|Year : 2015 | Volume
| Issue : 2 | Page : 43-49
A comparative study of intrathecal dexmedetomidine and fentanyl as additives to bupivacaine
Ahmed El-Attar, Mohamed Abdel Aleem, Ragab Beltagy, Wafaa Ahmed
Department of Anaesthesiology and Surgical Intensive Care, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
|Date of Submission||01-Jan-2015|
|Date of Acceptance||01-Feb-2015|
|Date of Web Publication||30-Dec-2016|
Medical Colledge, Alexandria
Source of Support: None, Conflict of Interest: None
In recent years, the use of intrathecal adjuvants has gained popularity. The quality of spinal anesthesia has been reported to improve with the addition of opioids and other drugs, but until now there is no single drug with no side effects. The aim of this study was to compare the addition of either dexmedetomidine or fentanyl to intrathecal bupivacaine as regards the onset and duration of sensory and motor block, hemodynamic effects, postoperative analgesia, and adverse effects of either drug.
Materials and methods
Sixty patients classified in American Society of Anesthesiologists as classes I and II scheduled for lower abdominal and lower limb surgeries were studied. Patients were randomly allocated to three groups (20 patients each): group B, group F, and group D. Group B patients received 3 ml (15 mg) of 0.5% hyperbaric bupivacaine plus 0.5 ml of normal saline intrathecally. Group F patients received 3 ml (15 mg) of 0.5% hyperbaric bupivacaine plus 0.5 ml (25 μg) of preservative-free fentanyl intrathecally. Group D patients received 3 ml (15 mg) of 0.5% hyperbaric bupivacaine plus 0.5 ml (5 μg) of diluted, preservative-free dexmedetomidine intrathecally.
Patients in the dexmedetomidine group (D) had faster sensory and motor onsets compared with those in the fentanyl group (F) and the bupivacaine group (B) (P = 0.000 for both sensory and motor). Patients in group D had significantly longer sensory and motor durations compared with those in groups F and B (P = 0.000). Patients in the dexmedetomidine group (D) did not have significant hemodynamic changes; they had prolonged analgesic effect with less 24 h requirements of analgesics, and they had nonsignificant adverse effects.
Dexmedetomidine has faster onset compared with fentanyl and bupivacaine when injected intrathecally along with bupivacaine; it prolonged the sensory and motor blocks and was hemodynamically stable, with no significant side effects and with less requirements of postoperative analgesic needs during the first 24h.
Keywords: Bupivacaine, dexmedetomidine, fentanyl, spinal anaesthesia
|How to cite this article:|
El-Attar A, Aleem MA, Beltagy R, Ahmed W. A comparative study of intrathecal dexmedetomidine and fentanyl as additives to bupivacaine. Res Opin Anesth Intensive Care 2015;2:43-9
|How to cite this URL:|
El-Attar A, Aleem MA, Beltagy R, Ahmed W. A comparative study of intrathecal dexmedetomidine and fentanyl as additives to bupivacaine. Res Opin Anesth Intensive Care [serial online] 2015 [cited 2017 Oct 22];2:43-9. Available from: http://www.roaic.eg.net/text.asp?2015/2/2/43/161328
| Introduction|| |
Lower abdominal and lower limb surgeries may be performed under local, regional (spinal or epidural), or general anesthesia, but neuraxial blockade is the preferred mode of anesthesia. Spinal block is still the first choice because of its rapid onset, superior blockade, low risk of infection as from catheter in situ, less failure rates, and cost effectiveness, but has the drawbacks of shorter duration of block and lack of postoperative analgesia. In recent years, the use of intrathecal adjuvants has gained popularity with the aim of prolonging the duration of block, better success rate, patient satisfaction, decreased resource utilization compared with general anesthesia, and faster recovery. Adequate pain management is essential to facilitate rehabilitation and accelerate functional recovery, thus enabling patients to return to their normal activity more quickly. The quality of spinal anesthesia has been reported to improve with the addition of opioids (such as morphine, fentanyl, and sufentanil) and other drugs (such as dexmedetomidine, clonidine, magnesium sulfate, neostigmine, ketamine, and midazolam), but no drug to inhibit nociception is without associated adverse effects .
