Inactivation of heparin during extracorporeal circulation in infants.

Heparin anticoagulation is necessary to prevent clotting during procedures involving the extracorporeal circulation of blood. Our preliminary observations suggested that heparin was inactivated in the extracorporeal circuit during extracorporeal membrane oxygenation. We tested this hypothesis by comparing heparin pharmacokinetics in five infants during extracorporeal circulation with kinetics, respectively determined in each patient and in the isolated circuit immediately after discontinuation of the procedure. Heparin clearance was 1.6 +/- 0.5 ml/kg/min in the patient and 2.1 +/- 0.8 ml/kg/min in the separated circuit. In each patient, the total of heparin clearances in the patient and circuit, 3.7 +/- 1.0 ml/kg/min, was virtually identical with the heparin clearance during the procedure, 3.8 +/- 1.9 ml/kg/min (r = 0.94, p less than 0.01). We conclude that more than one half of the heparin administered to infants during extracorporeal membrane oxygenation is eliminated by the extracorporeal circuit itself or by blood components in the circuit. These data explain the relatively large heparin doses needed to maintain anticoagulation in infants during extracorporeal circulation. In light of these findings, a reexamination of the normal mechanisms of elimination of heparin activity appears to be warranted.

Intravenous glycerol and mannitol therapy in children with intracranial hypertension.

Acute intracranial hypertension may respond to intravenous mannitol, but frequent administration can cause cerebral edema or renal problems. We evaluated the use of 20% glycerol administered intravenously as an alternative to mannitol. Intravenous glycerol and mannitol were equally effective in lowering acute elevations of intracranial pressure. The duration of effect was similar for both agents. Side effects of intravenous glycerol were related to concentration, rate, and frequency of administration. In severe encephalopathies, such as Reye syndrome, we recommend infusions of 20% glycerol or 20% mannitol at a dose of 0.5-1.0 gm per kilogram. Glycerol should be administered in 0.45% or 0.9% saline, no faster than 1.5 ml (3.3 mOsm) per minute.

Comparison of self-hypnosis and propranolol in the treatment of juvenile classic migraine.

In a prospective study we compared propranolol, placebo, and self-hypnosis in the treatment of juvenile classic migraine. Children aged 6 to 12 years with classic migraine who had no previous specific treatment were randomized into propranolol (at 3 mg/kg/d) or placebo groups for a 3-month period and then crossed over for 3 months. After this 6-month period, each child was taught self-hypnosis and used it for 3 months. Twenty-eight patients completed the entire study. The mean number of headaches per child for 3 months during the placebo period was 13.3 compared with 14.9 during the propranolol period and 5.8 during the self-hypnosis period. Statistical analysis showed a significant association between decrease in headache frequency and self-hypnosis training (P = .045). There was no significant change in subjective or objective measures of headache severity with either therapy.

Cefpodoxime proxetil vs. penicillin V in pediatric streptococcal pharyngitis/tonsillitis.

This multicenter, randomized, parallel treatment, observer-blinded study was designed to evaluate the safety and efficacy of cefpodoxime proxetil (5 mg/kg twice daily for 10 days) compared with penicillin V (13.4 mg/kg three times daily for 10 days) for treatment of Group A streptococcal pharyngitis and tonsillitis in pediatric patients. Clinical and microbiologic results were evaluated before therapy, during therapy (Study Days 3 to 5), at the end of therapy (Study Days 14 to 18) and at long term follow-up (Study Days 30 to 32). Both drugs were well-tolerated in 578 patients evaluable for safety. Mild gastrointestinal complaints were noted in 6.7% of 386 cefpodoxime-treated patients and in 5.2% of 192 penicillin-treated patients. In 413 patients evaluable for efficacy, both treatment regimens resulted in comparably favorable clinical outcome; cure rates were 83.8% for 275 cefpodoxime-treated patients and 77.5% for 138 penicillin-treated patients. However, eradication of S. pyogenes at end of therapy was significantly higher with cefpodoxime (93.1%) than with penicillin (81.2%) (P < 0.01). Cefpodoxime proxetil provides an effective alternative to penicillin V for the treatment of streptococcal pharyngitis and tonsillitis.

