Document Type : Original Article
Authors
Anesthesiology and Intensive Care Department, Faculty of Medicine, Al-Azhar University
Abstract
Keywords
Main Subjects
COMPARATIVE STUDY BETWEEN THE EFFECT OF INTRATHECAL BUPIVACAINE AND INTRATHECAL BUPIVACAINE-MIDAZOLAM ON POST-OPERATIVE ANALGESIA
By
Ahmed Tharwat Mosallam Asfour, Mona Hanem Abd El-Ghaffar Ahmed and Nasr Abd Al-Aziz Mohammed Saad
Anesthesiology and Intensive Care Department, Faculty of Medicine, Al-Azhar University
Corresponding Author: Ahmed Tharwat Mosallam Asfour
E-mail: ahmedasfour551@gmail.com
ABSTRACT
Background: The central neuroaxial blockade is one of the most important and most commonly used regional anesthetic techniques for lower abdominal, perineal and lower limb surgeries. Administration of combinations of drugs intrathecal targeting multiple spinal cord receptors leads to prolonged analgesia with superior quality. This can be achieved by relatively small concentrations of individual drugs.
Objective: To compare the efficacy of intrathecal bupivacaine versus intrathecal bupivacaine-midazolam on post-operative analgesia.
Patients and Methods: This prospective randomized study was carried out on 60 patients. They were divided into two equal groups: bupivacaine group and bupivacaine-midazolam group and compare the effect of both groups on post-operative analgesia. They were admitted to Hospital for elective lower abdominal, perineal and lower limb surgeries. The study was conducted at Al-Azhar University Hospitals, from August 2019 till July 2020.
Results: The duration of post-operative analgesia was longer in the bupivacaine midazolam group (152.5 ± 20.44 minutes) compared to the bupivacaine only group (120.0 ± 31.54 minutes), but onset of sensory block was 1.55 ± 0.48 minutes in the bupivacaine only group, and 1.56 ± 0.55 minutes in bupivacaine midazolam group. There were no statistically significant differences in the two groups as regard onset of motor block, duration of motor block and there effect on postoperative nausea and vomiting.
Conclusion: The addition of midazolam to bupivacaine in spinal anesthesia resulted in prolonged postoperative analgesia with no significant increase in the duration of motor block.
Keywords: Intrathecal, Bupivacaine, Midazolam, Post-operative analgesia.
INTRODUCTION
The dose reductions may avoid drug-related side effects. In addition, the simultaneous targeting of several different receptor sites in the spinal cord may lead to improved pain relief (Stein, 2018). There are many drugs for spinal anesthesia, each having its own advantages and disadvantages. There has been growing emphasis on the advantages of combined pharmacological approach for pain relief. Discovery of analgesic effects of spinally administered opioids and other drugs such as benzodiazepines and alpha-2 adrenoreceptor agonists has opened the possibilities of optimizing on useful drug interactions at the level of spinal cord in the management of pain (Cowen et al., 2015). Intra-thecal midazolam reduces excitatory γ-aminobutyric acid-mediated neurotransmission in interneuron, leading to a decrease in the excitability of spinal dorsal horn neurons. Moreover, it causes the release of an endogenous opioid that acts at the spinal delta receptor. So, it can potentiate the effect of intrathecal bupivacaine and enhance the intraoperative anaesthesia and analgesia in addition to postoperative analgesia (Tesfaye et al., 2013).
The present work aimed to compare the efficacy of intrathecal bupivacaine versus intrathecal bupivacaine-midazolam on post-operative analgesia.
PATIENTS AND METHODS
This prospective randomized study was carried out on 60 patients admitted to Hospital for elective lower abdominal, perineal and lower limb surgeries. The study was conducted at Al-Azhar University Hospitals from August 2019 till July 2020. After approval from ethical committee, informed consents were obtained from all patients.
Patients were divided into 2 equal groups:
Group A (control group) was given 3.5ml of 0.5% hyperbaric bupivacaine plus 0.4 ml saline 0.9% .
