Intravenous anesthesia with propofol infusion has been used widely in clinical practice. It has been demonstrated that the use of a target controlled infusion (TCI) system can accurately predict plasma concentrations of propofol.1 Also previous work showed that in healthy young patients there is a good correlation between the predicted effect-site concentration (Ce) of propofol and the depth of anesthesia as recorded by various monitoring variables, such as bispectral index (BIS), auditory evoked potential (AEP), and entropy.2,3 The concept of a minimum alveolar concentration (MAC) for volatile anesthetics is well known and widely used to ensure that in the clinic patients receive sufficient anesthesia to prevent awareness during surgery.4 A similar concept exists for intravenous anesthetics agents. It is referred to as the effective concentration 50 (EC50), which is defined as the concentration of an intravenous anesthetic at which 50% of patients will not respond to skin incision.5 A previous study6 showed the EC50 and EC95 of propofol at which adult Chinese patients loss of consciousness. However, there are few published data to assess whether the Ce of propofol may predict anesthetic depth in elderly patients. Therefore, we designed this prospective clinical study to evaluate the relationship between the Ce of propofol and the depth of anesthesia during anesthesia induction using the TCI technique in elderly patients. Our study was to determine the Ce of propofol required for loss of consciousness and tracheal intubation during TCI induction, and the suitable TCI technique in elderly patients.
Patients' selection and preparation
Ninety patients, aged 60 to 80 years, with an American Society of Anesthesiologists (ASA) physical status of 1-3 who were undergoing scheduled abdominal and thoracic surgery under general anesthesia were included in this study. Exclusion criteria were body mass index <18 or > 30, a history of mental disorders and hepatic or renal diseases, recent administration of sedative or opioid drugs and drug addiction.
The patients were fasted for 8 hours before surgery and received no premedication. After patients entered the operating room routine monitoring was applied. A 20-gauge plastic cannula was inserted into the radial artery for continuous arterial blood pressure (BP) monitoring and a 18-gauge intravenous (IV) catheter was inserted into an upper limb vein for IV administration of drugs and fluid. After a stabilization period of 10 minutes, baseline values of BP and heart rate (HR) were obtained from the average of three measurements obtained 2 minutes apart. Then the skin of the forehead was prepared with 75% alcohol and a BIS variable was taken with a A-2000 BIS Monitor (Aspect Medical Systems, Natick, MA, USA; Xp Version). Before drug administration 5 ml/kg of Lactated Ringer's solution was given by IV and then maintained at an infusion rate of 7 ml•kg-1•min-1.
Patients were randomly allocated into one of three groups (Groups S1, S2 and S3, 30 patients in each group). Randomization was performed using computer generated random numbers in sealed envelopes. The patients in Group S1 received propofol with a target plasma concentration of 4.0 μg/ml; patients in Group S2 initially received with a target plasma concentration of 2.0 μg/ml that was raised to 4.0 μg/ml 3 minutes later; patients in Group S3 received an infusion scheme of 3 steps, starting from a target plasma concentration of 2.0 μg/ml that was increased stepwise by 1 μg/ml until a target plasma concentration of 4.0 μg/ml was achieved, the interval between the two steps was 3 minutes (Figure 1). Target-controlled infusion of propofol was performed using a motor-driven syringe pump (Graseby 3500, Smiths Medical International, Watford, UK) with an Astra-Zeneca Diprifusor TCI system, which contains a Marsh's pharmacokinetic model. This system can display the predicted Ce of propofol.
A modified Observer's Assessment of Alertness/Sedation (OAA/S) scale (Table 1) was used to assess the depth of both sedation and anesthesia.7 It was tested one time every 15 seconds. If the patient was not responsive to shaking and calling his or her name loudly, it was considered that an OAA/S score of 1 had been achieved. When an OAA/S score of 1 was achieved, remifentanil, with a Ce of 4.0 ng/ml and rocuronium at 0.9 mg/kg, were administered by IV. The patient was ventilated via a facemask with 100% oxygen. If any difficulty was encountered in performing facemask ventilation, the patient was withdrawn from the study, and his/her card was resealed in an envelope and randomly placed among the remaining envelopes to be used later. Tracheal intubation was started 2 minutes after IV injection of rocuronium. The patients requiring more than one attempt to achieve successful intubation were excluded from statistical analysis of the data.
Ce, BP, HR and BIS were recorded at four points: baseline values before induction (T0), OAA/S score of 1 (T1), immediately before intubation (T2), and immediately after intubation (T3). BIS was recorded 5 seconds after each time point. To minimize the bias, assessments of sedation levels during the tracheal intubations were performed by one anesthesiologist. Also investigators involved in recording data were blinded to patient group assignment.
The hypothesis of this study was that there would be significant differences in the cardiovascular intubation responses among the three groups. From a clinical point of view, we considered that a 20% difference in systolic blood pressure (SBP) and HR changes during the observation would be a clinically important difference. Power calculations8 indicated that at least 28 patients in each group would be required to detect this difference between groups with a power of 80% and a P value of 0.05. Allowing for possible exclusions due to difficulties in facemask ventilation and intubation, we chose to examine a minimum of 30 patients in each group.
