Anesthesia: Essays and Researches  Login  | Users Online: 470 Home Print this page Email this page Small font sizeDefault font sizeIncrease font size
Home | About us | Editorial board | Ahead of print | Search | Current Issue | Archives | Submit article | Instructions | Copyright form | Subscribe | Advertise | Contacts


 
Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 12  |  Issue : 2  |  Page : 328-332  

Intrathecal bupivacaine with neostigmine and bupivacaine with normal saline for postoperative analgesia: A cost-effective additive


Department of Anaesthesia, Sri Devaraj Urs Medical College, R L Jalappa Hospital, SDUAHER, Kolar, Karnataka, India

Date of Web Publication14-Jun-2018

Correspondence Address:
Dr. Ravi Madhusudhana
Department of Anaesthesia, Sri Devaraj Urs Medical College, Kolar, Karnataka
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/aer.AER_184_17

Rights and Permissions
   Abstract 

Context: In day-to-day practice, subarachnoid block remains the most common type of anesthesia. Bupivacaine is commonly used local anesthetic of neuraxial blockade, though earlier 5% xylocaine and now ropivacaine and levobupivacaine are also used. Additives such as opioids and α2agonists are also used. We are using neostigmine as an additive with bupivacaine to see the duration of postoperative analgesia. Aims: To compare the efficacy of intrathecal hyperbaric bupivacaine with neostigmine when compared to hyperbaric bupivacaine with normal saline with regard to time of onset and duration of sensory and motor blockade, time to two-segment regression. Settings and Design: Randomized, double-blinded study. Subjects and Methods: One hundred patients admitted for lower abdominal and lower limb surgeries done under spinal anesthesia (SA) during the period of February 2015–August 2016. Statistical Analysis Used: Data were entered into Microsoft excel data sheet and analyzed using SPSS 22 version. Categorical data were represented in the form of frequencies and proportions. Chi-square was used as a test of significance. Continuous data were represented as a mean and standard deviation. Independent t-test was used as a test of significance to identify the mean difference between two groups. Results: Mean onset of sensory blockade with neostigmine group was 174.1 ± 107.1 s and in normal saline group 171 ± 35.6 s. Mean onset of motor blockade with neostigmine group was 197.4 ± 111.6 s and in normal saline group was 219.4 ± 73.2 s. Mean two-segment regression with neostigmine group was 110.6 ± 22.7 s and in normal saline group was 71.5 ± 17.1 min. Duration of analgesia with neostigmine group was 336.3 ± 54.5 min and in normal saline group was 188.8 ± 18.4 min. Conclusions: Intrathecal neostigmine is associated with significantly prolonged sensory, motor blockade, and effective postoperative analgesia.

Keywords: Analgesia, anesthesia, bupivacaine, neostigmine, spinal


How to cite this article:
Kumari Vasantha NS, Madhusudhana R. Intrathecal bupivacaine with neostigmine and bupivacaine with normal saline for postoperative analgesia: A cost-effective additive. Anesth Essays Res 2018;12:328-32

How to cite this URL:
Kumari Vasantha NS, Madhusudhana R. Intrathecal bupivacaine with neostigmine and bupivacaine with normal saline for postoperative analgesia: A cost-effective additive. Anesth Essays Res [serial online] 2018 [cited 2018 Oct 22];12:328-32. Available from: http://www.aeronline.org/text.asp?2018/12/2/328/234416


   Introduction Top


Spinal anaesthesia is a commonly used technique for lower abdominal and lower limb surgeries. Hyperbaric bupivacaine 0.5% is 3–4 times more potent than lignocaine and has prolonged duration of action. Its disadvantage is a slow onset of action. Additives such as systemic benzodiazepines, synthetic and semi-synthetic opioids are a simple, effective, and commonly adopted way of postoperative pain relief. Neostigmine represents one of the promising methods of providing postoperative analgesia. Its analgesic property can be explained by its inhibiting action on breakdown of acetylcholine which is an endogenous neurotransmitter. It blocks the activity of both true and pseudocholinesterase and thereby enhancing the accumulation and binding of acetylcholine at various cholinergic sites.

