Services on Demand
Print version ISSN 0034-7094
Rev. Bras. Anestesiol. vol.51 no.6 Campinas Dec. 2001
Effects of combined clonidine and 0.5% hyperbaric bupivacaine on spinal anesthesia*
Efecto de la clonidina asociada a la bupivacaína a 0,5% hiperbárica en la anestesia subaracnóidea
Neuber Martins Fonseca, M.D.I; Clarissa Aires de Oliveira, M.D.II
IProfessor Adjunto de Anestesiologia
do Departamento de Clínica Cirúrgica e Responsável pelo CET-SBA
da Disciplina de Anestesiologia da Faculdade de Medicina da Universidade Federal
de Uberlândia, Membro da Comissão de Normas Técnicas da Sociedade
Brasileira de Anestesiologia
IIAnestesiologista do HC/FAEPU da FMUFU
BACKGROUND AND OBJECTIVES:
Clonidine is an imidazolynic compound which exhibits partial alpha2-receptor
agonist action, with anxiolytic and hypnotic properties. When spinally administered,
it produces selective effects in pain modulation and may prolong surgical anesthesia
and motor block. This study aimed at evaluating the effects of combined clonidine
and 0.5% hyperbaric bupivacaine on spinal anesthesia.
METHODS: Thirth ASA I or II patients off both genders, aged between 16 and 57 years and scheduled to undergo surgical inguinal hernia repair were randomly divided into three groups in this prospective double blind study. After monitoring, patients were sedated with 2 mg venous midazolam 10 minutes before surgery, followed by paramedian spinal puncture (L3-L4) in the left lateral position with a 25G Quincke needle. After CSF confirmation, 1 ml of one of the proposed solutions were injected with 15 mg hyperbaric bupivacaine: Group I - 150 µg clonidine; Group II - 75 µg clonidine + 0.5 ml bi-distilled water; and Group III - 1 ml bi-distilled water. The following parameters were evaluated: sensory block level at 5, 20 and 30 minutes, time for two metamers regression, sedation scores through a 0 to 3 scale, motor block by a modified Bromage's scale, postoperative pain and analgesics requirement.
RESULTS: Demographics and maximum sensory level (mode) were similar for all groups. Anesthesia regression and muscle relaxation were longer for Group I. There were no difference in sedation and hemodynamic parameters between groups. Group I had a prolonged analgesia as compared to other groups, what was confirmed by the less need for analgesics as a function of time.
CONCLUSIONS: Clonidine has not changed cephalad spread and hemodynamic effects of spinal anesthesia with 0.5% hyperbaric bupivacaine. However, it has promoted better analgesia during the four hours observed after blockade and a prolonged anesthesia.
Key Words: Analgesics: Clonidine; ANESTHETICS, Local: bupivacaine; ANESTHETIC TECHNIQUES, Regional: spinal block
JUSTIFICATIVA Y OBJETIVOS:
La clonidina es un compuesto imidazolínico agonista parcial de los receptores
a2-adrenérgicos con propiedades ansiolíticas
e hipnóticas. Administrada en el espacio subaracnóideo produce efectos
selectivos en la modulación del dolor, pudiendo aumentar la duración
de la anestesia quirúrgica y del bloqueo motor. El objetivo del estudio
fue evaluar el efecto de la clonidina asociada a la bupivacaína 0,5% hiperbárica
en la anestesia subaracnóidea.
MÉTODO: Fueron estudiados 30 pacientes de ambos sexos, escalados para herniorrafia inguinal, estado físico ASA I ó II, con edades entre 16 e 57 años, distribuidos aleatoriamente en tres grupos. Después de monitorización, los pacientes fueron sedados con midazolam (2 mg), por vía venosa, 10 minutos antes del procedimiento anestésico, seguido de punción subaracnóidea, L3-L4, paramediana, con aguja Quincke 25G, en decúbito lateral izquierdo. Después de la salida del LCR se inyectó 1 ml de una de las soluciones propuestas de acuerdo con el grupo estudiado juntamente con 15 mg de bupivacaína hiperbárica: Grupo I - 150 µg de clonidina, Grupo II - 75 µg de clonidina + 0,5 ml de agua bidestilada y Grupo III - 1 ml de agua bidestilada. Fueron evaluados el nivel del bloqueo con 5, 20 e 30 minutos, tiempo para regresión de dos metámeros, sedación por la escala de 0 a 3, bloqueo motor por la escala modificada de Bromage, dolor pós-operatorio y necesidad de analgésico.
