Comparison of Different Doses of Clonidine as an Additive to Intrathecal Isobaric Levobupivacaine in Patients Undergoing Infraumbilical Surgeries.

BACKGROUND: Spinal anesthesia is a safe, reliable, and inexpensive technique with the advantage of providing surgical anesthesia and prolonged postoperative pain relief, and it also blunts autonomic, somatic, and endocrine responses to surgical stimulus. AIM: The aim of this study was to assess the efficacy 15 μg and 30 μg of intrathecal clonidine along with 3 mL of 0.5% isobaric levobupivacaine in comparison with plain 0.5% isobaric levobupivacaine. SETTING AND
DESIGN: The prospective, interventional, randomized, comparative, double-blinded study was conducted after obtaining approval from the institutional ethical committee.
MATERIALS AND METHODS: Seventy-five patients posted for elective lower-limb orthopedic surgeries were randomly divided into three groups with 25 patients in each group as L (levobupivacaine 0.5%), LC-15 (levobupivacaine 0.5% + clonidine 15 μg), and LC-30 (levobupivacaine 0.5% + clonidine 30 μg). All the patients were given spinal anesthesia using the study drugs, and various parameters were monitored. STATISTICAL ANALYSIS: The three groups were compared statistically using analysis of variance and Student's t-test (independent samples t-test). P < 0.05 was considered statistically significant.
RESULTS: There was a statistically significant difference among the three groups with respect to the onset of time for maximum sensory blockade and duration of analgesia. A statistically significant difference was noted among the three groups with respect to the onset of time for maximum motor blockade.
CONCLUSION: Both doses of clonidine produced prolonged sensory block compared to the control. It has been found that 30 μg of clonidine as an adjuvant has produced faster onset and prolonged duration sensory block compared to 15 μg of clonidine. Copyright:

INTRODUCTION

Intrathecal anesthesia and epidural anesthesia are the most popular regional anesthesia techniques used for lower-limb orthopedic surgeries.[1] Spinal anesthesia is a safe, reliable, and inexpensive technique with the advantage of providing surgical anesthesia and prolonged postoperative pain relief, and it also blunts autonomic, somatic, and endocrine responses to surgical stimulus.[2] For decades, lidocaine had been the local anesthetic of choice for spinal anesthesia. However, its use was limited due to short duration of action and its implication in transient neurologic symptoms and cauda equina syndrome following intrathecal injection.[3] Till recently, hyperbaric bupivacaine 0.5% was the only drug used for spinal anesthesia in India after the discontinuation of lidocaine. Levobupivacaine does not provide prolonged duration of postoperative analgesia; hence, clonidine is used in combination which has been found to prolong postoperative analgesia but has produced significant perioperative hypotension and bradycardia.[4] Minimal effective dose of intrathecal clonidine along with a local anesthetic to produce prolongation of postoperative analgesia without cardiovascular side effects is not yet known. Hence, the present study was conducted comparing 15 μg and 30 μg of intrathecal clonidine along with 3 mL of 0.5% isobaric levobupivacaine.

MATERIALS AND METHODS

After obtaining the Institutional Ethics Committee approval of our institution, this randomized double-blind study was conducted on 75 patients in the age group of 20–60 years of either sex of physical status American Society of Anesthesiologists (ASA) Classes I and II admitted for elective infraumbilical surgeries under spinal anesthesia. Patients who refused to undergo procedure, who were pregnant or lactating, or with some coagulating/neurological disorders or with spine injury or previous spine surgery or infection over the spine or with morbid obesity or allergy to study drugs or with any moderate-to-severe disease were excluded from the study. An informed and written consent was obtained from all the patients who met the inclusion criteria of our study. The study population was randomly divided by shuffled sealed opaque envelope technique into three groups with 25 patients in each group (n = 25):

Group L (n = 25): levobupivacaine 0.5% isobaric (3 mL) with normal saline (0.5 mL) (total volume – 3.5 mL), Group LC-15 (n = 25): levobupivacaine 0.5% isobaric (3 mL) with clonidine 15 μg (in 0.5 mL normal saline) (total volume – 3.5 mL), and Group LC-30 (n = 25): levobupivacaine 0.5% isobaric (3 mL) with clonidine 30 μg (in 0.5 mL normal saline) (total volume – 3.5 mL).

