Orthopedic surgeries are commonly performed under regional anaesthesia, with spinal anaesthesia being preferred technique for lower limb surgeries. Spinal block has rapid onset, deep block, lower risk of infection and cost effective.[1] During spinal block, as patient will be awake, it helps in minimizing the problems associated with airway manipulation, polypharmacy and untoward effects like postoperative nausea, vomiting, need for supplemental intravenous analgesia. However, these advantages are sometimes offset by relatively short duration of action and thus making the postoperative period uncomfortable to the patient, when its action wears off. Various adjuvants are being used with local anaesthetics for prolongation of intraoperative and postoperative spinal analgesia[1, 2] including opiods, alpha-2 agonists, neostigmine, vasoconstrictors, etc. Dexmedetomidine is highly selective alpha-2 adrenergic agonist,[2, 3] which has been used as premedication and as an adjuvant to general anaesthesia and it has property to potentiate the action of local anaesthetic used in spinal anaesthesia.[3] It reduces the requirement of opioids and inhalational anaesthetics and has been widely used for intensive care unit sedation.[3, 4, 5] And intrathecal alpha-2 agonistic action has shown antinociceptive action for both somatic and visceral pain,[3, 4, 5] prolongs the duration of both motor and sensory spinal blockade.[6, 7] Fentanyl is a synthetic opiod with central action, which is widely used for pain control. Intrathecal fentanyl is usually added to local anaesthetics to increase anaesthesia and analgesia. And it improves the quality of intraoperative and early postoperative anaesthesia with lesser dose of local anaesthetic.[3, 8, 9] This study was designed to compare efficacy of dexmedetomidine and fentanyl added to intrathecal bupivacaine in orthopedic lower limb surgeries in terms of block strength and time.

A prospective randomized double blinded comparative study was planned on 64 patients, aged 18-50 years, belonging to American Society of Anesthesiologists class I and II, posted for elective orthopedic lower limb surgery. Exclusion criteria being, patients posted for emergency surgeries, having uncontrolled hypertension or diabetes mellitus, renal or hepatic failure, cardiac block or dysrhythmia, coagulopathies, neurologic disorder, hypersensitivity to any of the study drugs or patients with known contraindications to spinal anesthesia. After obtaining clearance from the institutional ethical committee and informed written and valid consent, patients were randomly allocated to two groups D and F, according to computer-generated randomized number table. Allocation was done by serially numbered opaque sealed envelope (SNOSE) method. (Figure 1) The study drugs were drawn and diluted in identical syringes to make a volume of 3ml by an anaesthetist who was not a part of the study. Patients and investigators were blinded to the study medication. After pre-anaesthetic evaluation, patients were advised to be nil per oral as per current ASA guidelines. An 18G intravenous access was secured, preloaded with Ringer lactate solution (5 ml/kg body weight). Standard ASA monitoring including noninvasive blood pressure (NIBP), Electrocardiogram (ECG), heart rate (HR) and pulse oximetry was done and baseline vitals were noted. Under proper aseptic conditions, spinal anesthesia was given at the level of L3-L4 interspace in sitting position using a midline or paramedian approach by a 25G Quincke spinal needle. Group D (n=32) patients received 2.5 ml hyperbaric Bupivacaine plus Dexmedetomidine 5 micrograms intrathecally. Group F (n=32) patients received 2.5 ml hyperbaric Bupivacaine plus Fentanyl 25micrograms intrathecally. The anesthetic medication injected at a rate of approximately 0.2 ml/sec; and then all patients made supine. Intravenous fluids continued intraoperatively. Sensory blockade was assessed by loss of pin prick sensation at the surgical site of incision, tested with a 23G sterile hypodermic needle, immediately after the spinal injection, then every 2 min after injection until reaching the highest sensory level. The motor dermatome level was assessed according to the Modified Bromage scale: • Bromage 0: Free movement of legs, feet with ability to raise extended legs. • Bromage I: Inability to raise extended legs, but able to move knees and feet. • Bromage II: Inability to raise extended legs or move knee, able to move feet. • Bromage III: Inability to raise extended legs, flex knees, ankle or move toes. Motor status was assessed