Anesth Analg 2003;96:1651-1655
© 2003 International Anesthesia Research Society
ANESTHETIC PHARMACOLOGY
Effect-Site Concentration of Propofol for Recovery of Consciousness Is Virtually Independent of Fentanyl Effect-Site Concentration
Hiroko Iwakiri, MD*,
Osamu Nagata, MD*,
Takashi Matsukawa, MD
,
Makoto Ozaki, MD*, and
Daniel I. Sessler, MD
*Department of Anesthesiology, Tokyo Women’s Medical University, Tokyo, Japan;
Department of Anesthesiology, Yamanashi Medical University, Yamanashi, Japan;
OUTCOMES RESEARCHTM Institute, Department of Anesthesiology and Pharmacology, University of Louisville, Louisville, Kentucky; and Ludwig Boltzmann Institute, University of Vienna, Vienna, Austria
Address correspondence and reprint requests to Makoto Ozaki, MD, Department of Anesthesiology, Tokyo Women’s Medical University, Tokyo 162-8666, Japan. Address e-mail to mozaki{at}anes.twmu.ac.jp
 |
Abstract
|
|---|
Fentanyl reduces the amount of propofol necessary to prevent responses to surgical stimuli. However, opioids have relatively little effect on consciousness. We, therefore, tested the hypothesis that fentanyl minimally alters the effect-site concentration of propofol associated with awakening. Fifty women having gynecologic laparotomy with propofol anesthesia were randomly allocated into the following target effect-site fentanyl concentrations: 0.8, 1.0, 1.4, 2.0, and 3.0 ng/mL. Fentanyl was continued at the designated rate through the initial postoperative phase. The propofol effect-site concentration associated with eye opening in response to verbal command was regarded as the awakening concentration. The estimated propofol effect-site concentrations at awakening did not differ significantly among the groups and were 1.9 ± 0.5 µg/mL with a fentanyl effect-site concentration of 0.8 ng/mL; 1.6 ± 0.4 µg/mL with 1.0 ng/mL of fentanyl; 1.6 ± 0.2 µg/mL with 1.4 ng/mL of fentanyl; 1.7 ± 0.4 µg/mL with 2.0 ng/mL of fentanyl; and 1.6 ± 0.34 µg/mL with 3.0 ng/mL of fentanyl (mean ± SD). Seventy percent of the subjects in the 0.8 ng/mL fentanyl group spontaneously complained of pain, whereas none of the patients in the 2 or 3 ng/mL groups did. Five (56%) of 9 women in the 3 ng/mL group had a postoperative respiratory rate <6 breaths/min. Heart rate in one of these women decreased to <40 bpm. These data suggest that the optimal fentanyl effect-site concentration in patients recovering from gynecologic laparoscopy is between 1.4 and 2.0 ng/mL.
IMPLICATIONS:The effect-site concentration for propofol at awakening was virtually independent of the fentanyl effect-site concentration over the range of 0.8 to 3.0 ng/mL; however, 0.8 ng/mL of fentanyl was associated with inadequate postoperative analgesia, and 3.0 ng/mL of fentanyl was associated with respiratory toxicity. The optimal postoperative fentanyl effect-site concentration during recovery from propofol general anesthesia for laparotomy thus appears to be near 2 ng/mL.
|
Introduction
|
|---|
It is well established that opioid administration reduces the minimum alveolar concentration (MAC) and Cp50 of propofol required to prevent movement in response to surgical stimulation or tracheal intubation (1,2). Because opioids are excellent analgesics, it is hardly surprising that they blunt responses to painful stimulation.
However, analgesic doses of opioids have little effect on consciousness per se (3). It thus seems likely that opioids will have little effect on postoperative awakening. We, therefore, tested the hypothesis that propofol effect-site concentrations at awakening are similar over a clinically relevant range of fentanyl effect-site concentrations. Simultaneously, we evaluated opioid-related complications, including hypoventilation and bradycardia, in the immediate postoperative period. Confirming our hypothesis would suggest that patients should not be denied adequate intraoperative opioids for fear of prolonging the initial recovery from general anesthesia.
|
Methods
|
|---|
The Hospital Ethics Board on Human Experiments at Tokyo Women’s Medical University approved this study, and written, informed consent was obtained from each participant. All were ASA physical status I or II and were scheduled for gynecologic laparotomy; they were between 20 and 62 yr old. Patients with advanced cardiovascular, pulmonary, liver, or renal disease or obesity (body mass index >30 kg/m2) were excluded.
