INTRODUCTION:

Labioschisisis a congenital abnormality of the lips that originates during facial development during pregnancy, requires surgical correction, and necessitates early-life surgical therapy¹. The incidence of Labioschisisis 1 in 600 to 700 live births globally².

With a pain score of 4, labioplasty surgery might produce mild postoperative pain. Several factors must be considered for effective pain management, including pain evaluation, type selection, and route of drug administration. Adequate postoperative analgesia can accelerate mobilization and healing³.

Opioids, paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), and nerve blocks have been utilized to manage postoperative labioplasty pain⁴. When the peak concentration of paracetamol in plasma is reached during intravenous administration of paracetamol, the risk of toxicity increases⁵. NSAIDs can cause nephrotoxicity, thrombocytopenia, asthma exacerbation, gastrointestinal ulcers, and hepatotoxicity. The use of NSAIDs decreases the occurrence of opioid-related side effects and reduces the dose of opioids required, including vomiting, hypotension, and Respiratory suppression. Diclofenac, Ketorolac, and Ibuprofen arecommonly used NSAIDs⁶. Opioids can cause respiratory depression and diminished gastrointestinal motility. Opioids are deemed safe for postoperative pain relief in children overone year old⁷. Children hospitalized postoperative need more comfortable conditions, and hospitalization is a crisis in a child's life because this situation is full of tremendous stress. Therefore, it must be conditioned to relieve stress due to pain, fear, and anxiety in children^8,9.

Inadequately managed postoperative pain may predispose to complications and extended rehabilitation. Suitable pain relief during the postoperative period leads to reduced hospital stays and better patient satisfaction. As a result, postoperative pain management is increasingly monitored as a quality measure in health care⁶. Regional anesthetic is more effective and safer for postoperative pain management.

Varghese¹⁰ suggests using high doses of opioids to relieve the stress of anesthesia. However, there are drawbacks, such as poor response to stimuli during the induction period, delayed emergence, and inability to evaluate early neurological recovery post-surgery. Therefore, a better solution appears to be a combination of regional anesthesia together with general anesthesia, which has the potential to reduce opioid requirements and also attenuate the hemodynamic response anticipated during the early period of surgery.

Regional anesthesia has a limited duration of action, so adjuvants are required to increase potentiation and prolong the analgesic effect. Advantages of regional anesthesia include the faster return of intestinal motility, absence of respiratory depression, and adequate postoperative analgesia, resulting in more rapid postoperative recovery¹¹. However, regional anesthesia has a limited duration of action, so adjuvants are required to increase potentiation and prolong the analgesic effect¹².

The infraorbital nerve block is the procedure of choice for postoperative pain management in labioplasty, which can be performed intraorally and extraoral with minimum problems¹². It was reported that Bupivacaine and Ropivacaine are widely used long-acting local anesthetic agents in regional anesthesia¹³. As a local anesthetic, 0.25 percent bupivacaine can be utilized in the infraorbital block procedure for labioplasty. The infraorbital block's efficacy for labioplasty surgery is long-established¹⁴. Opioids, clonidine, and ketamine are adjuvants that can be utilized for the local anesthetic to prolong the duration of the block effect¹⁵.

Few studies have employed ketamine as an adjuvant for postoperative analgesia¹⁶, despite its widespread use for peri-operative analgesia. Ketamine in sub-anesthetic doses can be used as an adjuvant for local anesthesia with minimal side effects of nausea, vomiting, and salivation, according to the findings of a study. As an adjunct to Bupivacaine, Ketamine has no cardiorespiratory depressive effect, more prolonged postoperative analgesia, an earlier onset of sensory block, and it offers sufficient anesthesia¹⁷ . Another study reported that using low-dose buprenorphine (45μg) when added to bupivacaine as an adjuvant for the subarachnoid block in lower segment cesarean section provides prolonged postoperative analgesia with reduced rescue analgesic requirements and decreased incidence of maternal and neonatal adverse events¹⁸.

