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From the Departments of *Anesthesia and Pain Management and Neurosurgery, Children's Hospital and Regional Medical Center, University of Washington School of Medicine; Department of Pharmacy, University of Washington School of Pharmacy; Department of Bioengineering, University of Washington College of Engineering and the School of Medicine, Seattle, Washington.
Address correspondence to Anne M. Lynn, MD, Department of Anesthesia and Pain Management, W 9824, Children's Hospital and Regional Medical Center, 4800 Sandpoint Way, NE, Seattle, WA. 98105. Address e-mail to anne.lynn{at}seattlechildrens.org.
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Abstract |
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 Top Abstract IntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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METHODS: In this double-blind, placebo-controlled study, ketorolac pharmacokinetic, safety, and analgesic effects were studied in 37 infants and toddlers (aged 6–18 mo) postoperatively. On postoperative day 1, infants were randomized to receive placebo, 0.5, or 1 mg/kg ketorolac as a 10-min IV infusion. Blood samples were collected up to 12-h after dosing. The data were analyzed using noncompartmental and compartmental (nonlinear mixed-effects model) means. The patient covariates, including body weight, age, and surgical procedure, were analyzed in a stepwise fashion to identify their potential influence on ketorolac pharmacokinetics.
RESULTS: The data were best described by a two-compartmental model. Inclusion of covariates did not significantly decrease the nonlinear mixed-effects model objective function values and between-subject variability in the pharmacokinetic parameters of nested models. The mean and standard error of the estimates of the R(+) isomer were central volume of distribution 1200 ± 163 mL (coefficient of variation of interindividual variability, 13.6%), peripheral volume of distribution 828 ± 108 mL (13.0%), clearance from the central compartment 7.52 ± 0.7 mL/min (9.3%), and extrapolated elimination half-life 238 ± 48 min. Those of the S(–) isomer were 2320 ± 34 (14.6%), 224 ± 193 mL (86.2%), 45.3 ± 5.5 mL/min (12.1%), and 50 ± 42 min respectively. Dosing simulations, using population pharmacokinetic parameters, showed no accumulation of S(–) ketorolac but steady increases in R(+) ketorolac. Safety assessment showed no adverse effects on renal or hepatic function tests, surgical drain output, or continuous oximetry between placebo and ketorolac groups. Cumulative morphine administration showed large interpatient variability and was not different between groups.
CONCLUSION: The stereo-isomer-specific clearance of ketorolac in infants and toddlers (aged 6–18 mo) shows rapid elimination of the analgesic S(–) isomer. No adverse effects on surgical drain output, oximetry measured saturations, renal or hepatic function tests were seen. Simulation of single dosing at 0.5 or 1 mg/kg every 4 or 6 h does not lead to accumulation of S(–) ketorolac, the analgesic isomer, but does result in increases in R(+) ketorolac. Shorter dose intervals may be needed in infants older than 6 mo.
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Introduction |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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A survey of British anesthetists in 1996 reported use of NSAIDs postoperatively in 11% of neonates, increasing to 59% in infants 3–12 mo of age (4). The only parenteral NSAID currently available in the United States is ketorolac tromethamine, a racemic mixture with COX-1 and COX-2 effects. A small case series of infants who received ketorolac after abdominal surgery reported a decrease in morphine use (5).
Information on the pharmacokinetics of ketorolac in infants is sparse, making dosing problematic (6–11). Extrapolation of dosing guidelines from data for older children or adults may put infants at risk for inadequate effect or increased toxicity. There are multiple examples of the error of such extrapolations, including chloramphenicol and morphine (12,13), and suggest that investigation of infant pharmacokinetic parameters and safety assessments are the best way to evaluate drugs being administered to this population.
We are reporting results from a randomized, blinded, placebo-controlled study of ketorolac pharmacokinetics, safety, and efficacy when used in infants postoperatively. This report includes infants aged 6–12 mo and toddlers aged 12–18 mo.
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METHODS |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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On postoperative day 1, with the attending surgeon's approval, infants were randomized to receive study medication in 2 mL D5W (placebo, 0.5, or 1 mg/kg racemic ketorolac) as a 10-min IV infusion. Blood was sampled serially (1 mL at 0, 5 or 10 min, 30 or 60 min, 2, 4, 8 h and 2 mL at 12 h after infusion) up to 7 times during the next 12 h, either from the in-dwelling IV catheter or arterial catheter. At 12 h, liver and renal functions were re-tested and urine was sent for analysis.