Patients were given 0.5 mg of atropine sulfate and 50 mg of hydroxyzine hydrochloride 30 min before the start of surgery. Preceding anesthetic introduction, a fentanyl infusion was started with a target concentration of 2 ng/mL. Five minutes later, propofol administration was initiated with a target concentration of 3 to 4 µg/mL. It is important to recognize that our protocol was based on targeted effect-site concentrations rather than measured plasma concentrations. Effect-site concentrations of both propofol and fentanyl were controlled by a Graseby 3500 syringe pump connected to a ConGrase controller (4). This system provides real-time estimates of blood concentrations for propofol and fentanyl according to a three-compartment model. The pharmacokinetic variables of Marsh et al. (5) and Shafer et al. (6) were used for propofol and fentanyl, respectively. Numerical analysis was based on the Runge-Kutta method (7); this is the same method that the Diprifusor target-controlled infusion (TCI) system uses for propofol.
After loss of consciousness, 0.15 mg/kg of vecuronium bromide was given, and the trachea was intubated. Additional vecuronium was given as necessary to maintain one to two twitches in response to supramaximal electrical stimulation of the ulnar nerve at the wrist. During surgery, the fentanyl infusion was adjusted as necessary to maintain heart rate near 60 bpm. The propofol target effect-site concentration was regulated to maintain the bispectral index near 50 (A-1050, software Version 3.0; Aspect Medical, Inc., Newton, MA).
Fifteen minutes before the end of surgery, patients were randomly assigned to 1 of 5 fentanyl effect-site concentration groups: 0.8, 1.0, 1.4, 2.0, or 3.0 ng/mL. Randomization was based on computer-generated codes that were kept in opaque, sealed envelopes until 30 min before the anticipated end of surgery. Fentanyl, at the designated target concentration, was continued throughout the remainder of the operation and into the initial postoperative recovery period.
Neuromuscular block was antagonized with 1.0 mg of atropine sulfate and 2.0 mg of neostigmine. When spontaneous ventilation resumed, patients were extubated. Propofol administration was discontinued after surgery was complete and all bandages had been applied. The patients’ names were called out in 30-s intervals until they opened their eyes; this defined awakening from anesthesia. Return of consciousness was assessed by a single physician who was not blinded to fentanyl concentration.
Morphometric and demographic characteristics of the participants were recorded. Blood pressure and heart rate were determined oscillometrically and recorded at 5-min intervals. Bispectral index was similarly recorded.
The estimated propofol effect-site concentration on awakening was recorded. During the initial 15 min after awakening, heart rate and respiratory rate were recorded at 5-min intervals. A heart rate <40 bpm was considered evidence of fentanyl-induced cardiac toxicity. Similarly, a respiratory rate <6 breaths/min or an end-tidal PCO2 >50 mm Hg was considered evidence of fentanyl-induced respiratory toxicity.
Spontaneous complaints of pain were catalogued and, for the first 15 min after awakening, the patients were asked at 5-min intervals if they had pain. Patients were treated with nonsteroidal antiinflammatory drugs given IV, IM, or rectally.
Our primary outcome was the effect-site concentration of propofol on awakening. Continuous data were compared by using one-way analysis of variance with Tukey-Kramer post hoc analysis. Categorical results were compared by using 
2 analysis. Data are reported as percentages or means ± SD in the text and tables and as means ± 95% confidence intervals in the figures; P < 0.05 was considered statistically significant.
|
Results
|
|---|
Morphometric and demographic characteristics of the participants were similar in each target fentanyl effect-site group, as was the duration of anesthesia (Table 1). During surgery, propofol was maintained at an estimated effect-site concentration between 2.5 and 4.0 µg/mL, whereas fentanyl effect-site concentrations were maintained between 2 and 4 ng/mL. One patient, who was given 3.0 ng/mL fentanyl, failed to awaken 30 min after propofol administration was discontinued at a propofol effect-site concentration of <1 µg/mL. We, therefore, discontinued fentanyl administration and excluded her results from our analysis. Propofol effect-site concentrations at the time of awakening did not differ significantly at any fentanyl effect-site concentration and ranged from 1.6 ± 0.2 µg/mL to 1.9 ± 0.5 µg/mL (Fig. 1).
