Comparison of Perineural and Intravenous Dexamethasone as an Adjuvant to Levobupivacaine in Ultrasound-Guided Infraclavicular Brachial Plexus Block: A prospective Randomized Trial.

BACKGROUND: The effect of perineural versus intravenous (i.v.) dexamethasone (4 mg) when added to levobupivacaine as an adjuvant has not been well studied. AIMS: This study was conducted to compare the analgesic efficacy of perineural and i.v. dexamethasone as an adjuvant to levobupivacaine in infraclavicular brachial plexus (ICBP) block. SETTINGS AND
DESIGN: This was a prospective, randomized, double-blind study.
MATERIALS AND METHODS: This study was conducted on 68 patients with the ultrasound-guided ICBP block, randomly allocated into two groups (34 each). Four patients had failed block (2 in each group) that was excluded from the study. Group A received 25 mL of levobupivacaine 0.5% and 1 mL of normal saline for the block and i.v. dexamethasone 4 mg. Group B received 25 mL of levobupivacaine 0.5% with 4 mg of perineural dexamethasone for the block. Postoperative vitals and different block characteristics were assessed. STATISTICAL ANALYSIS USED: Student's independent sample t-test and Chi-square test were used for statistical analysis.
RESULTS: The duration of motor block and analgesia in Group A was 1245.94 ± 153.22 min and 1310.16 ± 151.68 min, respectively. However, in Group B, the duration of motor block and analgesia was 1768.13 ± 309.86 min and 1743.59 ± 231.39 min, respectively, which was more when compared to Group A (P < 0.001). The Visual Analog Scale score of ≥3 in Group A was 37% and in Group B was 9% (P = 0.008). Four cases had delayed regression of motor block in the perineural group.
CONCLUSIONS: Perineural dexamethasone significantly prolonged the duration of motor block promoted by levobupivacaine in infraclavicular brachial plexus block, reduced pain intensity and rescue analgesia needs in the postoperative period when compared with the intravenous dexamethasone. Copyright:

INTRODUCTION

Pain is a sensory indication transmitted by specific nerve fibers and is amenable to modulation or interruption anywhere along the nerve's pathway, which is crucial to modern nerve blocks. Over the decade, anesthesia has evolved with a lot of improvements and decreased complications.[1]

The magnificence of ultrasound-guided infraclavicular brachial plexus (ICBP) block gives off an impression of being related with the high success rate, low complication rate, and excellent analgesia even when a tourniquet is used and also it avoids the risk of phrenic nerve block, making it an excellent choice specifically in patients with respiratory disorders.[2]

Several adjuvants were used with local anesthetics during blocks such as alpha-2 agonists (clonidine and dexmedetomidine), opioids (fentanyl and tramadol), and steroids (dexamethasone), which have been used to prolong neural blockade.[3] Based upon previous studies as an adjuvant to regional analgesia, perineural dexamethasone significantly shortened the onset of sensory and motor block, prolongs the duration of analgesia, prolongs the time to 1st analgesic request with minimal side effects.[4] i.v. dexamethasone during general anesthesia has proven beneficial in reducing pain, postoperative nausea, and vomiting (PONV) and decreasing airway complications in patients with bronchial hyperreactivity.[56]

Because of worry of adverse physiochemical impacts from perineural adjuvant dexamethasone, few authors have suggested against its use as an adjuvant to the local anesthetic or have proposed that alternative routes of administration (i.v.) are preferable.

The present study is undertaken with the null hypothesis that perineural and i.v. administration of dexamethasone has no clinical difference in terms of onset time, duration of motor block, sensory block, and postoperative analgesia. The primary objectives of the study are time to complete sensory and motor block and duration of postoperative analgesia. The secondary objectives are to compare the hemodynamic changes following the block and side effects of drugs used or complications.

