Anesthesiology 2003; 99:34759

2003 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc.

Propofol Reduces Perioperative Remifentanil Requirements in a Synergistic Manner

Response Surface Modeling of Perioperative RemifentanilPropofol Interactions
Martijn J. Mertens, M.D., Ph.D.,* Erik Olofsen, M.Sc., Frank H. M. Engbers, M.D.,* Anton G. L. Burm, M.Sc., Ph.D., James G. Bovill, M.D., Ph.D., F.F.A.R.C.S.I., Jaap Vuyk, M.D., Ph.D.*

Background: Remifentanil is often combined with propofol for induction and maintenance of total intravenous anesthesia. The authors studied the effect of propofol on remifentanil requirements for suppression of responses to clinically relevant stimuli and evaluated this in relation to previously published data on propofol and alfentanil. Methods: With ethics committee approval and informed consent, 30 unpremedicated female patients with American Society of Anesthesiologists physical status class I or II, aged 18 65 yr, scheduled to undergo lower abdominal surgery, were randomly assigned to receive a target-controlled infusion of propofol with constant target concentrations of 2, 4, or 6 g/ml. The target concentration of remifentanil was changed in response to signs of inadequate anesthesia. Arterial blood samples for the determination of remifentanil and propofol concentrations were collected after blood effect site equilibration. The presence or absence of responses to various perioperative stimuli were related to the propofol and remifentanil concentrations by response surface modeling or logistic regression, followed by regression analysis. Both additive and nonadditive interaction models were explored. Results: With blood propofol concentrations increasing from 2 to 7.3 g/ml, the C50 of remifentanil decreased from 3.8 ng/ml to 0 ng/ml for laryngoscopy, from 4.4 ng/ml to 1.2 ng/ml for intubation, and from 6.3 ng/ml to 0.4 ng/ml for intraabdominal surgery. With blood remifentanil concentrations increasing from 0 to 7 ng/ml, the C50 of propofol for the return to consciousness decreased from 3.5 g/ml to 0.6 g/ml. Conclusions: Propofol reduces remifentanil requirements for suppression of responses to laryngoscopy, intubation, and intraabdominal surgical stimulation in a synergistic manner. In addition, remifentanil decreases propofol concentrations associated with the return of consciousness in a synergistic manner.

therefore a promising combination for total intravenous anesthesia. The pharmacodynamics of propofol and its interaction with alfentanil have been studied extensively.1 The pharmacodynamics of remifentanil when given in combination with other intravenous agents have been less well described. In the current study, we investigated the pharmacodynamics of remifentanil and its interaction with propofol. To that end, various clinically relevant end points were studied in surgical patients when given remifentanil in combination with propofol.

Materials and Methods

Patients and Study Design With local Medical Ethics Committee (Leiden, The Netherlands) approval and informed consent, 30 female patients with American Society of Anesthesiologists physical status I or II, aged 20 65 yr, who were scheduled to undergo lower abdominal surgery were asked to participate in the study. Patients with known cardiac, pulmonary, or renal disease and patients receiving medication or consuming more than 20 g alcohol daily were excluded from the study. The patients were randomly assigned to one of three study groups to receive, in a double-blind manner, a target propofol concentration of 2 g/ml (group A), 4 g/ml (group B), or 6 g/ml (group C) in combination with remifentanil. The patients did not receive premedication. An anesthesiologist who took no further part in the study prepared the solutions of propofol. For patients in group A, 40 ml glucose (5%) was added to 20 ml propofol (10 mg/ml) to obtain 60 ml propofol (3.3 mg/ml). For patients in group B, 20 ml glucose (5%) was added to 40 ml propofol to obtain 60 ml propofol (6.7 mg/ml). For patients in group C, the propofol solution was not diluted. The investigators were blinded to the propofol solution being used. Materials A palm-top computer was provided with three-compartment pharmacokinetic data of remifentanil2 to control3 an infusion pump for the infusion of remifentanil. The same computer was provided with three-compartment pharmacokinetic data of propofol4 and used to control another infusion pump for the infusion of propofol. 347

REMIFENTANIL is a new synthetic opioid that is characterized by a rapid onset of action due to a short blood effect site equilibration half-time and a rapid offset of action due to its high clearance by nonspecic blood and tissue esterases. Propofol and remifentanil are both short-acting anesthetic agents that complement each others pharmacodynamic proles (i.e., hypnosis and analgesia). Remifentanil combined with propofol is

* Staff Anesthesiologist, Research Associate, Professor of Anesthesiology and Head of the Anesthesia Research Laboratory, Professor of Anesthesiology. Received from the Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands. Submitted for publication December 3, 2001. Accepted for publication April 1, 2003. Supported by GlaxoSmithKline BV, Zeist, The Netherlands. Presented in part at the annual meeting of the European Society of Anaesthesiologists, in Gothenburg, Sweden, October 4, 2001. Address reprint requests to Dr. Mertens: Department of Anesthesiology, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands. Address electronic mail to: m.j.mertens@lumc.nl. Individual article reprints may be purchased through the Journal Web site, www.anesthesiology.org.

Anesthesiology, V 99, No 2, Aug 2003

348

MERTENS ET AL.

In the operating room, an intravenous cannula was inserted into a large forearm vein for infusion of remifentanil and propofol, and another cannula was inserted into a radial artery for continuous measurement of arterial blood pressure and collection of blood samples. The electrocardiogram, heart rate, arterial blood pressure, peripheral oxygen saturation, end-tidal carbon dioxide partial pressure, Bispectral Index (version A1000; Aspect Medical Systems Inc., Natick, MA), and the spectral edge frequency were monitored continuously throughout the study. Neuromuscular transmission was monitored by percutaneous stimulation of the ulnar nerve using the train-of-four method. Study Protocol After breathing 100% oxygen for 3 min, 0.1 mg/kg atracurium was given intravenously, and anesthesia was induced by computer-controlled infusion of propofol with a target concentration set at 6 g/ml. Depending on the propofol solution in the syringe, the actual target concentrations were 2, 4, or 6 g/ml for the patients in groups A, B, and C, respectively. The target propofol concentration was maintained constant throughout the surgical procedure until the peritoneum was closed. Five minutes after the start of the propofol infusion, the remifentanil infusion was started with a target concentration of 2 ng/ml. Ten minutes (i.e., four to ve times the blood-effect site equilibration half-time [T1/2ke0] of propofol)5 after the start of the propofol infusion, and provided that the patients had lost consciousness, 0.4 mg/kg atracurium was given intravenously. If a patient had not lost consciousness by 10 min after the start of the propofol infusion, the target remifentanil concentration was increased by 210 ng/ml to induce unconsciousness before the administration of atracurium. Subsequently, laryngoscopy was performed. To optimally determine the remifentanil concentration effect relation for this stimulus, a second and third laryngoscopy were performed with different target remifentanil concentrations, and the presence or absence of a response was recorded. If a patient did not respond to the rst or second laryngoscopy, the target remifentanil concentration was decreased by 1 ng/ml. When patients did respond to the rst or second laryngoscopy, the target remifentanil concentration was increased by 210 ng/ml, depending on the intensity of the response, for the following laryngoscopy. Five minutes (i.e., six to seven times the T1/2ke0 of remifentanil)6 after a new target remifentanil concentration was reached, the following laryngoscopy was performed. The aim was to achieve at least one response and at least one nonresponse to laryngoscopy in each patient. A response to laryngoscopy was dened using the same criteria as used to dene inadequate anesthesia.
Anesthesiology, V 99, No 2, Aug 2003

