Department of Anaesthesiology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
Corresponding author. E-mail: nkenji@mva.biglobe.ne.jp This article is accompanied by Editorial II.
Accepted for publication: August 21, 2002
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Abstract |
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Methods. After institutional approval and informed consent, 45 patients having cardiac surgery were assigned randomly to receive propofol infusions at 4 (Group A), 5 (Group B) and 6 (Group C) mg kg1 h1 during normothermic CPB. In all patients, small to moderate doses of fentanyl were also administered. Plasma propofol concentration and burst suppression ratio (BSR) were measured at the following times: (1) 10 min before CPB, (2) 10 min after the start of CPB, (3) 30 min after the start of the CPB, (4) just after aortic declamping, and (5) 60 min after CPB.
Results. At baseline, plasma propofol concentrations were similar among the three groups. After the start of CPB, the concentrations of propofol decreased significantly by 41, 35, and 30% of control values in Groups A, B, and C, respectively. In Group A, the concentration of propofol during CPB remained unchanged at less than the concentration before bypass. In Groups B and C, plasma propofol concentrations gradually increased during CPB to the pre-bypass concentrations. In Group A, BSR values did not change significantly during CPB. In Groups B and C, BSR values gradually increased and became significantly greater than baseline values. No patient reported intraoperative awareness.
Conclusion. The pharmacokinetics and pharmacodynamics of propofol change during normothermic CPB. During normothermic CPB, the efficacy of propofol may be enhanced compared with before CPB.
Br J Anaesth 2003; 90: 1226
Keywords: anaesthetics i.v., propofol; monitoring, electroencephalography; surgery, cardiovascular
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Introduction |
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For the past 25 yr, hypothermia has been used predominantly during CPB for cardiac surgery. Hammaren and colleagues5 studied plasma propofol concentration and the latency of the Nb wave of the auditory evoked potential, as a possible indicator of anaesthetic depth, during hypothermic CPB. They found that CPB decreased mean propofol concentration from 2.6 to 1.7 µg ml1 during a propofol infusion at a rate of 3 mg kg1 h1, and the latency of the Nb wave was prolonged compared with baseline values measured before CPB. Dawson and colleagues6 found concentrations of propofol ranging from 0.64 (SD 0.07) to 0.91 (0.11) µg ml1 during a propofol infusion of 3 mg kg1 h1 during hypothermic CPB. Schmidlin and colleagues7 measured the bispectral index (BIS), an index derived from the EEG that can indicate anaesthetic effect, during hypothermic CPB. With a mean propofol infusion rate of 2.0 mg kg1 h1 (range from 1.6 to 2.4 mg kg1 h1), the median BIS score was 41 (95% confidence interval 3942), suggesting that this dose was sufficient. In these studies, intraoperative awareness was not documented. Although plasma concentrations of propofol from 2 to 4 µg ml1 are considered to be effective when propofol is combined with opioids,8 the data above suggest that smaller concentrations of propofol could provide sufficient anaesthesia in patients undergoing hypothermic CPB.
Many centres now use normothermic CPB because bypass and operating time are less, and myocardial protection and coagulation function are better preserved. However, normothermic CPB could allow awareness during surgery more easily. Schmidlin and colleagues7 found that with similar propofol doses, BIS scores were greater during normothermic CPB than hypothermic CPB, suggesting that more propofol is required for normothermic patients. In addition, the effects of CPB on pharmacokinetics may differ between hypothermia and normothermia, but we know little about the pharmacokinetics and pharmacodynamics of propofol during normothermic CPB. We therefore studied the plasma propofol concentration while propofol was given at rates of 4, 5, and 6 mg kg1 h1 during normothermic CPB. We also assessed a processed EEG to measure burst suppression ratio (BSR) as an index of cerebral cortical activity.
