Ketamine infiltration improves analgesia after thyroid surgery

Background: Postoperative pain increases the risk of postoperative complications and may predispose patients to chronic post-surgical pain. This study aims to evaluate the impact of ketamine wound infiltration versus placebo at the end of thyroid surgery on postoperative pain and analgesic requirements. Methods: In this randomized controlled trial, we prospectively studied patients who underwent thyroid surgery. Patients were randomized into two groups: group S, where local infiltration was performed using 10 ml of a physiological saline solution; and group K, where 10 ml of a solution containing 2 mg/kg ketamine was infiltrated. Standardized thyroidectomies were performed in the 2 groups. Pain perception was measured using a visual analog scale (VAS) every 10 minutes in the post-anesthetic care unit (PACU) for 2 hours and thereafter every 6 hours during the first 24 hours. The opioid requirement in the PACU was evaluated. A comparison between the 2 groups was carried out. Results: Postoperatively, the mean VAS was higher in group S compared to group K during all PACU stay periods and the first 24 hours. Pain scores during swallowing were significantly lower for group K in the PACU at 0, 10, and 20 minutes. The mean morphine consumption in the PACU was 0.71 mg and 0 mg respectively in group S and group K (p=0.03). The incidence of nausea and vomiting was similar in both groups. Conclusions: Ketamine wound infiltration is an efficient modality to reduce postoperative opioid consumption compared to a placebo after thyroid surgery.


Introduction
Thyroid surgery is known to be responsible for mild to moderate postoperative pain during the first 24 hours after surgery. 1 Postoperative pain can result in significant discomfort, delay in hospital discharge, and the development of chronic pain. 2 Postoperative pain control is fundamental for better recovery and quick return to daily activities.Opioids are effective for postoperative analgesia, but they cause sedation, respiratory depression, nausea, and vomiting. 3he modern concept in pain management includes a multimodal approach that involves the use of systemic analgesics associated with locoregional anesthesia techniques to reduce postoperative pain and opioid requirement. 4,5The locoregional anesthesia technique has mainly included bilateral superficial cervical plexus block and local wound infiltration with a local anesthetic agent. 1,6,7Bilateral block of the superficial cervical plexus is an effective technique that ensures better postoperative analgesia and has been widely used in thyroid surgery. 6,8Wound infiltration with a local anesthetic agent is a simple and safe procedure for reducing post-operative pain. 6,7[11][12] Ketamine has a high affinity for N-methyl-D-aspartate receptors; it can also bind to opioid mu and sigma receptors that provide central and peripheral analgesic effects. 13e purpose of this study was to assess the impact of local wound infiltration using ketamine at the end of thyroid surgery on postoperative pain and opioid requirement.

Selection of patients, ethical approval and consent
Ethical approval for this study was given by the Committee for the Protection of People in Southern Tunisia (approval number 0117/18).This randomized double-blind study was achieved through collaboration between the ENT department and the anesthesia department of the university hospital, Habib Bourguiba in Sfax, Tunisia.
Patients scheduled for thyroid surgery were enrolled after having provided written informed consent, which they also gave for publication of their data, in de-identified form.
Patients aged 18 to 65 years were included in this study if they had an ASA score (American Society of Anesthesiology) of I or II.Patients with unstable diabetes, an allergy to study drugs, a history of previous cervical surgery, or a history of cardiac or respiratory disease, as well as patients on long-term analgesics or corticosteroids and patients with predictable difficult airways were not included in this study.Patients who had major complications, such as allergic reactions to anesthetic drugs and major bleeding, as well as patients whose intubation required more than 2 attempts or whose surgery duration exceeded 3 hours, were excluded from this study.Patients who underwent a neck dissection associated with thyroid surgery were also excluded from the study.

The patients and randomization
The patients were informed about the anesthetic protocols and were educated about the use of the visual analog scale (VAS) to evaluate the severity of the pain.All patients in the study were blinded to the drug they received for postoperative pain.

