Abstract
This study aimed to compare the effects of intrathecal dexmedetomidine, fentanyl and magnesium sulfate added to ropivacaine on the onset and duration of sensory and motor blocks in lower abdominal surgery. This double-blind randomized clinical trial included 90 patients scheduled for lower abdominal surgery at Vali-Asr Hospital in Arak, Iran. The enrolled patients were randomly divided into three equal groups and then underwent spinal anesthesia. The first group received 10 μg of dexmedetomidine, the second group received 50 μg of fentanyl, and the third group received 200 mg of 20% magnesium sulfate intrathecally in addition to 15 mg of 0.5% ropivacaine. In the dexmedetomidine group, the mean arterial blood pressure was lower than the other two groups (P = 0.001). Moreover, the time to onset of sensory block (P = 0.001) and the mean duration of sensory block (P = 0.001) were shorter and longer, respectively, in the dexmedetomidine group than in the other two groups. In the dexmedetomidine group, the mean time to onset of motor block (P = 0.001) and the mean duration of motor block (P = 0.001) were lower and higher than in the other two groups, respectively. There was no significant difference in visual analog scale score, heart rate, administered opioid, and drug side effects among the three groups. Dexmedetomidine caused early sensory and motor blocks while prolonging the duration of sensory and motor blocks compared with the other two groups. In addition, dexmedetomidine reduced mean arterial blood pressure in patients. Based on the findings of this study, it is recommended that dexmedetomidine can be used in order to enhance the quality of sensory and motor block in patients.
Keywords: dexmedetomidine, fentanyl, intrathecal administration, lower abdominal surgery, magnesium sulfate, motor block, sensory block, visual analog scale
INTRODUCTION
The stimulation of α-2 adrenergic agonist in the spine has postoperative analgesic effects. Dexmedetomidine belongs to this group of medications.1,2,3,4,5,6,7 Dexmedetomidine has higher analgesic effects postoperatively and prolongs the duration of sensory and motor block with the least side effects.8 Based on the studies carried out on the effects of the addition of dexmedetomidine to ropivacaine, it has been suggested that dexmedetomidine lengthens the time and onset of block.8,9,10,11 Fentanyl is a strong analgesic with fast onset and prolonged duration, which has been successfully used for pain relief in emergency wards. Fentanyl is a potent agonist of μ-opioid receptors which is 80 times stronger than morphine in pain relief, which was first introduced in 1960’s as an opioid and intravenous anesthetic. Nowadays, fentanyl is vastly used in anesthesia and analgesia.12 According to the studies from Jagtap et al.13 and Chandhury et al.,14 intrathecal administration of fentanyl can prolong the patients’ motor block.
Magnesium is the fourth most abundant cation in human body, which has analgesic effects in living things.15 These effects are due to calcium regulation inside the cell in the first place. In addition, magnesium is a noncompetitive antagonist of N-methyl-D-aspartate receptors.16 N-methyl-D-aspartate receptors are ionotropic (stimulating the nervous system), which allow the flow of electric signals between neurons, brain and the spine. The administration of N-methyl-D-aspartate antagonists (like magnesium) can block such a passage. On the other hand, the permeability of calcium is reduced with the administration of local anesthetics.17,18,19,20,21 Moreover, studies has shown that calcium channel blockers increase the analgesic effects of anesthetics.22,23
Ropivacaine is a fast-acting anesthetic agent, which has a short onset of action like lidocaine, but side effects such as cauda equina syndrome not observed in ropivacaine. Therefore, the desire to use it is gaining momentum every day. Its onset of action is shorter than that of bupivacaine, which is a very important issue in anesthesia.2 In 2016, Sharma et al.10 explored the effects of adding dexmedetomidine to 2% ropivacaine on femoral block and found that postoperative analgesia and duration of block were prolonged in patients.
Since there has been no comparative study on the effects of adding the drugs in question (i.e. in the form of triple drugs) in spinal anesthesia with ropivacaine, the current study endeavored to compare the effects of intrathecal dexmedetomidine, fentanyl and magnesium sulfate added to ropivacaine on the onset time and duration of sensory and motor blocks in lower abdominal surgery.
