|Year : 2023 | Volume
| Issue : 2 | Page : 113-120
Comparison of intrathecal bupivacaine with different doses of clonidine for spinal anesthesia in adults: A systematic review
Sangeetha Dattatri1, SB Hareesh2, Devanahalli V Ashokanand3
1 Department of Anaesthesia, Institute of Nephrourolog, Fortis Hospital, Bengaluru, Karnataka, India
2 Department of Anaesthesia, Institute of Nephrourology, Fortis Hospital, Bengaluru, Karnataka, India
3 Department of Anaesthesia, Fortis Hospital, Bengaluru, Karnataka, India
|Date of Submission||31-Dec-2022|
|Date of Decision||28-Feb-2023|
|Date of Acceptance||11-Mar-2023|
|Date of Web Publication||18-Apr-2023|
#18/1, First Cross, Gavi Puram Extension, Bengaluru - 560 019, Karnataka
Source of Support: None, Conflict of Interest: None
Background: Evaluating the optimal dose of intrathecal clonidine adjuvant has a great impact on day-to-day practice of anesthesia, as spinal anesthesia is one of the most commonly performed anesthetic procedure.
Objectives: Evaluate for the minimal dose of intrathecal clonidine as an adjunct to bupivacaine heavy for spinal anesthesia that can produce optimal sensory and motor blockade with minimal hemodynamic effects.
Methods: Randomized control trials carried out on adult patients, of both genders undergoing elective infraumbilical surgeries under spinal anesthesia with bupivacaine heavy and different doses of clonidine having ethical committee approval were included and articles published in non-English languages were excluded. Databases (PubMed and Google Scholar) and websites of the Indian Journal of Anaesthesia and anesthesia essays and researches journals were systematically searched and interpreted in accordance with the PRISMA guidelines. Quality assessment was done using the Risk of Bias assessment 2.O tool. The mean time taken for the onset of sensory and motor blockade, mean duration of sensory and motor blockade and significant adverse effects were the key outcome variables. Nonstatistical synthesis of quantitative data of the selected articles was done.
Results: The efficacy in terms of sensory and motor blockade was comparatively more with 1 μg/kg of intrathecal clonidine than with lower doses, however, cardiovascular adverse effects were dose-dependent, with 15 μg intrathecal clonidine causing least cardiovascular disturbance.
Conclusion: 15–30 μg intrathecal clonidine as an adjunct to bupivacaine heavy would produce optimal sensory and motor block with minimal hemodynamic disturbances.
Keywords: Intrathecal, bupivacaine heavy, clonidine
|How to cite this article:|
Dattatri S, Hareesh S B, Ashokanand DV. Comparison of intrathecal bupivacaine with different doses of clonidine for spinal anesthesia in adults: A systematic review. MRIMS J Health Sci 2023;11:113-20
|How to cite this URL:|
Dattatri S, Hareesh S B, Ashokanand DV. Comparison of intrathecal bupivacaine with different doses of clonidine for spinal anesthesia in adults: A systematic review. MRIMS J Health Sci [serial online] 2023 [cited 2023 Oct 4];11:113-20. Available from: http://www.mrimsjournal.com/text.asp?2023/11/2/113/374278
| Introduction|| |
Spinal anesthesia is a commonly performed procedure, in which local anesthetics are routinely used. However, they fail to provide long-lasting analgesia, requiring early supplementation., Adjuvants like opioids are in use to extend the period of analgesia. Clonidine, an imidazole compound and a selective agonist of α2-Adrenoreceptor, acts by blocking pain conduction in C and Aδ fibers, spinal and supraspinal areas. Different doses of clonidine ranging from 15 to 200 μg has been studied as an intrathecal adjunct.,,,,,, Wide variation in the dose range of clonidine is associated with different ranges of effectiveness and adverse effect profile. We evaluated the minimum dose of clonidine adjunct that would produce optimal efficacy and minimal hemodynamic effects.
Evaluate for the minimal dose of intrathecal clonidine as an adjunct to bupivacaine heavy for spinal anesthesia, that can produce optimal sensory and motor blockade with minimal hemodynamic effects.
