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From the Department of Anesthesia and Intensive Care Unit, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
Address correspondence to: Dr. Yatindra Kumar Batra, Anesthesia and Intensive Care unit, Postgraduate Institute of Medical Education and Research, Chandigarh-160012, India. Phone: +91-172-2715545; Fax: +91-172-2744401; E-mail: ykbatra{at}glide.net.in
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Abstract |
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Methods: A prospective, randomized, double blind study was conducted on 40 ASA I or II adult patients undergoing upper limb surgeries under supraclavicular brachial plexus block. Patients were randomly divided into two groups. Patients in Group B (n = 20) were administered 30 mL of 0.5% bupivacaine and Group BM (n = 20) were given 30 mL of 0.5% bupivacaine with midazolam 50 µg·kg–1. Hemodynamic variables (i.e., heart rate, noninvasive blood pressure), pain scores and rescue analgesic requirements were recorded for 24 hr postoperatively.
Results: The onset of sensory and motor block was significantly faster in Group BM compared to Group B (P < 0.05). Pain scores were significantly higher in Group B compared to Group BM from two hours to 24 hr postoperatively (P < 0.05). Rescue analgesic requirements were significantly less in Group BM compared to Group B (P < 0.05). Hemodynamics and sedation scores did not differ between groups in the post-operative period.
Conclusion: Midazolam (50 µg·kg–1) in combination with 30 mL of bupivacaine (0.5%) hastened onset of sensory and motor block, and improved postoperative analgesia when used in brachial plexus block, without producing any adverse events.
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Introduction |
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Methods |
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The patients were randomly divided into two groups. Patients in Group B (n = 20) received 30 mL of 0.5% bupivacaine while those in Group BM (n = 20) received 30 mL of bupivacaine 0.5% along with preservative free midazolam 50 µg·kg–1 (Neon laboratories Ltd., Mumbai, India). The patient and anesthesiologist observer were blinded to the test drug administered. The observer monitored the anesthesia and analgesia up to 24 hr in the postoperative period in all 40 patients. The assessment for onset of sensory and motor block was done every minute from the time of injection of test drug until the block was established. Sensory block was evaluated by temperature testing using spirit soaked cotton on skin dermatomes C4–T2, whereas motor block was assessed by asking the patient to adduct the shoulder and flex the fore-arm and hand against gravity.9 Onset of sensory block was defined as the time elapsed between injection of drug and complete loss of cold perception of the hand, while onset of motor block was defined as the time elapsed from injection of drug to complete motor block. Only patients with complete motor block were included in the study. Sedation was assessed using the sedation score described by Culebras et al.6 (1- awake and alert, 2- sedated, responding to verbal stimulus, 3- sedated, responding to mild physical stimulus, 4- sedated, responding to moderate or severe physical stimulus, 5- not arousable). Heart rate, noninvasive blood pressure, oxygen saturation and sedation score were measured every five minutes until the end of surgery. Duration of sensory block (the time elapsed between injection of the drug and appearance of pain requiring analgesia), and duration of motor block (time elapsed between injection of the drug to complete return of motor power) were also recorded. Pain was assessed using a numerical rating pain score scale where zero (0) represents no pain, and 100 means the worst possible pain. Fentanyl 2 µg·kg–1 iv was given as rescue analgesic when the pain score was more than 40. Postoperatively, heart rate, noninvasive blood pressure, pain and sedation scores were recorded at 0 min, 30 min, 2 hr, 6 hr, 12 hr and 24 hr.
Statistics
Assuming 90% statistical power and setting the level of significance at 5%, a sample size of 17 per group was considered adequate to discern improvement in pain scores at 24 hr. To allow for any incomplete studies, we enrolled 20 patients in each group. An unpaired t test was used to compare demographic variables, intraoperative hemodynamic variables (heart rate, systolic blood pressure) oxygen saturation, and onset and duration of sensory and motor block between the groups. Sedation scores and pain scores were compared by Mann Whitney U test, while rescue analgesic requirements in both groups were compared by Chi-square test. A P value less than 0.05 was considered statistically significant.
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Results |
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). Sensory and motor block appeared earlier in Group BM than in Group B (P < 0.05). In Group BM, onset of sensory block occurred in 12 ± 2.9 min compared to 20 ± 3.8 min in Group B. Onset time of motor block in Group BM was 9.2 ± 2.38 min compared to 17.1 ± 3.83 min in Group B. In both groups, motor block occurred earlier than sensory block (P < 0.05) but the duration of motor block was not different between groups (Table II).