SUBJECTS AND METHODS
Study design
This randomized clinical trial with parallel design included 90 patients who were candidates for lower abdominal surgery at Vali-Asr Hospital in Arak, Iran. Patients were enrolled in the study after being informed of the conditions of surgery and anesthesia, and after giving written informed consent. The Ethical Committee of Arak University of Medical Sciences approved this study protocol (approval No. IR.ARAKMU. REC.1397.354) on February 24, 2019. Also, the protocol of this study was registered in the Iranian Registry of Clinical Trials (registration No. IRCT20141209020258N118) on July 27, 2019. The patient enrollment continued from May 2019 to April 2020. The study followed the CONsolidated Standards Of Reporting Trials (CONSORT) statement.
Subjects
The inclusion criteria were (1) 18-60 years old, (2) The American Society of Anesthesiologists class I and II patients, (3) both sexes, (4) patients who were candidates for lower abdominal surgery, and (5) a body mass index greater than 30 kg/m2. The exclusion criteria were (1) having a history of taking β-blockers, α-2 agonists, and calcium channel blockers, (2) having cardiovascular conditions, (3) being pregnant, or having coagulation disorders, (4) any regional infection in the spine, (5) history of allergy to dexmedetomidine, ropivacaine, fentanyl and magnesium sulfate, (6) arrhythmia, absence of mental disorders, and (7) peripheral and central neuropathy. The exclusion criteria were unwillingness to continue the study, having serious side effects, and failure in spinal anesthesia.
Surgical preparation and intervention
All the patients were hospitalized and kept fasting overnight (8 hours) before the operation. When the patients entered the operating room on the morning of the surgery, their demographic information was recorded and two sites were identified on different parts of their veins, one for the administration of the drugs and the other for the crystalloid fluid (Ringer). At first, the heart rate (HR) and mean arterial blood pressure (MAP; by noninvasive monitoring) and saturation of arterial blood oxygen were measured as baseline data. All the patients were placed in the supine position and received 100 mL/kg crystalloid serum (Ringer). After serum administration and registration of vital signs, patients were assigned using permuted balanced block randomization.24 Spinal anesthesia was done using a 25–26 Quincke needle through L3–L4 or L4–L5 intervertebral space. Ropivacaine (5%, Molteni, Florence, Italy) was used for spinal anesthesia for all the patients.2 The first group received 3 mL (15 mg) of ropivacaine added with 10 μg of dexmedetomidine (in 1 mL volume)12; the second group received 3 mL (15 mg) of ropivacaine added to 50 μg of fentanyl (in 1 mL volume)12; and the third group received 3 mL (15 mg) of ropivacaine added to 1 mL of 20% magnesium sulfate (200 mg). The administrations were done intrathecally in all the patients during spinal anesthesia. Dexmedetomidine was a product of Iranian Exir Company (Exir Company, Broujerd, Lorestan Province, Iran); fentalnyl was purchased from Abou-Reyhan Company (Tehran, Iran) and 20% magnesium sulfate was a product of Samen Pharmaceutical Company (Razavi Khorasan Province, Mashhad, Iran).
Measurements
After spinal anesthesia, the patients were placed in the supine position. In the first 15 minutes, the mean MAP, HR and percentage of oxygen saturation (SPO2) in all three groups were measured by a medical intern every 5 minutes. During the operation, these data were registered every 15 minutes and in recovery. Hypotension < 20% of baseline, bradycardia < 45 beats/min and reduction in oxygen saturation < 92% were detected and treated. In case of consistency, appropriate treatment was performed and recorded. It was decided to administer 5 mL of ephedrine to control hypotension, 0.05 mg of atropine for bradycardia, and 4 L/min of oxygen via nasal cannula for SPO2 < 92%.8 The sensory motor block till dermatome T8 or above was measured by the intern. The sensory block was tested after anesthesia every 1 minute with the needle (pin prick method) and the motor block was tested via the Bromage scale (range from 0 to 3) every 5 minutes.25 The level of postoperative pain was measured by the visual analogue scale (VAS) during recovery and 1, 2, 4, 6, 12 and 24 hours after the operation. According to this scale, 0 refers to the minimum and 10 to the maximum value. If postoperative VAS score was more than 4, 0.5 mg/kg pethidine (meperidine) was intramuscularly administered.16 In addition, the times to reach dermatome T12 and L1 of sensory block and to obtain the Bromage scores of 0 and 1 were also recorded. Side effects such as nausea, vomiting, bradycardia, shivering, hypotension and dizziness were recorded, and in the case of exacerbation, appropriate treatment was administered and recorded.
