Full text of DOI:10.1007/BF03020731

47
Brief Clinical Reports
Midazolam premedica-
tion reduces propofol
requirements for seda-
tion during regional
anesthesia
Masashi Nakagawa MD,
Tadanori Mammoto MD,
Ayako Hazama MD,
Takashi Kita MD,
Tetsuya Akamatsu MD,
Noriko Kambara MD,
Toshiko Sakai MD,
Yoshihiko Kishi MD
Purpose: Propofol is often used for sedation during spinal anesthesia. We investigated the effects of midazolam pre-
medication on the propofol requirements and incidence of complications during sedation.
Methods: In a prospective randomized, controlled, and single-blinded study, 50 patients undergoing elective gyneco-
logical surgery were randomly divided into control and midazolam groups. Patients in the midazolam group received 2
mg midazolam im 30 min before arrival at the operation room. After spinal anesthesia was instituted with intrathecal
injection of hyperbaric tetracaine, we provided sedation using continuous infusion of propofol. The level of sedation was
controlled at a level between “eyes closed but rousable to command” and “eyes closed but rousable to mild physical
stimulation” by adjusting the infusion rate. During sedation, the propofol requirements and complications were record-
ed and patients were asked, two hours after the end of operation, whether they remembered intraoperative events.
Results: In the midazolam group, the loading dose, steady state infusion rate, and overall infusion rate of propofol were
0.74 mg·kg–1, 2.86 mg·kg–1·hr–1, and 3.32 mg·kg–1·hr–1, respectively, which were about 17% lower than those in the
control group (P < 0.05). Moreover, midazolam premedication reduced the incidence of intraoperative memory (P <
0.05), but had no effects on other complications.
Conclusion: Midazolam premedication reduced propofol requirements and the incidence of intraoperative memory
during sedation. These effects on sedation using propofol during spinal anesthesia are considered beneficial for patients.
Objjectiif : Le propofol est souvent utilisé pour la sédation pendant la rachianesthésie. Nous avons exploré les effets de la
prémédication avec du midazolam sur les besoins en propofol et sur l’incidence de complications pendant la sédation.
Méthode : Lors d’une étude prospective, randomisée, contrôlée et à simple insu, 50 patientes pour qui une interven-
tion gynécologique avait été prévue ont été réparties de façon aléatoire en un groupe témoin et un groupe midazolam.
Les patientes du groupe midazolam ont reçu 2 mg de midazolam im, 30 min avant l’arrivée en salle d’opération. Après
la mise en route de la rachianesthésie avec une injection intrathécale de tétracaïne hyperbare, nous avons administré la
sédation par une perfusion continue de propofol. La sédation a été contrôlée à un niveau se situant entre le moment
où les patientes ont «les yeux fermés mais peuvent être éveillées sur commande» et le moment où elles ont «les yeux
fermés mais peuvent être éveillées sous une légère stimulation physique», en ajustant la vitesse de perfusion. Pendant
la sédation, les besoins de propofol et les complications ont été notés et on a demandé aux patientes, deux heures
avant la fin de l’opération, si elles se rappelaient des événements peropératoires.
Résultats : Dans le groupe midazolam, la dose de charge, la vitesse de perfusion à l’état d’équilibre et la vitesse glo-
bale de perfusion du propofol ont été de 0,74 mg·kg–1; 2,86 mg·kg–1·h–1 et 3,32 mg·kg–1·h–1, respectivement, mesures
qui sont de 17 % plus basses que celles du groupe témoin (P < 0,05). De plus, la prémédication avec du midazolam
a réduit l’incidence de rappel peropératoire (P < 0,05), mais n’a pas eu d’effet sur d’autres complications.
Conclusion : La prémédication avec du midazolam a réduit les besoins de propofol et l’incidence de souvenir de la
période peropératoire pendant la sédation. Ces effets sur la sédation utilisant le propofol pendant la rachianesthésie sont
considérés comme bénéfiques pour le patient.
From the Department of Anesthesiology, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi Higashinari,
Osaka City, 537-8511, Japan.
Address correspondence to: Dr. M. Nakagawa. Phone: 81-6-6972-1181(Ext. 3316); Fax: 81-6-6981-4060
Accepted for publication 24 September 1999.
CAN J ANESTH 2000 / 47: 1 / pp 47–49

