Pharmacokinetics of Levobupivacaine and Epinephrine for Transversus Abdominis Plane (TAP) Block for Cesarean Section Postoperative Analgesia
Description:
Introduction.
Post cesarean section pain control is a challenging task since it is one of the ten most
painful surgeries. Multiple strategies have been proposed for pain control, including
neuraxial analgesia, systemic opioids, non-opioid drugs and peripheral nerve blocks, among
others.
Transversus abdominal plane (TAP) blocks have been proven to provide effective analgesia when
used as part of a multimodal analgesic regimen after abdominal surgery and is becoming a
popular technique for post cesarean section analgesia, although recent reports of local
anesthesia toxicity have raised concerns about its safety in this population. Currently there
is no information on the pharmacokinetics of levobupivacaine of the technique in pregnant
patients to guide dosing in a safer way.
Our objective is to generate a pharmacokinetic model to characterize the plasmatic levels of
levobupivacaine co-administered with epinephrine and its effect on the ECG, for TAP block in
post cesarean section patients.
Methods.
After institutional ethics committee approval and written informed consent, 12 term pregnant
patients American Society of Anesthesiologists physical status I or II, scheduled for
elective cesarean section were recruited in this prospective, single-blind pharmacokinetic
study. Patients were excluded if they had any allergy/sensitivity to local anaesthetic,
significant renal or liver dysfunction.
An intravenous (18-gauge) catheter was placed under local anesthesia for co hydration. After
the initiation of standard monitoring (continuous electrocardiogram, noninvasive arterial
blood pressure, and pulse oximetry), all patients received a spinal anesthesia in the L3-L4
or L4-L5 interspace with hyperbaric bupivacaine 0,75% 1,4 ml plus 20 ug fentanyl to achieve a
bilateral anesthetic level of T4 determined by pinprick. After surgery, a TAP block was
performed with 20 mL of 0.25% levobupivacaine, with epinephrine 1:200.000 (5 ug/ml) on each
side, under ultrasound (US) guidance.
One anesthesiologist experienced in the technique performed all of the TAP blocks using a US
Sonosite M-Turbo US machine (Sonosite Inc, Washington) with an L38x 10-5 megahertz (MHz),
38-mm broadband linear array probe. A second anesthesiologist evaluated and approved the US
images before administration of the mixture. Blocks were performed with a 21 gauge (G),
110-mm spinal Quincke needle (N. Medical Industries Ltd., Japan) using an in-plane approach.
The extent of sensory blockade of the TAP block to temperature, light touch, and sharp touch
was determined using ice, cotton wool, and pinprick, respectively at 1, 2, 6 and 12 hrs post
block and the metameric extent of the blockade was recorded. 2 mL venous blood samples were
obtained at 2, 5, 10, 30, 45, 60, 90 and 180 minutes after the block. The duration of the
blockade was also recorded and symptoms of local anesthetic systemic toxicity were assessed
on every control.
Concomitantly we studied the effects of the local anesthetic on myocardial electrical
conduction to characterize the pharmacodynamics of TAP block. Briefly, a portable 12-lead
Holter (NorthEast Monitoring®, Boston, USA) will record continuously the electrocardiogram
(ECG). The information will be stored in an external flash memory card to be analyzed
retrospectively with ad hoc software (NorthEast Monitoring®, Boston, USA). We will correlate
the eventual changes in the QTc segment with levobupivacaine free plasma levels, which
translates the effect of local anesthetics on the heart.
Levobupivacaine Assay.
Levobupivacaine was extracted from plasma using liquid-liquid extraction according to the
methods described by Adams et al. The internal standard solution (10 mL of mepivacaine, 30
ug/mL) was added to 0.2 mL of plasma, 100 micro(u)L of sodium hydroxide (2 mol/L solution),
and 0.6 mL diethyl ether. The mixture was stirred for 1 minute and centrifuged for 5 minutes
at 3000 revolutions/min. Subsequently; the organic phase was transferred to another tube to
which 0.25 mL of 0.05 N sulfuric acid was added. The mixture was stirred again for another
minute and centrifuged for 5 minutes at 3000 revolutions/min. The aqueous phase was
transferred to another tube for subsequent injection. An aliquot of 100 micro(u)L was
injected into the high-performance liquid chromatography system. The linearity of the method
was evaluated in the range of 0.125 to 10 ug/mL, and 3 concentrations (0.75, 3, and 7.5
ug/mL) were extracted during each protocol as controls.
Knudsen have recently reported the unbound bupivacaine plasma levels thresholds for
neurologic symptoms in volunteers of 0,11 ug/ml (SD 0,1 ug/ml). Ikeda et al. found that
although there were no differences between the concentrations of bupivacaine and
levobupivacaine in plasma, levels of unbound bupivacaine in the cerebral extracellular fluid
were significantly higher than levobupivacaine. Consequently, we opted to guide our analysis
using bupivacaine pharmacokinetic (PK) data.
Statistical analysis.
Based on the design of relatively frequent sampling planned for each patient and assuming a
interindividual variability of 50%, similar to that found in a previous study, which allowed
the investigators to characterize the pharmacokinetics of levobupivacaine in 11 healthy
volunteers with good accuracy, an estimated number of 12 patients is suitable for the
purposes of this study.
Pharmacokinetic Analysis
Population parameter estimations
A one-compartment model with first-order input and elimination was used to describe the time
profile of serum levobupivacaine concentrations. Population parameter estimates were
calculated using nonlinear mixed effects modelling implemented in the program NONMEM (NONMEM
7.3, Icon Development Solutions, USA). The population parameter variability was modeled in
terms of random effect (η) variables. Each variable was assumed to have a mean = 0, and a
variance, denoted by ω2, was estimated.
Condition:
Pain, Postoperative
Treatment:
Levobupivacaine
Start Date:
December 15, 2016
Sponsor:
Pontificia Universidad Catolica de Chile
For More Information:
https://clinicaltrials.gov/show/NCT02852720