MATERIALS AND METHODS

After approval of the Institutional Ethics Committee (VIEC/2016/APP/127, Ethical Committee Registration no: ECR/747/Inst/KA/2015 dated October 10, 2016), this prospective, comparative, randomized trial was conducted during the period of January 2017–June 2018. The study followed to the Helsinki Declaration (World Medical Association, 1995). All study parts were reviewed according to the strengthening of the reporting of randomized clinical trials in “CONSORT guidelines.” Informed and written consent was taken from all the patients before enrollment in the study and the use of the patient data for research and educational purposes. Patients with American society of anesthesiologists physical status class I or II, between 18 and 70 years of either gender, posted for upper-limb surgery below mid humerus for orthopedics, plastic surgery, and general surgery were included in the present study. Patients who refused to give informed consent, contraindication to brachial plexus block, severe lung disease, contralateral diaphragmatic paralysis, preexisting neuropathy involving the surgical limb, infection at the injection site, coagulopathy, pregnancy and lactating women, nerve injury secondary to trauma, failed block (considered as “dropped” case), those on sedative medication and perioperative i.v. steroids, known hypersensitivity to local anesthetic drugs and dexamethasone, uncontrolled diabetes mellitus, morbid obesity, history of significant cardiovascular, pulmonary, renal, hepatic diseases, and peripheral vascular disease were excluded from the study.

A preanesthetic evaluation was performed on the day before surgery. The procedure of block and possible complications was explained to the patients. All patients have given oral alprazolam 0.5 mg and ranitidine 150 mg on the night before the surgery and were fasting overnight.

Sixty-eight patients were divided randomly into two groups (Group A, n = 34 and Group B, n = 34) using computer-generated randomization numbers with a sealed envelope method to ensure concealment of allocation sequence. The anesthesiologist, who was not participated in the study, opened the envelope in the operation theatre and prepared the drug. The principal investigator was blinded to the drug, performed the block, observed, and recorded the parameters. Hence, both attending anesthesiologist and patients were blinded to the medication. On arrival in operation theatre, i.v. access was secured with an appropriate sized cannula on the non-operating hand. Following placement of standard monitors, heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), peripheral oxygen saturation (SpO2), and three-lead electrocardiogram were noted. Noninvasive blood pressure was monitored by sphygmomanometer on the opposite upper limb. Premedication with injection fentanyl 50 mg i.v. and injection glycopyrrolate 0.2 mg i.v. was given before the procedure.

The ICBP block was performed using a portable Siemens ACUSON Freestyle™ (Siemens Healthcare, Camberley, UK) using a linear ultrasound transducer (8–13 MHz) at least 30 min before the start of surgery. Under all aseptic precautions with the patient in the supine position, arms by the side or abducted 90° and head turned to the other side. The brachial plexus was visualized by putting the transducer beneath the clavicle and medial to the coracoid process. The plexus either look such as a cluster of grapes or hypoechoic circles with the hyperechoic outer ring. A 22G short beveled 10-cm stimulating needle (Stimuplex Ultra, B. Braun Melsungen AG) was used for localization. On the basis of group allocation, after incremental injection of the local anesthetic mixture with a negative aspiration to avoid accidental intravascular needle puncture, the spread of drug was observed in tissue planes. Group A (n = 34) received 0.5% levobupivacaine 25 mL with 1 mL of normal saline for the block plus i.v. dexamethasone 4 mg (1 mL), and Group B (n = 34) received 0.5% levobupivacaine 25 mL plus perineural dexamethasone 4 mg (1 mL) around the brachial plexus and 1 mL of normal saline intravenously. The patients were evaluated at 5-min interval for 30 min for developing the sensory and motor block. In case of inadequate blockade due to any reason, the case was converted to general anesthesia at the end of 30 min and it was not considered in the study.

Onset of the sensory blockade was defined as the time interval between the injection of local anesthetic and abolition of pinprick response. It was evaluated in four nerve areas (radial, ulnar, median, and musculocutaneous) at every 5 min until 30 min after the injection. The block was decided to fail if anesthesia was absent in at least two peripheral nerve distributions and such patients were excluded from the study. Sensory block (four nerve territories) was assessed by pinprick test using a three-point scale graded as Grade 0: Sharp pain felt, Grade 1: Dull sensation felt – analgesia, and Grade 2: No sensation felt – anesthesia. Grade 2 was considered for success of sensory block. Time of onset of sensory block was defined as pinprick score 2 for all nerves. The duration of sensory blockade was defined as the time interval between the onset of action and return of pinprick response and it was assessed every 60 min in at least three major nerve territories.

