|Year : 2016 | Volume
| Issue : 3 | Page : 432-439
Comparative study of intrathecal midazolam versus fentanyl as adjuvants to ropivacaine for lower-limb surgery
Sanaa M Elfawal, Aktham A Shoukry MD , Walid H Nofal
Department of Anesthesiology, Intensive Care and Pain Management, Faculty of Medicine, Ain Shams University, Cairo, Egypt
|Date of Submission||15-Oct-2015|
|Date of Acceptance||19-Feb-2016|
|Date of Web Publication||31-Aug-2016|
Aktham A Shoukry
Department of Anesthesiology, Intensive Care and Pain Management, Faculty of Medicine, Ain Shams University, Cairo
Source of Support: None, Conflict of Interest: None
The current prospective randomized double-blind study was designed to compare the clinical efficacy of intrathecal midazolam versus fentanyl when added to hyperbaric ropivacaine, evaluating the effect of each on the duration and quality of spinal blockade produced by hyperbaric ropivacaine.
Patients and methods
The study was conducted on 90 patients of both sexes, aged 20-60 years, of class I or II of the American Society of Anesthesiologists classification, who were undergoing elective lower-limb surgery. Patients were randomly assigned to three groups (30 patients each): group R (control group) received 3 ml (15 mg) of hyperbaric ropivacaine plus 0.5 ml of normal saline (0.9%) at a total volume of 3.5 ml intrathecally, whereas group RF received 3 ml (15 mg) of hyperbaric ropivacaine plus 0.5 ml of 25 μg fentanyl (50 μg/ml) at a total volume of 3.5 ml intrathecally and group RM received 3 ml (15 mg) of hyperbaric ropivacaine plus 0.5 ml of 1 mg midazolam (2 mg/ml) at a total volume of 3.5 ml intrathecally. The onset and duration of sensory and motor blockade, postoperative pain, and the time to first rescue analgesia request were noted. Patients were observed for hypotension, bradycardia, sedation, respiratory depression, pruritus, and postoperative nausea and vomiting.
The onset times and the duration of motor blockade were comparable among groups, whereas the time to sensory block regression was longer in group RM and group RF as compared with group R (P < 0.001). The duration of postoperative analgesia was significantly longer in group RM and group RF as compared with group R (P < 0.001), whereas there was no difference between group RM and group RF. The incidence of pruritus and vomiting was higher in group RF.
Adding midazolam to hyperbaric ropivacaine in spinal anesthesia for lower-limb surgeries is considered a good alternative for improving the duration of sensory block and decreasing the analgesic requirement in the early postoperative period with minimal side effects compared with hyperbaric ropivacaine alone or fentanyl combined with hyperbaric ropivacaine.
Keywords: analgesia, fentanyl, intrathecal, midazolam, ropivacaine
|How to cite this article:|
Elfawal SM, Shoukry AA, Nofal WH. Comparative study of intrathecal midazolam versus fentanyl as adjuvants to ropivacaine for lower-limb surgery. Ain-Shams J Anaesthesiol 2016;9:432-9
|How to cite this URL:|
Elfawal SM, Shoukry AA, Nofal WH. Comparative study of intrathecal midazolam versus fentanyl as adjuvants to ropivacaine for lower-limb surgery. Ain-Shams J Anaesthesiol [serial online] 2016 [cited 2021 Apr 14];9:432-9. Available from: http://www.asja.eg.net/text.asp?2016/9/3/432/189574
| Introduction|| |
Spinal or intrathecal anesthesia has a long history of success and has become more popular, mostly because of an increasing number of ambulatory procedures and interventions, for which the ideal spinal anesthetic would provide rapid and adequate surgical anesthesia together with early ambulation and early discharge .
Ropivacaine is an amide local anesthetic agent with similar local anesthetic properties as bupivacaine. Ropivacaine has a potentially improved safety profile compared with bupivacaine . More recent studies on ropivacaine have shown that it produces predictable and reliable spinal anesthesia for surgery .
