ANESTH ANALG

1982;61:933-7

Premedication with Intramuscular Midazolam:

A Prospective Randomized Double-Blind
Controlled Study
H. Ronald Vinik, MD,* J. G. Reves, MD,P and Debra Wright, RN$
VINIK, H. R., REVES,J. G., AND WRIGHT, D.:Premedication with intramuscular midazolam: a prospective randomized
double-blind controlled study. Anesth Analg 1982;61:933-7.
One hundred A.S.A. physical status I and II surgical patients were randomized to receive midazolam, 0.07 mg/kg
(group M, 31 patients), hydroxyzine, 1 .O mg/kg (group H, 34 patients), or midazolam diluent as a placebo (group P,
35 patients). Drugs were administered in the vastus lateralis muscle 60 to 90 minutes before anesthesia induction.
Anesthesia was induced with thiopental, 3.0 mg/kg, followed by 1.O-mg/kg increments if required. An entry criterion
was that patients score 250% on a subjective Anxiety Visual Analog Test (AVAT). Anxiety was also objectively rated
on a six-point scale by a trained observer. Patients and observer were unaware of type of premedication used.
Midazolam and hydroxyzine produced significantly ( p c 0.05) greater reduction of anxiety than placebo on both the
AVAT and objective anxiety evaluations. Peak onset appeared between 30 and 60 minutes after drug administration.
Hemodynamic changes were similar in all groups, and no untoward reactions were encountered before anesthesia.
The injection site 24 and 48 hours after administration showed evidence of mild tissue irritation in 68% of patients in
group H, 26% of patients in group M, and none of the patients in group P. Midazolam is an efficacious, safe
premedicant in relatively healthy patients. It has a prompt onset of action with only minimal tissue irritation.
Key Words: PREMEDICATION: midazolam; HYPNOTICS: benzodiazepines, rnidazolam.

IDAZOLAM is an imidazobenzodiazepine the

pharmacology of which has been shown in
animals to be similar to other 1-4-benzodiazepines
(1).It has been used clinically for intravenous induction of anesthesia (2-6). It has hypnotic, anxiolytic,
and amnestic properties that make it suitable for
preanesthetic medication. Intravenous midazolam
produces satisfactory premedication (3). The purpose
of this investigation was to determine the safety and
efficacy of intramuscular midazolam used for preoperative sedation. To accomplish this purpose, midazoiam was compared with an active compound, hydroxyzine, and placebo using a double-blind randomized experimental design.

* Associate Professor of Anesthesiology.

t Professor

of Anesthesiology and Director of Anesthesia Research.

$ Research Assistant.
Received from the Departments of Anesthesiology and Anesthesia Research, The University of Alabama Medical Center, Birmingham, Alabama. Accepted for publication June 7, 1982.
Reprint requests to Dr. H. R. Vinik, Department of Anesthesiology, The University of Alabama Medical Center, Birmingham,
AL 35294.

Methods
Patients in A.S.A. physical status I or I1 scheduled
for elective surgery composed the study population.
One hundred patients were randomly assigned to one
of three premedication groups (Table 1).Patients with
a subjective anxiety score of 250% on an Anxiety
Visual Analog Test (AVAT) were eligible for participation in the investigation. The AVAT is a visual
analogue quantitative measure of anxiety (Figure). To
determine the AVAT score, patients are given a sheet
of paper with a 100-mm length line and asked to rate
their anxiety along the line (from 0 to 100 mm). Of
233 patients screened, 133 (57%) were excluded because their AVAT score was less than 50. Also excluded were patients who had a history of drug abuse
and/or chronic hypnotic, tranquilizer, and narcotic
therapy. All patients gave informed consent, and the
investigation was approved by the Institutional Review Board of the University of Alabama in Birmingham.
Test drugs were administered 60 to 90 minutes
before anesthesia. All medications were given with a
4-cm, 22-gauge needle in the vastus lateralis muscle.
ANESTHESIA AND ANALGESIA
Vol61, No 1 1 , November 1982

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INTRAMUSCULAR MIDAZOLAM PREMEDICATION

Patients in group M received 0.07 mg/kg of midazolam hydrochloride (5 mg/ml), those in group H received hydroxyzine 1.0 mg/kg (50 mg/ml), and those
in group P midazolam diluent in a volume equal to
TABLE 1
Three Premedication Experimental Groups
Group

Midazolam
(n = 31)
Hydroxyzine
(n = 34)
Placebo
(n = 35)

Age

yr
31 ? 1 . 7

Sex
(M/F)

Weight

5/26

kg
75 ? 4.2

Drug dose

0.07 mg/kg IM

30 f 1.8

3/31

70 f 3.3

1 .O mg/kg IM

36 f 1.8

9/26

71 i 2.4

Midazolam
vehicle?

