Background: Spinal anesthesia has always had problems with the timing of the onset and the length of the motor and sensory block. By combining local anesthetics with an adjuvant, one can lengthen the block's effect and lessen its side effects. In this study, patients undergoing elective infra-umbilical surgeries were given 25mcg/50mcg of neostigmine in addition to bupivacaine and the efficacy was studied. Aims: The assessment and comparison of: Onset of the Sensory Blockade Duration of the Sensory Blockade, Onset of the motor blockade, Duration of the motor blockade, Adverse effects. Materials and Methods: About 60 patients scheduled for elective infra-umbilical surgeries under spinal anesthesia were enrolled in our study. One of the three groups (each with 20 patients) was randomly assigned to patients: Group BS: Hyperbaric 0.5% Bupivacaine 3ml+0.5mL Normal Saline, Group BN 25: Hyperbaric 0.5% Bupivacaine 3mL+25mcg Neostigmine (0.5 mL), Group BN 50: Hyperbaric 0.5% Bupivacaine 3mL+50mcg Neostigmine (0.5 mL). The onset of anesthesia, duration of postoperative analgesia, time to use first rescue analgesia, overall, 24-hr VAS pain scores, are recorded for 24-hr post drug administration. Intra operative and postoperative blood pressure, heart rate, oxygen saturation, incidence of adverse effects and the total amount of analgesic consumed in overall 24-hr were recorded. Results: The duration of sensory and motor block was significantly prolonged with addition of 25mcg/50 mcg neostigmine to Bupivacaine for patients undergoing infra-umbilical surgeries under spinal anesthesia. It might cause a delay in attaining the discharge criteria in day care surgeries and there was a dose-dependent increase in the severity of nausea, vomiting with the highest PONV score in the group of patients who received 50mcg of neostigmine along with Bupivacaine intrathecally. Conclusion: Intrathecally administered doses of 25mcg or 50mcg neostigmine and Bupivacaine increased the duration of sensory and motor block, reduced the need for rescue analgesia and delayed postoperative pain for 5–6hours.Hense we recommend the addition of 25mcg of Neostigmine to Bupivacaine for Spinal anesthesia with minimal adverse effects.
In the modern era, anesthesiologists are pioneers in the development of pain management. Pain has been defined as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage” [1]. Acute procedural pain has a high likelihood of developing into chronic pain if the right measures are not taken to treat it [2]. Postoperative pain is linked to catecholamine release and one mechanism thought to be involved in postoperative pain persistence is central sensitization.
An effective post-operative analgesic should have minimum side effects and be long-lasting and continuous [3]. Neuraxial blocks have been introduced to produce superior analgesia, decrease the blood loss and the incidence of deep venous thrombosis and pulmonary embolism, minimize the adverse effects of general anaesthesia and improve the patient’s outcomes. Better pain control may result in an earlier hospital discharge during the postoperative period [3]. For the purpose of preventing acute perioperative pain, intrathecal neostigmine has been used in conjunction with spinal anesthesia. It has been demonstrated to increase the opioid analgesic effect while lowering negative side effects like somnolence and respiratory depression. The first analgesic request was delayed by intrathecal neostigmine and bupivacaine, but no side effects were reported from its use [3–6]. We undertook this study to determine the most effective dose of intrathecal Neostigmine for prolongation of the subarachnoid block with minimum side effects.
Sample Size Calculation
Using the results of a previous study conducted by Vandana Pandey on the Comparative evaluation of different doses of Intrathecal Neostigmine as an adjuvant to Bupivacaine for postoperative analgesia [1], the sample size was calculated as below:
Sample size: minimum of 60 cases n = (Z1-α/2+Z1-β) 2 (σ12+σ2/r2)/(μ1-μ2)
α = 0.05
β = 0.2
μ1 = 18.4(mean in group1)
σ1 = 2.92(standard deviation in group1)
μ2 = 16.24(mean in group2)
σ2 = 1.85(standard deviation in group1)
Ratio = (Group2/Group1) = 1
Sample size = 42 but taking into consideration of drop out, we are taking 60 subjects that are 20-20 in the study group and 20 in the control group.
After obtaining ethical committee clearance, a prospective randomized comparative study was conducted on 60 patients undergoing infra-umbilical surgeries under spinal anesthesia. Informed written consent in their own language was obtained.
