Clinical trial NCT05124704
Conditions: Gastric Cancer
Keywords: Propofol EC50 Epidural anesthesia Gastric cancer Gastrectomy
Sponsor: Wang Jiangling
Start date: 2021-11-20; Completion date: 2022-05-25
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The beneficial of perioperative usage of thoracic epidural anesthesia and analgesia in various thoracic and upper abdominal surgery are well studied. However, intraoperative data are lacking whether combined thoracic epidural and general anesthesia have effect on the median (50%) effective effect-concentration (EC50) of propofol for inducing loss of consciousness (LOC). We performed this study among patients undergoing open gastrectomy in gastric cancer patients.

Sixty patients undergoing open gastrectomy were randomly assigned to two groups with thoracic combined general anesthesia (TEA+GA) or general anesthesia (GA) alone. Target-controlled infusion (TCI) of propofol was used for anesthesia induction. The initial propofol concentration of target effect-site (Ceprop) was 3.5 ug/ml and was increased stepwise by 0.5ug/ml at each 4 min intervals by an un-down sequential method to reach LOC. The predicted Ceprop at the time of LOC, intravenous anesthetics, vasopressor requirement, emergency time from anesthesia and postoperative numeric rating scale (NRS) were recorded and analyzed between two groups.

Detailed description:
After received the approvement of ethics committee of the Cancer Hospital of the University of Chinese Academy of Sciences (approval number IRB- 2021-214). 60 adult gastric cancer patients between 18-75 yrs, ASA physical state I and II, undergoing open gastrectomy, were enrolled in this study. The exclusion criteria included: patients with contraindications to epidural puncture or catheter placement; chronic or acute (within 48 h) intake of psychotropic drugs, benzodiazepines, anticonvulsants, or opioids; alcoholism; hepatic, renal, neurological or other organ dysfunction; younger than 18 years or older than 75 years; with allergic to local anesthetic solutions or opioids; received neo-adjuvant chemotherapy; as well as patients who refuse to receive epidural puncture.

Patients were randomly assigned to either TEA+GA group of GA group. The requirement for the modified up-down method was used to confirm sample size (1).

Preoperative arrangements 3-lead electrocardiogram, pulse oximetry and continuously invasive artery blood pressure via left radial artery() were measured for basic monitoring. A central venous catheter was placed in the right internal jugular vein for fluid input and central venous pressure measurement and its position was confirmed by ultrasound. Bispectral Index (BIS) monitor (VT94306, Aspect VISTA, Covidien IIc, MA, USA) was measured for monitoring the depth of anesthetic.

Thoracic Epidural Anesthesia Epidural puncture was performed in the left lateral position through the interspace between the eighth to ninth thoracic vertebra (T8-T9). Epidural catheter was inserted by median approach using "loss-of-resistance"technique and was placed advanced 4 cm cephalad. A test dose of 3ml, 1%, lidocaine was injected through the catheter after the aspiration test for blood and cerebrospinal fluid shows negative results. Non sensory and motor anesthesia after 4 min of test dose injection indicate the absence of accidental subarachnoid placement of the catheter. In group TEA+GA, 5-8ml of 0.375% ropivacaine depend on the height and weight of the patient was administrated through the epidural catheter at least 20 min before induction, by the second anesthesiologist, to obtain a bilateral segmentary sensory block to pinprick between T4 and T12 dermatomes. Continuous infusion of 4-6 ml 0.375% ropivacaine was applied using micro-infusion pump after induction(2). In group GA, same dose of normal saline was administered before induction and during surgery.

General Anesthesia General anesthesia was induced by propofol plasma target-controlled infusion (TCI) (). To explore the EC50 of propofol for inducing LOC in two groups. We started induction using a series of predicted effect-site concentrations of propofol (Ceprop) with an equal step wise of 0.5 ug/ml, according to the up-down method of Dixon(1). The initial Ceprop for the first patient of each group was 3.5 ug/ml based on previous studies (3) . Positive response to propofol was defined as LOC happened within 4 min after start of TCI under initial concentration. Otherwise the response was taken as negative and propofol concentration was increased 0.5 ug/ml more each 4 min until patient reach LOC (LOC was defined as loss of response to verbal commands). The initial TCI Ceprop was increased by 0.5 ug/ml for the next patients if the previous patient shows negative in the same group. The initial TCI Ceprop was decreased by 0.5 ug/ml for the next patient if the previous patient shows positive in the same group. All the patients were increased by 0.5 ug/ml stepwise at 4 min intervals until they showed LOC. An interval of 4 min was based on the pharmacokinetic and pharmacodynamic (PK-PD) character of propofol in order to obtain the steady-state effect-site concentrations (4; 5). An intravenous of 0.25 mg/Kg oxycodone and 0.6 mg/Kg rocuronium were given after LOC to facilitate tracheal intubation.

