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Original Article Efficacy of intrathecal midazolam in potentiating the analgesic effect of intrathecal fentanyl in patients undergoing lower limb surgery

Anshu Gupta, Hemlata Kamat1, Utpala Kharod1

Departments of Anaesthesia, Lady Hardinge Medical College, New Delhi, 1Pramukhswami Medical College, Anand, Gujarat, India

Corresponding author: Dr. Anshu Gupta, Department of Anaesthesia, Lady Hardinge Medical College, New Delhi, India. E‑mail: [email protected]

Abstract Introduction: The intrathecal administration of combination of drugs has a synergistic effect on the subarachnoid block characteristics. This study was designed to study the efficacy of intrathecal midazolam in potentiating the analgesic duration of fentanyl along with prolonged sensorimotor blockade. Materials and Methods: In a double‑blind study design, 75 adult patients were randomly divided into three groups: Group B, 3 ml of 0.5% hyperbaric bupivacaine; Group BF, 3 ml of 0.5% hyperbaric bupivacaine + 25 mcg of fentanyl; and Group BFM, 3 ml of 0.5% hyperbaric bupivacaine + 25 mcg of fentanyl + 1 mg of midazolam. Postoperative analgesia was assessed using visual analog scale scores and onset and duration of sensory and the motor blockade was recorded. Results: Mean duration of analgesia in Group B was 211.60 ± 16.12 min, in Group BF 420.80 ± 32.39 min and in Group BFM, it was 470.68 ± 37.51 min. There was statistically significant difference in duration of analgesia between Group B and BF ( P = 0.000), between Group B and BFM (P = 0.000), and between Group BF and BFM (P = 0.000). Both the onset and duration of sensory and motor blockade was significantly prolonged in BFM group. Conclusion: Intrathecal midazolam potentiates the effect of intrathecal fentanyl in terms of prolonged duration of analgesia and prolonged motor and sensory block without any significant hemodynamic compromise.

Key words: Analgesia, fentanyl, intrathecal, midazolam

This is an open access article distributed under the terms of the Creative Commons Access this article online Attribution‑NonCommercial‑ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non‑commercially, as long as the author is credited Website DOI Quick Response Code and the new creations are licensed under the identical terms. www.aeronline.org 10.4103/0259-1162.164650 For reprints contact: [email protected]

How to cite this article: Gupta A, Kamat H, Kharod U. Efficacy of intrathecal midazolam in potentiating the analgesic effect of intrathecal fentanyl in patients undergoing lower limb surgery. Anesth Essays Res 2015;9:379-83.

