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* From the Departments of Anesthesiology, Osaka Medical Center for Cancer and Cardiovascular Diseases, and
Osaka University Graduate School of Medicine, Osaka, Japan.
Address correspondence to: Dr. Masashi Nakagawa, Department of Anesthesiology, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Osaka City, 537-8511, Japan. Phone: 81-6-6972-1181; Fax: 81-6-6981-4060; E-mail: m.h.naka{at}f4.dion.ne.jp
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Abstract |
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Methods: In a prospective randomised, controlled, double-blinded study, 60 patients undergoing elective gynecological surgery were studied. They were given premedication with 0.15-mg clonidine (Group-CL, n=20), 5-mg diazepam (Group-DZ, n=20), or placebo (Group-P, n=20) po. After spinal anesthesia was established, sedation was provided with propofol and controlled using a five-point sedation score at 3, "eyes closed but rousable to command", and 4, "eyes closed but rousable to mild physical stimulation". During sedation, blinded anesthesiologist recorded occurrence of complications. At two hours after end of sedation, patients were asked if they had intraoperative dream and memory.
Results: The loading dose, steady-state infusion rate, and overall mean infusion rate in Group-CL were 0.80 mg•kg–1, 2.35 mg•kg–1•hr–1 and 2.89 mg•kg–1•hr–1, compared with 0.97 mg•kg–1, 3.13 mg•kg–1•hr–1 and 3.59 mg•kg–1•hr–1 in Group-DZ, and 1.38 mg•kg–1, 4.10 mg•kg–1•hr–1 and 4.36 mg•kg–1•hr–1 in Group-P, respectively. Indices of both Group-CL (P <0.001) and Group-DZ (P <0.05) were smaller than those of Group-P. Moreover, clonidine reduced the incidence of uncontrolled movement (P <0.01), while diazepam reduced the incidence of intraoperative memory and increased the incidence of dream (P <0.05). Premedication did not affect the incidence of other complications.
Conclusion: Both premedicants reduced propofol requirements and exerted beneficial effects on the incidence of some complications during sedation with propofol as an adjunct to regional anesthesia.
REGIONAL anesthesia with supplemental sedation is often performed for patient comfort during lower abdominal surgery. Propofol infusion is useful for providing sedation during regional anesthesia.1,2 However, the sedatives may also cause uncontrolled movement,3 and dose-dependent cardiovascular and respiratory depression. These may be important clinical considerations for its use as an adjunct to spinal anesthesia.
Clonidine has some ideal properties for premedication, such as producing sedation, attenuating autonomic nervous system responses and reducing anesthetic requirements.4–6 Thus, preanesthetic clonidine may modify the clinical course of propofol sedation. Diazepam is also often prescribed for premedication due to its anxiolytic, sedative, and amnesic effects. Moreover, benzodiazepines and propofol act synergistically.3,7,8 It is possible that preanesthetic diazepam reduces the propofol requirements and decreases the complications. Both drugs are useful for premedication, however, there are few reports to investigate the differences between them when used as premedicants for sedation with propofol. The aim of this study is to compare the effects of the two premedicants on quality of sedation with propofol.
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In the operating room an iv line was inserted and all patients were monitored with ECG, non-invasive automatic blood pressure and pulse oximetry. After baseline measurements, an epidural catheter was placed through the L 2–3 interspace for postoperative pain relief and epidural placement was ascertained by injection 2 ml lidocaine 1% with epinephrine (1:100000). Then, according to patient height, spinal anesthesia was instituted with an intrathecal injection of 2.5 or 3 ml tetracaine 0.4% and glucose 10% via a 25-gauge needle through the L 3–4, and analgesia was obtained to at least the T4 level.
After placement of a small sampling tube in the nasal vestibule to monitor respiratory rate and expired carbon dioxide partial pressure, sedation was started. Propofol was given at a rate of 6 mg•kg–1•hr–1 until verbal command diminished or disappeared. Then, the infusion rate was reduced to 3 mg•kg–1•hr–1 and adjusted to maintain a sedation score between 3 and 4 on a 5-point scale1 (Table I
) by a blinded anesthesiologist. 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 requirements among the groups. The 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 duration of sedation.
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The overall sedation score and complications such as apnea, uncontrolled movement, frequency of ephedrine or atropine injection, and supplemental oxygen requirements were also recorded. Uncontrolled movement is purposeless movement of arms or trunk, which might disturb the operative procedure.
Two hours after the end of sedation, patients were asked if they had dreamed or remembered intraoperative questions that we asked about nausea and pain during sedation.
Continuous data were summarised using mean ± SD and analysed using one-way ANOVA. Alternations in heart rate or blood pressure were analysed using the repeated-measure MANOVA. Discrete data was reported as numbers and analysed using a chi-square test. A value of P <0.05 was considered statistically significant.
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Results |
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). Clonidine reduced LD dose, SS rate, and OA rate to 58.0%, 57.3% and 66.3% compared with those in Group-P, respectively (P <0.001). Diazepam also decreased LD dose, SS rate, and OA rate to 70.3%, 76.3% and 82.3% compared with those in Group-P, respectively (P <0.05) (Table II).
