TITLE: To Compare the Effects of Different Doses of Dexmedetomidine on Intrathecal Bupivacaine in Infraumbilical Surgeries: A Prospective, Randomized, Double-blind Clinical Study

  ABSTRACT.INTRODUCTION:
Spinal anesthesia is preferred technique of choice in infraumbalical surgeries. Limitation of this technique is shorter duration of analgesia, so various adjuvants have been used with intrathecal bupivacaine such as fentanyl, clonidine, and dexmedetomidine. Dexmedetomidine is a highly selective alpha 2 adrenergic agonist. The aim of our study was to know the effect of different doses of dexmedetomidine on intrathecal bupivacaine.

ABSTRACT.MATERIALS AND METHODS:
The prospective, randomized, double-blind study was conducted in tertiary health care center, on ninety patients of the American Society of Anesthesiology Class I and II, of age group 18–60 years of either sex. They were randomly allocated into three groups. Group BD5 (n = 30): intrathecal bupivacaine 12.5 mg (2.5 ml) + dexmedetomidine 5 μg (0.5 ml), Group BD10 (n = 30): intrathecal bupivacaine 12.5 mg (2.5 ml) + dexmedetomidine 10 μg (0.5 ml), Group BD15 (n = 30): intrathecal bupivacaine 12.5 mg (2.5 ml) + dexmedetomidine 15 μg (0.5 ml) administered intarthecally. The onset and maximum level of sensory block, time to reach maximum level of sensory block, time of two-segment sensory regression, the total duration analgesia, time of rescue analgesia, onset and duration of motor block and heart rate, systolic blood pressure, diastolic blood pressure, mean arterial pressure, respiratory rate, and oxygen saturation were recorded at various intervals. Moreover, any adverse effects such as bradycardia, hypotension, nausea, vomiting, and sedation were recorded.

ABSTRACT.RESULTS:
The onset time of sensory block in Group D5-2.76 ± 1.32, Group D10-2.45 ± 1.50, and Group D15-1.86±0.93, which is statistically significant (P = 0.025). The time taken for two-segment sensory regression Group D5-96.66 ± 33.67, Group D10-116.80 ± 36.27, and Group D15 120.96 ± 30.24, (P = 0.014). The time taken for complete sensory recovery in Group D5-319.83 ± 61.41, Group D10-336.13 ± 61.38, and Group D15-415.20 ± 96.6, which is statistically highly significant (P = 0.000). Time for rescue analgesia in Group D5-377.46 ± 60.05, in Group D10-401.60 ± 61.11, and in Group D15-517.96 ± 97.30, which is statistically highly significant (P < 0.000).

ABSTRACT.CONCLUSION:
We concluded that there was decrease in onset of sensory and motor blockade with the prolongation of duration of anesthesia and analgesia in a dose-dependent manner.

BODY.I:
Spinal anesthesia is the most commonly used technique for lower abdominal surgeries as it is very economical and easy to administer.[1] Postoperative pain is a major problem in infraumbilical surgeries because shorter duration of spinal anesthesia using only local anesthetics, and thus, early analgesic intervention is needed in postoperative period. Various adjuvants such as fentanyl, midazolam, and clonidine have been tried along with local anesthetics, to prolong the intraoperative block and postoperative analgesia.  A most common problem during infraumbilical surgeries under subarachnoid block is visceral pain, nausea, and vomiting.[2] Addition of an adjuvant to the intrathecal local anesthetics will improve the quality of the intraoperative block and early postoperative analgesia. The addition of opioids to local anesthetics has disadvantages, such as pruritus and respiratory depression, nausea, vomiting.  In recent years, α2 adrenoreceptor receptor gains wide popularity as an anesthetic adjuvants and also as analgesics. Their primary effect is sympatholytic. They reduce peripheral norepinephrine release by the stimulation of prejunctional inhibitory α2 adrenoceptors. They also inhibit the central neural transmission in dorsal horn by presynaptic and postsynaptic mechanism. They also have direct sympatholytic effect on spinal preganglionic sympathetic neurons. Sedative, anxiolytic, and analgesic properties of alpha agonists favor the wide clinical use. The addition of dexmedetomidine to the local anesthetics provides effective analgesia for acute and chronic pain.[3]  Dexmedetomidine is a selective alpha 2 agonist when compared to clonidine (affinity for alpha 2 receptor is 1600:1, clonidine 200:1). Hence, it is used in clinical practice as an adjuvant to regional, local, and general anesthesia. Dexmedetomidine is approved by the Food and Drug Administration as an intravenous (IV) additive for Intensive Care Unit (ICU) sedation, but recently, it is widely used an adjuvant to the local anesthetics. The addition of dexmedetomidine for intrathecal local anesthetics prolongs the duration of both sensory block, motor block, and postoperative analgesia without severe sedation. This effect is due to the sparing of supraspinal central nervous system so that it reduces the requirement of immediate postoperative analgesics.[34]  It produces dose-dependent sedation, anxiolysis, and analgesia without respiratory depression. Activation of the receptors in the brain and spinal cord inhibits neuronal firing causing hypotension, bradycardia, sedation, and analgesia.[4]  The previous studies revealed prolongation of spinal block by intrathecal 5 and 10 μg dexmedetomidine as an adjuvant with no significant effect on blood pressure or heart rate (HR).[5]  Not many studies have been done to compare the effect of different doses of dexmedetomidine as an adjuvant with intrathecal bupivacaine in infraumbalical surgeries, and hence, we designed this study to evaluate the effects of different doses of dexmedetomidine as an adjuvant to hyperbaric bupivacaine.