The research question was described using PICO framework. P – Population was adults patients posted for elective infraumbilical surgeries; I – Intervention was spinal anesthesia with bupivacaine heavy and clonidine adjunct; C – Comparison was drawn between different doses of intrathecal clonidine; O – Outcome variable assessed were onset and duration of sensory and motor blockade, hypotension, and bradycardia.
| Methods|| |
The systematic review was done in accordance with the PRISMA guidelines.
Eligibility criteria – Inclusion criteria were – Study design being a randomized controlled trial, adult patients (18–60 years), both genders, patients undergoing elective infraumbilical surgeries under spinal anesthesia with bupivacaine and different doses of clonidine having ethical committee approval and written informed consent, articles on human trials, Studies in the English language, full-text open access articles with creative commons attribution license were included in the study. Exclusion criteria were cesarean section, intrathecal adjuvants other than Clonidine, Unpublished manuscripts, Conference proceedings, abstracts, letters, and commentaries. Information sources – A predefined search of databases (PubMed and Google Scholar) and website of the Indian Journal of Anaesthesia (https://journals.lww.com > ijaweb > pages) and anesthesia essays and researches journals (https://www.aeronline.org/) was done. Search strategy was based on the subject heading and Keywords. The keywords like intrathecal clonidine, bupivacaine heavy, spinal anesthesia were combined using Boolean operators such as “AND” and upper-case letters. The articles published from inception till November 9, 2022, were searched.
Data collection process
Two reviewers collected data from each selected report independently. Disagreements about study selection, data collection, and assessment were resolved by discussion with the third reviewer. The conclusions were drawn by corresponding author by mutual consensus after discussion among all reviewers. EndNote X9 software was used to search, store, organize, and de-duplicate the citations. No automation tools were used to collect data. Articles published in the English language were only selected and hence no translation was required. PRISMA 2020 flow diagram template for new systematic reviews, which included searches of the databases, registers, and other sources was used to map out number of records identified, included, and excluded.
Data items were as follows primary outcomes: onset of sensory and motor blockade, duration of sensory and motor blockade, secondary outcomes: Hypotension and bradycardia. patient's baseline characteristics: Sample size, age, type of surgery, American Society of Anesthesiologists grading, gender, height, weight, details of interventions: Premedication, preloading, site of intrathecal injection, drugs used for spinal anesthesia were assessed.
Data extraction table was completed using above-mentioned data items. Only outcome variables relevant to our study were collected when multiple outcomes had been enumerated in the study.
Risk of bias assessment
The methodological quality of the study was assessed independently by two authors using Cochrane collaboration's Risk of Bias assessment tool (ROB 2.O) across all the five domains, independently for each study. The domains studied for ROB were D1 – Bias arising from randomization process, D2 – Bias due to deviation from intended intervention, D3 – Bias due to missing outcome data, D4 – Bias in measurement of outcome, D5 – Bias in selection of reported result. After independently assessing the ROB for each study across all five domains, a summary was drawn. The summary of the ROB was represented using a table and robvis (visualization tool). Robvis visualization tool is a web application designed for visualizing ROB in systematic reviews to judge the distribution of the ROB across individual domain.
Synthesis of results
Studies which were eligible for synthesis were tabulated with relevant intervention characteristics and compared. In case of missing data in a study, the available data in other studies only were interpreted. No specific measures were taken to assess ROB due to missing results in a synthesis. Tabular structures and pictorial presentation of data were used to display the results. A nonstatistical synthesis of quantitative data from the selected articles was done. The key outcome variables were categorized into primary and secondary outcomes. Primary outcomes were mean time taken for the onset of sensory and motor blockade and mean duration of sensory and motor blockade. Secondary outcomes were hypotension and bradycardia. The outcomes were organized on an Excel sheet and linked with narrative text to draw conclusions.
| Results|| |
Thirty-three citations from databases and 218 citations from websites were identified using the predetermined search strategy. Thirty citations from databases and 215 citations from websites were excluded due to various reasons such as the inclusion of study population such as elderly and pediatric age groups; surgeries performed included cesarean section; surgeries performed were under general anesthesia; other routes of administration of clonidine such as oral, intravenous, epidural, peripheral nerve blocks were used; comparative groups included other additives such as fentanyl, dexmedetomidine, midazolam, and neostigmine different baricity of bupivacaine was used such as hypo and isobaric bupivacaine. Other reasons included were presence of duplicates, inability to retrieve full text of articles, and lack of creative commons license. Six studies were selected for final analysis after the exclusion of ineligible articles, due to various reasons as explained above. [Figure 1] The total number of study subjects was 420. Sample size across studies ranged from 50 to 100. The quality of the study as assessed by the Cochrane ROB 2.O showed low ROB across all domains. There were some concerns in the measurement of the outcome and reported result in one study. However, the overall ROB was low risk (80%) [Figure 2] and [Figure 3] and [Table 1].
