Koh et al-2014-anaesthesia

Original Article

Use of hyaluronidase as an adjuvant to ropivacaine to reduce

axillary brachial plexus block onset time: a prospective,

randomised controlled study

W. U. Koh,1 H. G. Min,1 H. S. Park,2 M. H. Karm,2 K. K. Lee,3 H. S. Yang4 and Y. J. Ro4

1 Clinical Assistance Professor, 2 Resident, 3 Clinical Lecturer, 4 Professor, Department of Anesthesiology and PainMedicine, University of Ulsan, Asan Medical Center, Seoul, Korea

SummaryWhen considering brachial plexus block as a practical alternative to general anaesthesia for upper limb surgery, the

time to achieve complete sensory block is a clinically important variable. In this prospective randomised double-blind

controlled trial, we investigated the hypothesis that addition of hyaluronidase to ropivacaine may reduce the time to

achieve complete sensory block after axillary brachial plexus block. The patients were randomly assigned into a hyal-

uronidase group (n = 24) and a control group (n = 24). The hyaluronidase group received ropivacaine 0.5% with

100 IU.ml�1 of hyaluronidase, and the control group received ropivacaine alone. The primary endpoint was the time

to achieve complete sensory block. The hyaluronidase group demonstrated significantly shorter mean (SD) sensory

block onset time (13.8 (6.0) min) compared with the control group (22.5 (6.3) min, p < 0.0001). Addition of hyal-

uronidase to ropivacaine resulted in a reduction in the time needed to achieve complete sensory block..................................................................................................................................................................

Correspondence to: H. G. Min

Email: [email protected]

Accepted: 20 August 2014

IntroductionBrachial plexus blocks are useful for anaesthesia and

postoperative pain control in surgery performed on

the upper limbs [1, 2]. The axillary approach blocks

the brachial plexus at the terminal branch and pro-

vides anaesthesia suitable for surgery performed on the

forearm [3, 4]. The axillary brachial plexus is superfi-

cial in location, and has no risk of complications such

as pneumothorax or phrenic nerve paralysis that can

occur with other brachial plexus approaches [3, 5].

The widespread use of ultrasound guidance and nerve

stimulation has improved the reliability of axillary bra-

chial plexus blocks, yielding higher success rates with a

reduced number of needle passes [6, 7]. Time to

achieve complete sensory block is clinically important,

as it may influence the decision of whether or not to

perform a brachial plexus block, especially in theatres

where turnover time is an important factor [8, 9].

Hyaluronidase depolymerises hyaluronic acid,

which is a major component of the extracellular

matrix. Through this mechanism of action, hyaluroni-

dase is known to accelerate the onset and improve the

quality of anaesthesia for retrobulbar, peribulbar and

subcutaneous infiltration blocks by increasing the

spread and dispersion of local anaesthetics [10–12].

In the present study, we hypothesised that addi-

tion of hyaluronidase to a local anaesthetic would

reduce the time to achieve complete sensory block of

282 © 2014 The Association of Anaesthetists of Great Britain and Ireland

Anaesthesia 2015, 70, 282–289 doi:10.1111/anae.12879

an axillary brachial plexus block compared with that

of the local anaesthetic alone.

MethodsThis prospective, randomised, double-blind, single-

centre trial was conducted at the Asan Medical Center

in Seoul, Republic of Korea. Permission to conduct this

study was approved by the Institutional Review Board of

Asan Medical Center, and written informed consent was

received from each patient who participated in the

study. This study was registered at the Clinical Research

Information Service (cris.nih.go.kr/KCT0000964).

Adult patients (> 19 years of age) scheduled for

elective surgery of the forearm and hand who were

classified as ASA physical status 1–2 were considered

eligible for inclusion in the study. Patients presenting

with neurological deficits of the upper arm, severe co-

agulopathy, chronic obstructive pulmonary disease,

cardiopulmonary compromise, chronic renal failure,

cerebral vascular disease, pregnancy, chronic cortico-

steroid use, hypersensitivity to hyaluronidase or local

anaesthetics or local infection at the site of the axillary

block were excluded from the study.