All infants received morphine sulfate by continuous IV infusion at 5–30 µg · kg–1 · h–1 with bolus doses (0.05 mg/kg) as needed for pain control. An infant pain scale (14) was assessed every 2 h to assure consistent pain management. Low scores (<12 of 20 possible comfort points) mandated analgesic treatment. Acetaminophen was held for >6 h before the study drug administration and for the following 12 h.
Safety assessments included the renal (blood urea nitrogen (BUN), creatinine) and hepatic function (aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
glutamyl transferase), blood and urine analyses sent before and 12 h after study drug administration, as well as continuous pulse oximetry (Masimo Radical SET, Irvine, CA). Blood loss from any surgical drains was recorded. Hemoccult testing of stools and any gastric output was also performed.
Ketorolac Assay
Plasma concentrations of the R(+) and S(–) enantiomers of ketorolac were determined by high pressure liquid chromatography on a Varian Pro Star 210 gradient system with UV detection at 313 nm. Standards were prepared at 7 ketorolac plasma concentrations using 100 µL steroid-free plasma to attain final concentrations of 0.025, 0.05, 0.10, 0.25, 0.5, 1.0, and 2.0 µg/mL. Plasma samples (100 µL) and standards were added to silanized tubes containing the internal standard, loxapine HCL. Before extraction with 4 mL of methyl tert-butyl ether, proteins were precipitated with 30 µL of 10% weight to volume solution of trichloroacetic acid. Samples were then shaken for 10 min, centrifuged for 10 min, and the organic layer transferred to silanized culture tubes and evaporated under N2. Mobile phase (50 µL) was added, the samples were transferred to autosampler vials, and 30 µL was injected onto the high pressure liquid chromatography column. Baseline separation of the isomers was achieved using a chiral column (Astec Chirobiotic R (250 x 4.6 mm2) obtained from Advanced Separation Technologies, Inc. Whippany, NJ) using a binary gradient mobile phase of 0.07 g ammonium formate and 24 µL glacial acetic acid per liter methanol and increasing to 100% methanol for 17.5 min at a flow rate of 1.0 mL/min. The retention times of the internal standard, loxapine and (R) and (S) ketorolac were 4.9, 6.6, and 7.2 min, respectively. The lower limit of detection was 0.01 µg/mL, and the standard curve was linear with a coefficient of variation <10% for duplicate samples.
Population Pharmacokinetic Analysis
For both the noncompartmental (see below) and compartmental (mixed-effects modeling) pharmacokinetic analysis, the dose of the R(+) and S(–) ketorolac isomers was considered to be 50% of the racemic dose given, i.e., a 1 mg/kg dose of racemic ketorolac was taken to be composed of 0.5 mg/kg each of R(+) ketorolac and of S(–) ketorolac. The R(+) ketorolac and S(–) ketorolac pharmacokinetic data were characterized by a two-compartmental model with first-order elimination from the central compartment. For parameter estimation, the model was parameterized in clearance (CL), central volume of distribution (V1), intercompartmental clearance (Q) and peripheral volume of distribution (V2). The model was fitted to the pharmacokinetic data using the Nonlinear Mixed Effects Modeling (NONMEM) software (version V, ADVAN3, TRANS4; NONMEM Project Group, University of California, San Francisco, San Francisco, CA), interfaced with PDx-Pop Version 1.1j Release 4 (GloboMax LLC, Hanover, MD). Following a procedure described by Beal (15), measurements that were below the limit of quantification (0.001 µg/mL) were replaced with a value equal to half the quantification limit before the NONMEM analysis.
Between-Subject Variance Model
The between subject variability in the R(+) ketorolac and S(–) ketorolac pharmacokinetics was modeled according to an exponential model. In particular, it was assumed that the pharmacokinetic parameters were log-normally distributed:
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where 
i is the vector of pharmacokinetic parameters of the ith individual, 
is the vector of population median parameters, and exp(
i) expresses the (random) differences between and i.
The values for the random effects terms i were assumed to be independently multivariate normally distributed, with mean zero and respective variances of 
CL2, V12 and V22. The covariance between CL and V1 was simultaneously estimated. Furthermore, it was assumed that Q did not change across subjects, because early modeling attempts indicated low variability.
