Anaesthesia 2012 doi:10.1111/j.1365-2044.2012.07102.

Original Article
A randomised controlled trial comparing rocuronium priming,
magnesium pre-treatment and a combination of the two methods*
M. H. Kim,1 A. Y. Oh,2 Y. T. Jeon,3 J. W. Hwang3 and S. H. Do4

1 Full-time Instructor, 2 Assistant Professor, 3 Associate Professor, 4 Professor, Department of Anesthesiology and Pain
Medicine, Seoul National University, Bundang Hospital, South Korea

Summary
We investigated whether magnesium sulphate combined with rocuronium priming shortens the onset of neuromuscular
blockade, compared with these methods used alone. Ninety-two patients scheduled for general anaesthesia
were randomly allocated to one of four groups: controls were given 0.6 mg.kg)1 rocuronium; patients in the prime
group were given 0.06 mg.kg)1 rocuronium three minutes before a further dose of 0.54 mg.kg)1 rocuronium; patients in
the magnesium group were given an infusion of 50 mg.kg)1 magnesium sulphate before rocuronium and patients in the
magnesium and prime group were given both the magnesium sulphate and the priming dose of rocuronium. Tracheal
intubation was attempted 40 s after the rocuronium injection. The time to onset of neuromuscular blockade was the
primary outcome; duration of blockade and tracheal intubating conditions were also measured. The group allocation and
study drugs were coded and concealed until statistical analyses were completed. The magnesium and prime group had
the shortest mean (SD) onset time (55 (16) s; p < 0.001), and best tracheal intubating conditions (p < 0.05). No
statistical difference was found for the duration of blockade. As for adverse events, a burning or heat sensation was
reported in eight (35%) and six (26%) patients in the magnesium and magnesium and prime groups, respectively. The
combination of magnesium sulphate and rocuronium priming accelerated the onset or neuromuscular blockade and
improved rapid-sequence intubating conditions, compared with either magnesium sulphate or priming used alone.
. ..............................................................................................................................................................
Correspondence to: Dr S. H. Do
Email: shdo@snu.ac.kr
*Presented in part at the Annual Scientific Meeting of the Korean Society of Anesthesiologists, Seoul, South Korea,
November 2011.
Accepted: 27 January 2012

Rapid-sequence intubation and resistance to neuromus-
cular blocking drugs are clinical situations in which
producing sufficient neuromuscular blockade for tra-
cheal intubation may be difficult [1, 2]. In such cases, the
depth of neuromuscular block at the time of tracheal
intubation can be inadequate, because insufficient time
has been allowed for the drugs to take effect. Inadequate
neuromuscular blockade may lead to failure of the vocal
cords to open fully, failed tracheal intubation [3], and
poor intubating conditions [4], which can cause
laryngeal injury, vocal cord morbidity and postoperative
hoarseness [5].
Suxamethonium is generally considered to be the
drug of choice when rapid neuromuscular block is
required [6]. However, it is associated with a number of
serious complications and contraindications, leading to

Anaesthesia ª 2012 The Association of Anaesthetists of Great Britain and Ireland 1

