Pharmacokinetics of naratriptan in adolescent subjects with a history of migraine.

Naratriptan is a novel 5-HT1 agonist developed to treat acute migraine. The study objective was to characterize the pharmacokinetics of oral naratriptan in adolescent migraine patients outside a migraine attack. Subjects received a single 2.5 mg naratriptan tablet. Serial serum samples for naratriptan concentrations were collected over 24 hours. Blood pressure, pulse rate, and 12-lead ECG were recorded at baseline and at regular intervals after dosing. Seven patients--3 males and 4 females, 12 to 16 years of age--received drug and completed the study. The geometric mean and 95% confidence interval maximum concentration (Cmax) was 8.0 ng/mL (5.9-10.7), elimination half-life (t1/2) was 4.9 hours (4.5-5.4), area under the concentration-time curve (AUC) was 74.6 ng.h/mL (56.6-98.2), and apparent total clearance (Cl/F) was 558.8 mL/min (424.3-735.9). The median time to maximal concentration (tmax) was 4 hours, with a range of 1.5 to 4. Blood pressure, pulse rate, and ECG parameters did not change significantly from baseline. No serious adverse events or subject withdrawal after drug administration occurred. Oral naratriptan pharmacokinetic parameters in adolescents were similar to values reported in adults. Naratriptan doses for adolescents older than 12 years of age would be expected to be similar to adult doses.

Altered phenytoin pharmacokinetics in children with severe, acute traumatic brain injury.

The purpose of this study was to determine if phenytoin protein binding and metabolism were altered in prepubescent pediatric patients within the first 10 days following severe, acute traumatic brain injury. Patients (n = 10) received phenytoin loading doses (15-20 mg/kg) followed by a maintenance regimen (7 mg/kg/day) initiated within 12 hours of the loading dose. Phenytoin serum concentrations were measured serially on days 1, 2, 3, 5, 7, 9, and 10 at 1, 6, and 12 hours. Time-invariant and time-variant Michaelis-Menten pharmacokinetic models were fit to the unbound phenytoin concentration-time data (ADAPT II). Albumin concentrations significantly decreased over time (p < 0.001) and were predictive of the phenytoin binding ratio (r2 = 0.373, p < 0.0001). The time-variant model provided a superior fit of the data in 7 patients with no difference between models in 3 patients. Rapid inhibition of metabolism (Vmaxbaseline = 2.82 +/- 2.35 mg/kg/day) was observed initially following injury. This was followed by induction of metabolism as reflected by a Vmaxinduced of 20.79 +/- 13.71 mg/kg/day, which was approximately twofold higher than reported values for nonstressed children. Children with severe, acute neurotrauma were found to have markedly altered protein binding and phenytoin metabolism.

Use of intravenous valproate in three pediatric patients with nonconvulsive or convulsive status epilepticus.

OBJECTIVE: To report the pharmacokinetics of intravenous valproate (VPA) in children with generalized convulsive status epilepticus (GCSE) or nonconvulsive status epilepticus (NCSE). To provide loading and maintenance dosing for patients with hepatic induction secondary to concurrent anticonvulsants. CASE SUMMARY: Two patients (10 y, 34 mo) with GCSE refractory to benzodiazepines, phenobarbital, phenytoin, and pentobarbital received intravenous VPA. Apparent volume of distribution (Vd) following a 20 mg/kg loading dose was 0.29 L/kg. Maintenance infusions of 4-6 mg/kg/h produced steady-state total concentrations of 66 mg/L and 92.4 mg/L (unbound concentration 44.6 mg/L). Clearance ranged from 63-66 mL/h/kg. An eight-year-old with NCSE received intravenous VPA (13.4 mg/kg load followed by 9 mg/kg every 8 h). Total and unbound steady-state VPA concentrations were 32.9 mg/L and 21.2 mg/L, respectively. Elimination half-life was eight hours. DISCUSSION: We constructed a pharmacokinetic simulation using VPA parameters from children receiving mono- or polyanticonvulsants. Our Vd and elimination half-life rates were comparable with published pediatric values. Patients on hepatic inducers had clearance rates 2.5 times those of children receiving oral anticonvulsant polytherapy. Unbound fractions (48.3% and 66%) were significantly higher than normal. CONCLUSIONS: A 20 mg/kg loading dose should produce a concentration after the bolus dose of approximately 75 mg/L. Initial infusion should consider hepatic induction (noninduced = 1 mg/kg/h, polyanticonvulsant therapy = 2 mg/kg/h, and high-dose pentobarbital = 4 mg/kg/h). Adjustments should be based on response and serum concentrations.