Various intrathecal adjuvants to local anesthetics are used. When local anesthetics are combined with opioids the duration of analgesia is prolonged .
Fentanyl, a short-acting lipophilic opioid, is known to augment the quality of subarachnoid block. It was also shown that the addition of fentanyl to hyperbaric ropivacaine increased the intraoperative quality of spinal anesthesia in patients undergoing anorectal surgery , cesarean section , and transurethral resection of the prostate .
However, worrisome adverse effects such as pruritus, urinary retention, postoperative vomiting, and respiratory depression limit the use of opioids ,.
Midazolam is an imidazobenzodiazepine with unique properties when compared with other benzodiazepines. It is water soluble in its acid formulation but is highly lipid soluble in vivo. It has been reported to have a spinally mediated antinociceptive effect . Previous studies have shown that intrathecal administration of midazolam added to bupivacaine improves the duration and quality of spinal anesthesia .
There are no data showing the effect of intrathecal midazolam when added to ropivacaine. Therefore, this study was planned to compare the analgesic efficacy and safety of intrathecal midazolam and fentanyl as an adjunct to ropivacaine spinal anesthesia in patients undergoing lower-limb surgery.
| Patients and methods|| |
This study was conducted in the Orthopedic Surgery Department at Ain Shams University Hospitals between 2013 and 2014, after obtaining approval from the Medical Ethics Committee of Ain Shams University and informed consent from all patients. The study was conducted on 90 patients of both sexes, aged between 20 and 60 years, of class I–II of the American Society of Anesthesiologists (ASA) classification, who were undergoing elective lower-limb surgery (e.g. Pott's fracture, fracture tibia, knee arthroscopy, etc.) and having normal coagulation profile. Patients were excluded if they refused regional anesthesia, had coagulopathy, were on potent antiplatelets or anticoagulants, had spine deformity, back problems, local skin infection at the site of injection, poor myocardial contractility (ASA III or more), pre-existing neurological deficits in the lower extremities, psychological problems, or known allergy to the test drugs.
The study was conducted in a randomized, double-blind controlled manner. Patients were randomized in a double-blinded manner using the closed envelope method, and the master codes were kept with a person who does not share in the collection or analysis of the results. The patients were enrolled into three groups (30 patients each) on the basis of the adjuvant added to the anesthetic used. Group R (control group) received 3 ml (15 mg) of hyperbaric ropivacaine plus 0.5 ml of normal saline (0.9%) at a total volume of 3.5 ml intrathecally, whereas group RF received 3 ml (15 mg) of hyperbaric ropivacaine plus 0.5 ml of 25 μg fentanyl (50 μg/ml) at a total volume of 3.5 ml intrathecally and group RM received 3 ml (15 mg) of hyperbaric ropivacaine plus 0.5 ml of 1 mg midazolam (2 mg/ml) at a total volume of 3.5 ml intrathecally. Hyperbaric ropivacaine solution was prepared by adding together 4 ml of ropivacaine (7.5 mg/ml) (Naropin; Astra Zeneca, Sweden, London, United Kingdom) and 2 ml of dextrose 20%, which was prepared by mixing 3 ml of dextrose 25% and 1 ml of dextrose 5%. The final concentration results in 0.5% hyperbaric ropivacaine. The ropivacaine solutions were prepared aseptically immediately before injection. The study drug was prepared by an anesthesiologist not involved in the patient management and data collection.