* Values are means f SD.

t Volume of injection equal to that of midazolam group.

ANXIETY RATING SCALE
INSTRUCTIONS

WE WOULD L I K E TO ESTIMATE YOUR PRESENT LEVEL OF ANXIETY

REGAROING YOUR UPCOMING OPERATION

THE B O n O U

OF THE L I N E REPRESENTS

NO ANXIETY A T A L L A N D THE TOP OF THE LINE THE HIGHEST A N X I E T Y V O U CAN I M A G l N E

PLELJE MAUE A MARK A T THE LEVEL Y O U PRESENTLV FEEL RiGnT NOW
YES. V E R Y

uuw so

I
NO NOT A T ALL

FIGURE.Anxiety Visual Analog Test (AVAT) used to quantitate

subjective anxiety. Line is 100 mm in length. Patients are told to
mark line at point at which they feel their anxiety level rests.
Instructions for marking anxiety level are orinted above line.

that given to patients in group M. Anesthesia in all

patients was induced with thiopental, 3.0 mg/kg IV
(25 mg/ml), followed by I.o-mg/kg incremental doses
if the first and subsequent doses did not induce
anesthesia. Criteria for anesthesia induction were all
of the following: loss of response to verbal commands,
loss of eyelid reflex, and loss of voluntary movement.
Patients were observed before drug administration,
15, 30, 45, and 60 minutes after drug administration,
during anesthetic induction, during emergence from
anesthesia, and 24 and 48 hours after surgery. The
double-blind study design consisted of a floor nurse
administering a known drug to patients who were
unaware of which drug was administered, combined
with observations that were made by a different
trained nurse observer who was unaware of the medication administered. Measurements in the preoperative period included systolic, diastolic, and mean
blood pressures, heart rate, and objective evaluation
of sedation. The objective assessment of sedation
consisted of classification of patients into one of six
groups: hyperactive, awake/alert, awake but drowsy,
asleep but easily arousable, asleep and difficult to
arouse, and asleep and not arousable by verbal commands. These six categories were assigned a numerical value from 1 (asleep/no response) to 6 (hyperactive). AVAT was performed the night before surgery,
just prior to premedication, 60 minutes before premedication and/or just before the patient was transferred to the operating room. The observation made
before transfer to the operating room was defined as
the last observation. The time required for anesthesia
induction and amount of thiopental needed were
recorded. Postoperative nausea and vomiting were
noted and the injection site was evaluated 24 and 48
hours after premedication.
Statistical analysis included computation of mean
values for variables in each group. Analysis of variance or covariance was used to compare groups and

TABLE 2
Blood Pressure (BP) and Heart Rate (HR) after Premedication.
Group M
n

Before medication
15 mint
30 min
45 min
60 min

30
30
29
30
25

f 2.3
f 2.0
f 1.8
f 1.9
t 2.8

f 1.8
f 1.8
2 1.8
t 2.6
80 +. 2.6

33
33
32
33
30

79
78
75
87

Values are means & SD;n = number of patients

Minutes after administration of drug or placebo.

934

ANESTHESIA AND ANALGESIA

Voi 61. No 1 1, November 1982

Group P

__

HR

BP

92
88
88
93
90

Group H

.-

BP

91
92
91
95
89

t 2.4
? 2.0
f 2.3
t 2.3
+. 1.9

HR

77 -+ 2.1
76 f 1.9
73 f 2.0
81 f 1.8
78 k 2.3

34
34
32
34
28

BP

89
88
90
95
92

f 1.9
f 1.8
k 1.7
f 1.9
f 2.5

HR

76
76
75
82
82

f 2.2
f 1.9
f 2.0
f 2.4

* 2.3

VINIK, REVES, AND WRIGHT

determine statistically significant ( p < 0.05) differences. A one-sided test was used for the placebo
comparison and two-sided tests were used for active
drug comparisons. Fischer's exact test was used for
comparison among groups of the incidence of apnea,
nausea, vomiting, and quality of sedation.