Altered clearance of theophylline in children with Down syndrome: a case series.

Down syndrome (DS) is a common cause of mental retardation resulting from trisomy 21. Previous reports have described altered pharmacokinetics and pharmacodynamics in patients with DS. The authors report six cases of infants (2-19 months) with DS who demonstrated altered theophylline pharmacokinetics. Clearance was prolonged in most of these patients. No overt toxicity to theophylline was noted in any of the cases. The authors propose that patients with DS are at increased risk for altered theophylline pharmacokinetics. The etiology for altered pharmacokinetics of theophylline may be due to the interface between normal developmental changes and pharmacogenetic differences associated with DS and/or the secondary disease states and concomitant drug therapy.

Comparison of microparticle enzyme and fluorescence polarization immunoassays in pediatric patients not receiving digoxin.

Previously, investigators have measured endogenous digoxin-like immunoreactive substances (DLIS) in pediatric patients. Digoxin-like immunoreactive substances may cross-react with digoxin assays to produce false-positive digoxin concentrations; hence, the validity of digoxin concentrations in pediatric patients is questionable. The authors compared the presence and magnitude of apparent DLIS using the microparticle enzyme immunoassay (MEIA) AxSYM Digoxin II and the fluorescence polarization immunoassay (FPIA) TDx Digoxin II, in the serum of 80 pediatric patients who were hospitalized with normal serum creatinine but had not been administered digoxin. Patients ranged in age from 1 day to 16 years (mean age, 4.96 +/- 5.17 years). Serum creatinine and total bilirubin were 0.5 +/- 0.18 mg/dl and 1.3 +/- 0.17 mg/dl, respectively. Forty-eight percent of MEIA samples and 79% of FPIA samples had measurable DLIS values. Digoxin-like immunoreactive substance concentrations for the MEIA (0.07 +/- 0.09 ng/ml) and FPIA assays (0.1 +/- 0.1 ng/ml) were statistically different (p = 0.01); however, no sample had a DLIS value >0.38 ng/ml. A poor correlation was noted between patient age, serum creatinine, total bilirubin, and DLIS concentration. The MEIA and FPIA assays effectively minimized DLIS cross-reactivity making both technologies clinically acceptable for serum digoxin measurement in pediatric patients with normal serum creatinine and total bilirubin.

Routine monitoring of gentamicin serum concentrations in pediatric patients with normal renal function is unnecessary.

OBJECTIVE: Due to increasing demands for cost containment within the healthcare system, we evaluated the need for routine gentamicin concentrations (i.e., peak and trough with third dose). DESIGN: Single-institution study performed concurrently with hospitalization. SETTING: A 225-bed pediatric teaching hospital. PARTICIPANTS: The study population consisted of 150 hospitalized pediatric patients (53% medicine, 47% surgical patients) from 3 months to 15 years old with normal serum creatinine. OUTCOME MEASURES: If the administered dose produced diagnoses-appropriate peak concentrations of at least 4 micrograms/mL or 5 micrograms/mL in bacteremia/septicemia and at least 6 micrograms/mL or 8 micrograms/mL in patients with pneumonia if trough serum gentamicin concentrations were less than 2 micrograms/mL, if the patient was noted by the attending physician to be clinically responding as well as objectively having a decreased white blood cell count and was afebrile, and if there was not an increase of 0.5 mg/dL or more in serum creatinine during the course of therapy. RESULTS: Patients received a mean dose of gentamicin 2.51 +/- 0.14 mg/kg i.v. q8h, which resulted in a mean peak concentration of 6.1 +/- 1.7 micrograms/mL (range 2.4-11.7) and a mean trough concentration of 0.5 +/- 0.3 microgram/mL (range 0.1-1.8). Peak and trough concentrations were at least 4 micrograms/mL and less than 2 micrograms/mL in 96% and 100% of patients, respectively. No patient required a dosage change due to lack of clinical response. CONCLUSIONS: Our data do not support the routine monitoring of gentamicin concentrations in pediatric patients older than 3 months of age who are receiving appropriate standard doses of gentamicin and have normal renal function.

Hemodynamic response to intentionally altered flow continuity of dobutamine and dopamine by an infusion pump in infants.

