Anesthetic Clinical Pharmacology

E   Original Clinical Research Report

Rapid Sequence Induction With a Standard Intubation

Dose of Rocuronium After Magnesium Pretreatment
Compared With Succinylcholine: A Randomized
Clinical Trial
Christoph Czarnetzki, MD, MBA,*†‡ Eric Albrecht, MD,§∥ Philippe Masouyé, MD,*
Moira Baeriswyl, MD,§ Antoine Poncet, MS,¶ Matthias Robin, MD,* Christian Kern, MD,§∥
and Martin R. Tramèr, MD, DPhil*‡

BACKGROUND: Succinylcholine remains the muscle relaxant of choice for rapid sequence induc-
tion (RSI) but has many adverse effects. High-dose rocuronium bromide may be an alternative to
succinylcholine for RSI but recovery times are nearly doubled compared with a standard intubat-
ing dose of rocuronium. Magnesium sulfate significantly shortens the onset time of a standard
intubating dose of rocuronium. We set out to investigate whether intravenous (IV) pretreatment
with MgSO4 followed by a standard intubating dose of rocuronium achieved superior intubation
conditions compared with succinylcholine.
METHODS: Adults were randomized to receive a 15-minute IV infusion of MgSO4 (60 mg·kg–1)
immediately before RSI with propofol 2 mg·kg–1, sufentanil 0.2 μg·kg–1 and rocuronium 0.6 mg·kg–1,
or a matching 15-minute IV infusion of saline immediately before an identical RSI, but with succi-
nylcholine 1 mg·kg–1. Primary end point was the rate of excellent intubating conditions 60 seconds
after administration of the neuromuscular blocking agent and compared between groups using mul-
tivariable log-binomial regression model. Secondary end points were blood pressure and heart rate
before induction, before and after intubation, and adverse events up to 24 hours postoperatively.
RESULTS: Among 280 randomized patients, intubating conditions could be analyzed in 259 (133
MgSO4-rocuronium and 126 saline-succinylcholine). The rate of excellent intubating conditions was
46% with MgSO4-rocuronium and 45% with saline-succinylcholine. The analysis adjusted for gender
and center showed no superiority of MgSO4-rocuronium compared with saline-succinylcholine (relative
risk [RR] 1.06, 95% confidence interval [CI], 0.81-1.39, P = .659). The rate of excellent intubating con-
ditions was higher in women (54% [70 of 130]) compared with men (37% [48 of 129]; adjusted RR
1.42, 95% CI, 1.07-1.91, P = .017). No significant difference between groups was observed for sys-
tolic and diastolic blood pressures. Mean heart rate was significantly higher in the MgSO4-rocuronium
group. The percentage of patients with at least 1 adverse event was lower with MgSO4-rocuronium
(11%) compared with saline-succinylcholine (28%) (RR 0.38, 95% CI, 0.22-0.66, P < .001). With
saline-succinylcholine, adverse events consisted mainly of postoperative muscle pain (n = 26 [19%])
and signs of histamine release (n = 13 [9%]). With MgSO4-rocuronium, few patients had pain on injec-
tion, nausea and vomiting, or skin rash during the MgSO4-infusion (n = 5 [4%]).
CONCLUSIONS: IV pretreatment with MgSO4 followed by a standard intubating dose of
rocuronium did not provide superior intubation conditions to succinylcholine but had fewer
adverse effects.  (Anesth Analg 2021;133:1540–9)

KEY POINTS
• Question: Does a combination of magnesium sulfate pretreatment followed by a standard
intubating dose of rocuronium (0.6 mg·kg–1) produce superior intubation conditions to
succinylcholine?
• Findings: For rapid sequence induction, a combination of pretreatment with magnesium sul-
fate followed by a standard intubating dose of rocuronium does not provide superior intubat-
ing conditions compared with succinylcholine but has fewer adverse effects.
• Meaning: In view of our findings, we hypothesize that for rapid sequence induction, a
combination of pretreatment with magnesium sulfate and a standard intubating dose of
rocuronium might be an alternative to succinylcholine in circumstances where succinylcholine
administration is not warranted.

From the *Division of Anesthesiology, Department of Anesthesiology, University of Lausanne, Lausanne, Switzerland; and ¶Clinical Research
Clinical Pharmacology, Intensive Care and Emergency Medicine, Geneva Centre & Division of Clinical Epidemiology, Department of Health and
University Hospitals, Geneva, Switzerland; †Division of Anesthesiology, Community Medicine, University of Geneva & Geneva University Hospitals,
Department of Anesthesiology, Intensive Care and Emergency Medicine, Geneva, Switzerland.
Ospedale Regionale di Lugano, Lugano, Switzerland; ‡Faculty of Medicine, Accepted for publication November 5, 2020.
University of Geneva, Geneva, Switzerland; §Department of Anesthesiology,
Lausanne University Hospital, Lausanne, Switzerland; ∥Faculty of Medicine, Funding: The support was provided solely from institutional and/or departmen-
DOI: 10.1213/ANE.0000000000005324 tal sources (Geneva University Hospitals and Lausanne University Hospital).

