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Departments of
*Anesthesiology and
Cardiothoracic Surgery, University of Pittsburgh, School of Medicine, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania
Address correspondence to Peter J Davis, MD, Department of Anesthesiology, Children’s Hospital of Pittsburgh, 3705 Fifth Ave., Pittsburgh, PA 15213–2583.
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Abstract |
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- and ß-elimination half-life. Although the clearance values increased 20% in the postbypass period (from 38.7 ± 9.6 to 46.8 ± 14 mL · kg-1 · min-1, there was no meaningful change in the coefficient of variation (from 25% to 30%). Implications: After cardiopulmonary bypass the clearance of remifentanil increases in children. However, the relative lack of change in the coefficient of variation suggests that remifentanil should be a predictable drug in the postcardiopulmonary bypass period.
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Introduction |
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Remifentanil is a short-acting opioid that is metabolized by tissue and plasma esterases (10). Its extremely short half-life, small volume of distribution, and stable cardiovascular properties, coupled with its unique pathway of metabolism, make remifentanil a logical choice as an anesthetic for infants and children who are candidates for "fast tracking" after surgical repair of a congenital heart defect. This recent trend in cardiac anesthesia, involving early tracheal extubation, minimum intensive care unit stay, and reduced length of hospital stay, has led to evaluations of the influence of anesthetics (and consequently the effects that CPB has on anesthetics) on the fast-tracking process (11–14). At present, there is little information regarding the use of remifentanil in children (15), and no published information concerning the pharmacokinetic properties of remifentanil in children with CHD. Thus, this study was performed to determine the effects of CPB on the pharmacokinetics of remifentanil in pediatric patients undergoing open-heart surgery for atrial septal defect repair.
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Methods |
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All patients received either oral or nasal midazolam as a preanesthetic medication. In young patients, anesthesia was induced by mask with nitrous oxide, oxygen, and sevoflurane. In older patients, anesthesia was induced with IV propofol. After anesthesia was induced and an IV catheter was inserted, cisatracurium or pancuronium was administered to facilitate tracheal intubation, control ventilation, and prevent chest wall rigidity. Anesthesia was maintained with either halothane or isoflurane in an air–oxygen mixture. After the trachea had been intubated and an arterial catheter inserted, remifentanil (5 µg/kg) was administered over 1 min into a peripheral vein. Arterial blood samples (1 mL) were obtained at 0, 1, 2, 3, 5, 10, 20, 30, and 45 min. All samples were obtained prior to the onset of CPB. In some patients, after the induction of anesthesia and at the discretion of the attending anesthesiologist, morphine (75 µg/kg) was administered caudally for postoperative analgesia.
All patients underwent nonpulsating CPB with a membrane oxygenator. The circuit prime solution contained Plasmalyte. The volume of the CPB circuit was determined by the patient’s body weight. When the CPB prime volume would reduce the patient’s hematocrit to less than 15%, packed red blood cells were added to the circuit once bypass was initiated. During CPB, the patient’s core temperature was allowed to drift between 32° and 34°C, and anesthesia was maintained with isoflurane and intermittent small doses of midazolam and fentanyl. After CPB had been completed, cardiovascular stability achieved, normothermia reestablished, and the aortic cannula removed, a second dose of remifentanil 5 µg/kg was administered over 1 min into a peripheral vein. Arterial blood samples (1 mL) were again obtained at 0, 1, 2, 3, 5, 10, 20, 30, and 45 min after the infusion.
All blood samples were placed into citric acid and stored at -70°C until analysis. Phosphate-buffered saline and 100 µg/mL of alfentanil (internal standard) were added to the samples. Chlorobutane was then added to extract the sample, and the remifentanil concentration was determined using high-performance liquid chromatography. The inter- and intraassay coefficient of variations (CVs) were 4.6 and 4.0, respectively. The assay can determine remifentanil concentrations of 
0.5 ng/mL.