Maintenance of anesthesia Anesthesia was maintained with propofol, remifentanil and rocuronium during surgery. Ceprop was adjusted in stepwise of 0.5 ug/ml to keep the BIS between 45 to 55 in two groups. The lowest Ceprop was 2.0 ug/ml to avoid intraoperative awareness. Concentration for remifentanil was between 0.05 ug/Kg/min and 0.25 ug/Kg/ min during surgery depend on the blood pressure. The maintenance doses of rocuronium was 0.15mg/Kg as required to maintain surgical paralysis (6). Patients with hypertension were treated with 10 mg urapidil or 5 mg diltiazem i.v and hypotension was treated initially by speeding Ringger's solution, infusion voluven, then decrease concentration of remifentanil by 0.05 ug/Kg/min until reach the lower limit of 0.05 ug/Kg/min and finally given 5mg ephedrine i.v. 80 ug phenylephrine or 1mg metaraminol were then given if hypotension was remaining.

Postoperative management Anesthetics were stopped when the final surgical suture was done and then 2-4mg/Kg of sugammadex was applied according to the train-of-four (TOF) ratio. The duration between the time of discontinuation of anesthetics and the time of spontaneous opening of eyes was defined as anesthesia emergency time. All patients received postoperative patient-controlled epidural analgesia (PCEA) 0f 0.175% ropivacaine with 0.7ug/ml sufentanil. The PCEA continuous infusion dose was 3-4 ml with patient-controlled bolus dose of 4-5ml depend on the height and weight of patient.

Patients were transferred to PACU after extubation and stay at least 60 min there. In PACU, pain intensity using numerical analogue score of 0-10, postoperative nausea, vomiting and times of hypotension were evaluated and recorded at 30min, 60min and the time leave PACU.

Arms: arm 1: Patients in this group received 5-8ml of 0.375% ropivacaine depend on the height and weight of the patient was administrated through the epidural catheter at least 20 min before induction.Followed by a continuous infusion of 4-6 ml 0.375% ropivacaine was applied using micro-infusion pump after induction during surgery. arm 2: In this group, same dose of normal saline was administered before induction and during surgery.
Interventions: intervention 1: 5-8ml 0.375% ropivacaine intervention 2: 5-8ml normal saline
Intervention descriptions: intervention 1: 5-8ml of 0.375% ropivacaine depend on the height and weight of the patient was administrated through the epidural catheter at least 20 min before induction in experimental group. Followed by a continuous infusion of 4-6 ml/h using micro-infusion pump after induction during surgery. intervention 2: 5-8ml of normal saline depend on the height and weight of the patient was administrated through the epidural catheter at least 20 min before induction. Followed by a continuous infusion of 4-6 ml/h using micro-infusion pump after induction during surgery.

Protocol documents:
Prot_000.pdf: 
Protocal number.：202101
Version：2.0
- 2 -
Study Protocal
Official Title: Propofol EC50 for Inducing Loss of Consciousness in
General Combined Epidural Anesthesia
NCT05124704
Date of document: June 17th, 2021