After enrolment, patients were randomly assigned

into two treatment groups: a hyaluronidase group and a

control group. A computer-generated randomisation

program was used, and patients were allocated just

before performing the block. Study drugs were prepared

in unidentifiable syringes by a staff member who was

not involved in the study. The hyaluronidase group

received ropivacaine mixed 0.5% with 100 IU.ml�1

hyaluronidase (H-LASE�; KuhnilPharm, Seoul, Korea)

for the axillary brachial plexus block, with the total dose

of hyaluronidase not exceeding 3000 IU. The control

group received ropivacaine 0.5% alone.

All blocks were performed in the operating room

by the first author (WUK). Patients were not pre-

medicated and standard monitors including electrocar-

diography, non-invasive arterial pressure and pulse

oximetry were used. Five litres.min�1 of oxygen were

delivered via a facemask and 1 mg midazolam and

50 lg fentanyl were administered intravenously

(regardless of age or weight) for patient comfort dur-

ing the block procedure.

Subjects were positioned supine with the head

turned to the contralateral side and the ipsilateral arm

abducted with the elbow flexed. The skin was disinfec-

ted and infiltrated with lidocaine 1% before block nee-

dle insertion. After sterile drapes were applied, the

ultrasound probe was positioned vertically in the axilla

to obtain a short-axis view of the axillary artery. A 15–

16 MHz high-frequency linear array transducer

(HGL50x; SonoSite, Bothell, WA, USA) and ultrasound

system (S-NerveTM; SonoSite) were used. The probe

position was further adjusted to achieve a clear view of

the musculocutaneous nerve on the left side of the

ultrasound screen and the axillary artery in the middle

or slightly to the right side of the screen. For musculo-

cutaneous blockade and axillary brachial plexus block,

skin puncture was generally performed once, although

skin puncture was performed twice in patients where

the musculocutaneous nerve was identified in a deep

position or with a large muscle bulk. Using real-time

ultrasound guidance, a 22-G, 60-mm stimulating nee-

dle (Stimuplex�D; B.Braun AG, Melsungen, Germany)

was advanced in-plane initially towards the musculo-

cutaneous nerve. A nerve stimulator (MultiStim SEN-

SOR; PAJUNK�GmbH Medizintechnologie, Geisingen,

Germany) was used to localise the nerves using an

electrical current of 0.3–0.5 mA while observing

twitches of the corresponding muscle, and 5–7 ml

ropivacaine 0.5% with or without hylauronidase was

injected around the nerve. The needle was then

advanced to a four to six o’clock position (radial

nerve) relative to the axillary artery and after confir-

mation by nerve stimulation, 5–10 ml local anaesthetic

was delivered. The needle was withdrawn and

advanced to the two (ulnar nerve) and 10 (median

nerve) o’clock positions and 5–7 ml local anaesthetic

was sequentially injected in both positions [6, 13].

All surgery was performed with axillary brachial

plexus block as the sole anaesthetic technique. The need

for a supplementary block or conversion to general

anaesthesia was determined by the attending anaesthe-

tist 30 min after the last local anaesthetic injection. Dur-

ing the 30-min observation period, any signs of systemic

local toxicity were observed and managed (if present).

The surgeon, blinded to the treatment group, deter-

mined the need for additional local anaesthetic infiltra-

tion at the surgical site. After the operation, patients

were taken to the post-anaesthetic care unit for recovery

and then moved to a general ward or discharged.

