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Print version ISSN 0034-7094
Rev. Bras. Anestesiol. vol.54 no.4 Campinas July/Aug. 2004
Epidural clonidine or dexmedetomidine for post-cholecystectomy analgesia and sedation*
Clonidina y dexmedetomidina por vía peridural para analgesia y sedación pós-operatoria de colecistectomía
Antônio Mauro Vieira, TSA, M.D.I; Taylor Brandão Schnaider, M.D.II; Antônio Carlos Aguiar Brandão, TSA, M.D.III; Flávio Aparecido Pereira, M.D.IV; Everaldo Donizeti Costa, M.D.IV; Carlos Eduardo Povoa Fonseca M.D.V
IProfessor Adjunto Doutor
do Departamento de Fisiologia, Morfologia e Patologia. Responsável pela
Disciplina de Farmacologia da Faculdade de Ciências Médicas de Pouso
Alegre, UNIVAS. Co-Responsável pelo CET/SBA de Pouso Alegre, MG
IIProfessor Titular Doutor do Departamento de Clínica Cirúrgica nas Disciplinas de Anestesiologia e Metodologia Científica da FCM de Pouso Alegre, MG - UNIVAS
IIIProfessor Assistente Doutor do Departamento de Fisiologia, Morfologia e Patologia. Responsável pela Disciplina de Biofísica da FCM de Pouso Alegre, UNIVAS. Responsável pelo CET/SBA de Pouso Alegre, MG
IVEx-ME do CET do Serviço de Anestesiologia do HC da FCM de Pouso Alegre, MG
VME2 do CET do Serviço de Anestesiologia do HC da FCM de Pouso Alegre, MG
BACKGROUND AND OBJECTIVES:
Clonidine and dexmedetomidine are a2-adrenergic
agonists with analgesic proprieties which potentiate local anesthetic effects
when epidurally administered. The goal of this study was to evaluate the analgesia
and sedation promoted by clonidine or dexmedetomidine associated to epidural
ropivacaine, in the postoperative period of subcostal cholecystectomy.
METHODS: Forty patients of both gender participated in this randomized double-blind study , aged 18 to 50 years, weighing 50 to 100 kg, physical status ASA I or II, submitted to subcostal cholecystectomy. The subjects were distributed in two groups: Clonidine (CG), receiving clonidine (1 mL = 150 µg) associated to 0.75% epidural ropivacaine (20 mL); Dexmedetomidine (DG), receiving dexmedetomidine (2 µg.kg-1) associated to 0.75% epidural ropivacaine (20 mL). Analgesia and sedation were evaluated 2, 6 and 24 hours anesthetic recovery.
RESULTS: Both groups present some grade of sedation in the moments 2 and 6 hours , with statistically significant difference between the two moments for the dexmedetomidine group. There has been analgesia in both groups, especially at 2 and 6 hours. There have been statistically significant difference among periods of 2, 6 and 24 hours in the dexmedetomidine group; in the clonidine group, this statistically significant difference was observed between the periods of 2 and 6 hours and between 2 and 24 hours.
CONCLUSIONS: Our results allowed to conclude that the association of clonidine or dexmedetomidine to 0.75% ropivacaine induces analgesia and sedation in 2 and 6 hours after anesthetic recovery in patients submitted to subcostal cholecystectomy and that clonidine promotes more prolonged analgesia.
Key Words: ANESTHETICS, Local: ropivacaine; ANESTHETIC TECHNIQUES, Regional: epidural; DRUGS, a2-agonists: clonidine, dexmedetomidine
JUSTIFICATIVA Y OBJETIVOS:
La clonidina y la dexmedetomidina son agonistas alfa2-adrenérgicos
que, cuando administrados por vía peridural, poseen propiedades analgésicas
y potencializan los efectos de los anestésicos locales. La actual pesquisa
objetiva evaluar la analgesia y la sedación causadas por la clonidina o
dexmedetomidina asociadas a la ropivacaína, por vía peridural, en
el pós-operatorio de colecistectomía por vía subcostal.
