Spinal anesthesia is a safe and reliable for lower abdominal and lower limb surgery method, with the advantages of rapid onset of action, economical, ease of administration, relatively less side effects, and shorter post-anesthesia care unit stay. However, these advantages may be offset by the limited duration of action or an increased likelihood of motor power recovery delay, thus delaying ambulation and prolonged hospital stay.   To improve the quality of blockage, prolong the duration of analgesia, and reduce the required dose of local anesthetics, adjuvants are commonly used along with intrathecal local anesthetics. ^1,2

It has been found that many drugs, such as opioids (morphine, fentanyl, and sufentanil), α₂ adrenergic agonists (dexmedetomidine and clonidine), magnesium sulfate, neostigmine, ketamine, and midazolam, can be used as adjuvants for intrathecal hyperbaric bupivacaine local anesthetics to improve the quality of spinal anesthesia. However, opioids and α₂ adrenergic agonists are more commonly used as adjuvants in clinical practice.

Intrathecal fentanyl is commonly used with local anesthetic agents for perioperative anesthesia and analgesia. Unlike long-acting opioids, it is associated with decreased side effects and delayed onset respiratory depression.

Dexmedetomidine, a selective α₂ adrenergic receptor agonist, is a better adjuvant of local anesthetics for neuraxial blocks. The intrathecal dexmedetomidine prolongs the sensory block when combined with spinal bupivacaine and produces its analgesic effect by inhibiting the release of transmitters of C fibers and by hyperpolarizing postsynaptic dorsal horn neurons.³

Different doses ranging from 3 mcg to 15 mcg have been tried to find the optimal intrathecal dose.⁴,⁵

Low doses of intrathecal local anesthetics are commonly preferred in elderly patients to reduce the effect on hemodynamics, as many elderly patients are associated with cardiovascular, neuronal, endocrine, etc., diseases. However, the use of low-dose spinal local anesthetics can reduce the duration of analgesia due to rapid recovery.⁶ Elderly patients with trauma undergoing orthopedic surgery are also more vulnerable to the negative consequences of perioperative pain and analgesic medications. Hence, using intrathecal adjuvants is maximally beneficial in this group of patients, as dexmedetomidine can improve hemodynamic stability and duration of analgesia.

Limited evidence is available on the efficacy and safety of intrathecal dexmedetomidine on hemodynamic stability, intraoperative anesthesia, and postoperative analgesia in elderly patients undergoing orthopedic lower limb surgery.

The current study compared the efficacy of dexmedetomidine and fentanyl as adjuvants to intrathecal bupivacaine in elderly patients undergoing orthopedic lower limb surgery.

The primary objective is to compare the effect of dexmedetomidine and fentanyl additives on intrathecal bupivacaine to prolong the duration of analgesia (defined as a time to first analgesic request) in elderly patients undergoing orthopedic surgery. The secondary objective is to compare the two groups' onset and duration of sensory and motor block, hemodynamic effects, sedation, and complications.

After approval of the institutional ethics committee and written informed consent from all patients, 40 elderly patients undergoing elective orthopedic lower limb surgery were included in this prospective single-center, double-blind, randomized comparative study. This study was conducted in a tertiary care teaching hospital from October 2019 to January 2021.

Inclusion criteria include ASA Grade-II patients of either sex aged between 60-80 years. Exclusion criteria include patients with coagulation or bleeding abnormalities, severe spinal deformity, allergy to study medications, significant coexisting diseases like ischemic heart disease, impaired renal function, severe liver disease, and contraindication to the central neuraxial blockade. The patients were randomly allocated to bupivacaine and dexmedetomidine (group D) and bupivacaine and fentanyl (group F). The patients have received 2.5 ml of 0.5% Hyperbaric bupivacaine (manufactured by Neon laboratories, India) with 0.5 ml of 5 mcg dexmedetomidine in group D (manufactured by Neon laboratories, India) or 25 mcg fentanyl (0.5 ml) in group F (manufactured by Verve health care Ltd, India). The patients and the physicians evaluating the outcome of treatments were blinded to the group allocation.

