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Canadian Journal of Anesthesia 47:47-49 (2000)
© Canadian Anesthesiologists' Society, 2000
Brief Clinical Report

Midazolam premedication reduces propofol requirements for sedation during regional anesthesia

Masashi Nakagawa, MD, Tadanori Mammoto, MD, Ayako Hazama, MD, Takashi Kita, MD, Tetsuya Akamatsu, MD, Noriko Kambara, MD, Toshiko Sakai, MD and Yoshihiko Kishi, MD

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


   Abstract
TOP
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Purpose: Propofol is often used for sedation during spinal anesthesia. We investigated the effects of midazolam premedication on the propofol requirements and incidence of complications during sedation.

Methods: In a prospective randomized, controlled, and single-blinded study, 50 patients undergoing elective gynecological 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 recorded 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.


   Introduction
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 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
SPINAL anesthesia with adequate sedation is often employed for lower abdominal surgery. Propofol is a useful drug for providing sedation during regional anesthesia .1,2 However, it may also cause dose-dependent cardiovascular and respiratory depression.

Because synergistic interactions between midazolam and propofol have been reported,3,4 we assumed that midazolam premedication would reduce propofol requirements and the incidence of complications during sedation. The aim of this study was to examine this assumption.


   Patients and methods
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 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
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 premedication 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 IGo).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 recorded 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.


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  		TABLE I Sedation score
 
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 SpO2 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, administration of ephedrine or atropine, and supplemental oxygen 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.


   Results
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 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
Both groups were similar in age, weight, height, duration of the surgery and sedation, and distribution of disease. Propofol requirements in the midazolam group were lower than in the control group (P < 0.05) (Table IIGo). 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.


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  		TABLE II Demographic data, propofol requirements, and cases of intraoperative complications
 
During sedation, the blood pressure and heart rate slightly decreased and gradually returned to the baseline level at 50 min after the start of propofol infusion in both groups.

The baseline SpO2 value in the midazolam group was lower than in the control group (P < 0.05), but there was no case that SpO2 was < 96%. Although SpO2 decreased < 94% in both groups during induction, it was easy to manage this desaturation using supplemental oxygen.

Midazolam premedication reduced the incidence of intraoperative memory, but had no effect on the incidence of the other complications (Table IIGo).


   Discussion
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
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 propofol.5 The main factor, which influenced these results, was the interval between midazolam and propofol injections. It has been reported that t-max of intramuscular administrated midazolam is approximately 30 min.6,7 Thus, 2 mg midazolam im 30 min before arrival at the operation room could obtain nearly maximum effect of premedication and reduce induction dose of propofol.

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 sedation level was required in those studies. We speculated that 2 mg midazolam could reduce propofol for maintenance only when the level of sedation was controlled as light as we selected.

Although midazolam premedication could not reduce sedation induced circulatory and respiratory depression; midazolam premedication could reduce intraoperative memory. As memories of intraoperative events may cause patient discomfort, this effect is considered beneficial.

In conclusion, midazolam premedication reduces propofol requirements for sedation, increases the incidence of intraoperative amnesia, and has no effect on the incidence of other complications. Thus, midazolam premedication is helpful as a sedation adjunct to spinal anesthesia using with propofol.

Accepted for publication September 24, 1999.


   References
TOP
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1 MacKenzie N, Grant IS. Propofol for intravenous sedation. Anaesthesia 1987; 42: 3–6.[Medline]

2 Wilson E, David A, MacKenzie N, Grant IS. Sedation during spinal anaesthesia: comparison of propofol and midazolam. Br J Anaesth 1990; 64: 48–52.[Abstract/Free Full Text]

3 McClune S, McKay AC, Wright PMC, Patterson CC, Clarke RSJ. Synergistic interaction between midazolam and propofol. Br J Anaesth 1992; 69: 240–5.[Abstract/Free Full Text]

4 Tzabar Y, Brydon C, Gillies GWA. Induction of anaesthesia with midazloam and a target-controlled propofol infusion. Anaesthesia 1996; 51: 536–8.[Medline]

5 Oxorn DC, Ferris LE, Harrington E, Orser BA. The effects of midazolam on propofol-induced anesthesia: propofol dose requirements, mood profiles, and perioperative dreams. Anesth Analg 1997; 85: 553–9.[Abstract]

6 Avram MJ, Fragen RJ, Caldwell NJ. Dose-finding and pharmacokinetic study of intramuscular midazolam. J Clin Pharmacol 1987; 27: 314–7.[Abstract]

7 Holazo AA, Winkler MB, Patel IH. Effects of age, gender and oral contraceptives on intramuscular midazolam pharmacokinetics. J Clin Pharmacol 1988; 28: 1040–5.[Abstract]

8 Taylor E, Ghouri AF, White PF. Midazolam in combination with propofol for sedation during local anesthesia. J Clin Anesth 1992; 4: 213–6.[Medline]




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