Randomization and blindness
Participants were randomly divided into three equal groups using a permuted balanced block randomization24 with block size 3 and 6. Random sequence was created by an epidemiologist (AAH).
For the purpose of the blinded trial, data were gathered by an intern who was unaware of the grouping. Meanwhile, the drugs were prepared by an anesthesiologist, while an anesthesiology resident who was unaware of the contents of the syringes performed spinal anesthesia. All patients were blinded to group assignment.
Sample size
Using Stata software (version 13) and considering alpha 5%, study power 80%, and based on an earlier study,26 the mean time needed for sensory blockade at T10 in the dexmedetomidine and fentanyl groups was estimated to be 156 and 185 minutes with standard deviations of 34 and 35, respectively. The minimal sample size was estimated to be 24 cases in each group. Considering loss to follow-up, a total of 90 cases were included (30 cases in each group).
Statistical analysis
The mean (± standard deviation (SD)) and count (percentage) were used for describe the continuous and categorical variables, respectively. Likelihood ratio chi square test and one-way analysis of variance were used to compare the outcomes among groups. Scheffe post hoc comparison was used if required followed by analysis of variance test. Also, repeated measures analysis of variance was used to compare the variables measured over time. All analyses were done by Stata software at a significant level less than 0.05.
RESULTS
All 148 patients were evaluated and among those, 58 ineligible patients were excluded in the study and 90 eligible patients were enrolled and divided into intervention groups. All enrolled patients were followed to the end of study. The flowchart of patient enrollment is shown in Figure 1.
Figure 1.
The process of patient recruitment.
The baseline demographic and medical characteristics are listed in Table 1. The minimum and maximum age of the patients were 22 and 54 years, respectively, with the total mean age of 35.61 ± 8.00 years. In terms of sex, 45 (50%) patients were male. The body mass index was similar across the three groups, and the mean body mass index was 24.17 ± 2.37 kg/m2. The mean values of MAP, HR and SPO2 were 86.5 ± 6.5, 90.52 ± 6.9 and 96.88 ± 0.61, respectively. The age, body mass index, MAP, HR and SPO2 were similar across three groups at baseline.
Table 1.
Baseline demographic and medical characteristics of the participants
| Dexmedetomidine (n=30) | Fentanyl (n=30) | Magnesium sulfate (n=30) | Total (n=90) | |
|---|---|---|---|---|
| Age (yr) | 36.13±7.7 | 36.00±8.2 | 34.70±8.3 | 35.61±8.0 |
| Body mass index (kg/m2) | 24.33±2.1 | 24.20±2.2 | 24.00±2.8 | 24.18±2.4 |
| Mean arterial blood pressure (mmHg) | 85.97±7.8 | 87.23±6.3 | 86.37±5.5 | 86.5±6.5 |
| Heart rate (beat/min) | 92.37±6.1 | 89.00±7.6 | 90.20±6.6 | 90.52±6.9 |
| Oxygen saturation (%) | 96.97±0.61 | 96.90±0.61 | 96.77±0.63 | 96.88±0.61 |
Note: The data are presented as mean ± SD.
As shown in Table 2, repeated measure analysis suggested that the changes of MAP over time were significant (P < 0.001) and there was a remarkable interaction between time and groups (P < 0.001). Therefore, the MAP in the dexme-detomidine group was significantly lower than that in the other two groups over the study period (P < 0.001). HR in the dexmedetomidine group was decreased within the first 90 minutes and then increased, which significantly changed over time (P < 0.001). There was no significant difference among the three groups (P = 0.170), although the mean HR in the dexmedetomidine group was lower than that in the other groups (P for interaction = 0.001; Table 2). The three groups were comparable in terms of SPO2 and there was no significant difference among groups (P = 0.377) and the changes of this variable over time did not have a significant trend (P = 0.127). To compare the mean pain after surgery, VAS score was measured and analyzed. As shown in Table 2, the pattern of pain score was similar among the three groups (P = 0.231); however, the mean pain score had a significant increasing trend over time (P < 0.001).