Residual Unknown Variance Model
Various residual unknown variance models were tested: an additive error model, a proportional error model, and a combined proportional–additive error model:
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where Cijpred is the jth plasma concentration of the ith individual predicted by the pharmacokinetic model, Cijobs is measured concentration and 
ij represents the residual departure of the model from the jth observation available from the ith individual. ij is a normally distributed random variable with zero mean and variance 
2. The superscripts P and A on ij's in Eq. 2c denote proportional and additive, respectively. The values of the population parameters were estimated separately for R(+) ketorolac and S(–) ketorolac using the first-order conditional estimation (with interaction effects) method in NONMEM. The best model was selected by comparing objective function values and parsimony criteria, assessing residuals and weighted residuals versus time, and by graphical analysis of predicted versus observed concentrations (distribution of the points around the unity line).
Covariate Model
Once the final variance model was selected, covariate models were tested to assess the potential influence of covariates (i.e., age, body weight, and surgical procedure) on R(+) ketorolac and S(–) ketorolac disposition. Individual parameter estimates of CL and V1 were obtained using the POSTHOC option in NONMEM. Scatter plots of these pharmacokinetic parameters against each covariate were examined for trends. Covariates, identified visually as potential factors influencing the pharmacokinetics of ketorolac, were then tested formally using the stepwise approach. Influential covariates selected by model building and reduction process were tested for significance (P < 0.05) based on changes in the objective function value (OFV) obtained using NONMEM. The difference in NONMEM OFV for nested models was assumed to be asymptotically 
2-distributed with degrees of freedom equal to the difference in the number of parameters between models (16). If the difference in the two OFV exceeded the 2 critical value, the null hypothesis was rejected and it was concluded that the covariate had a significant effect. Examination of the precision of parameter estimates, the between-subject and residual unknown variability, and the residual plots was also used as an aid for model comparison.
Concentration Simulation
Stochastic simulation, using the SIML function in NONMEM, was used to separately predict the expected concentrations of R(+) ketorolac and S(–) ketorolac after single IV doses of 2.35 or 4.7 mg (10 min infusion), as well as 2 alternative multiple IV dosing regimens (repeated dosing every 6 or 4 h) of the same amounts and infusion time. These doses were chosen by multiplying 0.25 and 0.5 mg/kg, respectively, by the median weight (9.4 kg) of the studied patients. For all dosing schemes, observations were simulated in 500 individuals based on the values of the fixed-effects parameters and the variance–covariance matrix in the final models for the two isomers. The single and multiple dosing simulations were performed for 24 and 48 h, respectively. For all simulations, the median, and 2.5th and 97.5th percentiles of R(+) ketorolac and S(–) ketorolac concentrations were plotted. For the single dose prediction, the study data were included for comparison. For multiple dose predictions, the administered IV dose amount and infusion time were identical for each dosing event.
Noncompartmental Pharmacokinetic Analysis
To compare our results to previously published studies, we also performed a traditional noncompartmental pharmacokinetic analysis. Plasma concentrations of the R(+) and S(–) enantiomers of ketorolac were fitted to 1 or 2-compartment models using nonlinear least-squares regression analysis with the experimental data fitting program Scientist 2.1 (MicroMath Scientific Software, Salt Lake City, UT). The goodness of fit statistics provided by the statistical output were used to determine which model was most appropriate for the individual concentration time data. Final estimates of the terminal exponential rate constant (ß) were used to determine elimination half-life (T1/2) as 0.693/ß. Area under the concentration time curve (AUC) was determined by the trapezoidal rule. The terminal portion of the AUC was estimated as Cn/ß where Cn was the last measurable serum concentration. CL was calculated as a ratio of the dose to the AUC. The Vß was calculated as CL/ß.
Pharmacodynamic Analysis
Morphine bolus and cumulative doses were compared between groups for the 12 h before drug administration as well as for the 12 h after drug or placebo administration. Analysis of variance with Tukey's post hoc analysis was used to determine differences between the placebo, 0.5 and 1.0 mg/kg doses of ketorolac. Data obtained for the 0.5 and 1.0 mg/kg data were also evaluated combined compared to placebo using unpaired t test. Level of significance was determined at P < 0.05.
Safety data were compared among groups with unpaired t test and in each infant before and after ketorolac with paired t test at the P < 0.05 level of significance.
