Anaesthesia 2015, 70, 282289

doi:10.1111/anae.12879

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 Pain
Medicine, University of Ulsan, Asan Medical Center, Seoul, Korea

Summary
When 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 hyaluronidase 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 signicantly 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 hyaluronidase to ropivacaine resulted in a reduction in the time needed to achieve complete sensory block.
.................................................................................................................................................................

Correspondence to: H. G. Min

Email: anesthmin@hanmail.net
Accepted: 20 August 2014

Introduction
Brachial 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 provides anaesthesia suitable for surgery performed on the
forearm [3, 4]. The axillary brachial plexus is supercial 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 brachial plexus blocks, yielding higher success rates with a
reduced number of needle passes [6, 7]. Time to
282

achieve complete sensory block is clinically important,

as it may inuence 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, hyaluronidase is known to accelerate the onset and improve the
quality of anaesthesia for retrobulbar, peribulbar and
subcutaneous inltration blocks by increasing the
spread and dispersion of local anaesthetics [1012].
In the present study, we hypothesised that addition of hyaluronidase to a local anaesthetic would
reduce the time to achieve complete sensory block of
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Koh et al. | Hyaluronidase for axillary block

an axillary brachial plexus block compared with that

of the local anaesthetic alone.

Methods
This prospective, randomised, double-blind, singlecentre 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
classied as ASA physical status 12 were considered
eligible for inclusion in the study. Patients presenting
with neurological decits of the upper arm, severe coagulopathy, chronic obstructive pulmonary disease,
cardiopulmonary compromise, chronic renal failure,
cerebral vascular disease, pregnancy, chronic corticosteroid 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 unidentiable 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 rst author (WUK). Patients were not premedicated and standard monitors including electrocardiography, 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 during the block procedure.
Subjects were positioned supine with the head
turned to the contralateral side and the ipsilateral arm
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Anaesthesia 2015, 70, 282289

abducted with the elbow exed. The skin was disinfected and inltrated with lidocaine 1% before block needle 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 musculocutaneous 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 identied in a deep
position or with a large muscle bulk. Using real-time
ultrasound guidance, a 22-G, 60-mm stimulating needle (StimuplexD; B.Braun AG, Melsungen, Germany)
was advanced in-plane initially towards the musculocutaneous nerve. A nerve stimulator (MultiStim SENSOR; PAJUNKGmbH Medizintechnologie, Geisingen,
Germany) was used to localise the nerves using an
electrical current of 0.30.5 mA while observing
twitches of the corresponding muscle, and 57 ml
ropivacaine 0.5% with or without hylauronidase was
injected around the nerve. The needle was then
advanced to a four to six oclock position (radial
nerve) relative to the axillary artery and after conrmation by nerve stimulation, 510 ml local anaesthetic
was delivered. The needle was withdrawn and
advanced to the two (ulnar nerve) and 10 (median
nerve) oclock positions and 57 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 anaesthetist 30 min after the last local anaesthetic injection. During the 30-min observation period, any signs of systemic
local toxicity were observed and managed (if present).
The surgeon, blinded to the treatment group, determined the need for additional local anaesthetic inltration 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.
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Anaesthesia 2015, 70, 282289

During block insertion, the needling time, the time

interval between skin inltration 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 musculocutaneous 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 corresponding areas of the contralateral arm. Time to
achieve complete sensory block (the primary outcome
of this study) was dened 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 3point scale (2 = normal, 1 = reduced power, and
0 = paralysis). The maximal sensory score and motor
score were each 8 points, and thus the total sensorimotor 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
dened as the sum of the time to achieve surgical
anaesthesia and needling time. The total dose of ropivacaine 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 anaesthetist and the total injected dose was recorded. No
patients received sedatives other than midazolam or
opioids other than fentanyl during the operation. Postoperatively, patients received 325 mg paracetamol and
37.5 mg tramadol orally. Intravenous patient-controlled fentanyl analgesia was applied on demand in
patients who underwent surgery involving bone structures. For rescue analgesia, intravenous tramadol or
hydromorphone was administered if necessary, and the
time to request rst-rescue analgesia (which was
dened 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
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Koh et al. | Hyaluronidase for axillary block

