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RANDOMIZED CONTROL TRIAL OF NEOSTIGMINE AND
PLACEBO AS ADJUVANTS TO COMPOUND MIXTURE OF
LIGNOCAINE AND BUPIVACAINE FOR EPIDURAL ANALGESIA IN LOWER ABDOMINAL SURGERIES
Dr. Kiran M. D.1 Dr. Sanikop C. S.2 Dr. Kotur P. F.3
1. D.A., Resident
2. M.D., Prof.
3. M.D., Prof. & HOD
Dept. of Anaesthesiology,
Jawaharlal Nehru Medical College, Belgaum
Correspond to :
Dr. Kiran M.D.
E-mail : kiranmd@rediffmail.com
SUMMARY
Several studies using neostigmine as an adjuvant to local anaesthetics (LA) for epidural anaesthesia are available in literature, all claiming obvious advantages; but neostigmine as an adjuvant to compound mixture of local anaesthetics for epidural anaesthesia has not been studied yet. We have conducted a prospective double blinded randomized controlled trial on fifty ASA I and II patients of both sexes who were scheduled to undergo elective lower abdominal surgeries. The patients were allocated to two groups, viz. saline (S) and neostigmine (N) who received placebo or neostigmine respectively with compound mixture of lignocaine 2% and bupivacaine 0.5% in the ratio of 1:4 by mass for epidural analgesia. The onset of sensory block, duration of postoperative analgesia, associated hemodynamic changes, and sequelae between the two groups were studied. Pain was assessed using a 10 cm Visual Analogue scale (VAS). Addition of neostigmine to compound mixture of lignocaine and bupivacaine resulted in no change of onset of sensory analgesia but prolonged the duration of analgesia with no sequelae.
Introduction
Acute pain in the postoperative setting can have adverse physiological and psychological effects due to the stress hormone response induced by anaesthesia and surgery. Thus postoperative pain management plays a vital role in deciding the overall outcome of any surgery. Epidural analgesia with a local anaesthetics and opioid is one of the recommended techniques for control of postoperative pain,1 which at times may prove to be inadequate and may also be associated with side effects of the adjuvant opioid. Compounding of local anaesthetics for epidural administration is an accepted technique, which combines the advantages of individual constituents. Many a times this will not be enough to alleviate postoperative pain and so there is a continuous search for newer techniques and strategies wherein intra-operative analgesia is extended into post operative period. With the introduction of multimodality approach to pain management, wherein two or more drugs with different mechanisms of action are used, newer adjuvants like Clonidine, Ketamine, Tramadol, Fentanyl, Midazolam, Neostigmine etc have been all tried as adjuvants to local anaesthetic agents with varying success rates.2 But studies are scarce with adjuvants added to compound mixtures of local anaesthetic agents for epidural block. There is no study to our knowledge yet documented wherein neostigmine is added to compound anaesthetic mixtures of local anaesthetic agents for epidural analgesia. This study was designed to evaluate the effects of adding neostigmine to compound mixture of lignocaine and bupivicaine mixture for epidural analgesia for lower abdominal surgeries.
The objectives of the study were
1. to compare the onset of sensory block and duration of post-operative analgesia between compound mixtures of lignocaine, and bupivacaine with and without neostigmine.
2. to compare associated haemodynamic changes and any other associated sequelae.
Material and methods
After obtaining institutional ethical committee approval, and written informed consent, fifty patients between 18-55 years, of age, height of 150-175 cms and weight of 45-70 kgs of either sex and ASA classes I, II, undergoing elective lower abdominal surgeries under epidural anaesthesia were included in this prospective double blind randomized controlled trial. The patients were allocated into two groups viz Group S (Saline group n=25) and Group N (Neostigmine group n=25) as per computer generated randomization.
Patients with coagulopaty neurological diseases, spine deformities, diabetes mellitus, hypertension, allergic to study drugs, pregnant or lactating women were excluded from the study.
The patients of Groups S and Group N were scheduled to receive mixture of 8 ml of 2% Lignocaine hydrochloride with 8 ml of 0.5% bupivacaine with 1 ml normal saline and 8 ml of 2% Lignocaine hydrochloride with 8 ml of 0.5% bupivacaine with 1 ml of 0.01% neostigmine respectively.
