Exploring the Pharmacokinetic Profile of Remifentanil in Mid-Trimester Gestations Undergoing Fetal Intervention Procedures

Abstract

Background: Indications for surgery during pregnancy have increased. Specifically fetal interventions have increased from conditions that were considered lethal like twin-twin transfusion syndrome and severe fetal anemia to non-lethal conditions like myelomeningocele. The optimal anesthetic agent for in utero surgery is yet to be determined. Success of the procedure is often dictated by the efficacy of the anesthetic to immobilize the fetus without over-sedating mom. Remifentanil is used as preferred agent due to its short half-life however pharmacokinetics in pregnancy is unknown.Objective: To determine the pharmacokinetic parameters of remifentanil in a mid-trimester pregnant patient population undergoing fetal intervention.Study Design: A validated liquid chromatography assay with ultraviolet absorbance was employed to estimate maternal serum remifentanil levels. Blood samples were obtained at baseline and at selected time points: 5, 15, 30, 45, 60 min after the beginning of the remifentanil infusion and at 15, 30, and 60 min post end of infusion.Results: Ten pregnant patients were enrolled in the study however only eight patients had sampling obtained at all time points. The mean gestational age was 22.2 (±2.7) weeks, maternal age was 27.8 (±5.1) years and body mass index was 29.6 (±6.3). After receiving a continuous infusion of remifentanil, mean total dose was 975.3 μg, Cmin was 2.0 ng/mL and Cmax was 8.4 ng/mL. A two-compartment model best described the plasma remifentanil data. Mean pharmacokinetic parameters were: volume of distribution (Vdc) = 124.6 L (16.2–530.8 L), maternal remifentanil total clearance (Clt) = 170.7 L/h (17.7–486.9 L/h), and half-life (t½) = 0.6 h (0.2–0.9 h). The maternal remifentanil area under the curve (AUC) ranged from 2.7 to 21.7 μg/L*h. The mean alpha-acidic glycoprotein was 124.8 mg/dL (81.3–149.8).Conclusion: The pharmacokinetic profile of remifentanil in pregnant women is similar to previously reported general population profiles. This data did provide potential rationale for the clinical observations why when remifentanil is dosed based on non-pregnant guidelines, it did not uniformly provide adequate fetal immobilization as per anecdotal perception of operating fetal surgeons. These findings are important for the development of further clinical studies to optimize dosing for surgery during pregnancy including the estimation of placental transfer and total fetal exposure.

Use of Remifentanil for Open in utero Fetal Myelomeningocele Repair Maintains Uterine Relaxation with Reduced Volatile Anesthetic Concentration

“…Remifentanil readily crosses the placenta, providing fetal analgesia and reducing fetal sympathetic response to sur- gery [23,24]. It is also rapidly metabolized in both the mother and the fetus, and remifentanil pharmacokinetics in mid-gestation during fetal surgery has been shown to be similar to the general population [25]. One drawback of remifentanil is the potential development of opioid-induced hyperalgesia, which can lead to higher postoperative pain scores and delayed recovery after surgery [26].…”

A great tool that resurfaced during the pandemic: Remifentanil

“…41,42 Remifentanil clearance in pregnant patients appears to be twice as high as in non-pregnant patients, showing that physiological changes in pregnancy may be responsible for this difference due to the change in volume of distribution, lower plasma protein concentration, and increased nonspecific esterase activity. 43 The administration is intravenous via a continuous infusion pump with IV-drip support. The main adverse effects observed in pregnant patients were nausea, vomiting, pruritus, sedation, and respiratory depression.…”

Fetal Safety During Fetoscopic Spina-Bifida Repair: Anesthetic Concerns

“…Intravenous tocolytics for uterine relaxation may reduce the need for high concentrations of inhalational agents and hence reduce fetal exposure [34]. Use of remifentanil infusion is common to provide immobilization of the fetus as well as analgesia [36][37][38][39]. Remifentanil penetrates placenta more than other opioids and seem advantageous for fetal surgery [36,38].…”