© 2014 The Association of Anaesthetists of Great Britain and Ireland 283

Koh et al. | Hyaluronidase for axillary block Anaesthesia 2015, 70, 282–289

During block insertion, the needling time, the time

interval between skin infiltration and the last local

anaesthetic injection, was recorded. Immediately after

the block, sensory and motor blockade was assessed in

the distribution of the median, radial, ulnar and mus-

culocutaneous nerves [6, 13]. These were checked from

time 0 (immediately after the block needle exit from

the skin) to 2, 5, 7, 10, 15, 20, 25 and 30 min after the

block. The sensory block was graded on a 3-point scale

(2 = normal sensation, 1 = reduced and 0 = absent)

compared relative to the pinprick sensation of the cor-

responding areas of the contralateral arm. Time to

achieve complete sensory block (the primary outcome

of this study) was defined as the time to reach an

absent sensation in the pinprick test at all four nerve

distributions (or time to reach point 0 in the sensory

block grade). The motor block was also graded on a 3-

point scale (2 = normal, 1 = reduced power, and

0 = paralysis). The maximal sensory score and motor

score were each 8 points, and thus the total sensorimo-

tor score was 16 points. Patients were considered to

have achieved surgical anaesthesia when the total

composite score was ≤ 2 points, with a concomitant

sensory score ≤ 1 point. Total performance time was

defined as the sum of the time to achieve surgical

anaesthesia and needling time. The total dose of ropi-

vacaine for anaesthesia was recorded. All data were

recorded by an observer blinded to the composition of

the injected local anaesthetic solution.

During surgery, additional midazolam or fentanyl

was administered at the discretion of the attending an-

aesthetist and the total injected dose was recorded. No

patients received sedatives other than midazolam or

opioids other than fentanyl during the operation. Post-

operatively, patients received 325 mg paracetamol and

37.5 mg tramadol orally. Intravenous patient-con-

trolled fentanyl analgesia was applied on demand in

patients who underwent surgery involving bone struc-

tures. For rescue analgesia, intravenous tramadol or

hydromorphone was administered if necessary, and the

time to request first-rescue analgesia (which was

defined as the analgesic duration) was recorded. The

duration of the sensory and motor block was checked

every 2 h after operation by the nursing staff, who

were blinded to the study at the post-anaesthetic care

unit or general ward, and the time of complete

sensorimotor recovery was recorded. The duration of

sensory block was defined as the interval between the

last local anaesthetic injection and the complete resolu-

tion of sensation to pinprick in all four territories,

when the total sensory score reached 8 points in the 3-

point scale. The duration of motor block was defined

as the interval between the last local anaesthetic injec-

tion and the recovery of complete motor function in

the hand and forearm, when the total motor score

reached 8 points in the 3-point scale. The intensity of

postoperative pain was examined by nursing staff 8, 16

and 24 h after the operation using an 11-point numer-

ical rating scale (NRS) [14]. The total dose of intrave-

nous tramadol and opioid was recorded (in morphine

equivalents) during a 24-h postoperative period. Upon

discharge, patients were asked to rate their experience

of the anaesthesia using a 7-point Likert scale ques-

tionnaire (7 = very satisfied, 4 = fair, and

1 = extremely unsatisfied) [15]. After discharge,

patients revisited the outpatient clinic at postoperative

day 15 and were asked about complications including

numbness, paraesthesia, altered sensations, pain and

motor deficits (unrelated to the surgery).

The primary endpoint was the time to achieve

complete sensory block. Secondary outcomes were nee-

dling time, the time to achieve surgical anaesthesia,

total performance time, intra-operative and postopera-

tive analgesic requirements, analgesic duration, sensory

and motor block duration, postoperative pain scores

and patient satisfaction with anaesthesia.

The sample size calculation was based on the

primary endpoint. A preliminary test with 10 patients

in each group (the observer was not blinded) was

performed, and a difference of 7 min in time to

achieve complete sensory block was observed between

the two groups with a SD of 7 min. For a two-tailed

t-test with a error of 0.05 and b error of 0.1, 23

patients were required in each group. Twenty-five

patients were enrolled per group, after assuming a 10%

dropout rate due to block failure or complications.