Fentanyl is one of the short-acting narcotic analgesics with potent morphine-like action. It produces many of its clinical effects rapidly after intrathecal administration .
Neuroaxial administration of lipophilic opioids such as fentanyl and sufentanyl tends to provide a rapid onset of analgesia. Their rapid clearance from cerebrospinal fluid may limit cephalic spread and the development of certain side effects such as delayed respiratory depression .
Dexmedetomidine is a highly selective α2 adrenergic agonist, which has been used for premedication and as an adjunct to general anesthesia. It reduces opioids and inhalational anesthetic requirements. Intrathecal α2 receptor agonists are found to have antinociceptive action for both somatic and visceral pain .
Intrathecal α2 adrenoceptor agonist act by depressing the release of C-fiber transmitters and by hyperpolarization of postsynaptic dorsal horn neurons .
| Materials and methods|| |
The study was carried out in Alexandria Main University Hospitals, conducted after the approval of the ethical committee. Written informed consent was obtained from all patients. Inclusion criteria were patients between 18 and 50 years of age, of either sex, with height ranging from 160 to 190 cm,  American Society of Anesthesiologists (ASA) physical status I and II, scheduled for elective lower abdominal or lower limb surgeries. Exclusion criteria were pregnancy and lactation, allergy to the studied medications, heart block and dysrhythmias, hypertension, therapy with adrenergic receptor antagonist, calcium channel blocker, and/or angiotensin converting enzyme inhibitor, patients with opium addiction and sedative drug consumption, and patients with contraindications for spinal anesthesia. After history taking, complete physical examination, and laboratory investigations, patients were premedicated with H 2 antagonist (ranitidine 50 mg, intramuscularly, 2 h preoperatively). Before commencing regional anesthesia, standard monitoring was established using ECG, noninvasive arterial blood pressure, and oxygen saturation. They were preloaded with intravenous lactated Ringer's solution 10 ml/kg. Spinal anesthesia was induced in the sitting position at the L3-L4 interspace with midline or paramedian approach using a 25 G Quinke's spinal needle with all aseptic precautions. Patients were randomly categorized using closed envelope method in a double-blinded study into three equal groups (20 patients each) and injection was administered as follows: group B patients received 3 ml (15 mg) of 0.5% hyperbaric bupivacaine+0.5 ml of normal saline intrathecally; group F patients received 3 ml (15 mg) of 0.5% hyperbaric bupivacaine+0.5 ml (25 μg) of preservative-free fentanyl intrathecally; and group D patients received 3 ml (15 mg) of 0.5% hyperbaric bupivacaine+0.5 ml (5 μg) of diluted, preservative-free dexmedetomidine intrathecally. Injection was given over 10-15 s; immediately after being injected patients were made to lie supine. Low-flow oxygen (4 l/min) was administered through oxygen mask.
Patients' age in years and height in centimeters were recorded. In addition, duration of operation in minutes, hemodynamic measurements in the form of heart rate (beats/min), mean arterial blood pressure (mmHg), and oxygen saturation (%) were recorded. They were continuously monitored and recorded at the following periods.
- Before spinal anesthesia.
- Immediately after spinal analgesia, and every 15 min for 90 min and at the end of surgery.
- Every hour for 6 h postoperatively.
Hypotension was defined as a decrease in systolic blood pressure by more than 30% from baseline or fall below 90 mmHg and was treated with intravenous fluids and intravenous increments of 3 mg ephedrine. Bradycardia was defined as a heart rate less than 50 bpm and was treated with 0.6 mg of intravenous atropine. The incidence of adverse effects such as hypotension, bradycardia, nausea, vomiting, shivering, pruritus, respiratory depression, and sedation was recorded. These side effects were assessed at the first, second, fourth, sixth, and eighth hour, and every 4 h until 24 h. Sedation was assessed with the Ramsay Sedation Score :
- Anxious or restless or both.
- Cooperative, oriented, and tranquil.
- Responding to commands.
- Brisk response to stimulus.
- Sluggish response to stimulus.