REVISED Amendments from Version 1
This revised article features notable improvements.The title has been refined to "Ketamine infiltration improves analgesia after thyroid surgery," accurately encapsulating the essence of the study.
Methodologically, difficult airways were considered as an exclusion criterion, and we specified the ketamine concentration used, which was 50 mg/ml.We defined that rescue analgesic during hospitalization was Nefopam in the case of VAS values greater than 30.
The randomization method was specified.
Our data, including age and type of surgery, have been carefully validated.
We improved the discussion according to the recommendations of the reviewers.

Any further responses from the reviewers can be found at the end of the article
The patients were randomly assigned to the following two groups using an online random list generator (https://www.random.org): group K represents wound infiltration using 10 ml of a solution containing 2 mg/kg of ketamine (KETAMINE PANPHARMA ® 50 mg/ml) and group S (placebo group) represents wound infiltration using 10 ml of normal saline solution.The wound injection was performed at the end of the surgery after the skin suture.
General anesthesia procedure After 3 minutes of preoxygenation, anesthesia was induced with an injection of 3 μg/kg of Fentanyl followed by 3 mg/kg of Propofol; and with intubation using a silicone wire-reinforced tracheal tube with 0.2 mg/kg Cisatracurium.Anesthesia was maintained using isoflurane with a minimum alveolar concentration (MAC) of 1% in a 50% oxygen/air mixture.A 0.03 mg/kg Cisatracurium bolus was administered every 40 min, and a Fentanyl bolus of 0.1 μg/kg was injected whenever there was an increase of 20% of the base values in heart rate or systolic arterial blood pressure.
Before surgery, an anesthesiologist, not involved in the study, prepared an unlabeled sterile syringe using 10 ml of ketamine (2 m/kg) or 10 ml of a saline solution.After wound closure, the infiltration was performed by a blinded surgeon.The needle was introduced to a depth of 0.5 cm, an aspiration was then performed to avoid an intravascular injection followed by infiltrating the wound.The content of the syringe was used for homogenous infiltration of the subcutaneous wound sides by the surgeon.

Analgesic protocol
Thirty minutes before the end of the surgery, all patients received 1 g of paracetamol ad then were extubated before being moved to the post-anesthetic care unit (PACU) for close monitoring for 2 hours.In the PACU, intravenous morphine titration (2 mg every 5 min) was performed until the VAS value was less than 30.All patients were admitted for at least 24 hours postoperatively in the ENT department.They all received 1 g of paracetamol systematically every 6 hours during the first 24 hours.Nefopam (NEFOMED 20 mg in 30 minutes) was administered when VAS was greater than 30.An anesthesiologist blinded to the study groups collected intraoperative and postoperative parameters.

Evaluation criteria
The primary outcomes were to determine the intensity of the pain using VAS from 0-100 in the first 24 hours.The VAS score was assessed every 10 minutes in the PACU for 2 hours and every 6 hours during the first 24 hours after the operation in the ENT department.Nefopam was administered in the cases where VAS exceeded 30.Opioid requirements were recorded during the PACU admission period.The occurrence of side effects of opioids and ketamine was noted.

Statistical analysis
In each group, a total number of 27 patients was required to obtain a difference on the VAS scale of 20 mm (standard deviation of 25 mm), with a power of 0.9 and an α=0.05.To allow for some margin of error in the underlying assumptions, the baseline sample size was increased by 10 % to 32 patients per group.χ 2 test or Fisher statistical tests were used for the analysis of qualitative variables and the Student's T test for the analysis of quantitative variables (sample size of more than 30 patients per group; normality was typically ensured by the central limit theorem).A p-value < 0.05 was considered statistically significant (one-tailed test).Data entry and statistical analysis of data were performed with the software version 20 of Statistical Package for Social Sciences (SPSS) for Windows (SPSS Inc., Chicago, IL, USA).

Study population
The study lasted for a total of 6 months from September 2018 to March 2019.Sixty-four patients were included.Two patients were withdrawn from the study for prolonged surgery (more than 3 hours).The flow of patients is represented in the CONSORT diagram of the study, which is shown in Figure 1.Demographic and intraoperative characteristics of patients are represented in Table 1.