Protocal number.：202101
Version：2.0
- 3 -
Study population and randomization
This study was approved by the Ethics Committee of Zhejiang Cancer Hospital prior
to patient enrolment (IRB-2021-214, date of approval: 1 July 2021) and registered at
ClinicalTrials.gov (identifier: NCT05124704, registration date: 11 October 2021,
principal investigator: JW). We followed the consolidated Standards of Reporting
Trials (CONSORT) statement when conducting and reporting this trial. This study
was conducted between 20 November 2021 and 25 May 2022 at the Department of
Anesthesiology, Zhejiang Cancer Hospital.
After obtaining written informed consent, 60 ASA physical states II or III patients
with gastric cancer aged 18–75 years scheduled for open gastrectomy were enrolled in
this study. The exclusion criteria were as follows: contraindications to epidural
puncture or catheter placement; chronic or acute (within 48 h) intake of psychotropic
drugs, benzodiazepines, anticonvulsants, or opioids; alcoholism; hepatic, renal,
neurological, or other organ dysfunction; allergy to any drugs used in this study; or
refusal to receive epidural puncture.
The eligible patients were randomized to one of the two groups with different
anesthesia protocols: the GA + EA group (combined epidural-general anesthesia) or
the GA alone group (general anesthesia alone). Randomization was performed by a
research assistant who did not take part in the study using computer-generated
numbers (Microsoft Excel for MAC, Microsoft, Redmond, WA, United States). The
randomization codes were concealed in numbered, sealed opaque envelopes, one of
which was opened for each patient.
Before induction of anesthesia
No premedication was given. Upon arrival in the operating theater, standard
monitoring including electrocardiogram (ECG), pulse oximetry (SpO2), invasive
artery blood pressure (IBP) via the left radial artery, bispectral index (BIS), and
end-tidal carbon dioxide (EtCO2) was applied. A central venous catheter was placed


Protocal number.：202101
Version：2.0
- 4 -
in the right internal jugular vein and commenced an infusion of 37°C Ringer’s lactate
solution at a rate of 10 mL kg−1 h−1.
Induction of anesthesia
Prior to general anesthesia induction, all patients had an epidural catheter placed in
the left lateral position. Epidural anesthesia was performed based on the usual
procedure in our center and procedures described before. After skin infiltration with
lidocaine, epidural puncture was performed with a 16-gauge Tuohy needle at the
estimated T8–T9 vertebral interspace using a loss-of-resistance to saline technique
and then inserted a nylon multiport catheter 4 cm into the epidural space with the
needle orifice oriented cephalad.
An anesthesia nurse who was not involved in the study prepared the epidural
medication (normal saline or 0.375% ropivacaine) in a 20 mL syringe. A test dose of
3 mL of the epidural medication (normal saline for the GA group and 0.375%
ropivacaine for the GA + EA group) was given to exclude an intrathecal placement of
the epidural catheter. After 4 min, in the absence of significant sensory or motor
blockade, the patient received an extra 5 to 8 mL (depending on the height and weight)
of the epidural medication (normal saline for the GA alone group and 0.375%
ropivacaine for the GA + EA group) through the epidural catheter. The level of
sensory blockade was assessed bilaterally in the anterior axillary line by pinprick 15
min after epidural injection. The upper and lower limits of the block level were
recorded. If the upper block level reached T4 or above, but did not exceed T3, the
epidural infusion was then maintained with 0.375% ropivacaine at an infusion rate of
4–6 mL h−1.
General anesthesia was induced with propofol oxycodone and rocuronium by the
fixed attending anesthesiologists (JW, YS, and WG) who were blinded to the patient
grouping
and
epidural
administration.
Propofol
was
administered
via
a
target-controlled infusion (TCI) (Base Premea, Ochestraw, Fresenius Company,
Bre’zins France) with the pharmacokinetic model of Schnider et al. .


Protocal number.：202101
Version：2.0
- 5 -
To explore the EC50 of propofol-inducing LOC (defined as the loss of response to
verbal commands) in patients with or without prior epidural anesthesia, the
administration of propofol for each patient was applied according to that applied in
our previous study using the up–down sequential allocation method. The initial TCI
Ceprop for the first patient of each group was set at 3.5 μg mL−1. The initial TCI
Ceprop for the next patient was determined by the response of the previous patient to
the initial dose of propofol administered. A positive response was defined as LOC
occurring within 4 min of TCI propofol, and a negative response was defined as no
LOC within 4 min of TCI propofol. If a positive response happened, the initial TCI
Ceprop was decreased by 0.5 ug mL−1 for the next patient in the same group. If a
negative response happened, the initial TCI Ceprop was increased by 0.5 μg mL−1 for
the next patients. The TCI Ceprop for the negative patient would increase by 0.5 μg
mL−1 stepwise at 4 min intervals unti the patient showed LOC. After LOC, an
intravenous bolus of 0.25 mg kg−1 oxycodone was administered, and then 0.6 mg
kg−1 rocuronium was given to facilitate tracheal intubation.
Maintenance of anesthesia
Anesthesia was maintained with propofol and remifentanil. Ceprop was adjusted
immediately after intubation by increasing or decreasing in steps of 0.5 μg mL−1 to
keep the BIS value between 40 and 60 throughout the surgery. The lowest Ceprop
was 2.0 μg mL−1 in order to prevent intraoperative awareness. In the meantime,
intravenous infusion of remifentanil began at a rate of 0.1 μg kg−1 min−1 and was
then adjusted by increasing or decreasing in steps by 0.05 μg kg−1 min−1 to keep
adequate anesthesia. The criteria of inadequate anesthesia were as follows: (1)
hypertension: a mean blood pressure (MAP) >120% of baseline or >100 mmHg; (2)
tachycardia: heart rate >90 beats·min−1; (3) somatic arousal: signs of coughing,
chewing, and grimacing; and (4) somatic response: purposeful movement. The
maximum infusion rate was 0.25 μg kg−1 min−1. Hypotension, defined as a MAP
<80% of baseline or <60 mmHg, was treated initially by speeding intravenous
infusion and decreasing the remifentanil infusion rate by 0.05 μg kg−1 min−1 in a