A complete pre anaesthetic evaluation was carried out; base line pulse rate, blood pressure, respiratory rate were recorded. The concept of Visual Analog Scale (VAS) was introduced to all the patients before surgery.
After securing an I.V. access with appropriate cannula, all patients were premedicated with IV Ranitidine 2 mgkg-1 and IV Ondansetron 0.1 mgkg-1 45 min prior to shifting inside Operating Room (OR). All patients were preloaded with 15 mlkg-1 of Ringerlactate within 15 minutes before the block.
Non invasive monitors viz (ECG, NIBP, Pulse oximeter) were attached and epidural block was performed in lateral approach at L1–L2 space using 18 G Tuohy epidural needle, using loss of resistance technique and test dose with 3ml of the respective solution for the group was injected in all the patients. The patients were monitored for subjective and objective signs of any inadvertent intravascular injection. Patients were asked to report any unusual subjective sensation during epidural injection and also monitored for objective signs on ECG, NIBP, SpO2 and respiratory rate. In their absence, the total volume of drug mixture as allocated to the two groups was injected over 3 min by anaesthesiologist who was blinded to the drug composition.
The time of administration of the drug into epidural space was noted. The onset of sensory analgesia was defined as loss of senstion to of bilateral pin prick which was tested every 2 minutes in the initial 30 minutes and then every 5 minutes until surgery started.
Time to maximum cephalad spread was defined as time from onset of analgesia upto highest level of sensory analgesia achieved, and duration of sensory analgesia was defined as duration from maximum cephalad spread to postoperative VAS score > 3.
Throughout the procedure B.P was monitored every 5 minutes, pulse and SpO2 were monitored continuously. Onset of bradycardia was defined as fall in heart-rate less than 60 per minute and hypotension was defined as fall in B.P more than 20% below base line; both were treated with inj. Atropine 0.6 mg IV bolus, 0.3 mg increments if necessary and incremental doses of I.V. Ephedrine 6 mg respectively.
Surgery was permitted only when the block was adequate in density and spread. An upper sensory level of T6 and lower level of S5 were considered to be appropriate. General anaesthesia was instituted, whenever the block was inadequate.
Fluid management was done according to requirements including fluid deficit, maintenance, blood loss etc. Throughout the procedure patients were asked for any nausea, vomiting, shivering, pain and any discomfort.
Post operatively vital signs were recorded every 15 min and VAS score for pain every 30 min in 1st hour, then hourly until 1st dose of rescue analgesic viz. inj. Ketorolac 0.5 mgkg-1 I.M was administered.
Statistics
The sample size was determined from our pilot study as we could not find any similar study in literature for the allocated drug mixtures like in our study. In the pilot study control group had an onset time of 5.4±0.64 min, time to max cephalad spread of 15.8±2.2 min and duration of analgesia of 140.26±60.27 and the neostigmine group similarly had of 5.2±0.83 min, 14.29±2.8 min, 355.42±165.43 respectively. Keeping an a value of 0.05 and a power of 80 % a sample size calculated was very small, however looking at the variation of SD we increased the sample size to 25 to get a consistent results.
Results
The two groups S and N were comparable with respect
to age, gender, weight, height and ASA status.
(table 1)
The surgical time and distribution of surgical procedures
was not much different between the two groups
(table 2)
The two groups had a comparable onset of sensory
analgesia, time to maximum cephalad spread, the
duration of analgesia was significantly prolonged in
the group N (table 3) There were no excessively higher
blocks in any group although 1 patients showed T5 block.
Surgery was possible in 48 patients, however 2
patients were given general anaesthesia.
The onset of sensory analgesia (mean time in min) at
various dermatome levels is depicted in fig. 1.
The haemodynamic parameters (pulse, NIBP) were
recorded regularly as planned and plotted against
time (min) along X axis fig. 2.
The VAS for pain was plotted against mean time
(in min) from preop time to the first dose of rescue
analgesic among the two groups. Even though the first
dose was given at a VAS of 3 in both the groups, the
time of administration in group N is significantly delayed
as in fig. 3.