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). All patients in Group B required rescue analgesia, while only three patients (15%) of group BM required rescue analgesics (P < 0.05). The number of rescue analgesic doses required was significantly higher (n = 58) in Group B compared to Group BM (n = 8, P < 0.05) during the study period.
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Heart rate, systolic blood pressure, diastolic blood pressure, mean arterial pressure, oxygen saturation were comparable between groups and did not change significantly in the intraoperative or postoperative period. No adverse events were encountered in either group of patients.
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Discussion |
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Our results showed that sensory block tended to last longer as compared to motor block which agrees with the observation by de Jong et al.3 These authors explained that large fibres require a higher concentration of local anesthetic than small fibres. The minimal effective concentration of local anesthetic for large (motor) fibres is greater than for small (sensory) fibres. Thus, motor function return before pain perception and duration of motor block is shorter than the sensory block.3 However, in our study duration of sensory and motor blocks were not different between the groups.
Various studies in which midazolam was used in central neuraxial block found that midazolam with bupivacaine improves analgesic characteristics compared to bupivacaine alone.10–12 Gulec et al.17 found that a bupivacaine and midazolam combination prolonged postoperative analgesia compared to a bupivacaine-morphine combination when administered caudally. Nishiyama et al.11 added midazolam to a continuous epidural infusion of bupivacaine and observed improved analgesia. Batra et al.18 used bupivacaine with midazolam intrathecally and found a significantly lower visual analogue score compared to bupivacaine alone. Midazolam produces this additive effect on local anesthetics by its action on the GABA-A receptor complexes present in the spinal cord.10–12 The addition of midazolam in doses of approximately 1 to 2 mg intrathecally has a positive effect on perioperative and chronic pain therapy.19 Studies in animals have revealed no neurotoxic effects of intrathecally administered midazolam.20–22 More recently, Tucker and associates demonstrated that the administration of intrathecal midazolam causes potentiation of the analgesic effect of intrathecal fentanyl in labouring patients.23 The administration of intrathecal midazolam, 2 mg, did not increase the occurrence of neurologic or urologic symptoms.24
In our study, pain scores were significantly lower in patients who received midazolam in addition to bupivacaine. The number of patients who required rescue analgesia and the mean number of supplemental analgesic boluses required were also significantly lower in patients in Group BM. The prolonged analgesia in Group BM could be due to the action of midazolam on GABA-A receptors present in the brachial plexus and thus producing antinociception. Various authors have demonstrated the presence of GABA receptors in peripheral nerves. Brown and Marsh demonstrated GABA receptors in mammalian peripheral nerve trunk.13 Bhisitkul et al. showed that axonal GABA receptors are present on both normal and regenerated sensory fibres in rat peripheral nerve.14 Cairns et al. observed the presence of GABA receptors within the tempromandibular joint and that its activation could decrease the transmission of nociceptive signals.15 The action of midazolam on GABA receptors is well established.
We studied midazolam at a dose of 50 µg·kg–1, as others have used the same dosage in central neuraxial block without any significant adverse effects.17,18 In our study, sedation scores were higher in patients in Group BM compared to Group B, 15 min after injecting the drug until 30 min postoperatively. This may have been due to partial vascular uptake of the drug (midazolam), and its transport to the central nervous system where it acts and produces sedation.25 The limited duration of sedation could be explained by the fact that midazolam is highly lipophilic and diffuses faster into the blood vessels, by its rapid clearance (6–11 mL·kg–1·min–1) and short half-life (1.7–2.6 hr).25 Though mean sedation score in group BM was higher as compared to group B (P < 0.05), we did not observe clinically significant sedation in patients in Group BM. The highest sedation score was 3; i.e., the patient was asleep and arousable by mild physical stimulation. No patient experienced airway compromise or required airway assistance.
In conclusion, midazolam 50 µg·kg–1 when added to 30 mL of bupivacaine 0.5% for supraclavicular brachial plexus block, speeds the onset of sensory and motor blocks (P < 0.05). The combination produces improved analgesia, as manifested by lower pain scores, a prolonged effect and reduced requirements for rescue analgesics.