Anaesthesia 2012
various attempts to accelerate the onset of available non-
depolarising neuromuscular blocking drugs (NBDs) [6].
In this regard, the use of a large dose of rocuronium has
been suggested [6], but rocuronium may have a ceiling
effect for onset time [1]. Increasing the dose of
rocuronium beyond a particular amount does not
always guarantee a shortened onset time [1], and it
markedly prolongs the duration of action [1, 6]. Opioids
can be used to improve tracheal intubating conditions
without increasing the NDMR dose, thus avoiding
delayed recovery; however, this may be associated with
a higher incidence of failed tracheal intubation [6].
Injecting a small priming dose of NDMR before
administration of the full intubation dose has been
shown to speed up onset [7] without delaying recovery
[8]. Despite concerns for potential muscle weakness
produced by such a priming dose, this has been
investigated in a number of recent studies [7, 9–12].
Another method is the use of magnesium sulphate,
which can accelerate the onset of neuromuscular
blockade produced by rocuronium; the mechanism is
thought to be mainly by decreasing the presynaptic
release of acetylcholine [13].
In the present study, we combined magnesium
sulphate and a priming technique to investigate whether
this could further accelerate the onset of neuromuscular
blockade during rapid-sequence intubation. Secondary
outcomes included duration of neuromuscular blockade
and tracheal intubating conditions.
Methods
This double-blind randomised controlled study was
approved by the Institutional Review Board of Seoul
National University Bundang Hospital. Written in-
formed consent was obtained from all participating
patients; inclusion criteria were: age 18–65 years; ASA
physical status 1–2; body mass index 18.5–24.9 kg.m)2;
Mallampati grade 1–2; and elective surgery under
general anaesthesia (Fig. 1). Patients with neuromuscu-
lar disease, renal or hepatic insufficiency, allergy to the
study drugs, drugs that might influence neuromuscular
function, breast-feeding or pregnancy, and an antici-
pated difficult airway were excluded.
After connecting routine monitoring, including
electrocardiography, pulse oximetry, and non-invasive
blood pressure, patients were allocated in equal numbers
2 Anaesthesia ª 2012 The Association of Anaesthetists of Great Britain and Ireland
Kim et al. | Rocuronium priming versus magnesium
to one of four parallel groups using opaque sealed
envelopes: control; prime; magnesium; and magnesium
and prime. The group allocation and names were coded
and concealed until completion of the statistical analysis.
Magnesium, and magnesium and prime groups received
an intravenous infusion of 50 mg.kg)1 magnesium
sulphate over 10 min. Control and prime groups were
given the same volume of 0.9% saline. Neuromuscular
monitoring, adhering to the neuromuscular research
consensus [14], was performed with TOF-Watch SX
(Organon Ltd., Dublin, Ireland) after 0.04 mg.kg)1
midazolam was administered intravenously. Two pae-
diatric surface electrodes were attached 3–6 cm apart
along the ulnar nerve on one forearm without a blood
pressure cuff or intravenous cannula on this side. A
hand adapter (Organon) was placed on the thumb, and
the other fingers and forearm were immobilised. Single
twitches (0.1 Hz, stimulus duration of 200 ls, square
wave) were performed every 10 s, after calibration (with
implanted mode 2) and confirmation of stable twitches
(< 5% deviation, for 2 min).
Subsequently, 0.06 mg.kg)1 rocuronium (prime,
and magnesium and prime groups) or the same volume
of 0.9% saline (control and magnesium groups) was
administered. Propofol (2 mg.kg)1), remifentanil
(1 lg.kg)1) [15], and rocuronium (0.6 mg.kg)1 (mag-
nesium and control groups) or 0.54 mg.kg)1, diluted in
0.9% saline to a volume equal to 0.6 mg.kg)1 rocuro-
nium (prime, and magnesium and prime groups)) were
injected in rapid succession, 170 s after the priming
dose.
The time from injection of rocuronium (0.6 or
0.54 mg.kg)1) to 95% depression of the single twitch
(onset time) and return of adequate neuromuscular
transmission as measured by train-of-four (TOF) equal
to two (duration of neuromuscular blockade) were
measured. The stimulation mode was changed to TOF
(2 Hz, stimulus duration of 200 ls, square wave, 15-s
intervals) after measuring the onset time. Laryngoscopy
for tracheal intubation was commenced 40 s after the
injection of rocuronium, intubation was completed
within 20 s, and the intubation score (Appendix) [14]
was assessed by an experienced anaesthetist who was
blinded to the study drugs. If tracheal intubation was not
successfully completed within 20 s (i.e. 60 s after the
rocuronium), it was recorded as a failed attempt. After
Kim et al. | Rocuronium priming versus magnesium
Figure 1 Flow chart for enrolment and allocation.
intubation, total intravenous anaesthesia was maintained
with a target-controlled infusion of propofol and
remifentanil, titrated to maintain a bispectral index
between 40 and 60, with < 20% variation in baseline
mean arterial pressure and heart rate.
Patient temperature was maintained at > 35 C
measured using a rectal probe and > 32 C measured by
a skin probe at the hypothenar eminence. Controlled
ventilation with 50% oxygen in air was used to maintain
the end-tidal CO2 at 4.7–5.3 kPa.
Enrolment of patients, preparation of opaque sealed
envelopes, preparation and administration of drugs, and
collection and analysis of data were performed by
doctors, nurses, and research assistants who were
blinded to the study drugs.
Sample size calculation was based on a previous
study in which mean (SD) onset time using 0.6 mg.kg)1
rocuronium was 105.4 (29.9) s with the priming tech-
nique [7] and 77 (18) s with magnesium sulphate pre-
treatment [13]. We decided to look for a 20% reduction
in onset time in the magnesium and prime group
compared with both magnesium and prime groups
respectively. We calculated that we would therefore need
Anaesthesia ª 2012 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia 2012
23 patients in each group, using a two-sided test with
a = 0.05 and b = 0.2, allowing for 10% drop-outs.
The distributions of all data were assessed with the
Kolmogorov–Smirnov test; ANOVA (Welch’s ANOVA
in case of different variances) with a Bonferroni post-
hoc comparison or Kruskal–Wallis test (for skewed
data) was used for comparison of onset and duration of
neuromuscular blockade. The chi-squared or Fisher’s
exact test was used for comparing tracheal intubating
conditions. All statistical analyses were performed using
PASW Statistics 17, release version 17.0.2 (SPSS, Inc.,
Chicago IL, USA).
Results
All datasets were normally distributed. There were no
differences in mean arterial blood pressure or heart rate
between the groups at baseline or at the time of
rocuronium injection (Table 1).
The onset time was shortest in the magnesium and
prime group (p < 0.001) (Table 2). No significant dif-
ference was observed for duration of neuromuscular
blockade between the groups (p = 0.054) (Table 2). The
absolute value of the SD for the onset time was smallest
3
Anaesthesia 2012 Kim et al. | Rocuronium priming versus magnesium

