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 Table of Contents  
Year : 2018  |  Volume : 5  |  Issue : 1  |  Page : 58-66

Effects of intrathecal midazolam in potentiating the analgesic effect of intrathecal dexmedetomidine in elderly patient undergoing hip repair surgeries

Department of Anesthesia and Intensive Care, Minia University Hospital, Minia, Egypt

Date of Web Publication24-Jan-2018

Correspondence Address:
Haidy S Mansour
Department of Anesthesia and Intensive Care, Minia University Hospital, Minia, 61691
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/roaic.roaic_33_17

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Objective This study was designed to assess the effect of intrathecal midazolam on dexmedetomidine with a low-dose bupivacaine in elderly patients undergoing hip repair surgery.
Materials and methods This is a double-blind study involving 75 patients with American Society of Anesthesiologists physical status II and III aged over 60 years scheduled for elective hip repair surgery under intrathecal anesthesia. They were randomly divided into three groups: control (C group) received 7.5 mg of 0.5% hyperbaric bupivacaine, dexmedetomidine group (D group) received 7.5 mg of 0.5% hyperbaric bupivacaine+5 μg of dexmedetomidine, and dexmedetomidine+midazolam group (DM) received 7.5 mg of 0.5% hyperbaric bupivacaine+5 μg of dexmedetomidine+1 mg of midazolam. The onset and duration of sensory and motor blockade, intraoperative hemodynamic change, and postoperative analgesia were recorded.
Results Compared with group C, the groups D and DM had significantly faster onset of sensory block (P=0.032 and 0.0001, respectively), faster onset of motor block (P=0.024 and 0.006, respectively), prolonged duration of sensory block (P=0.003 and 0.0001, respectively), prolonged duration of motor block (P=0.015 and 0.002, respectively), prolonged duration of postoperative analgesia (P=0.0001), and significantly decreased postoperative visual analog scale sedation score for 12 h. Compared with group D, group DM had a significantly longer duration of sensory block (P=0.012), longer duration of postoperative analgesia (P=0.042), and postoperative visual analog scale significantly decreased for 12 h postoperatively.
Conclusion Intrathecal addition of 1 mg midazolam to 5 µg dexmedetomidine and 7.5 mg 0.5% hyperbaric bupivacaine provided intraoperative hemodynamic stability, prolonged motor, and sensory block as well as potentiating the postoperative analgesic.

Keywords: dexmedetomidine, intrathecal, low-dose bupivacaine, midazolam

How to cite this article:
Mansour HS, Mohamad AH. Effects of intrathecal midazolam in potentiating the analgesic effect of intrathecal dexmedetomidine in elderly patient undergoing hip repair surgeries. Res Opin Anesth Intensive Care 2018;5:58-66

How to cite this URL:
Mansour HS, Mohamad AH. Effects of intrathecal midazolam in potentiating the analgesic effect of intrathecal dexmedetomidine in elderly patient undergoing hip repair surgeries. Res Opin Anesth Intensive Care [serial online] 2018 [cited 2021 Jun 15];5:58-66. Available from: http://www.roaic.eg.net/text.asp?2018/5/1/58/223832

  Introduction Top

Perioperative hypotension with spinal anesthesia may affect postoperative recovery and also increases the risk of ischemia secondary to hypotension especially in elderly patients. Thus, to decrease the incidence of hypotension after spinal anesthesia, low dose of local anesthetics along with additives is preferred not only to reduce adverse effects of local anesthetics but also to prolong analgesia [1].

Administration of combinations of drugs intrathecal targeting multiple spinal cord receptors leads to prolonged analgesia with superior quality. This can be achieved by relatively small concentrations of individual drugs [2].

Dexmedetomidine is a selective α2-adrenergic receptor agonist. It has a synergistic effect when added to intrathecal bupivacaine, and it has a high binding affinity to spinal α2-adrenoreceptors [3]. Its antinociceptive properties were produced by inhibiting the release of C-fiber transmitters, glutamate, and substance P from the terminals of primary afferent and by G-protein-mediated activation of K+ channels, which induce hyperpolarization of postsynaptic dorsal horn neurons, whereas bupivacaine acts as a local anesthetic by blocking Na+ channels [4],[5].