Group B (study group) was given 3.5ml of 0.5% hyperbaric bupivacaine plus 2 mg (0.4ml) of 0.5% midazolam.
Inclusion criteria:
• Patients with ASA I –II.
• Age: between 18-60 years of age.
Exclusion criteria:
• Patient refusal
• Patients with contraindications to central neuroaxial blockade.
• Less than 18 more than 60 years old.
• Allergy to drugs used in the study.
• Respiratory, hepatic, renal impairment.
• Previous coronary heart disease, hypertension and diabetes.
• Neurological diseases.
Preoperative assessment:
• History (medical and surgical)
• Physical examination.
• Laboratory investigations (CBC, renal function tests, liver function tests. coagulation profile).
Premedication:
• Slow IV infusion of 50 mg Ranitidine and 10 mg Metoclopramide.
Anesthetic technique:
Intravenous access was established with a 18G Intravenous cannula and preloading was done with 15ml/kg lactated ringer’s solution. No sedative premedication was given.
Under all aseptic precautions, in sitting position with midline approach a lumbar puncture was done with a spinal needle (25G x 90 mm Uniever, Saitama, Japan).
After free flow of CSF, 3.5ml of 0.5% hyperbaric bupivacaine (Sunny pivacaine, Sunny medical, Bupivacaine HC 20 mg/ 4ml) plus 0.4 ml of saline 0.9% in control group. 3.5ml of 0.5% hyperbaric bupivacaine (Sunny pivacaine, Sunny medical, Bupivacaine HC 20 mg/ 4ml), plus 2mg of 0.5% midazolam (Dormicum, Roche, Swizerland, 5 mg/ml) in study group.
All patients were transferred from the post-anesthesia care unit to the surgical ward unless surgical practice required intensive care observation. Adjuvant analgesics such as ketorolac, and paracetamol were allowed at the discretion of the anesthesia pain service.
Basic monitoring for all patients (5 leads ECG, NIBP, pulse oximetry, capnography for endtidal CO2, and temperature monitoring by (Colin Bp- 608 Evolution)) monitor Manufactured by OMRON HEALTH CARE Co. Ltd (Japan).
Data collection:
• Demographic data: (age, gender, weight, height).
• Hemodynamic data:
• Mean arterial blood pressure.
• Heart rate.
• Primary outcome:
Evaluate the effect of intra thecal midazolam combined with bupivacaine on the duration of post-operative analgesia.
• Pain assessment will be done by Visual analogue scale (0.0 = no pain, 10.0 = worst pain imaginable) immediately after intra thecal injection then every 30 minutes till 210 minutes.
• Onset of sensory block (min).
• Onset of motor block (min).
• Sensory block duration (min).
• Motor block duration (min).
• Secondary outcome:
Including nausea, vomiting.
Sample size justification:
Epi info version 1.4.3 program was efficiently used for calculations of sample size. Statistical calculator based on 95% confidence interval and power of the study 80% with α error 5%. Assuming a drop - out ratio of 5%, the sample size was set as 60 cases in the study group.
Statistical analysis:
Data were analyzed using (IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp.). Numerical data were expressed as mean and standard deviation or median, and range as appropriate. Qualitative data were expressed as frequency and percentage. Chi-square test was used to examine the relation between qualitative variables. For quantitative data, comparison between two groups was done using t-test or Mann-Whitney test. P-value ≤ 0.05 was considered significant.
RESULTS
There was no statistically significant difference in demographic and clinical data among the two groups (Table 1).
Table (1): Comparison between groups according to demographic and clinical data
Groups
Demographic data |
Bupivacaine only group (N=30) |
Bupivacaine midazolam group (N=30) |
P-value |
Age (years) |
34.17±7.2 |
32.9±6.43 |
0.474 |
Gender |
|||
Female |
17(56.7%) |
12(40%) |
0.196 |
Male |
13(43.3%) |
18(60%) |
|
Weight (kg) |
85.26±5.39 |
84.77±6.12 |
0.743 |
Height (cm) |
176.33±7.56 |
178.08±6.50 |
0.340 |
There was no statistically significant difference in onset of sensory block and onset of motor block among the two groups (Table 2).