RESULTADOS: Hubo uniformidad de los datos antropométricos en los grupos. El nivel del bloqueo anestésico (moda) en los pacientes estudiados fue uniforme en los grupos. La regresión de la anestesia fue retardada en el grupo I, así como el relajamiento muscular, en relación a los otros grupos. No hubo diferencia en relación a la sedación y a los parámetros hemodinámicos entre los grupos. El grupo I presentó analgesia prolongada en relación a los demás grupos, confirmado por la menor necesidad de analgésicos en función del tiempo.
CONCLUSIONES: La clonidina no alteró la dispersión cefálica y los efectos hemodinámicos del bloqueo subaracnóideo con bupivacaína a 0,5% hiperbárica; sin embargo, fue efectiva en una mejor analgesia observada con cuatro horas después del bloqueo, bien como prolongó el tiempo de anestesia.
Clonidine is an imidazolynic compound with partial alpha2-receptor agonist action, exhibiting anxiolytic and hypnotic properties1. It was first introduced in the clinical practice as a nose decongestive and then as an anti-hypertensive drug. Its further use in anesthesia was dictated by its sedative, hypnotic and analgesic effects, both in preanesthetic medication and in general or spinal anesthesias2-5.
Spinal clonidine produces intense and selective effects, with the activation of a2 post-synaptic receptors of noradrenergic descending pathways and of cholinergic neurons. It plays an important role in pain modulation by inhibiting nervous conduction through Ad and C fibers and by activating gray matter a2-adrenoreceptors in the dorsal spinal cord1,3-7, thus prolonging intrathecal local anesthetic effect8-11.
Previous studies have shown that clonidine seems to prolong surgical anesthesia and motor block, as well as to improve anesthetic blockade quality, showing also a sedative activity and promoting postoperative analgesia, specially when associated to opioids3,11. Other studies, however, have not shown longer spinal anesthesia with clonidine association, what makes this subject still controversial12,13.
This study aimed at evaluating the effects of combined clonidine and 0.5% hyperbaric bupivacaine on spinal anesthesia.
After Hospital de Clínicas da Faculdade de Medicina, Uberlandia';s, committee approval, 30 ASA I or II patients of both genders, aged between 16 and 57 years and scheduled to undergo surgical inguinal hernia repair were randomly allocated into three groups following their written informed consent. Exclusion criteria were refusal to the blockade or to take part of the study, neurological, cardiopulmonary, liver-kidney and psychiatric diseases, or drug abusers.
No patient was premedicated. In the operating room, perioperative monitoring consisted of cardioscope at DII lead, sphygmomanometer for blood pressure control by Riva-Rocci's method with measurements at 5-minute intervals and pulse oximetry with continuous oxygen saturation readings. Hydration was performed with lactated Ringer's through a venous 18G catheter in an upper limb vein.
After 10 minutes of 2 mg venous midazolam sedation, spinal anesthesia was performed with the patient in the left lateral position, in L3-L4 interspace, with a 25G Quincke needle with no local anesthetic infiltration. After subarachnoid space identification, one of the proposed solutions was injected by the anesthesiologist,unaware of its nature, according to the studied group:
Group I - 150 µg clonidine
Group II - 75 µg clonidine + 0.5 ml bi-distilled water
Group III - 1 ml bi-distilled water
After the proposed solution administration in each group, prepared in 1 ml syringes, all patients received 15 mg hyperbaric bupivacaine and were immediately positioned in the supine position. All patients received the same volume in the subarachnoid space, that is, 1 ml of the proposed solution plus 3 ml of the anesthetic solution in separate syringes.
Block level was evaluated by skin pinprick at 5, 20 and 30 minutes after anesthetic injection, being registered the reached metamer at each point.
Time for 2 metamer regression was evaluated 60 minutes after puncture and at every 10 minutes after, until the exact regression time was defined.
Sedation was evaluated by Filos et al. modified numeric scale4 at 30, 60, 120 and 240 minutes. According to this scale, zero = patient awaken and oriented, 1 = drowsiness, 2 = patient sleeping but easily awakened, 3 = patient deeply asleep and hard to awake.
Motor block was evaluated by Bromage's14 modified scale (0 = complete block, 1 = feet movement, 2 = knees bending, 3 = absence of blockade) at 90, 105, 120, 135, 150 and 240 minutes after anesthesia performing.