The results of a study on ketamine adjuvants added to bupivacaine indicated that ketamine adjuvants provided prolonged postoperative analgesia than single-dosebupivacaine, which was more than 24hours postoperatively in the ketamine bupivacaine group¹⁹. According to research, using ketamine as a local anesthetic adjuvant is uncommon; therefore, this study aimed to assess the duration of action of bupivacaine and bupivacaine-ketamine for the infraorbital block in post-labioplasty patients using the FLACC pain scale.

Material and Methods:

This research has received approval from the Faculty of Medicine, UniversitasPadjadjaran, Bandung, Jawa Barat, Indonesia, No. LB.02.02/X.6.5/52/2022. The subjects of this study were 30 individuals who were to have labioplasty surgery with the infraorbital block using Bupivacaine and Ketamine. This investigation was conducted prospectively using a randomized, controlled clinical trial with double-blind (randomized controlled trial). The number of samples is established statistically by establishing a confidence level of 95% and a power test of 95%, resulting in a minimum sample size of 15 individuals per group and a total sample size of at least 30 participants.

Subject Criteria:

Patients who underwent elective labioplasty at Santosa Hospital Bandung Central, West Java, Indonesia, served as research subjects. The age range of individuals considered in this study is between 3 months and one year. The physical condition of these individuals is assessed using the classifications I-II as defined by the American Society of Anesthesiologists²⁰. Exclusion criteria included a history of blood coagulation issues and bupivacaine and ketamine allergies. The exclusion criteria were postoperative hemorrhage necessitating reoperation and ineffective infraorbital block.

Sample Preparation:

The bupivacaine and the bupivacaine-ketamine groups were established through randomization using the block permutation technique. The participants in the trial were asked to fast for six hours before surgery without premedication. During the intraoperative time, an electrocardiogram and oxygen saturation monitor was placed. Monitoring comprises electrocardiography, pulse rate, respiration rate, and oximeter; preoperative respiratory rate, pulse rate, and saturation are also monitored. The induction of anesthesia using eight vol% sevoflurane in 100 vol% oxygen through the Jackson Rees breathing circuit. Installation of intravenous access with maintenance fluid Ringer's lactate is administered according to the calculation of fluid requirements based on the patient's body weight, and atracurium 0.5 mg/KgBB is administered to relax the patient's muscles. Intubate according to patient size with an Endotracheal Tube (ETT), and maintain anesthesia by delivering sevoflurane 2-3 vol%, oxygen, and water (50:50%).

Infraorbital Block:

Before beginning surgery, researchers administered a bilateral infraorbital block to research volunteers under general anesthesia. The subject was supine with the head in a neutral position, and an alcohol swab was used for aseptic and antiseptic precautions. The infraorbital foramen is palpated in the sagittal plane, past the midpoint of the palpebral fissure and corner of the mouth, and perpendicular to the alar base (Figure 1). Injections are administered by feeling the infraorbital rim at the region of the infraorbital foramen to prevent foramen penetration and safeguard the orbit. The 25 G needle is administered until it reaches the zygomatic bone perpendicular to the skin. The needle was then retracted 1-2mm. Following a negative blood aspiration test, the research drug was injected by the investigator, who was unaware of the type of study drug used. This point was recorded as T0 for calculating the FLACC score. The block is regarded as walking if the pulse does not increase by more than 20 percent when the incision is made compared to when the block is not made. If the pulse rate increased by over 20%, patients were eliminated from the study and given 2/kgBW of rescue fentanyl. The intraoperative heart rate was then measured at 0th -1st hours.

Analgesics Evaluation:

After the procedure, the patient was awakened and extubated before being transported to the recovery area. When the patient was completely conscious in the recovery room, the research team, briefed on the project, conducted a postoperative pain evaluation. In addition, the PAED scale was utilized to evaluate agitation caused by sevoflurane. At T0 to T2 (intraoperative in the operation room), T3 to T4 (recovery room), T5 to T6 (inpatient room), and T8 to T24 (in a halfway house/rehabilitation), pulse and pain monitoring were performed. Using the patient's pain monitoring form and the FLACC score, the assessment period was limited to twenty-four hours (final T) postoperatively (Figure 2).

