Intraoperative analgesic effect of epidural ketamine, clonidine or dexmedetomidine for upper abdominal surgery

Abstracts

JUSTIFICATIVA E OBJETIVOS: A cetamina reduz a nocicepção, bloqueando os canais dos receptores NMDA, em doses sub-anestésicas. A ativação dos receptores alfa2-adrenérgicos induz intensa resposta analgésica. O objetivo desta pesquisa foi avaliar os efeitos da cetamina, clonidina e dexmedetomidina, por via peridural, em pacientes submetidos à cirurgia do abdômen superior. MÉTODO: Participaram deste estudo aleatório e duplamente encoberto, 70 pacientes, de ambos os gêneros, com idade entre 18 e 50 anos, estado físico ASA I e II, submetidos a colecistectomia por via subcostal, sob anestesia geral associada à peridural lombar. Na anestesia peridural foram administrados, aleatoriamente, 20 mL de ropivacaína a 0,75% e 1 mL de cloreto de sódio a 0,9% no grupo Controle (n = 10); 20 mL de ropivacaína a 0,75% e 0,5 mg.kg-1 de cetamina no grupo Cetamina (n = 20); 20 mL de ropivacaína a 0,75% e 1 mL de clonidina (150 µg) no grupo Clonidina (n = 20) ou 20 mL de ropivacaína a 0,75% e 2 µg.kg-1 de dexmedetomidina no grupo Dexmedetomidina (n = 20). A indução anestésica foi realizada com etomidato, alfentanil e rocurônio, sendo a manutenção obtida pela administração de isoflurano e alfentanil. A analgesia foi observada por meio dos sinais clínicos e a concentração inspirada do agente inalatório por meio do analisador de gases ins e expirados, durante o ato operatório. RESULTADOS: Nos pacientes em que foi administrada cetamina, clonidina ou dexmedetomidina, ocorreu diminuição da freqüência cardíaca e da pressão arterial sistêmica, e não houve necessidade de complementação analgésica peri-operatória. Com relação à concentração inspirada do isoflurano, as necessidades variaram entre 0,5vol% e 1vol%, não se observando sinais clínicos ou respostas que sugerissem níveis inadequados de anestesia. CONCLUSÕES: A administração de cetamina, clonidina ou dexmedetomidina, por via peridural, reduz o consumo de alfentanil e a concentração inspirada de isoflurano, no intra-operatório de cirurgia de abdômen superior.

ANALGESIA; ANALGÉSICOS; ANALGÉSICOS; ANALGÉSICOS; ANALGÉSICOS; ANALGÉSICOS; ANESTÉSICOS; ANESTÉSICOS; ANESTÉSICOS; ANESTÉSICOS; ANESTÉSICOS

JUSTIFICATIVA Y OBJETIVOS: La cetamina reduce la nocicepción, bloqueando los canales de los receptores NMDA, en dosis sub-anestésicas. La activación de los receptores alfa2-adrenérgicos causa intensa respuesta analgésica. El objetivo de esta pesquisa fue evaluar los efectos de la cetamina, clonidina y dexmedetomidina, por vía peridural, en pacientes sometidos a cirugía del abdomen superior. MÉTODO: Participaron de este estudio aleatorio y doblemente encubierto, 70 pacientes, de ambos sexos, con edad entre 18 y 50 años, estado físico ASA I y II, sometidos a colecistectomia por vía subcostal, bajo anestesia general asociada a la peridural lumbar. En la anestesia peridural fueron administrados, aleatoriamente, 20 mL de ropivacaína a 0,75% e a 1 mL de cloruro de sodio a 0,9% en el Grupo Control (n = 10); 20 mL de ropivacaína a 0,75% e a 0,5 mg.kg-1 de cetamina en el Grupo Cetamina (n = 20); 20 mL de ropivacaína a 0,75% e a 1 mL de clonidina (150 µg) en el Grupo Clonidina (n = 20) ó 20 mL de ropivacaína a 0,75% e a 2 µg.kg-1 de dexmedetomidina en el Grupo Dexmedetomidina (n = 20). La inducción anestésica fue realizada con etomidato, alfentanil y rocuronio, siendo el mantenimiento logrado por la administración de isoflurano y alfentanil. La analgesia fue observada por medio de los señales clínicos y la concentración inspirada del agente inhalatorio por medio del analizador de gases ins y expirados, durante el acto operatorio. RESULTADOS: En todos los pacientes en que fue administrada cetamina, clonidina o dexmedetomidina, ocurrió disminución de la frecuencia cardiaca y de la presión arterial sistémica, quiénes no necesitaron complementación analgésica peri-operatoria. Con relación a la concentración inspirada del isoflurano, las necesidades variaron entre 0,5vol% y 1vol%, no se observando señales clínicas o respuestas que sugiriesen niveles inadecuados de anestesia. CONCLUSIONES: La administración de cetamina, clonidina o dexmedetomidina, por vía peridural, reduce el consumo de alfentanil y la concentración inspirada de isoflurano, en el intra-operatorio de cirugía de abdomen superior.