Inadequate anesthesia was dened by the following criteria1: 1. An increase in systolic blood pressure by more than 15 mmHg above the preoperative mean systolic blood pressure, dened as the mean of three systolic blood pressures measured since admission 2. A heart rate exceeding 90 beats/min in the absence of hypovolemia 3. Other autonomic signs such as sweating or ushing 4. Somatic responses such as movements or swallowing During the study, three persons observed each patient continuously for evidence of inadequate anesthesia: a resident in anesthesia, an anesthesiologist, and a trained medical student. If inadequate anesthesia was detected, it was only accepted if veried by all three observers. To facilitate identication of somatic responses, atracurium was given at the minimal dose necessary for surgery (train-of-four levels 13. After the second or third laryngoscopy, the trachea of the patient was intubated, and the lungs were ventilated with 30% oxygen in air to an end-tidal carbon dioxide partial pressure of 29 34 mmHg. The target propofol concentration was maintained constant until the peritoneum was closed and nally discontinued after skin closure. The remifentanil administration was changed in response to the presence or absence of signs of inadequate anesthesia. When signs of inadequate anesthesia developed, the target remifentanil concentration was increased by 110 ng/ml. When no signs of inadequate anesthesia were observed, the target remifentanil concentration was decreased by 110 ng/ml. If, at induction of anesthesia, patients had not lost consciousness in the absence of remifentanil, the target remifentanil concentration was not decreased below the remifentanil effect site concentration, as displayed on the target controlled infusion device at the time of loss of consciousness. After a new target concentration was reached (as judged from the computer display) this was maintained for 6 min. Thirty minutes before skin closure, 0.2 mg/kg intravenous morphine was administered to provide postoperative pain relief. After skin closure, neuromuscular blockade was antagonized by neostigmine, 12 mg intravenously, and atropine, 0.51 mg intravenously, and the remifentanil infusion was discontinued. The patients were tested every 2 min by verbal commands to evaluate return of consciousness. This was dened as a positive response to a verbal command. Once adequate spontaneous ventilation was established (i.e., if the end-tidal carbon dioxide partial pressure was less than 46 mmHg, tidal volume was more than 7 ml/kg, and respiratory rate was more than 10 breaths/min), the trachea was extubated. After the trachea had been extubated, the patient was transported to the recovery room. Twenty-four hours

PROPOFOLREMIFENTANIL PHARMACODYNAMIC INTERACTION

349

postoperatively, the patients were interviewed to evaluate possible side effects and any recall of intraoperative events. Blood Samples and Assays Arterial blood samples for determination of propofol and remifentanil concentrations in whole blood were collected at laryngoscopy, intubation, skin incision, the opening of the peritoneum, awakening, and 6 min after a predicted target remifentanil concentration was reached during the intraoperative period. The total amount of blood sampled in each patient did not exceed 150 ml. Samples for the determination of blood propofol concentrations were transferred into test tubes containing potassium oxalate and stored at 4C. Propofol concentrations in blood were measured at the Anesthesia Research laboratory of the Leiden University Medical Center by reverse-phase high-performance liquid chromatography.7 The limit of quantitation was 11.7 ng/ml. The coefcient of variation of this method was 3% or less in the concentration range encountered in this study. Propofol assays were performed within 12 weeks. Samples for the determination of blood remifentanil concentrations were collected into tubes containing sodium heparin and immediately transferred to tubes containing 50% citric acid (to inactivate esterases) before freezing at 20C. The assay method is based on tandem mass spectrometry detection with a quantitation limit of 0.1 ng/ml and an interassay coefcient of variation of less than 10% for concentrations greater than 0.1 ng/ml. The remifentanil analyses were performed in a commercial laboratory (Analytico, Breda, The Netherlands). Data Analysis For each patient, one to three data points were available for laryngoscopy, intubation, skin incision, opening of the peritoneum, and return to consciousness. The interaction between propofol and remifentanil at these events was therefore determined over the group, for each event separately, using the response surface model described by Bol et al.9: Cprop Crem Cprop Crem C50,prop C50,rem C50,prop C50,rem Cprop Crem Cprop Crem 1 C50,prop C50,rem C50,prop C50,rem

0, a nonadditive describes an additive model; with model is described). For some end points, the obtained estimate of C50 was several orders of magnitude larger than the clinical concentration range and the concentrations encountered in this study. In these cases, estimates of were also extremely large, but the ratio of and C50 remained meaningful. Therefore, when estimates of C50,rem and were two or more orders of magnitude larger than the concentrations encountered in this study, the model was rewritten as:
C prop C prop C rem C 50,prop C 50,prop C prop C prop 1 C C 50,prop C 50,prop rem

(2)

where is the ratio of and C50,rem. In case the C50s of both drugs were much higher than the actually achieved concentrations, the model was further simplied to:

C prop C rem 1 C prop C rem

(3)

where ' is the ratio of and the product of C50,prop and C50,rem. The model parameters were estimated with the computer program NONMEM (version V, level 1.1; The NONMEM Project Group, University of California, San Francisco, CA), by minimizing the 2 log likelihood (2LL) for all observations: 2LL 2

i1

R lnP 1 R ln1 P
N i i

(4)

(1)

where N is the number of adequatenonadequate anesthesia or unconsciousawake data points, Ri is the observed response of the ith individual, being either 1 (i.e., no response to any of the perioperative stimuli or no response to a verbal command after termination of the propofol and remifentanil target-controlled infusion) or 0 (i.e., a response to any of the perioperative stimuli or a response to a verbal command after termination of the propofol and remifentanil target-controlled infusion), and P is the probability of the response for each concentration combination. The interindividual variabilities of the model parameters C50,prop, C50,rem, and were modeled using a log-normal variance model: individual typical,k e individual (5)

where is the probability of no response, Cprop is the blood propofol concentration, Crem is the blood remifentanil concentration, C50,prop and C50,rem are the steady state concentrations of propofol and remifentanil corresponding to a 50% probability of no response when either drug is administered alone, and and are the coefcients describing the shape of the response surface. The interaction parameter is equivalent to the Berenbaum interaction index10 (with 0, equation 1
Anesthesiology, V 99, No 2, Aug 2003

where individual is the value in the individual, typical,k is the typical value of the parameter in the population in patient k, and individual is a normally distributed random variable with a mean of zero and a variance of 2, which is estimated by NONMEM. The interindividual variability of was modeled using a normal variance model. The response surface models describe the probability of a

350

MERTENS ET AL.

Table 1. Patient Characteristics

Parameter Group A (2 g/ml Propofol) Group B (4 g/ml Propofol) Group C (6 g/ml Propofol)

n Age, yr Height, cm Weight, kg Duration of anesthesia, min

Data are mean SD. All patients were female.