Using the FLACC score, postoperative pain was evaluated at T0 (completion of the infraorbital block), 1, 2, 3, 4, 5, 6, 8, 12, and 24hours after surgery. The normal values for the FLACC score assessment are 0 (no pain), 1-3 (mild pain), 4-6 (moderate pain), and 7-10 (severe pain)²¹. When the patient's FLACC score is at least 4, analgesics are administered for the first time (T duration of action): paracetamol 15mg/kg BW intravenously if the subject is still in the hospital and paracetamol 15mg/kg BW orally if the subject is in a halfway home. The period between the delivery of the block and the first request for more postoperative analgesia was recorded as T duration of action, which is the duration of motion of the study medication. In addition, peri-operative adverse effects such as nerve or artery damage, vomiting, respiratory depression, hematoma, erythema, or edema were recorded.

Statistical Analysis:

The Paired T-test was used to compare subject characteristics, while the Independent T-test was used to compare heart rate. Chi-square (Fisher's exact) analysis revealed a significance level of p 0.005 for the FLACC value comparison. All statistical test results were examined with SPSS version 25.0.

RESULTS AND DISCUSSION:

Figure 1: Measurements and Infraorbital block with Bupivacaine and Ketamine in labioplasty subjects. Figure (I). Measurement of the location of the orbital nerve, (IA) horizontal line (IB) vertical line (IC), the meeting point between lines A & B. Figure (II). Infraorbital block (Infraorbital block is performed at the meeting point between the horizontal lines and the vertical lines from the middle of the eyeball and the corners of the lips). (https://www.brainkart.com/article/Trigeminal-Nerve-Block_27271).

Based on the site of pain, the trigeminal nerve block can be administered in the Gasserian ganglion itself, in one of its major divisions (ophthalmic, maxillary, or mandibular), or its minor branches (Figure 1). The roots of cranial nerve V emerge from the brainstem and combine to produce a crescent-shaped (Gasserian) sensory ganglion on Meckel's surface. A dural arm covers the majority of the ganglion. Three distinct trigeminal nerve branches emerge from the ganglia and leave the skull. Because pain is subjective, describing what the sufferer experiences is challenging. To properly employ pain scales, familiarize the subject with the pre-procedure level as the indicator of pain level. After surgery or treatments, pain medications are always administered to relieve or maintain a moderate pain level (5) or lower (Figure 2).

Table 1: The comparison of the subject's characteristics

Characteristic	Groups		p-value*
	Bupivacaine (n=15)	Bupivacaine-Ketamine (n=15)
	n (%)	n (%)
Sex
- Female	9 (60%)	5 (33.3%)	0,20
- Male	6 (40%)	10 (66.7%)	0,20
Ages (Month)	6.40 ± 3.48	6.66 ± 3.55	0,79
Body Weight (Kg)	6.39 ± 1.86	6.67 ± 1.04	0,48
Surgical Times (minute)	74 ± 12.98	83.67 ± 12.46	0,48
PAED Scale	7.13 ± 0.99	6.60 ± 0.74	0,11

* Paired T-Test, PAED (Pediatric Anesthesia Emergence Delirium)

The characteristics of the research subjects are listed in Table 1. The Paired T-test assessed subject homogeneity between the two treatment groups concerning age, weight, sex, length of operation, and PAED scale factors (Bupivacaine and Bupivacaine-Ketamine Groups). The statistical analysis revealed no statistically significant difference (p>0.05). This circumstance demonstrates that the subjects of the investigation are comparable and homogeneous. In addition, the subject was watched for 24 hours after an intraoperative infraorbital block was conducted. The subject's pulse rate and pain were evaluated using the FLACC pain score when the subject regained consciousness.