Objective of the study

The objective of the study was to study and compare the efficacy of intrathecal hyperbaric bupivacaine with neostigmine when compared to hyperbaric bupivacaine with normal saline with regard to time of onset and duration of sensory and motor blockade, time to two-segment regression, and any side effects.


   Subjects and Methods Top


It was a randomized double-blind study, and the anesthesiologist was not aware of the drug used. Patients were randomly allocated to two groups using a computerized randomization table. Patients of American Society of Anesthesiologists Classes I and II in the age group of 18-50 years of either sex, weight >45 kg, and height >150 cm posted for elective surgeries under spinal anesthesia (SA) were selected for the study. If there was patient's refusal, history of allergies to any study medications, gross spinal abnormality, localized skin sepsis, hemorrhagic diathesis, neurological involvement/diseases, with head injury, raised intracranial pressure, raised intraocular pressure, psychiatric disorders, asthma, epilepsy, thyroid, and peptic ulcer diseases were excluded from the study.

All patients were examined a day before surgery. All were kept fasting overnight after 10:00 pm and received tablet ranitidine 150 mg orally and tablet alprazolam 0.5 mg orally as premedication at night before surgery and at 6:00 am with sip of water in the morning on the day of surgery.

All patients were preloaded with 5 ml/kg Ringer's lactate solution after securing intravenous (i.v) access with 18G cannula. After the patient was brought to the operation theater, the monitoring of pulse rate, blood pressure, electrocardiography, and SPO2 was started.

Under all aseptic precautions after putting patient in left lateral position, using 25G Quincke spinal needle spinal block was performed at L3–L4.

Interspace through a midline approach and patient put to supine position. Patients in Group N received 3 ml of 0.5% hyperbaric bupivacaine with 50 μg (0.1 ml) neostigmine. Patients in Group C received 3 ml of hyperbaric 0.5% bupivacaine with 0.1 ml of normal saline.

Quality of analgesia was assessed by visual analog scale (VAS).

VAS for pain:

  • 0 - No pain
  • 1–3 - Mild pain
  • 4–6 - Moderate pain
  • 7–10 - Severe pain


Motor blockade was assessed using modified Bromage scale.

Bromage scale: Grade Definition

  • 0 - Full flexion of knee and feet
  • 1 - Inability to raise extended leg; able to move knee and feet
  • 2 - Inability to raise extended leg and move knee; able to move feet
  • 3 - Complete block of lower limb.


Data were entered into Microsoft excel data sheet and were analyzed using SPSS 22 version software (IBM). Categorical data were represented in the form of frequencies and proportions. Chi-square was used as a test of significance.

Continuous data were represented as a mean and standard deviation. Independent t-test was used as a test of significance to identify the mean difference between two groups. P<0.05 was considered statistically significant.

Sample size formula used was,



Za/2= 95% confidence level = 1.96 at α = 0.05

Zb= power at 90% = 0.842

d = mean difference

σ = average of Zα/2 + Zβ


   Results Top


In our study, mean onset of sensory blockade among neostigmine was 174.1 ± 107.1 s and in normal saline was 171 ± 35.6 s [Table 1].
Table 1: Onset of effects of anesthesia and duration of anesthesia between two groups

Click here to view


Mean onset of motor blockade among neostigmine was 197.4 ± 111.6 s and in normal saline was 219.4 ± 73.2 s [Table 1].

Mean two-segment regression among neostigmine was 110.6 ± 22.7 s and in normal saline was 71.5 ± 17.1 min [Table 1].

Duration of analgesia among neostigmine was 336.3 ± 54.5 min and in normal saline was 188.8 ± 18.4 min [Table 1].

There was no significant difference in onset of sensory and motor blockade between two groups, whereas significant difference was observed in two-segment regression and duration of analgesia between two groups.

A significant difference was observed in heart rate (HR) between two groups was observed at 5, 10, 60, 120, 240, 300, and 420 min. Lower HR was observed in neostigmine group than normal saline group during the above-said durations [Table 2].
Table 2: Heart rate variation between two groups

Click here to view


In our study, there was no incidence of hypertension and hypotension in both the groups during the follow-up.