Descriptive statistics and secondary outcome vari-

ables were compared using t-tests. The Mann–Whitney

U-test was used for continuous variables and the chi-

squared test with Yates’ correction or Fisher’s exact

test was used for categorical variables. Continuous

variables were all first assessed for normality using the


Anaesthesia 2015, 70, 282–289 Koh et al. | Hyaluronidase for axillary block

Shapiro–Wilk test. To compare the time to achieve

complete sensory block, time to achieve surgical anaes-

thesia and the proportion of patients not requiring

postoperative analgesics as a time-to-event analysis, the

log rank test was used and a Kaplan–Meier survival

curve was obtained. A value of p < 0.05 was consid-

ered significant and two-sided tests were used for all

experimental outcomes. SigmaPlot version 12.0 (Sistat

Software Inc, Richmond, CA, USA) was used for sta-

tistical analysis.

ResultsBetween November 2013 and March 2014, 80 patients

who presented for elective hand or forearm surgery

were screened for eligibility. Eighteen patients met the

exclusion criteria and nine patients refused to partici-

pate, while 53 patients agreed to participate in the

study. A further three patients were removed as they

received general anaesthesia due to surgical require-

ment for iliac bone grafts. One patient in the control

group required conversion to general anaesthesia

because of an incomplete block, while one patient in

the hyaluronidase group showed signs of mild systemic

local toxicity a few minutes after local anaesthetic

injection and was given additional midazolam, making

any further data collection impossible due to overseda-

tion. As a consequence, 24 patients who successfully

completed the study protocol were enrolled in each

group. There were no differences in patient and surgi-

cal characteristics between the two study groups

(Table 1). The site of surgery (bone or soft tissue) was

evenly distributed between the two study groups.

Time to achieve complete sensory block, time to

reach surgical anaesthesia and the total performance

time were significantly lower in the hyaluronidase

group (Table 2, Fig. 1). There was no difference in

Table 1 Characteristics of patients receiving axillary brachial plexus block with and without hyaluronidase, and thesurgery undergone. Values are number (proportion) or mean (SD).

Hyaluronidase(n = 24)

Control(n = 24)

Sex; M:F 9 (37.5%):15 (62.5%) 14 (58.3%):10 (41.7%)Age; years 55.1 (14.1) 54.6 (17.2)Height; cm 160.1 (10.1) 162.0 (10.8)Weight; kg 64.3 (12.1) 64.4 (14.4)SurgeryLeft:right 10 (41.7%):14 (58.3%) 12 (50%):12 (50%)Hand:forearm 7 (29.2%):17 (70.8%) 8 (33.3%):16 (66.7%)Soft tissue:bone 11 (45.8%):13 (54.2%) 11 (45.8%):13 (54.2%)Duration of surgery; min 70.7 (32.6) 74 (35.2)

Table 2 Block performance and placement details for patients receiving axillary brachial plexus block with and with-out hyaluronidase. Values are median (IQR [range]), mean (SD) or number (proportion).


Control(n = 24) p value

Needling time; min 6 (5–6.75 [4–9]) 5.5 (4–7 [4–10]) 0.776Time to achieve complete sensory block; min 13.8 (6.0) 22.5 (6.3) < 0.0001Time to achieve surgical anaesthesia; min 15.6 (6.3) 22.5 (6.9) 0.00074Total performance time; min 21.8 (6.2) 29.9 (5.8) < 0.0001Patients under surgical anaesthesia after 30 min 23 (95.8%) 20 (83.3%) 0.348Patients with supplemental blocks 1 2 (0.1%) 1.000Conversion into general anaesthesia 0 1 1.000Total administered fentanyl; lg 54.2 (14.1) 57.3 (17.3) 0.419Total administered midazolam; mg 3.3 (0.9) 3.2 (1.1) 0.726Total administered ropivacaine; mg.kg�1 2.2 (0.5) 2.2 (0.5) 0.617Total administered ropivacaine; mg 138.8 (16.7) 134.8 (18.8) 0.450



needling time, the number of patients under surgical

anaesthesia after 30 min or the number of patients

who required supplemental blocks (Table 2). The total

amount of fentanyl, midazolam and ropivacaine

administered was similar between the two groups

(Table 2).