10 35 4 165 12 68 13 210 67

10 39 10 168 8 65 10 185 67

9 39 9 166 9 67 11 182 40

dichotomous outcome (a response or no response during one of the above events) as a function of the measured blood propofol and remifentanil concentrations. In contrast, for the intraabdominal part of surgery, multiple data were available per patient. The concentration effect relation of the combination of remifentanil and propofol for suppression of responses to the intraabdominal part of surgery was therefore determined for each patient separately by logistic regression. The inuence of the mean measured intraoperative blood propofol concentration on the C50 of remifentanil during the intraabdominal part of surgery was then determined by tting a mechanistic model10 to the individual C50s of remifentanil versus the mean measured propofol concentrations data over all patients (see Appendix). Note that we initially explored the concentration response surface of the combination of propofol and remifentanil for laryngoscopy, intubation, skin incision, opening of the peritoneum, suppression of responses to surgical stimuli, and probability of return to consciousness according to the recently described response surface modeling technique by Minto et al.11 (see Discussion). The response surface was obtained by modeling of adequatenonadequate anesthesia data or the unconsciousawake data versus the corresponding measured blood propofol and measured blood remifentanil concentration combinations (see Appendix). Statistical Analysis Patient characteristics and the mean measured blood propofol and blood remifentanil concentrations, Bispectral Index, spectral edge frequency, systolic and diastolic blood pressures, and heart rate as observed in the three study groups during the intraoperative period (between opening of the peritoneum and skin closure) were compared between groups using the Kruskal-Wallis test with a post hoc MannWhitney U test for pairwise group comparison, if appropriate. To determine the nature of the interaction for suppression of responses to laryngoscopy, intubation, skin incision, the opening of the peritoneum, suppression of responses to intraabdominal surgical stimuli, and the probability of return to consciousness, the Akaike information-theoretic criterion12 (AIC 2LL 2p; where p is the number of parameters in the model) was used to assess the signicance of incorporating an interaction term in the reAnesthesiology, V 99, No 2, Aug 2003

sponse surface model. The model with the lowest AIC was considered optimal. Data are presented as mean SD unless stated otherwise. P 0.05 was considered the minimum level of statistical signicance except for multiple comparison tests when P 0.02 was considered signicant.

Results
All but one of the patients were evaluable. One patient in group C had to be excluded from the study due to improper handling of the blood samples. Age, weight, height, and duration of anesthesia of the remaining patients (n 29) did not differ among the three study groups (table 1). The mean measured blood propofol and blood remifentanil concentrations, Bispectral Index, spectral edge frequency, systolic and diastolic blood pressures, and heart rate during the intraoperative period (between opening of the peritoneum and skin closure) are shown in table 2. As intended, the mean measured blood propofol concentrations differed signicantly between the three groups. Required mean measured plasma remifentanil concentrations were lower in groups B and C compared to group A (P 0.02). One out of the 10 patients in group A, 6 out of the 10 patients in group B, and all but 1 of the patients in group C had lost consciousness 5 min after the start of the propofol infusion. In the 14 patients who remained conscious with the initial target remifentanil concentration, unconsciousness was induced when the target remifentanil concentration was increased to 4 15 ng/ml. The C50 of remifentanil for laryngoscopy and intubation decreased with increasing propofol concentrations. For laryngoscopy and intubation, the data were best characterized by a synergistic model (table 3). The addition of the interaction term in the response surface model resulted in a reduction in the AIC (from 62.41 to 59.51 for laryngoscopy and from 39.21 to 34.95 for intubation). Introduction of intraindividual variability did not result in a further reduction in the AIC. As blood propofol concentrations increased from 2 to 7.3 g/ml, the C50 of remifentanil decreased from 3.8 ng/ml to 0 ng/ml for laryngoscopy and from 4.7 ng/ml to 1.2 ng/ml for intubation (gs. 1 and 2). For skin incision and the opening of the peritoneum, the conguration of the data did not allow modeling.

PROPOFOLREMIFENTANIL PHARMACODYNAMIC INTERACTION

351

Table 2. Intraoperative Data of the Patients Available for Analysis*

Parameter Group A (2 g/ml Propofol) Group B (4 g/ml Propofol) Group C (6 g/ml Propofol)

Patients, No. Propofol concentration, g/ml Remifentanil concentration, ng/ml Bispectral Index Spectral edge, Hz Systolic blood pressure, mmHg Diastolic blood pressure, mmHg Heart rate, beats/min

8 2.2 0.4 7.3 3.8 59 15 14.6 3.5 116 8 67 7 67 9

10 4.5 0.8 2.2 2.2 56 20 13.9 5.6 119 10 69 7 67 6

8 7.8 1.7 1.1 2.2 43 23 11.4 4.1 107 12 61 8 68 10

Data are mean SD. Data are mean intraoperative measured blood propofol and blood remifentanil concentration, Bispectral Index, spectral edge frequency, systolic and diastolic blood pressures and heart rate. Data were compared between groups using the Kruskal-Wallis test with a post hoc Mann Whitney U test for pairwise group comparison, if appropriate. * In 3 of 29 patients, the data set for intraoperative stimuli did not allow modeling. These patients are therefore not included in this table. A vs. group B. P 0.02, group A vs. group C. P 0.02, group B vs. group C. P 0.02, group

In 3 of 29 patients, the data set for intraoperative stimuli did not allow modeling. The concentration effect relation of remifentanil for intraabdominal stimuli could therefore not be determined in these 3 patients. In 17 patients, no overlap existed between response and nonresponse data. Because the lowest measured plasma remifentanil concentration at which no response occurred and the highest blood remifentanil concentration at which a response was noted differed only marginally in these patients, the C50 of remifentanil was determined as the midrange between the lowest measured blood remifentanil concentration at which no response occurred and the highest blood remifentanil concentration at which a response was noted. If in any patient no responses occurred, even when the actual measured blood remifentanil concentration was below the detection limit, the C50 of remifentanil was set to 0 ng/ml. The measured blood propofol concentration remained stable throughout the surgical procedure in most patients (g. 3). The remifentanil concentration effect relations for the intraabdominal part of the surgical procedure in the individual patients of the three groups are shown in gures 4 6. Results are presented in table 4. The C50 of remifentanil versus mean blood propofol concentration relation for the intraabdominal part of surgery as deterTable 3. Additive and Nonadditive Interaction Models
Stimulus C50,
prop

mined over all patients is presented in gure 7. The C50 of remifentanil for suppression of responses to intraabdominal surgical stimuli decreased with increasing propofol concentrations. The data were best characterized by a synergistic model. The addition of the interaction term in the model resulted in a reduction in the AIC from 82.07 to 79.96. Because C50,rem and of the nonadditive model were very large, the model described in equation 9 was tted to the data. The parameters ( SE) describing the curve are C50,prop 9.02 2.47 g/ml and ' 0.557 0.306. Introduction of intraindividual variability did not result in a further reduction in the AIC. As mean blood propofol concentrations increased from 2 to 9 g/ml, the C50 of remifentanil for intraabdominal stimuli decreased from 6.3 to 0 ng/ml (g. 7). Remifentanil signicantly affected the blood propofol concentration at which the patients regained consciousness. According to the response surface modeling technique described by Bol et al.,9 the interaction between propofol and remifentanil was judged to be synergistic for the probability of unconsciousness (table 3). Introduction of intraindividual variability did not result in a further reduction in the AIC. With blood remifentanil concentration increasing from 0 to 10 ng/ml, the C50,prop for return of to consciousness decreased from 3.5 g/ml