Patients included in the study were:
Belonging to ASA 1-2
Undergoing elective infra-umbilical surgery under subarachnoid block
18 years of age and above
Giving written informed consent for subarachnoid block and for being a study subject
Patients excluded from the study were
Having spinal deformities
History of respiratory, cardiac, hepato-renal disorders/convulsions
Less than 18 years of age
History of drug allergy/addiction to the study drugs
Infection at the site of spinal anesthesia
Having bleeding disorders/coagulopathies
Having muscular disorder, central and peripheral neuropathies
A detailed pre-anaesthetic check-up was done pre-operatively. The procedure was explained to the patient and written consent was taken. On the day of surgery, the patients were randomly allocated to one of the groups using the closed envelope technique.
Group BS: Hyperbaric 0.5% Bupivacaine 3ml+0.5mL Normal Saline
Group BN25: Hyperbaric 0.5% Bupivacaine 3ml+25mcg Neostigmine (0.5mL)
Group BN50: Hyperbaric 0.5% Bupivacaine 3ml+50mcg Neostigmine(0.5mL)
The procedure of sub-arachnoid block was explained to the patient. An intravenous line was started in the pre-operative room and patients were preloaded with 0mL/kg ringer lactate,30 minutes before the spinal anaesthesia.
After shifting to the operation theatre, standard monitoring was carried out like the ECG, Noninvasive blood pressure, Heart rate and SpO2.Baseline values were recorded. Spinal anaesthesia was given to the patient in sitting position at the level of L3-4/L4-5.
Blinding was achieved with the use of equal volume of drugs(3.5mL).
Patients were placed in a supine position once the drug was administered. No tilt of the table was allowed till 20 minutes after the administration of the drug during which the time required to attain the level of block was noted (sensory dermatomal level) using the pin-prick method.
The Onset of sensory and motor block was assessed every 5 minutes. Time interval between injection of drug intrathecally to the patient’s inability to lift the straight extended leg was taken as the onset time of motor block (Bromage score 3).
The duration of motor block was taken from the time of injection to complete regression of motor blockade (Bromage 0).
VAS Score was explained to the patient pre-operatively in his own language and peri-operative analgesia was assessed using a VAS Scale (0 being no pain and 10 being unbearable pain).
The duration of analgesia was recorded from the time of intrathecal injection to the time of first request of analgesia or a VAS>3.Rescue analgesia administered was injection Tramadol 50mg iv.
Intra-operative hemodynamic monitoring was done. SBP, DBP, MAP, HR, SpO2 were recorded every 5 minutes for the first 20 minutes after the administration of subarachnoid block and thereafter every 15 minutes till end of surgery. Decrease in SBP of more than 20% or MAP <60mm Hg was treated with iv lactated Ringer’s Lactate (100mL) and Inj. Mephentermine 6 mg iv if required. Bradycardia (HR<60 bpm) was treated with Inj Atropine 0.6 mg iv. Post-operative nausea vomiting was assessed using PONV Score. Inj Ondansetron 4mg iv was given as a rescue treatment.
Statistical Analysis
All values are expressed as percentages, proportions and Mean±Standard Deviation p-value <0.05 was considered statistically significant using SPSS 25.0. Collected data is analyzed by mean, standard deviation, T-test, chi-square test and analysis of variance (ANOVA) for repeated measures for all the three groups.
The demographic data (age, sex, gender, height, BMI) was compared amongst the three groups. It showed no statistical differences.
All the patients were belonging to ASA 1 or 2 and had no statistical difference.
Sensory Block
The onset of sensory block was fastest in BN50 of 5.52±1.21 minutes, followed by BN25 of 10.45±0.82 minutes and 15.43±0.76 minutes for BS group. The p-value is 0.0001 which was highly significant.
The duration of sensory block was longest with BN50 8.33±1.65 hours, then 5.67±0.80 hours in BN25 and 2.12±0.95 hours in BS group. The p-value was 0.0001 which shows there was a significant difference between the groups.
The sensory block at 5 minutes and 10 minutes according to dermatomes showed no statistical difference at 5 minutes whereas at 10 minutes BN50, BN25 it was at T6 and T8 for BS group indicating a significant statistical difference.
