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ANESTHETIC PHARMACOLOGY

Low and Moderate Remifentanil Infusion Rates Do Not Alter Target-Controlled Infusion Propofol Concentrations Necessary to Maintain Anesthesia as Assessed by Bispectral Index Monitoring

Lars P. Wang, FANZCA^*, Peter McLoughlin, FANZCA^*, Michael J. Paech, FANZCA, DM WAust, Irina Kurowski, FANZCA^*, and Emma L. Brandon, FRCA^*

From the *Department of Anaesthesia and Pain Medicine, Royal Perth Hospital, Perth, Western Australia, Australia; and the Pharmacology and Anaesthesiology Unit, School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia.

Address correspondence and reprint requests to Lars Wang, FANZCA, Department of Anaesthesia and Pain Medicine, Royal Perth Hospital, Wellington St, Perth WA 6000, Australia. Address e-mail to lpwang{at}iinet.net.au.

	Abstract

Top Abstract Introduction METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
BACKGROUND: We investigated whether the EC₅₀ (the effective concentration that is required to achieve a response in 50% of patients) of propofol necessary to lower the Bispectral Index (BIS) value to 50 or less was reduced by coadministration of different remifentanil infusion rates.

METHOD: Seventy-two adult ASA I or II patients undergoing endotracheal intubation and target-controlled infusion (TCI) propofol anesthesia were allocated to six groups by stratified randomization. Group B received remifentanil 0.1 µg · kg^–1 · min^–1, Group C 0.15 µg · kg^–1 · min^–1, Group D 0.2 µg · kg^–1 · min^–1, Group E 0.3 µg · kg^–1 · min^–1 and Group F 0.4 µg · kg^–1 · min^–1. Group A served as control and received no remifentanil. The response of the first patient to propofol TCI at 4 µg/mL determined the effect-site concentration of propofol for the next patient in the same remifentanil group (Dixon's "up-and-down" method). If BIS was >50, the next patient received more propofol, and if BIS was 50, the next patient received less propofol. The hemodynamic effects of the combinations were also studied.

RESULTS: The EC₅₀ varied from 2.4 to 2.9 µg/mL. No additive effect of remifentanil on the EC₅₀ of propofol was observed. However, there was a wider variation in the response to propofol when the patients received no remifentanil. There was a decrease in heart rate in the remifentanil groups.

CONCLUSION: Infusion of remifentanil did not reduce propofol requirements in the unstimulated anesthetized patient. Propofol TCI levels should not be reduced because remifentanil is coinfused.

	Introduction

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The combination of a remifentanil and a propofol infusion allows for the administration of small doses of short-acting anesthetic drugs. This is advantageous in day surgery in procedures after which there is minimal postoperative pain and in some neurosurgical patients, because it is likely to reduce initial recovery time. Although effect-site concentrations of propofol in the range of 3–4 µg/mL are usually required to produce satisfactory anesthesia (1–3), our clinical impression was that the required propofol concentration is lower when remifentanil is coinfused.

Remifentanil, a potent opioid, is likely to produce useful obtundation of motor and autonomic responses to nociceptive stimuli when combined with propofol. Studies have investigated the dose combinations of propofol and remifentanil necessary to achieve a satisfactory level of anesthesia for intubation and endotracheal suctioning (4) or for gastrointestinal endoscopy in pediatric patients (5). These studies found that remifentanil reduced the necessary effect-site concentration of propofol (5) and that increasing the dose of remifentanil ablated the motor response to stimulation (4). Because of this synergy of propofol and remifentanil infusions on "anesthesia," coinfusion may allow a reduction in the infusion rates with the aim to promote recovery and still maintain anesthesia.

Bispectral index (BIS) monitoring assesses the hypnotic state during anesthesia, and the manufacturer recommends that it should be maintained in the 40–60 range. Below BIS of 55, patients are extremely unlikely to have recall of intraoperative events (6). The introduction of BIS has enabled a more detailed analysis of each of the anesthetic components of hypnosis and antinociception. Previous studies have found an additive effect of opioids (including remifentanil) on thiopental, etomidate, and propofol to reach a clinical end point (4,7–11). Few studies have exclusively evaluated the effects of opioids on BIS, and the influence of remifentanil on hypnosis is more debated in the literature than its influence on antinociception. Two studies have demonstrated a hypnotic effect of remifentanil, i.e., reduction of BIS values, in patients undergoing surgery (12,13).

We used BIS monitoring to examine the interaction between propofol and remifentanil with respect to the hypnotic properties of propofol in unstimulated, paralyzed, tracheally intubated patients. The aim of this study was to estimate the EC₅₀ of propofol required for lowering the BIS value to 50 or less, either alone or in the presence of five different infusion rates of remifentanil. The EC₅₀ is the effective concentration that is required to achieve a response in 50% of the patients; in our case a BIS value 50. Our hypothesis was that remifentanil would have an additive or synergistic effect and would reduce the EC₅₀ of propofol.