Table 2.
Comparison of mean arterial pressure, heart rate, oxygen saturation, and visual analogue scale score in dexmedetomidine, fentanyl and magnesium sulfate groups
| Dexmedetomidine (n=30) | Fentanyl (n=30) | Magnesium sulfate (n=30) | P-value | |
|---|---|---|---|---|
| Mean arterial blood pressure (mmHg) | PTime < 0.001 | |||
| Baseline | 85.96±7.79 | 87.23±6.31 | 86.36±5.51 | PInteraction < 0.001 |
| 5 min after the start of surgery | 85.20±7.72 | 87.23±6.31 | 86.36±5.51 | |
| 10 min after the start of surgery | 84.23±7.69 | 87.70±6.06 | 86.73±5.40 | |
| 15 min after the start of surgery | 83.63±7.62 | 87.53±6.35 | 87.03±5.29 | |
| 30 min after the start of surgery | 82.93±7.42 | 87.00±5.96 | 86.50±5.28 | |
| 45 min after the start of surgery | 81.93±6.98 | 86.10±6.04 | 85.90±5.04 | |
| 60 min after the start of surgery | 81.76±6.96 | 86.50±5.87 | 85.93±5.02 | |
| 75 min after the start of surgery | 81.33±6.55 | 86.96±5.51 | 86.30±4.77 | |
| 90 min after the start of surgery | 80.83±6.33 | 88.16±4.67 | 87.26±4.29 | |
| 105 min after the start of surgery | 79.50±6.59 | 88.16±4.67 | 87.26±4.29 | |
| 120 min after the start of surgery | 79.80±6.51 | 88.63±4.46 | 88.03±4.25 | |
| 135 min after the start of surgery | 80.46±6.49 | 88.63±4.46 | 88.03±4.25 | |
| 150 min after the start of surgery | 80.86±6.44 | 89.43±4.13 | 88.83±3.93 | |
| 165 min after the start of surgery | 81.93±6.15 | 89.43±4.13 | 88.83±3.93 | |
| Heart rate (beat/min) | PTime < 0.001 | |||
| Baseline | 92.36±6.12 | 89.00±7.62 | 90.20±6.61 | PInteraction = 0.170 |
| 5 min after the start of surgery | 90.36±5.87 | 88.33±7.12 | 89.86±6.26 | |
| 10 min after the start of surgery | 89.10±5.37 | 88.33±7.12 | 89.87±6.26 | |
| 15 min after the start of surgery | 88.06±4.92 | 87.40±6.55 | 89.26±6.06 | |
| 30 min after the start of surgery | 86.26±4.25 | 87.40±6.55 | 89.26±6.06 | |
| 45 min after the start of surgery | 85.43±4.26 | 86.50±5.86 | 88.90±5.88 | |
| 60 min after the start of surgery | 84.76±4.30 | 86.50±5.86 | 88.90±5.88 | |
| 75 min after the start of surgery | 84.43±4.12 | 86.20±5.74 | 88.16±6.18 | |
| 90 min after the start of surgery | 84.43±4.12 | 86.20±5.74 | 88.16±6.18 | |
| 105 min after the start of surgery | 84.43±4.12 | 86.90±5.74 | 89.66±5.75 | |
| 120 min after the start of surgery | 86.06±4.27 | 86.90±5.75 | 89.66±5.75 | |
| 135 min after the start of surgery | 87.33±4.06 | 88.36±4.95 | 90.36±5.53 | |
| 150 min after the start of surgery | 87.33±4.06 | 88.36±4.95 | 90.35±5.54 | |
| 165 min after the start of surgery | 88.63±4.27 | 88.70±5.24 | 90.70±5.50 | |
| Oxygen saturation (%) | PTime = 0.127 | |||
| Baseline | 96.96±0.61 | 96.90±0.60 | 96.76±0.62 | PInteraction = 0.377 |
| 5 min after the start of surgery | 96.93±0.58 | 96.90±0.60 | 96.76±0.62 | |
| 10 min after the start of surgery | 96.93±0.52 | 96.91±0.54 | 96.83±0.64 | |
| 15 min after the start of surgery | 96.96±0.55 | 96.96±0.55 | 96.76±0.56 | |
| 30 min after the start of surgery | 96.96±0.61 | 96.96±0.55 | 96.76±0.62 | |
| 45 min after the start of surgery | 96.96±0.61 | 96.90±0.60 | 96.73±0.63 | |
| 60 min after the start of surgery | 96.90±0.60 | 96.90±0.54 | 96.70±0.59 | |