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E  Original Clinical Research Report

GLOSSARY
ALT = alanine aminotransferase; ASA = American Society of Anesthesiologists; AST = aspartate
aminotransferase; BMI = body mass index; CI = confidence interval; CONSORT = Consolidated
Standards of Reporting Trials; GABAA = γ-aminobutyric acid A; IV = intravenous; Mag-Roc = magne-
sium (pretreatment) + rocuronium; RR = relative risk; RSI = rapid sequence induction; Sal-Succ =
saline (pretreatment) + succinylcholine; SD = standard deviation; TOF = train of four; ULN = upper
limit of normal

R
apid sequence induction (RSI) is a frequently but recovery was only prolonged by 25%.7 In addi-
used procedure for endotracheal intubation in tion, the interindividual variability in the onset of
the emergency setting or in unfasted patients the neuromuscular blockade was lessened with this
who are at risk of regurgitation. Succinylcholine magnesium-rocuronium regimen, suggesting that the
remains the muscle relaxant of choice for RSI,1,2 but it predictability of adequate intubating conditions was
has many adverse effects.3,4 There are alternatives that improved.7 We designed a randomized controlled
may be used instead of succinylcholine. For instance, trial to compare a combination of magnesium with
with a high dose of rocuronium bromide, 1.0–1.2 a standard intubating dose of rocuronium with suc-
mg·kg–1, the same intubating conditions with a similar cinylcholine in patients undergoing RSI. We chose a
onset time as with succinylcholine may be achieved.1,2 superiority trial design.
Also, pretreatment with intravenous (IV) magnesium
may accelerate onset time of a nondepolarizing neu- METHODS
romuscular blocking agent.5–7 The main problem with Study Design
high dose nondepolarizing neuromuscular block- This randomized, double-blind, gender-stratified trial
ing agents is prolonged recovery time.8 Today, this was conducted at 2 Swiss university hospitals (Geneva
might not be perceived as a major problem as even and Lausanne), following the recommendations of
deep, rocuronium-induced neuromuscular block Good Clinical Research Practice in Neuromuscular
can be antagonized with sugammadex.9 But in many Research.13 The study protocol, patient information
countries, sugammadex is not available or its use is sheet, and informed consent form were approved by
restricted due to its high costs and strategies to reduce the ethics committees of Geneva University Hospitals
its usage are welcomed.10 On the contrary, the role of (protocol no. CER11-235/NAC11-087) and Lausanne
magnesium in perioperative medicine is constantly University Hospital (protocol no. 306/12), and by the
increasing due to its analgesic and morphine sparing Swiss Agency for Therapeutic Products (Swissmedic;
properties, neuroprotective features, and its potency 2012DR3098). The trial was registered before patient
to decrease overall anesthetic requirements.11,12 This enrollment on clinicaltrials.gov (NCT01571908, prin-
begs the question as to whether a standard intubat- cipal investigator: Christoph Czarnetzki, date of
ing dose of, for instance, rocuronium, combined with registration: April 4, 2012). This article adheres to
magnesium, differs with regard to onset times and the applicable Consolidated Standards of Reporting
intubation conditions compared with succinylcholine. Trials (CONSORT) guidelines.
With a 15-minute IV infusion of magnesium sulfate
60 mg·kg–1 before a standard dose of rocuronium (0.6 Study Population and Recruitment
mg·kg–1), the onset time of the neuromuscular block The anesthesia teams of Geneva and Lausanne
was reduced by about 35% (from 120 to 72 seconds), University Hospitals identified eligible patients dur-
ing the preanesthetic consultation and obtained writ-
The authors declare no conflicts of interest.
ten informed consent before enrollment. Included
Supplemental digital content is available for this article. Direct URL citations were male and female patients aged 18–65 years with
appear in the printed text and are provided in the HTML and PDF versions of an American Society of Anesthesiologists (ASA) phys-
this article on the journal’s website (www.anesthesia-analgesia.org).
ical status I or II and scheduled for elective surgery
Clinical trial number and URL: clinicaltrials.gov NCT01571908, https://
clinicaltrials.gov/ct2/show/NCT01571908. lasting longer than 60 minutes. Exclusion criteria were
Reprints will not be available from the authors. a history of allergy or hypersensitivity to rocuronium,
Address correspondence to Christoph Czarnetzki, MD, MBA, Division succinylcholine, or MgSO4; neuromuscular disease;
of Anesthesiology, Department of Anesthesiology, Intensive Care and
Emergency Medicine, Ospedale Regionale di Lugano, Via Tesserete 46, 6900
history of malignant hyperthermia; preoperative
Lugano, Switzerland. Address e-mail to christoph.czarnetzki@eoc.ch. medications known to influence neuromuscular func-
Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, tion (eg, certain antibiotics [aminoglycosides], anti-
Inc. on behalf of the International Anesthesia Research Society. This is an
open-access article distributed under the terms of the Creative Commons convulsants [phenytoin]); electrolyte abnormalities
Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), (eg, hypermagnesemia or hyperkalemia); hepatic
where it is permissible to download and share the work provided it is prop-
erly cited. The work cannot be changed in any way or used commercially dysfunction (ie, bilirubin >1.5 × upper limit of normal
without permission from the journal. [ULN], alanine aminotransferase [ALT] >2.5 × ULN,

