A comparison between intrathecal clonidine and neostigmine as an adjuvant to bupivacaine in the subarachnoid block for elective abdominal hysterectomy operations: A prospective, double-blind and randomized controlled study.

BACKGROUND AND AIMS: Adjuvant to the local anesthetic agent has proven benefits when used intrathecally. With regards to intrathecal bupivacaine as control, we have compared in this study the effects of clonidine and neostigmine when co-administered intrathecally with hyperbaric (0.5%) bupivacaine for abdominal hysterectomy.
MATERIALS AND METHODS: This prospective, randomized, double-blind study was conducted from May 2009 to June 2011. A total of 150 patients of American Society of Anaesthesiology grades I and II scheduled for abdominal hysterectomy under spinal anesthesia were randomly allocated into three groups. A volume of 3 ml of 0.5% hyperbaric bupivacaine was respectively added 1 ml solution containing 5% dextrose and 75 mcg of neostigmine in Group N, 1 ml containing 5% dextrose and 30 mcg of clonidine in Group C and 1 ml of 5% dextrose in Group D (control). We compared the sensory and motor block, the surgical condition, the duration of spinal analgesia and the side-effect profile. RESULTS AND OBSERVATIONS: Sensory and motor blocks and duration of spinal analgesia were significantly increased in both Group C and Group N compared to Group D. More incidences of Nausea and vomiting were observed in Group N compared to other groups. The surgical condition was poorer in Group N compared to Group C.
CONCLUSION: Both intrathecal clonidine and neostigmine increase the bupivacaine-induced spinal block. However, clonidine provides better surgical condition and fewer incidences of nausea and vomiting.

RCT Entities:   Population Interventions Outcomes

Introduction

Patients undergoing lower abdominal, gynecological surgery under spinal anesthesia with bupivacaine alone, occasionally experience varying degrees of intra-operative pain and discomfort at the site of surgery during the end of the procedure when the operative time is prolonged. Bupivacaine is appropriate for procedures lasting for 2-2.5 h.[1] So when the procedure is prolonged patient may require supplementation of intravenous opioids or administration of general anesthesia (GA). Thus the advantages and reliability of spinal anesthesia are sometimes compromised.

Increasing the dose of intrathecal bupivacaine to raise the level of the block may increase the duration of the subarachnoid blockade, but at the same time also increase the risk of hypotension and bradycardia.[23]

Opioids are commonly used as adjuvants to bupivacaine but with undesirable side effects pruritus, nausea-vomiting, acute urinary retention, sedation. Hence, nonopioid drugs like clonidine, neostigmine etc. with bupivacaine are being investigated. However, each drug has its limitations and a need for alternative methods or drugs always exist.[45]

Clonidine is a selective partial α2 adrenergic agonist. These α2 adrenoreceptors are located in peripheral and spinal neurons, on neurons of the superficial lamina of spinal cord particularly on the substantia gelatinosa and within several brainstem nuclei implicated in analgesia. The activation of α2 adrenoreceptors by intrathecal clonidine inhibits the central transmission of nociceptive impulses. The analgesic effect of clonidine is believed to result from inhibition of release of substance P.[6] Spinal α2 adrenergic mediated antinociception also involves a cholinergic interaction, since the administration of clonidine results in increased acetylcholine concentration in sheep and humans.[7]

Intrathecal neostigmine causes analgesia in animals and humans by preventing the breakdown of synaptically released acetylcholine. The improved analgesia results from the increase in the concentration of acetylcholine and consequent action on muscarinic and nicotinic receptors in the spinal cord.[8]

Neostigmine and clonidine both are widely available at a very affordable price, and the absence of neurotoxicity has been established in several animal and human studies when administered intrathecally.[69] It has encouraged us to compare the effectiveness and adverse effects of these two drugs when used as adjuvant with intrathecal bupivacaine.

Aim of our study was to compare the duration of sensory and motor block, surgical condition, time to request for rescue analgesia and the adverse effects of the two drugs compared with a control group when administered intrathecally as adjuvant for abdominal hysterectomy.

