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C50 for Propofol-Remifentanil Target-Controlled Infusion and Bispectral Index at Loss of Consciousness and Response to Painful Stimulus in Chinese Patients: A Multicenter Clinical Trial

Section Editor(s): Durieux, Marcel E.; Gin, TonyXu, Zhipeng MD, PhD*; Liu, Fang MD*; Yue, Yun MD*; Ye, Tiehu MD; Zhang, Bingxi MD; Zuo, Mingzhang MD§; Xu, Mingjun MD; Hao, Rongrong MD; Xu, Yuan MD; Yang, Ning MD§; Che, Xiangming MD

doi: 10.1213/ane.0b013e31818f8a30
Anesthetic Pharmacology: Preclinical Pharmacology: Clinical Pharmacology: Research Reports
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BACKGROUND: In this study, we evaluated the predicted blood and effect-site C50 for propofol and remifentanil target-controlled infusion and the Bispectral Index (BIS) values at loss of consciousness (LOC) and response to a standard noxious painful stimulus in Chinese patients. We hypothesized that these values would be different from previously published data on Caucasians.

METHODS: Five medical centers enrolled 405 ASA physical status I and II unpremedicated Chinese patients (97 men, 308 women) aged 18–65 yr. Propofol was initially given to a predicted blood concentration of 1.2 μg/mL and thereafter increased by 0.3 μg/mL every 30 s until Observer’s Assessment of Alertness and Sedation score was 1. The propofol was kept constant, and remifentanil was given to provide a predict blood concentration of 2.0 ng/mL, and then increased by 0.3 ng/mL every 30 s until loss of response to a tetanic stimulus. BIS (version 3.22, BIS Quattro sensor) was also recorded.

RESULTS: The propofol effect-site C50 at LOC was 2.2 (2.2–2.3) μg/mL. The remifentanil effect-site C50 at loss of response to painful stimulus was 3.3 ng/mL. Fifty percent of patients lost consciousness at a BIS value of 58, and 95% had lost consciousness at BIS values <40. The BIS value at C50 at loss of response to painful stimulus was 65.4, which was higher than that at LOS (P < 0.001).

CONCLUSIONS: The predicted blood and effect-site concentrations of propofol and BIS values at LOC were lower than those in previously published studies of Caucasian populations.

IMPLICATIONS: Half of Chinese patients lose conscious response at an effect-site propofol concentration of 2.2 ng/mL and a Bispectral Index value of 58, and lose response to painful stimuli at a remifentanil effect-site concentration of 3.3 ng/mL. The propofol concentration and Bispectral Index values for loss of consciousness are lower than reported in Caucasian populations.

From the *Beijing Chaoyang Hospital, Capital Medical University, Beijing, People’s Republic of China; †Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; ‡Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of China; §Beijing Hospital, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; and ∥Beijing Gynecology and Obstetrics Hospital, Capital Medical University, Beijing, People’s Republic of China.

Accepted for publication September 23, 2008.

Supported by AstraZeneca Corp. Clinical Research Fund.

Address correspondence and reprint requests to Yun Yue, Beijing Chaoyang Hospital, Capital Medical University, 8#, Baijiazhuang Rd., Chaoyang District, Beijing 100020, People’s Republic of China. Address e-mail to yueyun@hotmail.com.

Target-controlled infusion systems (TCI) are commonly used in China. The purpose of this study was to estimate the predicted effect-site propofol concentration at which 50% of patients do not respond with movement to skin incision, the C50 for nonresponse to skin incision. The C50 for propofol used in the “Diprifusor” TCI system has been validated by Milne1 et al. in Caucasian patients. There is growing evidence that ethnicity can be a major factor in pharmacokinetics and pharmacodynamics, including sedatives and analgesics, and this is appropriately viewed as important by drug regulatory agencies.2–5 There has been no confirmation of these TCI parameters in Chinese patients. It is important to confirm whether TCI models based on Caucasians are suitable for clinical practice in China.

In a pilot trial we found Bispectral Index (BIS) values were lower in Chinese patients than in Caucasian patients at the same predicted blood and effect-site concentrations. We therefore performed a large prospective evaluation of the predicted blood and effect-site concentrations of propofol at loss of consciousness (LOC) and remifentanil concentrations at loss of purposeful movement to a painful stimulus in Chinese patients to evaluate whether the BIS values and the anesthetic concentrations were lower in Chinese patients. We concurrently recorded the BIS to assess the relationship among estimated C50, BIS and clinical assessments of sedation and analgesia.

