|Year : 2020 | Volume
| Issue : 2 | Page : 174-179
Effects of intrathecal midazolam-bupivacaine combination on postoperative analgesia
Rabab S.H El-Seddawy, Rasheda El Sayed Azzam, Thoraya A.-E Mohamed, Mohamed Abd-Allah Amin
Department of anesthesia, Intensive Care and Pain Management, Faculty of Medicine for Girls Al-Azhar University, Cairo, Egypt
|Date of Submission||09-Feb-2020|
|Date of Decision||11-Feb-2020|
|Date of Acceptance||19-Feb-2020|
|Date of Web Publication||29-Jun-2020|
Mohamed Abd-Allah Amin
Assistant Professor of Anesthesia and Intensive Care, Faculty of Medicine for Girls, AL-Azhar University, 75, Talal Mohamed Saad Allah Street, Omranya Sharqya, Giza, 12511
Source of Support: None, Conflict of Interest: None
Background and aim Subarachnoid injection of local anesthetic with midazolam potentiates spinal blockade. Midazolam is known to produce antinociception and to potentiate the effect of local anesthetic when given in the neuraxial block without significant side effects. This study was designed to assess the effects of adding midazolam to intrathecal bupivacaine in patients undergoing subumbilical surgery.
Patients and methods Sixty adult patients were randomly divided into two groups: Group I was administered 3 ml of 0.5% hyperbaric bupivacaine+0.4 ml of normal saline and Group II was administered 3 ml of 0.5% hyperbaric bupivacaine+2 mg (0.4 ml) of preservative-free midazolam. Time of onset of sensory analgesia, level of sensory blockade, time for maximum cephalic spread, and motor blockade as well as vital parameters and intraoperative complications were assessed and recorded. Postoperative pain scores were assessed using the visual analog scale immediately postoperatively.
Results The level of sensory blockade is higher in group II while the time of maximum cephalic spread was longer in group I. Concerning the postoperative visual analog scale, there were lower scores in group II than in group I. There was significant difference between groups I and II regarding total diclofenac sodium consumption in the postoperative 24 h with total consumption of 146.83±53.25 and 112.33±25.18 mg, respectively. The P value was found to be 0.002.
Conclusion Subarachnoid injection of preservative-free midazolam as an adjuvant to intrathecal bupivacaine potentiates its effect in terms of prolonged motor and sensory blockade without any significant hemodynamic compromise or sedation and with a significant decrease of postoperative analgesic requirements.
Keywords: analgesia, bupivacaine, midazolam, subarachnoid
|How to cite this article:|
El-Seddawy RS, El Sayed Azzam R, Mohamed TA, Amin MA. Effects of intrathecal midazolam-bupivacaine combination on postoperative analgesia. Sci J Al-Azhar Med Fac Girls 2020;4:174-9
|How to cite this URL:|
El-Seddawy RS, El Sayed Azzam R, Mohamed TA, Amin MA. Effects of intrathecal midazolam-bupivacaine combination on postoperative analgesia. Sci J Al-Azhar Med Fac Girls [serial online] 2020 [cited 2020 Jul 11];4:174-9. Available from: http://www.sjamf.eg.net/text.asp?2020/4/2/174/288267
| Introduction|| |
Subarachnoid block provides adequate anesthesia for patients undergoing subumbilical surgery. Among the local anesthetics, 0.5% hyperbaric bupivacaine is the most commonly used drug for spinal anesthesia. However, the most important disadvantage of a single subarachnoid bupivacaine injection is the limited duration of action. A number of adjuvants have been added to intrathecal local anesthetics for supplementation of intraoperative anesthesia and postoperative analgesia. Midazolam is known to produce antinociception and to potentiate the effect of local anesthetic when given in the neuraxial block without having significant side effects . By administrating intrathecal combinations of drugs, targeting different spinal cord receptors, prolonged and superior quality of analgesia can be achieved by relatively small concentrations of individual drugs. The dose reduction may avoid drug-related side effects. In addition, simultaneous targeting of several different receptor sites in the spinal cord may lead to improved pain relief .
