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Rev. Bras. Anestesiol. vol.58 no.3 Campinas May/June 2008
Remifentanil versus sufentanil en infusión continua en intervenciones quirúrgicas videolaparoscópicas. Estudio comparativo
Ricardo Francisco Simoni, TSAI; Antônio Márcio Sanfim Arantes Pereira, TSAI; Renato dos Santos BoregaII; Daniel Caldeira Pereira SimõesII
Co-Responsável pelo CET/SBA Instituto Penido Burnier e Centro Médico
de Campinas; Presidente do Comitê de Anestesia Venosa da SBA
IIMédico em Especialização (ME3 do CET/SBA Instituto Penido Burnier e Centro Médico de Campinas)
OBJECTIVES: Continuous infusion (CI) of remifentanil is common in total
intravenous anesthesia. On the other hand, CI of sufentanil for short/medium-term
surgeries has not been widely used. The objective of this study was to compare
two techniques of total intravenous anesthesia, using CI of remifentanil or
sufentanil, regarding their intraoperative behavior and characteristics of recovery
of patients undergoing videolaparoscopic surgeries.
METHODS: Sixty patients, equally divided in 2 groups (RG and SG), participated in this study. Continuous infusion of remifentanil was used for anesthetic induction in RG, while a bolus of sufentanil associated with CI of this drug was used in SG. The CI of remifentanil was discontinued at the end of the surgery, while the CI of sufentanil was discontinued 20 minutes before the end of the surgery. Patients received ketoprofen and dypirone intraoperatively. Tramadol was used for rescue analgesia in the recovery room. Variations of mean arterial pressure (MAP) and hard reate (HR), time for awakening, propofol consumption, intercurrences in the recovery room, and time of stay in the recovery room were analyzed.
RESULTS: Mean MAP was greater in SG than in RG (91.9 × 77.6, p < 0.0001). The incidence of pain was significantly greater in RG than on SG (22 × 1 patient, p < 0.0001). The incidence of postoperative nausea and vomiting (PONV) was greater in RG than in SG (10 × 2 patients, p < 0.0098). The mean time of stay in the recovery room was greater in RG than in SG (76 × 49 min, p < 0.0001).
CONCLUSIONS: Hemodynamic control was satisfactory in both groups. Continuous infusion of sufentanil promoted better postoperative pain control with decreased consumption of rescue analgesic and, consequently, reduced incidence of PONV and reduced time of stay in the recovery room.
Key Words: ANESTHETICS, Intravenous: remifentanil, sufentanil; SURGERY, abdominal, videolaparoscopic.
Y OBJETIVOS: La infusión continua (IC) de remifentanil en la técnica
de anestesia venosa total es una práctica común. Ya el sufentanil
en IC para cirugías de corta/media duración ha sido poco utilizado.
El objetivo de este estudio fue el de comparar dos técnicas de anestesia
venosa total, utilizando remifentanil o sufentanil en IC, en cuanto al comportamiento
anestésico en el intraoperatorio y en cuanto a las características
de la recuperación anestésica en pacientes sometidos a la videolaparoscopía.
MÉTODO: Participaron en el estudio 60 pacientes divididos en 2 grupos iguales (GR y GS). El GR fue inducido con remifentanil IC y el GS con sufentanil en bolus asociado a IC. La IC de remifentanil se desconectaba al final de la cirugía, mientras que la IC de sufentanil 20 minutos antes. Los pacientes recibieron en el intraoperatorio cetoprofeno y dipirona. Como analgésico de rescate en la sala de recuperación pos anestésica (SRPA) se usó el tramadol. Fueron analizadas las variaciones de la PAM y FC, tiempo de despertar, consumo de propofol, intercurrencias en la SRPA y tiempo de permanencia en la SRPA.
RESULTADOS: El promedio de la PAM fue mayor en el GS con relación al GR (91,9 × 77,6, p < 0,0001). La incidencia de dolor fue significativamente mayor en el GR con relación al GS (22 × 1 paciente, p < 0,0001). La incidencia de NVPO fue mayor en el GR con relación al GS (10 × 2 pacientes, p = 0,0098). El promedio del tiempo de permanencia en la SRPA fue mayor en el GR en con relación al GS (76 × 49 min, p < 0,0001).