Spontaneous and elicited complaints of pain were inversely related to estimated fentanyl effect-site concentration. When fentanyl effect-site concentration equaled or exceeded 1.4 ng/mL, for example, only a single patient among 10 spontaneously complained of pain. In contrast, 6 of 10 patients with a target effect-site concentration of 0.8 ng/mL spontaneously complained of pain. Pain scores at each fentanyl effect-site concentration are shown in Figure 2.
View larger version (14K):
[in this window]
[in a new window]
|
Figure 2. Mean pain scores (visual analog scale; VAS) at each effect-site concentration of fentanyl. The score at 0.8 ng/mL of fentanyl was different from those at all other concentrations. The scores at 1.0 and 1.4 ng/mL of fentanyl were similar, as were those at 2.0 and 3.0 ng/mL (one-way analysis of variance with Tukey-Kramer post hoc analysis; P < 0.05 was statistically significant). Data are presented as means with 95% confidence intervals.
|
|
Five of the 9 patients (56%) assigned to 3 ng/mL of fentanyl had a respiratory rate <6 breaths/min or an end-tidal PCO2 >50 mm Hg. However, none required ventilatory assistance or pharmacologic treatment. One patient’s heart rate, in the same group, decreased to 36 bpm (Table 2); her heart rate increased to 50 bpm on the administration of 0.5 mg of atropine sulfate.
|
Discussion
|
|---|
The original concept of MAC, as proposed by Eger (8) in 1971, was based on the volatile anesthetic partial pressure required to prevent movement in response to skin incision 50% of the time. However, the concept has been expanded to include the plasma concentration (CP50) of IV drugs (9) and a variety of clinically relevant responses, including learning (10), loss of consciousness (11), awakening (1), hemodynamic responses (12), and laryngoscopy (1).
In this study, we evaluated the effects of opioid administration on awakening from propofol general anesthesia. Estimated propofol effect-site concentrations were similar, near 1.7 µg/mL, in patients assigned to postoperative fentanyl effect-site concentrations ranging from 0.8 to 3.0 ng/mL. The estimated propofol effect-site concentration at awakening was similar to that predicted in a computer simulation by Vuyk et al. (13). Our results are also consistent with a previous study by Kazama et al. (1), in which the authors demonstrated that the propofol concentration associated with loss of consciousness was only slightly reduced by concomitant fentanyl administration: propofol concentration at loss of consciousness decreased only 11% at 1 ng/mL of fentanyl and 17% with 3 ng/mL of fentanyl.
TCI-based results can have a 50% performance error. However, we minimized the limitations of TCI by collecting data only when target concentration was stable. We did not collect data during the onset of drug effect or when the effect was dissipating.
Trivial effects of fentanyl on the propofol effect-site concentration associated with loss or return of consciousness differ markedly with the pronounced effect of opioids on other MAC analogs. For example, a plasma fentanyl concentration of 1 ng/mL reduces the propofol concentration required to block responses to tetanus, laryngoscopy, intubation, and skin incision by 31%–34%. A plasma fentanyl concentration of 3 ng/mL reduces the concentrations for each response by 50%–55% (1). Smith et al. (2) reported that the propofol Cp50 for skin incision was decreased by 63% with 1 ng/mL of fentanyl and by 89% with 3 ng/mL.
In a study similar to ours, intraoperative morphine (0.1 to 1.0 mg/kg) did not alter the sevoflurane concentration at awakening (14). The same group also showed that the MAC-awake of sevoflurane is only minimally reduced by fentanyl (15). Telford et al. (3) showed that the Cp50-asleep of thiopental did not change with 1 to 2.1 ng/mL of fentanyl. In addition, Splinter and Cervenko (16) and Bowdle and Ward (17) also found that a small dose of fentanyl (1.5 µg/kg; 2 ng/mL of peak plasma concentration) did not change the induction dose of thiopental. Therefore, that our clinically relevant fentanyl analgesic plasma concentration range of 1 to <3 ng/kg did not change the concentration of propofol at recovery of consciousness is not that surprising. Taken together, current and previous results indicate that opioids, which are excellent analgesics, significantly reduce the propofol concentration required to block the response to noxious stimulation. In contrast, they have little effect on loss or return of consciousness. Analgesia and consciousness thus appear to be mediated by separate mechanisms.