PB © 2015 Anesthesia: Essays and Researches | Published by Wolters Kluwer - Medknow © 2015 Anesthesia: Essays and Researches | Published by Wolters Kluwer - Medknow 379 Anesthesia: Essays and Researches; 9(3); Sep-Dec 2015 Gupta, et al.: Potentiation of analgesic effect of fentanyl by intrathecal midazolam INTRODUCTION explained about visual analog scale (VAS) scale, which they would be shown in the postoperative period. Using The central neuraxial blockade is one of the most computer generated table, patients were randomly divided important and most commonly used regional anesthetic into three groups. Group B received intrathecally 3 ml techniques for lower abdominal, perineal and lower limb of 0.5% hyperbaric bupivacaine + 0.7 ml of 0.9% saline. surgeries. Group BF received intrathecally 3 ml of 0.5% hyperbaric bupivacaine + 25 mcg of fentanyl in 0.5 ml along with There has been growing emphasis on the advantages 0.2 ml 0.9% saline. Group BFM received intrathecally 3 ml of combined pharmacological approach for pain relief. of 0.5% hyperbaric bupivacaine + 25 mcg of fentanyl in Discovery of analgesic effects of spinally administered 0.5 ml along with 1 mg of midazolam in 0.2 ml. opioids and other drugs such as benzodiazepines[1,2] and alpha‑2 adrenoreceptor agonists[3] has opened the The test drug was prepared by a person not involved possibilities of optimizing on useful drug interactions at in the study making sure that the total volume of the the level of spinal cord in the management of pain. drug remains 3.7 ml. In the operation theatre, baseline parameters in terms of pulse rate, respiratory rate (RR) By administrating intrathecal combinations of drugs, and blood pressure were recorded. All patients were targeting different spinal cord receptors; prolonged preloaded with 15 ml/kg of Ringer’s Lactate. After taking and superior quality analgesia can be achieved by adequate aseptic precautions, SAB was administered relatively small concentrations of individual drugs. The with the patient in left lateral or sitting position at L dose reductions may avoid drug‑related side effects. In 3‑4 or L interspace with 23‑gauge Quincke spinal needle. addition, the simultaneous targeting of several different 4‑5 The time to attain sensory level up to T10 and time to receptor sites in the spinal cord may lead to improved attain motor block up to modified Bromage grade‑3 were pain relief.[4] recorded. Vital parameters in terms of pulse rate, systolic The advantage of the use of opioids like fentanyl blood pressure (SBP), diastolic blood pressure (DBP), RR to facilitate effective postoperative analgesia is well and SpO2 were recorded before administration of SAB, documented in the literature.[5‑8] immediately after block (0 min), at 2, 5, 10, 15, 20, 25 and 30 min after the procedure and then at 15 min The administration of intrathecal benzodiazepine has interval thereafter till completion of surgery. Fall in its antinociceptive action mediated via benzodiazepine/ SBP or DBP >20% of the basal value was considered GABA‑A receptor complex which are abundantly as hypotension. Change in pulse rate 20% of the basal present in lamina II of dorsal horn ganglia of the spinal value was considered as bradycardia or tachycardia. Any cord.[9] Intrathecal midazolam also causes the release of intraoperative complications such as nausea, vomiting, an endogenous opioid, acting at spinal delta receptor.[10] hypotension, bradycardia, respiratory depression, and This has been proved as its nociceptive effect has been pruritus were recorded. The total duration of surgery was suppressed by “Naltrindole,” a delta selective opioid also noted. antagonist. Postoperative analgesia was assessed with VAS. This study was conducted to evaluate the efficacy of Injection diclofenac sodium 75 mg intramuscularly was intrathecal midazolam in potentiating the analgesic administered as rescue analgesia if VAS >3. The total effect of intrathecal fentanyl along with a prolonged duration of analgesia was also noted. In the postoperative sensorimotor block in patients undergoing lower limb room, vital parameters were recorded every half hourly surgery. for 4 hours and then every hourly till the supplementation of rescue analgesia. MATERIALS AND METHODS Time of recovery from the sensory block, as defined After taking approval from Hospital Ethical Committee by regression of block up to T12 level, was recorded. and written informed consent, 75 adult patients of Furthermore, time of recovery from motor block to American Society of Anesthesiologists I and II, undergoing modified Bromage scale‑2 was also recorded. lower limb surgeries under subarachnoid block (SAB) were Any postoperative complications such as nausea, vomiting, enrolled for the prospective, randomized study. hypotension, bradycardia, respiratory depression, pruritus, Patients in whom surgery lasted for more than 3 h and and urinary retention were recorded and treatment of with inadequate block requiring supplemental anesthesia complications planned accordingly. The observer involved were excluded from the study. in the assessment of the parameters was blinded to the test drug used. After doing a thorough preoperative evaluation, patients were explained about the procedure of lumbar puncture Statistical analysis was performed using SPSS version 9 and their participation in the study. They were also (Chicago, SPSS Inc.). Data were presented as mean and