Pain was evaluated by the following questions:
1. Is there pain or not?
2. If there is pain, how is it:
After surgery patients were referred to PACU and were evaluated by the same anesthesiologist who performed the blockade and was blind to the studied group. Patients remained in PACU until total motor and sensory block recovery.
Analgesics were administered only after spontaneous request by the patient and postoperative pain intensity was also evaluated.
Friedman's15,16 analysis of variance by posts was used to evaluate systolic and diastolic blood pressure results within groups.
Analysis of variance for non independent groups17 was used to evaluate heart rate and was complemented by Tukey's contrasts test when significant differences were detected. Kruskal-Wallis test15,16 was applied to confirm the existence of significant differences between groups by comparing data at each moment measurements were made. Student's t test was applied to compare two samples with interval or reason scale data. Motor block, blockade level, pain and sedation scores do not need statistical analysis because data are presented in nominal scale. For all tests, 5% was established as the level for null hypothesis rejection and significant values are highlighted by a star (*).
Demographic data were homogeneous between groups, as shown in table I.
Anesthetic blockade levels (mode) were uniform between groups, as shown in table II.
Table III shows a significant difference in group I, with longer anesthesia regression time, as compared to other groups.
Table IV shows motor block uniformity between groups and anesthetic motor block regression, according to Bromage's modified scale14. Motor regression was shorter in group III. There was no significant difference in sedation between groups, as shown in table V.
Table VI shows that group I patients had prolonged analgesia as compared to other groups. This was also confirmed by the lesser need for analgesics as a function of time: 321 ± 76, 284 ± 102 and 206 ± 45 minutes, respectively for Groups I, II and III.
Figure 3 compares heart rates between groups, with no significant difference.
Clonidine, an a2-adrenergic agonist, has been extensively studied as an anesthetic adjuvant, which promotes sedation2,18, reduces hemodynamic responses to laryngoscopy and tracheal intubation2,19, improves perioperative hemodynamic stability2,20 and decreases analgesics2,21 and volatile anesthetics requirements2,22. When spinally injected, it has no motor block properties and seems to decrease local anesthetics vascular absorption by reducing spinal blood flow, thus prolonging local anesthetics blockade, as confirmed by this study. This effect is probably due to a direct action of clonidine blocking Ad and C fibers stimuli conduction, increasing potassium conductance in isolated neurons and intensifying local anesthetics conduction block, as well as indirectly decreasing their absorption by a vasoconstrictor effect mediated by a2 post-synaptic receptors1,2.
Clonidine action in prolonging spinal anesthesia is not uniform and still controversial3-6,8,9,23,24. Brunschwiler et al.25 have shown an increase in surgical anesthesia time with the spinal administration of 0.15 mg clonidine associated to bupivacaine, fact confirmed by our study and by some authors3,26-30, but not by others31,32, especially when administered as oral premedication6,12,13,31. It is possible that spinal clonidine promotes higher local anesthetics concentrations in the central nervous system, thus prolonging the sensory and motor blocks. This effect would possibly be related to a higher side-effect rate shown by some authors13, but not confirmed by this study or by other authors3,6. As to analgesic and motor block onset, our results are in line with other studies12,13,29,30, which obtained similar results with spinal clonidine.
Clonidine's hemodynamic effects, usually hypotension and bradycardia, result from the activation of a2 pre-synaptic receptors of peripheral nervous terminations, as well as from its action on brain stem and spinal cord, decreasing sympathetic outflow1,14,33,34. Peripheral activation of a2 receptors, which inhibit norepinephrine's exocytosis, partially explains clonidine-induced hypotension and bradycardia30-32. Central activation of a2 receptors in the vasomotor center decreases sympathetic outflow and circulating catecholamines, which together with the exacerbation of parasympathetic activity, induces blood pressure decrease35,36. Our study has not shown significant hemodynamic differences between groups, probably due to the doses used, what was different from other findings30,32.
Clonidine's analgesic action is due to its ability to promote central sensitization produced by repeated stimulation of afferent C fibers, resulting in central release of P substance, A neurokinine, glutamate and aspartate which, once released, may act on AMPA, NMDA and metabotrophic receptors, preventing spinal cord central facilitation and synaptic plasticity phenomena37,38. These effects were confirmed in this study by the lower pain level in patients receiving spinal clonidine, and also in agreement with another study23.