We set our maximum fentanyl effect-site concentration to 3.0 ng/mL because the concentration associated with respiratory inhibition in 50% of patients is roughly 3.5 ng/mL (18). Although the propofol effect-site concentration on awakening was similar at each concentration, patients given 3.0 ng/mL of fentanyl experienced more side effects than those given smaller effect-site concentrations. One patient in the 3.0 ng/mL fentanyl group had delayed awakening, and, as a result, fentanyl was stopped before the patient awakened. Furthermore, inadequate ventilation (respiratory rate <6 breaths/min or end-tidal PCO2 >50 mm Hg) was observed in five (56%) of nine patients. This fraction was nearly identical to that reported by Vuyk et al. (13). In contrast, patients assigned to 
2 ng/mL of fentanyl did not experience respiratory or cardiac toxicity. Our data thus suggest that the fentanyl effect-site concentration should be 2 ng/mL when patients are discharged from the postanesthesia care unit.
Six (60%) of the 10 women assigned to 0.8 ng/mL of fentanyl spontaneously complained of pain soon after awakening from anesthesia. This outcome is consistent with a previous study in which a fentanyl concentration of 0.8 ng/mL was found to be insufficient in patients undergoing procedures similar to ours (19). It is also consistent with previous work suggesting that a fentanyl concentration near 1 ng/mL is required to control initial postoperative pain (20). Pain was also frequently reported when the fentanyl concentration was 1.0 or 1.4 ng/mL.
Taken together, these results indicate that effective postoperative pain relief requires an initial fentanyl effect-site concentration exceeding 1.4 ng/mL. However, respiratory and cardiac toxicity become evident at a fentanyl effect-site concentration of 3.0 ng/mL. We thus conclude that the optimal postoperative fentanyl effect-site concentration in women undergoing laparotomy is near 2 ng/mL.
A limitation of our protocol is that all our patients had gynecologic laparotomies; fentanyl effect-site concentrations <2 ng/mL will presumably be suitable for less-stimulating operations. Similarly, to avoid toxicity, it would be prudent to use smaller initial effect-site concentrations in elderly patients and those with certain underlying conditions. The effect-site concentrations of fentanyl we used were from 0.8 to 3.0 mg/mL. We should emphasize that our results are applicable only to the effect-site concentration range explored in this study.
In summary, we examined the relationship between the fentanyl effect-site concentration and the propofol effect-site concentration at awakening. Our results indicate that the propofol effect-site concentration at awakening was virtually constant at fentanyl effect-site concentrations of 0.8 to 3.0 ng/mL. However, fentanyl effect-site concentrations between 0.8 and 1.4 ng/mL were associated with numerous complaints of postoperative pain, whereas a fentanyl effect-site concentration of 3.0 ng/mL was associated with respiratory and cardiac toxicity. The optimal postoperative fentanyl effect-site concentration during recovery from propofol general anesthesia for laparotomy thus appears to be near 2 ng/mL.
|
Acknowledgments
|
|---|
Supported by National Institutes of Health Grant GM 58273 (Bethesda, MD) and the Commonwealth of Kentucky Research Challenge Trust Fund (Louisville, KY). None of the authors has any personal financial interests related to this study.
|
References
|
|---|
- 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: 213–27.[ISI][Medline]
- Smith C, McEwan AI, Jhaveri R, et al. The interaction of fentanyl on the Cp50 of propofol for loss of consciousness and skin incision. Anesthesiology 1994; 81: 820–8.[ISI][Medline]
- Telford RJ, Glass PS, Goodman D, Jacobs JR. Fentanyl does not alter the "sleep" plasma concentration of thiopental. Anesth Analg 1992; 75: 523–9.[Abstract/Free Full Text]
- Nagata O, Sawada K, Sato M, et al. [Evaluation of estimated blood concentration of propofol on wake-up using "ConGrase", a software to control the syringe pump for propofol infusion]. Masui 1998; 47: 1246–52.[Medline]
- Marsh B, White M, Morton N, Kenny GN. Pharmacokinetic model driven infusion of propofol in children. Br J Anaesth 1991; 67: 41–8.[Abstract/Free Full Text]
- Shafer SL, Varvel JR, Aziz N, Scott JC. Pharmacokinetics of fentanyl administered by computer-controlled infusion pump. Anesthesiology 1990; 73: 1091–102.[ISI][Medline]
- Benett WRJ. Scientific and engineering problem-solving with the computer. Englewood Cliffs, NJ: Prentice Hall, 1976.