SCIENTIFIC ARTICLE

Intraoperative analgesic effect of epidural ketamine, clonidine or dexmedetomidine for upper abdominal surgery^*

Efecto analgésico intra-operatorio de la cetamina, clonidina o dexmedetomidina, administradas por vía peridural, en cirugía de abdomen superior

Taylor Brandão Schnaider, M.D.^I; Antonio Mauro Vieira, M.D.^II; Antonio Carlos Aguiar Brandão, M.D.^III; Marcos Vinicius Tonante Lobo, M.D.^IV

^IProfessor Doutor Titular do Departamento de Clínica Cirúrgica. Responsável pelas Disciplinas de Anestesiologia e Metodologia Científica da FCM de Pouso Alegre, MG, UNIVAS

^IIProfessor Doutor Titular do Departamento de Fisiologia, Morfologia e Patologia. Responsável pela Disciplina de Farmacologia da FCM de Pouso Alegre, MG, UNIVAS. Co-Responsável pelo CET/SBA de Pouso Alegre, MG

^IIIProfessor Doutor Titular do Departamento de Fisiologia, Morfologia e Patologia. Responsável pela Disciplina de Biofísica da FCM de Pouso Alegre, MG, UNIVAS. Responsável pelo CET/SBA de Pouso Alegre, MG

^IVME₂ do CET do Serviço de Anestesiologia do HC da FCM de Pouso Alegre, MG, UNIVAS

^{Correspondence to}

SUMMARY

BACKGROUND AND OBJECTIVES: Low dose ketamine decreases nociception by blocking NMDA receptor channels. Alpha₂-adrenergic receptor activation triggers intense analgesic response. This study aimed at evaluating the effects of epidural ketamine, clonidine and dexmedetomidine, in patients undergoing upper abdominal surgery.

METHODS: Participated in this randomized double-blind study 70 patients of both genders, aged 18 to 50 years, physical status ASA I or II, submitted to subcostal cholecystectomy under general anesthesia associated to lumbar epidural anesthesia. Lumbar epidural anesthesia was randomly induced as follows: Control group: 20 mL of 0.75% ropivacaine and 1 mL of 0.9% saline solution (n = 10); Ketamine group: 20 mL of 0.75% ropivacaine and 0.5 mg.kg^-1 ketamine (n = 20); Clonidine group: 20 mL of 0.75% ropivacaine and 1 mL clonidine (150 µg) (n = 20); Dexmedetomidine group: 20 mL of 0.75% ropivacaine and 2 µg.kg^-1 dexmedetomidine (n = 20). Anesthesia was induced with etomidate, alfentanil and rocuronium and was maintained with isoflurane and alfentanil. Analgesia was evaluated by clinical signs and inhalational anesthetic inspired concentration was evaluated by anesthetic gases analysis during surgery.

RESULTS: All patients receiving ketamine, clonidine or dexmedetomidine had heart rate and systemic blood pressure decrease and have not required perioperative analgesic complementation. For the same patients, isoflurane inspired concentration varied from 0.5vol% to 1vol% and there were no clinical signs or responses suggesting inadequate anesthetic levels.

CONCLUSIONS: Epidural ketamine, clonidine or dexmedetomidine decreases alfentanil consumption and isoflurane inspired concentration in the intraoperative period of upper abdominal surgery.