Protocal number.：202101
Version：2.0
- 6 -
stepwise manner until the minimum rate of 0.05 μg kg−1 min−1, and finally,
ephedrine, phenylephrine, or metaraminol were given. Bradycardia was treated with
intravenous atropine 0.5 mg.
Recovery period
Both propofol and remifentanil infusions were discontinued when the final surgical
suture was completed. Emergence time from anesthesia was assessed by measuring
the duration between the time of discontinuation of anesthetics and the time of
spontaneous opening of eyes. Patient-controlled epidural analgesia (PCEA) with
0.175% ropivacaine mixed with 0.7 μg mL−1 sufentanil was applied for postoperative
pain for all patients. In the postanesthesia care unit (PACU), the modified
Aldrete-Score, postoperative nausea and vomiting, pain intensity (visual analog scale
of 0–10, 0 = no pain, 10 = worst pain imaginable), and other side effects were
recorded. All patients were visited on the 1st day postoperatively to check for adverse
effects of anesthesia, and patient satisfaction with the anesthesia procedure was
assessed using a scale of 0–10 rating (0 = completely dissatisfied and 10 = completely
satisfied) and the quality of postoperative analgesia with PCEA using the variables
such as pain VAS and the number of total PCE presses and effective presses.

SAP_001.pdf: 
Statistical Analysis Plan
Official Title: Propofol EC50 for Inducing Loss of Consciousness in
General Combined Epidural Anesthesia
NCT05124704
Date of document: June 17th, 2021


The sample size of 30 patients per group was determined based on the results of the
previous simulation study that suggested that 20 to 40 subjects or six crossovers were
sufficient to provide a stable estimate of the EC50 calculated by using the modified
Dixon up–down method for most realistic scenarios (16). Continuous variables were
tested for normality using the D’Agostino and Pearson tests. Variables with normal
distribution
were
presented
as
the
mean
±
standard
deviation
(SD),
and
intergroup comparisons were performed using student’s t-test. Variables with
non-normal distribution were presented as the median and interquartile range (IQR),
and intergroup comparisons were performed using the Mann–Whitney U-test.
Categorical variables were presented as number (%) and were analyzed using the
chi-square test.
The EC50 and EC95 values for EC50 of propofol were determined by calculating the
mean of the midpoints of pairs of Ceprop administered in successive patients in which
a positive response was followed by a negative response or a negative response was
followed by a positive response (turning points) according to the modified
up-and-down allocation method as described previously. At least six pairs of
negative–positive responses were needed in each group for the final analysis (13, 17).
The 95% confidence interval (CI) and SD for the EC50 values were calculated using
the method suggested by Choi (17). Probit regression analysis was applied as a
backup and sensitivity test by analyzing tallied numbers of positive patient and
negative patients for each dose category for each group; estimates of the EC50 for
propofol in each group were obtained and the difference between the two groups was
quantified by calculating the relative mean potency with 95% CI. Emergence time
was analyzed by using the Kaplan–Meier log-rank survival analysis to compare the
cumulative probability of patients remaining unconscious after the discontinuation of
propofol.
GraphPad Prism software version 5.0 (GraphPad Software Inc., San Diego, CA,
United States), SPSS version 22.0 (SPSS, Inc., Chicago, IL, United States), and R
package version 0.1.1 were used for statistical analysis. A p-value of <0.05 was
considered to be statistically significant.