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On-line version ISSN 1806-907X
Rev. Bras. Anestesiol. vol.57 no.1 Campinas Jan./Feb. 2007
Epidural S(+) ketamine and S(+) ketamine-morphine associated with ropivacaine in the postoperative analgesia and sedation of upper abdominal surgery*
Analgesia y sedación de la S(+) cetamina y de la S(+) cetamina-morfina, asociadas a la ropivacaína, por vía peridural, en el postoperatorio de intervención quirúrgica de abdomen superior
Taylor Brandão Schnaider, TSAI; Antônio Mauro Vieira, TSAII; Antônio Carlos Aguiar Brandão, TSAIII; Aretusa Chediak RoquimIV
Doutor Titular do Departamento de Clínica Cirúrgica. Responsável
pelas Disciplinas de Anestesiologia e Metodologia Científica da FCM de
Pouso Alegre, UNIVAS
IIProfessor Doutor Titular do Departamento de Fisiologia, Morfologia e Patologia. Responsável pela Disciplina de Farmacologia da FCM de Pouso Alegre, UNIVAS. Co-Responsável pelo CET/SBA de Pouso Alegre
IIIProfessor Doutor Titular 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
IVME3 do CET/SBA do HC da FCM de Pouso Alegre UNIVAS
OBJECTIVES: The association of drugs with different mechanisms of action
in the dorsal horn of the spinal cord decreases postoperative pain, with a reduction
in the incidence of side effects. The aim of this study was to evaluate postoperative
analgesia and sedation by epidural S(+) ketamine and S(+) ketamine-morphine
associated with ropivacaine in subcostal cholecystectomy.
METHODS: Seventy patients of both genders, physical status ASA I and II, participated in this study. The following drugs were administered epidurally: 0.75% ropivacaine associated with 0.9% sodium chloride in the Control Group (CG); 0.75% ropivacaine associated with S(+) ketamine (0.5 mg.kg-1) in the Ketamine Group (KG); 0.75% ropivacaine associated with S(+) ketamine (0.5 mg.kg-1) and morphine (2 mg) in the Ketamine-Morphine Group2 (KMG2); 0.75% ropivacaine associated with S(+) ketamine (0.5 mg.kg-1) and morphine (3 mg) in the Ketamine-Morphine Group3 (KMG3). Analgesia and sedation were evaluated 2h, 6h, and 24h after the end of the surgery.
RESULTS: Sedation was observed up to 2 hours after the end of the procedure in KG, KMG2, and KMG3. Analgesia was effective in CG up to 2 hours after the surgery, at 2h and 6h in KG, and at 2h, 6h, and 24h, in KMG2 and KMG3.
CONCLUSIONS: S(+) ketamine and the associations S(+) ketamine-morphine promoted sedation up to 2h after the end of the surgical procedure. S(+) ketamine promoted analgesia especially at the moment of the 2h observation, and the associations of S(+) ketamine-morphine promoted analgesia especially at 2h and 6h after the surgery.
Key Words: ANALGESIA: postoperative; ANALGESICS: morphine; ANESTHETICS, Dissociate: S(+) Ketamine; ANESTHETICS, Local: ropivacaine; ANESTHETIC TECHNIQUES, Regional: epidural.
Y OBJETIVOS: La combinación de fármacos, actuando por diferentes
mecanismos de acción en el cuerno dorsal de la médula espinal,
acarrea una disminución del dolor postoperatorio, con una menor incidencia
de los efectos colaterales. El objetivo fue el de evaluar la analgesia y la
sedación postoperatorias causadas por la S(+) cetamina y S(+) cetamina-morfina
asociadas a la ropivacaína, por vía peridural, en colecistectomía
por vía subcostal.