The effect of paraldehyde on intravenous tubing sets.

Paraldehyde is used in the treatment of status epilepticus, alcohol withdrawal, and delirium tremens. Because it is a solvent, concerns have been raised about infusing it through plastic intravenous tubing sets. In a three-phase study, 4% paraldehyde in 5% dextrose solution was analyzed over 24 hours for photodegradation, adsorption to polyvinylchloride- (PVC) and polyethylene- (PE) lined intravenous tubing, and the presence of di(2-ethylhexyl) phthalate (DEHP). Paraldehyde and DEHP samples were quantified by gas chromatography, and DEHP was confirmed by mass spectral analysis. On exposure to light for 24 hours, the concentration of paraldehyde decreased from 100 to 97%. This decrease is statistically significant but clinically insignificant. A 24-hour continuous infusion of paraldehyde through the two types of tubing revealed a decrease in concentration attributable to adsorption of 4% with PE and 13% with PVC tubing at 2 hours. In addition, there was no appreciable leaching of DEHP over 24 hours with either type of tubing. Concerns about paraldehyde's light instability and effects on tubing integrity appear to be unwarranted with commercially available intravenous administration sets.

Determination of theophylline bioavailability using saliva theophylline concentrations.

Substantial error occurs when individual saliva theophylline concentrations are used to predict serum theophylline concentrations. However, the use of saliva theophylline concentrations to determine product bioavailability has never been evaluated. Subjects in this study were 18 stable patients (20-51 yr) with a history of chronic obstructive pulmonary disease. Three preparations--a capsule (Elixophyllin 400 mg), elixir (Elixophyllin 373 mg), and tablet (Theolair 375 mg)--were administered in a randomized crossover design. Serum and saliva samples were obtained pre-dose and 0.25, 0.5, 1, 2, 4, 6, and 8 hours after theophylline administration. The saliva AUC0-infinity and serum AUC0-infinity were highly associated for the elixir (r = 0.84) tablet (r = 0.89), and capsule (r = 0.89). The bioavailability of the tablet and capsule calculated from elixir saliva and elixir serum AUC0-infinity were not significantly different (p = 0.2). The bioavailability of the tablet calculated from saliva and serum was 93% and 102%, respectively. The bioavailability of the capsule calculated from saliva and serum was 113% and 102% respectively. Our data suggests that theophylline bioavailability can be reliably estimated from saliva theophylline concentrations. However, study designs that include larger sample sizes and more frequent sampling may be necessary when determining bioavailability from saliva.

Pharmacokinetics of fluconazole in immune-compromised children with leukemia or other hematologic diseases.

STUDY OBJECTIVE: To describe the pharmacokinetics of fluconazole in immune-compromised children with leukemia or other hematologic disease. DESIGN: Prospective. SETTING: Children's Health Care-Minneapolis hematology/oncology inpatient ward and outpatient clinic. PATIENTS: Ten immune-compromised children (mean +/- SD age 7.4 +/- 4.0 yrs, weight 31.6 +/- 25.9 kg) with leukemia or other hematologic disease. INTERVENTIONS: Serum was sampled before and after a single 6-mg/kg intravenous dose and after seven oral 3-mg/kg doses of fluconazole. MEASUREMENTS AND MAIN RESULTS: Mean (SD) pharmacokinetics were distribution half-life 1.67 (1.25) hours, elimination half-life 15.62 (3.21) hours, total body clearance 0.63 (0.19) ml/min/kg, volume of distribution for the central compartment 0.56 (0.10) L/kg, volume of distribution at steady state 0.77 (0.12) L/kg, absorption half-life 0.41 (0.26) hour, and oral bioavailability 0.92 (0.09). Volume of distribution for the central compartment was highly correlated with body surface area (r2 = 0.891) and weight (r2 = 0.949). Volume of distribution at steady state correlated with body surface area (r2 = 0.986), and total body clearance correlated with body surface area (r2 = 0.867). CONCLUSIONS: Fluconazole elimination was well described using a two-compartment model. Oral absorption was rapid and nearly complete. Children have a larger volume of distribution for the central compartment and faster elimination rate than adults. Body surface area and weight are important factors in determining pharmacokinetics in these patients.