On arrival at the operation theater, following the introduction of an intravenous cannula (≥18 G) in the nondominant forearm, an infusion of normal saline 15 ml/kg/h was started as preload around 20 min before the administration of spinal anesthesia. Standard monitoring with five-lead ECG, noninvasive blood pressure at 5-min intervals, and pulse oximetry was instituted, and baseline measurements were taken. Before the commencement of anesthesia, methods of sensory (cold test) and motor (modified Bromage scale) assessments were explained to the patients. Spinal anesthesia was performed while the patients were placed in the sitting position. Sterilization of patients’ back was done with povidone iodine solution 10%, and then skin and subcutaneous infiltration with 2 ml of lidocaine 1% was performed. Spinal puncture was performed using a midline approach at the third to the fourth lumbar interspace with a 25-G Quincke spinal needle with the distal port facing laterally. Once free flow of cerebrospinal fluid was obtained, the study drug was injected at a rate of ~0.2 ml/s. The patient was then turned to the supine position with a 20° anti-Trendelenburg tilt. The spread of sensory block was determined bilaterally using a cold test (an ice pack was applied above the patient's clavicle as a reference point and they were asked to report when they felt a cold sensation. Once the patients stated that they could feel a cold sensation, they were asked to report when it felt icy cold without changing the reference point). Sensory block (the time between injection of intrathecal local anesthetic until loss of cold sensation at the level of T10) was assessed at 2 and 5 min after injection and at 5-min intervals thereafter until two consecutive levels of sensory block were identical (i.e. fixation of the level). Surgery was started when a sensory block reached T10 dermatome and at stage 2 of the modified Bromage scale (unable to flex the knee). The motor blockade (the time between injection of intrathecal local anesthetic until stage 2 of the modified Bromage scale) was assessed at the same intervals using a modified Bromage scale (0 = no paralysis; 1 = unable to raise extended leg; 2 = unable to flex knee; 3 = unable to flex ankle). The onset and duration of sensory and motor blockade were recorded.
The patients received oxygen at 6 l/min through a face mask during surgery. Intravenous fluids (crystalloids, colloids, or blood) were administered for maintenance and according to the surgical blood loss. Heart rate, blood pressure, and oxygen saturation (SpO2) were recorded at baseline, after intrathecal injection, and then every 5 min until the end of the surgical procedure.
Hypotension (mean arterial pressure <25% of baseline) and bradycardia (heart rate <40 beats/min) were treated with intravenous ephedrine 5 mg and atropine 0.5 mg, respectively. After the operation all patients were transferred to the Postanesthesia Care Unit (PACU). The patients were observed in the PACU for vitals and block characteristics by an anesthesiologist blinded to the group assignment. All patients were monitored for vital data every 2 h for the first 8 h and then at 12, 18, and 24 h postoperatively. Any adverse effects like bradycardia, hypotension, respiratory depression, pruritus, headache, and postoperative nausea and vomiting were recorded.
Postoperative pain was assessed by means of the verbal rating pain scale (0–10: 0 = no pain and 10 = worst imaginable pain) at 1 h intervals until requirement for supplementary analgesia arises. Rescue analgesia was provided with intravenous diclofenac1.5 mg/kg when the verbal rating pain scale (VRS) score was 4 or more.
The duration of postoperative analgesia – that is, the time from intrathecal injection until administration of the first rescue analgesia (primary outcome) – was recorded.
The level of sedation was assessed every hour for 6 h postoperatively by the Ramsay Sedation Score: Ramsay 1 = anxious, agitated, and restless; Ramsay 2 = cooperative, oriented, tranquil; Ramsay 3 = responsive to commands only. Patients meeting a modified Aldrete score greater than or equal to 9 were discharged from the PACU . Patients were notified to contact the emergency room team if any remote complications such as postdural puncture headache or transient neurological symptoms appeared over a period of 3 days postoperatively [Table 1].
Data were collected, tabulated, coded, and analyzed using MSTAT-C program (version 2.10 for Windows, Michigan State University, USA). Numerical variables were presented as mean ± SD, whereas categorical variables were presented as number of cases and percentage. Analysis of variance was used for comparison between groups as regards numerical variables, and Scheffe's test was used as a post-hoc test if analysis of variance revealed a significant difference. The χ2-test of significance was used to compare proportions between three qualitative parameters. Differences were considered statistically significant if P values were less than 0.05. Sample size was calculated on the basis of previous studies for detecting clinically significant difference of 30% in the duration of analgesia, assuming a power of 80% and a significance level of 5%.
| Results|| |
Regarding demographic data, no statistically significant differences were noted between the three groups with regard to age, sex, BMI, and ASA status, as well as duration of operation and type of surgery ([Table 2] and [Table 3]).