SE

C50,

rem

SE

SE

(, ) SE

AIC

Laryngoscopy Laryngoscopy Intubation Intubation Awakening Awakening

5.63 0.96 7.32 1.83 8.69 3.26 2.92 0.51 3.49 0.64

4.82 1.50 4.95 2.33 5.15 2.80

4.39 1.5 3.82 1.18 3.22 1.79 2.25 4.41 3.88 1.09 3.52 1.01

0.69 0.32 0.11 0.03 0.72 0.31

62.413 59.511* 39.213 34.950* 48.152 42.538*

Models are determined by response surface modeling according to equations 1, 2, or 3 and describe the inuence of the blood propofol and the blood remifentanil concentration on the probability of no response to laryngoscopy or intubation and on the probability of unconsciousness. Shown are the tted values of C50, prop C50, rem, , and SE, describing the shape of the response surface of the two response surfaces that were determined to explore the possibilities of an additive and of a nonadditive interaction between propofol and remifentanil for the suppression of responses to laryngoscopy, intubation, and for the probability of unconsciousness, and the AIC of these models. For some end points, C50,prop or C50,rem estimated with equation 1 were greater than 3 orders of magnitude higher than the maximum concentrations encountered in this study. In these cases, the coefcients describing the shape of the response surface correspond to those used in either equation 2 or 3. AIC is the Akaikes information-theoretic criterion.12 The model with the lowest AIC was considered to be optimal and is marked by an asterisk.

Anesthesiology, V 99, No 2, Aug 2003

352

MERTENS ET AL.

Fig. 1. Concentration effect relation of the combination of propofol and remifentanil for suppression of responses to laryngoscopy. The curve (top) was obtained by response surface modeling, according to equation 2, of the response (open squares)no response (closed squares) data versus the corresponding measured blood propofol concentrations and blood remifentanil concentrations. The displayed curve represents remifentanil and propofol concentrations associated with a 50% probability of no response, calculated using equation 2, and the tted values of the coefcients from table 3, describing the synergistic interaction model. In the concentration response surface (bottom) for the combination of propofol and remifentanil, the isoboles for 25, 50, and 75% probability of no response are shown.

Fig. 2. Concentration effect relation of the combination of propofol and remifentanil for suppression of responses to intubation. The curve (top) was obtained by response surface modeling, according to equation 3, of the response (open squares)no response (closed squares) data versus the corresponding measured blood propofol concentrations and blood remifentanil concentrations. The displayed curve represents remifentanil and propofol concentrations associated with a 50% probability of no response, calculated using equation 3, and the tted values of the coefcients from table 3, describing the synergistic interaction model. In the concentration response surface (bottom) for the combination of propofol and remifentanil, the isoboles for 25, 50, and 75% probability of no response are shown.

to 0.4 g/ml (g. 8). For this unimodal end point, the response surface modeling technique described by Minto et al.11 proved also adequate. The additive model with the lowest AIC is a model in which prop and rem are identical. Introduction of intraindividual variability did not result in a further reduction in the AIC. Because the addition of the interaction term 2,U50 (see Appendix) in the model resulted in a reduction in the AIC from 48.152 to 46.409, the interaction between propofol and remifentanil for the probability of unconsciousness based on the response surface modeling technique described by Minto et al.11 was also judged synergistic. The parameters ( SE) describing the response surface are E0 0, Emax 1, C50,prop 3.40 0.75 g/ml, C50,rem 8.91 2.35 ng/ml, prop 4.29 0.98, rem 4.29 0.98, and 2,U50 1.69 0.42. The C50 of propofol decreased from 3.4 g/ml to 0.5 g/ml as blood remifentanil concentrations increased from 0 to 8 ng/ml. The model described in equation 2 was selected as the nal
Anesthesiology, V 99, No 2, Aug 2003

Fig. 3. Measured blood propofol concentration versus time in the individual patients of group A ( target propofol concentration 2 g/ml), group B ( target propofol concentration 4 g/ml), and group C ( target propofol concentration 6 g/ml).

PROPOFOLREMIFENTANIL PHARMACODYNAMIC INTERACTION

353

Fig. 4. Remifentanil concentration effect relations in the individual patients for the intraabdominal part of surgery when remifentanil was given as a supplement to a target propofol concentration of 2 g/ml. The mean measured blood propofol concentrations were 2.1, 2.3, 2.8, 2.0, 1.9, 2.2, 1.9, and 2.9 g/ml in patients 1 8, respectively (table 5). The curves were determined by logistic regression of responseno response data versus the corresponding measured blood remifentanil concentrations of remifentanil, as shown beneath the curves. Dots blood remifentanil concentrations associated with a 50% probability of no response.

model for the return to consciousness because its AIC was lower than that for the model described by Minto et al.11 (42.538 vs. 46.409). All patients breathed adequately on awakening. None of the patients reported awareness for any intraoperative event.

Fig. 5. Remifentanil concentration effect relations in the individual patients for the intraabdominal part of surgery when remifentanil was given as a supplement to a target propofol concentration of 4 g/ml. The mean measured blood propofol concentrations were 4.1, 3.7, 3.9, 4.6, 6.2, 4.5, 3.5, 5.1, 4.7, and 4.4 g/ml in patients 110, respectively (table 5). The curves were determined by logistic regression of responseno response data versus the corresponding measured blood remifentanil concentrations of remifentanil, as shown beneath the curves. Dots blood remifentanil concentrations associated with a 50% probability of no response.

Discussion
The aims of this study were to determine the inuence of propofol on remifentanil requirements for suppression of responses to perioperative stimuli and return of consciousness in female patients and to determine the nature of these interactions. The study demonstrated that propofol reduces remifentanil requirements for suppression of responses to laryngoscopy, intubation, and intraabdominal surgical stimulation in a synergistic manner in female patients. In addition, the study demonstrated that remifentanil decreases propofol concentrations associated with the return of consciousness in a synergistic manner. Critique on Methods Theoretically, a pharmacodynamic interaction between two agents is best dened if data are obtained by studying the effect of the agents separately and in combination. In our study, however, no data were obtained for remifentanil as a sole agent because this would have
Anesthesiology, V 99, No 2, Aug 2003

resulted in awareness. In this study, we intentionally chose a target of 2 g/ml as the lowest target propofol concentration. Note that in the absence of premedication, a target propofol concentration of 2 g/ml is below that at which patients may be unconscious. With these low blood propofol concentrations, remifentanil is needed to supplement the hypnotic effect of propofol. In retrospect, this target propofol concentration may have been conservative. In previously described interaction studies between propofol and opioids, the synergistic nature of the interaction became predominantly apparent at subhypnotic propofol concentrations ( 2 3 g/ml).13,14 To further minimize the risk of awareness, the intraoperative target remifentanil concentration was never decreased below the predicted remifentanil effect site concentration at which patients had lost consciousness in the presence of propofol, if, at induction of anesthesia, patients had not lost consciousness in the absence of remifentanil. This may have led to the relatively large number of nonresponses compared to the number of responses to surgical stimuli during the intraabdominal part of surgery. Recently, Minto et al.11 described a novel method for drug interaction analysis by means of response surface modeling. We explored the interaction between propofol and remifentanil for suppression of responses to

354

MERTENS ET AL.

