Table of Contents  
Year : 2015  |  Volume : 8  |  Issue : 4  |  Page : 602-607

Does intrathecal midazolam improve hyperbaric bupivacaine-fentanyl anesthesia in elderly patients?

1 Department of Anaesthesiology, Theodor Bilharz Research Institute, Giza, Egypt
2 Department of Anaesthesiology, Faculty of Medicine, El-Fayoum University, Fayoum, Egypt

Date of Submission16-Oct-2014
Date of Acceptance08-Mar-2015
Date of Web Publication29-Dec-2015

Correspondence Address:
Maged L Boules
26 Atbara Street, Mohandessin, Giza
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1687-7934.172748

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To assess the effect of intrathecal midazolam with bupivacaine-fentanyl in elderly patients undergoing endourologic procedures.
Materials and methods
This prospective, randomized, double-blind study involved 60 ASA physical status II-III patients aged over 60 years scheduled for elective endoscopic urologic procedures under spinal anesthesia with hyperbaric bupivacaine 0.5% (5 mg/ml). They were randomized into one of three equal groups of 20 patients each: the first group, control group (group C), received 7.5 mg hyperbaric bupivacaine 0.5% in a volume of 1.5 ml; the second group, fentanyl group (group F), received 7.5 mg hyperbaric bupivacaine 0.5% in a volume of 1.5 ml and 10 mg fentanyl (0.1 ml); and the third group, fentanylmidazolam group (group FM), received 7.5 mg hyperbaric bupivacaine 0.5% in a volume of 1.5 ml and 10 mg fentanyl (0.1 ml) plus 1.0 mg of midazolam (0.2 ml). Sensory and motor effects were assessed. Postoperative pain, sedation, and adverse effects were also recorded.
The three studied groups were comparable in demographic and clinical characteristics. They were hemodynamically stable. There was no significant difference between the three groups in the onset of sensory (P = 0.721) and motor block (P = 0.342), duration of motor block (P = 0.286), and sedation score (P = 0.229). Duration of sensory block was prolonged in group F compared with the control group (P < 0.001) and prolonged more in group FM compared with the F group (P = 0.065). Time to first request of rescue analgesic was significantly longer in group F compared with the C group (P = 0.033) and in FM compared with the F group (P < 0.001). All patients reported excellent or good degree of satisfaction with anesthetic procedure (P = 0.547).
Adjuvant intrathecal midazolam resulted in intraoperative hemodynamic stability and safely potentiates postoperative analgesic effect of bupivacainefentanyl spinal anesthesia in elderly patients undergoing endourologic procedures.

Keywords: adjuvant, fentanyl, intrathecal bupivacaine, midazolam, spinal anesthesia

How to cite this article:
Ebied RS, Ali MZ, Boules ML, Samhan YM. Does intrathecal midazolam improve hyperbaric bupivacaine-fentanyl anesthesia in elderly patients?. Ain-Shams J Anaesthesiol 2015;8:602-7

How to cite this URL:
Ebied RS, Ali MZ, Boules ML, Samhan YM. Does intrathecal midazolam improve hyperbaric bupivacaine-fentanyl anesthesia in elderly patients?. Ain-Shams J Anaesthesiol [serial online] 2015 [cited 2023 Sep 28];8:602-7. Available from:

  Introduction Top

Spinal anesthesia is used in a variety of lower abdominal, urologic, orthopedic, and minor vascular procedures. It is easy to perform and provides rapid onset and effective sensory and motor block. Hyperbaric lidocaine, which is superior for short-lasting surgery, has been implicated in transient neurological symptoms and caudaequina syndrome [1],[2] . A small dose of hyperbaric bupivacaine produces a short-lasting spinal anesthesia, which may be clinically useful in ambulatory surgical procedures. It also reduces the risk for transient neurologic symptoms [3] .

