臺灣博碩士論文加值系統

背景：
硬膜外止痛術是自然生產常用的止痛方式，其止痛的效果十分良好。但是在硬膜外腔使用局部麻醉劑，會造成脊椎神經的阻斷，引起肌肉力量喪失、血管擴張，造成各種的副作用。近年來，為了減少對下半身運動與感覺神經的阻斷，硬膜外無痛分娩的配方做了一些調整。目前的做法是調降硬膜外局部麻醉劑的濃度，並且在硬膜外腔同時併用嗎啡類藥物。如此可讓止痛的效果不致因局部麻醉劑劑量的減少而受到影響，又可減少各種神經阻斷所產生的副作用，連帶的使器械生產的比率減少，並使產婦有更大的活動能力。
硬膜外局部麻醉劑除了會造成運動神經阻斷外，也會阻斷交感神經，致使血管阻抗下降與靜脈容積增加。交感神經阻斷讓大量的血液滯留在周邊血管，會使病患的血壓降低。由於產婦的子宮血流量和血壓成正相關，產婦血壓的降低會減少子宮血流，增加胎兒缺氧的危險。
目前大部分的研究認為，神經纖維對局部麻醉劑的敏感度和神經纖維的粗細有關。細小且不具髓鞘的神經纖維比較容易受到低濃度局部麻醉劑的阻斷，而較粗、具髓鞘的神經纖維則需要比較高濃度的局部麻醉劑才能阻斷其傳導。臨床上的觀察也得到相同的結論，亦即低濃度的硬膜外局部麻醉劑會阻斷痛覺等小神經纖維的傳導，但運動等大纖維神經則較不受影響。
因為人體的交感神經纖維比運動神經纖維更為細小，對於局部麻醉劑的敏感度可能比運動神經為高。即使降低硬膜外腔局部麻醉的劑濃度可以減少運動神經的阻斷，但是否也能同時減少交感神經的阻斷，目前並不清楚。因此本研究的目的，是要利用雷射都卜勒血流計測量產婦下肢皮膚血流的變化，來探討低濃度的硬膜外局部麻醉劑對於交感神經所產生的影響。
方法：
本計劃選取30位屬於美國麻醉醫學會體位分級第I及第II級、懷孕36-42週、子宮頸開約2-5公分、自然生產或住院引產並且要求硬膜外止痛術的初產婦。研究的排除標準為：體重大於90公斤、年齡大於40歲、抽煙、之前有使用嗎啡或心臟血管藥物、有產科方面併發症與對硬膜外止痛有禁忌的病人。
我們採用雙盲的實驗設計，將這些病人隨機平分為A、B兩組。在硬膜外導管植入之前，我們會先給予產婦靜脈注射500-1000 ml的林格氏溶液。產房的溫度保持在22-26°C之間。在給予硬膜外止痛前先記錄產婦的心跳、血壓、下肢力量、疼痛程度、體溫、手背、腳背皮膚溫度與血流。產婦疼痛程度的測量是使用100-mm visual analog scale，下肢力量的測量是使用modified Bromage score。
我們在產婦的腰椎第三、四節或第四、五節間植入硬膜外導管，並使用loss-of resistance technique來確定硬膜外針頭的位置。本研究不使用硬膜外試劑。在硬膜外給藥前，我們會由硬膜外導管回抽，來確定硬膜外導管是否置入椎管內腔或血管中。在硬膜外導管植入過程中不小心發生硬膜穿刺的產婦，將被排除於研究之外。
在A、B兩組中的每一位產婦，將分別給予不同的硬膜外止痛藥劑。A組中的產婦將給予15 ml含有50mg fentanyl的0.07% ropivacaine； B組中的產婦則給予15 ml不含fentanyl的0.25% ropivacaine。在給完這些藥劑之後，產婦將經由硬膜外導管每小時持續給予12 ml含有2 mg/ml fentanyl的0.07% ropivacaine。
在給藥三十分鐘後，我們將重新測量兩組產婦的產房溫度、體溫、疼痛程度、麻醉高度、下肢力量、手背、腳背的皮膚溫度與血流。此外我們同時也記錄產婦使用ephedrine的劑量與是否出現顫抖、噁心與嘔吐的現象。
結果：
本研究中的30位產婦均完成資料的收集，沒有產婦被排除於研究之外。兩組產婦在止痛前後的疼痛程度、麻醉高度、體溫、產房室溫、ephedrine使用量與噁心、嘔吐的發生率均近似，沒有顯著的差異。
在手部皮膚溫度與血流變化方面：止痛前後A組產婦手部的皮膚溫度上升了0.4 ± 2.4°C；皮膚血流上升了41.7 ± 193%。B組產婦手部的皮膚溫度下降了0.1 ± 1.6°C；皮膚血流下降了20.8 ± 52.5%。雖然A組手部的皮膚溫度略有上升，B組略有下降，但兩組間並無顯著差異。
在腳部皮膚溫度與血流變化方面：在止痛前後A組產婦腳部的皮膚溫度上升了0.5 ± 1.4°C；皮膚血流上升了19.3 ± 81.2%。B組產婦腳部的皮膚溫度則上升了3.7 ± 2.7°C；皮膚血流上升了175.5 ± 256%。A組產婦腳部的皮膚溫度與血流在硬膜外止痛後幾乎沒有改變，但B組卻有顯著的上升。兩組間腳部皮膚溫度變化差異的p值小於0.001；皮膚血流變化差異的p值為0.03，兩者都有顯著差異。
兩組產婦在硬膜外止痛後的心跳與血壓，均出現下降的情形。但除了B組產婦的舒張壓下降的程度明顯大於A組產婦以外 (p = 0.01)，其他均無顯著差異。
結論：
我們認為硬膜外混和使用0.07%的 ropivacaine與 50mg fentanyl比單獨使用0.25%的ropivacaine，對交感神經造成的影響比較少。

Background:
The pain of labor increases from the latent phase and reaches the maximal intensity at the second phase of the labor. About fifteen percent of pregnant women experience mild pain during labor, thirty-five percent experience moderate pain, thirty percent severe pain and twenty percent very severe pain.