Assessment of postoperative pain
Pain scores during swallowing were significantly lower for group K in the PACU at 0, 10, and 20 minutes (Table 2).
Regarding the first 24-hour postoperative hospitalization period in the ENT department, the mean VAS values were higher in group S compared to group K; either at rest or during swallowing, but the difference was not statistically significant (p>0.05)(Table 3).
None of the patients in group K received morphine while it was administered to four patients in group S. The mean morphine consumption in the PACU was 0.71 mg and 0 mg respectively in group S and group K.The difference in morphine consumption between both groups was statistically significant (p=0.04).Nefopam was not administered to any of our patients.No patient presented a hematoma at the injection points of the product.A patient in group K showed hallucinations during the stay in the PACU.Dizziness was recorded in three patients of group K and one patient of group S. No patients presented postoperative shivers.
Respiratory distress was not recorded in any of our patients.Nausea and vomiting were observed in a total of 11 patients but without significant differences between both groups.

Discussion
Acute pain is one of the most common complaints after surgery.Thyroid surgery is known to be responsible for mild to moderate postoperative pain during the first 24 hours, with a mean VAS score of 6.9 (AE1.7). 1,14Pain following thyroid surgery has several origins: surgery-induced inflammatory lesions, intraoperative neck hyperextension, postoperative drainage, incision site, and laryngotracheal mobilization at swallowing. 15,16e attempted locoregional anesthetic approaches to reduce post-thyroidectomy pain have included mainly bilateral superficial cervical plexus block and local wound infiltration with a local anesthetic agent. 1,6,7und infiltration with a local anesthetic agent is a simple and safe procedure to reduce postoperative pain with fewer side effects in comparison with cervical plexus block. 6,7Several molecules were used to infiltrate the thyroidectomy wound.Bupivacaine has been reported to effectively reduce post-thyroidectomy pain. 10,16,17   that infiltration of bupivacaine wounds is effective in reducing pain perception and opioid requirements after thyroidectomy.In a recent meta-analysis, Jiang et al. 17 recommended performing a local infiltration using bupivacaine before or after skin closure, 20 to 75 mg, as it significantly reduced postoperative pain and decreased rescue analgesic requirements.
Diclofenac has also been reported as an effective molecule to infiltrate the wound prior to surgery compared to Bupivacaine in reducing postoperative pain. 11In a randomized controlled trial, numerical rating scale pain scores were significantly lower during the initial 24 hours after radical thyroidectomy in the group that received pre-incision ropivacaine infiltration and postoperative flurbiprofen axetil, compared to the group that only received tramadol at the end of surgery. 18However, the use of ropivacaine alone was not associated with an analgesic effect. 12tamine also belongs to the molecules whose local wound analgesic effect has been studied.The local ketamine analgesic effect is related to different mechanisms: blocking sodium, calcium, and potassium channels, as well as binding to opioid, cholinergic, D2, and 5-HTE receptors and monoamine transporters. 9,19,20It also decreases microglial activation and migration and prevents local inflammation extension and exacerbation through its action on the prototype inflammatory mediators, the adenosine receptor system, and the activation of the NMDA receptors. 21However, only a limited number of studies demonstrated the analgesic effect of ketamine in thyroid surgery, either locally or systemically.
In our study, ketamine (2 mg/kg) was injected into the wound after skin closure.It was associated with a significant reduction in VAS scores during swallowing compared to the saline solution group in PACU at 0, 10, and 20 minutes.In a prospective, controlled, double-blind, randomized study, Abd EL-Rahman et al. 9 compared post-thyroidectomy analgesia in three different groups using local ketamine wound instillation, intramuscular ketamine injection, or placebo.He recorded that VAS scores at rest or during movement, as well as morphine consumption, were reduced in the local ketamine group compared to intramuscular ketamine and placebo.He then concluded that local ketamine instillation of 1 mg/kg of ketamine diluted in 10 ml of a saline solution was associated with a superior analgesic effect compared to the other groups.He also recorded that total morphine consumption and first analgesia demand were significantly lower in the local ketamine group.