The volume of the drug was kept constant (3.5 mL) in all the groups to avoid bias in the study. An anesthesiologist performing the subarachnoid block was also blinded to study drugs as the drugs were prepared by another anesthesiologist.

A thorough preanesthetic evaluation was conducted on the evening of day before surgery, and relevant investigations were done. Patients were kept nil per oral for 8 h before surgery. They were premedicated with tablet alprazolam 0.5 mg and capsule omeprazole 20 mg orally on the night before surgery.

The Visual Analog Scale (VAS) with 0–10 cm line was used to assess the level of analgesia in the postoperative period for 24 h and was described to the patient a day before surgery during the preanesthetic checkup. The first end mark “0” means “no pain” and the end marked “10” means “severe pain.” Rescue analgesia was given if VAS score >3.

On the day of surgery, pulse rate, heart rate, respiratory rate, noninvasive systolic and diastolic blood pressure, and saturation of oxygen of all the patients were recorded in the operation theater. After securing an intravenous line with 18G intracath, all patients were preloaded with 10 mL.kg−1 of Ringer's lactate solution over 15–20 min. Under aseptic precautions, lumbar puncture was performed at the level of L3–L4 interspace through a midline approach using 25G Quincke spinal needles in lateral position. After confirmation of needle tip in the subarachnoid space by free flow of CSF, a study drug prepared by another investigator to facilitate double blinding was injected.

Oxygen was given at the rate of 5–6 L.min−1 through a face mask. The anesthesiologist performing the technique recorded the intraoperative data and followed the patient postoperatively until discharged from postanesthesia care unit. Assessment of sensory block by the loss of sensation to a pinprick of a 22G blunt hypodermic needle and motor block by modified Bromage score was done every 2 min for first 10 min, then every 5 min up to 30 min, every 15 min up to 120 min, half-hourly up to 240 min, and hourly until 12 h of surgery. Continuous multiparameter monitoring of respiratory rate, heart rate, noninvasive systolic and diastolic blood pressure, SpO2, and electrocardiogram was done for hemodynamic response. Readings were recorded preoperatively, then intraoperatively at 0, 3, and 5 min, then at an interval of every 5 min up to 30 min, every 15 min up to 120 min, half-hourly up to 180 min, hourly until 12 h, and thereafter 3 hourly till 24 h of surgery in both the groups. Bradycardia (defined as heart rate <60 bpm) was treated with injection atropine sulfate intravenously according to heart rate. Hypotension (defined as systolic blood pressure <20% less than base value) was treated with intravenous ephedrine intravenously as per required and additional Ringer's lactate solution. The operation was started when surgical anesthesia (up to the T10 sensory dermatome) has developed. In case of failed or partial neuraxial block, the patient was given general anesthesia and that patient was excluded from the study. Time of administration of the study drug to time of administration rescue analgesic (VAS > 3) was considered as the duration of analgesia of the study drug. Intravenous morphine 0.1 mg.kg−1 was administered as a rescue analgesic. The changes in the cardiorespiratory parameters (heart rate, systolic BP, diastolic BP, SPO2, and respiratory rate) between the three groups were compared.

The results obtained in the study are presented in a tabulated manner and analyzed using all data was compiled and statistical analysis was performed by the Statistical Package for the Social Sciences (SPSS) program for Windows, version 20 (SPSS, Chicago, Illinois). The results of the present study between the three groups were compared statistically using analysis of variance and Student's t-test (independent samples t-test). P < 0.05 was considered statistically significant with 95% confidence interval.

RESULTS

In our present study, 75 individuals [Figure 1] were included, and the mean age of the study participants was 36.72 ± 9.76 years. There was no statistically significant difference in the age-wise distribution of patients between the three groups (P = 0.948). The present study consisted of 51 males and 24 females. There is no statistically significant difference in the sex distribution of the patients among the three groups (P = 0.832). The mean weight of the study participants was 57.52 ± 9.1 kg. There was no statistically significant difference in the type and duration of infraumbilical surgical procedures between the three groups (P = 0.970) [Table 1]. The mean time for the onset of sensory block was 6.76 min, 6.24 min, and 3.44 min in Group L, Group LC-15, and Group LC-30, respectively [Table 2]. There was no statistically significant difference between Group L and Group LC-15 (P = 0.642). However, when comparing Group LC-30 with Group L and Group LC-15, there was a statistically significant difference (P = 0.001). There was a statistically significant difference among the three groups (P = 0.014) with respect to time for attaining the maximum sensory block [Table 3]. There was a statistically highly significant difference among the three groups (P < 0.001) [Table 4] regarding duration of analgesia, and Group LC-30 has got the maximum duration analgesia. There was a statistically significant difference among Group L, Group LC-15, and Group LC-30 with regard to time for maximum motor blockade (P = 0.020) [Table 5], but there was no significant difference regarding duration of motor blockade (0.052) [Table 6]. There was no significant difference with respect to cardiorespiratory parameters between the groups [Table 7].

