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Print version ISSN 0034-7094
Rev. Bras. Anestesiol. vol.57 no.3 Campinas May/June 2007
Remifentanil: does the infusion regimen make a difference in the prevention of hemodynamic responses to tracheal intubation?*
Remifentanil: ¿el régimen de infusión es la diferencia en la prevención de las respuestas circulatorias a la intubación traqueal?
Fernando Squeff Nora, TSAI; Rodrigo KlipelII; Gustavo AyalaII; Getúlio Rodrigues de Oliveira Filho, TSAIII
do Hospital de Clínicas de Porto Alegre, Presidente da CE/TSA da Sociedade
Brasileira de Anestesiologia
IIMédicos em Especialização no CET/SBA Hospital de Clínicas de Porto Alegre
IIIResponsável do CET/SBA Integrado de Anestesiologia da SES-SC
AND OBJECTIVES: High doses of opioids decrease the hemodynamic response
to tracheal intubation. However, the slow recovery profile of traditional opioids
may limit the use of high doses. Remifentanil has a fast time of onset and is
short acting, which differentiates it from the other drugs in this class. The
primary objective of this study was to verify the hypothesis that there is no
need to initiate the administration of remifentanil before the induction with
METHODS: Thirty patients, divided in two groups, who received total intravenous anesthesia, were evaluated. In Group 1, the infusion of remifentanil (0.3 µg.kg-1.min-1) was initiated two minutes before induction, and in Group 2, at the same time of the induction. Systolic, diastolic, and mean arterial blood pressure (SBP, DBP, MAP), heart rate (HR), concentration of propofol (CEF-prop) and remifentanil (CEF-remi) in the effector area in three moments: baseline (M0), after losing verbal contact (M1), and after tracheal intubation (M2) were evaluated.
RESULTS: There were significant reductions in blood pressure in both groups at M1 and M2. CEF-remi was greater in Group 1, at M1, and greater in Group 2, at M2 (p < 0.05). There was a significant statistical correlation between the vascular overload index (VOI) and the variation of the systolic pressure after the loss of verbal contact in Group 1 (r = -0.80; p < 0.01) and in Group 2 after tracheal intubation (r = -0.60; p < 0.01).
CONCLUSIONS: Remifentanil administered two minutes before induction with propofol did not offer additional cardiovascular protection to tracheal intubation. This suggests that it is not necessary to start the infusion of remifentanil two minutes before anesthetic induction.
Key Words: ANALGESICS, Opioid: remifentanil; ANESTHETICS, Intravenous: propofol; ANESTHETIC TECHNIQUES, General: total intravenous.
Y OBJETIVOS: Los opioides en dosis elevadas disminuyen la respuesta circulatoria
a la intubación traqueal. Sin embargo, el lento perfil de recuperación
de los opioides tradicionales puede limitar la utilización en altas dosis.
El remifentanil posee tiempo de inicio y de término de acción
rápidos y previsibles, lo que lo diferencia de los demás. El objetivo
primario de este estudio fue verificar la hipótesis de que no hay necesidad
de iniciar la administración de remifentanil antes de la inducción
con el propofol.
MÉTODO: Fueron evaluados 30 pacientes, divididos en dos grupos, que recibieron anestesia general intravenosa total. En el Grupo 1, la infusión de remifentanil (0,3 µg.kg-1.min-1) se inició dos minutos antes de la inducción y, en el Grupo 2, conjuntamente con la inducción. Se evaluaron las presiones arteriales sistólica, diastólica y promedio (PAS, PAD, PAM), frecuencia cardiaca (FC), concentraciones en el local efector de propofol (CEF-prop) y de remifentanil (CEF-remi) en tres momentos: basal (M0); después de la pérdida del contacto verbal (M1); y después de la intubación traqueal (M2).
RESULTADOS: Las presiones arteriales presentaron reducciones significativas en los dos grupos: M1 y M2. La CEF-remi fue mayor en el Grupo 1, en M1 y mayor en el Grupo 2, en M2 (p < 0,05). Hubo correlaciones estadísticas significativas entre el índice de sobrecarga vascular (ISV) y la variación de tensión sistólica después de la pérdida del contacto verbal en el Grupo 1 (r = -0,80; p < 0,01) y después de la intubación traqueal en el Grupo 2 (r = -0,60; p < 0,01).