Statistical analysis of data was performed with SPSS (version 11.5; SPSS Inc., USA). All continuous data were tested for normality using the Kolmogorov-Smirnov method. The comparisons among the three groups were performed using one way analysis of variance (ANOVA). For multiple comparisons of inter-individual data, Friedman repeated-measures analysis of variance on ranks with subsequent all pairwise multiple comparison procedures (Tukey test) was applied. The correlation between the Ce and BIS was analyzed by linear regression and the Spearman correlation coefficients were calculated. A P value <0.05 was considered statistically significant.
Patients' characteristic and clinical data
A total of 90 patients (47 females and 43 males) were studied. No patient was excluded from the study because of difficult facemask ventilation or failed intubation at the first attempt. The three groups were comparable with respect to the patients' characteristic data (Table 2).
Clinical response, BIS values and Ce of propofol
When OAA/S was 1, BIS values and total dosages of propofol in the three groups were similar (P >0.05 between groups). The Ce value of propofol was significantly lower in Group S1 than in Groups S2 and S3 (P=0.044 and 0.024, respectively), but it did not differ significantly between Groups S2 and S3 (P=0.802). Immediately before intubation, Ce values of propofol and BIS were not significantly different among the three groups (Table 3).
Relationship between Ce of propofol and BIS values
By the linear regression analysis, a close correlation between Ce of propofol and BIS values was found. The regression equation was: BIS=76.2-8.7Ce (μg/ml) (r=-0.580, P <0.01) (Figure 2).
Changes in SBP
As compared to baseline values before induction, SBP and HR decreased significantly when the OAA/S score was 1. Before intubation, SBP and HR further decreased due to administration of remifentanil. Also SBP before intubation was significant lower in Group S1 than in Groups S2 and S3. SBP and HR after intubation in the three groups was significantly increased compared with those values before intubation, but they did not exceed baseline values (Table 4).
The aim of this study was to evaluate whether there was significant correlation between the Ce of propofol and the depth of anesthesia during induction using the TCI technique in elderly Chinese patients. In addition to the use of the OAA/S score as a clinical endpoint, BIS was also employed to assess the depth of anesthesia. In this study we also wished to determine whether the Ce of propofol and BIS are useful variables for predicting loss of consciousness and the suitable anesthetic depth required to perform tracheal intubation.
In our study, the patients were randomly divided into three groups and the stepwise infusion techniques were used in Groups S2 and S3 for the following reasons. First, previous researches suggest that a longer infusion time can result in a higher C50.9-11 Second, a prolonged infusion time helps to stabilize hemodynamic variables during anesthesia induction in elderly patients. Also anesthesia induction using a step-by-step TCI technique with propofol can result in stable hemodynamics, especially for the elderly patients, or in those with the cardiovascular diseases.12
Our results clearly show that at the OAA/S score of 1 and at intubation, total dosages of propofol did not differ among the three groups, but the Ce of propofol was lower in Group S1 than in Groups S2 and S3. SBP before intubation was significantly higher in Groups S2 and S3 than in Group S1. Also SBP increase by intubation was numerically smaller in Groups S2 (7.5%) and S3 (7.0%) than in Group S1 (13.2%), although no statistical differences among the three groups were achieved. These results suggest that compared with a non-stepwise TCI technique with propofol (Group S1), the stepwise TCI techniques of propofol (Groups S2 and S3) can achieve a more stable anesthesia induction and a more effective attenuation of cardiovascular intubation response in elderly patients. This is in agreement with the results of previous studies.9-12 Additionally, our study demonstrated that when the OAA/S score was 1, the Ce value of propofol did not significantly differ between Groups S2 and S3. Also, SBP and HR at all measuring points did not differ between Groups S2 and S3. It suggests that compared with a two-step TCI technique of propofol, a three-step TCI technique of propofol does not further improve features of anesthesia induction and control of cardiovascular intubation response while it required a longer infusion time. According to these results, we consider that compared with the non-stepwise TCI technique and three-step TCI technique, a two-step TCI technique may be a more reasonable method of anesthesia induction with propofol in elderly patients.