	METHODS

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The protocol received institutional ethics committee approval, and written informed consent to participate in the trial was obtained from all patients. The Dixon "up-and-down" sequential allocation method was used to determine the EC₅₀ of propofol at each remifentanil dose rate (14,15). This method requires a propofol dose schedule to be drawn up a priori, with doses evenly spread on a logarithmic scale and including the predicted EC₅₀. We chose a logarithmic dose interval of 0.1 which resulted in targeted effect-site concentrations of 5.0, 4.0, 3.2, 2.5, 2.0, or 1.6 µg/mL and assumed the EC₅₀ of propofol would be in the range of 3.0–4.0 µg/mL (1–3). Five infusion rates of remifentanil (0.1, 0.15, 0.2, 0.3, and 0.4 µg · kg^–1 · min^–1) were studied and compared to a control group without remifentanil.

When using the up-and-down method, the first patient in each group was assigned to a target propofol effect-site concentration close to the predicted EC₅₀. We chose 4.0 µg/mL for all groups except the two with the highest remifentanil rate, for which we chose 3.0 µg/mLas the starting dose because of concern about undesirable cardiodepressant effects. All patients after the first patient were given a target propofol effect-site concentration determined by the outcome of the preceding patient in the same (remifentanil) group. When the propofol effect-site concentration produced effective anesthesia (BIS 50), the next patient in the group received a propofol effect-site concentration one step lower in the schedule. When the propofol effect-site concentration produced ineffective anesthesia (BIS > 50), the next patient in the group received a propofol concentration one step higher in the schedule, so that the propofol effect-site concentration quickly approaches the real EC₅₀ (Fig. 1).

View larger version (10K): [in this window] [in a new window]   Figure 1. Example of "up-and-down" results in the remifentanil Group B (0.1 µg · kg–1 · min–1). X = success in achieving a Bispectral Index (BIS) value 50; O = failure to achieve a BIS value 50.

Patient Selection
We recruited ASA I or II patients who were between 20 and 65 years of age and who were having a procedure for which the anesthesiologist was planning to intubate using a nondepolarizing neuromuscular blocking drug. Patients were excluded from this trial if the anesthesia included awake intubation or rapid sequence induction, if they were hypovolemic or breast feeding or had a history of recent opioid, benzodiazepine or anticonvulsant treatment or alcoholism, or if they were obese (body mass index >30) or allergic to egg.

Groups
On the basis of a SD of the EC₅₀ of propofol of 0.32 µg/mL (16) and a clinically significant difference between steps of 0.5 µg/mL, we calculated that a sample size of seven patients in each group was required to have an 80% power of detection of a difference of 0.5 µg/mL of propofol at the 0.05 level. However, a group size of 12 patients would allow for stratification of patients based on age and gender to reduce bias from these potential confounders. After enrollment, 72 patients were randomized to one of five remifentanil groups and a control group (labeled A–F), using a random number sequence and sealed opaque envelope allocation. Each group consisted of six men and six women. Half the patients were 45 yr old.

Anesthetic Technique
The anesthetic regimen was standardized. The patients were not premedicated. In the operating room peripheral IV access was established and a 1000 mL crystalloid infusion commenced. A pre-filled propofol target-controlled infusion (TCI) syringe (Diprivan 1%, AstraZeneca UK, Macclesfield, Cheshire, UK) and a solution of remifentanil 50 µg/mL (Ultiva, GlaxoSmithKline, Australia) were connected to the IV cannula using a three-way tap. An IVAC Diprifusor TCI pump (Alaris Medical Systems, UK) was used to infuse propofol and a Graseby 3400 infusion pump (SIMS Graseby, Herts, UK) to administer remifentanil. Both these infusion pumps have an accuracy of ±2%.

An Aspect BIS Monitor (Model A2000, Aspect Medical Systems, Natick, MA) with a commercially available 4-in-1 BIS Quatro^TM sensor (Aspect Medical Systems International BV, Netherlands) was attached to the patient's forehead. Skin contact was tested for acceptable conductance. The Signal Quality Index, which provides information about the reliability of the BIS value on a scale from zero to 100%, was observed and the study only commenced once BIS signals with a Signal Quality Index of >50% were obtained.