MÉTODO: Participaron del estudio 70 pacientes, de ambos sexos, estado físico ASA I y II. Se administraron por vía peridural: ropivacaína a 0,75% asociada al cloruro de sodio a 0,9% en el Grupo Control (GC); ropivacaína a 0,75% asociada a la S(+) cetamina (0,5 mg.kg-1) en el Grupo Cetamina (GK); ropivacaína a 0,75% asociada à S(+) cetamina (0,5 mg.kg-1) y a la morfina (2 mg) en el Grupo Cetamina-Morfina2 (GKM2); ropivacaína a 0,75% asociada a la S(+) cetamina (0,5 mg.kg-1) y a la morfina (3 mg) en el Grupo Cetamina-Morfina3 (GKM3). La analgesia y la sedación fueron observadas a las 2h, 6h y 24h después del término de la operación.
RESULTADOS: La sedación fue observada en 2h después de la operación en los grupos GK, GKM2 y GKM3. La analgesia quedó efectiva en el GC en 2h después del postoperatorio, en el GK en la 2h y 6h; en los GKM2 y GKM3 en las 2h, 6h y 24h.
CONCLUSIONES: La S(+) cetamina y las asociaciones S(+) cetamina-morfina promovieron sedación hasta 2 horas después del término de la operación. La S(+) cetamina promovió analgesia especialmente 2 en horas y las asociaciones S(+) cetamina-morfina promovieron analgesia principalmente en los momentos de observación de 2h y 6h después del término de la operación.
The association of anesthetic agents and techniques has been used to decrease the nociceptive impulses during the intra- and postoperative periods, minimizing morbidity and mortality.
The actions of ketamine involve several receptors, such as: muscarinic and nicotinic; opioids mu, delta, and kappa; monoaminergic and voltage-dependent calcium channels; as a non-competitive antagonist, its action involves the phencyclidine area of the complex N-methyl-D-aspartate channel-receptor (NMDA). It also blocks sodium channels in the central and peripheral nervous systems 1.
The chyrality of the ketamine molecule produces two optical isomers. The S(+) isomer (levorotatory) of ketamine, due to its stereoaffinity for the phencyclidine receptor in the NMDA channel, which causes a non-competitive inhibition of the activation of the channel by glutamate, has more potent analgesic and anesthetic properties despite a pharmacologic profile that is similar to the R(-) isomer (dextrorotatory) and to racemic ketamine 2,3,4.
Morphine, a hydrophilic opioid, produces spinal analgesia due to its actions on the opioid receptors mu2, kappa1, and delta1, as well as supra-spinal analgesia due to its action on opioid receptors mu1, kappa3, and delta2 5. There is evidence that suggests that the loss of effectiveness of morphine administered in the postoperative period is secondary to the activation of the NMDA receptors 6.
Ropivacaine is a long-acting local anesthetic, chemically homologous to mepivacaine and bupivacaine. Clinical studies demonstrated that ropivacaine is less toxic to the cardiovascular and central nervous systems when compared with bupivacaine 7.
The aim of this study was to evaluate the epidural administration of S(+) ketamine and S(+) ketamine associated with morphine in combination with ropivacaine in the postoperative analgesia and sedation in upper abdominal surgeries.
This study was approved by the Ethics Committee on Human Research of the Universidade do Vale do Sapucaí. Patients were required to sign an informed consent after careful explanation of the procedures. Seventy patients, both genders, with ages ranging from 18 to 50 years, physical status ASA I and II, undergoing subcostal cholecystectomy under general anesthesia associated with thoracolumbar epidural anesthesia participated in this analytical, interventional, clinical, prospective, randomized, double-blind study.
Patients received oral diazepam (10 mg) the day before the surgery and oral midazolam (15 mg) 40 minutes before the procedure. Monitoring consisted of electrocardioscopy, non-invasive blood pressure, pulse oxymeter, and gas analyzer. A solution containing midazolam (5 mg), fentanyl (50 µg), and metoclopramide (10 mg) was administered after venous cannulation with an 18G catheter.