Labor pain stimulates respiration markedly. Minute ventilation increases three folds and the arterial carbon dioxide tension may be lower than 10-20 mmHg. Respiratory alkalosis associated with maternal hyperventilation increases the rate of hypoxic episodes and the risk of fetal distress. Therefore, proper administration of analgesia to the labor women not only decreases mortality and morbidity, but also decreases the risks of labor.
Pain during the first stage of labor results primarily from uterine contractions and dilation of the cervix. Pain is transmitted by visceral afferent nerve fibers that accompany the sympathetic nerves and enter the spinal cord at the T10 to L1 segments. During the late first stage and second stage of labor, pain results form distention of the pelvic floor, vagina, and perineum. Pain is transmitted by somatic nerve fibers, which enter the spinal cord at the S2 to S4 segments. To produce adequate analgesia, regional anesthesia must block pain fibers at these segments.
Epidural analgesia is a frequently used, vary effective analgesic method of vaginal delivery. Except blocking the nerve fibers transmitting pain, epidural local anesthetics also block other spinal nerve fibers and then result in motor blockade and sympathetic blockade. Many efforts were made to diminish the extent of the motor blockade and the related side effects such instrumental delivery. The regimen of epidural analgesia has been readjusted in the recent years. Diluted local anesthetics and opioids are used simultaneously in labor epidural analgesia. Consequently, the degree of motor block can be reduced and analgesic effects maintained.
In addition to the side effects resulting from motor blockade, sympathetic blockade that associated with epidural local anesthetics decreases systemic vascular resistance and increases venous capacitance. This will result in decreased systemic resistance, peripheral venous pooling of blood and then develop maternal hypotension. In general, the higher the level of sympathetic blockade, the greater the incidence and severity of hypotension. Because there is no autoregulation of blood flow to the uterus, so the fetus is highly sensitive to decreased maternal arterial blood pressure. The fetal consequences of the reduced uterine blood flow depend on the degree and duration of the fall of blood pressure. When uterine blood flow is inadequate, fetal asphyxia will then develop.