Patients were premedicated with oral ranitidine 150 mg and alprazolam 0.25 mg the night before and the morning of surgery. After confirming fasting status, solids for 8 hrs, and clear fluids for 2 hrs written and informed consent, patients were shifted to the operation theatre. The electrocardiogram (ECG), pulse oximetry (SpO₂), and non-invasive blood pressure were attached. Baseline heart rate, systolic, diastolic, mean blood pressure, and SpO₂ were monitored. Intravenous cannulation with 16G /18G was secured in all patients. Before the spinal block, each patient received an 8 ml/kg infusion of lactated Ringer's solution. Under strict aseptic precautions with patients in sitting or supine position, a 25G/23G quincke tip spinal needle was introduced into the L3-L4 subarachnoid space in the midline. After confirming the free flow of cerebrospinal fluid, patients received drugs over approximately 10-15 sec as per group randomization. Immediately after completion of the injection, patients are made to lie supine. Oxygen of 6 liters per minute was administered via facemask during the intraoperative period. After spinal anesthesia, hemodynamic variables (heart rate, systolic blood pressure, diastolic blood pressure) were recorded at a 5-minute interval for the 1^st 30 minutes, every 15-minute interval up to 60 minutes, and every 30-minute interval thereafter during surgery.

This was tested by the pinprick method in the midclavicular line. Dermatome levels were tested every 2 minutes until the highest level was stabilized by four consecutive assessments. On achieving the T10 sensory blockade level, surgery was allowed. Testing was then conducted every 10 min until the point of two-segment regression of the block was observed. Further testing was performed at 20-minute intervals until the recovery of the S1 dermatome. Data regarding the highest dermatome level of sensory blockade, the time to reach the highest sensory block level from the time of injection, and the time to S1 level sensory regression (defined as the duration of the sensory block) were recorded.

Motor block of lower limbs was assessed bilaterally using a modified Bromage scale [6] as 0=no paralysis, 1=cannot raise extended leg, 2=cannot flex the knee, and 3=cannot dorsiflex the ankle. Motor power assessment was done every five minutes, for 30 min after spinal anesthesia, and then every 20 min until the end of surgery. The time to achieve Bromage 3 was considered an onset of the motor block. Duration of motor block was considered until the Bromage score returned to 0.

Hypotension was defined as the fall of mean arterial pressure less than 20% from baseline and was treated with a 200 ml bolus of Ringer's lactate solution. Patients not responding to fluid bolus were administered mephenteramine 6 mg bolus. The number of events of hypotension, fluid boluses, and amount of mephenteramine administered were noted. If any patient develops hypotension due to bleeding or other known reasons, those episodes were not included in the statistical analysis. 

Bradycardia was defined as a heart rate of less than 50 bpm. Bradycardia was treated with an injection of atropine 0.6 mg. The number of episodes of bradycardia was noted. The incidence of adverse effects such as nausea, vomiting, shivering, pruritus, respiratory depression (respiratory rate <10), sedation, and hypotension or bradycardia were recorded. Time from intrathecal injection to the first demand for rescue analgesics was noted. Injection Paracetamol 1gm was used as a rescue analgesic. The study was concluded after the administration of rescue analgesia.

Statistical analysis:  

The sample size was determined based on a pilot study of 5 patients in each group, where the duration of analgesia was 190±30.21 minutes and 265.3±90.74 minutes in groups F and D, respectively. With an alpha error of 5% and a power of 90%, a sample size of 15 in each group was required to detect a difference of 75.3 minutes in the duration of analgesia. Hence, 20 patients in each group were recruited to account for possible exclusions.

The descriptive statistics were expressed as the mean and standard deviation for continuous data and frequency and percentages for categorical data. The continuous data were compared between the two groups using an independent sample t-test and categorical data using the chi-square test. A two-sided significance of <0.05 was considered a significant difference between the groups for all tests. Statistical analysis was performed using SPSS (Version 20).

A total of 40 elderly patients were enrolled and allocated to the two groups. None of the participants were excluded from the final analysis. There was no significant difference in demographic data (table 1). Hemodynamic variables like heart rate (table 2 and Figure 1) and mean arterial pressure (table 3 and Figure 2) are described in the tables. Except for heart rate, other baseline values were similar between groups. Even though there were statistically significant differences in hemodynamic variables and pulse oximetry at various study time points, none of the values were clinically significant. The highest sensory level attained is described in Table 4, and outcome variables are shown in Table 5.

Table 1: Patient characteristics in two groups. (F=fentanyl, D=dexmedetomidine).

