Discussion
Our data revealed that bolus injection followed by continuous infusion
of esketamine reduced sufentanil consumption during thyroidectomy.
Moreover, patients receiving esketamine reported lower pain scores
during the first postoperative 24 h and experienced higher sleep quality
on the night of surgery than those in Group CON. We observed no
between-group differences in psychotomimetic side effects.
Patients undergoing thyroid surgery experience mild to moderate pain
levels after the first week postoperatively,16 while
specialty and procedure-specific guidelines for pain management do not
presently exist within otorhinolaryngology–head and neck
surgery.17 Thus, our randomized controlled trial
helped develop an evidence-based approach for perioperative pain
management in patients undergoing thyroidectomy.
Multimodal analgesia involves the use of several different analgesic
medications to target multiple receptors within nociceptive and
neuropathic pathways to provide opioid-reduced anesthesia, thus reducing
acute postoperative pain.18,19 Activation of C-fiber
nociceptors evokes an NMDA receptor-mediated state of central
hyperexcitability in spinal cord neurons, which accounts for post-injury
pain and hyperalgesia.20,21 This has led to interest
in the pain-relieving properties of clinically available NMDA receptor
antagonists such as ketamine.6,22,23 Studies have
consistently reported the promising effect of ketamine in reducing
postoperative pain and opioid consumption,13,24,25 and
the analgesic effect can be achieved by far smaller doses than are
required in anesthesia.26 However, the most common
form of ketamine in clinical practice is a racemic mixture of two
optical isomers: levo-ketamine (R-ketamine) and extro-ketamine
(esketamine). The reported psychotropic side effects have reduced the
clinical use of racemic ketamine.27,28
Esketamine is a left-handed optical isomer of racemic ketamine. The
S-enantiomer has been postulated to be approximately twice as effective
than the racemic mixture of ketamine in preventing the central summation
of pain.9,29,30 The use of esketamine is increasing
worldwide and may be an attractive alternative to racemate for
perioperative use. Low-dose racemic ketamine is defined as an
intravenous bolus of less than 1 mg/kg and/or continuous intravenous
infusion at rates below 20 μg kg-1min-1.31 Thus, we chose a dose with
0.5 mg/kg bolus pre-incisional injection followed by 2.4 mg
kg-1 h-1 until the beginning of
wound closure. As hypothesized, patients receiving a low dose of
esketamine required 27% less intraoperative sufentanil and experienced
less pain intensity after thyroidectomy.
Our results are consistent with those reported by Argiriadou et al., who
showed that pre-incisional and repeated intraoperative esketamine added
to a combined anesthetic regimen improved pain relief after visceral
surgery.32 They also found that patients receiving
esketamine required a lower rate of additional analgesia than those
receiving placebo. However, we found no significant intergroup
differences in the incidence of rescue analgesia requirement. Compared
with major abdominal surgery in the study by Argiriadou et al.,
thyroidectomy might caused relatively less tissue trauma, which may have
led to lower postoperative pain. All patients were treated using
multimodal analgesia in our clinical practice. We chose sufentanil
because it is the most potent opioid in clinical
anesthesia.33,34 Additionally, we used parecoxib
sodium for pre-emptive analgesia, and dexamethasone could also serve as
an adjunctive analgesic.35 Moreover, good manipulation
abilities and skills of surgeons might have helped minimize the pain
experienced by patients, thus explaining the low number of patients
complaining of moderate-to-severe postoperative pain (NRS
>3) in both groups, and only one patient in Group CON
required rescue analgesia. Even then, infusion of esketamine helped
reduce postoperative pain scores, which may translate to better patient
experience.
Conversely, some studies have reported negative results for the
opioid-sparing effect of esketamine. In an opioid-naïve adult
population, injection of 0.5 mg kg-1 bolus of
esketamine followed by 0.12 or 0.6 mg kg-1h-1 infusion was not shown to be superior to placebo
in reducing opioid consumption after lumbar fusion
surgery.36 Similar conclusions also showed that
patients receiving a 0.5 mg kg-1 bolus of esketamine
before skin incision followed by a continuous infusion of 2 μg kg-1min-1 until 2 h after emergence
did not consume less morphine or report less pain during the first 5
days after knee arthroscopy.37 Different findings
between studies may be related to patient populations and surgical
procedures. Additionally, the opioid-sparing effects of esketamine have
been reported to be age, dosage, and infusion time
associated.22 Thus, further research is required to
evaluate the efficacy of esketamine in reducing opioid consumption and
pain intensity during different surgeries.
Patients in Group CON experienced reduced sleep quality after
thyroidectomy, which may be due to surgical trauma and postoperative
pain.38,39 However, intraoperative infusion of
esketamine maintained a sleep quality comparable to that preoperatively.
Meanwhile, patients receiving esketamine experienced higher sleep
quality than those receiving placebo postoperatively. Since ketamine has
been demonstrated to prolong the average duration of deep sleep and
modulate circadian rhythms by regulating clock
genes,40,41 our findings further suggest that
esketamine may be a favorable anesthetic regimen for its analgesic and
dormant effects.
Because of its higher affinity for NMDA receptors, low doses of
esketamine preferentially bind to postsynaptic NMDA receptors in the
dorsal horn of the spinal cord rather than in the brain. Hence,
analgesia may be achieved with a lower risk of psychotomimetic side
effects.42-45 We did not find increased
psychotomimetic adverse events in patients receiving esketamine, which
is consistent with previous studies.32 In addition,
ketamine increases blood pressure and HR via sympathetic
activation.9 With a low dose of esketamine, we
obtained stable hemodynamics during surgery without any uncontrollable
hypertension or tachycardia. Esketamine may compromise the monitoring of
anesthesia depth. In a previous study, patients randomized to the
esketamine group exhibited a higher perioperative bispectral index and
required higher doses of propofol during ambulatory hemorrhoidectomy,
which was speculated to be the reason for the delayed recovery
time.46 Therefore, the depth of anesthesia was
assessed based only on the clinical evaluation by the attending
anesthesiologist in our study. Extubation time was not delayed in Group
KET and no patients reported intraoperative awareness.
Our study has some limitations. First, we tested only a single dose of
esketamine. Further investigations employing a quantitative dosage of
esketamine on postoperative pain and opioid consumption in patients
undergoing thyroidectomy, are needed. Second, the NRS and sleep quality
scale are not objective indicators; therefore, they may affect the
efficacy of the evaluation. Third, while we found no differences in the
incidence of PONV or psychomimetic side effects, a larger-scale study is
needed to assess this properly.