In the conditions of our study, one may conclude that clonidine has not changed cephalad spread and hemodynamic effects of spinal anesthesia with hyperbaric bupivacaine; it was however effective in improving analgesia observed until the fourth hour after the blockade, as well as in prolonging anesthesia duration, being therefore useful as a coadjuvant of spinal blocks with hyperbaric bupivacaine.
01. Bernard JM, Quintin L, Pinaud M - Clonidine: du traitement de I´hipertension artérielle à I´utilisation en aneasthésie. II: Utilisation périopératorie. Ann Fr Anesth Réanim, 1990;9:423-432. [ Links ]
02. Eisenach JC - a2-adrenergic agonists in anesthesia practice. ASA Refresher Courses in Anesthesiology, 1999;25:55-62. [ Links ]
03. Racle JP, Benkhadra A, Poy JY et al - Prolongation of isobaric bupivacaine spinal anesthesia with epinephrine and clonidine for hip surgery in the elderly. Anesth Analg, 1987;66:442-446. [ Links ]
04. Filos KS, Goudas LC, Patroni O et al - Intrathecal clonidine as a sole analgesic for pain relief after cesarean section. Anesthesiology, 1992;77:267-274. [ Links ]
05. Chiari A, Lorber C, Eisenach JC et al - Analgesic and hemodynamic effects of intrathecal clonidine as the sole analgesic agent during first stage of labor. Anesthesiology, 1999;91:388-396. [ Links ]
06. Yaksh TL, Reddy SVR - Studies in the primate on the analgesic effects associated with intrathecal action of opiates, alpha adrenergic agents and baclofen. Anesthesiology, 1981;59: 743-750. [ Links ]
07. Yaksh TL - Pharmacology of spinal adrenergic systems which modulate spinal nociceptive processing. Pharmacol Biochem Behav, 1985;22:845-858. [ Links ]
08. Racle JP, Benkhadra A, Poy JY et al - Prolongation of isobaric bupivacaine spinal anesthesia with epinephrine and clonidine for hip surgery in the elderly. Anesth Analg, 1987;66:442-446. [ Links ]
09. Bonnet F, Brun-Buisson V, Saada M et al - Dose-related prolongation of hyperbaric tetracaine spinal anesthesia by clonidine in humans. Anesth Analg, 1989;68:619-622. [ Links ]
10. Nishikawa T, Dohi S - Clinical evaluation of clonidine added to lidocaine solution for epidural anesthesia. Anesthesiology, 1990;73:853-859. [ Links ]
11. Mogensen T, Eliasen K, Ejlersen E et al - Epidural clonidine enhances postoperative analgesics from a combined low-dose epidural bupivacaine and morphine regimen. Anesth Analg, 1992;75:607-610. [ Links ]
12. Bonnet F, Buisson V, Francois Y et al - Effects of oral and subarachnoid clonidine on spinal anesthesia with bupivacaine. Reg Anesth, 1990;15:211-214. [ Links ]
13. Ota K, Namiki A, Iwasaki H et al - Dose-related prolongation of tetracaine spinal anesthesia by oral clonidine in humans. Anesth Analg, 1994;79:1121-1125. [ Links ]
14. Bromage PR - A comparation of the hydrochloride and carbon dioxide salts of lidocaine and prilocaine in epidural analgesia. Acta Anaesthesiol Scand, 1965;16:55-59. [ Links ]
15. Spiegel S - Estadística no Paramétrica Aplicada a las Ciencias de la Conducta, 2ª Ed, México, Editorial Trilas, 1975;346. [ Links ]
16. HollanderM, Wolfe DA - Nonparametric Statistical Methods. New York, John Wiley & Sons, 1973;503. [ Links ]
17. Sokal RR, Rohlf FJ - Biometry. San Francisco, WH Freeman and Company, 1969;776. [ Links ]
18. Maze M, Tranquilli W - a2 Adrenergic agonists: defining the role in clinical anaesthesia. Anesthesiology, 1991;74:581-605. [ Links ]
19. Pouttu J, Scheinin B, Rosenberg PH et al - Oral premedication with clonidine: effects on stress responses during general anaesthesia. Acta Anaesthesiol Scand, 1987;31:730-734. [ Links ]