| 75 min after the start of surgery | 96.93±0.52 | 96.93±0.52 | 96.76±0.56 | |
| 90 min after the start of surgery | 96.93±0.58 | 96.90±0.54 | 96.76±0.56 | |
| 105 min after the start of surgery | 96.86±0.57 | 96.86±0.57 | 96.70±0.59 | |
| 120 min after the start of surgery | 96.96±0.55 | 97.00±0.64 | 96.76±0.67 | |
| 135 min after the start of surgery | 96.93±0.63 | 97.00±0.58 | 96.70±0.59 | |
| 150 min after the start of surgery | 96.86±0.57 | 96.87±0.62 | 96.70±0.59 | |
| 165 min after the start of surgery | 96.96±0.61 | 96.86±0.57 | 96.80±0.61 | |
| Visual analogue scale | PTime < 0.001 | |||
| At recovery | 0.0 (0.0) | 0.03±0.18 | 0.03±0.18 | PInteraction = 0.231 |
| 1 h post-operation | 0.03±0.18 | 0.13±0.43 | 0.13±0.43 | |
| 2 h post-operation | 0.36±0.55 | 0.53±0.77 | 0.70±0.74 | |
| 4 h post-operation | 1.36±0.55 | 1.56±0.78 | 1.70±0.74 | |
| 6 h post-operation | 2.35±0.56 | 2.57±0.77 | 2.70±0.75 | |
| 12 h post-operation | 3.40±0.56 | 3.43±0.62 | 3.50±0.62 | |
| 24 h post-operation | 4.23±0.43 | 4.40±0.49 | 4.40±0.50 |
Note: Data are presented as mean ± SD and were analyzed by repeated measure analysis of variance.
The mean time to onset (P = 0.001) and duration (P = 0.001) of sensory block were significantly different among groups. In the dexmedetomidine group, the onset time of sensory block was significantly lower than the other groups (P = 0.001) and duration of sensory block was significantly higher than the other groups (P = 0.001). The highest mean time to onset of sensory block and the lowest mean sensory block duration were observed in the magnesium sulfate group (Table 3).
Table 3.
Comparison of onset and duration of sensory and motor block in dexmedetomidine, fentanyl and magnesium sulfate groups
| Dexmedetomidine (n=30) | Fentanyl (n=30) | Magnesium sulfate (n=30) | P-value | |
|---|---|---|---|---|
| Onset time of sensory block (min) | 4.90±0.84 | 6.30±0.84 | 6.63±0.93 | 0.001 |
| Duration of sensory block (min) | 195.76±13.2 | 161.50±10.0 | 159.16±9.56 | 0.001 |
| Onset time of motor block (min) | 7.73±0.98 | 9.56±1.27 | 9.26±1.17 | 0.001 |
| Duration of motor block (min) | 150.66±11.79 | 114.16±4.16 | 114.5±4.22 | 0.001 |
Note: Data are presented as mean ± SD and were analyzed by one-way analysis of variance followed by Scheffe post hoc comparison.
As shown in Table 3, a significant difference in the mean onset time (P = 0.001) and duration (P = 0.001) of motor block was observed among the three groups. In the dexmedetomidine group, the time to the onset of motor block was significantly shorter than the other groups (P = 0.001) and the duration of motor block was significantly longer than the other groups (P = 0.001). There was no significant difference between the magnesium sulfate and fentanyl groups in terms of time to onset and duration of sensory and motor block.
As shown in Table 4, the surgery duration was comparable between the groups (P = 0.608). No significant difference was observed in administered opioid (P = 0.179), dose of administered opioid (P = 0.420) and drug side effects (hypotension, bradycardia, shivering, dizziness, nausea and vomiting) (P = 0.999). No significant side effects were observed in this study.
