Comparative Evaluation of Dexamethasone and Dexmedetomidine as Adjuvants for Bupivacaine in Ultrasound-Guided Infraorbital Nerve Block for Cleft Lip Repair: A Prospective, Randomized, Double-Blind Study.

PURPOSE: To compare dexamethasone (DA) to dexmedetomidine (DE) as adjuvants for bupivacaine during infraorbital nerve block (IONB) in a randomized clinical trial. PATIENTS AND METHODS: One hundred patients were randomized into two equal groups. By the guidance of ultrasound, the IONB was performed bilaterally in all patients, using 1 mL of the solution on each side. In DA group, 1 mL of 0.5% bupivacaine was added to 0.1 mg.kg-1 DA and diluted to 2 mL in DE group; 1 mL of 0.5% bupivacaine was added to 0.5 μg.kg-1 DE and diluted to 2 mL. The primary outcome was time to first rescue analgesic. The secondary outcomes included face legs activity cry consolability (FLACC) score rating during the first 24 h, hemodynamic variables, the incidence of postoperative vomiting, sedation score, and parent satisfaction.
RESULTS: During the first 24 h postoperatively, the DE group showed a significantly lower FLACC score and a longer time to first analgesic request compared to DA group. Sedation and parent satisfaction scores were significantly higher while heart rate and mean blood pressure were significantly lower in DE group compared to DA group. There were no differences in other secondary outcomes.
CONCLUSION: The use of DE as an adjuvant to bupivacaine in IONB for cleft lip repair resulted in lower pain score and more prolonged duration of analgesia compared to DA.

INTRODUCTION

Regional analgesia is considered the cornerstone for postoperative analgesia in pediatric patients. One of the most common birth defects which require surgical intervention early in life is the cleft lip. Infraorbital nerve block (IONB) has been used for postoperative analgesia in this delicate and sensitive area.[1]

As the assessment of pain may be very challenging especially in young children, the local anesthetics administration can be a safe alternative to opioids.[2] However, the regional block after a single dose of local anesthetic is of limited duration and efficacy. Hence, the coadministration of adjuvants with local anesthetics may be helpful for potentiation of analgesic effect.[2]

Dexmedetomidine (DE) is a potent α2 adrenoreceptor agonist. Many studies documented a prolonged duration and rapid onset of sensory block with the perineural injection of DE.[3] The use of steroids as adjuvants to local anesthetics significantly prolongs the duration of analgesia with a shorter onset of action in adult.[4] Dexamethasone (DA) acts through reducing ectopic neuronal discharge, inhibiting potassium channel-mediated discharge of nociceptive C-fibers and attenuating the release of inflammatory mediators.[5]

This prospective, randomized, double-blind study was performed to compare the efficacy of DA or DE as adjuvants for bupivacaine in IONB in pediatric patients for cleft lip repair. The primary outcome was to compare both groups regarding time to first rescue analgesic. Secondary outcomes were to evaluate postoperative face legs activity cry consolability (FLACC) scale, hemodynamic variables, the incidence of postoperative vomiting, sedation score, and parent satisfaction.

PATIENTS AND METHODS

Patients

After gaining approval of ethical committee (IRB: (R/17.05.85) and registration in Clinical Trials.gov (NCT03480607), 100 consecutive pediatric patients, of either sex, aged 3–6 months, American Society of Anesthesiologists physical Status I or II, and scheduled for surgical cleft lip repair were enrolled in this prospective randomized trial, in the period between August 2017 to May 2018. The exclusion criteria included the following: known allergy to any of drugs used, coagulopathy, thrombocytopenia, history of any lower or upper airway disorders, history of sleep apnea syndrome with a suspected need for postoperative ventilation, any wound or infection related to puncture site, major illness, and failure to gain the consent of parents. The same experienced surgeon performed all operations.

Randomization

Following parental informed consent, patients were randomly allocated using computer-generated randomization numbers with a closed-seal envelope into one of two groups (50 in each group). The principal investigator prepared the drug and performed the block, but the person observing and recording the parameters was blinded to the study.

In both groups, bilateral extraoral and infraorbital nerve block were performed using 1 mL of the solution on each side. In Group DE, 1 mL of 0.5% bupivacaine was taken and 0.5 μg.kg−1 DE (solution of 10 μg.mL−1 in 0.9% saline) (Precedex; Hospira Inc., Lake Forest, Illinois, USA) was added to it and completed to 2 mL with 0.9% saline. In Group DA, 1 mL of 0.5% bupivacaine was taken and 0.1 mg.kg−1 DA (solution of 1 mg.ml−1 in 0.9% saline) was added to it and completed to 2 mL with 0.9% saline.