20. Segal IS, Jarvis DJ, Ducan SR et al - Clinical efficacy of oral-transdermal clonidine combination during the perioperative period. Anesthesiology, 1987;74:220-225. [ Links ]
21. Ghignome M, Quintin L, Duke PC et al - Effects of clonidine on narcotics requirements and hemodynamic response during induction of fentanyl anesthesia and endotracheal intubation. Anesthesiology, 1986;64:36-42. [ Links ]
22. Ghignome M, Calvillo O, Quintin? - Anesthesia and hypertension: the effects of clonidine on preoperative hemodynamics and isoflurane requirements. Anesthesiology, 1987;67:3-10. [ Links ]
23. Eisenach JC, Hood DD, Cury RN - Intrathecal clonidine reduces acute pain more than IV clonidine. Reg Anesth Pain Med, 1998;23:3. [ Links ]
24. Fogarty DJ, Carabine UA, Milligan KR - Comparison of the analgesic effects of intrathecal clonidine and intrathecal morphine after spinal anaesthesia in patients undergoing total hip replacement. Br J Anaesth, 1993;71:661-664 [ Links ]
25. Brunschwiler M, Van Gessel E, Foster A et al - Comparison of clonidine, morphine or placebo mixed with bupivacaine during continuous spinal anaesthesia. Can J Anaesth, 1998;45: 735-740. [ Links ]
26. Racle JP, Benkhadra A, Poy JY et al - Prolongation of isobaric bupivacaine spinal anesthesia with epinephrine and clonidine for hip surgery in the elderly. Anesth Analg, 1987;66:442-446. [ Links ]
29. Bonnet F, Brun-Buisson V, Saada M et al - Dose-related prolongation of hyperbaric tetracaine spinal anesthesia by clonidine in humans. Anesth Analg, 1989;68:619-622. [ Links ]
30. Singh H, Liu J, Gaines GY et al - Effect of oral clonidine and intrathecal fentanyl on tetracaine spinal block. Anesth Analg, 1994;79:1113-1116. [ Links ]
31. Alves TCA, Braz JRC, Ganem EM - Influência da medicação pré-anestésica com clonidina sobre a associação de sufentanil e bupivacaína na anestesia subaracnóidea. Rev Bras Anestesiol, 1999;49:320-326. [ Links ]
32. Larsen B, Dorscheid E, Macher-Hanselmann F et al - Does intrathecal clonidine prolong the effect of spinal anesthesia with hyperbaric mepivacaine? Anaesthesit, 1998;47:741-746. [ Links ]
33. De Jonge A, Timmermans PB, van Zweiten PA - Participation of cardiac presynaptic a2-adrenoceptors in the bradycardic effects of clonidine and analogues. Naunyn Schmiedebergs Arch Pharmacol, 1991;137:8-12. [ Links ]
34. Kubo T, Misu Y - Pharmacological characterization on the a-adrenoceptor responsible for a decrease of blood pressure in the nucleus tractus solitaire of the rat. Naunyn Schmiedebergs Arch Pharmacol, 1981;317:120-125. [ Links ]
35. Alves TCA, Braz JR, Vianna PTG - a2-agonistas em anestesiologia: aspectos clínicos e farmacológicos. Rev Bras Anestesiol, 2000;5:396-404. [ Links ]
36. Klimscha W, Chiari A, Krafft P et al - Hemodynamic and analgesic effects of clonidine added repetitively to continuous epidural and spinal blocks. Anesth Analg, 1995;80:322-327. [ Links ]
37. Filos KS, Goudas LC, Patroni O et al - Hemodynamic and analgesic profile after intrathecal clonidine in humans. Anesthesiology, 1994;81:591-601. [ Links ]
38. Carvalho WA, Lemônica L - Mecanismos centrais de transmissão e de modulação da dor. Atualização terapêutica. Rev Bras Anestesiol, 1998;48:221-240. [ Links ]
Correspondence to Submitted for publication March 12, 2001 * Received
from CET/SBA da Faculdade de Medicina da Universidade Federal de Uberlândia
(FMUFU), Uberlândia, MG
Dr. Neuber Martins Fonseca
Address: Rua Antonio Luis Bastos, 300 - Altamira II
ZIP: 38411-116 City: Uberlândia, Brazil
Accepted for publication May 15, 2001
Submitted for publication March 12, 2001
* Received from CET/SBA da Faculdade de Medicina da Universidade Federal de Uberlândia (FMUFU), Uberlândia, MG