Tracheal intubation (TI) and skin incision (SI) induce clinically relevant hemodynamic changes (1), and various pharmacological strategies have been suggested to control cardiovascular responses induced by these nociceptive stimuli (2–5). Opioids, such as fentanyl, alfentanil, and sufentanil, are widely used to control cardiovascular responses induced by TI and SI (6,7), and a dose-effect relationship exists between increasing the opioid dose and reducing cardiovascular changes (8).
Remifentanil is a selective μ-opioid receptor agonist with a rapid onset, short duration, and a short blood/effect-site equilibration half-time (9). It is effective in preventing sympathetic responses induced by TI and other surgical stimuli (8–10). Because of its unique pharmacokinetic and pharmacodynamic profile, remifentanil is ideally suited for continuous IV infusion (9,10), whereas the use of a target-controlled infusion (TCI) using a computer-driven infusion device has been demonstrated to be more effective in maintaining cardiovascular stability as compared with traditional weight-adjusted infusions (11).
However, little information is available in the literature on the effect-site concentration of remifentanil required to control hemodynamic changes induced by different surgical stimuli during total IV anesthesia. We therefore conducted this prospective, randomized, double-blind study to determine the effect-site concentration of remifentanil blunting cardiovascular responses after TI and SI in patients receiving a bispectral index (BIS)-guided propofol anesthesia.
After obtaining the approval of our institutional ethics committee and written informed consent, 41 ASA physical status I–II patients, aged 20–65 yr, scheduled for elective abdominal surgery requiring TI were prospectively enrolled. Patients undergoing laparoscopic procedures, obese patients (body mass index >30) or patients with a history of cardiac, pulmonary, or renal diseases, drug or alcohol abuse, or current use of any medication affecting the cardiovascular system or blocking the adrenergic responses to TI and SI and patients at risk for gastric aspiration on induction of anesthesia or with upper airway abnormalities that might prolong the time required for intubation (Mallampati classification ≥2) were excluded. No local anesthetics, atropine, epinephrine, or others vasoactive medications were used before TI and SI. Muscle relaxation was obtained in all patients with IV bolus of cisatracurium bromide (0.2 mg/kg).
Patients fasted for 8 h before surgery and received no premedication. After arrival in the operating room 2 18-gauge IV cannulas were placed in forearm veins to keep the 2 infused drugs separate, and 10 mL/kg Ringer’s lactate solution was infused. Standard monitoring was used throughout the study, including noninvasive arterial blood pressure (Dinamap 1846SX, Critikon, FL, USA), electrocardiography, heart rate (lead II), and pulse oximetry. In all patients the BIS was also monitored using an electroencephalograph monitor (BIS XP monitor A 2000; Aspect Medical Systems Inc., Natick, MA). According to a computer-generated sequence of random numbers, patients were assigned to two groups: in the first group we determined the effect-site concentration of remifentanil required to control hemodynamic changes induced by TI (group TI, n = 20); in the second group, after TI was provided and a further 10-min period elapsed with stable hemodynamic variables and BIS values, we determined the effect-site concentration of remifentanil required to control hemodynamic changes induced by SI (group SI, n = 21).
Anesthesia was performed using a TCI (Marsh model, keo = 0.25) for administering propofol (fm anesthesia; B. Braun, Melsungen AG, Germany). Initially, a target plasma concentration of 4 μg/mL was chosen. After obtaining a stable BIS value ranging between 40 and 50 with a constant target controlled concentration the attending anesthesiologist pushed the “Lock” button of the fm anesthesia system. In this manner the pump uses the value of predicted propofol concentration at the effect site as the plasma target concentration to maintain a steady-state concentration with the same predicted values in the plasma and effect site. This steady-state infusion regimen for propofol was maintained for 15 min.