Study protocol

Without any premedication, participants were induced by inhalation of 8% sevoflurane in 100% oxygen. Standard monitoring was applied during the perioperative period including noninvasive blood pressure measurement, electrocardiography; pulse oximeter, and end-tidal CO2. Then, peripheral intravenous (IV) cannulation was done, and participants received intravenous fentanyl 1 μg.kg−1 and rocuronium bromide 0.1 mg.kg−1.

Intubation of trachea was performed in the supine position by a cuffed endotracheal tube of a proper size. Patients were maintained on 3%–4% sevoflurane in 50% air/oxygen mixture. Infusion of fluid (lactated Ringer) was at a rate of 15 mL.kg−1.h−1.

Before starting the surgery and under complete aseptic condition, infraorbital nerve block was performed in all participants bilaterally and extraorally. A landmark of the infraorbital nerve is a point approximately situated midway along a line drawn from the angle of the mouth to the midpoint of the palpebral fissure.[6] Ultrasound images were obtained using a portable ultrasound unit and 8–13 MHz linear probe. The probe was placed on the infraorbital ridge in a transverse scout scanning from lateral to medial up and down along the lower orbital margin. The infraorbital foramen was identified as hypoechoic depression along the hyperechoic infraorbital margin which was confirmed by using color mode to define infraorbital vessels along with infraorbital nerve. In-plane technique was used to block the nerve with the needle directed from lateral to medial under continuous US guidance. The tip off the needle directed both under and above the nerve (but not into the foramen) with the injectate circumscribing the nerve in a perineural fashion (donut appearance). Out-of-plane technique was not used to avoid injury of the nerve and vessels. Infraorbital nerve block was performed before the surgical procedure using 25-gauge 50-mm Sprotte needle, according to landmarks defined before.

After negative blood aspiration, the prepared solution was injected over 20 s on each side. Massage of injection point with pressure for 2 min was done. No additional local anesthetic was injected by the surgeon either peri-incisional or submucosal.

The absence of more than 20% increase in heart rate (HR) or mean arterial blood pressure compared to preoperative values recorded just before the first surgical incision was considered as a sign of successful block. If the block failed, IV fentanyl 0.5 μg.kg−1 was administered. A decrease in HR and mean blood pressure (MBP) by more than 30%, respectively, when compared to the basal values was treated with atropine or ephedrine as needed. Reversal of rocuronium was done by injection of atropine 0.02 mg.kg−1 and neostigmine 0.05 mg.kg−1. Children were extubated at the end of surgery after recovery of protective airway reflexes.

Patient monitoring

Hemodynamic variables (MBP, HR) were recorded (after the induction of anesthesia and before performance of block) as basal value then after 10, 20, 30, 60, 90, and 120 min.

The FLACC scale was used for assessment of postoperative pain.[7] The pain score was assessed at the end of surgery, then every 4 h for 24 h postoperatively. When the pain score exceeded 4, a 20 mg.kg−1 paracetamol suppository was given as rescue analgesic.

The time to the first analgesic request and the number of patients who received pain medication during the first 24-h were registered.

Postoperative sedation was evaluated hourly by Richmond scale for the first 3 h.[8]

Postoperative vomiting attacks were recorded.

Sample Size

A prior G power analysis was done. Using the results obtained from previous studies and assuming an alpha error of 0.05 and beta error of 0.2 (power of the study 80%), a sample size of 45 patients per group was calculated. A dropout of 10% of cases was expected, so; 50 cases per group were required.

Statistical analysis

Data were analyzed through SPSS (Statistical Package for Social Sciences), Program version 22 (IBM Corp. Released 2013. IBM SPSS Statistics for Windows, Version 22. Armonk, NY: IBM Corp). Distribution of data was first tested by Shapiro test. Data were presented as mean and standard deviation, median and range or numbers, and percentages. For normally distributed data, unpaired t-test was used to compare between mean values of both groups. For pain and sedation scores, Mann–Whitney U-test was used. Fisher's exact test was used for comparison of categorical data. P ≤ 0.05 was considered as the level of statistical significance.