immediately after the spinal injection, then every 2 min after injection until Bromage scale reaching to Bromage 3. Systolic and diastolic blood pressure and heart rate before regional anesthesia and in the 5, 10, 15, 30, 45 and 60 min after anesthesia were noted. All the data was recorded in a data sheet specified to each patient. After surgery, assessment was performed every 10 min until the time to regression of 2 sensory levels, then every 20 min until the regression time to the dermatome S1 and motor scale to Bromage 0. Severity of pain 2 and 4 hours after surgery was measured by Numeric Rating Scale (NRS), where patients were asked to rate their pain from a scale of 0 = no pain to 10 = the worst possible pain. Time for first rescue analgesic requirement in the postoperative period is also noted. Side effects of the drugs were assessed, and if any like nausea, vomiting, respiratory depression, hypotension, bradycardia and pruritis were recorded. Hypotension: It is defined as reduction in systolic blood pressure (SBP) of more than 20% below the base line or reduction in SBP less than 90mmHg and it will be treated with infusion of 250ml of iv fluids and if needed Injection Mephentermine 6mg iv in incremental dose. Bradycardia: It is defined as heart rate of less than 50 beats per minute and will be treated with injection Atropine 0.6mg iv in incremental dose. Statistical analysis: The sample size was calculated assuming the expected mean and standard deviation of the duration of analgesia, as per the previous study conducted by Mahima Gupta et al[10] on intrathecal dexmedetomidine as adjuvant to bupivacaine in spinal anaesthesia, published in Feb 3- 2014. The other parameters considered for sample size calculation included were 80% power of study and 5% two sided alpha error. Data was entered into Microsoft excel data sheet and was analyzed using statistical package for social sciences (SPSS) 22 version software. Quantitative data was presented as mean and standard deviation. Independent sample t- test was the test of significance for quantitative data. Chi square test was the test of significance for qualitative data. p value <0.05 was considered as statistically significant.

The trial was completed by all recruited patients. The demographic data were comparable between the two groups [Table 1]. On comparing the time of onset to both sensory and motor blockade was statistically significant between the groups (p<0.01) [Table 2]. T6 was the highest sensory level achieved in majority between the group [Figure 2]. The time of two segment regression from highest sensory level in group D was 143±15.8mins and in group F was 86.9±9 mins and was significantly longer in group D compared to group F (p<0.01) [Table 2]. The duration of both sensory and motor block was significantly prolonged in group D (p<0.01) [Table 2]. The time for sensory regression to S1 in group D was 517.5±43mins and in group F was 292.2±28.5 mins and was significantly prolonged in group D (p<0.01) [Table 2]. The time for motor regression to Bromage 0 in group D was 354.4±40.2mins and in group F was 181.3±19 mins and was significantly prolonged in group D (p<0.01) [Table 2]. The time for first postoperative rescue analgesia was delayed in group D than in group F (p<0.01) [Table 2]. The NRS score 2 hours after surgery was comparable between the two groups, whereas score after 4 hours was significantly lesser in group D as compared to group F (p<0.01) [Table 2]. There was gradual decrease in heart rate in group D after 30 mins of induction, and the bradycardia was treated with Injection Atropine 0.6mg iv [Figure 3]. The patients in group F showed fall in both systolic [Figure 4] and diastolic [Figure 5] blood pressure after 5 mins and 10 mins of induction respectively, but blood pressure was better maintained in group D. Hypotension developed was easily treated with Injection Mephentermine 6mg iv. Incidence of bradycardia was significantly higher in group D, which was treated with injection Atropine 0.6mg IV. and group F showed higher incidence of pruritis as side effects [Table 3]. Table 1: Demographic data Characteristics Group D (n=32) Group F (n=32) Total (n=64) p-value Mean (SD) Age (years) 42.8 (13.9) 38.1 (15.7) 40.4 (14.9) 0.216 Sex Male 27 (84.4%) 25 (78.1%) 52 (81.2%) 0.522 Female 5 (15.6%) 7 (21.9%) 12 (18.8%) Weight (in Kg) 58.5 (4.7) 57.7 (5.9) 58.1 (5.3) 0.544 Height (in cm) 157.5 (4.4) 156.1(4.3) 156.8 (4.4) 0.180 Body Mass Index (in Kg/m2) 23.6 (2.0) 23.6 (2.0) 23.6 (2.0) 0.901 (p<0.05 was considered significant.) Table 2 : Characteristics of block