Key Words: ANALGESIA, Intraoperative; ANALGESICS, Opioid: alfentanil, a₂-agonists: clonidine, dexmedetomidine; ANESTHETICS, Inhalational: isoflurane, Local: ketamine, ropivacaine

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: La cetamina reduce la nocicepción, bloqueando los canales de los receptores NMDA, en dosis sub-anestésicas. La activación de los receptores a₂-adrenérgicos causa intensa respuesta analgésica. El objetivo de esta pesquisa fue evaluar los efectos de la cetamina, clonidina y dexmedetomidina, por vía peridural, en pacientes sometidos a cirugía del abdomen superior.

MÉTODO: Participaron de este estudio aleatorio y doblemente encubierto, 70 pacientes, de ambos sexos, con edad entre 18 y 50 años, estado físico ASA I y II, sometidos a colecistectomia por vía subcostal, bajo anestesia general asociada a la peridural lumbar. En la anestesia peridural fueron administrados, aleatoriamente, 20 mL de ropivacaína a 0,75% e a 1 mL de cloruro de sodio a 0,9% en el Grupo Control (n = 10); 20 mL de ropivacaína a 0,75% e a 0,5 mg.kg^-1 de cetamina en el Grupo Cetamina (n = 20); 20 mL de ropivacaína a 0,75% e a 1 mL de clonidina (150 µg) en el Grupo Clonidina (n = 20) ó 20 mL de ropivacaína a 0,75% e a 2 µg.kg^-1 de dexmedetomidina en el Grupo Dexmedetomidina (n = 20). La inducción anestésica fue realizada con etomidato, alfentanil y rocuronio, siendo el mantenimiento logrado por la administración de isoflurano y alfentanil. La analgesia fue observada por medio de los señales clínicos y la concentración inspirada del agente inhalatorio por medio del analizador de gases ins y expirados, durante el acto operatorio.

RESULTADOS: En todos los pacientes en que fue administrada cetamina, clonidina o dexmedetomidina, ocurrió disminución de la frecuencia cardiaca y de la presión arterial sistémica, quiénes no necesitaron complementación analgésica peri-operatoria. Con relación a la concentración inspirada del isoflurano, las necesidades variaron entre 0,5vol% y 1vol%, no se observando señales clínicas o respuestas que sugiriesen niveles inadecuados de anestesia.

CONCLUSIONES: La administración de cetamina, clonidina o dexmedetomidina, por vía peridural, reduce el consumo de alfentanil y la concentración inspirada de isoflurano, en el intra-operatorio de cirugía de abdomen superior.

INTRODUCTION

N-methyl-D-aspartate (NMDA) receptor antagonists may prevent or block Central Nervous System hypersensitivity ¹. Interests have been focused on the involvement of excitatory aminoacids, especially on their post-synaptic actions on spinal cord via NMDA receptors ². In low doses, ketamine decreases nociception by blocking these receptors' channels ^1,2.

Alpha₂-adrenergic receptors activation triggers intense analgesic response by involving supra-spinal and especially spinal receptors, including the activation of post-synaptic noradrenergic descending pathways a₂ receptors, of cholinergic neurons, of nitric oxide and encephalin release ³.

Recent studies have shown that a₂-adrenergic agonists also play an important role in pain modulation by inhibiting nervous conduction of Ad and C fibers ⁴. Alpha₂-adrenergic agonists decrease the need for halogenate anesthetics during anesthesia. With the development of super-selective drugs, such as dexmedetomidine, this decrease may be approximately 95% when the halogenate is halothane ⁵.

This study aimed at evaluating intraoperative analgesia after lumbar epidural ketamine, clonidine or dexmedetomidine associated to 0.75% ropivacaine for upper abdominal surgery.

METHODS

This study was approved by the Research Ethics Committee, Universidade do Vale do Sapucaí and all patients gave their written consent after being thoroughly explained about the procedure they would be submitted to. Participated in this experimental, prospective, randomized and double-blind study 70 patients of both genders, aged 18 to 50 years, physical status ASA I and II, submitted to subcostal cholecystectomy under general anesthesia associated to lumbar epidural anesthesia.