A significant difference was observed in mean arterial blood pressure (MAP) between two groups and was observed at all the intervals except at baseline, 60, 300, and 360 min [Table 3].
Table 3: Mean arterial blood pressure variation between two groups

Click here to view


Lower MAP was observed in neostigmine group than normal saline group during the above-said durations. In the study, there was no incidence of hypoxia in both the groups during the follow-up [Table 3].

χ2 = 87.05, df = 4, P< 0.001*

In the neostigmine group, 68% had VAS score of 1, 26% had VAS score of 2, and 6% had VAS score of 3, whereas in normal saline group, 2% had VAS score 2, 20% had VAS score 3, 42% had VAS score 4, and 36% had VAS score 5. This difference in VAS score was statistically significant [Table 4].
Table 4: Visual analogue scale score between two groups

Click here to view


χ2 = 1.376, df = 3, P = 0.711

In neostigmine group, 4% of them had vomiting and 2% had bradycardia and Nausea [Table 5].
Table 5: Side effects between two groups

Click here to view


In normal saline group, 2% of them had nausea and vomiting, respectively. There was no significant difference in side effects between two groups [Table 5].


   Discussion Top


Subarachnoid block has been most extensively used for lower abdominal and lower limb surgeries because of its simplicity, speed, reliability, and advantage of avoiding polypharmacy. Subarachnoid block produces superior analgesia and decreases the blood loss and the incidence of deep venous thrombosis, pulmonary embolism, and to minimize the adverse effects of general anesthesia and improve the patients' outcomes. The aim of this study is to produce a long-lasting, continuous effective analgesia with minimum side effects.

Commonly used local anesthetics for intrathecal anesthesia are lignocaine and bupivacaine in India. Bupivacaine 0.5% heavy single intrathecal injection provides analgesia for about 2–2.5 h, but the postoperative analgesic duration is limited. Other method of prolonging analgesic effect is using a continuous epidural analgesia, which is technically more difficult and more costly. Hence, providing intrathecal additive to these local anesthetics forms a reliable and reproducible method of prolonging postoperative analgesia and to prolong the duration of anesthesia. As this technique is simple and less cumbersome, it has gained a wide acceptance.

Many additives have been used to enhance analgesic effect of neuraxial blocks such as clonidine, magnesium, ketamine, opioids, vasoconstrictor agents and steroids, and neostigmine. It has been reported that the inhibition of spinal cholinesterase by neostigmine produces great enhancement of endogenous acetylcholine, which is most likely released from intrinsic cholinergic neurons within the dorsal horn of the spinal cord, also action at nicotinic receptors at the dorsal horn ganglion, and at the spinal meninges have been demonstrated.[1],[2],[3] Muscarinic receptor antagonists have been shown to reverse the analgesic effects of intrathecal neostigmine.[4]

Unlike other opioids and α2 adrenergic agonists, neostigmine is not a direct agonist, but it inhibits break down of endogenous spinal neuromodulator acetylcholine which has been shown to have antinociceptive effects.

When we see the history, neostigmine is an old drug being used in laboratory in 1980s and humans in 1990s, started with a higher dose (750-1 mcg) which had side effects of nausea and vomiting, so smaller doses were recommended.[5]

In the present study, we hypothesized that neostigmine may provide a better pain relief after lower abdominal and lower limb surgeries under SA compared to conventional agents. In addition, unlike opioids, neostigmine does not produce pruritus, respiratory depression, or hyperalgesia.

In our study, mean time taken for the onset of sensory blockade among neostigmine (Group N) was 174.1 ± 107.1 s and in normal saline (Group C) 171 ± 35.6 s. There was no significant difference in onset of sensory and motor blockade between two groups. A significant difference was observed in two segment regression between two groups.

In our study, addition of 50 μg of neostigmine intrathecally did not enhance the onset of sensory block, and this correlates with that of study conducted by Saini's et al.[6] The two segment regression of block was prolonged in Group N as compared to Group C and this correlates with that of Saini's et al.[6]

Analgesic properties of neostigmine have been shown to depend on the release of nitric oxide in spinal cord and increasing acetylcholine in the spinal synapses which leads to the further stimulation of nicotinic and muscarinic receptors.[7]

Patients of Group C complained of pain earlier than that of Group N. There was a statistically significant delay in the onset of pain between Group C and Group N.