The sensitivity of nerve fibers to local anesthetics depends on nerve fibers’ thickness. Gasser et al proposed that thin, nonmyelinated nerve fibers with low transmission velocity are easy to be blocked by low concentrated local anesthetics than the thick, myelinated nerve fibers. Although this concept still has been questioned, however, many clinical observations support it. In clinical, low concentration of epidural local anesthetics blocks the pain fibers but leave the thick sensory and motor fibers unaffected. Because sympathetic fibers are thinner than motor fibers, they may be more sensitive to epidural local anesthetics. We do not know, when we dilute epidural local anesthetics in order to decrease the extent of motor block, whether can we also decrease the extent of sympathetic blockade at the same time.
Although sympathetic nerve system produces different effects on different kinds of organs, it is difficult to measure the sympathetic activity directly and there are no standardized criteria to define the strength of sympathetic action. Many investigators studied the extent of sympathetic blockade by indirect methods. Among the indirect methods, change of skin temperature and cutaneous blood flow are commonly used to detect the sympathetic blockade of spinal or epidural anesthesia.
In general, lumbar epidural or spinal anesthesia dilate the blood vessel of lower extremities then increase their blood flow and peripheral temperature. But reflex vessel constriction occurs on the unblocked upper body in response to decreased blood pressure and core temperature. Most anesthesiologists believe that epidural or spinal anesthesia produce higher level of sympathetic block than the level of sensory block. But some reports do not support it. Furthermore, because different study methods made different results, there are still arguments about spinal or epidural produce either complete or incomplete sympathetic blockade on lower extremities.
Laser Doppler flowmetry is an easy-applied, noninvasive and very sensitive method to measure tissue microcirculation. Laser Doppler flowmetry samples the circulating speeds of all red cells located within a measuring area corresponding approximately to a semi-sphere with a diameter of 1 millimeter. Because laser Doppler signal is proportional not only to the mean speed but also to the number of red cells moving through the sampled tissue volume, the signal may be considered as a semi-quantitative index of tissue perfusion.
By measuring the change of skin blood flow of extremities with laser-Doppler flowmetry, this study was designed to detect the different quality of sympathetic blockade between different concentrations of epidural local anesthetic.
Materials and Methods:
After institutional review approval and written informed consent were obtained, 30 nulliparous uncomplicated parturiates, classified as ASA physical status I or II, who presented in spontaneous labor or were scheduled to be admitted for elective induction of labor were enrolled. Study inclusion criteria were 36-42 weeks’ gestation, singleton pregnancy in the vertex position, a normal fetal heart rate pattern, requesting epidural analgesia, and 2-5 cm cervical dilatation at the time of epidural insertion. The exclusion criteria were: weight > 90 kg, age > 40 yr, smoking history, previous administration of opioids or vasoactive agents, the presence of obstetric complications (e.g. preeclampsia, diabetes mellitus) and a contraindication to epidural analgesia or allergic reaction to ropivacaine or fentanyl.
Under the double-blinded study design, study patients were randomly assigned into one of two groups. Following request for epidural analgesia each woman received 500-1000 ml of compound lactate solution before the initiation of epidural analgesia. Room temperature was kept at 22-26°C. Before the procedure was begun, the patients’ vital signs (blood pressure, heart rate, and respiratory rate) core temperature and peripheral temperature were documented. Each patient completed baseline assessments using a 100-mm visual analog scale (VAS) for pain and a modified Bromage score for muscle power of lower limbs. Patients were asked to relate any symptoms of nausea, vomiting or shivering during laboring. All of observations were performed by individuals blinded to the analgesic technique. During the course of labor all parturiates were under fetal heart beat monitor.
The epidural catheters were inserted at either the L3-4 or L4-5 interspaces under lateral position. The epidural space was identified with a 16-gauge epidural needle by using a loss-of-resistance technique. A multiple orifice epidural catheter was then inserted 4-5 cm into the epidural space. Aspiration was attempted from the epidural catheter in an effort to detect either intravascular or intrathecal placement of the catheter. Patients with any signs of accidental dural puncture or intravascular catheter placement would be excluded from this study. After the epidural catheter was secured, the parturient was asked to maintain lateral position.
