A Comparative Study of Intrathecal Bupivacaine and Bupivacaine with Different Doses of Clonidine in Lower Limb Surgeries.

BACKGROUND: Intrathecal clonidine is a very safe, nonopioid adjuvant to local anesthetics to prolong the duration of analgesia without any major side effects.
OBJECTIVE: The purpose of the present study was to evaluate the efficacy of clonidine in two different doses as an adjuvant to bupivacaine intrathecally in lower limb surgeries.
MATERIALS AND METHODS: A total of 75 adult patients scheduled to undergo lower limb surgeries were randomly allocated into either of three groups of 25 patients. Group I received 12.5 mg bupivacaine, Group II patients received bupivacaine 12.5 mg with clonidine 15 μg, and patients in Group III received bupivacaine 12.5 mg with clonidine 30 μg intrathecally. A total volume of 3 ml was made in all groups using normal saline. The hemodynamic parameters, onset, and duration of sensory block, highest dermatomal level of sensory block, motor block onset, time to complete motor block recovery, and mean time to request of the first analgesic were recorded. Side effects or any other complications were noted.
RESULTS: The mean time of onset of sensory block and motor block was less in clonidine groups. The mean duration of sensory block was significantly prolonged in clonidine groups as compared to study group. The duration of motor block (in minutes) was significantly prolonged in Group III (171.60 ± 38.20) as compared to Group I (113.20 ± 35.79) and Group II (115.20 ± 38.41). The time of analgesic request in Group I was 148.16 ± 43.99 min, 190.60 ± 38.08 in Group II, and 200.80 ± 59.85 min in Group III.
CONCLUSIONS: The addition of intrathecal clonidine 15 μg to small dose bupivacaine increased the spread, duration of analgesia, and produced effective spinal anesthesia with stable hemodynamics and did not prolong postoperative motor block.

INTRODUCTION

Spinal anesthesia is widely practiced for providing sensory and motor block for lower limb surgeries. The onset and the duration of anesthesia can be prolonged with addition of adjuvant drugs. It was the demonstration of opiate receptors in the brain and substantia gelatinosa of spinal cord that revolutionized the concept of pain relief.[1] The quest for an ideal adjuvant continued because opioid adjuvants were associated with side effects such as pruritis, nausea, and delayed respiratory depression. Clonidine was hence, evaluated as a viable alternative to spinal opioids for pain relief after surgery. Clonidine, an imidazoline compound, is a selective agonist for α2- adrenoceptors with an α2:α1 selectivity ratio of approximately 220:1.[2] The antinociceptive properties of clonidine were first described in 1974 by Paalzow.[3]

Analgesic effects of intrathecal clonidine are due to interruption of nociceptive stimulus in the periphery, in the spinal cord and in supraspinal sites. It blocks conduction of C and Aδ fibers by increasing potassium conductance.[4]

Many studies conducted in the past have used clonidine in doses of 15–150 μg intrathecally, but higher doses were associated with hemodynamic instability and systemic side effects at the cost of improved analgesia.[5]

We, therefore, conducted the present study using low doses of clonidine as an adjuvant to bupivacaine in lower limb surgeries. The aim of our study was to evaluate the efficacy of intrathecal clonidine in doses of 15 and 30 μg, and to find the dose of clonidine that would produce optimal analgesia with minimal hemodynamic instability and motor block.

MATERIALS AND METHODS

The present study was conducted in a randomized, double-blind manner after the approval of hospital ethics committee. A written informed consent was obtained from all patients. A total 75 adult patients of either sex belonging to physical status American Society of Anesthesiologists (ASA) Classes I and II scheduled to undergo pelvic and lower limb surgery, under subarachnoid block, were randomly allocated into either of three study groups of 25 patients each in a random manner. Patients in Group I received 12.5 mg with 0.5 ml of normal saline, in Group II patients received intrathecal bupivacaine 12.5 mg with clonidine 15 μg (0.1 ml), and 0.4 ml of normal saline and patients in Group III received bupivacaine 12.5 mg with clonidine 30 μg (0.2 ml) and 0.3 ml of normal saline intrathecally. A total volume of 3 ml was made in all groups using normal saline. The drugs used intrathecally were preservative free. These solutions were prepared by anesthesiologist not involved in the patient's care. The anesthesiologist and the patients were blinded to the study solutions. Patients with a history of significant coexisting disease, any contraindication to regional anesthesia, history of anaphylaxis to local anesthetic and allergy to the drugs to be used, history of disease predisposing to altered sensation such as diabetes mellitus and neuropathies, with spinal deformities, morbidly obese patients. Patients with coagulation disorder, local skin infection or disease, patients with increased intracranial pressures and patients with atrioventricular blocks were excluded from the study.