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Rapid Sequence Induction With Magnesium-Rocuronium

aspartate aminotransferase [AST] >2.5 × ULN); renal Study Drug Administration

insufficiency (ie, creatinine >1.5 × ULN, creatinine In the experimental group, patients received 1 mL·kg–1
clearance <60 mL·min–1 1.73 m–2, estimated by the of the MgSO4 solution as a pretreatment, which corre-
formula of Cockroft & Gault); atrioventricular heart sponded to 60 mg·kg–1 of MgSO4. In the control group,
block; patients with magnesium treatment; those with patients received a matching 1 mL·kg–1 infusion contain-
a body mass index <19 or >28 kg·m–2; pregnant or ing physiological saline (0.9% NaCl). Pretreatments were
breastfeeding women; expected difficult intubation or administered during 15 minutes using a volumetric infu-
mask ventilation; and patients having participated in sion pump (Infusomat, Braun Medical SA, Sempach,
any clinical trial within the previous 30 days. Switzerland). Once the pretreatment was finished, anes-
thesia was induced (see Induction and Intubation) and
Study Drug Preparation, Randomization, and 0.06 mL·kg–1 of the neuromuscular blocking agent was
Blinding administered using the matching 10-mL syringe. This
Each pharmacy of the 2 participating centers prepared regimen ensured that patients in the experimental group
study treatments and was responsible for randomization received rocuronium 0.6 mg·kg–1 and those in the con-
and maintenance of blinding in accordance with Good trol group received succinylcholine 1 mg·kg–1.
Manufacturing Practices. Randomization was stratified
in a 1:1 ratio for gender due to a greater sensitivity to Induction and Intubation
rocuronium in women.14 Study drugs were taken from The anesthesiologist in charge of the patient was free
a commercial batch, and the number and expiry date to administer oral midazolam as a premedication at
of each batch were recorded. To ensure blinding, the last 1 hour before induction of anesthesia or IV mid-
treatments of the control group (saline-succinylcholine) azolam in the preparation room. Standard noninvasive
and the experimental group (magnesium-rocuronium) monitoring included acceleromyography with a TOF
were matched (100-mL infusion bags containing 0.9% Watch SX monitor (Organon, Oss, the Netherlands).
saline or MgSO4 60 mg·mL–1 and 10-mL syringes con- For induction, patients were installed with the head
taining succinylcholine 16.6 mg·mL–1 or rocuronium 10 slightly raised (sniffing position). Preoxygenation via
mg·mL–1). Study drugs were prepared and randomized a facemask was begun, and IV sufentanil 0.2 μg·kg–1
24 hours in advance and delivered in sealed plastic bags was given. Anesthesia was induced 3 minutes later
identified by a randomization number, name and num- using IV propofol 2 mg·kg–1. On loss of conscious-
ber of the study, expiry date, mode of administration ness, patients received the neuromuscular blocking
(IV), and storage condition. agent according to randomization. Patients were not
In a previous study, the infusion of MgSO4 in ventilated before orotracheal intubation. No cricoid
awake patients was often accompanied by a sensation pressure was exerted. The procedure of intubation
of flush or slight heat in the arm where the perfusion was standardized. The time point of injection of the
was positioned.7 Also, the administration of succinyl- neuromuscular blocking agent was defined as time
choline may be associated with the occurrence of fas- 0. At time 45 seconds, the intubating anesthesiologist
ciculations.15 We therefore anticipated that adequate entered the room, approached the head of the patient,
blinding of the treatments would be difficult. Several started direct laryngoscopy at time 50 seconds, and
precautions were taken to minimize observer bias. intubated the trachea at time 60 seconds. All intubat-
First, patients were not asked actively by the inves- ing anesthesiologists were experienced consultants.
tigators about any symptoms related to the IV pre-
treatment, but patients could report spontaneously Study End Points
on symptoms and complaints. Second, an anesthesi- The primary end point was the percentage of patients
ologist and a nurse anesthetist were responsible for with excellent intubating conditions. Intubating con-
the administration of all drugs during induction and ditions were graded as excellent, good, or poor using
were in charge of the patient throughout the surgical a modified scale according to the recommendations
procedure, but they were not involved in the intubat- of Good Clinical Research Practice in Neuromuscular
ing procedure and scoring of intubating conditions. Research (Table  1).13 Scoring was based on ease of
Third, a second anesthesiologist blinded to study drug laryngoscopy, the position of the vocal cords, and the
administration, intubated the patient, and scored intu- patient’s reactions to the insertion of the endotracheal
bating conditions. This second, independent, anesthe- tube. In addition to these qualifiers, we added the out-
siologist entered the preparation room only on call come “intubating failure,” defined as a not completed
and only once the patient was ready to be intubated orotracheal intubation within 30 seconds after the start
(ie, not earlier than 45 seconds after injection of the of direct laryngoscopy (ie, 80 seconds after injection of
neuromuscular blocking agent). Finally, no more than the neuromuscular blocking agent). In the case of intu-
2 intubating anesthesiologists per center participated bating failure, the usual guidelines for a “can ventilate
in the study to limit interobserver variability. – cannot intubate” situation were followed.