Evaluation of a rapid monitoring system to study heparin pharmacokinetics and pharmacodynamics.

The pharmacokinetic and pharmacodynamic characteristics of heparin were studied in 10 healthy volunteers using the Hepcon/System B-10. This coagulation-monitoring system uses each patient's body weight, height, baseline activated clotting time (ACT), and heparin dose response values to determine initial heparin doses. We administered a calculated mean +/- SD heparin doses of 85 +/- 14 U/kg to 10 subjects to achieve a mean +/- SD target ACT of 364 +/- 29 seconds. This dose produced a mean +/- SD measured peak ACT of 337 +/- 53 seconds from a mean +/- SD baseline of 121 +/- 10 seconds. The measured peak ACT values resulting from the individualized heparin doses were within 20% of the desired peak in 9 (90%) of the subjects. Using the ACT values, the average mean residence time for heparin effect was 1.2 hours and half-life was 0.8 +/- 0.2 hours, with all the subjects' values returning to within 10% of baseline by 4 hours after the dose. Using the protamine-derived heparin concentrations, heparin total-body clearance ranged from 43 to 99 ml/hr/kg (mean +/- SD 73.3 +/- 14.5 ml/hr/kg). A linear relationship was found between heparin concentration and change in ACT that was described by delta ACT = 16.85 + 136.7.(heparin concentration). We conclude that this method is easy to perform and accurate for determining initial heparin dosage requirements, and could be an important improvement over existing approaches. In addition, it is a valuable research tool for studying heparin pharmacodynamics and pharmacokinetics.

Bronchodilation from intravenous theophylline in patients with cystic fibrosis: results of a blinded placebo-controlled crossover clinical trial.

Most patients with cystic fibrosis (CF) eventually develop chronic obstructive pulmonary disease and theoretically could benefit from theophylline therapy. The purpose of this study was to investigate the pharmacologic response to intravenous theophylline by pulmonary function tests (PFT) and the theophylline pharmacokinetics in patients with CF. A randomized, double-blind, placebo-controlled, crossover trial was conducted in 10 ambulant patients with CF (5 females, 5 males), aged 11 to 21 years. Each patient received an intravenous dose of theophylline and normal saline over 1/2 hour on consecutive days. Spirometry and whole-body plethysmography were performed at baseline, 1, 3, 5, and 7 h after the theophylline dose, and 10 blood samples were collected over 9 h on both study days. The percent change of PFT from the baseline was recorded. Analysis of variance for balanced two-period crossover design was used to evaluate the effectiveness of theophylline therapy. The serum concentration (Conc.) vs. time data were fitted using nonlinear least-squares regression analysis. The theophylline dose administered was 7.9 +/- 0.4 (mean +/- SD) mg/kg, which produced a maximal Conc. (Cmax) of 14.6 +/- 2.7 microgram/ml. The half-life (T1/2), volume of distribution (Vd), and total body clearance (TBC) were 4.9 +/- 1.9 h, 537 +/- 124 mL/kg, and 80 +/- 16 ml/h/kg, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Stability and delivery of vancomycin hydrochloride when admixed in a total parenteral nutrition solution.