The incidence of perioperative complications related to
the block and the total no of patients receiving atropine
and ephedrine in the two groups were comparable. (table 4 & 5)
Discussion
Neostigmine, an anticholinesterase drug, which is used to antagonize non-depolarizing muscle relaxants has been tried for post-operative analgesia as an off-label use. Being a quaternary amine, it does not cross blood-brain-barrier and by intrathecal (IT) route provides analgesia via M1 and M2 receptors in the spinal cord, inhibiting the break down of acetyl choline (ACh).3 ACh induces analgesia by increasing cyclic guanidino-mono phosphate by generating nitric oxide.4 Autoradiographic studies have shown muscarinic binding in substantia gelatinosa and to a lesser extent in lamina 2 and lamina 5 of dorsal gray matter of spinalcord.5 Neostigmine also displays peripheral and suprapinal analgesic activity, however the dose necessary to achieve this seems to be higher.6 However, IT neostigmine also carries dose dependent nausea and vomiting.
Several studies have demonstrated that the use of epidural neostigmine is associated with lesser adverse effects and the proposed mechanism of analgesia is by drug spreading into Cerebro Spinal Fluid (CSF) at the rate of 1/10th the epidural dose.7,8,9
Lauretti et al., have proven that epidural neostigmine in lignocaine produces dose independent analgesia. 9 Chittora et al in their study have concluded that epidural neostigmine with lignocaine at a dose of 100 mg provides prolonged analgesia with lesser adverse effects when compared to 50 mg and 150 mg. So we advocated the use of 100 mg as an optimum dose to be used in our study.10
Nakayama et al., have shown that epidural neostigmine with bupivicaine produces dose dependent analgesia than does bupivicaine alone after total abdominal hysterectomy.11
To our knowledge, this is the first study reported wherein neostigmine is added to mixture of LA utilizing the benefits of compounding, viz
a. Rapidity of onset of lidocaine with longer duration of action of bupivacaine
b. Mixtures of lignocaine and bupivacaine resulted in greater number of myotomes with complete motor block than if used alone.12
c. This mixture widens the safety window between median lethal dose and median convulsive dose with bupivacine and that convulsions from this mixture is less likely to be fatal than if bupivacaine is given alone.13
d. Intense motor blockade of lignocaine is necessary during surgery only but persistence of the same with
bupivacaine in the postoperative period is undesirable.
In our study, of the total 50 subjects, 27 were males and the remaining were females. The mean age, weight, height and distribution of gender were similar. The type and the mean duration of surgery between the two groups S (76.24±36.97) and N (86.2±30.9) were comparable. One patient undergoing appendicectomy had uneasiness during surgery and the other had pain with a VAS of 5, so both were given GA. These two were excluded for results.
We found not much difference in the onset times between the two groups and was comparable to onset times recorded by Magee et al14 (5 0.67 min) and Seow et al (6 min) even though Seow et al had used adrenaline in their mixtures.
The time to maximum cephalad spread was definitely shortened in the Group N although not statistically significant. The duration of analgesia is prolonged in Group N 470.48 ±161.68 when compared to Group S 144.32±68.27 which is statistically significant. In the Group S the preoperative VAS was 0.4, by 29 min VAS was 0 and surgery was allowed; by 90 min it was 0.5 and by 144 .32 min VAS was 3, demanding rescue analgesic. Similarly in Group N, preoperative VAS was 0.3, by 25 min VAS was 0, allowing surgical incision, by 180 min score tended to increase from 0.75 and by 470 min, rescue analgesic was given.
The haemodynamic changes were similar between both the two groups in the initial 30 min; and were in the order expected with the block heights achieved; the mean arterial BP decreased by 15% from baseline while the pulse rate tended to increase over the initial 15 min and then decreased.
Only two patients had hypotension and were given ephedrine 9 mg in increments and one patient had bradycardia treated with 0.6 mg of atropine.
The incidence of nausea & vomiting in our study was remarkably reduced (2%) when compared to Chittora et al (5-10%). Only one patient belonging to Group N had vomiting and the same patient had hypotension also.
No sequelae were observed in any of the patients at the time of discharge and at regular follow-ups.
Conclusion
Addition of neostigmine to compound mixture of Lignocaine and Bupivacaine for epidural administration does not shorten the onset of sensory block but prolongs the duration of post-operative analgesia, without causing any haemodynamic alterations and no sequelae. Neostigmine can be an optimal adjuvant to the compound mixture of lignocaine & bupivacaine for epidural analgesia.
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