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E  Original Clinical Research Report

Table 1. Intubating Conditions According to Good Clinical Practice in Neuromuscular Research

Evaluation of intubating conditionsa
Variable assessed Clinically acceptable Not clinically acceptable
Excellent Good Poor
Laryngoscopyb Easy Fair Difficult
Vocal cords position Abducted Intermediate/moving Closed
Reaction to insertion of the tracheal tube and cuff inflation None Slightc Vigorous/sustainedd
(diaphragmatic movement/coughing)
According to Fuchs-Buder et al.13
a
Intubation conditions: excellent (all qualities are excellent); good (all qualities are either excellent or good); and poor (the presence of a single quality listed
under “poor”).
b
Laryngoscopy: easy (jaw relaxed, no resistance to blade insertion); fair (jaw not fully relaxed, slight resistance to blade insertion); and difficult (poor jaw relax-
ation, active resistance of the patient to laryngoscopy).
c
One to 2 weak contractions and/or movement for <5 s.
d
More than 2 contractions and/or movement for longer than 5 s.

The intubating anesthesiologist rated the various saline-succinylcholine group was used as a reference
variables describing intubating conditions and their group for the calculation of relative risk.
quality immediately after orotracheal intubation. The rate of excellent intubating conditions
Patients with a Cormack & Lehane grade of 3 or 4 between groups stratified by gender, and by gender
were excluded from the analysis of the primary end and center, were also compared using χ2 test. In addi-
point as with these grades, the position of the vocal tion to the stratified analyses, we estimated interac-
cords cannot be assessed.16 However, these patients tion terms to test the differences in effects between
were considered for the analysis of adverse events. subgroups of patients. Subgroup analyses should
Secondary end points were heart rate and systolic be regarded as explorative only since they were not
and diastolic blood pressure immediately before described in the study protocol and they have low
intubation, and at 1 and 5 minutes after intuba- statistical power.
tion. Safety evaluation consisted of spontaneously Two-sided P < .05 were considered significant for
reported symptoms and complaints during the infu- all analyses. There was no adjustment of P values
sion of the pretreatment (nausea/retching, skin rash, to account for multiple comparisons. Analyses were
pain at injection) and the appearance of signs of his- performed using R software (Vienna, Austria; http://
tamine release (bronchospasm, erythema, edema, www.R-project.org).17
hypotension) after the injection of the neuromuscular
blocking agent. Arterial hypotension was defined as Sample Size Determination
a decrease in mean arterial pressure of >40%. At the This trial was designed as a superiority study. We
postanesthetic visit, the day after the intervention, tested the hypothesis that for RSI, a combination
patients were screened for intraoperative awareness, of magnesium with a standard intubating dose of
muscle pain, and for any minor or major adverse rocuronium was superior to succinylcholine. Sample
event. size was calculated by taking the level of statistical
significance as α = .05 (2-sided) and β = .1. To test the
Statistical Analysis primary hypothesis that the rate of excellent intubat-
Demographic characteristics were described as num- ing conditions was higher (80%) with magnesium-
bers of patients and percentages for qualitative data rocuronium compared with succinylcholine (60%),18
and as means and standard deviations for quantita- we needed 110 patients in each group. We intended to
tive data. Intubating conditions were described as randomize 2 times 140 patients in each group to allow
numbers of patients and percentages, and hemody- for dropouts. The total number of patients necessary
namic measurements as means and standard devia- for inclusion was therefore 280.
tions. All data were described overall and by group of
randomization. Due to the stratified randomization, RESULTS
the comparison of excellent intubating conditions Participant Flow
between groups was performed using a log-binomial In total, 280 patients were randomized between
regression model adjusting for gender and center September 20, 2012, and July 9, 2015 (magnesium-
(and no interaction term). Similarly, between-group rocuronium [141 patients]; saline-succinylcholine
differences on secondary end points were assessed [139 patients]) (Figure). In 21 patients (magnesium-
using linear regression models adjusting for gender rocuronium [8 patients]; saline-succinylcholine [13
and center. For the 3 variables of intubating condi- patients]), the primary end point could not be ana-
tions, both groups were compared using χ2 test. The lyzed for various reasons (Figure). Eventually, 259

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Rapid Sequence Induction With Magnesium-Rocuronium

Figure. Study flowchart.