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Methods |
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Morphine 0.15 mg kg1 i.m. and atropine 0.01 mg kg1 i.m. were given for pre-medication. Anaesthesia was induced with fentanyl 10 µg kg1 and propofol. Propofol administration was controlled with a computer-controlled syringe pump (Graseby 3400). The computer ran a program (Stelpump) written by Coetzee JF, MD (University of Stellenbosch, Department of Anaesthesiology, PO Box 19063, 7505 Tygergerg, South Africa) available from the website (http://www.sed.sun.ac.za). Stelpump adjusts the infusion rate to obtain a constant predicted concentration at the effect site. We used the model of Marsh9 in Stelpump. Coetzee and colleagues10 found that this model gave appropriate propofol target prediction within the range 36 µg ml1. For induction, the target effect-site concentration of propofol was set at 3 µg ml1. A 20- or 22-G Teflon cannula (2.5 cm in length, Baxter, Deerfield, IL, USA) was placed in the right radial artery to monitor arterial pressure and tracheal intubation was facilitated with vecuronium 0.2 mg kg1. Anaesthesia was maintained with an infusion of fentanyl 5 µg kg1 h1 (to a total of 30 µg kg1) and the target controlled propofol infusion. When CPB started, propofol was given according to the random allocation. The lungs were mechanically ventilated with oxygen 50% and nitrous oxide 50% to maintain a PaCO2 of between 35 and 45 mm Hg.
After induction of anaesthesia, a SwanGanz catheter (Baxter Healthcare Corp., Model 93A-741H-7.5F) was inserted through the right jugular vein and advanced until the tip lay in the pulmonary artery. The tympanic membrane temperature was also monitored continuously (Mon-a Therm, Mallinckrodt Co., St Louis, MO, USA).
The bypass machine was primed with crystalloid (Lactate Ringers solution containing NaHCO3, mannitol, tranexamic acid, flomoxef, and prednisolone: 2000 ml) and a non-pulsatile pump flow rate of 2.83.2 litre min1 m2 was set. Extracorporeal filtration was used to maintain haematocrit values >20%. After cross-clamping, cardioplegia was administered. Blood cardioplegia consisting of a mixture of four parts autologous blood to one part potassium-enriched cardioplegia solution (40 meq KCl and 30 units of insulin per litre crystalloid) was delivered every 2030 min. A membrane oxygenator and a 40-µm arterial cannula filter were used. PaCO2, uncorrected for temperature, was adjusted to normocapnic levels (3540 mm Hg) by varying fresh gas flow to the membrane oxygenator (alpha-stat regulation). The target rectal temperature was 36°C. Phenylephrine infusion was used during CPB to maintain mean arterial pressure (MAP) of 5070 mm Hg.
A Dräger monitor (Dräger AG, Lübeck, Germany) was used to monitor the continuously processed EEG. Disposable electrodes were placed over each frontal and mastoid area on both sides and a reference electrode was placed in the frontal midline. Electrodes were placed using EEG paste (Elefix, Nihon Koden Corp., Tokyo, Japan) and the impedance of the electrodes was checked every 3 min and maintained below 5 k during the study. The EEG was monitored continuously from induction of anaesthesia to emergence. EEG data were recorded onto a PC-compatible computer to display the trend of BSR and raw EEG waveform. After surgery the raw EEG was inspected to ensure that artifacts caused by diathermy were excluded in the off-line analysis. Burst suppression was measured as the BSR. To calculate BSR, suppression is recognized as those periods longer than 0.5 s during which EEG voltage amplitude is less than 5 mV. Time in a suppressed state is measured and BSR is reported as the fraction of the epoch where the EEG is suppressed. Because of the variable (non-stationary) nature of burst suppression, BSR is averaged over at least 15 epochs (60 s).11 Data for BSR were averaged over 10 consecutive artifact-free epochs.
For the measurement of propofol concentration, 5 ml samples were collected from the radial artery catheter. Each blood sample was immediately centrifuged (3000 rpm, 5 min) and serum was stored at 30°C until analysis. For extraction, 0.2 ml serum was placed in a polypropylene test tube and 1 ml ethyl acetate and 0.1 ml NaOH (50 mM) were added. The tube was shaken for 5 min. The mixture was centrifuged at 15 000 rpm for 5 min, and a 0.9 ml aliquot of the upper ethyl acetate phase was removed and freeze-dried. The freeze-dried pellet was re-dissolved by 0.05 ml mobile phase and injected into a high-pressure liquid chromatograph system: pump (655A-11; Hitachi, Japan), UV absorbance detector (Waters 486; Waters Associates, Milford, MA, USA), and phenyl reverse-phase column (Micro Bondasphere 5-micro phenyl 100A; Waters Associates, Milford, MA, USA). The mobile phase was methanol-100 mM phosphate buffer (pH 2.8) (6:4, v/v), and the flow-rate was 0.8 ml h1. The wavelength of UV detection was 270 nm. With this method, the standard curve for propofol concentrations in the plasma was linear between 0.2 and 15 µg ml1. Concentrations of serum total protein were measured with the Biuret method.