We also demonstrated that local injection of ketamine significantly reduced the average morphine requirement compared to the saline solution group.The use of opioids can be associated with severe side effects such as nausea, vomiting, and respiratory distress. 15Thus, modern analgesic approaches aim to reduce both postoperative pain and opioid requirements. 4,5m et al. 22 also studied the effect of intravenous ketamine infusion during the bilateral axilla-breast approach for robotic or endoscopic thyroidectomy and concluded that it significantly reduced postoperative pain scores compared to the saline solution group with no increase in adverse effects.Lee et al. 15 used ketamine infusion after robotic thyroidectomy and demonstrated that it was associated with a lower VAS score 24 hours after surgery and with a decrease in opioid needs.
The use of ketamine as a local wound infiltration agent was studied more frequently in oral, tonsillar, and abdominal surgeries.In their meta-analysis, Cho et al. 23 concluded that the use of ketamine locally or systematically could provide pain relief in children undergoing tonsillectomy without side effects.The addition of ketamine to ropivacaine for local tonsillar application was associated with better postoperative analgesia compared to the application of ropivacaine alone. 24Dal et al. 25 proved that locally injected ketamine effectively reduced pain scores in patients undergoing adenotonsillectomy.However, in a recent prospect guideline for post-tonsillectomy pain management, Aldalmulij et al. 26 did not recommend the use of ketamine infiltration in children due to the risk of systemic side effects after absorption, although different studies consistently concluded that it was effective in reducing pain and analgesic requirements after tonsillectomy in children.
Infiltrating the surgical site using ketamine in pediatric patients undergoing cleft palate surgery was superior to Bupivacaine with respect to analgesic requirements, quality of sleep after surgery, and speed of recovery. 27In third molar surgery, a meta-analysis based on prospective clinical trials and randomized controlled trials demonstrated the analgesic effect of local administration of ketamine and its anti-inflammatory potential during the first 24 hours. 28garding abdominal surgeries, Honarmad et al. 29 conducted a randomized, double-blind, prospective, placebocontrolled study, and concluded that intravenous or subcutaneous infiltration prior to incision of 0.5 mg/kg of ketamine improved analgesia during the first six hours after appendectomy with no significant side effects.The same authors reported that subcutaneous ketamine infiltration or intravenous ketamine administration for patients undergoing open cholecystectomy before the surgical incision provided auxiliary analgesia 24 hours after surgery.
In a randomized double-blind study, patients undergoing cholecystectomy who received subcutaneous ketamine infiltration at a dose of 2 mg/kg or intravenous ketamine at a dose of 1 mg/kg 15 minutes before surgical incision reported enhanced analgesia for 24 hours after surgery. 30The administered doses of ketamine varied in the literature within the range of 0.5 to 2 mg/kg. 31In our study, we infiltrated a solution containing 2 mg/kg ketamine based on established literature and clinical experience, in order to achieve effective analgesia while minimizing potential adverse effects.
Our study has several limitations.First, thyroid surgeries were performed by different surgeons.Second, we did not consider the size of the resected thyroid gland which can reflect the extent of surgery and influence postoperative pain.

Conclusions
In conclusion, local wound infiltration using 2 mg/kg of ketamine is an effective approach to reduce opioid requirements after thyroid surgery without increasing the side effects of ketamine.

Data availability
Underlying data Figshare: Underlying data for 'Ketamine infiltration decreases opioid requirement after thyroid surgery', https://doi.org/10.6084/m9.figshare.21365703.v1. 32is project contains the following underlying data: data ketamine thyroidectomy.sav(SPSS format; all datasets have been de-identified in accordance with the Safe Harbor method) -CONSORT checklist Data are available under the terms of the Creative Commons Attribution 4.0 International Public Licence (CC-BY 4.0).

