Tracheal Intubation with Rocuronium
“Timing Principle”
Thomas J. Sieber, MD*, Alex M. Zbinden,
George D. Shorten, MDt
*Department of Anesthesia and Intensive Care, University Hospital Bern, Bern, Switzerland;
Anesthesia and Intensive Care, Beth Israel Hospital, Boston, Massachusetts
We compared the endotracheal intubating conditions
after rocuronium, using the “timing principle,” with
those after succinylcholine. The timing principle entails
administration of a single bolus dose of nondepolariz-
ing muscle relaxant, followed by an induction drug at
the onset of clinical weakness. Forty-five patients were
randomly assigned to three groups. Patients allocated
to Groups 1 and 2 received rocuronium 0.6 mg/kg. At
the onset of clinical weakness (onset of ptosis), anesthe-
sia was induced with thiopental4-6 mg/kg; intubation
was accomplished after 45 s in Group 1 and after 60 s in
Group 2. Patients in Group 3 received vecuronium
(0.01 mg/kg) 3 min before the administration of thio-
pental and succinylcholine 1.5 mg/kg, and their tra-
cheas were intubated 60 s later by a blind anesthesiolo-
gist. Intubating conditions were assessed according to a
0
of the ideal muscle relaxant is a
ne characteristic
rapid onset of action. Succinylcholine reliably
produces muscle relaxation within 60 seconds
of its administration, but it can produce serious side
effects (l-5) and is contraindicated in certain patients
(6). Different techniques that have been used to de-
crease the effective onset time of nondepolarizing
muscle relaxants include priming (7) and the admin-
istration of large doses (8). Recently, a technique that
uses the “timing principle” has been applied to rap-
idly produce good intubating conditions with vecuro-
nium (9,lO) and atracurium (11). When this technique
is used, a single bolus dose of a muscle relaxant is
administered, and anesthesia is induced at the onset of
clinical weakness. In this way, the time from the in-
duction of anesthesia to complete muscle relaxation is
reduced, and the peak effect of the muscle relaxant
and IV induction drug may more closely coincide.
Accepted for publication February 4, 1998.
Address correspondence to Thomas J Sieber, MD, Department
Anesthesia and Intensive Care, Inselspital, 3010 Bern, Switzerland.
Address e-mail to tomsieber@compuserve.com.
01998 by the International Anesthesia Research Society
0003-2999/98/$5.#
Using the
MD*, Michele Curatolo, MD*, and
and tDepartment of
grading scale and were either good (5 patients in
Groups 1 and 2,4 patients in Group 3) or excellent (10
patients in Groups 1 + 2,11 patients in Group 3) in all
patients. Patients were interviewed postoperatively,
and all were satisfied with the induction of anesthesia.
We conclude that rocuronium 0.6 mg/kg provides
good to excellent intubating conditions 45 and 60 s after
the induction of anesthesia using the timing principle.
Implications: We compared the ease with which a
breathing tube could be placed in patients using three
techniques. The standard technique (succinylcholine)
was compared with two others in which a muscle-
relaxing drug (rocuronium) was administered just be-
fore the anesthetic drug (so-called timing principle). No
difference among the techniques was observed.
(Anesth Analg 1998;86:113740)
Rocuronium is a steroidal nondepolarizing muscle re-
laxant with an onset time (after 3-4 x the 95% effective
dose) not different from that of succinylcholine
(12-16). In a prospective, randomized, double-blind
clinical trial, we evaluated the intubating conditions
45 and 60 s after the induction of anesthesia using
rocuronium with the timing principle, and compared
them with those after the administration of succinyl-
choline 60 s after the induction of anesthesia.
Methods
With institutional ethical committee approval, and af-
ter having obtained written, informed consent from
each, 45 ASA physical status I or II patients (18-70 yr)
undergoing elective surgical procedures were stud-
ied. Exclusion criteria were: increased risk of pulmo-
nary aspiration, neuromuscular disease, medications
known to influence neuromuscular function, antici-
pated difficulty with airway management, and contra-
indications to succinylcholine.
The usual monitoring was used. Neuromuscular
of
function was measured using accelerography (TOF-
Guard@; Organon Teknika, Durham, NC). Patients
Anesth Analg 1998;86:113740 1137
1138 SIEBER ET AL. ANESTH ANALG
ROCURONIUM AND THE “TIMING PRINCIPLE” 1998;86:113740