Table 1 Patients’ characteristics and haemodynamic data in patients randomly allocated to rocuronium alone (Control),
priming with rocuronium, magnesium pre-treatment and a combination of rocuronium priming and magnesium. Data
are mean (SD) or number (proportion).

Control Prime Magnesium Magnesium and prime

(n = 23) (n = 23) (n = 23) (n = 23)
Age; years 39 (12) 46 (13) 46 (12) 41 (13)
Men 9 (39%) 8 (35%) 10 (43%) 10 (43%)
Weight; kg 58 (10) 59 (6) 56 (8) 61 (9)
Height; cm 163 (8) 163 (7) 160 (7) 164 (8)
BMI; kg.m)2 21.6 (2.0) 22.0 (1.4) 22.0 (2.3) 22.6 (1.9)
ASA status 1 or 2 22 (96%) 20 (87%) 21 (91%) 20 (87%)
MAP at baseline 84 (11) 82 (10) 85 (10) 84 (9)
HR at baseline 74 (11) 71 (12) 74 (10) 75 (8)
MAP at injection of rocuronium 67 (10) 70 (8) 70 (8) 70 (8)
HR at injection of rocuronium 72 (11) 67 (11) 72 (9) 70 (9)

BMI, body mass index; MAP, mean arterial blood pressure; HR, heart rate.

Table 2 Time until onset and duration of neuromuscular blockade after administration of rocuronium (total dose
0.6 mg.kg)1) in patients randomly allocated to rocuronium alone (Control), priming with rocuronium, magnesium pre-
treatment and a combination of rocuronium priming and magnesium. Data are mean (SD).

