Methods
Study Design
This prospective randomized controlled trial was approved by the Ethics
Committee of the Second Affiliated Hospital of Anhui Medical University
(approval no.: YX2021-106) and was prospectively registered in the
Chinese Clinical Trial Registry (ChiCTR2100053459) on November 21, 2021.
The study was conducted from December 2021 to May 2022 in the Department
of Anesthesiology and Perioperative Medicine at the Second Affiliated
Hospital of Anhui Medical University. This study was conducted in
accordance with the Consolidated Standards of Reporting Trials (CONSORT)
criteria10 and in compliance with the Helsinki
Declaration. Written informed consent was obtained from all the
patients.
Patients scheduled to undergo elective thyroidectomy were enrolled in
this study. The inclusion criteria were age between 18 and 65 years and
American Society of Anesthesiologists physical (ASA) status of I–II.
The exclusion criteria were body mass index (BMI) >30 kg
m-2, preoperative analgesic and sedative medication,
unstable ischemic cardiac disease, severe pulmonary hypertension,
uncontrolled hypertension, increased intracranial or intraocular
pressure, liver and kidney dysfunction, history of chronic pain,
psychiatric disorders or alcohol abuse, allergy to medication used in
the study, pregnancy, and lactation.
The enrolled patients were randomly assigned to either the control group
(Group CON) or the esketamine group (Group KET) using software at a 1:1
ratio. An assistant who was not associated with the study performed
random allocation by preparing coded and sealed opaque envelopes for
allocation concealment. A nurse unaffiliated with patient care opened
the envelopes shortly before induction and prepared the study medication
outside the operating room. The agent used for this study was diluted
with NaCl (0.9%) to yield two study drug syringes: a 10-mL syringe
containing either 5 mg/mL esketamine or NaCl (0.9%) and a 50-mL syringe
containing either 1 mg/mL esketamine or NaCl (0.9%), which were
identical in appearance and were labeled as “study medication” with
patient number. Thereafter, patients, anesthesiologists, nurses
providing postoperative care, surgeons, investigators, and outcome
assessors were blinded to the patients’ group allocation and did not
have access to randomization until the data analysis was complete.
Based on the assigned group, patients in Group CON received a bolus of
0.1 mL kg-1 intravenous NaCl (0.9%) immediately
before incision, followed by NaCl (0.9%) infusion of 0.24 mL
kg-1 h-1, which continued until the
beginning of wound closure. Patients in Group KET received a bolus of
intravenous esketamine (0.5 mg kg-1) immediately
before incision, followed by esketamine infusion of 0.24 mL
kg-1 h-1 (corresponding to an
esketamine dose of 0.24 mg kg-1 h-1)
that continued until the beginning of wound closure. An anesthesiologist
injected the bolus dose from a 5-mL syringe before incision and
initiated infusion from the 50-mL syringe.
After arrival in the operating room, intravenous access was established
and vital parameters, including heart rate (HR), electrocardiogram,
blood pressure, and pulse oximetry, were monitored throughout the
surgery. Intravenous dexamethasone (8–10 mg) was administered to
prevent postoperative nausea and vomiting (PONV). General anesthesia
induction and tracheal intubation were performed using midazolam (0.05
mg kg-1), sufentanil (0.4 μg kg-1),
etomidate (0.3 mg kg-1), and rocuronium (0.9 mg
kg-1). Parecoxib sodium (40 mg) was administered after
induction for pre-emptive analgesia. Maintenance of anesthesia was
achieved by continuous infusion with propofol (4–6 mg
kg-1 h-1) and remifentanil
(0.15–0.25 μg kg-1 min-1). Muscle
relaxation was achieved by weight-adjusted atracurium dosing by the
attending anesthesiologist. The assessment of the depth of anesthesia
was
based on clinical evaluation by the anesthesiologist, and a bolus of
sufentanil (5–10 μg) was administered when the patient’s HR or blood
pressure increased by >20% from basal measurements. At an
appropriate depth of anesthesia, an intermittent bolus of urapidil was
administered if the mean arterial pressure (MAP) was >90
mmHg or evaluated by >20% of baseline values. Esmolol was
administered if HR was >120 bpm. In case of hypotension,
defined as MAP <60 mmHg or reduction by >20% of
baseline values, additional fluid and an intermittent bolus of ephedrine
were administered. Atropine was administered to patients with severe
bradycardia (HR <50 bpm). The dosage of vasoactive agent was
at the discretion of the anesthesiologist.
