Ketamine infiltration improves analgesia 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.³ The 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.^4,5 The locoregional anesthesia technique has mainly included bilateral superficial cervical plexus block and local wound infiltration with a local anesthetic agent.^1,6,7 Bilateral block of the superficial cervical plexus is an effective technique that ensures better postoperative analgesia and has been widely used in thyroid surgery.^6,8 Wound infiltration with a local anesthetic agent is a simple and safe procedure for reducing post-operative pain.^6,7 In the current literature, different anesthetic agents for thyroid surgery wound infiltration were studied, including bupivacaine, diclofenac, ropivacaine, and, more rarely, ketamine.^9–12

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.¹³

The 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.

Methods

Results

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 Two patients were withdrawn from the study for prolonged surgery (more than 3 hours).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.

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

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

		Group S (N=31)	Group K (N=31)	P value
Demographic characteristics	Age (years)	47.9±13	41.8±38.5	0.04*
	Sex (M/F ratio)	3/28	1/30	0.3†
	Size (cm)	166±3	167±4	0.3*
	Weight (kg)	64.7±3.6	65±8	0.4*
The performed thyroid surgery	Total/partial thyroidectomy	14/17	24/7	0.009‡
Intraoperative anesthetic parameters (at 60 minutes)	HR (bpm)	72.9±8	72.7±11	0.3*
	SBP (mmHg)	94.7±15	98±14.6	0.4*
	MAP (mmHg)	70.7±10.4	75.2±10	0.15*
	DBP (mmHg)	58.6±9.5	63.2±10.2	0.1*
	SpO2 (%)	99.6±0.8	99.7±0.6	0.1*
	PetCO2 (%)	34.6±1.8	34.6±2.9	0.4*
Surgery duration	(minutes)	112±2	107±13	0.09*

* Student t-test.

† Fisher exact test.

‡ χ² test.

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 (±1.7).^1,14 Pain following thyroid surgery has several origins: surgery-induced inflammatory lesions, intraoperative neck hyperextension, postoperative drainage, incision site, and laryngotracheal mobilization at swallowing.^15,16

The 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.^1,6,7

Wound 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.^6,7 Several molecules were used to infiltrate the thyroidectomy wound. Bupivacaine has been reported to effectively reduce post-thyroidectomy pain.^10,16,17 Sellami et al.¹⁰ concluded 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.¹¹ In 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.¹⁸ However, the use of ropivacaine alone was not associated with an analgesic effect.¹²

Ketamine 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.^9,19,20 It 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.²¹ However, 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.¹⁵ Thus, modern analgesic approaches aim to reduce both postoperative pain and opioid requirements.^4,5

Kim 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.²⁴ Dal 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.²⁷ In 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.²⁸

Regarding abdominal surgeries, Honarmad et al.²⁹ conducted a randomized, double-blind, prospective, placebo-controlled 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.³⁰ The administered doses of ketamine varied in the literature within the range of 0.5 to 2 mg/kg.³¹ In 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.