BODY.M:
After obtaining the Institutional Ethical Committee approval, ninety patients of either sex of 18–60 years of age were scheduled for lower abdominal surgeries. All patients, who belong to the American Society of Anesthesiology Class I and II, were enrolled for this prospective randomized, double-blinded study. After obtaining written informed consent, all patients were examined and investigated a day before surgery. Patients were advised fasting for 6 h before surgery; they were advised to take tablet alprazolam 0.5 mg and tablet ranitidine 150 mg night before surgery.  On the day of surgery, the patient was preloaded with 15 ml/kg of Ringer lactate solution, after obtaining IV line, half an hour before the procedure. The patient was shifted to operation theater, connected to multiparameter monitor. Patients were randomly allocated using sealed envelope technique into three groups in a double-blinded manner (both attending anesthesiologist and patient were blinded).  The three groups are  
Group BD5: Intrathecal bupivacaine 12.5 mg (2.5 ml) + dexmedetomidine 5 μg (0.5 ml)Group BD10: Intrathecal bupivacaine 12.5 mg (2.5 ml) + dexmedetomidine 10 μg (0.5 ml)Group BD15: Intrathecal bupivacaine 12.5 mg (2.5 ml) + dexmedetomidine 15 μg (0.5 ml).
  Subarachnoid block was performed at L3-4 level with 25-gauge Quincke spinal needle with the patient in the left lateral position under aseptic precaution. Patients turned to the supine immediately after the block. The anesthesiologist who is performing the block will record the intraoperative data. O2 2 L/min were kept for all the patients.  The onset and maximum level of sensory block, time to reach maximum level of sensory block, and time of two-segment sensory regression were recorded using 25-gauge hypodermic needle by pinprick. The total duration analgesia, time of rescue analgesia, onset, and duration of motor block were recorded. Vitals were monitored HR, systolic blood pressure (SBP), diastolic blood pressure, mean arterial pressure (MAP), respiratory rate (RR), oxygen saturation (SpO2) for every 2 min in the first 10 min, for every 5 min in next 15 min, thereafter every 15 min till the end of surgery.  The sensory onset was defined as the time of intrathecal injection to the loss of pinprick sensation at T10 dermatome. The maximum level of sensory block was defined as loss of sensation for pinprick at midclavicular line anteriorly, for every 5 min in the first 20 min. The time of two-segment regression was defined as time of injection to regression of two-segment from highest level. The total duration of analgesia was defined as time of intrathecal injection to time of sensory regression to S1 dermatome. The duration of rescue analgesia is defined as the time intrathecal injection to time of patient demand for analgesics; then, the patient will be administered intramuscular diclofenac injection 75 mg.  The time of onset of motor block was defined as time of injection of intrathecal drug to modified Bromage 1. The total duration of motor block was defined as the time of intrathecal injection to complete motor regression. The motor level was assessed according to modified Bromage score.[6]  
Bromage 0: The patient can move the hip, knee, and ankleBromage 1: The patient is unable to move the hip, but able to move the knee and ankleBromage 2: The patient is unable to move hip and knee, but able to move the ankleBromage 3: The patient is unable to move the hip, knee, and ankle.
  Hypotension defines as decrease in SBP by 30% from baseline, and it was treated by incremental dosage of injection mephentermine 6 mg and crystalloid fluids.  Bradycardia was defined as <50 beats/min, was corrected using 0.6 mg of IV atropine sulfate. Other adverse effects such as sedation, nausea, and vomiting were recorded and treated accordingly. Sedation was assessed using modified Ramsay sedation scale.[7]

BODY.M.MODIFIED RAMSAY SEDATION SCALE:

Score 1 Anxious, agitated, restlessScore 2 Cooperative, oriented, tranquilScore 3 Responds to commands onlyScore 4 Brisk response to light glabellar tap or loud noiseScore 5 Sluggish response to light glabelar tap or loud noiseScore 6 No response.