There was no statistically significant difference between the three groups as regards intraoperative mean arterial blood pressure. Three patients out of 30 (10%) in group R, four patients out of 30 (13%) in group RF, and two patients out of 30 (7%) in group RM developed hypotension and needed intravenous ephedrine [Table 4].
|Table 4 Comparison between the three groups as regards intraoperative blood pressure (mmHg)|
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There was no statistically significant difference between the three groups as regards intraoperative heart rates and there was a high degree of hemodynamic stability. Three (10%) patients in group R and group RF and two (7%) patients in group RM developed bradycardia and received atropine [Table 5].
|Table 5 Comparison between the three groups as regards intraoperative heart rate (beats/min)|
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There were no statistically significant differences between the three groups as regards intraoperative SpO2 and respiratory rate.
In the postoperative period the mean arterial blood pressure values were significantly higher in group R than in groups RF and RM at 2 h postoperatively [Figure 1].
|Figure 1 Postoperative mean arterial blood pressure values in group R, group RF, and group RM. Lines represent mean changes in MAP. *Statistically significant. R, ropivacaine; RF, ropivacaine–fentanyl; RM, ropivacaine–midazolam.|
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The graph shows elevation of mean arterial pressure in the early postoperative period in group R, which is attributed to earlier sensory recovery.
Postoperatively the heart rate values were significantly higher in group R than in group RF and RM at 2 h. There were no significant differences between groups RF and RM throughout the whole postoperative period as regards heart rate values [Figure 2].
|Figure 2 Postoperative heart rate values in group R, group RF, and group RM. The graph shows elevation heart rate in the early postoperative period in group R explained by earlier sensory recovery. Line represents mean. *Statistically significant. R, ropivacaine; RF, ropivacaine–fentanyl; RM, ropivacaine–midazolam.|
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The three groups showed no significant differences as regards SpO2 (none reaching <95%) and respiratory rate throughout the postoperative period.
There was a statistically significant difference between the three groups regarding the time to first sensation of pain, which was earlier in group R (150 ± 31 min) than in group RF (205 ± 30 min) and group RM (195 ± 29 min). Time to first analgesic dose was earlier in group R (181 ± 26 min) than in group RF (242 ± 31 min) and group RM (233 ± 26.7 min). Group R showed significantly faster time to two-segment regression (122 ± 13.4 min) compared with group RF (162 ± 14.8 min) and group RM (151 ± 16.4 min) [Figure 3].
|Figure 3 Time to two-segment regression, time to first analgesic dose, and time to first sensation of pain in the three groups. Data expressed as mean. *Statistically significant. R, ropivacaine; RF, ropivacaine–fentanyl; RM, ropivacaine–midazolam.|
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The three groups showed no significant difference as regards onset and level of sensory block [Figure 4].
|Figure 4 Time of onset and time to achieve maximum sensory block in groups R, RF, and RM. Data represented as mean. R, ropivacaine; RF, ropivacaine–fentanyl; RM, ropivacaine–midazolam.|
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The three groups showed no significant difference as regards time to complete motor block and duration of motor block [Figure 5].
|Figure 5 Time to complete motor block and duration of motor block in the three groups. Data represented as mean. R, ropivacaine; RF, ropivacaine–fentanyl; RM, ropivacaine–midazolam.|
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There was no significant difference between the three groups as regards the degree of systemic sedation postoperatively. The highest sedation score expressed by the three groups was 2 (2 = cooperative, oriented, and tranquil).
There was one reported case of nausea and vomiting in groups R and RM and six cases in group RF (P = 0.004). There was one reported case of shivering in groups RF and RM and two cases in group R (P = 0.765). There were 10 reported cases of pruritus in group RF compared with one case in group RM and no cases in group R (P = 0.002) [Figure 6].
|Figure 6 Incidence of complications in the three groups. Data presented as percentage. *Statistically significant. R, ropivacaine; RF, ropivacaine–fentanyl; RM, ropivacaine–midazolam.|
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| Discussion|| |
Ropivacaine is a long-acting, enantiomerically pure (S-enantiomer) amide local anesthetic with a low lipid solubility that blocks nerve fibers involved in pain transmission (Aδ and C fibers) to a greater degree than those controlling motor function (Aβ fibers). Ropivacaine is less toxic to the cardiovascular and central nervous systems than is bupivacaine and was approved for intrathecal administration in the European Union in February 2004 .