Table 2: Comparison of pulse rates in the Bupivacaine and Bupivacaine-Ketamine groups in infraorbital blocks of labioplasty patients

Areal Evaluation	Times (Hour)	Groups		p-value*
		Bupivacaine (n=15)	Bupivacaine-Ketamine (n=15)	p-value*
		Mean±SD	Mean±SD
Intraoperative Room	0^th	117.13±2.8	118.07± 1.67	0.28
	1^st	116.13 ± 2.83	117.27 ± 1.53	0.18
	2^nd	115.93 ± 2.58	116.80 ± 1.57	0.27
Postoperative (Recovery Room)	3^rd	115.33 ± 2.80	116.73 ± 1.39	0.09
Postoperative (Recovery Room)	4^th	115.40 ± 2.80	116.80 ± 1.66	0.11
Postoperative (Care Room)	5^th	115.20 ± 2.73	116.87 ± 1.51	0.048**
Postoperative (Care Room)	6^th	114.73 ± 2.40	116.20 ± 1.,57	0.046**

* Independent T-test, ** p<0.05

Table 2 compares the pulse rates of the Bupivacaine and Bupivacaine+Ketamine groups in infraorbital block patients undergoing labioplasty. There was a significant difference between the average pulse rate at the fifth hour (T5) in the Bupivacaine group, which was 115.2 beats per minute, and the average pulse rate in the Bupivacaine+Ketamine group, which was 116.87 beats per minute (p<0.05;0.048). At the sixth hour (T6) measurement, there was a significant difference in the average pulse rates of the Bupivacaine and Bupivacaine-Ketamine groups, with the B group's pulse rate averaging 114.73 beats per minute and the Bupivacaine-Ketamine group's group's pulse rate averaging 116.20 beats per minute (p<0.05;0.046). There was a statistically significant difference (p 0.05) between the average pulse rates of the two groups. 0 to 1 month of age: 70 to 190 beats per minute. From 1 to 11 months, infants' heart rates range from 80 to 160 beats per minute. For children ages 1 to 2: 80 to 130 beats per minute based on conventional values, the pulse profiles of the two groups are normal²².It indicates that these two anesthetics do not influence pulse rate variations.

Table 3: Comparison of Bupivacaine and Bupivacaine-Ketamine of FLACC scores in infraorbital blocks of labioplasty patients

Areal Evaluation	FLACC Score (Analgesics Score)	Groups		p-value*
Areal Evaluation	FLACC Score (Analgesics Score)	Bupivacaine (n=15)	Bupivacaine- Ketamine (n=15)	p-value*
Intraoperative Room	0^thhour	N=15	N=15	-
Postoperative (Recovery Room)	Pain-free (0)	15 (100%)	15 (100%)	-
	1^sthour	N=15	N=15	-
	Pain-free (0)	15 (100%)	15 (100%)	-
	2^ndhour	N=15	N=15	-
	Pain-free (0)	15 (100%)	15 (100%)	-
	3^rd hour	N=15	N=15	-
	Pain-free (0)	15 (100%)	15 (100%)	-
	4^th hour	N=15	N=15	-
	Pain-free (0)	15 (100%)	15 (100%)	-
Postoperative (Care Room)	5^th hour	N=15	N=15	0.047**
	Pain-free (0)	8 (53,3%)	15 (100%)
	Mild Pain (1-3)	7 (46,7%)	0
	6^th hour	N=15	N=15	0.07
	Pain-free (0)	0	15 (100%)
	Mild Pain (1-3)	15 (100%)	0
Postoperative (Observation place outside the hospital)	8^th hour	N=15	N=15	0,03^**
	Mild Pain (1-3)	8 (53,3%)	0
	Moderate Pain (4-6)	7 (46,7%)	0
	12^th hour	N=15	N=15	0,0001^***
	Pain-free (0)	8 (53%)	15 (100%)	0,0001^***
	24^th hour	N=0	N=15	0,0001^***
	Pain-free (0)	Intervention assessment was stopped on the subject because they experienced moderate-severe pain	9 (60%)
	Mild Pain (1-3)		6 (40%)

*Chi square (Fisher exact), ** Signifikansi<0.05, *** Signifikansi<0.01

Table 3 compares the FLACC scores of bupivacaine and bupivacaine+ketamine in infraorbital blocks in patients undergoing labioplasty. Pain evaluation is measured by the FLACC scorein Table 3, which is subdivided into pain-free (0), mild pain (1-3), moderate pain (4-6), and severe pain (7-9) categories (7-10). From 0 o'clock (intraoperatively) to 4 o'clock (postoperatively), neither the bupivacaine-only group nor the bupivacaine-plus-ketamine group reported any pain.Changes in new mild pain occurred in the bupivacaine group within 5 hours in 46.7% of individuals and after 6 hours in 100% of subjects with mild pain. At 8 hours, seven patients in the Bupivacaine group experienced moderate pain, while eight patients in the placebo group experienced mild discomfort. In contrast, all individuals in the Bupivacaine-Ketamine group experienced no discomfort for 5 to 8hours following surgery. It indicates that the combination of regional anesthetic (Bupivacaine) and general anesthesia (Ketamine) offers good analgesic qualities for labioplasty patients.