380 Anesthesia: Essays and Researches; 9(3); Sep-Dec 2015 Gupta, et al.: Potentiation of analgesic effect of fentanyl by intrathecal midazolam standard deviation. Continuous variables were analyzed with P = 0.735. Similarly, fall in SBP and DBP was not using ANOVA test, while categorical data were analyzed statistically significant, both within the group, but using Chi‑square test. P <0.05 was considered significant. also between the groups with P = 0.148 and 0.171 The sample size was calculated based on previous studies respectively. with a clinically significant difference of 20% in the The incidence of side effects was 28% in Group BFM, and duration of analgesia, assuming a power of 80% and a significance level of 5%. 28% in Group BF, whereas it was 12% in Group B [Table 4]. In Group B, three patients had bradycardia whereas none RESULTS of the patients had hypotension, pruritus, and vomiting. In Group BF, four patients had bradycardia, three There was no statistically significant variation between patients had hypotension and none of the patients had the groups in terms of age, weight, height, and duration pruritus and vomiting. In Group BFM, two patients had of surgery [Table 1]. bradycardia, three patients had hypotension, one patient Mean duration of analgesia in Group B was had pruritus, and one patient had vomiting. There was no 211.60 ± 16.12 min, in Group BF 420.80 ± 32.39 min incidence of urinary retention in any of the three groups. and in Group BFM, it was 470.68 ± 37.51 min. There was statistically significant difference in duration of analgesia DISCUSSION between Groups B and BF (P = 0.000), between Groups B and BFM (P = 0.000), and between Groups BF and There was a significant potentiation of the duration of BFM (P = 0.000) [Table 2]. analgesia with the addition of intrathecal midazolam to the bupivacaine fentanyl mixture. Also, there was Mean time of onset of sensory block in Group B was 7.1 ± 1.19 min, in Group BF 4.54 ± 0.93 min and in Group BFM, it was 4.04 ± 0.86 min. There was statistically Table 1: Demographic profile significant difference in time for onset of sensory blockade Group B Group BF Group BFM P between Groups B and BF (P = 0.000) as well as Groups B Age (years) 40±2.5 39.1±10.2 42.9±12.6 >0.05 and BFM (P = 0.000). However, there was no statistical Weight (kg) 46.8±8.7 50.9±8.0 58.7±10.6 >0.05 significant difference in time for onset of sensory blockade Height (cm) 161.1±1.5 161.0±1.4 162.2±1.1 >0.05 between Groups BF and BFM (P = 0.054). Duration of surgery (min) 128.8±39.7 125.6±38.3 124.2±35.8 >0.05 Mean onset of motor block in Group B was 8.51 ± 0.56 min, in Group BF 7.68 ± 0.46 min and in Table 2: Duration of analgesia and block Group BFM, it was 7.64 ± 0.31 min. There was statistically characteristics significant difference in onset of motor blockade between Group B Group BF Group BFM Groups B and BF (P = 0.000) and between Groups B and Analgesia duration (min) 211.6±16.12 420.8±32.39 470.68±37.51 BFM (P = 0.000). But, there was no clinical or statistical Onset of sensory block (min) 7.1±1.19 4.54±0.93 4.04±0.86 significant difference in onset of the motor block between Onset of motor block (min) 8.51±0.56 7.68±0.46 7.64±0.31 Groups BF and BFM (P = 0.744). Duration of sensory block (min) 196.6±12.64 227.2±14.51 254±12.08 Mean duration of sensory block in Group B was Duration of motor block (min) 183.6±13.58 192.2±21.17 201.2±11.57 196.60 ± 12.64 min, in Group BF 227.20 ± 14.51 min and in Group BFM, it was 254.00 ± 12.08 min. There was Table 3: Hemodynamic parameters statistically significant difference in duration of sensory blockade between Groups B and BF (P = 0.00), Groups B Group B Group BF Group BFM and BFM (P = 0.000) and Groups BF and BFM (P = 0.000). Pulse (rate/min) 77.48±7.29 75.81±11.86 77.79±8.99 SBP (mm Hg) 115.78±10.21 111.79±12.16 117.76±10.09 Mean duration of motor block in Group B was DBP (mm Hg) 74.33±5.83 73.21±7.07 76.39±4.89 183.60 ± 13.58 min, in Group BF 192.20 ± 21.17 min SBP=Systolic blood pressure, DBP=Diastolic blood pressure and in Group BFM, it was 201.20 ± 11.57 min. There was statistically significant difference in duration of motor Table 4: Incidence of side effects blockade between Groups B and BF (P = 0.022), Groups B Group B Group BF Group BFM and BFM (P = 0.000), and Groups BF and BFM (P = 0.010). Bradycardia 3 4 2 All the baseline parameters in terms of pulse rate, SBP, Hypotension 0 3 3 and DBP were comparable in all the groups [Table 3]. Pruritus 0 0 1 The changes in the mean pulse rate between the groups Vomiting 0 0 1 and within the groups were not statistically significant Urinary retention 0 0 0