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Footnotes |
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References |
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2 De Jong RH. Axillary block of brachial plexus. Anesthesiology 1961; 22: 215–25.[Medline]
3 de Jong RH, Wagman IH. Physiological mechanisms of peripheral nerve block by local anesthetics. Anesthesiology 1963; 24: 684–727.[Medline]
4 McGlade DP, Kalpokas MV, Mooney PH, Chamley D, Mark AH, Torda TA. A comparison of 0.5% ropivacaine and 0.5% bupivacaine for axillary brachial plexus anesthesia. Anaesth Intensive Care 1998; 26: 515–20.[Medline]
5 Bazin JE, Massoni C, Bruelle P, Fenies V, Groslier D, Schoeffler P. The addition of opioids to local anaesthetics in brachial plexus block: the comparative effects of morphine, buprenorphine, and sufentanil. Anaesthesia 1997; 52: 858–62.[Medline]
6 Culebras X, Van Gessel E, Hoffmeyer P, Gamulin Z. Clonidine combined with a long acting local anaesthetic does not prolong postoperative analgesia after brachial plexus block but does induce hemodynamic changes. Anesth Analg 2001; 92: 199–204.
7 Bone HG, Van Aken H, Brooke M, Burkle H. Enhancement of axillary brachial plexus block anesthesia by coadministration of neostigmine. Reg Anesth Pain Med 1999; 24: 405–10.[Medline]
8 Keeler JF, Simpson KH, Ellis FR, Kay SP. Effect of addition of hyaluronidase to bupivacaine during axillary brachial plexus block. Br J Anaesth 1992; 68: 68–71.
9 Bedder MD, Kozody R, Craig DB. Comparison of bupivacaine and alkalinized bupivacaine in brachial plexus anesthesia. Anesth Analg 1988; 67: 48–52.
10 Edwards M, Serrao JM, Gent JP, Goodchild CS. On the mechanism by which midazolam causes spinally mediated analgesia. Anesthesiology 1990; 73: 273–7.[Medline]
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12 Kim MH, Lee YM. Intrathecal midazolam increases the analgesic effects of spinal blockade with bupivacaine in patients undergoing haemorrhoidectomy. Br J Anaesth 2001; 86: 77–9.
13 Brown DA, Marsh S. Axonal GABA-receptors in mammalian peripheral nerve trunks. Brain Res 1978; 156: 187–91.[Medline]
14 Bhisitkul RB, Villa JE, Kocsis JD. Axonal GABA receptors are selectively present on normal and regenerated sensory fibers in rat peripheral nerves. Exp Brain Res 1987; 66: 659–63.[Medline]
15 Cairns BE, Sessle BJ, Hu JW. Activation of peripheral GABAA receptors inhibits temporomandibular joint-evoked jaw muscle activity. J Neurophysiol 1999; 81: 1966–9.
16 Winnie AP, Tay CH, Patel KP, Ramamurthy S, Durrani Z. Pharmacokinetics of local anaesthetics during plexus blocks. Anesth Analg 1977; 56: 852–61.
17 Gulec S, Buyukkidan B, Oral N, Ozcan N, Tanriverdi B. Comparison of caudal bupivacaine, bupivacaine-morphine and bupivacaine-midazolam mixtures for post-operative analgesia in children. Eur J Anaesthesiol 1998; 15: 161–5.[Medline]
18 Batra YK, Jain K, Chari P, Dhillon MS, Shaheen B, Reddy GM. Addition of intrathecal midazolam to bupivacaine produces better post-operative analgesia with-out prolonging recovery. Int J Clin Pharmacol Ther 1999; 37: 519–23.[Medline]
19 Serrao JM, Marks RL, Morley SJ, Goodchild CS. Intrathecal midazolam for the treatment of chronic mechanical low back pain: a controlled comparison with epidural steroid in a pilot study. Pain 1992; 48: 5–12.[Medline]
20 Serrao JM, MacKenzie JM, Goodchild CS, Gent JP. Intrathecal midazolam in the rat: an investigation of possible neurotoxic effects. Eur J Pharmacol 1990; 7: 115–22.
21 Nishiyama T, Matsukawa T, Hanaoka K. Acute phase histopathological study of spinally administered mid-azolam in cats. Anesth Analg 1999; 89: 717–20.
22 Schweiger IM, Jorge-Costa M, Pizzolato GP, Foster A, Morel DR. Intrathecal midazolam reduces isoflurane MAC and increases the apnoeic threshold in rats. Can J Anaesth 1994; 41: 144–8.
23 Tucker AP, Mezzatesta J, Nadeson R, Goodchild CS. Intrathecal midazolam II: combination with intrathecal fentanyl for labor pain. Anesth Analg 2004; 98: 1521–7.
24 Tucker AP, Lai C, Nadeson R, Goodchild CS. Intrathecal midazolam I: a cohort study investigating safety. Anesth Analg 2004; 98: 1512–20.
25 Reeves JG, Fragen RJ, Vinik HR, Greenblatt DJ. Midazolam: phamacology and uses. Anesthesiology 1985; 62: 310–24.[Medline]
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