Consequently, the addition of dexmedetomidine intrathecally to low-dose bupivacaine produced a faster onset and longer duration of sensory block as well as a prolonged postoperative analgesia with minimal hemodynamic effects compared with bupivacaine alone [6],[7].

Furthermore, intrathecal midazolam reduces excitatory γ-aminobutyric acid-mediated neurotransmission in interneuron, leading to a decrease in the excitability of spinal dorsal horn neurons [8]. Moreover, it causes the release of an endogenous opioid that acts at the spinal delta receptor [9]. So, it can potentiate the effect of intrathecal bupivacaine and enhance the intraoperative anesthesia and analgesia in addition to postoperative analgesia [2],[10],[11],[12].

Some investigators recorded that the action of dexmedetomidine can be enhanced by midazolam owing to the facilitation of the release and or binding of γ-aminobutyric acid (inhibitory neurotransmitter) to its receptor. Moreover, dexmedetomidine can inhibit adenylate cyclase, thereby affecting the activity of cAMP-dependent protein kinase, which may affect the conductance properties of the Cl-channel [13]. Bol et al. [14] and Boehm et al. [15] measured the synergism combinations of midazolam and dexmedetomidine in rats. They found that the interaction was synergistic for all stimulus-response measures.

This study was conducted to evaluate the efficacy of adding midazolam to intrathecal dexmedetomidine and low-dose of hyperbaric bupivacaine in elderly patients undergoing hip repair surgery.


The primary outcomes were the onset and duration of sensory and motor blockade and postoperative analgesia. Secondary outcomes were hemodynamic changes and safety outcome.

  Materials and methods Top

After Institutional Ethics Committee approval, this prospective double-blind, randomized, controlled study was conducted at the Department of Anesthesia and Intensive Care Unit, El-Minia University Hospital, from December 2015 to February 2017. The study involved 75 adult patients older than 60 years of both sexes, with American Society of Anesthesiologists grades II and III, scheduled for surgery after hip fracture under intrathecal anesthesia. All patients gave written informed consent.

Exclusion criteria included spinal deformities like kyphoscoliosis, history of allergy or anaphylaxis to local anesthetics, morbidly obese patients, coagulopathies, severe cardiac or respiratory diseases, and uncontrolled hypertension.

The routine investigations were done for all patients; the drugs were prepared in the same volume (3 ml) outside the operating room by an assistant not involved in the procedure. The name of the drug to be given was sealed in envelopes numbered 1–75. A coded form of drug was then conveyed to another anesthesiologist who was blind to the type of drug given. The drugs used were dexmedetomidine [precedex 200 µg/2 ml (100 µg/ml); Hospira Inc., Lake Forest, Illinois, USA] and midazolam (dormicum 5 mg/ml; F. Hoffmann-La Roche Ltd, Basel, Switzerland).

The patients were randomly allocated into three study groups of 25 patients each as per computer-generated random number list:
  1. Group C received intrathecal 0.5% (5 mg/ml) hyperbaric bupivacaine 7.5 mg (1.5 ml)+preservative-free saline (1.5 ml).
  2. Group D received 0.5% hyperbaric bupivacaine 7.5 mg (1.5 ml)+5 μg dexmedetomidine diluted to 1.5 ml with preservative-free saline.
  3. Group DM received 0.5% hyperbaric bupivacaine 7.5 mg (1.5 ml)+dexmedetomidine 5 µg+midazolam 1 mg in 0.2 ml diluted to 1.5 ml with preservative-free saline.

We instructed the patients preoperatively about visual analog scale (VAS) (0 for no pain, 10 for the worst pain) [16] to measure the postoperative pain. Patients were moved to the operating room without premedication.

Noninvasive blood pressure, ECG, and peripheral oxygen saturation were monitored using a multiparameter monitor (Mindray iMEC12, Hi-Tech Industrial Park, Nanshan, Shenzhen, China). After an intravenous access was established, 500 ml of acetated Ringer’s solution was infused. Under all aseptic precautions in sitting position, a paramedian or median spinal puncture was performed at the L3–L4 interspinous spaces using a 22 G Quincke-type point spinal needle. Then, the patients were placed in the supine position for surgery. Oxygen was continuously given to the patients through a facemask.