381 Anesthesia: Essays and Researches; 9(3); Sep-Dec 2015 Gupta, et al.: Potentiation of analgesic effect of fentanyl by intrathecal midazolam statistically significant difference in duration of analgesia none of the studies,[14,25] there was significant decrease between Groups B and BF and Groups B and BFM. The in pulse rate with addition of fentanyl to bupivacaine, administration of a combination of drugs intrathecally however most of the studies were carried out by adding targets different spinal receptors resulting in prolonged fentanyl in a dose of 25 mcg or less. In this study also and superior quality of analgesia.[11] Various studies have there was no significant decrease in pulse rate in observed the prolongation of analgesia with the addition Group BFM. of midazolam or fentanyl. Tucker et al.[1] observed Martyr and Clark[26] found incidences of hypotension as a prolongation of the duration of analgesia in labor when a common complication when intrathecal fentanyl 20 mcg combination of intrathecal midazolam 2 mg and fentanyl was added to bupivacaine 7.5 mg in elderly patients, 10 mcg was used for labor analgesia. Shah et al.[2] also but the incidence and severity of hypotension were not observed prolongation of the duration of analgesia with significant. Shah et al.[2] observed no significant decrease the addition of 2 mg intrathecal midazolam to 15 mg in mean arterial pressures when intrathecal bupivacaine bupivacaine and 0.15 mg buprenorphine. Most of the 15 mg + buprenorphine 0.15 mg was compared studies done so far have used intrathecal bupivacaine with intrathecal bupivacaine 15 mg + buprenorphine combined with either fentanyl[12‑14] or midazolam.[15‑19] 0.15 mg + midazolam 2 mg. Ben‑David et al.,[14] Grewal All have shown a significant increase in duration of et al.[22] found increased incidence of hypotension by analgesia. adding fentanyl to bupivacaine in SAB. Bhattacharya There was statistically significant difference in time of et al.[24] did not find any significant change in blood onset of both sensory and motor block between Groups B pressure when intrathecal midazolam 2 mg was added to and BF (P - 0.000) as well as between Groups B and bupivacaine 15 mg. BFM (P = 0.000). There was no clinically or statistically The incidence of bradycardia was maximum in Group BF significant difference in the time for onset of sensory and while that of hypotension was same in Groups BF the motor block between Groups BF and BFM (P = 0.054). and BFM. No incidence of urinary retention was seen The variation in the onset may be because of the fact that in any of the three groups. In all the three groups, though there is fast onset on sensory and motor blockade the incidence of side effects was not found to be due to addition of opioid‑like fentanyl due to the action on opioid receptors, but there is no potentiation of the significant (P = 0.510). effect with the addition of midazolam. Usmani et al.[20] Rudra and Rudra[27] observed that when the two groups, observed a significant difference in time of onset of both one with combination of intrathecal bupivacaine (0.5%) sensory and motor block when fentanyl was combined 10 mg with fentanyl 12.5 mcg and other with intrathecal with bupivacaine intrathecally. When intrathecal bupivacaine (0.5%) 10 mg and midazolam 2 mg were midazolam was added to the bupivacaine, Agrawal et al.[15] compared, the incidence of nausea vomiting was found observed no significant difference in onset of sensory and to be less in the group with combination of intrathecal motor blockade time. bupivacaine with fentanyl than the group with intrathecal There was statistically significant difference in duration bupivacaine and midazolam combination. of sensory and motor block between Groups B and BF, Shah et al.[2] also observed that when intrathecal Groups B and BFM as well as Groups BF and BFM. Bharti bupivacaine 15 mg + buprenorphine 0.15 mg et al.[21] observed that the duration of motor and sensory was compared with intrathecal bupivacaine blockade was prolonged when intrathecal midazolam 15 mg + buprenorphine 0.15 mg + midazolam 2 mg, is added to bupivacaine. Grewal et al.[22] also observed incidences of nausea, vomiting, bradycardia, itching, significant prolongation of motor block by adding fentanyl headache, and urinary retention was same in both the to bupivacaine in SAB. Khanna and Singh[13] observed a groups. These were not found to be significant. significant increase in duration of the sensory block with fentanyl when added to bupivacaine intrathecally. Tucker CONCLUSION et al.[1] observed prolongation of the duration of the sensory block with intrathecal midazolam 2 mg added to Intrathecal midazolam potentiates the effect of intrathecal Fentanyl 10 mcg in labor analgesia. Roussel and Heindel[23] fentanyl in terms of prolonged duration of analgesia did not observe significant prolongation of sensory and and prolonged motor and sensory block without any motor block when intrathecal fentanyl was added to significant hemodynamic compromise. bupivacaine. Bhattacharya et al.[24] observed no significant prolongation of the sensory block with intrathecal Financial support and sponsorship midazolam 2 mg added to bupivacaine 15 mg. Nil. There was no significant variation in pulse rate, SBP, and Conflicts of interest DBP both within the group and between the groups. In There are no conflicts of interest.

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