Thoracolumbar epidural anesthesia was performed with the patient in the sitting position, in the T12-L1 space with a 15G Tuohy needle. Patients were randomly assigned to receive 20 mL of 0.75% ropivacaine associated with: 1 mL of 0.9% sodium chloride in the control Group (CG, n = 10); 0.5 mg.kg-1 of S(+) ketamine in the Ketamine Group (KG, n = 20); 0.5 mg.kg-1 of S(+) ketamine and 2 mg of morphine in the Ketamine-Morfine2 Group (KMG2, n = 20); and 0.5 mg.kg-1 of S(+) ketamine and 3 mg of morphine in the Ketamine-Morphine3 Group (KMG3, n = 20). A predetermined volume of the drug combinations was administered in the epidural space of every patient at a rate of 1 mL.sec-1. Afterwards, patients returned to the supine position and the level of the sensitive blockade was tested, as well as monitoring of the blood pressure and heart rate up to 15 minutes after the administration of the epidural anesthesia.
Ethomidate (0.2 mg.kg-1), alfentanyl (30 µg.kg-1), and rocuronium (0.6 mg.kg-1) were used for the anesthetic induction, while isoflurane (0.5 vol% to 3.0 vol% of inspired concentration) was used for the maintenance. When clinical or hemodynamic signs suggested inadequate levels of anesthesia (diaphoresis, tearing, hypertension, and tachycardia), intermittent doses of alfentanyl (500 µg) were administered intravenously.
Controlled ventilation was achieved with a low-flow anesthesia system, which allowed for the humidification and heating of the inspired gases. A tidal volume of 8 to 10 mL.kg-1 was used and the respiratory frequency was adjusted to maintain the expired pressure of carbon dioxide (PETCO2) between 30 mmHg and 35 mmHg.
Blood pressure, heart rate, hemoglobin saturation (SpO2), expired carbon dioxide (PETCO2), and the inspired concentration of isoflurane were recorded after placement of the monitoring system, epidural anesthesia, tracheal intubation, and every 15 minutes thereafter until the end of the surgery. After the procedure, patients were transferred to the recovery room.
Intraoperative analgesia was assessed by observing the clinical signs, while the inspired concentration of the inhalational agent was evaluated by a gas analyzer. An increase in heart rate and/or systolic blood pressure above pre-block levels were treated by increasing the inspired concentration of isoflurane (up to 3.0 vol%) and, when the parameters did not reach appropriate levels, a bolus of intravenous alfentanyl (500 µg) was administered and repeated as many times as necessary. A reduction in systolic blood pressure greater than 30% of pre-block levels or below 90 mmHg was treated with the intravenous administration of a mixed action sympathomimetic amine (ephedrine). A marked reduction in heart rate, below 50 bpm.min-1, causing a decrease in cardiac output, was treated with intravenous atropine.
Regarding postoperative analgesia, pain severity was analyzed by the Verbal Analogical Pain Scale in which zero corresponds to the absence of pain and ten corresponds to the worse pain possible. In this study, zero was used as a reference.
As for the postoperative sedation, continuous changes in the alertness status may be as profound as unconsciousness; the levels of depression of consciousness may vary from light to severe. With light sedation, the level of depression is minimal and the patient makes contact with the surrounding environment, follows commands, distinguishes events, and reports facts. The numerical scale proposed by Filos was used to evaluate the level of consciousness: 1 awaken and nervous; 2 awaken and calm; 3 sleepy, but easily arousable; 4 sleepy and difficulty to arise 8. In this study, a score of 3 was used as a reference of sedation.
Analgesia and sedation were evaluated at 2, 6, and 24 hours after the surgical procedure. Postoperative pain was treated systemically by the intravenous route. Initially, dypirone was administered as the analgesic agent. If the patient still complained of pain, tramadol, an opioid that causes less depression and is less sedative than morphine, was added.
The Analysis of Variance with Scheffé's proof was used for the statistical analysis of the anthropometrics data of the patients; Student t test was used to analyze the duration of the surgical procedure; Fisher exact test was used for the statistical analysis of the drops in systolic blood pressure and heart rate; Analysis of Variance with Tukey test were used for the statistical analysis of the inspired concentrations of isoflurane in CG, KMG2, and KMG3. Chi-square and Fisher exact tests were used for the statistical analysis of the analgesia. The Chi-square test was used for the statistical analysis of the sedation. A p < 0.05 was considered significant.
There were no statistically significant differences in weight and age among the groups (Table I).