Control Prime Magnesium Magnesium and prime

(n = 23) (n = 23) (n = 23) (n = 23)
Onset; s 150 (56)* 125 (47)* 94 (25)** 56 (16)
Duration; min 33 (12) 39 (18) 42 (12) 43 (10)

*p < 0.001 vs. magnesium and prime group; **p < 0.01 vs. magnesium and prime group.

in the magnesium and prime group, so we performed

Levene’s test to assess the homogeneity of variance
between the magnesium (which showed the second
smallest SD value) and the magnesium and prime
groups. The variance between the two groups was
heterogeneous (p = 0.038). Tracheal intubation was
successful within 60 s in all subjects. The intubating
conditions were best in the magnesium and prime group
(Fig. 2).
A burning or heat sensation was reported in eight
(35%) and six (26%) patients during magnesium
sulphate infusion, respectively, and mild pain at the
cannula site was noted in two (9%) and three (13%)
patients in the magnesium, and the magnesium and
prime groups, respectively. This was reported as toler-
able in each instance and did not require treatment or Figure 2 Tracheal intubating conditions in patients
randomly allocated to rocuronium alone (Control),
interruption of the magnesium sulphate infusion. No
priming with rocuronium, magnesium pre-treatment
adverse events such as difficulty with breathing or and a combination of rocuronium priming and
aspiration of gastric contents were observed after magnesium, evaluated as excellent ( ), good ( ), and
injection of the rocuronium priming dose. poor ( ).