BODY.M.STATISTICAL ANALYSIS:
The statistical analysis of the data was done using Statistical Package for Social Sciences evaluation version 20 (IBM SPSS Statistics for Windows, Armonk, NY: IBM Corp). The data were expressed as either mean or standard deviation for number and percentages. The demographic data of patients were studied for each of the three groups.  Level of significance:  
P is level of significanceP > 0.05; not significantP < 0.05; significantP < 0.01; highly significantP < 0.001; very highly significant.


BODY.R:
Patient demographic characteristics were comparable among the groups with respect to age, sex, weight, height, and body mass index, there was no statistically significant difference (P > 0.000) [Table 1].   Table 1 Demography   The onset time of sensory block [Figure 1] in Group D5-2.76 ± 1.32, Group D10-2.45 ± 1.50, and Group D15-1.86 ± 0.93, which is statistically significant (P = 0.025) as the dosage of dexmedetomidine increased the onset time of sensory block is significantly decreased.  Figure 1The onset time of sensory block in Group D5-2.76 ± 1.32, Group D10-2.45 ± 1.50, Group D15-1.86 ± 0.93, which is statistically significant (P = 0.025). As the dosage of dexmedetomidine increased the onset time of sensory block is significantly decreased  The time taken to achieve the maximum level sensory block is not statistically significant among the groups (P = 0.402) [Figure 2].  Figure 2The time taken to achieve the maximum level sensory block is not statistically significant among the groups (P = 0.402)  The time taken for two-segment sensory regression [Figure 3] Group D5-96.66 ± 33.67, Group D10-116.80 ± 36.27, and Group D15-120.96 ± 30.24, (P = 0.014), which is statistically significant, which is earlier in Group D5 when compared to Group D10 and Group D15 (Group D5 < Group D10 < Group D15) [Table 2].  Figure 3The time taken for two-segment sensory regression Group D5-96.66 ± 33.67, Group D10-116.80 ± 36.27, Group D15-120.96 ± 30.24 (P = 0.014), which is statistically significant, which is earlier in Group D5 when compared to Group D10 and Group D15 (Group D5 < Group D10 < Group D15)  Table 2 The results of characteristics of spinal block   The time taken for complete sensory recovery [Figure 4] in Group D5-319.83 ± 61.41, Group D10-336.13 ± 61.38, and Group D15-415.20 ± 96.6 which is statistically highly significant (P = 0.000; Group D15 > Group D10 > Group D5).  Figure 4The time taken for complete sensory recovery in Group D5-319.83 ± 61.41, Group D10-336.13 ± 61.38, Group D15-415.20 ± 96.6. Which is statistically highly significant (P = 0.000) (Group D15 > Group D10 > Group D5)  The sensory recovery time is maximum in Group D15 compared to Group D10 and Group D5 (Group D15> Group D10> Group D5).  Time of onset of motor blockade in Group D15-2.26 ± 1.048, Group D10-2.70 ± 2.08, Group D5-3.76 ± 7.38 though the onset of motor block is early in Group D15 when compared to D10 and D5 (Group D15 < Group D10 < Group D5), which is statistically not significant (P = 0.413).  The total duration of motor blockade in Group D15-401.23 ± 114.49 is prolonged when compared to Group D10-375.23 ± 72.39 and Group D5-340.93 ± 86.67 which is statistically significant (P = 0.046). The total duration of motor blockade depends on the dosage; more the dosage prolongs the block.