MÉTODO: Participaron del estudio aleatorio y duplamente encubierto 40 pacientes, de ambos sexos, con edad variando de 18 a 50 años, peso entre 50 y 100 kg, estado físico ASA I y II, sometidos a colecistectomía por vía subcostal, los cuales fueron distribuidos en dos grupos: clonidina (GC), en que fue administrada clonidina (1 ml = 150 µg) asociada a ropivacaína a 0,75% (20 ml) por vía peridural; dexmedetomidina (GD), en que fue inyectada dexmedetomidina (2 µg.kg-1) asociada a ropivacaína a 0,75% (20 ml) por vía peridural. La analgesia y la sedación fueron observadas 2, 6 y 24 horas después del término de la anestesia.
RESULTADOS: Ocurrió sedación después de 2 y 6 horas en ambos grupos, siendo que hubo diferencia estadística significante entre los tiempos de 2 y 6 horas en el grupo dexmedetomidina. Hubo analgesia en ambos grupos, especialmente después de 2 y 6 horas. Fue detectada diferencia estadística significante entre los tiempos de 2, 6 y 24 horas en el grupo dexmedetomidina; en el grupo clonidina esa diferencia estadística significante fue observada entre los tiempos de 2 y 6 horas y entre 2 y 24 horas.
CONCLUSIONES: Los resultados permitieron concluir que la clonidina o la dexmedetomidina asociadas a ropivacaína a 0,75% aseguraron analgesia y sedación en los tiempos de observación de 2 y 6 horas después del término de la anestesia, en los pacientes sometidos a la colecistectomia por vía subcostal y que la clonidina promueve analgesia más prolongada.
Alpha2-receptors are found both in the central and peripheral nervous system and in non-neuronal tissues such as platelets, hepatocytes and smooth muscle cells1, and may be pre or post-synaptic. Pre-synaptic receptors modulate norepinephrine and adenosine triphosphate via inhibitory feedback mechanisms, which inhibit adenyl cyclase and prevent calcium channels opening. So, when these receptors are activated, there is transmitters release inhibition. Post-synaptic receptors, such as those located in vessels smooth muscles, release transmitters when activated1.
Dexmedetomidine, made up of medetomidine's dextrogyrous enantiomer, is currently considered a super-selective a2-adrenergic agonists prototype. Clonidine is 200-folds more selective for alpha2 as compared to alpha1, while dexmedetomidine is 1600-folds more selective for alpha2 receptors. Major dexmedetomidine advantage is its higher selectivity as compared to clonidine, specifically for alpha2A receptors, responsible for hypnotic and analgesic effects of such drugs2-5.
Both clonidine and dexmedetomidine epidural have analgesic properties and potentiate local anesthetic effects6-8.
Pediatrics studies with the association of clonidine and ropivacaine for caudal epidural anesthesia have shown post-operative analgesia improvement as compared to ropivacaine alone, without excessive postoperative sedation9.
A randomized double-blind study with humans submitted to epidural anesthesia with clonidine associated to ropivacaine has led investigators to conclude that there is apparent synergy between clonidine and ropivacaine in this type of regional anesthesia. Clonidine increases analgesic and motor blocks length of ropivacaine's epidural anesthesia and prolongs postoperative analgesia, with increased sedation as additional advantage10.
The aim of this study was to evaluate the post-subcostal cholecystectomy analgesia and sedation induced by clonidine or dexmedetomidine associated to 0.75% epidural ropivacaine.
After the Research Ethics Committee, Universidade do Vale do Sapucaí approval and their informed and written consent, participated in this randomized double-blind study 40 patients of both genders (14 females and 6 males in the clonidine group; 18 females and 2 males in the dexmedetomidine group), aged 18 to 50 years, physical status ASA I and II, submitted to subcostal cholecystectomy under combined lumbar epidural and general anesthesia.
All patients were premedicated with oral diazepam (10 mg) the day before and oral midazolam (15 mg) 40 minutes before surgery. Monitoring in the operating room consisted of ECG, noninvasive blood pressure, pulse oximetry and capnometry. Venous puncture was achieved with 18G catheter and midazolam (5 mg), fentanyl (50 mg) and metochlopramide (10 mg) were infused.
Lumbar epidural anesthesia was induced with patients in the sitting position in L1-L2 interspace with 15G Tuohy needle. The following solutions were randomly administered: 20 mL of 0.75% ropivacaine associated to 1 mL clonidine containing 150 µg in the clonidine group (n = 20) or 20 mL of 0.75% ropivacaine associated to 2 µg.kg-1 dexmedetomidine in dexmedetomidine group (n = 20) at a rate of 1 mL.s-1. After puncture, patients were placed in the supine position.