Lauretti et al. conducted a study to know the effects of 50, 100, and 200 μg of intrathecal neostigmine on patients undergoing anterior and posterior vaginoplasty. They found that postoperative analgesia ranged from 8 h for 50 μg to 12 h for 100 μg.[8]

Klamt et al. studied the effect of intrathecal neostigmine on postoperative analgesia and on SA. They concluded that analgesia lasted for about 12 h in patients who underwent anterior and posterior vaginoplasty.[9] Krukowski et al. studied the efficacy of intrathecal neostigmine in 24 healthy pregnant women posted for elective cesarean section under combined spinal-epidural technique with doses of neostigmine ranging from 10 to 100 μg. They concluded that intrathecal neostigmine in doses of 30–50 μg produced 10 h of postoperative analgesia without adverse fetal effects.[10]

Lauretti et al. conducted a multicenter study to know the effect of intrathecal neostigmine in doses of 25, 50, and 75 μg on 92 patients undergoing vaginal hysterectomy under SA with 15 mg of bupivacaine and found that neostigmine produces a dose-dependent analgesia for 8 h after the surgery.[11]

Tan et al. evaluated intrathecal 50 μg neostigmine compared to 300 μg morphine in patients submitted to knee arthrodesis. The study revealed the occurrence of 7 h of postoperative analgesia with the use of neostigmine.[12]

Jain et al. conducted a study in patients undergoing total knee replacement (TKR) where comparison was between analgesic efficacy of low-dose intrathecal neostigmine in combination with fentanyl and bupivacaine. It was proven that addition of 1 mcg neostigmine intrathecal (IT) increased the duration of analgesia and decreased the analgesic consumption in 24 h in TKR.[13]

Khadke et al. conducted a study to know the effects of intrathecal neostigmine on characteristics of SA, hemodynamic stability, and postoperative analgesia when added to 0.5% hyperbaric bupivacaine for SA. They observed that mean duration of analgesia in neostigmine group was about 5.1 h.[14]

In our study, a significant difference was observed with duration of analgesia between two groups. The quality of analgesia was assessed using pain score and patients were asked to give a global assessment of the overall effectiveness of the analgesic treatment. Based on the score and quality of pain after the regression of block was controlled with nonsteroidal anti-inflammatory drugs such as diclofenac injection. Our present study showed that 50 μg of intrathecal neostigmine provided a good and efficacious postoperative pain relief which correlates with the study of Klamt et al.[9]

In our study, a significant difference was observed in MAP between two groups was observed at all the intervals except at baseline, 60, 300, and 360 min. Lower MAP was observed in neostigmine group than normal saline group during the above-said durations. However, there was no significant incidence of hypotension requiring fluid or vasopressors. Not much significant difference was observed in studies conducted by Krukowski et al. and Lauretti et al.[10],[11]

In our study, a significant difference was observed in HR between two groups was observed at 5, 10, 60, 120, 240, 300, and 420 min. Lower HR was observed in neostigmine group than normal saline group during the above-said durations. Bradycardia was observed in one patient in Group N which was treated with i.v atropine 0.6 mg.

In our study in neostigmine group, 4% of them had vomiting and 2% had bradycardia and nausea, whereas, in normal saline group, 2% of them had nausea and vomiting, respectively, and was not significant. Hood et al. studied that intrathecal neostigmine produces protracted nausea and vomiting in doses of 100–200 μg. They had also found that the incidence of nausea and vomiting was significantly with hyperbaric solutions.[15]

Strength and limitations of our study

Strength of our study was using a cost-effective medication as an additive with minimal side effects and efficient postoperative analgesia. Limitation being we could have compared with still smaller doses of neostigmine.