The aim of this study was to assess the effects of midazolam bupivacaine combination on the duration of sensory and motor blockades and postoperative analgesia in patients subjected to subumbilical surgeries.
| Patients and methods|| |
After obtaining Institutional Ethics Committee approval and patient’s informed consent, this study was conducted on 60 patients with physical status American Society of Anesthesiologists I and II, aged 21–60 years of both sexes, and subjected to elective subumbilical surgeries in Al-Zahraa University Hospital from January 2019 to November 2019. Exclusion criteria included age less than 21 years or over 60 years and those with any contraindication to regional anesthesia (allergy to local anesthetic drugs or midazolam and coagulation disorders, patients with unstable cardiac and psychological disorder, and pregnancy).
Patients were randomly assigned by computer-generated random number and sealed opaque envelopes into two equal groups. Group I patients received 3 ml of hyperbaric bupivacaine 0.5% +0.4 ml of 0.9% saline intrathecally. Group II patients received 3 ml of hyperbaric bupivacaine 0.5%+0.4 ml and preservative-free midazolam (2 mg) intrathecally.
The primary outcome was postoperative analgesia regarding visual analog scale (VAS) and requirement of rescue analgesic. The secondary outcomes were onset of sensory analgesia, maximum level of sensory analgesia, time to reach Bromage3, time of maximum cephalic spread, hemodynamic changes, and perioperative adverse effects.
Preoperative assessment was done and patients were instructed to use VAS for pain assessment postoperatively. In the operating room, an intravenous wide-bore cannula (18 G) was inserted and infusion started with Ringer’s lactate at 10 ml/kg over 15–20 min. Standard monitoring (noninvasive blood pressure, electrocardiography, and pulse oximetry) was attached and the baseline parameters [mean arterial blood pressure (MAP), heart rate (HR) and peripheral arterial oxygen saturation (SpO2%)] were recorded.
After that, the patient was prepared to receive spinal anesthesia under complete aseptic conditions. Subarachnoid injection was done using a 25 G Quincke spinal needle in the L3–L4 interspace in the midline or the paramedian approach with the patient in the sitting position, and after confirming free flow of the cerebrospinal fluid (CSF) obtained. A measure of 3.4 ml of the test drug mixture was injected over 10 s. Vital parameters were recorded before administration of the subarachnoid blockade, immediately after the block, and then every 5 min until completion of surgery. Time of onset of sensory analgesia, defined as the time taken from the end of the injection to the first dull response to pinprick in the distribution of any of the sensory nerves in the lower limbs, was recorded. The level of sensory blockade was assessed by the pinprick test using the VAS every minute until it reached its maximum level and the VAS at this level is 0. The time for maximum cephalic spread, defined as the time between injection and the time of peak sensory level, was recorded. Motor blockade was assessed by using the Bromage scale that was performed every minute after intrathecal injection until achieving a Bromage score of 3. Adverse effects in the form of hypotension, bradycardia, nausea and vomiting, and sedation were recorded and managed. Sedation was assessed by a modified Ramsay sedation scale ‘1=anxious, agitated, restless; 2=cooperative, oriented, tranquil; 3=responds to commands only; 4=brick response to light or loud noise; 5=sluggish response to light or loud noise; and 6=no response’ .
Postoperatively, HR and MAP were recorded every 30 min for 24 h. Pain scores with VAS were assessed immediately postoperatively, after 2, 6, 12, and 24 h or when the patient complained of pain. First time for requirement of analgesia was recorded. Intramuscular diclofenac sodium 1.5 mg/kg was given when the patient demanded it. Duration of pain relief was taken as the time from the onset of subarachnoid block to the time of administration of rescue analgesia or a VAS value greater than 4 cm, whichever is first. Total diclofenac sodium consumption during 24 h postoperatively was recorded.