A thorough preanesthetic check-up was conducted 1 day before surgery. It comprised of detailed history taking, general physical and systemic examination. All routine investigations such as complete hemogram, urine routine, random blood sugar, renal function test, electrocardiography (ECG), and chest radiograph were done. Special relevant investigations were conducted wherever indicated. Patients were familiarized with visual analog scale (VAS) preoperatively and about its use as a tool for measuring postoperative pain. Patients were kept nil orally for at least 6 h before surgery. All patients were premedicated with oral alprazolam 0.5 mg and ranitidine 150 mg at night before surgery and in the morning on the day of surgery with a sip of water. After shifting the patient to operation theater, baseline parameters like heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), respiratory rate (RR), peripheral oxygen saturation (SpO2), and ECG was recorded. Clonidine was measured by insulin syringe and mixed with bupivacaine. These solutions were prepared in a 5 ml syringe by an anesthesiologist (who was not participating in the study) after achieving intravenous access and preloading with 10 ml/kg of lactated Ringer's solutions.

Under strict aseptic conditions lumbar puncture was performed in lateral position at the level of L3–L4 or L4–L5 intravertebral space using 26G spinal needle after infiltrating the skin with 0.5–1 ml of 2% lidocaine. After obtaining free flow of cerebrospinal fluid, study drug was injected intrathecally at approximately 0.25 ml/s. After administering the drug, spinal needle was taken out, the patient turned to supine position immediately, and position of operation table was kept horizontal.

The onset and duration of sensory block, highest dermatomal level of sensory block, motor block onset, time to complete motor block recovery, and duration of spinal anesthesia were recorded.

The onset of sensory block was defined as the time between injection of intrathecal anesthetic and the absence of pain at the T8-9 dermatomes, assessed by pinprick.

The highest level of sensory block was evaluated by pinprick at midclavicular line anteriorly every 5 min for 20 min after injection and there after every 30 min. The duration of sensory block was defined as the time of regression of two segments in the maximum block height, evaluated by pinprick. Motor block onset was assessed with bromage score. Time for motor block onset was assumed when bromage score becomes three. Modified bromage scale was followed according to which: 0 – able to raise the whole lower limb at the hip, 1 – able to flex the knee but unable to raise the leg at hip, 2 – able to plantarflex ankle but unable to flex the knee, and 3 – no movement of lower limb. Complete motor block recovery was assumed when Bromage score became zero. The duration of spinal anesthesia/mean time to analgesic request was defined as the period from spinal injection to the first occasion when the patient complained of pain in the postoperative period.

Surgery was allowed to commence on achieving adequate sensory block height (T8–9). Sensory block was recorded every 5 min after intrathecal injection till 20 min from the time of injection. Motor block was recorded till the Bromage score became three. SBP, DBP, HR, RR, and SpO2 were recorded 5 min before intrathecal injection and then every 5 min for first 30 min and then at 45, 60, 75, 90, 120, 150, 180 min till the end of the surgery. Intravenous fluid (Lactated Ringer's solution) was given to maintain the blood pressure. If SBP was more than 30% below the baseline or 90 mm Hg, intravenous ephedrine, l0 mg, was given repeatedly. If HR was less that 50 beats/min, 0.5 mg of atropine sulfate was administered intravenously. The incidence of hypotension (fall in mean arterial pressure >20% of the baseline), bradycardia (HR <50 beats/min), hypoxemia, and excessive sedation was recorded. At the completion of surgery all hemodynamic parameters (HR, SBP, DBF, RR, and SpO2), sensory and motor block was recorded, and then, the patient was shifted to the recovery room.

Immediately after shifting the patient to postoperative recovery room, HR, SBP, DBF, RR, and SpO2 was recorded every 30 min, either till 3 h or till the time of analgesic request, which ever was longer. Pain scores using VAS was assessed in the postoperative period. Postoperative pain was treated using intravenous paracetamol 1 g every 6 hourly in all patients. For severe pain (VAS >5) diclofenac sodium 75 mg was given intravenously. Side effects such as sedation, nausea, vomiting, respiratory depression, or any other complications were noted. All observations were recorded by an anesthesiologist who was blinded to the group allocation of the patient.