sensorimotor recovery was recorded. The duration of

sensory block was dened as the interval between the
last local anaesthetic injection and the complete resolution of sensation to pinprick in all four territories,
when the total sensory score reached 8 points in the 3point scale. The duration of motor block was dened
as the interval between the last local anaesthetic injection 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 numerical rating scale (NRS) [14]. The total dose of intravenous 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 questionnaire
(7 = very
satised,
4 = fair,
and
1 = extremely unsatised) [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 decits (unrelated to the surgery).
The primary endpoint was the time to achieve
complete sensory block. Secondary outcomes were needling time, the time to achieve surgical anaesthesia,
total performance time, intra-operative and postoperative 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-ve
patients were enrolled per group, after assuming a 10%
dropout rate due to block failure or complications.
Descriptive statistics and secondary outcome variables were compared using t-tests. The MannWhitney
U-test was used for continuous variables and the chisquared test with Yates correction or Fishers exact
test was used for categorical variables. Continuous
variables were all rst assessed for normality using the
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Anaesthesia 2015, 70, 282289

ShapiroWilk test. To compare the time to achieve

complete sensory block, time to achieve surgical anaesthesia and the proportion of patients not requiring
postoperative analgesics as a time-to-event analysis, the
log rank test was used and a KaplanMeier survival
curve was obtained. A value of p < 0.05 was considered signicant and two-sided tests were used for all
experimental outcomes. SigmaPlot version 12.0 (Sistat
Software Inc, Richmond, CA, USA) was used for statistical analysis.

received general anaesthesia due to surgical requirement 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 oversedation. As a consequence, 24 patients who successfully
completed the study protocol were enrolled in each
group. There were no differences in patient and surgical 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 signicantly lower in the hyaluronidase
group (Table 2, Fig. 1). There was no difference in

Results
Between 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 participate, while 53 patients agreed to participate in the
study. A further three patients were removed as they

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

Sex; M:F
Age; years
Height; cm
Weight; kg
Surgery
Left:right
Hand:forearm
Soft tissue:bone
Duration of surgery; min

Hyaluronidase
(n = 24)

Control
(n = 24)

9
55.1
160.1
64.3

(37.5%):15 (62.5%)
(14.1)
(10.1)
(12.1)

14
54.6
162.0
64.4

(58.3%):10 (41.7%)
(17.2)
(10.8)
(14.4)

10
7
11
70.7

(41.7%):14 (58.3%)
(29.2%):17 (70.8%)
(45.8%):13 (54.2%)
(32.6)

12
8
11
74

(50%):12 (50%)
(33.3%):16 (66.7%)
(45.8%):13 (54.2%)
(35.2)

Table 2 Block performance and placement details for patients receiving axillary brachial plexus block with and without hyaluronidase. Values are median (IQR [range]), mean (SD) or number (proportion).

Needling time; min

Time to achieve complete sensory block; min
Time to achieve surgical anaesthesia; min
Total performance time; min
Patients under surgical anaesthesia after 30 min
Patients with supplemental blocks
Conversion into general anaesthesia
Total administered fentanyl; lg
Total administered midazolam; mg
Total administered ropivacaine; mg.kg 1
Total administered ropivacaine; mg

2014 The Association of Anaesthetists of Great Britain and Ireland

Hyaluronidase
(n = 24)

Control
(n = 24)

p value

6
13.8
15.6
21.8
23
1
0
54.2
3.3
2.2
138.8

5.5
22.5
22.5
29.9
20
2
1
57.3
3.2
2.2
134.8

0.776
< 0.0001
0.00074
< 0.0001
0.348
1.000
1.000
0.419
0.726
0.617
0.450

(56.75 [49])
(6.0)
(6.3)
(6.2)
(95.8%)

(14.1)
(0.9)
(0.5)
(16.7)

(47 [410])
(6.3)
(6.9)
(5.8)
(83.3%)
(0.1%)
(17.3)
(1.1)
(0.5)
(18.8)

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Anaesthesia 2015, 70, 282289

(a)

Koh et al. | Hyaluronidase for axillary block

(b)

Figure 1 KaplanMeier 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.
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 signicance. The analgesic duration
was shorter in the hyaluronidase group, but it did not
show statistical signicance and the numbers of
patients requiring rescue analgesics and the total
postoperative opioid and non-opioid analgesic consumption were not signicantly different between the
two groups (Table 3, Fig. 2). Postoperative NRS pain
scores were not signicantly different at any of the

