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PEDIATRIC ANESTHESIA

Age-Stratified Pharmacokinetics of Ketorolac Tromethamine in Pediatric Surgical Patients

Richard M. Dsida, MD^*, Melissa Wheeler, MD^*, Patrick K. Birmingham, MD^*, Zhao Wang, MD, Corri L. Heffner, RN^*, Charles J. Coté, MD^*, and Michael J. Avram, PhD

*Department of Pediatric Anesthesiology, Children’s Memorial Hospital, Chicago, Illinois; and Department of Anesthesiology, Northwestern University Medical School, Chicago, Illinois

Address correspondence and reprint requests to Richard M. Dsida, MD, Department of Pediatric Anesthesiology, Children’s Memorial Hospital, 2300 Children’s Plaza, Chicago, IL 60614. Address e-mail to r-dsida{at}northwestern.edu

	Abstract

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Published data suggest that ketorolac pharmacokinetics are different in children than in adults. We sought to better characterize ketorolac pharmacokinetics in children. Thirty-six children, aged 1–16 yr, were stratified into four age groups: 1–3 yr, 4–7 yr, 8–11 yr, and 12–16 yr. Each child received 0.5 mg/kg of ketorolac tromethamine IV after completion of elective surgery. A maximum of 16 venous blood samples (mean, 13 ± 2) were collected at predetermined times up to 10 h after drug administration. Plasma ketorolac concentrations were measured by high-performance liquid chromatography after solid-phase extraction. Individual concentration-versus-time relationships were best fit to a two-compartment pharmacokinetic model by using SAAM II. Body weight-normalized pharmacokinetic variables did not differ among the age groups and were similar to those reported for adults, including a volume of distribution at steady state of 113 ± 33 mL/kg (mean ± SD) and an elimination clearance of 0.57 ± 0.17 mL · min^-1 · kg^-1. Our study demonstrates that a single dose of ketorolac (0.5 mg/kg) results in plasma concentrations in the adult therapeutic concentration range for 6 h in most children. Our data provide no evidence that children require either larger weight-adjusted doses or shorter dosing intervals than adults to provide similar plasma drug concentrations.

IMPLICATIONS: The literature suggests that ketorolac disposition differs between children and adults. We characterized ketorolac pharmacokinetics in 36 children. Body weight-normalized two-compartment pharmacokinetic variables did not differ among pediatric patients <17 yr old and were similar to adult values.

	Introduction

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Ketorolac tromethamine (Toradol^®; Roche Pharmaceuticals, Nutley, NJ) is a nonsteroidal antiinflammatory drug with analgesic efficacy similar to commonly used opioids (1–5). Ketorolac is used to provide analgesia for moderate pain and as an adjunct to opioids for severe pain to reduce opioid requirements. The advantages of ketorolac include a lack of side effects associated with opioids, such as respiratory depression, pruritus, sedation, and nausea. The disadvantages include impairment of platelet function, the potential for gastrointestinal bleeding and delayed renal excretion, and the potential for acute renal failure in patients with preexisting renal disease (6).

Ketorolac is used in children to treat pain, including postoperative pain (1–5). Several studies indicate that the pharmacokinetic variables of ketorolac differ in children and adults (1,7–11). Some of these observations imply that children require either larger weight-adjusted doses (8,9) or shorter dosing intervals (9,10). The purpose of this study was to further characterize the pharmacokinetics of ketorolac in children to determine whether there are age-related pharmacokinetic differences.

	Methods

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Forty-three ASA physical status I, II, or III children scheduled for elective orthopedic or urologic operations were enrolled in this IRB-approved study. Written, informed parental consent and patient assent were obtained where appropriate. Patients had no history of hepatic, renal, or cardiac disease and were stratified into age groups of 1–3 yr, 4–7 yr, 8–11 yr, and 12–16 yr.

After the induction of general anesthesia, two IV catheters were inserted: one for fluid and drug administration and the other for blood sampling. Upon completion of the operative procedure and with assurance that hemostasis was achieved, ketorolac tromethamine (0.5 mg/kg) was administered by bolus injection. No dose exceeded 30 mg. A 2-mL blood sample was scheduled to be obtained before drug administration and at 5, 10, 15, 30, 45, 60, 90, 120, 180, 240, 300, 360, 420, 480, and 600 min thereafter. Sampling was terminated if neither IV catheter was functional, if there was early hospital discharge, or if the parent or patient objected to further blood sampling. Whole blood samples were transferred to a heparinized tube and centrifuged; the plasma was separated and frozen at -25°C for subsequent analysis.

