Clinical Study Maternal Hypotension during Fetoscopic Surgery: Incidence and Its Impact on Fetal Survival Outcomes

In this retrospective cohort study, we aimed to determine the incidence of intraoperative maternal hypotension during fetoscopic surgery for twin-twin transfusion syndrome (TTTS) and to evaluate the impact of intraoperative hypotension on fetal survival. A total of 328 TTTS patients with recipient twin cardiomyopathy who underwent fetoscopic surgery under epidural anesthesia were included. The exposure of interest was maternal medical therapy with nifedipine for the treatment of fetal cardiomyopathy. We found that intraoperative hypotension occurred in 53.4% (175/328 patients). There was no statistically significant difference in incidence of hypotension between nifedipine exposure and nonexposure groups (54.8% versus 50.8%, = 0.479). However, the nifedipine exposure group received a statistically significant higher dose of phenylephrine (7.04 ± 6.38 mcg/kg versus 4.70 ± 4.14 mcg/kg, = 0.018) and higher doses of other vasopressor, as counted by number of treatments (6.06 ± 4.58 versus 4.96 ± 3.42, = 0.022). There were no statistically significant differences in acute fetal survival rate (within 5 days) and fetal survival rate at birth between hypotensive and nonhypotensive patients. We concluded that preoperative exposure to nifedipine resulted in increased intraoperative maternal vasopressor requirement during fetoscopic surgery under epidural anesthesia. In patients who had intraoperative maternal hypotension, there was no correlation between the presence of maternal hypotension and postoperative fetal survival

Utilization of Optimal Study Design for Maternal and Fetal Sheep Propofol Pharmacokinetics Study: A Preliminary Study

Abstract: Multiple blood samples are generally required for measurement of pharmacokinetic (PK) parameters. D-optimal design is a popular and frequently used approach for determination of sampling time points in order to minimize the number of samples, while optimizing the estimation of PK parameters. Optimal design utilizing ADAPT (v5, BSR, University of Southern California, Los Angeles) developed a sparse sampling strategy to determine measurement of propofol in pregnant sheep. Propofal was administered as supplemental anesthetic agent to inhalation anesthesia to mimic anesthesia for open fetal surgery. In our preliminary study, propofol 3 mg/kg was given as a bolus to the ewe, followed by propofol infusion at rate 450 mcg/kg/min for 60 minutes, then decreased to 75 mcg/kg/min for 90 more minutes and then ceased. A three compartment model described the PK parameters with the fetus assumed as the third compartment. Initially, sampling times were chosen from thirteen time points as previously stated in the literature. Using priori propofol PK estimates, the final 9 sample time points were proposed in an optimal design with a change in infusion rate occurring between 65 and 75 minutes and sampling proposed at 5, 15, 25, 65, 75, 100, 110, 150, and 180 minutes. D-optimal design optimized the number and timing of samplings, which led to a reduction of cost and man power in the study protocol while preserving the ability to estimate propofol PK parameters in the maternal and fetal sheep model. Initial evaluation of samples collected from three sheep using the optimal design strategy confirmed the performance of the design in obtaining effective PK parameter estimates

Utilization of Optimal Study Design for Maternal and Fetal Sheep Propofol Pharmacokinetics Study: A Preliminary Study

Abstract: Multiple blood samples are generally required for measurement of pharmacokinetic (PK) parameters. D-optimal design is a popular and frequently used approach for determination of sampling time points in order to minimize the number of samples, while optimizing the estimation of PK parameters. Optimal design utilizing ADAPT (v5, BSR, University of Southern California, Los Angeles) developed a sparse sampling strategy to determine measurement of propofol in pregnant sheep. Propofal was administered as supplemental anesthetic agent to inhalation anesthesia to mimic anesthesia for open fetal surgery. In our preliminary study, propofol 3 mg/kg was given as a bolus to the ewe, followed by propofol infusion at rate 450 mcg/kg/min for 60 minutes, then decreased to 75 mcg/kg/min for 90 more minutes and then ceased. A three compartment model described the PK parameters with the fetus assumed as the third compartment. Initially, sampling times were chosen from thirteen time points as previously stated in the literature. Using priori propofol PK estimates, the final 9 sample time points were proposed in an optimal design with a change in infusion rate occurring between 65 and 75 minutes and sampling proposed at 5, 15, 25, 65, 75, 100, 110, 150, and 180 minutes. D-optimal design optimized the number and timing of samplings, which led to a reduction of cost and man power in the study protocol while preserving the ability to estimate propofol PK parameters in the maternal and fetal sheep model. Initial evaluation of samples collected from three sheep using the optimal design strategy confirmed the performance of the design in obtaining effective PK parameter estimates

Propofol Pharmacokinetics and Estimation of Fetal Propofol Exposure during Mid-Gestational Fetal Surgery: A Maternal-Fetal Sheep Model.

