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Zhang Jingwen,1 Kong Lingling,2 Juan11Department of Anesthesiology, West China Second Hospital, Sichuan University, Key Laboratory for Congenital Defects and Related Diseases, Ministry of Education, Sichuan University, Chengdu, Sichuan Province, 2Department of Obstetrics and Gynecology, West China Second Sichuan University Hospital, Birth defects, Key Laboratory of Sichuan University of Education and Related Diseases of the Ministry of Education, Chengdu, Sichuan Province Corresponding author: Ni Huang, Department of Anesthesiology, West China Second Hospital of Sichuan University, Key Laboratory of Congenital Defects and Maternal and Child Diseases of the Ministry of Education of Sichuan University, South San Renmin Road, Chengdu, Sichuan Province Duan 20, 610041 China, Tel +86 18180609890, Fax +86 28855503752, Email [email protected] Purpose: This study was designed to test the mean effective dose (ED50) and 95% effective doses of intravenous lidocaine administered at different doses (ED95), the effect of the induction dose of propofol, and determining the optimal dose. Group: saline (L0), lidocaine 0.5 mg/kg (L0.5), lidocaine 1.0 mg/kg (L1.0) and lidocaine 1.5 mg/kg (L1.5). Induce anesthesia with 1.0 µg/kg fentanyl. Prepared lidocaine or saline is administered later as directed, followed by propofol. The dose of propofol for each patient was determined using a sequential top-down study design. The primary endpoints were the ED50 and ED95 of the propofol induction dose. The total propofol doses, awakening time, and adverse events were recorded.Results: The ED50 (95% confidence interval) of propofol was significantly lower in groups L1.0 and L1.5 than group L0 (1.6 [1.5– 1.7] mg/kg and 1.8 [1.6– 1.9] mg/kg, versus 2.4 [2.3– 2.5] mg/kg, respectively; p1.0 and L1.5 (p> 0.05). However, surprisingly, the ED50 was significantly higher in group L0.5 than L0 (2.8 [2.6– 3.0] mg/kg vs 2.4 [2.3– 2.5] mg/kg; p1.0 and L1.5 were lower than those in groups L0 and L0.5 (p0.5 was greater than that in group L0 (p0.5 was greater than that in groups L0 and L1.0 (pConclusion: In patients who underwent first-trimester uterine aspiration, intravenous lidocaine 1.0 mg/kg prior to propofol injection significantly reduced the ED50 of propofol induction dose without severe side effects, equivalent to the effect of 1.5 mg/kg dose. We recommend 1.0 mg/kg as the optimal dose.Keywords: lidocaine, propofol, uterine aspiration, median effective dose The total propofol doses, awakening time, and adverse events were recorded. Results: The ED50 (95% confidence interval) of propofol was significantly lower in groups L1.0 and L1.5 than group L0 (1.6 [1.5–1.7] mg/ kg and 1.8 [1.6–1.9] mg/kg, versus 2.4 [2.3–2.5] mg/kg, respectively, p1.0 and L1.5 (p> 0.05). .5 than L0 (2.8 [2.6– 3.0] mg/kg vs 2.4 [2.3– 2.5] mg/kg; p1.0 and L1.5 were lower than those in groups L0 and L0.5 (p0.5 was greater than that in group L0 (p0.5 was greater than that in groups L0 and L1.0 (pConclusion: In patients who underwent first-trimester uterine aspiration, intravenous lidocaine 1.0 mg/kg prior to propofol injection significantly reduced the ED50 of propofol induction dose without severe side effects, equivalent to the effect of 1.5 mg/kg dose. Total propofol doses, awakening time, and adverse events were recorded. Results: The ED50 (95% confidence interval) of propofol was significantly lower in the L1.0 and L1.5 groups than in the L0 group (1.6 [1.5–1, 7] mg/ml). кг и 1,8 [1,6–1,9] мг/кг по сравнению с 2,4 [2,3–2,5] мг/кг соответственно, p1,0 и L1,5 (p>0,05), однако, как ни удивительно, ED50 была значительно выше в группе L0. kg and 1.8 [1.6–1.9] mg/kg versus 2.4 [2.3–2.5] mg/kg, respectively, p1.0 and L1.5 (p>0.05 ), however, surprisingly, the ED50 was significantly higher in the L0 group. 0.5 than L0 (2.8 [2.6–3.0] mg/kg vs. 2.4 [2.3–2.5] mg/kg; p1.0 and L1.5 were lower than in groups L0 and L0.5 (p0.5 greater than in groups L0 and L0.5) that in group L0 (p0.5 was greater than in groups L0 and L1.0 (pConclusion: in patients undergoing aspiration uterus in the first trimester, intravenous administration of lidocaine at a dose of 1.0 mg/kg before injection of propofol significantly reduced the ED50 of the induction dose of propofol)) without severe side effects, equivalent to the effect of a dose of 1.5 mg/kg. We recommend 1.0 mg/kg as the optimal dose. Key words: lidocaine, propofol, uterine aspiration, mean effective dose Total propofol dose, time to awakening, and adverse events were recorded.结果：L1.0 和L1.5 组异丙酚的ED50（95% 置信区间）显着低于L0 组（1.6 [1.5–1.7] mg/ kg 和1.8 [1.6–1.9] mg/kg，分别为2.4 [2.3–2.5] mg/kg；p1.0 和L1.5 (p> 0.05)。然而，令人惊讶的是，L0 组的ED50 显着更高.5 比L0 (2.8 [2.6– 3.0] mg/kg vs 2.4 [2.3– 2.5] mg/kg；p1.0 和L1.5 低于L0 和L0.5 组(p0.5 大于L0 组（p0.5 大于L0 和L1.0 组（p结论：在接受妊娠早期子宫抽吸术的患者中，丙泊酚注射前静脉注射利多卡因1.0 mg/kg 显着降低了丙泊酚诱导剂量的ED50）无严重副作用，相当于1.5 mg/kg剂量的效果。我们推荐1.0 mg/kg作为最佳剂量。关键词：利多卡因、丙泊酚、子宫抽吸、中位有效剂量结果： L1.0 和L1.5 组异丙酚的ED50（95% L0 mg/kg vs 2.4 [2.3– 2.5] mg/kg；p1.0 和L1.5 ： 在 接受 妊娠 早期 子 抽 吸术 的 患者 中 丙泊 酚 注射 前 静脉 注射利多卡因 注射利多卡因 注射利多卡因 注射利多卡因 1.0 mg/kg 显着 了 丙泊 酚 的 的 ed50） 严重 副作用 相当于 相当于 1.5 mg/kg 剂量的效果。