|Figure 1: PRISMA flow chart for study selection. *Reasons for exclusion were as follows: study population included elderly and paediatric age groups; surgeries performed included caesarean section; surgeries performed under general anaesthesia; other routes of administration of clonidine was used such as oral, intravenous, epidural, peripheral nerve blocks; comparative groups included other additives such as fentanyl, dexmedetomidine, midazolam, neostigmine, etc.; different baricity of bupivacaine were used such as hypo and isobaric bupivacaine; lack of creative common license; presence of duplicates were excluded, **Reasons for exclusion were as follows: Study population included elderly and paediatric age groups; surgeries performed included caesarean section; surgeries performed under general anaesthesia; other routes of administration of clonidine were used such as oral, intravenous, epidural, for peripheral nerve blocks; comparative groups included other additives such as fentanyl, dexmedetomidine, midazolam, neostigmine, etc.; different baricity of bupivacaine were used such as hypo and isobaric bupivacaine and duplicates were excluded, ***Full text could not be retrieved|
Click here to view
The selected 6 studies were randomized control trials with patient's mean age ranging from 18 to 60 years. The gender distribution was matched in all studies. The type of surgeries conducted were total abdominal hysterectomy, myomectomy, Manchester repair, inguinal herniorrhaphy, elective lower abdominal surgeries, and lower limb surgeries. All of which were conducted under spinal anesthesia. Preloading was done with 10–20 ml/kg of lactated ringer in all studies. Intrathecal bupivacaine heavy 0.5% was considered as the control group in all but one study in which parallel comparative groups were different doses of clonidine (15 μg and 30 μg, respectively) as an adjunct to bupivacaine heavy. The dose of intrathecal bupivacaine heavy ranged from 11 mg to 15 mg. The study groups were administered different doses of clonidine with bupivacaine heavy ranging from 15, 30, 50 to 1 μg/kg [Table 2] and [Table 3]. Outcomes among trials: The reviewed trials reported several outcomes. Outcomes relevant to our review have been described [Table 4] and [Table 5].
Onset of sensory blockade
Four studies assessed the onset of sensory blockade. There was no significant difference with respect to onset of sensory block between 15 and 30 μg of clonidine and bupivacaine heavy alone. The onset of sensory block was defined as the time between intrathecal injection of anesthetic to the absence of pain at T8–9 dermatomes two studies., Peak onset of sensory block defined as onset of sensory blockade in other two studies.,, Onset of sensory blockade was faster with 1 μg/kg clonidine group.
Onset of motor blockade
Three studies assessed the onset of motor blockade. The modified Bromage Scale was used to define motor block. The onset of motor block was defined as time taken to achieve maximum Bromage scale,, and as Bromage scale of three, There was no significant difference in the onset of motor block between 15 and 30 μg of intrathecal clonidine adjunct to bupivacaine heavy but was faster with 1 μg/kg clonidine group than the control group.
Duration of sensory blockade
All studies assessed the duration of sensory blockade. The duration of sensory blockade was defined as duration of analgesia,, time to first analgesic request, and time of regression of two segment block height.,, We observed that the duration of sensory block increased with increasing dose of intrathecal clonidine from 15–30 to 50 μg and 1 μg/kg, except in one study which did not show a significant difference between 15 and 30 μg group.
Duration of motor blockade
Four studies assessed the duration of motor blockade. It was similarly defined in all the groups. We observed that the duration of motor block increased with increase in the dose of intrathecal clonidine from 15–30 to 50 μg and 1 μg/kg except in one study which did not show significant difference between 15 and 30 μg group.
Hypotension observed in 1 μg/kg clonidine group was more frequent and persistent for a longer duration after the procedure. More episodes of hypotension occurred in 30 μg group than 15 μg clonidine group.
Bradycardia with 1 μg/kg clonidine was more prolonged and persistent. It was observed that 15 μg intrathecal clonidine does not cause much bradycardia compared to 30 μg intrathecal clonidine.