patients (magnesium-rocuronium [133 patients]; graded excellent with magnesium-rocuronium

saline-succinylcholine [126 patients]) were included (Table 3). Multivariable analysis adjusted for gender
in the primary end point analysis. and center showed no superiority of magnesium-
rocuronium on the rate of excellent intubating condi-
Characteristics of the Study Population tions (relative risk [RR] for magnesium-rocuronium
The demographic characteristics of both groups were compared with saline-succinylcholine 1.06; 95% con-
similar (Table 2); 50% of patients were women. fidence interval [CI], 0.81-1.39; P = .659) (Table  4).
The overall rate of excellent intubating conditions
Primary End Point: Evaluation of Intubating was higher in women (54% [70 of 130]) compared
Conditions with men (37% [48 of 129]; adjusted RR 1.42; 95% CI,
No significant difference was observed in the per- 1.07-1.91; P = .017).
centage of excellent intubating conditions between
both groups (magnesium-rocuronium 46% [61 Posthoc Subgroup Analyses
of 133]; saline-succinylcholine 45% [57 of 126]), Impact of Gender. In men, the rate of excellent intubating
although ease of laryngoscopy was more often conditions was 30% (20 of 66) in the magnesium-rocuronium

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E  Original Clinical Research Report

Table 2. Demographics and Baseline Characteristics of 259 Patients Included in the Efficacy Analyses
N = 259 Mag-Roc (N = 133) Sal-Succ (N = 126)
Gender (women), n (%) 130 (50) 67 (50) 63 (50)
Age, y (mean ± SD) 41.6 ± 12.1 41.9 ± 11.7 41.3 ± 12.5
Weight, kg (mean ± SD) 69.9 ± 10.5 70.2 ± 11 69.5 ± 9.9
Height, cm (mean ± SD) 171.2 ± 9.6 171.1 ± 9.9 171.3 ± 9.3
BMI, kg·m–2 (mean ± SD) 23.8 ± 2.3 23.9 ± 2.3 23.6 ± 2.3
Midazolam orally, n (%) 64 (25) 32 (24) 32 (25)
Midazolam IV, n (%) 77 (30) 38 (29) 39 (31)
Midazolam orally, and/or IV, n (%) 135a (52) 66 (50) 69 (55)
Abbreviations: BMI, body mass index; IV, intravenous; Mag-Roc, magnesium (pretreatment) + rocuronium; Sal-Succ, saline (pretreatment) + succinylcholine; SD,
standard deviation.
a
Six patients received midazolam orally, and IV.

Table 3. Variables of Intubating Conditions According to Study Treatment (N = 259)

n = 259 (%) Mag-Roc (n = 133) (%) Sal-Succ (n = 126) (%) P valuea
Intubating conditions
 Excellent 118 (46) 61 (46) 57 (45) .863
 Good 97 (37) 51 (38) 46 (37)
 Poor 44 (17) 21 (16) 23 (18)
Ease of laryngoscopy
 Excellent 236 (91) 127 (95) 109 (87) .016
 Good 21 (8) 5 (4) 16 (13)
 Poor 2 (1) 1 (1) 1 (1)
Vocal cords’ position
 Excellent 233 (90) 117 (88) 116 (92) .374
 Good 26 (10) 16 (12) 10 (8)
Reaction to insertion of the tracheal tube
 Excellent 134 (52) 68 (51) 66 (52) .768
 Good 83 (32) 45 (34) 38 (30)
 Poor 42 (16) 20 (15) 22 (17)
Abbreviations: Mag-Roc, magnesium (pretreatment) + rocuronium; Sal-Succ, saline (pretreatment) + succinylcholine.
a
Chi-square test.

Table 4. Primary End Point: Excellent Intubating Conditions

Variable Modality Excellent intubating conditions, n (%) Adjusted RR 95% CI P valuea
Treatment Mag-Roc (N = 133) 61 (46) 1.06 0.81-1.39 .659
Sal-Succ (N = 126) 57 (45) 1
Gender Men (N = 129) 48 (37) 1
Women (N = 130) 70 (54) 1.42 1.07-1.91 .017
Center B (N = 150) 74 (49) 1
A (N = 109) 44 (40) 0.91 0.67-1.20 .502
Multivariable analysis adjusted for treatment, gender, and center (N = 259).
Abbreviations: CI, confidence interval; Mag-Roc, magnesium (pretreatment) + rocuronium; RR, relative risk; Sal-Succ, saline (pretreatment) + succinylcholine.
a
Log-binomial regression model adjusting for gender and center.

group and was 44% (28 of 63) in the saline-succinylcholine Impact of Midazolam. Patients having received oral or
group (P = .139). In women, the rate of excellent intubating IV midazolam (N = 135) had a better rate of excellent
conditions was 61% (41 of 67) in the magnesium- intubating conditions than those having not received
rocuronium group and was 46% (29 of 63) in the saline- midazolam (N = 124) (53% [71 of 135] vs 38% [47 of 124]),
succinylcholine group (P = .120). The treatment effect was but without between-treatment group difference (52%
significantly different in men and women (interaction [34 of 66] in the magnesium-rocuronium group and 54%
term, P = .019) with a higher rate of excellent intubating [37 of 69] in the saline-succinylcholine group for patients
conditions with magnesium-rocuronium in women than having received midazolam versus 40% [27 of 67] and 35%
in men. Stratified analyses by gender and center showed [20 of 57], respectively, for patients having not received
a similar tendency. In 1 center, the difference in the rate of midazolam).
excellent intubating conditions in men was significantly
lower in the magnesium-rocuronium group (22% [6 of 27] Secondary End Points. There was no significant difference
compared with the saline-succinylcholine group (55% [16 between groups in systolic and diastolic blood pressure at
of 29]) (P = .025) (Table 5). any time point (Supplemental Digital Content 1, Table 1,