Each parturiates in two groups received different study solutions to initiated epidural analgesia. The study solutions consisted of either: 15 ml ropivacaine 0.07 % plus 50 mg fentanyl for group A；or 15 ml ropivacaine 0.25 % without fentanyl added for group B. If the parturiates did not have any signs of spinal blockade or other adverse sequelae, study solutions were injected through epidural catheter 5 ml each time every 3 minutes till total 15 ml. The total time permitted to inject the entire 15-mL volume of the study solution was less than 10 minuntes. After the study solution was given, the epidural catheter was connected to a infusion pump and continuous infusion of 0.07% ropivacaine plus 2 mg/ml fentanyl at 12ml/h was administered to patients in order to maintain labor analgesia.
After administration of the study solution, each parturient position was still kept on lateral position. Blood pressure was measured every five minutes. Any reduction of systolic blood pressure > 20% of the baseline value was promptly treated with 4 mg boluses ephedrine IV. The blood pressure was then checked on one minute later and the dose repeated if necessary. The total dose of ephedrine that each patient received would be recorded.
The plan for treating inadequate analgesia was also standardized. If a patient did not experience adequate analgesia 30 min after initial study dose, 8 ml of ropivacaine 0.25% was administered via epidural catheter after completion of data collection. If this rescue dose did not provide adequate pain relief after an additional 30 minutes, 5 ml of 2% lidocaine was then administered. If all these dose failure, the epidural catheter would be removed and the patient was excluded from this study.
Thirty minutes after finishing the epidural study solution, parturients were assessed as follows:
1. 100-mm visual analog scale (VAS)
2. Highest sensory block to cold (cold spirit)
3. Maximum degree of motor block in the lower limbs by the modified Bromage scale.
4. Skin blood flow of hand and foot
5. Skin temperature of hand and foot
6. Room temperature
7. Body temperature
8. Total dose of ephedrine each patient received
9. Presence of shivering, nausea or vomiting
Skin blood flow recording procedure
The patients were kept at the lateral position during the recording. Meanwhile the doors to the room were closed, the activity in the room was kept to a minimum. The flowmetry probe was placed on the nondependent sites of the limbs and attached to the skin with adhesive tape. The probe was placed at the following sites in sequence: dorsum of the hand (before analgesia), dorsum of the foot (before analgesia), dorsum of the hand (30 min after analgesia), and dorsum of the foot (30 min after analgesia). The probes were not to be removed between the two dorsum-foot recording sequences and were replaced on the same site of the hand after completion of foot recording. By the topography, thirty seconds’ recording started at 30 seconds after uterine contraction. The skin blood flow data is the average data of the 30 seconds’ recording. Differences in skin blood flow values were calculated according to the formula: (skin blood flow after epidural analgesia — skin blood flow before epidural analgesia) / skin blood flow before epidural analgesia. Values were expressed as %.
Visual analog scale (VAS):
0 representing no pain and 100 representing the worst possible pain.
Modified Bromage scale
1 = complete block, unable to move feet or knees； 2 = almost complete block, able to move feet only； 3 = partial block, just able to move knee； 4 = detectable weakness of hip flexion； 5 = no detectable weakness of hip flexion while supine with full flexion of knees
Shivering
0 = no shivering, 1 = mild shivering, 2 = severe shivering
Statistical analysis
Assuming skin blood flow difference in group A is 10% (SD 60%) and difference in group B 200% (SD 200%) with an a of 0.05 and a b of 0.9, it was determined that 13 patients would be required per group to detect this difference of two groups. To allow for parturients who might not complete the study, we enrolled 15 patients in each group.
Results were expressed as mean ± 1 SD or median (range). All interval data were compared using the t test. Frequency data were compared using Pearson’s chi-square or Fisher’s exact test. Visual Analogue Scale scores were compared using the Mann-Whitney U-test. Association between two groups of data was examined with R2 and F test. p ≦ 0.05 was considered to be significant.