In the Bupivacaine group, 7(46.7% of study patients) with an analgesic duration of 496 minutes had FLACC values four from observations at T8(8hours) (8hours 16 minutes). Thus, after 12hours, seven subjects in the Bupivacaine group did not participate in the measurement of the analgesics score (the intervention would be discontinued in patients with moderate-to-severe pain (FLACC score 4). Meanwhile, in the Bupivacaine + Ketamine group, the moderate pain group (FLACC value 4) was not obtained until observation at T24 (24 hours). Still, FLACC values four were obtained during observations at T24 (24hours) for as many as 6 (40%) subjects with pain-free, with an analgesia duration of 1440minutes (24hours), and as many as 9 (60%) subjects with mild pain.

Pain in patients undergoing labioplasty is superficial and somatic rather than visceral²³. The FLACC pain scale assigns a pain score of 4 (moderate pain) to pain following labioplasty surgery, indicating that pain management is crucial²⁴. Adequate postoperative analgesia can accelerate mobilization and healing²⁵. It is difficult to achieve adequate pain control using a single medication. Most analgesics cannot be prescribed at unlimited doses because of ceilings on efficacy and safety, and tolerability concerns. Rational combinations of analgesics with different mechanisms of action may improve efficacy, tolerability, and security compared to full analgesic doses individually²⁶. The mixing of regional anesthesia and general anesthesia can offer excellent peri-operative analgesia and reduce the need for postoperative analgesia²⁷. An infraorbital block is an anesthetic technique with a high success rate for labioplasty surgery procedures²⁸. This study compared patients in the 0.25 percent bupivacaine and 0.25 percent bupivacaine plus 0.5 milligrams per kilogram of body weight (mg/kg BW) ketamine groups. Each group contains fifteen individuals. The statistical homogeneity of subject attributes is based on collected data (Table 1).

Post-infraorbital block, there was no statistically significant change in pulse rate during the intraoperative period (Table 2). Changes in pulse rate correspond to an increase in the FLACC value, which signals pain that manifests along with a reduction in the analgesic efficacy of local anesthetic medicines with adjuvants²⁹. Because the infraorbital block with bupivacaine and the combination of Bupivacaine and Ketamine provided adequate analgesia during surgery and postoperatively and improved the quality of the healing period and early mobilization, intravenous opioids were not employed in this study (Table 3).

According to Table 3, the duration of action of bupivacaine for infraorbital blocks is between 8 and 12 hours after labioplasty surgery. Based on its mechanism of action, bupivacaine is an amide-class local anesthetic with high potency, low allergy risk, and a long duration of action³⁰. Bupivacaine 0.5% produced a quick onset of sensory and motor loss³¹. Bupivacaine's action method includes blocking infraorbital nerve transmission by preventing action potentials in the axons, binding directly with particular receptors on Na⁺ channels, thereby reducing the influx of Na⁺ ions, resulting in nerve impulse barriers³². Elimination of Bupivacaine is followed by spontaneous and complete recovery of nerve conduction without structural damage to nerve fibers due to local anesthetic medication effects³³.

In this study, the analgesic impact of ketamine mixed with bupivacaine was evaluated following labioplasty surgery (Table 2 and Table 3). Previous researchers have identified numerous benefits of ketamine, including its being a phencyclidine derivative and a non-competitive antagonist at the N-Methyl-D-Aspartate (NMDA) receptor, which plays a significant role in nociceptive processes³⁴. Ketamine inhibits the opening of sodium channels on the surface membranes of peripheral nerve cells, preventing depolarization and lowering the conduction of pain impulses³⁵. Ketamine causes analgesia by reducing nitric oxide production, is a mu-opioid receptor agonist, and decreases the release of local inflammatory mediators³⁶.