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Rapid Sequence Induction With Magnesium-Rocuronium

were mild; no patient needed treatment. There were

Table 5. Exploratory Subgroup Analyses Stratified
by Gender and Center 7 reports of minor adverse events, considered unre-
Mag-Roc Sal-Succ P valuea
lated to study treatments, and equally distributed
Overall (n) 259 133 126 between the 2 groups. They were mild or moderate
Men (n) 129 66 63 and resolved uneventfully.
  Excellent intubating conditions 48 (37%) 20 (30%) 28 (44%) .139 Two serious adverse events were identified dur-
Women (n) 130 67 63
ing the study period. In 1 patient in the control group,
  Excellent intubating conditions 70 (54%) 41 (61%) 29 (46%) .120
Mag-Roc Sal-Succ P valuea the content of the syringe with succinylcholine was
Center A (n) 109 58 51 accidentally injected into the pretreatment perfusion
Men (n) 73 39 34 bag and the infusion was commenced. As soon as the
  Excellent intubating conditions 26 (36%) 14 (36%) 12 (35%) 1
Women (n) 36 19 17
patient complained of muscle weakness, the error was
  Excellent intubating conditions 18 (50%) 11 (58%) 7 (41%) .504 discovered and anesthesia was induced. Anesthesia
Mag-Roc Sal-Succ P valuea and surgery were uneventful. Postoperatively, the
Center B (n) 150 75 75 patient had a psychological evaluation and assis-
Men (n) 56 27 29
  Excellent intubating conditions 22 (39%) 6 (22%) 16 (55%) .025 tance, and follow-up was uneventful. One patient in
Women (n) 94 48 46 the experimental group had to be reoperated due to
  Excellent intubating conditions 52 (55%) 30 (63%) 22 (48%) .221 postoperative hemorrhagic shock. The patient fully
Abbreviations: Mag-Roc, magnesium (pretreatment) + rocuronium; Sal-Succ, recovered and this event was considered to be unre-
saline (pretreatment) + succinylcholine.
a
Chi-square test.
lated to the study treatment.

DISCUSSION
http://links.lww.com/AA/D290). The mean heart rate was Our study showed no superiority of a combination of
significantly higher in the magnesium-rocuronium group MgSO4 60 mg·kg–1 and rocuronium 0.6 mg·kg–1 com-
by approximately 5 beats per minute at each time point. pared with succinylcholine 1 mg·kg–1 on the rate of
Safety Evaluation. Among the 280 randomized patients,
excellent intubating conditions during RSI in adult
54 (19%) presented at least 1 adverse event (Supplemental patients. There were more adverse events with suc-
Digital Content 2, Table 2, http://links.lww.com/AA/ cinylcholine, mainly muscle pain and symptoms that
D291). The percentage of patients with at least 1 adverse may be attributed to histamine release. Overall, the
event was almost 3 times lower with magnesium- rate of excellent intubating conditions was statisti-
rocuronium (11% [15 of 141]) compared with saline- cally higher in women. This was primarily due to the
succinylcholine (28% [39 of 139]) (RR 0.38, 95% CI, higher rate of women with excellent intubating condi-
0.22-0.66, P < .001). Five patients had symptoms related tions who received magnesium-rocuronium. Due to
to the perfusion of the study pretreatment (all in the small sample sizes in the subgroup analyses, statisti-
magnesium-rocuronium group [4%]): 3 had nausea or
cal power to detect clinically meaningful differences
retching or vomiting (2 wished to discontinue the study);
was insufficient.
1 patient had an erythema at the injection site; and 1 had
pain at the injection site (wished to discontinue the study). Magnesium has a direct impact on neuromuscular
Data of all 3 patients who wished to discontinue the study transmission by decreasing the calcium influx and
were excluded from the analysis of the primary end point reducing the amount of acetylcholine released.19–21
but were included into the safety analyses. After pretreatment with IV MgSO4, a reduction
Eighteen of the remaining 275 patients (7%) pre- in the onset time was observed with atracurium,
sented symptoms that may be attributed to the injec- vecuronium, and rocuronium.5–7 Several studies have
tion of the neuromuscular blocking agent: 5 of 138 tested the effect of various magnesium-rocuronium
(4%) in the magnesium-rocuronium group and 13 combinations on intubating conditions.22–24 Kim et al23
of 137 (9%) in the saline-succinylcholine group. One and Park et al24 compared a combination of MgSO4 50
case of bronchospasm of mild intensity that did not mg·kg–1 and rocuronium 0.6 mg·kg–1 with rocuronium
require treatment was observed in the saline-succinyl- 0.9 mg·kg–1. They did not include a control group
choline group. One episode of arterial hypotension receiving succinylcholine, the gold standard for RSI.
was reported in each study group. Arterial hypoten- We found no studies in the literature comparing
sion was easily treated with vasopressors. No patient MgSO4 60 mg·kg–1 and a standard intubating dose of
presented an edema of mucosa or skin due to hista- rocuronium 0.6 mg·kg–1 with succinylcholine 1 mg·kg–
mine release. 1
. One study compared succinylcholine 1 mg·kg–1
The most frequently reported adverse event at the with high-dose rocuronium (1.2 mg·kg–1) and a com-
24-hour postoperative visit was muscular pain (10%), bination of magnesium and high-dose rocuronium.22
mainly in patients who had received succinylcholine Results of this study must be interpreted with caution
(19% vs 1%, respectively, P < .001). With the excep- as only 20 patients were included in each arm and the
tion of 1 patient who had moderate pain, symptoms authors did not describe how intubation conditions