Results
The three groups were similar with regard to age,
sex, weight (Table I), and race. Blood pressure and
heart rate values were the same in each group at each
observation period (Table 2). There was no confusion,
restlessness, tremor, nausea, or apnea in any patient
from the time of premedication until the time of
induction. There were differences among the groups
in terms of objective degree of sedation (Table 3). The
mean base line values were similar in all groups, but
midazolam produced significantly ( p < 0.01)better
sedation than placebo. Midazolam also produced significantly (p 5 0.02) lower scores (better sedation)
than hydroxyzine at the 15, 30, and 60-minute observation periods. The results of AVAT are shown in
Table 4. The base line values were similar in all
groups, but midazolarn produced significantly ( p <
0.01) better scores than placebo at the last observation
and at the 60-minute period. Midazolam was also

significantly ( p = 0.04) superior to hydroxyzine at the

60-minute observation period, but not different at the
last observation. Both drugs were superior to placebo
at the last observation period. In groups M and H
satisfactory sedation scores were significantly ( p <
0.01)different from group P. The time for anesthesia
induction was significantly ( p < 0.02) shorter in
groups M (54 f 36.2 seconds) and H (45 & 26.7
seconds) than group P (73 f 45.1 seconds). The
induction dosage of thiopental was also significantly
( p < 0.05) less in groups M (3.2 & .54 rng/kg) and H
(3.1 f 0.58 mg/kg) than in group P (3.6 2 0.89 mg/
kg). Although not significantly different ( p = 0.20),

TABLE 4
Subjective Degree of Sedation after Prernedication: Anxiety
Visual Analog*
Midazolam

Hydroxyzine

Placebo

66 t 23.5
(31 1

52 i 28.3
(32)

35 f 21.4t
(28)

44 f 28.7t

51 f 27.7

29 f 20.ltS

46 f 30.1
(21)

Control (96)

61 t 22.8

Last observation

(28)
(96)
+60 min (%)

(1 5)
* Where %

(311

= percent anxiety. Values are means f

(32)
49 f 24.9
(22)
SD. Number of

patients is shown in parentheses.

t p < 0.01 versus placebo.
$ p < 0.02 versus hydroxyzine.

TABLE 3
Objective Degree of Sedation after Prernedication
Degree of Sedation *
Interval

Mean f SD

No. of
patients

2
5
15

0
0

0
4
8
5
6

1
1

30
30
29
27
16

Midazolam
Base line
15 min
30 min
45 rnin
60 min

5.0 f 0.37
4.6f 0.73t3
3.9 f 0.70t$
3.9 f 0.70t
3.5 f 0.63tS

2
0
0
0
0

26
21
6
3
0

Hydroxyzine
Base line
15 min
30 min
45 min
60 min

5.0 f 0.17
5.0 f 0.30
4.4 f 0.501.
3.9 f 0.60t
3.9 f 0.58t

0
1
0
0
0

32
30
13
4
3

1
2
18
20
16

0
0
0
7
5

0
0
0
0
0

0
0
0
0
0

33
33
31
31
24

Placebo
Base line
15 min
30 min
45 rnin
60 min

4.9 f 0.45
4.9 & 0.38
4.9 f 0.43
4.9 f 0.56
4.9k 0.60

1
0
0

29
32
28
27
18

2
1
2

2
1

1
2
1

0
0
0

0
0
0

34
34
31
31
23

18

0
0

* Numerical designations are: 6, hyperactive; 5, awake and alert; 4, awake and drowsy; 3, asleep/easily responds to verbal
command; 2,asleep/difficult to respond to verbal command; I , asleep/no response to verbal command.
t p < 0 01 versus placebo.
$ p < 0.02versus hydroxyzine.
ANESTHESIA AND ANALGESIA
Vol61, No 1 1 , November 1982

935

INTRAMUSCULAR MIDAZOLAM PREMEDICATION

TABLE 5

Evidence (YO)
of Tissue Irritation at Injection Site after 24
and 48 hours
Midazolam
~~

Pain
Erythema
Induration
Swelling
* p

< 0.01

Hydroxyzine

Placebo

26 *
0
0

68t

0
0
0
0

versus hydroxyzine and placebo.

+ p < 0.01 versus placebo

there was a trend toward more frequent apnea during

anesthesia induction in group M (52%) and group H
(50%)than in group I' (33%).
After surgery, patients in group H (2670)had a
significantly ( p < 0.05) lower incidence of nausea
than patients in group M (54%). The incidence of
nausea in patients in group P was 44%. The incidence
of vomiting was similar in all three groups of patients
(group M 2170, group H 1070,and group P 20%).
Evaluations of injection sites 24 and 48 hours after
drug administration are shown in Table 5 . The incidence of pain at the injection site, the same at 24 and
48 hours after injection, was greatest in group H
(68%), absent in group P, and 26% in group M. The
incidence of pain was significantly ( p < 0.01)greater
in group H than in group M. There was a 6%incidence
of erythema and induration in patients given hydroxyzine and an incidence of swelling of 9% in that
group.