Dealing with missing data
A detailed explanation of allocation concealment was missing in a few studies, where the assumption of high probability of performance was done. Few outcomes were not measured in some studies. In such cases, relevant outcomes were drawn from the studies which assessed the required outcomes. No specific measures were taken to assess ROB due to missing results in a synthesis (arising from reporting biases).
| Discussion|| |
Chiari et al. observed the effect of clonidine in labor analgesia. He observed that as the dose increased from 50 to 200 μg, analgesic effect improved at the cost of a high incidence of hypotension. Niemi reported that the prolonged sensory block produced by 3 μg/kg of clonidine adjuvant to bupivacaine was comparable to 1 μg/kg, with greater hemodynamic effects. Bajwa et al. noted that heart rate remained stable with 45 μg of clonidine adjuvant. while Klimscha et al. observed significant bradycardia with 150 μg Clonidine adjuvant. De Kock et al. suggested that a dose of 15–45 μg of clonidine adjuvant would provide adequate supplementation.
The present study included six randomized controlled trials. We reviewed the effectiveness and hemodynamic effects of clonidine in varying doses as spinal anesthesia adjuvant. All included studies were methodologically homogenous.
Our review suggests that irrespective of variously defined study outcomes, the onset of sensory block was faster with intrathecal clonidine of 1 μg/kg with bupivacaine compared to bupivacaine heavy alone. There was no significant difference with respect to the onset of sensory block between 15 and 30 μg of intrathecal clonidine. Duration of sensory block was prolonged significantly in a dose-dependent manner from 15–30 to 50 μg and 1 μg/kg, except in one study which did not show a significant difference between 15 and 30 μg group. The onset of motor blockade was faster with 1 μg/kg clonidine group than the control group. There was no significant difference in onset of motor block between 15 and 30 μg of intrathecal clonidine adjunct. Duration of motor blockade increased with increase in the dose of intrathecal Clonidine ranging from 15–30 to 50 μg and 1 μg/kg group, except in one study which did not show a significant difference between 15 and 30 μg group.
We observed that 15 μg intrathecal clonidine does not cause significant bradycardia compared to 30 μg intrathecal clonidine. Fall in heart rate in 50 μg clonidine is like bupivacaine heavy alone. However, 1 μg/kg clonidine causes more prolonged and persistent bradycardia. It was observed that hypotension was more persistent and prolonged with 1 μg/kg clonidine group and more episodes of hypotension occurred in 30 μg clonidine group than 15 μg clonidine group.
To summarize, 1 μg/kg and 50 μg intrathecal clonidine adjunct provide a longer duration of sensory and motor blockade with persistent hypotension and bradycardia. 15 μg clonidine provides almost similar sensory blockade to 30 μg clonidine; shorter duration of motor blockade than 30 μg clonidine with fewer episodes of bradycardia and hypotension. The onset of sensory and motor blockade was faster with 1 μg/kg intrathecal clonidine adjunct to bupivacaine heavy.
Limitations of the review were un-uniformly defined study outcomes, incomplete reporting of study outcomes, and use of different volumes and concentrations of bupivacaine heavy with different doses of clonidine. Considering the heterogeneity of the studies statistical analysis was not done.
| Conclusion|| |
The effectiveness of 1 μg/kg of intrathecal clonidine as an adjunct to bupivacaine heavy was comparatively more than 15 μg, 30 μg, and 50 μg groups, at the cost of persistent cardiovascular adverse effects. Cardiovascular adverse effects were dose dependent, with 15 μg intrathecal clonidine causing the least cardiovascular disturbance. 15–30 μg intrathecal clonidine as an adjunct to bupivacaine heavy would produce optimal sensory and motor block with minimal hemodynamic disturbances. We would like to conclude that depending on the requirements of sensory and motor blockade specific to the surgery and the patient's cardiovascular profile, choice of the intrathecal dose of clonidine should be made judiciously.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
Registration: This study is registered with Open Science Forum Registry on November 01, 2022. (https://osf.io/registries)
| References|| |
David LB. Spinal, epidural and caudal anesthesia. In: Miller RD, editor. Miller's Anesthesia. 6th
ed. Vol. 2. Philadelphia: Churchill Livingstone; 2005. p. 1653-83.