STUDY OBJECTIVE: To evaluate the effect of an intentional alteration in infusion pump flow continuity on the hemodynamic stability of infants receiving either dobutamine or dopamine. DESIGN: Prospective, open-label study. SETTING: A university-affiliated children's hospital. PATIENTS: Ten hemodynamically stable infants (age 2 wks-10 mo) in intensive care receiving dobutamine (5) or dopamine (5). Three patients received both agents and were studied at independent times. INTERVENTIONS: Dobutamine and dopamine were administered using the Flo-Gard VP pump that delivers an intentional alteration of flow continuity (rate pulse). Heart rate and mean arterial pressure (MAP) were recorded every second. Analysis was based on the measurements obtained from the first 5 minutes on the study pump and the 2 minutes before and after the rate pulse. MEASUREMENTS AND MAIN RESULTS: Although hemodynamic changes in pre- and post-rate pulses were statistically significant (p < 0.05) in some individuals, only one infant had a greater that 10% change in MAP 2 minutes after the rate pulse. Alterations in hemodynamics were not consistent among or within patients. CONCLUSION: In infants requiring dobutamine or dopamine, no clinically significant pharmacodynamic effects were associated with alteration in continuity of drug delivery caused by the single positive rate pulse. Therefore, we conclude there is no contraindication to the use of this infusion pump in hemodynamically stable infants receiving these drugs.

Absorption pharmacokinetics of atenolol in patients with the Marfan syndrome.

The negative inotropic and chronotropic effects of beta-blocker therapy have been reported to reduce morbidity and mortality in patients with Marfan syndrome; however, little is known about the pharmacokinetics of atenolol after oral administration of multiple doses to patients with the Marfan syndrome. We studied the pharmacokinetics of atenolol in 13 such patients aged 18.7 +/- 2.9 years who were receiving 1.78 +/- 0.58 mg/kg/day (70.1 +/- 20.3 mg/m2/day) of atenolol for 6 weeks or longer. Mean +/- SD percentage change in baseline heart rate after the administration of atenolol was -18.03 +/- 16.59% and mean +/- SD percentage change in exercise heart rate after atenolol was -33.22 +/- 14.75% (P < .01). Six to 8 atenolol serum concentrations were collected in each patient during a 12-hour dosing interval and were determined by high-performance liquid chromatography with ultraviolet detection. Serum atenolol concentrations at 0 (123 +/- 70 micrograms/L) and 12 (116 +/- 66 micrograms/L) hours were within 20% of each other and were thus assumed to be at steady-state. A one-compartment, steady-state pharmacokinetic model with first-order absorption and elimination was fitted to the concentration-time data for each patient using nonlinear regression. Maximal concentration was 343 +/- 120 micrograms/L, and the mean half-life was 4.72 hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of three theophylline dosing equations for use in infants up to one year of age.

To develop appropriate theophylline dosage recommendations for infants < or = 1 year of age, we evaluated the Nassif, Hendeles, and Hatzopoulos dosing equations in 75 infants who were receiving theophylline intravenously by continuous infusion. Postnatal age ranged from 1 to 52 weeks and postconceptional age from 33 to 93.8 weeks. Using each patient's measured theophylline clearance at steady state and the dose recommended by each of the three equations, we predicted a steady-state serum theophylline concentration for the three equations. The recommended theophylline dose and resultant serum concentrations differed significantly for the three equations. The Nassif, Hendeles, and Hatzopoulos equations resulted in 78.7%, 97.3%, and 93.8%, respectively, of serum theophylline concentrations between 5 and 15 mg/L. The Hendeles and Hatzopoulos equations tended to produce concentrations between 5 and 10 mg/L in the majority of infants; the Nassif equation generally resulted in values between 10 and 20 mg/L. Four percent of the calculated serum concentrations with the Nassif equation were > 20 mg/L. When a desired concentration of 10 mg/L was used in the Hatzopoulos equation, predictions of theophylline concentrations were consistently inflated. We conclude that the Hendeles equation ((0.008 x Postnatal age in weeks) + 0.21 = mg/kg per hour or mg/kg daily = (0.2 x Postnatal age in weeks) + 5) is preferred when intravenous theophylline therapy for apnea and bradycardia or for asthma is initiated. Regardless of the equation used to estimate an initial theophylline dose in infants < or = 1 year of age, serum theophylline concentrations should be monitored within 6 to 12 hours after the start of therapy.

Antipyretic therapy in the febrile child.

