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* From the Departments of Anesthesiology, and
Clinical Pharmacology, Gunma University Graduate School of Medicine, Maebashi, Japan.
Address correspondence to: Dr. Koichi Nishikawa, Department of Anesthesiology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi City 371-8511, Japan. Phone: 81-27-220-8454; Fax: 81-27-220-8473; E-mail: nishikaw{at}med.gunma-u.ac.jp
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Abstract |
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Methods: 12 patients undergoing abdominal surgery were enrolled in this study. Anesthesia was induced with propofol and vecuronium 0.1 mg·kg–1, and maintained using 67% nitrous oxide, sevoflurane in oxygen and constant infusion of propofol. Propofol was administered to all subjects via target-controlled infusion to achieve a propofol concentration at 6.0 µg·mL–1 at intubation and 2.0 µg·mL–1 after intubation. Before and after the administration of 10 mL of 1.5% mepivacaine from the epidural catheter and dopamine infusion at 5 µg·kg–1·min–1, CO and effective liver blood flow (LBF) were measured using indocyanine green. Blood propofol concentration was also determined using high-performance liquid chromatography.
Results: At one hour after epidural block and dopamine infusion, CO was significantly increased from 4.30 ± 1.07 L·min–1 to 5.82 ± 0.98 L·min–1 (P < 0.0001), and effective LBF was increased 0.75 ± 0.17 L·min–1 to 0.96 ± 0.18 L·min–1 (P < 0.0001). Propofol concentration was significantly decreased from 2.13 ± 0.24 µg·mL–1 to 1.59 ± 0.29 µg·mL–1 (P < 0.0001).
Conclusions: Propofol concentrations decrease with an increase in CO, suggesting the possibility of inadequate anesthetic depth following catecholamine infusion during propofol anesthesia.
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Introduction |
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Two cases of awareness during propofol anesthesia using target-controlled infusion have been reported.4,5 Propofol concentrations might be lower than predicted when cardiac output (CO) and LBF are increased resulting in an increased rate of propofol clearance. Previous reports have investigated the influence of CO on propofol concentrations,6–8 demonstrating an inverse relationship between CO and propofol concentration. However, these studies have been conducted in animals, and further investigations in humans are required.
Clinically, the reduction in blood pressure accompanying epidural block is frequently corrected by catecholamine infusions, resulting in a hyperdynamic state. The purpose of the present study was to investigate the effects of dopamine infusion during epidural block on CO and propofol concentration administered by target-controlled infusion.
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Methods |
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Sampling procedure
Before induction of anesthesia, routine monitoring was established, including pulse oximetry, electrocardiogram and non-invasive blood pressure. An iv catheter was placed in an antecubital vein for infusion of anesthetics and for fluid replacement. After insertion of an epidural catheter (Th9/Th10) and administration of 3 mL of 1% lidocaine as a test dose, anesthesia was induced using vecuronium 0.1 mg·kg–1 and propofol, and was maintained with 67% nitrous oxide, sevoflurane in oxygen and constant infusion of propofol. During the study, the dose of sevoflurane was kept constant at 1%. Propofol was administered to all subjects by target-controlled infusion (Diprifusor; AstraZeneka International, Wilmington, DE) to achieve a propofol concentration of 6.0 µg·mL–1 at intubation and 2.0 µg·mL–1 after intubation throughout the study. A double lumen iv catheter was inserted into an internal jugular vein for infusion of dopamine and injection of indocyanine green as an indicator for CO and effective LBF. A cannula was placed in the left radial artery for invasive blood pressure monitoring and blood sampling. Thirty minutes after the start of the operation, the predicted propofol concentration of 2.0 µg·mL–1 was achieved and a constant infusion rate was established in all patients. Then, indocyanine green (20 mg) was injected for the measurement of CO and effective LBF. Blood samples were collected from the arterial cannula for measurement of blood propofol concentration. Mepivacaine (1.5%, 10 mL) was administered in the epidural catheter and a dopamine infusion at 5 µg·kg–1·min–1 were started. One hour after the administration of mepivacaine, 20 mg of indocyanine green were injected again for the measurement of CO and effective LBF, and blood samples were collected to determine propofol concentration.
Analytical procedure
Indocyanine green was used for the measurement of CO and effective LBF, as described in a previous report.9,10 Propofol concentrations in whole blood were measured using high performance liquid chromatography as reported previously.11
Statistical analysis
Data are expressed as mean ± SD. Differences between propofol concentrations, CO, and effective LBF before and one hour after dopamine infusion were analyzed using a paired t test. A P < 0.05 was considered statistically significant.
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and 2).
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Discussion |
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Propofol has been shown in various studies to affect the cardiovascular system, including CO and systemic vascular resistance.12–14 However, relatively little attention has been given to the influence of CO on propofol concentration. Upton et al.6 reported that the initial arterial concentration of propofol after a short infusion was inversely related to CO in sheep. Myburgh et al. and Kurita et al. reported a similar relationship during constant rate infusions of propofol in ovine and in swine, respectively.7,8 Wilson et al. reported that predosing with esmolol reduced the propofol requirements for induction of anesthesia by 25%.15 No investigations, however, have assessed the influence of changing CO on propofol concentrations during constant rate infusion in humans. Epidural anesthesia has been reported as exerting no influence on the pharmacokinetics of propofol.16 During clinical anesthesia, however, the decline of blood pressure with epidural block is frequently corrected by catecholamine infusion. This might produce a hyperdynamic state and bring about decreases in propofol concentration. We demonstrated that propofol concentrations became lower than predicted following dopamine infusion with epidural block in humans.