A sample size of 25 patients in each group was selected to achieve a power of 80% and accepting an α error of 0.05, to be able to detect a difference of at least 50 min in the mean time of analgesic request in clonidine groups.

After completion of the study, observations obtained were tabulated and analyzed using statistical methods. The blind was opened at the end of the study for the purpose of evaluating the ethical efficacy of the treatment given to the patient. At the end of study all collected data were analysed using Statistical Package for Social Sciences version 16.0 statistical analysis software. The values were represented in number (%) and mean ± SD. Analysis of variance (ANOVA) was used for parametric data while Student's t-test and Chi-square test was used for non parametric data. P < 0.05 was considered statistically significant.

OBSERVATIONS AND RESULTS

There were no intergroup differences as regards to the demographic profile and ASA physical status of patients enrolled in our study [Table 1]. The mean age of patients in Group I was 40.04 ± 14.67, in Group II was 45.12 ± 16.82, and in Group III was 46.00 ± 18.07. The mean height of patients in Group I was 162.58 ± 5.98, in Group II was 161.96 ± 4.17 and in Group III was 165.34 ± 5.75. The mean weight of patients in Group I was 68.4 ± 9.51, in Group II was 63.53 ± 7.66 and 66.72 ± 7.35 in Group III. There were 15 male and 10 female in Group I, 17 males and 8 females in Group II and 16 males and 9 females in Group III which was statistically insignificant. The groups were also comparable in the duration of surgery with Group I lasting 74.00 ± 17.97 min, Group II for 66.8 ± 26.64 and Group III lasting for 62.80 ± 26.14 min. There were no significant differences between the three groups regarding preoperative HR, SBP, and DBP, RR, and oxygen saturation.

Table 1

Demographic profile of patients

The mean time of onset of sensory block was 6.80 ± 2.84 min in Group I, 5.80 ± 1.87 min in Group II and 5.20 ± 1.00 min in Group III, which was significantly shorter in Group III. The difference in time of onset of the block was not significant between Group II and Group III [Table 2].

Table 2

Sensory block-time of onset

The mean duration of sensory block was significantly prolonged in Group II and Group III, with Group I having 128.40 ± 33.00 min, 140.40 ± 43.05 min in Group II, and 175.20 ± 37.43 min in Group III [Table 3].

Table 3

Sensory block-duration

The mean time of onset of motor block was significantly shorter in Group II (5.60 ± 1.65) and III (5.0 ± 0) as compared to Group I (12 ± 2.50). However, there was no statistically significant difference between Group II and Group III [Table 4].

Table 4

Motor block-time of onset

The duration of motor block was significantly prolonged in Group III (171.60 ± 38.20) as compared to Group I (113.20 ± 35.79) and Group II (115.20 ± 38.41) whereas no significant difference in the motor block was found in between Group I and Group II [Table 5].

Table 5

Motor block-duration of motor block

The time of analgesic request in Group I was 148.16 ± 43.99 min, 190.60 ± 38.08 in Group II and 200.80 ± 59.85 min in Group III [Figure 1]. The time of analgesic request was significantly prolonged in Group II and Group III (P < 0.05). The vital signs such as HR, SBP, DBP, RR, oxygen saturation were comparable in all the three groups throughout the postoperative period.

Figure 1

Meantime of analgesic request

Among side effects, hypotension occurred in three patients in Group III, which was statistically significant as compared to Group I and Group II. Two patients had bradycardia in Group III which was statistically not significant. The incidence of sedation was higher in clonidine groups, two patients in Group II, and eight patients in Group III, which was statistically significant. None of the patients in any group developed respiratory depression or pruritis [Table 6].

Table 6

Adverse effects

DISCUSSION

Intrathecal clonidine is an α2 adrenergic agonist having potent antinociceptive properties. It results in the prolongation of sensory and motor blockade and a reduction in the amount or concentration of local anesthetic required to produce prolonged perioperative analgesia, thereby reducing the incidence of side effects.