- No response to stimulus. Scores 1, 2 and 3 = Awake/Scores 4, 5 and 6 = Asleep.
Sensory assessment was carried out with iced cubes to measure the following:
- Onset of sensory analgesia (defined as time in minutes to reach highest sensory level) was tested every minute after intrathecal injection until it reached the highest level.
- Sensory level of analgesia (defined as segmental level of highest sensory analgesia).
- Duration of analgesia (defined as time in minutes it takes for sensory level to decrease to dermatomal level S1) was measured from the highest obtained sensory level every 15 min. All durations were calculated considering the time of spinal injection as time zero.
Motor blockade was evaluated as follows:
- Onset of motor block (defined as time in minutes from the end of drug injection intrathecally until patient is unable to move the hip, knee, and ankle) was tested every minute after intrathecal injection.
- Duration of motor block in minutes was recorded from the time of onset of the block to the time when the patient was able to lift the legs in bed against gravity, and was tested every 15 min. This was based on the following modified Bromage score :
- The patient is able to move the hip, knee, and ankle, score = 0.
- The patient is unable to move the hip but is able to move the knee and ankle, score = 1.
- The patient is unable to move the hip and the knee but able to move the ankle, score = 2.
- The patient is unable to move the hip, knee, or ankle, score = 3.
Postoperatively, pain intensity was evaluated using a visual analog scale (VAS) starting from the first pain experienced by the patient until the end of study, with 0 corresponding to no pain and 10 to the worst pain imaginable; it was assessed at the first, second, fourth, sixth, and eighth hour, and every 4 h until 24 h. Time for first request of analgesia (defined as the time elapsed from the time of spinal injection until reaching VAS>4) was recorded and treated with intramuscular diclofenac sodium at a dose of 1 mg/kg to be repeated if needed after 12 h, but if pain persisted after 1 h from the first dose, 25 mg pethidine was administered intravenously. The total analgesic dose of both diclofenac sodium and pethidine taken within the first 24 h was recorded.
Statistical analysis was carried out using statistical package for social science (SPSS 20.0, Evaluation version IBM, USA). Qualitative data were described using number and percentage. Comparison between different groups as regards categorical variables was made using the χ2 -test. Quantitative data were described using mean and SD for normally distributed data, whereas abnormally distributed data were expressed using median, minimum, and maximum. For normally distributed data, comparison between two independent populations was made using independent t-test, whereas for more than two populations the F-test (analysis of variance) and post-hoc test (Scheffe) were used. Significance test results are quoted as two-tailed probabilities. Significance of the obtained results was judged at the 5% level. A P value less than 0.05 was considered statistically significant.
| Results|| |
The groups were comparable with respect to age, height, sex, duration of operation, and ASA physical status [Table 1].
The characteristics of the sensory block are shown in [Table 2]. The onset was significantly faster in group D compared with groups F and B; moreover, it was significantly faster in group F compared with group B. In group D, the mean time to reach highest sensory level was 4.32 ± 0.28 min; in group F it was 4.88 ± 0.42 min, and in group B it was 5.36 ± 0.45 min. As regards the sensory duration, group D had significantly longer duration compared with groups F and B; moreover, group F had significantly longer duration compared with group B, with a mean duration of sensory block of 327.75 ± 29.36 min, whereas in group F the mean duration of sensory block was 182.75 ± 13.91 min and in group B the mean duration of sensory block was 151.50 ± 16.55 min.
|Table 2 The onset and duration of sensory and motor blocks among the studied groups|
Click here to view
As regards motor block, the onset in group D was significantly faster compared with groups F and B; moreover, it was significantly faster in group F than in group B. In group D the mean onset of motor block was 3.41 ± 0.36 min, whereas in group F it was 3.80 ± 0.41 min and in group B it was 4.12 ± 0.49 min.
The regression time to modified Bromage score 0 was slower in group D compared with groups F and B, and it was slower in group F than in group B, with a total mean duration of motor block in group D of 251.85 ± 39.72 min; in group F it was 148.25 ± 12.49 min, and in group B it was 107.75 ± 12.08 min [Table 2].