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METHODS

After receiving IRB approval at each institution and written informed consent from each subject, we studied 405 (97 male, 308 female) ASA I-II Chinese patients scheduled for operations at 5 medical centers:

  1. Beijing Chaoyang Hospital, Capital Medical University,
  2. Peking Union Medical College Hospital, Chinese Academy of Medical Sciences,
  3. Beijing Tongren Hospital, Capital Medical University,
  4. Beijing Hospital, Chinese Academy of Medical Sciences,
  5. Beijing Gynecology and Obstetrics Hospital, Capital Medical University.

The a priori sample size calculation was not undertaken. The sample size was based on recruiting a substantial number of patients at each center. All the recruited patients in Peking Union Medical College Hospital and 51 patients in Beijing Gynecology and Obstetrics Hospital, Capital Medical University completed only the propofol part of the study. Exclusion criteria included age <18 yr or >65 yr, recent administration of sedative or opioid drugs, body weight <80% or >120% of ideal weight, and impairment of cardiac, respiratory, hepatic or renal function. No drugs were administered before induction of anesthesia. After insertion of a 20G venous cannula, patients received Ringer’s lactate solution 10 mL/kg. BIS was monitored with a BIS XP (A-2000, Aspect Medical System, USA, software version 3.22, BIS Quattro sensor) and recorded manually. Noninvasive arterial blood pressure, Spo2, electrocardiogram, and tidal volume were monitored routinely.

A TCI of propofol (Diprivan 1% AstraZeneca Corp with a pre-filled syringe) was administered using the DiprifusorTM (software version 2.0, Graseby® 3500 Syringe Pump, Smiths Medical, Watford, UK), which uses the Marsh pharmacokinetic model. Remifentanil was administered using a microcomputer-controlled pump (SLGO High-tech Development CO, Beijing, China), which uses the Minto pharmacokinetic model. These systems display both the predicted blood concentration and the effect-site concentration. The propofol infusion was started so as to provide a blood concentration of 1.2 μg/mL and increase by 0.3 μg/mL every 30 s until the Observer’s Assessment of Alertness and Sedation was 1, i.e., no response. This point was defined as LOC. BIS and predicted blood and effect-site propofol concentrations were recorded at this point. This predicted blood propofol concentration was kept stable for 3 min and a remifentanil TCI begun. The predicted blood remifentanil concentration was started at 2.0 ng/mL and increased by 0.3 ng/mL every 30 s until no purposeful movement was observed after a tetanic stimulus (50 Hz, 80 mA, 0.25 ms pulses for 4 s),1 which was applied to the wrist using a peripheral nerve stimulator. Twisting or jerking the head was considered a purposeful movement, but twitching or grimacing was not.4 This point was defined as “no response to a painful stimulus.” BIS and remifentanil concentrations were recorded and thereafter surgery proceeded as normal. The respiratory rate and tidal volume were measured with a Datex-Ohmeda Carnomac Ultima. Respiration depression was defined as tidal volume <300 mL, respiratory rate <10 breaths per minute, or Spo2 <95%.

Data are reported as mean ± (sd). SPSS (version 11.5, SPSS American) statistical software and Microsoft® Office Excel 2003 (version 11.5612.5606) were used to perform statistical analysis. P < 0.05 was considered as statistically significant. One-way analysis of variance and one-sample t test were used to compare values at baseline, LOC, and loss of response to noxious stimulation after testing continuous data (heart rate [HR], mean arterial blood pressure [MAP], and Spo2) for normality. A quantal response model (probit analysis) was used to calculate C05, C50 and C95 (concentrations associated with 5%, 50%, and 95% probabilities, respectively) at each end point based on predicted blood and effect-site concentrations of the 2 drugs. An identical method was applied to calculate C05, C50, and C95 at each end point of BIS.

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RESULTS

Four-hundred-five Chinese patients were studied. Their characteristics are shown in Table 1. HR remained stable during the infusion of propofol but MAP decreased. HR and MAP decreased sharply during the infusion of remifentanil. Oxygen saturation was stable throughout (Table 2). Induction of anesthesia was smooth in all patients.

Table 1

Table 1

Table 2

Table 2

Remifentanil depressed respiratory function significantly as evidenced by decreased respiratory rate and low tidal volume. Most patients had respiratory depression before they lost response to a painful stimulus. A facemask was used to deliver oxygen to all patients. Twenty-two patients required assisted ventilation by facemask. The predicted effect-site remifentanil concentrations in patients requiring ventilatory assistance were lower than that at the point of no response to pain (Table 3).