Materials and Methods

After obtaining Ethical Committee approval and informed consent from patients, this prospective, randomized, double-blinded study was conducted in the gynecology operation theatre of Midnapore Medical College from May 2009 to June 2011. 150 patients of American Society of Anaesthesiology (ASA) class I or II, aged between 40 and 65 years scheduled for elective abdominal hysterectomy under subarachnoid block were allocated randomly into three groups (Groups D, N and C) each comprising of 50 patients. The randomization sequence was generated by the statistical software “Microsoft Excel XP™ (2003).”

All patients received total 4 ml of drug intrathecally (3 ml of bupivacaine and 1 ml with or without study drug). Patients belonging to Group D (control group) received 1 ml of dextrose. Patients of Group N received 0.15 ml of neostigmine (each ml contains 0.5 mg of neostigmine) mixed with 0.85 ml of 5% dextrose (total volume of the study drug 1 ml containing 75 mcg of neostigmine). 0.2 ml of clonidine (each ml contains 150 mcg) mixed with 0.8 ml of 5% dextrose was prepared for the patients belonging to Group C (total volume of the study drug 1 ml containing 30 mcg of clonidine). All drug solutions were prepared by an anesthesiologist who was not involved in the administration of anesthesia or in observation of the patients which means blinding was maintained thoroughly.

Patients having relative and absolute contraindications to spinal anesthesia, known sensitivity to study drugs and local anesthetic, patients using any drug that modifies pain perception or using-adrenergic receptor antagonists, calcium channel blockers, angiotensin-converting enzyme inhibitors, anticoagulants, and diuretics were excluded from the study. Patients showing dysrhythmias in the electrocardiogram, history of coronary insufficiency, cerebrovascular accident or psychiatric disease were also excluded from the study.

Baseline heart rate (HR), non-invasive blood pressure (NIBP) and oxygen saturation (SpO2) was measured in the operation theater. After preloading with 500 ml of Ringer lactate over 20 min lumbar puncture was performed at L3-4 interspace with a 26-gauge Quincke needle with the patient in lateral position. Patients were positioned horizontally in the supine position after the drugs were administered. Maintenance fluid was administered as Lactated Ringer's solution. SpO2, HR and respiratory rate (RR) were monitored continuously. NIBP was measured at every 2 min interval for 20 min after induction of spinal anesthesia and at 5 min interval thereafter. During the postoperative period, HR, NIBP and RR were measured at 30 min interval for first 1 h and every hourly thereafter for 6 h. Hypotension was defined as systolic blood pressure (SBP) <90 mmHg or <70% of the baseline value and was treated with 300 ml of additional fluids or, if not responsive within 5 min, with mephenteramine (6 mg) intravenously. Blood loss >500 ml was replaced with maximally 1000 ml of hydroxyethyl starch or by packed red cells if hemoglobin was <90 g/L.

Bradycardia (60 or less heart beat per min) was treated with intravenous atropine (0.6 mg). Nausea and vomiting were treated with intravenous palenosetron (75 mcg).

Sensory block was assessed by the loss of sensation to a pinprick. Maximum level of sensory block achieved was noted. Dermatomal sensory loss at the level T8 was considered satisfactory. The time to two segment regression of sensory block by pinprick method was assessed for each patient. No other sedative or analgesic was given to the patients intra-operatively. Our plan was to exclude the patients; who received supplemental analgesic or converted to GA; from the study. However, fortunately no patients suffered from exclusion.

Motor block was assessed with modified Bromage score, described in [Table 1].[10] The motor block assessment was done on both sides up to 15 min at 3 min interval after administering spinal anesthesia. Time to recover from the motor block (score 6 = able to perform partial knee bend) was noted.

Table 1

Modified Bromage score

The severity of postoperative pain was measured using a 10 cm visual analogue scale (VAS) (0 - no pain, 10 - worst possible pain) every hourly till the patient requested for rescue analgesia. The duration of spinal analgesia was defined as the time interval between administration of a spinal injection to the first request for rescue analgesia. Rescue analgesia was provided first by intramuscular (IM) diclofenac sodium 75 mg (rescue analgesic) if VAS was ≥4. If pain was not relieved after 30 min of diclofenac sodium injection, IM pentazocine (30 mg) was administered (as 2nd analgesic). Time for 1st request for rescue analgesia (VAS ≥4) and total dose of analgesic required in 1st 24 h were noted. No of patients requesting for 2nd analgesic was also noted.