The time to first analgesia request was significantly longer in group D in comparison with group F (P = 0.013) and group B (P = 0.002). It was significantly longer in group F in comparison with group B (P = 0.015). There was no need for rescue analgesia in 75% of patients in group D, in 50% of patients in group F, and in 10% of patients in group B [Figure 1]. The total consumption of 24 h analgesics was significantly less in group D in comparison with groups F and B, and it was less in group F than in group B.
|Figure 1: Comparison between the three studied groups as regards time to first request for analgesia.|
Click here to view
There were no significant complications on comparing the three groups [Table 3].
| Discussion|| |
The mechanism by which intrathecal α2 adrenoceptor agonists prolong the motor and sensory block of local anesthetics is not well known. They act by binding to the presynaptic C-fibers and postsynaptic dorsal horn neurons. Their analgesic action is a result of depression of the release of C-fiber transmitters and hyperpolarization of postsynaptic dorsal horn neurons .
Local anesthetic agents act by blocking sodium channels. The prolongation of the effect may result from synergism between local anesthetic and α2 adrenoceptor agonist, whereas the prolongation of the motor block of spinal anesthetics may result from the binding of α2 adrenoceptor agonists to motor neurons in the dorsal horn .
Intrathecal α2 receptor agonists have been found to have antinociceptive actions for both somatic and visceral pain . Fentanyl is a lipophilic mu receptor agonist opioid. Intrathecally, fentanyl exerts its effect by combining with opioid receptors in the dorsal horn of the spinal cord and may have a supraspinal spread and action .
The aim of the study was to compare the addition of either dexmedetomidine or fentanyl to intrathecal bupivacaine as regards the onset and duration of sensory and motor block, hemodynamic effects, postoperative analgesia, and adverse effects of either drug.
The study was carried out on 60 patients admitted to the Alexandria Main University Hospitals and scheduled for elective lower abdominal or lower limb surgeries. They were divided into three groups.
Group B patients received 3 ml (15 mg) of 0.5% hyperbaric bupivacaine+0.5 ml of normal saline intrathecally.
Group F patients received 3 ml (15 mg) of 0.5% hyperbaric bupivacaine+0.5 ml (25 μg) of preservative-free fentanyl intrathecally.
Group D patients received 3 ml (15 mg) of 0.5% hyperbaric bupivacaine+0.5 ml (5 μg) of diluted, preservative-free dexmedetomidine intrathecally.
As regards age, height, sex, duration of surgery, and ASA classification, there was no significant difference between the three groups.
In the current study the mean heart rate was significantly lower in group D compared with group F at 45 min (P = 0.045), at 60 min (P = 0.027), and at 90 min (P = 0.047). As regards comparison between group F and group B, the mean heart rate was significantly lower in group B than in group F at 30 min (P = 0.040) and at 45 min (P = 0.048). Bradycardia occurred in four patients of group D (20%), in four patients of group F (20%), and in five patients of group B (25%). However, this was of no statistical significance (P = 0.685). Moreover, as regards the total atropine dose there was no significant change in the three groups (P = 0.352). As regards the mean arterial blood pressure, it was significantly lower in group D compared with group F at 45 min (P = 0.031). It was also significantly lower in group B compared with group D after the intrathecal block (P = 0.006) and at 15 min (P = 0.044). On comparing groups F and B, it was significantly lower in group B than in group F after the intrathecal block (P = 0.003) and at 15 min (P = 0.050). Hypotension occurred in eight patients in group D (40%), in six patients in group F (30%), and in seven patients in group B (35%), but this was of no statistical significance (P = 0.352). As regards the total ephedrine dose, there was no significant difference between the three groups as well (P = 0.462).
The decrease in heart rate in spinal anesthesia can be explained by three mechanisms:
- The Bainbridge reflex, in which stimulation of right atrial stretch receptors leads to vagal afferent stimulation of the medulla and subsequent inhibition of parasympathetic activity (increasing the heart rate, or, in the case of decrease atrial pressure, lowering heart rate);
- A direct effect on the sinoatrial node elicited by atrial stretching; and
- Anesthesia of T1-T4 cardioaccelerator fibers .