Table 3

Table 3

The effect-site propofol concentrations associated with a 50% probability of LOC was 2.2 (2.2–2.3) μg/mL (Table 4). The BIS associated with a 50% probability of LOC was 58 (58–59). There were no differences in predicted effect-site propofol concentration at LOC between males and females. The effect-site remifentanil concentration associated with 50% probability of nonresponse to tetanic stimulus was 3.3 (3.3–3.4) ng/mL (Table 5). The median BIS associated with 50% probability of nonresponse to tetanic stimulus was 65 (65–66).

Table 4

Table 4

Table 5

Table 5

The probabilities of LOC and no response to tetanic stimulus versus predicted effect-site propofol and remifentanil concentrations are shown in Figures 1 and 2, respectively. The effect-site propofol concentrations associated with 5% and 95% probability of LOC were 1.3 (1.2–1.4) and 3.2 (3.1–3.3) μg/mL, respectively (Table 4, Fig. 1). The effect-site remifentanil concentrations associated with 5%, 50%, and 95% probability of nonresponse to tetanic stimulus were 1.5 (1.4–1.6) and 5.1 (5.0–5.2) ng/mL, respectively (Table 5, Fig. 2). The probabilities of LOC and no response to the tetanic stimulus versus BIS are shown in Figure 3. Five percent and 95% of patients lost consciousness at BIS values of 77 (76–78) and 39 (39–40), respectively. BIS values associated with 5% and 95% probability of nonresponse to tetanus stimulus were 82 (81–83) and 49 (48–50), respectively. Interestingly, the BIS values associated with nonresponse to painful stimulus were higher than that at LOC (P < 0.05).

Figure 1

Figure 1

Figure 2

Figure 2

Figure 3

Figure 3

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DISCUSSION

We investigated whether predicted blood and effect-site propofol and remifentanil concentrations and values of BIS, all based on Caucasian data, are useful for predicting whether a Chinese patient is unconscious and unresponsive to painful stimulus. We found that the effect-site concentrations of propofol and the BIS values at LOC were lower in Chinese than patients that reported in Caucasians.1

The C50 of an IV hypnotic associated with nonresponse to painful stimulus is a concept analogous to minimum alveolar concentration and can be used as an estimate of how much IV drug needs to be administered to obtain an effect in 50% of the population.6 Unfortunately, unlike volatile anesthetics, which can be measured using end-tidal gas concentrations, the concentrations of IV administered drugs cannot be measured in real time. For this reason, the best approximation is that of a pharmacokinetic model, as implemented in TCI systems. We chose to study the DiprifusorTM system for TCI administration of propofol, which uses the Marsh pharmacokinetic model because it is widely available in China. The Diprifusor displays the predicted blood and effect-site concentrations, which is convenient for investigations such as ours. For remifentanil, we used the TCI system made by SLGO Corporation, which is widely used in China, and is designed for TCI administration of several IV anesthetics. The remifentanil module uses the Minto pharmacokinetic model.7,8

There have been two similar, but much smaller, studies of propofol C50 values: one in Chinese and one in Caucasian patients.1,9 In a study in Chinese patients, Irwin et al.9 used the Diprifusor and chose 1.5 μg/mL as the initial propofol target concentration. The propofol target concentration was increased by 0.5 μg/mL every 2 min until LOC. They found the effect-site propofol C50 for LOC was 2.66 μg/mL in Chinese patients. This is higher than that found in our study and may reflect the larger drug increments and longer intervals between increments. In a similar study in Caucasians, Milne et al.1 used the Diprifusor system and chose 1.5 μg/mL as the initial propofol target concentration. They increased the target concentration by 0.5 μg/mL every 30 s. They reported effect-site propofol C50 for LOC as 2.8 μg/mL in Caucasians. Despite the similarity in predicted effect-site concentrations between these two studies, they used substantially different dosing intervals. The interval used by Irwin et al. was four times longer than by Milne et al. Published studies10–12 indicate that a longer dosing interval results in a higher C50. In our study, we increased the predicted blood concentration of propofol by small increments every 30 s, exactly as did Milne et al.1 to facilitate comparing our results in Chinese with that in Caucasian patients.