Fig. 7. Blood remifentanil concentrations versus blood propofol concentrations associated with a 50% probability of no response to intraabdominal surgical stimuli. The curve represents a mechanistic function (see Appendix) tted to the data by unweighted least-squares nonlinear analysis described by the equation: C rem 1 (Cprop/9.02) 0.55 (Cprop/9.02)

Fig. 6. Remifentanil concentration effect relations in the individual patients for the intraabdominal part of surgery when remifentanil was given as a supplement to a target propofol concentration of 6 g/ml. The mean measured blood propofol concentrations were 5.8, 8.1, 8.6, 9.1, 4.6, 8.5, 8.7, and 9.1 g/ml in patients 1 8, respectively (table 5). The curves were determined by logistic regression of responseno response data versus the corresponding measured blood remifentanil concentrations of remifentanil, as shown beneath the curves. Dots blood remifentanil concentrations associated with a 50% probability of no response.

where Crem the blood remifentanil concentration (ng/ml) associated with a 50% probability of no response to intraabdominal surgical stimuli; Cprop the mean blood propofol concentration (g/ml) calculated in each patient. Dots C50s of remifentanil at corresponding mean blood propofol concentrations for suppression of responses to intraabdominal surgical stimuli as determined in the individual patients by logistic regression (Figs. 4 6).

various anesthetic end points (i.e., laryngoscopy, intubation, skin incision, opening of the peritoneum, and intraabdominal surgical stimuli) using this new analytical instrument but found that the responseno response data could not be analyzed in this way. However, the anesthetic state is a bimodal phenomenon, consisting of both a hypnotic and an analgesic component, and may therefore not be considered as a single measure of drug effect. Because the studied perioperative pharmacody-

namic end points of no response to nociceptive stimuli cannot be achieved by remifentanil alone in the absence of propofol, remifentanil has the pharmacodynamic characteristics of a partial agonist for these end points in the response surface modeling technique described by Minto et al.11 Because the basic concept in response surface modeling according to Minto et al.11 is that any given ratio of two drugs behaves as a new drug with its own sigmoidal concentrationresponse relation, this results in a model predicting that a maximal effect

Table 4. Blood Propofol and Blood Remifentanil Concentrations Associated with a 50% Probability of No Response to Intraabdominal Surgical Stimuli in the Individual Patients
Group A (2 g/ml) No. Cprop SD, g/ml C50,rem SE, ng/ml Group B (4 g/ml) Group C (6 g/ml)

No.

Cprop SD, g/ml

C50,rem SE, ng/ml

No.

Cprop SD, g/ml

C50,rem SE, ng/ml

1 2 3 4 5 6 7 8 9 10

2.1 0.1 2.3 0.2 2.8 0.2 2.0 0.2 1.9 0.2 2.2 0.2 1.9 0.3 2.9 0.2 2.1 0.1 1.7 0.5

15.9 3.4 5.8 0.2 5.5 1.8 3.8 0.8 3.4 0.4 3.5 5.3 0.6

36.4 2.0 5.4 8.7 8.0

1 2 3 4 5 6 7 8 9 10

4.1 0.4 3.7 0.2 3.9 0.3 4.6 0.5 2.9 0.6 4.5 0.4 3.5 0.4 5.1 0.9 4.7 0.4 4.4 0.6

0.0 1.0 5.6 0.4 0.0 2.4 1.3 4.1 1.1 0.0 0.3 0.1 0.9

2.3 2.6 2.5

1 2 3 4 5 6 7 8 9 10

5.8 0.4 8.1 0.5 8.6 0.5 9.1 0.6 4.6 0.7 8.5 0.9 8.7 0.5 9.1 1.0

0.0 0.0 0.1 0.0 5.7 0.8 0.0 0.0 0.0

6.9

Cprop; mean ( SD) measured blood propofol concentrations. Fitted C50 ( SE) and , for remifentanil characterizing the probability of no response to surgical stimuli observed during the intraabdominal period of surgery in patients receiving remifentanil as a supplement to propofol at target concentrations of 2 g/ml (group A), 4 g/ml (group B), or 6 g/ml (group C).

Anesthesiology, V 99, No 2, Aug 2003

PROPOFOLREMIFENTANIL PHARMACODYNAMIC INTERACTION

355

by response surface modeling, we conclude that although response surface modeling by Minto et al.11 is suitable for the analysis of unimodal end points such as loss of consciousness or the return to consciousness, it may not be suitable for the analysis of multimodal end points, such as adequacy of anesthesia. Pharmacodynamic end points of no response to nociceptive stimuli were therefore analyzed using the response surface model by Bol et al.9 as described in equation 1. The technique by Bol et al. allows for a response surface modeling technique that respects the two agents as separate drugs and thereby allows for the modeling of bimodal effects. Laryngoscopy and Intubation In keeping with the observations of Vuyk et al.1 on the interactions between propofol and alfentanil, the interactions between propofol and remifentanil for suppression of responses to laryngoscopy and intubation were best described by a synergistic interaction model. For laryngoscopy, the C50,rem and estimated with the model described by Bol et al.9 were very large, whereas for intubation, C50,rem, C50,prop, and were several orders of magnitude larger than the concentrations encountered in this study. Therefore, these effects were modeled with the modied models (equations 2 and 3, respectively). Similarly, Vuyk et al.1 have demonstrated that propofol decreases alfentanil requirements for suppression of responses to laryngoscopy and intubation in a synergistic manner. Remifentanil concentrations required to suppress responses to intubation are higher at any given propofol concentration compared to those required to suppress responses to laryngoscopy. This indicates that tracheal intubation is a stronger stimulus than laryngoscopy. The C50 of propofol for laryngoscopy in the absence of remifentanil, determined as the intercept of the interaction model with the x-axis (g. 1), is 7.3 g/ml. Because the interaction model for suppression of responses to intubation did not cross the x-axis in the concentration range studied (g. 2), the C50 of propofol alone for intubation could not be determined. These ndings are in accordance with the ndings of Kazama et al.,15 who

Fig. 8. Concentration effect relation of the combination of propofol and remifentanil for the probability of the return to consciousness. The curve (top) was obtained by response surface modeling, according to equation 2, of the awake unconscious data versus the corresponding measured blood propofol concentrations and the corresponding measured blood remifentanil concentrations. Closed squares concentrations of propofol and remifentanil at skin closure, at which time the individual patients were still unconscious; open squares concentrations of propofol and remifentanil when the patients regained consciousness. The displayed curve represents remifentanil and propofol concentrations associated with a 50% probability of the return to consciousness, calculated using equation 2, and the tted values of the coefcients from table 3, describing the synergistic interaction model. In the concentrationresponse surface (bottom) for the combination of propofol and remifentanil, the isoboles for 25, 50, and 75% probability of return to consciousness are shown.