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Changes of the SpO2, PETCO2 value and respiratory rate were comparable in the three groups during sedation (Table IV). Although transient desaturation during induction was commonly observed in all groups, it was easy to treat with supplemental oxygen.
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Discussion |
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Recently, we reported that preanesthetic clonidine relieved anxiety and reduced the requirement of propofol for general anesthesia.6 These beneficial effects of clonidine are produced by activation of 
2-adrenoceptor in the central nervous system.9 The propofol sparing effect of clonidine described in this paper is also probably related to this central nervous system attenuating effect of clonidine.
Spontaneous excitatory movement has been observed during induction and recovery from propofol anesthesia,10,11 and also during sedation using propofol.1 However, this excitatory movement seems to be different from uncontrolled movement. Communication with the patient is possible when the latter occur, but is impossible with the former. If uncontrolled movement occurs during sedation, it may interfere with surgery. Benzodiazepine had no effect3 but clonidine inhibited it. This effect of clonidine is an advantage for sedation with propofol.
The sympatholytic property of clonidine4 might induce serious bradycardia and hypotension when clonidine is used as premedication for sedation with propofol as an adjunct to spinal anesthesia. In our study, clonidine reduced heart rate compared with other groups but the incidence of bradycardia requiring treatment was similar in other groups. It is also reported that 0.15–0.2 mg clonidine is appropriate for premedication and high dose clonidine increases cardiovascular adverse effects.12,13 It is suggested that 0.15 mg preanesthetic clonidine could be used safely for sedation with propofol as an adjunct to spinal anesthesia.
Both benzodiazepines and propofol activate GABAA-coupled chloride channels, and produce anesthesia.14–17 Therefore, benzodiazepine reduces propofol requirements probably due to its synergistic action on GABAA- receptor.3,7,8
Although we maintained the same sedation level in all groups, fewer patients in Group-DZ recalled intraoperative events than in other groups. Benzodiazepines, including diazepam, produce anterograde amnesia, and this may contribute to this reduction of the memories of intraoperative events. As intraoperative memories may cause patient's discomfort, diazepam may be a useful preanesthetic medication for spinal anesthesia with sedation.
In conclusion, preanesthetic clonidine or diazepam reduced propofol requirements for sedation. In addition, clonidine decreased the incidence of uncontrolled movement, while diazepam decreased intraoperative memory. Both premedicants are useful premedicants when sedation with propofol is planned for regional anesthesia.
Accepted for publication November 9, 2000.
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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.
3
Nakagawa M, Mammoto T, Hazama A, et al. Midazolam premedication reduces propofol requirements for sedation during regional anesthesia. Can J Anesth 2000; 47: 47–9.
4 Ghignone M, Calvillo O, Quintin L. Anesthesia and hypertension: the effect of clonidine on perioperative hemodynamics and isoflurane requirements. Anesthesiology 1987; 67: 3–10.[Medline]
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McClune S, McKay AC, Wright PMC, Patterson CC, Clarke RSJ. Synergistic interaction between midazolam and propofol. Br J Anaesth 1992; 69: 240–5.
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10 Borgeat A, Dessibourg C, Popovic V, Meier D, Blanchard M, Schwander D. Propofol and spontaneous movements: an EEG study. Anesthesiology 1991; 74: 24–7.[Medline]
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Borgeat A, Wilder-Smith OHG, Despland PA, Ravussin P. Spontaneous excitatory movements during recovery from propofol anaesthesia in an infant: EEG evaluation. Br J Anaesth 1993; 70: 459–61.
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Carabine UA, Wright PMC, Moore J. Preanaesthetic medication with clonidine: a dose-response study. Br J Anaesth 1991; 67: 79–83.
13
Ota K, Namiki A, Iwasaki H, Takahashi I. Dose-related prolongation of tetracaine spinal anesthesia by oral clonidine in humans. Anesth Analg 1994; 79: 1121–5.
14 Concas A, Santoro G, Mascia MP, Serra M, Sanna E, Biggio G. The general anesthetic propofol enhances the function of -aminobutyric acid-coupled chloride channel in the rat cerebral cortex. J Neurochem 1990; 55: 2135–8.[Medline]
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Goodchild CS. GABA receptors and benzodiazepines. Br J Anaesth 1993; 71: 127–33.
16 Hara M, Kai Y, Ikemoto Y. Enhancement by propofol of the -aminobutyric acidA response in dissociated hippocampal pyramydal neurons of the rat. Anesthesiology 1994; 81: 988–94.[Medline]
17 Davies PA, Hanna MC, Hales TG, Kirkness EF. Intensitivity to anaesthetic agents conferred by a class of GABAA receptor subunit. Nature 1997; 385: 820–23.[Medline]
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  D. Hohener, S. Blumenthal, and A. Borgeat Sedation and regional anaesthesia in the adult patient Br. J. Anaesth., January 1, 2008; 100(1): 8 - 16. [Abstract] [Full Text] [PDF]
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