Arterial blood pressure, heart rate, and oxygen saturation were recorded at baseline and measurements repeated every 5 min throughout the trial period using a Datex Aestiva/5 anesthetic machine (Datex-Ohmeda Pty, Homebush, Australia) and Datex S/5 Anesthetic Monitor (Datex-Ohmeda, Finland). Anesthesia was commenced by infusion of propofol TCI at an initial target effect-site concentration of the anesthesiologist's choice. Also, a remifentanil infusion rate was selected by the anesthesiologist to blunt the hemodynamic response to intubation that was further facilitated by neuromuscular blockade. After intubation, the propofol and remifentanil infusion rates were immediately adjusted according to the study group allocation for that patient and allowed to run for a 15-min equilibration period to allow the effect-site concentration to decrease and stabilize at the target level. Ventilation was adjusted to maintain normoventilation (ET_CO2 30–45 mm Hg). During this time the patients were unstimulated and no surgical preparation was permitted. If the trend was that BIS exceeded 50 during the equilibration period it was clear that the targeted propofol level would not be reached in the presence of a BIS <50. The patient remained anesthetized for surgery at a TCI level above the protocol target value, but the study of this patient was discontinued at the point when BIS exceeded 50. The anesthetic was "unsuccessful" in terms of reaching the end-point of BIS 50 and the next patient would have a 25% higher propofol TCI level. This way it was anticipated that approximately 50% of the anesthetics would be successful and 50% unsuccessful.

Statistics
See Appendix for the calculation of EC₅₀ from the up-and-down data. The EC₅₀ results are presented as mean ± sem. Intergroup differences in EC₅₀ were compared by analysis of variance as was the variability of the SEM of the EC₅₀ value in each group at the 0.05 level. The demographic and hemodynamic data are presented as mean ± sd.

The hemodynamic data were analyzed by Student's t-test for differences within each group. A P value of <0.05 was considered indicative of statistical difference.

	RESULTS

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The mean age and weight were similar in all groups (Table 1). The EC₅₀ of propofol varied between 2.4 and 2.9 µg/mL. There was no significant difference in the EC₅₀ of propofol between the different remifentanil infusion rates. There was wide variability in the response to propofol infusion as assessed by BIS analysis (Table 2, Fig. 2). The addition of remifentanil reduced the variability of the response to propofol (P < 0.05).

View this table: [in this window] [in a new window]   Table 2. Mean Values of EC50 of Propofol to Obtain a Bispectral Index (BIS) 50

View larger version (8K): [in this window] [in a new window]   Figure 2. The response of each patient is indicated by a circle. The position along the lines indicates the propofol effect-site concentration in µg/mL. The position of the circle above or below the line indicates whether the BIS value exceeded 50 or if it remained 50, respectively. The EC50 in µg/mL of propofol is indicated on the line for each remifentanil group.

As expected, approximately half the patients did not complete the equilibration period as their BIS values exceeded 50, so that the study was discontinued in these cases. Therefore, hemodynamic values were only calculated for patients who maintained BIS levels of 50 or below during the entire trial. At the end of the 15-min equilibration period the systolic blood pressure was lower than the preinduction blood pressure in all groups (Table 3).

The blood pressure reduction was statistically significant in Groups A to E. A mean decrease in heart rate of 13% to 24% of preinduction values was noted in all groups receiving remifentanil. The decrease was statistically significant in Groups C and F. The heart rate in Group A was slightly higher at the end of the equilibration period. No inter-group differences in blood pressure or heart rate were noted. In 11 cases the anesthesiologist found it necessary to give anticholinergic medication because of bradycardia. Two of these patients were in the control group.

	DISCUSSION

Top Abstract Introduction METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
We found that the addition of remifentanil at a dose rate of 0.1–0.4 µg · kg^–1 · min^–1 did not alter the EC₅₀ values of propofol necessary to reduce BIS values to 50 or less.

Pre-BIS studies found a useful synergism between opioids and hypnotics with regard to clinical signs of anesthesia depth; i.e., opioids reduced the dose of hypnotic necessary to induce anesthesia or blunt the response to surgery (7,11). More recent articles have studied the effects of remifentanil on clinical indicators of anesthesia as well as the effects on BIS (17,18) and found that remifentanil displays synergy with propofol on clinical variables (loss of consciousness, unresponsive to voice or physical stimulation); i.e., less propofol is required to induce unconsciousness. The article by Struys et al. (19) clearly demonstrates that unconsciousness occurs at higher BIS values (i.e., at lower propofol concentrations) if remifentanil is coinfused. However, remifentanil does not affect the BIS values. Some studies have found a synergistic effect of remifentanil on propofol (12,13), but these studies were done during surgical stimulation. One study found no effect of remifentanil on BIS in 75 patients undergoing surgery (17). In conclusion, there is some confusion as to the effects of remifentanil on "unconsciousness," and hence on BIS. Our results suggest that although remifentanil may produce a deeper level of anesthesia it was not reflected by a reduction of BIS values. This means that there is a risk of awareness if a BIS monitor is not used in cases where the propofol-sparing effect of remifentanil is used to reduce the propofol target concentration.

