54 patients in our hospital were included from December 17 2019 to March 30 2020 in this study. These patients were transferred to the CS because of the failed vaginal trials by epidural labor analgesia. Each patient signed a research informed consent protocol. Once these women were determined to administrate cesarean delivery, we performed a combined spinal and epidural puncture and subarachnoid block to study the minimum effective dose of ropivacaine undergoing failed vaginal trial transfer to CS. This clinical study had been registered at www.chictr.org.cn(ChiCTR1900027527). The study was conducted in accordance with the Basic & Clinical Pharmacology & Toxicology policy for experimental and clinical studies .
We chose women between 25 and 35 years old in ASAI ~ II level with more than 36 weeks of pregnancy, first birth, single pregnancy and head position; Exclusion criteria included prenatal application of painkillers, sedative hypnotics, history of neurological and psychiatric disorders, high risk pregnancy (placental abruption, placenta previa, preeclampsia, pregnancy with severe hypertension), epidural puncture difficulty or bleeding; interruption of analgesia caused by epidural catheter falling out, maternal weight greater than 100 kg and height less than 150cm.
The research team consisted of three persons. The first one was an anesthesiologist with more than 10 years of experience in clinical anesthesia. He was responsible for spinal and epidural puncture during the transition from failed vaginal trial transfer to CS. The second one was not aware of the anesthetic drugs and research results and participated in the judgment of all research results, the third one was responsible for configuring all anesthetic drugs according to the requirements of the study.
After the patient entered the delivery room and she was ready to give birth, the veins of the upper limbs were opened immediately before labor analgesia, and 10 ml/kg/h lactated Ringer's solution was infused. The person who configured the anesthetics prepared the anesthetics in advance and the formula was: 100mg of 0.75% ropivacaine (AstraZeneca company batch: LBSK) and fentanyl injection (Yichang Renfu Pharmaceutical Co., Ltd. batch number: 91D03051) 0.2mg, diluted with saline to 100ml containing 0.1% ropivacaine and 2 μg/ml fentanyl. Monitor maternal heart rate, blood pressure, fetal heart rate, and contraction intensity. The patient was put the left lateral position, and we selected the puncture point between L2-3 lumbar spine. 18G epidural needle was used for puncture. After that, an epidural tube was placed 4~5 cm towards the head. No blood and cerebrospinal fluid were drawn out, and a test dose of 1% lidocaine 5 ml was given. After 5 minutes, ,if there was no sign of spinal anesthesia, no sign of catheter inserting into the blood vessels and 10 ml local anesthetic(0.1% ropivacaine and 2 μg/ml fentanyl) was administrated into the epidural space. If the maternal VAS score is greater than 3 after 10 minutes, add another 5 ml anesthetic . If the VAS score is still greater than 3 scores, change the standard mixture to 0.15% ropivacaine + 2 μg / ml fentanyl and continue to observe the analgesic effect. If only one limb had analgesic effect, we tried to pull out the 1cm epidural catheter and give 8~10ml 0.2% ropivacaine + 2ug / ml fentanyl again. If the analgesic effect was still unsatisfactory, the epidural puncture and recanalization were required.
Cesarean delivery procedure
After cesarean delivery was determined due to the termination of vaginal trial because of various obstetric factors during epidural labor analgesia, we suspended the administration of the epidural anesthetic. If the patient had been injected with more than 5 ml of epidural mixture within 30 minutes before the subarachnoid block, or if accidental break of the dura mater occurred during labor analgesia, the patient was eliminated. After the patient entered the operating room, Lactated Ringer's solution was maintained at 5~8ml/kg/h. Electrocardiogram was routinely monitored, SpO2, non-invasive blood pressure, and oxygen inhalation at 3 L/min. After the patient was scheduled in the left-lateral position, the preceding epidural tube was pulled out, and the combined spinal and epidural puncture was performed between L3~4 lumbar spine. Then, 0.5% ropivacaine were slowly injected through the 25G spinal anesthesia needle. After withdrawing the spinal anesthesia needle, inject epidural space into the epidural space with 3ml of normal saline for water injection test. Place an epidural catheter 3 ~ 5cm towards the head side and fix the catheter. After more than about 1 minute, the patient was required to lie flat.