BODY.R.HEMODYNAMIC AND OTHER PARAMETERS:
The HR, MAP, RR, and SpO2 were measured at various intervals and were comparable among the groups [Figures 5 and 6].  Figure 5Mean heart rate  Figure 6Mean of mean arterial pressure  The HR fall significantly at 105 and 120 min from basal rate within groups, we noticed bradycardia in 3 (10.0%) patients among Group D5, 4 (13.3%) patients in Group D10, 10 (33.3%) patients in Group D15, which is statistically significant (P = 0.044). MAP falls significantly at 30th, 45th, and 60th min from basal rate within the groups, we have noticed hypotension in 4 (13.3%) patients in Group D5, 6 (20.0%) patients in Group D10, 13 (43.3%) patients in Group D15, which is statistically significant (P = 0.020) [Table 3]. We have not noticed any respiratory depression and desaturation among the groups at various interval.   Table 3 Adverse effects 

BODY.D:
Spinal anesthesia is the preferred procedure in lower abdominal surgeries since a long time, as it is easy to perform, and economical. The limitation of the procedure is duration of action; hence, to prolong the duration, various adjuvants have been used along with local anesthetics, such as fentanyl, buprenorphine, clonidine, and dexmedetomidine.  Dexmedetomidine is a highly selective alpha 2 adrenergic Agonist. It can be used in ICU for sedation. It has got supraspinal analgesic effect when it is used intrathecally as an adjuvant to local anesthetics, it will prolong the motor and sensory block of local anesthetics. It may be an additive or synergistic effect secondary to different mechanism of action of local anesthetics.  It acts by binding to the presynaptic C fibers and postsynaptic dorsal horn neurons. Their analgesic action is due to depression of release of neurotransmitters of C fibers and hyperpolarization of postsynaptic dorsal horn neurons.[8]  In this prospective, randomized, double-blind study, in patients scheduled for elective lower abdominal surgeries between age groups of 18 and 60 years of either sex. We have compared the dose-dependent effect of 5 10, 15 μg of dexmedetomidine added to 12.5 mg of intrathecal bupivacaine. We have studied onset time and duration of motor and sensory block, as well as postoperative rescue analgesia, hemodynamic response, and associated adverse effects such as bradycardia, hypotension, sedation, respiratory depression, nausea and vomiting.  The demographic profile in all the three groups was comparable and statistically insignificant.  The onset of sensory block to T10 is dose dependent, Group D5-2.76 ± 1.32, Group D10-2.45 ± 1.50, Group D15-1.86±0.93, which is statistically significant (P = 0.025), our results can be compared with Shaikh and Dattatri[9] and Al-Mustafa et al.,[10] they have also noticed similar results.  We have not noticed any statistically significant difference to achieve the maximum level of sensory blockade in all the three groups.  The onset of motor block to Bromage 1 is dose dependent in Group D15-2.26 ± 1.048, Group D10-2.70 ± 2.08, and Group D5-3.76 ± 7.38, but which is statistically not significant (P = 0.413). Our study is comparable with Chaudhry et al.,[11] they used 5 and 10 μg dexmedetomidine with 12.5 mg of 5% hyperbaric bupivacaine in femur surgeries, they have also not noticed the any significant difference in motor onset time.  Our study is also comparable with Gupta et al.[12] study. Our results are also comparable with Gupta et al.,[1] they have also not noticed any significant difference in the motor onset, but they have compared only 5 μg of dexmedetomidine with fentanyl alone with hyperbaric bupivacaine.  The time taken for two-segment sensory regression is dose-dependent Group D5-96.66 ± 33.67, Group D10-116.80 ± 36.27, Group D15-120.96 ± 30.24 (P = 0.014), which is statistically significant. Our study is comparable with Shaikh and Dattatri.[9] study, they have also noticed the similar results. Our study is also comparable with Eid et al.'s[5] study which is also statistically significant.  The time taken for complete sensory recovery is dose-dependent Group D5-319.83 ± 61.41, Group D10-336.13 ± 61.38, Group D15-415.20 ± 96.6, which is statistically highly significant (P = 0.000). Our study is comparable with studies by Eid et al.[5] and Bansal et al.,[8] which is also statistically highly significant.  The total duration of analgesia [Figure 7] is dose dependent in Group D5-322.50 ± 71.87, Group D10-358.70 ± 73.89, Group D15-458.33 ± 95.21. (P = 0.000) which is statistically highly significant. Our results are comparable with Bansal et al.[8] and Gupta et al.,[1] they have also noticed a significant difference among the groups in a dose-dependent manner. Our study is also comparable with Gupta et al.[1] and Gupta et al.,[12] they have also noticed the prolonged duration of analgesia in their studies.  Figure 7Total duration of analgesia in Group D5-322.50 ± 71.87, Group D10-358.70 ± 73.89, Group D15-458.33 ± 95.21, which is statistically highly significant (P = 0.000) (Group D15 > Group D10 > Group D5)  The time for rescue analgesia [Figure 8] in Group D5-377.46 ± 60.05, in Group D10-401.60 ± 61.11, and in Group D15-517.96 ± 97.30, which is statistically highly significant, P < 0.000. Our study is comparable with Bansal et al.[8] (they have compared between dexmedetomidine 5 μg and 10 μg) and Eid et al.[5] (they have compared between dexmedetomidine 10 μg and 15 μg). They have also noticed the prolonged time for request of the first dose of analgesic in a dose-dependent manner, which is statistically significant.  Figure 8Time for rescue analgesia Group D5-377.46 ± 60.05, in Group D10-401.60 ± 61.11, in Group D15-517.96 ± 97.30, time of rescue analgesia is early in Group D5 compared to Group D10 and Group D15 (Group D5 < Group D10 < Group D15) which is statistically highly significant P < 0.000  Our study is also comparable with Gupta et al.,[1] Nayagam et al.,[13] Gupta et al.,[12] they have also noticed prolonged rescue analgesia with dexmedetomidine in comparison with fentanyl and clonidine.  The total duration of motor blockade in Group D15-401.23 ± 114.49 is prolonged when compared to Group D10-375.23 ± 72.39 and Group D5-340.93 ± 86.67 which is statistically significant (P = 0.046). The total duration of motor blockade depends on the dosage; more the dosage prolongs the block. Our study is comparable with Bansal et al.,[8] Eid et al.,[5] Gupta et al.[1] and Shaikh and Dattatri.,[9] in which they have also observed the dose-dependent prolongation of motor blockade. Our study is also comparable with Singh et al.,[14] they have also observed the similar results with dexmedetomidine in comparison with clonidine.  In our study, bradycardia was seen in 10% cases of Group D5 and 13.3% cases in Group D10, 33.3% cases in Group D15, which is statistically significant. In our study, hypotension was observed in 4 (13.3%) cases in Group D5, 6 (20%) cases in Group D10, 13 (43.3%) cases in Group D15, which is statistically significant. And is comparable with Al-Mustafa et al.[10] in their study, they found a dose-dependent decrease in MAP when compared to bupivacaine. Our study is also comparable with Khan et al.,[15] in which they have noticed the incidence of bradycardia and hypotension in dexmedetomidine group as compared to fentanyl group. Episodes of hypotension were treated with graded dose of IV injection mephentermine 6 mg, and bradycardia was treated with IV atropine 0.6 mg.  We observed 1 case of vomiting in Group D15 which was insignificant. There was no incidence of respiratory depression and desaturation in our study. Our study is comparable with Gupta et al.,[1] Eid et al.,[5] Chaudhry et al.,[11] and Shaikh and Dattatri.[9] with respect to these adverse effects.  In our study, we have noticed in all the three group Grade 2 Ramsay sedation score, which is statistically insignificant.