A pharmacodynamic study of propofol and remifentanil used TCI for both drugs (18). Other studies have used the statistical method of Response Surface Modeling, which is a simulation-based method, to describe the interaction between propofol and remifentanil (18,20). However, we chose to determine the EC₅₀ of propofol at predetermined and clinically useful remifentanil dose rates, as this approach more closely resembles clinical practice.

A BIS value of 50 is the middle of the manufacturer's recommended range, and at this value, the patient is highly likely to be unconscious. The variability of the EC₅₀ of propofol in the absence of remifentanil suggests that there is considerable inter-individual variation in the effect of propofol on the level of hypnosis. This supports previous observations (3). However, a simultaneous infusion of remifentanil reduces the variability of EC₅₀ during propofol anesthesia. It seems that even the lowest infusion rate of remifentanil (0.1 µg · kg^–1 · min^–1) used in this study was sufficient to ablate the discomfort caused by the presence of the endotracheal tube. As the patients were not stimulated in any other way, increasing doses of remifentanil did not change the EC₅₀ values of propofol (Table 2, Fig. 2).

Our study design had some limitations. After induction a 15-min interval was allowed for equilibration of the drugs at the predetermined target infusion rates. Since the estimated propofol effect-site concentration was displayed on the infusion pump, it was possible to verify whether the patients had reached the predetermined concentration during the equilibration period. However, the actual effect-site concentration may have differed from the calculated concentration for any given individual, and between individuals in each group, for several reasons. The effect-site concentration may be up to 16% higher than targeted as a result of the pharmacokinetic model used for the Diprifusor (3,21), and the patient age also affects effect-site concentration (22). We believe that the stratification of patients according to age and sex may have reduced age-dependant variations in effect-site propofol concentrations. For the remifentanil infusions, the 15-min equilibration interval was sufficient to ensure that <20% of any initial remifentanil dose remained in the effect-site compartment, based on an 80%-decrement tie of 11 min (23). The pharmacokinetics of remifentanil and propofol may interact. Ludbrook and Upton (24) suggested that remifentanil may reduce cardiac output and increase the arterial and effect-site propofol concentration. Bouillon et al. (25) on the other hand, suggested that propofol reduced remifentanil clearance. By studying ASA I and II patients younger than 65 yr, we believe any interaction between the drugs was of minimal significance across the groups.

A reduction of heart rate during remifentanil infusion has been well described. The small increase in heart rates in Group A (no remifentanil infusion) at the end of the equilibration period supports the absence of residual remifentanil. We chose to exclude obese patients because of pharmacokinetic concern about greater variability (26).

We conclude that remifentanil does not reduce propofol requirements for anesthesia, as defined by BIS values 50, in the unstimulated patient. The addition of remifentanil is very useful for reducing patient movement and autonomic responses to surgical stimulation during propofol TCI anesthesia. One could speculate that increasing remifentanil infusion rates might change the effect of surgical stimulation on BIS. We are currently examining the hypothesis. The combination of propofol and remifentanil infusions is safe, as evidenced by the lack of clinically significant hemodynamic changes. The use of a BIS monitor is strongly recommended in order to minimize the risk of awareness during TCI.

	APPENDIX

Top Abstract Introduction METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Determination of the EC₅₀ of propofol was performed according to the equation

where X_i denotes the cumulated log dose levels for the N nominal sample size trials, d denotes the log dose interval (0.1), and A is a tabulated value, whose numeric value depends on the difference between the numbers of successful and unsuccessful trials (14). The nominal sample size is the number of patients, beginning with the first pair of patients with unlike responses. A run of (>50 –>50 –<50) has a nominal sample size of two. To determine the SEM of the estimated EC₅₀ in each remifentanil group, EC₅₀ was determined in subgroups of consecutively studied patients, each subgroup with a nominal sample size of two (Fig. A1). For each small series EC₅₀ was calculated from the equation

View larger version (14K): [in this window] [in a new window]   Figure A1. Example of "Up-and-Down" results in the remifentanil group B (0.1 µg/kg/min). To calculate the standard error of the EC50, five series with a nominal sample size of two were identified.

where X_f denotes the final plasma concentration level, d is the log dose interval (0.1), and k is a tabulated value (14).

	Footnotes

 
Accepted for publication October 18, 2006.

	REFERENCES

Top Abstract Introduction METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Wang, L. P. Articles by Brandon, E. L. Search for Related Content PubMed PubMed Citation Articles by Wang, L. P. Articles by Brandon, E. L. Related Collections Anesthetic Techniques Pharmacology