我们推荐1.0 mg / kg Results: The ED50 (95% confidence interval) of propofol in the L1.0 and L1.5 groups was significantly lower than in the L0 group (1.6 [1.5-1.7] mg/kg and 1.8 [1, 6–1.9] mg/kg). кг соответственно 2,4 [2,3–2,5] мг/кг, p1,0 и L1,5 (p>0,05).Однако, как ни удивительно, ED50 была значительно выше в группе L0.5, чем в группе L0 (2,8 [2,6–2,6–2,6]). kg, respectively, 2.4 [2.3–2.5] mg/kg, p1.0 and L1.5 (p>0.05). However, surprisingly, ED50 was significantly higher in the L0.5 group than in group L0 (2.8 [2.6–2.6–2.6]). 3.0] mg/kg vs. 2.4 [2.3-2.5] mg/kg; p1.0 and L1.5 were lower than in groups L0 and L0.5 (p0.5 greater than in groups L0 (p0.5 greater than L0 and L1. 0 groups (p Conclusions). : In female patients, In patients undergoing first trimester uterine aspiration, intravenous lidocaine 1.0 mg/kg prior to propofol injection significantly reduced the ED50 of the propofol induction dose without serious side effects, equivalent to a 1.5 mg/kg dose We recommend 1.0 mg/kg kg as optimal dose Keywords: lidocaine, propofol, uterine aspiration, mean effective dose
Because propofol has a significantly shorter half-life than other drugs, propofol is commonly used as an intravenous anesthetic to provide sedation during outpatient operations. 1,2 However, sedation with only high doses of propofol is associated with respiratory and circulatory side effects. Higher doses of propofol increase the risk of apnea, upper airway collapse, and hypotension; 3-7 while lower doses result in inadequate sedation. Propofol in combination with other drugs reduces the risk of respiratory and circulatory complications and provides a safe and satisfactory sedative effect. Therefore, there is a need for an effective adjuvant to reduce the response to surgery and reduce the need for propofol. In recent years, both midazolam and dexmedetomidine have been used in outpatient surgery, but the half-life of midazolam is long, induction of dexmedetomidine is slow, and the drug is bulky, so use is limited. 8.9
Lidocaine is a widely used local anesthetic in clinical practice.10 Previous studies have found that intravenous lidocaine could enhance the sedative effect of propofol-based anesthesia.11–15 Other perioperative benefits of intravenous lidocaine include alleviated propofol injection pain, reduction of opioid requirement, accelerated recovery of gastrointestinal function after surgery, and decreased incidence of postoperative chronic pain.16–19 Intravenous lidocaine has a short half-life (90–120 min), and its blood concentrations reported in clinical studies remained below toxic concentrations (>5 µg/mL).20,21 Foo et al recommended in their newly published consensus guidelines that if intravenous lidocaine was used, an initial dose of no more than 1.5 mg/kg calculated using the patient’s ideal body weight was safe.21 A study by Lili et al already proved that administration of bolus intravenous lidocaine 1.5 mg/kg before anesthesia induction resulted in a 36% reduction in ED50 of propofo Лидокаин является широко используемым местным анестетиком в клинической практике. Предыдущие исследования показали, что внутривенное введение лидокаина может усиливать седативный эффект анестезии на основе пропофола. ускоренное восстановление функции желудочно-кишечного тракта после операции и снижение частоты послеоперационной хронической боли.16–19 Внутривенный лидокаин имеет короткий период полувыведения (90–120 мин), а его концентрация в крови, зарегистрированная в клинических исследованиях, оставалась ниже токсической концентрации (> 5 мкг). /мл)20,21 Foo et al. в своих недавно опубликованных согласованных рекомендациях рекомендовали, чтобы при внутривенном введении лидокаина начальная доза не более 1,5 мг/кг, рассчитанная с использованием идеальной массы тела пациента, была безопасной.21 Исследование Lili и др. уже доказали, что болюсное внутривенное введение лидокаина в дозе 1,5 мг/кг перед индукцией анестезии приводит к снижению ED50 пропофорона на 36%.利多卡因是临床实践中广泛使用的局部麻醉剂。 10 先前的研究发现，静脉注射利多卡因可以增强基于丙泊酚的麻醉的镇静作用。 11-15 静脉注射利多卡因的其他围手术期益处包括减轻异丙酚注射疼痛、减少阿片类药物需求、术后胃肠功能加速恢复，术后慢性疼痛发生率降低。 16-19 静脉注射利多卡因半衰期短（90-120 分钟），临床研究报告的其血液浓度仍低于毒性浓度（>5 µg /mL).20,21 Foo 等人在他们新发表的共识指南中建议，如果使用静脉注射利多卡因，使用患者理想体重计算的初始剂量不超过 1.5 mg/kg 是安全的。21 Lili 的一项研究等人已经证明，在麻醉诱导前静脉推注利多卡因 1.5 mg/kg 可使丙泊酚的 ED50 降低 36%利多卡 因 临床 实践 中 广泛 使用 的 局部 麻醉剂。 10 先前 研究 发现 ， 静脉 注射利多卡 因 可以 增强 基于 酚 的 麻醉 镇静 作用。 11-15 静脉 的 其他 手术 期益处 期益处 期益处 期益处 期益处包括 减轻 注射 疼痛 、 减少 阿片类 药物 需求 、 术后 胃肠 功能 恢复 ， 术后 慢性 疼痛 发生率 降低。 16-19 静脉 因 半衰期 短 (90-120 分钟） ， 临床 研究 研究 研究 研究 研究的 其 血液 仍 低于 毒性 浓度 （(> 5 мкг /мл).20,21 foo 等 在 他们 新 发表 的 识 指南 中 建议 ， 使用 静脉 注射利多卡因 使用 患者 体重 计算 的 初始剂量 不 如果 静脉 ， 患者 理想 计算 的 不 不 不 如果 注射利多卡因 患者 理想 计算 的 不 不超过 1,5 мг/кг 是 安全。 。21 lili 的 一 研究 等 人 证明 证明 ， 在 麻醉 诱导 前 推注利多卡因 推注利多卡因 1,5 мг/кг 可 丙泊 酚 的 ed50 降低 36% l 用 于 减轻 宫腔镜 手术 患者 对 宫颈 扩张 的 反应。。 22 liu 等 还 证明 ， 静脉 注射 注射 1,5 мг/кг 利多卡 可 显着 成人 患者 检查 期间 异丙酚 诱导剂量 的 ed50 ， 而 而 而 而 而 而 而 而 患者 检查 异丙酚 诱导剂量 的 的 的 ， ， ，不会显着影响血流动力学和呼吸曲线.23
Therefore, this study aimed to test the effect of different doses of intravenous lidocaine on the ED50 and ED95 of propofol-inducing doses during first trimester uterine aspiration, as well as to determine the optimal dose, which, to our knowledge, has not been studied in previous studies. .