Table 4.
Comparison of duration of surgery, opium use and side effects in dexmedetomidine, fentanyl and magnesium sulfate groups
| Dexmedetomidine (n=30) | Fentanyl (n=30) | Magnesium sulfate (n=30) | P-value | |
|---|---|---|---|---|
| Duration of surgery (min) | 51.90±5.47 | 50.70±5.80 | 50.60±5.54 | 0.608 |
| Opioid use | 8 (27) | 14 (47) | 14 (47) | 0.179 |
| Side effect | 2 (7) | 2 (7) | 2 (7) | 0.999 |
Note: Data in duration of surgery expressed as mean ± SD and were analyzed by one-way analysis of variance followed by Scheffe post hoc comparison. Data in opioid use and side effect are expressed as number (percentage) and were analyzed by likelihood ratio chi-square test.
DISCUSSION
The key results of this study suggested that no significant difference was obtained in the means of SPO2, HR, VAS score and duration of surgery among groups. In the dexmedetomidine group, the MAP was lower than the other two groups. Moreover, the mean time to onset and duration of sensory block in the dexmedetomidine group were lower and higher than the other two groups, respectively. However, the means of time to onset and duration of motor block in the dexmedetomidine group were more than other two groups.
The means of administered opioids and drug side effects (hypotension, bradycardia, shivering, dizziness, nausea and vomiting) were not different in all of the study groups. All in all, it can be deduced that dexmedetomidine causes early sensory-motor block and lengthens the duration of sensorymotor block. Although it brings about a reduction in MAP, it is similar to the other drugs in terms of VAS score, side effects and the amount of administered opioid.
Farokhmehr et al.27 found that an increased dose of dexme-detomidine accelerates the onset time of sensory and motor block. After treatment with 10 μg of dexmedetomidine the pain score was lower than that of the other groups, and an increased dose did not cause any side effect.27 It should be mentioned that in the current study, dexmedetomidine caused early sensory and motor block and prolonged their duration compared with the other two groups, but all groups were comparable in terms of pain management.
Anderson et al.8 demonstrated that dexmedetomidine prolongs the duration of sensory and motor block. The results of our study were consistent with those of Anderson et al.8 Ravipati et al.26 suggested that dexmedetomidine causes early onset and prolongation of sensory and motor block with no need for intraoperative sedation, which has been further confirmed in our study. Li et al.28 also indicated that magnesium sulfate can be used to facilitate blocks and prolong the analgesia duration along with the duration of sensory and motor block.
In our study, magnesium sulfate prolonged the duration of sensory and motor block, but dexmedetomidine was more effective than magnesium sulfate. A study by Zhang et al.29 concluded that increasing the dose of intrathecal dexmedeto-midine could prolong spinal anesthesia, but at the same time incresed bradycardia. This finding is in line with our study.
Singh et al.30 also found that 10 μg of dexmedetomidine could prolong analgesia without any adverse side effects. This was also consistent with the findings of our study. Chandhuri et al.14 found that the addition of fentanyl to ropivacaine is beneficial in prolonging the motor block duration without any side effects and hemodynamic changes. Although this finding was consistent with that of our study, dexmedetomidine in our study was more effective than fentanyl and magnesium sulfate in facilitating sensory and motor block.
One of the limitations of this trial was the availability of dexmedetomidine, a drug that is relatively rare in Iran. In conclusion, dexmedetomidine causes the early onset of sensory and motor block prolongs the duration of sensory and motor block compared with the other groups. Although there was no significant difference in the postoperative pain level and the amount of administered opioid among the three groups, the postoperative pain level and the amount of administered opioid in the dexmedetomidine group were less than those in the other groups. Furthermore, dexmedetomidine leads to a reduction in MAP. Also, it can be recommended that dexmedetomidine can be used to improve the quality of sensory and motor block in patients.
Acknowledgements
The authors hereby would like to express their sincere gratitude to the staff of clinical trial research advisory board of Vali-Asr Hospital of Arak for their consultation.
Funding Statement
Funding: This study was supported by Arak University of Medical Sciences.
Footnotes
Conflicts of interest
All the authors declared no conflict of interest.
Data availability statement
No additional data are available.
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