Remifentanil was administered using a pharmacokinetic model-driven computer-assisted continuous infusion system to achieve and maintain constant target effect-site concentrations (11,12). The system consisted of an Acer TravelMate 518TX computer connected to a Graseby 3500 infusion pump (Sims Graseby Limited, Watford, Herts, UK) using the Rugloop software (designed by Tom De Smet and Michel Struys, Department of Anesthesia, University Hospital, Ghent, Belgium) with the pharmacokinetic variables described in the model of Minto et al. (13,14). Remifentanil infusion was started when the “Lock” button of the fm anesthesia system was pushed and maintained at the designed target plasma concentration for at least 10 min before administering the randomized stimulation.
To cover stress responses induced by TI, patients in group SI received an initial effect-site concentration of remifentanil of 4 ng/mL. Then the effect-site concentration of remifentanil was set at the designed concentration according to the up-and-down sequence, and we waited for a 15 min period, in which hemodynamic variables were within 15% of values recorded before TI. In some patients in group SI, it was not possible to keep hemodynamic variables within 15% of values recorded before intubation for a 15-min period before SI; these patients were withdrawn from the study and the same concentration of remifentanil was repeated with the following case.
In group TI heart rate and mean arterial blood pressure (MAP) were recorded before induction of anesthesia, 1 and 2 min before TI (prestimulation values), at TI, and then at 1-min intervals during the first 5 min after TI. In group SI heart rate and MAP were recorded before induction of anesthesia, 1 and 2 min before SI (prestimulation value), at SI, then at 1-min intervals during the first 5 min after SI. The prestimulation value of MAP and heart rate was defined as the mean value of the 2-min and 1-min measurements before TI and SI for groups TI and SI, respectively. If MAP decreased before TI or SI to a level that required the administration of a vasoactive drug (MAP <50 mm Hg), the patient was withdrawn from the study, and the same concentration of remifentanil was repeated with the following case.
The effect-site concentration of remifentanil blunting cardiovascular responses to TI and SI in 50% of patients (Ce50) was then determined using a modified up-and-down sequential allocation technique (15–17). The first patient of group TI received an effect-site concentration of remifentanil of 6 ng/mL, and the first patient of group SI received an effect-site concentration of remifentanil of 4 ng/mL.
The response of each patient determined the effect-site concentration of remifentanil given to the succeeding patient. If the response of the preceding patient was positive (an increase in either heart rate or MAP ≥15% more than the mean of the values measured during the 2 min before TI or SI, respectively), the effect-site concentration given to the next patient was increased by 1 ng/mL. If the response was negative (neither heart rate nor MAP increased ≥15% more than the mean of the values measured during the 2 min before TI or SI, respectively), the effect site concentration of remifentanil given to the next patient was decreased by 1 ng/mL. The anesthesiologist recording cardiovascular variables and determining the positive/negative response to SI was blinded as to the effect-site concentration of remifentanil given to the patient.
To increase the precision of the final estimator we used a modified up-and-down method based on altering the test space (16). In this modified method the up-and-down sequence is in two stages: the first stage consists of an original up-and-down sequence on the predetermined equally spaced test levels until three to four changes of response type are observed. The second stage consists of reducing the initial test space and restarting the up-and-down sequence at the nearest level to the average and continuing the experiment at the next higher or the next lower level according to the response type on the reduced test space. According to this modified up-and-down method, after the first 3 negative-positive up-and-down crossovers, the initial test space was reduced to 0.5 ng/mL for an a priori number of independent negative-positive up-and-down crossovers of 4 with the new reduced test space (16). The mean (95% confidence intervals, 95% CI) of the Ce50 of remifentanil was then calculated from the midpoints of paired concentrations from consecutive patients in which a negative response was followed by a positive one after the initial test space was reduced (15–17). According to this design we predetermined to enroll 20 patients in each group.