Table 2: Perioperative heart rate (beats/min) in two groups. (F=fentanyl, D=dexmedetomidine)

Figure 1: Perioperative mean arterial pressure (MAP) in two groups. (F=fentanyl, D=dexmedetomidine)

Table 3: Perioperative mean arterial pressure (MAP) in two groups. (F=fentanyl, D=dexmedetomidine)

Figure 2: Perioperative heart rate between Group D and Group F

Table 4: Comparison of the highest sensory level achieved in two groups. (F=fentanyl, D=dexmedetomidine)

Table 5: Comparison of outcome variables in two groups. (F=fentanyl, D=dexmedetomidine)

The results of our study show that supplementation of spinal bupivacaine with 5 mcg dexmedetomidine significantly prolonged both sensory and motor blockade compared with intrathecal 25 mcg of fentanyl. However, the onset of sensory and motor blocks was similar between groups.

Epidural and intrathecal opioid and non-opioid adjuvant administration is undoubtedly one of the most significant advances in pain management. Various adjuvants such as opioids, ketamine, clonidine, and neostigmine are often added to enhance the duration of the quality of spinal anesthesia. Their use is limited because of significant adverse effects such as respiratory depression, hemodynamic instability, and urinary retention. α₂ adrenoceptor agonists prolong local anesthetics' motor and sensory block by a synergic effect. Local anesthetics block sodium channels, and α₂ agonists block presynaptic C fibers and postsynaptic dorsal horn neurons. They produce analgesia by depressing the release of C fiber transmitters and hyperpolarizing postsynaptic dorsal horn neurons. The complementary actions of local anesthetics and α₂ receptor agonists account for their profound analgesic properties. Dexmedetomidine is eight times more specific and highly specific α₂ adrenoceptor agonist than clonidine, making it a valuable and safe adjunct in diverse clinical applications.

Highly hydrophilic opioids such as morphine, though they provide excellent intra and postoperative analgesia, their use becomes limited because of delayed-onset respiratory depression. Fentanyl, a highly lipophilic opioid, has recently become a very popular additive to hyperbaric bupivacaine. However, fentanyl has a limited effect on prolonging the duration of analgesia. The rationale behind intrathecal administration of α₂ adrenergic agonists is to achieve a high drug concentration in the vicinity of α₂ adrenoceptors in the spinal cord, and it works by blocking the conduction of C and A-delta fibers, increasing potassium conductance, and intensifying the conduction block of local anesthetics.

Al-Mustafa MM et al., in their study, used intravenous (1mcg/kg dexmedetomidine bolus and an infusion of 0.5mcg/kg/hr) dexmedetomidine and found that it prolonged isobaric bupivacaine spinal anesthesia.⁷ However, prolonged analgesia was observed with very low doses (3mcg to 15mcg ) when dexmedetomidine was used intrathecally.⁸,⁹,⁴,¹⁰ Many authors evaluated the optimal dose of intrathecal dexmedetomidine as an adjuvant to local anesthetics. They have shown that 5 to 10 mcg of intrathecal dexmedetomidine may be optimal in most lower abdominal surgeries.⁸, ⁹.  However, limited evidence is available about the safety and optimal dose of intrathecal dexmedetomidine in the elderly population.

Chattopadhyay et al. their study showed that elderly patients (55-75Years) undergoing transurethral resection of the prostate (TURP) who received intrathecal low-dose bupivacaine and dexmedetomidine (3mcg) had quicker onset, with the time to reach T10 being faster, longer duration of motor block and increased time to first analgesic requirement. ¹⁰ Ji Eun Kim also obtained similar results for TURP surgeries.¹¹ The efficacy of these low doses in lower abdominal and orthopedic surgeries was not evaluated in the literature. As orthopedic surgeries are relatively more painful and need blockade of upper lumbar spinal nerves, they may require more than 3 mcg. Hence, we used 5 mcg of intrathecal dexmedetomidine in this study. 

Elderly patients have relatively low pain thresholds due to changes in pain perception and processing.¹²,¹³ The reasons include intrinsic plasticity of somatosensory pain pathways, dysregulation of the hypothalamic-pituitary axis, increased auto-immune response, and altered autonomic function. Elderly patients are more vulnerable to the negative consequence of poor postoperative pain control. Inadequate postoperative pain relief has been shown to be associated with increased morbidity, delayed recovery, and increased incidence of postoperative pain.¹⁴ Old-age patients are also more prone to the adverse effects of analgesic medications like nonsteroidal anti-inflammatory drugs, opioids, etc. However, the use of low-dose local anesthetic spinal anesthesia is a common practice in elderly patients to reduce intrathecal spread, thereby minimizing the effect on hemodynamics. This practice results in highly vulnerable elderly patients at an increased risk of postoperative pain-related adverse effects. 

