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.