CONCLUSIONES: El remifentanil administrado dos minutos antes de la inducción con el propofol no causó protección cardiovascular adicional a las maniobras de intubación traqueal. Eso nos sugiere que el inicio de la infusión de remifentanil dos minutos antes de la inducción sea innecesario.
Several authors have described that the reduction of the response to trauma during general anesthesia may be obtained by the use of high doses of intravenous opioids. However, high doses of opioids may cause important side effects, besides prolonging recovery time.
Context-dependent half-life is the time it takes to decrease the plasma concentration of an agent to half of what had been maintained after its administration has been discontinued. It is the parameter used most often, in intravenous anesthesia to determine the predicted time to the end of the action of a drug administered by continuous intravenous infusion 1. Plasma concentrations of sufentanil, fentanyl, and alfentanil capable of providing good protection against intraoperative nociceptive stimuli, during continuous infusion, present context-dependent half-lives that vary from 35 to 45 minutes. Due to this slow recovery profile, associated with an increase in the number of outpatient procedures, as well as the possibility of early extubation in large size surgeries, remifentanil was developed. Due to its pharmacokinetic characteristics, it was developed for continuous administration, which demonstrated predictable fast onset and end of action 2.
Among the adverse effects of opioids are bradicardia, hypotension, thoracic rigidity, respiratory depression, and myocardial depression. Their severity varies according to the speed of the injection, dose, physical status, concurring diseases, potency, and pharmacologic interaction. During induction of general anesthesia, opioids are used to protect against the responses to laryngoscopy and intubation, and should be used carefully. Due to the prolonged latency time of some opioids, they are routinely used a few minutes before induction. The onset of action of an opioid depends, among other factors, on its Ke0 pharmacokinetics variable that determines the speed in which an opioid moves from the plasma to the effector or receptor compartment. The faster the speed of entrance in the receptor, the faster the onset of action. Thus, remifentanil and alfentanil have a faster onset of action, while sufentanil and fentanyl have a slower onset of action 2,3.
This work postulated the hypothesis that it is not necessary to administer an initial bolus or initial doses in continuous infusion of remifentanil before induction, once its onset of action and peak action are fast.
The secondary objective of this work was to determine whether the use of remifentanil before induction would cause greater hemodynamic depression when compared with its administration at the beginning of induction.
After approval by the Ethics committee and signing of the informed consent, 30 patients were enrolled in the study, as outpatients, after the appropriate time of fasting. Patients did not receive any preanesthetic medication. Monitoring included non-invasive systolic (SBP), diastolic (DBP), and mean arterial (MAP) blood pressure, pulse oxymetry, electrocardiogram on DII derivation, and heart rate (HR). Venoclysis was performed with a 20G catheter and normal saline was administered at the highest rate allowed by the device in every patient. Intravenous remifentanil was used at a concentration of 0.1 mg.mL-1. It was administered at 0.3 µg.kg-1.min-1 with a mechanical infusion pump (Santronic®) in both groups. Patients were randomly divided in two groups. When the patients in Group 1 (n = 16) arrived at the operating room, SBP, DBP, MAP, and HR were recorded with the patient awake baseline measurements (M0). The infusion of remifentanil was initiated two minutes before induction and SBP, DBP, MAP, HR, and the dose of remifentanil infused in mL were recorded. Afterwards, the concentrations obtained in the effector (CEF-remi) compartment were calculated based on the time of infusion 4,5. These data were obtained using a software called TIVATRAINER®, whose pharmacokinetic parameters used to calculate the concentrations expected are described in table I. After this two-minute period, the infusion of propofol was initiated with a target-controlled infusion pump (Diprifusor®). The initial plasma target of propofol was 4 µg.mL-1 with the infusion time on the flash mode. The concentration in the effector area was provided by the propofol pump. For propofol, the pharmacokinetic model to predict the concentration on the effector area was the same incorporated to the infusion pump and described by Marsh et al. 6,7, whose attributes are described in table I. When the patient lost verbal contact, SBP, DBP, MAP, HR, volume of remifentanil infused (mL), and concentration of propofol in the effector area (provided by the infusion pump) were recorded (M1). After losing verbal contact, 0.6 mg.kg-1 of rocuronium was administered intravenously. Manual ventilation with oxygen using a facemask was initiated and maintained until the estimated concentration of propofol in the effector area achieved 2.7 µg.kg-1. At this moment, the patient was intubated. SBP, DBP, MAP, HR, and volume of remifentanil in mL were recorded immediately afterwards (M2). The study was interrupted after those measurements were obtained and the anesthesia proceeded according to the preference of the anesthesiologist. In Group 2 (n = 14), the same data were collected at the same moments (M0, M1, and M2). The only difference was that the infusion of remifentanil was initiated at the same time as the infusion of propofol.