achieved by propofol alone (i.e., a 100% probability of no response) is reduced by the addition of remifentanil (i.e., the Emax of the new drug is reduced). Based on our exploration of the data regarding the anesthetic state
Table 5. Propofol and Remifentanil Infusion Schemes
Infusion scheme Propofol C50 (2.0 g/ml)

Remifentanil C50 (6.3 ng/ml)

Remifentanil C50 (6.3 ng/ml)

Bolus Infusion 1 Infusion 2 Infusion 3

1 mg/kg 6 mg kg1 h1 for 20 min 5 mg kg1 h1 for 60 min 4 mg kg1 h1 thereafter

1 g/kg 24 g kg1 h1 for 5 min 18 g kg1 h1 thereafter

50 g kg1 h1 for 3 min 18 g kg1 h1 thereafter

Propofol and remifentanil infusion schemes required to maintain effect site concentrations of these agents at a level associated with a 50% probability of no response to surgical stimuli and the most rapid possible return of consciousness after termination of the infusions. For remifentanil, infusion schemes are given with or without the use of a bolus dose. Based on a 40-yr-old female patient with a height of 165 cm, a weight of 65 kg, and a lean body mass of 46.6 kg. Pharmacokinetic parameters for propofol and remifentanil by Marsh et al.26 and Egan et al.,6 respectively. T1/2ke0 for propofol and remifentanil by Kazama et al.5 and Egan et al.,6 respectively.

Anesthesiology, V 99, No 2, Aug 2003

356

MERTENS ET AL.

determined the C50s of propofol for laryngoscopy and intubation at 9.8 and 17.4 g/ml, respectively. Intraoperative Interaction Intraoperatively, propofol reduced remifentanil requirements for suppression of responses to lower abdominal surgical stimuli in a synergistic manner. In a similar study, Vuyk et al.,1 demonstrated that propofol signicantly reduced alfentanil requirements for suppression of responses to lower abdominal surgical stimuli in a synergistic manner. In previous interaction studies, opioids have been not to be able to replace completely inhalational16 21 or intravenous1,13 anesthetic agents to provide anesthesia (the so-called ceiling effect). Accordingly, when the model described by equation 8 (see Appendix) was tted to the data, the C50,rem for suppression of responses to lower abdominal surgical stimuli was six orders of magnitude higher than the maximum blood remifentanil concentration encountered in this study. Therefore, this effect was modeled with the modied model described in equation 9. Return of Consciousness The propofol C50 for return of consciousness of 3.5 g/ml corresponds well with the reported propofol concentrations at which consciousness was lost in 50% of the patients of 3.4 g/ml.7 However, the C50,prop for return of consciousness determined in our study is lower than the C50,prop for return of consciousness of approximately 4 g/ml determined in a similar study after total intravenous anesthesia with propofol and alfentanil.1 It is conceivable that 0.2 mg/kg morphine administered 30 min before the end of surgery to provide adequate initial postoperative pain control after remifentanil anesthesia may have lowered the concentration at which patients regained consciousness and delayed the return of consciousness in our study group. Remifentanil Potency in Relation to Alfentanil The synthetic opioids fentanyl, alfentanil, sufentanil, and remifentanil can be considered a homogeneous group from a pharmacodynamic point of view because they act at similar receptor systems and have similar effects and similar side effects.22 The relative potencies of the synthetic opioids for several clinical end points were found to equal their relative potencies determined on the basis of their effect on the electroencephalogram22 (the potency ratio for alfentanil to remifentanil being 1:30).6 For this reason, the nature and the degree of the pharmacodynamic interaction between propofol and alfentanil probably will be similar to that for propofol and remifentanil. The methodology, patient population, and type of surgery in this study were exactly the same as those in the study by Vuyk et al.1 on the pharmacodynamic interaction between propofol and alfentanil. Therefore, we
Anesthesiology, V 99, No 2, Aug 2003

Fig. 9. Remifentanil equivalents versus blood propofol concentrations associated with a 50% probability of no response to intraabdominal surgical stimuli, from this study (lled circles) and from the study by Vuyk et al.1 (open circles). The curve represents a mechanistic function (see Appendix) tted to the data by unweighted least-squares nonlinear analysis described by the equation: C 50,rem,eq 1 (Cprop/9.97) 0.68 (Cprop/9.97)

where C50,rem,eq is the remifentanil equivalent associated with a 50% probability of no response and Cprop is the mean blood propofol concentration calculated in each patient. The Calf,50s from the study by Vuyk et al.1 were transformed to C50,rem,eq, by estimation of the potency of remifentanil relative to that of alfentanil for suppression of responses to lower abdominal surgery as an additional parameter (C50,rem,eq C50,alf/31.1).

could analyze the pooled intraoperative data from the two studies. The inuence of the mean measured intraoperative blood propofol concentration on the C50 of an opioid during the intraabdominal part of surgery was determined using equation 8 or 9 (see Appendix). The potency of remifentanil relative to that of alfentanil for suppression of responses to lower abdominal surgery was estimated as an additional parameter, transforming the C50s of alfentanil from the study by Vuyk et al.1 to remifentanil equivalents (C50,alf/potency ratio). Both the possibility of an additive and the possibility of a nonadditive interaction were explored. The AIC was lower for the nonadditive model than for the additive model (241.355 vs. 246.807, respectively). Because C50,rem and of the nonadditive model estimated with equation 8 were very large, the model described in equation 9 was tted to the data. The results are presented in gure 9. The parameters ( SE) describing the response surface are C50,prop 12.1 2.28 g/ml, ' 0.830 0.304, and potency ratio 31.1 7.53. Introduction of intraindividual variability did not result in a further reduction in the AIC. The interaction between propofol and remifentanil was, therefore, judged to be synergistic. As the mean blood propofol concentrations increased from 2.0 to 9.0 g/ml, the C50 of remifentanil (or remifentanil equivalents) for intraabdominal stimuli decreased from 6.1 ng/ml to 0.4 ng/ml (g. 9). Based on this analysis, remifentanil was 31 times more

PROPOFOLREMIFENTANIL PHARMACODYNAMIC INTERACTION

357

potent than alfentanil for suppression of responses to lower abdominal surgery in combination with propofol. This corresponds well with the potency ratio of alfentanil to remifentanil based on their effect on the electroencephalogram. Remifentanil was 41 times more potent than alfentanil for suppression of responses to lower abdominal surgery when given as a supplement to nitrous oxide anesthesia.23,24 Computer Simulations To explore the time to return of consciousness after anesthesia with propofol and remifentanil C50 concentration combinations, we simulated, using an Excel (Excel 7.0; Microsoft Corp., Redmond, WA) spreadsheet, the decay in propofol and remifentanil effect site concentrations after termination of a target-controlled infusion of 60 and 180 min with equianesthetic C50 propofolremifentanil combinations. Effect site concentrations of propofol and remifentanil were calculated using equation 6: C e t A k e0 t B ke0 t D ke0 t e e e k e0 ke0 ke0