All patients were transferred to the post-anesthesia care unit (PACU)
for recovery after extubation. A nurse blinded to the protocols
evaluated the pain intensity at rest and coughing using an 11-point
numeric rating scale (NRS), which ranged from “0” (meaning no pain) to
“10” (meaning worst pain imaginable). When the NRS score was ≥4 or
patients verbalized the need for additional pain relief, the attending
anesthesiologist reviewed and provided intravenous boluses of sufentanil
at 0.1 μg kg-1 for rescue analgesia. The level of
alertness/sedation was assessed using the Richmond Agitation Sedation
Scale (RASS) 30 min postoperatively. The RASS is a 10-point scale
ranging from −5 to +4. A score of −5 denotes a patient who does not
respond to voice or physical stimulation, 0 characterizes a calm and
alert patient, and +4 denotes a combative and violent patient who poses
danger to the staff.11 MAP and HR were recorded
perioperatively. Once the PACU discharge criteria were met, patients
were transferred to the ward and non-steroidal anti-inflammatory drugs
were provided to the patients as needed for pain relief,
as
reviewed and decided by the attending surgeons.
The opioid-related side effects of PONV and psychotomimetic side effects
of nightmares, hallucinations, dizziness, and diplopia were assessed
postoperatively. Rescue droperidol was administered for PONV, and
psychotomimetic side effects were treated and monitored until discharge
according to hospital service guidelines. Patients were interviewed 24 h
postoperatively by the attending anesthesiologist using the following
questionnaire: 1. What is the last thing you remember before going to
sleep? 2. What is the first thing you remember waking up? 3. Do you
remember anything between going to sleep and waking up? 4. Did you dream
of the procedure? 5. What was the worst thing about your
operation?12
The primary outcome was perioperative sufentanil consumption. Secondary
outcomes included the NRS pain scores at rest and coughing, evaluated at
0.5, 2, 4, 6, 12, and 24 h postoperatively; quality of sleep in the
night following surgery, evaluated using a 4-point scale (1, slept well;
2, disturbed sleep; 3, nightmares; 4, sleepless); time to extubation,
defined as time from the end of surgery to extubation; incidences of
PONV and psychotomimetic side effects; incidences of hemodynamic
instability events; and chronic pain scores in 3 month postoperatively.
Statistical Analysis
The sample size of the study was calculated using PASS V.15.0 (NCSS,
Kaysville, UT) for Windows. According to a previous study showing that
patients receiving ketamine required 24% less intraoperative opiate
medications,13 we accepted that at least a 20%
reduction in perioperative sufentanil consumption was clinically
significant. Based on the results of our pilot study with five patients
in each group (mean sufentanil consumption was 32.0 μg and 25.5 μg for
Groups CON and KET, respectively, using a pooled standard deviation
[SD] of 5.7), two simple t-tests were performed and the group
allocation ratio was 1:1. Considering a power of 0.90, an alpha error of
0.01, and a loss to follow-up rate of 20%, the required sample size for
each group was calculated as 30. Therefore, 60 patients were included in
the study.
All statistical analyses were performed using SPSS (version 24.0; IBM,
Armonk, NY). Statistical significance was set at P<0.05. Kolmogorov–Smirnov tests were used to test the
normality of the data distribution. Continuous variables are expressed
as mean (SD) or median (interquartile range [interquartile range]).
Student’s t-test was used to compare parametric variables with a normal
distribution between the two groups. The Mann–Whitney comparison was
used to compare parametric variables without a normal distribution.
Categorical variables were expressed as numbers (percentages) and
intergroup differences were assessed using chi-squared or Fisher’s exact
tests, as appropriate.
Repeated measurements of intraoperative hemodynamic parameters and
postoperative pain scores were analyzed using a linear mixed
model14,15 to evaluate the association between
dependent variables over time and esketamine infusion. The Wilcoxon
matched-pairs signed-rank test was used for binary comparisons of sleep
quality within groups.