Table (2): Comparison between groups according to onset of sensory block and onset of motor block
Parameters
Groups |
Onset of sensory block (min.) |
P-value of Onset of sensory block |
Onset of motor block (min.) |
P-value of Onset of motor block |
Mean ± SD |
Mean ± SD |
|||
Bupivacaine only group (N=30) |
1.55 ± 0.48 |
0.940 |
2.46 ± 0.53 |
0.601 |
Bupivacaine midazolam group (N=30) |
1.56 ± 0.55 |
2.53 ± 0.5 |
There was no statistically significant difference in Mean Arterial Blood Pressure at Baseline, 5 min., 10 min., 15 min., 20 min., 30 min., 60 min., 120 min., and 180 min. among the two groups (Table 3).
Table (3): Comparison between groups according to Mean Arterial Blood Pressure (MAP)
Groups
MAP |
Bupivacaine only group (N=30) |
Bupivacaine midazolam group (N=30) |
P-value |
||||
Mean |
± |
SD |
Mean |
± |
SD |
||
Baseline |
95.7 |
± |
5.76 |
94.12 |
± |
6.8 |
0.335 |
5 min. |
85.9 |
± |
6.56 |
84.53 |
± |
5.36 |
0.379 |
10 min. |
86.15 |
± |
7.65 |
83.82 |
± |
4.96 |
0.167 |
15 min. |
87.5 |
± |
7.16 |
87.01 |
± |
5.34 |
0.764 |
20 min. |
88.05 |
± |
8.06 |
86.3 |
± |
5.57 |
0.332 |
30 min. |
89.2 |
± |
7.95 |
87.45 |
± |
6.11 |
0.343 |
60 min. |
89.35 |
± |
8.58 |
88.11 |
± |
6.94 |
0.540 |
120 min. |
90.75 |
± |
7.53 |
88.75 |
± |
5.65 |
0.249 |
180 min. |
93.2 |
± |
7.16 |
91.1 |
± |
6.54 |
0.240 |
There was no statistically significant difference in Heart rate at Baseline, 5 min., 10 min., 15 min., 20 min., 30 min., 60 min. and 120 min. among the two groups (Table 4).
Table (4): Comparison between groups according to heart rate (HR)
Groups
HR |
Bupivacaine only Group (N=30) |
Bupivacaine midazolam group (N=30) |
P-value |
||||
Mean |
± |
SD |
Mean |
± |
SD |
||
Baseline |
100.77 |
± |
8.90 |
98.66 |
± |
9.06 |
0.367 |
5 min. |
102.8 |
± |
9.02 |
101.45 |
± |
8.23 |
0.547 |
10 min. |
98.95 |
± |
8.93 |
96.35 |
± |
8.97 |
0.265 |
15 min. |
93.94 |
± |
8.46 |
92.34 |
± |
8.33 |
0.466 |
20 min. |
90.65 |
± |
8.05 |
89.7 |
± |
7.14 |
0.630 |
30 min. |
87.45 |
± |
8.77 |
86.23 |
± |
7.12 |
0.556 |
60 min. |
86.6 |
± |
9.34 |
85.6 |
± |
7.59 |
0.650 |
120 min. |
85.25 |
± |
9.18 |
84.1 |
± |
6.75 |
0.582 |
There was a statistically significant difference in duration of sensory block and there was no statistically significant difference in duration of motor block among the two groups (Table 5).
Table (5): Comparison between groups according to duration of sensory block and duration of motor block
Parameters
Groups |
Duration of sensory block (min.) |
P-value of Duration of sensory block. |
Duration of motor block (min.) |
P-value of Duration of motor block. |
Mean ± SD |
Mean ± SD |
|||
Bupivacaine only group (N=30) |
120.0 ± 31.54 |
<0.001 |
116.51 ± 19.54 |
0.126 |
Bupivacaine midazolam group (N=30) |
152.5 ± 20.44 |
123.57 ± 15.1 |
There was a statistically significant difference in VAS at 30 min., 60 min., 90 min., 120 min., 150 min., 180 min. and 210 min. among the two groups when p-value was (Table 6).