Figure 1

Consort flow diagram

Table 1

Different types of surgical procedure

Type of infraumbilical surgeries	Number of patients			Total	P
	L	LC-15	LC-30
Fracture both bones leg - closed intramedullary nailing	15	15	14	44	0.970
Fracture malleolus - open reduction and internal fixation	5	4	3	12
Bimalleolar fracture - open reduction and internal fixation	3	4	5	12
Fracture patella	2	2	3	7
Total	25	25	25	75

Table 2

Time of onset of sensory and motor block (min)

Groups	Mean±SD
	Sensory	Motor
L	6.76±0.34	3.36±0.78
LC-15	6.24±0.48	3.32±0.65
LC-30	3.44±0.52	3.16±0.45

SD=Standard deviation

Table 3

Time for maximum sensory blockade (min)

Groups	Mean±SD	P
L	12.24±5.04	0.014
LC-15	11.64±3.56
LC-30	9.08±2.91

SD=Standard deviation

Table 4

Duration of analgesia (min)

Groups	Mean±SD	P
L	251.72±31.62	<0.001
LC-15	294.68±43.33
LC-30	355.76±52.19

SD=Standard deviation

Table 5

The time for maximum motor block (min)

Groups	Mean±SD	P
L	9.88±4.16	0.020
LC-15	9.36±3.21
LC-30	7.40±1.82

SD=Standard deviation

Table 6

Duration of motor block (min)

Groups	Mean±SD	P
L	223.16±32.6	0.052
LC-15	229.44±32.55
LC-30	243.04±19.60

SD=Standard deviation

Table 7

Cardiorespiratory parameters (mean±standard deviation)

Groups	Heart rate (/min)	Systolic BP (mmHg)	Diastolic BP (mmHg)	Mean BP (mmHg)	SPO2 (%)	Respiratory rate (/min)
L	88.7±5.4	134.3±6.3	88.9±7.8	100.1±2.6	99.3±0.1	15.2±1.1
LC-15	82.5±3.6	130.8±4.1	85.5±6.4	99.8±4.3	99.7±0.5	14.2±2.1
LC-30	78.3±2.6	126.1±3.9	82.6±4.7	96.5±5.1	99.3±0.5	13.6±1.9
P	0.774	0.327	0.286	0.327	0.899	0.643

BP=Blood pressure

DISCUSSION

Spinal anesthesia is a safe, reliable, and inexpensive technique for infraumbilical surgeries with the advantage of providing surgical anesthesia and prolonged postoperative pain relief. It also blunts autonomic, somatic, and endocrine responses to surgical stimulus.[2] Till recently, hyperbaric bupivacaine 0.5% was the only drug used for spinal anesthesia after the discontinuation of lidocaine. Bupivacaine is available as a racemic mixture of its enantiomers, dextrobupivacaine and levobupivacaine. It has been found that D-enantiomer is the cause for cardiotoxicity and the levobupivacaine (S-1-butyl-2-piperidylformo-2’,6’-xylidide hydrochloride), the pure S (-) enantiomer, does not have the cardiotoxicity. Levobupivacaine has similar pharmacodynamic properties to racemic bupivacaine but a documented reduced central nervous system and cardiovascular toxicity. Traditionally, the dose of levobupivacaine used for spinal anesthesia is 15 mg. Levobupivacaine has been introduced in India in 2012 and is available as 0.5% isobaric 4 mL ampoules for intrathecal use. It is known that a single injection of levobupivacaine will not produce a prolonged duration of postoperative analgesia. Hence, addition of a drug which can prolong the analgesic effect of levobupivacaine will be required.

In our study, 75 patients belonging to ASA physical status Classes I and II posted for elective infraumbilical surgeries were randomized using shuffled sealed opaque envelope technique and divided into three equal groups of 25 each.