For motor block, the inability to flex the elbow and flex distal interphalangeal joint of second finger (musculocutaneous nerve and median nerve respectively) or inability to extend the wrist and abduct third and fourth fingers (radial nerve and ulnar nerve respectively) was tested. Motor block was determined by thumb opposition (median nerve), thumb adduction (ulnar nerve), thumb abduction (radial nerve), and flexion of the elbow (musculocutaneous nerve) as per modified Bromage scale on a three-point scale as Grade 0: Normal motor function with full flexion and extension of the elbow, wrist, and fingers, Grade 1: Motor strength is decreased with ability to move fingers only, and Grade 2: Inability to move the fingers – complete motor blockade achieved. Grade 2 was considered for success of motor block. Onset of motor block was defined as the time interval between the injection of local anesthetic and inability to move the joints. Onset of motor block was evaluated every 5 min and time to block minimum two major nerves were noted. The duration of motor blockade was assessed every 60 min the return of complete muscle power in at least two major nerve distributions.

Both sensory and motor blockade were assessed at 0, 5, 10, 15, 30, 45, 60, 90, and 120 min. After the completion of surgery till time to first rescue analgesia and thereafter till complete regression of block has achieved, both sensory and motor blockade were assessed. Intraoperatively, we were checking sensory and motor block at the same way of grading at nonsurgical area. Patients were asked to note the subjective recovery of sensation, pain, and movements. The severity of postoperative pain was assessed by using the Visual Analog Scale (VAS) using a straight line 10 cm long with the one end defined as “no pain” and the other end being “worst ever pain.” Patients were asked to make a mark on the line to describe the amount of pain. Pain was assessed by standardized VAS at 0, 2, 4, 6, 12, 18, and 24 h (h) postoperatively until the patient complains of pain and thereafter monitored until complete regression of sensory and motor block is achieved. Grade 0 was considered as recovery for both sensory as well as motor block. Both sensory and motor blockade were assessed at 0, 5, 10, 15, 30, 45, 60, 90, and 120 min. After the completion of surgery till time to first rescue analgesia and thereafter till complete regression of block has achieved, both sensory and motor blockade were assessed. Inj. diclofenac sodium 75 mg was given when VAS ≥ 3 (rescue analgesia) and second rescue analgesic inj. tramadol 50 mg intravenous was given if pain still persist. HR, SBP, DBP, and SpO2 were recorded preoperatively before drug administration, at 0 min (just after drug administration), 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 90 min, 2 h, 4 h, 6 h, 12 h, 18 h, and 24 h. The mean onset time of sensory and motor block and duration of motor block and analgesia were noted. The time for the first and second rescue analgesic noted and complications during the intra-operative and post-operative period were also noted.

The sample size calculation was based on estimating the difference between two means. Mean difference was 2.8; standard deviation (SD) in Group A and Group B were 6.2 and 5.5, respectively. CI was 95%, expected proportion and precision were 0.07 and 6%, respectively. So, the required sample size was calculated as 34 in each group.

The statistical analysis was performed by STATA 11.2 (College Station, TX, USA) and Shapiro–Wilk test was used to check normality. The continuous variables were represented as onset, duration, onset of pain, and pain score. The patients' data and characteristics, time of onset and duration of block, duration of analgesia, and pain score along with complication were categorized and analyzed appropriately using Student's independent t-test and Chi-square test. P < 0.05 was considered statistically significant.

RESULTS

Enrolled patients with successful ICBP block (32 in each group) completed the study and four patients had failed block (2 in each group) that was excluded from the study [Figure 1]. Demographic parameters such as age, gender, height, weight, body mass index, and duration of surgery between two groups were comparable [Table 1], and there was no statistical significance between both the groups. Hemodynamic parameters such as HR, SBP, DBP, MAP, and SpO2 have noted and compared the trends till 24 h postoperatively. There was no statistical significance between both the groups.

Figure 1

CONSORT flow diagram

Table 1

Demographic characteristics

Parameters	Group A (n=32)	Group B (n=32)
Age (years)	38.2±14.8	33.3±13.8
Gender (male/female)	23/9	24/8
Height (cm)	167.2±6.9	168.3±7.2
Weight (kg)	65.6±7.0	66.2±5.4
BMI, weight/height (m2)	23.5±2.5	23.4±2.0
Duration of surgery (min)	128.2±46.4	130.2±57.6

Values are presented as mean±SD. Results of students independent sample t-test. Chi-square test used for gender. Group A: levobupivacaine with 1 mL normal saline + 4 mg (1 mL) dexamethasone i.v., Group B: levobupivacaine + perineural dexamethasone + 1 mL normal saline i.v. BMI=Body mass index, SD=Standard deviation