Anesthesia was induced with etomidate (0.2 mg.kg-1), alfentanil (30 µg.kg-1) and rocuronium (0.6 mg.kg-1), and was maintained with isoflurane (1% to 3%). In the presence of clinical signs or hemodynamic responses suggesting inadequate anesthesia (sweating, tearing, arterial hypertension and tachycardia), intravenous alfentanil (500 to 1000 µg) was administered to both groups.
Controlled ventilation was achieved with low flow anesthesia machine allowing inspired gases moistening and warming. Tidal volume was 8 to 10 mL.kg-1 and respiratory rate was enough to maintain end tidal CO2 (PETCO2) between 30 and 35 mmHg.
Blood pressure, heart rate, oxygen peripheral hemoglobin saturation (SpO2) and end tidal CO2 (PETCO2) were recorded after monitoring, epidural anesthetic induction and tracheal intubation, and then at 15-minute intervals until surgery completion. After surgery patients were referred to the Post-Anesthetic Care Unit (PACU) where they remained for at least 6 hours. Analgesia and sedation were recorded at 2, 6 and 24 hours after anesthetic recovery by a professional blind to the anesthetic procedure.
Analgesia, defined as loss or absence of sensitivity to pain, was evaluated by the Pain Visual Analog Scale, being zero lack of pain and ten the worst imaginable pain. Zero was adopted as reference for this experiment.
The sedation state can vary from mild to deep consciousness depression levels. In mild sedation, consciousness depression levels are minor and patients are able to get in touch with the environment, respond to commands, devise events and report facts11. Filos' numerical scale was used to evaluate consciousness level: 1 - awaken and nervous; 2 - awaken and relaxed; 3 - sleepy by easily awakened; 4 - sleepy and hardly awakened12.
The following methods were used for statistical analysis: Scheffé's Analysis of Variance for demographics and Cochran's Chi-square with restrictions. Fisher's Exact test was used for sedation and analgesia analysis. Statistics were considered significant when p < 0.05, where p is the significance level associated to calculated statistics.
There have been no statistically significant differences in patients' weight and age. Results are shown in table I.
There have been no statistically significant differences in sedation for the clonidine group at 2 and 6 hours; there have been statistically significant differences in the dexmedetomidine group at 2 and 6 hours. There have been no statistically significant differences when comparing both groups at 2 and 6 hours. Results are shown in table II.
There have been statistically significant differences in analgesia for the clonidine group when 2 and 6 hours observations were compared to 24 hours; there have been statistically significant differences in the dexmedetomidine group when 2 hours observations were compared to 6 and 24 hours, as well as when 6 hours observations were compared to 24 hours; there have been statistically significant differences between groups at 24 hours. Results are shown in table III.
Alpha2-adrenergic agonists have sedative, anxyolitic, analgesic and hemodynamic stability properties, in addition to promoting less respiratory effects4.
In a study with patients submitted to hemorrhoidectomy under caudal epidural anesthesia, it has been observed that mean time for first analgesic request was longer in the group receiving clonidine and local anesthetics as compared to the group receiving saline and local anesthetics13.
In patients submitted to total hip replacement, mean time for first analgesic request was longer in the group receiving clonidine and levobupivacaine as compared to those receiving local epidural anesthetics alone6.
In a study with human beings it has been observed that clonidine infusions have significant pharmacologic activity that results in a progressive sedation state14.
In patients submitted to inguinal hernia correction, the combination of spinal clonidine-bupivacaine has prolonged anesthesia length and has promoted better analgesia observed 4 hours after blockade15.
In a randomized study with human beings using lidocaine and dexmedetomidine alone or in association, it has been observed decreased EEG delta wave, blood pressure and heart rate in the group receiving dexmedetomidine alone. In the group receiving the association of both drugs it has been observed longer anesthetic effect and decreased analgesic doses for postoperative pain relief8.
Our results allow to conclude that clonidine or dexmedetomidine associated to 0.75% ropivacaine have promoted analgesia and sedation at 2 and 6 hours after anesthetic recovery in patients submitted to subcostal cholecystectomy, and that clonidine prolongs analgesic length.
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Submitted for publication August
Accepted for publication November 14, 2003
* Received from CET do Serviço de Anestesiologia do Hospital de Clínicas da Faculdade de Ciências Médicas de Pouso Alegre (FCM - UNIVAS), MG