Plasma ketorolac concentrations were measured by a high-performance liquid chromatography technique developed in our laboratory (12). Two-hundred-fifty-microliter plasma samples were prepared in duplicate. This method is linear from ketorolac plasma concentrations of 0.05 to 10.00 µg/mL, with between-day coefficients of variation of 8.5% or less.

Venous plasma ketorolac concentration-versus-time data were fit with one-, two-, and three-compartment pharmacokinetic models by the SAAM II software system (SAAM Institute, Seattle, WA) by using a relative error model (13,14). Data were weighted by the reciprocal of their SD, assuming a fractional SD of 0.5. The a posteriori identifiability was verified on the basis of variable fractional SD. Possible systematic deviations of the observed data from the calculated values (i.e., goodness of fit) were sought with the one-tailed one-sample runs test, with P < 0.05, corrected for multiple applications of the runs test, as the criterion for rejection of the null hypothesis. Possible model miss-specification was also sought by visual inspection of the measured and predicted marker concentration-versus-time relationships. The appropriateness of the choice of model order was verified by using the Akaike information criterion and the Schwarz-Bayesian information criterion (13,14).

Statistical analyses were preformed with Sigma Stat^TM (Version 2.03; SPSS, Inc., Chicago, IL). The distribution of boys and girls among the stratified age groups was compared by using Fisher’s exact probability test. All other data were tested for normality of the underlying population by using the Kolmogorov-Smirnov test, with Lilliefors’ correction. The data were also tested for homogeneity of variance by using the Levene median test. If the data from the stratified age groups were normally distributed and had homogeneous variance, they were compared with the one-way analysis of variance (ANOVA); when indicated by the ANOVA, all pairwise comparisons were made post hoc by using Tukey’s multiple comparison test. When data were not normally distributed or had inhomogeneous variance, they were compared by using the Kruskal-Wallis one-way ANOVA; when indicated by the Kruskal-Wallis test, all pairwise comparisons were made post hoc by using Dunn’s test. The relationships between age or body mass and the pharmacokinetic variables were sought by using standard least-squares linear regression. The criterion for rejection of the null hypothesis was P < 0.05 for all tests.

	Results

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Full characterization of the elimination phase was possible in 36 of the 43 patients. In seven patients there was an inadequate sample number (i.e., blood sampling for 3 h or less) for complete analysis. Ages ranged from 1.27 to 16.9 yr, with weights of 10.9 to 80 kg. We obtained an average of 13 ± 2 of the 16 planned blood samples. There was no difference among age groups in sex, ketorolac dose, or the number of blood samples obtained. Eight to 10 patients were included in each of the four age ranges. Four patients in the 12- to 16-yr age range received <0.5 mg/kg because the maximum dose was limited to 30 mg, but there was no difference in the body mass-normalized ketorolac dose among the age groups.

Thirty-four of the 36 three-compartment fits were unidentifiable a posteriori. The two-compartment fits were all preferable to the one-compartment fits on the basis of both the Akaike information criterion and the Schwarz-Bayesian information criterion. Therefore, we judged that the plasma ketorolac concentration-versus-time relationships were best described by a two-compartment pharmacokinetic model (Fig. 1, A–D). The one-sample runs test confirmed that there were no systematic deviations of the observed data from the calculated values for the two-compartment fits.

View larger version (36K): [in this window] [in a new window]   Figure 1. Plasma ketorolac concentration-versus-time relationships for the 36 children participating in this study, by age group: A, 1–3 yr; B, 4–7 yr; C, 8–11 yr; and D, 12–16 yr. Simulated plasma ketorolac concentration-versus-time relationships after a 0.5 mg/kg IV dose based on mean pharmacokinetics for the group are illustrated with the dark solid line.

Because all pharmacokinetic variables that were correlated with age were also found to be correlated with patient weight by linear regression (R² ranged from 0.50 to 0.75, all P < 0.001) and because weight was correlated with age by linear regression (R² = 0.73), all pharmacokinetic variables except t_1/2ß were normalized for patient weight. There were no relationships of the weight-normalized variables to age, nor were there any differences in any of the pharmacokinetic variables among the age groups (Table 1). Average plasma ketorolac concentration-versus-time relationships of the four age groups after 0.5 mg/kg ketorolac tromethamine were remarkably similar, as indicated in Figure 2.

View larger version (21K): [in this window] [in a new window]   Figure 2. Mean (±SD) plasma ketorolac concentration-versus-time relationships after a 0.5 mg/kg IV dose for the four age groups. Note that the curves are virtually superimposable, particularly during the first 6 h after drug administration.