CONCLUSIONES: El control hemodinámico fue satisfactorio en los grupos. La IC de sufentanil generó un mejor control del dolor en el pos operatorio con menor consumo de analgésico de rescate, por lo tanto, se registró una menos incidencia de NVPO y un menor tiempo de permanencia en la SRPA.
Continuous infusion (CI) of remifentanil, as the analgesic component of total intravenous anesthesia is a common practice. On the other hand, CI of sufentanil in short and medium-term surgeries is not commonly done.
After remifentanil, sufentanil is the opioid with the most favorable pharmacokinetic profile for medium-term continuous infusion 1. However, there is a concern about the use of CI of this drug in short and medium-term surgeries due to the probable lengthening of awakening time and patient recovery. However, its residual effect can promote good quality analgesia in the postoperative period, which does not happen with remifentanil 1,2.
The objective of this study was to compare two techniques of total intravenous anesthesia, using CI of remifentanil or sufentanil, regarding the intraoperative anesthetic behavior and characteristics of the anesthetic recovery of patients undergoing non-gynecological videolaparoscopic surgeries.
After approval by the Ethics and Research Committee, 60 patients, ages 18 to 65 years, physical status ASA I and II, of both genders, randomly divided in two groups (RG and SG) according to the opioid used, participated in this study. Smokers, patients taking drugs that induce cytochrome P450, illicit drug users, and alcohol users, were excluded from the study. Patients were scheduled for non-gynecological videolaparoscopic surgeries and did not receive any pre-anesthetic medication. Monitoring use included non-invasive blood pressure, cardioscope, capnograph (after tracheal intubation), pulse oximeter (SpO2), and bispectral index (BIS). Before anesthetic induction patients were hydrated with 10 mL.kg-1 of Ringer's lactate. Intraoperatively fluid was infused at 5 mL.kg-1.h-1.
Anesthetic induction in RG consisted of a CI of remifentanil at 0.5 µg.kg-1.min-1 for 2 minutes followed by target-controlled infusion (TCI) of propofol with a target-dose of 4 µg.mL-1. Induction in SG consisted of a bolus of 0.5 µg.kg-1 of sufentanil followed by a CI of 0.5 µg.kg-1.h-1 and, after 5 minutes, TCI with propofol with a target-dose of 4 µg.mL-1 was instituted. When patients achieved a BIS of 50, they received 0.6 mg.kg-1 of rocuronium to facilitate tracheal intubation.
Intraoperatively, baseline CI of remifentanil and sufentanil was of 0.3 µg.kg-1.min-1 and 0.5 µg.kg-1.h-1, respectively. If the mean arterial pressure (MAP) increased by more than 15% of baseline values, CI of remifentanil was increased by 0.1 µg.kg-1.min-1 in RG, while in SG a 50 µg bolus of sufentanil was administered. However, if MAP fell more than 15% of baseline values the CI of remifentanil was reduced by 0.1 µg.kg-1.min-1 in RG, while in SG the CI was turned off until it returned to normal values.
The target-dose of propofol was adjusted to maintain BIS between 40 and 50. The continuous infusion of remifentanil was turned off at the end of the procedure, while the CI of sufentanil was turned off 20 minutes before the end of the surgery. All patients received 1.5 mg.kg-1 of ketoprofen and 30 mg.kg-1 of dypirone 20 minutes before the end of the procedure.
Intraoperative variations in MAP and heart rate (HR), time of awakening (spontaneous eye opening), consumption of propofol, incidence of pain, postoperative nausea and/or vomiting (PONV), respiratory depression in the recovery room, and length of stay in the recovery room were analyzed. Criteria used to diagnose respiratory depression included: SpO2 below 90%, and unresponsiveness to verbal and/or painful stimuli.
Mean arterial pressure and HR were recorded at the following moments: baseline in the operating room; after anesthetic induction; after tracheal intubation; at the beginning of surgery; after pneumoperitoneum, 5, 10, 15, 20, 25, 30, 45, and 60 minutes after pneumoperitoneum; at the end of the surgery; and at the end of anesthesia, after extubation.
