH). The optimal and effective blood volume for epidural injection is still controversial and under debated. This study is designed to compare the therapeutic efficacy of 7.5 ml blood vs 15 ml blood for EDBP via epidural catheter injection.Thirty-three patients who suffered from severe PDPH due to accidental dural puncture during epidural anesthesia for cesarean section or epidural analgesia for labor pain control were randomly allocated into to two groups. EDBP was conducted and autologous blood 7.5 ml or 15ml was injected via an epidural catheter in semi-sitting position in group I (N=17) and II (N=16). For all patients in both groups, the severity of the PDPH was registered on a four-point scale (no, mild, moderate, severe) and assessed 1 hour, 24 hours and 3 days after EDBP. The rates of different severity of PDPH (no, mild, moderate, severe) before EDBP were 0/17, 0/17, 2/17, 15/17 and 0/16, 0/16, 1/16, 15/16. 1 hour after EDBP in group I and II were 10/17, 6/17, 1/17, 0/17 and 8/16, 6/16, 2/16, 0/16 respectively, without any statistically difference. 24 hour after EDBP in group I and II were 12/17, 4/17, 1/17, 0/17 and 11/16, 4/16, 1/16, 0/16 respectively, without any statistically difference. 3 days after EDBP in group I and II were 15/17, 2/17, 0/17, 0/17 and 13/16, 3/16, 0/16, 0/16 respectively, without any statistically difference. No special side effects or complications happening to any patient in both Groups during or after EDBP injection was noted, except 2 patients (2/17) in Group I complaining nerve root irritating pain during 7.5 ml blood injection for EDBP and 9 patients (9/16) in Group II with the same complaint during blood injection.From the result of this study, we may conclude that half blood volume with 7.5 ml for EDBP could provide almost the same effect to treat PDPH, but reduce the incidence of nerve root irritating pain when compared with larger blood volume

並列關鍵字

preeclampsia ； genetic polymorphism ； endothelial nitric oxide synthase ； epidural painless ； uterine blood flow ； post-dural puncture headache ； pidural blood patch

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