The duration of the sensory block was shorter in

the hyaluronidase group than in the control group

(Table 3). The duration of the motor block was also

shorter in the hyaluronidase group, but it did not

show statistical significance. The analgesic duration

was shorter in the hyaluronidase group, but it did not

show statistical significance and the numbers of

patients requiring rescue analgesics and the total

postoperative opioid and non-opioid analgesic con-

sumption were not significantly different between the

two groups (Table 3, Fig. 2). Postoperative NRS pain

scores were not significantly different at any of the

(a) (b)

Figure 1 Kaplan–Meier survival plot of proportion of patients who achieved (a) a complete sensory block and (b)surgical anaesthesia after axillary brachial plexus block with (solid line) and without (dashed line) hyaluronidase.p < 0.001 vs control.

Table 3 Block duration, analgesic duration, postoperative analgesic requirements, and patient satisfaction with anaes-thesia after axillary brachial plexus block with and without hyaluronidase. Values are mean (SD) or number (propor-tion).


Control(n = 24) p value

Block duration; minDuration of sensory block 535.9 (200.2) 671.7 (148.1) 0.010Duration of motor block 558.4 (235.4) 670.4 (218.7) 0.094Analgesic duration 610.2 (237.4) 759 (206.2) 0.074

Postoperative (24 h) analgesic requirementsPatients with rescue analgesics 18 (75%) 17 (70.8%) 1.000Patients with rescue opioids 11 (45.8%) 9 (37.5%) 0.770Patients with tramadol 17 (70.8%) 13 (54.2%) 0.371Patients with patient controlled analgesia 10 (41.7%) 8 (33.3%) 0.766Mean intravenous tramadol; mg 47.9 (37.5) 37.5 (39.7) 0.332Mean opioid use in morphine equivalents; mg 19.6 (24.4) 13.5 (20) 0.490

Patient satisfaction with anaesthesiaGlobal perceived effect scale 6.75 (0.44) 6.42 (0.97) 0.259



time points (8, 16 and 24 h) examined. Overall satis-

faction ratings for anaesthesia and analgesia were

excellent for both groups (Table 3), and no patients in

either group reported significant neurological symp-

toms or possible complications during admission, after

discharge or at the revisit to the clinic.

DiscussionIn the present study, the addition of 100 IU.ml�1 of

hyaluronidase to ropivacaine 0.5% significantly short-

ened the time to achieve complete sensory block and

surgical anaesthesia, therefore reducing the anaesthetic

time before the start of the operation. The number of

patients requiring supplementary block or additional

analgesia was similar between the two groups. The use

of hyaluronidase reduced the duration of the sensory

block. The duration of motor block and ropivacaine

brachial plexus block analgesia were also reduced, but

this did not achieve statistical significance. There was

no difference in the total administered dose of postop-

erative analgesic medication.

