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 M pharmacology of which has been shown in animals to be similar to other 1-4-benzodiazepines (1). It has been used clinically for intravenous induc- tion 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 preop- erative sedation. To accomplish this purpose, mida- zoiam was compared with an active compound, hy- droxyzine, and placebo using a double-blind random- ized experimental design.

* Associate Professor of Anesthesiology. t Professor of Anesthesiology and Director of Anesthesia Re-

$ Research Assistant. Received from the Departments of Anesthesiology and Anes-

thesia Research, The University of Alabama Medical Center, Bir- mingham, Alabama. Accepted for publication June 7, 1982.

Reprint requests to Dr. H. R. Vinik, Department of Anesthe- siology, The University of Alabama Medical Center, Birmingham, AL 35294.

search.

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 partici- pation 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 be- cause their AVAT score was less than 50. Also ex- cluded 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 Re- view Board of the University of Alabama in Birming- ham.

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.

933 ANESTHESIA AND ANALGESIA Vol61, No 1 1 , November 1982

INTRAMUSCULAR MIDAZOLAM PREMEDICATION

Patients in group M received 0.07 mg/kg of midazo- lam hydrochloride (5 mg/ml), those in group H re- ceived 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

Drug dose Sex

Group Age (M/F) Weight

yr kg Midazolam 31 ? 1.7 5/26 75 ? 4.2 0.07 mg/kg IM

(n = 31) Hydroxyzine 30 f 1.8 3/31 70 f 3.3 1 .O mg/kg IM

(n = 34) Placebo 36 f 1.8 9/26 71 i 2.4 Midazolam

(n = 35) vehicle?

* Values are means f SD. t Volume of injection equal to that of midazolam group.

ANXIETY RATING SCALE

INSTRUCTIONS

REGAROING YOUR UPCOMING OPERATION

NO ANXIETY AT ALL AND THE TOP OF THE LINE THE HIGHEST ANXIETY VOU CAN IMAGlNE

PLELJE MAUE A MARK AT THE LEVEL YOU PRESENTLV FEEL RiGnT NOW

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

THE B O n O U OF THE LINE REPRESENTS

YES. VERY uuw so

i

I

I NO NOT AT 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 med- ication administered. Measurements in the preoper- ative 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 com- mands. These six categories were assigned a numeri- cal value from 1 (asleep/no response) to 6 (hyperac- tive). AVAT was performed the night before surgery, just prior to premedication, 60 minutes before pre- medication and/or just before the patient was trans- ferred 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 vari- ance or covariance was used to compare groups and

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

Group M Group H Group P .- __

n BP HR n BP HR n BP HR

Before medi- cation 30 92 f 2.3 79 f 1.8 33 91 t 2.4 77 -+ 2.1 34 89 f 1.9 76 f 2.2

15 mint 30 88 f 2.0 78 f 1.8 33 92 ? 2.0 76 f 1.9 34 88 f 1.8 76 f 1.9 30 min 29 88 f 1.8 75 2 1.8 32 91 f 2.3 73 f 2.0 32 90 k 1.7 75 f 2.0 45 min 30 93 f 1.9 87 t 2.6 33 95 t 2.3 81 f 1.8 34 95 f 1.9 82 f 2.4 60 min 25 90 t 2.8 80 +. 2.6 30 89 +. 1.9 78 k 2.3 28 92 f 2.5 82 * 2.3

Values are means & SD; n = number of patients t Minutes after administration of drug or placebo.

934 ANESTHESIA AND ANALGESIA Voi 61. No 1 1, November 1982

VINIK, REVES, AND WRIGHT

determine statistically significant ( p < 0.05) differ- ences. 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 sig- nificantly (p 5 0.02) lower scores (better sedation) than hydroxyzine at the 15, 30, and 60-minute obser- vation 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

TABLE 3 Objective Degree of Sedation after Prernedication

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

Control (96) 61 t 22.8 66 t 23.5 52 i 28.3 (28) (31 1 (32)

Last observation 35 f 21.4t 44 f 28.7t 51 f 27.7 (96) (28) (31 1 (32)

+60 min (%) 29 f 20.ltS 46 f 30.1 49 f 24.9 (1 5) (21) (22)

* Where % = percent anxiety. Values are means f SD. Number of patients is shown in parentheses.