Moreover, it was found that the most significant side effects reported on the use of intrathecal α2 adrenoceptor agonists are bradycardia and hypotension . This may be due to postsynaptic activation of central α2 adrenoceptors, which results in sympatholytic effect, leading to hypotension and bradycardia, an effect judiciously used to attenuate the stress response of surgery . This can explain the observations found in the dexmedetomidine group.
Considering the effect of subarachnoid blockade on the cardiovascular system, hypotension and bradycardia were most commonly expected, because the usual consequence of sympathectomy is a decrease in venous return and hypotension .
In agreement with the results of the present study, Al-Ghanem et al.  demonstrated significant decrease in the heart rate and mean arterial blood pressure on comparing the addition of 5 μg dexmedetomidine with intrathecal bupivacaine with 25 μg fentanyl in gynecological procedure. This was also supported by Abdelhamid and El-Lakany , who reported significant decrease in the heart rate in the dexmedetomidine group on comparing the use of 5 μg dexmedetomidine with hyperbaric bupivacaine only.
In agreement with the current study, there was no significant bradycardia or hypotension and no significant difference in the doses of atropine and ephedrine, as in the study by Sunil and Sahana , who compared addition of dexmedetomidine and magnesium sulfate to hyperbaric bupivacaine for spinal anesthesia. Sunil et al.  compared the addition of dexmedetomidine, fentanyl, and magnesium sulfate to hyperbaric bupivacaine. Sunil et al.  studied dexmedetomidine as an adjuvant to hyperbaric bupivacaine for spinal anesthesia.
However, this was in disagreement with the study by Kanazi et al. , who found no significant decrease in heart rate or mean arterial blood pressure when studying the effect of 3 μg dexmedetomidine and 30 μg clonidine added to intrathecal bupivacaine, but this may be attributed to the use of lower dose of dexmedetomidine and lower total volume injected in the intrathecal space, as they used 1.9 versus 3.5 ml in the current study.
As regards arterial oxygen saturation, there was no significant difference between the three groups all through the measuring intervals, which may be due to the following reasons: first, the dose of local anesthetic used while designing the study, which was kept to minimal possible levels with noninvolvement of the intercostal muscles and/or diaphragm during motor blockade ; second, supplemental oxygen administration through a face-mask throughout the procedure. This was in agreement with that deduced by Sunil et al. , and Shukla et al. .
As regards sensory onset, it was significantly faster in group D than in groups F and B (P = 0.000).
In agreement with the present study, the sensory onset of intrathecal dexmedetomidine as an adjuvant to bupivacaine was faster when compared with magnesium sulfate and hyperbaric bupivacaine by Shukla et al. . The mean onset time in the dexmedetomidine group in the current study was 4.32 ± 0.28 min in comparison with 2.27 ± 1.09 min in the study by Shukla and colleagues. In both studies those onsets were significantly faster than that reported for the other groups, and the difference between the two onsets may be because of the use of different definitions for the sensory onset. In the current study, it was until the highest sensory level was reached, whereas in the study by Shukla and colleagues it was until T10 only.
In another study, Sunil et al.  deduced that the onset of 10 μg dexmedetomidine was faster compared with 5 μg and faster than bupivacaine groups, with mean times of 3.1 ± 0.5, 3.5 ± 0.8, and 4.7 ± 1.1 min, respectively.
In contrast to the current study, Al-Ghanem et al.  found no significant difference between the onset times of the different groups in their study when comparing dexmedetomidine and fentanyl as adjuvants to bupivacaine in gynecological surgeries. This may be due to the following reasons: they used isobaric bupivacaine, versus hyperbaric bupivacaine in the current study; they had different definition for the onset time (until reaching T10, which can be reached similarly and rapidly by the studied drugs, versus until reaching the highest sensory level in the current study); lastly, the patients were made to lie in lithotomy position in their study, whereas in the current study they were made to lie supine.
As regards motor onset, in the current study there was statistically significant difference between the three groups with conclusion of faster onset in group D compared with groups F and B (P = 0.001, 0.000, and 0.016, respectively). This was in agreement with that concluded by Shukla et al.  and Sunil et al. . Moreover, Ogan et al.  had found faster motor onset in the dexmedetomidine group when compared with fentanyl as adjuvants to intrathecal bupivacaine on labor outcome.