VAS score of <3 and ≥3 was 63% and 37% in Group A, respectively, however, in Group B, it was 91% and 9%, respectively, which was statistically significant (P = 0.008). In this study, perineural dexamethasone has less VAS scores (<3), time of first rescue analgesia was more, and pain scores were less. Group A required second rescue analgesia. Hence, the total number of patients who received rescue analgesia was more in the i.v. group compared with the perineural group [Table 2]. In the present study, the mean time for the onset of complete sensory and motor block in Group A and Group B was statistically not significant [Table 2]. However, the mean time for the duration of motor block and duration of analgesia in Group A is less when compared with Group B, which was statistically highly significant.

Table 2

Infraclavicular brachial plexus block characteristics

Variables	Group A (n=32)	Group B (n=32)	P-value
Sensory block-onset (min)	22.2±4.6	24.5±7.1	0.12
Motor block-onset (min)	30.2±6.0	33.0±8.1	0.12
Duration of motor block (min)	1245.9±153.2	1768.1±309.9	<0.001
Duration of analgesia (min)	1310.2±149.3	1743.6±227.7	<0.001
Pain score (VAS)
<3	20	29	0.008
≥3	12	3
Time to request for first rescue analgesia (min)	1306.2±295.3	1740±272.8	<0.001
Time to request for second rescue analgesia (min)	1414.2±147.6	-
Complications (prolonged motor block)
Yes	0	4	0.113
No	32	28

Values are presented as mean±SD. Sstudent’s independent sample t-test has been used to find the significant difference between onset of sensory and motor block, duration of analgesia, time to rescue first analgesia. Chi-square test for pain score and Fisher’s exit test for complication (statistically significant at P < 0.05). Group A: levobupivacaine with 1 mL normal saline + 4 mg (1 mL) dexamethasone i.v., Group B: levobupivacaine + perineural dexamethasone + 1 mL normal saline i.v. VAS=Visual analogue score

Group A had no complications whereas, in Group B, four patients had complications of prolonged duration of motor block postoperatively, which was statistically significant [Table 2]. We did not found any other complications or side effects such as phrenic nerve palsy and Horner's syndrome and local anesthetic systemic toxicity.

DISCUSSION

Infraclavicular approach for brachial plexus block provides good anesthesia for surgery of the upper limb below mid humerus. The use of ultrasound appears to allow the precise deposition of the local anesthetic perineurally and can possibly improve the success and decrease the complications of ICBP block.[2] Ultrasound-guided ICBP block enables adequate block with a lower volume of local anesthetic and possible to cover all sensory territories of the distal part of the upper limb with only one puncture because it has the ability to simultaneously anesthetize the axillary, musculocutaneous, median, radial, and ulnar nerves. It has recently become a technique of increasing interest.[7] This approach can also easily block the ulnar segment of the medial cord and intercostal brachial nerve, which helps in preventing tourniquet pain.[28] Side effects such as pneumothorax, phrenic nerve injury, and stellate ganglion block are absent in this block.[9] We preferred the use of levobupivacaine over bupivacaine as an earlier study report showed that levobupivacaine has a higher toxic threshold and produces less cardiac effects, and has a similar duration of action compared to bupivacaine.[10] There has consistently been a quest for adjuvants to prolong the duration of analgesia but with lesser adverse effects. Analgesic effect of perineural dexamethasone has been evaluated before and it has been proved.[11] We started our study with the null hypothesis of perineural or systemic administration of dexamethasone has equipotent action. Clonidine, tramadol, dexmedetomidine, and neostigmine have been studied as an adjuvant to local anesthetics, but each drug has its own side effects.[12] Dexamethasone is a long-acting glucocorticoid which produces vasoconstriction and prolongs the action of local anesthetics by reducing the absorption of local anesthetics.[13] It is effective and widely used intravenously for prophylaxis of PONV. The analgesic effect of dexamethasone as an adjuvant to local anesthetics during brachial plexus block with no side effects was reported.[14] However, after perineural administration of dexamethasone, the analgesic effect was not fully explained and it was not clear whether it is due to systemic effects or not. In our study, we observed that perineural dexamethasone group, when compared to i.v. dexamethasone group, has increased duration of motor block, prolonged duration of analgesia and reduced pain intensity. Probable explanation for all this inconsistency regarding the onset and duration may relate to inter-patient variations in the study population, the anatomy of the plexus sheath and difference in the spread of local anesthetic in the plexus sheath, differences in the type of drug, type of nerve block, strength of the drug, the exact volume of mixture injected, and technique used to perform block. And also, dexamethasone increases the activity of inhibitory potassium channels on nociceptive C-fibers, and therefore prolongs sensory and motor blockade.