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RESULTS |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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Noncompartmental Pharmacokinetic Analysis
Twenty-five infants received ketorolac, with 15 cases collecting samples for the entire 12 h study duration. All data were used for population analyses; 21 data sets were used for noncompartmental pharmacokinetic analysis. There were significant differences between the active S(–) and the inactive R(+) enantiomers for all of the pharmacokinetic parameters. As shown in Figure 1, the Cmax at the end of infusion were approximately two times higher for the inactive R(+) enantiomer compared to the active S(–) enantiomer, for the 0.5 and 1.0 mg/kg racemic doses, respectively, (2.0 ± 0.9 and 1.2 ± 0.7 µg/mL) and (4.6 ± 1.8 and 2.8 ± 1.5 µg/mL).
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Population Pharmacokinetic Analysis
Population Model Selection
The residual error variability was best described with a proportional error model Eq. 2b for R(+) ketorolac and an additive error model Eq. 2a for S(–) ketorolac. Scatter plots of individual estimates of CL and V1 against age, body weight, and surgical procedure for both isomers revealed significant linear relationships in S(–) ketorolac between V1 and age (r2 = 0.299), and between CL and age (r2 = 0.249). The fact that body weight was not a significant covariate for R(+) ketorolac and S(–) ketorolac justified the usage of "raw" dose amounts (i.e., not normalized by individual body weights) during NONMEM analysis. Inclusion of the V1 versus age covariate model into the S(–) ketorolac base model yielded no significant improvement in the OFV (from –346.778 to –347.607). The CL versus age relationship produced insignificant improvement in OFV (from –346.778 to –347.834). Additionally, inclusion of age as a covariate of V1 and CL resulted in insignificant improvement in OFV (from –346.778 to –351.972, the difference of 5.194 being less than the 2 critical value of 5.99 with 2 degrees of freedom) (16). Accordingly, the base structural model (i.e., no covariates) was chosen as the final model for both R(+) ketorolac and S(–) ketorolac.
Population Model Selection
The estimates of the population pharmacokinetic parameters of R(+) ketorolac and S(–) ketorolac arising from the best overall models are shown in Table 2. The residual variability in the data was moderately low, with estimated values of 22% coefficient of variation and 0.08 µg/mL standard deviation for the R(+) ketorolac and S(–) ketorolac pharmacokinetic data, respectively. The extrapolated central compartment half-lives were 238.3 ± 48.1 and 50.1 ± 42.3 min for R(+) ketorolac and S(–) ketorolac, respectively. Between-subject pharmacokinetic variability for CL and V1 was fairly consistent for both isomers (46% and 58% for R(+) ketorolac, and 58% and 67% for S(–) ketorolac, respectively). Variability in V2 was similar (48%) for R(+) ketorolac, but higher (170%) for S(–) ketorolac. Random effect correlation between CL and V1 was 0.93 for R(+) ketorolac and 0.84 for S(–) ketorolac (percent standard errors on the covariance terms were 30% and 34%, respectively). The relative standard errors of the fixed-effect mean parameters were generally small between 1% and 15% (with one estimate having a precision of 86%), which suggests that these parameters were estimated with generally good precision.
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Figure 2 shows the plot of the population weighted residuals versus time for the R(+) ketorolac and S(–) ketorolac data. The majority of weighted residuals lie between ±2 standard deviations from the mean. In Figure 3 and Figure 4, respectively, population and individual predicted concentrations were plotted against observed concentrations.
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Concentration Simulations
Simulated R(+) ketorolac and S(–) ketorolac concentrations are depicted in Figures 5 –7 for the various IV dosing regimens for 500 simulated subjects. For the single-dose simulation plots (Fig. 5), the raw ketorolac concentration data, plotted for comparison, were generally within the predicted 95th prediction interval for the population. Simulated peak and trough R(+) ketorolac and S(–) ketorolac concentrations, reported as median, and 2.5th and 97.5th percentiles are summarized in Table 3. Because the terminal elimination half-life of S(–) ketorolac was shorter than that of R(+) ketorolac, simulated plasma concentrations of the two ketorolac isomers differed in one key way: for the two multiple dosing regimens, the peak and trough concentration of R(+) ketorolac increased with each repeated dosing event, whereas that of S(–) ketorolac remained constant for the studied time interval.