Figure 1: Visual Analogue Scale Score
Figure 2: Modified Bromage Scale
Figure 3: Post-Operative Nausea and Vomiting Score
Motor Block
Onset of Motor block for BN50 was 5.71±2.84 minutes as compared to 10.54±3.91 minutes in BN25 and it showed a statistical difference with p-value of 0.0002 indicating a faster onset of motor block with BN50 group.
The duration of motor block was longest in BN50 followed by BN25 and BS.
There was a significant statistical difference between the groups in terms of VAS Scores of subjects calculated at 0,2,4,6,12,24 hours. The VAS Score of group BS subjects was highest and group BN50 were the lowest at all intervals.
Rescue analgesia required was fastest in the BS group and then BN25 and last being BN50. The group BN50 showed a much longer duration of complete analgesia as compared to BN25/BS.
The mean duration of surgery was around ~132mins and the groups had no significant statistical difference.
Hemodynamically all the three groups were comparable with no significant difference. (SBP, DBP, MAP, HR) found.
Adverse Effects
BN50 35% patients had nausea whereas 20% in BN25 had similar episodes of nausea showing a significant statistical difference.
Incidence of vomiting was 25% in BN50 whereas 15% in BN25 group showing a statistically significant difference.
Requirement of antiemetic was definitely higher in BN50>BN25>BS, showing a significant statistical difference.
Despite the short duration of action when a local anesthetic is used alone, spinal anaesthesia is the most popular anesthetic technique for lower limb surgeries [7]. Controversies surround effective neostigmine intrathecal doses with fewer side effects. According to studies, 25g to 150g [8], of intrathecal neostigmine should be used as an adjuvant even though a dose-dependent increases the incidence of Postoperative Nausea Vomiting (PONV) [1,3,6–14].
When compared to epidural and general anesthesia, infra-umbilical surgeries are carried out under spinal anesthesia using a single shot technique. Its postoperative analgesia does, however, only last for a short time. The duration of the motor and sensory blocks could be extended with the help of additives, which would be advantageous in lowering postoperative morbidity [15]. Studies suggest that neostigmine is an effective adjuvant to prolong the duration of the subarachnoid block better hemodynamic stability [16], due to synergism between intrathecal neostigmine and local anaesthetic agents [14]. In this study we compared the effects of addition of Neostigmine (25mcg/50mcg) to Bupivacaine for Subarachnoid block. The demographic data (age, sex, gender, height, BMI), ASA grades are all comparable in our study to the studies done by Pandey V et al. [1], Yoganarasimha et al. [10], Faiz et al. [3], when the duration of the surgeries was compared similar results were found in studies done by Yoganarasimha et al. [13], Kamali et al. [6] and Joshi khadke et al. [7].
Table1: Demographic Data of the Patients
| Variables | Group BS | GroupBN25 | GroupBN50 | p-value |
| Age | 24.9±3.43 | 25.13±3.06 | 25.37±3.03 | 0.2871 |
| Gender, M/F | 15/5 | 19/1 | 16/4 | 0.91 |
| Height (cm) | 161.33±5.17 | 155.67±3.29 | 156.04±4.74 | 0.0914 |
| Weight (kg) | 69.53±5.37 | 55.73±6.14 | 56.87±5.32 | 0.0872 |
| BMI (kg/m2) | 24.47±2.39 | 23.44±2.41 | 23.48±2.35 | 0.1267 |
| ASA, I/II | 11/9 | 13/7 | 12/8 | 0.3804 |
| Duration of Surgery | 132.13±11.18 | 133±11.89 | 137.13±11.46 | 0.2498 |
Table2: Evaluation of Motor and Sensory Blockade
| Variables | Group BS | Group BN25 | Group BN50 | p-value |
| Sensory blockade onset (min) | 15.43±0.76 | 10.45±0.82 | 5.52± 1.21 | 0.0001 |
| Motor blockade onset (min) | 20.55±4.14 | 10.54±3.91 | 5.71± 2.84 | 0.0002 |