Pharmacokinetic data were analyzed with a model-dependent computation using the Scientist. The curvilinear decay curve for remifentanil was best described by a biexponential equation, and the goodness of fit was obtained from the coefficient of determination. In all patients, the weighted sum of the squares was not sufficiently reduced by the addition of a third compartment. Residual plots and the goodness of fit confirmed these findings. The pharmacokinetic variables were determined by standard formulas. The area under the concentration time curve (AUC) was calculated using the trapezoidal rule from t = 0 to t = 20 and from t = 0 to t = 
. A paired t-test was used to compare remifentanil pharmacokinetic parameters pre- and postbypass. The CV was used to quantify variability of the kinetic variables. The CV is defined as: CV = 
· 100, where SD and are the standard deviation and the mean of the sample size, respectively. Statistical significance was assumed for P < 0.05. It was estimated that a sample size of 12 patients would allow observation of a 20% difference in the clearance rate with an of 0.05 and a ß of 0.2 (power 80%).
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Results |
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) was 0.95 ± 0.03. A summary of the pharmacokinetic variables and their respective CVs are presented in Table 1. The average kinetic profile for the prebypass and postbypass decay curves are presented in Figure 1. In all patients the postbypass blood sample prior to injection of the second dose of remifentanil had no detectable remifentanil concentration. No significant difference in Vdss, Vc, t1/2a, or t1/2b was observed between the pre- and post-CPB values. Clearance of remifentanil was significantly increased post-CPB.
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Discussion |
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In pharmacokinetic studies of alfentanil, fentanyl, and sufentanil (i.e., drugs that undergo hepatic biotransformation and elimination, CPB is associated with marked changes in pharmacokinetic properties (1–9). After CPB, the elimination half-life of fentanyl is prolonged, plasma clearance is decreased, and volume of distribution is increased (7). For alfentanil, CPB appears to prolong the elimination half-life and increase the volume of distribution, whereas clearance is unchanged (8). In contrast with findings with other opioids, remifentanil kinetics appears to be minimally affected by CPB. Although clearance was increased 20% after CPB, the other pharmacokinetic variables (Vdss, Vc, and half-life) were unaffected. The pharmacokinetic profile of remifentanil in these young patients differed from that reported in adults. In adult cardiac surgical patients undergoing coronary revascularization procedures, Russell et al. (16) noted that hypothermic (28°–30°C) CPB decreased clearance by 20%, whereas normothermic CPB had no effect on remifentanil kinetics. Why there is an effect of CPB on remifentanil clearance in children is unclear. However, the presence of intracardiac shunts and differences in study design (i.e., relative ratio of CPB prime volume to body weight, body temperature control, and analytical assays) may all be contributing factors.
Some of these issues can be further addressed. In addition to age, the underlying disease states of the pediatric patients differed from the adults. Patients in our study had CHD, with increased pulmonary to systemic blood flow ratios secondary to their intracardiac shunt, whereas patients in the adult study had normal cardiac anatomy and presumed normal pulmonary-to-systemic blood flow ratios. Because of the lung’s metabolic function, changes in pulmonary blood flow may alter a drug’s pharmacokinetic profile (17). Although Roerig et al. (5) have shown that opioid pharmacokinetics can be affected by pulmonary sequestration and metabolism, and that this is especially significant for opioids whose pka exceeds 8.0 (fentanyl, sufentanil, meperidine), Duthie et al. (18) have noted that there was not evidence of pulmonary sequestration or extraction of remifentanil (pka 7.07) in adult patients during or after CPB.
Hemodilution during CPB can also significantly alter a drug’s pharmacokinetic profile. The ratio of the CPB circuit volume to the patients blood volume is greater for smaller patients than adults; consequently, this hemodilution effect and its effects on protein binding, volume of distribution, and drug clearance may be more pronounced in children as opposed to adults. For remifentanil, a drug cleared by red cell, plasma, and tissue esterases, hemodilution of the plasma and red cells may markedly alter remifentanil metabolism. However, preliminary in vitro hemodilution studies suggest that remifentanil half-life did not change until whole blood underwent at least a four-fold change in dilution (19). Of note in these in vitro studies was the minor role plasma and red cell esterases had in the half-life of remifentanil. When compared with the in vivo kinetics of remifentanil, the in vitro half-life of remifentanil in red cells and in plasma was prolonged 10 and 20 times, respectively.1 Thus, the hematocrit or hemoglobin level probably has a minor role in remifentanil kinetics.