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Pharmacodynamic Analysis
Renal function testing (BUN, creatinine) showed no deterioration from screening to the 12-h postdrug sample. There was a statistically significant decrease in BUN overall from the screening value (8.6 mg/dL) to the 12-h postdrug value (4.0 mg/dL), consistent with preoperative fasting. Individual group data are given in Table 1. Urinalyses were also unchanged except for the presence of red blood cells in infants who had urologic surgeries. Two infants showed increases in AST and ALT at the 12 h sample. One had undergone craniectomy surgery with transfusion intraoperatively and did not receive ketorolac (placebo group); the second infant had open-heart surgery on cardiopulmonary bypass. Both infants showed rapid normalization of the increased ALT and AST by 2–3 days after surgery. Continuous oximetry for the first postoperative day showed a mean percent time with saturations <90% not different in the three groups. For infants after craniectomy, surgical drain amounts were similar in all groups.
As shown in Table 4, ketorolac had no significant effect on the morphine cumulative doses, or the need for additional morphine boluses for the 12 h after drug or placebo administration. There were also no significant effects when the combined ketorolac data were evaluated in the patients receiving ketorolac compared to placebo.
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DISCUSSION |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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Table 5 compiles previous pediatric pharmacokinetic reports for ketorolac, and includes results from our traditional pharmacokinetic analysis for comparison. Most investigators analyzed the combined racemic (total) concentrations. Mandema and Stanski (6) reported a "half-maximal" analgesic effect at a total ketorolac concentration of (EC50) 0.37 µg/mL in adults. Applying this level as a target to our infant study to estimate effective duration is not possible, because we analyzed stereo-specific kinetics (unless one is willing to make assumptions about the isomers' volumes of distribution). Analysis of the separate R(+) and S(–) isomers may provide useful information about the analgesic efficacy of ketorolac, because S(–) ketorolac is responsible for ketorolac's analgesic properties. Kauffman et al. (7), in a study of children, reported a Cmax of 1.6 µg/mL for S(–) ketorolac after a 0.6 mg/kg IV dose, with the racemic concentration being 4.7 µg/mL. Our study found an S(–) ketorolac Cmax in infants and toddlers of 1.2 to 2 µg/mL after 0.5 or 1 mg/kg dose of racemic ketorolac respectively. These concentrations exceeded the minimum analgesic values found in adults (6). Simulations (Figs. 5–7) suggest that if Mandema and Stanski's EC50 concentration applies to infants older than 6 mo, dosing at 4 h intervals may be needed. Because all infants and toddlers in this study were also receiving morphine for postoperative analgesia, an interaction affecting ketorolac's metabolism is possible. However, because combining ketorolac with opioids is the most common clinical situation, we believe the data are relevant to clinical care.
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Stereoisomer-specific pharmacokinetics of ketorolac have been reported in children studied by Kauffman et al. (7) and Hamunen et al. (8), with different kinetic parameters reported. Accordingly, we felt it appropriate to evaluate stereoisomer kinetic parameters in the infant and toddler population. Kauffman et al., in a study of children (3–18 yr), reported both the racemic and stereoisomer kinetic values for ketorolac, and further showed that the racemic analysis reflects the R(+) isomer values predominantly. As Kauffman et al. (7) and Hamunen et al. (8) did, we found major differences in the pharmacokinetic parameter values for the isomers of ketorolac. In line with our observations that clearance of the active S(–) enantiomer was four to five times faster than that of the R(+) isomer, the extrapolated terminal half-lives of the R(+) and S(–) isomers were significantly different (238 ± 48 and 50 ± 42 min). In infants and toddlers (aged 6–18 mo), a similar clearance and shorter elimination half-life for S(–) ketorolac was found when compared with those reported by Kauffman et al. (Table 5). Hamunen et al. (8) also found a higher clearance for S(–) ketorolac than for R(+) ketorolac in children. Elimination half-life for S(–) ketorolac (792 min) in older children and adults reported by Hamunen et al. was much longer than that found by Kauffman et al. (107 min) in younger children or the present study in infants and toddlers (50 min) (7,8). The elimination half-life of the analgesically active isomer occurs even more quickly in infants than in children.
By performing a compartmental pharmacokinetic analysis using NONMEM, we were able to determine the V1 of the central compartment. V1 is useful for determining the dose needed to attain a targeted initial concentration (i.e., bolus dose = Ctarget x V1). Previous studies in children reported the noncompartmental estimate Vß, which can be affected by the overall elimination in the patient. In the infants and toddlers, both V1 and Vß were significantly larger for S(–) ketorolac than for R(+) ketorolac. Similar results were found in older children for Vß (7,8).