Statistical analysis was performed using the program Statistica 5.1 (StatSoft Italia, Vigonza, Padova, Italy). With all pooled data obtained from the up-and-down sequence in the two groups we also calculated the EC50 and EC95 using a probit transformation and a logistic regression analysis. Changes in heart rate and MAP after induction of general anesthesia were analyzed using a two-way analysis of variance for repeated measures with the Scheffé test and Fisher’s test for post hoc analysis. Student’s t-test with the Bonferroni’s correction for multiple comparisons was also used as indicated. A value of P < 0.05 was considered statistically significant. Data are presented as mean ± sd and 95% CI.
Forty-eight patients were screened; 2 patients refused the study before induction of general anesthesia, and 5 patients (2 in group TI and 3 in group SI) were withdrawn as a result of either hypotension requiring administration of vasoactive drugs before the designed stimulation (2 patients of group TI and 1 of group SI) or the impossibility of maintaining hemodynamic variables within 15% of preintubation values (2 patients of group SI). Forty-one patients completed the study.
There were no differences in patient characteristics, preoperative heart rate, arterial blood pressures (systolic and diastolic), baseline values of heart rate and MAP, or mean BIS values between the two groups (Table 1). Heart rate and MAP decreased significantly after induction of anesthesia in both groups (P < 0.0001 and P < 0.001, respectively, in group TI; P < 0.00001 and P < 0.0001, respectively, in group SI) (Table 1). The effect-site concentration of propofol maintaining a stable BIS value between 40 and 50 during the study period was 3.4 μg/mL (95% CI, 3.1–3.7 μg/mL).
Figures 1 and 2 show individual responses to TI and SI according to the up-and-down sequence. The mean (95% CI) Ce50 of remifentanil blunting the sympathetic response to TI was 5 ng/mL (95% CI, 4.7–5.4 ng/mL); the Ce50 of remifentanil blunting sympathetic responses to SI was 2.1 ng/mL (95% CI, 1.4–2.8 ng/mL). Using a probit transformation and logistic regression analysis we also calculated the EC50 and EC95 for blockade of cardiovascular responses to TI and SI: the EC50 and EC95 for block of cardiovascular responses to TI were 4.6 ng/mL (95% CI, 4.2 – 5 ng/mL) and 6.0 ng/mL (95% CI, 5.5–6.7 ng/mL), respectively, whereas the EC50 and EC95 for block of cardiovascular responses to SI were 2.2 ng/mL (95% CI, 2.0–2.4 ng/mL) and 3.6 ng/mL (95% CI, 3.2–4.0 ng/mL), respectively. The EC50 values calculated from the logistic regression analysis did not differ significantly from the Ce50 values obtained with the up-and-down method.
Figures 3 and 4 show individual changes in BIS values measured before and after TI or SI, respectively. Only one patient in group TI showed an increase of BIS to 60 after TI, without significant changes of hemodynamic variables. The day after surgery this patient was questioned about implicit or explicit recall of intraoperative events, but she did not report any.
Sympathetic responses to TI and SI are clinically relevant end-points to assess the depth of anesthesia (1). During inhaled anesthesia it is possible to determine the MAC of the volatile anesthetic blunting cardiovascular responses to surgical stimuli (MACBAR) and evaluate the effects of different drugs on this index (18); however, this is more difficult during total IV anesthesia even though the use of TCI systems has markedly increased the quantitative control of administered drugs (12). Several investigations have evaluated the use of TCI propofol for total IV anesthesia and the pharmacodynamic interactions between propofol and different opioids (6,19); however, little information is available on the effect-site concentration of remifentanil required to blunt cardiovascular responses to TI and SI. Our results showed that achieving and maintaining an effect-site concentration of remifentanil of 5 ng/mL and 2 ng/mL blunts sympathetic responses to TI and SI, respectively, in 50% of patients receiving a BIS-guided propofol anesthesia. Achieving an efficacy in only 50% of patients is not clinically useful because we must control stress responses in all patients. Accordingly, we calculated the EC95 of the required effect-site concentration of remifentanil using a logistic regression analysis, and obtained values as high as 6.0 ng/mL and 3.6 ng/mL to blunt hemodynamic responses to TI and SI, respectively.