Vancomycin hydrochloride, 400 mg/liter was mixed in six standard pediatric parenteral nutrition solutions with and without heparin added. The solutions were stored over a period of 8 days (192 hr) under refrigeration and at room temperature. Aliquots from all six solutions were assayed in duplicate for vancomycin at time 0, 24, 96, and 192 hr. All samples were run through an Ivex 0.22-micron filter, observed for physical incompatibilities, and frozen at -70 degrees C until assay. Our results indicate that vancomycin was stable and was delivered with loss in concentration of less than 5% with and without storage under refrigeration. This study suggests an alternative method for delivering vancomycin when treating a catheter-related infection. If vancomycin is delivered in this fashion, less manipulations of the line would be required. In addition, there may be a theoretical advantage of constantly bathing the catheter with vancomycin when the catheter is suspected of harboring the infecting organism.

Stability of epinephrine hydrochloride in an extemporaneously compounded topical anesthetic solution of lidocaine, racepinephrine, and tetracaine.

The stability of lidocaine, epinephrine (as racepinephrine, or racemic epinephrine), and tetracaine (LET) in a topical anesthetic solution under various conditions was studied. The LET solution was prepared by mixing together 100 mL of 20% lidocaine hydrochloride, 50 mL of 2.25% racepinephrine (as the hydrochloride salt), 125 mL of 2% tetracaine hydrochlorides 315 mg of sodium metabisulfite, and 225 mL of water. The solution was stored in three amber glass and two clear glass bottles. One amber container and one clear container were stored at 35 degrees C, one amber and one clear container were stored at room temperature (approximately 18 degrees C), and the third amber container was stored at 4 degrees C. Except for the refrigerated container, each bottle was subjected to continuous room light. Each of the five solutions was sampled at 0, 1, 2, 3, 4, 8, 16, and 26 weeks for visual inspection and high-performance liquid chromatography (HPLC). The HPLC assay was shown to be stability indicating for epinephrine only. All the drugs in the LET solution had no more than a 5% reduction from initial concentration, according to the assay, when stored for 4 weeks in amber or glass containers at 4 or 18 degrees C and when stored for 26 weeks in amber containers at 4 degrees C. Solution stored in clear containers discolored more quickly than solution stored in amber containers. Epinephrine in an extemporaneously prepared LET solution was stable in amber glass bottles for 4 weeks at 18 degrees C and for 26 weeks at 4 degrees C.

Activated clotting time tests with heparinase in the management of pediatric patients on cardiopulmonary bypass.

Routine ACT tests cannot distinguish between prolonged blood clotting due to heparin effect or acquired abnormalities of the coagulation system after a loading dose of heparin. The purpose of this study was to examine an ACT test that inactivates heparin with Heparinase allowing for ACT assessment with and without heparin effect (HR-ACT with/without Heparinase, HemoTec, Inc.). The HR-ACT values were compared with the standard OR procedure that employed the Hemochron ACT. Twenty pediatric patients undergoing cardiopulmonary bypass for repair of cardiac defects were examined. All comparative ACT values were obtained from the same blood sample. Five sampling times were examined: 1) A baseline ACT was obtained before heparin had been administered; 2) A pre bypass ACT after a single heparin dose; 3) On bypass; 4) A post protamine ACT at the conclusion of surgery; and 5) In the Intensive Care Unit (PICU), 1 hour post protamine. The HemoTec HR-ACT with Heparinase and HR-ACT tests differentiated clotting time results that reflected coagulation status without the heparin effect. It identified those patients on bypass who were less than 5 kg, with prolonged ACTs that were due in part to hemodilution despite efforts at hemoconcentration.

Predictive performance of three methods of activated clotting time measurement in neonatal ECMO patients.

Previously reported activated clotting time (ACT) data in adults demonstrated higher values with the HemoTec LRACT (HT) and TriMed ACTivator (TM) techniques than with the Hemochron System P214/215 (HC) technique throughout a range of heparin concentrations. This study sought to determine if a difference exists in ACT values of neonatal patients receiving ECMO. ACTs were performed in nine neonatal ECMO patients using the HC, HT, and TM techniques. Techniques were compared for positive or negative direction of any prediction difference (bias), and the typical value of a difference (precision). Simultaneous, duplicate, morning, and afternoon ACT comparisons were obtained using all three techniques. Forty-six comparisons of HC values in the 180-240 sec range were analyzed. All techniques produced results different from the same sample. The HT and TM techniques were upwardly biased by 51 and 148 sec, respectively, when evaluated against HC. HT was negatively biased by 123 sec when evaluated against TM. Because ACT values vary among techniques, ACT target ranges should be technique specific. Future references to ACT data should identify the equipment and procedures employed.