The use of analgesic adjuvants has been proven to be very valuable in maintaining the advantage of ropivacaine while improving the intraoperative quality of anesthesia .
This study was performed to determine the optimal analgesic adjuvant with the lowest possible complications. It demonstrated increased duration of sensory blockage and postoperative analgesia after subarachnoid injection of midazolam or fentanyl as an adjuvant to hyperbaric ropivacaine in spinal anesthesia. The analgesic effect of intrathecal midazolam was comparable with intrathecal fentanyl, with lesser incidence of complications in the midazolam group.
The results of the present study support the results of previous studies that have also reported no clinically relevant changes in blood pressure, heart rate values, SpO2, and respiratory function after intrathecal administration of fentanyl in combination with hyperbaric ropivacaine. For example, Yegin et al.  used intrathecal fentanyl added to hyperbaric ropivacaine for transurethral resection of the prostate under spinal anesthesia and concluded that addition of fentanyl to hyperbaric ropivacaine may significantly improve the quality and prolong the duration of analgesia without causing a substantial increase in the frequency of major side effects.
Similarly, Gunaydin and Tan  performed a study on 30 full-term parturients undergoing elective cesarean section under spinal anesthesia. The patients were randomly allocated to receive 15 mg hyperbaric ropivacaine coadministered with 20 μg fentanyl. None of the patients developed any hemodynamic instability.
Previous studies assessed the analgesic effects of intrathecal midazolam added to bupivacaine, and this study assessed the analgesic effect of intrathecal midazolam added to hyperbaric ropivacaine. Kim and Lee  compared two groups, one of which received 1 ml of 0.5% heavy bupivacaine plus 0.2 ml of 0.5% preservative-free midazolam and the other received 1 ml of heavy bupivacaine plus 0.4 ml of midazolam. There was no significant hemodynamic instability. Yun et al.  also observed similar results in three groups in which one group received 11 mg of intrathecal 0.5% hyperbaric bupivacaine alone, another received an adjuvant of 1 mg midazolam, and the third received an adjuvant of 2 mg of midazolam, with no differences in hemodynamic variables among the three groups.
As regards the characteristics of sensory and motor block, the three groups showed no significant difference as regards onset of sensory block, height of block, time for complete motor block, and duration of motor block. Ropivacaine group showed a significantly more rapid time to 2 segment regression than when combined to midazolam or fentanyl.
These results were consistent with a study performed by Kallio et al. , who included 56 patients undergoing surgery of the lower extremities who were receiving intrathecal 1.5 ml of ropivacaine 10 mg/ml and 0.5 ml of glucose 300 mg/ml (hyperbaric ropivacaine). Time to two-segment regression was 60 min. This can be explained by the low dosage of hyperbaric ropivacaine administered intrathecally in Kallio et al.'s  study.
The time to first sensation of pain was earlier with ropivacaine alone (150 ± 31) than when combined with fentanyl (205 ± 30) or midazolam (195 ± 29) and also the time to the first analgesic dose was earlier in the patients given ropivacaine alone (181 ± 26) than when combined with fentanyl (242 ± 31) or midazolam (233 ± 26.7).
The results of this study agree with those of Chavda et al.  who compared intrathecal fentanyl and sufentanil with heavy bupivacaine for postoperative analgesia in patients undergoing vaginal hysterectomy. Their study concluded that the addition of fentanyl (25 μg) and sufentanil (5 μg) intrathecally improved postoperative analgesia.