Regarding the duration of the surgery, there were no statistically significant differences among the groups (Table II).
The levels of the sensitive blockade achieved by the thoracolumbar anesthesia performed before the induction of general anesthesia were similar in CG, KMG2, and KMG3, with a median at the T6 level (margin of the rib cage). The median for KG was the T3 level (nipple).
Twelve patients in KG, 10 in KMG2, and 7 in KMG3 presented a decrease in systolic blood pressure greater than 30% of pre-blockade levels or below 90 mmHg. Fisher exact test demonstrated a statistically significant difference between the Control Group and the Ketamine and Ketamine-Morphine2 Groups (Table III).
A marked reduction in heart rate, below 50 beats.min-1, led to a reduction in cardiac output in 3 patients in KG (40 beats.min-1) and in 1 patient in KMG3 (30 beats.min-1). Fisher exact test did not demonstrate statistically significant differences among the groups (Table III).
There was a dose-dependent reduction in the inspired concentration of isoflurane related to morphine, with a mean of 0.65% vol in KG, 0.70% vol in KMG2, and 0.52% vol in KMG3. Using Analysis of Variance associated with Tukey test to compare the inspired concentrations of the inhalational agents used in the Ketamine, Ketamine-Morphine2, and Ketamine-Morphine3 Groups demonstrated a statistically significant difference between the Ketamine-Morphine3 Group and the Ketamine and Ketamine-Morphine2 Groups (Tabela IV).
Every patient in the Control Group, who received only 0.75% ropivacaine, needed a mean inspired concentration of isoflurane of 2.35% vol (Table IV) and four patients also received intermittent doses of alfentanyl that ranged from 500 µg to 1500 µg.
As for postoperative analgesia: at 2 hours, there was a statistically significant difference when comparing the Control Group to the other groups; at 6 hours and 24 hours, there was a statistically significant difference when comparing KG with the Ketamine-Morphine Groups (Table V).
In the Ketamine Group, patients who required supplemental analgesia received only dypirone 2 hours after the procedure; between 2 and 6 hours, 4 patients required the association of tramadol and dypirone; between 6 and 24 hours, 2 more patients required the association tramadol-dypirone (Table VI).
In KMG2, dypirone was administered to the patients that required supplemental analgesia up to 2 hours after the procedure; between 2 and 6 hours, patients received dypirone and 2 patients also required the association with tramadol; however, between 6 and 24 hours only dypirone was administered (Tabela VI).
In KMG3, dypirone was administered to every patient who needed supplemental analgesia at the 2-hour observation; between 2 and 6 hours, dypirone was administered but 2 patients also required the association with tramadol; between 6 and 24 hours, dypirone was administered to the patients who required supplemental analgesia and the association dypirone-tramadol was administered to the same patients of the prior period (Table VI).
There were no statistically significant differences regarding sedation at the 2-hour observation between the Ketamine Group and the Ketamine-Morphine Groups (Table VII).
Regarding intraoperative analgesia, there was a reduction in heart rate and blood pressure in every patient who received S(+) ketamine, S(+) ketamine-morphine2, or S(+) ketamine-morphine3 due to S(+) ketamine-mediated blockade of the NMDA receptors and/or morphine-induced peripheral vasodilation, decreased peripheral resistance, and inhibition of the baroreceptors, as well as the sympathetic blockade induced by the epidural administration of ropivacaine; patients did not need intraoperative supplemental analgesia. The doses of alfentanyl were the used during anesthetic induction, ranging between 1500 µg and 2700 µg.
There is a increasing number of studies demonstrating that low doses of ketamine may play an important role in the treatment of postoperative pain when used in association with local anesthetics, opioids, or other analgesic drugs 1. The concept of balanced analgesia deserves attention 9,10, stretching the limits of analgesia using opioids 11. The combination of drugs with different mechanisms of action in the dorsal horn of the spinal cord decreases postoperative pain and, at the same time, reduces the incidence of side effects. This approach is known as balanced or multimodal analgesia 12. In this study, we used a local anesthetic, ropivacaine, an opioid, morphine, and a non-competitive antagonist of the N-methyl-D-aspartate receptor, ketamine, to achieve the desired effects of the multimodal analgesia.