General principles of thermoregulation, the pathophysiology of fever, controversies concerning the use of antipyretic therapy, and nonpharmacologic and pharmacologic treatments commonly used for antipyresis in the pediatric population are reviewed. Several arguments can be made for not ameliorating the febrile response. Fever is an important diagnostic and prognostic clinical sign that may have beneficial effects for the host. In addition, body temperatures of < or = 41 degrees C (105.8 degrees F) are relatively harmless. Reasons for treating fever include patient discomfort, the potential for adverse sequelae, the possibility of seizures, and the possibility that fever could affect the pharmacokinetic profiles of drugs. Nonpharmacologic treatment for fever includes environmental measures to enhance dissipation of body heat and sponging. Aspirin and acetaminophen are the agents used most frequently for antipyresis in pediatric patients. However, aspirin use in children with a viral illness has been associated with development of Reye's syndrome. As a result, its use in children has declined in the United States. Acetaminophen is relatively free of adverse effects and is considered first-line pharmacologic antipyresis therapy. Ibuprofen suspension should be considered as second-line antipyretic therapy. Combination therapy with acetaminophen and aspirin may be considered if the patient fails to respond to other nonpharmacologic and pharmacologic therapies; however, combination therapy may result in increased risk of drug toxicity, increased probability of adverse reactions, and increased risk of intoxication. Aspirin, acetaminophen, and ibuprofen are equally effective for antipyresis in pediatric patients. However, because acetaminophen is the safest medication, it is currently the therapy of choice.

Prevalence of, and risk factors for, upper gastrointestinal tract bleeding in critically ill pediatric patients.

OBJECTIVE: To determine the occurrence of, and risk factors for, the development of upper gastrointestinal (GI) tract bleeding in critically ill pediatric patients. DESIGN: Prospective, descriptive, comparative study. SETTING: ICU in a tertiary care pediatric hospital affiliated with a university. PATIENTS: All patients < 19 yrs of age who were admitted to the ICU for a 4-month period (n = 429) were eligible for inclusion. A total of 221 patients were excluded for reasons listed below. Thus, 208 patients were studied. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Patients were evaluated for overt upper GI bleeding as indicated by coffee ground material or bright red blood in gastric aspirates or black, tarry stools. Excluded were patients who were transferred out of the ICU within 24 hrs of admission, were receiving medications that would alter their risk for upper GI bleeding, or had a GI tract surgical procedure. Patients were categorized by diagnoses and analyzed for relative risk for upper GI bleeding. Of the 208 patients included, 25% had evidence of upper GI bleeding. There was no association between upper GI bleeding and age, weight, race, or sex. Diagnoses independently associated with an increased risk for upper GI bleeding were: circulatory shock, an operative procedure > or = 3 hrs in duration, and trauma. No clinically important sequelae were directly attributable to upper GI bleeding in this group of patients; however, intervention with antacids and histamine-2 receptor (H-2) antagonists likely decreased the progression of GI bleeding. CONCLUSIONS: Overt evidence of upper GI bleeding is not uncommon in critically ill pediatric patients. Certain diagnoses or risk factors may predispose these patients to develop upper GI bleeding.

Ability of three pharmacokinetic equations to predict steady-state serum theophylline concentrations in pediatric patients.

The pharmacokinetic equations of Chiou, Koup, and Kurland are often used in the pediatric setting to predict steady-state theophylline clearance using non-steady serum theophylline concentrations. However, these equations have not been validated or compared in a pediatric population. We evaluated the ability of these equations to predict steady-state serum theophylline concentrations in 61 children (0.21-14.3 years) who received a continuous intravenous theophylline (0.79 +/- 0.12 mg/kg/h) infusion for a minimum of five half-lives. Theophylline concentrations used in the Kurland equation were obtained 10.8 +/- 4.5 h after initiation of therapy and the time between the two concentrations used in the Chiou and Koup equations was 9.2 +/- 3.9 h. Predicted steady-state theophylline concentration values for the three methods were not different from each other (p = 0.91), nor were they different from the observed steady-state concentration values (p = 0.92). The coefficient of determination for predicted vs. observed steady-state concentrations was statistically significant (p less than 0.001) and was comparable for the three methods. There was no difference in mean bias (p = 0.78), precision (p = 0.82), or % error (p = 0.86) values for the three methods. Regardless of the method used, 75 to 82% of all predicted theophylline concentrations were within 20% of the observed steady-state value. However, on average, all methods underpredicted the clearance and hence overpredicted the serum theophylline concentration. The Kurland method did not predict steady-state concentrations any better in patients who had received theophylline prior to admission.(ABSTRACT TRUNCATED AT 250 WORDS)

Toxicities of parenteral nutrition in the critically ill patient.