Ninety percent of patients will lose consciousness at predicted effect-site propofol concentrations between the C05 and the C95. For LOC, the range of effect-site concentrations to include 90% of patients was 1.3–3.2 μg/mL. A comparison of the results of our study performed on a Chinese population with the results of a study performed on Caucasian patients administered propofol in the same manner revealed differences in the predicted effect-site concentrations.1 The C50 for effect-site propofol concentration at LOC was 2.2 μg/mL in the Chinese population and 2.8 μg/mL in the Caucasian. The C95 was 3.2 μg/mL in the Chinese compared with 4.1 μg/mL in Caucasians. There was also a large difference in the predicted blood and effect-site concentrations, the concentration in the Chinese population was consistently lower. It is impossible to know if the differences observed were due to pharmacokinetic or pharmacodynamic factors because blood concentrations of the drugs were not measured in either study. Li et al.13 measured propofol blood levels in Chinese patients and compared them to those predicted by the Diprifusor TCI system. They found the relationship acceptable for clinical use. This suggests that a pharmacokinetic difference between Caucasians and Chinese may not explain our findings. Comparison of the results is further hampered by the fact that the studies were done at different times in different countries.

Several investigations have evaluated the use of TCI propofol for total IV anesthesia, and the pharmacodynamic interactions between propofol and different opioids14,15 However, little information is available on the effect-site concentration of remifentanil required to blunt body movement responses to skin incision. The lack of direct determination of remifentanil plasma concentrations is a shortcoming of our study. However, the pharmacokinetic model we used has been demonstrated as adequately accurate in predicting plasma and effect-site concentrations of remifentanil.7,8 Data from two published studies16,17 suggested, but did not clearly demonstrate, that the concentrations of remifentanil in the Chinese were lower than that in Caucasians. There is no direct evidence of this because of the differences in methods between the two previous studies and ours.

Tetanic stimulation of the ulnar nerve has the advantage of ease of performance, repeatability, reproducibility and is frequently used in lieu of skin incision.4,18–20 One study has shown no significant difference in somatic response between C50 tetanic stimulus and C50 skin incision, but there was a significant difference in hemodynamic response.21 Tetanic stimulus was therefore suitable for our study as we used patient movement, and not hemodynamics, in response to the stimulus as an outcome variable at different remifentanil concentrations.

Several investigators have studied the sensitivity of BIS as a measure of sedation22,23 and anesthesia24 in patients receiving propofol infusions. It has been shown to be a useful monitor of propofol sedation and anesthesia. Two previous studies1,9 have evaluated the BIS values at LOC when TCI propofol is used. The C50 and C95 of BIS were 71 and 53 respectively in Caucasians,1 whereas the values were 65 and 45, respectively, in Chinese,9 which is similar to our results. We noted that the C95 of BIS was 39 at LOC in our study, which is lower than the values appropriate for “surgical” anesthesia, 40–60, in Caucasians.25 Notably, the predicted blood and effect-site propofol concentrations in our Chinese population were lower than that in Caucasians at this point. Our results therefore suggest that the correlation between the predicted blood or effect-site propofol concentrations and BIS in Chinese patients differ from that in Caucasians23,26 and that the standard BIS values25 to predict the depth of hypnosis may not be suitable for Chinese patients. A different range of BIS values and propofol TCI concentrations should be used in clinical practice in Chinese patients.

The BIS50 at loss of response to tetanic stimulation was higher than the BIS50 at LOC. This might be because we measured the BIS after we applied the stimulation. Recording BIS before the stimulation is applied would have been better. However, this method did not work well as the interval between the two stages of drugs administration was too short for BIS stabilization. Guignard et al.16 evaluated the usefulness of BIS as an index of the analgesic component of anesthesia and suggested that under a steady propofol infusion BIS might be as sensitive to detect an inadequate analgesic component of anesthesia as changes in hemodynamic variables. Even so, it is generally accepted that BIS is not a good measure of analgesia; our study did not show BIS to be valuable in monitoring the probability of reaction to a painful stimulus when TCI propofol was combined with remifentanil.

In conclusion, the blood and effect-site concentrations of propofol and the BIS values at LOC in Chinese patients were lower than that in a previously published study of Caucasians.1 This may be due to pharmacodynamic differences between races and merits future study.

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ACKNOWLEDGMENTS

The authors thank Professor Adrian W. Gelb, Department of Anesthesia, University of California San Francisco, for help with the preparation of the manuscript.

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