Characteristics Group D (n=32) Group F (n=32) Total (n=64) p-value Time for highest sensory level (mins) 7.3 (1.8) 8.9 (1.1) 8.1 (1.7) <0.01* Time for onset to Bromage 3 (mins) 4.0 (1.1) 5.3 (0.9) 4.6 (1.1) <0.01* Time for 2 segment regression from the highest sensory level (mins) 143.0 (15.8) 86.9 (9.0) 114.9 (31.0) <0.01* Time for regression to S1 (mins) 517.5 (43.0) 292.2 (28.5) 404.9 (119.2) <0.01* Time for regression to Bromage 0 (mins) 354.4 (40.2) 181.3 (19.0) 267.8 (92.6) <0.01* Time for first postoperative rescue analgesia (mins) 439.1 (51.1) 236.6 (53.8) 337.8 (114.6) <0.01* NRS 2 hours after surgery 1.03 (0.17) 1.15 (0.44) 1.09 (0.34) 0.147 NRS 4 hours after surgery 1.93 (0.98) 4.12 (0.79) 3.03 (1.41) <0.001* (p<0.05 was considered significant.) Table 3 : Side effects Adverse events Group D (n=32) Group F (n=32) Total (n=64) p-value Bradycardia 17 (53.1%) 2 (6.3%) 19 (29.7%) <0.001* Hypotension 8 (25.0%) 10 (31.3%) 18 (28.1%) 0.578 Chills 0 1 (3.1%) 1 (1.6%) 0.316 Nausea 2 (6.3%) 5 (15.6%) 7 (10.9%) 0.230 Pruritis 0 12 (37.5%) 12 (18.8%) <0.001* (p<0.05 was considered significant.)

Regional anaesthesia carries many benefits for patients undergoing orthopedic lower limb surgeries like, providing perioperative analgesia, helping them to ambulate early and also, in maintaining hemodynamic stability. When local anaesthetics are used as only drug for spinal anaesthesia, they can limit the extent and duration of block, and it may lead to insufficient analgesia. To overcome this problem, several adjuvants are used like opioids and non-opioids. Although opioids are frequently employed as adjuvants and function to provide appropriate analgesia, they may produce undesirable effects like pruritis, respiratory depression, nausea, and vomiting. Furthermore, intrathecal alpha-2 agonists enhance the effects of local anaesthetics and aid in lowering their dosage without resulting in hemodynamic instability [4] or respiratory depression. The results of present study show that use of 5 µg dexmedetomidine as adjuvant to intrathecal bupivacaine, significantly prolonged both sensory and motor block, as compared to addition of 25 µg fentanyl as adjuvant. The mechanism by which intrathecal α2 adrenoreceptor agonists prolong the motor and sensory block of local anesthetics is not well known. There may be some additive or synergistic effect, other than mechanism of action of local anaesthetics and intrathecal α2 adrenoreceptor agonists. Local anesthetics act by blocking sodium channels and α2 adrenoreceptor agonists act by binding to the presynaptic C-fibers and postsynaptic dorsal horn neurons. Analgesia is produced by depressing the release of C-fiber transmitters and by hyperpolarization of post synaptic dorsal horn neurons. [6, 9] The complementary action of local anesthetics and α2 adrenoreceptor agonists accounts for their profound analgesic properties. The prolongation of the motor block of spinal anesthetics may be the result of binding of α2 adrenoreceptor agonists to the motor neurons in the dorsal horn. [6, 9] Dexmedetomidine was found to prolong the duration of spinal anaesthesia in a dose-dependent manner. [7] There has been a need for clinical studies, to substantiate the results of some studies related to intrathecal dexmedetomidine to prove its efficacy, safety, and suitable dose for supplementation to spinal local anaesthetics. [6, 7, 11] In the present study, the intrathecal dose of dexmedetomidine selected was based on previous human studies done, and observed no neurotoxic side effects. [6, 7, 9, 11] The study by Kanazi et al.,[6] noticed that in urological surgical patients, combining 3µg dexmedetomidine or 30 µg clonidine with 13 mg spinal bupivacaine generated a sensory and motor block that lasted for the same amount of time with the fewest side effects. And Gupta M et al.,[11] in their study on patients undergoing lower abdominal and lower limb surgeries, receiving 2.5, 5 or 10 µg of dexmedetomidine with spinal bupivacaine, showed significant early onset of sensory and motor block, along with pronged duration of block and analgesia in dose dependent manner with comparable side effects, whereas incidence of sedation was more with 10 µg of dexmedetomidine. On the basis of these, we assumed that addition of 5 µg of dexmedetomidine will make it a potent adjuvant for spinal anaesthesia. Time to reach highest sensory level was lesser with dexmedetomidine group (7.3±1.8mins) compared to fentanyl group (8.9±1.1 mins) which was statistically significant (p <0.01). These findings were similar with the results of Kalbande J V et