Table (6): Comparison between the two groups according to mean post-operative visual analogue scale (VAS)
Groups
VAS |
Bupivacaine only Group (N=30) |
Bupivacaine midazolam group (N=30) |
Mann- Whitney test |
||
Range |
Median |
Range |
Median |
P-value |
|
0 min. |
1-2 |
2 |
1-2 |
2 |
0.953 |
30 min. |
2-5 |
4 |
1-4 |
3 |
<0.001 |
60 min. |
2-6 |
4 |
1-4 |
2 |
<0.001 |
90 min. |
2-6 |
4 |
1-3 |
2 |
<0.001 |
120 min. |
2-6 |
4 |
1-4 |
2 |
<0.001 |
150 min. |
2-6 |
4 |
1-3 |
3 |
<0.001 |
180 min. |
2-5 |
3 |
1-4 |
2 |
<0.001 |
210 min. |
1-4 |
3 |
1-3 |
1 |
<0.001 |
There was no statistically significant difference in complications among the two groups (Table 7).
Table (7): Comparison between the two groups according to complications
Groups
Complications |
Bupivacaine only Group (N=30) |
Bupivacaine midazolam group (N=30) |
Chi-square |
||
N |
% |
N |
% |
P-value |
|
Nausea |
16 |
53.3 |
18 |
60.0 |
0.602 |
Vomiting |
4 |
13.3 |
5 |
16.7 |
0.718 |
DISCUSSION
Intrathecal midazolam has been shown to have analgesic properties and potentiates the effects of intrathecal local anaesthetics (Shadangi et al., 2011).
The mechanism by which midazolam provides analgesia has been explored in several studies (Shadangi et al., 2011). Some of which suggest that intrathecal midazolam is involved in the release of an endogenous opioid acting at spinal delta receptors (Shadangi et al., 2011). Therefore, adding intrathecal midazolam may potentiate the antinociceptive effect of morphine -like agents (Stuart, 2011). Some suggest that the mechanism of action of midazolam indirect and is related to GABA accumulation and its affinity to benzodiazepine receptor. Two separate receptors for GABA and benzodiazepine are coupled to a common chloride channel. It increases the frequency of chloride channel opening. Occupation of both the receptors causes membrane hyperpolarization and neuronal inhibition (De Paula et al., 2015).
We used 2 mg midazolam as an additive to bupivacaine for intrathecal administration, as most studies agree that 1-2 mg intrathecal midazolam is safe and efficacious (Shadangi et al., 2011).
In our study, the duration of sensory blockade was prolonged in the midazolam group, which is comparable to the results of previously reported studies.
Intrathecal midazolam 2 mg provided a moderate prolongation effect on postoperative analgesia as compared to 1 mg midazolam when used as an adjunct to bupivacaine in patients undergoing caesarean delivery (Bharti et al., 2015). However, the postoperative pain scores were lower in patients who received intrathecal midazolam (1 mg) along with bupivacaine (Bhure et al., 2012).
The duration of postoperative analgesia was significantly prolonged with the addition of intrathecal midazolam and that the effect was dose-dependent (Oliveira Júnior et al., 2016).
In our study, there were no significant difference between the two groups as regard the duration of motor block, contrasted with a study, which found the duration of motor blockade to be prolonged in the midazolam group compared with the control group (Mohsin and Kumari 2016), the differences in these results may be due to the difference in number of patients between the two studies, age group in both studies or concentrations of injected drugs.
In our study, the duration of post-operative analgesia was longer in the bupivacaine midazolam group compared to the bupivacaine only group, but onset of sensory block in the bupivacaine only group and in bupivacaine midazolam group showed no significant difference.