Critically ill patients have unique nutritional substrate requirements. Although important advances have been made in understanding these requirements in the face of pathophysiologic and biochemical alterations induced by stress or trauma, nutrition-associated toxicities still occur. The importance of these toxicities to the critically ill patients cannot be over-stated. Many of these toxicities can be avoided by conservative use of selected nutrition substrates in specific subsets of the critically ill population. Practitioners must continue to anticipate and recognize parenteral nutrition-associated toxicities, however, as well as delineate any toxicity from the progression or exacerbation of disease.

Determining efficacy of monitoring devices: evaluating new technologies.

We point out the connection between electronic monitoring and repeated screening tests, and suggest a flexible and practical method to determine the efficacy of monitoring devices and new technologies. We point out the benefits of the Mantel-Haenszel estimator of an odds ratio for determining diagnostic test indices. From estimates of sensitivities and specificities, we produce receiver operating characteristic (ROC) curves to compare the performance of two or more monitoring devices in a clinical setting.

Effect of an infusion device on the integrity of whole blood and packed red blood cells.

The effects of the Gemini PC-2 linear peristaltic infusion device on the integrity of packed red blood cells (RBC) and whole blood products are reported. Thirty-eight units of blood products were infused at rates of 999, 100, 50, and 5 mL/hr under simulated clinical conditions. To evaluate the effect of hematocrit on cell survival, fresh and stored packed RBCs preserved with adenine-saline 3 (AS-3) and fresh and stored packed RBCs and fresh and stored whole blood preserved with citrate-phosphate-dextrose-adenine 1 (CPDA-1) were used. No two units tested came from the same donor. Plasma potassium and plasma free hemoglobin concentrations were determined before and after simulated infusion for 80 experimental runs. Preinfusion plasma potassium and free hemoglobin concentrations varied significantly among the blood products. Stored products were associated with higher plasma potassium and free hemoglobin levels than fresh units, both before and after infusion. Concentrations also differed significantly between AS-3-preserved and CPDA-1-preserved fresh and stored packed RBCs. Infusion did not change plasma potassium values appreciably under any conditions. Plasma free hemoglobin increased in the fresh products only. Donor-specific differences were significant for potassium but not for free hemoglobin. There was no significant effect of infusion rate on either biochemical marker. In all the experimental runs, less than 0.01% of cells were lysed. The Gemini PC-2 linear peristaltic infusion device delivered a variety of blood products at a wide range of infusion rates without inducing a substantial degree of hemolysis.

Temporal dynamics of pituitary prolactin depletion and release in three strains of rats.

Previous reports have shown that pituitary prolactin is rapidly transformed to a less soluble, but much more releasable, form prior to release from the lactotroph. One manifestation of this transformation is that pituitary prolactin depletion is significantly greater than concurrent release both in vivo and in vitro. The objective of this study was to compare the magnitude and temporal dynamics of depletion and release from pituitaries of ovariectomized estrogen-treated rats of three different strains in vitro to assess the effect of strain on the transformation process. Mature ovariectomized Wistar-Furth (WF), Sprague-Dawley (SD) and Long-Evans (LE) rats (7-10/group) were killed by decapitation 7 days after a single s.c. injection of 100 micrograms of polyestradiol phosphate. The anterior pituitaries were quickly removed and cut into quarters which were incubated for up to 4 hrs in the absence of dopamine or other prolactin secretagogues. Representative fragments from each strain were not incubated but were snap frozen to measure pre-incubation content. Fragments from each strain were removed from incubation at 30, 60, 120, 180 and 240 min for prolactin content measurement. Medium was collected at 30 min intervals and replaced with fresh medium. The experiments were repeated twice. Prolactin in medium and pituitary homogenates was measured by radioimmunoassays using NIAMDD-RP-1 as standard. In all three stains release of prolactin was approximately 30-50% of the prolactin depleted from the pituitary in 4 hrs. Strains varied in the magnitude of this difference and the time course over which it occurred. WF and SD rats showed significantly greater depletion and release of prolactin than did LE rats when the data were expressed as micrograms prolactin/mg pituitary. When the data were expressed as a percentage of prolactin available for release, the differences in depletion between strains disappeared and the LE rats released a significantly greater percentage of the prolactin available for release than did the other two strains. We conclude that pituitary prolactin undergoes a process of transformation prior to release which causes it to disappear from the pituitary but not appear in culture medium. We further conclude that the magnitude and temporal dynamics of this process are not equivalent across all strains of rats.