RESULTS

A total of 100 children were enrolled in this study [Figure 1]. The two groups of participants did not show statistically significant difference regarding patient characteristics and duration of surgery [Table 1]. A significant decrease in HR and MBP in Group DE compared to Group DA. Also, a significant decrease was noted in both groups in comparison with basal values as shown in Tables 2 and 3.

Figure 1

Consort flow diagram

Table 1

Demographic data of the studied groups, duration of surgery, and satisfaction score

Patient’s number	Group DA (n=50)	Group DE (n=50)	P
Sex (female/male)	25/25	23/27	0.6
Age (months)	3.4±1.17	3.5±0.87	0.6
Weight (kg)	7.4±0.96	7.3±0.98	0.6
Height (cm)	64.3±5.7	66.8±8.3	0.08
Duration of surgery (min)	55±5.78	55±5.55	1
Parent satisfaction score
Excellent	10 (20)	30 (60)	0.0001*
Good	20 (40)	15 (30)	0.2
Fair	20 (40)	5 (10)	0.0006*

Data are presented as mean±SD/n (%). *P≤0.05 was considered as statistically significant between the two groups. DA=Dexamethasone, DE=Dexmedetomidine, SD=Standard deviation

Table 2

Heart rate of the studied groups (data are presented as mean±standard deviation)

HR (beat/min)	Group DA (n=50)	Group DE (n=50)	P
After induction	149±2.7	149±4.3	1
10 min after starting of surgery	147±3.4†	146±3.1†	0.1
20 min after starting of surgery	145±2.2†	144±2.5†	0.04*
30 min after starting of surgery	143±3.4†	141±2.7†	0.001*
45 min after starting of surgery	143±3.2†	140±2.6†	0.0001*
60 min after starting of surgery	144±2.1†	140±3.6†	0.0001*
90 min after starting of surgery	143±4.1†	141±3.6†	0.01*

*P≤0.05 was considered as statistically significant between the two groups, †P≤0.0001 was considered as highly significant in comparison with basal value. DA=Dexamethasone, DE=Dexmedetomidine, HR=Heart rate

Table 3

Mean blood pressure of the studied groups (data are presented as mean±standard deviation)

MBP (mmHg)	Group DA (n=50)	Group DE (n=50)	P
After induction	58±3.2	57±2.5	0.08
10 min after starting of surgery	55±2.5†	56±3.0	0.07
20 min after starting of surgery	54±2.2†	53±2.1†	0.02*
30 min after starting of surgery	50±3.6†	48±2.7†	0.002*
45 min after starting of surgery	50±3.5†	48±2.9†	0.002*
60 min after starting of surgery	51±4.2†	49±2.6†	0.005*
90 min after starting of surgery	52±3.6†	50±3.5†	0.005*

*P≤0.05 was considered as statistically significant between the two groups. †P≤0.0001 was considered as highly significant in comparison with basal value. DA=Dexamethasone, DE=Dexmedetomidine, MBP=Mean blood pressure

During the first 24-h postoperative, the FLACC score was significantly lower in Group DE compared to Group DA [Figure 2], consequently; the time to the first analgesic request was significantly longer in DE group compared to DA group [Figure 3]. Sedation score was significantly higher in DE group compared to DA group for the first 2-h postoperative [Table 4]. Higher scores of parent satisfaction were recorded in DE group compared to DA group [Table 1]. There was no difference between the two groups regarding the incidence of postoperative vomiting (4 cases in DE group and 3 cases in DA group) or in hematoma formation (2 cases in DE group and 3 cases in DA group).

Figure 2

Face legs activity cry consolability score of the studied groups. *P ≤ 0.05 was considered as statistically significant. DA=Dexamethasone, DE=Dexmedetomidine

Figure 3

Time to rescue analgesia of the studied groups, *P ≤ 0.05 was considered as statistically significant. DA=Dexamethasone, DE=Dexmedetomidine

Table 4

Sedation score of the studied groups (data presented as median [range])

Sedation score	Group DA (n=50)	Group DE (n=50)	P
Sedation score 1 h	1 (1-0)	-1 (0-(-1))	0.0001*
Sedation score 2 h	1 (1-0)	0 (0- (-1))	0.007*
Sedation score 3 h	0 (1-0)	0 (0-0)	0.1

*P≤0.05 was considered as a statistical significance. DA=Dexamethasone, DE=Dexmedetomidine

DISCUSSION

This study was aiming to compare efficacy of DA and DE as two different types of adjuvants to bupivacaine in IONB for postoperative analgesia after cleft lip repair in pediatrics. We noticed that DE produced a more prolonged duration of analgesia and a lower pain score than produced by DA.