- Eger EI II. MAC, MAP, and euphony. Anesthesiology 1971; 35: 552.
- Leslie K, Sessler DI, Smith WD, et al. Prediction of movement following painful stimulation during propofol/nitrous oxide anesthesia in volunteers. Anesthesiology 1996; 84: 52–63.[ISI][Medline]
- Leslie K, Sessler DI, Schroeder M, Walters K. Propofol blood concentration and the bispectral index predict suppression of learning during propofol/epidural anesthesia in volunteers. Anesth Analg 1995; 81: 1269–74.[Abstract]
- Doufas AG, Bakhshandeh M, Bjorksten AR, et al. Automated responsiveness test (ART) predicts loss of consciousness and adverse physiologic responses during propofol conscious sedation. Anesthesiology 2001; 94: 585–92.[ISI][Medline]
- Roizen MF, Horrigan RW, Frazer BM. Anesthetic doses blocking adrenergic (stress) and cardiovascular responses to incision: MAC BAR. Anesthesiology 1981; 54: 390–8.[ISI][Medline]
- Vuyk J, Mertens MJ, Olofsen E, et al. Propofol anesthesia and rational opioid selection: determination of optimal EC50-EC95 propofol-opioid concentrations that assure adequate anesthesia and a rapid return of consciousness. Anesthesiology 1997; 87: 1549–62.[ISI][Medline]
- Katoh T, Suguro Y, Kimura T, Ikeda K. Morphine does not affect the awakening concentration of sevoflurane. Can J Anaesth 1993; 40: 825–8.[Abstract/Free Full Text]
- Katoh T, Uchiyama T, Ikeda K. Effect of fentanyl on awakening concentration of sevoflurane. Br J Anaesth 1994; 73: 322–5.[Abstract/Free Full Text]
- Splinter WM, Cervenko F. Haemodynamic responses to laryngoscopy and tracheal intubation in geriatric patients: effects of fentanyl, lidocaine and thiopentone. Can J Anaesth 1989; 36: 370–6.[Abstract/Free Full Text]
- Bowdle TA, Ward RJ. Induction of anesthesia with small doses of sufentanil or fentanyl: dose versus EEG response, speed of onset, and thiopental requirement. Anesthesiology 1989; 70: 26–30.[ISI][Medline]
- Mildh LH, Scheinin H, Kirvela OA. The concentration-effect relationship of the respiratory depressant effects of alfentanil and fentanyl. Anesth Analg 2001; 93: 939–46.[Abstract/Free Full Text]
- Woodhouse A, Mather LE. The minimum effective concentration of opioids: a revisitation with patient controlled analgesia fentanyl. Reg Anesth Pain Med 2000; 25: 259–67.[ISI][Medline]
- Gourlay GK, Kowalski SR, Plummer JL, et al. Fentanyl blood concentration-analgesic response relationship in the treatment of postoperative pain. Anesth Analg 1988; 67: 329–37.[Abstract/Free Full Text]
Accepted for publication January 28, 2003.
This article has been cited by other articles:
|
|
|
|
 
H. Iwakiri, N. Nishihara, O. Nagata, T. Matsukawa, M. Ozaki, and D. I. Sessler
Individual Effect-Site Concentrations of Propofol Are Similar at Loss of Consciousness and at Awakening
Anesth. Analg.,
January 1, 2005;
100(1):
107 - 110.
[Abstract]
[Full Text]
[PDF]
|
|
|
Top
Abstract
Introduction
, along with mean values (
) and 95% confidence intervals for each fentanyl effect-site concentration. Propofol awakening effect-site concentrations were similar, approximately 1.7 µg/mL, at each fentanyl effect-site concentration.