The surgical condition was evaluated by the surgeon at the end of procedure using a 4 point scale based on adequacy of muscle relaxation (yes-1, no-0), excessive bleeding (yes-0, no-1), patient's response to surgical stimulus (yes-0, no-1), patient's movement during the procedure (yes-1, no-0).[11]

Level of sedation was assessed intra-operatively using a four-point sedation scale. 0-Fully awake, 1-mildly sedated (drowsy and responds to call), 2-moderately sedated (drowsy and responds to tactile stimulation), 3-severely sedated (deep sedation, unresponsive).

Incidence of side-effects like hypotension, bradycardia, hypertension (SBP ≥140 mmHg or diastolic blood pressure ≥90 mmHg), tachycardia (HR >100/min), nausea-vomiting, sweating, urinary retention, pruritus, respiratory depression was noted.

All values were expressed as mean ± standard deviation (SD). Sample size was estimated using the duration of the spinal analgesia as the main primary variable. On the basis of previous study,[12] assuming a SD of 35 min for all groups, accepting alpha risk 5% and beta risk 15% we needed 43 subjects in each group to evidence a difference averaging 30 min between the durations of spinal analgesia.

Results were analyzed by unpaired Student's t-test for parametric data and Mann-Whitney U-test for nonparametric data when two groups were compared. One-way ANOVA for parametric data and Kruskal-Wallis test for nonparametric data were used while comparing three groups. Fisher's exact test and Chi-square test were used for categorical data as appropriate. P < 0.05 was considered statistically significant. All statistical tests were done by “STATISTICA” version 9 (StatSoft, Inc. Tulsa, OK, USA).

Results and Observations

The groups were comparable in terms of age, weight, height, ASA status and duration of surgery (P > 0.05) [Table 2].

Table 2

Demographic profile

From [Table 3], it was observed that time for two segment regression of sensory block and time to recover from motor block were significantly high in both Groups N and C compared to Group D (P < 0.05) and there was no statistically significant difference between Groups C and N in this regard (P > 0.05). The level of sensory block and degree of the maximum motor block were comparable among the three groups (P > 0.05). Surgical condition assessed by the surgeon was significantly better in Group C (P < 0.05) compared to other two groups and was worst in Group N.

Table 3

Characteristic of sensory and motor block

In this study, it was observed that the duration of spinal analgesia was significantly prolonged in both Groups C and N compared to Group D (P < 0.05) [Table 4]. Total dose of 1st rescue analgesic (IM diclofenac sodium) required in the first 24 h was significantly less in both Groups C and N compared to Group D [Table 4]. No significant difference was observed between Groups C and N regarding the duration of spinal analgesia and requirement of 2nd analgesic in the form of single dose IM pentazocine in the first 24 h [Table 4].

Table 4

Characteristic of spinal analgesia

From Table 5, it could be noted that there were more incidences of hypotension and dry mouth in Group C (P < 0.05) compared to other groups. There were more incidences of nausea-vomiting and sweating in Group N compared to other groups. Fewer incidences of shivering and higher scores of sedation were observed in Group C (P < 0.05) compared to other groups [Table 5]. No incidence of respiratory depression and the neurological deficit was observed in any patient.

Table 5

Intra-operative complications in different groups

Discussion

Clonidine has widely been used now a days as adjuvant along with bupivacaine to prolong the duration of sensory and motor block but it is associated with side effects like hypotension and bradycardia due to stimulation of postsynaptic α2 adrenoceptors in brainstem and in the intermediolateral column of the spinal cord decreasing sympathetic outflow.[61314151617] Several studies also suggest neostigmine as an effective adjuvant to prolong the duration of the subarachnoid block and spinal analgesia with better hemodynamic stability but with an increased incidence of nausea and vomiting.[12181920] As in the previous studies direct comparison between intrathecal clonidine and neostigmine, as well as comparison of each of them to control is lacking, we have compared clonidine (30 mcg) with neostigmine (75 mcg) and compared each of them to control in this study. It is observed in previous studies with clonidine that without increasing the incidence of side-effects 30 mcg of clonidine was the minimum dose to provide significant increase in the duration of sensory block, motor block, and spinal analgesia.[1314] On the other hand, minimum dose of neostigmine which was observed to increase the duration of sensory block in adult was 75 mcg.[12]