The main finding of our study is that dexmedetomidine significantly prolonged the sensory and motor block duration of bupivacaine. The time for complete sensory recovery was 166.5±12.88 minutes in group F and 427.50±25.41 minutes in group D (p < 0.001) (table 6). The time to 2 segment regression was 79.50±12.8 in Group F and 123.2±16.0 in Group D.

Mohamed et al. conducted a randomized, double-blind trial on the analgesic efficacy of intrathecally administered dexmedetomidine or dexmedetomidine combined with fentanyl (dexmedetomidine+) in patients undergoing major abdominal cancer surgeries.¹⁵ Ninety patients were randomly assigned to receive intrathecally either 10 mg bupivacaine 0.5% (control group, n= 30), or 10 mg bupivacaine 0.5% plus 5 mcg dexmedetomidine (dexmedetomidine group, n = 30), or 10 mg bupivacaine 0.5% plus 5 mcg dexmedetomidine and 25 mcg fentanyl (dexmedetomidine+ group, n = 30). They concluded that dexmedetomidine five mcg given intrathecally improves the quality and duration of postoperative analgesia and provides an analgesic-sparing effect in patients undergoing major abdominal cancer surgeries. Furthermore, adding intrathecal fentanyl 25 mcg has no beneficial clinical effect.

As expected in the dexmedetomidine group, there is a decrease in heart rate compared to the fentanyl group, which is statistically significant at all time intervals and mean arterial pressure at 15 min, 45 min, 60 min, 90 min, 120 min, 150 min and 180 min after spinal anesthesia (table 2). However, none of the values were clinically significant, and no type of inotropic or chronotropic intervention was needed. No bradycardia was observed during our study in either of the groups. SpO₂ % was maintained in both groups; no patient developed hypoxia (SpO₂ % <88%) or respiratory depression. Our results confirm that low doses of dexmedetomidine or fentanyl to intrathecal bupivacaine cause no gross hemodynamic changes and respiratory depression.

The onset of sensory and motor blockade was similar between groups F and D. This suggests that both drugs may not significantly affect intrathecal local anesthetics' onset of action. Various authors also published similar results.¹⁶, ¹⁷

The time for complete motor recovery was 139.0±12.41 minutes in group F and 399.25±22.72 minutes in group D ( p < 0.001) (table 5). Although the precise mechanism is unknown, the binding of 2-adrenoceptor agonists to motor neurons in the dorsal horn may contribute to prolonging the motor block.¹⁸ Motor block prolongation by α₂ adrenoreceptor agonists might be caused by impairment of the release of excitatory amino acids from the spinal interneuron. Gupta R et al. evaluated the effects of dexmedetomidine (5 mcg) or fentanyl (25 mcg) as an adjuvant to intrathecal bupivacaine in patients undergoing lower abdominal surgeries.¹⁶ The mean time of sensory regression to the S1 level and the regression time of motor blockade to reach modified Bromage 0 were comparable with our results. Prolongation of the local anesthetic-induced motor blockade is one of the probable limitations of the use of intrathecal dexmedetomidine. Prolonged immobilization may increase the risk of venous thrombosis. However, most orthopedic patients are immobilized in the immediate postoperative period. Hence, considering the other beneficial effects, this may not be a big concern. 

The main limitation of this study is the small sample size, single-center study, pain quality was not monitored with pain scores, and the efficacy of different doses of intrathecal dexmedetomidine wasn't evaluated. We suggest further research to assess the safety and efficacy of intrathecal dexmedetomidine in this high-risk population.

The addition of 5 mcg of dexmedetomidine seems to be a better alternative to 25 mcg of fentanyl as an adjuvant to spinal bupivacaine in elderly patients undergoing orthopedic surgeries. Dexmedetomidine provides prolonged anesthesia and analgesia without side effects. As dexmedetomidine significantly prolonged the sensory and motor block duration, we suggest it can be the preferred choice for long operations requiring neuraxial anesthesia.

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