In the recovery room, pain was evaluated by the Visual Analogue Scale (VAS). If VAS was equal to or greater than 4, 100 mg of tramadol IV was administered. To treat PONV, 4 mg of ondansentron IV was used. In case of respiratory depression, ventilatory support was provided and, if necessary, titrated doses of intravenous naloxone was administered.
The Student t test was used to analyze parametric variables and the Chi-square test was used for the non-parametric variables. A difference was considered statistically significant when p was less than 0.05.
Both groups did not differ regarding the types of surgery (Table I). The groups also did not differ regarding age, gender, weight, height, physical status ASA, and baseline MAP and HR (Table II). However, mean MAP was greater in RG than in SG (91.9 e 77.6, respectively, p < 0.0001) (Figures 1 and 2).
The data gathered intraoperatively, consumption of propofol, time of awakening, time of anesthesia, and mean heart rate in all moments did not show statistically significant differences (Table II). However, mean MAP was greater in SG than in RG (91.9 and 77.6, respectively; p < 0.0001) (Figures 1 and 2).
Among the data gathered in the immediate postoperative period, the incidence of pain was significantly greater in RG than in SG (22 and 1 patient, respectively, p < 0.0001). The incidence of PONV was also greater in RG than in SG (10 and 2 patients, respectively, p = 0.0098). The time of staying in the recovery room was greater in RG than in SG (76 and 49 min, respectively, p < 0.0001). One patient in SG developed respiratory depression in the recovery room (Table IV).
The mean remifentanil consumption was 0.29 µg.kg-1.min-1, while the mean sufentanil consumption was 0.016 µg.kg-1. min-1 (Table V).
The great development and popularization of total intravenous anesthesia (TIVA) began at the end of the decade of 1980 when propofol was introduced in clinical practice; and the posterior introduction of remifentanil stimulated this technique even more.
Among the opioids, remifentanil is the only drug with organ-independent metabolism. It is degraded by plasma and tissue esterases, which is responsible for its very short half-life. Even in CI, its half-life context-sensitive varies from 4 to 6 minutes, regardless of the duration of the infusion 3. Therefore, it should be used as a CI. Annex II of resolution 1,802/2006 of the Conselho Federal de Medicina recommends that every total intravenous anesthesia should be administered with an infusion pump.
On the other hand, sufentanil has the second best pharmacokinetic profile for medium-term CI. Even with a greater volume of distribution (Vdss 2.5 to 3.0 L.kg-1) and elimination half-life (T½b 15 to 20 minutes) than alfentanil (Vdss 0.4 to 1.0 L.kg-1; T½b 4 to 17 minutes), the clearance of sufentanil (Cl 10 to 15 mL.min-1.kg-1) is greater than that of alfentanil (Cl 4 to 9 mL.min-1.kg-1), which is responsible for a context-sensitive half-life smaller than that of alfentanil for infusions of up to eight hours. This difference can also be explained by the fact that the pharmacokinetic profile of sufentanil has a larger peripheral compartment and slower balance than alfentanil, which contributes to decrease the concentration of sufentanil in the central compartment after the infusion is discontinued 3.
In this study, mean MAP was lower in RG than in SG (Figure 1). This can be explained by the difference in "analgesic mass" used in both groups. The equipotent relationship between sufentanil and remifentanil is 1:10 and, therefore, sufentanil is 10 times more potent than remifentanil 1. In the present study, the relationship between the consumption of sufentanil and remifentanil was 1:18, since the mean dose of sufentanil was 0.016 µg.kg-1.min-1, and the mean dose of remifentanil was 0.29 µg.kg-1.min-1 (Table V). Therefore, the consumption of opioid was smaller in the sufentanil group, which might explain the higher mean MAP values in SG. But the mean HR was similar in both groups (Figure 2).
Due to different pharmacokinetic profiles and potencies, the infusion schedule of opioids used in this study could not be similar. Patients in RG did not receive a bolus dose of remifentanil because it has a low T½Ke0 (1.3 minutes) that promotes a fast balance between the plasma concentration and the concentration at the site of action. However, patients in SG received a bolus dose of sufentanil to optimize its concentration at the site of action (0.4 to 0.6 ng.ml-1), since its T½Ke0 is much higher (3 minutes) 1.