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E  Original Clinical Research Report

were evaluated.22 They concluded that the magne- anesthesiologists (1 for the administration of drugs
sium-rocuronium combination significantly short- during induction and the follow-up of the patient dur-
ened the onset time of the neuromuscular block and ing the surgical procedure, and the second for the intu-
significantly improved intubating conditions com- bation and the scoring of intubation conditions), and
pared with high-dose rocuronium alone. Similar to no more than 2 intubating anesthesiologists per center,
our study, the combination of magnesium and high- were adopted to minimize observer bias and to main-
dose rocuronium provided comparable intubating tain proper blinding of treatments. All observers were
conditions to that of succinylcholine. experienced anesthesiologists. Also, group sizes were
Combining magnesium with a standard intubation much larger than in previous similar studies.18,22,23,24,30
dose of rocuronium (0.6 mg·kg–1), instead of using high- There was an imbalance between groups in the
dose rocuronium (1.2 mg·kg–1) alone, may be a more number of patients who could not be included into the
useful regimen for RSI as the duration of the neuromus- primary analysis since intubation was not completed
cular block was prolonged by 25% only when magne- within 80 seconds after injection of the study drugs or
sium was combined with rocuronium, compared with the patients had a Cormack-Lehane grade 3 or 4. The
rocuronium alone,7 while the recovery time with high- number of these dropouts was higher in the control
dose rocuronium was nearly doubled.8 Magnesium group. We may speculate that inclusion of these patients
in doses similar to our regimen is routinely used in into the analyses would have led to a more conservative
anesthesia due to its analgesic and morphine sparing estimate of treatment differences, and thus a larger dif-
properties.11,12 It is also used as part of opioid-free anes- ference between the intervention and control groups.
thesia.25,26 Usual magnesium regimens often include a Nineteen percent of patients had at least 1 adverse
loading dose similar to ours (40–60 mg·kg–1) which can event and almost three-quarters of those had received
be easily anticipated before anesthesia induction while succinylcholine. The most commonly reported suc-
the patient is monitored and prepared for anesthesia. cinylcholine-related adverse event was muscle pain.
Few emergency patients requiring RSI for full stomach Succinylcholine-related muscle ache is common and
may need immediate intubation and even then there is it may not necessarily be regarded as a true medical
often sufficient time to administer drugs before induc- problem as it is self-limiting, never becomes chronic,
tion, such as gastric prokinetic agents.27 and responds favorably to nonsteroidal anti-inflam-
Omitting high doses of rocuronium may allow matory drugs.15 Adverse effects during the injection
to await spontaneous recovery of the neuromuscu- of the neuromuscular blocking agent were also more
lar block and avoid expensive antagonization with frequent in the succinylcholine group; most of these
sugammadex under the premise that objective neuro- patients had erythema. All observed manifestations
muscular monitoring is available (documentation of were mild to moderate and did not require treatment.
train of four [TOF] ratio ≥0.9), which is the only method Five patients had symptoms related to the pretreat-
of assuring satisfactory recovery of neuromuscular ment with IV MgSO4 such as pain at the site of injec-
function.28 If reversal is needed in patients with a mag- tion, skin rash, or nausea and vomiting. Three of those
nesium pretreatment, the efficacy of recommended patients wished to terminate the study and were
doses of sugammadex for the reversal of a moderate excluded from the analysis of the primary end point.
or deep neuromuscular block is not diminished.29 Clinicians who choose a magnesium-rocuronium
Less than 50% of our patients had excellent intu- combination for RSI must be aware that such adverse
bating conditions with both experimental and con- events may occur in about 1%–8% of patients (5 of
trol treatment. These rates were low compared with 141, Clopper-Pearson 95% CI, 1.2-8.1). In general,
the literature. In the studies by Naguib et al, excellent adverse effects related to a preoperative magnesium
intubating conditions were found in 63% and 80% infusion are well tolerated.6,7,29 Two adverse events
of patients with succinylcholine 1 mg·kg–1.18,30 Kim that were classified as serious were identified during
et al23 reported on excellent intubating conditions in the study. One was related to the accidental admin-
nearly 80% of patients who had received MgSO4 50 istration of the neuromuscular blocking agent in an
mg·kg–1 and rocuronium 0.6 mg·kg–1. However, none awake patient. The other was not related to study
of these studies compared a magnesium 60 mg·kg– treatment. No significant difference between groups
1
-rocuronium 0.6 mg·kg–1 combination with suc- was shown for values of systolic and diastolic blood
cinylcholine 1 mg·kg–1. It remains unclear why our pressure before induction, and before and after intu-
rates of excellent intubating conditions were rela- bation. There was on average a significantly higher
tively low. The induction and intubation protocols heart rate in the magnesium-rocuronium group com-
were strictly standardized. Several measures such as pared with the succinylcholine group. This may be
matching of treatments, anonymous delivery of treat- attributed to a decrease in peripheral vascular resis-
ments, no systematic reporting of symptoms related tance through a magnesium-mediated vasodilator
to the IV pretreatment by patients, intervention of 2 effect.31 It has been suggested that MgSO4 improves