Systemic hypotension and bradycardia are the most common side effects observed during central neural block. Marked hypotension is dangerous, particularly in elderly patients with limited cardiac reserve [4] . In the elderly, gradual degeneration of the peripheral and central nerves, changes in the anatomical configuration of the lumbar and thoracic vertebrae, and the decrease in the cerebrospinal fluid volume may all contribute to the increase in sympathetic block level [5],[6],[7],[8] . The use of low-dose bupivacaine is recommended to reduce its cardiovascular side effects; however, this may not provide an adequate anesthesia level for surgery [9],[10] .

Therefore, combinations of very small doses of such anesthetic with adjuvants are frequently administered to reduce the adverse hemodynamic effects associated with the spinal anesthesia-induced medical sympathectomy [11],[12] . Highly lipophilic, short-acting opioids such as fentanyl are often added to local anesthetics as an adjuvant to improve the quality and duration of analgesia with hemodynamic stability [13],[14],[15],[16] .

Midazolam, a water-soluble imidobenzodiazepine, has also been reported to have a spinally mediated antinociceptive effect [17],[18] . Its intrathecal administration improves the quality of intraoperative anesthesia and analgesia and prolongs the duration of postoperative analgesia, without increasing adverse effects [19],[20] . Intrathecal analgesia can be improved by combining opioids with other classes of analgesics [21],[22] . Although the administration of intrathecal midazolam was proven to potentiate the analgesic effect of intrathecal fentanyl in laboring parturients, such combination and its optimal dose are not yet established as a suitable intrathecal local anesthetic adjuvant in surgery [21] .

This prospective, randomized, double-blind, comparative study is designed to assess the effectiveness of combining fentanyl and midazolam to intrathecal hyperbaric bupivacaine in elderly patients undergoing endourologic procedures under spinal anesthesia. The primary outcome of this study was set to be the effects of adjuvants added to intrathecal bupivacaine 0.5% on hemodynamic variables. The secondary outcome was to assess the motor, sensory, and regression of such drug combinations, as well as intraoperative and postoperative analgesia and complications.

  Materials and methods Top

After Ethical Committee approval and patients' written informed consent, 60 ASA physical status II-III patients, aged over 60 years, scheduled for elective endoscopic urologic procedures (diagnostic cystoscopy, ureterorenoscope, and transurethral resection of tumor) under spinal anesthesia were enrolled in this study. Any patient with contraindication to regional anesthesia, a history of chronic use of analgesic medications or hypersensitivity to the drugs under investigation was excluded. Patients were randomized using sealed envelope method and the drug combination used was prepared by an anesthetist not involved in the study for blinding purposes.

No premedication was given to any patient. On arrival to the operating room, standard monitoring, including five-lead ECG, noninvasive blood pressure, SpO 2 was attached to the patients and baseline hemodynamics were recorded. An 18 G intravenous Teflon cannula was inserted followed by an intravenous crystalloid preload of prewarmed 0.9% NaCl (7 ml/kg) administered slowly over 30 min in all groups. Oxygen supplementation at a rate of 3 l/min was also administered to the patients through nasal prongs.

Patients were then put in the sitting position. After preparation and draping of the patient's back under strict aseptic precautions, a skin wheal was made using 3 ml of lidocaine HCl 1% in the L3-L4 lumbar interspace. After a spinal introducer insertion, a 25 G Quincke spinal needle was passed through it by a midline or paramedian approach, according to the difficulty of the case. Following free flow of cerebrospinal fluid, 2 ml of the study solution was injected intrathecally according to the randomization list, by the anesthetist who prepared the drug and who was not involved in the study as follows: the control group (group C) (n = 20) received 7.5 mg hyperbaric bupivacaine 0.5% in a volume of 1.5 ml; the fentanyl group (group F) (n = 20) received 7.5 mg hyperbaric bupivacaine 0.5% in a volume of 1.5 ml and 10 mg fentanyl (0.1 ml); and the fentanylmidazolam group (group FM) (n = 20) received 7.5 mg hyperbaric bupivacaine 0.5% in a volume of 1.5 ml and 10 mg fentanyl (0.1 ml) plus 1.0 mg of preservative-free midazolam (0.2 ml). The injected volume in all groups was kept constant at 2 ml by adding preservative-free 10% dextrose. Patients were then returned to the supine position.