Sample size justification
MedCalc version 126.96.36.199 program (MedCalc Software, Ostend, Belgium) was used for calculations of sample size, statistical calculator based on 95% confidence interval, and power of the study 80% with an α error of 5%, According to a previous study, Fahmy et al.  showed that the VAS score was lower in the midazolam group (33.6±4.68 mm) when compared with the control group (56.6±8.64 mm). This difference was statistically highly significant with a P value of 0.001. Therefore, it can be relied upon in this study. On the basis of this assumption, the sample size was calculated according to these values and produced a minimal sample size of 57 patients which was enough to find such a difference. Assuming a dropout ratio of 5%, the sample size will be 60 patients, who were divided into two groups: group I (n=30) and group II (n=30).
Independent-samples t-test of significance was used when comparing between two means. χ2-test of significance was used in order to compare proportions between qualitative parameters. The confidence interval was set to 95% and the margin of error accepted was set to 5%. Therefore, a P value less than 0.05 was considered significant and a P value less than 0.001 was considered as highly significant while a P value greater than 0.05 was considered insignificant. Postoperative complications such as nausea, vomiting, and urinary retention were also noted. Recorded data were analyzed using the Statistical Package for the Social Sciences, version 20.0 (SPSS Inc., Chicago, Illinois, USA). Quantitative data were expressed as mean±SD. Qualitative data were expressed as frequency and percentage.
| Results|| |
Sixty patients participated in this study. These patients were divided into two equal groups: groups I and II. There was insignificant difference between both groups regarding demographic data, type of surgery, and its duration ([Table 1] and [Table 2]).
|Table 1 Comparison between the study groups according to demographic data and duration of operation|
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|Table 2 Comparison between groups I and II according to the type of operation|
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Regarding intraoperative HR, MAP, and SpO2% there were insignificant difference between the study groups ([Figure 1],[Figure 2],[Figure 3], respectively).
|Figure 1 Comparison between the study groups according to heart rate (beats/min).|
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|Figure 2 Comparison between the study groups according mean arterial blood pressure (mmHg).|
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|Figure 3 Comparison between the study groups according to peripheral arterial oxygen saturation.|
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Concerning the onset of sensory analgesia and time to reach Bromage3, there were insignificant differences between both groups. On the other hand, the maximum thoracic segment level of sensory analgesia was higher in group II and the time of maximum cephalic spread was longer in group I ([Table 3]).
|Table 3 Comparison between the study groups according to assessment of sensory and motor blockades|
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Concerning postoperative VAS, there were significant differences between both groups with lower scores in group II at 2, 6, and 12 h, while at 24 h there was insignificant difference between both groups ([Table 4]).
|Table 4 Comparison between the study groups according to visual analog scale|
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Concerning intraoperative adverse effects, there were insignificant differences between both groups ([Table 5]).
|Table 5 Comparison between the study groups according to intraoperative adverse effects|
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Regarding intraoperative administration of atropine and ephedrine, there were insignificant differences between both groups ([Table 6]). No postoperative adverse effects occurred in both groups.
|Table 6 Comparison between the study groups according to intraoperative administration of atropine and ephedrine|
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Concerning the time of first analgesic requirement postoperatively, there was a highly significant difference between both groups ([Table 7]).
|Table 7 Comparison between the study groups according to the time of first rescue analgesia (h)|
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There was significant difference between the two groups regarding postoperative total diclofenac sodium consumption in 24 h ([Table 8]).
|Table 8 Comparison between the study groups according to total diclofenac sodium consumption in 24 h|
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| Discussion|| |
Prolonging spinal anesthesia duration with postoperative pain relief without complications using fewer number and least doses of drugs is a goal for many researches all over the world. One of the methods of providing postoperative analgesia is to prolong the duration of intrathecal bupivacaine by using additives such as opioids, midazolam, and ketamine. Intrathecal midazolam induces antinociceptive effects in humans. Three possible mechanisms are suggested for the antinociceptive action of midazolam. First, the benzodiazepine/GABA-A receptor complex mediated analgesia, as they are abundantly present in lamina II of the dorsal horn of the spinal cord . It also causes release of endogenous opioids acting at spinal delta receptors such as naltrindole; a delta receptor opioid antagonist suppresses its analgesic effect . Third, it inhibits adenosine uptake or enhances adenosine release .