Propofol concentration, haemodynamic values, cerebral oxygenation data, and BSR were measured at the following times; (1) 10 min before the start of CPB (time 1), (2) 10 min after the start of CPB (time 2), (3) at 30 min after the start of CPB (time 3), (4) just after de-clamping of the aorta (time 4), and (5) 60 min after CPB (time 5).
Data were expressed as mean (SD). Statistical comparisons used two-way ANOVA for repeated measurement and 2-test. Fishers PLSD test was used for post hoc pair-wise comparisons. P<0.05 was considered significant.
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Results |
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Discussion |
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Starting hypothermic CPB can reduce propofol concentration probably by haemodilution. Russell and colleagues12 reported that propofol concentration decreased to 5078% of pre-bypass level at 210 min after starting hypothermic CPB. Dawson and colleagues6 reported that propofol concentration decreased to 60% at the start of hypothermic CPB. The present study supports these studies. Propofol concentrations decreased to 5970% of pre-bypass level after the onset of normothermic CPB. Since body temperature decreases for a short period after the induction of hypothermic CPB, the decrease in propofol concentrations after starting CPB may be dilution by the pump prime in both the normothermic and hypothermic patients.
However, in previous studies of propofol concentrations during hypothermic CPB, the concentration of propofol increased to the pre-bypass level promptly after the induction of CPB. Dawson and colleagues6 found that with propofol administration at 3 mg kg1 h1 the decrease in propofol concentration was maximal within the first 3 min of the onset of CPB and returned to pre-bypass level after 20 min. In our study, at an infusion rate of 4 mg kg1 h1 using propofol concentration did not return to the pre-bypass level. The reasons for this difference are unknown. Since the metabolic rate increases exponentially with body temperature, elimination might be greater during normothermic CPB than hypothermic CPB. McMurray and colleagues13 found that the clearance of propofol was reduced and the half-life was prolonged in cardiac surgery with hypothermic CPB.
It has been suggested that, during opioid supplementation, plasma concentrations of propofol should be >24 µg ml1 to avoid intraoperative awareness.8 However, in the present study, the mean propofol concentration was less than these values and ranged from 1.3 to 1.5 µg ml1 in Group A during infusion at 4 mg kg1 h1. In these patients, intraoperative awareness was not reported. Furthermore, burst suppression develops during CPB in Groups B and C, although the plasma concentration of propofol during CPB (time 4) is similar to baseline values. In Groups B and C the mean propofol concentrations, at which burst suppression developed, ranged from 2.1 to 2.2 µg ml1. Burst suppression usually needs higher concentrations of propofol without CPB. Doyle and colleagues14 reported that a mean infusion rate of 13.6 mg kg1 h1 (range 8.528.6 mg kg1 h1) of propofol was needed to suppress the EEG. Although the patient population was different, Van Hemelrijck and colleagues15 found that blood propofol concentrations of 6.3 (1.4) µg ml1 were needed to cause burst suppression during neuroanaesthesia. These results suggest that the efficacy of propofol during normothermic CPB may be enhanced compared with normothermia without CPB.
The action of propofol may be enhanced for the following reasons. Propofol exists in plasma in two forms: unbound and bound to protein. The unbound propofol is pharmacologically active. Kumar and colleagues16 postulated that haemodilution could affect the unbound fraction of drug. Hammaren and colleagues5 studied the changes in total and unbound propofol concentrations and the latency of Nb wave of auditory evoked potentials during hypothermic CPB. They found that although total propofol concentration decreased, unbound propofol concentration did not decrease and Nb wave latency was prolonged. This suggested that changes in total and unbound concentrations of propofol were not parallel during hypothermic CPB. Dawson and colleagues6 also reported that the onset of hypothermic CPB caused a decrease in total propofol concentrations, but the unbound concentrations remained stable. Although we did not measure the unbound propofol concentrations in the present study, our data suggest that the free propofol concentrations could remain unchanged or increase during normothermic CPB. This speculation requires further study.