Apparent inconsistent theophylline absorption from sustained release capsules.

Sustained release theophylline products can improve compliance and symptom control in children with asthma. This study examines theophylline serum concentration monitoring in pediatric patients. Fifteen children with documented asthma were randomized to receive either Slo-bid Gyrocaps or Theo-dur Sprinkle for 1 month, and then crossed over to the other product. On the last day of each study period, theophylline serum concentrations were obtained prior to the morning dose and 4 hours later. In two patients receiving Theo-dur Sprinkle and six with Slo-bid Gyrocaps, the 4-hour serum concentration was lower than the pre-dose concentration. The change between the pre-dose and post-dose serum concentrations for Theo-dur Sprinkle ranged from a decrease of 2.8 mg/L to an increase of 4.9 mg/L, and, for Slo-bid Gyrocaps, from a decrease of 4.6 mg/L to an increase of 10.5 mg/L. The inconsistent theophylline absorption with each product makes dosage adjustment difficult.

Theophylline therapy. Titrating dosage requirements.

Theophylline has long been a cornerstone of bronchodilator therapy for asthma and chronic obstructive lung disease, but until recently its use carried the risk of serious, even fatal, toxicity. With recent advances in understanding of this drug's pharmacologic properties and pharmacokinetic characteristics, serious toxicity now can usually be avoided. The dosage requirements for theophylline demonstrate wide interpatient and intrapatient variation. Several factors responsible for this variation, most notably age, have been identified and used in definition of dosage guidelines for different patient groups. However, substantial variation still exists within these groups, necessitating measurement of serum concentration in selected patients. The measurements obtained are used to titrate the patient's dosage requirement in such a way as to maximize therapeutic response while minimizing risk of toxicity.

The effect of carbonated beverages on ipecac-induced emesis.

To determine the effect of carbonated beverages on syrup of ipecac, 24 pediatric patients were randomly administered six ounces of water or a carbonated beverage with syrup of ipecac. Changes in the abdominal girth, the volume of emesis, and time of emesis were monitored in all patients. In the carbonated beverage group a significant difference (P less than 0.05) was observed between the baseline and 10-min post-ipecac administration abdominal girth measurements. The time of emesis and volume of emesis were not significantly different in the water or carbonated beverage groups. We conclude that carbonated beverage administration does not alter the effectiveness of syrup of ipecac.

Nitroglycerin adsorption to a combination polyvinyl chloride, polyethylene intravenous administration set.

Loss of nitroglycerin (NTG) from intravenous solutions to intravenous bags and administration sets has been well documented. This study was designed to examine a commercially available low adsorption administration set that was compatible with a volumetric infusion pump. A solution of NTG 100 micrograms/ml in dextrose 5% in glass bottles was used. Six study administration sets were tested. The infusion sets were connected to the NTG-containing glass bottles, filled as rapidly as possible, placed in the infusion pump, and set at the appropriate rate. Effluent was collected for NTG assay initially, and at 20 and 40 minutes, and 1, 1.5, 2, 3, 6, and 24 hours. The effects of flow rate were studied at 0.2 and 1.0 ml/min. The tubing performed similarly to other polyvinyl chloride (PVC)-containing sets at 0.2 ml/min and similar to non-PVC sets at 1.0 ml/min. The effect of an initial flush with 20-100 ml of 100 micrograms/ml NTG was also examined. An initial flush of 20 ml of 100 micrograms/ml NTG solution was found to enhance delivery of NTG immediately. NTG aliquots were stored frozen in glass vials prior to assay by high performance liquid chromatography.