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

Block duration; min

Duration of sensory block
Duration of motor block
Analgesic duration
Postoperative (24 h) analgesic requirements
Patients with rescue analgesics
Patients with rescue opioids
Patients with tramadol
Patients with patient controlled analgesia
Mean intravenous tramadol; mg
Mean opioid use in morphine equivalents; mg
Patient satisfaction with anaesthesia
Global perceived effect scale

286

Hyaluronidase
(n = 24)

Control
(n = 24)

p value

535.9 (200.2)
558.4 (235.4)
610.2 (237.4)

671.7 (148.1)
670.4 (218.7)
759 (206.2)

0.010
0.094
0.074

18
11
17
10
47.9
19.6

(75%)
(45.8%)
(70.8%)
(41.7%)
(37.5)
(24.4)

6.75 (0.44)

17
9
13
8
37.5
13.5

(70.8%)
(37.5%)
(54.2%)
(33.3%)
(39.7)
(20)

6.42 (0.97)

1.000
0.770
0.371
0.766
0.332
0.490
0.259

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Koh et al. | Hyaluronidase for axillary block

Figure 2 KaplanMeier survival plot of analgesic

duration after axillary brachial plexus block with (solid
line) and without (dashed line) hyaluronidase. Data
points were not studied if the patient did not receive
rescue analgesics. No signicant difference between
groups.
time points (8, 16 and 24 h) examined. Overall satisfaction ratings for anaesthesia and analgesia were
excellent for both groups (Table 3), and no patients in
either group reported signicant neurological symptoms or possible complications during admission, after
discharge or at the revisit to the clinic.

Discussion
In the present study, the addition of 100 IU.ml 1 of
hyaluronidase to ropivacaine 0.5% signicantly shortened 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 signicance. There was
no difference in the total administered dose of postoperative 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
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Anaesthesia 2015, 70, 282289

be used more efciently, especially in circumstances in

which there is no separate clinical area to perform a
block [9]. If establishment of a sensory block is prolonged, local anaesthetic block may be harder to justify
than general anaesthesia, especially for minor surgery
or in outpatient settings [8]. As a result, many strategies to reduce the total time to reach complete sensory
block during peripheral nerve blocks have been studied. These strategies include increasing the injection
volume or concentration of local anaesthetics, multiple
injection techniques, alkalinisation of injectate, combining different local anaesthetics or adding adjuvants
such as dexamethasone, dexmedetomidine, clonidine
and magnesium to the local anaesthetic. Alkalinisation
of local anaesthetics has revealed conicting study
results for hastening the onset of brachial plexus block,
and mixtures of different local anaesthetics have additive effects in toxicity [1619]. Some studies that used
dexmedetomidine and clonidine as adjuvants reported
favourable outcomes in terms of reduced total performance time [2022], 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 hyaluronidase mixed with bupivacaine signicantly reduced the
duration of the sensory and motor block, and had no
effect on the number of patients experiencing a complete sensory block after 30 min. These results were
similar to those obtained in the present study, as success rates for surgical anaesthesia were similar between
the two experimental groups tested, while the duration
of sensory anaesthesia was signicantly 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 complete 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 relatively lower block success rate for radial nerve compared with that in our study.
Hyaluronidase is widely used as an adjuvant to
local anaesthetics in regional anaesthesia for ophthalmic surgery, where it can reduce onset time and
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Anaesthesia 2015, 70, 282289

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

have shown that addition of hyaluronidase during
ocular blocks has benecial effects including higher
quality of anaesthesia and improved success rates [24].
Hyaluronidase has also been used for epidural injections 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 allergic 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
dene surgical anaesthesia can be criticised, as even if
the sensory composite score is 1, a supplementary block
or local inltration may be required if the incompletely
blocked nerve was the main site of the operation. However, 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 anaesthesia in the present study required a supplementary
block or local inltration. Third, although no adverse
events related to the use of hyaluronidase were reported
during this study, we could not present any denitive
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 inuence on the total analgesic duration
or the consumption of postoperative analgesics.
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Koh et al. | Hyaluronidase for axillary block

Competing interests
No external funding or competing interests declared.

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