According to the results of this study, the combination of Bupivacaine and Ketamine can enhance analgesic qualities for 24hours. This behavior can be explained by the fact that subanesthetic doses of ketamine can decrease nerve-activated pain. In sub-anesthetic doses, however, it can be utilized as an adjunct to local anesthesia³⁷. As an adjunct to Bupivacaine, Ketamine positively affects cardiorespiratory function, resulting in more extended postoperative analgesia, a faster onset, and appropriate anesthesia³⁸. Ketamine and xylazine were reported to significantly reduce the respiratory rate of rabbitsfrom 10 to 60 minutes, and a highly significant decrease was reported at 40 minutes³⁹.

The side effects of ketamine, including hallucinations, nystagmus, blurred vision, sleepiness, sedation, nausea, and vomiting, can be mitigated by administering ketamine adjuvants at sub-anesthetic doses (0.1-0.5 mg/kg)⁴⁰. A trial of ketamine adjuvants added to bupivacaine revealed that ketamine adjuvants gave prolonged postoperative analgesia over single doses of bupivacaine, which lasted more than 24 hours in the ketamine bupivacaine group⁴¹.

In this study, participants were aged three months to 1 year. This age group is incapable of successfully communicating their suffering. Consequently, most pain assessment is performed indirectly by examining physiological changes or behavioral responses to pain⁴². The FLACC score, which comprises Faces, Legs, Activity, Cry, and Consolability, can quantify the pain intensity of children who cannot verbalize their discomfort. The FLACC score has been established to measure postoperative pain in children aged two months to 7 years with mild to severe cognitive impairment⁴³. Behavioral techniques like distraction and imaginative involvement should be used to manage pain. They can be used independently or in conjunction with drug therapy⁸.

The infraorbital block provides excellent postoperative analgesia for labioplasty surgery, according to the findings of this study. The adjunctive use of ketamine will lengthen the duration of postoperative analgesia. The group that received ketamine as an adjuvant had a much longer duration of postoperative analgesia, lasting around 1440 minutes (equivalent to 24 hours), compared to the group that alone received bupivacaine, which experienced analgesia for 496 minutes (equivalent to 8 hours and 16 minutes). Ketamine may act similarly to local anesthetics by inhibiting the opening of sodium channels in the surface membrane of peripheral nerve cells, inhibiting depolarization, and reducing the conduction of pain impulses, thereby inhibiting the transmission of pain impulses from the dorsal root ganglion to the spinal cord^35,44.

Postoperative individuals who had a combination of Bupivacaine and Ketamine did not experience nausea, vomiting, hypotension, or bradycardia. As a non-competitive NMDA receptor antagonist, ketamine may limit the modulation of pain signals from second-order neurons to the thalamus, hence reducing the side effects of nausea, hypotension, and bradycardia^45,46. This method demonstrates that ketamine is an effective adjuvant in local anesthetics and that ketamine bupivacaine is superior to bupivacaine alone for infraorbital block and produces a longer duration of action. It may be due to ketamine's participation in the recruitment of inflammatory cells, cytokine synthesis, and control of inflammatory mediators, hence preventing the transmission of pain signals to first-order neurons⁴⁷.

Conclusion:

Based on the features, the distribution of subject data was uniform, and neither Bupivacaine nor Bupivacaine-Ketamine caused side effects or altered heart rate (standard category). In postoperative labioplasty patients, combining Bupivacaine and Ketamine has a more prolonged analgesic effect than bupivacaine alone for an infraorbital block. The Bupivacaine-Ketamine combination has a longer working time of up to 24 hours than bupivacaine, which has an 8-hour working time.

Conflict of Interest:

The authors declare no conflicts of interest.

Acknowledgment:

Thank you to the Padjadjaran University, Bandung, West Java, Indonesia, Academic Leadership Grant. No. 2203/UN6.3.1/PT.00/2022.

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Received on 02.02.2023 Modified on 13.06.2023

Research J. Pharm. and Tech 2024; 17(4):1441-1448.

DOI: 10.52711/0974-360X.2024.00228