Two previous studies have evaluated the relationship of the predicted Ce of propofol with clinical endpoints.13,14 Because of the different propofol infusion rates, there is a large difference in the predicted plasma concentrations between the two studies. However, the predicted Ce of propofol was similar in the two studies. The existence of considerable discrepancy between the predicted plasma concentration and Ce of propofol suggests that during induction and recovery, the predicted Ce of propofol may be a more useful clinical correlate than the predicted plasma concentration.11
The effect-site EC50 and EC95 of propofol at loss of consciousness have been shown to be 2.8 and 4.1 μg/ml in Caucasian populations13 and 2.7 and 3.8 μg/ml in Chinese populations.14 This indicates no difference in the effect-site EC50 and EC95 of propofol at loss of consciousness between Caucasian and Chinese populations. In a study by Xu et al,15 however, effect-site EC50 and EC95 of propofol at loss of consciousness were 2.2 and 3.2 μg/ml in the Chinese populations, which were lower than the results of a previous study in Caucasians populations.13 Zhong et al16 found that the effect-site EC50 and EC95 of propofol at loss of consciousness were 2.5 and 3.4 μg/ml during TCI with propofol in Chinese patients. This was similar with the results of Xu et al.15 Because the plasma concentration of propofol was not measured in all studies above, it is impossible to know whether these inconsistent results were due to pharmacokinetic or pharmacodynamic differences among the populations of different races. Therefore, further studies are required to confirm it.
When the OAA/S decreased to 1, the Ce of propofol was 4.5 μg/ml in the study of Iannuzzi et al17 which is higher than we found in our study. Barakat et al18 calculated the predicted Ce from the two pharmacokinetic models (Marsh/Schnider). The results showed that changes of both the sedation score and BIS index correlated better with the predicted Ce in using the Marsh model than in using the Schnider model. Also the Schnider model predicted much faster effect site equilibration in the blood than the Marsh model. This may explain the discrepancy in the Ce of propofol between Iannuzzi's study with a Schnider model and our study with a Marsh model. However, the Ce of propofol from other previous studies with a Marsh model were higher than our result.13-15 This may indicate significant differences in the pharmacokinetics and pharmacodynamics of propofol between patients of different ages.6 Elderly patients are reported to be more sensitive to propofol than are young patients.19 In the study of Milne et al,13 Caucasian patients aged 18-65 years were included. In the studies of Irwin et al14 and Xu et al,15 Chinese patients aged <65 years were included. In contrast, Chinese patients aged 60-80 years were selected in this study. According to the results from our work and from previous studies, we consider that when the TCI technique of propofol is used for anesthesia induction in the elderly patients, a lower plasma concentration should be best selected with the plasma-controlled TCI technique.
In the study of Iannuzzi et al,17 a good Spearman correlation between the Ce of propofol and BIS values was found (r=0.92). In their study, however, sample points included the baseline point at which the Ce of propofol was 0 μg/ml in all patients. This can result in a deviation in that the correlation coefficient (r value) is higher than the realistic state. In contrast, the baseline point (T0) was excluded in our study and only three points (T1, T2 and T3) were included to assess the relationship between the Ce of propofol and BIS values. If the baseline point is also included in our study, the calculated value of the correlation coefficient would exceed -0.9, being similar to the result of Iannuzzi et al.17 Previous studies have shown the existence of a significant correlation between the Ce of propofol and BIS values.20-22 It implies that, like MAC with inhaled anesthesia,23 during the TCI intravenous anesthesia with propofol, the Ce could indicate the depth of anesthesia. However, a further clinical trial with large samples is required to verify this point of view.
The OAA/S scores have been shown to have a good correlation with levels of sedation.21 Struys et al24 found that the BIS also correlated well with the levels of sedation observed by OAA/S. Otherwise, Iannuzzi et al17 confirm that neither BIS nor the A-Line ARX index (AAI) have the high level of discriminative power needed to be definitive methods for identifying depth of anesthesia endpoints. When using BIS and AAI to monitor depth of anesthesia, therefore, they must be considered with clinical judgment. Except for the use of Ce and BIS as endpoints in our study, clinical signs including OAA/S scores and cardiovascular changes are used to assess the depth of anesthesia and adequacy of anesthesia induction with the different TCI techniques.
A previous work suggests that SBP changes after anesthesia induction are more sensitive than BIS in prediction of movement response to laryngoscopy and intubation.25 Also BP and HR changes during a procedure may give an indirect indication of the distress. For this reason,26 we observed the cardiovascular intubation response by comparing the changes of SBP and HR before and after intubation. Based on the results of this study, we consider that cardiovascular changes by intubation may be suitable indicators for identifying the depth of anesthesia.
A limitation of our study was that the predicted plasma concentrations of propofol did not follow a geometric progression. This makes it impossible for us to calculate effect-site EC50 and EC95 of propofol at loss of consciousness and intubation. Therefore, further trials are required in elderly Chinese patients to determine the effect-site EC50 and EC95 of propofol at the different clinical endpoints.
In conclusion, this study has demonstrated that when the TCI technique with propofol and a Marsh model is used for anesthesia induction in elderly Chinese patients, the Ce of propofol at loss of consciousness is (1.9±0.3) μg/ml. In combination with remifentanil a Ce of 4.0 ng/ml and with rocuronium at 0.9 mg/kg, the Ce of propofol required for intubation is (2.8±0.3) μg/ml. The Ce of propofol has a close correlation with the BIS values. Also a two-step TCI technique seems to be a more suitable method of anesthesia induction in elderly patients compared with the non-stepwise TCI technique or the three-step TCI technique.
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