In our study, there were no statistically significant difference in the two groups as regard postoperative nausea and vomiting, although 1 mg and 2 mg intrathecal midazolam has been reported to decrease postoperative nausea and vomiting (Shadangi et al., 2011), the differences in these results may be due to the difference in number of patients between the two studies, age group in both studies.
CONCLUSION
The addition of midazolam to bupivacaine in spinal anaesthesia resulted in prolonged postoperative analgesia with no significant increase in the duration of motor block.
REFERENCES
10. Stuart, P. (2011): Novel additives to neuraxial blockade. Southern African Journal of Anaesthesia and Analgesia, 17(1): 86-89.
11. Tesfaye, S., Boulton, A. J. and Dickenson, A. H. (2013): Mechanisms and management of diabetic painful distal symmetrical polyneuropathy. Diabetes care, 36(9): 2456-2465.
دراسة مقارنة بين تأثير الحقن تحت الأم العنکبوتية لعقار البيوبيفيکين والبيوبيفيکين ميدازولام وتأثيرهما على تسکين الألم بعد العملية الجراحية.
أحمد ثروت مسلم عصفور، منى هانم عبد الغفار أحمد، نصر عبد العزيز محمد سعد
قسم التخدير والرعاية المرکزة، کلية الطب، جامعة الازهر
E-mail: ahmedasfour551@gmail.com
خلفية البحث: يعد الحصار العصبي المرکزي أحد أهم تقنيات التخدير الموضعي وأکثرها إستخدامًا في جراحات أسفل البطن والعجان والأطراف السفلية. يؤدي إستخدام مجموعة من الأدوية فى التخدير النخاعى التي تستهدف مستقبلات النخاع الشوکي المتعددة إلى تسکين طويل الأمد بجودة عالية. يمکن تحقيق ذلک بترکيزات صغيرة نسبيًا من الأدوية الفردية.
الهدف من البحث: مقارنة فعالية التخدير النخاعى للبيوبيفيکين مقابل بيوبيفيکين ميدازولام على تسکين الألم بعد الجراحة.
المرضى وطرق البحث: أجريت الدراسة على 60 مريضاً تم إدخالهم إلى المستشفى لإجراء جراحات اختيارية أسفل البطن والعجان والأطراف السفلية، وتم تقسيمهم الى مجموعتين متساويتين: مجموعة البيوبيفيکين (أ) ومجموعة البيوبيفيکين ميدازولام (ب). وقد أجريت الدراسة في مستشفيات جامعة الأزهر بالقاهرة فى الفترة ما بين أغسطس 2019 إلى يوليو 2020.
نتائج البحث: کانت مدة التسکين بعد الجراحة أطول في مجموعة البيوبيفکين ميدازولام (152.5 ± 20.44 دقيقة) مقارنة بمجموعة البيوبيفيکين فقط (120.0 ± 31.54 دقيقة)، ولکن بداية فقدان الإحساس کانت (1.55 ± 0.48 دقيقة) في مجموعة البيوبيفيکين فقط و(1.56 ± 0.55 دقيقة) في مجموعة البيوبيفيکين ميدازولام، ولا يوجد فرق معتد به إحصائياً في المجموعتين فيما يتعلق ببداية فقدان الحرکة، ومدة فقدان الحرکة، والتأثيرعلى الغثيان والقيء بعد العملية الجراحية.
الإستنتاج: أدت إضافة الميدازولام إلى البيوبيفيکين في التخدير النخاعي إلى تسکين طويل الأمد بعد العملية الجراحية مع عدم وجود زيادة کبيرة فى مدة التوقف الحرکى.
الکلمات الدالة : تحت الأم العنکبوتية – بيوبيفيکينى – ميدازولام – تسکين الألم بعد الجراحة .
REFERENCES
10. Stuart, P. (2011): Novel additives to neuraxial blockade. Southern African Journal of Anaesthesia and Analgesia, 17(1): 86-89.
11. Tesfaye, S., Boulton, A. J. and Dickenson, A. H. (2013): Mechanisms and management of diabetic painful distal symmetrical polyneuropathy. Diabetes care, 36(9): 2456-2465.