Previous studies have investigated the most appropriate dose of opioid to be given in combination with propofol to prevent cardiovascular changes induced by TI (12,20), especially when intubating without muscle relaxation (4), whereas no information was available on the dose of remifentanil required to control SI. Mertens et al. (20) evaluated the effect-site concentrations of the combination of propofol and remifentanil suppressing hemodynamic responses to TI in women and reported that a plasma concentration of propofol of 2 μg/mL was the Ce50 of propofol for intubation when combined with a remifentanil plasma concentration of 5 ng/mL. This difference can be reasonably explained by the different statistical approach used and the different patient populations involved in the two studies. In fact, optimizing the TCI of propofol based on the BIS value resulted in a much larger concentration of propofol as compared with Mertens et al.’s study, making the comparison between the two investigations difficult. Conversely, the mean plasma concentration of propofol required to maintain an adequate level of hypnosis in the present investigation (3.4 μg/mL) was almost the same as the one reported in a previous investigation to obtain loss of consciousness (21).
When evaluating the plasma concentration of propofol (CP50) required for TI and SI, Kazama et al.(3) reported values as high as 17.4 μg/mL and 10.0 μg/mL, respectively. However, opioids are not able to completely replace inhaled or IV anesthetics to provide anesthesia (22). In the present investigation we separated analgesia and hypnosis as different components of anesthesia, maintaining an adequate and stable level of hypnosis by using a TCI of propofol that maintained a BIS value ranging between 40 and 50 (23); in agreement with Wakeling et al.,(24) we administered these drugs to a target effect-site concentration rather than plasma concentration to minimize the hysteresis between blood concentration and drug effect.
Guignard et al. (5) evaluated the usefulness of monitoring changes in BIS as an index of the analgesic component of anesthesia and suggested that under a constant regimen of propofol administration BIS could be as sensitive as changes in hemodynamic variables after a painful stimulus to detect an inadequate analgesic component of anesthesia. In the present study BIS showed no significant changes in patients with positive sympathetic response to TI and SI except in one patient whose BIS value increased up to 60 after SI. In contrast with Guignard et al. (5), this finding suggests a poor efficacy of BIS and electroencephalographic monitoring in predicting a deficit in the analgesic component of anesthesia. Conversely, it must also be said that even with small doses of opioids patients can be aware of intraoperative events, despite the lack of changes in cardiovascular variables. Accordingly, changes in cardiovascular variables can be considered an effective goal to assess the depth of anesthesia only if an adequate level of hypnosis is assured by BIS monitoring.
The lack of direct determination of remifentanil plasma concentrations can be considered a shortcoming of the study. However, the pharmacokinetic model we used to achieve and maintain a stable plasma concentration of remifentanil has been demonstrated as adequately accurate in predicting plasma and effect-site concentrations of remifentanil (13,14).
In the present investigation we used a computer-assisted TCI to achieve and maintain stable effect-site concentrations of remifentanil. TCI of remifentanil has been demonstrated to allow an easy and rapid adaptation of the levels of analgesia, resulting in better stability of perioperative hemodynamics as compared with continuous weight-adjusted infusion (11). However, the use of TCI principles for remifentanil infusion still requires complex systems, including a computer to control the infusion pump. For practical purposes, when using a conventional weight-adjusted administration, similar results can be achieved in daily practice with infusing a 0.5 μg/kg bolus during a 60-second period followed by a continuous infusion of 0.2 μg · kg−1 · min−1 for the 5 ng/mL concentration and a 0.35 μg/kg bolus during a 60-second period followed by a continuous infusion of 0.08 μg · kg−1 · min−1 for the 2 ng/mL concentration.
In conclusion, this prospective, randomized double-blind study demonstrates that the target-controlled concentration of remifentanil blunting sympathetic responses to TI in 50% of patients when combined with a BIS-guided TCI of propofol is as large as 5 ng/mL, whereas the required effect-site concentration of remifentanil producing the same effect for SI decreases to 2 ng/mL.
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