The study design:
-Random grouping is unequal: The proportion of patients undergoing total thyroidectomy or partial thyroidectomy is much different between the two groups.Different types of surgery result in different level of pain.It make great influence on research results.
-The post-operative pain relief design is not appropriate.When VAS score > 30, author used Nefopam.Nefopam is a strong pain relief but it causes a tachycardia so it needs to be infused slowly, with an infusion time is 30 minutes or more.So, this medicine is not suitable for pain relief.
An NSAID group such as Ketorolac can be used.Furthermore, when using Nefopam, the dose must also be controlled, not exceeding 120mg per day.So if the patient has already taken 120 mg and still has pain, what is the next treatment?-Patients were assessed for pain both at rest or swallowing, but when swallowing, the VAS score was very high in the group not using Ketamine.This is not clinically appropriate in the first 120 minutes, because when author knew the patients were in pain, author still force the patient to perform swallowing for research without giving any additional pain relief.It can be said that author did not respect research ethics.Reviewer Expertise: Regional anesthesia, Anesthesiology, critical care, cardiac anesthesia, artificial intelligence We confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

Version 1
Reviewer Report 10 August 2023 https://doi.org/10.5256/f1000research.140082.r187838"However, the use of ropivacaine was not associated with an analgesic effect.12" Others studies had found different results and they should be considered 1 .

○
VAS was considered as a limitation while it is a validated tool.

Conclusion:
Please put "to reduce" instead of "to reducing".Reviewer Expertise: Anesthesia and intensive care I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.
In this study, researchers investigated the effects of local ketamine wound infiltration versus saline placebo on postoperative pain and opioid consumption in patients undergoing thyroid surgery.After randomizing 64 patients to receive either ketamine or saline infiltration, the researchers found that the ketamine group had lower VAS pain scores during the PACU stay for static pain at rest and dynamic pain on swallowing.The ketamine group consumed significantly less morphine in the PACU than the saline group.No adverse effects were reported.The authors concluded that local ketamine can reduce postoperative opioid use without increasing side effects.This study is well-designed and addresses an important clinical question.
We recommend you to : Provide more details regarding the randomization process: Was a computer random number generator used?Were block randomization or stratification techniques used?○ Presenting VAS scores graphically could better visualize trends.

Is the work clearly and accurately presented and does it cite the current literature? Yes
Is the study design appropriate and is the work technically sound?Yes

Are sufficient details of methods and analysis provided to allow replication by others? Yes
If applicable, is the statistical analysis and its interpretation appropriate?Yes The benefits of publishing with F1000Research: Your article is published within days, with no editorial bias • You can publish traditional articles, null/negative results, case reports, data notes and more • The peer review process is transparent and collaborative • Your article is indexed in PubMed after passing peer review • Dedicated customer support at every stage • For pre-submission enquiries, contact research@f1000.com

Figure 1 .
Figure 1.CONSORT 2010 flow chart for the patients in the study.

Table 1 .
Demographic characteristics and intraoperative anesthetic characteristics of both groups.

Table 3 .
Mean VAS values in group S and group K at rest and during swallowing in the first 24 hours postoperatively.
Group S: saline solution group, Group K: ketamine group, VAS: visual analog scale.

Table 2 .
Mean VAS values in group S and group K at rest and during swallowing in the PACU admission period.
Group S: saline solution group, group K: ketamine group, VAS: visual analog scale, PACU: post anesthetic care unit.

the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Partly Are the conclusions drawn adequately supported by the results? Yes Competing Interests:
2. Data results -It need to add a table of results about side effects of pain relief methods, especially hallucinations when using Ketamine.The research object and method section should clearly state: Criteria for diagnosing hallucinations, prevention and treatment.3. Discussion and conclusion -Discussion does not focus on the question research or the research results.No competing interests were disclosed.

have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.
Reviewer Report 04 September 2023 https://doi.org/10.5256/f1000research.154754.r197863Is

the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests:
No competing interests were disclosed.

Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Partly Are the conclusions drawn adequately supported by the results? Yes Competing Interests: No
competing interests were disclosed.