It should be mentioned that CI was discontinued at different moments for each group. In RG, it was discontinued at the end of the procedure because the context-sensitive half-life of remifentanil is short4. On the other hand, the context-sensitive half-life of sufentanil is longer (15 to 20 minutes for a 70-minute infusion), which would not allow for an early awakening if the infusion was maintained until the end of the procedure 5. The method used in the present study provided for an early awakening, which was similar in both groups (9 to 10 minutes).
The mean consumption of propofol was similar in both groups. The target-dose of propofol varied to maintain BIS between 40 and 50. The concentration of propofol at the site of action necessary to produce loss of consciousness is decreased in the presence of opioids, but a consistent relationship between the plasma concentration and propofol and BIS value does not exist 6,7.
Some authors have demonstrated, through computer simulations, that remifentanil is the opioid with greater synergism with propofol 8. Another study showed, through a clinical assay, a strong synergism between remifentanil and propofol 9. However, in the present study, the mean consumption of propofol in RG was not statistically different than in SG (118 and 110 µg.kg-1.min-1, respectively), suggesting that the association propofol-sufentanil is as or more synergic than the association propofol-remifentanil, considering that the "analgesic mass" was smaller in the sufentanil group. A recent study corroborates those results; however, in that study, the author considered an equipotent relationship of 1:30 between sufentanil/remifentanil 10.
Among the main intercurrences in the immediate postoperative period, the incidence of pain was especially relevant in the remifentanil group. In this group, 22 patients (73%) experienced postoperative pain with a VAS greater than 4. This shows that, even though videolaparoscopic surgeries are less invasive, the postoperative analgesic schedule used (non-opioid analgesic and non-steroidal anti-inflammatories) was not effective for pain control in the immediate postoperative period in GR.
Remifentanil has a fast metabolism and, therefore, does not have residual effects. On the other hand, sufentanil promotes good postoperative analgesia, even with plasma concentrations of 0.025 to 0.05 ng.mL-1. This is translated into a prolonged residual analgesic effect 1. In the sufentanil group, only one patient had important postoperative pain. This quality of postoperative analgesia promoted by sufentanil associated with the reduced postoperative consumption of analgesics was reported recently by other authors2,10. Postoperative hyperalgesia related with remifentanil cannot be discarded as being responsible for the high incidence of pain in RG 11.
Due to the greater consumption of rescue opioids (tramadol) in RG patients in the recovery room, the incidence of PONV was also greater in this group, prolonging even more their staying in that unit. Patients in RG stayed a mean of 27 minutes longer in the recovery room than SG patients. In a study with patients undergoing laparoscopy for cholecystectomy, the incidence of pain and PONV were the main factors responsible for a delay in discharge from the recovery room 12. In the same study, a transitory reduction in oxygen saturation was a secondary factor delaying discharge from the recovery room, but its clinical significance was questioned in the study 12.
The sufentanil group had one case of transitory respiratory depression. The ED50 of sufentanil for spontaneous breathing is 0.15 to 0.2 ng.mL-1 1. It is possible that sufentanil was redistributed during handling and transport of the patient from the operating room to the recovery room. This complication was easily resolved by ventilating the patient with 100% O2 with a face mask, and reversion with naloxone was not necessary. However, one should be ready to manage this type of occurrence, especially when using a high-potency intermediate-duration opioid.
To conclude, hemodynamic stability was satisfactory in both groups. The incidence of postoperative pain was greater in the remifentanil group, which increased the consumption of rescue opioids in the recovery room and, consequently, increasing the incidence of PONV and the length of stay in the recovery room. Even though remifentanil has pharmacokinetic properties responsible for a fast awakening and shorter recovery time, aggressive prophylaxis of postoperative pain should be initiated intraoperatively, even in surgeries with low postoperative morbidity.
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Correspondence to: Submitted em 28
de novembro de 2007 * Received from
CET/SBA Instituto Penido Burnier e Centro Médico de Campinas, SP
Dr. Ricardo Francisco Simoni
Rua Alzira de Aguiar Aranha, 552 Barão Geraldo
13084-768 Campinas, SP
Accepted para publicação em 19 de fevereiro de 2008
Submitted em 28
de novembro de 2007
* Received from CET/SBA Instituto Penido Burnier e Centro Médico de Campinas, SP