From the Departments of Anesthesiology and Perioperative Medicine.
Obstetrics and Gynecology, and.
Anesth Analg. 2022 Oct 1;135(4):777-786. doi: 10.1213/ANE.0000000000006064. Epub 2022 May 11.
Intraperitoneal chloroprocaine has been used during cesarean delivery to supplement suboptimal neuraxial anesthesia for decades. The short in vitro half-life of chloroprocaine (11-21 seconds) has been cited to support the safety of this approach. However, there are no data regarding the rate of absorption, representing patient drug exposure, through this route of administration. Accordingly, we designed a study to determine the in vivo half-life of intraperitoneal chloroprocaine and assess clinical tolerability.
We designed a single-center, prospective, cohort, multiple-dose escalation study of women 18 to 50 years of age undergoing cesarean delivery with spinal anesthesia. Chloroprocaine (40 mL) was administered after delivery of the newborn and before uterine closure. The first cohort (n = 5) received 1%, the second cohort (n = 5) received 2%, and the third cohort (n = 5) received 3% chloroprocaine solution. Maternal blood samples were obtained before administration and 1, 5, 10, 20, and 30 minutes after dosing. The primary objective was to define the pharmacokinetic profile of intraperitoneal chloroprocaine, including in vivo half-life. The secondary objective was to evaluate tolerability through determination of peak plasma concentration and prospective assessment for local anesthetic systemic toxicity.
The peak plasma concentration occurred 5 minutes after intraperitoneal administration in all 3 cohorts: 64.8 ng/mL (6.5 µg/kg), 28.7 ng/mL (2.9 µg/kg), and 799.2 ng/mL (79.9 µg/kg) for 1%, 2%, and 3% chloroprocaine, respectively. The in vivo half-life of chloroprocaine after intraperitoneal administration was estimated to be 5.3 minutes (95% confidence interval, 4.0-6.6). We did not detect clinical signs of local anesthetic systemic toxicity in any of the 3 cohorts.
The in vivo half-life of intraperitoneal chloroprocaine (5.3 minutes) is more than an order of magnitude greater than the in vitro half-life (11-21 seconds). However, maximum plasma concentrations of chloroprocaine (C max range, 0.05-79.9 µg/kg) were not associated with local anesthetic systemic toxicity and remain well below our predefined safe level of exposure (970 µg/kg) and levels associated with clinical symptoms (2.6-2.9 mg/kg). Therefore, our study suggests that intraperitoneal chloroprocaine, in a dosage ≤1200 mg, administered after fetal extraction, is well tolerated during cesarean delivery.
几十年来，氯普鲁卡因已被用于剖宫产术中以补充不理想的椎管内麻醉。氯普鲁卡因的体外半衰期较短（11-21 秒），这被认为是这种方法安全的原因。然而，目前尚无关于通过这种给药途径吸收的速率（代表患者的药物暴露量）的数据。因此，我们设计了一项研究来确定腹腔内氯普鲁卡因的体内半衰期并评估其临床耐受性。
我们设计了一项单中心、前瞻性、队列、多剂量递增研究，纳入年龄在 18 至 50 岁之间、接受脊髓麻醉行剖宫产的女性。在新生儿娩出后和子宫关闭前给予氯普鲁卡因（40 毫升）。第一组（n=5）接受 1%的氯普鲁卡因溶液，第二组（n=5）接受 2%的氯普鲁卡因溶液，第三组（n=5）接受 3%的氯普鲁卡因溶液。在给药前和给药后 1、5、10、20 和 30 分钟采集母亲的血样。主要目的是确定腹腔内氯普鲁卡因的药代动力学特征，包括体内半衰期。次要目的是通过测定峰血浆浓度和前瞻性评估局部麻醉全身毒性来评估耐受性。
在所有 3 个队列中，腹腔内给药后 5 分钟时达到血浆峰浓度：1%、2%和 3%氯普鲁卡因组分别为 64.8ng/mL（6.5μg/kg）、28.7ng/mL（2.9μg/kg）和 799.2ng/mL（79.9μg/kg）。腹腔内给予氯普鲁卡因后，体内半衰期估计为 5.3 分钟（95%置信区间，4.0-6.6）。在 3 个队列中均未检测到局部麻醉全身毒性的临床迹象。
腹腔内氯普鲁卡因的体内半衰期（5.3 分钟）比体外半衰期（11-21 秒）长一个数量级以上。然而，氯普鲁卡因的最大血浆浓度（C max 范围，0.05-79.9μg/kg）与局部麻醉全身毒性无关，仍远低于我们预先设定的暴露安全水平（970μg/kg）和与临床症状相关的水平（2.6-2.9mg/kg）。因此，我们的研究表明，在胎儿娩出后给予剂量≤1200mg 的腹腔内氯普鲁卡因，在剖宫产术中是耐受良好的。