Collins VJ, editor. Local anesthetics. In: Principles of Anesthesiology. 3rd
ed. Vol. 2. Philadelphia: Lea and Febiger; 1993. p. 1232-81.
Shetty PS, Picard J. Adjuvant agents in regional anaesthesia. Anaesth Intensive Care Med 2006;7:407-10.
Chiari A, Eisenach JC. Spinal anesthesia: Mechanisms, agents, methods, and safety. Reg Anesth Pain Med 1998;23:357-62.
Eisenach JC, De Kock M, Klimscha W. Alpha (2)-adrenergic agonists for regional anesthesia. A clinical review of clonidine (1984-1995). Anesthesiology 1996;85:655-74.
Sethi BS, Samuel M, Sreevastava D. Efficacy of analgesic effects of low dose intrathecal clonidine as adjuvant to bupivacaine. Indian J Anesth 2007;51:415.
Chiari A, Lorber C, Eisenach JC, Wildling E, Krenn C, Zavrsky A, et al
. Analgesic and hemodynamic effects of intrathecal clonidine as the sole analgesic agent during first stage of Labor: A dose-response study. Anesthesiology 1999;91:388-96.
Niemi L. Effects of intrathecal clonidine on duration of bupivacaine spinal anaesthesia, haemodynamics, and postoperative analgesia in patients undergoing knee arthroscopy. Acta Anaesthesiol Scand 1994;38:724-8.
Filos KS, Goudas LC, Patroni O, Polyzou V. Intrathecal clonidine as a sole analgesic for pain relief after cesarean section. Anesthesiology 1992;77:267-74.
Bajwa SJ, Bajwa SK, Kaur J, Singh A, Singh A, Parmar SS. Prevention of hypotension and prolongation of postoperative analgesia in emergency cesarean sections: A randomized study with intrathecal clonidine. Int J Crit Illn Inj Sci 2012;2:63-9. [Full text]
Klimscha W, Chiari A, Krafft P, Plattner O, Taslimi R, Mayer N, et al
. Hemodynamic and analgesic effects of clonidine added repetitively to continuous epidural and spinal blocks. Anesth Analg 1995;80:322-7.
De Kock M, Gautier P, Fanard L, Hody JL, Lavand'homme P. Intrathecal ropivacaine and clonidine for ambulatory knee arthroscopy: A dose-response study. Anesthesiology 2001;94:574-8.
da Costa Santos CM, de Mattos Pimenta CA, Nobre MR. The PICO strategy for the research question construction and evidence search. Rev Lat Am Enfermagem 2007;15:508-11.
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al
. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ 2021;372:n71.
Thakur A, Bhardwaj M, Kaur K, Dureja J, Hooda S, Taxak S. Intrathecal clonidine as an adjuvant to hyperbaric bupivacaine in patients undergoing inguinal herniorrhaphy: A randomized double-blinded study. J Anaesthesiol Clin Pharmacol 2013;29:66-70.
] [Full text]
Arora R, Pandey V, Sodhi GS, Mohindra BK. A comparative study of intrathecal bupivacaine and bupivacaine with different doses of clonidine in lower limb surgeries. Anesth Essays Res 2018;12:412-6.
] [Full text]
Tyagi A, Rastogi S, Tripathi M, Bhandari R, Bais PS, Singh M. Effect of intrathecal hyperbaric bupivacaine with small dose clonidine versus hyperbaric bupivacaine alone in lower abdominal surgeries: A comparative study. Anesth Essays Res 2016;10:195-200.
] [Full text]
Singh RB, Chopra N, Choubey S, Tripathi RK, Prabhakar , Mishra A. Role of Clonidine as adjuvant to intrathecal bupivacaine in patients undergoing lower abdominal surgery: A randomized control study. Anesth Essays Res 2014;8:307-12. [Full text]
Yallapragada SV, Vemuri NN, Shaik MS. Effect of adding clonidine to intrathecal bupivacaine on the quality of subarachnoid block: A prospective randomized double-blind study. Anesth Essays Res 2016;10:451-4.
] [Full text]
Yentis SM, Lucas DN, Brigante L, Collis R, Cowley P, Denning S, et al
. Safety guideline: Neurological monitoring associated with obstetric neuraxial block 2020: A joint guideline by the association of anaesthetists and the obstetric anaesthetist's association. Anaesthesia 2020;75:913-9.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]