Measuring fetal drug concentrations is extremely difficult in humans. We conducted a study in pregnant sheep to simultaneously describe maternal and fetal concentrations of propofol, a common intravenous anesthetic agent used in humans. Compared to inhalational anesthesia, propofol supplemented anesthesia lowered the dose of desflurane required to provide adequate uterine relaxation during open fetal surgery. This resulted in better intraoperative fetal cardiac outcome. This study describes maternal and fetal propofol pharmacokinetics (PK) using a chronically instrumented maternal-fetal sheep model.Fetal and maternal blood samples were simultaneously collected from eight mid-gestational pregnant ewes during general anesthesia with propofol, remifentanil and desflurane. Nonlinear mixed-effects modeling was performed by using NONMEM software. Total body weight, gestational age and hemodynamic parameters were tested in the covariate analysis. The final model was validated by bootstrapping and visual predictive check.A total of 160 propofol samples were collected. A 2-compartment maternal PK model with a third fetal compartment appropriately described the data. Mean population parameter estimates for maternal propofol clearance and central volume of distribution were 4.17 L/min and 37.7 L, respectively, in a typical ewe with a median heart rate of 135 beats/min. Increase in maternal heart rate significantly correlated with increase in propofol clearance. The estimated population maternal-fetal inter-compartment clearance was 0.0138 L/min and the volume of distribution of propofol in the fetus was 0.144 L. Fetal propofol clearance was found to be almost negligible compared to maternal clearance and could not be robustly estimated.For the first time, a maternal-fetal PK model of propofol in pregnant ewes was successfully developed. This study narrows the gap in our knowledge in maternal-fetal PK model in human. Our study confirms that maternal heart rate has an important influence on the pharmacokinetics of propofol during pregnancy. Much lower propofol concentration in the fetus compared to maternal concentrations explain limited placental transfer in in-vivo paired model, and less direct fetal cardiac depression we observed earlier with propofol supplemented inhalational anesthesia compared to higher dose inhalational anesthesia in humans and sheep

Visual predictive check of prediction-corrected concentration of propofol in ewe and fetus for the final model.

<p>Circles demonstrate prediction corrected observations. Red lines demonstrate 5th, 50th and 95th prediction percentiles.</p

Pharmacokinetic Model.

<p>The maternal- fetal pharmacokinetic model of propofol was best fitted using a 2 maternal compartment with a separate fetal compartment model. Vc = maternal central volume of distribution (L), Vp = maternal peripheral volume of distribution (L), Q = inter-compartmental clearance (L/min), CL = clearance from the maternal central compartment (L/min), Q_M-F = transfer rate between maternal and fetal compartment (L/min), V_Fetus = volume of distribution of fetal compartment (L).</p

The mean difference between maternal and fetal propofol plasma concentration in sheep after a bolus of propofol 3 mg/kg via the maternal femoral venous line, followed by an intravenous infusion of propofol (450 mcg/kg/min) for 60 minutes and then propofol infusion (75 mcg/kg/min) for 90 more minutes.

<p>The mean difference between maternal and fetal propofol plasma concentration in sheep after a bolus of propofol 3 mg/kg via the maternal femoral venous line, followed by an intravenous infusion of propofol (450 mcg/kg/min) for 60 minutes and then propofol infusion (75 mcg/kg/min) for 90 more minutes.</p

Between-subject random effects (η) for maternal clearance versus heart rate (HR) from the base (A) and final models (B).

<p>Each box represents data from one sheep. The lines in the box correspond to median values; the bottom and top of the box are the first and third quartiles (the 25th and 75th percentiles); the upper whiskers extend from the box to the highest value within 1.5 times of inter-quartile range (IQR); the lower whisker extend from the box to the lowest value within 1.5 times of IQR. The individual variability (Random effect, η) for maternal clearance (ηCL) is narrower in the final model than in the base model.</p

Propofol concentration time profiles for each fetal-maternal sheep unit (n = 8).

<p>Propofol was administered to the ewes as a bolus of 3 mg/kg, followed by an infusion of 450 μg/kg/min for 60 minutes. After that, propofol infusion rate was decreased to 75 μg/kg/min for 90 more minutes, and then stopped.</p

Goodness-of-fit plots for the final PK model.

<p>(A) Population prediction versus observed concentration. (B) Individual prediction versus observed concentration. (C) Conditional weighted residuals (CWRES) versus population prediction. (D) Conditional weighted residuals (CWRES) versus time. Dashed red line, a locally weighted least-squares regression; solid black line, line of identity.</p