Midazolam produces an analgesic action through the benzodiazepine GABA-A complex in the spinal cord. Previous preclinical studies have demonstrated that midazolam either intrathecally or epidurally produces a dose-dependent modulation of pain without neurotoxicity, respiratory depression, or sedation .
This study has shown that administration of bupivacaine with midazolam intrathecally prolongs the duration of sensory blockade as evidenced by lower scores of VAS, delayed time of first analgesia requirement, postoperatively, and decreased total analgesic requirement after surgery. These effects were achieved without additional complications or hemodynamic changes.
Comparing the results of this study with other studies showed agreement among them in many aspects, most apparently that midazolam bupivacaine combination leads to prolongation of sensory block with hemodynamic stability. Shadangi et al.  studied 100 patients for the effect of intrathecal midazolam compared with placebo, and they found that the duration of effective analgesia was significantly longer in the midazolam group compared with the control group.
Comparing the onset time of sensory blockade between the two studies, there were insignificant differences between both groups in our study (71.07±8.11 and 68.93±7.47 s, respectively) and Shadangi et al. study  (4.8±0.6 and 4.6±0.7 min in group B and group BM, respectively). There was obvious long time of sensory blockade onset in their study because they defined it as the time interval between the completion of intrathecal drug injection to the onset of complete loss of pinprick sensation at T8 in contrary to ours which defined it as the time taken from the end of the injection to the first dull response to pinprick in the distribution of any of the sensory nerves in the lower limb. The same conclusion is that intrathecal midazolam improves and prolongs postoperative analgesia. This conclusion was one of the results of a metanalysis on 13 randomized control studies involving 672 patients conducted by Ho and Ismail .
Vibhuti and Hetavi  found that intrathecal midazolam has analgesic properties and potentiates the effects of intrathecal local anesthetic when they added 1 mg midazolam to 15 mg hyperbaric bupivacaine. Contrary to our study, they found no statistically significant differences between the two groups of their study regarding the time of onset of sensory block. This difference between the two studies might be due to the lower dose of midazolam (1 mg) used. Also, a study done by Fahmy et al.  showed insignificant difference between the two groups of their study regarding the time of sensory analgesia onset (T10 dermatome) and time to peak sensory level although they used the same doses of our study.
Regarding the time to reach Bromage 3 motor blockade, there was no significant difference between the two groups in our study. This coincides with the study done by Fahmy et al. .
Concerning MAP, HR, SpO2, adverse effects, and the use of atropine, and/or ephedrine, there were no significant differences between the study groups and these results coincide with the results of studies by Fahmy et al. , Vibhuti and Hetavi , and Shadangi et al.  Contrary to our study, Karbasfrushan et al  compared intrathecal midazolam to placebo as an adjuvant in 112 cases who had undergone a cesarean section. They found a decrease in the incidence of nausea and vomiting in the midazolam group and this may be due to the difference in the type of patient, and the operation performed in their study and ours. In addition, a study by Shadangi et al.  and a metanalysis conducted by Ho and Ismail  showed that intrathecal midazolam reduced postoperative nausea and vomiting.Regarding the pain score using VAS, the difference between both groups was highly significant and this coincides with the study by Nanjegowda et al. , where they found that the difference between group M (patients who received a combination of 2 ml bupivacaine with 2 mg midazolam) and group S (patients who received a combination of 2 ml bupivacaine with 0.4 ml normal saline) was highly significant. In addition, this result of pain score reduction coincides with the study by Bhattachary et al.  in which they studied the analgesic effect of intrathecal midazolam with bupivacaine after major gynecologic surgeries. On the contrary, a study by Kim et al.  found that VAS was lower in the midazolam group but this difference was insignificant.
Regarding the time of first analgesia requirement postoperatively, the difference between the study groups was highly significant and this coincides with the study of Vibhuti and Hetavi  as they found that the mean time to first analgesic drug was significantly prolonged in the midazolam group.
| Conclusion|| |
Subarachnoid injection of preservative-free midazolam potentiates the effect of intrathecal bupivacaine in terms of prolonged motor and sensory blockade without significant hemodynamic compromise or sedation and with a significant decrease of postoperative analgesic requirements.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]