All patients were premedicated with oral diazepam (10 mg) the day before and with oral midazolam (15 mg) 40 minutes before surgery. In the operating room patients were monitored with ECG, noninvasive blood pressure, pulse oximetry and inspired and expired gases analyzer. After venous puncture with 18G catheter patients were given solutions with midazolam (5 mg), fentanyl (50 µg) and metoclopramide (10 mg).

Lumbar epidural anesthesia was induced with patients in the sitting position in L₁-L₂ interspace with 15G Tuohy needle and the following solutions were randomly administered: Control group: 20 mL of 0.75% ropivacaine associated to 1 mL of 0.9% saline solution (n = 10); Ketamine group: 20 mL of 0.75% ropivacaine associated to 0.5 mg.kg^-1 ketamine (n = 20); Clonidine group: 20 mL of 0.75% ropivacaine associated to 1 mL clonidine with 150 µg (n = 20); Dexmedetomidine group: 20 mL of 0.75% ropivacaine associated to 2 µg.kg^-1 dexmedetomidine (n = 20). All patients received the same volume of drug combinations in the epidural space at the rate of 1 mL.sec^-1. After puncture patients were returned to 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 (0.5vol% to 3vol%). When clinical signs or hemodynamic responses suggested inadequate anesthesia (sweating, tearing, hypertension and tachycardia), intermittent intravenous alfentanil (500 µg) was administered.

Controlled ventilation was achieved with low flow anesthesia system to allow inspired gases humidification and warming. Tidal volume was 8 to 10 mL.kg^-1 and respiratory rate was enough to maintain P_ETCO₂ between 30 and 35 mmHg.

Blood pressure, heart rate, peripheral hemoglobin saturation (SpO₂), expired CO₂ (P_ETCO₂) and inspired isoflurane concentration were recorded after monitoring, epidural anesthesia and tracheal intubation, and then every 15 minutes until the end of surgery when patients were referred to the Post-Anesthetic Recovery Unit (PACU).

Analgesia was evaluated by clinical signs and inhalational agent inspired concentration was evaluated by inspired and expired gas analysis. Increases in heart rate and/or systemic systolic pressure above pre-blockade levels were treated by increasing isoflurane inspired concentration (until 3vol%) and when analyzed parameters did not reach desirable levels, bolus intravenous alfentanil (500 µg) was administered and repeated as needed; systemic systolic pressure decrease below 30% of pre-blockade levels or below 90 mmHg was corrected with intravenous sympathomimetic amine primarily indirect-acting (ephedrine); marked decrease in heart rate below 50 beat.min^-1 promoting low output was treated with intravenous muscarinic antagonist (atropine).

Analysis of Variance with Scheffé's proof was used for demographics data; Student's t test was used for statistical analysis of surgery duration; Fisher Exact test was used for systemic systolic pressure and heart rate variations; Analysis of Variance with Tukey's method was used for isoflurane inspired concentrations in ketamine, clonidine and dexmedetomidine groups; p < 0.05 was considered significant.

RESULTS

There were no statistically significant differences in patients weight and age according to Analysis of Variance with Scheffé's proof (Table I).

There were also no statistically significant differences in surgery duration among groups according to Student's t test (Table II).

All patients receiving ketamine, clonidine or dexmedetomidine had decreased heart rate and systemic blood pressure as a consequence of NMDA receptors block by ketamine, or of pre-synaptic self-inhibitory feedback mechanism of a₂-adrenergic receptors by clonidine and dexmedetomidine, and of epidural block by ropivacaine and had no need for intraoperative analgesic complementation. Alfentanil doses were those used during anesthetic induction and varied from 1500 µg to 2700 µg.

There has been mean isoflurane inspired concentration decrease of 0.65vol% in the Ketamine group, 0.87vol% in the Clonidine group and of 0.84vol% in the Dexmedetomidine group. According to ANOVA with Tukey's method, there has been statistically significant difference in inhalational agent inspired concentrations for the Ketamine group as compared to Clonidine and Dexmedetomidine groups (Table III).

All Control group patients receiving 0.75% ropivacaine plain needed isoflurane inspired concentration of 1vol% to 3vol% (Table III) and four Control group patients needed analgesic complementation with intermittent alfentanil doses varying from 500 µg to 1500 µg.