Reducing the time to reach complete sensory block

has practical advantages, as the turnover time between

operations can be optimised and operation rooms can

be used more efficiently, especially in circumstances in

which there is no separate clinical area to perform a

block [9]. If establishment of a sensory block is pro-

longed, local anaesthetic block may be harder to justify

than general anaesthesia, especially for minor surgery

or in outpatient settings [8]. As a result, many strate-

gies to reduce the total time to reach complete sensory

block during peripheral nerve blocks have been stud-

ied. These strategies include increasing the injection

volume or concentration of local anaesthetics, multiple

injection techniques, alkalinisation of injectate, com-

bining different local anaesthetics or adding adjuvants

such as dexamethasone, dexmedetomidine, clonidine

and magnesium to the local anaesthetic. Alkalinisation

of local anaesthetics has revealed conflicting study

results for hastening the onset of brachial plexus block,

and mixtures of different local anaesthetics have addi-

tive effects in toxicity [16–19]. Some studies that used

dexmedetomidine and clonidine as adjuvants reported

favourable outcomes in terms of reduced total perfor-

mance time [20–22], but most other adjuvants have

failed to demonstrate any superiority over control. A

previous study reported the effect of the addition of

hyaluronidase to bupivacaine 0.5% for axillary brachial

plexus blocks [23]. In that study, 3000 IU hyaluroni-

dase mixed with bupivacaine significantly reduced the

duration of the sensory and motor block, and had no

effect on the number of patients experiencing a com-

plete sensory block after 30 min. These results were

similar to those obtained in the present study, as suc-

cess rates for surgical anaesthesia were similar between

the two experimental groups tested, while the duration

of sensory anaesthesia was significantly shorter in the

hyaluronidase group and the duration of motor block

showed a shorter trend. However, the former study

performed pinprick tests only twice, at 15 and 30 min

after the block placement, so the exact time of com-

plete sensory block was not measured. Furthermore,

the block was conducted via the landmark-guided

technique without the use of a nerve stimulator or

ultrasound guidance, which may have led to the rela-

tively lower block success rate for radial nerve com-

pared with that in our study.

Hyaluronidase is widely used as an adjuvant to

local anaesthetics in regional anaesthesia for ophthal-

mic surgery, where it can reduce onset time and

Figure 2 Kaplan–Meier survival plot of analgesicduration after axillary brachial plexus block with (solidline) and without (dashed line) hyaluronidase. Datapoints were not studied if the patient did not receiverescue analgesics. No significant difference betweengroups.



increase the success rate [24, 25]. A number of studies

have shown that addition of hyaluronidase during

ocular blocks has beneficial effects including higher

quality of anaesthesia and improved success rates [24].

Hyaluronidase has also been used for epidural injec-

tions with local anaesthetics and steroids for control of

chronic back pain [26, 27]. The optimal dose of

hyaluronidase is unknown. For ocular surgery, the

concentration of hyaluronidase varies from 3.75 to

300 IU.ml�1 for effective retrobulbar or peribulbar

blocks [25, 28], and for epidural blocks or adhesiolysis

the commonly used dose is 1500 IU [12, 27]. Reports

of adverse effects associated with hylauronidase are

rare, with most reported adverse effects involving aller-

gic reactions to hyaluronidase [24, 29, 30]. No adverse

effects were associated with the use of hyaluronidase

in the present study.

This study has a number of limitations. The time

required to achieve a satisfactory ultrasound image of

the target area was not recorded, although the block

was performed by a single blinded practitioner, and

only a minimal variation in scanning time was

expected. Second, the validity of the 16-point scale to

define surgical anaesthesia can be criticised, as even if

the sensory composite score is 1, a supplementary block

or local infiltration may be required if the incompletely

blocked nerve was the main site of the operation. How-

ever, the 16-point scale has proven to be a useful

method for surgical anaesthesia after brachial plexus

block in many previous studies [6, 8, 21, 31], and none

of the patients who met the criteria for surgical anaes-

thesia in the present study required a supplementary

block or local infiltration. Third, although no adverse

events related to the use of hyaluronidase were reported

during this study, we could not present any definitive

conclusions about the tolerance to hyaluronidase when

used during axillary brachial plexus block as the sample

size was relatively small.

In conclusion, the present study shows that the

use of hyaluronidase as an adjuvant to ropivacaine

reduces the time to reach complete sensory block of

axillary brachial plexus blocks and therefore shortens

the total anaesthetic time before operation. Although it

also reduces the block duration, hyaluronidase had

only a small influence on the total analgesic duration

or the consumption of postoperative analgesics.

Competing interestsNo external funding or competing interests declared.

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