After completing the design of this clinical trial, we skipped the previous ethical review of the West China Second Hospital, and the next one is still a few months away. Therefore, we sought ethical review from the China Clinical Trials Registration Ethics Committee, an independent institutional ethics committee organized by the China Clinical Trials Registration Center. This study protocol was approved by the Ethics Committee of the Chinese Clinical Trials Registry (ChiECRCT20210401) and registered with the Chinese Clinical Trials Registry (ChiCTR2100049263). The study was conducted in accordance with the Declaration of Helsinki from September 2021 to May 2022, and we obtained written informed consent from 100 study participants prior to the start of the study.
This prospective study was conducted in female patients scheduled to undergo first trimester outpatient hysteroscopy under general anesthesia at Sichuan University West China Second Hospital. The study included patients with ASA physical status I or II, aged 18-50 years and fasted for 6 hours (solids) and 2 hours (liquids) before surgery. Exclusion criteria were as follows: patients with body mass index (BMI) >28 kg/m2 or BMI <18 kg/m2; Exclusion criteria were as follows: patients with body mass index (BMI) >28 kg/m2 or BMI <18 kg/m2; Критерии исключения были следующими: пациенты с индексом массы тела (ИМТ) >28 кг/м2 или ИМТ <18 кг/м2; Exclusion criteria were as follows: patients with body mass index (BMI) >28 kg/m2 or BMI <18 kg/m2;排除标准如下：体重指数（BMI）>28 kg/m2或BMI<18 kg/m2的患者；排除标准如下：体重指数（BMI）>28 kg/m2或BMI<18 kg/m2的患者； Критерии исключения: пациенты с индексом массы тела (ИМТ) > 28 кг/м2 или ИМТ < 18 кг/м2; Exclusion criteria: patients with body mass index (BMI) > 28 kg/m2 or BMI < 18 kg/m2; patients with body weight <40 kg; patients with body weight <40 kg; пациенты с массой тела <40 кг; patients weighing <40 kg;体重<40公斤的患者；体重<40公斤的患者； Пациенты с массой тела < 40 кг; Patients weighing <40 kg; Patients with vaginal delivery and a history of cervical dilatation within 6 months; patients who are allergic to local anesthetics, propofol, fentanyl, or other drugs associated with this study; patients with severe hepatic and renal insufficiency, endocrine diseases, patients with metabolic disorders, cardiovascular diseases, diseases of the respiratory system or diseases of the central nervous system Long-term use of sedatives, analgesics, drugs that can affect the metabolism of local anesthetics or patients during 7 days Accepted other experiments within 3 months prior to the study Drugs or patients who participated in other clinical trials; patients addicted to alcohol or recreational drugs; patients with Mallampati III-IV scores. All participants were informed about the purpose of the study.
Briefly, 100 patients were randomized into groups L0, L0.5, L1.0, and L1.5 according to a computer-generated random sequence with a block size of 4. The unique number was sealed in an opaque envelope. Anesthesiologists who prepare and administer drugs know group tasks. The researchers, patients, surgeons, and nurses who collected the data were task blind.
No other drugs were administered prior to induction of anesthesia. A 22 gauge cannula was inserted into the vein and Ringer’s lactate infusion (2 ml/kg/h) was started. Upon entering the operating room, the patient was given inhalation of oxygen through a mask at a rate of 10 L/min for 3 minutes before induction, and invasive blood pressure, electrocardiogram, respiratory rate, and peripheral capillary oxygen saturation (SpO2) were monitored until the patient was released. from anesthesia. and was transferred in the postoperative period to the anesthesia department. SpO2, heart rate (HR) and invasive blood pressure were recorded at the following three time points: at the time of preparation for induction of anesthesia (T0), at the end of induction of anesthesia (T1), at the end of cervical dilatation (T2). All preparations were prepared at room temperature. temperature, stored and used immediately. Lidocaine (Sinopharm Rongsheng Pharmaceutical Co., Ltd.) 0.5 mg/kg, 1.0 mg/kg and 1.5 mg/kg were diluted to 10 ml with saline in a 10 ml syringe. Also prepare an equal volume of saline in a 10 ml syringe. Introduction to anesthesia was started with a single bolus injection of fentanyl 1.0 μg/kg (Yichang Renfu Pharmaceutical Co., Ltd., China). A minute later, prepared lidocaine or saline was administered as prescribed for about 30 seconds, and then propofol (Corden Pharma SPA, Italy) was administered to all patients at a rate of 0.4 ml/s. The first patient in each group received propofol 2.0 mg/kg. In subsequent patients, the propofol dose was increased or decreased by 0.2 mg/kg, depending on the response of the previous patient. The Modified Observer Alertness/Sedation Rating Scale (MOAA/S) was used to assess the depth of sedation. 