Remifentanil is metabolized by esterases, and because enzyme kinetics can be altered by changes in body temperature, differences in the pre- and postbypass body temperature could have been a factor influencing our study results. Differences in the pre- and postbypass temperature ranges were a variable we could not clinically control. In the prebypass period, body temperature was allowed to passively drift, whereas in the postbypass period, body temperature was actively maintained (heating blanket, convection air heating, and increased room temperature). Although pre- and postbypass temperatures on average differ by 1.2°C (range of 0.2° –2.0°C), our small sample size cannot exclude body temperature as a factor influencing remifentanil clearance.
Another difference between our study and that of Russell et al. (16) was our use of high-performance liquid chromatography instead of gas chromatography high-resolution mass spectroscopy in the determination of the remifentanil concentrations. We could only detect remifentanil in blood samples for 20 min after the 1-min bolus infusion. In view of the drug’s half-life of 7–8 min and our ability to detect the drug for 20 min or about 3 half-lives, we may have underestimated our half-life. Although larger doses (>5 µg/kg) may have allowed us to detect remifentanil for longer time periods and more accurately described the terminal half-life, we noted that the 5 µg/kg dose used in a previous pharmacokinetic study in children resulted in a 17% incidence of hypotension after a 1-min bolus injection. When we compared the results of this study with the kinetic profiles of children in our other study where gas chromatography high-resolution mass spectroscopy was used for the remifentanil assay, we noted similar plasma decay curves (i.e., similar plasma concentrations at a given time after the injection and similar lengths of time that remifentanil could be detected) (20). Thus, we decided to limit our bolus dose to 5 µg/kg. In addition, although remifentanil could be detected for only 20 min, after injection, nonetheless, the AUC20 was 95% of the AUC to infinity.
In addition to quantitative changes in drug kinetics, CPB can also introduce further pharmacokinetic variability. Variability can be assessed by the CV. In a study of alfentanil kinetics in adult cardiac surgical patients undergoing CPB, in which each patient received a single bolus of alfentanil both before and after CPB, Hug et al. (8) noted that the volume of distribution and half-life of alfentanil increased, but its clearance was unchanged. Nevertheless, the CV for clearance increased from 30% in the prebypass period to 80% in the postbypass period (8). By contrast with the CV for clearance of alfentanil (a drug that undergoes hepatic biotransformation and elimination), the CV for clearance of remifentanil, a drug that undergoes plasma and tissue esterase metabolism, is relatively unaffected by CPB. In a study in adults by Russell et al. (16), the CV for remifentanil clearance increased from 41% to 50% after CPB, whereas in our pediatric study the CV of remifentanil clearance increased from 25% to 30% after CPB. This small change in the CV for remifentanil clearance before and after bypass should mean little patient-to-patient variability.
As efforts increase to control patient care costs through decreasing use of hospital resources (postoperative ventilation, length of intensive care unit stay, and length of hospitalization), the use of predictable anesthetics becomes important. Although remifentanil clearance increased after CPB, CPB had minimal effect on its CV. The lack of variability in remifentanil pharmacokinetics after CPB suggests that remifentanil should be a highly predictable drug in the postbypass period of cardiac surgical procedures. To define its utility as a "fast-track" anesthetic, however, further studies of remifentanil in pediatric patients undergoing CHD repair are needed to assess its pharmacodynamic properties and variability.
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Footnotes |
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  A. E. Rigby-Jones, M. J. Priston, J. R. Sneyd, A. P. McCabe, G. I. Davis, M. A. Tooley, G. C. Thorne, and A. R. Wolf Remifentanil-midazolam sedation for paediatric patients receiving mechanical ventilation after cardiac surgery Br. J. Anaesth., August 1, 2007; 99(2): 252 - 261. [Abstract] [Full Text] [PDF]
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P.-A. Lonnqvist and N. S. Morton Postoperative analgesia in infants and children Br. J. Anaesth., July 1, 2005; 95(1): 59 - 68. [Full Text] [PDF]
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 A. K. Ross, P. J. Davis, G. deL. Dear, B. Ginsberg, F. X. McGowan, R. D. Stiller, L. G. Henson, C. Huffman, and K. T. Muir Pharmacokinetics of Remifentanil in Anesthetized Pediatric Patients Undergoing Elective Surgery or Diagnostic Procedures Anesth. Analg., December 1, 2001; 93(6): 1393 - 1401. [Abstract] [Full Text] [PDF]
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