In our study, we have observed that the time taken for two segment regression of sensory block was significantly prolonged in both clonidine and neostigmine group compared to control group. Dobrydnjov et al.[14] with 30 mcg clonidine and Gupta[12] with 75 mcg neostigmine have observed the similar result. Strebel et al.,[13] Kaabachi et al.[15] and Sethi et al.[16] have also noted increase in the duration of the sensory block with higher doses of clonidine. Klamt et al.[20] had observed prolongation of the sensory block by 33% of the control (3.7 h vs. 4.9 h) when they used 100 mcg of neostigmine, which is comparable to our study. In pediatric patients undergoing lower abdominal and urogenital surgery, significant prolongation of sensory block was observed with different doses of neostigmine.[21] Studies which have used neostigmine in doses ≤50 mcg have not seen any significant prolongation of sensory block.[1922]

Motor block was significantly prolonged in both clonidine and neostigmine group compared to control in this study. Previous studies with 30 mcg clonidine,[14] and 75 mcg neostigmine[12] have also observed prolongation of the motor block similar to our study. Similar result was observed by a different observer with different doses of clonidine[1314151617] but there is some controversy about the prolongation of the motor block with neostigmine.[23]

The increase in the duration of spinal analgesia was significantly more in both neostigmine and clonidine group compared to control group in this study. We have not observed any significant difference in the duration of spinal analgesia between clonidine and neostigmine group. Total dose of postoperative analgesics required in the 1st 24 h following surgery was also similar in both clonidine and neostigmine group. Our observation in this regard was similar to the previous observations.[13141516171819202122232425] All the studies who have used clonidine or neostigmine intrathecally have observed an increase in the duration of spinal analgesia.

Incidence of hypotension was significantly more in clonidine group compared to control group in our study which was similar to the previous observations but there was no significant increase in the incidence of bradycardia in clonidine group in the present study.[1314151617] Hypotension and bradycardia, whenever occurred, was well managed with fluid, vasopressor, and atropine. Our observation with 30 mcg of clonidine was similar to the observation made by Dobrydnjov et al.[14] On the other hand, the incidence of hypotension was significantly less in neostigmine group compared to the control may be due to increased sympathetic outflow. Similar results were noted by the previous observers.[12192023]

The incidence of sedation was significantly more in clonidine group compared to other two groups probably due to its action on the locus ceruleus of the brain stem. Similar observation was made by previous studies with different doses of intrathecal clonidine.[13141516]

Similar to previous studies; with neostigmine nausea and vomiting were on the higher side compared to other two groups.[1218192023] We have used 5% dextrose to make adjuvant solutions hyperbaric because in some studies when hyperbaric solution of neostigmine was used the incidence of nausea and vomiting was reduced by preventing cephalic spread of the drug to brain stem.[1012] However, in our study we have not observed any decrease in the incidence of nausea and vomiting.

Increase in the duration of motor block resulting in better surgical relaxation during repair of the vaginal vault and higher sedation score were probably responsible for better surgical condition expressed by the surgeons in clonidine group compared to the control group (3.75 ± 0.11 vs. 3.2 ± 0.38). On the contrary, in neostigmine group increased incidence of nausea and vomiting resulting in frequent abdominal contractions during operative procedures has made surgical condition poor (2.95 ± 0.35 vs. 3.2 ± 0.38) in significant number of cases compared to control group. Our experience in this regard was similar to the observation made by Klamt et al.[20] where surgical team complained of poor operating condition due to vomiting and bladder evacuation when intrathecal neostigmine was used in anterior and posterior vaginoplasty.

Conclusion

We can conclude from this study that both intrathecal clonidine and neostigmine improve the bupivacaine-induced subarachnoid block. However, clonidine provides better surgical condition with fewer incidences of nausea and vomiting compared to neostigmine. Clonidine is the adjuvant of choice to bupivacaine for abdominal hysterectomy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.