Mean blood pressure and heart rate were recorded every 5 min up to 15 min and then every 15 min up to 90 min. Hypotension was defined as a decrease of SBP of more than 30% below baseline or of less than less than 90 mmHg. If hypotension occurred, it will treated with intravenous 5 mg ephedrine and repeated every 5 min if necessary. Bradycardia was defined as heart rate less than 55 beats/min for which 0.5 mg of atropine sulfate was administered intravenously.

The assessment of sensory level of block was done by using the loss of sensation to pinprick every 2 min, and the surgeons started the procedures when the block level was T10 (The onset of sensory block was the time from drug injection to the loss of sensation to pinprick at T10 level, and the peak block level was the level that persists during four consecutive tests). Testing was then conducted every 15 min until two-segment regression (the duration of sensory block was the time from drug injection to two-segment regression of sensory block by pinprick method).

Further testing was then done at 20 min intervals in the recovery room until the sensory level recovered to S2 dermatome. In case the block failed to reach the level of T10 within 20 min of intrathecal injection, the intrathecal dose was considered as inadequate and excluded from the study.

Motor block assessment was done using a modified Bromage scale (0=no paralysis, 1=unable to raise extended leg, 2=unable to flex knee, and 3=unable to flex ankle) [17]. It was recorded every 2 min from injection till Bromage scale=3 (the onset of motor block was the time from drug injection to Bromage grade 3), and then, every 15 min to the end of surgery. Further assessment was then performed every 20 min in the recovery room until Bromage score returned to 0 (the duration of motor block).

The level of sedation was recorded before administration of anesthesia, and assessment was repeated every 10 min for the first 30 min and then every 20 min until the end of surgery using Ramsay sedation scale [18].
  1. Anxious and agitated or restless, or both.
  2. Co-operative, oriented, and calm.
  3. Responsive to commands only.
  4. Exhibiting brisk response to light glabellar tap or loud auditory stimulus.
  5. Exhibiting a sluggish response to light glabellar tap or loud auditory stimulus.
  6. Unresponsive.

The maximal sedation score was recorded in each group. We can use midazolam intravenously in doses of 2 mg for sedation as and when required.

Intraoperative analgesia was recorded every 10 min from the beginning of surgery using a 10 cm visual analog pain scale (VAS). In the event of a patient complaining of pain during surgery with a pain score over 3, then 1 mg/kg of fentanyl was given intravenously.

Postoperative analgesia was assessed at rest with VAS at 1, 2, 4, 6, 8, 12, and 24 h, and if it was more than 3, the diclofenac sodium 75 mg intramuscularly was administered as rescue analgesia. The duration of analgesia was the time from intrathecal block to the first dose of rescue analgesia according to the patient’s demand.

Postoperative vital parameters were recorded every half an hour for 4 h and then every hour till the administration of rescue analgesia. Any perioperative complications, including behavioral changes, confusion, dizziness, bradycardia, hypotension, nausea and vomiting, shivering, and urinary retention, were recorded by a registered nurse who was blinded to the study.

All patients were shifted from PACU only when regression of sensory block occurred to S2 level and Bromage score of 0 was achieved.

Sample size estimation was made based on a previous study [19]; the primary endpoint of this study was the time to the regression of two-dermatomes from the peak sensory block level. The sample size was calculated using power analysis (α=0.05, β=0.8) to detect an increase in 30 min in the two-dermatome sensory regression time with an SD of 28 min, and was found to require at least 18 patients per group. Thus, we decided to include 25 patients per group to allow for possible dropout. Statistical analysis was performed with IBM SPSS version 22 software (SPSS Inc., Chicago, Illinois, USA). Data were presented as median (with interquartile range) or mean±SD. Qualitative data were presented as number (frequency distribution). χ2, Kruksal–Wallis, and Mann–Whitney tests were used to test the significant differences of qualitative data in between the studied groups, whereas analysis of variance test and then post-hoc test Scheffe’s test was used for pairwise comparison. The probability of less than 0.05 was considered as a cut-off value for significance.

  Results Top

A total of 75 elderly patients undergoing hip repair surgery under spinal anesthesia completed this study ([Figure 1]). Patient’s demographic data in the three groups were comparable ([Table 1]).
Figure 1 Flow diagram for participants.