were informed that they might feel weak before going 2. Did you feel short of breath immediately before
to sleep. going to sleep for your operation?
All patients received midazolam (l-3 mg) and fen- 3. Do you have muscle pains now?
tanyl (1 pg/kg) IV on arrival in the operating room. 4. If you were to have an operation in the future,
Patients were randomly assigned to one of three would you choose to be put to sleep in a different
groups: rocuronium 45s (Group l), rocuronium 60s way?
(Group 2), and succinylcholine (Group 3). Cutaneous Age, body weight, sex, thiopental doses (all three
electrodes were placed for measurement of the train- groups), and time to clinical onset of neuromuscular
of-four (TOF) response of the first dorsal interosseous blockade (Groups 1 and 2 only) were compared by
muscle of the hand to stimulation of the ulnar nerve. using one-way analysis of variance when data were
Patients allocated to Groups 1 and 2 received rocu- normally distributed; otherwise, the Kruskal-Wallis
ronium (0.6 mg/kg) administered over 5 s through a one-way analysis of variance on ranks was used. Nor-
rapidly running infusion placed in the forearm. Pa- mality of distribution of the data was checked by
tients were asked to keep their eyes widely open as using the Kolmogorov-Smirnov test (17). A P value
long as possible and were closely observed for the co.05 was considered statistically significant. The sta-
first signs of weakness, specifically the onset of ptosis tistical package used was Sigma Stat, version 2.0 (Jan-
(i.e., furrowing of the forehead, which indicates that de1 Corporation, San Rafael, CA).
the occipitofrontalis muscle is being used to compen-
sate for neuromuscular weakness of the levator palpe-
brae superioris muscle). At this time, thiopental (4-
Results
6 mg/kg) was administered IV. TOF monitoring was
commenced on loss of the eyelid reflex. Supramaximal There were no significant demographic differences
square wave stimuli were applied to the ulnar nerve at among groups with respect to age and weight, but
2 Hz for 2 s (i.e., TOF stimulation). This was repeated there were significantly more female patients in
at 10-s intervals until no response was detected. After Group 3 compared with Groups 1 and 2. There was no
statistically significant difference in the thiopental
the administration of thiopental (45 s in Group 1 or
doses of the three groups (Table 1). Tracheal intuba-
60 s in Groups 2 and 3), the TOF count was recorded,
tion score results (all three groups) and TOF counts at
and tracheal intubation was performed by an experi-
the time of intubation (Groups 1 and 2 only) are sum-
enced anesthesiologist unaware of the group to which
marized in Figure 1 and Table 3. Intubating conditions
the patient belonged. This person was waiting outside
were either good or excellent in all patients. The mean
the induction area and did not enter until the patient (2 SD) onset time to clinical weakness was not differ-
was ready for intubation. Intubating conditions were
ent in the two rocuronium groups: 32 -+ 4.9 s in Group
assessed according to a previously described grading 1 and 32 f 5.3 s in Group 2.
scale (Table 2) (9). In addition, a second blind observer In the postoperative interview, none of the patients
observed the abdomen for evidence of diaphragmatic complained about weakness or shortness of breath
response to endotracheal intubation. On capnographic before induction of anesthesia, and only one patient in
confirmation of correct tube placement, controlled Group 3 (succinylcholine) experienced postoperative
positive pressure ventilation was commenced using muscle pain. All patients were satisfied with the man-
70% nitrous oxide in oxygen (6 L/min fresh gas flow) ner in which anesthesia had been induced.
and isoflurane (inspired concentration l%-1.5%).
Patients in Group 3 (succinylcholine) were treated
according to the protocol described for those in
Groups 1 and 2 with the following exceptions. Discussion
Three minutes after the administration of a defascicu- Using the timing principle, the administration of rocu-
lating dose of vecuronium (0.01 mg/kg), thiopental ronium (0.6 “g/kg) resulted in adequate intubating
(4-6 mg/kg) and succinylcholine (1.5 mg/kg) were conditions 45 seconds after the induction of anesthesia
administered in succession over 5 s. Sixty seconds or approximately 77 s after the injection of the muscle
after administration of thiopental, tracheal intubation relaxant. All patients found the manner in which an-
was performed. TOF monitoring was not performed esthesia had been induced to be acceptable. Using the
in Group 3. timing principle with rocuronium, it is possible to
All patients were interviewed by the investigator reduce the interval between induction of anesthesia
(nonblinded) 4-24 h after the surgical procedure. Four and intubation of the trachea to <60 s.
questions were asked: Such a technique is desirable because of the signif-
icant side effects associated with the use of succinyl-
1. Did you feel weak immediately before going to choline (l-5). Alternative strategies to reduce the on-
sleep for your operation? set time of nondepolarizing muscle relaxants, such as
ANESTH ANALG SIEBER ET AL. 1139
1998;86:113740 ROCURONIUM AND THE “TIMING PRINCIPLE”