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Rapid Sequence Induction With Magnesium-Rocuronium

hemodynamic stability during orotracheal intubation ACKNOWLEDGMENTS

through a vasodilator effect related to reduced cat- The authors thank Béatrice Gil-Wey, Claudine Carera,
echolaminergic release and calcium channel block.31 and Patrick Huwiler, research assistants, Division
Overall, the rate of excellent intubating conditions of Anesthesiology, Geneva University Hospitals,
Geneva, Switzerland. They also thank Carine Marcucci
was significantly higher in women. This was related
and Mélanie Boand, Department of Anesthesiology,
to a higher rate of women who had excellent intu- Lausanne University Hospital, Lausanne, Switzerland,
bating conditions after having received magnesium- for their efforts in data collection, and to the Clinical
rocuronium. This result, although not the primary Research Centre, University of Geneva & Geneva
interest of our study, was not unexpected as it is well University Hospitals, Geneva, Switzerland and the
known that there is an impact of gender on the action Clinical Research Centre, University of Lausanne &
of nondepolarizing neuromuscular blocking agents. Lausanne University Hospital, Lausanne, Switzerland
Adamus et al14 have shown an increased susceptibil- for study monitoring.
ity of aminosteroidal blockers such as rocuronium in
women.32,33 In these studies, the delay in the instal- DISCLOSURES
lation of the neuromuscular block was shortened, Name: Christoph Czarnetzki, MD, MBA.
Contribution: This author helped with the study concept and
while the duration of the block was prolonged in
design, acquisition of subjects and data, analysis and interpre-
women compared with men. Our observations may tation of data, and preparation of manuscript.
be regarded as an opportunity to define a research Name: Eric Albrecht, MD.
agenda to further study gender differences in phar- Contribution: This author helped with the study concept and
macology. Future trials may test the hypothesis that a design, acquisition of subjects and data, analysis and interpre-
magnesium-rocuronium combination has a more pro- tation of data, and preparation of manuscript.
Name: Philippe Masouyé, MD.
nounced effect in women than in men. Contribution: This author helped with acquisition of subjects
Post hoc subgroup analyses also suggested an and data, analysis and interpretation of data, and preparation
improvement in intubating conditions in patients of manuscript.
receiving midazolam. Midazolam has muscle relax- Name: Moira Baeriswyl, MD.
ant properties via α2 γ-aminobutyric acid A (GABAA) Contribution: This author helped with acquisition of subjects
and data, analysis and interpretation of data, and preparation
receptors.34–36 Additionally, anxiolytic properties of of manuscript.
midazolam may reduce basal tone in airway mus- Name: Antoine Poncet, MS.
cles.37 Midazolam also potentiates the effects of Contribution: This author helped with the interpretation of
opioids and propofol.38–40 When used as a premedica- data and preparation of manuscript and was responsible for
tion, midazolam has shown improved conditions of the statistical analysis.
Name: Matthias Robin, MD.
facial mask ventilation and insertion of a laryngeal
Contribution: This author helped with analysis and interpreta-
mask.36,41 However, no data has so far identified a ben- tion of data, and preparation of manuscript.
efit of midazolam, alone or in combination with other Name: Christian Kern, MD.
drugs, on intubating conditions. It may be assumed Contribution: This author helped with study concept and
that the improvement in intubating conditions after design, analysis and interpretation of data, and preparation of
manuscript.
premedication with midazolam was caused by mus-
Name: Martin R. Tramèr, MD, DPhil.
cle relaxant effects and synergy with anesthetic induc- Contribution: This author helped with the study concept and
tion agents. design, acquisition of subjects and data, analysis and interpre-
tation of data, and preparation of manuscript.
CONCLUSIONS This manuscript was handled by: Ken B. Johnson, MD.
We designed this trial as a superiority study.
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