| Sensory blockade duration (hours) | 2.64±0.85 | 7.73±0.97 | 11.34±0.93 | 0.0001 |
| Motor blockade duration (hours) | 2.12±0.95 | 5.67±0.80 | 8.33±1.65 | 0.0001 |
| Duration of absolute analgesia (minutes) | 160.8±18.6 | 326.67±27.7 | 377.60±35.4 | 0.0001 |
| Pinprick thoracic Dermatome (T) at 5/10 minutes | T9/T8 | T8/T6 | T8/T6 | 0.287 |
Table3: VAS Score
| Variables | Group BS | Group BN25 | Group BN50 | p-value |
| 0 hour (VAS) | 1.47±0.25 | 1.03±0.87 | 0.63±0.53 | 0.01 |
| 2 hours (VAS) | 2.4±0.5 | 1.93±0.78 | 0.87±0.44 | 0.01 |
| 4 hours (VAS) | 2.9±0.55 | 2.4±1.67 | 2.23±0.73 | 0.001 |
| 6 hours (VAS) | 4.01±0.87 | 3.96±1.63 | 3.57±1.08 | 0.05 |
| 12 hours (VAS) | 4.13±0.73 | 3.98±1.73 | 3.23±1.73 | 0.05 |
| 24 hours (VAS) | 4.57±0.68 | 3.57±1.81 | 3.17±1.68 | 0.05 |
Table 4: Rescue Analgesia
| Variables | Group BS | Group BN25 | Group BN50 | p-value |
| Time for 1st Rescue analgesics | 5.30±1.18 | 8±1.89 | 8.38±1.46 | 0.0001 |
| Frequency of rescue analgesia | 2.5(1.2–3) | 1(1–1) | 1(1–2) | 0.03 |
| Rescue analgesia required yes/no | 20/0(100%) | 10/10(50%) | 5/15(25%) | 0.001 |
Table 5: Incidence of Nausea and Vomiting
| Variables | Group BS | Group BN25 | Group BN50 |
| Nausea yes/no | 2/18 | 4/16 | 7/13 |
| Vomiting yes/no | 1/19 | 3/17 | 5/15 |
| Ondansetron use yes/no | O/20 | 3/17 | 5/15 |
Figure 4: Systolic Blood Pressure Trend
Sensory Block and Motor Block
When the onset of sensory and motor block was compared, it showed a siliar value in studies done by Chittora et al. [14], Solaiappan et al. [15], Bhar et al. [16], indicating faster onset of analgesia with intrathecal 50mcg Neostigmine along with Bupivacaine.
Studies done by Apfelbaum et al. [17], Sosnowski et al. [18], McQuary HJ et al. [19], also showed that the duration of analgesia was longest with 50mcg Neostigmine of almost 378.95±1.61 mins. The time for requirement of rescue analgesia is longest for 50mcg Neostigmine which was supported with studies done by Lauretti et al. [20], Pan et al. [21] and Carp et al. [22].
The frequency of rescue analgesia are the least for BN50>BN25>BS.
The similar results were shown by Martinez KA et al. [23], Bhosle et al. [24] and Marzieh khezri et al. [25].
Figure 5: Diastolic Blood Pressure Trend
Figure 6: MAP Trend of the Patient
Figure 7: Heart Rate Trend in Patients
Intra-operative hemodynamics (SBP, DBP, MAP, HR) were compared and results were similar to studies done by Cowans et al. [26], Akanmu et al. [27], Banihashem et al. [28].
When incidence of nausea and vomiting were compared across the groups Bupivacaine with 50mcg Neostigmine showed a higher incidence of it and the requirement of antiemetics. Similar results were showed by Vasure et al. [29], Shakya et al. [30] and Biswas et al. [31].
In patients undergoing infra-umbilical surgeries, intrathecal neostigmine administered at 25mcg or 50mcg enhances the effects of intrathecal bupivacaine anaesthesia and provides dose-dependent analgesia for about 4.5–7.5 hours. Both regimens had a faster onset of blockade; longer duration of blockade; longer duration of absolute analgesia; lesser VAS score; less postoperative rescue analgesia requirement; no adverse effects on hemodynamic parameters compared with the usage of bupivacaine alone.
The prolongation of motor and sensory blockade was seen more in Bupivacaine with 50mcg Neostigmine as compared to Bupivacaine with 25mcg Neostigmine, it might cause a delay in attaining the discharge criteria in day care surgeries and the incidence of side effects like nausea and vomiting and the antiemetic requirement was more with 50mcg neostigmine.
Hence, we recommend the use of intrathecal neostigmine 25mcg as an adjuvant for plain bupivacaine in infra-umbilical surgeries.
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