Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04562103 |
| Other study ID # |
ID 2979 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
July 3, 2020 |
| Est. completion date |
September 3, 2020 |
Study information
| Verified date |
July 2020 |
| Source |
Fondazione Policlinico Universitario Agostino Gemelli IRCCS |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Introduction The posterior Quadratus Lumborum Block (pQLB) has been used in postoperative
pain management after Cesarean Section (CS). However, there are no data about pQLB safety in
pregnants, at increased risk of local anesthetic systemic toxicity (LAST). The purpose of the
present study was to explore the efficacy and the safety of adding epinephrine to ropivacaine
for bilateral pQLB vs. bilateral pQLB performed with ropivacaine alone in CS.
Methods Fifty-two pregnants were consecutively allocated to one of 2 groups [e-pQLB (0.375%
ropivacaine+100 mcg epinephrine) or pQLB (0.375% ropivacaine)] and the investigators
evaluated if the adjunct of epinephrine to ropivacaine increases of efficacy (measured as
opioid consumption during the first 24 postoperative hours, time for first request of opioid
and pain values reported by patients) and the safety (measured as peak and plasmatic
concentration of ropivacaine) of pQLB.
Description:
BACKGROUND The posterior Quadratus Lumborum Block (pQLB) is a posterior abdominal wall block
in which local anesthetic (LA), administered posteriorly to Quadratus Lumborum (QL) muscle,
spreads underneath intermedium layer of thoracolumbar fascia, into a triangular space named
lumbar interfacial triangle. This interfascial plane is in close relation to thoracic
paravertebral (PV) space. Local anesthetic spread into this space could explain analgesic
efficacy of pQLB1. Compared to lateral QLB, in which LA is administered laterally to QL
muscle, pQLB is safer (needle tip is separated from the peritoneum by QL muscle) and easier
to perform (injection point is more superficial). Posterior QLB efficacy has been
demonstrated in major abdominal surgery. In Cesarean Section (CS) pQLB efficacy vs placebo
and superior efficacy vs TAP block was showed. Ropivacaine arterial concentration after QLB,
in laparoscopic gynaecological surgery has been studied. To the best of our knowledge no
author investigated pQLB safety in obstetric population, at increased risk of local
anesthetic systemic toxicity (LAST) because of physiological modifications occurring during
pregnancy (increased cardiac output, increased arterial and venous blood tissue flow,
decreased concentration of plasma binding protein). Adding epinephrine to local anesthetic,
determining a delayed AL systemic reabsorption and a reduced plasmatic concentration, could
improve pQLB efficacy and safety, as demonstrated for Transversus Abdominal Plain (TAP) block
and sciatic and femoral block.
METHODS Patients were consecutively allocated into one of two groups: e-pQLB (0.375%
ropivacaine+ 100 mcg epinephrine) or pQLB (0.375% ropivacaine). Before surgery, under local
anesthesia, 2 venous accesses were founded, one for fluids and drugs injection and the second
one, contralaterally, for venous samples only. During surgical procedure standard hemodynamic
monitoring was provided; fetal wellbeing was registered by cardiotocographic monitoring.
Supplemental oxygen has was provided by Venturi mask. SA was administered in sitting
position, at L3-4 lumbar interspace, using hyperbaric bupivacaine 0.5% 9 mg plus sufentanil 5
mcg. Surgical procedure started when T4 level has been reached. Posterior QLB was
administered at the end of surgical procedure, with patient in supine position, under
monitoring and after cleaning the skin with surgical solution (ChloraPrep, Carefusion, 244
LTD, UK). A Sonosite M-Turbo echograph ( FUJIFILM Sonosite Europe, Amsterdam, Netherlands)
and a broadband (5-8 MHz) convex probe covered with a sterile plastic sheath have been used.
The probe was placed at the level of the anterior superior iliac spine and moved cranially
until the three abdominal wall muscles were identified. The external oblique muscle was
followed posterolaterally until its posterior border was found. The probe was tilted down to
identify the bright hyperechoic line that corresponds with the intermediate layer of the
thoracolumbar fascia. The needle (Ultraplex 360, B.Braun Melsungen, Germany) was inserted in
plane from medial (anterior) to lateral (posterior). The optimal point of injection was
determined using hydrodissection. In e-pQLB group ropivacaine 0.375%+epinephrine 100 mcg 20
ml for each side was administered; in pQLB group ropivacaine 0.375% 20 ml for each side was
administered. After block, venous samples (2 ml each) were performed at 10, 30, 45, 60, 120
minutes. The ropivacaine concentration was set at 2.2 mcg/ml, which represents the venous
threshold value of systemic toxicity14. To evaluate LAST patients have been asked for
perioral tingling, metallic taste, tinnitus, visual disturbance or slurred speech at the time
that each blood sample has been obtained.