The most common use of DA in perioperative period is to control postoperative nausea and vomiting[9] in addition to its analgesic effect.[910] This analgesic effect was reported when DA was added to local anesthetic during brachial plexus block with no side effects.[11] The analgesic effect of DA after perineural administration is not fully explained and it is not clear if it is due to systemic effects or not.

Liu et al. detected that DA in a dose of 1 mg, 2 mg, and 4 mg prolonged analgesia by about 10 h compared to control group for ambulatory shoulder surgery using 0.25% bupivacaine.[12] All patients in Liu's study including those in the control group received IV DA as antiemetic.

There is conflicting information about dosing; some randomized controlled trials documented that high doses of systemic and perineural DA are equivalent; however, perineural DA in low doses (1–2 mg) appears to prolong nerve block duration compared to equivalent or higher doses of IV DA (4 mg).[13]

A study done by Ribeiro et al. in pediatric patients received either bupivacaine alone or bupivacaine with perineural DA (0.1 mg.kg−1) for supraclavicular nerve block. They concluded that DA resulted in a statistically significant increase in the duration of postoperative analgesia (27 ± 13.42).[5]

In this study, DA was used in a dose of 0.1 mg.kg−1 added to bupivacaine 0.5% that resulted in duration of analgesia of 546 min (9.1 h) which is shorter than reported by Ribeiro et al. who used the same dose. This can be explained by the presence of prevertebral fascia that extends behind the carotid vessels and in front of the scalene muscles. It forms a sheath for the brachial nerves, subclavian artery, and subclavian vein in the posterior triangle of the neck. The presence of this fascia may limit the spread of local anesthetic – DA mixture and prolong the duration of analgesia.

DE is a potent α2 agonist which is highly selective for α2 adrenoreceptor seven times more than clonidine. It is proposed that the mechanism of peripheral nerve block produced by α2 adrenoreceptor agonists includes central analgesia, anti-inflammatory effect.[14] Another suggested mechanism is that DE may exert its action through blocking the hyperpolarization-activated cation current after the transient sodium influx.[15]

Obayah et al. demonstrated that the use of DE in a dose of 1 μg.kg−1 as an adjuvant to 0.25% bupivacaine prolonged the postoperative analgesia duration by about 50% compared to bupivacaine alone.[16] The time to first analgesic request as reported by Obayah et al. was 21 ± 24 h, while a shorter time was reported in our study – 689 ± 58.2 min. This difference can be attributed to a different dose of DE as we used 0.5 μg.kg−1 DE added to 0.5% bupivacaine.

Participants in DE group showed a statistically significant lower pain score compared to Group DA. Time to the first request of analgesic was about 20% longer in DE group (689 ± 58.2) compared to DA group (546 ± 41.6) with highly statistically significant difference (P = 0.0001). Both DA and DE were tolerable with no significant difference regarding the incidence of postoperative nausea and vomiting or intraoperative hemodynamic changes; however, patients belonging to DE were more sedated postoperatively compared to patients of DA group; the difference was statistically significant. This was on the contrary of Obayah et al. who did not record sedative effect; but, this can be attributed to heterogenicity of the scales used. However, Vorobeichik et al.[17] mentioned in their systemic review and meta-analysis that perineural DE was followed by excessive postoperative sedation that was recorded using many scales, including Modified Wilson,[18] Richmond,[19] four-point sedation scales,[20] and University of Michigan.[21] Participants who received perineural DE had greater odds of showing high postoperative sedation, with an odds ratio of 17.2 (1.04–286.5), (P = 0.05). However, it was not recorded in three trials.[222324]

In the current study, using perineural DE in a dose of 0.5 μg.kg−1 for IONB resulted in a relatively short period of analgesia; however, recommendation to use higher doses should be weighed carefully against the increased risks of sedation or possible hypotension and bradycardia. Increased sedation is an obstacle against fast-tracking and bypassing of the recovery room.

Limitations

It was difficult to follow up the hemodynamic variables in this age group after discharge from the PACU, also; the number of participants was relatively small.

CONCLUSION

The use of DE as an adjuvant to bupivacaine in IONB for cleft lip repair resulted in lower pain score and more prolonged duration of analgesia and increased sedation compared to DA.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.