The dosages used in our study are based on data from various studies, where hemodynamic stability and a significantly reduced incidence of side effects have been reported in dosages ranging between 15 and 150 μg of clonidine.[678]

The onset of sensory block was significantly early in Group II and Group III as compared to Group I. The duration of sensory block (in minutes) was significantly prolonged in clonidine groups, i.e., Group II (140.40 ± 43.05) and III (175.20 ± 37.43) as compared to Group I (128.40 ± 33.00).

The results of our study are in accordance with observations of various studies which concluded that the duration of sensory block was significantly prolonged by the addition of intrathecal clonidine.[79101112] The possible mechanisms involved in potentiating the sensory block include suppression of the activity of wide dynamic range of neurons and release of substance P in the dorsal horn of spinal cord by activation of pre- and post-synaptic α2 adrenergic receptors on small primary afferents; release of norepinephrine and acetylcholine in spinal cord dorsal horn; direct inhibition of impulse conduction in A delta and especially C fibers, possibly by increasing potassium conductance.[1314]

Duration of motor block was prolonged in our study with clonidine which is comparable to the findings of Dobrydnjov.[7] Niemi observed comparable prolongation of motor blockade in clonidine groups.[11] However, duration of motor block prolongation was much higher in their study due to higher dose of clonidine (3 μg/kg) used by them.

Clonidine causes motor block by inducing cellular modification in the ventral horn of spinal cord (motor neuron hyperpolarization) and potentiating the action of local anesthetics. However, the motor block induced by clonidine seems to be dose-related because 30 μg and not 15 μg, of clonidine added to bupivacaine potentiated motor block which was similar to our study.[7]

The time of analgesic request was significantly prolonged in clonidine groups as compared to study group. Our results are in agreement with the results of other studies which observed prolonged duration of spinal anesthesia in clonidine groups with same doses.[78]

Chiari et al. in dose-response study using intrathecal clonidine during first stage of labor found 50–200 μg of intrathecal clonidine produces dose-dependent analgesia. Although duration of analgesia were more potent with 100 and 200 μg than with 50 μg, but higher incidence of hypotension was observed with doses of 200 μg.[15]

With regard to variation in mean arterial pressure, we observed relative stable hemodynamics in all groups in our study as we ensured adequate preloading before subarachnoid block and optimal intraoperative volume replacement. Niemi observed significant reductions in mean arterial pressures in doses of 3 μg/kg clonidine, which was a larger dose as compared to our study.[11] Sia also used 15 μg and 30 μg of clonidine and observed higher incidence of hypotension in 30 μg clonidine group.[16]

Clonidine after neuraxial or systemic administration affects arterial blood pressure in complex manner. The α2 adrenergic agonist produce sympatholysis and reduced arterial blood pressure by acting on specific brainstem nuclei and sympathetic preganglionic neurons in the spinal cord. On the other hand, α2 adrenergic agonist cause direct vasoconstriction by acting on the peripheral vasculature.[10]

In accordance with our study, two other studies showed similar results in which no patient developed bradycardia with the dose of 15 μg clonidine.[78] Klimscha et al. reported a significant fall in HR with 150 μg of clonidine which can be due to higher dose used.[17] Bajwa et al. also did not observe bradycardia by the addition of clonidine even up to 45 μg. This can be explained on the basis of low doses of clonidine and bupivacaine used.[18]

We did not observe sedation with use of clonidine. Markedly increased sedation scores were observed by with higher doses clonidine.[1011] Kothari et al. also found 35%–45% patients drowsy by addition of 50 μg of clonidine to bupivacaine.[19] Clonidine is reported to cause a significant decrease in power of theta, α, and β bands of the electroencephalography. This hypnotic response may be mediated through locus coeruleus where α2 adrenergic receptors are abundant.[20]

A potential limitation of our study was that we did not observe dose-response relationship using various doses of clonidine intrathecally for postoperative analgesia.

CONCLUSION

We, therefore, concluded that clonidine is a useful additive when used in appropriate dosage. Clonidine led to a rapid onset, prolonged duration of sensory and motor block along with prolonged and adequate postoperative analgesia with moderate sedation. Clonidine 30 μg is associated with prolonged recovery of motor block and causes hypotension and bradycardia. Clonidine 15 μg is associated with a stable hemodynamic profile and can be a useful adjuvant in spinal anesthesia for ambulatory procedures as it does not cause prolongation of motor blockade.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.