Effect of peripheral dexamethasone as an adjuvant to local anesthetic was studied in brachial plexus block, and it was concluded that it significantly improved postoperative pain, the onset of sensory and motor block was delayed, and duration of motor block was prolonged.[15] However, perineural dexamethasone was used in all the patients who were not compared with i.v. dexamethasone. A multicenter randomized trial concluded that perineural dexamethasone provides a longer duration of motor block, sensory block, and postoperative analgesia, but no intergroup differences were observed (P > 0.05) on a comparison between i.v., and perineural dexamethasone for ultrasound-guided ICBP block.[16]

In a meta-analysis, it was observed perineural administration in comparison to i.v., and it was associated with an overall increase in the mean duration of analgesia by 3 h, but on subgroup analysis, this was statistically significant only with bupivacaine and not with ropivacaine.[17] There was no difference in the incidence of PONV between perineural and i.v., dexamethasone. A recent study concluded that the addition of dexamethasone (perineural or intravenous) i.v. as an adjuvant with ropivacaine to ulnar nerve block did not show any significant benefits over saline.[18] On concerns about the dose of dexamethasone, it was concluded that dexamethasone produced late onset of sensory and motor block with prolongation of motor block duration and that the smaller doses of dexamethasone (4–5 mg) were as equally effective as higher doses of dexamethasone (8–10 mg).[15] On comparing various studies regarding sensory and motor block onset, there were mixed results. Most of the studies did not comment on the onset of action when given systemically. In our study, on comparing sensory and motor block onset, most of the clinical studies correlate with our findings of early onset of a sensory blockade than motor blockade in both groups. This can be explained by the fact that induction of blockade depends on nerve fiber size and minimum blocking concentration (Cm). The Cm of different local anesthetics also differs for different nerve fibers. The motor nerve fibers Aα and Aβ are relatively thicker than sensory nerve fibers Aδ and C and motor fibers have higher Cm than sensory fibers, and this explains the reason why sensory block occurs earlier than a motor block.[19]

VAS <3 was more in the perineural group compared with the i.v. group. First rescue analgesia was given to patients of VAS ≥3 which was more in the i.v. group compared to the perineural group. In a study compared i.v. and perineural dexamethasone in interscalene brachial plexus block demonstrated that group ropivacaine alone had 3.91 times higher probability for analgesic need during first 48 hours compared with group ropivacaine-perineural dexamethasone and group ropivacaine-i.v. dexamethasone.[20] Our study was not comparable with the similar studies as in our study perineural dexamethasone has less VAS scores (<3), time of first rescue analgesia was more, and pain scores were less. In this study, we did not encounter any vascular puncture during the block, pain during the block, neuropathy, and postoperative sequel such as hematoma or paresthesia in any groups. The perineural group of the patients had complications of prolonged duration of motor block which was statistically significant (P < 0.05). The reason attributed to this prolonged motor block might be the perineural dose of dexamethasone. Given the lack of clinical benefit and the concern of dexamethasone neurotoxicity as demonstrated in animal studies, the practice of perineural dexamethasone administration needs to be further evaluated.[21] Since individual nerves involving all the cords were affected and not a single cord in toto and also complete regression is seen, brachial plexus injury was ruled out. Our concerns on the safety of perineural use of dexamethasone whether harmful effects on nerve fibers are or not, but we did not find reports available regarding long-term effects on peripheral nerves.[22]

Limitations of our study were that we did not assess the duration of sensory block by repeated neurologic examinations (duration until first analgesic request noted as a marker of the sensory block) and we have given a fixed dose of 4 mg of dexamethasone, not given according to the body weight of the patient.

CONCLUSIONS

In systemic and perineural administration of dexamethasone in infraclavicular brachial plexus block as an additive to 0.5% levobupivacaine suggests that perineural dexamethasone significantly prolonged the duration of motor block, reduces pain intensity and rescue analgesia needs in the postoperative period when compared with the intravenous dexamethasone without any adverse effects.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.