48
CANADIAN JOURNAL OF ANESTHESIA
PINAL anesthesia with adequate sedation is
often employed for lower abdominal surgery.
Propofol is a useful drug for providing seda-
tion during regional anesthesia .1,2 However,
TABLE I Sedation score
Score
Degree of sedation
1
2
3
4
Fully awake and orientated
Drowsy
Eyes closed but rousable to command
Eyes closed by rousable to mild physical stimulation
(earlobe tug)
S
it may also cause dose-dependent cardiovascular and
respiratory depression.
Because synergistic interactions between midazo-
lam and propofol have been reported,3, 4we assumed
that midazolam premedication would reduce propofol
requirements and the incidence of complications dur-
ing sedation. The aim of this study was to examine this
assumption.
5
Eyes closed but unrousable to mild physical stimulation
TABLE II Demographic data, propofol requirements, and cases
of intraoperative complications
Control group Midazolam group
(n=25)
(n=25)
Patients and methods
The Hospital Ethics Committee approved this study
and informed consent was obtained from 50 patients
undergoing elective gynecological laparotomy under
spinal anesthesia. Criteria for entry into this study were
ASA physical status I or II, age 25-65 yr., and no recent
prescription of psychotropic medication. The patients
were randomly divided into control and midazolam
groups according to the computer generated random
number. In the control group, patients received no pre-
medication and in the midazolam group patients
received 2 mg midazolam im as premedication 30 min
before arrival at the operating room.
On arrival in the operating room, an intravenous
line was secured and all patients were monitored with
ECG, noninvasive automatic blood pressure and pulse
oximetry. After baseline measurements, an epidural
catheter was placed at L2-3 interspace for postoperative
analgesia. Then, spinal anesthesia was instituted with
an intrathecal injection of 2.5 or 3 ml of tetracaine
0.4% and glucose 10% via a 25 gauge needle through
L 3-4, and analgesia was obtained to the Th4 level.
After placing a small sampling tube in the nasal
vestibule to monitor respiratory rate and expired carbon
dioxide partial pressure, sedation was started. Propofol
was infused at a rate of 3 mg·kg– 1·hr– 1, and 10 mg bolus
injections at three minute intervals were added until
response to verbal command diminished or disappeared.
Thereafter the infusion rate was adjusted to maintain a
sedation score of 3 or 4 (Table I).1 Infusion of propofol
was stopped at the end of the operation. The loading
dose (LD dose), steady state infusion rate (SS rate), and
overall infusion rate (OA rate) of propofol were record-
ed to compare the requirement between the groups. The
definition of these indices were as follows; LD dose was
the dose administered until response to verbal command
diminished or disappeared, SS rate was the infusion rate
when steady state sedation level was obtained, and OA
rate was the value divided total dose of propofol during
sedation by sedation time.
Demographic data
Age (yr)
Weight (kg)
47.7 8.7
53.7 7.3
46.3 9.9
55.1 7.8
104.5 25.8
69.5 28.8
Duration of anesthesia (min) 107.8 27.4
Duration of surgery (min)
Propofol requirements
LD dose (mg·kg– 1)
SS rate (mg·kg– 1·hr– 1)
OA rate (mg·kg– 1·hr– 1)
Cases of complication
Intraoperative memory
Intraoperative dream
Uncontrolled movement
Application of oxygen
Apnea
68.3 27.2
0.89 0.28
3.47 0.91
3.98 1.00
0.74 0.16*
2.86 0.76*
3.32 0.86*
7
2
2
22
11
1
7
6
1*
5
4
25
13
0
8
8
13
Vomiting
Airway obstruction
Securing a patent airway
Pressor use
11
*P < 0.05
Ephedrine ( 4 mg iv) was administrated when
blood pressure was < 80% of baseline level, and 0.25
mg atropine was injected when heart rate was < 45
min–1. Supplemental oxygen was given when SpO
2
was < 95%. Apnea was defined that absence of expired
CO2 and respiratory movement were > 15 sec.
The level of sedation and the complications such as
transient apnea, uncontrolled movement, administra-
tion of ephedrine or atropine, and supplemental oxy-
gen requirement were also recorded. Two hours after
the end of sedation, patients were asked if they had
dreamed or remembered intraoperative question
about nausea and pain.
Continuous data were summarized using mean
SD and analyzed using the unpaired t test. Discrete
data were reported as numbers and analyzed using a
chi-square test. A value of P < 0.05 was considered
statistically significant.

Nakagawa et al.: PROPOFOL SEDATION
49
Results
depression; midazolam premedication could reduce
intraoperative memory. As memories of intraoperative
events may cause patient discomfort, this effect is con-
sidered beneficial.
In conclusion, midazolam premedication reduces
propofol requirements for sedation, increases the inci-
dence of intraoperative amnesia, and has no effect on
the incidence of other complications. Thus, midazo-
lam premedication is helpful as a sedation adjunct to
spinal anesthesia using with propofol.
Both groups were similar in age, weight, height, dura-
tion of the surgery and sedation, and distribution of dis-
ease. Propofol requirements in the midazolam group
were lower than in the control group (P < 0.05) (Table
II). Midazolam premedication reduced the LD dose, SS
rate, and OA rate to 83.1%, 82.4% and 83.4% compared
with those of the control group, respectively.
During sedation, the blood pressure and heart rate
slightly decreased and gradually returned to the base-
line level at 50 min after the start of propofol infusion
in both groups.
References
The baseline SpO value in the midazolam group
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Discussion
In this study, the propofol requirement for inducing
sedation in the midazolam group was 16.9% lower
than in the control group. It is controversial whether
midazolam reduces the dose of propofol to induce
anesthesia. Small amounts of midazolam (1-4 mg iv)
administered two to four minutes prior to propofol
infusion can reduce the propofol requirement for
induction of anesthesia.3, 4 On the contrary, 30
µg·Kg–1 midazolam administered immediately before
induction did not reduce the induction dose of propo-
fol.5 The main factor, which influenced these results,
was the interval between midazolam and propofol
injections. It has been reported that t-max of intra-
muscular administrated midazolam is approximately
30 min.6, 7Thus, 2 mg midazolam im 30 min before
arrival at the operation room could obtain nearly max-
imum effect of premedication and reduce induction
dose of propofol.
5 Oxorn DC, Ferris LE, Harrington E, Orser BA. The
effects of midazolam on propofol-induced anesthesia:
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Midazolam premedication also reduced propofol
requirement to maintain sedation. Two previous
reports were unable to detect any effect of midazolam
on propofol requirement for maintaining sedation or
anesthesia.5,8 Propofol requirement for maintenance
was larger than that in our study, that is, deeper seda-
tion level was required in those studies. We speculated
that 2 mg midazolam could reduce propofol for main-
tenance only when the level of sedation was controlled
as light as we selected.
Although midazolam premedication could not
reduce sedation induced circulatory and respiratory