priming (7) and administering large doses (8), have
not been completely successful. The objective of the
use of the timing principle is not to increase the speed
of onset of the muscle relaxant, but to induce muscle
relaxation and general anesthesia simultaneously
rather than sequentially.
When the timing principle is used, the initial signs
of clinical weakness precede loss of consciousness. A
potential risk, therefore, is that patients would expe-
rience an uncomfortable feeling during the induction
sequence. In our study, no patient demonstrated rest-
lessness at the time that ptosis was observed. This
suggests that patient satisfaction with the manner in
which they went to sleep (in response to the postop-
erative questionnaire) was not because of amnesic ef-
fects of anesthetics, but because the degree of muscle
weakness present was not associated with discomfort.
Debaene et al. (18) demonstrated that onset of neuro-
muscular blockade in the diaphragm was similar to
that in orbicularis oculi but faster than that in adduc-
tor pollicis. Koh and Chen (11) also used ptosis (rather
than handgrip strength) as the marker for the onset of
clinical weakness, postulating that onset time for neu-
romuscular block at levator palpebrae superioris
would be similar to that in orbicularis oculi and, there-
fore, that in the diaphragm. In Koh and Chen’s (11)
study of the use of the timing principle with atra-
curium (0.5, 0.75, or 1.0 mg/kg), only one patient
expressed dissatisfaction with the anesthetic tech-
nique used, and three felt discomfort. It is unlikely
that the absence of such complaints in our study was
It is more likely due to the administration of midazo-
lam and fentanyl before the muscle relaxant.
Because of the rapid speed of onset of neuromuscu-
lar block after rocuronium and the narrow range of
standard deviation in the time to onset of clinical
weakness (32 t 4.9 and 32 2 5.3 s), another approach
of the timing principle might be not to wait for the
onset of clinical weakness, but to induce anesthesia
after a fixed interval, e.g., 20 s after the administration
of rocuronium. Further studies are needed to address
a safe time interval.
There are several reports about pain on injection of
rocuronium (19), even in subparalyzing doses. In our
study, only 5 of 30 (16.7%) patients who received
rocuronium withdrew their forearm during the injec-
tion of rocuronium. This withdrawal was interpreted
as a reaction to a painful stimulus. Because the issue of
pain on injection was not actually raised until the
study was under way, we had not included any ques-
tions concerning this problem specifically in the post-
operative interview. Nevertheless, none of the patients
complained postoperatively about a uncomfortable
event during the induction of anesthesia. A possible
explanation is the prior administration of midazolam
and fentanyl, which has been used to reduce pain on
injection (20), plus the fact that the IV cannulas were
Intubating conditions
12
I Gr 1 (Rot 45)

due to a pharmacodynamic effect of rocuronium, be- 10 I

v)
cause the times to onset of clinical weakness in our =.a, 8- Gr 3 (Succinylcholine)
study (32 +- 4.9 and 32 + 5.3 s) were similar to those
after atracurium (32 + 9.3, 29 + 1.0, and 28 t 11.7 s). ii! 6-
‘i;
4-
Table 1. Grading of Intubating Conditions z”
(Intubation Score) 2-

Grade Definition
2 1 0
3 ELxcellent
(jaw relaxed,cordsabducted,no movement)
lntubation score
2 Good (jaw relaxed,slightcough)
1 Poor (jaw poorly relaxed,cordsmoving, or bucking) Figure 1. Intubating conditions. Intubation scores: 3 = excellent
0 Unableto intubate (jaw relaxed, cords abducted, no movement), 2 = good (jaw relaxed,
slight cough), 1 = poor (jaw poorly relaxed, cords moving or buck-
See also Reference 9. ing), 0 = unable to intubate.

Table 2. Demographic Data and Thiopental Doses

Group 1 Group 2 Group 3
(rocuronium 45 s) (rocuronium 60 s) (succinylcholine)
Age (~4 46.9 -+ 15.8 45.3 + 14.6 42.9 + 12.2
Weight (kg) 70.9 -c 14.4 79.1 + 11.2 67.1 + 14.0
Sex
Male 7 9 4*
Female 8 6 11*
Thiopental (mg/kg) 5.1 +- 0.4 5.2 + 0.4 5.2 t 0.4
----
Values are mean t SD.
* P < 0.05 compared with Groups 1 and 2.
1140 SIEBER ET AL. ANESTH ANALG
ROCURONIUM AND THE “TIMING PRINCIPLE” 1998;86:113740

Table 3. TOF Count Immediately Before Endotracheal Intubation

Group 1 Group 2 Group 3
TOF count (rocuronium 45 s) (rocuronium 60 s) (succinylcholine)
4/4 12 7 -
3/4 3 6 -
2/4 0 0 -
l/4 0 0 -
Diaphragm movement 9% 4 3
TOF = train-of-four.
* P < 0.05 compared with Groups 2 and 3.

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