Can the degree of sedation be assessed by BSR? Originally we planned to use spectral edge frequency 90 to assess sedation. However, the presence of burst suppression during normothermic CPB affected the interpretation of this index. Therefore, we used the BSR. In Groups B and C, as the BSR increased during normothermic CPB at least, the level of sedation seems to be more than pre-bypass. Although there was no intraoperative awaking, it is not clear if the sedation level is appropriate in Group A from the BSR values alone. Hirschi and colleagues17 demonstrated that bispectral EEG remained unchanged with a continuous infusion of propofol [4.4 (1.8) mg kg1 h1, mean (SD)] during normothermic CPB compared with pre-bypass level. These are compatible with the present study. However, further studies are needed using other methods such as bispectral EEG analysis and mid-latency auditory evoked potentials, for the assessment of sedation level.
In summary, we investigated plasma propofol concentrations and burst suppression during normothermic CPB. The results suggest that the pharmacokinetics and pharmacodynamics of propofol could change under normothermic CPB. With propofol infusion at a rate of 5 and 6 mg kg1 h1, anaesthesia can be achieved with mild to moderate doses of fentanyl. The efficacy of propofol appears to be enhanced during normothermic CPB. When propofol is given at 4 mg kg1 h1, monitoring of sedation level is recommended.
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References |
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2 Andersson LG, Bratteby LE, Ekroth R, et al. Renal function during cardiopulmonary bypass: influence of pump flow and systemic blood pressure. Eur J Cardiothorac Surg 1994; 8: 597602[Abstract]
3 Hampton WW, Townsend MC, Schirmer WJ, et al. Effective hepatic blood flow during cardiopulmonary bypass. Arch Surg 1989; 124: 4589[Abstract]
4 Hynynen M, Hammaren E, Rosenberg PH. Propofol sequestration within the extracorporeal circuit. Can J Anaesth 1994; 41: 5838[Abstract]
5 Hammaren E, Yli-Hankala A, Rosenberg PH, et al. Cardio pulmonary bypasss-induced changes in plasma concentrations of propofol and auditory evoked potentials. Br J Anaesth 1996; 77: 3604
6 Dawson PJ, Bjorksten AR, Blake DW, et al. The effect of cardiopulmonary bypass on total and unbound plasma concentrations of propofol and midazolam. J Cardiovasc Anaesth 1997; 11: 55661[CrossRef][ISI]
7 Schmidlin D, Hager P, Schmid ER. Monitoring level of sedation with bispectral EEG analysis: comparison between hypothermic and normothermic cardiopulmonary bypass. Br J Anaesth 2001; 86: 76976
8 Shafer SL. Advances in propofol pharmacokinetics and pharmacodynamics. J Clin Anesth 1993; 5 (Suppl 1): 14S21S[CrossRef][Medline]
9 Marsh B, White M, Kenny GNC. Pharmacokeinetic model driven infusion of propofol in children. Br J Anaesth 1991; 67: 418[Abstract]
10 Coetzee JF, Glen JB, Wium CA, et al. Pharmacokinetic model selection for target controlled infusions of propofolassessment of three parameter sets. Anesthesiology 1995; 82: 132845[ISI][Medline]
11 Rampil IJ. A primer for EEG signal processing in anesthesia. Anesthesiology 1998; 89: 9801002[ISI][Medline]
12 Russell GN, Wright EL, Fox MA, et al. Propofol-fentanyl anaesthesia for coronary artery surgery and cardiopulmonary bypass. Anaesthesia 1989; 44: 2058[ISI][Medline]
13 McMurray TJ, Collier PS, Carson IW, Lyons SM, Elliott P. Propofol sedation after open heart surgery: a clinical and pharmacokinetic study. Anaesthesia 1990; 45: 3226[ISI][Medline]
14 Doyle PW, Matta BF. Burst suppression or isoelectric encephalogram for cerebral protection: evidence from metabolic suppression studies. Br J Anaesth 1999; 83: 5804
15 VanHemelrijck J, Tempelhoff R, White PF, et al. EEG-assisted titration of propofol infusion during neuroanesthesia: Effect of nitrous oxide. J Neurosurg Anesth 1992; 4: 1120[ISI]
16 Kumar K, Crankshaw DP, Morgan DJ, et al. The effect of cardiopulmonary bypass on plasma protein bindings of alfentanil. Eur J Clin Pharmacol 1988; 35: 4752[CrossRef][ISI][Medline]
17 Hirschi M, Meistelman C, Longrois D. Effects of normothermic cardiopulmonary bypass on bispectral index. Eur J Anaesthesiol 2000; 17: 499505[CrossRef][ISI][Medline]