There was no significant difference regarding the age, gender, body weight, and height between the three groups. There was no significant difference regarding type of surgical procedures and also mean duration of surgeries among the three groups.

In our study, the mean time for the onset of sensory block was 6.76 min, 6.24 min, and 3.44 min in Group L, Group LC-15, and Group LC-30, respectively. There was no statistically significant difference between Group L and Group LC-15 (P = 0.642). However, when comparing Group LC-30 with Group L and Group LC-15, there was a statistically significant difference (P = 0.001) with Group LC-30 having the least time of the onset of sensory block. Our study is comparable with the study done by Saxena et al.[5] who also found a significant difference in the onset of sensory block between the control (hyperbaric bupivacaine 0.5%) and clonidine 30 mg groups.

In our study, the time taken for maximum level of sensory block in the control and 15 mg and 30 mg clonidine groups was 12.24 min, 11.64 min, and 9.08 min, respectively, and this is statistically significant (P = 0.014). Our study can be compared with the studies conducted by Anastsslou et al.,[6] Dubrydnjov et al.,[7] Thakur et al.,[8] Yadava et al.,[9] Prabha et al.,[10] Saxena et al.,[5] and Agarwal et al.[11] who also found a statistically significant difference in the duration of analgesia. In all these studies, there was also a statistically significant prolongation of analgesia in the clonidine groups as in our study. In our study, the duration of analgesia in Group LC-15 was 294.68 ± 43.33 min which was statistically significant compared to Group L which was 251.72 min.

Our study is comparable with the study done by Yadava et al.[9] with the duration of analgesia with the clonidine LC-15 group (315 min compared to the control group of 204 min) which was statistically highly significant. In the above study by Yadava et al., the local anesthetic agent used was bupivacaine 15 mg, but, in our study, levobupivacaine 15 mg has been used.

Thakur et al.[8] have also found a statistically highly significant difference between the clonidine 15 mg group (223 min) and the control group (140 min) with respect to duration of analgesia. In comparison to our study, the duration of analgesia in both the groups was less, and this is because of a lesser dose of bupivacaine (11 mg) used compared to our study (levobupivacaine 15 mg).

In our study, the time required for the onset of motor block was 3.36 min, 3.32 min, and 3.16 min in the control group, clonidine 15 mg group, and clonidine 30 mg group, respectively, and this is statistically not significant. The same result has been obtained by Yadava et al.[9]

Similarly, observations were made by Yadava et al.[9] who also did not find any significant difference in the duration of motor blockade.

Our study does not compare with studies conducted by Dubrydnjov et al.,[7] Sagiroglu et al.,[12] Thakur et al.,[8] Prabha et al.,[10] and Agarwal et al.[11] where they have found longer duration of motor blockade in the clonidine groups compared to the control group.

In our study, there is a statistically significant difference regarding the duration of motor blockade in the clonidine 30 mg group compared to the control group. Our study compares with the studies done by Dubrydnjov et al.,[7] Agarwal et al.,[11] Sagiroglu et al.,[12] Thakur et al.,[8] and Prabha et al.[10]

In our study, there was no statistically significant difference regarding the duration of motor block between the clonidine 15 mg and 30 mg groups (P = 0.080). The same thing has been observed in the studies conducted by Sagiroglu et al.,[12] Thakur et al.,[8] Yadava et al.,[9] Agarwal et al.,[11] and Kock et al.[13]

The variations in cardiorespiratory parameters in the three groups are comparable, indicating that the addition of relatively higher dose of clonidine to levobupivacaine did not bring about any significant change in the homeostasis of the patients.

Hence, in this study, we observed that the addition of 30 μg of clonidine as an adjuvant to levobupivacaine has produced faster onset and prolonged duration sensory block compared to 15 μg of clonidine without significant changes in the cardiorespiratory parameters. However, the limitation of the study is that we have not compared with further higher doses of clonidine with regard to sensory and motor characteristics and also adverse effects profile.

CONCLUSION

The addition of 30 μg of clonidine as an adjuvant to subarachnoid block can be safely used with prolonged duration of postoperative analgesia when compared to 15 μg clonidine. However, further comparative studies have to be done with further higher dose of clonidine before 30 μg of clonidine can be considered as the suitable dose for subarachnoid block as an adjuvant.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.