The simulations demonstrated a lack of accumulation of the S(–) isomer, even when administered every 4 or 6 h, due to its rapid elimination half-life. This is in contrast to the resulting accumulation of the R(+) isomer, especially if administered every 4 h. In rodent models, the antiinflammatory and analgesic activity of the S(–) isomer is 57 and 230 times more potent then the R(+) isomer (17). The relative potency of the isomers in causing renal, hematological, or other side effects has not been established. In addition, the significance of the difference in isomeric potency has not been determined in humans. Therefore, the clinical importance of accumulation of the R(+) isomer is not known.
Safety assessments showed no adverse effects from a single 0.5–1 mg/kg dose of ketorolac in infants older than 6 mo. Serum creatinine and BUN remained in the normal range after drug administration; urinalyses showed red blood cells only in infants who underwent urologic surgeries. Serum transaminases showed increases (to 2–2.5 x normal) in 2 of the 37 infants studied, one whose surgery included cardiopulmonary bypass and one who was transfused during surgery and did not receive ketorolac. Drug administration did not result in increases in hepatic enzymes in other infants in this study. The two infants with increases in ALT and AST rapidly corrected, with normal values by 48–72 h postoperatively. We also found an asymptomatic increase of transaminases in three infants on screening laboratory assessment, requiring exclusion of these infants from study.
Continuous oximetry showed no difference in percent time with room air saturations <90% in infants given drug versus placebo (Table 1). Surgical drains were used in all craniectomy surgery infants and drainage totals were not different in the treated versus placebo groups (Table 1).
Infants aged 6 mo or more should have active COX systems allowing NSAIDs such as ketorolac to exert analgesic effects. Lieh-Lai et al. (18) reported the analgesic effects of ketorolac after a single dose (0.6 mg/kg) postoperatively in children in intensive care compared with IV morphine (0.1 mg/kg). In both groups, pain relief was achieved in 68% (ketorolac) or 58% (morphine). Most children required remedication for pain within 4 h; 58% for ketorolac and 63% for morphine. Papacci et al. (19) reported significant analgesic efficacy within 0.5 h and up to 6 h after dose in an observational unblinded study of 18 neonates and premature babies given 1 mg/kg IV ketorolac for postoperative or procedure-related pain.
The lack of difference in concomitant morphine usage between treated and placebo patients in our study was a surprising, but potentially explicable, finding in our institution. This finding might suggest that ketorolac is not analgesic in postoperative infants, contrary to the reports of Papacci et al. and Lieh-Lai et al. An alternative hypothesis, and one we believe more likely, is that concomitant morphine administration is not a good reflection of analgesic efficacy of ketorolac. Continuous morphine infusions are the standard for postoperative care at our institution after major surgery. Although infusions could potentially be weaned by the bedside nurse after study drug administration under this protocol, they proved unlikely to be immediately discontinued if the infant was receiving a satisfactory pain score and had no limiting side effects. We hypothesize that this obscured the measurement of an analgesic effect from ketorolac as measured by decrease in total morphine dose. The interpatient variability in morphine usage was large as has been previously reported (20) and could further obscure any difference in treated versus placebo infants. The short elimination half-life of the analgesic isomer S(–) of 50 min in infants and toddlers compared with values in children of 107 min (7) may also play a role in a shorter duration of analgesia.
We found the stereo-specific pharmacokinetics of ketorolac in infants and toddlers aged 6–18 mo showed differences in handling of the R(+) and S(–) isomers, with more rapid elimination of the analgesic (S) isomer. No adverse effects on renal or hepatic function tests were seen. In the 37 infants studied, no difference in morphine usage was seen between treated and placebo groups, but this may be explained by the preexisting institutional morphine infusion protocol. Dosing simulations suggest dosing every 4 h may be necessary to achieve serum concentrations at or above the adult EC50 level (6). This will result in accumulation of R(+) ketorolac with unknown clinical implications. Continuing evaluation of younger infants (<6 mo) will help assess ketorolac's place in the postoperative care of infants.
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ACKNOWLEDGMENTS |
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Footnotes |
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Supported by FDA Orphan Product Development Grant FD-R-001815. The population analysis was partially supported by NIH grant P41 EB001975, and safety assessments were partially supported by NIH grant M01-RR-00037.
Reprints will not be available from the author.
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