24 The MOAA/S scale is a 6-point scale and is described as 5: an easy-to-pronounce name in a normal tone; 4: sleep reaction to a name pronounced in a normal tone; 3: only with a loud and/or repetitive response after calling a name; 2: response only to mild stimulation or shaking; 1: response only to painful contraction of the trapezius muscle; 0: no response to trapezius muscle contraction. After the MOAA/S score was <1, the surgeon was allowed to begin placement of the vaginal speculum, which signaled the start of the operation. After the MOAA/S score was <1, the surgeon was allowed to begin placement of the vaginal speculum, which signaled the start of the operation. После того, как оценка MOAA/S была <1, хирургу было разрешено начать установку вагинального зеркала, что сигнализировало о начале операции. Once the MOAA/S score was <1, the surgeon was allowed to begin inserting the vaginal speculum, signaling the start of the operation.在MOAA/S 评分<1 后，外科医生被允许开始放置阴道窥器，这标志着手术的开始。在 MOAA/S После того, как оценка MOAA/S <1, хирургу было разрешено начать установку вагинального зеркала, что ознаменовало начало процедуры. Once the MOAA/S score was <1, the surgeon was allowed to begin inserting the vaginal speculum, marking the start of the procedure. All operations are performed by the same surgeon. The result was considered invalid if MOAA/S was ≥1 after the first dose of propofol or if limb movements were observed from onset to cervical dilatation; otherwise, the result was considered significant. In ineffective cases, the dose of propofol was increased by 0.2 mg/kg in subsequent patients. Propofol was reduced by 0.2 mg/kg in subsequent patients for effective cases. If MOAA/S is ≥1 or limb movements are observed during surgery, propofol 0.5–1.0 mg/kg is given according to clinical need. After induction of anesthesia, if the apnea time exceeded 1 min, it was defined as respiratory depression and mechanical ventilation was performed until spontaneous respiration was restored. If upper airway obstruction is observed, elevate the lower jaw to allow ventilation. If SpO2 <92%, hypoxia was defined and the procedure was stopped, and an assisted face mask ventilation was applied to normalize the oxygen saturation. If SpO2 <92%, hypoxia was defined and the procedure was stopped, and an assisted face mask ventilation was applied to normalize the oxygen saturation. При SpO2 <92% определяли гипоксию и процедуру прекращали, а для нормализации сатурации кислородом применяли вспомогательную лицевую масочную вентиляцию легких. At SpO2 <92%, hypoxia was determined and the procedure was stopped, and an auxiliary facial mask ventilation was used to normalize oxygen saturation.如果SpO2 < 92%，则定义为缺氧并停止手术，并应用辅助面罩通气以使氧饱和度正常化。如果SpO2 < 92%，则定义为缺氧并停止手术，并应用辅助面罩通气以使氧饱和度正常化。 Если SpO2 < 92%, определите гипоксию и прекратите операцию, а также примените искусственную вентиляцию легких с помощью маски для нормализации насыщения кислородом. If SpO2 < 92%, determine hypoxia and terminate surgery, and ventilate with a mask to normalize oxygen saturation. If the HR was <50 beats/min, atropine 0.5 mg was administered. If the HR was <50 beats/min, atropine 0.5 mg was administered. Если ЧСС <50 уд/мин, вводили атропин 0,5 мг. If heart rate <50 bpm, atropine 0.5 mg was administered.如果HR <50 次/分钟，则给予阿托品0.5 mg。如果HR<50次/分钟，则给予阿托品0.5 mg。 Если ЧСС <50 уд/мин, введите 0,5 мг атропина. If heart rate <50 bpm, give 0.5 mg atropine. Hypotension was defined as SBP, diastolic blood pressure (DBP), or mean arterial pressure (MAP) decreased by more than 20% of the baseline, or SBP<80 mmHg. Hypotension was defined as SBP, diastolic blood pressure (DBP), or mean arterial pressure (MAP) decreased by more than 20% of the baseline, or SBP<80 mmHg. Гипотензия определялась как снижение САД, диастолического артериального давления (ДАД) или среднего артериального давления (САД) более чем на 20% от исходного уровня или САД <80 мм рт.ст. Hypotension was defined as a decrease in SBP, diastolic blood pressure (DBP), or mean arterial pressure (MAP) by more than 20% of baseline, or SBP <80 mmHg.低血压定义为SBP、舒张压(DBP) 或平均动脉压(MAP) 下降超过基线的20%，或SBP<80 mmHg。 20%，或SBP<80 mmHg。 Гипотензию определяли как снижение более чем на 20% от исходного уровня САД, диастолического артериального давления (ДАД) или среднего артериального давления (САД) или САД <80 мм рт.ст. Hypotension was defined as a decrease of more than 20% from baseline in SBP, diastolic blood pressure (DBP), or mean arterial pressure (MAP), or SBP <80 mmHg. If hypotension occurs, 0.2–0.4 mg of metahydroxylamine or 5–10 mg of ephedrine are administered, depending on the situation. The total propofol dose, time of operation, and recovery time at the end of the operation were recorded. Myoclonus and side effects of local anesthetics have also been reported, such as tinnitus, perioral numbness, and palpitations following propofol.
The primary endpoints were the ED50 and ED95 of the propofol induction dose. Secondary endpoints were total propofol dose, postoperative recovery time, respiratory depression, upper airway obstruction, hypoxia, bradycardia, hypotension, and postpropofol myoclonus.
The independence and unknown distribution of data studied in a top-down sequential manner makes it difficult to formulate theoretically rigorous rules for calculating sample size. 25 The sample size was determined by the stopping rule. Patients must be enrolled before at least six pairs of invalid results are converted to valid results. Simulation studies have shown that, in most cases, inclusion of at least 20-40 patients can provide a stable estimate of the target dose. Other anesthesia trials using this approach also typically involve 20-40 patients. 26,27 In our study, each group included 25 patients, which was sufficient for statistical analysis.