4 Anaesthesia ª 2012 The Association of Anaesthetists of Great Britain and Ireland

Kim et al. | Rocuronium priming versus magnesium
Discussion
The onset of neuromuscular blockade was shortened
compared to control by 17%, 37%, and 63% with
priming, magnesium sulphate, and the combination of
magnesium sulphate plus priming respectively, consis-
tent with previous reports (19% and 36% decreases with
priming [16] and magnesium sulphate [13], respec-
tively). In previous studies, suxamethonium (1 mg.kg)1)
[16] and high-dose rocuronium (1.2 mg.kg)1) [17] had
40% and 39% faster onset times, respectively, compared
with a standard dose of rocuronium (0.6 mg.kg)1).
Therefore, it is conceivable that the magnesium and
priming combination method may result in faster
neuromuscular block than that achieved with suxame-
thonium, although we have not studied this.
Facilitated neuromuscular blockade with magne-
sium involves the following mechanisms: (1) decreased
pre-junctional release of acetylcholine via the inhibition
of voltage-dependent calcium channels [18]; (2) reduced
sensitivity of the endplate to acetylcholine; and (3)
attenuated direct excitability of muscle fibres, presum-
ably by altering the electrical threshold of the muscle
membrane [18]. The concept behind the priming
technique is that the initial sub-paralysing dose of
NDMR occupies the acetylcholine receptors, which
decreases the time that the remaining receptors can be
occupied by the subsequent paralysing dose, causing
profound neuromuscular blockade [19]. The specific
sites or stages at which neuromuscular transmission is
impaired seem to differ between magnesium and
priming. Therefore, the number of phases of neuromus-
cular transmission that are inhibited presumably
increase with the combination of magnesium and
priming, which may cause the synergistic acceleration
of the effects of rocuronium.
Magnesium sulphate is associated with a lower
variance for rocuronium onset time compared with that
in controls [13]. In our study, the absolute value of the
SD for the onset time was consistently smaller in the
magnesium group than in the controls. The magnesium
and prime group showed significantly smaller SD and
variance compared with those in the magnesium group.
Hence, the magnesium sulphate ⁄ priming combination
not only facilitated the onset of neuromuscular blockade
but also reduced the variability of onset time, providing
Anaesthesia ª 2012 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia 2012
a more predictable onset than with magnesium sulphate
alone.
We set the interval from rocuronium injection until
laryngoscopic manipulation at 40 s in this study to
minimise the apnoeic period during rapid-sequence
tracheal intubation. This was at the expense of sufficient
time for the induction agents to take effect, which is
likely to entail poor intubating conditions. Intubating
conditions can be influenced by not only the neuro-
muscular block but also various other factors including
the choice of induction agent [6]. Hence, we chose
propofol and remifentanil, which provide superior
rapid-sequence intubating conditions compared with
many other induction agents [6, 15]. Nevertheless,
clinically unacceptable intubating conditions were found
in the three other groups except for the magnesium and
prime group. In contrast, the intubating conditions in all
patients in the magnesium and prime group were
clinically acceptable (good to excellent), probably due to
the rapid neuromuscular block.
Duration of neuromuscular blockade in our study
increased by 27% and 30% in the magnesium, and
magnesium and prime groups, respectively; however, the
increases were not statistically different between the
groups, possibly due to group size. In a previous study,
magnesium sulphate prolonged duration of neuromus-
cular blockade by 27–34% [13]. In contrast, magnesium
sulphate decreases the amount of rocuronium required
to maintain adequate neuromuscular blockade during
surgery [20, 21], which may offset the possible prolon-
gation of neuromuscular blockade. In addition, the time
from skin closure to tracheal extubation was not
delayed, even though magnesium sulphate was infused
continuously throughout surgery after the bolus
(50 mg.kg)1) [20]. Thus, the duration of neuromuscular
blockade of 43 min in the magnesium and prime group
is not likely to have substantially greater clinical
implications than the 33 min duration in the control
group.
Rocuronium (1.6 mg.kg)1) is required to achieve
intubating conditions equivalent to the magnesium and
prime group using high-dose rocuronium and opioids
[22], and its duration is extended by 2.5 times compared
to 0.8 mg.kg)1 rocuronium [22]. Therefore, the magne-
sium sulphate ⁄ priming combination would seem to be
5
Anaesthesia 2012
better than high-dose rocuronium in terms of faster
recovery from neuromuscular block.
The onset time of 0.6 mg.kg)1 rocuronium in this
study (150 s) was longer than that reported (90 s) in a
previous study [16]. Onset time is influenced by various
factors, including body mass index, anaesthetic agents,
modes or devices of nerve stimulation, and the defini-
tion of onset time [14]; thus, results from different
protocols cannot be directly compared. Consequently,
variable rocuronium (0.6 mg.kg)1) onset times of 178–
226 s have been reported [2, 23–25].
Magnesium sulphate (50–60 mg.kg)1) was not asso-
ciated with serious complications in the present or
previous studies [13, 26]. The dose used was less than that
used for the treatment of pre-eclampsia [21]. Priming
with 0.06 mg.kg)1 rocuronium did not result in critical
complications such as hypoxia, respiratory difficulty, or
aspiration in previous studies either [9, 11]. No signif-
icant reduction in evoked laryngeal electromyography is
observed during the priming period [7]. However,
surveillance should be conducted for potential compli-
cations related to magnesium sulphate and priming.
A limitation of this study is that the sample size may
have been too small to detect a difference in the duration
of neuromuscular blockade, because the sample size was
calculated for the primary outcome.
In conclusion, pre-treatment with both magnesium
sulphate and a priming dose of rocuronium provided
faster onset of neuromuscular blockade and superior
tracheal intubating conditions for rapid-sequence intu-
bation, compared with magnesium sulphate or priming
alone.
Acknowledgements
This study was financially supported by a grant from the
Seoul National University Bundang Hospital Research
Fund. No competing interests declared.
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Appendix
Assessment of intubating conditions. Excellent, all qualities excellent; good, all qualities either excellent or good; poor, a
single quality assessed as poor [14].

Clinically acceptable Clinically unacceptable

Variable
evaluated Excellent Good Poor
Laryngoscopy Easy Fair Difficult
Jaw Relaxed Not fully relaxed Poor relaxation
Blade insertion No resistance Slight resistance Active resistance
Vocal cords Abducted Intermediate ⁄ moving Closed
Reaction to None One to two weak More than two movements for > 5 s
intubation movements for < 5 s

Anaesthesia ª 2012 The Association of Anaesthetists of Great Britain and Ireland 7