There has been systemic systolic blood pressure decrease below 30% of pre-blockade levels or below 90 mmHg in 12 Ketamine group, 5 Clonidine group and 6 Dexmedetomidine group patients. According to Fisher Exact test, there has been statistically significant difference in the Ketamine group as compared to Control and Clonidine groups (Table IV).

Marked heart rate decrease below 50 beat.min^-1, has promoted low output in three ketamine (40 beat.min^-1) and two Dexmedetomidine group patients (30 beat.min^-1). There were no statistically significant differences among groups according to Fisher Exact test (Table IV).

DISCUSSION

In patients submitted to abdominal procedures under general anesthesia and receiving remifentanil and desflurane in constant minimum alveolar concentration of 0.5% associated or not to ketamine, low ketamine doses have promoted decreased intraoperative opioid consumption. Authors have just reported constant minimum desflurane alveolar concentration of 0.5vol%, below 2.4vol%, when there is return of voluntary response to command in 50% of patients ⁶.

A human trial with clonidine as sole analgesic agent in abdominal surgeries with initial 2 µg.kg^-1 (Group 1), 4 µg.kg^-1 (Group 2) and 8 µg.kg^-1 (Group 3) epidural doses, followed by 0.5 µg.kg^-1.h^-1 (Group 1), 1 µg.kg^-1.h^-1 (Group 2) and 2 µg.kg^-1.h^-1 (Group 3) continuous infusion until 12 postoperative hours has observed that intra and postoperative analgesia have been dose-dependent ⁷.

A prospective, randomized and double-blind study with caudal S(+) ketamine associated to clonidine and combined with general anesthesia with sevoflurane for pediatric inguinal hernia correction has observed excellent intraoperative analgesia with minor side effects ⁸.

A human study with epidural ketamine for thoracotomies has observed significant decrease in the need for intraoperative fentanyl as compared to the group receiving saline ⁹.

Our study has observed that both epidural ketamine (0.5 mg.kg^-1), NMDA receptors antagonist, and epidural clonidine (150 µg) or dexmedetomidine (2 µg.kg^-1), a₂-adrenergic agonists, in single dose, have promoted decreased intraoperative opioid consumption since no patient in these groups needed analgesic complementation with alfentanil.

As to isoflurane inspired concentration, needs have varied between 0.5vol% to 1vol%, without clinical signs or responses suggesting inadequate anesthesia (sweating, tearing, hypertension and tachycardia) in all patients receiving ketamine, clonidine or dexmedetomidine.

A prospective, randomized, double-blind human study using epidural ketamine or fentanyl associated to bupivacaine and combined to general anesthesia has evaluated intraoperative cardiovascular effects on patients submitted to total gastrectomy. Both fentanyl and ketamine associated to bupivacaine have promoted satisfactory intraoperative analgesia, however fentanyl has increased the incidence of systemic systolic pressure decrease. There were no statistical differences in heart rate between fentanyl and Ketamine groups ¹⁰.

A multicenter human study has shown that the association of epidural and general anesthesia has decreased systemic systolic response in 31% of patients and has decreased heart rate in 12.7% of patients; patients receiving epidural clonidine had a higher incidence of heart rate decrease ¹¹.

Our study has observed decreased systemic systolic pressure in 10% of Control, 60% of Ketamine, 25% of Clonidine and 30% of Dexmedetomidine group patients; heart rate was decreased in 15% of Ketamine and 10% of Dexmedetomidine group patients.

Results allow us to conclude that epidural ketamine, clonidine or dexmedetomidine decreases alfentanil consumption and isoflurane inspired concentration in the intraoperative period of upper abdominal surgeries.

REFERENCES

Submitted for publication July 12, 2004

Accepted for publication June 1, 2005

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^*

Received from CET-SBA do Hospital das Clínicas da Faculdade de Ciências Médicas de Pouso Alegre, MG, UNIVAS

Publication Dates

• Publication in this collection
  13 Feb 2006
• Date of issue
  Oct 2005

History

• Accepted
  June 2005
• Received
  12 July 2004