A ke0 B ke0 D ke0 Ce0 eke0t (6) ke0 ke0 ke0

where Ce is the decreasing effect site propofol or remifentanil concentration; t is the time elapsed after termination of infusion; A, B, D, , , and were derived according to Hull3 from the pharmacokinetic parameter sets for propofol4 and remifentanil2; ke0 is the blood effect site equilibration rate constant of propofol5 or remifentanil6; and Ce(0) is the effect site propofol or remifentanil concentration when the infusion was terminated at t 0. The time to the return of consciousness was calculated by substituting Ce,prop(t) and Ce,rem(t) along with the estimates of and as obtained in this study in equation 2. Using the Excel optimizer function, t was iterated until the probability of unconsciousness given by equation 2 equaled 50%. The results of these simulations are displayed graphically in gure 10. Similar computer simulations were performed using the pharmacodynamic interaction model for propofol and alfentanil described by Vuyk et al.1 To allow comparison of the two studies, the results of the study by Vuyk et al.1 were translated to remifentanil equivalents, as described elsewhere,25 using the alfentanil/ remifentanil potency ratio as described above. The results of these simulations are displayed in gure 11. The computer simulations showed that the decay of the remifentanil concentration after termination of the infusion is so much more rapid than that of propofol that the propofolremifentanil concentration combination that provides both adequate anesthesia and the most rapid return of consciousness is the one with the lowest possible propofol concentration. The time from termiAnesthesiology, V 99, No 2, Aug 2003

Fig. 10. Computer simulation of the effect site propofol4,5 and remifentanil2,6 concentrations versus time during the rst 40 min after termination of target-controlled infusions of propofol and remifentanil that had been maintained for 60 (top) or 180 min (bottom), respectively, at constant target blood concentrations combinations associated with a 50% probability of no response to surgical stimuli. These concentration combinations are represented by the line on the bottom of the gure in the xy plane. The decrease in the concentrations following various intraoperative propofol-remifentanil combinations is represented by the curves running upward from the xy plane. The curved lines in parallel to the xy plane represent consecutive 1-min time intervals. The bold line represents the propofolremifentaniltime relation at which the probability of regaining consciousness is 50%.

358

MERTENS ET AL.

Fig. 11. Computer simulation of the time to return of consciousness after termination of target controlled infusions of propofol4,5 and remifentanil2,6 that had been maintained for 180 min at constant blood concentrations associated with a 50% probability of no response to surgical stimuli. The x-axis shows these blood concentration combinations associated with a 50% probability of no response to surgical stimuli. Bold line results of these simulations based on the models described in this study; dotted line results of the simulations based on the models described by Vuyk et al.1 for the combination of alfentanil and propofol, whereby alfentanil concentrations were converted to remifentanil equivalents, assuming a potency ratio of 31.1. The difference between the two curves probably results from the fact that in the remifentanil study morphine for postoperative pain relief was given before the end of surgery.

guidelines during target-controlled infusion. The actual target concentrations during anesthesia will have to be titrated to the desired effect. Dosing guidelines to rapidly achieve these adequate effect site concentrations without target controlled infusion are given in table 5.5,6,26 A low target propofol concentration of 2.0 g/ml in combination with a relatively higher remifentanil concentration of 6.3 ng/ml should only be used in the absence of signicant muscle relaxation. When maximum muscle relaxation is required for surgery, we advise use of a target propofol concentration of 3 g/ml or greater to reduce the risk of awareness. To avoid unrecognized awareness, premedication will further increase the margin of safety. None of the patients in our study had recall of any perioperative event. Patients in group A (the lowest target propofol concentration of 2.0 g/ml) were hemodynamically stable, and the mean intraoperative Bispectral Index value was 59 (table 2). Because the level of intraoperative neuromuscular blockade was maintained at a train-of-four level of 13, patients were able to move in response to inadequate anesthesia at all times.

Conclusions
In conclusion, this study shows that propofol reduces remifentanil requirements for suppression of responses to laryngoscopy, intubation, and intraabdominal surgical stimulation in a synergistic manner. In addition, remifentanil decreases propofol concentrations associated with the return of consciousness in a synergistic manner. Computer simulations revealed that the optimal blood propofol and blood remifentanil concentrations with respect to satisfactory intraoperative anesthetic conditions and speed of recovery are 2.0 g/ml and 6.3 ng/ml, respectively.

nation of a 180-min infusion of propofol and remifentanil to awakening was found to be shortest (6.5 min) after infusion of a constant target propofol concentration of 1.5 g/ml combined with a constant target remifentanil concentration of 9.0 ng/ml. This optimal propofol remifentanil concentration is not affected by the duration of anesthesia and corresponds well with that predicted on the basis of the interaction models determined by Vuyk et al.25 Infusion duration also has very little inuence on the time to awakening at this optimal concentration combination. However, with suboptimal propofolremifentanil concentration combinations (high propofollow remifentanil), return of consciousness is rapidly postponed with increasing infusion duration. The time to return of consciousness in our study group was longer for all suboptimal propofolremifentanil concentration combinations (g. 11). As mentioned before, 0.2 mg/kg morphine administered intravenously 30 min before the end of surgery for postoperative pain control may have delayed the return of consciousness in our study group. Based on the results of this study and our clinical experience, we recommend a minimum effect site propofol concentration of 2.0 g/ml in combination with an effect site remifentanil concentration of 6.3 ng/ml in female patients with American Society of Anesthesiologists physical status I or II in the absence of premedication and signicant muscle relaxation. These optimal effect site concentrations can be used as
Anesthesiology, V 99, No 2, Aug 2003

Appendix
Data Analysis of the Interaction during the Intraabdominal Part of Surgery
Multiple response and nonresponse data were available for each patient for the intraabdominal part of surgery. Therefore, the concentration effect relation of remifentanil for suppression of responses to intraabdominal surgical stimuli could be determined in each patient individually. This was performed by means of logistic regression. The logistic function is described by equation 5:

e 0 1lnCrem 1 e01lnCrem

(7)

where is the probability of no response, Crem is the blood remifentanil concentration, and 0 are the coefcients describing the shape of the curve. The remifentanil concentrations associated with a 50% probability of no response to lower abdominal surgery (C50), determined in each patient by logistic regression, were related to the corresponding mean intraoperative propofol concentrations with a

PROPOFOLREMIFENTANIL PHARMACODYNAMIC INTERACTION

359

mechanistic model over all patients by nonlinear regression analysis. The mechanistic function is described by equation 810: C prop C prop C rem C rem 1 C 50prop C 50rem C 50prop C 50rem (8)