The test t Student (continuous variables) and Fisher Exact test (categorical variables) were used to analyze the demographic data. The comparison between groups at each moment of the study (intergroups) and of the moments in each group (intragroup) was done by the bifatorial Analysis of Variance for repeated measurements followed by the post hoc Student-Newman-Keuls test for SBP, DBP, MAP, HR, and CEF-remi (M1 and M2 only). The Delta SBP was calculated according to the formula: Delta SBP = ((SBP at the moment baseline SBP) / baseline SBP) × 100. The vascular overload index was also calculated (VOI = 1.33 SBP 0.33 DBP 133) 8.
Linear regression analysis between VOI and CEFI-remi (independent) and Delta SBP at M1 and M2 in each group was also done.
Both groups were demographically homogenous (Table II). The systolic, diastolic, and mean arterial blood pressures presented statistically significant reductions in both groups after loss of verbal contact (M1) and after tracheal intubation (M2) when compared with baseline measurements (M0), but there were no differences between the groups (Figures 1 to 3). There were no differences in heart rate at any time and between both groups (Figure 4). Analysis of Delta SBP did not show any statistically significant difference at any time or between both groups (Figure 5). CEF-remi showed statistically significant differences between the groups and at the moments evaluated. After loss of verbal contact (M1), CEF-remi was greater (4 - 5.8 ng.mL-1) in Group 1 (remifentanil was initiated two minutes before induction) when compared with Group 2 (3.0 - 6.5 ng.mL-1). After tracheal intubation (M2), CEF-remi was smaller in Group 1 than in Group 2 (Figure 6). There were statistically significant correlations between VOI and the variation of systolic blood pressure after loss of verbal contact, in Group 1 (r = -0.80; p < 0.01), and after tracheal intubation in Group 2 (r = -0.60; p < 0.01) (Figure 5).
Hemodynamic changes secondary to anesthetic induction during general anesthesia are common. The use of opioids during induction, among other aspects, helps to block the reflexes secondary to laryngoscopy and tracheal intubation. The major problems associated with the use of opioids are related to the doses needed to achieve adequate protection and to the cardiovascular effects secondary to increasing the dose. Higher doses are necessary for a more effective protection against the reflexes of laryngoscopy and tracheal intubation. Long-acting opioids used in higher doses can cause bradycardia and hypotension, besides respiratory depression. Remifentanil, an opioid with fast onset of action and short acting, can be a good option when compared to the other opioids in clinical use. The routes of administration and the doses of remifentanil to be used in general anesthesia are controversial. Some authors recommend elevated infusion doses (1 µg.kg-1.min-1) while others recommend smaller doses (0.3 to 0.5 µg.kg-1.min-1) 9-11. The time to begin the administration of remifentanil has not been described in the literature. Under the conditions of this study, it was possible to demonstrate that, when remifentanil was administered two minutes before induction with propofol, there was no additional cardiovascular protection against the maneuvers of tracheal intubation. The prior administration of remifentanil did not cause circulatory changes different than those observed with the simultaneous administration of propofol. This suggests that the administration of remifentanil two minutes before anesthetic induction is not necessary. The hypothesis that the prior administration of remifentanil could cause greater respiratory depression was not confirmed, although the correlations between VOI and the variation of the systolic blood pressure were significant at some moments. Thus, in patients who received remifentanil two minutes before induction, during the loss of verbal contact (M1) the ventricular overload index was inversely proportional to the systolic blood pressure. The same correlation between VOI and Delta SBP could be observed in Group 2 after tracheal intubation. Note that, in Group 2, after tracheal intubation CEF-remi was more elevated than in Group 1, which could explain the greater reduction in systolic pressure in those patients. The higher CEF-remi in the group of patients with smaller infusion time was a surprise.