The height and regression of the sensory block was determined at 2-min intervals by pinprick. A T10 sensory level was a prerequisite for beginning surgery. Immediately before the start and at the end of surgery, motor blockade was determined using a Bromage score (1 = free movements of legs; 2 = just able to flex the knees; 3 = unable to flex the knees; 4 = unable to move the leg or feet) [Table 1]. Perioperative complications in the form of nausea, vomiting, pruritus, or respiratory depression were recorded using a four-point scale (0 = none, 1 = mild, 2 = moderate, and 3 = severe). In the event of nausea or vomiting, the patients were given ondansetron 4 mg intravenously. Sedation was rated using a four-point scale (1 = responds readily to name spoken in a normal tone, 2 = lethargic response to name spoken in a normal tone, 3 = responds only after name is called loudly or repeatedly, and 4 = responds only after mild shaking). Intraoperatively, heart rate, noninvasive blood pressure, and SpO 2 were recorded every 5 min until the end of the surgical procedure and then every 15 min until discharge from postanesthesia care unit (PACU). Intraoperative hypotension defined as 20% drop of the systolic blood pressure from baseline was treated with increments of 3 mg ephedrine intravenously, whereas bradycardia defined as a drop of the heart rate below 45 beats/min was treated with atropine sulfate 0.6 mg intravenously.
Table 1 Bromage score [23]

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Recovery milestones were assessed at 10-min intervals. Full motor and sensory recovery were prerequisites for ambulation. PACU discharge eligibility was determined using a modified Aldrete score. Time ambulation eligibility was calculated as the time from spinal anesthesia until total regression of motor and sensory blockade. On PACU discharge, patient satisfaction with the anesthetic management was assessed (excellent, good, and poor).

After complete neurologic recovery and with the first dose of postoperative analgesia needed, this study is assumed to be completed.

Statistical methods

Data were analyzed using IBM SPSS Advanced Statistics, version 20.0 (SPSS Inc., Chicago, Illinois, USA). Numerical data were expressed as mean and SD or median and range as appropriate. Qualitative data were expressed as frequency and percentage. c2 -test (Fisher's exact test) was used to examine the relation between qualitative variables. For quantitative data, comparison between the three groups was made using analysis of variance test or KruskalWallis test as appropriate, then post-hoc 'Schefe test' was used for pairwise comparison. A P-value less than 0.05 was considered significant.

  Results Top

The three studied groups were comparable in the demographic and clinical characteristics [Table 2]. Statistically, there was no significant difference between the three groups in mean arterial pressure and heart rate. Moderate fluctuations were observed up to the end of surgery in three groups. However, all these changes were within the clinically accepted ranges (±20% of baseline). Comparable values were observed in the three groups [Figure 1] and [Figure 2]. [Figure 3] shows mild changes in SpO 2 in the three groups.
Figure 1: Changes in heart rate till the end of surgery in the three studied groups

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Figure 2: Changes in the mean arterial pressure (MAP) till the end of surgery in the three studied groups

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Figure 3: Changes in SpO2 till the end of surgery in the three studied groups. SpO2, oxygen saturation

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Table 2 Demographic and clinical characteristics of the studied groups

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The onset of sensory block (time to T10 sensory deficit, min.) was comparable in the three groups (P = 0.721), similar to the onset of motor block (P = 0.342). However, the duration of sensory block was prolonged in group F compared with the control group (P < 0.001) and prolonged more in group FM compared with group F, but the difference was not statistically significant (P = 0.065). There was no significant difference in the onset or duration of motor block between the three groups (P = 0.342 and 0.286, respectively). Bromage score was comparable in the three groups at the beginning and end of surgery. Time to first request of rescue analgesic was significantly longer in group F as compared with group C (P = 0.033) and in group FM compared with group F (P < 0.001). On the other hand, sedation score was comparable in the three groups (P = 0.229). All patients reported excellent or good degree of satisfaction with anesthetic procedure (P = 0.547). None of the patients had nausea, vomiting, pruritis, or respiratory depression [Table 3].
Table 3 Anesthetic criteria in the three studied groups