Intraoperative ketorolac 30 mg and acetaminophen 1 g were administered. After surgery, in
Post Anesthesia Care Unit (PACU), a PCA pump was connected to patients and programmed to
deliver 1 mg morphine bolus on demand with a lock out interval of 8 min and no background
infusion. All patients received regular intravenous paracetamol 1g 6 hourly and intravenous
ketorolac 30 mg 12 hourly.
Experimental procedure Chemicals, reagents and equipment Methanol and acetonitrile were HPLC
grade and were purchased from VWR Chemicals (Radnor, PA, USA). Water was purified by
Millipore Synergy-UV-System (Bedford, MA, USA). 20 % ammonium hydroxide solution was provided
by Carlo Erba Reagents (Milan, Italy), acetic acid 99-100% and phosphoric acid ≥ 85% were
provided by Sigma-Aldrich (St. Louis, MO, USA). Ropivacaine and Ropivacaine-d7 hydrochloride
(used as internal standard, IS) were purchased by USP (Rockville, MD, USA) and Toronto
Research Chemicals (North York, ON, Canada), respectively. Neostigmine methylsulphate was
provided by LGC Standards (Luckenwalde, Germany).OASIS HLB SPE cartridges (3 mL, 60 mg) were
supplied by Waters (Milford, MA, USA). PTFE disposable filters (0.45 µm) were purchased from
Membrane solutions (Plano, TX, USA). Visiprep DL SPE Vacuum Manifold was purchased by
Supelco/Sigma-Aldrich (St. Louis, MO, USA). The heating block "Pierce - Reacti-Therm III" was
purchased from ThermoFisher Scientific (Waltham, MA, USA). Centrifuge 5415D supplied by
Eppendorf (Hamburg, Germany).1 mg mL-1 stock solutions of ropivacaine and ropivacaine-d7 were
prepared in methanol. Working standard solution dilutions were prepared from these latter
solutions and were finally diluted by serial dilution to spike blank plasma samples for the
construction of matrix-matched calibration curve in order to have final ropivacaine
concentrations in the interval of 0.8 - 13.2 ng mL-1. Working solutions were stored at -20 °C
and prepared daily. Stock solutions were analysed regularly up to six month after the
preparation to assess their stability in the time and whether there was degradation of the
analytes.
Plasma sampling Patients' blood samples (5 mL) were collected in tubes containing
ethylenediaminetetraacetic acid (EDTA) and were added to 25 µL of 20 mg mL-1 neostigmine
methylsulfate solution to block esterase activity in the plasma14. The samples were stored in
ice-water bath for 10-15 min and then centrifuged at 1300 × g at 4°C for 5 min to obtain
plasma. Collected plasma samples were stored at -20 °C until analyzed.
Sample preparation A modified procedure of Toonoka K was used. A 0.2-mL-aliquot of plasma
sample was added to 0.3 mL of purified water and vortex-mixed. The diluted sample was spiked
with 25 µL of a methanolic solution of ropivacaine-d7 (IS) (85.0 ng mL-1) and added to 0.5 mL
of 4 % phosphoric acid solution. The mixture was vortex-mixed and centrifuged (16110 × g, 2
min). The supernatant is then loaded on the OASIS HLB SPE cartridge which was previously
conditioned with 2 mL of methanol and equilibrated with 2 mL of purified water. After the
washing steps with 2 mL of 5% methanol solution and 2 mL of 2% ammonium hydroxide in a 10%
methanol solution, sample was eluted with 2 mL of methanol/ 2% acetic acid (70/30, v/v)
solution. The extract was next evaporated under a stream of nitrogen at 30°C and the dry
residue was dissolved in 0.2 mL of the mobile phase and filtrated prior to LC-MS/MS analysis
(10 μL injection).