   Conclusions Top


Intrathecal neostigmine is associated with significantly prolonged sensory, motor blockade, and effective postoperative analgesia.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
   References Top

1.
Genzen JR, Van Cleve W, McGehee DS. Dorsal root ganglion neurons express multiple nicotinic acetylcholine receptor subtypes. J Neurophysiol 2001;86:1773-82.  Back to cited text no. 1
[PUBMED]    
2.
Ummenhofer WC, Brown SM, Bernards CM. Acetylcholinesterase and butyrylcholinesterase are expressed in the spinal meninges of monkeys and pigs. Anesthesiology 1998;88:1259-65.  Back to cited text no. 2
[PUBMED]    
3.
Zhuo M, Gebhart GF. Tonic cholinergic inhibition of spinal mechanical transmission. Pain 1991;46:211-22.  Back to cited text no. 3
[PUBMED]    
4.
Naguib M, Yaksh TL. Characterization of muscarinic receptor subtypes that mediate antinociception in the rat spinal cord. Anesth Analg 1997;85:847-53.  Back to cited text no. 4
[PUBMED]    
5.
Lauretti GR. The evolution of spinal/epidural neostigmine in clinical application: Thoughts after two decades. Saudi J Anaesth 2015;9:71-81.  Back to cited text no. 5
[PUBMED]  [Full text]  
6.
Saini S, Sethi S, Malhotra N. Evaluation of intrathecal neostigmine for post operative analgesia. J Anaesth Clin Pharmacol 2006;22:35-40.  Back to cited text no. 6
    
7.
Kayalha H, Mousavi Z, Sadat Barikani A, Yaghoobi S, Khezri MB. The effects of intrathecal neostigmine added to bupivacaine on postoperative analgesic requirement in patients undergoing lower limb orthopedic surgery. Middle East J Anaesthesiol 2015;23:199-204.  Back to cited text no. 7
[PUBMED]    
8.
Lauretti GR, Reis MP, Prado WA, Klamt JG. Dose-response study of intrathecal morphine versus intrathecal neostigmine, their combination, or placebo for postoperative analgesia in patients undergoing anterior and posterior vaginoplasty. Anesth Analg 1996;82:1182-7.  Back to cited text no. 8
[PUBMED]    
9.
Klamt JG, Slullitel A, Garcia IV, Prado WA. Postoperative analgesic effect of intrathecal neostigmine and its influence on spinal anaesthesia. Anaesthesia 1997;52:547-51.  Back to cited text no. 9
[PUBMED]    
10.
Krukowski JA, Hood DD, Eisenach JC, Mallak KA, Parker RL. Intrathecal neostigmine for post-cesarean section analgesia: Dose response. Anesth Analg 1997;84:1269-75.  Back to cited text no. 10
[PUBMED]    
11.
Lauretti GR, Hood DD, Eisenach JC, Pfeifer BL. A multi-center study of intrathecal neostigmine for analgesia following vaginal hysterectomy. Anesthesiology 1998;89:913-8.  Back to cited text no. 11
[PUBMED]    
12.
Tan PH, Chia YY, Lo Y, Liu K, Yang LC, Lee TH, et al. Intrathecal bupivacaine with morphine or neostigmine for postoperative analgesia after total knee replacement surgery. Can J Anaesth 2001;48:551-6.  Back to cited text no. 12
    
13.
Jain A, Jain K, Bhardawaj N. Analgesic efficacy of low-dose intrathecal neostigmine in combination with fentanyl and bupivacaine for total knee replacement surgery. J Anaesthesiol Clin Pharmacol 2012;28:486-90.  Back to cited text no. 13
[PUBMED]  [Full text]  
14.
Khadke SJ, Khadke VV, Patel SJ, Borse YM, Kelkar KV, Dighe JP, et al. Efficacy of spinal additives neostigmine and magnesium sulfate on characteristics of subarachnoid block, hemodynamic stability and postoperative pain relief: A randomized clinical trial. Anesth Essays Res 2015;9:63-71.  Back to cited text no. 14
[PUBMED]  [Full text]  
15.
Hood DD, Eisenach JC, Tuttle R. Phase I safety assessment of intrathecal neostigmine methylsulfate in humans. Anesthesiology 1995;82:331-43.  Back to cited text no. 15
[PUBMED]    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

Top
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
    Abstract
   Introduction
   Subjects and Methods
   Results
   Discussion
   Conclusions
    References
    Article Tables

 Article Access Statistics
    Viewed217    
    Printed4    
    Emailed0    
    PDF Downloaded41    
    Comments [Add]    

Recommend this journal