SPSS 26.0 (IBM Inc., Armonk, NY, USA) was used to analyze the results. The Shapiro-Wilk test was used to determine the normal distribution of the data. Continuous normally distributed variables were expressed as mean ± standard deviation and compared between groups using one-way ANOVA. Non-normally distributed data were presented as a median (interquartile range) and compared using the Wilcoxon rank sum test. Categorical data are presented as n (%) and analyzed using a chi-square test. The ED50 (95% CI) for propofol was calculated as the mean of the midpoint of zero significant crossover using one-way ANOVA with Bonferroni’s method for comparison between groups. ED95 (95% CI) was estimated using probabilistic regression. For all analyses, p<0.05 was considered to indicate statistically significant differences. For all analyses, p<0.05 was considered to indicate statistically significant differences. Для всех анализов считалось, что p<0,05 указывает на статистически значимые различия. For all analyses, p<0.05 was considered to indicate a statistically significant difference.对于所有分析，p<0.05 被认为表明有统计学意义的差异。 p<0.05 被认为表明有统计学意义的差异。 Для всех анализов считалось, что p<0,05 указывает на статистически значимое различие. For all analyses, p<0.05 was considered to indicate a statistically significant difference.
A total of 121 patients were registered and examined. Of these, 100 patients were randomized into 4 groups and included in the final analysis (Figure 1). The baseline characteristics of the four groups of patients, including age, BMI, heart rate (T0), SBP (T0), DBP (T0) and SBP (T0), did not differ significantly (Table 1).
A top-down sequence showing dose and patient response is shown below (Figure 2). The mean propofol infusion doses in the L0, L0.5, L1.0, and L1.5 groups were 2.3±0.2, 2.7±0.3, 1.6±0.2, and 1.7±0. 2 mg/kg, respectively. On fig. 3 shows an analysis of the dose response of lidocaine and propofol in four patient groups. Table 2 shows the ED50 and ED95 (95% CI) of propofol for the four arms, based on Dixon-Massey ordinal up-down order and probability regression, respectively. The ED50 of propofol in groups L1.0 and L1.5 were significantly less than that in group L0 (1.6 [1.5–1.7] mg/kg; 1.8 [1.6–1.9] mg/kg vs 2.4 [2.3–2.5] mg/kg, p<0.001). The ED50 of propofol in groups L1.0 and L1.5 were significantly less than that in group L0 (1.6 [1.5–1.7] mg/kg; 1.8 [1.6–1.9] mg/kg vs 2.4 [2.3–2.5] mg/ kg, p<0.001). The ED50 of propofol in the L1.0 and L1.5 groups was significantly lower than in the L0 group (1.6 [1.5–1.7] mg/kg; 1.8 [1.6–1.9] mg/kg). kg versus 2.4 [2.3–2.5] mg/kg). кг кг, р<0,001). kg kg, p<0.001). L1.0 和L1.5 组异丙酚的ED50 显着低于L0 组（1.6 [1.5–1.7] mg/kg；1.8 [1.6–1.9] mg/kg vs 2.4 [2.3–2.5] mg/kg公斤，p < 0.001）。 L0 ，p < 0.001）。 The propofol ED50 was significantly lower in the L1.0 and L1.5 groups than in the L0 group (1.6 [1.5–1.7] mg/kg; 1.8 [1.6–1.9] mg/kg). kg versus 2.4 [2.3–2.5] mg/kg). /кг кг, p < 0,001). /kg kg, p < 0.001). The value of ED50 was higher in group L0.5 than in group L0 (2.8 [2.6–3.0] mg/kg vs 2.4 [2.3–2.5] mg/kg, p<0.05). The value of ED50 was higher in group L0.5 than in group L0 (2.8 [2.6–3.0] mg/kg vs 2.4 [2.3–2.5] mg/kg, p<0.05). Величина ED50 была выше в группе L0,5, чем в группе L0 (2,8 [2,6–3,0] мг/кг против 2,4 [2,3–2,5] мг/кг, p<0,05). The ED50 was higher in the L0.5 group than in the L0 group (2.8 [2.6–3.0] mg/kg vs. 2.4 [2.3–2.5] mg/kg, p<0 .05). L0.5 组的ED50 值高于L0 组（2.8 [2.6-3.0] mg/kg vs 2.4 [2.3-2.5] mg/kg，p<0.05）。 L0.5 组的ED50 值高于L0 组（2.8 [2.6-3.0] mg/kg vs 2.4 [2.3-2.5] mg/kg，p<0.05）。 Группа L0,5 имела более высокие значения ED50, чем группа L0 (2,8 [2,6–3,0] мг/кг против 2,4 [2,3–2,5] мг/кг, p<0,05). The L0.5 group had higher ED50 values ​​than the L0 group (2.8 [2.6–3.0] mg/kg vs. 2.4 [2.3–2.5] mg/kg, p<0, 05). There was no significant difference in ED50 of propofol between groups L1.0 and L1.5 (p>0.05). There was no significant difference in ED50 of propofol between groups L1.0 and L1.5 (p>0.05). Не было существенной разницы в ED50 пропофола между группами L1.0 и L1.5 (p>0,05). There was no significant difference in propofol ED50 between the L1.0 and L1.5 groups (p>0.05). L1.0组和L1.5组异丙酚的ED50差异无统计学意义（p>0.05）。 L1.0组和L1.5组异丙酚的ED50差异无统计学意义（p>0.05）。 Не было существенной разницы в ED50 пропофола между группой L1.0 и группой L1.5 (p>0,05). There was no significant difference in propofol ED50 between the L1.0 group and the L1.5 group (p>0.05).
Table 2 ED50 and ED95 (95% CI) of the four propofol groups based on upper and lower order Dixon-Massey distribution and Probit regression
Figure 2 Dixon at the top and bottom of the four groups. “●” means valid, “○” means invalid.