	Discussion

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Pediatric ketorolac pharmacokinetics reported by other investigators differ from this study and from one another. The Cl_E of Kauffman et al. (9) is nearly twice that of this study and that of Olkkola and Maunuksela (8) but is similar to that of Gonzalez-Martin et al. (10). Although Kauffman et al. (9) report volume of distribution as VDß, their VDß is more than 3 times our V_SS and nearly 50% larger than those reported by others (8,10). The t_1/2ß (four hours) of Kauffman et al. is intermediate between our results and those of others (8,10). Some of the differences in the study of Kauffman et al. may reflect the patient population studied. Inclusion of patients undergoing cardiac surgical procedures and other types of surgery that require blood transfusions (dilution of drug) or result in large blood loss (loss of drug from the body) would be expected to alter the apparent volume of distribution, especially for drugs such as ketorolac, which have a small volume of distribution.

Our t_1/2ß was only slightly longer than that reported by Gonzalez-Martin et al. (10) (3.00 vs 2.26 hours); however, our V_SS and Cl_E were nearly half those reported by these same investigators (113 vs 250 mL/kg and 0.57 vs 1.3 mL · min^-1 · kg^-1, respectively). Our Cl_E was only slightly less than that reported by Olkkola and Maunuksela (8) (0.570 vs 0.70 mL · min^-1 · kg^-1), but our V_SS and t_1/2ß were nearly half those they reported (113 vs 260 mL/kg and 3.00 vs 6.14 hours, respectively). Differences in the reported variables between this study and those of other investigators (8,10) may be caused by differences in experimental design. In those studies, blood was sampled only three or four times during the elimination phase, when drug concentrations are closest to the lower limit of detection. This may make it difficult to completely characterize the elimination phase, especially if the last sample was collected many hours after the penultimate sample. Our study collected up to 10 samples at a maximum of two-hour intervals throughout the elimination phase (approximately three t_1/2ß).

Our results are similar to the pharmacokinetic variables reported for adults (7,11). The V_SS reported by Jung et al. (7) was identical to that of this study, whereas the Cl_E reported by Jallad et al. (11) for oral and IM ketorolac was nearly identical to ours. The difference between our mean half-life (three hours) and those of others (7,11) (5.09 and 4.69 hours) may also be related to study design; as discussed previously, we sampled relatively frequently for up to 10 hours, whereas the other investigators sampled relatively infrequently up to 24 hours, with a 12- to 16-hour interval between the penultimate and ultimate samples.

The clinical formulation of ketorolac is a racemic mixture of stereoisomers, each with different analgesic potency (18–20). We chose not to measure the concentrations of the individual enantiomers because a previous study demonstrated that the disposition of the enantiomers in an adult volunteer was not different (20). Studies of enantioselective ketorolac pharmacokinetics in children produced confounding results (8,9,21). The pharmacokinetic variables describing racemic ketorolac disposition were not intermediate between those of the two enantiomers, as one would expect. Rather, they were similar to those describing the disposition of the inactive R(+)-ketorolac enantiomer. One possible explanation of these observations is undetected racemization of the S(-) enantiomer, such as has been reported in earlier stereospecific ketorolac assays (22).

When ketorolac was introduced, the recommended initial dose in adults was 60 mg, with additional doses of 30 mg at six-hour intervals. However, a population-based pharmacokinetic and pharmacodynamic study recommends 30 mg as the initial dose in adults (6,23). As with other drugs used in the pediatric population, ketorolac dosing in children has been estimated from recommended adult dosing, with adjustments based on clinical efficacy. Clinicians caring for children initially used 1 mg/kg, with subsequent doses of 0.5 mg/kg every six hours (3,24) When the recommended initial dose was decreased by 50% in adults, that in children was similarly reduced to 0.5 mg/kg (2). Basing the initial and maintenance dose of ketorolac in children on their body weight, rather than using a fixed dose, as in adults, is justified by the clear relationship of pediatric ketorolac volumes of distribution to body weight. The ketorolac concentration at half-maximal effect for analgesia in adults is 0.37 µg/mL (23); no half-maximal effect for analgesia has been established for children. Results of this study indicate that a 0.5 mg/kg dose will produce adult therapeutic ketorolac concentrations in most children for the six-hour interval before redosing is necessary. Our data provide no evidence that children require either larger weight-adjusted doses or shorter dosing intervals.

	Acknowledgments

 
Supported in part by a Grant from Hoffman-La Roche, Inc., Nutley, NJ.

	Footnotes

 
Presented in part at the annual meeting of the American Society of Anesthesiologists, San Diego, CA, 1997.

	References

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