Tests were performed sequentially. The initial dose of 0.5% ropivacaine was 13mg, because the recommended dose of 0.5% ropivacaine in Chinese guidelines for obstetric anesthesia is 10mg to 15mg. And the dose of the latter case was increased and decreased according to the results of the previous patient. The dose of ropivacaine differed by 1 mg and the concentration remained unchanged. The CS operation of the patient after failed vaginal trial was determined by an operation researcher, and another researcher configured a dose of ropivacaine.
Judgment of anesthesia effect
The effect of anesthesia was evaluated during the operation by observing the highest block level, the onset time and duration of sensory block; In addition, Bromage classification of lower limb motion block and hip motor function score were also recorded.
The effect of sensory nerve block was evaluated by needle punching, and the degree of maternal pain was recorded by visual analog scale (VAS): 0 painless, mild pain <4 scores, moderate pain (4 to 6 scores), and severe pain (7 ~ 9 scores), 10 scores of severe pain. If the intraoperative pain score exceeded 3 scores, the next study dose was increased by 1 mg. If there was doubt about the effect of anesthesia, the next dose was repeated. We judged the effect of motor block by the motor score of any of the lower limbs within 5 minutes after the subarachnoid injection. The scoring criteria were based on the Bromage score and hip motor function score (Bromage score: 0, Free movement of knees and feet; 1, Only move the knee joint; 2, Can't move the knee joint, but can move the feet; 3, No movement of knees and feet; Hip motion score: 0, Raise leg（>30°）; 1, Raise leg（<30°）; 2, Can't lift leg). If the score of both lower limbs was 0 within 5 minutes after the injection, the motor nerve block was judged to be ineffective, and the next patient's ropivacaine would be added to the previous one by 1 mg. Conversely, if the movement score of the limb was greater than 0 within 5 minutes after the injection, the motor block was judged to be effective, and the ropivacaine of the next patient would be reduced by 1 mg compared with the previous one.
Anesthesia and surgery procedure
In order to prove that ropivacaine accurately entered the subarachnoid space, we tested the sensory plane of the patient through a 25G puncture needle. If the sensory anesthesia level appeared quickly within 5 minutes, it could be determined that the anesthetic drug had successfully entered the subarachnoid space. Otherwise, we thought that the patient had failed, which was excluded from the statistics. If the anesthesia level could not meet the surgical requirements, we could add 2% lidocaine 5ml through the epidural catheter. If the surgical requirements could not be met within 5 minutes, we would give 2% lidocaine 5~15ml by 3~4 times. If the patient could not tolerate the pain of the operation, the anesthesia mode was changed into general anesthesia, and the relevant data about intravertebral or general anesthesia are recorded. All patients’ complications also were recorded after intravertebral anesthesia.
During the surgery, the systolic blood pressure decreased by more than 20% of the base value or the systolic blood pressure was <90mmHg. Ephedrine was injected 6~12mg, and repeated injection was given if necessary. Atropine was administrated at a heart rate of <50bpm, 0.3~0.5mg each time. We was extremely vigilant about high-level block, and regularly asked the patient if she had difficulty to speak, breath, swallow and other symptoms of high-level block during the CS.
Each average dose of ropivacaine was obtained through the intermediate point between effective and ineffective dose. According to Paul and Fisher's study , individual studies will have differences, and these differences would decrease when the number of patients increased. Therefore, our study was completed when the average dose of our study exceeded 6 pairs. The number of effective and ineffective patients were recorded, and the minimum effective dose and 95% confidence interval of the patients were also calculated.
The distribution of anesthesia with effectiveness or no effect was analyzed using SPSS22.0 statistical software. The measurement data that conformed to the normal distribution were expressed as mean ± standard deviation, comparisons between groups were performed using t test, and count data were used χ2 test. Hypotension, bradyarrhythmia and nausea, vomiting and chills were analysed by Pearson Chi-square test. P <0.05 was considered statistically significant. The ED50 value and its 95% confidence interval were calculated using the formula of the Dixon-Massey sequential allocation test method. LogED50 = , SmlogED50=d*, we calcualated the antilogarithm of LogED50-1.96*SmlogED50 and LogED50+1.96*SmlogED50 to get 95% CI value of ED50.