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  Discussion Top

Addition of midazolam to a combination of intrathecal bupivacainefentanyl prolonged the duration of sensory block in elderly patients undergoing endourologic procedures. In addition, midazolam potentiated the postoperative analgesic effect without prolongation of motor block or sedation. This combination attained a high degree of patient satisfaction with minimal side effects.

Our results are concordant with previous investigations. Batra et al. [24] reported better postoperative analgesia and a prolonged sensory blockade with intrathecal administration of midazolam with bupivacaine. Others investigators confirmed the analgesic effects of intrathecal midazolam during leg surgery [18] , chronic lumbar pain [25] , and lower abdominal surgery [10],[21] . Tucker et al. [26] assessed the analgesic effect and safety of intrathecal midazolam in combination with fentanyl during labor. It enhanced the analgesic effect of fentanyl without increasing maternal or fetal adverse effects.

In contrast with our results, Bharti and colleagues found that the duration of motor blockade was prolonged in the midazolam group when compared with the control group. These patients received 3 ml of 0.5% hyperbaric bupivacaine intrathecally with 1 mg of midazolam. The difference in the intrathecal bupivacaine dose might explain such prolongation [19] . Comparing intrathecal midazolam with clonidine, Joshi and colleagues also reported prolonged motor block in the midazolam group yet with adequate hemodynamic stability. They used double the dosage of our study being 15 mg bupivacaine with 2 mg midazolam [10] .

A previous meta-analysis concluded that the addition of intrathecal midazolam in a dose of 1 or 2 mg prolonged the postoperative analgesic effect of bupivacaine by ~2 and 4.5 h, respectively, after hemorrhoidectomy [27] .

The mechanism of analgesic effect of midazolam has been explored in many studies [19],[28],[29],[30] . Three possible mechanisms were suggested. First, the benzodiazepine/g-aminobutyric acid receptor complex mediated analgesia [30],[31] . It also causes release of endogenous opioid acting at spinal delta receptors as naltrinadole, a delta receptor opioid antagonist suppressing its analgesic effect [32] . Third, it inhibits adenosine uptake or enhances adenosine release [33] .

We did not observe any significant adverse effects of intrathecal midazolam in the current study. A prospective study on 1100 patients who received intrathecal midazolam for various surgical procedures under spinal anesthesia confirmed such safety. They did not observe symptoms of neurological impairment as motor or sensory changes and bladder or bowel dysfunction [34] . They concluded that 2 mg of intrathecal midazolam did not increase symptoms suggestive of neurological damage compared with conventional therapies. This was confirmed by other investigators [28],[35],[36] . On the contrary, Karbasfrushan and colleagues showed that combination of intrathecal bupivacaine 10 mg with midazolam 2 mg in women undergoing elective cesarean section increased the incidence of nausea and vomiting. The duration of effective analgesia and the time for regression of sensory analgesia was the same in both groups. The increased incidence of nausea and vomiting may be attributed to increase in the midazolam dose and type of patients as pregnant women are more prone to nausea and vomiting [37] .

  Conclusion Top

The addition of 1 mg midazolam to 7.5 mg hyperbaric bupivacaine and 10 mg fentanyl injected intrathecally is a safe combination for spinal anesthesia for endourologic procedures in elderly patients. It provided intraoperative hemodynamic stability, extended sensory block as well as potentiation of postoperative analgesic effect with minimal complications.

  Acknowledgements Top

This research work has been done in Theodor Bilharz Research Institute.

Conflicts of interest

None declared.

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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2], [Table 3]

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