Yegin et al.  showed comparable results as regards time to first sensation of pain [saline (120 ± 32 min) and fentanyl (150 ± 33 min); P = 0.011] and time to first analgesic requirement [saline (180 ± 26 min) and fentanyl (210 ± 31 min); P = 0.016].
In another study performed by Obara et al. , who explored the effect of intrathecal fentanyl added to hyperbaric bupivacaine on the characteristics of subarachnoid block in patients undergoing cesarean section, addition of intrathecal fentanyl to hyperbaric bupivacaine improved the duration of sensory block.
This was supported by Prakash et al. , who conducted a study to investigate the analgesic efficacy of two doses of intrathecal midazolam as an adjunct to bupivacaine for spinal anesthesia in patients undergoing cesarean delivery. They concluded that intrathecal midazolam 2 mg provided a moderate prolongation of postoperative analgesia when used as an adjunct to bupivacaine.
It also agrees with a study performed by Yun et al.  in which the onset and duration of sensory block to T10 was not different among the groups. However, the duration of sensory block to T10 in the midazolam groups was significantly longer than in the saline group.
This also coincides with a study done by Agrawal et al.  who compared the efficacy of intrathecal bupivacaine with intrathecal bupivacaine–midazolam combination for pain relief. Patients were randomly divided into two groups. Group B received 3 ml (15 mg) of heavy bupivacaine (0.5%) with 0.2 ml of 0.9% saline intrathecally. Group BM received 3 ml (15 mg) of heavy bupivacaine (0.5%) with 0.2 ml of preservative-free midazolam (1 mg) intrathecally. Time to first analgesic dose in group B was 4 ± 3.5 h, significantly earlier than in group BM (17.6 ± 8.87 h).
As regards intrathecal midazolam, a meta-analysis done by Ho and Ismail  who searched MEDLINE (from 1966 to 1 July 2007) and included 13 studies with data from 672 patients confirmed that intrathecal midazolam has significant analgesic effect.
This coincides with the results of a study performed by Kim and Lee , who aimed to evaluate the analgesic effects of intrathecal midazolam with bupivacaine following hemorrhoidectomy. In their study the control group received 1 ml of 0.5% heavy bupivacaine plus 0.2 ml of 0.9% saline intrathecally; group BM1 received 1 ml of 0.5% bupivacaine plus 0.2 ml of 0.5% preservative-free midazolam; and group BM2 received 1 ml of 0.5% bupivacaine plus 0.4 ml of 0.5% midazolam. Time to first analgesia was significantly greater in the midazolam groups than in the placebo group and significantly less in the BM1 group than in the BM2 group.
In the present study the level of sedation was assessed by the Ramsay Sedation Score. None of the patients in our study developed a moderate or deep level of sedation that might compromise their respiratory function or protective airway reflexes. The highest sedation score expressed by the three groups was 2 (2 = cooperative, oriented, and tranquil).
Bharti et al.  performed a study that included 40 ASA I or II adult patients undergoing lower abdominal surgery. The patients were randomly allocated to receive 3 ml of 0.5% hyperbaric bupivacaine intrathecally either alone or with 1 mg of midazolam using a combined spinal epidural technique. Sedation scores were comparable in the two groups.
As regards complications, one patient complained of nausea and vomiting in groups R and RM and six patients in group RF. Ten patients complained of pruritus in group RF in comparison with just one patient in group RM and no cases in group R, which was considered statistically significant (P < 0.05).
Shah et al.  performed a study comparing the effect of the addition of ropivacaine or bupivacaine upon pruritus induced by intrathecal fentanyl in labour and concluded that intrathecal ropivacaine and, to a greater extent, intrathecal bupivacaine reduce the incidence and severity of pruritus from intrathecal fentanyl.
| Conclusion|| |
Adding midazolam to hyperbaric ropivacaine in spinal anesthesia for lower-limb surgeries is considered a good alternative for improving the duration of sensory block and decreasing the analgesic requirement in the early postoperative period with minimal side effects compared with hyperbaric ropivacaine alone or fentanyl combined with hyperbaric ropivacaine in spinal anesthesia.
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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], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]