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Table 1 Demographic profile

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The onset of sensory and motor block was significantly faster in dexmedetomidine and midazolam (DM) group and dexmedetomidine (D) group compared with the control (C) group with no significant difference was observed between groups D and DM. The difference in the highest sensory block levels between group C and other groups was statistically significant, with no significant difference between groups D and DM ([Table 2]).
Table 2 Spinal block and postoperative characteristics

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The DM group shows a significantly prolongation on the time to two-segment regression compared with groups C and D, and it was significantly longer in the D group compared with the control group. Although the time to motor block regression to Bromage 0 was significantly longer in the DM group compared with the control group and it was significantly longer in the D group compared with the control group, but there was no statistically significant difference between groups D and DM ([Table 2]).

Mean time of administration of analgesia was significantly prolonged in DM group when compared with other groups, and also significantly prolonged in group D when compared with group C. Moreover, the total amount of analgesia was significantly increased in group C when compared with other groups ([Table 3]).
Table 3 Postoperative analgesia

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The postoperative VAS score was significantly lower in the DM when compared with the group C at all times, whereas it also significantly lower in the D when compared with the C group for 12 h postoperatively. Moreover, the pain score was significantly lower in the DM group compared with the D group for up to 12 h postoperatively ([Table 4]).
Table 4 Postoperative pain scores at rest in the three groups

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There were no significant differences between the three groups regarding hemodynamic change ([Figure 2],[Figure 3],[Figure 4]). The SBP showed moderate fluctuations to the end of surgery in three groups. However, all these fluctuations were within the clinically conventional range.
Figure 2 Perioperative changes in heart rate in three groups.

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Figure 3 Perioperative changes in mean blood pressure in three groups.

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Figure 4 Oxygen saturation over time in three groups.

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The percentage of patients’ satisfaction (excellent) shows significant differences between the three groups at 24 h with significant increases in the percentage of patients in groups DM and D when compared with group C ([Table 5]).
Table 5 Patient’s satisfaction in the three groups at 24 h

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Regarding adverse effects, sedation, bradycardia, and hypotension were commensurate between groups, and none of the patients had nausea, vomiting, dry mouth, pruritis, or respiratory depression ([Table 6]).
Table 6 Incidence of adverse effects

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  Discussion Top

The addition of midazolam (1 mg) to an intrathecal low dose of 0.5% hyperbaric bupivacaine (7.5 mg) and dexmedetomidine (5 μg) mixture prolonged the duration of the sensory block. In addition, it prolonged the duration of analgesia and potentiated the postoperative analgesic effect of dexmedetomidine. These combinations provide a considerable effect as it produces minimal hemodynamic changes with improvement in the patient satisfaction.

The fast extension of the sympathetic block associated with subarachnoid block will increase the risk of prolonged and severe hypotension. The elderly patients cannot adapt this hemodynamic change owing to impairment of physiological compensatory mechanisms. So these patients must be provided with anesthesia of adequate duration and with high quality to avoid the adverse effects of any other additional anesthesia. Some investigators reported that the use of a small dose of local anesthetic may reduce the severity and incidence of hypotension after spinal block [20],[21] but it increases the incidence of inadequate blocks [22].

In our study, there was no clinically or statistically significant difference in the time for onset of sensory and the motor block between groups D and DM. The fast onset on sensory and motor blockade was because of the addition of dexmedetomidine, but there is no potentiating of the effect of adding midazolam.

The mechanism of motor blockade potentiated by dexmedetomidine is not well understood but is suggested to be related to the interference with neuromuscular activity [3] or binding of α2 agonists to motor neurons in the dorsal horn or an additive or synergistic effect to the local anesthetics [23],[24].

Our results were quite similar to that of Kanazi et al. [25], as they studied 60 patients undergoing bladder tumor or transurethral resection of prostate or bladder tumor under intrathecal anesthesia with bupivacaine. They showed that dexmedetomidine produced a faster onset of both motor and sensory blockade with prolonged duration of both motor and sensory blockade with minimal adverse effects.

Al-Mustafa et al. [19] also observed significant prolongation of motor block by adding 5 μ dexmedetomidine to intrathecal 12.5 mg 5% hyperbaric bupivacaine in urological operation.