There were no significant differences among groups in surgery duration and awakening time as listed in Table 3 (p>0.05). There were no significant differences among groups in surgery duration and awakening time as listed in Table 3 (p>0.05). Не было никаких существенных различий между группами в продолжительности операции и времени пробуждения, как указано в таблице 3 (p>0,05). There were no significant differences between the groups in the duration of the operation and the time of awakening, as indicated in table 3 (p>0.05).各组手术时间和苏醒时间差异无统计学意义（p>0.05），见表3。 p>0.05），见表3。 Не было существенной разницы во времени работы и времени пробуждения между группами (p>0,05), как показано в таблице 3. There was no significant difference in work time and wake time between groups (p>0.05), as shown in Table 3. The mean doses of total propofol required for the whole surgery were significantly greater in groups L0 and L0.5 than the other two groups (p<0.05, Table 3). The mean doses of total propofol required for the whole surgery were significantly greater in groups L0 and L0.5 than the other two groups (p<0.05, Table 3). Средние дозы общего пропофола, необходимые для всей операции, были значительно выше в группах L0 и L0,5, чем в двух других группах (p<0,05, таблица 3). The mean doses of total propofol required for the entire operation were significantly higher in the L0 and L0.5 groups than in the other two groups (p<0.05, Table 3).整个手术所需的总丙泊酚平均剂量在L0 和L0.5 组显着高于其他两组（p<0.05，表3）。整个手术所需的总丙泊酚平均剂量在L0和L0.5 Средняя доза общего пропофола, необходимая для всей процедуры, была значительно выше в группах L0 и L0,5, чем в двух других группах (p<0,05, таблица 3). The mean dose of total propofol required for the entire procedure was significantly higher in the L0 and L0.5 groups than in the other two groups (p<0.05, Table 3). There were no significant differences among groups in the occurrence of upper airway obstruction (p>0.05). There were no significant differences among groups in the occurrence of upper airway obstruction (p>0.05). Существенных различий между группами по частоте возникновения обструкции верхних дыхательных путей не было (p>0,05). There were no significant differences between the groups in the incidence of upper airway obstruction (p>0.05).上气道阻塞发生率组间差异无统计学意义（p>0.05）。上气道阻塞发生率组间差异无统计学意义（p>0.05）。 Достоверной разницы в частоте обструкции верхних дыхательных путей между группами не было (p>0,05). There was no significant difference in the incidence of upper airway obstruction between the groups (p>0.05). The incidence of respiratory depression in group L0.5 was greater than that in groups L0 and L1.0 (p<0.05). The incidence of respiratory depression in group L0.5 was greater than that in groups L0 and L1.0 (p<0.05). Частота угнетения дыхания в группе L0,5 была выше, чем в группах L0 и L1,0 (p<0,05). The frequency of respiratory depression in the L0.5 group was higher than in the L0 and L1.0 groups (p<0.05). L0.5组呼吸抑制发生率高于L0、L1.0组（p<0.05）。 L0.5组呼吸抑制发生率高于L0、L1.0组（p<0.05）。 Частота угнетения дыхания в группе L0,5 была выше, чем в группах L0 и L1,0 (p<0,05). The frequency of respiratory depression in the L0.5 group was higher than in the L0 and L1.0 groups (p<0.05). There were no significant differences among groups in the occurrence of hypotension (p>0.05), but the SBP decline after anesthesia induction in group L0.5 was greater than that in group L0 (p<0.01). There were no significant differences among groups in the occurrence of hypotension (p>0.05), but the SBP decline after anesthesia induction in group L0.5 was greater than that in group L0 (p<0.01). Достоверных различий между группами по частоте гипотензии не было (p>0,05), но снижение САД после индукции анестезии в группе L0,5 было больше, чем в группе L0 (p<0,01). There were no significant differences between the groups in the incidence of hypotension (p>0.05), but the decrease in SBP after induction of anesthesia was greater in the L0.5 group than in the L0 group (p<0.01).低血压发生率组间差异无统计学意义（p>0.05），但L0.5组麻醉诱导后SBP下降幅度大于L0组（p<0.01）。低血压发生率组间差异无统计学意义（p>0.05），但L0.5组麻醉诱导后SBP下降幅度大于L0组（p<0.01） Не было существенной разницы в частоте гипотензии между двумя группами (p>0,05), но снижение САД после индукции анестезии в группе L0,5 было больше, чем в группе L0 (p<0,01). There was no significant difference in the incidence of hypotension between the two groups (p>0.05), but the reduction in SBP after induction of anesthesia was greater in the L0.5 group than in the L0 group (p<0.01). None of the patients developed bradycardia and hypoxia. No patient reported nausea, tinnitus, perioral numbness, and palpitations. Patient #20 in group L1.0 developed facial myoclonus after the first dose of propofol 1.8 mg/kg, and patient #10 in group L1.5 developed myoclonus of the face and extremities after the first dose of propofol 1.4 mg/kg. . Myoclonus stops after 30-60 seconds. There were no significant differences among groups in the incidence of myoclonus (p>0.05). There were no significant differences among groups in the incidence of myoclonus (p>0.05). Достоверных различий между группами по частоте миоклонуса не было (p>0,05). There were no significant differences between the groups in the incidence of myoclonus (p>0.05).肌阵挛发生率组间差异无统计学意义（p>0.05）。肌阵挛发生率组间差异无统计学意义（p>0.05）。 Достоверной разницы в частоте миоклонуса между группами не было (p>0,05). There was no significant difference in the frequency of myoclonus between the groups (p>0.05).
To our knowledge, this is the first prospective study showing the effect of different doses of intravenous lidocaine on the ED50 and ED95 of the induction dose of propofol in patients undergoing first trimester hysteroscopy. The results showed that intravenous administration of lidocaine at a dose of 1.0 mg/kg before injection of propofol significantly reduced ED50, ED95 and total propofol dose, which is equivalent to the effect of a dose of 1.5 mg/kg. We therefore recommend a lower dose of 1.0 mg/kg as the optimal dose for effective adjunctive therapy for intravenous anesthesia with propofol. We were surprised to find that intravenous administration of 0.5 mg/kg lidocaine increased the ED50 of propofol, indicating a complex effect of lidocaine.
