Pharmacokinetics and Tolerability of Intraperitoneal Chloroprocaine After Fetal Extraction in Women Undergoing Cesarean Delivery

Brandon M. Togioka, MD; Yalda Zarnegarnia, PhD, MS; Lisa A. Bleyle, BS; Dennis Koop, PhD; Kathleen Brookfield, MD, PhD, MPH; N. David Yanez, PhD; Miriam M. Treggiari, MD, PhD, MPH

Disclosures

Anesth Analg. 2022;135(4):777-786. 

In This Article

Abstract and Introduction

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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 (Cmax 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.

Introduction

Cesarean delivery represents the highest-volume inpatient surgical procedure in the United States,[1] with the majority of women receiving neuraxial anesthesia.[2] Unfortunately, 9% of cesarean deliveries with spinal anesthesia require intravenous anesthesia supplementation,[3] and conversion to general anesthesia is not uncommon: 2% when a new neuraxial block is performed[4] and 5% when a labor epidural is used.[5] There are limited options for supplementing inadequate neuraxial anesthesia, including low-dose propofol, opioids, benzodiazepines, ketamine, nitrous oxide, and, as a last resort, general anesthesia. Whereas the aforementioned options alter the maternal birth experience and may cause neonatal neurobehavioral depression, nausea, and pruritis,[6] an intraperitoneal local anesthetic with volumes between 10 and 60 mL has been administered after fetal extraction to provide intraoperative and postoperative anesthesia for cesarean delivery without causing these systemic adverse effects.[7–10]

Despite limited published data showing efficacy,[9] intraperitoneal chloroprocaine is used to provide intraoperative anesthesia, when systemic uptake may be higher due to lacerated vasculature, because it is believed to have low potential for systemic toxicity due to its very short in vitro half-life (11–21 seconds).[11,12] However, chloroprocaine can be detected in plasma for up to 30 minutes after epidural and paracervical administration in patients with normal pseudocholinesterase activity.[13–16] Hence, the in vitro half-life of chloroprocaine is not indicative of its potential for local anesthetic systemic toxicity (LAST) after epidural, paracervical, and likely intraperitoneal administration. While the in vivo half-life (t1/2) of epidural chloroprocaine (3.1 minutes)[11] has been estimated, the t1/2 of intraperitoneal chloroprocaine has not been determined, nor has tolerability.

Given that tolerability of intraperitoneal chloroprocaine is uncertain, we designed a prospective cohort study to define the (pharmacokinetics [PK]) profile of intraperitoneal chloroprocaine, including t1/2, and assess tolerability through consideration of maximum plasma concentration (Cmax) and the occurrence of LAST. We posited that the t1/2 of intraperitoneal chloroprocaine would be longer than the in vitro half-life.

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