This can be explained by the way the simulations to obtain the CEF-remi were performed. The volumes of remifentanil administered at the moments of the measurements were used to obtain, through a simulation, the CEF-remi. Although there were no statistically significant differences between both groups regarding age, when the simulation is performed in the TIVATRAINER it alters pharmacokinetic parameters, such as volume of distribution in the compartments and Ke0 when the age of the patient is informed. Therefore, patients older than 50 years have smaller volumes of distribution in the first compartment and Ke0 when compared with younger patients. In this study, the dose of remifentanil administered was the same in both groups, what could have caused a greater plasmatic concentration in Group 2, despite the length of infusion, due to age. Although we did not find important differences between both groups when age was analyzed, the higher mean age in Group 2 could have caused this result, since the simulator alters the pharmacokinetic parameters of remifentanil when the age of the patient is informed. Increasing the size of the study sample might prove that. Nevertheless, this result is an important reinforcement of the need to use target-controlled infusion pumps for remifentanil. Although the profiles of beginning and end of action of remifentanil show little change with the doses used, the changes in the concentration in the effector area generated by age justify the correction of this variable when calculating the dose of infusion in order to decrease the side effects of remifentanil. Several authors have demonstrated that the dose of remifentanil during anesthetic induction in patients older than 50 years should be reduced by 50% and, for patients above 80, it should be reduced by 66% 12. The absolute number of patients above 50 years in Group 2 was greater than in Group 1; however, the doses used were not reduced. When the simulation was run to calculate CEF-remi, the concentrations generated in patients older that 50 years were higher, explaining the differences between Groups 1 and 2, regardless of the duration of the infusion. The elevated dilution of remifentanil (0.1 mg.mL-1) used in this study could have limited the flow of the infusion pump and, therefore, generated greater variations in the total volume administered. This could have caused greater distortion when extrapolating the volume administered for later simulation to obtain the CEF-remi. The pharmacokinetic distortion caused by the interpersonal variability and pharmacokinetic model used are other factors that could have contributed for these results. Several authors indicated the importance of using computerized infusion systems for intravenous drugs to avoid fluctuations in plasma levels during total intravenous anesthesia 12,13. The hemodynamic variations were significant and similar in both groups and compatible with those described in the literature. Likewise, there are controversies regarding the use of a bolus dose of remifentanil during anesthetic induction 11,14,15.
Glass et al. described that minimal doses remifentanil, between 0.1 and 0.3 µg.kg-1.min-1, should be administered by infusion during anesthetic induction to maintain adequate protection 3,9. Myre et al. studied two different administration regimens of remifentanil and found similar results regarding protection of tracheal intubation reflexes 16. They administered a dose of 0.13 µg.kg-1.min-1 to a group of patients and 0.39 µg.kg-1.min-1 to another group. Note that they used the second decimal to demonstrate the doses for each group. Small variations in the administration of remifentanil are responsible for faster and greater variations in plasma concentration due to its distribution profile. Under the conditions of this study, we concluded that the prior administration of remifentanil did not cause circulatory changes different from those when remifentanil was initiated at the same time as propofol. The hemodynamic changes after tracheal intubation were the same, regardless of when the infusion of remifentanil was initiated. The greater incidence of bradicardia and hypotension with the prior administration of remifentanil, as originally suspected, did not occur. The simultaneous administration of remifentanil during induction was as effective as the prior administration of this drug. There were significant reductions in SBP, DBP, and MAP after induction and after tracheal intubation in both groups. The vascular overload index predicts the reduction in blood pressure after induction only when remifentanil is administered before induction. When it is administered simultaneously with propofol it only predicts the reduction of the systolic pressure after tracheal intubation. The direct measurement of the plasma concentration could explain this result.
This study allowed us to conclude that the prior administration of remifentanil during induction did not bring additional benefits. The prior administration of this drug did not cause greater cardiovascular depression when compared with the simultaneous administration. The correction of the pharmacodynamic parameters of infusion of remifentanil for age, done by the target-controlled pumps, can make a difference when compared with manual pumps.
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Fernando Squeff Nora
Rua Almirante Abreu, 235 Rio Branco
90420-010 Porto Alegre, RS
em 22 de maio de 2006
Accepted para publicação em 29 de janeiro de 2007
* Received from CET/SBA Hospital de Clínicas de Porto Alegre e CET/SBA Integrado de Anestesiologia da Secretaria de Estado da Saúde de Santa Catarina (SES-SC), Florianópolis, SC