Discussion
I'remedication traditionally has several goals: reduction of anxiety, pain, and secretions, and provision
of basal or background sedation. Of these, the primary purpose of prescribing drugs in the immediate
preoperative period is to allay patient anxiety. Midazolam is a hypnotic with anxiolytic properties which
has been used intravenously for preoperative medication (3). Our study was designed so that both the
patient and observer were unaware of the medication
(double-blind). Randomization produced groups with
similar demographic characteristics and all patients
received the same visits, tests, and treatments.
The results demonstrate that midazolam may be
safely given intramuscularly to produce satisfactory
premedication. Intravenous midazolam can produce
respiratory depression (7-lo),but our study did not
use tests sensitive enough to detect this potential
adverse effect. The degree of respiratory depression
from intramuscular midazolam has not been deter-

936

ANESTHESIA AND ANALGESIA

Vol 61, No 1 1 , November 1982

mined, but presumably it should be similar to the

respiratory depression associated with intravenous
midazolam as similar blood levels may be attained
(11).Also, it is important to realize that the present
investigation included relatively young, healthy patients and the safety of midazolam in older, more ill
patients has not been demonstrated.
Midazolam and hydroxyzine proved to be effective
anxiolytic drugs. Patients had high preoperative anxiety levels (>SO% AVAT scores), and both compounds
were clearly superior to placebo in reducing preoperative anxiety. Midazolam proved to be slightly superior to hydroxyzine in terms of subjective (AVAT)
(Table 4) and objective scoring (Table 3) of sedation.
Fragen and co-workers (12) have reported preliminary
data also demonstrating efficacy of midazolam for
intramuscular premedication. In that study, using
slightly higher doses of midazolam (0.075 mg/kg) and
hydroxyzine (1.5 mg/kg) in smaller groups of patients, midazolam and hydroxyzine were superior to
placebo in anxiolytic effects. Additionally, in the same
study, Fragen et a1 (12) demonstrated that intramuscular midazolam caused significantly greater lack of
recall than either hydroxyzine or placebo 30 minutes
after premedication. We did not investigate the
amnestic properties of the drugs in this study.
The preoperative interview itself is known to have
a calming effect (13). Indeed, some anesthesiologists
subscribe to a pharmacologic nihilism, feeling that
proper preanesthetic interview, examination, and consultation obviate the need for preoperative anxiolytic
drug therapy. The present findings demonstrate
clearly that despite identical preoperative visits, the
active compounds, midazolam and hydroxyzine,
proved significantly superior to placebo in reducing
patient anxiety. In our experimental setting, the effect
on anxiety of the preoperative interview per se was
not examined.
Of particular interest was the rapidity of onset of
sedative action associated with midazolam. Fifteen
minutes after premedication, midazolam had significantly reduced the objective ratings of anxiety from
a score of 5.0 to 4.5 with the peak effect measured at
60 minutes. With both active drugs a time-response
effect pattern emerged, both drugs producing progressive effect as time elapsed, whereas the anxiety
remained constant in patients given placebo injections
(Table 3). The pharmacodynamic measures of drug
activity (anxiety levels) are consistent with the pharmacokinetic studies. Amrein and co-workers (14), for
example, demonstrated in six subjects rapid absorption of midazolam folIowing intramuscular adminis-

VINIK, REVES, A N D WRIGHT

tration with peak blood levels after 30 minutes. The

rapid absorption of intramuscular midazolam contrasts to the more variable absorption of another 1-4benzodiazepine, diazepam (15-17), when given intramuscularly. The vastus lateralis muscle, the site of
administration in the present study, is known to
influence favorably the absorption of intramuscular
benzodiazepines (16).
The postoperative evaluation of the injection site
revealed minimal tissue reaction to midazolam (group
M) and midazolam vehicle (group P). This is not
surprising as laboratory evidence reveals that midazolam produces little tissue reaction (18), and this
confirms the findings of Fragen et al, who also administered midazolam intramuscularly (0.075 mg/kg)
(12). Water solubility of midazolam occurs only at a
pH <4.0 (I), but the acid vehicle is nonirritating to
the muscle.
Postoperative nausea was more prevalent in patients given placebo injections and in patients given
midazolam than in patients receiving hydroxyzine.
This probably reflects the known antiemetic effect of
hydroxyzine (19),as all patients received similar anesthetic drugs and postoperative analgesics. The incidence of nausea was similar after placebo and midazolam, which indicates that midazolam has no antiemetic action. There was no nausea or vomiting before
anesthesia in any group.
In summary, patients premedicated with intramuscular midazolam and hydroxyzine are better sedated
than are patients given placebo injections. The sedation results in lower anesthesia induction requirements. There are no untoward side effects associated
with midazolam and hydroxyzine except for a tendency toward more apnea during induction. Midazolam is a safe and effective premedicant when given
intramuscularly in relatively young, healthy patients.

ACKNOWLEDGMENTS
The authors appreciate the clerical assistance and excellence of
Rae Kerutis and the cooperation of Jay Miller of Hoffman-La Roche
who helped with the statistical evaluation of the data.

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