BODY.C:
In our study depending on the data basis, we have concluded that the addition of adjuvant-like dexmedetomidine to hyperbaric bupivacaine intrathecally produces a rapid onset of sensory blockade and prolonged duration of sensory and the motor block. With prolonged duration for rescue analgesia postoperatively, which is statistically significant in a dose-dependent manner.  We have also concluded that significant hypotension and bradycardia were noticed with the intrathecal use of 15 μg of dexmedetomidine although there was significant duration of analgesia. We have also concluded that the ideal intrathecal dose of dexmedetomidine is 10 μg with minimal side effects and hemodynamic response with prolonged postoperative analgesia.

BODY.C.FINANCIAL SUPPORT AND SPONSORSHIP:
Nil.

BODY.C.CONFLICTS OF INTEREST:
There are no conflicts of interest.

Question: Compared to baseline what was the result of Group BD15 (n = 30): intrathecal bupivacaine 12.5 mg (2.5 ml) + dexmedetomidine 15 μg (0.5 ml), Group BD5 (n = 30): intrathecal bupivacaine 12.5 mg (2.5 ml) + dexmedetomidine 5 μg (0.5ml) , Group BD10 (n = 30): intrathecal bupivacaine 12.5 mg (2.5 ml) + dexmedetomidine 10 μg (0.5 ml) on Heart rate falls?
Evidence: Time for rescue analgesia in Group D5-377.46 ± 60.05, in Group D10-401.60 ± 61.11, and in Group D15-517.96 ± 97.30, which is statistically highly significant (P < 0.000).
Answer: significantly increased