Due to its rapid onset of action and rapid recovery, propofol is often used for sedation in outpatient surgical procedures. However, higher doses of propofol increased the risk of apnea, upper airway collapse, and hypotension, while lower doses resulted in inadequate sedation. Therefore, there is a need for an effective adjuvant to reduce the response to surgery and reduce the need for propofol. In recent years, numerous studies have demonstrated the analgesic effects of intravenous lidocaine, including reduction in pain after propofol injection, reduction in opioid requirements, and reduction in chronic postoperative pain. In their published consensus recommendations, Foo et al. recommend that an initial dose of no more than 1.5 mg/kg calculated using ideal body weight be safe for intravenous lidocaine. Recently, Liu et al. and Yu et al. demonstrated that intravenous administration of lidocaine prior to induction of anesthesia resulted in a reduction in the ED50 of propofol in gastroscopy and hysteroscopy patients. Thus, our study aimed to test the effect of different doses of intravenous lidocaine on propofol-induced ED50 and ED95 during first trimester uterine aspiration and to determine the optimal dose. We excluded patients with a history of vaginal delivery and who had cervical dilatation within 6 months because we assumed that patients with a history of vaginal delivery or a history of cervical dilatation had less cervical stimulation during surgical dilation than patients no history of cervical dilatation. dilation of the cervix of the patient. 28 This may lead to more accurate results.
Intravenous lidocaine has a half-life of only 5-8 minutes, starting from the vascular bed and penetrating into peripheral tissues, first through areas of high perfusion (heart, lungs, liver, spleen), and then into areas of hypoperfusion. muscle and adipose tissue). 10 In our study, we administered lidocaine prior to propofol induction to maintain its plasma concentration within the effective range. As a result, the use of 1.5 mg/kg lidocaine before propofol resulted in a 26% reduction in the ED50 of propofol, and 1.0 mg/kg lidocaine resulted in a 30% reduction. These results are consistent with those of Liu and Xu, showing that lidocaine at these doses has analgesic and antihyperalgesic effects. Surprisingly, however, the ED50 was increased with intravenous lidocaine at 0.5 mg/kg, suggesting that the effect of the 0.5 mg/kg dose may be reversed and that very low doses of intravenous lidocaine may be associated with more severe hypersensitivity reactions associated with nervous excitability. Lidocaine acts on multiple molecular targets involved in acute and chronic nociception, including N-methyl-D-aspartate (NMDA) and muscarinic cholinergic (m1, m3) receptors, which are 100-1000 times more sensitive than other targets. 20,29 The NMDA, m1 and m3 receptors remain sensitive at lidocaine concentrations below clinically relevant plasma concentrations. Lidocaine inhibits the activation of human NMDA receptors at nanomolar concentrations with maximum inhibition in the millimolar range, resulting in pain relief. Lidocaine acts on muscarinic cholinergic receptors in a concentration- and time-dependent manner. Claes et al. showed that intravenous administration of lidocaine at doses of 10 and 30 mg/kg increased intraspinal acetylcholine release and induced central analgesia by activating muscarinic receptors in rats, but a dose of 1 mg/kg lidocaine did not significantly increase intraspinal acetylcholine release. 30,31 Studies have also shown that lidocaine blocks the m1 and m3 muscarinic receptors at very low nanomolar concentrations (IC50 of 18 nM for m1 and 370 nM for m3). In addition, long-term exposure to lidocaine at IC50 resulted in a biphasic alteration of the m1 and m3 receptors with initial inhibition followed 8 hours later by increased signaling. 32 Thus, our single bolus of very low doses of lidocaine 0.5 mg/kg without prolonged exposure may be effective primarily through inhibition of the m1 and m3 receptors. Inhibition of m1 and m3 receptors was more pronounced, which may explain the increase in ED50 in the L0.5 group in our study. However, in our study, we did not measure the plasma concentration of lidocaine. Further research and verification is needed to confirm this assumption.
The mean dose of total propofol required for the entire operation was significantly higher in the L0 and L0.5 groups than in the other two groups. The frequency of respiratory depression in the L0.5 group was higher than in the L0 and L1.0 groups. The decrease in SBP after induction of anesthesia in the L0.5 group was greater than in the L0 group. None of the patients developed hypoxia, as we performed a chin lift or mask ventilation in a timely manner. The increased dose of total propofol, the frequency of respiratory depression, and the decrease in systolic blood pressure after induction of anesthesia in the L0.5 group also suggested that high doses of propofol may increase the risk of respiratory and circulatory depression. There were no differences in the incidence of adverse events between groups L0, L1.0 and L1.5. However, given the design of our study, the mean propofol-inducing dose in each group was close to the ED50 but below the ED95. Thus, the incidence of adverse events may have been higher if patients in the L0 group were induced with propofol at a dose of ED95 (2.8 [2.6–3.2] mg/kg). However, the effect of lidocaine resulted in an ED95 of 2.0 (1.9–2.4) mg/kg and 2.1 (1.9–2.4) mg/kg in the L1.0 and L1.5 groups, respectively, at relatively low doses. The above discussion explains why we believe that the analgesic effect of intravenous lidocaine at appropriate doses and at the right time is useful in reducing propofol-induced anesthesia complications. In our study, there were no significant differences in ED50, total propofol dose, awakening time, and adverse events between the L1.0 and L1.5 groups. We therefore recommend a lower dose of 1.0 mg/kg IV lidocaine as the optimal dose.
There are some limitations of our study. First, only patients with ASA I or II were included in this study, but patients with ASA III or IV may be more prone to respiratory and cardiovascular depression when taking propofol. 33 Moreover, all participants in this study were pregnant women, and the results may be related to physiological differences, differences in the male population. Second, we use the MOAA/S score as an indicator of the level of sedation rather than objective indicators such as BIS monitoring. 34 Third, lidocaine was administered as a single bolus and we did not measure plasma levels of lidocaine. Finally, ED95 is determined by ED50, so further research is needed to obtain more accurate data.
The results of our present study showed that intravenous administration of 1.0 mg/kg lidocaine prior to propofol injection significantly reduced ED50, ED95, and total propofol dose in patients undergoing first-trimester ambulatory hysteroscopy under anesthesia, equivalent to an effective dose of 1.5 mg /kg. We consider a dose of 1.0 mg/kg to be the optimal dose. Surprisingly, an intravenous dose of 0.5 mg/kg lidocaine increased the ED50 of propofol, indicating a complex effect of lidocaine. Further studies of the underlying mechanisms are needed to confirm our results.
The data obtained during the study can be obtained from the corresponding author (Ni Huang).
I would like to thank Dr. Huang Han from our department and the nurses in the operating room for their strong support.