This was in disagreement with that reported by Al-Ghanem et al. , and this can be defended by the same reasons for the differences in the sensory onset. Moreover, the motor onset was not significantly faster in the dexmedetomidine group compared with the other groups as observed by Mahendru et al.  when comparing intrathecal dexmedetomidine, clonidine, and fentanyl as adjuvants to hyperbaric bupivacaine. This may be due to lower total volume injected intrathecally by the author, total of 3 versus 3.5 ml in the current study.
Group D significantly had longer sensory and motor durations compared with groups F and B (P = 0.000); moreover, group F had significantly longer duration compared with group B (P = 0.000). This was in agreement with the study by Mahendru et al. , who found significantly prolonged durations of sensory and motor blocks. This was again concluded by Al-Ghanem et al. , Kanazi et al. , and Al-Mustafa et al. , who studied the effect of dexmedetomidine on spinal bupivacaine for urological procedures and observed dose-dependent prolongation of motor and sensory blockade when increasing the dose of dexmedetomidine from 5 to 10 μg.
Li and Eisenach  observed that glutamate is involved in excitatory neurotransmission nociception and plays an essential role in relaying noxious stimuli in the spinal cord. Intrathecal injection of α2 adrenergic agonists produces potent antinociceptive effects by altering spinal neurotransmitter release and effectively treats acute pain.
The time to first analgesia request was significantly longer in group D in comparison with groups F (P = 0.013) and B (P = 0.002). It was significantly longer in group F in comparison with group B (P = 0.015). Moreover, there was no need for rescue analgesia in 75% of patients in group D, in 50% of patients in group F, and in 10% of patients in group B. There was significantly reduced 24 h requirements of total analgesics (pethidine and diclofenac sodium) in group D compared with groups F and B. This was similar to that reported by Mahendru et al.  when comparing 5 μg dexmedetomidine to 30 μg clonidine and 25 μg fentanyl, which supports the analgesic efficacy of dexmedetomidine as an intrathecal adjuvant. Similarly, significantly improved analgesic efficacy was reported by Gupta et al.  when studying the comparison of dexmedetomidine and fentanyl as intrathecal adjuvant. Moreover, Al-Mustafa et al.  noticed reduced analgesic requirement in a dose-dependent pattern when comparing 5 with 10 μg of dexmedetomidine.
As regards the VAS, similar to our current study, Gupta et al.  noticed lower VAS values in the dexmeditomidine group compared with the bupivacaine group. Similarly, Mahendru et al.  reported lower VAS values in the dexmedetomidine group than in the other compared groups.
As regards side effects such as nausea, vomiting, shivering, pruritus, respiratory depression, and sedation, the occurrence was of no significant value in all groups in this study. This was in agreement with that deduced by Sunil et al. . In the current study all patients were 'awake' by Ramsay Sedation Score; however, in contrast to this, Hala et al. , who studied different intrathecal doses of dexmedetomidine (5, 10, and 15 μg) added to bupivacaine, showed significantly higher sedation scores when using 15 μg, which can be beneficial for patients undergoing lengthy complex surgeries as an alternative to epidural or prolonged general anesthetics and can preclude the use of intravenous sedatives. However, such high sedation scores may be harmful in elderly and high-risk surgical patients owing to the risk associated with excessive sedation and respiratory depression.
In disagreement with the current study, Abdelhamid and El-Lakany  had found significant shivering in the bupivacaine group (12 patients) compared with the dexmedetomidine group (two patients), and this may prove that α2 adrenergic agonists have antishivering property as observed by Talke et al. .
| Conclusion|| |
Using dexmedetomidine as an adjuvant to intrathecal bupivacaine compared with fentanyl was associated with more rapid onset, as well as prolonged durations of both sensory and motor blockade. In addition, postoperatively it was associated with prolonged analgesia, as well as less analgesic consumption. Moreover, it did not cause marked sedation or severe side effects.
| Acknowledgements|| |
Conflicts of interest
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[Table 1], [Table 2], [Table 3]