References
1. Vuyk J, Lim T, Engbers FH, Burm AG, Vletter AA, Bovill JG: The pharmacodynamic interaction of propofol and alfentanil during lower abdominal surgery in women. ANESTHESIOLOGY 1995; 83:8 22 2. Minto CF, Schnider TW, Egan TD, Youngs E, Lemmens HJ, Gambus PL, Billard V, Hoke JF, Moore KH, Hermann DJ, Muir KT, Mandema JW, Shafer SL: Inuence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil: I. Model development. ANESTHESIOLOGY 1997; 86:10 23 3. Hull CJ: A toolbox for compartmental models, Pharmacokinetics for Anesthesia, 1st edition. Edited by Hull CJ. Oxford, Butterworth-Heinemann, 1991, pp 36776 4. Gepts E, Camu F, Cockshott ID, Douglas EJ: Disposition of propofol administered as constant rate intravenous infusions in humans. Anesth Analg 1987; 66:1256 63 5. Kazama T, Ikeda K, Morita K, Kikura M, Doi M, Ikeda T, Kurita T, Nakajima Y: Comparison of the effect-site keOs of propofol for blood pressure and EEG Bispectral Index in elderly and younger patients. ANESTHESIOLOGY 1999; 90:151727 6. Egan TD, Minto CF, Hermann DJ, Barr J, Muir KT, Shafer SL: Remifentanil versus alfentanil: Comparative pharmacokinetics and pharmacodynamics in healthy adult male volunteers. ANESTHESIOLOGY 1996; 84:82133 7. Vuyk J, Engbers FH, Lemmens HJ, Burm AG, Vletter AA, Gladines MP, Bovill JG: Pharmacodynamics of propofol in female patients. ANESTHESIOLOGY 1992; 77:39 8. Bender J, van den Elshout J, Selinger K, Broeders G, Dankers J, van der Heiden C: Determination of remifentanil in human heparinised whole blood by tandem mass spectrometry with short-column separation. J Pharm Biomed Anal 1999; 21:559 67 9. Bol CJ, Vogelaar JP, Tang JP, Mandema JW: Quantication of pharmacodynamic interactions between dexmedetomidine and midazolam in the rat. J Pharmacol Exp Ther 2000; 294:34755 10. Berenbaum MC: What is synergy? Pharmacol Rev 1989; 41:93141 11. Minto CF, Schnider TW, Short TG, Gregg KM, Gentilini A, Shafer SL: Response surface model for anesthetic drug interactions. ANESTHESIOLOGY 2000; 92:160316 12. Akaike H: A new look at the statistical model identication. IEEE Trans Automat Contr 1974; 19:716 23 13. Smith C, McEwan AI, Jhaveri R, Wilkinson M, Goodman D, Smith LR, Canada AT, Glass PS: The interaction of fentanyl on the Cp50 of propofol for loss of consciousness and skin incision. ANESTHESIOLOGY 1994; 81:820 8 14. Ropcke H, Konen-Bergmann M, Cuhls M, Bouillon T, Hoeft A: Propofol and remifentanil pharmacodynamic interaction during orthopedic surgical procedures as measured by effects on bispectral index. J Clin Anesth 2001; 13:198 207 15. Kazama T, Ikeda K, Morita K: Reduction by fentanyl of the Cp50 values of propofol and hemodynamic responses to various noxious stimuli. ANESTHESIOLOGY 1997; 87:21327 16. Brunner MD, Braithwaite P, Jhaveri R, McEwan AI, Goodman DK, Smith LR, Glass PS: MAC reduction of isourane by sufentanil. Br J Anaesth 1994; 72:42 6 17. Hall RI, Murphy MR, Hug CC Jr: The enurane sparing effect of sufentanil in dogs. ANESTHESIOLOGY 1987; 67:518 25 18. Hall RI, Szlam F, Hug CC Jr: The enurane-sparing effect of alfentanil in dogs. Anesth Analg 1987; 66:128791 19. Hecker BR, Lake CL, DiFazio CA, Moscicki JC, Engle JS: The decrease of the minimum alveolar anesthetic concentration produced by sufentanil in rats. Anesth Analg 1983; 62:98790 20. Murphy MR, Hug CC Jr: The anesthetic potency of fentanyl in terms of its reduction of enurane MAC. ANESTHESIOLOGY 1982; 57:485 8 21. Sebel PS, Glass PS, Fletcher JE, Murphy MR, Gallagher C, Quill T: Reduction of the MAC of desurane with fentanyl. ANESTHESIOLOGY 1992; 76:529 22. Shafer SL, Varvel JR: Pharmacokinetics, pharmacodynamics, and rational opioid selection. ANESTHESIOLOGY 1991; 74:53 63 23. Ausems ME, Hug CC Jr, Stanski DR, Burm AG: Plasma concentrations of alfentanil required to supplement nitrous oxide anesthesia for general surgery. ANESTHESIOLOGY 1986; 65:36273 24. Drover DR, Lemmens HJ: Population pharmacodynamics and pharmacokinetics of remifentanil as a supplement to nitrous oxide anesthesia for elective abdominal surgery. ANESTHESIOLOGY 1998; 89:869 77 25. Vuyk J, Mertens MJ, Olofsen E, Burm AG, Bovill JG: Propofol anesthesia and rational opioid selection: Determination of optimal EC50-EC95 propofolopioid concentrations that assure adequate anesthesia and a rapid return of consciousness. ANESTHESIOLOGY 1997; 87:1549 62 26. Marsh B, White M, Morton N, Kenny GN: Pharmacokinetic model driven infusion of propofol in children. Br J Anaesth 1991; 67:41 8

where Cprop is the mean intraoperative blood propofol concentration (g/ml) calculated in each patient; Crem is the C50 of remifentanil (ng/ml) for suppression of responses to intraabdominal surgical stimuli as determined in each patient by logistic regression; C50,prop and C50,rem are the blood propofol (g/ml) and remifentanil (ng/ml) concentrations that are associated with a 50% probability of no response if each drug would be administered as a single agent; and is a dimensionless parameter characterizing the shape of the curve (with 0, the result is a straight line suggesting additivity; with 0, the result is a curved line suggesting nonadditivity). Both the possibilities of an additive and nonadditive interaction were explored. The model was tted to the data with Crem as a dependent variable and Cprop as an independent variable. When C50,rem was more than three orders of magnitude higher than the maximum concentration encountered in this study, equation 8 was rewritten as: C prop C prop C 1 C 50,prop C 50,prop rem (9)

The model was tted to the data with Crem as a dependent variable and Cprop as an independent variable.

Data Analysis of Interaction for Return of Consciousness

In the data analysis of the interaction for return of consciousness, according to Minto et al.,11 the response surface was obtained by modeling of the unconsciousawake data versus the corresponding measured blood propofol concentrations and the corresponding measured blood remifentanil concentrations. The response surface is described by equation 1011: Uprop Urem U50 E E 0 E max E0 Uprop Urem 1 U50

(10)

where E is the combined drug effect; E0 corresponds with the return of consciousness; Emax corresponds with unconsciousness at the end of anesthesia just before termination of the target controlled infusions of propofol and remifentanil; Uprop Cprop/C50,prop and Urem/C50,rem; Cprop is the blood propofol and Crem is the blood remifentanil concentration; C50,prop is the blood propofol and C50,prop is the blood remifentanil concentration that results in 50% of maximal drug effect; U rem ; U prop U rem (11)

() is the steepness of the concentrationresponse relation at ratio described by: () prop (rem prop 2,) 2,2, where prop and rem are the when propofol and remifentanil are given as sole agents, and 2, is a model parameter estimated from the data; C50() is the number of units (U) associated with 50% of maximum effect at ratio described by: U50() 1 2,U50 2,U502, where 2,U50 is a model parameter estimated from the data; and Emax () is the maximum possible drug effect at ratio described by: Emax () Emax,prop (Emax,rem Emax,prop).

Anesthesiology, V 99, No 2, Aug 2003