1. Godsiff L., Magee L., Park GR. Propofol versus propofol plus midazolam for laryngeal mask insertion. Eur J anesthetic additive. 1995;12:35-40.
2. Seti S, Wadhwa V, Tucker A, et al. Propofol versus traditional sedatives for advanced endoscopic surgery: a meta-analysis. Dig out the endoscope. 2014; 26:515–524. doi: 10.1111/den.12219
3. Eastwood P.R., Platt P.R., Shepherd K. et al. Upper airway collapse at various concentrations of propofol anesthesia. Anesthetic. 2005; 103:470–477. doi: 10.1097/00000542-200509000-00007
4. Maddison K.J., Walsh J.H., Shepherd K.L. et al. Comparison of upper airway collapse in humans during anesthesia and during sleep. Anesthesia and comfort. 2020;130:1008–1017. doi:10.1213/ANE.0000000000004070
5. Fang Yi, Xu Yi, Cao C et al. Incidence of hypoxia and risk factors for deep sedation with propofol in patients undergoing induced abortion before medication. 2022;9:763275. doi:10.3389/fmed.2022.763275
6. Chen S, Wang Jie, Xiaohan S, et al. Efficacy and safety of remazolam tosylate compared with propofol in patients undergoing colonoscopy: a phase III multicenter randomized clinical trial with active control. I am J Transl Res. 2020;12:4594–4603.
7. Garcia Guzzo M.E., Fernandez M.S., Sanchez Novas D. et al. Deep sedation in endoscopic gastrointestinal surgery using controlled propofol infusion: a retrospective cohort study. Anesthetic BMK. 2020;20:195. doi: 10.1186/s12871-020-01103-w
8. Garcia-Pedrajas F., Arroyo J.L. Midazolam in anesthesiology. Reverend Medical University of Navarra. 1989;33:211-221.
9. Nishizawa T, Suzuki H, Hosoe N, et al. Dexmedetomidine versus propofol for gastrointestinal endoscopy: a meta-analysis. Joint European Journal of Gastroenterology 2017; 5:1037–1045. doi: 10.1177/2050640616688140
10 Beaussier M, Delbos A, Maurice-Szamburski A, et al. Perioperative intravenous administration of lidocaine. medicine. 2018;78:1229–1246. doi: 10.1007/s40265-018-0955-x
11. Altermatt F.R., Bugedo D.A., Delfino A.E. and others. The effect of intravenous lidocaine on the need for propofol during total intravenous anesthesia was measured by the bispectral index. Br Jay Anast. 2012; 108:979–983. doi: 10.1093/bja/aes097
12. Weber W., Crammel M., Linke S. et al. Intravenous administration of lidocaine increases the depth of anesthesia with propofol for skin incisions – a randomized controlled trial. Acta Anaesthesiol Scand. 2015;59:310–318. doi: 10.1111/aas.12462
13. Forster C, Vanhaudenhuyse A, Gast P, et al. Intravenous lidocaine significantly reduces propofol dose at colonoscopy: a randomized, placebo-controlled trial. Br Jay Anast. 2018; 121:1059-1064. doi:10.1016/j.bja.2018.06.019
14. Ates I, Enes Aydin M, Albayrak B, et al. Preoperative intravenous lidocaine with propofol for endoscopic retrograde cholangiopancreatography: a prospective, randomized, double-blind study. J Gastrointestinal heparin. 2021; 36:1286–1290. doi: 10.1111/jgh.15356
15. Liu J., Liu S., Peng L.P. Efficacy and safety of intravenous lidocaine in propofol-based procedural sedation in ERCP: a prospective, randomized, double-blind, controlled trial. Gastrointestinal endoscopy. 2020; 92:293–300. doi:10.1016/j.gie.2020.02.050
16. Lichina A, Silvers A. Systematic review and meta-analysis of perioperative intravenous lidocaine for postoperative analgesia in patients undergoing spinal surgery. Pain medicine. 2022;23:45-56. doi: 10.1093/pm/pnab210
17. Tian C, Zhang D, Zhou W, et al. Mean effective dose of lidocaine for the prevention of pain from propofol injection containing medium and long chain triglycerides, based on lean body mass. Pain medicine. 2021; 22:1246–1252. doi: 10.1093/pm/pnaa316
18 Song X, Sun Y, Zhang X et al. Effect of perioperative intravenous lidocaine on recovery after laparoscopic cholecystectomy – a randomized controlled trial. International Journal of Surgery. 2017;45:8-13. doi:10.1016/j.ijsu.2017.07.042
19. De Oliveira G.S. Jr., Paul F., Streicher L.F. and others. Systemic administration of lidocaine improves the quality of postoperative recovery after outpatient laparoscopic operations. Anesthesia and comfort. 2012; 115:262–267. doi: 10.1213/ANE.0b013e318257a380
20. Hermans H., Hollmann M.V., Stevens M.F. et al. Molecular mechanisms of action of systemic lidocaine in acute and chronic pain: a descriptive review. Br Jay Anast. 2019;123:335–349. doi:10.1016/j.bja.2019.06.014
21. Foo I, Macfarlane AJR, Srivastava D, et al. Treatment of postoperative pain and recovery with intravenous lidocaine: an international consensus on efficacy and safety. anesthesia. 2021; 76:238–250. doi: 10.1111/anae.15270
22. Lily H, Wang C, Dai C et al. Intravenous lidocaine attenuates hysteroscopy response to cervical dilatation: a randomized controlled trial. Br Jay Anast. 2021; 127:e166–e168. doi:10.1016/j.bja.2021.07.020
23. Liu Hai, Chen Ming, Lian C et al. Effect of intravenous lidocaine on ED50 of induced propofol during gastroscopy in adult patients: a randomized controlled trial. J. Clean Farm Ter. 2021; 46:711–716. doi: 10.1111/jcpt.13335
24. Pastis N.J., Hill N.T., Yarmus L.B. et al. Correlations between vital signs and depth of sedation were assessed during bronchoscopy using a modified observer activity and sedation assessment (MOAA/S). J Bronchology Interv Pulmonol. 2022;29:54-61. doi: 10.1097/LBR.0000000000000784