The meta-analysis of the preemptive analgesia demonstrated a possible efficacy of this method in the treatment of acute postoperative pain in selected analgesia regimens (epidural, local anesthesia, antagonists of the N-methyl-D-aspartate acid, non-steroidal anti-inflammatories and opioids) based on pain scores, consumption of analgesics, and length of time until the patient requests the first analgesic 13.
A study with patients who underwent gastrectomy showed that the group that received epidural morphine associated with intravenous ketamine had lower Visual Analogic Scale values and required less morphine than the groups who received epidural morphine, intravenous ketamine, and control groups (epidural and intravenous normal saline). The medications were administered before the conclusion of the surgical procedure in every group 14.
A study with patients who underwent upper abdominal surgeries under general anesthesia and continuous epidural anesthesia demonstrated that the patients who received pre-incisional epidural ketamine, morphine, and bupivacaine experienced a greater relief of postoperative pain than the patients who received the same drugs via the same route after the skin incision 15.
A study with patients who received patient-controlled epidural analgesia for lower abdominal surgeries showed that analgesia was more effective in patients who were treated with the association morphine-ketamine, being necessary a lower dose of morphine, and with a reduced incidence of side effects when compared with the patients who were treated with morphine alone 16.
The study of Pugh et al. with children who presented low risk in the evaluation of liver function by the modified Child classification, suggested that the postoperative analgesia provided by a single epidural injection of morphine associated with low-dose ketamine is effective and safe, representing an alternative technique of analgesia in patients with cirrhosis who undergo any type of surgical intervention in the upper abdomen 17.
A study with patients treated with patient controlled epidural analgesia (PCEA) with morphine, bupivacaine, and epinephrine, with or without ketamine, for surgeries involving the thorax and upper abdomen, concluded that adding ketamine to a multimodal PCEA regimen reduces postoperative pain and the use of analgesics 18.
Another study evaluated the safety and efficacy of epidural ketamine associated with morphine in the postoperative period of upper abdominal surgeries, demonstrated that the addition of ketamine improved analgesia but did not increase the incidence of side effects 19.
In this study, we observed that the use of multimodal analgesia with S(+) ketamine, morphine, and ropivacaine promoted a more prolonged analgesia and decreased the use of analgesics, which is similar to the results of other studies, but increasing the dose of morphine did not improve analgesia and did not decrease the use of analgesics.
A study with children with liver disease concluded that there were no statistically significant differences between the morphine and morphine-ketamine groups regarding the respiratory variables (partial arterial pressure of carbon dioxide and respiratory rate) and sedation 17.
A study with patients who received morphine, bupivacaine, and epinephrine, with or without ketamine, for surgeries in the thorax and upper abdomen concluded that the patients presented an easy awakening without statistically significant differences regarding sedation between the groups that received morphine, bupivacaine, and epinephrine and the group receiving the same drugs associated with ketamine 18.
A work with patients who received epidural morphine associated with ketamine for surgeries of the upper abdomen demonstrated that patients who received ketamine with morphine had higher sedation scores in the first two hours after the surgery then patients treated with morphine alone 19.
In the current study, patients who received S(+) ketamine or S(+) ketamine associated with morphine were sedated 2 hours after the surgical procedure without statistically significant differences among the groups, which confirms the results of two of the authors mentioned before but goes against the results of another author.
Epidural S(+) ketamine and S(+) ketamine-morphine associated with ropivacaine produced longer lasting sedation and analgesia and reduced the amount of analgesics used in the postoperative period of surgeries of the upper abdomen.
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Dr. Taylor Brandão Schnaider
Av. Francisca R. de Paula, 289
37550-000 Pouso Alegre, RS
Submitted em 20
de março de 2006
Accepted para publicação em 23 de outubro de 2006
* Received from Centro de Ensino e Treinamento do Serviço de Anestesiologia do Hospital das Clínicas da Faculdade de Ciências Médicas de Pouso Alegre, (HC-FCM-UNIVAS) Pouso Alegre, MG