Results:
A total of 30 nulliparous parturients were entered in the study. No patient was excluded because technique failure, dural punctures, intravascular catheters, inadequate pain relief, or baby born before completing data collection. Therefore, 15 patients were in group A and 15 were in the group B.
Table 1 shows demographic data. No differences were noted with respect to age, height, weight, gestation, ASA classification, oxytocin usage, or cervical dilatation at the time of epidural insertion. Room temperature and body temperature are also similar between two groups (Table 2). No differences were noted in Visual Analogue Scale scores before epidural insertion, and 30 minutes after epidural insertion. There were also no significant differences in sensory level, ephedrine usage, and incidence of nausea, vomiting, and shivering (Table 4).
Hand temperature of group A is 30.2 ± 2.1°C before epidural insertion, and 30.6 ± 2.3°C after epidural; group B is 31.7 ± 1.5°C before epidural, and 31.7 ± 1.3°C after epidural. The change of hand temperature in group A is 0.4 ± 2.4°C, in group B is -0.1 ± 1.6°C. No significant difference in hand temperature change was observed between group A and group B.
Hand cutaneous blood flow of group A before epidural insertion is 4.7 ± 5.9 ml/min/100g tissue, and 3.4 ± 1.9 ml/min/100g tissue after epidural; group B is 5.9 ± 4.6 ml/min/100g tissue before epidural insertion, and 3.6 ± 2.3 ml/min/100g tissue after epidural. The change of hand cutaneous blood flow in group A is 41.7 ± 193%; in group B is -20.8 ± 52.5%. No significant hand blood flow change was observed between group A and group B.
Dorsal foot temperature of group A is 28.1 ± 1.8°C before epidural insertion, and 28.7 ± 2.7°C after epidural; group B is 29.1 ± 1.9°C before epidural insertion, and 32.8 ± 2.5°C after epidural. The change of dorsal foot temperature in group A is 0.5 ± 1.4°C, in group B is 3.7 ± 2.7°C. The increase of group B dorsal foot temperature is significantly more than the increase of group A. (p < 0.001).
Foot cutaneous blood flow of group A is 2.7 ± 1.3 ml/min/100g tissue before epidural insertion, and 3.5 ± 3.0ml/min/100g tissue after epidural; group B is 1.7 ± 0.9 ml/min/100g tissue before epidural insertion, and 4.7 ± 5.0 ml/min/100g tissue after epidural. The change of foot cutaneous blood flow in group A is 19.3 ± 81.2%, in group B is 175.5 ± 256%. The increase of group B foot cutaneous blood flow is significantly more than the increase of group A (p = 0.03).
Thus, changes in average skin temperature of the hand and the foot seem to go parallel with average changes in the cutaneous blood flow. However, when the intra-individual relative changes in skin temperature were plotted against the relative changes in cutaneous blood flow, no consistent correlation was found (Fig. 14-17).
In respect to hemodynamic data, heart rate, systolic and diastolic blood pressure decreased both parturients in group A and B after epidural analgesia. But the decrease of diastolic blood pressure of group B is more than that of group A (p = 0.01).
Discussion:
Our results show that lumbar epidural 0.25% ropivacaine 15ml (group B) produced significant skin temperature elevation and blood flow increase at lower extremities. But there was little change of lower extremities skin temperature and blood flow on parturients using 15 ml epidural 0.07% ropivacaine plus 50 mg fentanyl (group A). Being the control regions, hand skin temperature amd blood flow didn’t change in the same pattern of foot. There is a remarkable contrast that, when foot skin temperature and blood flow increased in group B, hand skin temperature and blood flow of group B parturients decreased mildly after epidural analgesia. In addition, skin temperature and blood flow of hands and feet both only slightly increased after epidural analgesia in group A. Because parturients in group B using more concentrated ropivacaine than parturients in group A, it is supposed that sympathetic blockade and reflex vessel constriction of group B parturients will be more severe than group A. Our results well support this hypothesis.
Difference of sympathetic blockade may be due to different anesthetic levels. Because we used the same volume of lumbar epidural solution, there were similar sensory levels between two study groups. The sympathetic effects of sensory level difference are minimal.