al. [12] and of Ravipati P et al. [5] studies that also found a better onset time for sensory action with 5 µg of dexmedetomidine. But a study, by Mahendru V et al. [2] showed the time of onset of sensory block was comparable between group with fentanyl and dexmedetomidine (p <0.11). T6 was the highest level of sensory blockade achieved in both groups, in majority. Dexmedetomidine 5 µg used as an adjuvant in the current trial, provided sensory blockade for a longer period of time of around 517.5±43 mins as compared to 25 µg fentanyl (292.2±28.5 mins) (p <0.01). These outcomes were consistent with the results of Rahimzadeh P et al. [1] , Mahendru V et al. [2], Ravipati P et al. [5] and Al-Ghanem S M et al. [9] who demonstrated significant prolongation of sensory blockade with the use of dexmedetomidine. Additionally, the present study showed that the two-segment regression is also being prolonged in dexmedetomidine group, with the length of 143±15.8 mins which is statistically significant (p-<0.01) as compared to fentanyl group (86.9±9 mins). The studies conducted by Kalbande J V et al. [12] and Rahimzadeh P et al. [1], showed the results that corroborated ours and demonstrated a significant prolongation of two segment regression. According to the present study, time for onset to Bromage 3 was lesser in dexmedetomidine group (4±101 mins) compared to fentanyl group (5.3±0.9 mins) (p <0.01). Kalbande J V et al. [12] had similarly demonstrated decreased time for onset to Bromage 3, contrary to the study by Gupta R et al. [8] which showed the time for onset to Bromage 3 was comparable (p- 0.14) between dexmedetomidine and fentanyl groups. The duration of motor block was increased with dexmedetomidine (354.4±40.2 mins) as compared to fentanyl (181.3±19mins) (p <0.01), these findings were similar to studies by Rahimzadeh P et al. [1], Mahendru V et al. [2] who found prolonged motor blockade in dexmedetomidine group. When compared to 25 µg fentanyl (236.6±53.8 mins), we found that the need for rescue analgesic was significantly delayed with 5 µg dexmedetomidine (439.1±51.1 mins), supporting the intrathecal adjunct dexmedetomidine's analgesic efficacy. Similar to this, Gupta R et al. [8], Mahendru V et al. [2] and Rahimzadeh P et al. [1] found that using dexmedetomidine as an intrathecal adjuvant considerably increased analgesic efficacy. Six hours after surgery when assessed by numeric rating scale for pain, the patients reported less pain in dexmedetomidine group than in fentanyl group, which is consistent with the dexmedetomidine group's longer postoperative analgesia duration. Hemodynamic changes are common with the use of anaesthetic medications. Shah A et al. [4] conducted a study to observe hemodynamic stability with the usage of 5µg of dexmedetomidine intrathecally and reported no hypotension or bradycardia with usage of dexmedetomidine. We have observed significant changes and fall in SBP and DBP in fentanyl group after 5 mins and 10 mins respectively after induction. In contrary, Belgrami SA et al. [13] observed higher changes in SBP, DBP and HR with dexmedetomidine, the highest decline occurred between 5 min and 15 min after spinal injection and was rather stable later. And Ravipati P et al. [5] observed fall in both SBP and DBP in both the groups, which was statistically insignificant. The present study showed significant fall in HR in dexmedetomidine group after 30 mins of induction. Khan AL et al. [3] has also showed early, continuous and sustained fall in HR in dexmedetomidine group. In contrary, Ravipati P et al. [5] and Gupta R et al. [8] showed comparable changes in HR with dexmedetomidine and fentanyl. We found no discernible difference between groups in the incidence of nausea, vomiting, or chills. And fentanyl group showed increased incidence of pruritis, similarly showed by Gupta M et al. [11] Limitations: In the present study, patients who are otherwise healthy made up the population included, and it is still unknown how the intervention may affect older patients with comorbidities. The present study did not take into account the total analgesic requirement for 24 hours. Prolonged duration of motor blockade with dexmedetomidine may be undesirable for short term surgical procedures or ambulatory surgeries.

Using Dexmedetomidine (5mcg) as an intrathecal adjuvant to hyperbaric Bupivacaine in orthopedic lower limb surgeries has longer duration of sensory and motor blockade, longer postoperative analgesia with lower side effects as compared to Fentanyl (25mcg).

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