Kim et al. [7] observed that addition of dexmedetomidine to bupivacaine intrathecally in elderly patients undergoing transurethral resection of prostate or bladder tumor showed a significant shortening in the onset of both sensory block and motor block. They used 3 μg dexmedetomidine with 6 mg bupivacaine, but they found that the onset time in their study was delayed than our result. This is because we used the larger dose of both bupivacaine (7.5 mg) and dexmedetomidine (5 μg). Esmaoğlu et al. [26] also in agreed with our results, who observed that the dexmedetomidine significantly shortened the onset of sensory block and motor block. Moreover, Agrawal et al. [1]and Gupta et al. [2], agree with us as they observed that 1 mg intrathecal midazolam with bupivacaine showed no significant difference in onset of sensory and motor blockade.

In contrast to our results, the result by Karbasfrushan et al. [11] demonstrated that adding 2 mg midazolam to bupivacaine significantly shortened the onset of sensory and motor block in women scheduled for cesarean delivery. This difference may be because of the large dose of midazolam.

Regarding the duration of sensory and motor block, the duration of sensory block in group DM was significantly prolonged when compared with group D. In addition, we founded that dexmedetomidine prolonged the analgesia, and addition of midazolam potentiated this action. The pain score was significantly decreased in the first 12 h postoperatively in both D and DM groups, with significant difference between DM and D groups for 12 h postoperatively.

These results are concordant with previous investigations. The study conducted by Kulkarni et al. [27] showed that addition of 1 mg of midazolam to 3 ml intrathecal bupivacaine prolong the duration of sensory block and provides effective and prolonged postoperative analgesia without significant adverse effect in patients scheduled for elective lower limb and lower abdomen surgeries. Bharti and colleagues [10],[28], reported that addition of 1 mg midazolam to 3 ml of 0.5% hyperbaric bupivacaine in patients undergoing lower abdominal surgery enhanced the duration of motor and sensory blockade reported with better postoperative analgesia. Moreover, Batra et al. [28] demonstrated that administration of midazolam with bupivacaine improved the duration of sensory block with better postoperative analgesia in patients undergoing knee arthroscopy without any adverse effects.

Gupta et al. [2] found that the duration of a motor and sensory block and the duration of analgesia were prolonged by administration of 1 mg midazolam to intrathecal 25 µg fentanyl without any significant hemodynamic compromise in patients scheduled for lower limb surgery.In our study, 7.5 mg of bupivacaine with 5 µg of dexmedetomidine or 5 µg of dexmedetomidine+midazolam resulted in a peak sympathetic block level of median T8 [T5–T12] and T7 [T5–T11], respectively, which did not produce significant hypotension or bradycardia perioperatively. Despite dexmedetomidine producing hypotension by acting on the spinal cord [23], a small dose of dexmedetomidine injected intrathecally at the lumbar level does not cause significant hypotension. Moreover, the sympathetic block is usually optimum with the standard doses of local anesthetics [4]. So, a low dose of local anesthetics is preferred especially in elderly people to avoid significant hypotension. However, most studies inject a low dose of intrathecal dexmedetomidine with a low dose of local anesthetic and they showed comparative hemodynamic responses similar to those of the current study [25],[29]. We did not observe any other significant adverse effects of intrathecal midazolam or dexmedetomidine in the current study, which is in accordance with previous studies [29],[30],[31]. On the contrary, Karbasfrushan et al. [11], showed that the use of intrathecal bupivacaine with midazolam 2 mg increased the occurrence of nausea and vomiting in women undergoing a cesarean delivery. The pregnant women are more predisposed to nausea and vomiting. Moreover, the high dose of midazolam may increase the incidence of nausea and vomiting.

Limitations and recommendation

First, there was a difficulty to standardize the pain variable as it is a personnel phenomenon especially with the elderly patients as there was a wide variability of responses among those patients.

Second, our used doses of dexmedetomidine (5 μg) and midazolam (1 mg) are low doses. This was done with the intention of providing safe and prolonged postoperative analgesia, so more studies should be done to compare different doses of the same drugs to identify the appropriate dose.

  Conclusion Top

The addition of intrathecal (1 mg) midazolam to (5 µg) dexmedetomidine and low dose (7.5 mg) hyperbaric bupivacaine is a safe combination for intrathecal anesthesia for hip repair surgery in elderly patients. It provided intraoperative hemodynamic stability, prolonged motor and sensory block as well as potentiating the postoperative analgesic effect with minimal complications compared with dexmedetomidine–bupivacaine.

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Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]

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