In our study, we used skin temperature to assess the change of sympathetic activity. Therefore, factors that alter skin temperature may interfere study results. These interfering factors include room temperature, body temperature, and shivering. Because group A and group B had similar room temperature, body temperature and incidence of shivering. The lower extremities temperature difference between two groups doesn’t seem to be caused by these factors.
In addition to sympathetic tone, there are also several factors may modify cutaneous blood flow. Among these factors, aortocaval compression is the most important one. Pregnant patients near term develop signs of aortocaval compression easily when they assume the supine position. Because aortocaval compression alters the lower extremities blood flow markedly, we collected all the blood flow data at lateral position. But the vena cava is a low pressure system, even mild compression will produce significant venous congestion at lower extremities. This makes skin blood flow unstable. It may be due to this reason, in our study, the standard variation of skin blood flow is greater than the standard variation obtained from nonpregnant patients.
Because labor pain stimulates sympathetic nerve system greatly, it is very important to keep similar pain intensity in two compared groups when measuring the parturients’ sympathetic activity. So, in group A parturients, we added 50μg fentanyl to study solution of 0.07% epidural ropivacaine in order to maintain the same analgesic effects of group A and group B regimens. In our study, parturients in both groups had similar VAS scores before and after epidural analgesia. Thus, the difference of sympathetic tone of the two study groups doesn’t come from the difference of pain intensity.
In order to keep the same pain intensity, the epidural regimen of group A contained not only ropivacaine but also fentanyl. Since we don’t know whether epidural fentanyl produce sympathetic, thermoregulatory, or vascular effects or not, this study results cannot be interpreted as the simple comparison between two different concentrations of epidural ropivacaine.
Oxytocin is frequently used in labor. Because its structure is analogous to vasopressin, oxytocin does have some but weak vascular effects. Although oxytocin produces mild actions on uterine, placental, visceral and renal vessels, there are little literatures talking about the oxytocin’s cutaneous vascular effects. In group A, there were 9 parturients receiving oxytocin; in group B, there were 11 parturients receiving oxytocin. There is no significant difference between two groups. Because we cannot rule out the interference of oxytocin completely, we hope that this effect can be minimized by the random-controlled study design.
Usage of ephedrine also makes the interpretation of study results difficult. Parturients who developed hypotension may have stronger sympathetic blockade and more severe vessel dilatation. But the vessel constriction effect of ephedrine can reduce the extent of vessel dilatation. Therefore, due to the counteraction by ephedrine, the change of cutaneous blood flow in parturients with marked sympathetic blockade will be less than the predicted values. This effect will shift the results to insignificant direction. It was fortune that all the parturients in our study had acceptable blood pressure after epidural analgesia. It is not necessary to treat them with ephedrine.
Epidural test dose is used to detect intravascular or intrathecal catheters. Epidural test dose usually contains 3ml 2% lidocaine or equivant dose of local anesthetics and 1/200,000 epinephrine. Because the goal of our study is to find out the difference of sympathetic blockade between 0.07% and 0.25% ropivacaine, high concentrated local anesthetic in the test dose may mask these difference. Indeed, the report of Valley et al revealed that 60mg lidocaine in the epidural space will increase skin blood flow of lower limbs up to 169%. Consequently we omitted the test dose and used negative withdraw method to identify the position of epidural catheters.
Conclusions:
In conclusion, our study results support our hypothesis that epidural 0.07% ropivacaine plus 50μg fentanyl has less sympathetic blockade effects than epidural 0.25% ropivacaine.

一、 中文摘要 ．．．．．．．．．．．． 1
二、 緒論 ．．．．．．．．．．．．．． 3
三、 研究方法與材料 ．．．．．．．．．19
四、 結果 ．．．．．．．．．．．．．．23
五、 討論 ．．．．．．．．．．．．．．29
六、 展望 ．．．．．．．．．．．．．．47
七、 論文英文簡述 ．．．．．．．．．．52
八、 參考文獻 ．．．．．．．．．．．．60
九、 圖表 ．．．．．．．．．．．．．．70

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