This phenomenon can be explained by two mechanisms. The first is the direct indicator dilution effect between venous injection site and arterial blood. A fixed dose in the presence of a higher CO results in less drug per unit blood volume, and therefore lower concentrations. Indeed, the contribution of the first pass dilution effect to steady state arterial concentration will simply be the drug clearance over the CO. This effect is therefore most significant for drugs with a high clearance.17 Secondly, higher CO implies higher blood flows to the organs of drug elimination and distribution, increasing the rate of clearance and distribution and resulting in lower concentrations. Since propofol is a high clearance drug, its concentration is considered to be greatly influenced by CO.
Johnson et al. reported arousal following isoprenaline administration during propofol anesthesia.4 They also examined the effect of iv epinephrine on bispectral index (BIS) and sedation, reporting that mean BIS value increased from 63 to 76 and exogenous catecholamines seem to display an arousal effect.18 This could be due to changes in neurotransmitter levels in the brain. The adrenergic system has a role to play in the process of arousal from anesthesia, and this has been previously demonstrated.19 Beta receptors in the reticular activating system interact with information processing in the thalamus. In previous reports, however, another possible explanation, that propofol concentration decreased due to increased CO on administration of a catecholamine, had not been discussed. In the present study, we showed decreases in propofol concentration with increased CO.
In summary, propofol concentrations decrease with an increase in CO, suggesting the possibility of inadequate anesthetic depth following catecholamine infusion during propofol anesthesia.
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Footnotes |
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2 Hiraoka H, Yamamoto K, Okano N, Morita T, Goto F, Horiuchi R. Changes in drug plasma concentrations of an extensively bound and highly extracted drug, propofol, in response to altered plasma binding. Clin Pharmacol Ther 2004; 75: 324–30.[Medline]
3 Lange H, Stephan H, Rieke H, Kellermann M, Sonntag H, Bircher J. Hepatic and extrahepatic disposition of propofol in patients undergoing coronary bypass surgery. Br J Anaesth 1990; 64: 563–70.
4 Johnson IA, Andrzejowski J, Sikiotis L. Arousal following isoprenaline (Letter). Anaesth Intensive Care 1999; 27: 221.
5 Oglilvy AJ. Awareness during total intravenous anaesthesia with propofol and remifentanil (Letter). Anaesthesia 1998; 53: 308.
6 Upton RN, Ludbrook GL, Grant C, Martinez AM. Cardiac output is a determinant of the initial concentrations of propofol after short-infusion administration. Anesth Analg 1999; 89: 545–52.
7 Myburgh JA, Upton RN, Grant C, Martinez A. Epinephrine, norepinephrine and dopamine infusions decrease propofol concentrations during continuous propofol infusion in an ovine model. Intensive Care Med 2001; 27: 276–82.[Medline]
8 Kurita T, Morita K, Kazama T, Sato S. Influence of cardiac output on plasma propofol concentrations during constant infusion in swine. Anesthesiology 2002; 96: 1498–503.[Medline]
9 Imai T, Takahashi K, Fukura H, Morishita Y. Measurement of cardiac output by pulse dye densitometry using indocyanine green. Anesthesiology 1997; 87: 816–22.[Medline]
10 Haruna M, Kumon K, Yahagi N, et al. Blood volume measurement at the bedside using ICG pulse spectrophotometry. Anesthesiology 1998; 89: 1322–8.[Medline]
11 Plummer GF. Improved method for the determination of propofol in blood by high performance liquid chromatography with fluorescence detection. J Chromatogr 1987; 421: 171–6.[Medline]
12 Puttick RM, Diedericks J, Sear JW, Glen JB, Foex P, Ryder WA. Effect of graded infusion rates of propofol on regional and global left ventricular function in the dog. Br J Anaesth 1992; 69: 375–81.
13 Pagel PS, Warltier DC. Negative inotropic effects of propofol as evaluated by the regional preload recruitable stroke work relationship in chronically instrumented dogs. Anesthesiology 1993; 78: 100–8.[Medline]
14 Lowe D, Hettrick DA, Pagel PS, Warltier DC. Propofol alters left ventricular afterload as evaluated by aortic input impedance in dogs. Anesthesiology 1996; 84: 368–76.[Medline]
15 Wilson ES, McKinlay S, Crawford JM, Robb HM. The influence of esmolol on the dose of propofol required for induction of anaesthesia. Anaesthesia 2004; 59: 122–6.[Medline]
16 Wessen A, Persson PM, Nilsson A, Hartivig P. Clinical pharmacokinetics of propofol given as a constant-rate infusion in combination with epidural blockade. J Clin Anesth 1994; 6: 193–8.[Medline]
17 Upton RN. Relationships between steady state blood concentrations and cardiac output during intravenous infusions. Biopharm Drug Dispos 2000; 21: 69–76.[Medline]
18 Andrzejowski J, Sleigh JW, Johnson IA, Sikiotis L. The effect of intravenous epinephrine on the bispectral index and sedation. Anaesthesia 2000; 55: 761–3.[Medline]
19 Berridge CW, Foote SL. Enhancement of behavioral and encephalographic indices of waking following stimulation of noradrenergic ß-receptors within the medial septal region of the basal forebrain. J Neurosci 1996; 16: 6999–7009.
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