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

Interval Mean f SD No. of patients

Degree of Sedation *

6 5 4 3 2 1

Midazolam Base line 5.0 f 0.37 2 26 2 0 0 0 30 15 min 4.6 f 0.73t3 0 21 5 4 0 0 30 30 min 3.9 f 0.70t$ 0 6 15 8 0 0 29 45 rnin 3.9 f 0.70t 0 3 18 5 1 0 27 60 min 3.5 f 0.63tS 0 0 9 6 1 0 16

Base line 5.0 f 0.1 7 0 32 1 0 0 0 33 15 min 5.0 f 0.30 1 30 2 0 0 0 33 30 min 4.4 f 0.501. 0 13 18 0 0 0 31 45 min 3.9 f 0.60t 0 4 20 7 0 0 31 60 min 3.9 f 0.58t 0 3 16 5 0 0 24

Base line 4.9 f 0.45 1 29 2 2 0 0 34 15 min 4.9 & 0.38 0 32 1 1 0 0 34 30 min 4.9 f 0.43 0 28 2 1 0 0 31 45 rnin 4.9 f 0.56 1 27 1 2 0 0 31 60 min 4.9 k 0.60 2 18 2 1 0 0 23

Hydroxyzine

Placebo

~

* Numerical designations are: 6, hyperactive; 5, awake and alert; 4, awake and drowsy; 3, asleep/easily responds to verbal

t p < 0 01 versus placebo. $ p < 0.02 versus hydroxyzine.

command; 2, asleep/difficult to respond to verbal command; I , asleep/no response to verbal command.

935 ANESTHESIA AND ANALGESIA Vol61, No 1 1 , November 1982

INTRAMUSCULAR MIDAZOLAM PREMEDICATION

TABLE 5

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

Midazolam Hydroxyzine Placebo ~~ ~

Pain 26 * 68 t 0 Erythema 0 6 0 Induration 0 6 0 Swelling 0 9 0

* p < 0.01 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 inci- dence 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 hy- droxyzine and an incidence of swelling of 9% in that group.

Discussion

I'remedication traditionally has several goals: re- duction of anxiety, pain, and secretions, and provision of basal or background sedation. Of these, the pri- mary purpose of prescribing drugs in the immediate preoperative period is to allay patient anxiety. Mida- zolam is a hypnotic with anxiolytic properties which has been used intravenously for preoperative medi- cation (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-

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 pa- tients 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 anx- iety levels (>SO% AVAT scores), and both compounds were clearly superior to placebo in reducing preop- erative anxiety. Midazolam proved to be slightly su- perior 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 pa- tients, midazolam and hydroxyzine were superior to placebo in anxiolytic effects. Additionally, in the same study, Fragen et a1 (12) demonstrated that intramus- cular 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 con- sultation 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 signifi- cantly 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 pro- gressive 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 phar- macokinetic studies. Amrein and co-workers (14), for example, demonstrated in six subjects rapid absorp- tion of midazolam folIowing intramuscular adminis-

936 ANESTHESIA AND ANALGESIA Vol 61, No 1 1 , November 1982

VINIK, REVES, A N D WRIGHT

tration with peak blood levels after 30 minutes. The rapid absorption of intramuscular midazolam con- trasts to the more variable absorption of another 1-4- benzodiazepine, diazepam (15-17), when given intra- muscularly. 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 mida- zolam produces little tissue reaction (18), and this confirms the findings of Fragen et al, who also ad- ministered 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 pa- tients 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 an- esthetic drugs and postoperative analgesics. The in- cidence of nausea was similar after placebo and mid- azolam, which indicates that midazolam has no antie- metic action. There was no nausea or vomiting before anesthesia in any group.

In summary, patients premedicated with intramus- cular midazolam and hydroxyzine are better sedated than are patients given placebo injections. The seda- tion results in lower anesthesia induction require- ments. There are no untoward side effects associated with midazolam and hydroxyzine except for a tend- ency toward more apnea during induction. Midazo- lam 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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