LC-MS/MS analysis Analyses were carried out using a LC system Perkin Elmer Series 200 Micro
Pump equipped with a PE Series 200 auto sampler (Perkin Elmer, USA). The chromatographic
separations were obtained under gradient conditions at room temperature (25°C) using a
reverse phase HPLC column Kinetex 2.6 µm EVO C18 100 Å (100 × 3 mm) (Phenomenex, USA) with
C18 guard column (4 mm × 2 mm) (Security Guard, Phenomenex, USA). The mobile phase was
composed of ammonium hydroxide 0.53 mM pH 10.3 (mobile phase A) and acetonitrile (mobile
phase B) and the flow rate was 0.3 mL min-1. The gradient profile began at 70 % A and held
for 1 min, then changed to 25 % in 2 min and held for 3 min. The profile returned to 70 % A
in 1 min and held for 1 min (total run: 8 min).
The API 3000 triple quadrupole mass spectrometer (AB Sciex, Canada) was equipped with an
Electro Spray Ionization (ESI) source, and was set in positive ionization mode (source
temperature: 450 °C; ionspray voltage: 5500 V; ultra-pure nitrogen as curtain and collision
gas; ultra-pure air as nebulizer and auxiliary gas). One precursor ion and two product ions
(two transitions) for ropivacaine and ropivacaine-d7 were monitored by MRM (Multiple Reaction
Monitoring): 275.2 m/z > 126.1 m/z (most abundant ion used for quantification) and 275.2 m/z
> 84.2 m/z (Figure 1). Collision energy (CE), declustering potential (DP), entrance potential
(EP), and collision cell exit potential (CXP) were adjusted in MRM mode for each transition
monitored in order to reach the highest sensitivity for all the analytes.
Plasma samples, used for the construction of five points matrix-matched calibration curves,
were previously tested and shown to contain no residues of the compounds of interest. The
ropivacaine concentration levels were set as follows: 0.82, 1.64, 3.28, 6.56 and 13.12 ng
mL-1. The correlation between concentration and the detector response was determined by using
a weighted (1/x) linear regression model (equation y = 0.117x + 0.00409; correlation
coefficient r > 0.998; relative accuracy percentage for each point of the curve within the ±
5 % of the expected concentrations). Sample was appropriately further diluted to obtain
concentrations of ropivacaine within the calibration ranges.
The main performance characteristics of the method were evaluated. Limit of detection (LOD)
and limit of quantification (LOQ) values were 0.30 and 0.82 ng mL-1 of ropivacaine,
respectively. Repeatability expressed as intra-day coefficient of variation (CV %) was in the
interval of 1.99 - 11.44 % whereas intermediate precision expressed as inter-day CV % was in
the interval 7.61 - 13.60 %. Recovery percentages were 99.03 - 110.7 %.
Statistical analysis Sample size estimation was based on a recent article from Hansen et al,
who demonstrated that transmuscular quadratus lumborum block for elective CS significantly
reduces postoperative opioid consumption and prolongs time to first opioid request when
compared to placebo. In this single-center, randomized, placebo-controlled study, the mean 24
hours postoperative oral morphine equivalents was 65,3 mg vs 94,3 mg in the control group.
Our primary hypothesis was that epinephrine added to ropivacaine for pQLB would result in a
minimum 30% reduction of opioid consumption in the first 24 postoperative hours. Based on
previous studies on opioid consumption, a SD of 40% was estimated. A sample size of at least
35 patients would give 80% power to detect a 30% reduction in opioid consumption, using
t-tests with α=0,05. Fifty-two patients, twenty-six per group were included in the study to
allow missing data or dropouts. The analysis was performed using Stata IC/15.1 (Stata Corp)
and Microsoft Excel. Ordinal data and continuous data were analyzed using Wilcoxon rank sum
test and Student's t-test as appropriate. Shapiro-Wilk test was used to assess normality of
data distribution and the sd-test to verify equality of variances. For non-normally
distributed data, a Mann-Whitney test was performed. Differences between categorical data
were analyzed using the χ 2 or Fisher's exact test. Variables were presented as means (SD) or
median (range). The data were given as ratio of means and 95% confidence intervals (CIs).A
mixed-effects model for repeated measures ANOVA was used to assess the treatment-by time
interaction; the p value included Box's conservative F test for the lack of compound symmetry
assumption. The investigators applied log-rank tests to compare Kaplan-Meier plots, for
duration of time until first analgesic request. Statistical significance level was 0.05%.
